Document mq03qd5wZoX4Ga5dbZgVaZOqb

FOR DU PONT USE ONLY AR226-2954 Du Pont HLO 19-91 Study Title Skin Sensi'tizati'on Test w1t)fB|in Guinea Pigs Study Coinpleted On March 25. 1991 Contracting Laboratory Pharmakon Research International, Inc. P.O. Box 313 Waverly, Pennsylvania 18471 for Haskell E. I. du Pont de Nemours and Company Laboratory for Toxicology and Industrial P.O. Box 50, Elkton Road Newark, Delaware 19714 Medicine Medical Research Mo. Laboratory Project No. Haskell Laboratory Report No. 19-91 Page 1 of 74 Company Sanitized. Does not contain TSCA CBI Amended FPiHnAaRl MRAeTpKoOrNt RESEARCH INTE^R^N,AT^I,O^N,AL, . ^IiN^C0. 1^ WAVERLY. PENNSYLVANIA 18471 HLO 19-91 PHONE (717)586-2.411 COMPLIANCE STATEMENT FAX (717)586-3450 This study was conducted in compliance with the Principles of Good Laboratory Practices (GLP) as promulgated by the following regulatory agencies: U.S. Food and Drug Administration, as stated in the Federal Register, 21 CFR Part 58, Friday, September 4, 1987. U.S. Environmental Protection Agency as stated in the Federal Register, 40 CFR Part 160, Thursday, August 17, 1989. U.S. Environmental Protection Agency as stated in the Federal Register, 40 CFR Part 792, Thursday, August 17, 1989. Organization for Economic Co-operation and Development Guidelines for Testing Chemicals (OECD), ISBN 92-64- 12221-4, adopted by the council at its 535th meeting on 12th May, 1981. Study No.: PH 424-DU-007-90 "To the best of my knowledge, this study was conducted in accordance with applicable Good Laboratory Practice regulations; there were no deviations from these regulations that impacted on study conclusions." _ ^\ . m^a. ^ArmcmcL f}\ai\r^L^1, lit/ Study Director Date / Company Sanitized. Does not contain TSCA CBI GENERAL INFORMATION Du Pont HLO 19-91 Material Tested:" Medical Research Mo.: Haskell No.: Haskell Test Code No. Phannakon Study No.: Physical Form: Purity: Composition: Synonyms: Stability: Material Tested: Purity: Synonyms: Other Codes: CAS.Registry No.: Stability: 18,267 Amber Dispersion l3 In the absence of visible evidence to the contrary, the test material was assumed to be stable under the conditions of administration. Positive Control Material N-Phenyl -1,4-Phenyi enediami ne 1,4-Benzenedi'annne p-phenylenedi'amine e PPD Aldrich Chemical Co., Lot #05012MK Aldrich Chemical Co., Catalog i?24139-3 101-54-2 In the absence of visible evidence to the contrary, the test material was assumed to be stable under the conditions of administration. ^ 3 - - Company Sanitized. Does not contain TSCA CBI GENERAL INFORMATION (CONT.) Du Pont HLO 19-91 Sponsor: Material Tested Submitted By: Du Pont Chemicals E. I. du Pont de Nemours and Company Wi'lmi'ngton, Delaware c Du Pont Chemicals E. I. du Pont de Nemours and Company Jackson Laboratory Deepwater, Mew Jersey Pharmakon Notebook No.: Study Initiated - Completed: In-Life Phase Initiated - Completed: 8/11/90 - 9/17/90 There are 74 pages in this report. Distribution: - 4 - Company Sanitized. Does not contain TSCA CBI DU PONT CENTRAL RESEARCH AND DEVELOPMENT HASKELL LABORATORY FOR TOXICOLOGY AND INDUSTRIAL MEDICINE Du Pont HLO 19-91 March 25, 1991 Pont Chemicals Jackson Laboratory Deepwater, New Jersey Skin Sensitization Test witi n Guinea Pigs Attached is a report from Pharmakon Research International, Inc. (PH 424-DU-007-90). Included in the report are test methods, results and conclusions. IwUBHKJat a topical induction concentration of 100% and challenge Is! concentrations of 100% and 10% in distilled water, was tested on the shaved y intact skin of 5 male and 5 female guinea pigs. Appropriate positive, negative and vehicle control groups were used during this study. During the challenge phasie^^TTQQ^^rrvyyyiieemmaa was observed in any test animals treated with either 100 or 10%g|HBF.J As was expected, a positive sensitization response (slight^frSnhdd//oorrmmiTiTdd erythema) was observed in 5 out of 10 positive control animals. In contrast, no dermal responses were observed in any of the 5 negative or 5 vehicle control animals when challenged with the test material, positive control material, and/or vehicle. Under the conditions of this study jflUHBfh'd not produce delayed hypersensitivity in guinea pigs. (TLA. Dolores E. Maiek, Ph.D. Research Toxicologist DEM/a1w(HL09.43) Company Sanitized. Does not contain TSCA CBI Amended Final Report PHARMAT<ON Du Pont RESEARCH INTERNATIONAL, INC. WAVERLY, PENNSYLVANIA 18471 HLO 19-91 PHONE (717) 586-2411 FAX (717)586-3450 Skin Sensitization Test with H-18,267 in Guinea Pigs PH 424-DU-007-90 Submitted to I. E. Du Pont De Nemours Newark, Delaware MkQW(n iy\rr^ cr^d^ Susan E. Armondi, LAT Study Director Date YwL^\mi Tes't Facility Management // Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 Skin Sensitization Test with H-18,267 In Guinea Pigs SUMMARY Test Article H-18,267 at an induction concentration of 100% and challenge 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 the vehicle control animals. Slight erythema was observed at 24 and 48 hours in the animals receiving the test article at a 100% concentration. No signs of erythema were observed in the test article-treated animals at a 10% concentration. Slight erythema was observed at 24 hours in two positive control animals receiving PPD at a 35% concentration. During the challenge phase, no to mild erythema was observed in the positive control group treated with p-phenylenediamine at a 35% concentration. No signs of erythema were observed in the test article-treated animals at the 100 or 10% concentration sites. No signs of erythema were observed in the vehicle control animals. No signs of erythema were observed in the negative control animals receiving the positive control at 35% or receiving the vehicle. No signs of erythema were observed in the negative control animals receiving the test article at the 100 or 10% concentrations. Under the conditions of this study, H-18,267 did not "produce delayed contact hypersensitivity in guinea pigs.^--.^ ,, , Work by: _/^^^^_j^^^^,g^^__ ~^Charles Boy^frsky y^ Techn.