Document 9313DjZVMqnqq9ypxo7rxaqq6

r Copied by MCA September 17, 1974 33103 [21CFR Part 333] as drug regulations should be promul OVER-THE COUNTER DRUGS Proposal To Establish a Monograph for OTC Topical Antimicrobial Products gated. The present Federal Food, Drug, and Cosmetic Act provides no legal au thority under which the Agency can re- . classify cosmetics as drugs, but does per Pursuant to Part 330 (21 CFR Part mit regulation of cosmetic Ingredients. 330). the Commissioner of Food and It Is the Commissioner's intent to pro- . Drugs received on July 24, 1974. tile pose regulations under sections G01(a) report of the Advisory Review Panel on und 602(a) of the act to apply the same over-the-counter (OTC) antimicrobial safety and labeling standards to cos drug products for repeated daily human metics containing antimicrobial ingredi- ' use. In accordance with (5 330 10(a)(6), ents subject to this notice as are applied the Commissioner Is publishing U) a to OTC drug products containing these proposed regulation containing the lnon- ingiedicnts. ogrnph recommended by the X'apcI It is also the Commissioner's Intent to establishing conditions under which promulgate regulations In the Tentative OTC topical antimicrobial drugs arc gen I inal Monograph to distinguish between erally recognized as safe and effective preservative and active levels of antimi-' and not misbranded. (2) a statement of crobials. While the Commissioner takes the conditions excluded from Hie mono no position at this time on the preserva graph on the basis of a determination tive test recommended In the Panel re by the Panel that they would result in port. it is his intent to require either a r the drugs not being generally recognized preservative test or specific maximum as safe and effective or would result in preservative levels for antimicrobial 5 misbranding, <3) a statement of the con ingredients In OTC drug products and ditions excluded from the monograph on cosmetics. the basis of a determination by the Panel In accordance with 9 330.10(a) (2), all that tl 10 avutlahP' data arc insufficient to dal a and inlormalion concerning OTC' classify such condition's under either (1) antimicrobial drug products for renented or (2) above, and il) the conclusions and daily liuman use submitted for consider recommendations of the Jbuiel to the ation by the Advisory Review Panel have Commissioner. The summary minutes of been handled as confidential by the Panel the Panel meetings are oil public display and the Food and Drug Administration. in the Office of the IIcui ing Clerk, Food All such data and information shall be and Drug Administration, Rm 4-65, 5600 Fishers Lane. Rockville, MO. 20852. put on public display at the office of the Hearing Clerk, Food and Drug Adminis Tile OommisMuiH'r cautions Unit the tration on or before October 15, 1974, ex conclusions and recommendations of the Panel must lie lead and evaluated care cept to the extent that tile person sub mitting it demonstrates that It still falls fully, to differentiate hypotheses from proven facts. In particular, substantial controversy has already emerged in tile course of the Panel deliberations with respect loathe hypothesis that the use of antimicrobial agents in bar soaps may selectively kill non-pathogcnic gram pos itive microorganisms resulting in an in crease in pathogenic gram negative microorganisms. The Panel has stated^ and the Commissioner recognizes, that! this hypothesis has not yet been proved by reliable evidence- within the confidentiality provisions of 18 U S.C. 1905 or section 301 (J) of the Federal Food, Drug, and Cosmetic Act (21 U S.C. 331(J)). Requests for confi dentiality shall be submitted to the Food and Drug Administration, Bureau of Drugs, OTC Drug Products Evaluation Staff (HFD-I09), 5600 Fishers Lane, Rockville, MD 20852. Based upon the conclusions and rec ommendations of the Panel, the Com missioner proposes, upon publication of the finnl regulation: 1. That the monograph (Category I)' The purpose of issuing the unaltered be effective 30 days after the date of conclusions and recommendations of the publication of the final monograph in the 1 Panel, including tins hypothesis, is to Federal register. ' stimulate discussion, evaluation, and comment on the full sweep of the Panel's 2. That the conditions excluded from the monograph on the basis of the Panel deliberations. The Commissioner has not yet evaluated the report, but has con- determination that they would result in the drug not being generally recog i eluded that it should first be issued as nized as safe and effective or would re a formal proposal in order to oBIairt full public comment before any decision is sult in misbranding (Category II) be eliminated from OTC drug products ef - made on the recommendations of the fective 6 months after the date of publi Panel. The report of this Panel repre- cation of the final monograph in the i scuts their best scientific Judgment. It Federal Register, regardless whether."' lias been prepared independent of the further testing is undertaken to justify*' , Food and Drug Administration and does their future use. . not necessarily reflect the Agency's po.xi- 3. That the conditions excluded from tion on any particular matter contained the monograph on the basis of the Pan i therein. After a careful review of tilts el's determination that the available i document and all comments submitted in data are insufficient to classify surli con response to it, the Commissioner will pre ditions cither ns generally recognized ns pare a tentative final regulation to es mifo ami offontivo and nut mUbi nmled or tablish a monogruph for OTC topical us not being generally recognized as safe antimicrobial pi millets. nnd effective or would result in mis TUeCouunl' i ,nor has concluded that, branding (Category HI) be permitted to to assure lmplim. nlulloii of the Pnncl's remain In use for 1 year after the date recominendal ion both cosmetic as well of publication of the final monograph T ** v i* hdiral iroism. vot. 39, no ir?--rmoAT, uruMati u, 1974 ASI 00003643 I PROPOSED RULES In the Federal Register, If the nianufactuior or distributor of any such drug utilizing such conditions In the Interim conducts tests and studies adequate and nppioprlate to satisfy the qnrsl.imi.i i ,n i d with respect to the particular condjuuu by the ['unci. The conclusions and recommendations contained in the report of the Advisory Review Pane! on Over-The-Counter (OTCi iiiitliiucioblal drug products for repeated dally use to the Commissioner are as follows: Melvin Lessing. M S., R.Ph. as Drug In formation Analyst. In addition to the Panel members and liaison representatives, the Panel utilized tlie advice of one consultant, Richard Marples. B.M., M.Sc. Tlie following individuals were given an opportunity to appear before the Panel to express their views either at their own or at the Panel's request: Richard lluughtimn, M 0; Alio Cuulor, Ph D; Sulvaloro Do Snlva, PhD; Hans P. Drobcck, Ph D.; Mr. T, E, Furla; Sol Gershon, PhD. Donovan E, Gordon, DV.M. PhD; Alfird Kivlpcrn. PhD; Gavin Ilildlck*Smlth, Ml), tra Hill, riiD; John Koolslra. Ph.D; l'Vtnk. Lyruiiu, M D.; Milton Manowll/., Ph D ; lint Marr-Lunman. Ml); Mr Nicholas Molnar; Joseph Page, Esq ; Gerald nice, M P : Dan Roman. PhD; Louis Sehurpf, PhD; Edward Singer, Ph D . Richard Sykes, PJi I> ; David Tftbcr, Ph 0 ; Mr. puvld Tuplln; Mouroo Trout, M D.; Leonard*Vlnson, Ph D,; Mr. Anthony Young. No other person requested an opportu nity to appear before the Panel. In the Federal Register of January 5. 1972 <37 FR 85), the Commissioner of Food and Drugs announced a proposed review of the safety, effectiveness and labeling of all OTC drugs by independent advisory review panels. The Commis sioner issued in the Federal Register of Submission of Data and Information Pursuant to the notices published in the Federal Register of January 7, 1072 (37 FR 235) and April 4, 1972 <37 FR 6775) requesting the submission of data and information on antimicrobial ingredients in OTC drugs, the following Arms made submissions relating to marketed products; Finn Marketed Products January 7, 1972 (37 FR 235) a request Alexander Manufacturing Co., Texarkana, Alexander's Dand-Ex, for data and information on all anti Ark.75501, microbial active ingredients in drug products for repeated daily topical hu man use. A clarifying call for data and information was published in the Fed eral Register of April 4, 1972 (37 FR 6775). On May 8, 1972, the Commissioner signed the final regulations providing for the OTC drug review under 5 330.10 (for merly S 130.301) published in the Fed Apple-Crone Drugs Laboratories, Southfield, Mich. 48075. Armour-Dial, Inc., Chicago, 111. 60608 Ayerst Laboratories, New York, N.Y. 10017.* Bowman Pharmaceuticals, Inc*., Canton, Ohio 44702. Calhoun's Laboratory, Savannah, Ga. 31405-. Campana Corp., Batavia, IU. 60510................. C R Canfield Sc Co., Minneapolis, Minn. 55408. Chase Chemical Co,, Cleveland, Ohio 44110..* eral Register of May 11, 1972 (37 FR Chosebrough-Fond's, Inc, Canton, Conn. 9464), which were made effective im 06412. mediately. The Commissioner appointed the fol Ctba-Gelgy Corp.. Ardsley, N.Y. 10502.,*,.__* lowing Panel to review the data and in Colgate-Palmolive Co.. New York, N.Y. 1Q022_ formation submitted and to prepare a report on the safety, effectiveness, and labeling of OTC products containing Eby Chemical Co, Harrisburg, Pa. 17100___antimicrobial ingredients for topical hu Factor, Max and Co., Hollywood, Calif, 90028_ man use, which includes soaps, surgical The Falk Co., Wayznta, Minn, 65301_________ scrubs, skin washes, skin cleansers and Ferro Corp , Toledo, Ohio 43G05.,__.-**,,*** first-aid preparations, pursuant to Finn Organics, Inc, Lodi, N J. 07644--, 5 330.10(a) (1). Gaby, Inc, Philadelphia, Pa. 19125, Harvey Blank, M.D.. Chairman; Frank II, Engley, Jr,, Ph D.; William L. Epstein, M.D.; Wallace L. Guess, Ph D.; Florence K. Klno- shlta, PhD. (resigned from the Pnncl In September, 1973); Mary Marples, M A,, M.D., D.T.M. and H. (resigned from the Panel In January. 1974); Paul D. Stolley, M D. T R Gibbs Medicine Co., Inc., Washington, D C, 20020. Givaudan Corp., Clifton, N J. 07014---___... Goyoscas Corp. of Florida, Miami. Fla. 33142. Gypsy Remedy Co., Ocala, Fla. 32670............ .. Harrison's Laboratories, Jackson. Miss. 30201. Herald Pharmacal, Inc., Bedford, Va. 24523.. The Panel was convened first on June 29. 1972, in an organizational meeting. Fifteen working meetings were held on August 16, 17, and 18; September 14, 15, and 16; October 19, 20, and 21; Novem High Chemical Co., Philadelphia. Pa. 19122__ Huntington Laboratories. Inc., Huntington, Ind.46750, Indiana Botanic Gardens, Hammond, Ind. Apple-Crone Hair and Scalp Conditioner, Dial Soap. Dermoplast Aerosot. Surgical Soap with 2 percent hexachloro- pheue. Dyper-Rash-Eze and Fung-O Ointment. Cuticura Medicated Soap. Sebaclde. Donovo and Glov-Kote, Vaseline First Aid. Carbolated Petrolatum Jelly and Vlrac Topi cal Germicide Irgmnu11 DP-300 (Trlclosan), Irgason* CF 3 (Clotlucarban). Dei-mass.\ge Lotion, P-300 Soap Bar. Tackle Gel, Washklns, Wash'n Drl, and Wash n Drt Washkins for Babies. Ecco Medicated Powder. SEBB Lotion. Falk's Camfo Creme. Ottasept. Temnsept IV (Trlbromsalan). Gaby Greaseless Suntan Lotion and 0-63. T. R. Solution. G-ll (Hcxachlorophene), Prlnceladas Qoyescas. Gypsy's Wonder Ointment. Harrison's Lotion. II A F. Ansel Antlseborrhclc Lotion and Seborld Shampoo. Klorlyptus Oil and Klorlyptus Ointment. Q S I. Iodine Surgical Detergent and Sana* Prep Prc-Surgtcal Preparation. Vanishing Balm. ber 18. 19, and 20; December 14, 15, and 16, 1972; February 8, 9, and 10; March 3, 4. and 5; April 25, 26, and 27; June 7, 8, and 9; July 7, 8, and 9; August 30, 31, and September 1; September 27. 28, and 29: November 29 and 30, 1973; February 3, 4, and 5; and June 1 and 2, 1974, Three non-voting liaison representa tives. Ms. Sarah Newman nominated by 46325. Tlie Jola Co, Milwaukee. WIs. 53210. F. N. Kalcrt Co., St. Louis. Mo. 63125_____ * King Laboratories. Richardson, Tex, 75080-. Laboratory Robalna, Inc , Hialeah, Fla 33010. Lam Enterprises, Honolulu, Hawaii 06817... Larson Laboratories, Inc., Erie, Pa. 1G505___ Lcgulo Pharmaceutical Mfr., Chicago, III. 00034. "Jola" Xeem Cream. Formula 59 Foot Soap. Pedolfttum. Acetolla Robalna and Jabon Acetolla. Liquid Talzcma, Green Remedy, Tnlzcma Ointment, and Zenji Sul. Foot Note. 1 Lcgulo and Lcgulo. Mild. an ad hoc group of consumer organiza tions; Joseph M, FisaQl, M.D., nominated by the Proprietary Association; and Rob ert Giovarchlnl* PhD., nominated by the Cosmetic, Toiletry and Fragrance As sociation, participated In Panel discus sions. Food and Drug Administration em ployees Included Ms. Mary Brurh who I.yne Laboratories, Winchester, Mass. 01890,.Macsll Inc.. Philadelphia, Pa. 19125 Marika of Albuquerque. Albuquerque, NM. 87106. Mccob, Inc., New Orleans. La. 70113.,.____ Merck. Sharp and Dolune Research Labora tories, West Point, Pa. 194B0. Merl Jo Inc., Tampa, Fla 33014,. Miles Laboratories, Inc , Elkhardt, Ind. 4G614. Hoxa-Cct Balmcx Medicated Lotion. Verdi Lotion, Wylon Scalp Treatment. Approve, F.P 8. Skin Cleaner, and fl.T. 37 Antiseptic Solution. Fine Fungicide and Korn Kure, Bactlnc. Bactlno Aerosol, and Bactlne Towel* cites. served as Executive Secretary, Michael Mon-Ray Chemical Co., Forest City, NC, Mon-Ray Formula 222, Kennedy as Panel Administrator, and 28043. TLOCftAl HCGlSrCft, VOL. 39, NO. 177--fRlOAV, SCPTCM6ER 13, 1974 00003644 AS I 1 PROPOSED RULES .`i'll or. '& i* S:*, fc Firm 9 Monsanto Industrial Chemicals Co,, 8t. Louis, Mo, G31GG. Nitlne. Inc,, Clifton. NJ. 07015.......................... Norwich Pharmacal Co,. Norwich. N Y. 13818* i 11 a i| ChciiikulH, Atlanta, Oa. 30341_____ _ Parke, Davis ami Co . Detroit. Mich, 48232. -- lMlMcr Chemical Inc . Ridgefield, N J. 07C07-l'hcttcx Antiseptic Laboratories, Inc . Chi- plough, Inc, McniphlM, Trim 3010! . ,, Win, r. Poythress and Co, Inc., Richmond, Va 23217. 0 The Procter and Gamble Co., Cincinnati, Ohio 45217. The Purdue Frederick Co.. Yonkers. N.Y. 10701. Red Foot Products Co,, Inc., Detroit. Mich. 48228. Reslnol Chemical Co., Baltimore. Mu. 2i20i_* The Rllox Co, New Orleans. La. 70122 Rystan Company, Inc., Little Falls, NJ, 07424. Savoy Drug and Chemical Co , Michigan City, Ind.46300, n Schutmer Co,. Washington, DC. 200J0.. Bherwin Williams Chemicals, Toledo, Ohio 43G08. Smith, Kline and French Laboratories, Philadelphia. Pa. 19101. Sterling Drug Inc., New York, N.Y. 10016,..,., United States Borax and Chemical Corp., Los Angeles, Calif. 90010. The Upjohn Co., Kalamazoo, Mich. 49001___ R. T. Vanderbilt Company, Inc., New York, NY. 10017. Vestal Laboratories. St. Louts, Mo. 63110...^ Wade Chemical Corp., Shreveport. La. 7H03-West Chemical Products, Inc., Long ItJand City, N.Y. 11101, Woolley Chemical Co, Ogden. Utah 84401.. MarKi'frd Products Trlcloctvrban. Nltex. tTnr.uont.hie Aerosol, Unguentlne Original Formula, Uhguanllna Flu*, and UngueilUne Spray Oai'vodennn. Oxford 1`hcrt. Oxford 1`io-Med. Oxford ITO-McU (odorless), Oxford flanO-Sup, and Oxford Sep. I,l<pikl Germicidal Detergent, The mend Solution, rhetnerol Tincture, and Phemero! Topical. THU 100 (Trlbromsalan). rtiencx Antiseptic, Phonex Ointment 30',, , and 1`hefM'X Skin f,oli<<n (dean `N Trent, Me v.ana Medlraled Powder. Soluieulne (`ream. Solarenlne Foam, Solnrcalnc Lotion, and Snlarcnlnc Spray. llcncuIfoUl Lotion, Safeguard Soap. Betadlnc Aerosol Spray. Botadme Ointment, Betndlne Skin Cleanser, Betadlne Solu tion, Bctadlnc Surgical Scrub, and Betadine Surgical Scrub/Sktn Cleanser. Rcdfoot Corn and Callus Remover, and Rcdfool Powder. Reslnol Grca.selcss Cream and Resinol Oint ment. Geneva Ointment and Shave Losh. Prophyllin Ointment and Frophyllln Powder. Special Ointment and Special Foot Towdcr. Oradcrm Lip Lotion and Chlorflderm. Trlbromosal lcylanilldc. Acnomcl Cake, Acnomel Cream, and Pragmatar, Campho-Pheulquc Liquid, Campho-Phenique Powder, Flsohox, Hcxachlorophene, McdlQulk, PhisoHcx, Thlso-Scrub, RoccaI. Snrcnc, Soapure. Zephlrau Aqueous, Zeplilrail Chloride, Zephlran Chloride Tincture, Zcphlran Spray, Zephlran TowcleitM, Zobenol Aqueous, and Zobenol Tincture. Luron Lotion Soap. MD*7 Lotion Soap, and Tomac Lotion Soap. Mercresln Tincture, Vancide 89RE and Vanclde FP. Septisol Jim Wade Foot Medicine. lonol, Trepodync Scrub. Prepodvne Solution, Prrpodyne Concentrate, Tamed-Iodine Scrub, and Wesoodvno. Trcu-Youth Hand Balm and Treu-Youth Lotion rack. In addition, the following firms made related submissions; Firm SubNu.iMoni Armour-Dlat, Inc., Chicago, III. COGOTL., llcxachlorophcuc. lYibromsalan, and Trl- clorarbau. Lever Brothers Co., Edgewatcr. N.J. 07020___ TrlbrnmMiian. MMlmastcr Onyx Corp., Jersey City, NJ. Quaternary Ammonium Sails. 07302. The Procter and Gamble Co., Cincinnati, Cloflucarban, TTexachlorophene, Trlbrom- Ohio 46217. sftlan, and Trlclocarban. The Purdue Frederick Co., Yonkers, N,Y. lodophors. 1070t Sterling Drug Inc., New York, N Y, 10016____ Benzalkoiilum Chloride. Methylbcnbcthon- lum Chloride, and TrlbromosallcylmnUlde. We*t Chemical Products Inc., Long Island lodophors. City. N Y. 11101, The labeled ingredients contained in these products are as follows: Acetone Alkvl amine of Jano!h` artiln AUautaUv Alnu.ul Aluminum hydrox ide } .Aluminum potas''iiim feulfato Anunnnla : uluttoli Peru Bentonite Itm/.iikonUtm chloride iK'ii/i-thmilum chloride Mon/ucaln* Ih'ii/olo acid Ikur/uln tluldoxtract lioii/.yl alcohol Bismuth subcarbon- ate Bismuth subnltrateboric acid Boric acid glycerlte BuLvlatcd hydrox- > tolueno Calamine Camphor Capiau (N-tri- chloro-methylthlo4-cyclohcxene-l, 2-dlcarboxlmlde) Castor oil Cetyl alcohol Cetyl alcohol-coal tar distillate Chlorobu tanol Chlorophyll Chlorothymol curie acid Clollucarban Coal tar, crude Coconut oil Collodion Cornstarch DlpropyJcne glycol Dodccjlbeuaouc sul fonate Entsu fort Ether Kucalyptol Eucalyptus dlchJo- rido Eucalyptus oil Fugcnol Ferric chloride Fluoros&lan Glycerin Goose grease Hexylrcsorclnol Hcxachlorophene 8-HydroxyquinoIin< benzoate Iodine complexed with phosphate eMer or alkylnryl polyethylene glycol Juniper tar Kaolin Lanoltrx Lanolin, anhydrous Lanolin, cholcstcrols Lanolin, modified, ethoxylatcd Lanolin, hydrous Lecithin Lldocainc hydrochloride Maunt'fdum Mx ju.uc Mrllllml Mi I'funr chloride Mei hylhen/.cihouhim chloride Kiel hylcrllulO'ic McLhyl|mraben Methyl salicylate Mineral oil, refined NnnvJpbonoxypoJy- cthuxyellmuol Nuiiv Iphonoxypuly* (cthylencoxy) cth- anoliodluu complex Oleostcarln Orthocluoromcrcurlphencl Orrhoh\droxy phenyimercuric chloride Oxyquluollne sulfate Para-chloro-meta- xyJenol Parahydrccln Pc trohitum Phenol Phenyl salicylate Pine oil Pine tar Poloxamer-lodlne complex Polyoxyethylene lnurylether Polysorbate Potysorbate 20 Potassium alum Potassium coconut SOap Potassium salt of cocoyl - polypep tide condensate Fovidone-lodme complex Propylene glycol Propionic acid Propylparaben Quaternary ammo nium compounds Quince seed muci lage Resorcinol Resorcinol monoac* etate RoMn Salicylic acid 1 Saponified greased Secondary - amyltricrcsols Sequestrene 50 K3 Silicone Sodium blphosphate Sodtu/n borato Sodium citrate Soditim phenolate (phenate) Sodium pniplonatc Sodium salicylate Sodium salicylic acid phenolate Sodium ui^decyle- naic Storax Sucwee octaacetate Sulfur riOIRAL RECISUR, VOl. 39, NO. 179--FRIDAY, SEPTEMBER 13, 1974 00003645 ftSl L` 33106 PROPOSED ROLES' Sulfur, colloidal Sulfur, flowcrn of Sulfur, precipitated Tannic acid powder TcLnuumo hydro chloride Thymol Yr:if*iu an I lx I i till i MU .ll.Ul Tj It Iih ,u I MU l( U Iw./.tU Triethanolamine Triton X-100 Umlccoyllum chlo- rldc-lodln* Umlceylcnlc add White oil of thyme Zinc acetate Zinc carbonate Zluo oxide Classification or Ingredients Thu Pnncl has chLsslflcd tlic following Ingredients Into groups identified below; ANTlMICnoeiAL INCUKniPNrS Quaternary ammonium compounds; Hru/jilkonluux chloride Ucit/clhoni\im chloride Mothylbonzethonlum chloride Clollucarban FlvioroftMan llexachlorophene Hexylresorclnol lodophors: Nonylphenoxypoly (ethyleneoxy) etha nol--Iodine complex Poloxamcr*--iodine complex Povidone--iodine complex Iodine complexed with phosphate ester of atkylaryl polyethylene glycol Undocoyllum chloride--Iodine complex Para-chloro-meta-xylcnol Phenoi(s>: Sccondary-amyl tricresol* Sodium phenolate Tincture of iodine Tribromsalan Trlclocarban Trtclosan Triple dye (see discussion elsewhere In the document). antimicrobial ingredients combined WITH NON-ANTIMICROBIAL ACTIVE IN GREDIENTS It a product contains an antimicrobial Ingredient and meets the definitions adopted by the Panel, it may be com bined with other non-antimicrobial ac tive tngredient(s): Provided, (1) The antimicrobial ingredient re mains safe and effective; (2) The non-antimicrobial active In gredient is sate and effective; < 3) The labeling indicates the pharma cologic effects of all active ingredients; (4) The combination provides rational concurrent therapy for a significant por tion of the target population; (5) The combination meets the re quirement of the definitions for the an timicrobial product categories. The Panel Is particularly concerned that the combination not delay wound healing. If a skin antiseptic claim Is made it must meet the requirement of the def inition of a skin antiseptic described elsewhere In this document, INGREDIENTS DEFERRED TO ANTIMICROMAL II PANEI, Antimicrobial Ingredients formulated In products labeled for use for specific Indications. such ns dnndruff nnd seborlhca. acne, athlete's foot, and otitis ex terna will be Included In the second part o( the Panel'* review. Antimicrobial II. Captan Coal tar, crude Juniper tar I'lno Lur Propionic acid Ucsorcluol Hcsorcinol nmnoaectate Salicylic acid Siilol-- phenyl .sallcylato Sodltim undocylcnate UU>rax Sulfur, colloidal Sulfur, llowcre of Sulfur, precipitated Tannic acid Thymol Undccylcnlc add While oil of thyme INGREDIENTS DEFERRED TO OTHER PANELS Data fur several Ingredients, frequently formulated with auUinlcroblals, were also submitted. The following ingredients are all topi cal analgesics and have been deferred for review to the Topical Anulgcsic Panel; Bcnzocatne Camphor (refer to statements for phenol) Lhlocalne hydrochloride Menthol Methyl salicylate Tetracaine hydrochloride The following ingredients are all mer curials and have been deferred for re view to the Miscellaneous Topical Panel: Mercuric chloride Orthoch loromercurlplienol OrthohydroxyphenyimercuriC chloride Preservative Levees of Active Ingredients The active antimicrobial ingredients reviewed by the Panel can be 'formulated in topical products at various concentra tions. The minimum concentration re quired for effectiveness as an active In gredient will be established by in vitro and in vivo efficacy testing as will the range of concentrations which can be safely used, 'the Panel recognizes that many of these antimicrobial ingredients might also be added to products at much lower levels to prevent the spoilage of products and to protect them from the growth of microorganisms introduced as a result of customer use.* Many of the antimicrobials reviewed are primarily active against gram positive microorga nisms and would not generally be con sidered as good candidates for use as preservatives. However, some of these may be considered for use as part of a preservative system. If an antimicrobial Ingredient Is to be used as a preservative, evidence should be available to demonstrate that the concentration used Is the minimum at which it is effective as a preservative. The procedure for establishing the minlnuim effective preservative concentra tion (s> is the United States Pharma copeia (USP>, ``Antimicrobial Agents-- Effectiveness Test" under Microbiological Tests (currently, USP XVIII, p. 845), The safety should also lie established accord ing Lo the statements on Individual In gredients and the Guidelines In this document. Considerations other thnn antimicro bial activity arc Important in the selec tion of a preservative nnd usually In clude; Activity at low concentrations. solubilities and partition coefficients In the various types of formulations In which they arc used. Hased on the data presently available. Category II Ingredients which arc Cate gory n for all product categories (see discussion elsewhere in lids document) are not recommended for use as pro* servalivcs under,any circumstances. The question of the adequacy of t.he following ingredients its preservatives will not be discussed at this time but will be considered by the OTC Antl^_ microbial II Panel. Benzole acid Benzyl alcohol Ilnrtc acid C'hlorobictnnol Chlorotliymol 8-Hydroxyqulrvollne benzoate Mcthylparnben Oxyquluollue sulfate Propylparaben Sodium propionate One manufacturer submitted data claiming oxvnmnoUne sulfate as an ac tive ingredient In a formulated product (Ref. 1>. The Panel has classified this ingredient as a preservative, similar to those submitted in other formulations. As has been stated, the concentration of the antimicrobial and time of expo sure, among other parameters, deter mines the clinical effectiveness of an antimicrobial. The claim submitted for oxyquinollne sulfate at a 0.03 percent level is based entirely on tn vitro data. The agar-well technique to determine zones of Inhibi tion was used. The tests were conducted with 0.03 percent oxyquinoline sulfate plus other preservatives (vnethylparaben and propylparaben). Zones of Inhibition were determined for the formulation but not for individual ingredients. Methylparaben. propylparaben and oxyquinoline sulfate are listed as active Ingredients in the formulation at levels currently used in many lotion formula tions as preservatives to maintain the quality of the lotion and prevent micro bial contamination with use. No ill vivo studies were submitted to support the effectiveness of oxyquinoline sulfate as a clinically active ingredient on the skin. Therefore, the Panel has classified the ingredient as a product preservative. References (1) OTV Volume 020054.' Inactive Ingredients Inactive ingredients are useful In the manufacturing of pharmaceutical prep arations to enhance the quality and/or appearance of the product. This list re flects only those Inactive ingredients con tained in the labeled ingredients submlt-1 1 Cited OTC Volumes rotor lo the submis sions made by Interested persons pursuant to the call for data notice published tn tho Ffoesai, Register. The volumes are on Olo In tho oiOoe or the Hearing Clerk. Food and Dm* AilmlnlsLrntlnn, Urn. 4-08, SQQO Fishers Lane. Rockville, MD 20802, no.rtofRAL rccimcr. voi. 19, 179--iriday, sepiimbu n, 1974 ASI 00003646 4 t T-* X V.' & * . y* V' 5jS; i? im PROPOSED RULES .Til 07 ted to the Panel and is not Intended to be an exhaustive list. Acetono Alkyl xinlno of lnnalla iuiUI* AII.MiO.IJl A1 i./i.naim hydroxide A!.in<i:luia jiotns- s.um sumne Ammonia solution Balsam Peru Bentonite Benzoin fluid extract Bismuth subnltrate Bismuth subettrbonate Boric acid glyeerlte Butylated hydroxytoluene Calamine Castor oil Cetyt alcohol Chlorophyll Citric acid Coconut oil Collodion Cornstarch Dlpropylenc glycol Dodccylhenzene sulfonate Entsufon Ether Eucalyptol Eucalyptus dlchlorlde Eucalyptus oil Eugenol Ferric chloride Glycerin Goose grease Kaolin Lanolin Lanolin, anhydrous Lanolin. chlotesterols Lanolin, modified ethoxylated tamolln, hydruux l.ociihtii Magnesium sienrat* Methylcchulose Mineral oil. refined Nonylphenoxypolycthoxyethanol Olcoste arln Piiraliydieciu Tetrolatum Pine oil Polyoxyethylene lanryl ether Polysorhotc Polysorbate 20 Potassium alum Potassium coconut soap Potassium salt of cocoyt--polypep tide condensate Propylene glycol Quince seed muci lage Rosin Saponified greases Scquestrene 50 K3 Silicone Sodium blphorphate Sodium borate Sodium citrate Sodium salicylate Sodium salicylic acid phenolatc Sucrose octaacetate Tragacanth Triethanolamine Triton X 100 Zinc acetate Zinc cat Donate Zinc oxide The OTC Antimicrobial I Pnncl a ns charged with the review and evaluation of safety and effectiveness data on anti microbial ingredients and combinations in topically applied OTC products. An outline was developed by the Panel to evaluate the data from all the submis sions for ingredients (Ref. 1). The out line was made at the beginning of the Panel's deliberations to provide a check list for the information in the data sub missions supplied to the Panel. During its deliberations, other modified guide lines for the evaluation of antimicrobial Ingredients were developed and are In cluded in this document. The report of this Panel deals with antimicrobial Ingredients In the follow ing products: Soaps, surgical scrubs, skin washes, skin cleansers, first-aid prepa rations. and additional products defined by the Panel. The Panel defined an "antimiciobial Ingredient" as an agent which kills or Inhibits the growth and reproduction of micro-organisms. Many products foi mu tated with antimicrobials for use ns handwashing products, surgical scrubs or so-called "antiseptics'' are marketed as concentrates with label dhections for dilution prior to use. The dilution recommended for use, as distinguished from the marketed concentrates. Is de fined in this report as the "use concen tration" or the "'i ' 'lilultnn." The 1'nnel In its ...................... considered the ac tivity of these Ini iedlcnts at "use con centrations". The Panel recognised that many In gredients rediieu tin* number of micro organisms on the skin. The normal flora of micro-organisms on the skin has been divided traditionally into "transient" and "resident" flora 'Ref. 2*. The transient fioia can be considered the organisms whlrh aic plelced up from contact wilh the environment or from other persons anti which are not part of the established normal llora. These organisms are easily removed from the upper layer of the skin along with dirt partirles and oil. However, n transient organism nmy be come part of the resident established flora. In contrast, the resident flora Is usually considered the organisms which constitute the established flora of the skin. Tile ingredients reviewed by tbc Panel arc formulated In products designed to reduce microbial flora on the skin. The intended effect ranges from the reduc tion of acquired pathogens on the skin to the reduction of the normal resident flora to low levels. Some products arc used on the skin with more than one Intended effect. There has been wide spread use of antimicrobials in soap, surgical scrubs and pre-operative prep arations based on the view' that tbc reduction of normal flora to as low a level as possible will have a positive ef fect on the prophylaxis of disease, flfhe interrelationship of the concentration, time of action or contact time, the micro bial spectrum, and the possible deleteri ous effect of drastic changes in the nor mal skin flora have been largely ignored in the past or only superficially investi gated. The Panel concludes the interrela tion of findings of this type to the mitiga tion, treatment or prevention of infec tion has not been established by the data submitted. Since topical products without an ac tive Ingredient frequently have a sub stantial effect, there should be some demonstration that the formulated prod uct with the active Ingredient is better than the vehicle alone. In the case where a test of effectiveness is performed, the vehicle should bo used as a control. Emollient effect Is obvious with the ve hicle of many topical products. For In stance, the contribution of this effect to wound healing, or Its relationship to (he effect iveness of an antimicrobial product Is unknown. ItklTRENCFS <l| OTC AntlmU'iobiiU I rauri Summary Minutes for tlio AnguM. 10 1(1, 1072 meeting. (2) I*i Ire, P. II., "The llaelerlology of Nor mal Bit In. A New GiiaiiLllallin To-.t Applied to a Study or the Baeterlal Flora and the Dls- Infrrtnnt Action of Mechanical C leansing," Journal of Infectious Diseases, 03:301-318, 1038. ,J. Effectiveness of antimicrobial bar soap--Balance of normal skin flora. It Is well recognized that the human skin car ries a population of micro-organisms known as the normal flora. Tbc numheis vnty among Individuals and In dlffcmit local inns on t he same Individual. "T he predominant members ol the noimnl (loin am arum-positive cocci and dlplillietolilx. Them pinups me tud oulv icgauled as lianule... on tin i.i u i : :.n. h-.t me consult'i rd lo have .< p. u: * * 11. * i * * : against polCnU(>I palhn..... . i.,i. morfiuiiismrqEmail humbers ni i:i.nn nega tin' species, such as the miniums and ielided nigamsms, as well ns higher forms, such ns yeasts may bo residents of the skin of healthy Individuals. In cer tain circumstances, wheic the composi tion of the gram positive miero-orgnnisms arc altered, dense populations of gram negative micro-organisms may develop, ft has been demonstrated by Flnrnkianz et al. (Ref. 1) Hint with continued washing of the feet twice a day for 2 weeks, a Pseudomonas colonization was j established on the foot washed with anl.i- , bacterial soap (containing triclocaiban, ^ ^ tnbromsalnn and cloflucarhnn) and not - , on the (control) soap-washed foot. This i . voik has been confirmed with ft larger J group of subjects by Amoncttc ami Ro- 1 . senberg (Ref. 2> by Taplln (Ref. 28) and , c by Mnrplos (Ref. 3). With other anti- J microblnls, Taplin 'Ref. 4) has reported.* . to the panel that their use removes somets '* protective advantages of the gram posi tive flora, especially against colonization with Pseudomonas. These studies demon strate the potential harmful shift in the normal floi a of the skin which may oreiir with the repeated use of gram-positive bacteriostatic products. Marplcs has shown the enormous increase m the resi dent microflora occurring when the skin is covered with an impel mcablc film us well as the influence of gram-positive baclci iostals in this test system which can result in the occuuence of a high gram-negative population on the skin (Rel. 29 and 30). Reports that changes in the normal flora of tire hands occurred after the use of products continuing gram-positive bactenostats and resulted in carriage of gram negative oiganisins ba\e been made by Utuun and Solbeig (Ref. 31) and by Brown (Ref. 32>. A piotcctlvc function of resistance Lo certain infections lias been postulated for the normal llora. particularly the diphlhe> roid population of the skin by Marplcs < Ref. 3, 4 and 28). 'The Panel states their concern to that ahcad.v widely expressed In the scientific community Unit the widespread use of niitt-gnim-posilHo antilitel ics, antimi crobials on the skin, and haul surface disinfectant products which aic ftoqiiently active only against gram po:ltive organi-mr; hits produced a licmiiidmis Inn case in gram negative Infcelluns in hospilals and other closed cuvuoil men Ls (Ref. 33), Tlic Panel recognizes that the isolation of any one factor as responsible for cause and effect ls diffi cult.. However, they believe that there is sufficient evtdenre to postulate an effect from tlic use of topical antimicrobials. FEDERAL REGISTER, VOL. 39. NO. 179--FRIDAY, SEPTEMBER 13. 1974 ASI 00003647 3.1108 PROPOSED RULES Deodorant effect. The reduction of the normal skin flora, particularly the gram positive flora, has a deodorant cflert. Dravnlckg ct al. (Ref. 5), Meyer-Rohn (Ref. 8). SUchadch and Kllgman rilef. 7) and Shelley et al. <Ret. 8) have cstiibli .hi d lilt- relationship of the gram posi tive f lot a to odor, it was the estimate ot a group ol experts lrotn industry and academia la ho appeared before the Panel to discuss the effectiveness of antimicro bials In the classes of products currently being reviewed by the Panel) that ap proximately a "70 percent reduction" in the microbial flora (as measured by hand-washing tests) would produce a deodorant effect. The exact percent re duction required to achieve n deodorant effect either on the entire body or in the axillae was not established by the data submitted. The view of the Panel is that perhaps some bar soaps which achieve a 90 percent or more reduction of gram positive organisms may be so active as to be harmful (Refs. 1 through 4). The concentration of any antimicro bial incorporated into a bar soap should be set at a level which reduces the micro bial flora sufficiently to produce a de odorant effect. Currently, neither the amount of the antimicrobial needed nor the degree of reduction of the hand flora (measured in handwashing tests) needed to achieve this can be stated conclusively. The Panel hopes that these uncertainties can be resolved w(Ch increasing refine ment of effectiveness tests and expansion of effectiveness testing to include areas of the body other than the hands. Classical ecological studies have shown only too clearly the dangers of altering a stable community of any type, includ ing microorganisms (Marplcs, Ref. 9; Rosebury. Ref. 10). "While a reduction of the cutaneous population of gram positive microorganisms does haye a de odorant effect, such a change may lie dis advantageous to the host, since not only is there no conclusive evidence that the antimicrobial reduces or prevents infec tion, but its action may even enhance the growth of a potentially pathogenib microorganism.- -- Data are accumulating which indicate that shifts and/or alteration in ttie com position of the normal skin flora are harmful (Refs. 1, 2, 3, 29, 31 and 32). It is the Judgment of the Panel that until definitive data are available It is prudent to avoid significant alterations in the normal flora. These shifts or alterations in normal flora may even be more haz ardous In an Instltutloiml setting (closed population) or with Individuals who have altered suseeptiblllllesj Wound hrnlino. In anhniil models I lie use of certain aid liideiolilivls In liquid , soap retarded wound healing. Dalanl et al. (Ref. 11) and Custer ct nl (Ref. 12) showed retardation of healing In arti ficially contaminated animal wounds treated with polyvinyl pyirolUlonelodmc complex and 3 percent hexachlorophcnc. Edllch ct al. (Ref. 13) Indi cate that tile ratio of ethylene oxide to propylene oxide In tire block polvmets (pluronlc polyols) determines the tissue toxicity of surfactants used alone or coinplexcd with Iodine (for fuithcr de tails refer to c'-oonrnt on lodophorsi. Data with respect lo wound healing with bar soaps were nol submitted. In u iccent study in humans by Ruby and Nelson (Ref, 14). however, scrubbing the lesions of tmi>ctigo with a hcxachloro- plicnc soap had no appreciable bene ficial or adverse effect on wound healing. Prevention ol skin infections Attempts have been made to demonstrate clinical effectiveness In the prevention of minor skin infections with the use of soaps con taining an antimicrobial. Three studies, performed at tire mili tary service academics, were designed and executed m the attempt to show that prophylaxis of minor skin infections can be achieved with tire use of an anti microbial bar soap. There were variations in the control of the subjects, tire extent of laboratory analysis of cultures, and tile critical character of the diagnosis of lesions and followup of the subjects. Es sentially. the overall design was similar. Certain companies of men were assigned to "test soap" and others to "control soap". The collective description of cutaneous infection or cutaneous pyodermas is divided into specifically defined clinical entities in tire discussion of the results of these studies. The terms used to define specific skin infections are furuncles, furunculosis, or multiple fiiumculosis, paronychia, pustular folliculitis, impe tigo, and secandaiily infected abrasions and blisters. These are all commonly used medical terms. In all cases attempts were made to eliminate the concomitant use of other drug and cosmetic products containing an nnUmlevobial. Chronologically, the first was a 2 month study performed by Leonard at West Point in 19GG. The test soap bar contained a 2 percent mixture of three nulimicrobinl ingredients: Tribiomsnlan, trleloenrbau. and eloflucnrhnn. The author's summary (Ref. 15) indicates a 44 percent reduction in superficial cu taneous infections. When a direct comparison of total in cidence of cutaneous infections is made, there appears to he a significant differ ence. The incidence of single furuncles was significantly higher in the control gioup. However, if only the incidence of multiple furunculosis is examined, the difference Is not significant Also, there were more pnron.vehlal infections among the men using the antibacterial soap bar than among those using the control liar. Dr. Cliuoncc Inviugood illef 1C,), who has closely ( becked the results of I he three studies, lm:; conuiuiipcated his view Unit I lie iinnly.