nr 2010;44(6) The Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals 143. Phosphate triesters with flame retardant properties Bengt Sjögren, Anders Iregren and Jill Järnberg arbete och hälsa | vetenskaplig skriftserie isbn 978-91-85971-23-7 issn 0346-7821 Arbete och Hälsa Arbete och Hälsa (Work and Health) is a scientific report series published by Occupational and Environmental Medicine at Sahlgrenska Academy, University of Gothenburg. The series publishes scientific original work, review articles, criteria documents and dissertations. All articles are peer-reviewed. Arbete och Hälsa has a broad target group and welcomes articles in different areas. Instructions and templates for manuscript editing are available at http://www.amm.se/aoh Summaries in Swedish and English as well as the complete original texts from 1997 are also available online. Arbete och Hälsa Editorial Board: Editor-in-chief: Kjell Torén Tor Aasen, Bergen Gunnar Ahlborg, Göteborg Co-editors: Maria Albin, Ewa Wigaeus Kristina Alexanderson, Stockholm Tornqvist, Marianne Törner, Lotta Dellve, Berit Bakke, Oslo Roger Persson and Kristin Svendsen Lars Barregård, Göteborg Managing editor: Cina Holmer Jens Peter Bonde, Köpenhamn Jörgen Eklund, Linköping © University of Gothenburg & authors 2009 Mats Eklöf, Göteborg Mats Hagberg, Göteborg Arbete och Hälsa, University of Gothenburg Kari Heldal, Oslo SE 405 30 Gothenburg, Sweden Kristina Jakobsson, Lund Malin Josephson, Uppsala ISBN 978-91-85971-23-7 Bengt Järvholm, Umeå ISSN 0346–7821 Anette Kærgaard, Herning http://www.amm.se/aoh Ann Kryger, Köpenhamn Printed at Geson Hylte Tryck, Gothenburg Carola Lidén, Stockholm Svend Erik Mathiassen, Gävle Gunnar D. Nielsen, Köpenhamn Catarina Nordander, Lund Torben Sigsgaard, Århus Staffan Skerfving, Lund Gerd Sällsten, Göteborg Allan Toomingas, Stockholm Ewa Wikström, Göteborg Eva Vingård, Uppsala Preface The main task of the Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals (NEG) is to produce criteria documents to be used by the regulatory authorities as the scientific basis for setting occupational exposure limits for chemical substances. For each document, NEG appoints one or several authors. An evaluation is made of all relevant published, peer-reviewed original literature found. The document aims at establishing dose-response/dose-effect relationships and defining a critical effect. No numerical values for occupational exposure limits are proposed. Whereas NEG adopts the document by consensus procedures, thereby granting the quality and conclusions, the authors are re- sponsible for the factual content of the document. The evaluation of the literature and the drafting of this document on Phosphate triesters with flame retardant properties were done by Dr. Bengt Sjögren, Karolinska Institutet, Sweden, Dr. Anders Iregren and Dr. Jill Järnberg, Swedish Work Environment Authority, Sweden. The draft versions were discussed within NEG and the final version was accepted by the present NEG experts on September 28, 2009. Editorial work and technical editing were performed by the NEG secre- tariat. The following present and former experts participated in the elaboration of the document: Present NEG experts Gunnar Johanson Institute of Environmental Medicine, Karolinska Institutet, Sweden Kristina Kjærheim Cancer Registry of Norway Anne Thoustrup Saber National Research Centre for the Working Environment, Denmark Tiina Santonen Finnish Institute of Occupational Health, Finland Vidar Skaug National Institute of Occupational Health, Norway Mattias Öberg Institute of Environmental Medicine, Karolinska Institutet, Sweden Former NEG experts Maria Albin Department of Occupational and Environmental Medicine, Lund University Hospital, Sweden Vidir Kristjansson Administration of Occupational Safety and Health, Iceland Kai Savolainen Finnish Institute of Occupational Health, Finland Karin Sørig Hougaard National Research Centre for the Working Environment, Denmark NEG secretariat Jill Järnberg and Swedish Work Environment Authority, Sweden Anna-Karin Alexandrie This work was financially supported by the Swedish Work Environment Authority, the former Swedish National Institute for Working Life, and the Norwegian Ministry of Labour. All criteria documents produced by the Nordic Expert Group may be down- loaded from www.nordicexpertgroup.org. Gunnar Johanson, Chairman of NEG Contents Preface Abbreviations and acronyms 1. Introduction 1 2. Substance identification 1 3. Physical and chemical properties 8 4. Occurrence, production and use 12 5. Measurement and analysis of workplace exposure 17 6. Occupational exposure data 18 6.1 Airborne exposure 18 6.2 Dermal exposure 22 7. Toxicokinetics 23 7.1 Uptake 23 7.2 Distribution 25 7.3 Biotransformation 28 