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Generally recognized as safe

Generally recognized as safe (GRAS) is a designation under federal law exempting certain substances used in from the premarket approval process required for food additives, provided that qualified experts generally recognize them as safe for their intended use based either on a history of safe common use in prior to January 1, 1958, or on scientific data and procedures demonstrating adequate safety. Enacted through the 1958 Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act, the GRAS provision aimed to distinguish established ingredients—like , , and spices—from novel additives needing rigorous FDA evaluation, thereby streamlining regulation while preserving safeguards rooted in expert consensus rather than bureaucratic fiat. Under this framework, food manufacturers can self-affirm GRAS status by convening independent expert panels to review safety data, or they may voluntarily submit a GRAS notice to the FDA detailing the basis for the determination, which the agency reviews for consistency with statutory criteria but does not endorse as an approval. The system has enabled thousands of ingredients to enter the market efficiently, with peer-reviewed analyses affirming no known incidents linked to GRAS notices since their formalization, underscoring the reliability of expert-driven safety assessments over mandatory pre-approvals. Nevertheless, the pathway has drawn scrutiny for lacking mandatory FDA notification or oversight, potentially allowing undisclosed uses or insufficiently vetted substances to proliferate, as highlighted in legal and critiques urging reforms to enhance and post-market monitoring without dismantling the core expert-recognition mechanism.

Definition and Legal Framework

Core Definition and Scope

Generally recognized as safe (GRAS) denotes a regulatory status under federal law for substances intentionally added to , exempting them from the premarket approval process otherwise required for food additives when qualified scientific experts deem them safe for their intended conditions of use based on either scientific procedures or, for substances in common use in food prior to January 6, 1958, historical evidence of safety. This status hinges on the consensus among experts in relevant scientific fields, such as , , and , that the substance poses no significant risk to human health under specified exposure levels. The scope of GRAS encompasses a wide array of food ingredients, including but not limited to flavorings, preservatives, stabilizers, and processing aids used in foods, with parallel application to animal feeds via separate FDA oversight. It excludes substances requiring color additive petitions or those classified as pesticides, which fall under distinct regulatory pathways. GRAS determinations must account for the intended use, such as dosage, subgroups (e.g., infants or sensitive individuals), and potential dietary , ensuring is evaluated in rather than in isolation. Public availability of supporting data is essential for achieving "" recognition, distinguishing GRAS from proprietary safety assessments that do not confer the status. As of 2023, over 10,000 substances hold GRAS status, ranging from essential oils to enzymes, reflecting both pre-1958 culinary staples like and and modern innovations validated through toxicological studies. While allows industry to conclude GRAS without mandatory FDA pre-approval, the agency maintains oversight through voluntary notifications and reserves the right to challenge determinations if new evidence emerges indicating risks. This framework prioritizes expert-driven safety over blanket prohibitions, though critics from advocacy groups argue it enables insufficient scrutiny of novel chemicals; however, FDA evaluations consistently emphasize empirical data over unsubstantiated concerns.

Statutory Basis in the FD&C Act

The statutory basis for substances generally recognized as safe (GRAS) is established in section 201(s) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), codified at 21 U.S.C. § 321(s). This provision defines a "" as any substance whose intended use may reasonably result in its becoming a component of or affecting characteristics, provided such substance is not generally recognized among experts qualified by scientific training and experience to evaluate its safety as having been adequately shown to be safe under its intended conditions of use. The GRAS exclusion applies if safety is demonstrated through scientific procedures or, for substances used in prior to January 1, 1958, through either scientific procedures or experience based on common use in . By carving out GRAS substances from the food additive definition, section 201(s) exempts them from the premarket approval requirements imposed on food additives under section 409 of the FD&C Act (21 U.S.C. § 348), which mandates that food additives be shown safe by adequate scientific testing before use. This exemption reflects congressional intent in the 1958 Food Additives Amendment to accommodate substances with established safety profiles, avoiding redundant regulation where expert consensus exists on safety equivalent to that required for food additive petitions. The safety standard for GRAS—reasonable certainty of no harm under intended use—mirrors the food additive standard, ensuring that GRAS determinations rely on the same rigorous evidence threshold, whether via published scientific data or historical consumption patterns. Section 201(s) emphasizes that GRAS status pertains to the use of a substance under specific conditions, not the substance in isolation; thus, a substance GRAS for one application may require food additive approval for another. Exceptions within the food additive definition, such as for pesticides, color additives, or prior-sanctioned substances, do not alter the GRAS carve-out but delineate separate regulatory categories. This framework empowers industry self-determination of GRAS status based on expert evaluation, with the Food and Drug Administration (FDA) retaining enforcement authority under sections 402(a)(2)(C) and 409 to challenge uses not meeting GRAS criteria as adulterated.

