• The ingredient’s source and matrix. The approach to evaluate ingredients new to infant formulas should be driven by the class of the functional substances and by the full characterization of the ingredient in the matrix of the infant formulas. In other words, the general approach is to deal with the targeted ingredient, as well as the nontargeted compounds, such as metabolites of the targeted ingredient, the vehicle required for delivery of the targeted ingredients, and impurities introduced in the manufacturing process.


In considering how to construct guidelines for preclinical studies of ingredients new to infant formulas, the committee drew on existing guidelines for the testing of food ingredients and infant formulas. In the United States these are included in Sections 409 and 412 of the Federal Food Drug and Cosmetic (FD&C) Act (21 U.S.C. §301) and in the FDA Redbook (OFAS, 2001, 2003). The committee suggests that the risks of adding ingredients to sole nutrient sources, such as infant formulas, are not adequately addressed; however some aspects of the more stringent guidelines applied to new ingredients as articulated in the Redbook are appropriate for some, if not all, ingredients new to infant formulas.

Sections 409 and 412 of the Federal Food, Drug and Cosmetic Act

There are no explicit requirements for preclinical testing of infant formulas specified under Section 409 of the FD&C Act. The section stipulates that a petition to establish safety of a food additive shall contain “all relevant data bearing on the physical or other technical effect such additive is intended to produce…” (21 U.S.C. §301), but it does not dictate a specific type of preclinical study.

Under Section 412, which applies to infant formulas, a formula shall be deemed to be adulterated if it does not meet the quality factor requirements prescribed by the Secretary of Health under Subsection (b)(1). Subsection (b)(1) then states, “The secretary shall by regulation establish requirements for quality factors for infant formulas to the extent possible consistent with current scientific knowledge, including quality factor requirements for the nutrients required by subsection (i).” Currently, only protein quality is named as a quality factor in FDA regulations but there are no specific requirements to be met regarding quality factors. Subsection (i) specifies levels of certain nutrients (e.g., protein, fat, and specific vitamins) that are required to be met. There is no other requirement for any specific preclinical studies.

FDA Redbook

The FDA Redbook II and Redbook 2000 (OFAS, 2001, 2003) provide comprehensive guidelines for conducting preclinical studies to test the safety of food and color additives. Chapters IV and V in the Redbook II and 2000 describe:

  • general guidelines for designing, conducting, and reporting results of toxicity studies,

  • special considerations in toxicity studies (e.g., pathology, statistics), and

  • guidelines for specific toxicity studies (e.g., genetic, acute, subchronic, chronic, immunotoxicity, and neurotoxicity).

These guidelines, however, do not consider the unique characteristics of having infants as consumers.

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