NOTICES 38163 such written comments upon the ap­ be used by Soo Line only for overhead City, Hinckley, and Sandstone. The plicant, the Secretary of Transporta­ traffic. Soo Line, would not serve any transaction proposed by Soo Line is tion, the Attorney General and all par­ local industries located on^the line be­ subject to the execution of an appro­ ties of record in Finance Docket No. tween Schley (Soo Junction), Minn., 28583 (Sub-1F). priate agreement between Soo Line and Superior, Wis. and BN. This application has been ac­ By the Commission. Interested persons may participate formally in this proceeding by submit­ cepted and assigned Finance Docket H. G. H omme, Jr., ting written comments in regard to No. 28583 (Sub-No. 6F). Acting Secretary. the application. Such submissions This application has been filed in re­ [FR Doc. 78-24076 Filed 8-24-78; 8:45 am] shall indicate the proceeding designa­ sponse to Finance Docket No. 28583 tion (F.D. No. 28583 (Sub-5F)), and the (Sub-No. IF), Burlington Northern, original and two copies thereof shall Inc.—control and merger—St. Louis- [7035-01] be filed with the Secretary, Interstate San Francisco Railway Co. Soo Line is Commerce Commission, Washington, seeking the imposition of these track­ [Finance Docket No. 28583 (Sub-5F)] D.C. 2Q423, not later than October 10, age rights as a condition in the event 1978. Such written comments shall in­ the BN-Frisco merger is approved by SOO LINE RAILROAD CO. clude the following: the person’s posi­ tion, e.g., party protestant or party in the Commission in order to offset pro- Trackage Rights Over Burlington Northern, Inc., jeted gross revenue losses. This pro­ Between Schley (Soo Junction), Minn, and support, regarding the proposed trans­ Superior, Wis. action; and specific reasons why ap­ ceeding will be consolidated with Fi­ proval would or would not be in the nance Docket No. 28583 (Sub-No. IF). Soo Line Railroad Co. (Soo Line), a public interest. This proceeding has Soo Line operates approximately Minnesota corporation, with general been set for oral hearing. Additionally, 4,588 miles of railroad in the States of offices at 804 Soo Line Building, P.O. interested persons who do not intend Illinois, Michigan, Minnesota, Mon­ Box 530, Minneapolis, Minn. 55440 to participate formally in a proceeding tana, North Dakota, South Dakota, represented by F. W. Crouch, vice but who desire to comment thereon, and Wisconsin. Canadian Pacific Lim­ president and general counsel, and may file such statements and informa­ Robert G. Gehrz, general solicitor, ited (CP) controls Soo Line and had tion as they may desire, subject to the the right to vote 56.23 percent of Soo each of the foregoing address, hereby filing and service requirements speci­ gives notice that on the 26th day of fied herein. Persons submitting writ­ Line’s common stock, as of March 10, July 1978, it filed with the Interstate ten comments to the Commission 1978. Soo Line is operated indepen­ Commerce Commission at Washing­ shall, at the same time, serve copies of dently of CP. ton, D.C. an application under section such written comments upon appli­ The trackage involved is approxi­ 5(2) of the Interstate Commerce Act cant, the Secretary of Transportation, mately 126.4 miles in length and would for a decision approving and authoriz­ Attorney General, and all parties of be used by Soo Line only for overhead ing the grant of trackage rights to record in Finance Docket No. 28583 traffic. Soo Line would not serve any permit Soo Line to operate its own lo­ (Sub-1F). local industries located on the line be­ comotives, cars and trains with its own By the Commission. tween Bald Eagle, Minn., and Superi­ crews for “bridge” purposes, only be­ or, Wis. tween Schley (Soo Junction), Minn., H. G. H omme, Jr., and Superior, Wis., over trackage of Acting Secretary. Interested persons may participate Burlington Northern, Inc. (BN), and formally in this proceeding by submit­ to construct an appropriate connec­ [FR Doc. 78-24077 Filed 8-24-78; 8:45 am] ting written Comments in regard to tion at Superior, Wis. The transaction the application. Such submissions proposed by Soo Line is subject to the [7035-01] shall indicate the proceeding designa­ execution of an appropriate agree­ tion (F.D. No. 28583 (Sub.-No. 6F)), ment between Soo Line and BN. This [Finance Docket No. 28583 (Sub-No. 6F)] and the original and two copies there­ application has been accepted and as­ of shall be filed with the Secretary, In­ signed Finance Docket No. 28583 (Sub- SOO LINE RAILROAD CO. 5F). terstate Commerce Commission, This application has been filed in re­ Trackage Rights Over Burlington Northern, Inc., Washington, D.C. 20423, not later sponse to Finance Docket No. 28583 Between Bald Eagle, Minn., and Superior, Wis. than October 10, 1978. Such written (Sub-1F), Burlington Northern, Inc.— Soo Line Railroad Co. (Soo Line), a comments shall include the following: control and merger—St. Louis-San Minnesota corporation, with general The person’s position, e.g., party prot- Francisco Railway, Co. Soo Line is offices at 804 Soo Line Building, P.O. estant or party in support, regarding seeking the imposition of these track­ Box 530, Minneapolis, Minn. 55440. the proposed transaction, and specific age rights as a condition in the event Represented by F. W. Crouch, Vice reasons why approval would or would the BN-Frisco merger is approved by President and General Counsel, and not be in the public interest. This pro­ the Commission in order to offset pro­ Robert G. Gehrz, General Solicitor, ceeding has been set for oral hearing. jected gross revenue losses. This pro­ each of the foregoing address, hereby Additionally, interested persons who ceeding will be consolidated with Fi­ gives notice that on the 26th day of do not intend to participate formally nance Docket No. 28583 (Sub-1F). July 1978, it filed with the Interstate in a proceeding, but who desire to Soo Line operates approximately Commerce Commission at Washing­ 4,588 miles of railroad in the States of comment thereon, may file such state­ ton, D.C,, an application under section ments and information as they may Illinois, Michigan, Minnesota, Mon­ 5(2) of the Interstate Commerce Act tana, North Dakota, South Dakota, for a decision approving and authoriz­ desire, subject to the filing and service and Wisconsin. Canadian Pacific Lim­ ing the grant of trackage rights to requirements specified herein. Persons ited (CP) controls Soo Line and had permit Soo Line to operate its own lo­ submitting written comments to the the right to vote 56.23 percent of Soo comotives, cars and trains with its own Commission shall, at the same time, Line’s common stock, as of March 10, crews for “bridge” purposes only be­ serve copies of such written comments 1978. Soo Line is operated indepen­ tween Bald Eagle, Minn., and Superi­ upon the Applicant, the Secretary of dently of CP. or, Wis., over trackage of Burlington Transportation, the Attorney General, The trackage involved is approxi­ Northern, Inc. (BN), via White Bear and all parties of record in Finance mately 146.2 miles in length and would Lake, Forest Lake, Rush City, Pine Docket No. 28583 (Sub-No. IF).

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 38164 NOTICES By the. Commission. This application has been filed in re­ ceivers it currently serves through re­ sponse to Finance Docket No. 28583 ciprocal switching arrangements. H. G. H omme, Jr., Acting Secretary. (Sub-No. IF), Burlington Northern, Interested persons may participate Inc.—control and merger—St. Louis- formally in a proceeding by submitting [FR Doc. 78-24078 Filed 8-24-78; 8:45 am] San Francisco Railway Co. SP is seek­ written comments in regard to the ap­ ing the imposition of these trackage plication. Such submissions shall indi­ rights as a condition in the event the cate the proceeding designation (F.D. [7035-01] BN-Frisco merger is approved by the No. 28583 (Sub-No. 18F)), and the Commission in order to offset project­ original and two copies thereof shall [Finance Docket No. 28583 (Sub-No. 18F)] ed gross revenue losses. This proceed­ be filed with the Secretary, Interstate ing will be consolidated with Finance Commerce Commission, Washington, SOUTHERN PACIFIC TRANSPORTATION CO. Docket No. 28583 (Sub-No. IF). D.C. 20423, not later than October 10, SP and its subsidiaries operate ap­ 1978. Such written comments shall in­ Trackage Rights Over Burlington Northern, Inc., clude the following: the persons posi­ and the Union Pacific Railroad Co. Between proximately 13,356 miles of railroad in the Connection of BN and the Portland Ter­ the States of Arizona, Arkansas, Cali­ tion, e.g., party protestant or party in minal Railroad Co. and (1) Trackage Serving fornia, Illinois, Louisiana, Missouri, support, regarding the proposed trans­ North Rivergate and (2) the Barnes Yard of Nevada, New Mexico, Oregon, Tennes­ actions; and specific reasons why ap­ see, Texas, and Utah. The Southern proval would or would not be in the Union Pacific Railroad Co. Pacific Co. owes 100 percent of the public interest. This proceeding has Southern Pacific Transportation Co. stock of SP. been set for oral hearing. Additionally, (SP), One Market Plaza, San Francis­ The trackage involved is approxi­ interested persons who do not intend co, Calif. 94105, represented by mately 16.3 miles in length. SP would to participate formally in a proceed­ Charles W. Burkett, general solicitor, use the line to directly serve the Ri- ing, but who desire to comment there­ of the same address, hereby gives vergate industrial area. SP would pro­ on, may file such statements and in­ notice that on the 27th day of July vide the service over the BN double formation as they may desire, subject 1D78, it filed with the Interstate Com­ main track from its point of connec­ to the filing and service requirements merce Commission at Washington, tion with trackage of the Portland specified herein. Persons submitting D.C., an application under section 5(2) Terminal Railway Co. (1) to a connec­ written comments to the Commission of the Interstate Commerce Act for a tion with North Rivergate trackage at shall, at the same time, serve copies of decision approving ’and authorizing North Portland and (2) to a connec­ such written comments upon Appli­ the grant of trackage rights to permit tion with the tracks of UP near UP cant, the Secretary of Transportation, SP to operate over trackage of Bur­ Barnes Yard; thence over the UP the Attorney General, and all parties lington Northern, Inc. (BN) and the trackage over which BN has rights of record in Finance Docket No. 28583 Union Pacific Railroad Co. (UP) in through UP’s Barnes Yard to the (Sub-No. IF). Portland, Oreg. The transaction pro­ south Rivergate industrial lead tracks. posed by SP is subject to the execu­ All of this trackage is in the city of By the Commission. tion of an appropriate agreement ^be­ Portland, 'Oreg. Currently, SP serves tween SP, BN, and UP. This applica­ the Rivergate area through reciprocal H.G. H o m m e , Jr., tion has been accepted and assigned switching with BN and UP. SP will use Acting Secretary. Finance Docket No. 28583 (Sub-No. the trackage rights to provide im­ 18F). proved service to the shippers and re­ [FR Doc. 78-24089 Filed 8-24-78; 8:45 am]

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 38165

sunshine act meetings

This section of the FEDERAL REGISTER contains notices of meetings published under the “ Government in the Sunshine Act” (Pub. t. 94-4 0 9 ), 5 U.S.C. 552b(e)(3).

eral R e g is t e r for publication, and these changes or the delayed receipt CONTENTS mailed to parties to docketed cases af­ of our notices. Item fected by the change. We regret any [S-1699-78 Filed 8-23-78; 8:55 am] Civil Aeronautics Board...... 1, 2, 3 inconvenience that may be caused by Commission on Civil Rights...... 4 these changes or the delayed receipt Commodity Futures Trading of our notices. [6320-01] Commission...... 5, 6, 7 [S-1698-78 Filed 8-23-78; 8:55 am ]. Federal Energy Regulatory 3 Commission...... 8 [M-156, August 17, 1978] * Federal Home Loan Mortgage Corporation-...... 9 [6320-01] CIVIL AERONAUTICS BOARD. Federal Reserve System (Board 2 TIME AND DATE: 10 a.m., August 24, of Governors)...... 10 CIVIL AERONAUTICS BOARD. 1978. PLACE: Room 1027, 1825 Connecticut Notice of addition of item to the Avenue NW., Washington, D.C. 20428. [6320-01] August 23, 1978, Agenda; M-155, Amdt. 2, August 18, 1978. SUBJECT: Oral Argument—Docket 1 32786, Philadelphia-Bermuda Nonstop TIME AND DATE: 1:30 p.m., August Proceeding. CIVIL AERONAUTICS BOARD. 23, 1978. STATUS: Open. Notice of addition of item to the PLACE: Room 1027, 1825 Connecticut August 23, 1978, agenda; M-155, amdt. Avenue NW., Washington, D.C. 20428. PERSON TO CONTACT: 1, August 18,1978. SUBJECT: 16a. Docket 27631, Fore- Phyllis T. Kaylor, the Secretary, TIME AND DATE: 1:30 p.m., August most International Tours v. Qantas 202-673-5068. 23, 1978. Airways, Enforcement Proceeding—Pe­ CS-1700-78 Filed 8-23-78; 8:58 am] titions for review of initial decision PLACE: Room 1027, 1825 Connecticut holding that Qantas’ inclusive tour op­ Avenue NW., Washington, D.C. 20428. eration was not unlawful (Memo 8131, [6335-01] OGC). SUBJECT: 9a. Dockets 32364, 32577 4 and 32365, Application of Air New STATUS: Open. England to amend its certificate to U.S. COMMISSION ON CIVIL allow it to serve Hartford/Springfield PERSON TO CONTACT: RIGHTS. on a subsidy-ineligible basis; Applica­ Phyllis T. Kaylor, the Secretary, DATE AND TIME: Wednesday, tion of Allegheny to amend its certifi­ 202-673-5068. August 30,1978, 9 a.m. to 12 noon; 1:30 cate for Route 97 to allow nonstop SUPPLEMENTARY INFORMATION: p.m. to 4:30 p.m. Thursday, August 31, Burlington-Hartford authority; Appli­ 1978, 9 a.m. to 12 noon. cation of Air New England for exemp­ Because of the time consumed in tion authority to serve Hartford/ making changes in the draft order in PLACE: Room 512, 1121 Vermont Springfield (BPDA). the Office of the General Counsel Avenue NW., Washington, D.C. after submission for supervisory ap­ STATUS: Open to the public. STATUS: Open. proval, this item did not reach the PERSON TO CONTACT: Secretary in time to place it on the MATTERS TO BE CONSIDERED*. calendar for August 23. In order to Wednesday, August 30, 9 a.m. to 12 Phyllis T. Kaylor, the Secretary, meet the announced target date of noon. 202-673-5068. August 25, 1978, however, Board I. Approval of agenda. SUPPLEMENTARY INFORMATION: action is required by August 23. Ac­ II. Approval of minutes from last meeting. Consideration of this item will insure cordingly, the following Members have * III. Staff Director’s Report: that the Board will make its show voted that agency business requires A. Status of fluids. the addition of Item 16a to the August B. Personnel report. cause order final before the promised C. Correspondence: deadline of September 1, 1978. Accord­ 23, 1978 agenda and that no earlier an­ 1. Letter from McDonald Fraser re ingly, the following members have nouncement of this addition was possi­ pregnancy disability. voted that agency business requires ble: 2. Letter from OMB Director James the addition of Item 9a. to the August Chairman, Alfred E. Kahn McIntyre re Commission recommenda­ 23, 1978, agenda and that no earlier Vice Chairman, G. Joseph Minetti tion on affirmative action in Cleve­ announcement of this addition was Member, Richard J. O’Melia land. Member, Elizabeth E. Bailey 3. Letter from Reorganization Task possible: Force Director Jeffrey Miller re Com­ Chairman, Alfred E. Kahn All amendments to previously an­ mission comments. Vice Chairman, G. Joseph Minetti nounced agendas are publicly posted D. Office Director’s reports. IV. Report on Civil Rights Developments Member, Richard J. O’Melia at the Board's offices, sent to the F e d ­ Member, Elizabeth E. Bailey in the Rocky Mountain Region. eral R e g is t e r for publication, and V. Approval of Contract for Followup to All amendments to previously an­ mailed to parties to docketed cases af­ Battered Women Consultation. nounced agendas are publicly posted fected by the change. We regret any VI. Action on Recommendation re Women at the Board’s offices, sent to the Fed­ inconvenience that may be caused by in Poverty Report.

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38166-38204 SUNSHINE ACT MEETINGS

VII. Discussion of Advisory Committee for PLACE: 2033 K Street NW., Washing­ TIME AND DATE: 2:30 p.m., August Pacific Trust Territories. ton, D.C., 8th floor conference room. 31, 1978. MATTERS TO BE CONSIDERED: STATUS: Closed. PLACE: 1700 G Street NW., sixth Wednesday, August 30, 1978, 1:30 p.m. MATTERS TO BE CONSIDERED: floor, Washington, D.C. to 4:30 p.m. Judicial session. STATUS: Open meeting. Review of School Desegregation Update. CONTACT PERSON FOR MORE IN­ CONTACT PERSON FOR MORE IN­ MATTERS TO BE CONSIDERED: FORMATION: FORMATION: Thursday, August 31, 9 a.m. to 12 noon. Jane Stuckey, 254-6314. Mr. Henry Judy, 202-789-4734. [S-1703-78 Piled 8-23-78; 8:55 am] Review of School Desegregation Update MATTERS TO BE CONSIDERED: (continued). FOR FURTHER INFORMATION [6351-01] Consideration of Corporation Bylaws. Consideration of New Building Status PLEASE CONTACT: 7 Report. Loretta Ward, Publications Office, COMMODITY FUTURES TRADING Consideration of Foley Building Lease. 254-6697. COMMISSION. Consideration of Refinance Loans. [S-1701-78 Piled 8-23-78; 8:55 am] TIME AND DATE: 11 a.m., September No. 175, August 23, 1978. 1, 1978. R onald A. Snider, [6351-01] PLACE: 2033 K Street NW., Washing­ Assistant Secretary. 5 ton, D.C., 8th floor conference room. [S-1707-78 Piled 8-23-78; 3:32 pm] COMMODITY FUTURES TRADING STATUS: Closed. COMMISSION. MATTERS TO BE CONSIDERED: TIME AND DATE: 10 a.m., August 29, Market surveillance matters. [6210-01] 1978. CONTACT PERSON FOR MORE IN­ 10 PLACE: 2033 K Street NW., Washing­ FORMATION: BOARD OF GOVERNORS OF THE ton, D.C., 5th floor hearing room. Jane Stuckey, 254-6314. FEDERAL RESERVE SYSTEM. STATUS: Parts of this meeting will be [S-1704-78 Piled 8-23-78; 8:55 am] “FEDERAL REGISTER” CITATION open to the public. The rest of the OF PREVIOUS ANNOUNCEMENT: meeting will be closed to the public. [6740-02] 43 FR 37332, August 22, 1978. MATTERS TO BE CONSIDERED: 8 PREVIOUSLY ANNOUNCED TIME Portions open to the public: FEDERAL ENERGY REGULATORY AND DATE OF THE MEETING: 11 a.m., Friday, August 25,1978. Minimum financial requirements. COMMISSION. Request by the New York Coffee and “FEDERAL REGISTER” CITATION CHANGES IN THE MEETING: Addi­ Sugar Exchange for approval of lower daily OF PREVIOUS ANNOUNCMENT: 43 tion of the following closed items to price fluctuation limits in sugar. Pinal rule imposing a temporary moratori­ FR 37073, published August 21, 1978. the meeting: um on the offer and sale of leverage con­ PREVIOUSLY ANNOUNCED TIME 1. Proposals relating to mandatory retire­ tracts. AND DATE OF MEETING: 10 a.m., ment for Federal Reserve System employ­ ees. Portions closed to the public: August 23, 1978. 2. Appointment of an officer at a Federal Enforcement matters/institution of ad­ CHANGE IN THE MEETING: The Reserve Bank. (This matter was previously ministrative proceedings. following item was added: announced for a meeting on Friday, August 18, 1978.) CONTACT PERSON FOR MORE IN­ Item No., Docket No., and Company 3. Personnel appointments within the FORMATION: Board’s staff. (This matter was previously CAM-3. RM78-19, Delegation of the Com­ announced for a meeting on Wednesday, Jane Stuckey, 254-6314. mission’s Authority to Various Staff Office Directors. August 16, 1978.) [S-1702-78 Piled 8-23-78; 8:55 am] K enneth F. P lumb, CONTACT PERSON FOR MORE IN­ Secretary. FORMATION: [6351-01] [S-1705-78 Piled 8-23-78; 11:50 am] Mr. Joseph R. Coyne, Assistant to the Board, 202-452-3204. 6 [6720-02] COMMODITY FUTURES TRADING Dated: August 23,1978. COMMISSION. 9 G r iffith L. G arwood, Deputy Secretary of the Board. TIME AND DATE: 10 a.m., August 30, FEDERAL h o m e lo a n m o r t ­ 1978. g a g e CORPORATION. [S-1706-78 Piled 8-23-78; 3:32 pm]

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 FRIDAY, AUGUST 25, 1978 PART II

DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Food and Drug Administration

SUNSCREEN DRUG PRODUCTS FOR OVER- THE-COUNTER HUMAN DRUGS

Proposed Safety, Effective and Labeling Conditions 38206 PROPOSED RULES from the monograph on the basis of a In accordance with § 330.10(a)(2) (21 [4110-03] determination by the Panel that the CFR 330.10(a)(2)), all data and infor­ available data are insufficient to clas­ mation concerning OTC sunscreen DEPARTMENT OF HEALTH, sify such conditions under either (1) drug products submitted for considera­ EDUCATION, AND WELFARE or (2) above; and (4) the conclusions tion by the Panel have been handled and recommendations of the Panel to as confidential by the Panel and FDA. Food and Drug Administration the Commissioner. The minutes of the All such data and information will be [21 CFR Part 352] Panel meetings are on public display put on public display at the office of in the office of the hearing Clerk the Hearing Clerk, Food and Drug Ad­ [Docket No. 78N-0038] (HFA-305), Food and Drug Adminis­ ministration, after September 25, 1978, tration (address given above). except to the extent that the person SUNSCREEN DRUG PRODUCTS FOR OVER-THE- The purpose of issuing the Panel’s submitting it demonstrates that it still COUNTER HUMAN USE unaltered conclusions and recommen­ falls within the confidentiality provi­ Establishment of a Monograph; Notice of dations is to stimulate discussion, eval­ sions of 18 U.S.C. 1905 or section Proposed Rulemaking uation, and comment on the full sweep 301(j) of the Federal Food, Drug, and of the Panel’s deliberations. The Com­ Cosmetic Act (21 U.S.C. 331(j)). Re­ AGENCY: Pood and Drug Administra­ missioner has not yet fully evaluated quests for confidentiality should be tion. the report; the Panel’s findings are submitted to William E. Gilbertson, ACTION: Proposed rule. being issued as a formal proposal to Bureau of Drugs (HFD-510) (address SUMMARY: This proposed rule would obtain public comment before the given above). establish conditions for the safety, ef­ agency reaches any decision on the Based on the conclusions and recom­ fectiveness, and labeling of over-the- Panel’s recommendations. The report mendations of the Panel, the Commis­ counter (OTC) sunscreen drug prod­ has been prepared independently of sioner proposes the following: ucts. The proposed rule, based on the the Food and Drug Administration 1. That the conditions included in recommendations of the Panel on (FDA). It represents the best scientific the monograph, under which the drug Review of Topical Analgesic including judgment of the Panel members but products would be generally recog­ antirheumatic, otic, bum, and sunburn does not necessarily reflect the agency nized as safe and effective and not treatment and prevention drugs is part position on any particular matter con­ misbranded (category I), be effective of the Pood and Drug Administra­ tained in it. 30 days after, the date of publication tion’s ongoing review of OTC drug The Commissioner recognizes that of the final monograph in the F ederal products. extensive changes will result in the R e g is t e r . current marketing practices of these 2. That the conditions excluded DATES: Comments by November 24, products if the Panel recommenda­ from the monograph because they 1978; reply comments by December 26, tions are fully implemented. The would cause the drug to be not gener­ 1978. Panel’s recommendations include ally recognized as safe and effective or ADDRESSES: Written comments to many labeling revisions. One of these to be misbranded (category II), be the Hearing Clerk (HFA-305), Pood labeling recommendations is the state­ eliminated from OTC drug products and Drug Administration, Room 4-65. ment “Overexposure to the sun may effective 6 months after the date of 5600 Fishers Lane, Rockville, Md. lead to premature aging of the skin publication of the final monograph in 20857. and skin cancer. The liberal and regu­ the F ederal R e g is t e r , regardless lar use over the years of this product whether further testing is undertaken FOR FURTHER INFORMATION may help reduce the chance of prema­ to justify their future use. CONTACT: ture aging of the skin and skin 3. That the conditions excluded William E. Gilbertson, Bureau of cancer.’” As with other of the Panel’s from the monograph because the Drugs (HFD-510), Food and Drug recommendations, the Commissioner available date are insufficient (catego­ Administration, Department of is not at this time making a final deci­ ry III) to classify such conditions health, Education, and Welfare, 5600 sion with regard to this labeling. How­ either as category I or category II be Fishers lane, Rockville, Md. 20857, ever, he finds it necessary to comment permitted to remain on the market, or 301-443-4960. that the issue is important and re­ to be introduced into the market after SUPPLEMENTARY INFORMATION: quires careful study. Because of the the date of publication of the final Pursuant to part 330 (21 CFR Part critical nature of the disease condi­ monograph in the F ederal R e g iste r , 330), the Commissioner of Food and tions involved, the wording of any provided that FDA receives notifica­ Drugs received on December 14, 1977, claim concerning them must be very tion of testing in accordance with a report of the Advisory Review Panel carefully considered especially because § 330.10(a)(13) (21 CFR 330.10(a)(13)). on Over-The-Counter (OTC) Topical three of the seven panel members The Panel recommended that a period Analgesic, Antirheumatic, Otic, Burn, oppose the use of the recommended of 2 years be permitted for the com­ and Sunburn Prevention and Treat­ statement. Special attention must be pletion of studies to support the move­ ment Products. In accordance with given to assure that consumers are not ment of category III conditions to cat­ § 330.10(a)(6) (<21 CFR 330.10(a)(6)), misled or confused. The Commissioner egory I. The Commissioner will review the Commissioner is issuing (l)a pro­ recognizes the potential for such a that recommendation as well as all posed regulation containing the mono­ statement to mislead the public, and is comments on this document, and will graph recommended by the Panel, concerned about its use. However, the determine what time period to permit w^iich establishes conditions under issue is open and will receive the ful­ for category III testing after that which OTC sunscreen drugs are gener­ lest attention before any claim with review is completed. ally recognized as safe and effective regard to skin cancer or aging of the In the F ederal R e g is t e r for January and not misbranded; (2) a statement of skin is included in any OTC drug 5, 1972 (37 FR 85), the Commissioner the conditions excluded from the monograph. of Food and Drugs announced a pro­ monograph on the basis of a determi­ After careful review of all comments posed review of the safety, effective­ nation by the Panel that they would submitted in response to this proposal, ness and labeling of all OTC drugs by result in the drugs not being generally the Commissioner will issue a tenta­ independent advisory review panels. In recognized as safe and effective or tive final regulation in the F ederal the F ederal R e g is t e r of May 11, 1972 would result in misbranding; (3) a R e g is t e r to establish a monograph for (37 FR 9464), the Commissioner pub­ statement of the conditions excluded OTC sunscreen drug products. lished the final regulations providing

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38207 for the OTC drug review under 27, 1976), Kathleen A. Blackburn OTC topical sunscreen drugs, the fol­ §330.10 which were made effective im­ (from July 6, 1976 to August 24, 1977) lowing firms made submissions related mediately. Pursuant to these regula­ and Emily Londos (from October 25, to the indicated products: tions, the Commissioner issued in the 1977). Each was nominated by an ad Federal Register of December 12, hoc group of consumer organizations A. S ubmissions by F irms 1972 (37 FR 26456) a request for data and served as the consumer liaison; Firms and Marketed Products and information on all active ingredi­ and Joseph L. Kanig, Ph. D., nomi­ AVA, Inc., Garland, Tex. 75040, AVA ents utilized in topical analgesic, in­ nated by the Proprietary Association, Suntan Lotion. cluding antirheumatic, otic, burn, sun­ and Ben Marr Lanman, M.D., nomi­ Bonne Bell, Lakewood, Ohio 44107, Sure burn prevention and treatment drug nated by the Cosmetic, Toiletry, and Tan Gel and Sure Tan Lotion. products. Fragrance Association, served as the Paul B. Elder Co., Bryan, Ohio 43506, RVP The Commissioner appointed the industry liaisons. Wide Range Sunscreen, RVP Ultra-Range following Panel to review the data and The following FDA employees Sun Protection, RVPlus, RVPaque Ultra- information submitted and to prepare served: C. Carnot Evans, M.D., Served Violet Occlusive Agent, RVP ABA Lipstick. a report pursuant to § 330.10(a)(1) on Elizabeth Arden, Inc., New York, N.Y. as Executive Secretary. Lee Geismar 10022, Sun Gelee and Suncare. the safety, effectiveness and labeling served as Panel Administrator. Lee Greiter Corp., Inc., Weidling, Austria, Piz of those products: Quon, R.Ph., served as Drug informa­ Buin Exclusiv Suntan Cream, Piz Buin Thomas G. Kantor, M.D., Chairman, John tion Analyst until July 1975, followed 'Exclusiv Extrem Suntan Cream, Piz Buin Adriani, M.D., Col. William A. Akers, M.D., by Timothy T. Clark, R.Ph., until July Exclusiv Suntan Liquid Cream. Maxine Bennett, M.D., Minerva S. Buerk, 1973, followed by Thomas H. Gingrich, G. S. Herbert Laboratories, Irvine, Calif. M.D., Walter L. Dickison, Ph. D., and Jerry R.Ph., until July 1976, followed by 92664, Eclipse Sunscreen Lotion. Mark Shuck, M.D. Lanvin-Charles of the Ritz, Inc., Holmdel Victor H. Lindmark, Pharm.D. Township, N.J. 07733, Alexandra de Mar­ The Panel was charged to review The following individuals were given koff Lip Emollient, Alexandra de Markoff submitted data and information for an opportunity to appear before the Allevia Body Treatment, Alexandra de OTC topical analgesic ingredients, in­ Panel to express their views either at Markoff Allevia Travel Stick, Bain de cluding antirheumatic, otic, burn, and their own or the Panel’s request on Soleil Suntan Creme White, Bain de Soleil the issues before the Panel: Suntan Cream, Bain de Soleil Suntan sunburn prevention and treatment Lotion, Bain de Soleil Leg Make-Up, Bain active ingredients. For purposes of this Joseph P. Armellino, M.D., Charles Blues- de Soleil Foam Concentrate, Bain de review, the Panel grouped the active tone, M.D., Stuart Ericksen, Ph. D., Alexan­ Soleil Bronzer, Imperial Nutricia Moisture ingredients and labeling into four der A. Fisher, M.D., Thomas Fitzpatrick, Tint, Revenescence Sun Bronze, Revenes- major phamacologic groups, i.e., exter­ M.D., Ph. D., J. M. Glassman, M.D., Peter cence Protective Cream for the Face, Re­ nal analgesics, skin protectants, topi­ Hebbom, Ph. D., George E, Heinze, Ken­ venescence Extra Protective Creme for cal otics, and sunscreens. neth R. Johannes, Albert M. Kligman, M.D., the Face, Revenescence Moisture Glow- Howard Maiback, M.D., Edward Marlowe, Bronze Shade, Revenescence Moisture The Panel presents its conclusions Ph. D., Kenneth L. Milstead, Ph. D., John Glow Liquid-Bronze Shade. and recommendations for sunscreen Parrish, M.D., Madhue Pathak, M.D., Menley & James Laboratories, Philadel­ active ingredients in this document. Robert Sayre, Ph. D., Joseph P. Soyka, phia, Pa. 19101, Sea & Ski Golden Tan, The Panel’s conclusions for topical M.D., Garrett Swenson, Esq., Stephen M. Sea & Ski Block Out. otic active ingredients were published Truitt, Esq., and Frederick Urbach, M.D. Miles Laboratories, Inc., Elkhart, Ind. 46514, in the F ederal R e g is t e r of December Sungard Lotion. 16, 1977 (42 FR 63556), and its conclu­ No person who so requested was Plough, Inc., Memphis, Tenn. 38101, Cop- sions for skin protectant active ingre­ denied an opportunity to appear pertone Improved Shade Suntan Lotion, before the Panel. Coppertone Lipkote Lip Balm, Coppertone dients were published in the F ederal The Panel has thoroughly reviewed Noskote Sunscreen, Coppertone Suntan R e g is t e r of August 4, 1978 (43 FR the literature and data submissions, Cream, Coppertone Suntan Foam, Cop­ 34628). The Panel’s conclusions and pertone Suntan Lotion, Coppertone recommendations for external analge­ has listened to additional testimony Suntan Oil, Coppertone Suntan Oil Aero­ sic ingredients will be presented in a from interested persons and has con­ sol Spray, Q.T. Foam, Q.T. Lotion, Sudden sidered all pertinent data and informa­ later issue of the F ederal R e g is t e r . Tan, Sun Protective Foam, Sun Shielding The Panel was first convened on tion submitted through December 14, Lotion. March 6, 1973 in an organizational 1977, in arriving at its conclusions and Rowell Laboratories, Inc., Baudette, Minn. recommendations for OTC sunscreens. 56623, Duoshield One and Duoshield Two. meeting. Working meetings were held Texas Pharmacal Co., San Antonio, Tex. on May 8 and 9, July 12 and 13, Sep­ In accordance with the OTC drug review regulations (21 CFR 330.10), 78296, A-Fil Cream, Sundare Creamy tember 27 and 28, November 3 and 4, Lotion, Sundare Cleai; Lotion, SunStick November 26 and 27, 1973; January 30 the Panel’s findings with respect to Lip Protectant, SunSwept Cream. and 31, March 6 and 7, April 10 and 11, sunscreen active ingredients are set Westwood Pharmaceuticals, Inc., Buffalo, May 8 and 9, June 10 and 11, July 17 out in three categories: N.Y. 14213, Presun Lotion. and 18, September 24 and 25, October Category I. Conditions under which sunscreen products are generally rec­ In addition, the following firms 22 and 23, November 26 and 27, 1974; made related submissions: January 21 and 22, March 13 and 14, ognized as .safe and effective and are April 17 and 18, May 21 and 22, July not misbranded. Amerchol, Edison,' N.J. 08817, Amerscreen 15 and 16, September 30 and October Category II. Conditions under which P. 1, November 12 and 13, 1975; March 4 sunscreen products are not generally Chattem Laboratories, Chattanooga, Tenn. and 5, May 19 and 20,''June 22 and 23, recognized as safe and effective or are 37409, Alpaba. misbranded. EM Laboratories, Inc., Elmsford, N.Y. September 27 and 28, November 18 10523, Eusolex 161, Eusolex 232, Eusolex and 19, 1976; February 23 and 24, May Category III. conditions for which 4360, Eusolex 6300, Eusolex 3573, Eusolex 25 and 26, August 22, 23, and ’24, Octo­ the available data are insufficient to 5563. ber 25, and December 13, 14, and 15, permit final classification at this time. Felton International, Inc., Brooklyn, N.Y. 1977. 11237, Sunarome. Seven nonvoting liaison representa­ I. S u b m i s s i o n o f D ata a n d GAF Corp., New York, N.Y. 10020, Suliso- tives served on the Panel: Mrs Jacque­ I n f o r m a t io n benzone. Givaudan Corp., Clifton, N.J. 07104, Giv- line Pendleton (at the initial meeting), Pursuant to the notice published in Tan-F, Parsol MCX and Parsol Hydro. Mrs. Valerie Howard (from May 8, the F ederal R e g is t e r of December 12, Greiter Corp., Tulsa, Okla. 74101, Exclusiv 1973 to September 28, 1973), Lynn 1972 (37 FR 26156) requesting the sub­ Creme, Exclusiv Milk, Exclusiv Moisture Berry (from November 3, 1973 to April mission of data, and information on Creme, Exclusiv Oil Lotion, Exclusiv

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38208 PROPOSED RULES

Stick, Extrem Creme, Extrem Glacier Mineral oil Triethanolamine salicylate Creme, Extrem Junior Creme, Extrem Octyl dimethyl PABA 2. Inactive ingredients. Milk, Piz Buin. Oleth-3-phosphate The Panel has classified the following as Haarmann and Reimer Corp., Springfield, Oxybenzone inactive ingredients or pharmaceutical ne­ N.J. 07081, Neo Heliopan AV. Padimate cessities. In some cases, depending upon Hill Top Research, Inc., St. Petersburg, Fla. Padimate A 33709, Sun Block 253E, Sun Block 256E, Padimate O dosage and claim, some of the ingredients Sun Block U-2575. 4 Parabens may be classified as skin protectants, which Ingram Pharmaceutical Co., San Francisco, Paraffin will be discussed more fully in a later issue Calif. 94111, 2-Ethylhexyl 2-cyano-3,3-di- PEG 2 stearate of the F ederal R egister. phenylacrylate. Petrolatum Alcohol Scher Chemicals, Inc., Clifton, N.J. 07012, 2-Phenylbenzimidazole Allantion Dipsal (Dipropylene Glycol Salicylate). Polyoxyl-40-stearate Beeswax Van Dyk & Co., Inc., Belleville, N.J. 07109, Polysorbate 60 Benzyl alcohol Escalol 106, Escalol 506, Escalol 507. Propellant 46 Propellant 12/114 BHA B. Labeled I ngredients Contained in M ar­ Propoxylate of p-aminoethylbenzoate BHT keted P roducts and Other Ingredients Propylparaben 2-Bromo - 2 - nitropropane-l,3-diol S ubmitted to the P anel. Propylene glycol Camphor Propylene glycol stearate Carbomer 934 Alcohol Carboset Allantoin Quaternium 15 Allantoin-p-aminobenzoic acid complex Red petrolatum Cellulose gum p-Aminobenzoic acid SD alcohol 40 Cetyl alcohol Amyl dimethyl PABA Sesame oil Cetyl palmitate Amyl para-dimethylaminobenzoate Silaca Cetyl stearyl glycol Amyl-p-dimethylaminobenzoate Sodium carbomer Citric acid Sorbitan oleate Clove oil Beeswax Sorbitan stearate Benzophenone-3 Cocoa butter Stabilized aloe vera gel Color Benzyl alcohol Stearyl alcohol BHA Sulisobenzone Dimethicone BHT Synthetic spermaceti Dimethyl polysiloxane 2-Bromo-2-nitropropane-l,3-diol Titanium dioxide Ethyl alcohol Camphor Triethanolamine FD&C yellow No. 5 Carbomer 934 Triethanolamine salicylate FD&C red No. 4 Carboset Triethanolamine stearate Fragrances Cellulose gum Water Glycerin Cetyl alcohol Wax Glyceryl stearate Cetyl palmitate Zinc oxide Isopropyl myristate Cetyl stearyl glycol Isopropyl palmitate Cinoxate C. Classification of Ingredients Lanolin Citric acid Lanolin alcohol Clove oil 1. Active ingredients. Cocoa butter Allantoin combined with aminobenzoic acid Lanolin derivatives Color (allantoin p-aminobenzoic acid complex) Lanolin oil Digalloyl trioleate Aminobenzoic acid (p-aminobenzoic Menthol Dihydroxyacetone acid)Cinoxate Methylparaben Dimethicone Diethanolamine p-methoxycinnamate (p- Microcrystalline titanium-coated mica plate­ 5-(3,3-Dimethyl-2-norbomyliden)-3-penten- methoxycinnamic acid diethanolamine) lets 2-one Digalloyl trioleate Microcrystalline wax 3,4-Dimethylphenyl-glyoxylic acid sodium 5-(3,3-Dimethyl - 2 - norbornyliden)-3- Mineral oil salt penten-2-one Oleth 3-phosphate Dimethyl polysiloxane Dioxybenzone Parabens Dioxybenzone Dipropylene glycol salicylate Paraffin Dipropylene glycol salicylate Ethyl 4-[bis(hydroxypropyl)l aminoben- PEG 2 stearate Ethyl alcohol zoate (propoxylate of p-aminoethylben­ Petrolatum 2-Ethylhexyl 2-cyano-3,3-diphenylacrylate zoate) Polyoxyl-40-stearate Ethylhexyl-p-methoxycinnamate 2-Ethylhexyl 2-cyano-3,3-diphenylacrylate Polysorbate 60 2-Ethylhexyl 4-phenylbenzophenone-2'-car- Ethylhexyl p-methoxycinnamate Propellant 46 boxylic acid 2-Ethylhexyl 4-phenylbenzophenone-2-car­ Propellant 12/114 2- Ethylhexyl salicylate boxylic acid Propylparaben FD&C yellow No. 5 2- Ethylhexyl salicylate Propylene glycol FD&C red No. 4 Glyceryl aminobenzoate (glyceryl PABA) Propylene glycol stearate Fragrances Homosalate Quaternium 15 Glycerin Lawsone with dihydroxyacetone [dihydrox­ Glyceryl PABA yacetone; lawsone (2-hydroxy-l,4-naphth­ SD alcohol 40 Glyceryl stearate oquinone)] • Sesame oil Homosalate Menthyl anthranilate Silica Isopropyl myristate 3- (4-Methylbenzylidene)-camphor Sodium carbomer Isopropyl palmitate Oxybenzone (benzophenone-3) Sorbitan oleate Lanolin Padimate A (amyl p- Sorbitan stearate Lanolin alcohol dimethylaminobenzoate, amyl para- Stabilized aloe vera gel Lanolin derivatives dimethylaminobenzoate, amyl dimethyl Stearyl alcohol Lanolin oil PABA, padimate) Synthetic spermaceti Lawsone (2-hydroxy-1,4-naphthoquinone) Padimate O (octyl dimethyl PABA) Triethanolamine Menthol 2-Phenylbenzimidazole - 5 - sulfonic acid (2- Triethanolamine stearate Menthyl anthranilate phenylbenzimidazole sulfonic acid) Water p-Methoxycinnamic acid diethanolamine Red petrolatum Wax 3- (4-Methylbenzyliden)-camphor Sodium 3,4-dimethylphenyl - glyoxylate Zinc oxide Methylparaben (3,4-dimethylphenyl-glyoxylic acid sodium Microcrystalline titanium-coated mica plate­ salt) 3. Ingredients deferred to other OTC advi­ lets Sulisobenzone sory review panels or other experts. Microcrystalline wax Titanium dioxide • None.

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38209 D. REFERENCED OTC VOLUME SUBMISSIONS cusses these harmful effects elsewhere particularly susceptible to the immedi­ All “OTC Volumes” cited through­ in this document. (See part II. para­ ate and cumulative effects of sunlight out this document refer to the submis­ graph D. below—The Harmful Effects exposure and for health reasons sions made by interested persons pur­ of Sunlight on the Skin.) In fact, jthe should protect themselves from the suant to the call for data notice pub­ statutory definition of a drug in part harmful UV radiation from the sun. lished in the F ederal R e g is t e r of De­ states “articles (other than food) in­ cember 12, 1972 (37 FR 26456). The tended to affect the structure or any B. TYPES OF SOLAR RADIATION volumes will be put on public display function of the body of man or other For practical purposes, the solar after September 25, 1978, in the Office animals * * (21 U.S.C. 321(g)). spectrum at the earth’s surface con­ of the Hearing Clerk (HFA-305), Food The Panel has evaluated the claimed sists of wavelengths of electromagnet­ and Drug Administration, Room 4-65, active ingredients contained in the ic energy between 295 and 1,800 nano­ 5600 Fishers Lane, Rockville, Md. products submitted for review. The meters (nm) (ref. 1). The sun’s rays as­ 20857. Panel finds that these preparations sociated with diseases are related to reduce by varying amounts the solar the light sensitivity range from 290 to II. G en er a l S t a t e m e n t s a n d radiation absorbed by the skin and 800 nm. The UV spectrum lies between R ecommendations thereby affect the physiological re­ 290 and 400 nm, visible light between sponse and extent of the erythemal re­ A. INTRODUCTION 400 and 770 nm, and the infrared rays action (redness) produced. Indeed, beyond 770 „nm. Ultraviolet radiation As part of its review, the Panel was these products affect the structure from both sunlight and artificial charged to evaluate data and informa­ and function of the body by screening, sourSès is sometimes subdivided into tion on the safety, effeetiveness, and reflecting, or scattering the harmful, three bands from the longer to the labeling of OTC sunburn prevention burning rays of the sun. This is a de­ shorter wavelengths as follows: active ingredients. In general, the sirable alteration to a normal physio­ 1. UV-A (black light radiation, long­ Panel found upon reviewing submis­ logical response to solar radiation for wave UV radiation, near UV radi­ sions, the scientific literature, and individuals with sensitive and extra ation) wavelength 320 to 400 nm. UV- other evidence that over-exposure to sensitive skin. A radiation can cause tanning of the sunlight damages the skin and can The Panel has classified products in­ skin, but is weak in causing reddening lead to various skin lesions. In the tended to be used for preventing sun­ of the skin. About 20 to 50 Joules/cm2 long run, suntanning is not good for burn and similar conditions as drugs of UV-A energy is required to produce the skin. The cumulative exposure to regardless of claims made for the a minimally perceptible redness reac­ sunlight from childhood into adult­ products and has identified them as tion (the Minimal Erythema Dose or hood can lead to skin cancer. Persons sunscreen products. Sunscreens may MED). The Panel has further dis­ most at risk to the harmful effects of act either chemically or physically. cussed MED below. (See part II. para­ sunlight are those with light eyes and The majority of sunscreens commonly graph D. below—The Harmful Effects light skin of northern European de­ used in the OTC drug market act of Sunlight on the Skin.) The eryth­ scent who now live in sunny climates. chemically to absorb specific portions ema (redness)^ reaction is maximal in Susceptible persons can avoid the sun­ of the UV spectrum. Ail example of a intensity about 72 hours after expo­ shine between 10 a.m. to 2 p.m. solar chemical sunscreen is aminobenzoic sure. time by covering their skin with cloth­ acid (para-aminobenzoic acid). Physi­ 2. UV-B (sunburn radiation, middle ing, wearing broad brim hats,'applying cal sunscreens act by providing an UV radiation) wavelength 290 to 320 opaque cosmetics, or staying indoors. actual physical barrier to solar radi­ nm. Radiation causes the sunburn, re­ Avoidance of excessive sun exposure ation. Instead of absorbing UV light, action, which also stimulates pigmen­ would be best, but it is often impracti­ these agents scatter and reflect such tation (tanning) in the skin. Approxi­ cal because of occupational demands light, thereby reducing the likelihood mately 20 to 50 millijoules/cm2 of UV- or is often undesirable for leisure pur­ of sunburn. An example is titanium B energy is required to produce one suits. Another protective measure dioxide. Regardless of the mechanism MED (about 1,000 times less than the available to the consumer is to apply employed, the active ingredients in dose of UV-A). The erythema reaction sunscreens to prevent sunburn imme­ such products, which either absorb, re­ is maximal in intensity at 6 to 20 diately and to prevent further sun flect, or scatter UV light between 290 hours after exposure. damage. and 777 nanometers (nm), have been The action spectrum causing sun­ The Panel recognizes that many of classified as drugs and identified as burn lies between 290 and 320 nm in these products have been traditionally sunscreen agents which are more fully the UV-B band, with a maximum considered by the Food and Drug Ad­ discussed below. effect at 296.7 nm, although the quan­ ministration as cosmetics with labeling The Panel further recognizes that tity reaching the earth’s surface is such as “for tanning” and “for fast ingredients that are not sunscreens small. Under optimal environmental suntanning”. This is due in part to the may be contained in sunscreen prod­ conditions for sunburn, only 0.2 per­ statutory definition of a cosmetic as ucts and may also be classified as cent of the total solar radiation causes “articles intended to be rubbed, drugs. These include skin protectants, erythema of the skin. Ninety-five per­ poured, sprinkled, or sprayed on, in­ and repellants to ward off flying in­ cent of this burning radiation may be troduced into, or otherwise applied to sects. absorbed by the normal white skin. the human body or any part thereof No perfect topical preparation for Different amounts of energy reach thè for cleansing, beautifying, promoting preventing sunburn is available, but earth’s surface at various wavelengths attractiveness, or altering the appear­ there are many satisfactory prepara­ from 295 to 320 nm. At 307.4 nm the ance * * *.” (21 U.S.C. 321(i)). The tions on the market. Interestingly, no maximal amount -of energy to cause Panel believes that, regardless of “prescription only” products are avail­ sunburn is delivered by the sun to the claims, products intended to be used able to protect the sunsensitive skin (ref. 2). for prevention of sunburn or any person. All currently marketed sun­ 3. UV-C (germicidal radiation, short other such similar condition should be screen products are sold OTC. The UV radiation, far UV radiation) wave­ regarded as drugs. The use of sun­ majority of consumers who purchase length 200 to 290 nm. UV-C radiation screens may mitigate the harmful ef­ sunscreen products have no pathologi­ from sunlight does not reach the fects of the ultraviolet (UV) radiation cal conditions, but desire to acquire a earth’s surface, but artificial UV from the sun on the exposed skin of suntan and to prevent a painful sun­ sources can emit this radiation. Al­ susceptible individuals. The Panel dis­ burn. Some individuals, however, are though UV-C is not effective in stimu-

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 38210 PROPOSED RULES lating pigmentation {tanning), it does Man,” M. A. Pathak, et al., eds., University burn and the effects of overexposure cause erythema requiring about 5 to of Tokyo Press, pp. 751-765, 1974. as discussed below. 20 millijoules/cm2 of UV-C energy to (3) Measurement of Ultraviolet Radiation Urbach stated, “All of us, even those produce one MED. in the United States and Comparisons with with dark complexions, can develop Skin Cancer Data, U.S. Department of skin cancer if we expose ourselves to R eferences Health, Education, and Welfare, National Institutes of Health (DHEW No. 76-1029), the sun long enough. But that would (1) Keston, S. F.f “Diseases Related to November 1975. take 200 to 300 years in some cases, Light Sensitivity,” Archives of Dermatology and we just don’t live that long” (ref. and Syphilology, 67:284-301, 1953. D. THE HARMFUL EFFECTS OF SUNLIGHT ON 2). (2) Schulze, R., “Effectiveness of UV Ab­ THE SKIN Some commercial preparations on sorbers and Commercially Available Sun­ the OTC drug market today that screens (Wirksamkeit von UV-Absorbem The UV energy absorbed by the skin und handelsueblicher Sonnenschutzmit- can produce an erythemal reaction permit suntanning without painful tel),” Journal of the Society of Cosmetic (redness). The intensity of the reac­ sunburn fall into four groups, each Chemists, 14:544-565, 1963. tion is dependent upon the amount of aimed at a certain consumer group. energy absorbed. As discussed above, M arketed S unscreen P reparations (R ef. 3) C. FACTORS AFFECTING THE AMOUNT OF UV radiation from both sunlight and SUNLIGHT EXPOSURE artificial sources has been divided into Indication and Solar Transmission three bands (UV-A, UV-B, and UV-C), For quick tanning—Transmit about 15 per­ At sea level, the UV energy of sun­ which emit different quantities of cent of the sunbuming rays. light is greatest between the hours of energy and therefore produce an For normal skin—Transmit from 4 to 8 per­ 10 a.m. and 2 p.m. in midsummer, erythemal reaction at different time cent of the sunbuming rays. when the sun is overhead (ref. 1). For sensitive skin—Transmit from 1 to 4 intervals after exposure. The amount percent of the sunbumig rays. Even within the most intense 4-hour of energy from any source required to For extra sentive skin—Transmit under 1 period, the sunlight intensity varies. produce a minimally perceptible red­ percent of the sunburning rays. Exposure at noon results in more UV- ness reaction of the skin is termed the The Panel emphasizes that sun­ B energy falling on the skin than ex­ Minimal Erythema Dose or MED. The posure at 10 a.m. or 2 p.m. In the screen preparations only extend the morning and late afternoon, the sun is length of time required to produce an time it takes the sun to produce a sun­ at a lower angle, sharply reducing the MED is dependent, as discussed above, burn. Tanning cannot be rushed, sunlight’s intensity by 75 percent, and on the quantity of energy emitted by taking about 2 weeks in most white sunburn is not likely to occur. Atmos­ the source and the response of the people, if painful erythema is to be pheric conditions similarly alter the host’s skin to sunlight. Sunscreen avoided. The most rapid way to cause solar erythemic intensity. Reflection agents decrease the amount of energy tanning is to allow the sun to produce of additional ultraviolet light from absorbed by the skins by limiting the erythema of the skin. Erythema suffi­ snow and white sand may greatly total amount of available energy that cient to induce tanning yet not so shorten the time to sunburn (ref. 2). reaches the skin. Besides the UV severe as to cause pain requires only Depending upon the latitude, the aver­ source and the sunscreen agent, the one-half of the time of exposure that age unprotected, untanned, white­ pigmentation of an individual’s skin is required to produce a painful sun­ skinned person requires approximately determines the length of time required burn. Suntanning can occur at UV wa­ the following exposures in June to to produce an MED. Less time is re­ velengths from 320 to 400 nm, but de­ cause the observed reaction: quired to produce an MED in light­ velops slowly under natural condi­ skinned individuals than is required to tions. Tanning most commonly devel­ G uide for Fair-Skinned P eople (R ef. 2) produce an MED in dark-skinned indi­ ops after exposure to the “sunburn” viduals. The source of the UV radi­ UV wavelengths between 290 and 320 ation, the type of sunscreen agent nm, the UV-B band. New Florida used, and the pigmentation of the in­ Reaction from exposure Jersey Keys As previsously noted, sunscreen 40 N 25 N dividual’s skin determine the length of preparations contain certain chemicals time required to produce an MED. which absorb UV light at various wa­ (minutes) (minutes) The tanning ability of an individual velengths or contain an opaque sub­ Minima) redness (erythema) is genetically predetermined and is stance that physically reflects or scat­ (the minimal erythema . dose, MED)...... 21 10 governed by the individual’s capacity ters the UV light rather than absorb­ Vivid redness (erythema), no to produce melanin pigment within ing the rays (refs. 4 and 5). pain...... 42 25 the pigment cells (melanocytes) when In our cosmetically conscious soci­ Painful sunburn------... 80 50 165 120 stimulated by UV-B and UV-A. There ety, most persons consider a suntan to Blistering sunburn...... is a spectrum of pigmentation in be healthy. Certainly, sun exposure humans, ranging from Negro (black) forms vitamin D in the skin, and this An average white-skinned person to Caucasian (white). The extent of enhances absorption of calcium from would be exposed to an average of 19 any erythemal response is a function the intestine and prevents rickets. MED’s during the entire day atop of skin color, and the MED for Dark- However, dermatologists are well Mauna Loa on the island of Hawaii. skinned blacks is about 33 times as aware th at light-eyed and fair-skinned To date, this is the highest reading ob­ high as that for light-complexioned individuals are particularly susceptible tained by network of UV recording Caucasians (ref. 1). to premature aging of the skin and meters (ref. 3). About 4 MED’s are re­ The Panel finds that the current la­ skin cancers caused by sunlight (ref. quired to cause a painful sunburn; beling of sunscreen products makes no 3 ). about 8 MED’s will produce blistering. reference to skin color because such A recent study in the United States products are actually intended for in­ reported a high incidence of sun-in­ R eferences dividuals whose skin color falls within duced cancer in susceptible people (1) Kreps, S. L, “Sunburn Protection and the pigmentation spectrum that would (ref. 6). In 1973, in the United States Suntan Preparations,” American Perfumer have an erythemal response to the UV alone, 1,409 deaths were due to sun-in­ and Cosmetics, 78:73-77, 1963. duced skin cancers (excluding melano­ (2) Fitzpatrick, T. B., M. A. Pathak and J. light of the sun. Thq Panel empha­ A. Parrish, “Protection of the Human Skin sizes that despite the fact that deeply mas) in susceptible people (ref. 7). An­ Against the Effects of the Sunburn Ultra­ pigmented skin has more inherent pro­ nually in the United States with a violet (290-320 nm),” in “Sunlight and tection, it is still susceptible to sun­ population of over 210,000,000, an esti-