Criteria for GRAS Designation

Requirements for Scientific Recognition

The scientific recognition of a substance as generally recognized as safe (GRAS) under the Federal Food, Drug, and Cosmetic Act relies on establishing general recognition of safety through scientific procedures, which demands the same quantity and quality of scientific evidence required for approving a substance as a direct food additive. This equivalence ensures rigorous evaluation, typically encompassing toxicological studies such as acute and subchronic toxicity tests, chronic feeding studies, genotoxicity assessments, reproductive and developmental toxicity evaluations, and, where warranted, carcinogenicity bioassays conducted under Good Laboratory Practice standards. Additional data on absorption, distribution, metabolism, and excretion (ADME) profiles, as well as quantitative exposure estimates from intended use conditions, are essential to demonstrate a reasonable certainty of no harm, accounting for variability in human populations including sensitive subgroups like infants or the elderly. General recognition further mandates that this be widely known and accepted within the community of qualified experts—those with scientific training and experience in evaluating the of substances—fostering a that the affirm without significant unresolved safety questions. Unlike confidential industry , supporting information must be publicly accessible, often through peer-reviewed publications in scientific journals or authoritative textbooks, enabling independent verification and precluding reliance on proprietary or unpublished findings. The FDA has emphasized that mere absence of reported adverse effects or limited studies insufficient for additive approval does not suffice; instead, the must comprehensively address potential risks under realistic exposure scenarios, with margins of derived from no-observed-adverse-effect levels (NOAELs) extrapolated via factors. In practice, scientific procedures for GRAS may incorporate data on analogous substances sharing structural or functional similarities, provided extrapolations are justified by mechanistic reasoning and empirical correlations, but primary reliance remains on substance-specific studies to mitigate uncertainties in or . As of 2023, the FDA's GRAS notification inventory reflects this standard, with notices often detailing multi-study dossiers reviewed for adequacy, though self-affirmations bear the full evidentiary burden on the notifier without presumptive agency endorsement. This framework prioritizes causal evidence of safety over correlative observations, ensuring determinations withstand scrutiny from independent experts unbound by commercial interests.

Role of Expert Consensus and Historical Use

The GRAS status of a food substance hinges on the general recognition of its safety by qualified experts, typically those with expertise in , , , or related sciences, who evaluate publicly available demonstrating no significant risk under intended conditions of use. This expert consensus requires that the data—encompassing toxicological studies, metabolic profiles, dietary exposure estimates, and long-term usage patterns—be sufficiently robust and widely disseminated to support a collective judgment of , rather than mere opinion or proprietary findings. For instance, the FDA's regulations stipulate that such recognition must derive from scientific procedures yielding the same certainty as premarket food additive approvals, ensuring the substance is not a requiring . Expert panels, often convened by industry or independent bodies, play a central role in formalizing this by independently reviewing evidence against established safety benchmarks, such as no-observed-adverse-effect levels (NOAELs) from extrapolated to humans via uncertainty factors. The FDA has outlined best practices for these panels, emphasizing , documentation of methodologies, and of potential conflicts to uphold the "general" nature of recognition beyond any single entity's view. Historical FDA-affirmed GRAS substances, like those reviewed by the Select on GRAS Substances (SCOGS) from to 1980, exemplify this process, where expert reports affirmed safety for over 300 substances based on peer-reviewed data, leading to regulatory affirmations or affirmations of no objection. Complementing scientific consensus, historical use provides an evidentiary pathway for GRAS designation, particularly for substances in common use prior to January 1, 1958, where safety is inferred from extensive human exposure without evident harm, akin to empirical validation over decades. Under 21 CFR 570.30, such prior use must mirror current intended applications in type, amount, and to qualify, distinguishing it from novel exposures requiring modern data; examples include staples like , , , and , explicitly regarded as GRAS in 21 CFR 182.1 due to their longstanding dietary roles. This criterion acknowledges causal safety signals from -level experience, as seen in FDA's initial 1959 GRAS list compilation, but demands corroboration if post-1958 changes in production or use introduce uncertainties. The interplay of expert consensus and historical use ensures GRAS reflects both contemporary rigor and accumulated evidence, though the FDA cautions that historical reliance alone may not suffice amid evolving analytical capabilities, prompting periodic SCOGS-like re-evaluations for affirmed substances.

Conditions of Intended Use

The GRAS status of a substance applies specifically to its intended conditions of use in , meaning the safety evaluation must demonstrate a reasonable of no from under those precise parameters, rather than in isolation or under unspecified scenarios. These conditions encompass the technical effect provided by the substance (e.g., as a enhancer, , or nutrient), the categories in which it is incorporated (e.g., beverages, baked goods, or ), the maximum levels of incorporation, the duration and frequency of consumption, and the target population (e.g., general consumers or sensitive subgroups like infants). Failure to align actual use with these notified or self-affirmed conditions can render the substance subject to regulations, requiring premarket approval via petition. In GRAS self-affirmations or notifications to the FDA, proponents must provide scientific data—such as toxicological studies, exposure assessments, and dietary intake estimates—tailored to the proposed conditions, often using models like the maximum anticipated daily intake (MADI) or estimated daily intake (EDI) to quantify potential exposure. Expert panels evaluate whether the substance is safe at those levels, considering factors like metabolism, bioavailability, and potential interactions with other dietary components under real-world consumption patterns. For instance, a substance deemed GRAS for use at 0.1% in confectionery may not retain that status if reformulated for higher concentrations in infant foods, as altered exposure could elevate risks undetected in prior assessments. The specificity of intended use conditions stems from the statutory exemption in the Federal Food, Drug, and Cosmetic Act, where GRAS substances are excluded from definitions only insofar as qualified experts recognize their safety under those uses based on scientific procedures or prior common use in food before January 1, 1958. This requirement prevents overgeneralization of safety claims; for example, FDA has objected to GRAS conclusions where data failed to address subpopulation exposures or long-term cumulative effects under specified uses. Manufacturers bear responsibility for ongoing monitoring, as evolving dietary trends or new data could necessitate reevaluation or restriction if conditions deviate.

