difficulty of feeding formulas to a preweanling rodent. The nonhuman primate and the piglet are more amenable for these types of studies.


This chapter describes the importance and the unique aspects of conducting preclinical studies to assess the safety of infant formulas. Current regulatory guidelines for preclinical studies are described, and a two-level assessment process is proposed. The committee’s recommended two-level process is a flexible approach that can accommodate a variety of potential ingredients. For example, safety assessment might not be as intense for an ingredient that is not absorbed systemically. The manufacturer, in consultation with an expert panel, determines the types of tests conducted. The extent of this investigation will be determined on the basis of previous experience with the ingredient in other populations and on theoretical concerns based on the putative biological effects of the ingredient, its metabolite, and its matrix. Finally, the committee recommends the following preclinical tests described in detail below:

  1. preanimal tests (including structure, stability, and solubility tests of the ingredients; genetic tests; and cellular studies)

  2. absorption, distribution, metabolism, and excretion studies

  3. toxicity studies (including acute, subchronic, chronic, developmental, and organ studies)

  4. neurological studies

Neurological studies are described in a section separate from other toxicity studies because the scope of work defined for this project placed special emphasis on the potential effect of ingredients on the rapidly developing infant brain.


Preclinical studies must be performed before an ingredient can be considered for clinical studies in humans in order to determine the potential toxicity of the ingredient and its metabolites and their effects in the matrix. Preclinical studies allow researchers to expose cell cultures and experimental animals to doses of ingredients not normally encountered in human consumption. Results of such assessments are used to determine the threshold of toxicity for the given ingredient (i.e., the margin of safety).

Guidelines for preclinical studies to assess the safety of infant formulas must be based on considerations of:

  • The diversity of the potential new ingredients. The new ingredients will possess different chemical characteristics, nutritional contributions, pharmacological activities, and physiological activities. The ingredients may be a conventional synthetic or an extracted single component, a plant extract, or a complex mixture. The ingredients may also be derived from novel sources or processes (e.g., products of fermentation or biotechnology). Such diversity requires preclinical guidelines that are clear but not overly prescriptive because of the disparity in the issues that each class of ingredient may represent. Nevertheless, given the vulnerability of the population to receive the ingredient (infants), it is incumbent upon the manufacturer, in consultation with the expert panel, to be overly conscientious in considering potential safety issues.

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