Nickel sulfate - The Danish Environmental Protection Agency

Transcription

Nickel Sulphate
CAS-No.: 7786-81-4
EINECS-No.: 232-104-9
RISK ASSESSMENT
Final version
March 2008
Chapters 0, 1, 2, 4, 5, 6 & 7 – human health only
Danish Environmental Protection Agency
R312_0308_hh_chapter0124567_clean.doc
Information on the rapporteur
Rapporteur for the risk assessment report on nickel sulphate is the Danish Environmental Protection Agency.
The Rapporteur is responsible for the risk evaluation and for the contents of this report.
Contact persons:
Poul Bo Larsen & Henrik Tyle
Chemicals Division
Danish Environmental Protection Agency
Strandgade 29
DK-1401 Copenhagen K
DENMARK
Tel: +45 72 54 40 00
E-mail: PBL@mst.dk / HTY@mst.dk / DEPA-ESR@mst.dk
Acknowledgements.
The scientific assessments included in this report have been prepared by the following organisations by order of the
Rapporteur:
•
•
•
•
The Danish National Working Environment Authority (Occupational Exposure, Chapter 4)
Danish Technological Institute (Chapter 3 and assistance with Chapters 1 & 2)
Department. of Toxicology and Risk Assessment, Danish Food and Veterinary Research, (Consumer and
Indirect Exposure, Human health effects, Chapter 4)
National Environmental Research Institute, Denmark (Terrestrial effects Assessment, Chapter 3).
The Rapporteur would also like to acknowledge the contributions from the following individuals:
• Professor Aage Andersen and Dr. Tom K. Grimsrud of the Cancer Registry of Norway, Institute of Populationbased Cancer Research, for their assistance in the preparation of the section on cancer epidemiology in Chapter
4,
• Drs Adriana Oller, Katherine Heim, Lisa Ortego and Chris Schlekat, Hudson Bates, NiPERA, Durham, North
Carolina, USA, for providing information on the health and environmental effects of nickel sulphate,
• Jim Hart, Sherborne, Dorset, UK, for the preparation of Chapters 1 & 2, and sections of Chapter 4,
• Dr.-Ing. Claus Meyer-Wulf, Hüttenwerke Kayser AG, Lünen, Germany, for providing information on the
production and use of nickel sulphate,
• Prof. Tore Sanner, Institute of Cancer Research, Montebello, Oslo, Norway, for providing the calculation of the
quantitative risk assessment of the carcinogenicity of nickel and nickel compounds
• Dr. Sally Pugh Williams, INCO, Wales, UK for general information on nickel.
2
Foreword to Draft Risk Assessment Reports
This risk assessment of the priority substance covered by this Draft Risk Assessment Report is carried out in accordance
with Council Regulation (EEC) 793/93 (EEC, 1993) on the evaluation and control of the risks of “existing” substances.
Regulation 793/93 provides a systematic framework for the evaluation of the risks to human health and the environment
of these substances if they are produced or imported into the Community in volumes above 10 tonnes per year.
There are four overall stages in the Regulation for reducing the risks: data collection, priority setting, risk assessment
and risk reduction. Data provided by Industry are used by Member States and the Commission services to determine the
priority of the substances which need to be assessed. For each substance on a priority list, a Member State volunteers to
act as “Rapporteur”, undertaking the in-depth Risk Assessment and if necessary, recommending a strategy to limit the
risks of exposure to the substance.
The methods for carrying out an in-depth Risk Assessment at Community level are laid down in Commission
Regulation (EC) 1488/94 (EC, 1994a) which is supported by a technical guidance document (European Commission
1996, 1997a). Normally, the “Rapporteur” and individual companies producing, importing and/or using the chemicals
work closely together to develop a draft Risk Assessment Report, which is then presented to the Competent Group of
Member State experts for endorsement. Observers from Industry, Consumer Organisations, Trade Unions,
Environmental Organisations and certain International Organisations are also invited to attend the meetings. The Risk
Assessment Report is then peer-reviewed by the Scientific Committee on Health and Environmental Risks (SCHER)
which gives its opinion to the European Commission on the quality of the risk assessment.
This Draft Risk Assessment Report is currently under discussion in the Competent Group of Member State experts with
the aim of reaching consensus. During the course of these discussions, the scientific interpretation of the underlying
scientific information may change, more information may be included and even the conclusions reached in this draft
may change. The Competent Group of Member State experts seek as wide a distribution of these drafts as possible, in
order to assure as complete and accurate an information basis as possible. The information contained in this Draft Risk
Assessment Report does not, therefore, necessarily provide a sufficient basis for decision making regarding the hazards,
exposures or the risks associated with the priority substance under consideration herein.
This Draft Risk Assessment Report is the responsibility of the Member State rapporteur. In order to avoid possible
misinterpretations or misuse of the findings in this draft, anyone wishing to cite or quote this report is advised to contact
the Member State rapporteur beforehand.
3
Contents
0.
OVERALL RESULTS OF THE RISK ASSESSMENT...................................................................................... 11
0.1
OVERALL CONCLUSIONS FOR ENVIRONMENT: .................................................................................................... 11
0.2
OVERALL CONCLUSIONS FOR HUMAN HEALTH ................................................................................................... 11
0.2.1
OCCUPATIONAL ASSESSMENT ............................................................................................................ 11
0.2.2
CONSUMER ASSESSMENT..................................................................................................................... 11
0.2.3
INDIRECT EXPOSURE VIA THE ENVIRONMENT................................................................................ 12
0.2.4
COMBINED EXPOSURE......................................................................................................................... 12
0.2.5
PHYSICOCHEMICAL PROPERTIES ...................................................................................................... 12
1.
GENERAL SUBSTANCE INFORMATION ....................................................................................................... 13
1.1
IDENTIFICATION OF THE SUBSTANCE ................................................................................................................. 13
1.2
PURITY / IMPURITIES, ADDITIVES. ..................................................................................................................... 14
1.3
PHYSICO-CHEMICAL PROPERTIES ...................................................................................................................... 16
1.3.1
Conversion factors:................................................................................................................................... 17
1.3.2
Solubility of nickel sulphate. ..................................................................................................................... 17
1.3.3
Summary ................................................................................................................................................... 17
1.4
CLASSIFICATION ................................................................................................................................................ 18
1.4.1
Current classification ............................................................................................................................... 18
1.4.1.1
1.4.1.2
1.4.2
2.
UN Transport labelling. ..........................................................................................................................................18
Classification according to Directive 67/548/EEC. ................................................................................................18
Proposed classification according to Directive 67/548/EEC. ......................................................... 18
GENERAL INFORMATION ON EXPOSURE .................................................................................................. 20
2.1
PRODUCTION ..................................................................................................................................................... 20
2.1.1
Production methods. ................................................................................................................................. 20
2.1.1.1
2.1.1.2
2.1.1.3
2.1.1.4
2.1.1.5
2.1.1.6
2.1.1.7
2.1.1.8
2.1.1.9
Nickel sulphate production from nickel matte. .......................................................................................................20
Nickel sulphate production from secondary nickel matte and roasted residues. .....................................................21
Other leaching processes ........................................................................................................................................21
Nickel sulphate production from copper refining. ..................................................................................................21
Purification of impure nickel sulphate. ...................................................................................................................22
Nickel sulphate production from metallic nickel. ...................................................................................................22
Nickel sulphate production from nickel carbonate..................................................................................................23
Other methods of nickel sulphate production. ........................................................................................................23
Anhydrous nickel sulphate production....................................................................................................................23
2.1.2
Production volumes .................................................................................................................................. 23
2.1.3
Production sites ........................................................................................................................................ 24
2.2
USE PATTERN .................................................................................................................................................... 25
2.2.1
Current Use Pattern.................................................................................................................................. 25
2.2.1.1
2.2.1.2
2.2.1.3
2.2.1.4
2.2.1.5
Production of metallic nickel. .................................................................................................................................26
Nickel plating .........................................................................................................................................................27
Nickel sulphate used in the production of catalysts ................................................................................................27
Nickel sulphate used in the production of chemicals ..............................................................................................28
Nickel sulphate used in production of Nickel-containing batteries.........................................................................28
2.2.2
Recycling................................................................................................................................................... 28
2.2.3
Discontinued Uses of the Substance ......................................................................................................... 28
2.2.4
Industrial and use categories for nickel sulphate ..................................................................................... 28
2.3
TRENDS ............................................................................................................................................................. 30
2.4
LEGISLATIVE CONTROLS ................................................................................................................................... 30
2.4.1
General Measures..................................................................................................................................... 30
2.4.1.1
2.4.1.2
2.4.1.3
2.4.2
2.4.3
2.4.3.1
2.4.4
2.4.4.1
Directive 67/548/EEC on dangerous substances.....................................................................................................30
Directive 1999/45/EC on dangerous preparations...................................................................................................30
National Initiatives..................................................................................................................................................30
Protection of workers................................................................................................................................ 31
Protection of consumers. .......................................................................................................................... 32
Food supplements, additives, contaminants............................................................................................................32
Emissions to water .................................................................................................................................... 33
Directive 96/61/EC concerning integrated pollution prevention and control (IPPC) ..............................................33
4
2.4.4.2
2.4.4.3
2.4.4.4
2.4.4.5
2.4.4.6
2.4.5
Directive 76/464/EEC on pollution of the aquatic environment by certain dangerous substances. ........................33
Directive 2000/60/EC establishing a framework for Community action in the field of water policy. ....................33
Directive 80/68/EEC on the protection of groundwater against pollution caused by certain dangerous substances
33
Directive 2000/76/EC on the incineration of waste. ...............................................................................................33
National legislation. ................................................................................................................................................33
Emissions to air. ....................................................................................................................................... 34
2.4.5.1
2.4.5.2
2.4.5.3
2.4.6
Directive 96/61/EC concerning integrated pollution prevention and control (IPPC) ..............................................34
Directive 2000/76/EC on the incineration of waste. ...............................................................................................34
National Legislation................................................................................................................................................34
Emissions to Soil....................................................................................................................................... 34
2.4.6.1
2.4.7
National legislation. ................................................................................................................................................34
Waste management. .................................................................................................................................. 34
2.4.7.1
2.4.7.2
Directive 96/61/EC concerning integrated pollution prevention and control..........................................................34
Council Directive 91/689/EEC of 12 December 1991 on hazardous waste ............................................................34
3.
ENVIRONMENT ................................................................................................................................................... 36
4.
HUMAN HEALTH................................................................................................................................................. 37
4.1
HUMAN HEALTH (TOXICITY) .................................................................................................................... 37
4.1.1
Exposure assessment................................................................................................................................. 37
4.1.1.1
General ...................................................................................................................................................................37
Skin exposure. ..............................................................................................................................................37
4.1.1.1.1
4.1.1.1.2
4.1.1.1.3
Respiratory exposure....................................................................................................................................37
Oral exposure. ..............................................................................................................................................37
Occupational exposure............................................................................................................................................37
4.1.1.2.1 General.........................................................................................................................................................37
4.1.1.2.1.1 Scenarios for the occupational exposure assessment. ................................................................................38
4.1.1.2.1.2 Measurement techniques. ..........................................................................................................................39
4.1.1.2.2 Production of nickel sulphate .......................................................................................................................41
4.1.1.2.2.1 Scenario A1 – Ni sulphate production from nickel matte..........................................................................44
4.1.1.2.2.1.1 Exposure by inhalation – nickel species.............................................................................................44
4.1.1.2.2.1.2 Exposure by inhalation – measured exposure levels ..........................................................................44
4.1.1.2.2.1.3 Exposure by inhalation – modelled data (EASE 2.0) .........................................................................45
4.1.1.2.2.1.4 Dermal exposure – measured exposure levels....................................................................................45
4.1.1.2.2.1.5 Dermal exposure – modelled data (EASE 2.0)...................................................................................47
4.1.1.2.2.1.6 Discussion and conclusions................................................................................................................48
4.1.1.2.2.2 Scenario A2– Ni sulphate production from secondary nickel matte and roasted residues.........................48
4.1.1.2.2.2.2 Exposure by inhalation – measured and modelled exposure levels....................................................49
4.1.1.2.2.2.3 Dermal exposure – measured and modelled exposure levels .............................................................49
4.1.1.2.2.3 Scenario A3 – Ni sulphate production from other leaching processes.......................................................50
4.1.1.2.2.4 Scenario A4 – Ni sulphate production from copper refining .....................................................................52
4.1.1.2.2.5 Scenario A5 – Ni sulphate production by purification of impure nickel sulphate .....................................54
4.1.1.2.2.5.2 Dermal exposure – measured and modelled exposure levels. ............................................................55
4.1.1.2.2.5.3
Discussion and conclusions...............................................................................................................55
4.1.1.2.2.6 Scenario A6 – Ni sulphate production from metallic nickel ......................................................................55
4.1.1.2
5
Use of nickel sulphate. .................................................................................................................................59
4.1.1.2.3.1 Scenario B1 – Production of metallic nickel. ............................................................................................59
4.1.1.2.3.1.6 General discussion and conclusion.....................................................................................................65
4.1.1.2.3.2 Scenario B2 – Nickel plating.....................................................................................................................65
4.1.1.2.3.3 Scenario B3 – Production of catalysts .......................................................................................................74
4.1.1.2.3.3.2 Exposure by inhalation – measured exposure levels. .........................................................................75
4.1.1.2.3.4 Scenario B4 - Nickel sulphate used in the production of chemicals ..........................................................80
4.1.1.2.4 Overall conclusions ......................................................................................................................................83
4.1.1.3
Consumer exposure ................................................................................................................................................85
4.1.1.4
Exposure of man via the environment ....................................................................................................................85
4.1.1.5
Combined exposure ................................................................................................................................................85
4.1.1.2.3
4.1.2
Human health effects assessment.............................................................................................................. 86
4.1.2.1
Toxico-kinetics, metabolism and distribution.........................................................................................................86
Absorption....................................................................................................................................................86
4.1.2.1.1.1 Animal studies...........................................................................................................................................86
4.1.2.1.1.1.1 Inhalation ...........................................................................................................................................86
4.1.2.1.1.1.2 Oral ....................................................................................................................................................87
4.1.2.1.1.1.3 Dermal ...............................................................................................................................................87
4.1.2.1.1.2 Human data ...............................................................................................................................................88
4.1.2.1.1.2.1 Inhalation ...........................................................................................................................................88
4.1.2.1.1.2.2 Oral ....................................................................................................................................................88
4.1.2.1.1.2.3 Dermal ...............................................................................................................................................88
4.1.2.1.1.3 In vitro studies ...........................................................................................................................................88
4.1.2.1.2 Distribution and elimination.........................................................................................................................89
4.1.2.1.2.1 Animal studies...........................................................................................................................................89
4.1.2.1.2.1.1 Inhalation ...........................................................................................................................................89
4.1.2.1.2.1.2 Oral ....................................................................................................................................................90
4.1.2.1.2.2 Human data ...............................................................................................................................................90
4.1.2.1.2.3 Transplacental transfer ..............................................................................................................................91
4.1.2.1.2.4 Cellular uptake ..........................................................................................................................................91
4.1.2.1.3 Discussion and conclusions..........................................................................................................................92
4.1.2.1.3.1 Absorption .................................................................................................................................................92
4.1.2.1.3.1.1 Inhalation ...........................................................................................................................................92
4.1.2.1.3.1.2 Oral ....................................................................................................................................................93
4.1.2.1.3.1.3 Dermal ...............................................................................................................................................93
4.1.2.1.3.2 Distribution and elimination ......................................................................................................................94
4.1.2.2
Acute toxicity .........................................................................................................................................................95
4.1.2.2.1 Animal studies..............................................................................................................................................95
4.1.2.2.1.1 Inhalation...................................................................................................................................................95
4.1.2.2.1.2 Oral............................................................................................................................................................95
4.1.2.2.1.3 Dermal.......................................................................................................................................................95
4.1.2.1.1
6
4.1.2.2.1.4
4.1.2.2.1.5
4.1.2.2.2
4.1.2.2.3
Other routes ...............................................................................................................................................96
Conclusion, animal studies ........................................................................................................................96
Human data ..................................................................................................................................................96
Conclusion ...................................................................................................................................................97
Irritation /corrosivity...............................................................................................................................................97
4.1.2.3.1 Animal studies..............................................................................................................................................97
4.1.2.3.1.1 Skin and eye irritation ...............................................................................................................................97
4.1.2.3.1.2 Respiratory irritation .................................................................................................................................98
4.1.2.3.2 Human data ..................................................................................................................................................98
4.1.2.3.2.1 Skin irritation.............................................................................................................................................98
4.1.2.3.2.2 Respiratory irritation .................................................................................................................................99
4.1.2.3.3 Conclusion ...................................................................................................................................................99
4.1.2.4
Sensitisation............................................................................................................................................................99
4.1.2.4.1 Animal studies..............................................................................................................................................99
4.1.2.4.1.1 Skin sensitisation .......................................................................................................................................99
4.1.2.4.1.1.1 Conclusion, animal studies, skin sensitisation..................................................................................100
4.1.2.4.1.2 Respiratory sensitisation..........................................................................................................................100
4.1.2.4.2 Human data ................................................................................................................................................100
4.1.2.4.2.1 Skin sensitisation .....................................................................................................................................101
4.1.2.4.2.1.1 Experimental sensitisation................................................................................................................101
4.1.2.4.2.1.2 Occupational sensitisation................................................................................................................101
4.1.2.4.2.1.3 Elicitation of allergic response .........................................................................................................101
4.1.2.4.2.1.4 Thresholds for Sensitisation and elicitation......................................................................................102
4.1.2.4.2.1.4.1 Elicitation..................................................................................................................................102
4.1.2.4.2.1.4.2 Sensitisation..............................................................................................................................102
4.1.2.4.2.1.5 Conclusion, human data, skin sensitisation ......................................................................................103
4.1.2.4.2.2 Respiratory sensitisation..........................................................................................................................103
4.1.2.4.2.2.1 Conclusion, human data, respiratory sensitisation............................................................................103
4.1.2.4.3 Conclusion .................................................................................................................................................103
4.1.2.5
Repeated dose toxicity ..........................................................................................................................................104
4.1.2.5.1 Animal studies............................................................................................................................................104
4.1.2.5.1.1 Inhalation.................................................................................................................................................104
4.1.2.5.1.1.1 NTP studies on rats and mice ...........................................................................................................104
4.1.2.5.1.1.1.1 16-day rat study ........................................................................................................................104
4.1.2.5.1.1.1.2 13-week rat study......................................................................................................................105
4.1.2.5.1.1.1.3 2-year rat study .........................................................................................................................106
4.1.2.5.1.1.1.4 16-day mouse study ..................................................................................................................107
4.1.2.5.1.1.1.5 13-week mouse study................................................................................................................108
4.1.2.5.1.1.1.6 2-year mouse study ...................................................................................................................109
4.1.2.5.1.1.2 Studies examining mechanism of lung injury ..................................................................................110
4.1.2.5.1.1.3 Summary and conclusions, inhalation ..............................................................................................111
4.1.2.5.1.2 Oral..........................................................................................................................................................113
4.1.2.5.1.2.1 General toxicity................................................................................................................................113
4.1.2.5.1.2.1.1 Rats ...........................................................................................................................................113
4.1.2.5.1.2.1.2 Dogs..........................................................................................................................................115
4.1.2.5.1.2.2 Kidney toxicity.................................................................................................................................115
4.1.2.5.1.2.3 Immunotoxicity ................................................................................................................................116
4.1.2.5.1.2.4 Other toxicity studies .......................................................................................................................117
4.1.2.5.1.2.5 Summary and conclusions, oral administration................................................................................117
4.1.2.5.1.3 Dermal.....................................................................................................................................................118
4.1.2.5.1.3.1 Summary and conclusions, dermal application ................................................................................118
4.1.2.5.1.4 Other routes .............................................................................................................................................118
4.1.2.5.2 Human data ................................................................................................................................................118
4.1.2.3
4.1.2.5.3
Conclusion .................................................................................................................................................119
Mutagenicity.........................................................................................................................................................120
4.1.2.6.1 In vitro studies............................................................................................................................................120
4.1.2.6.1.1 DNA damage and repair ..........................................................................................................................120
4.1.2.6.1.2 Gene mutations........................................................................................................................................121
4.1.2.6.1.2.1 Prokaryotes ......................................................................................................................................121
4.1.2.6.1.2.2 Eukaryotes........................................................................................................................................121
4.1.2.6
7
4.1.2.6.1.3 Chromosomal effects...............................................................................................................................122
4.1.2.6.1.3.1 Sister chromatid exchanges (SCE) ...................................................................................................122
4.1.2.6.1.3.2 Chromosomal aberrations (CA) .......................................................................................................122
4.1.2.6.1.3.3 Other studies ....................................................................................................................................122
4.1.2.6.1.4 Cell transformation..................................................................................................................................123
4.1.2.6.1.5 Discussion and conclusion, in vitro studies .............................................................................................125
4.1.2.6.2 In vivo studies.............................................................................................................................................126
4.1.2.6.2.1 DNA damage...........................................................................................................................................126
4.1.2.6.2.2 Gene mutations........................................................................................................................................126
4.1.2.6.2.3 Chromosomal effects...............................................................................................................................126
4.1.2.6.2.4 Discussion and conclusion, in vivo studies..............................................................................................132
4.1.2.6.3 Conclusions................................................................................................................................................132
4.1.2.7
Carcinogenicity.....................................................................................................................................................133
4.1.2.7.1 Animal data ................................................................................................................................................133
4.1.2.7.1.1 Inhalation.................................................................................................................................................133
4.1.2.7.1.2 Oral..........................................................................................................................................................134
4.1.2.7.1.3 Dermal.....................................................................................................................................................135
4.1.2.7.1.4 Other routes of administration .................................................................................................................135
4.1.2.7.1.5 Promoter studies ......................................................................................................................................135
4.1.2.7.1.6 Discussion and conclusions, carcinogenicity in experimental animals....................................................137
4.1.2.7.1.6.1 Inhalation .........................................................................................................................................137
4.1.2.7.1.6.2 Oral ..................................................................................................................................................137
4.1.2.7.1.6.3 Dermal .............................................................................................................................................137
4.1.2.7.1.6.4 Other routes of administration..........................................................................................................137
4.1.2.7.1.6.5 Promoter studies...............................................................................................................................138
4.1.2.7.1.7 Conclusion...............................................................................................................................................138
4.1.2.7.2 Human data ................................................................................................................................................138
4.1.2.7.2.1 Overview of the epidemiological cancer studies .....................................................................................138
4.1.2.7.2.2 Exposures ................................................................................................................................................140
4.1.2.7.2.3 Results of the epidemiological studies.....................................................................................................143
4.1.2.7.2.3.1 Clydach, South Wales ......................................................................................................................143
4.1.2.7.2.3.2 Kristiansand, Norway.......................................................................................................................144
4.1.2.7.2.3.3 Port Colborne, Canada .....................................................................................................................146
4.1.2.7.2.3.4 Harjavalta, Finland...........................................................................................................................148
4.1.2.7.2.4 Discussion of cancer epidemiology .........................................................................................................149
4.1.2.7.2.5 Summary of cancer epidemiology ...........................................................................................................152
4.1.2.7.2.6 Conclusion of cancer epidemiology ........................................................................................................152
4.1.2.7.3 Overall evaluation of carcinogenicity.........................................................................................................152
4.1.2.7.3.1 Epidemiology ..........................................................................................................................................153
4.1.2.7.3.2 Animal studies.........................................................................................................................................153
4.1.2.7.3.3 Mechanistic considerations......................................................................................................................154
4.1.2.7.3.4 Conclusions .............................................................................................................................................154
4.1.2.8
Toxicity for reproduction......................................................................................................................................155
4.1.2.8.1 Animal studies............................................................................................................................................155
4.1.2.8.1.1 Effects on fertility....................................................................................................................................155
4.1.2.8.1.2 Developmental toxicity............................................................................................................................157
4.1.2.8.2 Human data ................................................................................................................................................160
4.1.2.8.2.1 Effects on fertility....................................................................................................................................160
4.1.2.8.2.2 Developmental toxicity............................................................................................................................160
4.1.2.8.3 Summary and conclusions..........................................................................................................................160
4.1.3
Risk characterisation ............................................................................................................................. 164
4.1.3.1
General aspects .....................................................................................................................................................164
Exposure assessment summary ..................................................................................................................164
4.1.3.1.1.1 Inhalational exposure...............................................................................................................................164
4.1.3.1.1.2 Dermal exposure......................................................................................................................................166
4.1.3.1.1.3 Oral exposure. .........................................................................................................................................167
4.1.3.1.2 Effects assessment summary. .....................................................................................................................167
4.1.3.1.2.1 Toxicokinetics. ........................................................................................................................................168
4.1.3.1.2.2 Acute toxicity ..........................................................................................................................................169
4.1.3.1.2.3 Irritation/corrosivity. ...............................................................................................................................169
4.1.3.1.2.4 Sensitisation ............................................................................................................................................169
4.1.3.1.1
8
4.1.3.1.2.5 Repeated dose toxicity.............................................................................................................................170
4.1.3.1.2.6 Mutagenicity............................................................................................................................................170
4.1.3.1.2.7 Carcinogenicity. ......................................................................................................................................171
4.1.3.1.2.8 Reproductive toxicity. .............................................................................................................................173
4.1.3.1.2.9 Groups of particular concern. ..................................................................................................................174
4.1.3.1.2.10 Completeness of the database................................................................................................................174
4.1.3.2
Risk characterisation for Occupational exposure..................................................................................................174
4.1.3.2.1 Acute toxicity .............................................................................................................................................175
4.1.3.2.1.1 Acute inhalational toxicity.......................................................................................................................175
4.1.3.2.1.2 Acute dermal toxicity. .............................................................................................................................176
4.1.3.2.2 Irritation and corrosivity.............................................................................................................................176
4.1.3.2.3
Sensitisation ...............................................................................................................................................176
Skin .........................................................................................................................................................177
Respiratory tract ......................................................................................................................................177
4.1.3.2.4 Repeated dose toxicity ...............................................................................................................................177
4.1.3.2.4.1 Repeated dose Inhalational Toxicity........................................................................................................177
4.1.3.2.4.2 Repeated dose dermal Toxicity ...............................................................................................................178
4.1.3.2.5 Mutagenicity ..............................................................................................................................................178
4.1.3.2.3.1
4.1.3.2.3.2
4.1.3.2.6
Carcinogenicity ..........................................................................................................................................178
Carcinogenicity after inhalational exposure ............................................................................................178
Carcinogenicity after dermal exposure. ...................................................................................................179
4.1.3.2.7 Toxicity for reproduction ...........................................................................................................................179
4.1.3.2.7.1 Effects on fertility after inhalational exposure.........................................................................................179
4.1.3.2.7.2 Effects on fertility after dermal exposure ................................................................................................180
4.1.3.2.7.3 Developmental toxicity after inhalational exposure ................................................................................180
4.1.3.2.7.4 Effects on developmental toxicity after dermal exposure........................................................................181
4.1.3.2.8 Summary of risk characterisation for workers............................................................................................182
4.1.3.3
Risk characterisation for Consumers. ...................................................................................................................183
4.1.3.4
Risk characterisation for Man via environment. ...................................................................................................184
4.1.3.5
Combined Exposure..............................................................................................................................................184
4.1.3.5.1 Oral exposure. ............................................................................................................................................184
4.1.3.2.6.1
4.1.3.2.6.2
4.2
HUMAN HEALTH (PHYSICO-CHEMICAL PROPERTIES). ................................................................................. 185
4.2.1
Exposure assessment............................................................................................................................... 185
4.2.2
Effects assessment: ................................................................................................................................. 185
4.2.2.1
4.2.2.2
4.2.2.3
4.2.3
5.
Explosivity............................................................................................................................................................185
Flammability.........................................................................................................................................................185
Oxidising potential................................................................................................................................................185
Risk characterisation. ............................................................................................................................. 185
CONCLUSIONS/RESULTS................................................................................................................................ 186
5.1
ENVIRONMENT ........................................................................................................................................... 186
5.2
HUMAN HEALTH ........................................................................................................................................ 186
5.2.1
OCCUPATIONAL ASSESSMENT .......................................................................................................... 186
5.2.2
CONSUMER ASSESSMENT................................................................................................................... 187
5.2.3
INDIRECT EXPOSURE VIA THE ENVIRONMENT.............................................................................. 187
5.2.4
COMBINED EXPOSURE....................................................................................................................... 187
5.2.5
PHYSICOCHEMICAL PROPERTIES .................................................................................................... 188
6.
REFERENCES ..................................................................................................................................................... 189
7.
APPENDICES....................................................................................................................................................... 203
7.1
7.2
7.3
7.4
7.5
7.6
EUSES RISK CHARACTERISATION RESULT TABLE ........................................................................................... 203
EUSES SUMMARY REPORT .............................................................................................................................. 203
IUCLID DATA SET .......................................................................................................................................... 203
REVISED ANNEX I ENTRY TO DIR. 67/548 ........................................................................................................ 204
BACKGROUND DOCUMENT ON THE SENSITIVITY OF THE NTP STUDIES ............................................................ 205
NIPERA COMMENTS ON THE NEGATIVE NTP STUDY WITH NICKEL SULFATE HEXAHYDRATE AND ITS
SIGNIFICANCE WITH REGARD TO MODE OF ACTION FOR WATER SOLUBLE NICKEL COMPOUNDS ................................... 211
7.7
NIPERA COMMENTS ON MECHANISTIC CONSIDERATIONS ON NICKEL ION CARCINOGENICITY........................ 221
9
7.8
7.9
FURTHER STATISTICAL ANALYSIS OF THE SLI 2000B 2-GENERATION REPRODUCTIVE TOXICITY STUDY .......... 222
INFLUENCE OF A POTENTIAL NICKEL SENSITIVITY ON THE FREQUENCIES OF POSTIMPLANTATION/PERINATAL
LETHALITY IN F1 AND F2 OFFSPRING ............................................................................................................................ 225
10
0. OVERALL RESULTS OF THE RISK ASSESSMENT
0.1 OVERALL CONCLUSIONS FOR ENVIRONMENT:
Not included in this report.
0.2 OVERALL CONCLUSIONS FOR HUMAN HEALTH
0.2.1
OCCUPATIONAL ASSESSMENT
(X)
i)
There is need for further information and/or testing
(X)
ii)
There is at present no need for further information and/or testing or for risk reduction measures
beyond those which are being applied
(X)
iii)
There is a need for limiting the risks: risk reduction measures which are already being applied
shall be taken into account
Conclusion (i) (on hold) is reached because:
• There is a need for further studies to evaluate the possible effects of nickel sulphate on germ cells, but further
testing is not considered practicable.
Conclusion iii) is reached because:
• The risk assessment has shown that following inhalational exposure and for the endpoints: acute toxicity,
respiratory sensitisation, repeated dose toxicity, carcinogenicity, effects on fertility and development; concern
is expressed for all inhalational exposure scenarios in relation to worst case exposure levels. For typical
exposure levels concern is expressed to the majority of the end points/ exposure scenarios..
Conclusion ii) is reached because:
• The risk assessment has shown that following typical inhalational exposure for some scenarios effects on
fertility and development, and for all scenarios for dermal exposures for acute and repeated dose toxicity,
irritation, sensitisation, carcinogenicity and reproductive toxicity there is no need for limiting the risks taking
into account the risk reduction measures that are already being applied.
0.2.2
CONSUMER ASSESSMENT
(X)
i)
(X)
ii)
(X)
iii)
• Patients with severe nickel sensitisation constitute a particularly sensitive population to oral challenge with
nickel and are potentially at risk from excessive exposure to nickel in food and water. Additional risk reduction
measures may be needed to limit exposure to nickel in food supplements.
11
•
0.2.3
There is no concern for the general population that are not already sensitised to nickel from exposure to nickel
in food supplements. There is no concern for patients with severe nickel sensitisation for other endpoints than
there possible reaction to oral challenge with nickel.
INDIRECT EXPOSURE VIA THE ENVIRONMENT
See the common MvE RAR for the nickel substances (nickel; nickel carbonate; nickel chloride; nickel dinitrate and
nickel sulphate): “Humans exposed indirectly via the environment and combined exposure - exposure assessment
and risk characterisation”.
0.2.4
COMBINED EXPOSURE
(X)
i)
( )
ii)
(X)
iii)
• Patients with severe nickel sensitisation constitute a particularly sensitive population to oral challenge with
nickel and are potentially at risk from excessive exposure to nickel in food and water. This patient group
should have relevant information on possibilities for nickel contamination of food and drinking water and on
the natural contents of nickel in food to avoid or minimize the risk.
o There is no concern for the general population that are not already sensitised to nickel from exposure to nickel
in food and water. There is no concern for patients with severe nickel sensitisation for other endpoints than a
possible reaction to oral challenge with nickel.
See the updated assessment in the common MvE RAR for the nickel substances (nickel; nickel carbonate; nickel
chloride; nickel dinitrate and nickel sulphate): “Humans exposed indirectly via the environment and combined
exposure - exposure assessment and risk characterisation”
0.2.5
PHYSICOCHEMICAL PROPERTIES
( )
i)
(X)
ii)
( )
iii)
• There is no reason for concern with respect to the physico-chemical properties of nickel sulphate.
12
1. GENERAL SUBSTANCE INFORMATION
1.1 IDENTIFICATION OF THE SUBSTANCE
Table 1.1.A: Substance Identification
CAS No.:
7786-81-4
EINECS No.:
232-104-9
EINECS Name:
nickel sulphate
Synonyms:
nickel monosulphate; nickelous sulphate; nickel sulfate (1:1); nickel (II)
sulphate; nickel (2+) sulphate; sulphuric acid, nickel (2+) salt (1:1); NCIC60344.
Molecular formula:
H2SO4.Ni (given in EINECS)
Structural formula:
Molecular weight:
154,72
The substance forms a number of hydrates. These are shown in the Table below.
Table 1.1.B: Hydrates of nickel sulphate.
Species
CAS-No
Molecular weight
Stability Range
NiSO4
7786-81-4
154.72
above 330 °C
NiSO4 .H2O
172.71
above 102°C
NiSO4 .2H2O
190.70
detected in solution above 98°C
NiSO4 .3H2O
208.69
NiSO4 .4H2O
226.68
NiSO4 .5H2O
244.67
262.66
crystallised at 30.7 - 53.8 °C
262.66
crystallised above 53.8 °C
280.65
crystallised below 30.7 °C
α- NiSO4 .6H2O
10101-97-0
β- NiSO4 .6H2O
NiSO4 .7H2O
10101-98-1
The EINECS number shown in Table 1.1.A applies to all the hydrates of nickel sulphate shown in Table 1.1.B. The
criteria for reporting for the EINECS Inventory (CEC, 1982) states in Point 14:
“Hydrates of a substance or hydrated ions, formed by association of a substance with water should not be reported. The
anhydrous form can be reported and will, by implication, represent all hydrated forms.”
The EINECS inventory therefore lists the CAS number for the anhydrous form (7786-81-4) together with the EINECS
number (232-104-9) associated with this CAS number. As the rule quoted above indicates, this EINECS number
represents by implication all hydrated forms, whether or not they are shown with a CAS number in Table 1.1. B above.
Nickel sulphate with CAS No.: 7786-81-4 is included in the European Customs Inventory of Chemical Substances
(ECIS, 1997) with the number 20762. The substance is also included in the European Community’s Combined
Nomenclature (eight digit CN code). The CN is based on the “Harmonized Commodity Description and Coding
13
System” emanating from WCO, in use throughout the world. The CN number is 2833 24 00, and relates to sulphates of
nickel. Other metal sulphates are not included in this CN number.
1.2 PURITY / IMPURITIES, ADDITIVES.
Nickel sulphate is available as the heptahydrate at > 99% purity and as the hexahydrate at 99% purity (Aldrich
Chemical Co., 1988 quoted in IARC, 1990).
The purity of commercially available nickel sulphate depends on the type of raw material and the efficiency of
purification. An example of the purity of nickel sulphate hexahydrate from a secondary copper smelter is shown in
Table 1.2.A (Meyer-Wulf, 2002b).
Table 1.2.A: Purity of a commercially available nickel sulphate hexahydrate (Meyer-Wulf, 2002b).
CAS-No 1.
Name
Value
Purity:
Nickel
> 24 %
Impurities:
Cobalt
< 100 ppm
Iron
< 10 ppm
Lead
< 5 ppm
Copper
< 5 ppm
Zinc
< 10 ppm
Cadmium
< 4 ppm
Arsenic
< 1 ppm
1: No CAS numbers are included for these metals, as the limit values shown here do not relate specifically to the metal
but relate to the total amounts of metallic impurity.
Information is available in a national standard (DIN 50970) for the maximum levels of impurities for nickel sulphate
used in electroplating.
Table 1.2.B: Maximum levels of impurities for nickel sulphate hexahydrate used in electroplating (DIN
50970) (Meyer-Wulf, 2001).
Purity:
Impurities:
CAS-No. 1
Name
10101-97-0
Nickel sulphate
hexahydrate
Value (ppm)
Cobalt
5,000
Zinc
30
Iron
20
Copper
20
Lead
10
Cadmium
10
Arsenic
10
Table 1.2.C shows details of the purity of commercially available nickel sulphate solutions used in catalyst production.
Table 1.2.C: Analysis of nickel sulphate solution used in catalyst production (Meyer-Wulf, 2001).
Minimum
Maximum
1
14
Minimum
Maximum
Nickel
sulphate
g/l
~ 250
Ni
g/l
90
Cu
mg/l
10
Zn
mg/l
50
Fe
mg/l
10
As
mg/l
5
Al
mg/l
17
Pb
mg/l
10
Cr
mg/l
15
Co
mg/l
250
Cd
mg/l
5
Mn
mg/l
15
Mg
mg/l
750
Ca
mg/l
600
1
1): related to 100 g Ni/l
Table 1.2.D shows the characteristic composition of the crude nickel sulphate produced mainly from copper tank house
liquor (see Chapter 2.1.1.5). The nickel sulphate produced as a result of this process is moist nickel sulphate
monohydrate which according to Table 1.1.B is not allocated a CAS number. However, for the reasons described above,
this material in included in the EINECS entry 232-104-9.
Table 1.2.D: Purity and impurities for crude nickel sulphate (Meyer-Wulf, 2001).
CAS No. 1
Purity
Impurities:
Name
Value (range)
Nickel
28 – 30%
H2SO4
2,2-5,5 %
Copper
1,700 - 6,000 ppm
Zinc
2,500 - 5,000 ppm
Iron
1,000 - 2,000 ppm
Arsenic
1,500- 3,000 ppm
Antimony
1,500 - 3,500 ppm
Lead
140 - 460 ppm
Cobalt
50 - 100 ppm
Cadmium
50 - 125 ppm
Manganese
20 - 30 ppm
15
1.3 PHYSICO-CHEMICAL PROPERTIES
Table 1.3.A: Summary of the physico-chemical properties
Value
Comment
Reference
Solid
cubic greenish-yellow crystals
US ATSDR (1997)
Physical State
hydrate:
Melting Point:
anhydrous:
840°C
US ATSDR (1997)
848°C
Decomposition
IARC (1990)
hexahydrate:
53°C
Loss of water of crystallisation
on heating.
IARC (1990)
heptahydrate:
99°C
Boiling Point:
-
IARC (1990)
-
IARC (1990)
Density:
anhydrous
3.68 g/cm3
UK HSE (1987),
US ATSDR (1997).
hexahydrate:
2.07 g/cm3
US ATSDR (1997).
3
heptahydrate:
1.95 g/cm
US ATSDR (1997).
Vapour Pressure
no data
US ATSDR (1997).
Log Kow
no data
US ATSDR (1997).
see also section 1.3.2 below.
Water Solubility:
293 g/l at 20°C
IARC (1990), US
ATSDR (1997),
TERA (1999),
873 g/l at 100°C
TERA (1999)
625 g/l at 0°C
IARC (1990),
655 g/l at 0°C
TERA (1999)
3407 g/l at 100°C
TERA (1999)
heptahydrate:
756 g/l at 20°C
IARC (1990),
Surface Tension
not applicable
IUCLID
Flash Point
non-flammable
US ATSDR (1997)
Autoflammability
non-flammable
US ATSDR (1997)
Flammability
non-flammable
US ATSDR (1997),
Explosive
Properties
Not explosive
IUCLID
Oxidising
Properties
Not oxidising
IUCLID
Viscosity
Not applicable
IUCLID
anhydrous:
hexahydrate:
16
1.3.1
Conversion factors:
(101 kPa, 20 °C):
1.3.2
1 ppm = [...] mg/m³; 1 mg/m³ = [...] ppm
Solubility of nickel sulphate.
The available literature on the aqueous solubility of inorganic nickel compounds has been reviewed (Carlsen, 2001).
NiSO4 is found with varying amount of water attached to the salt, the number of water molecules ranging from 1 to 7.
The actual number of water molecules attached to solid NiSO4 in equilibrium with a saturated NiSO4-solution is
dependent of the solution temperature. Thus, in the temperature range up to ca. 30°C NiSO4•7H2O prevails, whereas at
temperatures up to 90 - 100°C NiSO4•6H2O is dominant (Linke, 1965) (see also Table 1.1.B).
A priori, it could have been expected that the presence of different amounts of crystal water might dramatically affect
the solubility. However, in the case of nickel sulphate it appears that independently of the number of water molecules
attached as crystal water, the compound is readily soluble in water (Carlsen, 2001).
The solubility of NiSO4 at 25°C is given as 29 g/100 g solution (CRC, 2000) corresponding to a concentration of 2.64
mol/L (40.8 g/100 g water; Gmelin, 1966). A smooth increase in the water solubility of nickel sulphate with increasing
temperature can be noted. (Table 1.3.B).
Table 1.3.B. Solubility of nickel sulphate as function of temperature (Gmelin, 1966)
Temperature (°C)
Solubility
(g/100 g water)
Solubility
(mol/L)
Solid phase
NiSO4•xH2O;
x
0
27.6
1.78
7
5
30.1
1.95
7
10
32.7
2.11
7
15
35.4
2.29
7
20
38.0
2.46
7
25
40.8
2.64
7
30
43.7
2.82
7
35
45.8
2.96
6
40
47.9
3.10
6
45
50.2
3.24
6
50
52.4
3.39
6
It should be noted that these figures are somewhat lower than the solubility of 120 g/L solution as nickel (equal 316 g
NiSO4) at 20°C mentioned by Maximilien (1989). The corresponding figure based on the above table is 275.4 g/L
solution. The solubility of NiSO4 significantly decreases with increasing amount of sulphuric acid in the solution
(Gmelin, 1966). The same effect, which must be ascribed to the presence of excess sulphate ions, has been observed if
potassium sulphate is present (Carlsen, 2001).
The dissolution process appears to be significantly more rapid for the hydrated form of the salt, which apparently is
rapidly dissolved and the anhydrous form that is dissolved only in 1 to 2 days at 37°C (Maximilien, 1989).
1.3.3
Summary
The data on physico-chemical properties are based on information from reviews and IUCLID. The data are considered
sufficiently reliable to fulfil Annex VIIA requirements.
17
1.4 CLASSIFICATION
1.4.1
Current classification
1.4.1.1 UN Transport labelling.
Nickel sulphate is not included as a specific entry in either the UN Recommendations on the Transport of Dangerous
Goods (UN, 2001), ADN (UN ECE 2001a) or in the ADR (UN ECE, 2001b).
According to information from industry, nickel sulphate is transported under ADR/RID/IMDG under UN 3077:
Environmentally hazardous substance solid N.O.S. Class 9, M7 (pollutant to the aquatic environment, solid), Packaging
Group III (Meyer-Wulf, 2002a).
1.4.1.2 Classification according to Directive 67/548/EEC.
The current classification and labelling entry (028-009-00-5) in Annex I to Council Directive 67/548/EEC (EC, 1998b)
is:
Classification
Xn; R22
Carc. Cat. 3; R40
R42/43
N; R50-53
Labelling
Symbols
Xn; N
R Phrases
22-40-42/43-50/53
S-Phrases
(2-)22-36/37-60-61
1.4.2
Proposed classification according to Directive 67/548/EEC.
The revised entry for nickel sulphate (028-009-00-5) in Annex I of Council Directive 67/548/EEC agreed in the 30th.
ATP is 1:
Classification
Carc. Cat. 1; R49 Muta. Cat. 3; R68
Repr. Cat. 2; R61
T; R48/23
Xn; R20/22
Xi; R38
R42/43 N; R50-53
Labelling
Symbols
T; N
R Phrases
49-61-20/22-38-42/43-48/23-68-50/53
S-Phrases
53-45-60-61
Notas
E
Concentration limits according to Annex I of Council Directive 67/548/EEC:
C>25%:
T, N; R49-61-20/22-38-42/43-48/23-68-50/53
20%<C<25%:
T, N; R49-61-38-42/43-48/23-68-51/53
2.5%<C<20%:
T, N; R49-61-42/43-48/23-68-51/53
1%<C<2.5%:
T; R49-61-42/43-48/23-68-52/53
0.5%<C<1%:
T; R49-61-43-48/20-52/53
1
The 30th ATP was adopted by a Technical Progress Committee in February 2007, but has not yet been adopted by the
Commission or published in the Official Journal. This classification is therefore not yet legally binding.
18
0.25%<C<0.5%:
T; R49-43-48/20-52/53
0.1 %<C<0.25 %:
T; R49-43-48/20
0.01%<C<0.1%:
Xi; R43
These limits are specific for R38 (20%), R43 (0.01%) and R48/23 (1%).
The revised entry for Annex I to Directive 67/548/EEC is given in Appendix 7.4.
19
2. GENERAL INFORMATION ON EXPOSURE
Nickel sulphate belongs to the group of inorganic nickel compounds. A list of inorganic nickel compounds in EINECS
and in the inventory maintained by the US EPA in support of TSCA regulation is shown as an Appendix in the
Background Report on Nickel and Nickel compounds.
Nickel sulphate occurs naturally as the heptahydrate as the mineral morenosite (Grandjean, 1986, quoted in IARC).
2.1 PRODUCTION
2.1.1
Production methods.
Nickel ores are mined for the production of nickel matte and metallic nickel. Details of this process are described in the
risk assessment report for metallic nickel. Nickel sulphate is obtained from nickel matte used in the production of
metallic nickel.
Nickel sulphate is also produced as a secondary product from ores mined primarily for their content of copper and other
metals. The nickel present in these ores is recovered as nickel sulphate as a product of the leaching process.
The major source of nickel used in current European nickel sulphate production is nickel matte and nickel concentrates
produced from a variety of secondary materials. These include spent nickel catalysts, nickel/cobalt residues, coppernickel alloys as well as drosses. These materials are recycled with nickel sulphate as either the main product or as a byproduct.
Production of nickel sulphate directly from nickel metal or from other nickel compounds such as black nickel oxide or
nickel carbonate no longer occurs in the EU.
Normally, nickel sulphate is produced as the hexahydrate or as a nickel sulphate solution.
2.1.1.1 Nickel sulphate production from nickel matte.
Nickel sulphate is produced by leaching nickel matte.
The production of the nickel matte used in the production of nickel metal has been described in chapters 2.1.1 to 2.1.3
of the risk assessment report for metallic nickel. This matte, the product of smelting process, contains nickel, copper,
iron, sulphur, cobalt and precious metals (Laine, 2001).
At the Outokumpu Harjavalta refinery, nickel matte is leached in three steps: two atmospheric leaching and one
pressure leaching as described in Chapter 2.1.4.2.1 of the nickel metal risk assessment report.
The nickel raw solution obtained from the leaching is cleaned with solvent extraction. First the solution is washed with
kerosene in order to separate possible organic impurities. Cobalt is also removed in this stage. After the solvent
extraction, part of the pure nickel sulphate solution is fed to the nickel hydrogen reduction process (described in chapter
2.1.4.3 of the nickel metal report) or nickel electro winning (described in chapter 2.1.4.2 of the nickel metal report).
This pure nickel sulphate solution is also used in the production of commercial nickel sulphate hexahydrate (Laine,
2001).
Additional nickel sulphate is obtained from the leaching residue from the pressure leaching of the nickel matte. This
residue is copper sulphide containing some nickel (3-6%) and precious metals. Copper sulphide leaching residue is
smelted together with copper concentrates. Nickel is recovered in copper anodes, which are refined in copper
electrolysis (See chapter 2.1.1.4 below). The solution in copper electrolysis is purified in two steps, first the copper
sulphate crystallisation and then the solution is taken to nickel removal (Laine, 2001).
Nickel is crystallized as nickel sulphate monohydrate (crude nickel sulphate) in a vacuum evaporator (Laine, 2001).
Nickel sulphate monohydrate is transported back to the nickel refinery in Harjavalta, and fed into the leaching process
together with nickel matte from the nickel smelter (Laine, 2002).
20
At the Kokkola works of OMG in Finland, nickel sulphate solution from the nickel refinery at Harjavalta is crystallised,
followed by screw separation, drying and packing into plastic bags. All processes are carried out in closed systems
(Meyer-Wulf, 2001).
At the Falconbridge refinery, nickel matte is leached by chlorine gas and nickel metal prepared by electrowinning (see
section 2.1.4.1 and 2.1.4.2 of the risk assessment report for nickel metal). The chlorine leach residue containing copper
goes to the roasting plant. Calcine from the roaster is pumped to copper leach system and copper is recovered by
electrowinning. Nickel sulphate crystals are removed in this stage and fed back into the nickel metal production (Laine,
2003a).
2.1.1.2 Nickel sulphate production from secondary nickel matte and roasted residues.
Nickel matte and roasted intermediate products are produced from secondary materials (e.g. spent catalysts) at
Nickelhütte Aue in Germany (see section 2.1.3.3 in the risk assessment report for metallic nickel) (Meyer-Wulf, 2001).
The matte and concentrates are then processed further in the hydrometallurgical department at Nickelhütte Aue. Matte
and concentrates are autoclaved and dissolved. Solutions are subjected to electrolysis to produce copper cathodes. Iron,
zinc and other trace elements removed by precipitation. Nickel sulphate solution and the nickel sulphate hexahydrate
produced by crystallisation are of sufficient purity to be used in electroplating and manufacture of catalysts (MeyerWulf, 2002a).
2.1.1.3 Other leaching processes
At the Olen works of Umicore 2, mixed nickel / cobalt secondary raw materials are dissolved and extracted with
sulphuric acid. Purification of the resulting solution is achieved by neutralisation (removal of iron and copper) and
solvent extraction (removal of cobalt). Finally, nickel sulphate hexahydrate is crystallised and purified by
recrystallisation (Meyer-Wulf, 2001).
Solutions of impure nickel sulphate from copper refinery production is mixed with impure nickel sulphate solution from
cobalt refinery production in closed tanks. The iron is removed in high tanks to avoid Ni output. Solids are removed by
filtration on continuous band filters. Decantation is carried out in closed tanks, followed by filtration on pressure filters
and solvent extraction in closed tanks. The resulting liquor is stored in closed tank before crystallisation. The nickel
sulphate crystals produced are separated by centrifuge, dried with hot and cold air, and finally stored and packed
(Meyer-Wulf, 2001).
At Siegfried Jacob Metallwerke, Ennepetal, nickel / zinc / copper residues are dissolved and extracted with a mixture of
different waste acids. The solution obtained is then refined by typical chemical separation steps. Nickel sulphate and
zinc sulphate are separated by solvent extraction, whilst copper is produced by electrolysis (Meyer-Wulf, 2001).
2.1.1.4 Nickel sulphate production from copper refining.
Copper production is based on a multistage smelting process followed by electrolytic refining. The copper-containing
raw materials for smelting may be primary ores or secondary copper materials containing nickel (Meyer-Wulf, 2001).
Copper and nickel-containing ores are sometimes associated. Pentlandite, an important nickel containing ore which is
almost always found associated with chalcopyrite, an important copper containing ore (see introduction to chapter 2 in
nickel metal report). There are also other copper sulphide ores. Some copper is mined in the EU, mostly in Spain and
Portugal, but most copper concentrates are imported from outside the EU (mainly from Chile and South East Asia
(Laine, 2002).
Among secondary materials, recycled copper nickel alloys and drosses play an important role (Meyer-Wulf, 2001).
The nickel obtained from the Outokumpu plant at Pori is derived from nickel in from the copper ore/concentrates, as
well as nickel from secondary raw materials (Laine, 2002). Much of the copper-tank house liquor used at other plants
(including Boliden in Sweden) comes from secondary materials (Meyer-Wulf, 2002).
2
Formerly Union Minière
21
During the smelting operations that are carried out to produce copper anodes, nickel remains in the metal phase. The
copper is electrolytically refined (transferred from anode to cathode). The products of copper smelting are copper
anodes containing about 99% copper which are refined to copper cathodes containing 99.99% copper in the tank house
liquor, which is based on 20 % sulphuric acid (Meyer-Wulf, 2002b). During this process, the nickel remains in the
liquor as nickel sulphate (Meyer-Wulf, 2001).
To keep the nickel content in the tank house liquor at a constant level, part of it has to be withdrawn and treated in a
special purification unit. In a first step, copper is removed from the tank house liquor. This is usually carried out by
reduction electrolysis. In addition, copper sulphate can be produced by evaporation / crystallisation processes before
electrolysis takes place. After the copper has been removed, crude nickel sulphate is produced by evaporation /
crystallisation (Meyer-Wulf, 2001).
The crude nickel sulphate produced is a monohydrate which contains impurities of other metals sulphates and sulphuric
acid as well as water. The nickel content is about 25 to 29 %. Dissolution and recrystallisation result in the formation of
nickel sulphate hexahydrate. Additional purification steps are needed in order to prepare a product of sufficient purity
for plating and other applications (see section 2.1.1.7 below) (Meyer-Wulf, 2001).
At Olen works of Umicore, the tank house liquor withdrawn from the process is used to dissolve other by-products
containing Cu-As and Ni. After removal of copper, the impure nickel sulphate is produced by crystallisation. These
crystals are separated by centrifugation, and then re-dissolved and sent to the production line for further purification
(see chapter 2.1.1.5) (Meyer-Wulf, 2001).
Production facilities at Outokumpu Harjavalta represent a special case, where crude nickel sulphate from the copper
tank house is used in the nickel refinery (see chapter 2.1.1.1. above) (Meyer-Wulf, 2001).
2.1.1.5 Purification of impure nickel sulphate.
As described in 2.1.1.6 above, the nickel sulphate from copper refining is a crude product. An example of the
composition of impure (crude) nickel sulphate is shown in Table 1.2.B. As the crude nickel sulphate is too impure for
usual applications, further purification is needed. This is either done directly on-site or off-site by other nickel sulphate
producing companies. The quantities of crude nickel sulphate undergoing off-site purification are shown in the
following table (Meyer-Wulf, 2001).
Table 2.1.1.B Crude nickel sulphate undergoing off-site purification (t / year) (Meyer-Wulf, 2001).
1994
1999
2000
Crude nickel sulphate (total)
3,000
4,500
4,500
calculated as NiSO4
2,100
3,200
3,300
calculated as NiSO4 x 6H2O
3,600
5,500
5,600
Calculated as Ni
800
1,200
1,200
2.1.1.6 Nickel sulphate production from metallic nickel.
Nickel sulphate can be produced from nickel pellets by dissolving the pellets in sulphuric acid to give nickel sulphate.
The major production steps are described below (Meyer-Wulf, 2001).
Nickel pellets are transferred from the pellet production plant to a pellet feed hopper in the nickel sulphate plant
(feeding step). Nickel pellets are treated with hot sulphuric acid in a closed vessel to produce a strong liquor
(dissolution step). The strong liquor is then pumped to the crystallisers via three filters in parallel to remove any
suspended solids (filtration step). The strong liquor is fed to the crystallisers where the temperature of the contents is
controlled by means of cooling water coils. The slurry is siphoned off at a controlled rate to the centrifugal separators
(crystallisation step). The nickel sulphate crystals are separated from the mother liquor in a centrifuge where they are
washed by fine water sprays. The wet crystals are transported to a fluid bed dryer while the separated liquor flows to the
mother liquor tank. It is recycled from here to the reactors (separation step). The wet crystals are dried in a vibrating
fluid bed dryer using hot and cold fluidising air (drying step). The exhaust air is scrubbed before discharge to the
atmosphere. The fluid bed dryer is maintained under slightly negative pressure to prevent dust emission to atmosphere.
The exhaust air passes through a cyclone, exhaust fan and scrubber before discharge to atmosphere.
22
Packing is fully automated for the saleable product. The packing units is equipped with dust extraction filters fitted with
a sequenced high pressure air pulse for cleaning the filter bags, and is discharged into a completely sealed container.
All plant surface drains are connected directly to the effluent treatment plant. Feeding and Packing are closed batch
processes. The other steps are continuous, dissolution and filtration being totally closed, crystallisation, separation and
drying partly closed.
This process was carried out at the INCO Europe Ltd. until the plant closed in 1996. Nickel sulphate is no longer
produced from nickel metal in the EU (Meyer-Wulf, 2001).
2.1.1.7 Nickel sulphate production from nickel carbonate.
Nickel sulphate has been described as produced by the reaction of nickel carbonate and dilute sulphuric acid.
(Antonsen, 1981, quoted in IARC, 1990). According to Antonsen (1996) in 1994 the price of nickel sulphate was $2.50
/kg, whilst the price of nickel carbonate was $4.00/kg. NiPERA (1996) also describes nickel carbonate as a feedstock
for nickel sulphate production. Nickel sulphate is not produced by this process in the EU (Meyer-Wulf, 2002a).
Nickel sulphate is the main feedstock for nickel carbonate production (see Chapter 2.1.1.1 in risk assessment report for
nickel carbonate).
2.1.1.8 Other methods of nickel sulphate production.
In describing the feedstocks used in the production of nickel sulphate, NiPERA (1996) describes the use of other
feedstocks as shown in the Table below.
Table 2.1.1.C: Characteristics of cobalt-nickel sulphides and nickel arsenide used as feed stocks in nickel
sulphate production (NiPERA, 1996).
Description
Physical
Container
Handling
Quantity t/y
partially
manual
1500
mechanical
3000
Chemical
Cobalt-nickel sulphides
<100 mesh powder 18% Ni
Nickel arsenide
<300 mesh powder 40% Ni
special design
Cobalt-nickel sulphides (produced for example in Cuba) are used to produce nickel sulphate, as this is a normal way to
process sulphidic products. Nickel arsenides were used to produce nickel sulphate as a by-product of the copper
industry (Eramet, 2002).
Nickel sulphate is not produced by these processes in the EU (Meyer-Wulf, 2002a).
2.1.1.9 Anhydrous nickel sulphate production.
Large-scale manufacture of the anhydrous form may be achieved by gas-phase reaction of nickel carbonyl with sulphur
dioxide and oxygen at 100°C or in a closed-loop reactor that recovers the solid product in sulphuric acid (Antonsen,
1981, quoted in IARC, 1990). No European production of anhydrous nickel sulphate has been reported by Industry.
2.1.2
Production volumes
The countries that produce nickel sulphate in the largest volumes in the present EU are Belgium, Germany, Finland and
the UK (ERAMET-SLN, 1989 quoted in IARC, 1990)
The figures for more recent nickel sulphate production are shown in the table below. (Meyer-Wulf, 2001).
Table 2.1.2.A: First production of nickel sulphate in Europe (t / year) (Meyer-Wulf, 2001).
calculated as NiSO4
1994
1999
2000
16,000
13,700
14,200
23
1994
1999
2000
calculated as NiSO4.6H2O
27,100
23,300
24,200
calculated as Ni
6,000
5,200
5,400
There are no centralised data available on production and use of nickel sulphate. The data in Tables 2.1.2.A and 2.1.2.B
were obtained by asking companies shown in 2.1.3.A for their production and export data (Meyer-Wulf, 2002a).
First production includes the primary production processes listed above in sections 2.1.1.1 to 2.1.1.5. The crude nickel
sulphate purification described in section 2.1.1.8 is not included, as the primary production is already included in the
earlier processes.
Production of nickel sulphate was discontinued at Inco, UK, in 1996. This led to a fall in the amounts produced in
Europe from 1994 to 1999. This fall in production was partly compensated by raising production from the remaining
companies (Meyer-Wulf, 2001).
A little over one third of the primary nickel sulphate produced is exported outside Europe, predominantly to the Far
East. (Meyer-Wulf, 2001).
Table 2.1.2.B: Export of nickel sulphate to non-EU countries (tons / year) (Meyer-Wulf, 2001).
1994
1999
2000
calculated as NiSO4
n.a.
5,000
5,200
n.a.
8,500
8,800
calculated as Ni
n.a.
1,900
2,000
Other countries and regions producing large volumes are the former Republic of Czechoslovakia, Japan, Taiwan, USA
and the former USSR (ERAMET-SLN, 1989 quoted in IARC, 1990).
Annual world production volume is about 60000 t of the commercial form of pure nickel sulphate hexahydrate (Laine,
2002). EU production thus represents roughly 40% of world production.
Unlike the customs statistics for many other nickel salts, nickel sulphate is reported under a specific CN number:
28.33.24.00 (ECIS, 1997). No imports of nickel sulphate to the EU are reported for 1999 or 2000 (Meyer-Wulf, 2001).
The gross weight of all nickel salts imported to the EU in 2000 was 3980 t (Laine, 2003b). The amount of nickel
sulphate imported is estimated to be approximately 2000 t.
2.1.3
Production sites
In 1988, nickel sulphate hexa- and heptahydrates were produced by five companies in Germany, four companies in the
UK, two each in Austria, Belgium and Italy, and one each in Finland, Spain, Sweden (Chemical Information Services
Ltd. 1988, quoted in IARC, 1990).
The companies more recently producing nickel sulphate in the EU/EEA are shown in the Table below (Meyer-Wulf,
2001). The table shows the different raw materials and products produced in each company.
Table 2.1.3.A: Nickel sulphate producing companies in Europe (Meyer-Wulf, 2001).
Company
Location
Raw materials
Products
(1)
Inco Europe Ltd.
Swansea, UK
Nickel pellets
OMG Kokkola
Chemicals Oy
Kokkola, Finland
Nickel/cobalt matte (2)
Nickelhütte Aue GmbH
Aue, Germany
Crude nickel sulphate
Nickel sulphate hexahydrate
(6)
Mixed copper/nickel/cobalt
24
Company
Location
Raw materials
secondary raw materials (3)
Products
Nickel sulphate solution
Crude nickel sulphate (6)
Umicore
Olen, Belgium
Mixed nickel/cobalt
secondary by-products (4)
Copper tank house liquor (5)
Norddeutsche Affinerie
AG
Hamburg, Germany
Siegfried Jacob
Metallwerke GmbH
Ennepetal, Germany
Mixed copper/nickel/zinc
secondary raw materials (4)
Montanwerke Brixlegg
AG
Brixlegg, Austria
Hüttenwerke Kayser
AG
Lünen, Germany
Boliden Mineral AB
Skelleftehamn, Sweden Copper tank house liquor (5)
Mansfelder Kupfer Und
Messing GmbH
Hettstedt, Germany
Outokumpu Harjavalta
Metals Oy
Pori, Finland
1): see section 2.1.1.6. Nickel sulphate production finished in 1996;
2): see section 2.1.1.1;
6): see section 2.1.1.5; Crude nickel sulphate purchased from other EU companies.
7): Companies selling crude nickel sulphate for further purification.
8): Crude nickel sulphate used in nickel refinery
The Table shows that of the 11 companies listed, 7 companies are copper smelters which produce nickel sulphate from
their tank house liquor. Only one company (INCO) has used metallic nickel to produce nickel sulphate and this
production is now discontinued. One other company (OMG Kokkola Chemicals Oy) uses nickel obtained directly from
ore mined for nickel metal production. Three companies use secondary by-products or secondary raw materials for
nickel sulphate production.
Nickel sulphate hexa- and heptahydrates were also produced outside the EU at sites in Japan, the US, India, Argentina,
Mexico, Canada, Brazil, Australia, the former republic of Czechoslovakia, Switzerland, Taiwan and the former USSR.
(Chemical Information Services Ltd. 1988, quoted in IARC, 1990).
2.2 USE PATTERN
2.2.1
Current Use Pattern
Nickel sulphate is used for:
• Production of nickel metal by electrolysis
• Electroplating
• Production of catalysts
• Production of other nickel compound / salts
• Production of nickel-containing batteries.
25
Annual worldwide use of nickel sulphate in 1994 was 15,000 t. The price was $2.50 /kg (Antonsen, 1996). This figure
is small compared to the world production of 60,000 reported by Laine (2002) (see 2.1.2 above).
Table 2.2.1.A: Use of Nickel sulphate in the EU (t / year) (Meyer-Wulf, 2001)
1994
1999
2000
calculated as NiSO4
n.a.
8,700
9,000
n.a.
14,800
15,400
calculated as Ni
n.a.
3,300
3,400
The data in table 2.2.1.A were calculated from the data shown in Tables 2.1.2.A and 2.1.2.B.
The main use of nickel sulphate is as an electrolyte primarily for nickel plating. It is also used in ‘electro-less’ nickel
plating, as a nickel strike solution for replacement coatings or for nickel flashing on steel that is to be porcelain
enamelled, as an intermediate in the manufacture of other nickel chemicals, such as nickel ammonium sulphate, and it is
a raw material for the production of catalysts (Antonsen, 1981, quoted in IARC, 1990). It is also used in the fabrication
of jewellery. (IPCS, 1991).
Nickel sulphate is also used in the production of nickel metal and nickel (hydroxy)carbonate (see below). However, this
use does not appear in the production or use figures as nickel sulphate is a non-isolated intermediate in these production
processes.
Information on other uses of nickel sulphate is limited. Information from the Swedish Product Registry indicates that
nickel sulphate is used in products mainly related to industries for the treatment and coating of metals, industry for
fabricated metal products and industry for chemical products. A limited number of products are listed as being used as
degreasing agents or for other uses (rust preservatives) in industry for the treatment and coating of metals. No products
are listed for consumer use (Kemi, 2002).
Nickel sulphate concentration in the products listed is shown below.
Table 2.2.1.B: Concentration of nickel sulphate in products (Kemi, 2002).
Concentration range
Quantity (%)
No. of products
less than 10%
0.16%
14
> 10% and less than 20%
0.08
4
99.8%
15
0
0
Data from the Danish Product Registry (1998) show that practically all nickel sulphate reported is in the concentration
range 80 – 100%.
It is estimated that at present the two main uses are electroplating (50% – 75%) and catalysts manufacture (25% – 50%)
with a smaller volume for other uses (Meyer-Wulf, 2002a). Data from ECMA (2002) indicates that nickel sulphate is
used in catalyst production and that this estimate of rather more than 1000 t nickel sulphate (expressed as Ni) is a
realistic estimate for this risk assessment.
A minor use of nickel sulphate (by weight) is as a food supplement (see chapter 4.1.1.3).
2.2.1.1 Production of metallic nickel.
The production of metallic nickel by electrowinning has been described in the risk assessment report of metallic nickel
in section 2.1.4.2.2. In some processes, nickel metal is produced in electrolytic cells filled with nickel sulphate solution.
26
In addition to the production of commercial nickel sulphate at Outokumpu, the nickel sulphate produced by leaching
the nickel matte (see chapter 2.1.1.1 above) is used as a source of electrolyte for the electrowinning process and for the
hydrogen reduction process for the production of nickel metal (see sections 2.1.4.2.2. and 2.1.4.3.2 of the risk
assessment report for nickel metal) (Laine, 2003a).
In this context nickel sulphate functions as an intermediate in nickel metal production.
2.2.1.2 Nickel plating
Nickel plating processes have been described extensively in the risk assessment report on nickel metal.
The majority of the nickel sulphate produced in Europe is used in electroplating. No specific figures for this use have
been provided by Industry.
There are specific requirements to the quality of the nickel sulphate used in plating processes. These are shown in Table
1.2.A.
There are four main types of nickel sulphate-containing solutions used in electroplating. The composition is shown in
the Table below.
Table 2.2.1.C: Composition of nickel electroplating solutions (g/l). (modified from Atkins, 2001, Eramet,
2001).
Watts
Solution
1)
Hard Nickel
Solution
High Chloride
Higher Throwing
Power Solution
Nickel sulphate, NiSO4.6H2O 240 – 300 1)
180
200
30
Nickel chloride, NiCl2.6H2O
40 – 60
30
560
38
Boric acid, H3BO3
25 – 40
30
25 – 30
25
Eramet (2001) gives a lower value: 125 – 250 g/l.
Nickel sulphate is the source of most of the nickel ions and is generally maintained in the concentration range of 150300 g/l. It is the least expensive nickel salt and the sulphate anion has little effect on deposit properties. Nickel sulphate
is usually maintained at the high end of the range for very bright applications where throwing power is not a major
consideration. It is maintained at the lower range for applications where throwing power is needed, such as in barrel
plating (Eramet, 2001).
2.2.1.3 Nickel sulphate used in the production of catalysts
The use of nickel metal in the production of catalysts has been described in the risk assessment report on nickel metal.
According to information supplied by ECMA (2002), nickel sulphate is used as a feedstock for nickel catalyst
production. Nickel sulphate is an important source of nickel for catalyst production, although significantly less sulphate
is used as a feedstock than either nickel metal or nickel nitrate.
Nickel sulphate is used in the production of catalysts as an aqueous solution. Solutions of nickel sulphate, nitrate and
carbonate are treated with sodium carbonate or sodium hydroxide to precipitate nickel hydroxide. This is applied to a
supporting system, e. g. kieselguhr. After filtration and drying of this mixture the nickel hydroxide is reduced in several
stages by hydrogen, giving finally nickel in a very fine distribution. The raw product is coated with fat and
agglomerated to catalyst product, which is packed in barrels. (Meyer-Wulf, 2001).
Composition of the commercial nickel sulphate solution used in catalyst production is shown in Table 1.2.C.
Further details of nickel catalyst production are given in chapter 2.2.1.5.2 of the risk assessment report for metallic
nickel. Additional information is also given in Appendix 7.7 of the nickel metal report.
27
2.2.1.4 Nickel sulphate used in the production of chemicals
The nickel sulphate produced by leaching the nickel matte at Outokumpu (see chapter 2.1.1.1 above) is used together
with caustic soda for the production of nickel hydroxycarbonate (see section 2.1.1.1 of the Risk Assessment Report for
nickel carbonate) (Laine, 2003a).
In this context nickel sulphate functions as an intermediate in nickel hydroxycarbonate production.
Nickel sulphate is also used as an intermediate in the manufacture of other nickel chemicals, such as nickel ammonium
sulphate (Antonsen, 1981, quoted in IARC, 1990).
Nickel sulphate can also be used to produce nickel nitrate, nickel chloride and nickel oxide (Meyer-Wulf, 2002a). No
additional information is available about these production processes.
Nickel sulphate is not listed as a feedstock for the production of colorants (Eurocolour, 2002).
2.2.1.5 Nickel sulphate used in production of Nickel-containing batteries.
There is a new market for nickel sulphate in the production of nickel-based batteries. Nickel sulphate can be used to
produce special chemicals for the production of nickel-based batteries (Meyer-Wulf, 2002a).
Battery production using nickel metal as a feedstock is described in the risk assessment report for metallic nickel
section 2.2.1.4.1. No additional information on the use of nickel sulphate in the production process is available.
2.2.2
Recycling
The major uses of nickel sulphate described above result in the production of plated products, catalysts and other nickelcontaining chemicals. In these processes nickel sulphate is converted into other nickel-containing compounds. Plated
products and catalysts are recycled, and the recycling of these products is described in Chapter 2.2.3. of the Risk
Assessment report for metallic nickel.
Whilst the recycling process is for nickel rather than for nickel sulphate specifically, the products of this recycling
system are often used for the production of new nickel sulphate as described in Chapter 2.1.1.4.
Galvanic sludges can also be recycled, but little is known about recycling rates (Meyer-Wulf, 2002a).
2.2.3
Discontinued Uses of the Substance
Nickel sulphate was used therapeutically in human medicine to relieve rheumatism from 1850 - 1900 (Hausinger, 1993,
quoted in Eisler, 1998).
2.2.4
Industrial and use categories for nickel sulphate
Tables 2.2.4.A and 2.2.4.B show the amounts of nickel sulphate used in the EU and the industrial and use categories.
Table 2.2.4.A: Tonnes / year calculated as NiSO4. Data for 1999 and 2000 (Meyer-Wulf, 2002a).
1999
Tonnes / year
Production
(1)
2000
%
Tonnes / year
%
13,700
14,200
Import
(2)
2,000
2,000
Export
(3)
5,000
36%
5,200
37%
10,7000
64%
11,000
63%
Used in the EU (4)
1): Data from table 2.1.2.A (first production).
2). No import has been reported by the companies asked. The amount is estimated from customs figures provided by
Laine (2003).
3): Data from table 2.1.2.B (export).
28
4). Data from table 2.2.1.A (use).
Table 2.2.4.B: Industrial and use categories.
Scenario
Lifecycle
Stage
Industry category
Use category
Main category
Tonnes / year
A1
Production
IC8 (Metal
extraction, refining
and processing)
UC55 (Others)
MC 1c
14.200
B1
Processing
IC3 (Basic
chemical used in
synthesis)
UC 33
(Intermediates,
other salts,
catalysts)
MC3
3,800
35 (1)
IC8 (Metal
extraction, refining
and processing)
UC 17
(Electroplating
agents)
MC3
7,000
63 (2)
IC 15 (Others)
UC 55 (Others)
MC3
200
<2
B2
%
1): Catalysts manufacture estimated as 25 – 50% of use (9000 t); figure used: 35%.
2): Electroplating estimated as 50 – 75% of use (9000 t), figure used: 63%
Note that Scenario B1 covers the use of nickel sulphate for both catalyst production and chemicals production. As
pointed out in the text, the figure quoted above is considered to be a realistic estimate for the amounts used in catalyst
production alone. Nickel sulphate is also used to produce between 5000 and 6000 t nickel carbonate (as NiCO3) is
described in the nickel carbonate risk assessment report.
The following flow diagram for the primary production and use of nickel sulphate production has been developed in
close collaboration with Sally Williams (Inco) and Ivor Kirman (NiDI).
Figure 2.2.4.A. Nickel Sulphate. Primary production and first use.
Nickel ore:
Sulphidic
nickel oxide
Secondary materials
crude nickel sulphate
nickel matte
Copper ores
copper matte
Nickel metal*
Nickel sulphate
EU Production 14000 t
2,000 t Import
Export 5,200 t
Plating
Catalysts
EU Use: 7000t
EU Use: 3,800t
Chemicals
EU Use: small **
29
* process no longer operated in the EU
** This does not include production of nickel hydroxycarbonate where nickel sulphate is a non-isolated intermediate
2.3 TRENDS
The number of nickel sulphate production sites in Europe has fallen significantly in the past two decades. In 1988, there
were 17 European companies producing nickel sulphate (Chemical Information Services Ltd. 1988). Of the 11
companies listed in Table 2.1.3.A above, Inco Europe Ltd. closed their nickel sulphate production in 1996. Siegfried
Jacob is planning to shift nickel sulphate production from Ennepetal to its daughter company Nickelhütte Aue (MeyerWulf, 2001). The number of companies with current (2000) nickel sulphate production is ten and this will decrease to
nine.
Future trends in nickel sulphate production are difficult to predict. According to information from the nickel sulphate
producers, some companies are planning to increase production. There is a question of the availability of raw materials
and nickel sulphate and increasing recycling of nickel containing residues would increase sulphate production. The
producers also see growth in the different uses of nickel sulphate, (i.e. plating, catalysts and nickel-based batteries) so
that in general an increasing use is predicted (Meyer-Wulf, 2002a). The analysis of trends for the use of metallic nickel
(chapter 2.3.2 in the risk assessment report for metallic nickel) supports this assessment for the growth in the use of
nickel for batteries, but suggests that there is little growth expected in total nickel use in plating. The low growth in use
seen for plating uses reflects, in part, a trend for products to be imported into Europe from lower cost countries
(especially Asia) rather than to be made in Europe (NiDI, 2002).
2.4 LEGISLATIVE CONTROLS
The following section follows the description of risk reduction measures described in the Nordic Risk Reduction report
(NMR, 2002) and the TGD for risk reduction (European Commission, 1998)
2.4.1
General Measures.
2.4.1.1 Directive 67/548/EEC on dangerous substances.
Nickel sulphate is included in Annex I to the Directive (EEC, 1992a) with a harmonised classification (for details of the
classification, see Chapter 1.4.1.2). The classification was first introduced in the 15th. Adaptation to technical progress
(EEC, 1991a). The current listing, which now includes classification for dangers to the environment, is included in the
25th. Adaptation (EC, 1998b). A revised Annex I entry is included in the 30th ATP.
Professional users of users have to be provided with a Safety data sheet by the manufacturer or supplier. The format for
Safety data sheets is described in a separate Directive, EC (2001d).
Nickel sulphate is included in EINECS. As described in Chapter 1, the EINECS number shown in Table 1.1.A applies
to all the hydrates of nickel sulphate.
2.4.1.2 Directive 1999/45/EC on dangerous preparations.
This Directive (EC, 1999) should have been implemented into national law by the Member States by 30th. July 2002. It
replaces Directive 88/379/EEC (EEC, 1988).
Classification of hazards of preparations containing nickel sulphate follows the general rules set out in the Directive.
Where health or environment hazards are based on a calculation method, the general concentration limits set out in the
Directive apply. . No specific concentration limits to replace the general concentration limits are included for nickel
sulphate in the current entry in Annex I to Directive 67/548/EEC, but specific concentration limits for R38 (skin
irritation), R43 (skin sensitisation) and R48/23 (serious effects after repeated exposure) are included in the 30th ATP.
2.4.1.3 National Initiatives.
Nickel sulphate, like other nickel compounds (see Background report on nickel and nickel compounds) is included in
the Danish list of undesirable substances (Danish EPA, 2000).
30
2.4.2
Protection of workers.
The occupational use of nickel sulphate is covered by the provisions of Directive 98/24/EC on the protection of the
health and safety of workers from the risks related to chemical agents at work (EC, 1998a).
The Directive (Article 3) provides a framework for setting occupational exposure limit values and biological limit
values. The Directive requires that risks arising from chemical agents are identified by employers through risk
assessment (Article 4) and reduced by application of a set of general principles (Articles 5 and 6), which include
substitution, prevention, protection and control. In those instances where a national OEL is exceeded, the employer is to
remedy the situation through preventative and protective measures. The values for OELs for nickel sulphate in force in
various countries are shown in Table 2.4.A.
Table 2.4.A: Occupational Exposure Limits (OEL) for nickel sulphate in force in various countries (NIPERA,
1996 with updates).
Country/Body
mg/m3 as nickel (1) Comments
Austria
0.05
Soluble nickel compounds
Belgium
0.1
Denmark
0.01
Soluble nickel compounds, Arbejdstilsynet, 2000
France
0.1
Soluble nickel compounds, VME (Valeur Moyenne d’exposition)
Finland
0.1
Germany
0.05
Nickel compounds as inhalable droplets. TRK (Technische
Richtkonzentrationen) (2, 3) (TRGS 900, 2000)
Greece
not available
Not available
Ireland
0.1
Italy
0.1
Luxembourg
0.1
The Netherlands
0.1
Portugal
0.1
Spain
0.1
Sweden
0.1
United Kingdom
0.1
Soluble nickel compounds. MEL (Maximum exposure limit) based
on ’total inhalable’ aerosol as measured with the seven-hole
sampler (UK HSE, 2000).
EU (proposed)
[0.1]
Soluble nickel species. NiPERA (1996) proposal under discussion
in SCOEL.
Norway
0.05
Nickel and nickel compounds
USA (OSHA)
1.0
Soluble nickel compounds. PEL (Permissible exposure limit)
1): 8-hour TWA (Time-Weighted Average) unless otherwise noted.
2): In Germany, nickel compounds are classified by MAK as Carc. Cat. 1 if they occur as respirable droplets, and
therefore MAK values cannot be fixed for these substances. The MAK list also notes the risk of sensitisation of the skin
and respiratory tract (BAuA, 2003a).
3) According to German national regulations, nickel sulphate is classified as Carc. Cat. 1 (TRGS 905, 2002, in
connection with EU Regulations) (BAuA, 2003b)
ACGIH (1998) has an inhalable Threshold limit Value (TMV) of 0.1 mg Ni /m3 for soluble nickel compounds.
Nickel sulphate is not currently classified as a category 1 or category 2 carcinogen, and is hence not covered by the
provisions of Directive 90/394/EEC on the protection of workers from the risks related to exposure to carcinogens at
work (EEC, 1990). Preparations containing nickel sulphate may or may not be covered by this Directive, depending on
31
the presence of other substances classified as Category 1 or 2 carcinogens. Changes to the classification included in
Annex I to Directive 67/548/EEC in the 30th ATP will bring the substance within the scope of this Directive when these
changes come into force.
Nickel sulphate is covered by the provisions of Directive 92/85/EEC on the introduction of measures to encourage
improvements in the safety and health at work of pregnant workers and workers who have recently given birth and are
breastfeeding (EEC, 1992b). For such workers, this Directive requires that the employer shall assess the nature, degree
and duration of exposure in the undertaking and/or establishment concerned, of pregnant workers, workers who have
recently given birth and workers who are breast feeding in all activities liable to involve a specific risk of exposure to
the agents.
The possibility for young people to work with nickel sulphate and nickel sulphate-containing preparations classified as
harmful under Directive 88/379/EEC is covered by the provisions of Directive 94/33/EC (EC, 1994b) on the protection
of young people at work. This Directive prohibits the employment of young people for work involving exposure to such
harmful agents.
The use of personal protective equipment at the workplace is regulated by Directive 89/656/EEC (EEC, 1989). The
labelling required by Directive 67/548/EEC includes three relevant Safety advice phrases: S22 (Do not breath dust), S36
(Wear suitable protective clothing) and S37 (Wear suitable gloves).
2.4.3
Protection of consumers.
2.4.3.1 Food supplements, additives, contaminants.
Nickel sulphate is not included as a food supplement in Annex I or II of Directive 2002/46/EC of the European
Parliament and the Council on food supplements in foodstuffs for human consumption (EC, 2002b) or in Council
Directive 70/524/EEC concerning additives in feedingstuffs for animal nutrition (EEC, 1970).
Article 15 of Directive 2002/46/EC requires Member States to bring into force the laws, regulations and administrative
provisions necessary to comply with this Directive by 31 July 2003. “Those laws, regulations and administrative
provisions shall be applied in such a way as to … prohibit trade in products which do not comply with the Directive
from 1 August 2005 at the latest”. However, Article 4 (6) provides a derogation for Member States to allow the sale of
vitamins and minerals not listed in Annex I, if these are used in one or more food supplements marketed in the
Community on the 12th. July, 2002, and if the European Food Safety Authority has not given an unfavourable opinion
in respect of the use of that substance on the basis of a dossier supporting use of the substance in question to be
submitted to the Commission by the Member State not later than 12. July 2005. If granted, this derogation will apply
until 31. December 2009. The list of vitamins and minerals which may be used in the manufacture of food supplements
(Annex I) can be modified by a Committee procedure.
In Member States that do not intend to apply the derogation in Article 4 (6) of the Directive, nickel is not permitted in
food supplements from 1. August 2005. Member States that intend to make use of the derogation can allow the sale of
these food supplements until 31. December 2009.
Directive 2002/46/EC is implemented in England by the Food Supplements (England) Regulations 2003. Separate,
equivalent legislation has been made in Scotland, Wales and Northern Ireland. The Statutory Instrument includes
measures that make use of the derogation in Article 4(6) of the Directive since the UK intends to allow, subject to the
criteria in Article 4(6) being met and where there are no safety concerns, the continued sale of products containing
vitamin and mineral sources not yet on the permitted lists in Annexes I and II of the Directive until 31 December 2009
(UK FSA, 2003a). Following publication of the report of the UK Expert Group on Vitamins and Minerals on 8 May
2003, the UK FSA has issued advice to consumers on consumption of food supplements containing nickel (UK FSA
2003b). Advice agreed by the Food Standards Agency and food supplements industry representatives recommends that,
for food supplements containing nickel, industry should be asked to introduce a label warning: “Nickel may cause a
skin rash in sensitive individuals” (UK FSA, 2004).
A dossier has been submitted to the UK FSA for nickel sulphate hexahydrate, and as a result, a derogation has been
granted for the continued sale of food supplements in the UK containing nickel sulphate (UK FSA, 2005).
32
Apart from a dossier for nickel chloride, no additional dossiers for other nickel compounds have been received by the
European Commission (European Commission, 2005). It should be noted that the European Food Safety Authority’s
NDA Panel have given an Opinion on the tolerable levels of nickel in the diet (NDA, 2005). This opinion concludes
that it is not possible to set a tolerable upper intake level for nickel.
The validity of Directive 2002/46/EC has been challenged at the European Court of Justice, and the Court has found
that examination has revealed no factor of such a kind as to affect the validity of the articles in question (European
Court, 2005).
