tubes, intended solely for use when necessary to maintain drainage from the uterine cavity.

(b) On the basis of this consensus of expert opinion and the supporting evidence of many known injuries, the Food and Drug Administration concludes that stem-type and wing-type intracervical and intrauterine pessaries are dangerous to health, and regardless of their labeling, may be shown to be misbranded within the meaning of sections 502 (f) (1) and (2) and 502 (j) of the Federal Food, Drug, and Cosmetic Act. It is recommended that distributors of these devices remove them from the interstate market at once. Regulatory action may be instituted in connection with any such devices found within the jurisdiction of the act.

[22 F.R. 865, Feb. 12, 1957]

§ 3.50 Status of salt substitutes under the Federal Food, Drug, and Cosmetic Act.

(a) As a result of reported poisonings from salt substitutes containing lithium chloride, under date of March 8, 1949, the Food and Drug Administration announced that it would regard each salt substitute as a new drug within the meaning of section 201 (p) of the Federal Food, Drug, and Cosmetic Act, and that interstate distribution of each salt substitute should be discontinued until a new-drug application had been filed and become effective. Substantial information concerning the safety of many of the ingredients used in salt substitutes has been developed and published since the announcement was made. It is now possible to evaluate the safety of many individual salt substitutes and to determine whether they are new drugs requiring effective applications prior to distribution in interstate commerce.

(b) The Food and Drug Administration no longer regards all salt substitutes as new drugs. Upon request, the Administration will express its opinion whether a new-drug application is necessary for any particular product if complete information concerning its composition and proposed labeling is submitted. [22 FR. 10685, Dec. 25, 1957]

been designated as D-isoascorbic acid. However, this designation is capable of misleading purchasers of food in which it is used as an ingredient because of the similarity of such designation to the chemical name and the common name of vitamin C, which is ascorbic acid. Ascorbic acid (vitamin C) is capable of preventing the deficiency disease scurvy, but D-isoascorbic acid is ineffective for this purpose.

(b) The Joint Committee on Nomenclature of the American Institute of Nutrition and the Society of Biological Chemists has considered this matter, and pursuant to the Committee's recommendation the respective scientific organizations approved resolution to drop the use of the designation D-isoascorbic acid and to adopt as a common name the name erythorbic acid for Derythroascorbic acid.

(c) The compound D-erythroascorbic acid is not specified as an ingredient of any food for which a standard has been established. For foods other than those for which standards have been established, section 403 (i) (2) of the Federal Food, Drug, and Cosmetic Act requires that ingredients be listed on labels by their common or usual names. If the label on a food that contains D-erythroascorbic acid designates that ingredient by the name erythorbic acid, the requirement that the label bear the common or usual name of the ingredient will be regarded as having been met. (Sec. 403, 52 Stat. 1047, as amended; 21 U.S.C. 343) [23 F.R. 5874, Aug. 21, 1958]

§ 3.52 Dimethylsulfoxide (DMSO) preparations; clinical testing and investigational use.

(a) (1) Chronic-toxicity studies with dimethylsulfoxide (DMSO) in animals, including dogs, rabbits, and swine, reported by a consulting laboratory in England and by a number of laboratories in the United States show that the administration of dimethylsulfoxide (DMSO) causes changes in the refractive index of the lens of the eyes of such animals. On the basis of these reports, clinical testing of dimethylsulfoxide (DMSO) preparations was discontinued for a time and later resumed under restricted conditions.

(2) An adequate, controlled human toxicity study (Phase I) involving shortterm cutaneous application of 1 gram of dimethylsulfoxide (DMSO) per kilogram of body weight daily for 14 consecutive days has recently been completed. Data

obtained, not previously available, show that when dimethylsulfoxide (DMSO) was applied topically to the skin of healthy volunteers, it did not produce adverse effects upon the eyes of the subjects. Mild, apparently reversible, changes were seen suggesting that the drug may have some effect upon the liver and upon the hemopoietic system in some subjects.

(b) A comprehensive evaluation of all available data on dimethylsulfoxide (DMSO) preparations justifies further clinical investigation of the drug in treating certain serious conditions. Although reports concerning the use of dimethylsulfoxide (DMSO) in relatively benign conditions are equivocal regarding its efficacy, short-term clinical use has been established as reasonably safe by adequate Phase I studies. Under appropriate protocols, further short-term clinical investigations in the treatment of such benign conditions can be justified.

