DEHP Exposure - Risk Prevention in Infusion Therapy

DEHP Exposure
Effects of plasticizers on Health and Environment
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erapy.com
DEHP Exposure
Definition
PVC and Plasticizers
Polyvinyl chloride (PVC) plastic is used to
manufacture a huge number of articles for daily
life, e.g. toys, building material such as flooring,
cables, as well as medical products.1
Unplasticized PVC is hard and brittle at room
temperature. As a result, plasticizers are necessary
to impart flexibility to the polymer. Plasticizers are
additives, most commonly phthalate ester, which
work by embedding themselves between the
chains of polymers, spacing them apart, and thus
significantly making it softer (see Fig. 1). For plastics
such as PVC, the more plasticizer added, the more
flexible and durable it will be (see Fig. 4 for the
average content of substances in PVC).2
Common Plasticizers
Besides di-(2-ethylhexyl) phthalate (DEHP), most commonly-used
plasticizers today are phthalates, first and foremost, the following:
− DIDP (di-isodecyl-phthalate)
− DINP (di-isononyl-phthalate)
− DBP (dibutylphthalate)
− BBP (butylbenzylphthalate)
Various plasticizers have been used as plasticizers for PVC.
The plasticizer of choice for PVC medical devices is DEHP
(see Fig. 2).3 The content of DEHP in flexible polymer materials
varies widely but is often around 30 % -35 % (w/w). Contrary
to that, polyethylen and polypropylen normally do not contain
any plasticizers.4, 5
In addition to phthalates, there are also non-phthalates available
on the market, although their current market share is only 8-10 %.
These include adipates, citrates, phosphates, trimellitates, etc.
Common non-phthalates include TOTM and Hexamoll DINCH, as
well as the newly developed DEHT/DOTP (DEHT = Di(2-ethylhexyl)
terephthalate resp. DOTP = Dioctyl terephthalate).
Phthalates are plasticizers, commonly used to soften PVC.
PVC World Consumption – The Trend
0-5% 0-5%
0 - 10 %
PVC polymer
1 - 50 %
Plasticizer
Stabilizer
Lubricant
0.1 - 2 %
Filler
0.2 - 5 %
Reinforcement
Pigment
PVC powder
plasticizer liquid
Sundry
PVC compound
(granulate)
0 - 50 %
Source: Solvay
Fig. 1: Composition of PVC
2
Fig. 2: Calotte model of DEHP
Fig. 3: PVC World Consumption
50 - 95 %
Source: Keml Report 4/97.
Fig. 4: Average content of substances in PVC (Kermel report 4/97)
3
DEHP Exposure
Definition
Areas of use of DEHP
DEHP is not known to occur naturally.
The worldwide production of DEHP has been increasing during
recent decades. PVC is the second largest commodity plastic after
polyethylene with world production currently over 18 million
tonnes a year (see Fig. 3 for world consumption). The chemical
process for making PVC involves three steps: first, production of
the monomer, vinyl chloride; then the linking of these monomer
units in a polymerisation process; and finally the blending of the
polymer with additives.6
The industrial use and end-use of DEHP can be divided into three
main product groups1:
I) PVC
II) non-PVC polymers
III) non-polymers
Around 97 % of DEHP is used as plasticizer in polymers, mainly PVC.
Polymers (PVC and non-PVC-polymers, see Fig. 5)
Some examples of flexible PVC end products containing DEHP are
n Insulation of cables and wires
n Profiles, hoses
n Sheets, film, wall- and roof covering and flooring
n Coatings and leather imitations (car seats, home furniture),
shoes and boots, out-door and rainwear
n Pastes for sealing and isolation and Plastisols e. g. car undercoating
n Toys and child-care articles (pacifiers, teething rings, squeeze
toys, crib bumpers etc.)
n Medical products
Non-polymers
DEHP is used among other plasticizers as an additive to rubbers,
latex, mastics and sealant, inks and pigments, lubricants (European
Union Risk Assessment Report).1
Some examples of non-polymer end products containing DEHP:
n Lacquers and paints
n Adhesives and Fillers
n Printing inks
n Dielectric fluids in capacitors
n Ceramics
PVC and DEHP in medical products
The use of PVC in medical devices represents a very minor
percentage of the total amounts of PVC manufactured each year.
Nonetheless the use of plasticized PVC in a wide range of
medical devices has been very important for a number of reasons7:
n Flexibility in a variety of physical forms from tubes to
membranes
n Chemical stability and possibility to sterilise
n Low cost and wide availability
n Lack of evidence of significant adverse consequences in patients
Approximately 3×104 tons of plasticized PVC is used for medical
applications annually in Europe7, such as IV and blood bags and
infusion tubing, enteral and parenteral nutrition feeding bags,
and tubing used in devices for cardiopulmonary bypass and
extracorporeal membrane oxygenation (see Fig. 6, 7, 8).
Exposure to DEHP varies widely, and is depending on
n The medical procedure,
n The lipophilicity of the fluid that comes into contact with the
medical devices
n The PVC surface size
n The temperature
n The flow rate
n And the contact time8, 9, 10, 11, 12, 13
Polyethylene linings of PVC articles (e. g. tubings) do not seem to
substantially prevent the release of DEHP.14, 15
16 %
28 %
Profiles
3%
Pipes and fittings
Rigid and flexible
6%
foils, sheets, plates
Cables
7%
Flooring
Coated fabrics
Other uses, including
17 %
23 %
Source: The European PVC industry initiative vinyl 2010.
medical devices
Fig. 6: PVC intravenous solutions bag
Fig. 7: PVC blood bag
Fig. 8: PVC infusion administration set
Fig. 5: Areas of use of PVC in Europe
4
5
DEHP Exposure
Causes
Why are DEHP containing medical devices of concern?
