Document 3eEGvaJbgKjLn4ZXe2DV1Lg9D

2. vi.v i^u J.UKX uor. uti.L.j. AR226-2963 Du Font HLO 433-91 Study Title Skin Sensl.tlzation Test vith^BBBw?111 Guinea Pigs Study Completed On August 14, 1991 Contracting Laboratory Pharmakon Research International, Inc. P.O. Box 313 Waverly, Pennsylvania 18471 Author Susan Armondi for Haskell E. I. du Font de Nemours and Company Laboratory for Toxicology and Industrial Elkton Road, P. 0. Box 50 Newark, Delaware 19714 Medicine Study Monitor Scott E. Loveless Medical Research No. Laboratory Project ID Haskell Laboratory Report No. 433-91 Page 1 of company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 COMPLIANCE STATEMENT This study Laboratory Pwaras cctiocnedsuc(tGedLP)inascopmrpolmiaunlcgeatewdithbyththeePfroinllcoiwpilnegs of Good regulatory agencies: RU.eSg.isFtoeord, a2n1dCDFRrugPaArtdm58in, isFtrriadtaioyn, , Saesptesmtabteerd4,in 1t9h8e7. Federal U.S. Environmental Protection Agency Register, 40 CFR, Part 792, Thursday as stated in the August 17, 1989. Federal UFe.Sd.erEanl vRireognimsteenrt,al 40PrCoFtRe,ctiPoanrtA1g6e0n,cyTahsurssdtaatye, dAiungutshte 17, 1989. GOurgidaenliiznaetsionfofroTr eEsctionngomCicheCmoic-oalpser(aOtEioCnD)a, ndISBDNevelopment 12221-4, adopted by the council at its 92-64 535th meeting on 12th May, 1981. Study No.: "To the best of accordance with my knowledge, this study was conducted in applicable Good Laboratory Practice regulations; there study were no deviations conclusions." from these regulations that impacted on /dwxw(f,d^wrU- Study Director ; A,0^3,m/ Date(r7j7 Company Sanitized. Does not contain TSCA CBI Material Tested: Medical Research No. Haskell No.; Haskell Test Code No. Pharmakon Study No.: Physical Form; Purity; Composition; GENERAL INFORMATION Test Material 18,920 Uu Font HLO 433-91 Synonyms: Other Codes: Contaminants; CAS Registry Number: Stability; In the absence of visible evidence to the contrary, the test material was assumed to be stable under the conditions of administration. q __ - - Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 GENERAL INFORMATION (CONT.) Material Tested; Purity; Synonyms; Positive Control Material N-Phenyl-.!,4-Phenylenediamine o 1,4-Benzenediamine o p.-phenylenediamine o PPD Other Codes; CAS Registry No.; o Aldrich Chemical Co., Lot #05012MK ,o Aldrich Chemical Co., Catalog #24139-3 101-54-2 Stability: Sponsor; In the absence of visible evidence to the contrary, the test material was assumed to be stable under the conditions of administration. '''. ^ Du Font Chemicals ^ I. E. du Font de Nemours and Company " ^ffilmington, Delaware .* Materials Submitted By: Pharmakon Notebook No.; ' K. Spencer Prowse ^ ' Du Font Chemicals I. E. du Font de Nemour^ and *, 'Jackson Laboratory ^ :. ' Deepwater, New Jersey i Company 1470, pp. 389? 392, 395, and 399 1489, pp.,13-29 Study Initiated - Completed: 4/11/91 - 8/14/91 In-Life Phase Initiated - Completed; 4/29/91 - 6/14/91 There are 68 pages in this report. Distribution: 4 - Company Sanitized. Does not contain TSCACBI Company Sanitized. Does not contain TSCA CBI Company Sanitized. Does not contain TSCA CBI DU Font PHARMAKON RESEARCH INTERNATIONAL. INC. WAVERLY. PENNSYLVANIA 18471 HLO 433-91 PHONE (717)586-2411 FAX (717) 586-3450 Skin Sensitization Test with H-18,920 in Guinea Pigs Submitted to E. I. Du Pont De Nemours Newark, Delaware mdf^G- g/?/m Susan E. Armondi, LAT Study Director Test Facility Managfertent Date \hla^,mi Date /y/ /^/ /^ Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 Skin Sensitization Test with H-18.920 In Guinea Pigs SUMMARY Test Article H-18,920 at an induction concentration of 1.0% (w/v) and challenge and rechallenge concentrations of 100% and 10% (w/v) in distilled water was tested on the clipped, intact skin of male and female guinea pigs. p-Phenylenediamine (PPD) as a 35% (w/v) suspension in distilled water was used to demonstrate the ability of the test system to detect a skin sensitizer (positive control group). Distilled water served as a vehicle control. During the primary irritation phase, no dermal irritation was observed in vehicle control animals. No signs of erythema were observed at 24 or 48 hours in animals receiving the test article at 10% or 100% concentrations. No erythema was observed in positive control animals receiving PPD at a 35% concentration. During the challenge phase, no to severe erythema was observed in the positive control group treated with p-phenylenediamine at a 35% concentration. Slight erythema was observed in one test article-treated animal at the 100% concentration site at 24 hours. One animal exhibited severe erythema at the 100% site at 24 hours with mild erythema at 48 hours. Slight erythema was observed in the same test article-treated animal at the 10% concentration site. No signs of erythema were observed in vehicle or negative control animals. Due to the spurious positive response observed in one animal at challenge, all test article-treated animals, along with an additional group of five naive control animals (2 males and 3 females), were rechallenged with test article at 100% and 10% concentrations. Slight erythema was observed at 24 hours in one test article-treated animal at the 100% concentration site. Nosigns of erythema were observed at 24 or 48 hours after rechallenge in test article-treated animals at 10%. No signs of erythema were observed at 24 or 48 hours in naive control animals at the 100% or 10% concentration sites. 7 Company Sanitized. Does not contain TSCA CBI Du Font HDD 433-91 Under the conditions of this study protocol, H-18,920 produced weak delayed contact hypersensitivity in one guinea pig at a 100% concentration at challenge. Delayed contact hypersensitivity was not observed at 10% after challenge. During rechallenge, H-18,920 did not produce sensitization at 100% or 10% concentrations. Rechallenge results did not reinforce the spurious response observed at challenge, and after evaluation of all data, H-18,920 did not produce Delayed Contact Hypersensitivity in Guinea Pigs. The results of the rechallenge support that the reaction observed at challenge was indicative of irritation and not sensitization. Work by: /y /^ y^ / (^^X^ ^^<^^d^/ ^farles Boyarsky^/^ Technician ^ y Study Director: U/if}^^ A[MU)G .A^A/JuAO U . IA/I ^OlQfL^ Susan E. Armondi, LAT Reviewed and Approved for Issue: /W//liA.^,,UM-) (/(^^. Wf/j ^wT^/^ ' Susan E. Armondi, LAT Study Director Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 QUALITY ASSURANCE UNIT STATEMENT Study Director: Susan E. Armondi This study was conducted in compliance with the Good Laboratory Practice Regulations. The Quality Assurance Unit conducted the inspections listed below and reported the results to the study director and to management on the dates indicated. The following inspections were performed: Interval Date In Life Phase April 29, 1991 Reporting Phase July 23, 1991 Date OAU Report Issued: To Study Director July 23, 1991 To Management July 23, 1991 ^^.