(c) No person may ship dimethylsulfoxide (DMSO) within the jurisdiction of the Federal Food, Drug, and Cosmetic Act for clinical testing in man until a "Notice of Claimed Investigational Exemption for a New Drug," pursuant to § 130.3 of this chapter, is on file with the Food and Drug Administration and all the following conditions are met:

(1) Proposed long-term clinical studies (Phase II) are restricted to the use of DMSO to cutaneous application in serious conditions, such as the incapacitating arthropathies, scleroderma, dermatomyositis, and intractible pain due to malignancy, are to be conducted in medical centers having adequate facilities and well-trained, experienced medical personnel, and are to include the following essential conditions in the study protocol. All subjects will receive a full examination including:

(1) An eye evaluation by an ophthalmologist to include actual refractive error measurements and slit-lamp findings as well as other parameters of the ocular examination prior to receiving the drug, at intervals not exceeding 3 months during the study and 3 months after discontinuing the drug.

(ii) Liver function tests and a complete blood count (CBC) prior to receiving the drug, at intervals not exceeding 4 weeks during the study and 4 weeks after discontinuing the drug.

(2) Proposed short-term studies (Phase II) restrict the use of dimethylsulfoxide (DMSO) to cutaneous applica

tion for not more than 14 days in closely monitored investigations, with appropriate control groups, that may include studies of use in such conditions as acute musculoskeletal conditions (acute arthritis, peri arthritis, capsulitis, bursitis, tendonitis, synovitis, and post-traumatic lesions) and soft tissue injuries. The proposed studies shall provide for pretreatment liver function studies and a complete blood count (CBC), to be repeated within 7 days after commencing treatment and at the conclusion of the study. Routine monitoring of effects upon the eye is not required.

(3) All proposals must show that patient consent requirements will be carefully observed and shall include a commitment that patients will be fully informed of: The effects of dimethylsulfoxide (DMSO) in animals, the possibility that these may occur in humans, and the known possible effects of the drug in humans.

(d) Dimethylsulfoxide (DMSO) preparations may be shipped within the jurisdiction of the act for tests in vitro and in laboratory research animals in accord with 130.3a (a) of this chapter and for clinical investigation in animals in accord with § 130.3a (b) of this chapter. (Sec. 505, 52 Stat. 1052-53, as amended; 21 U.S.C. 355) [33 F.R. 12776, Sept. 10, 1968] § 3.53 Oral prenatal drugs containing

fluorides intended for human use.

(a) The Food and Drug Administration finds that there is neither substantial evidence of effectiveness nor a general recognition by qualified experts that prenatal drug preparations containing fluorides promote tooth development in the fetus, prevent dental caries in the offspring, or prevent dental caries in pregnant women.

(b) Any such drug preparation that is so labeled, represented, or advertised will be regarded as misbranded and subject to regulatory proceedings unless such recommendations are covered by a newdrug application, including substantial evidence of effectiveness, approved pursuant to section 505 of the Federal Food, Drug, and Cosmetic Act. Any such drug preparation that is labeled, represented, or advertised as containing fluorides as an active ingredient of the drug for prenatal use will similarly be regarded as misbranded and subject to regulatory proceedings.

(c) A completed and signed "Notice of Claimed Investigational Exception for

a New Drug," Form FD-1571 set forth in 130.3 of this chapter, must be submitted to cover clinical investigations designed to obtain evidence that such preparations are effective for such uses.

(d) Regulatory proceedings may be initiated with respect to drug preparations shipped within the jurisdiction of the act that are contrary to provisions of this statement after 30 days from the date of publication of this statement in the FEDERAL REGISTER.

(Secs. 502 (a), (f), 505, 52 Stat. 1050, 1051, 1052, as amended; 21 U.S.C. 352 (a), (f), 355) [32 F.R. 4850, Mar. 22, 1967]

emer

§ 3.54 Epinephrine injection 1: 000 in 10-milliliter containers for gency treatment of anaphylactoid shock in cattle, horses, sheep, and swine.

(a) Anaphylactoid reactions in 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 overthe-counter sale of epinephrine injection 1:1000 can be prepared.

(b) In view of the above, the Commissioner of Food and Drugs has concluded that it is in the public interest to make epinephrine injection 1: 1000 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 required 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 fol

lowing. These symptoms ́ may appear shortly after injection of a bacterin, vaccine, or antibiotic.

[81 F.R. 11888, Aug. 27, 1966]

§ 3.55

Antibiotics used in veterinary medicine and for nonmedical purposes; required data.