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38211 mated 9,000 individuals develop cutan­ dence in males than in females may be of skin cancer, i.e., the protective eous malignant melanoma, 300,000 de­ explained by the increased exposure mechanism of skin pigmentation velop other skin cancers, and 600,000 of males to the sun from their outdoor which is genetically determined. The develop cancers of all other organs ex­ occupations. Skin cancer occurs most susceptibility to skin cancer is de­ clusive of the skin (ref. 8). Other spe­ frequently in those areas of the body creased in individuals with deeply pig­ cific diseases of congenital, metabolic, that are exposed to the sun, such as mented skin. Epidemiological evidence toxic, immunologic, allergic, or idio­ the neck, head, arms, and hands. Con­ indicates that susceptible individuals pathic origins are caused or aggravat­ sequently, the frequency of skin have a fair complexion, light hair, ed by sunlight exposure. The pain and cancer is higher in farmers, sailors, blue or gray eyes, tan less and to a blistering of sunburn from overexpo­ and construction workers (ref. 12). lighter color, and sunburn more easily sure is known to many. The Panel dis­ The Panel agrees with the concept and more severely than individuals not cusses below, in detail, the more that sunlight plays an important role developing skin cancer. Studies show common harmful effects that may be in the etiology of skin cancer in man. that skin cancer patients have greater induced by the UV radiation from the The Panel recognizes the epidemiolog­ outdoor exposure than those not af­ sun, i.e., skin cancer and premature ical evidence for the carcinogenic fected. aging of the skin. properties of UV radiation from the The Panel concludes that continu­ 1. Skin cancer in susceptible individ­sun and the relationship to human ous and prolonged exposure over the uals. As described above, one of the skin cancer, such as premalignant ker­ years to sunlight increases the risk of risk factors of chronic exposure to the atoses, and malignant basal cell epith­ skin cancer in susceptible individuals sun is the development of keratoses eliomas and squamous cell epithelio­ and that the use of sunscreens by such and skin cancer. Epidemiological evi­ mas. The Panel is particularly con­ individuals may mitigate the harmful dence shows that the incidence of skin cerned about recurrent sunburn and effects of overexposure to the sun. cancer is increased in populations lo­ overexposure to the sun throughout Below, the Panel assesses the overall cated in the southern latitudes as com­ the years, because the lower wave­ harmful effects of sunlight exposure pared with populations in northern length limit of cancer-producing radi­ and recommends that the labeling of latitudes. Auerbach (ref. 9) showed a ation on the skin of mice and rats has sunscreen products, alert the consum­ constant rate of increase of skin been shown to be 325 nm, i.e., the er to these harmful effects. cancer incidence approaching the same spectral range that produces 2. Premature aging of the skin in equator from north to south; the inci- sunburn in human skin (ref. 16). Al­ susceptible individuals. Another dence doubled for every 3° 48' reduc­ though the epidemiological evidence harmful effect that may result from tion in latitude. This geographical re­ favors a casual relationship between the cumulative action of chronic pro­ lationship has been accepted as indi­ sunlight and skin cancer in man, pro­ longed exposure to the UV radiation rect evidence that skin cancer in man spective direct evidence to substanti­ from the sun is a condition which has is related to the greater exposure of ate the relationship will be difficult to been commonly referred to as prema­ individuals to sunlight in southern obtain for ethical and moral reasons. ture aging of the skin. Premature latitudes than in northern latitudes. However, the evidence indicates that aging of the skin refers to the thin­ Several epidemiological studies rein­ there is a lower risk in heavily pig­ ning, dryness, and fine wrinkling pro­ force the conclusion that prolonged mented individuals; that there is a duced by the exposure of the skin to sun exposure is a factor in the etiology continued rise in the incidence with in­ sunlight. Although the external char­ of skin cancer (refs. 9 through 14). creasing age, thusindicating a cumula­ acteristics of this condition, i.e., dry, The damage due to sunlight is insid­ tive effect from sunlight exposure; and wrinkled, thin skin with a loss of elas­ ious and cumulative. that the incidence rate is higher ticity, are similar to the characteristics Retrospective studies have been among susceptible populations living of the aging process, premature aging done to identify those characteristics in subtropical and tropical latitudes. of the skin due to UV radiation has in individuals that may increase their Physical, genetic, and environmental histological and biochemical charac­ susceptibility to skin cancer if overex­ factors interact, apparently, to alter teristics that differ qualitatively and posed to sunlight. These contributory the causal effect of sunlight on tumor quantitatively from those seen in the factors proved to be age, sex, skin pig­ development (ref. 10). aging process. The changes that are mentation, and occupation. The gener­ In addition, factors unrelated to sun­ associated with premature aging of al conclusion drawn from these studies light may operate in the development the skin are seen in the dermis of the was that they corroborated the evi­ of basal cell carcinoma in man. This skin. In addition to these dermal dence for a cumulative influence of conclusion is based on the observa­ changes are the effects that UV radi­ sun exposure on tumor development tions that one-third of all basal cell ation induces in the epidermal layer of and that they indicated the protective carcinomas occur in areas of the skin the skin, where the basal and squa­ effect of pigmented skin. For example, receiving little or no UV radiation. mous cell epitheliomas (skin cancers) the incidence of cancer was reported The ratio of the incidence of basal cell casually related to sunlight exposure to increase with age among Caucasian carcinoma to squamous cell carcinoma occur. The relationship between the adults in a rural county of Tennessee shows a great north-south difference changes in the dermal connective (ref. 12). The incidence increased from varying from approximately 10 to 1 in tissue of the skin and epidermal car­ 0.7 per 100 up to the age of 44 years to favor of basal cell carcinoma in north­ cinogenesis are not understood, al­ 13.6 per 100 between age 65 and 74 ern cities, to 4 to 1 in northern and though dermal changes associated years for males. For females in these central rural areas, and to 2 or 3 to 1 with premature aging of the skin have age groups, the incidence of skin in southern rural areas (ref. 9). These often been associated with skin cancer cancer increased from 0.4 per 100 to observations suggest that increasing formation (ref. 17) 6.8 per 100. The incidence for males exposure to sunlight has a greater The dry, wrinkled, atrophic condi­ was higher than the incidence for fe­ effect on the development of squa­ tion of sunlight-exposed skin was first males. Other studies indicated a mous cell carcinoma than on that of reported by Unna from observations in higher incidence of skin cancer in basal cell carcinoma, nevertheless, sailors. Since that observation, bio­ whites than in nonwhite populations some association between basal cell chemical and histological studies have (refs. 14 and 15), implying that the carcinoma and sunlight is indicated been done comparing the changes in dark pigmentation of nonwhites pro­ from epidemiological studies. sunlight-exposed and unexposed skin tects against the harmful effects of The Panel recognizes the influence of white and non white individuals. the UV radiation. The higher inci­ of genetic factors on the development Prolonged UV radiation from the sun

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38212 PROPOSED RULES on the dermal layer of exposed skin chronic exposure to UV radiation from skin cancer from today’s exposure ap­ ultimately produces elastic degener­ the sun, as discussed above. pearing 10 to 20 years hence. ation and elastic tissue dissolution. 3. Conclusions. The Panel recognizes Therefore, the Panel recommends This effect is qualitatively and quanti­ the epidemiological evidence that skin the following statement in the label­ tatively different from the aging unex­ cancer, and degenerative skin changes ing for all sunscreen products: “Over­ posed skin of white individuals and, in (elastotic degeneration) commonly re­ exposure to the sun may lead to pre­ addition, is less pronounced in both ferred to as premature aging of the mature aging of the skin and skin the exposed and unexposed skin of skin are causally related to chronic ex­ cancer. The liberal and regular use nonwhite (pigmented) individuals (ref. posure to the UV radiation from the over the years of this product may 18). sun. The Panel is concerned that be­ help reduce the chance of these harm­ The quantity of elastic tissue in the cause it is difficult to substantiate this ful effects.” or “Overexposure to the dermis of sunlight-exposed skin in­ evidence by adequate and direct infor­ sun may lead to premature aging of creases with age in both white and mation, susceptible individuals will the skin and skin cancer. The liberal nonwhite individuals. This elastic continue to be subjected to the harm­ and regular use over the years of this tissue hyperplasia is greater than that ful effects of continuous sun exposure product may help reduce the chance seen in unexposed skin and is appar­ without using whatever protection is of premature aging of the skin and ently accompanied by a decrease in presently available. The Panel is fully skin cancer.” collagen and eventually culminates in aware of the limitations of the present 4. Minority report. The Panel voted the disintegration of the elastic fibers sunscreens, i.e., primarily the inability 4 to 3 to support a claim which can be into an amorphous mass as seen in to remain on the skin under diverse used on labels of all sunscreen prod­ stained histological tissue sections. conditions, and the apparent irreversi­ ucts. This claim suggests that skin The loss of the elasticity of exposed bility of UV radiation damage to the cancer may be prevented by the use of skin is the result of the dissolution of skin. any of these products. The claim pre­ the elastic fibers. Quantitative bio­ However, the Panel feels that be­ supposes that the person using the chemical changes occur in elastic de­ cause skin cancer is extremely product will use it correctly. It also generation of exposed skin that differs common in susceptible individuals, presupposes that alterations in the from that seen in the aging process in amounting to one-third to one-half of skin are not yet present which could unexposed skin. In contradistinction all cancers of all anatomical sites as re­ result in skin cancer, whether the to aging unexposed skin, it has been ported in the United States (ref. 10), product is used or not. Because data shown that in chronically sunlight-ex­ the use of sunscreens properly and are not yet conclusive that skin can­ posed skin the concentration of hexo- regularly applied may aid in reducing cers are preventable by these OTC samine is increased and the concentra­ this high incidence. products, the minority suggests that a tion of hydroxyproline is decreased. The Panel believes that sunscreens claim of “may reduce harmful effects Glucosamine is also increased in would be beneficial for children and of the sun” is acceptable, but the final chronically exposed skin which is adolescents with the susceptible skin step of preventing cancer is unwar­ thought to correlate with the in­ coloration, genetic background, and ranted at this time. The consumer rep­ creased staining for mucopolysacchar­ geographical environments making resentative concurs with the minority ides in the skin (refs. 19 and 20). them likely to be subject to repeated report. Just as in studies on the effect of sunburns. The damage is cumulative R eferences pigmentation on the incidence of skin and 20~ to 50 years may pass before (1) Olson, R. L., et al., “Skin Color, Mela­ cancer in man, it has been reported skin changes including skin cancers nin and Erythema,” Archives of Dermatol­ that biopsies of exposed skin of elderly appear. ogy, 108:541-544, 1973. nonwhite individuals showed little of Experimental studies in mice have (2) Cleary, D. M., “Is There Too Much the elastic degenerative changes seen been reported to show that the topical Sunshine in Your Life?”, The Sunday Bulle- in biopsy specimens obtained from application of 3-benzoyl-4-hydroxy-6- tin/Discoverer, Philadelphia, pp. 12-16, May similar exposed regions of elderly methoxy-benzenesulfonic acid and 15, 1977. white individuals, and that biopsy aminobenzoic acid decreased the (3) Kreps, S. I., “Sunburn Protection and Suntan Preparations,” American Perfumer specimens of unexposed areas were erythematous and carcinogenic effect and Cosmetics, 78:73-77, 1963. almost identical in similar age groups of UV radiation (ref. 21). Whether (4) Klarman, E. G., “Sunburn and of both white and nonwhite individ­ such results derived from animal stud­ Suntan,"American Perfumer and Cosmetics, uals. The evidence pointed to a corre­ ies can be extrapolated to chronic sun 54:126-135, 1949. lation between the degree of pigmen­ exposure in man remains, of course, (5) Master, K. J., B. M. Sayre, and M. S. tation and the degree of elastosis. The undetermined, but the Panel feels Everett, “New Evaluation Techniques for less pigmented individuals showed a that the topical application of sun­ Sunscreens,” Journal of the Society for Cos­ metic Chemists, 17:581-594, 1966. greater amount of degeneration. The screens by susceptible individuals may (6) Measurement of Ultraviolet Radiation reports indicate that pigmentation 1ms mitigate the harmful effects of chron­ in the United States and Comparisons with a protective effect and that the elasto- ic exposure to the sun. Skin Cancer Data, U.S. Department of tic degenerative effects of UV radi­ Dermatologists routinely instruct Health, Education, and Welfare, National ation from the sun are not simply the their patients who have skin cancer of Institutes of Health (DHEW No. 76-1029), result of the aging process. the sun-exposed areas to wear long November 1975. The Panel concludes that because sleeves and a wide-brim hat, to avoid (7) Breeze, E. G., Letter solicited by Panel pigmentation of the skin appears to Chairman in OTC volume 060150. sun exposure between 10 a.m. to 2 p.m. (8) Scotto, J., A. W. Kopf, and P. Urbach, have an influence in preventing the solar time, and to use a sunscreen lib­ “Non-melanoma Skin Cancer Among Cauca­ harmful effect of elastotic degener­ erally every day (women may substi­ sians in Four Areas of the United States,” ation in sunlight-exposed skin, the use tute a heavy opaque makeup) “even Cancer, 34:1333-1338, 1974. of sunscreens may mitigate elastotic just to take out the garbage.” Most (9) Auerbach, H., “Geographic Variation degenertion in light skinned individ­ physicians recommend sunscreens for in Incidence of Skin Cancer in the United uals (susceptible individuals). It ap­ skin cancer patients, not to heal States,” Public Health Reports, 76:345-348, pears that elastotic degeneration (pre­ 1961. damage that occurred years earlier, (10) Urbach, F., J. H. Epstein and P. D. mature aging of the skin) is more nor to prevent skin cancers due to the Forbes, “Ultraviolet Carcinogenesis: Experi­ likely to occur in individuals with the lag time of 10 to 30* or more years be­ mental, Global and Genetic Aspects,” in characteristics that make them sus­ tween the time the damage occurred “Sunlight and Man,” Edited by T. B. Fitzpa­ ceptible to the harmful effects of and the tumor appears, but to prevent trick, M. A. Pathak, L. C. Harber, M. Seigi,

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38213 and A. Kurkita, University of Tokyo Press, The Panel finds SPF values to be a ters all light in the UV and visible Tokyo, 1974. practical guide and has included them range at wavelengths from 290 to 777 (11) Dorn, J. P. “Illness from Cancer in in the labeling to aid the consumer in nm and thereby prevents or minimizes the United States,” Public Health Reports, selecting the most suitable sunscreen suntan and sunburn. Transparent 59:33-48, 65-67, and 97-115, 1944. for his/her own purposes. sunblock agents are not yet available (12) Zagula-mally, Z. W., E. W. Rosenberg in the OTC drug marketplace. and M. Kashgarian, “Frequency of Skin F. SUNSCREEN AGENTS The Panel realizes that these defini­ Cancer and Solar Keratoses in a Rural Southern County as Determined by Popula­ The Panel has discussed the use of tions are based on the UV-absorbing tion Sampling,” Cancer, 34:345-349,1974. OTC sunscreen drug products in re­ properties of a single active ingredient (13) Urbach, F., S. O’Beim and P. Judge, ducing by varying amounts the solar of a sunscreen product and not on how “The Influence of Environmental and Ge­ radiation absorbed by the skin. The an ingredient may perform in a formu­ netic Factors on Cancer of the Skin (ab­ amount of UV light from the sun that lation or in a combination product stract),” Tenth International Cancer Con­ penetrates the skin depends upon the during actual use on the skin. There­ gress, J. B. Lippincott, Philadelphia, pp. amount of energy selectively screened fore, the Panel has recommended final 109-110,1970. by the product. Consequently, the product testing of each formulation to (14) Pillsbury, D. M., “Dermatology,” physiological effect on the skin, mani­ assure proper use. (See part III. para­ W. B. Saunders, Philadelphia, p. 1145, 1956. fested as erythema, is determined in graph D. below—Sunscreen product (15) Movshovitz, A. and B. Modan, “Role large part by the quantity of radiation testing procedures for determination of Sun Exposure in the Etiology of Malig­ of the sun protection factor (SPF) nant Melanoma: Epidemiologic Inference,” of the sunscreen product permits the value and related labeling claims.) Journal of the National Cancer Institute, skin to absorb, or conversely, the 51:777-779, 1973. quantity of UV energy the product -G. CATEGORIES OF SUNSCREEN PRODUCTS (16) Blum, H. F., “Carcinogenesis by UV prevents the skin from absorbing. The Light,” Princeton University Press, Prince­ intensity of the erythemal response To aid the consumer in selecting the ton, New Jersey, pp. 285-305,1959. correlates with the amount of radi­ type of sunscreen product best suited ation absorbed by the individual’s to the Individual’s complexion (pig­ (17) Epstein, J. H., K. Fukuyama, and R. mentation), response to UV light and L. Dobson, “Ultraviolet Light Carcinogene­ skin. Therefore, the Panel has classi­ fied sunscreen active ingredients into the type of outdoor activity, the Panel sis,” in “The Biologic Effects of Ultraviolet recommends the following product Light Radiation,” Edited by F. Urbach, Per- categories based upon their UV screen­ category designations (PCD’s) for the gamon Press, London, pp. 551-568,1969. ing capacity. product or formulation to be market­ (18) Kligman, A. M., “Solar Elastosis in The scientific literature contains ed: Relation to Pigmentation” in “Sunlight and definitions of sunscreen types, describ­ 1. Minimal Sun Protection Product Man,” Edited by T. B. Fitzpatrick, M. A. ing the chemicals and substances used Sunscreen products that provide an Pathak, L. C. Harber, M. Seigi, and A. Kur­ to prevent sunburn. However, informa­ SPF value of 2 to under 4, and offer kita, University of Tokyo Press, Tokyo, pp. tion from consumer groups revealed 157-164, 1974. the least protection, but permit sun­ that the terms used, such as “sun­ tanning. (19) Smith, J. G., E. A. Davidson, W. M. screen,” “sunshades,” and “sunblock” Sams, and R. D. Clark, “Alterations in 2. Moderate Sun Protection Product Human Dermal Connective Tissue with Age might not be meaningful to the gener­ Sunscreen products that provide an and Chronic Sim Damage,” Journal of In­ al population. The Panel considered SPF value of 4 to under 6 and offer vestigative Dermatology, 39:347-350, 1962. many terms in an effort to find a noun moderate protection from sunbuming, (20) Smith, J. G., E. A. Davidson, J. P. or adjective that would describe the but permit some suntanning. Tindall, and W. M. Sams, “Hexosamine and use of these preparations. 3. Extra Sun Protection Product Hydroxyproline Alterations in Chronically The Panel adopts the following defi­ Sunscreen products that provide an Sun-Damage Skin,” Proceedings of the Soci­ nitions for therapeutic sunscreen SPF value of 6 to under 8, offer extra ety of Experimental Biology and Medicine, types: protection from sunbuming and 108:533-535, 1961. 1. Sunscreen sunburn preventive permit limited suntanning. (21) Knox, J. H., A. C. Griffen, and R. E. agent An active ingredient that ab­ 4. Maximal Sun Protection Product Hakim, “Protection from Ultraviolet Car­ sorbs 95 percent or more of the light Sunscreen products that provide an cinogenesis,” Journal of Investigative Der­ in the UV range at wavelengths from SPF value of 8 to under 15, offer maxi­ matology, 34:51-58,1960. mal protection from sunburning, and 290 to 320 nm and thereby removes permit little or no suntanning. E. SUN PROTECTION FACTORS the sunbuming rays. 5. Ultra Sun Protection Product 2. Sunscreen suntanning agent An Sunscreen products that provide an The “Sim Protection Factor” (SPF) is active ingredient that absorbs at least SPF value of 15 or greater, offer the used in Europe on sunscreen products. The 85 percent of the light in the UV Sun Protection Factor, which is related to most protection from sunbuming and the Protective Index gives the consumer a range at wavelengths from 290 to 320 permit no suntanning. guide as to how the product will act on his nm, but transmits UV light at wave­ The Panel reviewed the effects of skin. The SPF value may be defined as the lengths longer than 320 nm. Such UV light on the skin (ref. 2). The ratio of the amount of energy required to agents permit tanning in the average Panel has summarized the following produce a minimum erythema dose (MED) individual and also permit some red­ compilation of skin types, sunscreen or minimal sunburn through a sunscreen dening (erythema) without pain. Sun Protection Factors, and Product product film to the amount of energy to 3. Sunscreen opaque sunblock agent Category Designations discussed in produce the same MED without any treat­ An opaque agent that reflects or scat­ this document: ment. The following equation represents this ratio: Skin types and recommended sunscreen products SPF value=MED Protected Skin/MED Un­ Skin type Sunburn and tanning history Recommended sun protection factor protected Skin and product category designation The European experience over the I ...... Always burns easily; never tans (sen- 8 or more < maximal, ultra). past 20 years has shown the following sitive). protection factors based upon skin I I ...... Always bums easily; tans minimally 6 to 7 < extra > (sensitive). types (ref. 1): III ...... Burns moderately; tans gradually 4 to 5 (moderate» (light brown) (normal). SPF value and skin type IV ...... — ...... —...... Bums minimally; always tans well 2 to 3 (minimal) SPF 3—For nonsensitive skin and skin al­ (moderate brown) (normal). V;...... Rarely bums; tans profusely (dark 2 (minimal» ready accustomed to the sun (minimal brown) (insensitive). protection). V I...... Never burns; deeply pigmented (in- None indicated. SPF 4—For normally sensitive skin (moder­ sensitive). ate protection). SPF 6—For sensitive skin (extra protection). 1 Based on first 30 to 45 minutes sun exposure after winter season or no sun exposure.

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38214 PROPOSED RULES

The Panel recommends that the fol­ (2) Jimbow, K., M. A. Pathak, G. Szabo (2) For moderate sunscreen products. lowing compilation of skin types and and T. B. Fitzpatrick, “Ultrastructural (i) “Affords moderate protection product category designations be ap­ Changes in Human Melanocytes after Ultra­ violet Radiation,” in “Sunlight and Man,” against sunburn.” propriately included in labeling as a Edited by M. A. Pathak, L. C. Harber, M. (ii) “Prolongs exposure time before guide: Seiji and A. Kukita, University of Tokyo sunburn occurs”’ Press, Tokyo, pp. 195-215, 1974. (iii) “Permits tanning (or suntan­ R ecommended S unscreen P roduct G uide ning) and reduces chance of (or mini­ Sunburn and Tanning History and H. LABELING OF SUNSCREEN PRODUCTS mizes) sunburning.” Recommend Sun Protection Product I. Indications. The indications for (iv) “Helps prevent sunburn on mod­ Always burns easily; never tans.—Maximal, use of a sunscreen are to be simply erate exposure of untanned skin.” Ultra. (v) “Allows you to stay in the sun 4 Always burns easily; tans minimally.— and clearly stated. Statements of indi­ Extra. cations for use are to be specific and times longer than without sunscreen Burns moderately; tans gradually.—Moder­ confined to thu conditions fpr which protection.” ate. the product is recommended. The di­ (vi) “Provides 4 times your natural Burns minimally; always tans well.—Mini­ rections for use are to be clear and protection from sunburn.” mal. provide the user a reasonable expecta­ (3) For extra sunscreen products, (i) Rarely bums; tans profusely.—Minimal. tion of the results anticipated from “Affords extra protection against sun­ The Panel believes this “Recom­ use of the product. burn.” mended Sunscreen Product Guide” The indications for use may contain (ii) “Prolongs exposure time before will benefit the consumer. On first any of the following: sunburn occurs.” using this scale some people may mis­ a. For all (minimal, moderate, extra, (iii) “Permits limited tanning (or judge the reactivity of their skin to maximal, and ultra) sunscreen prod­ suntanning) and reduces chance of (or sunlight. Elevated heat and humidity, ucts. (1) “Sunscreen to help prevent minimizes) sunburn.” sweating, and swimming may lower sunburn.” (iv) “Helps prevent sunburn.” the SPF value at any one time for an (2) “Filters (or screens) out the sun’s (v) “For sun-sensitive skin.” individual. In practical terms, a person (vi) “Extra protection against sun­ who usually gets red in the sun after burning rays to prevent sunburn.” (3) “Screens out the sun’s harsh and burn for blondes, redheads and fair­ 20 minutes should be able to stay in skinned persons.” the sun for 120 minutes (2 hours) if he often harmful, rays to prevent sun­ burn.” (vii) “Allows you to stay in the sun 6 applies a sunscreen of extra protection times longer than without sunscreen (SPF 6), i.e., 20 minutes X 6, provided (4) “Overexposure to the sun may lead to premature aging of the skin protection.” the product is not washed or sweated (viii) “Provides 6 times your natural off. and skin cancer. The liberal and regu­ lar use over the years of this product protection from sunburn.” As noted above, the Panel suggests (4) For maximal sunscreen products. five PCD categories, i.e., minimal, may help reduce the chance of these harmful effects.” (i) “Affords maximal protection moderate, extra, maximal, and ultra against sunburn.” (5) “Overexposure to the sun may protection. The maximal protection (ii) “Prevents sunburn and limits (SPF 8) category would protect, for lead to premature aging of the skin tanning.” 320 minutes, the average person who and skin cancer. The liberal and regu­ would be burned in 40 minutes or lar use over the years of this product (iii) “For sun-sensitive skin.” through the dangerous sunburning may help reduce the chance of prema­ (iv) “Maximal protection against hours of 10 a.m. to 2 p.m. Once the ture aging of the skin and skin sunburn for blondes, redheads and skin has become accustomed to the cancer.” fair-skinned persons.” sun, the individual’s self-protection b. Additional indications. In addi­ (v) “Allows you to stay in the sun 8 period is longer, and in practice this tion to the indications provided above times longer than without sunscreen means that gradually a product with a in item a., the following may be used: protection.” lower PCD can replace a product with (1) For minimal sunscreen products. (vi) “Provides 8 times your natural a higher PCD because the risk of sun­ (i) “Affords minimal protection protection from sunburn.” burn has become smaller. against sunburn.” (5) For ultra sunscreen products, (i) The Panel recommends the use of (ii) “Prolongs exposure time before “Affords the most protection against the guideline outlined above with the sunburn occurs.” sunburn.” inclusion of the ultra protection (SPF (ii) “Prevents tanning and sunburn.” (iii) “Permits tanning (or suntan­ (iii) “For highly sun-sensitive skin.” 15 or more) category for highly sensi­ ning) and reduces chance of (or mini­ tive individuals needing this degree of (iv) “Greatest protection against mizes) sunburning.” sunburn for blondes, redheads and protection against UV light. The Panel (iv) “Helps prevent sunburn on limit­ fair-skinned persons.” emphasizes that the PCD for the ed exposure of untanned skin.” package labeling is determined for the (v) “Provides the highest degree of (v) “Helps to protect the skin sunburn protection and permits no final product or furmulation, not the against sunburn while permitting tan­ tanning.” active ingredient alone. ning.” (vi) “Provides the highest degree of R eferences (vi) “Allows you to stay in the sun 2 sunscreen protection and permits no (1) Greiter, F., “Sonnenschutzmittel- times longer than without sunscreen tanning.” Typen und Anwendung,”*5onderdrMc/c aus protection.” c. For all (maximal and ultra) sun­ Parfumerie und Kosmetick, 55:199-202, (vii) “Provides 2 times your natural screen products that contain sun­ 1974. protection from sunburn.” screen Opaque sunblock ingredients.

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38215

••Reflects the burning rays of the its sun protection for at least 30 min­ I. SUNSCREEN PRODUCTS CONTAINING sun.” utes of heavy sweating.” DIHYDROXY ACETONE 2. Statement on product perform­ (ii) “Sweat resistant.” Dihyroxyactone (DHA) is an ingredi­ ance—(a) Product Category Designa­ 3. Warnings—(a) For all (prdnimal, ent included in sunscreen prepara­ tion (PCD). The Panel concludes that moderate, extra, maximal, and ultra) tions. Based upon the discussion improved, more informative labeling sunscreen products. The labeling of all below, the Panel concludes that DHA should be provided to the consumer to sunscreen products should contain the is a cosmetic in all cases except when aid in selecting the most appropriate following warnings: used in sequential conjuction with law- sunscreen product. The Panel recom­ (1) “For external use only, not to be sone. mends that the following labeling swallowed.” s DHA is also know as 1,3-dihydroxy- statements be prominently placed on (2) “Avoid contact with the eyes.” 2-propanone. It is produced from glyc­ the principal display panel of appro­ (3) “Discontinue use if signs of irri­ erol by Aerobacter species under aero­ priate products: tation or rash -appear.” bic conditions. It is a fairly hygrosco­ (1) Products containing active ingre­ (b) Specific warnings—(1) For sun­ pic, crystalline powder having a char­ dients that provide a SPF value of 2 to screen products providing an SPF acteristic odor and a sweet and cooling under 4: “Minimal Sun Protection value of 2 to under 4: “Use on children taste. DHA normally occurs as a dimer Product (SPF 2)—Stay in the sun under 2 years of age only with the in which form it is slowly soluble in 1 twice as long as before without sun- burning.” advice of a physician.” part water and 15 parts alcohol. When (2) Products Containing active ingre­ (2) For sunscreen products providing freshly prepared, DHA reverts rapidly dients that provide a SPF value of 4 to an SPF value of 4 or greater. “Use on to a monomer in solution, in which children under' 6 months of age only form it is very soluble in water, alco­ under 6: “Moderate Sun Protection hol, ether, and acetone. DHA is a Product (SPF 4)—Stay in the sun 4 with the advice of a physician.” times as long as before without sun- 4. Directions for use. The Panel be­ three-carbon sugar and is an interme­ burning.” lieves than many consumers use inad­ diate in the metabolism of carbohy­ equate amounts of sunscreen. Offering drates in higher plants, animals, and (3) Products containing active ingre­ man (refs. 1 and 2). dients that provide a SPF value of 6 to more detailed guidelines would benefit the consumer. DHA has a unique property of pro­ under 8: “Medium Sun Protection ducing a reddish brown color when in Product (SPF 6)—Stay in the sun 6 Based on a review of the available times as long as before without sun­ data, the Panel recommends that the direct contact with the keratin of the “Directions for Use” state: “Apply lib­ skin. The mechanism of action for pro­ burning.” ducing this color is not completely un­ (4) Products containing active ingre,- erally before sun exposure and reap­ derstood, but most studies agree that dients that T>ro vide a SPF value of 8 to ply after swimming or after excessive DHA reacts with certain amino acids under 15: “Maximal Sun Protection sweating.” of the stratum comeum to form the Product (SPF 8)—Stay in the sun 8 However, for sunscreen products color, the intensity of which is directly times as long as before without sun­ that satisfy the water resistance, wa­ related to the skin’s thickness (refs. 1, burning.” terproof, and sweat resistance testing 3, and 4). Because the epidermis con­ (5) Products containing active ingre­ procedures described elsewhere in this taining keratin varies over different dients that provide a SPF value of 15 document, the directions for use in the areas of the body, different degrees of or greater: “Ultra Sun Protection labeling of these products may be coloration may result. Areas such as product (SPF 15)—Stay in the sun 15 modified in accordance with the re­ the palms of the hands, warts, and cal­ times as long as before without sun- sults of the test. (See part III. para­ loused skin react to a greater extent burning.” graph D. below—suncreen product than surfaces where skin is thinner. (b) Labeling claims related to the testing procedures for determination Scar tissue does not react to the PCD and SPF value. The Panel recom­ of the sun protection factor (SPF) extent of normal skin and may show mends any of the following labeling value and related labeling claims.) The up as a light-colored contrast. The claims for sunscreen products that sat­ Panel recommends that for sunscreen nails and hair of the body show less isfy the sunscreen product testing pro­ products that satisfy these testing pro­ affinity for DHA and therefore do not cedures described elsewhere in this cedures the following labeling modifi­ react as readily to coloration. Repeat­ document. (See part III. paragraph D. cations replace the directions-for-use ed application will cause an increased below—Sunscreen product testing pro­ progressive darkening, as also will an cedures for determination of the sun labeling indicated above: (a) For all (minimal, moderate, increase in concentration. Alcohols, protection factor (SPF) value and re­ change 4n pH, and surfactants may lated labeling claims.) extra, maximal, and ultra) sunscreen products that satisfy the water resis­ also increase the rate of reaction. It (1) For all (minimal, moderate, should be noted that human sweat extra, maximal, and ultra) sunscreen tant testing procedures. “Apply liberal­ also contains the amino acids neces­ products that satisfy the water resis­ ly before sun exposure and reapply sary to promote coloration (refs. 1, 3, tance testing procedures, (i) “Water re­ after 40 minutes in the water or after and 4). sistant.” excessive sweating.” One manufacturer submitted data (ii) “Retains its sun protection for at (b) For all (minimal, moderate, for a sunscreen product composed of least 40 minutes in the water.” extra, maximal, and ultra) sunscreen two separate lotions containing DHA (iii) “Resists removal by sweating.” products that satisfy the waterproof and lawsone, respectively: The lotions (2) For all (minimal, moderate, testing procedures. “Apply liberally are to be applied to the skin only in extra, maximal, and ultra) sunscreen before sun exposure and reapply after the stated sequence. Labeling for the products that satisfy the waterproof 80 minutes in the water or after exces­ product includes claims such as “sun­ testing procedures, (i) “Waterproof.” sive sweating.” screen lotion,” “for protection of sun- (ii) “Retains its sun protection for at (c) For all (minimal, moderate, sensitive skin,” and “water-resistant least 80 minutes in the water.” extra, maximal, and ultra) sunscreen barrier to sun’s ultraviolet rays.” (iii) “Resists removal by sweating.” products that satisfy the sweat resis­ Therefore, the Panel addressed the (3) For all (minimal, moderate, tance testing procedures. “Apply liber­ product not as a cosmetic, but as a extra, maximal, and ultra) sunscreen ally before sun exposure and reapply sunscreen. Safety and efficacy of DHA products that satisfy the sweat resis­ after 30 minutes of excessive sweat­ in conjunction with lawsone is dis­ tance testing procedures, (i) “Retains ing.” cussed below. (See part III. paragraph

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 38216 PROPOSED RULES B.1.1. below—Lawsone with dihydrox- Studies were performed to deter­ In this study, however, the homosa­ yacetone.) mine the protective effectiveness of late lotion (average of 0.42+ and DHA has not been shown to be ef­ two sunscreen lotions, each containing 0.96+ for pretanned and nontanned fective as a topical sunscreen when 8 percent homosalate with and with­ areas, respectively) provided slightly used alone. Current scientific evidence out 3.5 percent dihydroxy acetone, better protection than the homosa- shows that DHA, except in conjunc­ against erythema induced by UV light late/dihydroxyacetone lotion (average tion with lawsone, has no appreciable exposure on nontanned and dihydrox- of 0.17+ and 0.62+ for pretanned and sun-screening activity. y ace tone-tanned skin (ref. 9). In the nontanned areas, respectively). This Shaffer et al., using 10 white male first study, a strip of skin on the lower difference was explained by the vari­ volunteers, tested the suhscreening abdomen of a subject was tanned by able thicknesses at which these sun­ properties of DHA. Each subject had six applications of a dihydroxyacetone screen lotions were applied. three test areas, each measuring 1 lotion over a 6-hour period. The next The Panel concludes that DHA inch by 1 inch, marked on the arm. day a template was uged to mark off alone is not a sunscreen, but a cosmet­ One of the test areas contained amino- eight comparable areas, four non­ ic. The Panel further concludes that benzoic acid, the second area con­ tanned and four dihydroxyacetone- DHA is a sunscreen when used sequen­ tained 2 percent DHA in isopropyl al­ tanned. Within each set, two areas tially with lawsone. were used as controls, one area was cohol, and the third area was used as a R eferences control. The areas were subjected to a covered with the homosalate/dihy- 4+ erythema dose of UV light with a droxyacetone lotion, and the remain­ (1) OTC Volume 060067. ing area was covered with the homosa­ (2) The Merk Index, 9th Ed., Merk and fluorescent UV lamp. Observations Co., Inc., Rahway, N.J., p. 598, 1976. from the test showed the aminoben- late lotion. All areas were then ex­ (3) OTC Volume 060066. zoic acid test area with no erythema; posed to 1 hour of late morning sun­ (4) OTC Volume 060069. the control area developing a 4+ light and were scored 24 and 48 hours (5) Shaffer, B., M. M. Cahn and E. J. Levy, erythema; and the DHA area showing afterwards on a scale from 0 (no eryth­ “The Use of Dihydroxyacetone for Skin ema) to 4+ (deep red and painful blis­ Tanning,” Archives of Dermatology, 83:437- 6 subjects with 4+ erythema, 2 sub­ 438, 1961. jects with 3+ erythema, and 2 subjects ters). The previously tanned control areas showed slight erythema (1 + ) at (6) Fusaro, R. M., W. J. Runge, F. W. with 2+ erythema (ref. 5). Lynch, and C. J. Watson, “Sunlight Protec­ Studies performed by Fusaro et al. 24 hours and were lighter (0.5 + ) by 48 tion in Normal Skin,” Archives of Dermatol­ (ref. 6) and Rice (ref. 4) demonstrated hours, whereas the nontanned control ogy, 93:106-111, 1966. that test sites treated with single areas were scored 3+ (deep red with (7) Mumford, P. B., “Dihydroxyacetone,” slight pain) at 24 and 48 hours. Those British Journal or Dermatology, 72:279-280, active ingredient preparations of DHA areas treated with the two sunscreens 1960. or lawsone were essentially unprotect­ showed no erythema except for the (8) Maibach, H. I. and A. M.“ Kligman, “Di­ ed when compared with those sites nontanned areas treated with the ho­ hydroxyacetone—A Suntan Stimulating treated with both ingredients either in mosalate lotion, which were scored 1 + Agent,” AM A Archives of Dermatology, a freshly prepared combination prepa­ (definite pink or light red) at 24 and 82:505-507, 1960. ration or in separate vehicles. 48 hours. Similar results were ob­ (9) Black, A. and R. A. Casini, “Ultraviolet Mumford (ref. 7) states that DHA Light Screening Effects of Homomenthyl tained in another study wherein the Salicylate Lotions on Nontanned and DHA does not diminish the response to UV undersides of three subjects’ forearms Tanned Skin,” Draft of unpublished paper radiation. Comparative testing showed were prepared in the above-described in OTC Volume 060067. equal erythema when applied to paint­ manner and exposed to the light of a ed and unpainted skin. Repeated ap­ sunlamp at a distance of 12 inches. In J. COMBINATIONS plication of DHA to recently excised a third study a strip across the back of 1. Combinations of sunscreen active human mammary skin did not appear each of 12 subjects (six male and six ingredients. The Panel has reviewed to develop melanin type of pigment. female) was tanned with two applica­ the submitted data and finds that a Maibach and Kligman tested sun­ tions of a dihydroxyacetone prepara­ majority of marketed sunscreen prod­ screening with 5 percent DHA. The tion, one application in the forenoon ucts contain only one or two sunscreen backs of 10 White male subjects, half and a second later in the afternoon. active ingredients. Additional sun­ of the back of which were painted The next day, templates were used to screen active ingredients are included with 5 percent DHA, and the other mark off three 1 inch squares each of primarily to enhance the performance half serving as a control, were subject­ nontanned and tanned skin. Within of the final product formulation. Be­ ed to UV radiation and observed for each set, one area served as a control; cause each final product formulation erythema. Results of this test proce­ one was treated with the homosalate/ intended for OTC use is requred to dure found that DHA neither in­ dihydroxyacetone lotion; and the re­ comply with the testing procedure creased nor decreased the erythema or maining square was treated with the provided for in the OTC sunscreen tanning response to UV light (ref. 8). homosalate lotion. Owing to rain con­ monograph described below, the Panel There were no product submissions ditions, a sunlamp instead of natural has established no upper limit to the made to the Panel using DHA as a sunlight was used as the light source, number of sunscreen active ingredi­ single ingredient. However, sunscreen with the nontanned control areas ents a product may contain. However, products containing DHA were sub­ being irradiated for 4 minutes while the Panel believes it is reasonable to mitted to the Panel for review in com­ all other areas were irradiated for 8 require that additional sunscreen bination with the sunscreen ingredi­ minutes at a distance of 12 to 14 active ingredients must make a contri­ ents homosalate and padimate A. inches. All areas were scored 24 and 48 bution to the designated indications These products are not for sequential hours afterwards using the above-de­ for the product and not merely be in­ use. The safety and effectiveness of scribed scale. The pretanned control cluded for marketing promotion pur­ the sunscreens homosalate and padi­ areas (1.67+ average) showed slightly poses. mate A are reviewed separately below. less erythema than the nontanned The Panel concludes that two or (See part III. paragraphs B.l.k. and o. control area (2+ average), even more sunscreen active ingredients may below—Homosalate; Padimate A). though the pretanned areas were irra­ be combined provided that: These submissions label DHA a cos­ diated twice as long. The protective a. Each is present in sufficient quan­ metic and do not make any claims action of pretanning with dihydroxya­ tity to act additively or by summation showing that DHA will afford any ad­ cetone was demonstrated by those to produce the claimed therapeutic ditional sun-screening protection. areas treated with the two sunscreens. effect when the ingredients are within

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38217 the effective concentration range spec­ are not to be used on children under canal, produce a waxy, protective se­ ified for each ingredient in the mono­ the age of 6 months. This margin of cretion which may further limit the graph. safety is considered important because juxtaposition of medication to the b. The ingredients do not interact of the problems of medicating young skin surface; mucous membranes in with each other and one or more do children. Biologic systems which me­ close apposition to the skin as found not reduce the effectiveness of the tabolize and excrete drugs absorbed in the mouth, the inner aspects of the other or others, by precipitation, through the skin may not be fully de­ labia, and the inside of the eyelids, change in alkalinity or acidity, or in veloped in children under the age of 6 commonly absorb medications many some other manner that reduces the months. times more readily'than does the skin. claimed therapeutic effect. b. Sex. Although obvious differences (4) Human skin appears to be c. The partition of the active ingredi­ are known between male and female unique, and its characteristics and re­ ents between the skin and the vehicle skin, the Panel believes that these are lation to drug absorption are not mim­ in which thay are incorporated is not not likely to affect the safety or effi- icked exactly by any other species. impeded and the therapeutic effective­ ciacy of the various ingredients consid­ b. Physicochemical conditions. (1) ness of each remains as claimed or is ered as sunscreens. The skin can absorb considerable not decreased. 2.' Skin penetration. The Panel has quantities of water. By hydrating the 2. Combinations of sunscreen and recommended that sunscreens be dis­ skin, absorption is facilitated. Com­ nonsunscreen active ingredients. The continued if signs of irritation or rash plete occlusion by physical means can Panel also concludes that sunscreen appear. However, possible penetration increase absorption 100-fold. active ingredients may be combined of sunscreens through the intact skin (2) The varying temperatures ranges with other active ingredients* e.g., skin was considered by the Panel. obtainable in human environments protectants, provided that the ingredi­ Skin penetration is a complex proc­ greatly affect absorption. ents are generally recognized as safe ess that is modified by numerous fac­ (3) In general, increasing concentra­ and effective, i.e., Category I active in­ tors. Three portals of entry are possi­ tion leads to increased absorption of gredients. ble through the human skin. They are drugs applied to the skin. However, in the epidermal barrier, the hair folli­ almost every instance, a plateau effect III. S u n s c r e e n s cles, and the sweat glands. For practi­ occurs because there may be a reduced A. GENERAL COMMENT cal purposes, all absorption occurs rate of absorption in high concentra­ through the epidermal barrier and tion due to the effects of the drug on A considerable number of OTC sun­ sweat glands. The epidermal barrier the skin itself. screen preparations are now available consists of the stratum comeum, (4) The Panel accepts the Meyer- to the American public for prevention which is a keratophospholipid com­ Overton theory that lipid-soluble sub­ of sunburn. As was mentioned above, plex up to 1,500 microns thick. Absorp­ stances diffuse through the lipid por­ other ingredients that are not sun­ tion of the skin barrier and water solu­ screens may be included in marketed tion through these barriers depends products. These may also be active in­ primarily on the physicochemical ble substances diffuse through the hy­ gredients, but not sunscreens, or de­ structure of the drug and less so on drated component of the proteins clared as inactive ingredients used as the vehicle is which it is. contained. found within this barrier (ref. 1). The emollients or moisturizers. Regardless However, the vehicle is important and partition coefficient is rate-limiting of composition, the final formulation will be considered later. when related to the drug in its vehicle for marketing should be evaluated by Three important conditions of the and the stratum comeum. the procedures described below. (See skin affect drug penetration. The con­ Substances soluble in both water part III. paragraph C. below—Data ditions are physiological, physicoche­ and lipid readily penetrate the skin Required For Evaluation.) As back­ mical, and abnormal skin. barrier. ground to a survey of the safety and a. Physiological conditions. (1) Skin (5) Generally, smaller molecules efficacy of such preparations, it is nec­ age which is discussed above. penetrate more rapidly than larger essary to understand certain aspects of (2) Blood flow within the skin may molecules; substances up to the size of the anatomy and physiology of the increase or decrease penetration, but 1,000 daltons are usually well ab­ skin, as well as give some considera­ this effect is questionable and may not sorbed, while larger ones have more tion to the penetration of materials directly affect absorption by the flow difficulty. Polar groups show less ab­ into and through the skin barrier. rate alone. sorption than nonpolar groups. Al­ 1. The skin. The anatomy and physi­ (3) Data on penetration based on though molecular configuration un­ ology of the skin was considered by skin site is conflicting and includes questionably affects absorption, the the Panel using standard references variations of absorption in the same mechanisms involved are not well un­ and texts. Concerning certain features site for reasons that are unclear. Stud­ derstood. on which there was little objective ies in cadaver skin suggest that ab­ (6) Vehicles are important in deter­ data, the following decisions were sorption is directly related to skin mining the state of the drug with re­ made: thickness and that it is greater in spect to absorption and will be consid­ a. Age. The Panel accepted adult areas where large hair follicles are ered below. human skin to be older than 6 months present. The vehicles in which drugs are con­ of age. It is possible that geriatric skin Various skin sites have considerable tained are secondary in importance to requires special consideration, the pa­ difference in dermal thickness, in sec­ other conditions discussed, but they rameters of which are poorly under­ ondary skin appendages including the are important nonetheless. For exam­ stood. Human skin, under the age of 6 number of sweat glands and hair folli­ ple, a drug should not bind too strong­ months, may well have different ab­ cles, and in the physical location of ly to any component of its vehicle so sorptive characteristics. The Panel the skin. For example, in areas well that its partition with respect to the concludes that products providing a supplied with sweat glands in close ap­ skin barrier favors the vehicle. Low ve­ mainimal SPF value of 2 to under 4 position to other skin areas, such as hicular affinity is desirable. should not be used on children under 2 the axilla (armpit) and the groin Although the original charge to the years, and products providing a mini­ (crotch), medications applied may be Panel was to review only the active in­ mal SPF value of 4 should not be used more irritating than in other locations gredients for safety and effectiveness, on children under 6 months of age. because of the presence of constant the Panel believes that the vehicle in To provide an added margin of moisture and friction. Specialized which the ingredient or combination safety, the ingredients reviewed below sweat glands, as found in the ear of ingredients resides may have con-

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38218 PROPOSED RULES siderable effect on the effectiveness of greasing, nonirritant, nondehydrating, oral route or by injection. Such animal the ingredient or ingredients involved. nondrying, odorless, efficient on all testing is necessary, whether or not The Panel stresses that continued kinds of human skin, hold at least 50 substantivity or absorption has been contact of a film of the active ingredi­ percent water, be easily compounded shown, because individuals, especially ent is essential for efficacy in most of known chemicals, and have infinite children, may accidentally ingest or cases. Therefore, the medium in which stability during storage. There is no inhale the agents, or absorb them an active ingredient is incorporated ideal vehicle. Vehicles in common use through the skin. must provide not only the necessary represent a compromise of advantages Clinical use and marketing experi­ solubility and stability, but also main­ against disadvantages, many of which ence were also used by the Panel in es­ tain contact of the active ingredient have been noted previously. It is diffi­ tablishing the safety of sunscreen in­ with the skin. A medium must not cult to predict with any degree of ac­ gredients. The Panel accepted the retard the passage of the drug into the curacy the influence of vehicular for­ data on “complaints per unit sold,” skin, thereby decreasing its bioavaila­ mulations on the percutaneous absorp­ submitted by the various companies, bility. tion of drugs. Many authorities believe as one indicator of human safety for The rate of diffusion of a drug that medicináis are absorbed more final preparations. However, anecdotal within its vehicle bears a direct rela­ readily from animal or vegetable oils descriptions of toxicity were not seri­ tionship to its ability to penetrate the than from petrolatum bases. ously considered by the Panel unless skin barrier, as does the rate of release Vehicles for topical delivery of active they were supported by data that in­ of the drug from the vehicle. The ve­ ingredients are complex mixtures of cluded the units of actual use. hicle may have an effect on the hydra­ substances designed to impart a cer­ When a drug is available for wide­ tion of the stratum comeum. In gener­ tain characteristic to the finished spread use as in OTC sunscreen prod­ al, vehicles which increase or maintain product. Although classified as inac­ ucts, its safety must be well-document­ hydration promote drug absorption, tive or inert ingredients, many vehicles ed by data on its toxicology, excretion, but this is not universally true. are involved in physical and chemical and pharmacologic action. The Panel Surface-active agents (surfactants) interactions with the outer layer of evaluated the submitted toxicological within the vehicle may change the human skin (the stratum comeum). data and classified the ingredients as physical state of the water within the The persistance, penetration, and re­ described below. skin and thereby increase absorption sistance of the active ingredients to A number of patch test methods are of polar compounds. Cationic and non­ abrasion, sweating, and washing often applicable to human safety testing of ionic groups are considerably less depends upon the vehicle. Ingredients category III ingredients or final prod­ active than anionic groups. Most vehi­ reviewed by this Panel were catego­ ucts. These tests have proven valuable cles consist of emulsions in which rized on the basis of their currently in predicting skin irritancy and sensiti­ there is at least one immiscible liquid employed topical vehicles. zation. The Panel recommends the fol­ within another consisting of a discon- The Panel strongly recommends lowing methods of patch testing: tinous, internal, or dispersed phase that all inactive ingredients, including (1) The Draize human skin irritancy and a continous, external, or nondis- those in the vehicle, be listed with or and sensitization tests and the various persed phase. At the interface, surface without a statement of their quantity. modifications utilizing the subject’s tensions are smaller than the largest The consumer, his/her physican, or back or arm may be Used (ref. 2). value of any of the elements of an his/her pharmacist may need to know (2) The method of Shelanski and emulsion. Within an emulsion, there all the ingredients in a product for a Shelanski (ref. 3) is one in which the may be surface-active agents which variety of reasons, including possible active ingredient or formulation is ap­ are compounds strongly absorbed at adverse responses on the part of the plied regularly to the test site for 3 to surfaces which have polar and/or non­ user. 4 weeks. Then, following a rest period polar groups. Therapeutic claims cannot be made of 2 weeks, a single challenge applica­ Other ingredients combined with an on the basis of inactive ingredients or tion of the drug or formulation is active ingredient may also affect effec­ vehicles alone. Because, these sub­ made (ref. 3). The early applications tiveness by altering the pH of the stances are intended for topical appli­ are to detect primary skin irritants medium in which the active ingredient cation where cosmetic elegance and and initiate sensitization. The chal­ is incorporated, thereby changing its cosmetic acceptance are considerations lenge dose is to detect skin sensitizers. ionization and lipophilic qualities. An for the consumer, a fair statement de­ (3) The maximization procedure of active ingredient which is effective in scribing the vehicle formulation is rea­ Kligman or its modifications uses an the form of a free base may be less ef­ sonable, such as nongreasy, nonstain­ irritant on the test site, thereby has­ fective or ineffective as a salt. ing, oily, greaseless, velvety, emollient, tening and accentuating the skin sen­ Other semisolid dermatological vehi­ moisturizer, nonsticky, etc. sitizing potential of a substance (ref. cles, which may or may not be emul­ c. Abnormal skin. Any skin abnor­ 4). sions, are classified as follows: Oint­ mality tends to increase absorption of b. Effectiveness. The effectiveness of ments; cerates or pastes (stiffer than chemicals through it, but a few skin all category I sunscreens has been ointments); oleaginous or hydrocarbon abnormalities decrease absorption. demonstrated by appropriate studies. vehicles (generally consisting of fatty The Panel recognizes that drugs ef­ The UV absorbance of the individual acids which may become rancid); ab­ fective on the mucous membrane may sunscreen between 290 and 320 nm sorption bases which specifically not be effective on the intact skin. In was established. In addition, in most absorb water; emulsion bases; vanish­ some cases, concentrations effective on instances data were available for ing creams which contain approxi­ mucous membranes may be inad­ human subjects treated either with ar­ mately 75 percent water; and com­ equate on the skin. Therefore, trials of tificial sunlight or with natural sun­ pletely water soluble agents such as drug absorption on mucous mem­ light. low molecular weight carbowaxes or branes are not acceptable indications 4. Percutaneous absorption. As polyethylene glycol. Some of the for use on intact or damaged skin. noted above, certain ingredients are latter, with molecular weights of 1,500 3. Determination of safety and effec­efficacious in relation to their percu­ daltons or more, have approximately tiveness—a. Safety. It was decided by taneous absorption which may also be the same solid characteristics as petro­ the Panel that all materials applied to related to toxicity. Therefore, the latum. the human skin should also be tested Panel considers certain in vitro studies An ideal sunscreen vehicle would be for toxicity in test animals given the to be applicable both for safety and ef­ stable, neutral, nongreasy, nonde­ ingredient internally, by either the ficacy. Penetration studies of drugs in

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38219 animals are, unfortunately, hot direct­ B. CATEGORIZATION OF DATA The oral LD,o for the mouse and the rat were 17 g/kg and 6 g/kg, respec­ ly applicable to man. Some drugs can 1. Category I conditions under which be applied to large surface areas of the tively (ref. 1). The percutaneous (topi­ sunscreen active ingredients are gener­ cal) LDso was determined in mice by body, and drug penetration can be de­ ally recognized as safe and effective, termined from blood level and excre­ repeated applications of the alcoholic and are not misbranded. The Panel solution of aminobenzoic acid every 15 tion detection. Inferences of safety recommends that the category I condi­ minutes to the shaved skin of the ani­ can then be made based on the drug tions be effective 30 days after the mals. The, percutaneous LD50 was 180 levels obtained when related to toxic­ date of publication of the final mono­ g/kg. Death occurred within 24 to 48 ity studies. Methods to detect minute graph in the F ederal R e g is t e r . hours and was preceded by ataxia and quantities of some substances are not CATEGORY I ACTIVE INGREDIENTS coma (ref. 1). The toxicity was attrib­ available, and in general, no standard uted to the alcohol in the aminoben­ procedure to measure skin penetration The Panel has classified the follow­ zoic acid solution. in man exists. Animal studies should ing sunscreen active ingredients as In monkeys, a commercial prepara­ be performed as a preliminary to safe and effective and not misbranded: tion of aminobenzoic acid applied di­ human ih vivo testing. Aminobenzoic acid rectly to the eyes, produced reversible 5. Photosensitization. Photosensiti­ Cinoxate corneal opacity of short duration, zation is a broad term used to describe Diethanolamine p-methoxycinnamate minimal conjunctivitis, and moderate a rare but abnormal or adverse cutan­ Digalloyl trioleate chemosis. At the end of the test on Dioxybenzone. day 7, no toxic effects remained. In a eous reaction to light energy including Ethyl 4-[bis(hydroxypropyl)] aminoben- both the more common phototoxic zoate second monkey study, a 5 percent ami­ and the uncommon photoallergic re­ 2-Ethylhexyl 2-cyano-3,3-diphenylacrylate nobenzoic acid solution in alcohol was Ethylhexyl p-methoxycinnamate instilled in the eyes. Observations sponses. 2-Ethylhexyl salicylate were made at 10 minutes, 1 hour, 24 a. Photoallergy. Photoallergy (ref. 5) Glyceryl aminobenozate hours, and 2, 3, 4 and 7 days posttreat­ is an acquired altered photoreactivity Homosalate ment. Corneal haze, fluorescein stain­ dependent on an antigen-antibody or Lawsone with dihydroxyacetone ing, minimal conjuctivitis, minimal cell-mediated hypersensitivity state. Menthyl anthranilate Oxybenzone chemosis, and corneal epithelial haze The reactions may be produced by the Padimate A were seen in some monkeys. The cor­ sun alone or may depend on the pres­ Padimate O neal damage was transient, with no ence of a photosensitizer. The clinical 2-Phenylbenzimidazole-5-sulfonic acid permanent damage. The effects on the pattern may range from immediate ur­ Red petrolatum conjuctiva were minimal and cleared ticarial lesions to delayed papular and Sulisobenzone readily (ref. 1). In a third eye irrita­ Titanium dioxide tion study in rhesus monkeys, it was eczematous lesions. The Panel knows Triethanolamine salicylate of no universally acceptable test to concluded that an immediate precipi­ detect potential photoallergy in man. a. Aminobenzoic acid. The Panel tation of some component in the com­ concludes that aminobenzoic acid is pound caused the corneal and epithe­ b. Phototoxicity. Many dermal prep­ safe and effective for OTC use as a lial damage, possibly the result of an arations fluoresce under UV light sunscreen as specified in the dosage additive effect of the test compound stimulation, and the energy produced section discussed below. and the vehicle. The opacity that oc­ may cause lesions. This process is There are three isomers of amino­ curred could severely restrict vision in called phototoxicity. Tests for photo­ benzoic acid—the ortho, meta, and man, but this effect seems to be tran­ toxicity are extant in animals and para. The ortho and meta isomers sient. Possible secondary damage man. Sunlight-induced injury of the have little, if any, use in human thera­ could not be excluded (ref. 1). skin is generally toxic and independ­ peutics. The Panel recognizes only the In an oral toxicity study, rats were ent of allergic mechanisms. It can be para isomer, para-aminobenzoic acid, fed 2 g/kg aminobenzoic acid daily for likened to a primary irritant reaction. in its deliberations. Aminobenzoic acid 1, 2, 3, or 6 months. No significant dif­ The responses are characterized clini­ has been the official name for this ferences from controls were reported cally by erythema and edema which compound since the publication of the with respect to body weight, rate of may occur within minutes after irra-v National Formulary (NF XII) in 1965. growth, organ weights, or reproduc­ diation, but are usually delayed. The Prior to that time the official name tion. Histological changes were only usual response appears as an exagger­ was PABA (p-aminobenzoic acid). This seen in the thyroids of the treated rats obsolete designation occasionally still (ref. 2). ated sunburn. appears in the published literature. Prior to the broad spectrum antibi­ R eferences Aminobenzoic acid is an aromatic otics, aminobenzoic acid was used to (1) Idson, B., “Percutaneous Absorption,” acid. It is widely distributed in plant treat rickettsial diseases and typhus. Journal of Pharmaceutical Sciences, 64:901- and animal tissues besides being a Later it was used in treating diseases 923, WTO. structural component of the vitamin such as scleroderma and chronic fibro- (2) Draize, J. H., in “Appraisal of the folic acid, a member of the vitamin B tic disease as an antifibrotic agent. Safety of Chemicals in Poods, Drugs, and complex. Aminobenzoic acid consists Aminobenzoic acid has the ability to Cosmetics,” Association of Pood and Drug of white to slightly yellowish crystals cross-sensitize to a limited number of Officials of the United States, Austin, Tex., 1959. or crystalline powder. It discolors on structurally similar analogs. Amino­ (3) Shelanski, H. A. and M. V. Shelanski, exposure to air and light. One g dis­ benzoic acid belongs to a group of aro­ “A New Technique of Human Patch Tests,” solves in about 170 ml of water, in 8 ml matic amines and nitro compounds ca­ Proceedings Scientific Section, Toilet Goods of alcohol, and in 50 ml of ether. It pable of cross-reaction with each other Association, 19:46-49, 1953. melts at 188° C. because of similar chemical configura- (4) Kligman, A. M., “The Identification of (1) Safety. Clinical use and market­ tons. The cross-reacting is dependent Contact Allergens by Human Assay,” Jour­ ing experience have confirmed that on previous sensitization to the other nal of Investigative Dermatology, 47:369- related chemical compounds which in­ 374, 1966. aminobenzoic acid is safe in the dosage (5) Epstein, J. H., “Phototoxicity and Pho­ range used as an OTC sunscreen. clude sulfonamides, aniline dyes, para- toallergy Clinical Syndromes” in “Sunlight Acute toxicity studies have been phenylenediamine, “caine” anesthe­ and Man,” Edited by M. A. Pathak et al., done in the mouse and rat with an al­ tics, and others. Theoretically, an indi­ University of Tokyo Press, 1974. coholic solution of aminobenzoic acid. vidual with contact allergic hypersen-

