Substances Generally Recognized as Safe

DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Parts 170 and 570 [Docket No. FDA-2025-N-3262] RIN 0910-AJ02 Substances Generally Recognized as Safe AGENCY: Food and Drug Administration, HHS. ACTION: Proposed rule. SUMMARY: The Food and Drug Administration (FDA or we) is proposing to require the submission of generally recognized as safe (GRAS) notices for the use of a human or animal food substance purported to be GRAS under the conditions of its intended use under the Federal Food, Drug, and Cosmetic Act (FD&C Act). DATES: Either electronic or written comments on the proposed rule must be submitted by December 9, 2026. Submit comments (including recommendations) on the collection of information under the Paperwork Reduction Act of 1995 by December 9, 2026. ADDRESSES: You may submit comments as follows. Please note that late, untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until 11:59 p.m. Eastern Time at the end of December 9, 2026. Comments received by mail/hand delivery/courier (for written/paper submissions) will be considered timely if they are received on or before that date. Electronic Submissions Submit electronic comments in the following way: • Federal eRulemaking Portal: https://www.regulations.gov . Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to https://www.regulations.gov will be posted to the docket unchanged. Because your comment will be made public, you are solely responsible for ensuring that your comment does not include any confidential information that you or a third party may not wish to be posted, such as medical information, your or anyone else's Social Security number, or confidential business information, such as a manufacturing process. Please note that if you include your name, contact information, or other information that identifies you in the body of your comments, that information will be posted on https://www.regulations.gov. • If you want to submit a comment with confidential information that you do not wish to be made available to the public, submit the comment as a written/paper submission and in the manner detailed (see “Written/Paper Submissions” and “Instructions”). Written/Paper Submissions Submit written/paper submissions as follows: • Mail/Hand Delivery/Courier (for written/paper submissions): Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. • For written/paper comments submitted to the Dockets Management Staff, FDA will post your comment, as well as any attachments, except for information submitted, marked, and identified, as confidential, if submitted as detailed in “Instructions.” Instructions: All submissions received must include the Docket No. FDA-2025-N-3262 for “Substances Generally Recognized as Safe.” Received comments, those filed in a timely manner (see ADDRESSES ), will be placed in the docket and, except for those submitted as “Confidential Submissions,” publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500. • Confidential Submissions—To submit a comment with confidential information that you do not wish to be made publicly available, submit your comments only as a written/paper submission. You should submit two copies total. One copy will include the information you claim to be confidential with a heading or cover note that states “THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.” We will review this copy, including the claimed confidential information, in our consideration of comments. The second copy, which will have the claimed confidential information redacted/blacked out, will be available for public viewing and posted on https://www.regulations.gov. Submit both copies to the Dockets Management Staff. If you do not wish your name and contact information to be made publicly available, you can provide this information on the cover sheet and not in the body of your comments and you must identify this information as “confidential.” Any information marked as “confidential” will not be disclosed except in accordance with 21 CFR 10.20 and other applicable disclosure law. For more information about FDA's posting of comments to public dockets, see 80 FR 56469, September 18, 2015, or access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf. Docket: For access to the docket to read background documents, the plain language summary of the proposed rule of not more than 100 words as required by the “Providing Accountability Through Transparency Act,” or the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in the heading of this document, into the “Search” box and follow the prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500. Under the Paperwork Reduction Act (PRA), comments on the information collection provisions are best assured of consideration if your comments are received by December 9, 2026. Submit your comments on FDA's need for this information, the accuracy of the provided burden estimates, and any suggested methods for minimizing respondent burden to FDA using the docket identified at the beginning of this rulemaking. FDA will respond to any information collection-related comments in the final rule. You may also send your information collection-related comments to OMB's Office of Information and Regulatory Affairs using the interface at https://www.reginfo.gov/public/do/PRAMain. Find this particular information collection by selecting “Currently Under Review—Open for Public Comments” or by using the search function. The title of this proposed collection is “Substances Generally Recognized as Safe: Notification Procedure.” FOR FURTHER INFORMATION CONTACT: With regard to substances that would be used in human food: Paulette Gaynor or Christopher Kampmeyer, Office of Pre-Market Additive Safety, Human Foods Program, Food and Drug Administration, 5001 Campus Dr., College Park, MD 20740, 240-402-1200; Carrol Bascus or Alexandra Beliveau, Office of Policy and International Engagement, Human Foods Program, Food and Drug Administration, 5001 Campus Dr., College Park, MD 20740, 240-402-2378. With regard to substances that would be used in animal food: Charlotte Conway, Tonia Bair, or Marla Keller, Office of Surveillance and Compliance, Center for Veterinary Medicine, Food and Drug Administration, 5001 Campus Dr., College Park, MD 20740, 240-402-6768. With regard to the information collection: Michael Ellison, Office of Operations, Food and Drug Administration, Three White Flint North, 10A-12M, 11601 Landsdown St., North Bethesda, MD 20852, 240-402-2093, PRAStaff@fda.hhs.gov. SUPPLEMENTARY INFORMATION: Table of Contents I. Executive Summary A. Purpose and Coverage of the Proposed Rule B. Summary of the Major Provisions of the Proposed Rule C. Legal Authority D. Costs and Benefits II. Table of Abbreviations/Commonly Used Acronyms in This Document III. Background A. Statutory and Regulatory History B. The Need To Mandate GRAS Notifications IV. Legal Authority A. Statutory Framework B. Legal Basis for the Proposal V. Description of the Proposed Rule A. Proposed Revisions to § 170.3—Definitions B. Proposed Revisions to § 170.30—Eligibility for Classification as GRAS C. Proposed Revisions to § 170.38—Determination of Food Additive Status D. Proposed Revisions to § 170.39—Threshold of Regulation (TOR) for Substances Used in Food or as a Food Contact Substance E. Proposed Revisions to § 170.203—Definitions Pertaining to GRAS Notices F. Proposed § 170.205—Creation of a Mandatory GRAS Notification Program G. Proposed Revisions to § 170.210—Mandatory Electronic Submission of GRAS Notices to FDA H. Proposed Revisions to § 170.220—Requirement To Submit English Translations of Material Included in a GRAS Notice I. Proposed Revisions to § 170.250—Identification of Data and Information Exempt From Disclosure Under the Freedom of Information Act J. Proposed Revisions to § 170.265—Circumstance Where FDA Would Not Consider the Mandatory GRAS Notice Notification Requirement To Be Met K. Proposed Revisions to § 170.275—Public Disclosure of a GRAS Notice L. Proposed Revocation of § 170.285—Disposition of GRAS Affirmation Petitions M. Proposed Addition of Subpart F—Establishment of Definitions and Pathway for Submission of Certain Information During Time-Limited Option for Substances Introduced Into Interstate Commerce Under the GRAS Provision of Section 201(s) of the FD&C Act Before the Effective Date of A Final Rule N. Proposed Revision to the Header of Part 170 O. Non-Substantive Edits to Part 170 P. Table Summarizing the Proposed Changes to Part 170 Q. Proposed Revisions to Part 570 for Food Substances Used in Animal Food and Incorporation by Reference VI. Request for Comments on Alternatives VII. Proposed Effective/Compliance Dates VIII. Preliminary Economic Analysis of Impacts IX. Analysis of Environmental Impact X. Paperwork Reduction Act of 1995 XI. Federalism XII. Consultation and Coordination With Indian Tribal Governments XIII. References I. Executive Summary A. Purpose and Coverage of the Proposed Rule The proposed rule, if finalized, would amend our regulations at parts 170 and 570 (21 CFR parts 170 and 570) to require the submission of GRAS notices for the use of a human or animal food substance that is purported to be GRAS under the conditions of its intended use under section 201(s) of the FD&C Act (21 U.S.C. 321(s)) . Food substances include both ingredients and substances added indirectly, such as from food packaging. The proposed rule would require any person introducing a substance into interstate commerce under the GRAS provision of section 201(s) of the FD&C Act to notify FDA of the basis for their conclusion that the substance is GRAS under the conditions of its intended use unless an exception to the requirement to submit a GRAS notice applies. This change would provide greater transparency about substances that are added to food (including substances already in the food supply and those being introduced into interstate commerce for use in food for the first time), so that FDA can more efficiently determine if the use of a substance constitutes a food additive use that is subject to FDA review and approval under the FD&C Act. This change is expected to provide FDA with information to help identify the use of potentially unsafe substances in food, thereby enabling FDA to take action as appropriate and regulate the safety of food substances more effectively. B. Summary of the Major Provisions of the Proposed Rule The proposed rule, if finalized, would: • Convert the voluntary GRAS notification program to a mandatory GRAS notification program and explain that if the notification requirement is not met for a substance's conditions of intended use, FDA would consider such noncompliance as a factor in its prioritization of food substances for post-market review; • Establish certain exceptions to the requirement to submit a GRAS notice, including a time-limited option to make a streamlined submission to FDA for certain intended uses of substances already in interstate commerce instead of initially submitting a GRAS notice; and • Revise our procedural regulations for a threshold of regulation (TOR) exemption for human food to reflect updated scientific guidance and to include uses of substances in food and as a food contact substance (FCS). C. Legal Authority We are issuing this proposed rule consistent with our authority in sections 201, 402, 409, and 701 of the FD&C Act (21 U.S.C. 321, 342, 348, 371). D. Costs and Benefits This proposed rule would revise the procedures by which a person introducing a human or animal food substance into interstate commerce notifies FDA of a conclusion that the use of such substance is GRAS. Specifically, the proposed rule would require the submission of GRAS notices to FDA for certain uses of food substances. A substance that is GRAS under the conditions of its intended use is not subject to FDA premarket review and approval as a food additive for that particular use (see sections 201(s) and 409 of the FD&C Act). Under our current regulations, a person who concludes that the use of a substance is GRAS under the conditions of its intended use may, but is not required to, notify FDA of this conclusion. The submission