CFR Subpart E

CFR Subpart E
in effect

21 C.F.R. § 570.203 Definitions.

The definitions and interpretations of terms in § 570.3 apply to such terms when used in this subpart. The following definitions also apply: Amendment means any data and information that you submit regarding a filed GRAS notice before we respond to your notice by letter in accordance with § 570.265(b)(1) or cease to evaluate your notice in accordance with § 570.265(b)(3). GRAS means generally recognized as safe. GRAS notice means a submission that informs us of your view that a substance is not subject to the premarket approval requirements of the Federal Food, Drug, and Cosmetic Act based on your conclusion that the substance is GRAS under the conditions of its intended use in accordance with § 570.30. Notified substance means the substance that is the subject of your GRAS notice. Notifier means the person (e.g., an individual, partnership, corporation, association, or other legal entity) who is responsible for the GRAS notice, even if another person (such as an attorney, agent, or qualified expert) prepares or submits the notice or provides an opinion about the basis for a conclusion of GRAS status. Qualified expert means an individual who is qualified by scientific training and experience to evaluate the safety of substances under the conditions of their intended use in animal food. Supplement means any data and information that you submit regarding a filed GRAS notice after we respond to your notice by letter in accordance with § 570.265(b)(1) or cease to evaluate your notice in accordance with § 570.265(b)(3). We, our, and us refer to the United States Food and Drug Administration (FDA). You and your refer to a notifier.

21 C.F.R. § 570.205 Opportunity to submit a GRAS notice.

Any person may notify FDA of a view that a substance is not subject to the premarket approval requirements of section 409 of the Federal Food, Drug, and Cosmetic Act based on that person's conclusion that the substance is GRAS under the conditions of its intended use.

21 C.F.R. § 570.210 How to send your GRAS notice to FDA.

(a) Send your GRAS notice to the Division of Animal Feeds (HFV-220), Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish Pl., Rockville, MD 20855. (b) When you submit your GRAS notice, you may do so either in an electronic format that is accessible for our evaluation or on paper. If you send your GRAS notice on paper, a single paper copy is sufficient.

21 C.F.R. § 570.215 Incorporation into a GRAS notice.

You may incorporate into your GRAS notice either specifically identified data and information that you previously submitted to the Center for Veterinary Medicine (CVM), or specifically identified publicly available data and information submitted by another party, when such data and information remain in CVM's records, such as data and information contained in a previous GRAS notice or a food additive petition.

21 C.F.R. § 570.220 General requirements applicable to a GRAS notice.

(a) A GRAS notice has seven parts as required by §§ 570.225 through 570.255. You must submit the data and information specified in each of these parts on separate pages or sets of pages. (b) You must include each of the seven parts in your GRAS notice. If you do not include a part, you must include with your GRAS notice an explanation of why that part does not apply to your GRAS notice.

21 C.F.R. § 570.225 Part 1 of a GRAS notice: Signed statements and certification.

(a) Part 1 of your GRAS notice must be dated and signed by a responsible official of your organization, or by your attorney or agent. (b) Except as required by paragraph (c)(8) of this section, you must not include any information that is trade secret or confidential commercial information in Part 1 of your GRAS notice. (c) In Part 1 of your GRAS notice, you must: (1) Inform us that you are submitting a GRAS notice in accordance with this subpart; (2) Provide the name and address of your organization; (3) Provide the name of the notified substance, using an appropriately descriptive term; (4) Describe the intended conditions of use of the notified substance, including stating whether the substance will be added to food (including drinking water) for animals in which the substance will be used; identifying the foods to which it will be added, the levels of use in such foods, and the animal species for which these foods are intended (including, when appropriate, a description of a subpopulation expected to consume the notified substance); and the purposes for which the substance will be used; (5) Inform us of the statutory basis for your conclusion of GRAS status (i.e., through scientific procedures in accordance with § 570.30(a) and (b) or through experience based on common use in animal food in accordance with § 570.30(a) and (c)); (6) State your view that the notified substance is not subject to the premarket approval requirements of the Federal Food, Drug, and Cosmetic Act based on your conclusion that the notified substance is GRAS under the conditions of its intended use; (7) State that, if we ask to see the data and information that are the basis for your conclusion of GRAS status, either during or after our evaluation of your notice, you will: (i) Agree to make the data and information available to us; and (ii) Agree to both of the following procedures for making the data and information available to us: (A) Upon our request, you will allow us to review and copy the data and information during customary business hours at the address you specify for where these data and information will be available to us; and (B) Upon our request, you will provide us with a complete copy of the data and information either in an electronic format that is accessible for our evaluation or on paper; (8) State your view as to whether any of the data and information in Parts 2 through 7 of your GRAS notice are exempt from disclosure under the Freedom of Information Act, 5 U.S.C. 552 (e.g., as trade secret or as commercial or financial information that is privileged or confidential); (9) Certify that, to the best of your knowledge, the GRAS notice is a complete, representative, and balanced submission that includes unfavorable information, as well as favorable information, known to you and pertinent to the evaluation of the safety and GRAS status of the use of the substance; and (10) State both the name and the position or title of the person who signs the GRAS notice.