Determination Processes

Self-Affirmation Pathway

The pathway permits a manufacturer or other interested party to independently conclude that a substance is generally recognized as safe (GRAS) for its intended conditions of use in , without mandatory pre-market notification or by the U.S. (FDA). This process relies on the notifier establishing that qualified experts, informed by scientific training and experience, generally recognize the substance's safety, defined as reasonable certainty of no harm from intended use. Unlike approvals requiring FDA petitions under 21 U.S.C. § 348, GRAS leverages either rigorous scientific procedures or historical evidence of common use, bypassing formal agency evaluation while placing full evidentiary and legal responsibility on the sponsor. Eligibility under 21 CFR § 170.30 hinges on two primary bases: scientific procedures, which demand data and information of the same quantity, quality, and scope as for safety assessments—typically including toxicological studies, data, and dietary estimates derived from published studies, accepted scientific principles, or corroborated unpublished submissions—or common use in food prior to , 1958, supported by generally available historical records without needing equivalent scientific rigor. For the latter, safety derives from extensive consumption experience corroborated by independent surveys or analyses, though uses outside the U.S. may qualify if documented equivalently and notified to FDA under subpart E of 21 CFR part 170. The determination must account for specific intended conditions, such as levels, forms, and populations exposed, ensuring no subgroup vulnerabilities undermine general recognition. In execution, sponsors typically assemble a panel of independent, qualified —such as toxicologists, chemists, and exposure assessors with no financial conflicts tied to outcomes—to evaluate the totality of evidence, deliberate on potential biases, and document a affirming GRAS status. Best practices include establishing a written on expert selection to mitigate conflicts, providing panels with all relevant including concerns, and recording deliberations to reflect broader views rather than isolated opinions. Upon conclusion, the sponsor retains internal records of the evidence, expert opinions, and rationale, which must be available for FDA inspection but are not proactively submitted. This pathway contrasts with the voluntary GRAS notification program established in , where submitters provide FDA with detailed dossiers for review, potentially receiving a "no questions" response indicating concurrence or an objection letter if evidence proves inadequate, thus offering regulatory validation absent in self-affirmation. Self-affirmation facilitates expedited by avoiding delays from FDA queues—notification reviews averaged 90-180 days historically—but exposes firms to sole liability for unsubstantiated claims, with FDA retaining post-market authority to contest status through warnings, seizures, or rulemaking if data reveal risks or procedural flaws. As of October 2025, the pathway persists despite ongoing FDA proposals for mandatory notifications to enhance , underscoring its role in enabling while demanding rigorous, defensible internal validation.

FDA Notification and Review

The GRAS Notification Program, codified in 21 CFR part 170 subpart E following the final rule published on August 17, 2016 (81 FR 54960), provides a voluntary pathway for notifiers to inform the FDA of their determination that a substance is generally recognized as safe for a specific intended use in food. Under this program, a notifier—typically a manufacturer or expert panel—submits a comprehensive GRAS notice to the FDA's Office of Food Additive Safety, detailing the substance's identity, manufacturing process, intended conditions of use, estimated dietary exposure, and the basis for the GRAS conclusion, which must rely either on scientific procedures demonstrating safety or on a history of common use in food prior to 1958. The submission must include publicly available evidence supporting general recognition among qualified experts, often supplemented by toxicological studies, metabolism data, and dietary exposure assessments to establish a reasonable certainty of no harm from intended use. Pre-submission consultations with FDA are recommended to ensure completeness and address potential deficiencies. Upon receipt, the FDA acknowledges the notice in writing within 30 days, confirming the filing date and initiating to determine whether the provided substantiates the notifier's GRAS conclusion. The process involves assessing the scientific data for adequacy in demonstrating safety under the intended conditions, evaluating potential risks, and verifying general recognition through expert ; if the substance is intended for use in or products, the FDA consults the U.S. Department of Agriculture. While no statutory timeline mandates completion, the FDA adheres to proposed periods outlined in its 1997 interim policy (62 FR 18938), aiming for an initial assessment within 30 days and a full response thereafter, though actual durations vary based on notice complexity and workload. Notifiers may amend their notice during to address FDA inquiries, but if evaluation ceases at the notifier's request or upon withdrawal, the substance cannot be marketed under GRAS status without further action. Possible outcomes of the FDA's review include issuance of a letter stating "no questions," indicating concurrence with the GRAS determination and allowing the notifier to market the substance; a letter objecting due to insufficient basis for safety or general recognition; or modification of the notice's scope if concerns are limited to specific uses. The FDA maintains a public GRAS Notice Inventory tracking all submissions since the program's inception in , including responses, withdrawals, and ceased evaluations, to promote transparency without constituting formal approval or endorsement of safety. Even after a no-questions response, the FDA retains authority for post-market oversight, potentially revoking GRAS status if emerging scientific evidence indicates risks, as demonstrated by historical re-evaluations of substances like . This program, distinct from mandatory premarket approval for food additives, encourages voluntary FDA input while upholding the notifier's responsibility for GRAS self-affirmation.