Nickel sulphate is not included in the list of additives for specific nutritional purposes in foods for particular nutritional
uses (Commission Directive 2001/15/EC of 15 February 2001, EC 2001c).
2.4.4
Emissions to water
Legislation on emissions to water normally addresses concerns related to the nickel ion rather than to nickel sulphate
specifically.
2.4.4.1 Directive 96/61/EC concerning integrated pollution prevention and control (IPPC)
The Directive (EC, 1996) applies to many industrial installations involved in the production and use of metallic nickel
and the nickel compounds currently under review. The Directive is described in the background report in support of the
individual risk assessment reports.
Emission limit values shall be based on best available techniques. The Commission has published eight IPPC BAT
Reference Documents (BREFs) on Best Available techniques in a number of industries (EC, 2002a).
2.4.4.2 Directive 76/464/EEC on pollution of the aquatic environment by certain dangerous
substances.
Nickel is included in List II of families and groups of substances covered by the Directive (EEC, 1976). For further
details, see Background report on nickel and nickel compounds.
2.4.4.3 Directive 2000/60/EC establishing a framework for Community action in the field of
water policy.
Nickel and nickel compounds are specifically listed in the Decision (EC, 2001f) establishing the list of priority
substances in the field of water policy and amending Directive 2000/60/EC (EC, 2000a). For further details, see
Background report on nickel and nickel compounds.
2.4.4.4 Directive 80/68/EEC on the protection of groundwater against pollution caused by
certain dangerous substances
Nickel is included in List II of families and groups of substances covered by the Directive (EEC, 1980). According to
the Water Policy Framework Directive (2000/60/EC, see section 2.4.4.3) the Groundwater Directive will be repealed
with effect from 13 years after the data of entry into force of the Directive, that is 22.12.2013. For further details, see
2.4.4.5 Directive 2000/76/EC on the incineration of waste.
Nickel and its compounds are included in Annex III of the Directive (EC, 2000b) which sets emission limit values of
0.5 mg/l (expressed as nickel, Ni) for discharges of waste water from the cleaning of exhaust gases. For further details,
see Background report on nickel and nickel compounds.
2.4.4.6 National legislation.
In Finland, the IPPC Directive is implemented by the Environmental Protection Act (2000/86) (Finland, 2000). In
addition to installations listed in Annex I of the IPPC Directive, several other activity categories and activities not
exceeding capacity thresholds set in the IPPC Directive require a permit according to the Finnish Act. Concerning
nickel emissions, the most important difference is that all surface treatment installations using electrolytic or chemical
process require a permit regardless of the capacity. So far permit conditions for nickel have been included in permits
33
issued for the following sectors: mines, smelters, metal refiners, primary and secondary steel production, electrolytic
and chemical metal plating (including aluminium anodising) and waste handling (Heiskanen, 2003).
In the Netherlands there is a general prohibition on discharge of nickel to surface water (Netherlands, 1974).
2.4.5
Emissions to air.
Legislation on emissions to air normally addresses concerns related to the nickel ion rather than to nickel sulphate
specifically.
2.4.5.1 Directive 96/61/EC concerning integrated pollution prevention and control (IPPC)
See section 2.4.4.1 above.
2.4.5.2 Directive 2000/76/EC on the incineration of waste.
The Directive (EC, 2000b) sets air emission limit values for nickel and its compounds. For further details, see
2.4.5.3 National Legislation.
In Finland, the IPPC Directive is implemented by the Environmental Protection Act (2000/86) (Finland, 2000). The
Finnish legislation also contains additional provisions concerning nickel. See Chapter 2.4.4.6 above.
Nickel sulphate emissions are regulated in Germany by TA Luft (2002) under section 5.2.2 (inorganic dusts) in hazard
class II, with emission limits expressed as nickel of 2.5 g/h or 0.5 mg/m3. Nickel sulphate is included in section
5.2.7.1.1. (Carcinogens) with emission limits expressed as nickel of 1.5 g/h or 0.5 mg/m3.
The Netherlands Emissions Guidelines for air (NeR) regard nickel and nickel compounds as category C.2 carcinogens.
C2 carcinogens are carcinogens without a threshold value and compulsory minimisation of emissions is required.
Specifically, in the case of an untreated mass flow of 5.0 grams per hour or more, an emission standard of 1.0 mg/mo3
(calculated as nickel) applies (Netherlands, 2001). From 1. April, 2003, nickel and nickel compounds are regarded as
carcinogens for which compulsory minimisation applies. For an untreated mass flow of 0.15 g/hr, an emission standard
of 0.05 mg/m3 applies. An immission assessment must be carried out once every five years. (InfoMil, 2003)
2.4.6
Emissions to Soil
2.4.6.1 National legislation.
In the Netherlands, there is a general prohibition against discharge of liquids containing nickel into soil, although
exceptions are possible (Netherlands, 1997).
2.4.7
Waste management.
2.4.7.1 Directive 96/61/EC concerning integrated pollution prevention and control
See section 2.4.4.1 above.
2.4.7.2 Council Directive 91/689/EEC of 12 December 1991 on hazardous waste
Annex II of the Directive (EEC, 1991b) includes C5 nickel compounds as constituents of wastes in Annex IB which
render them hazardous when they have the properties described in Annex III of the Directive. For further details, see
Lists of hazardous wastes of hazardous wastes have been published as two Commission Decisions (EC, 2001a, 2001b).
Decision 2001/118/EC (EC, 2001a) divides wastes into different chapters. These include a number of categories
relevant to nickel sulphate production and use:
10 Wastes from thermal processes
11 Wastes from chemical surface treatment and coating of metals and other materials; non-ferrous
hydro-metallurgy
34
Spent catalysts are included in Chapter 16: Wastes not otherwise specified in the list.
In general, wastes are classified as hazardous if they fulfil the same classification criteria for dangerous substances and
preparations given in Directives 67/548/EEC and 88/379/EEC.
35
3. ENVIRONMENT
Please consult separate document
36
4. HUMAN HEALTH
4.1 HUMAN HEALTH (TOXICITY)
4.1.1
Exposure assessment
4.1.1.1 General
The human population may be exposed to nickel sulphate:
• at the workplace and
• indirectly via the environment.
Humans may be exposed to nickel sulphate by different routes:
• by skin exposure,
• by respiratory exposure, and/or
• by oral exposure
4.1.1.1.1 Skin exposure.
Skin exposure to nickel is due to occupational contact with nickel sulphate, either as a solid or in solution.
4.1.1.1.2 Respiratory exposure.
Respiratory exposure to nickel sulphate occur s only in an occupational exposure context, by inhalation of aerosols
containing nickel sulphate.
4.1.1.1.3 Oral exposure.
Oral exposure to nickel from nickel sulphate occurs either by ingestion of nickel aerosols at the workplace, or by
indirect exposure to nickel sulphate released during production or processing. This latter exposure is a contribution to
the total nickel intake in food and drinking water, and forms only part of the indirect nickel intake via the environment.
4.1.1.2 Occupational exposure
4.1.1.2.1 General
Occupational exposure to nickel sulphate may occur by skin contact or by inhalation of aerosols containing nickel
sulphate. Nickel-containing aerosols may also be ingested by nickel workers. By definition an aerosol is an assemblage
of small particles, solid or liquid, suspended in air, while dust is an assemblage of small solid particles. Occupational
exposure to aerosols may often involve many different substances (metals and non-metals) acting in concert, and nickelbearing aerosols may contain various chemical species of nickel. Occasionally exposure may be to a refined form of
nickel, but usually exposure is mixed and involves several nickel compounds and other contaminants. Such mixed
exposure complicates the interpretation of health effects related to specific components of the air contaminants.
Previous epidemiological studies have based estimates of exposure to different nickel species on knowledge of the
metallurgical process, but recent speciation results indicate that this can lead to serious misjudgements (Andersen et al,
1998).
Data used for the occupational exposure assessment are:
• Data available from the literature
• Exposure data from the HEDSET
• Data regarding the production processes and use pattern of the products
• Measured data for nickel compounds
• When available monitoring data of the workers
• Physico-chemical data and physical appearance
• Results from exposure models (EASE-model).
37
EASE is a general-purpose predictive model for workplace exposure assessments. It is an electronic, knowledge based,
expert system which is used where measured data are limited or not available. The model is in widespread use across
the European Union for the occupational exposure assessment of new and existing substances. All models are based
upon assumptions. Their outputs are at best approximate and may be wrong. EASE is only intended to give generalized
exposure data and works best in an exposure assessment when the relevance of the modelled data can be compared with
and evaluated against measured data.
It is noted that published data and results provided by industry may have a natural bias towards high levels since it is
not practice to carry out extensive air sampling surveys where the levels are known or suspected to be low. Another
natural bias is introduced if historical and current data are included for the assessment. Symanski et al. (2000) evaluated
temporal changes in exposure to nickel aerosols in the nickel-producing and nickel-using industries, and provided
evidence of largely downward trends in exposure to nickel aerosols in industries involved with the primary production
of nickel and in the manufacture of nickel alloys. However, the decline in nickel aerosols appeared greater for
exposures first evaluated during the 1970s compared with data collected in the 1980s and onwards. For the period 19731995 Symanski et al. (2001) reported statistically significant trends towards lower levels of exposure in the smelting (6%/year) and refining (-8%/year) sectors of the nickel industry. To minimize bias from trends in exposure the
assessment has focus on current data. The exposure is assessed using the available information on the products,
processes and work tasks. More detailed information on these parameters may lead to a more accurate exposure
assessment.
In this part of the assessment, external exposure is assessed using the available information on substance, processes and
work tasks. Internal dose depends on external exposure and the percentage of the substance that is absorbed (through
the respiratory system, the gastro-intestinal system, and through the skin). According to the Technical Guidance
Document, exposure by inhalation is defined as the concentration of substance in the breathing zone and is usually
expressed as a time average concentration over a reference period. By convention this reference period may be either 8
hours to represent long-term exposure or 15 minutes to represent short-term exposure. In general it is difficult to
estimate personal exposure from data obtained by area (static) sampling (Leidel et al., 1977), and for this assessment
priority is given to personal sampling.
The exposure is assessed without taking account of the possible influence of personal protective equipment (PPE). If the
assessment as based on potential exposure indicates that risks are to be expected, the use of PPE may be one of the
methods to decrease exposure, although other approaches (technical and organizational) are to be preferred. In fact this
is obligatory following harmonized European legislation. The efficiency of PPE is largely dependent on site-specific
aspects of management, procedures and training of workers. Thus no default factors for reduction of exposure as a
result of the use of PPE are used in this part of the assessment.
4.1.1.2.1.1
Scenarios for the occupational exposure assessment.
The production and use of nickel sulphate involve several industrial sectors as outlined in section 2. The scenarios
considered for the occupational exposure assessment are listed below (Table 4.1.1.2.1.1.A). The list of sectors is not to
be considered exhaustive in terms of risk of exposure to nickel sulphate. As described elsewhere (the risk assessment
report for metallic nickel) other sectors, including the nickel refining sector and the battery production sector, may
involve a risk of exposure to soluble nickel (including nickel sulphate).
Table 4.1.1.2.1.1.A: Scenarios for the risk assessment
Scenario Lifecycle stage
Industry
category A
Use category Additional
A1
8
55
Nickel sulphate production from nickel matte
A2
8
55
Nickel sulphate production from secondary nickel
matte or roasted residues
A3
8
55
Other leaching processes
A4
8
55
Nickel sulphate production from copper refining
A5
8
55
Purification of impure nickel sulphate
A6
8
55
Nickel sulphate production from metallic nickel
8
55
Production of metallic nickel
B1
Production
Processing
B
38
B2
8
17
Nickel plating
B3
3
33
Production of catalysts
B4
15
55
Production of chemicals
A: 3=Chemical industry, chemicals used in synthesis, 8=Metal extraction industry, refining and processing industry;
15=Others.
B: 17=Electroplating agents, 33=Intermediates (substances used for synthesis of other chemicals); 55=Others.
The following parameters of exposure are assessed for each scenario:
full shift reasonable worst-case inhalation exposure level: the exposure level considered representative for a high
percentile (90 to 95 percentile) of the distribution of full shift exposure levels. If limited data sets are available
(e.g. only measurements from one site or only small numbers of measurements or data with little detail on tasks,
working conditions, etc.) often the highest measured value is used or the upper range of the results of modelling
are preferred;
full shift typical inhalation exposure level: the exposure level considered representative for a median percentile (50
percentile) of the distribution of full shift exposure levels;
short term inhalation exposure level: the exposure level considered representative for a high percentile (90 to 95
percentile) of the distribution of short term exposure levels; short term exposure is considered to be exposure for
less than one hour, with typical duration of approximately 15 minutes;
dermal exposure level: the exposure level considered representative for a high percentile (90 to 95 percentile) of
the full shift dermal exposure levels.
4.1.1.2.1.2
Measurement techniques.
Over the years, a number of aerosol sampling (and subsequent analytical) procedures have been applied in worker
exposure assessment and this may compromise comparison of results. Traditionally sampling was based on the concept
of so-called 'total' aerosol with implication that the sample taken was uniformly representative of all the particles
present in workplace air. At this point, it should be noted that the term 'total' aerosol does not actually represent all the
particles that are airborne. In reality, it has only been defined by whatever sampling instrument has been chosen to
measure it. However, in the workplace or the ambient atmosphere health-related sampling of aerosols should be based
on biologically relevant fractions. Three aerosol fractions are defined; the inhalable, thoracic, and respirable fractions
(CEN, 1992; ISO, 1992). The inhalable fraction is the mass fraction of airborne particles which is inhaled through the
nose and mouth. The thoracic fraction is the mass fraction of inhalable aerosols penetrating beyond the larynx, and the
respirable fraction is the mass fraction of inhalable aerosols penetrating to the unciliated airways. When the data are
expressed in terms of a health-related aerosol fraction, this raises some interesting issues about how such exposure
information might be related to health effects. For example, if the health effect of interest in a given study were lung
cancer, then it might be argued that the aerosol fraction most relevant to the health-related dose is the thoracic fraction.
A new generation of sampling instruments has been developed to match the criteria for health-related sampling, and
perhaps the IOM sampler is the most common for personal sampling of the inhalable fraction. Comprehensive data on
the sampling characteristics of the IOM sampler are available (Mark et al., 1986; Vincent et al., 1990; Mark et al.,
1994). For comparison of results it is important to establish conversion factors to translate traditional data of 'total'
aerosol into inhalable aerosol. Such conversion factors should take into account the design of the 'total' aerosol sampler
and the size distribution of the aerosol under consideration. Thus there is no simple relationship from concentrations
given as ’total’ aerosols to concentrations given as inhalable aerosols. However, it has to be noted that a concentration
in terms of inhalable aerosols often is high compared to the concentration of ’total’ aerosols due to an insufficient
sampling efficiency of a ’total’ aerosol sampler.
Kenny et al. (1997) summarized technical characteristics of common (statutory or recommended) instruments within
Europe for personal sampling of aerosols. The sampling efficiency of the instruments was compared in the laboratory at
well-defined ambient air velocities (wind tunnel experiments) and the obtained correction factors to obtain satisfactory
performance in sampling inhalable aerosols are tabulated below (Table 4.1.1.2.1.2.A). It is noted that the sampling
efficiency for many sampler types decreased as wind speed increased. In typical workplaces wind speeds range from
0.04 to 2.02 m/s and have an arithmetic mean value of 0.3 m/s. Therefore, the current inhalable convention, which is
based on tests conducted at higher wind speeds (0.5-4.0 m/s) may not fully reflect human inhalability at lower wind
speeds (Li et al., 2000). In low air movement environments (wind speed less than 0.1 m/s) Aitken et al. (1999) found
that human inhalability is significantly greater than the current inhalable convention.
39
Table 4.1.1.2.1.2.A: Correction factors to obtain aerosol concentrations in terms of inhalable aerosols
(Kenny et al., 1997)
Sampler type
Manufacturer
Correction factor
0.5 m/s*
Correction factor
1.0 m/s*
IOM
SKC
0.9
1.0
Seven-hole
Casella, SKC, JS Holdings
1.0
1.2
GSP
Ströhlein
1.0
1.0
PAS-6
University of Wageningen
1.0
1.25
PERSPEC
Lavoro e Ambiente
1.0**
NA***
CIP10-I
Arelco
1.15
1.15
37-mm open face
Millipore
1.15
1.15
37-mm closed face
Millipore
1.0
1.2
* Ambient air velocity; ** Inlet losses recovered and included in sample; *** Not available.
It is difficult to simulate workplace conditions in the laboratory. Thus the correction factors tabulated in Table
4.1.1.2.1.2.A may not be valid to convert 'total' aerosol concentrations into 'inhalable' aerosols. Some workplace
comparisons of sampler types have been carried out most extensively for the IOM and 37-mm closed face samplers, the
IOM and 37-mm open-face samplers, and the IOM and seven-hole samplers. Limited data are also available comparing
the CIP10-I and the IOM samplers. As reviewed by Kenny et al. (1997) the field comparisons of IOM and 37-mm
samplers (both closed and open face) generally show the IOM samplers collecting 2-3 times as much as the 37-mm
sampler in contrast to the factor of 1.2 as tabulated in Table 4.1.1.2.1.2.A. The comparisons of IOM and seven-hole
samplers showed a median IOM/seven-hole ratio of 1.17, and the comparisons of IOM and CIP10-I showed a median
IOM/CIP10-I ratio of 1.5. Both of these latter results are reasonably consistent with the data tabulated in Table
4.1.1.2.1.2.A but are based on a relatively small number of field tests. Data from comprehensive field studies in the
nickel-producing and -using industries has been published (Tsai et al., 1995; Tsai et al., 1996a; Tsai et al, 1996b) in
which the closed-face 37-mm filter holder was compared with inhalable aerosol as measured using the IOM sampler.
The statistical analysis of the results has been summarized (NIPERA, 1996) and the regression results are tabulated in
Table 4.1.1.2.1.2.B for each sampled industry sector.
Table 4.1.1.2.1.2.B: Comparison between the IOM and the 37-mm samplers. Regression results from each
sampled facility process.
Industry sector
Regression results
Total aerosol
Total nickel
2
Mining
3.64±0.50
N=30
R =0.88
3.20±0.48
N=32
R2=0.86
Milling
2.61±0.46
N=20
R2=0.88
2.72±0.67
N=21
R2=0.78
Smelting
1.97±0.23
N=39
R2=0.89
1.65±0.17
N=35
R2=0.92
Smelting
2.43±0.69
N=23
R2=0.71
2.84±0.73
N=23
R2=0.75
Refining
2.50±0.34
N=37
R2=0.86
2.12±0.45
N=36
R2=0.72
Nickel alloy production
1.94±0.45
N=45
R2=0.86
2.29±0.39
N=46
R2=0.76
Electroplating
2.77±0.44
N=25
R2=0.87
2.02±0.53
N=21
R2=0.76
Electroplating
3.29±0.70
N=26
R2=0.79
3.01±0.93
N=21
R2=0.70
The values in the table correspond to 'S±standard error' in the relationship EIOM=S×E37; N corresponds to the number of
samples analysed; R2 corresponds to the regression coefficient.
The nickel data (Table 4.1.1.2.1.2.B) show the levels of 'total' aerosol exposure to be markedly lower than those of
inhalable aerosol, with the bias ranging from about 1.7 to 3.2 depending on the industry sector and workplace in
40
question. Consistent with what would be expected from aerosol sampling theory, the observed biases tended to be
greater for workplaces where aerosols are coarser.
In this part of the assessment exposure levels measured with the 37-mm closed-face cassette are converted to inhalable
aerosols taking into account the conversion factors listed in Table 4.1.1.2.1.2.B. Perhaps droplets are the predominant
aerosol in the nickel sulphate production scenarios. For such cases the two conversion factors for electroplating are
considered useful for the assessment, and the upper factor (=3.0) are taken forward for the assessment. For other cases a
factor of 2.5 is used as recommended for dust by Werner et al. (1996). Aerosols as measured with the seven-hole
sampler is converted to inhalable aerosols by a factor of 1.17 while aerosols collected with the CIP10-I sampler is
converted to 'inhalable' taking into account a conversion factor of 1.5. Aerosols collected with the GSP sampler is
considered inhalable. It is recognized that the factor of 3.0 for droplets was derived from rather solid data (work place
sampling in the nickel industry), while other converting factors were derived from work place sampling in other
industries or from experiments in the laboratory.
During the production and use of nickel sulphate a number of nickel species may occur in the workroom air to which
workers are exposed. The International Committee on Nickel Carcinogenesis in Man (Doll, 1990) identified four classes
of nickel compounds as having different intrinsic activity or biological availability as cancer causing agents. The
specific categories identified were sulfidic, oxidic, metallic and water-soluble nickel. Few methodologies are currently
available for chemical speciation of nickel in workroom air. However, for speciation of aerosols originating from
sulfide ore processing, a sequential leaching scheme has been developed by Zatka et al. (1992) for the determination of
the four mentioned nickel fractions. It is noted that the scheme does not identify individual nickel species and the
soluble fraction includes all nickel salts (e.g. sulphate and chloride). On the basis of the Zatka-scheme Andersen et al.
(1998) introduced a simplified procedure allowing analysis for only two groups (soluble/insoluble) of nickel species.
Based mainly on the Zatka-scheme Bolt et al. (2000) introduced a flow-injection analytical system to reduce the time
required for the analysis in the laboratory. For the assessment exposure to nickel is given in terms of ‘total’ mass of
nickel (nickel species let alone). If possible exposure is also given by nickel species. It is noted that exposure by nickel
species is given in terms of mass of nickel.
4.1.1.2.2 Production of nickel sulphate
The following scenarios follow the descriptions of the different nickel sulphate production processes described in
Chapter 2.1.1.
41
Table 4.1.1.2.2.A: Scenarios A1-A8: Nickel sulphate production - current exposure by inhalation of 'total' nickel.
Reference.
Process
N
Year
Type of
Sampler
Aerosol
Fraction
Exposure to ’total’ nickel μg/m3
'Total' aerosol fraction
Inhalable aerosol fraction
th
Range
Median
95 perc. Range
Median
95th perc.
'Total'
7-460
41
340
20-1400
120
1000
'Total'
2-260
10
32
6-780
30
90
Scenario A1: Nickel sulphate production from nickel matte
HEDSET
Comp. #3
Hughson, 2004
Ni-sulphate production
Packing Ni sulphate
Leaching plant
34
NA++
24
++
4
3
NA
2004
2004
Personal8
8
Static
14
Inhalable
4-15
7
15
14
Inhalable
30-220
60
220
Personal
Personal
Scenario A2: Nickel sulphate production from secondary nickel matte and roasted residues
Morgan et al, 1984
17
1981-82
Personal 1
‘Total’
30-150
9010
NA
35-180
11010
-NA
3
1988
Personal 9
‘Total’
NA
310
NA
NA
4.510
NA
1988
Personal
9
9
Scenario A3: other leaching processes
HEDSET
Comp. #4
Ni-sulphate production, drying
Ni-sulphate production, packing
5
Ni-sulphate production,
purification
2
1990
Personal
Ni sulphate production
NA
NA
54
‘Total’
NA
10
20
10
NA
NA
30
10
NA
10
NA
‘Total’
NA
44
NA
NA
66
Static 5
‘Total’
6-97
2313
64
18-300
7013
190
19901999
Static 7
‘Total’
5-30
10
20
5-30
10
20
55
19901999
Personal 7
‘Total’
5-300
34
150
5-300
34
150
6
1992
Personal 7+
‘Total’
9-46
30
40
9-46
30
40
14
1994
Personal
7+
‘Total’
7-39
20
30
7-39
20
30
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
Scenario A4: Nickel sulphate production from copper refining
HEDSET Comp. #5
HEDSET
Comp. #2
Ni-sulphate production,
pulverized
Scenario A5: Purification of impure nickel sulphate
ND***
ND
Scenario A6: Nickel sulphate production from metallic nickel
42
19
19911993
Personal 3
‘Total’
10-60
2111
NA
12-70
2511
NA
22
19911993
Personal 3
‘Total’
10-180
3811
NA
12-210
4411
NA
70
19911993
Static 3
‘Total’
10-130
2511
NA
12-150
2911
NA
34
19911993
Static 3
‘Total’
10-530
8611
NA
12-620
10011
NA
HEDSET,
57
19921997
Personal 6
‘Total’
10-600
20
100
12-700
23
120
Comp. #1
Effluent plant workers
29
19951997
Personal 6
‘Total’
10-660
40
200
12-770
47
230
Control laboratory workers
54
19921997
Personal 6
‘Total’
10-390
30
180
12-460
35
210
412
1985
Static 2
‘Total’
160-200
18010
EIS Data, 1993*
Comp. 16
UK HSE-40, 1985*& Ni-powder dissolution
12
1985
Personal
/Static 2
4
’Total’
NA
-
-
-
24-55
37
10
NA
-
-
-
Packaging of Ni-sulphate
5
Donaldson et al.
1978*
Ni-sulphate prod. from nickel or
NiO
12
19761977
Personal 5
‘Total’
9-590
5711
NA
27-1800
17011
NA
Warner, 1984
Ni-sulphate prod. from nickel or
NiO
12
NA
Personal 2
‘Total’
9-590
11710
NA
-
-
-
ND
ND
ND
ND
ND
ND
ND
ND
ND
Scenario A7: Nickel sulphate production from nickel carbonate
ND
ND
ND
*: Data listed by NIPERA (1996). **: Non-specified method of production. ***: No data available for the assessment. &: UK HSE (Health and Safety Executive, UK) provided the data from its NEDB
(National Exposure Data Base). +: Presumably personal sampling. ++: Presumably data from the late 1990s.
1: Casella personal dust monitor. 2: Unknown type of aerosol sampler. 3: Unknown type of aerosol sampler; NIPERA (2001a) noted that the sampler was the seven-hole cassette. 4: 25-mm closed face filter
cassette. 5: 37-mm open face filter cassette. 6: Seven-hole sampler. 7: Unknown type of aerosol sampler (presumably the GSP-sampler). 8: The 37-mm closed face filter cassette. 9: CIP-10 sampler. 10:
Arithmetic mean. 11: Geometric mean. 12: The number of observations was estimated from the arithmetic mean and the range using the approach given by Vincent and Werner (2003). 13: The arithmetic
mean was estimated from the range using the approach given by Vincent and Werner (2003). 14: The IOM-sampler.
43
4.1.1.2.2.1
Scenario A1 – Ni sulphate production from nickel matte
Nickel sulphate is produced from nickel sulphate solution from the nickel refinery. The salt is crystallized, followed by
screw separation, drying and packing into plastic bags (see Chapter 2.1.1.1). From the listed processes it has to be
expected that workers within the overall scenario may not have similar tasks. As an effort to identify tasks (subscenarios) with high risk of exposure the available data on exposure were summarized in one table and tabulated by
sub-groups of workers with similar tasks. Such listing was kept within a given set of data (study) and no attempt was
made to join similar tasks cross data sets. The reason not to join similar tasks cross data sets was that prior to the
collapse of data sets a statistical analysis is required for identity of data sets in terms of type of statistical distribution,
mean and variance. The data for the assessment were not available in details to allow such statistical analysis.
4.1.1.2.2.1.1 Exposure by inhalation – nickel species
The production of nickel sulphate may cause an emission of aerosols. At a nickel refinery Hughson (2004) measured
exposure to inhalable dust in the leaching plant, and in the chemical plant. In the chemical plant nickel sulphate solution
was used to produce nickel sulphate hexahydrate and nickel hydroxycarbonate. The dust was analysed for the content of
soluble and insoluble nickel. The reported data are listed below. As a percentage of total nickel the dust had a content of
soluble nickel ranging from 18% to 73%. The median of the medians is considered a typical content of soluble nickel
(≈60%), while a content of 100% is considered a worst-case situation.
Process3
N
Exposure
3
Dust (mg/m )
Leaching
3
4
Packing of
4
Ni carbonate
3
Content of
Content of
total Ni as % soluble Ni as
of dust
% of total Ni
Soluble Ni (μg/m )
Insoluble Ni (μg/m )
19
42
7.6
31
(16-39)
(14-180)
(3.8-8.8)
(18-53)
0.5
4
2
2
60
(0.2-0.7)
(2-11)
(2-4)
(0.7-5)
(50-73)
0.4
6
3
1
60
(0.3-5.9)
(1-41)
(1-20)
(0.5-4.7)
(50-71)
1
0.8
(0.8-2.5)
Packing of
Ni sulphate
3
2
1: Median. 2: Range. 3: The two different packing processes are the specific jobs of workers but the jobs occur in the same work area
and workers rotate between these processes so exposure are a combination of both processes.
4.1.1.2.2.1.2 Exposure by inhalation – measured exposure levels
Four sets of data (Table 4.1.1.2.2.A) on occupational exposure were obtained from industry. If possible data are listed
using the format of the specific company data submission scheme i.e. year(s) of measurement(s), number of samples,
range, median and 95th percentile value. It is noted that the vast majority of the data sets were given in terms of full-shift
time weighted averages. Thus the listed data are considered full-shift exposure. The information available on the
sampling technique and aerosol fraction is included in the listed data. One of the data sets was collected by an approach
of static sampling. It is well known (see section 4.1.1.2.1.2) that data from static sampling may not be valid for an
assessment of personal exposure. Thus data from static sampling did not enter the present assessment of exposure. The
three remaining sets (41 observations) report the exposure for groups of workers with the tasks of Ni-sulphate
production. For the large set (34 observations) data measured in terms of the ‘total’ aerosol fraction were converted to
the inhalable fraction by a factor of 3.0 (37-mm closed or open face cassettes). Current median exposure to ‘total’ nickel
(‘total’ aerosol fraction) was 41 μg/m3 for the workers with the task of Ni-sulphate production. In terms of the inhalable
aerosol fraction median exposure for the large data set was 120 μg/m3. The medians of the two smaller data sets were 7
μg/m3 (N=4) and 60 μg/m3 (N=3). For the assessment the median of the large data set (120 μg/m3) is considered the
typical exposure level. The 95th percentile of the large data set was 1000 μg/m3 and this level was considered an
estimate of the reasonable worst-case exposure. Data on short-term exposure to ‘total’ nickel seem unavailable, and it is
difficult (if not impossible) to derive an estimate on short-term exposure from data characterizing full shift exposure.
For the risk assessment of zinc metal (Netherlands Rapporteur, 1999) no data were available on short-term exposure
and an estimate was derived as twice the worst-case exposure level. A similar approach (‘expert judgement’) was taken
for the present risk assessment. Thus the short-term exposure was estimated at a level of 2×1000=2000 μg/m3. For the
scenario no data seem available on the size distribution of aerosols in the workroom air.
44
4.1.1.2.2.1.3 Exposure by inhalation – modelled data (EASE 2.0)
Packaging is a common task in the production of nickel sulphate, and the task may cause risk of exposure. Thus the
typical and the reasonable worst-case exposure were modelled for this task. Any manipulation of a dry material enters
the EASE model by the term ‘dry manipulation’. To model the exposure EASE requires input on the tendency of a
material to aggregate. No data are available on the tendency of nickel sulphate to aggregate, and the chemical was as a
worst-case considered non-sticky (aggregate is false).
Estimation of the typical exposure level
If sufficient care is exercised to reduce potential exposure the task enter the EASE model as ‘low dust technique’, and
for the modelling this description was considered to be true. For the modelling the control of exposure by local exhaust
ventilation was considered present.
Model input:
The name of the substance is nickel sulphate
The temperature of the process is 20
The physical-state is solid
Dust-inhalation is true
Solid-vp is false
The exposure-type is dust
The particle-size is inhalable
The operations is low dust techniques
The dust-type is non-fibrous
Aggregates is false
The pattern-of-control is local exhaust ventilation present
Model output:
Conclusion: The predicted dust exposure to nickel sulphate is 0-1 mg/m3
Estimation of the reasonable worst-case exposure level
Model input:
Except for the type of operation and the pattern-of-control model input was kept identical to the input for estimation of
the typical exposure level. The type of operation was specified as dry manipulation (includes any manipulation, also dry
brushing) and the pattern-of-control was specified as no local exhaust ventilation.
Model output:
Conclusion: The predicted dust exposure to nickel sulphate is 5-50 mg/m3.
The predicted typical exposure level is rather close to the measured data as listed in Table 4.1.1.2.2.1.B, while the
predicted reasonable worst-case exposure is high. The measured data provide more detailed information than the EASE
model, and the measured data are used for the assessment. Considering the assessed data on nickel species in workroom
air (Table 4.1.1.2.2.6.A) current exposure to groups of nickel species is estimated as listed below (Table 4.1.1.2. 2.A). It
has to be noted that soluble nickel salts may include other salts than nickel sulphate, but for the assessment the soluble
fraction is considered all nickel sulphate (worst-case).
Table 4.1.1.2.2.1.A: Estimated exposure by inhalation of groups of nickel species in the production of nickel
sulphate from nickel matte.
Nickel
Species
Typical exposure
Worst-case exposure
Shortterm
exposure
(μg/m3)
Nickel species
as % of ‘total’
nickel
Exposure to
inhalable
‘total’ nickel
(μg/m3)
Exposure to
inhalable
nickel
species
(μg/m3)
SO
60
120
70
100
1000
1000
2000
U
40
120
50
0
1000
0
0
(1)
Nickel
Exposure to
species as %
inhalable
of ‘total’
‘total’ nickel
nickel
(μg/m3)
Exposure to
inhalable
nickel
species
(μg/m3)
1: SO = Soluble nickel salts considered to be all nickel sulphate (worst-case); U = Other nickel species than soluble nickel salts.
4.1.1.2.2.1.4 Dermal exposure – measured exposure levels
45
Hughson (2004) did a comprehensive study on occupational dermal exposure to nickel in a refinery where nickel
sulphate crystals are produced by a leaching process. The chemical plant used nickel sulphate solution to produce nickel
sulphate hexahydrate and nickel hydroxycarbonate. The chemical reactions and transfer of compounds to the packing
area was entirely automatic and completely enclosed. The packing area was highly automated with modern robotic
packing and bag handling equipment. The nickel compounds (nickel sulphate hexahydrate and nickel
hydroxycarbonate) were packed into 25 kg sacks using this equipment and there was no manual involvement with the
bag filling operation whatsoever. The 25 kg sacks were automatically stacked onto pallets by robotic arms and the
pallets were automatically shrink-wrapped before being conveyed through to the warehouse area. The workers were
required to supervise the machinery and correct any faults that developed. There were four workers on one-day shift,
involved with supervising the process. All of these workers were monitored.
One of the workers had some involvement in machine repair work, involving replacement of a pneumatic cylinder and
considerable time was spent preparing the machine for production. Otherwise, the remaining packing lines were
relatively trouble free and the workers had only incidental contact with the packing equipment and final products.
Nickel hydroxycarbonate in powder, paste or granular form was also packed into containers (‘big bag’) at a number of
fill points. One operator was involved with this work. The main involvement comprised removing the spout of the
container from the filling nozzle and tying this up with the cord provided. The empty bag was attached to the filling
nozzle and the full bag transferred to the warehouse area by forklift truck. The forklift truck had an enclosed cab.
During the bag replacement task, there was some noticeable spillage of powder onto the surface of the bag, but this was
a minor amount.
All workers in the chemical plant wore air assisted filtering visors, cotton overalls and rigger type gloves. The workers
returned to the main control room area when they were not required to directly observe the process. There were hygiene
procedures in place for entering the control room, involving removal of work footwear and outer clothing, with handwashing prior to accessing the clean areas.
The measured dermal exposure to nickel is tabulated below (Table 4.1.1.2.2.1.B). The measurement method was
repeated wiping of the skin using a commercial moist wipe (Jeyes ‘Sticky Fingers’ Wet Ones) and an acetate template
with an open aperture of 25 cm2 pressed onto the relevant anatomical area at the time of sampling. Wipe samples were
collected from the palm and back of each hand and from both forearms. This was done before rest breaks so that
contamination was not lost from the skin prior to washing. Samples of skin contamination were collected at three
different intervals over the working day in order to assess contamination while at work. Additional samples were
collected from the side of the neck, face and chest. The neck and face samples were used to provide an estimate of
exposure for the head and also help make informed estimates about the potential for ingestion exposure. The sample
from the chest was used to assess the degree of contamination under work clothes. The face, neck and chest samples
were collected once, near the end of the shift i.e., before the afternoon break or before showering. The sampling
efficiency of the method was tested in the laboratory by applying pre-weighted quantities of nickel powder onto the
surface of a section of chamois leather. This leather was intended to act as a surrogate for human skin. The procedure
was repeated using a solution of nickel sulphate hexahydrate in solution, applied to the surrogate skin surface using a
pipette. The method showed an acceptable level of recovery (≈92%) for solid nickel particles, although there was poor
recovery (≈16%) for water-soluble salts in solution. Using a different cured soft leather product as a surrogate skin
improved the recovery of water-soluble salts to a level of ≈97%. All wipe samples were analysed to determine the
soluble and insoluble nickel content using a variation of a published method (Zatka et al., 1992). The modification of
the method used only the first step in the Zatka method to differentiate between the soluble nickel salts (e.g. nickel
sulphate hexahydrate, nickel chloride hexahydrate) and the other nickel substances that less readily dissolve or corrode
(e.g. nickel subsulphide, nickel metal, nickel oxide). Therefore, the soluble nickel fraction is predominantly
representative of the nickel salts, while the insoluble fraction contains the more refractory nickel substances (i.e. the
"intermediate, sparingly, or insoluble" nickel substances).
For hands and arms of nickel compound packing operators the median dermal exposure to total nickel was 0.6 μg/cm2.
This median is considered an estimate of the typical exposure level, while the 90th percentile (1.0 μg/cm2) is considered
to be an estimate of the reasonable worst-case exposure level. For soluble nickel the median is 0.4 μg/cm2 (the typical
exposure level), while the 90th percentile is 0.7 μg/cm2 (the reasonable worst-case exposure level). For insoluble nickel
the median is 0.2 μg/cm2 (the typical exposure level), while the 90th percentile is 0.4 μg/cm2 (the reasonable worst-case
exposure level). Both nickel hydroxycarbonate and nickel sulphate are packed in the same area, with workers rotating
between packing of the two substances so dermal exposure data for the operations reflects exposure to both substances.
46
Table 4.1.1.2.2.1.B: Measured dermal nickel exposure (μg/cm2) for nickel compound packing operators
(Hughson, 2004).
Anatomical area
N1
Soluble nickel A
Insoluble nickel A
Total nickel
Nickel compound packing operators
Average Hands
82
Median (range)
90th %
Median (range) 90th % Median (range)
90th %
0.6 (0.2-0.9)
0.8
0.3 (<0.1-0.7)
0.5
0.9 (0.2-1.4)
1.4
8
2
0.3 (<0.1-0.9)
0.7
0.1 (<0.1-0.4)
0.3
0.4 (<0.1-1.3)
0.9
Hands & Arms
8
3
0.4 (0.1-0.9)
0.7
0.2 (<0.1-0.4)
0.4
0.6 (0.1-1.3)
1.0
Neck
84
Average forearms
Face (perioral region)
Chest
0.5 (0.1-1.0)
0.8
0.2 (<0.1-0.6)
0.3
0.7 (0.1-1.5)
1.1
8
4
0.5 (<0.1-1.5)
1.3
0.2 (<0.1-0.6)
0.5
0.8 (<0.1-2.0)
1.8
8
4
0.2 (<0.1-0.9)
0.6
<0.1 (<0.1-0.3) 0.2
0.2 (<0.1-1.1)
0.7
Control group (non-occupationally exposed volunteers)
Average Hands
10
NA
NA
NA
NA
0.03 (0.01-0.09)
0.05
Average forearms
10
NA
NA
NA
NA
0.01 (0.01-0.06)
0.03
Hands & Arms
10
NA
NA
NA
NA
0.02 (0.01-0.07)
0.04
1: number of subjects. The exposure of the packing operators (N=4) was measured two times (day No. 1 and day No. 2).
2: per subject dermal exposure was measured three times during a shift (first break; mid-shift break; end of shift); every time one
sample was collected from palms of both hands and another was taken from back of both hands.
3: exposure is given as an area weighted average of the measured data for the hands (area 840 cm2) and forearms (area 1140 cm2).
4: at end of shift one sample was collected per person.
A: The soluble and insoluble nickel content was analysed using a variation of a published method (Zatka et. al, 1992).
4.1.1.2.2.1.5 Dermal exposure – modelled data (EASE 2.0)
Hughson (2004) did a comprehensive study on occupational dermal exposure to nickel in a chemical plant that used
nickel sulphate solution to produce nickel sulphate hexahydrate and nickel hydroxycarbonate. Hughson (2004) included
a description of the workplace conditions in terms of the EASE model. The tasks covered by the study were assigned
EASE exposure criteria of non-dispersive use with intermittent direct contact. Thus this scenario is modelled.
Estimation of dermal exposure for nickel compound packing operators
Model input:
The name of the substance is nickel
Dust-inhalation is false
Solid-vp is false
The exposure-type is dermal
The use-pattern is non-dispersive use
The pattern-of-control is direct handling
The contact-level is intermittent
Model output:
The predicted dermal exposure to nickel is 0.1-1 mg/cm2/day.
The level of dermal exposure in the nickel sulphate production from nickel matte was estimated by two approaches, (i)
by measured data and (ii) by modelling. The measured dermal exposures were much less than predicted values
generated by the EASE model. In addition, the measured dermal nickel levels were lower than levels of exposure
previously obtained from the zinc industry (Hughson and Cherrie, 2001). This might be due to the higher levels of
engineering controls applied to the nickel sulphate production, combined with specific hygiene measures such as the
consistent use of personal protective equipment (Hughson, 2004). The measured data were obtained at conditions
typical of normal production, so the measured exposures can be considered representative of normal production
47
conditions (Hughson, 2004). Thus the measured data are taken forward to the risk characterization. The estimated
typical and reasonable worst-case exposure levels for hands and forearms are summarized below. It is noted that the
measured data (Table 4.1.1.2.2.1.B) indicate that there is potential for inadvertent ingestion of nickel, either through
hand to mouth contact or from deposition into or around the perioral region.
Nickel species
Typical exposure
2
Reasonable worst-case exposure
μg/cm2/day
mg/day 1
1.2
1.0
2.0
0.8
0.7
1.4
0.4
0.4
0.8
μg/cm /day
mg/day
Total nickel
0.6
Soluble nickel
0.4
Insoluble nickel
0.2
2
2
1
2
1: The area is 1980 cm (hands: 840 cm ; forearms: 1140 cm ).
4.1.1.2.2.1.6 Discussion and conclusions
Three data sets were available for the assessment of exposure by inhalation of ‘total’ nickel in the nickel sulphate
production from nickel matte, and the exposure was estimated from a large set of data (34 observations). An emphasis
was made to assess exposure in terms of inhalable aerosols. Recent data on nickel species indicated that approx. 60% of
total nickel is soluble nickel (typical level). A higher level of soluble nickel (≈75%) was seen, and 100% was
considered an estimate for the reasonable worst-case situation. For the assessment soluble nickel was considered as
nickel sulphate.
For the production of nickel sulphate from nickel matte comprehensive measured data were available on dermal
exposure to soluble and insoluble nickel. The exposure was estimated by two approaches, (i) from measured data and
(ii) by modelling. The predicted exposure level was much higher than the level estimated from measured data.
However, the predicted exposure levels produced by EASE are intended to be estimates of potential exposure and do
not therefore take into account the attenuating effect of gloves and other protective clothing. Thus it appears prudent to
take the exposure estimated from measured data forward to the risk characterization. In conclusion the estimated levels
of exposure to groups of nickel species are summarized below.
Exposure by inhalation (μg/m3)
Nickel species
(1)
Dermal exposure (mg/day)
Typical
Worst-case
Short term
Typical
Worst-case
SO
70
1000
2000
0.8
1.4
U
50
~0
~0
0.4
0.8
1: SO = Soluble nickel salts considered to be all nickel sulphate (worst-case); U = Other nickel species than soluble
nickel salts.
4.1.1.2.2.2
Scenario A2– Ni sulphate production from secondary nickel matte and roasted residues
The secondary matte and roasted residues are autoclaved and dissolved. Solutions are subjected to electrolysis to
produce copper cathodes. Iron, zinc and other trace elements are removed by precipitation. The purified solution is
marketed as such or worked up to crystallized nickel sulphate hexahydrate (see Chapter 2.1.1.2). From the listed
processes it has to be expected that workers within the overall scenario may not have similar tasks. As an effort to
identify tasks (sub-scenarios) with high risk of exposure the available data on exposure were summarized in one table
and tabulated by sub-groups of workers with similar tasks. Such listing was kept within a given set of data (study) and
no attempt was made to join similar tasks cross data sets. The reason not to join similar tasks cross data sets was that
prior to the collapse of data sets a statistical analysis is required for identity of data sets in terms of type of statistical
distribution, mean and variance. The data for the assessment were not available in details to allow such statistical
analysis.
The production of nickel sulphate may cause an emission of aerosols. No nickel speciation data on such aerosols seem
available for the assessment, and by analogy the speciation data listed for scenario A1 were considered useful for the
48
assessment. As a percentage of ‘total’ nickel in air 60% (typical exposure) or 100% (worst-case exposure) was
considered to be nickel sulphate.
4.1.1.2.2.2.2 Exposure by inhalation – measured and modelled exposure levels
One data set (Table 4.1.1.2.2.A) on occupational exposure was available for the assessment. If possible data are listed
using the format of the specific company data submission scheme i.e. year(s) of measurement(s), number of samples,
range, median and 95th percentile value. It is noted that the data set is considered full-shift exposure. The information
available on the sampling technique and aerosol fraction is included in the listed data. The reported data were collected
in the early 1980s for a group of workers with the tasks of Ni-sulphate production. The Casella personal dust monitor
was used for sampling of the ‘total’ aerosol fraction. Perhaps this monitor was not identical with the seven-hole sampler
listed above (Table 4.1.1.2.2.A) but for the assessment the reported ‘total’ aerosol fraction was converted to the
inhalable fraction by a factor of 1.17. In terms of ‘total’ nickel (‘total’ aerosol fraction) the mean exposure level was 90
μg/m3 while the mean exposure was 110 μg/m3 in terms of the inhalable aerosol fraction. As mentioned above (Chapter
2) the steps involved in the production of nickel sulphate from nickel matte (scenario A1) are rather similar to the steps
involved in the nickel sulphate production from secondary nickel matte and residues (scenario A2). While the data
available for scenario A2 were collected in the early 1980s more recent data were available for scenario A1. Thus it
appears prudent by an approach of analogy to consider exposure by inhalation as estimated for scenario A1 useful as an
estimate for exposure by inhalation for scenario A2. The estimated exposure is listed below (Table 4.1.1.2.2.2.A).
Modelled data (EASE 2.0) and further details in deriving the estimates are given above (scenario A1).
sulphate from nickel matte.
Nickel Typical exposure
Species
(1)
Nickel species Exposure to
as % of ‘total’ inhalable
nickel
‘total’ nickel
(μg/m3)
Worst-case exposure
Exposure to
inhalable
nickel
species
(μg/m3)
Nickel
species as %
of ‘total’
nickel
Exposure to
inhalable
‘total’ nickel
(μg/m3)
Exposure to
inhalable
nickel
species
(μg/m3)
Shortterm
exposure
(μg/m3)
SO
60
120
70
100
1000
1000
2000
U
40
120
50
0
1000
0
0
4.1.1.2.2.2.3 Dermal exposure – measured and modelled exposure levels
No measured data seem available for the scenario. Hughson (2004) did a comprehensive study on occupational dermal
exposure to nickel in a refinery where nickel sulphate crystals are produced by a leaching process. The chemical plant
used nickel sulphate solution to produce nickel sulphate hexahydrate and nickel hydroxycarbonate. The dermal
exposure was measured during packing of the final product. For nickel sulphate production from secondary nickel matte
and roasted residues the highest exposure to nickel sulphate is expected to be during packing of the final product. The
exposure is expected to be similar to the exposure measured in the packing of nickel sulphate produced from nickel
matte (scenario A1). Thus the dermal exposure is estimated at the levels tabulated below. Further details of the
estimated data are given above (section 4.1.1.2.2.1.4 and 4.1.1.2.2.1.5).
Nickel species
Typical exposure
μg/cm2/day
mg/day 1
1.2
1.0
2.0
0.8
0.7
1.4
0.4
0.4
0.8
μg/cm2/day
mg/day
Total nickel
0.6
Soluble nickel
0.4
Insoluble nickel
0.2
2
2
1
2
1: The area is 1980 cm (hands: 840 cm ; forearms: 1140 cm )
A single data set (collected in the early 1980s) was available for the assessment of exposure by inhalation of ‘total’
nickel in the nickel sulphate production from nickel matte. The steps involved in the production of nickel sulphate from
49
nickel matte (scenario A1) are rather similar to the steps involved in the production of nickel sulphate from secondary
matte and roasted residues (scenario A2). Thus it appears prudent to consider the more recent data available for scenario
A1 useful for the assessment of exposure to nickel in the production of nickel from secondary nickel matte and roasted
residues.
For the production of nickel sulphate from secondary nickel matte and roasted residues no data were available on
dermal exposure to nickel sulphate, and the exposure was estimated by two approaches, (i) by analogy to measured
dermal exposure in nickel sulphate production from nickel matte and (ii) by modelling. The measured data focused on
nickel compound packing operators (scenario A1). The predicted exposure was much higher than the level estimated
from measured data. However, the predicted exposure levels produced by EASE are intended to be estimates of
potential exposure and do not therefore take into account the attenuating effect of gloves and other protective clothing.
For nickel sulphate production from secondary nickel matte and roasted residues the highest exposure to nickel sulphate
is expected to be during packing of the final product. Thus it appears prudent to take the data obtained by analogy
forward to the risk characterization. In conclusion the estimated levels of exposure to groups of nickel species are
summarized below.
Nickel species
(1)
Dermal exposure
(mg/day)
Typical
Worst-case
Short term
Typical
Worst-case
SO
70
1000
2000
0.8
1.4
U
50
~0
~0
0.4
0.8
nickel salts.
4.1.1.2.2.3
Scenario A3 – Ni sulphate production from other leaching processes
A variety of leaching processes are used to gain nickel sulphate from by-products including mixed nickel/cobalt byproducts, impure tank house liquor from copper/cobalt refinery production, or nickel/zinc/copper residues. Further
details of various leaching processes are given above (section 2.1.1.5). From the listed processes it has to be expected
that workers within the overall scenario may not have similar tasks. As an effort to identify tasks (sub-scenarios) with
high risk of exposure the available data on exposure were summarized in one table and tabulated by sub-groups of
workers with similar tasks. Such listing was kept within a given set of data (study) and no attempt was made to join
similar tasks cross data sets. The reason not to join similar tasks cross data sets was that prior to the collapse of data sets
a statistical analysis is required for identity of data sets in terms of type of statistical distribution, mean and variance.
The data for the assessment were not available in details to allow such statistical analysis.
Three current data sets (Table 4.1.1.2.2.A) on occupational exposure were obtained from industry. If possible data are
listed using the format of the specific company data submission scheme i.e. year(s) of measurement(s), number of
samples, range, median and 95th percentile value. It is noted that the vast majority of the data sets were given in terms of
full-shift time weighted averages. Thus the listed data are considered full-shift exposure. The information available on
the sampling technique and aerosol fraction is included in the listed data. Exposure measured in terms of the ‘total’
aerosol fraction was converted to the inhalable fraction by a factor of 1.5 (CIP-10 dust monitor). For the scenario it
appears that current exposure to ‘total’ nickel (‘total’ aerosol fraction) ranged from a mean level of 3 μg/m3 to 44 μg/m3.
In terms of the inhalable aerosol fraction current ‘total’ nickel exposure ranged from a mean level of ~5 μg/m3 to 66
μg/m3. The median of the mean levels was 30 μg/m3 of inhalable ‘total’ nickel. Such an exposure was seen for a subgroup of workers with the task of nickel sulphate packing. The three data sets (personal sampling) available were rather
small and none of them had information on the range of the measured exposure or the 95th percentiles. The highest
mean exposure (66 μg/m3) was seen for a small data set of 2 observations. By contrast the exposure was low (4.5 μg/m3)
for another small data set of 3 observations. In between was an exposure of 30 μg/m3 for a data set of 5 observations. As
mentioned above (Chapter 2) the steps involved in the nickel sulphate production from nickel matte (scenario A1) are
50
rather similar to the steps involved in the nickel sulphate production from other leaching techniques (scenario A3).
While the three small data sets available for scenario A3 were collected in the late 1980s more recent and
comprehensive data were available for scenario A1. Thus it appears prudent by an approach of analogy to consider
exposure by inhalation as estimated for scenario A1 useful as an estimate for exposure by inhalation for scenario A3.
The estimated exposure is listed below (Table 4.1.1.2.2.3.A). Modelled data (EASE 2.0) and further details in deriving
the estimates are given above (scenario A1).
sulphate.
Nickel
Species
Typical exposure
Worst-case exposure
Nickel species
as % of ‘total’
nickel
Exposure to
inhalable
‘total’ nickel
(μg/m3)
Exposure to
inhalable
nickel
species
(μg/m3)
SO
60
120
70
100
1000
U
40
120
50
0
1000
(1)
Nickel
Exposure to
species as %
inhalable
of ‘total’
‘total’ nickel
nickel
(μg/m3)
Exposure to
inhalable
nickel
species
(μg/m3)
Shortterm
exposure
(μg/m3)
1000
2000
0
No measured data seem available for the scenario. Hughson (2004) did a comprehensive study on occupational dermal
exposure to nickel in a refinery where nickel sulphate crystals are produced by a leaching process. The chemical plant
used nickel sulphate solution to produce nickel sulphate hexahydrate and nickel hydroxycarbonate. The dermal
exposure was measured during packing of the final product. For nickel sulphate production from other leaching
processes the highest exposure to nickel sulphate is expected to be during packing of the final product. The exposure is
expected to be similar to the exposure measured in the packing of nickel sulphate produced from nickel matte (scenario
A1). Thus the dermal exposure is estimated at the levels tabulated below. Further details of the estimated data are given
above (section 4.1.1.2.2.1.4 and 4.1.1.2.2.1.5).
Nickel species
Typical exposure
μg/cm2/day
mg/day 1
1.2
1.0
2.0
0.4
0.8
0.7
1.4
0.2
0.4
0.4
0.8
2
μg/cm /day
mg/day
Total nickel
0.6
Soluble nickel
Insoluble nickel
1
1: The area is 1980 cm2 (hands: 840 cm2; forearms: 1140 cm2).
Three current data sets were available for the assessment of exposure by inhalation of ‘total’ nickel in the nickel
sulphate production by other leaching processes. The steps involved in the production of nickel sulphate from nickel
matte (scenario A1) are rather similar to the steps involved in the production of nickel sulphate from other leaching
techniques. Thus it appears prudent to consider the more recent and comprehensive data available for scenario A1
useful for the assessment of exposure to nickel in the production of nickel sulphate from other leaching techniques.
For the production of nickel sulphate by other leaching processes no data were available on dermal exposure to nickel
sulphate, and the exposure was estimated by two approaches, (i) by analogy to measured dermal exposure in nickel
sulphate production from nickel matte and (ii) by modelling. The measured data focused on nickel compound packing
operators (scenario A1). The predicted exposure was much higher than the level estimated from measured data.
not therefore take into account the attenuating effect of gloves and other protective clothing. For nickel sulphate
production from other leaching processes the highest exposure to nickel sulphate is expected to be during the packing of
the final product. Thus it appears prudent to take the data obtained by analogy forward to the risk characterization. In
conclusion the estimated levels of exposure to groups of nickel species are summarized below.
51
Nickel species
(1)
Dermal exposure
(mg/day)
Typical
Worst-case
Short term
Typical
Worst-case
SO
70
1000
2000
0.8
1.4
U
50
~0
~0
0.4
0.8
nickel salts.
4.1.1.2.2.4
Scenario A4 – Ni sulphate production from copper refining
Copper raw materials may contain nickel and in the electrolytic refining process nickel remains as nickel sulphate in the
tank house liquor. After the copper has been removed (usually by reduction electrolysis) crude nickel sulphate is
produced from the liquor by evaporation/crystallization. Further details of the process are given above (section 2.1.1.6).
From the listed processes it has to be expected that workers within the overall scenario may not have similar tasks. As
an effort to identify tasks (sub-scenarios) with high risk of exposure the available data on exposure were summarized in
one table and tabulated by sub-groups of workers with similar tasks. Such listing was kept within a given set of data
(study) and no attempt was made to join similar tasks cross data sets. The reason not to join similar tasks cross data sets
was that prior to the collapse of data sets a statistical analysis is required for identity of data sets in terms of type of
statistical distribution, mean and variance. The data for the assessment were not available in details to allow such
statistical analysis.
Current data (Table 4.1.1.2.2.A) on occupational exposure were obtained from industry. Four different data sets were
available for the assessment. If possible data are listed using the format of the specific company data submission
scheme i.e. year(s) of measurement(s), number of samples, range, median and 95th percentile value. It is noted that the
vast majority of the data sets were given in terms of full-shift time weighted averages. Thus the listed data are
considered full-shift exposure. The information available on the sampling technique and aerosol fraction is included in
the listed data. The data were collected by an approach of personal or static sampling. It is well known (see section
4.1.1.2.1.2) that data from static sampling may not be useful for an estimate of personal exposure. Thus data from static
sampling did not enter the assessment. Exposure measured in terms of the ‘total’ aerosol fraction was converted to the
inhalable fraction by a factor of 1.0 (GSP dust monitor). For the scenario it appears that current exposure to ‘total’
nickel (‘total’ aerosol fraction) ranged from a median level of 20 μg/m3 to 34 μg/m3. In terms of the inhalable aerosol
fraction current ‘total’ nickel exposure ranged from a median level of 20 μg/m3 to 34 μg/m3. The median of the median
levels was 30 μg/m3 of inhalable ‘total’ nickel (typical exposure level). An exposure at such level was seen for subgroups of workers with the task of Ni-sulphate production. One large data set (55 observations) reported the 95th
percentile at a level of 150 μg/m3 while a smaller data set (6 observations) reported the 95th percentile at 40 μg/m3.
Taking the number of observations per data set into consideration it seems prudent to consider the 95th percentile of the
large data set (55 observations) as an estimate of the reasonable worst-case exposure. Thus a level of 150 μg/m3 was an
estimate of the reasonable worst-case exposure. Data on short-term exposure to ‘total’ nickel seem unavailable, and it is
difficult (if not impossible) to derive an estimate on short-term exposure from data characterizing full shift exposure.
For the risk assessment of zinc metal (Netherlands Rapporteur, 1999) no data were available on short-term exposure
and an estimate was derived as twice the worst-case exposure level. A similar approach (‘expert judgement’) was taken
for the present risk assessment. Thus the short-term exposure was estimated at a level of 2×150=300 μg/m3. For the
scenario no data seem available on the size distribution of aerosols in the workroom air.
Packaging is a common task in the production of nickel sulphate, and the task may cause risk of exposure. Thus the
typical and the reasonable worst-case exposure was modelled for this task. Any manipulation of a dry material enters
52
material to aggregate. No data are available on the tendency of nickel sulphate to aggregate, and the chemical was as a
worst-case considered non-sticky (aggregate is false).
Model input:
Solid-vp is false
Aggregates is false
Model output:
Model input:
Model output:
The predicted typical exposure level is rather close to the measured data as listed in Table 4.1.1.2.2.A, while the
air (see scenario A1) current exposure to groups of nickel species is estimated as listed below (Table 4.1.1.2.2.4.A). It
has to be noted that soluble nickel salts may include other salts than nickel sulphate, but for the assessment the soluble
fraction is considered all nickel sulphate (worst-case).
sulphate from copper refining.
Nickel
Species
Typical exposure
Worst-case exposure
Shortterm
exposure
(μg/m3)
Nickel species
as % of ‘total’
nickel
Exposure to
inhalable
‘total’ nickel
(μg/m3)
Exposure to
inhalable
nickel
species
(μg/m3)
SO
60
30
18
100
150
150
300
U
40
30
12
0
150
0
0
(1)
Nickel
Exposure to
species as %
inhalable
of ‘total’
‘total’ nickel
nickel
(μg/m3)
Exposure to
inhalable
nickel
species
(μg/m3)
No measured data for dermal exposure to nickel seem available for the assessment. Hughson (2004) did a
comprehensive study on occupational dermal exposure to nickel in a refinery where nickel sulphate crystals are
produced by a leaching process. The chemical plant used nickel sulphate solution to produce nickel sulphate
hexahydrate and nickel hydroxycarbonate. The dermal exposure was measured during packing of the final product. For
nickel sulphate production from copper refining the highest exposure to nickel sulphate is expected to be during packing
53
of the final product. The exposure is expected to be similar to the exposure measured in the packing of nickel sulphate
produced from nickel matte (scenario A1). Thus the dermal exposure is estimated at the levels tabulated below. Further
details of the estimated data are given above (section 4.1.1.2.2.1.4 and 4.1.1.2.2.1.5).
Nickel species
Typical exposure
μg/cm2/day
mg/day 1
1.2
1.0
2.0
0.4
0.8
0.7
1.4
0.2
0.4
0.4
0.8
2
μg/cm /day
mg/day
Total nickel
0.6
Soluble nickel
Insoluble nickel
1
Comprehensive data sets were available for the assessment of exposure by inhalation of ‘total’ nickel in the nickel
sulphate production from copper refining. An emphasis was made to assess exposure in terms of inhalable aerosols. No
data on nickel species in workroom were available and by analogy speciation data from a perhaps rather similar
scenario (nickel sulphate production from metallic nickel) were used. It is noted that the validity of such an approach
remains unknown. The estimated exposure to soluble nickel includes all soluble nickel salts as no speciation data were
available on soluble salts. Thus the estimated exposure to soluble salts is considered worst-case exposure to nickel
sulphate.
For the production of nickel sulphate from copper refining no data were available on dermal exposure to nickel
sulphate, and the exposure was estimated by two approaches, (i) by analogy to measured dermal exposure in nickel
sulphate production from nickel matte and (ii) by modelling. The measured data focused on nickel compound packing
operators (scenario A1). The predicted exposure level was much higher than the level estimated from measured data.
not therefore take into account the attenuating effect of gloves and other protective clothing. For nickel sulphate
production from copper refining the highest exposure to nickel sulphate is expected to be during packing of the final
product. Thus it appears prudent to take the data obtained by analogy forward to the risk characterization. In conclusion
the estimated levels of exposure to groups of nickel species are summarized below.
Nickel species
(1)
Dermal exposure
(mg/day)
Typical
Worst-case
Short term
Typical
Worst-case
SO
18
150
300
0.8
1.4
U
12
~0
~0
0.4
0.8
4.1.1.2.2.5
Scenario A5 – Ni sulphate production by purification of impure nickel sulphate
Impure nickel sulphate is purified to produce pure nickel sulphate. This is described in 2.1.1.5. No data on personal
exposure are available for the assessment. The steps involved in the production of nickel sulphate by purification of
impure nickel sulphate are rather similar to the steps involved in nickel sulphate production from nickel matte (scenario
A1). By analogy the data for scenario A1 were considered useful as a rough estimate of exposure to the production
nickel sulphate by purification of impure nickel sulphate. The estimated exposure is tabulated below and further details
are given above (section 4.1.1.2.2.1).
54
Nickel species (1)
Typical
Worst-case
Short term
SO
70
1000
2000
U
50
1): SO = Soluble nickel considered to be all nickel sulphate (worst case); U = Other nickel species than soluble nickel.
4.1.1.2.2.5.2 Dermal exposure – measured and modelled exposure levels.
No measured data for dermal exposure to nickel seem available for the assessment. Hughson (2004) did a
comprehensive study on occupational dermal exposure to nickel in a refinery where nickel sulphate crystals are
produced by a leaching process. The chemical plant used nickel sulphate solution to produce nickel sulphate
hexahydrate and nickel hydroxycarbonate. The dermal exposure was measured during packing of the final product. For
nickel sulphate production by purification of impure nickel sulphate the highest exposure to nickel sulphate is expected
to be during packing of the final product. The exposure is expected to be similar to the exposure measured in the
packing of nickel sulphate produced from nickel matte (scenario A1). Thus the dermal exposure is estimated at the
levels tabulated below. Further details of the estimated data are given above (section 4.1.1.2.2.1.4 and 4.1.1.2.2.1.5).
Nickel species
Typical exposure
μg/cm2/day
mg/day 1
1.2
1.0
2.0
0.4
0.8
0.7
1.4
0.2
0.4
0.4
0.8
2
μg/cm /day
mg/day
Total nickel
0.6
Soluble nickel
Insoluble nickel
1
No data on exposure by inhalation are available for the assessment. By analogy the exposure was estimated to be
similar to the exposure in the production of nickel sulphate from leaching nickel matte.
For the production of nickel sulphate by purification of impure nickel sulphate no data were available on dermal
exposure to nickel sulphate, and the exposure was estimated by two approaches, (i) by analogy to measured dermal
exposure in nickel sulphate production from nickel matte and (ii) by modelling. The measured data focused on nickel
compound packing operators (scenario A1). The predicted exposure level was much higher than the level estimated
from measured data. However, the predicted exposure levels produced by EASE are intended to be estimates of
potential exposure and do not therefore take into account the attenuating effect of gloves and other protective clothing.
For nickel sulphate production by purification of impure nickel sulphate the highest exposure to nickel sulphate is
expected to be during packing of the final product. Thus it appears prudent to take the data obtained by analogy forward
to the risk characterization. In conclusion the estimated levels of exposure to groups of nickel species are summarized
below.
Nickel species (1)
Typical
Worst-case
Short term
Typical
Worst-case
SO
70
1000
2000
0.8
1.4
U
50
0.4
0.8
4.1.1.2.2.6
Scenario A6 – Ni sulphate production from metallic nickel
Nickel pellets are dissolved in hot sulphuric acid followed by crystallization, centrifuging, drying and packing. From the
listed processes it has to be expected that workers within the overall scenario may not have similar tasks. As an effort to
55
analysis.
NIPERA (1996) have provided comprehensive data on occupational exposure to nickel and nickel compounds. The data
included information on exposure by inhalation of ‘total’ and soluble nickel in the production of nickel sulphate from
nickel pellets dissolved in sulphuric acid. The measured concentrations are listed below (Table 4.1.1.2.2.6.A). As a
percentage of exposure to ‘total’ nickel the data indicate that exposure to soluble nickel may range from 45% to 59%.
For the assessment 50% is considered typical while 100% is considered a worst-case.
Table 4.1.1.2.2.6.A: Data on the concentration of airborne ‘total’ and soluble nickel in the production of
nickel sulphate from nickel pellets dissolved in sulphuric acid.
Ref.
EIS Data A
1993
Comp 16
Operation
Nickel sulphate
production
N
Type of
sampler
Aerosol
fraction
Concentration of
‘total’ Ni (μg/m3)
Concentration of
soluble Ni (μg/m3)
Range
Average B
Range
Average B
Soluble
* Ni %
22
Personal 1
‘Total’
10-180
38
10-180
17
45
34
Static 1
‘Total’
10-530
86
10-230
51
59
A: Data listed by NIPERA (1996). B: Geometric mean. *: Soluble Ni (as a percentage) was estimated as the average concentration
of soluble Ni in proportion to the average concentration of ‘total’ Ni.
1: Unknown type of aerosol sampler; NIPERA (2001a) noted that the sampler was the seven-hole cassette.
Current data (Table 4.1.1.2.2.A) on occupational exposure were obtained from industry and from literature. If possible
data are listed using the format of the specific company data submission scheme i.e. year(s) of measurement(s), number
of samples, range, median and 95th percentile value. It is noted that the vast majority of the data sets were given in terms
of full-shift time weighted averages. Thus the listed data are considered full-shift exposure. The information available
on the sampling technique and aerosol fraction is included in the listed data. Some of the data sets were collected by an
approach of static sampling. It is well known (see section 4.1.1.2.1.2) that data from static sampling may not be valid
for an estimate of personal exposure. Thus data from static sampling were excluded from the estimation of personal
exposure. Exposure measured in terms of the ‘total’ aerosol fraction was converted to the inhalable fraction by factors
of 3.0 (37-mm open face cassettes) and 1.17 (seven-hole sampler). For the scenario it appears that current exposure to
‘total’ nickel (‘total’ aerosol fraction) ranged from a median or mean level of 20 μg/m3 to 120 μg/m3. In terms of the
inhalable aerosol fraction current ‘total’ nickel exposure ranged from a median or mean level of 23 μg/m3 to 170 μg/m3.
It has to be noted that the information available on sampling techniques did not allow some high levels of exposure
observed in the early 1980s to be converted to the inhalable fraction. The median of the median or mean levels was ~40
μg/m3 of inhalable ‘total’ nickel (typical exposure level). A median exposure at this level was reported for two large
data sets of sub-groups of workers with the task of Ni-sulphate production (22 observations) or control laboratory (54
observations).
By definition the reasonable worst-case exposure is the exposure experienced in a reasonable unfavourable but not
unrealistic situation and the prediction should also consider upper estimates of the extreme use. In the Risk Assessment
Report on Zinc Oxide (Netherlands Rapporteur, 2003) the reasonable worst-case exposure was estimated at the 90th
percentile value of the available data. A similar approach was used for the present exposure assessment. Detailed data
sets are required to allow an estimate of the true 90th percentile value. Data were not available at such details and a
rough estimate of the 90th percentile was derived using the following three-step procedure. Simple calculations are used
for the first two steps while the third step involves ’professional judgement’ taking into account the quality of the data
sets with an emphasis on the size of the data sets, the medians and the year of sampling. A given data set included the
range of observations. The upper limit of the range was used for ranking the data sets, and all data sets (sub-scenarios)
at or above the 90th percentile were considered important for the estimation of the reasonable worst-case exposure. The
90th percentile of the available data sets (N=6; 193 observations) was ≈ 770 μg/m3 inhalable ‘total’ nickel. An upper
limit of exposure at this level was reported for a recent (1995-97) and large data set (29 observations) of workers with
the task of effluent plant. One small data set (12 observations) reported a median of 170 μg/m3 and an upper limit at
56
1800 μg/m3. The 95th percentile for the large data set of effluent plant workers was 230 μg/m3. Two other large and
recent data sets (111 observations) reported 95th percentiles at a similar level. Thus it appears prudent to consider 230
μg/m3 as an estimate of the reasonable worst-case exposure level. Data on short-term exposure to ‘total’ nickel seem
unavailable, and it is difficult (if not impossible) to derive an estimate on short-term exposure from data characterizing
full shift exposure. For the risk assessment of zinc metal (Netherlands Rapporteur, 1999) no data were available on
short-term exposure and an estimate was derived as twice the worst-case exposure level. A similar approach (‘expert
judgement’) was taken for the present risk assessment. Thus the short-term exposure was estimated at a level of
2×230=460 μg/m3. For the scenario no data seem available on the size distribution of aerosols in the workroom air.
Packaging is a common task in the production of nickel sulphate, and the task may cause risk of exposure (see Table
4.1.1.2.2.A). Thus the typical and the reasonable worst-case exposures were modelled for this task. Any manipulation of
a dry material enters the EASE model by the term ‘dry manipulation’. To model the exposure EASE requires input on
the tendency of a material to aggregate. No data are available on the tendency of nickel sulphate to aggregate, and the
chemical was as a worst-case considered non-sticky (aggregate is false).
Model input:
Solid-vp is false
Aggregates is false
Model output:
Model input:
Model output:
The predicted typical exposure level is rather close to the measured data as listed in Table 4.1.1.2.2.1.B, while the
air (Table 4.1.1.2.2.6A) current exposure to groups of nickel species is estimated as listed below (Table 4.1.1.2.2.6.B).
It has to be noted that soluble nickel salts may include other salts than nickel sulphate, but for the assessment the
soluble fraction is considered all nickel sulphate (worst-case).
Table 4.1.1.2.2.6.B: Estimated exposure by inhalation of groups of nickel species in the production of nickel
sulphate from nickel metal.
Nickel
Typical exposure
Worst-case exposure
Short-
57
Species
Nickel species
as % of ‘total’
nickel
Exposure to
inhalable
‘total’ nickel
(μg/m3)
Exposure to
inhalable
nickel
species
(μg/m3)
SO
50
40
20
100
U
50
40
20
0
(1)
Exposure to
inhalable
nickel
species
(μg/m3)
term
exposure
(μg/m3)
230
230
460
230
0
0
Nickel
Exposure to
species as %
inhalable
of ‘total’
‘total’ nickel
nickel
(μg/m3)
Hughson (2004) did a comprehensive study on occupational dermal exposure to nickel in a refinery where nickel
sulphate crystals are produced by a leaching process. The chemical plant used nickel sulphate solution to produce nickel
sulphate hexahydrate and nickel hydroxycarbonate. The dermal exposure was measured during packing of the final
product. For nickel sulphate production from metallic nickel the highest exposure to nickel sulphate is expected to be
during packing of the final product. The exposure is expected to be similar to the exposure measured in the packing of
nickel sulphate produced from nickel matte (scenario A1). Thus the dermal exposure is estimated at the levels tabulated
below. Further details of the estimated data are given above (section 4.1.1.2.2.1.4 and 4.1.1.2.2.1.5).
Nickel species
Typical exposure
μg/cm2/day
mg/day 1
1.2
1.0
2.0
0.4
0.8
0.7
1.4
0.2
0.4
0.4
0.8
2
μg/cm /day
mg/day
Total nickel
0.6
Soluble nickel
Insoluble nickel
1
Rather solid data in terms of the ‘total’ aerosol fraction were available for the assessment of exposure by inhalation of
‘total’ nickel in the nickel sulphate production from metallic nickel. An emphasis was made to assess exposure in terms
of inhalable aerosols. However, a few data sets did not specify sufficient details on sampling methods to allow ‘total’
aerosols to be converted to inhalable aerosols. Data on nickel species in workroom air were sparse. A single study
provided data on exposure by inhalation of soluble/insoluble nickel species, and by analogy the speciation data were
considered useful for the scenario. However, the validity of such an approach remains unknown. The estimated
exposure to soluble nickel includes all soluble nickel salts as no speciation data were available on soluble salts. Thus the
estimated exposure to soluble salts is considered worst-case exposure to nickel sulphate.
No data were available on dermal exposure, and the exposure was estimated by two approaches, (i) by analogy to
measured dermal exposure in nickel sulphate production from nickel matte and (ii) by modelling. The measured data
focused on nickel compound packing operations (scenario A1). The predicted exposure level was much higher than the
levels estimated from measured data. However, the predicted exposure levels produced by EASE are intended to be
estimates of potential exposure and do not therefore take into account the attenuating effect of gloves and other
protective clothing. For nickel sulphate production from metallic nickel the highest exposure to nickel sulphate is
expected to be during packing of the final product. Thus it appears prudent to take the data obtained by analogy forward
to the risk characterization. In conclusion the estimated levels of exposure to groups of nickel species are summarized
below.
Nickel species
(1)
Dermal exposure
(mg/day)
Typical
Worst-case
Short term
Typical
Worst-case
SO
20
230
460
0.8
1.4
U
20
~0
~0
0.4
0.8
58
4.1.1.2.3 Use of nickel sulphate.
4.1.1.2.3.1
Scenario B1 – Production of metallic nickel.
The production of metallic nickel by electrowinning has been described in the risk assessment report of metallic nickel.
In some processes, nickel metal is produced in electrolytic cells filled with nickel sulphate solution. In addition to the
production of commercial nickel sulphate at Outokumpu the nickel sulphate produced by leaching the nickel matte is
used as a source of electrolyte for the electrowinning process and for the hydrogen reduction process for the production
of nickel metal. From the listed processes it has to be expected that workers within the overall scenario may not have
similar tasks. As an effort to identify tasks (sub-scenarios) with high risk of exposure the available data on exposure
were summarized in one table and tabulated by sub-groups of workers with similar tasks. Such listing was kept within a
given set of data (study) and no attempt was made to join similar tasks cross data sets. The reason not to join similar
tasks cross data sets was that prior to the collapse of data sets a statistical analysis is required for identity of data sets in
terms of statistical distribution, mean, and variance. The data for the assessment were not available in details to allow
such statistical analysis.
The scenario has focus on current exposure and it has to be noted that the section on carcinogenicity holds data on
exposure to soluble nickel in the nickel-producing industries for a period ranging from the past to the present. As
mentioned above (section 0.1.1.1.1) Symanski et al. (2000) did an evaluation of temporal changes in exposure to nickel
aerosols in the nickel-producing and nickel-using industries, and provided evidence of largely downward trends in
exposure to nickel aerosols in industries involved with the primary production of nickel and in the manufacture of
nickel alloys. Thus it is difficult to compare the exposure as estimated from the present scenario with the tabulated
exposure in the section on carcinogenicity.
Thomassen et al. (1999) provided detailed data on airborne nickel species from the Monchegorsk refinery in Russia.
Sulphidic ore are processed at this facility and personal air sampling (inhalable aerosols) was conducted in the
roasting/anode casting and the electrowinning departments. For the electrowinning departments soluble nickel as a
percentage of total nickel ranged from 55% to 99%. Although the data collected by Thomassen et al. (1999) represent
processes and industrial hygiene practices that are not common in current European operations the exposure to soluble
nickel as a percentage of total nickel is considered useful for the assessment. For hydrometallurgy processes (leaching,
solution purification, electrowinning of nickel) at the Outokumpu Harjavalta facility (Finland) Kiilunen et al. (1997a)
observed that water-soluble nickel sulphate represented more than 95% of the total concentration of nickel in air, except
at the leaching site, where the proportion of water-insoluble nickel was 11%. For the concentration of airborne inhalable
nickel Hughson (2004) reported that the proportion of soluble nickel ranged from 18% to 53% (3 observations) in
leaching while the proportion ranged from 72% to 96% (9 observations) in electrowinning. It is recognized that data are
few on airborne nickel species. As a percentage of total nickel a typical aerosol composition was considered as 95%
soluble nickel and 5% non-soluble nickel. An aerosol composed of 100% soluble nickel was considered a worst-case
estimate. For the scenario soluble nickel was considered being nickel sulphate (worst-case).
The risk assessment report of nickel metal has two scenarios on occupational exposure in nickel refining and data
considered useful for the present scenario were extracted from the risk assessment report on nickel metal and tabulated
(Table 4.1.1.2.3.1.A) by sub-groups of workers with similar tasks. If possible data are listed using the format of the
specific company data submission scheme i.e. year(s) of measurement(s), number of samples, range, median and 95th
percentile value. It is noted that the vast majority of the data sets were given in terms of full-shift time weighted
averages. Thus the listed data are considered full-shift exposure. The information available on the sampling technique
and aerosol fraction is included in the listed data. Exposure measured in terms of the 'total' aerosol fraction was
converted to the inhalable fraction by factors of 2.12 (37-mm/25-mm open or closed face cassettes). Most of the
available data sets were collected by an approach of personal or personal/static sampling. As mentioned above (section
4.1.1.2.1.2) data obtained by static sampling may not be valid for an estimate of personal exposure. Thus data from
static sampling do not enter the assessment of exposure while data obtained by personal/static sampling as a
compromise enter the assessment. For the scenario it appears from Table 4.1.1.2.3.1.A that current exposure to ’total’
nickel (’total’ aerosol fraction) ranges from a median or mean level of 0.002 mg/m3 to 1.3 mg/m3. The level of 1.3
mg/m3 was reported for a data set collected in the late 1970s. The nickel results tabulated mainly relate to full shift,
time-weighted average exposures. However, short-term emissions to high aerosol levels may occur within operations
59
such as solution purification. Usually RPE (respiratory protective equipment) is used during these stages. In terms of the
inhalable aerosol fraction current exposure (19 data sets; more than 1036 observations) ranges from a median or mean
level of 0.003 mg/m3 to 0.38 mg/m3, and the median of the levels is 0.04 mg/m3 (typical exposure level). An exposure at
such level was observed for a sub-group of workers with a task of manufacturing of starting sheets.
sets with an emphasis on the size of the data sets, the medians and the year of sampling. A given data set included the
range of observations. The upper limit of the range was used for ranking the data sets, and all data sets (sub-scenarios)
at or above the 90th percentile were considered important for the estimation of the reasonable worst-case exposure. The
90th percentile of the available data sets (N=19) was 1.5 mg/m3 inhalable ‘total’ nickel. Three data sets had an upper
limit at or above this level. A limit of 1.5 mg/m3 was reported for a large (66 observations) data set for a sub-group of
workers with the task of copper refining. A higher upper limit of exposure was seen for two other sub-groups of
workers: the upper limit was 2.3 mg/m3 for workers with the task of chlorine leaching (84 observations), while an upper
limit of 4.5 mg/m3 was seen for a large data set (125 observations) of workers with the task of copper refining
(maintenance). The 95% percentile of the leaching workers (84 observations) is 0.66 mg/m3, while the median of the
copper refining workers (125 observations) is less than 0.38 mg/m3. The median of the workers in electrowinning (66
observations) is low (less than 0.18 mg/m3). Taking the size and the medians of the three different data sets into
consideration it seems prudent to consider the 95% percentile for leaching workers (0.66≈0.7 mg/m3) as a reasonable
worst-case exposure level. Data on short-term exposure to nickel seem unavailable, and it is difficult (if not impossible)
to derive an estimate on short-term exposure from data characterizing full shift exposure. For the risk assessment of zinc
sulphate (Netherlands Rapporteur, 1999) no data were available on short-term exposure and an estimate was derived as
twice the worst-case exposure level. A similar approach (’expert judgement’) was taken for the present risk assessment,
and the short-term exposure was estimated at a level of 2×0.7 mg/m3~ 1.4 mg/m3.
60
Table 4.1.1.2.3.1.A: Scenario B1: Production of metallic nickel – current exposure to ’total’ nickel.
Exposure to ’total’ nickel mg/m3
Range
Median
95th perc.
Range
Median
95th perc.
3,4
5,6
0-0.16
0.002-0.012
NA
0-0.34
0.004-0.025
NA
Ref.
Process
N
Year
Type of
Sampler
Aerosol
Fraction
UNC Data*
UNC, 1995
Copper refining: furnaceman,
anode helper
Copper refining: electrowinning
244
Personal 1
’Total’
66
Personal 1
’Total’
0.001-0.72
0.026-0.0833,4
NA
0.002-1.5
0.055-0.185,6
NA
Copper refining: lead welder
17
Personal 1
’Total’
0.002-0.019
0.008
NA
0.004-0.04
0.017
NA
Copper refining: maint.
125
Personal 1
’Total’
0.001-2.1
0.018-0.183,4
NA
0.002-4.5
0.038-0.385,6
NA
Copper refining: unknown
124
Personal 1
’Total’
0.001-0.53
0.003-0.063,4
NA
0.002-1.1
0.006-0.135,6
NA
Boysen et
al., 1982
Electrolysis
NA5
19771992
19791992
19811984
19771988
19771992
19791980
Static 2
’Total’
<0.1
NA
NA
-
-
-
Doll et al.,
1990*
EIS Data*
EIS, 1993
Comp. 10
Electrolysis
NA
’Total’
<2.0
0-1.33,4
NA
-
-
-
Chlorine leaching
NA
’Total’
0.03-0.08
NA
NA
-
-
-
Solvent extraction
NA
’Total’
0.02-0.05
NA
NA
-
-
-
Electrowinning
NA
’Total’
0.02-0.05
NA
NA
-
-
-
Crystallization
NA
Personal
/static 2
Personal
/static 2
Personal
/static 2
Personal
/static 2
Personal
/static 2
’Total’
0.04-0.06
NA
NA
-
-
-
19781984
19881992
19881992
19881992
19881992
*: Data listed by NIPERA (1996).
1: 37-mm closed face filter cassette. 2: unknown type of sampler. 3: arithmetic mean. 4: range. 5: not available.
61
Table 4.1.1.2.3.1.A: Scenario B1: Production of metallic nickel – current exposure to ’total’ nickel (continued).
Ref.
Process
N
Year
Type of Sampler
Aerosol
Fraction
Kiilunen et
al., 1997a
Leaching
Solution purification
Manufacturing of
starting sheets
Stripping of mother
sheets
Crane operators
Leaching
Solution purification
Tank house #1
Tank house #2
Tank house #3
Small cells (tank house
#2)
Other sites
Leaching
Leaching
Electrowinning
Electrowinning
Cu-electrowinning
Ni-electrowinning
Chlorine leaching
Purification system
Leaching plant
Electro-winning
Cathode cutting
8
NA
6
1991-1992
1991-1992
1991-1992
Personal 1
Personal 1
Personal 1
’Total’
’Total’
’Total’
Exposure to ’total’ nickel mg/m3
Range
Median
95th perc.
Range
Median
95th perc.
