shows that such use of potassium permanganate is not effective in producing abortion, but that instead the drug produces serious and painful injury to the walls of the vagina, causing ulcers, massive hemorrhage, and infection. Such dangerous and useless employment of potassium permanganate is apparently encouraged among the misinformed by the mistaken idea that the vaginal bleeding caused by the corrosive action of the drug indicates a termination of pregnancy, which it does not.

(b) Potassium permanganate is a strong oxidizing agent, a highly caustic, tissue-destroying chemical, and a poi

son.

There are no circumstances under which crystals and tablets of potassium permanganate constitute safe dosage forms for use in self-medication. It is the consensus of informed medical opinion that the only dosage forms of potassium permanganate known to be safe for use in self-medication are aqueous solutions containing not more than 0.04 percent potassium permanganate. Such solutions are safe for use in self-medication only by external application to the skin.

(c) In view of the very real potentiality for harmful effect, and the actual injuries caused by the misuse of potassium permanganate, the Food and Drug Administration believes that in order adequately to protect the public health:

(1) Potassium permanganate and potassium permanganate tablets intended for human use are drugs subject to section 503(b)(1) of the Federal Food, Drug, and Cosmetic Act and should be restricted to prescription sale. Such drugs will be regarded as misbranded if at any time prior to dispensing the label fails to bear the legend, "Caution: Federal law prohibits dispensing without prescription.”

(2) Potassium permanganate labeled for use as a prescription component in human drugs under the exemption provided in § 1.106 (k) of this chapter or labeled for manufacturing use under the exemption provided in § 1.106(1) will be regarded as misbranded unless the label bears the statement, "Caution: Federal law prohibits dispensing without prescription."

(3) These drugs will be regarded as misbranded when intended for veteri

nary use unless the label bears the legend, "Caution: Federal law restricts this drug to sale by or on the order of a licensed veterinarian”; Provided, however, That this shall not apply to a drug labeled and marketed for veterinary use if such drug contains not more than 50 percent of potassium permanganate and includes other ingredients which make it unsuitable for human use and unlikely that the article would be used in an attempt to induce abortion.

(4) Any preparation of potassium permanganate intended for over-the-counter sale for human use internally or by application to any mucous membranes or for use in the vagina will be regarded as misbranded under the provisions of section 502(f) (1) and (2) and section 502 (j) of the act.

(5) Any other preparation of potassium permanganate intended for overthe-counter sale for human use will be regarded as misbranded under section 502(f) (1) and (2) and section 502 (j) of the act unless, among other things, all of the following conditions are met:

(i) It is an aqueous solution containing not more than 0.04 percent potassium permanganate.

(ii) The label and labeling bear, in juxtaposition with adequate directions for use, clear warning statements designated as "Warning," and to the effect: "Warning-For external use on the skin only. Severe injury may result from use internally or as a douche. Avoid contact with mucous membranes.”

(d) The labeling or dispensing of any potassium permanganate preparations intended for drug use within the jurisdiction of the Federal Food, Drug, and Cosmetic Act contrary to this statement after 60 days from the date of its publication in the FEDERAL REGISTER may be made the subject of regulatory proceedings.

(Secs. 502(f) (1), (2), (j), 503(b)(1), 705 (b), 52 Stat. 1050, 1051, 1052, as amended, 1057; 21 U.S.C. 352(f) (1), (2), (1), 353 (b) (1), 375(b)) [25 F.R. 8078, Aug. 23, 1960, as amended at 27 FR. 1010, Feb. 3, 1962] §3.8 Amphetamine and methamphetamine inhalers regarded as prescription drugs.

(a) Recurring reports of abuse and misuse of methamphetamine (also known as desoxyephedrine) inhalers show that they have a potentiality for

harmful effect and that they should not be freely available to the public through over-the-counter sale. From complaints by law-enforcement officials, health officials, individual physicians, parents, and others as well as from Food and Drug Administration investigations, it is evident that the wicks from these inhalers are being removed and the methamphetamine they contain is being used as a substitute for amphetamine tablets. Amphetamine tablets and amphetamine inhalers have been restricted to prescription sale because of their potentiality for harm to the user.

(b) It is the considered opinion of the Food and Drug Administration that, in order to adequately protect the public health, inhalers containing methamphetamine or methamphetamine salts (ddesoxyephedrine, or dl-desoxyephedrine, or their salts), as well as amphetamine inhalers should be restricted to prescription sale and should be labeled with the legend "Caution: Federal law prohibits dispensing without prescription."

(Secs. 503 (b) (1) (B), 52 Stat. 1052 as amended; 21 U.S.C. 353(b) (1) (B)) [30 FR. 1845, Feb. 10, 1965]

§ 3.9

Label declaration of vitamin E in food for special dietary use.

