+(,121/,1(

Citation: 47 Fed. Reg. 436 1982

Content downloaded/printed from HeinOnline (http://heinonline.org) Wed May 26 12:34:44 2010

-- Your use of this HeinOnline PDF indicates your acceptance of HeinOnline's Terms and Conditions of the license agreement available at http://heinonline.org/HOL/License

-- The search text of this PDF is generated from uncorrected OCR text. 436 Federal Register / Vol. 47, No. 2 / Tuesday, January 5, 1982 / Proposed Rules

DEPARTMENT OF HEALTH AND statement of the conditions excluded The unaltered conclusions and HUMAN SERVICES from the monograph because the Panel recommendations of the Panel relating determined that they would result in the to OTC -containing drug 21 CFR Part 333 drugs' not being generally recognized as products for topical antimicrobial use [Docket No. 75N-0183] safe and effective or would result in are issued to stimulate discussion, misbranding; (3) a statement of the evaluation, and comment on the full Mercury-Containing Drug Products for conditions excluded from the sweep of the Panel's deliberations. The Topical Antimicrobial Over-the- monograph because the Panel statement has been prepared Counter Human Use; Establishment of determined that the available data are independently of FDA, and the agency a Monograph insufficient to classify these conditions has not yet fully evaluated the Panel's recommendations. The Panel's findings AGENCY: Food and Drug Administration, under either (1) or (2) above; and (4) the conclusions and recommendations appear in this document to obtain public HHS. of the Panel. comment before the agency reaches any ACTION: Advance notice of proposed decision on the Panel's Because mercurial ingredients are rulemaking. recommendations. This document marketed in OTC drug products for represents the best scientific judgment SUMMARY: The Food and Drug topical antimicrobial use, FDA has of the Panel members, but does not Administration (FDA) is issuing an determined that the Miscellaneous necessarily reflect the agency's position advance notice of a proposed External Panel's recommendations on on any particular matter contained in it. rulemaking that would classify over-the- OTC mercury-containing drug products counter (OTC) mercury-containing drug should be included as part of the After reviewing all comments submitted in response to this document, products for topical antimicrobial use as proposed rulemaking for topical FDA will issue in the Federal Register not generally recognized as safe and antimicrobial drug products. an amended tentative final monograph effective and as being misbranded. This Development of this rulemaking has for OTC topical antimicrobial drug notice related to the development of a been ongoing for some time. monograph for topical antimicrobial products, including mercury-containing In the Federal Register of September drug products, as an amended notice of drug products in general, which is part 13, 1974 (39 FR 33103), FDA issued an of the ongoing review of OTC drug proposed rulemaking. Under the OTC advance notice of proposed rulemaking drug review procedures, the agency's products conducted by FDA. This notice to establish the monograph for OTC also reopens the position and proposal are first stated in administrative record topical antimicrobial drug products. In for OTC topical antimicrobial drug the tentative final monograph, which the Federal Register of January 6, 1978 products to allow for consideration has the status of a proposed rule. Final of (43 FR 1210), FDA issued a tentative recommendations on mercury- agency action occurs in the final final monograph (notice of proposed containing drug products monograph, which has the status of a that have been rulemaking) for OTC topical received from the Advisory Review final rule. antimicrobial drug products. In the Panel on OTC Miscellaneous External The agency's position on OTC topical Federal Register of March 9, 1979 (44 FR Drug Products. antimicrobial drug products will be 13041) FDA reopened the administrative DATES: Written comments by April 5, restated when the amended tentative record and announced its intent to final monograph is published in the 1982, and reply comments by May 5, publish an updated (amended) tentative 1982. Federal Register as an amended notice final monograph (amended notice of of proposed rulemaking. In that ADDRESS: Written comments to the proposed rulemaking) for OTC topical amended notice of proposed rulemaking, Dockets Management Branch (formerly antimicrobial drug products. FDA the agency also will announce its initial the Hearing Clerk's Office) (HFA-305), advises that it is again reopening the determination whether the proposed Food and Drug Administration, Rm. 4- administrative record for OTC topical rule is a major rule under Executive 62, 5600 Fishers Lane, Rockville, MD antimicrobial drug products in order to Order 12291 and will consider the 20857. allow for the consideration of the requirements of the Regulatory FOR FURTHER INFORMATION CONTACT: Miscellaneous External Panel's Flexibility Act (5 U.S.C. 601-612). The William E. Gilbertson, Bureau of Drugs recommendations on mercury- present notice is referred to as an (HFD-510), Food and Drug containing drug products. An amended advance notice of proposed rulemaking Administration, 5600 Fishers Lane, tentative final monograph (amended to reflect its actual status and to clarify Rockville, MD 20857, 301-443-4960. notice of proposed rulemaking) will be that the requirements of the Executive SUPPLEMENTARY INFORMATION: In published in a future issue of the Federal Order and the Regulatory Flexibility Act accordance with Part 330 (21 CFR Part Register. At that time, comments will be considered in the amended 330), FDA received on October 6, 1980 a received on this advance notice of notice of proposed rulemaking. At that report on OTC mercury-containing drug proposed rulemaking concerning time FDA also will consider whether the products for topical antimicrobial use mercury-containing drug products will proposed rule has a significant impact from the Advisory Review Panel on 'be addressed. Also, the proceeding to on the human environment under 21 OTC Miscellaneous External Drug develop a monograph for mercury- CFR Part (proposed in the Federal Products. FDA regulations (21 CFR containing drug products will be merged Register of December 11, 1979; 44 FR 330.10(a)(6)) provide that the agency with the general proceeding to establish 71742). issue in the Federal Register a proposed a monograph for OTC topical The agency invites public comment rule containing (1) the monograph antimicrobial drug products. Because regarding any impact that this recommended by the Panel, which the Panel has recommended that rulemaking would have on OTC established conditions under which mercury-containing drug products be mercury-containing drug products for OTC mercury-containing drug products classified in Category II, no new topical antimicrobial use. Types of for topical antimicrobial use are sections to Part 333 are being included impact may include, but are not limited generally recognized as safe and in this advance notice of proposed to, the following: Increased costs due to effective and not misbranded; (2) a rulemaking. relabeling, repackaging, or