21 C.F.R. § 570.230 Part 2 of a GRAS notice: Identity, method of manufacture, specifications, and physical or technical effect.

In Part 2 of your GRAS notice, you must include: (a) Scientific data and information that identifies the notified substance. (1) Examples of appropriate data and information include the chemical name, applicable registry numbers (such as a Chemical Abstracts Service (CAS) registry number or an Enzyme Commission (EC) number), empirical formula, structural formula, quantitative composition, and characteristic properties. (2) When the source of a notified substance is a biological material, you must include data and information sufficient to identify: (i) The taxonomic source (e.g., genus, species), including as applicable data and information at the sub-species level (e.g., variety, strain); (ii) The part of any plant or animal used as the source; and (iii) Any known toxicants that could be in the source; (b) A description of the method of manufacture of the notified substance in sufficient detail to evaluate the safety of the notified substance as manufactured; (c) Specifications for material that is of appropriate grade for use in animal food; and (d) When necessary to demonstrate safety, relevant data and information bearing on the physical or other technical effect the notified substance is intended to produce, including the quantity of the notified substance required to produce such effect.

21 C.F.R. § 570.235 Part 3 of a GRAS notice: Target animal and human exposures.

In part 3 of your GRAS notice, you must provide data and information about exposure to the target animal and to humans consuming human food derived from food-producing animals, regardless of whether your conclusion of GRAS status is through scientific procedures or through experience based on common use in food, as follows: (a) For exposure to the target animal, you must provide: (1) The amount of the notified substance that different target animal species are likely to consume in the animal food (including drinking water) as part of the animal's total diet, including the intended use and all other sources in the total diet; and (2) When applicable, the amount of any other substance that is expected to be formed in or on food because of the use of the notified substance (e.g., hydrolytic products or reaction products); (3) When applicable, the amount of any other substance that is present with the notified substance either naturally or due to its manufacture (e.g., contaminants or by-products); (4) The data and information you rely on to establish the amount of the notified substance and the amounts of any other substance in accordance with paragraphs (a)(1) through (a)(3) of this section that different target animal species are likely to consume in the animal food (including drinking water) as part of the animal's total diet; and (b) When the intended use is in food for food-producing animals, you must provide: (1) The potential quantities of any residues that humans may be exposed to in edible animal tissues, including: (i) Residues of the notified substance; (ii) Residues of any other substance that is expected to be formed in or on the animal food because of the use of the notified substance; and (iii) Residues from any other substance that is present with the notified substance whether naturally, due to its manufacture (e.g., contaminants or by-products), or produced as a metabolite in edible animal tissues when the notified substance is consumed by a food-producing animal; and (2) The data and information you rely on to establish, in accordance with paragraph (b)(1) of this section, the potential quantities of any residues that humans may be exposed to in edible animal tissues.

21 C.F.R. § 570.240 Part 4 of a GRAS notice: Self-limiting levels of use.

In circumstances where the amount of the notified substance that can be added to animal food is limited because animal food containing levels of the notified substance above a particular level would become unpalatable or technologically impractical, in Part 4 of your GRAS notice you must include data and information on such self-limiting levels of use.

21 C.F.R. § 570.245 Part 5 of a GRAS notice: Experience based on common use in food before 1958.

If the statutory basis for your conclusion of GRAS status is through experience based on common use in animal food, in Part 5 of your GRAS notice you must include evidence of a substantial history of consumption of the notified substance for food use by a significant number of animals of the species to which the substance is intended to be fed prior to January 1, 1958, and evidence of a substantial history of consumption by humans consuming human foods derived from food-producing animals prior to January 1, 1958.