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38220 PROPOSED RULES sitivity to any one of these chemicals not reach a steady state until 1 to 2 through dielectric effects, solvent- might develop an allergic dermatitis hours after application. Aminobenzoic solute interaction, variations in pH upon exposure to aminobenzoic acid. acid diffuses into the horny layer as a and solvent concentration (ref. 1). Despite this potential for phototoxi­ reservoir type of sunscreen. A reser­ Aminobenzoic acid does not penetrate city, contact sensitization and allergic voir type of sunscreen is strongly resis­ the human skin in any detectable reaction, “a review of the literature to tant to sweating and - partially resis­ level. One g of aminobenzoic acid dis­ date reveals no case reports of photo­ tant to immersion (ref. 6). solves in 170 ml water and in 8 ml eth­ toxicity and extremely few case re­ No systemic or dutaneous side ef­ anol aminobenzoic acid is currently ports of questionable photocontact al­ fects were noted in the course of an in­ marketed as a hydroalcoholic solution lergy and contact allergy to aminoben­ vestigation in which 30 ml of a 5 per­ and foam. It has been employed in 5 to zoic acid and its esters” (ref. 3). Willis cent alcohol solution of aminobenzoic 15 percent concentrations in creams has concluded “that PABA possesses acid was applied once daily to the face, and ointments. only the weakest potential for sensiti­ neck, truck, and upper extremities of Aminobenzoic acid has been used zation. It is indeed fortunate that we 10 healthy adult men for 30 days. No successfully as an effective sunscreen have such a highly effective sun­ changes occurred in blood cell count, up to approximately 315 nm and af­ screening agent which appears not to urinalysis, blood protein level, albu- fords protection for the short UV sun­ cause any serious side effects in the minglobulin ratio, blood urea nitrogen, burn wavelength range of 290 to 320 majority of users.” fasting blood glucose, serum glutamic nm. In a study with 46 individuals hyper­ oxaloacetic transaminase and serum For over 40 years, aminobenzoic acid sensitive to para-phenylenediamine creatinine levels. has been known to be an effective sup- with which aminobenzoic acid reacts, Ninety ml of aminobenzoic acid screen. Recent studies show it to be only 3 individuals cross-reacted follow­ lotion were applied to the entire body superior to many of the popular sun­ ing the application of 5 percent amino­ 3 times at 30 minute intervals in 4 sub­ screens marketed today for preventing benzoic acid (ref. 4). Although amino­ jects. Blood alcohol levels were deter­ sunburn. benzoic acid has been determined to mined at 15, 30, 60, 240 minutes and The efficacy of aminobenzoic acid is be the allergen in some cases of photo­ pretreatment controls. All failed to due to diffusion into the homy layer sensitivity, Kligman (ref. 5) in a study show any detectable amount of alco­ of skin and acting as a reservoir type with 25 subjects reported no sensitiza­ hol. of sunscreen. The agent is more effi­ tion in maximization tests using 20 Five subjects tested with 5 percent cient when applied 2 hours before sun percent aminobenzoic acid. He ob­ aminobenzoic acid lotion for 21 days exposure, to allow for maximal diffu­ served no sun sensitization over sever­ failed to show any significant irrita­ sion. This feature results in longer al years of testing. tion of this particular preparation protection and there is continuing sun­ Ten percent concentration of amino­ (ref. 1). screen effectiveness after sweating and benzoic acid produced no reactions of Aminobenzoic acid has been used on to a lesser extent after immersion. a phototoxic nature when occlusive thousands of patients with only a rare The sunscreening efficacy of amino­ applications were made to cellophane individual intolerance. The incidence benzoic acid in ethanol has been stud­ tape-stripped sites of 10 subjects who of adverse reaction is low indeed. Ami­ ied in experimental animals following were irradiated with the photoactivat­ nobenzoic acid has also been used as a exposure to artifical light sources, ing range of the ultraviolet spectrum. systemic and antifibrotic agen. (ref. 1). The results demonstrated that No inflammatory reactions greater The Panel concludes that extensive aminobenzoic acid protected the ani­ than the unirradiated control were in­ animal and human toxicological and mals against 40 to 50 minimal eryther- duced. Ten percent concentrations in pharmacological data attest to the mal doses (MED) in one study and petrolatum also showed no significant safety of aminobenzoic acid as a sun­ against 30 to 38 MED’s in another potential for inducing photocontact al­ screen ingredient for OTC use. study. In studies done under simulated lergy (ref. 6). (2) Effectiveness. There are studies swimming and sweating conditions, Kilgman (ref. 5) has stated that: documenting the effectiveness of ami­ the protection of aminobenzoic acid as * * * field experience has documented the nobenzoic acid as an OTC sunscreen. a sunscreen was diminished, but still claim that 5 percent hydroalcoholic solu­ The effectiveness of aminobenzoic remained (ref. 1). Cellophane stripping tions of aminobenzoic acid are substantially acid as a sunscreen agent is demon­ of the stratum of the skin in hairless superior to any other marketed sunscreen. dogs showed that aminobenzoic acid Evidence is accumulating that such solu­ strated by its in vitro UV light absorp­ tions are beneficial in other light-sensitive tion characteristics. Qualitative spec- does substantially penetrate the horny dermatoses * * *. Though we must now con­ trographic methods have demonstrat­ layer (ref. 9). cede that an occasional subject will become ed that aminobenzoic acid totally ab­ In albino mice, 5 percent aminoben­ sensitized, it iis our opinion that the merit of sorbs radiation between the wave­ zoic acid applied daily to the ears fol­ the product outweighs this risk. lengths of 260 nm and 313 nm of the lowed by 20-minute exposure to UV ir­ The prevention of acute sunburn is per­ mercury spectrum, with a maximum radiation, over a period of 5 months, haps the least important of the benefits indicated that the carcinogenic and provided. Our major interest in developing absorption at 288.5 nm (ref. 7). The superior sunscreens has been to prevent the curve is broad and such that at the erythematous effects of UV light can aging changes that underlie cancers and wavelengths effective for erythema, be reduced by the topical application precanceroses in sunlight-sensitive subjects. the absorption spectrum is enormous of aminobenzoic acid. The authors In this context, we would prefer to have and completely encloses the sunburn concluded that aminobenzoic acid is a such products regarded as drugs rather than action spectrum. In vitro study recog­ highly effective sunscreen that is ca­ cosmetics. Their important role is to pre­ nizes aminobenzoic acid as a potential pable of providing adequate protection vent disease and not simply to please. protective against sunburn. It has a against the damaging effects of sun­ As a general rule, low molecular cutoff point at 313 nm which allows light in man (ref. 10). weight substances with both lipid and UV rays with beneficial, biologic ef­ In a study comparing an aminoben­ water solubility are most likely to pen­ fects to be transmitte (ref. 8). Its in zoic acid lotion (5 percent aminoben­ etrate the horny layer. Aminobenzoic vivo efficacy can be affected by varia­ zoic acid in alcohol) and an aminoben­ acid is none of these agents. Amino­ bles in formulation and the effects of zoic acid foam (5 percent in alcohol) in benzoic acid permeability is about that physiological conditions, such as per­ rabbits, the foam preparation was 5 of water which penetrates the horny spiration and sebum on the skin. The times more effective as a UV blocking layer well. Even for these low molecu­ solvent in which the sunscreen is ap­ agent than the lotion. The lotion had lar weight substances, diffusion does plied also influences effectiveness a protective efficacy of 7.9; the foam

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38221 38.19. After elution, the lotion had a screens tested and was maintained for the same whether this was achieved protective efficiacy of 2.91; the foam 7 hours following applications (ref. by a single or multiple applications. In 2.96. Apparently the primary blocking 13). The protective action was reduced a formulation, erythemal protection was enhanced by the vehicle. (The upon induced sweating and fell to zero has been found to be maximal in vehi­ protective efficacy represents the following showering. cles containing between 50 percent number of MED’s against which the A 5 percent solution of aminobenzoic and 60 percent alcohol. However, in sunscreeen will protect (ref. ID.) acid in 55 percent alcohol with emol­ some studies, concentrations of 10 per­ The sunscreening effectiveness of a lients was evaluated with the xenon cent and 15 percent aminobenzoic acid 5 percent hydroalcoholic solution of arc lamp in 8 subjects. The protection have been reported to be effective as aminobenzoic acid was demonstrated was enhanced by applying greater sunscreen agents in a cream base. by Pathak, Fitzpatrick, and Frank amounts of solution. An application of The Panel concludes that aminoben­ (ref. 12) and later confirmed by other 60 fil/cm2 afforded protection against zoic acid is an effective sunscreen in­ investigators. Its effectiveness is such 25 to 30 MED’s. Protection following gredient for OTC use. that it is the recognized comparison immersion was reported to be greatest (3) Dosage, (i) For products provid­ standard for sun-screening efficacy. when 2 hours elapsed following appli­ Pathak et al. (ref. 12) compared the cation. Three applications at 2-hour ing a minimum SPF value of 2 to efficacy of 5 percent aminobenzoic intervals was superior to one (ref. 14). under 4 containing 5 to 15 percent acid in 70 to 95 percent ethyl alchohol Aminobenzoic acid was found to be aminobenzoic acid: Adult and children with 24 commercially available sun­ more effective than three brand name over 2 years of age topical dosage is screen preparations and various sunscreen products. liberal application before sun exposure chemical agents in a 3-year study In a study by Rossman, Knox and and reapply after swimming or after (1965-1968). The effectiveness of a Freeman (ref. 15), aminobenzoic acid excessive sweating. There is no recom­ single application of the 5 percent so­ was reported to be more effective as a mended dosage for children under 2 lution of aminobenzoic acid was great­ sunscreen than over 100 other sun­ years of age except under the advice er than that of the other UV-absorb- screen formulations tested. Ten per­ and supervision of a physician. ing compounds and brand name prep­ cent aminobenzoic acid in a vanishing (ii) For products providing a mini­ arations tested. It afforded very sig­ cream base was effective in excess of mum SPF value of 4 containing 5 to 15 nificant (p is less than 0.05) and effec­ 12 minutes in 17 patients irradiated percent aminobenzoic acid: Adult and tive protection. In vitro tests demon­ with the Hanovia hot quartz mercury children over 6 months of age topical strated that the prolonged effective­ vapor lamp, and extended from 20 to dosage is liberal application before sun ness of aminobenzoic acid results from 60 minutes in 13 additional patients as exposure and reapply after swimming adsorption of aminobenzoic acid by compared with an approximate mini­ or after excessive sweating. There is the intact epidermis and partial mal erythemal dose of 15 seconds on no recommended dosage for children chemical conjugation of aminobenzoic unprotected skin. under 6 months of age except under acid with constituents of the homy Rothman and Henningsen (ref 16) the advice and supervision of a physi­ layer. An alcoholic solution of amino­ studied the effectiveness of 15 percent cian. benzoic acid at pH 4.5 to 4.8 was found aminobenzoic acid in Ruggles’ cream (4) Labeling. The Panel recommends to be substantive to the homy layer in a film thickness of 0.03 mm. They the category I labeling for sunscreen even after repeated washings with found that these conditions increased active ingredients. (See part III. para­ water. In Arizona, where the study the amount of irradiation from a mer­ graph B.l. below—category I labeling.) was conducted, a single application of cury vapor lamp necessary to produce aminobenzoic acid provided total, day­ threshold erythema 50 to 100 times R eferences long protection for subjects who were the amount of irradiation producing (1) OTC Volume 060057. not swimming or engaged in activity. the same effect when the vehicle alone (2) Upton, A. C. and C. J. D. Zarofonetis, During periods of sweat-producing ex­ is used in the same film thickness. In “Histologic Findings in Rats Subjected to ercise, aminobenzoic acid gave 100 per­ the same study, these authors found Prolonged Administration of Para-amino- benzoic Acid,” Proceedings of the Society for cent protection from erythemogenic that in 32 subjects highly sensitive to Experimental Biology and Medicine, 75:450- solar radiation for 2 hours and over 75 the erythemal action of UV light, an 452, 1950. percent protection thereafter. These 0.08 mm aminobenzoic acid film pro­ (3) Willis, J., “Sensitization Potential of investigators estimated the amount of vided complete protection to natural Para-aminobenzoic Acid,” Cosmetics and protection mainly by visually rating sunlight exposure. The experimental Toiletries, 91:63-64, 1976 the degrees of redness. data suggest that the sunburn-protect­ (4) Fisher, A., A. Pelzig, A. Kanof and N. In contrast to the findings by ing action of aminobenzoic acid is in­ B. Kanof, “The Persistence of Allergic Ecze­ Pathak et al., Willis and Kligman (ref. tense enough to protect the skin matous Sensitivity and the Cross Sensitivity Pattern to Paraphenylenediamine,” Journal 6) reported that after immersion, they againt sunburn in case of extremely of Investigative Dermatology, 30:9-12, 1958. found aminobenzoic acid less effective strong UV irradiation such as found (5) Kligman, A., M., “Allergenic Aromatic than did the former authors. Willis on glaciers or on the ocean. Amines,” Archives of Dermatology, 105:459- and Kligman estimated the amount of Five subjects received 12 g amino­ 460, 1972 protection by use of the individually benzoic acid daily in divided doses for (6) Willis, I. and A. M. Kligman, “Amino­ determined MED, which they defined 10 days. The immediate protective benzoic Acid and Its Esters,” Archives of as the least amount of radiation that index was determined before dosing Dermatology, 102405-4i7, 1970. (7) The Merck. Index, 9th Ed., Merck and will just produce a uniform redness and again on the last day. The protec­ Co., Inc., Rahway, N. J., p. 57, 1976. with sharp borders. They stated that tive index was not increased after oral (8) Rothman S. and J. Rubin, “Sunburn “Claims of effectiveness after swim­ administration of aminobenzoic acid. and Para-aminobenzoic Acid,” Journal of In­ ming must be strongly qualified.” Aminobenzoic acid has been found vestigative Dermatology, 5:445-454, 1952. Amounts of 0.12 ml and 0.3 ml of 5 to be an effective sunscreen in concen­ (9) Yankell, S. L„ L. Khemanic and M. H. percent aminobenzoic acid in 70 per­ trations from 2 percent. Effectiveness Dolan, “Sunscreen Recovery Studies in the cent ethanol were applied on the increases linearly up to 2.5 percent Mexican Hairless Dog,” Journal of Investi­ gative Dermatology, 55:31-33, 1970. backs of 13 normal subjects over a with a clear-cut tendency to plateau at (10) Knox, J. H., A. C. Griffen and R. E. fixed area of the skin. The area was ir­ 5 percent. Doubling the concentration Hakin, “Protection from Ultraviolet Car­ radiated at 305 nm with a 1,600 watt does not afford twice the protection. It cinogenesis,” Journal of Investigative Der­ xenon arc. The efficacy of aminoben­ was found that for equal amounts of matology, 34:51-58, 1960. zoic acid was higher than other sun­ aminobenzoic acid, the protection was (11) OTC Volume 060072.

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 38222 PROPOSED RULES

(12) Pathak, M. A., T. B. Fitzpatrick and primary irritant, fatiguing agent, or clinical trial, after using the 1.75 per­ E. Frenk, “Evaluation of Topical Agents sensitizer. In this test, the active ingre­ cent cinoxate solution for 10 days to that Prevent Sunburn—Superiority of Para- dient and the vehicles were applied on over 1 year, results were rated as 111 aminobenzoic Acid and its Esters in Ethyl Alcohol,” New England Journal of Medi­ 15 separate occasions under an occlu­ (of 150) excellent, 35 good, 1 fair, 1 cine, 280:1459-1463, 1969. sive patch (ref. 5). poor, and 2 not rated (ref. 9). In an in­ (13) Macleod, T. M. and W. Frain-Bell, “A After applying 2 percent cinoxate in dependent clinical trial done overseas, Study of the Efficacy of Some Agents Used a cream base to both arms of six vol­ 85 of 86 patients reported adequate for the Protection of the Skin From Expo­ unteers, 96 percent of the cinoxate protection from sunlight and no im­ sure to Light,” British Journal of Dermatol­ was recovered after 4 hours contact portant adverse effects (ref. 12). ogy, 84:266-281, 1971. with the skin. A photoreactivity test at Based upon the available data, the (14) Langer, A. and A. M. Kligman, “Fur­ Panel concludes that cinoxate is an ef­ ther Sunscreen Studies of Aminobenzoic 1, 25, and 60 MED in 26 subjects with Acid,” Archives of Dermatology, 105:851-855, 4 mg cinoxate/cm2 applied to the back fective sunscreen ingredient for OTC 1972. revealed no photoxicity (ref. 6). One use. (15) Rossman, R. E., J. M. Knox and R. G. documented case of photodermatitis (3) Dosage, (i) For products contain­ Freeman, “Acrylonitriles, A New Group of to cinoxate has been reported (ref. 7). ing a minimum SPF value of 2 to Ultraviolet Absorbing Compounds,” Journal Cinoxate is used as a sunscreen in under 4 containing 1 to 3 percent cin­ of Investigative Dermatology, 39:449-453, several commercial preparations. One oxate: Adult and children over 2 years 1962. of age topical dosage is liveral applica­ (16) Rothman, S. and A. B. Henningsen, manufacturer reported receiving no “The Sunburn Protecting Effect of Para- complaints per 400,000 units of a 2 tion before sun exposure and reapply aminobenzoic Acid,” Journal of Investiga­ percent cinoxate sunscreen lotion sold, after swimming or after excessive tive Dermatology, 9:307-313, 1947. and 8 minor complaints and one aller­ sweating. There is no recommended gic contact dermatitis per 2,100,000 dosage for children under 2 years of b. Cinoxate. The Panel concludes units of a 1.7 percent cinoxate solution age except under the advice and Super­ that cinoxate is safe and effective for sold, with a ratio of complaints per vision of a physician. OTC use as a sunscreen as specified in 100,000 units sold of 0.41 (refs. 8 and (ii) For products providing a mini­ the dosage section discussed below. 9). mum SPF value of 4 containing 1 to 3 Cinoxate is also known as 2-ethox- The Panel concludes that the animal percent cinoxate: Adult and children yethyl-p-methoxycinnamate. Cinoxate and human toxicological data and the over 6 months of age topical dosage is is a practically odorless,- slightly widespread use of cinoxate since its in­ liberal application before sun exposure yellow, viscous fluid, with a specific troduction in the late 1950’s with few and reapply after swimming or after gravity of 1.000. It is stable to sunlight adverse reports attest to the safety of excessive sweating. There is no recom­ for 30 days. The empirical formula is, cinoxate as a sunscreen ingredient for mended dosage for children under 6 C14H180 4, with a molecular weight of OTC use. months of age except under the advice 250.29. The UV absorption at 1 per­ (2) Effectiveness. There are studies and supervision of a physician. cent concentration is 270 to 328 nm, documenting the effectiveness of cin­ (4) Labeling. The Panel recommends being total from 280 to 320 nm with a oxate as an OTC sunscreen. the category I labeling for sunscreen maximum at 310 nm. Cinoxate is mis­ The UV absorbance of cinoxate at 1 active ingredients. (See part III. para­ cible in 95 percent ethanol, 99 percent percent concentration in isopropyl graph B.l. below—category I labeling.) propylene glycol monomuristate, iso­ myristate is less than 10 percent at 270 R eferences propyl myristate, oleyl alcohol and and 338 nm, but total between 280 to soya vegetable oil. It is slightly soluble (1) “Giv-Tan F: A new Sunscreen Agent,” 320 nm with the maximum at 310 nm. Draft of unpublished paper in OTC Volume in water (0.05 percent), 0.5 percent in "* Two percent cinoxate in seven experi­ 060002. glycerol, and 3 percent in mineral oil mental vehicles was applied to the (2) Wolven, A. and I. Levenstein, “Acute (ref. 1). Cinoxate can be formulated as backs of seven volunteers and the Oral Toxicity of Compound Giv-Tan F,” an aerosol, oil, hydroalcoholic lotion, treated sites were exposed to 7 MED’s Draft of unpublished paper in OTC Volume and as an emulsified lotion and cream. from fluorescent sunlamps. On a scale 060021. (1) Safety. Clinical use and market­ of 0 (best score) to 6 (worst score), pro­ (3) “Animal Safety Data,” Draft of unpub­ ing experience have confirmed that lished paper in OTC Volume 060002. tection varied according to the formu­ (4) Wolven A. and I. Levenstein, “Eye Irri­ cinoxate is safe in the dosage range la, with the highest erythema index tation—Rabbits,” Draft of unpublished used as an OTC sunscreen. being 2.25 and the lowest 0.5 (ref. 8). paper in OTC Volume 060021. Cinoxate has low toxicity on animal A 2 percent cinoxate lotion was com­ (5) Shelanski, M. V., “Human Patch testing. Human toxicology tests, clini­ pared with a 1.75 percent cinoxate so­ Tests,” Draft of unpublished paper in OTC cal trials and wide use attest to its lution in a controlled study in 10 sub­ Volume 060021. safety for human use. jects at a medical school. After expos­ (6) Edelson, E., “Photoreactivity Studies Acute toxicity studies have been of Giv-Tan ‘F,’ Giv-Tan ‘P’ and ing the treated sites to fluorescent Tetrachlorsalicylanilide,” Draft of unpub­ done in rats with full strength cinox­ sunlamps, the lotion afforded 5.1 lished paper in OTC Volume 060021. ate. The oral LD50 for the rat was 3.8 times greater MED protection than (7) Goodman, T. F., “Photodermatitis ml/kg (ref. 2). In a single dose acute the vehicle, while the solution afford­ from a Sunscreening Agent,” Archives of oral toxicity study of 2 percent cinox­ ed 3.3 time greater MED protection Dermatology, 102:563, 1970. ate in a lotion, a single dose level of 5 than its vehicle (ref. 10). (8) “Efficacy Data,” Draft of unpublished g/kg administered to 10 rats caused no Two dermatologists independently paper in OTC Volume 060002. fatalities during the 14-day observa­ evaluated a 2 percent cinoxate lotion (9) “Human Safety Data,” Draft Of un­ published paper in OTC Volume 060003. tion period or gross organ abnormali­ in 48 patients (27 with photosensiti­ (10) Smith, E. G., “Clinical Report: Pre­ ties at autopsy (ref. 3). The Draize vity) during the summer. There were vention of Ultraviolet Erythema with 0.5 rabbit eye irritancy test revealed no ir­ 33 females and 15 males, with a mean percent 2-Ethoxyethyl Paramethoxycin- ritation when 3 percent cinoxate in age of 23 (range 3 to 52 years of age). namate Solution,” Draft of unpublished equal parts of mineral oil and corn oil Results of use were rated by the inves­ paper in OTC Volume 060002. was instilled into the rabbits’ eyes (ref. tigators as 31 (of 48) excellent, 12 (11) “Suntan Creamy Lotion—Clinical 4). good, and 5 fair. Thirty-four of 41 pa­ Trial,” Draft of unpublished paper in OTC The repeated insult patch method of Volume 060002. tients rated suntanning as good to ex­ (12) Abbott, L. G., M. J. Diakin, R. A. Shelanski and Shelanski in 50 subjects cellent (ref. 11). Of 150 patients evalu­ Langley, and R. M. Tipping, “Clinical Trial revealed that 2 percent cinoxate in an ated clinically by six physicians in a of Two Sunscreening Creams,” The Medical oil and lotion formulation was not a company-sponsored, uncontrolled Journal of Australia, 1:1094-1095, 1970.

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38223 c. Diethanolamine p-methoxycinna- applications were 1, 3, and 4 days. all were superior* to a commercial mate. The Panel concludes that dieth­ Readings were recorded each time the preparation containing 5 percent ami- anolamine p-methoxycinnamate is patches were removed. After a 2-week nobenzoic acid. Eleven subjects, also safe and effective for OTC use as a rest period, challenge patches were ap­ under conditions of passive sunbath­ sunscreen as specified in the dosage plied to both inner deltoid areas and ing, were used in testing 12 products. section discussed below. were removed 2 days later, with read­ The mean indices for the product con­ Diethanolamine p-methoxycinna- ings being recorded immediately and taining diethanolamine p-methoxycin­ mate is also known as p-methoxycin- 24 hours afterwards. No reactions were namate were 1.5 after 30 minutes of namic acid diethanolamine salt. observed during any of the above read­ exposure, 3.0 after 60 minutes and 4.2 Diethanolamine p-methoxycinna- ings following the removal of either and 4.6, respectively, after 90 and 120 mate is a pale tan microcrystalline the sensitization or challenge patches. minutes. powder which is readily water soluble. It was concluded that the test material In a forth study using the same for­ Its molecular weight is 283.33 and its did not manifest either primary irrita­ mulation the product had a mean pro­ fusion point at 87.0° C minimum. It is tion or sensitizing effects (ref. 3). tective index of 4.6. stable to light and moderate heat and Another Draize repeated insult Based upon the available data, the is not hygroscopic. It is suitable for patch test on 54 subjects (17 males and Panel concludes that diethanolamine use in aqueous or alcohol/water for­ 37 females) was conducted in the same p-methoxycinnamate is an effective mulations, gels, and emulsions (ref. 1). manner as the above test except that a sunscreen ingredient for OTC use. (1) Safety. Clinical use and market­ 7.5 percent diethanolamine p-methox­ (3) Dosage, (i) for products providing ing experience have confirmed that ycinnamate in water solution was em­ a minimum SPF value of 2 to under 4 diethanolamine p-methoxycinnamate ployed, and the patches were removed containing 8 to 10 percent diethanola­ is safe in the dosage range used as an every 48 hours, except for three 72- mine p-methoxycinnamate: Adult and OTC sunscreen. hour weekend periods and a 24-hour children over 2 years of age topical Animal and human toxicological period at the outset, to observe wheth­ dosage is liberal application before sun data attest to its safety for human er the full group presented any irrita­ exposure and reapply after swimming topical application. The oral LDS0 is tive or sensitization reactions before or after excessive sweating. There is greater than 5 g/kg in male rats and proceeding further with the test. no recommended dosage for children 3.7 g/kg for female rats (ref. 2). Except for 16 patients who experi­ under 2 years of age except under the Application of a 2.0 percent diethan­ enced reactions to the adhesive tape advice and supervision of a physician. olamine p-methoxycinnamate solution used to secure the patches, no reac­ (ii) For products providing a mini­ on guinea pig epidermis was found to tions to the test material were noted mum SPF value of 4 containing 8 to 10 be nonirritating following a single ap­ following the removal of the sensitiza­ percent diethanolamine p-methoxycin­ plication, and after repeated applica­ tion and challenge patches, thereby namate: Adult and children over 6 tions for 21 consecutive days. Repeat­ leading to the conclusion that the test months of age topical dosage is liberal ed applications of 6 and 20 percent so­ material was neither a primary irri­ application before sun exposure and lutions on 21 consecutive days pro­ tant nor an allergic sensitizing agent reapply after swimming or after exces­ duced very light medicament carrier Xref. 4). sive sweating. There is no recommend­ irritation. Sensitization tests on guinea Based upon the available data, the ed dosage for children under 6 months pigs treated for 3 weeks with 2, 6, and Panel concludes that diethanolamine of age except under the advice and su­ 20 percent concentrations determined p-methoxycinnamate is a safe sun­ pervision of a physician. that allergic sensitization did not screen ingredient for OTC use. (4) Labeling. The Panel recommends occur. Draize tests measuring the irri­ (2) Effectiveness. There are studies the Category I labeling for sunscreen tation of the rabbit’s eye revealed that documenting the effectiveness of active ingredients. (See part III. para­ a 1 percent perfumed solution of the diethanolamine p-methoxycinnamate graph B.l. below—category I labeling.) ingredient can be tolerated without re­ as an OTC sunscreen. R eferences action following a single and repeated Its absorbance is between 280 and (7 days) applications, whereas 3 and 10 310 nm, with the maximum absor­ (1) OTC Volume 060083. (2) “Animal Safety Data,” Draft of unpub­ percent concentrations produced weak bance at 290 nm. Readily water solu­ lished paper in OTC Volume 060083. irritation of the conjunctiva (ref. 2). A ble, it is practically insoluble in nonpo­ (3) “Human Safety Data,” Draft of un­ commercial sunscreen lotion contain­ lar organic solvents, oil, and fatty ma­ published paper in OTC Volume 060083. ing 10 percent diethanolamine p-meth­ terials. It can be incorporated into gel, (4) OTC Volume 060110. oxycinnamate applied twice to rabbits’ lipstick emulsion, and aqueous formu­ (5) “Efficacy Data,” Draft of unpublished eyes caused a reddening of the margin lations (ref. 5). paper in OTC Volume 060083. of the eyelid and the conjunctiva for In several studies by Pathak, Fitzpa­ d. Digalloyl trioleate. The Panel con­ the duration of 4 hours, after which trick and Parrish (ref. 1), the same for­ cludes that digalloyl trioleate is safe any irritation effect disappeared (ref. mulation containing diethanolamine and effective for OTC use as a sun­ 2 ). p-methoxycinnamate gave the follow­ screen as specified in the dosage sec­ A Draize repeated insult patch test ing results: tion discussed below. on 53 (42 female and 11 male) subjects Using a hot quartz mercury arc lamp Digalloyl trioleate is a mixture of was performed to evaluate the irrita­ on 12 subjects and comparing 8 differ­ several derivatives of tannic acid. It is tive and sensitizing potentialities of a ent sunscreen formulations against 5 the triester produced by the reaction 2 percent diethanolamine p-methoxy­ percent animobenzoic acid in ethanol, of digallic acid and oleic acid and con­ cinnamate solution. Each patch con­ diethanolamine p-methoxycinnamate forms generally to the formula tained 0.5 ml of the test material and was shown to have a protective index CssHiosOiz. It is a clear, viscous, brown was secured to the test site by overly­ range of 4 to 15, with a mean mini­ liquid with a slight smell. It is insolu­ ing strips of occlusive adhesive tape. mum of 7.37 and a mean maximum of ble in water but soluble in vegetable The patches were alternately placed 10.3 (8 or more is 100 percent protec­ oils, 95 percent alcohol, and mineral on the medial surface of the right and tion). All products were found to give oil to which has been added 10 to 15 left deltoid area. Because of the two significant protection against erythe- percent vegetable oils. It 4s incompati­ holidays and a weekend which oc­ mogenic radiation. ble with alkalies, tannic acid, and curred during the study, the period of Eight subjects were used under con­ triethanolamine. The specific gravity contact and rest period could not con­ ditions of passive sunbathing to test is 1.040 to 1.045, and the refractive sistently be 48 hours and 3 of the 10 four formulations. It was found that index is 1.515 to 1.525 (ref. 1). Digal-

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38224 PROPOSED RULES loyl trioleate'can be formulated as an ing the results on days 3, 9, and 11 lotion and a cetyl alcohol-ethanol ve­ oil, emulsified lotion or cream, oint­ (ref. 1). A repeated-insult irritation hicle on two treated sites with each ment, alcoholic solution, and lipstick. study in 10 white men revealed no irri­ site compared to an untreated site. (1) Safety. Clinical use and market­tation or toxicity to a product contain­ Both preparations offered adequate ing experience have confirmed that di- ing 3.5 percent digalloyl trioleate as screening against 5 minutes’ irradia­ galloyl trioleate is safe in the dosage the sole active ingredient. One subject tion at a distance of 40 inches from a range used as an OTC sunscreen. developed some erythema on the 9th quartz mercury arc sunlamp. The ve­ Extensive animal and human toxico­ day (ref. 2). hicles afforded no protection. Tanning logical testing attests to its safety for The medical literature contains one was attractive. Unfortunately, the topical application. verified case report of contact photoal­ number of subjects was not given (ref. Acute toxicity studies have been lergy (ref. 3). This case has been men­ 1). done in mice and rats with digalloyl tioned directly or indirectly in 16 A product containing 3.5 percent di­ trioleate. The oral LD50 for both mice other publications (ref. 4). Another re­ galloyl trioleate in a vanishing cream and rats was 24.5 g/kg (ref. 1). In a ported case of possible contact pho­ base had 34 unsolicited mentions in chronic "topical application study, toallergy to digalloyl trioleate in a 5- the literature from 25 authors con­ eight groups of three rabbits per year-old boy with solar dermatitis had cerning its effectiveness as a sunscreen group had digalloyl trioleate applied no documentation (ref. 5). by 1973 (ref. 4). For example, it was as follows: 0.5 ml/kg of bodyweight From 1952 through 1972, nearly cited as an effective sunscreen for neat (straight chemical as applied) for 4,000,000 units of a sun-protective lip­ managing photosensitivity dermatitis 90 days; 4.0 ml/kg of bodyweight neat stick product containing 2.5 percent (ref. 9), discoid lupus erythematosus for 31 days; in lotion 4.0 ml/kg of digalloyl trioleate were distributed. (ref. 10), hydroa aestivale in children bodyweight for 90 d&ys and one group Only one complaint of “irritation” had (ref. 11), and for protection from sun­ with 2 hours of sunlight exposure been received by the company from all light (ref. 12). In vivo, it protected daily; in ointment 4.0 ml/kg of sources (ref. 6). During a 20-year better than glyceryl p-aminobenzoate bodyweight for 93 days plus one group period, almost 2,000,000 units of a sun­ and red petrolatum, but it did not pro­ with sunlight exposure; and in cetyl screen lotion containing 3.5 percent di­ tect as well as several other sunscreens alcohol-ethanol vehicle 4.0 ml/kg of galloyl trioleate were distributed. The (ref. 13). bodyweight for 93 days; and two company received a total of six com­ Digalloyl trioleate has been used groups of vehicles applied alone. No plaints from consumers, yielding a over 40 years by patients and consum­ dermal toxicity not effect upon the rate of 0.3 per 100,000 units distribut­ ers and has been considered an effec­ hemogram occurred. The 4.0 ml/kg ed. Of the six complaints, four were tive sunscreen by authorities. Based dose produced some erythema; and concerned with irritation or sensitiza­ on the available data, the Panel con­ due to its physical nature, some mat­ tion. Only one of the four complaints cludes that digalloyl trioleate is an ef­ ting of the fur which, when removed, seemed to be a legitimate contact pho­ fective sunscreen for OTC use in the resulted in some depilation. No visible tosensitization, though this was not dosage range specified below. toxicity resulted, and the fur regrew proven. One person developed redness, (3) Dosage, (i) For products provid­ normally. The 0.5 ml/kg application but was also “allergic to weeds,” while ing a minimum SPF value of 2 to caused some erythema, but no toxic­ two reported a “reaction.” Correspon­ under 4 containing 2 to 5 percent di­ ity. The vehicle containing a cetyl al­ dence with these complainants re­ galloyl trioleate: Adult and children cohol-ethanol combination also caused questing more details went unan­ over 2 years of age topical dosage is erythema. All animals remained in swered (ref. 4). The Panel received no liberal application before sun exposure good condition, gained weight, and submissions from other companies and reapply after swimming or after showed no gross pathology on autopsy who use digalloyl trioleate in their excessive sweating. There is no recom­ (ref. 1). Three almost-albino shoats products. mended dosage for children under 2 had a weighed amount of 2.5 percent The Panel concludes that the animal years of age except under the advice digalloyl trioleate in a lotion, oint­ and human toxicological data and the and supervision of a physician. ment, and cetyl alcohol-ethanol vehi­ extensive use of the substance with (ii) For products providing a mini­ cle applied daily to the back, shoulder, few reported complaints attests to the mum SPF value of 4 containing 2 to 5 and neck for 82 applications. Three safety of digalloyl trioleate as a sun­ percent digalloyl trioleate: Adult and swine and a control boar received 2 screen agent for OTC use. children over 6 months of age topical hours of sunlight daily. After 93 days, (2) Effectiveness. There are studies dosage is liberal application before sun all animals were in good condition, documenting the effectiveness of di­ exposure and reapply after swimming gained weight, showed no severe skin galloyl trioleate as an OTC sunscreen. or after excessive sweating. There is irritation or toxicity, and demonstrat­ A 1 percent digalloyl trioleate con­ no recommended dosage for children ed no gross or histological pathology centration in ethanol absorbs UV light under 6 months of age except under of the skin or visceral organs at autop­ from 270 to 320 nm, with the maxi­ the advice and supervision of a physi­ sy. The cetyl alcohol-ethanol treated mum at 300nm. It has been in use cian. animal showed some visible irritation since the early 1930’s. No complete (4) Labeling. The Panel recommends (ref. 1). A modified Landsteiner tech­ data on controlled clinical trials in the Category I labeling for sunscreen nique for skin sensitization was nega­ man were submitted. The United active ingredients. (See part III. para­ tive in 10 guinea pigs injected intracu- States Army tested and selected 3 per­ graph B.l. below—category I labeling.) taneously with 0.1 ml of 0.1 percent di­ cent digalloyl trioleate as one of the galloyl trioleate in cottonseed oil on four “approved” sunscreens for acqui­ R eferences alternate days for 10 injections and a sition under Military Specifications (1) Hazelton, J. and E. P. Marsh, “Physi­ final injection 10 days later (ref. 1). Sunburn Preventative Preparation cal, Pharmacological and Dermatological An independent study in 200 sub­ Cream Base MILf-S-11262 (Quarter­ Studies on a Sunscreen,” Proceedings of the jects revealed no primary irritation, master Corps) July 10, 1951, and MIL- Scientific Section, Toilet Goods Association, while one subject developed a sensitiv­ S-11262A March 10, 1953 (refs. 7 and 13:1-8, 1950. (2) “Human Safety Data,” Draft of un­ ity reaction to digalloyl trioleate. The 8). The efficacy data were not availa­ published paper in OTC Volume 060044. closed-patch test consisted of applying ble to the Panel. Abbreviated results (3) Sams, W. M., “Contact Photodermati­ a 1-cm blotting paper disc saturated were given of a sunscreen test on the tis,” Archives of Dermatology, 73:142-148, with digalloyl trioleate under a patch backs of men and women employing 1956. for 48 hours on days 1 and 7, and read­ 2.5 percent digalloyl trioleate in a (4) OTC Volume 060044.

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38225

(5) Kern, A. B., “Solar Dermatitis in a irritation of the skin. It was reported simulator as the primary light source Child,” Archives of Dermatology, 73:92-93, that “there was no evidence of any in­ in the UV spectrum provided data in­ 1956. flammatory reaction on the site of ap­ dicating that the padimate A-monogly- (6) OTC Volume 060004. plication immediately, 15 minutes, and cerol p-aminobenzoate and p-amino­ (7) Wells, P. V. and I. I. Lubowe, “Cosmet­ ics and the Skin,” Rheinhold Publishers, 24 hours after removal of the 48-hour benzoate products were most effective New York, p. 383, 1964. patch test.” From the above-described in that order, followed by the dioxy­ (8) “Military Specifications: Sunburn-Pre­ data it was concluded that the combi­ benzone-padimate A lotion and the pa­ ventive-Preparation, Cream Paste,” Draft of nation product is not a primary irri­ dimate A product last; and unpublished paper in OTC Volume 060065. tant (ref. 1). (v) The dioxybenzone-padimate A (9) Fisher, A. A., “Dermatitis Medi-camen- Based on the available data, the lotion “is an effective agent to protect tosa,” in “Current Therapy,” W. B. Panel concludes that dioxybenzone is against ultraviolet radiation in the Saunders and Co., Philadelphia, p. 464, 1962. a safe sunscreen ingredient for OTC erythemogenic range, and has good (10) Haserick, J. R., “Lupus Erythemato­ use. substantivity.” sus, in “Current Therapy,” W. B. Saunders (2) Effectiveness. There are studies Based on the available data, the and Co., Philadelphia, p. 445, 1963. documenting the effectiveness of diox­ Panel concludes that dioxybenzone is (11) Perlman, H. H., “Hydroa Aestivale,” ybenzone as an OTC sunscreen. an effective sunscreen ingredient for in “Current Pediatric Therapy,” 5th Ed., Human efficacy data were obtained OTC use. Edited by S. S. Gellis and B. M. Kagan, W. from three clinical studies comparing B. Saunders and Co., Philadelphia, 1971. (3) Dosage, (i) For products contain­ (12) Perry, H. O., “Discoid Lupus Erythe­ the effectiveness of a combination ing a minimum SPF value of 2 to matosus and Photosensitive Eruptions,” product (3 percent dioxybenzone and under 4 containing 3 percent dioxy­ Modem Treatment, pp. 909-915, Sept., 1965. 2.5 percent padimate A) with one to benzone: Adult and children over 2 (13) Kahn, G. and G. Wilcox, “Compari­ three other marketed sunscreen prep­ years of age topical dosage is liberal son of In-vitro and In-vivo Sunscreen Test­ arations (ref. 1). One product con­ application before sun exposure and ing Methods,” Journal of the Society of Cos­ tained 5 percent p-aminobenzoate; an­ reapply after swimming or after exces­ metic Chemists, 20:807-824, 1968. other contained a 5 percent combina­ sive sweating. There is no recommend­ e. Dioxybenzone. The Panel con­ tion of padimate A and monoglycerol ed dosage for children under 2 years of cludes that dioxybenzone is safe and p-aminobenzoate; and the third con­ age except under the advice and super­ effective for OTC use as a sunscreen tained 2.55 percent padimate A. vision of a physician. as specified in the dosage section dis­ The reference contained the conclu­ (ii) For products providing a mini­ cussed below. sions that: mum SPF value of 4 containing 3 per­ Dioxybenzone is also know as 2,2'-di- (i) “It is felt that the total effect of cent dioxybenzone: Adult and children hydroxy-4-methoxybenzophenone. It these two sunblocking agents will pro­ over 6 months of age topical dosage is is an organic benzophenone derivative vide greater effective absorption of liberal application before sun exposure designated as benzophenone-8 and ex­ ultra-violet rays than the effect of and reapply after swimming or after hibits a wider UV absorbance range either agent used independently, in excessive sweating. There is no recom­ than does padimate. the range of 260-380 nm (2600-3800 mended dosage for children under 6 (1) Safety. Clinical use and market­ Angstrom units)”; months of age except under the advice ing experience have confirmed that (ii) A double-blind, randomized and supervision of a physician. dioxybenzone is safe in the dosage study involving a total of 33 subjects (4) Labeling. The Panel recommends range used as an OTC topical sun­ and four different tests performed si­ the category I labeling for sunscreen screen. multaneously (passive sunbathing; active ingredients. (See part III. para­ Animal and human safety data have sweating and passive sunbathing; graph B.l. below—category,I labeling.) been obtained from studies evaluating swimming and passive sunbathing; and a sunscreen lotion containing dioxy­ passive sunbathing, sweating, swim­ R eference benzone in combination with another ming, and walk-around) and compar­ (1) OTC Volume 060116. sunscreen agent, padimate A. On the ing the first three preparations listed f. Ethyl 4-ibis(hydroxypropyl)l basis of five animal toxicity studies above provided data indicating that aminobenzoate. The Panel concludes the investigators concluded that: “Nei­ the photoprotective potency of the that ethyl 4-[bis(hydroxypropyl)] ther erythema nor edema was pro­ dioxybenzone-padimate A lotion was aminobenzoate is safe and effective for duced in any animal following the equal to and in some respects greater OTC use as a sunscreen as specified in challenge dose” and “these results than that for the p-aminobenzoate the dosage section discussed below. suggest that the sunscreen lotion for­ and padimate A-monoglycerol p-amin­ Ethyl 4-[bis(hydroxypropyl)] amino­ mulation should not cause either skin obenzoate products; benzoate is also known as the 2-mole sensitization or allergic contact derma­ (iii) Stress, efficacy and protective propoxylate df aminoethylbenzoate titis in man”; “these findings suggest index tests comparing the dioxyben­ and ethyldihydroxypropyl PABA. that this sunscreen formulation zone-padimate A lotion with the padi­ The absorbance range of ethyl 4- should be safe for repeated dermal use mate A-monoglycerol p-aminobenzoate [bis( hy droxypropyl) ] aminobenzoate in man”; the acute oral toxicity was product revealed that “there were no is between 280 and 330 nm, with the determined to be 17.5 ml/kg for the significant differences in stinging or absorbance maximum at 308 to 311 rat and 14.7 rpl/kg for the rabbit sug­ burning sensations noted after appli­ nm. It is soluble in ethyl and isopropyl gesting that accidental ingestion cation,” but “there was an increasing alcohol, propylene glycol, castor oil, “should present little risk of serious incidence of both as additional stress and isopropyl myristate; but it is in­ toxicity in man”; and the likelihood of was carried out.” Both gave highly sig­ soluble in water, mineral oil, and glyc­ serious ocular damage following acci­ nificant protection from erythemas as erin. Ethyl 4-[bis(hydroxypropyl)] dental ocular instillation would appear compared to untreated areas, and aminobenzoate is. usually formulated to be low but such contact may cause there were no significant differences in an emulsion base. “slight to moderate redness of the con- regarding the MED, or the degree of (1) Safety. Clinical use and market­ junctivae” (ref. 1). pigmentation, and both increased the ing experience have confirmed that Patch test involving 100 white fe­ MED significantly compared to the ethyl 4-Cbis(hydroxypropyl)] amino­ males were performed to determine untreated area; benzoate is safe in the dosage range whether the ingredients contained in (iv) A double-blind, randomized used as an OTC sunscreen. the combination product were capable study comparing the four formula­ Animal and human toxicological of producing an immediate or primary tions listed above and using a solar data attest to its safety for human

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 38226 PROPOSED RULES topical application. The oral LDS0 is 20 10 minutes immersion, the subjects tate, methyl pyrrolidone, and n-vinyl ml/kg in rats while the intraperitoneal were exposed to 6 MED’s. Barely per­ pyrrolidone. It is incorporated in aero­ LDso in rats was found to be 5.0 ml/kg ceptible erythema was noted on the sols, alcohol-type solutions, creams, (ref. 1). test areas treated with the 2.5 and 5 emulsions, and oil formulations. Animal safety data indicated that 5 percent formulations whereas eryth­ (1) Safety. Clinical use and market­ percent ethyl 4-[bis(hydroxypropyl)] ema was easily recognized on test ing experience have confirmed that 2- aminobenzoate in carbowax ointment, areas treated with the 1 percent for­ ethylhexyl 2-cyano-3,3-diphenylacry- U.S.P. is not a primary irritant to the mulation. Skin treated with an unspe­ late is safe in the dosage range used as skin. It is not an ocular irritant, and cified commercial lotion showed deep an OTC sunscreen. will not induce comedones (black­ redness and swelling after a waterbath Animal and human toxicological heads) (ref. 1). immersion test. It was concluded that data attest to its safety for human Human safety data indicated that the ethyl 4-[bis(hydroxypropyl)] topical application at a concentration studies employing a 5 percent ethyl 4- aminobenzoate formulations “showed of 7 percent (ref. 1). The oral LD50 in [bis( hy droxypropyl) ] aminobenzoate excellent promise of retaining sunburn Sherman-Wister strain of rats is great­ formulation demonstrated that protection after bathing.” er than 64 m l/kg (ref. 2). The Draize normal and stripped skin sites on 10 Based on the available data, the rabbit eye irritancy test revealed no ir­ healthy male volunteers showed no Panel concludes that ethyl 4- ritation when 0.1 ml of the undiluted evidence of phototoxicity and a very [bis(hydroxypropyl)] aminobenzoate material was instilled into the eyes of low level of irritancy. Liberal applica­ is an effective sunscreen ingredient for rabbits (ref. I). A primary skin irrita­ tion to the faces of 15 healthy male OTC use. tion study in six albino rabbits pro­ volunteers showed not instances of (3) Dosage. Cl) For products provid­ duced minimal effects when the stinging or burning or irritation at 5, ing a minimum SPF value of 2 to chemical was applied for 72 hours (ref. 10, and 30-minute intervals and 24 under 4 containing 1 to 5 percent ethyl 1 ). hours after application. A maximiza­ 4-[bis(hydroxypropyl)] aminoben­ A modified Draize-Shelanski human tion test (ref. 2) performed on 25 zoate: Adult and children over 2 years repeated insult patch test in 52 men healthy male volunteers resulted in no of age topical dosage is liberal applica­ and woment from 18 to 65 years of age instances of contact sensitization with tion before sun exposure and reapply revealed 2-ethylhexyl 2-cyano-3,3-di- the conclusion that it was unlikely after swimming or after excessive phenylaerylate not to be a strong irri­ that the formulation would present a sweating. There is no recommended tant or photosenitizer. After applying danger of contact sensitization in dosage for children under 2 years of the chemical to the upper back of the normal, intended use. Topical applica­ age except under the advice and super­ subjects, patch strips were applied for tion to the entire area of the chests, vision of a physician. 24 hours. The patches were removed backs, shoulders and faces of 20 (ii) For products providing a mini­ and the test sites were read. No patch­ healthy male volunteers once daily for mum SPF value of 4 containing 1 to 5 es were in place for 24 hours, then an­ 21 days resulted in a very low ley el of percent ethyl 4-[bis(hydroxypropyl)] other application was made to the irritancy with erythema being barely aminobenzoate: Adult arid children same site and the patches applied. perceptible in some subjects with no over 6 months of age topical dosage is This was repeated until 10 insults had repetition on successive days of the liberal application before sun exposure been applied to the same site. A 10- to slight irritation in most cases (ref. 1). and reapply after swimming or after 14-day rest period followed. At the end Based upon the available data the excessive sweating. There is no recom­ of the rest period a challenge dose and Panel concludes that ethyl 4- mended dosage for children under 6 patch were applied to the original site [bis(hydroxypropyl)] aminobenzoate months of age except under the advice and remained in place for 48 hours. No is a safe sunscreen ingredient for OTC and supervision of a physician. reactions occurred during the entire use. (4) Labeling. The Panel recommends induction period. There were two reac­ (2) Effectiveness. There are studies the category I labeling for sunscreen tions (1+, mild erythema) seen during documenting the effectiveness of ethyl active ingredients. (See part III. para­ the challenge. On repeated challenge 4- [bis( hy droxypropyl)] aminobenzoate graph B.l. below—category I labeling.) to these two subjects, only one gave a as an OTC sunscreen. repeated 1+ reaction. The reactions Human efficacy data has been re­ R eferences were considered to be nonspecific irri­ ported. The protective index of 2 to 5 (1) OTC Volume 060084. tation, disappearing by 72 hours (ref. percent ethyl 4-[bis(hydroxypropyl)l (2) Kligman, A. M., “The Identification of I). Twenty-five of the above subjects aminobenzoate in various vehicles Contact Allergens by Human Assay,” Jour­ also had phototoxicity testing done si­ ranged from 20 (2 percent formulation nal of Investigative Dermatology, 47:393- multaneously with the skin irritancy in alcohol/glycerlne/water and 5 per­ 409, 1966. and sensitization testing. Patches were cent formulation in oil base) to 70 (5 g. 2-Ethylhexyl 2-cyano-3,3-dipheny- applied as bqfore. At induction, patch­ percent formulation in carbowax lacrylate. The Panel concludes that 2- es 1, 4, 7, and 10, and at the first chal­ base). Fifty mg of 1, 2.5 and 5 percent ethylhexyl 2-cyano-3,3-diphenylacry- lenge patch, the treated sites were ex­ formulations were applied to 1-square late is safe and effective for OTC use posed to a Hanovia Kromeyer Lamp inch patches of skin on six healthy as a sunscreen as specified in the filtered through window glass “for 30 male volunteers, who were then ex­ dosage section discussed below. seconds. All photopatch tests were posed using a xenon lamp to 20, 40 and 2-Ethylhexyl 2-cyano-3,3-diphenyla- negative. 60 times the radiation necessary to crylate is also known as 2-Ethylhexyl- Additional skin and eye irritation produce mild erythema on untreated alpha - cyano - beta - phenylcinnamate tests have been carried out but details skin, with only barely perceptible and is listed-in the CFTA Dictionary were not supplied. Various concentra­ erythema being observed at the high­ as UV Absorber 3. The chemical for­ tions of 2-ethylhexyl 2-cyano-3,3-di- est radiation dose and minimal concen­ mula is C24H29O2N. It is a nonstaining phenylacrylate (4, 8, and 16 percent) tration. Fifty mg of 1, 2.5 and 5 per­ pale yellow liquid with a specific grav­ were incorporated in dimethylphtha- cent formulations were applied to 1- ity of 1.0478 (25° C/25° C), a freezing late or petrolatum as vehicles. The square inch patches of skin on the point of —10° C, and a boiling point of Draize skin irritancy test in 6 rabbits, forearms of six healthy male volun­ 200° C at 0.1 mm. It is insoluble in the Draize eye irritancy test in 6 rab­ teers. Their forearms were then im­ water, but miscible in methanol, eth­ bits, and skin patch tests (unspecified) mersed in an agitated water bath ther­ anol, ethyl acetate, methyl ethyl in 14 humans revealed no effects ob­ mostatically controlled at 37° C. After ketone, mineral oil, isopropyl myris- servable in all cases (ref. 2).

