Scientific Committee on Emerging and Newly-Identified Health Risks SCENIHR PRELIMINARY REPORT ON THE SAFETY OF MEDICAL DEVICES CONTAINING DEHP- PLASTICIZED PVC OR OTHER PLASTICIZERS ON NEONATES AND OTHER GROUPS POSSIBLY AT RISK Approved for public consultation by the SCENIHR during the 19th plenary of 21-22 June 2007 The safety of medical devices containing DEHP-plasticized PVC or other plasticizers on neonates and other groups possibly at risk About the Scientific Committees Three independent non-food Scientific Committees provide the Commission with the sound scientific advice it needs when preparing policy and proposals relating to consumer safety, public health and the environment. The Committees also draw the Commission's attention to the new or emerging problems, which may pose an actual or potential threat. They are: the Scientific Committee on Consumer Products (SCCP), the Scientific Committee on Health and Environmental Risks (SCHER) and the Scientific Committee on Emerging and Newly-Identified Health Risks (SCENIHR) and are made up of external experts. In addition, the Commission relies upon the work of the European Food Safety Authority (EFSA), the European Medicines Evaluation Agency (EMEA), the European Centre for Disease prevention and Control (ECDC) and the European Chemicals Agency (ECHA). SCENIHR Questions concerning emerging or newly-identified risks and on broad, complex or multi- disciplinary issues requiring a comprehensive assessment of risks to consumer safety or public health and related issues not covered by other Community risk- assessment bodies. In particular, the Committee addresses questions related to potential risks associated with interaction of risk factors, synergic effects, cumulative effects, antimicrobial resistance, new technologies such as nanotechnologies, medical devices, tissue engineering, blood products, fertility reduction, cancer of endocrine organs, physical hazards such as noise and electromagnetic fields and methodologies for assessing new risks. Scientific Committee members Anders Ahlbom, James Bridges, Wim De Jong, Jana Hajslová, Philippe Hartemann, Thomas Jung, Mats-Olof Mattsson, Jean-Marie Pagès, Konrad Rydzynski, Dorothea Stahl, Mogens Thomsen, David Williams Contact: European Commission Health & Consumer Protection DG Directorate C: Public Health and Risk Assessment Unit C7 - Risk Assessment Office: B232 B-1049 Brussels [email protected] © European Commission 2007 The opinions of the Scientific Committees reflect the views of the independent scientists who are members of the committees. They do not necessarily reflect the views of the European Commission. The opinions are published by the European Commission in their original language only. http://ec.europa.eu/health/ph_risk/risk_en.htm 2 The safety of medical devices containing DEHP-plasticized PVC or other plasticizers on neonates and other groups possibly at risk ACKNOWLEDGMENTS Members of the working group are acknowledged for their valuable contribution to this memorandum. The members of the working group are: The SCENIHR members: Prof. Jim Bridges (chair) Dr. Wim De Jong Prof. Jana Hajslová Prof. Dorothea Stahl1 External experts: Dr. Kristofer Almdal, Risø National Laboratory, Denmark Prof. Jurgen Angerer, Institut für Arbeits-, Sozial- und Umweltmedizin der Universität Erlangen-Nürnberg, Germany Prof. Gisela Degen, Scientific Committee on Consumer Products (SCCP) Prof. Jouni Jaakkola, University of Birmingham, United Kingdom Prof. Bo Jansson, Scientific Committee on Health and Environmental Risks (SCHER) Dr. Ole Ladefoged, Scientific Committee on Health and Environmental Risks (SCHER), (rapporteur) Prof. G. Latini, Clinical Physiology Institute, Italy Prof. Kimmo Peltonen, EVIRA, Finland Prof. Elizabeta Ranucci, University of Milano, Italy Dr. Suresh Rastogi, Scientific Committee on Consumer Products (SCCP) Dr. Jorge Rodrigues Inacio, Karolinska University Hospital, Sweden ABSTRACT The Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) has evaluated the exposure to DEHP for the general population and patients during medical procedures. In many cases the exposure is significant and exceeds the toxic doses observed in animal studies. There is limited evidence indicating a relation between DEHP exposures and certain effects in humans. However, it is recognised that especially the potentially high exposure during medical treatments raise a concern, even in the absence of clinical or epidemiological evidence, for harmful effects in humans. For certain uses of DEHP alternative plasticizers for PVC are available. The Committee got access to toxicity data for eight possible alternative plasticizers and compared their toxicity with that of DEHP. In respect to reproductive toxicity in animal studies DEHP induces more severe effects