EPA/635/R-07/006F www.epa.gov/iris TOXICOLOGICAL REVIEW OF 2,2',4,4',5-PENTABROMODIPHENYL ETHER (BDE-99) (CAS No. 60348-60-9) In Support of Summary Information on the Integrated Risk Information System (IRIS) June 2008 U.S. Environmental Protection Agency Washington, DC DISCLAIMER This document has been reviewed in accordance with U.S. Environmental Protection Agency policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. ii CONTENTS—TOXICOLOGICAL REVIEW OF 2,2',4,4',5-PENTABROMODIPHENYL ETHER (CAS No. 60348-60-9) LIST OF TABLES ........................................................................................................................... v LIST OF FIGURES ......................................................................................................................... v LIST OF ACRONYMS ................................................................................................................. vii FOREWORD ................................................................................................................................. ix AUTHORS, CONTRIBUTORS, AND REVIEWERS ................................................................... x 1. INTRODUCTION...................................................................................................................... 1 2. CHEMICAL AND PHYSICAL INFORMATION ..................................................................... 3 3. TOXICOKINETICS................................................................................................................... 5 3.1. ABSORPTION ................................................................................................................. 5 3.2. DISTRIBUTION .............................................................................................................. 7 3.2.1. Human Data ........................................................................................................... 7 3.2.1.1. Adipose Tissue ........................................................................................ 7 3.2.1.2. Liver ......................................................................................................... 9 3.2.1.3. Human Milk ............................................................................................. 9 3.2.1.4. Blood ..................................................................................................... 11 3.2.1.5. Placental Transport ................................................................................ 12 3.2.2. Animal Data......................................................................................................... 14 3.3. METABOLISM .............................................................................................................. 18 3.4. ELIMINATION .............................................................................................................. 21 3.4.1. Half-life Determinations ...................................................................................... 23 3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS ..................................... 23 4. HAZARD IDENTIFICATION ................................................................................................. 24 4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS ................................................................................................................ 24 4.2. SHORT-TERM, SUBCHRONIC, AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL AND INHALATION ..................................... 24 4.2.1. Short-term and Subchronic Studies ..................................................................... 24 4.2.1.1. Mice ....................................................................................................... 24 4.2.1.2. Rats ........................................................................................................ 26 4.2.2. Chronic Studies and Cancer Bioassays ............................................................... 26 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES ..................................................... 26 4.3.1. Mice ..................................................................................................................... 26 4.3.1.1. Eriksson et al. (2001) ............................................................................. 26 4.3.1.2. Eriksson et al. (2002) ............................................................................. 27 4.3.1.3. Viberg et al. (2002) ................................................................................ 28 4.3.1.4. Viberg et al. (2004a) .............................................................................. 29 4.3.1.5. Viberg et al. (2004b) .............................................................................. 30 4.3.1.6. Ankarberg (2003)................................................................................... 31 4.3.1.7. Branchi et al. (2002) .............................................................................. 31 4.3.1.8. Branchi et al. (2005) .............................................................................. 33 iii 4.3.2. Rats ...................................................................................................................... 34 4.3.2.1. Kuriyama et al. (2005) ........................................................................... 34 4.3.2.2. Viberg et al. (2005) ................................................................................ 36 4.3.2.3. Talsness et al. (2005) ............................................................................. 37 4.4. OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES ..................................... 38 4.4.1. Subcutaneous Exposures ..................................................................................... 38 4.4.1.1. Lilienthal et al. (2005) ........................................................................... 38 4.4.1.2. Lilienthal et al. (2006) ........................................................................... 38 4.4.1.3. Ceccatelli et al. (2006) .......................................................................... 39 4.4.2. Receptor Site Interactions ................................................................................... 41 4.4.2.1. Aryl Hydrocarbon Receptors ................................................................. 42 4.4.2.2. Other CYP-450 Inducing Receptors ...................................................... 44 4.4.2.3. Estrogen Receptors ................................................................................ 45 4.4.2.4. Androgen Receptors .............................................................................. 47 4.4.2.5. Acetylcholine Receptors ........................................................................ 47 4.4.3. Thyroid Effects .................................................................................................... 49 4.4.4. Neurotoxicity ....................................................................................................... 50 4.4.5. Immunotoxicity ................................................................................................... 51 4.4.6. Cytotoxicity ......................................................................................................... 52 4.4.7. Genotoxicity ........................................................................................................ 52 4.5. SYNTHESIS OF MAJOR NONCANCER EFFECTS ................................................... 52 4.5.1. Oral ...................................................................................................................... 52 4.5.2. Inhalation ............................................................................................................. 53 4.5.3. Mode-of-Action Information ............................................................................... 53 4.6. EVALUATION OF CARCINOGENICITY ................................................................... 55 4.7. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ................................................ 55 4.7.1. Possible Childhood Susceptibility ....................................................................... 55 4.7.2. Possible Gender Differences ............................................................................... 56 5. DOSE-RESPONSE ASSESSMENTS ..................................................................................... 57 5.1. ORAL REFERENCE DOSE (RfD) ................................................................................ 57 5.1.1. Choice of Principal Study and Critical Effect—with Rationale and Justification ...................................................................................................... 57 5.1.2. Methods of Analysis ............................................................................................ 60 5.1.3. RfD Derivation .................................................................................................... 63 5.1.4. Previous RfD Assessment.................................................................................... 64 5.2. INHALATION REFERENCE CONCENTRATION (RfC) ........................................... 65 5.3. CANCER ASSESSMENT.............................................................................................. 65 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE RESPONSE ..................................................................................................