^ian ^ Study Director: (\ r /] . ^UM^C^ . [lA^Wl^' Susan E. Armondi, LAT Reviewed and Approved for Issue: W^PTO^ /\/lJL;w/lQ/iAU\^r. I . Susan E. Armondi, LAT Study Director Company Sanitized. Does not contain TSCA CBI Amended Final Report PHARMAKON RESEARCH INTERNATIONAL, WAVERLY. PENNSYLVANIA 18471 QUALITY ASSURANCE UNIT STATEMENT Study No.: PH 424-DU-007-90 Du Font HLO 19-91 INC. PHONE (7i 7) 586-2411 PAX (717)586-3450 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 August 13. 1990 Reporting- Phase September 26, 1990 Date QAU Report Issued To Study Director September 26, 1990 To Management September 26, 1990 r^^ 94^^ /' ""I Quality Assurance ^w.3/, im . Date \) Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 19-91 INTRODUCTION The purpose of this study was to evaluate the potential of H-18,267 to produce delayed hypers ensitivity 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 p-phenylenediamine. This study was conducted according to Good Laboratory Practice Regulations as stated on page 2 of this report. Areas of noncompliance are documented in the study records. Mo 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, i" 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 (6677F) 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 as Appendix A. Preliminary range-finding tests were 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 3 phases: a primary irritation phase, an induction phase and a challenge phase. During each phase, skin responses were scored according to the system presented in Table I. weekly. During the study, body weights were recorded The topical range-finding test was conducted on 1 female and 2 male guinea pigs ranging in weight from 502 to 628 grams. Aliquots (approximately 0.05 mL) of 12.5%, 25%, 50% and 100% (w/v) suspensions of k^ the test material in distilled water were applied and lightly rubbed onto four separate test sites on the clipped, intact skin on the back of each animal. The intradermal range-finding test was conducted in 1 female and 2 male guinea pigs ranging in weight from 438 to 496 grams. Aliquots (0.1 ml) of 1.0, 10, 50 and 100% (w/v) suspensions of the test material in 0.9% 9 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 saline were injected intradermaliy into four separate test sites on the clipped, intact skin on the back of each animal. Irritation responses were scored approximately 24 and 48 hours after treatment. The primary irritation phase was conducted in 10 guinea pigs (5 males and 5 females) , weighing from 400 to 461 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 clipped, intact skin of each animal. In addition, 10 positive control guinea pigs (5 males and 5 females) , weighing from 409 to 452 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 404 to 435 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. The test article was minimally irritating topically when dosed as received and was also suspendable, not soluble in common vehicles. Therefore, topical route of administration was employed. Induction consisted of a series of 9 topical applications (3 each week) of 0.05 mL of the neat test material. The same A induction procedure was followed for the 10 positive control guinea pigs using 0.05 mL of a 35% (w/v) suspension of p-phenylenediamine in distilled water. The vehicle control animals were similarly treated with 0.05 ml distilled water. Skin responses were evaluated approximately 24 hours after each induction. Two weeks after the last induction treatment, the test guinea pigs were challenged for sensitization by applying and lightly rubbing in 1 drop 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 p-phenylenediamine in distilled water onto two separate sites of clipped, intact skin. The vehicle control animals were treated at two sites with distilled water, in the same manner. Also, 2 male and 3 female previously untreated guinea pigs, weighing 408 to 440 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 control animals. In addition, these animals received 0.05 ml of distilled water and 0.05 ml of p-phenylenediamine at 35%. These animals also served as negative control animals for the vehicle and positive control materials. C. Records Retention All raw data, protocol, correspondence and the final report will be stored in the archives of Pharmakon Research International, Inc., Waverly, PA. ^ Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 19-91 RESULTS AND CONCLUSIONS Weekly body weights are presented in Appendix B. is presented in Appendix C. A copy of the raw data In the intradermal range-finding test, slight to moderate erythema with or without edema was observed. The test article was minimally irritating in the topical dose-range-finding study and as per protocol, the dose concentrations used for the primary irritation phase were 100% and 10%. The dose concentration used for induction was 100%. The dose concentrations chosen for challenge were 100% and 10%. In the topical range-finding test, slight erythema was observed in one animal at 100%. During the primary irritation phase, no signs of erythema were observed in the test article-treated animals at the 10% concentration site. Slight erythema was observed in the test article-treated animals at the 100% concentration site. Slight erythema was observed in two positive control animals at 24 hours. No erythema was observed in the vehicle control animals receiving distilled water. Individual animal data are presented in Table II. During the induction phase, no signs of erythema were observed in the test article-treated animals. Slight erythema was observed in one positive control animal. No erythema was observed in the vehicle control group. Individual animal data from the induction phase are presented in Table III. Dermal responses observed during the challenge phase are summarized in the following table (page 12). Individual animal data are presented in Table IV. Hf;c^i AT903 11 Company Sanitized. Does not contain TSCA CB1 Amended Final Report Du Pont HLO 19-91 Responses No erythema Slight erythema Mild erythema Summary of Skin Responses: Challenge Phase ]?os itiv e Centre)i P;PD 3;.?