Animal drugs, feeds, and related products (21 CFR 500.23-500.1410)

5 SUBCHAPTER E—ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS PART 500—GENERAL Subpart A [Reserved] Subpart B—Specific Administrative Rulings and Decisions Sec. 500.23 Thermally processed low-acid foods packaged in hermetically sealed con tainers. 500.24 Emergency permit control. 500.25 Anthelmintic drugs for use in ani mals. 500.26 Timed-release dosage form drugs. 500.27 Methylene blue-containing drugs for use in animals. 500.29 Gentian violet for use in animal feed. 500.30 Gentian violet for animal drug use. 500.45 Use of polychlorinated biphenyls (PCB’s) in the production, handling, and storage of animal feed. 500.46 Hexachlorophene in animal drugs. 500.50 Propylene glycol in or on cat food. Subpart C—Animal Drug Labeling Requirements 500.51 Labeling of animal drugs; mis branding. 500.52 Use of terms such as ‘‘tonic’’, ‘‘tone’’, ‘‘toner’’, or ‘‘conditioner’’ in the labeling of preparations intended for use in or on animals. 500.55 Exemption from certain drug-labeling requirements. Subpart D—Requirements for Specific Animal Drugs 500.65 Epinephrine injection 1:1,000 in 10 milliliter containers for emergency treatment of anaphylactoid shock in cat tle, horses, sheep, and swine. Subpart E—Regulation of Carcinogenic Compounds Used in Food-Producing Animals 500.80 Scope of this subpart. 500.82 Definitions. 500.84 Conditions for approval of the spon sored compound. 500.86 Marker residue and target tissue. 500.88 Regulatory method. 500.90 Waiver of requirements. 500.92 Implementation. Subpart F—Methods for Detection of Resi dues of Carcinogenic Compounds Used in Food-Producing Animals 500.1410 N-methyl-2-pyrrolidone. AUTHORITY: 21 U.S.C. 321, 331, 342, 343, 348, 351, 352, 353, 360b, 371, 379e. SOURCE: 40 FR 13802, Mar. 27, 1975, unless otherwise noted. Subpart A [Reserved] Subpart B—Specific Administrative Rulings and Decisions § 500.23 Thermally processed low-acid foods packaged in hermetically sealed containers. Except as provided in § 507.5(b) of this chapter, the provisions of parts 507 and 113 of this chapter apply to the manu facturing, processing, or packing of low-acid foods in hermetically sealed containers, and intended for use as food for animals. [80 FR 56337, Sept. 17, 2015] § 500.24 Emergency permit control. The provisions of part 108 of this chapter shall apply to the issuance of emergency control permits for the manufacturer or packer of thermally processed low-acid foods packaged in hermetically sealed containers, and in tended for use as food for animals. [61 FR 37681, July 19, 1996] § 500.25 Anthelmintic drugs for use in animals. (a) The Commissioner of Food and Drugs has determined that, in order to assure that anthelmintic drugs, includ ing animal feeds bearing or containing such drugs, which do not carry the pre scription statement are labeled to pro vide adequate directions for their effec tive use, labeling of these anthelmintic drugs shall bear, in addition to other required information, a statement that a veterinarian should be consulted for VerDate Sep<11>2014 10:06 Apr 14, 2016 Jkt 238075 PO 00000 Frm 00015 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 6 21 CFR Ch. I (4–1–16 Edition) § 500.26 assistance in the diagnosis, treatment, and control of parasitism. (b) The label and any labeling fur nishing or purporting to furnish direc tions for use, shall bear conspicuously the following statement: ‘‘Consult your veterinarian for assistance in the diag nosis, treatment, and control of para sitism.’’ (c) For drugs covered by approved new animal drug applications, the la beling revisions required for compli ance with this section may be placed into effect without prior approval, as provided for in § 514.8(c)(3) of this chap ter. For drugs listed in the index, the labeling revisions required for compli ance with this section may be placed into effect without prior granting of a request for a modification, as provided for in § 516.161(b)(1) of this chapter. (d) Labeling revisions required for compliance with this section shall be placed into effect by February 25, 1975, following which, any such drugs that are introduced into interstate com merce and not in compliance with this section will be subject to regulatory proceedings. [40 FR 13802, Mar. 27, 1975, as amended at 71 FR 74782, Dec. 13, 2006; 72 FR 69120, Dec. 6, 2007] § 500.26 Timed-release dosage form drugs. (a) Drugs are being offered in dosage forms that are designed to release the active ingredients over a prolonged pe riod of time. There is a possibility of unsafe overdosage or ineffective dosage if such products are improperly made and the active ingredients are released at one time, over too short or too long a period of time, or not released at all. Drugs marketed in this form, which are referred to by such terms as timed-re lease, controlled-release, prolonged-re lease, sustained-release, or delayed-re lease drugs, are regarded as new animal drugs within the meaning of section 201(v) of the Federal Food, Drug, and Cosmetic Act. (b) Timed-release dosage form animal drugs that are introduced into inter state commerce are deemed to be adul terated within the meaning of section 501(a)(5) of the act and subject to regu latory action, unless such animal drug is the subject of an approved new ani mal drug application, or listed in the index, as required by paragraph (a) of this section. (c) The fact that the labeling of this kind of drug may claim delayed, pro longed, controlled, or sustained-release of all or only some of the active ingre dients does not affect the new animal drug status of such