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38227 Marketing data involving 15,000 same vehicle protected 13 subjects for Ethylhexyl p-methoxycinnamate is units sold over a 24-month period re­ 2.2 minutes (9 MED’s). The 10 percent also known as 2-methoxycinnamic acid vealed no complaints of sensitivity or benzophenone formulations on 34 sub­ 2-ethylhexyl ester. intolerance to 2-ethylhexyl 2-cyano- jects protected in excess of 12 minutes Ethylhexyl p-methoxycinnamate is 3,3-diphenylacrylate (ref. 1). 2-Ethyl- 48 MED’s). The 10 percent aminoben­ a practically odorless, pale yellow, hexyl 2-cyano-3,3-diphenylacrylate in zoic acid formulation protected 17 sub­ slightly oily liquid with a molecular lower dosage has been used by a least jects for more than 12 minutes (48 weight of 290, a boiling point at 3 mm three cosmetic manufacturers for sev­ MED’s) and in 13 more subjects from of 198-200° C, and a specific gravity of eral years to protect ingredients in cos­ 20 to 60 minutes. In general, the pro­ 1.01-1.02. The ingredient is miscible in metics against UV degradation (ref. 3). tection offered by commercially avail­ alcohols, propylene glycol monomyris- Based upon the available date, the able products, available in the early tate, and various oils, but insoluble in Panel concludes that 2-ethylhexyl 2- 1960’s was limited to 2 minutes or less water. It is “stable to light and re­ cyano-3,3-diphenylacrylate is a safe (mean 1.5 minutes or 6 MED’s) (ref. 4). mains essentially unchanged on expo­ sunscreen for OTC use. sure to moderate heat.” It is often for­ (2) Effectiveness. There are studies The 7 percent 2-ethylhexyl 2-cyano- mulated with other sunscreens. Absor­ documenting the effectiveness of 2- 3,3-diphenylacrylate was field tested bance in pure ethanol is 84 percent at ethy 1-hexyl 2-cy ano-3,3-diphenylacry- in Florida, California, Hawaii, the 2 percent, 94 percent at 3 percent, and late as an OTC sunscreen. Indian Himalayas, Panama, the Gulf 98.8 percent at 5 percent concentra­ 2-Ethylhexyl 2-cyano-3,3-diphenyla- of Mexico, Mt. McKinley, Guadalupe, tions. crylate in a 7 percent gel base was Israel, France, and England, but the (1) Safety. Clinical use and market­ tested on the backs of 10 fair skin vol­ data were not submitted to the Panel. ing experience have confirmed that unteers using a xenon lamp-solar sim­ Based on the available data, the ethylhexyl p-methoxycinnamate is ulator (ref. 1). The subjects’ MED was Panel concludes that 2-ethylhexyl 2- safe in the dosage range used as an determined the day before the test. cyano-3,3-diphenylacrylate is an effec­ OTC sunscreen. The test product and a 3 percent ami- tive sunscreen ingredient for OTC use. Extensive animal toxicological test­ nobenzoic acid in alcohol control solu­ (3) Dosage, (i) For products provid­ ing and widespread use attest to its tion were applied to separate circular ing a minimum SPF value of 2 to safety for application to humans. sites 1.9 cm in diameter at a rate of 5 under 4 containing 7 to 10 percent 2- Animal toxicity data for ethylhexyl /il/cm2. Irradiated sites were 1.2 cm in ethylhexyl 2-cyano-3,3-diphenylacry- p-methoxycinnamate indicated that diameter. 2-Ethylhexyl 2-cyano-3,3-di- late: Adult and children over 2 years the LDso exceeds 8 g/kg in mice. The phenylacrylate sites were exposed to 3, of age topical dosage is liberal applica­ Draize rabbit eye irritancy test re­ 4, and 5 MED’s while the 3 percent tion before sun exposure and reapply vealed little irritation when 0.1 ml of aminobenzoic acid solution was ex­ after swimming or after excessive the pure chemical was instilled into posed to 4 and 5 MED’s. Test sites sweating. There is no recommended the rabbit’s eyes (ref. 11. The chemical were read 24 hours later. The mean dosage for children under 2 years of was considered practically nonirritat­ SPF for the 7 percent 2-ethylhexyl 2- age except under the advice and super­ ing to the eye. To determine epicutan- cyano-3,3-diphenylacrylate was 4.2 vision of a physician. eous tolerance and possible sensitiza­ (standard deviation=0.92). In the tion in the guinea pig, four guinea pigs same test, 10 percent 2-ethylhexyl 2- (ii) For products, providing a mini­ received either 0.05 ml of the undilut­ cyano-3,3-diphenylacrylate in an oil in mum SPF value of 4 containing 7 to 10 ed chemical unjected intracutaneously water lotion was tested simultaneous­ percent 2-ethylhexyl 2-cyano-3,3-di- on 5 subsequent days or 0.025 ml of a ly. Five fd/cm 2 of the material was ap­ phenylacrylate: Adult and children 50 percent acetone solution applied plied. The mean SPF for the 10 sub­ over 6 months of age topical dosage is topically daily for 3 weeks to 2 cm 2 jects was 4.6 (standard deviation=0.85) liberal application before sun exposure areas on their shaved sides. The for the 10 percent formulation. and reapply after swimming or after amount injected intracutaneously or Rossman, Knox, and Freeman (ref. excessive sweating. There is no recom­ topically administered was approxi­ 4) compared 100 sunscreen products mended dosage for children under 6 mately 500 mg/kg. There was no aller­ and formulations on the untanned months of age except under the advice gic sensitization by either topical or backs of white men. Different test and supervision of a physician. intradermal route (ref. 1). agents were arranged in six vertical (4) Labeling. The Panel recommends Human safety studies have been re­ strips extending from the waist to the the category I labeling for sunscreen ported. Tests using a 5 percent concen­ upper scapular areas. Test sites were active ingredients. (See part III. para­ tration and performed on 50 subjects, 36 one-inch squares arranged in six graph B.l. below—category I labeling.) approximately one-third of whom had rows of six each. 2-Ethylhexyl 2- extremely sensitive skin, including cyano-3,3-diphenylacrylate was tested R eferences some with eczema and sensitization, in 10 and 20 percent concentration (1) OTC Volume 060171. demonstrated that the product is very while 10 percent 3-benzoyl-4-hydroxy- (2) Technical Report GAF Corporation, well tolerated on the skin. Patch tests Draft of unpublished paper in OTC Volume 6 methoxy benzenesulfonic acid in a 060150. using an unspecified concentration on vanishing cream base and 10 percent (3) Strobel, A. and J. J. Inserra, “The Use 27 men and 22 women, 18 to 60 years aminobenzoic acid in the same vanish­ of UV* Absorbers in Cosmetic Products,” of age, produced no positive results ing cream base were used as control American Perfumer and Cosmetics, 83:25-30, after 24 and 48 hours, thereby leading standard sunscreens. The light source 1968. to the conclusion that the product was a hot quartz mercury vapor lamp (4) Rossman, R. E., J. M. Knox and R. G. would not act as a primary irritant or and the test sites were irradiated at a Freeman, “Acrylonitriles, A New Group of would not act, under longer use, as an fixed 75 cm distance. The average Ultraviolet Absorbing Compounds,” The Journal of Investigative Dermatology, allergenic substance. Photosensitiza­ MED for the light source wa^ 15 sec­ 39:449-453, 1962. tion tests “showed that the product onds (range 10 to 25 seconds). did not provoke photosensitization” In 32 subjects, 20 percent 2-ethyl- h. Ethylhexyl p-methoxycinnamate. (ref. 1). hexyl 2-cyano-3,3-diphenylacrylate in The Panel concludes that ethylhexyl In a line of products where the in­ a vanishing cream base protected for p-methoxycinnamate is safe and effec­ gredient was combined with a benzo­ 9.1 minutes (36 times the average tive for OTC use as a sunscreen as phenone, over 8 million units were MED) while 10 percent 2-ethylhexyl 2- specified in the dosage section dis­ sold, 38 complaints of skin irritation cyano-3,3-diphenylacrylate in the cussed below. were received by the manufacturer,

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38228 PROPOSED RULES but not a single case of skin irritation April sun in Arizona. The formula­ application before sun exposure and could be clearly related to the use of tions had as SPF value of 2.8 to 10.1 reapply after swimming or after exces­ the products. Over 209 tons of ethyl- (ref. I). The next outdoor experiment sive sweating. There is no recommend­ hexyl p-methoxycinnamate were sold involved testing 12 products, 10 con­ ed dosage for children under 6 months in 27 countries in 2 years (ref. 1). taining 2.5 to 5 percent ethylhexyl p- of age except under the advice and su­ A human Draize test was performed methoxycinnamate on 11 men exposed pervision of a physician. in 54 men and women. Ethylhexyl p- to 30, 60, 90, and 120 minutes sunlight (4) Labeling. The Panel recommends methoxycinnamate 7.5 percent in pet­ from 11 a.m. to 1 p.m. Each man had the category I labeling for sunscreen rolatum was applied to the deltoid three formulations and an untreated active ingredients. (See part III. para­ area alternately under occlusion for 48 control applied. All formulations per­ graph B.l. below—category I labeling.) hours for 11 applications. Two weeks formed well. One product containing 4 R eferences later the challege dose was reapplied. percent ethylhexyl p-methoxycinna­ mate alone had an SPF value of 2J. (1) OTC Volume 060083. No reactions occurred to the ethyl- (2) OTC Volume 060110. hexyl p-methoxycinnamate (ref. 2). No after 120 minutes exposure, while an (3) Pathak, M. A., T. B. Fitzpatrick and J. adverse reports were found in the lit­ aerosol product containing 2.5 percent A. Parrish, “Evaluation of Piz Buin erature to the use of topical ethyl- ethylhexyl p-methoxycinnamate had (Greiter, AG) Sunscreen Formulations hexyl p-methoxycinnamate. an SPF value of 2.9 after 120 minutes under Laboratory and Field Conditions/’ Based on the available data, the exposure. The third field experiment Draft of unpublished paper in OTC Volume Panel concludes that ethylhexyl p- tested three products in six subjects 060083. methoxycinnamate is a safe sunscreen after exercising 0.5 hour then exposed i. 2-Ethylhexyl salicylate. JThe Panel ingredient for OTC use. to the noon sun for 30, 60, 90, and 120 concludes that 2-ethylhexyl salicylate (2) Effectiveness. Thfere are studies minutes. All formulations performed is safe and effective for OTC use as a documenting the effectiveness of eth­ well. The fourth experiment tested suncreen as specified in the dosage ylhexyl p-methoxycinnamate as an three products under conditions simu­ section discussed below. OTC sunscreen. lating normal usage like exercise (30 2-Ethylhexyl salicylate is also known Efficacy data reviewed by the Panel minutes), walking (30 minutes), sun­ as octyl salicylate. included in vitro studies of the absorp­ bathing passively (60 minutes), and Its absorbance is between 280 and tion, solubility, and stability proper­ two swims. Each product was tested in 320 nm with a maximum absorbance ties of ethylhexyl p-methoxycinna­ nine subjects along with the 5 percent wide peak at about 300 nm. It is an mate (ref. 1). Absorption at 308 nm is PABA control. The mean SPF values odorless, clear, white-to-slightly yel­ 84 to 90 percent for 2.0 to 2.5 percent were 9.1, 5.9, and 9.3. The last experi­ lowish liquid with a molecular weight concentrations. ment in the series compared the same of 250.33, a specific gravity of 1.013 to The ingredient absorbs UV light in three formulations in six subjects 1.022, and a boiling point of 144° C at the 290 to 320 nm range, with the after a 15-minute swim followed by 1mm. It is completely soluble in min­ maxima at 308 to 310 nm. Like many sun exposure to 90 minutes. Each sub­ eral oil and two parts of 95 percent sunscreens, the percent of absorption ject tested two products and had an ethanol. It has been used as a sun­ depends upon the concentration. As untreated control site. The mean SPF screen since 1938 and is incorporated noted above, absorption in pure eth­ values were 4.2, 1.04, and 4.4 or greater in emulsion, oil, ointment, and paste anol is 84 percent at 2 percent, 94 per­ (ref. 3). Evaluation of the tanning re­ formulations. cent at 3 percent, and 98.8 percent at 5 sponse to two products containing 4.0 (1) Safety. Clinical and marketing percent concentrations. It is often for­ and 2.5 percent ethylhexyl p-methoxy­ experience have confirmed that 2-eth­ mulated with other sunscreens (ref. 1). cinnamate exhibited a pigmentary re­ ylhexyl salicylate is safe in the dosage In a series of five well-designed, con­ sponse on clinical and skin reflecto- range used as an OTC sunscreen. trolled, randomized, singleblind labo­ meter evaluation, but it was less than Animal and human toxicological ratory and field trials, ethylhexyl p- the untreated control sites. Another data and long use attest to its safety methoxycinnamate alone and in com­ similar series of outdoor testing was for human topical application. bination performed well. Each subject performed in Australia, with similar The Draize rabbit eye irritation test had his/her MED and skin reflectance results (ref. 1). revealed it to be a nonirritant when measured. In outdoor tests the solar Several partially controlled studies 0.1 ml 2-ethylhexyl salicylate was in­ energy flux was measured. In the labo­ of formulations containing ethylhexyl stilled into the eyes of nine albino rab­ ratory test, 2.5 to 5.0 percent ethyl­ p-methoxycinnamate were submitted bits. In three rabbits the eyes were not hexyl p-methoxycinnamate in combi­ by the manufacturer (ref. 1). washed, while the other rabbits and nation with other sunscreens was ap­ Based on the available data, the the eyes washed in 2 or 4 seconds with plied to the back of 12 men and Panel concludes that ethylhexyl p- 20 ml of lukewarm water. Evaluations women. Each subject had four sites; methoxycinnamate is an effective sun­ were made at 1 hour, 24 hours, and 7 each site had three rows; and each row screen ingredient for OTC use. days. No damage was observed of the had five (2.5 X 2.5 cm) windows. Each (3) Dosage, (i) For products provid­cornea or iris, while the conjuctiva site had only one product applied to a ing a minimum SPF value of 2 to had a mild reaction (ref. 1). row, an untreated control row, and a 5 under 4 containing 2.0 to 7.5 percent The oral LDS0 in Sherman strain percent PABA in ethanol control row. ethylhexyl p-methoxycinnamate: albino rats was found to be 4.8 ± 0.3 g/ A hot-quartz mercury lamp delivered Adult and children over 2 years of age kg (ref. 2). U.S. Army Military Specifi­ 3, 5, 9, 12, and 15 MED’s to each sub­ topical dosage is liberal application cation MIL-S-11262E lists 2-ethyl­ ject. Readings were made about 24 before sun exposure and reapply after hexyl salicylate among the approved hours later. All formulations contain­ swimming or after excessive sweating. suncreening agents, with a maximum ing ethylhexyl p-methoxycinnamate There is no recommended dosage for amount of 5 parts by weight approved performed well (ref. 3). An experiment children under 2 years of age except for toxicity for use with the basic in 8 men compared two products, an under the advice and supervision of a cream formulation specified therein untreated control, and a 5 percent physician. (ref. 2). PABA in ethanol control on the back (ii) For products providing a mini­ Patch tests were performed on 10 of each man. Three products contain­ mum SPF value of 4 containing 2.0 to randomly selected human subjects. A ing ethylhexyl p-methoxycinnamate 7.5 percent ethylhexyl p-methoxycin­ 5 percent 2-ethylhexyl salicylate prep­ were tested; The men sunbathed pas­ namate: Adult and children over 6 aration in mineral oil was applied to sively from 11 a.m. to 1 p.m. in the months of age topical dosage is liberal the inner surface of the upper right

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38229 arm of each subject. The patches were with maximal absorbance at 305 nm. swimming or after excessive sweating. removed after the test material had Changing the concentration and vehi­ There is no recommended dosage for been in contact with the skin for 24 cle changes the percentage of absorp­ children under 6 months of age except hours. No reactions were observed at tion. For example (refs. 1 and 3): under the advice and supervision of a that time or after 72 hours. After a 7- physician. day test period the above-described (4) Labeling. The Panel recommends Cream concentration Erythema transmission procedure was repeated, and again no (percent) (percent) the category I labeling for sunscreen reactions were noted either upon re­ active ingredients. (See part III. para­ moval of the patches or after 72 hours. 290 to 310 nm graph B.l. below—category I labeling.) It was concluded that the test material 3.0 0.3 4.0 0.4 R eferences did not contain primary and/or sec­ 290 to 320 nm ondary skin irritants (ref. 2). 9.5 4.0 (1) OTC Volume 060151. In a human Draize repeated-insult 7.0 8.0 (2) OTC Volume 060088. 5.2 15.0 (3) OTC Volume 060006. patch test, no primary irritation, “fati­ (4) Kreps, S. I., “The Structure, Function guing,” or sensitization reactions were and Formulation of Topical Sunscreens. I. observed when 0.5 ml of 2-ethylhexy To meet the special requirements of Theoretical Considerations,” Journal of the salicylate was applied under occlusion a sunscreen, a compound must be able Society of Cosmetic Chemists, 14:625-630, to the intact skin of 25 subjects for 10 to resonate between alternate ionic 1963. applications at 48-hour intervals, with forms. This ionization change must re­ J. Glyceryl aminobenzoate. The the 11th application 2 weeks later (ref. quire an energy quantum within the Panel, concludes that glyceryl amino- 1). UV region. This corresponds to elec­ benzoate is safe and effective, for OTC The phototoxicity potential of 5 per­ tronic transition (ionization) energies use as a sunscreen as specified in the cent 2-ethylhexyl salicylate in ethanol of 91.4 to 99.4 kilocalories per gram dosage section discussed below. was tested in 10 subjects. The solution mole (kc al/g mol) for compounds Glyceryl aminobenzoate is also was applied to normal skin sites and to with absorption maxima, between 290 known as glyceryl p-aminobenzoate. cellophane tape-stripped sites. The and 315 nm, the sunburn erythema Glyceryl aminobenzoate is soluble in sites were irradiated after either a 1- range. Few classes of compounds satis­ ethyl and isopropyl alcohol and glyc­ hour contact (stripped sites) or 24- fy this basic requirement. The salicy­ erine and propylene glycol; but it is in­ hour contact (normal skin). All sub­ lates, cinnamates, p-aminobenzoates, soluble in water, mineral oil, and jects had a 3 percent demeclocycline and p-dialkyl aminobenzoates are ex­ peanut oil. Glyceryl aminobenzoate hydrochloride solution positive con­ amples of aromatic compounds meet­ can be incorporated into aerosols, trol. The sites were irradiated from ing this basic requirement, and they emulsions, hydroalcoholic solutions, 322 to 410 nm with a xenon arc lamp have performed as effective sun­ and lipstick formulations. Its absor­ system. All subjects had a positive screens in use (ref, 4). bance is between 264 and 315 nm, with phototoxicity response to the demeclo­ The Quartermaster Corps of the maximum absorbance at 295 nm (ref. 2 cycline, but none responded to the - U.S. Army approved 5-percent-by- 1.). ethylhexyl salicylate (ref. 1). weight 2-ethylhexyl salicylate as a (1) Safety. Clinical use and market­ Over a 10-year period, about 55,000 sunburn preventative (U.S. Specifica­ ing experience have confirmed that pounds of 2-ethylhexyl salicylate were tion MIL-S-11 262 E, 15 March 1972). glyceryl aminobenzoate is safe in the sold each year. Several companies It was first approved for military pro­ dosage range used as an OTC sun­ market products containing it, but the curement in 1951 (ref. 1). The efficacy screen. only data were supplied to the Panel data from the Army tests were not Animal and human toxicological by the manufacturer of the basic available to the Panel. data attest to its safety for human chemical (ref. 2). One product manu­ Testimonial letters from six cosmetic topical application in 3 percent con­ facturer indicated that it had pro­ manufacturers stated that they found centration (refs. 2 and 3). The oral duced over a million units in 6 years 2-ethylhexyl salicylate to be an effec­ LDso is 17.3 ml/kg in rats (ref. 4). and had had no complaints or reports tive sunscreen and that it was chosen A 20-day acute toxicity test of a of dermatitis, skin irritation, allergies, for use in their products because of its preparation containing 20 percent gly­ or sensitivity to the two products con­ efficacy and desirable characteristics ceryl aminobenzoate in a base solution taining 2-ethylhexyl salicylate (ref. 2). (ref. 3). No data were given. Being one was performed using New Zealand Another product manufacturer wrote of the older sunscreens, such record­ strain male rabbits with abraded and that before marketing its product in keeping was not necessary. intact skin. A shaved area of skin ap­ 1946, it had conducted patch tests on Based on the available data, the proximately 10 percent of the body 50 persons, with favorable results (ref. Panel concludes that 2-ethylhexyl sa­ surface was inuncted daily with 1, 2, 2). The Panel found no adverse reports licylate is an effective sunscreen ingre­ and 4 g/kg of body weight, with con­ to the topical use of 2-ethylhexyl salic­ dient for OTC use. trol animals receiving 4 g/kg of the ylate in the literature. (3) Dosage, (i) For products provid­solvent only. No toxic manifestations Based on the available data, the ing a minimum SPF value of 2 to were observed in any of the test ani­ Panel concludes that 2-ethylhexyl sa­ under 4 containing 3 to 5 percent 2- mals; There were no abnormal, irrita­ licylate is a safe sunscreen ingredient ethylhexyl salicylate: Adult and chil­ tive, deteriorative, or coagulative ef­ for OTC use. dren over 2 years of age topical dosage fects on the intact or abraded skin (2) Effectiveness. There are no con­ is liberal application before sun expo­ (ref. 1). trolled studies documenting the effec­ sure and reapply after swimming or Toxicological studies employing a tiveness of 2-ethylhexyl salicylate as a after excessive sweating. There is no marketed sunscreen lotion containing sunscreen. However, it is the Panel’s recommended dosage for children 3 percent glyceryl aminobenzoaJte and conclusion that clinical use and mar­ under 2 years of age except under the 3 percent amyl p-dimethyl- aminoben­ keting experience have confirmed ef­ advice and supervision of a physician. zoate indicated that the product was fectiveness. (ii) For products providing a mini­ nontoxic to mice and rats when admin­ The effectiveness of 2-ethylhexyl sa­ mum SPF value of 4 containing 3 to 5 istered in a single oral dose of 50 ml/ licylate as a sunscreen is demonstrated percent 2-ethylhexyl salicylate: Adult kg (ref. 2). For 32 consecutive days, 0.2 by its in vitro UV light absorption and children over 6 months of age ml of lotion was applied to the shaved characteristics. The ingredient absorbs topical dosage is liberal application intrascapular area of albino rats with­ UV radiation between 280 and 320 nm, before sun exposure and reapply after out any dermal toxicity being noted in

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 38230 PROPOSED RULES any of the eight animals so treated hours and was reduced to very slight plied. It was reported that none of the (ref. 2). at 48 hours, with none noted at 72 test materials were rated as significant Using two sunscreen lotions each hours. There was no edema formation irritants, with only a few readings in­ containing 3.15 percent glyceryl- amin- noted in any of the 12 test animals dication erythema over the entire test obenzoate and 3.15 percent amyl p- (ref. 2). site. All the remaining responses were dimethylaminobenzoate, acute eye ir­ Another evaluation was made as to equivocal, with erythema present over ritation studies were performed on 12 the primary irritation potential of two part, but not the entire, test site. New Zealand albino rabbits. Two drops preparations, each containing 3.15 per­ Fifty human subjects were selected of one lotion were instilled into the cent glyceryl aminobenzoate and 3.15 on the basis of their general good left eye of each rabbit, while the con­ percent amyl p-dimethyl- aminoben­ health and absence of any skin dis­ tralateral eyes were treated with an zoate. Twelve adult female New Zea­ eases which might be confused with equal amount of the other lotion. Two land albino rabbits were prepared in skin reactions form the test material minutes after administration, both the same manner as described above. and were treated with glyceryl amino­ eyes of six rabbits were rinsed with 20 In the case, 0.2 ml instead of 0.5 ml of benzoate to determine whether this in­ ml of lukewarm water. One hour later the test preparation was applied to gredient was capable or irritating the rinsed eyes were stained with one each test site. The results were essen­ human skin under controlled test'con­ drop of 2 percent fluorescein for obser­ tially similar to those noted in the ditions. Sites on the upper arm of each vation under UV light. Twenty-four study discussed above (ref. 2). subject were designated to receive a hours after instillation, the unrinsed Each ingredient in the above-de­ series of 16 applications, each of 24 eyes were treated in the same manner. scribed sunscreen preparation was hours’ duration, of the test material. A The eyes were scored for toxicity (ref. evaluated for potential dermal irrita­ lintine pad treated with the test mate­ 5). No toxicity was noted in any of the tion by combining the ingredient with rial was placed on its predesignated rinsed and unrinsed eyes, although a suitable vehicle, i.e., petroleum, site, covered, and sealed with overlap­ mild to moderate discomfort charac­ methanol, or distilled water and apply­ ping strips of an occlusive tape. At the terized by repeated blinking was ob­ ing it topically to rabbit skin for 7 con­ end of 24 hours the seal was broken served to last from 15 to 30 seconds in secutive days. Twenty-four hours prior and the patch was removed. The test both the rinsed and unrinsed eyes. to the onset of the study, the dorsal sites were examined, and any gross Slight conjunctival irritation was ob- region in each of 15 rabbits was shaved changes were graded on a scale of servèd immediately following instilla­ free of hair and divided into 4 quad­ from 1 to 4, with the absence of any tion in both groups; the condition sub­ rants of no less than 25 cm2 each. visible changes being assigned a 0 sided within 1 hour following rinsing Three times daily, 0.2 ml of each test value. After the removal of the patch, and after 24 hours postinstillation in material was placed onto a test quad­ the test sites were rested for 24 hours, the unrinsed group (ref. 2). rant in each of three rabbits by using except on weekends when the rest An evaluation was made as to the a glass disposable syringe and then period was extended to 48 hours. Prior primary irritation potential of the two gently inuncted onto the skin with a to reapplication the test sites were ex­ lotions described in the previous para­ clean stainless steel spatula. The test amined again to determine whether graph by applying 0.5 ml of the prep­ sites were observed regularly for irrita­ any changes had occured. The test ma­ arations to abraded and intact (oc­ tion, physical appearance, and general terial was reapplied to the same site if cluded and unoccluded) rabbit skin. behavior, with dermal reactions being the contact site manifested no Twenty-four hours prior to the onset graded (ref. 5). Glyceryl aminoben­ changes. If significant irritation (2+ of the study, the dorsal area of 12 zoate (3 percent) elicited no untoward or more) was observed, the investiga­ adult female New Zealand albino rab­ dermal reactions, while amyl p- tor could at his option rest 'the subject bits was shaved free of hair. The fol­ dimethylaminobenzoate (3 percent) or apply the test material to a new site lowing day the shaved area was divid­ elicited very slight erythema. Slight to for the next contact period. After the ed into 4 quadrants of no less than 4 moderate erythema was noted on test fifteenth application the subjects were square inches each. Two of the test sites treated with several other ingre-. rested for 2 weeks before being chal­ sites on each rabbit were abraded by dients (ref. 2). lenged by applying the test material making four epidermal incisions The above-described sunscreen was under occlusion for 24 hours to the through the stratum comeum with a tested in the rabbit ear for comedo- previously used sites. Following remov­ sterile needle in a “tic-tac-toe” pat­ genicity, along with two other sun­ al of the patch, the test sites were ex­ tern. The abraded and intact sites screens, one containing 10 percent amined immediately and after 24 and were diagonally located from one an­ sulisobenzone and the other contain­ 48 hours. In no instance were visible other. Each of the two lotions was ap­ ing 3 percent dioxybenzone and 3 per­ changes noted signifying reaction to plied to six rabbits by using a glass dis­ cent oxybenzone. It was reported that injury. It was concluded by the investi­ posable syringe.under to gauze patch the preparation containing 3 percent gator that “under the test conditions, secured by adhesive tape. The test glyceryl aminobenzoate and 3 percent glyceryl para-aminobenzoate was not sites for three rabbits in each group amyl p-dimethylaminobenzoate capable of eliciting visible skin were occluded. After 24 hpurs contact showed marginal hyperkeratosis and changes consistent with criteria being time the patches were removed and produced small comedones, whereas characteristic of a primary irritant, fa­ the resulting reactions were graded the other two preparations produced tiguing agent or a sensitizer” (ref. 8). through 72 hours in accordance with a huge comedones. No specifics were On the basis of the test results for 50 described method (ref. 5). Variations given as to the testing procedure (ref. subjects, the investigator predicted in the reactions noted for the two 6). with 95 percent certainty that at least preparations were minimal. Essential­ Controlled human studies of the ra- 92.89 percent of the general popula­ ly, there was slight erythema (value of lative irritancy potential of eight prep­ tion will not be sensitized by this ma­ 1 or less) noted at 24 hours in the rab­ arations were performed using the terial. bits of the abraded-occluded and method outlined by Phillips et al. (ref. Maximization tests (ref. 9) to deter­ intact-occluded groups. Little or no ir­ 7). The materials to be tested were ap­ mine the contact-sensitizing potential ritation was noted at 48 hours and was plied daily for 21 days to Webril of a sunscreen product containing 3 absent at 72 hours. Likewise, in rabbits patches and attached to the skin with percent glyceryl aminobenzoate and 3 of the abraded-unoccluded and intact- an occlusive tape. Each day the patch­ percent amyl p-dimethylaminobenzo- unoccluded groups slight erythema es were removed, the sites examined ate were performed on 25 healthy (value of 1 or less) was noted at 24 and scored, and fresh patches reap­ adults male volunteers. The test mate-

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38231 rial was applied under occlusion to the products were not provided. One-inch lating radiation. One study evaluated same sites on the volar forearms of all square Webril patches were loaded protection immediately after applica­ subjects for 5 alternate 48-hour peri­ with 25 percent liquor carbonis deter­ tion and involved each site immediate­ ods. The test sites were pretested for gents (LCD) and occluded to four sites ly after inunction receiving 10 MED’s 24 hours with 5 percent aqueous on the forearm skin of each patient individually determined beforehand sodium lauryl sulfate under occlusion. for 1 hour, after which the site was for each subject. The skin was evaluat­ After a 10-day rest period, challenge cleaned with mineral oil before the ap­ ed 24 hours later, with any reactions patches were applied under occlusion plication of thin film of the test for­ being graded on a 4-point scale (0— to new sites for 48 hours, but were pre­ mulation. Each site then received 6 negative, 1—mild response, 2—moder­ ceded by 1-hour applications of 10 per­ minutes of long-UV radiation. A con­ ate redness, and 3—sharp redness). In cent sodium lauryl sulfate under oc­ trol LCD site was irradiated on each the second study, postimmersion pro­ clusion. It was indicated that the chal­ subject without the application of any tection was evaluated. Previously irra­ lenge sites were réad immediately test formulation. The test sites were diated sites were avoided. The sub­ upon removal of the patch and 24 examined 24 hours later, and any jects’ forearms were immersed for 10 hours thereafter. However, individual gross changes were graded on a scale minutes in a water bath at room tem­ subject data indicated that the chal­ of 1 to 4, with the absence of any visi­ perature 2 hours after application of lenge sites were read after 48 and 72 ble changes being assigned a 0 value. the test formulations. Following the hours. It was reported that there were The preparation containing 3 percent immersion, 10 MED’s were adminis­ no instances of contact-sensitization glyceryl aminobenzoate and 3 percent tered, and the skin reactions were and that it was unlikely that the test amyl p-dimethylami nobenzoate was evaluated 24 hours later and graded material would present a danger of one of two formulations found to using the above-described scale. In contact-sensitization in normal, in­ almost completely block the photo­ both studies, it was concluded that a tended use (ref. 10). toxic response. It was concluded that sunscreen formulation containing 3 The phototoxicity and photocontact these two formulations provide excel­ percent glyceryl aminobenzoate and 3 allergenicity potential of a sunscreen lent protection in the phototoxic percent amyl p-dimethylamino- benzo­ formulation containing 3 percent gly­ model, permitting the inference to be ate provided excellent protection im­ ceryl aminobenzoate and 3 percent made that they efficiently absorb mediately after application (0.45 aver­ amyl p-dimethylaminobenzoate were long-UV radiation in the spectral age value) and postimmersion (0.55 evaluated in 35 healthy adult male range of 320 to 400 nm and that average value). Moderate protection volunteers (ref. 11). “these two formulations therefore was provided by a formulation con­ To test for phototoxicity, 0.2 ml of may be regarded as broad-spectrum taining unspecified concentrations of the test materials was applied occlusi- sunscreens, providing excellent protec­ glycerly aminobenzoate and amyl p-di- vely to duplicate 2 cm2 normal and tion against sunburning radiation as methyl- aminobenzoate immediately stripped skin sites on the upper backs well as longer rays which activate pho­ after application (1.30 average value) of the subjects. Each stripped site re­ tosensitization reactions” (ref. 12). and postimmersion (1.55 average ceived 6 MED’s of xenon solar simulat­ The photosensitivity* irritancy, and value). Poor protection was provided ing radiation filtered through window allergic sensitization potential of a by preparations containing unspecified glass. The normal site was similarly sunscreen formulation containing 3 concentrations of the single active in­ exposed to the same dose of long-UV percent glyceryl aminobenzoate and 3 gredients glycerly aminobenzoate and radiation after 24 hours of occlusion. percent amyl p-dimethylaminobenzo- amyl p-dimethylaminobenzoate imme­ Observations were made a 1, 3, and 24 ate was evaluated in 15 healthy female diately after application (1.90 and 2.50 hours after irradiation. To test for and 25 healthy male subjects. The test average values, respectively) and pos­ photocontact allergenicity , 0.2 ml of material was applied daily for 30 days timmersion (2.20 and 2.50 average the test materials was applied to ohe to the face and upper trunk of each values, respectively) (ref. 14). 2-inch square of stripped skin on the subject, after which the subjects were Double-blind studies were performed upper backs of the subjects, and the irradiated with 3 MED’s from a bank on a series of single active ingredient sites were then exposed to 3 MED’s of of fluorescent lamps. Individual sub­ and combination sunscreen prepara­ xenon solarsimulating radiation and ject data were not provided, but it was tions in a water-resistant emollient occluded. This procedure was repeated reported that 12 subjects (4 females cream base using natural sunlight and five times at intervals of 48 hours. Ten and 8 males) complained of very mild ocean swimming. For the purposes of days after the final induction expo­ itching around the eyes but that there the present review, the Panel only sure, the subjects were challenged by were no visible signs of irritation in considered the results for those for­ applying 0.2 ml of the test materials to these subjects. It was further reported mulations containing 3 percent gly­ both normal and stripped skin sites, that there were no instances of photo­ ceryl aminobenzoate and 3 percent followed by exposure to 3 MED’s of sensitivity of allergenicity in this test amyl p-dimethylaminobenzoate alone xenon solarsimulating radiation fil­ (ref. 13). and in combination and for a market­ tered through window glass. The sites Based on the extensive animal and ed sunscreen containing 5 percent were occluded, and observations were human toxicological data, the Panel aminobenzoate. Opaque white tape make at 24, 48, and 72 hours after irra­ concludes that glyceryl aminobenzoate was used to mark out a series of 7.5 cm diation. The results of the tests re­ is a safe sunscreen ingredient for OTC x 7.5 cm approximately 6 cm below the vealed no instances of phototoxicity or use. base of the neck and centered between photocontact allergenicity among any (2) Effectiveness. There are studies the shoulder blades on the backs of 30 of the subjects (ref. 11). documenting the effectiveness of gly­ untanned light-skinned Caucasian vol­ Test were performed using 10 adult ceryl aminobenzoate as an OTC sun­ unteers. Using a randomized medica­ subjects for the purpose of discrimin­ screen. tion schedule, each test site was treat­ ating among four formulations report­ Doubleblind studies were performed ed with 0.05 ml of a test formulation. ed to be equally effective in providing comparing nine formulations for sun­ The subjects were simultaneously ex­ protection against sunburn in the im­ screening efficacy in 10 healthy adult posed to 2 hours of sunlight (10 am. to mediate and post-immersion assays. white males. The fomulations were ap­ noon on a clear day in Miami, Fla., in One formulation contained 3 percent plied in random fashion to 2 cm2 on August 1971). Following this exposure, glyceryl aminobenzoate and 3 percent the medial forearm skin surface at the the subjects swam for 10 minutes amyl p-dimethylaminobenzoate; the rate of 60 ul/cm2. A 1,600 watt xenon while totally immersed in the ocean. formulations for the three remaining lamp was used to provide solar-simu­ Immediately thereafter they were

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 38232 PROPOSED RULES again exposed for 2 more hours until moderate erythema, 3—marked eryth­ for OTC use as a sunscreen as speci­ the 2 p.m. conclusion. At this point ema, and 4—marked erythema with fied in the dosage section discussed the tape was removed, the test sites edema). Complete data for only 22 below. photographed, and instructions were Homosalate is also known as 3,3,5- given to the subjects not to apply any­ subjects were considered in the statis­ thing other than water to the test tical evaluation, as 3 subjects failed to trimethylcyclohexyl salicylate, and sites. Evaluations were made and pho­ return for the final evaluation and 5 was formerly called homomenthyl sa­ tographs were taken of the test sites subjects had an uneven suntanning re­ licylate. 24 and 72 hours following exposure. At sponse. The results for the formula­ Homosalate is an oily, colorless-to- tions under consideration in this faint-yellow liquid which does not pre­ each point the reactions were graded cipitate when cooled at 15° C for 12 (0—no change, 1—mild erythema, 2— review were as follows: hours (ref. 1). Means and standard deviations of severity gradings (1) Safety. Clinical use and market­ ing experience have confirmed that homosalate is safe in the dosage range 24-hour 72-hour evaluation evaluation used as an OTC sunscreen. Animal and human toxicological Mean Standard Mean Standard data attest to its safety for human value deviation value deviation topical use. The acute oral LD50 in rats for ho­ 1. 3 pet glyceryl aminobenzoate...... '...... 2.1727 0.0917 1.6818 0.1169 mosalate has been determined to be 2. 3 pet amyl p-dimethylaminobenzoate...... 2.3545 .0789 1.8728 .0893 3. 3 pet glyceryl aminobenzoate, 3 pet amyl p-dimethylaminobenzoate 2.0227 .0696 1.7818 .1084 greater than 8.0 ml/kg of body weight 4. 3 pet glyceryl aminobenzoate, 3 pet amyl p-dimethylaminobenzoate 2.2045 .0710 1.8000 .1509 (ref. 2). The acute oral LDn in rats for 5. 5 pet aminobenzoate...... 3.0727 .0838 2.4955 .0862 a sunscreen lotion containing 8 per­ cent homosalate was found to be The two combination formulations (4) Labeling. The Panel recommends greater than 10,000 pl/kg of body listed above differed only in a single the category I labeling for sunscreen weight (ref. 3). Two rabbit eye irrita­ base ingredient. Both of these formu­ active ingredients. (See part III. para­ tion studies of a sunscreen lotion and lations and the preparation containing graph B.l. below—category I labeling.) oil containing 8 and 9 percent homosa­ glyceryl aminobenzoate of the formu­ late, respectively, demonstrated no lations tested were found to provide R eferences deleterious effects when 0.1 ml of the the maximum absorption in the criti­ (1) OTC Volume 060019. undiluted test material was instilled cal erythema range (290 to 320 nm) (2) OTC Volume 060103. into the conjunctival sac of the right (3) OTC Volume 060104. eye of nine albino rabbits, with the and maximum resistance to water (4) “Acute Oral LDU, Glyceryl Para-Ami­ wash-off if one excludes a similar for­ nobenzoate,” Draft of unpublished paper in left eye serving as a control (ref. 4). mulation which also contained 2.5 per­ OTC Volume 060103. Homosalate was applied full- cent 2-hydroxy-4-methoxy-benzophen- (5) “Appraisal of the Safety of Chemicals strength to the arms, abdomens, and one and which provided the lowest in Foods, Drugs and Cosmetics,” Association faces of five subjects without any re­ mean values at both the 24- and 72- of Food and Drug Officials of the United ported untoward effects. An ointment hour evaluation periods. The latter States, pp. 48-51, 1965. containing unspecified amount^ of the formulation, however, produced sensi­ (6) “Test for Comedogenicity,” Draft of sunscreens homosalate and ethyl unpublished paper in OTC Volume 060103. aminobenzoate was applied to 22 sub­ tivity reactions traced and attributed (7) Phillips,'L., M. Steinberg, H. I. Mai- to the benzophenone component in bach, and W. A. Akers, “A Comparison of jects without any reported cases of^ followup human irritation studies (ref. Rabbit and Human Skin Response to Cer­ sensitivity (ref. 5). 15). tain Irritants,” Toxicology and Applied In 1964, the military approved, on Based on the extensive data, the Pharmacology, 21:369-383, 1972. the basis of toxicolgical consider­ Panel concludes that glyceryl amino­ (8) “Evaluation of Potential Hazards of ations, a maximum of 8 percent homo­ benzoate is an effective sunscreen in­ Glyceryl Para-Aminobenzoate by Dermal salate for sunburn preventative prep­ Contact (Maximization Test),” Draft of un­ arations in a cream paste formulation gredient for OTC use. published paper in OTC Volume 060104. (3) Dosage, (i) For products provid­ (9) Kligman, A. M., “The Identification of (ref. 6). ing a minimum SPF value of 2 to Contact Allergens by Human Assay,” Jour­ Patch tests of 25 human subjects (9 under 4 containing 2 to 3 percent gly­ nal of Investigative Dermatology, 34:51-58, males and 16 females) treated with a 6 ceryl aminobenzoate: Adult and chil­ 1960. percent homosalate sunscreen oil for dren over 2 years of age topical dosage (10) "Maximization Test,” Draft of unpub­ 48 hours demonstrated that the test is liberal application before sunexpo- lished paper in OTC Volume 060104. material was not a primary irritant, as (11) “Determination of Phototoxicity and no reactions were noted at 30 and 60 sure and reapply after swimming or Photocontact Allergenicity Potential of after excessive sweating. There is no Eclipse™ Sunscreen Lotion,” Draft of un­ minutes and at 24 hours following re­ recommended dosage for children published paper in OTC Volume 060104. moval of the patches from the inner under 2 years of age except under the (12) “Acute Eye Irritation Study on Eclip­ aspect of each subject’s upper left arm advice and supervision of a physician. se™ Sunscreen Lotion,” Draft of unpub­ (ref. 4). Thereafter, these 25 subjects lished paper in OTC Volume 060103. applied the preparation to an area ap­ (ii) For products providing a mini­ (13) “Photosensitivity, Irritancy and Aller­ proximately 1 inch in diameter on the mum SPF value of 4 containing 2 to 3 gic Sensitization Potential of G. S. Herbert skin of the dorsal surface or outer percent glyceryl aminobenzoate: Adult Sunscreen Z, GSH-1136,” Draft of unpub­ aspect of the left forearm daily for 3 and children over 6 months of age lished paper in OTC Volume 060104. (14) “Clinical Studies, Protection Immedi­ weeks, with subsequent exposure to topical dosage is liberal application ately After Application and Post Immer­ sunlight. Weekly evaluations of the before sun exposure and reapply after sion,” Draft of unpublished paper in OTC application site for each patient re­ swimming or after excessive sweating. Volume 060104. vealed no evidence of reaction. Follow­ There is no recommended dosage for (15) “Efficacy—Clinical Studies,” Draft of ing a 2-week rest period after cessation children under 6 months of age except unpublished paper in OTC Volume 060104. of use, challenge patches saturated under the advice and supervision of a k. Homosalate. The Panel concludes with the test material were applied to physician. that homosalate is safe and effective the upper left arm of each patient.

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38233 After 48 hours of skin contact the sunscreen lotion is absorbed through burn curve is at 308 nm. The greater challenge patches were removed. the unbroken skin. Five g of the test the extinction coefficient at this wave­ Readings recorded at 30 and 60 min­ material (8 percent homosalate) were length the greater will be the effec­ utes and at 24 hours afterwards applied by inunction to each arm, in­ tiveness of the compound as a sunburn showed no evidence of reaction. It was cluding fingers and forearm to elbow, preventive. Aminobenzoate was found concluded that the test material was and rubbed in for a period of 5 min­ to have approximately four times the not a primary irritant or skin sensitiz­ utes. Urinary salicylate excreted by screening power of homosalate (ref. er (ref. 7). each patient during the following 24 16). Two Shelanski Repeated Insult hours ranged from 4.3 to 17.7 mg. The Sunburn and suntan curves were es­ Patch Tests were performed on each testing laboratory reported, however tablished and plotted by Vicklund by of 50 human volunteers. In one test that experience has shown the “values multiplying the intensity of radiation each subject received 15 applications of less than 20 milligrams salicylate in of each wavelength by its effectiveness of a sunscreen lotion containing 8 per­ 24 hours can be obtained with control in producing sunburn and suntan, cent homosalate, while in the other urines in subjects who -are in no with the height of the curve at any test each subject received 15 applica­ manner exposed to salicylate” (ref. 1). wavelength indicating the ability of tions of an aerosol spray preparation It was concluded that the product is such radiation to cause erythema or containing 4 percent homosalate. In not absorbed through the unbroken tan. The development of a deep, both tests no reactions were observed, skin (ref. 12). bronze, long-lasting tan requires the and it was concluded that the test ma­ Marketing experience for seven mar­ formation of melanin pigmentation terials were not a primary irritant, keted sunscreen products containing stimulated by the erythema-producing sensitizing agent, or a fatiguing agent between 4 and 9 percent homosalate rays of the energy range 290 to 320 nm and may be considered safe for contact indicated the ratio of minor untoward and the thickening of the stratum cor- with human skin (ref. 8). effect complaints to the number of neum of the skin effected by the The safety of a sunscreen lotion con­ units distributed between 1963 and erythema-producing shorter wave­ taining 8 percent homosalate was eval­ 1972 ranged from 1:294,814 to lengths. Longer wavelengths only uated by the Draize patch test method 4:919,892. No complaints of serious un­ darken the preformed melanin, and in a study involving 2Q0 male and toward effects were reported, that is, the thickening of the stratum cor- female subjects. A patch containing complaints alleging serious illness or neum provides natural protection the test material was applied to the injury, prolonged illness or injury, or from sunburn, not tanning. A compari­ skin of the arm or back of each sub­ hospitalization. Of the 316 total com­ son of the UV sunscreen curve of ho­ ject. After 24 hours of contact the plaints of minor untoward effects mosalate with the sunburn and suntan patch was removed, and any reactions three had been confirmed; that is, the curves indicates that homosalate pro­ were graded and recorded. Following a complaint had been verified by appro­ tects against, but does not provide 24-hour rest period a second patch ap­ priate medical procedures (ref. 13). total absorption of, the erythema-pro­ plication was made. This procedure Based upon the available data, the ducing rays of the UV spectrum (ref. was repeated until each subject experi­ Panel concludes that homosalate is 17). enced 16 exposures. A challenge dose safe for use as an OTC sunscreen. Kreps found that a 2 percent gly­ was applied thereafter following a 14- (2) Effectiveness. There are studies ceryl aminobenzoate lotion and an 8 day rest period. Among the 200 sub­ documenting the effectiveness of ho­ percent homosalate lotion transmit 7.0 jects one isolated reaction occurred in mosalate as a sunscreen. and 7.5 percent incident E-viton units one subject at the ninth primary ap­ Absorbance occurs from 295 to 315 (unit of erythema flux), respectively, plication. This reaction consisted of a nm, with a maximum at 306 nm (ref. which in both cases will prevent a well-defined erythema, but did not 14). Depending upon the vehicle, 4 to minimum perceptible erythema recur. It was concluded (ref. 9) that 15 percent'homosalate is effective. An (MPE). Exposing skin patches to a the product was not a primary irri­ 8 percent (W/V) lotion acts as a per- standarized UV lamp for 3.5 minutes tant, a fatiguing agent, or a sensitizing mits-suntanning sunscreen agent, each hour over a 4-hour period (a total agent. while a 15 percent lotion will prevent of 14 minutes of radiation which is The safety of a sunscreen cream con­ suntanning and acts as a prevents-sun- equivalent to 4 hours of midday mid­ taining 4 percent homosalate was eval­ bum sunscreen agent. Homosalate can summer sunlight) produced a vivid uated by the Draize patch test method be formulated as an aerosol spray, oil, erythema without any sensitivity in in 200 male and female subjects. Six of emulsified cream, ointment, and foam. the case of the skin patch treated with the 200 subjects experienced slight to Homosalate demonstrates very high the 2 percent glyceryl aminobenzoate moderate erythema on 1 to 3 occasions absorption at 297 nm, the maximum of lotion, whereas an extremely painful between the third and ninth primary the erythema action spectrum. The sunburn resulted in the skin patch applications. It was concluded (ref. 10) extinction coefficient as determined treated with the 8 percent homosalate that the product possessed a mild fati­ by the Lambert-Beer Law at 297 nm lotion. Kreps concluded that the 2 per­ guing action, but was neither a prima­ includes the density readying from the cent glyceryl aminobenzoate lotion ry irritant nor a sensitizing agent. Beckman spectrophotometer, the con­ was the more effective of the two, as it The safety of a sunscreen oil con­ centration, and the thickness of the did not disappear by absorption into taining 9 percent homosalate was eval­ absorbing medium as variables, and the skin as rapidly as did the 8 percent uated by the Draize patch test method was found by Geise to be 6,720 at a homosalate lotion. He further con­ in 200 male and female subjects. Two concentration of 2.5xlO-4 mol/liter, cluded that when the rate of percutan­ of the 200 subjects experienced slight whereas that for aminobenzoate was eous absorption of the sunscreen com­ to moderate erythema on two occa­ 21,750 at a concentration of 2xl0~4 pound is marked, the concentration re­ sions between the fourth and tenth mol/liter (ref. 15). quired to provide a desired degree of primary applications. It was (ref. 11) A sunburn curve was determined and protection is greater than that indicat­ concluded that the product possesses a plotted by Kumler and Daniels by ed by in vitro spectrophotometric mea­ mild fatiguing effect, but is neither a multiplying the ordinates of the surements (ref. 18). primary irritant nor a sensitizing erythema curve by those of the sun­ Yankell at al. evaluated a 7.7 percent agent. light distribution curve. Such a curve homosalate lotion for sunscreen effica­ Salicylate excretion tests were per­ shows graphically the wavelengths cy using a xenon solar simulator and formed in six subjects to determine which should be screened out to pre­ applying 1 ml of the test material over whether homosalate as contained in a vent sunburn. The peak of this sun­ a 2 X 7 cm area on four sites of male

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 38234 PROPOSED RULES albino guinea pigs (ref. 19). Reactions recommends that homosalate be used (13) “Finished Drug Product: Marketing were read 18 hours after irradiating as an internal control standard for in Experience,” Draft of unpublished paper in these sites at multiples of the previ­ vivo efficacy testing in man. OTC Volume 060065. (3) Dosage, (i) For products provid­ (14) “Calculated Percent Absorption of a ously determined minimum erythema Film of Pure Compound 0.001 mm in Thick­ dose (MED). For the unwashed test ing a minimum SPF value of 2 to ness,” Draft of unpublished paper in OTC sites, the percent protection from under 4 containing 4 to 15 percent ho­ Volume 060065. erythema was calculated to be 100 per­ mosalate: Adult and children over 2 (15.) Giese, A. C., E. Christensen and J. cent at 1 MED, 100 percent at 2 MED’s years of age topical dosage is liberal Jeppson, “Absorption Spectra of Some Sun­ and 38 percent at 3 MED’s. For the application before sun exposure and screens for Sunburn Preparations.” Journal test sites which were washed to simu­ reapply after swimming or after exces­ of the American Pharmaceutical Association sive sweating. There is no recommend­ (Sci Ed). 39:30-36, 1950. late swimming and sweating condi­ (16) Kumler, W. D. and T. C. Daniels, tions, the percent protection from ed dosage for children under 2 years of "Sunscreen Compounds,” Journal of the erythema at 1 MED was 38 percent, age except under the advice and super­ American Pharmaceutical Association (Sci with no protection at 2 and 3 MED’s. vision of a physician. Ed), 37:474-476, 1948. Willis and Kligman reported that (ii) For products providing a mini­ (17) Vicklund, R. E., “Sun Tanning,” the protective index offered by homo- mum SPF value of 4 containing 4 to 15 Sindar Reporter, No. 2, 1959. salate was reduced from 4.75 to 1.75 at percent homosalate: Adult and chil­ (18) Kreps, S. I., “The Structure, Function 4 hours postsweating. They further dren over 6 months af age topical and Formulation of Topical Sunscreens, I. determined that the penetration of dosage is liberal application before sun Theoretical Considerations.” Journal of the exposure and reapply after swimming Society of Cosmetic Chemists, 15:625-630, homosalate is limited to the loose, 1963. noncoherent upper zone of the stra­ or after excessive sweating. There is (19) Yankell, S. L., et al., “Solar Simulator tum corneum, based on their observa­ no recommended dosage for children Sunscreen Evaluations in Guinea Pigs,” tion that the sun-screening effects of under 6 months of age except under Journal of the Society of Cosmetic Chemists, homosalate were almost completely the advice And supervision of a physi­ 27:607-611, 1970. eliminated after 4 strippings with cel­ cian. (20) Giese, A. C. and J. M. Wells, “Sweat lophane tape. (4) Labeling. The Panel recommends and Water Resistant Sunburn Prepara­ the Category I labeling for sunscreen tions,” Journal of the American Pharmaceu­ Human studies reported by Giese tical Association (Sci Ed), 35:208-212, 1946. and Wells indicated that “Of some 100 active ingredients. (See part III. para­ (21) “Finished Drug Product: Efficacy formulations tried, a bentonite clay graph B.l. below—Category I Label­ Data, General Summary,” Draft of unpub­ ointment, a stearate mixture base ing.) lished paper in OTC Volume 060065. ointment, a vanishing cream, and an R eferences I. Lawsone with dihydroxy acetone. ethocel lotion, nearly all containing (1) OTC Volume 060065. The Panel concludes that lawsone in homomenthyl salicylate and in some (2) Vogin, V. E., “Homomenthyl Salicy­ conjunction with dihydroxyacetone is cases also ethyl p-aminobenzoate as late: Approximate Acute Oral LD» in safe and effective for OTC use as a sunscreens and titanium dioxide as the Rats,” Food and Drug Research Laborato­ sun screen as specified in the dosage pigment proved most satisfactory. The ries, Draft of unpublished paper in OTC value of the ointments in sunburn pro­ Volume 060065. section discussed below. tection was tested by comparing the (3) Paynter, O. E., “Dose Range Oral Ad­ Lawsone is also known as 2-hydroxy- ratio of the dosage required in the ministration-Rats,” Hazelton Laboratories, 1.4- naphthoquinone. Lawsone is the control patch of skin. Sweating and Inc., Draft of unpublished paper in OTC principal dye component of henna, washing with water decrease the pro­ Volume 060065. which has been used since antiquity to (4) Shelanski, M. V. and H. R. Gittes, dye skin and hair (ref. 1). Lawsone has tective value of the ointments but not “Coppertone Suntan Lotion—Code 3MM,” as much as in the case of commercial Industrial Biology Laboratories, Inc., 1965, a low vitamin K activity by means of ointments tried” (ref. 20). Draft of unpublished paper in OTC Volume its chemical relationship to 2-methyl- Controlled human studies of market­ 060065. 1.4- naphthoquinone (menadione) (ref. ed homosalate preparations demon­ (5) “Human Safety Data,” p. 83, Draft of 2 ). strated the significance of the way in unpublished paper in OTC Volume 060065. Dihydroxyacetone (DHA) is also which a homosalate preparation is for­ (6) "Military Specification, Sunburn Pre­ known as l,3-dihydroxy-2-propanone. ventive Preparation, Cream Paste, MILt8- DHA is also a dye used as a skin mulated on sunburn protection. Oil 11262A,” Draft of unpublished paper in formulations produced the thinnest OTC Volume 060070. browning agent. DHA is discussed ear­ films on the skin and accumulated the (7) Tusing, T. W., “Sensitization Studies lier in this document. (See part II. least after repeated applications under on Coppertone,” Hazelton Laboratories, paragraph I. above—Sunscreen Prod­ normal use application. Oil formula­ Inc., 1956, Draft of unpublished paper in ucts Containing Dihydroxyacetone.) tions provided approximately one-half OTC Volume 060065. DHA is produced from glycerol by the protection of cream formulations (8) Shelanski, M. V., “Repeated lnsult Aerobacter sp. .. under aerobic condi­ Patch Test with Plough, Inc., Coppertone tions. It is a fairly hygroscopic, crys­ of the same concentration. Oil-less lo­ Suntan Lotion—9KK,” Industrial Biology tions and creams were found to pro­ Research and Testing Laboratories, Inc., talline powder and has a characteristic duce thicker films and to accumulate 1959. odor and a sweet and cooling taste. It to a greater extent, thereby producing (9) Shelanski, M. V. and H. R. Gittes, normally occurs as a dimer, in which a reduction in tanning but facilitating “Coppertone Suntan Lotion—Code 3XC,” form it is slowly soluble in 1 part the adjustment of the formulation to Industrial Biology Laboratories, Inc., 1964, water and 15 parts alcohol. When Draft of unpublished paper in OTC Volume freshly prepared, DHA reverts rapidly a wide range of skin sensitivities. A 060065. cream formulation containing 4 per­ (10) Shelanski, M. V. and H.R. Gittes, to a monomer in solution, in which cent homosalate provided greater sun­ “Draize Patch Test Study of Coppertone form it is very soluble in water, alco­ burn protection than did a lotion for­ Suntan Cream—Code 3K087,” Draft of un­ hol, ether, and acetone (ref. 3). mulation containing 8 percent homo­ published paper in OTC Volume 060065. The Panel received one submission salate based upon protective factor de­ (11) Shelanski, M. V. and H. R. Gittes, for a marketed product composed of terminations, that is, the ratio of MED “Draize Patch Test Study of Coppertone two lotions which are packaged to­ Suntan Oil—Code 3QC,” Draft of unpub­ gether and labeled to be applied sepa­ of protected skin to that of unprotect­ lished paper in OTC Volume 060065. ed skin (ref. 21). (12) Kucker, G., “Copperton Suntan rately and in sequence. The first lotion Based on the available data, the Lotion Excretion Test,” Elizabeth Bio­ to be applied contains 3 percent DHA, Panel concludes that homosalate is an chemical Laboratory, Draft of unpublished to be followed by application of a effective sunscreen for OTC use. It paper in OTC Volume 060065. second lotion containing 0.25 percent

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38235 lawsone. The manufacturer claims rabbit was weighed weekly. Hematolo­ just prior to the application to the that the product is effective, when ap­ gy, urinalysis, and blood chemistries arms of each of 103 male and female plied as directed, in preventing sun­ were performed prior to the initial ap­ subjects. The patches were applied on burn and photosensitivity reactions plication of the test materials and just Mondays, Wednesdays, and Fridays caused by sunlight. The dual product prior to the sacrificing of the animals for 3 consecutive weeks. Duplicate is claimed to have an action spectrum at the end of 13, weeks. Hematology challenge applications of each test ma­ that spans both short-UV (290 to 320 was also performed at 7 weeks. Follow­ terial were made after a 2-week rest nm) and long-UV (320 to 400 nm) wa­ ing sacrifice, gross necropsies and his- period, with one set of patches being velengths. topathology of all organ systems were placed on the original test sites and The manufacturer claims “the prod­ performed. The investigators conclud­ the other set being placed on adjacent uct is unique in that it gains its effec­ ed from the data that “No significant sites. The patch sites were scored on tiveness not from forming a film on differences were noted among the the second through tenth visits and at the surface of the skin, but rather groups with respect to body weight 48 and 96 hours following the chal­ from its active ingredients fixed to the gains, gross appearance and behavior, lenge applications. Very slight irrita­ keratin layer to form a permanent, mortalities, hematological findings, tion was observed following repeated non-washable barrier. How this occurs blood chemistry findings, urine find-, applications of the 0.125 percent law­ is not fully understood. It is postulat­ ings or gross or microscopic pathologi-* sone lotion and its lotion base. The ed that dihydroxyacetone (DHA) cal findings. The control animals 0.125 percent lawsone and 3.0 percent reacts with certain amino acids of ker­ showed mild to marked spotty eryth­ DHA lotion was found to be essential­ atin and frees moieties for further re­ ema and mild to moderate desquama­ ly nonirritating. None of the above- action with lawsone. One theory is tion during the study. The animals in noted test materials showed evidence that DHA splits the disulfide bonds the remaining groups showed occa­ of sensitization. and lawsone then reacts with the free sional mild desquamation only” (ref. A total of 9 patients received com­ sulfhydryl groups by 1,4 addition.” 4). plete blood counts, SMA-12 profiles, The Pastel has evaluated the submit­ Hanke and Talaat (ref. 1) reported a and urinalyses at baseline and after 3 ted data and concludes that when the study in which 3 g ground whole to 6 months of continuous administra­ two ingredients are used separately henna leaf equivalent to 30 mg of law­ tion of a sunscreen preparation in a and sequentially, the combination is sone were orally administered daily to lotion formulation containing 0.25 per­ classified as Category I. Each ingredi­ 90 patients with intestinal amoebiasis cent lawsone and 3.0 percent DHA. All ent when used alone cannot be classi­ for periods of from 4 to 6 or 8 weeks. of the above values remained in the fied as a Category I sunscreen. The Seven patients, who relapsed during normal range throughout the studies. submitted data indicate that the two the 6-week followup period, were given One patient experienced what ap­ solution product provides sunscreen a second course of treatment. One pa­ peared to be acne vulgaris, which coin­ protection which varies considerably tient experienced severe diarrhea, and cided with the initiation of oral con­ among individuals, depending on such treatment was discontinued after 3 traceptive therapy. Another patient factors as susceptibility of the skin to days. Transient diarrhea was experi­ experienced transient irritation of the fixing of the active ingredients, thick­ enced by five other patients whose cheek during the initial 2 weeks, but ness of the keratin layer where the treatment was continued full course. responded to topical steroid therapy sunscreen resides, number of daily ap­ These were the only observed side ef­ and continued in the study (refs. 14 plications, degree of the individual fects. and 15). photosensitivity, and amount of UV Fusaro, Runge, and Johnson report­ A total of 56 photosensitive patients radiation received. ed their experiences with 77 patients were treated with a sunscreen prepara­ (1) Safety. The Panel concluded on with various forms of recalcitrant sun­ tion in a lotion formulation containing the basis of toxicity studies that law­ light sensitivity, who received topical 0.25 percent lawsone and 3.0 percent sone in conjunction with DHA is safe applications of mixtures of 0.13 per­ DHA. Adverse reactions consisted of in the dosage range used as an OTC cent lawsone and 3.0 percent DHA in one case of an aggravation of a previ­ sunscreen. vanishing cream and 50 percent iso­ ous dermatitis condition and a case of Data were submitted for subacute propyl alcohol/distilled water vehicles. a burning sensation on application dermal toxicity and irritation studies They reported that “During these which was tolerated upon continued in which 20 healthy young adult clinical trials, not a single incident of use (refs. 14, 15, and 16). albino rabbits were divided into 5 cutaneous sensitization was observed” Based on the available data, the groups of 4 rabbits per group, includ­ (ref. 5). panel concludes that lawsone with ing a control group (lotion base^. Four The Panel reviewed several other DHA are safe sunscreen ingredients concentrations (0.29, 0.58, 1.16, and published studies by Fusaro et al., rep­ for OTC use. 2.32 ml/kg) of a lotion containing resenting 10 years experience in the (2) Effectiveness. There are con­ 0.125 percent lawsone and 3.0 percent use of dihydroxyacetone/lawsone trolled studies documenting the effec­ DHA were applied to the shaved ab­ preparations in more than 350 pa­ tiveness of lawsone in conjunction dominal skin area for 6-hour periods, 5 tients with various types of photosen­ with DHA as an OTC sunscreen. days a week for 13 weeks for a total of sitivities. No adverse reactions attrib­ The use of lawsone in conjuction 65 applications. The application of utable to these two active components with DHA as a topical sunscreen is re­ 0.29 ml/kg of the lotion was consid­ were reported (refs. 6 through 13). ported to be effective against both ered to be equal to the normal human The primary irritant and sensitiza­ short-UV (290 to 320 nm) and long-UV single dose. The shaved area in a male tion effects of a 0.125 percent lawsone (320 to 400 nm) wavelengths, to alter and female rabbit of each group was lotion, the lotion base, a 3.0 percent the keratin layer and strengthen its abraded initially and at the beginning DHA lotion, the lotion base, and a inherent light-screening characteris­ of each subsequent week by using a 0.125 percent lawsone and 3.6 percent tics, to be permanently affixed to the hyperdermic needle to make a series DHA lotion were evaluated in a con­ skin thereby resisting bathing, sweat­ of parallel minor epidermal incisions. trolled study using an adaptation of ing and swimming, and to be especially The test materials were held in place the repeated-insult patch test proce­ recommended for light-sensitive indi­ by an occlusive bandage with an initial dure of Draize (ref. 14). Webril patch­ viduals (ref. 17). layer of plastic film. Twice daily each es affixed to the center of elastic ad­ Fusaro et al. evaluated the protec­ animal was examined for signs of hesive bandages were moistened with tive effects of 50 percent isopropanol dermal of systemic toxicity. Each 0.5 ml of the respective test material solutions of 3.0 percent DHA in combi-