FDA Affirmation and Objections

The FDA's GRAS affirmation process, established through rulemaking in 1972 following a comprehensive review of substances used in food prior to 1958, allowed interested parties to voluntarily petition the agency to affirm the GRAS status of a substance under specific conditions of use. Successful petitions resulted in the issuance of affirmative regulations listing the substance as GRAS, providing regulatory certainty but requiring significant agency resources for scientific review and public comment. By the late 1990s, the process had become burdensome, with FDA receiving few petitions amid evolving scientific data and limited staff capacity; in 1997, the agency proposed eliminating it in favor of a voluntary notification system to encourage industry self-determination while allowing FDA input. The 2016 final rule, effective January 2017, formally revoked the GRAS affirmation petition procedures under 21 CFR 570.35 (for animal ) and replaced them with the GRAS notification program codified at 21 CFR 170.36, marking the end of affirmative listings as the primary FDA mechanism for GRAS validation. Post-2016, FDA no longer accepts or processes GRAS affirmation petitions, though pre-existing affirmative regulations remain in effect unless amended or revoked based on new . This shift emphasized by qualified experts, with notifications serving as an optional pathway for FDA concurrence rather than formal approval. Under the current GRAS notification program, submitters inform FDA of their GRAS conclusion, and the agency may respond with a letter stating it has "no questions" if the notice appears to provide a sufficient basis for the determination, signaling no immediate objection but not constituting binding approval. FDA may object or withhold concurrence if data inadequacies, such as flawed exposure estimates or insufficient toxicological evidence, undermine the GRAS claim; for example, in GRN 000633 (2018), FDA did not concur with the notifier's use of micellar casein as a proxy for estimating intake of a casein-derived peptide mixture, citing potential underestimation of exposure. Such responses prompt notifiers to withdraw or amend notices, with FDA historically raising concerns in fewer than 20% of cases, often leading to voluntary withdrawals to avoid formal disagreement. If unresolved safety issues persist post-notification, FDA retains enforcement authority under the Federal Food, Drug, and Cosmetic Act to challenge uses deemed unsafe, regardless of prior GRAS self-determination.

Historical Development

Origins in Early Food Regulation

The framework for distinguishing safe food ingredients from hazardous additives emerged with the of June 30, 1906, which marked the first federal legislation to prohibit the interstate commerce of adulterated or misbranded foods and drugs. Sponsored by chemist Harvey W. Wiley and driven by exposés on toxic preservatives such as , , and in processed foods, the act defined adulteration as including any added poisonous or deleterious substance that might render the food injurious to health. Enforcement relied on post-market inspections and prosecutions rather than pre-approval, allowing common seasonings, spices, and naturally occurring components with historical safe use to evade scrutiny unless proven harmful. The Federal Food, Drug, and Cosmetic Act of 1938 built upon this foundation by expanding the adulteration definition to encompass any food containing a poisonous or deleterious substance in quantities making it injurious under normal conditions of use, while also requiring labels to declare artificial flavors, colors, or preservatives. This legislation, enacted amid public outcry over the disaster that killed over 100 consumers due to untested solvents, introduced mandatory safety demonstrations for new drugs but applied a less stringent standard to food additives, presuming safety for ingredients with established prior use absent evidence of harm. By 1938, the act had implicitly accommodated hundreds of traditional food components—such as salt, , and —through regulatory practice, without demanding toxicological data, as these were not viewed as novel risks comparable to emerging synthetics. These early statutes established a causal precedent for regulatory deference to empirical experience and expert judgment in assessing , prioritizing enforcement against demonstrable adulterants over blanket pre-market reviews. The 1938 act's use of "generally recognized" phrasing in safety evaluations for certain provisions foreshadowed later exemptions, as FDA officials like Commissioner George P. Larrick later attested, citing the successful processing of over 10,000 new drug applications since as validation of reliance on qualified rather than exhaustive testing for established substances. This approach reflected a pragmatic that long-term common use in , absent adverse outcomes, constituted evidence of innocuousness under typical consumption levels.

Post-1958 Amendments Evolution

Following the enactment of the Food Additives Amendment on September 6, 1958, the U.S. (FDA) promptly implemented the GRAS provision by publishing an initial list of substances generally recognized as safe in the on December 9, 1958, drawing from substances in common use prior to January 1, 1958, or supported by scientific evidence of safety. These were codified in 21 CFR Parts 182 (flavoring substances and general additives), 184 (direct food additives), and 186 (indirect additives), without initial comprehensive scientific review, as the amendment exempted such substances from premarket approval if expert consensus affirmed their safety under intended conditions of use. In 1959, the FDA further clarified GRAS status through regulatory listings, and throughout the 1960s, it issued opinion letters responding to industry inquiries on specific substances' eligibility, a practice later discontinued in 1970. The removal of cyclamates from the GRAS list in due to emerging concerns prompted President Nixon to direct a systematic of all GRAS substances, leading to the formation of the Select Committee on GRAS Substances (SCOGS) in under the Federation of American Societies for Experimental Biology (FASEB). SCOGS conducted reviews of over 400 substances from to 1982, issuing 151 reports that informed FDA decisions on , resulting in affirmations for substances like certain gums and salts, partial restrictions, or revocations where data indicated risks under prior uses. Concurrently, the FDA established a formal GRAS affirmation process in via (21 CFR 170.35), allowing industry petitions for affirmative determinations through or historical use, with affirmed statuses published in Parts 184 and 186. In 1976, the FDA refined GRAS criteria under 21 CFR 170.30, distinguishing determinations based on scientific procedures (yielding "current good manufacturing practice" levels) from those relying on pre-1958 common use in food, emphasizing that safety must be demonstrated for intended conditions without assuming perpetual exemption from evolving evidence. This was expanded in 1988 to include safe common use outside the U.S. as a basis for GRAS (21 CFR 170.30(c)(2)), broadening eligibility while requiring quantitative safety data. By the 1990s, the affirmation petition process proved cumbersome, with only 24 completions averaging 7.9 years each, prompting the FDA in 1997 to propose a voluntary notification procedure (62 FR 18938) to streamline self-affirmations by industry experts while allowing FDA review and objection, marking a shift from mandatory rulemaking to enhanced post-determination oversight.

