Approach for Evaluating Safety

Safety evaluation of food ingredients in the United States is based on “reasonable certainty of no harm.” Sections 201(s), 201(z), 409, and 412 of the Federal Food, Drug and Cosmetic (FD&C) Act, associated regulations, and FDA’s Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food, also known as the Redbook,1 provide guidelines that are used to assess the safety of food ingredients and infant formulas. The Canadian Food and Drugs Regulations, administered by Health Canada, include specific requirements for infant food, novel food, and food ingredients.

In Canada and the United States, the food additive petition processes are similar and require premarket review and approval. In the United States, under the proposed GRAS Notification rule, a manufacturer can declare that a substance is GRAS if there is scientific consensus among qualified experts about its safety under the conditions of intended use. The manufacturer then notifies FDA, and if the agency has no questions, a letter of no objection is issued.

A primary difference between the two routes is that the Food Additive Petition places the responsibility of declaring that a substance is safe and approved under the conditions of use with the regulatory agency, whereas the GRAS Notification process places the responsibility of demonstrating that a substance is GRAS, and therefore safe under the conditions of use, with the manufacturer. The GRAS Notification and Food Additive Petition procedures are intended to ensure the safety (“a reasonable certainty of no harm”; FD&C Act Section 409), not the efficacy, of the proposed ingredient. The vast majority of new ingredients will likely follow the GRAS process to establish safety.

In addition to the regulations, FDA provides preclinical guidelines in its Redbook. This document was prepared to assist in the design of protocols for animal studies conducted to test the safety of food ingredients and includes detailed guidelines for testing the effects of food ingredients on mothers and their developing fetuses. However the special conditions surrounding infancy require distinct procedures to ensure the safety of infant formulas.

The GRAS process is rigorous, flexible, credible, and transparent. However its application does not clearly address possible concerns for the multitude of potential new ingredients in infant formulas. New ingredients may possess a variety of chemical characteristics, nutritional contributions, and pharmacological and physiological activities. Ingredients may be derived from novel sources or processes (e.g., products of fermentation or biotechnology). Such diversity requires safety guidelines that are clear but not overly prescriptive because of the disparity in the issues that each class of ingredient to be added to infant formulas may present. Because of its wide use, the committee used the GRAS Notification process as a starting model in developing its proposed approach for assessing the safety of new ingredients added to infant formulas, without being prescriptive. Some elements of the system proposed by the committee are currently in place.

Infant formula is the only source of nutrition for many infants and, therefore, additional safeguards have been established for infant formulas to which new ingredients are added that are not required for other foods. Regulations under Sections 201(s), 201 (z), and 412 of the FD&C Act have been implemented to ensure the safety of an infant formula to be marketed with a new ingredient. Under these sections of the Act, a proposed rule would


This FDA document should not be confused with the American Academy of Pediatrics’ Red Book of childhood infectious diseases.

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