%.a 24 hr 48 hr ^ 24 hr 48 hr Test f Lnimals H-1S1,267 100 % 24 hr 48 hr 101% 24 hr 48 hr 8/10 8/10 6/10 8/10 10/10 10/10 10/10 10/10 2/10 1/10 4/10 1/10 0/10 0/10 0/10 0/10 0/10 1/10 0/10 1/10 0/10 0/10 0/10 0/10 Responses No erythema Slight erythema Mild erythema 100% H-18,267 Negative Control PPD 10% 35% 24 hr 48 hr 24 hr 48 hr 24 hr 48 hr 5/5 5/5 5/5 5/5 5/5 5/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 0/5 Distilled Water 24 hr 48 hr 5/5 5/5 0/5 0/5 0/5 0/5 No erythema Vehicle Control 24 hr 48 hr 5/5 5/5 .left shoulder right shoulder Under the conditions of this study, H-18,267 did not produce delayed contact hypersensitivity in guinea pigs. ) 12 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 TABLE I SCORING SYSTEM USED TO EVALUATE SKIN RESPONSES Score Skin Reaction 0 No erythema or Edema 1 Slight erythema (barely perceptible, usually nonconfluent) 2 Mild erythema (well defined, usually confluent) 3 Moderate erythema 4 Severe erythema (beet redness, with or without edema, eschar formation or necrosis) If edema, blanching, necrosis or eschar formation occurred, they were indicated using the following code: ED = Edema H = Necrosis E = Eschar B = Blanching SM = Superficial Necrosis 13 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 TABLE II PRIMARY IRI?IT.A1PION PHAS3E SKIN RESPONSES OBSEIWED IN TEST GUINEA PIGS FOLLOWING TOPICAL EXPC)SURE TO H-18,267 GUINEA PIG NUMBER -3440 3441 3442 3443 3470 3445 3446 3447 3448 3449 LEFT FRONT 100% 24 hr 48 hr 0 1 0 1 0 0 0 1 0 0 0 0 1 1 1 1 0 1 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 14 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pent HLO 19-91 TABLE II (Cont'd) PRIMARY IRRITATION PHASE SKIN RESPONSES OBSERVED IN VEHICLE CONTROL GUINEA PIGS FOLLOWING TOPICAL EXPOSURE TO DISTILLED WATER GUINEA PIG NUMBER 3450 LEFT FRONT Distilled water 24 hr 48 hr 3451 3452 3453 3454 15 Company Sanitized. Does not contain TSCA CB1 Amended Final Report Du Font HLO 19-91 TABLE II (Cont'd) PRIMARY IRRITATION PHASE SKIN RESPONSES OBSERVED IN POSITIVE CONTROL GUINEA PIGS FOLLOWING TOPICAL EXPOSURE TO p-PHENYLENEDIAMINE GUINEA PIG NUMBER 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469 LEFT FRONT 35% 24 hr 48 hr 0 0 0 0 0 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0 D 16 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pent HLO 19-91 TABLE III INDUCTION PHASE SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OF 100% H-18,267 WEEK I SCORES GUINEA PIG NUMBER Dose ttl (LEFT) Dose #2 (RIGHT) Dose. #3 (LEFT) 3440 0 0 0 3441 0 0 0 3442 0 0 0 3443 0 0 0 3470 0 0 0 3445 0 0 0 3446 0 0 0 3447 0 0 0 3448 0 0 0 3449 0 0 0 17 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 TABLE III (continued) INDUCTION PHASE SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OF DISTILLED WATER WEEK I SCORES GUINEA PIG NUMBER Dose #1 (LEFT) Dose #2 (RIGHT) Dose #3 (LEFT) 3450 3451 3452 3453 3454 18 \) Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 19-91 TABLE III (continued) INDUCTION PHASE SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OF 35% p-PHEMYLENEDIAMIHE WEEK I SCORES GUINEA PIG NUMBER Dose #1 (LEFT) Dose #2 (RIGHT) Dose #3 (LEFT) 3460 0 0 0 3461 0 0 0 3462 0 0 0 3463 0 0 0 3464 0 0 0 3465 0 0 0 3466 0 0 0 3467 0 0 0 3468 3469 0 0 0 0 0 0 D 19 Company Sanitized. Does not contain TSCA CBI Amended Final Report DU Pont HLO 19-91 TABLE III (continued) INDUCTION PHASE SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OP 100% H-18,267 GUINEA PIG NUMBER 3440 WEEK II SCORES Dose #4 (LEFT) 0 Dose #5 (RIGHT) 0 Dose #6 (LEFT) 0 3441 0 0 0 3442 0 0 0 3443 0 0 0 3470 0 0 0 3445 3446 0 0 0 0 0 0 3447 0 0 0 3448 0 0 0 3449 0 0 0 20 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 TABLE III (continued) INDUCTION PHASE SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OF DISTILLED WATER WEEK II SCORES GUINEA PIG NUMBER 3450 3451 3452 3453 3454 Dose #4 (LEFT) Dose #5 (RIGHT) Dose #6 (LEFT) 21 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 TABLE III (continued) INDUCTION PHASE SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OF 35% p-PHENYLENEDIAMINE WEEK II SCORES GUINEA PIG NUMBER 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469 Dose #4 (LEFT) 0 0 0 0 0 0 0 0 0 0 Dose #5 (RIGHT) 0 0 0 0 0 0 0 0 0 0 Dose #6 (LEFT) 0 1 0 0 0 0 0 0 0 0 "\ 22 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 19-91 TABLE III (continued) INDUCTION PHASE SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OF 100% H-18,267 WEEK III SCORES GUINEA PIG NUMBER 3440 3441 3442 3443 3470 3445 3446 3447 3448 3449 Dose #7 (LEFT) 0 0 0 0 0 0 0 0 0 0 Dose #8 (RIGHT) 0 0 0 0 0 0 0 0 0 0 Dose #9 (LEFT) 0 0 0 0 0 0 0 0 0 0 23 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 TABLE III (continued) INDUCTION PHASE SKIN RESPONSES OBSERVED IN TEST GUINEA PIGS 24 HOURS FOLLOWING TOPICAL ADMINISTRATION OF DISTILLED WATER WEEK III SCORES GUINEA PIG NUMBER 3450 3451 3452 3453 3454 Dose #7 (LEFT) Dose #8 (RIGHT) Dose #9 (LEFT) 24 :^ Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 TABLE III (continued) 11STDUCTI:ON PHAS]3 SKIN RESPONE;ES OBSER1TED IN' TEST GIJINEA ]PIGS 24 HOURS FOLLOWING TOPIC;AL ADMIN][STRAT'ION OF :i5% p-]PHENYLENEDIAMINE WI2EK II I SCORE; GUINEA PIG NUMBER 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469 Dose #7 (LEFT) 0 0 0 0 0 0 0 0 0 0 Dose #8 (RIGHT) 0 0 0 0 0 0 0 0 0 0 Dose #9 (LEFT) 0 0 0 0 0 0 0 0 0 0 25 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 TABLE IV CHAL]LENGE PHASE SKIN RESPONSES OBSI3RVED IN TEST GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF H-18,267 GUINEA PIG NUMBER 3440 3441 3442 3443 3470 3445 3446 3447 3448 3449 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 fc) 26 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 TABLE IV (cont'd) CHALLENGE PHASE SKIN RESPONSES OBSERVED IN VEHICLE CONTROL GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF DISTILLED