Especially with IV fluid containers made of DEHP containing PVC,
there are three main effects of concern:
n DEHP leaches out of the PVC into the solutions stored in the
fluid container and is thus incorporated by patients with unclear
but, with regards to substances affected (see Fig. 9, 13),
very likely serious health consequences
n A significant number of drugs are not compatible with PVC and
adhere to it (see Fig. 9)
n During the production and disposal process of PVC, dioxins and
furans, which are environmentally detrimental, are produced1
These three points will be further discussed below:
Leaching of DEHP
Everyone is exposed to small levels of DEHP in day to day life.
However, some individuals can be exposed to high levels of DEHP
through certain medical procedures. DEHP can leach out of plastic
medical devices into solutions that come in contact with the plastic
(see Fig. 9).
Outside
PVC-Bag-Wall
Inside
Leaching
The amount of DEHP that will leach out depends on the temperature,
the lipid content of the liquid, and the duration of contact with the
plastic. Seriously ill individuals often require more than one of these
procedures, thus exposing them to even higher levels of DEHP.16
On a weight basis, DEHP may constitute 30–40 % of a typical blood
bag.17 Jaeger and Rubin18 reported the leaching of DEHP from PVC
blood bags into stored blood components; their data suggest a
leaching rate of 0.25 mg DEHP/100 ml/day for whole blood stored
at 4°C. For a blood transfusion in adults, a DEHP exposure of 600 mg
has been reported.19
For platelet concentrate stored in blood bags, a leaching of DEHP
has been quantified in the stored platelets. It was estimated that
each patient received a total of 26.4 to 82.4 mg DEHP for 5 bags.17
Because infusion of platelets requires typically 30 min, and
assuming a linear leaching rate of DEHP with time, the tubing
involved in administering platelets might contribute at most 1.0 mg,
a minor contribution which may be ignored.20 Others have reported
considerable amounts of DEHP leaching into infusion solutions
stored in IV PVC bags, such as parenteral nutrition21, 11, cytostatics22, 23
or antibiotics.24, 25
Due to the short time of contact of infusion solutions to the
infusion tubings compared to the quite long time of contact
to the container wall and due to the linear leaching of DEHP,
the contribution of the tubing can be neglected.20
Sorption is a physical and chemical process by which one
substance becomes attached to another. Specific cases of
sorption are:
Adsorption
Leaching – Substance from bag wall migrates into the solution
Adsorption – Drug from solution, e. g. Diazepam27, is bound to
the inner bag wall
Absorption
DEHP (di-ethylhydroxy-phtalat)
Drug, e. g.
Diazepam27
Drug, e. g.
Isosorbide dinitrate
Fig. 9: Interactions between drugs and PVC container materials
6
Absorption – Drug from solution, e. g. Isosorbide dinitrate,
migrates into the bag wall28
Interaction of drugs stored in PVC bags
Besides the amount of DEHP leaching from the container into
its stored solution, the question whether the solutions are stable
in their container has been investigated thoroughly. Storage in
PVC usually is compared to storage in polyolefine materials, i. e.
polyethylene (PE) and polypropylene (PP). There is a reasonable
amount of drugs for which storage in PVC containers cannot be
recommended since they are not completely stable, e. g. cytotoxics26,
sedatives27, 29 and critical substances like nitroglycerine29, isosorbide
dinitrate30, warfarin sodium30 and thyroxine.31
Environmental exposure
Regarding the environment, two aspects have to be taken into
consideration: One being the amount of DEHP which is released
from plastics during or after the product lifetime, the other being
side products during production and destruction of PVC.
Release of DEHP into the environment
Large amounts of DEHP in polymers are building up in:
n End products with long service lives (e. g. building material)
n Land fills
n Waste remaining in the environment (pieces of polymer)
DEHP is assumed to be persistent as long as the molecule remains
in the polimer matrix. Due to this high persistency the amount of
DEHP in the technosphere (incl. the waste) is still increasing.
The overall distribution of DEHP is 2 % to air, 21 % to water and
77 % to urban/industrial soil.1
Side products of production and destruction of PVC
During production and especially incineration of PVC, a number of
toxic by-products is released into the environment: Polychlorinated
dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and
dioxin-like polychlorinated biphenyls (PCBs) are a group of structurally related chemicals that persist in the environment and may
bioaccumulate in animal sources of food and in human tissues.32
Their half-life time in the body is estimated to be seven to eleven
years.33
Example: Ciprofloxacin
The labeling information for Cipro® IV (Bayer AG, INN:ciprofloxacin)
points out that DEHP can leach from the PVC container used to
store and deliver this drug at a concentration up 5 parts per million
(ppm). To estimate the dose of DEHP received by patients being
administered this drug, information is needed on the volume of
solution containing the drug and the frequency with which it is
administered. For mild urinary tract infections, the recommended
dose of ciprofloxacin is 200 mg every 12 hours. The drug comes
packaged in a flexible PVC container that contains 200 mg in 100 ml
of solution. If the concentration of DEHP in solution is 5 ppm or
5 mg/L, the dose of DEHP received by a patient receiving this drug
to treat a urinary tract infection would be: 5 mg DEHP/L x 100 ml/
administration x 2 administrations/day x 0.001 L/ml = 1 mg DEHP/
day. More aggressive treatment is required to treat more severe
infections. For example, a dose of 400 mg of ciprofloxacin is
recommended every 8 hours to treat severe infections of the
respiratory tract, bones, joints, or skin. The dose of DEHP received
in this dosing regimen would be:
5 mg DEHP/L x 200 ml/administration x 3 administrations/day x
0.001 L/ml = 3 mg DEHP/day.
Example: Multiple Drug Infusions
Often, multiple drugs are co-infused in the same IV infusion. One
such case is the co-infusion of quinine along with multivitamin
preparations. It has been shown that little DEHP is released from
PVC bags containing quinine alone in solution; however, the
presence of the lipophilic multivitamin cocktail dramatically
increased the extent of DEHP release from the bag. Following
storage of quinine/multivitamin combinations for 48 hours at
45°C, the concentration of DEHP in the bags reached 21 mg/ml.