articles. A new ani mal drug application or index listing is required in any such case. (d) New animal drug applications for timed-release dosage form animal drugs must contain, among other things, data to demonstrate safety and effectiveness by establishing that the article is manufactured using proce dures and controls to ensure release of the total dosage at a safe and effective rate. Data submitted in the new animal drug application must demonstrate that the formulation of the drug and the procedures used in its manufacture will ensure release of the active ingre dient(s) of the drug at a safe and effec tive rate and that these release charac teristics will be maintained until the expiration date of the drug. When the drug is intended for use in food-pro ducing animals, data submitted must also demonstrate that, with respect to possible residues of the drug, food de rived from treated animals is safe for consumption. [42 FR 8635, Feb. 11, 1977, as amended at 60 FR 38480, July 27, 1995; 72 FR 69120, Dec. 6, 2007] § 500.27 Methylene blue-containing drugs for use in animals. (a) New information requires a re evaluation of the status of drugs con taining methylene blue (tetramethylthionine chloride) for oral use in cats or dogs. (1)(i) It has been demonstrated that two orally administered urinary anti septic-antispasmodic preparations that contained methylene blue cause Heinz body hemolytic anemia in cats when used according to label directions. The specific cause of the reaction was de termined to be the methylene blue con tained in the preparations. The reac tion can be severe enough to cause death of treated animals. (ii) The Heinz body hemolytic anemia reaction to methylene blue has also VerDate Sep<11>2014 10:06 Apr 14, 2016 Jkt 238075 PO 00000 Frm 00016 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 7 Food and Drug Administration, HHS § 500.45 been demonstrated in dogs under lab oratory conditions. The precise mecha nism by which methylene blue pro duces the characteristic erythrocytic inclusion bodies (Heinz bodies) and as sociated hemolytic anemia is unclear. (2) The effectiveness of orally admin istered methylene blue as a urinary an tiseptic is open to question. It appears that following oral administration, methylene blue is poorly and errati cally absorbed and also slowly and er ratically excreted in the urine. Studies in the dog indicate it is excreted in the urine essentially as leukomethylene blue stabilized in some manner. Meth ylene blue itself is stepwise demethylated in alkaline solutions (al kaline urine being a frequent con sequence of urinary infection) to Azure B, Azure A, and Azure C. The antiseptic efficacy of all of these excretion prod ucts is unsubstantiated. (3) In view of the foregoing, the Com missioner has concluded that animal drugs containing methylene blue for oral use in cats or dogs are neither safe nor generally recognized as effective within the meaning of section 201(v) of the act and are therefore considered new animal drugs. Accordingly, all prior formal and informal opinions ex pressed by the Food and Drug Adminis tration that such drugs are ‘‘not new drugs’’ or ‘‘no longer new drugs’’ are hereby revoked. (b) Animal drugs that contain meth ylene blue for oral use in cats or dogs and not the subject of an approved new animal drug application (NADA) are deemed to be adulterated under the provisions of section 501(a) (5) and/or (6) and/or misbranded under section 502(a) of the act and subject to regulatory ac tion as of April 10, 1978. (c) Sponsors of animal drugs that contain methylene blue for oral use in cats or dogs and not the subject of an approved new animal drug application (NADA) may submit an application in conformity with § 514.1 of this chapter. Such applications will be processed in accordance with section 512 of the act. Submission of an NADA will not con stitute grounds for continued mar keting of this drug substance until such application is approved. (d) New animal drug applications re quired by this regulation pursuant to section 512 of the act shall be sub mitted to the Food and Drug Adminis tration. Center for Veterinary Medi cine, Office of New Animal Drug Eval uation (HFV-100), 7500 Standish Pl., Rockville, MD 20855. [43 FR 9803, Mar. 10, 1978; 43 FR 12310, Mar. 24, 1978, as amended at 54 FR 18279, Apr. 28, 1989; 57 FR 6475, Feb. 25, 1992; 60 FR 38480, July 27, 1995] § 500.29 Gentian violet for use in ani mal feed. The Food and Drug Administration has determined that gentian violet is not generally recognized as safe for use in animal feed and is a food additive subject to section 409 of the Federal Food, Drug, and Cosmetic Act (the act), unless it is intended for use as a new animal drug, in which case it is subject to section 512 of the act. The Food and Drug Administration has de termined that gentian violet is not prior sanctioned for any use in animal feed. [56 FR 40506, Aug. 15, 1991] § 500.30 Gentian violet for animal drug use. The Food and Drug Administration (FDA) has determined that gentian vio let is not generally recognized as safe and effective for any veterinary drug use in food animals and is a new ani mal drug subject to section 512 of the Federal Food, Drug, and Cosmetic Act. FDA has determined that gentian vio let is not exempted from new animal drug status under the ‘‘grandfather’’ provisions of the Drug Amendments of 1962 (21 U.S.C. 342). [56 FR 40507, Aug. 15, 1991] § 500.45 Use of polychlorinated biphenyls (PCB’s) in the produc tion, handling, and storage of ani mal feed. (a) Polychlorinated biphenyls (PCB’s) represent a class of toxic industrial chemicals