-.ls of the results In all three studies are equivocal and may be explained, in part, ns follows: < l> There was variation in (lingua.,is rcsulLing from Hie use of more than one Physician for diagnosis. (2> It seemed probable that a 2 month study was too short to establish the ex pected results. (3) The results of the bacterloiogic cultures were not Included. <4) The Initial Infection rale was not uniform In the test groups. At about the same time as the West Point Study. MacKeiutlo (Rof. 17) con ducted a B month study at the Naval Academy at Anuaimlls with a soap ennInlnlpg 0.75 percent trlclocarban and 0 75 percent liexorhloroplirne. The effect of soap usage on different t vpr-. m lesr m\ was described ip the n-poiL ol Hie ,study. The incidence ol both liuuiieulosis and secondarily lnlcrU'd skin lai eiatioii.s was nlso the same in the control anti treated groups. However, there was a lower In cidence of cellulitis secondary to trauma and pustular folliculitis in the test group using antibacterial soap. The results of another but unpublished study at Annapolis were also commented on by Dr. Livingood. In this ease, a soap containing 2 percent mixture of tribromsalan. triclocnrban. and cioflucarban, dif ferent from that used In the first Anna polis study, was tested. The results showed no reduction in furunculosis or paronychia in the groups using the anti microbial soap. Again, there was a re duction in infections as complications of minor traumatic injuries. It is the Panel's view that conclusions cannot be drawn with respect to the prophylaxis of cutaneous skin infections from a comparison of the specific lesions which occurred in both groups. In 19G9 Duncan et al. (Ref. 18) com pared inhabitants of two Texas prison farms, one of which used an antimicro bial soap bar (2 percent mixture of tribromsnlnn, cioflucarban, and trlclocarbai\) while the other did not. This study, monitored by the Armed Eorees Epi demiology Board, was performed in an attempt to resolve the persistent ques tions of effectiveness raised by the two earlier published studies. Again, une quivocal conclusions could not be diown from data presented comparing the inci dence of skin infection in the treated and control groups. A study was performed in a home for (he mentally retnided in Elllsvllle, Mis sissippi by Wheatley ct al. (Ref. 19', The authors reported that the use of an anti microbial soap bar significantly reduced the incidence of superficial cutaneous pyogenic infeel ions, A careful review of this unpublished paper by the Panel and by a statistician led to the conclusion that the interpretation of the data by the authors could not be accepted due to problems of study design and analysis. The most important difficulty encoun tered was tlie assumption that the "ob servations'' were Independent (an obser vation was the weekly Infection rales!. Inappropriate slafi-.tlral Irsts of slguiflTMnu' were applied. The ba.-.le outcome men.me (weekly Infection nile-i) win called lido question and (he law data ne irqiir-.lrd tui (lint Die study could lie i e-analv/ed. The company .-.ponsorhw: the study was imnhlc to supply these data and it was felt Lhat no Inferences as to effectiveness could lie drawn from 1 la- data presented in Ihc report Lhat was submitted to the Fauci. Similes among eouilmlants in Vietnam and also among military personnel and children in Colombia, South America pci limned by Allen and Taplln et nl. (Ref. 20 and 21) suggested thnt the use FEDERAL REGISTER, VOL 39, NO. J 79--FRIDAY, SEPtEMBER 13, 1974 ASI 00003648 T \-- -' I V-:,. * i i. PROPOSED RULES :i:il0i) of an antimicrobial soap did not prevent Infection under stress conditions. And in fact, streptococcal skin inlectlon con tinued to be the most common rause ot disability from Miperncliii infections .1 muni: the tioops. These studies also In dicated that hygiene and climate are Im portant determinants in the develop ment of superficial staphylococcal and streptococcal Infections. The Panel reviewed the clinical studies designed to show eifectivencss in the prevention of minor skin infec tions. These studies were found insuffi`(icnf to support a. conclusion of ciTcctlvcncss'. Acute glomerulonephritis is one of the more serious complications which may follow streptococcal skin infection. Ne phritis may also follow streptococcal throat Infections. No all strains of Strep tococcus are nephritogenic. The strep tococcal types associated with nephri tis following impetigo or pyoderma arc not the same ones associated with ne phritis following streptococcal pharyn gitis (Ref. 22). The risk of nephritis fol lowing a streptococcal skin infection with a nephritogenic strain is about 12 percent (Ref. 23). This relationship has also been described by Dillon et nl. (Ref. 24), Department of the Army (Ref. 25) and Kelly and Taplin (Ref. 2(i>. Allen and Taplin (Ref. 20>, Taplin et al. (Ref. 21) and Dillon (Ref. 27) have shown tile high incidence of streptococcal sores in indigent children and in children in tropical climates. In addition, the Panel's concern is also based in part on tire great increase in all types of gram negative infections, including Pseudomottas infectious, in hospitals where anti-gram positive agents are In wide use (Ref. 33). 'Because of tire information called to the Panel's attention they have been concerned that routine use of antimicro bial soaps may have a long-term harm ful effect by reducing tlie protective effect of tiro normal skin llora. It is possible that contrary to what might be expected from an antibacterial prod uct that certain bacterial infections due to gram-negative and streptococcal organisms might be increased, rather than decreased. If this is proven to be true, the deodorant benefit would prob ably be considered outweighed by tire potential hazard. In addition, because these chemicals are absorbed into the bloodstream, tire Panel Is concerned about the prudence of exposing the en tire body surface to these chemicals when alternative methods of odor con trol are available,! The Panel has been particularly con cerned that some soap and detergent bars containing antimicrobial ingredi ents for winch only deodorant claims arc made ai*e classified legally as cos metics lather than drugs These prod uctare formulated with ingredients which have been placed in Category III by tlie Panel but wlileh will be moved to Category I or II at the cud of the period allowed for submission of data to prove safety and effectiveness These products aie now in Category III but might be moved into Category II in the future, if tin- food and Drug Admin istration com hides from the data before it that they aie not generally recognized im mile and offcctivo. However, the (lata might not support a finding that they arc adulterated cosmetics, thus there is a risk that these products may con tinue to be marketed as cosmetics with out adequate substantiation of safety. Regardless of the legal classification of these products, it is important from a public health standpoint that they be subject to the same stiiet requirements for safely and effectiveness as the drug products which the Panel lias reviewed in this Report. As long as the antimicrobial ingredients of these products are effectively regu lated. the Panel is not concerned whether they be classified as cosmetics or as drugs. If, for example, a regulation can be promulgated imposing the kind of testing requirements recommended in this Report upon all cosmetics contain ing antimicrobial agents at levels higher than tlio.se necessary for preservative use, the Panel's concerns will be met. If it is not possible adequately to control products classified as cosmetics in this way. then the Panel would strongly rec ommend that the Food and Drug Admin istration institute whatever action is nec essary to rcclassily cosmetic products containing antimicrobial agents as drugs. In the view of the Panel, the Food and Drug Administration should take this regulatory action in the near future. If it turns out that the Food and Drug Admmisti ation has no legal basis to re quire that eosmetic products containing antimicrobial ingredients be adequately tested for safety, the Panel would urge Congress to furnish the necessary authority. REFEKENCFS (1) Ehrenkranz, N. J.. D. T.iplUl and P, Butt, "luitlbloUc-rvM.slnnt BiwU'na on (he Nose nnd Skin: Colonl/ntion and CrossInfection." Antimtciabiat Agents an<l C/irmn. therapy--13GG, American Society for Mtciobiology, Ann Arbor, pp. 255-2G4, 10GG. (2) Anionette, R. A. and E. W. Rosenberg, "Infection of Toe Webs by Gram-Negative Bacteria." Archives Of Dermatology, 107:71- 73. 1073. (3) Personal communication from R Mar- pies (Dec. 14. 1072) to the OTC Antimicro bial I Panel Is reported In Lhe December 14. 1072 minutes and accompanying tnbles and Is Included In OTC Volume 020180. (4) OTC Antimicrobial I Panel Summary Minutes for the September 14-10, 1972 meeting. (5) Dravnlcks, A., B. K. Krotoszynski, W. E. Lleb and E. Jungermann, "Influence of an AntlliacLerlal Soup on Various Kllluonts Prom Axillae." Journal of tlie Society of Cosmetic Chemists, 19.011-020, 1000. (0) Mejcr-Rohn, J,, "Ubcr die Ursacheu Lnsilgcu KorpergcrucUes," ("On the Causes of Tiniililreomc flody Odor"). Fettc-Sei/eit Anstneh inittet, 07 3.9:1-384. 190S. (7) Shchadoh. N. and A. M Kllgniau, "The Bacteria Responsible for Axillary Odor. II," Journal of Ini estigatirc Dermatology, 41:3, 1003. (11) Sbelb-y, \v. R., H. J. Ilmley, .Jr. and A. c. Nleboh , "Axulurv Odor: Experimental Study of (be Role of Bacteria, Apocrine Sweat and Deodorants," American Mcditul Association Archives of Dermatology and Syfihtlology. 00:430-440, 1051 (9) Marplcs, M. J, "The Ecology of the Human Skin/1 Charles C. Thnmnfl, ftprlngMol d. 1905, (10) Roisobury. T, "Mu'ttnaynni-ms Indig enous to Mu/l," McGraw-Hill, New York 1002. (11) Dajanl, A. S, P. L, Hill and L. W. Wannamaker, Experimental Infection of the Skin In the Hamster Simulating Human Impetigo. II Assessment of Various Thciapenile Regimens," Fccftafrir*, 48.83-90. 1071. (12) Custer, J.. R. F. Edlich. M, Prusak, J Madden. P Panek and O. H, Wangensteen, `Similes In The Management of the Con taminated Wound V. An Assessment of the Directivencb.s of pHlsoIlex and Bctadme Sur gical Scrub Solutions," The American Jour nal of Surgery, 121:572-575, 1071. (13) Edlich. R. F, I. R. Schmolka. M, P. Fruf.ak and M T. Edgcvton, "The Molecular Basis for Toxicity of Surfactants In Surgical Wounds," Draft of unpublished paper Is In cluded In OTC Volume 020186. (14) Ruby, n. J. and J. D. Nelson. "Tlie Influence of Ilcxachlorophcne Scrubs on the Response to Placebo or Penicillin Therapy In Impetigo." redtatrics, 62-854-859, 1073. ! 16) Leonard, R. R, "Prevention of Super ficial Cutaneous Infections." Archives of Dermatology, 95:520-521, 1UC7, (1G) Letters solicited by the Panel Chair man from C Llvmgood (dated September 8 and October 3, 1972) are Included In OTC Volume 02018G, (17) MaeKemde, A. R,, "ElTecHvencss of Antibacterial Soaps In a Healthy Popula tion," Journal of the American Medical As sociation, 211:973-970, 1070. (18) Duncan, W. C , B. G, Dodge and J. M. Knox, "The Prevention of Superficial Pyogen ic Skin Infections," Draft of unpublished paper Is Included in OTC Volume 020178. (19) Wc,alley, M. I,, C. Oden, O. A. de la Bretoune, Jr. and J, A. Koolstra, "Antibac terial Soap Bar Usage for the Prevention of Superficial pyogenic Infections," Diafl of unpublished paper Is included In OTC Vol ume 020178. (20) Allen, A. M, D. Taplin and L. Twfgg, "Cutaneous Streptococcal Infections In Viet nam," Are/uuca of Dermatology, 104.271280. 1971. (21) Taplin, D,, L. Lansdell, A. M. Allen, R. Rodriguez and A. Cortes, "Prevalence of .Streptococcal Pyoderma in Relation to Cli mate and Hygiene," Lancet, 7802:501-503, 1973, (22) Wannamakcr, L. W.. "Differences Be tween Stieptococcal Infections of the Throat and on the Skin," New England Journal of Medicine, 282.23-31 and 282:78-85, 1970. (21) Anthony, B. F. E. L. Kaplan, L W. Wannamakcr. F. W. Brlc.so and S. S. Chap man, "Attack Rates of Acute Nephritis oiler l'ypo 49 streptococcal Infection of the Skin and of the Respiratory Tract," Journal of Clinical Investigation, 48:1G97-1704, 1069. (24) Dillon, Jr., H, C.. M. D. Moody. W. R, Maxtod and M. T. Parker, "The Epidemiology of Impetigo and Acute Glomerulonephritis,'* American Journal of Epidemiology, 80:710721, 19G7. (25) "Treatment and Prevention of Strep tococcal Dlsoni.e and Its Sequelae," Depart ment of (he Army Technical Bulletin. TU MED 259, NAVMED P-5052-17, AFP 1G0* 5 24, ior.r. (2G) Kelly, C,, D. Tapitn and A, M Alien. "Streptococcal Ecthyma: Ti raiment With Don/.athtue Penicillin G,." Archive* of Dcr* viatologi/, 103:306-310, 1971. (27) Dillon. Jr. H. C,, "Impetigo Con tagiosa: Suppurntlvo and Nou-suppurailve Complications: I. Clinical, Daclci lologie, and Epidemiologic Characteristics of Impetigo." No 170--Pt II------ 2 HDCRAL REGISTER, VOl 39, NO. 179--FRIDAY, SEPTEMBER 13, 1974 ASI 00003649 n:mo PROPOSED RULES American Journal ol Disease* of Children, 115 5:lo 541, lt)C8. (2H) Tn.|illii. D, "The Ua* of Antibiotics lu Dermatology," Advances in Biology of the Skin, Volume XII, Pharmacology anti the yl.in. Ftlllcd l>y Mnnlagns, W,, R, H Slougb- ment of Erythrasma of The Toe Webs." Cutis, 5 Ml-00.1, I'jd'.i. (0) Taplin, D,. N /akm and G Rebel!, "Environmental Inilm'nces on the Microbiol* ogy of the Skin," Archives of Environmental Health, 11:54U-5Gd. 1*185. the complex is in contact with the skin Is not only available to kdl micro-orga nisms, but is only available and is adsoi lied by dead skin cells or other organic material oh the skin. Tlie action of Io t .i i-u! r ,r v.ni svoit, Appicuui-Cuitury* 1 , r , \, ,1 I ,,i I,. I I i `M M upli , 1,` R mill A, M Klli'illuli, 3. Effectiveness of surnu al hand scrubs ('onlmiiinq unTiTntcrohnils. Since Simii- dine is broad spectrum, im hiding gum positive and gram negative mirto-oig.ini .iiis, fungi and viruses, rj. ' i`,i,`i inn,. ni 12,'.tin,niui, T,*pu;.vl Annbai.n'rlul Ai'l-mL^ mi Human bkln," Antnniciohial Aijt'HM mill Vhemothernpi/, 5 52,1 32!), 11)74. (,li)> Muiplc:i, R R, *' [ lit* tJteel iif Ilydni' thin mi i.liu Hiu l(`rlul I'liira of Die M',iii," ,S7,iu Harlvna untl Tllclr Bole lit Infection, 11 I Miilliacli iiml O, IlllUlck-HmlLli, McGraw-Hill Honk Ciim[tiiiiy. Now York, 10(15, (111) lit mm, J, N. mill C. O Holhcrg, '* I l.n n I Cai i Inga ot Gram-negative Bacilli iiml Stnph- yloeoccus AureusBritish Medical Journal 2:51)0-582, 1073. (32) Brown, D,, Abstract of pnpor pre sented at tlie American Public Heal 111 As sociation meeting, San Francisco. 11)7:1 in In cluded In OTC Volume 020100. (33) Proceedings of the International Con ference on Noscomial In/cotions (Center for Disease Control), Edited by T. C. Elkhoit and P. S. Brnchmnnn, Tlie Arttcrlcan Hospital As sociation, Chicago, 1071. ,2. Efficacy for cn/thrasma. Definite evidenceiias been presented for the ther apeutic effectiveness of antimicrobialcontaining; soaps against erythrasma. Erytlirasma is a skin disease caused by Coiyncbactcrium minut-issimum. This skin inicroorEanism lias been identified by Sarkany et al. (Ref. 1, 2 and 3) and Gougerot and Ducltc (Ref. 4), While definitive evidence was present ed for the therapeutic effectiveness of antimicrobial-containing soap against tins disease by Kooistra (Ref. 5), Dodge et al. (Ref. 6), Rosenberg and Allen (Ref. 7), Taber et al. (Ref. 8) and Taplin et al. (Ref. the Panel agreed tiiat this observation alone ermid not support claims of antimicrobial activity against other Infections. Erytlirasma cannot be diagnosed except by a physician using special techniques and therefore, OTC use and labeling would not be appropri ate. Rrmit nci * (U Sarkany, I,, D Taplin and it, Wank. "Th L'.Uolnj'y umi Treatment of l-'t vl liras- ina," Jotiruai of Investigative Dermatology, 37 2H3-21H). VJQl. (2) Sarkany, I, D. Taplin and It. Blank, molwetV mimduLe in the period 10-41 1840, published in lHfil Ulof. l>, that the pliysicnuV.s cxhnimmfT fmeers he washed and dismfiwtrd with ohlnrmr to picvcnl childbed fever, llieie has been con troversy MUTonndnirr Hie desirability of disinfection of the smToon s h;mds. The inlciveninf* jean h:ive produced only a little evidence to clarily the situation. rnre*s work m lib'llt (Ref. 21 initiated attempts to quantify reduction m the microbial flora The picture has become more confused with Mir introduction of new antimicrobial npriit.q. particularly those with a substantive cfTect. A sub stantive effect is the retention or bind ing of the chemical In the stratum corneum of the skin after rinsing. Historically, the effectiveness of a sur gical scrub product has been juclrrcd by the reduction in microbial count achieved after the use of the scrub. These hand washing tests have usually been per formed utilizing one of the several basin tests described by Pnre <Ref. 2), Cade <5ff- 3' and Quinn IRcf. 4). In tlie past, the single criterion lor cflrclivciicss of a surgical scrub pioduct lias been a companson of tlie microbial count oil tlie lmiuls before and after handwasliing.J The comparison lias usually been made from the results of these standard handwashing tests. The Glove Juice Test (see guidelines for test ing) , included in the suggested protocols, is an unproved Lest which die Panel feels is necessary to evaluate two aspects of microbial reduction m tlie efficacy test ing of surgical hand scrubs: the initial reduction of microbial count las meas ured before and after hand scrubbing) and, 111 addition, any subsequent build up of microbial count over time. The in crease in count Is measured by a com parison of the baseline count and/or (lie reduced count, after scrubbing, with the count determined at a selected time period after donning surgical gloves. 'Data delineating the balance between the release or iodine from an iodophor and availability to the microorganisms on lhe skin were not submitted and are required heroic unequivocal judgment concermng the elTcrtivcncss of lodophors on the slim can be made, fodophois usu ally do not possess any siibslanLivily. It is desirable for surgical hand scrubs to contain substantive antimicrobials. Although hcxachlorophene is substan tive, especially with repented use. its loxuaty Is of such concern to the Panel that they recommend that an alternative should be sought. While a one-time scrub with a substantive antimicrobial may not reduce tlie count initially as low as an iodophor. or indeed, any lower than scrubbing with soap and water, repeated use does reduce tlie level of the microbial flora on the skin. Three to five days arc usually required to demonstrate the sub stantive activity of these products. The action of a substantive product may also reduce the rapidity with which the count rises after the surgeon's gloves are donned Tlie assumption should be veri fied using the Glove Juice Protocol. Actually, while products formulated ith cither fast-acting or substantive an timicrobials possess attractive character istics. neither one alone possesses ideal characteristics for a surgical hand scrub. The obvious solution, where chcnucal computabilities permit., is a combination of tlie use of both products. The con- M.'.tcut use of a substantive antimicro bial-containing product daily at home and in the hospital would yield a reduced level of flora and some subslantivity on the skin. Scrubbing with an iodophor would reduce tlie llora to an even lower level prior to surgery. The substantive characteristic might also be made avail able in a glove iiowdcr, lotion, or foam to be applied to ilie hands prior to donning the gloves. "Inrldcnce and Bacteriology of Erythiasma," Archives of Dermatology, 85.578 582, 1952, (J) Sarkany, I. D Taplin and H. Blank, "Organism. Causing EryUimsma," Lancet. 3: 304-J05, 1K>2, (4) OouRcrot, H. and J, Duchc, "Los Troia Teiutcs Drune, Brun-Vlolaco, Rou^c dt: I'Ery- thrtVima a la Lumicrc do Wood," Annates rfc Dermatologic at do SyphtUgraphxc (Paris), 1:277-280.1941. (5) Kooistra, J. A., "Prophylaxis ami Con trol of Erytlirasma of the Toe Webs." Journal of tlivesLigaLii'Q Dermatology, 4f> 3!)l> *U>0, The use of surgical antiseptics dates back to Semmelweis and Lister. The lat ter disinfected the skin at the operative site, dressings, and instruments in a 1:29 solution of carbolic acid, and degermed tlie hands. Godiec (Ref. 5) has recorded tlie historical aspects of tlie development of Lester's methods. In more recent times, tincture of green soap followed by alcohol rinse was in common usage until the llibO's. Sinee then, surgical scrubs roiilammg an iodophor or he.vichloro- Tlie proof that one surgical hand srrub, or for that matter, any surgical hand scrub is etlectlve as a prophylaxis for post surgical infection would be idea,'; however, the data are probably impossible to acquire since there axe multiple fac tors Involved in post-surgical infection. The concept of reducing the microbial count to as low a level as possible Is cer tainly prudent, since the longer the surgery, the greater the risk to tlie pa tient from post-surgical infection. {!'.) DtJrtijc. B. G . W, ft. Knowles. M E. Me- pheue have been in common usage, as !Tlie punctured surgeon's glove hm BrUir, VV C Dtmqnn and J, M. Knox, "Trcat- reported in a survey by King and Zim been hypothesbed. and in some cases ni'Mit of r:ryihra..ma With an AntIhaHerlal merman (Ref. 9). Iodine scrubs in (lie shown, to be the source of iwst-sundcnl Simp." Archive* of Dermatology, 07:548 552, 10C4. CM UtxicnBprft. F. W. and l*. Allan, ' EHlrleiK y of ah Antlhnctertul iiottp in 'l reatmout ami Control of Tf/C-Web ErylhrfWviim," Draft ol unpublished paper is Included In QIC Volume U20178. form of iodophor form illations have been widely accepted. Polyvinyl pvnohdone nml various surtacLant carriers arc used to slow iodine release and Unis reduce tlie iitilatimi of tlie sktu caused by iodine, Tlie acLivily of any Iodophor is dependent wound infection, as reported by Dcvrnh.h and Miles, tltef. 6). It is estimated that liclwcen one-third and one-half ol the surgical gloves are punctured or tom during surgeryj From the results of research on skin (8) 'Tuber. D., A. l\. Ward anti F, Yut'knvli h# on the release of tiir,liable Iodine from flora, it is now apparent that wearing "Ufic of an Antibacterial Soap In the Treat the complex. The Iodine released when of occlusive surgical gloves or wrapping rcOERAL REGI5IER, VOl. 39, NO, 1/9--FRIDAY, 5EPIEMDER 13, 19/4 ASI 00003650 PROPOSED RULES .'Bill the skin with occlusive plastic allows the growth of high populations of imcrooiganlsins and lias been dcscl died by Marples rlief. 7) and Peterson (lief. 81. Tlio Panel, thcrcfoie, recognizes Hint diiiiuii.': of the surgical glove may itself piodme a. rapid increase in microbial count on the hands, cion after a surgical scrub product lias been used. Considering these facts, the Panel feels that an clfective surgical scrub should rcduco the Initial count of both Lho tran sient and normal Horn to as low a level as possible and prevent the build-up of high microbial counts in the clove with lime. The exact shape of the curve indi cating Increase in microbial count with time after the use of a fast-acting scrub or a substantive antimicrobial scrub has not yet been determined. REFERENCES (1) Scnimelwcls. I., "Ole Aetiologic. dcr BegrlfT und die Prophylaxis des Klndbettllebers," Pest, med-chir, Prase.. 1661, (2) Price, P. B., "The Bacteriology of Nor mal Skin: A New Quantitative Test Applied to a Study of the Bacterial Flora and the Disinfectant Action of Mechanical Cleans ing,1* Journal of Infectious Diseases, 63:301318, 1338. (3) Cade, A. R, "A Method for Testing the Degerming Efficiency of Hcxachloiophene Soaps," Journal o/ the Society o/ Cosmetic Chemists, 2:281-200. 1051. (4) Quinn, H., J. Q. Voss and H S Whitehouse, "A Method for the In Viro Evalu ation of Skin Sanitising Soaps," Applied Microbiology, 2:202 204, 1054. (5) Godlec, R. J . "Six Papers liy Lord Lister," Jon Bale, Sons and Danlelsson Ltd , London. 1921. (6) Dcvenlsh, E. A, and A. A Miles, "Con trol of Siupliyioeocrws aureus in an Operat ing-Theatre.** Lane,!, 1,1088-10*14. III:)1! (7) OTC Antimicrobial I Panel Summary Minutes for the December 14. 1972 meeting, (8) Peterson, A. F, "The Microbiology of the Hands: Evaluating the Eirccts of Sur gical Scrubs," Draft of paper submitted for publication 19 Included in OTC Volume 020186. (9) King, T. C. and J, M Zimmerman, "Skin Dcgerming Practices: Chaos and Con fusion," American Journal o/ Suigery, 109;G95-G98. 19G5. Jl, Use of health-carc personnel handwash. The overriding reason for the washing and degerming of the hands of nursing and other hospital person nel Is the prevention of the transfer of pathogenic organisms from infected pa tients to the attending personnel and to other patients. The development and testing of products for this purpose has lagged. The ideal preparation would be a broad-spectrum, fast-acting, substan tive antimicrobial which could realisti cally be used for the numerous repeated dally handwashings requited m patient cate. The Ideal ptoducl must inline the transient Hora to the level present be fore the manipulations reunited by pa tient care and must have eliaraeteristies which will allow repeated use and confoiimt.v to routine use without excessive li i il at Ion. Transient imci om rani:,ms tail be leiitlilv milled to the I loin of Ihe skin and be retained for varying pci tods of time depending on the environmental and nueio-eiivii oumental conditions en countered. The viii icty of transient or ganisms acumied depends upon the con tacts which the hands tiavc made, Oi Ca libans encountered und relumed on Urn skin have been enumerated and described by Mai pies (lief. 1 v. Blank et nl. (Kef. 21 and Roscbury (Ref. 3) and Include numerous giam negative species 'Ref. 6) and a variety of fungi. Thc plea was first made bv Price in 10,SO i lief 1) and repealed by Kim; and ZUimiei mall (lief, ,'ji for a rompai alive study of hand degerming and scrubbing products using staiulaid laboratory tech niques so that some rational recom mendation for use can bo made. Tins Panel would also recommend controlled comparative studies in an attempt to reduce the conflicting and ambiguous claims by nuiniifactums and possibly to resolve laboratory data from studies where the design vanes virtually with every study performed. References (1) Marples, M, J, "The Ecology of the Human Skin," Charles C, Thomas, Spring field. 19G5. (2) Blank,, H. N Zains, D. Tap)In and G, Rcbcll, "Swamp Fox II." Volume VII. U S. Army Materiel Command. Washington, DC, 19G4, (3) Roscbury. T,, "Microorganisms Indig enous to Man," McGraw-Hill, New York, 19G2, (4) Price, P B, "present Day Methods of Disinfecting Ihe Skin." Arrhites of Surgery, 61:583-588. 1050. (5) King, T. C and J. M. Zimmerman, "Skin Degerming Prncllecs. Chaos and Con fusion. " Aniencan Journal of Surgery 109: G95-698, 19G5. (63 Bruun. J N and C O, Solbcrg. "Hand Carriage of Gram-negative bacilli ami Staphylococcus Aureus." British Medical Journal, 2:580-582. 1973. 5. Use of prc-optyjlii'e_ skin jircpnraflPTfs. An antimicrobial product for use in the preparation of the operative site may possess characteristics different from surgical scrubs or handwashing products. Since the product is normally and routinely applied only once to pre pare tlie skin for surgery or manipulative procedures, the antimicrobial should be fast acting and broad spectrum. The product should not cause injury to the she where it is applied. It is desirable to reduce the microbial population (resi dent and transient) to as low a level as possible prior to the .surgical procedures (Ref. 2). Five percent phenol solution was preferred by Lister, while iodine, or ganic mercury compounds, quaternary ammonium compounds and ethyl alcohol have been used in more recent times as recorded by King and Zimmerman (Ref. 1>. There arc some dilficull ics associated with the testing of jire-opeiajhe skin preparations, iSce discussion in the guidelines of efficacy testing of a patient pre-operativo skin preparation.) Fre quently, the skin is not rinsed after ap plication of a pre-operative skin picparalion If In vivo Icsls of effeetiveness aie undertaken, the eariy-over of the re sidual aiil.lmii iohial Ingredient fiom the skin to Ihe < ulLmo medium In Ihe process of sampling of the skin becomes a prob lem. In order to counteract the antimi crobial activity of any chemical inadvert ently canicd-ovcr, neutralizers specific for tlie antimicrobial should be added to (lie culture medium. Neutralizer devel opment has made reliable le.-.llng of anti septics and disuihclaiil., possible Ihe lack of rinsing of tlie skin and tlie sub sequent carry-over of tlie antimicrobial ingredient during testing has stimulated development of a variety of neutralizing fui inulations for use in tlie testing of antimicrobial skin products Including a universal one as desenhed by Engley and Doy (Ref. 3). IT neutralizers are utilized, tlie Inherent toxicity of tile neutralizer fur the specific miicroorganisms being tested should be determined, as well as verification that the neutralizer is ef fective for the antimicrobial chemical hciiiff tested. Effectiveness testing of a Patient Pre-Operative Skin Preparation is described in the Guidelines for Testing in this document. References (1) King. T. C. and J. M. Zimmerman, "skill Degerming Practices: Chaos and Con fusion." American Journal of Surgery, 109: 695-698, 19G5, (2) Lowbiuy, E. J. L.. "Removal of Bacteria from tlie Operation Site," Skin Bacteria and Their Bole in Infection, Edited by Malbach, H. I. and G. Hlldlck-Smlth, McOraw-HIU, New York, 1965. (3) Engley. Jr,, F, B and B. P. Dey. "A Universal Nentiallz.lng Medium for Anti microbial Cbcmlcale," Proceedings of the Chemical S/iecialty Manufacturers Associa tion iCMSA), Mid-year Meeting, pp 100-106, 1970. 6. Use of antimicrobial products in the refraction of staphylococcal colonisation in the nursery. Studies by Rammclkamp ct al. (Ref. 1). Love et al. (Ref. 2> and others, have shown a reduction in the incidence of pathogenic organisms in the nursery with antiseptic hand care. Gluck and Wood (Ref. 3) showed, in a con trolled study, that routine practice of hcxachloi'ophenc bathing of newborn in fants in Ihe nursery reduced staphylococ cal colonization. Many washing proce dures for infants utilizing dilutions of the commonly available 3 percent hexachlorophene products with variations in regimen have been in use since hexachlorophene bathing was introduced. Questions have been raised over the years concerning the influence of the use of a gram positive bacteriostatic agent on the incidence of gram negative infections ill the nursery. One such comment is m the report by Light and Sutherland (Ref. 4). Some nurseries have operated with out tlie use of hoxachlorophcnc bathing at all and still maintain low Infection rates. Indications are that tlie recent ces sation of use of hexuchlorophcne to huthe infants in tlie nursery has resulted in increased staphylococcal infect ions In nurseries. These nut breaks have been documented by Go/on (Rot. 5*. Dixon ct al. (Ref. G) and Kaslow et al (Ref, 7). The Food and Drug Adinini'.li iition. ui)on the advice of the OTC Antimicro bial f Panel, took action and Issued m the I*T iiKfiAi. Ri.cisTcn of September 27, 1972 (37 Fit 20100) n final order making liexaehlorophenc available only by piesciip- 11 ULRAL EICISHR, VOl 37, NO. 1/9 -- KMOAK, UPKMSIR 13, 1974 ASI 000031. Ml 12 PROPOSLD rule; tlon, except at concentrations less than 0.1 percent as part of a preservative sys tem. and limiting the Indications In the labeling under 21 CFR 3.81. The use of hexarldorophcne In nurseries Is now lim ited to handwashing by personnel and i! i ir-c to bathe the infants is recom mended only in the lace of an unchecked iduphylm oecal outbreak. The indications CM Kai.low. tl A II uismi, p. M Mar tin. G F. MuIMmom n a Oniunmnn, .1 M. Llmlney, 11, F. 54. 1111 imp i,nil J, V lltmneU., "Sl.sphylnrnrt'al DlM'.r.f Related Ln llmjillal Nui'cvy tlaUUng LTarl ires - a Nationwide npldemlologtc Investigation," rediatrtci. 81 (Snppt. J), Part IJ.4IH 42(1. 1973, (8) Hurst, V., ''Colonization or the New born." Skin Bacteria nut Their Pole in In fection. Edited by Malbarh, H. f. and O. as specified in the Anal regulation are Hlldlck-Snitth, McGraw-Hill, New York. 1965. as follows: (9) Fairchild. J P, "Management of the (a) Bacteriostatic skill cleanser for surgi cal scrubbing or handwashing as part of patient care. (b) For topical application to control an outbreak of gram positive Infection where other Infection control procedures have been unsuccessful. Use only as long aa necessary lor Infection control. Other antimicrobial products may eventually replace hexachlorophene as a means of reducing staphylococcal coloni zation. Authors generally agree that the umbilical stump is the site initially colonized with Staphylococcus in the newborn. This observation has been veri fied by Hurst (Ref. 8) and Fairchild (Ref. 9). Studies designed to show reduction in colonization with stapliylococci and sub sequent prevention of staphylococcal dis ease will be difficult to perform m the future with new antimicrobial products. The major difficulties are the projected large number of patients necessary for a prospective study and the need to ob tain patient consent. . The Panel has reviewed triple dye (a combination of bacteriostatic dyes) which was in use prior to the introduc tion of hexachlorophene bathing of neo nates <Ref. 10). This dye combination has been used to supplant the formerly used hexachlorophene (Ref. 11). Be cause of the renewed interest in Triple Dye. the Panel has reviewed the exist ing literature and has included this prod Umbilicus." Skm Bacteria and Their Rote in Infection. Edited by Malbach, H. I. and G. Hildick-Smith, McGraw-Hill. New York. 1905. (10) Jellard, J., "Umbilical Cord as Reser voir of Infection In Maternity Hospital," British Medical Jnurnat. 1*929-928, 1957. (11) Tildes, R S,. R. 5 Ramamnrthy and D. Vldyasagar. "Ellert of 'Triple Dye' on Staphylococcal Colonization In the Neonate," Draft of unpublished paper Is Included ln OTC Volume 920188. 7. Use o[ skiti_woujid cleanser. The re moval of foreign material from minor, superficial wounds without retardation of healing is regarded by the Panel as the primary use for this category of products. The Panel is aware that there is a wide array of products which are to be used on tile skirt for cleansing wounds or with the intent of pi eventing infections. His torically tiiese products have contained an antimicrobial ingredient based on the theory that use of such an ingredient was beneficial for use in or on a minor cut, scrape, burn or wound. Little, if any, scientific evidence exists to substantiate tire assumption of prophylaxis against infection by the topical use of antimicro bial ingredients. The Panel, after review of the infor mation submitted, has concluded Mint tile primary treatment of the wound should be the thorough cleansing of that wound to remove foreign material, dirt and debris. uct in the report. Statement on Safety Factors for retercnces Topically Applied Antimicrobial (l> Rammcikamp. Jr.. C. H.. E. A. Mor Ac ents timer, Jr. Aiut E. Wollnsky, "rian.'imisMon of Streptococcal and Staphylococcal infections." Annals of Internal Medicine, 60:753-758. 1904. (2) Love, O. J., H. NT. Gcfcon, D, J. Thomp son. K. D. Rogers and T. F, Hatch, "Relation of Intensity of Staphylococcal Infection In Newborn Infants to Contamination of Nurses' In the field of toxicology it lias been traditional ill estimating safety factors for topically applied materials to relate the "effect" and "no-cllect" level result ing in pathological alterations Irom the orally (intravenous, mtraperitoneal and inhalation have also been used) and Hands and Surrounding Environment." Pc* diatrics, 32 956-965. 1963. (3) Gluck. L. and If. F. Wood. "Effect of an Antiseptic Sktn-Cnre Rcgttnrn In Reduc* lint Staphvlororcal Colonization In Newborn Infants," New Finland Journal of Medicine, 205-1177-1181. 1061. (4) Light. I. J. and J. M. Sutherland, "What Is the Evidence that Hexachlorophene is Nut dermally administered dose. Some multi ple of the highest no-cfTcct dose, based on body weight <mg,kg>, has been used in calculating a safely factor The Panel in coiiMilci mg tins approach Ln solely factors examined oilier evidence that suggested that Hnological clfects of the applied chemical me often best extrap Effective?", Pediatrics, 51 (Suppl. 2), Part JI 315-399 1973. (5) Cezon. If M, M, J. So ha her;: and J. O. Klein. "Concurrent Spldemlcs of Staph ylococcus aureus and Group A Streptococ cus Disease In a Newborn Nurserv -Control Wtlh rcnlrlllln Q and Hoxachlnropheno Bathing," pediatrics, GI (Suppl, 2), Tart II: 383-390, 1973. olated among specie*, on the basis of relative sin luce areas tllef. 2 and 1(1) a Tile Panel utilized this InLtcr approach initially in its calculations for safety factors for topically applied antimicro bial ingiedlcnt.*: In addition, the Panel is cognizant of the fact that analytical chemical techniques can now lie utilized (0) Dixon, It. E.. R A. Kaslow, G. F, Mai* llson and J. V. Bennelt. "Staph\lorncral Disease Outbreaks In Hospital Nur'ertrs in thn United States--December 1971 through March 1072." Pediatrics, 51 (Suppl. 2), Part to determine concentrations of chemicals in blood. This then rail permit correla tion or LIic topically applied dose to blood levels and any resultant patho 11:413-416. 1973. logical alterations. Knowledge of the blood level.'; achieved by application of a chemical In varying foi inulutlons at dlllerent dear levels and routes of adminlstialign ran help in the lindeistanding of the blopliarmncolo-v of a chemical suhsl.mce lai n hrime Ur topically applied maU.ii ,I I.. into the blood there are many conuitioii.*. width influence the rate arid amount absorbed through the skin. There arc great dif ferences among animal species, among skin areas on the body, among normal, irritated, diseased or previously treated skin areas and often variations from one individual to another. For these reasons systemic toxicological Information from topically applied materials can at best be only supplementary to that from ad ministration by another route which by passes the cutaneous barrier and insures appropriate amounts in the blood. Addi tionally, the rate of absorption, the rate of excretion, the metabolic fate, and the amount stored in depots also aflcct the relationship between the applied dose and pathological alteration. Blood levels therefore may be a more reliable conelate of pathologic effects to aid in the de termination of safety factors than ad ministered dosages. The Panel believes that it is important to develop, such information whenever possible, and to take it mto consideration in the develop ment and setting of safety factors. This blood level data should be required in toxicological studies as it may be a more direct measure of absorbed dose than can be obtained from merely a measure of topically applied dose. Many methods were presented to the Panel for the determination and/or pre diction of the toxicity of an active chemical ingredient in man based on data obtained from laboratory animals. A variety of calculations of applied dose, absorption, blood levels and appro priate safety factors have been reviewed by the Panel and discussed with various persons. The Panel has decided to detail specific examples of their calculation procedures used in the estimation of possible toxic clTrcls among species, and they are included herein. The Panel recognizes the difficulty in the transla tion of tile results of toxicity testing from one species to another and paiticularly, to man. Various assumptions have been made in the past concerning the relative sensitivity of man compared to various animal species, but established compari sons do not exist primarily bemuse of variation in efTert willl different drugs PaiacelMis (119,1 -1541 I wrote* "All llimr*; aie poisons, for there is nothing without poisonous qualities. It is only the dose which makes a tiling a poison," In addition to the "poisonous qualities" a cheimeal may possess, at ceilaiti ronrentrations and routes of adiiiiiiistralion, other characteristics such as subject idiosyncrasy, allergy, and tolerance must be < onsidered to evaluate safety of an clfccUvc dose. The Initial toxicological evaluations are conducted in animals to determine the qua Id a! ivo and quanlilal ivc phai macological aspects of I lie chemical. Deline ators of ie:.ponsc which may varv from species to species are routes of admlnls- FEDERAL REGISTER, VOL. 39, HO- 179--FRIDAY, SEl'tEMBCR 13, 1974 ASI 0000365? l /i i X e 3 n' st ,, /** ;3 1 l*i te ie . iC o' U. os . h. " to >J- * - ia' in re kXX eve on. Is-. ed , o- ed its ail i on of nd tel latm iy. on ive lUS iiof .S. AU ing Lhe In 'a Oil.' on, sect tut an ons One ds- PROPOSED RULES .1:11 l.'l tration, dose and plasma levels, rate of absorption, rate and route of excretion, distribution throughout tile body, and nature and number of metabolites. Be nue e species (lUTercnccs can be consider able, multiple animal species i rodent and nonunlent' should be used. Further, si mu Hunt; should be known of the ellect of the active chemical agent in all the snceies tested so that some comparison can be made with man. Blood levels ol the active lnnretlicnl In animals arc of value In the overall eval uations of "elfcct" (lowest dose which produces a toxic elfcct) "no-c(Tect" (highest dose which produces no toxic effect) response dose levels. They are the result of several interrelated mecha nisms, among them being (1) absuiptlou rate from the site of application, (2) metabolism by enzymes, (3) distribution and storage In the tissues, and (4) ex cretion. Absorption is not the same in all animals or from all sites of adminis tration, This may bo related to species differences and/or to the physicalchemical properties of the active chem ical. The metabolic rate and fate of an Ingredient is a direct reflection of the animals' enzyme systems which charac terize the individual animal species. Therefore, blood levels of the active chemical and or metabolites are im portant determinants after a particular mode ofjiosmg in a paiticular species of animal. As demonstrated by Spinks (Ref. 1) when 100 ing/kg of suliadiinUline was fed orally to 10 different species of ani mals, doses produced blood levels in the various species which had little relation ship to body size or blood volume. As stated earlier, absorption is not the same in all animals, or from all sites of ad ministration. Of course, experienced in vestigators would shave the site of appli cation for the testing of topically applied products and dose seven days a week. The active ingredients which are re viewed here are formulated in topically applied products. The importance of ve hicle In the delivery of the active ingre dient is well recognized. Not only should there be an investigation of toxic effect after topical application, but the charac ter and effect of the vehicles alone should also be examined. The toxicity of a spe cific ingredient can be dramatically af fected by selection of a vehicle. The Panel recognizes the difficulty in translating the results of animal toxicity to man. Sufficient animal data must be collected to construct a dose, iespouse curve. This should Include adequate data on absorption, blood level (s', metabolic rate and fate, and excretion, so that an analysis for threshold elfcct and sale use level for that particular annual can be determined. Then an extrapolation to man may bo.made. Any error In transla tion of effects to man must be on the side of human safety. A safety factor fioqucntlv has been applied to the lowest effect level in animals when that paillcular dose is tiauslatcd to potential and/or possible toxic effects in mail. For exam ple, a 100-fold safety factor has generally been used for the applied dose for food additives. Actually, it vailos from 10 to 500 in application to food additives. The safety factor used in any given case de pends upon tlie nature of the adverse ef fects noted in animals and on the amount of data derived from human studies. The 100-fold margin of safety is a uscfuTgcneral guide. If, however, a different safety factor is used, it should be based on ade quate scientific studies that establish safe levels of use. The Panel has used the methods of Paget and Barnes (Ref. 2) to translate toxic oral or topical doses In animals to the dose where an expected toxic effect might appear In man. This was done because safety data of the type recommended by the Panel were not available. The following methods weie used by the Panel In an effort to calculate these safety factors: The Panel made calculations from data presented for various ingredients. The calculations presented here arc hypo thetical, show the assumptions made and arc intended to explain the method. 