DRAFT – DO NOT CITE OR QUOTE EPA/635/R-11/004A www.epa.gov/iris TOXICOLOGICAL REVIEW OF VANADIUM PENTOXIDE (V2O5) (CAS No. 1314-62-1) In Support of Summary Information on the Integrated Risk Information System (IRIS) September 2011 NOTICE This document is an External Review draft. This information is distributed solely for the purpose of pre-dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by EPA. It does not represent and should not be construed to represent any Agency determination or policy. It is being circulated for review of its technical accuracy and science policy implications. U.S. Environmental Protection Agency Washington, DC. DISCLAIMER This document is a preliminary draft for review purposes only. This information is distributed solely for the purpose of pre-dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by EPA. It does not represent and should not be construed to represent any Agency determination or policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. This document is a draft for review purposes only and does not constitute Agency policy. ii DRAFT – DO NOT CITE OR QUOTE CONTENTS – TOXICOLOGICAL REVIEW OF VANADIUM PENTOXIDE (CAS No. 1314-62-1) LIST OF TABLES ......................................................................................................................... vi LIST OF FIGURES ..................................................................................................................... viii LIST OF ACRONYMS AND ABBREVIATIONS ...................................................................... ix FOREWORD ................................................................................................................................ xii AUTHORS, CONTRIBUTORS, AND REVIEWERS ............................................................... xiii 1. INTRODUCTION .......................................................................................................................1 2. CHEMICAL AND PHYSICAL INFORMATION .....................................................................3 3. TOXICOKINETICS ....................................................................................................................6 3.1. ABSORPTION .....................................................................................................................6 3.1.1. Inhalation Exposure ...................................................................................................6 3.1.2. Oral Exposure ............................................................................................................7 3.1.3. Dermal Exposure .......................................................................................................8 3.1.4. Other Routes of Exposure ..........................................................................................8 3.2. DISTRIBUTION ..................................................................................................................8 3.2.1. Inhalation Exposure ...................................................................................................8 3.2.2. Oral Exposure ............................................................................................................9 3.2.3. Dermal Exposure .....................................................................................................10 3.2.4. Other Routes of Exposure ........................................................................................10 3.3. METABOLISM..................................................................................................................10 3.4. ELIMINATION AND EXCRETION ................................................................................10 3.4.1. Inhalation Exposure .................................................................................................10 3.4.2. Oral Exposure ..........................................................................................................11 3.4.3. Dermal Exposure .....................................................................................................11 3.4.4. Other Routes of Exposure ........................................................................................11 3.5. PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS ...........................................................................................................................11 4. HAZARD IDENTIFICATION ..................................................................................................12 4.1. STUDIES IN HUMANS–EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS ...................................................................................................12 4.1.1. Oral Exposure ..........................................................................................................12 4.1.2. Inhalation Exposure .................................................................................................12 4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS–ORAL AND INHALATION ............................................36 4.2.1. Oral Exposure ..........................................................................................................36 4.2.2. Inhalation Exposure .................................................................................................38 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL, INHALATION, INTRAPERITONEAL AND INJECTION .............................................55 4.3.1. Oral Studies ..............................................................................................................55 4.3.2. Inhalation Studies.....................................................................................................56 4.3.3. Intraperitoneal and Injection Studies .......................................................................57 4.4. OTHER DURATION – OR ENDPOINT—SPECIFIC STUDIES ....................................59 This document is a draft for review purposes only and does not constitute Agency policy. iii DRAFT – DO NOT CITE OR QUOTE CONTENTS (continued) 4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF ACTION FOR PULMONARY FIBROSIS AND CANCER .........................59 4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS ......................................................60 4.6.1. Oral ..........................................................................................................................60 4.6.2. Inhalation .................................................................................................................62 4.6.3. Mode of Action Information ....................................................................................66 4.7. EVALUATION OF CARCINOGENICITY ......................................................................68 4.7.1. Summary of Overall Weight of Evidence ................................................................68 4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence...............................69 4.7.3. Mode of Action Information ....................................................................................70 4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ..................................................70 4.8.1. Possible Childhood Susceptibility ...........................................................................70 4.8.2. Possible Gender Differences ....................................................................................70 4.8.3. Other Susceptible Populations .................................................................................71 5. DOSE-RESPONSE ANALYSIS ...............................................................................................73 5.1. ORAL REFERENCE DOSE (RFD) ..................................................................................73 5.1.1. Choice of Principal Study and Critical Effect with Rationale and Justification .............................................................................................................73 5.1.2. Methods of Analysis—Including Models (e.g., PBPK and BMD) .........................75 5.1.3. RfD Derivation—Including Application of Uncertainty Factors ............................77 5.1.4. Previous RfD Assessment ........................................................................................78 5.2. INHALATION REFERENCE CONCENTRATION (RFC) .............................................78 5.2.1. Choice of Principal Study and Critical Effect with Rationale and Justification .............................................................................................................78 5.2.2. Methods of Analysis ................................................................................................81 5.2.3. RfC Derivation—Including Application of Uncertainty Factors .............................86 5.2.4. Previous RfC Assessment ........................................................................................87 5.3. UNCERTAINTIES IN THE ORAL REFERENCE DOSE (RFD) AND THE INHALATION REFERENCE CONCENTRATION (RFC) ...................................87 5.4. CANCER ASSESSMENT .................................................................................................89 5.4.1. Choice of Study/Data—with Rationale and Justification ........................................89 5.4.2. Dose-Response