2
3
2
0.004-0.019
0.005
NA
0.008-0.040
0.011
NA
0.0003-0.018
0.0132
NA
0.0006-0.038
0.0282
NA
0.0046-0.040
0.0182
NA
0.010-0.085
0.0392
NA
26
1991-1992
Personal 1
’Total’
0.0001-0.008
0.0012
NA
0.0002-0.016
0.0032
NA
8
16
12
22
19
20
3
1991-1992
1991-1992
1991-1992
1991-1992
1991-1992
1991-1992
1991-1992
Personal 1
Static 5
Static 5
Static 5
Static 5
Static 5
Static 5
’Total’
’Total’
’Total’
’Total’
’Total’
’Total’
’Total’
0.0005-0.012
0.003-0.027
0.057-0.16
0.069-0.16
0.19-0.56
0.35-0.68
NA
0.0022
0.012
0.098
0.11
0.28
0.45
0.48
NA
NA
NA
NA
NA
NA
NA
0.001-0.025
-
0.0042
-
NA
-
48
16
28
110
200
76
89
84
37
3
9
3
1991-1992
1992-1993
1992-1993
1992-1993
1996
1994-1997
1994-1997
1994-1997
1994-1997
2004
2004
2004
Static 5
Personal 1
Static 1
Personal 1
Static 1
Personal 4
Personal 4
Personal 4
Personal 4
Personal 7
Personal 7
Personal 7
’Total’
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
Inhalable
0.001-0.035
0.005-0.15
0.01-0.1
0.005-0.02
0.2-0.6
0.005-0.046
0.006-0.22
0.009-1.1
0.005-0.19
0.008
0.086
0.026
0.026
0.226
0.0192
0.0272
0.0292
0.0252
NA
NA
NA
NA
NA
0.037
0.055
0.31
0.13
0.01-0.30
0.02-0.2
0.01-0.04
0.4-1.2
0.011-0.097
0.013-0.47
0.019-2.3
0.011-0.40
0.03-0.22
0.015-0.13
0.007-0.022
0.166
0.046
0.046
0.446
0.040
0.057
0.061
0.053
0.06
0.032
0.022
NA
NA
NA
NA
0.078
0.12
0.66
0.28
0.22
0.13
0.022
HEDSET
Comp. 6
HEDSET
Comp. 5
Hughson,
2004
1: presumably the sampler was the 37-mm/25-mm closed face filter cassette. 2: geometric mean. 3: not available. 4: 37-mm closed face filter cassette. 5: 37-mm filter
cassette (presumably closed face) operated at a flow rate of 20 l/min. 6: Arithmetic mean as estimated from the number of observations and the range using the approach given by
Vincent and Werner (2003). 7: The IOM-sampler.
62
If the electrolyte is agitated vigorously by air bubbles nickel sulphate in the form of mist is generated from bursting
bubbles. Such bubbles are considered an important mechanism for air contaminants in the process of electrowinning. At
present stage EASE does not allow modelling of exposure to mist generated from bursting bubbles. Thus modelled data
are not available for the assessment.
Considering the assessed data on nickel species in workroom air (section 4.1.1.2.3.1) and the estimated exposure to
‘total’ inhalable nickel (section 4.1.1.2.3.2) current exposure to groups of nickel species is estimated as tabulated below
(Table 4.1.1.2.3.1.B).
Table 4.1.1.2.3.1.B: Estimated exposure by inhalation of groups of nickel species in the production of
metallic nickel.
Nickel
Species
Typical exposure
Worst-case exposure
Shortterm
exposure
(μg/m3)
Nickel species
as % of ‘total’
nickel
Exposure to
inhalable
‘total’ nickel
(μg/m3)
Exposure to
inhalable
nickel
species
(μg/m3)
SO
95
40
38~40
100
700
700
1400
U
5
40
2
≈0
700
≈0
≈0
(1)
Nickel
Exposure to
species as %
inhalable
of ‘total’
‘total’ nickel
nickel
(μg/m3)
Exposure to
inhalable
nickel
species
(μg/m3)
Hughson (2004) did a comprehensive study on occupational dermal exposure to nickel in the electrowinning plant of a
nickel refinery producing nickel metal by recovering elemental nickel from nickel matte using an electrolytic process.
In the electro-winning plant approximately 10 workers per shift were involved in the process. Starter sheets were
produced using tungsten sheets as cathodes, which were placed in electrolytic tanks containing nickel sulphate solution.
Nickel was deposited onto the cathodes and after two days the plated tungsten sheets were removed. Loading and
unloading of the cathodes was done using a travelling crane, with the assistance of two to three operators who
manipulated the load as it was being loaded or unloaded. The plated starter sheets were washed down with water and
transferred to the stripping machine which separated the nickel plate from the tungsten sheet. This was a semi-automatic
process and involved two workers with supervising the loading and unloading of the machine conveyors. The nickel
plates were transferred to the main process area where they were used as starter sheets for electrolytic recovery of nickel
in the main tank room area. The workers that handled the starter sheets were known as cathode ’strippers’. The starter
sheets were configured as nickel cathodes on the cathode machine. This was another automatic process, supervised by
one or two workers. The machine trimmed the nickel plates to size and fixed a copper electrode bar to one end of each
plate. The resultant cathodes were loaded onto racks and then placed into the process tanks using an overhead crane.
The workers in this main tank house area were known as cathode ’lifters’. It was usual practice for workers to rotate
around tasks in order to limit the time spent in the tank area. The cathodes were left in the tanks for seven days and were
removed, washed down and then transferred to the cathode cutting area in a different part of the plant. All workers were
required to wear an air-assisted filtering visor with P3 filter element. The workers wore cotton overalls and coated
rigger gloves. New gloves were worn at the start of each shift. Gloves were worn continuously in the area due to the
risk of cuts from contact with sharp metal surfaces and also due to the corrosive nature of the process liquor.
The measured dermal exposure to nickel is tabulated in Table 4.1.1.2.3.1.C. Details of the measurement method are
given above (section 4.1.1. 2.2.4.1.4). For hands and arms of electrowinning operators the median dermal exposure to
total nickel was 0.3 μg/cm2. This median is considered to be an estimate of the typical exposure level, while the 90th
percentile (1.9 μg/cm2) is considered to be an estimate of the reasonable worst-case exposure level. For soluble nickel
the median is 0.3 μg/cm2 (typical exposure level), while the 90th percentile (worst-case exposure level) is 0.9 μg/cm2.
For insoluble nickel the median is 0.1 μg/cm2 (typical exposure level), while the 90th percentile (worst-case exposure
level) is 1.0 μg/cm2.
63
Table 4.1.1.2.3.1.C: Measured dermal nickel exposure (μg/cm2) for electrowinning operators (Hughson,
2004).
Anatomical area
N1
Soluble nickel A
Insoluble nickel A
Total nickel
Electrowinning operators
9
2
0.4 (0.1-2.3)
1.4
0.2 (<0.1-1.9)
1.9
0.6 (0.1-4.2)
3.3
9
2
0.2 (0.1-1.4)
0.5
0.1 (<0.1-1.1)
0.4
0.3 (0.1-2.5)
0.9
9
3
0.3 (0.1-1.8)
0.9
0.1 (<0.1-1.4)
1.0
0.3 (0.2-3.2)
1.9
Neck
9
4
0.3 (<0.1-1.4)
1.3
0.1 (<0.1-0.8)
0.6
0.4 (<0.1-2.2)
1.9
Face (perioral region)
94
0.1 (<0.1-1.5)
0.8
<0.1 (<0.1-0.6) 0.5
0.5 (<0.1-2.2)
1.1
4
0.1 (<0.1-0.2)
0.2
<0.1 (<0.1-0.2) 0.1
0.1 (<0.1-0.2)
0.2
Average Hands
Average forearms
Hands & Arms
Chest
9
Control group (non-occupationally exposed volunteers)
Average Hands
10
NA
NA
NA
NA
0.03 (0.01-0.09)
0.05
Average forearms
10
NA
NA
NA
NA
0.01 (0.01-0.06)
0.03
Hands & Arms
10
NA
NA
NA
NA
0.02 (0.01-0.07)
0.04
1: number of subjects.
2: per subject dermal exposure was measured three times during a shift (first break; mid-shift break; end of shift); every time one
sample was collected from palms of both hands and another was taken from back of both hands.
3: exposure is given as an area weighted average of the measured data for the hands (area 840 cm2) and forearms (area 1140 cm2).
4: at end of shift one sample was collected per person.
A: The soluble and insoluble nickel content was analysed using a variation of a published method (Zatka et. al, 1992).
The report by Hughson (2004) on occupational dermal exposure to nickel in the electrowinning of nickel included a
description of the workplace conditions in terms of the EASE model. For electrowinning operators Hughson assigned
the EASE exposure criteria of non-dispersive use with extensive direct contact. Thus this scenario is modelled.
Estimation of dermal exposure for electrowinning operators
Model input:
The name of the substance is nickel
Solid-vp is false
The contact-level is extensive direct contact
Model output:
The predicted dermal exposure to nickel is 1-5 mg/cm2/day.
The level of dermal exposure in the electrowinning of nickel was estimated by two approaches, (i) by measured data
and (ii) by modelling. The measured dermal exposures were much less than predicted values generated by the EASE
model. In addition, the measured dermal nickel levels were lower than levels of exposure previously obtained from the
zinc industry (Hughson and Cherrie, 2001). This might be due to the higher levels of engineering controls applied to the
nickel production processes generally, combined with specific hygiene measures such as the consistent use of personal
protective equipment (Hughson, 2004). The measured data were obtained at conditions typical of normal production, so
the measured exposures can be considered representative of normal production conditions (Hughson, 2004). Thus the
measured data are taken forward to the risk characterization. The estimated typical and reasonable worst-case exposure
levels for hands and forearms are summarized below. It is noted that the measured data (Table 4.1.1.2.3.1.C) indicate
that there is potential for inadvertent ingestion of nickel, either through hand to mouth contact or from deposition into or
around the perioral region.
64
Nickel species
Typical exposure
2
μg/cm2/day
mg/day 1
0.6
1.9
3.8
0.6
0.9
1.8
0.2
1.0
2.0
μg/cm /day
mg/day
Total nickel
0.3
Soluble nickel
0.3
Insoluble nickel
0.1
2
2
1
2
4.1.1.2.3.1.6 General discussion and conclusion
‘total’ nickel in the production of metallic nickel from nickel sulphate. An emphasis was made to assess exposure in
terms of inhalable aerosols. However, a few data sets did not specify sufficient details on sampling methods to allow
‘total’ aerosols to be converted to inhalable aerosols. As a percentage of ‘total’ nickel the data available on groups of
nickel species in workroom air indicated that aerosols are to be considered high in content of soluble nickel. The
estimated exposure to soluble nickel includes all soluble nickel salts as no speciation data were available on soluble
salts. Thus the estimated exposure to soluble salts is considered worst-case exposure to nickel sulphate.
For the production of nickel metal comprehensive measured data were available on dermal exposure to soluble and
insoluble nickel. The exposure was estimated by two approaches, (i) from measured data and (ii) by modelling. The
predicted exposure level was much higher than the level estimated from measured data. However, the predicted
exposure levels produced by EASE are intended to be estimates of potential exposure and do not therefore take into
account the attenuating effect of gloves and other protective clothing. Thus it appears prudent to take the exposure
estimated from measured data forward to the risk characterization.
Nickel species
(1)
Dermal exposure
(mg/day)
Typical
Worst-case
Short term
Typical
Worst-case
SO
40
700
1400
0.6
1.8
U
2
~0
~0
0.2
2.0
1: SO = Soluble nickel salts considered to be all nickel sulphate (worst-case); U = Other nickel species than soluble nickel.
4.1.1.2.3.2
Scenario B2 – Nickel plating
The most common method of applying a nickel coating is electroplating, although a similar process called electroless
plating is widely used. In electroplating, an object to be plated (the work piece) and a bar of nickel metal are connected
to a source of direct current such that the work piece is negatively charged with respect to the nickel bar. The work
piece is frequently called the cathode and the nickel bar is called the anode. The work piece and the nickel anode are
immersed in a solution of nickel salts and other chemicals called the plating bath. In the solution, the nickel exists as
divalent ions (Ni--) complexed with water molecules or other chemical species also present in the solution. The nickel
ions migrate to the cathode, where they receive electrons and are converted to nickel metal. In essence, nickel is
transferred from the metal anode through the aqueous plating bath to the work piece. The salts commonly used in
electroplating, listed in order of decreasing solubility, are: nickel fluoroborate, nickel sulphamate, nickel formate, nickel
chloride, nickel sulphate, nickel ammonium sulphate, and nickel acetate. Plating baths can also contain boric acid,
phosphoric acid, phosphorous acid, ammonium chloride, fluoroboric acid, sodium thiocyanate and a variety of
proprietary ingredients that help in the formation of a nickel coating with the desired physical characteristics. The
temperature of plating baths may range from 25 to 70ºC (Kiilunen et al., 1997b). The most commonly used electrolyte
(Tsai et al., 1996a) is the Watts bath, containing mainly nickel sulphate (usually in the range 220 to 370 kg/m3 water),
nickel chloride (from 30 to 60 kg/m3), and boric acid (from 30 to 45 kg/m3). However, the actual composition may
differ considerably from shop to shop. The process known as electroless plating also deposits metallic nickel onto work
piece, but the conversion of nickel ion in solution to the metal is mediated by a chemical reducing agent rather than
through electrolysis. The nickel salts used in electroless plating are among those also used in electroplating baths.
65
During the deposition of nickel metal onto the work piece nickel ions are removed from the solution around the work
piece. Although nickel ions are migrating into this area from the bulk of the plating bath, nickel ions may plate onto the
work piece faster than they are replenished by migration. The resultant decrease in the concentration of nickel around
the work piece may adversely affect the quality of the plated coating or decrease the efficiency of the process. To
counter this depletion, plating baths are agitated, commonly by bubbling air through them. As the air bubbles rise to the
surface and break, small droplets of the plating solution are released into the air. Large drops fall back into the tank or
deposit on surfaces nearby. Smaller droplets become airborne and drift into the general plant air where the workers can
inhale them. Small droplets rapidly lose their water by evaporation, leaving behind solid particles made up of crystals of
nickel salts and the other components of the plating bath.
Different methods of nickel plating are common including manual plating, semi-automatic and automatic plating.
Manual plating is a series of tanks that contain the appropriate plating and cleaning solutions. Parts are placed on racks
or hangers and manually transferred from tank to tank. This type of plating process is labour intensive and, as platers
spend a larger proportion of their working time at the tanks, there is a relatively higher risk of exposure. However, the
use of this method is declining because of the high costs associated with labour intensive processes. In semi-automatic
plating, parts are manually loaded on to jigs and then the operator moves the jigs between the baths using an overhead
hoist in a predetermined sequence. The operator usually stands on a platform by the side of the plating line. This
method usually results in lower exposure than manual plating as the operators can distance themselves from the plating
solutions for large amounts of time. The main difference between automatic and semi-automatic plating is that the
movement of the jigs is controlled electronically in automatic plating and therefore the operator spends very little time
near the plating solutions, except when there is a problem with the process. From the listed processes it has to be
expected that workers within the overall scenario may not have similar tasks. As an effort to identify tasks (subscenarios) with high risk of exposure the available data on exposure were summarized in one table and tabulated by
sub-groups of workers with similar tasks. Such listing was kept within a given set of data (study) and no attempt was
made to join similar tasks cross data sets. The reason not to join similar tasks cross data sets was that prior to the
collapse of data sets a statistical analysis is required for identity of data sets in terms of type of statistical distribution,
mean and variance. The data for the assessment were not available in details to allow such statistical analysis.
Soluble nickel predominates in electroplating shops, but there is some evidence to suggest that lesser amounts of
relatively less soluble nickel compounds may be present under some circumstances. Tsai et al. (1996a) reported data on
exposure to inhalable aerosols for two electroplating shops (A and B) in North America. Some of the samples were
analysed for content of four groups of nickel species and the reported data are summarized below (Table 4.1.1.2.3.2.A).
Consistently Kiilunen et al. (1997b) reported that soluble nickel predominated the occupational exposure in Finnish
electroplating shops (Table 4.1.1.2.3.2.B). For a specific electroplating shop in Finland Tola et al. (1979) reported that
most of the airborne nickel was in the form of soluble nickel sulphate, but the observation was not supported by detailed
data.
Table 4.1.1.2.3.2.A: Nickel speciation data for inhalable aerosols collected from two electroplating shops (A
and B) in North America (Tsai et al., 1996a).
Shop
Exposure level (μg/m3)
N
Soluble
(SO)
Sulfidic
(SU)
Oxidic
(O)
Nickel speciation (%)
Metallic Soluble
(M)
1
Sulfidic 2 Oxidic 3 Metallic 4
Insoluble 5
A
12
68.9
0.98
4.6
1.8
90
1.3
6.0
2.4
10
B
11
8.7
1.4
2.0
1.6
64
10
15
12
36
1: Estimated as SO/(SO+SU+O+M). 2: Estimated as SU/(SO+SU+O+M); 3: Estimated as O/(SO+SU+O+M); 4: Estimated as
M/(SO+SU+O+M); 5: Estimated as (SU+O+M)/(SO+SU+O+M)
Table 4.1.1.2.3.2.B: Nickel speciation data for aerosols collected in Finnish electroplating shops (Kiilunen et
al., 1997b)
Job
N
Plating tank workers
NA1
Plating tank area
1
Type of sampler Aerosol fraction
Personal 2
Static
3
Concentration of
‘total’ Ni (μg/m3)
Soluble Ni
(%)
‘Total’
0.5
30 - ~100
‘Total’
0.05
60
66
Plating tank area
‘Near’ a Ni-bath
Maintenance
Electroplaters
‘Near’ nickel baths
Plating tank area
1
Static 3
1
3
1
6
NA
NA
Static
‘Total’
0.2
25
‘Total’
26
~ 100
Personal
2
‘Total’
0.7
80
Personal
2
‘Total’
5.6-78.3
18 – 90
Static
3
‘Total’
73.3
~ 90
Static
3
‘Total’
12-18
~ 90
1: Not available.
2: 37-mm filter cassette (presumably closed face).
3: 37-mm filter cassette (presumably closed face) operated at 20 l/min.
For the assessment a typical aerosol composition in terms of nickel species was estimated as given in Table
4.1.1.2.3.2.C. In terms of exposure to soluble nickel the data provided by Kiilunen et al. (1997b) was considered a
worst-case.
Table 4.1.1.2.3.2.C: Estimation of typical and worst-case nickel speciation of aerosols collected in
electroplating. The data are given as a percentage of ‘total’ airborne nickel.
Ref.
Comment
Tsai et al., 1996a
Kiilunen et al.,
1997b
‘Typical’ nickel
speciation
‘Worst’ case
speciation***
Soluble
Insoluble
Metal
Oxidic
Sulfidic
Shop A
90
~10*
2.4
6.0
1.3
Shop B
64
~36*
12
15
10
30-~100
~0-70
-
-
-
Plating tank area
60
40
-
-
-
Plating tank area
25
75
-
-
-
~100
~0
-
-
-
Maintenance
80
20
-
-
-
Electroplaters
18-90
10-82
-
-
-
‘Near’ Ni-baths
~90
~10
-
-
-
Plating tank area
~90
~10
-
-
-
~70**
~30**
(2.4+12)/2~10
(6.0+15)/2~15
(1.3+10)/2~5
100
0
0
0
0
* Estimated as ‘Metal’+’Oxidic’+’Sulfidic’. **Estimated as the median of the listed data ***In terms of exposure to soluble nickel
the speciation data for plating tank workers provided by Kiilunen et al. (1997b) were considered a worst-case.
Current data (Table 4.1.1.2.3.2.D) on occupational exposure were obtained from industry and the literature. If possible
data are listed using the format of the specific company data submission scheme i.e. year(s) of measurement(s), number
of samples, range, median and 95th percentile value. It is noted that the vast majority of the data sets were given in terms
of full-shift time weighted averages. Thus the listed data are considered full-shift exposure. The information available
on the sampling technique and aerosol fraction is included in the listed data. Most of the data sets available for the
assessment were collected by a strategy of personal sampling. A few data sets were collected by an approach of static
sampling. It is well known (see section 4.1.1.2.1.2) that data from static sampling may not be valid for an estimate of
personal exposure. Thus data from static sampling were excluded from the assessment. A few data sets were collected
by an approach of personal/static sampling and such sets entered the assessment as a compromise. One large data set
(Stamm et al., 1998) had no information on the sampling strategy and the data were excluded from the assessment.
Exposure measured in terms of the ‘total’ aerosol fraction was converted to the inhalable fraction by factors of 3.0 (37mm/25-mm open or closed face cassettes) and 1.17 (25-mm seven hole sampler). For the scenario it appears that current
exposure to ‘total’ nickel (‘total’ aerosol fraction) ranged from a median or mean level of 0.4 μg/m3 to 120 μg/m3. In
67
terms of the inhalable aerosol fraction current exposure ranged (21 datasets; more than 426 observations) from a median
or mean level of 1.2 μg/m3 to 350 μg/m3, and the median of the median or mean levels was 21.5 μg/m3 ≈ 25 μg/m3
(typical exposure level). A median exposure at such level was seen for a large data set (22 observations) of a sub-group
of workers with the task of jiggers.
sets with an emphasis on the size of the data sets, the medians and the year of sampling. In general a given data set
included the range of observations. The upper limit of the range was used for ranking the data sets, and all data sets
(sub-scenarios) at or above the 90th percentile were considered important for the estimation of the reasonable worst-case
exposure. The 90th percentile of the available data sets (N=19) was ≈ 480 μg/m3 inhalable ‘total’ nickel. An upper limit
of exposure at this level was reported for a large data set (20 observations) of plating tank workers. The 95th percentile
of the data set was 420 μg/m3. A higher upper limit of exposure (2400 μg/m3) was reported for a large data set (102
observations) of workers with the task of electroplating. This data set had no information on the 95th percentile, but for
sub-groups of electroplaters the median exposure ranged from 1 μg/m3 to 240 μg/m3. The upper limit of the medians
(240 μg/m3) was below the 95th percentile of the data set on plating tank workers. The highest upper limit of exposure
(5400 μg/m3) was seen for a data set of workers with the task of electroplating. This data set had no information on the
number of samples, the median and the 95th percentile. Noting that the 95th percentile of the data set for plating tank
workers (420 μg/m3) was above the upper limit of the medians (240 μg/m3) for the large data set on electroplaters it
appears prudent to estimate the reasonable worst-case exposure from the data set on plating tank workers. The 95th
percentile (420 μg/m3 ≈ 400 μg/m3) of the data set was considered a rough estimate of the reasonable worst-case
exposure level. Data on short-term exposure to nickel seem unavailable, and it is difficult (if not impossible) to derive
an estimate on short-term exposure from data characterizing full shift exposure. For the risk assessment of zinc metal
(Netherlands Rapporteur, 1999) no data were available on short-term exposure and an estimate was derived as twice the
worst-case exposure level. A similar approach (‘expert judgement’) was taken for the present risk assessment. Thus the
short-term exposure was estimated at a level of 2×400=800 μg/m3.
For the scenario no data were available on the size distribution of aerosols in the workroom air. Perhaps electroplating
and electrowinning operations may be similar in terms of the size distribution of the aerosols in workroom air. If so the
aerosols in electroplating are rather coarse as most particles have a diameter (by count) above >5 μm (Kiilunen et al.,
1997a). The extrathoracic aerosol fraction was reported (Thomassen et al., 1999) to be responsible for the nickel
exposure experienced by the electrowinning workers at the Monchegorsk refinery in Russia. In contrast Werner et al.
(1999a) reported that approx. 40% of the inhalable nickel exposure in electrowinning was fine aerosols (thoracic and
respirable fraction).
68
Table 4.1.1.2.3.2.D: Electroplating - current exposure by inhalation of 'total' nickel.
Ref.
Process
N
Year
Type of
Sampler
Aerosol
Fraction
Range
Median
95th perc.
Range
Median
95th perc.
Tola et al., 1979
Bernacki et al.,
1978
Bernacki et al.,
1980
Ghezzi et al., 1989
UM Data*A
UM, 1995
Stamm et al., 1998
Oliveira et al., 2000
Kiilunen et al.
1997b
Electroplaters;
intermittent exposure
Electroplaters
20
11
NA
∼1978
Personal 1
Personal 1
‘Total’
30-160
807,8
1408
90-480
2407,8
4208
'Total'
0.04-2
0.8
NA
0.12-6
2.4
NA
15
∼1979
Personal 1
‘Total’
0.5-21
9.39
19
1.5-63
289
57
Electroless plating
Electroless plating
Electroplaters
Electroplaters
Plating tank area
Maintenance
‘Near’ the Ni-baths
Plating tank area
Electroplaters
23
29
26
340
NA
NA
2
1
1
6
NA
NA
41
∼1988
1993-1994
1993-1994
1989-1992
~1998
~1995
~1995
~1995
~1995
~1995
~1995
~1995
~1993
Personal 2
Personal 3
Personal 3
NA 4
Personal 1
Personal 2
Static 5
Static 5
Personal 2
Personal 2
Static 5
Static 5
Personal 1
'Total'
Inhalable
Inhalable
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
NA
NA
NA
NA
0.05-0.2
5.6-78
NA
12-18
0.1-42
4.2-197,10
2.0
2.8-1177,10
0.511
0.111
26
0.7
NA
7311
NA
2.37
NA
1012
NA
NA
NA
NA
NA
19.8
NA
1-37
8-180
NA
NA
17-230
0.3-130
13-577,10
10
59
8-3507,10
1.511
2.1
NA
6.97
NA
NA
NA
NA
NA
NA
59
Bavazzano et al.,
1994
Bright et al., 1997
9
9
Bath operators
34
~1994
Personal 6
‘Total’
5-93
26.59
NA
5.9-110
319
Jiggers
22
~1994
Personal 6
‘Total’
0.5-83
21.29
NA
0.6-97
259
Managers
4
~1994
Personal 6
‘Total’
0.5-6
2.69
NA
0.6-7.0
3.09
4
Warner, 1984
Sulphate bath, 45ºC
16
Pre 1984
Static
‘Total’
<5-<8
<6
NA
3
Static 4
‘Total’
<2-<7
<4
NA
6
Personal 4
‘Total’
<7-<16
<11
NA
6
Static 4
‘Total’
<2-<3
<3
NA
*: Data listed by NIPERA (1996). A: Including the data reported by Tsai et al. (1996a).
1: 37-mm closed face filter cassette. 2: 37-mm filer cassette (presumably closed face) operated at a flow rate of 3 l/min. 3: IOM-sampler. 4: unknown type of sampler. 5: 37-mm filter
cassette (presumably closed face) operated at 20 l/min 6: 25-mm filter seven-hole cassette. 7: geometric mean; 8: data estimated from graphs given by Tola et al. (1979). 9: arithmetic
mean; 10: range. 11: presumably the arithmetic mean. 12: 90th percentile.
NA
NA
NA
-
69
Table 4.1.1.2. 3.2.D: Electroplating - current exposure by inhalation of 'total' nickel (continued).
Range
Median
95th
Range
Median
95th
perc.
perc.
0.1-800
0.4-795,7
NA
0.3-2400
1.2-2405,7
NA
1-1800
NA
NA
3-5400
10-50
<236
NA
-
Ref.
Process
N
Year
Type of
Sampler
Aerosol
Fraction
Hery et al., 1990
Mahieu et al., 1990
EIS Data*
Electroplating
Electroplating
Electroless plating
102
NA
4
Personal 1
Personal/Static 2
Personal/Static 3
‘Total’
‘Total’
‘Total’
EIS-05, 1993
Electrolytic plating
4
Personal/Static 3
‘Total’
20-190
100
NA
-
-
-
HSE Data* HSE-02&
HSE Data* HSE -03&
HSE Data* HSE-15&
HSE Data* HSE-17&
HSE Data* HSE-28&
HSE Data* HSE-52&
HSE Data* HSE-53&
Bicknell et al. 1989
Electroplating
Electroplating
Electroless plating
Ancillary operations
Electro-arming
Electroplating
Electroforming
Electroforming
NA
6
10
159
39
NA
789
109
2
9
Personal/Static 4
Personal/Static 4
Personal/Static 4
Personal/Static 4
Personal/Static 4
Personal/Static 4
Personal/Static 4
Personal/Static 4
Personal 1
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
‘Total’
NA
NA
51-360
4-15
NA
1-100
1-70
13-19
3-51
Trace
106
1206
106
<1006
106
206,8
166
186
NA
NA
NA
NA
NA
NA
NA
NA
NA
3-210
9-150
606,8
546
NA
Daniels & Gunter 1987
Daniels et al., 1988
Mortimer, 1982
HSE Data§ A
NA
NA
NA
Electroplating
7
10
4
50
Personal/Static 1
Personal/Static 1
Personal 1
Personal/static 3
‘Total’
‘Total’
‘Total’
‘Total’
<1-4.5
<1-39
3-6
1-80
2.55
66
46
8.65
NA
NA
NA
50
<3-13
<3-120
9-18
-
7.55
186
126
-
NA
NA
NA
-
HEDSET, Data from 40
different German shops A
HEDSET, Comp #1 A
Electroplaters
60
Pre-1990
1990
19911993
19911993
1985
1985
1985
1985
1985
1985
1985
1985
19871988
1986
1987
1982
19891999
NA
Personal 3
'Total'
-38
2.55
13
-
-
-
Electroplaters
6
Personal 1
‘Total’
9-30
225
NA
27-90
665
NA
HEDSET, Comp #2 A
Electroplaters
2
Personal 1
‘Total’
3-45
245
-
9-140
725
-
19911996
1976
*: Data listed by NIPERA (1996). &: UK HSE provided the data from its NEDB (National Exposure Data Base). §: UK HSE’s NEDB. A: data listed in the Risk Assessment Report on
nickel metal.
1: 37-mm closed face filter cassette. 2: 37-mm filer cassette (open and closed face). 3: unknown type of sampler. 4: 25-mm closed face filter cassette (personal sampling) and unknown
type of static sampler. 5: geometric mean. 6: arithmetic mean; 7: range. 8: mean based upon personal sampling. 9: The number of observations was estimated from the arithmetic mean
and the range using the approach given by Vincent and Werner (2003).
70
If the electrolyte is agitated vigorously by air bubbles nickel sulphate in the form of mist is generated from bursting
bubbles. At present stage EASE does not allow modelling of exposure to mist generated from bursting bubbles. The
task of plating tank workers may include many specific operations such as the preparation of solutions. The preparation
may involve manipulation of dry nickel sulphate and such an operation was considered useful for modelling. Thus the
typical and the reasonable worst-case exposures were modelled for this task. Any manipulation of a dry material enters
material to aggregate. No data are available on the tendency of crystallized nickel sulphate to aggregate, and the
chemical was considered non-sticky (aggregate is false).
Model input:
Solid-vp is false
Aggregates is false
Model output:
Model input:
Model output:
The predicted typical exposure level is rather close to the measured data as listed in Table 4.1.1.2.3.2.D, while the
reasonable worst-case exposure is high. The measured data provide more detailed information than the EASE model,
and the measured data are used for the assessment. Considering the assessed data on nickel species in workroom air
(Table 4.1.1.2.3.2.C) current exposure to groups of nickel species is estimated as listed below (Table 4.1.1.2.3.2.E).
Table 4.1.1.2.3.2.E: Estimated exposure by inhalation of groups of nickel species in electroplating.
Nickel
Species
Typical exposure
Worst-case exposure
Shortterm
exposure
(μg/m3)
Nickel species
as % of ‘total’
nickel
Exposure to
inhalable
‘total’ nickel
(μg/m3)
Exposure to
inhalable
nickel
species
(μg/m3)
SO
70
25
~18
100
400
400
800
U
30
25
7
≈0
400
≈0
≈0
(1)
Nickel
Exposure to
species as %
inhalable
of ‘total’
‘total’ nickel
nickel
(μg/m3)
Exposure to
inhalable
nickel
species
(μg/m3)
71
Bavazzano et al. (1994) performed a study on hand and facial contamination in 41 male subjects employed in
electroplating operations in 25 small factories in Italy. Male subjects (N=15) non-professionally exposed to nickel
served as control subjects. In most cases the sub-group of electroplating workers performed manual dipping operations
(no automation) and local exhaust systems were operated on the electroplating tanks. No information was given on the
use of personal protective equipment such as gloves. The data provided by Bavazzano et al. (1994) are considered valid
for the assessment of dermal exposure in electroplating operations.
Table 4.1.1.2.3.2.F: Measured* dermal exposure to nickel in electroplating operations (Bavazzano et al.,
1994).
Percentiles
Electroplaters (N=41)
Control subjects (N=15)
Facial
contamination
(μg/day)
Contamination of the
hands (μg/day)
Facial
contamination
(μg/day)
Contamination of the
hands (μg/day)
5
1.1
5.6
-
-
50
9.0
39
0.79
0.30
95
60
370
-
-
1.0-86
1.9-550
0.01-5.3
Range
0.01-2.4
2
*Samples were taken by wiping worker’s hands and face with a paper filter (10×10 cm ) moistened with benzalconium chloride
1:750 and alcohol 20%. The surface area measured in the study was quite high since the exposure of both hands and fingers were
included. Sampling was performed at the end of the work shift.
The drag-out of articles from the baths is a common task in electroplating. Thus the typical and the reasonable worstcase exposures were modelled for this task. The drag-out is carried out by a sub-group of workers with the knowledge
of the process. For input to the EASE model such practice is characterized as non-dispersive use. For the modelling it is
assumed that the workers handles all materials directly. For input to the EASE model such method of production is
characterized as direct handling.
The level of process activity may be low and 2-10 events per day was assumed. For input to the EASE such level of
activity is characterized as intermittent level of contact.
Model input:
Mobile-solid is true
Solid-vp is false
The contact-level is intermittent
Model output:
Conclusion: The predicted dermal exposure to nickel sulphate is 0.1-1 mg/cm2/day
Except for the type contact level model input was kept identical to the input for estimation of the typical exposure level.
The drag-out of articles was assumed being an extensive process (more than 10 events per day). For input to the EASE
such level of activity is characterized as an extensive level of contact.
Model input:
The contact-level is extensive
Model output:
Conclusion: The predicted dermal exposure to nickel sulphate is 1-5 mg/cm2/day
72
On condition that the palms of both hands are exposed (420 cm2) the estimated typical exposure level ranged from 42
mg/day to 420 mg/day, while the reasonable worst-case exposure level ranged from 420 mg/day to 2100 mg/day.
Compared to the measured data (Table 4.1.1.2.3.2.F) the predicted exposure level was high by several orders of
magnitude. The measured data were obtained by an approach of wipe sampling. Such a method is well known in
characterizing the contamination of surfaces including the skin. It has to be noted than skin wipes may not collect all of
the contaminant deposited on the worker’s skin during exposure. As pointed out by McArthur (1992) the mass of
material that has penetrated into the epidermis during exposure may not be recovered and for such cases the quantity of
contaminant remaining on the skin is excluded from the exposure estimates. The sampling efficiency in wiping settled
dust from a range of non-specified types of solid surfaces was as a rough estimate reported at a level of 50%, but the
degree of precision was considered low (Lichtenwalner, 1992). By contrast to wipe sampling from solid surfaces it
appears prudent to assume a low efficiency in sampling from the skin, but no data are available to estimate the bias of
dermal exposure as estimated from wiping. Thus the dermal exposure data reported by Bavazzano et al. (1994) should
be considered biased towards low levels. As already mentioned the Bavazzano study has no details on the use of gloves.
Thus the data might characterize a sub-group of workers at low risk of exposure by the use of gloves. It is emphasized
that no information is available for testing the validity of such hypothesis. The EASE model is only intended to give
generalized exposure data while the measured data provided by Bavazzano et al. (1994) were specific for electroplating.
Although the bias of the Bavazzano study remains unknown the reported data are taken forward to the risk
characterization. On condition the contaminants deposited on the skin have a content of nickel species similar to the
airborne dust (Table 4.1.1.2.3.2.C) the typical (50th percentile) and worst-case (95th percentile) dermal exposure of the
hands to nickel sulphate is estimated as given below. These levels can be used in risk characterization comparison with
acute toxicity data.
Nickel
species (1)
Typical exposure 2
Worst-case exposure 2
Nickel species
as % of ‘total’
nickel
Exposure to
‘total’ nickel
(μg/day)
Exposure to
nickel
species
(μg/day)
Nickel species as %
of ‘total’ nickel
Exposure to
‘total’ nickel
(μg/day)
Exposure to
nickel species
(μg/day)
SO
70
39
27
100
370
370
U
30
39
12
0
370
0
2: The exposure is given for both hands, including the fingers and back of the hands. The mean surface area of the hands should be
used to estimate the amount of nickel per square centimetre of the skin. For a man, the average is 840 cm2 (US EPA, 1997). Thus,
the worst-case exposure would be 0.44 µg Ni/cm2/day and the typical exposure would be 0.046 µg Ni/cm2/day for soluble and other
nickel species.
‘total’ nickel in electroplating operations. An emphasis was made to assess exposure in terms of inhalable aerosols.
However, a few data sets did not specify sufficient details on sampling methods to allow ‘total’ aerosols to be converted
to inhalable aerosols. The data available on groups of nickel species in workroom indicated that nickel species are not
uniform among electroplating shops. Nevertheless an estimate was made for a typical and a worst-case nickel
speciation, but the validity of the estimated data remains unknown. The estimated exposure to soluble nickel includes
all soluble nickel salts as no speciation data were available on soluble salts. Thus the estimated exposure to soluble salts
is considered worst-case exposure to nickel sulphate. TERA (1999) reviewed the toxicology of soluble nickel salts and
on basis of the data on occupational exposure provided by NIPERA (1996) it was concluded that the median exposure
by inhalation of soluble nickel salts was about 20 μg/m3 in electroplating operations. The present estimate of the typical
exposure was at a level rather similar to the TERA-estimate. It is noted that electroplating operations may involve
exposure by inhalation to sulphuric acid at concentrations ranging from 0.01 to 7.6 mg/m3 for chromium plating (IARC,
1992).
Some measured data specific for dermal exposure in electroplating operations were available. Compared to the
modelled (EASE) exposure the measured data were low by several orders of magnitude. It is recognized that the
measured data are biased at unknown extent towards low exposure levels. The EASE model is only intended to give
generalized exposure data while the measured data were specific for electroplating. Thus the measured data are taken
forward to the risk characterization. As a first approximation nickel speciation of contaminants deposited on the skin
73
was assumed to be similar to the speciation of the aerosols in workroom air, but it has to be emphasized that no data
were available for validation of such an approach. Personal protective equipment is a common approach to reduce
dermal exposure in electroplating operations. However, contamination of the protective gear is almost impossible to
avoid (Wall & Calnan, 1980). Thus an additional risk of exposure caused by contaminated personal protective
equipment cannot be excluded. In conclusion the estimated levels of exposure to groups of nickel species are
summarized below.
Nickel species
(1)
Dermal exposure
(mg/day)
Typical
Worst-case
Short term
Typical 2
Worst-case 2
SO
18
400
800
0.027
0.37
U
7
~0
~0
0.012
0
1: SO = Soluble nickel salts considered to be all nickel sulphate (worst-case); U = Other nickel species than soluble nickel.
2: The exposure is given for both hands, including the fingers and back of the hands. The mean surface area of the hands should be
used to estimate the amount of nickel per square centimetre of the skin. For a man, the average is 840 cm2 (US EPA, 1997). Thus,
the worst-case exposure would be 0.44 µg Ni/cm2/day and the typical exposure would be 0.046µg Ni/cm2/day for soluble and other
nickel species.
4.1.1.2.3.3
Scenario B3 – Production of catalysts
Nickel is an important hydrogenation catalyst because of its ability to chemisorb hydrogen. The feedstock and unit
operations of the processes for making catalysts are as various as the different catalyst products themselves. Commonly,
however, catalyst production utilizes feedstock such as nickel metal, finely divided Raney nickel, nickel nitrate crystals
or solutions, nickel carbonate pastes or solutions, and nickel oxide. Production processes are described in chapter
2.2.1.3. More detailed descriptions are given in chapter 2.2.1.5.2 and with additional information shown in Appendix
7.7. of the risk assessment report for nickel metal.
Personal exposure to catalyst aerosols may occur at different operations including catalyst manufacturing, on-site
catalyst handling operations including charging/discharging operations, and treatment of spent catalyst. From the listed
processes it has to be expected that workers within the overall scenario may not have similar tasks. As an effort to
analysis.
Data on nickel species in the production of catalysts are sparse. In the early 1980s Warner (1984) reported
comprehensive data on occupational exposure to airborne nickel in producing and using primary nickel products. The
data included information on exposure by inhalation of ‘total’ and soluble nickel in the catalyst production from nickel
sulphate. The measured concentrations are listed below (Table 4.1.1.2.3.3.A). As a percentage of exposure to ‘total’
nickel the data indicate that exposure to soluble nickel ranged from 1 % to ~6 %. For the assessment the median (3.5 %)
is considered typical while the upper limit of the range (~6 %) is considered a worst-case.
Table 4.1.1.2.3.3.A: Nickel speciation data for aerosols collected in catalyst production from nickel sulphate
(Warner, 1984).
Type of
sampler
Personal A
Static
A
Exposure level (μg/m3)
N
Soluble nickel
Nickel speciation (%)
Other nickel species than soluble
nickel
Soluble
nickel 1
Insoluble
nickel 2
Range
Average
(SO)
Range
Average (U)
NA B
2-9
3
12-160
52
5.8
94.2
B
1-7
3
13-1200
290
1.0
99.0
NA
74
A: type of dust sampler not specified. B: not available.
1: Estimated as SO/(SO+U). 2: Estimated as U/(SO+U).
It has to be noted that the European Catalyst Manufactures Association (ECMA) has provided comprehensive data on
occupational exposure by inhalation of nickel during catalyst production (Delabarre, 1989). In general data were given
in terms of ‘total’ nickel but Delabarre (1989) did compare workers exposed to soluble nickel compounds to workers
exposed to insoluble nickel compounds (Table 4.1.1.2.3.3.B). Unfortunately the two groups of data were not collected
from similar environments so the soluble nickel fraction cannot be estimated as a percentage of ‘total’ nickel.
Table 4.1.1.2.3.3.B: Exposure by inhalation of soluble and insoluble nickel in catalyst production
(Delabarre, 1989)
N
Workers exposed to soluble nickel
Workers not exposed to soluble nickel
34
49
Type of
sampler
Exposure to nickel (μg/m3)
Range
Mean 2
1986-87
Personal 1
<10-1560
20
1986-87
1
<10-1740
250
Year
Personal
1: the seven-hole sampler. 2: geometric mean.
4.1.1.2.3.3.2 Exposure by inhalation – measured exposure levels.
Current data on exposure were obtained from industry and the literature. The risk assessment report for nickel metal has
a section for a scenario on the production of nickel catalysts. That section holds comprehensive data on exposure by
inhalation of ‘total’ nickel in the production of nickel catalysts. Data sets considered useful for the present scenario
were extracted from the risk assessment on nickel metal. Data for the scenario were tabulated (Table 4.1.1.2.3.3.C) by
sub-groups of workers with similar tasks. If possible data are listed using the format of the specific company data
submission scheme i.e. year(s) of measurement(s), number of samples, range, median and 95th percentile value. It is
noted that the vast majority of the data sets were given in terms of full-shift time weighted averages. Thus the listed data
are considered full-shift exposure. The information available on the sampling technique and aerosol fraction is included
in the listed data. Most of the data were collected by an approach of personal sampling. A few data sets included data
obtained by static sampling. It is well known (see section 4.1.1.2.1.2) that data collected by static sampling may not be
valid for an estimate of personal exposure. Thus data by static sampling were excluded from the assessment given
below. As a compromise data collected by personal/static sampling entered the assessment. Exposure measured in terms
of the ‘total’ aerosol fraction was converted to the inhalable fraction by a factor of 2.5 (37-mm/25-mm open or closed
face cassettes) as recommended for dust by Werner et al. (1996). A factor of 1.17 was used for the seven-hole sampler.
The powders used in catalyst manufacturing are likely to be ’fine’. As mentioned above (section 4.1.1.2.1.2) the smaller
the particles, the smaller the conversion needed to convert ’total’ dust to inhalable dust. The factor 2.5 is close to the
factors listed above (Table 4.1.1.2.1.2.B) for mining, milling, smelting, refining, nickel alloy production, and
electroplating. No specific conversion factor is available for catalyst manufacturing and the factor of 2.5 recommended
for dust by Werner et al. (1996) is used as a rough estimate. It is recognized that such an approach may bias the
estimated exposure to inhalable dust towards high levels.
For the scenario it appears that current exposure to ‘total’ nickel (‘total’ aerosol fraction) ranged from a median or mean
level of 4 μg/m3 to 11600 μg/m3. The upper limit was seen for a small data set (2 observations) for workers with the
task of reactor off loading. One of the observations was taken as a personal sample while the other one was collected by
static sampling. In terms of the inhalable aerosol fraction current exposure ranged (13 datasets; 388 observations) from
a median or mean level of 70 μg/m3 to 1700 μg/m3, and the median of the median or mean levels was 94 μg/m3 ≈ 100
μg/m3 (typical exposure level). A median exposure of 94 μg/m3 was reported for a large data set (48 observations) of
workers with the task of catalyst production.
sets with an emphasis on the size of the data sets, the medians and the year of sampling. In general a given data set
75
included the range of observations. The upper limit of the range was used for ranking the data sets, and all data sets
(sub-scenarios) at or above the 90th percentile were considered important for the estimation of the reasonable worst-case
exposure. The 90th percentile of the available data sets (N=13) was 4400 μg/m3 inhalable ‘total’ nickel. An upper limit
of exposure at this level was reported for a large data set (127 observations) of a sub-group of workers with the task of
catalyst production. It is noted that the median of the data set was rather low (70 μg/m3). An even higher upper limit
(5300 μg/m3) was reported for a small data set (5 observations) of workers with the task of reprocessing spent catalyst
from an oil refinery. It has to be noted that the mean exposure for this small group was high (1700 μg/m3). None of the
two data sets mentioned had information on the 90th or 95th percentiles. Taking the size of the two data sets into
consideration it appears prudent to put emphasis on the large data set. The upper limit of exposure for this data set was
considered as a rough estimate of the 90th percentile. Thus the reasonable worst-case exposure was estimated at a level
of 4400 μg/m3. Data on short-term exposure to nickel seem unavailable, and it is difficult (if not impossible) to derive
an estimate on short-term exposure from data characterizing full shift exposure. For the risk assessment of zinc metal
(Netherlands Rapporteur, 1999) no data were available on short-term exposure and an estimate was derived as twice the
reasonable worst-case exposure level. A similar approach (‘expert judgement’) was taken for the present risk
assessment. Thus the short-term exposure was estimated at a level of 2×4400=8800 μg/m3. For the scenario no data
were available on the size distribution of aerosols in the workroom air.
76
Table 4.1.1.2.3.3.C: Catalyst production – current exposure by inhalation of ‘total’ nickel.
Ref.
Process
N
Year
Type of
Sampler
Aerosol
Fraction
Warner, 1984
Ni-catalyst production from nickel
sulphate
Ni-catalyst production from nickel
sulphate
Ni-catalyst production - routine and nonroutine operations
7
NA**
Static 1
‘Total’
Range
Median 95th perc.
Range
Median 95th perc.
5
10-600
150
NA
25-1500
3805
NA
5
NA
Personal 1
'Total'
190-530
3705
NA
480-1300
9305
NA
47
2000
Personal/Static
‘Total’
10-380
48
220
12-450
58
260
Personal/Static
‘Total’
10-240
38
160
12-290
46
190
HEDSET Comp. #1
2+
59
2001
2+
HEDSET Comp. #5
NA
NA
Static 4
‘Total’
<0.4
NA
NA
-
-
-
NA
NA
NA
'Total'
13-67
NA
NA
-
-
NA
127
Personal 2
‘Total’
<10-3790
606
NA
<12-4400
706
NA
Personal 2
'Total'
<10-1740
806
NA
<12-2000
946
NA
10
19851986
19861987
~1992
Personal 3
'Total'
9-55
295
NA
23-140
735
NA
11
~1992
Personal 3
'Total'
10-820
1105
NA
25-2100
2805
NA
14
~1992
Personal 3
'Total'
5-950
1405
NA
13-2400
3505
NA
16
~1992
Personal 3
'Total'
<5-180
295
NA
<13-450
735
NA
16
~1992
Personal 3
'Total'
<5-97
415
NA
<13-240
1005
NA
5
~1992
Personal 3
'Total'
100-2100
6705
NA
250-5300
17005
NA
11
~1992
Personal 3
'Total'
<5-150
345
NA
<13-380
855
NA
19
~1992
Personal 3
'Total'
<5-880
755
NA
<13-2200
1905
NA
11
58
34
1986
1985
19901993
19901993
Static 3
Static 4
Personal/Static 4
’Total’
’Total’
’Total’
4-290
150-580
<1-260
485
3305
2707
NA
NA
NA
10-730
1205
NA
Personal/Static 4
’Total’
-
6805
-
-
Ni-catalyst production from nickel metal,
nickel sulphate and nickel dichloride
Reworking spent nickel catalyst with
sulphuric acid
Catalyst production
Delabarre, 1989
Catalyst production
48
Hery et al., 1994
Catalyst (cobalt oxide and molybdenum
oxide on alumina) discharge from diesel
fuel hydrodesulphurization reactor
Reprocessing of spent catalyst from an oil
refinery – stripping of catalyst
refinery – sulphur removal, unit 1
refinery – incineration, unit 1
refinery – incineration, unit 2
refinery – presulphidation of catalysts
Catalyst prod, from Ni oxide powder
Reacting spent catalyst with sulphuric acid
Misc, duties in catalyst prod.
Davies, 1986
Almaguer, 1987
HSE-20, 1985*&
EIS-02, 1993*
Misc duties
1
77
1990Personal/Static 4
’Total’
870-22000
116007
NA
1993
EIS-11, 1993*
Granulating
4
1990Static 4
’Total’
1700-25600
89005
NA
1992
Compacting
2
1984Static 4
’Total’
4400-7300
58005
NA
1987
Milling
2
1987
Static 4
’Total’
1100-1400
13005
NA
4
Mixing
2
1987Static
’Total’
480-900
6905
NA
1989
Tabletting
5
1987Static 4
’Total’
90-1600
6905
NA
1992
Others
6
1987Static 4
’Total’
37-3700
11005
NA
1992
EIS-14, 1993*
Production (all aspects)
170
1985
Personal/Static 4
‘Total’
1-24
45
NA
Operator/supervisor/maintenance
19
1985
Personal/Static 4
’Total’
1-26
55
NA
*: Data listed by NIPERA (1996). **: Not available. &: UK HSE provided the data from its NEDB (National Exposure Data Base). A: converted from ‘total’ nickel by a guessed factor
of 2.5. +: Presumably.
1: 37-mm open face filter cassette. 2: the seven-hole sampler. 3: 37-mm closed face filter cassette. 4: type of sampler not specified. 5: arithmetic mean. 6: geometric mean. 7: weighted
average. 8: The number of samples was estimated from the arithmetic mean and the range using an approach given by Vincent and Werner (2003).
Reactor off loading
2
78
For the assessment packaging of catalysts was considered a common task. Thus the typical and the reasonable worstcase exposures were modelled for this task. Any manipulation of a dry material enters the EASE model by the term ‘dry
manipulation’. To model the exposure EASE requires input on the tendency of a material to aggregate. No data are
available on the tendency of a catalyst to aggregate, and a catalyst was considered non-sticky (aggregate is false).
Model input:
Solid-vp is false
Aggregates is false
Model output:
Model input:
Except for the type of operation and the pattern-of-control model input was kept identical to the input for estimation of the typical
exposure level. The type of operation was specified as dry manipulation (includes any manipulation, also dry brushing) and the
pattern-of-control was specified as no local exhaust ventilation.
Model output:
The predicted typical exposure levels are rather similar to the measured exposure levels as tabulated in Table
4.1.1.2.3.3.C. The measured data provide more detailed information than the EASE model, and the measured data are
used for the assessment. Considering the assessed data on nickel species in workroom air (Table 4.1.1.2.3.3.A) current
exposure to groups of nickel species is estimated as listed below (Table 4.1.1.2.3.3.D).
Table 4.1.1.2.3.3.D: Estimated exposure by inhalation of groups of nickel species in catalyst production.
Nickel
Species
Typical exposure
Worst-case exposure
Shortterm
exposure
(μg/m3)
Nickel species
as % of ‘total’
nickel
Exposure to
inhalable
‘total’ nickel
(μg/m3)
Exposure to
inhalable
nickel
species
(μg/m3)
SO
3.5
100
4
6.0
4400
≈250
500
U
96.5
100
~100
94
4400
≈4200
8400
(1)
Nickel
Exposure to
species as %
inhalable
of ‘total’
‘total’ nickel
nickel
(μg/m3)
Exposure to
inhalable
nickel
species
(μg/m3)
No measured data for dermal exposure to nickel seem available for the assessment. Hughson (2004) did a study on
dermal exposure in the packing of nickel sulphate at a chemical plant producing nickel sulphate and nickel
hydroxycarbonate. Since nickel sulphate crystals are used as feedstock for catalyst production, nickel sulphate packing
data would provide the worst-case exposure data for this scenario until measured data is available. Thus the dermal
exposure is estimated at the levels tabulated below. Further details of the estimated data are given above (section
4.1.1.2.2.1.4 and 4.1.1.2.2.1.5).
79
Nickel species
Typical exposure
2
μg/cm2/day
mg/day 1
1.2
1.0
2.0
0.8
0.7
1.4
0.4
0.4
0.8
μg/cm /day
mg/day
Total nickel
0.6
Soluble nickel
0.4
Insoluble nickel
0.2
2
2
1
2
Data from literature were available on exposure by inhalation of ‘total’ nickel. An emphasis was made to assess
exposure in terms of inhalable aerosols, and it is noted that a guessed factor was used to convert some recent large data
sets from ‘total’ to inhalable nickel. It is recognized that such an approach may bias the exposure towards high levels,
and it is not possible to quantify the bias. No recent data on nickel species in workroom air were available and, as an
alternative, speciation data reported in the 1980s were used for the assessment. Such an alternative may appear
reasonable on the condition that no major changes in technology have taken place since the 1980s. The estimated
exposure to soluble nickel includes all soluble nickel salts as no speciation data were available on soluble salts. Thus the
estimated exposure to soluble salts is considered worst-case exposure to nickel sulphate.
For the catalyst production from nickel sulphate no data were available on dermal exposure to nickel sulphate, and the
exposure was estimated by two approaches, (i) by analogy to measured dermal exposure in nickel sulphate production
from nickel matte and (ii) by modelling. The measured data focused on nickel compound packing operations (scenario
A1). The predicted exposure level was much higher than the levels estimated from measured data. However, the
predicted exposure levels produced by EASE are intended to be estimates of potential exposure and do not therefore
take into account the attenuating effect of gloves and other protective clothing. For the catalyst production from nickel
sulphate the highest exposure to nickel sulphate is expected to be during packing of the catalyst. Thus it appears prudent
to take the data obtained by analogy forward to the risk characterization. In conclusion the estimated levels of exposure
to nickel species are summarized below.
Nickel species
(1)
Dermal exposure
(mg/day)
Typical
Worst-case
Short term
Typical
Worst-case
SO
4
250
500
0.8
1.4
U
100
4200
8400
0.4
0.8
4.1.1.2.3.4
Scenario B4 - Nickel sulphate used in the production of chemicals
Hughson (2004) reported exposure by inhalation of nickel at a chemical plant using nickel sulphate solution to produce
nickel sulphate hexahydrate and nickel hydroxycarbonate. The dust was analysed for the content of soluble and
insoluble nickel. The reported data are listed above (section 4.1.1.2.3.4.2). As a percentage of total nickel the dust had a
content of soluble nickel ranging from 50% to 73%. The median of the data is considered a typical content of soluble
nickel (≈60%), while a content of 100% is considered a worst-case situation. For the exposure assessment soluble nickel
is considered to be all nickel sulphate (worst-case).
Hughson (2004) measured exposure by inhalation of soluble and insoluble nickel at a chemical plant that used nickel
sulphate solution to produce nickel sulphate hexahydrate and nickel hydroxycarbonate. The chemical reactions and
transfer of compounds to the packing area was entirely automatic and completely enclosed. The study focused on
80
workers operating the packing equipment and further details of the tasks are given above (section 4.1.1.2.2.1.4). The
reported data are listed below.
Table 4.1.1.2.3.4.A Scenario B4: Production of chemicals – current exposure to soluble and insoluble nickel
(Hughson, 2004).
Ref
Process2
N Year
Exposure to nickel
μg/m 3
Type of Aerosol
sampler fraction
Range
Hughson,
2004
Packing Ni
Carbonate
4 20032004
Personal Inhalable
Packing Ni
Sulphate
4 20032004
Personal Inhalable
90th percentile
Median
1-41
SO1
6
SO
41
SO
1-20
U
3
U
20
U
2-11
SO
4
SO
11
SO
2-4
U
3
U
4
U
1: SO = Soluble nickel considered to be all nickel sulphate (worst case). U = Other nickel species than soluble nickel.
2: The two different processes noted are the specific job of the workers but the jobs occur in the same work area and workers rotate
between these processes so exposure are a combination of both processes.
The RAR on nickel metal has a scenario (C5) for nickel metal in the production of nickel containing chemicals. That
scenario covers an enormous range of processes and the typical exposure to total nickel for the scenario was estimated
at levels ranging from 6 μg/m3 to 450 μg/m3, while the worst exposure was estimated to be 7000 μg/m3. The Hughson
(2004) data indicate an exposure rather similar to the lower limit of the typical exposures estimated for scenario C5 in
the RAR on nickel metal. The data set reported by Hughson (2004) is rather small and the data may not reflect exposure
to nickel for the enormous range of processes covered by the scenario. Thus it appears prudent to estimate the exposure
for the scenario by analogy to scenario C5 in the RAR for nickel metal. It is recognized that the validity of the analogy
remains unknown.
For the assessment packaging of nickel chemicals was considered a common task. Thus the typical and the reasonable
worst-case exposures were modelled for this task. Any manipulation of a dry material enters the EASE model by the
term ‘dry manipulation’. To model the exposure EASE requires input on the tendency of a material to aggregate. No
data are available on the tendency of a nickel chemical to aggregate, and a chemical was considered non-sticky
(aggregate is false).
Model input:
Solid-vp is false
Aggregates is false
Model output:
Model input:
81
Except for the type of operation and the pattern-of-control model input was kept identical to the input for estimation of the typical
exposure level. The type of operation was specified as dry manipulation (includes any manipulation, also dry brushing) and the
pattern-of-control was specified as no local exhaust ventilation.
Model output:
The predicted typical exposure levels are rather similar to the exposure levels estimated by analogy to scenario C5 in
the RAR on nickel metal. The measured data of scenario C5 provide more detailed information than the EASE model,
and the data from scenario C5 are used for the assessment. Current exposure to groups of nickel species is estimated as
listed below (Table 4.1.1.2.3.4.B).
Table 4.1.1.2.3.4.B: Estimated exposure by inhalation of nickel in the production of chemicals.
Nickel
Species (1)
Typical exposure
Short-term
exposure
(mg/m3)
Worst-case exposure
Nickel
Exposure to Exposure to
Nickel
Exposure to
species as
inhalable
species as %
inhalable
nickel
% of ‘total’
‘total’
of ‘total’
‘total’ nickel
species
nickel
nickel
nickel
(mg/m3)
(mg/m3)
(mg/m3)
Exposure to
nickel
species
(mg/m3)
SO
60
0.006-0.45
0.004-0.27
100
7.0
7.0
14
U
40
0.006-0.45
0.002-0.18
≈0
7.0
≈0
≈0
1: SO = Soluble nickel considered to be all nickel sulphate (worst case). U = Other nickel species than soluble nickel.
Hughson (2004) did a study on dermal exposure in the packing of nickel sulphate and nickel carbonate at a chemical
plant that used nickel sulphate solution for the production of nickel sulphate and nickel hydroxycarbonate. The dermal
exposure is estimated at the levels tabulated below. Further details of the estimated data are given above (section
4.1.1.2.2.1.4 and 4.1.1.2.2.1.5).
Nickel species
Typical exposure
μg/cm2/day
mg/day 1
μg/cm2/day
mg/day 1
Total nickel
0.6
1.2
1.0
2.0
Soluble nickel
0.4
0.8
0.7
1.4
0.4
0.4
0.8
Insoluble nickel
0.2
2
2
2
Recent measured data were available for an assessment of exposure by inhalation of aerosols in the production of
chemicals from nickel sulphate solutions. The data reported exposure in terms of two groups of nickel species: (i)
soluble nickel and (ii) insoluble nickel. The data set was rather small and the exposure was low compared to the
exposures seen in a scenario on nickel metal in the production of nickel containing chemicals (scenario C5 in the RAR
for nickel metal). The scenario covers an enormous range of processes and it appears prudent to estimate the exposure
by analogy to scenario C5 in the RAR for nickel metal. It is recognized that the validity of the analogy remains
unknown. For the exposure assessment soluble nickel was considered to be all nickel sulphate (worst case).
Comprehensive data were available on dermal exposure to soluble and insoluble nickel. The exposure was estimated by
two approaches, (i) from measured data and (ii) by modelling. The measured data focused on nickel compound packing
operations. The predicted exposure level was much higher than the levels estimated from measured data. However, the
predicted exposure levels produced by EASE are intended to be estimates of potential exposure and do not therefore
take into account the attenuating effect of gloves and other protective clothing. For the production of chemicals the
highest exposure to nickel sulphate is expected to be during packing of the chemicals. Thus it appears prudent to take
82
the exposure estimated from measured data forward to the risk characterization. In conclusion the estimated levels of
exposure to groups of nickel species are summarized below.
Nickel species (1)
Exposure by inhalation (mg/m3)
Typical
Worst-case
Short term
Typical
Worst-case
SO
0.004-0.27
7.0
14
0.8
1.4
U
0.002-0.18
≈0
≈0
0.4
0.8
4.1.1.2.4 Overall conclusions
Comprehensive data on exposure by inhalation of ’total’ nickel were available for some scenarios while data were
sparse on other scenarios. In general data were sparse on exposure to groups of nickel species and for some scenarios
‘total’ airborne nickel was considered being all nickel sulphate (worst-case). Most data on exposure by inhalation were
reported in terms of the ’total’ aerosol fraction and for the assessment an effort was made to convert the data to the
inhalable fraction. Within a scenario data on exposure by inhalation of nickel were given, if possible, for sub-groups of
workers with similar tasks. By such grouping it proved possible to identify high-risk sub-groups of workers within some
scenarios.
Measured data on dermal exposure were available for some scenarios (A1, B1-B2 and B4). However, based on
expected similarities in the tasks performed by workers in the production of nickel sulphate extrapolation of exposure
measured for scenario A1 to other scenarios (A2-A6) of nickel sulphate production appears prudent. For the production
of catalysts (scenario B3) exposure was estimated by analogy to measured exposure for operators in the packing of
nickel sulphate hexahydrate and nickel hydroxycarbonate. The handling of nickel sulphate in the production of catalysts
is expected to be less intensive than in the packing of nickel sulphate. Thus the exposure estimated by analogy is
considered biased towards high levels. The predicted exposure level by EASE was much higher than the levels
estimated from measured data. However, the predicted exposure levels produced by EASE are intended to be estimates
of potential exposure and do not therefore take into account the attenuating effect of gloves and other protective
clothing.
It is recognized that more detailed information on exposure by inhalation of dust and by dermal exposure may lead to a
more accurate exposure assessment. The estimated exposure levels for the scenarios taken forward to risk
characterization are summarized below (Table 4.1.1.2.4.A). It is noted that the list of sectors is not exhaustive in terms
of risk of exposure to nickel sulphate. As described elsewhere (the risk assessment report for metallic nickel) other
sectors, including the battery production sector, may involve a risk of exposure to soluble nickel (including nickel
sulphate).
83
Table 4.1.1.2.4.A: Estimated exposure by inhalation of nickel sulphate throughout scenarios taken foreword to risk characterization. Estimated dermal
exposure levels are included in the table.
Scenario
Comment
Time scale of
exposure
Duration Frequency
(hr/day) (day/year)
6-8
200
Estimated exposure to inhalable nickel (mg/m3)
Full shift (8 hour time weighted average)
Typical level Method Worst-case level Method
0.07 SO1
1.0
SO
Meas.
Meas. 2
1
0.05
U
~0
U
0.07
SO
Ana3
1.0
SO
Ana3
0.05
U
~0
U
Short-term
Level
Method
2.0
SO
Exp. 2
~0
U
2.0
SO
Exp.
~0
U
Typical
1.4 4
0.8 4
1.4 520005
0.8 5
SO
U
SO
U
SO
1.4 5
0.07
SO
Ana3
1.0
SO
Ana3
2.0
SO
Exp.
0.8 5
U
0.05
U
~0
U
~0
U
0.4 5
0.8 5
5
A4
Nickel sulphate production
6-8
200
0.018 SO
Meas.
0.15
SO
Meas.
0.3
SO
Exp.
0.8
SO
1.4 5
from copper refining
0.012
U
~0
U
~0
U
0.4 5
0.8 5
U
3
3
5
SO
1.4 5
A5
Purification of impure nickel
6-8
200
0.07
SO
Ana
1.0
SO
Ana
2.0
SO
Exp.
0.8
5
U
sulphate
0.05
U
~0
U
~0
U
0.4
0.8 5
SO
1.4 5
A6
6-8
200
0.02
SO
Meas.
0.23
SO
Meas.
0.46
SO
Exp.
0.8 5
U
from metallic nickel
0.02
U
~0
U
~0
U
0.4 5
0.8 5
4
B1
Production of nickel metal
6-8
200
0.04
SO
Meas.
0.7
SO
Meas.
1.4
SO
Exp.
0.6
SO 1.8 40.37 8,9
0.002
U
~0
U
~0
U
0.2 4
2.0 4
U
4,6
B2
Nickel plating
6-8
200
0.018 SO
Meas.
0.4
SO
Meas.
0.8
SO
Exp.
0.027
SO
0.37 4,6
0.007
U
~0
U
~0
U
0.012
U
~0
SO
1.4 5
B3
6-8
200
0.004 SO
Meas.
0.25
SO
Meas.
0.5
SO
Exp.
0.8 5
U
0.1
U
4.2
U
8.4
U
0.4 5
0.8 5
4
B4
Production of nickel
6-8
200
0.004 SO
Meas
7.0
SO
Meas
14
SO
Exp
0.8
SO
1.4 4
compounds/salts
-0.27
U
0
U
0
U
0.4 4
0.8 4
U
0.002
-0.18
1: SO = Soluble nickel considered to be all nickel sulphate (worst-case); U = Other nickel species than soluble nickel salts.
2: Meas. = Measured data. Exp. = Expert judgement. Ana. = Analogy to measured data for other scenarios.
3: Estimated by analogy to scenario A1.
4: Estimated from measured data.
5: The estimate was derived from analogy to scenario A1
6: The exposure is given for both hands, including the fingers and back of the hands. The mean surface area of the hands should be used to estimate the amount of nickel per square
centimetre of the skin. For a man, the average is 840 cm2 (US EPA, 1997). Thus, the worst-case exposure would be 0.44 µg Ni/cm2/day and the typical exposure would be 0.046 µg
Ni/cm2/day for soluble and other nickel species.
SO
U
SO
U
SO
U
SO
U
SO
U
SO
U
SO
U
SO
U
A1
A2
A3
from nickel matte
from secondary nickel matte
and roasted residues
6-8
6-8
200
0.8 4
0.4 4
0.8 5
0.4 5
Worst-case
SO
U
SO
U
200
84
4.1.1.3 Consumer exposure
Nickel is available as a component of multivitamin/mineral food supplements in a number of countries throughout the
EU.
A wide range of nickel-containing food supplements are available in the Netherlands (Netherlands RIVM, 2003). Two
brands, “Omnium” from Solgar and “Vita-Complete AA”, contain 2.5 μg Ni as nickel sulphate per tablet, and the
recommended dose is 2 tablets daily. “After A” also contains 2.5 μg Ni as nickel sulphate per tablet, but the number of
tablets/day is not stated. “Vita-Complete” contains 5 μg Ni as nickel sulphate per tablet; again the recommended daily
dosage is not stated. “Compleet van A tot Zinc” from Centrum contains 5 μg Ni per tablet, with a recommended dose of
1 tablet/day. These tablets are similar to the tablets on the market in other European countries (see below).
In addition, there are two types of product on the Netherlands market not seen elsewhere. These are two liquid
preparations and two preparations containing substantially higher levels of nickel. “Trace minerals” from Nutrition for
Life contains an unstated concentration of nickel. The recommended dosage is 3 drops daily. “Nikkel tinctuur” from
Heidak contains 0.7 μg/ml, and the recommended dose is 5 ml twice daily. This corresponds to a daily dose of 7 μg Ni.
“Totaal 30” contains 50 μg Ni per tablet and “Vitaal 50+”, both marketed by Dagravit contains 100 μg Ni. The
recommended dose for both products is l tablet per day.
Nickel is available as a component of a number of different products in the UK. According to information published by
the UK EGVM (2003), nickel is not available as a single nutrient supplement. The nickel is added as nickel sulphate
(Holland & Barrett, 2003, Tesco, 2003). Nickel is included in products for adults at a level of 5 μg and in products for
children at a level of 1 μg (UK EGVM, 2003) per tablet. Two Holland & Barrett products, “ABC Plus” and “ABC Plus
Senior”, contain 5 μg nickel (as sulphate) (Holland & Barrett, 2003). Two Centrum products also include 5 μg
nickel/tablet in “Centrum Complete from A to Z” and “Centrum Select 50+” (Centrum, 2003). Nickel is also present in
“Sanatogen Gold A-Z” and “Supradyne Recharge Effervescent” (UK HSE, 2003). Not all multivitamin products
contain nickel. One product intended for children’s use, “Centrum Junior” does not contain a nickel supplement
(Centrum, 2003). An estimated 122 million tablets are sold in the UK (UK EGVM, 2003). This represents a total of 610
g nickel.
Nickel is also available in products on the Spanish market. “Supradyne” from Roche contains 5 μg nickel added as
nickel sulphate. It is also available at the same level in “Multicentrum” from White-Hall and “Multibionta” from Merck
(Cámara-Gonzalez, 2003). A Centrum multivitamin product containing nickel is also available in Austria (Austrian
UBA, 2003) and two Centrum products containing nickel in Malta (Malta Standards Authority, 2003).
No products containing nickel are known to be available on the Belgian (Belgian Ministry of Health, Food Chain Safety
and Environment), Danish (Danish Veterinary and Food Administration, 2002), Finnish (Finland STTV, 2003), German
(BauA, 2003), Irish (Irish HAS, 2003) or Norwegian (Norwegian SNT, 2003) markets.
No information is available on food supplements in other Member States.
4.1.1.4 Exposure of man via the environment
4.1.1.5 Combined exposure
85
4.1.2
Human health effects assessment
This section deals with the health effect assessment of nickel sulphate. Studies performed with nickel sulphate are
described here. Other nickel compounds now under review under EU Regulation 793/93 are nickel metal, nickel
chloride, nickel nitrate, and nickel carbonate. The results of studies carried out on other nickel compounds may have
relevance for the effect assessment of nickel sulphate. Studies performed with other nickel compounds are described in
either the Risk Assessment reports for the specific compound or in the Background document in support of the
individual Risk Assessment Reports. Where considered relevant, results obtained from other nickel compounds can be
included in the discussion sections, and may influence the final conclusion for nickel sulphate.
A lot of information has been provided by industry. Much additional data on nickel and nickel compounds have been
published. Much of these data have been reviewed in good quality reviews including UK HSE (1987), IARC (1990),
IPCS (1991, 1996), US ATSDR (1995) and a Nordic Expert Group (Aitio, 1995). The effects of nickel on the skin have
also been reviewed (Maibach & Menné, Eds. 1989). NiPERA in collaboration with Eurométaux have also produced a
criteria document for nickel and nickel compounds for the European Commission (NiPERA 1996). Toxicology
Excellence for Risk Assessment (TERA) has prepared a toxicological review of soluble nickel salts for Metal Finishing
Association of Southern California Inc., US-EPA and Health Canada (TERA1999).
These reviews plus (where considered relevant) the primary literature, have been used widely in this risk assessment
report as it is felt that much of the essential data to establish possible hazards and risks of nickel for human health has
already been adequately evaluated. This implies that not all the studies cited in this risk assessment report have been
checked and studies have often been described in a summary form. When information is cited from reviews, the
primary source is given with the notation “quoted from”.
When expressing results, the term “significant” is used only if the result is statistically significant at a p-level lower than
0.05.
4.1.2.1 Toxico-kinetics, metabolism and distribution
4.1.2.1.1 Absorption
4.1.2.1.1.1
Animal studies
4.1.2.1.1.1.1 Inhalation
No studies providing specific information about the absorbed fraction of nickel following inhalation or intratracheal
instillation of nickel sulphate have been located. However, the following two studies provide some information in
relation to absorption of nickel sulphate.
In an inhalation study (Benson et al. 1995), groups of 90 male F344/N rats were exposed whole-body to nickel sulphate
hexahydrate (aerosol, mean mass median aerodynamic diameters (MMADs) ranged from 2.0 to 2.4 µm) at
concentrations of 0, 0.12, or 0.5 mg NiSO4·6H2O/m3 (corresponding to 0, 0.03, or 0.11 mg Ni/m3) for 6 hours per day, 5
days per week, for up to 6 months. Groups of B6C3F1 mice were similarly exposed to concentrations of 0, 0.25, or 1.0
mg NiSO4·6H2O/m3 (corresponding to 0, 0.06, or 0.22 mg Ni/m3). After 2 months of nickel exposure, subgroups of rats
and mice from each exposure level were exposed nose-only for 2 hours to 63NiSO4 (subgroup A animals) to determine
the effect of repeated nickel inhalation on the pulmonary deposition and retention of subsequently inhaled particles.
Subgroup A animals were returned to the appropriate whole-body inhalation chambers where exposures were resumed
until the scheduled euthanization which took place at eight time points (0 to 30 days) after the acute exposure to the
63
Ni-labelled aerosols. After 6 months of exposure, additional groups of animals from each nickel sulphate exposure
level were exposed by inhalation to 63NiSO4 (subgroup C animals) to further evaluate lung clearance. After the
radiolabelled particle exposures, animals in Subgroup C were euthanized as described for Subgroup A animals.
Upon evaluation of nickel lung burdens resulting from repeated inhalation exposure, amounts of nickel in lungs of
control or exposed rats and mice were below the limits of detection of the method (1.10 to 2.48 µg Ni/lung) at all
euthanization times. The histopathological examination of the lungs showed that no particles were present in the lungs
of either rats or mice.
Subgroup A and C rats euthanized immediately after the 63NiSO4 exposure had 3.9 to 11.6 µg Ni/lung (Subgroup A
animals) or approximately 9 to 14 µg Ni/lung (Subgroup C animals) contributed by the 63NiSO4. The nickel contributed
86
by the acute 63NiSO4 exposure cleared rapidly from the lungs of both Subgroup A and C control and 63NiSO4-exposed
rats. Amounts of nickel present in lungs of control and 63NiSO4-exposed rats 32 days (Subgroup A animals) or 29 days
(Subgroup C animals) after the 63NiSO4 exposure were less than 1% of those present on the day of exposure. More than
99% of the initial lung burden (ILB) cleared with a half-time of approximately 2 to 3 days; a small fraction (<0.5%)
appeared to be retained in the lung, with essentially no clearance over an approximately 30-day period. No significant
differences were observed in the clearance of 63Ni from the lungs of Subgroup A and C controls and from rats exposed
to either concentration of NiSO4.
Approximately 1 µg or less of nickel (from the 63NiSO4 exposure) was present in the lungs of Subgroup A mice after
the acute exposure to 63NiSO4 with 1.2 to 1.5 µg Ni being present in the lungs of Subgroup C mice. In Subgroup A
mice, the majority of the 63Ni (78-96%) cleared with a half-time of approximately 1.5 days. In Subgroup C mice, the
majority of the 63Ni (90% or more) cleared with a half-time of 1.1 to 1.5 days. The clearance half-time for the ‘slower’
component varied from approximately 5 days (Subgroup A controls and high-dose) to 17 days (Subgroup A low-dose);
for Subgroup C mice, the clearance half-time for the ‘slower’ component was 5 to 6.5 days. As for rats, no significant
differences were observed in the clearance of 63Ni from the lungs of Subgroup A and C controls and from mice exposed
to either concentration of NiSO4.
In conclusion, clearance of 63NiSO4 from the lungs of rats and mice was rapid, and unaffected by previous inhalation of
nickel sulphate for up to 6 months by either species.
Medinsky et al. (1987) administered 63Ni labelled nickel sulphate (as a solution in isotonic saline) by intratracheal
instillation to male and female F344 rats. One of three dosing solutions was given to 15 animals: 17, 190, or 1800
nmoles Ni per rat (corresponding to 1, 11.2 or 105.7 μg Ni/rat). Nickel was rapidly cleared from the lungs into the
blood (measured as radioactivity in the blood). The nickel concentration in blood was highest four hours after the
instillation, with blood levels decreasing at 24 and 96 hours after instillation. By 4 hours of instillation, from 8% (at the
highest dose) to 49% (at the lowest dose) remained in the lungs; by 24 hours of instillation, from 10% (at the highest
dose) to 28% (at the lowest dose); and by 96 hours of instillation, from 1.4% (at the highest dose) to 12% (at the lowest
dose). With increasing nanomoles of nickel instilled, a decreasing percentage of the amount instilled was cleared with a
long-term half-time. In addition, the half-time for clearance of nickel from the lungs decreased with increasing amount
of nickel instilled. The half-time for lung clearance ranged from 36 hours at the lowest dose to 21 hours at the highest
dose. The major route of 63Ni excretion was in urine and accounted for 50% of the dose (at the two lower doses), and
80% (at the highest dose).
4.1.2.1.1.1.2 Oral
Following administration of a single dose of 10 mg nickel (nickel sulphate in 5% starch saline solution) by gavage to
male Wistar rats, the absorbed fraction was 11% 24 hours after oral administration (Ishimatsu et al. 1995).
Blood nickel levels in mice rose with increasing dose and duration following ingestion of 1, 5, or 10 g/l solutions of
nickel sulphate hexahydrate and reached their maximum at 180 days of exposure when the experiment was terminated
(Dieter et al. 1988 – quoted from NiPERA 1996).
4.1.2.1.1.1.3 Dermal
Nickel sulphate in saline solution was applied daily to male albino rats at doses equivalent to 40, 60, or 100 mg Ni/kg
bw, for 15 or 30 days. Microscopic changes were observed in the liver after 15 and 30 days of treatment and in the
testes after 30 days of treatment indicating that nickel can be absorbed through the skin of rats. For further details, see
section 4.1.2.5.1.3. (Mathur et al. 1977 – quoted from IPCS 1991).
Norgaard (1957 – quoted from IPCS 1991) applied 10 µl of a 5% solution of 57Ni (as nickel sulphate heptahydrate) to a
shaved area of 5 x 5 cm on the back of guinea-pigs and rabbits (two of each species). The radioactivity was measured in
organs and body fluids, 24 hours after the application. The relative distribution levels of radioactivity in urine, blood,
kidney, and liver (measured as impulses/minute) indicate that nickel can be absorbed through the skin of guinea pigs
and rabbits.
Mild penetration of nickel was only observed in the stratum corneum of guinea-pig skin when nickel sulphate was
applied as a 5% solution. Sodium lauryl sulphate enhanced the penetration of nickel through the stratum corneum as
slight penetration of nickel could be seen as deep as the dermis when sodium lauryl sulphate (5% solution) was applied
together with nickel sulphate. (Lindberg et al. 1989 – quoted from NiPERA 1996).
87
4.1.2.1.1.2
Human data
No data have been located.
4.1.2.1.1.2.2 Oral
Sunderman et al. (1989) studied the kinetics of nickel absorption in healthy human volunteers who ingested nickel
sulphate in the drinking water (experiment 1) or added to food (experiment 2) at doses of 12 (n = 4), 18 (n = 4), or 50
µg Ni/kg bw (n = 1). In experiment 1, each of the subjects fasted 12 hours before and 3 hours after drinking one of the
specified nickel sulphate doses dissolved in water. In experiment 2, the subjects fasted 12 hours before consuming a
standard American breakfast that contained the identical dose of nickel sulphate added to scrambled eggs. Nickel levels
were determined in samples of serum, urine, and faeces collected during 2 days before and 4 days after the
administration of nickel sulphate. Peak nickel concentrations in serum after ingestion of nickel sulphate in drinking
water averaged 33 times the corresponding values when nickel sulphate was ingested in food. Absorbed nickel averaged
27 ± 17 % of the dose ingested in water compared with 0.7 ± 0.4 % of the same dose ingested in food as estimated by
urinanalysis.
Cumulative urinary excretion of nickel in non-fasting volunteers given a single oral dose of 5.6 mg Ni (as nickel
sulphate hexahydrate in lactose) indicated an intestinal absorption of 1-5% (Christensen & Lagesson 1981 – quoted
from IARC 1990).
After oral administration of 5.6 mg nickel (as the sulphate), increased nickel excretion was found over the following 2
to 3 days (Menné et al. 1978).
After ingestion of nickel sulphate during fasting, 4 to 20% of the dose was excreted in the urine within 24 hours (Cronin
et al. 1980 – quoted from IARC 1990, IPCS 1991).
Solomons et al. (1982) estimated the bioavailability of nickel in humans by serial determination of changes in plasmanickel concentrations following a standard dose of 22.4 mg of nickel sulphate hexahydrate (5 mg nickel), given in each
of two standard meals, in the drinking-water, and in five different beverages (cow’s milk, coffee, tea, orange juice, and
Coca Cola®). The plasma-nickel concentration was stable in the fasting state and after an unlabelled test meal, but was
elevated after the standard dose of nickel in water. When nickel was added to each of the 5 beverages, the rise in the
plasma concentration was significantly suppressed with all but Coca Cola®.
Gawkrodger et al. (1986) measured serum nickel levels in nickel-sensitive subjects following oral exposure to nickel
sulphate heptahydrate, which was administered in lactose either as a dose of 2.5 mg Ni (8 individuals) before breakfast
on two successive days or as a single dose of 5.6 mg Ni (5 individuals). Seventy-two hours after the single 5.6 mg dose
or the second 2.5 mg dose, the mean serum nickel concentration was 2.6 µg/l and 2.7 µg/l, respectively. The mean basal
serum nickel level in individuals with quiescent dermatitis prior to challenge was 1.2 µg/l and the level 72 hours postplacebo (lactose) was 1.0 µg/l.
4.1.2.1.1.2.3 Dermal
Hostýnek et al. (2001) measured in vivo penetration of nickel salts (nickel sulphate, nickel chloride, nickel nitrate and
nickel acetate) in humans using tape stripping. A dose of 37.1 µg/cm2 (100 µl of a solution of nickel sulphate
hexahydrate in methanol) was applied on the volar forearm or on the back of non-atopic human volunteers (skin area:
2.83cm2). For negative control, all reagents and materials taken from the non-exposed area on the same skin region of
the respective subject were analysed for nickel content. Thirty minutes following exposure of the forearm (n = 3),
around 89% of the dose of nickel sulphate was recovered on the surface of the skin, while 24 hours following exposure
of the back (n = 2), around 53% of the dose was recovered on the skin surface. According to the authors, most of the
nickel dose applied remains on the skin surface or is adsorbed in the uppermost layers of the stratum corneum.
4.1.2.1.1.3
In vitro studies
Fullerton et al. (1986) used in vitro diffusion cells to investigate the permeation of nickel from nickel sulphate solution
through human full skin (from breast skin operations) under occlusion. An aqueous solution of nickel sulphate was
applied to the skin surface of 1.8 cm2 in a concentration resulting in application of 184 μg nickel/cm2. The permeation
88
process was slow with a lag time of about 50 hours. After about 240 hours, about 7% of the nickel from a nickel
sulphate solution was present in the skin matrix.
The diffusion of 63Ni (as the sulphate, specific activity 1 µCi/ml, 0.1, 0.01, or 0.001 mol/litre in physiological salt
solution) through the human epidermis (studied in in vitro in diffusion cells) was only slight after 17, 24, and 90 hours,
respectively. Diffusion did not take place within the first 5 hours. Sweat or surfactants slightly enhanced the diffusion of
nickel. (Samitz & Katz 1976 – quoted from IPCS 1991).
Tanojo et al. (2001) quantified the in vitro permeation of several nickel salts (nickel sulphate, nickel chloride, nickel
nitrate and nickel acetate) through human stratum corneum from cadaver leg skin by using a continuous flow-through
diffusion cell system. An aqueous solution of nickel sulphate hexahydrate (at 1% Ni2+ concentration) was used as the
donor solution with pure water as the receptor fluid. Nickel concentrations in the donor and receptor fluid, as well as in
the stratum corneum were analysed. After 96 hours, around 97% of the dose was recovered in the donor solution with
around 1% in the receptor fluid and 0.6% in the stratum corneum.
