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OCR for page 183
Infant Formula: Evaluating the Safety of New Ingredients C Redbook Table of Contents Chapter I. Introduction A. Major Changes in the Revised Guidelines 1. Introduction 2. Changes in Determining Concern Levels and Recommended Toxicity Studies for Food Ingredients 3. Changes in Toxicity Testing Guidelines 4. Other Changes B. Flexibility and Consistency in Guidelines for Toxicity Testing C. Applicability of These Guidelines to the Safety Evaluation of all Food Ingredients Chapter II. Agency Review of Toxicology Information Submitted in Support of the Safety of Food Ingredients A. Introduction B. Expediting Review of Toxicology Information C. Evaluating Toxicology Information Chapter III. Concern Levels and Recommended Toxicity Studies A. Introduction B. Concern Concentration Levels C. Recommended Toxicity Tests Chapter IV. Guidelines for Preclinical Toxicity Studies A. Introduction B. General Recommendations for Toxicity Studies 1. General Guidelines for Designing and Conducting Toxicity Studies 2. Guidelines for Reporting Results of Toxicity Studies 3. Pathology Considerations in Toxicity Studies
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Infant Formula: Evaluating the Safety of New Ingredients 4. Statistical Considerations in Toxicity Studies 5. Diets for Toxicity Studies a. Types of Diets i. Natural Ingredient Diets ii. Purified Diets b. Issues to Consider when Selecting Diets for Animals in Toxicity Studies C. Guidelines for Specific Toxicity Studies 1. Short-Term Tests for Genetic Toxicity a. Bacterial Reverse Mutation Test b. In Vitro Mammalian Chromosome Aberration Test c. In Vitro Mouse Lymphoma TK+/– Gene Mutation Assay d. In vivo Mammalian Erythrocyte Micronucleus Test 2. Acute Oral Toxicity Tests 3. Short-Term Toxicity Tests with Rodents and Non-Rodents a. Short-Term Toxicity Studies with Rodents b. Short-Term Toxicity Studies with Non-Rodents 4. Subchronic Toxicity Tests with Rodents and Non-Rodents a. Subchronic Toxicity Studies with Rodents b. Subchronic Toxicity Studies with Non-Rodents 5. One-Year Long-Term Toxicity Tests with Non-Rodents 6. Carcinogenicity Studies with Rodents 7. Combined Chronic Toxicity/Carcinogenicity Studies with Rodents 8. In Utero Exposure Phase for Addition to Carcinogenicity Studies with Rodents 9. Reproduction and Developmental Toxicity Studies a. Guidelines for Reproduction Studies b. Guidelines for Developmental Toxicity Studies 10. Neurotoxicity Studies Chapter V. Additional Recommended Studies A. Introduction B. Metabolism and Pharmacokinetic Studies 1. Recommended Metabolism and Pharmacokinetic Studies 2. Considerations in the Design of Pharmacokinetic Studies a. Test Substance b. Animals c. Route of Administration d. Dosage Regimen e. Sampling f. In Vitro Studies: Dose Response, Mechanism g. Analysis of Data h. Pregnancy/Lactation/Reproductive Studies 3. Analysis and Use of Data from Pharmacokinetic Studies a. Data Reporting and Parameter Estimation b. Pharmacokinetic Models: Data Interpretation and Predicting Effects 4. Use of Pharmacokinetic Results for Study Design and Risk Assessment a. Design of Toxicity Studies b. Setting Dose Levels c. Determining Mechanisms of Toxicity
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Infant Formula: Evaluating the Safety of New Ingredients d. Improving the Risk Assessment Process/Safety Assessment 5. References C. Immunotoxicity Studies 1. Immunity: A Brief Review 2. Key Concepts in Immunotoxicity Testing 3. Indicators of Possible Immune Toxicity 4. Expanded Type 1 Immunotoxicity Tests 5. Type 2 Immunotoxicity Tests 6. Relevance of Primary Indicators of Immune Toxicity to Health 7. Adequacy and Reliability of Primary Indicators of Immune Toxicity 8. Recommendations for Further Immunotoxicity Testing when Primary Indicators are Positive 9. Animal Models for Immunotoxicity Tests 10. Recommended Strategy for Assessing the Immunotoxic Potential of Food Ingredients 11. Conclusion Chapter VI. Human Studies A. Clinical Evaluation of Food Ingredients 1. General Considerations for Clinical Studies of Food Ingredients 2. Specific Considerations for Clinical Studies of Food Ingredients 3. Sequence of Clinical Studies for Food Ingredients 4. Submitting Reports of Clinical Studies on Food Ingredients 5. Appendix A—Principles of Institutional Review and Informed Consent B. Epidemiology Studies Chapter VII. Emerging Issues A. Introduction B. Macro-Additives C. Safety of Food Ingredients Developed by Biotechnology D. Enzymes E. Microbially Derived Food Ingredients F. Advances in the Development of Alternatives to Toxicity Testing G. Heritable and Somatic Genetic Toxicity Chapter VIII. Glossary: Acronyms and Definitions NOTE: Food ingredients include: direct food additives, color additives used in food, Generally Recognized as Safe substances, food contact substances, and constituents or impurities of any of the above. Bolded text denotes a section that has been finalized and is found only online in the Redbook 2000 (OFAS, 2003); the other information is found only in Redbook II-Draft (OFAS, 2001). REFERENCES OFAS (Office of Food Additive Safety). 2001. Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food. Redbook II-Draft. Washington, DC: OFAS, Center for Food Safety and Applied Nutrition, Food and Drug Administration. OFAS. 2003. Redbook 2000. Toxicological Principles for the Safety of Food Ingredients. Online. Center for Food Safety and Applied Nutrition, Food and Drug Administration. Available at http://www.cfsan.fda.gov/~redbook/red-toca.html. Accessed November 19, 2003.