DEHP In Medical Devices

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DEHP In Medical Devices

DEHP In Medical Devices

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.

DEHP - A Chemical Subtance

DEHP in Medical Devices

Diethylhexylphthalate (DEHP)1 is a phthalate, a chemical substance that is frequently used to soften PVC (Polyvinyl Chloride) medical devices, such as blood bags, tubing, catheters and disposable gloves to make materials more pliable and comfortable to use. Various plasticizers have been used as softeners for PVC. The plasticizer of choice for PVC medical devices is DEHP. The content of DEHP in flexible polymer materials varies widely but is often around 30% -35% (w/w). On the contrary, polyethylene and polypropylene normally do not contain any plasticizers.2-3

Areas of Use

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. PVC is manufactured through polymerisation of vinyl chloride monomer (VCM). Firstly, chlorine is extracted from sea water and combined with ethylene to create ethylene dichloride (EDC). EDC is then decomposed at high temperatures to create VCM. VCM then polymerises with other VCM molecules to create PVC. PVC can then combine with additives to modify the properties of PVC for various applications. 4, 60 

The industrial use and end-use of DEHP

Around 97 % of DEHP is used as plasticizer as an additive to rubbers, latex, mastics and sealant, inks and pigments, lubricants.5 

Some examples of non-polymer end products containing DEHP:

  • Insulation of cables and wires
  • Profiles, hoses
  • Sheets, film, wall- and roof covering and flooring
  • Coatings and leather imitations (car seats, home furniture), shoes and boots, out-door and rainwear
  • Pastes for sealing and isolation and Plastisols e. g. car undercoating
  • Toys and child-care articles (pacifiers, teething rings, squeeze toys, crib bumpers etc.)
  • Medical products
  • Lacquers and paints
  • Adhesives and Fillers
  • Printing inks
  • Dielectric fluids in capacitors
  • Ceramics

 

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 reasons6:

  • Flexibility in a variety of physical forms from tubes to membranes
  • Chemical stability and possibility to sterilise
  • Low cost and wide availability
  • Lack of evidence of significant adverse consequences in patients

Approximately 3×104 tons of plasticized PVC is used for medical applications annually in Europe6, 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.

Exposure to DEHP varies widely, and is depending on

  • The medical procedure,
  • The lipophilicity of the fluid that comes into contact with the medical devices
  • The PVC surface size
  • The temperature
  • The flow rate
  • And the contact time 7-12

Concerns Over Use Of DEHP

Leaching

 

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.

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 DEHP13. On a weight basis, DEHP may constitute 30–40 % of a typical blood bag.14 Jaeger and Rubin 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.15 For a blood transfusion in adults, a DEHP exposure of 600 mg has been reported.16

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.14

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.17

Others have reported considerable amounts of DEHP leaching into infusion solutions stored in IV PVC bags, such as parenteral nutrition18, cytostatics or antibiotics.20,21

 

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 solution21
  • Absorption – Drug from solution, e. g. Diazepam22, is bound to the inner bag wall
  •  Absorption – Drug from solution, e. g. Isosorbide dinitrate, migrates into the bag wall23

 

Consequence of leaching

Numerous studies have shown that the chemical group of the phthalates and especially DEHP impair testicular testosterone production in the rat .62 Very recent investigations have presented proof that DEHP can inhibit testosterone production in the adult human testis.24

Furthermore, adverse reproductive system outcomes, including reduced semen quality and altered male genital development, have been reported.25

In support of that, many phthalates are identified as anti-androgenic endocrine disrupting chemicals in mammalian models.26

Endocrine disrupting compounds are chemicals that can alter hormonal signalling with potential effects on developing reproductive and nervous systems, metabolism, and cancer26
Serious concerns have been raised on exposure of ill newborns and neonates to DEHP.27 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.28

 

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.24, 25

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.25,29

DEHP has been reported to be carcinogenic in liver in rats and mice with routes of induction being well investigated.30 Other adverse effects on lung, heart and kidney have been reported as well.31 The International Agency for Research on Cancer, part of the WHO, classified DEHP as possibly carcinogenic to humans (Group 2B)30, an opinion which has been adopted by many others, e. g. the US department of Health and Human Service.32

DEHP was downgraded by IARC in 2000, but massive criticism has been raised in the medical scientific community that IARC disregarded significant reports.63

 

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. Therefore, many authors advise the use of polyethylene or polypropylene containers rather than PVC21, and an increasing number of manufacturers of pharmaceuticals exclude the use of PVC bags for their drug preparations, e. g. for paclitaxel or temsirolimus.

