Until 2010, diethylhexylphthalate (DEHP) was the most frequently used plasticiser to soft PVC medical devices, because of the favourable properties of the products. The increasing knowledge of the effects of phthalate exposure, which can be teratogenic, carcinogenic or induce reproductive toxicity, has led to the development of alternative plasticisers.
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.
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).
Besides di-(2-ethylhexyl) phthalate (DEHP), most commonly-used plasticizers today are phthalates, first and foremost, the following:
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).
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
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:
II) non-PVC 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
DEHP is used among other plasticizers as an additive to rubbers, latex, mastics and sealant, inks and pigments, lubricants1.
Some examples of non-polymer end products containing DEHP:
PVC and DEHP in medical products
The use of PVC in medical devices represents a very minor percentage of the total amounts of PVC manufactured each year. Nonetheless the use of plasticized PVC in a wide range of medical devices has been very important for a number of reasons7:
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
Polyethylene linings of PVC articles (e. g. tubings) do not seem to substantially prevent the release of DEHP.14, 15
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1 European Union Risk Assessment Report. bis(2-ethylhexyl)phthalate (DEHP)
2 Cadogan DF, Howick CJ (2000) Plasticizers in Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim. doi: 10.1002/14356007.a20_439.
4 Umweltbundesamt, Berlin, Hrsg. (2/2007) Phthalate – die nützlichen Weichmacher mit den unerwünschten Eigenschaften: 3, 10.
5 Kroschwitz JI (1998) Kirk-Othmer Encyclopedia of Chemical Technology. Fourth Edition. John Wiley and Sons, New York.
7 SCENIHR opinion on the safety of medical devices containing DEHP plasticized PVC or other plasticizers on neonates and other groups possibly at risk (2008).
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.
9 Hanawa T, Muramatsu E, Asakawa K, Suzuki M, Tanaka M, et al. (2000) Investigation of the release behavior of diethylhexyl phthalate from the polyvinyl chloride tubing for intravenous administration. Int J Pharm: 210:109-15
10 Hanawa T, Endoh N, Kazuno F, Suzuki M, Kobayashi D, et al. (2003) Investigation of the release behavior of diethylhexyl phthalate from polyvinyl chloride tubing for intravenous administration based on HCO60. Int J Pharm; 267:141-9.
11 Loff S, Kabs F, Witt K, Sartoris J, Mandl B, Niessen KH, Waag KL (2000) Polyvinylchloride infusion lines expose infants to large amounts of toxic plasticizers. J Pedriatr Surg; 35;1775-81.
12 Loff S, Kabs F, Subotic U, Schaible T, Reinecke F, Langbein M (2002) Kinetics of diethylhexylphthalate extraction from polyvinylchloride-infusion lines. JPEN J Parenter Enteral Nutr; 26:305-9
13 Loff S, Subotic U, Reinicke F, Wischmann H, Brade J (2004) Extraction of Di-ethylhexyl-phthalate from Perfusion Lines of Various Material, Length and Brand by Lipid Emulsions. J Pediatr Gastroenteral 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.
15 de Lemos ML, Hamata L, Vu T. (2005) Leaching of diethylhexyl phthalate from Polyyvinyl chloride materials into etoposide intravenous solutions. J Oncol Pharm Pract; 11(4): 155-7
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