(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 the Food and Drug Administration has considered vitamin E as among those vitamins for which the need in human nutrition has not been established. However, in the opinion of nutrition scientists, recent evidence showed that this vitamin is needed in human nutrition. The scientific studies upon which this conclusion is based demonstrate that the vitamin E utilized in the physiological processes of the human body is that derived only from the diet. The Food and Drug Administration therefore considers the requirement of

§ 125.3(a) (2) of this chapter, quoted in paragraph (a) of this section as no longer applicable to food offered for special dietary use by reason of vitamin E.

(c) The difficulty of producing experimental dietary deficiency of vitamin E emphasizes that the diets used in this country are amply supplied with this vitamin. Any claim in the labeling of drugs or of foods offered for special dietary use by reason of vitamin E that there is need for dietary supplementation with vitamin E, will be considered false. (Sec. 403(1), 52 Stat. 1048; 21 U.S.C. 343 (J)) [24 F.R. 8792, Oct. 29, 1959; 24 F.R. 8927, Nov. 3, 1959]

§ 3.10 Notice to manufacturers and users in food products of monosodium glutamate.

In the light of information now before the Food and Drug Administration on the manner of use of monosodium glutamate in foods, this Agency is not disposed to maintain the position previously expressed by it on April 11, 1940, in a trade correspondence letter designated as TC 233 that monosodium glutamate be designated as an artificial flavoring on labels of foods to which it is added. Where it is used as an ingredient in a food for which a standard of identity has not been promulgated under the Federal Food, Drug, and Cosmetic Act, its presence should be declared on the label by its common or usual name, monosodium glutamate, in compliance with section 403(i) (2) of the act. Since none of the standards of identity for food so far promulgated under section 401 provide for the inclusion of monosodium glutamate as an optional ingredient, this substance may not be used in such standardized foods unless and until the appropriate standards are amended after hearing. If in any case the addition of monosodium glutamate has the effect of concealing damage or inferiority, or of making the article appear to be of better or greater value than it is, the article would be classed as adulterated regardless of labeling.

[20 F.R. 9544, Dec. 20, 1955]

§3.11 Notice to manufacturers, packers, and distributors of estrogenic hormone preparations.

Some drug preparations fabricated wholly or in part from estradiol and la

beled as to potency in terms of international units or in terms of international units of estrone activity have been marketed. The international unit of the estrus-producing hormone was established by the International Conference on the Standardization of Sex Hormones at London, England, on August 1, 1932. This unit was defined as "the specific estrus-producing activity contained in 0.1 gamma (=0.0001 mg.) of the standard" hydroxyketonic hormone found in urine (estrone). The International Conference declared that it did not recommend the determination of the activity of nonhydroxyketonic forms of estrogenic hormones in units of estrone because of the varying ratios between the activity of such nonhydroxyketonic estrogenic hormones and estrone, when measured by different methods on test animals. There is no international unit for measuring the activity of estradiol and no accepted relationship between its activity and that of estrone, either in test animals or in humans. The declaration of potency of estradiol in terms of international units or in terms of international units of estrone activity is therefore considered misleading, within the meaning of 21 U.S.C. 352(a). The declaration of the estradiol content of an estrogenic hormone preparation in terms of weight is considered appropriate.

[20 F.R. 9544, Dec. 20, 1955, as amended at 22 F.R. 10685, Dec. 25, 1957]

§3.12 Tannic acid and barium enema preparations.

(a) It has become a widespread practice for tannic acid to be added to barium enemas to improve X-ray pictures. Tannic acid is capable of causing diminished liver function and severe liver necrosis when absorbed in sufficient amounts. The medical literature reports a number of deaths associated with the addition of tannic acid to barium enemas. There

is a lack of scientific evidence to establish the conditions, if any, under which tannic acid is safe and effective for use in enemas. Tannic acid for rectal use to enhance X-ray visualization is regarded as a new drug within the meaning of section 201 (p) of the Federal Food, Drug, and Cosmetic Act.

(b) In view of the hazards involved when tannic acid is used in barium enemas, any shipments of tannic acid

labeled to come within the exemptions under 502(f) of the Act containing such phrases as: "Caution: For manufacturing, processing, or repackaging," "For prescription compounding," or "Diagnostic reagent-For professional use only" will be regarded by the Commissioner of Food and Drugs as misbranded within the meaning of section 502(f) of the Federal Food, Drug, and Cosmestic Act unless the label and the labeling bear conspicuously a warning to the effect: "Warning-Not for use in enemas.”

