April 2, 2012
Although it is widely known that the acronym GRAS 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 GRAS 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 list 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, GRAS listed substances 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.
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 listed substances 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.
Another of the widely held misconceptions about GRAS status is that it means that an ingredient is considered safe by the FDA, irrespective of how much is used and for what purpose. This interpretation is, however, quite different than what is stated in Section 201(s) of the Federal Food Drug & Cosmetic Act wherein GRAS refers to a conclusion regarding safety of a food substance “under the intended conditions of use.”
Thus, GRAS is a conditional designation rather than a broad acknowledgment of safety. The intended conditions of use under which a substance is considered to be GRAS are noted in the CFR in Sections 182, 184, and 186. These sections pertain to direct addition to foods in order to achieve a physical, nutritional, or other technical effect in the food (Sections 182 and 184 of the CFR) or indirect incorporation in foods as result of use of the substance in food manufacturing, processing, or packaging (Sections 182 and 186 of the CFR).
Many substances have been designated GRAS for their intended use(s) based solely on knowledge of their common use in foods prior to 1958. The presumption of safety for such substances is based on the assumption that a history of safe use adequately predicts future safe use provided that the level and type of use remains essentially the same. For these substances, the absence of a safety concern in the past obviates the need for extensive testing.
Many GRAS substances do not, however, have a history of common use in foods prior to 1958 and GRAS status has been affirmed based on “scientific procedures.” In this context, “scientific procedures” refers to human, animal, analytical, and other scientific studies appropriate to establish the safety of a substance. However, even for substance affirmed to be GRAS based on scientific procedures, this does not necessarily mean that a full battery of safety studies has been completed.
Review of the safety assessments made by the Select Committee on GRAS Substances (SCOGS) in the 1970s for substances later affirmed as GRAS, shows that in many cases safety judgments were made in the absence of a complete safety study dataset. In some cases, the design of toxicity studies was not optimal (e.g., incomplete assessment of usual safety endpoints or small numbers of animals). In other cases, some types of safety studies were missing (e.g., the absence of reproduction studies). In fact, some substances were determined by SCOGS not to present a safety risk with little toxicity data on the specific substance. Safety assessments for chemicals with only very limited substance-specific safety studies may have been based on data showing common metabolites with other more fully-studied substances or on known exposures through the diet to the constituents parts of other GRAS substances (e.g., for salts). These types of arguments supporting safety are widely accepted by qualified experts and support the finding that many substances are GRAS.
In some cases, GRAS substances are broadly characterized by the type of intended effect and in other cases very specific limits on the type of use considered to be GRAS are specified. Irrespective of whether the use description is broad or narrow, it is a stipulation of the GRAS designation that when a substance is directly added to food for an intended purpose, the amount used is not greater than what is needed to achieve the intended effect.
In most cases the CFR does not specify what use levels are acceptable for a specific use, leaving the discretion about how much to use to the food manufacturers. However, many substances are determined to be GRAS only when used at levels below a certain maximum. If a manufacturer uses a GRAS-designated substance for purposes other than those described in the CFR or in amounts much greater than what is reasonably needed to achieve the specified effect described in the CFR, the substance may no longer be considered GRAS.
Even substances designated as GRAS for multiple purposes were given GRAS status taking into consideration the total potential exposures based on known uses in foods at the time that the designation was made.
New uses or amounts of use that deviate significantly from those envisioned at the time that the GRAS determination was made may not necessarily be considered GRAS; even for those substances with a multipurpose GRAS designation.
Limitations on exposure are often found for GRAS substances that have the potential to migrate into foods during manufacturing, processing, or packaging. Consistent with the concept of not using more of a GRAS substance than is needed for an intended effect when that substance is intentionally added to foods, the FDA stipulates that the amounts of GRAS substances that indirectly migrate into foods should be minimized.
Thus, even though maximum use levels are not stipulated in most cases in Sections 182, 184, and 186 of the CFR, potential exposure is a principal determinant of whether a substance is considered to be GRAS. Potential exposure should also be considered when citing a substance’s GRAS status as evidence of safety of a substance for a non-food use. Any conclusion regarding the safety of a substance that relies on GRAS status should consider the route and extent of exposure for the non-food to assure that it does not deviate in significant ways from the GRAS food use cited in the CFR.
Ultimately, it is the weight of the available evidence that determines whether a substance is GRAS. Many GRAS substances have been extensively studied for safety and that information constitutes the basis for their GRAS determinations. However, it is important to recognize that a GRAS designation does not necessarily mean that a substance has been thoroughly tested for safety.
Do you have questions about the GRAS approval process? We can help you get through FDA successfully.
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