of a GRAS notice is therefore currently voluntary. If the proposed rule is finalized, GRAS notices will be required for certain uses of substances in human and animal food. The primary benefits of the proposed rule, if finalized, would come from increased information being made available to FDA and the public regarding substances used in human and animal foods. This information would enable us to more effectively determine if the use of a substance constitutes a food additive use that is subject to premarket review and approval under the FD&C Act. This information is also expected to provide FDA with information to help identify the use of potentially unsafe substances in food, thereby enabling FDA to take action as appropriate and regulate the safety of food substances more effectively. A mandatory GRAS notification program would allow FDA to ensure that GRAS conclusions have a scientific basis and that appropriate documentation supporting those conclusions exists. The proposed rule, if finalized, is in part intended to help strengthen public confidence in FDA's ability to oversee the safety of the U.S. food supply. One-time costs of the proposed rule to persons who introduce a substance into interstate commerce under the GRAS provision of section 201(s) of the FD&C Act include reading the rule and revising standard operating procedures regarding GRAS notices. Other one-time per manufacturer costs of the proposed rule are preparing and submitting streamlined submissions related to uses of substances introduced into interstate commerce under the GRAS provision of section 201(s) of the FD&C Act before the effective date of a final rule, for firms that choose to submit this information during the window of availability for this time-limited option for such submissions. Costs associated with these activities may include translation costs for manufacturers in non-English speaking countries. Recurring costs to affected manufacturers would include preparing and submitting GRAS notices for new uses of substances introduced into interstate commerce under the GRAS provision of section 201(s) of the FD&C Act after the effective date of a final rule that would otherwise have been the subject of an independent conclusion of GRAS status ( i.e., a GRAS conclusion has been reached without submitting a GRAS notice) (see sections III and VII of this document for further discussion of independent conclusion of GRAS status and effective and compliance dates, respectively). Costs to FDA would include one-time costs of reviewing streamlined submissions related to uses of substances introduced into interstate commerce under the GRAS provision of section 201(s) of the FD&C Act before the effective date of a final rule during the time-limited period for such submissions, and annual costs of evaluating ongoing submissions of GRAS notices regarding uses of substances that would otherwise have been the subject of an independent conclusion of GRAS status. Other effects of the proposed rule may include transfers of market share and revenue between manufacturers of products with similar ingredients. For example, the submission of a GRAS notice may lead to a determination by FDA that there is an insufficient basis for concluding that a substance that happens to be used in only certain of the products was GRAS. We acknowledge the potential for such transfers if the rule is finalized. We do not estimate the magnitude of such effects because we cannot identify which substances may be the subject of an insufficient basis letter, which products they are in, or the market share of such products. We estimate that the present value of the costs of the proposed rule would be approximately $89.6 million, with a lower bound of $34.9 million and an upper bound of $210.0 million, discounted at 3 percent at 10 years in 2024 dollars. At a 7 percent discount rate, the present value of costs would be approximately $82.3 million, with a lower bound of $31.5 million and an upper bound of $195.9 million. We estimate that the annualized costs of the proposed rule would be approximately $10.5 million, with a lower bound of $4.1 million and an upper bound of $24.6 million, discounted at 3 percent over 10 years. At a 7 percent discount rate, annualized costs would be approximately $11.7 million, with a lower bound of $4.5 million and an upper bound of $27.9 million. EP11AU26.043 III. Background On March 10, 2025, the Secretary of Health and Human Services, Robert F. Kennedy Jr., directed FDA to explore rulemaking to eliminate the pathway for firms to introduce purported GRAS uses of substances into the market without notifying FDA of the basis for their GRAS conclusions (Ref. 1). Secretary Kennedy's call for a reformed GRAS notification process aligns with the Administration's Make America Healthy Again initiative by providing increased transparency about the substances being added to the nation's food supply (Ref. 2). A mandatory GRAS notification program would require any person introducing a substance into interstate commerce under the GRAS provision of section 201(s) of the FD&C Act to notify FDA of the basis for their conclusion that the substance is GRAS under the conditions of its intended use. A mandatory program would enable FDA to more effectively ensure the safety of the U.S. food supply—one that has grown far more complex in recent years—by providing us with information needed to help identify the use of potentially unsafe substances in food or additives that require FDA's review and approval to be lawfully marketed, so we can take action as appropriate. A mandatory GRAS notification program would therefore address growing concerns about the increasingly complex U.S. food supply. For example, firms are introducing substances into food without publicly disclosing the underlying safety information about the use of such ingredients and FDA sometimes becomes aware of the need to take action regarding unsafe substances in food only after adverse public health events occur. Further, a mandatory program that includes the continued public