DRAFT Guidance for the Preparation of Toxicological Profiles Agency for Toxic Substances and Disease Registry Department of Health and Human Services April 2018 GUIDANCE FOR THE PREPARATION OF TOXICOLOGICAL PROFILES ii CONTENTS CONTENTS .................................................................................................................................................. ii GENERAL ................................................................................................................................................... vi PURPOSE AND SCOPE OF ATSDR TOXICOLOGICAL PROFILES .................................................. xiv QUALITY CRITERIA FOR ANIMAL AND HUMAN STUDIES .......................................................... xvi GENERAL GUIDANCE FOR PREPARING A TOXICOLOGICAL PROFILE ................................... xviii FRONT MATTER ..................................................................................................................................... xxi CHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................ 1 1.1 OVERVIEW AND U.S. EXPOSURES ........................................................................................ 2 1.2 SUMMARY OF HEALTH EFFECTS .......................................................................................... 3 1.3 MINIMAL RISK LEVELS (MRLS) ............................................................................................. 4 CHAPTER 2. HEALTH EFFECTS ............................................................................................................. 6 OVERVIEW ......................................................................................................................................... 6 Epidemiological Studies ............................................................................................................. 11 Levels of Significant Exposure (LSE) Tables and Figures ......................................................... 11 Classification of Endpoints as NOAELs, Less Serious LOAELs, or Serious LOAELs ............. 12 Assessment of Organ Weight Change ........................................................................................ 14 Adaptive Response Consideration .............................................................................................. 15 Mechanisms of Action ................................................................................................................ 16 2.1 INTRODUCTION ..................................................................................................................... 17 2.2 DEATH ...................................................................................................................................... 20 2.3 BODY WEIGHT ....................................................................................................................... 21 2.4 RESPIRATORY ........................................................................................................................ 21 2.5 CARDIOVASCULAR............................................................................................................... 22 2.6 GASTROINTESTINAL ............................................................................................................ 23 2.7 HEMATOLOGICAL ................................................................................................................. 24 2.8 MUSCULOSKELETAL ............................................................................................................ 24 2.9 HEPATIC .................................................................................................................................. 25 2.10 RENAL ...................................................................................................................................... 26 2.11 DERMAL .................................................................................................................................. 27 2.12 OCULAR ................................................................................................................................... 28 2.13 ENDOCRINE ............................................................................................................................ 28 2.14 IMMUNOLOGICAL ................................................................................................................. 29 2.15 NEUROLOGICAL .................................................................................................................... 31 2.16 REPRODUCTIVE ..................................................................................................................... 34 2.17 DEVELOPMENTAL................................................................................................................. 35 2.18 OTHER NONCANCER ............................................................................................................ 41 2.19 CANCER ................................................................................................................................... 43 2.20 GENOTOXICITY ..................................................................................................................... 45 2.21 MECHANISM OF ACTION (AS NEEDED) ........................................................................... 45 ***DRAFT – DO NOT CITE OR QUOTE*** GUIDANCE FOR THE PREPARATION OF TOXICOLOGICAL PROFILES iii CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS ......................................................................................... 48 3.1 TOXICOKINETICS .................................................................................................................... 48 3.1.1 Absorption ........................................................................................................................ 50 3.1.2 Distribution ....................................................................................................................... 51 3.1.3 Metabolism ....................................................................................................................... 54 3.1.4 Excretion ........................................................................................................................... 56 3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ......... 58 3.1.6 Animal-to-Human Extrapolations .................................................................................... 59 3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE .... 59 3.3 BIOMARKERS OF EXPOSURE AND EFFECT ...................................................................... 65 3.3.1 Biomarkers of Exposure ................................................................................................... 67 3.3.2 Biomarkers of Effect......................................................................................................... 67 3.4 INTERACTIONS WITH OTHER CHEMICALS ....................................................................... 68 CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ............................................................ 71 4.1 CHEMICAL IDENTITY ............................................................................................................. 73 4.2 PHYSICAL AND CHEMICAL PROPERTIES .......................................................................... 73 CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ........................................................................ 75 5.1 OVERVIEW ................................................................................................................................ 76 5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL .................................................. 78 5.2.1 Production ......................................................................................................................... 79 5.2.2 Import/Export ................................................................................................................... 81 5.2.3 Use .................................................................................................................................... 81 5.2.4 Disposal ............................................................................................................................ 81 5.3 RELEASES TO THE ENVIRONMENT .................................................................................... 82 5.3.1 Air ..................................................................................................................................... 84 5.3.2 Water ................................................................................................................................ 84 5.3.3 Soil .................................................................................................................................... 85 5.4 ENVIRONMENTAL FATE ........................................................................................................ 86 5.4.1 Transport and Partitioning ................................................................................................ 86 5.4.2 Transformation and Degradation ...................................................................................... 88 5.5 LEVELS IN THE ENVIRONMENT .......................................................................................... 90 5.6 GENERAL POPULATION EXPOSURE