HeinOnline -- 47 Fed. Reg. 436 1982 Federal Register / Vol. 47, No. 2 / Tuesday, January 5, 1982 / Proposed Rules 437 reformulating; removal of unsafe or products that are subject to this than an 'active ingredient.' ") In the ineffective products form the OTC monograph would be generally Federal Register of August 27, 1975 (40 market; and testing necessary, if any, to recognized as safe and effective and not FR 38179) a notice supplemented the elevate Category III conditions to misbranded (monograph conditions) will original notice with a detailed, but not Category I. Comments regarding the be effective 6 months after the date of necessarily all inclusive, list of impact of this rulemaking on OTC publication of the final monograph in the ingredients in miscellaneous external mercury-containing drug products for Federal Register. On or after that date, drug products to be considered in the topical antimicrobial use should be no OTC drug products that are subject OTC drug review. The list, which accompanied by appropriate to the monograph and that contain included ingredients described as documentation. Comments will not be nonmonograph conditions, i.e., "mercurials," was provided to give accepted at this time on any portion of conditions which would cause the drug guidance on the kinds of active the OTC topical antimicrobial to be not generally recognized as safe ingredients for which data should be rulemaking other than that relating to and effective or to be misbranded, may submitted. The notices of November 16, mercury-containing drug products. be initially introduced or initially 1973, and August 27, 1975, informed OTC In accordance with § 330.10(a)(2), the delivered for introduction into interstate drug product manufacturers of their Panel and FDA have held as commerce. Further, any OTC drug opportunity to submit data to the review confidential all information concerning products subjects to this monograph at that time and of the applicability of OTC mercury-containing drug products which are repackaged or relabeled after the monographs from the OTC drug for topical antimicrobial use submitted the effective date of the monograph review to all OTC drug products. for consideration by the Panel. All the must be in compliance with the Under § 330.10(a)(1) and (5) the submitted information will be put on monograph regardless of the date the Commissioner of Food and Drugs public display in the Dockets product was initially introduced or appointed the following Panel to review Management Branch, Food and Drug initially delivered for introduction into the information submitted and to Administration, after February 4, 1982, interstate commerce. Manufacturers are prepare a report on the safety, except to the extent that the person encouraged to comply voluntarily with effectiveness, and labeling of the active submitting it demonstrates that it falls the monograph at the earliest possible ingredients in these OTC miscellaneous within the confidentiality provisions of date. external drug products: 18 U.S.C. 1905 or section 301(j) of the Statement of the Advisory Review Panel William E. Lotterhos, M.D., Chairman Federal Food, Drug, and Cosmetic Act on OTC Miscellaneous External Drug (21 U.S.C. 331(j)). Requests for Products on Mercury-Containing Drug -Rose Dagirmanjian, Ph. D. confidentiality should be submitted to Products for Topical Antimicrobial Use. Vincent J. Derbes, M.D. (resigned July 1976) William E. Gilbertson, Bureau of Drugs George C. Cypress, M.D. (resigned November (HFD-510) (address above). A proposed review of the safety, 1978) FDA published in the Federal Register effectiveness, and labeling of all OTC (46 drugs by-independent advisory review Yelva L. Lynfield, M.D. (appointed of September 29, 1981 FR 47730] a October 1977) final rule revising the OTC procedural panels was announced in the Federal regulations to conform to the decision in Register of January 5, 1972 (37 FR 85). Harry E. Morton, Sc. D. Cutler v. Kennedy, 475 F. Supp. 838 The final regulations providing for this Marianne N. O'Donoghue, M.D. (D.D.C. 1979). The Court in Cutler held OTC drug review under § 330.10 were Chester L. Rossi, D.P.M. that the OTC drug review regulations (21 published and made effective in the J. Robert Hewson, M.D. (appointed CFR 330.10) were unlawful to the extent Federal Register of May 11, 1972 (37 FR September 1978) that they authorized the marketing of 9464). In accordance with these Representatives of consumer and Category III drugs after a final regulations, a request for data and industry interests served as nonvoting monograph has been established. information on all active ingredients members of the Panel. Marvin M. Accordingly, this provision is now used in OTC miscellaneous external deleted from the regulations. The drug products was issued in the Federal Lipman, M.D., of Consumers Union regulations now provide that any testing Register on November 16, 1973 (38 FR served as the consumer liaison. Gavin necessary to resolve the safety or 31697). (In making their categorizations Hildick-Smith, M.D., served as industry effectiveness issues that formerly with respect to "active" and "inactive" liaison from January until August 1975, resulted in a Category III classification, ingredients, the advisory. review panels followed by Bruce Semple, M.D., until and submission to FDA of the results of relied on their expertise and February 1978. Both were nominate by that testing or any other data, must be understanding of these terms. FDA has the Proprietary Association. Saul A. done during the OTC drug rulemaking defined "active ingredient" in its current Bell, Pharm. D., nominated by the process before the establishment of a good manufacturing practice regulations Cosmetic, Toiletry, and Fragrance final monograph. (§ 210.3(b)(7), (21 CFR 210.3(b)(7))), as Association, also served as an industry Although it was not required to do so "any component that is intended to liaison since June 1975.' under Cutler,FDA will no longer use the furnish pharmacological activity or other Two nonvoting consultants, Albert A. terms "Category I," "Category II,' and direct effect in the diagnosis, cure, Belmonte, Ph. D., and Jon J. Tanja, "Category II" at the final monograph mitigation, teatment, or prevention of R.Ph., M.S., have provided assistance to stage in favor of the terms "monograph disease, or to affect the structure of any the Panel since February 1977. conditions" (old Category I) and function of the body of man or other The following FDA employees "nonmonograph conditions" (old animals. The term includes those assisted the Panel: John M. Davitt Categories II and H1).This document components that may undergo chemical served as Executive Secretary until retains the concepts of Categories I, II, change in the manufacture of the drug August 1977, followed by Arthur Auer and III because that was the framework product and be present in the drug until September 1978, followed by John in which the Panel conducted its product in a modified form intended to T. McElroy, J.D. Thomas D. DeCillis, evaluation of the data. furnish the specified activity or effect." R.Ph., serVed as Panel Administrator The agency advises that the An "inactive ingredient" is defined in until April 1976, followed by Michael D. conditions under which the drug § 210.3(b)(8) as "any component other Kennedy until January 1978, followed by

