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available clinical studies and postmarket surveillance (Personal communication, A. Rulis, FDA, January 25, 2002).


Based on the 1958 amendment for food additives to the FDCA, FDA developed specific processes to determine whether substances used in foods were safe for their intended use (see previous section). Food additives, as defined in the amendment, are subject to premarket approval by FDA unless they are GRAS or fall within another statutory exception (21 U.S.C. § 321(s)).

Following the passage of the FAA, FDA assumed a lenient approach to dealing with the GRAS exception. In the early 1970s, however, in response to public concern about the apparent carcinogenicity of cyclamate, which FDA had listed as GRAS, FDA adopted a more rigorous approach (Degnan, 2000). In 1972 FDA contracted with the Life Sciences Research Office (LSRO) of the Federation of American Societies for Experimental Biology for assistance with a comprehensive review of GRAS substances. LSRO established a Select Committee on GRAS Substances that examined monographs that provided all known data on physical and chemical properties of a substance, human exposure data, animal and human toxicity data, and reports of special studies on mutagenicity, carcinogenicity, and teratogenicity of each substance. The Select Committee reached one of five conclusions on each GRAS substance reviewed: (1) continue as GRAS, (2) continue as GRAS with limitations, (3) uncertainties exist—issue interim food additive order requiring further testing, but continue as GRAS until tests are evaluated, (4) evidence of adverse effects—establish conditions of safe use or remove GRAS status, or (5) inadequate data precludes evaluation—rescind GRAS status. The review was completed in 1982.

In 1972 FDA also established procedures for petitioning to affirm the GRAS status of a substance, which while still in use have rarely been used due to the significant amount of documentation required. Currently, in order to achieve GRAS status for a substance not used in food prior to 1958, four key criteria must be met: (1) general recognition of safety by qualified experts, (2) the experts must have the scientific training and experience necessary to evaluate the safety of the substance, (3) the experts must base their safety determination on scientific procedures, and (4) GRAS determination must fully consider the intended use of the substance (Hallagan and Hall, 1995).

In 1997 FDA proposed to replace the current GRAS affirmation petition scheme with one of notification, allowing any organization to notify FDA of a self-determination of GRAS. The interim policy allows this method to be used pending issuance of final regulations. The proposed rule would

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