The safety of the use of bisphenol A in medical devices Scientific Committee on Emerging and Newly Identified Health Risks SCENIHR Opinion on The safety of the use of bisphenol A in medical devices SCENIHR adopted this opinion by written procedure on 18 February 2015 1 The safety of the use of bisphenol A in medical devices About the Scientific Committees Three independent non-food Scientific Committees provide the Commission with the 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 Safety (SCCS), the Scientific Committee on Health and Environmental Risks (SCHER) and the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR). In addition, the Commission relies upon the work of the European Food Safety Authority (EFSA), the European Medicines Agency (EMA), the European Centre for Disease prevention and Control (ECDC) and the European Chemicals Agency (ECHA). SCENIHR This Committee deals with questions related to emerging or newly identified health and environmental risks and to broad, complex or multidisciplinary issues requiring a comprehensive assessment of risks to consumer safety or public health and related issues not covered by other Community risk assessment bodies. Examples of potential areas of activity include potential risks associated with interaction of risk factors, synergic effects, cumulative effects, antimicrobial resistance, new technologies such as nanotechnologies, medical devices including those incorporating substances of animal and/or human origin, tissue engineering, blood products, fertility reduction, cancer of endocrine organs, physical hazards such as noise and electromagnetic fields (from mobile phones, transmitters and electronically controlled home environments), and methodologies for assessing new risks. It may also be invited to address risks related to public health determinants and non-transmissible diseases. Scientific Committee members Michelle Epstein, Igor Emri, Philippe Hartemann, Peter Hoet, Norbert Leitgeb, Luis Martínez Martínez, Ana Proykova, Luigi Rizzo, Eduardo Rodriguez-Farré, Lesley Rushton, Konrad Rydzynski, Theodoros Samaras, Emanuela Testai, Theo Vermeire Contact: European Commission DG Health and Food Safety Directorate C Public Health Unit C2 – "Health Information and Scientific Committees" Office: HTC 03/073 L-2920 Luxembourg [email protected] © European Commission 2015 ISSN 1831-4783 ISBN 978-92-79-30133-9 Doi: 10.2772/75546 ND-AS-13-003-EN-N The opinions of the Scientific Committees present 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/scientific_committees/emerging/opinions/index_en.htm 2 The safety of the use of bisphenol A in medical devices ACKNOWLEDGMENTS Members of the working group are acknowledged for their valuable contribution to this Opinion. They are: SCENIHR members: Dr. Emanuela Testai - Istituto Superiore di Sanità, Environment & Primary Prevention Dept., Mechanisms of Toxicity Unit, Roma, Italy. Chair of the Working Group since April 2013. Prof. Philippe Hartemann - Université de Lorraine, Faculté de Médecine, Nancy, France. Prof. Eduardo Rodriguez-Farré – Barcelona Institute of Biomedical Research, Barcelona, Spain. SCCS member: Dr. Suresh Chandra Rastogi. External experts: Dr. Wim De Jong - National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. Chair of the Working Group until March 2013 and rapporteur. Dr. Juana Bustos - National Food Centre - Spanish Food Safety and Nutrition Agency (AESAN), Spain. Dr. Laurence Castle - FERA, York, United Kingdom. Prof. Ursula Gundert-Remy - Medical School (Charité), Berlin, Germany. Prof. Arne Hensten- UiT The Arctic University of Norway, Tromsö, Norway. Dr. Hilde Molvig Kopperud - Nordic Institute of Dental Materials, Oslo, Norway. Prof. Nicolás Olea - University of Granada, Granada, Spain. Prof. Aldert Piersma - National Institute for Public Health and the Environment, Bilthoven, the Netherlands. All Declarations of working group members and supporting experts are available at the following webpage: http://ec.europa.eu/health/scientific_committees/emerging/members_wg/index_en.htm 3 The safety of the use of bisphenol A in medical devices ABSTRACT Bisphenol A (BPA) is a key building block of polycarbonate plastic and a precursor for the manufacturing of monomers of epoxy resins. The BPA exposure of the general population is via food as a result of the use of BPA in food packaging and via skin as a result of contact with thermal paper. The vast majority of the population (91–99%) has detectable levels of BPA-conjugates in their