Page 29 | Bulletin 86 | July 2014 Polyvinylchloride, phthalates and packaging

Plastics are synthetic resins, are either thermosetting or thermoplastic. Thermoplastic resins can be re-softened by heating, and include polyethylene (PE), polystyrene (PS), polypropylene (PP), and polyvinylchloride (PVC) which is very widely used in disposable medical devices.

Polyvinylchloride (PVC) Di(2-ethylhexyl) phthalate (DEHP)

Vinyl chloride (CH2=CHCl or chloroethylene) DEHP (sometimes referred to as bis is polymerized by free-radical initiators to (2-ethylhexyl) phthalate) is the diester of open the double bond and to link together phthalic acid and 2 ethylhexanol (Figure 2). vinyl chloride monomers, to form repeating Dr A M Walton units of polymers (Figure 1). Figure 2 The structure of di(2-ethylhexyl) phthalate DEHP. Anaesthesia ST 7, Figure 1 The phthalic moiety is common to all phthalates; University Hospital The chemical structure of vinyl chloride and PVC the pair of symmetrical aliphatic chains depends Southampton on the esterified alcohol

PVC is a rigid structure at room temperature. Heating gives the molecules energy, widens the distance between between the molecules and softens the resin. To give PVC flexibility at room and body temperatures, plasticisers Dr J M T Pierce are added non-covalently to the PVC when Consultant Anaesthetist, At room temperature it is a colourless, oil- University Hospital molten and serve as molecular spacers so soluble viscous liquid and is used to form Southampton; RCoA when cooled the polymer has a softness even up to 40% of the mass of the PVC product. Environmental Advisor at room temperatures. The most commonly The annual global production of DEHP is used plasticisers are phthalates. estimated to be 1–4 million tonnes.1

Phthalates The absence of chemical bonding between the Phthalates are esters of phthalic acid, and are phthalate and the polymer allows leaching of made by esterification of phthalic anhydride the phthalate over time and typically makes with variable chain length alcohols. Low the plastic more brittle. molecular weight phthalates have three to six carbon atoms in their alcohol chain and high DEHP and health molecular weight phthalates have more than Environmental exposure to DEHP is inevitable six carbon atoms. The longer the chain, the in low levels, given the widespread use of greater the permanency and durability of the PVC. 2 Animals exposed to DEHP develop renal plastic. The most commonly used phthalate in medical devices, such as intravenous papillary mineralisation, have an increased cannulae, giving sets and blood product bags, incidence and severity of chronic progressive have been Di(2-ethylhexyl) phthalate (DEHP), nephropathy, hepatomegaly and hepatocellular and less commonly, diisononyl phthalate tumours.3,4 Long term exposure results in (DINP) and diisodecyl phthalate (DIDP). testicular atrophy and testicular tumours.5 Page 30 | Bulletin 86 | July 2014