4.1.2.1.2 Distribution and elimination
4.1.2.1.2.1
Animal studies
In a comparative inhalation study in F344 rats and B6C3F1 mice (5 animals of each sex per group), nickel sulphate
hexahydrate was administrated as aerosols (mass median aerodynamic diameter of 1.9 + 0.2 μm) at concentrations of 0,
3.5, 15, or 30 mg/m3 (equivalent to 0, 0.8, 3.3 or 6.7 mg Ni/m3) for 6 hours per day, 5 days per week, for 16 days. Lung
burdens (expressed as μg Ni/g lung) in rats were 5.1 ± 0.7 for males and 7.6 ± 0.7 for females after inhalation of 3.5
mg/m3; 9.4 ± 2.1 for males and 10.5 ± 2.4 for females after inhalation of 15 mg/m3; and 7.7 ± 2.7 for males and 9.2 ±
4.8 for females after inhalation of 30 mg/m3. Lung burdens (expressed as μg Ni/g lung) in mice were 3.53 ± 0.94 for
males and 3.69 ± 1.03 for females after inhalation of 3.5 mg/m3. (Benson et al. 1988).
In an inhalation study (Benson et al. 1995), groups of 90 male F344/N rats were exposed whole-body to nickel sulphate
hexahydrate (aerosol, mean mass median aerodynamic diameters (MMADs) ranged from 2.0 to 2.4 µm) at
concentrations of 0, 0.12, or 0.5 mg NiSO4·6H2O/m3 (corresponding to 0, 0.03, or 0.11 mg Ni/m3) for 6 hours per day, 5
days per week, for up to 6 months. Groups of B6C3F1 mice were similarly exposed to concentrations of 0, 0.25, or 1.0
mg NiSO4·6H2O/m3 (corresponding to 0, 0.06, or 0.22 mg Ni/m3). The amounts of nickel in lungs of control or exposed
rats and mice were below the limits of detection of the method (1.10 to 2.48 µg Ni/lung) at all time points. The
histopathological examination of the lungs showed that no particles were present in the lungs of either rats or mice.
In an NTP-study (NTP, 1996a), F344 rats and B6C3F1 mice were exposed to nickel sulphate hexahydrate aerosols
(mass median aerodynamic diameter of 1.8-3.1 + 1.6-2.9 μm) by inhalation for 6 hours per day, 5 days per week, for 13
weeks or 2 years.
In the 13-week studies, rats and mice (6 animals of each sex per group) were exposed at concentrations of 0, 0.12, 0.5,
or 2 mg/m3 (equivalent to 0, 0.027, 0.11, or 0.45 mg Ni/m3). The concentration of nickel in the lungs of 0.5 and 2
mg/m3 rats was significantly greater than that in the controls at 4, 9, and 13 weeks for males and at 13 weeks for
females. Nickel concentration in the lung of high-dose females was significantly greater than that in the lungs of
controls.
In the 2-year studies, rats were exposed at concentrations of 0, 0.12, 0.25, or 0.5 mg/m3 (equivalent to 0, 0.027, 0.056,
or 0.11 mg Ni/m3) and mice were exposed at concentrations of 0, 0.25, 0.5, or 1.0 mg/m3 (equivalent to 0, 0.056, 0.11,
or 0.22 mg Ni/m3). Lung nickel burdens were evaluated after 7 months (7 rats of each sex and 5 mice of each sex from
each group) and after 15 months (5 of each sex from each group). In rats, lung nickel burdens were significantly higher
than control values at 0.5 mg/m3 after 7 months and from 0.12 mg/m3 after 15 months; lung nickel burden values
increased with increasing exposure concentration. In mice, lung nickel burdens were below the limit of detection.
Dunnick et al. (1989) found similar concentrations of nickel in lungs of rats and mice sacrificed after 4, 9, and 13 weeks
of inhalation to nickel sulphate (0.027, 0.11, or 0.45 mg Ni/m3 as nickel sulphate hexahydrate), indicating that the
amount of nickel in the lungs had reached a steady state consistent with a short half-life of less than 2 days. On a µg
Ni/g of lung basis, deposition in lungs of rats was considerably greater than in lungs of mice.
89
Medinsky et al. (1987) administered 63Ni labelled nickel sulphate (as a solution in isotonic saline) by intratracheal
instillation to male and female F344 rats at doses equivalent to 1, 11.2 or 105.7 μg Ni/rat. One group of animals from
each dose level was placed in metabolism cages and urine and faeces were analysed for 63Ni at 4, 7, 10, 16, 24, 36, 38,
60, 72, and 96 hours after instillation. A second group of animals was sacrificed at 4, 24, 48, or 72 hours post-treatment.
Tissues analysed for 63Ni levels included liver, brain, thyroid, thymus, spleen, femur, kidney, larynx, heart, lung,
trachea, nasal turbinates, muscles, perineal fat, adrenals, testes or ovaries, stomach, small and large intestine, urinary
bladder, and pelt.
The highest concentrations of 63Ni at 4, 24, and 96 hours were found in the lung, trachea, larynx, kidney, urinary
bladder, adrenals, blood, large intestine, and thyroid. Muscle, fat, bone, liver, and brain contained the lowest
concentrations. After 4 hours, 49, 21 and 8%, respectively, of the instilled doses/g tissue was found in the lungs. Of
nickel remaining in the body after 96 hours, over 50% was in the lungs. The major route of 63Ni excretion was in urine
and accounted for about 50% of the dose (at doses of 1 and 11.2 μg Ni/rat), and 80% (at the dose of 105.7 μg Ni/rat).
The half-time for urinary excretion increased from 4.6 hours at the highest dose to 23 hours at the lowest dose. Faecal
elimination of the initial dose was around 30% (1 and 11.2 μg Ni/rat) and 13% (105.7 μg Ni/rat).
In another study performed with intratracheal instillation, a single dose of 263 µg nickel sulphate hexahydrate (1052
µg/kg bw equivalent to 235 µg Ni/kg bw) was administered to F344 rats in order to administer 1 µmol of nickel. Groups
of 6 rats (3 males, 3 females) were sacrificed at 1 or 7 days following instillation for determination of nickel lung
burden. The lung burden of nickel (expressed as µmol Ni in the lungs) was 0.14 ± 0.06 at day 1 following instillation
and 0.03 ± 0.01 at day 7. (Benson et al. 1986).
4.1.2.1.2.1.2 Oral
Severa et al. (1995) studied the distribution of nickel in body fluids and organs of rats exposed to nickel sulphate. Male
and female rats were given 100 mg Ni/l as nickel sulphate in drinking water for 6 months. Nickel sulphate
administration was associated with an increased concentration of nickel in body fluids and organs. The highest
concentrations of nickel were found in the liver of both male and female rats. In male rats, nickel levels decreased in the
order: liver > kidney = whole blood = serum > testes > urine. In female rats, the decreasing order was similar: liver >
kidney = whole blood = serum = plasma > urine > ovaries. No significant differences were found between nickel
concentrations in organs (except ovaries), blood and urine of rats exposed for 3 months and those exposed for 6 months.
Obone et al. (1999) gave adult male Sprague-Dawley rats 0, 0.02, 0.05, or 0.1% nickel sulphate hexahydrate (equivalent
to 0, 44.7, 111.8, or 223.5 mg Ni/l) in their drinking water for 13 weeks. The bioaccumulation of nickel in different
organs was increased, in general, with increasing exposure concentrations of nickel in the drinking water, but the
change was not significant in most of the situations. The relative order of bioaccumulation of nickel in different organs
when treated at 0.1% nickel sulphate (223.5 mg Ni/l) was kidneys > testes > lung = brain > spleen > heart = liver.
Blood nickel levels rose with increasing dose and duration following ingestion of 1, 5, or 10 g/l solutions of nickel
sulphate hexahydrate in mice. Blood nickel levels reached maximum at 180 days of exposure when the experiment was
terminated. Nickel levels were higher in kidney than in liver. Nickel levels in the lung were not measured. (Dieter et al.
1988 – quoted from NiPERA 1996).
Daily oral administration of 2.5 mg nickel sulphate per rat for 30 days resulted in accumulation of nickel in trachea >
nasopharynx > skull > oesophagus > intestine > skin > liver = spleen > stomach > kidney > lung = brain > heart
(Jiachen et al. 1986 – quoted from IARC 1990).
When 2.5 μg nickel sulphate/animal was administered orally to rats for 30 days, the nickel contents in the trachea,
nasopharynx, lungs, skull, bone, heart, spleen, and kidneys were significantly higher than those in the control animals
(Huang et al. 1986 – quoted from IPCS 1991).
In dogs fed nickel sulphate (0, 100, 1000, or 2500 ppm in the diet) for 2 years, 1 to 3% of the ingested nickel was
excreted in the urine (Ambrose et al. 1976).
4.1.2.1.2.2
Human data
From biological monitoring in small groups of electroplaters exposed to nickel sulphate and nickel chloride, the half-life
for urinary elimination of nickel has been estimated to range from 17 to 39 hours (Tossavainen et al. 1980 – quoted
from NiPERA 1996).
90
Sunderman et al. (1989) studied the kinetics of nickel distribution and elimination in healthy human volunteers who
ingested nickel sulphate in the drinking water (experiment 1) or added to food (experiment 2) at doses of 12 (n = 4), 18
(n = 4), or 50 µg Ni/kg bw (n = 1). In experiment 1, each of the subjects fasted 12 hours before and 3 hours after
drinking one of the specified nickel sulphate doses dissolved in water. In experiment 2, the subjects fasted 12 hours
before consuming a standard American breakfast that contained the identical dose of nickel sulphate added to scrambled
eggs. Nickel levels were determined in samples of serum, urine, and faeces collected during 2 days before and 4 days
after the administration of nickel sulphate. Peak urine levels after ingestion of nickel sulphate in drinking water
averaged 22 times the corresponding values when nickel sulphate was ingested in food. Absorbed nickel averaged 27 ±
17 % of the dose ingested in water compared with 0.7 ± 0.4 % of the same dose ingested in food as estimated by
urinanalysis. Faecal elimination averaged 76 ± 19 % of the dose ingested in water versus 102 ± 20 % of the dose
ingested in food. The rate constants for absorption, transfer, and elimination were not significantly influenced by the
oral vehicle. The elimination half-time for absorbed nickel averaged 28 ± 9 hours (range 17 to 48). Renal clearance of
nickel averaged 8.3 ± 2.0 ml/min/1.73 m2 in experiment 1 versus 5.8 ± 4. ml/min/1.73 m2 in experiment 2.
Christensen & Lagesson (1981 – quoted from IARC 1990) gave a single oral dose of 5.6 mg Ni (as nickel sulphate
hexahydrate in lactose) orally to eight human volunteers. Most of the nickel present in blood was in serum. Serum and
whole blood nickel concentrations showed a very high positive correlation (r = 0.99). The half-time of nickel in serum
was 11 hours (one compartment model during the first 32 hours). The serum nickel concentration and urinary nickel
excretion showed a highly positive correlation (r = 0.98).
Following a single oral dose of 2.5 mg Ni (as nickel sulphate heptahydrate in lactose) to normal individuals (2 subjects),
all showed increases in serum nickel levels at 3 hours but the magnitude of the increases varied from around 30 times of
the normal value (around 1 µg/l) to only a 5-fold increase. Serum nickel levels fell subsequently but were still elevated
above the normal value in all three subjects at 48 hours post-dosing. The peak serum level was inversely related to the
age of the subjects. The 24-hour urinary nickel excretion did not exactly mirror the serum values. The subject, who had
the highest peak serum level, excreted the largest amount of nickel in the urine (over 10 times his control value during
each of the two post-24-hour periods), whereas the subject, who had the lowest serum level, excreted larger amounts of
nickel in the urine than the subject, who had a serum level between the two other subjects.
(Gawkrodger et al. 1986).
After administration of a tablet of 5.6 mg nickel (as the sulphate) to six females and seven males, the excretion
increased by 3 to 4 times after 1 to 2 days. After 3 days, the nickel content in the urine was still twice as high as before
the administration. No significant difference between the sexes was observed before or after oral administration of
nickel. (Menné et al. 1978).
After ingestion of nickel sulphate during fasting, 4 to 20% of the dose was excreted in the urine within 24 hours (Cronin
et al. 1980 – quoted from IARC 1990).
In workers, who accidentally drank water contaminated with nickel sulphate and nickel chloride (1.63 g Ni/l), serum
nickel concentrations one day post-exposure averaged 0.286 mg Ni/l compared with 0.004 mg Ni/l in a control group of
workers. The mean serum half-time of nickel was 60 hours. Urinary nickel concentrations in exposed workers averaged
5.8 mg Ni/l compared to the control level of 0.050 mg Ni/l. The estimated oral intake of nickel by the symptomatic
workers ranged from 0.5 to 2.5 g. (Sunderman et al. 1988 – quoted from TERA 1999, US ATSDR 1995).
Nickel sulphate is rapidly absorbed and transported as the divalent nickel ion bound to serum albumin (Glennon &
Sarkar 1982 – quoted from NiPERA 1996).
4.1.2.1.2.3
Transplacental transfer
No studies on transplacental transfer following administration of nickel sulphate have been located. Transplacental
transfer has been demonstrated in rodents following administration of nickel chloride and nickel has been shown to
cross the human placenta. These aspects are addressed in the Risk Assessment Report on nickel chloride as well as in the
Background document in support of the individual Risk Assessment Reports.
4.1.2.1.2.4
Cellular uptake
According to TERA (1999), nickel can enter animal cells by three different mechanisms: uptake via metal ion transport
systems, diffusion of lipophilic nickel compounds through the membrane, and phagocytosis. The cellular uptake of
soluble and insoluble nickel compounds are different as insoluble nickel compounds enter the cell via phagocytosis,
91
while soluble nickel compounds are not phagocytised, but can enter the cell via ion transport systems or through
membrane diffusion. These aspects are discussed in the Background document in support of the individual Risk
Assessment Reports.
4.1.2.1.3 Discussion and conclusions
The toxicokinetics of nickel sulphate have been investigated after inhalation, intratracheal instillation, oral
administration, and dermal application.
4.1.2.1.3.1
Absorption
No studies providing specific information about the absorbed fraction of nickel following inhalation or intratracheal
instillation of nickel sulphate have been located. However, two studies in experimental animals provide some
information in relation to absorption of nickel sulphate. No human data are available.
The study by Benson et al. (1995) showed that clearance of nickel sulphate (administered by inhalation of nickel
sulphate hexahydrate aerosol, mean mass median aerodynamic diameters (MMADs) ranging from 2.0 to 2.4 µm) from
the lungs of rats and mice is extensive with 99% of inhaled nickel sulphate being cleared with a half-time of 2 to 3 days
in rats and with 80-90% being cleared with a half-time of less than one day in mice. Repeated inhalation of nickel
sulphate hexahydrate aerosol did not result in accumulation of nickel in the lungs of either rats or mice and did not
affect the clearance of 63NiSO4 inhaled after either 2 or 6 months of nickel sulphate hexahydrate exposure. No nickel
sulphate particles were observed histologically in the lungs of nickel sulphate exposed animals. Nickel levels in blood
and urine were not measured, so this study does not provide evidence for whether clearance was via absorption from the
lungs into the blood stream or by clearance from the respiratory tract via the mucociliary mechanisms.
The intratracheal instillation study by Medinsky et al. (1987) showed that nickel sulphate (administered as a solution in
isotonic saline) is rapidly absorbed from the lungs into the blood in a dose dependent manner as the urinary excretion of
nickel increased with increasing dose levels (50% at the two lower dose levels and 80% at the high dose level).
The absorbed fraction of nickel following inhalation exposure to nickel sulphate cannot be quantified based on the
available data. The deposition of particles in the respiratory tract depends on the particle sizes (MMADs) as well as on
other characteristics of the particles, and the absorption of nickel from the respiratory tract into the blood stream
depends on the solubility of the nickel compound inhaled. Soluble nickel compounds, such as nickel sulphate, are
expected to be absorbed from the respiratory tract following inhalation exposure. This is supported by data from the
study by Medinsky et al. (1987), which showed that 50 to 80% of a dose (dependent on the dose) of nickel sulphate can
be absorbed from the respiratory tract. By assuming that the absorption of nickel following inhalation exposure to
nickel sulphate is similar to absorption following intratracheal instillation, the absorption of nickel from the respiratory
tract following inhalation of nickel sulphate might be as high as up to 80%. Furthermore, the inhalation study by
Benson et al. (1995) showed that clearance of nickel sulphate from the lungs of rats and mice is rapid and extensive (up
to 99% with a half-time of 2-3 days in rats and 80 to 90% with a half-time of less than one day in mice). By assuming
that the clearance of nickel sulphate particles (respirable particles, MMADs ranging from 2.0 to 2.4 µm) from the lungs
in the inhalation study is due to absorption rather than to deposition or by mucociliary action, the absorption of nickel
from the lungs following inhalation of nickel sulphate might be as high as up to 99% (at concentrations up to 0.11 mg
Ni/m3 in rats and up to 0.22 mg Ni/m3 in mice). Other inhalation studies in rats (Benson et al. 1988, NTP 1996) indicate
that lung nickel burdens increase with increasing concentrations of nickel sulphate (at least up to about 0.8 mg Ni/m3) in
the inhaled air as well as with duration of exposure.
Studies in rats using intratracheal instillation of nickel chloride (Carvalho & Ziemer 1982, English et al. 1981, Clary
1975) showed that up to approximately 97% of a dose of nickel chloride can be absorbed from the respiratory tract. For
further details, the reader is referred to the Risk Assessment Report on nickel chloride as well as to the Background
document in support of the individual Risk Assessment Reports.
In conclusion, the available data on nickel sulphate and nickel chloride indicate that the absorption of nickel following
inhalation of these nickel compounds might be as high as up to 97-99%; it should be noted that the fraction absorbed
apparently depends on the concentration of the nickel compound in the inhaled air as well as on the duration of
exposure. For the purpose of risk characterisation, a value of 100% is taken forward to the risk characterisation for the
absorbed fraction of nickel from the respiratory tract following exposure by inhalation of nickel sulphate for particulates
with an aerodynamic diameter below 5 µm (respirable fraction). For nickel particulates with aerodynamic diameters
above 5 µm (non-respirable fraction), the absorption of nickel from the respiratory tract is considered to be negligible as
92
these particles predominantly will be cleared from the respiratory tract by mucociliary action and translocated into the
gastrointestinal tract and absorbed. Hence, for the non-respirable fraction, 100% clearance from the respiratory tract by
mucociliary action and translocation into the gastrointestinal tract is assumed and the oral absorption figures can be
taken.
For further details, the reader is referred to the Background document in support of the individual Risk Assessment
Reports.
4.1.2.1.3.1.2 Oral
Absorption of nickel following oral ingestion of nickel sulphate has been evaluated in a number of human studies;
however, it is impossible to give a general estimate for the fraction of nickel absorbed after oral administration of nickel
sulphate. The available studies indicate that the extent of absorption is influenced by whether nickel sulphate is
administered in drinking water, to fasting subjects, or together with food. One study in human volunteers (Sunderman et
al. 1989) showed that 27% of a dose was absorbed when nickel sulphate was administered in drinking water to fasting
subjects compared with around 1% when administered together with food to fasting subjects. Another study
(Christensen & Lagesson 1981 – quoted from IARC 1990) supports an absorption around 1 to 5% when nickel sulphate
was administered in lactose. A higher absorption fraction of 4 to 20% was observed after ingestion of nickel sulphate
during fasting (Cronin et al. 1980 – quoted from IARC 1990). In addition, absorption of nickel was apparently slower
when administered together with food compared with water.
One study in rats (Ishimatsu et al. 1995) showed an absorption of 11% when nickel sulphate was administered in a 5%
starch saline solution.
The absorption of nickel sulphate following oral exposure can be as high as 27% when nickel sulphate is administered
in drinking water to fasting individuals while absorption seems to be around 1 to 5% when administered together with
food and to non-fasting individuals.
A study on volunteers (Nielsen et al. 1999), in which the nickel compound administered was not specified, showed that
25.8% of the administered dose was excreted in the urine following administration of nickel in drinking water to fasting
individuals compared with 2.5% when nickel was mixed into a meal. Based on experimental data from various human
studies, Diamond et al. (1998 – quoted from TERA 1999) have used a biokinetic model to estimate nickel absorption;
the results showed that estimated nickel absorption ranged from 12-27% of the dose when nickel was ingested after a
fast, to 1-6% when nickel was administered either in food, in water, or in a capsule during (or in close proximity to) a
meal. For further details, the reader is referred to the Background document in support of the individual Risk Assessment
Reports.
In conclusion, the available data indicate that the absorption of nickel following administration in the drinking water to
fasting individuals might be as high as up to about 25-27% and about 1-6% when administered to non-fasting
individuals and/or together with (or in close proximity to) a meal. For the purpose of risk characterisation, a value of
30% is taken forward to the risk characterisation for the absorbed fraction of nickel from the gastrointestinal tract
following oral exposure to nickel sulphate in the exposure scenarios where fasting individuals might be exposed to
nickel sulphate. In all the other exposure scenarios, a value of 5% is used for the absorbed fraction of nickel from the
gastrointestinal tract.
Reports.
4.1.2.1.3.1.3 Dermal
When considering dermal absorption, a distinction should be made between penetration of nickel into skin and
percutaneous transport, where nickel is transported through the skin and into the blood stream. For further details, the
reader is referred to the Background document in support of the individual Risk Assessment Reports.
In a recent human in vivo study of nickel sulphate (Hostýnek et al. 2001), a large part of the administered dose remained
on the surface of the skin after 24 hours or, according to the authors, is adsorbed in the uppermost layers of the stratum
corneum. In an in vitro study (Tanojo et al. 2001) using human skin (stratum corneum from cadaver leg skin), about
97% of the dose was recovered in the donor solution after 96 hours, with about 1% in the receptor fluid and 0.6% in the
stratum corneum. Limited data obtained from other in vitro studies using human skin (Fullerton et al. 1986, Samitz &
Katz 1976 – quoted from IPCS 1991) indicate that absorption following dermal contact may have a significant lag time.
93
Studies in experimental animals indicate that nickel can be absorbed through the skin of rats (Mathur et al. 1977 –
quoted from IPCS 1991) and guinea-pigs and rabbits (Norgaard 1957 – quoted from IPCS 1991). Another study in
guinea pigs (Lindberg et al. 1989 – quoted from NiPERA 1996) showed that nickel only penetrated into the stratum
corneum.
Absorption of nickel can take place following dermal contact to nickel sulphate; however, the absorption seems to be
low with a large part of the applied dose remaining on the skin surface or in the stratum corneum.
A recent human in vivo study of nickel metal (Hostýnek et al. 2001) has shown that a large part of the administered
dose remained on the surface of the skin after 24 hours or had penetrated into the stratum corneum. For further details,
the reader is referred to the Risk Assessment Report on nickel metal.
In vitro studies using human skin support the findings in the human in vivo studies as most of the dose remained in the
donor solution and only minor amounts were found in the receptor fluid; the in vitro studies also indicate that absorption
following dermal contact may have a significant lag time. For further details, the reader is referred to the Background
document in support of the individual Risk Assessment Reports.
In conclusion, the available data indicate that absorption of nickel following dermal contact to various nickel
compounds can take place, but to a limited extent with a large part of the applied dose remaining on the skin surface or
in the stratum corneum. The data are too limited for an evaluation of the absorbed fraction of nickel following dermal
contact to nickel sulphate. The in vitro study of soluble nickel compounds (nickel sulphate, nickel chloride, nickel
nitrate, and nickel acetate) using human skin (Tanojo et al. 2001) showed about 98% of the dose remained in the donor
solution, whereas 1% or less was found in the receptor fluid and less than 1% was retained in the stratum corneum.
According to the revised TGD, the amount absorbed into the skin, but not passed into the receptor fluid, should also be
included in the estimate of dermal absorption. For the purpose of risk characterisation, a value of 2% is taken forward to
the risk characterisation for the absorbed fraction of nickel following dermal contact to nickel sulphate.
Reports.
4.1.2.1.3.2
Distribution and elimination
Two inhalation studies in rats (Benson et al. 1988, NTP 1996) indicate that lung nickel burdens increase with increasing
concentrations of nickel sulphate (at least up to around 0.8 mg Ni/m3) in the inhaled air as well as with duration of
exposure. The study by Benson et al. (1988) indicates that the lung nickel burden may rise to a steady state level as the
lung nickel burdens were almost similar in rats exposed to 15 or 30 mg/m3. A third study (Dunnick et al. 1989) found
similar concentrations of nickel in the lungs of rats and mice after 4, 9, and 13 weeks of inhalation to nickel sulphate
(0.02 to 0.4 mg Ni/m3). Of nickel remaining in the body after 96 hours following a single dose of nickel sulphate
administered by intratracheal administration, over 50% was in the lungs. The deposition of nickel in the lungs of rats is
apparently greater than in the lungs of mice. No human data have been located.
Generally, nickel tends to deposit in the lungs of workers occupationally exposed to nickel compounds and in
experimental animals following inhalation or intratracheal instillation of nickel compounds. The tissue distribution of
nickel in experimental animals does not appear to depend significantly on the route of exposure (inhalation/intratracheal
instillation or oral administration) although some differences have been observed. Low levels of accumulation in tissues
are observed (generally below 1 ppm). A primary site of elevated tissue levels is the kidney. In addition, elevated
concentrations of nickel are often found in the lung, also after oral dosing, and in the liver. Elevated nickel levels are less
often found in other tissues. Limited information exists on tissue distribution in humans.
Absorbed nickel is excreted in the urine, regardless of the route of exposure. Most ingested nickel is excreted via faeces
due to the relatively low gastrointestinal absorption. In humans, nickel excreted in the urine following oral intake of
nickel sulphate accounts for 20-30% of the dose administered in drinking water to fasting subjects compared with 1-5%
when administered together with food or in close proximity to a meal.
From biological monitoring in small groups of electroplaters exposed to nickel sulphate and nickel chloride, the half-life
for urinary elimination of nickel has been estimated to range from 17 to 39 hours.
Inhaled nickel particles can be eliminated from the respiratory tract either by exhalation, by absorption from the
respiratory tract, or by removal due to mucociliary elimination.
Reports.
94
4.1.2.2 Acute toxicity
4.1.2.2.1 Animal studies
A number of studies on nickel sulphate have been carried out with different species and by different routes. Relevant
studies for the assessment of acute toxicity have only been found for the oral route and are shown in Table 4.1.2.2.1A.
4.1.2.2.1.1
Inhalation
No proper acute inhalation study with nickel sulphate has been found. A study with intratracheal instillation has been found
(Benson et al. 1986). This study has not been used for the risk assessment, because the relevance of intratracheal
instillation in relation to acute toxicity via inhalation is not known.
4.1.2.2.1.2
Oral
The oral acute toxicity study by FDRL (1983) has been performed according to GLP. Groups of 5 Sprague-Dawley rats
of each sex received single oral doses of 22, 40, 70, 125 or 223 mg Ni/kg (100, 178, 316, 562, or 1000 mg/kg of 98.8%
pure nickel sulphate hexahydrate) at a constant concentration. After dosing, the rats were observed for 15 days. A gross
necropsy was performed on all animals. Symptoms observed include decreased activity, diarrhoea, swollen limbs, and
ataxia. The LD50 for males was determined as 72 mg Ni/kg (325 mg nickel sulphate hexahydrate/kg), and for females
61 mg Ni/kg (275 mg nickel sulphate hexahydrate/kg).
In a dose range-finding study for a micronucleus test (Covance 2003), groups of 6 male Sprague-Dawley rats were
given oral doses by gavage of 0, 27.5, 55, or 110 mg Ni/kg bw/day (0, 125, 250, or 500 mg/kg bw/day of 99.99% pure
nickel sulphate hexahydrate) for 3 days. One animal at 55 mg Ni/kg/day was found dead after the second dose; clinical
signs of toxicity included salivation, slight hypoactivity, irregular/audible/laboured respiration. Clinical signs of toxicity
at the highest dose level included salivation, slight hypoactivity and hypersensitivity to touch.
In a second dose range-finding study, oral doses of 0, 165, 220, 275, 330, or 385 mg Ni/kg bw/day (0, 750, 1000, 1250,
1500, or 1750 mg/kg bw/day of 99.99% pure nickel sulphate hexahydrate) were administered for 3 days. One animal at
275 mg Ni/kg bw/day was found dead after the first dose. Following the second dose, the mortality (found dead,
sacrificed due to severe toxicity, or sacrificed due to severe toxicity in the dose group) was: 1/6 at 220 mg Ni/kg
bw/day, 5/6 at 275 mg Ni/kg bw/day, 6/6 at 330 mg Ni/kg bw/day, and 6/6 at 385 mg Ni/kg bw/day. Following the third
dose, the mortality (found dead, sacrificed due to severe toxicity, or sacrificed due to severe toxicity in the dose group)
was: 4/6 at 165 mg Ni/kg bw/day, and 3/6 at 220 mg Ni/kg bw/day. Clinical signs of toxicity included hypoactivity,
squinted and/or closed eyes, salivation, irregular respiration, lateral recumbency, piloerection, cold to touch, sensitive to
touch, and black/soft feces.
In the main study, oral doses of 0, 27.5, 55, or 110 mg Ni/kg bw/day (0, 125, 250, or 500 mg/kg bw/day of 99.99% pure
nickel sulphate hexahydrate) were given for 3 days. No mortality was seen in any dose group. Clinical signs of toxicity
noted in some animals included hypoactivity and/or salivation. Additional clinical signs of toxicity in four of the top
dose animals included black feces, irregular respiration, squinted eyes, and/or closed eyes.
Table 4.1.2.2.1A: Summary of acute oral toxicity studies
Species
End point
Dose
Result
Reference
Rat
LD50
50% aqueous solution
112 mg Ni/kg
Kosova (1979 - quoted
from UK HSE 1987)
(500 mg NiSO4.6H2O/kg)
Rat
4.1.2.2.1.3
LD50
22, 39, 70, 124 and 220
mg Ni/kg (100, 178, 316,
562, 1000 mg nickel
sulphate hexahydrate/kg)
72 mg Ni/kg (325 mg
NiSO4.6H2O /kg) (males)
FDRL (1983)
61 mg Ni/kg (275mg
NiSO4.6H2O/kg) (females)
Dermal
For the dermal route, a study has been found where NiSO4.6H2O corresponding to 40, 60, 100 mg Ni/kg in 0.25%
normal saline daily for 30 days was administered to the skin of male rats (amount of NiSO4.6H2O not given) (Mathur et
al. 1977a.). No clinical signs of poisoning or mortality were found. This study has not been performed according to the
Annex V method and does not allow the determination of a dermal LD50 for nickel sulphate.
95
4.1.2.2.1.4
Other routes
A study has been found where nickel sulphate was administered intraperitoneally in doses of 6.7 mg Ni/kg bw/day and
8.9 mg Ni/kg bw/day for 2 days (Adler & Adler 1977). At the lower dose no rats died, while 8/9 rats died after 48 h at
the higher dose.
4.1.2.2.1.5
Conclusion, animal studies
Data on acute toxicity of nickel sulphate are mainly based on studies using nickel sulphate hexahydrate as the test substance.
Acute oral LD50 for nickel sulphate ranging from 61 – 72 mg Ni/kg (275-325 mg NiSO4.6H2O/kg) (FDRL 1983) to 112 mg
Ni/kg (500 mg/kg NiSO4.6H2O) (Kosova 1979) have been reported. The FDRL study is a GLP study and otherwise well
performed and is used for the risk characterisation. The LD50 for the most sensitive sex, females, in the study is 61 mg Ni/kg
(275 mg NiSO4.6H2O/kg). This value is taken forward to the risk characterisation.
Nickel sulphate hexahydrate fulfils the Annex VI criteria for classification as Harmful with Xn; R22 (Harmful if
swallowed). If the FDRL female LD50 value is recalculated as anhydrous nickel sulphate, a value of 162 mg/kg results, and
classification as Toxic with T; R25 (Toxic if swallowed) is appropriate. The calculated LD50 for nickel sulphate
monohydrate, which is marketed as a High Production Volume Chemical (see Chapter 2) would also result in classification
as T; R25. Based on the 300 mg/kg cut-off in the GHS criteria, all the commercially available products including the
hexahydrate would be classified for acute toxicity in Category 3 on the basis of the female LD50 from the FDRL study.
There is no data for acute inhalational toxicity from properly conducted Annex V inhalation tests for nickel sulphate.
Nickel sulphate can be absorbed via inhalation, and thus relevant toxicity cannot be excluded. For the purpose of the risk
characterisation the LOAEC of 0.7 mg Ni/m3 for reduced body weight and adverse effects in the respiratory tract
(atrophy and inflammation) from the 16-day repeated dose toxicity study by NTP (1996a) is used. The use of results
from this repeated dose study is considered to be a conservative approach, since greater toxicity is expected from
repeated exposure (12 exposures during 16 days) compared to a single 4h exposure as in the Annex V test.
Data from repeated dose studies are not directly useful for classification, since greater toxicity is expected from
repeated exposure (12 exposures during 16 days) compared to a single 4h exposure as in the Annex V test. The NTP 16
day repeated dose toxicity inhalation study (NTP, 1996a) however showed mortality in rats at a level roughly 30 times
lower than the lower cut-off for classification for T; R23 and 100% of the female and 40% of the male rats died at the
highest dose before the end of the study. There is evidence for acute oral toxicity for soluble nickel compounds and
absorption via inhalation is considerably greater than via the oral route.
There is no data on which an acute dermal LD50 can be estimated. However, acute toxicity is expected to be low in view of
the poor absorption by this route. Classification for this effect is not considered to be relevant.
4.1.2.2.2 Human data
In the 19th century, nickel salts were used medicinally. In a report from 1883, treatment with 65-195 mg nickel sulphate
(probably equivalent to 15-44 mg Ni, as the nickel is likely to be given as the hexahydrate salt) for diarrhoea and
epilepsy was well tolerated and therapeutically beneficial, whereas a dose of 325 mg (73 mg Ni) induced giddiness,
nausea, variable slowing of the pulse, and light reduction of body temperature. (Da Costa 1883 - quoted from
Sunderman et al. 1988).
In an accident, a 2½ year-old girl died after having swallowed an estimated dose of at least 5 g of crystalline nickel
sulphate. The child rapidly became stuporous and developed nuchal rigidity, erythema, dilated pupils, tachycardia, and
pulmonary congestion. Despite repeated resuscitations after cardiac arrests, the child died 8 hours after the poisoning,
and the autopsy revealed acute hemorrhagic gastritis. (Daldrup et al. 1983).
In an industrial accident, 32 electroplating workers drank water contaminated with nickel sulphate and chloride (1.63 g
Ni/l). Twenty workers developed symptoms (e.g., nausea, vomiting, abdominal discomfort, diarrhoea, giddiness,
lassitude, headache, cough, shortness of breath) that typically lasted for a few hours, but in 7 cases persisted for 1-2
days. The nickel doses in workers with symptoms were estimated to range from 0.5-2.5 g. This corresponds to a dose of
7.1-35.7 mg Ni/kg bw for an adult weighing 70 kg. Serum nickel concentrations in 15 workers had a range of 13-1340
microgram Ni/1 and urine nickel concentrations had a range of 0.15-12.0 mg Ni/g creatinine on day 1 after exposure.
Laboratory tests showed elevated levels of blood reticulocytes, urine albumin and serum bilirubin. All workers
recovered rapidly without evident sequelae, and returned to work by the eighth day after exposure. (Sunderman et al.
1988).
96
4.1.2.2.3 Conclusion
An LD50 for acute oral toxicity of 61 mg Ni/kg (275 mg NiSO4.6H2O) (the LD50 for females from the FDRL study) is
used for the risk characterisation. The current classification of nickel sulphate as Harmful with Xn; R22 (Harmful if
swallowed) remains unchanged in the 30th ATP.
No data for acute inhalational toxicity has been found. Considering the acute oral toxicity of the substance, the potential
for absorption via the respiratory tract and observed lethality in a 16-days inhalational study, additional classification for
acute inhalational toxicity is considered to be justified. The TC C&L has agreed to classify nickel sulphate as Harmful
with Xn; R20. This classification is included in the Annex I entry in the 30th ATP.
With respect to the risk characterisation the LOAEC of 0.7 mg Ni/m3 for reduced body weight and adverse effects in the
respiratory tract (atrophy and inflammation) from the 16-day repeated dose toxicity study by NTP (1996a) is used. The
use of results from this repeated dose study is considered to be a conservative approach, since greater toxicity is
expected from repeated exposure (12 exposures during 16 days) compared to a single 4h exposure as in the Annex V
test.
Further testing of acute inhalational toxicity is not considered necessary for the risk assessment of nickel sulphate.
There is no data on which to evaluate acute dermal toxicity. However, acute toxicity is expected to be low in view of the
poor absorption by this route.
4.1.2.3 Irritation /corrosivity
4.1.2.3.1.1
Skin and eye irritation
The skin and eye irritation potential of nickel sulphate has been tested in several studies, which are summarised in Table
4.1.2.3.A.
The skin irritation potential has been examined in a study performed by the Annex V method (SLI 1999a). Nickel
sulphate gave only slight irritation (erythema) in the test.
Three other studies have been found. In two of these, the application was repeated for 30 days, and resulted in adverse
effects on the skin.
Table 4.1.2.3.A: Summary of skin and eye irritation studies
Skin
Species
Result
Grading
(irritation scores)
Method
Reference
rabbits,
not irritant
0.42 (erythema)
Annex V
SLI 1999a
Adult New
Zealand White: 2
male, 1 female
0.00 (oedema)
Rabbits
Pustules seen on
wounded skin but
not intact skin
50%
aqueous
solution
Wahlberg &
Maibach 1981
Rats
skin atrophy,
acanthosis and
hyperkeratinisation
40 – 100
mg Ni/kg
bw/day
Mathur et al.
1977a.
repeated
application
for 30 days
97
Eye
Species
Result
Rats
Erythema, eschar
Rabbits,
not irritant
Adult New
Zealand White: 2
male, 1 female
Grading
(irritation scores)
Method
Reference
50%
Kosova (1979
aqueous
– quoted from
solution
UK HSE 1987)
daily for 30
days
0. 00 (corneal opacity) Annex V
SLI 1999b
0.33 (iris lesion)
0.67 (conjunctival
redness)
0.44 (conjunctival
oedema)
The results of the two recent SLI (1999) GLP studies shown above indicate that nickel sulphate is not corrosive, and does
not fulfil the EU criteria for classification for either skin or eye irritation.
There is however older data quoted by UK HSE (1987) from Wahlberg & Maibach (1981), Mathur et al. (1977), and
Kosova (1979) that indicates that the salt does have effects on the skin. In two of these studies the effects were seen after
repeated administration during 30 days. These data are, however, not readily interpretable in terms of the classification
criteria (EC 1999).
4.1.2.3.1.2
Respiratory irritation
No studies examining the respiratory irritation caused by a single exposure to nickel sulphate have been found. Several
studies have shown lung inflammation and degeneration of the olfactory epithelium following relatively short periods of
exposure (Benson et al. 1988 (aerosol inhalation 12 days), Dunnick et al. 1989 (inhalation – 13 weeks), Benson et al. 1989
(aerosol inhalation 13 weeks) - all quoted from NiPERA, 1996). Nickel sulphate induces atrophy of the olfactory epithelium
and lung inflammation in mice and rats after only 16 days inhalation exposure (NTP, 1996a). The lowest dose tested was 0.7
mg Ni/m3 and this was a LOAEL.
4.1.2.3.2.1
Skin irritation
In a study performed to develop a new test for skin irritancy, nickel sulphate was included as one of the test agents
(Frosch & Kligman, 1976). A volume of 0.1 ml of nickel sulphate in various concentrations was pipetted on to a disc of
two thicknesses of non-woven cotton cloth. The disc was mounted in a chamber designed for use in tests of contact
sensitisation, which was sealed to the skin with non-occlusive tape or Dermicel®. The advantage of the chamber
compared with the use of patches was that there was no loss of test material and uniform contact with the skin. The test
subjects were groups of 5-10 light-skinned, young Caucasians. The test material was applied on the mid-volar forearm
once daily for 3 days with readings made at 72h, 30 min after removal. The test was conducted on both intact and
scarified skin. The reactions were graded on a five-point scale from 0 to 4 (1: erythema, 2: increased erythema, 3:
severe erythema with partial confluency with or without other lesions, 4: confluent severe erythema sometimes
associated with oedema, necrosis or bulla formation). On scarified skin nickel sulphate gave a dose-dependent response
in the test, ranging from a score of 1 at a concentration of 0.13% to 4 at 1%. The dose-response plot is very steep for
nickel sulphate. The authors describe their results as “a marginal irritant” at 0.13% but “a ferocious one at 1%”.
The sensitivity of the assay on scarified skin was compared with the sensitivity on normal skin. No details of the results
on normal skin are shown. The threshold concentration to produce “just an irritation reaction in 3 days” on normal skin
was 20.0% while on scarified skin it was 0.13%. The ratio of threshold concentration on normal skin and threshold
concentration on scarified skin was 154. This was the highest ratio among the substances tested, which included
surfactants, inorganic salts, antimicrobials, and acids (Frosch & Kligman, 1976).
Skin irritancy of nickel sulphate has also been reported in studies primarily concerned with skin sensitisation.
98
Kalimo & Lammintausta (1984) tested nickel chloride and nickel sulphate in patch tests with 24 and 48 h exposures. A
5% nickel chloride solution also caused irritation under occlusion, whilst a 2.5% solution could be used for patch
testing. The standard patch test material for nickel sulphate (assumed to be 5%) was also irritant after occlusion.
Fullerton et al. (1989) tested various concentrations of nickel chloride hexahydrate in a hydrogel as a possible
alternative to the standard patch test material of 5% nickel sulphate pet. A 5% standard nickel sulphate patch, as well as
the 0.5% - 2% nickel chloride hydrogels caused some irritation.
Storrs et al. (1989) recorded 8 cases of irritancy in 1123 subjects patch tested with 2.5% nickel sulphate in petrolatum.
Wahlberg (1990) reported that nickel chloride is more irritating than nickel sulphate when applied in equal
concentration.
Twenty-five healthy volunteers with no previous history of eczema underwent 5 patch tests with nickel sulphate in
concentrations of 5, 10, and 20%, and 2 control areas. It was concluded that in non-nickel-sensitive subjects, aqueous
solutions of nickel sulphate between 5 and 20 % did not evoke irritation on the skin (Seidenari et al. 1996).
4.1.2.3.2.2
Respiratory irritation
A number of case reports describe the relation between nickel sulphate and occupational asthma. Please see section
4.1.2.4.2.
No information on non-allergic respiratory irritation in relation to short-term exposure has been found.
In an Annex V test in rabbits, nickel sulphate was not a skin irritant. However, human data indicate that nickel sulphate
in concentrations above 20% can induce skin irritation. Based on this human data, t nickel sulphate is classified as Xi;
R38 with a specific concentration limit of 20% in the 30th ATP.
Nickel sulphate is not an eye irritant in experimental animals. The TC C&L has agreed not to classify nickel sulphate
for eye irritation.
The available data do not allow any conclusion on respiratory irritation. The criteria for classification for respiratory
irritation are mainly based on human experience, which is lacking. There is a concern for respiratory irritation. However, this
concern is considered to be more appropriately covered by the proposed classification for chronic effects (T; R48/23) with a
specific concentration limit lower than the general limit in the Preparations Directive (EC, 1999).
4.1.2.4 Sensitisation
4.1.2.4.1.1
Skin sensitisation
A number of studies on skin sensitisation in guinea pigs have been performed with nickel sulphate. Some of these
studies are summarised in Table 4.1.2.4.A.
Table 4.1.2.4.A: Summary of skin sensitisation studies in animals
Species
Result
Method
Reference
Guinea pig
11/22*, 4/7
Skin painting
Lammintausta et
al. (1985, 1986)
Guinea pig
20/20, 7/20, 12/20
Optimization test
Maurer et al.
(1979)
Guinea pig
13/14
Intradermal 1%, challenge
2%
Guinea pig
21/30, 27/30
Open adm. + SLS + potassium alun
injections
Bezian et al.
(1965)
Zissu et al. (1987)
99
Species
Result
Method
Reference
Guinea pig
Maximum response 40%
positive after 3% i.d.
induction
GPMT
I.d. induction 0.01%-3% aqueous
Topical induction
0.25%-10% pet
Challenge 1% pet
Rohold et al.
(1991)
Guinea pig
1% lanolin: 57-93% pos.
Open epicutaneous
pretreatment SLS
0.3%-3% in lanolin or 0.3%-3% in
hydroxypropyl cellulose
i.d. injections of adjuvant
Nielsen et al.
(1992)
3% lanolin: 60-100% pos.
1% hydroxypropyl
cellulose: 67-75% pos.
The dose-response relationship for nickel sulphate hexahydrate has been studied in the guinea pig maximization test.
Six intradermal (0.01%-3.0% solutions in water) and six topical (0.25%-10.0% pet.) concentrations were chosen for
induction and nickel sulphate hexahydrate 1% in petrolatum was used for challenge in the first instance. At 48 h, a
linear relationship was obtained between the intradermal induction dose (but not topical dose) and the response,
resulting in a maximum sensitisation rate of 40% after intradermal induction with 3% nickel sulphate. The reactivity
disappeared at re-challenge 1 week later. Following a booster closed patch on day 35, using 10% nickel sulphate in
petrolatum, the animals were challenged with nickel sulphate 2% in petrolatum and statistical analyses of 72-h readings
revealed a non-linear dose-response relationship, giving a maximum response frequency of 40% after initial induction
with nickel sulphate 3% intradermally and 2% after topical application. (Rohold et al. 1991).
As the maximum response rate of 40%, found in the study cited above was found to be low, an open epicutaneous
application method was tried, and found to be more efficient. Immediately after pre-treatment with 1% aqueous sodium
lauryl sulphate, the upper back skin was treated daily for 4 weeks with 0.3%-3% nickel sulphate in either a 1% lanolin
cream (Vaseline, pH 5 SAD cream) or hydroxypropyl cellulose. Weekly intradermal injections with aluminium
potassium sulphate were used as adjuvant. The animals were challenged twice with a one-week interval, with nickel
sulphate 2% in water and 1% in petrolatum, respectively. Considering both readings at both challenges concentrations,
the frequency of sensitisation was 57-93% (8 /14 to 13/14 animals) in the group treated with 1% in the lanolin cream,
60-100% (9/15 to 15/15 animals) in the group treated with 3% in the lanolin cream, and 67-75% (8/12 to 9/12 animals)
in the group treated with 1% in hydroxypropyl cellulose. Rechallenge of initially sensitised animals 10 weeks later
confirmed that a lasting contact allergy had been obtained. (Nielsen et al. 1992). Basketter & Scholes (1992) tested
nickel sulphate in the local lymph node assay (LLNA) in mice at concentrations of 0.5, 1 and 2.5%. Nickel sulphate was
negative in the LLNA.
Several studies have demonstrated that immunological tolerance to nickel can be achieved in animals (Vreeburg et al.,
1984; van Hoogstraten et al., 1992a and b; van Hoogstraten et al., 1993; Ishii et al., 1993; van Hoogstraten et al., 1994;
Troost et al., 1995; and Artik et al. 1999). In a number of experiments on mice and guinea pigs, persistent immune
tolerance to nickel was induced by oral dosing with nickel prior to cutaneous exposure (Ishii et al., 1993; van
Hoogstraten et al., 1992; Vreeburg et al., 1984). It was observed that intragastric priming with nickel sulphate prior to
sensitisation successfully reduced the cutaneous delayed type hypersensitivity response to cutaneous application of the
same antigen in mice in a dose-dependent manner, as measured by ear swelling (van Hoogstraten et al., 1993).
Although the objective of these studies was to investigate the possibility to induce immunological tolerance to nickel,
indirectly they provide evidence that nickel sulphate can induce skin sensitisation in mice.
4.1.2.4.1.1.1 Conclusion, animal studies, skin sensitisation
A number of studies using different protocols showed that nickel sulphate is a skin sensitiser in guinea pigs and mice.
4.1.2.4.1.2
Respiratory sensitisation
No data regarding respiratory sensitisation in animals have been located.
100
4.1.2.4.2.1
Skin sensitisation
Nickel allergy is induced by skin exposure to nickel ions, which are considered to be exclusively responsible for the
immunological effect of nickel (Menné 1994). Most cases of primary nickel sensitisation are caused by skin contact
with metallic items such as ear ornaments, ear stickers, jewellery, jeans buttons, and other nickel releasing items
(European Environmental Contact Dermatitis Group 1990). But occupational sensitisation may be caused by nickel
sulphate and sensitisation to nickel sulphate has also been established experimentally.
Nickel allergy is normally diagnosed by patch testing with nickel sulphate. Thus there is an abundance of data from
patch test studies where nickel sulphate has been used as the source of nickel ions. Most of these studies are relevant for
nickel metal sensitisation and can be found in the Background document on nickel and nickel compounds. Three patch
test studies with nickel sulphate relevant for determining the threshold for elicitation of nickel allergy are summarised in
the present document.
4.1.2.4.2.1.1 Experimental sensitisation
Kligman (1966) established a human maximisation test with the purpose to test whether a given substance was able to
induce skin sensitisation. Further, the test was designed to yield allergenicity ratings depending on the frequency of
sensitisation in a group of 25 test persons. The test was carried out for nickel sulphate, where the induction procedure
consisted of 5 sequences of 48 hours treatment with 10% nickel sulphate. The treatments were performed on the same
place on one extremity (forearm or calf of the leg) under occlusion. Whether the subjects became sensitised or not were
tested with the challenge concentration of 2.5% nickel sulphate. Twelve out of 25 attempts were successful, data, which
the author interprets as categorising, nickel sulphate as a moderate human sensitiser.
4.1.2.4.2.1.2 Occupational sensitisation
In order to study the appearance of nickel sensitisation in places where nickel sulphate is used one may turn to
occupational settings with nickel plating. We know that nickel sulphate has been used in the nickel-plating industry for
many years, but we do not know to which extent other soluble nickel compounds have been used.
In occupational settings, nickel dermatitis was recognised already in 1889 as “Das Galvanizierekzem” (Blaschko 1989).
Until 1930, nickel dermatitis was common among nickel platers, and in 1925 patch testing proved nickel allergy to be
the cause of dermatitis in the electroplating industry. During the next 10 years there was a successive decrease in nickel
sensitisation largely due to improved industrial hygiene. In a series of 621 nickel sensitive patients from Denmark, only
25 were nickel platers (Marcussen 1960). Since 1960, reports of nickel sensitivity in the electroplating industry have
been sparse (Mathur 1984). Schubert et al. (1987) found only 2 nickel sensitive electroplaters among 176 nickel
sensitive individuals.
A workplace survey was conducted in all 38 Finnish electroplating plants. All workers (n = 163) who worked with
nickel plating (bath workers, hangers and solution makers) were interviewed with a questionnaire about symptoms of
nickel dermatitis, hand dermatitis, and about protective measures, atopy, etc. Patch testing with nickel sulphate was
done with the TRUE Test™ method. All the workers, 94 men and 69 women, answered the questionnaire. The mean age
of women was 41.1 years, and of men 43.1 years, respectively. Men had longer occupational exposure to nickel (14
years) than women (10 years). Most workers used protective gloves. 35% of women and 30% of men reported present
or past hand dermatosis. 19% reported a history of atopic dermatitis. 15% of women (n = 8) and 4% (n = 2) of men had
an allergic patch test reaction to nickel sulphate. 70% of those with an allergic patch test reaction to nickel reported past
or present hand eczema. The prevalence of nickel allergy among the electroplaters was similar to that of patients in
patch test clinics in Finland. (Kanerva et al. 1997).
4.1.2.4.2.1.3 Elicitation of allergic response
Elicitation or provocation of nickel allergy can either be as a result of skin exposure with nickel sulphate or as a result
of oral intake of nickel sulphate. Data on oral intake and elicitation of allergic response can be found in the background
document on nickel and nickel compounds.
In order to consider how much nickel is needed for skin elicitation, Uter et al. (1995) patch tested 462 nickel sensitised
patients with serial dilutions of nickel sulphate in concentrations ranging from 264 - 0.026 µg Ni2+/cm2 (Table
4.1.2.4.2.A). Andersen et al. (1993) tested 72 nickel-sensitive patients with a 10-step nickel sulphate dilution series
(using the TRUE test) and two placebo patches using concentrations from 67 - 0.002 µg Ni2+/cm2. The results of these
studies are discussed in the background document.
101
Table 4.1.2.4.2.A: Total/threshold reactions (modified after Uter et al. 1995)
µg Ni++/
cm2
Ni conc
264.0
Of all reactions a)
No.
+-+++/thresh
%(+)
%(++)
%(+++)
5%
36.7
50.0
13.3
39
105.6
2%
42.2
47.1
10.7
17
52.8
1%
49.4
42.5
8.1
37
26.4
0.5%
60.7
31.4
7.9
70
5.3
0.1%
68.3
26.0
5.7
65
2.64
0.05%
68.9
24.6
6.5
30
0.53
100 ppm
83.8
16.2
-
19
0.264
50 ppm
100
-
-
5
0.053
10 ppm
100
-
-
4
0.026
5 ppm
-
-
-
0
0 ppm
- **) -
-
N
(tested)
462
372
329
92
462
a) %s are calculated from all reactions to a given concentration ‘all reactions’ are equal to or more than the cumulative
frequency of threshold reactions, as patients without a determinable threshold’) are included here.
‘)
patients without a determinable threshold are those with a negative reaction (few) or a questionable reaction to the
next higher concentration.
**) Uter (2003).
In the patch test nickel sulphate is applied under occlusion for 48 hours in order to enhance the penetration.
Repeated immersion in nickel solutions has also been studied. Allenby & Basketter (1994) studied immersion of the
hands in 1 ppm Ni (0.0001%) as nickel sulphate 2x10 min/day for one week where penetration was enhanced with the
skin irritant sodium dodecyl sulphate. No elicitation of allergic reaction in nickel sensitive subjects was found.
4.1.2.4.2.1.4 Thresholds for Sensitisation and elicitation
Determination of a threshold (NOEL) for both sensitisation and elicitation are important for both risk assessment and,
where relevant, setting specific concentration limits for the classification of mixtures of chemicals.
4.1.2.4.2.1.4.1
Elicitation
For diagnostic purposes in patch tests 2.5 or 5% nickel sulphate in petrolatum is used. Empirically this concentration
(132 or 264µg Ni/cm2 ) induces a positive reaction in nickel allergic individuals. The biological variation in this
response is substantial. On the basis of the available data it is not possible to set a scientifically based threshold for
elicitation (NOEL) in nickel-sensitised individuals. For use in the risk characterisation of occupational exposure an
empirical threshold based on the data from Uter et al. (1995) may be estimated. In the Uter study, a significant number
of patients react to a 48 hours patch with 0.5 µg Ni/cm2 (19/329). In the next dose group 5/92 patients react to 0.26 µg
Ni/cm2. These patients only react with a one plus reaction and must be considered to belong to the very most sensitive
part of the population. As it is unlikely that an occupational exposure will last for 48 hours and that workers in the
nickel industry have extremely sensitive nickel allergies we suggest an empirical threshold (NOEL) of 0.3 µg Ni/cm2.
4.1.2.4.2.1.4.2
Sensitisation
Estimating the risk from a certain exposure must include the dose per unit area of skin exposed (Robinson et al. 2000)
and the possibility of penetration i.e. duration of exposure and possible occlusion.
There are no data from skin exposure to nickel sulphate to allow an estimate of the dose of nickel sulphate that may
cause skin sensitisation. The empirical elicitation threshold of 0.3 µg Ni/cm2 is suggested as the best estimate of a
threshold for sensitisation. As sensitisation is assumed to require higher doses than elicitation this estimate for
sensitisation is more conservative than the estimate for elicitation.
102
This empirical threshold for elicitation and sensitisation of 0.3 µg Ni/cm2 is equivalent to a concentration of slightly
greater than > 0.005%. A specific concentration limit of 0.01% is proposed.
4.1.2.4.2.1.5 Conclusion, human data, skin sensitisation
Nickel sulphate is a skin sensitiser in humans, and meets the criteria for classification with R43.
In sensitised subjects patch tests with nickel sulphate may elicit positive response at low concentrations. On the basis of
the available data it is not possible to set a scientifically based threshold for elicitation (NOEL) in nickel-sensitised
individuals. However for use in risk characterisation we suggest an empirical threshold of 0.3 µg Ni/cm2 based on the
description above. If the exposure is not under occlusion the potential risk of elicitation of an allergic response may be
less.
There are no data from skin exposure to nickel sulphate to allow an estimate of the dose of nickel sulphate that may
cause skin sensitisation. However for use in risk characterisation we suggest an empirical threshold of 0.3 µg Ni/cm2
based on the description above.
The current classification with R43 is considered appropriate. In addition, a specific concentration limit of 0.01%, a
level 100 times lower than the general concentration limit normally associated with this effect, is also considered to be
justified.
4.1.2.4.2.2
Respiratory sensitisation
Five single cases of work related asthma due to exposure to nickel sulphate in electro- or metal plating have been
reported (Block et al. 1982, Malo et al. 1982, Malo et al. 1985, McConnell et al. 1973, Novey et al. 1983).
In all five cases, the diagnosis was based on clinical picture and specific bronchial inhalation test with nickel sulphate. 3
patients reacted to bronchial inhalation provocation with an isolated late asthmatic response, one with an isolated early
and one with a dual response. Skin test was positive in 3 cases (Malo et al. 1982, McConnell et al. 1973, Block et al.
1982) and negative in 2 persons (Malo et al. 1985, Novey et al. 1983). Specific IgE antibodies were detected in two
cases (Malo et al. 1982, Novey et al. 1983), both cases had an early response either isolated or as part of a dual
response. RAST for specific IgE antibodies were negative in one case (Malo et al. 1985) and not performed in two
(Block et al. 1982, McConnell et al. 1973). Also a case of work related rhinitis due to nickel in soldering fumes was
seen. A provocation test with instillation of nickel sulphate into nostrils was positive (Niordson 1981). These results
indicate that nickel may induce asthma by both immunological and non-immunological mechanisms (Malo et al. 1985).
4.1.2.4.2.2.1 Conclusion, human data, respiratory sensitisation
Nickel sulphate is a respiratory sensitiser, and meets the criteria for R42.
There is no evidence on which a proposal for a specific concentration limits can be based.
Nickel sulphate is a skin and respiratory sensitiser in humans and a skin sensitiser in experimental animals, and meets
the criteria for classification as R42 and R43.
In sensitised subjects, patch tests with nickel sulphate may elicit a positive response at low concentrations. On the basis
of the available data it is not possible to set a scientifically based threshold for elicitation (NOEL) in nickel-sensitised
individuals. However for use in risk characterisation we suggest an empirical threshold of 0.3 µg Ni/cm2. If the
exposure is not under occlusion, the potential risk of elicitation of an allergic response may be less.
It is not possible to establish a NOAEL for oral challenge in patients with nickel dermatitis. The LOAEL established
after provocation of patients with empty stomach is 12µg/kg body weight (Nielsen et al. 1999). It should be noted that
this dose is the acute LOAEL in fasting patients on a 48h diet with reduced nickel content. A LOAEL after repeated
exposure may be lower and a LOAEL in non-fasting patients is probably higher because of reduced absorption of nickel
ions when mixed in food. For more details see the Background report on nickel and nickel compounds.
For use in risk characterisation an empirical threshold of 0.3 µg Ni/cm2 for skin sensitisation is suggested.
103
Nickel sulphate is already classified as R42/43. The existing classification of nickel sulphate as R42/43 has been
confirmed in the 30th ATP with the addition of a specific concentration limit of 0.01% for R43.
4.1.2.5 Repeated dose toxicity
The most recent review (TERA 1999) identifies the target organ for non-cancer effects of inhalation exposure to nickel
sulphate as the respiratory tract, with effects seen in both the lungs and the nose. For oral exposure, the most sensitive
target is stated to be the kidney, specifically decreased glomerular function. For the dermal route, general toxicity is not
mentioned. In the following, the available studies on repeated dose toxicity are described.
There are a number of studies on repeated dose toxicity of nickel sulphate using the three major routes of dosing.
Thirteen studies have been found, where repeated dose toxicity via inhalation has been investigated (rats: 16 days, 13
weeks (3 studies), 6 months, 9 months, 2 years, shown in table 4.1.2.5.G; mice: 16 days, 13 weeks (3 studies), 6
months, 2 years, shown in table 4.1.2.5H).
Eight studies of effects of repeated oral exposure have been found (rats: 13 weeks - drinking water, 90 days – gavage, 3
and 6 months - drinking water, 7 months - gavage, 2 years - diet; dogs: 2 years – diet; mice: 21 days – diet, 180 days drinking water, 7 of these shown in table 4.1.2.5I).
Three studies of repeated dermal toxicity have been found, none of which are considered useful for the risk assessment.
4.1.2.5.1.1
Inhalation
The National Toxicology Program (NTP) performed a comprehensive investigation of the possible toxic effects in rats
and mice after subacute, subchronic and chronic inhalation of nickel sulphate hexahydrate (NTP, 1996a). The chronic
studies performed were combined chronic/carcinogenicity studies. The mass mean particle diameter was 1.8-3.1
micrometer ± 1.6-2.9; and the test substance was greater than 98% pure. The data concerning the chronic toxicity of
nickel sulphate hexahydrate are dealt with in the present section with the most important toxic effects observed listed in
tables, and the data concerning carcinogenicity is described in section 4.1.2.7.1.
4.1.2.5.1.1.1 NTP studies on rats and mice
4.1.2.5.1.1.1.1
16-day rat study
Groups of five male and five female F344/N rats were exposed to NiSO4.6H2O in concentrations equivalent to 0, 0.7,
1.4, 3.1, 6.1, or 12.2 mg Ni/m3 (0, 3.5, 7, 15, 30, or 60 mg NiSO4.6H2O (greater than 98% pure) /m3). Rats were
exposed for 6h/day on weekdays only, for a total of 12 exposure days during a 16-day period. Additional groups of four
or five male and female F344/N rats were exposed to NiSO4.6H2O in concentrations equivalent to 0, 0.7, 3.1, or 6.1 mg
Ni/m3 (0, 3.5, 15, or 30 mg NiSO4.6H2O /m3) for tissue burden studies. The results of the study is summarised in Table
4.1.2.5A.
In the core study, two 12.2 mg Ni/m3 males, one 6.1 mg Ni/m3 female, and all 12.2 mg Ni/m3 females died before the
end of the study. Final mean body weights of all exposed groups of males and females were significantly lower than
those of the controls, as were mean body weight gains of male rats. Clinical findings included increased rates of
respiration and reduced activity levels in rats in all exposure groups, except those exposed to 0.7 mg Ni/m3. Absolute
and relative lung weights in all exposed groups were significantly greater than those of the controls. In spite of
markedly reduced body weight (20 to 50%), absolute lung weights were increased by 45-100%. Inflammation
(including degeneration of the bronchiolar epithelium) occurred in the lungs of all exposed groups of males and
females. Necrosis of the bronchial epithelium was observed in females at 12.2 mg Ni/m3. Atrophy of the olfactory
epithelium occurred in the nasal passages of all exposed groups of males and females. Degeneration of respiratory
epithelium of the nose was observed at 3.1 mg Ni/m3 in both males and females, but not at 12.2 mg Ni/m3 in males and
at 6.1 and 12.2 mg Ni/m3 in females. Lymphoid hyperplasia in the bronchial lymph nodes was observed in 3.1 mg Ni/m3
males and in 1.4 and 3.1 mg Ni/m3 females. The concentration of nickel in the lungs of all exposed groups of males and
females was greater than in control animals. The lowest exposure level, 0.7 mg Ni/m3 (3.5 mg NiSO4.6H2O/m3), was a
LOAEC in both sexes for 20% reduced body weight, 45% increased absolute lung weight, atrophy of the olfactory
epithelium and lung inflammation.
104
Table 4.1.2.5A: Summary of 16-day rat study (NTP, 1996a)
Exposure level
mg Ni/m3
Effects observed
Response rate
NOAEC/
LOAEC
mg Ni/m3
0, 0.7, 1.4, 3.1,
6.1, 12.2
Lung inflammation in males
0/5, 5/5, 5/5, 5/5, 5/5, 4/5
- /0.7
Lung inflammation in females
0/5, 5/5, 5/5, 5/5, 5/5, 5/5
- /0.7
Degeneration, bronchial epithelium in males
0/5, 5/5, 5/5, 5/5, 5/5, 0/5
- /0.7
Degeneration, bronchial epithelium in females
0/5, 5/5, 5/5, 5/5, 4/5, 0/5
- /0.7
Necrosis, bronchial epithelium in males
- ,-, -, -,-,-
Necrosis, bronchial epithelium in females
0/5, 0/5, 0/5, 0/5, 0/5, 4/5
6.1/12.2
Lymph node, bronchial hyperplasia in males
0/2, 4/5, 4/4, 5/5, 0/3, 0/5
1.4/3.1
Lymph node, bronchial hyperplasia in females
0/3, 3/4, 4/4, 4/4, 0/2, 0/4
0.7/1.4
Lymph node, mediast. Hyperplasia in males
0/2, 2/3, 3/3, 2/3, 0/3, 0/3
-
Lymph node, mediast. Hyperplasia in females
0/3, 3/5, 3/4, 2/3, 0/4, 0/2
-
Atrophy of olfactory epithelium in males
0/5, 5/5, 5/5, 5/5, 5/5, 4/5
- /0.7
Atrophy of olfactory epithelium in females
0/5, 5/5, 5/5, 5/5, 5/5, 5/5
- /0.7
Degeneration of resp. Epitelium in males
0/5, 1/5, 1/5, 5/5, 4/5, 0/5
1.4/3.1
Degeneration of resp. Epitelium in females
0/5, 0/5, 0/5, 5/5, 2/5, 2/5
1.4/3.1
4.1.2.5.1.1.1.2
-
13-week rat study
Groups of ten males and ten female F344/N rats were exposed to NiSO4.6H2O in concentrations equivalent to 0, 0.027,
0.056, 0.11, 0.22, or 0.44 mg Ni/m3 (0, 0.12, 0.25, 0.5, 1, or 2 mg NiSO4.6H2O /m3), 6h/day, 5 days per week for 13
weeks. Additional groups of six male and six female F344/N rats were exposed to NiSO4.6H2O in concentrations
equivalent to 0, 0.027, 0.11 or 0.44 mg Ni/m3 (0, 0.12, 0.5, or 2 mg NiSO4.6H2O /m3) for tissue burden studies. The
results of the study is summarised in Table 4.1.2.5B.
In the core study, one 0.44 mg Ni/m3 male rat died before the end of the study; all other males and all females survived
until the end of the study. Final mean body weights and body weight gains of all exposed groups were similar to those
of the controls. There were no significant clinical findings noted during the study. Exposure-related increases in
neutrophile and lymphocyte numbers occurred and were most pronounced in female rats. With the exception of 0.027
mg Ni/m3 rats, absolute and relative lung weights of all exposed groups were generally significantly greater than those
of the controls.
Exposure-related increases in the incidence and severity of inflammatory lesions (alveolar macrophages, chronic
inflammation, and interstitial infiltration) occurred in the lungs of all exposed groups of males and females (Lymphoid
hyperplasia of the bronchial and/or mediastinal lymph nodes occurred in males exposed to 0.22 mg Ni/m3 or greater).
Atrophy of the olfactory epithelium occurred in males and females exposed to 0.22 and 0.44 mg Ni/m3. The
concentration of nickel in the lungs of 0.11 and 0.44 mg/m3 rats was greater than the concentrations in the lungs of
control animals at 4, 9, and 13 weeks for males and at 13 weeks for females.
Further, for the later evaluation on reproductive effects, at terminal sacrifice sperm samples were collected from all
male animals in the three highest exposure groups for sperm morphology evaluations (sperm density, morphology and
motility). The right epididymis and right testis were weighed. Vaginal samples were collected for up to seven
consecutive days prior to the end of the studies from all females for vaginal cytology evaluations (relative frequency of
oestrus stages, oestrus cycle length). There were no significant effects on sperm morphology or vaginal cytology.
In this study, chronic lung inflammation was the most serious adverse effect detected. Females were more sensitive than
males. Accumulation of macrophages was found at all exposure levels, and it has been debated whether the reaction
should be interpreted as an adaptive repair response, or as an adverse event in a sequence leading ultimately to fibrosis.
A definitive conclusion regarding the biological significance of macrophage accumulation is not possible according to
the TERA review (1999). Macrophage accumulation may not in itself be considered as an adverse reaction. However,
105
as macrophage accumulation is very closely linked to the development of inflammation, this could in relation to risk
assessment be taken as a sign of an adverse event. In the absence of a definitive conclusion regarding the toxicological
significance of macrophage accumulation it is difficult to base a NOAEC/LOAEC from this study on this effect. The
NOAEC/LOAEC for inflammation which is regarded as a clear adverse effect is 0.056/0.11 mg Ni/m3 (0.25/0.5 mg
NiSO4.6H2O /m3).
Table 4.1.2.5.B: Summary of 13-week rat study (NTP, 1996a)
Exposure level
mg Ni/m3
Effects observed
Response rate
NOAEC/
LOAEC
mg Ni/m3
0, 0.027, 0.056,
0.11, 0.22, 0.44
Inflammation, chronic active in males
0/10, 0/10, 0/10, 2/10, 10/10, 8/9
0.11/0.22
Inflammation, chronic active in females
0/10, 0/10, 0/10, 4/10, 10/10, 10/10
0.056/0.11
Interstitial infiltrate in males
1/10, 0/10, 1/10, 5/10, 10/10, 9/9
0.11/0.22
Interstitial infiltrate in females
0/10, 0/10, 0/10, 6/10, 10/10, 10/10
0.056/0.11
Macrophage hyperplasia in males
0/10, 10/10, 10/10, 10/10, 10/10, 9/9
- /0.027
Macrophage hyperplasia in females
0/10, 8/10, 10/10, 10/10, 10/10, 10/10
- /0.027
0/5, - , 0/8, 4/10, 8/10, 9/9
0.11/0.22
0/7, - , 0/10, 4/10, 9/9, 10/10
0.11/0.22
Lymph node, mediast. Hyperplasia in males
0/5, - , - , 0/10, 9/10, 7/9
0.11/0.22
Lymph node, mediast. Hyperplasia in females
0/9, - , - , 0/8, 8/10, 9/10
0.11/0.22
0/10, 0/10, 0/10, 1/10, 10/10, 9/9
0.11/0.22
0/10, 0/10, 1/10, 2/10, 10/10, 10/10
0.11/0.22
4.1.2.5.1.1.1.3
2-year rat study
Groups of 63 to 65 male and 63 to 64 female F344 rats were exposed to NiSO4.6H2O by inhalation at concentrations
equivalent to 0, 0.027, 0.056, or 0.11 mg Ni/m3 (0, 0.12, 0.25, or 0.5 mg NiSO4.6H2O/m3. Animals were exposed for 6
hours a day for 5 days per week for 104 weeks. At 7 months, five male and five female rats from each group were
evaluated for histopathology, and an additional seven males and seven females from each group were evaluated for
nickel tissue burden in the lung and kidney. At 15 months, five males and five females from each group were evaluated
for alterations in haematology, nickel tissue burden in the lung and kidney, and histopathology. The results of the study
is summarised in Table 4.1.2.5C.
Survival, body weights, clinical findings, and haematology:
The survival rates of all exposed groups of males and females were similar to those of the controls. Throughout the
second year of the study, mean body weights of 0.11 mg Ni/m3 female rats were slightly lower (6% to 9%) than those of
the controls. At the end of the study final mean body weights of all exposed groups of males and 0.027 and 0.056 mg
Ni/m3 females were similar to those of the controls. There were no clinical findings or haematology differences that
were considered to be related to nickel sulphate hexahydrate administration. At the 15 months interim evaluation
increased relative lung weights (males and females) were seen at all exposure levels, however only significantly
increased at the highest dose level.
Pathology findings:
There were no histopathological findings in other organs than the lung which could be attributed to nickel sulphate.
Increased incidences of inflammatory lung lesions were generally observed in all exposed groups of male and female
rats at the end of the study. The incidences of chronic active inflammation, macrophage hyperplasia, alveolar
proteinosis, and fibrosis were statistically significantly increased in male and female rats exposed to 0.056 or 0.11 mg
Ni/m3. The severity grade of chronic active inflammation, alveolar proteinosis, and fibrosis increased with increasing
dose. Chronic active inflammation was described as multifocal, minimal to mild accumulations of macrophages,
neutrophils, and cell debris in alvolar spaces. Fibrosis was described as “increased connective tissue and collagen
involving alveolar septae in the parenchyma and subjacent to the pleura and focal sclerotic areas either subjacent to the
106
pleura or at the tips of the lung lobes”. The alveolar hyperplasia was described as being of minimal to mild severity and
consisted of “macrophages (usually with abundant pale vacuolated cytoplasm) within alveolar spaces”. Increased
incidences of lymphoid hyperplasia in the bronchial lymph nodes occurred in 0.11 mg Ni/m3 male and female rats at the
end of the 2-year study. The incidences of atrophy of the olfactory epithelium (average severity grade minimal-mild) in
0.11 mg Ni/m3 males and females were significantly greater than those in controls at the end of the study.
At the 7 months interim evaluation there was an increase in the chronic active inflammation in male rats in all exposure
groups. A corresponding trend was observed in female rats.
Tissue burden analyses:
Lung nickel burdens in exposed male and female rats were greater than those in the controls at the 15-month interim
evaluation. At the 7-month interim evaluation the lung nickel burden was increased at the highest concentration only. At
15 months, lung nickel burden values increased with increasing exposure concentration.
Trends towards increased lung weights and increase in chronic inflammation at the lowest exposure level of 0.027 mg
Ni/m3 (0.12 mg NiSO4.6H2O/m3) at the 15 months and 7 months interim evaluations indicate possibly adverse effects at
this level. This makes it difficult to decide whether this level may serve as a NOAEC or a LOAEC. Therefore, 0,056 mg
Ni/m3 as a clear effect level in relation to inflammation, fibrosis and macrophage hyperplasia is taken as a LOAEC. It
should be noted that data indicates that adverse effects possibly occur at lower levels.
Table 4.1.2.5.C: Summary of 2-year rat study (NTP, 1996a)
Exposure level
mg Ni/m3
Effects observed, 24 months
Response rate
0, 0.027, 0.056,
14/54, 11/53, 42/53, 46/53
NOAEC/
LOAEC
mg Ni/m3
0.027/0.056
0.11
14/52, 13/53, 49/53, 52/54
0.027/0.056
7/54,9/53, 35/53, 48/53
0.027/0.056
Macrophage hyperplasia in females (*)
9/52, 10/53, 32/53, 45/54
0.027/0.056
Alveolar proteinosis in males
0/54, 0/53, 12/53, 41/53
0.027/0.056
Alveolar proteinosis in females
1/52, 0/53, 22/53, 49/54
0.027/0.056
Lung fibroses in males
3/54, 6/53, 35/53, 43/53
0.027/0.056
Lung fibroses in females
8/52, 7/53, 45/53, 49/54
0.027/0.056
0/51, 0/48, 3/47, 10/52
0.056/0.11
2/50, 1/52, 0/51, 11/49
0.056/0.11
0/54, 0/53, 3/53, 7/53
0.056/0.11
0/51, 1/52, 1/53, 7/54
0.056/0.11
Macrophage hyperplasia in males (*)
(*) There is no clear conclusion with regard to whether macrophage hyperplasia response should be interpreted as an
adverse effect.
4.1.2.5.1.1.1.4
16-day mouse study
Groups of five male and five female B6C3F1 mice were exposed to NiSO4.6H2O in concentrations equivalent to 0, 0.7,
1.4, 3.1, 6.1, or 12.2 mg Ni/m3 (0, 3.5, 7, 15, 30, or 60 mg NiSO4.6H2O (greater than 98% pure) /m3). Mice were
exposed on weekdays only, for a total of 12 exposure days during a 16-day period. Additional groups of five male and
five female B6C3F1 mice were exposed to NiSO4.6H2O in concentrations equivalent to 0 or 0.7 mg Ni/m3 (0 or 3.5 mg
NiSO4.6H2O /m3 for tissue burden studies. The results of the study is summarised in Table 4.1.2.5D.
All core study mice exposed to 1.4 mg Ni/m3 or greater died before the end of the study; all control and 0.7 mg Ni/m3
mice survived to the end of the study. Final mean body weights and weights gains of 1.4, 3.1, 6.1, and 12.2 mg Ni/m3
males and females were significantly less than those of the controls, and clinical findings in these groups included
emaciation, lethargy, and rapid respiration rates. Absolute and relative lung weights of male and female mice exposed
to 1.4 mg Ni/m3 or greater were significantly greater than those of the controls. Only tissues from mice exposed to 0,
0.7, or 1.4 mg Ni/m3 were examined histopathologically. Inflammation occurred in the lungs of 0.7 and 1.4 mg Ni/m3
107
males and females; necrosis of the alveolar and bronchiolar epithelium was a component of the inflammation in 1.4 mg
Ni/m3 males and females. In addition, atrophy of the olfactory epithelium of the nasal passages was observed in 0.7 mg
Ni/m3 males and females. Nickel concentrations in the lungs of mice exposed to 0.7 mg Ni/m3 were greater than in the
controls.
The lowest exposure level in this study, 0.7 mg Ni/m3 (3.5 mg NiSO4.6H2O/m3), was a LOAEC for lung inflammation
in both sexes. The higher dose level, 1.4 mg Ni/m3 (7 mg NiSO4.6H2O/m3), was clearly toxic as all mice died.
Table 4.1.2.5.D: Summary of 16-day mouse study (NTP, 1996a)
Exposure level
mg Ni/m3
Effects observed
Response rate
0, 0.7, 1.4
Lung inflammation in males
0/5, 4/5, 5/5
-/0.7
Lung inflammation in females
0/5, 5/5, 5/5
-/0.7
0/4, 0/3, 0/4
-
0/2, 1/4, 0/4
-
0/5, 5/5, 0/5
-/0.7
0/5, 0/5, 0/3
-/-
4.1.2.5.1.1.1.5
NOAEC/ LOAEC
mg Ni/m3
13-week mouse study
Groups of ten male and ten female B6C3F1 mice were exposed to NiSO4.6H2O in concentrations equivalent to 0, 0.027,
0.056, 0.11, 0.22, or 0.44 mg Ni/m3 (0, 0.12, 0.25, 0.5, 1, or 2 mg NiSO4.6H2O /m3), 5 days per week for 13 weeks.
Additional groups of up to five or six male and female B6C3F1 mice were exposed to NiSO4.6H2O in concentrations
equivalent to 0, 0.027, 0.11, or 0.44 mg Ni/m3 (0, 0.12, 0.5, or 2 mg NiSO4.6H2O/m3) for tissue burden studies. The
results of the study is summarised in Table 4.1.2.5E.
In the core study, four control males, three control females, and one 0.027 mg Ni/m3 male died before the end of the
study; the deaths were not considered to be chemical related, and all other mice survived to the end of the study. The
final mean body weights and body weight gains of all exposed groups were similar to those of the controls. There were
no chemical-related clinical findings. Haematology changes similar to those reported in female rats (increases in
neutrophile and lymphocyte numbers) occurred in female mice, but the mice were minimally affected. The absolute and
relative lung weights of 0.22 mg Ni/m3 males and 0.44 mg Ni/m3 males and females were significantly greater than
those of the controls. Increased numbers of alveolar macrophages occurred in all males and females exposed to 0.11 mg
Ni/m3 or greater. At the 0.44 mg Ni/m3 level chronic active inflammation was observed in females, the occurrence of
interstitial infiltrate in both males and females as well as the occurrence of fibrosis also in both males and females. Also
at the 0.44 mg Ni/m3 level atrophy of the olfactory epithelium were observed in the nasal passages of males and
females. Nickel concentration in the lung of 0.44 mg Ni/m3 females was significantly greater than in control animals.
Further, for the later evaluation on reproductive effects, at terminal sacrifice sperm samples were collected from all
male animals in the three highest exposure groups for sperm morphology evaluations (sperm density, morphology and
motility). The right epididymis and right testis were weighed. Vaginal samples were collected for up to seven
consecutive days prior to the end of the studies from all females for vaginal cytology evaluations (relative frequency of
oestrous stages, oestrous cycle length). There were no significant effects on sperm morphology or vaginal cytology.
The most serious adverse effect in this study was chronic lung inflammation. Females were more sensitive than males.
Accumulation of macrophages has been found to occur at lower concentrations than other lesions, and it has been
debated whether the reaction should be interpreted as an adaptive repair response, or as an adverse event in a sequence
leading ultimately to fibrosis. A definitive conclusion regarding the biological significance of macrophage accumulation
is not possible according to the TERA review (1999). Macrophage accumulation may not in itself be considered as an
adverse reaction. However, as macrophage accumulation is very closely linked to the development of inflammation, this
could in relation to risk assessment be taken as a sign of an adverse event. In the absence of a definitive conclusion
regarding the toxicological significance of macrophage accumulation it is difficult to base a NOAEC/LOAEC from this
study on this effect. The NOAEC/LOAEC for inflammation, fibrosis and atrophy which are regarded as clear adverse
effects is 0.22/0.44 mg Ni/m3 (1 and 2 mg NiSO4.6H2O /m3).
108
Table 4.1.2.5.E: Summary of 13-week mouse study (NTP, 1996a)
Exposure level
mg Ni/m
Effects observed
Response rate
NOAEC/
LOAEC
mg Ni/m3
0, 0.027, 0.056,
0.11, 0.22, 0.44
0/6, 0/9, 0/10, 0/10, 2/10, 2/10
-
0/7, 0/10, 0/10, 0/10, 1/10, 9/10
0.22/0.44
Interstitial infiltrate in males
0/6, 0/9, 0/10, 0/10, 2/10, 8/10
0.22/0.44
Interstitial infiltrate in females
1/7, 0/10, 0/10, 1/10, 1/10, 8/10
0.22/0.44
Macrophage hyperplasia in males (*)
0/6, 0/9, 0/10, 10/10, 10/10, 10/10
0.056/0.11
Macrophage hyperplasia in females (*)
0/7, 0/10, 0/10, 10/10, 10/10, 10/10
0.056/0.11
Fibrosis in male
0/6, 0/9, 0/10, 0/10, 2/10, 10/10
0.22/0.44
Fibrosis in female
0/7, 0/10, 0/10, 0/10, 1/10, 8/10
0.22/0.44
2/6, - , - , - , 6/10, 8/10
-
4/7, - , - , - , 7/10, 10/10
-
0/6, 0/9, 0/10, 0/10, 0/10, 10/10
0.22/0.44
0/7, 0/10, 0/10, 0/10, 0/10, 5/10
0.22/0.44
(*) There is no clear conclusion with regard to whether macrophage hyperplasia response should be interpreted as an
adverse effect.
4.1.2.5.1.1.1.6
2-year mouse study
Groups of 80 male and 80 female mice were exposed to nickel sulphate hexahydrate by inhalation at concentrations
equivalent to 0, 0.056, 0.11, or 0.22 mg Ni/m3 (0, 0.25, 0.5, or 1 mg NiSO4.6H2O /m3). Animals were exposed for 6
hours a day for 5 days per week for 104 weeks. At 7 months, five male and five female mice from each group were
evaluated for histopathology, and five males and five females from each group were evaluated for nickel tissue burden
in the lung and kidney. At 15 months, five males and five females from each group were evaluated at 15 months for
alterations in haematology and histopathology; and five males and five females from each group were evaluated for
nickel tissue burden in the lung and kidney. The results of the study is summarised in Table 4.1.2.5F.
Survival, body weights, clinical findings, and haematology:
The survival rates of all exposed groups of males and females were similar to those of the controls. The mean body
weights of 0.22 mg Ni/m3 males and of all exposed groups of females were lower than those of the controls during the
second year of the study. There were no clinical findings or haematology differences considered to be related to
chemical exposure.
Pathology findings:
Inflammatory lesions of the lung generally occurred in all exposed groups of male and female mice at the end of the 2year study. These lesions included macrophage hyperplasia, chronic active inflammation, bronchialization (alveolar
epithelial hyperplasia), alveolar proteinosis, and infiltrating cells in the interstitium. Incidences of macrophage
hyperplasia and/or lymphoid hyperplasia occurred in the bronchial lymph nodes of most of the 0.22 mg Ni/m3 males
and females and in some 0.11 mg Ni/m3 females at the end of the 2-year study. Atrophy of the olfactory epithelium was
observed in 0.11 and 0.22 mg Ni/m3 males and in 0.22 mg Ni/m3 females at the end of the 2- year study. No other
organs showed nickel sulphate-related changes.
