Fragrance Ingredients and Dermal Sensitization

Fragrance Ingredients and
Dermal Sensitization
Anne Marie Api, PhD
Vice President, Human Health Sciences
Personal Care Products Council
Safety Seminar
October 4, 2012
Fragrance Ingredient Safety
Member
Companies
Code of
Practice
&
Standards
I
F
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F
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Expert
Panel
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Research
& Testing
Safety
Evaluations
Human Health Research:
Fragrance Allergy
 Autoxidation (2003 – 2008)
 Investigate the fundamental scientific basis of the
autoxidation of 4 important structurally related fragrance
ingredients and one essential oil
 Elicitation Threshold – Eugenol (2012)
 To determine the threshold for elicitation of contact allergy
using two methods - patch testing and repeated open
application testing
 Epidemiology (2006-2011)
 Determine the prevalence of fragrance allergy in the general
population
 Supplying Patch Test Materials
 Supply fragrance ingredients to patch test suppliers free of
charge to ensure that good quality commercial samples are
tested.
 Other Diagnostic Patch Tests
 Work with dermatologists to monitor the implementation of
the QRA
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Autoxidation
 2007- 2009, peroxide values were determined using the
FMA method for 875 freshly manufactured fragrances to be
used in various consumer products. The sum of dlimonene plus linalool concentration ranged from 0 to
89.67%.
 All had peroxide values< 15 mmol/liter
 34 hydroalcoholic perfume products were retrieved from
retail establishments (20 women’s and 14 men’s products).
 None of the hydroalcoholic perfumes retrieved from retail
establishments had peroxide values > 5 mmol/liter
 80 hydroalcoholic fragrance products were retrieved from
end-use consumers. These had been opened and used by
the consumers for variable periods of time ranging from a
few months to 5 years
 None of the fragrances retrieved from consumers had
peroxide values exceeding 10 mmol/l
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Elicitation Threshold Studies
 Elicitation Threshold – Eugenol (planned 2012)
 To determine the threshold for elicitation of contact
allergy using two methods - patch testing and repeated
open application testing
 Pilot 1 - Does the New Standard for Eugenol Designed
to Protect Against Contact Sensitization Protect Those
Sensitized From Elicitation of the Reaction?
Svedman et al., Dermatitis 23(1):32-38, 2012
 Pilot 2 - A pilot study aimed at finding a suitable
eugenol concentration for a leave-on product for use in
a repeated open application test.
Svedman et al., Contact Dermatitis 66(3), 132-139, 2012
Further Elicitation Threshold studies on other
weak sensitizers used in fragrances
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EDEN Epidemiology Study
2005-2006
Phase I
Validation
Questionnaire
Development
Reviewed by
Dr. S. Chen,
Emory
University
2007-2008
Phase II
Pilot Study
600 subjects
(100/center)
Statistical analyses
• All subjects patch
tested
Validation
Study modalities
evaluation
Reproducibility
Definition of sampling
procedures and subject
recruitment
Patch Test
Procedures
6th center added
(Portugal) by RIFM
request afterwards
2008-2011 Full
Study
Protocol reviewed &
approved by
RIFM Board
recommendation: full
independent
epidemiologist, Dr. H study extended over 3
Rockette, Univ. of
yrs to defer costs
Pittsburgh
EDEN delayed in
getting all data; 2
centers started later
Each patch test center
was monitored by
expert in patch testing
- Dr. M. Isaksson,
Skane University
Hospital
EDEN needed time to
consolidate & analyze
all data in database
• >12,000 subjects
• >3,000 patch tested
Each center was
monitored by
independent
epidemiologist, Dr.
B.M Zaadstra
Epidemiology: Instrument
 Original and landmark study
 Rigorous scientific quality
 Patch testing- 50 materials
 29 materials - European Standard
Series
 20 “fragrance materials”
 Standardization of patch testing;
unprecedented calibration
performed
 Training – video & classes for patch
testing
 Controlled commercial grade
samples
 Blind comparison patch test &
history
 Website established
 Baseline data particularly for
introduction of QRA
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Epidemiology: Instrument
published 2010 (peer-reviewed)
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QRA: Why?
