after January 1, 1958, which may reasonably be expected significantly to alter the composition of the substance.

(2) Any substance of natural biological origin that has been widely consumed for its nutrient properties in the United States prior to January 1, 1958, without known detrimental effect, for which no health hazard is known, that has had significant alteration of composition by breeding or selection after January 1, 1958, where the change may be reasonably expected to alter the nutritive value or the concentration of toxic constituents.

(3) Distillates, isolates, extracts, and concentration of extracts of GRAS substances.

(4) Reaction products of GRAS substances.

(5) Substances not of a natural biological origin, including those for which evidence is offered that they are identical to a GRAS counterpart of natural biological origin.

(6) Substances of natural biological origin intended for consumption for other than their nutrient properties.

(g) A food ingredient that is not GRAS or subject to a prior sanction requires a food additive regulation promulgated under section 409 of the act before it may be directly or indirectly added to food.

(h) A food ingredient that is listed as GRAS in part 182 of this chapter or affirmed as GRAS in part 184 or § 186.1 of this chapter shall be regarded as GRAS only if, in addition to all the requirements in the applicable regulation, it also meets all of the following requirements:

(1) It complies with any applicable food grade specifications of the Food Chemicals Codex, 2d Ed. (1972), or, if specifically indicated in the GRAS affirmation regulation, the Food Chemicals Codex, 3d Ed. (1981), which are incorporated by reference, except that any substance used as a component of articles that contact food and affirmed as GRAS in § 186.1 of this chapter shall comply with the specifications therein, or in the absence of such specifications, shall be of a purity suitable for its intended use. Copies may be obtained from the National Academy Press, 2101 Constitution Ave. NW., Washington, DC 20418, or may be examined at the

Office of the Federal Register, 800 North Capitol Street, NW., suite 700, Washington, DC 20408.

(2) It performs an appropriate function in the food or food-contact article in which it is used.

(3) It is used at a level no higher than necessary to achieve its intended purpose in that food or, if used as a component of a food-contact article, at a level no higher than necessary to achieve its intended purpose in that article.

(i) If a substance is affirmed as GRAS in part 184 or § 186.1 of this chapter with no limitation other than good manufacturing practice, it shall be regarded as GRAS if its conditions of use are not significantly different from those reported in the regulation as the basis on which the GRAS status of the substance was affirmed. If the conditions of use are significantly different, such use of the substance may not be GRAS. In such a case a manufacturer may not rely on the regulation as authorizing the use but must independently establish that the use is GRAS or must use the substance in accordance with a food additive regulation.

(j) If an ingredient is affirmed as GRAS in part 184 or § 186.1 of this chapter with specific limitation(s), it may be used in food only within such limitation(s) (including the category of food(s), the functional use(s) of the ingredient, and the level(s) of use). Any use of such an ingredient not in full compliance with each such established limitation shall require a food additive regulation.

(k) Pursuant to §170.35, a food ingredient may be affirmed as GRAS in part 184 or $186.1 of this chapter for a specific use(s) without a general evaluation of use of the ingredient. In addition to the use(s) specified in the regulation, other uses of such an ingredient may also be GRAS. Any affirmation of GRAS status for a specific use(s), without a general evaluation of use of the ingredient, is subject to reconsideration upon such evaluation.

(1) New information may at any time require reconsideration of the GRAS status of a food ingredient. Any change in part 182, part 184, or § 186.1 of this

chapter shall be accomplished pursuant to § 170.38.

[42 FR 14483, Mar. 15, 1977, as amended at 49 FR 5610, Feb. 14, 1984; 53 FR 16546, May 10, 1988]

§ 170.35 Affirmation of generally recognized as safe (GRAS) status.

(a) The Commissioner, either on his initiative or on the petition of an interested person, may affirm the GRAS status of substances that directly or indirectly become components of food.

(b)(1) If the Commissioner proposes on his own initiative that a substance is entitled to affirmation as GRAS, he will place all of the data and information on which he relies on public file in the office of the Dockets Management Branch and will publish in the FEDERAL REGISTER a notice giving the name of the substance, its proposed uses, and any limitations proposed for purposes other than safety.