Tissue burden analyses:
At 15 months, absolute lung weights of 0.11 and 0.22 mg Ni/m3 lung burden study females were significantly greater
than those of the controls. In this study, there was no dose level without chronic lung inflammation. Females were more
sensitive than males.
The LOAEC for chronic lung inflammation is 0.056 mg Ni/m3 (0.25 mg NiSO4.6H2O /m3), while a NOAEC cannot be
determined.
109
Table 4.1.2.5.F: Summary of 2-year mouse study (NTP, 1996a)
Exposure level
mg Ni/m3
Effects observed
Response rate
NOAEC/
LOAEC
mg Ni/m3
0, 0.056, 0.11,
0.22
1/61, 2/61, 8/62, 29/61
0.056/0.11
1/61, 7/60, 14/60, 40/60
0/0.056
Bronchialisation in males
1/61, 4/61, 19/62, 39/61
0.056/0.11
Bronchialisation in females
0/61, 9/60, 32/60, 45/60
0/0.056
Macrophage hyperplasia in males
6/61, 9/61, 35/62, 59/61
0.056/0.11
Macrophage hyperplasia in females
7/61, 24/60, 53/60, 59/60
0/0.056
Interstitial infiltration in males
1/61, 0/61, 3/62, 17/61
0.11/0.22
Interstitial infiltration in females
0/61, 4/60, 16/60, 39/60
0.056/0.11
Alveolar proteinosis in males
0/61, 0/61, 0/62, 42/61
0.11/0.22
Alveolar proteinosis in females
0/61, 0/60, 11/60, 45/60
0.056/0.11
2/46, 4/49, 2/45, 17/54
0.11/0.22
15/50, 9/54, 16/58, 26/56
0.11/0.22
0/61, 0/61, 12/61, 37/60
0.056/0.11
0/61, 2/59, 1/60, 17/60
0.11/0.22
4.1.2.5.1.1.2 Studies examining mechanism of lung injury
Benson et al. (1995) studied particle clearance and histopathology in lungs of male F344/N rats and B6C3F1 mice
inhaling nickel sulphate hexahydrate. Mice and rats were whole-body exposed for 6 hours/day, 5 days/week for up to 6
months in exposure chambers. Rats were exposed to NiSO4.6H2O at concentrations equivalent to 0.027 or 0.11 mg
Ni/m3 (0.12 or 0.5 mg NiSO4.6H2O) and mice to NiSO4.6H2O at concentrations equivalent to 0.056 or 0.22 mg Ni/m3
(0.25 or 1.0 mg NiSO4.6H2O/m3). After 2 and 6 months of whole-body exposure, groups of rats and mice were acutely
exposed nose-only to 63NiSO4 6H2O or to 85Sr-labelled polystyrene latex (PSL) microspheres to evaluate lung clearance.
In addition, groups of rats and mice were euthanized after 2 and 6 months of exposure and at 2 and 4 months after the
whole-body exposures were completed to evaluate histopathological changes in the left lung and to quantitate nickel in
the right lung. Lung clearance of 63NiSO4 6H2O after the acute exposure was not impaired in rats or mice previously
exposed for 2 or 6 months. Clearance of microspheres was impaired in rats after 2 but not 6 months of exposure. Nickel
was not found to accumulate in the lungs of rats or mice exposed to NiSO4.6H2O. Mice showed minimal
histopathological changes, while rats showed alveolar macrophage hyperplasia and chronic alveolitis. It is important to
note that while the clearance of 85Sr-labelled microspheres was impaired in one group of rats administered nickel
sulphate for 2 months (with continuing exposure to nickel sulphate during administration of microspheres), clearance
was not impaired in another group of rats administered nickel sulphate for 2 months, with no further exposure to nickel
sulphate. Likewise, rats exposed up to 6 months of nickel sulphate and administered styrene particles showed no
impaired lung clearance. Benson suggested that the fact that only one exposure scenario resulted in impaired clearance
might be artifactual, due to the use of non-concurrent controls from a different experiment. This idea is substantiated by
the fact that impairment of 85Sr-labelled particle clearance was not observed in rats or mice exposed to nickel sulphate
for 6 months or in rats or mice exposed to NiO for 2 or 6 months and having more severe pulmonary lesions and much
greater nickel lung burdens.
Benson et al. (1992) studied the effects of nickel sulphate on lung biochemistry. Male and female F344/N-rats and
B6C3F1-mice were exposed by inhalation for 6 hours a day, 5 days a week for 13 weeks to 0.12 to 2.0 mg nickel
sulphate/m3 (equivalent to 0.027 to 0.44 mg Ni/m3). This subchronic exposure resulted in increases in lactatedehydrogenase (LDH) and beta-glucuronidase (BG) activity and in total protein (TP) and collagenous peptide (CP)
content. This indicates damage or death of cells within the lung, increased phagocytic activity, increased vascular
permeability, and turnover of the extracellular collagen matrix, respectively. The magnitude of the increase in BG was
110
greater than that of LDH, indicating that increases in BG were due to the presence of active phagocytic cells and not
due solely to release of enzyme from dying or damaged phagocytic cells. Fibrosis developed in mice, but not in rats.
Benson et al. (1989) evaluated the biochemical responses of lungs of male and female rats (6/sex/group) and mice
(8/sex/group) exposed to NiSO4.6H2O in concentrations equivalent to 0, 0.027, 0.11 or 0.44 mg Ni/m3 (0,0.12, 0.5 or
2.0 mg NiSO4.6H2O) for 6 hours/day 5 days/week for 13 weeks. Biochemical responses were measured in
bronchoalveolar lavage fluid recovered from lungs of exposed animals. Parameters evaluated were lactate
dehydrogenase (LDH), beta-glucuronidase (BG), and total protein (TP). Total and differential cell counts were
performed on cells recovered in the bronchoalveolar lavage fluid. Histological analyses of the lungs were also
conducted. The authors stated that no significant sex-related differences were observed, and so results were reported
for both sexes combined. Marked concentration-related and statistically significant increases in LDH and betaglucuronidase were observed in rats and mice at the mid-and high-exposure levels, and for total protein in rats at the
same concentrations. A concentration-related, statistically significant increase in total nucleated cells was observed in
rats at 0.02 mg Ni/m3 and higher, and in mice at 0.1 mg Ni/m3; and higher. In rats, the percent neutrophiles was
significantly elevated and the percent macrophages was significantly depressed at the mid and high concentrations.
Chronic inflammation and interstitial infiltrates were observed in rats at 0.1 mg Ni/m3 and higher, and macrophage
accumulation was observed at all exposure levels. In mice, macrophage accumulation and interstitial infiltrates were
observed at the mid and high concentrations, and chronic inflammation and fibrosis were observed only at the high
concentration. Increases in BG were greater than increases in LDH and TP for both rats and mice. Chronic active
inflammation, macrophage hyperplasia, and interstitial phagocytic cell infiltrates were observed histologically in rats
and mice. Statistically significant increases in BG, TP, neutrophiles, and macrophages correlated well with the degree
of chronic active inflammation.
In a poorly reported study, Kosova (1979 – quoted from UK HSE 1987) administered nickel sulphate (as dust) to rats in
doses of 0, 1.1 or 2.2 mg Ni/m3 (0, 5.0, or 10.0 mg/m3 ‘nickel sulphate’ (presumed to be NiSO4.6H2O)) for four hours
daily for 9 months. The principal effect noted were in the lung at the dose level 2.2 mg Ni/m3, with destruction of the
epithelial cells, intraalveolar septal thickening and emphysematous dilation of the alveolar lumina. Liver damage and
kidney tubular necrosis was also recorded. Minor pathological changes and decreased body weight were noted at 1.1 mg
Ni/m3.
4.1.2.5.1.1.3 Summary and conclusions, inhalation
The inhalation toxicity of nickel sulphate has been investigated in a number of studies in mice and rats. The studies by
NTP (1996a) are of good quality. The rat appears more sensitive than the mouse to the toxic effects. The respiratory
system was the primary target organ with severe effects occurring in both the lungs (chronic inflammation and fibrosis)
and the nose (atrophy of olfactory epithelium).
Tables 4.1.2.5.G and 4.1.2.5.H give an overview of repeated dose inhalation studies with nickel sulphate in rats and
mice. The studies show that inhalation of nickel sulphate induces chronic lung damage in rats and mice. The 2-year
studies by NTP are the most relevant for human lifetime exposure. In rats no NOAEC could be identified as signs of
possible adverse effects were seen in the interim evaluation periods after 7 and 15 months at the lowest exposure level
of 0.027 mg Ni/m3. Therefore, the exposure level of 0.056 mg Ni/m3 where clear adverse effects (lung inflammation
and fibrosis) were seen is taken as a LOAEC. In mice, only higher dose levels were tested, and a NOAEC was not
identified. The LOAEC in mice was 0.056 mg Ni/m3. For the risk characterisation a LOAEC of 0.056 mg Ni/m3 (0.25
mg NiSO4.6H2O /m3) is used.
Table 4.1.2.5.G: Repeated dose inhalation studies with nickel sulphate in rats
Duration
Dose levels
As mg Ni/m3
16 days
13 weeks
NOAEC
mg Ni/m3
LOAEC
mg Ni/m3
Effect at
LOAEC
Reference
0, 0.7, 1.4, 3.1, 6.1, No dose level
12.2
without effect
0.7
Atrophy of
olfactory
epithelium, lung
inflammation
NTP (1996a)
0, 0.027, 0.056,
0.11, 0.22, 0.44
0.056
0.11
Chronic active
inflammation
NTP (1996a)
No dose level
without effect
0.027
Macrophage
accumulation
111
13 weeks
0.027, 0.11, 0.44
13 weeks
0.027, 0.44
0.027
0.11
2 or 6 months, plus 0.027, 0.11
exposure-free
interval of 0, 2, or
4 months
Chronic
inflammation
Benson et al.
(1989)
Increases in
indices of cell
damage
Benson et al.
(1992)
Chronic
alveolitis
Benson et al.
(1995)
9 months
0, 1.1, 2.2
No dose level
without effect
1.1
Decreased
bodyweight,
lung effects at
2.2
Kosova (1979)
2 years
0, 0.027, 0.056,
0.11
No definitive
NOAEC due to
increased lung
weights and
increase in chronic
inflammation at
0.027 at the 7 and
15 months interim
evaluations
0.056
Chronic lung
inflammation,
fibrosis (both
sexes)
NTP (1996a)
Table 4.1.2.5.H: Repeated dose inhalation studies with nickel sulphate in mice
Duration
Dose levels
as mg Ni/m3
NOAEC
mg Ni/m3
LOAEC
mg Ni/m3
Effect at
LOAEC
Reference
16 days
0, 0.7, 1.4
No dose level
without effect
0.7
Atrophy of
olfactory
epithelium, lung
inflammation
NTP (1996a)
13 weeks
0.027, 0.11, 0.44
0.11
0.44
Chronic
inflammation,
fibrosis
Benson et al.
(1989)
13 weeks
0.027, 0.44
Increases in
indices of cell
damage and
fibrosis
Benson et al.
(1992)
13 weeks
0, 0.027, 0.056,
0.11, 0.22, 0.44
NTP (1996a)
0.056
0.11
Macrophage
hyperplasia
0.22
0.44
inflammation,
fibrosis and
atrophy
2 or 6 months,
0.056, 0.22
plus exposurefree interval of 0,
2, or 4 months
No dose level
without effect
0.056
Minimal
Benson et al.
histopathological (1995)
changes
2 years
No dose level
without effect
0.056
Chronic lung
inflammation in
females
0, 0.056, 0.11,
0.22
NTP (1996a)
The question of a NOAEC for non-cancer effects has been discussed extensively in the European Commission (2000)
Ambient Air Position Paper. This contains an analysis of the NTP (1996a) 2-year inhalation studies in mice and rats by
the Ambient Air Working Group. They conclude (European Commission, 2000) “In rats, there are clear adverse effects
at 0.06 mg Ni/m3. With respect to lung fibrosis, there is a slight increase in male rats at 0.03 mg Ni/m3 in the 2-year
112
study which is not statistically significant. However, in male rats there is an increasing trend in lung weight for the 15month interim evaluation. These results indicate possibly adverse effects at 0.03 mg Ni/m3, and therefore 0.03 mg Ni/m3
may be not a NOAEL in rats. This means that the LOAEL for mice is 0.06 mg Ni/m3, the LOAEL for rats is probably
lower than 0.06 mg Ni/m3, and a NOAEL has neither been found for rats nor for mice in the NTP study of nickel sulfate
hexahydrate.” The CSTEE in their Opinion of the Position Paper concurs and considers that the 0.03 mg Ni/m3 level
“does not clearly represent a NOAEL value” (CSTEE, 2001). The Commission Position paper also states the position
of the Industry members of the Working Group on the 0.03 mg/m3 exposure level. This level was identified by Industry,
the NTP, the California EPA and the members of the TERA risk assessment peer review group as a NOAEC in the
study.
No new data to elucidate this aspect further has been available to the rapporteur since this CSTEE evaluation. The
rapporteur agrees with the CSTEE assessment and therefore the LOAEC of 0.056 mg Ni/m3 is taken forward to the risk
characterisation.
4.1.2.5.1.2
Oral
4.1.2.5.1.2.1 General toxicity
4.1.2.5.1.2.1.1
Rats
A 90-day oral gavage study in rats using nickel sulphate hexahydrate has been performed as a range-finding study for a
2-year carcinogenicity study. The study was performed according to GLP. Groups of 10 male and 10 female rats were
given 0, 11, 17, 22, 28, and 33 mg Ni/kg bw/day (0, 50, 75, 100, 125, and 150 mg/kg bw/day of nickel sulphate
hexahydrate). Because of significant weight loss in males at the high doses early in the study, the 125 and 150 mg
NiSO4.6H2O /kg bw/day doses were reduced to 30 and 15 mg/kg bw/day, respectively, on day 28 for males only. One
female rat in the 150 mg NiSO4.6H2O /kg bw/day group was found dead on study day 44, the cause of death could not
be established. Clinical observations included post-dosing salivation and decreased activity, most pronounced during
the first two weeks and in the highest dose groups.
A variety of statistically decreased absolute or increased relative organ weights were noted in the treated rats. These
effects were not accompanied by histopathological changes. The only significant adverse affects seen in this study were
weight loss in all dosed groups (8-13% lower body weight compared to controls). No notable macroscopic or
microscopic changes were observed. There was no dose level without effect on body weight, and the LOAEL was thus
7 mg Ni/kg bw/day (30 mg NiSO4.6H2O/kg bw/day (reduced from 125 mg/kg bw/day at day 28)) for males and 11 mg
Ni/kg bw/day (50 mg NiSO4.6H2O /kg bw/day) for females (SLI, draft not dated, submitted 2002).
Obone et al. (1999) treated groups of 8 adult male Sprague-Dawley rats with NiSO4-6H2O at concentrations
corresponding to 0, 44.7, 111.75, and 223.5 mg Ni/l (0, 0.02, 0.05, and 0.1% nickel sulphate hexahydrate (NiSO46H2O), in their drinking water ad libitum for 13 weeks. Before sacrifice, urine was collected for 24h in metabolism
cages and content of glucose, protein, and activity of N-acetyl-β-D-glucosaminidase, γ-glutamyl transpeptidase were
determined. The animals were weighed and sacrificed. Blood samples were taken for haematology and clinical chemical
parameters including plasma cholinesterase activity, and organ weights were measured. Histopathological examination
was done on liver, kidney, heart, brain, testis, lung, spleen, thymus and intestines. Bronchoalveolar lavage fluid was
analysed for indication of cell injury. Lung tissue homogenate was examined for various enzymes. Activities of various
enzymes and protein content in testicular tissue homogenate was measured. Immunotoxic parameters in spleen and
thymus tissue homogenate were determined. DNA damage in liver and kidney cell lysates was evaluated by
fluorometry. Tissue nickel content was determined by mass spectrometry.
All animals survived to the end of treatment, and no apparent clinical signs of toxicity were noted. At the highest
dosage level a slight, but statistically significant decrease in final mean body weight (4%) was found; body weight was
not affected at lower dose levels.
There were no gross or microscopic changes in any of the tissues examined at any dose level.
Both the absolute and relative liver weights were decreased (by 15%, estimated from figure by rapporteur) at the two
highest dose levels.
The relative kidney weight was increased at the low and the highest dose (by 10%, estimated).
113
The absolute lung weight was increased at the lowest and highest dose levels (by 10%, estimated), while the relative
lung weight was increased only at the highest dose level.
The absolute, but not the relative, weights of testes and heart were decreased in all groups (by 5%, estimated).
The relative weight of the spleen was increased at all dose levels (by 5%, estimated).
The splenic and thymic lymphocyte subpopulations (T and B cells) were affected in a non-monotonic fashion. In both
spleen and thymus, the total number of cells were increased at the middle dose (111.75 mg Ni/l), and reduced at the
high dose (223.5 mg Ni/l) compared with control.
In the middle and the highest dose group, significant decreases in urine volume (reduced to 1/3) and urine glucose
(reduced to ¼) was found. In the highest dose group, blood urea nitrogen was significantly increased (nearly doubled).
According to the authors, this could indicate glomerular damage. Of the lung enzymes examined, only alkaline
phosphatase was affected; a decrease was found in bronchioalveolar fluid. No effects on testicular enzymes were found.
Plasma acetylcholinesterase was unaffected.
In this study, repeated oral exposure to Ni did not induce marked toxic effects on specific endpoints. A slight reduction
in body weight was induced at the highest dose level. As the changes in the weights of the various organs were small
and not accompanied by morphological evidence of lesions, they cannot be readily interpreted as adverse.
Histopathological examination of the immunologically relevant organs spleen and thymus did not reveal adverse
changes. The weight of the spleen was increased, which does not indicate suppression of immune function. Other
immunologically relevant organs (lymph nodes, bone marrow) were not examined. Various effects on the number of
thymic and splenic B and T cells were identified, but the toxicological significance of these effects is uncertain,
especially since no consistent dose relation was found. With respect to the kidney, the increased relative organ weight,
the decreased urinary volume and increased blood urea nitrogen could indicate adverse effects. However, in the absence
of histopathological changes, the clinical chemical changes cannot be readily interpreted. It is possible that the reduced
urine volume could be related to reduced water intake, possibly caused by reduced palatability of the nickel sulphatecontaining water. Unfortunately, although water consumption was reportedly measured, no data are provided in the
publication.
The study has several limitations. The group size was only 8, and only males were included. Detailed clinical
observations, behavioural testing and eye examinations were not done. Histopathological evaluation was not performed
on all tissues, which normally would be assessed in a repeated dose toxicity study, including tissues relevant for the
assessment of effects on the immune system. Nevertheless, the study appears well performed and is considered useful
for the evaluation of repeated dose toxicity of nickel sulphate.
The LOAEL of the present study is set to 111.75 mg Ni/l based on the 4% reduction in body weight and the increased
relative weights of kidney and lungs, which although not considered very serious, are considered as biologically
important adverse effect. The NOAEL is 44.7 mg Ni/l. Although food and water consumption was reported to be
measured in the study, no data were given in the publication. Based on an assumed intake of 0.1 litre/kg bw/day, the
oral LOAEL is 11 mg Ni/kg bw/day (49 mg NiSO4.6H2O/kg bw/day) and the NOAEL is 4.5 mg Ni/kg bw/day (20 mg
NiSO4.6H2O/kg bw/day).
Ambrose et al. (1976) conducted a chronic feeding study where they exposed groups of 25 male and 25 female
weanling Wistar rats to dietary nickel sulphate hexahydrate in concentrations of 0, 100, 1000, or 2500 ppm Ni
(corresponding to 0, 10, 100 or 250 mg Ni/kg bw/day, based on an assumed food intake of 100 g/kg bw/day,
Rapporteur´s calculation). The actual concentrations of NiSO4.6H2O in the diet were not given in the publication, but
are calculated to be 0, 45, 450, or 1121 mg NiSO4.6H2O/kg bw/day. The rats were exposed for up to 2 years.
Information on the amount of nickel in the basal diet was not reported. Blood and urine samples were obtained from 5
rats of each sex/group every 3 months. Survival was poor in all groups, including control (68-92% mortality). For this
reason, only 2-8 rats per group were available for gross and microscopic pathological examination at sacrifice. Heart,
spleen, kidney, liver and testes were weighed and histopathologically examined. In addition, lung, urinary bladder,
stomach, small and large intestine, skeletal muscle, brain, skin, bone marrow, pituitary, thyroid, adrenal, pancreas, and
gonad were histopathologically examined. Body weights were significantly lower than control values in females at
>1000 ppm from week six and in both sexes at 2500 ppm from the beginning of the study. At 78 weeks, body weights
were decreased by 18% in mid-dose females and 8% in mid-dose males; corresponding decreases at the high dose were
32% and 35%. No exposure-related changes in haematology (hemoglobin, hematocrit and differential leukocyte counts)
114
or urinalysis (reducing substances and protein) endpoints. Relative liver weights were significantly decreased in
females at 1000 ppm and relative heart weights were statistically significantly increased in the same group, although
there was no clear dose-response. Histological findings were essentially negative and not indicative of any
characteristic effect of nickel in the diet. This study is limited by the high mortality in all groups, resulting in only a
small number of animals being exposed for the total period of 2 years and being available for sacrifice and
histopathology. Based on the 18% decreased body weight in females, which is considered a biologically important
adverse effect, a NOAEL of 10 mg Ni/kg bw/day (45 mg NiSO4.6H2O/kg bw/day) and a LOAEL of 100 mg Ni/kg
bw/day (450 NiSO4.6H2O/kg bw/day) can be determined.
Itskova et al. (1969 – quoted from UK HSE 1987) exposed rats by gavage to nickel sulphate in doses equivalent to 0.5,
5, 50, 500 or 5000 μg Ni/kg daily for 7 months. A statistically significant decrease in weight gain was claimed for the
highest dose group. There were no effects on haematological parameters or in the limited number of serum clinical
parameters examined. The only significant histological change noted was a marked proliferation of the epithelium in the
intestinal villi, with round cell infiltration and occasional apical necrosis at 500 and 5000 μg Ni/kg. According to the
UK HSE report the study was poorly reported and no further details were given. Because of these limitations, the study
will not be used for the risk assessment.
A two-year oral (gavage) OECD 451 carcinogenicity study with nickel sulphate hexahydrate in Fischer rats has been
conducted (CRL 2005). Groups of 60 male and 60 female rats were dosed with 0, 2.2, 6.7 and 11 mg Ni/kg bw/day (0,
10, 30 and 50 mg/kg bw/day of nickel sulphate hexahydrate) once daily for 104 weeks. The test substance was
dissolved in water and given in a gavage volume of 10 ml/kg bw. In males a statistically significant and dose-related
reduced body-weight gain was observed in the dosed groups (5%, 11%, and 12% respectively) compared to the control
group. Similarly, in females a dose-related reduced body weight gain (4%, 8% and 10% respectively) was observed
when compared to controls but only achieved statistical significance in mid- and high-dose females. The reduced body
weight gain had no correlation with the amount of food consumed. Survival of the females was reduced in a doserelated manner and reached the level of statistical significance at the two highest dose levels. The mortality rates for the
females at the end of the study were 23%, 33%, 43% and 45% at 0, 2.2, 6.7 and 11 mg Ni/kg bw/d, respectively. There
was no apparent treatment-related effect on survival in males (mortality rates 60%, 48%, 50% and 57% at 0, 2.2, 6.7
and 11 mg Ni/kg bw/d, respectively).
None of the non-neoplastic microscopic findings were considered as being related to dosing with the test substance.
4.1.2.5.1.2.1.2
Dogs
Ambrose et al. (1976) also conducted a chronic dog study. Groups of 3 male and 3 female beagle dogs were exposed to
nickel sulphate hexahydrate by ingestion with diet. The dietary concentrations were 0, 100, 1000, and 2500 ppm Ni
(equivalent to 0, 7.5, 75, or 188 mg Ni/kg bw/day (assuming that 1 ppm in diet equals 0.075 mg/kg bw/day (OECD
1999)). The dogs were exposed for 2 years. At the 100 and 1000 ppm no effects were seen. The highest dosage level
resulted in depressed body weight gain, this high dose caused vomiting and required stepwise increases from 1700 ppm
to reach the final dose of 2500 ppm. One high-dose male and female had polyuria when measured at the end of 2 years.
Haematologic values obtained at three-month intervals were variable but within normal range. There was a tendency
towards lower haematocrit values in the highest dose group. Dogs in this group also showed high urine volume during
the last two months on study. Relative liver and kidney weights were statistically significantly increased (18%
compared with control) in the highest dose group. In this group 5 of 6 dogs displayed multiple subpleural peripheral
cholesterol granulomas, and 2 dogs had granulocytic hyperplasia of the bone marrow. No histopathological effects were
found at the low and middle dose. In this study, the NOAEL is 75 mg Ni/kg bw/day with a LOAEL of 188 mg Ni/kg
bw/day (decreased body weight, lung granulomas, bone marrow hyperplasia). Although the study appears well
performed, the small group size makes the interpretation of the pathological findings (e.g. lung granulomas) in relation
to nickel sulphate difficult.
4.1.2.5.1.2.2 Kidney toxicity
Vyskocil et al. (1994b) treated Wistar rats (20/sex/group) with 0 or 100 ppm nickel as nickel sulphate (hydration state
not noted) in drinking water for up to 6 months, with an interim sacrifice of 10/sex/group at 3 months. Nickel intake
was calculated by the authors based on drinking water consumption. Averaged over the two 3-month periods, males
consumed 6.9 mg Ni/kg bw/day, and females consumed 7.6 mg Ni/kg bw/day. Urine analysis was conducted after 3
and 6 months of exposure; histopathology was not evaluated. Parameters measured in urine were albumin as a marker
115
of glomerular function, and lactate dehydrogenase (LDH), P2-microglobulin (p2m), and N-acetyl-p-Dglucosaminidase
(NAG) as markers of tubular function, as well as total protein. Kidney and body weights were also determined. There
was no effect on body weight gain in either sex. Kidney weights in both sexes at all time points were slightly higher in
the exposed groups, and a slight but statistically significant increase in kidney weight was observed in males at 6
months. There was no effect on the markers of tubular function. However, urinary albumin levels, a marker of
glomerular function, were significantly increased in females at 6 months. Although the increase in urinary albumin in
males was not statistically significant, evaluation of the individual animal data showed a clear increase at 6 months; the
lack of a statistically significant effect in males was attributable to two control males with abnormally high values.
Thus, the single dose in this study, 6.9 mg Ni/kg bw/day in males and 7.6 mg Ni/kg bw/day in females, was a LOAEL
for increased urinary albumin. A limitation of this study is that there was considerable variability in response in both
males and females. As part of this assessment, the study authors were contacted in order to obtain the individual animal
data and to evaluate the implications of the variability, including a determination of whether individual nickel exposed
animals showed increased albuminuria between the 3 and 6-month analyses (baseline values were not obtained).
However, the individual data were no longer available. The results in the males are less reliable than those in the
females in light of the high degree of variability in urinary albumin levels seen in male rats in general, and because the
results in the males were not statistically significant (although they did reflect a population shift). Therefore, the study
LOAEL is the LOAEL in females of 7.6 mg Ni/kg bw/day for increased urinary albumin.
4.1.2.5.1.2.3 Immunotoxicity
Dieter et al. (1988) conducted a mouse study in order to determine a threshold response for myelotoxicity and immunetoxicity, and to identify which of the populations of lymphoreticular cells were most sensitive to the toxic effects of
nickel. Groups of 10 female B6C3F1 mice were exposed to graded doses of nickel sulphate (hydration state not
reported). The animals were given free access to the chemical in the drinking water at 0, 1, 5 or 10 g/l for 180 days. The
measured intake was 0. 115.7, 285.7, and 395.7 mg nickel sulphate/kg bw/day (equivalent to 0, 44, 108 and 150 mg
Ni/kg bw/day, or if the reported doses were as nickel sulphate hexahydrate the nickel doses were equivalent to 0, 25, 64,
and 88 mg Ni/kg bw/day). Water consumption, blood and tissue nickel concentrations, body and organ weights,
histopathology, immune responses, bone marrow cellularity and proliferation, and cellular enzyme activities were
evaluated. There was no mortality. Mice in the 285.7, and 395.7 mg nickel sulphate/kg bw/day dose groups drank less
water than controls; the responses measured in the 395.7 mg nickel sulphate/kg bw/day dose group may have been due
to a combination of dehydration and chemical toxicity. Blood nickel was measured at 4, 8, 16, and 23 weeks of
exposure. The mean blood nickel values showed increases in the time period between 4 and 8 weeks that were
proportional to time and dose. After the 8 weeks there was no substantial increase in blood nickel in any of the dose
groups, except for an increase in the mean blood concentration in the 395.7 mg nickel sulphate/kg bw/day dose group at
23 weeks. The kidney was the major organ of nickel accumulation.
Decreases in body and organ weights were confined to mice in the 395.7 mg nickel sulphate/kg bw/day dose group,
except for the dose-related reductions in thymus weights. Histopathology was evaluated in 6 animals/group. Mild
tubular nephrosis was observed in all evaluated mid and high-dose mice, but not at the low dose or in controls. Mild
thymic atrophy, characterised by a decrease in size of the lymphocyte-rich thymic cortex was observed in all treated
mice (6/6 in all groups) while minimal atrophy was observed in on1y 1 of 6 control animals. The histology finding of
thymic atrophy was supported by statistically significant decreases in thymus weight at all dose levels. The primary
toxic effects of nickel sulphate were expressed in the myeloid system. Immune function assays included measurements
of plaque-forming cell (PFC) response to sheep red blood cells (SRBC), lymphoproliferative response, natural killer
(NK) cell activity of spleen cells, and resistance to challenge with the bacterium Listeria monocytogenes.
Myeloproliferative assays included bone marrow cellularity and stem cell proliferative response. A significant decrease
in the lymphoproliferative response to a B-cell mitogen, but not to a T-cell mitogen, was observed at all doses. In
addition, statistically significant decreases in PFC response and spleen cellularity were observed at the high dose. A
statistically significant, dose-related decrease in the granulocyte-macrophage proliferative response was observed at all
doses, and a decrease in bone marrow cellularity occurred at the two highest doses. Although the decrease in
lymphoproliferative response was observed at the low dose, the study authors considered this effect to be secondary to
effects on the myeloid system because other immune function parameters were not affected. However, based on the
histologically-observed thymic atrophy and decreased thymic weight, the LOAEL in this study was 115.7 mg nickel
sulphate/kg bw/day (equivalent to 44 mg Ni/kg bw/day, or if the reported doses were as nickel sulphate hexahydrate the
nickel doses were equivalent to 25 mg Ni/kg bw/day). No NOAEL could be determined. The study is considered to be
of good quality and relevant for the evaluation of effects of nickel sulphate on the immune system.
Schiffer et al. (1991, quoted from TERA, 1999) administered 2700 ppm nickel sulphate hexahydrate (600 ppm Ni) with
the diet to female SJL mice for 4 weeks. They observed a decrease in both in vivo and in vitro proliferative response to
116
T-cell-dependent antigens, and in in vitro proliferative response to B-cell-dependent antigen. The concentration used
corresponds to approximately 120 mg Ni/kg bw/day, assuming that a mouse consumes 200 g feed/kg bw/day.
4.1.2.5.1.2.4 Other toxicity studies
Chatterjee et al. (1979) studied the influence of high intake of vitamin C in the young growing rats under administration
of nickel sulphate. Groups of male Wistar weanling rats were given 0 or 33 mg Ni/kg bw/day as nickel sulphate in the
diet for 21 days. A third group received 33 mg Ni/kg bw/day and 200 mg/kg bw/day ascorbic acid for the same period
of time. Ingestion of nickel sulphate depressed the growth rates of the rats. Liver and kidney weights were normal. The
results of the study indicate that administration of vitamin C in high doses to rats fed nickel salts in toxic doses can
restore not only the growth rates but also certain enzyme activities to a significant extent. The LOAEL of this study is
33 mg Ni/kg bw/day for growth depression and changes in various biochemical parameters.
4.1.2.5.1.2.5 Summary and conclusions, oral administration
Long-term studies of toxicity after oral exposure have been conducted in rats, mice and dogs. Mainly non-specific
indications of toxicity, such as decreased survival and decreased body weight, have been observed. In addition,
increased urinary albumin (indicator of diminished kidney function), mild tubular nephrosis, as well as immunosuppressive effects have been observed.
Table 4.1.2.5.I gives an overview of relevant repeated dose oral studies with nickel sulphate in rats, mice and dogs. The
studies show that oral exposure to nickel sulphate at low doses (7.6 – 11.2 mg Ni/kg bw/day) induces relatively mild
effects such as a small decrease in body weight and increased urinary albumin, and at higher doses (25-188 mg Ni/kg
bw/day) causes more serious effects such as marked weight loss, atrophy of the thymus and mild tubular nephrosis. The
2-year studies by Ambrose et al. are the most relevant for human lifetime exposure, but are not the most sensitive
studies, as effects were found at lower doses in the studies of shorter duration. The Obone et al. 13-week rat study
shows a small body weight reduction at a lower dose level than in the 2-year studies (11.2 mg Ni/kg bw/day), and the
Vyskocil et al. (1994b) 3 - 6 month study shows increased urinary albumin at approximately the same dose level as the
13-week rat study (7.6 mg Ni/kg bw/day). In agreement with the Obone et al. study, the SLI draft 2002 90-day oral
gavage study in rats showed 8% body weight reduction at 7-11 mg Ni/kg bw/day. In a 2-year OECD 451
carcinogenicity study, decreased body weight gain ranging from 4% to 12% was recorded (males and females
combined) following oral gavage of 2.2 to 11 mg Ni/kg bw/day. A dose-related reduced survival achieving statistical
significance at the two highest dose levels was seen in females. No non-neoplastic microscopic findings, which could be
attributed to administration of the test substance, were observed (CRL 2005).
For repeated dose oral toxicity a LOAEL of 6.7 mg Ni/kg bw/day is set based on reduced body weight and increased
mortality (based on CRL, 2005). From the same study a NOAEL of 2.2 mg Ni/kg bw/day is used. However,
uncertainties remain whether this should actually be considered as a NOAEL, as reduced body weight gain (both sexes)
and increased mortality (females) occurred to a statistically non-significant extent.
Table 4.1.2.5.I: Repeated dose oral studies with nickel sulphate
Duration and
species
Dose levels
mg Ni/kg bw/day
NOAEL
mg Ni/kg bw/day
LOAEL
mg Ni/kg bw/day
Effect at
LOAEL
Reference
4 weeks,
mice,
food
120
No dose level
without effect
120
Decrease in
Schiffer et al.
indices of
(1991)
immune function
13 weeks,
rats,
drinking water
0, 4.5, 11.2, or 22.4 4.5
11
4% reduction in
body weight
Obone et al.
(1999)
90 days,
rats
gavage
0, (7)11, 17, 22, 28, No dose level
and 33
without effect
(7) 11
8% reduction in
body weight
SLI draft not
dated (submitted
2002)
3 or 6 months,
rats,
drinking water
0 or 6.9 (males) or
7.6 (females)
No dose level
without effect
7.6
Increased
urinary albumin
Vyskocil et al.
(1994b)
6 months,
mice,
0, 25, 64 or 88
(assuming
No dose level
without effect
25
Reduced thymus Dieter et al.
weight, thymus (1988)
117
drinking water
hexahydrate was
given)
atrophy
2 years,
rats,
food
0, 10, 100, or 250
10
100
18% reduction in Ambrose et al.
body weight in
(1976)
females
2 years,
dogs,
food
0, 7.5, 75, or 188
75
188
Decreased body
weight gain,
lung
granulomas,
bone marrow
hyperplasia
Ambrose et al.
(1976)
2 years,
rats,
gavage
0, 2.2, 6.7, or 11
2.2*
6.7
Decreased
survival rate,
(females)
reduced body
weight gain
(both sexes)
CRL (2005)
* associated with a slight decrease in body weight gain (both sexes) and survival (females)
4.1.2.5.1.3
Dermal
Mathur et al. (1977) studied the cytopathological and histopathological changes in skin, liver, kidney and testis of rats
after dermal administration of nickel sulphate. Groups of male rats were painted for 15 (4 rats/group) or 30 days (4
rats/group) on a 4x4 cm lateroabdominal clipped skin area with a test substance consisting of nickel sulphate
hexahydrate dissolved in 0.25 ml normal saline in concentrations corresponding to 0, 40, 60 and 100 mg Ni/kg bw/day.
There was no mortality or clinical symptoms. Skin, liver, kidney and testis were examined macroscopically and
histopathologically. More pronounced effects were found after 30 days administration compared to 15 days. Skin of
nickel sulphate painted rats at 60 and 100 mg Ni/kg bw/day showed hyperkeratinization, vacuolization, hydropic
degeneration of basal layer and atrophy of epidermis. At 40 mg Ni/kg bw/day only a slight skin effect was found at 30
days. The testis was normal after 15 days, but showed degeneration and oedema of seminiferous tubules at 30 days at
60 and 100 mg Ni/kg bw/day. In the liver swollen hepatocytes and feathery degeneration was found at 15 days at 60 and
100 mg Ni/kg bw/day, at 30 days more severe lesions (areas of focal necrosis, congestion and dilatation of sinusoids)
were found in these two groups. In the kidney, no changes were found. In the study, 40 mg Ni/kg bw/day was a
NOAEL for liver and testis degenerative changes, and a LOAEL for local effects on the skin. This study has limitations
in experimental design and reporting. E.g., the group size in the study is small, only male animals were included, and
only a limited number of organs were examined. Information on food intake and body weight were not given in the
publication. Therefore, this study is not considered useful for the risk assessment.
In addition, two poorly reported studies of effects after repeated dermal application of nickel sulphate have been found
(Kosova 1970 - quoted from UK HSE 1987). No systemic effects were found after 14 days application to tails (25 or
50% solution), or after 30 days application to backs (50% solution). Among other limitations, the doses are not stated,
and the studies are therefore not useful for the risk assessment.
4.1.2.5.1.3.1 Summary and conclusions, dermal application
A study of good quality of repeated dose toxicity via the dermal route has not been found. In the Mathur et al. study
(1977), several effects were reported which have not been found in the oral studies (testes and liver degenerative
changes). Because of the limitations of this study these findings are not considered reliable, and a NOAEL/LOAEL for
repeated dose dermal toxicity cannot be determined.
4.1.2.5.1.4
Other routes
The toxicity of nickel sulphate given repeatedly by intramuscular or intraperitoneal injection has been studied (Knight
et al. 1991, Mathur et al. 1977b, Mathur & Tandon 1979, Mathur & Tandon 1981, Kasprzak et al. 1983). As these
routes of administration are not considered relevant for the risk assessment, no further description will be given here.
A mortality study of nickel platers in an engineering firm in England reported an increased standardized mortality ratio
(SMR) for respiratory disease in those with more than one year of exposure (Burges 1980). This study was in male
118
workers exposed only to soluble nickel, not to chromium or to other nickel compounds. The study size was relatively
small (508 workers, 101 deaths) and no other risk factors were assessed. In a more recent study that added an additional
16 years of follow-up to the cohort (Pang et al., 1996), there were no significant differences between observed and
expected non-carcinogenic respiratory effects. This study is essentially negative for non-malignant respiratory disease
and is in agreement with another study involving workers exposed to combinations of soluble and insoluble nickel in a
nickel refinery (Roberts et al., 1989). No mortality from non-malignant respiratory disease was found in these workers
either. No other epidemiological studies of non-cancer effect of nickel were located
Renal changes have been dealt with in several publications. Vyskocil et al. (1994a) examined biochemical markers of
kidney damage in 14 male and 12 female workers highly exposed to soluble nickel compounds in a chemical plant. The
main source of exposure was NiSO4 and NiCl2. No other heavy metals or nephrotoxic compounds were present. The
measured biomarker results were compared to similar results obtained in 12 male and 12 female matched controls. The
mean duration of exposure in male and female workers was 25 and 15 years. In the chemical plant the workers were
exposed to high concentrations of nickel which exceeded 4-26 times the threshold limit values (TLV) of 0.05 mg/m3.
The concentration of nickel in the urine from male and female workers averaged 5.0 and 10.3 μg/g creatinine. No
difference was found in the mean urinary excretion of lactate dehydrogenase, albumin and transferrin in both sexes,
total proteins, β2-microglobulin (β2-m) and retinol-binding protein (RBP) in males and lysozyme in females. Lysozyme
and N-acetyl-β-D-glucosaminidase (NAG) were elevated in male and total proteins, β2-m, NAG and RBP in female
exposed workers. Significant correlation between urinary concentrations of nickel on one side and that of β2-m in
women (r=0.462, p=0.022) and men (r=0.4, p=0.018) and of NAG in men (r=0.405, p=0.019) on the other side were
found in exposed subjects. The results indicate adverse effects of soluble nickel compounds on the kidney tubular
function. The authors conclude that in agreement with literature data it seems that those effects occur only at high
exposure levels.
The most recent review identifies the target organ for non-cancer effects of inhalation exposure to nickel sulphate as the
respiratory tract, with effects seen in both the lungs and the nose. For oral exposure, the most sensitive target is stated to
be the kidney, specifically decreased glomerular function. For the dermal route, general toxicity is not mentioned
(TERA 1999).
The rapporteur agrees with the TERA review that the type of toxicity caused by repeated exposure to nickel sulphate
depends on the route of exposure.
When nickel sulphate is inhaled, the main target is the respiratory system, where serious effects are induced in the form
of chronic inflammation and fibrosis. The most sensitive study was the 2-year rat study by NTP. The data from this
study do not allow identification of a clear NOAEC due to the difficulties with a definitive interpretation of the
biological significance of the observed effects at the lowest exposure level (0.027 mg Ni/m3). Therefore, a LOAEC of
0.056 mg Ni/m3 (0.25 mg nickel sulphate hexahydrate/m3) for lung inflammation and fibrosis is used in the risk
characterisation. It should be noted that data indicates that adverse effects possibly occur at lower levels. This is in line
the CSTEE evaluation of non-cancer effects of nickel and nickel compounds in relation to the Ambient Air Position
Paper (European Commission, 2000).
The TERA review concluded that the kidney is the most sensitive target organ following oral exposure. No studies have
shown marked histopathological kidney damage. The occurrence of albuminuria in rats indicates kidney effects, but
histopathology did not confirm the presence of lesions. However, a mouse study showed mild tubular nephropathy at
higher dose levels. The rapporteur agrees that nickel sulphate does seem to induce adverse effects on the kidney, but
that marked kidney toxicity has not been demonstrated. A weight reduction of the thymus and various effects on
immunological cells indicates interference with the immune system. The effects on the immune system have been
demonstrated at dose levels above those causing body weight loss, while the increased urinary albumin occurs at
approximately the same dose level as the reduction in body weight.
In the study by Obone et al. (1999), the 13-week LOAEL for nickel sulphate hexahydrate given in the drinking water
was 11 mg Ni/kg bw/day based on the 4% reduction in body weight and increased relative organ weights. The NOAEL
was 4.5 mg Ni/kg bw/day. Another 90-day study, using gavage, showed 8% body weight reduction at 7-11 mg Ni/kg
bw/day (SLI, draft not dated, submitted 2002). In the 3-6-month drinking water study by Vyskocil et al. (1994b),
increased urinary albumin was found at 7.6 mg Ni/kg bw/day. In the 2-year rat study by Ambrose et al. (1976) where
nickel sulphate hexahydrate was administered in the diet, similar effects on body weight were induced, since a NOAEL
119
of 10 mg Ni/kg bw/day and a LOAEL of 100 mg Ni/kg bw/day was determined for 18% decreased body weight in
females. In the 2-year dog study by Ambrose et al. (1976), a NOAEL of 75 mg Ni/kg bw/day and a LOAEL of 188 mg
Ni/kg bw/day was determined for decreased body weight, lung granulomas, and bone marrow hyperplasia, but because
of the small group size (3 dogs/sex) of this study it is possible that effects at the lower dose levels were missed. In a 2year OECD 451 carcinogenicity study, decreased body weight gain ranging from 4% to 12% was recorded (males and
females combined) following oral gavage of 2.2 to 11 mg Ni/kg bw/day. A dose-related reduced survival achieving
statistical significance at the two highest dose levels was seen in females (CRL 2005).
The LOAEL of 6.7 mg Ni/kg bw/day based on reduced body weight and increased mortality together with a NOAEL of
2.2 mg Ni/kg bw/day from the CRL (2005) study is taken forward to the risk characterisation for oral repeated dose
toxicity. However, uncertainties remain whether this NOAEL should actually be considered as a NOAEL, as reduced
body weight gain (both sexes) and increased mortality (females) occurred to a statistically non-significant extent.
It was not possible to determine a NOAEL/LOAEL for the dermal route based on the available information.
Nickel sulphate fulfils the criteria for classification as T; R48/23 since chronic lung inflammation including lung
fibrosis results from long-term exposure via inhalation to a concentration of 0.056 mg/Ni/m3 ∼ 0.25 mg nickel sulphate
hexahydrate/m3. Nickel sulphate is classified as T; R48/23 with a specific concentration limit of > 1% for T; R48/23
and > 0.1 % for Xn; R48/20 in the 30th ATP.
Looking across to data on other nickel compounds does not affect the conclusion for nickel sulphate (see background
document on nickel and nickel compounds).
4.1.2.6 Mutagenicity
The genotoxicity of nickel sulphate and other nickel compounds have been extensively reviewed by IPCS (1991), IARC
(1990), UK HSE (1987), ECETOC (1989), US ATSDR (1997), NiPERA 3 (1996) and TERA (1999). This assessment is
based primarily on the published reviews listed above and the HEDSET and other information submitted by Industry. A
few additional studies not listed in the above-mentioned reviews are also included.
4.1.2.6.1 In vitro studies
4.1.2.6.1.1
DNA damage and repair
A few studies for DNA damaging effect have been performed with nickel sulphate, see Table 4.1.2.6.1.A.
As shown in the table, nickel sulphate induced gene conversion in yeast cells and was an inhibitor of DNA synthesis in
human bronchial epithelial cells (Lechner et al. 1984). However, no DNA damage/strand breaks were induced in human
fibroblasts or human gastric mucosal cells.
Table 4.1.2.6.2.1.A: In vitro studies with nickel sulphate on DNA damage and repair
Species (test system) Endpoint
Result
Reference
Review
Positive
Singh (1984)
NiPERA (1996), UK
HSE, TERA
Fungi
S. cerevisiae D7
(diploid strain)
gene conversion
Mammalian cells
Human diploid
fibroblasts
XP cells
DNA strand breaks, Negative
alkaline elution
Fornace (1982)
IPCS, IARC,
NiPERA (1996),
TERA
Human gastric
mucosal cells
DNA damage
Negative
Pool-Zobel et al.
(1994)
US ATSDR, TERA
Human bronchial
inhibition of DNA
Positive
Lechner et al.
IPCS, US ATSDR,
3
NiPERA has pointed out that this review was produced by independent scientists for NiPERA and that the conclusions
of the report do not necessarily reflect the current position of NiPERA.
120
epithelial cells
4.1.2.6.1.2
synthesis
(1984)
NiPERA (1996),
TERA
Gene mutations
The studies on gene mutations are summarised in Table 4.1.2.6.1.B.
4.1.2.6.1.2.1 Prokaryotes
Only one study with nickel sulphate has been conducted with Salmonella typhimurium (TA 1535, TA 1537, TA1538,
TA 98, TA 100) and Escherichia coli WP2 uvrA- (pKM 101) (repair deficient strain) (Arlauskas et al. 1985). Nickel
sulphate was tested together with 23 other metal salts. No data was shown for nickel sulphate, but it was stated that
nickel sulphate did not induce reverse mutations in these bacterial strains with the applied test conditions. Also nickel
sulphate did not induce forward mutations in T4 phage. (Corbett et al. 1970 - quoted from IPCS, IARC, UK HSE,
NiPERA, 1996).
4.1.2.6.1.2.2 Eukaryotes
Nickel sulphate did not induce point mutations in the yeast strain Saccharomyces cerevisiae D7 in a reverse mutation
assay at the ilv locus (Singh, 1984 – quoted from UK HSE, NiPERA 1996, US ATSDR, and TERA). No mutations
were seen at the hprt locus in human lymphoblasts, TK6 (Skopek, 1995). Also, nickel sulphate did not induce ouabain
resistence in primary Syrian hamster embryo cells in a poorly reported study, but the mutagenic effect of benz(a)pyrene
was greatly enhanced when nickel sulphate was also present, indicating that nickel sulphate is a co-mutagen (Rivedal &
Sanner 1980 – quoted from UK HSE, IPCS, IARC). A few studies indicate that nickel sulphate is weakly mutagenic in
mammalian cells in culture. A weak positive response was seen in a mammalian test system with mouse lymphoma
L5178Ycells (tk+/- locus) (McGregor et al., 1988), and in a human lymphoblast TK6 cell line nickel sulphate induced
slow-growing tk mutants but not normal-growing tk mutants. However, in addition to point mutations, both assays may
also detect multilocus deletions, which can lead to chromosomal aberrations. A positive response was obtained with
nickel sulphate in Chinese hamster G12 cells (a hprt Chinese hamster V79 cell line stably transfected with a bacterial
gpt gene) at the gpt locus (Christie et al. 1992). It was shown in subsequent studies, though, that the induced gpt
inactivation by water insoluble nickel compounds were not true mutations but due to enhanced DNA methylation of the
gene (Klein 1994; Lee et al. 1995).
Table 4.1.2.6.1.B: In vitro studies with nickel sulphate on gene mutations
Species (test system) End point
Result
Reference
Review
Prokaryotes
T4 Bacteriophage
forward mutation
Negative
Corbett et al. (1970) IPCS, IARC, UK
HSE, NiPERA
(1996)
S. typhimurium
TA 1535, TA 1537,
TA1538, TA 98, TA
100
reverse mutation
Negative
Arlauskas et al.
(1985)
IPCS, IARC, US
ATSDR, NiPERA
(1996)
E. coli WP 2 uvrA-
reverse mutation
Negative
Arlauskas et al.
(1985)
IPCS, IARC,
NiPERA (1996)
reverse mutation
Negative
Singh (1984)
NiPERA (1996), UK
HSE, US ATSDR,
TERA
Syrian hamster
embryo cells
ouabain resistance
Negative
Rivedal & Sanner
(1980)
IPCS, IARC, UK
HSE
Syrian hamster
embryo cells
ouabain resistance
Positive
(co-mutagenic with
BaP)
Rivedal & Sanner
(1980)
IPCS, IARC, UK
HSE
Fungi
S. cerevisiae D7
(diploid strain)
Mammalian cells
121
Mouse lymphoma
L5178Y tk+/tk- cells
thymidine kinase
locus
positive (weak)
at toxic levels
McGregor et al.
(1988)
Chinese Hamster
G12 cells (V79 hprttransfected with
bacterial gpt)
gpt+/-/hprt- locus
positive (weak) (*)
Christie et al. (1992) IARC, NiPERA
(1996)
Human lymphoblasts
TK6
hprt locus
negative: hprt
negative: tknormal
positive: tkslow
Skopek (1995)
tk locus
IPCS, US ATSDR,
NiPERA (1996),
TERA
NiPERA (1996)
1): Due to DNA methylation of the gene (see text)
4.1.2.6.1.3
Chromosomal effects
The studies on chromosomal effects are summarised in Table 4.1.2.6.1.C.
4.1.2.6.1.3.1 Sister chromatid exchanges (SCE)
Nickel sulphate has been tested for sister chromatid exchanges (SCE) in ten different studies. Different cell lines have
been used in the studies including mouse mammary carcinoma cells, mouse macrophages, Chinese and Syrian hamster
cells, and human peripheral lymphocytes. Positive results were obtained in all ten studies as shown in Table 4.1.2.6.1.C.
As indicated in Table 4.1.2.6.1.C, a dose response relationship was found in some, but not all studies.
4.1.2.6.1.3.2 Chromosomal aberrations (CA)
Two different studies were performed with nickel sulphate on the ability to induce structural chromosomal aberrations
(CA). The effect was studied in Syrian hamster embryo cells, rat lung epithelial cells, and in human peripheral
lymphocytes. An increase in chromosomal aberrations, including gaps, breaks and exchanges, was seen in all test
systems as shown in table 4.1.2.6.1.C.
4.1.2.6.1.3.3 Other studies
In one study (Andersen 1985 – quoted from IPCS, NiPERA, 1996), nickel sulphate induced spindle disturbances
indicating that nickel sulphate might also be able to induce numerical chromosomal aberrations. Seoane & Dulout
(2001) tested nickel sulphate in a kinetochore-stained micronucleus test in human diploid fibroblasts at doses ranging
from 0 to 800 μM. The differential staining was used to distinguish between clastogens and substances causing
aneuploidy, with kinetochore-positive micronuclei presumably containing the entire chromosome. Nickel sulphate
showed a positive dose-related increase in micronuclei in both kinetochore-positive and negative cells. The effects were
greater and more statistically significant in kinetochore-positive fibroblasts. Nickel chloride was also tested and showed
similar effects. The effect was seen at much higher doses than the cadmium salts and chromates also tested.
Table 4.1.2.6.1.C: In vitro studies with nickel sulphate on chromosomal effects
Species (test system)
Endpoint Result
Reference
Review
Mammalian cells: Sister chromatid exchange (SCE)
Mouse mammary
carcinoma cells
FM3A
SCE
Positive
Nishimura &
Umeda (1979)
IPCS, TERA
Mouse
macrophage cell line
P338D1
SCE
Positive
Andersen (1983)
IPCS, IARC, US ATSDR
Don Chinese hamster
cells
SCE
Positive
at LC50
Ohno et al. (1982)
IPCS, IARC, UK HSE, US
ATSDR, NiPERA (1996),
TERA
Chinese hamster ovary
cells
SCE
Positive
at 0.75 mg/l
Deng & Qu (1981) IPCS, IARC, UK HSE
Positive
(dose response)
Larramendy et al.
(1981)
Syrian hamster embryo SCE
cells
122
TERA
Human peripheral
lymphocytes
SCE
Positive
(dose response at 20,
200 μmol/l)
Wulf (1980)
ATSDR, NiPERA (1996)
Human peripheral
lymphocytes
SCE
Positive
(dose response)
Deng & Qu (1981) IPCS, IARC, UK HSE
Human peripheral
lymphocytes
SCE
Positive
(dose response)
Larramendy et al.
(1981)
TERA
Human peripheral
lymphocytes
SCE
Positive
Andersen (1983)
IARC, US ATSDR
Human peripheral
lymphocytes
SCE
Positive
Katsifis et al.
(dose response;
(1996)
interactions with Cr(VI),
UV-light and X-rays.)
Mammalian cells: Chromosomal aberrations (CA)
Syrian hamster embryo CA
cells
Positive
(gaps, breaks,
exchanges, minutes,
dicentrics)
Larramendy et al.
(1981)
TERA
Rat lung epithelial cells CA
Positive
(exchanges)
Brooks & Benson
(1988)
NiPERA (1996)
Human peripheral
Lymphocytes
Positive
Larramendy et al.
(breaks, rings, minutes) (1981)
CA
TERA
Mammalian cells: Other studies
Human peripheral
lymphocytes
Spindle
Positive
disturbance
Andersen (1985)
Human diploid
fibroblasts
kinetochor
e-stained
micronucle
us assay
Seoane & Dulout
(2001)
4.1.2.6.1.4
Positive (kinetochorepositive cells)
weakly positive
(kinetochore-negative
cells)
IPCS, NiPERA (1996)
Cell transformation
The studies on cell transformation are summarised in table 4.1.2.6.1.D.
Several studies indicate that nickel sulphate can induce cell transformation in rodent and human cells. In combined
treatment of nickel sulphate with other carcinogenic compounds like benzo(a)pyrene, a synergistic effect was observed
when the cells were treated sequentially with the compounds, and in some studies, nickel sulphate was positive when
added alone (see table 4.1.2.6.1.D). These studies indicate that nickel sulphate can act both as an initiator and promotor
(Rivedal & Sanner 1980, 1981 – quoted from IPCS, NiPERA 1996, UK HSE, TERA). Some studies show a synergistic
effect of nickel sulphate and cigarette smoke extract indicating that nickel sulphate may enhance the effect of smoking
(Rivedal et al. 1980 - quoted from IPCS, NiPERA 1996, UK HSE). Additionally, there is evidence that nickel sulphate
can inhibit intercellular communication via gap junctions in Chinese hamster V79 cells and other mammalian cell lines
(Loch-Caruso et al. 1991, Miki et al. 1987 – quoted from TERA).
Table 4.1.2.6.1.D: In vitro studies with nickel sulphate on cell transformation and intercellular
communication
Species (test system) Endpoint
Mouse embryo
Result
cell transformation Negative
Reference
Review
Miura et al. (1989) US ATSDR,
123
fibroblasts
NiPERA (1996),
TERA
Rat hereditary renal
tumour cells (HRT)
initiation and
promotion test
Positive (both as
initiator and
promotor)
Eker & Sanner
(1983)
IPCS, UK HSE
Rat embryo cells
infected with
Rauscher leukaemia
virus
transformed foci
Positive
Traul et al. (1981)
IPCS, UK HSE
Normal rat kidney
transformed foci
cells (NRK) infected
with Makoney
murine sarcoma virus
Positive
max at 10 mg/l
Wilson &
Khoobyarian
(1982)
IPCS, IARC, UK
HSE
Syrian hamster
embryo cells (SHE)
transformed foci
Positive
(dose response)
Di Paolo & Casto
(1979)
IPCS, IARC, UK
HSE, NiPERA
(1996), TERA
Syrian hamster
embryo cells (SHE)
transformed foci
Positive at 19, 76
μmol/l –
synergistic effect
with BaP
Rivedal & Sanner
(1980)
IPCS, IARC, UK
HSE, NiPERA
(1996)
Syrian hamster
embryo cells (SHE)
transformed foci
Positive –
synergistic effect
with BaP
Rivedal & Sanner
(1981)
IPCS, IARC, UK
HSE, NiPERA
(1996)
Syrian hamster
embryo cells (SHE)
transformed foci
Positive with
cigarette smoke
extract only
(synergistic effect)
Rivedal et al.
(1980)
IPCS, IARC, UK
HSE, NiPERA
(1996)
Syrian hamster
embryo cells (SHE)
transformed foci
Positive
Pienta et al.
(1977)
IARC
124
Syrian hamster
embryo cells (SHE)
transformed foci
Positive
Zhang & Barrett
(1988)
Syrian hamster
embryo cells (SHE)
transformed foci
Positive
Kerckaert et al.
(1996)
Syrian hamster
embryo cells (SHE)
transformed foci
Positive –
enhanced
transformation of
cells by SA7
simian adenovirus
Casto et al. (1979) UK HSE,
NiPERA (1996)
Human
bronchial epithelial
cells
growth control and Positive
morphology
Lechner et al.
(1984)
IPCS, IARC,
NiPERA (1996),
TERA
Human foreskin
fibroblasts
anchorage
independence
Positive
Biedermann &
Landolph (1987)
IPCS, IARC,
NiPERA (1996),
US ATSDR
NIH3T3 cells
inhibition of
intercellular
communication
Positive
(dose response)
Miki et al. (1987)
IPCS, IARC,
TERA
Chinese hamster V79 inhibition of
Positive
cells
metabolic coupling
4.1.2.6.1.5
IARC, NiPERA
(1996)
Loch-Caruso et al. TERA
(1991)
Discussion and conclusion, in vitro studies
Nickel sulphate gave negative results in bacterial assays with S. typhimurium and E. coli. However, only one not
appropriate study was performed and the data was not shown. In addition it is shown with other metallic ions like
cobalt(II) that the results in bacteria are greatly influenced by the tester strain and the test conditions used (Arlauskas et
al. 1985; Pagano & Zeiger 1992; Beyersmann 1994; Binderup 1999;). In two studies, it was shown that cobalt(II) was
only genotoxic in the Salmonella strain TA97 and considerable more genotoxic in the preincubation assay than in the
standard plate assay (Pagano & Zeiger 1992; Binderup 1999). No studies have been carried out with nickel sulphate
using TA97 and this test condition.
There was no evidence for point mutations in yeast cells. Only few gene mutation studies were performed with
mammalian cell lines, and the positive results in these assays could possibly be due to other genetic events
(chromosomal aberrations and DNA methylation) than point mutations. Therefore, there is no convincing evidence that
nickel sulphate induces point mutations.
There are ten different studies showing positive effects on sister chromatid exchange (SCE) and two further studies
showing chromosome aberrations. These effects occurred in both human and mammalian cells.
There are several studies showing that nickel sulphate can induce cell transformation in rodent and human cells.
Synergistic effects were observed in combined treatment of nickel sulphate with other carcinogenic compounds like
benzo(a)pyrene, (Rivedal & Sanner, 1980, 1981). Some studies show a synergistic effect of nickel sulphate and
cigarette smoke extract indicating that nickel sulphate may enhance the effect of smoking (Rivedal et al. 1980). The
results of Miki et al. (1987) and Loch-Caruso et al. (1991) indicate that nickel sulphate can inhibit intercellular
communication.
These synergistic effects and the in vitro effects on intracellular communication are seen by NiPERA (2002) as
evidence that nickel sulphate appears to be a more potent promoter than initiator (Rivedal & Sanner, 1980, 1981;
Christie & Tummolo, 1987). Consistent with its promoting activity, Ni sulphate at non-cytotoxic concentrations has
been observed to increase the concentration of proliferin mRNA 1000-fold above control values. Only compounds with
promoting activity have been shown to induce proliferin in C3H10T1/2 cells (Parfett, 1992).
In conclusion, there is no convincing evidence that nickel sulphate induces point mutations, but nickel sulphate is
clearly clastogenic in vitro producing chromosomal aberrations and sister chromatid exchanges in different mammalian
cells.
125
4.1.2.6.2 In vivo studies
4.1.2.6.2.1
DNA damage
The studies on DNA damage are summarised in Table 4.1.2.6.2A.
Nickel sulphate inhibited DNA synthesis in rat hepatic epithelium cells but not in kidney epithelium cells. The study
was not sufficiently characterised for conclusions to be drawn. (Amlacher & Rudolf 1981 – quoted from UK HSE).
Benson et al. (2002) have performed a comprehensive in vivo study in rats in order to throw some light on the
differences and similarities in the mechanism of cancer induction by insoluble and soluble nickel compounds in the
lung, which is the target organ for cancer development after inhalation. Several endpoints were investigated after
inhalation of insoluble nickel subsulphide and soluble nickel sulphate hexahydrate. The most important endpoints for
the evaluation of genotoxicity / carcinogenicity are DNA damage measured as DNA strand breaks and oxidative DNA
damage in the comet assay, DNA degradation, DNA methylation and cell proliferation.
Both compounds induce DNA strand breaks in the comet assay at the highest exposure levels (for nickel sulphate 0.22
mg Ni /m3). In this assay there was no indication of oxidative DNA damage. DNA strand breaks were induced earlier
and at lower concentrations with nickel subsulphide than with nickel sulphate and persisted after a 13 weeks recovery
period. These findings are in accordance with in vitro studies of nickel and other metals, and are presumably due to
higher intercellular concentrations of insoluble than soluble metals due to phagocytosis. At the highest nickel sulphate
concentration primarily small DNA fragments were found, which might have influenced the comet assay results.
Inflammation was evident at the same exposures where DNA strand breaks were observed. This might lead to
confounding of the comet assay by apoptosis. However, there seems to be only a few seriously damaged cells, since the
median scores were all well below 800 at all exposure levels. Moreover, there was no indication that oxidative damage
caused the strand breaks as would be expected if they were secondary to inflammation. The genotoxic damage is
therefore most likely unrelated to inflammation or apoptosis. In addition, DNA degradation reported in the study was
not measured in the cells used for the comet assay but in whole lung tissue homogenate, and therefore a correlation
between DNA strand breaks in the comet assay and the DNA degradation cannot be made.
The Benson et al. (2002) study is in accordance with the earlier reviewed studies in the nickel risk assessment reports
showing that both soluble and insoluble nickel compounds primarily induce structural DNA damage. In this in vivo
study the most relevant exposure pathway (inhalation) and target organ (the lung) were studied at a reasonable range of
exposure concentrations. The study gives a fair explanation of the differences in carcinogenic potency of Nickel
subsulphide and nickel sulphate but underlines the genotoxic potential of both compounds in the target organ, although
cytotoxicity cannot be ruled out for nickel sulphate.
Table 4.1.2.6.2.A: In vivo studies with nickel sulphate on DNA damage
Species/Strain
Endpoint/test condition
Result
Reference
Review
Mouse, CBA strain
Intraperitoneal
Inhibition of DNA
synthesis at
15-30% of LD50
Negative:
kidney epithelium
Positive:
hepatic epithelium
Amlacher & Rudolf
(1981)
UK HSE
Rats, F344
Inhalation
DNA damage (Comet
assay)
0, 0.125, 0.5, 1 mg/m3
0, 0.03, 0.11, 0.22 mg
Ni/m3
significant increase at Benson et al., (2002)
highest dose after 13
weeks but
cytotoxicity cannot
be ruled out
Mammals
4.1.2.6.2.2
Gene mutations
There are no available in vivo studies on gene mutation.
4.1.2.6.2.3
Chromosomal effects
The studies on chromosomal effects are summarised in Tables 4.1.2.6.2.B – D.
126
Nickel sulphate induced sex-linked recessive lethal mutations, as a measure of deletion mutations in D. melanogaster.
In the same study, a weak effect of sex chromosome loss, as a monitor of aneuploidy induction, was observed
(Rodrigues-Armaiz & Ramos 1986 – quoted from IPCS, IARC, UK HSE, US ATSDR, NiPERA 1996, TERA).
Mathur et al. (1978) studied nickel distribution and cytogenetic changes in rats after intraperitoneal administration of
nickel sulphate. Two treated groups were given 3 or 6 mg Ni/kg daily as nickel sulphate hexahydrate dissolved in
saline, the control group received saline. Three animals/group were sacrificed after 7 or 14 days of treatment for CA
analysis. The distribution of nickel in various organs was also studied. No results of the CA analysis are shown. The
study concludes that “nickel treatment for a period of 7 or 14 days at doses of 3 or 6 mg Ni/kg did not induce marked
chromosomal changes either in bone marrow or spermatogonial cells of rats”. “The bone marrow cells of rats
administered 6 mg/kg for 14 days showed a few chromatid breaks. The frequency of chromatid breaks and mitotic index
in experimental and control animals, however, did not differ significantly. Spermatogonial cells did not show any
chromosomal aberration or abnormal mitotic index at both the concentrations and durations of nickel exposure”. Given
that no data is given to support the negative results reported, it is difficult to see this study as providing convincing
evidence of a negative effect.
Nickel concentrations in bone and testis were measured at both doses.
Distribution of nickel (mg/g fresh weight) in rats exposed to nickel sulphate hexahydrate i.p. (Mathur et al.
1978).
Tissue
Control
3 mg/kg
6 mg/kg
7 days
14 days
7 days
14 days
Testis
0.32 + 0.01
0.49 + 0.01
0.75 + 0.03
0.67 + 0.06
1.03 + 0.002
Bone
0.15 + 0.01
0.37 + 0.009
0.72 + 0.07
0.60 + 0.05
1.12 + 0.05
All the treated groups were significantly higher than the controls (P < 0.001) and the values after 14 days significantly
higher (P < 0.001) than the value after 7 days. NiPERA has commented that the total dose given in this study ranged
from 21 mg (3 mg x 7 days) to 84 mg (6 mg x 14 days) Ni/kg bw with 100% absorption. These negative results were
seen in animals whose bones had about 10-fold higher nickel levels than controls and at overall higher absorbed doses
than those used in the oral Sobti & Gill (1989) and Sharma et al. (1987) studies (NiPERA, 2002).
Nickel sulphate (anhydrous) has been reported to induce the frequency of chromosome abnormalities (rings, fragments)
in mice after oral administration of 73 mg/kg bw (28 mg Ni/kg bw) for 4, 8, 12 or 16 days (Sharma et al., 1987). The
CAS No. (7786-81-4) given for the substance identifies it as the anhydrous salt. Nickel chloride and nickel nitrate were
also studied. There is only limited information in the study description. One exposure level only was tested, together
with a control but no positive control. It is not stated how many animals were studied per group (NiPERA, 2003 quotes
1 animal/group). The animals were treated daily for 4, 8, 12 or 16 days. It is not stated when sampling took place in
relation to the final dose. 100 metaphases/animal were scored, but there is no indication whether the scoring was blind.
There is no specific mention of whether gaps were scored. The results are shown as single figures (with no mean). The
frequency of chromosomal aberrations/cell for nickel sulphate ranged from 0.26 to 0.45 as against the control values of
0.02 to 0.06. The results for all three nickel compounds tested peaked at day 12 and were highest for nickel sulphate and
lowest for nickel chloride. With only one dose, direct information on a dose-response relationship is not available.
NiPERA (1996) reports the results of this study as positive. NiPERA (2003) has evaluated this study as equivocal,
based on a significant increase in at least one dose group, but unclear scoring of gaps, insufficient number of animals,
single exposure level and no blind scoring. The study is not included in the IARC, IPCS, US ATSDR or the TERA
reviews, or the paper prepared for the Specialised Experts (van Benthem, 1997). In the same study, significant increases
in inversion of chromosomes in a mosquito (Anopheles stephensi) after treatment at 4 μg/ml were also reported.
Nickel sulphate has been tested in the micronucleus test as part of a large-scale collaborative study (Morita et al., 1997).
Nickel chloride (hexahydrate) and nickel oxide was also tested in the same study. Nickel sulphate hexahydrate was
tested in groups of 5 male ddY mice by a group led by H Shimada at Daiichi Pharma Co. Ltd. The test substance was
identified specifically as the hexahydrate with reference to CAS No. 10101-97-0 and dissolved in saline. The test
substance was given twice intraperitoneally at doses of 0, 5, 10 and 20 mg/kg bw (corresponding to 0, 1.1, 2.2 and 4.4
mg Ni/kg bw). A dose of 20 mg/kg bw was stated to be the maximum tolerated dose. Two doses were given at 24 hour
127
intervals and bone marrow was sampled 24 hours after the final treatment. 1000 immature erythrocytes were scored. As
this is a collaborative study covering a large number of chemicals, details for each study are limited.
Frequency of micronucleated PCEs in bone marrow cells (Morita et al, 1997).
Dose
mg/kg
harvest
time h
% Mn-PCEs
NCE/PCE ratio
mean
SE
Mean
0
24
0.16
0.11
-
5
24
0.16
0.11
-
10
24
0.30
0.19
-
20
24
0.24
0.11
-
SE
There is no documentation in the article for the statement that the dose of 20 mg/kg is the MTD. No figures are given
for the effect on NCE/PCE ratios, and this information is not available in the conclusion. The conclusion of the
collaborative study was that nickel sulphate “did not induce micronucleated polychromatic erythrocytes in ddY mouse
bone marrow 24 hr after the second peritoneal treatment”. This study was not reviewed by TERA (1999). NiPERA
(2003) considers that the power of the study is considered to be high with appropriate numbers of animals and exposure
groups, sampling times and analysis. The exposure level is sufficiently high (MTD) (NiPERA, 2003).
An in vivo bone marrow micronucleus study of nickel sulphate in rats after oral administration has been conducted
(Covance 2003). This study was conducted using the Annex V B12 (OECD 474) protocol. A repeated dose protocol
(one dose administered every 24 hours on three consecutive days) was selected to maximize exposure to the bone
marrow. The bone marrow was sampled at a single time, 24 h after the final dose.
The levels chosen for the study were 125, 250 and 500 mg nickel sulphate hexahydrate/kg bw/day x 3 days (27.5, 55,
110 mg Ni/kg/day x 3 days). In a range-finding study, no bone-marrow cytotoxicity (significant decrease in PCE:NCE
ratio) was seen at doses of 750 or 1000 mg nickel sulphate hexahydrate/kg bw/day x 3 days. However the range-finding
study showed significant mortality (4 animals died out of 6 dosed) at a dose of 750 mg nickel sulphate hexahydrate/kg
bw/day x 3 days. For comparison, the LD50 seen in the FDRL study and used for the risk characterisation is 325 mg
NiSO4.6H2O /kg.
In the main study, no mortality was seen at the top dose of 500 mg/kg bw/day, but clinical signs of toxicity included
hypoactivity and salivation. Nickel sulphate hexahydrate was not significantly cytotoxic to the bone marrow at this dose
and did not induce any significantly significant decreases in the PCE:NCE ratio. Nickel sulphate hexahydrate did not
induce any statistically significant increases in micronucleated PCEs at any of the three dose levels examined.
Treatment
Dose
(mg/kg/day)
Vehicle (water)
Harvest time
% Mn -PCEs
Ratio PCE:NCE
mean
S.E.
mean
S.E.
24 h
0.07
0.02
1.14
0.14
Cyclophosphamide
60mg/kg
24 h
2.22*
0.15
0.79**
0.03
Nickel sulphate
hexahydrate
125mg/kg
bw/day
24 h
0.01
0.01
0.93
0.14
250mg/kg
bw/day
24 h
0.07
0.03
1.13
0.11
500mg/kg
bw/day
24 h
0.06
0.02
0.91
0.10
* Significantly greater than the corresponding vehicle control, p <0.01.
** Significantly less than the corresponding vehicle control, p <0.05.
128
Nickel concentration in the plasma and the bone marrow was also measured in this study. The results are shown in the
Table below. The increases in plasma nickel concentration are statistically significant, the increase in bone marrow
concentrations are not.
Plasma (ppb)
Bone Marrow (ppb)
Mean
SD
Mean
SD
Vehicle Control
<50
0
11.0
5.5
125 mg/kg/day
163*
80.9
13.2
2.7
250 mg/kg/day
519*
272.4
27.9
24.1
500 mg/kg/day
1568*
786.2
38.5
43.4
* Significantly greater than the corresponding vehicle control, p ≤0.01.
Sobti & Gill (1989) have also tested nickel sulphate, nickel nitrate and nickel chloride in a micronucleus test. Nickel
sulphate was given as a single oral dose of 73 mg/kg bw (28 mg Ni/kg bw) in water to Lacca mice. The CAS No.
(7786-81-4) given for the substance identifies it as the anhydrous salt. A negative control was included, but no positive
control is reported. The number of animals treated per group was not given. Bone marrow samples were taken 6 and 30
hours after treatment, and smears of spermatozoa were made from the epididymis five weeks after the last exposure. It
is not clear how many cells were scored per animal, or whether these were scored blind. There is a reference to Robert
& Bernard (1982) for slide preparation techniques and to Schmid (1973, 1975) for staining but no other details are
given.
Frequency of micronucleated PCEs in bone marrow cells and in spermatozoa (Sobti & Gill, 1989).
Dose
mg/kg
harvest
time
Mn-PCEs/1000
NCE/PCE ratio
mean
SE
Mean
6h
1.33
0.272
-
30 h
1.66
0.272
-
6h
2.33.
0.272
-
30 h
4.33
0.272
-
SE
bone marrow
0
73
Spermatozoa
0
5 weeks
8.66
0.547
73
5 weeks
25.66
0.982
Significant increases (p<0.05) in micronuclei were seen at both 6 and 30 hours after treatment. A significant increase
(p<0.01) in sperm head anomalies was also seen after 5 weeks. The different types of abnormal spermatozoa were
described as Daphnia, polyp, amorphous, giant amorphous and anvil-shaped. The authors note that their results agree
with their earlier findings on chromosomal aberrations (Sharma et al. 1987). The study is reported as positive in the US
ATSDR, NiPERA (1996) and TERA reviews. It is included in the paper prepared for the Specialised Experts (van
Benthem, 1997). NiPERA (2003) considers the result equivocal based on significant increases at one dose, but no
information on trend, single recommended sampling time, insufficient animals, single exposure level, unclear units of
exposure, no blind scoring (NiPERA 2003).
CA and SCE were studied in peripheral lymphocytes of refinery workers with office workers as controls (Waksvik &
Boysen, 1982) and a significant increase in gaps but not sister chromatid exchanges were seen. All were non-smokers,
non-alcohol consumers and did not take drugs routinely. A number of other confounders were also excluded. Two
exposed groups were studied. One group of 9 workers was engaged in crushing/roasting/smelting processes and
exposed to mainly nickel monoxide and subsulphide. The other group of 10 workers, engaged in electrolysis, were
exposed mainly to nickel chloride and nickel sulphate for an average of 25.5 years (range 8 – 31 years) at an air nickel
129
concentration of 0.2 mg/m3 (range 0.1 – 0.5 mg/m3) and with a mean plasma level of 5.2 μg/l had 18.3% of metaphases
with gaps. Mean control levels of 3.7% of metaphases with gaps were seen in 7 office workers with plasma levels of 1
μg/l. The office workers were matched for age and sex. (Waksvik & Boysen, 1982, quoted from IARC).
Waksvik et al. (1984) investigated nine ex-workers from the same plant who had been retired for an average of 8 years
who had had similar types of exposure to more than 1 mg/m3 atmospheric nickel for 25 years or more. They were
selected from among a group of workers known to have nasal dysplasia and who still had plasma nickel levels of 2 μg/l
plasma. these retired workers showed some retention of gaps (p < 0.05) and an increased frequency of chromatid breaks
to 4.1 % of metaphases versus 0.5% (p < 0.001) in 11 unexposed retired workers controlled for age, life style and
medication status (Waksvik et al., 1984, quoted from IARC).
NiPERA (2003) does not consider that the Waksvik & Boysen (1982) or Waksvik et al. (1984) studies can be used as
evidence that nickel exposures induced chromosomal aberrations in these workers. The data reporting in the papers is
confused 4, very few workers were sampled and no correlation with plasma nickel levels were found. UK HSE (1987)
has evaluated the Waksvik & Boysen (1982) study and considers that in whilst chromosome breaks were no more
frequent in the nickel workers than in office workers, and there is no significant differences in the numbers of SCEs per
metaphase, the increase in chromosome gaps seen in the lymphocytes of process workers may be an indication of a
genetic effect of nickel on somatic cells. IARC includes their conclusions on the Waksvik & Boysen (1982) and
Waksvik et al. (1984) studies in their summary of other relevant data. The studies are also included in IPCS. US
ATSDR mentions the Waksvik & Boysen (1982) study, but refers only to the results for sulphidic nickel. These studies
were not included in the review prepared for the Specialised Experts by van Benthem (1997).
Deng et al. (1983, 1988) studied the frequencies of sister chromatid exchange and chromosomal aberrations in
lymphocytes from 7 electroplating workers exposed to nickel. Air nickel concentrations were 0.0053 – 0.094 mg/m3
(mean 0.024 mg/m3). Control subjects were ten administrative workers from the same plant matched for age and sex.
Other confounders were also considered. The exposed workers had an increased frequency of sister chromatid exchange
(7.50 + 2.19 (SEM) versus 6.06 + 2.30 (SEM) p < 0.05). The IARC Working Group noted that this is a small difference
between the groups. The frequency of chromosomal aberrations (gaps, breaks and fragments) was increased from 0.8%
of metaphases in controls to 4.3% in nickel platers (Deng et al., 1983, 1988, quoted from IARC)
Senft et al. (1992) measured chromosomal aberrations in peripheral lymphocytes from workers at a chemical plant in
the Czech Republic producing nickel sulphate and nickel oxide. Samples were taken from 15 nickel sulphate production
workers, 6 nickel oxide production workers and 19 control subjects. There was a significant although small (1.6 fold)
increase in the mean value of chromosomal aberrations (gaps, chromatid and chromosome breaks) in the combined
exposed group compared to that in the control group. A simple relationship between CA level and years of employment
or levels of nickel in urine, serum or hair was not apparent (quoted from NiPERA, 1996). Subsequent analysis of the
data by NiPERA (2002) shows that the incidence of chromosomal aberrations in the subgroup of 15 workers exposed
mainly to nickel sulphate was not statistically different (5.2 + 1.9%) in the nickel sulphate production workers than in
the controls (4.05 + 2.27%). Senft et al. (1992) notes that the incidence of chromosomal aberrations in the control group
(4.05 + 2.27%, range 1 – 10%) is significantly higher than the normal value found for chromosomal aberrations in
peripheral lymphocytes (up to 2%). Senft et al. suggest that this is due to the nickel-polluted environment of the whole
chemical plant. NiPERA (2003) does not consider that the Senft et al. (1992) study can be used as evidence that nickel
exposures induced chromosomal aberrations in these workers.
Table 4.1.2.6.2.B: In vivo studies with nickel sulphate on chromosomal effects in plants and insects.
Species / Strain
Endpoint / test
system
Result
Reference
Review
mitotic effects
Positive
Komczynski et al.
(1963)
IPCS
Plants
Vicia faba
4
The material on which the Waksvik & Boysen (1982) study is based appears to be largely the same as the two
Waksvik et al. (1981a & 1981b) studies. NiPERA (2003) has pointed out that data for the two treated groups studied
(Group 1: electrolysis workers, Group 2: roasting-smelting workers) appears to have been transposed between the two
1981 papers and the 1982 paper. IARC notes that the exposures of these workers was clarified in an erratum to the
original article published subsequently in Mutat. Res., 104, 395 (1982).
130
Insects
D. melanogaster
white-males
BASC-females
sex-linked recessive
lethal mutation
Positive
Rodrigues-Armaiz & IPCS, IARC, UK
Ramos (1986)
HSE, US ATSDR,
NiPERA (1996),
TERA
D. melanogaster
XC2y B/sc8 Y-males
y2wa-females
sex chromosome loss
assay
Positive (weak)
Rodrigues-Armaiz & IPCS, IARC, UK
Ramos (1986)
HSE, US ATSDR,
NiPERA (1996),
TERA
Table 4.1.2.6.2.C: In vivo studies with nickel sulphate on chromosomal effects in mammals
Species/Strain /
Endpoint/ test
system
Route of
administration /
Dose / No. of doses
Result
Reference
Review
Mammals – chromosomal aberrations (CA) in bone marrow and spermatogonia
Rat
Intraperitoneal
3, 6 mg Ni/kg
repeated dosing for 7
and 14 days
Negative
Mathur et al. (1978)
IPCS, IARC, US
ATSDR, TERA,
NiPERA (2003)
Mammals – chromosomal aberrations (CA) in bone marrow
Mouse (Lacca)
Oral
73 mg/kg
[28 mg Ni/kg]
for 4, 8, 12 or 16 days
Positive
Sharma et al. (1987) NiPERA (1996)
equivocal
NiPERA (2003|)
Mammals – micronucleus test (MN) in bone marrow
Mouse ddY
Intraperitoneal
Negative
2 x 0, 5, 10 and 20
mg/ kg
[2 x 0, 1.1, 2.2 and 4.4
mg Ni/kg ]
Morita et al. (1997).
Rat (SpragueDawley)
Oral
3 x 125, 250, 500
mg/kg bw
[3 x 28, 56, 112 mg
Ni/kg bw
for 3 days
Covance (2003)
Negative
NiPERA (2003).
Mammals – micronucleus test (MN) in bone marrow and spermatozoa
Mouse (Lacca)
oral
73 mg/kg
[28 mg Ni/kg]
Positive
Sobti & Gill (1989)
equivocal
US ATSDR, NiPERA,
TERA
NiPERA (2003)
Table 4.1.2.6.2.D: In vivo studies with nickel sulphate in humans.
CA, SCE, peripheral lymphocytes
Electrolysis workers
n=10
Control: Office
workers.
n=7
Roasting-smelting
workers also studied
soluble nickel: NiSO4, Positive (gaps) Negative Waksvik & Boysen
NiCl2 exposure
(breaks) Negative SCE (1982)
0.1 – 0.5 mg Ni/m3
Retired nickel
25 years exposure to > Positive gaps and breaks Waksvik et al.
Cannot be used as
evidence.
UK HSE, IARC,
IPCS, (US ATSDR),
NiPERA (1996)
NiPERA (2003)
IARC, IPCS,
131
refinery workers,
n=9
Control
n = 11
1 mg Ni/m3 –
combined NiSO4,
NiCl2, NiO and Ni3S2,
Negative SCE
Electroplating
workers
n=7
Control
n = 11
nickel exposure:
0.0053 – 0.094 mg/m3
mainly gaps, but also
breaks & fragments
small increase in SCE
Deng et al. (1983,
1988)
IARC
Positive for combined
exposure groups
(gaps and breaks)
Senft et al. (1992)
NiPERA (1996)
(1984)
Cannot be used as
evidence
NiPERA (1996)
NiPERA (2003)
CA peripheral lymphocytes
Nickel sulphate
chemical plant
n = 15
Control
n = 19
Nickel oxide
production workers
(n=6) also studied
4.1.2.6.2.4
NiSO4
(0.31-2.86 mg Ni/m3)
NiO
(0.28-1.52 mg Ni/m3)
Cannot be used as
evidence
NiPERA (2003)
Discussion and conclusion, in vivo studies
The study by Benson et al. (2002) is the most comprehensive part of the database on in vivo genotoxicity of Ni
compounds. The study has been criticized because it cannot discriminate direct induction of DNA damage from indirect
damage secondary to inflammation or apoptosis. The nickel compounds tested seem to induce inflammation and
genotoxicity at approximately the same concentrations.
