Effects of plasticizers on Health and Environment

DEHP Exposure

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Definition

DEHP Exposure

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

Fig. 1: Composition of PVC

Phthalates are plasticizers, commonly used to soften PVC.

PVC powder plasticizer liquid PVC compound (granulate)

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)

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).

PVC polymer

Plasticizer

Stabilizer

Lubricant

Filler

Reinforcement

Pigment

Sundry

50 - 95 %0 - 50 %

0.2 - 5 %

0.1 - 2 %

1 - 50 %

0 - 10 %0 - 5 % 0 - 5 %

Fig. 4: Average content of substances in PVC (Kermel report 4/97) Fig. 3: PVC World Consumption

PVC World Consumption – The Trend

Fig. 2: Calotte model of DEHP

Source: Keml Report 4/97.Source: Solvay

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

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Fig. 6: PVC intravenous solutions bag Fig. 7: PVC blood bag Fig. 8: PVC infusion administration set

PVC and DEHP in medical productsThe 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 membranesn Chemical stability and possibility to sterilisen Low cost and wide availabilityn 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 devicesn The PVC surface sizen The temperaturen 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

Definition

DEHP Exposure

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) PVCII) non-PVC polymersIII) 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 wiresn Profiles, hosesn Sheets, film, wall- and roof covering and flooringn Coatings and leather imitations (car seats, home furniture), shoes and boots, out-door and rainwearn Pastes for sealing and isolation and Plastisols e. g. car undercoatingn Toys and child-care articles (pacifiers, teething rings, squeeze toys, crib bumpers etc.)n Medical products

Non-polymersDEHP 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 paintsn Adhesives and Fillersn Printing inksn Dielectric fluids in capacitorsn Ceramics

Pro�les

Pipes and �ttings

Rigid and �exible

foils, sheets, plates

Cables

Flooring

Coated fabrics

Other uses, including

medical devices

28 %

23 %17 %

7 %

6 %

3 %

16 %

Fig. 5: Areas of use of PVC in Europe

Source: The European PVC industry initiative vinyl 2010.

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DEHP Exposure

CausesThe 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

Interaction of drugs stored in PVC bagsBesides 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 exposureRegarding 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 environmentLarge amounts of DEHP in polymers are building up in:n End products with long service lives (e. g. building material)n Land fillsn 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 PVCDuring 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 struc-turally 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: CiprofloxacinThe 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 InfusionsOften, 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

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 consequencesn 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 DEHPEveryone 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).

InsidePVC-Bag-WallOutside

adsorption

DEHP(di-ethyl-hydroxy-phtalat)

f.e. Diazepam

leaching

adsorptionpermeation

InsideBagOutside

Lipophillic -> leaching f.e. Taxol Carmustin Paclitaxel

Leaching

Drug, e. g. Isosorbide dinitrate

DEHP (di-ethyl-hydroxy-phtalat)

Drug, e. g. Diazepam27Drug, e. g. Diazepam

Absorption

Leaching: Substance from bag wall migrates into the solution

Adsorption: Drug from solution, e. g. Diazepam, is bound to the inner wall

Adsorption: Drug from solution, e. g. Isosorbide dinitrate, imigrates into the bag wall

Adsorption

Fig. 9: Interactions between drugs and PVC container materials

Sorption is a physical and chemical process by which one substance becomes attached to another. Specific cases of sorption are:

Leaching – Substance from bag wall migrates into the solution

Adsorption – Drug from solution, e. g. Diazepam27, is bound to the inner bag wall

Absorption – Drug from solution, e. g. Isosorbide dinitrate, migrates into the bag wall28

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

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Consequences

DEHP Exposure

Consequences of leaching of DEHP

Negative effects of DEHP on human beingsNumerous 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-androgenicendocrine 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 proce-dures, 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

Health concerns about phthalate plasticizers are currently the subject of considerable media, legis-lative 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

