of purity or quality if they are not sterile. They should be so packaged as to maintain sterility until the package is opened and be so labeled, on or within the retail package, as to afford adequate directions and necessary warnings to minimize the hazard of injury resulting from contamination during use.

[29 F.R. 12458, Sept. 1, 1964]

§ 3.29 Chlorcyclizine, cyclizine, meclizine; warnings; labeling require

ments.

(a) The Food and Drug Administration, pursuant to its responsibility for the safety and effectiveness of drugs, has conducted active investigations of reports of available animal data which reveal that chlorcyclizine hydrochloride, cyclizine hydrochloride and lactate, and meclizine hydrochloride exert a teratogenic response in animals such as the rat, mouse, rabbit, pig, and dog. While clinical studies to date are inconclusive, scientific experts are of the opinion that these drugs may possess a potential for adverse effects on the human fetus. Investigations have led to the conclusion that there exists sufficient evidence of teratogenicity in animals administered these drugs to justify warnings against their use in pregnancy except on advice of a physician. An Ad Hoc Advisory Committee on the Teratogenic Effect of Certain Drugs, comprised of scientists in various branches of medicine concerned with the problem, has submitted its findings and conclusions to the Commissioner of Food and Drugs and has recommended that all over-the-counter preparations containing chlorcyclizine, cyclizine, or meclizine or their salts bear a warning.

(b) On the basis of studies made by the Food and Drug Administration and on the recommendations of the Advisory Committee, the Commissioner of Food and Drugs has concluded that it is necessary for the protection of users that the label and labeling of all over-the-counter preparations containing chlorcyclizine, cyclizine, or meclizine or their salts bear a statement to the following effect: "Warning-Not for use by women who are pregnant or who may possibly become pregnant, unless directed by a physician, since this drug may have the potentiality of injuring the unborn child."

(c) The marketing of oral and parenteral drugs containing chlorcyclizine, cyclizine, or meclizine or their salts may

be continued provided that all the following conditions are met:

(1) Within 30 days from the date of publication of this statement in the FEDERAL REGISTER.

(i) The label and applicable labeling of drugs containing chlorcyclizine, cyclizine, or meclizine or their salts, at acceptable levels for over-the-counter distribution, shall prominently and conspicuously display the statement: "Warning-Not for use by women who are pregnant or who may possibly become pregnant, unless directed by a physician, since this drug may have the potentiality of injuring the unborn child."

(ii) The package labeling and other labeling providing professional use information concerning prescription drugs containing chlorcyclizine, cyclizine, or meclizine or their salts and not contraindicated for use in pregnancy because of some other ingredient, shall bear, in accordance with § 1.106(b)1 of this chapter, a section under "Adverse Reactions" headed "Use in Pregnancy," as follows:

The following information should be taken into account in determining whether the potential benefits of [chlorcyclizine, cyclizine, meclizine, or their salts] outweigh the risks of their use in women of childbearing age and particularly during pregnancy. A review of available animal data reveals that this drug exerts a teratogenic response in the [rat, mouse, rabbit, pig, dog]. While available clinical data are inconclusive, scientific experts are of the opinion that this drug may possess a potential for adverse effects on the human fetus. Consequently, consideration should be given to initial use of a nonphenothiazine agent that is not suspected of having a teratogenic potential. In any case, the dosage and duration of treatment should be kept to a minimum.

This statement shall be followed with an appropriate summary of the pertinent animal studies and adverse clinical experiences, with adequate references to the scientific literature. Also, the labeling shall contain, in juxtaposition with any representation for use in the treatment of nausea and vomiting in pregnancy, the following statement: The effectiveness of for the prevention and treatment of nausea and vomiting of pregnancy has not been established, and the decision to use should be based on the seriousness of the situation, remembering that while this drug has been

1 Section 1.105 will require that prescription drug advertising contain this warning.

In

used clinically for a decade, there are yet no controlled studies to demonstrate its usefulness in an objective fashion. In most cases, nausea and vomiting of pregnancy may be unpleasant but do not present a serious threat to the health of the patient or to the progress of her pregnancy. view of the desirability of keeping the administration of all drugs to a minimum during pregnancy, management by physiologic means such as proper nutrition and by psychologic support is preferable to antiemetic therapy.

(2) Within 30 days from the date of publication of this statement of policy in the FEDERAL REGISTER, the applicant under an approved new-drug application for a drug containing chlorcyclizine, cyclizine, or meclizine or their salts shall submit a supplement to his new-drug application, providing for appropriate labeling changes as described in subparagraph (1) (i) or (ii) of this paragraph.

(3) Within 90 days from the date of publication of this statement of policy in the FEDERAL REGISTER, the manufacturer, packer, or distributor of any drug containing chlorcyclizine, cyclizine, or meclizine or their salts for which a new-drug approval is not in effect shall submit a new-drug application containing satisfactory information of the kinds required in the new-drug application form contained in § 130.4 (c) of this chapter, including appropriate labeling as described in subparagraph (1) (i) or (ii) of this paragraph.