manufactured and sold under a variety of trade names, including: Aroclor (United States); Phenoclor (France); Colphen (Germany); and Kanaclor (Japan). PCB’s are highly sta ble, heat resistant, and nonflammable chemicals. Industrial uses of PCB’s in clude, or did include in the past, their VerDate Sep<11>2014 10:06 Apr 14, 2016 Jkt 238075 PO 00000 Frm 00017 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 8 21 CFR Ch. I (4–1–16 Edition) § 500.45 use as electrical transformer and ca pacitor fluids, heat transfer fluids, hy draulic fluids, plasticizers, and in for mulations of lubricants, coatings, and inks. Their unique physical and chem ical properties and widespread, uncon trolled industrial applications have caused PCB’s to be a persistent and ubiquitous contaminant in the environ ment, causing the contamination of certain foods. In addition, incidents have occurred in which PCB’s have di rectly contaminated animal feeds as a result of industrial accidents (leakage or spillage of PCB fluids from plant equipment). These accidents in turn cause the contamination of food in tended for human consumption (meat, milk, and eggs). Investigations by the Food and Drug Administration have re vealed that heat exchange fluids for certain pasteurization equipment used in processing animal feed contain PCB’s. Although heat exchange fluids in such equipment are considered to be in closed systems, leakage has occurred that resulted in direct contamination of animal feed with PCB’s and subse quently resulted in the transfer of PCB’s to human food produced by ani mals consuming the contaminated feed. The use of PCB-containing coat ings on the inner walls of silos has re sulted in the contamination of silage which has in turn caused PCB residues in the milk of dairy cows consuming the contaminated silage. Since PCB’s are toxic chemicals, the PCB contami nation of food as a result of these and other incidents represent a hazard to public health. It is therefore necessary to place certain restrictions on the in dustrial uses of PCB’s in the produc tion, handling, and storage of animal feed. (b) The following special provisions are necessary to preclude accidental PCB contamination of animal feed: (1) Coatings or paints for use on the contact surfaces of feed storage areas may not contain PCB’s or any other harmful or deleterious substances like ly to contaminate feed. (2) New equipment or machinery for handling or processing feed in or around an establishment producing animal feed shall not contain PCB’s. (3) On or before Sept. 4, 1973, the management of establishments pro ducing animal feed shall: (i) Have the heat exchange fluid used in existing equipment or machinery for handling and processing feed sampled and tested to determine whether it contains PCB’s, or verify the absence of PCB’s in such formulations by other appropriate means. On or before Sept. 4, 1973, any such fluid formulated with PCB’s must to the fullest extent pos sible commensurate with current good manufacturing practices, be replaced with a heat exchange fluid that does not contain PCB’s. (ii) Eliminate to the fullest extent possible commensurate with current good manufacturing practices from the animal feed producing establishment any PCB-containing lubricants for equipment or machinery used for han dling or processing animal feed. (iii) Eliminate to the fullest extent possible commensurate with current good manufacturing practices from the animal feed producing establishment any other PCB-containing materials, whenever there is a reasonable expecta tion that such materials could cause animal feed to become contaminated with PCB’s either as a result of normal use or as a result of accident, breakage, or other mishap. (iv) The toxicity and other character istics of fluids selected as PCB replace ments must be adequately determined so that the least potentially hazardous replacement should be used. In making this determination with respect to a given fluid, consideration should be given to (a) its toxicity; (b) the max imum quantity that could be spilled onto a given quantity of food before it would be noticed, taking into account its color and odor; (c) possible signaling devices in the equipment to indicate a loss of fluid, etc.; (d) and its environ mental stability and tendency to sur vive and be concentrated through the food chain. The judgment as to wheth er a replacement fluid is sufficiently non-hazardous is to be made on an indi vidual installation and operation basis. (c) For the purpose of this section, the provisions do not apply to elec trical transformers and condensers containing PCB’s in sealed containers. VerDate Sep<11>2014 10:06 Apr 14, 2016 Jkt 238075 PO 00000 Frm 00018 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 9 Food and Drug Administration, HHS § 500.51 (d) For the purpose of this section, the term animal feed includes all arti cles used for food or drink for animals other than man. § 500.46 Hexachlorophene in animal drugs. (a) The Commissioner of Food and Drugs has determined that there are no adequate data to establish that animal drugs containing hexachlorophene are safe and effective for any animal use other than in topical products for use on non-food-producing animals as part of a product preservative system at a level not to exceed 0.1 percent; that there is no information on the poten tial risk to humans from exposure to hexachlorophene by persons who apply animal products containing the drug at levels higher than 0.1 percent; and that there is likewise no information on human exposure to animals on which these animal drugs have been used and no information