“GRAS” is an acronym for the phrase Generally Recognized As Safe. Under sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act (the Act), any substance that is intentionally added to food is a food additive, that is subject to premarket review and approval by FDA, unless the substance is generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use, or unless the use of the substance is otherwise excluded from the definition of a food additive.
Under sections 201(s) and 409 of the Act, and FDA’s implementing regulations in 21 CFR 170.3 and 21 CFR 170.30, the use of a food substance may be GRAS either through scientific procedures or, for a substance used in food before 1958, through experience based on common use in food.
- Under 21 CFR 170.30(b), general recognition of safety through scientific procedures requires the same quantity and quality of scientific evidence as is required to obtain approval of the substance as a food additive and ordinarily is based upon published studies, which may be corroborated by unpublished studies and other data and information.
- Under 21 CFR 170.30(c) and 170.3(f), general recognition of safety through experience based on common use in foods requires a substantial history of consumption for food use by a significant number of consumers.
History of the GRAS Status and Program
Under the 1958 Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act, any substance intentionally added to food is a food additive and is subject to pre-market approval by FDA unless the use of the substance is generally recognized as safe (GRAS; the GRAS provision) (or otherwise excepted from the definition of food additive – e.g., color additive). By 1961, FDA had amended its regulations to include a list of food substances that are GRAS under certain conditions of use (“the GRAS list”). During the 1960’s, many manufacturers requested FDA’s opinion on whether their conclusions of GRAS status were justified and received “opinion letters.” In 1969, FDA removed cyclamate salts from its GRAS list as a result of safety questions, and then-President Nixon directed FDA to reexamine the safety of GRAS substances. In the 1970’s, FDA announced that it was conducting a “comprehensive review” of presumed GRAS substances and established rulemaking procedures to affirm the GRAS status of substances that were either on the GRAS list or the subject of a petition (“GRAS affirmation”). To eliminate the resource-intensive rulemaking procedures, in 1997, FDA proposed to replace the GRAS affirmation petition process with a notification procedure (“GRAS notification”).
Legislative History of GRAS (exerpts)
“Proof of the pudding is in the eating” – Origins of Generally Recognized . . .
Mr. Dies (Texas Congressman): “I think that it [the concept of GRAS] is so vague and indefinite and general that it puts the manufacturer, the processor, in a very bad situation.”
“So it seems to me the standard ought to be simplified and eliminate this thing of saying “generally recognized. If you go into the courthouse, who is an expert? How many would have to agree to be generally recognized?”
Mr. Larrick (FDA Commissioner): “Congressmen, all I can say is that we have used this language since 1938 and we have successfully handled over 10,000 new drug applications, and in my opinion the proof of the pudding is the eating . . .”
From Commissioner Larrick’s opening remarks
“We believe only those chemicals should be automatically exempted from the new law which are recognized among competent experts as safe for their intended use. This would make it unnecessary, for example, to do studies on table salt, but would not approve the continued use, without proof of safety, of the synthetic emulsifiers now widely used in some fabricated foods.”
Creation of the “GRAS List”
- 1958 Food Additives Amendment: Congress recognized that many food substances would not require a formal premarket review by FDA to assure their safety, either because:
- Their safety had been established by a long history of use in food; or
- By virtue of the nature of the substances, their conditions of use, and the information generally available to scientists.
- Two-step definition of “food additive:”
- Broadly includes any substance that becomes a component of food or otherwise affects the characteristics of food.
- Excludes substances that are recognized, among qualified experts, as having been adequately shown through scientific procedures (or, in the case of a substance used in food prior to January 1, 1958, through experience based on common use in food) to be safe under the conditions of their intended use.
- December 9, 1958: FDA published a list of GRAS substances and incorporated the list in Title 21 of the Code of Federal Regulations. The current list appears in 21 CFR Parts 182, 184, and 186.
Opinion Letters on GRAS
- Many substances that were considered GRAS by the food industry were not included in FDA’s 1958 GRAS list.
- Many manufacturers wrote to FDA and requested an opinion letter in which an FDA official would render an informal opinion on the GRAS status of use of the substance
- Often available only to requestor
- Revoked in 1970 (21 CFR 170.6; 35 FR 5810; April 9, 1970)
- October 30, 1969: President Nixon directed FDA to make a critical evaluation of the safety of GRAS food substances.