1. Expected no-effect dose level In man: Determine the lowest toxic effect and the highest no-effcct dose in mg/kg topically applied in an animal species, (If an effect cannot be determined in a topical application, the oral route of ad ministration should be employed). Take tlie highest no-effcct dose in that animal species and calculate the absolute dose using the method described in Paget and Barnes (Ref, 2). From the absolute dose the multiplication can be mndc with the factor given in this reference fur the specific animal used In Lhe test and this, then, is the dose level at which no-eifect might also be expected in man. 2. Expected blood level from product use in man; Assume a bar soap with 3 pci cent active antimicrobial is used for one batli per day. Assume that 7 grams of soap arc used in one batli. Tills would give an exposure of 0.21 grams or 210 mg. per bath ol active ingredient. As sume retention of all 210 mg. active in gredient on the skin (there Is very little Ann data presently available on the amount of antimicrobial retained on the skin after exposure). If 3 percent of the applied active ingredient is absorbed Into tiie blood stream, the dose per bath would be: 003x210.0 mg.^-630 mg. active Ingredient absorbed. If the assumption is made that the total dose is immediately absorbed, the dose distributed in the blood of a 70 kg. human would be: i 30 me 5.000 mj blw.il. aTkTlmnem - ' -'n s ^ "v,` '"H""1"'"! I'-r "'I181>`r of l-Uxxl The assumption Is made here that the amount of chemical piescntcd to the in dividual in a single bath is all retained on the skin and absorbed and distrib uted in the blood giving a blood level of 1.26 mcg/ml. As a further example, assuming reten tion of 0.5 meg. of active ingredient per sq. cm. of skin and the product is to be used over the entire skin area, as in a bar soap, tire total dose retained would be 9,25 mg, over the entire body. The cal culation would be 0 5 meg, per sq. cm. X 18,500 sq. cm. of skin (based on a 70 kg, 5T0" human). Assuming for this case, a 10 percent absorption: 9 25 mg x0.10 = 0 93 mg. dose per bath If the assumption is also made that the total dose is immediately absorbed, the dose distributed in the blood of a 70 kg. human would be: VIM) tit) 0 03 tuff blood,70 1<K bihiUiu -li IS jik'6 sii'tivp ingrrflirni pn millililor of blood Safety factors were calculated using the available evidence. For tire specific calculations, see the individual Ingredient statements. These two hypothetical calculations using known facts with stated assump tion are examples of the type of safety factor calculations considered by the Panel. In tins calculation, the informa tion required is the retention of the chemical by the skin after exposure. The missing information here is the absorp tion excretion kincLics for that chemical. A direct comparison can he made and thus a safely factor ran lie estimated by a comparison of the calculated human biood level with the blood level hi ani mals, ir known. A comparison of the dose where there is no effect In animals trans lated to the dose in which no effect may he expected In humans against the hypo thetical dose to which a person is exposed from the use of a product containing the ingredient can he made if blood level data are not available. It must be stressed again that the best calculations and Judgments arc made wlicii nil ol the pertinent data arc avail able and frequent assumptions do not have to be made. The variety of calcu lations presented to the Panel have been t lie result of making assumptions because the data were not available. fin the Panel's judgment, submitted studies to determine effect/no-effect level have been inadequate._For example, where two dose levels were run (100 mg/ kg; 500 mg/kg) and the lower dose dem onstrated no-cffcct while the higher dose demonstrated an effect, additional stud ies must he conducted using appropri ate intermediate doses to determine the highest no-effect level. If the safely factor is extrapolated from an animal species to man, consider ing surface area, the highest no-effect dose should be used for the multiplier. In the absence of complete dal a, at least a one hundred-fold safety factor should be applied when translating the animal highest no-cffcct dose to man. Tlie ideal situation would occur where enough animal data have been collected to construct a dose response curve with concurrent blood levels so that analysis for threshold effect and safe level esti mation for tlie animal can lie made Man tel and Bryan (Ref. 3), Mantel (Ref. 4) FEDERAL REGISTER, VOL. 3*), NO. 179--FRlOAV, SEPTEMBER 13, 1974 AS I 00003653 .run PROPOSED RULES and Gross ct al. (Kef. 5'. Additional references supporting the ideas expressed here are found in Crampton (Ref. G>. Litchfield (Ref. 7 and 8) and World Health Organization Teciinleal Report (Ref. 9). in summary, the Panel recommends that toMculogicul studies, where appropiiafe. contain applicable administered doses, achieved blood levels, and observed pathological alterations in the same study and the same species. , REFERENCES (1) Spinks. A., "Justification of Clinical Trial of New Drugs," Evaluation o/ Sew Drugs in Man, Edited by E. Zalmls, Macmil lan. New York. pp. 7-19. 1905. (2) Paget, Q. E. and J. M. Barnes, "Toxi city Tests," Evaluation oj Drug Activities: Pliarmacomctncs, Edited by i.aurenco. D R. and A, L. Bacharach, Academic Press, New York, 1904. (3) Mantel, N. and W, R. Bryan, "'Safety' Testing of Carcinogenic Agents," Journal o/ the National Cancer Institute, 27:455-470, 1001. (4) Mantel, N,, "The Concept of Threshold In Carcinogenesis," Chnunl pharmacology and Thrrapeutics, 4:104-1011, 1903, (5) Gross, M A., O, G. I'llahugh and N. Mantel, "Evaluation of .Safety for Food Ad ditives: An Illu.lrntlon Involving the PiUu- cnco ot Methyl Salicylate on Rat Reproduc tion," Biometrics, 26:181-194, 1970, (G) Crampton. R. F, "Problems of Food Additives, with Special Reference to Cyclamates," British. Medical Bulletin, 20:222-226, 1970. (7) Litchfield, Jr , J. T., "Evaluation of the Safety of New Drugs by Moans of Testa In Animals," Chntcal Pharmacology and Thera peutics. 3:665-672, 19G2 (8) Litchfield. Jr, J. T,, "Predictability of Conventional Animal Toxicity Tests," An nals New York Academy oj Science, 123:2G8- 272, 1965. (9) World Health Organization Technical Report Series No, 348, "procedures for Inves tigating Intentional and Unintentional Food Additives." World Health Organization, Geneva, 1907. (10) Paget, G E. "Toxicity Tests: A Guide for Clinicians," Journal oj New Drugs, 2:78- 83. 1002. Definitions of PnooucT Categories Not all antimicrobial products are used for the same purpose nor should the re quirements for effectiveness be the same. In an attempt to classify topically ap plied antimicrobial Ingredients and prod ucts, one of the important concepts con sidered in the development of definitions is the distinction between the determina tion of effectiveness in preventing or combatting clinical infection (sepsis) and the reduction of resident or transi ent microorganisms on the skin. Label claims for handwashing, surgi cal scrubs and first-aid products pres ently include prevention of Infection, reduction in spread of Infection, and re duction of normal flora. Frequently, claims against specific organisms arc made with Clinical implications based solely on In vitro data. Tho following specific definitions of anllmlcroblnl product eutegortes liavo been developed by the Panel in an at tempt to simplify ralegoi Iznllon of In gredients and thereby eliminate labeling confusion. The most rigid definition with respect to effectiveness requirements is fur a "skin nnii i piic". The other six defini tions relate In the "skin antiseptic" def inition and their distinctive effective ness requirements are described. Each defined product requires specific studies to support effectiveness. The Panel lias adopted definitions for tlie following categories of topical prep arations when applied at acceptable use concentrations: Skin Antiseptic Patient Pre-Opcrattve Skin Preparation Surgical Haml Scrub IlealUi-Caro Personnel Handwash Skin Wound Cleanser Skin Wound Protectant Antimicrobial Soap 1. Skin antiseptic--"A safe, non-lrrltaring, antimicrobial-containing prepa ration which prevents overt skin infec tion. Claims stating or implying an effect against microorganisms must be sup ported by controlled human studies winch demonstrate prevention of in fection." There lias been misunderstanding, confusion and.exaggeration m the def inition and use of the term "antiseptic " The literal translation from the Greek means "against putrefaction." In re cent tunes tlie definition has been in terpreted as activity against infection or microbial sepsis. The term "anti septic" is comparable to accepted defini tions for a "disinfectant." Even though they are often confused, there has been a traditional restriction of tlie term "antiseptic" for antimicrobial formula tions applied to living tissues, particular ly on the human body, and tlie term "disinfectant" to inanimate objects. The distinction between antiseptics and dis infectants, for regulatory purposes, lias also been made on the basis of these defi nitions. Tlie Panel's view is that "anti sepsis" pioperiy refers to the use of antimicrobial chemicals on the skin or on human tissue and that "disinfection" properly refers to their use on inanimate objects. Disinfectants or antimicrobial chemicals labeled for use on inanimate objects are regulated as economic poisons under tlie Federal Environ mental Pesticide Control Act (7 U.S.C. 13(3). Antiseptics labeled for use on human or animal tissue are regulated as drugs under the Federal Food, Drug and Cosmetic Act. The traditionally accepted definition metic Act delines an "antiseptic" ns "Tlie representation of a drug in its labeling as an antiseptic shall be considered In be a representation that It is a germicide except in the civic of a ding purporting to Ik; or lepicscnlcd us an aullsepllc lor inhibitory use as a wet dressing, oint ment. dusting powder or such other use as involves prolonged contact with the body." Tho traditionally ncccptcd definition of an antiseptic by the sclcntinc com munity lias Included activity against in fection when applied to living human tissues and 1ms been recorded in publica tions by Reddish (Ref. 1) anti Patterson iRcf. 2). A current definition by Sykes (Ref. 3) states that antiseptics arc prep arations possessing antibacterial or an tifungal activities which arc suitable for application to living tissues of the human body. Over tlie years, the exaggerated label ing rluim.s 011 11 bilge variety of pruducts containing aiitmueiobials lues led to mis use and abuse of the term "antiseptic." Tlie rami lias nttcinptcd to eliminate tlie confusion by developing a rigorous definition of a Skin Antiseptic. The re maining definitions can be explained in terms of their own effectiveness require ments and in tlie manner in which their use and composition differs from a skin antiseptic. 2. Patient pre-operative skin preparation--"A safe, fast-acting, broad-spec trum antimicrobial-containing prepara tion which significantly reduces the number of microorganisms on intact skin." Any product labeled as a Patient PreOperative Skin Preparation must be ef fective against all types of organisms eomptising the skin mlcroflora so as to obtain as low a number of micro-orga nisms as possible in a short period of time without injury to tlie operative site. Con trolled studies, conclusively demonstrat ing that tlie use of antimicrobial-con taining products are superior to soap and water in the prevention of post-surgical wound infections do not exist. The In escapable logic in the use of products designed to reduce tlie microbial flora In the operative field is apparent and is supported by a long history of use. The use of these products is specialized, un der professional supervision, and will generally be for a single application, 3. Surgical hand scrub--"A safe, non-irritating antimicrobial-containing preparation which significantly reduces tlie number of micro-organisms on the intact skin. A surgical hand scrub should be broad-spectrum, fast-acting and per sistent." Tlie use of this category of products Is normallv limited to the hands and fore arms. The comments concerning postsurgical infection made under Patient Pre-Operative Skin Preparation apply here. A discussion of the effectiveness, difficulties to be considered and rationale for the product is presented in the Pan el's comment concerning effectiveness under Surgical Hand Scrub. The term persistent refers to the possibility of ex tended activity with time of an applied antimicrobial by a mode, Including among others, substantlvlty. 4. Ilcalth-carc personnel handwash-- "A sa/e, non-Trrltaliiig preparation de signed for frequent use. which reduces tlie number of transient microorganisms on intact skin to an Initial baseline level after adequate washing, rinsing and dry ing. If the preparation contnlns an anti microbial agent. It should lie brondsprrl.rum, fast-acting, and If possible, persistent." A product fitting tills definition should be designed to be used repeatedly, per haps as many as 100 times a day, to re duce and, If possible, eliminate "tran sient" microorganisms present on the riocnAi urcitmi, vot 37, no. 179--imoAr, sepkmbck 13, 1974 ASI 00003654 tail fi ts m- C M itc 0113 rc- . in veitMr kin ra- ecra- the act 're ef' ms to ga- i me >nat>nnd cal In,cts ora i is ife, m ces the ild er- i Is re st ent ply ss, ale m- rm x- led lag Jeces ms vel ry. tl(1le. ild r- rc- 4 PROPOSED RULES .rnir. skin rr'Miltlng from contact with con taminated poisons or mutci Inis. In nil likelihood, tlx; specified rlfccl, ic.. re moval of ti nnsicnt ni'guiii'un:; rnn 1)0 achieved v. lth ft wrll-fommluted non- nitl mm loin,it mu|) or ileleiunit, product, la mo Using: uoulil tie inuniliitmy to show tin' cllcclivciic.ss of such ft product (Soc suggested testing procedures In Guidelines In tills ilociiniriil). Any Iron* Blent oiKiiiPMii can become pail of the established "resident" Horn ivitli lime. Obviously, in a health-cure sitimtion, tbe fast, eircctive removal of transient or ganisms Ls a requiiciiient sinee they may be pathogenic. Such products containing an anti microbial Ingredient should be broadspectrum. The term broad-spectrum when used with reference to microbio logical spectrum means that the anti microbial lias activity against more than one type of microorganism. For example, many of the active ingredients discussed In this report have significant activity against only gram positive bacteria whereas a broad-spectrum antimicrobial would have to demonstrate activity against gram positive and gram negative bacteria and would very likely also have activity against fungi and viruses. A product containing an antimicrobial with substantive (retention of the chemi cal in the skin) properties which acts to prevent the growth or establishment of transient microorganisms as part of the normal baseline or resident flora would provide an added benefit. Essential qualities of all health-care personnel handwash preparations must be low toxicity and little or no irritancy with repeated use. The adherence to washing regimens Is an important con sideration in the formulation of products in this category and health care person nel reject the repeated use of irritating and/or unpleasant formulations. 5. Skin wound cleanser--"A safe, nonIrritating liquid preparation (or product to be used with water) which assists in the removal of foreign material from small superficial wounds and does not delay wound healing." A product in this category is designed to aid, by its cleansing activity, in the re moval of foreign materials from a minor superficial wound. Such a product may or may not contain an antimicrobial ingre dient. Included in the term "safe" are the considerations that the skin wound cleanser should be non-irrltntlng and not delay wound healing. It is obvious that a product such as a bar soap with water could serve us a Skin Wound Cleanser. There is no necessity that such a product show effectiveness in the pre vention of wound infection. G. Skin wound protectant--"A safe, non-lnitaLing preparation applied to small cleansed wounds which provides ft protective (physical and/or chemical) barrier and neither delays healing nor favors the growth of inieionrguiil.Miis." A product la this cutegory whether ft liquid, senn olid, or solid preparation, when applied !u u properly prc-cleansed superficial minor wound, provides ft physical and/or rhrmicul barrier lo piolecl the wound from further contami nation with foreign material or inicio- organlsius. Tins type of product may or may not contain an antimicrobial in gredient. These products, by definition. :ne not designed for extended icpealcd Use or lor use on huge or deep wounds, 7 Aidiiniciobial soap--"A soap con- la fnTnirirrraHTveTngreTllent with in vitro and in vivo aclivlly against skin micro- oi gam sms " Soups n il bout uiituniiTuhliil ingredi ents las defined in 21 CPU 3 <1521 arc exempt from regulation under the Fed eral Food, Drug, and Cosmetic Act. An antimicrobial soap must, by defini tion, contain an active antimicrobial in gredient. A product in this category is designed to reduce the microbial flora of the skin, noth the resident and transient pathogenic and lion-pathogenic flora of .the skin may be reduced by the use of an antimicrobial soap. The relationship of this reduction to the prevention of minor skin infection has not been established, For a more detailed review, see the Panel's comments on the effectiveness of Antimicrobial soaps,) Antimicrobial soaps should be designed and tested for safety, when used repeatedly and for extended periods, potentially for a life long duration with tolal body exposure. In recent years the addition of antimi crobial agents to soaps has greatly In creased, and many individuals arc Invol untarily. unknowing captive consumers of such soaps (Ref. 4), Because a largo portion of the population is exposed to this potential hazard, the Panel recom mends that any soap or detergent con taining an active antimicrobial ingredi ent state on its label the United States Adopted Names (USAN) or common name of the active Ingredient. htrinrHLES 11) Reddish, O. F.. "Anft.cpi lo, piiiTi/cctaats, find Funr/u tdr\," 2nd IXI,. Lin uml Frldgcr. 1 'hIl:nl Ijilil;i, i'lr.V, (3) Puli<*im,n, A M.. "Mi .tiling uf'AulLw'pHc', UlsbifriUiiiL', anil ItelulrU Words," Anu-tirnn Journal 0/ Public Health. 22.4U5472. K,:i2. (.'II Sykes, G.. "Piiln/gclkJii and Steriliza tion." 2inl Kd,, J. li. Lippincoit, Philadelphia, 1!IG5. (4) Fisher, A. A. "Contact Dermatitis** 2in! Mil , ben nm! Fcblgcr, Philadelphia, 107(1, The OTC Antimicrobial I Panel has thoioughly reviewed the literature, and the various data submissions, lias listened to additional testimony from Interested parties and lias considered all pertinent data and information submitted through June 15. 1973 in arriving at its conclu sions and recommendations. Active Ingredients The Panel reviewed all active ingredi ents which were the subject of submis sions made to the Panel pursuant to the standards for safety, effectiveness, and labeling set out in the regulations. In accordance with the regulations, the Panel's findings with respect to these ingredients are set out in three cate gories; I. Conditions under which antimicrobial products are generally recognized as safe and effective and aro not misbranded. II. Conditions under which antimicrobial products arc not generally recognised as safo and effective or nre misbranded. III. Conditions lor which the available data are Insufficient to permit final classifi cation at tills time. A table listing the active Ingredients, classified Into one of the three categories, for use in preparations defined by the Panel is included for easy reference. At uv<* liicip'li' iit A i*(Jtnu'fnl'lnl Health* r.uo pt-rsniwirl hruul hiu.Ii 1`aMnnt prrxip ^ktn lui'itnritium Skin &nU<4cptlc Rkln wotiml flkln Rurjrlcnl voiiikJ linixi pruhcialn-mb i n<'M7illkohillin rlllnlKlr.. NA 2 Brn/t'lhoiuMtn rltlorldf.... NA` 3 1 'li.nil, hi lun.,.,,................ m 4 Kluorosnl.-m ................... 11 A 1 It tiit hloru|ilii`in_ li (1 ll,'\vlrt`.Mrt nidi................... NA' 7 IimIiiii'i ftinipl'Tfil with NA' pliusphttlf i.'.tt't of ulLy |- itij 1o\y jHtljvlbylour clw oi 8 Mr(hyllM`ii*(`iliO<itutu chlo- NA* 9 Nni.M |ihft|M\\ (wily (Vi It} NA' t ill ox v) I'l luimllntliMt*. 10 I'm .t t hliHoiiicUuyii ool ... III 11 I'lit'iin) (u) <#it uti'f limn l (ll'ItUotl.X lllftlliOh l,i....................... <hj 1 6' or |t > (tit|lltv. 11 nil i ult oiinlli ),,,. in V* I'ttloMimrt h,<UtU` rotiipU't* N A * u hot ItltUif luilim't nillplt x... NA 11 '1 lot l tirr tf iimJimi*,*..*.,... NA * 16 'rnlnomsulttM................. II 111 1 i|t |i urUui.................... . III 17 IVI, Ur nit................... 111 1A '|*ii|i|r tlvr.. .............. NA* 19 Ctuh-t uylluiii clllorltji'- NA* lotlim- <'it|ii|tlt'it. 111 111 111 II Jl 11! Ill III 111 III Jl III \\\ III IJ If III 11 N A* 111 Iff 111 II 11 If III ill in nr in ii nr nt in f n ii n NA m iri m 11 IJ If III III III III in u TIT in in u it H III m> in r m III i mm n ii nn if n n ii u i in jn m in m i in m ni m in in n i in H n it w TIT m III 111 m III It m ii m n Hnn 11 n HI in ii n NA1 NA* NA* m 1U 111 * s/A <Noi ntrllrnM*)'- I>w in n jiliyslrnl iimlor rlifmlcul ImointiithtbUUy lit furmuUUoib i < 'lit** i lift I In i iii pin y III win'll Mtrnmiiih-d |n q titr .ump lo wllli wntnr, 1 ItiMi |< l< <| Ini u <' only In thti lirniiutfeJ littl ,uy. Nun. J`oi diIh i pln niiLt uiu| vi UkU*, m-o Iwuly of rcjtorL FfDIRAl REGISTER, VOL, 39, NO. 179--FRIDAY, SEPTEMBER 13, 1974 00003655 .1.11 If. PROPOSED RULES X. Conditions under which antimicro prior to surgerv and must be removed (4i llu^o, W, n, "TnHJbitfon and Destruc bial product arc pcneralt;/ recognized as immcdiatch upon (hying with 70 percent tion of the Microbial Cell,'* Academic Prcm. sale and effective and are not mis alcohol nflcr application, or used as di Now York, 1971. branded. The Panel recommends that the rected by a pinMciaii. Labeling conditions specified In Category I be made effective 3U days after publication of the final monograph In the Federal Register. Active Ingredient A. The active ingredients generally recognized as safe and effective for use in uu `'antimicrobial soap" and not mis branded are: I. None listed. The acceptable composition for tinc ture of iodine is not leu* than 1.8 grams and not more tiian 2.2 grams of iodine ill. and not less than 2.1 grnms and not more than 2 6 grams of sodium iodide (Nall in each 100 ml, of 44-50 percent ethyl alcohol or an appropriate dena tured alcohol. ]IEX YLRESORCINOL FOR USE AS A SKIN WOUND CLEANSER OTC product* which contain active Ingredient* listed in Cutogoty I may us any phrase that is in the definition for that product.category or any of Lho fol lowing additional terms: A. ANTIMICROBIAL SOAP 1 Antimicrobial Hoap. 2. Antibacterial soap. 3. Reduces odor. 4. Deodorant soap. B. The active ingredients generally recognized as safe and effective for use In a "health-care personnel handwash" and not misbranded are: 1. None listed. It is obvious to the Fauci from their review of the toxicity data In the litera ture and in the submissions to the Panel that hexylrcsorcmol is safe for topical use ill small superficial wounds. The con centration of hexylresorcinol for use in D. HEALTH.CAR* PERSONNEL HANDWASH 1. Decreases bacteria on skin. 2. Reduces risk (and/or chance) cross-lnfcctlon. 3. Recommended for repeated use. of C. The active ingredients generally recognized as safe and effective for use in a "patient pre-operative skin prepara tion" and not misbranded are: 1. Tincture of Iodine. a skin wound cleanser should be limited to a use concentration not greater than 1/1000. Tiie major reason for the place ment of hexylresorcinol In Category Ilf was the paucity of effectiveness data for uses in other topical products. Tiie reader O. PATIENT PRE-OPERATIVE SKIN PREPARATION 1. Kills microorganisms. 2. Reduces the number of microorganism* on the treated ares. 3. Broad spectrum (If applicable). D. SKIN ANTISEPTIC D. The active ingredients generally is referred to tiie discussion of hexylre recognized as safe and effective for use sorcinol under Category III. 1. Prevents overt skin Infection. 2. Controls Infection, In a "skin antiseptic" and not misbranded are: l. None listed. E. The active ingredients generally recognized as safe and effective for use in a "skin wound cleanser" and not mis QUATERNARY AMMONIUM COMPOUNDS FOR USE AS A SKIN WOUND CLEANSER Reference is made to the discussion of quaternary ammonium compounds ("quats") under Category III. Because of the reported delay in wound healing 3. Degerming. 4. Kills germs. 6. Bacteriostatic and/or bactericidal. G. Reduces the risk of infection cross-infection. 7. Microbiocidal. 8. Flrst-ald product. and branded are: with quaternary ammonium compounds E. SKIN WOUND CLEANSE* 1. Dcnzalkonlum chloride. 2. Benzethonlum chloride. in animal model studies reported by Cus ter et al. I Ref. 1> and Edlich et al. 1. To clean superficial wounds. 2. Wash superficial (small) wounds. 3. Hexylresorcinol. (Ref. 2). only infrequent use in small 3. Flrst-ald product. 4. Methylbenzethonlum chloride. superficial wounds is recommended by 4. Aids in removal of foreign materials F. The active ingredients recognized tiie Panel. Since many "quats" have a such as dirt and debris. as safe and effective for use in a "skin detergent action (Ref. 3 and 4) which F. SKIN WOUND PROTECTANT wound protectant" and not misbranded can aid in the removal of foreign mate 1. Protects Rgalnst contamination. arc: rial from a small wound, their use in the 2. Protects wounds. f 1. None listed. formulation of a skin wound cleanser is reasonable, and in the opinion of the 3. Protectant, 4. Flrst-ald product. G. The active ingredients generally Panel, safe. The concentration of the recognized as safe and effective for use in quaternary ammonium compound (as a "surgical hand scrub" and not mis bcnzalkomum chloride, benzethonium G. SURGICAL HAND SCRUB I. Only phrases In definition. branded are: chloride, or mcthylbenzothonium chlo Tiie Panel was concerned that the 1. None listed. TINCTURE OF IODINE AS A PATIENT PRE-OPERATIVE SKIN PREPARATION ride) should be limited to a use concen tration not greater than 1/750. As defined hy the Panel, an ingredient formulated in a skin wound cleanser need not pos phrases used in the definitions would not always be easily understood by the or dinary individual. For that reason they believe that the above listed terms are There is an approximate 50-year his tory of the use of elemental Iodine on the skin and mucous membranes. Iodine is soluble in alcohol and only slightly soluble in water but the presence of iodides increases its solubility in water. Iodine is a microbiocidal agent lor cells sess antimicrobial activity. The dilution recommended for use of "quats" as a skin wound cleanser under Category I is regarded as safe provided that the prod uct is not used repeatedly, covered with occlusive bandaging, or used in deep or extensive wounds. necessary so that OTC drugs will have labeling that is truthful and can be un derstood by consumers, II. Conditions under which antimicrobial products are not generally recog nized as sale and effective or are mis branded. Tiie Panel recommends that the on the skin nt low concentrations. It PifERPNcES conditions specified In Category- II. ex must be recognized that the nctiviLy of (1) Cosier, J , R. F. Fdlleli, M. Priisak, J. cept for hexachloroplicne and tribom- Iodine is dramatically influenced by tile r. Futick and O, IT, Wangensteen, salan which have been handled sepa presence of organic material. A tincture "Studies tn the Management of tho Con rately (see hexnchlorophcne and tri- product containing approximately 2 per taminated Wound V. An Assessment of tho bromsalan discussions in this section) cent iodine has been used for many years. There is some irritation of the skin associated ^ith the use of tincture of iodine. On the basis of risk-benefit con sider ations. the one-time use of this for mulation as a patient pre-operative skin preparation can, in tlio Panel'* view, be EiTcotlvcness of piiiKoHcx and tteiAdinc sur gical Scrub Solutions," American Journal of Surgery, 121:572-575,1971. (2) Edlich. R. P-. I. R Sehmolkft, M. P. Prusnk and M. T. Edperton, "Tho Moleculnr Basis for Toxicity of Disinfectants In Sur gical Wound"." 1. EO;PO Block Polymers. Draft of unpublished paper U Included lit be made effective six months after publi cation of the final monograph in tiie Federal Register. Active Ingredients A. the active ingredients not gen erally rueoinbod ft* *ali mid effective justified considering the efficacy of tinc OTC Volume 020185. for use in an "antimicrobial soap'* and ture of iodine on the microorganisms on (3) Reddish, G, F,, "Antiseptic*. Oum* fcctantx cud Fungicides and Chemical and misbranded are; tiie skin. The use of this formulation U Physical simulation" 2nd. Ed., Lea and 1. Fluorosalan. limited to painting of the operative site Febiger, Philadelphia, 1957. 2. Hcxachloropheno. FEDERAL REGISTER, VOL. 39, NO. 179--FRIDAY, SEPTEMBER 13, 1974 ASI 00003656 n. J. of (ON mi' 'V < * the not oriey are iVQ mro>0the exm>a- irl- >n) uHihe nive nd ,y /- PROPOSED RULES :?:su7 0 I'hrnol greater Until 1.6 percent *queoufl/Alrnhollc, 4. TrlbromsaUn. n. The BCtWn InerariiotiU not gen erally irunynizod fta Htife and effective for \i .c in a "hraUh-earc personnel hand wash" ami misbranded arc: 1. PIUOIOSHllMl. 2 HetuchUirophciie. 3- Phenol greater than 1,5 percent aqueous/alcohotlc. 4. Tincture of Iodine. ' 5. Trlforomsalivn. C. Trtehlosan. C. The active ingredients not gen erally recognized as safe and effective for use in a "patient pre-operative skin preparation" and misbranded are: 1* CloHucarbftu. 2. Piuorosulau. 3. Hcxachlorophene. 4. Phenol greater than 1 5 percent nqueoub/alcoholic. 5. Trlbrornsalan. 6. Trlchlocarban. 7. Trlclosmn. D. The active ingredients not generally reeognized as safe and effective for use in a "skin antiseptic" and misbranded are: \. Cloflucarbati. 2. Fluorosalan. 3. Hexaelorophene. 4. Phenol greater than 1 6 percent aque ous/alcoholic* 5. Tincture of Iodine. 6. Trlbromsnlan. 7. Trlclocarban. E. The active ingredients not generally recognized as safe and effective for use in a "skin wound cleanser" and misbranded are: 1. Cloflucarban.1 2. Fluorosalan. 3. Hcxachlorophene. 4. Phenol greater than 1 6 percent aqueous/alcoholic. 5. Tincture of Iodine, 6. Trlbromsalan, 7. Trlclorcarban,* F. The active ingredients not generally recognized as safe and effective for use in a "skin wound protectant" and mis branded arc: 1. Cloflucnrbftn, 2. Fluorosalan, 3. Hcxachlorophene. 4. Phenol greater than 1.6 percent nque* oufi/alcoholtc, 6. Tincture of Iodine. 6. Trlbromr.alan, 7. Trlclocarban. G. The active ingredients not generally recognized as safe and effective for use In a "surgical hand scrub" and mis branded are: 1. Cloflucarban. 2. Fluorosaikn. 3. Hcx*cl\iorophene. 4 Phenol greater than I 6 percent a<pieOUS/alcoholic, A. Tlneturo of loUlno. 0. 1 rlbroiiisulun. 7. Ti lclocarban. 8. Trlclobau. 4Ciofit>incd In Category III when formu lated In a bur ffftuj) to Ih: ulmI with wuLit, nr\ .cHLononiENE 1. The OTC Antlmlcrolilal I Fnncl thoroughly reviewed tiic submissions, lileinhno and report* anil listened to additional testimony from interested parties concerning the safely and clfcettvrncKs of hexachlotophcnc <iICl\ 2. 2" rnethvlcnobls (3, 4. G iiIchlorophcnol) . Tlie Panel assumed that a topical anti microbial OTC preparation should have at least a hundred-fold safety factor (applied to tire administered dose) when used as directed. The data indicated that, with the presence of 1500 OTC formulations containing hcxachlorophene, there would be potential toxicity from use of multiple products by one individual. Therefore, the Panel recom mended to tire Commissioner that hexacliloropliene lie considcicd not safe for general use ns an OTC antimicrobial In gredient in man. Accordingly, a regula tion, 21 CFR 3.91, delineates the future use of hcxachlorophene only as a pre scription drug, except when used ns part of a preservative system in a concentra tion no greater than 0.1 percent. Much of the Information which sup ported this decision is part of the public record and is summarized below. A key reference by Lockhart (Ref. 1) presents a review of early toxicological studies with hcxachlorophene. She re views the work of Kimbrough and GaJncs (Ref, 2) and others who showed that hcxachlorophene fed to rats for a few weeks produced central nervous system toxicity which Is pathologically char acteristic, If not absolutely diagnostic (Ref. 3), Lesions occurred In the cerebellum, brain stem, and the cord. The tissues showed marked vacuolization of the grey and white matter. This lesion lias been termed "status spongiosis" and has been described by Inncs (Ref. 4). Virtually identical lesions have been found in the brains of other hexnchlorophenc-trcnted laboratory animals such as rabbits, dogs and monkeys as reported by Kimbrough (Ref. 2). Hart (Ref. 5), Curley (Ref. 24) and OTC Volumes 020044-020046, and 0200(19-020070 (Ref. G). These lesions are sufficiently characteristic so that a trained neuropathologist can detect them 111 an examination of coded histopatho logic sections. Furthermore, hcxnchlornphene-treated animals have been used as positive controls In evaluating potential neurotoxicity of other chemically related antimicrobial agents, providing nn illus tration of the consistency with which these lesions may he produced. (See OTC Volumes 020139 and 020148 (Ref. G>>. Faiually lmpoitant was the develop ment of an necurate and reliable method for measuring hcxachlorophene blood levels bv Browning (Ref. 7) and its appli cation to the toxicological studies. As pointed out in the review by Ixvkhart (Ref. 1 and 11) results of several studies Indicate that a blood level of greater Ilian 1 mcg/nil is generally associated willi pathological changes lu the animal brains. Lockhart (Ref. I) also reviews in some detail a report to the Food and Diug Ad ministration of ft ninety-day biilliiug study of newborn rhesus monkeys with 3 percent hcxachlorophene emulsion. Com pared to no Incidence lu Llie conti ols, all live of the hcxachloropohene-trcated monkeys developed .Lnitm pnnniuls brain lesions and had mean blood levels about 1 meg / ml. Oilier l cl rot f. have cunlirincd tlie toxicity Irnin repealed bath ing of rabbits tOTC Volume 020148, Ref. G) nnd In newborn monkey bathing studies (Ref. 14). In this study ill new born monkeys (Ref. 14), only seven days cxt>osure was required to induce the lesions. Nicminen et al. (Ref. 25) have shown that hcxachlorophene begins to have a toxic effect on the brains of ex posed rats after they are about one week old. They noted vacuolization of the white matter, Increased brain weight and water content along with paralysis of the hind legs. The new-born rats succumbed to a much lower oral dose of hcxachloro- pliene ttian older rats. Martin-Bouyer (Ref. 2G) has indicated the presence of lesions with electron microscopy as early as two hours after exposure to hexachlorophcne. Lockhart (Ref. 1 > reported that these toxic effects appear to be re versible in some circumstances after stopping exposure, provided tiiat the ani mals survive. In addition, Lockhart (Ref. 11) reviews hcxachlorophene toxicity in man. Oral poisoning occurred In a number of cases usually after accidental Ingestion. When hcxachlorophene was used therapeuti cally in large doses for treatment of chlonorchlasls for 3 to 6 days, reversible central nervous system and gastroin testinal symptoms were produced In studies reported by Chung et al. (Ref. 8) nnd Liu et al. (Ref. 9). Topical use of hcxachlorophene In tlie treatment of bums also has resulted In toxic effects and very high blood levels as reported in 1908 by Larson (Ref. 10). Mullick (Ref. 13) examined the brain tissue sections of four children poisoned by topical exposure to hcxachlorophene and confirmed that the lesions were iden tical to those seen In the animal studies. Additional evidence of toxicity was re ported from France when, during the summer of 1972, It became apparent that many Infants had been poisoned by a topical baby powder Inadvertently con taminated with tip to 6 percent hexachlnrophcnc (Ref. 12). More than 40 balucs died during tills episode. These data were supplied by the French Gov ernment nnd arc currently confidential to the Food nnd Drug Administration nnd lluis are not part of the public record of tills Panel. Nevertheless. It is clear that the blood and tissue of Infants who died contained high levels of hcxachloro phene, an dlhc central nervous system abnormalities observed histologically were Indistinguishable from those pro duced In experimental animals. While hexa-chlorophcnc is adsorbed onto tlie outer layers of skin. It is nlso absorbed systeinlcntiy in relatively small amounts. Approximately 3 percent of the applied dose (in acetone) was absorbed Into tlie systemic circulation In one study by Maibach (Ref. 15). Significant blood levels have been detected In u number of studies of new- No. 170--ft. It----- 3 FEDERAL REGISTER, VOL. 39, NO, 179--FRIDAY, SEPTEMBER 13, 1974 AST 00003657 r.UH PROPOSED RULES borns bathed In hcxachlorophcne prepa Infants with low birth weight and/or American Medical Association, 224(2) :176- rations, ranging Irom .000 mcg/inl to 0.78 premature Infants with broken skin ap 178,1973 meg/ ml reported by Curley ct nl ittef. 10 and 241, Cunningham diet. 17 mul 20', and Kopcltnan (Hef. 18t. In one study of 10 "problem babies." it was found Vo irinee from 0 1 to 159 mcg/ml with a mi-.in of 0 52 meg ml Giving toxic levels m '.niiie mtniith. lterent studies Over a pel aid ot three to lour weeks of total bodv Pallium studies with 'J percent hexai'ldiiroplii iie In adults have shown blood levels as high as 1 42 mep/ml U?ef .10). Also surgical scrubs of hands and fore arms of adults, five times a day. with 3 percent hexachlorophene preparations have given, in selected Individuals, levels after 10 days of 0 5 mcg/ml or higher. These findings are a result of a series of blood level studies using a specific hand and arm scrubbing regimen sug gested In a Food and Drug Administra tion protocol. This protocol was used in studies designed to fulfill the requirement for blood level studies for products con taining hexachlorophene for continued marketing ns prescription drugs. These levels are considered as potentially toxic levels. The highest level recorded from blood level studies using this specific hand and arm scrubbing regimen has been 0 84 mcg/ml. These data are in cluded in OTC Volume 020186 (Ref. 6>. Ulsamer et al. (Ref. 27) measured the hexachlorophene concentrations in the blood of volunteers who used a variety of hexachlorophene-containing pioducts. Blood concentrations ranged from 0.38 mcg/ml. of blood fin an individual using a 3 percent hexachlorophene liquid prod uct on his whole body) to 0 02 to 0.14 mcgm/ml. in subjects only washing their hands with a 3 percent product. They established that routine use of these products produced detectable blood levels, some nearly as high as 0 4 meg/ ml. The number of subjects (12) was small. A further review by Lockhart (Ref. 28) emphasizes the impact of the demon stration that hexachlorophene applied topically can result In systemic toxirity and the consequences of this informal ion to the regulatory activities of the Food and Drug Administration. The pertinent details of the toxicity resulting from blood levels in animals and the blood levels resuting from use in humans is summarized. Shuman. Leech and Alvord fRcf, 19 through 22) did a retrospective patho logical study of coded brainstem tissue from infants who died of causes unre lated to hexachlorophene which was con ducted at two different hospitals, one of which washed all newborns routinely with 3 percent hcxaelilornphcne, while the other did not. Only one of 111!) huhics not bathed In 3 percent hexachloropliene showed brain lesions characteristic ot hexachloroph&ic toxicity, whereas 20 of 61 babies receiving from one to as many as six hexachlorophene baths showed these brain changes, I'owi II et ul. (Ref. 23) have icportcd peared to be a Mieeiai risk of developing thc.so lesions after hexachlorophene exposure. Retcrences (1) Lockhart. J, D. "How Toxic Is HcxaChlorophone?." Pediatrics, 50:220 235, 1072, (2) Kimbrough, U D, and T. 13 Galtu-y, "ltaxHi'lilorophcue Eilccts on the Rat Bruin," Archives of hnvironmcntnl Health. 