Consequently, a patient receiving a 500 ml infusion of quinine
with a multivitamin cocktail would receive 10.8 mg of DEHP.
Non-PVC bags are available for the administration of drugs that
require a lipophilic vehicle for solubilization. No DEHP is expected
to be released from non-PVC bags. Consistent with this expectation,
it was demonstrated that no DEHP was detected in a solution of
paclitaxel stored in a polyethylene container for 15 days.16
7
DEHP Exposure
Consequences
Consequences of leaching of DEHP
Health concerns about phthalate plasticizers are
currently the subject of considerable media, legislative and scientific debate. Academia and industry
have continually worked together to address the
concerns and conduct necessary research, making
phthalates some of the most researched and best
understood chemicals today.34
Negative effects of DEHP on human beings
Numerous studies have shown that the chemical group of the
phthalates and especially DEHP impair testicular testosterone
production in the rat. Very recent investigations have presented
proof that DEHP can inhibit testosterone production in the adult
human testis.35 Further more, adverse reproductive system outcomes,
including reduced semen quality and altered male genital development,
have been reported.36
In support of that, many phthalates are identified as anti-androgenic
endocrine disrupting chemicals in mammalian models.37 Endocrine
disrupting compounds are chemicals that can alter hormonal
signaling with potential effects on developing reproductive and
nervous systems, metabolism, and cancer.38
Serious concerns have been raised on exposure of ill newborns
and neonates to DEHP (see Fig. 12).39 Premature neonates in
intensive care units, being dependent on multiple medical procedures, can receive even higher DEHP exposures than adults relative
to their body weight. This exposure may be even higher than the
doses observed to induce reproductive toxicity in animals.7
Fig. 10: Risk group pregnant women
8
Fig. 11: Risk of altered male genital development
Negative effects on developing fetuses
Animal studies have shown DEHP to be particularly harmful to
developing fetuses leading to adverse effects in the reproductive
system, including changes in the testes.40 Pregnant women exposed
to high levels of phthalates may have increased risk of having sons
with malformations of the genitals (hypospadias and cryptorchidism),
low sperm count and increased risk of testis cancer (see Fig. 10, 11).41
Carcinogenicity of DEHP
DEHP has been reported to be carcinogenic in liver in rats and
mice with routes of induction being well investigated.42 Other
adverse effects on lung, heart and kidney have been reported as
well.43, 44 The International Agency for Research on Cancer, part
of the WHO, classified DEHP as possibly carcinogenic to humans
(Group 2B)45, an opinion which has been adopted by many others,
e. g. the US department of Health and Human Service.46
DEHP was downgraded by IARC in 2000, but massive criticism
has been raised in the medical scientific community that IARC
disregarded significant reports.47
Thrombogenicity of DEHP
PVC materials are well known to be of thrombogenic nature and
there is substantial evidence that the extent of platelet aggregation
is due to the presence of DEHP in the material and not the PVC itself.
In addition, complement activation, a process associated with adverse
hematological effects, is greater following exposure of blood to
DEHP-plasticized PVC than to other polymers. Each of these effects
can have adverse clinical consequences in patients.49, 50
Peritoneal sclerosis associated with DEHP
Peritoneal sclerosis is a serious complication of peritoneal dialysis
therapy. Beneath other factors, DEHP seems to have a role in the
pathogenesis of this condition. Research results suggest that levels
of DEHP in dialysate stored in DEHP bags are sufficient to initiate
the process of peritoneal sclerosis and to produce sclerosis.
The clinical significance of peritoneal sclerosis cannot be underestimated, because patients with reduced dialytic capacity of the
peritoneal membrane must be switched to hemodialysis.3
Lipophilic substances are of greatest concern
DEHP diffuses into lipophilic tissues and fluids and is thus
distributed in the body, the route of ingestion, be it oral, parenteral,
per inhalation or dermal, will not make a difference. Since this
leaching effect is depending on time, temperature etc. especially
long-term storage e. g. of drug solutions in PVC containers is of major
concern. Short term contact with PVC devices, such as catheters or
infusion sets, is regarded neglectable.20 Therefore, many authors
advise the use of polyethylene or polypropylene containers rather
than PVC22, and an increasing number of manufacturers of
pharmaceuticals exclude the use of PVC bags for their drug
preparations, e. g. for paclitaxel23 or temsirolimus.48
Fig. 12: Treatment risk through DEHP-tubings
9
DEHP Exposure
Consequences
Consequences of sorption of PVC
Environmental consequences
Sorption of drugs to PVC and consequences for therapy
Whereas the discussion of leaching of plasticizers is focussed
on the toxicological properties of a drug packaging system, the
sorption (superordinate of absorption and adsorption) of drug
formulation compounds has an influence on the dosage of the
active pharmaceutical ingredient resulting in a reduced drug
delivery to the patient. Therefore, sorption has an influence on
the effectiveness and success of the therapy.51
A list of drugs which are incompatible with PVC is given in Fig. 13.
Considering these examples and their intended uses, the conceivable
consequences result from significant underdosage of the substances:
Consequences from environmental exposure
The effects of DEHP leaching into the environment are the same
as described above: via accumulation in the chain of food, they
accumulate and reach the human body. Possible results may be
endocrine disruption, cancer and a number of other malformations
and diseases.