Key Regulatory Milestones to 2025

The Food Additives Amendment of , enacted on September 6, established the GRAS exemption within the Federal Food, Drug, and Cosmetic Act, allowing substances used in prior to or deemed safe by qualified experts to bypass pre-market approval as food additives if their use met conditions of general recognition. On December 9, 1958, the FDA published its initial list of approximately 700 GRAS substances in the , drawing from expert evaluations and historical usage data to affirm safety without exhaustive toxicology testing for each. In the and , the FDA's Select Committee on GRAS Substances (SCOGS) conducted systematic reviews of listed ingredients, culminating in affirmations of GRAS status for over 150 substances by , based on available and safety data, while delisting others like cyclamates due to emerging concerns. This period marked a shift toward evidence-based affirmations, though SCOGS reviews ceased after as the FDA prioritized case-by-case determinations amid resource constraints. On April 17, 1997, the FDA proposed a voluntary notification for self-determined GRAS conclusions, aiming to enhance by inviting submissions for review without mandating pre-market clearance, a process finalized after public comment. In August 2016, the FDA issued the final rule (effective October 17, 2016) codifying the GRAS Notice program, standardizing submission requirements including safety data dossiers and expert consensus evidence, with the committing to responses within 180 days (extendable by 90 days) while maintaining the option for without notice. Guidance on April 23, 2010, from the FDA outlined best practices for GRAS self-determinations, emphasizing comprehensive toxicological, microbiological, and dietary exposure assessments to support expert agreement on safety. By 2020, the GRAS Notice inventory had processed over 1,000 submissions, with the FDA objecting to fewer than 10% based on insufficient safety evidence, underscoring the program's role in facilitating innovation while identifying gaps. In March 2025, HHS Secretary directed the FDA to explore rulemaking revising the GRAS pathway, citing concerns over unnotified self-affirmations potentially evading agency oversight, though the directive emphasized voluntary notifications' prior encouragement without mandating them. On September 9, 2025, the FDA announced a Notice of Proposed Rulemaking (NPRM) scheduled for October 2025 publication, proposing to eliminate unnotified self-affirmed GRAS determinations and require mandatory pre-market notifications for new uses, with revised criteria to ensure FDA review of safety data for substances not historically used in . This , projected for finalization in 2026, responds to petitions alleging regulatory loopholes but has drawn industry criticism for potentially delaying ingredient approvals without commensurate safety gains.

Enforcement Mechanisms

FDA Oversight and Compliance

The U.S. (FDA) oversees GRAS substances through a combination of voluntary pre-market notifications and post-market surveillance, rather than mandatory pre-approval, as GRAS status exempts these ingredients from the definition under section 201(s) of the Federal , Drug, and Cosmetic Act. Manufacturers bear primary responsibility for determining and documenting GRAS safety under intended conditions of use, either via expert panels or scientific data, but the FDA encourages submission of GRAS notices to facilitate agency review and public transparency. Upon receipt of a complete GRAS notice, the FDA conducts a safety assessment within 180 days (extendable by mutual agreement), evaluating whether the notifier's conclusion is supported by sufficient of general recognition among qualified experts. FDA responses to GRAS notices include "no questions," indicating the concurs with the conclusion or has no basis to question it; issuance of questions for clarification; or an objection if the do not support GRAS status, potentially requiring of the ingredient from the . As of September 2024, the FDA's GRAS Notice Inventory lists over 1,000 notices since 1998, with objections issued in fewer than 10 cases, reflecting a low rate of formal challenges but underscoring the voluntary nature of the program, where self-affirmed GRAS determinations without notification remain outside direct pre-market scrutiny. The maintains that GRAS substances must meet the same rigorous standard as approved additives, based on scientific procedures or prior safe use, to prevent adulteration. Post-market compliance is enforced through FDA inspections of food facilities, sampling and analysis of products, and monitoring of adverse events or scientific literature for emerging safety concerns. If a GRAS substance is misused, exceeds intended conditions, or is later found unsafe—evidenced by new data—the FDA can deem the food adulterated under section 402(a)(1), triggering enforcement actions such as warning letters, product seizures, injunctions, or recalls. Historical examples include FDA objections to certain self-affirmed GRAS uses, like potassium bromate in bread, where post-market evidence of carcinogenicity led to regulatory restrictions despite initial GRAS listings. The FDA's Office of Food Additive Safety coordinates these efforts, integrating GRAS oversight with broader food chemical safety programs, though critics note resource constraints limit proactive monitoring of the estimated thousands of self-affirmed GRAS ingredients in commerce. Compliance ultimately relies on industry adherence, with the FDA prioritizing high-risk violations through risk-based inspections conducted under the Food Safety Modernization Act of 2011.