 Goal or ideal state is to
eliminate fragrance allergy
in the general population
 Core strategy for primary
prevention of dermal
sensitization to fragrance
ingredients in consumer
products
 Prevent induction of
sensitization to fragrance
ingredients (primary
prevention) more effectively
than we have in the past
Lead with a scientifically
rigorous strategy
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Regulatory , Toxicology &
Pharmacology
Special Issue Oct. 2008
Dermal Sensitization QRA for
Fragrance Ingredients
7 manuscripts including
Api et al. - QRA method
QRA paperMcNamee
is
et al. - HRIPT
scientific review
among the 10 most
Politano & Api - HRIPT
cited papers in RIFM method
Kimber et al. - Dose Metric
Reg. Tox. & Pharm.
for 2007-2008
Peer review: an
essential part of
scientific publication
QRA paper represents
recognition of the
approach by the
scientific community
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Risk Assessment –
General Principles
 Acceptable Exposure Level (RfD or
AEL) Estimate of a daily exposure to an
agent that is assumed to be without a
health impact in the human population
Acceptable
NOEL
Exposure Level =
Uncertainty Factor (UF)
(RfD or AEL)
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QRA For Dermal Sensitization
Fragrance Ingredients
Application to induction of skin
sensitization - a threshold phenomenon
 Step 1: Hazard Identification
 Determine potential (hazard) to induce
sensitization from:
 Pre-clinical studies e.g. Guinea-Pig Test,
Local Lymph Node Assay (LLNA)
 Human data (historical)
 Structure based predictive approach
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QRA For Dermal Sensitization
Fragrance Ingredients
Step 2: Dose response
assessment:
Takes into account key factors:
Determine the No-ExpectedSensitization Induction-Level (NESIL)
based on the Weight of Evidence
(WoE)
Calculate Sensitization Assessment
Factor (SAF)
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SAF Definition
 Extrapolation from controlled
experimental situation to real life
exposure scenarios
 Defined more effectively the areas of
assessment in extrapolating from
experimental to real-life scenarios
 Use of WoE approach to determine values for
the defined areas of assessment
 Decisions supported by peer-reviewed
scientific literature references
 Three areas of extrapolation
 Inter-individual susceptibility
 Matrix effects
 Use considerations
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SAF Summary
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Inter-individual Variability
(Age, gender, ethnicity, inherent dermal barrier and
genetic effects)
1
10
3
Vehicle or Product Matrix Effects
(e.g. presence of irritants, penetration enhancers)
1
3
Use Considerations
(Site of contact, barrier function, occlusion)
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SAF Examples
Product
Inter-Indiv.
Variation
Deodorant
SAF = 10
Same as
general
toxicology
Shampoo
Matrix
Effects
SAF = 3
Product Matrix
different from
experimental
conditions; may
contain irritating
actives
Use
Considerations
SAF = 10
Area = underarm;
skin easily
irritated, highly
follicular; area
may be shaved.
Occlusion similar
to experimental
conditions33-36
SAF = 10
SAF = 3
SAF = 3
Same as
Product Matrix
Area is the head;
general
very different
highly follicular;
toxicology from experimental scalp is more
conditions; may permeable33,49
contain irritating
ingredients
Total
SAF
300
100
QRA For Dermal Sensitization
Fragrance Ingredients
Step 3: Exposure
Dose metric: expressed in Dose/Area
Understand consumer exposure
expressed as product categories
How consumers are exposed: amount,
duration and frequency
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Influence of Area Exposed