WATER VEHICLE GUINEA PIG NUMBER 3450 3451 3452 3453 3454 LEFT FRONT Distilled water 24 hr 48 hr RIGHT FRONT Distilled water 24 hr 48 hr 27 D Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 TABLE IV (Cont'd) CHALLENGE PH?LSE SKI:N KESPOli1SES OBS ERVED IN NEGATIVE CONTROL GUINEA E'IGS FOLI.OWING T OPICAL AFPLICATION OP H-18, 267 DUSTILLEEI WATER AND p-PHE;NYLENEDIAMINE GUINEA PIG NUMBER 3455 3456 3457 3458 3459 LEFT FRONT H-18 ,267 100% 24 hr 48 hr 0 0 0 0 0 0 0 0 0 0 RIGHT FRONT H-18 ,267 10% 24 hr 48 hr 0 0 0 0 0 0 0 0 0 0 LEFT REAR DISTILLED WATER 24 hr 48 hr 0 0 0 0 0 0 0 0 0 0 RIGHT REAR PPD 35% 24 hr 48 hr 0 0 0 0 0 0 0 0 0 0 28 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 TABLE IV (Cont'd) CHALLENGE PHASE SKIN RESPONSES OBSERVED IN POSITIVE CONTROL GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF p-PHENYLENEDIAMINE GUINEA PIG NUMBER 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469 LEFT FRONT 35% 24 hr 48 hr 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 1 2 0 0 RIGHT FRONT 35% 24 hr 48 hr 1 0 0 0 0 0 0 0 1 0 0 0 1 2 1 0 0 1 0 0 29 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 APPENDIX A PROTOCOL AND PROTOCOL AMENDMENT 30 v Company Sanitized. Does not contain TSCA CBI Amended Final Report PHARMAKON RESEARCH INTERNATIONAL. V.'.Wl.l'l.V. l't.I<l;:;VIV.1\-l,l 1!1.:1 Protocol - 4240 INC. Skin Scnsitization Test in Guinea Pigs Du Font HLO 19-91 I-HONE (7171SBG.2<11 FAX 17171586-3<SO Sponsor: Testing Facility: Test Facility S.O.P. No.; Study Ho.: Purpose of the Study: Ownership of the Study: Study Monitor: Study Director: Q.A.U. Responsible Personnel: Dates of Performance; Good Laboratory Practices Statement: IACUC Statement: Tentative Date of Submission of Draft Report: E.I. dupont de Nemours Haskell Laboratory for Toxicology and Industrial Medicine Newark, DE 19714 Phannakon Research International, Inc. Waverly, Pennsylvania 18471 PH-424 To be assigned upon study initiation. \' \\ i-^<4 _^)(y-y; ri _c ^ This study is designed to evaluate the dermal sensitization potential of the test material in guinea pigs. The sponsor owns the study. All raw data, analysis, and reports are the property of the sponsor. Dolores E. Malek. Ph.D., E.I. duPont de Nemours Susan Arroondi, LAT^ Phannakon Research International, Inc. Leslie J. Pinnell, M.S. Study will begin within one month of the receipt of the test chemical and authorized protocol. This study will be conducted following the U.S. Environmental Protection Agency Toxic Substances i. Control Act.Good Laboratory Practice Standards (40 CFR W\\ Part leof'-'er Good Laboratory Practice Standards (40 CPR Part 792). This protocol has been reviewed by the Institutional Animal Care and Use Committee (IACUC) and complies with acceptable standard animal welfare and humane care. Within three weeks following the completion of the in-life phase of the study. 080489 31 Company Sanitized. Does not contain TSCA CBI Amended Final Report Protocol - A2W' Shin Scnsitisation Ttfr.t. in Guinea i'icp Du Font HLO 19-91 Records Maintained: Raw Data: Record Retention: Analytical Chemistry: Species: Strain; Supplier: (Source); Sex: Age: Weight at Initiation: AH raw data, final reports, documentation and protocol will be maintained in the Pharmakon Central Files. Amendments to protocol Feed Lot Number Body weights, initial, weekly and final . Compound preparation Volume administration Observed signs Observed skin reactivity Maintained in a Standard Pharmakon' 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, Pharmakon 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, Pharmakon 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, Pharnakon Research International, Inc. will collect the sample at appropriate designated intervals during the study and transmit the samples to the sponsor for analysis. TEST SYSTEM Guinea pig Hartley BuckberG Lab Animals, Tonkins Cove, New York or from any other U.S.D.A acceptable source. Hale and Female (the sex used will be documented in the study records and final report). Young.Adult 400 - 650 grams 32 080489 Company Sanitized. Does not contain TSCA CBI Amended Final Report Protocol - 1;<D Shin Scnuiti:ation Test in Guinea 1'iqs Du Font HLO 19-91 1<0. 1)11 StUllv: Method and Justification for Randomization: Acclimation Period: System of Identification: Research Facility Registration: Animal Rooms: Housing: Sanitization: Food; Dosc-Kaiiye-liiidiny; 2, 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: 'l0 Positive control: XO (at the discretion of the Study Director after consultation with the Study Monitor, this group may be excluded from the study.) Treatment groups will be housed by vertical cage positioning. Any animals showing evidence of clinical signs during acclimation will be eliminated from randomization. Randomization is carried out by use of a computer generated random number table. Before treatment commences, all guinea pigs will be weighed, ranked according to body weight and assigned to treatment groups using a table of random numbers so that each treatment group will have a similar distribution according to body weight. Guinea pigs If beyond the extremes of the body weight range will not be assigned to treatment groups. there is a statistically significant difference in mean body weight between any two groups of the same sex after allocation to the treatment groups, substitution from spare animals will be used to correct the situation. 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 No. 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 22-C 3"C and a humidity of 30 to 70%. Guinea pigs are housed individually in stainless steel h" wire mesh cages. Size in accordance with the "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. R Purina Certified Guinea Pig Chow 05026 or acceptable substitute will be provided ad libitua. Feeders are 080489 33 Company Sanitized. Does not contain TSCA CBI Amended Finpl Report Protocol - '.24D Skin Scnr.il.izatioii Test in Guinea I'iqs Du Font HLO 19-91 Food Analysis: Water: Water Analysis: Rationale for Test System: Rationale for Dose Selection: Justification for Test System: Compound Preparation: Absorption of the Test Material: dcsiyillid to reduce Boil in';, biid^inq, and scotterir.g. 