23 1111 Ul. lii/] (3) Annotation, ".Spongy Changes In the plain," Untish Medical Journal, J:4Jj`43L 1072. (4) Tunes. ,7. R, M , "Status Sponglosus and Hoxuehlorophcuo Toxicity In Children, Ex* perimonUl Monkeys, Rats and Other Species." UuUctin of the, Society of Pharmacologic and Environmental Pathologists, 2 8-9. 1973. (5) Hart, E. R,. Blonettcs Research Labora tories, Tnc.. Reports Submitted to FDA, No* vember U. 1971 are Included In OTC Volume 020180. (6) OTC Volumes 020044-020046, 020069020070. 020139. 020148 and 02018G. (7) Browning, Jr,, R. S-, J. Grego and H. P. Warrington, Jr.. "Gas Chromatographic De* termination of Hexachlorophene In Blood and Urine," Journal of Ph armaceu.hrat Sciences. 57:2105 21C6. 19fi8. (8) Chung, H. L., ct al, "Hexachlorophene (G-ll) as a New Specific Drug Against Clonorrhlnsi.s Sinensis." C/imesc Afediecd Journal, 82.G01-701. 1963. (9) Liu, J,. ct al.. "Hexachloroplune In the Treatment of ClonorchluMs Sinensis," C7Hnc*e Medical Journal, 82:702-711. IDG3. (10) Larson, D L., "Studies Show Hcxa* chlorophene Causes Burn Syndrome," Jour nal of American Hospital Association, 42.6304, 19G8. (11) Lockhart, J. D.. a Food and Drug Administration Medical OMcer's Review of a Manufactmcr'-s Comments Submitted to the FkOLitAt* RrcisTf r Proposal of January 7, 1972 (HCP) Is Included Iti OTC Volume 020186. (12) OTC Antimicrobial Panel Summary Minutes for the September 15. 1972 meeting are Included. U\ OTC Volume 02018C. (13) Mulllck, F, G,, "Hexachlorophene Toxicity-Human Experience at the Armed Forces Institute of Pathology," Pediatrics, 51 (Suppl. 2) :395-399, 1973. (14) Woodard, a. "Dermal Application of pHtsolIrx and I'lih.crflenn to Rhesus Monkeys Beginning at Ago One Day." Contract Report, FDA Contract No 038-973 Is Included lit OTC Volume O'jniHG. (15) Maihaeh. H. L. "Skin Penetration of Hexachlorophene tn Living Man," Draft of unpublished paper la included lu OTC Vol* lime 020186. (1C) Curley. A , R. E. Hawk, R. D. Kim* brough. G Natheuson and L. Flnberg. "Dermal Absorption of Hexachlorophene lit Infants." LaTiccf, 2.296-297, 1071. (17) Cunningham, M, D and N, O. Tsoulos, "The Growth and Development of Newborns with Known Hoxachlorophono (HCP) Levels," Pcritalncs Research, Q`43l 1972. (18) Kopelman. A E. "Cutaneous Absnrptlnii of Ilexaf hloiophene in 1/iw-MlrtUWrlghl Inlunis," Journal of Pediulries, 82:072 975. 1973. ( W Shuman, R. M.. It. \V. Leech and E C. Alvord, Jr, "Neuropathology lit Newborn In* fiutU Bathed with Hexachtorophcne," Mor bidity and Mortality Weekly Report, 22:9308, 1973, ("0) Letter from Alvord, Jr., 1*1 C to J D. Ti<>f*kliart (August. 31, 1972) l Included In (22) Shuman, R M.. R. W. Letch and E C AKuiU. Jr. "NeuroUixlrlty of Ucxuchluro- pheno In the Human; A CMuiro-prithulogic Study of 218 Children," Draft of unpublished paper 1* Included In OTC Volume 020180. (23) Powell. H., O. Swarncr, L (iluik and P I.ampert, ' Hexachlorophene Mjeluuip.uhy tfi Premaluie Infants," Journal of Pediatries, 82 97G -981, I973.t (24) Curley. A* et al., "The Absorption of Hcxiu`hlnrt>pleno through the Iniact Skin of Infants," Dnitt of unpublished paper Is In cluded In OTC Volume 020180. (25) Ntemlneu, L. K. BJondahl and M. Mottonen, "EfTect of Hexachlorophene on the Rat I3ratn During Ontogenesis." Food and Cosmetic Toxicology. U.G35-G39. 3973. (20) Letter to Bruch, M from G Martln- Bouycr Is included In OTC Volume 020186, (27) Ulsamer, A G., F, N. Marzulli and ft. W. Coen. "Hexachlorophene Concentra tions In Blood Associated With the Use of Products Containing Hexachlorophene," Food and Cosmetic Toxicology, 11:625-633, 1973. (28) Lockhart, J. D., "Hexachlorophene and the Food and Drug Administration," Journal of Clinical Pharmacology, 13:445450. 1973, (29) Letter solicited by Dr. Jean Lockhart from Dr M Douglas Cunningham is Included in OTC Volume 020186. (30) Calesnick. B., "Percutaneous Absorp tion of Hexachlorophene Following Dally Whole Body Washings." Draft of unpub lished paper Is included In OTC Volume 020106. TRIOROMSALAN ^)The OTC Antimicrobial I Panel finds that tnbromsalan (TBS. 3. 4*. 5 tribromosalicylaruhde> cannot be generally recognized as safe for general use as an OTC antimicrobial agent in man. It is a bromniated salicylanihdc which even when free of related chemicals can cause photosensitive eruptions in man and its use can result in disabling skin disorders. In addition to the problem of photosensitizatlon, the Panel is con cerned about the potential toxicity of this compound, which is intended for daily, total body use, possibly for a life time. Animal and human toxicological data made available to the Panel fall to provide a basis for establishment of a safe level for use. With regard to effi cacy. there was no clear evidence that it did anything except to help control body odor, for which other safer agents are available. a. Toxicology (Animal), Although sev eral submissions rei>orted blood levels ob tained after varying doses administered both orally and topically, serious dis crepancies in the reported toxicity of the drug were not completely resolved. Thus, in rats a report of brain and testicular damage after 25 mg/kg subchronic feed ing. OTC volumes 020133 and 020139 was not substantiated in several other stud ies nl higher concentrations, OTC Vol umes 020102, 02013G and 020173 <Hcf. 1>. Two of these studies in which Ani mals were dosed with 500 ppm showed measurable blood levels, but reported no organ toxicity, OTC Volumes 020102 and 020130 iftef. I). However. In yet another .vLudy, OTC Volume 020103, spongiform changes in myelinated tracts 0*1*0 Voluino nJuiMU. brain and eye damage was reported nt of the brainstem of seven Infants wllb (21) Medh iiJ Nt-wn. "Study of Hoxuchloro- dn.se levels of 3,750 ppm and question multlplo exposures to hexachlorophene. pheuo Llfcct Continues," Journal of the able changes were seen at 750 and 1000 FEDERAL REGISTER, VOL. 39. NO. 179--FRIDAY, SEPTEMBER 13, 1974 ASI 00003658 PROPOSED RULES :nir>- ppm allhough similar changes were teen In the controls (Ref. 1> Pei cutane ous toxicity studies in rabbits generally produced negative results, OTC Volumes ti?(HMn, (V-ioim. ojoMU mid oaoi.io (Her. 1 ' In OTC Volume 0200-48, ttl addition, thou- aas a po-ilive eoliliol with hexachloiophene winch produced biain dam age (Kef. li, However, in the one study showing positive lcsulls, the animals wete dosed at 1,000 mg kg bv loiucal application, OTC Volume 02(1133. The results of tills study were later reputed ns being due to oral ingestion of the drug by the animals, neveithclc:>s, brain toxicity was repot Led (Ref. It. A study done in dogs, OTC Volumes 020181 to 020183. was reported to the Panel as producing negative results but showed some questionable liver changes. In this study there was a positive control dosed with liexachlorophene showing brain damage (Ref. II. The carcinogenic, mutagenic and tera togenic potentials of this agent, which is absorbed through the skin, have not been adequately studied. b. Microbioloou and clinical eflicncy. Fiom the standpoint of effectiveness, lab oratory studies revealed that tnbromsalan isnot a unique antimieioliial agent. It has antimicrobial activity against gram positive organisms, pailicularly against Staphylococcus aureus and other staphylococcal species, but not against fungi such as Candida albicans, gram negative organisms such as pseudomn- nas species or cohfonnlype microor ganisms. Furthermore, evaluation of several clinical studies utilizing ti ibromsalan-conlaining soaps including data by Leonard (Ref. 2>. Duncan et al. (Ref. 3) and Whcatly et al, (Ret. 4) revealed no unequivocal or significant prophy lactic eflect of tribromsnlaii-containing preparations against superficial skin In fections. The reader is referred to the extensive discussion of the efficacy and clinical tests of antimicrobial soaps under the ElTecliveness of Antimicrobial Bar Soaps. A therapeutic effect of titbromsalan <as one of tluee ingredients) against erythrasmn. a skin infection, was reported by Kooistra (Ref 5>, Dodge et al. (Ref. 6) and Rosenberg and Allen (Ref. 7). This finding of effectiveness against cutaneous Corynebaclcrmm rninulissimum infections cannot be taken to support OTC claims for effectiveness against more serious clinical pyogenic infections caused by other organisms. See also discussion under Erytlirasma. The use of a soap containing 1 percent trlbromsalan in combination with 1 per cent triclosan was repoi ted In a study (Ref 8> In which leukemic patients weio ballied to reduce the total microbial lima on the skin. The aid hors reported I hat CO percent of the 18G strains of organisms initially cultured were eliminated within two weeks after bathing with the lest soap. The patients were not only In a highly artificial "life Island unit" hut they nlso received a number of bolh tupl( al and systemic antibiot les al Ihc same time us the soap was Ic.'.lcd The le .iills could hardly tie projected to com lode that trlbromsalan la efficacious In the prevention of infeel ion or the elimination of potential pathogens fiom the skin. Tins study Is also discussed In detail In the Panel's statement on triclosan. Thd authors of the study <llcf. 8) themselves suggest that their skin sam pling techniques were only semi-quantltative and that they estimate only 40-G0 percent of the oigamsms were recovered with their moist swab technique. The cul tural lechimiues wei e out opl uual fm the isolation of the vaiictY ol organisms present on the skin. The Panel cannot snppoi l llie conclusions that tribromalan is effective m the piophylaMs ol skill in fection lrom the data piescnled in this sliuly. In fact In a .subsequent publication (Ref. 9), these same authors describe an other study of tins type and conclude that although 76 percent of aerobic bacteiia were eliminated by cleansing with a soap containing a combination of tri closan. and trlbromsalan, strains of po tential pathogens such as Enterobacter species, a Klebsiella species, Proteus spe cies and P, aerurnilosa persisted. Thirlylliree pci cent of the patients had persist ent pathogenic baclciia and 40 pci cent had persistent fungi. Despite intensive systemic and topical antibiotic therapy and washing with an antimicrobial soap as a protective measure, the oigaiilsiiis persisting were those must likely to cause fatal infections in lhe.se serious ill pnlients. In the judgment of the Panel, clini cal effectiveness in the prophylaxis ami treatment of superficial pyogenic Infec tions of the skin has not been established, Deodoiant effectiveness for trlbromsalan has been demonstrated in the reports reviewed, but safer, alternative agents for the reduction of body odor exist (see dis cussion of toxinty for triclosan, trlelocarban and clofluearban included elsewhcrc in this documenti. c. Photascnsitivihi~l--Historical re view. Shortly after the first use in Europe of halogenated salicylanidcs (e.g. tetrarhlorsnlicylanilidei as antibacterial agents in soaps they were shown to cause a severe photodermatitis and had to bo removed lrom the market (Ref. 10 and 11). A related chemical, bithionol, caused the same type of light-induced dermatitis (Ref. 121 and also was removed from products for human use. In 19G5 the related tribromosalirylanilide (trlbromsalan, TDSi was Incorpo rated into bar soaps in the United States and product related eases of photoderniatitis began to appear (Ref. 13-17). It is impoitant to note that the pholosensitization reaction occurs with trlbrom salan at the level formulated in bar soaps for consumer use. In 111G7 ami 1908, pa tients with li ibromsaluu pliolodoriiiatitls weio being reported throughout the United Stales (Wisconsin, Ref. 14; New York. Ref. 17. 18; Florida. Ref. 19. 20; Minnesota. Ref. 21; and Ualllorina. Ref. 2gi ns well as Fram e (Ref. 23 >. Deumaik i Kef 24, 2!ii, Canada (Ref, 2G i, Australia < del 27 >. mill Japan ( Re! 2111. Wherever 1 lie 11 ibi oui.-.alan soap was Used pliotuderm.il il i.s appeared. The volumi nous literal me was summarized in a book in 1972 (Ref. 29) and is also reviewed m OTC Volume 020056 (Ref 1). Because pholodermatiUs I.s not an of ficially reportable disease arcuraLc fig ures oil Its Incidence urn not nvnllnblc. As "soap pholodermulilis" became well known to practicing dei matolom.sts and oilier physicians <19G0-1U72>, them was less need and ldss likelihood of such pa tients being referred to special centers studying photuderinatills and recording eases. As a icsull because they are rec ognized. fewer cases were likely to be seen and recorded by the photobiologisls. In 1972, the second most popular bar soap in the United Stales removed tribromsnlun from its formula and there at ter only several less widely distributed brands continued to include it in their products. Trlbromsalan was never in cluded as an active ingiedient In the most widely sold antimicrobial bar. The Panel believes that the number of cases reported by dermatologists in photobi ology centers has decreased during 1973 as a result of these factors. The above reasons may account for the impression that trlbromsalan photodermatitis is less common than it was. Tile Panel, however, wanted to know Jf the disease had disappeared or If It was still o<cuii'ing. Therefore, In 197273, they questioned 8 dermatologists In different parts of the United .States who hud studied or published oil tins disease. Although mast agreed that the Incidence was declining hi their practices. 0 of the 8 repoi ted that It was still a problem and that new cases were occurring (Ref. 1 hi OTC Volume 020164). Pholosensitization has been reported with liexachlorophene, tiieloeaiban and clollurarban (Ref. 28). However, these reports in the literature document the existence of only a very few, rare cases. These ingredients have not caused per sistent light reactions as far as is known. Only a few case reports exist in spite of the widespread use of these ingredients compared to the many reported cases of Liibromsalan pliotosensitization. 2. Clinical appearance and nature of the problem. Photocontact dermatitis appears as an inflammation of the areas of the skin exposed to light. II begins as redness with itching and burning usually oil the face and then hands, arms, and neck. The eruptions are frequently lim ited to the exposed portions of the hands, arms and face and characteristically spare the upper eyelid and submental area. However, a patchy eczematous rash oil the trunk and other covered areas is not uncommon. Many cases proceed to get worse so that the red areas develop blisters, senhs and pus. If the process continues, the skin thickens wiLh a fur rowed pebbly surface and tbc patient Is rhronicnlly incapacitated. In most cases whether acute or chronic, the terrible ttcbinr: and burning disturb sleep, and tlie unsightly appearance prevents the patients from working. In most victims If the photosensitizing ('In inleal such as ti Ibioiiistilan Is dis covered mid completely avoided, tlio dei nialitis will clear in a few weeks. How ever, in some patients, the reaction coii- FFDERAL REGISTER, VOl. 3V, NO, 179--fRIOAV, SEPTEMBER 13, 1974 ASI 00003659  120 PROPOSED RULE! linucs without apparent further exposure to the chemical. A persistent light re actor is an Individual, who, though not exposed to any further dose of the sensi tizing chemical, continues to have typical ,11,d Imiuenlh ivveie symptoms of plinliK ,in' .a f di i in,il it is for mouths or \, ,ii-. u Inn ex pi* id to hr. lit. Such a per sistent li :lit reactor Is severely disabled and freiiueutlv unable to earn a liveli hood Ordinary duvhghl alone is Milbcient to cause swelling of the face and exposed skin. In the more chronic eases. :,oiiie of these patient.', develop markedly thickened skin and ears which may irsemhle the clinical appearance ol lepi o .y. Such patients are ``dermatological cripples" and are confined to dark rooms and the indoors during all daylight hours and are unable to work. This condition may continue for months or even years. To trigger such a reaction with a prod uct containing tribromsalan is to cause a disaster to an unsuspecting user of an unnecessary product. Persistent light re actions as well as photocontact derma titis have been reported after using soaps containing tribromsalan from all parts of the United States (Ref. 29). d. Animal models. Attempts lo develop an animal assay fur photoeonlacl sensi tizers have not been altogether success ful. On the basis of their annual model studies, Vinson and Borsclll (Ref, 30) claimed that tribromsalan "is neither a photosensitizer nor a cross photnsenxl- tizer". They reiterated this view in 19G9 (Ref. 31). However, Ilarber ct al. (Ref. 18), with tribromsalan, produced contact photosensitivity in 7 animals; combined with contact sensitivity, in 1 '21 animals. Using tetrachlorosalicylanihdc on G5 guinea pigs they Induced contact photo sensitivity alone In 20 animals, contact sensitivity alone In four animals and both types of reaction in a further twelve guinea pigs. Thus Harbcr et al. (Ref. 18) found In animals and m man that tri bromsalan is a photoscnsitizcr and a cross-photosensitizcr and suggest that tho disagreement of their results with those of Vinson and Dorscltl may be due to a, variety of experimental differences, e. Discussion. In addition to the prob lems of efficacy and safety enumerated above, an overriding consideration for the Panel was the recognized fact that tribromsalan can lead to severe and perslstciiL light reactions In sensitized Indi viduals. The question therefore, was whether Its use should be allowed In the face of ft benefit limited to deodorant activity. Osmundsen (Ref. 21), In the summer of 19C7, diagnosed 39 cases of pholocoutact dermatitis caused by a soap con taining tribromsalan and 27 additional cases (Ref. 32),Jater that year. Thus, hi one vear contact pholodcrinalills caused by t.i ibromo.saUeylanfiidc has been diag nosed in GG paLicuts (11 females mid r>5 malts' in Copenhagen Photo-cross-rcaetlon lo dillcrcnt halogiaiated sahcylanihdes was also found. Indicating the I'-bi'Oinoxallrylanllido ellelled positive .`.linplc pula h li '.l'. hi 11 out of 20 pal links. II was suggested by Osimimlscn that, the 'I'-po.'illlon and the halogen Mil* .III ill Ion was a key point In the sensitization process. It was also shown by Osmundsen in J0G8 (Ref. 24) I hat ``pure" tribromsalan may elicit a positive photonatch test in a eoneentratlon as low as 0 0001 percent. II seemed probable to lmn that tribrom- salun, rather than an impurity, is the photoscnsitizcr Harbcr el al. In 19GG (Ref, 17> addressed themselves to the possibility that Iribromsakin impuiilics, not tribromsalan itself, were re.x|K>nsil)lc for the photosensitizing reaction. They pholopaleli teslcil a I nhi'iim: skill photo sensitive patient with a more (hall 09 percent 'pure" preparation of liihromsal.m (0.1 percent m petrolatum) and elicited a 3 |- reaction. This reaction was of the same intensity as the one produced in the same patient with less "pure" tri bromsalan preparations obtained from other sources. These authors concluded that it was highly unlikely that the photocontact responses were due to a contaminant. Ison and Tucker (Ref. 19) published similar results. According to the manufacturer, the offending soap marketed m Copenhagen contained 2 percent tribromsalan. A recently published book, "Soap Photodeiinatiti.s." by Herman and Sams (lief. 29) deals exclusively with pliolodermatitis caused by antimicrobial In gredients especially snllcylanilidcs In soap. This hook, other aiticies, and addi tional conversations between the Panel and Ill's. Herman and Pams leave no doubt as to the authors' view that tri bromsalan causes photocontact derma titis and is a primary photosensitizer (Ref. 29 and 33). One manufacturer has claimed that the contamination of tribromsalan with the known photoscnsitizcr, dihromsalan is the cause of photoscnsitization, and that with the increasing purity of tri bromsalan the incidence of photosensit ization has decreased and will disappear. The Panel accepts the fact that the in cidence has decreased (see discussion above). However, it definitely has not disappeared for cases are still reported (OTC Volume 0201G4, Ref. 1). Tribromsalftn can also cause a photoscnsitization reaction in individuals who have been primarily sensitized with other salicylunihdes. To the individual sensitized. It makes little difference what tho com pound causing the original sensitization was. Purlhcrmorc hard surlace cleansers still (May, 1974) contain dihromsalan as well as Itubromsulan so that .sources of photosensitizing chemicals exist today in oilier than bar soap products. The Panel's serious concent about tri bromsalan comes from rci>orts that pa tients arc sLIll appearing m the United Stales who have disabling pholodorma.litls winch has been caused by soaps con taining the current purified tribromsalan material. Piiolopatclr testing of these patients has confirmed the chnienl diag nosis and Identification of tribromsalan as the cause of their dermatitis, Polcn(llally confusing pliolosoiijati/.cis, Midi ns TH.HA. me no loncer used In photopatch testing and the Panel believes I hat the run cut phul.np.ilrh tests ueeiiralely menmmatc tribromsalan as the cause of the dermatitis. f. Conclusion and summary. The Panel believes that the benefit from using tri bromsalan containing soaps Is Insignifi cant alien faced with tho risk. Tims, even if the number of p; I'm .1 .ml light leiulois is small 111 relation to Ule amount of tribromsalan used, when there Is so little benefit. It is unjustified to subied even a few individuals to such a risk. In addition, the Panel was unable to resolve tlie inconsistencies in the reporled loxicily data. For tliLs reason, hut v.penally because of Hie photodcrmullti... il was the Panel's judgment that it would l>e safer for society not to have tills drug sold over the counter. From their review of the data con cerning photoscnsitization, Ule Panel be lieves that tiie evidence is clear that both dibromsalans (3, 5 dibromosnlicylanilidc and 4', 5 dibroinosallcylanilide) and telrachlorosaUcylanilide (TCSA, 3, 3\ 4', 5 tctraehlorosalicylanilide) arc more po tent photosensitizers than tribrom salan. Therefore, regardless of the fact that these ingredients were not submit ted to the Panel for review, the Panel concludes that the Food nnd Dm* Administration should move to also ban completely the use of dihromsalan and teliachlorosalicylanilide in drugs and cosmetics. Therefore, after a thorough review of all of the available data, tho Panel recommends to the Commissioner that Inbromsalan bo considered not snfe for general use as an OTC antimicrobial ingredient in man and that the Food and Drug Administration take action to ban tribromsalan, dihromsalan, and tetrachlorosalicylanihde from OTC anti microbial products. The Panel concludes that these salicylantlidcs should not be implemented in a manner similar to oilier Category II ingredients but should be handled more expeditiously by pub lication of a separate Federal Register notice m a manner similar to that used for hcxachlorophene. Furthermore, they also recommend that Hie Food and Drug Administration inlorm (lie appropriate rcgulaLory agen cies of tlte Panel's recommendations that dibromsalans (4', 5 dibroinosalicylanilidc and 3. 5 dibromosalicynnihdc) and 3, 3', 4', 5-tctrachlorosalicylanillde bo icmoved from drugs and cosmetics and also inform them of tho risk associated with tho marketing of these ingre dients in hard surface cleansers and disinfectants. References (1) OTC Volumes: 020010, 02008G, 020081. 021M02. 020107. 020111. 020112, 02f>i:i.l, 020110, 0201M0, 020140. 020161. 020166, 020160, 02010.V 020104, 0201C8. 020172, 020173. 020181-02018^ find 020180. 12) T/'Otiftrd. Tt, R,, 'TrmenllQn of fluper* flolfU Culnneous Infecl Iomm," Archirrg of Dcrtnatolofiy, 05;G2O'S2;i, 1007. f J > Duncan. W, C,, n Q. Dodgo and J. M. Knot, "Prevention of Superficial Pyogenic Skin InfoclloiLV Arc/liptfJ of Dermatology, i>0 106 ion. iwoo. ( D Wheat ly, M. L, G. Oden. Q, A, di* la nretunno, Jr. and J. A, KonlMra, "Antl- Ori tertul Muiip liar Umu'u fur tho Prevention rtDCRAl REGISTER, VOl. 39, NO. 179--FRIDAY, SEPTEMBER 13, 1974 ASI 00003660 PROPOSED RULES of Superficial PyogciUc Infections.'' Draft of unpublh-hni paper Is Included in OTC Vol ume 920170. 15) Koolstra, J, A, "PropHylaxl.*; and Con trol of KryUirasma of the Too Web*." Journal (! ! ni r\HyaUt'C Dermatology, 45.399- 400, 1 pl)5 i0i DoU^O, u G.W n Knowles, M. E Mclit <U\ W. <J. Diuic.in, and J, M Knox, "Treat* im'uL of luylhnu.ma With an Antll);\cterml Soup," Archives of Dermatology. 07.648-552, 196U, (7) Rosenberg, K W. unci t, Allen, "Eniclency of an Antibacterial Soap m Treat ment and Control of Toe-Web Erythrnsmn.'' Draft of unpublished paper Is includrd tn OTC Voltimo 020178 t8) Bodey, G. P. and I). Ra-enbaum, ''Evaluation of a Bacteriostatic Soap, P-300, on Skin Flora of Patients hi Protected En vironments," Current Therapeutic Research, 15`253-200, 1973. (9) Bodey, G. P. and B, Rosenbamn, '`Effect of Prophylactic Measures on tho Microbial Flora of Patients m Protected En vironment Units/* Medicine, 53:209-228, 1974. (10) Wilkinson, D. S. "Patch Tesl Re actions to Certain Halogcnated Salicylanllldesj" British Journal of Dermatology. 74'302-300, 1962. til) Wilkinson, D, S,, "Further Expe riences with Halogcnated SnllcylanUides/* Dntiah Journal of Dermatology, 74 295-301, 1962. (12) Baughman, R, D, "Contact PhoUxler- nuttlls from Blthlonul," ArWiirrs of Der matology, 90,163 107,1964 (13) Epstein, S. and T Euta, "Pholoallerglc Contact Dermatitis." Journal of the American Medical Association, 104 :101G-- 1017, 1906. (14) Epstein, S, 'Thotosensitizers In Soaps." Journal of the American Medical Association, 195:878, 190G. (15) Molloy, J, F, "Pliotosensitizers In Soaps," Journal of the American Medical Association, 195:878. 19C6. (16) Monash, S, "Composition of Sunlight and a Number of Ultraviolet Tamps," Archives of Dermatology, 91.495 496, 19G6. (17) Harper, I C , II Harris and R. L. Bner, "Structural Features of Photoallorgy to Sal- lcylnnilldos and Related Compounds,'* Journal of Investigative Dermatology, 46:303305. 1966. (18) Harber. L. C . S E. Tnrgovnik and R, L. Baer, "Contact Photosensitivity Patterns to Halogcnated SaUcylanllldcs." Archives of Dermatology, 9G G4G-G50, 19G7, (19) Ison, A. E. and J, B, Tucker, "Photo sensitive Dermatitis from Soaps." Hew England Journal of Medicine, 278:81-84, 1968. (20) Ison, A. E and J. B. Tucker, "Delayed Reactions In Positive Photopatrh Tests to Halogcnated SallcylanllUIrs/* Arr/iii'cs of Dermatology, 9G:59-Glt 1907. (21) Sams, Jr., W. M., "Soap Photoallergy." Mayo Clinic Proceedings, 43:783*794, 1968. (22) Epstein, J. H , K. D. Wtiepper and H. I. Malbach, "Photocontact Dermatitis in Halogcnated Salley (anilides ami Ilebilrd Com pou mis," Archives of Dermatology, 07*230 244, 1060. (27) Midaim. A,, G Zina and CV llonu, "Allergic do Contact et Photo-Allergic uux Bactericides Hnjocenes dans le.s Prodults d'Hvgtene," Socle tc de Dermntotogic et dc Eypinh/jraphir, 74:249-251. 1967. (2 1) Osmund4.on, p. E , "Confael Ptwilo- de final. I tis Due to TnbromsaMrylnnihdc,'* ttnttih Journal of Dermatology, 80 22B 234, 1068 <25) Osmundsen. P E, "Conlael IMintoulb rgy to Trlbroim alley! anilide," lt> ttish Journal of Dermatology, Hl-,429 4 li, I'm!) <2G) Tan. K S. and J. C Mliehcll. "f'uU-h and Photopatch 'pests on Contact Dermatitis and Photodcrma tills." Canadian Medical Association Journal, 98:252 255, HIGH. (27) Burry, J N and G F, Donald, "PhotoCouLact DtTnnP iir, fmm Soup." Unhsh Journal nf Do mididooy. U0:7ll 718, 1908, (28) Masuda, T. ct ah, "Contact Dermatitlft Dm> to Hoxachiorophene, Irpn/um ( PI, Ttv. TBS and Dlaphenc," Japanese Journal of Dermatology (Series B). 81 245-248, 1971, (29) Herman, P. 5, and W, M Sams. Jr, "Neap Photodermatitis: Photosensitivity to Halogcnated SnlicytunUtdes" C, C. Thomas, Sprlngllrld. 1972 (39) Vlnsuii. Ij, J and V. F Borselll, "A Guinea Pig A .say of (be PholoscnsH.l/.lng Potential of Topical Germicides." Journal of Vic Society of Cosmetic Chemists. 17*123130, 1966. (31) Vinson. I., J, V. F. Borselh. W, SOlcnlaez and E J. Singer, *'La>oratory and Clinical rrurcdurcs for Assessing Photosen sitizing Potential of Topical Agents," Torirology ami Applied Pharmacology, Supple ment 3:103-112, 19G9. (32) Osmundscn, P. E., "Contact Photodermatitis Due to Tribromsaheyianillde (Cross-reaction Pattern)/' Dermatologica, 140 65-74. 1070. (33) Sams. W. M. Jr, "Stresses Role of Sun as Skin Disease Cause," Skin and Allergy News, 5:4, 1974. FLUOnQSALAN 3. Tlie OTC Antimicrobial I Panel has reviewed the submission (Ref. li con* corning the safety and effectiveness of lluorosalan Uluorophenc, 3, 5-dibromo3'-trinuoiomclhyl saUcylamhdc) and Is of llie opinion that fluorosalan cannot be Generally regarded as safe for use as an OTC antimicrobial agent In man. The data submitted for this ingredient were minimal. The similarity of tins molecule to tribromsalan requires that sufficient data be submitted to properly assess the risk-benefit ratio from the use of this chemical as an antimicrobial. Included in the reasons for this opinion are the following. The chemical, even In pure form, may, as a dibromo-substituted sahcylnnilide, possess potential for photo,sensi tization in man. and its use could result in a serious dermatological condition known as persistent light reaction (see discussion of tribromsalan). Evidence demonstrating that phototoxicity and/or photosensitivity would not result from tlie use of fluorosalan lias not been submitted. The absorption, tissue distribution, route(s) of metabolism and excretion, and blood levels attained after topical application arc not available. Information about the rolalionslnp between blood levels and toxtciLy Is not available. SLudics on the can inogenirilv, muta genicity. teratogenicity and reproductive effects arc not available. Tn addition, controlled studies demon strating clinical elTocliveiicss arc not available. The Panel agreed that any use of this ingredient should be under a Notice of Claimed Investigational Exemption for a New Drug and a New Drug Application until further data arc collected. RKFrnr-NCE (11 OTC Volume 020050. eiiCNin. nm.ivn u than I 5 cliu unt AQUEOUS, ALCOHOLIC SOLUTION 4. The Panel icvicwed a number of products containing phenol in a variety of vehicles. There was a paucity of data submitted delineating the influence of vehicle on the elfcctlvcncss or toxicity of phenol, A search of the literature was productive In preparing tills statement relating the coiicenti.itiou of phenol in aqueous or alcoholic vehicles to toxicity. It is the reconimendation of the Panel that Phenol conccntiations greater than 1.5 percent in aqueous or alcoholic vehicles be placed into Category II. Tlie data supporting this decision may be found in standard reference texts such as Goodman and Gilman s Tlie Pharmacological Basis of Therapeutics iRef. 1), AMA Drug Evaluations (Ref. 2), Patty's Industrial Hygiene and Toxi cology (Ref, 3) and in Deichmann's re view of phenol (Ref. 4). Basically, these references document the toxicity of phenol when applied topically. For example, tlie authors have noted that a 2 percent ointment resulted in blood levels of 0.8 mg. of free phenol or 2.3 mg, of conjugated phenol per 100 ml. of blood. It should be noted that 30 mg. of free and 1 mg. of conjugate are fatal concentrations. One to 5 percent phenol applied as a dressing or compress has caused gangrene. It lias also been recorded that 2 per cent and higher concentrations of phenol in aqueous vehicles have caused serious hazards, including gangrene, anesthesia, mummification and even, coma. Phenol is more soluble in alcohol than in water and would penetrate to deeper layers of the skin producing severe burns and might be systemically absorbed m higher concentrations. Therefore, for these reasons phenol in concentrations greater than 1.5 percent is placed in Category II. The acute systemic toxic effects of phenol in man and animals is observed piimarily as an eifect on the central nervous system, Sudden physical collapse has been observed in man after systemic exposure associated with other ellecis such ns myocardial depression and marked blood pressure fall'. There may also be marked dyspnea and a decrease in body temperature (Ref. 3). These sys temic effects are related to the amount of free phenol in the blood. A blood level of 30 mg. of free phenol per 100 ml. of blood can be fatal and death is usually the result of respiratory failure (Ref. 3). Chronic poisoning in man results in digestive distui bailees, such ns vomit ing, difficulty in swallowing, diarrhea, and anorexia. Nervous disorders, such as headache, fainting, vertigo, and mental disturbances also occur. In severe cases, sometimes fatal, there may be extensive damage to tlie kidneys and liver. Most of the reported cases of chrome poisoning have resulted from ingestion or inhnlation (Ref. 3>. However, it is possible that repeated topical application over large surfaces of the body could lead to the systemic ctTeets described nbo\e. After absorption, phenol Is cxereted In the free form in the urine or is conju gated in the liver to tlie glucuronidc or sulfate, pi lor to excretion in tlie urine. Some is expired in tlie air. In tlie rabbit, after a single oral dose, 23 percent was oxidized in tlie body to carbon dioxide and water plus pyrocatccliol and hydro- fEDERAL REGISJER, VOl. 3, NO. 179--FRIDAY, SEPTEMBER 13, 1474 O0003f-61 .TJ122 PROPOSED RULES qulnonc. Of the 72 percent excreted in as, the presence of 10.9 percent camphor lays wound healing, especially when oc the urine, 48 percent was excreted as the combined with 4.5 perrent phenol re clusive dressings arc applied. free phenol and 52 percent as the con sulted In the absorption of only 16 mg. Itei HttNcxs jugates. Only 1 (icrcent of the total ad phenol (Ref. 7). (1) T.awrcncc. C. A, and S. 8 Block, "Olj- ministered dose was excreted In the loces No data have been submitted with tn/ertton, Strritiznttnrj, and Prricrvtton,tr 11I. ;i i. In addilion. rioulwell and lloseh regard to absorption of phenol from l.ca (Uni f'l'litqi'r. l'UUstli'lphi.L, Pat.a tlii l, 5) have repotted that phenol is a mucous niemlirniics. although this Is a (31 llni'ii, W M, " l tih itni tun mu/ tinlrur- cue.u\ mugeii in uiuuud.x. With local dermal application of high concentrations, a pelhrle of denatured protein is formed which may turn led route of application described in the la beling submitted for some products. Information citing the local toxicity and absorption of phenol, lias been re lion of thr Mirrobiul CYll," Ai-mU'inlc 1`rrsa, New York, 1071. (3) Sykes. G, "Dtsin/reHon and Steriliza tion," 2iul Fd. J. b Lipplnvoit, Philadelphia. 10(g). and slouch, leaving a luown slain. Pro longed contact of phenol with the skin, resulting in deep penetration of the skin, can produce gangrene and necrosis (Ref. 1 and 3). Ochronosis (darkening of the tissue! can also result from prolonged dermal contact (Ref. 3). If applied to mucous membranes or swallowed, phenol can cause swelling, corrosion, necrosis and hemorrhages of the mucous mem branes of the throat or gastrointestinal tract. In the past, preparations of 1 to 5 percent phenol m aqueous solutions have been used with dressing and compresses. , This lias resulted in gangrene, primarily when applied to fingers and toes (Ref. 3), Preparations containing 1 to 2 per cent phenol have been formulated fre quently in salves or ointments and with vegetable oil or calamine lotion for anti pruritic effects. The use of 2 percent phe nol ointment has resulted as reported above in blood levels of 0.8 mg. of free phenol and 2.3 mg. of c.oniugaled phenol per 100 ml. blood (Ref. 3). Iflood levels of phenol attained after application of phenol in liquid preparation have not been presented. The use of low concentrations of phe nol (1 to 2 percent) in ointments, lolions, salves or solutions can rouse toxicity leadmg to severe incidence of gangrene with prolonged contact and, or occlusion of the treated area (Ref. 3). Rat studies have shown that a 1.78 percent phenolliquid petrolatum solution will cause gangrene and necrosis after 8 hours of ex posure in 2 to 3 days. A 4.15 percent aque ous phenol Solution raused gangrene in the same period of lime (Ref. G). The use of oil in the formulation may en hance the toxicity. Camphor also has been used in formu lations containing phenol. Camphor may in fact retard the absorption and avail ability of phenol from the solution. How ever, the local toxicity of phenol In a rnmphor-containine preparation de pends upon (he aqueous/phenol phase resulting from the prei.rni'C of tP-Mip fluids or pcrsplrntiou iRcf. 3). Camphor, ported by Bass and Welch (Ref. 8), Con ning and Hayes (Ref. 9). Deichmann tllef, K, Freeman cl ill i Ref. 10 (, Mann- lieimer and Adriam (Ref. ID, Rucdctnann (Ref. 12>, and Woolley (Ref. 13', The Panel concludes that phenol in concentrations greater than 1 5 percent in aqueous or alcoholic vehicles is not safe for general use as an OTC antimi crobial agent in man. riEFERENCrS (11 EipUn. D. W. "Antiseptics and Disin fectants: Fungicides; Ectopnra^iUclqeV' "The Pharmacological Basis of Therapeutics " Edited bv Goodman* L and A Gilman, 4Lh Ed., MacMillan, New YoiK, 1970. (2) A\fA Drug Evaluations- 1971, 2nd Ed., American Medical Association. Acton, 1071. (3) Deichmann. W. B and M L. Kepllnger. "Phenols and Phenolic: Compounds." "In- ilustrial Hygiene and ToxicologyVolume It, 2nd Revised Ed.. Edited by Patty. F A, In- ter^clcnce Publishers. New York, 1003 (4) Deichmann, W, U,, "I.ocal and Sys temic Effects Following Skin Conlnct With Phenol--A Review of the Literature," Jour* nal of Industrial Hygiene and Toxicology, 3l:14fl. 15-1 (1040). (5) rioutwcll, R, K. and D. K. Bosch, "The Tumor-promoting Action of phenol and Re lated Compounds for Mouse Skin," Ctmeer Research. 10413-124, 1959. (0) OTC Volumes 020022, 020030, 020032. 0?,<KVU 0200 13. 020008. (7) Deichmann, W. II, T. Miller and J B, Robert*, "Local and Svstemic Effects Fol lowing Application of Dilute Solutions of Phenol In Water And In Camphor Liquid Petrolatum on Skin of Animals," Archive* of Industrial Hygiene and Occupational Medi cine. 2,454-401, 1950. (8i ?, A and S. C. Werch. "The Absorp tion of Thenol In Oily Solutions by the Rab bit Skin," Society for Pharmacology and Ex perimental Therapeutics, G 308-109. 1D47. (9) Conning. D. M. and M. J. Hayes, "The Dermal Toxicity of Phenol: An Investiga tion of the Most Effective First-Aid Meas ures," British Journal of Industrial Medi cine, 27:155-159, 1970. (10) Freeman. M, V,, J. H Dm Ire and E, Alv.iicr, "Culancous Absorption of Phenol," Journal of Laboratory and CLinwat Medicine, 3S:`/G2 2Hfi. mr>j. (11) Miiunhrhner. W. and J. Adrlanl. "Mode of Arlhm jvml EUVrt im TIhhhoi of I.on[;-AMlm: Local Anrsthedi-s." J<>unu/t of CtOFLUCAflOAN 6. The Panel has determined that It Is aimropnate to Include cloflucarban in Category II tor the follow mg product uses; Patient Pre-operative Skin Prep aration, Skin Antiseptic, Skin Wound Cleanser, Skin Wound Protectant and Surgical Hand Scrub. Cloflucarban Is classified in Category III as a Skin Wound Cleanser when formulated in a bar soap to be used with water. The Panel Included cloflucarban In Category II for these uses since no data, were presented to support its use for the product categories identified. This state ment is not to be construed to mean that the ingredient may not be shown to be safe and effective lor the product cate gories listed. Tlie Panel's concern is that consumer use of tlie ingredient may occur before adequate researcli is conducted. TniCLOCAKPAN 7. The Panel lias determined that It Li appropriate to include triclocarbnn In Category II for tlie following product uses: Patient Pre-operative Skin Prep aration, Skin Antiseptic, Skin Wound Cleanser, Skin Wound Protectant and Surgical Hand Scrub. Triclocarbon is classified in Category III as a Skin Wound Cleanser when formulated in a bar soap to be used with water. The panel included triclocarban in Category II for these uses since no data were presented to support its use for the product categories identified. This state ment is not to be construed to mean that the ingredient may not be shown to be safe and effective for tlie product cate gories listed. Tlie Panel's concern Is tliat consumer use of the ingredient may occur before adequate researcli is conducted. TRICLOSAM 8. The Panel recognizes that a HealthCSrt Personnel Handwash, Patient PicOperative Skill Preparation, or a Sur gical Hand Scrub arc designed primarily for extensive use In the hospital or other closed environment. The Panel hns there If present with phenol, will "hold" the phenol, as is evidenced by the study which demonstrated that, while GO per cent of the phenol in a saturated solu tion of liquid petrolatum is in the aque ous phase, o/ily 22 percent of the phenol In n 4 8 percent phenol 10 percent cam phor combination in liquid petrolatum is m the aqueous phase. When the camphor concentration was raised to 21 perrent, onlv 10 perrent of the phenol was in nil iiiincou;; pluire iRcf G> The presence of nuuplior nl.'.o retards llie tib- m ptinn of plienor nfer topical mipllcatlun a l-liouv expo,'.me of the ml. I.tll to n 4 (I pireiiil the American Medical Association, 154*2931, 1051. (121 nnedominn, R, *ind W, B Deichmann, "fdovt Phenol level Af;cr Thnlonl Applica tion of Phc'u'l-Cont hnif: : Preparations." Journal Of the a African Mi diet! Azwiztton. 