on possible residues of hexachlorophene in edible products of food-producing animals treated with new animal drugs that contain any quantity of hexachlorophene. (b) Animal drugs containing hexachlorophene for other than pre servative use on non-food-producing animals at levels not exceeding 0.1 per cent are considered new animal drugs and shall be the subject of new animal drug applications (NADA’s). (c) Any person currently marketing animal drugs that contain hexachlorophene other than as part of a product preservative system for prod ucts used on non-food-producing ani mals at a level not exceeding 0.1 per cent shall submit a new animal drug application, supplement an existing ap plication, or reformulate the product by September 29, 1977. Each application or supplemental application shall in clude adequate data to establish that the animal drug is safe and effective. If the animal drug is currently subject to an approved new animal drug applica tion, each reformulation shall require an approved supplemental application. The interim marketing of these animal drugs may continue until the applica tion has been approved, until it has been determined that the application is not approvable under the provisions of § 514.111 of this chapter, or until an ex isting approved application has been withdrawn. (d) After September 29, 1977, animal drugs that contain hexachlorophene other than for preservative use on non food-producing animals at a level not exceeding 0.1 percent that are intro duced into interstate commerce shall be deemed to be adulterated within the meaning of section 501(a)(5) of the act (21 U.S.C. 351(a)(5)) unless such animal drug is the subject of a new animal drug application submitted pursuant to paragraph (c) of this section. Action to withdraw approval of new animal drug applications will be initiated if supple mental new animal drug applications have not been submitted in accordance with this section. (e) New animal drug applications sub mitted for animal drugs containing hexachlorophene for use in or on food producing animals shall include ade quate data to assure that edible prod ucts from treated animals are safe for human consumption under the labeled conditions of use. [42 FR 33725, July 1, 1977; 42 FR 37975, July 26, 1977] § 500.50 Propylene glycol in or on cat food. The Food and Drug Administration has determined that propylene glycol in or on cat food is not generally recog nized as safe and is a food additive sub ject to section 409 of the Federal Food, Drug, and Cosmetic Act (the act). The Food and Drug Administration also has determined that this use of propylene glycol is not prior sanctioned. [61 FR 19544, May 2, 1996] Subpart C—Animal Drug Labeling Requirements § 500.51 Labeling of animal drugs; mis branding. (a) Among the representations on the label or labeling of an animal drug which will render the drug misbranded are any broad statements suggesting or implying that the drug is not safe and effective for use when used in accord ance with labeling direction, or sug gesting or implying that the labeling does not contain adequate warnings or VerDate Sep<11>2014 10:06 Apr 14, 2016 Jkt 238075 PO 00000 Frm 00019 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 10 21 CFR Ch. I (4–1–16 Edition) § 500.52 adequate directions for use. Such state ments include, but are not limited to: (1) Any statement that disclaims li ability when the drug is used in accord ance with directions for use contained on the label or labeling. (2) Any statement that disclaims li ability when the drug is used under ‘‘abnormal’’ or ‘‘unforeseeable’’ condi tions. (3) Any statement limiting the war ranty for the products to a warranty that the drug in the package contains the ingredients listed on the label. (b) This regulation is not intended to prohibit any liability disclaimer that purports to limit the amount of dam ages or that sets forth the legal theory under which damages are to be recov ered. (c) Any person wishing to obtain an evaluation of an animal drug liability disclaimer under this regulation may submit it to Division of Compliance, (HFV–230), Center for Veterinary Medi cine, Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855. A supplemental NADA providing appro priately revised labeling shall be sub mitted for any approved new animal drug the labeling of which is not in compliance with this regulation. [41 FR 8473, Feb. 27, 1976, as amended at 54 FR 18279, Apr. 28, 1989; 57 FR 6475, Feb. 25, 1992] § 500.52 Use of terms such as ‘‘tonic’’, ‘‘tone’’, ‘‘toner’’, or ‘‘conditioner’’ in the labeling of preparations in tended for use in or on animals. (a) The use of terms such as tonic, tone, toner, and similar terms in the la beling of a product intended for use in or on animals implies that such prod uct is capable of a therapeutic effect(s) and causes such a product to be a drug within the meaning of section 201(g) of the Federal Food, Drug, and Cosmetic Act. The unqualified use of such terms in a product’s labeling fails to provide adequate directions and indications for use of such product and causes it to be misbranded within the meaning of sec tion 502(a) and (f)(1) of the act. The terms tonic, tone, toner, and similar terms may be used in labeling only when appropriately qualified so as to fully inform the user regarding the in tended use(s) of the product. (b) The unqualified use of the term conditioner and similar terms in the la beling of a product intended for use in or on animals implies that such prod uct is capable of a therapeutic effect(s) and causes such a product to be a drug within the meaning of section 201(g) of the