1 Australian Government Department of Health and Ageing NICNAS Human Health Toxicity Risk Assessment of DEHP in Medical Devices NICNAS November 2007 334-336 llIawarra Rd, MARRICKVILLE NSW 2204 GPO Box 58 SYDNEY NSW 2001 Phone: 02 8577 8800 Fax: 02 8577 8888 WEBSITE: http://www.nicnas.gov.au 3 5. OVERSEAS AGENCY DECISIONS .................................................................................... 77 5.1 ·Health Canada ................................................................................................................ 77 5.2 US Food and Drug Administration ................ � .......... ..................................................... 79 5.3 European Commission ScientificCommittee on Medicinal Products and Medical Devices ....................................................................................................................................... 83 5.4 EU Risk Assessment (draft 2006) .................................... ...................................... ....... 84 5.5 NTP CERHR..................................... ............................................................................ 85 APPENDIX A: EXPOSURE CALCULATIONS ..................................................................... 87 ADULT ...................................................................................................................................... 87 NEONATES .............................................................................................................................. 98 APPEND IX B ............................................................................................................................. 1 05 APPENDIX C ............................................................................................................................. 127 REFERENCES ........................................................................................................................... 129 4 List of Tables Table 1. Summary of physico-chemical properties ofDEHP ....................................... 13 Table 2. Typical Formulation of a PVC Blood Bag ...................................................... 14 Table 3. DEHP extraction into drug formulations .........................................: ............... 19 Table 4. DEHP content in blood products stored in PVC bags ..................................... 21 Table 5. DEHP exposure during heart surgery .................................................... .......... 24 Table 6. DEHP measurement in plasma fo llowing haemodialysis ................................ 26 Table 7. DEHP content on TPN solutions ..................................................................... 27· Table 8. DEHP concentration fo llowing exchange transfusion..................................... 34 Table 9. DEHP concentration fo llowing ECMO ........................................................... 35 Table 10. DEHP doses and MOE in adults and neonates undergoing medical procedures .................... .............................................................. ............................................. 39 Table 11. Acute effects ofDEHP .................................................................................. 42 Table 12. Comparison of Tolerable Intake (TI) values to the dose ofDEHP received by adult and neonatal patients undergoing various medical procedures .................... 82 Table 13. MOS fo r medically treated persons exposed to DEHP . ................................ 85 Table 14. Effects of DEHP fo llowing repeat administration ....................................... 105 Table 15. Effects ofDEHP on body and liver weight in pregnant females fo llowing repeated oral administration................................................................................. 114 Table 16. Important reproductive studies with DEHP in laboratory animals .............. 116 Table 17. Key reproductive studies with MEHP in laboratory animals .............. ........ 125 5 ABBREVIATIONS 2-EH 2 ethylhexanol ACD acid citrate dextrose AGD ano-genital distance ATSDR Agency fo r Toxic Substances and Disease Registry AUC area under the curve CAPD continuous ambulatory peritoneal dialysis CPB cardiopulmonaryby pass DEHP diethylhexyl phthalate ECMO extracorporeal membrane oxygenation FDA Food and Drug Administration FPP fresh frozenplasma GD gestational day IARC International Agency fo r Research on Cancer IPCS International Programme on Chemical Safe ty LOAEL lowest observable adverse effect level MCL mononuclear cell leukaemia MEHP mono-ethylhexyl phthalate MOE margin of exposure NICU neonatal intensive care unit NOAEL no observable adverse effect level NTP CERHR National Toxicology Program. Center fo r Evaluation of Risks to Human Reproduction OR odds