Underdosing of carmustine, an anti-cancer agent used for chemotherapy in glioblastoma (a brain tumor), might lead to non-effectiveness of the therapy and thus progression of cancer
n
Underdosing of heparin or warfarin, both anti-coagulating drugs, might result in blood clotting and / or lung embolism
n
Underdosing of thiopenthal, a rapid-onset short-acting
barbiturate general anaesthetic, might result in unintened
awareness of the patient
n
Underdosing of isosorbide dinitrate and nitroglycerin, both dilating agents being used during angina pectoris, might be useless and angina pectoris might result in cardial infarction
The effects of dioxins and furans released into the environment
during production and incineration of PVC have been shown to
exert a number of toxic responses, including dermal toxicity,
neuro-developmental deficits, immunotoxicity, reproductive effects
and teratogenicity, endocrine disruption, metabolic syndrome and
carcinogenicity.32
In 1997, the International Agency For Research on Cancer classified
TCDD (2,3,7,8-tetrachlorodibenzop-dioxin), most toxic compound
of the group, as a group I carcinogen (sufficient evidence of
carcinogenicity)52, and a recent review of both existing and new
evidence supports this decision.53
As described above („Causes“), the amount of DEHP from building
material, waste and landfills is continuing to increase in air, soil, and
water. This environmental exposure adds to the exposure from food,
medical devices and others and thus the described risks.
n
Chlordiazepoxide and diazepam are both sedatives and
anxiolytics, might not be as effective as intended
n
In case the effect of sorption is known to the user and thus the
amount of drug given is increased, this results in considerable
preventable additional cost to the provider and payer.
10
The dioxins and furans, toxic side products released by the production
and destruction of PVC, (e. g. PCDDs, PCDFs and PCBs) are characterized
by very long half-life times. Concentrations increase as they move
up the food chain, mainly in fatty tissue. The median DEHP intake
per age group is shown in Fig. 15.
Dioxins and furans are some of the most toxic chemicals known to
science. Short-term exposure of humans to high levels of dioxins
may result in skin lesions, such as chloracne and patchy darkening
of the skin, and altered liver function. Long-term exposure is linked
to impairment of the immune system, the developing nervous system, the endocrine system and reproductive functions.
Chronic exposure of animals to dioxins has resulted in several types
of cancer. TCDD was evaluated by the WHO’s International Agency
for Research on Cancer (IARC) in 1997.54 Based on animal data and
on human epidemiology data, TCDD was classified by IARC as a
„known human carcinogen”.
The health effects from exposure to dioxins and furans have been
documented intensively in epidemiologic and toxicological studies.55 As well, a number of significant consequences are known from
serious accidents such as the disaster in Seveso, Italy, in 1976.
A cloud of toxic chemicals, including 2,3,7,8-Tetrachlorodibenzop-dioxin, or TCDD, was released into the air and eventually contaminated an area of 15 square kilometres where 37,000 people lived.33
Critically ill male infant
Serious concern for
adverse effects
Male infants younger than one year
Male offspring of woman
undergoing certain medical
treatments during pregnancy
Concern for adverse
effects
Male offspring exposed during
pregnancy
Male children older than one year
Some concerns for
adverse effects
Reproduction in adults
Minimal concerns for
adverse effects
Negligible concern for
adverse effects
Insufficient hazard
and/or exposure data
Fig. 14: Conclusion of the “National Toxicology Program” regarding
the possibilities that human development or reproduction might be
adversely affected by exposure to DEHP.46
Drug
In PVC
In polyolefin
(PE and PP)
Calcitriol
50 % loss / 24 h
Stable
Carmustine
65 % loss / 2 h
Insignificant loss / 2h
Chlordiazepxide
10-20 % loss / 2 h
Stable
Diazepam
80-90 % loss / 24 h
Stable
Heparin
15-25 % loss / 1-3 h Stable
Age Group
Median DEHP intake
(g/kg bw/day)
Adult (20 - 70 years)
8.2
Teen (12 - 19 years)
10
Child (5 - 11 years)
18.9
Isosorbide dinitrate 80-90 % loss / 24 h
Insignificant loss /
24h
Nitroglycerin
70 % loss / 24 h
Stable
Toddler (7 month - 4 years)
25.8
Thiopental
25 % loss / 8 h
Stable
Warfarin
29 % loss / 8 h
Stable
Infant (0 - 6 month)
Formula-fed
Breast-fed
5
7.3
Fig. 13: Overview of the sorption behavior and amount of
selected drugs stored in different IV container materials27
Fig. 15: Median DEHP intake per age group46
11
DEHP Exposure
Consequences
Economic consequences
The exposure of human beings and especially developing children
to DEHP can have significant health consequences, as shown above
(see Fig. 14).
These disorders lead to significant economic consequences with
more severe diseases leading to high economic burdens.
Examples of complications resulting from DEHP exposure
Liver cancer
Severity
High
Cardiac infarction
Peritoneal sclerosis
Metabolic syndrome
Medium
Clinical Treatment
As an example, some of the health consequences to DEHP have
been selected and their additional treatment costs according
to reports from the current literature are displayed below (see Fig. 16).
Additional Costs US$
12,314 - 86,369
The Straits Times, Thu, Oct 29, 2009 Accessed at http://www. asiaone.com/ print/Health/News/Story/A1Story20091028-176464.html
Full ICU treatment + normal
ward, continuous outpatient
treatment
13,061 – 20,594
The costs of myocardial infarction-a longitudinal analysis using data from a large German health insurance company
Reinhold T, Lindig C, N. Willich S, Brüggenjürgen B. Journal of Public Health 2011 19:6 (579-586)
Cost of myocardial infarction to the Australian community: A prospective, multicentre survey Ioannides-Demos L.L.,
Makarounas-Kirchmann K, Stoelwinder J, McNeil JJ, Ashton E. Clinical Drug Investigation 2010 30:8 (533-543)
Hemodialysis,
Renal transplantation
44,000
25,000 - 150,000
Nephrol Dial Transplant (2009) 24: 3209–3215. The Pan-Thames EPS study: treatment and outcomes of encapsulating peritoneal
sclerosis. Gowrie Balasubramaniam, Edwina A. Brown, Andrew Davenport, Hugh Cairns, Barbara Cooper, Stanley L. S. Fan, Ken
Farrington, Hugh Gallagher, Patrick Harnett, Sally Krausze and Simon Steddon.