on Sensitization
Sensitization Rate
62.5mg DNCB
85%
1.8 cm2 Site
62.5mg DNCB
8%
7.1 cm2 Site
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Reviewed in Contact Dermatitis 1992, 27:281-286
QRA For Dermal Sensitization
Fragrance Ingredients
 Step 4: Risk Characterization
 Acceptable Exposure Levels (AELs) to
fragrance ingredients that are dermal
sensitizers can be determined in specific real
life consumer product types
WoE NESIL
Acceptable
=
Exposure Level (AEL) Sensitization Assessment
Factor (SAF)
 Comparison of Acceptable Exposure Levels
(AEL) to calculated Consumer Exposure
Level (CEL)
AEL ≥ CEL to be Acceptable
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QRA Dermal Sensitization
Citral
Weight of Evidence NESIL
 Guinea-pig data – weak sensitizer [14]
 Local Lymph Node Assay
 EC3 = 1414 µg/cm2 [11]
 Human data
 HRIPT NOEL = 1400 µg/cm2
 WoE NESIL = 1400 µg/cm2
SAF
 Considerations
 Inter-individual variability
 Product matrix differences
 Variations in use patterns
 Hydroalcoholic Unshaved SAF is 100
 Deo/AP SAF is 300
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Exposure
Consumer exposure to:
 Hydroalcoholic (unshaved skin)
= 2.2 mg/cm2
 AEL = 1400/100
= 14.0 µg/cm2
 AEL/CEL (14.0 ug/cm2 x 0.001
mg/µg)  2.2 mg/cm2/day =
0.006
 AEL≥CEL  0.6%
 DEO/AP = 9.1 mg/cm2
 AEL = 1400/300 = 4.7 µg/cm2
 AEL/CEL = 0.0005
 AEL≥CEL  0.05%
QRA Dermal Sensitization: Citral
In Hydroalcoholic Unshaved Skin Induction
1.7%
0.6%
37μg/cm2
13 μg/cm2 14
CEL
CEL μg/cm2
1400 μg/cm2
WoE NESIL
AEL
SAF = 100
AEL/CEL
Acceptable
0.01
0. 1
1.0
AEL/CEL
Unacceptable
10
100
Citral Level - log μg/cm2
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1000
10,000
QRA Dermal Sensitization
Citral In Solid AP - Induction
4.7 μg/cm2
AEL
1400 μg/cm2
Woe NESIL
0.05%
4.3 μg/cm2
CEL
AEL/CEL
Acceptable
0.01
0. 1
SAF = 300
1.0
10
100
Citral Level - log μg/cm2
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1000
10,000
IFRA Product Categories
Based On QRA
IFRA Category
Examples of Products
Category 1
Lip Products, Toys
Category 2
Deodorants/Antiperspirants
Category 3
Hydroalcoholic Products for Shaved Skin, Eye Products, Men’s
Facial Cream & Balms, Tampons
Category 4
Hydroalcoholic Products for Unshaved Skin, Hair Styling Aids &
Sprays, Body Creams
Category 5
Women’s Facial Cream/Facial Make-up/ Wipes or Refreshing
Tissue, Hand Cream, Facial Masks
Category 6
Mouthwash, Toothpaste
Category 7
Intimate Wipes, Baby Wipes
Category 8
Make-up Remover, Hair Styling Aids Non-Spray, Nail Care
Category 9
Shampoo, Rinse-Off Conditioners, Bar Soap, Feminine Hygiene
Pads & Liners, Other Aerosols (including air fresheners sprays but
not including deodorant/antiperspirants, hair styling aids spray)
Category 10
Detergents, Hard Surface Cleaners, Diapers
Category 11
All Non-Skin or incidental skin contact products
IFRA Product Categories
Based On QRA
IFRA
Category
SAF
Category
Consumer
Exposure
mg/cm2/day
Product Type
Designating IFRA
Consumer
Category
Exposure
Level
Solid Antiperspirant
mg/cm2/day
Category 5
AEL derived from QRA
Consumer
AEL derived from QRA
Exposure
Aftershave
AEL derived from QRA
Type
Category SAF
1
300 Product
11.7
Lipstick
Category 2
300
9.1
Category 3
300
2.2
Category 4
100
Category 5100 100
Category 6
100
Category 7
Category 8
Maximum Pragmatic
Level
IFRA
2.2
Perfume
Facial
Cream/
4.2
Hand Cream 3.17
Make-up
AEL derived from QRA
AEL derived from QRA
1.4
Toothpaste
AEL derived from QRA
300
4.4
Intimate Wipes
4.2 from QRA
AEL derived
100
1.0
Hair Styling Aids
Max conc. ≤2%
Category 9100 100
Hand
0.2 Cream
Conditioners, 4.2
Rinse-Off
Category 10
100
0.1
Category 11
10
0.00033
Hard Surface Cleaners
Candles
Max conc. ≤5%
Max conc. ≤2.5%
QRA Dermal Sensitization:
Does It Work?