Post-Market Revocations and Challenges

The U.S. (FDA) maintains authority to review substances marketed under GRAS determinations post-market, particularly when new safety data emerges or expert consensus shifts, potentially leading to findings that a substance does not meet GRAS criteria under the Federal Food, Drug, and Cosmetic Act. Such determinations classify the substance as an unapproved , subjecting it to enforcement actions including warning letters, product seizures, or injunctions. These reviews are typically initiated based on reports, , or targeted assessments rather than routine surveillance, reflecting resource constraints that limit systematic post-market oversight. A prominent example is partially hydrogenated oils (PHOs), long affirmed as GRAS for use in shortenings and margarines. In June 2015, the FDA issued a final determination that PHOs are not GRAS due to their content of trans fatty acids, which epidemiological studies linked to increased risk, including higher rates of coronary heart disease events. The agency set a date of June 18, 2018, extended to January 1, 2020, for full removal from foods, resulting in industry reformulation and near-elimination of PHOs from the U.S. market. This action revised prior GRAS affirmations for specific oils like and containing PHOs. Other post-market determinations have targeted substances self-affirmed or notified as GRAS but later deemed unsafe for food use, often novel botanicals or extracts. For instance, (Piper methysticum) received a 2002 FDA advisory on potential , followed by a 2020 memo confirming it is not GRAS due to risks of documented in clinical cases and studies. Similarly, tara flour, used as a thickener, was determined not GRAS in April 2024 after reports of esophageal obstructions and choking hazards in vulnerable populations. The FDA has issued such memos for approximately 15-20 substances historically, including betel nut () for oral cancer risks and () for insufficient safety data in food, underscoring that while revocations are infrequent, they address causal links to health harms established post-introduction. Challenges to GRAS status also arise from litigation, petitions, or state actions prompting FDA reassessment, though federal revocations remain rare owing to evidentiary burdens requiring demonstration of lack of among qualified experts. groups have petitioned for reviews of substances like certain synthetic flavors, citing animal , but FDA responses emphasize the need for human-relevant . Empirical indicate that most GRAS substances withstand post-market , with few instances of widespread harm, yet critics argue under-resourcing hampers proactive monitoring.

Recent Developments

GRAS Notice Updates 2023-2025

In 2023, the FDA received and reviewed multiple GRAS notices, issuing "FDA has no questions" letters indicating concurrence with the notifier's of for intended uses. Examples include GRN No. 1025, for which the letter was issued on January 6, 2023, and GRN No. 1094 on November 28, 2023. These responses followed the standard review process, where the agency evaluates scientific data on and may request additional information before closing the docket. Overall, from 2021 through 2023, 231 notices were submitted, with 117 receiving "no questions" letters, reflecting a of high concurrence rates—approximately 81% across the program's history—though approvals showed a declining trend in later years. The GRAS Notice Inventory expanded steadily in , with filings for diverse substances such as enzymes, polypeptides, and novel sweeteners. Notable entries included GRN No. 1171 for polypeptide produced by K-12 S9188 (October 22, 2024) and GRN No. 1167 for produced by Komagataella phaffii (date not specified in inventory summary but within 2024 filings). Approximately 57 notices were submitted that year, with 13 receiving "FDA has no questions" letters by early 2025, while 55 remained pending and 7 were ceased due to insufficient data or notifier withdrawal. The FDA's averaged around 75 notices annually during this period, focusing on dietary exposure estimates, toxicological data, and expert consensus. Through mid-2025, activity persisted, with GRN numbers reaching 1189 for dry whole (filed September 24, 2024) and GRN No. 1188 for D-psicose (November 19, 2024), among others involving galacturonase enzymes and fucosyllactose derivatives. Status updates covered 59 substances in the first half of 2025, including 34 "no questions" letters, 15 pending reviews, and 10 cessations. These notices primarily involved microbial-derived and hydrolyzed proteins, underscoring the program's role in facilitating innovation while relying on notifier-provided of under intended conditions of use. The , updated monthly, now exceeds 1,100 entries since the program's inception in 1998.

Proposed Rulemaking on Mandatory Notifications

In September 2025, the U.S. (FDA) included a notice of proposed (NPRM) in its Fall Unified Regulatory Agenda to amend the Generally Recognized as Safe (GRAS) regulations under 21 CFR parts and 570, shifting from voluntary to mandatory GRAS notifications for substances intended for use in human and animal food. The proposal, assigned Regulatory Identification Number (RIN) 0910-AJ02, targets the self-affirmed GRAS pathway, under which manufacturers currently determine a substance's GRAS status based on without required FDA pre-notification, allowing market entry prior to agency review. This reform would mandate submission of GRAS notices to FDA before commercialization, providing details on the substance's identity, intended use, and safety data, with FDA retaining authority to object if the determination lacks substantiation. The rulemaking builds on longstanding critiques of the voluntary GRAS notice program, established in , which has seen over 1,000 notices submitted by October 2023 but leaves an estimated thousands of self-affirmed GRAS uses undisclosed, potentially complicating FDA's oversight of safety. Exemptions under the proposal include substances already affirmed as GRAS by FDA or listed in regulations, prior-sanctioned ingredients, and certain processing aids, aiming to balance enhanced with minimal disruption to established uses. FDA plans to maintain and regularly update a inventory of GRAS notices and determinations, improving and enabling post-market surveillance, while clarifying that no objection from FDA constitutes "no questions" on the GRAS conclusion but does not equate to formal affirmation. As of October 2025, the NPRM is scheduled for publication in the , with a projected final rule in 2026 following public comment periods, amid broader regulatory shifts under the administration's emphasis on reforms. stakeholders anticipate increased compliance burdens, including data submission costs estimated in the millions for novel ingredients, though proponents argue it addresses gaps without halting , as evidenced by the program's historical low objection rate (fewer than 10% of notices challenged since ). The aligns with congressional , such as a 2025 Senate bill seeking similar mandatory notifications and GRAS pathway restrictions, reflecting empirical concerns over undisclosed additives linked to isolated safety incidents like uses.