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 nm>( onitored for contaminants at periodic interkva3l according to Standard Operating Procedure 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. Spmi-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 34 Company Sanitized. Does not contain TSCA CBI Amended Final Report Protocol - 4:^0" F-.in .Sc-iisit-ir.Li-^ioii Test. in Guinea I'igs Du Pont HLO 19-91 Vehicle: Volume Administration: Route of Adrainistration: Rationale for Route of Administration: No. and Description of Animals per Dose Grouo: Method of Study Performance: The choice 01 vehicle varies, depfiidiny on the ii.3l.uin of the Cost substance. Commonly used vehicles are distilled water, saline, echanol-.distillcd water (80:20, v/v), dimethyl phthalate. acetone:dimethyl phthalatc (l: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 intradennally, 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 animsis 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 may 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 nl) 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. 35 080189 ^ Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 Skir. Sc-nsi tir.ation lY'st in Guinea Pigs OLiijC-ivatioiis for signs ol dermal irril-ution vil l'irccorded at 24 and 48 hours after application- At each observation, all treated sites will be scored according to Table I- Primary Irritation Phase For the test guinea pigs there will be 2 sites per animal in the area between the shoulder and the middle of the back- One site will receive the highest concentration u-hich is no more than mildly irritating as determined from the dose-range-finding study. The second site will receive one-tenth of that concentration. Each site "ill receive 'l 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 run in diameter. The vehicle control guinea pigs, if used, will be treated at 1 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 dermal observation is made for the primary irritation phase. If the test material is soluble in appropriate vehicle, e.g., 0.91 salineor .dimethyl phthlate, induction will be performed by intradennai injection. If the test material is insoluble in the commonly used vehicles a topical induction procedure will be used. The hair at the appropriate application site will be clipped on the day prior to each application or, if 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 intradennai injections will be made, l per week at l week intervals. A virgin site will be used for each injection. A 0.1 ml aliquot of a 11 solution of the test material in an acceptable solvent (e.g., 0-9 saline, dimethyl phthalate, etc.) will be administered by intradennai injection to the clipped sacral area of each test guinea pig. If distilled water is used as a vehicle in the primary irritation phase, 0.91 saline will be used for the intradennai injections. The vehicle control guinea pigs will be 35 080489 Company Sanitized. Does not contain TSCA CBI Amended Final Report !'rol.0t:o) - 4L''".1)J Sl'.in acnsiti^ai.ioii Test in Guinea Du Pent HLO 19-91 Method Validation/ Positive Control: Evaluation of Dermal Resoonse: Li/uated dy dbove using Llie ucliiclii unly. The po^n-iv^; control guinea pigs vill be treated as above using the positive control material. .Topical Administration A total of 9 applications "ill be made to the sacral circa, 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 phthalatc, 0-91 saline, etc- "ill be applied directly to the skin and then gently rubbed in with the end of the syringe, to cover an area approximately 25 urn in diameter on each test guinea pig. The vehicle control guinea pigs will receive similar treatments using the vehicle only. The positive control quinea 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 may 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. 37 080489 l) Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 19-91 Protocol - -l:'.u'1 !.; Skin Scnsiti;a^ioi; Test in Guinea Piof. Interpretation of Results: Sensitization Intervals a. Primary Irritation Test - Dermal 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 Rechallcnge (if required) - Dermal evaluations will be made approximately 24 and 4G hours after the test material applications. All test sites will be graded on a. scale of 0 to 4 as follows: TABLE I Score Skin Reaction 0 No erythema or edema 1 Slight erythema (barely perceptible, usually nonconfluent) 2 Mild erythema (veil defined, usually confluent) 3 Moderate erythema 4 . Severe erythema -(beet redness, with or without edema, eschar formation or necrosis) If edema, blanching, necrosis, superficial necrosis or eschar formation occur, they will also be indicated using the following code: ED = Edema M = Necrosis E = Eschar B = Blanching SN = Superficial Necrosis Sensitization is defined as a 2-or-more step increase (e.g., from 0 to 2, from 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 1 to 2/10 3 to 4/'i0 38 Degree of Sensitization Weak Sensitizer Mild Sensitizer 080489 Company Sanitized. Does not contain TSCA CBI riot^n-d?.4oFinal Report Shin ;;i.'ii:;iti r.ntion Test in Guinea I'iqs Du Font HLO 19-91 Necroosv: Euthanasia: Statistical Analysis: Rechallenqe: Positive Control Article: Supplier (Source): Special Handling Instructions: Analysis of Purity: How Supplied: Rationale for Positive Control Article: Kutio ol l;<.-rii'>onscra Uem'cc- o: ..'.ciisH-i.^tioii 5 to 6/10 Moderate Senitizcr 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 "ill be classified as a weak, mild, etc. sensitizer. Pathological evaluations of test animals will riot 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 N-Phenyl-'i,4 phenylenediamine (PPD) Aldrich Chemical Company, Milwaukee, Wisconsin Standard precautions The purity is the responsibility of the manufacturer. 