Treatment according
to clinical signs and
symptoms
4,603 - 12,287
IVF treatment
12,400 – 16,700
Cryptorchism
Orchidopexy
7,500 – 10,928
Operation (various techniques)
4,300 - 14,000
Hospital treatment
3,911 -
Thrombosis
Moderate
References
Antineoplastic Therapy
Liver transplant
Infertility
Hypospadia
These figures only take into account pure costs for treatment.
Not included are any overall economic effects such as loss of
labour, gross domestic product, joblessness, etc.
9,590
Prevalence rates and costs of metabolic syndrome and associated risk factors using employees' integrated laboratory data and health
care claims. Birnbaum H.G., Mattson M.E., Kashima S., Williamson T.E. Journal of Occupational and Environmental Medicine 2011
53:1 (27-33)
Health economics perspective of the components of the cardiometabolic syndrome
Tamariz L., Palacio A., Florez H., Tamariz L., Palacio A., Yang Y., Parris D., Florez H., Tamariz L., Palacio A., Florez H., Ben-Joseph R.
Journal of Clinical Hypertension 2010 12:7 (549-555)
Long-term economic benefits attributed to IVF-conceived children: A lifetime tax calculation. Connolly M.P., Pollard M.S., Hoorens S.,
Kaplan B.R., Oskowitz S.P., Silber S.J., Silber S.J. American Journal of Managed Care 2008 14:9 (598-604)
Resource allocation of in vitro fertilization: A nationwide register-based cohort study. Klemetti R., Sevón T., Hemminki E., Gissler M.,
Sevón T., Hemminki E. BMC Health Services Research 2007 7 Article Number 210
Economic Analysis of Infant vs Postpubertal Orchiopexy to Prevent Testicular Cancer. Hsieh M.H., Roth D.R., Meng M.V.
Urology 2009 73:4 (776-781)
Staged reconstruction of hypospadias with chordee: Outcome and costs. Svensson H, Reychman M, Åberg M, Troëng T, Svensson H.
Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery 1997 31:1 (51-55)
Proximal hypospadias comparative evaluation of staged urethroplasty (modified Thiersch Duplay followed by Mathieu) and single
stage on-lay island flap repair. Samuel M., Capps S., Worth A., Samuel M. European Urology 2001 40:4 (463-468)
One-year costs in patients with a history of or at risk for atherothrombosis in the United States. Mahoney E.M., Wang K., Cohen D.J.,
Hirsch A.T., Alberts M.J., Eagle K., Mosse F., Jackson J.D., Steg P.G., Bhatt D.L., REACH Registry Investigators Circulation. Cardiovascular
quality and outcomes 2008 1:1 (38-45)
Cost of atherothrombotic diseases - Myocardial infarction, ischaemic stroke and peripheral arterial occlusive disease - In Germany
Brüggenjürgen B., Rupprecht H.-J., Spannagl M., Berger K., Ehlken B., Smala
DEHP exposure
Fig. 16: Estimation of possible additional costs as a consequence of complications caused by DEHP exposure. In order
to facilitate the attribution of each complication to the cost calculation, severity levels (Dean & Barber Scale 1) were introduced.
12
13
DEHP Exposure
Preventive strategies
International and national laws and guidelines:
As outlined in the previous chapters, there is common agreement
that the use of DEHP as plasticizer is of concern and scientific
panels throughout the world recommended to limit its use.1, 4, 7,
16, 24, 34, 39, 45, 46, 57, 58
Further more, there are nowadays a number of
alternatives available, either using other plasticizers for PVC or
completely different PVC-free materials.
A number of international, national and regional activities have
resulted from that, partly with legislative action, in the health care
sector as well as in a number of other industries, such as toys or
food and beverages.
“The available reproductive and developmental
toxicity data and the limited but suggestive human
exposure data indicate that human exposures in this
situation approach toxic doses in rodents, which
causes the panel serious concern that exposure may
adversely affect male reproductive tract development.” 46
1. In the EU-regulation No. 143/2011, bis(2-ethylhexyl)phthalate
(DEHP) is classified as toxic to the reproductive system. From
January 21st 2015 onwards, the placing on the market and the
use of DEHP without special permission will be prohibited.59
2. The European Union recommends the use of other materials
instead of DEHP-PVC for medical devices.57
3. The European Community’s regulation EC 1907/2006
“Registration, Evaluation, Authorisation and Restriction of
Chemical substances” (REACH) came into force on June 1st,
2007. It classifies DEHP as substance of Very High Concern.
Such substances are subject to authorization through the
European Chemicals Agency (ECHA) in Helsinki.60
4. According to EC.directive 2007/47, medical devices containing
DEHP have to be labelled accordingly (see Fig. 17).61
5. Effective August 2008, the United States Congress signed the
Consumer Product Safety Improvement Act (CPSIA) in which
section 108 specified that as of February 10th, 2009, it is unlawful
to manufacture for sale, offer for sale, distribute in commerce,
or import any children’s toy or child care article that contains
concentrations of more than 0.1 % of DEHP, DBP, or BBP.
6. In January 2010, the Australian Consumer Affairs Minister Craig
Emerson announced a ban on items containing more than 1%
DEHP because of reproductive difficulties.62
7. With regards to food packaging, the use of DEHP in food contact
materials is already restricted under Commission Directive
2007/19/EC of 30 March 2007 relating to plastic materials and
articles intended to come into contact with food and Council
Directive 85/572/EEC laying down the list of simulants to be
used for testing migration of constituents of plastic materials
and articles intended to come into contact with foodstuffs.
