EPA/635/R-08/003F www.epa.gov/iris TOXICOLOGICAL REVIEW OF PROPIONALDEHYDE (CAS No. 123-38-6) In Support of Summary Information on the Integrated Risk Information System (IRIS) September 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 PROPIONALDEHYDE (CAS No. 123-38-6) LIST OF TABLES.......................................................................................................................... v LIST OF FIGURES ........................................................................................................................ v LIST OF ACRONYMS ................................................................................................................. vi FOREWORD ................................................................................................................................ vii AUTHORS, CONTRIBUTORS, AND REVIEWERS ...............................................................viii 1. INTRODUCTION ...................................................................................................................... 1 2. CHEMICAL AND PHYSICAL INFORMATION .................................................................... 3 3. TOXICOKINETICS ................................................................................................................... 5 3.1. ABSORPTION.................................................................................................................... 5 3.1.1. Oral.............................................................................................................................. 5 3.1.2. Inhalation..................................................................................................................... 5 3.2. DISTRIBUTION................................................................................................................. 6 3.3. METABOLISM .................................................................................................................. 6 3.4. ELIMINATION .................................................................................................................. 7 3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS........................................ 7 4. HAZARD IDENTIFICATION................................................................................................... 8 4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS.......................................................................................................................... 8 4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL AND INHALATION .......................................................................... 8 4.2.1. Oral Studies................................................................................................................. 8 4.2.2. Inhalation Studies........................................................................................................ 8 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES―INHALATION............................. 9 4.4. OTHER STUDIES............................................................................................................ 12 4.4.1. Genotoxicity.............................................................................................................. 12 4.4.1.1. Bacteria.............................................................................................................. 12 4.4.1.2. Mammalian Cells In Vitro................................................................................. 14 4.4.1.2.1. Mutagenicity. ............................................................................................. 14 4.4.1.2.2. Chromosomal aberrations......................................................................... 17 4.4.1.2.3. DNA damage.............................................................................................. 18 4.4.1.2.4. Non-DNA adduct formation....................................................................... 21 4.4.1.3. Genotoxicity Summary...................................................................................... 21 4.4.2. Cardiovascular Effects .............................................................................................. 22 4.4.3. Immunotoxicity ......................................................................................................... 24 4.4.4. Cytotoxicity............................................................................................................... 25 4.4.5. Comparative Toxicity of Related Aldehydes ............................................................ 25 4.5. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS ................ 29 4.5.1. Oral............................................................................................................................ 29 4.5.2. Inhalation................................................................................................................... 30 iii 4.6. WEIGHT-OF-EVIDENCE EVALUATION AND CANCER CHARACTERIZATION 32 4.6.1. Summary of Overall Weight of Evidence ................................................................. 32 4.7. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ................................................. 34 4.7.1. Possible Childhood Susceptibility............................................................................. 34 4.7.2. Possible Gender Differences ..................................................................................... 34 4.7.3. Possible Genetic Differences .................................................................................... 34 4.7.4. Possible Sensitive Subgroups - Asthmatics .............................................................. 34 5. DOSE-RESPONSE ASSESSMENTS...................................................................................... 36 5.1. ORAL REFERENCE DOSE (RfD).................................................................................. 36 5.2. INHALATION REFERENCE CONCENTRATION (RFC)............................................ 36 5.2.1. Choice of Principal Study and Critical Effect........................................................... 36 5.2.2. Methods of Analysis.................................................................................................. 39 5.2.3. RfC Derivation—Including Application of Uncertainty Factors (UFs).................... 39 5.3. CANCER ASSESSMENT................................................................................................ 42 5.4. GENERAL UNCERTAINTY IN THE PROPIONALDEHYDE NONCANCER AND CANCER ASSESSMENT .................................................................................................. 42 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE RESPONSE.............................................................................................................................. 45 6.1. HUMAN HAZARD POTENTIAL................................................................................... 45 6.2. DOSE RESPONSE ........................................................................................................... 47 7. REFERENCES ......................................................................................................................... 49 APPENDIX A. SUMMARY OF EXTERNAL PEER REVIEW AND PUBLIC COMMENTS AND DISPOSITION ............................................................................................................. A-1 APPENDIX B. BENCHMARK CONCENTRATION MODELING RESULTS...................... B-1 iv LIST OF TABLES Table 2-1. Chemical and physical properties of propionaldehyde ................................................. 3 Table 4-1. Summary of nasal lesion incidence data in female and male rats exposed to various concentrations of propionaldehyde............................................................................................... 11 Table 4-2. Mutagenicity of various aldehydes in Salmonella typhimurium ................................. 13 Table 4-3. Mutagenicity of various aldehydes in mammalian cells ............................................. 16 Table 4-4. Aldehyde-induced chromosome damage in mammalian cells in vitro ....................... 18 Table 4-5. Aldehyde-induced DNA damage in vitro.................................................................... 19 Table 4-6. Effects of inhalation of propionaldehyde on blood pressure and heart....................... 23 Table 4-7. RD50 values for propionaldehyde and selected, related aldehydes measured in B6C3F1 and Swiss-Webster mice............................................................................................................... 27 Table 4-8. Concentration [M] of selected aldehydes required to produce a 50% change from control in each cytotoxic endpoint................................................................................................ 29 Table 5-1. Propionaldehyde References for Exposure-Response Array ...................................... 37 Table 5-2. Summary of general uncertainty in the propionaldehyde noncancer and cancer risk assessments ................................................................................................................................... 42 Table B-1. Olfactory