(c) Any tannic acid intended for use by man and found within the jurisdiction of the Federal Food, Drug, and Cosmetic Act labeled contrary to this section after 60 days from the date of its publication in the FEDERAL REGISTER may be made the subject of regulatory proceedings. (Sec. 502, 52 Stat. 1051, as amended; 21 U.S.C. 352) [29 F.R. 3621, Mar. 21, 1964] §3.13

Grain seed treated with poisonous substances; color identification to prevent adulteration of human and animal food.

(a) In recent years there has developed increasing use of poisonous treatments on seed for fungicidal and other purposes. Such treated seed, if consumed, presents a hazard to humans and livestock. It is not unusual for stocks of such treated food seeds to remain on hand after the planting season has passed. Despite the cautions required by the Federal Seed Act (53 Stat. 1275, as amended 72 Stat. 476, 7 U.S.C. 1551 et seq.) in the labeling of the treated seed, the Food and Drug Administration has encountered many cases where such surplus stocks of treated wheat, corn, oats, rye, barley, and sorghum seed had been mixed with untreated seed and sent to market for food or feed use. This has resulted in livestock injury and in legal actions under the Federal Food, Drug, and Cosmetic Act against large quantities of food adulterated through such admixture of poisonous treated seeds with good food. Criminal cases were brought against some firms and individuals. Where the treated seeds are prominently colored, buyers and users or processors of agricultural food seed for food purposes are able to detect the admixture of the poisonous seed and thus reject the lots; but most such buyers, users, and processors do not have the facilities or scientific equipment to determine the presence of the poisonous chemical at the time

crops are delivered, in cases where the treated seeds have not been so colored. A suitable color for this use is one that is in sufficient contrast to the natural color of the food seed as to make admixture of treated, denatured seeds with good food easily apparent, and is so applied that it is not readily removed.

(b) On and after December 31, 1964, the Food and Drug Administration will regard as adulterated any interstate shipment of the food seeds wheat, corn, oats, rye, barley, and sorghum bearing a poisonous treatment in excess of a recognized tolerance or treatment for which no tolerance or exemption from tolerance is recognized in regulations promulgated pursuant to section 408 of the Federal Food, Drug, and Cosmetic Act, unless such seeds have been adequately denatured by a suitable color to prevent their subsequent inadvertent use as food for man or feed for animals.

(c) Attention is called to the labeling requirements of the Federal Hazardous Substances Labeling Act, where applicable to denatured seeds in packages suitable for household use.

(Secs. 402 (a), 408, 52 Stat. 1046 as amended; 68 Stat. 511; 21 U.S.C. 342(a), 348; sec. 2(f) (1), 74 Stat. 372; 15 U.S.C. 1261) [28 F.R. 11925, Nov. 8, 1963]

§3.14 Notice to manufacturers and distributors of foods and drugs containing artificial sweeteners. Chronic-toxicity studies conducted by the Department of Health, Education, and Welfare show that the artificial sweeteners dulcin (also known as sucrol, or 4-ethoxyphenylurea, or paraphenetolcarbamide) and P-4000 (also known as 1-n-propoxy-2-amino-4-nitrobenzene) cause injury to rats when fed at relatively low levels for approximately 2 years. Consequently, the Secretary of Health, Education, and Welfare regards these chemicals as poisonous substances which have no place in any food.

Pending further evaluation of available data, it is not possible to state the conditions under which dulcin or P-4000 would render a drug in which it is used dangerous to health. Since other artificial sweeteners are available which have a much greater margin of safety in chronic-toxicity studies, the use of dulcin and P-4000 as sweetners of drugs is to be discouraged.

[20 F.R. 9545, Dec. 20, 1955]

§3.15 Potassium salt preparations intended for oral ingestion by man.

(a) The Food and Drug Administration will initiate no regulatory action with respect to the continued marketing of coated tablets containing potassium chloride or other potassium salts which supply 100 milligrams or more of potassium per tablet provided all the following conditions are met:

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

(i) The labeling of the drug bears the prescription caution statement quoted in section 503 (b) (4) of the Federal Food, Drug, and Cosmetic Act;

(ii) The labeling on or within the package from which the drug is to be dispensed bears adequate information for its use by practitioners in accord with the "full disclosure" labeling requirements of § 1.106(b) of this chapter, including the following warning statement: "Warning-There have been several reports, published and unpublished, concerning nonspecific small-bowel lesions consisting of stenosis, with or without ulceration, associated with the administration of enteric-coated thiazides with potassium salts. These lesions may occur with enteric-coated potassium tablets alone or when they are used with nonenteric-coated thiazides, or certain other oral diuretics. These small-bowel lesions have caused obstruction, hemorrhage, and perforation. Surgery was frequently required and deaths have occurred. Based on a large survey of physicians and hospitals, both United States and foreign, the incidence of these lesions is low, and a causal relationship in man has not been definitely established. Available information tends to implicate enteric-coated potassium salts, although lesions of this type also occur spontaneously. Therefore, coated potassium-containing formulations should be administered only when indicated, and should be discontinued immediately if abdominal pain, distention, nausea, vomiting, or gastrointestinal bleeding occur. Coated potassium tablets should be used only when adequate dietary supplementation is not practicable."

