to the skin and eyes. The underlying purpose of this method is to insure effective therapeutic concentrations of the drug in local areas of infection. In many instances it may be used as an adjunct to parenteral injections. However, after parenteral injection penicillin does not penetrate readily to the eyes, into spinal fluid, or, unless in extremely high unitage, into the milk. Therefore the topical method appears to be the only practicable one of treating local infections involving the eyes, spinal canal, or udder.

(c) Dosage-(1) Systemic infections. For therapy of systemic infections caused by most strains of penicillin-sensitive organisms a minimum of 2,000 units per pound of body weight should be administered, preferably by intramuscular injection. Further information concerning this recommendation may be obtained by request from the Food and Drug Administration. The required dosage of water-soluble salts of penicillin dissolved in proper aqueous solvents should be repeated every 3 to 4 hours to establish and maintain effective therapeutic concentrations of the drug in the body fluids and tissues. The necessary amount of penicillin in oil and wax should be given every 12 hours. The indicated quantity of procaine penicillin in oil or of certain of the newer certifiable repository penicillin products may be given as infrequently as once every 24 hours or longer. However, severe infections or infections caused by less sensitive organisms may require up to double the minimum dosage or more frequent injections or both. Since the objective of penicillin therapy is to bring the infection under control as quickly as possible, the minimum dosage or frequency of injection or both should be increased materially in all conditions known to be caused by sensitive organisms if no definite indication of clinical improvement is noticed 12 to 14 hours after the initial injection.

(2) Bovine Streptococcus agalactiae mastitis. Effective treatment of udders infected with penicillin-sensitive organisms depends on maintaining therapeutically effective concentrations of peniIcillin in the area of infection. Available experimental data indicate that the following methods for introducing adequate amounts of the drug into infected quarters can be depended upon to overcome the infection in a majority (75 percent or more) of Streptococcus agalactiae mastitis cases:

(i) Aqueous solutions (sodium, calcium, or crystalline penicillin dissolved in sterile distilled water):

(a) Inject 25,000 to 30,000 units under aseptic conditions through the teat canal into each infected quarter. Repeat after each milking or once every 12 hours until five to seven injections have been made. One repeat injection may be sufficient in the chronic form without induration.

(b) In cows producing up to 40 pounds of milk per day a total of 100,000 units per infected quarter administered as five injections of 20,000 units each at intervals of 12 hours or as four injections of 25,000 units each at intervals of 24 hours. In cows producing more than 40 pounds of milk per day or in acute cases a total of 200,000 units per infected quarter administered as four injections of 50,000 units each at intervals of 24 hours. It may be desirable to skip one milking after the last injection in the series to prolong a therapeutic concentration of penicillin in the treated quarters. Volume of vehicle should be adequate to favor immediate distribution throughout the cistern area. Usually 50 cc. is adequate.

(c) Large udders: First day, 200,000 units per infected quarter; second and third days, 100,000 units per infected quarter each day. Small to moderatesized udders: First day, 100,000 units per infected quarter; second and third days, 50,000 units per infected quarter each day. All quarters infected with Streptococcus agalactiae at the time of drying off should be infused with 100,000 to 200,000 units sometime during the dry period, preferably during the interval between 2 weeks after the last milking and 3 weeks before parturition.

(ii) Emulsified solutions (soluble salts of penicillin dissolved in oil and water emulsified with lanolin derivatives): Inject 100,000 units under aseptic conditions through the teat canal into each infected quarter. Repeat treatment if subsequent bacteriological examination shows infection to be still present.

(iii) Bougies (25,000 or more units of sodium, calcium, potassium, or procaine penicillin in a milk-soluble base shaped in slender, elongated form to permit easy insertion into the milk cistern of the udder through the teat canal). Aseptically insert one bougie into each infected quarter after each milking for as long as the infection persists.

(iv) Oil and wax suspensions (calcium or crystalline penicillin in refined peanut or sesame oil and white wax) and ointments (calcium or crystalline penicillin in an ointment base suitable for udder instillation). In view of the scarcity of information concerning this use of such products, basic directions for use may be different in individual cases. Adequacy of directions as a whole depends primarily on the penicillin potency of each product and the nature of supportive data.

(3) General.