act. The unqualified use of such terms in a product’s labeling fails to provide adequate directions and indica tions for use of such product and causes it to be misbranded within the meaning of section 502(a) and (f)(1) of the act. The term conditioner and simi lar terms may be used in labeling only when appropriately qualified so as to fully inform the user regarding the in tended use(s) of the product. A product labeled as a ‘‘conditioner’’ or with a similar term can be either a food or drug depending upon the manner in which the term is qualified in the la beling to reflect the product’s intended use. (c) An article so qualified as to be represented as a drug must be the sub ject of an approved new animal drug application unless the use of the article under the conditions set forth in its la beling is generally recognized as safe and effective among experts qualified by scientific training and experience to evaluate the safety and effectiveness of animal drugs. § 500.55 Exemption from certain drug labeling requirements. (a) Section 201.105(c) of this chapter provides that in the case of certain drugs for which directions, hazards, warnings, and use information are commonly known to practitioners li censed by law, such information may be omitted from the dispensing pack age. Under this proviso, the Commis sioner of Food and Drugs will offer an opinion, upon written request, stating reasonable grounds therefore on a pro posal to omit such information from the dispensing package. (b) The Commissioner of Food and Drugs has considered submitted mate rial covering a number of drug prod ucts and has offered the opinion that the following drugs when intended for those veterinary uses for which they are now generally employed by the vet erinary medical profession, should be exempt from the requirements of VerDate Sep<11>2014 10:06 Apr 14, 2016 Jkt 238075 PO 00000 Frm 00020 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 11 Food and Drug Administration, HHS § 500.80 § 201.105(c) of this chapter, provided that they meet the conditions pre scribed in this paragraph. Preparations that are not in dosage unit form (for example, solutions) will be regarded as meeting the conditions with respect to the maximum quantity of drug per dos age unit if they are prepared in a man ner that enables accurate and ready ad ministration of a quantity of drug not in excess of the stated maximum per dosage unit: Atropine sulfate. As an injectable for cattle, goats, horses, pigs, and sheep, not in excess of 15 milligrams per dosage unit; as an injectable for cats and dogs, not in excess of 0.6 milligram per dosage unit. Barbital sodium. For oral use in cats and dogs, not in excess of 300 milligrams per dosage unit. Epinephrine injection. 1:1,000. For cats, dogs, cattle, goats, horses, pigs, and sheep (ex cept as provided in § 500.65). Morphine sulfate. As an injectable for dogs, not in excess of 15 milligrams per dosage unit. Pentobarbital sodium. For oral use in cats and dogs, not in excess of 100 milligrams per dosage unit. Phenobarbital sodium. For oral use in cats and dogs, not in excess of 100 milligrams per dosage unit. Procaine hydrochloride injection. Containing not in excess of 2 percent procaine hydro chloride, with or without epinephrine up to a concentration of 1:50,000. For use in cats, dogs, cattle, goats, horses, pigs, and sheep. Thyroid. For oral use in dogs, not in excess of 60 milligrams per dosage unit. Subpart D—Requirements for Specific Animal Drugs § 500.65 Epinephrine injection 1:1,000 in 10-milliliter containers for emer gency treatment of anaphylactoid shock in cattle, horses, sheep, and swine. (a) Anaphylactoid reactions in cattle, horses, sheep, and swine occur occa sionally from the injection of anti biotics, bacterins, and vaccines. Ade quate directions for use of these anti biotics, bacterins, and vaccines can generally be written for use by the laity and thus are available to live stock producers. Epinephrine injection is effective for the treatment of anaphylactoid reactions in animals and would be of value in saving lives of ani mals if it were readily available at the time of administration of the causative agents. In connection with this prob lem the Food and Drug Administration has obtained the views of the Advisory Committee on Veterinary Medicine, and other experts, and has concluded that adequate directions for over-the counter sale of epinephrine injection 1:1,000 can be prepared. (b) In view of the above, the Commis sioner of Food and Drugs has concluded that it is in the public interest to make epinephrine injection 1:1,000 available for sale without a prescription provided that it is packaged in vials not exceed ing 10 milliliters and its label bears, in addition to other required information, the following statements in a promi nent and conspicuous manner: ‘‘For emergency use only in treating anaphylactoid shock. Usual Dosage: Cattle, horses, sheep, and swine—1 cubic centimeter per 100 pounds of body weight. Inject subcutaneously’’. (c) The labeling must also bear a de scription of the symptoms of anaphylactoid shock including glassy eyes, increased salivation, grinding of the teeth, rapid breathing, muscular tremors, staggering gait, and collapse with death following. These symptoms may appear shortly after injection of a bacterin, vaccine, or antibiotic. Subpart E—Regulation of Carcino genic Compounds Used in Food-Producing Animals SOURCE: 52 FR 49586, Dec. 31, 1987, unless otherwise noted. § 500.80 Scope of this subpart. (a) The Federal Food, Drug, and Cos metic Act requires that sponsored com pounds intended for use in food-pro