HeinOnline -- 47 Fed. Reg. 437 1982 438 Federal Register / Vol. 47, No. 2 / Tuesday, January 5, 1982 / Proposed Rules

John T.-McElroy, J.D. Joseph Hussion, R. drug products for topical antimicrobial Mercuric salicylate Ph., served as Drug Information Analyst use and classified all 18 in Category II. Mercuric sulfide 1976, H. Mercury until April followed by Victor 1. Submissions of Data and Information Lindmark, Pharm. D., until March 1978, Mercury chloride Mercury oleate followed by Thomas J. McGinnis, R.Ph. In an attempt to make this review as extensive as possible and to aid The Advisory Review Panel on OTC Ortho-chloromercuriphenol Miscellaneous External Drug Products manufacturers and other interested Para-chloromerctiriphenol was charged with the review of many persons, the agency compiled a list of Vitromersol categories of drugs. Due to the large ingredients recognized, either through Yellow mercuric oxide number of ingredients and varied historical use or in marketed products, Zyloxin as mercurial active ingredients. Fourteen labeling claims, the Panel decided to C. Classificationof Ingredients. review and publish its findings ingredients were identified as follows: separately for several drug categories Ammoniated mercury, bichloride of 1. Active ingredients. and individual drug products. The Panel mercury, calomel, mercuric salicylate, Calomel (mercurous chloride) presents in this document its mereuric sulfide, mercurochrome, Merbromin conclusions and recommendations on mercury, mercury chloride, mercury Mercuric chloride (bichloride of mercury) OTC mercury-containing drug products oleate, nitromersol, para- Mercury, ammoniated (ammoniated mercury] for topical antimicrobial use. The chloromercuriphenol, vitromersol, Ortho-hydroxyphenylmercuric chloride Panel's findings on other categories of yellow mercuric oxide, and zyloxin. miscellaneous external drug products Notices were published in the Federal Thimerosal are being published periodically in the Register of November 16, 1973 (38 FR 2. Inactive ingredients. 31697) and August 27, 1975 (40 FR 38179) Federal Register. None. The Panel was first convened on requesting the submission of data and * January 13, 1975 in an organizational information on these ingredients or any 3. Other ingredients. Mercury oleate meeting. Working meetings which dealt other ingredients used in OTC mercurial was submitted to this Panel for the with the topic in this document were drug products. In addition, in the Federal treatment of psoriasis only and will be held on: January 27 and 28, March 7 and Register of September 13, 1974 (39 FR included in the Panel's 8, April 20 and 21, June 22 and 23, 33103), the following ingredients were recommendations on dandruff, August 3 and 4, and October 5 and 6, deferred from the OTC Antimicrobial I seborrheic dermatitis, and psoriasis drug 1980. Panel to the Miscellaneous Topical products to be published in a future The minutes of the Panel meetings are Panel (later renamed the Advisory issue of the Federal Register. on public display in the Dockets Review Panel on OTC Miscellaneous Mercuric oxide, yellow (yellow Management Branch (HFA-305) Food External Drug Products) for review: mercuric oxide) was reviewed as an and Drug Administration (address mercuric chloride (also included in the ophthalmic anti-infective by the above). call-for-data as bichloride of mercury), Advisory Review Panel on OTC No individuals requested to appear ortho-chloromercuriphenol, and ortho- Ophthalmic Drug Products in its report before the Panql to ciscuss mercury- hydroxyphenylmercuric chloride. published in the Federal Register of containing drug products for topical A. Submissions. May 6, 1980 (45 FR 30002). antimicrobial use, nor was any The Panel was not able to locate nor individual requested to appear by the Pursuant to the above notices, the is it aware of data demonstrating the Panel. following submissions were received: safety and effectiveness of the following The Panel has thoroughly reviewed Firms and MarketedProducts ingredients when'used as OTC the literature and data submissions, and Becton, Dickinson and Co., Rochelle Park, mercurial topical antimicrobial active has considered all pertinent information NJ 07662-Mercurochrome. ingredients. The Panel, therefore, submitted through October 6, 1980 in Bowman Pharmaceuticals, Inc., Canton, classifies these ingredients as Category arriving at its conclusions and OH 44702-Merphol, Mercuronate, Ointment. II, not generally recognized as safe and recommendations. Corona Manufacturing Co., Atlanta, GA effective for this use, and they will not In accordance with the OTC drug 30301--Corona Ointment. be discussed further in this document. Eli Lilly and Co., Indianapolis, IN 4620- review regulations set forth in § 330.10, Merthiolate. Mercuric oxide, yellow (yellow mercuric the Panel reviewed OTC mercury- Marion Health and Safety, Inc., Rockford, oxide) containing drug products for topical IL 61101-Kip Ointment, Merthiolate Swabs, Mercuric salicylate antimicrobial use with respect to the Mercurochrome Swabs. Mercuric sulfide, red (mercuric sulfide following three categories: Whitehall Laboratories, New York, NY Mercury Category I. Conditions under which 10017-Sperti. Mercury chloride Mercury oleate OTC mercury-containing drug products B. Ingredients Reviewed by the Panel. for topical antimicrobial use are Nitromersol 1. Labeled ingredients containedin Ortho-chloromercuriphenol generally recognized as safe and Para-chloromercuriphenol effective and are, not misbranded. marketedproducts submitted to the Panel. Vitromersol Category II. Conditions under which Zyloxin OTC mercury-containing drug products Ammoniated mercury for topical antimicrobial use are not Merbromin D. Referenced OTC Volumes. generally recognized as safe and Orthohydroxyphenylmercuric chloride Phenylmercuric nitrate The "OTC Volumes" cited in this effective or are misbranded. document Thimerosal include submissions made by Category III.- Conditions for which the interested persons in response to the available data are insufficient to permit 2. Other ingredients reviewed by the call-for-data notices published in the final classification at this time. Panel. Federal Register of November 16, 1973 The Panel reviewed 18 active Calomel (mercurous chloride) (38 FR 31697) and August 27, 1975 (40 FR ingredients in OTC mercury-containing Mercuric chloride (bichloride of mercury) 38179). All of the information included in

HeinOnline -- 47 Fed. Reg. 438 1982 Federal Register / Vol. 47, No. 2 / Tuesday, January 5, 1982 / Proposed Rules 439