(d) In view of the fact that no substantial evidence has been offered for the effectiveness of chlorcyclizine, cyclizine, and meclizine or their salts in the prevention and treatment of nausea and vomiting of pregnancy, but mindful of the fact that some practicing physicians believe that these drugs exert a beneficial effect upon this condition, the Food and Drug Administration will permit a modified claim in indications for this use for a period not exceeding 2 years. However, this modified indication for use of these drugs in the prevention and treatment of nausea and vomiting of pregnancy will be deleted from the labeling unless substantial evidence is offered before the expiration of this period of time. The Food and Drug Administration will also continue to follow the large-scale surveys of clinical experience and any reports of adverse reaction that may be due to the use of these drugs under the revised labeling.

[30 F.R. 13628, Oct. 27, 1965; 30 F.R. 14047, Nov. 6, 1965]

§ 3.30 Ipecac syrup; warnings and directions for use for over-the-counter sale.

(a) It is estimated that each year about 500,000 accidental poisonings occur in the United States and result in approximately 1,500 deaths, of which over 400 are children. In the emergency treatment of these poisonings, ipecac syrup is considered the emetic of choice. The immediate availability of this drug for use in such situations is critical, since rapid treatment may be the difference between life and death. The restriction of this drug to prescription sale limits its availability in emergencies. On the other hand, it is the consensus of informed medical opinion that ipecac syrup should be used only under medical supervision in the emergency treatment of poisonings. In view of these facts, the question of whether ipecac syrup labeled as an emergency treatment for use in poisonings should be available over the counter has been controversial.

(b) In connection with its study of this problem, the Food and Drug Administration has obtained the views of medical authorities. It is the unanimous recommendation of the American Academy of Pediatrics, the American Association of Poison Control Centers, the American Medical Association, and the Medical Advisory Board of the Food and Drug Administration that ipecac syrup in 1 fluid ounce containers be permitted to be sold without prescription so that it will be readily available in the household for emergency treatment of poisonings, under medical supervision, and that the drug be appropriately packaged and labeled for this purpose.

(c) In view of the above recommendations, the Commissioner of Food and Drugs has determined that it is in the interest of the public health for ipecac syrup to be available for sale without prescription, provided that it is packaged in a quantity of 1 fluid ounce (30 milliliters), and its label bears, in addition to other required label information, the following, in a prominent and conspicuous manner:

(1) A statement conspicuously boxed and in red letters, to the effect: "For emergency use to cause vomiting in poisoning. Before using, call physician, the Poison Control Center, or hospital emergency room immediately for advice." (2) A warning to the effect: "Warning-Keep out of reach of children. Do

not use in unconscious persons. Ordinarily, this drug should not be used if strychnine, corrosives such as alkalies (lye) and strong acids, or petroleum distillates such as kerosine, gasoline, coal oil, fuel oil, paint thinner, or cleaning fluid have been ingested."

(3) Usual dosage: 1 tablespoon (15 milliliters) in persons over 1 year of age. [30 F.R. 13628, Oct. 27, 1965]

§ 3.31 Label declaration of salt in frozen vegetables.

(a) In a number of diseases or disease conditions it is important to restrict the intake of sodium. Sodium cccurs in all natural foods, but added salt makes the most important contribution to the total sodium intake in the diet. Most fresh vegetables are of low sodium content and consumers generally regard frozen vegetables as being free of added salt and suitable for use in low-sodium diets. While salt may not be added directly as a seasoning ingredient during the processing of frozen vegetables, the use of salt brine in quality separation of such vegetables as peas and lima beans preparatory to freezing may contribute substantial amounts of salt to the finished article. The failure of the labels of frozen vegetables to declare the presence of salt has been the basis of complaints to the Food and Drug Administration.

(b) Section 403 (i) (2) of the Federal Food, Drug, and Cosmetic Act requires the label of a fabricated food to bear the common or usual name of each ingredient present. The Department of Health, Education, and Welfare regards any frozen vegetable containing salt, added directly or indirectly, as misbranded in violation of section 403 (i) (2) of the Federal Food, Drug, and Cosmetic Act unless its label names salt as an ingredient.

[20 FR. 9549, Dec. 20, 1955]

§ 3.32

Label declarations of vitamin B12 and folic acid in foods for special dietary uses.

(a) Section 125.3 (a) (2) of this chapter, issued under the authority of section 403 (j) of the Federal Food, Drug, and Cosmetic Act (sec. 403(j), 52 Stat. 1048; 21 U.S.C. 343 (j)) requires that if a food purports to be or is represented for special dietary use by man by reason, in whole or in part, of a vitamin for which the need in human nutrition has not been established, the label of such food

shall bear the statement "The need for in human nutrition has not been established," the blank to be filled in with the name of such vitamin.