ducing animals be shown to be safe and that food produced from animals ex posed to these compounds be shown to be safe for consumption by people. The statute prohibits the use in food-pro ducing animals of any compound found to induce cancer when ingested by peo ple or animals unless it can be deter mined by methods of examination pre scribed or approved by the Secretary (a function delegated to the Commis sioner of Food and Drugs) that no res idue of that compound will be found in the food produced from those animals VerDate Sep<11>2014 10:06 Apr 14, 2016 Jkt 238075 PO 00000 Frm 00021 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 12 21 CFR Ch. I (4–1–16 Edition) § 500.82 under conditions of use reasonably cer tain to be followed in practice. This subpart identifies the steps a sponsor of a compound shall follow to secure the approval of the compound. FDA guidance documents contain the proce dures and protocols FDA recommends for the implementation of this subpart. These guidance documents are avail able from the Division of Dockets Man agement (HFA–305), Food and Drug Ad ministration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Requests for these guidance documents should be identified with Docket No. 1983D–0288. (b) If FDA concludes on the basis of the threshold assessment that a spon sor shall conduct carcinogenicity test ing on the sponsored compound, FDA will also determine whether and to what extent the sponsor shall conduct carcinogenicity testing on metabolites of the sponsored compound. The bio assays that a sponsor conducts must be designed to assess carcinogenicity and to determine the quantitative aspects of any carcinogenic response. (c) If FDA concludes on the basis of the threshold assessment or at a later time during the approval process that the data show that the sponsored com pound and its metabolites should not be subject to this subpart, FDA will continue to consider the compound for approval under the general safety pro visions of the act for risks other than cancer. (d) This subpart does not apply to es sential nutrients. [52 FR 49586, Dec. 31, 1987, as amended at 59 FR 14365, Mar. 28, 1994; 62 FR 66983, Dec. 23, 1997; 65 FR 56480, Sept. 19, 2000; 67 FR 78174, Dec. 23, 2002; 68 FR 24879, May 9, 2003; 69 FR 17292, Apr. 2, 2004] § 500.82 Definitions. (a) The definitions and interpreta tions contained in section 201 of the act apply to those terms when used in this subpart. (b) The following definitions apply to this subpart: Act means the Federal Food, Drug, and Cosmetic Act (sections 201–901, 52 Stat. 1040 et seq. as amended (21 U.S.C. 301–392)). Essential nutrients means compounds that are found in the tissues of un treated, healthy target animals and not produced in sufficient quantity to support the animal’s growth, develop ment, function, or reproduction, e.g., vitamins, essential minerals, essential amino acids, and essential fatty acids. These compounds must be supplied from external sources. FDA means the Food and Drug Ad ministration. Limit of detection (LOD) means the lowest concentration of analyte that can be confirmed by the approved regu latory method. Marker residue means the residue se lected for assay whose concentration is in a known relationship to the con centration of the residue of carcino genic concern in the last tissue to de plete to its Sm. Preslaughter withdrawal period or milk discard time means the time after ces sation of administration of the spon sored compound at which no residue is detectable in the edible product using the approved regulatory method (i.e., the marker residue is below the LOD). Regulatory method means the aggre gate of all experimental procedures for measuring and confirming the presence of the marker residue of the sponsored compound in the target tissue of the target animal. Rm means the concentration of the marker residue in the target tissue when the residue of carcinogenic con cern is equal to Sm. Residue means any compound present in edible tissues of the target animal which results from the use of the spon sored compound, including the spon sored compound, its metabolites, and any other substances formed in or on food because of the sponsored com pound’s use. Residue of carcinogenic concern means all compounds in the total residue of a demonstrated carcinogen excluding any compounds judged by FDA not to present a carcinogenic risk. Sm means the concentration of a res idue of carcinogenic concern in a spe cific edible tissue corresponding to no significant increase in the risk of can cer to the human consumer. For the purpose of § 500.84(c)(1), FDA will as sume that this Sm will correspond to the concentration of residue in a spe cific edible tissue that corresponds to a VerDate Sep<11>2014 10:06 Apr 14, 2016 Jkt 238075 PO 00000 Frm 00022 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 13 Food and Drug Administration, HHS § 500.86 maximum lifetime risk of cancer in the test animals of 1 in 1 million. So means the concentration of a res idue of carcinogenic concern in the total human diet that represents no significant increase in the risk of can cer to the human consumer. For the purpose of § 500.84(c)(1), FDA will as sume that this So will correspond to the concentration of test compound in the total diet of test animals that cor responds to a maximum lifetime risk of cancer in the test animals of 1 in 1 mil lion. Sponsor means the person or organi zation proposing or holding an ap proval by FDA for the use of a spon sored compound. Sponsored compound means any drug or food additive or color additive pro posed for use, or used, in food-pro ducing animals