EPA/635/R-08/002F www.epa.gov/iris TOXICOLOGICAL REVIEW OF Cerium Oxide and Cerium Compounds (CAS No. 1306-38-3) In Support of Summary Information on the Integrated Risk Information System (IRIS) September 2009 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 CERIUM OXIDE AND CERIUM COMPOUNDS (CAS NO. 1306-38-3) LIST OF TABLES .......................................................................................................................... v LIST OF FIGURES ....................................................................................................................... vi LIST OF ABBREVIATIONS AND ACRONYMS ...................................................................... vii FOREWORD ................................................................................................................................. ix AUTHORS, CONTRIBUTORS, AND REVIEWERS ................................................................... x 1. INTRODUCTION ..................................................................................................................... 1 2. CHEMICAL AND PHYSICAL INFORMATION .................................................................... 3 3. TOXICOKINETICS .................................................................................................................. 8 3.1. ABSORPTION ................................................................................................................. 8 3.1.1. Oral Exposure ......................................................................................................... 8 3.1.2. Inhalation Exposure .............................................................................................. 11 3.2. DISTRIBUTION ............................................................................................................. 12 3.2.1. Oral Exposure ....................................................................................................... 12 3.2.2. Inhalation Exposure .............................................................................................. 13 3.3. METABOLISM .............................................................................................................. 14 3.4. ELIMINATION .............................................................................................................. 15 3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS .................................... 16 4. HAZARD IDENTIFICATION ................................................................................................ 17 4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS .................................................................................................................... 17 4.1.1. Oral Exposure ....................................................................................................... 17 4.1.2. Inhalation Exposure .............................................................................................. 18 4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL AND INHALATION .................................................................... 20 4.2.1. Oral Exposure ....................................................................................................... 20 4.2.2. Inhalation Exposure .............................................................................................. 22 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION .. 30 4.4. OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES ..................................... 30 4.4.1. Acute Toxicity Studies (Oral and Inhalation) ...................................................... 30 4.4.2. Acute Studies (Injection) ...................................................................................... 31 4.4.2.1. Neurobehavioral and Neurodevelopmental Effects ................................ 31 4.4.2.2. Neurological Effects ............................................................................... 32 4.4.2.3. Hepatic Effects ........................................................................................ 33 4.4.2.4. Cardiovascular Effects ........................................................................... 35 4.4.2.5. Hematological Effects ............................................................................. 36 4.4.2.6. Renal Effects ........................................................................................... 37 4.4.3. Genotoxicity ......................................................................................................... 37 4.5. MECHANISTIC DATA AND OTHER STUDIES ....................................................... 38 4.5.1. In Vitro Studies .................................................................................................... 38 iii 4.5.2. Ex Vivo Studies .................................................................................................... 40 4.5.3. Nanoparticle Studies............................................................................................. 40 4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS ................................................... 45 4.6.1. Oral ....................................................................................................................... 45 4.6.2. Inhalation .............................................................................................................. 45 4.6.3. Mode-of-Action Information ................................................................................ 46 4.6.3.1. Respiratory Tissues ................................................................................. 46 4.6.3.2. Other Tissues .......................................................................................... 50 4.7. EVALUATION OF CARCINOGENICITY ................................................................... 52 4.7.1. Summary of Overall Weight of Evidence ............................................................ 52 4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence ........................... 52 4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ............................................... 52 4.8.1. Possible Childhood Susceptibility ........................................................................ 52 4.8.2. Possible Gender Differences ................................................................................ 52 4.8.3. Possible Susceptible Populations ......................................................................... 53 5. DOSE-RESPONSE ASSESSMENTS ..................................................................................... 54 5.1. ORAL REFERENCE DOSE (RfD) ................................................................................ 54 5.1.1. Choice of Principal Study and Critical Effect—with Rationale and Justification 54 5.1.2. Previous RfD Assessment .................................................................................... 55 5.2. INHALATION REFERENCE CONCENTRATION (RfC) ........................................... 55 5.2.1. Choice of Principal Study and Critical Effect—with Rationale and Justification 55 5.2.2. Methods of Analysis—Including Models (PBTK, BMD, etc.) ............................ 57 5.2.3. RfC Derivation—Including Application of Uncertainty Factors (UFs) ............... 59 5.2.4. RfC Comparison Information ............................................................................... 61 5.2.5. Previous RfC Assessment .................................................................................... 64 5.3. UNCERTAINTIES IN THE ORAL REFERENCE DOSE (RfD) AND INHALATION REFERENCE CONCENTRATION (RfC) ..................................................................... 64 5.4. CANCER ASSESSMENT .............................................................................................. 67 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE RESPONSE ............................................................................................................................. 68 6.1. HUMAN HAZARD POTENTIAL ................................................................................. 68 6.2. DOSE RESPONSE ......................................................................................................... 70 6.2.1. Noncancer/Oral .................................................................................................... 70 6.2.2. Noncancer/Inhalation ........................................................................................... 71 6.2.3. Cancer/Oral and Inhalation .................................................................................. 73 7. REFERENCES ........................................................................................................................ 74 APPENDIX A: SUMMARY OF EXTERNAL PEER REVIEW AND PUBLIC COMMENTS AND DISPOSITION .............................................................................................................. 83 APPENDIX B: BENCHMARK DOSE MODELING RESULTS FOR THE DERIVATION OF THE RFC ................................................................................................................................ 99 iv LIST OF TABLES Table 2-1. Physical properties of cerium and cerium