injections, ophthalmic solutions, surgical sutures, and surgical dressings sterilized by means of irradiation are regarded as new drugs within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act. An effective new-drug application pursuant to section 505 of the act is therefore a prerequisite to interstate shipment of such articles, except as provided by section 505 (i).

(Secs. 201, 505, 52 Stat. 1040, as amended, 1052, as amended; 21 U.S.C. 321, 355) FR. 9554, Dec. 20, 1955]

§ 3.48

[20

Cobalt preparations intended for use by man.

The present state of scientific knowledge concerning the use of cobalt salts as hemopoietic agents is limited, in that the mechanism of their action is not known and the possible deleterious effects of prolonged administration have not been fully determined. Serious toxic effects have been reported to be associated with such use of cobalt preparations, but there is a difference of opinion whether the cobalt preparations were causative agents in these injuries. In view of the limitations of the current state of scientific knowledge regarding cobalt and in the interest of public health protection, the Food and Drug Administration is adopting the following policies concerning cobalt preparations intended for use by man.

(a) Preparations containing per dosage unit more than 10 milligrams of cobalt chloride, or more than 2.5 milligrams of cobalt in the form of any cobalt salts are not safe for use except under the supervision of a practitioner licensed by law to administer the drug.

(1) Such preparations should be labeled with the statement "Caution: Federal law prohibits dispensing without prescription."

(2) Such preparations are regarded as new drugs within the meaning of section 201 (p) of the Federal Food, Drug, and Cosmetic Act if their labeling or advertising sponsored by or on behalf of their distributor prescribes, recommends, or suggests the administration of more than 15 milligrams of cobalt in the form of any of its salts; for example, more than 60 milligrams of cobalt chloride per 24-hour period.

(3) The labeling of such preparations should bear adequate information for their use by physicians including, among other things, the following:

(1) A statement that substantial quantities of iron salts should usually be administered simultaneously with the administration of cobalt, to obtain the maximum hemopoietic effect.

(ii) A forthright disclosure of the toxic and adverse effects reported to be associated, with the use of cobalt, including those effects in which the role of cobalt may be controversial.

(iii) Disclosure of the fact that the possible deleterious effects of prolonged administration of cobalt are not fully known.

(b) Articles containing per dosage unit more than 2 milligrams but not more than 10 milligrams of cobalt chloride, or more than 0.5 milligram but not more than 2.5 milligrams of cobalt in the form of any cobalt salts may be labeled with adequate directions for use in the selfmedication of simple iron-deficiency anemia only; but such articles will be regarded as misbranded under the provisions of section 502 (f) (1) and/or section 502 (f) (2) and/or section 502 (j), and may be regarded as new drugs within the meaning of section 201 (p) of the act, unless all the following conditions are met:

(1) The dosages prescribed, recommended, or suggested in the labeling do not exceed 40 milligrams of cobalt chloride or 10 milligrams of cobalt in the form of any cobalt salts per 24-hour period.

(2) When used as directed in the labeling, the preparations supply not less than 100 milligrams of iron (Fe) in the form of ferrous sulfate or other assimilable salts of iron per 24-hour period.

(3) The labeling bears, in juxtaposition with the directions for use, clear warning statements, so designated, against:

(1) Exceeding the recommended dosage.

(ii) Administration to children under 12 years of age unless directed by a physician.

(iii) Use for more than 2 months unless directed by a physician.

(c) The policies stated in paragraph (b) of this section also apply to any article containing, per dosage unit, not more than 2 milligrams of cobalt chloride or not more than 0.5 milligram of cobalt in the form of any cobalt salts if the directions for its use prescribe, recommend, or suggest the use of more than

2 milligrams of cobalt chloride or its cobalt equivalent per dose, or more than 8 milligrams of cobalt chloride or its cobalt equivalent per 24-hour period.

(d) Any cobalt-containing drug intended for use by man and which is marketed within the jurisdiction of the act contrary to the provisions of this statement after 60 days from the date of its publication in the FEDERAL REGISTER may be made the subject of regulatory proceedings under the act.