^PAA^JJ/ QITIusal lI i"t^yir Assurance 71 tft-^T*l'QM/^^^ v W^3/97/ Dat^T^T Company Sanitized. Does not contain TSCA CBI Du Pont HLO 433-91 INTRODUCTION The purpose of this study was to evaluate the potential of H-18,920 to produce delayed hypersensitivity or allergic reactions when applied to the skin of guinea pigs. Sensitization was defined as a significant score increase at challenge over the response observed after the primary application of the test material to the test guinea pigs, or the response observed in the negative controls. A significant score increase defined as a 2-or-more step increase (e.g., from 0 to 2, from 1 to 3, etc.) has been used at Haskell Laboratory as the criterion in this study protocol to identify compounds that are sensitizers. The sensitivity of the test system to detect chemical sensitizers was evaluated with pphenylenediamine. This study was conducted according to Good Laboratory Practice Regulations as listed on page 2 of this report. Areas of noncompliance are documented in the study records. No deviations existed that significantly affected the validity of the study. MATERIAL AND METHODS A. Animal Husbandry Young adult male and female Duncan Hartley albino guinea pigs were received from BuckberG Lab Animals, Tomkins Cove, New York. The guinea pigs were housed singly in suspended, stainless steel, h11 wire-mesh cages. Each guinea pig was assigned a unique identification card on which the animal number, study number, dose level and sex were recorded and affixed to the cage. Guinea pigs were ear tagged. Purina Certified Guinea Pig Chow" #5026 and water were available ad libitum. Guinea pigs were acclimated and observed for general health during a period of approximately five days. Animal rooms were maintained on a timer-controlled, 12-hour light/12-hour dark cycle. Environmental conditions of the rooms were targeted for a temperature of 22 3C (66- 77F) and relative humidity of 30% - 70%. Any excursions outside these ranges were of small magnitude and/or brief duration and did not adversely affect the validity of the study. B. Protocol A copy of the signed original protocol is attached in Appendix A. A preliminary range-finding test was conducted to estimate the primary irritation potential of the test material. The results of the range-finding studies were used to select the exposure concentrations for the main study. The main sensitization study consisted of 4 phases: a primary irritation phase, an induction phase, a challenge phase and a rechallenge phase. During each phase, skin responses were scored according to the system presented in Table I. During the study, body weights were recorded weekly. 10 Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 The topical range-finding test was conducted on 2 male and 1 female guinea pigs ranging in weight from 318-332 grains. Aliquots (approximately 0.05 mL) of 1.0%, 10%, 50% and 100% (w/v) suspensions of the test material in distilled water were applied and lightly rubbed onto four separate test sites .on the clipped, intact skin of the back of each animal. The primary irritation phase was conducted in 10 guinea pigs (5 males and 5 females), weighing from 400-440 grams, by applying and lightly rubbing in 1 drop (approximately 0.05 mL) of 100% and 10% (w/v) suspensions of the test material in distilled water onto two separate sites of the clipped, intact skin of each animal. In addition, 10 positive control guinea pigs (5 males and 5 females), weighing from 401-451 grams, were treated by applying and lightly rubbing in 1 drop of a 35% (w/v) suspension of p-phenylenediamine in distilled water onto the clipped, intact left shoulder skin of each animal. Five vehicle control guinea pigs (3 males and 2 females), weighing from 406-441 grams, were treated with distilled water in the same manner at one site only. Dermal responses were scored approximately 24 and 48 hours after application of the test material. Two days after the primary dermal irritation phase, the induction phase of the study was initiated using the same 10 test guinea pigs in which primary irritation had been evaluated. Induction consisted of a series of 4 intradermal applications (1 each week) of 0.1 mL of the test material at a 1.0% (w/v) concentration in 0.9% saline. A virgin site on the back of each animal was used for each induction. The same induction procedure was followed for the 10 positive control guinea pigs using 0.1 mL of a 1.0% (w/v) solution of p-phenylenediamine in saline. The vehicle control animals were similarly treated with 0.1 mL saline. Skin responses were evaluated approximately 24 hours after each induction. Approximately two weeks after the last induction treatment, the test guinea pigs were challenged for sensitization by applying and lightly rubbing in 1 drop (approximately 0.05 mL) of 100% and 10% (w/v) suspensions of the test material in distilled water onto two separate sites of clipped, intact shoulder skin. The sites used during challenge were the same used on each animal during the. primary dermal irritation phase, respectively. The positive control animals were challenged for sensitization by applying and lightly rubbing in 1 drop of a 35% (w/v) suspension of pphenylenediamine distilled water onto one site of clipped, intact skin. The vehicle control animals were treated at one site with distilled water, in the same manner. Also, 2 male and 3 female previously untreated guinea pigs, weighing 410-450 grams at study initiation, were treated by applying 1 drop each of 100% and 10% (w/v) suspensions of the test material in distilled water onto two separate sites of clipped, intact skin and served as negative 11 Company Sanitized. Does not contain TSCA CB) DU Font HLO 433-91 control animals. In addition, these animals received 1 drop of distilled water and 1 drop of p-phenylenediamine at 35%. These animals also served as negative control animals for the vehicle and positive control materials. Seven days following the primary challenge, all test article- treated animals, along with an additional group of five negative control animals (2 males and 3 females) were rechallenged with the test article at 100% and 10% concentrations. C. Records Retention All raw data and the final report will be stored in the archives of Pharmakon Research International, Inc., Waverly, PA. RESULTS AND CONCLUSIONS Weekly body weights are presented in Appendix B. A copy of the raw data is presented in Appendix C. In the range-finding test, no signs of erythema were observed. Based upon the results of the range-finding study, the test article was dosed as received, and as per protocol, dose concentrations used for the primary- irritation phase were 100% and 10%. The dose concentration used for induction was 1% and as per protocol, dose concentrations chosen for challenge and rechallenge were 100% and 10%. During the primary irritation phase, no signs of erythema were observed in the test article-treated animals at 100% or 10% concentration sites. No erythema was observed in positive control animals. No erythema was observed in vehicle control animals receiving distilled water. Individual animal data are presented in Table II. During the induction phase, no to mild erythema, with and without edema, was observed in test article-treated animals. No to mild erythema, with and without edema, was observed in positive control animals. No signs of erythema were observed