disclosure of information about GRAS uses of substances would substantially increase the public's access to information concerning the substances being added to human and animal food. In 1958, Congress enacted the Food Additives Amendment to the FD&C Act (the 1958 amendment) (Pub. L. 85-929, 72 Stat. 1784), which expanded FDA's broad authority under the FD&C Act to ensure the safety of the U.S. food supply. Among other things, the 1958 amendment created a new framework for FDA's oversight of substances being added to food. The 1958 amendment defined the term “food additive” and established a premarket review and approval framework for these food substances (sections 201(s) and 409 of the FD&C Act). Notably, in defining what constitutes a food additive subject to premarket review and approval, the 1958 amendment excluded substances that are GRAS under the conditions of their intended use (section 201(s) of the FD&C Act). Congress therefore exempted substances that are GRAS under the conditions of their intended use from the premarket review and approval requirements for food additives under the FD&C Act. However, as discussed elsewhere in this document, Congress struck a balance: although it exempted substances that are GRAS under the conditions of their intended use from premarket review and approval, Congress granted FDA the authority to review food substances on the market, including new and existing substances introduced into food that are purported to be GRAS under the conditions of their intended use, to assess whether these substances meet the definition of a food additive that requires premarket authorization (sections 409(a) and (d) of the FD&C Act). In the over 60 years since the enactment of the 1958 amendment, FDA has regulated GRAS uses of substances in food through various mechanisms, including by: listing certain substances as GRAS under the conditions of their intended use in our regulations; conducting a comprehensive study of purported GRAS uses of substances to determine whether certain uses of substances required FDA's review and approval as food additive uses; and establishing a GRAS affirmation process, through which interested parties could petition us to affirm the GRAS status of a particular use of a substance. Our current GRAS notification program was first proposed in 1997, and under this program, parties can voluntarily notify us of a conclusion that a substance is GRAS under the conditions of its intended use. Through a GRAS notice, parties can share with us the underlying data and other scientific information used to support their conclusion that the use of a substance is GRAS under the conditions of its intended use. A GRAS conclusion constitutes an assertion on the part of the notifier ( i.e., the person responsible for the GRAS notice; see § 170.203 (21 CFR 170.203) and § 570.203 (21 CFR 570.203)) that the intended use of a substance is not a food additive use that is subject to the premarket review and approval requirements of section 409 of the FD&C Act. Importantly, a person's conclusion that a substance is GRAS under the conditions of its intended use (or similar claims by a person that they have independently “certified” the use of a substance as GRAS) does not necessarily mean that such a use is GRAS or that the use is not an unapproved food additive use. For example, FDA may determine, based on an assessment of evidence, that the use of a substance is not GRAS or that it is otherwise an unapproved food additive. As part of our voluntary GRAS notification program, once we file a GRAS notice, we conduct an evaluation to determine whether the data and information presented, and other information available to FDA, provide a sufficient basis for a conclusion that the substance is GRAS under the conditions of its intended use. In general, FDA will respond to a GRAS notice in one of three ways: (1) by indicating that we do not question the basis for the GRAS conclusion contained in the notice (“no questions” letter); (2) by indicating that we have concluded that the notice does not provide a sufficient basis for a GRAS conclusion ( e.g., because the notice does not include appropriate data and information or because key data and information are not publicly available); or (3) by stating that we have granted a request by the notifier for us to cease our evaluation of the GRAS notice. There is no requirement that a notifier must wait to receive a response from FDA regarding their GRAS conclusion before introducing the substance into interstate commerce. We provide information about GRAS notices and our responses on our website (Refs. 3 and 4). While the current GRAS notification program has been informative and beneficial to our administration of the FD&C Act, our nearly 30 years of experience with the program, and particularly our experience administering the program since it was finalized in 2016, has highlighted several challenges. The voluntary nature of the GRAS notification program has meant that information gaps persist for both FDA and the public about substances being added to food, an issue covered extensively in a 2010 U.S. Government Accountability Office (GAO) report (see section III.B.1.c of this document for further discussion) (Ref. 5). Our lack of complete information about what substances are being added to food has, at times, prevented early engagement with industry about new uses of substances in food and frustrated our ability to carry out our public health and safety responsibilities under the FD&C Act (see section III.B of this document for further discussion). At the same time, recent changes in our country's food supply, such as evolving consumer demand for different types of products and ongoing innovation in food manufacturing and ingredient development, have resulted in a more diverse food supply. It was estimated that, as of January 2011, more than 10,000 additives were being used in food, including an estimated 1,000 human food substances for which firms had claimed independent conclusions of GRAS status ( i.e., they had reached a GRAS