compared with some of the alternatives. A risk assessment of these available alternative plasticizers could not be performed due to a lack of exposure data from medical devices. Each alternative to DEHP, however, must also be evaluated with regard to their functionality in respect to medical devices. The risk and benefits of using alternative plasticizers should be evaluated case by case. Keywords: SCENIHR, scientific opinion, DEHP, medical devices, neonates, alternative plasticizer, risk To be cited as: SCENIHR (Scientific Committee on Emerging and Newly-Identified Health Risks), Preliminary report on the safety of medical devices containing DEHP-plasticized PVC or other plasticizers on neonates and other groups possibly at risk, 21-22 June 2007 1 Resigned in February 2006. 3 The safety of medical devices containing DEHP-plasticized PVC or other plasticizers on neonates and other groups possibly at risk EXECUTIVE SUMMARY The Scientific Committee on Medicinal Products and Medical Devices (SCMPMD) published its Opinion on Medical Devices containing Di-(2-ethylhexyl)phthalate (DEHP) plasticized PVC in 2002. That Opinion stated that there were no reports concerning any adverse effects in humans following exposure to DEHP-PVC, even in neonates or other groups of relatively high exposure. In addition, there were no indications that neonates of high DEHP exposure have any altered long term fertility patterns. Since 2002, substantial new information on exposure to DEHP has become available as well as data on reproductive toxicity obtained in laboratory animal and human studies. Also for DEHP a so called tolerable daily intake (TDI) was calculated in recent risk evaluations. Therefore an overview is presented on the safety of DEHP in medical devices. In addition, the availability, suitability and safety of alternative plasticizers for DEHP have been evaluated. Certain medical procedures used in high risk groups result in a significant exposure to DEHP. In view of the reproductive toxicity observed in animal studies in which young immature animals were more susceptible to DEHP toxicity, newborn and pre-term born male infants are of special concern. Exchange transfusion in neonates, total parenteral nutrition in neonates, multiple procedures in sick neonates, and haemodialysis in peripuberal males are examples of procedures applied in high risk groups. Other risk groups are pregnant women in haemodialysis or lactating women. Also massive infusion of blood into trauma patients is of concern due to exposure levels substantially exceeding the TDI of DEHP. The toxicity of DEHP in laboratory animals is summarized. The reproductive effect of DEHP in developing and postnatal pups appears at low levels with a TDI of 48 µg/kg bw/d, derived from a two generation study in rats with a No Observed Adverse Effect Level (NOAEL) of 4.8 mg/kg bw and applying a safety factor of 100. Possible alternative plasticizers were evaluated for their potential toxicity and ranked according to toxicity and leaching, or leaching resulting in exposure. For reproductive toxicity the dose of DEHP is an order of magnitude lower compared with some of the alternative plasticizers. For some of the alternative plasticizers a complete evaluation could not be performed due to lack of data on either toxicity or exposure. For most of the alternative plasticizers added in similar concentrations to PVC as DEHP, the leaching seems to be of the same order of magnitude, which is in part due to the similar properties of these compounds. Nonetheless, for some alternatives considerable lower leaching was observed. There is limited evidence indicating a relation between DEHP exposures and certain effects in humans. However, it is recognised that especially the potentially high exposure during medical treatments raise concern, even in the absence of clinical or epidemiological evidence for harmful effects in humans. Some alternatives may be suitable to replace DEHP in certain medical devices, while for other devices it may be difficult to achieve the same functionality as PVC plasticized with DEHP. The risk and benefit of using alternative plasticizers should be evaluated case by case. 4 The safety of medical devices containing DEHP-plasticized PVC or other plasticizers on neonates and other groups possibly at risk TABLE OF CONTENTS ACKNOWLEDGMENTS ................................................................................................. 3 ABSTRACT ....................................................................................................................... 3 EXECUTIVE SUMMARY ................................................................................................ 4 1. BACKGROUND.......................................................................................................