in vehicle control animals. Individual animal data is presented in Table III. During the challenge phase, no to severe erythema was observed in the positive control group treated with p-phenylenediamine at a 35% concentration. Slight erythema was observed in one test article-treated animal at the 100% concentration site at 24 hours. One animal exhibited severe erythema at the 100% site at 24 hours with mild erythema at 48 hours. Slight erythema was observed in the same test article-treated animal at the 10% concentration site. No signs of erythema were observed in vehicle or negative control animals. Due to the spurious positive response observed in one animal at challenge, all test article-treated animals, along with an 12 Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 additional group of five naive control animals (2 males and 3 females)/ were rechallenged with test article at 100% and 10% concentrations. Slight erythema was observed at 24 hours in one test article-treated animal at the 100% concentration site. No signs of erythema were observed at 24 or 48 hours after rechallenge in test article-treated animals at 10%. No signs of erythema were observed at 24 or 48 hours in naive control animals at the 100% or 10% concentration sites. Under the conditions of this study protocol, H-18,920 produced weak delayed contact hypersensitivity in one guinea pig at a 100% concentration at challenge. Delayed contact hypersensitivity was not observed at 10% after challenge. During rechallenge, H-18,920 did not produce sensitization at 100% or 10% concentrations. Rechallenge results did not reinforce the spurious response observed at challenge and after evaluation of all data, H-18,920 did not produce Delayed Contact Hypersensitivity in Guinea Pigs. The results of the rechallenge support that the reaction observed at challenge was indicative of irritation and not sensitization. Dermal responses observed during the challenge phase are summarized in the following table (page 14). Individual animal data are presented in Table IV. ACT/RP14 13 Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 Summary of Skin Responses: Challenge Phase Positive Centre51 PP D Test An imals H-18 ,q 20 Resoonses 35 % 24 hr 48 hr 100 5. 24 hr 48 hr 1 0% 2 4 hr 48 hr No erythema 1/10 1/10 8/10 9/10 9/10 10/10 Slight, erythema 2/10 4/10 1/10 0/10 1/10 0/10 Mild erythema 5/10 3/10 0/10 1/10 0/10 0/10 Moderate erythema 1/10 1/10 0/10 0/10 0/10 0/10 Severe erythema with necrosis 1/10 1/10 1/10 0/10 0/10 0/10 Responses 100% H-18,,920 Necrative Control PPD 10% 35% 24 hr 48 hr 24 hr 48 hr 24 hr 48 hr Vehicle Distilled Water 24 hr 48 hr No erythema 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 No erythema Vehicle Control 24 hr 48 hr 5/5 5/5 At challenge, H-18,920 produced weak delayed contact hypersensitivity at a 100% concentration but did not produce delayed contact hypersensitivity at a 10% concentration. Due to the responses observed at challenge, a rechallenge was performed. Dermal responses during the rechallenge phase are summarized in the following table (page 15). Individual animal data are presented in Table V. 14 Company Sanitized. Does not contain TSCA CBI Responses No erythema Slight erythema Mild erythema Responses No erythema Du Pont HLO 433-91 Summary of Skin Responses: Rechallcnqe Phase Test Animals H-18.920 100% 24 hr 48 hr 10% 24 hr 48 hr 9/10 10/10 10/10 10/10 1/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 Naive Control H-18,,920 1 00% 10% H-18,,920 100% 10 % 24 hr 48 hr 24 hr 48 hr 24 hr 48 hr 24 hr 48 hr 5/5 5/5 5/5 5/5 5/5 5/5 5/5 5/5 The results of the rechallenge did not reinforce the spurious response observed at challenge and after evaluation of all data, H-18,920 did not produce Delayed Contact Hypersensitivity in Guinea Pigs. The results of the rechallenge support that the reaction observed at challenge was indicative of irritation and not sensitization. 15 Company Sanitized. Does not contain TSCA CBI DU Font HLO 433-91 TABLE I SCORING SYSTEM USED TO EVALUATE SKIN RESPONSES Score 0 1 2 Skin Reaction No erythema or Edema Slight erythema (barely perceptible, usually nonconfluent) Mild erythema (well defined, usually confluent) 3 Moderate erythema 4 Severe erythema (beet redness, with or without edema, eschar formations or necrosis) If edema, blanching, necrosis or eschar formation occurred, they were indicated using the following code: ED = Edema N = Necrosis E = Eschar B = Blanching SN = Superficial Necrosis 16 Company Sanitized. Does not contain TSCA CBI GUINEA PIG NUMBER 1131 1132 1133 1134 1135 1136 1137 1138 '" 1139 1140 Du Pont HLO 433-91 TABLI3 II PRIMARY IRRnPATION Pffi^SE S1KIN RESPONSES OBSERVE D IN TEST GUINEA 1PIGS FOLLOWING TOPICAL E3(POSURE TC) H-18,92 0 LEFT FRONT 100% 24 hr 48 hr 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 RIGHT FRONT 10% 24 hr 48 hr 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 17 Company Sanitized. Does not contain TSCA CBI Du Pon-t HLO 433-91 TABLE II (Cont'd) PRIMARY IRRITATION PHASE SKIN RESPONSES OBSERVED IN VEHICLE CONTROL GUINEA PIGS FOLLOWING TOPICAL EXPOSURE TO DISTILLED WATER GUINEA PIG NUMBER 1141 LEFT FRONT Distilled Water 24 hr______48 hr 1188 1143 1144 1197 18 Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 TABLE II fCont^dJ PRIMARY IRRITATION PHASE SKIN RESPONSES OBSERV:ED IN POSITIVE CONTROL GUINEA PIGS FOLLOWING TOPICAL EXPOSURE TO p--PHENYLENEDIAMINE GUINEA PIG NUMBER 1121 1122 1123 1187 1125 1193 1194 1128 1129 1195 LEFT FRONT 35% 24 hr 48 hr 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 19 Company Sanitized. Does not contain TSCA CBI Du Pont HLO 433-91 TABLE III IN1AUCTION PHASE SKIN RESP ONSES OBSERVED IN TEST GUINEA PIGS 2^[ HC)URS FOLLOWING INTRADERMAL ADMINISTRATION OF 1.0% H -18 .920 GUINEA PIG NUMBER 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 ED = Edema Week 1 Dose #1 (LEFT) 1ED 2ED 1 1 2ED 1 1 1 2ED 1 Week 2 Dose #2 (RIGHT) 1 1ED 2ED 1 2 2 1 1 1 1 Week 3 Dose #3 (LEFT) 1ED 2ED 1 1 1 0 1 1 1 1 Week 4 Dose # 4 (RIGHT) 1 2ED 1 1ED 1 2 1 1ED 1 1 20 Company Sanitized. Does not contain TSCA CBI Du Pont HLO 433-91 TABLE III (continued^ INDUCTION PHASE SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING INTRADERMAL ADMINISTRATION OF DISTILLED WATER GUINEA PIG NUMBER 1141 1188 1143 1144 1197 Week 1 Dose #1 (LEFT) Week 2 Dose #2 (RIGHT) Week3 Dose #3 (LEFT) Week 4 Dose #4 (RIGHT) 21 Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 TABL13 III fcontinuRd) 11EDUCTION PHASE SKIN K ESPONSES OBSER.VED IN TEST GlJINEA PIGS 24 H(3URS FOLLOWING INTRADEIUSAL A DMINISTRATION OF T3-PHENYLENE13IAMINE - GUINEA PIG NUMBER Week 1 Dose #1 (LEFT) Week 2 Dose #2 (RIGHT) Week 3 Dose #3 (LEFT) Week 4 Dose #4 (RIGHT) 1121 0 1122 0 1123 0 1187 1 1125 1 1193 0 119^4 0 1128 0 1129 1 1195 0 ED edema 2ED 2ED 1 1 1 1 1ED 1 1 1 0 1 0 1 1 1 1 0 1ED 1 0 0 1ED 1 1 0 2ED 1 0 1 22 Company Sanitized. Does not contain TSCA CBI GUINEA PIG NUMBER 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 DU Pont HLO 433-91 TABLE IV CHALLENGE PHASE SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF H-18.920 ~LE~~F~T F--RONT 100% 24 hr 48 hr 0 0 0 0 0 0 0 0 4 2 0 0 0 0 0 0 1 0 0 0 RIGHT FRONT 10% 24 hr 48 hr 