8. For food, PVC packaging which may or may not contain DEHP,
has been either banned or restricted in a number of countries,
including Canada, Spain, South Korea and the Czech Republic.63
9. The German Federal Institute for Drugs and Medical Devices
(BfArM) recommends using alternative products to DEHPsoftened PVC medical devices for premature infants and new
borns. BfArM also urges medical devices manufacturers to label
products containing DEHP and put more effort into developing
safer alternatives.64
10. Similarly, the US Food and Drug Administration has issued an
FDA Safety Assessment and a Public Health Notification urging
health care providers to use alternatives to DEHP-containing
devices for certain, vulnerable patients.16
11. Health Canada’s scientific expert panel on DEHP recommended
among others that storage bags used for the administration
of lipophilic drugs, should not contain DEHP.65 As well, Health
Canada has proposed to prohibit the sale, advertisement, and
importation of toys for children under three years of age and
products for children under three years of age that are likely
to be mouthed and contain DEHP.66
12. Argentina, Austria, Cyprus, the Czech Republic, Denmark, Fiji,
Finland, Germany, Greece, Italy, Japan, Mexico, Norway, and
Sweden have restricted phthalates in children’s toys.58
13. The latest draft of the guideline 2002/95/EG RoHS on the
restriction of the use of certain hazardous substances in
electrical and electronic equipment, the European Union has
included DEHP into the list of prohibited substances.
14. Since 1st April 2005 cosmetic products containing DEHP shall
not be supplied to consumers in the EU, in accordance with
Commission Directive 2004/93/EC of 21st September 2004
amending Council Directive 76/768/EEC concerning cosmetic
products.
15. The requirements of the Stockholm Convention for releases
of dioxins and other by-product Persistent Organic Pollutants
(furans, hexachlorobenzene and PCBs) are that each party
shall, at a minimum reduce the total releases derived from
anthropogenic sources of each of the chemicals … with the
goal of their continuing minimization and, where feasible,
ultimate elimination.67
16. Concerns about dioxin from garbage incineration led the
Japanese government to enact a new container and wrapping
materials law requiring producers to recycle waste products by
the year 2000. The law prompted several major Japanese makers
of household goods and cosmetics to announce timetables by
which they would switch to polypropylene and other materials
for various types of cosmetic, food and pharmaceutical packaging.68
17. The Health Care Without Harm campaign is an international
coalition of 420 organisations in 51 countries; organisations
include hospitals and health care systems, medical professionals,
community groups, health affected constituencies, labor unions,
environmental and health organisations and religious groups.
One of the goals of the campaign is to phase out the use of
PVC and persistent toxic chemicals, and to build momentum
for a broader PVC phase out campaign.71
Fig. 17: According to EC-directive 2007/4761 medical devices
containing DEHP have to be labelled accordingly.
14
15
DEHP Exposure
Preventive strategies
Initiatives and campaigns
Research and Industry
1. In November 2011, the Food and Drug Administration (FDA)
has revealed a new maximum allowable level (0.006 mg/l) for
diethylhexyl phthalate (DEHP) in bottled water and manufacturers are required to monitor the levels.69
2. The managed health-care provider Kaiser Permanente said it will
no longer purchase intravenous solution bags made from PVC or
that contain the plasticizer as part of its continuing effort to
better protect the health and safety of the 8.9 million people
who get care at its hospitals, doctors’ offices and health-care
facilities.70
3. Kaiser Permanente, Miller Children‘s Hospital in Long Beach,
Lucile Packard Children‘s Hospital at Stanford University, and
John Muir Medical Center in Walnut Creek are phasing out PVC
medical devices from NICUs.71
4. The Confederation for Environmental and Nature Conservation
Germany (Bund für Umwelt und Naturschutz Deutschland),
Health Care Without Harm (HCWH) and the European Academy
for Environmental Medicine (EUROPAEM) have started the
initiative “pollution-free hospital”. The environmental organizations have called on the hospitals in Germany to forego PVCcontaining medical devices.72 The Pediatric Clinic Glanzing of the
Vienna Hospital Association is the first Neonatology Unit world
wide to announce it will manage completely without PVC
plastic.71
5. In Spain, over 60 municipalities have approved PVC phase-out
measures. The same applies to Germany, where an increasing
number of cities approved by their own statements avoid PVC in
public buildings.58
6. The OSPAR List of Chemicals for Priority Action includes several
substances which are by-products of the production of chlorine
and PVC, or additives in PVC: dioxins & furans, chlorinated
paraffins, mercury and organic mercury compounds, lead and
organic lead compounds, organic tin compounds, certain
phthalates (DBP & DEHP).73
1. B. Braun has bought and further developed Di(2-ethylhexyl)
terephthalate resp. Dioctyl terephthalate (DEHT or DOTP, resp.),
a non-phtalate plasticizer with a different chemical structure.
DEHT or DOTP is the only plasticizer known for flexible PVC
which does not show any toxic side effects in tests (see Fig. 18).7, 74
2. Alternative plasticizers have been developed and manufactured
by a growing number of chemical manufacturers. Comprehensive
and thorough research is necessary before these plasticizers will
be approved, such as TOTM/TEHTM and Hexamoll® DINCH.
3. A number of medical device companies including B. Braun have
invested into research on other materials than DEHP-PVC for
medical devices (see Fig. 19).
16
Further details on these three approaches are given below (p. 17-19
and Fig. 22).
DEHP
Characteristics of the alternative plasticizer DEHT
Di(2-ethylhexyl) terephthalate (DEHT) is a general purpose
non-phthalate plasticizer which is in commercial use since 1975.
For example, Coca-Cola and other companies have used DEHT
ever since for their bottles. Terephthalate is the „T“ in PET (see Fig. 20).
As well, the toy industry heavily uses this plasticizer.
DEHT has been invented and produced by the Eastman Company,
thus, one of its trade names is Eastman 168.