(2) The FEDERAL REGISTER notice will allow a period of 60 days during which any interested person may review the data and information and/or file comments with the Dockets Management Branch. Copies of all comments received shall be made available for examination in the Dockets Management Branch's office.

(3) The Commissioner will evaluate all comments received. If he concludes that there is convincing evidence that the substance is GRAS as described in §170.30, he will publish a notice in the FEDERAL REGISTER listing the substance as GRAS in part 182, part 184, or part 186 of this chapter, as appropriate.

(4) If, after evaluation of the comments, the Commissioner concludes that there is a lack of convincing evidence that the substance is GRAS and that it should be considered a food additive subject to section 409 of the Act, he shall publish a notice thereof in the FEDERAL REGISTER in accordance with § 170.38.

(c)(1) Persons seeking the affirmation of GRAS status of substances as provided in § 170.30(e), except those subject to the NAS/NRC GRAS list survey (36 FR 20546; October 23, 1971), shall submit a petition for GRAS affirmation pursuant to part 10 of this chapter. Such petition shall contain information to establish that the GRAS criteria as set

forth in §170.30 (b) or (c) have been met, in the following form:

(i) Description of the substance, including:

(a) Common or usual name.

(b) Chemical name.

(c) Chemical Abstract Service (CAS) registry number.

(d) Empirical formula. (e) Structural formula.

(Specifications for food grade material, including arsenic and heavy metals. (Recommendation for any change in the Food Chemicals Codex monograph should be included where applicable.)

(g) Quantitative compositions.

(h) Manufacturing process (excluding any trade secrets).

(ii) Use of the substance, including: (a) Date when use began.

(b) Information and reports or other data on past uses in food.

(c) Foods in which used, and levels of use in such foods, and for what purposes.

(iii) Methods for detecting the substance in food, including:

(a) References to qualitative and quantitative methods for determining the substance(s) in food, including the type of analytical procedures used.

(b) Sensitivity and reproducibility of such method(s).

(iv) Information to establish the safety and functionality of the substance in food. Published scientific literature, evidence that the substance is identical to a GRAS counterpart of natural biological origin, and other data may be submitted to support safety. Any adverse information or consumer complaints shall be included. Complete bibliographic references shall be provided where a copy of the article is not provided.

(v) A statement signed by the person responsible for the petition that to the best of his knowledge it is a representative and balanced submission that includes unfavorable information, as well as favorable information, known to him pertinent to the evaluation of the safety and functionality of the substance.

(vi) If nonclinical laboratory studies are involved, additional information and data submitted in support of filed petitions shall include, with respect to

each nonclinical study, either a statement that the study was conducted in compliance with the requirements set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.

(vii) [Reserved]

(viii) A claim for categorical exclusion under § 25.30 or §25.32 of this chapter or an environmental assessment under § 25.40 of this chapter.

(2) Within 30 days after the date of filing the petition, the Commissioner will place the petition on public file in the office of the Dockets Management Branch and will publish a notice of filing in the FEDERAL REGISTER giving the name of the petitioner and a brief description of the petition including the name of the substance, its proposed use, and any limitations proposed for reasons other than safety. A copy of the notice will be mailed to the petitioner at the time the original is sent to the FEDERAL REGISTER.

(3)(i) If intended uses of the substance include uses in meat, meat food product, or poultry product subject to regulation by the U.S. Department of Agriculture (USDA) under the Poultry Products Inspection Act (PPIA) (21 U.S.C. 451 et seq.) or Federal Meat Inspection Act (FMIA) (21 U.S.C. 601 et seq.), FDA shall, upon filing of the petition, forward a copy of the petition or relevant portions thereof to the Food Safety and Inspection Service, USDA, for simultaneous review under the PPIA and FMIA.

(ii) FDA will ask USDA to advise whether the proposed meat and poultry uses comply with the FMIA and PPIA or, if not, whether use of the substance would be permitted in products under USDA jurisdiction under specified conditions or restrictions.

(4) The notice of filing in the FEDERAL REGISTER will allow a period of 60 days during which any interested person may review the petition and/or file comments with the Dockets Management Branch. Copies of all comments received shall be made available for examination in the Dockets Management Branch's office.