7.4 Excretion 31 7.5 Summary 32 8. Biological monitoring 33 8.1 Markers of exposure 33 8.2 Markers of effect 33 9. Mechanisms of toxicity 35 9.1 Neurotoxicity 35 9.2 Carcinogenicity 36 9.3 Hormonal and reproductive effects 36 10. Effects in animals and in vitro studies 37 10.1 Irritation and sensitisation 37 10.2 Effects of single exposure 41 10.3 Effects of short-term exposure (up to 90 days) 45 10.4 Neurotoxicity 49 10.5 Mutagenicity and genotoxicity 67 10.6 Effects of long-term exposure and carcinogenicity 74 10.7 Reproductive and developmental toxicity 85 10.8 Summary 100 11. Observations in man 102 11.1 Irritation and sensitisation 102 11.2 Effects of single and short-term exposure 103 11.3 Effects of long-term exposure 104 12. Substance summaries with dose-effect and dose-response relationships 108 13. Previous evaluations by national and international bodies 116 14. Evaluation of human health risks 129 14.1 Assessment of health risks 129 14.2 Groups at extra risk 131 14.3 Scientific basis for an occupational exposure limit 131 15. Research needs 133 16. Summary 134 17. Summary in Swedish 135 18. References 136 19. References reviewed by others 151 20. Data bases used in search of literature 156 Appendix 1. Dose-effect and dose-response relationships in animals 157 Appendix 2. Occupational exposure limit values 217 Appendix 3. Previous NEG criteria documents 218 Abbreviations and acronyms Phosphate triesters TBEP tris(2-butoxyethyl) phosphate TBP tri-n-butyl phosphate TCEP tris(2-chloroethyl) phosphate TCP tricresyl phosphate TDCPP tris(1,3-dichloro-2-propyl) phosphate TEHP tris(2-ethylhexyl) phosphate TEP triethyl phosphate TIPP isopropylated triphenyl phosphate including triisopropylated phenyl phosphate TMCP tri-meta-cresyl phosphate, tri-m-cresyl phosphate TMCPP tris(monochloropropyl) phosphate, all isomers TOCP tri-ortho-cresyl phosphate, tri-o-cresyl phosphate TPCP tri-para-cresyl phosphate, tri-p-cresyl phosphate TPP triphenyl phosphate Other ACGIH American Conference of Governmental Industrial Hygienists AChE acetylcholinesterase BDCPP bis(1,3-dichloro-2-propyl) phosphate bw body weight CAR constitutively active receptor CAS Chemical Abstracts Service ChE cholinesterase CHO Chinese hamster ovary CNS central nervous system CYP cytochrome P450 ECETOC European Centre for Ecotoxicology and Toxicology of Chemicals ED50 effective dose for 50 % of the population exposed EPA Environmental Protection Agency EU European Union GC gas chromatography HPRT hypoxanthine-guanine phosphoribosyl transferase IPCS International Programme on Chemical Safety LC50 lethal concentration for 50 % of the exposed animals at single administration LD50 lethal dose for 50 % of the exposed animals at single administration LOAEL lowest observed adverse effect level MAK Maximale Arbeitsplatzkonzentration (maximum concentration at the workplace) MN-PCE micronucleus containing polychromatic erythrocyte NADPH nicotinamide adenine dinucleotide phosphate NOAEL no observed adverse effect level NTE neurotoxic or neuropathy target esterase NTP National Toxicology Program (United States) OECD Organisation for Economic Co-operation and Development OEL occupational exposure limit OPIDN organophosphorus-induced delayed neuropathy PNS peripheral nervous system PVC polyvinyl chloride RACB reproductive assessment by continuous breeding protocol SCE sister chromatid exchange SP(M)E solid-phase (micro)extraction TLV threshold limit value TWA time-weighted average US United States 1. Introduction Phosphate esters are frequently utilised as flame retardants and plasticisers but also as stabilisers and additives in products such as floor polishes, lubricants and hydraulic fluids. Both phosphorous and chlorine provide the flame retardant pro- perties. The organic parts of the molecule make it possible for the substance to be incorporated in organic materials. These parts can also interpose themselves between the polymer chains in a plastic and in that way plasticise it. The global consumption of organophosphorus compounds used as flame retardants was estimated to about 207 000 tonnes in 2004 and the consumption is expected to increase (52). In Western Europe, the consumption, evenly distributed between chlorinated phosphate and non-chlorinated organophosphorus flame retardants, increased from 58 000 to 83 000 tons between the years 1998 and 2001 (145). In 2006, the estimated annual consumption of chlorinated phosphate and non-chlorinated organophosphorus flame retardants within the European Union (EU) was 51 000 and 40 000 tons, respectively (52). This document reviews some phosphate triesters with flame retardant properties, as particularly requested by the Swedish Work Environment Authority. The phosphorylated mono- and diesters