GRAS Determination in the USA: FDA Requirements and Regulatory Pathway
In the United States, substances intentionally added to food are regulated as food additives and must be demonstrated to be safe for their intended use, and subject to premarket review and approval by the USFDA, unless they qualify as Generally Recognized as Safe (GRAS). A GRAS determination is a science-based regulatory pathway grounded in toxicological evidence and expert evaluation. While submission of a GRAS Notice to the FDA is voluntary, the legal responsibility for ensuring ingredient safety always remains with the manufacturer or distributor.
To be considered GRAS, the safety of a substance must be generally recognized among qualified experts under the conditions of its intended use, either through generally accepted scientific procedures or through a substantial documented history of common use in food prior to 1958.
What GRAS Means Under U.S. Law
Under U.S. law, a substance is considered GRAS if it is generally recognized, among qualified experts, as having been adequately demonstrated to be safe under the conditions of its intended use.
This recognition must be based on one of two types of evidence:
Scientific procedures, which rely on publicly available and well-controlled toxicological and safety studies that are generally accepted, or
Common use in food, where a long history of consumption in the U.S. prior to 1958 can be documented and shown to be safe.
Unlike food additives, which require formal FDA approval before they can be legally used, a GRAS substance may be marketed based on the company’s independent safety conclusion. However, the underlying evidence must support a “reasonable certainty of no harm” under the intended conditions of use - the same legal safety standard that applies to approved food additives.
In short, a GRAS conclusion must be scientifically defensible, transparent, and supported by a robust toxicological and exposure assessment record that can withstand FDA review, commercial due diligence, and post-market scrutiny.
The Role of Toxicology in GRAS Safety Assessment
Toxicology is central to demonstrating that a substance is safe at its intended levels of use. A GRAS determination is not based solely on the identity of the ingredient, but on a scientific comparison between anticipated human exposure and the levels at which adverse effects may occur.
Key toxicological elements typically include:
Hazard identification, to characterize potential adverse effects across relevant biological systems.
Dose–response evaluation, to understand how toxicity changes with increasing exposure.
Safety margin estimation, to define the separation between human exposure and effect levels observed in studies.
Assessment of sensitive populations, such as children, pregnant individuals, or individuals with high dietary exposure.
Together, these evaluations form the scientific basis for concluding that an ingredient can be consumed safely under its intended conditions of use. Without robust toxicological evidence, a GRAS conclusion lacks scientific defensibility and may not withstand regulatory or commercial review.
Pathways to a GRAS Determination
In the United States, there are two recognized pathways for establishing GRAS status for a food ingredient: GRAS self-determination and Voluntary FDA GRAS notification. Both pathways rely on the same scientific standard of general recognition of safety among qualified experts, but they differ in regulatory interaction and external review.
GRAS Self-Determination
Under this pathway, an organization independently concludes that its ingredient is GRAS based on a comprehensive scientific evaluation. The conclusion is typically supported by a formal GRAS dossier that includes toxicological, exposure, and regulatory assessments conducted or reviewed by qualified experts.
While no submission to the FDA is required, the manufacturer or distributor retains full legal responsibility for the safety of the ingredient. The organization must be prepared to provide its supporting data, expert opinions, and safety rationale to the FDA upon request to substantiate the GRAS conclusion.
Voluntary FDA GRAS Notification
Under this pathway, an organization submits a GRAS Notice to the FDA for review. The FDA evaluates whether the notice provides an adequate basis for the notifier’s GRAS conclusion and may issue one of three responses:
A letter stating the agency has no questions regarding the GRAS conclusion
A notice that the FDA has ceased to evaluate the submission
A response indicating that the notice does not provide a sufficient basis for a GRAS determination
Although this pathway is voluntary, many companies choose FDA notification to demonstrate regulatory transparency, support commercial confidence, and strengthen defensibility in the event of regulatory or market scrutiny.
Common Scientific and Regulatory Challenges
GRAS determinations often encounter scientific and regulatory challenges, particularly for novel, complex, or biotech-derived ingredients. Common issues include:
Limited toxicology data for new substances, fermentation-derived materials, or structurally complex ingredients
Reliance on outdated, unpublished, or non-GLP safety studies that may not meet current scientific or regulatory expectation
Insufficient characterization of manufacturing impurities, residuals, or reaction by-product
Lack of independent expert review to support general recognition of safety among qualified experts
Inadequate dietary exposure assessment that does not reflect realistic consumption patterns or cumulative intake
Misalignment between intended conditions of use and the supporting toxicological evidence
A toxicology-led approach anticipates these gaps early in development and helps ensure that the GRAS conclusion remains scientifically defensible, regulator-ready, and resilient under both regulatory and commercial scrutiny.
How GRAS Determinations Support Faster U.S. Market Entry
A well-structured GRAS determination can significantly reduce the time required to bring a food ingredient to the U.S. market compared to the formal food additive approval process. By establishing safety through generally accepted scientific procedures and realistic dietary exposure assessments, organizations can move forward with commercialization while maintaining regulatory confidence.
For international manufacturers and innovative brands, a robust GRAS dossier also serves as a regulatory “bridge” to the U.S. market. Documentation aligned with FDA expectations and internationally recognized toxicology principles helps reduce follow-up questions, supports customer and partner due diligence, and facilitates downstream regulatory acceptance in other jurisdictions.
When executed correctly, a GRAS determination becomes more than a compliance exercise. It demonstrates scientific accountability, strengthens commercial credibility, and supports responsible innovation while protecting consumer safety.
Conclusion
GRAS determination in the United States is both a regulatory pathway and a scientific responsibility. Whether pursued through self-determination or voluntary FDA notification, the process demands rigorous toxicological evaluation, realistic exposure assessment, and transparent documentation. By embedding safety science at the center of regulatory strategy, companies can protect consumers, strengthen regulatory confidence, and support successful market entry for food ingredients in a highly scrutinized regulatory environment.
FAQs – GRAS Determination in the USA
When is FDA GRAS notification recommended instead of self-determination?
FDA notification is often recommended for novel ingredients, high-exposure uses, international market entry, or when commercial partners, investors, or customers require formal regulatory transparency.
Is submitting a GRAS Notice to the FDA mandatory?
No. GRAS determinations can be self-determined by organization, while the manufacturer or distributor retains full legal responsibility for the safety of the ingredient. Submitting a GRAS Notice to the FDA is voluntary and can provide regulatory transparency.
What kind of evidence supports a GRAS conclusion?
Scientific procedures require the same quantity and quality of evidence that would support food additive approval, including toxicology, pharmacokinetic, and exposure data.
How long does it take for the FDA to respond to a GRAS Notice?
The FDA typically aims to respond within 180 days, although this period may be extended if additional information or clarification is required.
How does a GRAS determination differ from a New Dietary Ingredient (NDI) notification?
NDI (New Dietary Ingredient) applies to ingredients intended for use in dietary supplements, while GRAS (Generally Recognized as Safe) applies to ingredients used in common foods. An NDI must be submitted to the FDA for premarket review before marketing. In contrast, a GRAS determination can be made through self-determination or voluntary FDA notification, meaning FDA submission is optional, although the manufacturer remains fully responsible for the ingredient’s safety.