152 1053 03) Woolley, r B. * F^ngon m.i CVhrono- sls." ffrjfi5i Mi,lieal Journal 2 700 7G1. IP5-L TiNCTVne OF TODpyg / 5. The P.mi'l considers the use of rleimwilal millin' In nuuriHis or hiilro-aleoholir soliilli.il iiii .:ifi' for r.'in i.il 11 r no t In' skin nl hr > I bull n ; n But U ni I'l i -l >| cialive Bi.m I'reparalimi II has liren fore Included these uses in Category II for trielosnn. Tlie Panel has concluded (see discus sion m Category III for Trlclosan' that foi initiations cont.unir.g tins ingredient should not be used in these environments berair-e of possible increased one-way en vironmental pressures toward gram neg ative (especially /'.'Y!iifo**i",:i,s' mfeefirns. In the cient that data arc sub mitted to show that the Panel s conclu sion is not justified, consideration .should he given for meliisiou of the ingredient tu IIh'm' product c iliT.orlex eOMIUNATION ANTtMienOlllAI. PRODUCTS uqueom, phenol .solution resulted In the u.'II do. linnqili'il (lief. 1, 2 mid (l> Hint The Panel, in its deliberations, rc- absorption of 71 nig. <>( phenol: where imlmr Is it i-11:lI in': In lirnki'U skin and dc- eeived two .`.uliiuisMons on iintliiilcrobial nn.RM urGcum, vot 39, no irv-.ruioAV, sri'UMBi* 13, 14 74 ASX 00003662 PROPOSED RULES .1112.'] bar soaps containing a combination of active ingredients, and one of these con taining trlclocarban and clnflucarban iv.iq rlaaatncHt In Catouni'y 111, Tho other . ;m|) combination contained tribiomsalan and tiuUia.in and leas been placed in f.deiany U. Infonnalioll Oh tlie safely and elieetiveuess of other eomiiinations of Ingredients were not received. There fore, for lack of data they me not gen erally recognized as safe and/or eireetive. Conditions possibly exist where the bene fit-io, risk ratio is such that their use may tiff ot^valuc, if not necessity. How ever. such combination antimicrobial agents should not be available for over the counter use until suflieieut safety and efficacy data are submitted. The level of each antimicrobial ingre dient in the combination must make a contribution to the claimed effect for the product. The total amount of individual antimicrobial ingredients, in combina tion, should result in an effect that is at least equal to that achieved when any one of tile Individual ingredients is used alone at the same total concentration without significantly reducing safety. In some instances the Panel has established maximum dose levels of an antimicrobial when used alone. If such antimicrobials are placed in combinations no individ ual antimicrobial In the combination may exceed the dose level approved by the Panel. The Panel feels that a rational combination of antimicrobials should have one of the following purposes: Ex pansion of the microbial spectrum, re duction of the toxicity of one or both of the Ingredients, or result in a syner gistic effect. Furthermore, when two or more In gredients are combined, toxicity data must be available to show that neither the metabolism, excretion or target organ toxicity are enhanced, or are synergistically affected by the combina tion, for example, through the metabo lism or excretion of one of the Ingredi ents. The Panel feels that the safety of combinations is sufficiently important to recommend that when such ingredi ents are used In combinations in anti microbial soaps, an approved New Drug Application should be obtained prior to marketing. At a later date, when suf ficient safety and effectiveness data warrant It, combinations of these In gredients may be placed In Category I. Labeling Tho Panel concludes that there arc Insufficient data to support certain labeling terms or claims. Ilecause no data uro available these terms and claims are misleading to the consumer and result Jn misbranding of the prod uct. The claims that shall not be al lowed are: I A. RperilR. promotes or aids healing (or ] Any i.nnllur iitAir'inriil). j il Siinltl/os the skin or wound j titerilt/.vn the bktn or wound, : J) kiiHureu bncUirhdly cliun '.tin. j E Di.',Infects Die skill nr wound. I F. I Leals (wounds). I O. Controls Infection. Iff. Conditions for which I hr (mailable data me iiisujflcwnl III jiciinit limit classification at this time. The Panel recommends Unit the conditions speci fied 111 Category TTf be made effective 1 your after publication of the filial mono graph In Lite Federal Register. Active Increments A. The active ingredients for whleh tho available data are insufficient to permit final clu.v.iflcalion for use In "antimictoblal soa|>s" are: 1. Clofluenrhan, 2. I':ira-chloro-nicta-xylcuol. 3. I 5 percent Plicnoi -or less--aqueoti3/ alcoholic. 4. Ti iclocarban. 5. Triclosan. n. Tlie active ingredients for which tho available data are insulfieicnt to permit final classification for use In a "health-care personnel handwash" are: 1. nenxalkonlum chloride. 2. lUm/ctlioiumn chloride. 3. Ciollucarlian. 4. Hoxylresorclnol. 5. Iodine complexed with phosphate ester of alkylaryloxy polyethylene glycol. G. Metliyl-bcnccttionlum chloride. 7. Nonylphenoxypoly (ethylencoxy) ethanol-lodlno. 8 rwra-chloro-meln-xylcnol. 0 15 percent Phenol or less aqueous/ alcohollc10. Poloxaincr-lodtne complex. 11. PovIdone-lodlne complex, 12. Triclorcarban. 13. Uudecoyllum chloride-iodine complex. C. The active ingredients for which the available daLa are insufficient to permit final classification for use In a Patient "pre-operative skin preparation" are: 1. Bcnzalkonlum chloride. 2, Bcnzcthonlnm chloride. 3 Hexyiresorclnol, 4, Iodine complexed with phosphate ester of alkylaryloxy polyethylene glycol. 5. MethylbcU7Cthomum chloride. 8. Nonyi phenoxypoly (othylcneoxy) etha nol-iodine, 7. rara-chloro-metn-xylcnol. R. 1 5 percent Phenol or less--aqueous/ alcoholic. 0. Poloxamer-iodinc complex, 10. Provldone-lodtnc complex. 11. Undecoyllum-chlorldc complex. D. The active ingrecticnts for which the available data are insufficient to permit final classification for use in a "skin anti septic" are: 1. Bcnvalkonlum chlorlda. 2. Bcu/.cUionlum chloride. 3. Hcxylrcsnrelnol. 4. Iodlno complexed with phosphate ester of alkylaryloxy poljelhylene glycol. 5. klethvl-hen/ethonlum ehlortde. G, Nooyl phenoxypoly (ethylencoxy) eLhanni-iodlne. 7 Pimi-rliloro-niel n-xylcnoh 8. 1 5 percent Phenol or less aqueous/ alcoholic. 0. Poloxamer-lodlne complex. 10. Povidone-Iodine complex, 11. Trlclosan. 12 Triple Dye. 1.1. Undeeoyllum chlorlde-lodtnc complex, K. The active ingredients for whit h tlie available data are inxuilh lent to iieiuut final cla:.: lilcatioll lor use ill u "skill wound elunuser" arc: 1. Iodine complexed wilh phosphate ester of ulk yhu yloxy pnlyeLhlene glycol. 2. Nonyi phi Iioxypoly (( IhyiCIlcOXy) CllIUnoModhic i oinplcx. 3. rara-chloro-mota-xylenol. 4.15 perceut Phenol or lesa--aqueous/ alcoholic. 5 Poioxamcr--Iodine complex. d PtivlUntiD --Iodine cninplex. 7. TrMos.m 8 bmh cuyllnm chloride--Iodine complex, F. Tlie active Ingredients for which tlie available'data are insufficient to per mit final classification for use In a "skin wound luufectanL" arc: 1 neiv/ulkonlum chloride. 2. Bcnzcihontum chloride. 3 llexylrcsorclnol, 4. Iodine complexed with phosphate ester Of alkylaryloxy polyethylene glycol. 5. Methyl-beujtcthontum chloride. G, Nonyi phenoxypoly (ethylencoxy) eth- nttol Iodine. 7, Pf\rA-chloro-mcta*xylenol. 8. 1.6 percent Phenol or lcss^-aqueous/ alcoholic. 9 Poloxamer-lodlne complex. 10. rovldone*lodluc complex, 11. Trlclosan. 12. Undeeoyllum chlorlde-lodlne complex. G. The active ingredients for which the available data are insufficient to per mit final classification for use tn a "sur gical hand scrub" are: 1. Ilcmmlkonlum chloride. 2. Benycihoiilum chloride. 3. Ilexylrcsorelnol. 4 Iodine complexed with phosphate ester of alkylaryloxy polyethylene glycol. 5. Methyl-bensethonlum chloride. 8 Nonyl-phenoxypoly (ethyleneoxy) ethanol-lochne. 7. Para-chloro-mcta-xylenol. 8, 1,5 percent Phenol or tese--aqueous/ alcoholic. 0. Poloxnmcr-lodlne complex, 10 Povldnne-lodlnd complex, 11. Undecoyllum-clilorlde Iodine complex. GENERAL COMMENT APPLICABLE TO ALL INGREDIENTS IN CATEGORY m The Panel has concluded that ade quate and controlled studies are not available at this time to permit the final classification of tlie active ingredients listed above. Tho recent hexachlorophene experi ence lias made apparent to the scientific community that toxic levels of antimicro bial chemicals applied to tile skin can be absorbed into tile body. The greatest lack of substantial data Is in the follow ing areas: Retention and/or substantivity. absorption, blood level, organ distri bution, possible tissue denoting, metabo lism, and excretion. In many cases an alytic procedures for the determination or active ingredients and/or metabo lites in tissues and secretions have been developed only recently. A major emphasis In the past has been on Lhc collection of data to support tho clTcclivcncs.s of antimicrobial products applied to the skin. These data have ofLcn been reported as "percent reduc tion" of the microbial floi a on tlie hands. Such data reflect tlie reduction of the normal skin rniciohtul flora or of that acquired by contact with the environ* inenl. More sophisticated procedures for the analy.M.s of microbial reduction data wtiU h Involve techniques fur dealing with initial high variation in microoigninsm counts, and the correlation of reduction in microbial flora with prophylaxis of in fection, arc required. In addition In liuiiici mil reduction, data must be uccu- UOIRAL RCCISftn, VOL, 37, NO. 179--FRIDAY, UPUMBER 13, 1974 AM 00003663 ,1:1121 PROPOSED RULES mutated on tlio effect of antimicrobials on the balance of the noim.il microbial liora, including the diplhcroids. These aspects of effectiveness data are essen tial before risk-benefit judgments can be It'd- onably made. Tno I'anel lias deternnneil that Catcgoiy HI ingredients may be petmitteil to remain in use until 1 year after publica tion of the final monograph in the Fedkrai. Rkiuster, if tile manufacturer or distributor of any such product conducts tests and studies to satisfy the questions raised by the Panel. The Panel recognizes the complexity of this report and the difficulties that may be encountered in interpreting the rcquii ed studies necessary for an ingredient included in Category III. The following sections of this report should be collec tively considered before undertaking any proposed studies: <1> The historical dis cussion of the product category in the Panel's comments concerning effective ness in the use of antimicrobial products. <2) the guidelines for testing, (3) the product category definition and subse quent discussion and < 4 * the specific statement for the ingredient to be tested. TRICtOCARBAN 1, The OTC Antimicrobial I Panel has determined that the only permitted use of triclocarban (TCC, 3, 4. 4'-l i ichlorocarbanilide) at the present time should be as an antimicrobial ingredient nr bar soap Tlie manufacturer gave assurances to the Panel that, tins was the onlv use for which the chemical is being sold at this time. However, the Panel also iceog- mzes that the maiuifacUuci s patent on triclocarban expires within two years, and expressed their concern about tiie possible future proliferation of its use in various OTC products, thereby increas ing the possible total body burden. r Tlie Panel reviewed tile available ef fectiveness and safety data on tneloearban and concludes that adequate data are not yet available to permit final clas sification of triclocarban for use in bar snapj Other applications were not con sidered. The available evidence does not indicate that Die use of triclocarban in liar soaps presents any known hazard to (lie general public. For example, the I,D . of triclocarban intraporitonrully in rals is reported to be in excess of 2,000 mg/kg compared to 6.25 mg/kg for hexachloro- phene. See OTC Volume 020139 (Ref. 1), Based on blood level data, which is not complete at this time, triclocarban docs not appear to be as toxic as liexachlorophenc. Therefore, tlie Panel recommends to the Commissioner that 1riclorarban use In bar soaps be permitted at a con centration not to exceed 1 5 pen cut lor a peuod of 1 year following publication or the final monograph in order to allow interested parties time to conduct tlie necessary research to correct tile defi ciencies Indicated below. A otimary area of concern is I lie data defining tlie laiget organ for toxicity. At high blood levels ol ti ll local ban. hn exless ol 2(10 ppm TCC/TCC uu I aliollle >. the apparent target oigan in rat:. Is the testicles. In the opinion of the Panel, llio data relating the blood level of triclocnrbun to testicular damage aio siill not definitive. Fin example, one set of data in OTC Volume (1201119 i Ref. 1 estimated tlial blood eom entrations of 50 to 70 ppm TCC/TCC metabolite caused pathologi cal changes in the testicle* ol test ani mals. More recent data from a feeding study at 400 mg/Kg day in OTC Volume 020165 I Ref. 1) suggests that 200 ppm TCC/TCC metabolite in the blood was an "effect level" and ttiat a dose of 200 mg/ Kg/day giving a blood concentration of 100 ppm TCC/TCC metabolite was a "no effect'' level. Still other data m the OTC Volume 020130 i Ref. 11 suggested testicu lar lesions at. oral doses lower than those which resulted in tlie "no clTeet" blood levels mentioned above (100 ppm!. In view of these conflicting data regarding blood levels and ensuing testicular dam age, the Panel regards this as an area of significant deficiency in the data. Ade quate data lclating blood level to target organ toxicity and "no-effect'' levels will be required. Maibach i Ref. 2) has shown that triclocarban may be absorbed through human skin after topical application. In tins one study, 14 percent of the dose applied in acetone solution was absothed. Elimination of triclocarban after topical application was slower than alter inges tion, suggesting possible accumulation in the body. However, the adequacy of ana lytical methods for the detection of tnclorarban and all its metabolites is still questionable, and is made more difficult by the veiy low levels which must be delected m blood or tissue. Based on some theoretical and some actual dal a, calculations of potential blood levels in man weie made. It is tlie conclusion of the Panel that, until definitive data are accumulated to show blood levels in man fiom actual use, the concentration of tuclooarhan in bar soaps should be lim ited to 1.5 percent. Tlie calculation which led to this conclusion follows, but it should be emphasized that the cause of testicular lesions has not yet been deter mined to lie triclocarban (parent com pound), TCC-mctabolitc or tlie combi nation, (TCC/TCC metabolite). Addi tionally, Inadequate data on rate of elimination weie a factor m .setting this 1 5 percent limit The following, talculalion.s make certain assumptions which may prove tb be inaccurate once ade quate data are obtained: 1. Assume that a bar soap contains 2 percent triclocarban and that an aver age bath uses 7 0 gtu of soap. The total available triclocarban, if instantaneous absorption occurred would be' 140 mg ti iclocarban. 2. Assume 2 percent of tins 140 mg triclocarban remains on the skin as a substantive agent. This retention pre sents to the body a total of 2.8 mg of triclocarban for absorption, 3. Assume that 14 percent of the avail able 2 8 mg were absorbed, as shown by Maibach (Ref. 2'. This would allow 0 392 nig of triclocarban to be absorbed from a single bath. 4. Assume that an average size human has 5.000 ml of blood, and that 0.392 mg of triclocarban were instantaneously ab sorbed. Tlie concentration of triclocarban in the blood would be approximately 0.1 ppm. Considering that some part of the population takes two baths per day. and assuming that the total triclocarban to which the individual was exposed acrmmilatod during that day, the blood level would be 0 2 ppm. Data from tlie mnnufactuier indicate that triclocarban as I lie parent compound disappears from the blood within minutes. The exact mechanismfs) of absorption and elimi nation is not yet clear. 5. If we take the most recent data submission to the Panel indicating that 100 ppm total TCC (TCC/TCC metabo lite) in the blood is the "no-effect" ievcl. then a safety factor could be calculated as follows: HO |i|inl __ | fXXprobt 0 i nmi f.irlnr (-lupli* hullp 1 o | IIMl _ rj(l.ftlj,i ,,:,I,.|y fa,.[,,( (`j hulli<; per Uny) 2 ]*|)||1 Since these safety factors have been calculated from blood levels, they would certainly be reasonable safety factors for allowing tlie continued use of triciocarban in bar soaps. However, it should be stressed that several assumptions have been made in deriving these calculations and the Panel urges that definitive data to clarify these assumptions lie gener ated. For example, assumptions were made ns to suhstanUvity that 14 percent of applied TCC is ahsoibed, that instan taneous absorption results in certain blood levels, that accumulation docs not ocrur. that skin condition did not influ ence blood levels, and that metabolism wus an uiiealculatcd factor. The Panel .strongly iccommeiids Hint adequate toxcart h include studies to do11 -1 in 11 its I lie Mibstaniivily of U'tclorarIin11 over a pci lod of lime and in various aieax of lie: hotly, the amount of Iriclocarban dcixi.-.llcd on tlie skin from a single bath, and tlie blood levels attained in individuals in various age groups and with various skin conditions following use of soap containing triclocarban. Unconfirmed data suggesting addition al toxic effects were submitted to the Panel and it is felt that clarification of these data is necessary. For example, brain and splenic changes were noted by two pathologists in one study reported in OTC Volume 020139 iRcf. D, while other data indicated that no such tissue changes occurred. Ttie Panel believes that these eoiitluTing data need IniUicr clarification even though the initially re ported toxic effects could not be con firmed in further, similar experiments. Tlie suggestion of lira in and splenic changes is of such importance that It cannot lie ignoied. IL is conceded Unit tlie animal strain used in the initial cxpci uncut whs unusual (Cox strain of i a is i. Definitive research in at least tw o animal species at exaggerated dose levels is recommended in order to specifically answer the questions nbout potential brain or splenic changes. Where changes 11 111 It At RiemiR, VOl 39, NO. 179--IRIDAT, SCPIfMOlR 13, 1974 ASI 00003664 T r nf 'll ie- 113 r- l.il .113 mg mg . a' re- of a!-' by 92 om1 t an1 ng: ibir-:, Jly-of iy.; an 'C-: od lie ita. at iO- el, cd ng nhe of le, by ed die ue es icr re* 'ti ts. ale It ml :x- of :i .3 PROPOSED RULES x-u2r> are seen, conrninilant blood levels of triclui aibnn should lie investigated. H is the opinion of the Panel that mlenuale slothes have been submitted (Hof. I . i,. nan. ale lhat Lnilocarban has no i..d ji.iiential fig' the induction ol cartiiui eiii-sis, iiiuL.iUcnesls, or Leiatogcne- sis. liuiiever, the data submission in OTC Volume 0301G5 (Ref. 1) suggested that alili tndociuban orally administered in rats, there was a tleerense m militant atlon sites and a decrease in the number SNoIfspring at hii'.h dose levels of tilcloeaiban (1.000 ppm) in the diet. Jn fact, the results or Uie.se studies in OTC Volumes 0201G5 and 020189 (Uef. 1) orig inally directed attention to testicular ef fect. The Panel recommends that ade quate reseatch be conducted to define more clearly the implications of the data. A major route of elimination of triclocarban froni the body is reported to be via conjugation to the glucuronide in the liver. This mechanism is deficient ill young animals and human infants. The Panel felt that inadequate data concern ing elimination and toxicity in young animals were submitted, and recom mends that adequate research in young animals with blocked formation or un available glucuronide systems be con ducted in order to define the toxicity po tential for human infants who may be battled in a soap containing ti ldocarban. Since the liver is eonsideied the major organ for conjugation, the cifect of in adequate or impaired liver function on elimination and toxicity should also be determined. Therefore, the Panel recommends that unless such studies as described above are conducted within 1 year following publication of the final monograph m the Fedfral Rec.istfr, tins ingredient should be restricted from use m infants. The label for the preparation containing the ingredient would state: "Not to be used on infants under G mouths ol age '' The literature sources documenting the im pairment of glocuiouidc capacity in in fants arc listed separately under, "Olucuronide Capacity in Infants" (Refs, 1 through 7). The Panel rccogniv.es the triclocarban will decompose at elevated temperatures ill aqueous solution to yield rhlnroanilincs. There arc lcixirted incidences of methemoglobinemia resulting from high temperature decomposition by triclocar ban by Johnson et nl. (Uef. 3). There fore, soaps or soap products containing triclocarbnn should not he heated and subsequently used in or on the human body. Additionally, since ! hloioanilmes do have a potential for mducmg met hemoglobinemia at higher blood levels, tile ellloroanilinc content in bar soaps containing 'triclocarban should bo moni tored to limit it to less than 100 ppin, (Sec the data In OTC Volume 020127. page 15. line 22 (Ref. 11. The Panel felt ttiat adequate daLo were picseuted to indicate Unit 100 ppm eliloioaniline. or lev;. In bar soaps would picscnl. no hazard to humans even lifter multiple batiis witii such soaps. In addition to the data submissions already referenced, additional reler enow, were renewed to obtain specific background u.ila. Most of tlie.se icler- enees deni with ctfectiveness (Rets 4 through 11). tail a few refer to specific problems such as photodcrmutilis and contact dermatitis (Refs 8, 9, 10 and 12. 13, 14). The Panel concluded from lliese references and duta submissions that photosensifiv.alion and contact derma titis from Irielocnrban were of such rani V that they present no major prob lem to (he general user of a soap con taining triclocarban. The question of the percent of active ingredient icquired to pindure a micro bial reduction on the skin which can bo correlated with significant odor reduc tion unfortunately cannot bo answered with certainty. Independent studies to show effectiveness, as incasuied by standard handwashing studies, OTC Volumes 020031. 020044 to 020046 (Ref. 1 and 5). have produced a variety of reduction values depending on active in gredient! si _ their concentration, number of subjects initial variation in the hand count of the subjects, and tlie method of analysis. Maikoted soaps containing 1.5 jiercent triclocarban have been tested for effectiveness ns measured bv handwash ing tests and have produced values rang ing from 80 to 90 percent reduction (Ref. 15). The deficiencies inherent in the con sideration of reduction in such simplistic terms should be recognized. Data com piled from severnt studies, unfortunately frequently conducted will) an inadequate number of subjects, suggested a reduc tion of approximately 80 percent with a 1 percent soap. No significant difference was shown with a 1,5 percent soap. Claims have been made for greater odor reduction with the 1 5 pci cent soap formulation based on odor evaluation tests. However, such tests ate highly sub jective and reliable only alien rigidly continued and analyzed with an appro priate slate,lieal model. Tests to evaluate odor should be correlated with tests of microbial reduction in the same study with an adequate number of subjects. ITandw nslung studies must be per- foimcd will) an increased number of sub jects (sec suggestions for Cade and Quinn Handwashing Studies in the Specific Protocolsi selected from individuals with a specified high initial count on the hands. The studies must have appiopriatc analysis with statistical piocedurrs designed to account for high initial vanution, .such as analyses of variance and covariance and hypothesis testing including power calculations of the re duction found with use of Ihc test inoduct against an expected or established reduction. On the basis of nsk/benefil consider ations the Panel concludes that the only permitted use of triclocarban should be as an antimicrobial ingredient in bar soap at a concent ration not to exceed 1 5 percent and only for a period of 1 year following publication of file final inunogiapli ill Hie I'cmaiAi. Jin.isri r. Dining tins peiiod. testing where appli cable, as mil lined in the "Guidelines lor Safety anil Fllirucy 'resting of OTC Topical Anfiinlci obial.x'' should he per formed Data to be developed must in(lude absorption and blood level studies in humans; identification of target organ's) In chronic studies to resolve questions of potential t.-.llriil.tr, brain or splenic (liaui.es wllh oineomilaut blood levels where change-, occur, repro duction studies; studies to deteimtne the effect of glucuronide deficiency in in fant.-.; and demonstration of sltb.stantivitv over time in various body areas in cluding the amount of triclocarban de posited on the skin from a single bath. ftF* FfuSNcFl i ttrci,oc\finAN (1) ore Volumes: 020031, 020044-020046. 020083. (>20133, 020130. 020148, 0201G5, <2i Muibach, II I.. "Skin Penetration Of Hexachlomphcne In Living Man." Draft of unpublished paper Is included la 03C Volume 02018G (3) Johnson. R R,, R, Navone and E. L. Lftnon, "An Unusual Epidemic of Methemo globinemia," Pediatrics. 31*222 225, 19G3. f4) Duncan, W. C., B. G. Dodge and J M, Knox, "Prevention of Superficial Pyogenic Skin Infections," Archives of Dermatology, 99 4G5- 4G8, 19G9. (5) Hurst, A , L., W. Stuttard. and R. C 5. WvodrofTe, "Disinfectants for Use In BarSoaps," Journal of Hygiene from Cambridge, 58 150-17G, 1900, (G) Leonard, ft. ft, "Prevention of Super ficial Cutaneous Infectious," Archives of Dcnnatotoay, 05.520-523, 19G7. (7) MacKenzle, A. ft., "Effectiveness of Antibacterial Soaps in a Healthy population," Journal of the American Medical Association* 211 .073 97G. 1970. (8) Roman, D. P , E H. Barnett and R. J, Uahke, "Cutaneous Antiseptic Acthlty of 3, 4, 4'^Trlchlorocarbamlldc," Proceedings of Scientific Section. The Toilet Goods Associa tion 28*12-13, 1957, (0) Stents, J,, W. E. Jordan and C. F. To* well, * Effects of Skin Cleansing Products on Gratn-Nrgutive Bacteria hi Vitm and on Human Skin." Draft of unpublished paper is included In OTC Volume 02018G (10) Svkes, O, "Distnfcrlion and Stcnlx* zafton/' 2nd Ed., J. E. Llpplncott, Philadel phia. 19G5 (M) Wilson, p. E., "A Comparison of Methods fin Assessing the Value of Antlbnc* tmlal Soaps." Journul Of Applied Ractcnolaa//, 33*571 -581, 1970. 112) Burry, J, N , "The Hazards of Modern Soap; A Review of Photo-Contact Dermati tis trom HalngptiAtcii Phenolic Compounds in the United Kingdom, The United Stales of Amciica, Denmark and Australia,** JfedteaZ Journal of Australia, 2:1114-1115. 1900. (13) Mar/.um, V. N. and H I Maibach, "Antimicrobials* Experimental Contact Sen. sitl/ntton in Man," Journal of (he Society of Cosmetic Chemists, 24 .399-121, 1973, (14) Mas lida, T., ct ftl., "Con (act Dermati tis Due to Ilrxachlorophene, frgiuum C'Efl, Tt-C, TBS. and Dlnphcue," Japanese. Journal of Dermatology, Scries H., 81*215 240, 1971. (15) Lawrence, C A amis 8 Work, "Diitn/erf inn. Strrili^nttnn, and preservation/* Lea and Fcblger, Philadelphia. 1908. RFrrnrNer s CLircuaoNim; capacity irf infants (!) Di '1`uro, ft. I., Lupi and V, Auh-vuc'U. "GloomtmldiiUoti of the Liver in Piomaturc Babies," Nature. 219 205-207, 1008. (2) L.mey, J. r., "Hyperbilirubinemia of Die Newborn Infant" "I'ediutrtr Therapy." EdMed by Shlrkcy, If. C, Mo.-by, Ct. Lomu, 1972. (3) Mantle!, II. G, "Pathways of Drug Bluiranafoi mat ion; Biochemical Conjuga* UiK 170-PL, U --4 IC0CPAL RCGISTCR, VOL 39, NO. 179--fRIDAY, StPTCMflCR 13, 1974 ASI 00009665 Til 26 PROPOSED RULES tlon," "Fnnitamcnluh oj Drug Metabolism and Drug Dlsposilion.' Edited by LftCn, li. N , Williams and Wilkins, Baltimore. 1971. (4) Mlcttlucii. T. A. mid E, I-eskliim, " Metahnlie Conjugation and Mrtnhnlin Ity- ifM'i'.'ii " Volunia l, Academic I'vcss. pp. 205ly ,0. l!i| N}tinii, W L. "I'liaiinacoliigy," "The l.wlotjic Bans oj Tc(hatrie Practice," Edited by Cook, R E,, McGraw-Hill. New York, 1998. (d) Vast, M, `'tmiuMirlont, OlnrvirouUle I'minilllim 111 the Nrivliorn and Its Rclatlonshlp to the ratnottL'ni'nls ot Ictcnif, Nooim- tnrnm," Arcltfrcs oj Diseases oj Childhood, 39.473-470, 1958. (7) Vest, M. F. and R. R. Streitr, "SItidies oil Glucuronide Formation In Newborn In- rants and Older Children,'* Anirncnn Medi cal Association Journal oj Diseases oj Chil dren, 98.088-U93, 1059. Cloflucahhan 2. The OTC Antimicrobial I Panel has reviewed the safety and toxicity data submitted and has concluded that ade quate safety and effectiveness data are not yet available to permit final classifi cation of cloflucarban (TFC. CF;, 3-trlhuoiomcthyl, 4, 4' didhlorocaibanilidc) lor use in bar soaps. Ollier applications were not considered. The Panel concluded that enough data were submitted to convince them that there Is no known hazard to the public from the continued use of clollucaiban in bar soaps at the maximum concen tration and for the interim period speci fied below. The basis for tins was the oral LD,i of cloflucarban in rats as compared with hexachlorophene. The oral LD ,> for cloflucarban is reported to be in excess of 5 gm/kg body weight while the LD,, for hexachlorophene is only 0.12 gup kg as reported In OTC Volume 020133 < Ref. 1). Also, based on blood level data for cloflucarban (which is not complete at this time), the Panel does not consider clollucarban as toxic as hexachlorophene. Therefore, the Panel recommends that cloflucarban (or a combination of clollurarban with tnclocarbau) whop used in bar soaps, not exceed a total concentra tion of 1 5 percent and that this recom mendation be permitted to extend for a period of 1 year following publication of flic final monograph in the Federal Reg ister in order to allow interested parlies time to conduct the necessary research to correct the deficiencies listed below. At the beginning of the work of the Panel there was a paucity of information submitted on the safety and effectiveness of cloflucarban. Since that time, addi tional data have been submitted to the Panel for consideration. However, the Panel still finds several areas of defici encies In the dnta base. One of Ihcsc is the lack of blood level dala following topical application. In fact, no dala were submitted showing the following; a, SulistftUtlvlty of clonitcnvlitut to the skin following ono nod KCvernl htiihs lifting a do* Ilncnrlmn-coiUftlnlng h;ir simp, 1), Degree of absorption of elolliunrbnii fol low log depositlou on tile vftrlons t>pen of skin I young, mill nre. ngt tl, dlsomcd j. i- lvtik blood levels follow log mulMpln Imi let d. Metabolic rulo nnd fair of rioibu iirhim in tbo body. c, 7 I'.suo ylornge of clonucfirbnrt. It Is the Panel's opinion that final classification ot cloflucarban for use in bar soaps cannot be made until such data arc provided. From a purely toxicological viewpoint, the Panel believes that inadequate dala were submitted showing a dose/effect re lationship, Conflicting data were sub mitted that were at such variance that inter-labmalory differences could not possibly account for the discrepancies. For example, data in OTC' Volume 020133 iRef. 1) showed that cloflucarban caused testicular effects in rats after 4, 8, If and 13 weeks of study at the lowest oral feed ing level, 25 mg'kg, nnd liver changes at 1,000 mg/kg. This .study showed that a "nu-efrcct" oral feeding level was some where below, 25 mg, kg `OTC Volume 020133, Tab 1C). In contrast to this study, another study in Volume 0201GG, Tab 1 (Ref. 1) indicated that the "no-cllcct" oral level was 100 mg kg with no testicu lar or oi her pathologic finding. The Panel therefore was presented two controlled studies with widely varying results. It is the recommendation of the Panel that these discrepancies be re solved through adequate!}' controlled re search which will show the "effect1' and "no-effect" level in the same .study. Just as important Is a determination of the "effect" nnd "no-eflect" blood level of cloflucarban. As a word of caution, It should be pointed out that tire Panel was presented suggestions in OTC Volume 020133 (Ref. 1) that on adequate analyti cal procedure for cloflucarban in biologic fluids was not available. In view of these conflicting data and in the absence of definitive data on nbsoiption through human skin, the Panel rec ommends to tlie Commissioner that a limit of 1.5 percent cloflucaiban, or a combination of cloflucarban and triclo- carban) be set until such time ns ade quate data relating hlood levels and toxic efleets arc mac!e available. Data submissions, in OTC Volume 020133. Tab 11. 12, 13 (Ref, 1), to the Panel arc adequate at this tune to assure tile Panel that cloflucarban has no sig nificant potential for the induction of carcinogenesis, lerntogenesis or muta genesis. The Panel therefore docs not consider those to be problem areas. Tile Panel was concerned about the potential for cloflucarban to cause con tact sensitization nnd. to a lesser degree, photosensitization. More to the point, perhaps, was the lack of adequate re search addressing this polcntlnt. The papers drawing attention to contact sensitization and to photosensitizatlon are those bv Fpsleln et al. (Ref, 2`. Sol omon nnd Illuefnib `Ref. 3i and Masmla ct al. (Hof. 4). These authors indicated that the potential for contact or photosensitization from ciofiucarban was greater than that from trirlocarban, but far less than that from certain other antimicrobial agents, Tn the absence of adequate dal a. It can only lie a.v.umcd flint clollucarlian mnv have the same ionic and mode of elim ination from the body os triclocarban .since Kiev arc Miiiilar molecules. A major route of elimination ot tri rlocarban from tile body is reported to bo via conjugation to the glucuronide in tho liver. Tills mechanism may be defi cient tn young animals and human in fants. The Panel felt that inadequate data concerning elimination and toxicity in young animals were submitted. The Panel recommends that adequate researcli in young animals with blocked formation or unavailable glucuronide systems can be conducted in order to de fine tile toxicity potential for human infants. Since tlie liver is considered Lire major organ for conjugation, the effect of in adequate or Impaired liver function on elimination and toxicity should also be determined. Therefore, the Panel recommends that unless such studies as described above are conducted within 1 year following the publication of the final monograph in tire Federal Register this ingredient should be restricted from use in infants. Tlie label for the preparation containing the Ingredient would slate: "Not to be used on infants under G months of age." The literature sources documenting the impairment of glucuronide capacity in infants is listed separately under the sec tion on trirlocarban. The deficiencies for ciofiucarban re lated to effectiveness are similar to those for triclocarban and have been discussed in other sections under the Comment concerning Efficacy of Antimicrobial Soap and in the statement of the Panel on triclocarban. In summary, the Panel has concluded that cloflucarban or a combination of cloflucarban with triclocarban can be used in bar soap at a total concentra tion not to exceed 1.5 percent and only for a period of 1 year following publica tion of tire final monograph in the Fed eral Register. The deficiencies discussed for trirlocarban, and data required to allow placement of that ingredient in Category I, are similar for cloflucarban. If used in combination with triclocarban toxicity studies will be required to dem onstrate that there is no increased toxic ity with the combination, The toxicity studies outlined in the Guidelines will be required and should Include determina tion of the oral toxicity including target organ determination witli blood levels and "eflect" and "no effect" dose In the same study, The studies for cloflucarban alone arc enumerated in the statement on the com bination of triclocarban nnd cloflucarbnu. Ur,FPHf,Nci` OTC VoUimen: 020133, 020148. 030153, 020(00. (2) KpftlMn, J. II.. K. H. Wtirppcf find It. 1. Mftlbrtcli, "Plunocontuct UrrmsiitfN Ur trwUiKOMfttoii SaMcyjnnUid^ and nfinfod Com* pmimls*,*' Arr/ifucs Of Dcmatvlogtf, 07: 2;ili * 244. 1008. <31 Solomon, S. ruul 8. M, niurfurb, '`PhoimUoinlc Coninrl Dr^rmnUila," Indus* trial McdU'inf. 30,224-227. 1000. Ml M.tMidu, T. S. Uomln, Y. NnkmtcM, II. Ho. M Kluosiutft, S. Itarmin, H. Yaoltn, nnd M, Mtfoguchl* "Contact Dcrmntllta Po<* to jfUtRAl RICP'MK, VOI *19, NO 179- fBtbAY, SlMIMUr* 13, 1974 ASI 0000366A T * iw e In in- m,.iie . ny The reked aide dcuan iajor f ki ll on o be that eare the h in licnt ,mLs. nine o be age." : the ,y In sec- i rethose isscd rncnt iuded 'll of n be ntraonly jllcaFedussed d to tit in rban. trban dctnoxicxlcity ill be linaarget levels ti the ic are coinlofiu- '20163, r and (Us to Com: 336- .cfnrb, Intl'is* m# to PROPOSED RULES 127 Hexnchlorophcne. Irgsisnn CF3, TCC, TDS mid The pi mmi > target organ for toxicity corning the toxicity from longer term Dlnphene," Japanese Journal of Dermatology, from trlcl'i- in is the liver. There is still exposure to trielosan by any route of Senes B , 8D246-248. 1071. a <|ucsflon a . to whether the damage to admmlsti allot). THE COMBINATION OF TRICI.OC ARRAN AND tlif liver is due to the intact molecule, a l Lut-i.utlAKbAN tN BAH SOAt1 The Panel is placing the combination of li iclocai ban and clollucat ban In Cate gory III. These two chemicals aie quite similar in their use, mode and spectrum of antimicrobial action, and, in all like lihood, toxicity. However, it is the view moLniiiilltP, nr o I'lilllllitiallull uf tlId two (trielo.snn and or trielosan metabolitei. A snbiliioiite (90 day) oral study m dogs revealed liver damage at bloutl lev els of 67.4 ppm total tiiclosan (free trlclosan plus metabolite) resulting from an oral dose of 25 mg/kg, day. A lio-effeet oral dose of 12 5 ing kg'day. In the same of tlie Panel that additional data are needed oil the individual ingredieiiLs. No data-ware submitted on tlie toxicity of the combmhtion of ingredients, although it Is the understanding of tlie Panel that such studies are currently being con slndy. icsulted in a total blood level of 13G. t ppm i OTC Vol. 020167. Ref. ID. Similar studies, using the same oral dos ing regimen, in which blood levels were not determined, showed liver toxicity in dogs (OTC Volumes 020154 and 020034, ducted. The studies outlined under tlie discussion of tnclocarban and cloiluearban required to characterize tlie toxicity of tlie individual chemicals also apply to the combination and should include Ref. ID. The dose-related hi.stopathologieal damage in the dogs was described ns pciiportal to midzona! hepntocylic de generation which led to focal necrotic hepatitis. This change appears to be re determination of substantivity, absorp tion. distribution, blood levels, cxciclion versible when exposure to trielosan is terminated (OTC Vol. 020167, Ref. ID. and clfeet no clfccL dose with the estab In other studies, when trlelos.in was ad lishment of toxic ellccls, especially on the ministered m the diet to dugs or rals target organ dclci mined in the same for 90 days, at (loses erimvalent to those study. used in previously discussed studies, no Since the excretion of both chemicals liver damage resulted (OTC Volumes from tlie body is thought to be by 020166 and 020167. Ref. ID . the glucuronide pathway, the recom mendations for studies and labeling on Insufficient data was submitted con- Taking Into consideration animal toxi city nlul human absorption and blood levels, safety factors were calculated. It was found in subclu unic 90-day dog stud ies that tlig highest no-ellcit dose ad ministered \t:as 12,5 mg/kg. The absolute dose given the dog was 75 mg (12.5 mg/ kgxC kg dog). Extrapolated to man by surface aira, using tlie technique of Paget and Barnes (Ref. 12), tlie no-effect level might be expected to be 232.5 mg ill tlie human. The value was calculated by multiplying tlie absolute dose in dogs showing no effect by tlie conversion fac tor for surface area (75 mgx3,l). If we assume that a bar soap con tains 1 percent trielosan as tlie active ingredient and that an average bath consumes 7 0 grams of soap, then the total available trielosan would be 70 mg. If we assume that 1 percent of the 70 mg of the available trielosan remains on the skin as a substantive agent, then a total of 0,7 mg of trielosan would be available for absorption. If we assume that 8.9 per cent of the 0.7 mg of trielosan is absorbed (Ref D, then 0.062 mg would be in the blood. Thus, the following safety factor, using surface area can be calculated: this aspect should apply also to the com bination. J.U r. tuir no i'lfiu j iliv* lt*vc| In nnm) O *-! mu (n|mu P-tl tlt^c In nun 3,rM-fuW fnt lor Until adequate studies arc submitted to make a filial determination, tho Panel recommends a limitation of the total combination of tnclocarban and cloflucarban to 1.5 percent for a period not to exceed 1 year after publication of the final monograph in the Federal Register. thiclosan 3. After reviewing the extensive safety and effectiveness data, the Panel has concluded that adequate data are not yet Another wav to calculate a safety fac tor is to assume that an average size human has 5,000 ml of blood, and if we assume that the 0.062 mg of trielosan is instantaneously nbsoibed from the skill, the concentration of trielosan (frcei in the blood would be approxi mately 12 parts per billion <ppb>. If It is assumed tiiat some segment of the population takes two baths per day, and that the total trielosan is absorbed and accumulates, the blood level would be suggest that rapid conversion of free trielosan to the glucuronide occurs, and that within a few minutes, most of the absorbed trielosan exists only as the metabolite. (OTC Volume 020154. If we take tlie lowest "no-clfcct" blood level data <36,100 ppb trlclosan/tilclosan metabolite) in dogs (OTC Volumes 020182-020185 and 020186, Ref. 11) and recognizing that the data was reported from a 90 day study (Ref. 15). the fol available to permit the final classification 24 ppb. Data from the OTC submissions lowing safety factor could be calculated: of trielosan for use In topically applied antimicrobial products. From the daLa submitted, the Panel concluded that .1", Ulp|,U l J ppb i,lilDtnl li'vvl of (ih losm (mhii ii Mill'll' hnih> = sitfHy furl nr there was no known hazard to the gen eral public from the use of triclosnn in .'I ppb (blood Ii-vi-I of 11h Ih'.iih fiom 1! Ituth-.) = 1 ..VwVfuM qifrly fur|or concentrations not greater than 1 per cent in marketed products. Based on blood level data (discussed below) triclosan appears to the Panel to be safe for use in such formulations. The Panel therefore recommends that trielosan be permitted for use in topically applied an Based on the highest `'effect'' blood level (67,400 ppb triclosan/triclosan metabolite), the following calculation could be made. f,7,100 r\iiU 1/ Mill ,*,,*!. UuUo = r''CIX>"ful` talnf or ftf.inopph ,, ' io ppli o! t,si( li-T)= -,hnMT**1** ssiR'1)' (Rotor timicrobial products sold to the general public for a period of 1 year following publication of the final monograph in the Federal Register in order to allow The above calculations are. as mentioned, based on theoretical assumptions. Prelimmaiy data from humans (Ref. 15) revealing a blood level of 44 ppb of triclosan/triclosan metabolite allow the following calculations to be made: Interested parties time to conduct the necessary research to supply data in the OT.lfirt ppb (blond li'vt`1 ul flTri t iluxr in dotf-d 41 |)|,I. ---- I,Ml-fold sftfrjy furl or areas indicated as deficient in the fol lowing summary: It has been shown In animal experi On ppb (Mood It \ I i! no i (Tr 1 |mm* in i|im*-0 VI (il<l uft f} fin lor ______ 'D'l'U ments (OTfc! Vol, 020027, Ref. ID that trielosan can be absorbed through in tact skin. Tins has been vcnfied by Malbacii (Ref D and also lepoited in OTC Volume 020154 (Ref. ID which details These calculations would indicate a sub stantial safety factor, but It should be pointed out that studies to date, relating blood levels to toxic effects, arc shoitlerm studies Humans may he exposed namely, the degree of substantivity, and rate and amount of absorption. These as sumptions must be tested to provide clarification. Tills research should In clude humans in various age groups and human blood levels following the Use lo bar snap dally over their entire life willi varvlng skin conditions. of u trlclosun-coiilulnlng soap on lliluel span. Alo, .