100 gm bottle As per sponsor's request. ATXPL4 080489 39 Company Sanitized. Does not contain TSCA CBI Amended Final Report Protocol - }?.'{'> ,o Skin Scm.i.ti^at-io-i Tc-st in Guinea I'iqs Du Font HLO 19-91 Test Article (Name or Code): Chemical Abstract No. 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.and 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: Shipping'' Instructions: AMENDMENTS Date Date ATXPL4 ^7--?-<10 ^1^ho APPROVAL OF PROTOCOL Study Monitor ____ ^-z^a ^L-E-.AJL^ Study Director /W/M^G- . (JAfwntrL^- 40 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pent HLO 19-91 APl'ENOn: A Test Article Information Identification: Test Article (Name or Code) : //- /{-, ZC.T- Lot or Sample No:___ Physical Description: ^ivse'v gisflifAiiom Purity:_____^^ Expiration Date: Density/Specific Gravity: Solubility (check one) : ts'atcr pifre^r--j Ethanol i/wxfMwt/ Corn Oil Acetone vx^ow f'K^'-'v DKSO c-^Ku-oi^^ Chemical Other (please Classification: Fslpamecmiafbyl)e__________C_o_r.ros_iv_e________ Other /W=- J- ^ II Storage Infonnation: Material Storage (check one): Room Temperature ' ; Refrigerator Freezer _____; Other (specify) ___ III Handling Information: Known Hazards: Precautions: Routine use of protective clothing includes laboratory coats, latex gloves, dust masks, and safety glasses. Other recommended precautions In Case of Emergency Related to this substance, contact: Soiafes MAtf/< (person) ^ WfioA/r (company/division) at Soi-Sl.!,-^^^ (phone number) IV Disposition: All materials will be returned to the sponsor three months submission of the final report to the sponsor. Person and whom test articles are to be returned. Name: /life. Cociiy <f^' S^-(/IL rt.ooM following address to Address: /^iUt:en. i/s6ot*ff^yBt/C70^ ^CAO Arew^K tie .oiyzM/7 VI Signature: ~^^^ P. |M ^ ^ Date: f-^-^ ATXPL4 41 Company Sanitized. Does not contain TSCA CBI Amended Final Report Protocol Amendment Skin Sensitization Test in Guinea Pi9s PH 424-DU-007-90 Test Article: H-18,267 Du Font HLO 19-91 Method of Study Performance: (page 5 of protocol, Dose-Range-Finding). Original Statement Prior to initiation of the main study, a dose-range-finding study will be performed. Corrected Statement Prior to initiation of the main study, a topical and an interdermal dose-range-finding study will be performed. Reason for Deviation: In order to determine the route of exposure to be used in the main study and in discussion with the sponsor on July 26, 1990 /Uo^K)^ UAr^cmcJC Susan E. Annondi, LAT S4t-uiid^<yr Dn-ii^rne^ct-^orPhannakon Research International, Inc. fi' /LPif.^ iflO Date (j V AT903 ?~\ 42 Company Sanitized. Does not contain TSCAICBI Amended Final Report Du Font HLO 19-91 APPENDIX B WEEKLY BODY WEIGHTS (g) 43 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 Animal Number____Sex .Test Group 3440 M 3441 M 3442 M 3443 M 3470 M 3445 F 3446 F 3447 F 3448 F 3449 F Initial 404 432 432 442 400 442 461 413 414 401 WEEKLY BODY WEIGHTS (g) Week II Week III Week IV Week V 423 . 475 449 514 459 516 478 526 433 490 474 542 504 569 433 477 426 471 427 476 525 580 567 618 577 650 585 554 517 544 579 645 658 708 515 541 481 518 503 550 Week VI Final 630 673 683 716 700 728 697 746 582 606 701 732 794 823 591 585 574 595 591 623 ID 44 Company Sanitized. Does not contain TSCA C81 Amended Final Report Du Pont HLO 19-91 Animal Number____Sex Initial Vehicle Control Group 3450 3451 3452 3453 3454 M 414 M 431 M 429 F 404 F 435 WEEKLY BODY WEIGHTS (g) Week II Week III Week IV Week V 445 492 445 505 468 541 428 492 461 490 552 589 562 630 616 670 527 578 548 566 Week VI Final 639 673 676 719 715 753 616 640 634 673 45 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 Animal Number____Sex Initial Positive Control Group 3460 3461 3462 3463 3464 3465 3466 3467 3468 3469 M 409 M 418 M 429 M 425 M 452 P 422 F 412 F 421 F 439 F 427 WEEKLY BODY WEIGHTS (g) Week II Week III Week IV 438 499 544 458 526 599 453 506 529 459 509 564 483 535 589 453 469 503 447 502 534 439 490 518 451 485 513 452 496 534 Week V Week VI Final 594 651 685 656 722 750 595 651 696 620 682 713 640 698 711 517 547 573 592 620 . 644 571 620 641 554 580 594 567 606 621 (D 46 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 Animal Number____Sex Initial Negative Control Group 3455 3456 3457 3458 3559 M 423 M 437 F 440 F 408 F 435 WEEKLY BODY WEIGHTS (g) Week II Week III Week IV 454 509 574 462 513 556 481 528 606 452 517 533 480 482 540 Week V Week VI 624 656 646 699 630 688 598 616 554 639 Final 695 731 728 651 650 47 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 APPENDIX C COPY OF RAW DATA 48 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 ^ rHAPMKON 1;1::".1;AI.;CH IIiTl^NATIONA',.. 1M-. Skin Scnsitization Test in Guinea 1'icis ^ ' ^ r ^ Dose-Ranqe-Findinq Study Sponsor = C f ///// /T^yf //^/y-^) >.<-u--'"------.^.-,,^ Purpose: /7^' //fl^.'n'^^. T^y/^y/.l^/^^^A^Z^^^^ ^ ^ study No. = ^^j y- 6i^ w^-w_____/ Method: ^f.OA^.. /A^fe^ ^^(T t'______ ^//-jl^n Date of Initiation: uD<ant-ee OoLf TAe.erzmTii^inxaan^t<ifioi<-ni'u!;n;____7 // // yrj' ' n J^^ ;//-/^ '^^^/.'t'A^'.) Test Article: ^6 7 / De scrip tioh: ^L?Jr^^^--'J^t^W^I'i^-^} /-- ^ ^ ^ f^O^ Amount Received: \ 0'^). I P~/T^M/\.( V)h ) Date Submitted: ' fV/'//^ C^ /_?/9^_____ ^{[w Vehicle = y/^ ///^7^______ Dose Levels: /^.S 0 S" .^ Oaw^//)^ ^g Route of Adminis tration; J ^/P^[ /Yv^yX.__________________________ Aniaal P.O. S-. ^D//-n^/</0^_______________________________ Species;^^^__________ Food Lot S: ^>i/^^^'^ /^ No. of Animals on Study:_ J- Scales: Y Animals Clipped: 7//^/^> Cfi_______ Strain: HQ/\L^,____________ - /.^ Identification ^/)/?ft(^jyft/^/^ ^ <- ^ / Sex: Hale Female Light Cycle Checked: 7//t ^S.' ^A//^-^^^- Compound preparation; (^ /000/0:?WW/{0/^. MU/'A^, 0.5C>!^7'/.A>{/ 0/ ^Wy/iW^M^-A^ ^A^^^/.n^fYt^..M^L, /i^^Oiy^../^4/^y/^-A^-;^Yi)/-;y^;;^-^ -^A^ ^'^ ^ y-j^f.wh&U^^ ^/i^^.P^^^/^/i^y^^^ ^ ^K'^O; ^^/^jCC^tiM^^^^A gy<^^^^^^^^^^ ^zonA 7^ ^5~^ /^^nA,i^^ArniPnc^i'u>h<^^ ...