The results from the oral and intraperitoneal in vivo studies are conflicting. There are two studies for chromosomal
aberrations. One intraperitoneal study (Mathur et al., 1978) is negative, although no data is presented to support this
conclusion. The oral study (Sharma et al., 1987) is widely regarded as positive, although NiPERA (2003) regards the
results as equivocal. Unlike nickel chloride, there are no studies with nickel sulphate which show clearly positive effects
on chromosomal aberrations in vivo. Of the three micronucleus studies, there is one positive study after oral
administration (Sobti & Gill, 1989) whilst the two more recent studies (Morita et al., 1997 after intraperitoneal
administration and Covance 2003 after oral administration) are both negative. The Sharma et al. (1987), Sobti & Gill
(1989) and Morita et al. (1997) studies have both been discussed in more detail in the nickel chloride risk assessment.
The Morita (1997) study suggests that strain differences may be an explanation for the conflicting results.
Three of the studies in man included here included exposure to both nickel sulphate and nickel chloride. These three
studies (Waksvik & Boysen, 1982, Waksvik et al. 1984, Deng et al., 1983, 1988) are regarded by IARC as relevant
data. In addition, Senft has studied effects on workers at a chemical plant. NiPERA (2003) does not believe either the
Waksvik or the Senft studies can be used as evidence that nickel exposure induces chromosomal aberrations in the
exposed workers studied.
4.1.2.6.3 Conclusions
From the data reviewed above there is clear evidence indicating that nickel sulphate is genotoxic in vitro, and in
particular, is clastogenic. There are a number of in vivo studies in both animals and man. The study by Benson et al.
(2002) is the most comprehensive part of the database on in vivo genotoxicity of Ni compounds and shows that nickel
sulphate given by inhalation seems to induce inflammation and genotoxicity in lung cells at approximately the same
concentrations. The results from some of the other animal studies are conflicting. Results of two recent micronucleus
studies, one after oral and one after intraperitoneal administration are negative. Evidence from human studies is limited.
There are no definitive studies on germ cells, and little evidence concerning hereditable effects. Whilst there is evidence
that the nickel ion reaches the testes, no effect on spermatogonial cells was seen in the Mathur et al. (1978) study. The
effects seen in the Sobti & Gill (1989) study may reflect toxic effects on germ cells rather than chromosomal damage.
The opinion of the Specialised Experts has been sought with regard to the classification of nickel sulphate as Muta. Cat.
3; R68 at their meeting in April 2004. The Specialised Experts concluded that nickel sulphate, nickel chloride and
nickel nitrate should be classified as Muta. Cat. 3; R68. This conclusion is based on evidence of in vivo genotoxicity in
132
somatic cells, after systemic exposure. Hence the possibility that the germ cells are affected cannot be excluded. The
Specialised Experts did not consider that further testing of effects on germ cells was practicable (European
Commission, 2004).
Further testing in an in vivo comet assay in lung cells after inhalational exposure is also considered to be unnecessary
for the purposes of risk characterisation. A positive result would not alter the conclusions for the classification as a
mutagen, and a negative result would not be regarded as sufficient evidence to justify the use of a threshold approach in
the carcinogenicity risk characterisation. Hence, further testing for this effect would not produce additional information
that would significantly change the outcome of this risk assessment.
Nickel sulphate is classified as Muta. Cat. 3; R68 in the 30th ATP.
4.1.2.7 Carcinogenicity
4.1.2.7.1 Animal data
4.1.2.7.1.1
Inhalation
The National Toxicology Program (NTP) has performed a comprehensive investigation of the toxic effects in rats and
mice after chronic inhalation of nickel sulphate hexahydrate (NTP 1996a). The studies performed are combined
chronic/carcinogenicity studies. The data concerning the carcinogenic effects of nickel sulphate hexahydrate are
summarised in this section with the most important effects observed listed in Tables 4.1.2.7.1.A and 4.1.2.7.1.B; for
data concerning other effects, see section 4.1.2.5.1.
The NTP-studies are well-designed studies. The results as concluded in the study seem reliable, i.e., neither rats
(F344/N) nor mice (B6C3F1) developed exposure related neoplasms after being exposed to nickel sulphate hexahydrate
(mass median aerodynamic diameter of 1.8-3.1 + 1.6-2.9 μm) by inhalation at concentrations up to 0.11 mg Ni/m3 or
0.22 mg Ni/m3, respectively.
Table 4.1.2.7.1.A: Summary of inhalation carcinogenicity studies on nickel sulphate hexahydrate in
experimental animals.
Route of
administration
Species, group Concentration,
size and sex
exposure duration
Inhalation
F344/N rats
63-65 males,
63-64 females
per group
Inhalation
B6C3F1 mice
80 males,
80 females per
group
Results
References
0, 0.03, 0,06 or 0.11 mg Ni/m3 No exposure related
neoplasms observed
6 hours/day, 5 days/week,
NTP (1996a)
2 years
0, 0,06, 0.11 or 0.22 mg Ni/m3 No exposure related
neoplasms observed
6 hours/day, 5 days/week,
NTP (1996a)
2 years
Table 4.1.2.7.1.B: Summary of relevant primary tumour rates at terminal sacrifice (in lungs and in all
organs) reported in the NTP (1996a) inhalation study.
Organ:
Male F344 rats
Female F344 rats
Male B6C3F1 mice
Female B6C3F1 mice
Neoplasm
Dose groups: ppm Ni
Dose groups: ppm Ni
Dose groups: ppm Ni
Dose groups: ppm Ni
0
0.03 0.06 0.11 0
0.03 0.06 0.11 0
0.06 0.11 0.22
0
0.06 0.11 0.22
0/54
0/53
0/53
2/53
0/52
0/53
0/53
1/54
5/61
5/61
3/62
5/61
3/61
3/60
2/60
0/60
Lung: Alveolar/
1/54
Bronchiolar carcinoma
0/53
1/53
1/53
0/52
0/53
0/53
0/54
9/61
13/61 4/62
3/61
4/61
3/60
9/60
2/60
Lung: Alveolar/
Bronchiolar adenoma
133
Lung:
1/54
0/53
1/53
3/53
0/52
0/53
0/53
1/54
13/61 18/61 7/2
8/61
7/61
6/60
10/60 2/60
Alveolar/ Bronchiolar
carcinoma or
Alveolar/ Bronchiolar
adenoma
All organs:
49/54 50/53 50/53 51/53 35/52 42/53 35/53 36/54 24/61 16/61 25/62 16/62
27/61 34/60 23/60 16/60
37/54 43/53 41/53 41/53 35/52 33/53 37/53 29/54 20/61 22/61 25/62 13/62
26/61 27/60 26/60 26/60
Benign tumours
All organs:
Malignant tumours
All organs:
53/54 52/53 51/53 51/53 49/53 52/53 50/53 48/54 38/61 35/61 41/62 27/62* 41/61 45/60 40/60 36/60
Malignant and benign
tumours
4.1.2.7.1.2
Oral
The carcinogenicity of nickel sulphate following oral administration has been studied in rats and dogs. An oral (gavage)
OECD 451 carcinogenicity study in Fischer rats has been conducted. The data concerning the carcinogenic effects are
summarised in Table 4.1.2.7.1.C; for data concerning other effects, see section 4.1.2.5.1.
No neoplasms were revealed in either rats or dogs in the studies by Ambrose et al. (1976). However, these studies are
limited because of the low number of animals (rats and dogs), the high mortality in all groups of rats (causes of death
not reported) resulting in only a small number of animals being exposed for the total period of 2 years and being
available for sacrifice and histopathology, and the limited reporting of the study design and results.
In the study by CRL (2005) groups of 60 male and 60 female rats were dosed with 0, 2.2, 6.7 and 11 mg Ni/ kg bw/day
(0, 10, 30 and 50 mg/kg /bw/day of nickel sulphate hexahydrate) once daily for 104 weeks. The test substance was
dissolved in water and given in a gavage volume of 10 ml/kg bw. Statistical analysis of the tumour data revealed a
statistical significant increase in the incidence of keratoacanthoma of the tail in low-dose males (9/59) compared to the
control group (0/60); the increased incidence was not dose-related and did not reach level of statistical significance at
mid dose (4/60) and high dose (3/60). An almost identical pattern – also in males- was noted for keratoacanthoma of the
skin. The incidence of pituitary tumours (pars distalis adenomas – a rather common tumour type in this strain of rats)
was increased (not statistically significant) in treated females (26/60, 22/59, and 10/58 in low-, mid- and high-dose
females, respectively) when compared to the control group (16/60), but no positive dose-response relationship was
found. An increased incidence of dermal squamous papillomas was observed in treated males (5/60, 2/60, and 4/58 in
low-, mid- and high-dose males, respectively) when compared to the control group (0/60), but no positive dose-response
relationship was found. Overall, daily oral administration of nickel sulphate hexahydrate did not induce dose-related
increases in any common tumour type or in any rare tumours.
Table 4.1.2.7.1.C: Summary of oral carcinogenicity studies of nickel sulphate hexahydrate in experimental
animals.
Route of
Species, group size
administration and sex
Oral, dietary
Wistar rats
Oral, dietary
Beagle dogs
Results
Reference
0, 100, 1000 or 2500 ppm Ni in feed No treatment related Ambrose et
neoplasms observed al. (1976)
25 males and females 2 years
per group
3 males and females
per group
Oral, gavage
Concentration,
exposure duration
Fischer rats
0, 100, 1000 or 2500 ppm Ni in feed No treatment related Ambrose et
neoplasms observed al. (1976)
2 years
0, 2.2, 6.7, 11 mg Ni/kg bw/day
(gavage)
60 males and females
per group
2 years
No treatment related CRL (2005)
neoplasms observed
134
4.1.2.7.1.3
Dermal
No studies on the carcinogenicity of nickel sulphate following dermal contact have been found.
4.1.2.7.1.4
Other routes of administration
Studies on the carcinogenicity of nickel sulphate following intramuscular injections or implants, or intraperitoneal
injections have been performed in rats; these studies are summarised in Table 4.1.2.7.1.D. Tumours were observed
following administration by intraperitoneal injections and by intramuscular implants, but not by intramuscular
injections.
Table 4.1.2.7.1.D: Summary of carcinogenicity studies of nickel sulphate in experimental animals by other
routes of administration than inhalation, oral administration, and dermal contact.
Route of
administration
Species, group
size and sex
Concentration,
exposure duration
Results
Intramuscular
injections to one
or both thigh
muscles
Wistar rats,
Single dose of 5 mg of
nickel sulphate
hexahydrate
No local tumours at
Gilman (1962 –
the injection sites, no quoted from IARC
other treatment-related 1990, TERA 1999)
tumours
32 males and
females
No control group
Intramuscular
implants (in
sheep fat pellets)
Intramuscular
injections
NIH black rats, 35 3 implants (interval
animals per group unspecified) of 7 mg of
nickel sulphate (hydration
not stated)
Vehicle controls
Observation for 18
months
Implantation-site
sarcomas in 1/35
Wistar rats
15 injections of 0.26 mg
of nickel as nickel
sulphate (hydration not
stated) every second day
during one month
No injection site
tumours in treated
animals or in negative
controls
Observation for 2 years
Local sarcomas in
positive controls
(16/20)
20 males
Positive (nickel
subsulphide) and
negative (sodium
sulphate) controls
Intraperitoneal
injections
Observation for 603 days
Wistar rats
30 females
Controls:
50 injections of 1 mg
nickel as nickel sulphate
heptahydrate twice
weekly
1 ml saline x 3
1 ml saline x 50
Observation for 132
weeks
2 ml saline x 4
4.1.2.7.1.5
No tumours in
controls (0/35)
Reference
Payne (1964 –
quoted from IARC
1990, TERA
1999). Reported as
an abstract.
Kasprzak et al.
(1983 – quoted
from IARC 1990,
TERA 1999)
Abdominal tumours in Pott et al. (1989,
6/30 (p<0.05)
1992)
(1 mesothelioma, 5
(Pott et al, 1992
sarcomas)
cited in IARC and
1/33 (sarcoma)
TERA 1999 as,
1990)
0/34
3/66 (1 mesothelioma,
3 sarcomas)
Promoter studies
Three studies evaluating the promoting effect of nickel sulphate in experimental animals have been located; these
studies are summarised in Table 4.1.2.7.1.E. The studies may indicate a promoter effect of nickel sulphate, if applied
locally to the nasopharynx or the oral cavity, or by the feed to pups from initiated dams; however, the indications are
rather weak. Based on these studies, it is not possible to draw any conclusion regarding a promoting potential of nickel
sulphate.
Table 4.1.2.7.1.E: Summary of promoter studies of nickel sulphate in experimental animals.
Route of
administration
Species, group
size and sex
Concentration,
exposure duration
Results
Reference
135
Route of
administration
Species, group
size and sex
Concentration,
exposure duration
Results
Rats
Initiation (*) followed by
Ou et al. (1980 –
quoted from IARC
1) Two tumours in the 1990, TERA 1999,
nasopharynx (one
IPCS 1991)
papilloma, one early
carcinoma)
1) Topical
12 animals
insertion into the
nasopharynx
1) 0.02 ml 0.5% nickel
sulphate in 4% aqueous
gelatin once a week (0.04
mg Ni/week),for 7 weeks
2) In drinking
water
2) 1 ml of aqueous 1%
nickel sulphate (3.8 mg
Ni/day) for 6 weeks
3) Topical
insertion in the
oral cavity
Rats
Initiation (*) followed by
22 animals
3) 0.02 ml 0.5% nickel
sulphate in 4% aqueous
gelatin once a week (0.04
mg Ni/week), for 7 weeks
3) 5/22 developed
carcinomas (2 in the
nasopharynx, 2 in the
nasal cavity, 1 of the
hard palate)
4) 1 ml of aqueous 1%
nickel sulphate (3.8 mg
Ni/day) for 6 weeks
4) No tumours
developed
Controls:
Initiated only or
nickel sulphate
only
Feed
2) Two tumours in the
nasopharynx (one
squamous cell
carcinoma, one
fibrosarcoma)
Controls:
Initiated only or
nickel sulphate
only
4) In drinking
water
Rats
13 females
Reference
No tumours in any of
the controls
Liu et al. (1983 –
quoted from IARC
1990, TERA 1999,
IPCS 1991).
Reported in an
abstract.
No tumours in any of
the controls
Initiation (*)on day 18 of
gestation followed by:
Pups of treated dams fed 5/21 pups (24%)
0.05 ml of 0.05% nickel
developed carcinomas
sulphate (9.5 µg Ni/day)
of the nasal cavity
daily for one month
increasing every month
with 0.1 ml (19µg Ni/day)
for further 5 months
Untreated pups of treated
dams
3/11 pups (27%)
developed tumours
(one nasopharyngeal
squamous-cell
carcinoma, one
neurofibrosarcoma of
the peritoneal cavity,
one granulosa-thecalcell carcinoma of the
ovary)
Untreated pups of
uninitiated dams
No tumours
Controls:
Initiated dams
No tumours (0/13)
Ou et al. (1983
quoted from IARC
1990, TERA 1999,
IPCS 1991).
Reported in an
abstract.
(*) Initiation: single s.c. injection of 9 mg/ml dinitrosopiperazine
136
4.1.2.7.1.6
Discussion and conclusions, carcinogenicity in experimental animals
Inhalation studies of nickel sulphate hexahydrate (mass median aerodynamic diameter of 1.8-3.1 + 1.6-2.9 μm) have
been performed in rats and mice (NTP 1996a); no exposure related neoplasms were observed in neither rats (F344/N)
nor mice (B6C3F1) after exposure to nickel sulphate hexahydrate by inhalation in concentrations up to 0.11 mg Ni/m3
or 0.22 mg Ni/m3, respectively for 2 years. It should be noted, as discussed in the Background document in support of
the individual Risk Assessment Reports, that some arguments have been raised that the negative evidence from the NTP
studies on nickel sulphate cannot be considered definitive.
Inhalation studies on nickel oxide (NTP, 1996b) and nickel subsulphide (NTP, 1996c) showed some evidence and clear
evidence, respectively, for carcinogenic activity following inhalation in rats, and there was equivocal evidence for
nickel oxide in female mice.
The results of the NTP studies on nickel sulphate, nickel oxide, and nickel subsulphide raise the question of whether
soluble forms of nickel differ from insoluble forms of nickel in carcinogenic potential or in potency in experimental
animals following exposure by inhalation; however, the available data are not sufficient for an evaluation of this
question. For further details, the reader is referred to the Background document in support of the individual Risk
Assessment Reports.
No other data considered as being relevant for the conclusion on the carcinogenicity of nickel sulphate in experimental
animals following inhalation have been located.
In conclusion, the available data on carcinogenicity of various nickel compounds, including the data on nickel sulphate
itself, is considered as being insufficient for a conclusion on the carcinogenic potential of nickel sulphate in
experimental animals following inhalation.
4.1.2.7.1.6.2 Oral
The carcinogenicity of nickel sulphate following oral administration has been studied in two old non-guideline studies
with rats and dogs; no neoplasms were revealed in either rats or dogs in these studies. . A 2-year carcinogenicity study
with rats performed according to OECD 451 did not show any carcinogenic potential of exposure to nickel sulphate
following oral (gavage) administration. Data on other nickel compounds are limited to a drinking water study of nickel
acetate in rats and mice in which no exposure-related neoplasms was observed.
In conclusion, there is sufficient oral carcinogenicity data to show that nickel sulphate does not show any carcinogenic
potential in experimental animals following oral administration.
4.1.2.7.1.6.3 Dermal
No data regarding carcinogenicity following dermal contact to nickel sulphate in experimental animals have been
located.
Data on other nickel compounds are limited to a study in male hamsters in which no tumours developed in the buccal
pouch, oral cavity, or intestinal tract following painting on the mucosa of the buccal pouches with α-nickel subsulphide.
In conclusion, the available data are too limited for an evaluation of the carcinogenic potential in experimental animals
following dermal contact to nickel sulphate.
4.1.2.7.1.6.4 Other routes of administration
Studies on the carcinogenicity of nickel sulphate following intramuscular injections or implants, or intraperitoneal
injections have been performed in rats; tumours were observed following administration by intraperitoneal injections
and by intramuscular implants but not by intramuscular injections.
Data on other nickel compounds show that these compounds, with a few exceptions, produce local tumours following
injection at various sites to experimental animals.
137
In conclusion, the available data show that nickel compounds, with a few exceptions, produce local tumours following
injection at various sites to experimental animals. It should be noted that these routes of administration are irrelevant for
human beings who will only be exposed via inhalation, oral intake or dermal contact to nickel sulphate. However, the
positive findings in these studies might be considered as part of the weight of the evidence when evaluating the
carcinogenic potential of nickel sulphate to human beings.
4.1.2.7.1.6.5 Promoter studies
Three studies evaluating the promoting effect of nickel sulphate in experimental animals have been located, which may
indicate a promoter effect of nickel sulphate, if applied locally to the nasopharynx or the oral cavity, or by the feed to
pups from initiated dams; however, the indications are rather weak.
Data on nickel chloride and nickel metal indicate that these compounds also might have a promoting effect.
In conclusion, the available data indicate that nickel sulphate, nickel chloride, and nickel metal might have a promoting
effect in combination with selected initiators. However, based on the available studies, it is not possible to draw any
conclusion regarding a promoting potential of nickel sulphate as well as of other nickel compounds. Furthermore, such
information is difficult to use with respect to evaluating the carcinogenic potential of nickel sulphate.
4.1.2.7.1.7
Conclusion
Inhalation
The available experimental animal data on carcinogenicity of various nickel compounds, including the data on nickel
sulphate itself, is considered as being insufficient for a conclusion on the carcinogenic potential of nickel sulphate in
experimental animals following inhalation.
Oral exposure
A well-conducted OECD 451 study in rats did not show any carcinogenic potential of nickel sulphate following oral
administration.
Dermal exposure
The available data concerning dermal exposure are too limited for an evaluation of the carcinogenic potential in
experimental animals following dermal contact to nickel sulphate. However, as oral exposure to nickel sulphate does
not show any carcinogenic potential, there are good reasons to assume that cancer is not a relevant end-point with
respect to dermal exposure either.
Most of the studies on cancer in humans have considered the risk related to exposure to “water-soluble nickel”, thereby
meaning nickel salts with a high solubility in water. The predominating forms of water-soluble nickel salts to which
exposure has occurred are nickel sulphate and nickel chloride. There are many other water-soluble nickel compounds
(see Appendices to the Background report on nickel and nickel compounds), and some of these other water-soluble
nickel compounds may have been present. However, their influence on the cancer risk in either direction is considered
to be negligible. The distinction between sulphate and chloride, however, is of interest in the present evaluation and will
be commented on in the exposure, results, and discussion sections.
4.1.2.7.2.1
Overview of the epidemiological cancer studies
The first indication of an excess risk of respiratory cancer among nickel exposed workers was reported from Clydach,
Wales in 1933, from a refinery based on the nickel carbonyl process (Bridge, 1933). Firm evidence was published two
decades later (Doll, 1958). The cancer risk, which had been originally ascribed to the nickel carbonyl process, was
subsequently thought to be associated with the feed preparation prior to carbonyl formation, including the arsenic
content of the raw material (Morgan, 1958), and with sulphidic and oxidic nickel as in studies from Canada
(Mastromatteo, 1967) and Norway (Løken, 1950, Pedersen et al., 1973 & Magnus et al., 1982).
In these first publications from Clydach the analyses were performed according to departments and duration of
employment only. There was indication of a considerable cancer risk among workers who had experienced significant
exposures to nickel sulphate, namely in workers from the copper sulphate department, from the nickel sulphate
department, and from the calcining (roasting) department (Morgan, 1958). In the two former areas, the workers had
been treating aqueous solutions rich in nickel sulphate, and in the latter department most of the nasal cancer cases were
138
reported to arise in workers who were engaged in cleaning of the flues, where the presence of nickel sulphate later has
been indicated (Warner, 1984, Thomassen et al., 1999).
The two Norwegian studies (Pedersen et al., 1973, Magnus et al., 1982) also indicated an increased risk of lung cancer
among workers in the electrolysis departments where the nickel exposure mainly involved water-soluble forms of
nickel. The water-soluble nickel exposures in these departments were mainly nickel sulphate but also nickel chloride
was involved in certain departments after 1952. These findings were in contrast to those from Canada, where similar
types of work were not associated with an increased risk of lung cancer (Roberts et al., 1984).
Cancer in sites other than lung and nasal sinuses have also been found in excess of expected numbers in groups of
workers exposed to nickel-containing substances. It is however unclear whether these are chance findings or indicators
of increased risk caused by exposure to some form of nickel or other confounding occupational exposures. An excess of
laryngeal cancer has been seen at the Norwegian refinery and increased risk of stomach cancer is reported from a
Russian refinery (Saknyn, 1973).
In a number of nickel refineries nickel sulphate was the predominant form of water-soluble nickel, as no nickel chloride
were used in the production (Clydach, Wales; Kristiansand, Norway 1910-1952; Harjavalta, Finland; and Port Colborne
1926-1942). In general, the workers at these plants and in these periods were exposed to several forms of nickel, but
there were groups of workers in which the main nickel exposure was nickel sulphate. Besides, the nickel sulphate
concentrations in air reported at these plants range among the highest observed.
The present review is therefore based on lung and nasal cancers related to work in nickel refineries processing sulphidic
nickel ores or mattes and one study among nickel electroplaters. It includes 7 cohort studies and one case-control study
from four countries. Six of the studies were from nickel refineries (table 4.1.2.7.2.A - B). Another study from 1991 on
workers in nickel mines and in production of nickel-copper concentrate (matte) (Shannon et al., 1991) is commented on
in the discussion section only.
Table 4.1.2.7.2.A: Description of the cohort studies included in the evaluation.
Cohort
Study
size
Length of
employment
Follow-up
Type of
analysis
Included in Exposure
ICNCM
data
Data on
smoking
Refineries
Clydach I
2521
5 years
1907-1984
SMR
yes
yes
no
2524
5 years
1931-1985
SMR
Regression
analysis
yes
yes
no
Port Colborne*
2614
1 year
1950-1984
SMR
yes
yes
no
Kristiansand I
3250
1 year
1953-1984
SMR
yes
yes
no
II
4764
1 year
1953-1993
SIR
Regression
analysis
no
yes
yes
Kristansand IV
5297
1 year
1953-2000
SIR
Regression
analysis
no
yes
yes
Outokumpu,
Harjavalta
1155
3 months
1953-1995
SIR
no
yes
no
284
3 months
1945-1995
SMR
Regression
analysis
no
no
no
“
II
“
Electroplaters
Great Britain
*Non leaching, sintering, calcining
Table 4.1.2.7.2.B: Description of case-control study included in the evaluation.
139
Cohort
Cancer site;
study size
Period of
employment
Length of
employment
Period of
diagnosis
Type of
analysis
Exposure
data
Data on
smoking
Kristiansand III
lung cancer;
1910-1994
1 year
1953-1995
conditional
logistic
regression
yes
yes
213 cases,
525 controls
The material consists of information on more than 11,000 nickel refinery workers (all the 3,250 workers from the
Norwegian refinery (Kristiansand I) were also included in the cohort of 4,764 workers (Kristiansand II), which were
included among 5,297 workers in the most recent cohort study from the same refinery (Kristiansand IV). These studies
have previously been published, and studies of four of the cohorts were included in the International Committee on
Nickel Carcinogenesis in Man, ICNCM report (Doll et al., 1990). The follow-up period was more than 30 years. All
studies in the ICNCM report had some exposure data and traditional analysis of standardised mortality rates (SMR) was
performed. After the ICNCM report was published, two incidence reports from Finland and Norway have been
published. The Norwegian cohort studies (Kristiansand II and IV) also included information on tobacco smoking and
were analysed both with external and internal reference rates. The case-control study on lung cancer performed within
the Norwegian cohort and the most recent cohort study (Kristiansand IV) included department- and time-specific
exposure data, which were based on 5,900 personal measurements of nickel in the working atmosphere between 1973
and 1994, as well as speciation analyses of refinery dust and aerosols from the 1990s (Grimsrud et al., 2000). Exposures
before 1973 were extrapolated from these measurements, based on the relative changes in concentrations over time
according to assumed and reported changes in the occupational hygiene. The case-control study also included details on
smoking habits collected through interviews.
The analysis in the ICNCM report was based on mortality and the reference rates were from the male population in each
country/state. The Finnish and one of the Norwegian studies were based on SIR analysis with data from the cancer
registries. The Finnish study used a regional population as reference for the incidence rates while the Norwegian results
was based on the national male population.
The loss of follow-up was a minimal problem in all cohorts except the sub-cohort of workers with first entry before
1930 at Clydach and the mortality study from the Port Colborne refinery.
4.1.2.7.2.2
Exposures
The report of the International Committee on Nickel Carcinogenesis in Man (Doll et al., 1990) was the first published
study to incorporate exposure measures in the analysis of cancer risk in nickel exposed workers. Estimates of exposure
before 1950 were based on knowledge of the chemical process, the workers impressions of relative dustiness, and
information on technical and physical conditions at the worksites. For the years from 1950 to 1970 there were a few
available particle counts as well as stationary filter samples analysed for dust and total nickel. After 1970 aerosol
sampling with personal carried filter pumps had been performed at several plants. In some instances proxy measures
were used, like nickel concentration in air leaving the building through the roof. Some of the estimated average
exposure levels in the ICNCM report (Doll et al., 1990) were reported to be extremely high with total nickel
concentrations above 100 mg/m3, corresponding to a total dust level some 1.5 to 2 times higher.
No analysis of individual nickel species in aerosol samples existed for the ICNCM study, and the proportions of
individual forms of nickel (metallic, oxidic, sulphidic, and water-soluble nickel) were mainly believed to reflect the
composition of the nickel-containing substances found in the process line.
In most of the 10 cohorts of nickel exposed workers included in the ICNCM the water-soluble nickel compound in
question was nickel sulphate. Nickel sulphate was produced from leaching of nickel oxides with dilute sulphuric acid,
and subsequently found in aqueous solution and aerosols. Dry crystals were produced and delivered to secondary
metallurgical industry. Nickel sulphate was also formed in pyrometallurgical plants where fine particles were sulphated
in the flue from ovens where sulphidic matte was roasted to produce metal oxides.
Exposures to nickel sulphate in the cohorts considered in the ICNCM report (Doll et al., 1990) and some other studies
are summarised in Table 4.1.2.7.2.C.
Table 4.1.2.7.2.C: Ranges of proportions and absolute concentrations of water-soluble nickel in cohorts
from the ICNCM report (1990) and some other studies
140
Cohort
NiSO4
exposure
Period
considered
Soluble nickel Soluble nickel in air,
as percent of indicated level
total nickel
(mg*m-3)
Hydrometallurgy
+
1902-1979
30-100%
0.7-2
Copper plant
+
1902-1960
5-10%
0.04-1.1
Pyrometallurgy and nickel plant
+
1902-1984
0-15%
0-0.75
Falconbridge operations, Ontario
(Canada)
(+)
1933-1978
0-50%
<0.01
Hanna Nickel Smelting Company,
Oregon (USA)
–
1953-1977
0
0
Huntington Alloys, West Virginia (USA) (+)
1948-1984
0-80%
<0.05
Copper Cliff sinter plant, Ontario
(Canada)
+
1948-1963
n.r.
<4
Coniston sinter plant, Ontario (Canada)
+
1914-1972
n.r.
0-1
Leaching, calcining, sintering plant +
1926-1958
n.r.
<3
Electrolysis department
1950-1976
n.r.
generally: <0.3;
Clydach refinery, Wales (UK)
Port Colborne refinery, Ontario (Canada)
+
highly exposed: 1-3
Other
+
1950-1976
n.r.
<0.2
+
1950-1976
n.r.
<0.2
Roasting and smelting
departments*
+
1946-1984
0*
0*
Electrolysis departments
+
1946-1984
33-100%
0.3-1.3
Oak Ridge Gaseous Diffusion Plant,
Tennessee (USA)
–
1948-1953
0
0
Outokumpu Oy refinery (Harjavalta,
Finland) †
+
1960-1985
90%‡
Societé Le Nickel mine and smelter
(New Caledonia)
+
1926-1982
n.r.
0.1
Henry Wiggin Alloy Company, Hereford +
(UK)
1953-1985
0-50%
<1
Sudbury non-sinter areas, Ontario
(Canada)
Kristiansand refinery (Norway)
0.1-0.4 ‡
Monchegorsk nickel refinery, Kola
Peninsula (Russia)
+
(+)
–
n.r.
*
Electrolysis department §
+
1990s
55-99%
0.04-0.3
Roasting and smelting dep. §
+
1990s
1.5-22%
0.04-0.7
reported exposure
reported low exposure
no exposure +/– exposure reported in some departments
not reported
more recent studies on exposure (Andersen et al., 1998; Thomassen et al., 1999; Werner et al., 1999b; and
Grimsrud et al., 2000) have indicated the presence of water-soluble nickel as nickel sulphate even in these
departments
141
†
‡
§
exposures reported in Kiilunen et al., 1997a, epidemiology reported in ICNCM 1990 and Anttila et al., 1998
between 1960 and 1973 the air in the refinery probably was contaminated with nickel sulphides from the smelter
(Kiilunen et al., 1997a)
exposures reported by Thomassen et al., 1999
The amount of nickel sulphate showed a great variation between different departments in the ICNCM report (Doll et al.,
1990). In hydrometallurgical plants, where pure nickel or copper were deposited in electrolytic tanks; or where metal
salts were obtained through crystallisation, precipitation, filtering, and drying; nickel sulphate was one of the prevailing
forms of nickel exposure (30 to 100 percent of total nickel). In pyrometallurgical departments, where roasting, smelting,
sintering, metallisation, and volatilisation were performed, water-soluble nickel compounds constituted a smaller
proportion (0 to 15 percent) of total nickel, but still, due to high levels of total nickel, the concentration of nickel
sulphate often may have been considerably higher in these areas than in the hydrometallurgical departments. This was
the case in Clydach (Wales, UK), and in Copper Cliff, Coniston, and Port Colborne (Ontario, Canada). The exposure
matrix for the roasting and smelting departments at the refinery in Kristiansand, Norway, differed from the others in this
respect, as the work atmosphere at these sites in the ICNCM report was considered to contain negligible amounts of
water-soluble nickel (taken to be zero).
However, the historical exposures at the Kristiansand (Norway) nickel refinery have been reassessed by Grimsrud et al.
(2000) in a study including 5,900 personal samples from the years 1973-1994, from filter pumps worn by workers
throughout the whole working day for later analysis of total nickel. The results indicated that the exposures generally
were lower than earlier assumed. Additional information from speciation analyses of water-soluble, metallic, sulphidic,
and oxidic nickel in dust samples from the 1990s supported the views expressed elsewhere that water-soluble species
were present in considerable amounts even in roasting and smelting areas resulting in concentrations of nickel sulphate
in air that are higher in the roasting and smelting departments than those in many of the hydrometallurgical operations.
At the Kristiansand refinery, nickel sulphate was the prevailing form of water-soluble, until a mixed sulphate and
chloride process was introduced in the nickel electrolysis in 1952, with 78% of the nickel present as chloride and 22%
as sulphate. The copper electrolysis, however, continued to be performed with an electrolyte containing a high
concentration of nickel sulphate.
In a report to Nickel Producers Environmental Research Association (NiPERA), Aitken et al. (1998) at Institute of
Occupational Medicine (IOM), Edinburgh, UK found indications that the proportion of water-soluble nickel species
rose with decreasing particle size in aerosols from the roasting and smelting department, from 26% of total nickel in the
inhalable fraction to 72% of total nickel in the respirable fraction. The respirable fraction comprises the smallest
particles which are expected to pass to the deepest parts of the lung (Table 5 in Aitken et al., 1998). Recent studies have
suggested a more equal distribution of water-soluble nickel across particle fractions, and a possible explanation may be
that the particle size affects the degree of solubility in water.
Some estimates of the proportion of water-soluble nickel in the matte grinding, roasting, and smelting departments at
the Kristiansand refinery were also published by Werner and co-workers in 1999 (Werner et al., 1999b), showing some
8 to 10 % water-soluble nickel by weight in aerosols from these areas, probably nickel sulphate.
During the late 1990s Thomassen et al. (1999) investigated occupational exposures in a Russian nickel refinery at the
Kola Peninsula which is running a combined refining process with roasting, smelting, and electro-refining steps. The
highest concentrations of total nickel were encountered in the roasting and smelting departments, and the highest levels
of water-soluble nickel was observed at the top of the roaster. Although the total mass of the smallest particles (the
respirable fraction) was low compared to the total mass of all inhalable particles, the amount of nickel in the respirable
fraction was higher in the roasting and smelting areas than anywhere else at the plant. The exposures at this plant were
considered to correspond to similar departments in nickel refineries outside Russia during the 1960s and earlier
(Roasting and old Anode Casting Departments), or the 1970s and early 1980s (New Anode Casting and Electrorefining
Departments). Still, the effect on workers’ health from these exposure levels will depend on where the workers spend
most of their time.
In 1997 Kiilunen et al. (1997a) studied historical and present exposures to water-soluble nickel salts in electrolytic
nickel refining at the Outokumpu nickel refinery in Harjavalta, Finland. Parts of the process consisted of leaching
(metal extraction), purification of solution, and nickel electrowinning. These departments were studied with stationary
air samplers, personally borne filter pumps sampling from the inside and outside of protective masks, and biological
measurements (urine and blood). Water-soluble nickel sulphate constituted 95% of total nickel in the areas studied,
142
except for the leaching plant where the proportion of less soluble nickel species was 11%. Nickel chloride was not used
at this plant, and most of the water-soluble nickel in question was nickel sulphate.
The stationary samples at the Harjavalta refinery indicated exposure in the range 0.17-0.80 mg/m3 with the highest
levels recorded in the 1980s. Personal measurements taken during the years 1979 to 1981 showed a yearly mean value
based on 6 to 28 samples varying between 0.16 and 0.23 mg/m3, and no masks were used during these years. Personal
measurements sampled outside of masks from the 1990s typically showed lower levels with a maximum arithmetic
mean of 71 μg/m3 (during welding). Protective masks were used in areas with the highest concentrations, and
measurements from inside these masks showed a maximum average of 7 μg/m3. It was reported that airborne nickel
levels in the tank houses still exceed 0.1 mg/m3.
The average particle size at the Harjavalta nickel refinery was estimated to 12 μm, suggesting a more pronounced
deposition in the upper airways than in the lungs. The authors also found indications that urine nickel values reflected
not only inhaled nickel, but rather the total uptake including nickel ingested after contamination of the hands at work.
Elevated urine nickel concentrations after 2 to 4 weeks vacation was interpreted as indications of retention of watersoluble nickel salts in the body. This would be in agreement with studies of exposure to water-soluble nickel
compounds in animals (Benson et al., 1995, NTP, 1996a).
In another study Kiilunen et al. (1997b) studied exposures in Finnish nickel platers and reviewed earlier reports of
exposures in plating industry. Concentration of nickel up to 170 μg/m3 had been found in the breathing zone in the
1970s and –80s (Finland, Germany), but other studies mostly report lower levels, between 0.5 and 15 μg/m3. The
finding of elevated concentration of nickel in urine in platers after 1 to 5 weeks vacation was supportive of the findings
of Tossavainen et al. (1980), who studied elimination of nickel in platers exposed to water-soluble species.
Tossavainen found indications of a urine clearance half-time ranging from 17 to 39 hours, and these studies were both
interpreted as indications of accumulation taking place when man is exposed to water-soluble nickel species. In a study
at two nickel plating shops Tsai et al. (1996a) identified exposure to insoluble nickel species.
4.1.2.7.2.3
Results of the epidemiological studies
4.1.2.7.2.3.1 Clydach, South Wales
Risk of lung and nasal cancer from the refinery in Clydach, South Wales has been published several times, the most
recent results with relevant exposure estimates was presented by the ICNCM-report (Doll et al., 1990) and included
2,521 men followed with respect to deaths until the end of 1984. A clear trend towards decreasing respiratory cancer
risk over time was evident. The overall results showed 216 lung cancers (SMR 273; 95% CI 238-313) and 75 nasal
cancers (SMR 14033; 95% CI 11107-17682). Among 1,348 workers with first employment before 1930 172 lung
cancer deaths were observed (SMR, 393; 95% CI, 336-456) and 74 nasal cancer deaths (SMR, 21120; 95% CI 1658426514)
There were only a few areas at the refinery where the workers were exposed mainly to single species of nickel. The men
who had worked in the hydrometallurgy department were believed to have been exposed primarily to nickel sulphate.
Those with 5 or more years in that department and 15 or more years since first exposure had an excess risk with 5
observed lung cancer cases (SMR, 333; 95% CI, 108-776) and 4 nasal cancer (SMR, 36363, 95% CI 9891-93089),
(table 4.1.2.7.2.D). The lung cancer risk in the Copper plant was somewhat higher than the risk in the hydrometallurgy
department, but there was no difference in risk of nasal cancer between these two departments.
The cross-tabulations according to cumulative exposures at the Clydach refinery suggested that sulphidic, and possibly,
oxidic nickel were responsible for increased risk of lung and nasal cancer, with additional effect from water-soluble
nickel. The authors underlined that care should be taken in the interpretation, as no environmental measurements
existed. Still, they point out that the strong lung and nasal cancer risk in the Copper plant may have been associated
with exposure to water-soluble nickel alone, or with the combined exposure to oxidic and soluble nickel. The watersoluble form of nickel was predominantly nickel sulphate, as no chloride was used in the process.
The cancer data from the Clydach refinery was later evaluated with a multivariate regression analysis by Easton and coworkers (Easton et al. 1992). They used the exposure estimates prepared for the international study (ICNCM, Doll et
al., 1990) and computed cumulative exposures to the four groups of nickel compounds. The best fitting model
suggested risks associated with exposure to water-soluble and metallic nickel, while much less, if any, risk was ascribed
143
to nickel oxides and nickel sulfides. The authors stressed the uncertainty in the analyses, as none of the exposure levels
were known with certainty. Still, while the results for the insoluble nickel compounds were rather unstable, the
strongest effect was seen from water-soluble nickel. The results were therefore interpreted as suggestive of “some of the
risk” to be due to water-soluble nickel (nickel sulphate), and, additionally, of a contribution to the risk from at least one
of the insoluble species.
Table 4.1.2.7.2.D: MOND/INCO (Clydach, South Wales, UK) nickel refinery – average nickel exposure
levels and cancer risks in “high-risk” departments in workers with 15 or more years since first exposurea
Duration in department
Estimated airborne
concentration
(mg/m3 Ni)a
≥5 years
Metallic nickel
Oxidic nickel
Sulphidic nickel
Soluble nickel
Ever
5.6
6.4
2.6
0.4
9
409
3
24781
1
370
3
1000
18.8
6.8
0.8
16
725
7
44509
12
1244
6
78280
13.1
0.4
1.1
17
317
5
13912
8
541
2
14541
Department
Furnaces,
Lung cancer
Nasal cancer b Lung cancer
Nasal cancer b
Obs
Obs
Obs
SMR
(95% CI)
SMR
Obs
(95% CI)
SMR
(95% CI)
SMR
(95% CI)
1905-63
Linear calciners, 5.3
1902-30;
Milling and
grinding,
1902-36
Copper plant,
-
before 1937
(185-507)
1938-60
-
Hydrometallurgy 0.5
1902-79
0.4
0.01
0.01
-
0.9
0.05
1.3
7
(450732415)
-
196
(79-404)
4
(2331066)
-
18779
(510848074)
5
(175952493)
-
333
(108-776)
4
36363
(989193089)
a From Doll et al. (1990). Estimated airborne concentrations of nickel species and mortality from or incidence of lung
cancer and nasal cancer by department.
Standardised mortality ratio (SMR) and 95% confidence interval (CI).
b The working group expressed reservations about the accuracy of these estimates.
4.1.2.7.2.3.2 Kristiansand, Norway
The Norwegian cohort of refinery workers included in the ICNCM report comprised 3,250 men, restricted to those first
employed 1946-69 with at least one year of employment and followed with respect to cancer incidence and deaths to the
end of 1984. During the follow-up period there were 77 lung cancer deaths (SMR, 262; 95% CI, 207-327), three nasal
cancer deaths (SMR; 453; 95% CI, 93-1324) and a further four incident cases. In the group of workers with 5 years or
more in the electrolysis department and 15 or more years since first exposure, with no experience in calcining, roasting
or smelting departments 19 lung cancer deaths were observed (SMR, 476; 95%, CI 287-744), and 2 nasal cancers (see
table 4.1.2.7.2.E).
144
Table 4.1.2.7.2.E: Falconbridge (Kristiansand, Norway) nickel refinery – average nickel exposure levels
and cancer risks in workers with 15 or more years since first exposure a
Duration in department
Estimated airborne
concentration
Calcining, roasting, 0.3smelting; never in 1.3
electrolysis
Electrolysis; never
in calcining,
roasting smelting
5.010.0
nickel
Soluble nickel
nickel
Sulphidic
Oxidic
Department
Metallic nickel
(mg/m3 Ni) a
0.3
Ever
≥5 years
Lung cancer Nasal cancer b
Lung cancer
Nasal cancer b
Obs SMR
Obs
(95% CI)
Obs
Obs
SMR
(95% CI)
5
-
2
-
Negl. c 14
Negl.- Negl.- Negl.- 0.31.3
1.3
1.3
5.0
225
5
SMR
(95% CI)
-
(95% CI)
8
(122-377)
30
385
SMR
254
(109-500)
2
-
(259-549)
19
476
(287-744)
a From Doll et al. (1990). Estimated airborne concentrations of nickel species and mortality from or incidence of lung
cancer and nasal cancer by department.
Standardised mortality ratio (SMR) and 95% confidence interval (CI).
b Three deaths and four incident cases.
c Negl., negligible exposure.
Since the concentration of soluble nickel was taken to be higher in the electrolysis department than elsewhere in the
refinery it was concluded that soluble nickel was responsible for the observed risk. The analyses also gave a strong
evidence of increased lung cancer risk at the highest levels of soluble nickel exposure. In addition, it was suggested that
electrolysis workers had a higher lung cancer risk than the roasting, smelting, and calcining workers.
There was also evidence that exposure to water-soluble nickel at levels seen in the electrolysis department increased the
nasal cancer risk, the two nasal cancers occurred in workers with long periods of work almost exclusively in that
department.
In a more recent report (Andersen et al., 1996), including all workers with first entry back to 1916 (4764 workers), the
Norwegian data were analysed using a multivariate regression method with soluble nickel, nickel oxide, smoking, and
age included in the model. The analysis showed a three fold increased risk for lung cancer in the group with highest
exposure to water-soluble nickel when the other variables were adjusted for (table 4.1.2.7.2.F). For nickel oxide only a
modestly increased risk was observed. The study suggested a multiplicative effect of smoking and nickel exposure. The
effect from sulphidic nickel was not addressed, as oxidic nickel was considered to play the most important role in the
earlier epidemiological findings (Doll et al., 1990). According to the exposure matrix the exposures to oxidic and
sulphidic nickel with few exceptions followed each other rather closely.
Table 4.1.2.7.2.F: Falconbridge (Kristiansand, Norway) nickel refinery – Relative risks (RR) of lung cancer
by cumulative exposure to water-soluble nickel and nickel oxide, considering the two variables
simultaneously by a multivariable Poisson regression analysis a
Variable
Mean exposure
[(mg/m3)*years]
Cases (n)
RR
95% CI
Test for
linear trend
P < 0.001
Water-soluble nickel
3
[(mg/m )*years]:
<1
0.1
86
1.0
Referent
1-4
2.3
36
1.2
0.8-1.9
145
5-14
8.8
23
1.6
1.0-2.8
≥ 15
28.9
55
3.1
2.1-4.8
Nickel oxide
[(mg/m3)*years]:
P = 0.05
<1
0.4
53
1.0
Referent
1-4
2.5
49
1.0
0.6-1.5
5-14
8.3
53
1.6
1.0-2.5
≥ 15
44.3
45
1.5
1.0-2.2
a
From Andersen et al., 1996; adjusted for smoking habits and age; workers with unknown smoking habits excluded
(three cases of lung cancer).
In a recent case-control study (Grimsrud et al., 2002) conducted within the Norwegian cohort, a new job-exposurematrix (Grimsrud et al., 2000) was used to compute individual cumulative exposures. With adjustment for smoking, the
results strongly indicated a dose-response relationship between exposure to water-soluble nickel and risk of lung cancer.
An increase in risk from other types of nickel irrespective of dose could not be excluded (table 4.1.2.7.2.G).
Table 4.1.2.7.2.G: Falconbridge (Kristiansand, Norway) nickel refinery – Relative risks (Odds ratio) of lung
cancer by cumulative exposure to nickel, no lagging of exposure, with adjustment for smoking, in a nested
case-control study a
Nickel exposure
Water-soluble nickel, continuous, logetransformed
Odds
ratio
95% CI
Exposed
cases
Exposed
controls
N (% of all)
N (% of all)
1.7
1.3-2.2
204 (96%)
472 (90%)
1.5
0.6-3.5
204 (96%)
472 (90%)
Likelihoodratio test
P = 0.0001
Rise in OR per unit of ln(CEw-s + 1)b
Ever versus never exposed to any form
of nickel
a From Grimsrud et al., (2002).
b ln = the natural logarithm; CEw-s = cumulative exposure to water-soluble nickel in (mg/m3)*years
The three results from the Kristiansand refinery (ICNCM, Doll et al., 1990; Andersen et al., 1996; Grimsrud et al.,
2002) do not specify the type of water-soluble nickel that is responsible for the increased cancer risk. Before 1952 the
dominating form was nickel sulphate. Nickel chloride was introduced in 1952 in a mixed sulphate and chloride nickel
electrolysis (with 78% of the nickel present as chloride and 22% as sulphate), while the type of nickel exposure in the
copper electrolysis department was unaffected by this change (still being nickel sulphate).
In the most recent update of cancer incidence in the Kristiansand refinery cohort (Grimsrud et al., 2003), the lung
cancer risk was analysed by duration of work in departments and by cumulative exposure to water-soluble nickel and
nickel oxide based on the job-exposure matrix developed after reassessment of the exposures (Grimsrud et al., 2000). A
highly elevated incidence rate was found for long-term workers in the copper electrolysis, copper leaching, and nickel
sulphate production (15 years or more; less than 1 year in roasting, smelting, and calcining). Exposure to nickel sulphate
was the predominating form of nickel exposure in this group (SIR, 700; 95% CI, 370-1200). Long-term workers in the
nickel electrolysis, copper cementation, and electrolyte purification between 1910 and 1952 (15 years or more; less than
1 year in roasting, smelting, and calcining), a period with sulphate based nickel electrolysis, also had a highly increased
lung cancer risk (SIR, 550; 95% CI, 300-920). Internal comparisons with Poisson regression analyses showed a doserelated effect of nickel exposure, when age and smoking habits were adjusted for, more clearly seen for water-soluble
nickel than for oxidic nickel. In the latter analyses, however, it was not possible to adjust for the effect of other forms of
nickel.
4.1.2.7.2.3.3 Port Colborne, Canada
146
The Port Colborne electrolysis department was a part of the INCO cohort included in the ICNCM report, and included
men followed from 1950 to 1984. Before 1942, these workers had exposures to water-soluble nickel that were primarily
nickel sulphate. From 1942 chlorine was introduced in the process, giving a mixed sulphate and chloride electrolyte.
About 60% of the nickel was present as chloride and 40% as sulphate (Ullmanns Encyklopädie, 1979). The strongest
evidence of an increased risk of nasal cancer (four cases) in the electrolysis department was in the group of men with 15
years of service and less than 5 years in leaching, calcining, and sintering. One of these men had less than 3 months
experience from leaching, calcining, and sintering and more than 20 years from the electrolysis department. Workers in
the electrolysis department with no exposure in leaching, calcining or sintering plant, but with 15 or more years since
first exposure, gave no evidence of increased lung cancer risk, with an SMR of 88 based on 19 deaths (95% CI, 53137). In addition, there were no nasal cancer cases among these workers (see table 4.1.2.7.2.H). In a small group of
electrolysis workers (25 persons) with more than 5 years of high exposure to water-soluble nickel and less than 5 years
in the leaching, calcining, and sintering department no deaths of nasal cancer were observed, but 3 lung cancer deaths
were reported, representing a lung cancer mortality 3 times higher than expected.
Table 4.1.2.7.2.H: INCO (Ontario, Canada) nickel refinery facilities – average nickel exposure levels and
cancer risks in workers with 15 or more years since first exposure a
Estimated airborne concentration Duration in department
(mg/m3 Ni) a
Coniston,
sinter
Negl. b 0.10.5
1-5
Total nickel
Soluble nickel
Sulphidic nickel
Oxidic nickel
Period
≥5 years
Ever
Metallic nickel
Plant,
department
Negl. 1-5
Lung cancer
Nasal cancer b Lung cancer
Nasal cancer b
Obs SMR
Obs SMR
Obs SMR
(95% CI)
8
292
Obs SMR
(95% CI)
0
-
(95% CI)
6
(126-576)
492
(95% CI)
0
-
4
13146
(1811073)
Copper Cliff,
sinter
1948-54
Negl. 25-60 15-35 <4
40-100 63
307
1955-63
Negl. 5-25
8-40
(238-396)
3-15 <2
6
3617
33
(13277885)
789
(5431109)
(357633654)
Port Colborne,
leaching,
calcining, sinter
1926-35
Negl. 20-40 1020 <3
30-80
1936-45
Negl. 3-15
2-10 <3
5-25
1946-58
Negl. 5-25
3-15 <3
8-40
<0.5
<0.5
<1
Port Colborne,
electrolysis d
<0.2
<0.3
72
239
(187-302)
19
88d
19
7776
(468112144)
0 c,d -
38
366
(259-502)
10 d,e 89
15
18750
(1050030537)
0 c,d -
(53-137)
a From Doll et al. (1990). Estimated airborne concentrations of nickel species and mortality from lung cancer and
nasal cancer by department. Standardised mortality ratio (SMR) and 95% confidence interval (CI);
b Negl., negligible exposure;
c Two nasal cancer deaths occurred in men with >20 years in electrolysis and only short exposure (three months and
seven months) in leaching, calcining and sintering;
d Never worked in leaching, calcining and sintering;
e Workers with ≥10 years in electrolysis
147
In the Sutherland report (1959) on respiratory cancer between 1930 and 1957 in workers employed at the Port Colborne
nickel refinery, an elevated risk of lung and nasal cancer was ascribed to work at the cupola and sinter furnaces, which
were believed to have been associated with extremely high levels of insoluble nickel exposure (Doll et al., 1990). Still,
among the nasal sinus cancer cases, two out of a total of 12 cases had 3 and 10 times longer employment in the
electrolysis department than in other exposed jobs altogether. As to pulmonary cancer, 4 out of 22 cases had between 19
and 22 years of work in the electrolysis department, while none of these four cases had experience from the sinter
furnace, and only two of them had ever been at the cupola furnace for periods of less than two years. However, no firm
conclusions can be drawn from these data as the expected rates were prepared to evaluate the effect from furnace work.
4.1.2.7.2.3.4 Harjavalta, Finland
The Finnish refinery included 1155 male workers, of whom 418 were refinery workers (Anttila et al., 1998). The
refinery started operation in 1960 and the follow up of incident cases of cancer ended in 1995. In the refinery the
exposure was mainly nickel sulphate, in 1991 it was measured to 90%. During the 25 years follow up period, the group
of refinery workers showed 6 lung cancer (SIR, 261; 95% CI 96-567) and 2 nasal cancers (SIR, 4110; 95% CI 4971480) (table 4.1.2.7.2.I). In the group with 20 years latency the same 6 lung cancer cases and 2 nasal cancers were
included. In another group of 566 smelters with negligible exposure to nickel sulphate the SIR of lung cancer was 139
and no nasal cancers were observed in this group.
Table 4.1.2.7.2.I: Harjavalta, Finland. Levels of cancer risks *
Exposures
(mg/m3 Ni)
Duration in department and latency time
Smelter
Total Nickel
NiSO4 as % of
total Ni
Department
Ever
> 20 years latency
> 5 years employment
Lung cancer
Nasal cancer Lung cancer
Nasal cancer Lung cancer
Nasal cancer
Obs SIR
Obs SIR
Obs SIR
Obs SIR
Estimated 0.02-0.2 15
10%
Refinery Measured 0.1-0.4 6
90%
(95% CI)
139
Obs SIR
(95% CI)
0
-
(95% CI)
13
(78-228)
261
(96-567)
200
Obs SIR
(95% CI)
0
-
(95% CI)
8
(107-342)
2
4110
(49714800)
6
338
(124-736)
101
(95% CI)
0
-
2
7520
(43-198)
2
6710
(81224200)
3
199
(41-580)
(91027100)
* From Anttila et al., 1998.
In the period 1960 to 1973 the grinding, leaching, and electrolysis activities took place in the same building and the
exposures consisted of a mixture of soluble and insoluble nickel compounds. The authors however concluded that since
the nasal and lung cancer risks were confined to the refinery, where the primary exposure was to nickel sulphate, it was
likely that nickel sulphate was mainly responsible for the elevated respiratory cancer risk.
Other refineries
Saknyn & Shabynina (1970) and Saknyn (1973) reported elevated lung cancer mortality among process workers in four
nickel smelters in USSR (SMRs, 200, 280, 380, 400). Electrolysis workers, exposed mainly to nickel sulphate and
nickel chloride were reported to be at particularly high risk of lung cancer (SMR, 820).
Electroplaters
There are several studies among nickel plating workers. In most of these studies was it difficult to evaluate nickel and
nickel sulphate, because of a possible confounding effect of chromium exposure. However, the cancer mortality cohort
study among 284 British electroplaters is much less likely to be confounded by other types of exposure (Pang et al.,
1996). This cohort included all men first employed in 1945-1975 with at least 3 months employment. The follow up of
death was to the end of 1993. The overall SMR for lung cancer was 108 based on 11 cases only, and there was no
significant elevated risk in those exposed for more than one year. The risk for stomach cancer was elevated (8 observed
cases, SMR, 322; 95% CI 139-634).
148
To our knowledge this is the only study of nickel platers in the metal finishing industry where workers were exposed
primarily to nickel sulphate. However, the study had several weaknesses with small number of workers, less than 7000
person years in total. Most of the workers had less than one year in exposed work (median 0.86 years), and there was an
absence of exposure data.
4.1.2.7.2.4
Discussion of cancer epidemiology
The substantial excess risk of lung and nasal cancer among Clydach hydrometallurgy and the Kristiansand electrolysis
workers is likely to be due, at least partly, to the workers’ exposure to nickel sulphate. The Norwegian study (Andersen
et al., 1996) showed a threefold risk in a multivariate regression analysis after adjustment for smoking and oxidic
nickel. The study from Finland was small, but supported strongly the results from Clydach and Norway. The indications
of water-soluble compounds as an important factor were strengthened by the results from the Norwegian case-control
study. By contrast, the refinery workers at Port Colborne with no sinter plant experience seemed to have no increased
risk of lung cancer or nasal cancer. The study among British electroplaters was small but showed no elevated risk of
respiratory cancer.
In sum, a combined group of workers from the three refineries included in the ICNCM-study (Clydach, Kristiansand,
and Port Colborne) with 5 years or more employment in a department with high nickel sulphate exposure (Clydach
hydrometallurgy and copper plants; Falconbridge electrolysis departments, and Port Colborne electrolysis department)
and 15 years’ latency showed 42 lung cancer deaths (SMR; 231; 95% CI 166-312) and 8 nasal cancer deaths (or
incident cases) SMR>1,500 (tables 4.1.2.7.2.D-E and H).
All cohorts of refinery workers have had restrictions for inclusion according to time of employment, from 3 months in
the Finnish refinery to 5 years in the Clydach refinery. The Finnish cohort included therefore a number of short-term
workers who often show a higher risk of lung cancer but not nasal cancer. However, in the group of workers with 5
years or more in employment the observed number of lung cancers was reduced from 6 to 3 and the SIR decreased from
261 to 199. The Canadian and the Norwegian studies had an inclusion criterion of one year’s employment and shortterm workers had a minor influence on these results. The Norwegian studies (Andersen et al., 1996 and Grimsrud et al.,
2003) used both external and internal reference populations in the analyses.
In all studies except the Finnish national reference rates were used for calculation of SMRs/SIRs. Finland used rates
from the region where the factory was located. In analyses of risk of nasal cancer, a disease that is very rare in the
general population, the use of national rates would have been preferable because these rates are more stable than rates
from a region.
The Clydach refinery lost 400 workers of follow-up, mainly workers with first employment before 1930 and lost to
follow-up in a period with incomplete information on identity. These subjects were under observation until the last day
they were known to be alive. The tracing of the Finnish and the Norwegian cohorts was almost complete. In addition
the cancer registries in these two countries are known to have a complete registration of all new cancer cases. The
linkage between the cohorts and the cancer registries was based the unique personal identity numbers. The observed and
expected number of cases also share the same base and are strictly comparable.
Roberts et al. (1989) reported on the follow-up of the Canadian cohorts. For the Port Colborne workers, vital status at
end of follow-up was lacking for 1820 (42%) out of the 4,287 subjects included in the cohort. Still, in the analyses of
the ICNCM-study, the Canadian workers with unknown vital status were presumed to be alive until the end of the total
follow-up period. This procedure led to an overestimation of the expected numbers of deaths, combined with a deficit in
the observed numbers, resulting in SMRs that probably were too low.
There was at Port Colborne an elevated risk of nasal cancer and a suggestion of increased lung cancer risk among longterm electrolysis workers who had less than 5 years of furnace work. Additionally, there was a suggestion of increased
lung cancer risk in the sub-group of long-term electrolysis workers of the ”high soluble exposure” group. However,
these workers all had some exposure (though less than 5 years) from the leaching, calcining, and sintering department,
which was identified as a high risk area at Port Colborne. It is therefore difficult to draw firm conclusions based on the
Port Colborne data.
There is often an element of uncertainty in studies where lung cancer is involved and no information on smoking exists.
The results from the refineries demonstrated a consistent trend in risk with number of years employed and number of
years since first employment. There was little evidence of a higher smoking rate among those with short employment
time compared with those with extended employment. The study by Andersen et al. (1996) included smoking data and
149
exposure estimates in the analysis. This study showed a significant excess risk associated with soluble nickel (primarily
nickel sulphate). The Andersen et al. (1996) study included an analysis of the lung cancer rate ratio in a merged group
of refinery workers and men from a representative sample of the general Norwegian population with known smoking
habits from a survey in the 1960s. Nickel exposure was associated with elevated risk among smokers as well as among
never smokers. These findings were supported by the results from the case-control study (Grimsrud et al., 2002), where
the exposure levels had been reassessed based to a higher degree on direct measurements of nickel in the work
atmosphere, and with a better control of the effect from smoking. There is also some evidence that nasal cancer is
associated with smoking, but occupational exposure is obviously more important (Doll, 1996). The results from nickel
refinery studies cannot be explained by smoking alone.
The evaluation of carcinogenicity of individual nickel species is hampered by the fact that most cohorts of nickel
refinery workers have been subject to mixed exposures. For the evaluation of nickel sulphate, however, there are
subgroups which are especially relevant because nickel sulphate constituted the dominating form of nickel exposure.
Even within these subgroups there may be workers who have been exposed to oxidic, metallic, or sulphidic nickel, but
the levels of exposure were generally low. If the concentration and duration of exposure to oxidic or sulphidic nickel
were low it would be appropriate to ascribe a potential cancer hazard to nickel sulphate.
A comparison of nickel concentrations estimated in different refineries at different times, with the number of
measurements from each refinery varying from zero to several hundreds, is of course vulnerable to misclassification.
Despite chemical similarities, the technical, physical, and organisational conditions can vary greatly, and lead to large
differences in exposure characteristics like chemical composition and particle size. Therefore, a demonstration of cancer
risk within a group with relatively constant exposure characteristics, with the finding of a dose response relationship
when the data are analysed by duration or cumulative exposure, even on a relative scale, deserves more attention than
comparisons made between different refineries where the absolute nickel concentrations are bound to be very insecure.
Still, a comparison of risk across cohorts with clear qualitative differences in exposure may be of interest, although
diverging results always will leave insecurity as to whether they should be explained by differences in exposure
(qualitatively or quantitatively), by chance, or by deficiencies in the epidemiological conduct of the studies.
The exposure assessment performed by Grimsrud et al. (2000) indicated generally that the levels of total nickel were
lower at the Norwegian refinery than those presumed in the ICNCM study (Doll et al., 1990). Table 4.1.2.7.2.J shows
the reduced level of nickel exposure in the electrolytical departments in Norway based on a more comprehensive
analysis of the personal measurements. The levels of water-soluble nickel in the electrolysis departments were reduced
from the range 0.3-1.3 mg/m3 to approximately 0.1 mg/m3 for the copper tank house and nickel tank house. It could be
anticipated from the Andersen et al. (1996) study that workers with highest cumulative soluble exposure have a
threefold increase risk of lung cancer compared to the reference population, but at a lower level of soluble nickel than
earlier believed. In the case-control study, the strong dose-related effect on cancer risk from exposure to water-soluble
nickel was confirmed.
Similar associations were also found in the Finnish study, but were not reported from the Canadian cohort.
Table 4.1.2.7.2.J: Details of concentration of total nickel and soluble nickel in air in selected nickel
refineries and departments
Refinery
Reference
Time
period
Measurements
Typical
level of
total
nickel
(mg/m3)
Typical
level of
soluble
nickel
(mg/m3)
Clydach,
hydrometallurgy area,
NiSO4 and CuSO4
ICNCM
(Doll et al.,
1990)
1902-1930
Virtually no measurements
2
0.7-2
Kristiansand, Copper
tank house,
electrowinning
ICNCM
(Doll et al.,
1990)
1946-1984
Stationary and personal
measurements as basis for
expert estimates (ranges)
0.3-1.6
0.3-1.3
Grimsrud et
al., 2000
1945-1977
Personal measurements
and speciation analyses
from the 1990s
0.13
0.10
150
leach
ICNCM
(Doll et al.,
1990)
1946-1984
0.6-5.6
0-1.3
Grimsrud et
al., 2000
1945-1977
from the 1990s
0.87-1.47
0.43-0.72
Outokumpu, Nickel
tank house,
electrowinning
Kiilunen et al.,
1997a
1979-1981
0.16-0.23
0.14-0.18
Kristiansand, Nickel
tank house,
electrorefining
ICNCM
(Doll et al.,
1990)
1946-1984
0.3-1.9
0.3-1.3
Grimsrud et
al., 2000
1945-1977
Personal measurements,
speciation analyses from
the 1990s
0.12
0.10
ICNCM
(Doll et al.,
1990)
1946-1984
0.9-3.9
0.3-1.3
Grimsrud et
al. 2000
1945-1977
Personal measurements,
speciation analyses from
the 1990s
0.18-1.16
0.14-0.52*
Port Colborne, Nickel
tank house,
electrorefining
ICNCM
(Doll et al.,
1990)
1950-1984
measurements
less than
0.5
less than
0.15
Monchegorsk, Nickel
tank house,
electrorefining
Thomassen et
al., 1999
1990s
with speciation analysis
0.05-0.3
0.04-0.3
cementation etc.
* In the Copper cementation department the air concentration of metallic nickel was taken to be equally high as the
level of water-soluble nickel
In the electrolysis of the Norwegian refinery departments 80% or more of the nickel in air was estimated to exist as
soluble forms. The nasal cancer risk was identified in workers exposed before 1956. In that period the soluble species
were dominated by nickel sulphate.
In the exposure matrix developed by Grimsrud et al. (2000) the proportion of total nickel found as soluble species in the
Norwegian refinery was estimated to be 10% or more in all departments, even the pyrometallurgical departments
previously thought to have negligible amounts of soluble nickel in air. These estimates were, however, in accordance
with Warner (1984) and Thomassen et al. (1999), and partly based on earlier published results by Andersen et al.
(1998). Water-soluble nickel found in roasting and smelting departments in amounts was mainly nickel sulphate,
present at levels comparable to the hydrometallurgical departments, especially in the flues and on the top floors in
furnace buildings. These findings suggest an important role of nickel sulphate in cancer development even in roasting
and smelting departments.
In the study by Shannon and co-workers (1991) among workers engaged in mining and production of nickel-copper
concentrate (matte), exposure to nickel sulphate was only considered to take place in a few departments (feed
preparation and pyrrhotite plant). However, at the refinery that received the matte for processing into pure nickel
(Kristiansand, Norway), 12% of the nickel in air was thought to present in water-soluble form in the unloading,
crushing, and grinding department, prior to further treatment (Grimsrud & al., 2000). According to knowledge from
other refineries (Doll & al., 1990; Grimsrud & al., 2000; Thomassen et al., 1999) one would expect nickel sulphate to
be generated in the sintering departments where sulphidic nickel was transformed into oxidic nickel. The evidence of
occupational cancer, although weak, could even here be associated with exposures to nickel sulphate, alone or together
with insoluble forms of nickel.
151
4.1.2.7.2.5
Summary of cancer epidemiology
The present evaluation includes 7 cohort studies from four countries; six of the studies were based on data from four
different nickel refineries, and one study was based on nickel electroplaters. In addition, the evaluation includes one
case-control study from one of the nickel refineries. These studies provide the epidemiological evidence concerning
potential risk of lung and nasal cancer associated with exposure to nickel sulphate. All the studies from nickel refineries
included estimates on nickel exposure, and two of the Norwegian studies included smoking data.
For one of the refineries, the exposure estimates were based virtually on no measurements (Clydach). Some estimates
were based on a combination of stationary measurements and personal measurements of total nickel (Kristiansand, Port
Colborne, Harjavalta), with most confidence given to the personal samples, although none of these were taken earlier
than 1970. For periods before 1970 most estimates were based on experience from the work environment and
knowledge of the chemical process. Likewise, the proportions of specific groups of nickel compounds (metallic, oxidic,
sulphidic, and water-soluble nickel) were mainly believed to reflect the composition of the material found in the
process. The case-control study in the Norwegian cohort (Kristiansand) was based on a high number of personal
measurements taken, in part, in the presence of an identified cancer hazard. Additional data on the proportions of watersoluble nickel were derived from analyses of refinery dusts and aerosols in the 1990s.
Previously, exposure to nickel sulphate in refineries was believed to take place mainly in electrolysis and
hydrometallurgical departments, but later analyses have proved that such exposure exists in concentrations that should
not be neglected even in roasting and calcining departments. The levels of exposure to water-soluble nickel have been
given as ranges, varying from 0.1 to 0.4 mg Ni/m3 in the Canadian and the Finnish electrolysis departments. In the
Norwegian plant estimates of water-soluble nickel before 1978 were mainly between 0.3 and 1.3 mg/m3, according to
the ICNCM, or between 0.1 and 0.7 mg/m3according to more recent estimates. The refinery in Wales was believed to
have much higher levels of water-soluble nickel in the hydrometallurgical department (0.7-2.0 mg/m3). Recent studies
in a Russian refinery showed concentrations of water-soluble nickel in the range 0.04-0.3 mg/m3 in an electrolysis
department similar to the one in Canada and to the nickel electrolysis in Norway before 1978.
From all three refineries in Wales, Norway, and Finland significant excess risks of lung and nasal cancer were
demonstrated, associated to water-soluble nickel by duration of exposure. In Wales and Norway, the cumulative
exposure to water-soluble nickel was also closely related to lung cancer risk. In addition, two of the most recent
Norwegian studies (Andersen et al., 1996 and Grimsrud et al., 2002) showed a three- to fourfold risk in workers with
the highest level of cumulative exposure to water-soluble nickel, after adjustment for smoking and less soluble forms of
nickel. The relationship was confirmed with a significantly positive test for trend in the cohort study. The results from
the Canadian electrolytic refinery were not equally clear as those from the three other refineries, with only weak
evidence of a lung and nasal cancer risk from exposure to water-soluble nickel.
Although the nickel electrolysis departments in the Canadian and Norwegian refineries had a mixed nickel sulphate and
nickel chloride exposure after 1942 and 1952, respectively, the main water-soluble exposure from 1926 and 1910 in the
same departments, respectively, was nickel sulphate. At the Norwegian refinery there was strong evidence of a high
cancer risk during the period when nickel sulphate was the dominating soluble form of nickel. The type of water-soluble
nickel associated with cancer in the refineries in Clydach and Harjavalta was also nickel sulphate, as no (or negligible
amounts) of nickel chloride had been used in these plants.
The British study of electroplaters although negative, gave little additional information, as it included only a few person
years and no data on exposure.
4.1.2.7.2.6
Conclusion of cancer epidemiology
The present evaluation of the epidemiological data demonstrated a strong relationship between lung and nasal cancer
and exposure to nickel sulphate as it occurs in nickel refineries. The demonstration of a relatively high proportion of
nickel sulphate in the nickel exposures occurring in smelting and roasting areas, suggests a possible contribution to the
cancer risk from nickel sulphate even in these areas.
4.1.2.7.3 Overall evaluation of carcinogenicity
152
4.1.2.7.3.1
Epidemiology
Epidemiological studies from three nickel refineries processing sulphidic nickel ores has demonstrated elevated risk of
lung and nasal cancer in workers exposed mainly to nickel sulphate in the presence of variable amounts of water
insoluble nickel compounds: the Clydach refinery in Wales, UK; the Kristiansand refinery in Norway; and the refinery
in Harjavalta, Finland. Among electrolysis workers at the Port Colborne refinery in Canada the association between
respiratory cancer and exposure to nickel sulphate was not clear.
In Clydach, elevated risk for death from lung or nasal cancer was found in workers employed in the hydrometallurgy
department where nickel sulphate was the dominating form of nickel in the exposures. Exposure to nickel sulphate also
took place in other departments, and there was evidence of a dose-response relationship with cancer risk, in workers
with high oxidic and/or sulfidic exposure when the data were cross-tabulated. Regression analyses offering adjustment
for exposure to other types of nickel or adjustment for work in other high-risk departments also showed a doseresponse. No exposure measurements existed, but the high risks left no doubt as to their occupational origin. In the
nickel refinery groups exposed mainly to nickel sulphate for more than 5 years, the lung cancer risk was 3 times higher
than expected from national data. Nickel chloride was not used in the production. It was not possible to adjust for
tobacco smoking, but the increase in lung cancer risk was far too high to be explained by confounding from smoking.
The risk of nasal cancer in the same group was reported to be more than 100 times the expected rates in the general
population. The nasal cancer risk is only slightly affected by smoking habits.
At the Kristiansand refinery, nickel sulphate was the dominating exposure in the electrolysis departments between 1910
and 1952. The overall lung cancer risk in the Norwegian refinery workers has been elevated with a factor of 3 compared
to the national rates. For the cohort as a whole, the risk for nasal cancer has been 18 times the expected rates in the
general population, mainly affecting workers employed before 1952. A dose-response has been demonstrated for lung
cancer according to duration of work in the electrolysis departments. The lung cancer rates suggested a higher risk
among electrolysis workers compared to other high-risk groups (as roaster and smelter workers). Those employed for
the first time before 1945 seem to have a higher risk than those employed in later years. These results concerning the
period before 1952 give strong evidence of an association between cancer risk and exposure to nickel sulphate.
Additional data from later years, although not restricted to nickel sulphate, support these findings.
In 1952, the process was changed in some of the electrolysis departments, leading to a replacement of 80% of the nickel
sulphate by nickel chloride. Still, the same elevated lung cancer risk has been found among workers employed between
1952 and the 1970s as in those employed before 1952. In a regression analysis, a dose-response was demonstrated for
lung cancer according to cumulative exposure to water-soluble nickel (nickel sulphate and nickel chloride) with
adjustment for age, smoking (ever smoker versus never smokers), and cumulative exposure to oxidic nickel. A recent
case-control study performed within the same cohort, used cumulative exposures to four forms of nickel computed from
a new exposure matrix, which was based largely on personal full-shift measurements and speciation analyses in dusts
and aerosols. The earlier finding of a dose-response between lung cancer and water-soluble nickel was confirmed in the
analyses, which offered an optimal adjustment for smoking (life-time habits), and adjustment for exposure to less
soluble forms of nickel.
The refinery in Harjavalta also treated a sulphidic nickel concentrate, as did the two refineries in Clydach and
Kristiansand. Elevated risk for lung and nasal cancers was demonstrated in the group of workers where nickel sulphate
was the dominating form of nickel in the working atmosphere. The historical nickel exposures were well documented.
No adjustment for smoking could be performed in the analyses of lung cancer risk. No dose-response was found, but the
number of cancer cases was low.
The electrolysis workers at the Port Colborne refinery were exposed mainly to nickel sulphate until 1942 and from that
year subjected to a mixed sulphate and chloride exposure. It was not possible to ascribe the mortality from respiratory
cancer in this group to the exposure to nickel sulphate only.
The epidemiological data summarized above demonstrates a positive association in a dose-dependent manner between
exposure to soluble nickel compounds (e.g., nickel sulphate) and increased respiratory cancer risk in at least three
separate cohorts.
4.1.2.7.3.2
Animal studies
Long-term inhalation experiments with nickel sulphate hexahydrate have been performed in male and female rats and
mice. No carcinogenic activity was found from inhalation of nickel sulphate when the tumour yield was compared
153
between exposed animals and controls. Due to high acute toxicity, the maximum nickel dose obtained with nickel
sulphate was not as high, in general, as that obtained with less soluble nickel compounds. Nickel subsulphide tested at
0.11 mg Ni/m3 for two years was positive in rats while nickel sulphate hexahydrate tested at the same concentration of
0.11 mg Ni/m3 was negative.
Two old studies and one well-conducted OECD 451 study on orally administered nickel sulphate were negative. Three
oral promoter studies had deficiencies in the documentation but suggested a promoter effect, confirming results seen for
other water-soluble nickel compounds. With respect to other routes of administration, intraperitoneal injections led to
carcinogenic activity in rats, and some activity was reported (in an abstract only) after implantation of pellets
intramuscularly in rats. By contrast, five intramuscular injection studies in rats with the hydrated and anhydrous forms
of nickel sulphate were negative.
A working group at the International Agency for Research on Cancer (IARC) concluded that there was limited evidence
in animals for the carcinogenicity of nickel salts. When the evaluation was restricted to the effect specifically from
nickel sulphate in animals, the strongest evidence of carcinogenicity was found after intraperitoneal injection in rats.
Although the effect was clear, the route of administration was not relevant for the evaluation of carcinogenicity in
humans. This 1990 evaluation preceded the more recent negative inhalation, and intramuscular injection studies with
nickel sulphate.
A key issue identified in discussions with Industry relates to the interpretation of the differences between the positive
epidemiological results seen in man, and the negative results seen in the NTP inhalation studies.
The NTP inhalation study has been considered by the Commission Scientific Committee on Toxicology, Ecotoxicity
and the Environment (CSTEE, 2001) in the context of the Commission Position paper on ambient air pollution. The
CSTEE concluded “that the lack of carcinogenicity of nickel sulphate hexahydrate in the NTP study cannot be taken as
evidence of lack of carcinogenic potential for soluble nickel compounds. Nickel carcinogenicity will be dependent on
the time-integrated intracellular concentration of nickel ions as the active entity, so that the relative potency of various
nickel species will be related to their bioavailability and lung burden”.
Arguments have been put forward by Sanner and Dybing (see Appendix 7.5) that nickel sulphate would have shown
carcinogenic activity if tested at higher concentrations.
Other arguments have been put forward by NiPERA (see Appendix 7.6) that nickel sulphate hexahydrate, by itself,
would not show carcinogenic activity even if a higher concentration could have been tested. The NTP inhalation studies
of rats and mice clearly indicate that exposure to nickel sulphate hexahydrate can induce respiratory toxicity manifested
by inflammation and fibrosis in rats and mice. Chronic inhalation of nickel sulphate hexahydrate at concentrations
above those that cause chronic inflammation may enhance the carcinogenicity of concomitant exposures to respiratory
carcinogens such as nickel subsulphide, certain nickel oxides and/or cigarette smoke (non genotoxic mechanism). This
is in agreement with the findings from the epidemiological studies (NiPERA, 2002).
The mechanisms for the carcinogenic effect from water-soluble nickel are not completely understood. There may be
specific effects from water-soluble nickel, other than that of inflammation, which can induce and promote the
development of cancer.
4.1.2.7.3.3
Mechanistic considerations
The carcinogenic effect from nickel has been studied in a large number of experiments. It has been suggested by
Industry that water-soluble nickel has a promoting effect rather than an initiating effect, and it has been proposed that
water-soluble nickel may not be a complete carcinogen. However, in epidemiology it is not possible to distinguish
between the carcinogenic mechanisms. Different models have been launched for these mechanisms, but the present
knowledge is incomplete. Some of the prevailing models are presented by NiPERA in Appendix 7.7.
4.1.2.7.3.4
Conclusions
The epidemiological evidence is sufficient to classify nickel sulphate in Category 1, known to be carcinogenic to man.
This evidence has been reviewed by the Specialised Experts at their meeting in April , 2004. The Specialised Experts
concluded that nickel sulphate and nickel chloride should be considered as human carcinogens (Carc. Cat. 1). The data
was considered to be sufficient to establish a causal association between the human exposure to the substances and the
154
development of lung cancer. There was supporting evidence for this conclusion from more limited data on nasal cancer
(European Commission, 2004).
In drawing this conclusion regarding lung cancer, it was recognised that the epidemiological data showed a clear
exposure response relationship for water-soluble compounds, consistency across and within studies and time periods,
and high strength of association. Improved exposure characterisation based on personal air sampling and improved
analysis of the water-soluble fractions added to the reliability of the findings. Confounding factors such as co-exposure
to insoluble nickel compounds and smoking were adequately addressed, and did not lower the level of confidence in
reaching the conclusion (European Commission, 2004).
Whilst there is clear evidence for the carcinogenicity of nickel sulphate in humans following inhalation, evidence for
lack of a carcinogenic potential has been found in an OECD 451 study with oral administration of nickel sulphate to rats
(CRL, 2005). The available data concerning dermal exposure are too limited for an evaluation of the carcinogenic
potential in experimental animals. However, as oral exposure to nickel sulphate does not show any carcinogenic
potential, there are good reasons to assume that cancer is not a relevant end-point with respect to dermal exposure
either.
The TC C&L has agreed to classify nickel sulphate as Carc. Cat. 1; R49 (May cause cancer by inhalation), as there is no
concern for carcinogenic potential with other routes of administration 5.
4.1.2.8 Toxicity for reproduction
4.1.2.8.1.1
Effects on fertility
A 3-generation reproduction study in Wistar rats was briefly described by Ambrose et al. (1976). Groups of 30
weanling rats per sex per group were fed 0, 250, 500, or 1000 ppm nickel as nickel sulphate hexahydrate for 11 weeks.
Twenty females/group were mated individually with males from the same group for up to three successive 7-day
rotations. The number of mated animals, number of pregnancies, alive and dead litters, pups in litter at 1, 5, and 21
days, and total litter weight at weaning was recorded. The F1a pups were sacrificed and necropsied at weaning, and the
parental (Po) rats were remated to produce the F1b generation. Mating of the F1b and F2b generations was as for the
parental generation (17-20 rats mated/group). A complete histopathology examination was conducted on F3b weanlings
(10/sex/group). No food consumption data was reported and therefore only rough estimates of the animal’s exposure
can be made. In the SLI 2-generation study, males consume 25-28 g/day and females 18-20 g/day. Using an average
body weight of 350 g and a food consumption of 18-28 g/animal/day rough exposure levels of 0, 13-20, 26-40 and 5280 mg Ni/kg bw/day can be calculated. Body weights of the F0 rats were slightly decreased at the high dose, with an
average decrease of 13% reported for males and 8% reported for females. The fertility index was slightly lower at 250
and 1000 ppm in the Fla generation, and at 1000 ppm in the F2b generation (around 60% compared to 70-79% in the
controls), however, the differences were not statistically significant. The fertility index in exposed animals was similar
to control values at the high dose in F1b, F2a, F3a and F3b. Based on the results of the study, the NOAEL for effects on
fertility seems to be 1000 ppm (52-80 mg Ni/kg bw/day), but due to the limited reporting of the data there is
uncertainties concerning this NOAEL.
A range-finding one-generation study in Sprague-Dawley rats was performed prior to the performance of the twogeneration study described below (SLI 2000a). Groups of 8 males and 8 females were given nickel sulphate
hexahydrate exposures of 0, 10, 20, 30, 50, 75 mg/kg bw/day by gavage. Dosing began two weeks prior to mating and
dosing of F1 began on postnatal day 21. These doses had no effects on F0 survival, growth, gross necropsy findings or
fertility. However, as a limited number of animals per group was used a clear NOAEL of 75 mg/kg bw/day (16.8 mg
Ni/kg bw/day) cannot be established based on these results.
In a 2-generation reproduction study compliant with the OECD 416 test guidelines in place of January 1999, SpragueDawley rats were administered nickel sulphate hexahydrate exposure levels of 1, 2.5, 5.0, and 10 mg/kg bw/day by
gavage (SLI 2000b). Animals of the parental (F0) generation were dosed during growth and for at least one
spermatogenic cycle or several complete oestrous cycles. No effects on fertility, sperm quality, oestrous cyclicity or
sexual maturation were found. Also, there were no effects on parental survival and growth. Furthermore, there were no
5
This classification is included in the Annex I entry in the 30th ATP.
155
treatment-related clinical signs of toxicity or histopathological changes in liver, reproductive organs, or other tissues
examined in the study. The study is well described and –performed. However, since the highest dose level did not
induce any signs of toxicity in the F0 animals, the study does not fulfil OECD TG guidelines concerning the dose levels
used. Therefore, the results of the study are not conclusive concerning the potential for effects of nickel sulphate on
fertility at higher dose levels than the NOAEL of 10 mg/kg bw/day (2.2 mg Ni/kg bw/day).
Following oral administration of 5.6 mg Ni/kg bw/day as nickel sulphate (25 mg/kg bw/day) to male rats for 4 months,
the rats were caged with females in oestrus for 24 hours (Waltschewa et al. 1972 – quoted from UK HSE 1987). While
3/10 female rats caged with control males became pregnant, 0/10 females caged with nickel-treated males became
pregnant. As a decreased in sperm count and testicular flaccidity were also reported, this study suggests a possible
effect of nickel sulphate on male sex organs in rats. The LOAEL is 5.6 mg Ni/kg bw/day and a NOAEL was not found.