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 23 Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 TABLE IV (cont^d) CHALLENGE PHASE SKIN RESPONSES OBSERVED IN VEHICLE CONTROL GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF DISTILLED WATER GUINEA PIG NUMBER LEFT FRONT Distilled water 24 hr 48 hr 1141 1188 1143 1144 1197 24 Company Sanitized. Does not contain TSCA CBI GUINEA PIG NUMBER 1146 1147 1198 1149 1150 Du Pont HLO 433-91 TABLE IV (Conk'd} CHALLENGE PHASE SKIN RESPONSES OBSERVED IN NEGATIVE CONTROL GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF H-18,920 DISTILLED WATER AND P-PHENYLENEDIAMINE LEFT FRONT H-18.920 100% 24 hr 48 hr 0 0 0 0 0 0 0 0 0 0 RIGHT FRONT H-18.920 10%____ 24 hr 48 hr 0 0 0 0 0 0 0 0 0 0 LEFT REAR Distilled Water _24__h_r100%48 hr RIGHT REAR PPD 35% 24 hr 48 hr 0 0 0 0 0 0 0 0 0 0 25 Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 TABLE IV fCont^d) CHALLENGE PHASE SKIN RESPONSES OBSERVED IN POSITIVE CONTROL GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF D-PHENYLENEDIAMINE GUINEA PIG NUMBER 1121 1122 1123 1187 1125 1193 1194 1128 1129 1195 LEFT FRONT 35% 24 hr 48 hr 2 2 2 2 4 3 2 1 2 1 3 4 1 1 2 2 1 1 0 0 26 Company Sanitized. Does not contain TSCA CBI GUINEA PIG NUMBER 1131 1132 1133 1134 1135 1138 1137 1138 1139 1140 Du Font HLO 433-91 TABLE V RECHALLENGE PHASE SKIN RESPOtISES OBSERVED IN TES1P GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF H-18.,920 LEFT FRONT H-l 8,920 1 00% 24 hr 48 hr RIGHT FRONT H-18. 920 10% 24 hr 48 hr 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 t 0 0 0 0 0 0 0 0 0 0 27 Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 TABLE V (Continued) RECHALLENGE PHASE SKIN RESPONSES OBSERVED IN NAIVE CONTROL GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF H-18.920 GUINEA PIG NUMBER 5821 5822 5823 5824 5825 LEFT FRONT H-18.920 100% 24 hr 48 hr 0 0 0 0 0 0 0 0 0 0 RIGHT FRONT H-18.920 ___10% 24 hr 48 hr 0 0 . 0 0 0 0 0 0 0 0 28 Company Sanitized. Does not contain TSCA CBI Du Pont HLO 433-91 APPENDIX A PROTOCOL 29 Company Sanitized. Does not contain TSCA CBI >;liiiS'-i Du Pont HLO 433-91 PHARMAKON RESEARCH INTERNATIONAL. WAVERLY. PENNSYLVANIA 18471 Protocol - 424D1 INC. Skin Sensitization Test in Guinea Pigs PHONE (717)586-2411 FAX (717)586-3450 Sponsor; E.I. duPont de Nemours Haskell Laboratory for Toxicology and Industrial Medicine Newark, DE 19714 Testing Facility; Pharmakon Research International, Inc. Waverly, Pennsylvania 1847X . ' Test Facility S.O.P. Ho.; Study Ho.: Purpose of the Study; To be assigned upon study initiation. W^u-OU^o^i This study is designed to evaluate the dermal sensitization potential of the test material in guinea pigs. Ownership of the Study: Study Monitor: Study Director.- Q.fL.V. Responsible Personnel: The sponsor owns the study. All raw data, analysis, and reports are the property of the sponsor. 5't-iri f? . l_^ye^*a >t7h-ii^ Dolores E. Md.lefe-, Ph.D., E.I. duPont de Hemours Susan Annondi, LAT, Pharmakon Research International, Inc. Leslie J. Pinnell, M.S. Dates of Performance: Study will begin within one month of the receipt of the test chemical and authorized protocol. Good Laboratory Practices Statement: This study will be conducted following the U.S. Environmental Protection Agency Toxic Substances Control Act Good Laboratory Practice Standards (40 CFR Part 160) or Good Laboratory Practice Standards (40 CFR Part 792). IACUC Statement: This protocol has been reviewed by the Institutional Animal Care and Use Committee (IACDC) and complies with acceptable standard animal welfare and humane care. Tentative Date of Submission of Draft Report: Within three weeks following the completion of the in-life phase of the study. 080489 company Sanitized. Does not contain TSCA CBI ..... A.B.S Protocol - 424D"'" 2 Skin Sensitization Test in Guinea Pigs Du Pont HLO 433-91 Records Maintained: Raw Data: Record Retention: Analytical Chemistry: Species; Strain: Supplier: (Source): Sex: Age: Weight at Initiation: All raw data, final reports, documentation and protocol will be maintained in the Phannakon Central Piles. Amendments to protocol Feed Lot dumber Body weights, initial, weekly and final Compound preparation Volume administration Observed signs Observed skin reactivity Maintained in a Standard Phanaakon' Notebook All raw data and completed notebooks. Analysis and stability of the test article and test article/carrier Mixture is the responsibility of the sponsor. If requested by the sponsor, Phannakon Research International, Inc. will, through its subcontractor, conduct appropriate analytical analysis and will indicate the additional cost involved following receipt and evaluation of the appropriate analytical method. In the case where a satisfactory method is not provided, Phannakon Research International, Inc. or its subcontractor, at additional cost to the sponsor, will develop appropriate methods. If the sponsor elects to analyze the test article/carrier mixtures, Phannakon Research International, Inc. will collect the sample at appropriate designated intervals during the study and transmit the samples to the sponsor for analysis. T&ST SYSTEM Guinea pig Hartley BuckberG Lab Animals, Tonkins Cove, Hew York or from any other U.S.D.A acceptable source. Male and female (the sex used will be documented in the study records and final report). Young Adult 400 - 650 grams 080489 Company Sanitized. Does not contain TSCA CBI 424D1 3 Protocol 'Skin Sehsitization Test in Guinea Pigs Du Font HLO 433-91 Ho. on Study: Method and Justification for Randomization: Dose-Range-finding; 3 Vehicle control: 5 (at the discretion of the Study Monitor, this group may be excluded from the study.) Negative control: 5 (if re-challenge is necessary, a second set of 5 naive, age-matched negative control animals will be used.) Test article: 10 Positive controls 10 (at the discretion of the Study Director after consultation with the Study Monitor, this group nay be excluded from the study.) If Treatment groups will be housed by vertical cage showing evidence of clinical psiogsnistiodnuirningg, afctncyRliamannaditomiomanilzsawtiiolnl bise eclaimrriiendateodutfrboymuse of randomization. a computer generated random number table. Before treatment commences, all according to body guinea weight pigs will be and assigned weighed, to ranked treatment groups using a table of random numbers so that each -treatment group according to will body have a similar weight. Guinea pigs distribution of the body weight range will not beyond the extremes be assigned to treatment groups. there is a statistically significant difference groups of the in mean body same sex after weight between any two allocation to the treatment groups, substitution from spare animals will be used to correct the situation. Acclimation Period; System of Identification; Research Facility Registration: Animal Rooms: Housing: Sanitization; Food: Minimum: five (5) days Cages marked with an animal group number, sex and treatment group. Guinea pigs are ear tagged. HUSBANDRY U.S.D.A. Registration Ho. 23-107 under the Animal Welfare Act 74: SC 2131 et seq. Separate isolation by test system. Light cycle - 12 hours light, 12 hours