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38236 PROPOSED RULES nation with 0.035 and 0.13 percent law- sunscreen mixture was applied by Three fair-skinned female Volun­ sone on normal skin using natural sun­ spraying five times daily for 3 days teers participated in a controlled study light under controlled conditions (ref. prior to the first exposure and once or wherein application schedules for 3.0 6). The DHA and lawsone solutions twice daily thereafter, depending on percent DHA and 0.125 percent law­ were not mixed until shortly before the individual patient’s degree of pho­ sone creams and 6.0 percent DHA and application. Six consecutive applica­ tosensitivity. It was reported that 84 0.25 percent lawsone lotions were com­ tions of the test materials were made percent of the patients experienced pared. Five test sites, including one at 1-hour intervals and then were al­ good (unlimited protection) or fair control, were marked on the midthigh lowed to remain on the skin from 10 to (mild erythema after several hours ex­ area of each leg, and the light source 12 hours prior to washing the test sites posure to sunlight) results. Among the was a xenon-mercury lamp equipped with soap and water. Sunlight expo­ explanations offered for treatment with a filter which excluded all radi­ sure was started 2 hours afterwards. failures were improper application of ation below 260 nm and whose output From 2Vz to 3 MED’s protection was the sunscreen by the staff and uncoo­ between 280 and 320 nm was about 6.5 provided the 18 subjects treated with perative patients who refused to be percent of the total energy. The MED the combination of the 3.0 percent sprayed regularly and/or washed the was determined for each subject. One DHA and 0.035 percent lawsone prep­ treated area immediately following of the two preparations tested consist­ arations. The four subjects treated spraying (ref. 12). ed of equal amounts of 6 percent DHA with the mixture of the 3.0 percent Fusaro and Runge reported studies and 0.25 percent lawsone mixed just DHA and 0.13 percent lawsone prep­ involving seven patients with erythro­ prior to application. The other consist­ arations received greater than 5 MED poietic protoporphyria wherein 3.0 ed of two single preparations in which protection, as did the subject who in­ percent DHA and 0.13 percent lawsone a 3.0 percent DHA cream was applied creased the number of applications of preparations in both a vanishing 15 minutes before the application of a the 0.035 percent lawsone preparation. cream base and a 50 percent isopropyl 0.125 percent lawsone cream. One of Results obtained for five subjects indi­ alcohol/distilled water solution were the two application schedules tested cated that neither the 3.0 percent applied after the patients’ cutaneous involved making three applications of DHA solution nor the 0.13 percent eruption had cleared by means of topi­ both preparations at 30-minute inter­ lawsone solution provided significant vals on days 1 and 2, while the other protection when applied alone as com­ cal steroid therapy and avoidance of consisted of three applications of both pared with the application of the mix­ sufficient light exposure to cause preparations at 30 minute intervals on ture of these two solutions. The pro­ symptoms. The topical preparations day 2 only. On day 3, the treated and tective barrier provided by the applica­ were applied six to eight times daily control sites on one leg of each patient tion of DHA and lawsone solutions is for the first 2 days and thereafter were exposed to 3 MED’s radiation, resistant to washing with soap and three times daily for the next 5 days. while the test sites on the other leg water on the basis of the above-de­ At the end of the first week each pa­ were exposed to 6 MED’s. On days 4 scribed results. tient was allowed to be exposed to sun­ and 5, the test sites were scored on a 0 Fusaro et at. evaluated 77 patients light for a period of time which was (no perceptible erythema) to 4 with various forms of recalcitrant sun­ equivalent to the time based upon past (marked erythema and blisters) scale. light sensitivity, who received topical experience when there would be an Minimal protection was afforded by applications of mixtures of 0.13 per­ outbreak of cutaneous symptoms or three or six applications of DHA and cent lawsone and 3.0 percent DHA in eruption. Following the first exposure, lawsone when applied as freshly pre­ vanishing cream and isopropyl alco- each patient, depending on his/her pared mixtures, as the scores mostly hol/water vehicles. The degree of pro­ degree of light sensitivity would apply fell into the 2 (moderate erythema) to tection received by each patient was the preparations one to four times 4 (marked erythema and blisters) determined by the change in the pa­ daily. Only two patients applied the range. Scores ranged generally be­ tient’s tolerance to sunlight exposure preparation in the alcohol/water vehi­ tween 0 (no perceptible erythema) and during use of the test materials. The cle, and upon receiving virtually no 2 (moderate erythema) when the DHA median tolerance time prior to the ap­ protection they were restarted on the cream was applied 15 minutes prior to plication of the test materials was less preparation in the cream base. Fusaro the lawsone cream, with the applica­ than 1 hour, which was increased to 3 and Runge reported that after protec­ tion shedule involving three applica­ hours following use of the sunscreen. tion with the above-described prepara­ tions on both days 1 and 2 providing Of the 77 subjects, 51 (66 percent) ob­ tion in the cream base, all seven pa­ significantly more protection than tained 3 or more hours of protection, 8 tients “were able to change their daily that in which the applications were (10 percent) received less than 1 hour lives from one of predominantly ‘in­ only made 24 hours prior to exposure. of protection, and 9 (12 percent) failed doors’ to that of ‘outdoors’ ” and that The control sites generally showed to obtain any benefit. Fusaro et al. re­ the five children among the patients marked erythema with and without ported that because DHA and lawsone were able for the first time to go swim­ blisters (ref. 19). will react and deteriorate when mixed ming and participate in outdoor Fusaro treated 16 patients with together, the active ingredients should sports. For the seven patients the time severe photosensitivities of varied eti­ be given in separate vehicles, with the necessary to produce symptoms or le­ ologies. The test preparations consist­ DHA preparation being applied first sions from sunlight exposure was from ed of a 3.0 percent DHA lotion and a (ref. 5). less than 10 minutes to 2 hours at ba­ 0.25 percent lawsone lotion applied Fusaro and Runge reported 9 years seline and ranged from more than 3 during spring, summer, and fall prior experience with a total of 267 mental hours to more than 8 hours after re­ to exposure to potentially damaging patients with photosensitivity caused ceiving protection from the DHA prep­ light. Each application was made in by chlorpromazine therapy, who re­ aration in the vanishing cream base. the evening prior to retiring with the ceived topical applications of equal Fusaro and Runge pointed out, howev­ treated areas being bathed in the amounts of 6.0 percent DHA and 0.25 er, that the total amount of electro­ morning and throughout the day as percent lawsone both in 50 percent iso­ magnetic radiation available in Minne­ required. The DHA lotion was applied propyl alcohol/distilled water vehicles apolis, where the study was conducted, 15 minutes before the application of which were not mixed until just prior is much less than in other areas of the the lawsone lotion. Initially, two or to application. Approximately 10 per­ country and that the Minnesota area three applications were made each cent of the patients received the sun­ has fewer sunny days than elsewhere evening, with 15 minutes elapsing screen for more than one season. The (ref. 18). from the time the lawsone lotion was

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38237 applied prior to the reapplication of only treated with the single ingredient testinal Amoebiasis,” Transactions of the the DHA lotion. Either three applica­ lotions or the lotion vehicle (Ref. 15). Royal Society of Tropical Medicine and Hy­ tions each night for 2 nights .or two Based on the available data, the giene, 55:56-62, 1961. applications each night for 3 nights Panel concludes that lawsone with (2) “Animal Safety Data,” Draft of unpub­ lished paper in OTC Volume 060069. were made. Thereafter, the protection DHA are effective sunscreen ingredi­ (3) The Merck Index, 9th Ed., Merck and was maintained by making one or two ents for OTC use. Co., Rahway, New Jersey, p. 422, 1976. daily applications. The tolerance of (3) Dosage, (i) For products com­ (4) “Subacute Dermal Toxicity and Irrita­ the subjects to sunlight prior to the posed of two separate formulations tion Studies on Sunscreen Formulations,” use of the test materials ranged from 5 (Solution 1: containing 3 percent dihy- Draft of unpublished paper in OTC Volume minutes to 3 hours, with a median droxyacetone. Solution 2: containing 060069. time of 10 minutes. Following the 0. 25 percent lawsone) providing a (5) Fusaro, R. M., W. J. Runge and J. A. minimum SPF value of 2 to under 4: Johnson, “Protection Against Light Sensi­ above applications, the median time tivity with Dihydroxyacetone/Napthoquin- increased to 2 hours, with the toler­ Adult and children over 2 years of age one,” International Journal of Dermatology, ance ranging from 25 minutes to more topical dosage is liberal application 11:67-70, 1972. than 8 hours for these subjects consid­ before sun exposure as follows: First (6) Fusaro, R. M., W. J. Runge, F. W. ered to have benefited from the use of application. The evening prior to sun Lynch and C. J. Watson, “Sunlight Protec­ the sunscreens. In the opinion of the exposure: Apply Solution 1. Wait 15 tion in Normal Skin.” Archives of Dermatol­ investigator, 13 or 80 percent of the 16 minutes; then apply Solution 2 to the ogy, 93:106-111, 1966. subjects exhibited excellent to good same areas of skin. Wait until dried. (7) Fusaro, R. M. and W. J. Runge, “Clini­ cal Experiences with a Topical Light response (ref. 16). Then repeat application of solutions Filter,” Journal of the American Medicdl As­ O’Quinn treated 14 patients of alternately as before until a total of sociation, 182:144-145, 1962. whom 12 had allergic contact photo­ three applications of both lotions has (8) Fusaro, R. M. and J. A. Johnson, “Di­ dermatitis, and all but 2 were Blacks. been applied. Leave on skin without hydroxyacetone Napthoquinone Sun­ A 3.0 percent DHA lotion and a 0.25 washing. Repeated application. After screen,” Journal of the American Medical percent lawsone lotion were applied in first day, apply one application of Association, 222:1651, 1972. the same manner as described above each lotion. Reapply after swimming (9) Dunham, W. B. and W. J. MacNeal, or after excessive sweating. There is “Culture on the Chick Chorioallantosis as a except that two or three daily applica­ Test of Inactivation of Caccinae Virus,” tions were in most cases made follow­ no recommended dosage for children Journal of Bacteriology, 44:413-424, 1942. ing the initial exposure to sunlight to under 2 years of age except under the (10) Fusaro, R. M. and W. J. Runge, “Pro­ maintain protection. O’Quinn reported advice and supervision of a physician. tection Against Cutaneous Sensitivity to that excellent or good protection was (ii) For products composed of two Light,” University of Minnesoto Medical achieved in eight patients (57 percent), separate formulations (Solution 1 con­ Bulletin, 34:178-180, 1963. fair protection in one, poor protection taining 3 percent dihydroxyacetone. (11) Runge, W. J. and R. M. Fusaro, in three, and no protection in two. Solution 2: containing 0.25 percent “Studies on Light Sensitivity and Protec­ lawsone) providing a minimum SPF tion,” Excerpta Medica, International Con­ Four of the eight patients with good gress Series No. 55, Proceedings of the to excellent protection had previously value of 4: Adult and children over 6 Twelfth International Congress on Derma­ used various proprietary sunscreens, months of age topical dosage is liberal tology, pp. 739-741, September 1962. including those containing aminoben- application before sun exposure as fol­ (12) Fusaro, R. M. and W. J. Runge, “Sun­ zoate (PABA). The investigator experi­ lows: First application. The evening light Protection in Patients with Chlorpro­ enced difficulty clearing the dermati­ prior to sun exposure: Apply Solution mazine Light Sensitivity,” International tis in several patients and was of the 1. Wait 15 minutes; then apply Solu­ Journal of Dermatology, 10:198-200, 1971. opinion that increased protection tion 2 to the same areas of skin. Wait (13) Sletten, I. H., R. M. Fusaro and W. J. until dried. Then repeat application of Runge, “A New Topical Spray Agent to Pro­ would have been obtained had the tect Patients on Chlorpromazine from Sun-' treated areas been normal throughout solutions alternately as before until a light,” American Journal of Psychiatry, the study (Ref. 14). total of three applications of both lo­ 119:991-992, 1963. Rice treated 26 photosensitive pa­ tions has been applied. Leave on skin (14) Greenwell, B. E., “Rowell Summary tients. A 3.0 percent DHA lotion and a without washing. Repeated applica­ of O’Quinn Clinical Study,” Draft of unpub­ 0.25 percent lawsone lotion were ap­ tion. After first day, apply one applica­ lished paper in OTC Volume 060069. plied in the same manner as in the tion of each lotion. Reapply after (15) Greenwell, B. E., “Rowell Summary preceding two studies, with one appli­ swimming or after excessive sweating. of Rice Clinical Study,” Draft of unpub­ There is np recommended dosage for lished paper in OTC Volume 060069. cation daily following the initial expo­ (16) Greenwell, B. E., “Rowell Summary sure to light. In addition, a part of the children under 6 months of age except of Fusaro Clinical Study,” Draft of unpub­ test area was treated with 3.0 percent under the advice and supervision of a lished paper in OTC Volume 060069. DHA lotion in three cases, with 0.25 physician. (17) “Proposed Physicians Only Profes­ percent lawsone lotion in two cases, (4) Labeling. The Panel recommends sional Literature,” Draft of unpublished the category I labeling for sunscreen study in OTC Volume 060069. and with the lotion vehicle in two active ingredients. (See part III. para­ (18) Fusaro, R. M. and W. J. Runge, cases. At baseline, three patients toler­ graph B.l. below—category I labeling.) “Erythropoetic Prophyria: IV. Protection ated from 1 to 2 hours. Rice reported In addition, based upon the discussion from Sunlight,” British Medical Journal, that all 26 patients achieved good to 1:730-731, 1970. excellent protection as 11 patients tol­ above, the Panel recommends the fol­ (19) “Sunscreen Efficacy Study of DHA lowing warnings: (i) “This is a two and Lawsone Cream Formulations,” Draft erated 6 to 8 hours of sunlight expo­ lotion product. Do not mix the con­ sure, 5 tolerated 4 to 6 hours and 10 of unpublished paper in OTC Volume tents of the two solutions. Use both so­ 060069. tolerated 2 to 4 hours. Median toler­ lutions, for use of one alone will not ance time increased from less than 1 provide protection.” m. Menthyl anthranilate. The Panel hour prior to treatment to about 5 (ii) “Use only on skin free of rash concludes that menthyl anthranilate hours during treatment before the pa­ and abrasions.” is safe and effective for OTC use as a tients experienced eruptions or burn­ (iii) “May stain clothing when fresh­ sunscreen as specified in the dosage ing. Before the study, 12 patients had ly applied.” section discussed below. used commercial sunscreens contain­ Menthyl anthranilate is the menthyl ing aminobenzoate (PABA) without R eferences ester of anthranilic acid. It belongs to obtaining adequate protection. Rice (1) Hanke, M. E. and S. M. Talaat, “The the group of ortho-aminobenzoate also reported that those test sites were Biochemistry and Physiology of Henna compounds which are much weaker considered unprotected which were (Lawsonia alba): Its Use as a Remedy for In­ sensitizers than are the para-amino-

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38238 PROPOSED RULES benzoate compounds. Menthyl anth- contact with the skin of the back of in preventing erythema, with no sig­ ranilate is insoluble in water, and is each patient by means of an occlusive, nificant differences among them being soluble in 7 parts of 80 percent eth­ impermeable plastic tape. The patches discernible at 3 X 10" ■’M and 3 X 10" *M anol. were replaced. daily for 10 days or concentrations. Tannic acid and amin­ (1) Safety. Clinical use and market­until redness appeared, after which no obenzoate were decidedly superior to ing experience have confirmed that further applications were made at that the remaining compounds which in de­ menthyl anthranilate is safe in the test site. In the case of the menthyl creasing order were glyceryl amino­ dosage range used as an OTC sun­ anthranilate/titanium dioxide cream, benzoate, menthyl anthranilate, and screen. all but three subjects completed the phenyl salicylate. In the second aspect Animal and human toxicological study, with the tests being concluded of the investigation, 2 drops or ap­ data and wide use attest to its safety on the fourth, seventh, and ninth days proximately 0.4 ml of 5 percent solu­ for human topical application. The for these subjects. As for the menthyl tions of each test material were placed oral LDso is 8.39 g/kg in rats (ref. 1). anthranilate/ethylhexyl p-methoxy- on the backs of the subjects. The An in vivo percutaneous absorption cinnamate cream, all subjects complet­ source of irradiation was again the study was performed in which 50 mg ed the study, except for one patient D.C. Hanovia lamp at 30 inches for 60 of a sunscreen cream containing 5 per­ who was terminated on the seventh seconds. The investigator reported cent menthyl anthranilate and 4 per­ day when redness appeared at the test that phenyl salicylate and menthyl cent ethylhexyl p-methoxycinnamate sites for both of the above-named anthranilate provided protection only was applied to the inner surface of creams. On the basis of a 0 to 4 scale, minimally different from that of the each arm of six healthy adult subjects. the average index was 1.3 for the 95 percent ethyl alcohol control; It was reported that 98 percent of the former preparation and 0.4 for the whereas when compared to the con­ menthyl anthranilate was recovered latter. The investigator concluded that trol, both tannic acid and aminoben­ after 4 hours’ contact with the skin these preparations were virtually non­ zoate provided excellent protection, (ref. 2). irritating (ref. 6). and glyceryl aminobenzoate protection Sams reported a study in which a The incidence of complaints for a was rated as good. In the third part of 1:100 alcoholic solution of a perfume sunscreen containing 5 percent the experiment, approximately 0.4 ml was streaked on the undersurface of menthyl anthranilate and 5 percent ti­ of each test material was applied to the right forearm of a subject and al­ tanium dioxide was reported to be the test sites on the subjects’ backs, lowed to dry. A 5 percent menthyl slightly less than one complaint per anthranilate in alcohol solution was 100,000 units distributed. Approxi­ which were then exposed to 2 hours of then applied across this streak, and mately 13 percent of the complaints midday natural sunlight. The investi­ the arm was exposed to the midday involved reports of contact dermatitis gator reported that both tannic acid sun for 1 hour on a bright day. It had and possible photocontact dermatitis, and aminobenzoate were excellent in previously been demonstrated that the but in the latter case photopatch tests preventing erythema. Glyceryl amino­ perfume solution under such exposure were negative or photosensitivity from benzoate and phenyl salicylate had would provoke a sensitivity reaction systemic medication was suspected fair sun-screening ability, and the pro­ with erythema and mild vesiculation. (ref. 7). tection provided by menthyl anthrani­ It was reported that the 5 percent Based on the available data, the late was poor. Harber stated, however, menthyl anthranilate solution ade­ Panel concludes that menthyl anth­ that “Under rigid statistical analysis, quately blocked the erythema from ranilate is a safe sunscreen ingredient no significant differences could be es­ sun exposure (ref. 3). for OTC use. tablished in the sunscreening proper­ The erythema response with equi­ (2) Effectiveness. There are studies ties of phenyl salicylate, menthyl molar (3xl0-4 M) solutions of various documenting the effectiveness of anthranilate, or glyceryl para-amino- topical sunscreens was evaluated in 10 menthyl anthranilate as an OTC sun­ benzoate. It is the author’s belief that subjects and scored on a scale of 0 to 4 screen. further studies may demonstrate that following exposure to UV radiation Insoluble in water, but soluble in menthyl anthranilate is the poorest from an artifical light source. The ethanol, menthyl anthranilate can be erythema-protecting agent of all com­ average value for the preparations was incorporated into emulsion, oil, and pounds tested in this study” (ref. 9). tannic acid—0.25, aminobenzoate— paste formulations. It is often used in Seven Caucasian males were in­ 0.95, glyceryl aminobenzoate—1.7, combinations with other sunscreens. volved in a study comparing the pro­ menthyl anthranilate—2.2, phenyl sa­ At higher concentrations it does offer tection to graded dose of UV irradia­ licylate—2.8, and ethyl alcohol control 290 to 320 nm range absorption, with tion by a sunscreen containing 5 per­ (common vehicle)—3.5 (ref. 4). peak UV absorption at approximately cent menthyl anthranilate and 4 per­ On the subject of the ortho-amino- 340 nm (ref. 8). cent ethylhexyl p-methoxycinnamate benzoates, Fisher reported that “The Harber evaluated the protection and a 5 percent menthyl anthranilate ‘prtho’ compounds are essentially the from light provided by five compounds cream. The radiation provided by a anthranilates—methyl, phenyl, containing the benzoic acid nucleus hot quartz UV lamp at 30 inches for 15 menthyl and benzyl—which are much with various substituted side chains. seconds was calibrated to be equiva­ less commonly sensitizers than are the Each ingredient was dissolved in 95 lent to 1 MED. The test materials ‘para’ compounds” (ref. 5). percent ethyl alcohol, as this solvent were applied to different sides of the Repeat-insult patch tests were per­ was found to have no significant UV subjects’ backs. Three patients who formed on 11 healthy Caucasian males absorption. Fifty volunteers (32 fe­ had ingested aspirin both before and to study the relative irritancy of six males and 18 males) with no skin le­ after as much as 10 MED’s irradiation topical preparations among which sions on their backs were involved in showed no reaction on either side and were a marketed sunscreen cream con­ the study. In the first experiment, the were retested at different sites on taining 5 percent menthyl anthrani­ test materials were placed in cylindri­ their backs several days later because late and 5 percent titanium dioxide cal quartz cups and were not in con­ of the suppressive effects of aspirin. and another sunscreen cream contain­ tact with the skin. UV radiation was The final test results showed that the ing 5 percent menthyl anthranilate provided by a D.C. Hanovia lamp at 30 menthyl anthranilate/ethylhexyl p- and 4 percent ethylhexyl p-methoxy- inches for 60 seconds which approxi­ methoxycinnamate cream provided cinnamate. Each test material was ap­ mated lVfe times the empirical minimal complete protection up to and includ­ plied to a 1-inch square nonwoven erythema dose. All test materials at a ing 14 MED’s, whereas the 5 percent cloth patch which was then placed in 3 X 10_ concentration were effective menthyl anthranilate cream provided

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38239 protection from erythema up to at is liberal application before sun expo­ (1) Safety. Clinical use and market­ least 4 MED’s in all cases (ref. 10). sure and reapply after swimming or ing experience have confirmed that The protective ability of menthyl after excessive sweating. There is no oxybenzone is safe in the dosage range anthranilate against long-wave ultra­ recommended dosage for children used as an OTC sunscreen. violet (UV-A) radiation constituting under 2 years of age except under the Extensive animal and human toxico­ the spectrum between 320 and 400 nm advice and supervision of a physician. logical data and wide use attest to its was determined using 8 sensitized (ii) For products providing a mini­ safety for human topical application. albino guinea pigs. Seven hours prior mum SPF value of 4 containing 3.5 to The LDso is over 12.8 g/kg in rats to exposure the abdominal skin was 5 percent menthyl anthranilate: Adult treated orally and in excess of 1.6 g/kg shaved and depilatorized. One hour and children over 6 months of age in mice treated intraperitoneally (refs. prior to exposure the test animals topical dosage is liberal application 1, 2, and 3). were sensitized to UV-A by intraperi- before sun exposure and reapply after Pads,- each 4 cm2 and containing 0.5 toneal injections of 88 mg/kg of 8- swimming or after excessive sweating. g oxybenzone moistened in distilled methoxypsoralen. The UV-A light There is no recommended dosage for water, were applied to shaved areas on source was a Black-Ray UVL-56 which children under 6 months of age except the backs and flanks of six New Zea­ was placed inches from the ani­ under the advice and supervision of a land white rabbits. The test sites in mals. A 5 percent menthyl anthrani­ physician. one-half of the rabbits had been previ­ late in alcohol solution and a placebo (4) Labeling. The Panel recommends ously abraded with a skin scraper. solution were applied to test sites on the Category I labeling for sunscreen After 24 hours, the pads were re-, the first animal, and the test sites active ingredients. (See part III. para­ moved, and the test sites were rinsed were irradiated at 5-minute incre­ graph B.l. below—category I labeling.) with water to remove residues of the ments from 5 to 20 minutes. A 5 per­ substance. Daily examinations were cent menthyl anthranilate prepara­ R eferences made the next week for signs of sys­ tion in its cream base, but without its (1) “United States Patent Office, Menthyl temic poisoning and skin changes in other active sunscreen component (ti­ Anthranilate and the Process of Preparing the test site areas. It was reported tanium dioxide), was applied to test Same,” Draft of unpublished paper in OTC that both the intact and abraded sites sites on the remaining seven animals Volume 060001. (2) “Percutaneous Absorption Study, In- remained free of irritation throughout and exposed at 3-minute increments vivo, Maxafil Cream (2-ethoxyethyl p-meth- the 7-day observation period. The in­ from 3 to 15 minutes. The test sites oxycinnamate, and menthyl anthranilate),” vestigators instilled 0.1 g oxybenzone were read at 24 and 72 hours following Draft of unpublished paper in OTC Volume into the conjunctival sac of the left exposure and were scored on a scale 060001. eye of each of three New Zealand from 0 (no erythema) to 4+ (necrotic (3) Sams, W. M., “Contact Photodermati­ white rabbits, with the right eye serv­ erythema). In the case of the first test tis,” Archives of Dermatology, 73:142-148, ing as a control. Daily examinations animal, the readings after 20 minutes’ 1956, during the following week revealed exposure at 24 and 72 hours were 2+ (4) Harber, L. C., “Degenerative Skin Changes Associated with Excessive Ultravio­ that the eyes remained completely (medium erythema) at the menthyl let Exposure,” Proceedings of the Scientific free of irritation (refs. 2 and 3). anthranilate-treated site and 3+ Section—Toilet Goods Association, 41:26-31, The subchronic dermal toxicity of a (maximum erythema) and 4+ (necro­ 1964. sunscreen containing 6 percent oxy­ tic erythema) at the placebo-treated <5) Fisher, A. A., “Contact Dermatitis,” benzone and 12 percent homosalate and untreated sites, respectively. After Lea and Febiger, Philadelphia, p. 174, 1967. was evaluated by applying 0.5 g or 2 g/ 15 minutes exposure the readings for (6) “Evaluation of Relative Irritancy of kg of the test material to the shaved the menthyl anthranilate-treated site Six Different Formulations,” Draft of un­ published paper in OTC Volume 060001. intact or slaved abraded skin of albino in the seven remaining animals were 0 (7) “Human Safety Data,” Draft of un­ rabbits daily, five times weekly, for 3 (no erythema) at 72 hours following published paper in OTC Volume 060001. weeks (15 applications), with 2 g/kg of exposure, whereas five of these ani­ (8) “Acute Oral LD50, Menthyl Anthrani­ 0.6 percent methycellulose being ap­ mals demonstrated slight erythema late,” Draft of unpublished paper in OTC plied to the controls. All test animals (1 + ) at 24 hours following exposure. Volume 060125. remained healthy and vigorous For the placebo-treated test sites the (9) Harber, L. C., “Clinical Evaluation of throughout the study. Hematology, latter seven animals had 3+ (maxi­ Quantitative Differences in Ultraviolet Ab­ sorption of Compounds Containing the Sub­ clinical biochemistry, necropsy re­ mum erythema) readings at 24 hours stituted Benzoic Acid Nucleus,” Journal of ports, . histopathology, weight gain, and 4+ (necrotic erythema) readings Investigative Dermatology, 23:427-435, 1954. and food consumption of all test ani­ at 72 hours after exposure. The inves­ (10) “Protection Effect of Menthyl An­ mals were within normal limits. tigators concluded that “The unique­ thranilate to UV-B,” Draft of unpublished During the early stages the intact and ness of menthyl anthranilate as an UV paper in OTC Volume 060125. abraded skin of all test animals, in­ absorber has been demonstrated in (11) “UV-A Protection in the Guinea Pig cluding the controls, exhibited mild this study. Although menthyl anth­ with Menthyl Anthranilate,” Draft of un­ erythema, which appeared to be dose ranilate showed some absorption in published paper in OTC Volume 060125. related and disappeared early, thereby the mid-UV region, as manifested by n. Oxybenzone. The Panel concludes suggesting some degree ot dermal har­ reduced erythema compared with pla­ that oxybenzone is safe and effective dening. From the second week, the ab­ cebo and untreated sites, it absorbs for OTC use a sunscreen as specified raded skins of all test animals, includ­ preferentially in the near UV as dem­ in the dosage section discussed below. ing the controls, exhibited drying and onstrated by its protective effect on Oxybenzone is also known as 2-hy- scaling of the skin, but this condition psoralensensitized albino guinea pigs” droxy-4-methoxybenzophenone and was considered to be of no major con­ (ref. 11). benzophenone-3. sequence (ref. 4). Based on the available data; the Its absorbance is between 270 and A sunscreen containing 6 percent ox­ Panel concludes that menthyl anth­ 350 nm, with the maximum absorb­ ybenzone and 12 percent homosalate ranilate is an effective sunscreen in­ ance at 290 nm. It is soluble in ethyl was evaluated by instilling 0.1 ml of gredient for OTC use. and isopropyl alcohol and in mineral the product into the conjunctival sac (3) Dosage, (i) For products provid­oil and linseed oil, but it is virtually in­ of one eye of each of six New Zealand ing a minimum SPF value of 2 to soluble in water. Oxybenzone is incor­ white rabbits, with the the opposite under 4 containing 3.5 to 5 percent porated in emulsion, oil, and lipstick eye serving as a control. Following in­ menthyl anthranilate: Adult and chil­ formulations. It is frequently used in stillation, no erythema or edema was dren over 2 years of age topical dosage combination with other sunscreens. observed, and no subsequent irritation

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 38240 PROPOSED RULES was detected. Detailed visual and average of 95.41 and 96.51 percent of 2-week rest period from initial testing. ophthalmoscopic examinations were the homosalate and oxybenzone, re­ Results from observations taken im­ performed 24, 48, and 72 hours after spectively, was recovered from the mediately after removal of the patches instillation and did not reveal any skin. Within the technical limits of showed mild irritational responses positive overt ocular abnormalities the above-described percutaneous ab­ from the challenge tests, but no aller­ (ref. 5). In a similar study, 0.1 ml of sorption study, essentially complete gic response (ref. 11). the above-named sunscreen product recovery of the test material was indi­ Based on the available data, the was instilled into the left eye of each cated by the data (ref. 7). Panel concludes that oxybenzone is a of 12 albino rabbits, with the right eye Patch tests of a sunscreen formula­ safe sunscreen ingredient for OTC use. serving as the control. Six test animals tion containing 3 percent oxybenzone, (2) Effectiveness. There are studies received no further treatment, while 3 percent padimate A, and 4 percent documenting the effectiveness of oxy­ the treated eyes of the remaining six padimate -0 on 100 female volunteers benzone as an OTC sunscreen. rabbits were irrigated with 20 ml of showed no evidence of any inflamma­ By means of a solar simulator, the lukewarm tap water approximately 4 tory reaction at the test sites on the protective indices (P.I.) of a lotion ve­ seconds after instillation of the test upper back of the subjects immediate­ hicle, 3 percent oxybenzone in the material. One hour after instillation ly, 15 minutes, and 24 hours following lotion vehicle, 3 percent padimate A in and once daily thereafter until any ob­ the removal of the 48-hour patch tests the lotion vehicle, and 4 percent padi­ served eye irritation subsided com­ (ref. 8). Further patch tests of the mate 0 in the lotion vehicle were de­ pletely, or for a maximum of 14 days, above-described preparation on 203 termined to be 1.31±0.3, 2.37±0.82, the eyes were observed both for irrita­ female volunteers, who were subjected 6.03±1.03, and 7.06±1.25, respectively. tion and gross signs of systemic toxic­ to ten 48-hour repeated patch tests The tests were performed by applying ity from mucous membrane absorption and a challenge dose 14 days later, 100 ml of the test material to a 5x10 of the test material. The irritative ef­ confirmed that the preparation is not cm2 area on each subject’s back. The fects in both the irrigated and nonirri- a primary irritant and also demon­ number of subjects varied from 9 to 17 gated eyes were limited to mild con­ strated that any “sensitizing potential, for each test material. Fifteen minutes junctivitis, which was observed at the if existent at all, is exceedingly low” after application, each subject had 1-hour reading only. No evidence of (ref. 9). The photosensitization poten­ areas of 1 cm2 exposed to UV light systemic toxicity resulting from tial of the above-described formulation from a solar simulator with a graded mucous membrane absorption was ob­ was evaluated by subjecting 25 female series of exposures being administered served, nor was corneal opacity or volunteers to repeated-insult patch to both the test sites and adjacent un­ iritis noted (ref. 6). tests with an UV light source. The treated control, sites. Twenty-four Photosensitization studies were con­ light source was used to determine the hours later, the minimal delayed ducted in which the hair of the saddle MED for each subject. Comparison of erythemic responses were evaluated, area of each of nine albino rabbits was the light-protected control site and and the protective indices were then removed with electric clippers, and 0.4 the test site treated with the test ma­ calculated. The above-stated values re­ ml of a sunscreen containing 6 percent terial and irradiated with the MED es­ flect the mean protective index and oxybenzone and 12 percent homosa­ tablished for the subject revealed no standard deviation for the respective late was applied to 2-inch square test change in skin character 24 and 48 test material (ref. 12). In a similarly sites on six of the rabbits, with the re­ hours later. It was concluded that the conducted solar simulator test of a maining three rabbits being untreated photosensitization potential of the for­ preparation in which the above-stated and serving as controls. -These applica­ mulation, if existent at all, is exceed­ three ingredients had been combined tions were made daily, five times ingly low (ref. 10). in the lotion vehicle in the same con­ weekly, for 2 weeks (10 applications). In another study by Kantor, a prod­ centrations as stated above, the mean Following each application the control uct containing 7 percent padimate 0 protective index was determined to be and test animals were irradiated with and 3 percent oxybenzone was tested 20.4± 5.8 based on the data for 18 sub­ UV light for 15 minutes using a sun­ on 150 subjects according to a modi­ jects (ref. 13). lamp at a distance of 12 to 14 inches. fied Draize-Shelanski repeated-insult Katz evaluated the relative effective­ Readings were made 24 hours after patch procedure. Several non-specific ness of four sunscreen preparations, each application and were graded on a irritation reactions were observed i.e., 3 percent oxybenzone and 3 per­ scale from 0 (no erythema) to 3 under occlusive conditions, but none cent dioxybenzone its a cream base, 2.5 (erythema and trauma, or marked showing signs of being a primary irri­ percent padimate A in 65 percent eth­ edema or desquamation). No signifi­ tant. The same test material was ap­ anol with emollients, 5 percent amino- cant increases in the severity of the re­ plied to the backs of 26 subjects for benzoate in 70 percent ethanol with action during the course of the study photpatch testing. Ultraviolet light, emollients, and 5 percent aminoben- were noted between the control and from a Hanovia Tanette Mark I lamp, zoate in 70 percent ethanol (ref. 14). test animals. Mild erythema and was directed on the subjects’ backs for Previously ? - xposed skin of the but­ èdèma were generally observed in all a period of 1 minute, from a distance tocks or > xnaven suprapubic test animals throughout the study. of 12 inches. Results following 48 areas of n > objects was divid­ Desquamation was noted after the hours from initial testing showed no ed into six -qual 2- or 3-inch fifth application to the test animals adverse reactions observed in the 26 square p; h adhesive tape. and after the eighth application in the subjects tested (ref. 11). The four s - were liberally ap­ controls. It was reported that the reac­ Jordan evaluated a product contain­ plied to ra i areas on one side tions were not considered manifesta­ ing 7 percent padimate 0 and 3 percent of each sub ? a¡lowed to dry for tions of photosensitization, but repre­ oxybenzone applied to the backs of 15 minutes ■ > dimming in a fresh sented a normal response to repeated 150 healthy adult patients. The test water pool for IP minutes, the previ­ dermal insult (ref. 6). material was evaluated according to a ously untreated side of each subject One ml (approximately 0.5 g) of a modified Draize repeated-insult patch was thoroughly dried and the same sunscreen lotion containing 6 percent test. The material tested was applied test materials were applied to random­ oxybenzone and 12 percent homosa­ to the scapular back under occlusive ized areas. The test sites were then ex­ late was applied to a IV2 X 3 inch area patches three times a week for 10 ap­ posed to the maximum possible natu­ on the posterior forearm of each of 14 plications. Two consecutive occlusive ral sunlight for 1 hour. Erythema was subjects. After 4 hours, the lotion was challenge tests were applied to differ­ evaluated by three independent ob­ removed. It was calculated that an ent areas on the scapular back after a servers 24 hours later and graded on a

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38241 scale from 0 (no reaction) to 4 (bright (5) Schiavo, D. M. and F. G. Fielder, definitely eye irritants (corneal opac­ and fiery red). Except for the 2.5 per­ “Acute (Single Administration) Eye Irrita­ ity, conjuntival redness, chemosis, and cent padimate A preparation, all sun­ tion Study in Rabbits,” Draft of unpub­ iritis) probably due to the alcoholic screens were considered to have pro­ lished paper in OTC Volume 060070. nature of the vehicle (ref. 2). (6) Estep, C. L. and R. H. Teske, “Acute vided good protection from the erythe- Toxicity and Photosensitization Studies on Draize eye irritation tests of a sun­ matogenic rays of the sun on the side Sunblock RB 95-240,” Draft of unpublished blocking lotion containing 3 percent treated following swimming, as the paper in OTC Volume 060070. padimate A, 4 percent padimate 0 and scores ranged from 0 (no reaction) to 2 (7) “Sunblock Formulation Skin Recovery 3 percent oxybenzone were performed (pink) for these three preparations. Tests,” Draft of unpublished paper in OTC on nine New Zealand white rabbits by However, none of the preparations was Volume 060070. instilling 0.1 ml of the test material (8) OTC Volume 060131. into the conjunctival sac of one eye of considered to have provided consist­ (9) Blau, S., “Repeated Insult Patch Test, ently satisfactory protection when ap­ In Use Test, Photosensitization Test,” Draft each rabbit, with the remaining eye plied to the test sites after swimming, of unpublished paper in OTC Volume serving as a control. Three animals re­ but slightly more protection was pro­ 060131. ceived no further treatment. Three vided than when the preparations (10) Blau, S., “Repeated Insult Patch animals had their eyes gently flushed were applied prior to swimming. In the Test, In Use Test, Photosensitization Test,” with 20 ml of lukewarm physiological latter instance, - it was thought that Draft of unpublished paper in OTC Volume saline 2 seconds after treatment, and 060131. the remaining 3 animals had their the failure of the aminobenzoate prep­ (11) OTC Volume 060164. arations to provide satisfactory protec­ (12) Sayre, R., “Sunscreen Evaluations. eyes flushed in the above-described tion when the subjects swam after ap­ Human Testing,” Draft of unpublished manner 4 seconds after instillation. plication may be due to the short in­ paper in OTC Volume 060131. Observations were made at 24, 48, and terval between application and swim­ (13) Sayre, R., “PSL Formula, RB 360- 72 hours later and at 4 and 7 days ming (i.e., 15 minutes) which lessened 272A, PLB 75-238,” Draft of unpublished later. Except for one test animal in the penetration of the aminobenzoate paper in OTC Volume 060131. the untreated group, which experi­ (14) Katz, S.T., ‘Relative Effectiveness of enced a very mild erythematous re­ molecules into the stratum corneum. Selected Sunscreens,” Archives of Dermatol­ Based on the available data, the sponse in the palpebral conjunctiva ogy, 101:466-468, 1970. which cleared prior to the 72 hour ob­ Panel concludes that oxybenzone is an o. Padimate A. The Panel concludesservation, none of the test animals effective sunscreen ingredient for that padimate A is safe and effective showed any evidence of eye irritation. OTC use. for OTC use as a sunscreen as speci­ The investigator concluded that the (3) Dosage, (i) For products provid­ fied in the dosage section discussed preparation was not an eye irritant ing a minimum SPF value of 2 to below. (ref. 3). under 4 containing 2 to 6 percent oxy­ Padimate A is also known as amyl p- Willis and Kligman (ref. 4). reported benzone: Adult and children over 2 dimethylaminobenzoate, isoamyl p- on their study of the records of several years of age topical dosage is liberal A^A^-dimethylaminobenzoate, and hundred test subjects and their find­ application before sun exposure and pentyl 4-(dimethylamino) benzoate. ing that some subjects have com­ reapply after swimming or after exces­ Padimate A is a yellow, mobile plained of burning and itching of the sive sweating. There is no recommend­ liquid, with a faint aromatic odor. It face during hot weather following ap­ ed dosage for children under 2 years of has a molecular weight of 277. It is plications of 2.5 and 5 percent padi­ age except under the advice and super­ soluble in isopropyl alcohol, mineral mate A in alcohol solutions and that vision of a physician. oil, and ethyl alcohol. It is insoluble in this reaction has been reported by up (ii) For products providing a mini­ water, glycerin, and propylene glycol to 20 percent of the subjects using the mum SPF value of 4 containing 2 to 6 (ref. 1). 5 percent solution. No eyesor skin irri­ percent oxybenzone: Adult and chil­ (1) Safety. Clinical use and market­tation has been observed by them in dren over 6 months of age topical ing experience have confirmed that patients using 5 percent aminoben­ dosage is liberal application before sun padimate A is safe in the dosage range zoate in alcohol solutions applied to exposure and reapply after swimming used as an OTC sunscreen. the face and trunk while fishing or or after excessive sweating. There is Extensive animal and human toxico­ sunbathing. no recommended dosage for children logical data attest to its safety for Wilson et al. (ref. 5) reported that 3 under 6 months of age except under topical application to human skin. percent of their patients have com­ the advice and supervision of a physi­ Acute oral toxicity studies determined plained of a stinging or burning sensa­ cian. that the LD54 of padimate A in mice tion when a 5 percent padimate A (4) Labeling. The Panel recommends was 4.5 ml/kg, whereas it was 13.0 ml/ preparation was applied to the face, the category I labeling for sunscreen kg in rats, indicating that the ingredi­ especially around the eyes. It was indi­ active ingredients. (See part III. para­ ent is approximately three times more cated, however, that this reaction was graph B.l. below—category I labeling.) toxic in mice than in rats (ref. 2). not observed until the beginning of Primary skin irritation and eye irri­ hot summer weather. In some patients R eferences tation tests conducted on six female the reaction was noticeable only when (1) Lewerenz, H. G., G. Lewerenz and R. albino rabbits demonstrated that padi­ the face perspired. Some patients ex­ Plass, “Acute and Subchronic Toxicity In­ mate A produced no erythema or perienced the reaction following each vestigations of the UV Absorber MOB in edema 24 and 72 hours after the appli­ Rats,” Food Cosmetics and Toxicology, application; others experienced a 10:41-50, 1972. cation of 0.5 g (0.5 cc) on intact and stinging sensation initially which did (2) “Eusolex 4360, Investigation of Acute abraded skin and that very slight con­ not recur upon continued use. Oral Toxicity in Rats, Intraperitoneal Tox­ junctival redness was observed 24, 48, A primary irritation test was per­ icity in Mice and Primary Skin and Musco- and 72 hours following the instillation formed on 100 white female subjects sal Irritation in Rabbits,” Draft of unpub­ of 0.1 ml padimate A into the conjunc­ to determine the degree of irritation lished paper in OTC Volume 060090. tival sac (ref. 2). to the intact skin of the upper back (3) “Animal Safety Data,” Draft of unpub­ Similar animal (albino rabbit) stud­ from a sunscreen lotion containing 2.5 lished paper in OTC Volume 060083. (4) Castellano, R. F., A. Fabry, M. J. ies of sunscreen formulations contain­ percent padimate A and 3.0 percent Eggert and F. G. Fielder, “Subacute Dermal ing 3 and 5 percent padimate A dem­ dioxybenzone. One-half inch square Toxicity in Rabbits, Part A: Intact Skin, onstrated that the preparations are patches impregnated with the test ma­ Part B: Abraded Skin,” Draft of unpub­ mild skin irritants (generally very terial were applied to the test sites and lished paper in OTC Volume 060070. slight erythema and edema) and are held in place with plaster. Following

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38242 PROPOSED RULES removal of the patches 48 hours later, and that it can be predicated with 95 vehicles was comparable. Additional the test sites were observed immedi­ percent certainty based on the number test sites were treated with 3 percent ately and after 15 minutes and 24 of test subjects that at least 94 percent aminobenzoate in a hydroalcoholic ve­ hours. The erythema intensity was or more of the general population will hicle and commercial sunscreen scored on a scale from 0 (no erythema) not be sensitized by the test material. creams, i.e., 2.5 percent padimate A in to 3+ (vesiculation with edema). It Repeat insult patch tests of an oint­ the same hydroalcoholic vehicle, 2.5 was concluded by the investigator that ment containing 4 percent padimate A percent padimate A, 4.4 percent homo­ the preparation was not a primary irri­ in white petrolatum USP were per­ salate, and a 3 percent oxybenzone tant, as all readings showed no evi­ formed on the upper arms of 50 and 3 percent dioxybenzone combina­ dence of erythema (ref. 6). human volunteers (ref. 10>. The repeat tion. One hour after application the An irritation test of a sunblock insult and challenge dose applications treated sites were rinsed for 1 minute lotion containing 3 percent padimate were-made in the sequence described with a moderate stream of warm (37° A, 3 percent oxybenzone, and 4 per­ above except that there were 15 repeat C) water to simulate exercise, swim­ cent padimate O was conducted on the insult applications and 48-hour rest ming, etc. and allowed to air dry upper backs of 100 female subjects fol­ periods on weekends. None of the 50 before being tape stripped 13 times. In lowing the same procedures as de­ subjects exhibited visible skin changes the case of the two ingredients in hy­ scribed for the previous study. Based at any time throughout the study. It droalcoholic vehicles, 30.8 percent pa­ on data which showed no evidence of was concluded that the test material dimate A and 2.9 percent aminoben­ any inflammatory reaction immediate­ did not demonstrate characteristics of zoate were recovered. The remaining ly, 15 minutes, and 24 hours following a primary irritant, fatiguing agent, or data indicated that 5.9 percent padi­ the removal of the 48-hour patch sensitizer. mate A in the other formulation, 13.1 tests, the investigator concluded that A report indicated that adverse reac­ percent of homosalate, and less than 1 the test material was not a primary ir­ tion complaints for millions of units of percent oxybenzone and dioxybenzone ritant (ref. 7). padimate A-containing sunscreens were recovered. The investigators re­ Irritation tests have indicated that used during the 1967-1972 period aver­ ported that the data demonstrated the irritation effect of padimate A is aged less than one complaint per that “sunscreens in alcoholic vehicles apparently dose related. Various lo­ 100,000 units sold (ref. 11). provide more protection than many tions were applied to areas below the Based on the available data, the available preparations in lotion or eyes, and after 5 to 10 minutes, deter­ Panel concludes that padimate A is a cream vehicles.” mination was made as to whether safe sunscreen ingredient for OTC use. Yankell et al. (ref. 14), using a solar there was any irritation or burning. (2) Effectiveness. There are studies simulator to produce erythema, evalu­ Lotions containing 5 percent homosa- documenting the effectiveness of padi­ ated eight sunscreens on male albino late in combination with 0.5 or 1.2 per­ mate A as an OTC sunscreen. guinea pigs both with and without cent padimate A produced slight facial Padimate A absorbance is between washing after application. The mini­ irritation in 2 of 57 and 1 of 51 sub­ 290 and 315 nm, with the peak absor­ mum erythemal dose (MED) for the jects, respectively. A lotion containing bance at 310 nm. Soluble in isopropyl shaved and depilated test areas was 5 percent padimate A when applied to and ethyl alcohol, mineral oil, and determined to be 2 seconds of solar the faces of 31 subjects produced mod­ peanut oil, but insoluble in water, simulator exposure time. One-tenth erate irritation in one case and slight glycerine, and propylene glycol, padi­ ml (0.1 ml) of each test material was irritation in 9 others, whereas an 8 mate A is formulated in anhydrous applied over a 2 x 7 cm area on four percent homosalate lotion produced emulsion, hydroalcoholic solutions, oil, sites on each side of dorsal surfaces. slight facial irritation in 2 of 53 sub­ and ointment preparations (ref. 12). Two different test materials were jects tested (ref. 8). Yankell et al. (ref. 13) determined by tested in at least four guinea pigs. The Repeated insult patch tests of a gel tape stripping, combined with spectro- unwashed sites 1 hour after applica­ containing 3 percent padimate A were photometric analysis, the recovery of tion of the test materials were exposed performed on the upper arms of 55 various sunscreens from the stratum to UV irradiation from the solar simu­ adult human subjects (ref. 9). The test corneum of Mexican hairless dogs. lator at 1, 2, and 3 MED levels. Con­ material was applied to approximately The sunscreens tested consisted of 3 trol areas were exposed to 1 MED irra­ 0.5 square inch lintine discs, which and 5 percent concentrations of padi­ diation. Other test sites 1 hour after were then applied to the test sites and mate A and aminobenzoate in 75 per­ application of the test materials were held in place with occlusive patches. cent ethanol and 75 percent isopro­ rinsed for 1 minute under a stream of Each 24-hour period the patches were panol vehicles. The solutions were ap­ warm (35° C) water, dried with a soft removed, and the reactions were plied on 1.5 cm2 sites on the animals’ cloth, and then exposed to 1, 2, and 3 graded on a scale from 0 (no ery­ flanks. One hour after application the MED irradiation with control areas re­ thema) to 4+ (marked erythema, test sites were stripped 13 times by re­ ceiving 1 MED irradiation. The test edma, with vesicles and oozing). After peatedly applying and removing 2 cm2 materials consisted of a sunscreen con­ a 2 4-hour rest period, repeat applica­ cellulose tape squares. This procedure taining 2.5 percent padimate A in a tions of the test material were made. was repeated on other test sites, water-repellent cream base with This sequence was repeated 10 times, except that 1 hour after application opaque constituents (I), a sunscreen after which there was a 2-week jest the test sites were swabbed with damp containing 2 percent padimate A in 75 period before a challenge dose was ap­ absorbent cotton squares prior to percent ethyl alcohol (II), a sunscreen plied. Of the 55 subjects tested, three being tape stripped in the above-de­ containing 2.5 percent padimate A in a patients exhibited slight erythema scribed man- ner. The swabs were as­ hydroalcoholic lotion with emollients (1+ reading) following the tenth ap­ sayed along with the tapes as part of (III), a sunscreen containing 1.1 per­ plication. One of these subjects also the determination of ingredient recov­ cent padimate A in oils (IV), a sun­ experienced slight erythema following ery. In the case of the unwashed test screen lotion containing 2 percent gly­ the seventh application. Otherwise, all sites, 70 to 90 percent padimate A and ceryl aminobenzoate (V), a sunscreen other readings for the repeat insult 40 to 48 percent aminobenzoate were lotion containing 7.7 percent homosa­ and challenge dose applications recovered, whereas 24 to 32 percent late (VI), a sunscreen lotion contain­ showed no evidence of erythema. It padimate A and 2 to 7 percent amino­ ing 3 percent oxybenzone and 3 per­ was concluded by the investigator that benzoate were recovered from the cent dioxybenzone (VII), and a sun­ the test material was neither a pri­ tapes for the washed test sites. Recov­ screen containing 5 percent aminoben­ mary irritant nor a sensitizing agent ery from the ethanol and isopropanol zoate in 75 percent ethyl alcohol