- March 28, 1972: – Life Sciences Research Office (LSRO) of the Federation of American Societies for Experimental Biology (FASEB) began its contract with FDA to summarize the available scientific literature and to recommend what restrictions, if any, on the use of the substances would be needed to ensure their safe use in food.
- 1970’s: LSRO selected qualified scientists (designated as the Select Committee on GRAS Substances (SCOGS)) as consultants to review and evaluate the available information on each of the GRAS substances. The Select Committee’s evaluations were made independently of FDA or any other group, governmental or nongovernmental.
- 1970’s – 1980’s: FDA made tentative reports from SCOGS available to the public and provided opportunity for the public to appear before the Select Committee at a public hearing. SCOGS considered the data, information, and views presented at the hearing in developing its final reports. By 1982, SCOGS had submitted opinions to the FDA on the health aspects of more than 400 substances.
- 1972: FDA conducted rulemaking to establish the procedures (21 CFR 170.35) that it would use to affirm the GRAS status of substances that were the subject of the GRAS review. That rulemaking included a mechanism (the GRAS affirmation petition process) whereby an individual could petition FDA to review the GRAS status of substances not being considered as part of the agency’s GRAS review.
- 1970’s – 1980’s: GRAS Affirmation based on the SCOGS Review
- After receiving a final SCOGS report, FDA reviewed the report and related information
- When appropriate, FDA issued a notice of proposed rulemaking to affirm GRAS status
- If, after reviewing comments to the proposal, FDA concluded that the available data and information supported GRAS status, FDA issued a final rule affirming GRAS status by amending 21 CFR 184 (direct food ingredients) or 186 (indirect food substances).
Examples: Gums, dextrans, various salts (e.g., sodium, potassium, calcium and iron salts),
- 1973 – 1997: GRAS Affirmation Petition Process
- Industry submits GRAS Affirmation Petition
- FDA publishes notice of filing and requests comment
- When appropriate after considering comments, FDA issues a final rule affirming GRAS status
Examples: Canola oil, enzyme preparations, whey, cocoa butter substitute
- April 17, 1997: FDA proposed to establish a notification procedure whereby a person may inform FDA of a determination that the use of a substance is GRAS (62 FR 18938; April 17, 1997).
- Industry submits GRAS notice
- FDA is evaluating whether each submitted notice provides a sufficient basis for a GRAS determination and whether information in the notice or otherwise available to FDA raises issues that lead the agency to question whether use of the substance is GRAS
- FDA is responding to the notifier by letter
Examples: Phytosterols, DAG oil, enzyme preparations
GRAS Notice Inventory
The inventory of GRAS notices provides the following information about GRAS notices filed within each year since 1998, when FDA received its first GRAS notice:
- The name of the substance
- The file number (GRN No.) that FDA has assigned to the notice
- A hyperlink to the letter that FDA sent in response to the notice. The text of this link also indicates the date of the letter.
The file number for each GRAS notice also serves as a hyperlink to additional information corresponding to the proposed “GRAS exemption claim” (proposed 21 CFR 170.36(c)(1)), including the following information, which FDA proposed to make readily accessible to the public:
- The name of the person who made the GRAS determination (notifier)
- The notifier’s address
- The intended conditions of use of the substance
- The statutory basis for the GRAS determination
Additional information includes:
- The date when FDA filed the notice
- The date when the evaluation process came to closure
- When applicable, a hyperlink to additional correspondence that FDA has issued regarding the GRAS notice
- The petition number if the substance was originally the subject of a GRAS petition
- In some cases, a hyperlink to the notice itself
Persons interested in obtaining additional data and information in the notice may obtain a copy of those data and information that are disclosable by requesting the information under the Freedom of Information Act.
GRAS Notice Inventory Database – Searchable
How to Submit a GRAS Notice (62 FR 18937 – April 17, 1997)
Guidance for Industry: Assessing the Effects of Significant Manufacturing Process Changes, Including Emerging Technologies, on the Safety and Regulatory Status of Food Ingredients and Food Contact Substances, Including Food Ingredients that are Color Additives
Pertinent Federal Regulations
21 CFR Part 181 (Prior Sanctioned Food Ingredients)
21 CFR Part 182 (Substances Generally Recognized as Safe
21 CFR Part 184 (Direct Food Substances Affirmed as GRAS)
21 CFR Part 186 (Indirect Food Substances Affirmed as GRAS)