conclusion without submitting a GRAS notice) (Refs. 6 and 7). In light of the issues we have identified with the voluntary GRAS notification program, and the challenges we face due to ongoing food innovation and evolving consumer demands, we find ourselves in a situation much like the years before the 1958 amendment's enactment. At that time, numerous substances with unknown safety profiles were being added to or used in connection with food without sufficient FDA oversight. Today, an unknown number of substances are being introduced into the market under the GRAS provision of section 201(s) of the FD&C Act. The proposed rule would address our current circumstances by requiring the submission of GRAS notices. Mandatory submission of GRAS notices would increase knowledge and improve the transparency about substances in the U.S. food supply that are purported to be GRAS under the conditions of their intended use. It would give FDA, state regulators, consumers, industry, and consumer advocacy groups more information about substances being used in human and animal food. Once filed, information about all purported GRAS uses of substances is expected to enable FDA to more efficiently determine whether the use of a substance meets the definition of a food additive use under the FD&C Act, and therefore whether the use of the substance requires FDA's review and approval to be lawfully marketed. Further, mandatory submission of GRAS notices would help FDA ensure that GRAS conclusions have a scientific basis and are appropriately documented and maintained. It would also provide an earlier opportunity for us to engage with industry if questions arise regarding a conclusion that a substance is GRAS under the conditions of its intended use. Mandatory submission of GRAS notices would enable FDA to administer and enforce the FD&C Act more effectively and efficiently. A. Statutory and Regulatory History 1. The Food Additives Amendment of 1958 In 1950, to address emerging health concerns about the use of new chemicals in food, the U.S. House of Representatives established a committee chaired by Representative James Delaney of New York (the Delaney Committee) to investigate the substances being added to or used in connection with the nation's changing food supply. The Delaney Committee issued a report in June 1952 summarizing its findings (Ref. 8). The report found, among other things, that food substances were being used “without adequate and sufficient testing of their possible long-range injurious effects” (id. at 27). The report further concluded that the public was “entitled to greater protection with respect to the foods it must necessarily consume[,]” and that “such protection [was] not afforded by existing legislation, under which the Government may take no action until after the food has been placed upon the market and injury may have occurred” (id. at 27). The Delaney Committee therefore recommended that the FD&C Act be amended to require premarket safety reviews for “chemicals employed in or on foods” (id. at 27). In 1958, based in part on the Delaney Committee's report, as referenced in the corresponding House Report (Ref. 9), Congress enacted the Food Additives Amendment to the FD&C Act to strengthen government oversight of substances being added to or used in connection with food. “Food” includes articles used for food or drink for humans or other animals and articles used for components of such food (see section 201(f) of the FD&C Act); therefore, the 1958 amendment covered additives in both human and animal foods. Echoing the Delaney Committee's call for premarket oversight of food substances, Congress's stated purpose in passing the 1958 amendment was “[t]o protect the public health by amending the [FD&C Act] to prohibit the use in food of additives which have not been adequately tested to establish their safety” (Pub. L. 85-929, 72 Stat. 1784). Specifically, the 1958 amendment requires that, before certain substances may be added to food, FDA must authorize their use through a premarket review and approval process (sections 409(b) through (e) of the FD&C Act). Among other things, the 1958 amendment: • defines what constitutes a “food additive” subject to premarket review and approval (now codified at section 201(s) of the FD&C Act); • creates a detailed premarket authorization process for food additives that can result in a food additive regulation establishing the safety of a food additive for a particular use (sections 409(a) through (e) of the FD&C Act); • enables any person to submit a food additive petition to propose the issuance of a food additive regulation (section 409(b) of the FD&C Act); • empowers the Secretary of the U.S. Department of Health and Human Services (the Secretary) to at any time, on their own initiative, propose the issuance of a food additive regulation (section 409(d) of the FD&C Act); and • deems adulterated any food that is, or bears or contains, a “food additive that is unsafe within the meaning of section 409 [of the FD&C Act]” (now section 402(a)(2)(C)(i) of the FD&C Act). With some exceptions, section 409(a) of the FD&C Act provides that food additives are deemed “unsafe” for purposes of the adulteration provision of section 402(a)(2)(C)(i) of the FD&C Act unless their use conforms with a food additive regulation issued pursuant to the premarket review and approval process of section 409 of the FD&C Act. Congress later added to this premarket authorization framework by establishing a mandatory food contact notification program for human foods (see section 409(h) of the FD&C Act) and certain requirements specific to food additives intended for use in animal food (see section 409(k) of the FD&C Act). 