dark. Temperature/Humidity - Maintained at a temperature of 22C 3C and a humidity of 30 to 70%. Guinea pigs are housed individually in stainless Size in accordance with the steel h" wire mesh cages. "Guide for the Care and Use of Laboratory Animals" of the Institute of Laboratory Animal Resources, National Research Council. Waste material will be removed daily. Cages and feeders will be sanitized every two weeks. p Purina Certified Guinea Pig Chow S5026 or acceptable substitute will be provided ad libitum. Feeders are 080489 3 2 Company Sanitized. Does not contain TSCA CBI Protocol - 424D 4 Skin Sensitization Test in Guinea Pigs Du Font HLO 433-91 Food Analysis; Water; Water Analysis: Rationale for Test System; Rationale for Dose Selection: Justification for Test System: Compound Preparation; Absorption of the Test Material: designed to reduce soiling, bridging, and scattering. The potential effects of dietary contaminants have been considered, and based on the manufacturer's data, contaminant levels are believed to be within acceptable limits. There are no contaminants expected to be present, in the dietary material known to be capable of interfering with the purpose or conduct of the study. Availability - fresh tap water, ad libitum. Water is monitored for contaminants at periodic intervals according to Standard Operating Procedure PH-018. METHODS This study is intended to provide information on the health hazards likely to arise from exposure to the test material by the dermal route; skin contact is a possible worker and consumer exposure route. Based upon the.results of the dose-range finding study and/or at the sponsor's request. According to EPA Health Effect Test Guidelines EPA 560/6-82-001. The guinea pig has historically been used in the evaluation of chemicals for dermal sensitization. Liquids Liquids will be applied as received except when specific instructions request dilution or mixing. The use of a vehicle for dilution will be described in the study records and final report. Solids The test material will be pulverized if appropriate. The test material may be moistened with distilled water or a suitable vehicle to ensure good contact with the skin. When a vehicle is used, the influence of the vehicle on penetration of the skin by the test substance will be considered. Semi-Solids Extremely viscous liquids may be heated to approximately 50C to dosing, with the approval of the Study Monitor. The procedure used will be documented in the study records and included in the final report. For the purpose of this study, all of the test material applied to the test sites is assumed to be absorbed by the test system. All calculations and the evaluation of effects will be based on the applied dose. 080489 3 3 Company Sanitized. Does not contain TSCA CBI Protocol - 424D 5 Skin Sensitization Test in Guinea Pigs Du Font HLO 433-91 Vehicle; Volume Administration; Route of Administration: Rationale for Route of Adminis (.ration: So. and Description of Animals per Dose Group; Method of Study Performance; The choice of vehicle varies, depending on the nature of the test substance. Commonly used vehicles are distilled water, saline, ethanol:distilled water (80:20, v/v), dimethyl phthalate, acetone;dimethyl phthalate (1:9, v/v) or propylene glycol. The vehicle used will be documented in the study records and the final report. Approximately 0.05 ml/dose The test and control materials will be applied topically and/or injected intraderma'lly, to the clipped, intact shoulder skin. Skin contact is a possible worker and consumer exposure route. Dose-range-finding; 3 Vehicle control; 5 (at the discretion of the Study Director, this group may be excluded from the study). Negative control: 5 (if re-challenge is necessary, a second set of 5 naive, age-matched negative control animals will be used). Test Article; 10 Positive control; 10 (at the discretion of the Study Director, after consultation with the Study Monitor, this group may be excluded from the study). Dose-range-finding Study Prior to initiation of the main study, a dose-range-finding study will be performed. In order to evaluate the irritation potential of the test material, 3 animals will be subjected to preliminary studies as follows: Animals will be closely clipped over the back and sides. The test material concentrations will be based on the solubility of the test compound (solids will be tested at the maximum soluble concentration and at 2 or 3 lower concentrations). Liquids will be tested at 100% (as received or as prepared per the Sponsor's instructions) and at 2 or 3 lower concentrations. Each guinea pig nay be dosed with up to 4 different concentrations at different sites (1 concentration/ site). In some cases where the solid is not soluble in a common solvent it will be tested as received by topical application. One drop (approximately 0.05 ml) of each concentration will be applied directly on the appropriate test site and rubbed gently with the end of the dosing syringe to cover an area of approximately 25 mm in diameter. 080489 34 Company Sanitized. Does not contain TSCA CBI Protocol - 424D1 6 Skin Sensitization Test in Guinea Pigs Du pont HLO 433-91 Observations for signs of dermal irritation will be recorded at 24 and 48 hours after application. At each observation, all treated sites will be scored according to Table I. O^^f^ Primary Irritation Phase ft - For the test guinea pigs there will be 2 sites per A\'!\111 animal in the area between the shoulder and the middle . of the back. One site will receive the highest vili'gM +o n^-,.^4-^-,^ concentration ^^-^-r^-^-^ <-i^n "1 ^r i rr- 'I'-i T-J as determined from the dose-range-finding study. The second site will receive one-tenth of that concentration. Each site will receive 1 drop (approximately 0.05 ml) of the appropriate concentration, rubbed gently into the clipped skin with the end of the dosing syringe to cover an area approximately 25 mm in diameter. The vehicle control guinea pigs, if used, will be treated at X site as above using the vehicle only. The positive control guinea pigs will be treated at 1 site with the positive control. The negative control guinea pig will remain untreated until the challenge phase. Observations for signs of dermal irritation will be recorded at 24. and 48 hours after application. Sensitization Phase (Induction) The first induction application will be made after the 48-hour deraal observation is made for the primary irritation phase. If the test material is soluble in appropriate vehicle, e.g., 0.9% saline or dimethyl phthlate, induction will be performed by intradermal injection. If the test material is insoluble in the commonly used vehicles a topical induction procedure will be used. if The hair at the appropriate application site will be clipped on the day prior to each application or, a topical induction procedure is employed, at least weekly during induction. After clipping, the area to be treated may be delineated for the convenience of -- and at the discretion of the study director or the experimenter. The hair will be clipped as needed during the study for evaluation of the dermal irritation. A total of 4 intradermal injections will