21 C.F.R. § 570.250 Part 6 of a GRAS notice: Narrative.

In Part 6 of your GRAS notice, you must include a narrative that provides the basis for your conclusion of GRAS status, in which: (a)(1) You must explain why the data and information in your notice provide a basis for your view that the notified substance is safe under the conditions of its intended use for both the target animal and for humans consuming human food derived from food-producing animals. In your explanation, you must address the safety of the notified substance, considering all animal food (including drinking water) as part of the animal's total diet, taking into account any chemically or pharmacologically related substances in such diet. In your explanation, you must also address the safety of the notified substance in regard to human exposure, considering all dietary sources and taking into account any chemically or pharmacologically related substances; (2) In your explanation, you must identify what specific data and information that you discuss in accordance with paragraph (a)(1) of this section are generally available, and what specific data and information that you discuss in accordance with paragraph (a)(1) of this section are not generally available, by providing citations to the list of data and information that you include in Part 7 of your GRAS notice in accordance with § 570.255; (b) You must explain how the generally available data and information that you rely on to establish safety in accordance with paragraph (a) of this section provide a basis for your conclusion that the notified substance is generally recognized, among qualified experts, to be safe under the conditions of its intended use for both the target animal and for humans consuming human food derived from food-producing animals; (c) You must either: (1) Identify, discuss, and place in context, data and information that are, or may appear to be, inconsistent with your conclusion of GRAS status, regardless of whether those data and information are generally available; or (2) State that you have reviewed the available data and information and are not aware of any data and information that are, or may appear to be, inconsistent with your conclusion of GRAS status; (d) If you view any of the data and information in your notice as exempt from disclosure under the Freedom of Information Act, you must identify the specific data and information; and (e) For non-public, safety-related data and information considered in reaching a conclusion of GRAS status, you must explain how there could be a basis for a conclusion of GRAS status if qualified experts do not have access to such data and information.

21 C.F.R. § 570.255 Part 7 of a GRAS notice: List of supporting data and information in your GRAS notice.

(a) In part 7 of your GRAS notice, you must include a list of all of the data and information that you discuss in Part 6 of your GRAS notice to provide a basis for your view that the notified substance is safe under the conditions of its intended use as described in accordance with § 570.250(a)(1). (b) You must specify which data and information that you list in accordance with paragraph (a) of this section are generally available, and which data and information are not generally available.

21 C.F.R. § 570.260 Steps you may take before FDA responds to your GRAS notice.

(a) You may submit a timely amendment to your filed GRAS notice, to update your GRAS notice or in response to a question from us, before we respond to your notice by letter in accordance with § 570.265(b)(1) or cease to evaluate your notice in accordance with § 570.265(b)(3). (b) At any time before we respond to your notice by letter in accordance with § 570.265(b)(1), you may request in writing that we cease to evaluate your GRAS notice. Your request does not preclude you from submitting a future GRAS notice in accordance with this subpart with respect to the notified substance.

21 C.F.R. § 570.265 What FDA will do with a GRAS notice.

(a)(1) We will conduct an initial evaluation of your submission to determine whether to file it as a GRAS notice for evaluation of your view that the notified substance is GRAS under the conditions of its intended use. (2) If we file your submission as a GRAS notice, we will send you a letter that informs you of the date of filing. (3) If we do not file your submission as a GRAS notice, we will send you a letter that informs you of that fact and provide our reasons for not filing the submission as a GRAS notice. (4) We will consider any timely amendment that you submit to a filed GRAS notice, to update your GRAS notice or in response to a question from us, before we respond to you by letter in accordance with paragraph (b)(1) of this section, if we deem that doing so is feasible within the timeframes established in paragraph (b) of this section. If we deem that considering your amendment is not feasible within the timeframes established in paragraph (b) of this section or if we have granted your request to cease to evaluate your notice, we will inform you that we are not considering your amendment. (b)(1) Within 180 days of filing, we will respond to you by letter based on our evaluation of your notice. We may extend the 180 day timeframe by 90 days on an as needed basis. (2) If we extend the timeframe, we will inform you in writing of the extension as soon as practicable but no later than within 180 days of filing. (3) If you ask us to cease to evaluate your GRAS notice in accordance with § 570.260(b), we will send you a letter informing you of our decision regarding your request. (c) If circumstances warrant, we will send you a subsequent letter about the notice.

21 C.F.R. § 570.275 Public disclosure of a GRAS notice.

(a) The data and information in a GRAS notice (including data and information submitted in any amendment or supplement to your GRAS notice, or incorporated into your GRAS notice) are: (1) Considered a mandatory, rather than voluntary, submission for purposes of their status under the Freedom of Information Act and our public information requirements in part 20 of this chapter; and (2) Available for public disclosure in accordance with part 20 of this chapter as of the date that we receive your GRAS notice. (b) We will make the following readily accessible to the public: (1) A list of filed GRAS notices, including the information described in § 570.225(c)(2) through (c)(5); (2) The text of any letter that we issue under § 570.265(b)(1) or (c); and (3) The text of any letter that we issue under § 570.265(b)(3) if we grant your request that we cease to evaluate your notice. (c) We will disclose all remaining data and information that are not exempt from public disclosure in accordance with part 20 of this chapter.

21 C.F.R. § 570.280 Submission of a supplement.

If circumstances warrant, you may submit a supplement to a filed GRAS notice after we respond to your notice by letter in accordance with § 570.265(b)(1) or cease to evaluate your notice in accordance with § 570.265(b)(3).

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