(a) An ad hoc committee, Committee on the Veterinary Medical and Nonmedical Uses of Antibiotics, was formed by the Food and Drug Administration to study, and advise the Commissioner on, the uses of antibiotics in veterinary medicine and for various nonmedical purposes as such uses may affect the enforcement of the Federal Food, Drug, and Cosmetic Act with respect to the safety and effectiveness of such substances. A copy of the report may be obtained from the Food and Drug Administration, Office of Education and Information, Washington, D.C. 20204.

(b) On the basis of the report of the Committee and other information, sponsors of drugs containing any antibiotic intended for use in food-producing animals shall submit data for determining whether or not such antibiotics and their metabolites are present as residues in edible tissues, milk, and eggs from treated animals; however, in the case of a drug for which such data have already been submitted and for which a regulation has been promulgated under section 409 of the act, only such data as has been accumulated since the issuance of the regulation need be submitted.

(c) The required data shall be submitted within 180 days of the date of publication of this section in the FEDERAL REGISTER; except that in the case of data on intramammary infusion preparations, the data shall be submitted within 60 days of such publication. Data demonstrating the absence in milk of residues of intramammary infusion preparations when used as directed in their labeling are needed within the 60-day period because of the importance of milk in the human diet.

(d) Regulatory proceedings including revocation of prior sanctions, or actions to suspend or amend new drug or antibiotic approvals granted prior to passage of the Food Additives Amendment of 1958 (72 Stat. 1784), may be initiated with regard to the continued marketing of any antibiotic preparation on which the required information is not submitted within the period of time prescribed by paragraph (c) of this section.

(e) Questions relating to the acceptability of proposed research protocols and assay methods for determining the amount of antibiotic residues in food should be directed to the Director of The Bureau of Veterinary Medicine, Food and Drug Administration, Washington, D.C. 20204.

(Secs. 409, 505, 507, 52 Stat. 1052, as amended, 59 Stat. 463, as amended, 72 Stat. 1785; 21 U.S.C. 348, 355, 357) [31 F.R. 11141, Aug. 23, 1966]

§ 3.56 Labeling of articles intended for lay use in the repairing and/or refitting of dentures.

(a) The American Dental Association and leading dental authorities have advised the Food and Drug Administration of their concern regarding the safety of denture reliners, repair kits, pads, cushions, and other articles marketed and labeled for lay use in the repairing, refitting, or cushioning of ill-fitting, broken, or irritating dentures. It is the opinion of dental authorities and the Food and Drug Administration that to properly repair and properly refit dentures a person must have professional knowledge and specialized technical skill. Layman cannot be expected to maintain the original vertical dimension of occlusion and the centric relation essential in the proper repairing or refitting of dentures. The continued wearing of improperly repaired or refitted dentures may cause acceleration of bone resorption, soft tissue hyperplasia, and other irreparable damage to the oral cavity. Such articles designed for lay use should be limited to emergency or temporary situations pending the services of a licensed dentist.

(b) The Food and Drug Administration therefore regards such articles as unsafe and misbranded under the Federal Food, Drug, and Cosmetic Act, unless the labeling:

(1) (i) Limits directions for use for denture repair kits to emergency repairing pending unavoidable delay in obtaining professional reconstruction of the denture;

(ii) Limits directions for use for denture reliners, pads, and cushions to temporary refitting pending unavoidable delay in obtaining professional reconstruction of the denture;

(2) Contains in a conspicuous manner the word "emergency" preceding and modifying each indication-for-use statement for denture repair kits and the

word "temporary" preceding and modifying each indication-for-use statement for reliners, pads, and cushions; and

(3) Includes a conspicuous warning statement to the effect:

(i) For denture repair kits: "Warning-For emergency repairs only. Longterm use of home-repaired dentures may cause faster bone loss, continuing irritation, sores, and tumors. This kit for emergency use only. See Dentist Without Delay."

(ii) For denture reliners, pads, and cushions: "Warning-For temporary use only. Long-term use of this product may lead to faster bone loss, continuing irritation, sores, and tumors. For Use Only Until a Dentist Can Be Seen."

(c) Adequate directions for use require full information of the temporary and emergency use recommended in order for the layman to understand the limitations of usefulness, the reasons therefor, and the importance of adhering to the warnings. Accordingly, the labeling should contain substantially the following information:

(1) For denture repair kits: Special training and tools are needed to repair dentures to fit properly. Home-repaired dentures may cause irritation to the gums and discomfort and tiredness while eating. Long-term use may lead to more troubles, even permanent changes in bones, teeth, and gums, which may make it impossible to wear dentures in the future. For these reasons, dentures repaired with this kit should be used only in an emergency until a dentist can be seen. Dentures that don't fit properly cause irritation and injury to the gums and faster bone loss, which is permanent. Dentures that don't fit properly cause gum changes that may require surgery for correction. Continuing irritation and injury may lead to cancer in the mouth. You must see your dentist as soon as possible.

