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TOXICOLOGICAL REVIEW of UREA (CAS No EPA/635/R-10/005F www.epa.gov/iris TOXICOLOGICAL REVIEW OF UREA (CAS No. 57-13-6) In Support of Summary Information on the Integrated Risk Information System (IRIS) July 2011 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 UREA (CAS No. 57-13-6) LIST OF TABLES .......................................................................................................................... v LIST OF FIGURES ........................................................................................................................ v LIST OF ABBREVIATIONS AND ACRONYMS ...................................................................... vi FOREWORD ............................................................................................................................... viii AUTHORS, CONTRIBUTORS, AND REVIEWERS ................................................................. ix 1. INTRODUCTION ..................................................................................................................... 1 2. CHEMICAL AND PHYSICAL INFORMATION ................................................................... 3 3. TOXICOKINETICS .................................................................................................................. 6 3.1. ABSORPTION ................................................................................................................... 7 3.2. DISTRIBUTION .............................................................................................................. 10 3.3. METABOLISM ................................................................................................................ 12 3.4. ELIMINATION ................................................................................................................ 13 3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS ..................................... 15 3.6. ROLE OF UREA TRANSPORTERS .............................................................................. 19 4. HAZARD IDENTIFICATION ................................................................................................ 20 4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS AND CLINICAL CONTROLS ...................................................................................................................... 20 4.1.1. Oral Exposure ........................................................................................................... 20 4.1.2. Inhalation Exposure .................................................................................................. 21 4.1.2.1. Cohort Studies .................................................................................................. 21 4.1.2.2. Experimental Studies ....................................................................................... 23 4.1.3. Dermal Exposure ...................................................................................................... 23 4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL AND INHALATION ...................................................................... 26 4.2.1. Oral Exposure ........................................................................................................... 26 4.2.1.1. Subchronic Studies........................................................................................... 26 4.2.1.2. Chronic Studies ................................................................................................ 26 4.2.2. Inhalation .................................................................................................................. 28 4.2.3. Other Routes of Exposure ......................................................................................... 28 4.2.3.1. Subchronic Studies........................................................................................... 28 4.2.3.2. Chronic Studies ................................................................................................ 28 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES – ORAL AND INHALATION .... 28 4.3.1. Oral Exposure ........................................................................................................... 28 4.3.2. Intrauterine, Intraperitoneal, or Intravenous Exposure ............................................. 31 4.3.3. Other Studies............................................................................................................. 32 4.4. OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES ...................................... 34 4.4.1. Acute Studies ............................................................................................................ 34 4.4.2. Short-Term Studies ................................................................................................... 36 4.4.3. Cardiotoxicity ........................................................................................................... 39 4.4.4. Pituitary Effects ........................................................................................................ 42 4.4.5. Dermal Toxicity ........................................................................................................ 42 4.4.6. Intracranial and Intraocular Effects .......................................................................... 42 iii 4.4.7. Urea Toxicity in Ruminants and Non-Laboratory Animals ..................................... 43 4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF ACTION ............................................................................................................................ 43 4.5.1. Mechanistic Data from In Vivo and In Vitro Studies ............................................... 43 4.5.1.1. Neurological Effects ........................................................................................ 43 4.5.1.2. Effects on the Renal System ............................................................................ 46 4.5.1.3. Hematological Effects ...................................................................................... 48 4.5.2. Gene Expression Studies .......................................................................................... 49 4.5.3. Genotoxicity.............................................................................................................. 52 4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS ..................................................... 57 4.6.1. Oral Exposure ........................................................................................................... 57 4.6.2. Inhalation Exposure .................................................................................................. 59 4.6.3. Dermal Exposure ...................................................................................................... 60 4.6.4. Additional Studies..................................................................................................... 60 4.6.5. Mode of Action ......................................................................................................... 61 4.7. EVALUATION OF CARCINOGENICITY .................................................................... 62 4.7.1. Summary of Overall Weight of Evidence................................................................. 62 4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence ............................... 64 4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ................................................. 65 5. DOSE-RESPONSE ASSESSMENTS ..................................................................................... 66 5.1. ORAL REFERENCE DOSE (RfD) .................................................................................. 66 5.1.1. Choice of Principal Studies and Critical Effect—with Rationale and Justification . 66 5.1.2. Previous RfD Assessment ......................................................................................... 67 5.2. INHALATION REFERENCE CONCENTRATION (RfC) ............................................ 67 5.2.1. Choice of Principal Study and Critical Effect—with Rationale and Justification .... 67 5.2.2. Previous RfC Assessment ......................................................................................... 68 5.3. CANCER ASSESSMENT ................................................................................................ 68 5.3.1. Choice of Study/Data—with Rationale and Justification ......................................... 69 5.3.2. Previous Cancer Assessment .................................................................................... 69 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE RESPONSE ........................................................................................................................... 70 6.1. HUMAN HAZARD POTENTIAL ................................................................................... 70 6.2. DOSE RESPONSE ........................................................................................................... 71 6.2.1. Noncancer/Oral ......................................................................................................... 71 6.2.2. Noncancer/Inhalation ...............................................................................................
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