these volumes, except for those to say, mercury inhibits the growth of surface of a wound were in contact with deletions which are made in accordance bacteria, but does not act swiftly to kill serum, pus, or other body fluids. with the confidentiality provisions set them (Ref. 6). In 1933 Birkhaug (Ref. 16) calculated forth in § 330.10(a)(2), will be put on In late 1939 and early 1940,.important extremely high coefficients public display after February 4, 1982, in discoveries were made showing that the (measurements of the killing power of a the Dockets Management Branch [WA- bacteriostatic action of mercury can be compound compared to that of phenol) 305), Food and Drug Administration, Rm. reversed by many types of sulfur- for mercury compounds. The method of 4-62, 5600 Fishers Lane, Rockville, MD containing compounds. Brewer (Refs. 7 measurement, however, was imprecise 20857. and 8) formulated a culture medium, so that one could not distinguish thioglycollate, which allowed the growth I. General Discussion between the bacteriostatic and of anaerobic microorganisms by the use bactericidal activity. Today, Mercury is a -white, heavy, of aerobic techniques. Marshall, measurement techniques for bactericidal liquid metal with an atomic weight of Gunnison, and Luxen (Ref. 9) activity have demonstrated that the 200.59. It forms alloys with most metals demonstrated that the thioglycollate phenol coefficient for OTC mercury- except iron and combines with sulfur at medium was capable of inactivating the containing topical antimicrobial ordinary temperatures. bacteriostatic action of thimerosal and preparations is nonexistent when their Mercury has been known to humans supported the growth of contaminants. bacteriostatic action is neutralized. This perhaps longer than any other metal, Morton, North, and Engley (Refs. 10 and has been demonstrated by Morton, and humans have used it in various 11) demonstrated that inhibited bacteria North, and Engley (Ref. 11) in studies ways for treating illness. With the are not completely killed by mercury- demonstrating advent of the science of chemistry, new the effect of merbromin containing compounds. When these and thimerosal on Streptococcus compounds of mercury were developed inhibited bacteria are cultured in pyogenes and by Engley (Ref. 17) in' and used in treatment of different thioglycollate , growth resumes pathological conditions. additional studies of the effect of With the advent because the solution chemically mercuric chloride, phenylmercuric of the science of bacteriology, mercury removes the mercury and eliminates any compounds were among the borate, and other mercurial compounds residual bacteriostatic activity (Ref. 12]. on this strain of bacteria. preparations chosen for antimicrobial Intraperitoneal injections of the sodium therapy. thioglycollate culture proved fatal to After reviewing all data and It has been the general course of mice and hemolytic streptococci were information submitted on mercury- events that, whenever a mercury isolated from the heart's blood after containing products for which topical compound has been tried for a death bf the mice (Ref. 11). These antimicrobial activity is claimed, and particular therapeutic function, it has discoveries made it necessary to after a careful review of the literature. been used enthusiastically at first, only reexamine all previous reports in the the Panel concludes that some mercury- to be replaced eventually by a safer or literature claiming a killing activity for containing preparations are not effective more effective drug. mercurial compounds. and others are not safe and effective for Elemental mercury, especially when It has been found that, if mercury is OTC topical antimicrobial use. A vaporized, is toxic and readily absorbed first allowed to combine with the bacteriostatic action that is capable of through intact skin, the respiratory tract, sulfhydryl groups in bacterial cells, being reversed by contact with body and the gastrointestinal tract (Ref. 1). growth is inhibited, but the introduction fluids and other organic matter does not The mercury compounds exhibit varying of additional sulfhydryl groups to the constitute an effective topical degrees of toxicity, and sensitivity to cell-mercury complex neutralizes this antimicrobial action, and the Panel has these compounds is not unusual. The action, and growth again takes place therefore placed all mercury compounds literature includes a number of cases of (Ref. 6). Brewer (Ref. 13) examined a in Category 11 for topical antimicrobial sensitivity to mercury-containing ' hospital's stock of sutures, some of use. preparations ranging from topical salves which had been stored for up to 10 References and to tooth fillings years. Some of the sutures were (Refs. 2 and 3). Both organic and nonsterile even though they had been (1) Windholz, M., editor, "The Merck inorganic mercury compounds produce Index," 9th Ed., Merck and Co., Rahway, NJ, stored in a solution containing a high pp. 766-767, 1976. allergic contact dermatitis, and cross- concentration of mercury. Viable sensitivity has been noted (Ref. 3). (2) Fisher, A., "Contact Dermatitis," 2d Ed., Staphylococcus aureus were recovered Lea & Febiger, Philadelphia, p. 299, 1973. The decline in the importance of from sodium thioglycollate solution after (3 Kahn, G., "Three Thousand Years of mercury in antimicrobial therapy since exposure to a phenylmercuric nitrate Mercury. A Plea for Abandonment of a midcentury can be attributed more to preparation for 24 hours (Ref. 14). Dangerous, Unproven Therapy," CUTIS; the discovery of its lack of effectiveness The presence of serum has also been Cutaneous Medicine for the Practitioner. for this purpose than lack of safety, shown to reduce the antibacterial action 6:537-542, 1970. however. Work done in the field of of mercury compounds. Three hundred (4] Harvey, S. S., "Heavy Metals," in "The enzyme chemistry clarifying the mode of times more mercuric chloride, 800 times Pharmacological Basis of Therapeutics," 6th action of mercury against bacterial and more merbromin, and'14,000 times more Ed., edited by L. S. Goodman and A. Gilman, fungal cells has shown that mercury thimerosal were required to inactivate The Macmillan Co., New York, pp. 975-976, compounds as a class are of dubious half the Salmonella typhosa cells 1980. value for antimicrobial use (Ref. 4). suspended in 10 mL of an 80-percent (5) Engley, F. B., Jr., "Evaluation of Mercuric ions combine with free serum solution than were required to Mercurial Compunds as ," Annals sulfhydryl groups in the bacterial cells of The New York Academy of Sciences, achieve comparable results in the same 53:197-206, 1950. and thus deprive the cells of these period of time when the microorganisms sulfhydryl groups which are necessary (6) Fildes, P., "The Mechanism of the Anti- were suspended in a salt solution (Ref. bacterial Action of Mercury," BritishJournal to insure that metabolism and growth 15). Thus, the activity of mercury of ExperimentalPathology, 21:67-73, 1940. take place. The action of mercury is preparations as topical antimicrobial (7)Brewer, 1.H., "Clear Liquid Mediums for primarily bacteriostatic, but it may act agents would be markedly affected if the 'Aerobic' Cultivation of Anaerobes," slowly as a bactericide (Ref. 5). That is the microorganisms on the skin or the Journalof Bacteriology, 39:10, 1940.