Fig. 12: Treatment risk through DEHP-tubingsFig. 11: Risk of altered male genital development Fig. 10: Risk group pregnant women

Negative effects on developing fetusesAnimal studies have shown DEHP to be particularly harmful todeveloping 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

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

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 DEHPPeritoneal 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 undere-stimated, because patients with reduced dialytic capacity of the peritoneal membrane must be switched to hemodialysis.3

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Consequences

DEHP Exposure

Consequences of sorption of PVC

Sorption of drugs to PVC and consequences for therapyWhereas 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:

n 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

n Chlordiazepoxide and diazepam are both sedatives and anxiolytics, might not be as effective as intended

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.

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

Toddler (7 month - 4 years) 25.8

Infant (0 - 6 month) Formula-fed Breast-fed

5 7.3

Fig. 15: Median DEHP intake per age group46Fig. 13: Overview of the sorption behavior and amount of selected drugs stored in different IV container materials27

Drug In PVCIn 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

Isosorbide dinitrate 80-90 % loss / 24 hInsignificant loss / 24h

Nitroglycerin 70 % loss / 24 h Stable

Thiopental 25 % loss / 8 h Stable

Warfarin 29 % loss / 8 h Stable

Environmental consequences

Consequences from environmental exposureThe 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.

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.

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 sys-tem, the endocrine system and reproductive functions.

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 effectsNegligible concern for adverse effectsInsufficient 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

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 stu-dies.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-Tetrachlorodibenzo- p-dioxin, or TCDD, was released into the air and eventually conta-minated an area of 15 square kilometres where 37,000 people lived.33

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High

Medium

Moderate

DEHP exposure

Full ICU treatment + normal ward, continuous outpatient treatment

Hemodialysis, Renal transplantation

Orchidopexy

Operation (various techniques)

Hospital treatment

IVF treatment

Treatment according to clinical signs and symptoms

Infertility

Cryptorchism

Hypospadia

Thrombosis

Metabolic syndrome

Peritoneal sclerosis

Cardiac infarction

Liver cancer

Examples of complications resulting from DEHP exposure Clinical Treatment Additional Costs US$ ReferencesSeverity

Antineoplastic TherapyLiver transplant The Straits Times, Thu, Oct 29, 2009 Accessed at http://www. asiaone.com/ print/Health/News/Story/A1Story20091028-176464.html

The costs of myocardial infarction-a longitudinal analysis using data from a large German health insurance companyReinhold 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)

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.

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 syndromeTamariz 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 bene¦ts 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)

Proximal hypospadias comparative evaluation of staged urethroplasty (modi¦ed Thiersch Duplay followed by Mathieu) and singlestage on-lay island §ap repair. Samuel M., Capps S., Worth A., Samuel M. European Urology 2001 40:4 (463-468)

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)

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 GermanyBrüggenjürgen B., Rupprecht H.-J., Spannagl M., Berger K., Ehlken B., Smala

13,061 – 20,594

44,000 25,000 -150,000

4,603 - 12,287

7,500 – 10,928

4,300 - 14,000

3,911 - 9,590

12,400 – 16,700

12,314 - 86,369

Consequences

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.

Economic consequencesThe 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.

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).

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.

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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

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 DEHP- softened 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.

International and national laws and guidelines:

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.

DEHP Exposure

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 develop-ment.” 46

Preventive strategies

Fig. 17: According to EC-directive 2007/4761 medical devices containing DEHP have to be labelled accordingly.

16 17

DEHP Exposure

Research and Industry

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).

Further details on these three approaches are given below (p. 17-19 and Fig. 22).

Initiatives and campaigns

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 manu- facturers 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 organi- zations have called on the hospitals in Germany to forego PVC- containing 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

DEHP DEHT

Characteristics of the alternative plasticizer DEHTDi(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 DEHTDEHT 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 onreproductive 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 contactsensitization.