urine. BPA is also present in medical devices including implants, catheters, tubing, and some dental materials. This Opinion describes the risk assessment of exposure to BPA via medical devices that are manufactured with materials that potentially leach BPA leading to oral (via dental material), subcutaneous and intravenous (e.g. during heamodialysis) routes of exposure. After oral exposure BPA is readily absorbed from the gastro-intestinal tract and due to the first pass effect in the liver and the small intestine is rapidly conjugated to non-toxic metabolites. By the oral route BPA has a low systemic bioavailability (1-10% in humans) and has a half life time of a few hours. For parenteral routes of exposure (intravenous, intraperitoneal, subcutaneous), BPA can be considered 100% systemically bioavailable. However, BPA will also be conjugated in the liver and the clearance of free BPA from the circulation appears to be relatively fast. Toxicity studies indicate that the kidney and the liver are relevant target organs for BPA toxicity. The lowest NOAEL after oral repeated exposure identified in several studies, including multigeneration reproductive toxicity studies, was approximately 5 mg/kg b.w./day. By applying the benchmark dose (BMD) approach, a BMDL10 of 8.96 mg/kg b.w./day was derived (EFSA 2015), based on the alteration in kidney weight. BPA is not likely to pose a genotoxic hazard to humans and has no carcinogenic activity, although there are some effects observed in the mammary gland, which currently are of unknown significance to human health. Neither reproductive nor prenatal developmental toxicity are critical end-points in BPA toxicity, though BPA is associated with reproductive toxicity at doses higher than those causing liver and kidney damage. There are several indications that BPA might have biological effects below the recently determined BMDL10. However, the evidence is inconsistent, mainly obtained in dedicated studies focussing on different selected health effects and dose-response relationships could not be established. Regarding possible low dose effects, some concern remains for effects on mammary gland, metabolism and adiposity and neurobehaviour. The SCENIHR adopts the temporary oral TDI (t-TDI) of 4 µg/kg b.w./day derived by EFSA which considers the BMDL10 as point of departure, and the uncertainties related to some effects using a BPA-specific assessment factor of 150. This t-TDI represents a useful base for carrying out a BPA risk assessment for the use of BPA in medical devices. The BMDL10 dose was translated into a human dose inducing similar effects, the human equivalent dose (HED). The HED of 609 µg/kg b.w./day was determined considering the ratio of internal exposure in mice (the species used in the study from which BMDL10 was derived) versus the internal exposure in humans based on toxicokinetic studies. For medical devices, several exposure scenarios were evaluated taking into account the material used, information related to BPA leaching, duration of a single treatment and the frequency of treatments, giving rise to toxicologically relevant acute, short and long term exposure. The information available is very limited and in many cases due to the lack of experimental data, only estimations were used. The uncertainties related to the exposure assessment indeed represent the weakest part of this evaluation. For this reason only the highest value obtained in the estimate was indicatively used. The estimated BPA exposures were: 1) 3000 ng/kg b.w./day (3 µg/kg b.w./day) for prematurely born infants in neonatal intensive care units; 2) 685 ng/kg b.w./day for prolonged medical procedures (such as extracorporeal circulation or transplantation/ implantation of an artificial organ) in infants (b.w. around 5 kg); 3) 57 ng/kg b.w./day for dialysis patients; 4) 0.4 - 12ng/kg b.w./day for long-term exposures to medical devices; 5) 140 to 200 ng/kg b.w./day for, respectively, children and adults due to 4 The safety of the use of bisphenol A in medical devices contact with dental materials (<24 h); 6) 2 to 12 ng/kg b.w./day due to long-term contact with dental materials. Exposure via medical devices consisting of BPA containing PVC might even be higher with values estimated for adults up to 5000 ng/kg b.w./day and infants up to 12000 ng/kg b.w./day. However, exposure to BPA via BPA-containing PVC has been estimated based on extrapolation from data on phthalate leakage from PVC and has a high degree of uncertainty. Notably, European PVC