be made, 1 per week at 1 week intervals. A virgin site will be used for each injection. A 0.1 ml aliquot of a 1% solution of the test material in an acceptable solvent (e.g., 0.9'ii saline, dimethyl phthalate, etc.) will be administered by intradennal injection to the clipped sacral area of each test guinea pig. If distilled water is used as a vehicle in the primary irritation phase, 0.9% saline will be used for the intradermal injections. The vehicle control guinea pigs will be 080489 ...,. Company Sanitized. Does not contain TSCA CBt 35 Protocol - 424D 7 Skin Sensitization Test in Guinea Pigs Du Font HLO 433-91 Method Validation/ Positive Control: Evaluation of Dermal Response; treated as above using the vehicle only. The positive control guinea pigs will be treated as above using the positive control material. Topical Administration & total of 9 applications will be made to the sacral area, 3 applications per week for 3 weeks. One drop (approximately 0.05 ml) of a minimally irritating concentration of the test material in the acceptable solvent (e.g., dimethyl phthalate, 0.9% saline, etc. will be applied directly to the skin and then gently rubbed in with the end of the syringe, to cover an area approximately 25 torn in diameter on each test guinea pig. The vehicle control guinea pigs will receive similar treatments using the vehicle only. The positive control guinea pigs will receive similar treatments using the positive control article. Challenge Phase Approximately 14 days after the last induction treatment, the challenge treatment will be administered. The test material will be administered in the same manner as in the primary irritation phase, treating with the same concentrations at the same sites. Following the same procedure the negative control animals will be treated with the same concentrations of the test material, and may be treated with the vehicle and positive control material (up to 4 separate test sites). The vehicle control animals will be treated with the vehicle only. The positive control animals will receive the positive control article. If the test results are conclusive and the test material has either clearly caused allergic sensitization or is not a sensitizer, the test is terminated and the guinea pigs are euthanized. If the reactions are less than conclusive, a second challenge (rechallenge) may be performed approximately 1 week after the initial challenge using the same test guinea pigs and additional naive control guinea pigs. The vehicle and positive control animals may not be rechallenged. The procedures and test system will be evaluated with a known dermal sensitizer to confirm the validity of the test. Evaluation of the test system with a known dermal sensitizer nay not be conducted concurrently with every study, but testing with a known dermal sensitizer will be performed periodically. Dermal evaluations will be made between 23-25 hours and/or 47-49 hours following treatment, but the data will be reported as the 24- or 48-hour evaluations. 080489 36Company Sanitized. Does not contain TSCA CBI Protocol - 424D1 8 Skin Sensitization Test in Guinea Pigs Du Font HLO 433-91 Interpretation of Results; Sensitization Rating; Intervals a. Primary Irritation Test - Dennal evaluations will be made approximately 24 and 48 hours after the test material application. b. Induction - Dermal evaluations will be made approximately 24 hours after each induction treatment. c. Challenge and Rechallenge (if required) evaluations will be made approximately 24 Dennal and 48 hours after the test material applications. All test sites will be graded on a. scale of 0 to 4 as follows: TABLE I Score 0 Skin Reaction Ho erythema or edema 1 Slight erythema (barely perceptible, usually nonconfluent) Mild erythema (well defined, usually confluent) Moderate erythema Severe erythema (beet redness, with or without edema, eschar formation or necrosis) eIfscehdaermfao, rmblaatniocnhinogcc, unre, ctrhoesyisw, islul paelsroficbiealinndeiccraotseids or using the following code: y.n = Edema H = Necrosis E = Eschar B "s Blanching SH "s Superficial Necrosis Sensitization is defined as a 2-or-more step increase (e.g., from 0 to 2, fron 1 to 3, etc.) in dermal irritation scores in the test animals over those observed in the negative controls at challenge. When the test and negative control animals have similar dermal irritation scores, the test material will not be considered a sensitizer. The rating of a sensitizer is as follows: Ratio of Responsers Degree of Sensitization 1 to 2/10 Weak Sensitizer 3 to 4/10 Mild Sensitizer 080489 37 Company Sanitized. Does not contain TSCA CBI Protocol - 424D 9 Skin Sensitization Test in Guinea Pigs Du Font HLO 433-91 Kecropsy; Euthanasia; Statistical analysis: Rechallenge; Positive Control Article: Supplier (Source); Special Handling Instructions; Analysis of Purity: How Supplied; Rationale for Positive Control Article: Ratio of Responsers Degree of Sensitization 5 to 6/10 Moderate Senitizer 7 and above Strong Senitizer This rating scale is not fixed rigidly. Scientific evaluation of the data and judgement will be used to decide whether a material will be classified as a weak, mild, etc. sensitizer. Pathological evaluations of test animals will not ordinarily be performed. Exceptions will be noted in the study records and final report- Animals that surive the test period will be euthanized according to the Testing Facility's Euthanasia SOP and incinerated. Statistical analyses of data will not be performed, unless requested by the sponsor. The sponsor will be notified of animals that are considered sensitized. Verbal instructions for rechallenge will be given by the Sponsor, followed by written confirmation. All test article animals, along with an additional group of four naive guinea pigs, can be rechallenged six (6) days after primary challenge, but not before. The negative and positive control groups will not be rechallenged. POSITIVE CONTROL ARTICLE M-Phenyl-1,4 phenylenediamine (PPD) Aldrich Chemical Company, Milwaukee, Wisconsin Standard precautions The purity is the responsibility of the manufacturer. 100 gin bottle As per sponsor's request. ATXPL4 060489 Qi8npany Sanitized. Does not contain TSCA CBI ,,: .,;i>syi Protocol - 424D 10 Skin Sensitization Test in Guinea Pigs Du Porrt HLO 433-91 Test Article (Same or Code); Chemical Abstract Ho. or Code No.: Analysis of Purity/Stability; Carrier Mixtures: Analysis of the purity and stability of the test article is the responsibility of the sponsor. Analysis for stability, uniformity.an8 correctness of concentration of the test article in the carrier is the responsibility of the sponsor. __ Return Test Article Carrier Mixtures to the Sponsor \(~ Dispose of Test Article Carrier Mixtures Person to whom carrier mixtures should be sent: hfPr Shipping Instructions: ^j!> f nuL^iS r^u-jL(, -, AMENDMENTS 4 3 e< f f III ^) ATXPL4 APPROVAL OF PROTOCOL Study Monitor /'^^^^L. qp^^Ci-^ Study Director /IflMl^ E.. //6/\nw7Y//C 39 Company Sanitized. Does not contain TSCA CBI IX Du Pont HLO 433-91 APPENDIX A Test Article Information I Identification: Test Article (Name or Code); 14~ Lot or Sample No: Physical Deyripl purity:__j^||m Expiration Date: Density/Spcci-fit' -- , , Solubility (check .Mi d.i.5 .Mr.