HeinOnline -- 47 Fed. Reg. 439 1982 440 Federal Register / Vol. 47, No. 2 / Tuesday, January 5, 1982 / Proposed Rules

(8) Brewer, I. H., "A Clear Liquid Medium Mercury, ammoniated incorporate mercury in its hyphae, thus for the 'Aerobic' Cultivation of Anaerobes," Organic mercury compounds: reducing the amount of biologically (Abstract), Journal of the American Medical Merbromin active mercury in its environment and Association, 115:598-600, 1940. Thimerosal (9) Marshall, M. S., J. B. Gunnison, and M. Ortho-hydroxyphenylmercuric chloride permitting other microorganisms to grow P. Luxen, "Test for the Sterility of Biologic Phenylmercuric nitrate that would have been inhibited by the mercury (Ref. 8). Products," Proceedingsof the Society for a. Inorganic mercury compounds-(i) ExperimentalBiology and Medicine, 43:672- Calomel. Calomel (mercurous chloride) (i) Merbromin.Merbromin is soluble 673, 1940. in water and alcohol but practically (10) Morton, H. E., L. L. North, Jr., and F. B. is practically insoluble in water and therefore relatively nonpoisonous for insoluble in acetone, chloroform, and Engley, Jr., "In Vivo and In Vitro Studies on ether. This compound produces a the Bacteriostatic and Bactericidal Actions of humans unless it remains in the body for Mercurial on Hemolytic a long enough time to be oxidized. Once carmine red solution that stains the skin Streptococci," (Abstract), Journalof oxidized to mercuric chloride, it is highly a deep red, not a desirable property for Bacteriology, 50:125-126, 1945. toxic (Ref. 1). It has been used in the an antimicrobial agent, as this can mask (11) Morton, H. E., L. L. North, Jr., and F. B. past by inunction (rubbing into the skin) inflammation, and inflammation is a Engley, Jr., "The Bacteriostatic and as a prophylactic against venereal warning sign of infection. Bactericidal Actions of Some Mercurial disease and internally as a cathartic. In a 1928 study Simmons (Ref. 9) Compounds on Hemolytic Streptococci. In pointed out that most of the killing Vivo and In Vitro Studies," Journalof the The Panel concludes calomel may be American Medical Association, 136:37-41, safe as a topical antimicrobial agent, but action of merbromin in an alcohol- 1948. is not effective for this purpose. acetone vehicle was due to the vehicle. (12) Smith, A., "Organomercurial (ii) Mercuric chloride. Mercuric Aqueous merbromin, 2 percent, failed to Compounds. Report to the Council on chloride (bichloride of mercury) is a kill two strains of Staphylococcus Pharmacy and Chemistry," Journalof the bivalent mercury salt that exhibits a aureus in an exposure of 10 minutes and American Medical Association, 136:36, 1948. high toxicity for tissue cells, a low lethal one strain of hemolytic streptococci in (13) Brewer, J. H., "The Present Status of action for microorganisms, and an an exposure of 5 minutes. The cultures the Sterility of Catgut Sutures on the inability to protect against infection were killed under similar conditions by American Market," Journal of the American (Ref. 1). The Panel concludes that Medical Association, 108:722-727, 1937. merbromin, 2 percent, in an alcohol- (14) Richards, J. P., and A. E. E.El Khouly, mercuric chloride is not safe and not acetone vehicle and by the alcohol- "The Recovery of Phenylmercuric Nitrate- effective as a topical antimicrobial acetone vehicle alone, which was treated Bacteria Using Sodium agent. -, included as a control. It was shown in Thioglycollate," Journal of Pharmacyand (iii) Mercury, ammoniated. 