Toxicity profile of DEHT
DEHT has been studied in a wide variety of in vitro and in vivo
studies on its toxicity profile. Acute toxicity studies on oral, dermal,
and ocular exposure as well as inhalation have been conducted,
with focus on acute, sub-acute and sub-chronic toxicity. All studies
have shown an excellent toxicological profile.
Developmental toxicity tests revealed neither an alteration of male
rat sexual differentiation during development nor an effect on male
organ development. There was no estrogenic effect either.
Tests for genotoxicity and mutagenicity were all negative. There
was no effect upon tumor incidence and tumorigenicity and there
was no induction of liver peroxisomes, which are regarded as sign
for potential tumorigenicity.
A GLP-conform toxicity study in male and female rats with
continuous intravenous infusion of DEHT over 4 weeks showed that
DEHT administered via IV infusion was tolerated systemically and
locally without adverse effects up to and including 381.6mg/kg/day
(NOAEL=381.6mg/kg×day). In particular, there were no effects on
reproductive tissues/organs, kidneys, liver hepatocytes and peroxisomes,
as known targets of DEHP-toxicity. A clinical study on 203 volunteers
was conducted in order to test DEHT on its irritation skin potential.75
DEHT was concluded to not be irritating, and did not induce contact
sensitization.
These data indicate that DEHT (Eastman 168) plasticizer has a low
order of acute toxicity, is essentially non-irritating, and is not likely
to induce contact sensitization in humans.76
n
n
n
General purpose non-phthlate plasticizer
In commercial use since 1975!
Chemical name: bis(2-ethylhexyl) – 1,4-benzene dicarboxylate
synonyms: Di(2-ethylhexyl)terephthalate (DEHT)
Terephthalate is the “T“ in PET of soda bottles
DEHT
Fig. 18: DEHT means Di-(2-ethylhexyl)-terephthalate, also named
DOTP (Dioctylterephthalate). The chemical structure is not identical
to the one of DEHP.
Fig. 19: DEHP-free tubing
Fig. 20: PET soda bottles
17
DEHP Exposure
Preventive strategies
Regulatory profile of DEHT
DEHT Eastman 168 has been thoroughly evaluated by several
government agencies around the world and placed on approved lists.
n USA: recognized by the Food Contact Notification (FCN) for a
Variety of Food Contact Applications77
n European Union: European Food Safety Authority (EFSA)
approval; SCENIHR review for use in medical applications.
DEHT is not classified as CMR (carcinogenic, mutagenic or
toxic to reproduction) by REACH.60
Products not containing DEHP can be
marked as DEHP-free with appropriate
symbols.
n Germany: approved for use in plasticized PVC including beverage
tubing, cap liners, and food wrap by the “Bundesinstitut für
Risikobewertung (BfR), (German Institute for Risk Assessment)
n Switzerland: DEHT is not listed on Swiss toxic list, thus not
considered as toxic
n Japan: Japan Hygienic PVC Association includes DEHT on its
positive list
Environmental profile:
The solubility of DEHT in water is very low. In distilled water the
solubility has been reported to be 0.4 µg/l. The aquatic toxicity
data indicates that there were no acute or chronic effects for any
species tested at concentrations at or near the water solubility limit
of the material. One study also indicated no impact on survival at
concentrations that were orders of magnitude above the solubility
limit for the test conditions. Sub-lethal effects such as growth,
reproduction, shell deposition, and egg hatchability were also not
adversely impacted in any of the studies at the concentrations
tested. Because DEHT would have a strong tendency to sorb to
sediments in the aquatic environment, an OECD sediment-water
chironomid toxicity test using spiked sediments was conducted to
demonstrate that DEHT would not have cause adverse impacts to
aquatic sediment dwelling organisms. The sediment test indicated
that the EC50 was greater than the highest test concentration
recommended by the method.
With regards to biodegration, studies have shown that 37-56 %
of the original DEHT was degraded in 28 days.
These studies indicate that DEHT is susceptible to both ultimate
and primary degradation.76
Further material for Medical Devices and Drug Containers
Bearing in mind the shortcomings of PVC, especially the sorption
effects having an influence on the effectiveness and success of the
therapy, other materials for medical devices and drug containers
have been subject to research. More inert polymers like polyethylene terephthalate (PET) or polyamide (PA) result in a lower
interaction.78,79 On the other hand, not every polymer is suitable for
packaging of pharmaceuticals. Due to its rigid mechanical properties, PET for example can hardly be used for flexible tubes or bags.51
Considerations like these have also led to compound materials such
as multi-layer foils, where the inner layer is made of polypropylene
and further outer layers consist of polyethylene and polyester.
Fig. 21: DEHT has a positive regulatory profile
18
Sorption behaviour of polyethylene / polypropylene
Polyethylene (PE) and polypropylene (PP), both belonging to the
class of polyolefines, are two such materials which have been
proven suitable for manufacturing of IV containers. Following
the European Pharmacopoeia80 drug containers made from medical
grade PE are free from plasticizers, additives and other compounds
that may potentially migrate into the finished preparation. They
are chemically inert and toxicologically safe.
As representative examples for the well known group of drugs
exhibiting significant sorption to PVC, nitroglycerin and diazepam
have been investigated for their sorption behaviour towards
alternative plastics. For both drugs, PE and PP showed significantly
lower sorption rates than standard PVC tubes (see Fig. 23).51
A number of further studies have shown that PE/PP exert the lowest
sorption potential on drugs, compared to other plastics (see Fig. 23).81, 82, 83
In general, modeling of the solution interaction properties of plastic
materials used in pharmaceutical container systems has revealed that
PP has the lowest binding propensity for drugs, followed closely by PE.84
DEHP
DEHP causes reproductive and developmental damage
in animal studies. These studies are plausibly relevant to
human, especially male infants, children and pregnant
and lactating woman.