(Secs. 201, 502, 52 Stat. 1041, as amended, 1050, as amended; 21 U.S.C. 321, 352) [21 F.R. 8395, Nov. 2, 1956, as amended at 21 FR. 10274, Dec. 21, 1956]

§ 3.49

Pessaries for intracervical and intrauterine use.

(a) Because of the limited evidence previously available concerning the hazards attending the use of intracervical and intrauterine pessaries, the shipment of such devices within the jurisdiction of the Federal Food, Drug, and Cosmetic Act, with labeling limiting them to sale only on prescription, has not been subjected to regulatory proceedings. A recent survey shows that it is now the consensus of medical opinion among experts qualified by scientific training and experience to evaluate the safety of such devices that stem-type and wing-type intracervical and intrauterine pessaries are too dangerous for use under any form of labeling and serve no useful purpose. This opinion is particularly applicable to pessaries offered or intended for contraceptive use. These views do not apply to those pessaries, made with hollow 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 F.R. 10685, Dec. 25, 1957]

§ 3.51 Label declaration of D-erythroascorbic acid when it is an ingredient of a fabricated food.

(a) The article D-erythroascorbic acid (D-araboascorbic acid, D-erythro-3-ketohexonic acid lactone) has sometimes 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 a 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; termination of clinical testing and investigational use.

(a) Chronic-toxicity studies with dimethylsulfoxide (DMSO) in animals, including dogs. rabbits, and swine, reported by a consulting laboratory in England and by at least two laboratories in the United States show that the administration of dimethylsulfoxide (DMSO)

causes changes in the refractive index of the lens in the eyes of such animals. On the basis of these reports, sponsors of investigations with dimethylsulfoxide (DMSO) have discontinued clinical testing of dimethylsulfoxide (DMSO) preparations in man. All exemptions for clinical testing of dimethylsulfoxide (DMSO) in man are hereby terminated effective on signature of this order. No person may ship dimethylsulfoxide (DMSO) within the jurisdiction of the Federal Food, Drug, and Cosmetic Act for clinical testing in man until his proposal for such studies has had advance approval by the Commissioner of Food and Drugs on the basis of a Notice of Claimed Investigational Exemption for a New Drug (form FD 1571) justifying such studies.

(b) On the basis of these reports, the Commissioner of Food and Drugs further finds that it is not safe to initiate or continue investigations with any preparation containing dimethylsulfoxide (DMSO) in animals other than animals used solely for laboratory research. The Commissioner of Food and Drugs hereby terminates, effective upon signature of this order, all exemptions under § 130.3 of this chapter and section 505 of the act, for the use of dimethylsulfoxide (DMSO) or any preparation containing any amount of dimethylsulfoxide

(DMSO) for investigational use in animals, except in compliance with the provisions of § 130.3 (f) of this chapter, in animals used solely for laboratory research purposes and which are not to be used subsequently for food production. (c) Sponsors of all clinical investigations with dimethylsulfoxide (DMSO) should immediately recall all outstanding stocks of investigational drugs containing dimethylsulfoxide (DMSO), except those involving investigations in laboratory animals.

(Sec. 505, 52 Stat. 1052, as amended; 21 U.S.C. 355) [30 F.R. 14639, Nov. 25, 1965] Subpart B-Informal Statements of General Policy or Interpretation

§ 3.201

FOODS

Declaration of pyroligneous acid in food.

Pyroligneous acid may be used in foods insofar as the Federal Food, Drug, and Cosmetic Act is concerned, if it is of a degree of purity suitable for food use and does not serve to conceal damage or inferiority, or to make the food appear better or of greater value than it is. If the food is one for which an identity standard has been promulgated, pyroligneous acid should not be used unless it is an ingredient provided for in the definition and standard of identity. When used, it should be declared as an artificial flavor by some such phrase as "pyroligneous acid, an artificial flavor," "pyroligneous acid, an artificial smoke flavor," or "artificially flavored with pyroligneous acid." There should be no representation in the labeling, either directly or implied, that a product flavored with pyroligneous acid has been smoked or has a true smoke flavor, nor should there be any representation in the labeling of a seasoning, sauce, or similar product containing pyroligneous acid and used to season or flavor other foods that their use will result in a smoked product or one having a true smoked flavor.