Controversies and Debates

Criticisms of Self-Regulation as a Loophole

Critics contend that the self-affirmation pathway under GRAS regulations enables food manufacturers to unilaterally determine the safety of new substances without mandatory FDA notification or pre-market review, effectively creating a regulatory that circumvents statutory oversight intended for food additives under the Federal Food, Drug, and Cosmetic Act. This process allows companies to market ingredients based solely on internal expert evaluations, often funded by industry, raising concerns about inherent conflicts of interest and insufficient independent scrutiny. Advocacy organizations such as the argue that this self-regulation has permitted thousands of untested or minimally reviewed substances to enter the U.S. supply since the 1997 FDA guidance formalized , with no requirement for or FDA concurrence. A primary criticism centers on deficits, as self-affirmed GRAS ingredients—particularly aids—frequently evade ingredient labeling, leaving consumers and regulators unaware of their presence and cumulative risks. For instance, between 2000 and 2010, an estimated 1,000 new substances were self-affirmed as GRAS without FDA notification, according to analyses by groups like , potentially including compounds later scrutinized for endocrine disruption or carcinogenicity in international jurisdictions. Critics, including , highlight that this opacity has hindered post-market surveillance, as evidenced by cases where substances like certain flavorings were self-GRAS'd despite emerging data on respiratory toxicity in workers, only prompting voluntary withdrawals years later. Public health advocates further assert that the loophole incentivizes minimal safety testing to expedite market entry, prioritizing commercial interests over rigorous causal assessment of long-term effects such as or interactions in complex food matrices. has called for eliminating self-certification entirely, arguing it undermines the empirical foundation of GRAS by allowing determinations based on proprietary data rather than broadly disseminated . This perspective gained traction in 2025 when FDA leadership proposed to mandate notifications for all GRAS claims, implicitly acknowledging self-affirmation's role in evading additive requirements and enabling undisclosed introductions of novel chemicals. Such criticisms, often voiced by non-governmental organizations with environmental or mandates, emphasize systemic risks over isolated incidents, positing that the absence of pre-approval fosters a permissive for substances that might not withstand FDA's additive standards, which demand demonstration of reasonable certainty of no harm from lifetime exposure. However, these claims rely heavily on hypothetical exposures rather than documented outbreaks directly attributable to self-affirmed GRAS, reflecting a precautionary stance amid acknowledged challenges in attributing outcomes to specific additives.

Alleged Public Health Risks and Advocacy Claims

Critics of the GRAS self-affirmation pathway, including advocacy organizations such as the Center for Science in the Public Interest (CSPI) and the (EWG), contend that it functions as a regulatory permitting companies to introduce novel chemical additives into foods without mandatory FDA premarket safety reviews, potentially exposing consumers to undisclosed health hazards. CSPI has specifically argued that GRAS status should not apply to new synthetic ingredients or those flagged as potential risks by international bodies like the FAO/WHO Expert Committee on Food Additives, asserting that self-determinations by industry experts—often internal to the manufacturer—lack sufficient independence and transparency. Alleged risks highlighted by these groups include carcinogenicity, endocrine disruption, and contributions to chronic conditions such as , , and neurodevelopmental disorders, particularly in children, due to cumulative exposure from multiple GRAS substances in processed foods. For example, CSPI's 2024 report on flavoring chemicals identified hundreds of self-affirmed GRAS substances with limited or proprietary safety data, claiming that secretive formulations in products like cereals and snacks could include genotoxic compounds without public or regulatory scrutiny. EWG has pointed to instances where GRAS-designated additives, such as certain emulsifiers and preservatives, are linked in preliminary studies to gut alterations and , though causal mechanisms remain under investigation. Peer-reviewed analyses have amplified these concerns, noting that between 1997 and 2019, over 1,000 GRAS notices were submitted to the FDA, with approximately 30% relying solely on company-internal expert opinions, potentially bypassing rigorous toxicological testing for long-term effects like or allergenicity. The Natural Resources Defense Council (NRDC) and Breast Cancer Prevention Partners have alleged that this opacity enables additives with suspected links to hormone-related cancers, citing epidemiological correlations between dietary chemical exposures and incidence, though they emphasize the need for mandatory disclosure to enable independent verification. Advocacy efforts, including lawsuits and petitions to the FDA, demand the elimination of self-affirmed GRAS in favor of required premarket approvals akin to petitions, arguing that the current system has allowed an estimated 10,000 undisclosed GRAS uses since 1997, undermining public confidence and epidemiological tracking of diet-related harms. and have claimed this framework prioritizes industry speed over safety, with historical examples like the delayed scrutiny of —a GRAS substance later linked to renal carcinogenicity in animal models—illustrating purported failures. These groups, often aligned with precautionary regulatory approaches, maintain that without reform, vulnerable populations face elevated risks from bioaccumulative or synergistic effects untested in real-world consumption patterns.