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

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

Preventive strategies

n General purpose non-phthlate plasticizern In commercial use since 1975!n Chemical name: bis(2-ethylhexyl) – 1,4-benzene dicarboxylate synonyms: Di(2-ethylhexyl)terephthalate (DEHT) Terephthalate is the “T“ in PET of soda bottles

18 19

DEHP Exposure

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 toxicn 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 ContainersBearing 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 polyethy-lene 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 proper-ties, 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.

Preventive strategies

Fig. 21: DEHT has a positive regulatory profile Fig. 23: PE and PP show lower sorption rates for drugs than PVC

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.

BBPStudies 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

Sorption behaviour of polyethylene / polypropylenePolyethylene (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 diazepamhave 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

Environmental effects of polyethylene / polypropyleneMost 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

(CH2)n +CO2COCOCOCO2CO22

CO2

H2O

20 21

Risk prevention

DEHP Exposure

Ecofl ac® plusThe state of the art IV solution container that off ers 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 inertn Toxicologically safen Free from plasticizers, additives and other compounds n Free from substances that may potentially migrate into the fi nished preparation

ConComp®Free database on drugs compatible with Ecofl ac® plus. n Off ers information on interactions between certain drugs, carrier solutions and container materials n Off ers overview of scientifi c literature on drug compatibility with the container

www.concomp-partner.com

NuTRIflex® SystemThe NuTRIflex® System is the “ready-to-infuse” multi-chamber 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.

Cyto-Set® System with transparent light protectionThe 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 materialn is not genotoxic, and therefore not harmful for patients or environment

Cyto-Set® SystemThe 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 occurn Free from plasticizers: harm to patients is excluded

Mini-Plasco®Mini-Plasco® is a family of small volume parenteralcontainers 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 fi nished preparation.

22 23

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 occurn Free from plasticizers: harm to patients is excluded

Risk prevention

DEHP Exposure

Venofix® SafetyWinged IV needle for short-term infusions, blood collection, injection and transfusion. Venofix® Safety is free of DEHP and Latex.

Needle free extension setsExtension 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.

Discofix C extension setsExtension 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 valveExtension 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.

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.

24 25

DEHP Exposure

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[8] Haishima Y, Seshimo F, Higuchi T, Yamazaki H, Hasegawa C, et al. (2005) Development of a simple method for predicting the levels of di(2-ethylhexyl) phthalate migrated from PVC medical devices into pharmaceutical solutions. Int J Pharm 2005; 298:126-42.

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[13] Loff S, Subotic U, Reinicke F, Wischmann H, Brade J (2004) Ex-traction of Di-ethylhexyl-phthalate from Perfusion Lines of Various Material, Length and Brand by Lipid Emulsions. J Pediatr Gastroen-teral Nutr; 39:341-345.

[14] Bourdeaux D, Sautou-Miranda V, Bagel-Boithias S, Boyer A, Chopineau J (2004) Analysis by liquid chromatography and infrared spectrometry of di(2-ethylhexyl)phthalate released by multilayer infusion tubing. J Pharm Biomed Anal; 35:57-64.

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[33] WHO Factsheet no 225, 2010, Dioxins and their effect on human health, May 2012

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[36] Dodson RE, Nishioka M, Standley LJ, Perovich LJ, Brody JG, Ru-del RA Endocrine Disruptors and Asthma-Associated Chemicals in Consumer Products http://dx.doi.org/10.1289/ehp.1104052 Online 8 March 2012

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[38] Colborn T, vomSaal F, Soto A (1993) Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect 101(5):378-385.

[39] CERHR and Health Care Without Harm, HCWH, FDA, C. f. D. a. R. H. (2002) Safety Assessment of Di(2-ethylhexyl)phthalate (DEHP). Released from PVC Medical Devices.

[40] Rais-Bahrami et al. Environmental Health Perspectives, 2004;13/112.