 Evidence of proven
effectiveness for
other materials
 Since 2006, >100
materials have IFRA
Standards based on
the QRA dermal
sensitization
 Need to build
evidence in
fragrance ingredients
 Cinnamic aldehyde
 Citral
 Isoeugenol
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RA
Risk
Mgmt
Clinical
Reports
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QRA Dermal Sensitization: Does it
work?
Fragrance
Ingredient
Cinnamic
Aldehyde
Industry Survey or
Limit
Prior to QRA-based
Standard
QRA –based Limit
Skin level:
0.05% Deo/AP:
Hydroalcoholics:
1.7%
Deo/AP:
0.05% Deo/AP:
Skin level:
0.2%
0.02%
Hydroalcoholics: 0.6%
Citral
Isoeugenol
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0.05%
Hydroalcoholics: 0.02%
Database U. Hospital Leuven
2000-2007
Fragrance
Ingredient
Cinnamic
Aldehyde
Citral
Isoeugenol
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Positive Patch Test
Reactions to Product
Confirmed & Not Confirmed
Product Type
Deodorant
4
Intimate Hygiene Wipes
1
Hair Care
1
Hydroalcoholic
9
Skin Care
2
Deodorant
1
Hydroalcoholic
14
Skin Care
4
Deodorant
2
Hair Dye
1
Api et al, Dermatitis, 21(4): 207-213, 2010
QRA Implementation Status
 40th Amendment May 2006 – 4 materials
 42nd Amendment May 2007 – 28 Standards on 51
materials
 43rd Amendment July 2008 - 18 Standards on 31
materials
 44th Amendment May 2009 – 12 Standards
 45th Amendment June 2010 – 4 materials
 46th Amendment June 2011 – 6 materials
 only 2 existing Standards remain to be converted to a
QRA based Standard
 47th Amendment Spring 2013
 Expert Panel: Compliance with IFRA Standards
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IFRA/RIFM INFORMATION BOOKLET
VERSION 6.0 (July 2011)
 How new and existing IFRA Standards will
be set
 Definition of the IFRA product categories
 Changes in product categorization, for
example
 Product types not previously included
 Re-categorization (new/updated exposure)
 Definition of the IFRA product categories
 Guidance on preparing IFRA Certificates
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Benefits of QRA Method
 Lead with a scientifically robust strategy
 Major improvement over the former approach
 addresses elements of exposure-based risk
assessment - unique to induction of dermal
sensitization
 consistent with the principles of general toxicology risk
assessment
 Risk management strategies
 10 different product categories for skin contact
products.
 Category 11 - non-skin or incidental skin contact
products
 Exposure - key element of category determination
 enables maintenance of relevant exposure and
therefore safety
 Categories provide greater flexibility to the perfumer
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QRA Recognition
 An important step forward as scientific
method
 Refinements will occur as new data
becomes available
 Full trust from the fragrance industry
and its customers regarding application
and use of the QRA method
 Industry will continue implementation
and validation
 SCCP opinion of June 2008 – moderately
optimistic
 Methodology used by Australian
regulators
 Interest from US FDA and US EPA
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Overview of The Changes in Human
Health Safety Assessment Paradigm
 Focus is on individual substance Safety Assessments
 Key endpoints to be assessed were identified
 Prioritized materials will be assessed using a series of
tiered data relevant to each endpoint:
 Available data on the material itself and/or closely related
materials (new groupings)
 Screening level toxicity data
 Higher tier toxicity studies
 Assessments will result in acceptable use levels for each
material (exact form of publication to be determined but it
is envisioned various forms of safety assessments will
result )
 Assessment program underpinned by foundation science
initiatives
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Human Health Science Program
Human Health Safety Assessment
(individual material assessment)
E
x
p
o
s
u
r
e
Foundation Science
Sensitization
Emerging Issues
Genotoxicity
Exposure
Methodologies
Phototoxicity
Alternate Test
Methodologies
Repeat Dose
Reproduction
In Silico Models
Respiratory
 Interrelated streams
– Robust but flexible substance assessment program (ability to adapt to new learnings)
– Leading knowledge development for the safety assessment of fragrance ingredients
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Human Health Criteria Document I
 Published 2000
 Prioritized Materials
• Volume of Use
• Exposure
• Structural Alerts
 Helps direct Human
Health research &
testing program and
group summary
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Human Health Criteria Document II
