recommended algorithms to guide decisions about the type of safety assessments to apply. The asterisk with corresponding text underlined does not imply that the step was not performed or considered by the qualified experts, but that the information was not available for review by the committee. Note that under the proposed recommendation (Chapter 4), the expert panel can choose to include or not include certain tests in the submission.


For the case of LC-PUFAs, the committee applied the information given to the Food and Drug Administration available through the Freedom of Information Act in Generally Recognized as Safe (GRAS) Notices 000041 and 000080 to its recommended algorithms, comparing the steps taken by the manufacturer, notifier, or expert panel to determine the safety of ARASCO (arachidonic acid-rich single-cell oil) and DHASCO (docosahexaenoic acid-rich single-cell oil) in infant formulas. Figure D-1 provides an overview of the proposed process. The sources of ARASCO and DHASCO have no prior use in foods in the United States, but they are used in infant formulas in Europe.

Preclinical Studies

As shown in Figure D-2, structure, stability, and solubility characterization studies are an important part of preclinical assessment. Figure D-3 illustrates that level 2 assessments would have been applied in determining the safety of the LC-PUFAs. These in-depth measures of the organ and neurological systems would further investigate abnormalities and/or are theoretically related to structure or function. In this case it appeared that there were some minor effects on organ systems. It is not obvious which of the proposed testing regimes in Chapter 5 were followed. The nonhuman primate studies were limited. These are considered an appropriate model to study changes in general behavior and speed of neural processing in response to the addition of LC-PUFAs. Chapter 5 provides more details on structure, stability, and solubility characterization, as well as the committee’s recommendations for level 2 assessments.

Clinical Studies

As seen in the overview of the proposed clinical guidelines (Figures D-4, D-5, and D-6), it is not clear whether assessments of body composition, immune response, auditory function, and temperament were conducted. Several of these tests (to be determined by expert panels), applied at level 2 or level 3, are especially important to determine the safety of LC-PUFAs because theoretical safety concerns exist. For example, LC-PUFAs affect immune response, and they have been linked to neural development. Chapter 6 provides the committee’s findings and recommendations on body composition and immune, auditory, and temperament assessment.

In-Market Surveillance

Figure D-7 illustrates the levels of proposed in-market surveillance. Selection of an appropriate type of in-market surveillance should be based on theoretical concerns about the new ingredient and/or results from preclinical and clinical studies. As long as preclinical and clinical studies are properly conducted, adverse outcomes should be rare and it would take a considerable period of time to collect sufficient data in order to reaffirm the GRAS status

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