(b) Heretofore this Department has considered vitamin B12 and folic acid as among those vitamins for which the need in human nutrition has not been established. However, recent scientific evidence shows that these vitamins are needed in human nutrition. The Department therefore considers the requirement of § 125.3 (a) (2) quoted in paragraph (a) of this section as no longer applicable to food offered for special dietary use by reason of these vitamins.

(Sec. 403, 52 Stat. 1047, as amended; 21 U.S.C. 343) [20 F.R. 9549, Dec. 20, 1955]

§ 3.33 Status of foods containing added coumarin.

Manufacturers of coumarin have reported pharmacological investigations showing that it has toxic properties. They have informed the Food and Drug Administration that it will no longer be sold for food use. The Federal Food, Drug, and Cosmetic Act defines food as adulterated if it contains any added poisonous or deleterious substance not required in the production or avoidable in good manufacturing practice. Food containing coumarin added as such or as a constituent of tonka beans or tonka extract will be regarded as adulterated under this provision of the law.

(Secs. 402, 406, 52 Stat. 1046, as amended, 1049, as amended; 21 U.S.C. 342, 346) [20 F.R. 9549, Dec. 20, 1955]

§ 3.34 Labeling of imported crabmeat.

(a) For many years canned crabmeat has been imported into the United States from Japan. Such imports have consisted primarily of a product designated as "King crabmeat." There have been limited importations of articles designated as "Korean crabmeat" and "Snow crabmeat." Two closely allied species of crab have been packed in Japan for export to the United States, under the designation "King crabmeat." These species are Paralithodes camtschatica (taraba-gani) and Paralithodes platypus (abura-gani). A third species of crab, Paralithodes brevipes, has been labeled either as "King crabmeat" or "Hanasaki crabmeat" when intended for export to the United States. The Department of Health, Education, and Welfare considers the term "King

crabmeat" as an acceptable common name for the product prepared from any one of the three species Paralithodes camtschatica, Paralithodes platypus, and Paralithodes brevipes. The Department also considers the name "Hanasaki crabmeat" as an alternative common name for the product prepared from Paralithodes brevipes.

(b) Prior to World War II, there was a limited pack of crabmeat from the species Erimacrus isenbeckii at canneries located on the coast of Korea, but only a small quantity of this product was imported into the United States. To distinguish the product from the various species of Paralithodes and to connote its geographic origin, the article was designated by the name "Korean crab." For the past several years there has been a limited amount of the species Erimacrus isenbeckii packed in Japan or on Japanese factory ships operating in the Bering Sea. This species of crab is generally known in Japan as "Kegani." This product, packed in Japan, when offered for entry into the United States has been designated by a variety of names, including "Korean crabmeat," "Snow crabmeat," "Eliza crabmeat," "Kegani crabmeat," and "Zuwai crabmeat," with resulting confusion to importers and consumers. The term "Korean crab" is no longer applicable to the product as an indication of its geographic origin. The long absence of the product from the domestic market, until its recent reintroduction under a variety of names, has largely eliminated consumer recognition of the identity of the product under the name "Korean crabmeat." The Department therefore considers the designation "Korean variety crabmeat" or, alternatively, "Kegani crabmeat" as suitable common names for the product packed from the species Erimacrus isenbeckii.

(c) There has also been a limited pack of Chionectes opilio (zuwai-gani) offered for entry into the United States. This product has for many years been designated by the name "Snow crabmeat." The Department regards the designation "Snow crabmeat" as the common or usual name for the product when distributed in the United States.

(d) Section 403 (i) (1) of the Federal Food, Drug, and Cosmetic Act requires that the label of a food for which there is no definition and standard of identity shall bear the common or usual name of

the food, if any there be. No definition and standard of identity has been established for crabmeat under the act. The Department of Health, Education, and Welfare regards the label designations for canned crabmeat prepared from the various species of crab as stated in paragraphs (a), (b), and (c) of this section as satisfactory compliance with section 403 (i) (1) of the act.

(Sec. 403, 52 Stat. 1047, as amended; 21 U.S.C. 343) [20 F.R. 9549, Dec. 20, 1955]

§ 3.35 Labeling of drug preparations containing significant proportions of wintergreen oil.

(a) Because methyl salicylate (wintergreen oil) manifests no toxicity in the minute amounts in which it is used as a flavoring, it is mistakenly regarded by the public as harmless even when taken in substantially larger amounts. Actually, it is quite toxic when taken in quantities of a teaspoonful or more. Wintergreen oil and preparations containing it have caused a number of deaths through accidental misuse by both adults and children. Children are particularly attracted by the odor and are likely to swallow these products when left within reach.