 Written to use the best science available to
support the safety of a fragrance material;
 the studies to do this will take regulatory requirements
into consideration but will not be specifically designed
to ensure the acceptance of a fragrance material for a
specific regulatory approval
 Purpose of the criteria document
 external audience is important;
 roadmap to how a safety assessment is completed;
 need document for internal industry audience as an
overview of the (new) safety process;
 for industry members to use to safety assess their
substances and for external audience
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Human Health Criteria Document II
 Intelligent Testing Strategy: Need to achieve an
appropriate balance between the level of testing
required for all ingredients versus the development of
criteria which clearly identifies the need for endpoint
specific testing
 Integrate latest tools
 TTC on all endpoints
 QSARs/SARs
 Screening assays to increase our understanding of key
endpoints & provide a biological anchor for QSARs & material
relationships
 Improved grouping & read-across approaches to ensure a
more sophisticated and scientifically credible way of
extrapolating test results from one substance to another
 Will be published in peer reviewed scientific journal
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Human Health Criteria Document II
 Threshold for Toxicological Concern
 Conservative first level approach in the absence of
material specific data
 Defines daily levels of exposure (thresholds) to a material
below which there is no expected safety concern
 Allows materials to be cleared based only on low
consumer exposure
 Read Across –uses common endpoint
data
 Physicochemical properties
 Toxicity
 Metabolism
 Exposure
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RIFM Systemic Aggregate
Exposure to Fragrance Materials
 Current Method: Cumulative dermal exposure
from 10 cosmetic products
 Modify the current method to include
 Oral exposure (toothpaste/mouthwash)
 Inhalation from air care products
 Indirect oral and inhalation exposure (e.g. oral
exposure from dishwashing products; inhalation
exposure from cleaners)
 Aggregate exposure - preferably World Wide but
initially for Europe and North America
 The data will also be made available in a software
model which can be used by industry and
regulators
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RIFM Aggregate Exposure Model –
Products Included
Phase I
 Body Lotion (prestige vs.

mass market)
 Deodorant/antiperspirants

 Face cream
 Shampoo
 Hair Styling Products
(excluding hair spray)
 Hand Cream

 Hydroalcoholics
 Lipstick
 Liquid/Makeup Foundation
 Mouthwash
 Shower Gel
 Toothpaste
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Phase II
Liquid hand soap and bar
soap
Inhalation
 Air Fresheners
 Candles
 Hair Spray, Perfume,
Deodorant Spray
Combined Food and
Cosmetics exposure
These products cover
the major exposure
contribution to
fragrance ingredients
Sensitization Read Across
Approach
 A good RA material…
 Is in the same reaction mechanistic
domain
 Within that domain is similar in reactivity
 Has similar hydrophobicity (for some
domains)
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Sensitization: Applying Read
Across
 Comparison with similarly reactive
(&hydrophobic) compounds from same
mechanistic domain
 Calculation from Quantitative Mechanism
Model (QMM or a QSAR) when equation is
available and parameters are known for
the target compound
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Reaction Mechanistic Domains
 Michael acceptors – QSAR available, but based
on experimental rate constants
 Schiff base formers – QSAR available, based on
structure-derived parameters
 Acylating agents – no QSAR, but some SAR
insights
 SN2 electrophiles – no general LLNA QSAR,
evidence for dependence on reactivity with
hydrophobicity
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Intelligent Testing Strategy
 LLNAs -Data will be used to build the domain
mechanism in order to help predict other similar
materials
 Review continues of predicted reactive materials
 Determine materials to help complete
mechanistic domains
 Conduct experiments to determine rate constants
 Select materials for LLNA testing to show accuracy
of predictability from the rate constants
 Select key materials for human testing to confirm
NOEL in humans
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MORE INFORMATION
Research Institute for
Fragrance Materials, Inc.
Tel.: +1-201.689.8089
amapi@rifm.org
RIFM: www.rifm.org
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