(5) The Commissioner will evaluate the petition and all available informa

tion including all comments received. If the petition and such information provide convincing evidence that the substance is GRAS as described in § 170.30 he will publish an order in the FEDERAL REGISTER listing the substance as GRAS in part 182, part 184, or part 186 of this chapter, as appropriate.

(6) If, after evaluation of the petition and all available information, the Commissioner concludes that there is a lack of convincing evidence that the substance is GRAS and that it should be considered a food additive subject to section 409 of the Act, he shall publish a notice thereof in the FEDERAL REGISTER in accordance with § 170.38.

(7) The notice of filing in the FEDERAL REGISTER will request submission of proof of any applicable prior sanction for use of the ingredient under conditions different from those proposed to be determined to be GRAS. The failure of any person to come forward with proof of such an applicable prior sanction in response to the notice of filing will constitute a waiver of the right to assert or rely on such sanction at any later time. The notice of filing will also constitute a proposal to establish a regulation under part 181 of this chapter, incorporating the same provisions, in the event that such a regulation is determined to be appropriate as a result of submission of proof of such an applicable prior sanction in response to the notice of filing.

(Information collection requirements were approved by the Office of Management and Budget under control number 0910-0132)

[42 FR 14488, Mar. 15, 1977, as amended at 50 FR 7492, Feb. 22, 1985; 50 FR 16668, Apr. 26, 1985; 53 FR 16547, May 10, 1988; 62 FR 40599, July 29, 1997; 65 FR 51762, Aug. 25, 2000]

(a) The Commissioner may, in accordance with $170.35(b)(4) or (c)(5), publish a notice in the FEDERAL REGISTER determining that a substance is not GRAS and is a food additive subject to section 409 of the Act.

(b)(1) The Commissioner, on his own initiative or on the petition of any interested person, pursuant to part 10 of this chapter, may issue a notice in the FEDERAL REGISTER proposing to determine that a substance is not GRAS and

is a food additive subject to section 409 of the Act. Any petition shall include all relevant data and information of the type described in §171.130(b). The Commissioner will place all of the data and information on which he relies on public file in the office of the Dockets Management Branch and will include in the FEDERAL REGISTER notice the name of the substance, its known uses, and a summary of the basis for the determination.

(2) The FEDERAL REGISTER notice will allow a period of 60 days during which any interested person may review the data and information and/or file comments with the Dockets Management Branch. Copies of all comments shall be made available for examination in the Dockets Management Branch's office.

(3) The Commissioner will evaluate all comments received. If he concludes that there is a lack of convincing evidence that the substance is GRAS or is otherwise exempt from the definition of a food additive in section 201(s) of the Act, he will publish a notice thereof in the FEDERAL REGISTER. If he concludes that there is convincing evidence that the substance is GRAS, he will publish an order in the FEDERAL REGISTER listing the substance GRAS in part 182, part 184, or part 186 of this chapter, as appropriate.

as

(c) A FEDERAL REGISTER notice determining that a substance is a food additive shall provide for the use of the additive in food or food contact surfaces as follows:

(1) It may promulgate a food additive regulation governing use of the additive.

(2) It may promulgate an interim food additive regulation governing use of the additive.

(3) It may require discontinuation of the use of the additive.

(4) It may adopt any combination of the above three approaches for different uses or levels of use of the additive.

(d) If the Commissioner of Food and Drugs is aware of any prior sanction for use of the substance, he will concurrently propose a separate regulation covering such use of the ingredient under part 181 of this chapter. If the Commissioner is unaware of any such

applicable prior sanction, the proposed regulation will so state and will require any person who intends to assert or rely on such sanction to submit proof of its existence. Any regulation promulgated pursuant to this section constitutes a determination that excluded uses would result in adulteration of the food in violation of section 402 of the Act, and the failure of any person to come forward with proof of such an applicable prior sanction in response to the proposal will constitute a waiver of the right to assert or rely on such sanction at any later time. The notice will also constitute a proposal to establish a regulation under part 181 of this chapter, incorporating the same provisions, in the event that such a regulation is determined to be appropriate as a result of submission of proof of such an applicable prior sanction in response to the proposal.