Whenever practicable, accurate diagnosis should be established by identification of the causative organism. No case of mastitis should be considered cured unless bacteriological examination of the milk taken from treated quarters approximately 3 weeks after the last application of penicillin shows the absence of causative organisms. Augmenting penicillin therapy with proper surgical treatment yields best results when treating abscesses, empyema, suppurative arthritis, and infections of body cavities and joints caused by penicillin-sensitive organisms. Collections of pus should be removed prior to each local application of 25,000 to 50.000 units of penicillin in sterile aqueous solution two to three times every 24 hours. Sterile dressings, saturated with an aqueous solution containing at least 1,000 units of penicillin per milliliter, applied one or more times per day as the condition indicates, may be effective for treating superficial infections of the skin caused by penicillin-sensitive organisms. If indicated, supplement local therapy with systemic medication.

(d) Precautions. If reactions occur which cannot be adequately controlled and are more serious than the condition being treated, use of the drug should be discontinued.

§ 3.9 Notice to manufacturers, packers, and distributors of salt substitutes. The recent reported poisonings from salt substitutes containing lithium chloride have focused attention upon this entire field. Salt substitutes have been regarded in the past as special dietary foods. They are also drugs, since they are employed in the mitigation and treatment of disease. There is considerable doubt as to the safety of unrestricted use of any salt substitute in the presence of cardio-vascular-renal disease and a low sodium diet. Consequently, the Department of Health, Education, and Welfare

believes that each salt substitute is a new drug within the meaning of section 201 (p) of the Federal Food, Drug, and Cosmetic Act. The interstate distribution of each salt substitute should be discontinued until a new-drug application has been filed and has become effective with respect to the substitute.

§ 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.

§3.11 Notice to manufacturers, packers, and distributors of estrogenic hormone preparations. Some drug preparations fabricated wholly or in part from alpha-estradiol and labeled 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 non-hydroxyketonic estrogenic hormones and estrone, when measured by different methods on test animals. There is no international unit for measuring the activity of alpha-estradiol and no accepted relationship between its activity and that of estrone, either in test animals or in humans. The declaration of potency of alpha-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 alpha-estradiol content of an estrogenic hormone preparation in terms of weight is considered appropriate.

§3.12 Temporary permits for interstate shipment of experimental packs of food varying from the requirements of definitions and standards of identity. (a) The Department of Health, Education, and Welfare recognizes that appropriate investigations of potential advances in food technology sometimes require tests in interstate markets of the advantages to and acceptance by consumers of variations in foods from applicable definitions and standards of identity prescribed under section 401 of the Federal Food, Drug, and Cosmetic Act.

(b) It is the purpose of the Department to permit such tests where they are necessary to the completion or conclusiveness of an otherwise adequate investigation and where the interests of consumers are adequately safeguarded. The Department will therefore refrain from recommending regulatory proceedings under the act on the charge that a food does not conform to an applicable standard, if the person who introduces or causes the introduction of the food into interstate commerce holds an effective permit from the Secretary providing specifically for those variations in respect to which the food fails to conform to the applicable definition and standard of identity.

(c) Any person desiring a permit may file with the Secretary a written application in triplicate containing as part thereof the following:

(1) Name and address of the applicant.

(2) A statement of whether or not the applicant is regularly engaged in producing the food involved.

(3) A reference to the applicable definition and standard of identity (citing applicable section of regulations).

(4) A full description of the proposed variation from the standard.

(5) The basis upon which the food so varying is believed to be wholesome and nondeleterious.

(6) The amount of any new ingredient to be added; the amount of any ingredient, required by the standard, to be eliminated; any change of concentration not contemplated by the standard; or any change in name that would more appropriately describe the new product under test. If such new ingredient is not a commonly known food ingredient, a description of its properties and basis for concluding that it is not a deleterious substance.

(7) The purpose of effecting the variation.

(8) A statement of how the variation is of potential advantage to consumers. (9) The labeling proposed to be used for the food so varying.

(10) The period during which the applicant desires to introduce such food into interstate commerce, with a statement of the reasons supporting the need for such period.

(11) The probable amount of such food that will be distributed.

(12) The areas of distribution.

(13) The address at which such food will be manufactured.

(14) A statement of whether or not such food has been or is to be distributed in the State in which it was manufactured.

(15) If it has not been or is not to be so distributed, a statement showing why.

(16) If it has been or is to be so distributed, a statement of why it is deemed necessary to distribute such food in other States.

(d) The Secretary may require the applicant to furnish samples of the food varying from the standard and to furnish such additional information as may be deemed necessary for action on the application.

(e) If the Secretary concludes that the variation may be advantageous to consumers and will not result in failure

of the food to conform to any provision of the act except section 403 (g), a permit shall be issued to the applicant for interstate shipment of such food. The terms and conditions of the permit shall be those set forth in the application with such modifications, restrictions, or qualifications as the Secretary may deem necessary and state in the permit.