1942 that a 1:20 dilution of merbromin Pharmacology,(Supplement), 19:209S-215S, Ammoniated mercury is insoluble in failed to kill Staphylococcus aureus and 1967. water and alcohol, but readily soluble in Escherichiacoli during an exposure of (15) Smith, D. E., E. J. Czarnetzky, and S. warm hydrochloric, nitric, and acetic 10 minutes at room temperature Mudd, "The Mechanism of Inactivation of (Ref. acids. If ingested, it causes epigastric 10). A 1:20 dilution is two and one-half Mercurial Antiseptics by Serum, and Its pain, nausea, and purging. Implications Regarding the Possibility of times more concentrated than the 2- Ammoniated mercury has been used percent aqueous solution of merbromin Intravenous Antiseptics," American Journal topically in the treatment of impetigo, of Medical Sciences, 192:790-808, 1936. that is marketed OTC for topical (16) Birkhaug, K. E., "Phenyl-mercuric- ringworm, psoriasis, pruritus ani, antimicrobial use. pinworm, and infestations with pubic nitrate," Journal of Infectious Diseases, The Panel concludes that merbromin 53:250-261, 1933. lice (Refs. 2 and 3). Prolonged use may (17) Engley, F. B., Jr., "Mercurials as cause chronic , local is safe for topical use but lacks a Disinfectants. Evaluation of Mercurial pigmentation of skin and eyelids (Ref. 4), bactericidal action and is not an Antimicrobial Action and Comparative and/or hypersensitivity to mercury (Ref, effective topical antimicrobial active ingredient. Toxicity for Skin Tissue Cells," Soap and 5). Chemical Specialties, 30:199-205 and 223- Of 70 patients treated for psoriasis (ii) Thimerosal.Thimerosal is a 225, 1956. with ammoniated mercury, 33 showed cream-colored crystalline powder that is Ill. Categorization of Data signs of mercury poisoning (Ref. 6). The stable in air, but not in sunlight. One Panel concludes that ammoniated gram (g) is soluble in approximately 1 A. Category I Conditions. mercury is not safe for use as a topical milliliter (mL) water and in 8 mL alcohol, These are conditions under which antimicrobial agent. but is practically insoluble in ether and active ingredients used as OTC b. Organic mercury compounds. benzene. At the cellular level, mercury-containing drug product9 for brganic mercury compounds were first thimerosal has been found to be more topical antimicrobial use are generally synthesized in an attempt .to decrease toxic for human epithelial cells in vitro recognized as safe and effective and are the toxicity of the mercuric ion. That the than mercuric chloride, phenylmercuric not misbranded. This document contains attempt was not wholly successful is nitrate, and merbromin (Ref. 7). It was no Category I conditions. shown by the fact that, while merbromin found to be 35.3 times more toxic for and phenylmercuric embryonic chick heart tissue than for B. Category II Conditions. nitrote have been found to be less toxic than bichloride of Staphylococcus oureus (Ref. 11). These are conditions under which mercury for human epithelial cells in Moller and Trofast (Ref. 12) active ingredients used as OTC vitro, thimerosal was found to be more demonstrated that 10 of 20 guinea pigs mercury-containing drug products for toxic (Ref. 7). The toxicities of these sensitized to thimerosal developed a topical antimicrobial use are not compounds were not in proportion to delayed hypersensitivity. This generally recognized as safe and their mercury content. production of a hypersensitivity effective or are misbranded. Some microorganisms have exhibited condition in 50 percent of laboratory 1. CategoryII ingredients. a tolerance to organic mercury animals demonstrates that the Inorganic mercury compounds: compounds. For example, a strain of substance is very allergenic and it is Calomel Penicillium roquefortiresistant to reasonable to expect that thimerosal Mercuric chloride phenylmercuric acetate was shown to will act similarly in humans.

