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Published on 13 July 2009

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Release of a plasticiser from polyvinylchloride tubing

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Diethylhexylphthalate (DEHP) is suspected of having a toxicity on reproduction and development in human populations. So it is important to find DEHP-free alternatives for infusion medical devices

Valérie Sautou-Mirandaa,b
PharmD PhD

Sandrine Bagel-Boithiasa
PharmD

Jean Chopineaua,b
PharmD PhD

aPharmacy Service
G Montpied Hospital

bClinical Pharmacy and
Biotechnical Laboratory
Faculty of Pharmacy
University of Clermont 1
Clermont-Ferrand

France

Polyvinylchloride (PVC) is a plastic widely used in medical applications. Because of its excellent and varied properties, this inexpensive material is used in a number of medical devices that often come into direct or indirect contact with critically ill patients. PVC is a relatively stiff polymer that needs added plasticisers to increase its flexibility, with diethylheyxylphthalate (DEHP) especially being used for this. As DEHP is not covalently bound to the plastic matrix, it can diffuse throughout the PVC and leach out into its environment, resulting in exposure to body tissues and fluids. DEHP has been suspected of having a certain toxicity in humans, particularly young children.

Risks related to DEHP and populations exposed
Risk assessments regarding DEHP have been carried out by various expert panels in Europe and the USA.[1-5] Rodent studies identified adverse effects on the liver, kidney, thyroid gland tissues and testes. But it is difficult to extrapolate these data to humans, and there are only a few studies concerning human toxicity. However, specialists appear to agree that DEHP has the potential to cause adverse effects on reproduction and development in human populations. It turns out that DEHP is the phthalate that has the highest toxicity, resulting in the definition of specific risk groups such as children under one year of age, critically ill children and pregnant women undergoing therapies or medical treatments using medical devices with DEHP.

The European Chemicals Bureau (ECB) has defined tolerable daily intake values for DEHP at 20 μg/kg bw/ day for newborns less than three months old and for women of childbearing age, 25 g/kg bw/day for newborns 3-12 months old and 48 g/kg bw/day for the rest of population.[3]

Sources of medical exposure to DEHP
Various clinical situations can provide exposure to high levels of DEHP, including blood transfusion, extracorporeal membrane oxygenation, artificial ventilation, enteral feeding, haemodialysis and lipophilic infusions.[6-11] Regarding infusions, DEHP can be released not only from PVC bags but also from infusors and tubings during contact with lipid emulsions, such as parenteral nutrition solutions and drug solutions containing polysorbate 80 or castor oil. It has been known for several years that high quantities of DEHP are released from PVC bags into infusion lipid emulsions. Consequently, manufacturers have also produced a range of PVC-free containers, such as ethylene-vinyl acetate (EVA) bags for parenteral nutrition, multilayer bags, or low-density polyethylene containers for drug solutions.

However, infusion systems include not only containers but also infusors and tubing. For a long time it has been thought that no substantial amounts of DEHP were released from these PVC lines because of the way the solution flowed along the lines. However, it now turns out that considerable leaching of DEHP from these tubings does occur, from the beginning of the infusion.[12,13] The quantity of released DEHP increases with length of tubing, concentrations of lipids, polysorbate or castor oil in emulsions, and temperature.[13,14] A neonate in an incubator at 37°C who is infused with a lipid emulsion is exposed to high levels of DEHP, especially when several metres of PVC infusion lines are needed. Thus, the effective dose of
DEHP for a typical 2 kg newborn through the nutrition itself (aminoacid/glucose/lipids) is at least 13 mg – 300 times higher than the tolerable daily intake defined by the ECB.[3,15] And this level of DEHP is reached only with PVC infusion lines. We also know that the extraction rate of DEHP is significant during the first 24 hours of infusion and dies down afterwards. Consequently, the more often infusion lines are changed, the more the patients are exposed to DEHP.[16]

DEHP-free alternatives
It has long been thought that coextruded PVC and polyethylene (PE) and triple-layered PVC, EVA and PE intravenous extension tubings could be used as alternatives to PVC in tubing. These alternatives are of interest because they limit the adsorption and absorption of drugs but do not prevent the release of DEHP. It has even been established that the amount of DEHP extracted from multilayer tubing is as high as the amount released from PVC tubing.

Today, only lines made of PE do not release DEHP, but these are expensive and present practical drawbacks, especially in terms of stiffness and opacity. The most interesting possible solution is replacing DEHP with a different plasticiser in PVC materials. Such a plasticiser would need to be nontoxic for humans and allow no or negligible amounts of release from PVC devices. There are certain plasticisers that do seem to fit these requirements: diethyhexyladipate (DEHA), trioctyltrimellitate (TOTM) and, particularly, di-(isononyl)- cyclohexane-1,2-dicarboxylate (DINCH).17-18 Some manufacturers already include these components in medical devices, including nasogastric tubes (TOTM), haemodialysis lines (DEHA), feeding sets (DINCH) and infusors (TOTM). However, at present it’s quite difficult to find PVC infusion tubings free of DEHP.