BBP
Studies report reproductive toxicity in adult rats and
developmental toxicity in rats and mice are assumed
relevant to humans.
DBP
Studies report development toxicity among exposed
rats and mice.
DINP
Child exposure via children’s products is common and
children may be exposed to 10- to 100-fold higher
levels than adults by mouthing toys and other articles
containing DINP. Quality of toxicological evidence is
weaker than for DEHP.
DIDP
Children may have higher levels of exposure than adults
if they mouth toys and other objects that contain DIDP.
Fig. 22: Risk of common plasticizers56
Environmental effects of polyethylene / polypropylene
Most of the medical waste is nowadays subject to incineration.
For example, in the UK, the “Landfill Directive” sets the rule that
clinical waste may not be disposed on landfills, but needs to be
incinerated. As outlined before, disposal of PVC via incineration
is associated with the generation and dispersal of polychlorinated
dibenzo[p]dioxins (PCDDs) and polycarbonated dibenzo-p-furans
(PCDFs) into the environment, both of which are present in flue
gases and ash.
Polyethylene and polypropylene, like all hydrocarbons, are burning
very well. The only residues from complete combustion are carbon
dioxide and water as combustion products, which are not toxic and
do not pose any environmental risk.85
CO2
(CH2)n
CO
CO2

+
2
H2O
Fig. 23: PE and PP show lower sorption rates for drugs than PVC
19
DEHP Exposure
Risk prevention
Ecoflac® plus
The state of the art IV solution container that offers safe and
convenient application of all IV procedures from drug admixture
to drug delivery. Container based incompatibilities are prevented
by a special polyethylene container material which is:
n Chemically inert
n Toxicologically safe
n Free from plasticizers, additives and other
compounds
n Free from substances that may potentially
migrate into the finished preparation
NuTRIflex® System
The NuTRIflex® System is the “ready-to-infuse” multichamber bag system for Total Parenteral Nutrition (TPN).
It combines convenience with safety by ensuring the exact
dosage of the drug to be administered to
the patient. The NuTRIflex® System bag is
Latex, DEHP and PVC-free.
Mini-Plasco®
Mini-Plasco® is a family of small volume parenteral
containers made of medical grade polyethylene or
polypropylene. These polymers are chemically
inert and toxicologically safe, free from
plasticizers, additives and other compounds
that may potentially migrate into the finished
preparation.
Cyto-Set® System
The complete system solution for safe and easy toxic drug
application, which prevents interactions between certain
drugs and material:
n Consists of biocompatible tube material made of PUR
(polyurethane) which is chemically inert (may be used with
drugs which are not recommended to be applied with PVC
material, e. g. Taxol®)
n Free from halogens (like chlorine): thus there
are no problems regarding the disposal because
no emissions of hydrochlorid acid gas
or Dioxin occur
n Free from plasticizers: harm to patients
is excluded
ConComp®
Free database on drugs compatible with Ecoflac® plus.
n Offers information on interactions between certain
drugs, carrier solutions and container materials
n Offers overview of scientific literature on drug
compatibility with the container
www.concomp-partner.com
20
Cyto-Set® System with transparent light protection
The complete system solution for safe and easy application
of light sensitive toxic drugs.
Tubing does not contain DEHP plasticizer but the new type
of safe plasticizer called DEHT (Eastman 168), which therefore
n prevents interactions between certain drugs
and material
n is not genotoxic, and therefore not harmful
for patients or environment
21
DEHP Exposure
Risk prevention
B. Braun Infusion sets
Infusion sets for safe and convenient infusion come with
tubing made of PVC which does not contain DEHP plasticizer
but the new type of safe plasticizer called DEHT (Eastman 168),
which is not genotoxic, and therefore not
harmful for patients or environment. The label
of the products shows that they are free of
DEHP.
Intrafix® SafeSet Neutrapur® (PVC-free)
IV set for safe and convenient infusions, which prevents
interactions between certain drugs and material:
n Consists of biocompatible tube material made of PUR
(polyurethane) which is chemically inert (may be used
with drugs which are not recommended to be applied with
PVC material, e. g. Taxol®)
n Free from halogens (like chlorine): thus there
are no problems regarding the disposal because
no emissions of hydrochlorid acid gas or Dioxin
occur
n Free from plasticizers: harm to patients
is excluded
Needle free extension sets
Extension sets with integrated swabbable 2-way valves
allow for safe manipulation away from the injection site.
Extension sets are free of PVC, DEHP and Latex.
22
Discofix C extension sets
Extension sets with integrated 3-way stop cock allow
for safe manipulation away from the injection site.
Discofix C extension sets are free of DEHP and Latex.
Discofix C extension sets with integrated valve
Extension sets with integrated 3-way stop cock and
swabbable valve allow for closed system manipulation
away from the injection site. Discofix C extension sets
are free of DEHP and Latex.
Venofix® Safety
Winged IV needle for short-term infusions, blood
collection, injection and transfusion.
Venofix® Safety is free of DEHP and Latex.
23
DEHP Exposure
Literature
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27
Microbiological
Contamination
Chemical
Contamination
Particulate
Contamination
Sharps
Injury
Air
Embolism
Medication
Error
Infusion Therapy
Risks
DEHP
Exposure
Drug
Incompatibility
The summarized scientific information in this document has been prepared for healthcare professionals. It is based on an analysis of
public literature and guidelines. The intention is to give an introduction to the risks commonly associated with infusion therapy and to
increase the awareness of healthcare workers to these kinds of problems. Due to its summary nature, this text is limited to an overview
and does not take into account all types of local conditions. B. Braun does not assume responsibility for any consequences that may
result from therapeutical interventions based on this overview.
B. Braun Melsungen AG | Hospital Care | 34209 Melsungen | Germany
Tel. +49 5661 71-0 | www.bbraun.com | www.safeinfusiontherapy.com
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