^/)fr\\^^--hh.!./V/i/jrrfAi\\jj rQ^^MMjM^^ 7^///^^/Q/P?)P/^'/Q / (/ ^fwlsst.i.qa.tor -* ^^MM^L Study Director Date' ATABL3(1) t) 49 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 PHARMAKON RESEARCH INTERNATIONAL, INC. Skin Sensitization Test in Guinea Pigs Dose-Banqe-Finding Study 1----------^ pPace ^!i --------\ ------ 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 Figure D Site 1 Site 2 Site 3 Site 4 /o^^ J.3" /fc 5-0 ^o /or YC: Animal No. / a 3 1-4; Test Sites 24 Hour Scores Test article Sex and dose Initial Time of Site Wt. (gins) Dose 1 ^ //J^ //-//.? (^/AT <r<93-. 0 ^ / / - 9:> &0(f^H>0% <?AT //.'3'i^Ai (2. Q ff.on'y^/u^w ff/? //J^/ft 7/n(f0 1^ 7//7(?tK .n. ^^ur <t^ ^L 0 Site 2 0 0 0 0 0 Site 3 0 0 V Site Final Wt. (gms w/^ / D ^ 6 / Scores ^ 0 0 0 b-S^- J^L 0 0 0 o"J^<^ ATABL3(2) 50 Company Sanitized. Does not contain TSCA CBI Amended Final Report PHARMAKON KESEAHCIl 3 N'TKPNATIONAL, INC. Du Font HLO 19-91 Skin Sensitization Test in Guinea Pigs Dose-Range-Finding Study n^woi^^ s-ip."o-n---so-r: (' ,1 . {], Pcmi (in c\Q \''--i 11^-i >.-< n^ < n: / r-i/in.-i^i.-r--'---------------------------------------------------------- y/^ 7)vdeDAiwiiuL, ^L^ i^V\bMMfwUL iJSMUtf^ poW^i. r^ fl^i. purPose tF^ i^- ^ih^ Picn._______i._______u ^l^tS ^///)" Study No.: Method: fWW-m-OWO_______________________________ {)J\O^CO{ Date of w^o Initi^atiio~n.:^L,//-.^ Test Article: ./-/--/ Amount Received: ^0^, [fHo.'w^.f 1 ^ 0 Date of Termination: Description: ^f^ 1wl^i p-.vww/^Wl1r1^ >n))-. ) Date Submitted: ^'i//',S))//'^. Vehicle; 0 .I % ^"YLf/Ag^_________ Dose Levels: f,0 . JiV-^ Jn,^J /CO"- Route of Administrationi;: up3j\a^Afm&l', ^ ^ / J A A , 0=^/w^1 Ani^l P.O. .= ^0^-O^mO^_______________________ Species: JhiHt)ftC< . /Jq_________ Strain: HO^-WH^'_______ : Food Lot Jt= ^OlTOf^ Identification: J^dniw^ No- of Animals on Study: Tw{JUL>J':^))Sex: -Male cr-' Feinale WA. ^^ gyj^^y^n - ScaleS: Q UTni'VlO-'^.) ^ 'SS-SiQ. QinT^iLjLight Cycle Checked:: I^U'^O'SA- Aniinals Clipped; 7/W^^?--_________ 5^'i /^ ^T Compound Preparation: (".A 07t> ^SOYno'L^ ^OA^CUL^.S . '$^A-, ^'_______ -75gp^af^ta^Idj. .(?5. ^ ^7)% -y? .5IL ^ b ^/i7^^. 1^ ^M ^A./ ^ g ^ Q^ Am^^(Q^^^jL). ^W^r^ ' ' Ai.^- wi\^'nyi/\ Jff-"ir^" i/y^- 'i'Y\re^/i ^IhfU/yC'a. ^^LAj^irYy^' (^ ^ j ^ r w h ^fAinm'it/^? ^Murr-^^ (4ai(r\^U!-. i wpfW/^^/Lf ilhul^\srri\. -jTl^I^lqOn^^fAA^ "' 0 ATABL3(1) - ^ l ^ ) ^ ^ 6/1rm^ Investigator /i \^; ^-^ M^/n)<^. Study Director 51 '7y6^/yn Date ^l^oho Date Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 PHARMAKON RESEARCH INTERNATIONAL, INC. Skin Sensitization Test in Guinea Pigs Dose-Ranqe-Findinq atudy m f \ Pace i^--------|. 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 Site 1 Site 2 Site 3 Site- 4 /.0?6 =/0'7o =5D^ = ^QQc, 1-4: Test Sites 24 Hour Scores Animal No. Sex / ^ ^-^,^(3 ^^ ^1 ^ ^ w^ ^..^^y5^s p^ ,7 ^ Test article and dose 1.0 ^/O^D /.rvUoO^ Initial Tiiae of Site Wt. (gms) Dose 1 yjs^ ^'ICL 0 CL w 0 71^7110 71571^0 /"> SUifW v JL ^ &- Site 2 0 Site 3 1 Site Final 4 Wt.(gms) ^ / 0 (^ ^ 0 ^^ / , W. i4r8MHooaur^S-cores &^ "/^ } 0^. )^{--lOQ/- / o 0 0 ^ ^ %^ i^-/ ATABL3(2) Investigator r\ \j /-/ i\lW^k. iwr^mv^L Study Director y/^?/^6 Date 7/y^o Dace 52 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 PHARMAKON RESEARCH INTERNATIONAL, INC. Skin Sensitization Test in Guinea Pigs N.B.t(f------R,| Page ^|^^RJ Title: A'l(l^wrAlti\n-/iu^^?/it ^ A.u^'a. Pi.'<^ I \ i-'A',r i/i Sponsor: (^.A (ii-uf^. ffe f}^OLUl.'^ ^^^^ Purpose: ^Q PW.H^n.^C ^.f^t,! ^AitwnC^ O-W^h.i c/ ftvCUir yiTKi.U'.-j.s^. t-i'^tin';l /','r.^,______ Study No.: Wfi l^i Wir\i-I[)f\U:i -00-7-^0 A ^r\_n/^'77^^/37 Method = (\P.U'\ ^ p.lOlnft^^^l^- Technical Initiation: T/n J ^O_____ Technical Termination: "lIlll^Q -CPfO) Test Article:- ^--1^-,^'']________ Positive Control .^'-Phfnul-1, 'i^hc'^,J'r"dl^1'"<- ^W Lot Number: CUSiiJ/f^g/i-U7______ Lot Number: n^o ( ^-K\ i^,_________ Descripti'oh:^),sc6^ L. c^,W/W^'^) ^' f^pj'ji. Description; /^Atf//^^______ . Vehicle:-^ ^,j[J^ L^<d7/. fijf^ t^^w^ f, -> /^Z^g^Vehicle: ft^^.fP;,P DtfeL._________ Amount Submitted: fOS^' c WjSU,Ct->(L-t : ]OCy)V-o /t^. (^-/it; Receipt Date: '^/v5 190 Route of Administration: ff(l_A_n_Y_}_H_J_l _ Anunal P.O. S; ^'Ol/" _________ mW^Q C. Toxicology Lab. No.: hi/cig/ft.^ ^. Species: ^U^^.^O___________ Strain: 4^ 1^0^' . _______^.670W^ ^^^<^?^ )^,L. ^^0"^^^^, wWeeight Range: ^9^'' . Food Lot 8: -^-5-0 7 70 /-^J-^ s-/^0 /W. Ho. of Animals on Study: So_______ --3C>f^.W^Ct/^\ ^f/^ATf Sex: Male fS^ __ Female /^_'_______ Checked:^^^,?!.?!^';^-)! W) Scale ti:< Light Cycle '- i i----/ - / ' Animals Clipped: J7/o/yi fy^ g///^_____ ' s ^ --e\ j'i S j .(-^^ IoS^ -- ^ s/i'ilii ^^^ ar/^/K <^ {l.alils 6-i / 8-y/<-/(tf fefl s-ls-<,/}o o-^ f//3,/9, f/!> Fonnat for Primary irritation. Induction and Challenge Phases 1-2 Primary Irritation and Challenge 3-6 Sensitization Phase (Induction) ATABLE3 Study Director 53 Date / ^nho Date' Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 PHARMAKON RESEARCH INTERNATIONAL, INC. N P oteb aqe -ook 8 p e Skin Sensitization Test in Guinea Pigs GENERAL OBSERVATIONS Study No. : ['H^O^I'Du-OOl-'iV Test Article: H-/y:3/<.7 Date _________Sponsor :t. t/. rf,i i'rn{' rf.< n^.yr'n><..f.^ AN = (appears normal.) Initials ^//-pfeo.--/)^?n^^: C'^Mfcl - Atu:(k.f / ^ -^'/^-/, S ^ /- / / / / / /" / / / / / ^: / y / 54 ATABL3(7) Company Sanitized. Does not contain TSCA CBI Amended Final Report DU Font HLO 19-91 PHARMAKON RESEARCH INTERNAIONAL, INC. Skin Sensitization Test in Guinea Pigs- Notebook Page S w Body Weights (grains) . l / Sponsor: -/^ Test Article: A' W^ /Wjf' ')u'/yft(!iC<^ S tudy Number: ^>/- A^--d^--g^) // g ^^J Loc Number: f)r't- /? DpIl.l'^hU^ animal 'lumber sex 3^c> ^ 3^^\ cf w^ 3^^. <r ^ 3^70 ^ 5^^ ^ 3^ -? ^W7 ^ <=^^<f ^ 3W ^ Initial Week I s'eek II -<Ai</.. ^ '/JJL ^7 y^ ^1 yy^ ^7^ ^OCl yd3 ^/vyj- ^7^ ^//' V/J ^"3^ y/^ w^f. S'l 11 ty') /^ ^i^ ^^7 <s^ Week III y/r ^y J7^ ^^ y^ s-^ w ^77 ^7/ ^7^ ^A?/^ ^ Week IV ^-1.^ ^n ^-7^7 ^r^- ^7 W? 6^ 5/S' W S6^ f/oif/ye /^ Week.V S^ ^ (~^o ^ S^ ' ^vr 7G^ 5V/ ^r ^ f/5/^ /^ Week VI Final ^3.