or in their feed. Target animals means the production class of animals in which a sponsored compound is proposed or intended for use. Target tissue means the edible tissue selected to monitor for residues in the target animals, including, where appro priate, milk or eggs. Test animals means the species se lected for use in the toxicity tests. Threshold assessment means FDA’s re view of data and information about a sponsored compound to determine whether chronic bioassays in test ani mals are necessary to resolve questions concerning the carcinogenicity of the compound. [52 FR 49586, Dec. 31, 1987, as amended at 67 FR 78174, Dec. 23, 2002; 77 FR 50593, Aug. 22, 2012] § 500.84 Conditions for approval of the sponsored compound. (a) On the basis of the results of the chronic bioassays and other informa tion, FDA will determine whether any of the substances tested are carcino genic. (b) If FDA concludes that the results of the bioassays do not establish car cinogenicity, then FDA will not sub ject the sponsored compound to the re mainder of the requirements of this subpart. (c) For each sponsored compound that FDA decides should be regulated as a carcinogen, FDA will either ana lyze the data from the bioassays using a statistical extrapolation procedure as outlined in paragraph (c)(1) of this sec tion or evaluate an alternate procedure proposed by the sponsor as provided in § 500.90. In either case, paragraphs (c)(2) and (3) of this section apply. (1) For each substance tested in sepa rate bioassays, FDA will calculate the concentration of the residue of carcino genic concern that corresponds to a maximum lifetime risk to the test ani mal of 1 in 1 million. FDA will des ignate the lowest value obtained as So. Because the total diet is not derived from food-producing animals, FDA will make corrections for food intake. FDA will designate as Sm the concentration of residue in a specific edible tissue corresponding to a maximum lifetime risk of cancer in test animals of 1 in 1 million. (2) From the appropriate residue chemistry data FDA will calculate the Rm as described in § 500.86(c). The spon sor must provide a regulatory method in accordance with § 500.88(b). FDA will calculate the LOD of the method from data submitted by the sponsor under § 500.88. The LOD must be less than or equal to Rm. (3) FDA will conclude that the provi sions of this subpart are satisfied when no residue of the compound is detect able (that is, the marker residue is below the LOD) using the approved reg ulatory method under the conditions of use of the sponsored compound, includ ing any required preslaughter with drawal period or milk discard time. [52 FR 49586, Dec. 31, 1987, as amended at 67 FR 78174, Dec. 23, 2002; 77 FR 50593, Aug. 22, 2012] § 500.86 Marker residue and target tis sue. (a) For each edible tissue, the spon sor shall measure the depletion of the residue of carcinogenic concern until its concentration is at or below Sm. (b) In one or more edible tissues, the sponsor shall also measure the deple tion of one or more potential marker residues until the concentration of the residue of carcinogenic concern is at or below Sm. (c) From these data, FDA will select a target tissue and a marker residue and designate the concentration of VerDate Sep<11>2014 10:06 Apr 14, 2016 Jkt 238075 PO 00000 Frm 00023 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 14 21 CFR Ch. I (4–1–16 Edition) § 500.88 marker residue (Rm) that the regu latory method must be capable of measuring in the target tissue. FDA will select Rm such that the absence of the marker residue in the target tissue above Rm can be taken as confirmation that the residue of carcinogenic con cern does not exceed Sm in each of the edible tissues and, therefore, that the residue of carcinogenic concern in the diet of people does not exceed So. (d) When a compound is to be used in milk- or egg-producing animals, milk or eggs must be the target tissue in ad dition to the tissue selected to monitor for residues in the edible carcass. (Approved by the Office of Management and Budget under control number 0910–0228) § 500.88 Regulatory method. (a) The sponsor shall submit for eval uation and validation a regulatory method developed to monitor compli ance with FDA’s operational definition of no residue. (b) The regulatory method must be able to confirm the identity of the marker residue in the target tissue at a minimum concentration cor responding to the Rm. FDA will deter mine the LOD from the submitted ana lytical method validation data. (c) FDA will publish in the FEDERAL REGISTER the complete regulatory method for ascertaining the marker residue in the target tissue in accord ance with the provisions of sections 409(c)(3)(A), 512(d)(1)(I), and 721(b)(5)(B) of the act. (Approved by the Office of Management and Budget under control number 0910–0228) [52 FR 49586, Dec. 31, 1987, as amended at 67 FR 78174, Dec. 23, 2002] § 500.90 Waiver of requirements. In response to a petition or on the Commissioner’s own initiative, the Commissioner may waive, in whole or in part, the requirements of this sub part except those provided under § 500.88. A petition for this waiver may be filed by any person who would be ad versely affected by the application of the requirements to a particular com pound. The petition shall explain and document why the requirements from which a waiver is requested are not reasonably applicable to the com pound, and set forth clearly the rea sons why the alternative procedures will provide the basis for concluding that approval of the compound satisfies the requirements of the anticancer pro visions of the