An increase in abnormalities in spermatozoa from mice treated orally with a single dose of nickel sulphate (28 mg Ni/kg
bw/day) was reported 5 weeks after treatment (Sobti & Gill 1989).
Testicular degeneration was reported in a subacute inhalation study of rats and mice exposed to nickel sulphate (up to
1.6 mg nickel/m3) for 6 hours/day for 12 days over a 16-day period (Benson et al. 1988 –quoted from RTI 1995). The
authors indicate that testicular lesions were probably the result of emaciation rather than a direct effect of nickel
(Benson et al. 1987). This study was part of the range-finding work for the study reported by Dunnick et al. (see
below).
No effects on sperm morphology, sperm number or motility, or on vaginal cytology, were observed in rats or mice
exposed to concentrations ranging from 0.02 - 0.45 mg Ni/m3 as nickel sulphate hexahydrate for 6 hours/day, 5
days/week for 13 weeks (Dunnick et al. 1989, NTP 1996a). No exposure-related effects on mortality and only slight
effects on body weight gain were seen.
Groups of 3-5 rats received subcutanoues injections of 6.2 mg/kg bw nickel sulphate either as a single dose or as daily
doses for 30 days (Hoey 1966 – quoted from IARC 1989). Treatment interfered to some degree with spermatogenesis,
but this was temporary, and the testis ultimately recovered.
Tubular degeneration of the testes was reported in rats treated dermally with nickel sulphate hexahydrate at 60 mg/kg
bw/day for 30 days (Mathur et al. 1977 – quoted from IPCS 1991). This effect was more severe with exposure at 100
mg/kg bw/day for 30 days. No effects were found at 40 mg/kg bw/day after 30 days or at 100 mg/kg bw/day after 15
days of treatment. In this study, there was no indication that the rats were prevented from licking the chemical from the
skin, therefore, these effects could have resulted from oral exposure.
Forgacs et al. (1998) studied the effects of nickel sulphate heptahydrate on testosterone (T) production of mouse Leydig
cells in vitro following an in vivo or in vitro exposure. CFLP mice were subjected to repeated exposure (4 treatments,
subcutaneously, every 3 days) to 10, 20 or 40 mg nickel sulphate heptahydrate /kg bw (2.1, 4.2 or 8.4 mg Ni/kg bw) or
1.0 ml of 0.9% NaCl solution. Depressed human chorionic gonadotropin (hCG)-stimulated T response was seen over a
48-h culture of testicular interstitial cells obtained from the animals exposed to 4.2 mg Ni /kg bw/day or higher doses,
while the basal T production remained unaltered. There were no nickel-related changes in the body weights or in the
weights of testes, epididymis, adrenals, and kidneys. No histopathological alteration was found in the examined organs
except dose-dependent tubular lesions in kidney. To assess the direct effect on Leydig-cell T production, testicular
interstitial cells were cultured with Ni2+ (62.5 to 1000 μM) for 48 h in the presence or absence of maximally stimulating
concentration of hCG. Dose-dependent depression in hCG-stimulated T production was seen at 125 μM or higher dose
of Ni2+, while basal T production was unaffected. In order to evaluate the time dependency of this effect the cells were
cultured for various times in the presence or absence of 250 and 1000 μM Ni2+. Decreased hCG-stimulated T
production was found in the cultures maintained at least for 4 h in the presence of 1000 μM Ni2+, whereas at 250 μM at
least 16 h was required to elicit the depression. Cell viability was assessed by a metabolic activity assay. The viability
of cells was unaltered by 250 μM Ni2+, and only a slight decrease was found even at the end of the 48-h culture period
in the presence of 1000 μM Ni2+. The results showed a dose-related depression in stimulated T production of mouse
Leydig cells in culture following either in vivo or in vitro treatment at a dose that did not induce any general toxic or
significant cytotoxic action. The data of the time-course study indicate that the effect on Leydig-cell T production was
both time and concentration dependent, and not due to cytotoxicity. This study indicates that exposure to Ni can affect
testosterone production in Leydig cells but due to the use of subcutaneous dosing and limited reporting of the data, the
results are not used for the setting of NOAEL and LOAEL.
156
4.1.2.8.1.2
Developmental toxicity
No standard prenatal developmental toxicity studies with nickel sulphate were located.
A 3-generation reproduction study in Wistar rats was briefly described by Ambrose et al. (1976). Groups of 30
weanling rats per sex per group were fed 0, 250, 500, or 1000 ppm nickel as nickel sulphate hexahydrate for 11 weeks.
No food consumption data are reported but rough exposure levels of 0, 13-20, 26-40, and 52-80 mg Ni/kg bw/day can
be calculated (see 4.1.2.8.1.1). The number of mated animals, number of pregnancies, alive and dead litters, pups in
litter at 1, 5, and 21 days, and total litter weight at weaning was recorded. The F1a pups were sacrificed and necropsied
at weaning, and the parental (Po) rats were remated to produce the F1b generation. Mating of the F1b and F2b
generations was as for the parental generation (17-20 rats mated/group). A complete histopathology examination was
conducted on F3b weanlings (10/sex/group). Body weights of the F0 rats were decreased only at the high dose, with an
average decrease of 8% reported for females. The number of pups born dead was increased at all nickel doses in the F1a
generation and at 500 ppm and 1000 ppm in the F1b generation, but there was no effect on pup mortality in later
generations. There was a clear and consistent decrease averaging 27% in mean weanling body weight at 1000 ppm in all
generations. The study authors state that there was no evidence of teratogenicity, based on gross examinations, and no
histopathologic effects on the F3b generation, but present no supporting data.
Evaluation of this study is complicated by the lack of statistical analyses and the reporting of results using pups rather
than litters as the unit. Statistical analysis of the number of pups born dead show that the increased numbers at all doses
levels in F1a and at 500 and 1000 ppm in F1b is statistically significant (See Table 4.1.2.8.1.A below) . Consequently
the LOAEL in the study is set to the lowest dose level investigated, i.e. 250 ppm (13-20 mg Ni/kg bw/day).
Table 4.1.2.8.1.A: Statistical analysis of the number of pups born dead in the 3-generation reproduction
study by Ambrose et al. (1976).
F1a
F1b
Dose
Litters
Born
alive
Born
dead
0
250
500
1000
14
11
14
12
113
72
96
93
5
17*
13*
16*
Born,
total per
litter
8.4
8.1
7.8
9.1
0
14
143
3
10.4
250
16
164
6
10.6
500
14
109
27*
9.7
1000
15
93
31*
8.3
* p –values from 0.0-4.7%, Fishers exact test (rapporteur analysis)
Born
alive per
litter
8.1
6.5
6.9
7.8
Born
dead per
litter
0.4
1.5
0.9
1.3
% Born
dead per
litter
4.2%
19.1%
11.9%
14.7%
10.2
10.3
7.8
6.2
0.2
0.4
1.9
2.1
2.0%
3.5%
19.9%
25.0%
In a range-finding one-generation study in Sprague-Dawley rats, groups of 8 males and 8 female rats were given nickel
sulphate hexahydrate exposures of 0, 10, 20, 30, 50, 75 mg/kg bw/day by gavage (SLI 2000a). Dosing of F0 animals
began two weeks prior to mating and dosing of F1 offspring began on postnatal day 21. On lactation day 4, litters were
randomly culled to a maximum of 8 pups. The dosing had no effect on F0 survival, growth, gestation length or gross
necropsy findings. Evaluation of postimplantation/perinatal lethality among the offspring of treated parental rats (i.e.
number of pups conceived minus the number of live pups at birth) showed statistically significant increases at the 30,
50, and 75 mg/kg bw/day exposures. The values were also increased at the 10 and 20 mg/kg bw/day levels, however,
the difference was not statistically significant. The mean live litter size was significantly decreased at 75 mg/kg bw/day.
The number of dead offspring on lactation day 0 (stillbirth) was significantly increased in all exposure groups except
the 50 mg/kg bw/day group. The results of this range-finding study indicate a LOAEL for neonatal death of 10 mg/kg
bw/day (2.2 mg Ni/kg bw/day) and a NOAEL was not found.
Table 4.1.2.8.1.B: One-generation range-finding study (SLI, 2000a)
Dose
0
10
20
30
50
75
Postimplantation/ perinatal 0.4+0.3
lethalitya
2.6+1.9
1.6+0.6
2.3+0.8*
2.7+0.5**
4.8+0.8**
No. dead/live, day 0
12/100**
10/106**
10/92**
4/89
23/80**
1/128
157
a) meam+sem; * p< 5%; **p<1% (SLI 2000a)
In a 2-generation reproduction study compliant with the OECD 416 test guideline, nickel sulphate hexahydrate
exposure levels of 1, 2.5, 5.0, and 10 mg/kg bw/day (0.2, 0.6, 1.1 and 2.2 mg Ni/kg bw/day) were administered by
gavage to rats (SLI 2000b). The test substance was administered to F0 animals before mating and during mating,
pregnancy, and through the weaning of the first generation (F1). At weaning, the administration was continued to F1
offspring during growth into adulthood, mating and production of an F2-generation, and up until the F2-generation was
weaned. On lactation day 4, litters were randomly culled to a maximum of 8 pups. The dosing had no effects on F0 or
F1 growth and gestation length. The postimplantation/perinatal lethality until postnatal day 0 among the F1 offspring
(i.e. number of pups conceived minus the number of live pups at birth) was higher at 10 mg/kg bw/day, however, the
difference was not statistically significant (2.1 at 10 mg/kg bw/day vs. 0.9 in the control group, p = 8.6% in MannWhitney test). In F2 offspring, the value for postimplantation/perinatal lethality was similar to the F2 control value. The
authors state that the results indicate that the highest dose of 10 mg/kg bw/day (2.2 mg Ni/kg bw/day) was a NOAEL
for the developmental end points studied, including the variable of postimplantation/perinatal lethality.
Table 4.1.2.8.1.C: Two-generation study, F1 offspring (SLI, 2000b)
Dose
0
1
2.5
5
10
lethalitya, day 0
1.5+0.4
1.2+0.3
1.3+0.2
2.1+0.4
lethalitya, day 4 (%)
(7.1+1.5%)
1.2+0.2
1.2+0.3
1.4+0.2
2.3+0.4**
(8.1+1.4%)
(8.7+2.0%)
(11.0+2.2%)
(15.8+2.8%)*
a) meam+sem; * p< 5% (Rapporteur statistics); **p<1% (Sommer et al., 2002)
As perinatal lethality also occurs after the day of birth, the Danish EPA wanted to evaluate the whole time period from
implantation to perinatal day 4 as a continuum to which NIPERA agreed. For the dose group of 2.2 mg Ni/kg bw/day
the postimplantation/perinatal lethality is 2.29+0.43 (mean+sem) per litter and for the control group it is 1.00+0.22 per
litter. The statistical analysis gives a p-value of 5.8% in Mann-Whitney test.
When analysing post-implantation loss in prenatal developmental toxicity studies, this parameter is often calculated as
percentage lost per litter. A similar calculation for post-implantation/perinatal lethality until perinatal day 4 gives a
value of 7.1+1.5% (mean+sem) in the control group and 15.8+2.8% in the 2.2 mg Ni/kg bw/day group. This difference
is statistically significant in Mann-Whitney test (p = 4.4%).
The data includes several litters with no lethality (11 of 25 in the control, 8 of 28 at 2.2 mg Ni/kg bw/day) and the
distributions of data for the two groups do not seem have the same shape (Fig 1).
Although data for Mann-Whitney test are not assumed to follow a specific probability distribution, it is assumed that the
underlying populations are continuous and have the same shape. Consequently, the Mann-Whitney test may not be the
most appropriate test for the present data. Therefore, the data was also analysed by Fisher chi-square. In the control
group, 0 of 25 litters had more than 3 losses, while in the 2.2 mg Ni/kg bw/day group 8 of 28 litters (29%) had more
than 3 losses (range 4-7). The difference is statistically significant (p-value in Fisher chi-square test is 0.5%). Fisher chisquare test on the number of litters with more than 30% loss (0 of 25 in controls and 8 of 28 at 2.2 mg Ni/kg bw/day)
gives a similar result as for the number of losses above, i.e. the p-value is 0.5%.
The results in the first generation of the study were further analysed by Sommer et al. (2002) (). A slightly modified
version of this abstract is included in the present report as an annex (see Appendix 7.8). The data were analysed in a
general linear model with overdispersion and used the litter as the statistical unit. The main result shows a significant
raise in the peri-postnatal mortality rate in the group exposed to 2.2 mg Ni/kg bw/day compared to the control group (p
= 0.8%) and also when compared to the pooled data from the control group and the exposed groups 2, 3, and 4 (p =
0.04%). As the latter analysis includes values for exposed groups as control values, it may actually underestimate the
significance of the increased value for peri-postnatal loss in the group exposed to 2.2 mg Ni/kg bw/day.
Historical control group mean values for post-implantation/prenatal loss at day 0 from 8 studies range from 0.88-2.31
per litter. The value of 2.1 per litter for the group exposed to 2.2 mg Ni/kg bw/day is within this range. However, the
number of implantations and the number of live pups per litter in the historical controls are generally higher than the
values in the 2-generation study of nickel sulphate (see table below). Dams with a high ovulation may tend to show
158
higher pre-postimplantation losses to give normal litter size and therefore the historical control values for loss are not
considered as the most relevant for evaluating the loss in the 2- generation study. The concurrent control values for loss
appears relevant based on the number of implantation and consequently this value is used for evaluating the loss in the
exposed groups.
Table 4.1.2.8.1.D: Historical control values from 8 studies compared to Control group in SLI (2000b) 21year study.
Implantations per litter
Live pups per litter
Loss per litter
Historical control values (8
studies)
14.8-17.3
13.0-15.5
0.9-2.3
Control group in 2generation study
13.6
12.6
0.9
FIG 1. Post-implantation/Perinatal lethality (until day 4) in the 2-generation study
50
45
40
35
% litters
30
Control group
25
2.2 mg Ni/kg
20
15
10
5
0
11 8
0
6
6
1
5 4
3 2
2
3
1
4
3
5
3
6
1
7
Number of offspring lost per litter
In conclusion, statistical analysis using the litter as the unit of significance shows that there is a statistically significant
increase in litters with high post-implantation/perinatal lethality and in the mean percentage post-implantation/perinatal
lethality in F1 in the group dosed with 2.2 mg Ni/kg bw/day.
There was no statistically significant effect on postimplantation/perinatal lethality in F2 offspring. However, the
parental animals for this generation were selected from the F1 generation and obviously the F1 offspring that died preor postnatally are not represented. Consequently, the animals that may have had the highest sensitivity to the effect may
not have been included in the production of F2 (for further discussion related to this, see Appendix 7.9).
Based on the supplementary statistics using the litter as the statistical unit and showing that the increase in
postimplantation/perinatal lethality in F1 is statistically significant as well as the above consideration concerning the
finding of effects in F1 but not in F2, it is evaluated that the 10 mg/kg bw/day (2.2 mg Ni/kg bw/day) cannot be
regarded as a clear NOAEL. Consequently, the NOAEL is set to 5 mg/kg bw/day (1.1 mg Ni/kg bw/day) in this study.
Since the highest dose level in this 2-generation study did not induce any signs of toxicity in the F0 animals, the study
does not fulfil the OECD TG 416 guidelines concerning the dose levels used. As the results of the prior range-finding
one-generation study indicate that postimplantation/perinatal lethality is increased in the absence of maternal toxicity, it
is considered acceptable for the evaluation of developmental toxicity that the highest dose level did not induce maternal
toxicity.
According to an abstract from Morvai et al. (1982), the group has previously reported that nickel sulphate is
embryotoxic and teratogenic in mice and rats, and it is embryotoxic and induces spontaneous abortion in rabbits. These
159
studies have, however, not been located in published literature. The abstract describes a study where groups of
nonpregnant and pregnant rats were treated daily for 10 days or between the 6th and 15th days of the organogenesis
with 100 mg nickel sulphate /kg bw/day (22 mg Ni/kg bw/day) by gavage. Authors concluded that nickel caused
embryotoxic and teratogenic effects. The results reported from this study indicate that a dose level of 100 mg/kg bw/day
(22 mg Ni/kg bw/day) may cause malformations. However, the study is only reported in an abstract and the findings can
therefore not be properly evaluated.
4.1.2.8.2.1
Effects on fertility
No data are available.
4.1.2.8.2.2
A cross sectional study of female nickel hydrometallurgy workers in a Russian refinery plant reported increased rates of
congenital malformations and spontaneous abortions (Chashschin et al. 1994). The published report includes a
statement by the editors that the results are "incompletely documented and must be considered inconclusive," but are
presented '"because they identify a concern that requires investigation." No information is provided regarding the nickel
species, although the term hydrometallurgy means it was an electrolysis plant in which exposure is likely to be all, or
largely soluble nickel. The average nickel exposure levels were found to be around 0.2 mg/m3 in the electrolysis
department and 0.13 mg/m3 in the electrolyte purification department. The incidences of spontaneous abortions and
structural malformations were 15.9% (46/290) and 16.9% (60/290) in nickel-exposed women. In the control group
comprising 342 local female construction workers without any occupational exposure to nickel, the incidences recorded
for spontaneous abortions and malformations were 8.5% and 5.8%, respectively. The increased incidences of
spontaneous abortions and malformations are statistically significant (Chi-square test). However, there are limitations in
the sampling details of the pregnancies included in the study and there is no information on or control for confounders
as e.g. age, ethanol and smoking. In addition, other environmental conditions were present that may influence
reproductive outcome, including heat stress, lifting heavy anodes, and exposure to chlorine gas. Therefore, although the
study suggests increased incidences of spontaneous abortions and malformations during exposure to soluble nickel
exposure levels around 0.2 mg/m3, it is considered as inconclusive due to flaws in the study design and reporting.
A subsequent study by Vaktskjold et al. (2006) investigated genital malformations in newborns of female nickelrefinery workers using a register-based cohort study design. No negative effects on genital malformations was seen, but,
as is also stated by the authors, this result should be interpreted with caution since there were few cases in the higher
exposure groups.
4.1.2.8.3 Summary and conclusions
There is no information on effects of nickel sulphate on human reproduction. A cross sectional study of female nickel
hydrometallurgy workers in a Russian refinery plant suggesting increased incidences of spontaneous abortions and
malformations during exposure to soluble nickel exposure levels around 0.2 mg/m3 is considered as inconclusive due to
flaws in the study design and reporting.
The results from animal studies are summarised in Tables 4.1.2.8.3.A and 4.1.2.8.3.B.
Table 4.1.2.8.3.A: Summary of studies on fertility and reproductive organs
Test type/
Exposure
period
Route of
exposure
Species
Doses
NOAEL NOAEL
Parental repro
Endpoint
Reference
3-generation
diet
rat
0, 250, 500,
1000 ppm Ni
as nickel
sulphate
hexahydrate
500 ppm 1000 ppm?
(40 mg
(52-80 mg
Ni/kg
Ni/kg bw/day)
bw/day)
Fertility
Ambrose et
al. (1976)
160
Test type/
Exposure
period
Route of
exposure
Species
Doses
NOAEL NOAEL
Parental repro
Endpoint
Reference
1-generation gavage
range finding
rat
10, 20, 30,
75
50, 75 mg/kg mg/kg
bw/day
bw/day
(16.8 mg
Ni/kg
bw/day)
75 mg/kg
bw/day?
(16.8 mg Ni/kg
bw/day)
Fertility
SLI (2000a)
2-generation
gavage
rat
1, 2.5, 5, 10
mg/kg
bw/day as
nickel
sulphate
hexahydrate
10
mg/kg
bw/day
(2.2 mg
Ni/kg
bw/day)
>10 mg/kg
bw/day
(2.2 mg Ni/kg
bw/day)
Fertility and
sperm quality
SLI (2000b)
Repeated
dose, 4
months
gavage
rat
25 mg/kg
bw/day
25
mg/kg
bw/day
(5.6 mg
Ni /kg
bw/day)
< 25 mg/kg
bw/day
(5.6 mg Ni/kg
bw/day)
Sperm count
Waltschewa
et al.
(1972)*
Repeated
inhalation
dose, 6 h/day,
12 days over
16 day period
rat
1.6 mg
nickel/m3
< 1.6 mg < 1.6 mg Ni/m3 Testicular
degeneration
Ni/m3
(emaciati
on)
Repeated
dose study,
13 w
inhalation
rat, mice
0.45 mg
Ni/m3
?
0,45 mg Ni/m3
Sperm
morphology
and motility,
vaginal
cytology
Dunnick et
al. (1989),
NTP (1996a)
Single dose
or 30 days
sc
rat
6.2 mg/kg
bw/day
nickel
sulphate
?
< 6.2 mg/kg
bw/day
Reversible
sperm effects
Hoey
(1966)*
Single dose
oral
mice
28 mg Ni/kg
?
<28 mg Ni/kg
Abnormal
spermatozoa
Sobti & Gill
(1989)
30 days
dermal
rats
40, 60, 100
mg/kg
bw/day
?
40 mg/kg
bw/day
(ca. 10 mg
Ni/kg bw/day)
Testes effect
Mathur et al.
(1977)*
Benson et al.
(1988)*
* Secondary source evaluation based on UK HSE 1987, RTI 1995, IARC 1990, IPCS 1991
Table 4.1.2.8.3.B: Summary of studies on developmental toxicity
Test type
Route of
exposure
Species Doses
3-generation
diet
Rat
0, 250, 500, 1000 500 ppm (40 mg
ppm Ni as nickel Ni/kg bw/day)
sulphate
hexahydrate
< 250 ppm
Ambrose et
(13-20 mg Ni/kg
al. (1976)
bw/day)
Neonatal mortality
in F1
Rat
10, 20, 30, 50, 75 75 mg/kg bw/day
mg/kg bw/day as (16.8 mg Ni/kg
nickel sulphate
bw/day)
hexahydrate
< 10 mg/kg
SLI (2000a)
bw/day
(2.2 mg Ni/kg
bw/day)
Neonatal mortality
1-generation gavage
range-finding
NOAEL
Maternal
toxicity
NOAEL
Developmental
toxicity
Reference
161
Test type
Route of
exposure
Species Doses
NOAEL
Maternal
toxicity
NOAEL
Developmental
toxicity
2-generation
gavage
Rat
>10 mg/kg
bw/day
(2.2 mg Ni/kg
bw/day)
5 mg/kg bw/day
SLI (2000b)
(1.1 mg Ni/kg
bw/day) Peripostnatal mortality
in F1, but not F2 at
10 mg/kg bw/day
(2.2 mg Ni/kg
bw/day)
1, 2.5, 5, 10
mg/kg bw/day as
nickel sulphate
hexahydrate
Reference
Two oral multi-generation reproduction studies and a range-finding one-generation study of nickel sulphate are
available (Ambrose et al. 1976, SLI 2000a, SLI 2000b). No effects on fertility have been found in these studies
following oral administration; no data are available for inhalation and dermal contact. The study by Ambrose et al.
(1976) and the one-generation range-finding study (SLI 2000a) indicate NOAELs of 52-80 mg Ni/kg bw/day and 16.8
mg Ni/kg bw/day, respectively. However, the Ambrose et al. study has a limited reporting of data and the range-finding
study uses only a limited number of animals (8 per group). Therefore, the most reliable NOAEL is from the recent
OECD TG 416 two-generation study (SLI 2000b) where the NOAEL is the highest dose investigated, i.e. 2.2 mg Ni/kg
bw/day. This value is taken forward to the risk characterization; however, it should be considered that the NOAEL is
probably higher.
Effects on male sex organs in rats and mice have been reported in limited studies after oral, inhalation or subcutaneous
administration. These studies indicate a possible LOAEL for oral and inhalation exposure of 5.6 mg Ni/kg bw/day and
1.6 mg Ni/m3, respectively. A repeated dose toxicity study provides a NOAEL for effects on sperm and oestrus cyclicity
of 0.45 mg Ni/m3 for inhalation exposure. No effects on male sex organs including sperm quality were found in the
recent oral OECD TG 416 two-generation study (SLI 2000b) and the NOAEL is therefore the highest dose studied, i.e.
is 2.2 mg Ni/kg bw/day. The NOAELs for effects on male sex organs of 0.45 mg Ni /m3 for inhalation exposure and 2.2
mg Ni/kg bw/day for oral administration is taken forward to the risk characterization.
The highest dose level used in the recent OECD TG 416 two-generation study (SLI 2000b) was chosen based upon the
dose-response characteristics of the peri- postnatal loss previously observed in other studies, Consequently, the study
high dose did not induce any signs of toxicity in the F0 animals and does not fulfil OECD TG 416 guidelines
concerning the dose levels used. Therefore, the results of the study are not conclusive concerning the potential for
effects of nickel sulphate on fertility or sex organs at dose levels higher than 2.2 mg Ni/kg bw/day.
No standard prenatal developmental toxicity studies with Ni-sulphate via either the oral or inhalation routes were
located. The multi-generation studies and the one-generation range-finding study provide consistent evidence of
developmental toxicity (stillbirth, postimplantation/perinatal death) in rats at dose levels not causing maternal toxicity.
Based on the increased postimplantation/perinatal lethality in F1 generation in the OECD TG 416 two-generation study
(SLI 2000b) at 2.2 mg Ni /kg bw/day, the NOAEL used for developmental toxicity for regulatory purposes is set to 1.1
mg Ni/kg bw/day. This value is taken forward to the risk characterisation.
From the background document on nickel compounds it appears that studies on nickel chloride and an unspecified
nickel salt also provide evidence of increased postimplantation/perinatal lethality in rats after oral exposure. An
equivocal LOAEL of 1.33 mg Ni/kg bw/day for nickel chloride has been identified and this value is higher than the
NOAEL of 1.1 mg Ni/kg bw/day for nickel sulphate. Thus, looking across to data on other nickel compounds does not
affect the conclusion for nickel sulphate.
There is consistent evidence of developmental toxicity (stillbirth, postimplantation/perinatal lethality) in rats at dose
levels not causing maternal toxicity. The TC C&L has agreed to classify nickel sulphate as Repr. Cat. 2; R61 6.
There is a lack of standard prenatal developmental toxicity studies (OECD 414) and therefore the minimum data
requirement in the revised TGD is not fulfilled. However, the minimum data requirement in the prior TGD is more than
fulfilled as the multi-generation studies is more extensive than the OECD screening test for reproductive toxicity. Based
6
This classification is included in the Annex I entry in the 30th ATP.
162
on the findings of peri-/postnatal death in the multi-generation studies there is not considered to be urgent need for
further testing for developmental toxicity if nickel sulphate is classified in Category 2 for developmental toxicity.
The potential for effects of nickel sulphate on fertility have not been sufficiently investigated, since the highest dose
level in the recent OECD TG 416 two-generation study did not induce any signs of toxicity in the adult animals.
Therefore, to be able to draw clear conclusions regarding the potential for effects of nickel sulphate on fertility further
studies using higher dose levels would be relevant. However, there is no reason to expect that such testing would lead to
lower NOAELs than the ones already determined for fertility and developmental effects. Therefore, the results of such
testing are unlikely to influence the outcome of the risk assessment.
163
4.1.3
Risk characterisation 7
4.1.3.1 General aspects
This assessment deals with the production and use of nickel sulphate. The scenarios considered are shown in Table
4.1.3.1.A below. These cover the known production methods as well as one method that is no longer carried out in the
EU (Scenario A6). The industrial uses are all processes where nickel sulphate is used as a starting material, but where
other nickel compounds can also be used.
The only known consumer exposure to nickel sulphate is as a food supplement.
Table 4.1.3.1.A. Scenarios for the risk characterisation.
Scenario
Occupational
exposure
Consumer
exposure
Indirect
exposure
A1
Nickel sulphate production from nickel matte
yes
no
yes
A2
Nickel sulphate production from secondary nickel matte or roasted
residues
yes
no
yes
A3
yes
no
yes
A4
Nickel sulphate production from copper refining
yes
no
yes
A5
Purification of impure nickel sulphate
yes
no
yes
A6
Nickel sulphate production from metallic nickel
yes
no
yes
B1
yes
no
yes
B2
Nickel plating
yes
no
yes
B3
yes
no
yes
B4
yes
no
yes
C1
Food supplements
no
yes
no
4.1.3.1.1 Exposure assessment summary
Occupational exposure to nickel sulphate is described in chapter 4.1.1.2. Occupational exposure to nickel sulphate
occurs primarily by inhalation and by dermal exposure. Direct oral exposure is considered to be negligible and is
ignored in this risk characterisation.
Consumer exposure to nickel sulphate is described in chapter 4.1.1.3. The only known route of consumer exposure is by
oral exposure to food supplements.
The occupational exposures in the industrial production and use of nickel sulphate are summarised in Table 4.1.1.2.4.A.
The values for inhalational and dermal exposure used in the risk characterisation are shown in Tables 4.1.3.1.1.A and
4.1.3.1.1.B respectively.
4.1.3.1.1.1
Inhalational exposure.
Table 4.1.3.1.1.A: Estimated exposure to nickel sulphate by inhalation.
Scenario
7
Specia- Estimated exposure to inhalable nickel (mg/m3)
tion (1)
Full shift (8 hour time weighted average)
Short-term
Conclusion (i)
Conclusion (ii)
There is a need for further information and/or testing.
There is at present no need for further information and/or testing and no need for risk reduction measures beyond those which
are being applied already.
Conclusion (iii) There is a need for limiting the risks; risk reduction measures which are already being applied shall be taken into account.
164
A1
A2
A3
A4
A5
A6
B1
B2
B3
B4
Typical level
Worst-case level method (2) mg/m3
mg/m3
mg/m3
from nickel matte
SO
0.07
1.0
U
0.05
~0
from secondary nickel matte
and roasted residues
SO
0.07
1.0
U
0.05
~0
SO
0.07
1.0
U
0.05
~0
SO
0.018
0.15
U
0.012
~0
Purification of impure nickel SO
sulphate
U
0.07
1.0
Ana.
2.0
Exp.
SO
0.02
0.23
Meas.
0.46
Exp.
U
0.02
~0
Production of nickel metal
SO
0.040
0.7
U
0.002
~0
SO
0.018
0.4
U
0.007
~0
SO
0.004
0.25
U
0.1
4.2
Nickel plating
compounds/salts
Meas.
2.0
method (2)
Exp.
~0
Ana
2.0
Exp.
~0
Ana.
2.0
Exp.
~0
Meas.
0.3
Exp.
~0
0.05
SO
0.004-0.27
7.0
U
0.002-0.18
0
~0
Meas.
1.4
Exp.
~0
Meas.
0.8
Exp.
~0
Meas.
0.5
Exp.
8.4
3
Ana .
14
Exp.
0
2: Meas. = Estimate derived from measured data; Exp. = Expert judgement; Ana= Analogy to scenario A1.
3: Analogy to scenario for nickel metal in the production of nickel containing chemicals from the nickel metal RAR.
The estimated inhalation exposures for six of the ten processes (A1, A4, A6, B1 – B3) are based on measured data. The
typical exposure levels for nickel sulphate are based on measurements of the total nickel exposures, taking into account
available speciation information. The levels are expressed as soluble nickel and nickel species other than soluble nickel.
For the production processes described in scenarios A1 to A4 and A6, the speciation figures show that the proportion of
soluble species is about 50% of the total nickel exposure. The exposure in scenarios involving electrolysis (B1:
production of nickel metal and B2: nickel plating) the proportion of soluble nickel species is a much higher proportion
of the total nickel exposure than is the case for the production processes. In the case of nickel catalyst production, the
proportion of soluble nickel is a very small proportion of the total nickel exposure. In the case of production of nickel
compounds/salts there are rather detailed speciation data for a specific chemical plant, but it is noted that the scenario
covers an enormous range of processes. For this risk assessment, the “soluble nickel” fraction is assumed to be entirely
nickel sulphate.
For all scenarios except one, the “worst-case” and the “short-term” levels are calculated on the basis that the total nickel
exposure is regarded as exposure to nickel sulphate, i.e. these figures ignore speciation estimates. In the case of catalyst
production, (scenario B3) the proportion of soluble nickel in the exposure is very low (about 3%). In the worst-case
situation the high end of the range of soluble nickel proportions (6%) is used to estimate exposure to soluble nickel (i.e.
nickel sulphate) (see 4.1.1.2.3.3.1).
“Short-term” exposures are calculated as twice the “worst-case” full-shift exposures in all cases.
165
The typical levels are below the OEL of 0.1 mg Ni/m3 in force in most European countries 8, but the OEL is exceeded
for some processes in scenario B4. The OEL is exceeded in all “worst-case” scenarios.
As discussed in the toxicokinetics summary below, inhaled nickel particles may either be exhaled or deposited in the
respiratory tract. Absorption from retained nickel particles may either occur in the lung tissue after deposition and
release of nickel ions or lead to oral absorption, following mucociliary elimination and transportation to the
gastrointestinal tract. Werner et al. (1999b) has shown that the respirable fraction of aerosols collected in the
Kristiansand refinery is small (2 – 6.8%).
4.1.3.1.1.2
Dermal exposure.
Table 4.1.3.1.1.B: Estimated dermal exposure to nickel sulphate.
Scenario
Dermal exposure
Speciation
(1)
A1
A2
A3
A4
A5
A6
B1
B2
B3
B4
Worst-case (2)
Typical
mg/day
μg/cm2
Method (2)
mg/day
μg/cm2
Method (2)
0.8
0.4
Meas
1.4
0.7(4)
Meas
0.8
0.4
(4)
1.4
0.7(4)
0.8
0.4(4)
1.4
0.7(4)
0.8
0.4(4)
1.4
0.7(4)
0.8
0.4(4)
1.4
0.7(4)
0.8
0.4(4)
1.4
0.7(4)
0.8
0.4(4)
1.8
0.9(4)
2.0
1.0
(4)
0.37
0.44 (5)
Meas.
1.4
0.7(4)
Ana. (3)
0.8
0.4(4)
1.4
0.7(4)
0.8
0.4(4)
Nickel sulphate
production from
nickel matte
SO
U
0.4
0.2
Nickel sulphate
production from
secondary nickel
matte and roasted
residues
SO
0.8
0.4 (4)
U
0.4
0.2 (4)
Other leaching
processes
SO
0.8
0.4 (4)
U
0.4
0.2 (4)
Nickel sulphate
production from
copper refining
SO
0.8
0.4 (4)
U
0.4
0.2 (4)
Purification of
impure nickel
sulphate
SO
0.8
0.4 (4)
U
0.4
0.2(4)
Nickel sulphate
production from
metallic nickel
SO
0.8
0.4 (4)
U
0.4
0.2 (4)
metal
SO
0.6
0.3 (4)
0.2
(4)
Nickel plating
U
0.1
Ana. (3)
Ana. (3)
Ana. (3)
Ana. (3)
Meas
(5)
SO
0.027
U
0.012
Production of
catalysts
SO
0.8
0.4 (4)
U
0.4
0.2 (4)
compounds/salts
SO
0.8
0.4 (4)
U
0.4
0.2(4)
0.046
Ana. (3)
Meas.
Ana. (3)
Ana. (3)
Ana. (3)
Ana. (3)
Ana. (3)
Meas
~0
Ana. (3)
Meas
Meas
2: Meas.: Measured data. Ana: Analogy to other scenarios. The sampling strategy in measuring the dermal exposure was designed to
allow an estimation of the typical exposure in operating a given task. Thus personal protective equipment was used when required.
Workers involved in the production of nickel sulphate from nickel matte (scenario A1) wore cotton overalls and rigger type gloves.
Workers involved in the production of nickel metal from nickel sulphate (scenario B1) wore cotton overalls and coated rigger gloves.
8
In some countries the OEL is lower. In Denmark it is 0.01 mg Ni/m3, in Austria, Germany and Norway it is 0.05 mg
Ni/m3.
166
No information on the use of personal protective equipment was available for nickel plating operators (scenario B2). In the
production of nickel compounds (scenario B4) workers wore cotton overalls and rigger gloves.
3: Analogy to scenario A1 (tasks in packing nickel sulphate)
4: The exposure is given for both forearms and hands, including the fingers and back of the hands. For a man, the average mean
surface area of the forearms and hands is 1980 cm2.
5: The exposure is given for both hands, including the fingers and back of the hands. For a man, the average mean surface area of the
hands is 840 cm2
Some measured dermal exposure data is available for nickel sulphate production from nickel matte (scenario A1), for
production of nickel metal (scenario B1), for plating (scenario B2) and, for production of nickel compounds/salts
(scenario B4). The sampling strategy in measuring the dermal exposure was designed to allow estimation of the typical
exposure in operating a given task. Thus personal protective equipment was used when required. Workers involved in
the production of nickel sulphate from nickel matte (scenario A1) wore cotton overalls and rigger type gloves. Workers
involved in the production of nickel metal from nickel sulphate (scenario B1) wore cotton overalls and coated rigger
gloves. No information on the use of personal protective equipment was available for nickel-plating operators (scenario
B2). In the production of nickel compounds (scenario B4) workers wore cotton overalls and rigger gloves.
There is no measured data on dermal exposure in the other scenarios considered. The exposure levels have been
estimated by analogy to other scenarios. Based on expected similarities in the tasks performed by workers in the
production of nickel sulphate extrapolation of exposure measured for scenario A1 to other scenarios (A2-A6) of nickel
sulphate production appears prudent. For the production of catalysts (scenario B3) exposure was estimated by analogy
to measured exposure for operators in the packing of nickel sulphate hexahydrate and nickel hydroxycarbonate
(scenario A1). The handling of nickel sulphate in the production of catalysts is expected to be less intensive than in the
packing of nickel sulphate. Thus the exposure estimated by analogy is considered biased towards high levels. In the
absence of better measures for the dermal exposure in these scenarios, these estimates are used as the basis for the risk
characterisation.
The absorption by the dermal route is low (2%, see 4.1.3.1.2.1) and systemic effects from this route are not considered
to be of concern.
4.1.3.1.1.3
Oral exposure.
Occupational exposure to nickel sulphate by the direct oral route is considered to be negligible as it is assumed that this
is prevented by personal hygiene measures.
As discussed in the toxicokinetics summary below, absorbtion from inhaled nickel particles may either occur in the lung
tissue after deposition and release of nickel ions or in the gastrointestinal tract, following mucociliary elimination from
the respiratory tract and transportation to the gastrointestinal tract.
Consumers are exposed to nickel sulphate as a component of multivitamin/mineral food supplements. The dose per
tablet is often 5 μg Ni for adults (ca. 0.08 μg/kg for a 60 kg adult), but tablets with up to 100 μg Ni for adults (ca. 1.7
μg/kg for a 60 kg adult) have been reported. Tablets for children may contain 1 μg Ni (ca. 0.08 μg/kg for a 12 kg
toddler). The recommended dose for many of these mineral supplements is 1 tablet per day.
4.1.3.1.2 Effects assessment summary.
The endpoints and the NOAELs/LOAELs used in this risk characterisation are shown in Table 4.1.3.1.2.A below. This
data is taken from studies on nickel sulphate rather than based on extrapolation from data from other nickel compounds.
Table 4.1.3.1.2.A: Summary of effects.
Toxicological endpoint
Inhalation
(or respiratory tract)
Dermal
(or eye)
Oral
Acute toxicity
No data for single
exposure.
No data: acute toxicity
considered to be low.
LD50=61 mg Ni/kg bw
Harmful by inhalation
based on oral acute data,
toxico kinetic
considerations and
repeated exposure study
Xn; R22
167
(16 days inhalation study):
Xn; R20
LOAEC: 0.7 mg/m3
Irritation / corrosivity
Inconclusive with regard
to respiratory tract
irritation
Skin irritant, Xi; R38
Specific concentration
limit of 20% for R38
Not classified as an eye
irritant
Sensitisation
Respiratory sensitiser:
R42
Skin sensitiser: R43
limit of 0.01% for R43.
Empirical elicitation
threshold 0.3 µg/cm2
Elicitation:
LOAEL (oral challenge) =
0.012 mg Ni/kg bw
Empirical sensitisation
threshold 0.3 µg/cm2
Repeated dose toxicity
T; R48/23
limit of 1% for T; R48/23
LOAEC = 0.056 mg
Ni/m3 (lung inflammation,
fibrosis)
Not possible to
determine.
Not of concern due to
low absorption
LOAEL = 6.7 mg Ni/kg
bw/day (decreased survival
rate (females), reduced
body weight gain (both
sexes)) NOAEL = 2.2 mg
Ni/kg bw/day (however,
associated with a slight
decrease in body weight
gain (both sexes) and
survival in females)
Mutagenicity
Muta. Cat. 3; R68.
Carcinogenicity
Carc. Cat. 1; R49
-
-
Fertility impairment
No data
Calculated NOAEC:
0.55 mg/m3
No data.
low absorption
No LOAEL
NOAEL = 2.2 mg Ni/kg
bw/day
Effects on male sex organs
LOAEC = 5.6 mg Ni/m3
NOAEC = 0.45 mg Ni/m3
No data.
low absorption
bw/day
bw/day
Repr. Cat. 2; R61
No data.
low absorption
bw/day
bw/day
No data
Calculated NOAEC:
0.277 mg/m3
4.1.3.1.2.1
Toxicokinetics.
The toxicokinetics of nickel sulphate have been investigated after inhalation, intratracheal instillation, oral
administration, and dermal application.
The absorption of nickel following inhalation of nickel sulphate may be as high as 97-99%; it should be noted that the
fraction absorbed apparently depends on the concentration of the nickel compound in the inhaled air as well as on the
duration of exposure. A value of 100% is used for the absorbed fraction of nickel from the respiratory tract following
exposure by inhalation of nickel sulphate for particulates with an aerodynamic diameter below 5 µm (respirable
fraction). For nickel particulates with aerodynamic diameters above 5 µm (non-respirable fraction), the absorption of
nickel from the respiratory tract is considered to be negligible as these particles predominantly will be cleared from the
respiratory tract by mucociliary action and translocated into the gastrointestinal tract and absorbed. Hence, for the nonrespirable fraction, 100% clearance from the respiratory tract by mucociliary action and translocation into the
gastrointestinal tract is assumed and the oral absorption figures can be taken.
168
A value of 30% is used for the absorbed fraction of nickel from the gastrointestinal tract following oral exposure to
nickel sulphate in the exposure scenarios where fasting individuals might be exposed to nickel sulphate. In all the other
exposure scenarios, a value of 5% is used for the absorbed fraction of nickel from the gastrointestinal tract.
Absorption of nickel following dermal contact to various nickel compounds can take place to a limited extent, with a
large part of the applied dose remaining on the skin surface or in the stratum corneum. A value of 2% is taken as the
absorbed fraction of nickel following dermal contact to nickel sulphate.
Generally, nickel tends to deposit in the lungs of workers occupationally exposed to nickel compounds and in
experimental animals following inhalation or intratracheal instillation of nickel compounds. The tissue distribution of
nickel in experimental animals does not appear to depend significantly on the route of exposure (inhalation/intratracheal
instillation or oral administration) although some differences have been observed. Low levels of accumulation in tissues
are observed (generally below 1 ppm). A primary site of elevated tissue levels is the kidney. In addition, elevated
concentrations of nickel are often found in the lung, also after oral dosing, and in the liver. Elevated nickel levels are less
often found in other tissues. Limited information exists on tissue distribution in humans.
Absorbed nickel is excreted in the urine, regardless of the route of exposure. Most ingested nickel is excreted in the
faeces due to the relatively low gastrointestinal absorption. In humans, nickel excreted in the urine following oral intake
of nickel sulphate accounts for 20-30% of the dose administered in drinking water to fasting subjects compared with 15% when administered together with food or in close proximity to a meal. From biological monitoring in small groups
of electroplaters exposed to nickel sulphate and nickel chloride, the half-life for urinary elimination of nickel has been
estimated to range from 17 to 39 hours.
Inhaled nickel particles can be eliminated from the respiratory tract either by exhalation, by absorption in the respiratory
tract, or by removal due to mucociliary elimination.
4.1.3.1.2.2
Acute toxicity
An LD50 for acute oral toxicity of 61 mg Ni/kg (275 mg NiSO4.6H2O/kg) is used for this risk characterisation. Nickel
sulphate is classified as Xn; R22.
No data for acute inhalational toxicity has been found. Considering the acute oral toxicity of the substance and the
potential for absorption via the respiratory tract and observed lethality in a 16-days inhalational study, nickel sulphate is
classified as Xn; R20.
For the purpose of this risk characterisation, the LOAEC for local effects in the respiratory tract of 0.7 mg Ni/m3 from
the 16-day repeated dose toxicity study by NTP (1996a) is used. The use of this LOAEC is considered to be a
conservative approach, since greater toxicity is expected from repeated exposure (12 exposures during 16 days)
compared to a single 4h exposure as in the Annex V test.
There is no data for acute dermal toxicity. There is no concern for systemic effects from the dermal route of exposure,
due to poor absorption by this route.
4.1.3.1.2.3
Irritation/corrosivity.
Nickel sulphate is classified as Xi; R38 with a specific concentration limit of 20% on the basis of human data.
The animal data for nickel sulphate do not support classification for eye irritation.
There is a concern for respiratory irritation, even though the available data do not allow a conclusion on this effect. This
concern is however considered to be more appropriately covered by the risk assessment for repeated dose effects.
4.1.3.1.2.4
Sensitisation
There are two effects of relevance for the risk characterisation: the induction of nickel allergy in non-sensitive people,
and the elicitation of allergic reactions in people already sensitive to nickel.
Nickel sulphate is a skin and respiratory sensitiser in humans, and is classified as R42/43 with specific concentration
limits of 0.01% for R43.
169
In sensitised subjects, patch tests with nickel sulphate may elicit a positive response at low concentrations. On the basis
of the available data it is not possible to set a scientifically based threshold (NOEL) for elicitation or sensitisation in
nickel-sensitised individuals. Based on data from Uter et al. (1995) an empirical threshold for elicitation and
sensitisation of 0.3 µg/cm2 is used in the quantitative risk characterisation. If the exposure is not under occlusion, the
potential risk of elicitation of an allergic response may be less.
It is not possible to establish a NOAEL for oral challenge in patients with nickel dermatitis. The LOAEL established
after provocation of patients with empty stomach is 12µg/kg body weight (Nielsen et al. 1999). It should be noted that
this dose is the acute LOAEL in fasting patients on a 48h diet with reduced nickel content. A LOAEL after repeated
exposure may be lower and a LOAEL in non-fasting patients is probably higher because of reduced absorption of nickel
ions when mixed in food.
4.1.3.1.2.5
Repeated dose toxicity.
The type of toxicity caused by repeated exposure to nickel sulphate depends on the route of exposure. The target organ
for non-cancer effects of inhalation exposure to nickel sulphate is the respiratory tract, with effects seen in both the
lungs and the nose. For oral exposure, the most sensitive target is the kidney, specifically decreased glomerular
function. For the dermal route, general toxicity has not been determined.
When nickel sulphate is inhaled, the main target is the respiratory system, where serious effects are induced in the form
of chronic inflammation and fibrosis. The most sensitive study was the 2-year rat study by NTP. Nickel sulphate is
classified as T; R48/23 with a specific concentration limit of 1% for T; R48/23. The data from this study do not allow
identification of a clear NOAEC, due to the difficulties with a definitive interpretation of the biological significance of
the observed effects at the lowest exposure level (0.027 mg Ni/m3). Therefore, a LOAEC of 0.056 mg Ni/m3 (0.25 mg
nickel sulphate hexahydrate/m3) for lung inflammation and fibrosis is used in the risk characterisation. It should be
noted that data indicates that adverse effects possibly occur at lower levels.
CSTEE (2001) notes that soluble nickel species rather than other nickel species are “key contributors to the non-cancer
respiratory effects of nickel compounds” (CSTEE, 2001). Some exposure scenarios include cases where all the nickel is
assumed to be to soluble nickel salts (rather than other nickel species). This assumption is likely to overestimate the
possible effect.
Following oral administration, the 2-year NOAEL for nickel sulphate hexahydrate given by gavage in an OECD 451
study was 2.2 mg Ni/kg bw/day (CRL, 2005). This value is used in the risk characterisation, although uncertainties
remain whether this actually should be considered as a NOAEL as reduced body weight gain (both sexes) and increased
mortality (females) occurred to a statistically non-significant extent. The LOAEL seen in this study was 6.7 mg Ni/kg
bw/day based on reduced body weight and increased mortality. A LOAEL of 11 mg Ni/kg bw/day based on body
weight reduction (4%) and increased relative organ weights was seen in the Obone et al. (1999) study. Other studies
have shown similar LOAELs. The SLI (2002) 90-day study, using gavage, showed 8% body weight reduction at 7-11
mg Ni/kg bw/day. Vyskocil et al. (1994b), showed increased urinary albumin at 7.6 mg Ni/kg bw/day in a 3-6-month
drinking water study.
Whilst there are dermal studies, it was not possible to determine a NOAEL/LOAEL for this route based on the available
information. There is, however, no concern for systemic effects from the dermal route of exposure due to the low
absorption.
4.1.3.1.2.6
Mutagenicity
There is evidence indicating that nickel sulphate is genotoxic in vitro. The study by Benson et al. (2002) is the most
comprehensive part of the database on in vivo genotoxicity of nickel compounds and shows that nickel sulphate shows
genotoxicity in lung cells after inhalation. There is little direct evidence concerning hereditable effects on germ cells.
Nickel sulphate is classified as Muta. Cat. 3; R68 on the basis of the Specialised Experts’ conclusion. This conclusion
was based on evidence of in vivo genotoxicity in somatic cells, after systemic exposure, and hence the possibility that
the germ cells are affected cannot be excluded.
As there is concern for the genotoxic effects of nickel sulphate in somatic cells following inhalation, the carcinogenicity
risk characterisation is carried out using a non-threshold approach (see below).
170
There are remaining uncertainties with regard to mutagenicity for nickel sulphate for effects on germ cells, but the
Specialised Experts did not consider that further testing was practicable. Further information is not considered likely to
have an impact on the risk reduction measures and thereby the regulation of the substance. As a result, further studies
are not required at this time. This can be expressed as a conclusion (i) “on hold”.
4.1.3.1.2.7
Carcinogenicity.
Nickel sulphate is classified as Carc. Cat. 1; R49 on the basis of the Specialised Experts’ conclusion that nickel sulphate
should be considered as human carcinogens. The data was considered to be sufficient to establish a causal association
between the human exposure to the substances and the development of lung cancer. There was supporting evidence for
this conclusion from more limited data on nasal cancer.
As nickel sulphate is also classified as Muta. Cat. 3; R68, the risk characterisation is carried out using a non-threshold
approach.
A unit risk for cancer following inhalation has been calculated by a number of bodies.
The US EPA has estimated the lifetime cancer risk from exposure to nickel refinery dust as 2.4 x 10-4 / μg/m3, the
midpoint of a range from 1.1 x 10 –5 to 4.6 x 10 –4 / μg/m3 (US EPA, 1991a). The US EPA has also estimated the
lifetime cancer risk from exposure to nickel subsulfide. Since nickel subsulfide is a major component of nickel refinery
dust and has been shown to produce the highest incidence of tumours for nickel compounds in animals (supported by in
vitro studies), the incremental unit risk estimate of nickel refinery dust [2.4x10-4 / μg/m3] may be used with a
multiplication factor of 2 to account for the roughly 50% nickel subsulfide composition. An inhalation unit risk of
4.8x10-4 / μg/m3 (Range 2.2x10-5 – 9.2x10-4) was thus obtained for nickel subsulfide (US EPA, 1991b).
WHO (1999) has made an estimate of unit risk on the basis of the report of lung cancer in workers first employed
between 1968 and 1972 and followed through 1987 in Norway. Using the estimated risk of 1.9 for this group and an
exposure of 2.5 mg/m3, a lifetime exposure of 155 μg/m3 and a unit risk of 3.8x10-4 / μg/m3 were calculated. This figure
is the estimate accepted by the CSTEE in their opinion on the Commission Ambient Air Position Paper (CSTEE, 2001).
The Centre dÉtude sur lÉvaluation de la Protection dans le domaine Nucléaire (CEPN) performed a risk assessment
for nickel based upon respiratory cancer in humans and animals using a linear non-threshold approach (Lepicard et al.,
1997). The epidemiological studies of occupational exposure led to a unit risk estimate of 2.5 x 10 -4 / µg/m³. To
account for the physical and chemical exposure differences between nickel refinery workers and the general population,
adjustments were made to this value using the results of animal studies. In the view of the CEPN authors, this permitted
to distinguish between nickel oxide and nickel subsulfide. They derived unit risk estimates for lung cancer of 4.0 x 10 -5
/ µg/m³ for nickel oxide and 3.0 x 10 -4 / µg/m³ for nickel subsulfide (quoted from European Commission, 2000).
The Canadian Health Authorities (CEPA, 1994) estimate exposure in relevant environmental media is compared to
quantitative estimates of cancer potency, expressed as the concentration or dose that induces a 5% increase in the
incidence of or mortality due to relevant tumours (TD0.05, i.e. exposure/potency indices) to characterize risk. The
estimates of the TD0.05 for inhaled "oxidic", "sulphidic", and "soluble" nickel (combined) for lung cancer mortality
ranged from 0.04 to 1.0 mg/m3 [mean 0.33 mg/m3]. The TD0.05 for lung cancer mortality for "soluble" nickel, estimated
based on data for the Falconbridge cohort, was also within this range of values (i.e., 0.07 mg/m3).
The lifetime dose that theoretically will cause cancer in 25% of the exposed population (HT 25) can also be calculated
from the unit risk estimates shown above (Sanner et al., 2001, Sanner, 2002). The dose from 1 μg/m3 continuous daily
exposure is 1 μg/m3 x 20 m3/day x (1/70 kg) = 0.286 μg/kg/day. The risk estimate range is then divided by this dose, to
generate an oral slope factor in units of inverse dose.
Table 4.1.3.1.2.B: Calculated HT25 estimates (Sanner, 2002).
Source of estimate
Estimate
US EPA, refinery dust; midpoint
2.4 x 10 –4 / μg/m3
US EPA, nickel subsulfide; high
–4
9.2 x 10 / μg/m
78
WHO unit risk
3.8 x 10 –4/ μg/m3
188
HT 25 (μg/kg/day)
3
298
171
CEPN
2.5 x 10 –4/ μg/m3
286
CEPA data (TD0.05)
0.33 mg/m3
470
3
100
Falconbridge (TD0.05)
0.07 mg/m
Nickel oxide (NTP, 1996b)
484
Nickel subsulphide (NTP, 1996c)
53
1) The details of these calculations by Sanner (2002) are not included here.
The risk characterisation is based on the WHO unit risk estimate. This figure is the estimate accepted by the CSTEE in
their opinion on the Commission Ambient Air Position Paper (CSTEE, 2001) The exposures that resulted in the
increased lung cancer frequencies that were used as basis for the epidemiological studies represent complex mixtures of
different nickel species that may have varied from study to study as well as within a study. From these studies it is not
possible to identify the risk of the individual nickel species. The risk estimation is therefore based on the estimated total
exposure to nickel species. It is apparent that the HT25 data presented above differ by a factor of about 9 and that the
WHO risk estimate used is close to the average of the numbers presented. Thus, if the complex mixtures representing
the exposure scenarios are similar to those in the epidemiological studies and the dose response is linear also at low
doses, the actual lifetime cancer risk does probably not differ from the calculated risk by a factor of more than 3
(Sanner, 2002).
The risk characterisation shown below is based on the HT25 dose descriptor for humans based on epidemiological
studies (Sanner, 2002). The figure used is taken from the figure in WHO (1999) and is 188 μg/kg/day
The lifetime increased cancer risk at a workplace exposure level of 1 mg/m3 is equal to 95 x 10-3. A workplace exposure
of 1 mg/m3 corresponds to 200 μg/kg/day assuming a bodyweight of 70 kg and that a worker is breathing 13.9 m3
during the working day. The exposure has to be divided with 2.8 if the exposure is distributed over the whole lifetime
and not only during 5 days a week and 48 weeks a year and a working period of 40 years (7/5 x 52/48 x 75/40 = 2.8).
Exposure level 1mg/m3 :
Occupational lifetime increased cancer risk level:
1 mg/m3 x 13.9 m3/day x (1 / 70 kg)
(200 / 2.8) / (188 / 0.25)
= 200 μg/kg bw/day
= 95x10-3.
Whilst this calculation is based on the HT25 values shown earlier, the estimate does not presume an internal dose and
the figure for the lifetime increased cancer risk at an exposure level of 1 mg/m3 of 95 x 10-3, is based directly on the
WHO unit risk estimate corrected for the difference between continuous and workplace exposures.
The exposures in most scenarios involve varying degrees of mixed exposure to soluble nickel compounds (i.e. nickel
sulphate) and other nickel species. Several of the scenarios relate to refineries, and hence the exposure scenario is
similar to the exposures on which the lifetime increased cancer risk levels are based.
Since the effects seen are therefore due to the total nickel exposure rather than to the soluble nickel alone, the lifetime
increased cancer risk level is based on the total nickel levels rather than the soluble nickel levels alone.
In the other risk characterisations, the “worst-case” exposure has ignored speciation evidence and attributed the whole
of the estimated “total” nickel to “soluble” nickel, (i.e. nickel sulphate). Since the basis for the calculation reflects a
mixed exposure the lifetime increased cancer risk is calculated assuming the same speciation as for the “typical”
exposure scenario.
Short-term exposure is not considered relevant in this assessment. Worst-case exposure is also ignored, as this exposure
level does not reflect levels of lifetime exposure.
The methodology for the calculation is generally accepted and based on the WHO figure for the cancer risk. This figure
is in turn based on epidemiology data gathered mostly under exposure conditions similar to many of those considered
here.
The estimate is based on exposure to a mixture of nickel species. In the Ambient Air Position Paper (European
Commission, 2000) Industry argued that the WHO estimate is based mainly on the nickel subsulfide exposure. The
carcinogenic potential of nickel subsulfide is at least an order of magnitude higher than that of nickel oxide (i.e. NTP
172
data). Hence, the occupational cancer risk of nickel based on a linear extrapolation should be modified when applied to
ambient air (European Commission, 2000). The figures shown in Table 4.1.3.1.2.B indicate that the differences between
the different estimates are fairly small. In particular the HT25 of 100 μg/kg bw/day calculated from the TD0.05 for lung
cancer mortality for "soluble" nickel, estimated based on data for the Falconbridge cohort is less than a factor 2 below
the WHO estimate of 188 μg/kg bw/day. The Rapporteur does not consider that the differences in exposure evaluated
here are such as to invalidate the use of the WHO estimate.
The OEL in EU Member States for soluble nickel ranges from 0.01 to 0.1 mg/m3 as nickel (see Table 2.4.A). These
levels correspond to increased lifetime cancer risk of 1 and 10 x 10-3 respectively. However, as the OEL values are
based on other factors than strictly health based issues (e.g. technical and economical considerations), these values
cannot be used as an indicator of concern in the scenarios.
In the Ambient Air Position paper (European Commission, 2000) Industry argued that threshold-based carcinogenesis
should be considered. They suggest that a threshold-based extrapolation shows a threshold as occurring between 600
and 1100 ng Ni/m3. The threshold levels suggested by Industry of 0.001 mg/m3 or less are still substantially lower than
the estimated exposures seen in the different scenarios.
Additional arguments have been put forward by NiPERA (2002). Basing their calculations on the results of the NTP
studies, after adjusting for particle size and deposition/clearance differences between animals and humans, the highest
concentration to which rats were exposed in the NTP bioassay (0.1 mg Ni/m3 MMAD 2.2 um) is equivalent to 2-3 mg
Ni/m3 of workplace dust (“inhalable fraction” size particles) (Hsieh et al., 1999; Yu et al., 1998; Yu et al., 2001). Based
on these models, the differences in exposure levels between animals and humans cannot explain why rats exposed to
nickel sulphate hexahydrate did not get tumours in the NTP study while workers exposed to mixtures of nickel
compounds (containing nickel sulphate) did in the epidemiological studies. Still, if the rat data were relevant for
humans, a workplace exposure above 0.1-0.2 mg Ni/m3 may induce sufficient respiratory tract inflammation that could
enhance the tumourigenicity of inhalation carcinogens such as sulphidic or oxidic nickel, acid mists, soluble cobalt
compounds, or cigarette smoke (NiPERA, 2002). However, the present knowledge of the mechanisms and the exposure
levels of water-soluble nickel that lead to the carcinogenic effect is incomplete.
An oral (gavage) OECD 451 carcinogenicity study with rats did not show any carcinogenic potential of exposure to
nickel sulphate. There is no concern for carcinogenicity by the oral route of exposure (conclusion (ii)).
The available data concerning dermal exposure are too limited for an evaluation of the carcinogenic potential in
experimental animals following dermal contact to nickel sulphate. However, as oral exposure to nickel sulphate does
not show any carcinogenic potential, there are good reasons to assume that cancer is not a relevant end-point with
respect to dermal exposure either (conclusion (ii)).
4.1.3.1.2.8
Reproductive toxicity.
No effects on fertility have been seen in animal studies following oral administration; no data are available for
inhalation and dermal contact. The most reliable NOAEL for effects on fertility is from the recent OECD TG 416 twogeneration oral study in rats (SLI 2000b) where the NOAEL is the highest dose investigated, i.e. 2.2 mg Ni/kg bw/day
given by gavage. This value is used in the risk characterization although it is recognised that the NOAEL is probably
higher. A NOAEC for fertility can be calculated from this oral NOAEL. The equivalent inhalational concentration in
mg/m3 is calculated from the oral dose in mg/kg bw/day as follows:
2.2 mg/kg bw/day x absorbtion (5 %)/ 100 = an internal dose of 0.11 mg/kg bw/day.
On the basis of a 70 kg adult carrying out “light work” with a respiratory volume of 13.9 m3 / 8 hr working day, and
100% absorbtion following inhalation, the equivalent air concentration is calculated from
0.11 mg/kg bw/day x 70 kg / 13.9 m3 = 0.55 mg Ni /m3.
Additional data on the effects on male sex organs in rats and mice have been reported in other studies after oral,
inhalation or subcutaneous administration. These studies indicate a LOAEL/LOAEC for oral and inhalation exposure of
5.6 mg Ni/kg bw/day and 1.6 mg Ni/m3 respectively. However, the data are limited and only indicate a possible effect.
173
A repeated dose inhalational toxicity study provides a NOAEC for effects on sperm and oestrus cyclicity of 0.45 mg
Ni/m3. This is comparable to the value of 0.55 mg Ni /m3 calculated from the oral NOAEL for fertility.
No effects on male sex organs including sperm quality were found in the recent oral OECD TG 416 two-generation
study (SLI 2000b) and the NOAEL is therefore the highest dose studied, i.e. is 2.2 mg Ni/kg bw/day.
Nickel sulphate is classified as Repr. Cat. 2; R61, as the multi-generation studies and the one-generation range-finding
study provide consistent evidence of developmental toxicity (stillbirth, postimplantation/perinatal death) in rats at dose
levels not causing maternal toxicity. Based on the increased postimplantation/perinatal lethality in F1 generation in the
OECD TG 416 two-generation study (SLI 2000b) at 2.2 mg Ni/kg bw/day, the NOAEL used for risk characterisation is
1.1 mg Ni/kg bw/day.
No comparable data are available following inhalational exposure. The equivalent inhalational concentration in mg/m3
is calculated from the oral dose in mg/kg bw/day as shown above. The calculated NOAEC is 0.277 mg Ni /m3. This
NOAEC, calculated from the oral NOAEL, is used to calculate the MOS in comparison with the inhalational exposure
estimates.
4.1.3.1.2.9
Groups of particular concern.
The main group of people where there is particular concern are those who are already nickel-sensitive. Much of the
nickel allergy on the general population is due to prolonged and close contact with nickel-releasing metal objects. EU
legislation has come into force that is intended to prevent future exposure to this type of objects leading to nickel
allergy. Experience in Denmark suggests that this legislation may well be largely effective in preventing further cases of
nickel allergy. There are however already a substantial proportion of the general population who are already nickelsensitive, and this is a group especially at risk from both dermal and oral exposure to nickel.
No genetic variations that influence adverse reactions to nickel have been identified (UK EGVM, 2003).
There is no data on which to judge whether children are a group that is particularly sensitive to the adverse effects of
nickel.
4.1.3.1.2.10
Completeness of the database.
There is relevant data on which to evaluate the effects of nickel sulphate for almost all endpoints. However, there are a
number of data gaps.
There is no data on acute inhalational toxicity, but further testing is not considered relevant as this effect can be
adequately assessed using other data from repeated dose studies.
There is no basis on which to evaluate threshold values for respiratory sensitisation; however, further testing is unlikely
to provide data that would have any impact on relevant risk reduction measures.
There are remaining uncertainties with regard to mutagenicity of nickel sulphate for effects on germ cells, but the
Specialised Experts did not consider that further testing was practicable. Further information is not considered likely to
have an impact on the risk reduction measures and thereby the regulation of the substance. As a result, further studies
are not required at this time.
There is a lack of standard pre-natal developmental toxicity studies (OECD 414). There is no need for further testing as
nickel sulphate is classified in Category 2 for developmental toxicity. Nor has the potential for effects of nickel sulphate
on fertility been sufficiently investigated, since the highest dose level in the recent OECD TG 416 two-generation study
did not induce any signs of toxicity in the adult animals. There is no reason to expect that further testing with higher
dose levels would lead to lower NOAELs than the ones already determined for fertility and developmental effects and
therefore, the results of such testing are unlikely to influence the outcome of the risk assessment.
No additional toxicology studies are considered necessary for this risk assessment at the present time.
4.1.3.2 Risk characterisation for Occupational exposure.
Occupational exposure to nickel sulphate may occur by inhalation of aerosols containing nickel sulphate or by skin
contact.
174
Occupational exposure to nickel sulphate directly by the oral route is considered to be negligible as it is assumed that
this is prevented by personal hygiene measures. Some of the nickel sulphate inhaled and deposited in the respiratory
tract can be eliminated by mucociliary action and transported to the gastrointestinal tract (mainly the larger particles).
There is little data on which to base estimates for the exposure to nickel via this latter route. Therefore an assumption of
100 % absorption of inhaled nickel particles from the respiratory tract is assumed. This is considered a conservative
approach.
When a N(L)OAEC from an inhalational animal experimental study is used as a starting point for comparison with a
human inhalation exposure scenario, possible differences in the particle size distribution between the animal experiment
and the human scenario need to be considered. The controlled exposure used for animal exposure typically consists of a
rather uniform particle size distribution in the region of respirable particle sizes while also coarser particles are part of
the occupational exposure, typically measured as total or inhalable dust. Thus the exposure levels from the different
exposure situations may not be quite comparable with respect to the respirable fractions.
Particles in the respirable size are to a greater extent deposited in the lung and subjected to pulmonary absorption than
larger particles that are deposited in the upper respiratory tract. Therefore, considering the inhalable occupational
exposures as if they were of respirable size would tend to overestimate the pulmonary exposure and the risk to the
workers with respect to pulmonary toxicity.
On the other hand, when evaluating the risk for pulmonary toxicity it should also be kept in mind that recent models
concerning lung deposition of particles show that a considerable higher pulmonary deposition of respirable particles
occur in humans compared to rats (Netherlands RIVM 2002). This aspect would then cause an underestimation of the
risk to workers when extrapolation to humans is made from inhalation toxicity studies with rats.
More specific data regarding particle sizes in the occupational exposure would reduce the first point of this problem as
more precise estimation of the respirable fraction could be made. However, based on the available data on the
occupational exposure it has not been possible for the rapporteur to make estimations regarding respiratory fractions for
the occupational scenarios and therefore the issue regarding differences in particle size distribution can only be
addressed in a qualitative manner in the risk characterisation.
The risk characterisation for occupational exposure to nickel sulphate is shown for each of the relevant toxicological
endpoints. The exposure estimates which are used for this risk characterisation are shown in Table 4.1.3.1.1.A and
4.1.3.1.1.B.
The data for the different effects is summarised in Table 4.1.3.1.2.A. There is some inhalation data available for all
relevant endpoints except fertility and developmental toxicity. For fertility and developmental toxicity, a NOAEC has
been calculated from the oral NOAEL for these effects. There is little data related to dermal exposure, but there is no
concern for systemic effects following this route of exposure.
4.1.3.2.1 Acute toxicity
4.1.3.2.1.1
Acute inhalational toxicity.
The risk characterisation for acute inhalational toxicity from the estimated short term exposures presented in table
4.1.1.2.4.A is based on the LOAEC of 0.7 mg Ni/m3 for reduced body weight and adverse effects in the respiratory tract
(atrophy and inflammation) in the 16-day repeated dose toxicity rat study by NTP (1996).
Table 4.1.3.2.1.A: Occupational risk assessment for acute inhalational toxicity.
Scenario
Short term 1)
mg Ni/m3
MOS 2) Conclusion
A1 Nickel sulphate production from nickel matte
2.0
0,35
iii
A2 Nickel sulphate production from secondary nickel matte or roasted residues
2.0
0.35
iii
A3 Other leaching processes
2.0
0.35
iii
A4 Nickel sulphate production from copper refining
0.3
2.3
iii
175
A5 Purification of impure nickel sulphate
2.0
0.35
iii
A6 Nickel sulphate production from metallic nickel
0.46
1.5
iii
B1
1.4
0.5
iii
B2
Nickel plating
00.8
0.88
iii
B3
0.5
1.4
iii
B4
14
0.05
iii
1): Estimated short-term exposure to inhalable soluble nickel considered to be all nickel sulphate (worst-case) (from Table
4.1.1.2.4.A)
2): Based on a LOAEC of 0.7 mg Ni/m3 from a 16 day rat study (from Table 4.1.3.1.2.A).
The MOS is estimated on the basis of the calculated short-term exposures (see 4.1.3.1.1). These are estimated a) on the
basis of twice the estimate of the “worst-case” full-shift exposure (normally measured) and b) an assumption (in most
cases) that the whole of the nickel exposure is due to soluble nickel. This is considered to be a conservative approach,
since at least some of the exposure will be due to less toxic nickel species.
Other aspects to be considered in relation to the MOS value is inter- and intraspecies differences in susceptibility and
the use of a LOAEC value for rather severe effects (inflammation, epithelia cell degeneration and atrophy) instead of a
NOAEC value. However, a LOAEC from a repeated toxicity study is used and greater toxicity is to be expected from
repeated exposure (12 exposures during 16 days) compared to a single 4h exposure as in the Annex V test. Therefore
the use of a repeated dose study as a basis for the risk characterisation for acute effects is considered conservative.
For interspecies differences for local effects an assessment factor of 3 is considered appropriate while an assessment
factor of 5 is used for intraspecies differences in worker populations. Furthermore, a factor of 3 is used for LOAEC to
NOAEC extrapolation. An overall assessment factor of 3 x 5 x 3 = 45 is however to a certain extent counterbalanced by
the above mentioned conservative assumptions with regard to exposure and with regard to the use of a LOAEC from a
repeated toxicity study and not an acute study. All together an overall assessment factor of 5 seems appropriate and a
MOS < 5 is considered of concern with respect to occupational acute exposure.
Conclusion (iii) applies to all scenarios.
4.1.3.2.1.2
Acute dermal toxicity.
There is no concern for systemic effects following this route of exposure (conclusion (ii)).
4.1.3.2.2 Irritation and corrosivity
There is agreement to classify nickel sulphate as a skin irritant at concentrations > 20%. There is concern for this effect
for exposures to solid nickel sulphate and nickel sulphate in concentrations > 20%. However, uninhibited contact with
these compounds is of concern. Personal protective equipment, properly selected and worn, will significantly reduce
exposure. As classification for this effect will lead to appropriate risk reduction measures, conclusion (ii) applies to all
workplace situations.
Nickel sulphate does not cause eye irritation in an Annex V animal study, and there is agreement not to classify the
substance for eye irritation: conclusion (ii) applies to all workplace situations.
There is concern for respiratory irritation, as acute effects in the respiratory tract to some degree may be the
consequence of respiratory irritation. However, these concerns are better addressed under repeated dose toxicity,
requiring the use of appropriate protective equipment.
4.1.3.2.3 Sensitisation
Nickel sulphate is a skin and respiratory sensitiser in humans and a skin sensitiser in experimental animals, and is
classified as R42 and R43.
176
4.1.3.2.3.1
Skin
Based on patch test data from Uter et al. (1995) an empirical threshold for elicitation and sensitisation of 0.3 µg/cm2 has
been defined. This effect concentration can be used as a starting point for a quantitative risk characterisation for the
working population. The 0.3 µg/cm2 comes from patch test studies with nickel sulphate under occlusion for 48 hours.
Using this figure for risk evaluation of occupational exposure that is at most semi occluded (e.g. inside gloves) for 8
hours per day represents a worst-case scenario.
Scenario B2 (nickel plating) has the lowest typical dermal exposure of 0.039 mg/day for exposure to soluble and other
nickel compounds. This estimate is derived from measured data. This corresponds to 0.046 μg/cm2/day. Approximately
70% of this exposure is to soluble nickel. Thus the exposure is 0.033 μg/cm2 (soluble nickel) and 0.011 μg/cm2
(insoluble nickel). Scenario A1 (nickel sulphate production from nickel matte) has the highest typical dermal exposure
of 1.2 mg/day for exposure to soluble and other nickel compounds. This estimate is also derived from measured data.
This corresponds to 0.4 μg/cm2 (soluble nickel) and 0.2 μg/cm2 (insoluble nickel). For typical exposure to soluble
nickel the MOS values for the two scenarios are between 0.8 (scenario A1) and 10 (scenario B2). The MOS values are
considered to be acceptable as the empirical threshold of 0.3 µg/cm2 is based on evidence from human studies
(conclusion (ii)) involving prolonged and close contact to nickel sulphate. The estimated worst-case exposures to
soluble nickel range from 0.44 µg/cm2 (scenario B2) to 0.9 µg/cm2 (scenario B1) and the calculated MOS values range
from 0.3 to 0.7. Whilst the worst-case exposure levels are somewhat higher than the empirical cut-off of 0.3 µg/cm2,
this is still considered to be acceptable (conclusion (ii)) as the cut-off value is based on prolonged (48 h) contact under
occlusion exaggerating the assumed workplace exposure.
4.1.3.2.3.2
Respiratory tract
Work related asthma has been reported in workers. Nickel sulphate is therefore considered to be a respiratory sensitiser
in humans. From the data available it is not possible to determine a no-effect level or exposure-response relationship.
Thus it is not possible make a quantitative evaluation of the risk. However, given the severe nature of this effect, and
that once the hypersensitive state is induced in an individual, then even low levels of exposure might induce an
asthmatic response, there is cause for concern. Conclusion (iii) applies to all workplace situations resulting in
inhalational exposure.
4.1.3.2.4 Repeated dose toxicity
4.1.3.2.4.1
Repeated dose Inhalational Toxicity
A 2-year inhalational LOAEC in rats and mice of 0.056 mg Ni/m3 (0.25 mg nickel sulphate hexahydrate/m3) is based on
lung inflammation and fibrosis in the NTP study (NTP, 1996a). This LOAEC is used for the comparison with
inhalational occupational exposure estimates.
When evaluating the MOS considerations should be given to the conservative approach with respect to the exposure
evaluation, where the whole nickel exposure is considered to be due to soluble nickel sulphate. Further, considerations
should be given to inter- and intra species variations in susceptibility and to the use of a LOAEC value as a starting
point. At the LOAEC rather severe effects on the respiratory tract were observed and data indicated that adverse effects
may occur at lower levels.
An assessment factor of 3 is used for interspecies differences in susceptibility for local effects and a factor 5 is used for
intraspecies differences among workers. For LOAEC to NOAEC extrapolation an assessment factor of 3-5 is
considered appropriate. All together an overall assessment factor of 50 is considered appropriate and thus a MOS < 50
is considered to be of concern for repeated occupational exposure.
Table 4.1.3.2.4.A: Occupational risk assessment for repeated dose inhalational toxicity.
Scenario
Typical Full shift (8 hr TWA)
mg Ni/m
3
MOS
1)
Worst-case Full shift (8 hr TWA)
Conclusion
Mg Ni/m3 MOS 1) Conclusion
A1 Nickel sulphate production from nickel 0.07
matte
0.8
iii
1.0
0.06
iii
A2 Nickel sulphate production from
secondary nickel matte or roasted
residues
0.8
iii
1.0
0.06
iii
0.07
177
0.07
0.8
iii
1.0
0.06
iii
copper refining
0.018
3.1
iii
0.15
0.37
iii
0.07
0.8
iii
1.0
0.06
iii
metallic nickel
0.02
2.8
iii
0.23
0.24
iii
B1
0.04
1.4
iii
0.7
0.08
iii
B2
Nickel plating
0.018
3.1
iii
0.4
0.14
iii
B3
0.004
14
iii
0.25
0.22
iii
B4
0.0040.27
0.21-14 iii
7.0
0.008
iii
1): Based on a LOAEC of 0.056 mg Ni/m3 from a 2-year rat study (from Table 4.1.3.1.2.A).
Conclusion (iii) applies to all workplace situations resulting in inhalational exposure.
4.1.3.2.4.2
Repeated dose dermal Toxicity
4.1.3.2.5 Mutagenicity
Nickel sulphate is classified as Muta. Cat. 3; R68, as the possibility that the germ cells are affected cannot be excluded.
There is concern (conclusion (iii) for somatic cell mutagenicity linked to inhalational carcinogenicity.
There are remaining uncertainties with regard to mutagenicity for nickel sulphate for effects on germ cells. The
Specialised Experts concluded that further testing for effects on germ mutagenicity was not considered practicable.
Further information is unlikely to have an impact on the risk reduction measures and thereby the regulation of the
substance. As a result, further studies are not required at this time. This can be expressed as a conclusion (i) “on hold”.
4.1.3.2.6 Carcinogenicity
4.1.3.2.6.1
Carcinogenicity after inhalational exposure
The risk characterisation shown below is based on a lifetime increased cancer risk at an exposure level of 1 mg/m3 of 95
x 10-3. This figure is taken from the unit risk estimate of 3.8 x 10-4 per μg/m3 (WHO, 1999) corrected for the difference
between continuous exposure and occupational exposure. The figures in the table show the lifetime cancer risk x 10-3.
Short-term and worst-case exposures are not considered relevant in this assessment.
Table 4.1.3.2.6.A: Estimated full shift (8 hour time weighted average) typical exposure to nickel sulphate and
other nickel species by inhalation and the corresponding lifetime cancer risks (Sanner, 2002).
Speciation (1)
Scenario
A1
A2
A3
inhalable nickel
(mg/m3) - typical
level
from nickel matte
SO
0.07
U
0.05
from secondary nickel
matte or roasted residues
SO
0.07
U
0.05
SO
0.07
U
0.05
Lifetime cancer
risk (10-3)
Conclusion
11 (2)
iii
11 (2)
iii
11 (2)
iii
178
A4
A5
A6
B1
B2
B3
B4
SO
0.018
U
0.012
Purification of impure
nickel sulphate
SO
0.07
U
0.05
SO
0.02
U
0.02
Production of metallic
nickel
SO
0.04
U
0.002
Nickel plating
SO
0.018
U
0.007
SO
0.004
U
0.1
SO
0.004-0.27
U
0.002-0.18
3 (2)
iii
11(2)
iii
4 (2)
iii
4 (2)
iii
2 (2)
iii
10 (2)
iii
0.6-44
iii
2: SO and U have been added and the risk calculated for the total nickel exposure.
The WHO unit risk estimate of 3.8 x 10-4 used for calculating of the lifetime cancer risk in the table is most probably
derived from occupational nickel exposure measurements measured as ”total dust”. The exposure level for the exposure
scenarios in the table is given in the metric ”inhalable dust” which numerically is about twice as high a value as the
same exposure level given in the metric ”total dust" (section 4.1.1.2.1.2). If correction for this relationship should be
made then the lifetime risks in the table should be approximately 50% lower. However, a correction of this magnitude
would not lead to any significant changes in the evaluations of the risk levels as the indicated levels more properly
should be interpreted as order of magnitudes rather than exact values.
There is a concern for carcinogenicity in all the full shift scenarios (conclusion (iii)).
4.1.3.2.6.2
Carcinogenicity after dermal exposure.
As the carcinogenicity is only related to inhalational exposure, there is no concern for carcinogenicity following dermal
exposure (conclusion (ii)).
4.1.3.2.7 Toxicity for reproduction
4.1.3.2.7.1
Effects on fertility after inhalational exposure
There is no data for effects on fertility after inhalational exposure. A NOAEC of 0.55 mg/m3 has been calculated from
an oral NOAEL of 2.2 mg Ni/kg bw/day.
There is measured data for effects on male sex organs (see Table 4.1.3.1.2.A) which can be used as a surrogate for these
effects. A possible LOAEC for effects after inhalation was 1.6 mg Ni/m3. A NOAEC of 0.45 mg/m3 for effects on
sperm and oestrus cyclicity from a repeated dose study is used as the basis of this risk characterisation, as this measured
NOAEC is lower than the calculated NOAEC for fertility.
When evaluating the MOS considerations should be given to the conservative approach with respect to the exposure
evaluation, where the whole nickel exposure is considered to be due to soluble nickel sulphate. Considerations to interand intraspecies differences in susceptibility should be given. Further, it should be taken into account that the NOAEC
for fertility is probably higher than the one used as the NOAEC value was the highest dose used in the study. It should
also be noticed that only limited data concerning a possible effect on sex organs are available.
179
When using an interspecies factor of 10 and an intraspecies factor of 5 an overall factor of 50 would be obtained.
However, due to the conservatism in relation to exposure values and because the NOAEC value used was the highest
tested dose level an overall assessment factor of 10 seems more appropriate.
Values of the MOS < 10 for effects on fertility and sex organs are considered of concern for workers.
Table 4.1.3.2.7.A: Occupational risk assessment for effects on male sex organs (surrogate for fertility).
Scenario
mg Ni/m
3
MOS
1)
Conclusion
mg Ni/m3 MOS 1) Conclusion
matte
6.4
iii
1.0
0.45
iii
residues
0.07
6.4
iii
1.0
0.45
iii
0.07
6.4
iii
1.0
0.45
iii
copper refining
0.018
25
ii
0.15
3.0
iii
0.07
7.5
iii
1.0
0.45
iii
metallic nickel
0.02
23
ii
0.23
2.0
iii
B1
0.04
11
ii
0.7
0.6
iii
B2
Nickel plating
0.018
25
ii
0.4
1.1
iii
B3
0.004
113
ii
0.25
1.8
iii
B4
0.0040.27
1.7-110 ii-iii
7.0
0.08
iii
1): Based on a NOAEC of 0.45 mg Ni/m3 (Table 4.1.3.1.2.A).
The values of the MOS for the “typical” exposure scenarios are between 1.7 and 110. The MOS values for scenario B4
range from 1.7 to 110. The exposure for this scenario is based on data for the production of chemicals from metallic
nickel and may not accurately reflect the actual exposures. It is noted that scenario B4 covers an enormous range of
processes (see section 4.1.1.2.3.4) and conclusion (ii) applies to some processes of that scenario.
The MOS values for the “worst-case” full shift exposures are all less than 10, and in many cases, less than 1.
It can be debated whether conclusion (i)-on hold would be more appropriate than conclusion (iii) for this end-point
given the uncertainties regarding a proper NOAEC-value and proper studies for examining this end-point. However, as
all the conclusion (iii) scenarios for the fertility end-point are also conclusion (iii) for developmental toxicity for
(which a lower NOAEC value is used) this is academic, as risk reduction measures for these scenarios are already
recommended.
4.1.3.2.7.2
Effects on fertility after dermal exposure
4.1.3.2.7.3
Developmental toxicity after inhalational exposure
There is no data for effects on developmental toxicity after inhalational exposure. There is however data for effects on
development after oral exposure (see Table 4.1.3.1.B). A NOAEC of 0.277 mg/m3 has been calculated from the oral
NOAEL of 1.1 mg/kg bw/day.
When evaluating the MOS the conservative approach with respect to the exposure evaluation where the whole nickel
exposure is considered to be due to soluble nickel sulphate should be considered. Also the uncertainties with regard to
route-to-route extrapolation, severity of the effect, and inter- and intraspecies variations should be taken into account.
180
An assessment factor of 10 is used for interspecies differences in susceptibility and a factor of 5 is used for intraspecies
differences in the worker populations. Further a factor of 2-3 accounting for severity of the effects (death of foetuses)
should be considered. However, such a factor is considered outweighed by the above-mentioned conservative
assumptions with regard to exposure values and the conservative absorption factors used in the route-to-route
extrapolations. This leads to an overall assessment factor of 50 and thus MOS values < 50 are considered to be of
concern for workers.
Table 4.1.3.2.7.C: Occupational risk assessment for developmental toxicity after inhalational exposure.