Empirical Safety Record and Industry Benefits

The empirical safety record of GRAS substances demonstrates a low incidence of post-market safety failures relative to the volume of approvals and uses. The FDA's Select Committee on GRAS Substances reviewed over 370 substances between 1972 and 1980, concluding that most met contemporary safety standards for intended food uses based on toxicological, metabolic, and exposure data. Since the inception of the voluntary GRAS notification program in 1997, the FDA has processed over 1,100 notices as of 2024, with the agency issuing "no questions" letters—indicating concurrence with the notifier's GRAS determination—in the substantial majority of cases, while objections remain exceptional and typically tied to insufficient data rather than inherent toxicity. Revocations of GRAS status are infrequent; one prominent case involved partially hydrogenated oils in 2015, after accumulated epidemiological evidence linked trans fats to elevated cardiovascular disease risk, prompting a phase-out to avert an estimated thousands of heart attacks annually. Population-level data further supports this record, with adverse reactions to food additives, encompassing GRAS substances, occurring in less than 1% of adults and showing no causal patterns of widespread harm attributable to self-affirmed GRAS uses. For self-affirmed GRAS determinations—those not submitted for FDA notification—the absence of mandatory reporting limits direct tracking, yet the lack of documented outbreaks or epidemics linked to these substances underscores the framework's causal efficacy in filtering unsafe candidates via expert consensus and scientific procedures. Historical safe use prior to , which forms the basis for many GRAS affirmations, has similarly yielded no retrospective evidence of systemic risks when exposures align with intended conditions. Critics, including groups, highlight potential underreporting of long-term effects, but empirical through systems like the FDA's reporting shows no disproportionate signals from GRAS ingredients compared to baseline -related incidents. The GRAS process confers significant benefits to the by streamlining regulatory compliance and fostering innovation. Self-affirmation allows firms to introduce scientifically vetted substances—such as enzymes, flavors, and fortificants—without awaiting FDA premarket clearance, which can span years for petitions, thereby reducing development timelines and costs by up to 50% in some estimates. This efficiency has enabled over 600 GRAS notices for human uses alone by , facilitating substitutions for less safe alternatives and expanding product variety in categories like low-calorie sweeteners and preservatives. By prioritizing expert-driven assessments over bureaucratic hurdles, GRAS has historically accelerated market entry for safe innovations, supporting in the sector without compromising the overall integrity of the supply.

Broader Impacts

Effects on Innovation and Market Entry

The GRAS framework, particularly through self-affirmation, substantially lowers regulatory barriers for introducing new ingredients, enabling manufacturers to leverage expert on safety without awaiting FDA premarket approval, unlike the petition that often spans multiple years. This has positioned self-affirmed GRAS as the predominant pathway for entry, with companies conducting internal safety assessments based on toxicological , usage levels, and exposure estimates to affirm general recognition among qualified experts. By contrast, formal GRAS notices submitted voluntarily to the FDA, numbering over 1,200 since the program's in 1997, provide optional agency feedback but still allow conditional use pending review, further streamlining entry compared to additive approvals that require exhaustive FDA clearance. This accelerated access has empirically driven by incentivizing investment in novel substances, such as microbial proteins, botanical extracts, and flavor enhancers, where self-GRAS determinations can reduce timelines from years to months, fostering rapid iteration and commercialization in competitive sectors like functional foods and nutraceuticals. For instance, recent self-affirmations have enabled launches of fungi-based proteins, demonstrating how the pathway supports diverse applications without prohibitive delays, thereby enhancing responsiveness to demands for fortified or sustainable ingredients. stakeholders attribute the proliferation of over 10,000 estimated self-affirmed GRAS uses—far exceeding notified cases—to this flexibility, which mitigates financial risks for smaller firms and promotes R&D in areas like low-calorie sweeteners and preservatives. However, ongoing proposals to curtail self-affirmation in favor of mandatory notifications could extend time-to-market and elevate costs for safety dossiers and expert consultations, disproportionately affecting innovation among resource-constrained entities and potentially consolidating market power with larger players capable of absorbing regulatory burdens. Analyses indicate that such shifts might delay product launches by 6-18 months or more, based on current notice review cycles averaging 75-100 annually, thereby dampening incentives for exploratory ingredient development and limiting consumer access to emerging technologies. Empirical precedents from stricter regimes, like full additive petitions requiring 2-5 years of data compilation and review, underscore how GRAS's lighter touch has historically sustained a dynamic pipeline of safe, innovative additives without commensurate safety trade-offs in practice.

Public Health Outcomes and Economic Considerations

The GRAS designation has facilitated the introduction of numerous food ingredients without documented outbreaks or widespread adverse health events attributable to the notification or self-affirmation processes since the voluntary GRAS notice program began in 1997. The U.S. Food and Drug Administration (FDA) has reviewed over 1,000 GRAS notices as of 2023, objecting to safety conclusions in only six cases and requesting withdrawal in a handful more, with no subsequent crises linked to approved uses. Expert panels required for GRAS determinations rely on publicly available toxicological data and scientific procedures, mirroring standards for food additives, which has contributed to a safety profile where substances achieve consensus recognition based on of low under intended conditions. While historical GRAS affirmations, such as partially hydrogenated oils, were later reevaluated and restricted due to risks identified through long-term epidemiological studies, the modern notice system incorporates iterative safety assessments, with FDA maintaining authority for post-market revocation. Economically, the GRAS pathway reduces regulatory burdens compared to the food additive petition process, which can cost $1–5 million and require 2–5 years for FDA review and rulemaking, whereas GRAS self-affirmations or notices typically involve $100,000–500,000 in expert consultations and data compilation, enabling market entry in months. This efficiency has supported innovation in the food sector, allowing smaller firms and startups to introduce novel ingredients like natural flavors or processing aids without prohibitive upfront expenses, thereby fostering product diversity and consumer access to fortified or preserved foods. Industry analyses indicate that GRAS exemptions contribute to annual economic value through accelerated commercialization, estimated to save the sector hundreds of millions in compliance costs while aligning with market-driven safety incentives, though critics from advocacy groups argue it may underfund FDA oversight. Overall, the program's structure promotes causal efficiency in resource allocation, prioritizing substances with demonstrated safety data over blanket pre-approvals, which has correlated with sustained growth in the U.S. food additive market valued at over $40 billion in 2023.