(2) For denture reliners, pads, and cushions: Use of these preparations or devices may temporarily decrease the discomfort; however, their use will not make the denture fit properly. Special training and tools are needed to repair a denture to fit properly. Dentures that do not fit properly cause irritation and injury to the gums and faster bone loss, which is permanent and may require a a completely new denture. Changes in the gums caused by dentures that do not fit properly may require surgery for correction. Continuing irritation and injury

may lead to cancer in the mouth. You must see your dentist as soon as possible.

(3) If the denture relining or repairing material forms a permanent bond with the denture, a warning statement to the following effect should be included: "This reliner becomes fixed to the denture and a completely new denture may be required because of its use."

(d) Labeling claims exaggerating the usefulness or the safety of the material or failing to disclose all facts relevant to the claims of usefulness will be regarded as false and misleading under sections 201(n) and 502(a) of the Federal Food, Drug, and Cosmetic Act.

(e) Regulatory action may be initiated with respect to any article found within the jurisdiction of the act contrary to the provisions of this policy statement after 90 days following the date of publication of this section in the FEDERAL REGISTER.

[34 F.R. 14168, Sept. 9, 1969]

§ 3.57

Stocks of packages and labels not complying with section 4 of the Fair Packaging and Labeling Act.

(a) Implementation of the Fair Packaging and Labeling Act (Public Law 89755) will require changes in the labels of many foods, drugs, devices, and cosmetics now on the market. The law does not contemplate a disruption of legitimate business practices nor destruction of all stocks of labels and packages rendered not-in-compliance by the effective dates of the regulations promulgated pursuant to that Act. Section 6 of the Fair Packaging and Labeling Act provides that "no regulation adopted under this Act shall preclude the continued use of returnable or reusable glass containers for beverages in inventory or with the trade as of the effective date of this Act, nor shall any regulation under this Act preclude the orderly disposal of packages in inventory or with the trade as of the effective date of such regulation." Section 13 provides that the promulgating authority may by regulation postpone the effective date of the Fair Packaging and Labeling Act for an additional 12month period for classes or types of consumer commodities.

(b) In the orders published in the FEDERAL REGISTER of July 21, 1967, and September 20, 1967, it is stated that the effective date of that initial order covering food labels under the Fair Packaging and Labeling Act shall be December 31,

1967, for all new food packages, new label designs, and labels being reordered, and shall be July 1, 1968, for all food packages and labels being introduced into interstate commerce. Extensions for stocks of packages and labels beyond July 1, 1968, will be considered on an individual case basis and are grantable for good cause shown. Good cause would necessarily include a showing that:

(1) The stocks are in compliance with the present terms of the Federal Food, Drug, and Cosmetic Act and the regulations thereunder;

(2) Due diligence was expended in devising and obtaining labels and packages in compliance with the new regulations insofar as the facilities of the label and package manufacturers permit; and

(3) The stocks did not result from a deliberate attempt to overstock.

(c) The criteria set forth in paragraph (b) (1), (2), and (3) of this section will be equally applicable to stocks of packages and labels of drugs, devices, and cosmetics when the order of January 11, 1968 (33 F.R. 404), amending Part 1 of this chapter with respect to these items, becomes effective.

(d) Extension requests showing good cause, along with pertinent labels, packages, etc., shall be submitted in duplicate and shall consist of the following:

(1) A statement of the total number (not quantity) of labels or packages for which the extension is requested.

(2) Approximate dates revisions will be completed.

(3) The number of labels or packages which have been revised to comply with the Fair Packaging and Labeling Act.

(4) The number of labels or packages scheduled for revision by July 1, 1968.

(5) A duplicate set of representative product labels or packages for which extension is requested. The number to be submitted should be determined as follows:

(i) Ten products or less: Submit all. (ii) More than 10 products: Submit sufficient labels, but not less than 10, to be fully representative.

This procedure is not to be construed as label preclearance. Extension requests need not be submitted for products that are the subject of pending petitions for exemption pursuant to § 1.1a of this chapter.

(Secs. 4, 6, 80 Stat. 1297, 1299, 1800, 15 U.S.C. 1453, 1455) [33 F.R. 3426, Feb. 28, 1968]