-.cvci'al assumptions were No evidence of potential mutagenesis, skin. made because of unresolved data; carcinogenesis, tcrutology or reproductive FEDERAL REGISTER, VQl 34, NO. 179--FRIDAY, SEPTEMBER 13, 19Z4 ASI 00003667 .1.1128 PROPOSED RULES ellects were found in studies with various rodent species <OTC Volumes 020033, 020034. 020035, and 020154, Ref. 11). Data Indicate that the chemical can not tin rnutUtU-i'ccl it inlminy hen.sIlt/Uig in- |,hiii(, , i,.\itizmg intent hi animals tVnhiuii- 020101. Ret. 11) or in humans tO 1C Volume 02U033, Ref. 11), An in cident of Iiypci pigmentation and Irrita tion from the use of trlrlusan-eontalning soil)) has been reported <OTC Volume O2008G. Itcf. ID. Studies have not elimi nated possible cross-reactivity following previous sensitb,allou willi hexaelilorophenr, s.iileyliuiilidei. oe e.n hunilidct; iiihI fin llier ein.' s-`.eii.slti/iiliun .`.Indies should be peifoiined. A major route of elimination of tri closan from the body is reported to be via conjugation to the giucuronidc in the liver. This mechanism may be deficient in. young animals and human infants. The Panel felt that Inadequate data concern ing elimination and toxicity in young animals were submitted. The Panel rec ommends that adequate research in young animals with blocks formation or unavailable giucuronidc systems be con ducted in order to define the toxicity potential for human Infants. Since the liver is considered tile major organ for conjugation, the effect of inadequate or Impaired liver function on elimination and toxicity should also be determined. Therefore, the Panel recommends that unless sucli studies as described above are conducted within 1 year following the publication of the final monograph in the Federal Recister this ingredient should be restricted from use m infants. The label for the preparation containing the ingredient would state: "Not to be used on infants under 6 months of age " The literature sources documenting the Im pairment of glucuronide capacity in in fants is listed separately under the sec tion on triclocarban. Data submissions (OTC Volumes 020033-020040. 020037, 020070, 020142. 020153, 02010(5. 020170. 020183, 020185, Ref. 11) and a series of reports with re gard to the purported antimicrobial activity of triclosan have been studied, examined, and reviewed. These reports suggest that numerous gram positive bacteria are susceptible to its action at levels comparable to other substituted phenols, such as hexachlorophene. How ever, some gram positive skin residents appeared somewhat less susceptible than otliers. The lack of susceptibility of the grain positive streptococci Is a potential hazard (see discussion of glomerular nephritis In comments for antimicrobial bar soaps). In attempts to define the spectrum of Irirlos.in, some of 11 if giam negative bacterial .strains listed In the reports were revealed to be susceptible to triclosan. Those tuarn negative bacteria showing in vitro susceptibility to triclosan inrhulcd strains of Die various conforms. Protons and Salmonella. One type Of gram negative ori'anl-.iii of liu ieasing Impmlanec in the hospital cuvlioiiinent which was found to be quite re: li.Luil, was Pseudomonas aet uginoiii. Ollier nucrooinanisms showing low levels of suscep tibility Included various fungi and viruses, tiiirh as tin: polio vims. Inllueu/a, adeno- and vaennl.i viruses arc inhibited at a lower cone, ni ration. The reports suggest that reduction of the number of microorganisms in the skin niicrnflnra with Rio use nl trli-lonan tu soaps Is simi lar to that with other bisphcnols. Some repot Ls suggest the Pseudomonas can be selectively established at high levels on the skin with the topical use of bisphcnols i Itcf. 2. 3 and 4). tu addition, tiielosan can be utilized for the selective isolation of Pseudomonas from materials containing both grain positive and giam negalivc organisms These iimteiials in clude loud, and inicrulluta samples luim the skill (Ref. 3 and 5). Tins Isolation Is facilitated with the use of a patented Pseudomonas isolation agar containing triclosan <Rcf\ 13). Triclosan differs form other bacteriostats active primarily against gram positive bacteria, in that it does have in vitro and probable m vivo (Ref. 6) activ ity against some gram negative bacteria, but unfortunately not against Pseu domonas. With the widespread use of antibiotics and disinfectants selectively active, primarily against gram positive bacteria in the hospital environment, gram negative, nosocomial infections arc increasingly life-threatening (Ref. 7) especially Pseudomonas. With tile en vironmental pressures being pushed In one direction (one-way selective pres sure) toward the selection of gram nega tive organisms, i e., Pseudomonas, in the hospital environment, unexpected res ervoirs and mechanisms of transmission are being reported (Ref. 8 and 9). It is essential to eliminate sources of gram negatives in particular areas of the hos pital, for Instance, burn units, intensive care units in which immunosuppressive drugs are adininisteied and in neonatal nurseries. One study by Bodey and Rnsenbaum (Ref. 10) describes tlie use of a triclosan-containing soap in hospital ized and inimuuosuppressed patients. Tins study reports the results of the bathing of leukemic patients in a pro tected environment (Life Island) with a bar soap containing 1 percent tribromsalan and 1 percent triclosan. The au thors report reduction in total counts on various body sites, especially staphylo coccal species. It is the Panel's view that the results of tins in vivo study cannot be projected as applicable in a normal en vironment. The environmental problem with triclosan proposed by the Panel is foreseen as a problem in personnel trans mission with Pseudomonas carriage on the hands as a result of selective pres sures and with the widespread con tinuous use of trlelosan-rontalnhii: prod ucts in the hospital environment. Fur thermore. the pafients in this study, which had no contiols, were all lmmunosnpprcsscd and receiving concomi tant antibiotic therapy, both oral and topical. In nddition the skin sampling and cul ture techniques were not optimal lor Hie isolation of Pseudomonas from the skin. The serious possibility of carryover of in hibitory antlblolir residue from the topi cal therapy would Invalidate the cultural resull.-i, This Is a well-eoni'i lved .study with application for these particular patients. However, there Is certainly a risk involved wiLh the knowledge that the r.onp lieina applied ho* no activity ngnlnst Pseudomonas and umleiimii 11 .in d claimed in vivo activity against oilier pulenllal pathogens. In a .subsequent publication (Ref. U), these same authors describe another sutdy of tills type and conclude that although 7G peiccnl of aerobic bacteria were eliminated by cleansing with a soap containing a com bination of tnclosan, and tnbromsaJon,' strains of potential pathogens such as Knleiobai ter species, a Klebsiella .species. Proteus species and P. aerui/inosa per sisted, Thirty-three percent of tire patients had persistent pathogenic bac teria and 40 percent had persistent fungi. Despite intensive systemic and topical antibiotic therapy and washing with an antimicrobial soap as a protective meas ure, tire organisms persisting are those most likely to cause fatal infections in these seriously ill patients. In the judgment of the Panel, clinical effectiveness in the prophylaxis and treatment of superficial pyogenic infec tions of the skin has not been estab lished. Deodorant effectiveness has been demonstrated in the reports reviewed, but safer, alternative agents for the reduc tion of body odor exist. The Panel has reviewed the use of Iso lation' medium containing triclosan for the selective Isolation of Pseudomonas from tire skin. This fact per se would not Indicate a problem with the environ ment nor Is this the basis of the Panel's conclusions about triclosan in the hospi tal environment. Current thought among scientists investigating skin microflora raises the possibility that this chemical applied to the skin, considering the skin as a possible culture medium superior in many instances to those devised by mi crobiologists, would also act selectively to promote the shift of the skin flora es pecially in environments where Pseudo monas Is ubiquitous and life-threatening to many patients. The further widespread use of a prod uct containing an antimicrobial agent with some gram negative activity, but with little activity against Pseudomonas, might easily shift the microbial flora of the skin, especially on tlie hands after repeated daily use, to allow carriage of high numbers of potential pathogens on the hands of hopsltal personnel (Ref. 0 and 14). Because of this potential for Influenc ing tlie gram negative population and/or tlie addition of another potential sclccllvo agent for Pseudomonas, the Panel recommends that trlclosan-contalning products not be used In the hospital or other closed environments such as nurs ing homes, where Individuals are present who may be highly isusceptible to infec tion with microorganisms from the en vironment not normally pathogenic (op portunistic pathogens). This restriction on the use of triclosan also applies to any combination products containing triclosan. Triclosan should be used only In products where there is ho exposing to person.-; with dcblllliltliig dlx- FCOERAl REGISTER, VOL 39, NO. 179--FRIDAY, SEPTEMBER 13. 1974 ASI oooo <663 PROPOSED RULES 33129 eases, physical debilitation, persons who are Immunologically compromised or where the closed environment In the hos pital or other Institution would possibly ulltiw the tdUCt til envh'otiiiiatilttl preamiii1'. toward Pseudomonas. Many annual toxicity studies for tills ingicuiciit have been submitted and dis cussed above. Further work is necessary to determine whether the tnclo^an mole cule. the metabolite or a cumhmutUm produce the toxic eiTect. More data on levels following topical apneeded. A variety of skin and conditions should be studied. Possible mounting of blood levels with the use of multiple products should also be Investigated. It was the view of the Panel that in vitro data indicate activity against some gram negative microorganisms but that further verification of the speettum is required as well as in vivo demonstration of activity against Proteus. Salmonella, nnd Pseudomonas aeruginosa. Studies relating the use of triclosan in the hospital or closed environment to the Incidence of gram negative, and particulaily Pseudomonas, infections may be difficult to perform since the infection rate depends on many factors. Neces sarily, some approach to a solution must be made since the theoretical reasoning of an effect follows general ecological principles. Further .in vitro and in vivo susceptibility woik will establish the actual spectrum of this chemical on the skin since the Panel was presented with conflicting reports. Reference (1) Mnlhnrh, H. I,, "Skin Penetration of Hexfu'hloioplieno In Living Man." Draft of unpublished paper Is included In 07 C Vol ume 020180. (2) Tnplla, D. N gains and O Rebell. "En vironmental Influences on the Microbiology of the Skin," Archives of Environmental Health, 11 : 546-550, 1005. (3) OTC Antlmtcroblnl I Panel Snmmnry Minutes for the December 14, 1973 meeting. (41 Amunette, R. A. and E. W Rosenberg, "Inrectlon of Toe Webs by Clmm-Ncgatlve Bacteria." Archives of Dermatology. 107:7173, 1073 |5| Sol berg. M, V. S O'Leary and W E. Riba. "New Medium for tbe Isolation and Enumeration of pseudotnounds," Applied Microbiology. 24`644 -5SO, 1072. (61 Lymnn. P L. and T. Fitrla. "Toxicology of 2. 4, 4'-Trlrhlum-2'-lIydnixy-dlphcnyl Ether," Industrial Medicine. 38:45 52, 1'liiO. (7> Prot'ccdlng.s of the Internaliniml Conferenre on Nosocomial Infections (Center For lihteaMo Control), Edited by 3' c Kleknif nnd I*. 8. lirnehnian, 3 lie Amerlean IIohpltal AssoelaUon, L'bleago, 11171 (81 TnpUn, O and I*. M Mart/. "Elnnei Vases In ltospltnhi as Reservnhn of I'alhogenn." t.aneet, 2: 12711 I 2111, 11173 |0) Union. J N and t> Lolbrtg. "Maml Curt tape of Ciram-urgal Ive llarllll and Sta/ihytm;nrenf AnrenItriti.ih Medical Journal, 2 film 582. 1073, ` ltd) lledev, O l` and II, Ro'.enlMiOiii, *TVi loi 11.,o of a I tin 1 i'i 1 os I a lie Soup, r 300, on hktn llota ol lOillenla hi riolrilod |',n- vlnntnirol'i, ' Cm lent Therapeutic lit starch, 15 25 1 20(1, 11)7.1. (11) OKI Volumes: 020033 020040, 030086, 020104, 020110-020118, 020142. 020151. 0200(1020108, O20170, 020182 020185. 02016(5. (12) Paget, Ci E anti J, M, Ilnrnea, "Toxic ity Tesla." Evaluation of Drug Activities. Pharmacomrtm i, Edited by Laurence, D R. end A. I,. Bnehernrh, Acndcnile Press, New York, 1064. (13) Kurin, T. E,, "Method for the Deter mination of Pseudomonas tu nioloyleal Ma dia," United mates PatenL No. 3.816,256 Is sued October 20, 1071. (14) Brovin, D, Abstract of paper pre sented at the American Public Health Asso ciation Meeting, San Francisco, 1973 la In cluded In OTC Volume 020160, (15) 'Icf.llniotiy piri.cnted liv IIcBalvn, S J., bcfoic Hie AiiUmtcrohlnl I Panel dur ing the open sesMtui of November 29, 1973 s included In OTC Volume 020186. IoooruORS 4. The OTC Antiniiciobial I Panel recognizes the existence of ut least three categories of lodophors: (1) Solubilized inorganic elemental iodine, such as tinc ture of iodine, USP. or the aqueous iodine-iodide solubilized product; (2) iodine complexed or combined with vari ous surfactant compounds such as poloxamer-iodine complex; and (3) iodine complexed with various non-surfactant compounds such as PVF-iodine complex (polyvinyl pyrroltdone-iodine). The an timicrobial activity of all of these agents is dependent upon the release of elemen tal iodine. Iodine is recognized to be a broad spectrum antimicrobial with ac tivity against fungi, viruses, and both gram positive and gram negative bac teria. a. Solubilized inorganic elemental io dine. Iodine lias a long history of use as a broad spectrum antimicrobial agent. There is an extensive literature docu menting (lie effectiveness of aqueous and alcoholic solutions of elemental iodine as an antimicrobial. In fact, the United States Pharmacopeia lias listed iodine preparations since 1810. In the judgment of tile panel, elemental iodine hydroalcoholic solution is safe and effective when properly used on unbroken skin as a patient pre-operative skin preparation but its irritating properties and delay in wound healing make it unsafe for other uses. (See discussions in Categories I and II of tincture of iodine.) The data supporting these positions may be found in reference Iwnks such as those by Lawrence nnd Clock (Ref. 1) or Hugo (Ref. 2) nnd Sykes (Ref. 3) as well as the numerous articles contained in OTC Volume 020181 which is an extensive bibliography of rcfeicuces about iodine (Ref, 4). A variety of values lias been proposed for the minimum couccutraliou at which Iodine Is letlial to cells. It has been stated liv Myites iRef, 31 Lliat all mirroorgaiti.-.ms are killed by the same concentral.mn However, the organic load (hi a wound, wilh .'.(`rum, or on the skin) mid (ill (bt'ldll.vi may (ItiimalIctillv change the roitrriil ration required to achieve (lie desired killing effect on the skill. It is difficult to set a level of free iodine which is effective against all types of inirrobial lima. Viruses, fungi, spores. mid vegeta tive bacteria. The vai tallies luesent In any situation where Iodines are used as liacLei icldul agent-s on the skin must be tested In in vivo iiiitiian studies because it is necessary that they be controlled in experiments testing effectiveness ugainst high microbial populations. The results of these studies should be used to determine use dilution and label direc tions. It is probable Hint no single value In ppm of Iodine can be established tvs universally effective. Klciuenlnl Iodine Is discussed in tins statement since the effectiveness of all lodophors Is depend ent on the rcloo.se of free iodine as the active agent mid the compiexlng mole cule acts only us a carrier. li. Iodine comjdcrert with various sur factant compounds. The Panel recog nizes that elemental Iodine complexed with a surfactant type "carrier" molecule reduces the amount of Immediate "free" iodine, since most of the formulated iodine is bound in the complex. The Panel was not presented adequate data to determine if the complex is really a micellular solubilization of iodine at the molecular level or whether loose chemi cal bonding exists producing what could be termed a "sociable moiety". Indeed, the complexation of iodine with the carrier molecule is responsible for the changes in characteristics observed in staining, burning or irritation of the skin. The amount of "free" elemental Iodine in solution is a function of the equilibri um constant of each complexing formu lation. If all of the "free" elemental iodine is removed from solution (as in the case of application to a wound whore potentially all iodine present is bound by total organic load), then a finite period of lime would be required before a new equilibrium would be established. Once the iodine is released from the complex, it acts as elemental iodine, a broad spec trum antimicrobial agent. After release of Iodine, the carrier molecule remains at the site as ally other similar surfac tant molecule. The Panel has concluded from the data submissions that iodine complexed with a surfactant Is a way of presenting iodine as an antimicrobial agent to a wound site or the skin. The purpose of presenting iodine in such a form is to reduce the staining and toxic (locally) properties inherent in the iodine mole cule. Since most of the formulated iodine is lied up in the complex, tire amount of "free" iodine available at any given instant is relatively small. Therefore, theoretically, the degree of irritation should be lessened. Indeed, the data sub mitted does substantiate a reduced ricgtee of iodine bum from the complex. In many cases, the area covered by the indophor may be covered with adhesive tape or bandaged because ttic amount of "free" elemental iodine Is not enough to cause tissue burns. This is a signifi cant advantage for these iodine prepa rations over older iodine formulations, such as tincture of Iodine. The concern of the Pnncl has been 1.1ml tills advan tage of complexed iodine may also be ils most serious disadvantage. The ad vantage of I lie lodophor is that Hie urea can lie treated ami bandaged wILIioat irritation, while the serious disad vantage mav be that actunlly there is less free Iodine as an active antimicro bial. The Panel was presented no sig nificant data about the "release" or dlsassoclalion of Iodine from the com- FEDERAl REGISTER, VOL. 39, NO. 179--FRIOAV, SEPTEMBER 13, 1974 ASI 00003669 T 3:1 no PROPOSED RULES plcx. Additionally, the Panel was concoined about the lack ot stability data on iodophor fni mulal Ions. The Panel is aware of the proposed iin-i Ii.mlMn which lias been desciibed in (I ii Pal ll.H'.'i: (Ref 1 11 anil by l.iliiniilt ami Wiuiiiiv i Lief. 5i lliioil/.- mi; the establishment of an eiiuilibi'ium between free iodine and coinplexed io dine. The labeling fur a given product states the ainonnt of available or tltratable Iodine In the foinmlalion. However, iinlv a fi action is In the "free" elemental Iodine foim at the time of use. The eon- rein of the Panel was the lack of data in the cases of actual use of the product which identifies the fraction that is `'free". For example, once the ``free" elemental iodine is bound to an organic load <in a wound, with scium, or on the skin), how rapidly is new elemental plex take place at the same rate in the plcx? Does pH influence rate of release? (See OTC Volume 020077, Tab 118, Kef. 4). Only preliminary data weie pre sented in the form of rapidity of titration with thiosulfate or rapidity of parti tioning between two immiscible solvents. The Panel considers tins form of data inadequate since it docs not reflect ac tual conditions of use. For example, will the dissociation of iodine from the com plex take place at tire same time in the presence of iodine bound to an organic load? No such data were submitted to the Panel and before final classifica tion of these iodophors for most appli cations can be made, such data are necessary. Another area of concern for tiro Panel was the lack of stability data submitted for the several iodophor preparations. It is recognized that elemental iodine is a rather powerful oxidizing agent, as are all the halogens. It was suggested that some iodophors are not stable over a two year shelf life period (Ref. 12). The Panel recommends that the Food and Drug Administration ascertain the sta bility of iodophor products. The Panel has concluded that inade quate safety data were presented for all applications to permit final classifica tion of these surfactant iodophors at this tunc. Some data submitted to tile Panel in OTC Volume 020119 (Ref, 4i suggest that with certain of the surfactant idophors the volatile characteristics of iodine are not changed. In an occluded environment such formulations may corrode the tissue resulting in tissue burns. It was also suggested in tills same volume, that all surface active agents cause hemolysis and tissue irrita tion and for tills reason all surfaetant- eonlalning Iodophors should he removed from soft tissue or surgical wounds prior to their closure. The Panel noted only a very small number of clinical studies with the surfactant iodophors which could shed light on these problems. The Panel recommends that surfactant Iodophors be studied to dcllne retardation of wound healing and imitation before they are labeled as Skill Wound Cleansers, for all oilier uses the following coutioilrd i.ludles using both research lahoralot lea mid clinics should he conducted*. Hlood levels of Iodine land Iodide) and/or l.lic carrier or complcxing molecule following various types of usage of the product; systemic toxlelly after absorption of the rarrirr molecule (animals only I; the tar get organ for toxicity front the collier molecule as well as ntrlahohc fate of the can lei* molecule (animals only). One of the primary collect ns of the Panel was the Influence of smfaclanl. Iodophors on late or wound healing, f.'imllieling data weic pic* ruled to the Panel m the mca of elfect on wound healing. For example, screed citations were sub mitted indicating hide or no elfect fiom tlie iodophor on rale of wound healing (See OTC Volume 020071, Tab 49, Tab DO). In contrast to these, data were pre sented suggesting that certain nonsur- factant iodophors (PVP-iodinc type) delay the rate of wound healing see Cus ter ot al. (Ref. fii and Edlich ct al. (Ref. 7). In attempting to resolve this question, the Panel noted a paucity of controlled research that would define whether any dclav in wound healing is due to iodine, carrier molecule or the combination. It is therefore, recommended that definitive research be conducted on each surfactant iodophor used in or on wounds and the results of such research he reported to the Food and Drug Administration for final evaluation Another primary area of concern of tlie Panel was the paucity of clinical evaluation data dealing with the claimed effectiveness of most of the surfactant iodophors. There were many in vitro tests reported and the Panel is satisfied that, under the .specific conditions of test for the In vitro evaluation, the specified iodophor had the stated antimicrobial effects. The Panel does feel, however, that clinical claims made from extension of the in vitro data were largely unwar ranted in tlie absence of clinical research. The Panel again recommends that con trolled clinical studies lie conducted on each surfactant iodophor for which a specific claim is made. In specifying some shortcomings in the data submitted, the Panel docs not infer that a known hazard exists with these products. On tlie contrary, tlie Panel did receive enough toxicity data to convince them that there is no known hazard to the public from the use of these Iodophors. c. Iodine completed with non-sur/actant compound's. Tlie only example of this non-surfactant type Iodophor was polyvinyl pyrrolldone-lodlne complex (PVP-lodlne', Some testimony was pre sented to the Panel suggesting that PVPlodine Is a distinct chemical entity, while other testimony suggested Hint, PVPiodlne Is only a complex of poly vinyl pvrrolldonc and iodine. In the absence of definitive data, the Panel Is referring to PVP-lodlne ns a complex. Some evidence was presented tiiat indicates iodine is re leased more slowlv from PVP-iodlno complex than from the surfactant-iodine complex. Tlie Panel would require the same ralc-of-relcasc data in the presence of an organic load for the PVP-lodlne complex. The Panel has concluded that all de fined uses for PVP-lodlne will be placed Into Category III for a period of 1 year following publication of tlie final mono graph In the Ff:dmai. Rfcistkh In order to allow adequate time t.n obtain Hie data spccillcd below. Knoiigli data vrie pre sented to tin- I 'a i n I to ;: 111 tv I hem Huil no known liaz.ud to (lie public would result from the use of I'VP-iudme Tlie specific areas of concent that caused the placement of tills Iodophor into Cate gory Ilf follow. Data were presented to the Tanel that indicate that PVP-iodinc preparations were used In volume on large burn areas, on vaginal mucosa, in large open wounds and In abdominal surgery. Following such indiscriminate use, it was shown that some individuals showed altered protein bound iodine (P8I) levels and thyroid function. Therelorc, the Panel recom mends that more controlled research be conducted to show tlie conditions of use under which thyroid function would or would not be altered, and the amount of PVP-iodme required to Induce altera tion. The Panel would be more interested In data with current analytical proce dures. such as T3 and T4 levels, than In PBI levels (Ref. 4). Tlie Panel was presented conflicting data concerning the role of PVP-iodinc use on the rate of wound healing. Some data suggested that PVP-iodinc had no effect on rate of wound healing while oilier data suggested a delay In wound healing after the iodophor use in animal model studies by Custer et al. (Ref. 6) and Edhch ct al. (Ref. 7), In the opinion of the Panel, inadequately con trolled studies were reported and arc of only limited value in making a final judg ment as to effect on wound healing. Tlie Panel recommends controlled studies be conducted to answer the question as to the cause for delay in wound healing, if it occurs. The Iodine, PVP alone, formu lation aids, and final product should be evaluated in a controlled study. While reviewing the data submission, tiie Panel was concerned about stated lahel claims made without adequate sup porting clinical data. Statements imply ing "long-acting germicidal" activity or prolonged viricidal or sporicldal activity witli iodine suggested clinical effective ness over relatively long periods of time. Two questions arose from such impli cation: (1) What is the rate of release of "free" iodine from the complex in a clinical application and (2) what is tlie evidence of "germicidal" activity over a period of time in ft clinical application? Tlie Panel recommends that definitive research be conducted to answer these questions ns well as to define the param eters or limiting conditions for the germicidal activity of Iodine, whether free or bound In an Iodophor, Reports have appeared in the litera ture which have indicated possible lymph node changes by circulating polyvinyl pyrrohdonc. See Ashwood-Smith (Ref. 8), Towers (Ref. 9) and Dupont nud I-uhapolle (Ref. 10). The Panel recog nizes that certain molecular weights of polyvinyl pyrrohdonc have been used ns plasma expanders which liave caused the node changes. PVP-iodinc prepara- FIOfRAL REGISTER, VOL. 34, MO. 179 --IRIOAV, SEPTEMBER n, 1974 ASI 00003670 id ue ue e- n\*1 ;ds ` ch : iat ' dn'* da :n- ' be>: ise1 of 1 of' a-1" ed :e- in * j/ ng' .ne me ' no lle nd r ial OI Ig- iTie be. to . If iu-r be on, ted ip- iyor lty ve-- ne. >11ase ia the ra in? Ive ese m* the tier ra ph nyl tef. itid ra PROPOSED RULES mm tions have boon used in large open wounds and m the abdominal cavity, but the Panel feels that inadequate data were made available to prove positively Hint, uitplt lymph *ttnle cliauges ilo not l.il.r place billowing such uses of PVFiodiue. file prniiaiy recommendation for additional woik in this area Is to show tlic extent of scavenging of residual PVP-molecules by the reticuloendothelial system and possible lymph node involve ment following use In abdominal cavities qjMn large wounds. The Panel was convmPe^Jiytcstimony which is summarized In OTCvhntmc 020149 (Hof. 4) from Dr. Q. Rice of the National Cancer Institute and submitted data that there was little, If any, danger of carcinogenesis from residual PVP molecules. The general deficiencies noted with the lodophors involve both safety and effec tiveness. Tho whole question of Iodine release fioin the complcxed molecule in cluding rate of release and binding to other materials, as well as the influence of the release rate on effectiveness must be resolved. The stability of complcxed iodine over time and with varying envi ronmental conditions must be known and and controlled so a stable product is marketed and effectiveness can be as sured. The systemic absorption of topi cally applied iodine must be measured using the currently accepted assay pro cedures. In many cases, the toxicity of the carrier inoleeulC has been only super ficially characterized. Further detailed studies are necessary before toxicity can be determined (see discussion of animnl toxicity in guidelines). BSUlBENCf.3 (1) Lawrence. C. A. and S. S. Block. "Dis infection. Sterilization, antt Trcserration," Lea and Feblger. Philadelphia. 19G8. (2) Hugo, W. B., "Inhibition and Destruc tion of the Microbial Cell Academic Press, New York, 1071. (31 Sykes, Q.. "Dis<n/ecf(on and Steriliza tion," 2nd Ed., J. B. Llpplncott. Philadelphia, 1065. (4) OTC Volumes: 020063, 020071. 020072, 020077, 020008. 020101, 020119, 020140. 020145, 020181. (5) Schmidt. W. and M. Wlnlcov, "Prepa ration and Properties at Detergent Iodine Systems," Proceedings of the Chemical Spe cialties Manufacturers Association. Mid-Year Meeting, 1067. (0) Custer, J.. R. F. EdUch, M. Prusak, J. Madden, P, Pauck and O. H. Wangensteen. `Studies In tho Management of the Con taminated Wound. V. An Assessment of Die Effectiveness of ptflsolfex nnd Bel adlno Surg ical Scrub Solutions." The American Journal of Surgery, 121 -.572-615, 1071. (7) EdUch, R. F.. I. R. Schmolka, M. P, Pruaak, M. T. Edgorton, "The Molecular Basis for Toxlclly of Surfactants In Surgical Wounds r;o:rO Block Polymers," Draft of unpublished Paper Is Included hi OTC Vol ume 020180. V (HI Aflhwonil-Snilth, M. J.. 'Tnlyvhiylpyrrolldonc Solutions Used hi Plasma Ex panders: Potential Carcinogens?" Lancet, 1:1304,1071. (0) Towers, R, P , "Lymph-Node Changes Due to Polyvinyl PyrToUdone," Journal of Clinical Pathology, 10'175-177, 1067. (10) Dupont, A, and J. M. f.aehupeUe, "33irt Fato of Foreign MaeronioleeulCH." Iirtilsh Journal of Dermatology, 00:543-614, 1008. (U) Wlnirov, M. W. and W. Schmidt. "Cjcrinlcldul i ouipositlons and Methods for Preparing the Sauie," United States Patent No. 3,020.200, Issued April 3, 1002. (131 letter rif June 25, 1074 HoiPdtnd by Bruch, M from ,1 A. Uluuit Is included In OTO Volume 020188. QUArOHNAWV AMMONIUM POMI'OUNUS 5. Since the first Introduction In 1935 of quaternary ammonium salts ("quats") with surface active chnrnctci istlcs used as antimicrobial agents, there has been wide use and acreplanec of these com pounds as antiseptics and disiniectant.s. There lias also been much controversy concerning the microbial spectrum, in activation with incompatible materials, and potential hazard as a result of gram negative contamination, particularly with Pseudomonas. Quaternary ammonium compounds are cationic surface active agents. They can be differentiated from nonionic and anionic surface active agents in that they are basically organically substi tuted ammonium compounds which can be characterized by the following gen eral representation: [RiRNR,RJ( + ,X(->. "R" represents a lipophilic group such as long chain hydrogen alkyl or aryl-alkyl radicals or oilier groups: "X" represents a negative ion such as a halide, sulfate or other radical and "N" represents nitro gen. The inherent nature of this type of molecular structure allows tire synthesis of a large number of variants The chal lenge lias been met by the production of extremely large numbers of these com pounds. The Panel has reviewed only tlu'ce of these, restricting their com ments to those for which data were sub mitted : Benzalkonium chloride, benzethonium chloride, and methyl-benzethomum chloride. It should be under stood. however, that these compounds do contain characteristics which are common to the whole class of quaternary ammonium compounds. The microbial spectrum docs not vary significantly from compound to compound. There is an interference action between cationic and anionic surface active agents with the result that these ionic types of compounds cannot be formulated to gether without inactivation of the ger micidal activity of both compounds. Further discussion of the subject can be found In texts by Lawrence and Clock (Ref, 1) and Sykes (Ref. 2>, In contrast, the noiitonic compounds are often for mulated with cationic "quats" in prod ucts known as germicidal detergents. "Quats" and all surface antibacterials have been shown to affect membrane permeability. Indeed, tills group of com pounds have been called membrane-ac tive. Many authors have recorded the loss or leakage of cell contents after ex posure to "quats." Specific transport mechanisms may also be affected. "Quats" probably produce a generalized breakdown In the scmlpermcnhle char acteristics of the membrane as discussed by Hugo (lief. 3>, Lawrence and Clock (Ref. 1) and Sykes (Ref. 2). Gram positive microorganisms me generally more susceptible to llie effect of the "qunls" than gram negatives. The "qunts" arc non-speclllraily ad sorbed to the cell membrane in any caitp, tlie unprotected cell membrane i, sensi* live to Hie actum of the "qu.iU". Differ ence in sensitivity is confer)cd by access to the cell membrane. This difference is probably due to the differences in the cell wall of gram posi tive and gram negative microorganisms. Tlie adsorptive character of the cell wall probably determines the ability of the quaternary to reach and affect tlie cell membrane beneath the cell wall. Early reports of the bactericidal ac tivity of "quats" in low concentrations could not be supported when adequate neutralizing chemicals were added to the culture medium for testing antibacterial activity. In early tests, enough "quat" molecules adsorbed to tho cells were ear ned over into the subculture medium to prevent the cells from growing when transferred to culture media. The mean ing of the results of such tests was mis judged and misinterpreted during the early effectiveness testing of the "quats". Tlie gram negative Pseudomonas spe cies are frequently resistant to destruc tion by "quats." The lack of lethal ac tivity of "quats" against Mycobacterium tuberculosis has been well established and is reported by Sykes (Ref. 2). The fungicidal activity of "quats" is ques tionable and "quats" also lack significant antiviral activity. Tables listing the spec trum of "quats" against a variety of microorganisms are numerous and ex amples can be found in Lawrence and Block (Ref. 1) and Sykes (Ref. 2). Tlie presence of organic materials sub stantially reduces the antimicrobial ef fectiveness of "quats". Their surface active nature permits easy adsorption on surfaces of even glass and plastic and consequently, residues of "quats" may remain. In fact, the adsorption of "quats" onto the bacterial cell surface and sub sequent carry-over to the sub-culture medium in testing accounts for early ex aggerated claims of effectiveness for "quats," Tire cationic "quats" are Inactivated by anionic compounds, soaps, Tween 80, and sodium Jauryf sulfate as well as by certain metallic ions. Hard water and acidity also reduce the activity of the "nuats". These incompatabllltlos are dis cussed by Lawrence and Block (Ref. 1) and Sykes (Ref. 2). Because of their reported low toxlclly and case of use, especially with deter gents. these compounds have been widely used for dipping solutions and "cold" Instrument sterilization In hospitals. Or ganic material Is commonly ntlded to the solutions and as a result of failure to elenn materials or replace old solutions, added micro-organisms arc not Inactiv ated and can grow and reproduce. Sev eral serious outbreaks of gram negative infection, as well ns infections caused by oilier organisms, have been reported ns a result of contaminated quaternary am monium solutions (Ref. 7, 9, 10 and 14 through 21). FEDERAL REGISTER, VOL. 39, NO. 179--FRIDAY, SEPTEMBER 13, 1974 ASI 00003671 I I I 1 331.12 PROPOSED RULES Preservative Ingredients can be added to quaternary ammonium salts to pre vent the growth of gram negative micro organisms. particularly Pseudomonas, Such a preservative system must be ade quately challenged by effectiveness test ing. The minimum acceptable standard for challenge testing of the preservative system would be the USP XVIII Preserv ative Test (pages 845-846) and chemi cally, the Antimicrobial Agents-Content Test (pages 902-204). It is the finding of the OTC Antimicro bial I Panel that adequate safety and effectiveness data concerning these spe cific cationic surface active agents (benzalkonium chloride, benzethonium chlo ride, methyl benzethonium chloride) are not available to permit final classifica tion except as a Skin Wound Cleanser. Human systemic absorption and toxic ity after topical application cannot be established based on a review of the scientific literature or submitted data. The systemic toxicity of "quats" in ani mals Is low. The LDw and chronic oaral study values In OTC Volume 020179 (Ref. 4) in several animal species are reported. The toxicity reported Is Indicative of and reflects the surfactant nature of the molecule. The "use dilution" for the "quats" is usually about 1/750 for topical application. Specific absorption and systemic levels In humans have not been reported for the three "quats" reviewed. Considering the concentrations applied, and extrap olating from animal studies, toxic ef fects at use levels would be unlikely. The irritating nature of quaternary compounds on the skin, mucous mem branes and in the eye have been reported extensively in the submissions and are found in OTC Volumes 020017, 020018, 020128 and 020143 (Ref. 4). The degree of irritation is dependent on concentra tion and/or occlusion. There is little ir ritation potential with the use concen trations. Various reports of toxicity related to the detergent nature of these com-' pounds have been published. Landsdown and Grasso (Ref. 5) reported that re peated application of 1 percent benze thonium chloride to the skin caused damage with cellular degeneration. "Quats" have been shown by Bettley (Ref. 6) to alter the permeability of the human skin to sodium and potassium ions and to cause enhanced percutaneous absorption. Also, occasional reports of non-allerglc and allergic contact derma titis have been made by Flotkln and Aus trian (Ref. 7), Maliziaet al., (Ref. 8), Lee and Fialkow (Ref. 9) and Saunders (Ref. 30). Necrotic ulceration has occurred where detergent creams containing "quats" have been applied to moist areas of the skin of the genitals and buttocks under occlusion as reported by Coles and Wil kinson (Ref. 10) and Tilsley (Ref. 22). A number of published articles deal with the toxicity of the specific "quats" reviewed by the Panel (Ref. 23. 