2. Statutory Approach to Substances Generally Recognized as Safe (GRAS) In enacting the 1958 amendment, Congress recognized that many substances added to food would not need to go through formal premarket review and approval 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 substance, its customary or projected conditions of use, and the information generally available to scientists about the substance. Therefore, Congress adopted a two-step definition of “food additive” (see section 201(s) of the FD&C Act). The first step broadly includes any substance, the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of food. This includes substances added to food directly ( i.e., ingredients) and indirectly ( i.e., substances used in contact with food). As such, substances that migrate or may reasonably be expected to migrate into food from their intended use in contact with food ( e.g., from conveyor belts, containers for shipping, packaging for food) would be regulated as food additives unless such use is GRAS or otherwise excepted from the definition of a food additive. Further information about food contact substances is available on our website (see Ref. 10). The second step excludes from the definition of a “food additive” substances that are generally recognized, among experts qualified by scientific training and experience to evaluate their safety, as having been adequately shown through scientific procedures (or, in the case of substances used in food before January 1, 1958, through either scientific procedures or through experience based on common use in food) to be safe under the conditions of their intended use. Under section 201(s) of the FD&C Act, the conditions of intended use of a substance, rather than the substance itself, are eligible for GRAS status. Similarly, food additives are deemed unsafe when their conditions of use do not conform with a food additive regulation (see section 409(a) of the FD&C Act). The 1958 amendment created two distinct processes for the proposal and creation of food additive regulations. First, under section 409(b) of the FD&C Act, any person may propose the issuance of a food additive regulation by filing a petition with the Secretary. Under section 409(c) of the FD&C Act, in response to a food additive petition, the Secretary, and by delegation, FDA, will, by order, either: (1) deny the petition; or (2) establish a food additive regulation prescribing the conditions under which the food additive may be safely used. Second, under section 409(d) of the FD&C Act, Congress specifically authorized the Secretary, and by delegation, FDA, to at any time, upon the Secretary's own initiative, propose the issuance of a food additive regulation prescribing the conditions under which a particular food additive may be safely used. After 30 days, the Secretary, and by delegation, FDA, may issue an order establishing a food additive regulation based upon the proposal (section 409(d) of the FD&C Act). Section 409(d) of the FD&C Act thus authorizes us to propose food additive regulations of our own accord. As discussed further in section IV of this document, by granting FDA authority to propose food additive regulations upon our own initiative and at any time, Congress intended for FDA to play a critical role in determining whether a food substance being introduced into interstate commerce, including one already being added to food, meets the definition of a food additive and requires a food additive regulation to be lawfully marketed. 3. FDA's Regulatory Approach to the GRAS Provision of Section 201(s) of the FD&C Act We have periodically revised our regulations to adapt our approach to the GRAS provision of section 201(s) of the FD&C Act to the nation's changing food supply and to address issues we identified after years of experience under prior regulatory schemes. The revisions were intended to help us better understand what substances are being added to or used in connection with food under the GRAS provision of section 201(s) of the FD&C Act. The goal of these regulations was to give us, and the public, safety information about these substances and to enable us to take appropriate actions to assure the safe use of these substances in food. Shortly after Congress amended the FD&C Act in 1958, we clarified the regulatory status of many substances that were added to food before 1958, and we ultimately amended our regulations to include a list of food substances that, when used for the purposes indicated and in accordance with good manufacturing practices, are GRAS. The list, historically referred to as “the GRAS list,” can be found at part 182 (21 CFR part 182) for human food and part 582 (21 CFR part 582) for animal food. When creating the GRAS list, we acknowledged that it would be impracticable for us to list all substances that are GRAS for their intended use in our regulations (§ 121.101(a) (later renumbered as § 182.1(a) (21 CFR 182.1(a)) and § 582.1(a) (21 CFR 582.1(a))). Consequently, we did not include many substances considered GRAS under the conditions of their intended use by the food industry in the GRAS list. Despite the fact that a substance that is GRAS under the conditions of its intended use is not subject to FDA premarket review and approval as a food additive for that particular use (see sections 201(s) and 409 of the FD&C Act), firms who concluded on their own initiative that a use of a substance qualified for GRAS status frequently sought our opinion on whether their conclusion was justified. Many firms requested an “opinion letter,” in which FDA would render an informal opinion on the GRAS status of the conditions of use of a substance. Although convenient and expedient, these informal opinion letters were often available only to the requestor and were not binding on us even at the time they were issued. FDA updated the GRAS list over time. For example, in the Federal Register of October 21, 1969 (34 FR 17063), we deleted from the GRAS list various cyclamate salts, a family of nonnutritive sweeteners that had been added to food under the GRAS provision of section 201(s) of the FD&C Act, because they were implicated in the formation of bladder tumors in rats (Ref. 11). Later, in response to concerns raised by the new information on cyclamates, then-President Nixon directed FDA to reexamine the safety of all substances included on the GRAS list (Ref. 12). We subsequently announced that we were conducting a comprehensive