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38243 (VIII). For the unwashed sites all test nm wavelength range. The minimum no recommended dosage for children materials provided complete protec­ erythema! dose (MEDI) was deter­ under 6 months of age except under tion at 1 MED, but at 3 MED’s only mined for each subject. The test mate­ the advice and supervision of a physi­ preparation I was fully effective; prep­ rials were applied to 1-inch square test cian. arations II (50 percent), III (63 per­ sites on the subjects’ backs, which (4) Labeling. The Panel recommends cent), VII (50 percent) and VIII (87 were then exposed to 3 MED’s irradia­ percent) were less effective; prepara­ tion with the results being assessed 24 the category I labeling for sunscreen tions V (25 percent) and VI (38 per­ hours afterwards. Padimate A in the active ingredients. (See part III. para­ cent) were marginally effective; and petrolatum and propylene glycol base graph B.l. below—category I labeling.) preparation IV (0 percent) exhibited provided absolute protection (no R eferences no effect. In the case of the washed erythema), whereas just detectable to (1) OTC Volume 060018. test sites only preparations II and moderate erythema was observed in (2) “Animal Safety Data,” Draft of unpub­ VIII, the only sunscreens prepared in test sites treated yith padimate A in a lished paper in OTC Volume 060037. 75 percent ethyl alcohol vehicles, pro­ hydrophilic base. It was noted, howev­ (3) Keith, E. F., “Draize Eye Irritation vided protection above 1 MED. Prepa­ er, that test areas treated with the hy­ Test Sunblocking Lotion RB 292-240 A,” ration IV, which contained the lowest drophilic base only showed erythema Draft of unpublished paper in OTC Volume concentration of padimate A of the which in the case of four subjects was 060131. four padimate A-containing test mate­ worse than that for untreated sites ex­ (4) Willis, I. and A. M. Kligman, “Amino- rials and the lowest level of active in­ benzoic Acid and Its Esters,” Archives of posed to the above-specified light Dermatology, 102:405-417, 1970. gredient among all test materials, pro­ source. A hydroxybenzoate derivative (5) Wilson, W. W., R. Quero and K. J. vided the least protection to both the used as a preservative in the hydro­ Master, “The Search for a Practical Sun­ washed and unwashed sites. philic base was considered to be a pos­ screen,” Southern Medical Journal, 59:1425- Pathak et al. (ref. 15) reported their sible source of the above-described 1430, 1966. 3-year study (1965-68) of the protec­ phototoxic reaction. (6) "Human Safety Data,” Draft of un­ tive value of 24 sunscreens of various From 9 to 17 human subjects were published paper in OTC Volume 060116. chemical agents known to absorb UV (7) Blau, S. “Irritation Patch Tests RB treated with one of four test materials 292-292 B and RB 360-126 A,” Draft of un­ light. They indicated that 5 percent to determine their protective indices published paper in OTC Volume 060131. aminobenzoate in 70 to 90 percent using a solar simulator, i.e., 3 percent (8) “Irritation Test of Oil-Less Suntan ethyl alcohol and 2.5 percent padimate padimate A in the lotion vehicle, 4 per­ Lotion,” Draft of unpublished paper in OTC A in 65 to 95 percent alcohol “are by cent padimate 0 in the lotion vehicle, 3 Volume 060066. far the best sunscreen preparations” percent oxybenzone in the lotion vehi­ (9) Shelanski, M. V., “Coppertone Suntan and that these preparations, after a cle, and the lotion vehicle. The mean Gel-Sample No. RB 78-158, Repeated Insult single application, “can protect fair- protective indices and their respective Patch Test,” Draft of unpublished paper in OTC Volume 060131. skinned persons undergoing long expo­ standard deviation were 6.03±1.03, (10) Shelanski, M. V., “4.0 Percent Escalol sure (over 4 hours) under natural sun­ 7.06±1.25, 2.37±0.82, and 1.31±0.3, re­ 507 in U.S.P. White Petrolatum. Ointment light, and are more effective than 24 spectively (ref. 17). No. A-53-202 Repeated Insult Patch Test,” of the commercially available products Kreps (ref. 18) reported that padi­ Draft of unpublished paper in OTC Volume tested” and “afford excellent protec­ mate A transmits 10 percent of the in­ 060131. tion when subjects undergo exercise cident erythemal flux at a 1 percent (11) “Human Safety Data,” Draft of un­ accompanied by profuse sweating, and concentration and is a total sunblock published paper in OTC Volume 060037. tend to remain on the skin after bath­ (12) “Escalol 507. Technical Bulletin,” at a 2 percent concentration. Based on Draft of unpublished paper in OTC Volume ing or swimming and exert a partial determinations of percent erythema! 060131. yet very satisfactory protection.” (290 to 320 nm) and tanning (320 to (13) Yankell, S. L., L. Khemanic and M. H. Pathak et al. further found that these 375 nm) transmission, a 1.4 percent Dolan, “Sunscreen Recovery Studies in the preparations provided very effective concentration would provide a protec­ Mexican Hairless Dog,” Journal of Investi­ protection against sunburn “under in­ tive suntan for sensitive skin. A 1.1 gative Dermatology, 55:31-33, 1970. tensely bright sun with hot, dry cli­ percent concentration would provide a (14) Yankell, S. L., et al., "Solar Simulator matic conditions (in the Arizona Sunscreen Evaluations in Guinea Pigs,” regular suntan for average skin, and a Journal of the Society of Cosmetic Chemists, desert), under warm and humid condi­ 0.8 percent concentration would be 27:607-611, 1970. tions (during the months of July and suitable for a minimum-protection (15) Pathak, M. A., T. B. Fitzpatrick and August in the Northern Hemisphere, quick-tanning preparation. E. Rank, “Evaluation of Topical Agents 40° N. latitude) and on snow-covered Based on the available data, the That Prevent Sunburn. Superiority of Para- mountains at high altitudes that re­ Panel concludes that padimate A is an aminobenzoic Acid and Its Esters in Ethyl flect UV radiation causing sunburn of effective sunscreen ingredient for Alcohol,” New England Journal of Medi­ the exposed parts of the skiers.” In ad­ OTC use. cine, 280:1459-1463, 1969. (16) Armati, R. P. and A. Johnson, “The dition, it was determined by Pathak et (3) Dosage, (i) For products provid­Efficacy of Escalol 506 in Two Topical Bases al. that these preparations “only par­ ing a minimum SPF value of 2 to in Preventing Erythema From Artificial Ul­ tially inhibit tanning and allow imme­ under 4 containing 1 to 5.0 percent pa­ traviolet Light,” The Medical Journal of diate pigment darkening, as well as dimate A: Adult and children over 2 Australia, 23:1196-1197, 1972. melanogenesis by long-wave UV and years of age topical dosage is liberal (17) Sayre, R., “Sunscreen Evaluations, visible radiation” and “are cosmetical­ application before sun exposure and Human Testing,” Draft of unpublished ly acceptable, being invisible and with­ reapply after swimming or after exces­ paper in OTC Volume 060131. out odor or color on the skin.” (18) Kreps, S. I., “Sunburn Protection and sive sweating. There is no recommend­ Suntan Preparations,” American Perfumer Armati and Johnson (ref. 16) evalu­ ed dosage for children under 2 years of and Cosmetics, 78:73-77, 1963. ated the efficacy of two sunscreen age except under (¡he advice and super­ creams containing 2.5 percent padi­ vision of a physician. p. Padimate O. The Panel concludes mate A, one in a hydrophilic base and (ii) For products providing a mini­ that padimate O is safe and effective the other in a petrolatum and propy­ mum SPF value of 4 containing 1.0 to for OTC use as a sunscreen as speci­ lene glycol base, in nine human sub­ 5.0 percent padimate A; Adult and fied in the dosage section discussed jects with varying degrees of skin pig­ children over 6 months of age topical below. mentation. Fluorescent lights situated dosage is liberal application before sun Padimate O is also known as 2-ethyl- 25 cm from the skin surface were used exposure and reapply after swimming hexyl p-dimethylaminobenzoate, 2- to produce UV light in the 290 to 340 or after excessive sweating^ There is ethylhexyl 4-(dimethylamino)ben-

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38244 PROPOSED RULES zoate, octyl dimethyl PABA and 2-eth- the test material was not a primary ir­ frqm a Hanovia Tanette Mark I lamp ylhexyl PABA. ritant to the cornea and iris of the test was directed on the subjects’ backs for Padimate O is a yellow mobile liquid, animals, but was at the upper limit of a period of 1 minute, from a distance with a faint aromatic odor. It has a the mild primary irritant range in of 12 inches. Results following 48 molecular weight of 235. It is soluble regard to its effect on the conjuncti- hours from initial testing showed no in isopropyl alcohol, mineral oil and vae, as hyperemia was observed (ref. adverse reactions observed in the 26 ethyl alcohol. It is insoluble in water, 2). subjects tested (ref. 13). blycerin and propylene glycol (ref. 1). Eye irritation studies with 5 percent Jordan evaluated a product contain­ (1) Safety. Clinical use and market­padimate O in mineral oil were con­ ing 7 percent padimate O and 3. per­ ing experience have confirmed that ducted on the unwashed eyes of three cent oxybenzone applied to the backs padimate O is safe in the dosage range rabbits (refs. 9 and 10). A dose of 0.1 of 150 healthy adult patients. The test used as an OTC sunscreen. ml was instilled into the conjunctival material was evaluated according to a Animal and human toxicological sacs, and evaluations were made after modified Draize repeated insult patch data attest to its safety at 4 percent 1 hour, 24 hours, and daily thereafter test. The material tested was applied concentration for human topical appli­ until 7 days had elapsed. The test ma­ to the scapular back under occlusive cations. terial was determined not to be an irri­ patches three times a week for 10 ap­ The oral LD50 in rats of a 5 percent tant to the cornea or iris of the test plications. Two consecutive occlusive concentration in corn oil is over 64 ml/ animals. Slight redness (1 on a scale of challenge tests were applied to differ­ kg (refs. 2, 3, and 4). 0 to 3) of the palpebral and bulbar ent areas on the scapular back after a A primary irritation and sensitiza­ conjunctivae of each test animal was 2-week rest period from initial testing. tion study of a 5 percent padimate O noted on the first and second days fol­ Results from observations taken im­ sunscreen was conducted on the lowing treatment, but not during the mediately after removal of the patches shaved backs of 10 male albino guinea remaining 5 days of the study. showed mild irritational responses pigs. A 0.1 percent solution of the test Repeated insult patch tests of 4 per­ from the challenge test, but no aller­ material in sterile, pyrogen-free phys­ cent padimate O in which petrolatum, gic response (ref. 13). iological saline was injected intracu- U.S.P., were conducted on 50 human Based on the available data, the taneously three times weekly until a volunteers (refs. 11, and 12). Lintine Panel concludes that padimate O is a total of 10 injections was reached, pads moistened with the test material safe sunscreen ingredient for OTC use. after which there was a 12-week rest were placed on predesignated sites on (2) Effectiveness. There are con­ period before a challenge dose was in­ the upper arm of each subject and trolled studies documenting the effec­ jected just below the region of the 10 were then covered and seated with tiveness of padimate O as an OTC sun­ sensitizing injections. Each injection overlapping strips of tape. After 24 screen. consisted of a 0.1 ml dose except for hours the patches were removed. The Its absorbance is between 290 to 315 the initial and challenge doses, which test sites were evaluated on a scale of nm, with a maximum absorbance at were 0.05 ml each. Distilled water was 0 (no erythema) to 4+ (marked eryth­ 310 nm. Soluble in ethyl and isopropyl used as a control. Except for one test ema, edema, with vesicles and oozing). alcohol, mineral oil, and%,peanut oil, animal who exhibited barely percepti-' The test material was reapplied to the but insoluble in water, glycerine, and ble erythema throughout the study same sites after a 24-hour rest period propylene glycol, padimate O can be following injections of the test materi­ if less than marked erythema (less incorporated in emulsions, hydroalco­ al and distilled water, readings made than 2+ value) was observed. The holic solutions, and anhydrous formu­ 24 hours following each injection above-described cycle was repeated 15 lations (refs. 1, 14, and 15). * showed no evidence of erythema or times, except rest periods lasted 48 Cumpelik (ref. 16) evaluated the rel­ edema. It was concluded by the inves­ hours on weekends. Following the fif­ ative substantivity or retention by the tigator that the test material was nei­ teenth application, there was a 2-week skin of 2 percent padimate A in isopro­ ther a primary irritant nor a sensitizer rest period before a challenge dose was panol compared with isopropanol solu­ (refs. 2, 5, and 6). applied to each of the previous test tions containing 2 percent padimate O, The intact and abraded skin on the sites. After 24 hours the. challenge aminobenzoate, homosalate, cinoxate, clipped backs of three albino rabbits doses were removed, and readings were sulisobenzone, or ethyl 4-[bis- (hy- was used for a primary irritation study made immediately and 24 and 48 droxypropyl)] aminobenzoate. After of 5 percent padimate O in mineral oil hours afterwards. Throughout the the hands and the arms of the five (refs. 2, 7, and 8). Double-layered, light study none of the 50 subjects exhibit­ subjects were washed up to the elbows gauze patches, 2.5 cm2, were secured ed any evidence of erythema at the in isopropanol at 30° C, their left arms by thin bands of adhesive tape to four test sites. The investigator concluded were dipped into the 2 percent padi­ areas approximately 10 cm apart on that the test material was not a prima­ mate A solution for 1 minute. Each each test animal’s back. One-half ml ry irritant, a fatiguing agent, or a sen­ subject’s right arm was then dipped (0.5 ml) of the test material was intro­ sitizer. Based on the data for the for 1 minute into a 2 percent solution duced beneath each patch before above-described 50 subjects, the inves­ of one of the other sunscreen ingredi­ wrapping the animals’ trunks in clear tigator predicted with 95 percent cer­ ents listed above. The amount of each plastic trunk bands to hold the patch­ tainty that at least 92.89 percent of a solution deposited on the subject’s es in place and prevent the evapora­ general population would not be sensi­ arm was determined by weighing the tion of volatile substances during the tized by the test material. amount of test solution remaining and 24-hour exposure period. Following ex­ In another study by Kantor, a prod­ by spectrophotometric analysis of the posure the patches were removed, and uct containing 7 percent padimate O residual solution. Following air drying, readings were made immediately and and 3 percent oxybenzone was tested the subjects’ hands were submerged in 72 hours later. None of the readings on 150 subjects according to a modi­ 2 gallons of tap water at 25° C for 30 showed any evidence of erythema or fied Draize-Shelanski repeated insult minutes, during which time the hands edema. The investigator concluded patch procedure. Several non-specific and fingers were moved constantly that the test material was not a prima­ irritation reactions were observed without touching any surface of the ry irritant. under occlusive conditions, but none container. After air drying, the hands A Draize eye irritation study of 2.0 showed signs of being a primary irri­ were exposed to irradiation by a Hano­ percent padimate O in mineral oil was tant. The same test material was ap­ via UV lamp with a Corex D filter for performed on the unwashed eyes of plied to the backs of 26 subjects for 7 minutes, which was equivalent to 2 three rabbits. The data indicated that photopatch testing. Ultraviolet light hours of midsummer midday sun expo-

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38245 sure. Following the water insult and Robertson Meter and equivalent to a then rinsed in a stream of flowing irradiation, the residual sunscreen on total exposure of 4 to 6 MED’s was tepid water for 1 minute and allowed the subjects’ hands was extracted by then administered. Twenty-four hours to air dry before administering a immersing the hands in isopropanol at after this exposure the test sites were graded series of UV exposures from a 50° C for 2 minutes. The volumes of photographed and graded on a scale solar simulator to the treated and ad­ the solutions were then equalized and from 0 (no burn) to 4 (severe eryth­ jacent unprotected ' control areas. spectro-analyzed. The percent sub- ema, i.e., bright red, vesiculation, Twenty-four hours following this ex­ stantivity was then determined by edema, and painful to touch). Both posure, the minimal delayed erythe­ multiplying the amount of ingredient the photographs and scores demon­ mic responses were evaluated and the recovered after exposure by 100 and strate that the padimate O/padimate protective indexes were then calculat­ dividing this figure by the amount of A/oxybenzone lotion provided the ed. A substantive protective index of the ingredient initially deposited. The greatest degree of protection among 13.0±3.6 was determined by dividing percent substantivity of padimate A the preparations tested because little the MED for the treated area by that compared with that of each of the if any sunburn resulted under the for the control area. other test solutions was 42.2 vs. 58.6 above-described test conditions (mean The mean protective index of a sun­ for padimate O; 48.3 vs. 0.3 for amino- protective value of 0.292±0.396). In screen lotion containing 7 percent pa­ benzoate; 46.8 vs. 11.4 for homosalate; the order of decreasing protective dimate O and 3 percent oxybenzone 40.6 vs. 7.6 for cinoxate; 40.6 vs. 2.3 for value, the results for the remaining was found by a solar simulator study sulisobenzone; and 37.3 vs. 0.4 for preparations were 3 percent padimate to be 18.6±4.3 (ref. 19). For this and ethyl 4-[bis- (hydroxypropyl)] amino- A and 3 percent glyceryl aminoben­ the previous study, however, there benzoate. The data above correlated zoate (1.250±0.$66), 3 percent oxyben- were no results given for any determi­ very well with the relative differences zone and 3 percent dixoybenzone nation of the mean protective index of in the degree of reddening on the sub­ (2.833±0.937), 5 percent aminoben­ the lotion vehicle itself; thus, a deter­ jects’ hands and lower forearms 24 zoate (3.500±0.674), 10 percent suliso­ mination as to the contribution of the hours following irradiation. Because benzone (3.583 ±0.515), and control lotion vehicle to the product’s protec­ sunscreens containing aminobenzoate (3.667±0.651). From the data above, it tive index was not feasible. and homosalate contain concentra­ would appear that the 5 percent amin­ Based on the available data, the tions above 2 percent, the above-de­ obenzoate and 10 percent sulisoben­ Panel concludes that padimate O is an scribed test using 5 percent aminoben­ zone preparations were almost com­ effective sunscreen ingredient for zoate and a 10 percent homosalate was pletely removed during swimming, as OTC use. performed on another subject. The the resulting burns in the test sites (3) Dosage, (i) For products provid­ hand treated with aminobenzoate was treated with these preparations were ing a minimum SPF value of 2 to allowed to air dry 30 minutes and to as severe as in the untreated control under 4 containing 1.4 to 8 percent pa­ permit the material to attach itself to sites. The investigator concluded that dimate O: Adult and children over 2 the stratum coraeum before the 30- the padimate O/padimate A/oxyben­ years of age topical dosage is liberal minute water insult. As before, these zone preparation showed statistically application before sun exposure and preparations demonstrated poor resis­ significant protection and even after reapply after swimming or after exces­ tance to washoff. The data above did swimming should provide at least one- sive sweating. There is no recommend­ demonstrate, however, that in terms half day of protection without reappli­ ed dosage for children under 2 years of of percent substantivity or degree of cation for most users. age except under the advice and super­ skin retention under conditions involv­ Using a solar simulator, the mean vision of a physician. ing perspiration and/or swimming, pa­ protective indexes and their respective (ii) For products providing a mini­ dimate O was superior to padimate A, standard deviations were determined mum SPF value of 4 containing 1.4 to and both were decidedly superior to for the components of a sunblock 8 percent padimate O; Adult and chil­ aminobenzoate, homosalate, cinoxate, lotion consisting of lotion vehicle dren over 6 months of age topical sulisobenzone, and ethyl 4-[bis- (hy­ (1.31±0.3), lotion vehicle plus 3 per­ dosage is liberal application before sun droxypropyl)] aminobenzoate. cent padimate A (6.03 ±1.03), lotion ve­ exposure and reapply after swimming A comparative substantivity study of hicle plus 4 percent padimate O or after excessive sweating. There is six sunscreen lotions was conducted on (7.06±1.25), and lotion vehicle plus ox- no recommended dosage for children six untanned human subjects with fair ybenzone (2.37±0.82). Between 9 and under 6 months of age except under complexions. The lotions were a com­ 17 human subjects were used to test the advice and supervision of a physi­ bination of 4 percent padimate O, 3 each component. A 5x10 cm2 area on cian. percent padimate A, and 3 percent ox- each subject’s back was treated with (4) Labeling. The Panel recommends ybenzone; a combination of 3 percent 100 ul of the test material, and after the category I labeling for sunscreen padimate A and 3 percent glyceryl 15 minutes the test areas and adjacent active ingredients. (See part III. para­ aminobenzoate, 10 percent sulisoben­ untreated control areas were adminis­ graph B.l. below—category I labeling.) zone; a combination of 3 percent oxy- tered a graded series of 1 cm2 UV ex­ benzone and 3 percent dixoybenzone; posures from a solar simulator. R eferences and 5 percent aminobenzoate (ref. 17). Twenty-four hours after exposure the (1) OTC Volume 060010. Each test material was applied to two minimal delayed erythemic responses (2) “Animal Safety Data,” Draft of unpub­ sites on each subject’s back at the rate were evaluated and the protective in­ lished paper in OTC Volume 060010. of 2 ul/cm2 (20 ul applied to a 10 cm2 dexes were then calculated (ref. 18). In (3) Paul, J. D., “The Acute Oral LDM of 5 area) and allowed to dry for 1 hour another solar simulator study, the Percent Escalol 507 in Corn Oil Using 30 without sunlight exposure. Following Albino Rats,” Draft of unpublished paper in mean protective index for the above- OTC Volume 060131. a 10-minute swim in an indoor swim­ described sunblock lotion was deter­ (4) Paul, J. D., “The Acute Oral LD50 of 5 ming pool, the treated areas and un­ mined to be 20.4±5.8 (ref. 19). Percent Escalol 507 in Com Oil Using 30 treated control areas were delineated In another solar simulator study of Albino Rats,” Draft.of unpublished paper in with Dermical and masking tape the. above-described preparation (ref. OTC Volume 060135. before applying a 5 percent aminoben­ 20), the test material was applied to (5) Paul, J. D., “Sensitization Studies of 5 zoate lotion other than the one being the forearm of 14 human volunteers at Percent Escalol 507 in Guinea Pigs,” Draft tested and toweling to the remainder of unpublished paper in OTC Volume the rate of 2 ul/cm2 (100 mg applied 060131. of the body. Sunlight exposure meas­ to a 5x10 cm2 area) and allowed to dry (6) Paul, J. D., “Sensitization Studies of 5 ured at 1,200 counts on the Berger- for 15 minutes. The treated areas were Percent Escalol 507 on Guinea Pigs,” Draft

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38246 PROPOSED RULES of unpublished paper in OTC Volume salts of 2-phenylbenzimidazole-5-sul- the rabbits, a drop of one preparation 060135. fonic acid and two unidentified prep­ was instilled in the conjunctival sac of (7) Paul, J. D., “Primary Irritant Studies arations of the ingredient were per­ one eye, and a w€ek later a drop of the of 5 Percent Escalol 507 in Albino Rabbits,” formed on both the skin of the auricle other preparation was instilled into Draft of unpublished paper in OTC Volume and the mucous membrane of the con­ the conjunctival sac of the previously 060131. untreated eye. In each case the un­ (8) Paul, J. D., “Primary Irritant Studies junctiva of rabbits. Concentrations of of 5 Percent Escalol 507 in Albino Rabbits,” the test materials ranged from 1 to 5 treated eye was used as the control. Draft of unpublished paper in OTC Volume percent. The test materials were ad­ Evaluations were performed 1, 2, 3, 24, 06013. ministered twice daily for 5 days by and 48 hours following instillation. (9) Paul, J. D., “Eye Irritation Studies of 5 placing three drops on the conjunctiva Both animals reacted similarly to both Percent Escalol 507 on Rabbits,” Draft of and 0.5 ml on the auricle. In vitro preparations; that is, immediately unpublished paper in OTC Volume 060131. tissue tolerance tests were also per­ after instillation the rim of the eyelid (10) Paul, J. D., “Eye Irritation Studies of and the conjunctiva reddened slightly 5 Percent. Escalol 507 on Rabbits,” Draft of formed on growing chicken heart fi­ unpublished paper in OTC Volume 060135. broplastic cultures. The results report­ and the cornea showed “slight freck­ (11) Shelanski, M. V., “4 Percent Escalol edly demonstrated that the salts and les” for 1 to 2 hours. All these changes 507 in U.S.P. White Petrolatum. Ointment their preparations were Well tolerated, disappeared within 24 hours. The in­ No. A-53-202, Repeated Insult Patch Test,” with skin tolerance, in particular, vestigator rubbed a small quantity of Draft of unpublished paper in OTC Volume being very good. The ingredient itself each preparation into a conjunctival 060131. was found to have no irritating effect sac and reported that he experienced a (12) Shelanski, M. V., “4 Percent Escalol slight reddening of the conjunctiva 507 in U.S.P. White Petrolatum. Ointment on the mucous membrane of the con­ No. A-53-202, Repeated Insult Patch Test,” junctiva. There was no observable dif­ and a slight burning sensation, both of Draft of unpublished paper in OTC Volume ference in tolerance between the three which disappeared within 1 hour. It 060135. salts (ref. 2). was concluded by the investigator that (13) OTC Volume 060164. The subacute skin tolerance and sen­ these sunscreen preparations when (14) “Escalol 507, Technical Bulletin,” sitizing effect of 5 and 10 percent solu­ used as directed present no danger to Draft of unpublished paper in OTC Volume tions and a 5 percent cosmetic prepa­ the eyes (ref. 4). 060131. ration of the sodium salt of 2-phenyl- A manufacturer of 2-phenylbenzimi- (15) “Escalol 507, Technical Bulletin,” dazole-5-sulfonic acid reported that in Draft of unpublished paper in OTC Volume benzimidazole-5-sulfonic acid were 060135. evaluated by applying 4 ml of each the preceding 10 years more than 50 (16) Cumpelik, B. M., “Substantivity of test material to the shaved backs of tons of the compound were marketed Sunscreens,” Cosmetics and Toiletries, 9:59- five rabbits for a total of 30 times worldwide and that the suppliers have 62, 1976. during a 43-day period. Blood counts received no reports of adverse reac­ (17) Sayre, R., “PSL Formula RB 292- were performed at the beginning, mid­ tions from the .use of the ingredient in 240A, Lot #352206, Outdoor Testing of PSL point, and end of the test period. In sunscreen preparations (ref. 5). versus Comparative Products: Eclipse, Based on the available data, the PreSun, Sol-Bar, Super Shade and Uval,” addition, 1.5 ml of each test material Draft of unpublished paper in OTC Volume was applied to the shaved backs of five Panel conludes that 2-phenylbenzimi- 060131. guinea pigs for a total of 3 times dazole-5-sulfonic acid is a safe sun­ (18) Sayre, R., “Sunscreen Evaluations, during a 40-day period. A second group screen ingredient for OTC use. Human Testing,” Draft of unpublished of five guinea pigs received a total of (2) Effectiveness. There are con­ paper in OTC Volume 060131. 20 such treatments during a 25-day trolled studies documenting the effec­ (19) Sayre, R., “PSL Formula—RB 360- period. After a 14-day rest period tiveness of 2-phenylbenzimidazole-5- 272A, PLB 75-238. Protective Index Using sulfonic acid as an OTC sunscreen. Solar Simulator,” Draft of unpublished there were concurrent injections of 0.2 paper in OTC Volume 060131. ml of the test material intramuscular­ Its absorbance is between 290 and (20) Sayre, R., “Sunblocking Lotion—RB ly into the popliteal fossa and 0.1 ml 320 nm, with the maximum absor­ 360-272A, PLB 75-238. Human substantivity of the test material intracutaneously bance at 302 nm. This ingredient is Testing,” Draft of unpublished paper in into the skin of the neck. It was re­ used in the form of its sodium, mon- OTC Volume 060131. ported that no irritating effects were oethanolamine, and triethanolamine q. 2-Phenylbenzimidazole-5-sulfonic observed on the backs of any of the salts. Aqueous solutions of these salts acid. The Panel concludes that 2- rabbits or guinea pigs and that the are miscible with ethanol and ispro- phenylbenzimidazole-5-sulfonic acid is sensitization test was absolutely nega­ panol in almost any proportion. The safe and effective for OTC use as a tive. Blood counts' remained normal ingredient is practically insoluble in sunscreen as specified in the dosage throughout the study, and the animals alkali solutions, and at a pH below 6.3, ^section discussed below. did not experience any weight loss or the free acid is precipitated as insolu­ 2-Phenylbenzimidazole-5-sulfonic behavioral changes (refs. 2 and 3). ble matter. It is recommended for hy­ acid has a chemical formula of Oil/water emulsions of 3 percent 2- drous formulations, including emul­ CisHioNjOsS and a molecular weight of phenylbenzimidazole:5-sulfonic acid sions and transparent gels, and is fre­ 274.30. It is a white, finely crystalline were applied. daily for a period of 3 quently used in combination with powder, almost odorless. It is practical­ weeks to 21 human subjects of differ­ other sunscreens (ref. 6). ly insoluble in benzene, but it is solu­ ent sex and ages, some of whom suf­ Twelve subjects (8 females and 4 ble in water, ethanol, ether, and chlo­ fered from skin disorders (refs. 2 and males) participated in a laboratory roform (ref. 1). 3). It was reported that the prepara­ study to determine the protective in­ (1) Safety. Clinical use and market­tions were well-tolerated and did not dexes of a sunscreen containing 5 per­ ing experience have confirmed that 2- give any indication that they might cent aminobenzoate and 7 sunscreen phenylbenzimidazole-5-sulfonic acid is cause undesired skin reactions, par­ preparations containing 2-phenylben- safe in the dosage range used as an ticularly toxic acne, or might led to zimidazole-5-sulfonic acid in combina­ OTC sunscreen. sensitization of the skin. tion with ethylhexyl p-methoxy cinna­ Extensive animal and human toxico­ Eye irritation tests of two sunscreen mate with and without 2-hydroxy-4- logical data attest to its safety for lotions containing 1.5 and 2 percent 2- methoxy benzophenone (ref. 7). The human topical application. The oral phenylbenzimidazole-5-sulfonic acid test materials were applied to the sub­ LDso is more than 5 g/kg in mice (refs. and 2.5 and 4.5 percent ethylexyl p- jects’ backs 60 minutes prior to UV ex­ 2 and 3). methoxy cinnamate, respectively, were posures equivalent to 3, 6, 9, 12, and 15 Tolerance tests of the sodium, mon- performed on two rabbits and one times the minimal erythemal dose othanolamine, and triethanolamine human subject (ref. 4). In the case of (MED) of the subject. A hot quartz

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38247 mercury arc lamp was used as the fonic acid, 5 percent ethylhexyl p- 10 percent p-methoxycinnamic acid light source. Twenty-four hours after methoxy cinnamate, and 4 percent 2- diethanolamine salt lotion was easily exposure the test sites were evaluated hydroxy-4-methoxy benzophenone) removed from the skin during swim­ as to the degree of erythema by visual provided the best and most consistent ming and sweating and gave only par­ gradations which were used to deter­ protection. The protection afforded by tial protection. In terms of decreasing mine the protective index of each of the sunscreen containing 5 percent degree of protection under the above- the test materials. All test materials aminobenzoate only exceeded that described conditions as determined by were found to provide significant pro­ provided by the 10 percent p-methoxy their mean protective indexes, the tection against erythemnogenic radi­ cinnamic acid diethanolamine salt ranking of the test materials was prep­ ation. Three formulations were consid­ preparation, which itself was consid­ aration 3 (9.3), preparation 1 (9.1), a ered to have provided excellent protec­ ered to provide a good degree of pro­ sunscreen containing 5 percent amino­ tion, as their maximum protective in­ tection under the above-described con­ benzoate (6.8), preparation 2 (5.9), and dexes always exceeded 10. They were a ditions. a lotion containing 10 percent p-meth­ cream containing 2.75 percent 2-phen- Eleven subjects participated in an­ oxy cinnamic acid diethanolamine salt ylbenzimidazole-5-sulfonic acid, 4 per­ other passive sunbathing study to (4.6). cent ethylhexyl p-methoxycinnamate, evaluate the photoprotective proper­ Six subjects participated in a study and 3 percent 2-hydroxy-4-methoxy ties of the above-described and other to evaluate the photoprotective prop­ benzophenone (preparation 1); a lotion sunscreen preparations except that erties of preparations 1, 2, and 3 de­ containing 3 percent 2-phenyl-benzimi- the sunscreen containing 5 percent scribed above, wherein 60 minutes dazole-5-sulfonic acid and 4.5 percent aminobenzoate was not included. Sixty after two test materials were applied ethylhexyl p-methoxy cinnamate minutes prior to exposure, three prep­ to test sites on each subject’s back (preparation 2); and a cream contain­ arations were applied to test sites on there was a 15-minute swimming ing 2.75 percent 2-phenylbenzimida- the back of each subject and were period followed by the exposure of the zole-5-sulfqnic acid, 5 percent ethyl­ then exposed to 30-, 60-, 90-, or 120- test sites to 30-, 45-, 60-, or 90-minute hexyl p-methoxy cinnamate, and 4 minute periods of midday sunlight periods of midday sunlight. It was de­ percent 2-hydroxy-4-methoxy benzo­ without the subjects engaging in any termined that preparations 1 and 3 phenone (preparation 3). These prep­ physical activity. Preparation 3 de­ were not removed by swimming and arations provided greater protection scribed above again provided the best afforded fairly good protection, as no than a sunscreen containing 5 percent and most consistent protection. Sub­ test sites treated with these prepara­ aminobenzoate, but this was explained stantial protection was also provided tions showed evidence of erythema as resulting from the latter prepara­ by preparation 1 and 2 discussed even after 90 minutes of midday sun­ tion not exerting its maximum photo- above. A preparation containing 3 per­ light exposure. Preparation 2, howev­ protective effect at higher doses of UV cent 2-phenylbenzimidazole-5-sulfonic er, was readily removed as the result radiation (12 and 15 times the MED) acid, even though one of the least pro­ of swimming, and the test sites treated because of it being less protective tective of the 12 preparations tested, with this material showed evidence of against the erythemogenic effects of had a mean protective index of 5.0 a sunburn reaction. The mean protec­ 254 nm radiation emitted by the light after 120 minutes of exposure, which tive indexes were as follows: prepara­ source. The least protection (mean compared favorably with protective in­ tion 3 (greater than 4.4), preparation 1 minimum protective index of 6.7) was dexes of 6.6 and 7.0 for preparations 1 (greater than 4.2), and preparation 2 provided by a cream preparation con­ and 2, respectively, after similar expo­ (1.04). taining 1.5 percent 2-phenylbenzimida- sure. In the latter two studies described zole-5-sulfonic acid and 2.5 percent Six patients participated in a study above, the substantivity of preparation ethylhexyl p-methoxycinnamate. to evaluate the photoprotective prop­ 2 was decidedly less than that for A total of 39 untanned fair-skinned erties of preparations 1, 2, and 3 de­ either preparation 1 or 3. The formu­ male subjects participated in studies scribed above under conditions of lations for the three preparations are conducted in Arizona in the early sweating induced by exercise. Sixty quite similar, except that preparation spring to determine the photoprotec- minutes prior to 30 minutes of strenu­ 2 does not contain 2-hydroxy-4-meth- tive properties of the above-described ous calisthenics two preparations were oxy benzophenone. In regard to 2- and other sunscreen preparations applied to the back of each subject. phenylbenzimidazole-5-sulfonic acid, under conditions of passive sunbath­ Following the exercise period the test the second study cited above demon­ ing, swimming and/or sweating in­ sites were exposed to 30-, 60-, 90-, or strated that a lotion containing a 3 duced by exercise. The MED for each 120-minute periods of midday sun­ percent concentration of this com­ subject was determined by exposing light. All three preparations were con­ pound provided adequate protection appropriate sites to 5, 10, 20, 25, and sidered to have provided excellent pro­ after 120 minutes of midday sunlight 30 minutes of midday sun on the day tection, as it was concluded that they exposure, but the last two studies of the test (ref. 8). could protect normal skin against sun­ would appear to demonstrate that the In one study, 80 subjects participat­ burn reaction for a period of 2 hours. substantivity of this compound is ed in a passive sunbathing study to Nine patients participated in a study questionable. evaluate the photoprotective proper­ to evaluate the photoprotective prop­ A total of 41 fair-skinned male sub­ ties of the three formulations de­ erties of the five preparations involved jects participated in a series of four scribed above, a sunscreen containing in the first study in this series under studies under conditions similar to 5 percent aminobenzoate, and a lotion conditions of normal beach activities. those for the five studies described continirig 10 percent p-methoxy cinna­ Sixty minutes following the applica­ above to evaluate the photoprotective mic acid diethanolamine salt. Sixty tion of two test materials to different properties of several preparations minutes prior to exposure, two of the sides of each subject’s back, the sub­ which were 1.5 percent 2-phenylbenzi- above-described preparations were ap­ jects performed 60 minutes of passive midazole-5-sulfonic acid and 3 percent plied to test sites on the back of each sunbathing, 10 minutes of swimming, ethylhexyl p-methoxycinnamate subject. Each test material was then 30 minutes of passive sunbathing, 15 cream; 2.75 percent 2-phenylbenzimi- exposed to 1- or 2-hour periods of minutes of exercise to induce sweat­ dazole-5-sulfonic acid, 4 percent ethyl­ midday sunlight without the subject ing, and 30 minutes of walking. Total hexyl p-methoxy-cinnamate and 3 per­ engaging in any physical activity. “sun exposure was 150 minutes. Again, cent 2-hydroxy-4-methoxy benzophen­ Preparation 3 (cream containing 2.75 preparation 3 described above pro­ one cream; 2.75 percent 2-phenylbenzi- percent 2-phenylbenzimidazole-5-sul- vided the best protection, whereas the midazole-5-sulfonic acid, 5 percent eth-

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38248 PROPOSED RULES ylhexyl p-methoxycinnamate and 4 and erythema reactions were made im­ walking, and 30 minutes of sunbathing percent 2-hydroxy-4-methoxy benzo- mediately and 24 hours after expo­ while walking or in the sitting posi­ phenone cream; 7 percent ethylhexyl sure. Preparations 1, 2, 3, and 5 (com­ tion. Total sun exposure for each sub­ p-methoxycinnamate and 3 percent 2- mercial lotion containing 5 percent ject was 195 minutes. The results were hydroxy-4-methoxy benzophenone oil; aminobenzoate) were again found to identical to those described above for 5 percent aminobenzoate in 55 percent protect the skin against the immediate the previous study. -ethanol lotion; and 2.55 percent padi- erythema reaction and to provide good The four studies described above re­ mate A in 70 percent ethanol lotion protection against a sunburn reaction vealed that preparations 1, 2, and 3 are (ref. 9). The latter two preparations 24 hours after exposure. Preparation 2 significantly more protective and sub­ were commercial sunscreens. The stud­ was found to be especially substantive. stantive than preparation 4. Prepara­ ies were conducted in Australia under Test sites treated with preparations 4 tion 4 differed from preparations 1, % bright sunlight and high humidity and 6 showed evidence of immediate and 3 in that it lacked 2-phenylbenzi- (over 90 percent) in mid-November. vasodilation following sun exposure. midazole-5-sulfonic acfd and was for­ The MED for each subject was deter­ These latter two preparations did not mulated with an oil rather than a mined by exposing the appropriate prevent an immediate erythema reac­ cream base. sites to 5, 10, 15, 20, 25, and 30 minutes tion and demonstrated unsatisfactory Based on the available data, the of midday sun on the day of the study. protection 24 hours following expo­ Panel concludes that 2-phenylbenzimi- In one study (study 1), 11 male sub­ sure. Evaluations performed 5 days dazole-5-sulfonic acid is an effective jects were used to evaluate the photo- after exposure found no evidence that sunscreen ingredient for OTC use. protective properties of the above-de­ any of the formulations caused photo­ (3) Dosage, (i) For products provid­ scribed preparations against the stress toxic or photoallergic reaction:? or that ing a minimum SPF value of 2 to of prolonged sunbathing without seat­ they stimulated or inhibited the tan­ under 4 containing 1 to 4 percent 2- ing and swimming. Sixty minutes after ning response. phenylbenzimidazole-5-sulfonic acid: applying two test materials and one of Eleven male subjects (study 3) par­ Adult and children over 2 years of age the two commercial sunscreen lotions ticipated in a substantivity study to topical dosage is liberal- application to designated test sites on the back of evaluate the photoprotective proper­ before sun exposure and reapply after each subject, each test site received 45, ties of the six formulations under the swimming or after excessive sweating. 90, 135, or 180 minutes of midday sun­ combined stress of swimming and pro­ There is no recommended dosage for light exposure. Erythema response longed sunbathing. Sixty minutes fol­ children under 2 years of age. except was evaluated immediately and 24 lowing the application of two test ma­ under the advice and supervision of a hours later; 5 days following exposure terials and one of the two lotions to physician. an evaluation was made as to pigment designated test sites on the back of (ii) For products providing a mini­ response and evidence of any delayed each subject, the subjects swam in a mum SPF value of 4 containing 1 to 4 phototoxic or photoallergic reactions. chlorinated pool for 15 minutes prior percent 2-phenylbenzimidazole-5-sul- Preparations 1, 2, 3, and 5 (a lotion to exposing the test sites to 60 or 120 fonic acid; Adult and children over 6 containing 5 percent aminobenzoate) minutes of midday sun. In terms of months of age topical dosage is liberal were found to protect the skin against the immediate response, preparations application before sun exposure and an immedate erythema reaction and to 4, 5, and 6 showed definite presence of reapply after swimming or after exces­ provide good protection against a sun­ erythema, whereas the remaining sive sweating. There is no recommend­ burn reaction 24 hours following expo­ three formulations rarely showed any ed dosage for children under 6 months sure. Preparations 4 (lacking 2-phenyl- immediate sunburn response. Eryth­ of age except under the advice and su­ benzimidazole-5-sulfohic acid found in ema response 24 hours following expo­ pervision of a physician. preparations 1, 2, and 3) and 6 (a sure indicated that preparations 1, 2, (4) Labeling. The Panel recommends lotion containing 2.55 percent padi- and 3 were significantly more protec­ the category I labeling for sunscreen mate A) did not block an immediate tive than preparation 4 and the two active ingredients. (See part III. para­ erythema reaction and exhibited unsa­ sunscreen lotions. Most of the test graph B.l. below—category I labeling.) tisfactory protection 24 hours follow­ sites treated with the least protective ing exposure. All the above-described formulation (the commercial lotion R eferences preparations neither stimulated nor containing 5 percent aminobenzoate) (1) OTC volume 060090. inhibited a tanning reaction. A greater showed a fair degree of sunburn reac­ (2) “Animal Safety Data,” Draft of unpub­ tanning response was obtained with lished paper in OTC volume 060083. tion 24 hours after exposure. The pro­ (3) “Data Sheet for Eusolex 232,” Draft of the least protective formulations, tection provided by preparations 1, 2, unpublished paper in OTC volume 060086. namely, preparations 4 and 6 described and 3 was rated as good to excellent (4) “Human Safety Data,” Part IV.C.2., above. None of the 11 subjects showed for a 120-minute sun exposure period. Draft of unpublished paper in OTC volume evidence of immediate or delayed pho­ None of the formulations tested were 060083. totoxicity or evidence of any cell-medi­ found to be phototoxic or photosensi­ (5) “Human Safety Data,” Part IV.A.4., ated delayed hypersensitivity reac­ tizing. Draft of unpublished paper in OTC volume tions. Ten male subjects (study 4) partici­ 060083. (6) “Eusolex, sun-screening substance for Nine male subjects (study 2) were in­ pated in a substantivity study to evalu­ Cosmetics,” Draft of unpublished paper in volved in a substantivity study to ate the photoprotective properties of OTC volume 060086. evaluate the photoprotective proper­ the six formulations under the com­ (7) “Efficacy Data,” Part IV.C.l.a., Draft ties of the above-described formula­ bined stress of sweating, swimming, of unpublished paper in OTC volume tions under the combined stress of and prolonged sunbathing. Sixty min­ 060083. sweating and prolonged sunbathing. utes after aplying three test materials (8) “Efficacy Data,” Part V.C.l.a., Draft of Sixty minutes after the application of and one of the two sunscreen lotions unpublished paper4n OTC Volume 060083. two test materials and one of the two to designated test sites on the back of (9) OTC volume 060130. commercial lotions to designated test each subject, the volunteers engaged r. Red .petrolatum. The Panel con­ sites on the back of each subject, the in 75 minutes of passive sunbathing cludes that red petrolatum is safe and subjects performed 30 minutes of calis­ before swimming in a chlorinated pool effective for OTC use as a sunscreen thenics, running, and walking before for 15 minutes. This was followed by as specified in the dosage section dis­ the test sites were exposed to 90 or 180 60 minutes of passive sunbathing, 10 cussed below. minutes of midday sunlight exposure. minutes of calisthenics, 10 minutes of Red petrolatum is also known as red Evaluations of the pigment darkening jogging and running, 10 minutes of veterinary petrolatum. Red petrola-

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38249 turn is a product of oil refineries, as A 0.03 mm film of red petrolatum after swimming or after excessive are the other petrolatums. It is the absorbs UV-light below 320 nm. About sweating. There is no recommended product of minimal filtration, which 16 percent is transmitted at 334 nm dosage for children under 2 years of accounts for its red color. Specifica­ and 58 percent at 365 nm (ref. 3). Why age except under the advice and super­ tions, other than color, are similar to red petrolatum is also called red vet­ vision of a physician. those of the liquid, white or yellow erinary petrolatum is not clear be­ (ii) For products providing a mini­ petrolatum. cause veterinarians do not use it. Cur­ mum SPF value of 4 containing 30 to (1) Safety. Clinical use and market­ rently, the red pigment is thought to 100 percent red petrolatum: Adult and ing experience have confirmed that be the single ingredient responsible children over 6 months of age topical red petrolatum is safe in the dosage for its sun-protective effect. Red pet­ dosage is liberal application before sun range used as an OTC sunscreen. rolatum fluoresces brilliantly under exposure and reapply after swimming . Long use by millions of people attest Wood’s light (365 nm). or after excessive sweating. There -is to the safety of petrolatum. The pe­ In December 1942, the Army Air no recommended dosage for children trolatums (liquid petrolatum, white Corps requested the most effective under 6 months of age except under petrolatum, yellow petrolatum, and protective substance against sunburn the advice and supervision of a physi­ red patrolatum) are products of oil re­ for men marooned on life rafts or in cian. fineries. A parafinic base crude oil is the desert following airplane crashes. (4) Labeling. The Panel recommends subjected to distillation at the refinery The substance was required to have the category I labeling for sunscreen to remove the lighter hydrocarbons maximum protection per unit weight active ingredients. (See part III. para­ like gasoline and home fuel oil. The and volume so as to fit into life rafts graph B.l. below—category I labeling.) and emergency equipment* maximum residue is a complex mixture contain­ R eferences ing heavy lubricating oil and petrola­ skin coverage per unit weight and tum. This residue is mixed with a sol­ volume, stability and freedom from (1) Jillson, O. F., “Elder Red Petrolatum— rancidity, and should not burst on The Most Effective Sunscreen,” Current vent (usually methyl ethyl ketone) freezing. Red petrolatum was found to News in Dermatology, August, 1963. and chilled to precipitate the petrola­ (2) OTC Volume 060154. tum. The petrolatum is removed by be the most effective (ref. 3). Red pet­ (3) Chaplick, J., D. A. Sylvestre and G. C. special canvas filters. The petrolatum rolatum completely protected a sub­ Walker, “Red Veterinary Petrolatum as a remains on the canvas, is distilled to ject against erythema at a dose of 20 Sunscreen,” Bulletin of the Ontario College minutes’ exposure from an S-l type of of Pharmacy, pp. 52-55, May, 1965. remove the solvent, and is filtered sunlamp, the equivalent to 20 hours of (4) Owens, D; ,W„ J. M. Knox and R. G. through fuller’s earth to the desired the strongest sunlight in Cleveland, Freeman, “A Clinical Evaluation of Sun­ color. The red color passes through Ohio. screens,” Clinical Medicine, 74:45-46, 1967. the filter as part of the petrolatum A controlled clinical trial performed (5) Jillson, O. F. and R. D. Baughman, and is not an additive. Red petrolatum in Houston, Tex., on 30 light-complex­ “Contact Photodermatitis from Bithionol,” is the product of minimal filtration of ion white subjects compared red petro­ Archives of Dermatology, 88:409-418, 1963. ' the petrolatums (ref. 1). (6) Becker, S. W., “The Protection of Pa­ latum, a benzophenone, amyl p- tients’ Skin Who Have Chloasma,” Current \ The physical properties of the petro- dimethylaminobenzoic acid and 7 per­ News in Dermatology, April, 1964. t latums are vague in the “United States cent para-aminobenzoic acid, simulta­ (7) Schoch, A. G. and L. J. Alexander, i, Pharmacopeia XV,” where white and neously, for protection against expo­ “RVPlus—Improved Sunscreen Has Just yellow petrolatum are mentioned, but sure to the summer sun. Testing began Been Released,” Current News in Dermatol­ i red petrolatum is not. Penetrometer at noon and continued for periods of 5 ogy, September, 1967. I tests for consistency for both white to 60 minutes. Red petrolatum gave s. Sulisobenzone. The Panel con­ I and yellow petrolatum can vary from the following cumulative percent pro­ cludes that sulisobenzone is safe and j 100 to 275. Melting points vary from tection for duration of exposure in effective for OTC use as a sunscreen I 38° to 60° C. Red petrolatum conforms minutes: 100 percent for 20 minutes, as specified in the dosage sectin dis­ | to these tests. Red petrolatum con- 92 percent for 30 minutes, 92 percent cussed below. I tains the intrinsic red pigment from for 40 minutes, 84 percent for 50 min­ Sulisobenzone is also known as 2-hy- j crude oil and some paraffin wax. Be­ utes, and 65 percent for 60 minutes. droxy-4-methoxybenzophenone-5- cause it is the heaviest of the petrola- The end point was the minimal time sulfonic acid and is a sulfonic acid de­ I turns (industrial petrolatum number necessary to produce erythema. In rivative of oxybenzone (ref. 1). It has ; zero), it contains more wax than the this test, red petrolatum performed an approximate melting point of 145° other petrolatums; but red petrolatum second best (ref. 4). C and is soluble in water, methanol, spreads to a smooth, almost invisible Jillson and Baughman (ref. 5) rec­ and ethanol (ref. 2). film on the skin, and leaves no visible ommended red petrolatum as an effec­ (1) Safety. Clinical use and market­ greasy film that can be felt, as do the tive sunscreen following their study of ing experience have confirmed that other petrolatums (ref. 1). eight patients with photo-allergic der­ sulisobenzone is safe in the dosage The petrolatums are considered to matitis to bithionol, an antiseptic. range used as an OTC sunscreen. be inert when applied to the skin. They found it more effective than The oral LDN of sulisobenzone in They serve as vehicles for many drugs para-aminobenzoic acid for these pa­ rats is greater than 6.4 g/kg (ref. 3). In and cosmetics for topical application. tients (ref. 5). Other dermatologists a rabbit eye irritation study patterned The product manufacturer reports one have recommended red petrolatum for after the Draize method, 0.1 ml of a 5 complaint per 120,000 units sold (ref. patients and other consumers (refs. 6 percent aqueous solution of sulisoben­ 2). and 7). zone was instilled in the conjunctival The Panel concludes that the long Based on the available data, the sac of the right eye of each of nine and extensive use of the substance Panel concludes that red petrolatum is albino rabbits. Four seconds after in­ with no adverse effects being reported an effective sunscreen ingredient for stillation the treated eye of three test in the medical literature attests to the OTC use. animals was washed with 20 ml of safety of red petrolatum as a sun­ (3) Dosage, (i) for products providing lukewarm water. The left eye of each screen for OTC use. a minimum SPF value of 2 to under 4 rabbit served as a control. Every 24 (2) Effectiveness. There are well-con­ containing 30 to 100 percent red petro­ hours for the following 7 days, the trolled studies documenting the effec­ latum: Adult and children over 2 years cornea, iris, and conjunctiva of each tiveness of red petrolatum as an OTC of age topical dosage is liberal applica­ rabbit were examined for signs of irri­ sunscreen. tion before sun exposure and reapply tation and were graded according to

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38250 PROPOSED RULES the standard Draize scoring system. It the 10 percent sulisobenzone prepara­ (6) Knox, J. H., A. C. Griffen and R. E. was reported that none of the washed tion was only slightly less than that Hakim, “Protection from Ultraviolet Car­ or unwashed eyes treated with the test for the untreated control sites when cinogenesis,” Journal of Investigative Der­ material showed any involvement of the subjects, 1 hour after applying the matology, 34:51-58, 1960. the cornea, iris, or conjunctiva fat any test materials, swam in an indoor pool t. Titanium dioxide. The Panel con­ time during the 7-day period following for 10 minutes before the test sites cludes that titanium dioxide is safe instillation. It was thus concluded that were exposed to 4 to 6 MED’s of sun­ and effective for OTC use as a sun­ the test material was not an ocular ir­ light. This study was discussed else­ screen as specified in the dosage sec­ ritant. (ref. 3). where in this document. (See part III. tion discussed below. A repeated insult patch study was paragraph B.l.p. above—Padimate O.) Titanium dioxide is employed as a performed by applying 1-square inch The data would indicate that suliso­ physical sunscreen. It reflects and gauze pads wetted with 0.5 ml of a 5 benzone was for all practical purposes scatters UV and visible light rays pro­ percent aqueous solution of sulisoben- completely removed during the swim­ viding a barrier for sun-sensitive indi­ zone to the skin of 50 human subjects ming period (ref. 5). viduals, against the effects of the sun. for 24 hours. Following the removal of Knox et al. (ref. 6) evaluated the It is used to prevent sunburn and the patches the test sites were evaluat­ comparative ability of sulisobenzone suntan. ed. After a 24-hour rest the patches and aminobenzoate to prevent the de­ Titanium dioxide is found in nature were reapplied. This process was re­ velopment of ultraviolate-induced skin as the minerals rutile, ilmenite, per- peated until there had been 15 appli­ cancers in albino mice. In a series of ovskite, anatase or octahedrite and cations of the treated patches after studies, 5 and 10 percent solutions of brookite. It is a white powder, with a which there was a 2-week rest period sulisobenzone in alcohol and a 5 per­ melting point of 1,855° C, insoluble in before challenge doses were applied cent solution of aminobenzoate in al­ water, hydrochloric acid, nitric acid, for 24 hours to the previous test sites. cohol were employed. Both ingredients and diluted sulfuric acid. It is used as It was reported that the above-de­ were reported to decrease markedly a mordant in dyeing, as a pigment in scribed test material was determined the erythematous and carcinogenic the rubber industry, and in the manu­ not to be a primary irritant, a fatigu­ effect of UV light, with sulisobenzone facture of synthetic resins and oil ing agent, or a sensitizer in any of the being superior to aminobenzoate cloth. It is also used in preparations of 50 subjects tested (ref. 3). under certain conditions because of its face powders and beauty creams (ref. Based on the available data, the wider absorption spectrum. J). Panel concludes that sulisobenzone is Based on the available data, the Titanium dioxide scatters both UV a safe sunscreen ingredient for OTC Panel concludes that sulisobenzone is and visible light radiation (290 to 700 use. an effective sunscreen ingredient for nm) rather than absorbing the rays. It (2) Effectiveness. There are studies OTC use. may occasionally be so occlusive as to documenting the effectiveness of suli­ (3) Dosage, (i) For products provid­ produce miliaria (ref. 2). sobenzone as an OTC sunscreen. ing a minimum SPF value of 2 to (1) Safety. Clinical use and market­ Sulisobenzone is soluble in water, under 4 containing 5 to 10 percent ing experience have confirmed that ti­ ethanol, and methanol. It absorbs sulisobenzone: Adult and children over tanium dioxide is safe in the dosage throughout the UV range, with its 2 years of age topical dosage is liberal range used as an OTC sunscreen. maximum absorbance at 285 nm (ref. application before sun exposure and Because titanium dioxide is chemi­ 2). reapply after.swimming or after exces­ cally inert, no meaningful oral LD50 Using a solar simulator with a filter sive sweating. There is no recommend­ can be obtained in animals. For all to eliminate wavelengths below 295 ed dosage for children under 2 years of practical purposes, titanium dioxide is nm, 10 human subjects (8 females and age except under the advice and super­ inert, devoid of toxicity, and is not a 2 males) participated in a study to de­ vision of a physician. sensitizer or primary irritant. Being a termine the protective factors of 1 and (ii) For products providing a mini­ brilliant white powder, it is formulated 3 percent aqueous solutions of suliso­ mum SPF value of 4 containing 5 to 10 with cosmetic pigments for consumer benzone and similar concentrations of percent sulisobenzone: Adult and chil­ acceptance. Often other sunscreens aminobenzoate preparations (ref. 4). dren over 6 months of age topical are incorporated with titanium dioxide Once the MED for each subject was dosage is liberal application before sun in emulsion bases, lipsticks, and oint­ determined, 3.6 ul of each test materi­ exposure and reapply after swimming ments. al was applied to each cm 2 of test site or after excessive sweating. There is In a single dose, acute oral toxicity area. Each sulisobenzone-treated area no recommended dosage for children study in which a cream containing 5 was exposed to 1.5, 2, 2.5, and 3 times under 6 months of age except under percent titanium dioxide in combina­ MED. The 1 percent aminobenzoate- the advice and supervision of a physi­ tion with 5 percent menthyl anthrani- treated areas were exposed to 2.5, 3, cian. late was given in a dose of 5 g/kg to 10 3.5, and 4 times MED. Twenty-four (4) Labeling. The Panel recommends Sherman albino rats, no fatalities were hours after exposure, the test areas the category I labeling for sunscreen reported during a 14-day observation were graded for erythemal response active ingredients. (See part III. para­ period. Histopathological examination on a scale from 0 (no perceptible graph B.l. below—category I labeling.) revealed no gross organ abnormalities erythema) to 4 (severe erythema with R eferences (ref. 3). No reports of irritation.have been at­ blistering). The protection factor was (1) Remington’s Pharmaceutical Sciences, determined by dividing a test materi­ 15th Ed., Mack Publishing Co., Easton, Pa., tributed to titanium dioxide (ref. 4). al’s MED for protected skin by its p. 729, 1975. The probable lethal dose in humans is MED for unprotected skin, the mean (2) OTC volume 060128. reported to be above 15 g/kg, or more protection factors were 1.9 for 1 per­ (3) “Toxicity Information,” Draft of un­ than 1 qt for a 70 kg man. A pound (16 cent sulisobenzone, 2.5 for 3 percent published paper in OTC volume 060128. oz) has been ingested without appar­ sulisobenzone, 3.35 for 1 percent amin­ (4) “Efficacy Data,” Draft of unpublished ent harm or distress. It was eliminated obenzoate, and 4.6 for 3 percent amin­ paper in OTC volume 060128. in about 24 hours (ref. 5). (5) Sayre, R. E., “PSL Formula RB 292- Fisher proposed the inclusion of ti­ obenzoate. 240A, Lot No. 352206, Outdoor testing of A substantivity study of five sun­ PSL versus Comparative Products: Eclipse, tanium dioxide, “an effective non-sen­ screens, including one containing 10 PreSun, Sol-Bar, Super Shade and Uval,” sitizing sun-screen for all wavelengths percent sulisobenzone, found that the Draft of unpublished paper in OTC volume of UV light,” with other effective sun­ mean protective value exhibited by 060131. screens to possibly prevent photosensi-

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38251 tizing reactions caused by the latter under 4 containing 2 to 25 percent ti­ topical application. The oral LDso is 2.8 (ref. 2). tanium dioxide: Adult and children g/kg in rats (ref. 1). Between 1949 and 1972 almost 3.5 over 2 years of age topical dosage is Triethanolamine salicylate was ap­ million units of a sunscreen containing liberal application before sun exposure plied to the intact and abraded skin of 5 percent menthyl anthranilate and 5 and reapply after swimming or after six albino rabbits. The intact skin sites percent titanium dioxide were distrib­ excessive sweating. There is no recom­ showed no evidence of erythema or uted with less than one complaint re­ mended dosage for children under 2 edema 24 and 72 hours following treat­ ceived per 100,000 units marketed. years of age except under the advice ment except for two rabbits where None of the complaints could be at­ and supervision of a physician. very mild erythema was present after tributed to the inclusion of titanium (ii) For products providing a mini­ 24 hours, but disappeared by the time dioxide in the formulation (ref. 6). mum SPF value of 4 containing 2 to 25 of the 72-hour evaluation. The abrad­ Based on the available data, the percent titanium dioxide: Adult and ed skin sites generally showed moder­ Panel concludes that titanium dioxide children over 6 months of age topical ate erythema and mild edema 24 and is a safe sunscreen ingredient for OTC dosage is liberal application before sun 72 hours after application. A primary use. exposure and reapply after swimming irritation index of 1.5 was obtained, (2) Effectiveness. There are studies or after excessive sweating. There is but the compound was not considered documenting the effectiveness of ti­ no recommended dosage for children to be a primary irritant to the skin tanium dioxide as an OTC sunscreen. under 6 months of age except under (ref. 2). Titanium dioxide is a white, amor­ the advice and supervision of a physi­ A rabbit eye irritation study pat­ phous, odorless powder which is in­ cian. terned after the Draize method was soluble in water. It is used in oint­ (4) Labeling. The Panel recommends conducted in which 0.1 ml of triethan­ ments and lotions at a concentration the category I labeling for sunscreen olamine salicylate as instilled into the of 15 to 25 percent as a protective active ingredients. (See part III. para­ conjunctival sac of the right eye of against sunburn. It is also used in graph B.l. below—category I labeling.) each of nine albino rabbits, with the other protective preparations and in left eye serving as a control. Following dusting powders and face powders (ref. R eferences the instillation of the test material, 12). It is physiologically and pharma­ (1) OTC Volume 060001. the animals were divided into three cologically an inert substance (ref. 7). (2) Fisher, A. A., “Contact Dermatitis,” Lea and Febiger, Philadelphia, p. 151, 1967. groups with three rabbits having their Titanium dioxide was found to be an (3) “Animal Safety Data,” Draft of unpub­ treated eyes washed 2 seconds later, effective mechanical screen in humans lished paper in OTC Volume 060001. three rabbits having their treated eyes exposed to artificial UV light (ref. 8). (4) “Human Safety Data,” Draft of un­ washed 4 seconds later, and three rab­ It is effective in preventing or reduc­ published paper in OTC Volume 060001. bits having their treated eyes remain ing the passage of UV radiation to the (5) Gleason, M. N., R. E. Gosselin, H. C- unwashed. No corneal, iridial, or con­ skin. Titanium dioxide is “perhaps the Hodge and R. P. Smith, “Clinical Toxicol­ junctival irritation was observed after most suitable and widely used” light­ ogy of Commercial Products,” 3d Ed., The Williams and Wilkins Co., Baltimore, p. 144, 1, 2, and 3 days in the treated eyes scattering ingredient in sunburn pre­ 1969. which were washed 2 and 4 seconds ventives (ref. 9). (6) “Human Safety Data,” Draft of un­ following instillation of the test mate­ Titanium dioxide is recognized as an published paper in OTC Volmue 060001. rial. The unwashed treated eyes of two effective opaque chemical for use as a (7) “Animal Safety Data,” Draft of unpub­ rabbits showed very mild, transient physical sunscreen because it scatters lished paper in OTC Volume 060001. conjunctival irritation which cleared UV rays, thereby preventing sunburn. (8) “Efficacy Data,” Draft of unpublished by the second day. From the data Giese and Wells investigated the use paper in OTC Volume 060001. (9) Kesten, B. M. and M. Slatkin, “Dis­ above the investigator concluded that of various pigments such as titanium eases Related to Light Sensitivity,” Archives the test material was not a severe dioxide, zinc oxide, magnesium oxide, of Dermatology and Syphilology, 67:284-301, ocular irritant as defined by the magnesium carbonate, magnesium 1953. Draize procedure (ref. 3). stearate, etc. as fillers in vehicles for (10) Giese, A. C. and J. M. Wells, “Sweat Repetitive intracutaneous injections sunscreen preparations. Titanium and Water Resistant Sunburn Prepara­ of a 0.1 percent suspension of trieth­ dioxide was found to surpass the other tions,” Journal of the American Pharmaceu­ anolamine salicylate in physiological ingredients tested in terms of over­ tical Association, (SAci. Ed.), 35:208-212, saline into the closely clipped back coming the after-sticky or greasy feel 1946. (11) Schwartz, L. and S. M. Peck, “Cos­ and flanks of 10 white male guinea and improving the water resistance, metics and Dermatitis,” Paul B. Hoeber, pigs (Hartley strain) were performed covering power and screening power in Inc., New York, p. 145, 1947. every other day or three times weekly a mechanical way (ref. 10). They fur­ (12) “The United States Dispensatory,” until each animal had received a total ther concluded that “As a pigment, ti­ 27th Ed., Edited by A. Osol and R. Pratt, J. of 10 injections. Initially, 0.05 ml of tanium dioxide was found more satis­ B. Lippincott and Co., Philadelphia, P. 1198, the test material was injected, with 0.1 factory than magnesium oxide. The 1973. ml being administered during each of pigment gives covering power and me­ u. Triethanolamine salicylate. The the nine remaining injections. After a chanical screening.” Panel concludes that triethanolamine 2-week rest period, a 0.05 ml challenge Schwartz and Peck reported that salicylate is safe and effective for OTC dose was administered. Twenty-four “Heavily pigmented preparations (liq­ use as a sunscreen as specified in the hours following each injection, read­ uids, creams or powders) will prevent dosage section discussed below. ings of the diameter, height, and color or reduce the passage of the UV radi­ Triethanolamine salicylate is misci­ of any reactions were made. As none ation” but, “while preventing sunburn, ble in all proportions in water, glycer­ of the animals showed evidence of any such preparations will prevent also in, propylene glycol, ethyl and isopro­ response to any of the repetitive or suntan. Zinc oxide, calamine, and ti­ pyl alcohol but it is insoluble in miner­ challenge intracutaneous injections, tanium dioxide are most effective in al or vegetable oil. the investigator concluded that the this regard” (ref. 11). (1) Safety. Clinical use and market­test material was not a sensitizing Based on the available data, the ing experience have confirmed that agent as defined by the Draize proce­ Panel concludes that titanium dioxide triethanolamine salicylate is safe in dure (ref. 4). is an effective sunscreen ingredient for the dosage range used as an OTC sun­ The acute oral LD*» for a sunscreen OTC use. screen. gel containing 8.625 percent triethano­ (3) Dosage, (i) For products provid­ Animal and human toxicological lamine salicylate was greater than 21.5 ing a minimum SPF value of 2 to data attest to its safety for human ml/kg of body weight in albino rats.

