Table of Contents

Table of Contents

Introduction

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if such an approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach contact the FDA staff responsible for implementing this guidance (Office of Food Additive Safety, 202-418-3100).

For questions regarding the use or interpretation of this guidance, or to obtain printed copies of individual chapters of this document, contact the Office of Food Additive Safety (OFAS).

"Redbook 2000: Toxicological Principles for the Safety Assessment of Food Ingredients" is the new name for and represents the second major revision of "Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food" which was originally published in 1982 ("Redbook I"*) and subsequently revised in 1993 (draft "Redbook II"). The Agency has considered multiple sources of information in the preparation of "Redbook 2000". These sources include: comments received from the regulated and scientific communities and other stakeholders in response to the 1993 draft "Redbook II", and recent developments, publications, and other authoritative guidelines for toxicity testing. Written comments related to this document may be submitted at any time to the Office of Food Additive Safety. Such comments will be considered when determinations are made to amend this guidance.

"Redbook 2000: Toxicological Principles for the Safety Assessment of Food Ingredients" is a guidance document that is intended to assist petitioners and notifiers in the development and submission of information used by the Agency in the safety assessment of food ingredients. Sponsors should be aware that "Redbook 2000" contains information related to designing, conducting, and reporting the results of toxicity studies, including statistical analyses and the review of histological data. While information related to the determination of the extent and types of toxicity testing relevant to direct food additives and color additives is available in chapters II and V of "Redbook I" and chapter III of the 1993 draft "Redbook II" the sponsors are encouraged to become familiar with toxicology related guidance that is available at the following Internet address:

http://www.cfsan.fda.gov/~dms/guidance.html

Additionally, sponsors are encouraged to discuss the extent and types of toxicity testing they are considering with the appropriate regulatory divisions in the Office of Food Additive Safety (OFAS).

It should be noted that "Redbook 2000" is not complete in its present form. The Table of Contents provides a listing of chapter titles that are expected to be included when "Redbook 2000" is completed. Chapters that have been revised are available as linked documents via the Table of Contents and can be viewed and retrieved in their entirety. These documents are to be considered as final and substitute for, or supplement, the guidance that was available in "Redbook I" or the 1993 draft "Redbook II". As additional chapters of "Redbook 2000" are completed they will be similarly linked in this Table of Contents. Each individual chapter is dated at the top, indicating the date that the section was made publicly available, and also at the bottom, indicating the date that revisions were made to this chapter.

^* Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food (also known as Redbook I), U.S. Food and Drug Administration, Bureau of Foods (now CFSAN), 1982. May be purchased from: National Technical Information Services (NTIS), 5285 Port Royal Road, Springfield, VA 22161, Telephone (703) 605-6000, NTIS Order Number PB83-170696.

Table of Contents

(Note: If your browser does not display the Table of Contents and sections using Roman numerals and alphabetic characters, you may request a printed copy of the document by contacting the Office of Food Additive Safety.)

I. Introduction

1. Major Changes in the Revised Guidelines
2. Flexibility and Consistency in Guidelines for Toxicity Testing
3. Applicability of These Guidelines to the Safety Evaluation of all Food Ingredients

II. Agency Review of Toxicology Information Submitted in Support of the Safety Assessment of Food Ingredients

1. Introduction
2. Evaluating Toxicology Information

III. Concern Levels and Recommended Toxicity Studies

1. Introduction
2. Concern Levels
3. Recommended Toxicity Studies

IV. Guidelines for Toxicity Studies

1. Introduction
2. 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
   4. Statistical Considerations in Toxicity Studies
   5. Diets for Toxicity Studies
3. Guidelines for Specific Toxicity Studies
   1. Short-Term Tests for Genetic Toxicity
      1. Bacterial Reverse Mutation Test
      2. In vitro Mammalian Chromosomal Aberration Test
      3. In vitro Mouse Lymphoma TK ^+/- Gene Mutation Assay
      4. In vivo Mammalian Erythrocyte Micronucleus Test
   2. Acute Oral Toxicity Tests
   3. Short Term Toxicity Studies
      1. Short-Term Toxicity Studies with Rodents
      2. Short-Term Toxicity Studies with Non-Rodents
   4. Subchronic Toxicity Studies
      1. Subchronic Toxicity Studies with Rodents
      2. Subchronic Toxicity Studies with Non-Rodents
   5. One-Year Toxicity Studies 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
      1. Guidelines for Reproduction Studies
      2. Guidelines for Developmental Toxicity Studies
   10. Neurotoxicity Studies

V. Additional Studies

1. Introduction
2. Metabolism and Pharmacokinetic Studies
3. Immunotoxicity Studies

VI. Human Studies

1. Clinical Evaluation of Food Ingredients
2. Epidemiology Studies

VII. Emerging Issues

VIII. Glossary: Acronyms and Definitions

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