(b) To safeguard against fatalities from this cause, the Department of Health, Education, and Welfare will regard as misbranded under the provisions of the Federal Food, Drug, and Cosmetic Act any drug containing more than 5 percent methyl salicylate (wintergreen oil), the labeling of which fails to warn that use otherwise than as directed therein may be dangerous and that the article should be kept out of reach of children to prevent accidental poisoning.

(c) This statement of interpretation in no way exempts methyl salicylate (wintergreen oil) or its preparations from complying in all other respects with the requirements of the Federal Food, Drug, and Cosmetic Act.

(Sec. 502, 52 Stat. 1050, as amended; 21 U.S.C. 352) [20 F.R. 9549, Dec. 20, 1955] Thorium dioxide for drug use.

§ 3.36

(a) Thorium dioxide is a source of naturally occurring radioactivity that has been used over a period of years as a radiopaque medium. When thorium dioxide is injected, it is permanently stored in the body. Because of its radioactivity, this storage causes scarring and carcinogenesis in the area of storage. There are reports in the medical litera

ture of malignancy and deaths resulting from the injection of thorium dioxide. Therefore, the use in man of drugs containing thorium dioxide is justified only when this drug has a unique clinical usefulness and there is substantial evidence of limited life expectancy by reason of disease or advanced age. The administration of the drug to food-producing animals cannot be justified since it may result in residues of the drug in food.

(b) Drugs containing thorium dioxide are unsafe and are regarded as misbranded within the meaning of section 502 (f) (1), (2), and (j) of the Federal Food, Drug, and Cosmetic Act when labeled or advertised for administration to man except when they have a unique clinical usefulness and there is substantial evidence of limited life expectancy by reason of disease or advanced age.

for

(c) Drug preparations containing thorium dioxide may be approved marketing on the basis of new-drug applications containing labeling bearing, in addition to other requirements, information to the following effect, which differs substantially from the labeling that has been employed in the past in the marketing of such drugs:

(1) Warning. For use only when this drug has a unique clinical usefulness and there is substantial evidence of limited life expectancy by reason of disease or advanced age. Not for administration to food-producing animals.

(2) Precautions. Special precautions should be taken to prevent soft tissue extravasation of the injected material. Precautions should be taken to prevent injection of thorium dioxide into the subarachnoid space.

(3) Indications for use. For demonstration of primary or secondary tumors in the liver; for the delineation of the wall of a cystic malignant brain tumor when such delineation is deemed advantageous for purposes of progressive monitoring in the course of therapy.

(4) Dosage. Minimum amount necessary for adequate visualization should be utilized.

(d) A new-drug application will be regarded as approvable if it contains appropriate labeling conforming to the provisions of paragraph (c) of this section and satisfactory information of the kinds required by items 2, 3, 4, 6, 7, and 9 of the new-drug application form contained in § 130.4 (c) of this chapter.

(Secs. 502(f), 52 Stat. 1050 as amended; 21 U.S.C. 352 (f)) [30 F.R. 2104, Feb. 16, 1965]

§ 3.37

Acetophenetidin (phenacetin). containing preparations; necessary warning statement.

(a) In 1961, the Food and Drug Administration, pursuant to its statutory responsibility for the safety and effectiveness of drugs shipped in interstate commerce, began an active investigation of reports of possible toxic effects and renal damage due to misuse of the drug acetophenetidin. This study led to the decision that there was probable cause to conclude that misuse and prolonged use of the drug were in fact responsible for kidney lesions and disease. The Commissioner of Food and Drugs, in December 1963, appointed an ad hoc Advisory Committee of Inquiry on Possible Nephrotoxicity Associated With the Abuse of Acetophenetidin (Phenacetin) -Containing Preparations. This committee, composed of scientists in the fields of pharmacology and medicine, on April 23, 1964, submitted its findings and conclusions in the matter and recommended that all acetophenetidin (phenacetin) -containing preparations bear a warning as provided in section 502(f) (2) of the Federal Food, Drug, and Cosmetic Act.

(b) On the basis of the studies made by the Food and Drug Administration and the report of the Advisory Committee, the Commissioner of Food and Drugs has concluded that it is necessary for the protection of users that the label and labeling of all acetophenetidin (phenacetin) -containing preparations bear a warning statement to the following effect: "Warning-This medication may damage the kidneys when used in large amounts or for a long period of time. Do not take more than the recommended dosage, nor take regularly for longer than 10 days without consulting your physician."

[29 F.R. 11418, Aug. 7, 1964]

§ 3.38 Declaration of quantity of contents on labels for canned oysters. (a) For many years packers of canned oysters in the Gulf area of the United States have labeled their output with a declaration of the drained weight of oysters in the containers. Packers in other areas have marketed canned oysters with a declaration of the total weight of the contents of the container. Investigation reveals that under presentday practice consumers generally do not discard the liquid packing medium, but