change 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 subsequently resulted in the transfer of PCB's to human food produced by animals consuming the contaminated feed. The use of PCB-containing coatings on the inner walls of silos has resulted 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 contamination 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 industrial uses of PCB's in the production, 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 likely 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 producing 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 possible 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 handling 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 expectation 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 characteristics of fluids selected as PCB replacements 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 maximum 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 environmental stability and tendency to survive and be concentrated through the food chain. The judgment as to whether a replacement fluid is sufficiently non-hazardous is to be made on an individual installation and operation basis.

(c) For the purpose of this section, the provisions do not apply to electrical transformers and condensers containing PCB's in sealed containers.

(d) For the purpose of this section, the term "animal feed" includes all articles used for food or drink for animals other than man.

(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 potential 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 preservative use on non-food-producing animals at levels not exceeding 0.1 percent 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 products used on non-food-producing animals at a level not exceeding 0.1 percent shall submit a new animal drug application, supplement an existing application, or reformulate the product by September 29, 1977. Each application or supplemental application shall include 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 application, each reformulation shall require an approved supplemental application. The interim marketing of these animal drugs may continue until the application 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 existing 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 introduced 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 supplemental new animal drug applications have not been submitted in accordance with this section.

(e) New animal drug applications submitted for animal drugs containing hexachlorophene for use in or on

food-producing animals shall include adequate data to assure that edible products 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]

§ 500.49 Chlorofluorocarbon propellants.

The use of chlorofluorocarbons as propellants in self-pressurized containers is prohibited from use in all animal drugs, animal food, and related products as provided by § 2.125 of this chapter.

(Secs. 301, 402, 409, 501, 502, 505, 507, 512, 601, 701(a), 52 Stat. 1042-1043 as amended, 1046-1047 as amended, 1049-1054 as amended, 1055, 57 Stat. 463 as amended, 72 Stat. 1785-1788 as amended, 82 stat. 343-351 (21 U.S.C. 331, 342, 348, 351, 352, 355, 357, 360b, 361, 371(a)); sec. 102(2), 83 Stat. 853 (42 U.S.C. 4332))

[43 FR 11317, Mar. 17, 1978]

Subpart C-Animal Drug Labeling Requirements

§ 500.51 Labeling of animal drugs; misbranding.

(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 accordance with labeling direction, or suggesting or implying that the labeling does not contain adequate warnings or adequate directions for use. Such statements include, but are not limited to:

(1) Any statement that disclaims liability when the drug is used in accordance with directions for use contained on the label or labeling.

(2) Any statement that disclaims liability when the drug is used under "abnormal" or "unforeseeable" conditions.

(3) Any statement limiting the warranty 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 damages or that sets forth the legal theory

under which damages are to be recovered.

(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), Bureau of Veterinary Medicine, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. A supplemental NADA providing appropriately revised labeling shall be submitted for any approved new animal drug the labeling of which is not in compliance with this regulation.

[41 FR 8473, Feb. 27, 1976]

§ 500.52 Use of terms such as "tonic", "tone", "toner", or "conditioner” in the labeling of preparations intended for use in or on animals.

(a) The use of terms such as "tonic", "tone", "toner", and similar terms in the labeling of a product intended for use in or on animals implies that such product 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 section 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 intended use(s) of the product.

(b) The unqualified use of the term "conditioner" and similar terms in the labeling of a product intended for use in or on animals implies that such product 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 indications 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 similar terms may be used in labeling only when appropriately qualified so as to fully inform the user regarding the intended 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 labeling to reflect the product's intended use.

(c) An article so qualified as to be represented as a drug must be the subject of an approved new animal drug application unless the use of the article under the conditions set forth in its labeling 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 licensed by law, such information may be omitted from the dispensing package. Under this proviso, the Commissioner of Food and Drugs will offer an opinion, upon written request, stating reasonable grounds therefor on a proposal to omit such information from the dispensing package.