(Although the warning statement includes references to enteric-coated potassium salt preparations, it applies to any capsule or coated tablet of a potassium salt intended for oral ingestion without prior dilution with an adequate

volume of liquid to preclude gastrointestinal injury.)

(iii) Any other labeling or additional advertising for the drug conforms to the labeling described in subdivision (ii) of this subparagraph, in accord with §§ 1.105 and 1.106(b) of this chapter.

(2) Within 90 days from the date of publication of this statement of policy in the FEDERAL REGISTER, the manufacturer, packer, or distributor of the drug shall submit a new-drug application containing satisfactory information of the kind required by Items 2, 3, 4, 6, 7, and 9 of the new-drug application form contained in § 130.4 (c) of this chapter, with appropriate labeling as described in this paragraph.

(b) The Food and Drug Administration may initiate regulatory proceedings after 30 days from the date of publication of this section, with respect to the marketing of uncoated tablets containing potassium chloride or other potassium salts which supply 100 milligrams or more of potassium per tablet or with respect to liquid preparations containing potassium chloride or other potassium salts which supply 20 milligrams or more of potassium per milliliter, labeled or intended for human use, unless all the following conditions are met:

(1) The labeling of the drug bears the prescription caution statement quoted in section 503(b) (4) of the Federal Food, Drug, and Cosmetic Act; and

(2) The labeling on or within the package from which the drug is to be dispensed bears adequate information for its use by practitioners in accord with the "full disclosure" labeling requirements of § 1.106(b) of this chapter, including a recommendation that patients be directed to disslove any such tablets in an appropriate amount of liquid and to dilute any such liquid preparations adequately to assure against gastrointestinal injury associated with the oral ingestion of concentrated potassium salt preparations.

(Secs. 502(f), 503(b)(4), 505; 52 Stat. 1051, 1052; 21 U.S.C. 352(1), 353(b), 355) [30 F.R. 5790, Apr. 24, 1965; 30 FR. 6071, Apr. 29, 1965] §3.16 Use of ox bile from condemned livers from slaughtered animals in the manufacture of drugs.

Conferences have recently been held between members of the Department of Health, Education, and Welfare and representatives of the Agricultural Research Service, Department of Agriculture,

concerning requests made to that agency for the release of ox bile from condemned livers of slaughtered animals for use in the manufacture of certain drugs.

The Secretary of Health, Education, and Welfare has given careful consideration to this problem and has reached the conclusion that no hazard to public health will be involved in the release of such ox bile, after the addition to it of sufficient sodium hydroxide to give the mixture a sodium hydroxide content of not less than 5 percent, the mixture then being allowed to stand at least 24 hours. This Department will not regard as in violation of the provisions of the Federal Food, Drug, and Cosmetic Act such alkalized and aged ox bile, if labeled "Ox Bile and Sodium Hydroxide (or Ox Bile and Sodium Hydroxide Solution). Sodium hydroxide not less than 5 percent by weight. For manufacturing use only." together with a statement of the quantity of contents in the container (for example, "50 gallons") and the name and address of the manufacturer, packer, or shipper.

Bile from the condemned livers of sheep and goats also may be released, under the same conditions as outlined in the preceding paragraph, except that the words "Sheep Bile" or "Goat Bile," as the case may be, shall be substituted for the words "Ox Bile" upon the label. In the case of mixtures of bile from any two or all three of the sources mentioned, the label shall indicate the sources of such bile.

[20 F.R. 9541, Dec. 20, 1955, as amended at 22 F.R. 10685, Dec. 25, 1957]

§3.17 Labeling of oleomargarine or margarine.

The Federal Food, Drug, and Cosmetic Act was amended by Public Law 459, 81st Congress (64 Stat. 20) on colored oleomargarine or margarine by adding thereto a new section numbered 407. Among other things, this section requires that there appear on the label of the package the word "oleomargarine" or "margarine" in type or lettering at least as large as any other type or lettering on the label, and a full and accurate statement of all the ingredients contained in such oleomargarine or margarine. It provides that these requirements "shall be in addition to and not in lieu of any of the other requirements of this Act."

(a) Under section 403 (g) of the Federal Food, Drug, and Cosmetic Act, any article that is represented as or