as well as color additives, pesticide chemicals, new animal drugs, and dietary supplements (see the section on ''Components of Food'' in Appendix A). Some substances, such as dietary supplements, were potentially eligible for food additive status, but a subsequent amendment to the FD&C Act narrowed the legal definition to exclude them.

Substances determined to be generally recognized as safe (GRAS) are excluded from the food additive definition. GRAS status requires consensus, but not unanimity, among experts qualified by scientific training and experience. Under the FD&C Act, GRAS determination must be made "among experts qualified by scientific training and experience to evaluate its safety, as having been adequately shown through scientific procedures (or, in the case of a substance used in food prior to January 1, 1958, through either scientific procedures or experience based on common use in food) to be safe under the conditions of its intended use" (see the section on "Generally Recognized as Safe" in Appendix A). The phrase "scientific procedures" is defined under FDA regulations as data based upon "published studies which may be corroborated by unpublished studies or other data and information" (see the section on "Generally Recognized as Safe in Appendix A). Nevertheless, interpretation of the GRAS definition leaves room for judgment. The statute provides few details about the requirements of scientific substantiation, which has raised questions in GRAS determinations over the years. GRAS determinations can be made either by FDA upon petition, or by self-determination, in which case the sponsor may rely on a third party's review.

Following the enactment of the 1958 Food Additives Amendment, FDA affirmed that a number of food ingredients met the GRAS standard. After questions were raised about the safety of some GRAS ingredients, the agency initiated a review of these ingredients in 1972. The agency utilized the scientific expertise of an independent organization, the Federation of American Societies for Experimental Biology (FASEB), to assist in the evaluation, which spanned a decade. During that time, FASEB's Select Committee on GRAS Substances (SCOGS) evaluated over 450 food use ingredients, and recommended that only one percent of the ingredients on the original GRAS list be re-categorized as food additives. To date, nearly 200 substances appear on FDA's affirmed GRAS list for direct use in foods. The agency's review of the SCOGS reports has never been completed, and FDA has never intended that the GRAS lists be comprehensive.

As mentioned, a food substance does not need to be affirmed GRAS by the FDA to be eligible for GRAS status (and thus excluded from food additive requirements). An ingredient manufacturer, or a third party, may apply the scientific requirements and determine with or without notifying FDA that a substance is GRAS. In most cases, the ingredient manufacturer contracts with an independent organization to make such a determination. For example, both Proctor & Gamble and Nabisco sought FASEB review for ingredients they later marketed as GRAS. FDA has rarely challenged GRAS self-determinations, but there is some regulatory risk involved. GRAS determinations are never absolute. The agency retains the right to pursue enforcement proceedings, if it disagrees with a manufacturer's own GRAS determination.

GRAS self-determinations raise the legal question of who bears the burden of proof for a GRAS determination to be considered scientifically substantiated. There is disagreement on whether this burden lies with the agency or the ingredient manufacturer. A GRAS affirmation process whereby manufacturers submit a petition to FDA requesting the affirmation of a GRAS self-determination has been a primary mechanism for manufacturers to protect themselves from