\Ui!- Ethano_____ ^^..A"-- Other ?pTease1 Chemical Classification: Flainaiable Other__\ ^ ^20 II Storage- Inforaatioft: Material Storage ^' Room Temperature Freezer _____; III Handling Information: (check one); ; Refrigerator Other (specify) ___ Known Hazards; Precautions; Routine use of protective clothing includes .laboratory coats, latex gloves, dust masks, and safety glasses. Other recommended precaution In Case of Emergency Related to this substance, contact: $\^ i-^J^ (person) IV Disposi-tion: c^- c^ ^P^-r/^P of (company/division) l-^- ^/f-t-^7? at^ol^^-^ (phone number) -O^f^^ ^t- <-.'-<- All materials will be returned to the sponsor three months following submission of the final report to the sponsor. Person and address to whom test articles are to be returned. A/ /A- Name: Address; Company Sanitized. Does not contain TSCA CBI 40 Du Font HLO 433-91 APPENDIX B WEEKLY BODY WEIGHTS (a) 41 Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 I I Animal Number Sex Initial Week Test Group 1131 M 429 496 1132 M 421 470 1133 M 419 494 1134 M 422 479 1135 M 440 514 1136 F 408 462 1137 F 400 421 1138 F 412 465 1139 F 432 486 1140 F 417 454 WEEKLY BODY WEIGHTS (d) Week III Week IV Week V 556 607 632 530 579 683 552 616 689 529 576 624 590 652 717 528 571 628 474 513 558 519 531 603 519 585 599 503 570 603 Week VI 675 740 743 658 765 646 578 639 646 651 Wt. after Challenge Final 691 724 767 821 773 800 684 728 788 835 670 691 592 611 653 685 662 671 656 708 42 Company Sanitized. Does not contain TSCA CBI Du Pont HLO 433-91 Animal Number Sex Initial Positive Control Group 1121 1122 1123 1187 1125 1193 1194 1128 1129 1195 M 451 M 411 M 431 M 434 M 443 F 402 F 407 F 420 F 444 F 401 WEEKLY BODY WEIGHTS (a) Week II Week III Week IV 544 611 668 465 511 564 496 545 616 462 521 543 502 574 635 458 540 573 446 485 534 467 538 584 479 529 526 435 467 517 Week V 740 623 673 593 705 649 585 648 611 563 Week VI Final 804 830 669 680 737 736 612 604 741 780 676 722 615 638 678 651 629 626 593 613 43 Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 Animal Number Sex Initial Vehicle Control Group 1141 1188 1143 1144 1197 M 419 M 441 M 423 F 412 F 406 WEEKLY BODY WEIGHTS (a) Week II Week III Week IV Week V 478 539 595 659 520 607 683 761 498 . 585 657 743 459 508 561 622 420 459 502 554 Week VI Final 705 720 827 857 787 768 644 674 584 591 44 Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 Animal Number Sex Initial Negative Control 1146 1147 1198 1149 1150 M 450 M 433 F 421 F 410 F 432 WEEKLY BODY WEIGHTS fcf) Week II Week III Week IV Week V 512 542 577 623 510 594 672 739 463 527 574 641 482 513 579 639 481 543 581 636 Week VI Final 664 668 793 813 650 666 673 695 661 671 45 Company Sanitized. Does not contain TSCA CBI WEEKLY BODY WEIGHTS fcr) Animal Number___Sex Initial Final Naive Control (Rechallenge) 5821 5822 5823 5824 5825 M 642 638 M 521 525 M 551 556 F 477 473 F 530 542 Du Font HLO 433-91 46 Company Sanitized. Does not contain TSCA CBI ,,;;; i;i-i>-''.'t Du Pont HLO 433-91 PHABMAKOH RESEARCH INTEBMAIOHAI., INC. WO notebook I?ac^ ^f---- Skin Sensitization Test in Guinea Pigs Body Weights Sponsor; F.I-. hi^fVjt' hp. ^PjMMlug^ Test Article: A - f^U^F) WWW-00^'/^ (grams) Study Number ^^--hUL-QD I -^1 Lot Number; (-^-(-.(Wy^-bC^ ftnimal lumber S ex ^rY^E. ,0^ 11^1 ^ U^ ^ 1133 ^ -K^ ^ \{Q ^ ll^ ? w ^ l/^ ^ /sff ^ \^ ^ nitial 7eek I tfleck II ^l^ ^1 M 4l! ^ 431 ^ W 4bS 4-H3. ^ ^ w W M ^S> ^ W ^ ^61 ' W y.^34. ^ ^^^/ vC^ Week III 6'// ^\ ^ ^\ ^ J^6 W ^ ^1 f^^7 - S^ f teek IV Week V Teek VI Final ^ ^ ^ W b^ ^73 ^ M ^ ^if ^sx' y /^<<> ^^0 ^33 (^73 ^93 7o$' (.^ S^ ^f kn ^^ J7>'7/9/ ----p ^ ^P u.^ w 7^7 7^ <Wo? W W W W^ W U>/6 W W W t^ ^ ^f^'^Q^ WW. ATABL3(5) ^//^^^^^^^/ ^/~?W AlM^S. _^tIrif^veessttiiggaator Jr'/\ ^ ^ Da6e UAfWwrL ///7^/ Study Director ~kt ^ company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 ^ ^ SUS ^ 0 stts 8 0 ^ a pi g ^ 1 ^ . ^ ^ g 5 ^ Pi -ri a ^3~- - g H -^- & ^? i ^ 1-1 ia i g5 r g g0 ^. & 1 T< ' M "=^ rt M -< en 1-1 fli . ^5 <S! S z ^ ^ 3 <3r 1 Of i ? ^ 44g| ^ - g s (a CD 9 ' 0 y V i Q ^ <^ x ] - - - 5 M tP ^.^ g's ^ T< a &< K -, O.Q L^ s^ P'^ / ~. ^\^o p 1 < UP\ 00 QQh i T? ^ <J ^ 0 0 ^/CT < 3 Q Ct 0 B 3^1- 'M i 0 a m H Q B) >-< jji -^ ^^ ^ 35% i W lii^/^^4 ^ cq i 4 i3 c -^1 y c 1 1 i i^^^ c^ '^ Vt ! --4j-; O^CM- ^^; (T: n ^ ^ ^rj ^ m^" o^-S\^0q ( \ - U o r~ ^' a. M 1 r4 I.) 4-1 4 t: M Company Sanitized. Does not contain TSCA CBI 49 ,....: --.fiWK Du Pont HLO 433-91 ^ >^\o <= A; 0 A0 =* 0 c i-i r4 n * 'S3- 3 | 9^ Q ^ M in C-i < Z > O rgi 3 P 4J 0 Ul t-1 H / <? f^ -Tl Ss- t! ^ <? b (r y ^ ^ ^F h 0) CO .-< 0 .tJ! n n 0 < 01 c u 0 U) a a in E^ 0' c d) r4 g M O ri 0 13 E^ a K > t-1 ^i* t0 CM M M a d) ^ e(B--"..01 ri 0 0 & Q 0' g a) o e in ie ri 0 0) ^ B: M M t-1 a V H ^ N as , -^ ^ \ - 0 - - Q - Q - ft ^. 'Q 1 \ / . N^ '?l ?% ViC ^ s ^ ^ 1 ^Q ^ 1 \ S / ^ ^ ^I ^s Q <) ^ \ <-' 3S / ^ CP i ri 41 'a $ g H-l 10 ^ o a) E< M 0 M ^ d ''3 01 ^ T M N a (^ (^ --fc ^ s ^ / ^ 0>. n t4 ? ^ <? IU <D g 01 H <M 0 &< 0 Q 0' C ^ r< m a) &< 0 (K ^-1 .<? O; ^ ^ ^ \ ^ \ ^> ^ / fr s / } ^ ^ ^ '- ^ t-1 M 1C s a T H " a Q Q Q 0 0 0 Q^ ^ II! (U g >M in ^ H 0 0 & Q 0 0 B) C 0 0 Q U .--A ^ s^ ^ / ^'Js ) ^ f^ j /- ) . fl ^^1 f) ^ ''^ 7^ k- / {^ >o n ^ fo ^ s< C Q t0 0- ^ S ^ ^ <.^ - <} ^ <-> 11 r^ ir r~t 0 UJ --f 4J H C M 5(9ompany Sanitized. Does not contain TSCA CBI Du Pont HLO 433-91 ,. ^;:-;;;;iS;?i;'!: o' v c a) H r ^s^gY's'asj | <S~ U U) e 1-1 "i S 0 ai ^ 0 0) ^ OS = PS 50) 0) ^ ^ +1 o' c^O ia cu T in 1M U B N, 's, (U ^-- c o ~--t<i^-- ^s >-i a --^ cs- o U i-l fl) U J3 3 Ul C CP C 0 0 -H S Q u o; in u N "s^ ^5 < -L ^s t Q " s^ r~ fl! U t 3 ill c m o i ^ 0 0 < ;S f. ^ <a m ^~> Q u 1-1 en --- D' ct: g c -S7- j 8 \ ^ m ^ 0- / M E 44 1B ^ -2 ^y ri 0 CO H f ^ - < < a ^ ' .u iS 0 ^- r4 Q H .-I E IM " ^ o a & c; ^ (11 'N r n a: r <- <~ <y> d - < , 1 <1 ^| E0) iu (0!1) c& .3 o o E-i Q ? 's ^ / ^; ^ff C . +1 r4 o ^ 0 0 -^ .C Q u (a in '-- N ^ n tt) 1s-^ ^ / ^ ? ^ ^ 1 ? S. , ey- Sri- ^ u in I ^ ^ -^ ^n ^ (^ ^<Zn jj Os '^- U u 0 < ^ i-i ^ r-^ 10 (Tf C ia c- T ^ <r ^t: r4 4J ^ 0 i\ c, s 03 c-1 ^i : 0 < ^ ^ e i-i ^ Company Sanitized. Does not contain TSCA CBI PHARMAKOW RESEARCH INTERNATIONAL, IMC. N.B Page g .Uj^^ " Skin Sensitization Test in Guinea Pigs Dose-Range-Finding Study ^^^.^ Sponsor: /"". /, ^/^^cfjJl^:. ^^. '^^Z-^^_______________________ Purpose; ^^^^^ijfcC^^ ^^^^t^^a^^K^ ,^^^^^(4;^^^' Study No.. /t^'/w/^^f^-u-^h. i^fr-i W%^^.df-*- ^ftf_&____t___^__-_~__~_~__y__-_/_^_/_________ Method; ^^C^-^^^^?/________________ Date of Initiation: W^/. , "^i^yy^/ Test Article; Tr - / V.l'7^ ^f^ A///f' \-- '--/--^ '--^ amount Received: /^i^ (l^?^U Vehicle :_^^ ^fly^^ Route of Administration;= Date of Terroination: Description; Jr'^lj^^Ba____ 'w^^WH------IH Date Submitted; 4^7/7 / Dose Levels; /'6^J^% ^Sh /- / ^ ^KL- ^? Aninal P.O. *; :'^^^^ ''^^ // SPecies ' / /7 ------riir--u.-tfjTrr-^y-^iuiij hW^ffft Fd Ir^^>tt #;: 7 ? / Ho. of Animals on Study 5^--? Scaieffrv^C^MrnLfoJ='=ff^)-^ Animals Clipped; (-///(//'?/^ Compound Preparation: (^ / 0^ ^ (^^ _______________/7 /^^ - - ^ - __________/^/^ ^ ^^^ Strain: /%g^%a- Zdentification/^-^^^ *i^> Sex: Male c^^ff7 Female /-F Light Cycle Checked: 0^/ ^^WW/^^ ^/y-^^ ^'^tf ^7,$^^' ^C&^,7/^ Jgg^ -7J-^^' z?