Conclusion
It is very important that medical and pharmaceutical teams adapt their practices to the present situation concerning DEHP. Food-handling institutions have a maximum defined quantity of DEHP in food packaging.[19] The use of DEHP in toys intended for consumers younger than three years old was prohibited in the EU in 1999.[20] Hospital pharmacists have a major role to play in integrating this notion in the choice of medical devices. Morever, since March 2009 an official recommendation requires French hospital pharmacists to use DEHP-free medical devices in situations with high risks of exposure.[21]

References
1. Agency for Toxic Substances and Disease Registry. Toxicological profile for di(2-ethylhexyl)phthalate (DEHP). Atlanta (GA): US Department of Health and Human Services, Public Health Service; 2002.
2. Scientific Committee on Toxicity, Ecotoxicity and the Environment. Opinion on the results of a second risk assessment of bis(2-ethylhexyl) phthalate (DEHP). Human health part. Brussels: European Commission; 2004.
3. European Chemicals Bureau. European Union risk assessment report for bis(2-ethylhexyl) phthalate. Consolidated final report: February 2004. R042_0402_env_hh_4-6. Ispra: ECB; 2006.
4. NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Di (Ethylhexyl) Phthalate (DEHP). <http://www.ncbi.nlm.nih.gov/pubmed/
19407857?ordinalpos=10&amp;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_ DefaultReportPanel.Pubmed_RVDocSum> National Toxicology Program. Nov 2006.
5. Scientific Committee on emergency and newlyidentified health risks (SCENIHR). Opinion on the safety of medical devices containing DEHP-plasticized PVC or other plasticizers on neonates and other groups possibly at risk, February 2008.
6. Hinberg I. EAP on DEHP in medical devices MDB report: an exposure and toxicity assessment. Ottawa: Health Canada; 2002.
7. Health and Consumer Protection Directorate-General. Opinion on medical devices containing DEHP plasticized PVC: neonates and other groups possibly at risk from DEHP toxicity. EC-CHCPD 2002. Brussels: European Commission; 2002.
8. US Food and Drug Administration. Safety assessment of di(2-ethylhexyl)phthlate (DEHP) release from medical devices. Rockville (MD): FDA; 2001.
9. Tickner JA, et al. Health risks posed by use of di-2-ethylhexyl phthlate (DEHP) in PVC medical devices: a critical review. Am J Ind Med 2001;39:100-11.
10. Shea KM. Pediatric exposure and potential toxicity of phthalate plasticizers. Pediatrics 2003;111:1467-74.
11. Heuderf U. et al. Phtalates: toxicology and exposure. Int J Hyg Environ Health 2007;210(5):623-34.
12. Loff S, Kabs F, Witt K, et al. Polyvinylchloride infusion lines expose infants to large amounts of toxic plasticizers. J Pediatr Surg 2000;35(12):1775-81.
13. Bagel-Boithias S, Sautou-Miranda V, Bourdeaux D, et al. Leaching of diethylhexyl phthlate from multilayer tubing into etoposide infusion solutions. Am J Heath-Syst Pharm 2005;62:182-8.
14. Loff S, Subotic U, Reinicke F, et al. Extraction of di-2-ethylhexyl-phthalate from perfusion lines of various material, length and brand by lipid emulsions. J Pediatr Gastroenterol Nutr 2004;39(4):341-5.
15. Loff S, Kabs F, Subotic U, et al. Kinetics of diethylhexyl-phthalate extraction from polyvinylchloride infusion lines. JPEN 2002;26(5):305-9.
16. Bourdeaux D, Sautou-Miranda V, Bagel-Boithias S, et al. Analysis by liquid chromatography and infrared spectrometry of di(2-ethylhexyl) phthalate released by multilayer infusion tubing. J Pharm Biomed Anal 2004;35:57-64.
17. Welle F, Wolz G, Franz R. Migration of plasticizers from PVC tubes into enteral feeding solutions. Forschung Entwicklung 2005;3:17-21.
18. Kambia K, Dine T, Azar R, et al. Comparative study of the leachability of di(2-ethylhexyl) phthalate and tri(2-ethylhexyl)trimellitate from haemodialysis tubing. Int J Pharm 2001;229:139-46.
19. European Food Safety Authority. Statement of the scientific panel on food additives, flavouring, processing aids and materials in contact with food (AFC panel) on the reclassification of some phthalates for consistency with the new SCF guidelines for food contact materials.
Parma: EFSA; 2004.
20. European Commission. 1999/815/EC: Commission decision of 7 December 1999 adopting measures prohibiting the placing on the market of toys and childcare articles intended to be placed in the mouth by children under three years of age made of soft PVC containing one or more of the substances di-iso-nonyl phthalate (DINP), di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), di-iso-decyl phthalate (DIDP), di-n-octyl phthalate (DNOP), and butylbenzyl phthalate (BBP). Official Journal of the European Union 1999;L 315 09/12/1999:46-9.
21. Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS). Recommandations portant sur les phtalates dans les dispositifs médicaux. March 2009.



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