GRAS Notice: In-Depth Interpretation of the Critical Elements Across the Seven Dossier Modules

GRAS stands for Generally Recognized As Safe. It is the US FDA's primary framework for managing the safety of food ingredients. To obtain GRAS status, a company must compile a complete English‑language GRAS dossier and have it independently reviewed by a qualified panel of experts, who must reach a consensus on the ingredient’s safety. The dossier is a technical compilation that systematically explains the substance’s characteristics and its safety for consumption. Under 21 CFR Part 170 Subpart E, a GRAS notice must contain seven statutory parts.

Drawing on our years of project experience, the CIRS Group food team has summarized the critical preparation points for each of the seven parts.

Part 1 – Sign statements and commitments

Provide the company’s details, the substance under review, intended uses, and the basis for the GRAS conclusion. An authorized representative must sign statements attesting to the accuracy, completeness, and confidentiality of the materials.

Part 2 – Substance identification, manufacturing process, specifications, and physical/technical effects

Because GRAS hinges on demonstrating that every component of the substance (principal constituents and impurities alike) is safe under the intended conditions of use, businesses must thoroughly document basic attributes:

• Identification – Give the chemical name, molecular formula, structural formula, CAS No., etc. Include appropriate identification methods and results to confirm the substance’s identity. For biosynthetically produced materials, detail the production strain, key enzymes, and biosynthetic pathway.
• Manufacturing process – Describe raw‑material sources, processing steps, and purification in detail, supported by a narrative and a flow diagram. If genetic engineering is involved, fully explain its safety aspects. Transparent disclosure helps verify process reliability and product consistency.
• Quality specifications & test reports – Establish an authoritative specification (sensory properties; physicochemical parameters such as purity, moisture, ash) and impurity limits for heavy metals, residual solvents, microbes, mycotoxins, etc. Provide at least three non‑consecutive batch COAs.
• Physical/technical effects – Explain any functional effect in food (antioxidant, preservative, emulsifier, etc.) and demonstrate that use will not adversely affect food quality or safety.

Part 3 – Dietary exposure assessment

Estimate intake based on intended use levels, target populations, and all dietary sources of the substance, citing food‑consumption data and assumptions.

CIRS recommends using the latest consumption databases and validated exposure models. If data are scarce, analogous‑substance data may be referenced, but the choice must be fully justified.

Part 4 – Self‑limiting levels of use

Discuss whether inherent properties of the substance (such as solubility, flavor threshold, and processing constraints) naturally limit its level in food, supporting the reasonableness of the proposed use level.

Part 5 – Pre‑1958 history of use in food

Describe evidence of consumption before January 1, 1958. If robust documentation shows the substance was widely eaten by a substantial portion of the US population before that date, it can establish GRAS status. Historical evidence outside the US can also be cited, but such cases are rare; most modern GRAS determinations rely on scientific procedures rather than historical use.

Part 6 – Safety narrative

The safety assessment must be built on publicly available data, demonstrating that the substance is safe under its intended conditions of use. Any unpublished study data may be cited only as supporting evidence. Typical elements include:

• Toxicology studies – These form the backbone of the safety data and include, but are not limited to, genetic toxicity tests and sub‑chronic toxicity studies (e.g., 90‑day oral studies).
• ADME / kinetic studies – Investigations of absorption, digestion, distribution, metabolism, and excretion.
• Human clinical data.
• Allergenicity assessment – Required if the substance or its raw materials may contain protein allergens. Novel proteins generally need a comprehensive analysis combining literature review, reported reactions, and bioinformatic predictions.

Effectively leveraging published safety studies to underpin the GRAS conclusion is the key of the safety narrative. CIRS advises that, for novel food ingredients lacking adequate public data, businesses should plan toxicology studies early, publish the results in peer‑reviewed journals, and thereby ensure robust evidence is available when the GRAS dossier is assembled.

Part 7 – List of supporting data and information

Provide a complete bibliography (journal articles, test reports, patents, etc.) of all references cited in Module 6, clearly indicating which are public and which are non‑public.

By structuring the dossier around these seven modules, businesses can ensure that the GRAS submission is both scientifically sound and compliant.

Warm Reminder: The technical‑justification points differ markedly from one ingredient to another. Businesses must follow the regulatory requirements, give full consideration to the substance’s characteristics, carry out feasibility analyses in advance, and develop and execute their GRAS strategy with professional guidance to guarantee the dossier’s quality and credibility.

About Us

The Food Division of CIRS Group was established in 2012 and it has a professional team specializing in US GRAS notice. The CIRS Food Division has extensive experience in various fields, covering GRAS, new food ingredients, new food additives, food contact materials, synthetic biology foods, EU Novel Foods, dietary supplements, and special dietary foods.

CIRS operates a fully-owned subsidiary in the US. By leveraging the expertise of the CIRS USA and the international team, it is able to provide enterprise various US food services, including but not limited to:

• US FDA GRAS Notice;
• US FDA Dietary Supplement Structure/Function Claim Notification;
• US New Dietary Ingredient (NDI) Notification;
• US FDA Registration of Food Facilities; and
• US Food Label/Advertisement Information Review.

If you need any assistance or have any questions, please get in touch with us via service@cirs-group.com.