act. If the Commissioner determines that waiver of any of the requirements of this subpart is appro priate, the Commissioner will state the basis for that determination in the reg ulation approving marketing of the sponsored compound. (Approved by the Office of Management and Budget under control number 0910–0228) § 500.92 Implementation. (a) This subpart E applies to all new animal drug applications, food additive petitions, and color additive petitions concerning any compound intended for use in food-producing animals (includ ing supplemental applications and amendments to petitions). (b) This subpart E also applies in the following manner to compounds al ready approved: (1) For those compounds that FDA determines may induce cancer when in gested by man or animals, i.e., suspect carcinogens, §§ 500.80(b), 500.82, and 500.90 apply. (2) For those compounds that FDA determines have been shown to induce cancer when ingested by man or ani mals, §§ 500.82 through 500.90 apply. Subpart F—Methods for Detection of Residues of Carcinogenic Compounds Used in Food Producing Animals SOURCE: 76 FR 72618, Nov. 25, 2011, unless otherwise noted. § 500.1410 N-methyl-2-pyrrolidone. (a) Standard for residues. No residues of n-methyl-2-pyrrolidone may be found in the uncooked edible tissues of cattle as determined by a method enti tled ‘‘Method of Analysis: N-methyl-2 pyrrolidone,’’ September 26, 2011, Cen ter for Veterinary Medicine, Food and Drug Administration, which is incor porated by reference with the approval of the Director of the Federal Register under 5 U.S.C. 522(a) and 1 CFR part 51. You may obtain a copy of the method from the Communications Staff (HFV– VerDate Sep<11>2014 10:06 Apr 14, 2016 Jkt 238075 PO 00000 Frm 00024 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B 15 Food and Drug Administration, HHS § 501.1 12), Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish Pl., Rockville, MD 20855, 240– 276–9120; or go to http://www.fda.gov/ AboutFDA/CentersOffices/OfficeofFoods/ CVM/CVMFOIAElectronicReadingRoom/ default.htm. You may inspect a copy at the Division of Dockets Management (HFA–305), Food and Drug Administra tion, 5630 Fishers Lane, Rm. 1061, Rock ville, MD 20852, (301) 827–6860, between 9 a.m. and 4 p.m., Monday through Fri day or at the National Archives and Records Administration (NARA). For information on the availability of this material at NARA, call (202) 741–6030, or go to: http://www.archives.gov/federal register/cfr/ibr-locations.html. (b) Related conditions of use. See §§ 522.814 and 522.955 of this chapter. [76 FR 72618, Nov. 25, 2011, as amended at 77 FR 9528, Feb. 17, 2012] PART 501—ANIMAL FOOD LABELING Subpart A—General Provisions Sec. 501.1 Principal display panel of package form animal food. 501.2 Information panel of package for ani mal food. 501.3 Identity labeling of animal food in package form. 501.4 Animal food; designation of ingredi ents. 501.5 Animal food; name and place of busi ness of manufacturer, packer, or dis tributor. 501.8 Labeling of animal food with number of servings. 501.15 Animal food; prominence of required statements. 501.17 Animal food labeling warning state ments. 501.18 Misbranding of animal food. Subpart B—Specific Animal Food Labeling Requirements 501.22 Animal foods; labeling of spices, flavorings, colorings, and chemical pre servatives. Subparts C–E [Reserved] Subpart F—Exemptions From Animal Food Labeling Requirements 501.100 Animal food; exemptions from label ing. 501.103 Petitions requesting exemptions from or special requirements for label declaration of ingredients. 501.105 Declaration of net quantity of con tents when exempt. 501.110 Animal feed labeling; collective names for feed ingredients. AUTHORITY: 15 U.S.C. 1453, 1454, 1455; 21 U.S.C. 321, 331, 342, 343, 348, 371. SOURCE: 41 FR 38619, Sept. 10, 1976, unless otherwise noted. Subpart A—General Provisions § 501.1 Principal display panel of pack age form animal food. The term principal display panel as it applies to food in package form and as used in this part, means the part of a label that is most likely to be dis played, presented, shown, or examined under customary conditions of display for retail sale. The principal display panel shall be large enough to accom modate all the mandatory label infor mation required to be placed thereon by this part with clarity and conspicu ousness and without obscuring design, vignettes, or crowding. Where packages bear alternate principal display panels, information required to be placed on the principal display panel shall be du plicated on each principal display panel. For the purpose of obtaining uniform type size in declaring the quantity of contents for all packages of substantially the same size, the term area of the principal display panel means the area of the side or surface that bears the principal display panel, which area shall be: (a) In the case of a rectangular pack age where one entire side properly can be considered to be the principal dis play panel side, the product of the height times the width of that side; (b) In the case of a cylindrical or nearly cylindrical container, 40 percent of the product of the height of the con tainer times the circumference; (c) In the case of any otherwise shaped container, 40 percent of the total surface of the container: Provided, however, That where such container presents an obvious principal display panel such as the top of a triangular or circular package, the area shall consist VerDate Sep<11>2014 10:06 Apr 14, 2016 Jkt 238075 PO 00000 Frm 00025 Fmt 8010 Sfmt 8010 Q:\21\21V6.TXT 31lp o w e ll o n D S K 5 4 D X V N 1 O F R w ith $ $ JO B