(b) The Commissioner of Food and Drugs has considered submitted material covering a number of drug products and has offered the opinion that the following drugs when intended for those veterinary uses for which they are now generally employed by the veterinary medical profession, should be exempt from the requirements of § 201.105(c) of this chapter, provided that they meet the conditions prescribed 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 dosage unit if they are prepared in a manner that enables accurate and ready administration 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 (except 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 hydrochloride, 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

in

§ 500.65 Epinephrine injection 1:1,000 in 10-milliliter containers for emergency treatment of anaphylactoid shock in cattle, horses, sheep, and swine. (a) Anaphylactoid reactions cattle, horses, sheep, and swine occur occasionally from the injection of antibiotics, bacterins, and vaccines. Adequate directions for use of these antibiotics, bacterins, and vaccines can generally be written for use by the laity and thus are available to livestock producers. Epinephrine injection is effective for the treatment of anaphylactoid reactions in animals and would be of value in saving lives of animals if it were readily available at the time of administration of the causative agents. In connection with this problem 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 Commissioner of Food and Drugs has conIcluded 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 exceeding 10 milliliters and its label bears, in addition to other re

quired information, the following statements in a prominent 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 description 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 Carcinogenic 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 Cosmetic Act requires that sponsored compounds intended for use in foodproducing animals be shown to be safe and that food produced from animals exposed to these compounds be shown to be safe for consumption by people. The statute prohibits the use in foodproducing animals of any compound found to induce cancer when ingested by people or animals unless it can be determined by methods of examination prescribed or approved by the Secretary (a function delegated to the Commissioner of Food and Drugs under § 5.10 of this chapter) that no residue of that compound will be found in the food produced from those animals under conditions of use reasonably certain to be followed in practice. This subpart provides an operational definition of no residue and identifies the steps a sponsor of a compound shall follow to secure the approval of the compound. FDA guidelines contain the procedures and protocols FDA recommends for the implementation of this subpart. These guidelines are available from the Dockets Management Branch (HFA305), Food and Drug Administration, Rm. 4-62, 5600 Fishers Lane, Rock

ville, MD 20857. Requests for these guidelines should be identified with Docket No. 83D-0288.

(b) If FDA concludes on the basis of the threshold assessment that a sponsor shall conduct carcinogenicity testing 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 bioassays that a sponsor conducts must be oral, chronic, dose-response studies and 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 compound and its metabolites should not be subject to this subpart, FDA will continue to consider the compound for approval under the general safety provisions of the act for risks other than cancer.

(d) This subpart does not apply to essential nutrients.

(a) The definitions and interpretations 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 201901, 52 Stat. 1040 et seq. as amended (21 U.S.C. 301-392)).

"Essential nutrients" means compounds that are found in the tissues of untreated, healthy target animals and not produced in sufficient quantity to support the animal's growth, development, 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 Administration.

"Marker residue" means the residue selected for assay whose concentration is in a known relationship to the concentration of the residue of carcinogenic concern in the last tissue to deplete to its permitted concentration.

"Preslaughter withdrawal period" or "milk discard time" means the time after cessation of administration of the sponsored compound for the residue of carcinogenic concern in the edible product to deplete to the concentration that will satisfy the operational definition of no residue.

"Regulatory method" means the aggregate 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.

"R" means the concentration of the marker residue in the target tissue when the residue of carcinogenic concern is equal to Sm in the last tissue to deplete to its permitted concentration.

"Residue" means any compound present in edible tissues of the target animal which results from the use of the sponsored compound, including the sponsored compound, its metabolites, and any other substances formed in or on food because of the sponsored compound'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.

"S" means the permitted concentration of residue of carcinogenic concern for a specific edible tissue.

"S." means the concentration of the test compound in the total diet of test animals that corresponds to a maximum lifetime risk of cancer in the test animals of 1 in 1 million. For the purpose of this subpart, FDA will also assume that this S. will correspond to the concentration of residue of carcinogenic concern in the total human diet that represents no significant increase in the risk of cancer to people.

"Sponsor" means the person or organization proposing or holding an approval by FDA for the use of a sponsored compound.

"Sponsored compound" means any drug or food additive or color additive proposed for use, or used, in food-producing animals or in their feed.

"Target animals" means the production class of animals in which a sponsored compound is proposed or intended for use.