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38252 PROPOSED RULES The acute dermal LDS0 of this prepara­ after removal of the patches. None of blanching of the skin after slight pres­ tion in albino rabbits was determined the 11 subjects showed evidence that sure which cleared by the second day to be greater than 10.0 ml/kg of body the test material was a sensitizing of the study. Total salicylate recovery, weight (ref. 5). A primary skin irrita­ agent, and the test material was nonir­ including metabolites, in terms of free tion study of this preparation involv­ ritating to all but one subject. This salicylic acid, ranged from 4.3 to 26.8 ing the intact and abraded skin of six subject experienced erythema and pa­ (mean of 12.2) percent in those indi­ albino rabbits found that the irritative pules at the time of the seventh repeat viduals on whom the test material was effects were confined to very slight application which did not reappear applied by a wood applicator. Total sa­ erythema to two intact and three ab­ when subsequent applications were licylate recovery for those subjects on raded skin sites at the 24-hour reading made to adjacent test sites. Because whom the test material was massaged and had disappeared by the 72-hour this subject reacted similarly to two of for 5 minutes ranged from 0.8 to 32.5 reading. The primary irritation index seven other test materials that were (mean of 14.8) percent. Mean salicy­ was found to be 0.21 (ref. 5). When 0.1 applied concurrently during this late recovery for all 12 individuals was mT of this preparation was instilled study, the investigator concluded that 13.5 percent. No explanation was given into one eye of each of six albino rab­ “the pattern of reactions observed in­ for the little or no recovery (0.8 per­ bits, no irritative effects involving the dicates that these were probably due cent) of salicylate from one individual, cornea, iris, and conjuctiva were noted to cumulative irritation (skin fatigue)” but it is possible that additional salicy­ in any of the test animals 24, 48, and (ref. 7). late would have been recovered from 72 hours following instillation (ref. 5). Similar repeated insult patch tests all individuals if urine collection had A double-blind skin irritation study of a sunscreen lotion containing 8.5 extended beyond 24 hours. comparing a 10 percent methyl salicy­ percent triethanolamine salicylate Percutaneous absorption studies of late cream, 10 and 20 percent triethan­ were performed on the upper arms of various salicylates in rabbits demon­ olamine creams, and a placebo control 57 human subjects in which 0.2 to 0.3 strated that 15.6 percent of the salicyl­ or vehicle were performed on seven ml of the test material was placed on a ic acid contained in a triethanolamine female and three male human subjects patch at the time of each application. salicylate preparation having a base of wherein patches of each test material Eight subjects showed evidence of glyclo stearate, paraffin oil, and water were applied to four different areas of slight erythema on one or more occa­ was excreta in the urine over a 48- each individual’s back (ref. 6). The sions during the repeated insult tests. hour period (ref. 10). patches were evaluated at 0 hour Except for one subject who showed Based on available data, the Panel (preapplication) and at 4, 8, and 24 evidence of slight erythema from the concludes that triethanolamine salicy­ hours postapplication for evidence of first through the seventh application, late is a safe sunscreen ingredient for skin reactions such as erythema, scal­ this reaction was normally observed OTC use. ing, itching, dryness, and texture. once but no more than three times (2) Effectiveness. There are studies None of th e . formulations produced during the series for the other seven documenting the effectiveness of dermographia, ulceration, hair loss, patients. Another subject showed evi­ triethanolamine salicylate as an OTC eruption, or burning. It was concluded dence of slight erythema following re­ sunscreen: by the investigator that both the 10 moval of the challenge dose. The in­ Its absorbance is between 260 and and 20 percent triethanolamine salicy­ vestigator concluded that the above- 320 nm, with its maximum absorbance late creams were well-tolerated by all described test material was only slight­ at 298 nm. Miscible in all proportions 10 subjects and that the degree and ly more irritating than two other com­ in water, glycerine, propylene glycol, frequency of erythema resulting from pounds tested concurrently in the ethyl and isopropyl alcohol, but in­ these two preparations were very simi­ same population which were consid­ soluble in mineral or vegetable oil, it lar and did not differ significantly ered essentially not irritating through­ has been incorporated into aqueous lo­ from the degree and frequency result­ out the study (ref. 8). tions and gels (ref. 11). ing from the placebo. Significantly A percutaneous absorption study of The efficacy of a sunscreen lotion more erythema was caused by the 10 a cream containing 10 percent trieth­ containing 8.5 percent triethanola­ percent methyl salicylate cream, and anolamine salicylate was performed on mine salicylate was evaluated in 16 there was a statistically significant in­ 12 healthy male volunteers by apply­ human subjects at a St. Petersburg, crease in the erythema caused by this ing the contents of a 0.5 oz tube Fla. beach (ref. 12). Except for a few preparation from 4 to 24 hours postap­ (equivalent to 750 mg salicylic acid) to patients who participated in the study plication, whereas the degree of any a 25 cm x 30 cm area on the back of on a mid-November day when the tem­ erythema caused by the other prep­ each subject and determining the perature was 67° F and the sky was arations generally remained constant amount of salicylic acid and its meta­ partly cloudy, the tests were per­ throughout the evaluation period. bolites excreted in in the urine during formed on sunny days at a tempera­ Repeated insult patch tests of a sun­ the next 24 hours (ref. 9). In one ture of 73° F. Approximately 0.1 ml of screen gel containing 8.625 percent group of six individuals the test mate­ the test material was applied to four 1 triethanolamine salicylate were per­ rial was layered on the test site with a x lYa inch areas on the back of each formed on the upper arms of 11 wood applicator. In the second group subject, and each site received 45, 75, human subjects using an adaptation of of six individuals the test material was 120, or 180 minutes of sun exposure. the Draize method (ref. 7). For each applied to the test site and massaged The erythema response was graded on application, five drops of the test ma­ with gloved hands for 5 minutes. The a scale from 1 (no perceptible eryth­ terial were placed on a patch which empty tubes of the test material and ema throughout the study except in was then affixed to the designated test the application materials were then some instances when evaluations of site and left in place for 24 hours. Ap­ reweighed to determine the amount of erythema response were made 1 day plications were made every other day test material actually applied to each after sun exposure: The instances of or three times weekly until each pa­ test site. The test sites were protected erythema were just perceptible eryth­ tient received a total of nine applica­ with a polyethylene sheet covering. ema in two cases with 45 minutes’ ex­ tions. Evaluations of any skin reac­ The sheets were removed after 24 posure. Two subjects showed just per­ tions were made just prior to reappli­ hours, and the test sites were observed ceptible erythema, and one subject cation of the test material. After an then and 2 days later for any sign of showed moderate erythema with 75 approximately 3-week rest period, irritation. Only one individual experi­ minutes of sun exposure. One subject challenge doses were applied and eval­ enced any skin reaction, which consist­ had just perceptible erythema, and uations were made 24 and 72 hours ed of very mild transient pruritis with two subjects had moderate erythema

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38253 with 120 minutes of exposure. Moder­ (10) “Animal Safety Data,” Part III.A.2.e„ (/) “Provides 4 times your natural ate erythema was seen in four cases Draft of unpublished paper in OTC Volume protection from sunburn.” with 180 minutes exposure. The per­ 060024. (iii) For extra sunscreen products, (a) cent protection based upon the eryth­ (11) OTC Volume 060091. (12) “Sunscreening and Tanning Efficacy “Affords extra protection against sun­ ema scores for treated sites and un­ Study,” Draft of unpublished paper in OTC burn.” treated control sites was determined to Volume 060091. (6) “Prolongs exposure time before be 82, 75, and 76 percent after 75, 120, sunburn occurs.” and 180 minutes of sun exposure, re­ C a teg o ry I L a b el in g (c) “Permits limited tanning (or sun­ spectively. »Based on a scale from 00 The Panel recommends the follow­ tanning) and reduces chance of (or (no tanning) to 02 (marked tanning), it ing category I labeling for sunscreen minimizes) sunburn.” was determined that treated sites active ingredients to be generally rec­ (d) “Helps prevent sunburn.” showed a slight tan (score of 01) or ognized as safe and effective and not (e) “For sun-sensitive skin.” greater from the second to fifth day misbranded as well as any specific la­ (/) “Extra protection against sun­ after 120 and 180 minutes of sun expo­ beling discussed in the individual in­ burn for blondes, redheads and fair­ sure and generally showed more of a gredient statements. skinned persons.” tan than the untreated control sites a. Indications. The indications (g) “Allows you to stay in the sun 6 during the same period following simi­ should be limited to one or more of times longer than without sunscreen lar sun exposure. the following phrases: protection.” Based on available data, the Panel (1) For all (minimal, moderate, (h) “Provides 6 times your natural extra, maximal and ultra) sunscreen protection from sunburn.” concludes that triethanolamine salicy­ (iv) For maximal sunscreen prod­ late is an effective sunscreen ingredi­ products, (i) ^‘Sunscreen to help pre­ vent sunburn.” ucts. (a) “Affords maximal protection ent for OTC use. against suburn.” (3) Dosage, (i) For products provid­ (ii) “Filters (or screens) out the sun’s burning rays to prevent sunburn.” (b) “Prevents sunburn and limits ing a minimum SPF value of 2 to tanning.” under 4 containing 5 to 12 percent (iii) “Screens out the sun’s harsh and often harmful rays to prevent (c) “For sun-sensitive skin.” triethanolamine salicylate: Adult and sunburn.” id) “Maximal protection against sun­ children over 2 years of age topical (iv) “Overexposure to the sun may burn for blondes, redheads, and fair- dosage is liberal application before sun lead to premature aging of the skin skined persons.” exposure and reapply after swimming and skin cancer. The liberal and regu­ (e) “Allows you to stay in the sun 8 or after ^excessive sweating. There is lar use over the years of this product times longer than without sunscreen no recommended dosage for children may help reduce the chance of these protection.” under 2 years of age except under the harmful effects.” (/) “Provides 8 times your natural advice and supervision of a physician. (v) “Overexposure to the sun may protection from sunburn.” (ii) For products providing a mini­ lead to premature aging of the skin (v) For ultra sunscreen products, (a) mum SPF value of 4 containing 5 to 12 and skin cancer. The liberal and regu­ “Affords the most protection against percent triethanolamine salicylate: lar use over the years of this product sunburn.” Adult and children over 6 months of may help reduce the chance of prema­ (6) “Prevents tanning and sunburn- age topical dosage is liberal applica­ ture aging of the skin and skin *ing.” tion before sun exposure and reapply cancer.” (c) “For highly sun-sensitive skin.” after swimming or after excessive (2) Additional indications. In addi­ id) “Greatest protection against sun­ sweating. There is no recommended tion to the indications provided above burn for blondes, readheads and fair­ dosage for children under 6 months of in item (1), the following may be used: skinned persons.” age except under the advice and super­ (i) For minimal sunscreen products. (e) “Provides the highest degree of (a) “Affords minimal protection sunburn protection and permits no vision of a physician. tanning.” (4) Labeling. The Panel recommends against sunburn.” (b) “Prolongs exposure time before (/) “Provides the highest degree of the category I labeling for sunscreen sunburn occurs.” sunscreen protection and permits no active ingredients. (See part III. para­ (c) “Permits tanning (or suntanning) tanning.” graph B.l. below—category I labeling.) and reduces chance of (or minimizes) (3) For all (maximal and ultra) sun­ R eferences sunburning.” screen products that contain sun­ screen opaque sunblock ingredients. (1) “Acute Oral LD»—Triethanolamine (d) “Helps prevent sunburn on limit­ Salicylate,” Draft of unpublished paper in ed exposure of untanned skin.” “Reflects the burning rays of the OTC Volume 060091. (e) “Helps to protect the skin against sun.” (2) “Primary Skin Irritation—Triethanola­ sunburn while permitting tanning.” b. Statement on product perform­ mine Salicylate,” Draft of unpublished (/) “Allows you to stay in the sun 2 ance—(1) Product category designa­ paper in OTC Volume 060091. times longer than without sunscreen tion (PCD). The Panel concludes that (3) “Eye Irritation—Triethanolamine Sa­ protection.” improved, more informative labeling licylate,” Draft'"of unpublished paper in should be provided to the consumer to OTC Volume 060091. (g) “Provides 2 times your natural (4) “Intracutaneous Sensitization—Trieth­ protection from sunburn.” aid in selecting the most approriate anolamine Salicylate,” Draft of unpublished (ii) For moderate sunscreen prod­ sunscreen product. The Panel recom­ paper in OTC Volume 060091. ucts. (a) “Affords moderate protection mends that the following appropriate (5) “Acute Toxicity and Irritation Studies against sunburn.” labeling statements) be prominently of Suretan Gel,” Draft of unpublished (6) “Prolongs exposure time before placed on the principal display panel paper in OTC Volume 060091. sunburn occurs.” of the products: (6) “Evaluation for Potential Skin Irrita­ (c) “Permits tanning (or suntanning) (i) Products containing active tion of Mobisyl Cream,” Draft of unpub­ lished paper in OTC Volume 060156. and reduces chance of (or minimizes) ingredient(s) that provide an SPF (7) “Pilot Repeated Insult Patch Test of sunburning.” value of 2 to under 4: “Minimal sun Eight Samples,” Draft of unpublished paper (d) “Helps prevent sunburn on mod­ protection product (SPF 2)—Stay in in OTC Volume 060091. erate exposure of untanned skin.” the sun twice as long as before with­ (8) “Repeated Insult Patch Test,” Draft of (e) “Allows you to stay in the sun 4 out sunburning.” unpublished paper in OTC Volume 060091. times longer than without sunscreen (ii) Products containing active (9) OTC Volume 060144. protection.” ingredient(s) that provide an SPF

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38254 PROPOSED RULES value of 4 to under 6: “Moderate sun (1) “For external use only, not to be ly recognized as safe and effective or protection product (SPF 4)—Stay in swallowed.” as misbranded: the sun 4 times as long as before with­ (ii) “Avoid contact with the eyes.” 2- Ethylhexyl 4-phenylbenzophenone-2'-car- out sunburning.” (iii) “Discontinue use if signs of irri­ boxylic acid, (iii) Products containing active tation or rash appear.” 3- ( 4-Methylbenzylidene )-camphor, ingrediente s) that provide an SPF (2) Specific warnings—(i) For sun­ Sodium 3,4-dimethylphenyl-glyoxylate. value of 6 to under 8: “Extra sun pro­ screen products providing an SPF a. 2-Ethylhexyl 4-phenylbenzophen- tection product (SPF 6)—Stay in the value of 2 to under 4. “Use on children one-2'-carboxylic acid. The Panel con­ sun 6 times as long as before without under 2 years of age Only with the cludes that 2-ethylhexyl 4-phenylben- sunbuming.” advice of a physician.” zophenone-2'carboxylic acid is not safe (iv) Products containing active (ii) For sunscreen products provid­ and not effective for OTC use as a ingredient(s) that provide an SPF ing an SPF value of 4 or greater. “Use sunscreen. value of 8 to under 15: “Maximal sun on children under 6 months of age The ingredient 2-ethylhexyl 4-phen- protection product (SPF 8)— Stay in only with the advice of a physician.” ylbenzophenone-2'carboxylic acid is a the sup 8 times as long as before with­ d. Directions for use. The Panel be­clear, faintly brownish-yellow, highly out sunbuming.” lieves that many consumers use inad­ viscous oil with a faint characteristic (v) Products containing active equate amounts of sunscreen. Offering odor. It is miscible in all proportions ingredient(s) that provide an SPF more detailed guidelines would benefit with methanol, ethanol, ether, chloro­ value of 15 or greater: “Ultra sun pro­ the consumer. form and benzene, but is immiscible tection product (SPF 15)—-Stay in the Based upon a review of the available with water. It has a molecular weight sun 15 times as long as before without data, the Panel recommends that the of approximately 414 (ref 1). sunburning.” directions for use state: “Apply liberal­ (1) Safety. Clinical use and market­ (2) Labeling claims related to the ly before sun exposure and reapply ing experience are insufficient to con­ PCD and SPF value. The Panel recom­ after swimming or after excessive firm that 2-ethylhexyl 4-phenylbenzo- mends any of the following labeling sweating.” phenone-2'carboxylic acid is safe Tor claims for sunscreen products that Sat­ However, for sunscreen products use as an OTC sunscreen. isfy the sunscreen product testing pro­ that satisfy the water resistance, wa­ 2-Ethylhexyl 4-phenylbenzophen- cedures described elsewhere in this terproof and sweat resistance testing one-2'-carboxylic acid was tested for document. (See part III. Paragraph D. procedures described elsewhere in this acute toxicity using 40 rats of the below—Sunscreen products testing document, the directions for use in the Wistar strain. A dosage ranging from procedures for determination of the labeling of these products may be 8,000 mg/kg to 16,000 mg/kg was given sun protection factor (SPF) value and modified in accordance with the re­ to the rats in the form of a 20 percent related labeling claims.) sults of the test. (See part III. para­ solution of 2-ethylhexyl 4-phenylben- (1) For all (minimal, moderate, extra, graph D. below—Sunscreen product zophenone-2'carboxylic acid in peanut maximal, and .ultra) sunscreen prod­ testing procedures for determination oil. The test material was administered ucts— (a) That satisfy the water resis­ of the sun protection factor (SPF) by means of a gastric tube. Readings tance testing procedures. (1) “Water value and related labeling claims.) The on days 1, 7, and 14 showed an ap­ resistant.” Panel recommends that for sunscreen proximate LDso in excess of 16,000 mg/ (2) “Retains its sun protection for at products that satisfy these testing pro­ kg (ref. 2). least 40 minutes in the water.” cedures the following modifications re­ In another test the approximate (3) “Resists removal by sweating.” place the directions-for-use labeling in­ LDso of 2-ethylhexyl 4-phenylbenzo- (6) That satisfy the waterproof test­ dicated above: phenone-2'carboxylic acid was deter­ ing procedures. (I) “Waterproof.” For all (minimal, moderate, extra, mined by means of topical application. (2) “Retains its sun protection for at maximal and ultra) sunscreen prod­ One hour before the start of the test, least 80 minutes in the water.” ucts— (1) That satisfy the water resis­ 10 rats, with an average weight of 152 (3) “Resists removal by sweating.” tant testing procedures. “Apply liberal­ g, had the hair of the back and stom­ (c) That satisfy the sweat resistance ly before sun exposure and reapply ach removed with an electric clipper. after 40 minutes in the water or after 2-Ethylhexyl 4-phenylbenzophenone- testing procedures. (1) “Retains its sun 2-carboxylic acid was then applied un­ protection for at least 30 minutes of excessive sweating.” (2) That satisfy the waterproof test­ diluted onto the shorn skin area. The heavy sweating.” test material was left on the skin area (2 “Sweat resistant.”) ing procedures. “Apply liberally before sun exposure and reapply after 80 for 24 hours and then rinsed with (3) Labeling guide for recommended water. Observations of the area tested sunscreen product use. The Panel rec­ minutes in the water or after excessive sweating.” gave an approximate LDso reading in ommends the following compilation of excess of 10,000 mg/kg (ref. 2). skin types and PCD’s be appropriately (3) That satisfy the sweat resistance Skin irritation was studied using six included in labeling as a guide: testing procedures. “Apply liberally before sun exposure and reapply after white New Zealand rabbits. Twenty- R ecommended S unscreen P roduct G uide four hours prior to the test, the backs 30 minutes of excessive sweating.” and flanks of the animals were shorn Sunburn and Tanning History and 2. Category II conditions under with an electric clipper. In three of Recommended Sun Protection Product which sunscreen ingredients are not the animals the skin was scarified with Always bums easily; never tans: Maximal, generally recognized as safe and effec­ razor blade cuts. 2-Ethylhexyl 4- ultra. tive or are misbranded. The Panel rec­ phenyl - benzophenone - 2' - carboxylic Always bums easily; tans minimally: Extra. ommends that the category II condi­ acid, undiluted and in the amount of Burns moderately; tans gradually: Moder­ tions be eliminated from OTC sun­ 0.5 ml, was applied to the left side of ate. screen drug products effective 6 the test animals. An equal amount of Burns minimally; always tans well: Minimal. months after the date of publication Rarely burns; tans profusely: Minimal. peanut oil was applied to the right of the final monograph in the F ederal side. The 2-ethylhexyl 4-phenylbenzo- c. Warnings—For all (minimal, mod­R e g is t e r . phenone-2'-carboxylic acid was rinsed erate, extra maximal, and ultra) sun­ away 24 hours after initial testing. All screen products. The labeling of all CATEGORY II ACTIVE INGREDIENTS the rabbits were observed daily for sunscreen products should contain the The Panel has classified the follow­ any skin changes or toxicity. In all following warnings: ing sunscreen ingredients not general­ rabbits tested, none showed any sign

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38255 of behavioral changes, altered general practically insoluble in water. It has a ed to 0.1 g of 3-(4-methylbenzylidene)- condition, or any sign of skin irritation melting point of 65° to 67° C. It ab­ camphor suspended in 0.1 ml peanut in either 2-ethylhexyl 4-phenylbenzo- sorbs UV radiation primarily at 280 to oil. the right eye, untreated, served as phenone-2'-carboxylic acid or in 315 nm (ref. 1). a control. The other three rabbits had peanut oil (ref. 2). (1) Safety. Clinical use and market­0.1 ml peanut oil placed in the con­ 2-Ethylhexyl 4-phenylbenzophen- ing experience are insufficient to con­ junctival sac of the left eye. The right one-2'-carboxylic acid was also tested firm that 3-(4-methylbenzylidene)- eye again was left untreated. The rab­ for primary mucosal irritation in rab­ camphor is safe for use as an OTC bits were examined daily for 6 days, bit’s eyes. Three male white New Zea­ sunscreen. and changes were recorded according land rabbits with an average weight of 3 - (4 - Methylbenzylidene) - cam­ to the Draize test evaluation. Observa­ 2 kg were used in the test. All animals phor was studied in 30 rats of the tions showed no eye reaction or irrita­ were preexamined to ensure no patho­ Wistar strain. An aqueous suspension tion in any of the rabbits tested (ref. logical states existed in the eye before of 3-(4-methylbenzylidene)-camphor 1). actual testing. A 0.1 ml volume of 2- was administered orally by means of Based on the lack of human clinical ethylhexyl 4-phenylbenzophenone-2'- an esophageal tube to the rats, in dos­ and marketing data, the Panel con­ carboxylic acid was then instilled into ages ranging from 10,000 mg/kg to cludes that 3-(4-methylbenzylidene )- the conjunctival sac of the left eye. 16.000 mg/kg. Observations recorded camphor is not a safe sunscreen ingre­ The untreated right eye served as a on days 1, 7, and 14 of the study dient for OTC use. control. There was no rinsing of the showed the approximate LDso to be in (2) Effectiveness. There are no stud­ eye after instillation of the test sub­ excess of 16,000 mg/kg (ref. 1). ies documenting the effectiveness of 3- stance. The eyes were examined for 6 In another study, the approximate (4-methylbenzylidene)-camphor as an days by evaluation methods proposed LDso of 3-(4-methylbenzylidene)-cam- OTC sunscreen. by Draize. No eye irritation was ob­ phor was determined by means of topi­ One manufacturer submitted a book­ served in any of the rabbits tested (ref. cal applications. Ten Wistar rats had let suggesting use of the ingredient as 21 the hair of the back and stomach re­ a UV filter for cosmetics. The booklet Based on the lack of human clinical moved with an electric clipper. The 3- contained in vitro absorption data in­ and marketing data, the Panel con­ (4-methylbenzylidene)-camphor was dicating an absorption maximum at cludes that 2-ethylhexyl 4-phenylben- moistened with an equal amount of de­ 300 nm. It was recommended that a 1 zophenone-2'-carboxylic acid is not a salinated water and applied to the to 2.5 percent concentration be used in safe sunscreen ingredient for OTC use. shorn skin area. The dosage applied to sunscreen products. (2) Effectiveness. There are no stud­ the skin was 10 g/kg. Twenty-four 3 - (4 - Methylbenzylidene) - cam­ ies documenting the effectiveness of 2- hours following initial application the phor absorbs UV light plainly in the ethylhexyl 4-phenylbenzophenone-2'- test area was rinsed with water and range of 280 to 315 nm. Testing has carboxylic acid as an OTC sunscreen. observed for 2 weeks, any changes in shown that the UV permeability of 3- One manufacturer submitted a book­ the test area were recorded according (4-methylbenzy lidene )-camphor dis­ let suggesting the ingredient as a UV to the method of Draize. Readings on solved in chloroform at a concentra­ filter for cosmetics. It was recommend­ days 1, 7, and 14 of the study showed tion of .0005 g/100 ml and at a thick­ ed that a 2 to 4 percent concentration an approximate LDso in excess of ness layer of 1 cm, ranges from 53 per­ be used in the sunscreen products. , 10.000 mg/kg. Rats autopsied at the cent at 280 nm to 39 percent at 310 nm 2- Ethylhexyl 4-phenylbenzophen- end of the 14 days showed no evidence (ref. 2). one-2'-carboxylic acid absorbs UV light of abnormality (ref. 1). Based on the lack of sufficient data, mainly in the range of 290 to 340 nm. Skin irritation was studied in six the Panel concludes that 3-(4-methyl- Testing has shown that the UV perme­ white New Zealand rabbits. The rab­ benzylidene)-camphor is not an effec­ ability of 2-ethylhexyl 4-phenylbenzo- bits were prepared 24 hours prior to tive sunscreen ingredient for OTC use. phenone-2'-carboxylic acid dissolved in the start of the study by shaving the (3) Evaluation. Based on the lack of methanol at a concentration of 0.001 back and upper flanks with an electric clinical and marketing experience, the g/100 ml and at a thickness layer of 1 clipper. Three of the six rabbits had Panel concludes that 3-( 4-methylben­ cm, ranges from 98 percent at 340 nm the test area scarified by means of a zy lidene )-camphor is not safe and not to 27 percent at 290 nm (ref. 1). skin scraper consisting of 10 razor effective for OTC use. Based on the lack of sufficient data, blades spaced 1 mm apart. Each blade the Panel concludes that 2-ethylhexyl had an exposed blade area of 0.5 mm. R eferences 4 - phenylbenzophenone - 2' - carboxylic All of the rabbits received, on the left (1) OTC Volume 060090. acid is not an effective sunscreen in­ half of the test area, 5 g of 3-(4-meth- (2) OTC Volume 060083. gredient for OTC use. ylbenzy lidene )-camphor moistened c. Sodium 3,4-dimethylphenyl-glyoxy- (3) Evaluation. Based on the lack of with water and spread on pads 4 centi­ late. The Panel concludes that sodium clinical and marketing data, the Panel meters square. The right half of the 3,4-dimethylphenyl-glyoxylate is not concludes that 2-ethylhexyl 4-phenyl- back received an equal amount of safe and not effective for OTC use as a benzophenone-2'-carboxylic acid is not talcum powder applied by the same sunscreen. safe and effective for OTC use. method. An occlusive bandage was Sodium 3,4-dimethylphenly-glyoxy- then applied to the area. After 24 late is also known as 3,4-dimethyl- R eferences hours of skin contact, the test materi­ phenyl-glyoxylic acid sodium salt. (1) OTC Volume 060090. al was removed and rinsed with water. It is a white powder with no discern­ (2) OTC Volume 060093. The rabbits were then observed daily ible odor. It is very soluble in water b. 3-( 4-Methylbenzylidene)-camphor. for 6 days. No sign of any skin irrita­ but practically insoluble in ethanol, The Panel concludes that 3-(4-methyl- tion was found in any of the animals ether, chloroform and benzene. It has benzylidene )-camphor is not safe and tested (ref. 1). a molecular weight of approximately not effective for OTC use as a sun­ Another test studied 3-(4-methylben- 232 with no sharp melting point (ref. screen. zylidene )-camphor for primary muco­ 1). 3- ( 4-Methylbenzylidene )-camphor issal irritation oh the rabbit eye. Six (1) Safety. Clinical use and market­ a white crystalline powder, having a white New Zealand rabbits, preexa­ ing experience are insufficient to con­ faint characteristic odor not resem­ mined to exclude any eye abnormali­ firm that sodium 3,4-dimethylphenyl- bling camphor. It is soluble in ethanol, ties, were used for the test. The left glyoxylate is safe for use as an OTC chloroform, and vegetable oils, though eye of three of the rabbits was subject­ sunscreen.

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38256 PROPOSED RULES

Safety data included a study in mice 5-(3,3-Dimethyl-2-norbomyliden-3-penten-2- nobenzoic acid was applied to the which showed the oral toxic dose to be one, backs of 200 white females, and ob­ 8.0 g/kg (tachypnea) and the intrave­ Dipropylene glycol salicylate. served for any irritation. The allan­ nous toxic dose to be 2.0 to 4.0 g/kg a. Allantoin combined with amino­ toin-aminobenzoic acid solution was (giddiness, dyspnea, etc.). It was re­ benzoic acid. The Panel concludes placed on a 0.5 inch square of white ported that 0.3 ml of a 10 percent that allantoin combined with amino­ blotting paper, applied to the back and aqueous solution was tolerated with­ benzoic acid is safe, but there are in­ then covered. An equal square using out any adverse reaction. sufficient data to determine effective­ dry, white blotting paper served as a Based on the lack of sufficient ness as an OTC sunscreen. Other control. The patches remained on the animal data and lack of human clinical names used for allantoin-aminobenzoic skin for 48 hours. Observations were and marketing data, the Panel con­ acid are allantoin-p-aminobenzoic acid recorded immediately and 20 minutes cludes that sodium 3,4-dimethyl- and ALP ABA. after removal of the patch. Readings phenyl-glyoxylate is not a safe sun­ Allantoin-aminobenzoic acid is a tan- were based on a scale ranging from no screen ingredient for OTC use. nish-white powder having a 1 percent reaction to vesiculation with edema. (2) Effectiveness. There are no stud­ solubility in water. Results from both time observations ies documenting the effectiveness of Information sumbitted to the Panel showed that all 200 subjects in the ir­ sodium 3,4-dimethylphenyl-glyoxylate refers to allantoin-aminobenzoic acid ritation test showed no reaction to al­ as an OTC sunscreen. as a complex (refs. 1 and 2). No data lantoin-aminobenzoic acid (refs. 1 and Based on the lack of any data, the were supplied by the manufacturer to 2 ). Panel concludes that sodium 3,4-di- show that there was complexation in­ Based on the available data, the methylphenyl-glyoxylate is not an ef­ volved between allantoin and amino­ Panel concludes that allantoin com­ fective sunscreen ingredient for OTC benzoic acid, or that any modification bined with aminobenzoic acid is safe use. had resulted which would alter in any for OTC sunscreen use. (3) Evaluation. Based on the lack of way the individual characteristics of (2) Effectiveness. There are no well- clinical and marketing experience, the the two parent compounds. The panel controlled studies docmenting the ef­ Panel concludes that sodium 3,4-di- recognizes that allantoin-aminoben­ fectiveness of allantoin combined with methylphenyl-glyoxylate is not safe zoic acid in combination has shown aminobenzoic acid as an OTC sun­ and not effective for OTC use. sun-screening activity equivalent to screen. aminobenzoic acid. However, studies One study using three females R eference do not show that addition of allantoin tested allanatoin-aminobenzoic acid (1) OTC Volume 060086. to aminobenzoic acid, forming a com­ for its sun-screening ability. Allantoin- bination, in any way contributes to the aminobenzoic acid was applied by in­ CATEGORY II LABELING activity of the molecule, insomuch as unction into a 3 inch by 4 inch area The Panel has examined the submit­ to influence sunscreen potential or and exposed to UV light by means of a ted labeling claims for sunscreens and skin protection. It is to be noted that Hanovia sun lamp. An equal skin area for combination products with non­ allantoin, used as a single entity and served as a control. Both areas were sunscreen ingredients and has placed not in the combination form, has been exposed to the UV light daily until certain claims into category II. shown to have protectant properties. slight hypermia was induced in the The Panel found no evidence for la­ The Panel has reviewed the data sub­ untreated area. After 5 continuous beling claims for sunscreen products mitted and concludes that further days of treatment, none of the sub­ such as “promote suntanning,” “accel­ testing is required to show the ratio­ jects tested showed any signs of edema erate suntanning,” “fast tanning,” nale of combining allantoin with ami­ in the areas treated with allantoin- “rapid tanning,” “give a deeper nobenzoic acid. aminobenzoic acid. Two of the three suntan,” “give a longer lasting (1) Safety. Clinical use and market­untreated patients tested showed evi­ suntan,” “give a deeper, darker ing experience have confirmed that al­ dence of hypermia (refs. 1 and 2). suntan,” “permits even tanning,” “in­ lantoin combined with aminobenzoic Another study compared the effec­ creases your ability to achieve a rich acid is safe in the dosage range used as tiveness of aminobenzoic acid with al­ satisfying tan.” The Panel concludes an OTC sunscreen. lantoin-aminobenzoic acid. Ten sub­ that a prudent person can obtain natu­ Studies demonstrating the safety of jects, eight women and two men, were ral tanning without the use of these aminobenzoic acid as a single ingredi­ exposed to the midday sun for a substances. Suntanning results from ent are discussed elsewhere. (See part period of 2 hours. Each subject was sun exposure, but these substances III. paragraph B.l.a. above—Amino­ prepared by taping to the back a tem­ lessen the likelihood of painful sun­ benzoic acid.) plate consisting of three rows of four burn from a consumer’s carelessness A toxicity test using allantoin com­ 1-inch square holes. Four of the holes or ignorance of sun exposure. There­ bined with aminobenzoic acid was per­ were covered with a thin film of 5 per­ fore, claims such as the above are clas­ formed on five mature rats of the Cas- cent allantoin-aminobenzoic acid sified as category II. worth strain. The weights of the rats cream. A second group of four holes 3. Category III conditions for which ranged from 200 to 240 g. The allan­ was covered by a thin film of 5 percent available data are insufficient to toin-aminobenzoic acid was ground aminobenzoic acid in 60 percent alco­ permit final classification at this time. and suspended in a physiological hol. The last four holes were used to The Panel recommends that a period saline solution to form a concentration determine the minimum erythema of 2 years be permitted for the com­ of 10 mg/0.5 ml. Subcutaneous doses dose. The holes containing aminoben­ pletion of studies to support the move­ of the test material were injected once zoic acid and allantoin-aminobenzoic ment of category III conditions to cat­ daily for 5 days under the loose skin of acid were closed at 30-minute intervals egory I. the back, and observations were made after initial exposure, and the holes for any signs of toxic symptoms. The testing minimum erythema dosage CATEGORY III ACTIVE INGREDIENTS rats were autopsied on the 7th day were closed at 5-minute intervals. Two The Panel concludes that the availa­ from the start of the testing. No hours following start of exposure, the ble data are insufficient to permit deaths or any signs of toxie symptoms test area was dried and checked for final classification of the following or reactions were observed in any of tape bums and allergies. Subjects took the rats tested (refs. 1 and 2). a warm showrer 6 hours later, following claimed sunscreen active ingredients: In another study, a patch test using which the results were recorded. A Allantoin combined with aminobenzoic acid, a 5 percent solution of allantoin-ami­ subsequent observation was made 24

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38257 hours after initial exposure for any average weight of 2 kg. The conjucti- after 24 hours. No reactions (irritation further untoward effects. vae of three of the rabbits were or reddening) occurred (ref. I). Readings from the test were varied, washed with 20 ml water, 2 seconds Based on the available data, the mainly due to difficulty in matching after application. In three other rab­ Panel concludes that 5-(3,3-dimethyl- erythema produced with tanning ob­ bits the conjunctivae were washed 2-norbomyliden)-3-penten-2-one is a served in both products tested. Both with 20 ml, but after 4 seconds; and safe sunscreen ingredient for OTC use. the allantoin-aminobenzoic acid and the last three rabbits’ conjunctivae (2) Effectiveness. There are no stud­ the aminobenzoic acid showed equiva­ were not washed following application. ies documenting the effectiveness of 5- lent sun screening protection (refs. 1 Observations recorded after 24 hours (3,3 - dimethyl - 2 - norbornyliden) - 3- and 2). showed that the three rabbits with no penten-2-one as an OTC sunscreen. Based on the available data, the conjunctival washing and one rabbit in The Panel received one submission Panel concludes that there are insuffi­ the 2 second washing developed a for the ingredient. The manufacturer cient data to determine the effective­ slight reddening of the conjuctivae indicated the ingredient ‘"had been ness of allantoin combined with ami­ and a slight swelling of the eye lids. At marketed as a sunscreen since 1973 in nobenzoic acid as a sunscreen for OTC 48 hours no clearly defined eye irrita­ concentrations varying from 0.5 to 2.5 use. tion could be observed in any of the percent. No effectiveness data were (3) Proposed dosage, (i) For products nine test animals (ref. 1). submitted. However, the manufacturer providing a minimum SPF value of 2 A sensitivity dermatological patch stated that “we are in the process of to under 4 containing 2 to 5 percent al­ test using 5-(3,3-dimethyl-2-norbomy- performing the efficacy tests recom­ lantoin-aminobenzoic acid: Adult and liden)-3-penten-2-one was applied to 50 mended by your panel.” In a more children over 2 years of age topical healthy personnel and 50 skin disease recent communication, the same man­ dosage is liberal application before sun patients of the University Dermatolo­ ufacturer indicated that other sun­ exposure and reapply after swimming gical Hospital, Goettingen, Germany. screens have replaced 5-(3,3-dimethyl- or after excessive sweating. There is Testing of both groups was accom­ 2- norbomyliden)-3-penten-2-one in no recommended dosage for children plished using 100 percent marketed products (ref. 1 ). under 2 years of age except under the 5 - (3,3 - dimethyl - 2 - norbornyliden )-3- Based on the available data, the advice and supervision of a physician. penten-2-one and a 5 percent concen­ Panel concludes that there are insuffi­ (ii) For products providing a mini­ tration in Eucerin anhydricum base. cient data to determine the effective­ mum SPF value of 4 containing 2 to 5 The test material was applied to the ness of 5-(3,3-dimethyl-2-norbomyli- percent allantoin-aminobenzoic acid: upper arm or back using small disks of den)-3-penten-2-one as a sunscreen in­ Adult and children over 6 months of test adhesive for a period of 24 hours. gredient for OTC use. age topical dosage is liberal applica­ Readings were taken at 24 and 48 (3) Proposed dosage, (i) For products tion before sun exposure and reapply hours, and observations were recorded providing a minimum SPF value of 2 after swimming or after excessive on an evaluation ranging from no reac­ to under 4 containing 0.5 to 2.5 per­ sweating. There is no recommended tion to blistering type of reddening. cent 5-(3,3-dimethyl-2-norbomyliden)- dosage for children under 6 months of The first reading (24 hours) showed 3- penten-2-one: Adult and children age except under the advice and super­ two test subjects with slight redden­ over 2 years of age topical dosage is vision of a physician. ing, one of them showing the slight liberal application before sun exposure (4) Labeling. The Panel recommends reddening from both the 5 and 100 and reapply after swimming or after the category I labeling for sunscreen percent concentration. The other of excessive sweating. There is no recom­ active ingredients. (See part III. para­ the two subjects was affected by the 5 mended dosage for children under 2 graph B.l. above—category I labeling.) percent concentration only. A 48-hour years of age except under the advice (5) Evaluation. Data to demonstrate observation showed no reaction. and supervision of a physician. effectiveness will be required in ac­ The second group consisting of the (ii) For products providing a mini­ cordance with the guidelines set forth 50 skin-diseased patients showed reac­ mum SPF value of 4 containing 0.5 to below for sunscreen active ingredients. tions in 7 of those tested. The 100 per­ 2.5 percent 5-(3,3-dimethyl-2-norbor- (See' part III. paragraph C. below— cent concentration gave six readings of nyliden)-3-penten-2-one: Adult and Data required for evaluation.) slight reddening alter 24 hours. Five children over 6 months of age topical of these patients showed no reaction dosage is liberal application before sun R eferences at the second reading at 48 hours; the exposure and reapply after swimming (1) OTC Volume 060117. other showed a slight increase in red­ or after excessive sweating. There is (2) OTC Volume 060147. dening. Another patient showed no re­ no recommended dosage for children b. 5-( 3,3-Dimethyl-2-norbomyliden )- action at 24 hours, but a slight redden­ under 6 months of age except under 3-penten-2-one. The Panel concludes ing at 48 hours. The 5 percent concen­ the advice and supervision of a physi­ thatr 5-(3,3-dimethyl-2-norbomyliden)- tration showed three patient reac­ cian. 3-penten-2-one is safe, but there are tions, all three of which had also (4) Labeling. The Panel recommends insufficient data available to permit reacted to the 100 percent concentra­ the category I labeling for sunscreen final classification of its effectiveness tion. Two test subjects showed slight active ingredients. (See part III. para­ for use as an OTC sunscreen as speci­ reddening at 24 hours, but only one graph B.l. above—category I Label­ fied in the dosage section discussed showed no reaction at 48 hours. The ing.) below. third subject showed increased red­ (5) Evaluation. Data to demonstrate (1) Safety. Clinical use and market­dening at both 24 and 48 hour read­ effectiveness will be required in ac­ ing experience have confirmed that ings (ref. 1). cordance with the guidelines set forth 5 - (3,3 - dimethyl - 2 - norbornyliden) - 3- In another test, 1 and 2 percent below for sunscreen active ingredients. penten-2-one is safe in the dosage 5 - (3,3 - dimethyl - 2 - norbornyliden )-3- (See part III. paragraph C. below— range used as an OTC sunscreen. penten-2-one was placed on the upper data required for evaluation.) Eye irritation was studied using the back of 20 test subjects. Six prepara­ R eference Draize method. The investigator ap­ tions in oil, oil in water, and water in plied 0.1 ml of a 3 percent solution of oil emulsions were used. Irradiation (1) OTC Volume 060120. 5 - (3,3 - dimethyl - 2 - norbornyliden) - 3 - was by means of four Ostran Ultravi- c. Dipropylene glycol salicylate. The penten-2-one in isopropyl myristate to talux bulbs placed 16 inches from the Panel concludes that there are insuffi- the conjuctival sacks of nine albino skin surface for a maximum time of cent data available to permit final rabbits. The rabbits tested had an 11.2 minutes. Readings were taken classification of the safety and effec-

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38258 PROPOSED RULES tiveness of dipropylene glycol salicy­ A technical bulletin was submitted C. DATA REQUIRED FOR EVALUATION late for use as an OTC sunscreen as describing the physical and chemical The Panel considers the protocols specified in the dosage section dis­ properties of dipropylene glycol salicy­ recommended in this document for cussed below. late. The spectral absorption of a 0.1 the studies required to bring a catego­ Dipropylene glycol salicylate is a percent solution showing different ry III ingredient into category I to be clear viscous liquid with a specific values depending upon the thickness in agreement with the present state of gravity of 1.16 and a faint yellow color. of the film was included. The ingredi­ the art, and does not intend to pre­ It is soluble in alcohols, blycolesters, ent appears to absorb UV radiation be­ clude the use of any advances or im­ ketones, and glycols. It is insoluble in tween 290 and 320 nm. The submission proved methodology in the future. water and mineral oil. also included military specifications 1. General comments. Because the (1) Safety. Clinical use has not con­ for a sunburn-preventive preparation first sunburn preventive drugs were in­ firmed that dipropylene glycol salicy­ (cream-base) which was dated January troduced in 1928, when a general late is safe in the dosage range used as 30, 1967. The composition of the prep­ knowledge of photobiology already ex­ an OTC sunscreen. aration is described as containing light isted, testing in the field has been Toxicity testing was performed using amber petrolatum, stearyl alcohol, based on sound scientific methodolo­ normal, healthy CFW mice of the Car- mineral oil, sesame oil, calcium stear­ gy. Because of the increased medical, worth strain. Weights ranged from 18 ate, kaolin, and a sunscreen agent. regulatory, scientific and social sophis­ to 21 g. The mice received dipropylene There are six sunscreen agents listed tication, the Panel is of the opinion glycol salicylate by means of a rigid as approved for use in the above for­ that certain standards of evaluation stomach pump in groups of 10, in mulation. One of these sunscreens are now appropriate to increase effica­ doses of 2.5, 3.75, 5 and 10 ml per kg. listed is dipropylene glycol stearate. cy and to increase consumer satisfac­ The mice were observed for a period of No other information is given. tion. When an ingredient is available 7 days. Six deaths were observed in Based on the lack of available data, for widespread use in OTC products, the 3.75 ml/kg dose, 7 deaths in the 5 the Panel concludes that there are in­ its safety and efficacy must be well-do­ sufficient data to permit final classifi­ cumented by data regarding its toxi­ ml/kg dose, and all 10 mice died at the cation of the effective use of dipropy­ 10 ml/kg dose. There were no mice cology, absorption, excretion, and lene glycol salicylate as an OTC sun­ pharmacologic action. The drug must deaths at the 2.5 ml/kg dose (ref. 1). screen. In another test, three normal, meet certain standards of efficacy. (3) Proposed dosage, (i) For products The Panel concludes that it is rea­ healthy albino rabbits had a 0.1 ml so­ providing a minimum SPF value of 2 lution of a 7 percent dipropylene sonable to allow 2 years for the devel­ to under 4 containing 3 to 7 percent di­ opment and review of evidence that glycol salicylate instilled into the right propylene glycol salicylate: Adult and eye. There was no rinsing of the eye or will permit iinal classification of the children over 2 years of age topical effectiveness of the category III ingre­ any other treatment given to the eye. dosage is liberal application before sun The left eye served as a control. Ob­ dients. The ingredients pose no safety exposure and reapply after swimming problems for the consumer. Marketing servations were recorded every 24 or after excessive sweating. There is hours for 4 days and again on the 7th need not cease during this time if ade­ no recommended dosage for children quate testing is undertaken. If data re­ day. The findings of this test showed under 2 years of age except under the garding adequate effectiveness and that cornea, conjunctival, and iris irri­ advice and supervision of a physician. safety are not .obtained within 2 years, tation was not observed in any of the (ii) For products providing a mini­ thé ingredients should no longer be rabbits tested (ref. 1). mum SPF value of 4 containing 3 to 7 marketed in OTC products. A skin sensitivity test using a 7 per­ percent dipropylene glycol salicylate: 2. Methods of study—a. Toxicological cent concentration of dipropylene Adult and children over 6 months of data. A variety of toxicological data glycol salicylate was applied to the age topical dosage is liberal applica­ can be obtained to demonstrate that a clipped intact and abraded skin of tion before sun exposure and reapply sunburn preventive is safe. The Panel three healthy normal albino rabbits. after swimming or after excessive recommends that the following data The abraded area was chafed with sweating. There is no recommended be obtained in appropriate studies on minor abrasions penetrating the stra­ dosage for children under 6 months of the final formulation to be marketed tum comeum, but not influencing the age except under the advice and super­ for topical application: derma. The dipropylene glycol salicy­ vision of a physician. (1) Patch tests. A number of patch late was applied in a 0.5 ml volume (4) Labeling. The Panel recommends test methods are applicable to human and then covered with surgical tape. the category I labeling for sunscreen safety testing of products. These tests Evaluation of the skin for edema, active ingredients. (See part III. para­ have proven valuable for predicting erythema, and escher formation were graph B.l. above—Category I Label­ skin irritancy and sensitization. The recorded at 24 and 72 hours after ap­ ing.) Panel recommends one of the follow­ plication. Observations showed no irri­ (5) Evaluation. Data to demonstrate ing methods of patch testing: tation at these times on both abraded effectiveness will be required in ac­ (i) The Draize human skin irritancy and intact skin (ref. I). cordance with the guidelines set forth and sensitization tests and its various No human safety data or marketing below for sunscreen active ingredients. modifications in which the subject’s data were submited or were available. (See part III. paragraph C. below— back or arm may be used (refs. 1 Based on the lack of available human Data Required for EvaluatiQn.) through 4Y, safety data, the Panel concludes that (ii) The method of Shelanski and there are insufficient data to permit R e f e r e n c e Shelanski (ref. 5); or final classification of the safe use of (1) OTC Volume 060134. (iii) The maximization procedure of dipropylene glycol salicylate as an Kligman (ref. 6). OTC sunscreen. CATEGORY III LABELING In the first two tests, the formula­ (2) Effectiveness. There are no stud­ The Panel was unable to identify tion is applied many times to the test ies documenting the effectiveness of any category III labeling. Suitable la­ site for 3 to 4 weeks. A 2-week rest dipropylene glycol salicylate as an beling claims for the five product cate­ period follows, and then a single chal­ OTC sunscreen. gories have been discussed elsewhere lenge application of the drug or for­ A manufacturer of the chemical in­ in this document. (See part III. para­ mulation is made. The early applica­ gredient submitted data not related to graph B.l. above—Category I Label­ tions are to detect primary skin irri­ a marketed product. ing.) tants, and the last dose is to detect al-

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 3825Î

Iergic skin sensitizers. The Kligman SPF value=MED (protected Skin (PS))/ down to room temperature (15 to 30 test uses sodium lauryl sulfate to irri­ MED (unprotected skin (US)) C). Add sufficient purified water tc tate the test site, thereby hastening where, MED (PS) is the minimal obtain 100 g of standard sunscreer and accentuating the allergic skin sen­ erythema dose for protected skin after preparation. sitizing potential of a substance. application of 2 mg/cm2 or 2 jil/cm2 of c. Assay of the standard homosalaL b. Effectiveness data. For proof of the final formulation of the sunscreen sunscreen. Assay the standard homo effectiveness of sunscreen active ingre­ product, and MED (US) is the minimal salate sunscreen preparation by the dients and formulations, the Panel erythema dose for unprotected skin, following method to ensure propei recommends sunscreen product testing i.e., skin to which no sunscreen prod­ concentration: procedures for determining the Sun uct has been applied. (1) Preparation of the assay solvent Protection Factor (SPF) value and re­ The SPF value is the value that can The solvent consists of 1 percent gla lated labeling claims. (See part III, be directly compared between individ­ cial acetic acid (V/V) in dénaturée paragraph D, below—Sunscreen Prod­ uals and between products. ethanol. The denatured ethano uct Testing Procedures for Determina­ 3. Standard sunscreen.—a. Labora­ should not contain a UV-absorbing de tion of the Sun Protection Factor tory validation. The use of standard naturant. (SPF) Value and Related Labeling sunscreens for testing purposes per­ (2) Preparation of a 1 percent solu Claims.) mits the direct comparison of results tion of the standard homosalate sun between laboratories to assure uni­ screen preparation. Accurately weigh R eferences form evaluation of sunscreen products. 1 g of the standard homosalate sun (1) Draize, J. H., in “Appraisal of the Comparing the mean SPF values be­ screen preparation into a 100 ml volu Safety of Chemicals in Foods, Drugs, and tween laboratories assures that the metric flask. Add 50 ml of the assaj Cosmetics,” Association of Food and Drug proper SPF value categorization of a solvent. Heat on a steam bath and mi> Officials of the United States, Austin, Tex., product is maintained. By comparing well. Cool the solution to room tem 1959. (2) Finkelstein, P., K. Laden, and W. Mie- the standard deviations of the mean perature (15 to 30° C). Then dilute the chowski, “Laboratory Methods for Evaluat­ SPF values between laboratories, the solution to volume with the assay sol ing Skin Irritance,” Toxicology and Applied relative precision of sunscreen testing vent and mix well to make a 1 percent Pharmacology, 7:74-78,1965. can be monitored. solution. (3) Lanman, B. M., W. B. Elvers, and C. S. A sunscreen preparation containing (3) Preparation of the test solution Howard, “The Role of Human Patch Test­ homosalate was tested by five labora­ (1:50 dilution of the 1 percent solu ing in a Product Development Program,” in tories in a cooperative trial using solar tion). Filter a portion of the 1 percent “Proceedings, Joint Conference on Cosmetic simulators (ref. 1). The information Sciences,” The Toilet Goods Association, solution through number 1 filtei Inc., Washington, D.C., pp. 135-145, 1968. accumulated from these studies makes paper. Discard the first 10 to 15 ml oi (4) Philips, L., II, M. Steinberg, H. I. Mai- this preparation a suitable standard the filtrate. Collect the next 20 ml o bach, and W. A. Akers, “a Comparison of for use in monitoring the tests for SPF the filtrate (second collection). Rabbit and Human Skin Response to Cer­ value of sunscreen products. This Add 1 ml of the second collection oi tain Irritants,” Toxicology and Applied preparation gave a mean SPF value of the filtrate to a 50 ml volumetric flask Pharmacology, 21:369-382,1972. 4.24 (standard deviation=1.14). The Dilute this solution to volume with (5) Shelanski, H. A., and M. V. Shelanski, Panel, therefore, recommends this assay solvent and mix well. This is th< “A New Technique of Human Patch Tests,” sunscreen preparation as a standard Proceedings Scientific Section, Toilet Goods test solution (1:50 dilution of the 1 Association, 19:46-4, 1953. sunscreen. percent solution). (6) Kligman, A. M., “The Identification of b. Preparation of the standard homo­ (4) Spectrophotometric détermina Contact Allergens by Human Assay,” Jour­ salate sunscreen. The standard homo­ tion. The absorbance of the test solu nal of Investigative Dermatology, 47:369- salate sunscreen is prepared from two tion is measured in a suitable double 374,1966. different preparations (part A and part B) with the following composi­ beam spectrophotometer with the D. SUNSCREEN PRODUCT TESTING PROCE­ tions: assay solvent and reference beam at £ DURES FOR DETERMINATION OF THE SUN wavelength near 306 nm. PROTECTION FACTOR (SPF) VALUE AND P reparation of P art A and P art B of the (5) Calculation of the concentration RELATED LABELING CLAIMS S tandard S unscreen of homosalate. The concentration ol homosalate is determined by the fol 1. Sunscreen active ingredients con­ part A lowing formula which takes into con tained in sunscreen products. The sidération the absorbance of the active sunscreen ingredients of the Ingredients Percent by sample of the test solution, the dilu product consist of one or more of the weight tion of the 1 percent solution to pre ingredients classified as Category I pare the test solution (1:50), the Homosalate...... 8.00 within any established, maximum White petrolatum...... 2.00" weight of. the sample of the standard daily dosage limit and the finished Stearic acid...... 3.00 homosalate sunscreen preparation (1 product provides an SPF value of not Stearyl alcohol._____ 2.00 g), and the standard absorbance value less than 2. Propylparaben...... 0.015 (172) of homosalate as determined bj 2. Sun protection factor (SPF) value. averaging the absorbance of a large An SPF value is defined as the UV PART B number of batches of raw homosalate energy required to produce a minimal Concentration of homosalate=absorbance erythema dose (MED) on protected Methylparaben ...... 0.025 x 50 x 100/1 x 172=percent concentratior skin divided by the UV energy re­ Sequestrene Na, (EDTA disodium)_____ 0.05 by weight. Sodium lauryl sulfate____ 0.50 quired to produce an MED on unpro­ Propylene glycol______12.00 4. Light source and light monitor tected skin. In effect, the SPF value is Purified water U.S.P...... 72.41 ing.—a. Artificial light source (solai the reciprocal of the effective trans­ simulator) and monitoring. A solar mission of the product viewed as a Part A and part B are heated sepa­ simulator for sunscreen testing shal] light filter. The UV light (UVL) rately to 77 to 82° C with constant stir­ be defined as a light source having: energy is measured by various photo­ ring until the contents of each part (1) A continuous emission spectrum detectors as described below. are solubilized. Add part A slowly to in the UV-B (290 to 320 nm); The SPF value may also be defined part B while stirring. Continue stirring (2) Less than 1 percent of its total by the following ratio: until the emulsion formed is cooled energy contributed by nonsolar wave