study of these substances (35 FR 18623, December 8, 1970). The purpose of the study was to evaluate the available safety information for substances on the GRAS list. For substances determined safe under their conditions of use, we would then repromulgate each substance in a new ( i.e., affirmed) GRAS list, a food additive regulation, or an interim food additive regulation pending completion of additional studies. In conjunction with this comprehensive study, we revoked informal GRAS opinion letters issued before April 9, 1970, in part because many letters no longer resided in FDA's files; thus, in the absence of information concerning the names and uses of the substances in the letters, the safety of all such substances and uses could not be reexamined (35 FR 5810, April 9, 1970) (see § 170.6 (21 CFR 170.6) and § 570.6 (21 CFR 570.6)). In the notice announcing the comprehensive review of substances included on the original GRAS list, we proposed criteria that could be used to establish whether the use of these substances should be included on a new GRAS list, become the subject of a food additive regulation, or be listed in an interim food additive regulation pending completion of additional studies (35 FR 18623). We incorporated these criteria into our regulations as § 121.3 (21 CFR 121.3) (36 FR 12093, June 25, 1971) (renumbered as § 170.30 (21 CFR 170.30) for human food and § 570.30 (21 CFR 570.30) for animal food; see 41 FR 38618, September 10, 1976, and 42 FR 14302, March 15, 1977). We later announced that we were conducting a study of certain GRAS substances (36 FR 20546, October 23, 1971) and subsequently instituted a rulemaking to establish procedures that we could use, on our own initiative, to affirm the GRAS status of substances that were the subject of that review and were found to satisfy the criteria established in § 121.3 (proposed rule, 37 FR 6207, March 25, 1972; final rule, 37 FR 25705, December 2, 1972). We recodified these procedures at § 170.35(a) and (b) (21 CFR 170.35(a) and (b)) for human food (42 FR 14302) and § 570.35(a) and (b) (21 CFR 570.35(a) and (b)) for animal food (41 FR 38618). Because the GRAS review did not cover all GRAS substances ( e.g., substances that were marketed based on a firm's conclusion of GRAS status), the 1972 rulemaking included a mechanism (the GRAS affirmation petition process) whereby an individual could petition us to review the GRAS status of substances not being considered as part of our GRAS review. If we agreed that the substance was GRAS under the conditions of its intended use, we could affirm the use of the substance as GRAS in our regulations. Our affirmations of GRAS status are currently codified in parts 184 and 186 (21 CFR parts 184 and 186) for human food and part 584 (21 CFR part 584) for animal food. Petitions submitted as part of the GRAS affirmation process informed us, the domestic and international food industry, and the public of conclusions of GRAS status. However, this framework proved to be resource-intensive ( e.g., FDA issued a rule proposing to affirm a substance as GRAS under the conditions of its intended use and affirmed the GRAS status in a final rule). Therefore, in the Federal Register of April 17, 1997 (62 FR 18938), we proposed to: (1) clarify the criteria for eligibility for classification as GRAS; and (2) replace the voluntary GRAS affirmation petition process with a voluntary GRAS notification procedure. In the Federal Register of August 17, 2016 (81 FR 54960) (the 2016 GRAS final rule), we finalized the voluntary GRAS notification regulation in Subpart E of part 170 (21 CFR part 170) for human food and Subpart E of part 570 (21 CFR part 570) for animal food. The regulations provide that any person may notify FDA of a view that a substance is not subject to the premarket review and approval requirements of section 409 of the FD&C Act based on that person's conclusion that the substance is GRAS under the conditions of its intended use (see § 170.205 (21 CFR 170.205) and § 570.205 (21 CFR 570.205)). We explained that we would evaluate whether the data, information, and narrative in a GRAS notice support that conclusion (81 FR 54960 at 55035; see also § 170.265(b) (21 CFR 170.265(b)) and § 570.265(b) (21 CFR 570.265(b))). B. The Need To Mandate GRAS Notifications The voluntary GRAS notification program has improved our efficient administration of the FD&C Act by providing us with more data and information about uses of substances in food. GRAS notices have informed us about new food substances entering the market, including some substances into which we might not otherwise have insight. GRAS notices have therefore provided us with information that improved our understanding of the U.S. food supply and enhanced our ability to protect public health by helping to identify the use of potentially unsafe substances in food or additives that require FDA review and approval to be lawfully marketed, so we can take action as appropriate. As part of an interim pilot program created with the 1997 proposed rule, parties began notifying us about their conclusions of GRAS status (62 FR 18938 at 18954). FDA's former Center for Food Safety and Applied Nutrition (now called the Human Foods Program (HFP)) filed its first GRAS notice in 1998 under the interim pilot program. As of March 25, 2025, HFP has filed over 1,200 GRAS notices (Ref. 3). FDA's Center for Veterinary Medicine (CVM) established its interim pilot program more recently (75 FR 31800, June 4, 2010) and filed its first GRAS notice in December 2010. As of March 28, 2025, CVM has filed 75 GRAS notices (Ref. 4). In addition to providing us with more information about uses of substances in food, the voluntary GRAS notification program has improved our administration of the FD&C Act in other ways. For example, the voluntary GRAS notification program created new opportunities for us to engage with industry to learn more about the U.S. markets for human and animal food. Under the voluntary GRAS notification program, FDA routinely engages with industry through