ration PND postnatal day PVC polyvinyl chloride RBC red blood cells TI tolerable intake TOTM tris(2-ethyl hexyl)trimellitate EVA ethylvinyl acetate TPN total parenteral nutrition WHO W orId Health Organization 6 PREFACE As early as 1970, studies identifiedand measured di(2-ethylhexyl) phthalate (DEHP), a plasticiser fo und in a wide variety of medical devices made from polyvinyl chloride (PVC), leached out of devices during use. These studies identified DEHP and its metabolites in the blood and other tissues of patients receiving dialysis, blood transfusions, artificial ventilation, and exchange transfusions. Numerous studies have shown that in rodents, DEHP causes cancer of the liver, developmental and reproductive toxicity and nephrotoxicity. NICNAS was asked by the Office of Devices, Blood and Tissues to conduct a risk assessment for human health effe cts from DEHP exposure via medical devices. The risk assessment considers three main patient subgroups - adult males, pregnant women (prenatal development) and neonates. The toxicity of DEHP has been reviewed by the Expert Panel on Phthalates of the Center fo r Evaluation of Risks to Human Reproduction, National Toxicology Program (CERHR, 2005), Health Canada (2002), FDA (2002), ATSDR (2002) and the National Chemical Inspectorate (2005). This report principally relies on these reviews. References not examined by NICNAS but quoted from other reviews as secondary citations aremarked with an asterisk. In addition, the Medline and Toxline databases were searched to find the medical and scientific reports on any new toxicology studies and human exposure to DEHP, particularly from medical procedures published since the most recent review (2005). The last literature search was perfonned in August 2006. The report identifies and critically reviews the key scientific papers dealing with different aspects of exposure and toxicity to: identify the critical toxicity endpoints; estimate the no-observed-adverse-effect-Ievels (NOAEL) or lowest-observed-adverse­ effect-levels (LOAEL); assess the relevance of the findings in animals for patients exposed to DEHP from medical procedures; and assesses whether exposure to DEHP from medical procedures may cause adverse health effects in humans. The report does not detennine whether the health risks from DEHP exposure outweighits benefits. 7 SUMMARY Three critical fa ctors influence the conclusions of this risk characterisation (i) Choice ofNOAEL fromlaboratory animal studies (ii) Calculation of exposure estimate (iii) Acceptable marginof exposure Choice ofNOAEL The critical effe cts are considered to be reproductive and developmental effects in males. Testicular toxicity appears to be the most sensitive toxicity endpoint but is significantly influenced by the age at exposure. Developing and neonatal rats have been found to be much more sensitive to exposure to DEHP than adults. The younger animals responded to a much lower dose or produced a more serious lesion with a comparable dose on a mglkg bw/day basis. For this reason, risk characterisations fo r three patient populations were developed: pregnant women (prenatal development), neonates and adult males. In general, the animal model best suited would utilise the same route of exposure as the human situation. However, this was not possible for these characterisations as there were no suitable long-term studies fo llowing intravenous administration of DEHP fo r neonatal, adult males or pregnant animals. From the available short-term studies it appears that the NOAELs and LOAELs identified for intravenous exposure to DEHP are higherthan those reported fo llowing oral exposure. The NOAEL fo r testicular atrophy in young rats fo llowing intravenous administration was 60 mglkg bw/day after 21 days exposure (Cammack et aI, 2003) (note: the same study as AdvaMed*, 2001) while in a three generation oral study the NOAEL was 5.8 mg/kg bw/day, based on small male reproductive organ size and histopathologic changes in the testes in prenatally exposed rats (Wolfe & Layton, 2004). This may reflect a real difference in effe ct or differences in study design. It is biologically plausible that DEHP is less toxic by the intravenous route as conversion to MEHP is slower. However due to the inadequacy of data via the IV route, the more conservative NOAELs for oral exposure were used in the risk characterisation fo r parenteral exposure. The most sensitive endpoint fo r adult males was effects on fertility. The NOAEL was 14 mg/kg bw/day based on a continuous breeding study in mice (Lamb et aI, 1987). The most sensitive endpoint fo r fo etal and neonatal males was effects on the testes. The NOAEL in a three generation study was 5.8 mg/kg bw/day and was used for both prenatal and neonatal development (Wolfe