[42 FR 14488, Mar. 15, 1977, as amended at 42 FR 15673, Mar. 22, 1977; 54 FR 24896, June 12, 1989]

§ 170.39 Threshold of regulation for substances used in food-contact articles.

(a) A substance used in a food-contact article (e.g., food-packaging or food-processing equipment) that migrates, or that may be expected to migrate, into food will be exempted from regulation as a food additive because it becomes a component of food at levels that are below the threshold of regulation if:

(1) The substance has not been shown to be a carcinogen in humans or animals, and there is no reason, based on the chemical structure of the substance, to suspect that the substance is a carcinogen. The substance must also not contain a carcinogenic impurity or, if it does, must not contain a carcinogenic impurity with a TDso value based on chronic feeding studies reported in the scientific literature or otherwise available to the Food and Drug Administration of less than 6.25 milligrams per kilogram bodyweight per day (The TD50, for the purposes of this section, is the feeding dose that causes cancer in 50 percent of the test animals when corrected for tumors found in control animals. If more than one TD50 value

has been reported in the scientific literature for a substance, the Food and Drug Administration will use the lowest appropriate TD50 value in its review.);

(2) The substance presents no other health or safety concerns because:

(i) The use in question has been shown to result in or may be expected to result in dietary concentrations at or below 0.5 parts per billion, corresponding to dietary exposure levels at or below 1.5 micrograms/person/day (based on a diet of 1,500 grams of solid food and 1,500 grams of liquid food per person per day); or

(ii) The substance is currently regulated for direct addition into food, and the dietary exposure to the substance resulting from the proposed use is at or below 1 percent of the acceptable daily intake as determined by safety data in the Food and Drug Administration's files or from other appropriate sources;

(3) The substance has no technical effect in or on the food to which it migrates; and

(4) The substance use has no significant adverse impact on the environment.

(b) Notwithstanding paragraph (a) of this section, the Food and Drug Administration reserves the right to decline to grant an exemption in those cases in which available information establishes that the proposed use may pose a public health risk. The reasons for the agency's decision to decline to grant an exemption will be explained in the Food and Drug Administration's response to the requestor.

(c) A request for the Food and Drug Administration to exempt a use of a substance from regulation as a food additive shall include three copies of the following information (If part of the submitted material is in a foreign language, it must be accompanied by an English translation verified to be complete and accurate in accordance with §10.20(c)(2) of this chapter):

(1) The chemical composition of the substance for which the request is made, including, whenever possible, the name of the chemical in accordance with current Chemical Abstract Service (CAS) nomenclature guidelines and a CAS registry number, if available;

(2) Detailed information on the conditions of use of the substance (e.g., temperature, type of food with which the substance will come into contact, the duration of the contact, and whether the food-contact article will be for repeated or single use applications);

(3) A clear statement as to whether the request for exemption from regulation as a food additive is based on the fact that the use of the substance in the food-contact article results in a dietary concentration at or below 0.5 parts per billion, or on the fact that it involves the use of a regulated direct food additive for which the dietary exposure is at or below 1 percent of the acceptable dietary intake (ADI);

(4) Data that will enable the Food and Drug Administration to estimate the daily dietary concentration resulting from the proposed use of the substance. These data should be in the form of:

(i) Validated migration data obtained under worst-case (time/temperature) intended use conditions utilizing appropriate food simulating solvents;

(ii) Information on the amount of the substance used in the manufacture of the food-contact article; or

(iii) Information on the residual level of the substance in the food-contact article. For repeat-use articles, an estimate of the amount of food that contacts a specific unit of surface area over the lifetime of the article should also be provided. (In cases where data are provided only in the form of manufacturing use levels or residual levels of the substance present in the foodcontact article, the Food and Drug Administration will calculate a worstcase dietary concentration level assuming 100 percent migration.) A detailed description of the analytical method used to quantify the substance should also be submitted along with data used to validate the detection limit.

(iv) In cases where there is no detectable migration into food or food simulants, or when no residual level of a substance is detected in the food-contact article by a suitable analytical method, the Food and Drug Administration will, for the purposes of estimating the dietary concentration, consider the validated detection limit of