(Secs. 402, 403, 52 Stat. 1047, 1048; 21 U. S. C. 342, 343) [22 F.R. 9594, Nov. 30, 1957]

§ 3.202 Labeling of kosher and kosherstyle foods.

The term "kosher" should be used only on food products that meet certain religious dietary requirements. The precise significance of the phrase "kosher style" as applied to any particular product by the public has not

recognizes

(a) The Administration the need for sanitizing procedures in food-manufacturing plants; it recognizes that chemical sanitizing agents aid in the maintenance of plant cleanliness; and it recognizes that a number of sanitizing agents that are poisonous or deleterious may properly be employed so that they are effective and do not leave residues in food.

(b) The Food and Drug Administration does not object to the use of effective chemical sanitizing agents on food handling equipment in establishments

subject to its jurisdiction provided precautions are taken to prevent adulteration of food that comes in contact with the treated equipment.

(Sec. 402, 52 Stat. 1046; 21 U.S.C. 342) [23 F.R. 3774, May 30, 1958]

§ 3.206 Whipped cream products containing flavoring or sweetening.

The unqualified name "whipped cream" should not be applied to any product other than one made by whipping the cream that complies with the standards of identity for whipping cream (§§ 18.510, 18.511, and 18.515 of this chapter). If flavoring and/or sweetening is added, the resulting product is a flavored and/or sweetened whipped cream, and should be so identified.

(Secs. 401, 403, 52 Stat. 1047, 1048; 21 U. S. C. 341, 343) [22 F.R. 9594, Nov. 30, 1957] DRUGS

§ 3.502 Use of term "infant” in drug labeling.

The regulations affecting special dietary foods (§ 125.1(d) of this chapter) define an infant as a child not more than 12 months old. Apart from this, the Food and Drug Administration has not established any definition of the term "infant." Some question has arisen whether, for the purposes of drug labeling, an infant means a child up to 1 year

of age or a child up to 2 years of age. Until the term is more precisely defined by legislation or formal regulation, where the exact meaning of the term is significant, manufacturers should qualify any reference to "infant" to indicate whether it refers to a child who is not more than 1 year of age, or a child not more than 2 years of age.

(Sec. 502, 52 Stat. 1051; 21 U.S.C. 352) [22 F.R. 9594, Nov. 30, 1957]

§ 3.503 Magnesium sulfate heptahydrate; label declaration on drug products.

Magnesium sulfate heptahydrate should be listed on the label of a drug product as epsom salt, which is its common or usual name.

(Sec. 502, 52 Stat. 1051; 21 U.S.C. 352) [22 F.R. 9594, Nov. 30, 1957]

§3.505 Estradiol labeling.

The article presently recognized in The National Formulary under the heading "Estradiol" and which is said to be "17cis-beta estrodiol" is the same substance formerly recognized in the United States Pharmacopeia under the designation "Alpha Estradiol." The substance should no longer be referred to in drug labeling as "Alpha Estradiol." The Food and Drug Administration would not object to label references to the article as simply "Estradiol"; nor would it object if the label of a preparation containing this substance referred to the presence of "Estradiol (formerly known as Alpha Estradiol)."

(Secs. 201, 502, 52 Stat. 1040, 1051; 21 U. S. C. 321, 352) [22 F.R. 9594, Nov. 30, 1957] § 3.506 Use of octadecylamine in steam lines of food and drug establish

ments.

(a) Octadecylamine is classed as a poisonous and deleterious substance; therefore, it may not be used in the steam lines of steam that may be incorporated into food products unless it can be established that it is required in the production of the food and a tolerance is established for the amount that would be safe for such use.

