EPA/635/R -08/016F www.epa.gov/iris TOXICOLOGICAL REVIEW OF HYDROGEN CYANIDE AND CYANIDE SALTS (CAS No. various) In Support of Summary Information on the Integrated Risk Information System (IRIS) September 2010 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 HYDROGEN CYANIDE AND CYANIDE SALTS CONTENTS —TOXICOLOGICAL REVIEW OF HYDROGEN CYANIDE AND CYANIDE SALTS ........................................................................................................................ iii LIST OF TABLES .......................................................................................................................... v LIST OF FIGURES ....................................................................................................................... vi LIST OF FIGURES ....................................................................................................................... vi LIST OF ACRONYMS AND ABBREVIATIONS ..................................................................... vii FOREWORD ................................................................................................................................. ix AUTHORS, CONTRIBUTORS, AND REVIEWERS .................................................................. x 1. INTRODUCTION ..................................................................................................................... 1 2. CHEMICAL AND PHYSICAL INFORMATION ................................................................... 3 3. TOXICOKINETICS .................................................................................................................. 7 3.1. ABSORPTION .................................................................................................................. 7 3.2. DISTRIBUTION ............................................................................................................... 8 3.3. METABOLISM ............................................................................................................... 11 3.4. ELIMINATION ............................................................................................................... 16 3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS .................................... 17 4. HAZARD IDENTIFICATION ................................................................................................ 19 4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS .................................................................................................................... 19 4.1.1. Acute Oral, Inhalation, and Dermal Studies ......................................................... 19 4.1.2. Subchronic and Chronic Oral Studies .................................................................. 21 4.1.3. Subchronic and Chronic Inhalation Studies ......................................................... 21 4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL AND INHALATION .................................................................... 29 4.2.1. Oral Studies .......................................................................................................... 29 4.2.2. Inhalation Studies ................................................................................................. 41 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES ..................................................... 42 4.3.1. Oral Studies .......................................................................................................... 42 4.3.2. Inhalation Studies ................................................................................................. 45 4.4. OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES ..................................... 46 4.4.1. Acute Oral Studies ................................................................................................ 46 4.4.2. Acute Inhalation Studies ...................................................................................... 48 4.4.3. Neurotoxicity Studies ........................................................................................... 49 4.4.4. Immune Endpoints ............................................................................................... 50 4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF ACTION ....................................................................................................... 51 4.5.1. Genotoxicity ......................................................................................................... 51 4.5.2. Acute Neurotoxicity ............................................................................................. 52 4.5.3. Thyroid Disruption ............................................................................................... 52 4.5.4. Reproductive Effects ............................................................................................ 53 4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS AND MODE OF ACTION .......................................................................................................................... 54 4.7. EVALUATION OF CARCINOGENICITY ................................................................... 62 4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ................................................ 62 4.8.1. Possible Childhood Susceptibility ........................................................................ 62 4.8.2. Possible Gender Differences ................................................................................ 64 iii 4.8.3. Other Susceptible Populations .............................................................................. 64 5. DOSE RESPONSE ASSESSMENTS ..................................................................................... 66 5.1. ORAL REFERENCE DOSE (RfD) ................................................................................ 66 5.1.1. Choice of Principal Study and Critical Effect ...................................................... 66 5.1.2. Method of Analysis .............................................................................................. 70 5.1.3. RfD Derivation—Including Application of Uncertainty Factors (UFs) .............. 72 5.1.4. RfD Comparison Information .............................................................................. 75 5.1.5. Previous RfD Assessment .................................................................................... 77 5.2. INHALATION REFERENCE CONCENTRATION (RfC) ........................................... 78 5.2.1. Choice of Principal Study and Critical Effect ...................................................... 78 5.2.2. Method of Analysis .............................................................................................. 81 5.2.3. RfC Derivation—Including Application of Uncertainty Factors (UFs) ............... 82 5.2.4. Previous RfC Assessment .................................................................................... 84 5.3. UNCERTAINTIES IN THE ORAL REFERENCE DOSE AND INHALATION REFERENCE CONCENTRATION ..................................................... 84 5.4. CANCER ASSESSMENT .............................................................................................. 89 6. MAJOR CONCLUSIONS IN CHARACTERIZATION OF HAZARD AND DOSE RESPONSE................................................................................................................................... 91 6.1. HUMAN HAZARD POTENTIAL ................................................................................. 91 6.2. DOSE RESPONSE .......................................................................................................... 93 6.2.1. Noncancer—Oral .................................................................................................. 93 6.2.2. Noncancer—Inhalation ........................................................................................ 95 6.2.3. Cancer ................................................................................................................... 96 7. REFERENCES ........................................................................................................................ 97 APPENDIX A. SUMMARY OF EXTERNAL PEER REVIEW AND PUBLIC COMMENTS AND DISPOSITION .......................................................................................... A-1 APPENDIX B. BENCHMARK DOSE MODELING RESULTS ............................................ B-1 iv LIST OF TABLES 2-1. Physical and chemical properties of cyanide compounds ...................................................... 4 4-1. Thyroid uptake of 131I in electroplating workers .................................................................. 24 4-2. Thyroid parameters in former silver-reclaiming workers ..................................................... 26 4-3. Thyroid parameters in HCN-exposed and unexposed electroplating workers ...................... 28 4-4. Reproductive effects in male rats administered NaCN in drinking water for 13 weeks ...... 31 4-5. Reproductive effects in mice administered NaCN in drinking water for 13 weeks ............. 34 4-6. Summary of subchronic and chronic oral toxicity studies for cyanide in animals ............... 56 4-7. Summary of subchronic