I. Introduction

"Toxicological Principles for the Safety Assessment of Food Ingredients" ("Redbook 2000") is the new name for Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food" that was originally published in 1982 ("Redbook I") and a draft revision was published in 1993 ("Redbook II"). Major changes in this revised guidance are presented later in this chapter. This document provides guidance to industry and other stakeholders (e.g. academia, other regulatory groups) regarding toxicological information submitted to the Center for Food Safety and Applied Nutrition (CFSAN), Office of Food Additive Safety (OFAS) regarding food ingredients. It is a guidance document that is intended to assist petitioners and notifiers in:

• determining the need for toxicity studies
• designing, conducting, and reporting the results of toxicity studies
• conducting statistical analyses of data
• the review of histological data
• the submission of this information to the FDA as part of the safety assessment of food ingredients.

The term "food ingredients", as used in this guidance, includes food additives and color additives used in food, and those substances which are classified as food contact substances (formerly known as indirect food additives), and those substances which are classified as generally recognized as safe (GRAS). The toxicity studies included in this guidance document can also be used in the safety assessment of constituent residues.

Petitioners and notifiers are encouraged to become familiar with the information in this guidance document as well as other toxicology related guidance information available via the following internet links when considering the submission of a petition or notification:

• Food and Color Additive (Petition) Program
• Food Contact Substances Program
• GRAS Notification Program

Additionally, sponsors are encouraged to discuss with the appropriate regulatory divisions in the OFAS the extent and types of toxicity testing they are considering and the type of petition or notification they intend to submit. FDA consistently has taken the position that various types of scientifically valid information may be used to support a determination that the proposed use of an ingredient is safe. Sponsors should consult with the FDA to discuss the use of alternative information to support a determination of safety for the food ingredient prior to the submission of a petition or notification.

BACKGROUND

One of the responsibilities of the FDA and its CFSAN is to ensure the safety of food ingredients added to the food supply in the United States. The "safety" of these ingredients is provided for in Sections 70.3 and 170.3 of Title 21 of the Code of Federal Regulations (CFR) as, a reasonable certainty that a substance is not harmful under the intended conditions of use. Safety is generally determined by considering the potential cumulative effect of the substance in consumers and the probable consumption of the substance in the diet. The potential cumulative effects are determined by the outcome of toxicity studies and knowledge of compounds and their structures.

FDA's Bureau of Foods (former name of CFSAN) published its guidance, "Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food" (referred to as Redbook I) in 1982 to provide guidance for sponsors regarding the submission of food additive petitions. A revised draft of this document was issued in 1993 (see Notice of Availability, published in the Federal Register (FR) on March 29, 1993, 58 FR 16536) and is referred to as "Redbook II". The FDA has continued to review comments related to this draft which were received from the regulated and scientific communities and other stakeholders. Additionally, the FDA has considered publications and information regarding recent advances and increased knowledge in toxicology, science and the food industry, and other authoritative guidance for toxicity testing in preparing this guidance document.

Food additives are generally defined in Section 201(s) of the Federal Food, Drug, and Cosmetic Act (the Act) and in 21 CFR 170.3(e)(1) as substances whose intended use results or may reasonably be expected to result, directly or indirectly, in its becoming a component of food or otherwise affecting the characteristics of food. Food additives have historically, therefore, been referred to as direct or indirect food additives. It is generally understood that direct food additives are compounds that are directly added to the food to achieve a technical effect (i.e., emulsification, sweetening) and indirect food additives include substances used in the production, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding of food (i.e., can coatings, paper and paperboard, sanitizers, and adhesives). In 1997, the Food and Drug Administration Modernization Act (FDAMA) amended the Act creating a more efficient notification process for food contact substances. Color additives are generally defined in Section 201(t) of the Act as a dye, pigment or other substance which when added or applied to a food, drug, or cosmetic is capable of imparting a color thereto. A GRAS substance is one whose safety has been evaluated by qualified experts, and the determination of safety based on evidence and through scientific procedures to be safe under the conditions of its intended use. A description of the eligibility for classification as GRAS can be found in 21 CFR 170.30. Additionally, in 1997 FDA issued a proposed rule (62 FR 18937, April 17, 1997) to establish a voluntary notification procedure for notifying FDA of a determination that a particular use of a substance is GRAS.

MAJOR CHANGES IN THE REVISED GUIDANCE

This section summarizes major changes between "Redbook 2000" and "Redbook II". In general, these changes were derived from three major sources: 1) increased scientific knowledge and technological advances since 1993; 2) comments received on the draft 1993 "Redbook II"; and 3) a desire to achieve consistency and harmonization with guidance published by other agencies, countries, and international organizations, when such action does not compromise FDA's ability to ensure the safety of food ingredients.

• The title of this guidance document was changed from "Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food" ("Redbook II") to "Toxicological Principles for the Safety Assessment of Food Ingredients" ("Redbook 2000") to better describe the breadth of circumstances where this guidance is applicable. "Redbook 2000" is the year that the first chapters of the revised Redbook became available on the internet. Rather than change the name of this guidance document when another chapter is added or as revisions are made, the decision was made to retain the name "Redbook 2000".
• "Redbook 2000" is designed as an electronic document available on the internet. It will not be published as a printed and bound document as were previous versions.
• The overall format of this guidance document has changed to facilitate availability on the internet. Each chapter is a "stand alone" document and can be accessed independently. Because of this, general information related to toxicity testing has been repeated in the separate chapters so that information related to each type of study is complete.
• Chapter III. Concern Levels and Recommended Toxicity Tests in "Redbook II" has been reduced, revised, and renamed "Recommended Toxicity Studies" in "Redbook 2000". Readers are directed to petition and notification web sites for more specific guidance for recommended toxicity studies.
• Chapter IV. C. 1. Short-Term Tests for Genetic Toxicity has been expanded with more complete descriptions and explanations of four separate types of genetic tests.
• "Neurotoxicity Studies" guidance is now located in Chapter IV. Guidelines for Toxicity Studies. "Neurotoxicity Studies" was previously located in "Redbook II", Chapter V. Additional Recommended Studies.
• Chapter IV. C. 7 Combined Chronic Toxicity/Carcinogenicity Studies with Rodents in "Redbook II" is now available in "Redbook 2000" in the following two chapters:
  • IV.C.5a. Chronic Toxicity Studies with Rodents
  • IV.C.7. Combined Chronic Toxicity/Carcinogenicity Studies with Rodents
• Chapter VII. Emerging Issues has not been included in "Redbook 2000". Information related to the emerging issues presented in the "Redbook II" has been considered and incorporated in relevant chapters of "Redbook 2000". The reader is encouraged to become familiar with additional information available via the OFAS web page and to contact OFAS with specific questions.

FLEXIBILITY IN GUIDANCE FOR TOXICITY TESTING

FDA's guidance for toxicity studies for food ingredients continue to emphasize that there is no substitute for sound scientific judgement. This guidance presents recommendations--not hard and fast rules. If an investigator believes that he/she can provide the Agency with useful toxicological information by modifying a recommended study protocol, and is able to support the modification with sound scientific arguments, then the investigator should propose the modified protocol to the appropriate program division within OFAS. As always, petitioners and notifiers should consult with the FDA prior to and during the design of study protocols for toxicity studies and/or before commencement of studies.

FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

For the benefit of the reader and because each of the chapters and chapter sections of Redbook 2000 are stand alone documents and can be accessed independently on the internet, FDA is repeating the disclaimer in the box at the beginning of each chapter and chapter section of Redbook.