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 38260 PROPOSED RULES lengths (wavelengths shorter than 290 the investigator may use a color gauge, Joule (J)=lxl0 7 ergs=l watt.second nm); and a reflectometer, or a series of color- = 106 miCrowatt.second=2.4x10"4 kilo­ (3) Not more than 5 percent of its correcting red filters of increasing red calories. The UVL intensity of a solar erythemically effective energy contrib­ intensity. The filters are placed over simulator will be reported in J/m 2. uted by nonsolar wavelengths. the irradiated site where the correct b. Natural light source (sunlight) The instrument must be monitored filter will eliminate the erythema and and monitoring. Testing sunscreen periodically to assure that it delivers produce a uniform color. The reliabil­ products in sunlight offers several ad­ the appropriate spectrum described ity of reproducing results obtained vantages. The test situation more from such a system of filters would closely approximates the actual ways above. The monitoring procedure is the sunscreen product will be used by described below. have to be verified. In addition, it the consumer. The test subject is ex­ The xenon arc solar simulator is the would be difficult to translate such posed simultaneously to the full solar preferred artificial light source. Test data into SPF values unless there spectrum, the heat, and the humidity. data using other artifical light sources could be shown to be a 1:1 correlation Testing of several sunscreen products to establish the degree of efficacy at between a color filter and a known simultaneously can be done. An esti­ UV-B wavelengths of sunscreens must standard sunscreen. mation of tanning efficacy can be have corroborating natural sunlight (ii) The same dose of UV light pro­ made. Uncontrollable variables in out­ testing for acceptance. duces different intensities of erythema door testing include vagaries of the Xenon solar simulators presently in different people. This is why the weather, changing cloud cover, chang­ utilize xenon arcs from 150 to more MED must be determined for each ing radiation intensity with time, than 6,000 watts. For example, to pro­ subject whatever the light source. changing sun angle to the body sur­ duce 1 MED with a 150-watt lamp re­ (iii) Inherent differences in the face with time, and variable heat-in­ quires 120±30 seconds at the exit port erythemic exposure-color relationship duced sweating. Monitoring the of the instrument when the irradiated occur between individuals because the amount of exposure to natural sun­ site is 1 cm in diameter. Depending same dose of UV light causes different light is more difficult than for solar upon instrumental design, other irra­ degrees of erythema depending on the simulators. The vagaries of each envi­ diation sizes and times can be utilized. time or reading after exposure. ronment together with the changes in Solar simulators of 150 watts usually The advantages of a xenon lamp solar altitude with time make timing produce 10 or 12 solar constants. A solar simulator for in vivo testing in­ solar exposure inexact for determing solar constant is the total amount of clude the following: The continuous total erythemic exposure. If solar ex­ energy at all wavelengths per square spectrum mimics the sun in the UV posures based on time are utilized, the meter, available from the sun, at the range with comparable output over results of 1 day’s testing probably Earth’s surface. For example, if the the 290 to 400 nm range; a constant cannot be duplicated on another day. MED for a normal subject is 20 min­ spectrum at a constant angle with Recently, the Robertson-Berger utes of sunlight exposure, then the high output is obtained; and the lamp meter (R-B meter) (ref. 2) has proved solar simulator would produce an produces a stable spectrum over long successful in monitoring and reproduc­ MED of 2 minutes at 10 solar con­ use. ing solar erythemic exposures (ref. 3). stants in tlie same subjects. The more The disadvantages of using the An instrument of this type is recom­ powerful solar simulators can produce xenon lamp for in vivo testing include mended for monitoring all outdoor up to 40 solar constants. Irradiated the following: The full solar spectrum studies. Other recording radiometers sites more than 4 mm in diameter output is low in the visible and in­ are in use which permit continuous present no difficulty in determining frared wavelengths; using the xenon measurement of the sun’s intensity in J/m 2 (ref. 4). skin erythema. lamp is time consuming if only one The R-B meter records a measure of A solar simulator uses filters to test site can be irradiated at a time; the cumulative amount of UV radi­ absorb (cut off) the shorter UV wave­ and it is difficult to measure the ation that passes through its filters lengths which do not reach the earth’s output, but instrumentation is availa­ and photosensors after each 30-minute surface from the sun. The primary ble for this purpose. interval. Such 30-minute recordings filter is a suitable filter of colorless The xenon arc solar simulator can may range from 0 to slightly over glass, sharp cut in the UV grange, with be monitored. Calibrated thermopiles 1,000 depending on the geographical a °H (50 percent transmittance point) (instruments that measure the xenon location and the meteorological condi­ cut location approximately at 310 UV total output by converting it to tions prevailing at the test location. A nm±6. Dichroic or heat-absorbing fil­ heat energy) can be used to successful­ count of approximately 400 is estimat­ ters are used to reduce unnecessary ly measure the output of solar simula­ ed to produce one MED on the “typi­ visible and infrared radiation. tors. The total energy output (solar cal” Caucasian skin. Regardles of the light source em­ and nonsolar) of the xenon lamp solar 5. General guidelines for all testing ployed, some uncertainties in inter­ simulator can be measured by a ther­ procedures.— a. Selection of test sub­ preting results of in vivo testing, using mopile which should be accurate to 1 jects (male and female). Only fair-skin sunlight or artificial sources, include: percent. If the thermopile has a volunteers with skin types I, II, and (i) Between individual investigators window, it should be constructed of III, using the following guidelines, reading the minimal erythema dose re­ quartz. Such devices are accurate to at should be selected: sponse (MED) (the minimal percepti­ least 1 percent when properly used. ble erythema) on skin, the readings Other devices have been used to meas­ S election of F air-Sk in S ubjects vary ±20 percent. However, each indi­ ure solar simulators, including photo­ Skin Type and Sunburn and Tanning vidual investigator is remarkably con­ cells, photodiodes, photomultipliers, History 1 sistent after some experience. To par­ with and without filters. The basic re­ I— Always bums easily; never tains (sensi­ tially overcome the variation between quirements for a suitable monitoring tive). observers, the investigator indoors device are that they be stable for sev­ II— Always bums easily; tans minimally should use a constant light source like eral hours, be sensitive to UV-B radi­ (sensitive). an incandescent or a warm white flu­ ation, and provide values reproducible III— Bums moderately; tans gradually (light orescent lamp at a fixed distance and daily. brown) (normal). read the results on the subject in a The output of a solar simulator is room with white or light grey walls. measured in units of Joules. A Joule 1 Based on first 30 to 45 minutes sun expo­ No instrument has proven so reliable (J) is an absolute unit of work or sure after a winter season of no sun expo­ and consistent as the human eye, but energy equal to 1 million ergs. One sure.

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38261

IV— Burns minimally; always tans well which the test site area is exposed for tional subjects should be used to de­ (moderate brown) (normal). the determination of the MED as de­ termine the PCD, if a PCD does not V— Rarely bums; tans profusely (dark scribed below. fall within the limits of the standard brown) (insensitive). e. Application of test materials. To error. VI— Never burns; deeply pigmented (insensi­ tive). insure standardized reporting and to 6. Specific guidelines for all testing define a product’s SPP value, the ap­ procedures. The Panel has provided A medical history will be obtained plication of the product will be ex­ the following table of specific testing from each volunteer with emphasis on pressed on a weight basis per unit area procedures which are discussed more the effects of sunlight on his/her skin. which establishes a standard film. The fully below. To be ascertained are the general Panel recommends that the test sun­ health of the individual, the individ­ screen product and the sunscreen Summary of Sunscreen Testing Procedures ual's skin type (I, II, or III), whether standard application be 2 mg/cm2 or 2 for Determining Product labeling the individual is taking medication, ul/cm2. For some products, lesser topical or systemic, that is known to amounts may be justified based on in­ Type of test v Light1 Total test produce abnormal sunlight responses, tended usage. source time (min) e.g., declomycin or chlorpromazine, The specific gravity of the product is SPP Value...... i...... A i 2) and whether the individual is subject determined according to standard SPP Value...... N i 2) to any abnormal responses to sunlight, techniques. In testing situations, it is Sweat Resistance...... A 30 such as a phototoxic or photoallergic easier to accurately measure volumes Water Resistance...... A 40 response. for applications. Most sunscreen prod­ Waterproof...... A 80 b. Test site inspection. The physical ucts have a specific gravity near unity. 'A=artificial light source, N=natural light examination should determine the The 50 cm2 test site area previously source. presence of sunburn, suntan, scars, recommended above would require 100 ‘Variable. active dermal lesions, and uneven skin mg of a product or 100 ul (assuming a tones on the areas of the back to be specifc gravity of 1 to obtain a stand­ The Panel has not proposed tests to tested. The presence of nevi, blem­ ard 2 mg/cm2 test application. determine if a sunscreen product is ishes, or moles will be acceptable if in For oils and most lotions, the viscos­ water resistant, sweat resistant or wa­ the physician’s judgment they will not ity is such that the material can be ap­ terproof, using a natural light source interfere with the study results. plied with a volumetric syringe. For (sunlight), for several reasons. Excess hair on the back is acceptable creams, heavy gels, and butters, the There are three major difficulties if the hair is clipped or shaved. product is warmed slightly so that it with testing sunscreen products out­ Some investigators have found a re- can be applied volumetrically. On doors for water resistance, sweat resis­ flectometer useful to ensure uniform­ heating, care must be taken so as not tance, and waterproof claims. These ity of skin tone to the average skin re­ to alter the product’s physical charac­ are the lack of protection of the sub­ flectance in the test areas. Reflectance teristics, especially separation of the ject’s untreated skin against sunburn readings should not vary by more than formulations. Pastes and ointments during the long exposures, the deter­ 5 percent (refs. 4 and 5). should be weighed, then applied by mination of the quantity of sunlight c. Informed consent Legally effec­ spreading on the test site. Numerous striking the skin when immersed and tive written informed consent must be investigators have obtained more re­ penetrating the wet stratum comeum, obtained from each individual. producible results by spreading a prod­ and the maintenance of the protective d. Test site delineation.—(1) Test site uct using a finger cot than by spread­ template on the test site during water area. A test site area serves as an area ing with a glass or plastic rod. immersion. The exposed skin outside for determining the subject’s MED f. Waiting period. Before exposing the test sites can be protected by ap­ after application of either the sun­ the test site areas after applying a plying sunscreens between water im­ screen standard or the test sunscreen product, a waiting period is employed. mersions. Wet clothing usually trans­ product, or for determining the sub­ This waiting period will be at least 15 mits significant amounts of UVL. ject’s MED when the skin is unpro­ minutes, or depending upon the prod­ The Panel believes the testing of tected (control site). The area to be uct’s labeling to the consumer, the sunscreen products for water resis­ tested is the back between the beltline waiting period before testing will be tance, sweat resistance, and water­ and the shoulder blade (scapulae) and the amount of time specified on the la­ proof claims is easier and more repro­ lateral to the midline. The test site beling. . ducible in an indoor pool. The Panel areas may be horizontal or vertical, g. Number of subjects. The Panel rec­ believes that water immersion is a and rectangular or square. Depending ommends that groups of at least 20 more severe test of a sunscreen prod­ upon the test scheme, each test site subjects be used for each test panel. uct than is sweating. It, therefore, rec­ area for applying a product or stand­ One reason for the panel’s decision is ommends that the claim “Resists re­ ard control should be a minimum of 50 that the MED testing is done in 25 moval by sweating” is appropriate if cm2, e.g., 5x10 cm. The test sites are percent increments of exposure. The the product proves water resistant or outlined with ink. If the person is to 25 percent exposure increments are waterproof in the tests described be tested in an upright position, the reasonably close to the standard devi­ below. lines should be drawn on the skin with ations observed in test results (ref. 5). Because of the difficulties inherent the subject upright. If the subject is to The standard error for a 20-subject in sunlight water resistance, water­ be tested while prone, the markings test panel would be 25 percent divided by the square root of 20, i.e., proof and sweat resistance testing for should be made with the subject substantivity discussed above, the prone. Change of position between Standard error=(25 percent )/V20 Panel does not recommend that this marking and testing can change the The Panel agreed that a sunscreen method of testing be required. It does test area as much as 40 percent. product categorizes itself if the mean recommend that ways to test for sub­ (2) Test subsite area. Each test site of the SPF test values fall within the stantivity of sunscreen products area is divided into at least three test limits of a PCD as described elsewhere against water immersion and during subsite areas that are at least 1 cm2. in this doecument (see part II, para­ copious sweating in natural sunlight Usually four or five subsites are em­ graph A.7. above—Categories of sun­ be developed. ployed. Each test subsite area within a screen products.) The standard error a. Determination of SPF value using test site area is subjected for a time in­ should not exceed ± 5 percent of the artificial light source. This test deter­ terval, in a series of time intervals, in mean. An appropriate number of addi- mines the SPF value of a sunscreen

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38262 PROPOSED RULES product after UV-A and UV-B irradia­ materials when a suncreen is applied counts assures 3 MED’s in skin types I tion of the skin. to the exposed parts of the subject’s and II, and' 2 MED’s in normal skin A series of UV light exposures (units skin during the test. The subject will type III subjects. Greater exposures of time) are administered to the sub­ lie in the prone position in direct sun­ increase the risk of severe sunburn, sites on each volunteer with the solar light for a predetermined period of but provide little additional useful simulator. One series of exposures is time. The day of sun exposure may data. administered to the untreated, unpro­ not be the same for all subjects. How­ For test and standard sunscreen tected skin to determine the volun­ ever, sun exposure of individual sub­ products with different SPF values, teer’s inherent MED. The time inter­ jects will be completed during one con­ the dose of exposure will vary accord­ vals selected are a geometric series tinuous exposure period. Sun exposure ingly. Often a pilot study is performed represented by (1.25)", where in each of all subjects must be completed in three to six subjects to obtain the exposure time interval is 25 percent within 2 weeks for any one test and approximate SPF of a new product. greater than the previous time. The must be conducted at the same geo­ The SPF value of the test sunscreen reason for using the geometric se­ graphical location for any one test. using the R-B meter is calculated as quence of UV exposure is to maintain During each exposure, the sun intensi­ follows: the same relative uncertainity (ex­ ty will be measured continuously by a SPF value=exposure count interval (MED pressed as a constant percentage), in­ recording radiometer or a recording (PS))/exposure count interval (MED dependent of the volunteer’ sensitivity R-B meter. Empirically, approximate­ (US)). to UV light, regardless of whether the ly 6 x 10® Joules/m2, as measured by a subject has a high or low MED. One recording radiometer, will evoke 1 c. Determination of sweat resistance example is the time intervals of 1,1.25, MED in skin types I and II subjects using artifical light source. This test 1.56, 1.96, and 2.44 minutes. This series when read 16 to 24 hours later. Using determines the sweat resistance and would be suitable for a normal person the recording R-B meter, 400 counts substantivity of a sunscreen product exposed to the 150-watt xenon lamp are equivalent to 1 MED in skin type after 30 minutes of copious sweating solar simulator. Usually, the MED of a III subjects (ref. 3), and MED’s as low to substantiate the claim of sweat re­ person’s unprotected skin is deter­ as 200 counts may be expected of skin sistance. The claim as appropriate will mined the day prior to testing a prod­ type I. Duration of sun exposure will be allowed if the sunscreen product re­ uct. be documented in Joules/m2 or in R-B tains the same PCD, as described else­ The protected test sites (standard counts. Temperature and humidity where in this document, after the and/or test sunscreen product) usually will be measured in R-B meter counts. sweat test as before the sweat test. are exposed to UV light the next day. Temperature and humidity will be (See part II. paragraph A.7. above— The exact series of exposures to be measured at the beginning, the end, Categories of sunscreen products.) given is determined by the MED of and at the maximal sun intensity for The Panel concludes that a 30- the unprotected skin. For example, for the exposure period. Descriptive com­ minute period of copious sweating in­ the 8 percent homosalate standard ments about wind and cloud condi­ duced under controlled environmental sunscreen with an SPF of 4, the time tions will be made at times, but the conditions is an appropriate test for intervals to be selected are 4, 5, 6.24, primary measure of variations in cloud determinng sweat resistance and sub­ 7.84, and 9.76 minutes for a person stantivity claims of a sunscreen prod­ cover during exposure will be the con­ uct. If a subject fails to sweat profuse­ with an MED of 1.56 minutes on the tinuous radiometer or R-B meter unprotected skin. ly, he will be dropped from the study record. and another subject selected. The Specifically, what is needed is a At preestablished exposure times as MED of the unprotected test site area series of exposures of the sites in determined by the meter reading, the which the lower exposure times pro­ on each subject is determined using subsite areas of the test site area will the solar simulator. Usually the next duce no effect on the skin. Also, at 16 be exposed so that graded exposures to 24 hours later, the longer exposure day, the SPF of the test sunscreen will be obtained. Identical sequence of product is determined for each subject times should produce light and moder­ exposures will be administered to all ately red exposure sites. The MED is using the solar simulator. The same test sites. day or the next day the test sunscreen the time of exposure that produces The Panel has reviewed several sug­ the minimally perceptible erythema at product is applied. The subjects sit gested test protocols of varying design quietly in a controlled environment at 16 to 24 hours postexposure. The SPF that effectively determine the SPF of of the test sunscreen is then calculat­ a temperature of 35 to 38“ C (95 to a sunscreen product. One example test 100° F ) and a relative humidity of 70 ed from the exposure time interval re­ protocol follows. It assumes a subject quired to produce the MED of the pro­ to 80 percent. To prevent evaporative of skin type I with an MED of 15 min­ cooling of the skin with resulting de­ tected skin, and from the exposure utes, 4.5 x 10® Joules/m2, or 300 R-B time interval required to produce the creased sweating, there should be little meter counts (ref. 3). The study is a air movement. A few subjects may re­ MED of the unprotected skin (control controlled test of a sunscreen product, site), i.e., quire an air temperature of 105° F, a standard sunscreen product, and an with a relative humidity of 60 percent. SPF value=Exposure time interval (MED untreated control. For safety purposes, older persons • (PS))/Exposure time interval (MED With the protective template in should not be used. All subjects ex­ (US).) place, the approximate dose of sun ex­ posed to heat stress should have their b. Determination of SPF value using posure of individual subsites within pulse and temperature taken every 15 natural light source {sunlight). This the treated and unprotected test sites minutes. If a subject’s pulse exceeds test determines the SPF value of a were as follows: 160 counts per minute, and oral tem­ suncreen product in sunlight. Robertson-Berger Meter Counts {exposure perature of 38.9° C (102° F) or a rectal Applications will dry in at least 15 Count Intervals) {Ref. 3). 160, 213, 283, 376, temperature of 39.2° C (102.5° F ), the minutes or longer as specified on the 501, 666, and 886. subject’s participation must stop. labeling. Common practice utilizes an The R-B meter count intervals se­ The 30-minute test period begins opaque template or grid of opaque ma­ lected are a geometric series represent­ when the subject starts to sweat pro­ terials to cover the test sites to control ed by (1.33)", wherein each exposure fusely, drops or rivulets of sweat run­ the time exposures of the subsites to count interval is 33 percent greater ning down the test site. Most subjects the sun after the product has dried. than the previous exposure count in­ will sweat profusely within 10 minutes, The remainder of the back is covered terval. For the unprotected subsite, but a few may take up to 20 minutes with heavy toweling or other opaque usually a miximum of 800 R-B meter to develop copious sweating. After the

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38263

30-minute period of heavy sweating, 9:30—Apply sunscreen product (followed usually must also be produced. The the subject leaves the controlled envi­ by the waiting period after application of goal is to have some exposures that ronment, permits the test site area to the sunscreen product indicated on the produce absolutely no effect, while of air dry, and then the postsweating product labeling). those exposures that produce an 10:00—20 minutes moderate activity. SPP of the sunscreen product is deter­ 10:20—Rest period. effect, the maximal exposure should mined. The test sunscreen product 10:40—20 minutes moderate activity. be no more than twice the total must permit delivery of sweat through 11:00—Rest period. energy of the minimal exposure. The the film. No standard sweat resistant 11:20—20 minutes moderate activity. maximum exposure anticipated in product is available as yet. 11:40—Rest period. these tests corresponds to what most If the test sunscreen product retains 12:00—20 minutes moderate activity. 12:20—Conclude water test (air dry test individuals would describe as a light to the same PCD after the sweat test as sites without toweling). moderate sunburn. before the sweat test, the claim of 12:30—Begin solar simulator exposure to 8. Rejection of test data. These tests “sweat resistant” will be allowed. test sites in the manner described above. occasionally fail, and must be discard­ d. Determinating if a sunscreen is Sunscreen active ingredients dissolve ed. There are only the following two water resistant or waterproof using ar- much more slowly in seawater than in technical reasons for rejection of test tifical light source. This test deter­ freshwater because seawater contains data: mines the water resistance of a sun­ about 3 percent salts. Therefore, a a. Sometimes the exposure series screen product after 40 minutes of freshwater pool (21 to 32° C) should be fails to elicit an MED response on moderate activity (swim and play ac­ used. The Panel recommends that this either the treated or unprotected skin tivity) in water (swimming pool) to substantivity test should be conducted sites. In either event, that test is a substantiate the claim of water resis­ in an indoor pool to diminish the risk technical failure and must be discard­ tance, and after 80 minutes of moder­ of exposure to natural sunlight during ed. If the subject reacts to one or more ate activity to substantiate the claim the conduct of the test, especially in exposure on the unprotected control of waterproof. The claims as appropri­ skin types I and II. site, but not on the treated site, then a ate will be allowed if the sunscreen The solar simulator-exposed test site minimal estimate of the SPF can be product retains the same PCD, as de­ areas are read at 16 to 24 hours after obtained. scribed elsewhere in this document, exposure determine the SPF for the b. The responses on the treated sites after the test as before the test. (See subjects as described above. The Panel are randomly absent, which indicates part II., paragraph A.7. above—Cate­ the product was not spread evenly. gories of sunscreen products.) Because believes that a sunscreen product that it is impossible to produce even, con­ can withstand 80 minutes of water im­ Therefore, no assessment of protec­ trolled sweating among individuals, mersion can reasonably claim to be tion is possible. the Panel recommends that the claim waterproof. The Panel chose the 20- 9. Treatment of data. The SPF value “resists removal by perspiration” is ap­ minute water periods because some will be calculated for each test of a propriate if the product proves water unpublished marketing data revealed sunscreen product as follows: resistant or waterproof in the water that the average person goes into the a. Calculation of the SPF value from test. The Panel believes that water im­ water 3.6 times for an average dura­ data obtained in tests using a solar mersion is a more severe test of a sun­ tion of 21 minutes per immersion at simulator. The measurement units in screen product than is sweating. the beach or pool (Ref. 4). tests using a solar simulator to obtain No water resistant or waterproof 7. Response criteria. After UVL ex­MED’s for calculation of the SPF standard sunscreen product is availa­ posure to natural or artificial sources valuQ are time units, usually seconds. ble; so a standard sunscreen product is is completed, all immediate responses The following is an example of the cal­ not used in the test. are recorded. These include several culation of the SPF value from MED’s types of typical responses such as the obtained using a solar simulator: The Panel concludes that a 20- following: minute period of moderate activity in SPF value=Exposure time interval a. An immediate darkening or tan­ (MED(PS))/Exposure time interval the water in a swimming pool after ning, typically grayish or purplish in (MED(US)) the application of the test sunscreen color, fading in 30 to 60 minutes, and SPF value=180 seconds (MED(PS))/60 sec­ product, followed by a 20-minute rest attributed to photo-oxidation of exist­ onds (MED(US)) period, then a second 20-minute period ing melanin granules; of moderate activity is an appropriate b. Immediate reddening, fading rap­ Therefore, the SPF value=3. test for determining water resistance idly, and viewed as a normal response The PCD for a sunscreen product and substantivity claims of a sun­ of capillaries and venules to heat, visi­ with an SPF value of 3 would be cate­ screen product. The test site areas are ble and infrared radiation; and gorized as a minimal sun protection then exposed to the solar simulator. c. An immediate generalized heat re­ products because the SPF value of 3 is The pool and air temperature and the sponse, resembling prickly heat rash, more than a value of 2 and less than relative humidity should be recorded. fading in 30 to 60 minutes, and appar­ an SPF value of 4. A sample schedule of a water test for a ently caused by heat and moisture b. Calculation of the SPF value from water-resistant sunscreen product is as generally irritating to the skin’s sur­ data obtained in tests using a record­ follows: face. ing radiometer or a Robertson-Berger 9:30—Apply sunscreen product (followed After the immediate responses are by the waiting period after application of meter— (1) Recording radiometer. The the sunscreen product indicated on the noted, each subject shields the ex­ measurement units in tests using a re­ product labeling). posed area from further UV radiation cording radiometer are energy units, 10:00—20 minutes moderate activity. for the remainder of the test day. The Joules/m2. The following is an exam­ 10:20—Rest period MED is determined 16 to 24 hours ple of the calculation of the SPF value 10:40—20 minutes moderate activity after exposure. from MED’s obtained using a record­ 11:00—Conclude water test (air dry test Specifically, these tests depend upon ing radiometer: sites without toweling). determining the light energy corre­ 11:10—Begin solar simulator exposure to sponding to a minimally perceptible SPF value =Joules/m2 (MED(PS))/Joules/ test site area in the manner described above. erythema of a subject’s skin at 16 to m 2 (MED(US)) A sample schedule of a water test for 24 hours postexposure for each series SPF. value=28x106 Joules/m2 (MED(PS))/ a waterproof sunscreen product is as of exposures. To determine the MED, 6x 106 Joules/m 2 (MED(US)) follows: somewhat more intense erythemas Therefore, the SPF value=4.6.

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38264 PROPOSED RULES

The PCD for a sunscreen product 352.20 Combinations of sunscreen active wavelengths longer than 320 nano­ with an SPF value of 4.6 would be cat­ ingredients. meters. Such agents permit tanning in egorized as a moderate sun protection Subpart C— Testing Procedures the average individual and also permit product because the SPF value of 4.6 some reddening (erythema) without is more than a value of 4 and less than 352.40 Standard sunscreen. pain. ah SPF value of 6. 352.41 , Light source and light monitoring. (2) Robertson-Berger meter (R-B 352.42 General testing procedures. (c) Sunscreen opaque sunblock. An meter). The measurement units in 352.43 Determination of SPF value using opaque sunscreen active ingredient artificial light source. that reflects or scatters all light in the tests using a Robertson-Berger meter 352.44 Determination of SPF value using are counts. The following is an exam­ natural light source (sunlight). UV cind visible range at wavelengths ple of the calculation of the SPF value 352.45 Determination of sweat resistance from 290 to 777 nanometers and there­ from MED’s obtained using a Robert­ using artifical light source. by prevents or minimizes suntan and son-Berger meter: 352.46 Determination if a sunscreen is sunburn. water resistant or waterproof using arti­ (d) Sun protection factor (SPF) SPF value=Exposure count interval ficial light source. (MED(PS))/Exposure count interval value. An SPF value is defined as the (MED(US)) Subpart D— Labeling UV energy required to produce a mini­ SPF value=2,600 counts (MED(PS))/400 352.50 Labeling of sunscreen products. mal erythema dose (MED) on protect­ counts (MED(US)) ed skin divided by the UV energy re­ Authority: Secs. 201, 502, 505, 701, 52 Therefore, the SPF value=6.5. Stat. 1040-1042 as amended, 1050-1053 as quired to produce a MED on unpro­ amended, 1055-1056 as amended by 70 Stat. tected skin. In effect, the SPF value is The PCD for a sunscreen product 919 and 72 Stat. 948 (21 U.S.C. 321, 352, 355, the reciprocal of the effective trans­ with an SPF value of 6.5 would be cat­ 371) (5 U.S.C. 553, 554, 702, 703, 704). egorized as an extra sun protection mission of the product viewed as a product because the SPF value of 6.5 Subpart A— General Provisions light filter. The SPF value may also be is more than a value of 6 and less than defined by the following ratio: . § 352.1 Scope. an SPF value of 8. SPF value=MED (protected skin (PS)/MED An over-the-counter sunscreen prod­ (unprotected skin (US)). R e f e r e n c e s uct in a form suitable for topical ad­ (1) OTC Volume 060169. ministration is generally recognized as Where MED (PS) is the minimal (2) Proceedings of the Third Conference safe and effective and is not misbrand­ erythema dose for protected skin after on Climatic Impact Assessment Program, application of 2 milligrams per square February 26-March 1, 1974, DOT, TSC-OST ed if it meets each of the following 74-15. conditions and each of the general centimeter or 2 microliters per square (3) Measurement of Ultraviolet Radiation conditions established in § 330.1 of this centimeter of the final formulation of in the United States and Comparisons with chapter. the sunscreen product, and MED (US) Skin Cancer Data, U.S. Department of is the minimal erythema dose for un­ Health, Education, and Welfare, National § 352.3 Definitions. Institutes of Health (DHEW No. 76-1029), protected skin, i.e., skin to which no November 1975. (a) Product category designation sunscreen product has been applied. (4) OTC Volume 060158. (.PCD). A labeling designation for sun­ (5) OTC Volume 060166. screen products to aid in selecting the Subpart B— Active Ingredients type of product best suited to the indi­ The Food and Drug Administration vidual’s complexion (pigmentation) § 352.10 Sunscreen active ingredients. has determined that this document and desired response to ultraviolet The active ingredients of the prod­ does not contain an agency action cov­ (UV) light. uct consist of the following when used ered by 21 CFR 25.1(b) and considera­ (1) Mineral sun protection product. within the topical dosage limits estab­ tion by the agency of the need for pre­ Sunscreen products that provide an paring an environmental impact state­ lished and the finished product pro­ ment is not required. SPF value Of 2 to under 4, and offer vides a minimum SPF value of not less Therefore, under the Federal Food, the least protection, but permit sun­ than 2 as measured by the testing pro­ Drug, and Cosmetic Act (secs. 201, 502, tanning. cedure in subpart C of this part: 505, 701, 52 Stat. 1040-1042 as amend­ (2) Moderate sun protection product Aminobenzoic acid 5 to 15 percent. ed, 1050-1053 as amended, 1055-1056 Sunscreen products that provide an Cinoxate 1 to 3 percent. SPF value of 4 to under 6, and offer Diethanolamine p-methoxycinnamate 8 to as amended by 70 Stat. 919 and 72 moderate protection from sunburning, 10 percent. Stat. 948 (21 U.S.C. 321, 352, 355, 371) but permit some suntanning. Digalloyl trioleate 2 to 5 percent. and the Administrative Procedure (3) Extra sun protection product. Dioxybenzone 3 percent. Acts (secs. 4, 5, and 10, 60 Stat. 238 Ethyl 4-tbis(hydroxypropyl)] aminoben- and 243 as amended (5 U.S.C. 553, 554, Sunscreen products that provide an zoate 1 to 5 percent. 702, 703, 704) and under authority del­ SPF value of 6 to under 8, offer extra 2-Ethylhexyl 2-cyano-3, 3-diphenylacry- egated to him (21 CFR 5.1)), the Com­ protection from sunburning, and late 7 to 10 percent. missioner proposes that subchapter D permit limited suntanning. Ethylhexyl p-methoxycinnamate 2.0 to 7.5 of chapter I of title 21 of the Code of (4) Maximal sun protection product. percent. Federal Regulations be amended by Sunscreen products that provide an 2-Ethylhexyl salicylate 3 to 5 percent. SPF value of 8 to under 15, offer maxi­ Glyceryl aminobenzoate 2 to 3 percent. adding new part 352, to read as fol­ Homosalate 4 to 15 percent. lows: mal protection from sunburning, and Lawsone 0.25 percent with dihydroxyace- permit little or no suntanning. tone 3 percent. PART 352— SUNSCREEN PRODUCTS FOR (5) Ultra sun protection product. Menthyl anthranilate 3.5 to 5 percent. OVER-THE-COUNTER HUMAN USE Sunscreen products that provide an Oxybenzone 2 to 6 percent. SPF value of 15 or greater, offer the Padimate A 1 to 5 percent. Subpart A — General Provisions most protection from sunburning, and Padimate O 1.4 to 8.0 percent. Sec. permit no suntanning. 2-Phenylbenzimidazole-5-sulfonic acid 1 to (b) Sunscreen active ingredient. An 4 percent. 352.1 Scope. Red petrolatum 30 to 100 percent. 352.3 Definitions. active ingredient that absorbs at least 85 percent of the light in the UV Sulisobenzone 5 to 10 percent. Subpart B— Active Ingredients Titanium dioxide 2 to 25 percent. range at wavelengths from 290 to 320 Triethanolamine salicylate 5 to 12 per­ 352.10 Sunscreen active ingredients. nanometers, but transmits UV light at cent.

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38265 § 352.20 Combinations of sunscreen active (2) Preparation of a 1 percent solu­ controllable variables in outdoor test­ ingredients. tion of the standard homosalate sun­ ing include vagaries of the weather, ' Two or more sunscreen active ingre­ screen preparation. Accurately weight changing cloud cover, changing radi­ dients identified in § 352.10 may be 1 gram of the standard homosalate ation intensity with time, changing combined within the topical dosage sunscreen preparation into a 100 milli­ sun angle to the body surface with liter volumetric flask. Add 50 milliliter time, and variable heat-induced sweat­ limits established: Provided, The fin­ ing. A suitable meter should be used ished product provides a minimum of the assay solvent. Heat on a steam bath and mix well. Cool the solution for monitoring all outdoor studies. SPF value of not less than 2 as meas­ to room temperature (15 to 30° FC). ured by the testing procedures in sub­ Then dilute the solution to volume § 352.42 General testing procedures. part C of this part. with the assay solvent and mix well to (a) Selection of test subjects (male Subpart C— Testing Procedures make a 1 percent solution. and female). Only fair-skin volunteers (3) Preparation of the test solution with skin types I, II, and III using the § 352.40 Standard sunscreen. (.1:50 dilution of the 1 percent solu­ following guidelines shall be selected: (a) Laboratory validation. A stand­ tion). Filter a portion of the 1 percent S e l e c t io n o f F a ir S k i n S u b j e c t s ard sunscreen shall be used concomi­ solution through number 1 filter paper. Discard the first 10 to 15 millili­ Skin Type and Sunburn and Tanning tantly in the testing procedures for de­ History' termining the SPF value of a sun­ ters of the filtrate. Collect the next 20 screen product to assure the uniform milliliters of the filtrate (second col­ I— Always bums easily; never tans (sensi­ lection). Add 1 milliliter of the second tive). evaluation of sunscreen products. The II— Always burns easily; tans minimally standard sunscreen shall be an 8 per­ collection of the filtrate to a 50 millili­ ter volumetric flask. Dilute this solu­ (sensitive). cent homosalate preparation with a III— Bums moderately; tans gradually (light mean SPF value of 4.24 (standard de­ tion to volume with assay solvent and brown) (normal). viation =1.14). mix well. This is the test solution (1:50 IV— Bums minimally; always tans well (b) Preparation of the standard ho­ dilution of the 1 percent solution). (moderate brown) (normal). (4) Spectrophotometric determina­ V— Rarely bums; tans profusely (dark mosalate sunscreen. The standard ho­ tion. The absorbance of the test solu­ brown) (insensitive). mosalate sunscreen is prepared from tion is measured in a suitable double VI— Never bums; deeply pigmented (insensi­ two different preparations (prepara­ beam spectrophotometer with the tive). tion A and preparation B) with the assay solvent and reference beam at a A medical history shall be obtained following compositions: wavelength near 306 nanometers. from each volunteer with emphasis on C o m p o s i t i o n o f P r e p a r a t io n A a n d (5) Calculation of the concentration the effects of sunlight on their skin. P r e p a r a t io n B o f t h e S t a n d a r d S u n s c r e e n of homosalate. The concentration of To be ascertained are the general homosalate is determined by the fol­ health of the individual, the individ­ PREPARATION A lowing formula which takes into con­ ual’s skin type (I, II, or III), whether sideration the absorbance of the the individual is taking medication, Ingredients Percent by topical or systemic, that is known to weight sample of the test solution, the dilu­ ------:------♦ ------tion of the 1 percent solution to pre­ produce abnormal sunlight responses, Homosalate...... 8.00 pare the test solution (1:50), the and whether the individual is subject White petrolatum...... 2.00 weight of the sample of the standard to any abnormal responses to sunlight, Stearic acid...... 3.00 homosalate sunscreen preparation (1 such as a phototoxic or photoallergic Stearyl alcohol...... 2.00 response. Propylparaben...?...... 0.015 gram), and the standard absorbance value (172) of homosalate as deter­ (b) Test site inspection. The physical examination shall determine the pres­ PREPARATION B mined by averaging the absorbance of a large number of batches of raw ho­ ence of sunburn, suntan, scars, active dermal lesions, and uneven skin tones Methylparaben...... 0.025 mosalate: on the areas of the back to be tested. Sequestrene Ns* (EDTA disodium)...... 0.05 Sodium lauryl sulfate...... 0.50 Concentration of homosalate=absorbance The presence of nevi, blemishes, or Propylene glycol...... 12.00x 50 x 100/1 x 172=percent concentra­ moles will be acceptable if in the phy­ Purified water U.S.P...... ;...... 72.41 tion by weight. sician’s judgment they will not inter­ fere with the study results. Excess § 352.41 Light source and light monitor­ hair on the back is acceptable if the Preparation A and preparation B are ing. heated separately to 77 to 82° C with hair is clipped or shaved. constant stirring until the contents of (a) Artificial light source (solar sim­ (c) Informed consent. Legally effec­ each part are solubilized. Add prepara­ ulator). A solar simulator for sun­ tive written informed consent must be tion A slowly to preparation B while screen testing shall be defined as a obtained from each individual. stirring. Continue stirring until the light source having continuous emis­ (d) Test site delineation.— (1) Test emulsion formed is cooled down to sion spectrum in the UV-B (290 to 320 site area. A test site area serves as an nanometers) with less than 1 percent area for determining the subject’s room temperature (15 to 30° C). Add of its total energy contributed by non­ MED after application of either the sufficient purified water to obtain 100 solar wavelengths (wavelengths sunscreen standard or the test sun­ grams of standard sunscreen prepara­ shorter,than 290 nanometers) and not screen product, or for determining the tion. more than 5 percent of its erythemi- subject’s MED when the skin is unpro­ (c) Assay of the standard homosalatecally effective energy contributed by tected (control site). The area to be sunscreen. Assay the standard homo­ nonsolar wavelengths. The instrument tested shall be the back between the salate sunscreen preparation by the must be monitored periodically to beltline and the shoulder blade (scapu­ following method to ensure proper assure that it delivers the appropriate lae) and lateral to the midline. Each concentration: spectrum. test site area for applying a product or (1) Preparation of the assay solvent (b) Natural light source (sunlight). the standard sunscreen shall be a The solvent consists of 1 percent gla­ Sunlight more closely approximates minimum of 50 square centimeter, e.g., cial acetic acid (V/V) in denatured the actual ways the sunscreen product ethanol. The denatured ethanol will be used by the consumer. The test 1 Based on first 30 to 45 minutes sun expo­ should not contain a UV absorbing dé­ subject is exposed simultaneously to sure after a winter season of no sun expo­ naturant. the full solar spectrum. However, un­ sure.

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38266 PROPOSED RULES 5 x 10 centimeter. The test site areas heat and moisture generally irritating duces the minimally perceptible eryth­ are outlined with ink. If the person is to the skin’s surface. After the imme­ ema at 16 to 24 hours postexposure. to be tested in an upright position, the diate responses are noted, each subject The SPF value of the test sunscreen is lines shall be drawn on the skin with shall shield the exposed area from fur­ then calculated from the exposure the subject upright. If the subject is to ther UV radiation for the remainder time interval required to produce the be tested while prone, the markings of the test day. The MED is deter­ MED of the protected skin, and from shall be made with the subject prone. mined 16 to 24 hours after exposure. the exposure time interval required to (2) Test subsite area. Each test site Testing depends upon determining the produce the MED of the unprotected area shall be divided into at least 3 light energy corresponding to a mini­ skin (control site) as follows: test subsite areas that are at least 1 mally perceptible erythema of a sub­ SPF value=Exposure time interval (MED square centimeter. Usually 4 or 5 sub­ ject’s skin at 16 to 24 hours postexpo­ (PS))/exposure time interval (MED sites are employed. Each test subsite sure for each series of exposures. To (US)) are within a test site area is subjected determine the MED, somewhat more § 352.44 Determination of SPF value for a time interval, in a series of time intense erythemas must also be pro­ using natural light source (sunlight). intervals, in which the test site area is duced. The goal is to have some expo­ sures that produce absolutely no An opaque template or grid of exposed for the determination of the opaque materials shall be used to MED. effect, while of those exposures that produce an effect, the maximal expo­ cover the test sites in order to control (e) Application of test materials. To the time exposures of the subsite insure standardized reporting and to sure should be no more than twice the total energy of the minimal exposure. areas to the sun after the product has define a product’s SPF value, the ap­ dried. The remainder of the back shall plication of the product shall be ex­ (i) Rejection of test data. Test data shall be rejected if the exposure series be covered with heavy toweling or pressed on a weight basis per unit area other opaque materials when a sun­ which establishes a standard film. fails to elicit an MED response on either the treated or unprotected skin screen is applied to the exposed parts Both the test sunscreen product and of the subject’s skin during the test. the standard sunscreen application sites or if the responses on the treated sites are randomly absent, which indi­ The subject shall lie in the prone posi­ shall be 2 milligrams per square centi­ tion in direct sunlight for a predeter­ meter or 2 microliters per square cates the product was not spread evenly. mined period of time. The day of Sun centimeter. For oils and most lotions, exposure may not be the same for all the viscosity is such that the material § 352.43 Determination of SPF value subjects. However, sun exposure of in­ can be applied with a volumetric sy­ using artificial light source. dividual subjects shall be completed ringe. For creams, heavy gels, and but­ A series of UV light exposures (units during one continuous exposure ters, the product shall be warmed of time) are administered to the sub­ period. Sun exposure of all subjects slightly so that it can be applied volu- site areas on each volunteer with a shall be completed within 2 weeks for metrically. On heating, care shall be solar simulator. One series of expo­ any one test and shall be conducted at taken so as not to alter the product’s sures shall be administered to the un­ the same geographical location for any physical characteristics, especially sep­ treated, unprotected skin to determine one test. During each exposure, the aration of the formulations. Pastes the volunteer’s inherent MED. The sun intensity shall be measured con­ and ointments shall be weighed, then time intervals selected shall be a geo­ tinuously by a recording radiometer or applied by spreading on the test site metric series represented by (1.25)“, a recording Robertson-Berger meter. area. A product shall be spread by wherein each exposure time interval is Duration of sun exposure shall be doc­ using a finger cot. 25 percent greater than the previous umented in Joules per square meter or (f) Waiting period. Before exposing time to maintain the same relative un­ in Robertson-Berger meter counts. the test site areas after applying a certainty (expressed as a constant per­ Temperature and humidity shall be product, a waiting period of at least 15 centage), independent of the volun­ measured at the beginning, the end, minutes is required. teer’s sensitivity to UV light, regard­ and at the maximal sun intensity for (g) Number of subjects. Groups of at less of whether the subject has high the exposure period. Descriptive com­ least 20 subjects shall be used for each or low MED. One example is the time ments about wind and cloud condi­ test panel. A sunscreen product cate­ intervals of 1, 1.25, 1.56, 1.96, and 2.44 tions shall be made at times, but the gorizes itself if the mean of the SPF minutes. This series would be suitable primary measure of variations in cloud test values falls within the limits of a for a normal person exposed to the cover during exposure will be the con­ PCD. The standard error shall not 150-watt xenon lamp solar simulator. tinuous radiometer or Robertson- exceed ± } 5 percent of the mean. An Usually, the MED of a person's unpro­ Berger meter record. At preestablished appropriate number of additional sub­ tected skin is determined the day prior exposure times as determined by the jects shall be used to determine the to testing a product. The protected meter reading, the subsite areas of the PCD, if a PCD does not fall within the test sites (standard sunscreen and/or test site area shall be exposed so that limits of the standard error. test sunscreen product) usually are ex­ graded exposures will be obtained. (h) Response criteria. After UVL ex­ posed to UV light the next day. The Identical sequence of exposures shall posure to natural or artificial sources exact series of exposures to be given be administered to all test sites. The is completed, all immediate responses shall be determined by the MED of SPF value of the test sunscreen prod­ shall be recorded. These include sever­ the unprotected skin. For example, for uct using the Robertson-Berger meter al types of typical responses such as the 8 percent homosalate standard is calculated as follows: the following: An immediate darken­ sunscreen with an SPF value of 4.24, SPF value=Exposure count interval ing or tanning, typically greyish or the time intervals to be selected are 4, (MED(PS))/Exposure count interval purplish in color, fading in 30 to 60 5, 6.24, 7.84, and 9.76 minutes for a (MED(US)) minutes, and attributed to photo-oxi­ person with an MED of 1.56 minutes § 352.45 Determination of sweat resistance dation of existing melanin granules; on the unprotected skin. A series of using artificial light source. immediate reddening, fading rapidly, exposures of the sites in which the and viewed as a normal response of lower exposure times produce no A 30-minute period of copious sweat­ capillaries and venules to heat, visible effect on the skin is required. Also, at ing induced under controlled environ­ and infrared radiation; and an immedi­ 16 to 24 hours later, the longer expo­ mental conditions shall determine ate generalized heat response, resem­ sure times should produce light and sweat resistance and substantivity bling prickly heat rash, fading in 30 to moderately red exposure sites. The claims of a sunscreen product. A sub­ 60 minutes, and apparently caused by MED is the time of exposure that pro­ ject that fails to sweat profusely shall

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38267 be dropped from the study and an­ plication of the sunscreen product in­ may help reduce the chance of these other subject selected. The MED of dicated on the product labeling). harmful effects.” the unprotected test site area on each (2) 20 minutes moderate activity in (v) “Overexposure to the sun may subject shall be determined using the water. lead to premature aging of the skin solar simulator. Usually the next day, (3) 20 minute rest period. and skin cancer. The liberal and regu­ the SPF of the test sunscreen product <4) 20-minutes moderate activity in lar use over the years of this product is determined for each subject using water. may help reduce the chance of prema­ the solar simulator. The standard sun­ (5) Conclude water test (air dry test ture aging of the skin and skin screen is not used in this test. The sites without toweling). cancer.” same day or the next day the test sun­ (6) Begin solar simulator exposure to (2) Additional indications. In addi­ screen product is applied. The subjects test site areas in the manner described tion to the indications provided above sit quietly in a controlled environment above. in § 352.50(b)(1), the following may be at a temperature of 35 to 38° C (95 to A sunscreen product that can with­ used: 100° P) and a relative humidity of 70 stand 40 minutes of water immersion (i) For minimal sunscreen products: to 80 percent. To prevent evaporative may claim to be water resistant. (a) “Affords minimal protection cooling of the skin with resulting de­ (b) Procedure for testing the water­against sunburn.” creased sweating, there should be little proof claim of a sunscreen product. (6) “Prolongs exposure time before air movement. A few subjects may re­ The following procedure shall be used sunburn occurs.” quire an air temperature of 41° C (105° for the waterproof test: (c) “Permits tanning (or suntanning) F) with a relative humidity of 60 per­ (1) Apply sunscreen product (fol­ and reduces chance of (or minimizes) cent. For safety purposes, older people lowed by the waiting period after ap­ sunburning.” should not be used. All subjects ex­ plication of the sunscreen product in­ (d) “Helps prevent sunburn on limit­ posed to heat stress should have their dicated on the product labeling). ed exposure of untanned skin.” pulse" and temperature taken every 15 (2) 20 minutes moderate activity in (e) “Helps to protect the skin against minutes. If a subject’s pulse exceeds water. sunburn while permitting tanning.” 160 counts per minute, an oral tem­ (3) 20-minute rest period. (/) “Allows you to stay in the sun perature of 38.9° C (102° F), or a rectal (4) 20 minutes moderate activity in two times longer than without sun­ temperature of 39.2° C (102.5° F), his/ water. screen protection.” her participation shall stop. The 30- (5) 20-minutes rest period. (g) “Provides two times your natural minute test period begins when the (6) 20 minutes moderate activity in protection from sunburn.” subject starts to sweat profusely, water. (ii) For moderate sunscreen prod­ drops or rivulets of sweat running (7) 20-minutes rest period. ucts. (a) “Affords moderate protection down the test site. Most subjects will (8) 20 minutes moderate activity in sweat profusely within 10 minutes, but against sunburn.” water. (6) “Prolongs exposure time before a few may take up to 20 minutes to de­ (9) Conclude water test (air dry test sunburn occurs.” velop copious sweating. After the 30- sites without toweling). (c) “Permits tanning (or suntanning) minute period of heavy sweating, the (10) Begin solar simulator exposure subject leaves the controlled environ­ and reduces chance of (or minimizes) to test site areas in the manner de­ sunburning.” ment, permits the test site area to air scribed above. dry, and then the postsweating SPF of (d) “Helps prevent sunburn on mod­ the test sunscreen product is deter­ The solar simulator-exposed test site erate exposure of untanned skin.” mined. The test sunscreen product areas shall be read at 16 to 24 hours (e) “Allows you to stay in the sun must permit delivery of sweat through later to determine the SPF for the four times longer than without sun­ the film. If the-test sunscreen product subjects as described above. A sun­ screen protection.” retains the same PCD after the sweat screen product that can withstand 80 (f) “Provides four times your natural test as before the sweat test, the claim minutes of water immersion may claim protection from sunburn.” of “sweat resistant” will be allowed. to be waterproof. (iii) For extra sunscreen products, (a) “Affords extra protection against sun­ Subpart D— Labeling § § 352.46 Determining if a sunscreen is burn.” water resistant or waterproof using ar­ § 352.50 Labeling of sunscreen products. (6) “Prolongs exposure time before tificial light source. (a) Statement of identity. The label­ sunburn occurs.” The standard sunscreen is not used ing of the product contains the estab­ (c) “Permits limited tanning (or sun­ in the tests. An indoor fresh water lished name of the drug(s) identified tanning) and reduces chance of (or pool (23 to 32° C) shall be used in under §352.10 and identifies the prod­ minimizes) sunburn.” these testing procedures. uct as a “sunscreen.” (d) “Helps prevent sunburn.” (a) Procedure for testing the water (b) Indications. The labeling of the (e) “For sun-sensitive skin.” resistance of a sunscreen product. A product contains a statement of the (/) “Extra protection against sun­ 20-minute period of moderate activity indications under the heading burn for blondes, redheads and fair­ in the water in a swimmifxg pool after “Indication(s)” and is limited to one or skinned persons.” the application of the test sunscreen more of the following phrases: (g) “Allows you to stay in the sun six product followed by a 20-minute rest (1) For all (.minimal, moderate, times longer than without sunscreen period, then a second 20-minute period extra, maximal, and ultra) sunscreen protection.” of moderate activity shall be used to products, (i) “Sunscreen to help pre­ (h) “Provides six times your natural determine the water resistance and vent sunburn.” protection from sunburn.” substantivity claims of a sunscreen (11) “Filters (or screen) out the sun’s (iv) For maximal sunscreen prod­ product. The test site areas are then burning rays to prevent sunburn.” ucts. (a) “Affords maximal protection exposed to the solar simulator. The (iii) “Screens out the sun’s harsh against sunburn.” pool and air temperature and the rela­ and often harmful rays to prevent (&) “Prevents sunburn and limits tive humidity shall be recorded. sunburn.” tanning.” The following procedure shall be (iv) “Overexposure to the sun may (c) “For sun-sensitive skin.” used for the water resistance test: lead to premature aging of the skin (d) “Maximal protection against sun­ (1) Apply sunscreen product (fol­ and skin cancer. The liberal and regu­ burn for blondes, redheads and fair­ lowed by the waiting period after ap­ lar use over the years of this product skinned persons.”

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978 38268 PROPOSED RULES (e) “Allows you to stay in the sun and children over 6 months of age: lowing appropriate labeling statement eight times longer than without sun­ Apply liberally before sun exposure shall be prominently placed on the screen protection.” and reapply after swimming or after principal display panel of the prod­ (f) “Provides eight times your natu­ excessive sweating. There is no recom­ ucts: ral protection from sunburn.” mended dosage for children under. 6 (1) Products containing active (v) For ultra sunscreen products, (a) months of age except under the advice “Affords the most protection against and supervision of a physician. ingredient(s) that provide an SPF sunburn.” (2) For all (minimal, moderate, value of 2 to under 4: “Minimal Sun (6) “Prevents tanning and sunburn.” extra, maximal, and ultra) sunscreen Protection Product (SPF 2)—Stay in (c) “For highly sun-sensitive skin.” products—(i) That satisfy the water re­ the sun twice as long as before with­ id) “Greatest protection against sun­ sistant testing procedures. “Apply lib­ out sunburning.” burn for blondes, redheads, and fair­ erally before sun exposure and reap­ (ii) Products containing active skinned persons.” ply after 40 minutes in the water or ingrediente) that provide an SPF (e) “Provides the highest degree of after excessive sweating.” sunburn protection and permits no (ii) That satisfy the waterproof test­ value of 4 to under 6: “Moderate Sun tanning.” ing procedures. “Apply liberally before Protection Product (SPF 4)—Stay in (f) “Provides the highest degree of sun exposure and reapply after 80 the sun 4 times as long as before with­ sunscreen protection and permits no minutes in the water or after excessive out sunbuming.” tanning.” sweating.” (iii) Products containing active (3) For all (maximal and ultra) sun­ (iii) That satisfy the sweat resistance ingredient(s) that provide an SPF screen products that contain sun­ testing procedures. “Apply liberally value of 6 to under 8: “Extra Sun Pro­ screen opaque sunblock ingredients. before sun exposure and reapply after tection Product (SPF é)—Stay in the “Reflects the burning rays of the 30 minutes of excessive sweating.” sun.” (3) For sunscreen products contain­ sun 6 times as long as before without

FEDERAL REGISTER, VOL. 43, NO. 166— FRIDAY, AUGUST 25, 1978 PROPOSED RULES 38269

R ecommended S unscreen P roduct G uide be accompanied by a supporting memorandum or brief. Comments re­ Sunburn and tanning Recommended plying to comments may also be sub­ history sun mitted on or before December 26, protection 1978. Comments may be seen in the product above office between 9 a.m. and 4 p.m., Monday through Friday. Always burns easily; never tans...... Maximal, Ultra. In accordance with Executive Order Always bums easily; tans minimally.... Extra. 12044, the economic effects of this Burns moderately; tans gradually...... Moderate. proposal have been carefully analyzed, Bums minimally; always tans well...... Minimal. and it has been determined that the Rarely bums; tans profusely...... Minimal. proposed rulemaking does not involve major economic consequences as de­ Interested persons are invited to fined by that order. A copy of the reg­ submit their comments in writing ulatory analysis assessment support­ (preferably in quadruplicate and iden­ ing this determination is on file with tified with the Hearing Clerk docket the Hearing Clerk, Food and Drug Ad­ number found in brackets in the head­ ministration. ing of this document) regarding this proposal on or before November 24, Dated: August 8, 1978. 1978. Such comments should be ad­ dressed to the Office of the Hearing S h e r w i n G a r d n e r , Clerk (HFA-305), Food and Drug Ad­ Acting Commissioner of ministration, Room 4-65, 5600 Fishers Food and Drugs. Lane, Rockville, Md. 20857, and may [FR Doc. 78-22963 Filed 8-24-78; 8:45 am]

FEDERAL REGISTER, V O L 43, NO. 166— FRIDAY, AUGUST 25, 1978