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PART 1 TOXICITY-TESTING NEEDS IN THE SELECT UNIVERSE CONTENTS 1. INTRODUCTION 2. SAMPLE SELECTION me Universe and the Sampling Frame Pesticides and Inert Ingredients of Pesticide Formulations Cosmetic Ingredients Drugs and Excipients in Drug Formulations Food Additives Chemicals in Commerce Considerations in Developing the Sampling Strategy Sampling Strategy Sample Size Sampling Plan Screening the Sample for Minimal Toxicity Information 3. OPERATING POLICIES FOR IDENTIFICATION, ACQUISITION, AND ORGANIZATION OF DATA Restricted-Access or Confidential Information Information on Toxicity in Humans Chemical and Physical Characteristics, Manufacturing Processes, Production Volumes, Intended Uses, and Exposure of Humans Chemical Review Articles Articles in Foreign Languages Substances Structurally Similar to Those in the Sample 4. DATA EVALUATION The Dossier Concept General Principles for Evaluation of Toxicity-Testing Protocols Consideration of Exposure Purity of Selected Substances Guidelines for Assessing the Quality of Individual Studies Basic Criteria for Scientific Methods 23 Page 29 33 33 38 38 38 39 39 42 43 43 45 45 51 51 53 53 54 54 54 55 55 56 57 60 61 61

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Selection of Reference Protocols Reference Protocol Guidelines for Neuro- behavioral-Toxicity Tests Reference Protocol Guidelines for Genetic- Taxicity Tests Procedures for Evaluation of the Data Base Initial Considerations Adequacy Ratings Measures of Adequacy for Tests Not Meeting the Reference Protocol Guidelines Dossier Review Process Limitations of the Data Gathering Process Interpretation of Data on Testing Quality Characterizing the Sample and Options for Drawing Inferences to the Select Universe Construction of Tables for Analysis Statistical Analysis of Data Estimates Based on the Sample Alone Estimates Based on the Subsample alone Estimates Based on Both the Sample and the Subsample Machine-Readable Files 5. RESULTS Quantity and Nature of Testing Sample of 675 Substances Subsample of 100 Substances Quality of Testing Testing Needs Health-Hazard Assessment Interpretation and Analysis of Physicochemical and Exposure Data 6. SUMMARY AND CONCLUSIONS REFERENCES 24 62 64 64 65 65 66 67 68 72 74 75 76 76 76 78 79 80 81 82 83 85 91 97 99 120 125 127

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Tables 1. Characteristics of Chemical Lists from Which Sample Was Drawn 2. Six Codes of Chemical Classification in FDA Bureau of Foods Dictionary Used to Form Food-Additives Category from Which Food-Adaitive Sample Was Drawn 3. Required Studies in Screen of Sample of 675 Substances for Minimal Toxicity Information for Subsample of 100 4. Sample Sizes for Sample and Subsample 5. Information Sought in Exhaustive Literature Search for Each Substance in Subsample of 100 6. Committee Format for Recording Judgments about Protocol of Toxicity Study 7. Estimated Percentages of Substances in Seven Categories of Select Universe That Have Five Basic Tests Used in Screen for Prescribed Minimal Toxicity Information 8. Proportion of Substances Tested in Each Category of Subsample According to Each of Defined 33 Test Types 9. Quality of Testing on 100 Substances in Subsample, by Test Type 10. Distribution of 664 Quality Ratings of Tests Done on 100 Substances in Subsample, by Subsample Category 11. Comparison of Aggregate Quality Ratings (All G. A, and IN) for Selected Acute Test Types and Selected Chronic Test Types 25 Page 35 40 47 48 59 69 84 86 92 94 98

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12. Quality of Testing of 3,350 Pesticides and Inert Ingredients of Pesticide Formulations in Select Universe 13. Quality of Testing of 3, 410 Cosmetic Ingredients in Select Universe 14. Quality of Testing of 1, 815 Drugs and Excipients in Drug Formulations in Select Universe 15. Quality of Testing of 8,627 Food Additives in Select Universe 16. Quality of Testing of 12,860 Chemicals in Commerce in Select Universe with Production Levels of At Least 1 Million lb/yr 17. Quality of Testing of 13,911 Chemicals in Commerce in Select Universe with Production Levels less man 1 Million lb/yr 18. Quality of Testing of 21,752 Chemicals in Commerce in Select Universe with Unknown or Inaccessible Production Levels 19. Relative Comparison of Testing Need by Intended-Use Category of Select Universe 20. Ability to Conduct Health-Hazard Assessment of 100 102 104 106 108 110 112 114 Substances in Seven Categories of Select Universe 117 21. Availability of Specific Information on Substances in Seven categories of Select Universe 26 122

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Figures 1. Process used to draw sample and subsample from select universe 2. Steps in process of evaluating adequacy of toxicity testing for substances Outline of procedure for decision-making in evaluating adequacy of toxicity information on specific substance 4. Ability to conduct health-hazard assessment of substances in seven categories of select universe 27 Page 37 52 58 118

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Page Appendix A Sample of 675 Substances and Subsample of 100 Substances from the "Select Universe" 129 Appendix B Testing for Various Situations of Chemical Use and General Exposure to Direct and Indirect Food Additives Appendix C Testing for Various Situations of Chemical Use and General Exposure to Oral or Parenteral Drugs or Color Additives for Sutures Appendix D Testing for Various Situations of Chemical Use and General Exposure to Inhalation and Veterinary Drugs Appendix E Testing for Various Situations of Chemical Use and General Exposure to Cosmetics and Dermal, Vaginal-Rectal, Over-the-Counter, and Ophthalmic Drugs 151 153 155 157 Appendix F Testing for Various Situations of Chemical Use and General Exposure to Pesticides 159 Appendix G Testing for Various Situations of Chemical Use and General Exposure to Other Marketable Chemicals 161 Appendix H Reference Protocols for Toxicity Testing 165 Appendix I Reference Protocol Guidelines for Neurobehavioral-Ioxicity Tests 169 Appendix J Reference Protocol Guidelines for Genetic-Ioxicity Tests 175 Appendix K Conceptual Issues Concerning the Interpretation of Results of Studies of Reproductive and Developmental Toxicity 177 Appendix L Major Components of a Dossier Appendix M Procedures, Rationale, and Results of Data Identification and Acquisition 28 179 185