[41] Sharpe RM, Skakkebaek NE (2008) Testicular dysgenesis syn-drome: mechanistic insights and potential new downstream effects. Fertil Steril 2008; 89(2 Suppl):e33-e38.

26 27

[53] Steenland K, Bertazzi P, Baccarelli A, Kogevinas M (2004) Diox-in revisited: developments since the 1997 IARC classification of di-oxin as a human carcinogen. Environ Health Perspect 112:1265–1268.

[54] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans: Polychlorinated Dibenzo-Para-Dioxins and Polychlori-nated Dibenzofurans. IARC Monogr Eval Carcinog Risks Hum. 1997;69:1-631.

[55] EPA 2012 Reanalysis of key issues related to dioxin toxicity and response to NAS comments

[56] Wargo et al. Plastics That May Be Harmful to Children and Reproductive Health. Environment & Human Health, Inc. 2008

[57] European Commission, T. S. C. o. M. P. a. M. D. (2002). “Opinion on Medical Devices Containing DEHP Plasticised PVC; Neonates and Other Groups Possibly at Risk from DEHP Toxicity.”

[58] Greenpeace International (2003) PVC-Free Future: A Review of Restrictions and PVC-free Policies Worldwide.

[59] Änderung im Anhang der REACH-Regulation (PDF), Stand 17. Februar 2011

[60] REACH - Registration, Evaluation, Authorisation of Chemicals (2007) http://eur-lex.europa.eu/LexUriServ/site/de/oj/2007/l_136/l_13620070529de00030280.pdf

[61] RICHTLINIE 2007/47/EG DES EUROPÄISCHEN PARLAMENTS UND DES RATES vom 5. September 2007 zur Änderung der Richt- linien 90/385/EWG des Rates zur Angleichung der Rechtsvorschriften der Mitgliedstaaten über aktive implantierbare medizinische Geräte und 93/42/EWG des Rates über Medizinprodukte sowie der Richt-linie 98/8/EG über das Inverkehrbringen von Biozid-Produkten

[62] Emerson C, ALP Australia Bans Phthalates in Toys.

[63] PVC: The Poison Plastic. PVC Governmental Policies around the World. <http://www.besafenet.com/pvc/government.htm.>

[64] Referenz-Nr.: 9211/0506 DEHP als Weichmacher in Medizin-produkten aus PVC. Erstellt: 22.05.2006 http://www.bfarm.de/DE/Medizinprodukte/riskinfo/empfehlungen/dehp.html

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[66] Health Canada. Consumer Product Safety. (2007) Proposal for legislative action on di(2-ethylhexyl) phthalate under the Hazard-ous Products Act.

[67] http://chm.pops.int

[68] Japanese Makers to Switch from PVC to Eco-Based Contain-ers’, Nikkei, Tokyo, January 14, 1998.

[69] FoodBev.com, 31.01.2012

[70] http://www.plasticsnews.com/headlines2.html?ncat=&id=24284

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[72] Initiative „Schadstofffreies Krankenhaus“ gegen PVC-haltige Medizinprodukte. Deutsches Ärzteblatt, Ausgabe 15. November 2006; http://www.aerzteblatt.de/nachrichten/26355.

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[52] IARC (1997) Polychlorinated dibenzo-p-dioxins and polychlori-nated dibenzofurans. IARC Monogr Eval Carcinog Risks Hum 69:1–343.

DEHP Exposure

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[80] European Pharmacopoeia monograph 3.1.4 of the Polyethylene without additives for containers for preparations for parenteral use and for ophthalmic preparations.

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B. Braun Melsungen AG | Hospital Care | 34209 Melsungen | GermanyTel. +49 5661 71-0 | www.bbraun.com | www.safeinfusiontherapy.com

The summarized scientifi c 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.

MicrobiologicalContamination

AirEmbolism

DrugIncompatibility

MedicationError

SharpsInjury

ChemicalContamination

ParticulateContamination

DEHPExposure

Infusion Therapy Risks

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