GRAS – One of FDA’s Most Widely Misunderstood Acronyms (Part 1)
By Carrie Rabe, Ph.D
Although it is widely known that the acronym stands for “Generally Recognized as Safe” many individuals believe that GRAS substances have been rigorously reviewed for safety and approved for use by the FDA. In fact, as it was originally intended, GRAS was a definition of exclusion and referred to those substances used in foods that did not require review by the FDA for safety and approval for use. When Congress enacted the Food Additives Amendment to the Food, Drug, and Cosmetic Act in 1958, it required that any substance which is reasonably expected to become a component of foods, either through direct addition to foods or indirectly through contact with foods, be subject to premarket review except for substances that were generally recognized as safe. These GRAS substances were not considered to require FDA review either because their safety had been established by a long history of safe use or by information generally available to scientists about these substances. Specifically, the statute exempted from premarket review those substances that are generally recognized, among experts qualified by scientific training and experience to evaluate safety, as having been adequately shown through scientific procedures or through experience based on common use in food to be safe under the conditions of their intended use.
Soon after the passage of the food additives amendment, the FDA created a list of substances that were considered to be GRAS under certain conditions of use. This list formed the basis of sections 182, 184, and 186 of the CFR. The safety of the substances on the original GRAS list was not validated by the FDA until the cyclamate health scare in the 1960s when the President directed the FDA to critically review the safety of the substances on the GRAS list. In the 1970s, outside panels of experts known as the Select Committees on GRAS Substances (SCOGS) were commissioned by the FDA to review a large subset of the GRAS substances and provide recommendations as to what restrictions, if any, would be required to assure their safe use in foods. More than 400 substances were reviewed by the SCOGS panels and after review by the FDA and public comment; these substances (with any associated restrictions on use recommended by the SCOGS panels) were incorporated into the CFR by rulemaking. Many substances were not included in the original GRAS list and up until the late 1990s, a manufacturer of a substance could petition the FDA to add a substance to the GRAS regulations in the CFR. Consistent with the original statute, the GRAS affirmation petition process required the manufacturer to demonstrate safe use either through a history of use in foods predating 1958 or through consensus of qualified experts that publicly available scientific information supported safe use. The FDA would then review this information and, if appropriate, publish a rulemaking confirming the finding and adding the substance (with its associated conditions of safe use) to the CFR. Thus, substances listed as GRAS in the CFR may have never been rigorously reviewed by the FDA (likely because their use was uncontroversial), or reviewed by the FDA after recommendations from either the SCOGS panels or by manufacturers as part of the GRAS affirmation petition process.
A second class of GRAS substances does not appear in the CFR. In the late 1990s, the FDA faced a limitation of resources for the review of manufacturer-initiated GRAS affirmation petitions and proposed an alternative program in which manufacturers could notify the FDA that the use of a substance was GRAS. Upon receipt of such a notification, the FDA would review the supporting information provided and determine whether a sufficient basis for a GRAS determination had been made. If the FDA does not find a basis to question the manufacturer’s GRAS determination, the FDA issues a letter of “no objection.” This is meant to be distinct from an affirmation that the notified substance is GRAS and the subjects of such GRAS notifications are not added to the CFR lists of GRAS substances. In fact, in each “no objection” letter the FDA adds a statement that the Agency has not made its own determination regarding the GRAS status of the proposed use of the substance. Thus, GRAS substances may have undergone any of a variety of levels of FDA review and none have been the subject, per se, of an FDA approval. This does not mean that these substances are unsafe, but it should not be mistakenly assumed that the GRAS substances, listed in the CFR or posted on the FDA website, have all undergone a rigorous review by the FDA or that the FDA has issued an approval letter for a proposed food use.
Carrie Rabe, Ph.D. is a Senior Consultant at The Weinberg Group, the world’s leading food and drug consulting firm. If you have any questions or thoughts on this blog post or others, please contact us.