24, 25), References to sensitivity and contact der matitis produced with "quats" have been reported (Ref. 26 through 29). One aspect of the result of the use of "quats" deals with both effectiveness and safety. Over the years since their intro duction, the variety and frequency of their use has increased. Several reports by Plotkin and Austrian (Ref. 7), Malizia et al., (Ref, 8), Lee and Fialkow (Ref. 9) Indicate systemic infections by Pseu domonas aeruginosa and other gram neg ative bacteria resulting from contami nation of detergent fluids In which sur gical instruments had been stored. Refer also to other pertinent work concerning nosocomial infections (Ref. 7, 9, 10. and 14 through 21). The Panel concludes that the effec tiveness of the "quats" appears to be limited and their effects in vivo on either resident cutaneous flora or on potentially pathogenic transients on the skin have not been clearly demonstrated. This conclusion is based on the relevant fac tors which follow. While the growth of Staphylococcus aureus and certain other gram positive bacteria is inhibited by low concentra tions of the "quats" in vitro, their reac tion to these substances within the cutaneous ecosystem has not received sufficient attention. Since it has been shown by Ogden et al. (Ref, 11) and Sykes (Ref. 2) that "quats" are rapidly adsorbed to proteins and to cotton fibres and their germicidal activity is reduced in the presence of serum and of soap, their efficacy on the skin or in super ficial wounds is much less than would appear from results obtained with In vitro procedures. Many gram negative bacteria are re sistant to the germicidal action of "quats", and some strains of Pseudo monas can survive and multiply in aque ous solutions to these substances. Such strains may be resistant to related prep arations as has been described by Adair et al. (Ref. 12). Strains of the same spe cies can also vary in their sensitivity to the "quats" and this attribute can change as a result of artificial culture as shown by Carson et al, (Ref, 13). In vitro testing of a series of strains recently isolated from human infections and other appropriate habitats must be undertaken before the germicidal ef fects of the "quats" on gram negative species can be satisfactorily assessed. Mycobacterium tuberculosis, some spe cies of Clostridia, most dermatophytes and many viruses are not inactivated by the "quats". There are few reports on the in vitro or in vivo susceptibility of pathogenic fungi or protozoa to "quats". Various reports show that the applica tion of "quats" to the skin reduces both the bacterial count on hands and in the axilla with subsequent reduction of body odor. There do not appear to have been any studies on the composition of the residual bacterial populations. A reduc tion of the density of normal skin micro organisms may be followed by a selec tive increase in the populations of po tentially pathogenic microorganisms. Studies of the qualitative effects of "quats" on the skin should be under taken to insure that inhibition of the normal microbial flora does not produce results which ore hazardous to the human host. The three quaternary compounds re viewed by the Panel have been widely used for many years. Further toxicity data characterized by the ab.soiiJliuu and systemic toxicity in a rodent and nonrodent species shodid be generated prior to the placement of these "quats" into Category I for uses other than as a skin wound cleanser. Also, the In vivo effec tiveness of these ingredients for the product categories other than Skin. Wound Cleanser needs to be evaluated with modem techniques, including the use of specific neutralizers. References (1) Lawrence, C. A. and S. S. Block, "Disin fection, Sterilisation and Preservation," Lea and Febiger, Philadelphia. 1963. (2) Sykes, O.. "Disinfection and Steriliza tion," 2nd Ed., J. B. Llpplncott, Philadelphia, 1965. (3) Hugo, W. B,, "Inhibition and Destruc tion of the Microbial Celt" Academic Press, New York, 1971. (4) tDTC Volumes 020009-020018, 020021, 020029. 020051-020054. 020094, 020115, 020128, 020134. 020138. 020143, 020179. (5) Landsdown, A. S. O. and P. Grasso, "Physico-Chemical Factors Influencing Epi dermal Damage by Surface Active Agents," British. Journal of Dermatology, 36:361-373, 1972. (6) Bettley, F, R,, "The Permeability of the Skin in Relation to Cleansing Agents," Transactions of the St. John's Hospital Dermatological Society, 51:233-240, 1965. (7) Plotkin. S. A. and R. Austrian, "Bac teremia Caused by Pseudomonas sp. Follow ing the Use ot Materials Stored in Solutions of a Cationic Surface-Active Agent." Ameri can Journal of the Medical Sciences, 236:021- 627. 1958. (8) Malizia, W. F,, E. J. Gangarosa and A. F. Coley, "Benzalkonlum Chloride as a Source of Infection." Hew England Journal of Medicine, 263:800-802. 1960. (9) Lee, J. C. and P. J. Fialkow, "Benzal konlum Chloride--Source of Hospital Infec tion with Gram-Negative Bacteria." Journal of the American Medical Association, ITU 708-710. 1961. (10) Coles. R. B. and D. S. Wilkinson, "Necrosis and Dequallnlum. 1. Balanitis," Transactions of the St. John's Hospital Der matological Society, 51:46-48, 1065. (11) Ogden, A. E. and T. K. Rathmell. "Infections and Benzalkonlum Solutions," Journal of the American Medical Association, 193:978-979. 1965. (12) Adair. F. W.. S. G. Geftic and J. Gelzer, "Resistance of Pseudomonas to Quaternary Ammonium Compounds. IL Cross-Resistance Characteristics of a Mutant of Pseudomonas aeruginosa," Applied Micro biology. 21:1068-1063. 1971. (13) Carson. L. A., M. S. Favero, W. W. Bond and N. J. Petersen, "Factors Affecting Comparative Resistance of Naturally Occur ring and Subeulturcd Pseudomonas aerugi nosa to Disinfectants," Applied Microbiology, 23:863-869, 1973. (14) Anderson, K. and R. Keynes, "In fected Cork Closures and the Apparent Sur vival ot Organisms in Antiseptic Solutions," British Medical Journal. 2:274-275. 1968. (15) Ooss, W. A., "Germicidal Action of Zophlran Against Gram-Negative Bacteria." Draft of unpublished paper la Included in OTC Volume 020186. (16) Food and Drug Administration, "Warning: Contaminated Detergent Solu tion," Morbidity and Mortality Weekly Re port, 18:366, I960. FEDERAL REGISTER, VOL. 39, NO. 179--FRIDAY, SEPTEMBER 13, 1974 ASI 0000367? widely uxieiiy un mid il nunci pi lor s" Into 1 a skin o ctfeclor the il 6k in iduated ting the "Disin:on," Lea SterWua- Adelpbla. Destrucilc press, , 020021. 5. 020X29, arisao. cJn* Epi- Agents," :801-373, lty of the Agents." rital Dctt. tn, "Bacj. Follow- irosa and ride aa a d Journal , "Benzaltal Infec" Journal Hon, X77: Wilkinson, inlanltis." pitot Der- 7. Rathmcll, olutlons." laoctetlon, lc and J. nonag to unda. II. a Mutant led Mlcro- to. w. w. i Affecting dly Occuruu aerugicroblology, yne.T, "Inarent SurSolutions," 1098. Action of BacUrla," acluded in (at-'ratton, PROPOSED RULES aiim (17) Itcown, K. K , R. A. Oilman and C. P. Bailey. "Open Heart Surgery: Anesthesia and Surgical Experiences." Journal 0/ the Amer ican Medical Association, 1 lift'7BI --7H7, VIST. (16) liiwhury. at. J. L., "(JonUiiiiUntUiMi of t el i uuldo and Other fluids with Pscudo1 !j.:v pi;nei/,inea," British Journal of Jrt- ih,..trial Mciltt me. 9:22' 2.7, 1951, 11:1) Saulord. J, IV, "Disinfectants That Don't." Annals of Internal Medicine, 72:28228.1, 1070 (20) Shlekman, M D,, I, n Dure am! M 1. Pearce, "llartereinla Following Cardiac _CatheUrlrAtlon. Report <rf a Case and STtWigson the Source," New Piu/hintl Journal O/ Mrdf'DnvXWlini l 1111(1,11100 (Jl) Wel'ia, IV. A. and V P Halley. "FxtrnCnrporral Circulation In Cardiac .Surgery," Anesthesia and Annlpcoa, 39:438 400. 11)00. (22) Tilsley, D. A. and D 3. Wilkinson, "Necrosis and Dcqunllnlnm, IT. Vulval and Extrft-Oonltnl Dlccratlon," 7'rnnsnc(ions of St. Johns Hospital Dermatologic Society, 61:49-64, 1905. (23) Branetnark. P, I., et a!,, "Tissue Injury Canned by Wound Disinfectants." Journal of Bone and Joint Snrycn;, 49A.18 02. 1907, (24) Alfredsnu, B. -V, ct al , "Toxicity Studies on Alkyldlmcthylhcnrylnmmonlum Chloride In Rats and In Dogs," Journal of the American Pharmaceutical Association, 40:263-267, 1951, (25) Fttzhugh, O, a. and A. A. Nelson, "Chroida Oral Toxleltlea of Surface-Aeuva Agents." Journal of Hie Auirrienn rharinaccutlcal Association, 31/JO 32, 1910. (20) Flshor, A. A and M A Sllllnmn. "Al lergic Contact Sensitivity to rienmlkontum Chloride," Archives of Dermatology. 100 109- 171, 1973. (27) Ilurtez, C,, P. Agaetie, P, Martin. O. Vandamme, J, Menoreclor, "Allergy lt> Qua ternary Ammonium Salta." Drug Digest, 8.3430. 1005. (28) Salo, O P., V. Plrlla and E VUJanen, "Sensitlvtty to Topical Dequailne," Acta Al- lergologica, 23:490-490, loon. (2(1) Wahlberg, J E., "Two Cases of Hy persensitivity to Quaternary Ammonium Compounds," Acfa Dermato-Vencreolngica, 42:330-234, 10G2. (30) Saunders, W, "Contact Dermatitis Due to Denzalkonlum Chloride (Zephlran Cldorldel," Ncto York State Journal of Medi cine, 63:2700,1053. PHENOL 1,5 PERCENT OH LESS IN AQUEOUS/ ALCOHOLIC SOLUTION 6. Lister first demonstrated the useful ness of carbolic ncld (phenol'' as a germi cide in the surgical theater In 18G7. Al though It has been used since then, the topical use In particular has declined In recent years with the availability of new antimicrobials. Its germicidal mode of action ts as a protein dennturant. An easily dissociated complex of the plctiol molecule and protein Is formed. This complex formation permits the penetra tion of phenol through intact or abraded skin, mucous membranes or subcutane ous tissues with which It comes In contact. Phenol also may gain access to the pulmonary circulation through In halation of its vapors (Ref. I'. Many of the toxic 'effects discussed occur when phenol Is absorbed at levels of 1 5 per cent or less. However, toxic effects are more serious at concentrations greater than 1.5 percent, (Sec discussion of phe nol greater than 1.5 percent.) Although phenol Is no longer a sig nificantly used antimicrobial, It Is still formulated In topical products and there Is a large body of lltenitin e concerning Its cfTcctlvcncM (Ref. 3. 3. and 4). Phenol bandages or diapers In any form should was widely used and accepted as an anti not be used. Phcnol-contalnlng prepara septic when little else was available and tions should not bo used for the treat lls use Is certainly historically imiiortniiL. ment of diaper rush, The label should However, it Is now obvious that the level stale, `'Warning: Do not use for diapci of phenol required m a formulation to ia.\h or over large area,'; ol the body or be effective Is frequently so high that It cover the treated area with a bandage or cannot be used safely on the skin (Ref. dressings.'' 5). It Is recommended that the total con Phenol can be baelcristatic or bacteri centration of phenol in powders and 111 cidal depending on the coiirrntrution. aqueous, alcoholic or oil formulations be Phenol Is not. spot uitlnl. restricted to less than 1,5 percent. When The mn hour.m of action on the mi camphor is used with phenol In an oil crobial cell Is vciy likely llu* disruption formulation, l.hc concentration of phenol of Ihc cell wall and precipitation of the should be no more than 5 percent. Chem cellular proteins 1 Ref 3 and 4 . icals with phenol activity, such as sodium Because phenols have a high oil/watcr phcnolatc and secondary-amyltncresols partition coefficient 1 tendency for phe should be considered as phenol In the nol to remain In the oil phase), the calculation of the total phenol in any antimicrobial activity may be decreased formulation. The amount of phenol in the presence of excess oil or fats. available as a germicide will, of course, Since many phenol products are formu depend ujxm the particular formulation lated as ointments or creams, in vivo and the amount of phenol in a free state. studies must be conducted to show the The Panel has determined that phenol antimicrobial effectiveness of phenol In may be used In formulations, but at a these formulations. In addition, many of minimal concentration, for Its aromatic the reported effectiveness tests for phenol characteristics. published in the literature and/or sub mitted to the OTC Panel were carried out before the development and use of It seems apparent that even with Its long and illustrious history, the time has romo to recognize that the levels at neutralizers In antiseptic testing. which phenol In aqueous and alcoholic Phenol Is a classic example of a chemi formulations Is effective topically are cal which Is metabolized and eliminated also the levels at which topical and from the hndy by glururnniric rnniuga- systemic toxic.lty may occur. The fact Lion In the liver. This mechanism niay be- that tlieso two elements converge has dcffclent In young animals anti human made It necessary for the Panel to limit Infants. The Panel felt that inadequate Iho concentration which may be data concerning elimination and toxicity marketed while testing for safety Is con in young animals were submitted. Tlxe comitantly performed. Tlxe Panel has Panel recommends that adequate re described rather severe toxicity with the search in young animals with blocked dosing or application of phenol in ani formation or unavailable glucuronide mals or man and has limited the con systems be conducted in order to define centrations greater llinn 1.5 percent to the toxicity potential for human Infants. Category II. (See discussion of phenol Since the liver is considered the major greater than 1.5 percent aqueous/ organ for conjugation, the effect of in alcoholic.) adequate or Impaired liver function on elimination and toxicity should also be determined. Even though the effects of phenol toxicity at lower concentrations arc similar, the severity Is dependent on the Therefore, the Panel recommends that concentration. It Is the Panel's view unless such studies as described above that the demonstration of effectiveness are conducted within 1 year following at 1.5 percent or less may be exceedingly publication of the final monograph in llie difficult but that the use of this concen Federal Register this ingredient should tration does not present a known hazard be restricted from use in Infants. The to the consumer. The toxicity of phenol label for the preparation containing the has been extensively described. The ingredient would need to state: "Not major lack of data Is In in vivo efficacy to be used on Infants under 6 months of studies with concentration at 1.5 per age." The literature sources documenting cent or less. In vivo studies performed the Impairment of glucuronide capacity with modern testing and skin sampling 111 infants are listed separately under the procedures. Including the uso ol neu section on trlclocarbon. tralizers, are required. There is a report that phenol is a cocareinogen in animal tissue (Ref. 6). The Panel is of the opinion that enreinogenic studies should be done to determine whether in fact, phenol itself may have carcinogenic potential. No Infoi motion on the teratogenic or mutagenic potential of phenol lias been submitted and this data should he developed. Because of the reports of local and References (1) Deichmann, W. B. and M L. Kepiinger. "Fhunols find Phenolic Compounds." "Indus trial l/j/fjtnnc and Tn-neotoau" VoUimo II* Milled by Fas'-ott, O. W. and b. D. Jrlflh. 2nd ItevthOd Ed. Edited fov Patty, P. A, Inter* science Publisher*. 1 DGn. (2) Syl.es, G,, "/>*:/'* ?>'r and Sfrriti'tr- fron." 2nd Ed . J. B LipplncoLt. Philadelphia* loon systemic toxicity (Ref. 7) after the use (3) Hu^o, W B , "Inhibition and Dcstruc of phenol-containing products covered Mon o/ /Me Mirrohifll CeltAcademic Press, with bandages over large mens of the New Yoik, W7I. body, It Is recommended that the use of ( U r.awrcnre, C A. and S. 3. niock, "Dis- phenol be restricted to small areas of tn/rrtlon Sterilisation, and Preservation," the skin and that occlusive dressings, l.crt and Frhi^cr. Philadelphia. 1008, No. no--pt. n FEDERAL REGISTER, VOL. 39, NO. 179--FRIDAT, SEdCYiBER ) 3, 1974 ASt 00OO3673 I ' ' [ ( :m:n PROPOSED RULES (5) Esplln. D. W, "Anii:,cf>Ucs ftml Pliln- fecttints; Fungicides; Ef l.opara.`>IUcitic5.,` "The Pharmacological Bam* of Tltera- peultcr." Edited by Onodmnn I, S and A. (Ilhiinii. MiicMlItail, New Yurk, IU7I) dll 1 ii mi well, It K and D. K. Bosch. "The Tuiiim-piimndmg iVumi nf Phenol and He lmed (.'oinpimiula fur Muiiae SsKin," Cancer Research, 19:413-424. 1959 (7) Deichmann, W. 11 . * I.neal and Sys temic Efrccls Following Skin Contact with Phenol--A Review of the Literature," Journal of Industrial Hygiene and Tou- eology, 31.14G-I54, 1049, rAHA-CItl.OUO-META-XVl.ENOI. 7. Very little information whs sub mitted to the Panel with regard to parachloro-meta-xylcnol (Ref. 1). Only a a few acute oral and inhalation studies were submitted. These studies do not in dicate a high degree of acute toxicity with an oral LD,, of greater than 3 gm/ kg in rats. However, because the information that could be obtained from subchronic dosing by various routes of application, determination of target organ, dermal and mucosal absorption, and metabolic studies are not available, an evaluation of the safety of this chemical in a topical preparation could not be made. In ad dition, Information is not available re garding the effects of paia-cliloro-metaxylcnol on wound healing. The carcino genic, mutagenic and teratogenic poten tial of the chemical which might be used topically for prolonged periods of time has, to the best of tile Panel's knowledge, not been evaluated. There were two reports of contact dermatitis associated with para-chloro-metaxylenol (Ref. 3 and 4>. It has been reported by Zondek and Shapiro (Ref. 2) that parn-chlorometa-xylcnol Is metabolized by glucuronido and sulfate conjugation. Due to tho reported deficiency of metabolic conjugating mechanisms in infants, it is the opinion of the Panel that toxicolog ical safety evaluation of para-chloromela-xylcnol should include the studies to demonstrate safety in animals defi cient in these detoxification mech anisms. Since the liver is considered a major organ for conjugation, the effect of impaired liver function on elimination and toxicity would bo important. Therefore, the Panel recommends that unless such studies as described above are conducted within 1 year fol lowing publication of the filial mono graph 111 the PEDErtAL Register, this in gredient should be restricted from use in infants. The label for a preparation containing tho ingredient would need to stale; "Not to lie used on infants under six months of age". The literature sources documenting the impairment of gluouronide capacity in infants arc listed separately under the Statement of tiie Panel on triclocarban. A manufacturer of paia-chloro-metaxylcnol has indicated to ttic Panel (Vol. 0200G7, p. 31, Ref. 1) that further toxi cological studies were planned; however, no additional information has been made available to the Panel, Para-ohloro-mel.u-xylonol is a halo gen sub.'.lltuLed phenol compound Many of the ''liniments made for the cHeclivcness ti'-'niu of phenol apply here Halo gen substitution incieases the anliniirrnhial activity of phenol derivatives. The halogen In Lhe puru-positlon to the hy droxyl group is considered the most effective substitution. Ulus, tin; indica tions are that this compound would show good in vitro activity Very little in formation about Ll 10 ul vivo activity on the skin is published or was submitted to the Panel. At least one rcpoit. by Colebrook and Maxtcd in 1931 iRef. 5), using a serial washing technique in dicated only a slight ciTccl on resident bacterial flora of the skin. Another study reported approximately a 70 percent reduction in microbial count of the flora of the hands after 10 days of use. Para-chloro-meta-xylenol is pri marily active against gram positive organisms with activity against gram negative niici'organisms in vitro. Fun gicidal activity in vitro Is also reported (Ref, 2). The phenol coefficient is re ported to be around 40, but the results vary (Ref. 2). Claims for broad spectrum activity have been made for this compound. It has been tested as a preservative for cosmetic products (Ref. 2>. Unfortu nately the data submitted are not ade quate to support these claims. Very little eiTeelivcness data which could be evaluated were submitted. Many studies were old and not performed with modern antiseptic testing procedures. Effectiveness testing both in vitro and in vivo should be clone in accordance with tiie Guidelines developed by the Panel. There are so little data available tinit it is tiie view of tiie Panel, that this ingredient should be tested as tf it were a new chemical entity for use in anti microbial formulntioii(s). Only the most superficial toxicity data 111 animals have been reported to the Panel. It is the Panel s view that toxicity in rodent and non-rodent species, subslantivity, blood levels, distribution and metabolism as well as any subsequent systemic absorption studios must be characterized before this ingredient can be considered for placement in Category I. The carcinogenic, mutagenic and tera togenic potential of this ingredient must be determined before it can be listed under Category I for topically applied products. In vitro and in vivo efficacy studies with up to date sampling tech niques, including the use of neutralizers, are required. References (1) OTC Volumes: (120(130, 020041 020043, 02(1097, 020073, 020004, 020092. (2) Zondek, B, nnd B. Shnpho, "Fate ul Hnlogcnated Phenols in the Organism." Bio chemical Journal, 37.502-595, 1943. (3) Calnnii, C. D, "Contaet Dermatitis from Drugs." Proceeding* of the Royal Soriet 1/ of Medicine, T)5'39 42, 1902. (4) Schorr, W, E, "CoMnclu: Allergy: A Comjnehenstvo study ol lhe Mnny Croups of Chemical Amhmcroblnl AponUV Arehti'e* of Dcrnuitolni/;/, 104.459-490, 1971. (5) Culehrook. L. nnd W. R, Itfaxiod. "Anttsep.'.i'i In Midwifery," Journal of Obstetric* anil (l ynceidw/y, 40 999 (190. 1933, Hexylhesorcinol 8. The Panel has reviewed the submh sion regarding tiie safety and eilectivt ileus of liexylic.ini'cinol The few itnliti: toxicity studies submitted as summuui indicate a low outer hi toxuilv <Uef. I However^ no informalum lias been xut mitted regarding dermal or opthnlmi toxicity or absorption and blood levc. attained after application to tiie intai or abraded skin or mucous membrane Hexylrcsorcinol has a history of tv as an oral anthelminthic in humans. 1 these cases the dose used in children h: been G00-1100 mg. and in adults 1000 nv Ref. 2 and 4) without systemic toxtcilHowever, irritation and ulceration of tl oral and gastrointestinal mucosa liat been reported from these high dosi (Ref. 2 and 4). During its long history of use, thei have been a few reports of dermatit and allergic reactions following the top ca1 application of hexylrcsorcinol to ski (Ref. 3. 4, 5) and of Irritation of the ormucosa from the use of cough drops ni toothpaste containing hexylresorcin (Ref. 3 and 4 >. However, the Panel Is * the opinion that hexylresorclnol does n> present a known hazard to the gener public from use as a topical preparatio Data have been submitted demonstra ing in vitro effectiveness using techniqn available some years ago. Neutralizers V antiseptic testing were not in genci use at the time these studies were pe formed and their use was often Ignort Newer testing techniques are current available and should be used in furth studies to determine tiie in vitro activi of this ingredient. Adequate data to dci oustratc clinical or in vivo effectivenr or to substantiate label claims have n been submitted. Tiie Panel has reviewed rather e tensive reports of the oral administratt of hexylrcsorcinol to humans with oLh accompanying animal toxicity data (R 1) and lias concluded that topical npp ention, even where nbsorption mif occur at high levels, Is safe. The area which data arc lacking concerns the vitro and in vivo effectiveness of the i gredient and of formulations contain! it. Before hexylresorclnol can be mot to Category I for other product catci lies, these effectiveness data must generated using modern testing plot durcs and skin sampling techniques, i eluding the use of neutralizers. References (1) OTC Volume 020080. (2) Ducdinp, E., "Chemotherapy of Iitf Moms by Nematodes nnd Cestodcs," "t)n Thai maeolagy in Afcdiemc.'' 4th Ed.. Jidi by Dtralnm, J. R, McGraw-Hill, New Yo 1071. (3) Bleecker, P B,. "Marked Sensitivity Hcxvlrcriorcinol (ST 37)--Cft.sG Rcpiv Memphis Medical Journal, 15.02, 1540 (4) Sollmnnn, T , "A Manual of Pha* vta ogy and t/s Applications to Therapeutics Tuneology, 8th Ed-, W, B. Saunders, Ph dolphla. 1057. (5) Osier. K. A., "Chemotherapy of H tcual Infectious i: Antiseptics and Gen cides," "Drill's Pharmacology in Media* 4th Ed., Edited by DlTalma. J, R., McGr lltit, New York, 11)71. FEDERAL REGISTER, VOL. 39, NO. 179^fR|DAY, SEPTEMBER 13, 1974 ASI 00003674 9 <ial .cs li, ibaic els act ies. use In lias mg. tty. the ave >se3 iere >pl- kin >ral and mol 3 Of not *ral' ion. ratlues : for eral r>er- emness not ex* tlon ther Ref. >pllight iV in e in In ning oved *'goi be oce. hi- nfec-Inll's dlted York, i fcy to jort," acof* i and hlla- Bac- PROPOSED RULES :mr. TRIFLE DYE the Neonatal UmMlleus and Its Relation to be some demonstration that Lho formu 9. The OTC Antimicrobial Panel has thoroughly reviewed the publisher! liternturo mid him listi-ned to additional leall- ,:iv [11,hi mteic'-ted parties concerning the -.delv and effectiveness of the com the Incidence of .'i-pMa hi a Maternity Unit," Journal of Olutrlrtes and flynucc.Uocii of the Brttish Commonwealth, (38:170-187, ill'll. Lauclinu Tlie Panel has determined that label lated product Is better than the vehicle alnne. Testing of Hie complete formulaturn for cltcetlvcness and safety will lie required to judge the Importance of tlie vehicle hi the idense ot the active ingre , bination of dyes icrystal viulot, 1129 g: brilliant giecn, 2.29g and proflavine hetnixuUuLe, 1.14 g and sufficient water to ing claims not Identified ill Category I or Category II of this document continue to be used until 1 year after publication dient as well as the influence of formu lation on aspects of effectiveness and safety. make 1000 ml) known ns Triple Dye. of the final monograph 111 the Federal A. Safely. (Tests below to be per > The Panel has reviewed the use of Register providing tlie manufacturer or formed on suitable animals and then on " --.Triple Dye for the treatment of the utn- distributor of the product promptly un humans when applicable, appropriate bnte5_prior to the introduction of hexa- dertakes adequate testing to support such and ethically feasible.) chloropKfrhewand has reviewed its rerent statements. I. Topical (skin). Determine: use In the prevention of staphylococcal colonization of neonates ns a possible replacement for hexnchlorophene. It is the opinion of the Panel that I he evi dence indicates that a single application of triple dye to the umbilicus is effective In the reduction of staphylococcal coloni zation in infants in the hospital nursery (Ref. 1, 2, 3 and 4). Confirmatory studies would be desirable. It Is also the opinion of the Panel that additional safety data including the de gree of percutaneous absorption and con comitant toxicity of the combination is required. Additional effectiveness data are need ed to determine the duration of protec tion following a single application of dye. The difficulty in the establishment of ef fectiveness by skin sampling for staphy lococcal colonization is increased by the presence of small quantities of trans ferred dye In the culture medium used to isolato staphylococci and must be con sidered In further tests of effectiveness. It Is the opinion of the Panel that the Guidelines tor Testinc After exhaustive review of the data submitted for antimicrobial ingredients in soups, surgical scrubs, skin washes, skin cleansers, and first-aid products, the Panel lias developed guidelines for safety and effectiveness studies. These guidelines should be followed to develop data for specific ingredients where the information docs not currently exist. The Panel recognizes that antimicro bial use ranges lrom total body exposure to application oil small areas of the body. This may extend from daily, re peated to intermittent, occasional appli cation. The Panel also recognizes that the list of products may include solids, liquids, creams, powders, and aerosols, formulated with various chemical ex cipients. The guidelines which follow were de veloped primarily for antimicrobial agents applied to the entire body sur face. Appropriate tests from the guidelines a. Primary Irritation potential following acute And subacute exposure. Special atten tion devoted to eyes, mucous membranes, and gcntlulla. i>. Allergic contact dermatitis potential following acute and subacute eX|Kisure. r Photosensitivity potential (phototoxic and photoallergenlc). Tests to be conducted In appropriate age bracket In men and women and In sufficient numbers to deter mine safety. d. Elfect on wound healing. e Eircct on skin pigmentation, f. Eirect on total skin flora to Insure no detrimental over-growth of a particular bac terial or Tungal species. g Substautivlty or accumulation in or on the skin. Note The above tests should be performed using the chemical in pure form and In the final complete formulation to Judge the effect of vehicle In the release of active Ingre dient (s), 2 Si/vtcmic. Determine: a The adequacy of or development of chemical analysis and/or bioassay techniques for tlie detection of the chemical and meta bolites in biological tissues and secretions Is essential. data reviewed were not sufficient to per mit final classification of triple dye. The substantiation for this view Is found in OTC Volume 020144 (Ref. 1) , and in articles by Pildes et at (Ref, 2>, Jellard (Ref. 3), Hardyment et al. (Ref. 4) and Huntingford et al. (Ref. 5). should be chosen to reflect adequately the intended use of the product contain ing the antimicrobial agent. Aerosols, lor example, should Include Inhalation tests. The Panel recognizes that there may be honest disagreement among scien h. Degree of absorption (blood level) through Intnct and abraded (damaged, dis eased i akin and mucous membrane afler acute and subchronic exposure and where ap propriate, chroutc exposure If the product is an aerosol, adequate Inhalation studies should be conducted. c The target organ(s) for toxicity effects In summary the Panel reviewed this tists as to the most appropriate design via oral, topical and/or parenteral routes Re combination of antibacterial dyes pri of a protocol for many of the tests late toxicity to blood levels of chemical agent. marily as a result of their concern with the toxicity of hexachlorophcnc. The ap plication of triple dye to the umbilicus is a potential replacement for hexachloro- phene bathing of infants in the nursery to reduce staphylococcal colonization. required t,o provide the data on which a final determination of category can reasonably be made. In this event, conlerences with expert consultants and with representatives of the Food and Drug Administration are rceommended. Hclcimlno lho "no-effect" and "effect" level In 1 he same species and same study. d I lie I.D.. highest dose killing no animals and lowest (lose killing all the tost animals by oral and topical routes. 1C possible, e. Tissue distribution, metabolic rates, metabolic fate, and rate and routes of excre They have reviewed the literature and Tlie Panel also recognizes that they have tion. available Information concerning the recommended studies ill areas and with f. Teratogenic, mutagenic, carcinogenic, toxicity. Further data on the absorption, specified details lor which precedents nnd reproductive effects. possible carcinogenicity of the dye in gredients and corroborative efficacy data should be generated before triple dye can be placed in Category I for this limited Indication. are not common. Guideline for Satety and Efficacy TrsTiNc of OTC ToriCAL Antimiceodials Preparations applied to tile skin for Note: The above tests should he performed using the chemical In pure form and In the final complete formulation to Judge the effect of vehicle In the release of the active Ingredlcnt(s). RFFFRFrrCPS the purpose of reducing microbial counts B. Effectiveness. The Panel has estab (1) OTC Volume 020144. or to effect control of Infection may bo lished by its definition of a skin antisep (2) Hides, R. S , R S. Ramainurtliy and applied to limited areas or to entire tic that only this product category re D. Vidyosagar, "Effect of 'Triple Dye' oil Staphylococcal Colonization In the Neonate." Draft of paper sUbndttsd for publication is Included In OTC Volume 02018G. (1) Jellard, J, "Umbilical Cord os Reser voir of Infection In Malernlty Hospital," British Medical Journal. 1,925-928. lill,7. body surfaces. The following points are suggested as guidelines for the safety and effectiveness evaluation of topically ap plied chemicals. Since some products containing an antimicrobial agent(s) may be employed only over a llmiLod quires controlled clinical studies to estab lish efficacy. Tlie Panel accepts that in the definition and/or historical use of other product categories, the reduction of the normal flora, both transient and resident, has been sufficiently supported (4) Hardyment, A. P, R. A. Wilson. W. surface area and/or for a limited tunc, as an added benefit in all other products Cockcroft and B. Johnson, "Observations on the Bacteriology and Epidemiology of Nnraey Infections." Pediatrics, 25:007-927, I960. all of the specific tests in the guidelines list (as well as others) may not be re quired. where antimicrobials are included in the formulation. In the context of all of the definitions 15) Huntingford, P. J., O. Welch, IT. Olasa Since topical products frequently have the concept that the products must he and Q, Wctlicrloy-Melu, "Tlie Problem uf a considerable placebo effect, there must safe uud non-irritating Is expressed. rcocRAL register, voi. 39, no. 179--Friday, September n, 1974 '"Vs I.' 00003675 .`I.'ll.'JG PROPOSED RULES Testing of the irritation of topically ap plied products can be performed by ac cepted procedures. Since product categories which did not exist previously have been defined by the runel, there will be a need to develop .idciiuato texting procedures m some of these new areas. There is particularly need to develop in vivo procedures for the newly defined products. Tile guide lines which follow are designed as an outline of suggested procedure:, which the Panel feels will characteri/.o an anti microbial product or ingredient. Cer tainly, the Panel rccogniy.es that changes and additions will need to be made as newer techniques become accepted, 1. In vitro, a. Develop techniques for adequate neutralization of the chemical agent, before testing its antimicrobial1 spectrum. Insure that the neutralizer is not toxic to the test organisms. b. Determine the antimicrobial spec trum of the chemical's) alone and in its final formulation. Use both standard cultures and recently isolated strains of each species. Cultures representing nor mal skin flora and skin pathogens should be selected. The following outline has been pre pared to serve as a basic guide for the in vitro characterization of the activity of an antimicrobial ingredient: c. Determine the minimal inhibitory concentration (MIC) under standard conditions against standard organisms with known phenol coefficients and sus ceptibilities to other antimicrobial chemicals. A scries of recently isolated mcsophilic strains including members of the normal flora and cutaneous pathogens (100 iso lates) should be selected. Representatives of the following groups should be in cluded. Note; Special media anil'or environmental conditions may be required: I. Staphylococct-5 groups. 2 Micrococci. 3. Pyogenic Streptococci (Croup* A, C, D should be Included ) 4. Diphtlirroids-Llpopbillc, Noil-Lipophilic, Anaerobic (ProptonibnrteriKm). 5. Gram negative enteric bacilli: 1 Escherichia, Entvrobacter, Klebsiella, Protein, and Scrratia should be Included, It. Pseudomonas aeruginosa and Pscudo- monas species. G. Neisseria species. 7. Aerobic Spore-Formers. 0. Atypical mycobacteria--Cast growing strains. a. Fungi--Yenst-llke species. Pityrosporum ovate, PUiitosjiotiiiii orhi, uiare, Candida athieaiis. Candida parapsilesis, and 1'orulopsis giabrata. 10 Selected Filamentous Dormatnpliytlc species. II. Viruses--hydrophilic, lipophilic, d. Determine possibte development of resistance to the chemical. Sublcthal levels of the active ingredients) can be incorporated into the culture medium for au extended series of exposures. Use .standard methods to determine the oiiierreiicc nf resistance. e. Phenol coefficient ' "Ant Imlcrobial" Is d^/fiif*(l ns aultbiU'trrinl, imUvlrat. iuiUfunp,;\l mxl nnUpndo/onl, Use standard pnn edniu with and with out a specific neiii i alizer. If none is available, use 10 pricent scrum. Second subcultures, to determine'the viability of the strain, should he made. f. Other tests for antimicrobial effec tiveness--data substantiating antimicro bial action by standard procedures, such as the Sykes-Kelsey procedure, and others whete applicable, should be used. It would be advisable to include in the in vilro test a chemical * s I with rccoisiii/,cd antimicrobial activity, for purposes of comparison. 2. In vivo. a. Appropriate tests approximating use conditions for the clinical evaluation of each label claim of the formulated prod uct should be carried out. Some of these tests have been described. 1. Quantitative and qualitative estimation of tho skin flora, both transient and resident. 2. Glove Juice procedure. 3. Cado handwashing test. 4. Quinn handwashing test. 6 Skin-stripping or cup-scrubbing tech niques should bo used. b. Feasible methods of sampling mi crobial communities in several different areas of the body, such as axilla, groin, feet and hands, are necessary so tiiat the ecological effects of use of the product can be determined. This should include records, not only of alteration in total numbers, but of qualitative changes (such as dominance of a different type or change in antimicrobial resistance) in the residual cutaneous populations, c. Determine the minimal concentra tion of the chemical necessary to produce tile results named'in the label claim(s). Details of some of the specific tests referred to In the Guidelines can be found in Ref. 1 through 4. Reeeri nces (1) Hugo. W. B. "Inhibition and Destruc tion ol the Microbial Cell," Academic Press, New York. 1971, (2/ Kelsey, J C and G. Sykes. "A New Teat for I he Assessment of Disinfectants with Fnrlicular Reference to Their Use In Hos pitals,'' Pharmaceutical Journal, 202:607609. 1969. (3) Lawrence, C. A. and S. S. Block. Dis infection, Sterilisation, and Preservation, Lea and Febiger, Philadelphia, 1968. (4) Sykes, G.. Disinfection and Sterilisa tion, 2nd Ed., J. B Llppincott, Philadelphia, 1965, PRINCIPLES OF Cf.fNlt'AL EFFECTIVES ESS Studies In general, the Panel recommends that Uio principles specified In 21 CT'R K10.12 (a)'5)(il) be included as essential for adequate and well controlled clinical investigations. The reader is also referred to additional clinical testing guidelines (Ref. 1). The following specific recom mendations are made to emphasize their importance in conducting clinical trials for products in this class, A precise statement of the research gaols and olpcclives; definitions of the disease slate to he studied. Kxamplcs: To ilclcinuuc if "X" product reduces the incidence of supci llcmi skin Infections (specify type) If applied ispecify how), to reduce morbidity or cure ';Y" disease Since the Panel Is aware of the diffi culty in conducting this research, it might be preferable to conduct such studies ill a controlled laboratory setting rather than awaiting the apiuiinucuus occurrence of disease. The allocation of the subjects to treated and control groups so that bias In assignment is avoided (randomization or other suitable method). Demonstra tion of compai ability of control group (analysis by age, sex, previous medical history, etc.). ,- Hccau.se of the considerable "placebo effect" of topical medication, several piinciples should be incorporated, when ever possible, in clinical trials of topically applied formulations. a. Control groups should receive treat ment of cither inert vehicles of "nextbest" therapy. Identical In appearance, odor and consistency as the test medica tion; b. A double-blind procedure should be employed to minimize bias in reporting of results. Precise criteria for inclusion or exclu sion from study (clinical judgment; other diseases; social class, etc.). Verification of diagnosis of disease to be treated. Definition of outcome response vari ables (improvement: How measured? cure; How determined?). Are these ob jective or subjective measures? SUidv design: Is It blinded? Large enough sample to detect a difference? Ci oss-over, etc.? The rationale for tho design. Completeness of the study (how are messing data, dropouts, etc., treated). Data summarization and statistical analyses. Are the appropriate tests of significance used? Are tables clear and properly labeled? Are conclusions justi fied by the data? Basie principles applicable to clinical studies in general and references used in the development of these guidelines can be found in Ref. 2 through 4, References (t) "Guidelines lot Clinical Testing of Topical Anu-lnfecttve Drugs" developed by the Food and Drug Administration and the rharmaceutlcal Manufacturers Association Is Included in OTC Volume 020180, Copies arc available from the Freedom of Informa tion Olficer, Food and Drug Administration. Bureau of Drugs. 