Scenario
mg Ni/m
3
MOS
1)
Conclusion
mg Ni/m3 MOS 1) Conclusion
matte
4.0
iii
1.0
0.3
iii
residues
0.07
4.0
iii
1.0
0.3
iii
0.07
4.0
iii
1.0
0.3
iii
copper refining
0.018
15
iii
0.15
1.8
iii
0.07
4.6
iii
1.0
0.3
iii
metallic nickel
0.02
13.9
iii
0.23
1.2
iii
B1
0.04
6.9
iii
0.7
0.4
iii
B2
Nickel plating
0.018
15
iii
0.4
0.7
iii
B3
0.004
69
ii
0.25
1.1
iii
B4
0.0040.27
1.0-69
ii-iii
7.0
0.04
iii
1): Based on a calculated NOAEC of 0.277 mg Ni/m3.
The values of the MOS for the “typical” exposure scenarios are between 1.0 and 69. Scenario B4 has the lowest MOS
value, and the exposure for this scenario is based on data for the production of chemicals from metallic nickel and may
not accurately reflect the actual exposures. It is noted that scenario B4 covers an enormous range of processes (see
section 4.1.1.2.3.4) and conclusion (ii) applies to some processes of that scenario.
The MOS values for the “worst-case” full shift exposures are all less than 10, and in many cases, less than 1.
4.1.3.2.7.4
Effects on developmental toxicity after dermal exposure
.
181
4.1.3.2.8 Summary of risk characterisation for workers
Table 4.1.3.2.8.A: Summary of risk characterisation for occupational exposure.
Non-quantitative effects:
Conclusion (i) “on hold” applies to all workplace scenarios for germ cell mutagenicity, and conclusion (iii) for somatic cell mutagenicity linked to inhalational cancer.
Conclusion (ii) applies to all workplace scenarios involving dermal and eye exposure for irritation, and to all scenarios for skin sensitisation (induction and elicitation).
Conclusion (iii) applies to all workplace scenarios involving respiratory sensitisation.
Inhalation
Full shift
Dermal
Typical
/ Worstcase
Worstcase
Dermal
Worstcase
Inhalation
Full shift
Typical
Dermal
Developmental
toxicity
Typical
/ Worstcase
Inhalation
Full shift
Typical
Inhalation Dermal
– full-shift
Typical
Inhala Dermal
tional
Typical
/ Worstcase
Fertility
Worstcase
Carcinogenicity
Typical
Repeated dose
toxicity
Typical
/ Worstcase
Acute toxicity
Shortterm
Scenario
A1: Production from nickel matte
iii
Ii
iii
iii
ii
iii
ii
iii
iii
ii
iii
iii
ii
A2: Production from secondary nickel matte
or roasted residues
iii
Ii
iii
iii
ii
iii
ii
iii
iii
ii
iii
iii
ii
A3: Other leaching processes
iii
Ii
iii
iii
ii
iii
ii
Iii
iii
ii
iii
iii
ii
A4: Production from copper refining
iii
Ii
iii
iii
ii
iii
ii
ii
iii
ii
iii
iii
ii
A5: Purification of impure nickel sulphate
iii
Ii
iii
iii
ii
iii
ii
iii
iii
ii
iii
iii
ii
A6: Production from metallic nickel
iii
Ii
iii
iii
ii
iii
ii
ii
iii
ii
iii
iii
ii
B1: Production of metallic nickel
iii
Ii
iii
iii
ii
iii
ii
ii
iii
ii
iii
iii
ii
B2: Nickel plating
iii
Ii
iii
iii
ii
iii
ii
ii
iii
ii
iii
iii
ii
B3: Production of catalysts
iii
Ii
iii
iii
Ii
iii
ii
ii
iii
ii
ii
iii
ii
iii
ii
B4: Production of chemicals
iii
Ii
iii
iii
Ii
iii
ii
1
ii-iii
iii
ii
1
ii-iii
1) It is noted that scenario B4 covers an enormous range of processes (see section 4.1.1.2.3.4) and conclusion (ii) applies to some processes of that scenario.
182
4.1.3.3 Risk characterisation for Consumers.
The only known form of consumer exposure to nickel sulphate is as a food supplement. Many food supplements
for adults contain nickel at a dose of 5 μg/tablet. This corresponds to a dose of 0.08 μg/kg bw/day for a 60 kg
adult. Food supplements can contain as much as 100 μg/tablet, corresponding to 1.7 μg/kg bw/day for a 60 kg
adult. This is the dose considered in the Table below.
The population at risk of developing symptoms after oral challenge are patients with severe nickel sensitisation.
Less sensitive nickel allergic patients and the non-allergic population do not experience allergic symptoms after
oral nickel intake. Special measures relevant for the group of patients with severe nickel sensitisation are
addressed below.
No specific MOS calculation has been performed for small children, as there is no indication that they are
exposed to higher levels than adults due to their distinct behaviour or that they are more vulnerable. Severe
nickel sensitisation is only seen in older children and adults, and so toddlers are not present in this population.
Some tablets intended for children are marketed which contain 1 μg/tablet. This corresponds to a dose of 0.083
μg/kg bw/day for a 12 kg toddler, which is lower than the comparable amount taken by an adult.
Table 4.1.3.3.A: Risk characterisation for nickel sulphate as food supplement.
Endpoint
NOAEL / LOAEL
Dose for 60 kg adult
(100 μg tablet)
MOS
Sensitisation (elicitation
by oral challenge)
LOAEL: 0.012 mg Ni/kg
1.7 μg/kg bw/day
7
Repeated dose toxicity
LOAEL = 6.7 mg Ni/kg bw/day
(systemic effect)
NOAEL = 2.2 mg Ni/kg bw/day
(however slightly reduced body
weight and survival) (*)
1.7 μg/kg bw/day
1294
Fertility
No LOAEL
NOAEL: 2.2 mg/kg bw/day
1.7 μg/kg bw/day
1294
LOAEL = 2.2 mg Ni/kg bw/day
NOAEL: 1.1 mg/kg bw/day (*)
1.7μg/kg bw/day
647
(*) This value is used for calculation of the MOS
It is not possible to establish a NOAEL for oral challenge in patients with nickel dermatitis. The LOAEL
established after provocation of patients with empty stomach is 12µg/kg body weight (Nielsen et al. 1999). It
should be noted that this dose is the acute LOAEL in fasting patients with hand dermatitis on a 48h diet with
reduced nickel content. These patients are the most sensitive of the nickel allergic population to oral elicitation.
A LOAEL after repeated exposure may be lower and a LOAEL in non-fasting patients is probably higher
because of reduced absorption of nickel ions when mixed in food.
The population at risk of developing symptoms after oral challenge is patients with severe nickel sensitisation.
To avoid or minimize the risk, this patient group should have relevant information on possibilities for nickel
contamination of food and drinking water and on the natural contents of nickel in food. Whilst this information is
provided routinely to these patients in some countries, it is not clear if this is routine throughout Europe. It
should be noted in this context that the European Food Safety Authority’s NDA Panel have given an Opinion on
the tolerable levels of nickel in the diet (NDA, 2005). This opinion concludes that it is not possible to conclude a
tolerable upper intake level for nickel.
Since concern has been identified for this particular group of highly nickel-sensitised patients, conclusion (iii) is
drawn for the use of nickel sulphate as a food supplement.
These exposures are not considered to be of concern to other than severely nickel-sensitised patients (conclusion
(ii)).
When evaluation the MOS for repeated dose toxicity consideration should be given to inter- and intraspecies
differences in susceptibility. An assessment factor of 10 should be used to account for differences in
toxicokinetic and toxicodynamic properties when extrapolating from rats to humans and a further factor of 10
should be used to account for differences in the general population. A factor of 3 should be included to consider
the severity of the effect (mortality) and to take account of the effects observed at the NOAEL value (slight
183
reductions in body weight and survival). Thus an overall assessment factor of 300 can be calculated and MOS
values <300 should be considered of concern. The MOS value of 1294 for repeated dose toxicity leads to no
concern (conclusion (ii)).
When evaluation the MOS for fertility consideration should be given to inter- and intraspecies differences in
susceptibility. An assessment factor of 10 should be used to account for differences in toxicokinetic and
toxicodynamic properties when extrapolating from rats to humans and a further factor of 10 should be used to
account for differences in the general population. Thus an overall assessment factor of 100 can be calculated and
MOS values <100 should be considered of concern. The MOS value of 1294 for fertility leads to no concern
(conclusion (ii)).
When evaluation the MOS for developmental toxicity consideration should be given to inter- and intraspecies
differences in susceptibility. An assessment factor of 10 should be used to account for differences in
toxicokinetic and toxicodynamic properties when extrapolating from rats to humans and a further factor of 10
should be used to account for differences in the general population. Furthermore a factor of 2-3 is used to
consider the severity of effects (peri- and postnatal increased mortality) at only twice the dose level of the
NOAEL value. Thus an overall assessment factor of 200-300 can be calculated and MOS values <200-300
should be considered of concern. The MOS value of 647 for developmental toxicity leads to no concern
(conclusion (ii)).
The concerns for somatic cell mutagenicity are related to inhalational carcinogenicity, and as such are not
relevant in the context of consumer exposure, as the only exposure is by the oral route. There are remaining
uncertainties with regard to mutagenicity for nickel sulphate for effects on germ cells. The Specialised Experts
concluded that further testing for effects on germ mutagenicity was not considered practicable. Further
information is unlikely to have an impact on the risk reduction measures and thereby the regulation of the
substance. As a result, further studies are not required at this time. This can be expressed as a conclusion (i) “on
hold”.
There is no concern for carcinogenicity by the oral route of exposure (conclusion (ii)).
4.1.3.4 Risk characterisation for Man via environment.
See the common MvE RAR for the nickel substances (nickel; nickel carbonate; nickel chloride; nickel
dinitrate and nickel sulphate): “Humans exposed indirectly via the environment and combined exposure exposure assessment and risk characterisation”
4.1.3.5 Combined Exposure.
4.1.3.5.1 Oral exposure.
When considering possible risk reduction strategies for oral exposure, the conclusion should be seen in the light
of a number of other issues.
Nickel is probably an essential element for biological organisms, even though nickel deficiency has not been
demonstrated in human beings (Council of Europe, 2002). No recommended daily allowance has been set for
nickel.
The Council of Europe figure for daily intake of nickel from foodstuff is estimated at 0.15 – 0.7 mg Ni/day
(Council of Europe, 2002).
The amount consumed in the daily diet in the UK is estimated to be 0.21 mg Ni/day (UK EGVM, 2003). 2 l of
water containing the WHO recommended maximum of 20 μg Ni/l will contribute an additional 0.04 mg Ni/day.
The mean intake of 0.4 mg Ni/day given by the Council of Europe already exceeds the WHO PTWI of 2.1 mg
(i.e. 0.3 mg Ni/day) (Council of Europe, 2002). The somewhat lower total estimate of 0.25 mg Ni/day available
from the UK diet and drinking water conforming to the maximum concentration recommended by WHO is
already very close to the WHO PTWI.
A considerable number of nickel-sensitive patients have dermatitis at sites other than those in direct contact with
nickel-plated items. A fraction of these patients will benefit from a nickel-restricted diet (Veien & Menné 1990,
Veien et al. 1993).
184
The concerns for somatic cell mutagenicity are related to inhalational carcinogenicity, and as such as not relevant
in the context of consumer exposure as the only exposure is by the oral route. There are remaining uncertainties
with regard to mutagenicity for nickel sulphate for effects on germ cells. The Specialised Experts concluded that
further testing for effects on germ mutagenicity was not considered practicable. Further information is unlikely
to have an impact on the risk reduction measures and thereby the regulation of the substance. As a result, further
studies are not required at this time. This can be expressed as a conclusion (i) “on hold”.
It should be noted that the European Food Safety Authority’s NDA Panel have given an Opinion on the tolerable
levels of nickel in the diet (NDA, 2005). This opinion concludes that it is not possible to set a tolerable upper
intake level for nickel.
Since concern has been identified for highly nickel-sensitised patients, conclusion (iii) is drawn for the
combined exposure where there is the possibility of oral challenge (see also 4.1.3.3 above). These exposures are
not considered to be of concern to other than severely nickel-sensitised patients (conclusion (ii))
See the updated assessment in the common MvE RAR for the nickel substances (nickel; nickel carbonate;
nickel chloride; nickel dinitrate and nickel sulphate): “Humans exposed indirectly via the environment and
combined exposure - exposure assessment and risk characterisation”
4.2 HUMAN HEALTH (PHYSICO-CHEMICAL PROPERTIES).
Risk assessment concerning the properties listed in Annex IIA of Regulation 1488/94
4.2.1
Exposure assessment.
See section 4.1.1
4.2.2
Effects assessment:
Hazard identification and Dose (concentration) - response (effect) assessment
4.2.2.1 Explosivity.
Nickel sulphate has no explosive properties.
4.2.2.2 Flammability.
Nickel sulphate is not considered flammable.
4.2.2.3 Oxidising potential.
Nickel sulphate has no oxidising properties.
4.2.3
Risk characterisation.
There is no reason for concern with respect to the physico-chemical properties of nickel sulphate (conclusion
(ii)).
185
5. CONCLUSIONS/RESULTS
5.1 ENVIRONMENT
Not included in this report.
5.2 HUMAN HEALTH
5.2.1
OCCUPATIONAL ASSESSMENT
(X)
i)
(X)
ii)
There is at present no need for further information and/or testing or for risk reduction
measures beyond those which are being applied
(X)
iii)
There is a need for limiting the risks: risk reduction measures which are already being
applied shall be taken into account
• There is a need for further studies to evaluate the possible effects of nickel sulphate on germ cells, but
further testing is not considered practicable.
• The risk assessment has shown that for certain endpoints (acute toxicity, respiratory sensitisation,
repeated dose toxicity, carcinogenicity, effects on fertility and development) effects on human health
cannot be excluded following inhalational exposure for the following scenarios:
Inhalation
Full shift
Worstcase
Inhalation
Full shift
Typical
Developmental
toxicity
Worstcase
Fertility
Typical
Worstcase
Typical
Inhalation
– full-shift
Carcinogenicity 1
Inhalation Full
shift Typical
Repeated
dose
toxicity
Respiratory
sensitisation
Acute
toxicity
Inhalational
Short -term
Scenario
A1: Production from nickel
matte
iii
iii
iii
iii
iii
iii
iii
iii
iii
A2: Production from
secondary nickel matte or
roasted residues
iii
iii
iii
iii
iii
iii
iii
iii
iii
A3: Other leaching processes
iii
iii
iii
iii
iii
iii
iii
iii
iii
A4: Production from copper
refining
iii
iii
iii
iii
iii
iii
iii
iii
A5: Purification of impure
nickel sulphate
iii
iii
iii
iii
iii
iii
iii
iii
A6: Production from metallic
nickel
iii
iii
iii
iii
iii
iii
iii
iii
B1: Production of metallic
nickel
iii
iii
iii
iii
iii
iii
iii
iii
B2: Nickel plating
iii
iii
iii
iii
iii
iii
iii
iii
B3: Production of catalysts
iii
iii
iii
iii
iii
iii
iii
B4: Production of chemicals
iii
iii
iii
iii
iii
ii- iii
iii
ii- iii
iii 2
iii
2
186
1: Includes somatic cell mutagenicity linked to inhalational cancer.
2: The scenario covers an enormous range of processes (see section 4.1.1.2.3.4). Conclusion (ii) applies to some
processes.
• For all other scenarios for inhalational exposure for effects on fertility and development and for all
scenarios for dermal exposures for acute and repeated dose toxicity, irritation, skin sensitisation,
carcinogenicity and reproductive toxicity there is no need for limiting the risks taking into account the
risk reduction measures that are already being applied.
5.2.2
CONSUMER ASSESSMENT
(X)
i)
(X)
ii)
(X)
iii)
• Patients with severe nickel sensitisation constitute a particularly sensitive population to oral challenge
with nickel and are potentially at risk from excessive exposure to nickel in food and water. Additional
risk reduction measures may be needed to limit exposure to nickel in food supplements.
• There is no concern for the general population that are not already sensitised to nickel from exposure to
nickel in food supplements. There is no concern for patients with severe nickel sensitisation for other
endpoints than a possible reaction to oral challenge with nickel.
5.2.3
INDIRECT EXPOSURE VIA THE ENVIRONMENT
See the common MvE RAR for the nickel substances (nickel; nickel carbonate; nickel chloride; nickel
dinitrate and nickel sulphate): “Humans exposed indirectly via the environment and combined exposure exposure assessment and risk characterisation”
.
5.2.4
COMBINED EXPOSURE
(X)
i)
(X)
ii)
(X)
iii)
• Patients with severe nickel sensitisation constitute a particularly sensitive population to oral challenge
with nickel and are potentially at risk from excessive exposure to nickel in food and water. This patient
group should have relevant information on possibilities for nickel contamination of food and drinking
water and on the natural contents of nickel in food to avoid or minimize the risk.
187
•
There is no concern for the general population that are not already sensitised to nickel from exposure to
nickel in food and water. There is no concern for patients with severe nickel sensitisation for other
endpoints than a possible reaction to oral challenge with nickel.
See the updated assessment in the common MvE RAR for the nickel substances (nickel; nickel carbonate;
nickel chloride; nickel dinitrate and nickel sulphate): “Humans exposed indirectly via the environment and
combined exposure - exposure assessment and risk characterisation”
5.2.5
PHYSICOCHEMICAL PROPERTIES
( )
i)
(X)
ii)
( )
iii)
• There is no reason for concern with respect to the physico-chemical properties of nickel sulphate.
188
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202
7. APPENDICES
7.1 EUSES RISK CHARACTERISATION RESULT TABLE
To be included
7.2 EUSES SUMMARY REPORT
To be included
7.3 IUCLID DATA SET
To be included
203
7.4 REVISED ANNEX I ENTRY TO DIR. 67/548
Index No
Chemical name
Notes
related to
substances
EC No
CAS No
Classification
Labelling
Concentration limits
028-009-00-5
Nickel sulfate
E
232-104-9
7786-81-4
Carc Cat 1; R49
T; N
C>25%: T, N; R49-61-20/22-38-42/43-48/23-50/53
Muta. Cat. 3; R68
R: 49-61-20/22-38-42/4348/23-50/53
20% <C <25%: T, N; R49-61-38-42/43-48/23-51/53
Repr. Cat. 2; R61
T; R48/23
S: 53-45-60-61
Notes
2.5%<C<20%: T, N; R49-61-42/43-48/23-51/53
1%<C<2.5%: T; R49-61-42/43-48/23-52/53
Xn; R20/22
0.5%<C<1%: T; R49-61-43-48/20-52/53
Xi; R38
0.25%<C<0.5%: T; R49-43-48/20-52/53
R 42/43
0.1 %<C<0.25 %: T; R49-43-48/20
N; R50-53.
0.01%<C<0.1%: Xi; R43
The entry is included in the 30th ATP.
204
7.5 BACKGROUND DOCUMENT ON THE SENSITIVITY OF THE
NTP STUDIES
The conclusions of the inhalation studies recently published by US National Toxicology Program (NTP 1996b, c
and a) were: Nickel subsulfide; clear evidence of carcinogenic activity in male an female rats, nickel oxide;
some evidence of carcinogenic activity in male an female rats, and nickel sulfate hexahydrate; no evidence of
carcinogenic activity in male an female rats.
The present document will address the lack of alveolar/bronchiolar neoplasms in the rats exposed to nickel
sulfate hexahydrate and discuss whether this compound would have been expected to induce tumours if the
tumour inducing potency of the sulfate were the same as that of the subsulfide or oxide. The document is based
on NTP (1996b), NTP (1996c), NTP (1996a) and Dunnick et al. (1995).
Exposure levels of the nickel compounds
Table 7.5.1 shows the exposure levels of the nickel compounds used in the 2-year carcinogenicity studies. The
nickel concentration at the highest level of nickel sulfate hexahydrate corresponds to the low dose with nickel
subsulfide. The nickel concentration at the next higher dose of nickel subsulfide (which was the highest dose
used) is nearly 7 times higher than the nickel concentration at the highest dose of nickel sulfate hexahydrate. The
nickel level at the lowest exposure concentration of nickel oxide was almost 5 times higher than the nickel
concentration at the highest exposure level of nickel sulfate hexahydrate.
Table 7.5.1 Exposure levels of nickel compounds or nickel in 2-year rat studies and mean bodyweight
of the exposed male and female rats in per cent of that found in the control groups
Dose
Low dose
Compound
Nickel
Mean body weight (per cent of
controls) (males, females)
Medium dose
Compound
Nickel
High dose
Compound
Nickel
Nickel sulfate
hexahydrate
(22.3% nickel)
(mg/m3)
Nickel subsulfide
(73.3% nickel)
Nickel oxide
(76.6% nickel)
(mg/m3)
(mg/m3)
0.125
0.03
0.15
0.11
0.62
0.5
99, 97
98, 96
100, 96
0.25
0.06
1
0.73
1.25
1.0
101, 97
85, 78
95, 92
0.5
0.11
-
2.5
2.0
98, 94
93, 90
Survival of rats exposed to nickel sulfate, nickel subsulfide, and nickel oxide were in general similar to those of
the controls. The final mean body weights of the exposed rats relative to the controls are included in the table 1.
The relative mean bodyweights at the highest doses used for the rats exposed to nickel sulfate were 98% and
94% for the males and females, respectively, for nickel subsulfide the mean bodyweight was 85% and 78% for
males and females, respectively, and for nickel oxide the mean bodyweights were 93% and 90% for males and
females, respectively, compared to the untreated controls.
Increase in lung weights
Lung weights in exposed animals were greater than controls, and this was considered to be related to
inflammatory lung reactions that occurred in response to nickel exposure. Table 7.5.2 shows the increase in lung
weights after 7-months. The results at 7-months were used since the exposure increase in lung weights were
greater during the first 7 months than during the subsequent 8 months. The average of the absolute lung weights
in the male and female controls, respectively, were used in the calculation of the increase in lung weights. No
significant increase (P# 0.01) in the lung weights were found among the rats exposed to nickel sulfate. The lung
205
weights of the rats exposed to nickel subsulfide were significantly increased in all groups. The lung weights were
also significantly increased among the rats exposed to the medium and high dose of nickel oxide. At 15-months
the lung weights in the high-exposure nickel sulfate rats was 33-41% higher than in the controls; the highexposure lung weight in the nickel subsulfide rats was 300% higher than controls; in the nickel oxide studies the
high-exposure lung weight in rats was 86-94% higher than controls.
The finding that the lung weights increased more in the nickel subsulfide and nickel oxide exposed rats than in
the nickel sulfate exposed animals correlated with a more severe inflammatory response in the lungs after
exposures to the first two substances (Dunnick et al., 1995).
Table 7.5.2. Increase in lung weight after 7-months
INCREASE IN LUNG WEIGHT
(g)
DOSE
Nickel sulfate
hexahydrate
Nickel subsulfide
Nickel oxide
Low dose
Male
Female
-
0.63*
0.52*
0.10
0.08
Medium dose
Male
Female
-
1.73*
1.36*
0.71*
0.42*
High dose
Male
Female
0.14
0.22
-
0.84*
0.55*
*Significant (P # = 0.001)
Lung nickel burden
Analysis of the nickel lung burden data showed a considerable accumulation of nickel in the lungs of
the nickel oxide exposed animals (Table 7.5.3). Thus, at the same level of nickel exposure, the lung
nickel burden in the nickel oxide exposed animals was about 20 times higher than in the nickel
subsulfide-treated animals. On the other hand, the lung nickel burden in the nickel subsulfide exposed
animals was 6 times higher than that found in the nickel sulfate exposed rats at the same nickel
exposure level. The nickel lung burden reflects the half-life of the compounds in the rat lung. Thus, the
half-life of nickel oxide is approximately 120 days while nickel subsulfide has a half-life of 5 days and
nickel sulfate of 1 - 3 days.
Table 7.5.3. Nickel lung burden after 7-months
NICKEL LUNG BURDEN
(μg nickel/g lung)
DOSE
Nickel sulfate
Hexahydrate
Nickel subsulfide
Nickel oxide
Low dose
Male
Female
-
6
6
175
173
Medium dose
Male
Female
-
9
9
388
477
High dose
Male
Female
1
1
-
701
713
206
Lung tumour induction
Table 7.5.4. Total number of lung adenomas and carcinomas. The number of animals available in
each group for evaluation of tumours varied between 52 and 54.
ADENOMA/CARCINOMAS COMBINED
DOSE
A
Nickel sulfate
hexahydrate
Nickel subsulfide
Nickel oxide
Control
Male
Female
Sum
1A
1
2
1
1
2
1
1
2
Low dose
Male
Female
Sum
0
0
0
6
6
12
1
1
2
Medium dose
Male
Female
Sum
1
0
1
11
9
20
6
6
12
High dose
Male
Female
Sum
3
1
4
-
4
5
11
The average of the controls in the three groups has been used
There was a significant dose-related increase in adenoma/carcinomas combined both in male and
female rats exposed to nickel subsulfide (Table 7.5.4). There was a significant increase in adenoma/carcinomas combined both in male and female rats exposed to the two highest doses of nickel oxide.
The number of tumours at the two highest doses were similar. There was no significant increase of
lung tumours in rats exposed to nickel sulfate hexahydrate. No lung tumours was found in the low
dose groups, one carcinoma was found among the males in the medium dose groups, and two
adenomas and one carcinoma was found among the males and one adenoma among the females in the
high dose groups.
Number of tumours as a function of nickel-exposure, increase in lung weight, and
nickel lung burden
Fig. 7.5.1 shows the number of lung adenoma/carcinomas combined in male/female rats combined as
a function of the Ni-exposure in rats exposed to nickel sulfate, nickel subsulfide, and nickel oxide. The
results clearly demonstrate that nickel subsulfide is significantly more potent in inducing lung tumours
than nickel oxide and nickel sulfate. On the other hand, it would not be expected that nickel sulfate
should induce lung tumours at the doses tested if it had the same tumour inducing potency as nickel
oxide.
207
Tumours
(males + females)
Tumour formation after
Ni-exposure
Ni3S2
20
15
Ni3S2
NiO
NiO
10
5
NiSO4
NiO
0
0.0
0.5
1.0
1.5
2.0
Ni-exposure (mg/m3)
Fig 7.5.1. Number of alveolar/bronchiolar tumours (adenoma +carcinoma) after
inhalation exposure to nickel sulfate hexahydrate, nickel subsulfide, and nickel
oxide as a function of the nickel concentration
Number of tumours as function
of increase in lung weight
(MALES)
of increase in lung weight
(FEMALES)
15
10
Ni3S2
Ni3S2
5
NiO
NiSO4
0
0.0
Tumours
Tumours
10
NiO
Ni3S2
NiO
NiO
0.5
1.0
1.5
2.0
Increase in lung weigth (g)
Fig. 7.5.2. Number of alveolar/bronchiolar
tumours (adenoma + carcinoma) in male rats
after inhalation exposure to nickel sulfate
hexahydrate, nickel subsulfide, and nickel oxide
as a function of the increase in lung weight after
7-months.
Ni3S2
NiO
5
0
0.00
NiSO4
0.25
0.50
0.75
1.00
1.25
1.50
Increase in lung weigth (g)
Fig. 7.5.3. Number of alveolar/bronchiolar
tumours (adenoma + carcinoma) in female rats
after inhalation exposure to nickel sulfate
hexahydrate, nickel subsulfide, and nickel oxide
as a function of the increase in lung weight after
7-months.
The number of lung tumours as a function of increase in lung weight are shown in Figs 7.5.2 and 7.5.3. Both
among the males and females the number of tumours are directly proportional to the increase in lung weight. No
increase in lung weight was found among the rats exposed to the low and medium dose of nickel sulfate. The
208
results with the high dose of nickel sulfate fall slightly above the line for males and slightly below the line for the
females.
In Fig 7.5.4 is shown the number of tumours as a function of nickel lung burden. Since the nickel lung burden in
the animals exposed to nickel oxide was about 30 times higher than among the animals exposed to nickel
subsulfide the data for nickel oxide would clearly fall below the line if they were included. However, the data
clearly demonstrate that nickel sulfate fall on the same line as nickel subsulfide.
Based on the data presented it would have been expected that nickel sulfate could be equally potent as nickel
subsulfide in inducing lung tumours in the rats if the tumours are related to the increase in lung weight during the
first 7 months or nickel lung burden.
The exposure concentrations for nickel sulfate were selected based on the minimal to mild inflammatory lung
lesions observed in the 13-week toxicity studies. As pointed out above the increase in lung weights is considered
to be related to inflammatory lung reactions. Thus, the possibility should be considered that the nickel sulfate
hexahydrate exposure could have been higher without experiencing more toxic effects than that observed in the
experiments with nickel subsulfide and nickel oxide.
of Ni lung burden
Tumours
(males + females)
30
Ni3S2
20
Ni3S2
10
NiSO4
0
0.0
2.5
5.0
7.5
10.0
Lung burden (μg Ni/g lung)
Fig. 7.5.4. Number of alveolar/bronchiolar tumours (adenoma
+ carcinoma) in male and female rats combined after
inhalation exposure to nickel sulfate hexahydrate and nickel
subsulfide as a function of the increase in nickel lung burden
after 7-months
On the other hand, it was noted that nickel sulfate was more acutely toxic than nickel subsulfide or nickel oxide,
causing death of animals at exposure concentrations of 2 mg/m3 (Dunnick et al., 1995). Thus, the maximum
increase in the nickel sulfate hexahydrate concentration could not have been increased by more than a factor of
two to three due to its acute toxicity.
It was pointed out by members of the Technical Reports Review Subcommittee that it would have been possible
to use higher exposure concentration of nickel sulfate hexahydrate.
Conclusion.
The number of lung tumours in the NTP nickel inhalation studies was found to increase linearly with the
observed increase in lung weight. Thus, the results could be seen to fall on a straight line for all three nickel
compounds tested. The increase in lung weight is assumed to be caused by inflammatory processes in the lung.
Moreover, the number of tumours found for nickel sulfate and nickel subsulfide increased proportionally with
209
the nickel lung burden. It is concluded that nickel sulfate may have the same tumour inducing potency as nickel
subsulfide and nickel oxide when using concentrations giving the same increase in lung weight, and the same
tumour inducing potency as nickel subsulfide when using concentrations giving the same nickel lung burden.
Thus, it is likely that nickel sulfate would have shown carcinogenic activity if tested at a higher concentration. It
was pointed out by members of the Technical Reports Review Subcommittee that it could have been possible to
use higher exposure concentration of nickel sulfate hexahydrate than the one used.
210
7.6 NIPERA COMMENTS ON THE NEGATIVE NTP STUDY WITH
NICKEL SULFATE HEXAHYDRATE AND ITS SIGNIFICANCE
WITH REGARD TO MODE OF ACTION FOR WATER SOLUBLE
NICKEL COMPOUNDS
The relevancy of the negative NTP studies with nickel sulfate hexahydrate to evaluate human cancer
risk was raised in the appended comments by Sanner and Dybing (Appendix 7.5). First, it was
suggested that the maximum tolerated dose (MTD) was not reached in the NTP two-year bioassay
and that if concentrations higher than 0.5 mg/m3 of nickel sulfate hexahydrate (0.11 mg Ni/m3) would
have been tested, a positive tumor response would have been observed. This conclusion was based
on lung weights and lung burdens after 7 months of exposure. Based on their analyses, Sanner and
Dybing dismiss the negative studies by relevant route of exposure in two different animal species.
NiPERA’s response to these comments can be found below together with further discussion on how
the negative animal data can be reconciled with the human and in vitro data.
1) Sanner and Dybing indicated that concentrations tested in the NTP rat study were not
adequate, a higher (2-3-fold) concentration should have been tested
Sanner and Dybing suggested that the MTD was not reached in the NTP study and that a
3
3
concentration three times as high (0.3 mg Ni/m instead of 0.1 mg Ni/m , MMAD 2.2 µm) could have
been tested. As is typical, the two-year bioassay concentrations were selected based on the results
from the subchronic studies, and those results showed similar toxicities for 0.1 mg Ni/m3 of nickel
sulfate hexahydrate or nickel subsulfide. Nevertheless, the tumorigenic responses in the two-year
study were quite different, with a positive response for lung tumor induction for nickel subsulfide and a
negative response for nickel sulfate. In the two year study, nickel subsulfide seemed to cause more
lung toxicity than nickel sulfate (at same exposure levels) and it is fair then to consider what would
have happened if higher concentrations of nickel sulfate hexahydrate would have been tested. It is
known from studies by Dunnick et al. (1989) and Benson et al. (1988), that the dose-response curve
for whole animal toxicity (i.e., mortality) in rats is very steep. A recent short-term inhalation study of
nickel sulfate hexahydrate and nickel subsulfide in rats conducted by J. Benson at Lovelace Research
Institute (Benson et al., 2002), has confirmed that a higher dose (than 0.1 or 0.2 mg Ni/m3 of nickel
sulfate hexahydrate) in the two year bioassay would have resulted in an unacceptable level of toxicitybased mortality. J. Benson is the same investigator who conducted the cancer bioassay for NTP. The
original design of Benson’s recent study included exposure of rats to nickel sulfate hexahydrate at
0.03, 0.1, and 0.4 mg Ni/m3 for 13-weeks (a much shorter exposure than the 2 years of the NTP
bioassay). However, after the first week of the study, an adjustment to the nickel sulfate
concentrations had to be made because 12/39 rats (31%) exposed to the highest concentration of
nickel sulfate hexahydrate (2 mg/m3, 0.4 mg Ni/m3, MMAD 1.9 µm) had died. The highest
concentration of nickel sulfate hexahydrate was then reduced to 1 mg/m3 (0.2 mg Ni/m3), and new
animals were added to the study. These toxicity results confirm a steep dose-response for
toxicity/mortality and indicate that for a two-year study (rather than a 13-week exposure period) a
concentration at or below 0.2 mg Ni/m3 would need to be selected. Otherwise, decreased survival
would diminish, rather than increase, the chances of detecting tumors. These results confirm that the
0.5 mg/m3 (0.1 mg Ni/m3) exposure level used in the two-year NTP bioassay was indeed at or no more
than two-fold below the maximum tolerated dose (or minimum toxicity dose). A report on the results
from the short-term inhalation study will be available by 3rd quarter 2002. Further discussion of the
NTP bioassay study design and results (including selection of the MTD) can be found in Haber et al.
(2000, pages 219-220).
2) Sanner and Dybing suggest that a 2-3-fold higher exposure level of nickel sulfate
hexahydrate would have been positive based on: D-R for lung tumors versus lung
weight and D-R for lung tumors versus lung burdens
Based on the above toxicity discussion, at the most, a two-fold higher exposure level of nickel sulfate
hexahydrate could have been tested in rats. If a two-fold higher exposure was tested (0.2 mg Ni/m3
instead of 0.1 mg Ni/m3), there is no suggestion based on existing lung weight or lung burden data that
a positive tumor response would have been seen (Table 1).
211
Table 1. Results from the NTP rat carcinogenicity study (NTP Reports 1996)
Males absolute lung
Ni sulfate
Females absolute
Male lung burden
weight
(mg Ni/m3)
lung weight
(µg Ni/lung)
(3, 7, 15 months)
(3, 7, 15 months)
(3, 7, 15 month)
0
1.35 (1.24); 1.67; 2.12
1.02;1.25; 1.37
0 (0.08); 0; 0
0.03
1.25; 1.62; 2.48
1.02; 1.22; 1.58
0.15; 0; 0.37
0.06
1.51; 1.65; 2.50
1.16;1.22; 1.49
ND; 0; 1.12
0.11
(1.64, 1.89; 3.00
1.34;1.45; 1.82
(1.49; 1.43; 3.58
0.22
1.91; nd; nd
4.8; nd; nd
Figures in italics from Benson et al 2002
Female lung burden
(µg Ni/lung)
(3, 7, 15 month)
0; 0; 0
0; 0; 0.26
ND; 0; 0.74
1.40;1.32; 3.03
0
0.11
0.73
Males absolute lung
weight
(3, 7, 15 months)
1.15; 1.87; 2.27
1.56; 2.38; 3.31
nd; 3.48; 6.84
Females absolute
lung weight
(3, 7, 15 months)
0.85;1.31; 1.52
1.23; 1.75; 2.52
nd;2.59; 4.14
Male lung burden
(µg Ni/lung)
(3, 7, 15 month)
0; 0; 0
8; 12; 14
ND; 28; 21
Female lung burden
(µg Ni/lung)
(3, 7, 15 month)
0; 0; 0
6; 9; 9
ND; 23; 29
Ni oxide
(mg Ni/m3)
Males absolute lung
weight
Male lung burden
(3, 7, 15 month)
Female lung burden
(3, 7, 15 month)
0
0.5
1.0
2.0
(3, 7, 15 months)
1.18; 1.72; 2.20
1.35; 1.85; 2.15
1.47; 2.43; 3.30
1.70; 2.59; 4.09
Females absolute
lung weight
(3, 7, 15 months)
0.98;1.14; 1.56
1.03; 1.31; 1.79
1.13;1.65; 2.41
1.55;1.78; 3.02
Ni subsulfide
(mg Ni/m3)
0; 0; 0
86; 326; 696
ND; 930; 2439
276; 1817; 4573
nd; 0; 0
nd; 226; 471
ND; 792; 1703
nd;1279; 2810
If lung weights for 0.1 mg Ni/m3 nickel sulfate are compared to those corresponding to the lowest
concentrations at which positive tumor responses were observed for nickel subsulfide and nickel
oxide, they are found to be equivalent (differ by less than 10% males and 30% females) (values in
bold). Yet, nickel sulfate did not result in significant tumor induction while the other two compounds
did. This supports the fact that lung weights (as surrogate for lung inflammation) can be indicative of a
contributing factor to tumor formation but are not directly correlated with a tumor causing effect.
Therefore, speculations about what “could have happened” if higher lung weights had been achieved
for nickel sulfate are not justified when the data from all time points are used.
With regard to lung burdens, the lung burdens as a function of exposure levels to Ni (mg Ni/m3) can be
plotted for the different time points (Figure 1). The data indicates that at ≤ 0.22 mg Ni/m3 (2-fold higher
nickel sulfate exposures than the highest level tested in NTP), the nickel lung burdens would still be
below those seen for 0.11 mg Ni/m3 of nickel subsulfide for comparable lengths of exposure. These
results are in agreement with results showing that nickel lung burdens did not increased linearly with
high nickel sulfate exposures (Benson et al., 1988) and did not increase linearly with time of exposure
(Dunnick et al., 1989). The Benson et al. (1988) results may be due to the observed increased
clearance (decreasing T1/2) at higher soluble nickel exposures (Medinsky et al., 1987). Even if the
bioavailability of nickel from nickel sulfate was as high as it is for nickel subsulfide, there would not be
sufficient nickel in the lungs of the rats to reach the levels found in the animals that showed a positive
response for nickel subsulfide. The lack of relevance of lung nickel burdens for predicting lung cancer
risk is further illustrated by the fact that lung burdens for rats inhaling 0.5 mg Ni/m3 of nickel oxide
were much higher than those for rats inhaling 0.1 or 0.7 mg Ni/m3 of nickel subsulfide, yet not
treatment-related induction of tumors was observed in the nickel oxide exposure group.
It is clear then that nickel sulfate hexahydrate does not have the same cancer potency as nickel
subsulfide (at equal nickel exposure levels, 0.1 mg Ni/m3, nickel subsulfide was positive and nickel
sulfate hexahydrate was negative).
It is clear that if nickel sulfate had the same potency as nickel oxide, nickel sulfate would not have
been expected to be positive at 0.1 mg Ni/m3 (tested), 0.2 mg Ni/m3 (2-fold higher) or 0.5 mg Ni/m3 (5fold higher). If nickel sulfate had been tested at 1 mg Ni/m3 (which is the concentrations at which
nickel oxide gave a positive response), all the rats would have been dead and there would be no
tumors. Therefore, to speculate that nickel sulfate is carcinogenic because “it could have been positive
if tested at higher and lethal concentrations” is not justifiable. Because of the higher overall toxicity of
nickel sulfate hexahydrate in animals, animals cannot be exposed to concentrations high enough to
212
result in tumors in the absence of other exposures. The relevance of these results for humans is
discussed below.
35
30
3 m sulfate male
25
7 m sulfate male
lung burden ug Ni/lung
15 m sulfate male
3 m sulfate m Benson
20
3 m sulfate female
7 m sulfate female
15
15 m sulfate female
3 m subsulfide male
7 m subsulfide male
10
15 m subsulfide male
3 m subsulfide female
5
0
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
-5
mg Ni/m3
3) It has been suggested that even if the animal inhalation results are accepted as
negative, the exposures experienced by humans with excess cancer risks were higher
than those experienced by animals and that is why humans got tumors even if animals
did not.
The DRA document pointed out that the highest concentration to which rats were exposed in the NTP
3
bioassay was 0.1 mg Ni/m (MMAD 2.2 um) while workers in some of the cohorts studied by the Doll
et al. (1990) experienced soluble nickel exposures above 0.1 mg Ni/m3 (workplace dust).
Furthermore, it was suggested that the differences in exposure levels could explain why rats did not
get tumors in the NTP study while some workers did in the epidemiological studies.
To consider this point, it is crucial to note that the aerosol used in the NTP studies was carefully
prepared to have a narrow range of particle sizes with a mass median aerodynamic diameter (MMAD)
of 2-3 µm. In contrast, the particle size distribution of the aerosols in the workplace is broader and
characterized by coarser particles (e.g., MMAD> 30 - 50 μm, “inhalable aerosols”). Particles in the 2
µm range comprise less than 10% of the workplace total. Therefore to do a proper comparison
between animal and human exposures, the particle size of the aerosols as well as
deposition/clearance differences between animals and humans must be taken into consideration (U.
S. EPA, 1994). An animal to human extrapolation study based on deposition/clearance models for rat
and human lungs allows calculation of equivalent exposures (Hsieh et al., 1999; Yu et al., 1998; Yu et
al., 2001). These results indicate that after accounting for particle size distribution, the soluble nickel
exposure levels that did not induce tumors in rats are indeed higher than or equivalent to (in terms of
nickel lung burden) those experienced by workers in the nickel refinery epidemiological studies. Figure
3
3
2 shows that the highest concentration used in the rat study (0.5 mg Ni sulfate/m , 0.11 mg Ni/m ,
213
MMAD 2.2. um) is equivalent to 2-3 mg Ni/m3 of workplace dust. The workplace soluble nickel
exposure values showed in Table 4.1.2.7.2.C of the DRA are below this range, consistent with the fact
that if humans are as sensitive as rats to the toxic effects of nickel sulfate, levels above 2-6 mg Ni/m3
(equivalent to animal 0.22 mg Ni/m3, MMAD 2.2. µm; twice as high as tested in NTP study) would not
be tolerated by the workers without severe respiratory symptoms. So workers have experienced a
range of soluble nickel exposures that were not shown in the rat studies to induce tumors. However,
based on the rat data, workplace exposure above 0.1-0.2 mg Ni/m3 may induce sufficient respiratory
tract inflammation to enhance the tumorigenicity of inhalation carcinogens such as sulfidic or oxidic
nickel, acid mists, soluble cobalt compounds, or cigarette smoke.
5) Sanner and Dybing suggest that nickel sulfate hexahydrate is an animal carcinogen
(negative NTP rat inhalation study due to low exposure tested). Then, there must be
other positive studies with nickel sulfate or other soluble nickel compounds that
support this notion.
Contrary to the situation for nickel subsulfide, there are more than a dozen animal studies that were
negative after exclusive exposures to soluble nickel salts (Table 2). Besides the NTP inhalation
studies, five oral studies in mice, rats, and dogs (Schroeder et al., 1964; Schroeder et al., 1974;
Schroeder and Mitchner, 1975; Ambrose et al., 1976; Kurokawa et al., 1985) have also been negative.
Less relevant routes of exposure such as intramuscular injection also gave negative results in rats
(Gilman, 1962; Payne, 1964; Kasprzak et al., 1983; Kasprzak, 1994). In an intraperitoneal injection
study in rats, a relatively weak positive response for soluble nickel compounds at the injection site was
reported by Pott and collaborators (1992). The positive finding was not reproduced in another
intraperitoneal injection study conducted by Kasprzak et al. (1990).
There is only one study, an intraperitoneal transplacental study that can be considered positive (Diwan
et al., 1992). This study is a transplacental rat carcinogenicity study in which rat dams were injected
intraperitoneally with nickel acetate and the surviving pups were examined for tumors. In this study,
214
intraperitoneal injection of nickel acetate by itself did not induce kidney tumors in the offspring of
treated female rats. These results confirm the lack of kidney carcinogenicity seen with nickel acetate
alone by Kazprzak et al. (1990). Surprisingly, the Diwan et al. study shows increased pituitary tumors
in offspring of nickel acetate treated rats (42%) than in offspring of those exposed to sodium acetate
(13%). It should be noted that the historical data for the Fischer 344 rat indicate an average of 23
percent and 45 percent pituitary adenoma incidence for males and females, respectively (Haseman et
al., 1990). The observed increases in pituitary tumors in offspring of animals treated with nickel
acetate may be explained by the toxic effects of the Ni2+ ion (quite evident in this study with 88% pup
mortality) rather than to a carcinogenic effect. Toxicity can interfere with hormonal function. It has
been shown that in the rat, pituitary tumors can occur as a consequence of hormonal disruption
(Mennel, 1978).
The lack of pituitary tumors in other studies (with soluble and insoluble nickel compounds) such as the
transplacental study by Sunderman et al. (1981), intraperitoneal study by Kasprzak et al. (1990), oral
studies by Ambrose et al. (1976), Schoeder and Mitchener (1975), and the inhalation NTP studies
(NTP 1996 a,b,c) are consistent with this explanation, raising doubt about the relevance of this study
for evaluating human carcinogenic potential.
Table 2. Carcinogenicity Studies of Soluble Nickel Compounds
Reference
Material
Range or Highest
Exposure
Species
Result
NiSO4•6H2O
NiSO4•6H2O
0.5 mg/m3
1.0 mg/m3
Rats
Mice
−
−
Ni acetate
Ni acetate
Ni acetate
NiSO4•6H2O
NiSO4•6H2O
Ni Cl2•6H2O
5 ppm Ni
5 ppm Ni
5 ppm Ni
2500 ppm Ni
2500 ppm Ni
600 ppm Ni
Mice
Rats
Mice
Rats
Dogs
Rats
−
−
−
−
NiSO4•6H2O
NiCl2
NiSO4•6H2O
NiSO4•6H2O
NiSO4 anhy
100 mg Ni/kg
26 mg Ni/kg
19 mg Ni/kg
15 umol/site
60 umol/site
Rats
Rats
Rats
Rats
Rats
−
−
−
−
−
Ni acetate
Ni acetate
5.3 mg Ni/kg
5.3 mg Ni/kg
Rats
Rats
−
+ for pituitary*
NiCl2•6H2O
NiSO4•6H2O
Ni acetate
Controls
50 mg Ni
Rats
Inhalation Studies
NTP 1996
NTP 1996
Oral Studies
Schroeder et al 1964
Schroeder et al 1974
Schroeder & Mitchener 75
Ambrose et al 1976
Ambrose et al 1976
Kurokawa et al 1985
Intramuscular Studies
Gilman 1962
Payne 1964
Kasprzak et al 1983
Kasprzak 1994
Kasprzak 1994
Intraperitoneal Studies
Kasprzak et al 1990
Diwan et al 1992
[transplacental]
Pott et al 1992
+/− (4/32)
+/− (6/30)
+/− (5/31)
(0-1/33)
Ultimately, more than a dozen animal studies conducted to date, yield no evidence for the
carcinogenicity of soluble nickel salts by themselves, supporting the negative results from the NTP
inhalation study with nickel sulfate hexahydrate.
6) How can negative animal data be reconciled with positive association seen in
epidemiological studies?
Workers in epidemiological studies were never exposed solely to soluble nickel salts but always to a
mixture with more insoluble nickel compounds, soluble cobalt compounds, acid mists, arsenic
compounds, cigarette smoke, etc.
Epidemiological studies reveal that only respiratory tumors have been consistently associated with
inhalation exposure to certain nickel compounds. Based on data from ten different cohorts, the report
215
of the International Committee on Nickel Carcinogenesis in Man (ICNCM, 1990) concluded that more
than one form of nickel can give rise to lung and nasal cancer and that much of the respiratory cancer
risk seen among nickel refinery workers could be attributed to exposure to a mixture of oxidic and
sulfidic nickel, at very high concentrations (≥10 mg Ni/m3). The ICNCM also concluded that the
carcinogenicity of soluble nickel acting alone could not be ruled out, but the evidence to support this
hypothesis was unclear and somewhat contradictory. The ICNCM report suggested that an
explanation for the contradictions was that soluble nickel exposure increases the risk of respiratory
cancer by enhancing risks associated with exposures to less soluble forms of nickel.
The association between soluble nickel exposures and increased respiratory cancer risk continues to
be seen in more recent updates of some of these cohorts (Andersen et al., 1996, Anttila et al., 1998;
Grimsrud et al. in press). However, since mixed exposures (to more insoluble nickel compounds,
cobalt compounds, acid mists, cigarette smoking, etc) are present in these cohorts, it is not possible to
use these data alone to determine whether soluble nickel exposures by themselves can cause cancer
or if they merely act to enhance the risks of known carcinogens.
The only epidemiologic studies of workers exposed almost exclusively to soluble nickel are those of
nickel platers (Sorahan et al., 1987; Pang et al., 1996). These studies are small (in terms of workers),
3
but they provide no evidence to suggest that soluble nickel exposure at or below 0.1 mg Ni/m
increase respiratory cancer risk.
In addition, there are animal studies that suggest that although soluble nickel compounds are not
carcinogenic by themselves they may be able (at certain concentrations) to enhance the
tumorigenicity of carcinogenic substances. For these effects to occur, exposures to soluble nickel
have to be high enough to induce chronic toxicity and cell proliferation. Interestingly these effects are
manifested in lung (after inhalation) and kidney (after oral ingestion) which are the target sites for
toxicity.
In the Kasprzak et al. (1990) study, the administration of a soluble nickel compound by itself did not
induce any kind of tumor, while the administration of the non-genotoxic carcinogen sodium barbital
resulted in kidney tumors in male rats. When the soluble nickel compound was administered prior to
sodium barbital, a higher number of kidney tumors (male rats) were induced. This phenomenon was
later explained by the enhanced susceptibility of male rat kidneys to the sodium barbital effects,
possibly involving the α-2 microglobulin mechanism (Kurata et al., 1994). EPA and other regulatory
agencies agree that this type of tumor should not be considered in carcinogenicity hazard assessment
for humans. The results from Kasprzak et al. (1990) are consistent with a possible “enhancing” role
for soluble nickel in the kidney rather than an initiator/complete carcinogen role. These results are
also in agreement with the results from the Kurokawa et al. (1985) study, in which oral administration
of nickel chloride did not induce any kind of tumors, but it enhanced the formation of kidney tumors by
N-ethyl-N-hydroxyethylnitrosamine (EHEN) in male rats. There are a few studies with nickel sulphate
quoted in IARC that although not well described, tend to support the above findings from other soluble
nickel compounds.
Tumor Promoter Studies with Soluble Nickel Compounds
REFERENCE
SPECIES
MATERIAL
RANGE OR HIGHEST
EXPOSURE
RESULT
Ni Cl2•6H2O
EHEN+NiCl2
600 ppm Ni
600 ppm Ni
♂ Rats
•
•
−
+ for kidney
5.3 mg Ni/kg
♂ Rats
•
•
•
−
+ for kidney
+ for kidney
5.3 mg Ni/kg
Rats
Oral Studies
Kurokawa et al 85
•
•
Intraperitoneal Studies
Kasprzak et al 90
•
•
•
Diwan et al 92
[transplacental]
•
•
Ni acetate
NaBB
Ni acetate +
NaBB*
Ni acetate
Ni acetate +
NaBB*
• −for kidney
+ for pituitary*
• + for kidney (♂) &
+ for pituitary*
The NTP inhalation studies of rats and mice indicate that exposure to soluble nickel compounds can
induce respiratory toxicity manifested by inflammation and fibrosis in rats and mice. Chronic inhalation
216
of soluble nickel at concentrations above those that cause chronic inflammation does not appear to
produce tumors but it may enhance the carcinogenicity of concomitant exposures to respiratory
carcinogens such as nickel subsulfide, certain nickel oxides and/or cigarette smoke. Exposures to
concentrations of soluble nickel compounds below the threshold for respiratory toxicity would not be
expected to enhance carcinogenic effects of other substances.
7) How can the genotoxicity of soluble nickel compounds observed in in vitro studies be
reconciled with the general lack of carcinogencity of soluble nickel compounds in
animal studies
In general, studies of genotoxicity in bacteria or cultured cells have indicated that nickel compounds
can induce chromosomal aberrations and cellular transformation but not gene mutations. Most nickel
compounds (and perhaps metallic nickel) have the ability to induce these effects albeit at different
concentrations. Soluble nickel compounds require higher concentrations than particulate nickel
compounds to see the same effects. The lower genotoxic potency of soluble nickel compounds is
attributed to the ineffective cellular uptake of the nickel ion from soluble nickel compounds compared
to the effective phagocytosis mechanism for more insoluble nickel compounds.
Current models for nickel-mediated induction of respiratory tumors suggest that the main determinant
of the respiratory carcinogenicity of a nickel compound is likely to be the bioavailability of the Ni (II) ion
at nuclear sites of target epithelial cells (Costa, 1991; Oller et al., 1997; Haber et al., 2000). Only
those nickel compounds that result in sufficient amounts of bioavailable nickel ions at nuclear sites of
target cells (after inhalation) will be respiratory carcinogens.
The factors that will influence Ni (II) ion bioavailability in epithelial cells of the lung are: presence of
particles on bronchio-alveolar surface, mechanism of lung clearance (dependent on solubility),
mechanism of cellular uptake (dependent on particle size, particle surface area, particle charge), and
intracellular release rates of Ni (II) ion. Those nickel compounds that are: (1) insoluble enough to
allow accumulation of particles at the cell surface, (2) have an intermediate lung clearance rate that
allows them to persist in the lung, (3) have a high uptake of particles into epithelial cells via
phagocytosis, and (4) have increased release rates of Ni (II) ion inside the cells, will result in greater
accumulation of Ni (II) ion at nuclear target sites. Inhalable size particles of nickel subsulfide
represent a good example of a high Ni (II) bioavailable dust for respiratory carcinogenesis.
By contrast, water soluble nickel compounds will not be present as particles on the cell surface (rather
there will be Ni (II) ions and counter ions), will experience rapid clearance from the lung (decreasing
the availability of Ni (II) ions for transport into the cell), will have inefficient transport into the cells
through the cell membrane (e.g., magnesium channels, Hausinger, 1992), and will avidly bind to
proteins inside and out of the cells (Harnett et al., 1982). The end result is that even inhalation of very
high concentrations of soluble nickel compounds will not lead to high enough bioavailability of Ni (II)
ions (at nuclear target sites of lung epithelial cells) to induce tumors.
Only inhalation studies can be used to evaluate the interaction of all the above mentioned factors that
determine Ni (II) ion bioavailability at target sites. The NTP animal studies (NTP 1996 a,b,c) are
consistent with the nickel ion bioavailability theory described above.
The DRA document cites the Haber et al. (2000, pages 220-224) discussion of a mode of action that
suggests that soluble nickel compounds may have a different mode of action at low (non carcinogenic)
and high (carcinogenic) doses. This is a theoretical possibility that is consistent with the model
described above. In vivo, however, the high concentrations of soluble nickel compounds needed to
induce tumors (rather than simply to promote cell proliferation) are unlikely to be reached because
humans or animals would be expected to experience severe respiratory toxicity before high enough
levels are achieved at target nuclear sites. The available animal data support this contention.
The in vitro data can be reconciled with the negative animal data because in vitro studies do not
account for organ clearance. Therefore, if concentrations of soluble nickel are high enough in the
Petri dish, given enough time, some nickel ions will eventually reach the nucleus of the cells. In vivo,
this is not the case. The inefficient cellular uptake of nickel ions is complemented by the rapid
clearance of soluble nickel compounds. Because of the toxicity of soluble nickel compounds, exposed
animals are likely to die before a high enough concentration of nickel ions (i.e., the concentration
needed to induce tumors) can be reached in the nucleus of respiratory target cells.
217
The model discussed above fits not just the available respiratory data for various categories of nickel
compounds, but also fits with the lack of carcinogenicity for soluble nickel via oral exposure. After
ingestion, a fraction of the free nickel ion will be absorbed from the gastrointestinal tract into blood. In
blood, the nickel ion circulates mainly bound to albumin or amino acids. Bioavailability of nickel ions at
nuclear sites of systemic target cells will be limited by some of the same factors that operate in the
lung: inefficient cellular uptake, rapid kidney clearance, high affinity for blood amino acids and
proteins. Therefore, the lack of systemic carcinogenicity of oral nickel is consistent with the respiratory
mechanism of tumor induction by nickel compounds.
8) Can animal-based respiratory toxicity data (used as a surrogate for tumor promotion
effects) predict excess cancer risks seen in workers exposed to soluble nickel
compounds?
If soluble nickel compounds can enhance the respiratory carcinogenicity of inhalation carcinogens, this
enhancement will occur at concentrations above those that cause chronic lung inflammation, (i.e.,
chronic cell proliferation). Seilkop and Oller (2002) have used respiratory toxicity data from the NTP
inhalation study with nickel sulfate hexahydrate to predict excess cancer risk in workers exposed to
equivalent concentrations to those that induce chronic lung inflammation in rats.
Table 3 shows the estimated range of workplace inhalable exposures to soluble nickel (0.5 –1.0 mg
3
Ni/m , for model with best fit) that could result in enhanced tumorigenicity (SMR = 200) of other
exposures. These exposure levels can be compared with soluble nickel exposures at Kristiansand
shown in Table 4 (from Grimsrud et al., 2002).
Table 3. Occupational Exposure Limits and High Risk Concentrations Derived from Fitted Animal
Dose-Response Curves (from Seilkop and Oller, Respiratory Cancer Risks Associated with Low-level
Nickel Exposure: An Integrated Assessment Based on Animal, Epidemiological, and Mechanistic
Data, submitted to JOEM)
Nickel Compound,
Animal Endpoint
Nickel Oxide
Lung Tumors,
Male and
Female Rats[41]
Model
Weibull
Gamma
Nickel Sulfate
Lung Inflammation,
Weibull
Male and Female
Rats[42]
Gamma
Nickel Subsulfide
Lung Tumors,
Male and Female
Rats[40]
Nickel Subsulfide
DNA strand breaks,
Male Rats [57]
Linear
Model Fit
Observed (Obs) and Expected (Exp) Responses
Dose
(mg
Ni/m3)
0.0
0.5
1.0
0.0
0.5
1.0
0.0
0.03
0.06
0.0
0.03
0.06
0.0
0.11
0.44
n
Data
Model1
pvalue2
107
106
106
107
106
106
106
106
106
106
106
106
106
106
106
2
1
12
2
1
12
28
26
91
28
26
91
2
12
20
1.5
1.5
12
1.5
1.5
12
27.0
27.0
91.0
26.0
28.2
90.7
4.4
7.3
22.1
0.56
Occupational
Exposure Limit
Concentrations
Associated with 10-4
Risk3
(mg Inhalable Ni/m3)
0.5 – 1.1
(8-18)
“High Risk”
Concentrations
Associated with
SMR=2004
(mg Inhalable
Ni/m3)
9-19
(12-24)
0.56
0.6 – 1.4
(6-14)
9-19
(11-23)
0.72
0.1-0.2
(1.0-1.4)
0.5 – 1.0
(1.1-2.0)
0.50
0.2 – 0.4
(0.5-0.7)
0.6-1.1
(0.7-1.3)
0.002 – 0.010
(0.004- 0.015)
1.8 – 6.1
(2.8 – 9.4)
0.03
0.02 – 0.06
0.6-2.0
0
5
268
263
NA5
(0.8 – 2.8)
(1.2 –4.0)
0.04
4
256
263
0.11
5
316
316
0.44
5
339
339
1
2
2
Model prediction. p-value for Χ (1 df) goodness of fit test.
3
Range reflects upper and lower limits of estimated animal to human exposure extrapolation factors
(Table 6) applied to lower 95% confidence limit on exposure corresponding to 10-4 increased risk in
animals. Parenthesized range reflects animal to human extrapolation of maximum likelihood estimate
of exposure corresponding to 10-4 risk in animals.
Hill
218
4
Range reflects upper and lower limits of estimated animal to human exposure extrapolation factors
(Table 6) applied to lower 95% confidence limit on exposure corresponding to a 6x10-2 increased risk
in animals, which approximates the 75-year lifetime background lung cancer risk in U.S. white
males[36] and Canadian males[37]. Thus, the exposure corresponding to an increased risk of 6x10-2
would double the human background risk, producing an SMR of 200. Parenthesized range reflects
animal to human extrapolation of maximum likelihood estimate of exposure corresponding to 6 x 10-2
increased risk in animals.
5
NA – model has as many parameters as data points; goodness of fit statistic could not be calculated
Table 4. Exposure estimates for Kristiansand’s nickel refinery (based on data from Table 3 Grimsrud
et al., 2002).
Years
Total Ni
Inhalable
%
Inhalable
Inhalable
Ni
soluble
soluble
Insoluble
Crushing, grinding
1910-94
0.7-1.4
1.4-2.8
0.12
1.2-2.5
0.2-0.3
Old smelter building 1910-29
4.0
8
0.10
7.2
0.8
no. 1
30-50
4.0
8
0.10
7.2
0.8
51-77
2.6-4.4
5.2-8.8
0.10
4.5-7.9
0.5-0.9
Calcining smelting
51-77
1.5-3.4
3.0-6.4
0.10
2.7-5.8
0.3-0.6
dep
78-94
0.5
1.0
0.12
0.1
0.9
Roasting dep
1910-77
1.9-5.3
3.8-10.6
0.10
3.4-9.5
0.4-1.1
78-94
0.4
0.8
0.15
0.1
0.7
Copper leaching
1910-94
0.1-1.5
0.2-3.0
0.49
0.1-0.15
0.1-1.5
Copper electrolysis 1910-94
0.03-0.2
0.06-0.4
0.80
0.01-0.08
0.05-0.3
Copper
1927-77
0.6-1.2
1.2-2.4
0.45
0.66-1.3
0.5-1.1
cementation
Electrolysis
1927-77
0.2-0.5
0.4-1.0
0.80
0.1-0.2
0.3-0.8
purification
78-94
0.03-0.2
0.06-0.4
0.98
0.06-0.4
≤ 0.01
Nickel electrolysis
1910-77
0.1-0.2
0.2-0.4
0.87
0.03-0.05
0.2-0.3
78-94
0.03-0.1
0.06-0.2
0.83
0.05-0.2
0.01-0.03
Soluble exposure ranges in bold are all consistent with SMRs of 200 due to the tumor enhancing
effects of soluble nickel. Elevated SMRs (100 ≤ SMR ≤200) may be predicted for soluble nickel
exposure ranges in italics. Based on this analysis, the epidemiological data for Kristiansand would be
consistent with soluble nickel compounds acting as tumor promoters.
Together, the negative animal data, in conjunction with the epidemiological and mechanistic data
suggest a possible enhancing rather than a direct carcinogenic role for soluble nickel compounds.
References
[References are shown in Chapter 6. The references shown here are additional references].
Diwan, B. A., Kasprzak, K. S., and Rice, J. M. Transplacental carcinogenic effects of nickel(II) acetate
in the renal cortex, renal pelvis and adenohypophysis in F344/NCr rats. Carcinogenesis 13(8):13511357 (1992).
U.S. EPA. Methods for derivation of inhalation reference concentrations and application of inhalation
dosimetry. U.S. Environmental Protection Agency. EPA/600/8-90/66F, (1994).
Haseman, J.K.; Eustis, S.L.; and Arnold, J. Tumor Incidences in Fischer 344 Rats: NTP Historical
Data. In: Pathology of the Fischer Rat: Reference and Atlas, edited by Boorman, G.A.; Eustis, S.L.;
Elwell, M.R.; Montgomery, Jr., C.A.; and MacKenzie, W.F., pp. 555-564, Academic Press, San Diego,
California, (1990).
Harnett, P. B., Robison, S. H., Swartzendruber, D. E., Costa, M. Comparison of protein, RNA, and
DNA binding and cell-cycle-specific growth inhibitory effects of nickel compounds in cultured cells.
Toxicol. Appl. Pharmacol., 64: 20-30, (1982).
Hausinger, R. P. Biological utilization of nickel. In Nickel in human health: current perspectives (E.
Nieboer, and J. O. Nriagu, Eds. John Wiley and Sons, Inc. New York, NY. Pages 21-36, (1992).
219
Hsieh, T. H.; Yu, C. P.; Oberdörster, G. Deposition and clearance models of Ni compounds in the
mouse lung and comparisons with the rat models Aerosol Science and Technology, 31:359-372
(1999).
ICNCM. Report of the International Committee on Nickel Carcinogenesis in Man, Scand Work
Environ Health 1990; 16:1-82, (1990). [Listed in Chapter 6 as Doll et al. (1990)]
Kasprzak, K. S. Lack of carcinogenic activity of promptly soluble (hydrated) and sparingly soluble
(anhydrous) commercial preparations of nickel (II) sulfate in the skeletal muscle of male F334/NCR
rats. Toxicologist, 14:239 (1994).
Kurata Y, Diwan BA, Lehman-McKeeman L, Rice JM, Ward JM. Comparative hyaline droplet
nephropathy in male F344/NCr rats induced by sodium barbital and diethylacetylurea, a breakdown
product of sodium barbital.
Toxicol Appl Pharmacol. Jun;126(2):224-32, (1994).
Kurokawa, Y., Matsushima, M.; Imazawa, T.; Takamura, N.; Takahashi, M; and Hayashi, Y. Promoting
effect of metal compounds on rat renal tumorigenesis. J. Am. Coll. Toxicol. 4:321–330 (1985).
Kasprzak, K. S., Diwan, B. A., Konishi, N., Misra, M., and Rice, J. M. Initiation by nickel acetate and
promotion by sodium barbital of renal cortical epithelial tumors in male F344 rats. Carcinogenesis,
11(4):647-652 (1990).
Mennel, H.D. Transplantation of tumors of the nervous system induced by resorptive carcinogens.
Neurosurg. Rev., 1:123 (1978).
NTP (National Toxicology Program) Technical Report. Toxicological and carcinogenesis studies of
nickel subsulfide in F344/N rats and B6C3F1 mice. NTP TR 453, NIH Publication Series No. 96-3369.
(1996a). [Listed in Chapter 6 as NTP (1996b)]
nickel oxide in F344/N rats and B6C3F1 mice. NTP TR 451, NIH Publication Series No. 96-3363,
(1996b). [Listed in Chapter 6 as NTP (1996c)]
nickel sulfate hexahydrate in F344/N rats and B6C3F1 mice. NTP TR 454, NIH Publication Series No.
96-3370, (1996c). [Listed in Chapter 6 as NTP (1996a)]
Oller, A. R., Costa, M., and Oberdörster, G. Carcinogenicity assessment of selected nickel
compounds. Toxicol. Appl. Pharmacol., 143:152-166 (1997).
Seilkop, S.K. and Oller, A. R. Respiratory cancer risks associated with low-level nickel exposure: An
integrated assessment based on animal, epidemiological, and mechanistic data. Submitted to JOEM.
Sorahan, T., Burges D.C.L., Waterhouse, J. A. H. A mortality study of nickel/chromium platers. Br. J.
Ind. Med. 44: 250-258, (1987).
Sunderman, F.W; McCully, K. S.; Rinehimer, L. A. Negative test for transplacental carcinogenicity of
nickel subsulfide in Fischer rats. Res. Commun. Chem. Pathol. Pharmacol. 31:545-554 (1981).
Yu, C. P., Hsieh, T. H., and Oberdörster, G. Dosimetry of inhaled nickel compounds. Abstract and
presentation made at the American Association for Aerosol Research Annual Meeting held June 2226, 1998, Cincinnati, Ohio.Chem. Pathol. Pharmacol. 31:545-554 (1998).
Yu, C. P.; Hsieh, T. H.; Oller, A. R.; Oberdörster, G. Evaluation of the human Ni retention model with
workplace data. Regulatory Toxicology and Pharmacology, 33:165-72 (2001).
220
7.7
NIPERA COMMENTS ON MECHANISTIC CONSIDERATIONS
ON NICKEL ION CARCINOGENICITY
(The following text is an extract of the comments provided by NiPERA in April 2002 as agreed at the IndustryRapporteur meeting on carcinogenicity in April 12th 2002 ).
Current models for nickel-mediated induction of respiratory tumours suggest that Ni (II) ion bioavailability will
be the main determinant of the respiratory carcinogenicity of a nickel compound (Costa, 1991; Oller et al., 1997;
Haber et al., 2000). Only those nickel compounds that result in sufficient amounts of bioavailable nickel ions at
nuclear sites of target cells (after inhalation) will be respiratory carcinogens. The factors that will influence Ni
(II) ion bioavailability in epithelial cells of the lung are: presence of particles on bronchio-alveolar surface,
mechanism of lung clearance (dependent on solubility), mechanism of cellular uptake (dependent on particle
size, particle surface area, particle charge), and intracellular release rates of Ni (II) ion. Those nickel compounds
that are: (1) insoluble enough to allow accumulation of particles at the cell surface, (2) have an intermediate
lung clearance rate that allows them to persist in the lung, (3) have a high uptake of particles into epithelial cells
via phagocytosis, and (4) have increased release rates of Ni (II) ion inside the cells, will result in greater
accumulation of Ni (II) ion at nuclear target sites. Inhalable size particles of nickel subsulfide represent a good
example of a high Ni (II) bioavailable dust for respiratory carcinogenesis.
By contrast, water soluble nickel compounds will not be present as particles on the lung surface (rather there will
be Ni (II) ions and counter ions), will experience rapid clearance from the lung (decreasing the availability of Ni
(II) ions for transport into the cell), will have inefficient transport into the cells through the cell membrane (e.g.,
magnesium channels, Hausinger, 1992), and will bind to proteins inside and out of the cells (Harnett et al.,
1982). The end result is that even inhalation of very high concentrations of nickel sulphate hexahydrate will not
lead to high enough bioavailability of Ni (II) ions to induce tumours. These predictions are consistent with the
negative results in the NTP rat inhalation study and with the lack of systemic carcinogenicity of oral nickel.
These results do not contradict the positive in vitro studies. In vitro there is no clearance. If concentrations are
high enough and exposures long enough, eventually some Ni ion will reach the nucleus and cause a positive
genotoxic effect. This is precluded in vivo by the rapid clearance and the whole animal toxicity/mortality that is
evident at lower doses than those that can induce tumours.
The NTP inhalation studies of rats and mice clearly indicate that exposure to nickel sulphate hexahydrate can
induce respiratory toxicity manifested by inflammation and fibrosis in rats and mice. Chronic inhalation of
nickel sulphate hexahydrate at concentrations above those that cause chronic inflammation may enhance the
carcinogenicity of concomitant exposures to respiratory carcinogens such as nickel subsulfide, certain nickel
oxides and/or cigarette smoke (non genotoxic mechanism). This is in agreement with the findings from the
epidemiological studies. Exposures to concentrations of soluble nickel compounds below the threshold for
respiratory toxicity would not be expected to enhance carcinogenic effects of other substances.
221
7.8 FURTHER STATISTICAL ANALYSIS OF THE SLI 2000B 2GENERATION REPRODUCTIVE TOXICITY STUDY
Modified from an abstract to the International workshop on statistical modelling.
Generalized linear model with overdispersion
– a case study of the toxicogical effect of nickel sulphate hexahydrate on
postimplantation-perinatal mortality rate in rats
Helle M. Sommer, Ph.D., M.Science, statistician, The Danish Veterinary and Food Administration; Ulla Hass,
Ph.D, M. Science, reproductive toxicologist, The Danish Veterinary and Food Administration
Poul Thyregod, Associate Professor in Statistics, Danish Technical University
Keywords toxicity study, generalized linear model, binomial distribution, intralitter correlation, overdispersion.
This case study is based on the results of an oral (gavage) two-generation reproduction toxicity study in SpragueDawley rats with nickel sulphate hexahydrate (SLI 2000b).
In obtaining reliable results from toxicity studies one of the cornerstones is the choice of the statistical test
method. Depending on the choice of method, different results may be obtained, however, some methods are
usually more appropriate than others. In this presentation, an approach based upon binomial proportions (a
generalized linear model with overdispersion) is described and compared to the method suggested by the
industry (a Mann-Whitney test on the mortality rate per litter). A primary characteristic of the binomial
overdispersion model is that it accounts for the structure of the type of data and for the important issue of the
litter effect, and hence is believed to have greater power.
Toxicity study
Toxicity studies are performed to provide information concerning the toxic effects of a test substance, in this
case the toxic effect of the presence of the substance in food / drinking water. The purpose of the study was to
evaluate the potential effect of nickel sulphate hexahydrate on the integrity and performance of the male and
female reproductive systems and the effects on peri-postnatal mortality rate. In this presentation, focus is on the
mortality of the offspring due to maternal exposure during pregnancy and lactation. In order to determine the
dose of the substance (given to the parents) that has an effect on the perinatal mortality of the offspring, the study
was designed with a control group (group 1) and four test groups with increasing doses (group 2-5). The
estimation of / decision on the dose that causes no toxic change, e.g., the no-observed-effect level, lies outside
this presentation.
Each group contained between 25 to 28 female rats, which were given the substance orally dissolved in water at
dosage levels of 1.0, 2.5, 5.0 or 10.0 mg/kg/day (group 2-5 respectively). Dosing began at 10 week prior to
mating and continued until the day prior to scheduled euthanasia. Control animals were given water under the
same experimental conditions. After the euthanasia of the maternal rats after weaning of the offspring, the peripostnatal lethality in each litter was calculated (total number of implantations minus total number of live pups on
the 4th day after birth in each litter).
The response is given, as the number of dead versus the total number of implantations in the litter. Each litter
varies in size from 4 to 19, however there were no significant correlation between the size of the litter and the
mortality rate. An example of the structure of the data is given in Table 1.
Group
(control)
Litter 1
0/6
Litter 2
1 / 17
and so on … litter 28
…
“Mean mortality rate” 0,074
(percentage)
1 Group 2
1 mg/kg/day
2 / 12
2 / 13
…
0,084
Group 3
2.5 kg/kg/day
2 /16
0 / 14
…
0,090
Group 4
5 mg/kg/day
3 / 14
1 / 13
…
0,101
Group 5
10 mg/kg/day
3 / 16
1 / 12
…
0,169
222
Statistical analysis
The response data can be described by binomial distributions (number of dead versus total number of implants).
The data material can be analysed in pairs (e.g. a certain group versus the control) or as a regression due to the
increasing dose. In both cases the analysis is carried out in the generalized linear model with a logistic link
function (ln(p/(1-p) = ϑ ) due to the binomial distributed response data. The canonic parameter ϑ could now be
described by the linear function:
ϑ = β + gj , j = 1,2…5
or
(comparing of groups)
ϑ = β + γ·dj , j = 1,2…5 (regression)
where β is the intercept, g is the deterministic effect from the groups, γ is the slop of the regression line and d is
the dose level. A goodness of fit test for the level model and for the regression analysis revealed a bad fit (P =
0.0005) and it could be concluded that there was more variation in the system than could be explained by the
model and thereby by the binominal distribution.
The intralitter correlation among responses from offspring in the same litter was suspected to be significant
meaning that the biological variability between litters should not be ignored. Since the biological variability
between litters turned out to be significant, the linear functions given above are insufficient in describing the
system. This lack of fit is the so-called ‘litter effect’, and the tendency for fetuses from the same litter to respond
more alike than fetuses from different litters has long been recognized. Consequently, the conventional binomial
distribution provides poor fit to this kind of data, known as the “extra binomial variation” phenomenon, or
overdispersion, and hence, in the framework of generalized linear models, this extra binomial variation could be
modelled by introducing a dispersion parameter in the model. The dispersion parameter, φ, describes how many
times larger the actual variance is compared to the variance of the binomial distribution.
Results
The main result shows a significant raise in the peri-postnatal mortality rate in the offspring due to maternal
exposure of nickel sulphate hexahydrate before and during pregnancy. This result was found both
1) when analysing for total homogeneity comparing all 5 groups and
2) when comparing group 1 against 5 and
3) when comparing 1, 2, 3, and 4 against group 5 and
4) when using the regression analysis for all 5 dose levels.
The reason for pooling group 1 – 4 is due to the industry’s concern of the control group, which in their opinion
showed an unrealistically low mortality rate compared to historical control values.
The dispersion parameter was found to be 1.3, meaning that the actual variance is 30% larger than what could be
explained by the binomial distribution due to biological variability between the litters.
The significance level (P-values in Wald tests) for the mortality rate for analysis 1), 2), 3) and 4) for modelling
with and without the overdispersion was found to be:
Analyses
1)
2)
3)
4)
P-value without overdispersion
0.0004
0.0002
< 0.0001
< 0.0001
P-value with overdispersion
0.0115
0.0078
0.0004
0.0004
Programming in SAS
All analyses under the generalized linear model were performed using SAS Insight (fit option) with the number
of dead offspring set as response variable (Y), and the group indicator as explanatory variable (X). The Response
Distribution was chosen to binomial and the logit (or canonical) Link Function was chosen. The dispersion
parameter (Scale) was set to Deviance and Quasi-likelihood was chosen as estimation method. The Binomial
number of trials was set to the size of the litters.
Discussion
In the framework of experimental design, the litters act as blocks, and hence a possible litter effect might be
modelled as a random effect. In studies of maternal exposure during pregnancy, the litter effect could be
included by a hierarchical distribution structure. To account for the litter effect, the literature has suggested that
the beta-binomial distribution be used as a means to describe the extra binomial variation (e.g. Williams 1975,
Haseman and Kupper 1979).
223
Lee and Nelder (2000) note that for generalized linear models, the variance functions under an adjustable
dispersion parameter differs from that under a random effect model, and furthermore introduces a combined
approach in a so-called hierarchical generalized linear model.
However, in the present study it was found that the small span of dosage levels did not warrant such an
approach. Moreover an investigation of the deviance residuals did not suggest that a more detailed modelling
was relevant.
Comparing with the Mann-Whitney method.
In the sector of industry, the Mann-Whitney U-test is the test analysis that is most often employed for these kinds
of results from toxicity studies. Under this test, no significance was demonstrated for the present data set when
comparing group 1 to group 5. However, the Mann-Whitney test simply does not use all information that lie
within the data set and this fact contributes to a blurred picture compared to the generalized linear model and
therefore the Mann-Whitney tests has less power to detect potential differences.
We find that the use of the Mann-Whitney test is not very appropriate for the present toxicity study. As it is a
nonparametric test, it does not use information concerning the distribution of the data nor of the known sizes of
the litters. The assumption on identical distribution of data in each group is clearly violated because of the
varying litter sizes. Moreover a Mann-Whitney test assumes that there are no tied ranks (Altman 1991) which is
not achieved for the present set of data. If there are many identical data values, complicated correlations should
be applied to the large sample formula.
224
7.9 INFLUENCE OF A POTENTIAL NICKEL SENSITIVITY ON THE
FREQUENCIES OF POSTIMPLANTATION/PERINATAL
LETHALITY IN F1 AND F2 OFFSPRING
The influence of a potential genetic predisposition to nickel sensitivity/resistance on the frequency of
postimplantation/perinatal lethality in F2 offspring can be estimated based on the frequency of
postimplantation/perinatal lethality in F1 offspring. If it is assumed that there is a genetic predisposition to nickel
resistance, it is reasonable to assume that the predisposition to vulnerability is recessive as only some of the
offspring in the litters showed the effect in the F1 generation, and that inheritance is Mendelian.
The F0 generation and the F1 offspring will comprise homozygotes for nickel resistance and nickel sensitivity
and heterozygotes for nickel resistance (AA : Ab:Ab : bb; A = dominant, resistance; b = recessive, sensitive). If,
as a worst case, all of the F1 homozygous recessives were eliminated prior to weaning, the population would
consist of heterozygous recessives and homozygous dominant resistants (AA; Ab: Ab), all with a resistant
phenotype. At pairing of the F1 adults, the resulting F2 generation would again consist of AA, Ab and bb
individuals. The bb individuals would be affected by nickel, and there would be additional perinatal mortality,
greater than that seen in the controls.
The extent of the mortality would be determined by the relative frequencies of the gene types. The frequency of
this hypothetical recessive gene (or genes) is not known. If the additional mortality at 2.2 mg Ni/kg bw/day in F1
is due to heritable sensitivity, then the frequency of recessive homozygotes must be relatively low. If a lethal
recessive gene has a homozygous frequency of 1% in the first generation, the frequency in the second generation
will be 0.83%, while a frequency of 9% in the first generation will lead to a frequency of 5.33% in the second
generation. In other words, in successive generations, a rare recessive lethal gene is expressed at approximately
the same frequency. This explains why rare recessive heritable conditions such as Wilson’s disease and
Huntington’s chorea do not die out in the human population. However, the additional mortality in F1 is around
9% (control 7.4%, exposed 16.9%) and therefore the frequency of recessive homozygotes in the second
generation is estimated to be around 5.3%. This implies that hypothetical sensitivity to nickel could not be totally
eliminated by exposure at a single generation, but the frequency of sensitive offspring would be reduced from
9% to 5.3%. The mortality in F2 is 10.5% (37/252) and compared to the control value from F1 (7.4%) this gives
an additional mortality of 3.1% in F2. This is somewhat lower than the expected 5.3%, however, due to the
number of litters used and the variability in the end point, it cannot be expected to have an exact match.
Another test of this hypothesis can be made on this study since the study report allows investigation of paternity
(see Table 4.1.2.8.3.A in chapter 4). The F1 adults are numbered according to their F0 parents (e.g. an F1 adult
arising from F0 dam 308 is numbered 308-14). It is therefore possible to determine if the surviving offspring
from litters at 2.2 mg Ni/kg bw/day passed on any susceptibility to the F2 offspring. Examination of the resulting
lethality data demonstrates no obvious pattern at first glance (Table 7.9.A), even where both parents came from
‘susceptible’ litters. There are three cases where both F1 parents were from litters with high losses (> 25% loss)
and the results in F2 are one case with low loss (11%) and two cases of high losses (29.4% and 100% loss), i.e.
the frequency of affected litters is 67% (or 50% if the single case of total litter loss is excluded). The probability
that litters will be affected when both parents are from affected litters is 44.4%. Consequently, the observations
in the three litters of parents from affected litters, although based on low number of animals, is in agreement with
the hypothesis.
225
Table 7.9.A: Comparison of Perinatal Mortality between F1 litters and F2 litters
F1 (N =28)
F2 (N = 24)
Group 5 Dam No. Pre, peri and post natal
loss (%) F0F1 litter
Group 5 Dam
No.
Group 5 Sire No. Pre, peri and post natal
loss(%), F1F2 Litter
308
18.8
308-14
336-02
21.4
318
8.3
318-04
337-04
8.3
318-10
352-08
0.0
319
35.7
319-10
358-04
0.0
327
16.7
327-04
362-02
12.5
331
0.0
331-08
364-03
20.0
333
10.0
333-06
378-08
5.6
336
13.3
336-08
394-05
20.0
337
33.3
337-07
395-06
7.1
352
14.3
358
18.8
358-09
399-02
0.0
362
0.0
364
0.0
364-13
415-02
0.0
378
42.9
378-10
434-02
29.4
394
0.0
394-11
435-03
17.6
395
6.7
395-15
437-03
0.0
396
0.0
396-16
437-05
11.8
399
0.0
405
35.7
405-08
441-02
11.1
415
0.0
434
36.8
434-10
626-02
12.5
434-08
331-06
20.0
435
6.3
435-13
627-07
0.0
437
37.5
437-08
308-02
0.0
438
6.3
438-15
318-03
6.3
441
31.3
441-10
319-07
100.0
448
0.0
448-04
327-02
13.6
452
40.0
626
15.4
627
15.4
627-11
333-04
11.1
Numbers in bold indicate where there was F1 Perinatal Mortality > 25% (i.e., 1 in 4 mortality in a litter).
F1 adults arising from these litters and mortality in F2 litters where both parents are from these litter are also
shown in bold.
The assumption of some heritability is important for the argument that the lack of significant perinatal mortality
in the F2 generation is due to the death of susceptible individuals in the F1 generation. The calculations above
demonstrate that the increase in offspring mortality in the F2 generation will be of a smaller magnitude than seen
in the F1 generation, i.e. reduced from 9% in F1 to 5.3% in F2. The increase in F2 is around 3% and based on the
number of litters included and the variability in the end point it is not surprising that this increase is not
statistically significant. Therefore, it can be concluded that the finding of a significant effect in F1 but not in F2
may not be an inconsistency, but can be explained by the selection of the F1 parents (i.e. excluding sensitive,
homozygous recessives).
226

Nickel sulfate - The Danish Environmental Protection Agency

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