 

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.33, 34

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. 61 

The clinical significance of peritoneal sclerosis cannot be underestimated, because patients with reduced dialytic capacity of the peritoneal membrane must be switched to hemodialysis.13

Whereas the discussion of leaching of plasticizers is focused 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.35

Environmental issues

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:
  • End products with long service lives (e. g. building material)
  • Land fills
  • Waste remaining in the environment (pieces of polymer)
  • DEHP is assumed to be persistent as long as the molecule remains in the polymer 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.5

Consequences

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.

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.37

Chronic exposure of dioxins to animals has resulted in several types of cancer. 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)38,40 based on animal data and on human epidemiology data, and a recent review of both existing and new evidence supports this decision.39

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, and 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. 8.

Fig. 8: Median DEHP intake per age group.39

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.

The health effects from exposure to dioxins and furans have been documented intensively in epidemiologic and toxicological studies.41 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 TCDD, was released into the air and eventually contaminated an area of 15 square kilometres affecting 37,000 people.

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.38 Their half-life time in the body is estimated to be seven to eleven years.42

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. 2,5,6,13    Furthermore, 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.

Laws and Guidelines

  1. 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.43
  2. 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.44
  3. The European Union recommends the use of other materials instead of DEHP-PVC for medical devices.45
  4. 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.13
  5. 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.
  6. Argentina, Austria, Cyprus, the Czech Republic, Denmark, Fiji, Finland, Germany, Greece, Italy, Japan, Mexico, Norway, and Sweden have restricted phthalates in children’s toys.46
  7. 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, labour 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.47
  8. 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.
  9. 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.48
  10. 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.49
  11. According to EC Directive 2007/47, medical devices containing DEHP have to be labelled accordingly.50
  12. 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.
  13. Health Canada’s scientific expert panel on DEHP recommended among others that storage bags used for the administration of lipophilic drugs, should not contain DEHP23. 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.51
  14. 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.
  15. In January 2010, the Australian Consumer Affairs Minister Craig Emerson announced a ban on items containing more than 1% DEHP because of reproductive difficulties.52
  16. 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.53
  17. 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 is be prohibited.54

DEHP And Australian Regulations

DEHP is commonly used in Australia in various every-day products such as floorings, waterproofing materials, cable casing & insulation, PVC labels, surface repairs resin modules, epoxy & polyurethane products, rubber components in motorized brake assemblies and adhesives of hot melt nature that are meant for automatic assembly and repair. 55

DEHP in Australia is prominently used in the medical devices as a plasticiser in the blood bags as well as dialysis equipment. 56

Australia has an interim ban on only one phthalate, DEHP, limiting levels to 1% . There are no bans on any other phthalates.57

The government of Australia has been keen on restricting and banning if necessary unsafe products from the Australian markets under the Consumer laws of the country (Unsafe products permanently banned under Australian Consumer Law 2011)58. Considering the hazardous effects of the DEHP on health, the government brought a permanent ban on its use in the children’s toys and products and restricted its levels to 1% (10 times levels permitted in the EU and US). This ban prohibits the supply of such plastic products that are made for the children under the age of 36 months (Product Safety Australia, 2011).59 However, there is yet no lasting ban on the use of DEHP in the medical devices in Australia, it is banned in the Australian cosmetic products (Vinyl Council of Australia 2021)60

References:
1. FDA Guidance for Industry, 2012, Limiting the Use of Certain Phthalates as Excipients in CDER-Regulated Products, <https://www.fda.gov/media/83029/download>
2. Umweltbundesamt, Berlin, Hrsg. (2/2007) Phthalate – die nützlichen Weichmacher mit den unerwünschten Eigenschaften: 3, 10.
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5.  European Commission – Joint Research Centre (2008) European Union Risk Assessment Report. bis(2-ethylhexyl)phthalate (DEHP), Vol. 80.
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36 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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50. Council directive 2007/47/EC on amending Counil Directive 90/385/EEC on the approximation of the laws of the Member States relating to active implantable medical devices, Council Directive 93/42/EEC concerning medical devices and Directive 98/8/EC concerning the placing of biocidal products on the market, (2007) Official Journal of the European Union L247, p. 21-55. 
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