HeinOnline -- 47 Fed. Reg. 440 1982 Federal Register / Vol. 47, No. 2 / Tuesday, January 5, 1982 / Proposed Rules 441

In Sweden, where thimerosal is used broth, dextrose broth with 0.1 percent Cutaneous Medicine for the Practioner, mainly as a preservative in vaccines thioglycollate, and dextrose broth with 6:537-542, 1970. and test materials and is not sold as an 10 percent blood serum; and then (5) Fisher, A. A., "Contact Dermatitis," 2d OTC skin , Moller (Ref. 13) injected intraperitoneally into mice. The Ed., Lee &Febiger, Philadelphia, p. 319, 1973. reported a mean frequency of thimerosal latter two culture media neutralized the (6) Young, E., "Ammoniated Mercury Poisoning," British allergy of 3.7 percent Journalof Dermatology among bacteriostatic action of the mercury 72:449-455, 1960. dermatologic patients throughout a 5- compounds (Ref. 1). (7) Engley, F. B.. Jr., "Mercurials as year period during which 600 to 800 The Panel concludes that thimersal is Disinfectants. Evaluation of Mercurial patients were treated for contact allergy not safe for OTC topical use because of Antimicrobic Action and Comparative each year. Moller classified thimerosal a its potential for cell damage if applied to Toxicity for SkinTissue Cells," Soap and medium stong allergen in comparison to broken skin and its allergy potential. It Chemical Specialties, 30:199-205 and 223- nickel and balsam of Peru, which is not effective as a topical 225, 1956. (8) Russell, P., "Inactivation showed an incidence of reactions of 9 antimicrobial because its bacteriostatic of Phenyl percent and 7 percent, respectively. Mercuric Acetate in Groundwood Pulp by a action can be reversed. Mercury-Resistant Moller Strain of Penicillium also found that among healthy (iii) Ortho-hydroxyphenylmercuric Roqueforti Thorn. "Nature, 176:1123-1124, subjects 10 percent of school children, chloride. Ortho-hydroxyphenylmercuric 1955. 16 percent of military recruits, 18 chloride occurs as white to faint pink (9) Simmons, J. S., "Bactericidal Action of percent of twins, and 26 percent of feathery crystals that are soluble in Mercurochrome-220 Soluble and medical students had hypersensitivity to water, alcohol, and benzene (Ref. 2). It is Solutions in Skin Disinfection," Journalof the thimerosal. He concluded that the used in bum preparations. The Paiel American Medical Association, 91:704-708, periodic tuberculin testing of individuals 1928. concludes that this compound is safe for (10) Hoyt, A., R. T. Fisk, and G. Burde, "The in Sweden with vaccines containing topical use in the concentration thimerosal as a preservative affords an Antibacterial Action of Certain mnarketed for OTC use (0.056 percent). Disinfectants," Surgery, opportunity for the development of 12:786-790, 1942. However, as a topical antimicrobial, this ((11) Salle, A. I., and A. S. Lazarus, "A delayed hypersensitivity to thimerosal compound is not effective because its Comparison of the Resistance of Bacteria and in this population. action is bacteriostatic rather than Embryonic Tissue to Germicidal Substances. Underwood et al. (Ref. 14) patch bactericidal (Ref. 17). 1.Merthiolate," Proceedings of the Society for tested over Experimental 400 patients in which 160 (iv) Phenylmercuricnitrate. Biology and Medicine, 32:665- patients (40 percent) showed 667, 1935. a positive Phenylmercuric nitrate occurs as pearly, reaction to one or more of the remedies (12) Moller, H., and 1. Trofast, "The lustrous scales that are soluble in water Sensitizing Capacity of Merthiolate and its which had been applied before an initial (1 part to about 1,250 parts water) and visit to a dermatologist. Of the 160 Methyl Analogue," Journalof Biological slightly soluble in alcohol. Against Standardization,7:153-155, patients, 56 (35 percent) reacted to a 1979. human epithelial cells in vitro, (13) Moiler, H., "Merthiolate Allergy: A mercury compound, and thimerosal was phenylmercuric nitrate was found to Nationwide latrogenic Sensitization," Acto responsible for 90 percent of these be less toxic than bichloride of mercury Dermatovener,57:509-517, 1977. reactions. The North American Contact and thimerosal, but it was still very (14] Underwood, G. B, et