(f) The terms and conditions of the permit may be modified at the discretion of the Secretary or upon application of the permittee during the effective period of the permit.

(g) The Secretary may revoke a permit for cause, which shall include but not be limited to the following:

(1) That the permittee has introduced a food into interstate commerce contrary to the terms and conditions of the permit.

(2) That the application for a permit contains an untrue statement of a material fact.

(3) That the need therefor no longer exists.

(h) During the period within which any permit is effective, it shall be deemed to be included within the terms of any guaranty or undertaking otherwise effective pursuant to the provisions of section 303 (c) of the act.

(i) If an application is made for an extension of the permit, it shall be accompanied by a description of experiments conducted under the permit, tentative conclusions reached, and reasons why further experimental shipments are considered necessary.

(Secs. 401, 403, 52 Stat. 1046, as amended, 1047, as amended; 21 U. S. C. 341, 343)

§3.13 Supplying pharmacists with indications and dosage of drugs. (a) This Department is aware of statements that the regulations covering prescription drugs prevent the manufacturer from sending the pharmacist data he needs on indications and dosage in exercising his important professional function of checking against possible mistakes in the prescription.

(b) These regulations emphasize the importance of the profession of pharmacy: they are not intended to deprive the pharmacist of information necessary to the discharge of his professional duty of insuring the integrity of the drugs he dispenses on prescription.

(c) To discourage attempts at selfmedication with drugs which the layman

cannot safely and effectively use without the physician's guidance and which therefore should be dispensed only on doctor's orders, the regulations provide that the labeling of such drugs shall not bear indications or directions, except that the prescription package should bear the directions specified in the prescription. The law defines labeling as written, printed, or graphic matter accompanying the drug.

(d) The courts have given a broad interpretation to the definition of labeling, holding it to cover all pamphlets and the like used to inform consumers what the drug is for and how it is to be used. The Department of Health, Education, and Welfare regards the supplying of printed matter to the pharmacist for his professional information, and not as а means of over-the-counter sales promotion, such as by display to prospective purchasers, as a legitimate means of making information necessary for professional use readily available. This Department has no intention of recommending action based on the supplying or use of such material for that professional purpose.

§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-propoxy2-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 poisonous substances which have no place in any food.

as

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 sweeteners of drugs is to be discouraged.

§3.15 Notice to manufacturers and labelers of antibiotic and antibiotic-containing drugs. Recent investigations by the Department of Health, Education, and Welfare have revealed that a number of persons engaged in manufacturing

and selling antibiotic and antibioticcontaining drugs are introducing into interstate commerce shipments of these drugs that are unlabeled, or not fully labeled, and are not exempt from labeling under the provisions of § 146.18 of this chapter. This practice has been based upon the belief that interstate shipments of antibiotic and antibioticcontaining drugs to persons engaged in the export trade are not subject to certification.

When these drugs are introduced into interstate commerce they must be certified, exempted from labeling under § 146.18, of this chapter, or exempted from misbranding by meeting all the conditions specified in section 801 (d) of the Federal Food, Drug, and Cosmetic Act (21 U. S. C. 381 (d)). Section 801 (d) of the act is not satisfied merely by shipment of drugs to exporters. If exemption under this section is to be claimed, the drugs, at the time of introduction into interstate commerce, must be marked for export, must accord to the specifications of the foreign purchaser, and must not be in conflict with the laws of the country to which they are intended for export. The initial shipper has a responsibility to meet all the conditions of section 801 (d) if exemption is to be claimed. It is not enough that he is shipping to a person engaged in the export trade who will obtain a foreign purchaser, who will mark the goods for export, and who will obtain assurance that the drug is not in conflict with the laws of the country to which it is intended for export.

Section 146.18 of this chapter provides exemption from labeling. If the original shipper has an effective exemption permit under the regulations in Part 146, the exporting firm named in the exemption permit may be allowed to receive and to hold the unlabeled drugs under the exemption until the conditions of section 801 (d) of the act are satisfied.

§3.16 Notice to manufacturers, packers, and distributors of drug products. 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.

§ 3.17 Labeling of oleomargarine. The Federal Food, Drug, and Cosmetic Act was amended by the recently enacted legislation (64 Stat. 20) on colored oleomargarine. A new section numbered 407 was added. Among other things, the new 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 such label, and a full and accurate statement of all the ingredients contained in such oleomargine 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 purports to be oleomargarine must conform to the definition and standard of identity for oleomargarine promulgated under section 401 of the act (Part 45 of this chapter), and its label must bear the name "oleomargarine," which is the name specified in the standard. It is