(b) The Food and Drug Administration will not object to the use of octadecylamine in steam lines where the steam may be used for autoclaving surgical instruments and gauze if the octadecylamine in the steam is not more than 2.4 parts per million.

(Secs. 406, 502, 52 Stat. 1049, 1051; 21 U. S. C. 346, 352) [22 F.R. 9594, Nov. 30, 1957]

§ 3.507 Location of expiration date in drug labeling.

Drugs which require an expiration date should show the expiration date on the immediate container. When the immediate container is packaged in an individual carton, the expiration date should also be placed on the carton. When single-dose containers are packed in individual cartons, the expiration date may properly appear on the carton only. (Secs. 505, 506, 507, 52 Stat. 1052, as amended, 55 Stat. 851, 59 Stat. 463, 61 Stat. 12, 63 Stat. 409; 21 U. S. C. 355, 356, 357) [23 F. R. 5379, July 16, 1958]

§ 3.508

Significance of control numbers on drug labeling.

The lot number on the label of a drug should be capable of yielding the complete manufacturing history of the package. An incorrect lot number may be regarded as causing the article to be misbranded.

(Sec. 502, 52 Stat. 1050; 21 U. S. C. 352) [23 F. R. 5379, July 16, 1958]

§ 3.509 Labeling of drug preparations containing salicylates.

(a) The label of any oral drug preparation intended for sale without prescription and which contains any salicylate ingredient (including aspirin, salicylamide, other salicylates and combinations) must bear a conspicuous warning statement such as: "Warning: Keep out of the reach of children," or "Warning: Keep this and all medications out of the reach of children." Such a warning statement is required for compliance with section 502(f) (2) of the Federal Food, Drug, and Cosmetic Act and is intended to guard against accidental poisonings. Safety closures that prevent access to the drug by young children are also recommended to guard against accidental poisonings.

and

(b) Effervescent preparations preparations containing para-aminosalicylate as the only salicylate ingredient are exempted from this labeling requirement.

(c) Aspirin tablets sold as such and containing no other active ingredients, except enteric-coated tablets which cannot be subdivided to a child's dose, should always bear dosage directions for each age group down to 3 years of age, with a statement such as, "For children under 3 years of age consult your physician." It is recommended that aspirin tablets specially made for pediatric use be pro

duced only in 11⁄4-grain size to reduce the hazard of errors in dosage.

(d) Salicylate preparations other than aspirin tablets sold as such may, at the option of the distributor, be labeled for use by adults only, if their labeling and advertising clearly offer them for administration to adults only.

(e) (1) It is the obligation of the distributor who labels a salicylate preparation for administration to children to make certain that the article is suitable for such use and labeled with adequate directions for use in the age group for which it is offered, but in no case should such an article bear directions for use in children under 3 years of age. If the directions provide for administration to children as young as 3 years of age, the label should bear the statement, "For children under 3 years of age consult your physician." However, if the directions provide for administration to children only of an age greater than 3 years (for example, the dosage instructions provide for administration of the article to children only down to age 6), the label should bear a statement such as, "For younger children consult your physician."

(2) A statement such as, "For children under 3 years of age consult your physician" or "For younger children consult your physician," is not required on the label of an article clearly offered for administration to adults only.

(f) If the labeling or advertising of a salicylate preparation offers it for use in arthritis or rheumatism, the label and labeling should clearly state that the beneficial effects claimed are limited to: "For the temporary relief of minor aches and pains of arthritis and rheumatism." The qualifying phrase "for the temporary relief of minor aches and pains" should appear with the same degree of prominence and conspicuousness as the phrase "arthritis and rheumatism." The label and labeling should bear in juxtaposition with such directions for use conspicuous warning statements to the effect: "Caution: If pain persists for more than 10 days, or redness is present, or in conditions affecting children under 12 years of age, consult a physician immediately." The salicylate dosage should not exceed 60 grains in a 24-hour period or 10 grains in a 4-hour period. If the article contains other analgesics, the salicylate dosage should be appropriately reduced.

(g) (1) The label of any drug containing more than 5 percent methyl sali