al., Dermatitis Group (Ref. 15) tested 1,200 toxic (Ref. 7). Solutions of "Overtreatment of Dermatitis of the Feet," subjects with 16 allergens. Thimerosal Journalof the American Medical phenylmercuric salts in concentrations produced an incidence of 8 percent* Association, 130:249-256, 1946. of 1:1,500 and greater tend to cause reactions and ranked third highest of the (15) North American Contact Dermatitis blistering 16 allergens. Epstein, Rees, and Maibach of human skin and may act as Group "Epidemiology of Contact Dermatitis primary skin irritants (Ref. 16) tested a group of private and allergens (Ref. in North America: 1972," Archives of 18). The Panel Dermatology, 108:537-540, 1973. dermatological patients in the western finds phenylmercuric nitrate in the concentration submitted (16) Epstein, E., W. J. Rees, and H. I. United States with 26 substances. (1:10,000) (Ref. 19) safe for topical Maibach, "Recent Experience with Routine Thimerosal had-a 13.4-percent incidence application, but there is no evidence Patch Test Screening," Archives of of sensitivity, which was the third that this compound is an effective Dermatology,98:18-22, 1968. highest incidence of sensitivity. (17) Everett, E. T., et al., "Tissue topical antimicrobial at this Culture It has been suggested that Studies on Human Skin. A Method for concentration. hypersensitivity to thimerosal may be Evaluating the Toxicity of Certain Drugs. due to the thiosalicylate portion of the 2. Category 11 labeling. The Panel Employed Locally on the Skin," Texas Reports on Biology and Medicine, molecule and not the mercury (Ref. 5]; concludes that labeling of any OTC 9:281-291, mercury-containing product for topical 1951. however, this has not been confirmed. (18 Morris, G. E., "Dermatoses from Based on the above data, the Panel antimicrobial use is Category II because all mercury ingredients are placed in Phenylmercuric Salts," Archives of concludes that thimerosal is very Environmental Health, 1:53-55, 1960. allergenic. Category II. (19) OTC Volume 160271. A comprehensive study of several References C. CategoryIII Conditions. mercury compounds in 1950 (Ref. 1) (1) Engley, F. B., Jr., "Evaluationm of showed that these compounds were Mercurial Compounds as Antiseptics," These are conditions for which the bacteriostatic rather than bactericidal Annals of the New York Academy of available data are insufficient to permit and that thimerosal was no better than Sciences, 53:197-206, 1950. final classification at this time. This water in protecting mice from potential (2) Windholz, M., editor, "The Merck document contains no Category III fatal streptococcal infection under the Index," 9th Ed., Merck and Co., Rahway, NI, conditions. conditions of the study. The pp. 642 and 764-767, 1976. (3) Hoover, J. E., editor, "Remington's Interested persons may, on or before .streptococcal culture was added to the Pharmaceutical Sciences," 16th Ed., Mack April 5, 1982, submit to the Dockets various mercury antimicrobial Publishing Co., Easton, PA, p. 1110, 1980. Management Branch (HFA-305), Food preparations; the mixture held at the ° (4) Kahn, G., "Three Thousand Years of and Drug Administration, Rm. 4-62, 5600 temperature of skin (32 to 340 C) for 10 Mercury. A Plea for Abandonment of a Fishers Lane, Rockville, MD 20857, minutes; subcultured into dextrose Dangerous, Unproven Therapy." CUTIS written comments on this advance

HeinOnline -- 47 Fed. Reg. 441 1982 442 Federal Register / Vol. 47, No. 2 / Tuesday, January 5, 1982 / Proposed Rules notice of proposed rulemaking. Three copies of any comments are to be submitted, except that individuals may submit one copy. Comments are to be identified with the docket number found in brackets in the heading of this document. Comments replying to comments may also be submitted on or before May 5, 1982. Received comments may be seen in the office above between 9 a.m. and 4 p.m., Monday through Friday. Dated: September 23, 1981. Arthur Hull Hayes, Jr., Commissioner of Foodand Drugs. Dated: December 17, 1981. Richard S. Schweiker, Secretaryof Health and Human Services. iFR Doc. 82-7 Filed 1-4-82:8:45 am) BILLING CODE 4160-01-M

HeinOnline -- 47 Fed. Reg. 442 1982