^^ e^^/M^ .0^fa^ ^l^ ^^Mj^v^^^S^/, ATABL3(1) ^estlga^^-^ ^jf/^r/^i/. (^^^j.___ Study Director ^4/^_ D^ate'/ ''' "7 Date 52Company Sanitized. Does not contain TSCA CBI Du Poht HLO 433-91 PHABMAKON RESEARCH IMTERMATIONAL, INC. Skin Sensitization Test in Guinea Pigs _ M 1 N.B.ft PageT_3g_ Dose-Range-Finding Study In this test, both sides of the animal are shaved and exposed to four concentrations of the test material. The different concentrations are applied concurrently to four different test sites. A given concentration is applied to a different test site on each guinea pig so as to minimize variation in response due to dfferent skin'locations. The format for application of the test article is described below: Figure A Figure B Figure C .^ Site 1 = /-<?^> Site 2 10/c> Site 3 = J27%> Site 4 = /669o 1-4; Test Sites 24 Hour Scores ^" ^7- (^ Av Animal Test article Initial Time of Site Site Site Site Final No. Sex and dose Wt. (gins) Dose 1 2 3 4 Wt. (gms) / ^ /^-//^<2- 33;- /o'-^ JD, 0 0 0 ^ ^ ^ 1,0.10.^0 Sft \V J2- D r> D 396. ^ ^ an/-) I'OO^ ^ /O'^4^ Jl. 0 0 33^) //y^ Wvu u\. 1 k> -h/.>/ //<< i i 48 Hour Scores 6 0 <P a yz - D 0 Q 0 0 oD , /7/ ^ rA ATABL3(2) ^ ^ ^ ^ ^ ^ ^./y ^-^hvestigator^" A ^ H ./w^-UAi^rwrL Study Director ''/ y//^/ " Date ^Ii F Date' Company Sanitized. Does not contain TSCA CBI 53 Du Pon-t HLO 433-91 PHARMAKOH RESEARCH IKTEENATIOMAL, IHC. H.B.ft ^ffl WT^Jg^ Skin Sensitization Test in Guinea Pigs Title; ^^.a^^^g^-^.^/^^^^.^U^6H^ Sponso^/3^^^^^^ ,^^' i^/^________ , _ purpose; ^(l^iff^^/lA^.^^ Msteutdhyod^' .M.^^Tw^^^/T'^^r-^^V/^y1' Technical Initiation: Test Article: f^-- /^^6 Lot IJlumber; ^07" / /y_______ Technical Termination; ^ h i ffWI Positive Control .K'pWHMi ^ Nunfcer,- -,----M,,/,,U..K.. ^/M/KQ^l < Vehicle. ^^^^^^ ^A^ Description: y^^^r^^^i^ Vehicle; j(/^///^ Amount Submitted; Receipt Date: ,ite of Administration:^ ////! animal P.O. ftt,; 6f/-^/7^/^-0|l'^lS^lo&iog^y Lab. SHo..: ^ f f ^ ^ ^ ^ Species:; yy ., , ^^/)^'-y'fSsWoOwti-fl-o'-to>oWSsiVo^l(,twi6ff' w5Wi--pp-yps.tini^if /iaf" if SSftcrraaxinn;_ 3/ -^ -"---- ^Q^6U^_____ ^^P^li4f09W//ff Weight Range;- ^-- -ds^ Qb G/am5 ^---- F--oo--d L-- ot f.t.;. 1^ ^M^^^ ^T77 Study;^^.<?<^^sex; Ho. of Animal; Male Scale S; ^''~wISi ^^^e^^-'^^^Uj^ight Cycle Checked: ^-^.^^-^-'^ ^^^^/^-.s^^- Aninals Clipped- : '//2.fhf^'^^^^4^^4^f-- ^/^^^^ ^//W' 6/$/^? '<^4W / Format for Primary Irritation, Induction and Challenge Phases 1-2 Primary Irritation and Challenge 3-6 Sensitization Phase (Induction) ATABLE3 / ^ ^ ^ ^ ^ ^ ^ ^ ./aSwstigator-_'--------- ^ A F n "/- Ai/^flyKJ f/? . (^(YYi(Tf\r.i^- Study Director Date 54 Company Sanitized. Does not contain TSCA CBI Du Font HLO 433-91 /^? Notebook i= Pa^ # -^-^---- PHARMAKON RESEARCH INTERNATIONAL, INC. Skin Sensitization in Guinea Pigs (Modified Buehler Method) GENERAL OBSERVATIONS Study No.: ^y'^y-jOl/^fft,-^ Test Article; /f- -/ff.^lQ Sponsor; <gg<^^/^7^^ ^..^f--t^--^-t<- ^, = (appears Date/AN ^^y/'/^^^/^^W^^^^ normal)Initials " / " -^-'s //^/ -^<r. 1193, //9y. / ^/ //^ "^1 , - 'aw/ff /. / . ^. r. ' ^ " > 6yC^^^--^--^--' ^--.^--,^--^--^^--?--.~y~^/<m:.^ ^ ^ i / / ' ' ^ '///^^ 'W-^i-Qf n\W\- (IR W &^/^^'^ (^WJ~W^ / '-^^ ^m\Q ^-f; (/).M_ _Q_w_^ _ai_\a^d/d r h w . d W^nuuh ^4 bu"^-. f\aa1i^ aqiiuutftCfLa.Bf\layff AMfiffth'^rr,.ll^bi.\i^\qffr{.WA^ I_2Z___I_______/. /_ -^- / / -^ Z ~/ / / / / /__ ATABL3 ( 4) Company Sanitized. Does not contain TSCA CBI 55 DU Font HLO 433-91 N.B. . PageS IW ^ PHARMAKOM RESEARCH INTERNATIONAL, INC. Skin Sensitization Test in Guines Pigs Test Article Preparation /^/-^--^-^ //-/X^O A^^/^^;^^^^^ Study NNOo...:. /-/r/"? /Ut/ (/t/i^ f/_____________________________ Test Article: ^ Sponsor: Primary Irritation Phase (Week I) (^/ffCf?6'"P^^^W^Ll yi//'^,'W /^ Qj0^^^ ^^^>^^^y ~^s^^!,6^/^^^f. -^ ^1^^^'^^^^^^^^^^-^^^^^^ y ffCTy'-1^^r>-^' <-yt-".c '/ ;'/ i' /^^^/ '^//--^/z^'_____________^ y ' > / ' ^j^^j'^!^^. Induction (Week I): (ft^ / 0 ^^^/W^ 1 ^ ^^ - ^ S^^' /f^ ^-=^ ^fc^^^^^^/^- 9^^y n v " ^^ ./y^ ff^ < Anr/rT^^1^^^/^^/'^a^ ^/^ ^y^ ^l^M.. ^ ^ ^ , ^ f c ^'^y /^^/ Induction (Week II); (<v /.O^ ^ /OQAV^/yl^^/"^^^ [1^. -7 0. ? ^ ^^W ^ ^/) j'. s /P/M^;/^fe^w^E^c^/WM^^ ,^0^ /on/w^ -_!_____________'-____________^/^ induction (Week III): ^/ / ^ ^/ff0>1fl^^y^ ff. ^ //P^f^ ^^^^(/(^^ IW^ -=7 ^/^7/^^ ft^)1q /^f^' Tc^^n- ^J^^f^&^^/^^f^, ^ Q------<^fc / ATABL3(3) i. (. Company Sanitized. Does not contain TSCA CBI DU Poht HLO 433-91 N-13- Page # W1 fy PHARMAKOM RESEARCH INTERNATIONAL, INC. Skin Sensitization Test in Guinea Pxgs Test Article Preparation (Continued) Study No.: f^W-^-QO^Ql ^^^^^^A^!^ Test Article; // "/^^>____________Sponsor; Inducfrion (Week IV); ('"./I? ^0^ /PD/^/^.W/MT'ff^ W^ -^ ff^^^J^^^.^^ ^^f, ^^ ^^Jic,^^^^r^^^^ /f){i^) s /poM/p 3~/^A/^?'/ ~7 /?. J/^^fe^- g^^^^^^^^^^ -^^ Challenge (Week VI): gj ^0 ^-L<2^^ ^^^ ^ ^ ^^^:-^ ^^^^/y^^^^^^ y!^s /W f-^//n^^ /^/^^w^^^^ ^^^^^^ ^^4-/^ ^ Rechallenge Oieek VII) ^. ^7^ -9 r^^jfo^tf^loJI ,/\0^jl^ ^O.^M/\fi /O^^J^^A7/^^7^^C^^/ ^^/7^^/^/^y^^A ^A/ c,/^h^;/_____ _____________"________________^3^^?.__________________ ATABL3(4) Company Sanitized. Does not contain TSCA CBI 57 Du Font HLO 433-91 '^ Notebook ft PHARMAKON RESEARCH IMTEBMAIONAL, INC. Page S_ _ Skin Sensitization Test in Guinea Pigs Body Weights (grams) Sponsor: p-j. :t\->1>v<t-t^. ^KVllW^ Test Article: ^-lIsMn Animal "^ dumber Sex -T&sr Uj( i/s/ ;(35 ^ !f33 ^ fl54 ^ - 1/36 ^ 1/3L, ^ J^ !!3? 6 1^ ^ ;;^0 ^ Initial Week I ^ ^91 ^ W W ^ ^0 4ia 4^ 4n ^W^4, Week II ^ ^D W ^ ^ ^9 ^dl ^6 ^ ^ ^-<fc% Week III ^ 62C> ^ ^ ^> ^ ^ ^ ^ ^63 ^ n- ^a^ Study Number: Lot Number-, ^434-]^00(o-9/ D^ Mflir'^UMM-} j>. ^-.^-^ ^^i->"/ (jL4,ater Week IV Week V /Htsfa^ \7 T Coh;a--lle,fmccri-n,J1l i nw Z^>7. ^ ^ ^ bd^ 67/ M ^( W 6-76 sy--^^ Is^ l^'^ w ^ 7/7 ^7 -S^ ko3> ^ ^ ^ 51^1^1 s^ 6>7<5" ^1 ^n " ' fI in 7 ^^Irt^' i yg7y^// / ^u 7-^ ^^r (^^6 0/0 r^TS^ / ^y -LaO/ wfMfieJ> 773 \r^voi' / 1^ P 0 nlUr\ 59S /f^lj^u ^ tw ^/c7^3O0 bffy<2y<' w ^if w (o71 ^ ^ ^>-S^/ /yi^ ^SL w bW J^ ' ATABL3(5) ^ ^ f n ^ e _ s t i _ g a-^t^o--li 1r j'r" ' --' ^r ^-r-^^' l\ll/}(iAot.HMWffY^fi: SCtt-u.'-d^y-- "D-irector Date Company Sanitized. Does not contain TSCA CBI 58 Du Poht HLO 433-91 PHaEMKKON RESEARCH IlITERNAIOHM., INC. Notebook ft f^f)^ r?3i<3e w) Skin Sensitization Test in Guinea Pigs Body Heights (grams) Sponsor; ^-r.'hiiA^ijV^?, ^.W-iJjS^ Test Article-. -ft-V^aC^ Study Number: 4^Q4---hljL-(y^ -9/ Lot number; U/fir I I ftnimal 1 nitial limber S ex Week I ^teek ^ - t N ^ V M I ^ toL li4l ^ ^,9 W ifg /T ^4/ 6^> 11^ (? W W 1^4 ^ 4/9 ^ - ^ \W ^ te^ ^60 -+^y f:^^ Week III Heek IV Week V ?eek VI Final ^ W ^ ^ ^ m^ ^ {^5 ^ W ^ ^-^^ ffIS^ W 1^1 P^/S ^<2X ^r^/ 5l^f/ S-e- 7^ 7Pft ^ ^ ^7 ^ 6^/ W ^4 -W b(-WW e/7ff/ c& Mid-i^ . C(. ^/- h4(, (^ ^5 11^ ^ ^^ ll^ r 4^ 11^ ^ 4/o 11^ ^ 43^ ^ L f-^i^ 61-3. ^ W 4^ 4^1 W9;o54. ^ ^77 ^4 ^Q ^n W ^13 ^ 4-^ ^ ^( , ? j:M^^^6 ^S 1^4 ^ 7^7 ^ ^3 Ip^l f^o Qbv <^37. L>13 W .^,/ (W W ^( ^ ^ ^ ^-3-W .. , ATABL3(5) __,.^^y^^^ fi/^ -y' ^ ^> / y / ^^Thvestiqator. ^r -^"/--tZa"te wm^O.lblAfW\m\d 'Study Director Ccggpany Sanitized. 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