6600 Fishers Lane, Rock ville. Maryland 20852. (2) Burdette, W. J. and E. A. Oclian, "rimming and Analysis of Cliniral Studies Cnarlei c. Thomas. Springfield, 1970. (.11 IIIU, A. D, "Slallstlral Methods in Clinical and Preventive Medicine," E. and S. Livingstone. London, 1962. (4) Witts, L. J., "Medical Surveys and Clini cal Trials," 2nd Ed., Oxford University Press, New York, 1904. Specific Protocols Recommendep Byjche Panel In the course of Us deliberations, the Panel 1ms made certain suggestions and recommended tho development of spe cific piotocols. Some of Lhcso comments and piotocols follow. 1. Determination of shin flora (Other than on the hands), The development of .sampling techniques in recent years now IllHRAt RIOISIIR. VOL. 39, NO 1/9 -- IRlDAV. SCCTfMBLR 13, 19/4 ASI 00003('.76 PROPOSED RULES 33137 permit* a more accuiatc determination of the microbial flora of various parts of the body surface. Of the techniques which have been de veloped. UpdegrnIT (Ref. 1) has de nuded a reliable procedure for the de- P'liiiin.ition of qualitative chanties in the iiueinhi.il skm lima. This technique con sists ul skin stiippmg of microorganisms using cellophane tape The skin run be stripped In consccuUve luveix followed by culturing mid IdeiiLUlcallon ol 01 na nisms removed by consecutive strippings. Williamson (Ref. 2) and Pachtman. ct al. (Ref- 3), have described cut) proce dures utilizing a scrubbing solution placed in the cup which is attached to the skin. Some means of agitation of the liquid for more efficient removal Is used. The use of one or more of those tech niques allows the determination of the number of microorganisms per square cm. It will also allow the determination of the type of organisms residing on various areas of the skin as well as the assessment of the eiTect of the long-term use of antimicrobials on the normal flora. A potential benefit from the presence of the normal diphtheroid population of the skin has been a point of speculation. There are Indications (Ref. .4) that these organisms may discourage the develop ment of cutaneous infection by patho gens. If changes and shifts in population occur after the repeated use of anti microbial-containing products, then it must at least be known that the changes are occurring. In actual practice, the volar aspect of the forearm and the small of the back have been selected as areas for study of the flora because of ease of sampling and greater uniformity in type of flora. It is suggested that individuals with a high microbial skin count be selected as subjects for studies In which there is to be a determination of change in the number of microorganisms in any given area of the body surface. Such indi viduals will reasonably show changes in various elements of the flora more easily than those with low carriage or in those who lack certain types of organisms. In studies where quantitative changes are determined, the Investigator should consider the fact that the count data should be evaluated with appropriate statistical procedures and models to deal with high variability. References (1) Updegrafr, D. M,, "A Cultural Method of Quantitatively Studying the Microorga nisms In the Skin," Journal of Investigative Dermatology, `13:120-1.17, lilS'l (2) Wllllitrn'.nu, P , "Quantitative FT1.(f- nmtlon of Cut.menus Bacteria." '`Shin liar* trria and Their leolc in Infection," Edited bv Mnlhnch, II,,I. mid Q. Hlldtck-Smlth. Mc Graw-Hill, New1 York. 1005. (3) Pnchtnmn. E A, E. E. Vlrhor nnd M. 3, Brunner, "Tho BacLcrloioglc Flora In Sehori'Uele Dermatitis," The Join Vat of In vest igat Irr Dermatology. IhPIM'.l :eul. I'tr.l (II 03 C Antlinierul.lal I Panel .Summary Minutes fur the September 14, itr/2 meeting 2. Isolation of gram negative and other organisms from (lie skin. Grainnegative bacteria do not occur as resi dents of the skin of all Individuals, and when present nuiy be found only ns small locatb'cd populations. They occur most ftcquciilly in moist areas such as the axilla, the pcrl-anal region and the toe-webs. It lias however been shown by Tapi in (Ref. 1>, and Amonetlc and Ros- cnlieig (Ref. 2> that the repealed use of preparations containing antimicrobial .substances may lead Lo a change in the compnsll ion of llic cutaneous 1,00111111illly so that giam negative species, or even yeasts may become dominant. This may liaic very serious consequences as cutaneous or even systemic infections may develop. It is therefore Insufficient to study only the ellects of long-term repeated use of an antimicrobial prod uct on the total numbers of micro organisms on the skin. It is essential to know to what extent reduction of num bers is selective, and to study the com position of the residual skin population. Special attention should be given to de termining whether repeated use of the product leads to a relative increase of gram negative bacteria or yeasts In the total population. The Panel suggests the use of the fol lowing procedures as a means 0/ facili tating such studies. A. A preliminary investigation of groups of individuals should be made so that earners of gram negative organisms can be identified. To find these earners, samples should be taken from the fore head. axilla, groin and toe-webs as well as from hands and back. The groups of subjects selected for the testing of the preparation should include the gram negative earners previously Identified. B. Sampling techniques which can provide reasonably reproducible results should be employed. These have been listed in the general guidelines. The sample taken from the skin should be sufficiently large to permit tho quantita tive inoculation of several different solid media. C. The following types of media should be inoculated with a measured volume of the sample: 1. A nousctccttve medium such as bloodagnr or TSA (Tryptlcnsc Soy Agar). 2. Selective media appropriate for the Iso lation of microorganisms of special Impor tance ns skin Inhabitants: a EMU (Eosln-Mct liylcne Dine) or MacConkey Agar for coltform organisms. b. irgasau (Trlclosnn) --containing agar for Pseudomonas species. c. staph ylocorru 1 Isolation ngnr. c g . Staph IK). d. Crystal Violet-Blood Agar for betn- hacmolyUc streptococci. c, DTM (Dermatophyte Test Medium) for Candida and dermatophytes described by 3'nplin et nl. (Ref. 3) and Rcbcll and Tnp11II | (tef 4) . 1). While quantitative estimates of the (lllferent tvpc.x of urgaiilsms cnmposltir llie ruLanruiis populations may lie ob tained from these primary cultures, it may be net es: ary to study Individual isolates in much further detail before they can be identified and- the implica tion of tlielr presence assessed. The Panel la fully aware of the cllflU ruKies involved in the examination and hlcnttnrntlon of mU'roorrnnhuns living on Uie human skin. U tvuulri welcome the development of new .samplum tech niques and media especially selective for cutaneous microbial .strums. Elabora tion :md Improvement of the methods currently used \\\ lnvesUip\Uon of cu taneous ecology Is urgently required. Rkferen<j3 (1) TfipMn, D,. N. Znliui and O. Rcbcll. 'Environmental InMuCnces on the Micro biology of the Skin.** Archives of Environmental Health. 11:546-550. 1965. (2) Amonctte, R. A. and W. E. Rosenberg, '`Infection of Toe Wche hjr Oram-Negative Bacteria.1* Archives of Dermatology, 107: 71-73,1973. (31 TapUn, D.. N, Zaias. G. Rebell and H. Blank, "Isolation and Recognition of Dermat ophytes on a New Medium (DTM)," Arc/iices Of Dermatology, 99 203-209, 1969. (4) Rebeil, G. and D. Taplln, "Dcrmatophytes, Their Recognition and Identifiedfton," University of Miami Press, Coral Ga bles, 1970. 3. Effectiveness testing ol a surgical hand scrub iglovc juice test). Fancl members working with Food and Drug Administration personnel and other microbiologists (Ref. 6 and 9) recom mended the following which is required by the Food and Drug Administration. The test described must be performed to support the efficacy of a product labeled as a surgical hand scrub. Introduction. The determination of the microbial counts found in the accumu lated fluid in the surgeon's gloves has been suggested in the literature as a method for the determination of the ef ficacy of surgical scrub products. The use of routine hand-washing procedures derived from the Price Test described in 1938 (Ref. 1) have their place but the results of these tests are easily manipu lated by changes in the routine, timing, and recovery procedures. The develop ment of improved sampling (sampling solution) procedures and recovery tech niques (neutralizers) by Williamson (Ref. 2), Ulrich (Ref. 3) and Engley and Dey (Ref. 4) has greatly improved the reliability of skin sampling data. An ef fectiveness test which more closely simulates the actual procedures carried out by the surgeon is desirable and nec essary. This protocol Is meant to be a guide line for performing tests to support claims of elTectiveness as a surgical hand scrub. It will undoubtedly be modified with experience. Criteria for subject selection. 1. Mixed male and female. Race should be re corded. 2. Adults. 3. Subjects will vary greatly in the number of microorganisms curried on the skin. Subjects with a high hand count ns liieasuicd by sampling with the glove juice procedure should be used for the test. Counts should be in the range from 1.5 X 10" to 4x 10" Per hand. FEDERAL REGISTER, VOl. 34, NO. 179--FRIDAY, SEPTEMBER 13, 1974 ASI 00003677 33138 PROPOSED RULES 4. Medication. Subject receiving anti biotics or taking oral contraceptives should be excluded from the test. 5. Thirty <30 > subjects per test. Prc-tcst period. 2 weeks. The Mil)hels lor till., test should not use any pindia'ts containing antimicro bials lor .it least 2 weeks prior to the Lest. Tills restriction includes antimicrobial antlperspirunts and deodorants, sham poos, creams, lotions, soups, or powders. Subjects receiving antibiotic therapy or taking oral contraceptives should be dis qualified. Subjects should be issued rubber gloves to be worn during their daily routine when they come In contact with deter gents, acids, bases or solvents. Gloves for test. Gloves should be washed with sterile distilled water be fore use and applied wet. Gloves which are pre-powdered should be carefully washed free of powder ns many of these powders contain antimicrobials. Baseline period and sampling. The baseline period should be one week fol lowing the two weeks of the pre-test period. The baseline counts should begin on day one of the baseline period. This Initial count is a screen to determine eligibility. The day one count is also one count to be Included for the mean bnselinc count. The counting procedure should be performed oil day seven and also on cither day three or five for a total of three estimations of the baseline count. The baseline counts should be per formed using exactly the same sampling and recovery techniques used for the test products under the testing procedure. This Information will also be used to pro vide evidence to assess the assumption that the right and left hand gave com parable results. Both hands should be sampled for the baseline count. Subjects should not wash prior to the counting procedure on the day of the test. Baseline procedure Is as follows: Hands Including 2,j of the forearm are washed for 20 seconds with Camay soap and sterile distilled water at 35-40" C. The excess water Is shaken from the hands and the gloves are donned with tho hands wet. Sampling solution (sec Ap pendix) Is added to the gloves <volume of sampling solution should remain con stant for all tests). The glove is held closed at the wrist by the subject while an attendant massages the hand for one minute. A measured volume is withdrawn for Uic count. Testing Procedure Scrubbing procedure. The srrubbing procedure should be exactly ns diic<,led on the label of the product being tested, Including the use of nnll cleaner and/or a brush If Indicated. The hand and of the forearm should be scrubbed. Sampling technique and times. After the scrub is performed, loose-fitting sur geon's or examining gloves are donned. Leave the hands wet by slinking od excess water when the gloves are donned. Imme diately, the designated control hand Is sampled for the one minute count as fol lows: Sampling solut ion rontmning buf fer and suifactual K milled to the glove, the hand Is massaged 1 ir one minute, and a measured sample lemovcd for plat ing, The volume of the sampling solution added to the glove .should be kept con stant for all tests. The fluid should be shaken vigorously prior to dilution or cul turing. If diluent Is used, neutralizer should be ndded to dilution blanks. The glove is to rein,nil on Ihc other hand for the duration of Ihe time of the test. It is suggested that at least 1, 2, 3, 4, 5, and G hours post scrub should be tested. The times for winch a glove remains on one of the hands after scrub should be allocated by random selection among the subjects in groups of five. This pro cedure Is performed on day one and day two of the test period. The procedure should be repeated on day five after sciubbiug with the. product according to directions two additional times on day two and three times per day on day three and four nt one-hour Intervals. One scrub should be performed on day five and the gloves allowed to remain on the lctt hand for 1, 2, 3, 4, D, or G hours. The number of subjects used for the test should be 30 with randomization into six groups (n -five per group) cor responding to one hour, two hours, three hours, four hours, five hours and six hours. The allocation of subjects to groups remains constant after Initial randomization. Recovery media. A medium contain ing a neutralizer specific for the anti microbial being tested must be used. Media which have been used in the past include: I.cLheen and Trypticasc Soy Agar with Tween 80 and scrum added. The neutralizing system used for anti microbial agents must be tested, and the data from the tests submitted, to show that the system is adequate. The neutralizer should not be toxic to cells and must be effective in neutralizing tho specific chemical. This data must be submitted. The cultures should be Incubated at 30:* 2" C. for 48-72 hours. If culturing for specific organisms, such ns fungi or anaerobes, Is undertaken, appropriate culturing procedures should be Insti tuted. Dupliealc plates have been routinely used for plating in the past. Because of the inherent variability in counts nnd the presence of clumps of cells from skin sampling, it Is suggested that at least triplicate plating be used. A larger num ber may be required, depending ou the variability. The counts should be icpoitod as count per hand. There arc variations of this prorcduic 111 use. for instance, Instend of snmpllng directly from the glove, the glove is re moved, turned Inside out Into stripping fluid, and the hand rinsed with sampling solution as well. If variations of this test are to be used, the protocol should be checked with Food nnd Drug Adminis tration personnel first. Data handling--design--statistieal as~ pects. It is assumed that there arc no right versus loft hand dllfcrenees In microbial count. It is known that mi crobial handedness fa difference In count between hands) exists: however, Iheic is apparently no relationship to whether the subject Is left or right banded. The possible difference m count should be compensated for with the initial random allocution of subjects. ; This will be tested using the baseline count to validate assumptions about the mllurnce of handedness. It is licccssaiy. therefore, to keep data for the left and right hand disLinct, The assignment of hands Is as follows; I. Bight hand at 1 minute as observa tion of reduction from baseline fright hand baseline) on all subjects (30 sub jects) . The ohjcctlve of the design will be to test as follows: a. Test the log,* reduction from base line 1 minute after scrubbing with fastart mg broad spectrum antimicrobials, b. Test the initial log,,, reduction from baseline one minute after scrubbing with a substantattvc antimicrobial. e. Test the log,,, reduction from base line 1 minute after scrubbing following 3 days with three consecutive scrubs per day performed at one-hour intervals. Statistical Aspects a. A test of the assumption that the agent produces a given log,, reduction, such as 1-Jog,-, 2-Iog,or 3-log,-, reduc tion will be made using the data from (lie one minute result from the right hand compared to the average baseline uiglit baud baseline). A method like a paired l-test could be used. b. Left hand at a time designated by random assignment to one of six time periods (five subjects in each of .mx groups) will be compared to left hand baseline. The objective here will be to charac terize the trend (in microbial growth) with time up to six hours. It is desirable that the count, over six horns, with fastacting, broad-spectrum antimicrobials not exceed the baseline. It is expected Lliat the count will not exceed baseline hi six hours in the testing of substan tive antimicrobials. Analysis The analyses will be performed first on each replication. There Is replication of the entire test on day two and on day five after three consecutive washes nt hourly Intervals on day three, four, and five. Use the original group assign ments of subjects observed for the same time periods as determined by random allocation. Tests of trends may be done using cither un orthogonal procedure or some suitable regression method. A combined analysis using the results of the three replications Is possible using an appro priate annlysls of variance technique. For example; an analysis of variance ou the total set of experimental results using the model described on page 519 ("Blatislleal Principles In Experimental Design," B. J. Winer. McGraw-Hill Book Company, 19G1) where hours correspond to factor A and replications correspond to lEDERAl REGISTER, VOl. 39, NO. 179--ERIDAV, SEPTEMBER 13, 1974 A$I 00003678 PROPOSED RULES .rmo factor B. Baseline could be Introduced as a covariant. Tests of trends using the orthogonal procedures will be employed. Af'PKNftlX I yuinji'iHefsttlutum (WiiMiiinhon, Uuf 2). Ini'ui X 11)<>--u 1 percent ill 0.075 M jiliuhpiKito builer. pit 7 'I 2. Sampling fluid, (Peterson, Ref. 8 end 0). rotmMliun phoiphAto (monnba.Hlr)--0 4 g. Sodium phn.'ipluUft (UUitVblC)--10 1 g. Triton X-100--i 8 g. DlsiULcd wMcr-- 1 liter. Final pit **7.8, The Glove Juice Test Is required to show the effectiveness of ft product to be labeled for use as a surgical hand scrub. Other handwashing procedures should also be performed If there are Indications for personnel handwashing. The two preferred procedures are the Cade and the Quinn handwashing pro cedures. The details of these tests are published in the literature, following are some comments about these pro cedures are offered. 4. Effectiveness testing of handwash ing products--a. Comments applicable to all handwashing testing procedures. The numbers of micro-organisms present be fore and after scrubbing with various formulations have been enumerated and repotted in the literature over the years. One thing which has not been reported is the Identity of the micro-organisms re moved and those which remain. The spectrum of micro-organisms against which any one of the antimicrobial agents acts is variable. The effect of the prolonged use of such products on the normal human skin flora is essential information for all antimicro bials designed for repeated use. There are indications that replacement populations may indeed occur if certain micro-organisms are removed or sup pressed (Ref. 7 and 81. In addition it is becoming evident that the normal flora of tlie skin may protect against skin in fections. Tiie comments concerning the use of multiple plates in the culturing proce dures as well as the evaluation of specific neutralizers for use in the testing of anti microbial agents apply to all In vivo testing. b. Cade handwashing procedure. This test lias been described by Cade (Ref, 5) and is an adaptation of the Price (19381 handwashing test. This procedure has been widely used to estimate effectiveness. It has also been widely adapted. It has been the practice to use 6-10 subjects for basin tests. The count data aie utilized to compare the mean base line count witli the count after n:.c of the test product. The comparison is most often made as "percent reduction". This lms been the criteria of effectiveness, frequently without further analysis. If one considers Uto Inherent varia tion. the number of subjects is not at all adequate. Other, move sophisticated analysis, such ns analysis of covin lance ami hypothesis testing of whether the re duction meets an established criterion. Is required, rather than simple and possibly misleading percent reduction. Subjects must refrain from the use of all products containing anllmlnoblulH for two weeks pi lor to the test. The period for estab lishment of the bii'.ellnt! moot lor sub jects in the test should be at least two weeks. Sampling for baseline counts should be toward the end of the baseline control period and should be done at least three times. Subjects taking anti biotics or oral contraceptives should be disqualified. A non-antimicrobial soap should be used for washing when microbial counts are to be done. c. Quinn split-use test. This test has been described as a modification of the Cade Test (Quinn. 1954). Tile primary difference is thnt one hand is used as tlie control for the test hand instead of using an established baseline count as the control. Tlie comments made previously con cerning tlie number of subjects in the test apply here. Tlie comments concerning subjects also apply. There is normally no baseline count established. Subjects should re frain from tlie use of products contain ing antimicrobials for at least two weeks prior to tlie test (pre-test period) since many ingredients are substantive. Tlie Panel recommends the establishment of a baseline count during the week follow ing the pre-test period as a good addition to this testing procedure. d Testing health-care personnel hand washing product. Since the result ex pected from tlie use of this type of prod uct is the reduction of tlie transient flora acquired as a result of patient care or as a part of hospital routine, tlie testing must involve the artificial contamination of tiie hands and forearms. This proce dure can be executed by dipping the hands into a liquid culture with at least 10" organisms per ml. and allowing one minute before proceeding. The artificial contamination of tlie hands may also be produced by handling heavily contamin ated materials to simulate actual prac tice. Tlie product under test should be used according to the directions on the label. Since these products are designed to be used with multiple replication, the ef fectiveness testing procedure of hand contamination and washing followed by evaluation of the count of the contam inating organisms should be done at least 25 times in succession. Some period of time should be allowed between repeats. Evaluation of tlie count on tile hands can he done approximately every 5 washes. In order to reliably carry out this test, a murker strain of a millihiiganlsin should be selected for use which is not part of tlie normal liora and which may be easily identified on culture plates. Two organisms frequently selected for this purposp are Serrntia tnrtrepsecn* (pig mented strain) and Bacillus sublitis var. utacr (strain globlgll), Detrlch isolate-- ATCC 9372. Ri> rnrNrrjt (I | ITlro, P. II. " (be Bacteriology of Nor mal Skin; a Now Quantitative Test Applied to a Study of the Bacterial Flora and tho nislofpciout Action of Mechanical Cleans ing," Journal of Infectious Diseases, 03:301310. lO'IB, 131 Williamson, p, "QiiniitMallvn Tlsllrna- t If ill of CULaitfOUh Util 1 1-rlU." "s'1,111 thl.tr na and. Their Hole in /u/rrlioii," Kqilial l.y M.u- hiuh, H. I. and <i. llUdlck-SmUh. MctlrawHill. New York, i!)05. (3) Ulrich. J. A . '"Dynamics of Bactorlal Skill Populations." "Skin Paelerla and Their llnle In In/rrtwnEdited hy Malharh, U. r. and a. Uildlck-ainiLh, McQruw-IIlll, New York. 10115. (4) Englcy, F. and B. P. Dey, "A Universal Neutralizing Medium for Antimicrobial Chemicals." Proceedings of the Chemical Specialty Manufacturers Association (CSMA), Mid-Year Meeting, pp. 100-100. 1D70. (5) Cade. A, It., "A Method for Testing the Dcgermmg Efficiency of Hcxachlorophene Soaps." Journal of the Society of Cosmetic Chemists, 2:281-200, 1051. (G) Peterson, A. F.. "Tho Microbiology of the Hands: Evaluating the Effects of Surgical Scrubs," Developments in Industrial .lfiercibiotogy, 14. 1072, Draft of paper submitted for publication la Included In OTC Volume 020180. (7) Amoncttc. R. A. and R. W. Rosenberg, "Infection of Toe Webs by Oram Negative Bacteria." Archives of Dermatology, 107:7173. 1073. (8) Ehrenkranz, N. J,, D, Taplin and P. Butt, "Antibiotic-Resistant Bacteria on the Nose and Skin: Colonization and Cross-In fection." Antimicrobial Agents and Chemo therapy, 265-2G4, 19GG. (9) Peterson, A, F., "Tlie Microbiology of the Hands: Assessing New Scrubbing Devices and Procedures." Draft of paper submitted for publication Is included Ui OTC Volume 02018G. 5. Effectiveness testing of a patient pre-operative skin preparation. Tiie his torical use and basic effectiveness re quirements are presented under tlie gen eral discussion of efficacy of pre-operative skin preparations. Tlie reader is referred to the definition and discussion of tlie product. There are no established protocols for tho testing of this category of products. From the defined use of the product, the antimicrobial as well as the formulated product, should be tested for basic in vitro data to establish its broad-spectrum activity. (See Guidelines). The in vivo efficacy testing procedures should utilize the skin sampling proce dures in the Guidelines and in the dis cussion of efficacy. Since any given area of skin surface can be tested, the control area can be tlie same location on the other half of tlie same subject (bilateral paired comparison). Since tlie definition states that rapid activity is required, the lime for testing activity should be 30 minutes maximum. Tlie baseline count on tlie control area mulching the test area should be estab lished using cup-scrubbing, tnpc strip ping techniques or oilier appropriate sampling techniques. The same proce dure should be used for skin area treated with the active product, Tlie test must be dans lining an adequate population and with sampling tiom skin areas on var ious parts of tlie body and certainly, in cluding tlie genital areas. It Is essential that the sample from tlie skm be properly neutralized to inactivate active chemical carried over from tho fIOCRAL RCGISUR, VOl. 39, NO. 179--FRIDAY, SEP1FMGCR 13. 1974 ASI 00003679 mio PROPOSED RULES skin. The neutraliser used must be tested tor toxicity to cells and tor efficacy as a neutraliser. The snmplc as well ns the culture conditions must be adequate to determine the range ot organisms which ran he Isolated from the skin. 'Boo t mini tines tor suewoLed media). A mini mum oi iinu-l'.i: icdiieiion will be re turned to establish efficacy 1 or a product labeled as a pre-operative skin prepara tion. 6. Testing 0/ a skin wound cleanser. This product category has been estab lished and defined by this Panel. The reader Is referred to the definition and discussion of product category. Inherent in the definition is the concept of cleans ing and removal of foreign material. Absence of delay in wound healing must be established for a product in this category. The Panel recognizes that the testing of delay In wound healing, particularly In human subjects, is difficult. Animal models have been used with artificially contaminated wounds by some investigators (Ref. 1, 2 and 3). Sec Efficacy. Discussion and Iodophor State ment. There Is a need for the development of procedures to determine whether topi cal products applied to minor skin wounds would delay healing in human subjects. Until adequate human testing procedures are available, data from ani mal models will be required to support safety of a product to be labeled as a skin wound cleanser. XlEirnENr-Fs 1. Dajant, A. 8 , P. I*. Kill and L. W, Wunnam&kcr, "Experimental infection of the Skin in the Hamster Simulating Human Impetigo. 11. Assessment of Various Thera peutic Regimens," Journal of Pediatrics, 48 83-00. 1971. 2. Ectllcli. R. F. I, R. Schmolkn, M. P. Prusak and M. T. Edgerton, "The Molecular Basis for Toxicity of Surfactants in Surgical Wounds," Draft of the Unpublished Paper Is included In OTC Volume 020786. 3. Custer, J., R. F. EcUich, M. Prusak, J, Madden. P. Pauek and O. II, Wangensteen, "Studies in the Management of the Con taminated Wound. V. An Assessment of tho ETectivcncsa of pIllsoHex and Bctadlne Sur gical Scrub Solutions," The American Jour nal of Surgery, 121:672-675, 1971, 7. Effectiveness testing of a skin wound protectant. The reader Is referred to the definition and discussion of a skin wound protectant. From the definition, a skin wound protectant must act as a physical barrier. The testing of barrier materials ran be done with a model system and lluorescent pnrllclc challenge to the sys tem with subsequent detection of the challenge particles on the other side of the barrier. A model for this challenge will have to be developed. The second aspect of this definition to be tested Is the lark of promotion of the growth of microorganisms. This charac teristic can be tested first In an animal model system In which a wound Is arti ficially produced In the animal skin. The extent of the microblnl growth In such a system may be tested with various levels of microbial contamination added to the wounds. The growth or reduction of growth could be followed by appropriate skin sampling tccImlMiies pci tunned In a time sciles after uppllcatlop of the test product. The growth may also be assessed by using an Inoculum lower than the minimum Infective dose of a pnthogen for the animal followed bv determination of Infections in the treated animals. Animal tests should be followed with human testing. At the current level of development of techniques, artificial con tamination in humans cannot be recom mended. However, a standard wound, such as that produced by a skin punch biopsy, may be used to test whether the product to be labeled as a skin wound protectant promotes microbial growth in a minor wound. Another approach in the production of an artificial injury for human testing which might lie used Is the icpetitive skin stripping technique of Marples (Ref. 1). This procedure uses the repeated removal of skin layers with cellophane tape until tire glistening layer is exposed. This minjor injury can rea sonably be used for these testing pur poses hut would simulnte only very minor wounds. Skin graft donor sites might also be used. With any model selected for testing, particular attention should be given to testing the growth of anaerobic micro organisms where an occlusive system Is used. It Is expected that up-to-date techniques for Lire isolation and growth of anaerobes would be employed. REFERENCES (l) Margies, It. R. anti A. M. Kllgm.m, "Itartrrlal Infection of Superficial Wounds: A Human Model for Staph i/tocoerus aureus," Fpulrrnial Wonvd Itrahng, Edited by Mni- bach, H. I. and D. T. Rovce, Yearbook Medi cal Publishers, Inc , Chicago, 1072. Therefore, puisuant to provisions of tho Federal Food, Drug, and Cosmetic Act (secs. 201. 502, 505, 701, 52 Stat. 1040-42 as amended, 1055-56 as amended by 70 Stat. 019 and 72 Stat. 940; 21 U.S.C. 321, 352, 355, 371) and the Administra tive Procedure Act fsecs. 4, 5, 10, 60 Stat, 238 and 243 as amended; 5 U.S.C. 553, 554, 702, 703, 704) and under authority delegated to him <21 CFIt 2 120), the Commissioner of Food nnd Drugs pro poses that Subchnplcr D be amended, pursuant to the recommendations of the Advisory Review Panel on Over-thcCounter Topical Antimicrobial Drugs, by adding a new Part 333. effective 6 months after publication of the finnl monograph In the FenEnAL Reoisteii, to rend ns fol lows: PART 333--TOPICAL ANTIMICROBIAL PRODUCTS FOR OVER-THE-COUNTER HUMAN USE tire. nan 1 333 3 Subpart A--Gonaial provltians Scope. DctlulUom. 333.30 333.-10 Subplot O--Actlw* IngradiwntR Patient prc-opcratlvo skin prepara tion- Skin wound rlran-.cr, Subpart C--T,sling Procedure* 333 60 Preservative testing. See, 313 70 313 73 33.1111) ,-|,n ns 333 00 333 llf> 333 O') Subport IV--Labeling Antimicrobial unap 7Pal i h-earn pmiiimru-l haiifliviiMh raMcut, pre-operative Akin prrpmu- I Ion i'.l-.ln aou-rpua, Skin wound rle.iN'er Skin wound plot... turn Surgical hand m/iuIc Auriioiurv: I-'edcral t'orld, Drag. and Co-.. indie Act |f.ees 201. .302. fio.5, 701, 62 fllal 1040 -12 n) amended, jo.3,3 50 as amended by 72 still mil and 72 Slat USB; (21 U.S.C. 321. 3,32, 35.3, 371), and Administrative Frocegurc Act (secs. 4, 6, 10, Cl) Slat. 238 and 243. as amended; 6 U.SC 553, 554, 702, 703. 704). Subpart A--General Provisions .7.7.7,1 Scop,-. An over-the-counter antimicrobial product In a form suitable for topical use is gcneially recognized as safe and effec tive and is not misbranded if It meets each of the following conditions and cacl) of the general conditions estab lished in 5 330.1 of this chapter. 73.7,7 Di-firiiliun-i. For toplenl preparations when applied at acceptable use concentrations 'the dilution recommended for use ns distin guished from marketed concentrates) as used in this part: fa' Antimicrobial soap, A soap con taining an active ingredient with in vitro and In vivo activity against skin micro organisms (I)' Ucatth-carc personnel handwash. A safe, nonirnlating preparation de signed for frequent use which reduces the number of transient microorganisms on intact skin to an Initial baseline level after adequate washing, rinsing, and dry ing. If the preparation contains an anti microbial agent, it should be broadspcctrum, fast-acting, and if possible, persistent. (c) Patient pre-operative skin prepa ration. A safe, fast-acting, broad- spcctrum antimicrobial-containing prep aration which significantly reduces the number of micro-organisms on Intact skin. <d) Ekin antiseptic. A safe, non- irrilatliig, antimicrobial - containing preparation which prevents overt skin infection. Claims stating or implying an cITcct against micro-organisms must be supported by controlled human studies which demonstrate prevention of infec tion. (c) 57,i)i wound cleanser. A safe, nonImlaling, liquid ptemu'uUou (or product to be U cil will) wilier) which assists In the removal of foreign material from small superficial wounds and docs not delay wound healing. If) .S7,/. wound protectant, A safe, non-lmlating preparation applied to small i leansed wounds which piovldes a Pioteclive (physical and/or chemical> harrier and neither delava healing nor favors the giowlli of micro-organisms. <g> Surgical ham! scrub. A safe, non-lrrilatlng anti microbial-containing preparation which significantly minces I lie number of micro-organisms on the intnet skin. A surgical hand scrub should FEDERAL REGISTER, VOL. 39, NO. 179--FRIDAY, SEPTEMBER 13. 1974 ASI 00003680 PROPOSCO RULES :t:tl li be broad-spectrum, fast-acting, and per sistent. Subpart B--Active Ingredients 333.30 I'uticnl prc-opcriilivc akin prrp- i.i> Ail.., rmreilient. TVic active lnglriilChl ut the piuciuct cotiMsts of the f'ullov. mg v. itiun the maximum dosage limit established: (1) Tincture o/ iodine. Iodine tincture contains not less than 1.8 grams and not more than 2.2 grams of Iodine (I), and not-less than 2.1 grams and not more than 2.6 grams of sodium Iodide (Nal) in each 100 ml. of 44-50 percent ethyl alco hol or an appropriate denatured alcohol. 333.40 Skin wound cleanser. <al Active ingredients. The active In gredients of the product consists of one or more of the following within any max imum dosage limit established: (1) Quaternary ammonium containing active ingredients. Quaternary ammo nium compounds (as Bcnzalkouium chlo ride. Benzethonium chloride and Methylbenzethonium chloride) limited to a use concentration not greater than 1/750. All preservative systems Included in any such formulation must be tested accord ing to the procedure described in The United States Pharmacopeia XVIII (page 846). (2) Ilexylrcsorcinol. Hcxylresorcinol limited to a use concentration not greater than 1/1000. Subpart C--Testing Procedures 333.60 I'rcserwilivc testing. All antimicrobial Ingredients used singly or as part of a preservative sys tem for a topical product identified In 5 333.3 shall be tested to establish the minimum effective preservative con centration for each product formula tion. Determine the minimum effective preservative concentration according to the procedures described In the United States Pharmacopeia XVIII (page 845'. The resulting data shall be submitted to the Food and Drug Administration for approval prior to use. Subpart D--Labeling 333.70 Antimicrobial <oap. The labeling of the product may con tain any phrase in the definition of an antimicrobial soap established in I 333.3 (a). Labeling may also Include the phrase(s): "Antimicrobial soap", "anti bacterial soap", "reduces odor", "deodor ant soap", 333.75 Ilealth-care personnel hand wash. The labeling of the product may con tain any phrase in the definition of a hpnilh-carc personnel handwash estab lished In 5.1.l3.3ib>. i.uliciing may also Include Llio pliriuscc.' "I ice leases bac teria on the skin", "i educes risk and/or elmure of eross-lnfcetton", "recoin* inetiUud tor icpoiitau im0". 333.80 I'uliini |>r,-o|HTiili,c -kin prrpnrnlioti. la) Indications. The labeling of the product may contain any phrase in the definition of a patient pro-operative skin preparation established in 5 333.3(c). Labeling may also include the phrasels): "kills microorganisms", "reduces the number of microorganisms in the treated area", "bvoadspectrum" (if such applies). (b) Warnings. The labeling of tire product contains the following warnings: (1) "May delay healing or Irritate broken skin". (2) "Do not bandage". (c) Directions lor use. The labeling of the product contains the statement, "Ap ply to (paint) the operative site prior to surgery and remove immediately upon drying after application with 70 per cent alcohol, or use as directed by a physician". 333.85 Skin imii-cptic. (a) Indications. The labeling of tho product may contain any phrase in the definition of a skin antiseptic established in 5 333.3(d). Labeling may also include the plnaso<s>: "Prevents skin infection", "controls infection", "degerming", "kills germs", "bacteriostatic'', "bactericidal", "reduces the risk of infection and crossinfection", "mircobiocidal", "first-aid product". (b) Directions for use. Tile labeling of the product shall contain the state ment, "Apply to affected area", and con tain the recommended dosage for use. timo interval (if any) and method by which the product shall be used to pre vent overt skin infection for those par ticular organisms for which the product is. generally recognized as safe and effective. 333.DO Skin wound dcmi^r. (a) Indicaliotis. The labeling of the product may contain any phrase in the definition of a skin wound cleanser estab lished in 5 333.3(e). Labeling may also include the phrasels): "To clean super ficial wounds", "wash superficial (small) wounds", "aid In removal of foreign materials such as dirt and debris", "first- aid product". (b) Warnings. The labeling tor Quater nary ammonium containing products contains the following warnings: 111 Fur products ntnikctcd ns ronrniliali'v i|> "Until Inn: May cause eye Iri if iil.lon fir rye iIiuuukc unlc'.'i diluted " Hit Dilute before each use to avoid IW'llne (2) "Use of sol ut imi with . tli i .tv,dressing is not advisable". (c) Directions /or \u^\ The lain ling of the product shall contain the .statement, "Apply to affected area", and the recom mended dosage for use and method by which tho product shall be used to cleanse a small wound without further damage to tho injured area. 333.05 Skin wound prolrctunt. (a) Indications. The labeling of tile product may contain any phrase in the definition of a skin wound protectant established In 333.3(f) of this chapter. Labeling may also include the phrasels) : "Protects against contamination", "pro tectant", "protects wounds", "first-aid product". (b) Warnings. The labeling of the product shall contain the following warnings: (1) "Should not be used for lavge or deep wounds." (2) "Should not be used for more than (time certain) days except upon advice and supervision of a physician." (c) Directions lor use. Tile labeling of the product shall contain the statement, "cleanse wound thoroughly before ap plying", and contain the recommended dosage and the method by which the product should be used. 333.99 Surgical Iiiiiii! scrub. The labeling of the product may contain any phrase in the definition of a surgical hand scrub established In 5 333 3`g>. Interested persons are invited to sub mit their comments in writing (prefer ably in (mintunlicnte) regarding this proposal on or before November 12, 1974. Such comments should be addressed to the Office of tlie Hearing Clerk, Food and Drug Administration, Room 4-65, 5G00 Fishers Lane, Rockville, MD 20852, and may be accompanied by a memoran dum or brief in support thereof. Addi tional comments replying to any com ments so filed may also be submitted on or before December 12, 1974. Received comments may bo seen in tho above office during working hours, Monday through Friday. Dated: September 6, 1914. A. M. Schmidt. Commissioner o/ Food and Drugs. [Fit Doc.74 -3IOG6 Filed 0-12-74;8:4S om| No. 173---Pt. II- FEDERAL REGISTER, VOL. 39, NO. 179--FRIDAY, SEPTEMBER 11, 1974 AS I 0000-3681