Given the relatively small size of a Figure 3 neonate to the size of the medical These symbol arrangements indicate the ‘Within the EU, Directive inclusion of the phthalate DEHP within the devices it is not surprising that the 2005/84/EC effectively packaged product highest levels of urinary MEHP have banned DHEP, benzyl been measured amongst neonates in butyl phthalate (BBT) and Neonatal Intensive Care, and the greater dibutyl phthalate (DBT) the interventional support the higher 9 from children’s toys and the urinary excretion of MEHP. DEHP exposures in NICUs are potentially at childcare articles.’6 The future and safer or above levels known to cause adverse plasticisers health effects in animal studies.10 The European Parliament The regulatory view continues to be pressurised to work Concern that it may be both a towards a complete ban of DEHP in In 2007 the EU Scientific Committee carcinogen, albeit in rodents, medical devices.13 on Emerging and Newly-Identified and impair spermatogenesis has Health Risks (SCENIHR) addressed The toxicity depends on the plasticiser, encouraged toy manufacturers to use the issue of the toxicity of plasticisers the capacity to leach and the particular alternative plasticisers in plastics in the on neonates and other groups possibly organ system. If EU concern equates United States.2 Within the EU, Directive at risk in the light of the available with toxicity then DBT, DEHP, 2005/84/EC effectively banned DHEP, evidence from animal studies.7 The and BBT are potentially most toxic benzyl butyl phthalate (BBT) and high risk groups included, neonates and DNOP (di-n-octyl phthalate), dibutyl phthalate (DBT) from children’s and preterm males, those requiring DINP, DIDP intermediately toxic. toys and childcare articles.6 exchange neonatal transfusion or The plasticiser Tris (2-Ethylhexyl) receiving TPN as well as pregnant Trimellitate (TOTM) is not a phthalate DEHP and plastic medical mothers on haemodialysis and at all, leaches least and is least toxic. It devices adults receiving massive transfusion. is produced in much smaller quantities Fluid filling and passing through SCENIHR could not directly implicate worldwide and is more expensive than medical devices has the potential to leach any plasticiser with harmful human DHEP. Medical device manufacturers the phthalate into the patient, and this effects, but concluded that there was will continue to develop newer, less is dependent on the procedure and the sufficient concern regarding the health leaching plasticisers in order to lipophilicity of the fluid that comes into effects of DEHP to recommend that maintain functionality of the device in contact with the medical device, the PVC it should be substituted with other a PVC market without DEHP. surface size, the temperature, flow rate plasticisers so long as functionality was 7 and contact time. DEHP is metabolised maintained. In the UK, the Medicines Medical device choice at multiple sites, including the intestine, and Healthcare Products Regulatory There is great pressure to reduce to mono (2-ethylhexyl) phthalate Agency (MHRA) took the counter view procurement costs, and inevitably PVC 8 (MEHP) and 2-ethylhexanol. Human and, given the lack of proven evidence devices containing DEHP are cheaper exposure is assessed by measuring the linking DHEP to adverse male than devices containing purportedly urinary excretion of MEHP. reproductive health, concluded that it safer, newer plasticisers (see Figures 4 and 5). We believe it is of vital The neonate and the developing foetus would be premature to recommend importance to scrutinise the labelling represent the most vulnerable phases a change to other plasticisers. The and the nature of the plasticiser when of life with regard to developmental MHRA state that the use of a device, considering the device and the patient and reproductive toxicity. Neonates in which the anticipated benefits (for for whom that device will be used, in the Neonatal Intensive Care Unit example of a DEHP-PVC TPN feeding before any consideration of the relative (NICU) are exposed to multiple line) outweigh the potential risk from cost and performance. medical-device-related DEHP exposure exposure to DEHP, is acceptable and within the terms of the EU Medical from feeding tubes, infusion tubing, Devices Directive.11 umbilical catheters, PVC blood bags, transfusion tubing, and endotracheal Given the European concern over tubes. In the Paediatric Intensive Care phthalates and DEHP in particular, Unit (PICU) haemodialysis systems, the amended Medical Device Directive continuous peritoneal dialysis and 2007/47/EC introduced compulsory ECMO circuits and cardiopulmonary labelling from March 2010 indicating bypass circuits in the cardiac theatre all the inclusion of a phthalate (PHT) and may contain DEHP.7 specifically which one12 (Figure 3). Page 31 | Bulletin 86 | July 2014

Figure 4 The packaging from a DEHP containing blood giving set. The precautions specifically warn of the hazards of endocrine disruption with prolonged use in infants children and pregnant women

Figure 5 The packaging from a PVC blood administration set that does not contain DEHP indicated by NON DEHP

References 7 EU Scientific Committee on Emerging 12 Labelling of medical devices containing 1 Institute for Health and Consumer and Newly-Identified Health Risks DEHP. DEHP Information Centre Protection, toxicology and chemical (SCENIHR) Opinion on the safety of (www.dehp-facts.com/medlabelling) substance. Bis(2-ethylyhexyl) medical devices containing DEHP- (accessed 10 February 2014). phthalate. Summary risk assessment plastized PVC or other plasticizers on 13 MEP vote ‘is progress’ towards making report. European Commission, 2008 neonates and other groups possibly at medical devices safer. The Parliament. (http://bit.ly/R8sV4c) (accessed 11 risk (http://bit.ly/R8t73y) (accessed 10 com, October 2013 (http://bit.ly/SiwENS) February 2014). February 2014). (accessed 11 February 2014). 2 Toxicology Profile for Di(2-ethylhexyl) 8 Phthalates absorption distribution phthalate. Agency for Toxic Substances and metabolism (http://bit.ly/R8tevP) and Disease Registry. ATDSDR, 2002 (accessed 16 February 2014) (http://1.usa.gov/R8t07X) (accessed 11 9 Green R, Hauser R, Hu H. Use of February 2014). Di(2-ethylhexyl) Phthalate–containing 3 David RM et al. Chronic toxicity of di medical products and urinary levels (2-ethylhexyl) phthalate in rats. Toxicol of mono(2-ethylhexyl) phthalate Sci 2000;55(2):433–443. in neonatal intensive care unit 4 David RM et al. Chronic peroxisome infants. Environ Health Perspect proliferation and hepatomegaly 2005;113(9):1222–1225. associated with hepatocellular 10 Tickner JA et al. Health risks posed by tumorigenesis of di(2-ethylhexyl) use of di(2-ethylhexyl) phthalate in PVC phthalate and the effects on recovery. medical devices: a critical review. Am J Toxicol Sci 1999;50:195–201. Ind Med 2001;39(1):100–111. 5 Voss C et al. Lifelong exposure to di(2- 11 Phthalates/DEHP in PVC medical ethylhexyl) phthalate induces tumours devices (http://bit.ly/R8tj2O) (accessed 10 in liver and testes of Sprague-Dawley February 2014). rats. Toxicology 2005;206(3):359–371. 6 Directive 2005/84/EC of the European Parliament and of the Council of 14 December 2005 (http://bit.ly/R8t4Vi) (accessed 10 February 2014).