pre-submission meetings and related consultations. We also work with industry to improve GRAS notice submissions and recommend the necessary data and other information to facilitate a successful evaluation of a GRAS notice. These opportunities to engage with stakeholders provide us with more information about human and animal food substances, and they enable us to better achieve our ultimate goal of helping to identify the use of potentially unsafe substances in food or additives that require FDA review and approval to be lawfully marketed, so we can take action as appropriate. Despite the benefits of our GRAS notification program, we have identified challenges with our current voluntary approach to GRAS notifications. These challenges, which we describe in the sections that follow, have created obstacles to fulfilling our statutory responsibility to determine if the use of a substance constitutes a food additive use that is subject to the premarket review and approval requirements of section 409 of the FD&C Act. We are, therefore, proposing a mandatory approach to GRAS notifications to better serve these purposes. 1. Issues Identified Over the Course of the Voluntary GRAS Notification Program After nearly 30 years of receiving and evaluating GRAS notices, and after filing more than 1,200 GRAS notices, FDA has identified several issues with the current voluntary approach to GRAS notifications. We describe some issues we have identified with a voluntary approach to GRAS notifications in greater detail in the following sections. a. Issue #1: Inadequate analyses to support independent conclusions of GRAS status can result in unapproved food additive uses. Due to the voluntary nature of the GRAS notification program, we have periodically learned about the continued use of substances in food that we have publicly indicated constitute unapproved food additive uses. It may be unclear whether such substances are being used based on a new independent conclusion of GRAS status and, if so, what data and information a firm may be relying on to substantiate that conclusion. The continued use of stevia leaves and crude extracts of stevia leaves provide one such example. We first issued an import alert in 1991 for crude extracts of stevia leaves and foods containing stevia leaves or stevia extracts to prevent the importation of unsafe stevia products into the United States. We have updated the import alert to add firms subject to the import alert and to account for uses of purified extracts for which FDA does not have questions following the review of a GRAS notice. The most recent update issued in 2025 continues to recommend detention without physical examination of stevia leaves, crude extracts of stevia leaves, or foods containing these substances (Ref. 13). The import alert states that, when used in conventional foods, stevia leaf, or its crude extract, is not an approved food additive and is not considered GRAS due to inadequate toxicological information necessary to demonstrate safety. In contrast, the safety of high purity (greater than or equal to 95 percent pure) steviol glycosides, the sweetening molecules found in stevia leaves, is well-established, and FDA has evaluated and issued “no questions” letters in response to multiple GRAS notices regarding highly purified forms of steviol glycosides. Notwithstanding these developments regarding high purity steviol glycosides, FDA's position on stevia leaves and their crude extracts has remained clear and consistent since the 1991 import alert—their use is not considered GRAS and constitutes an unapproved food additive use. Despite our unambiguous position regarding stevia leaves and stevia leaf crude extracts since 1991, we continue to find products containing these substances. In 2022, for instance, FDA issued a warning letter about the use of an unapproved food additive—stevia leaf—in several green tea products (Ref. 14). Our experience under the voluntary GRAS notification program has further demonstrated that some firms may not be conducting sufficient analyses of whether their use of a substance in food is GRAS. FDA advises firms that preserving the applicable data and information that forms the basis of an independent conclusion of GRAS status represents prudent practice for those who assert that the statutory premarket review and approval requirements for food additives do not apply to the use of a substance in food (81 FR 54960 at 55028; see also 62 FR 18938 at 18947). We encourage firms to maintain the data and information that support the independent conclusion of GRAS status in the form of a GRAS notice (81 FR 54960 at 55027; see also Ref. 14). We also recommend that a firm make public the basis for its independent conclusion of GRAS status, as that aligns with FDA's practice to make GRAS notices publicly available (Ref. 15) and our goal of increasing transparency. Notwithstanding these recommendations, we have learned that some firms may not conduct an evaluation that is sufficient to establish that a substance is GRAS under the conditions of its intended use. Firms also may not have the data and information that adequately support the basis for an independent conclusion of GRAS status. These observations are troubling given that firms are responsible for the safe manufacture of food being introduced into interstate commerce, including assuring the safety of substances used in making a food product. Several examples illustrate the real-life consequences of these trends. In 2009, we received a letter from 18 Attorneys General and one city attorney expressing concerns about caffeinated alcoholic beverages (Ref. 16). FDA advised manufacturers that we were considering whether caffeine could lawfully be added to alcoholic beverages (Ref. 17). We informed these firms that there are no food additive regulations authorizing the use of added caffeine in alcoholic beverages, that such use was not prior sanctioned, and that we had not determined the use to be GRAS (id.). We gave them 30 days to submit their rationale, supporting data, and information for their