^ ^J ^3 7^ ^t <;) 7^r ^,97 7^ ^^ ^T ^^ ^ '^-7o/ .7^ ^ V7^ ^^ ^ 7^7 5Ts5' ^ ^^AW $^- 1 ^7^ <;^ ^//c, /-C- f/l?/f0 ^i D ATABL3(5) - ^ Y -^y^./1//^^AA,, ^^/^-^/^^rr^^Cf^a ^y////77//7^^ ^tigatbr/--'' D/^e u.^.^S. i.iAfwwrK- ^/I/j,7/9() Study Diractor Date 55 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 19-91 PHARMAKON RESEARCH INTERNAIONAL, INC. Note Page b -ook 8 |g 3 Skin Sensitization Test in Guinea Pigs_ Body Weights (grams) Sponsor:^../). (-^P^'. ck- fy-rfT.OU.^ Study Ntunber: f/-!''/^u-/)i./CLi7-</'^ Test Arrttiiccllee::/-/^--//-'/?g j^,7 J / , ' 7 > L o II Animal Initial. 'lumber S ex rfeek I Week JUL 6^v< \z^ 6^ y^ j^ro" ^ v/y' W Week III 5^/ d' 5W- ^ 5^5'3' P %?/ ^-T 4y< y^y ^ ^y/ Ytf</ ^ y^ 34^ ? yjj' ^nlfo /=<, ^^ M<s G^\ ^ ^ s/y9/9t> C^ t Number: Meek IV SS3-. s ^ &?/^ s^ ^ y <?PW^ /--w^"---- /"'/./- l", Week V 5^^ ^70 /.7^> ^7<^ S(.^ fh'/f ,^<-/ '^.1,1'sfif; // lteek VI ^J.^^^ J^a Qj 6W. ^Aw ^ky^ ^3^ ^//2/^ /^ Final ^13 ^ T^-^ (^VO 67? f/n/f' /=c A^.j^^z^a jy^r ^ 3^5-^ ^ S/^'7 ^ <sw ^ ^^ $? / /^w 0^v^ ^-r^ ^ r/j ^oJ ^7 W j ' ^ / ^-/or y35- s-li't^o ^^ ^ ^c2- 1^-7 W '7^ S'/i^o ^ ,<7^ S~^ 606. W ^ ?A^ /y. 6^1^ 6^ ^30 5'fr ^^Ay/^ /^^ ^J"^ ^9 ^(?r ^/^ ^37 ^/y^ ^(/. fof6" 7J/ 7?-^ ^; <;^'o 9//7^ ^<'^ ATABL3(5) ^^^^ ^^^^1 ( ^f/y^ <^T5nrv^eesittiiggaattoo"r /,^." y/' ^.^A) Study Director ^//-7/9^ /^ 6^te y//7/^ Date 56 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 PHARHAKON RESEARCH INTERNAIONAL, INC. Notebook Page Skin Sensitization Test in Guinea Pigs Body Weights (grams) Sponsor .-^.^.VA /W" Tlj^/lt^A^ Test Article: ]-f-l'S,9-J) -- -- -- -- -- -- -- y ^ j Animal 'lumber ^ sw 3^o 3^/ ^7 5^ 7^ ^-2- SW 45W-^ ^^ 34^3 ;ex r^~/^ (f ^ (f (f (f Initial | leek I Week 11 ^ C^n-b^L, W W y/^ ^ wr ^ /^- ^ ^A </^ Week III w 5-^ W Study Nuznber: f^W^U-COl-^O Lot Number: nc-f-0.fip^''---flh(L. Week IV Week V Irfeek VI Final .5r'r 5'^-? w (.5^ ^^.0 ^o c.^i (pfl 6&'1- ^ &r^" 752) ^^ 7/j' 7/1 3^< ? -?^^ z ^^7 ? 3^?- 3^9 ^ ^i <//^ yo?-/ ^7 ^.^ gllll'1'0 FC. 4^ ^q W ^\^s> ^jlS'jiCJ ^------ W Wl W ^ m ^^ S03 S^H- ^y ^/3 -5-J^ /^o rc, 5^ 5-^L 57/ 5-.5V W f/S/fQ ^c,, w 6^0 6X0 53-0 GOkf/yi/f-o /=r 5^ ^</(f ^/ ^/ <^/ %'' ATABL3(5) v -. fiA^r^ A/^J/r. ^^^^/^2 ;^$fe^-S^<^/^7/^ ^^^^^ee^yifi-cgEigaiatgtooartor.^. ^^ ^^/TDDaatt^^ MM^Ks, 9//7/^ Study Director DirectorDate 57 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du pont HLO ls-91 PHARMAKON RESEARCH INTERNATIONAL, INC. "'"'BBJ ^9^/fC' Skin Sensitization Test in Guines Pigs Test Article Preparation Study No.: ft/ y^^- hC( - 00 7 -^6________!.________________ ^ / Test Article: //-/<f, J^S" ^I^O Sponsor: TU^'^.Z^-i.'l--^ ^. ^^ //^^X^7 Primary Irritation Phase (Week I) : Zg.-<^ /?^-^-^"-^ ^.UXl^^ (M^ ^ --------^-----------------/^O-^^jL M^yclZO-t-^^ I ^-W O-O^M/jdik {lOo7o}cM^ /^/^^Yg26^^.^^' ^/^-C/K_^ ^'":> ^^^ ,A^AZ</^^^; /I<Lfe^^^^ ^ J5^' /^ - ^..S^< f^ '^o (0 yv^ f CO^^^^U^^'^-^. i/K^^^ tf^-<0 /Cus^/^ k)aJb^(\/L^i f^'(^/'U^6L(U.U&. i/eA^ r,/f^iL^eM^ -A^<-^ fyUjt!^-^~ u}{La ^ku^. /^c/fetAL^ (JtU^JLu -v d>CG^!^ ^/^S^' /^ ftiJ_ A /^c^ (L^Ci^ IAI^ /^^(L, ^////^ 6-^_______ Induction (Week I) 7'JJ^' QA/T^~/e ^0-^00 /7 j}- ,(f ^ fA JL^''f Di^O______ /'/I-C-^L PujcU^Cav^^^^/o ^A J-S^w^ /^fii ^ /^2<f/^)^g<.<-^ !\i,\ljt!f,i^J^^^ fyiw^ ^^.^^^[f^/7 f.U^y^ ULUJU^^tfL^' j ^ f}/fJllff <9Ajj r/7 tL/juutMt-t -^ijLCf^/^-jf:u}(^^uum /^^//k^7; ^^^ -^, ffl d[zt^in^i\ Q^^/^ ^.5'n^ dS^aAjkQU ^dMi^. ^oC^ Induction (Week II): 7L<L/" (UCCL'jU. 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B4----^1 Skin Sensi-tization Test in Guinea Piqs Test Article Preparation (Continued) Study No.: ^W^-f^U.-OOl^O Test Article-. H'/fl,3.^)7 ^ .onsor :('1"-.^. rli./,Pc;i-}t'n-g /^y'/ry.^j Induction (Week IV): ' 7 ^ " / ^ . Challenge (Week VI) : ICA/O.flfw^l^^^A^^^ D.^^A.P^/A/^^/Jfl'frWt^, ^A////-^///-^^^/^\ nJl^h^lO^^A^h^^^ .^L^^ ^^7^^^?pr.XrXfef7e ^ , .^. so^. ffir>^ A _ ~^^A^. . f/^/^ ^/^^. ^. fi,//^i 7^, - /. ^ s^/,1//.^/ 9/H/9D/^ _____________ Rechallenge (Week VII); ATABL3(4) 59 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 J -^--^ .^ -S"^r1 It 0 "S)\ < 1 1 3 a Q V ^ 0' ^ -S IT) j^ > "* <y &< a (X: 6 (J ' 1)2. ^ 'ja -^ ^ - - a*' S f . ^; 0-, ^r iy i u. C 0 n a o HI ^^QQOOOOOO Q- -0 .<: ^-o (ft a -x0--- - c& , c 0 -< 3 . . ' ^ ^ 1 ^ S .^ ' \ ^ 1-1 -< ' ^ /^ ' ^ ^ M 'S. z 0 >, ^ b i ^ n i ) ia 20^oooCQooO ^ QcQ m o' 0 c * -- o o -- e o S&^ ---- ---- ---- -- ^ ---- ---- '/>. 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Does not contain TSCA CBI Amended Final Report Du Pont HLO 19-91 0 ' c 1 cr 0 18 Z a, ^ ^r u M X 0) Z U i5" Z CP 0 C ^1-1 T4 0 MM E-i a) Z l4 1-10 u xui rt rt a H E 'in (d TC \ C; < z . -< o ii 2 -' K > a: -< a 'o e- c M ^\ ^ . ^ ^ -s .'^ ^ ^ J Q ^^ ? ^ \^, (N, -^^\" -C <^ 0^- C: "< ^1 01 1 .ga n in 3 a z >. z 0 3 P p o 1^w t-1 0) U in c 0 0 Q U tji ^ ^ B) 'o E u-i ra ^ ^ T H (M B (n ffl 0) 01 B M M h rt 0 0 0 &< Q u M ffl 0 H U) C o o M Q U a a 3. CP ri (U O e u-i (o 'ri 0 0) c-< a ^2 / y -s P ' /1 7--' /, > <r>\ ^7' ^ ^ 0 Os ^ ^ Q Q <^ 0 Q ^) 0 <; 0 0 ^ K \Q '0^< ^ ^ / -0 </C ^ ^ ^^ ! ^ / ^ ^ 77 ' 2^1 ^ ^ ^ ^ ^'^ ^ ^ ' ^ -^ '<^ <^ ^ 0) r-1 U ^ u.. U ^ ^ fl" K tM s ^e^ 0 c c c r'J\ 0 0 c 0 ^ ^400 0) 11 e u-i in bo ^ &- Q ^^ ^t j ~ ^ &^ v^ 0 U in c 0 0 Q U ^ (. ^ / ^ z ^^ ^ ^ b ^ ^- ^- ^ e4n1 ^v- ^JY^ 0 a: in c u 0 M &1 in 0 E- 1 ^ ^^ ^ ^t H^ ^^0 ^^^0, ri ^^ ^^ ^) 0\(^v&^) ^^ ^ ^ ^ 68 ^ ^ 'i^. m ^ .-) 10 H u ^ c Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 <.j 0" (^^ c 0) u-t T: E 0 ro rt (U < a: .c ' } ~-~ \ \ '"C ^ ^ . ', l^- 0 (/' '^ .-l-^ c G 0 G 0 <J 0 A; 0 0 31= .Q < --1 3 13 P< c ^ <N ^ <^ r^ .^^ ' ^ v v ~C^.' ^ "Ss a--3 ^^ -uc ^ ^ (j , a i0 3 U P 0 m ,j ^ ^ 1 ^ ^ IS >5 ^ ^ ? ^^ la - u u u n 0 rt: Ul c u 0 U) Oi U in E-i (U 0 p ^ 7^ i? ^ ^ 'P m~ c 0 0 Q U / r ' / ^ 7^ CP c ^ 0) 13 g m <o E--" 100 a. !^- 0 01 T H N S Q <) ^ r'\ r^^ 0< N. ^ ^s ^~ S / ^ - '-Si-s ^x <1 U) 0) '? L| ai ai 0 E 1" in U -1 0 0 w &< Q 5o t-t H M C; CP ^ fl) ? e 'u M --I 6^ 0 0) C; Oa Is^ \ (" / \/\ to ^ ;v; ^ ^ ^ ^ ^ !% 7 ^ )^^ / n 5 ^ 0 ^s ^ ^ n> U) <r u CM S Q Q C 0 <^ 0 ^ -Q C Q> Q \i 00 <^ ^ y; ^ ^ ^ ' ^ ^ ^ ? X 0) ^to fc> ^ ^ ^ ^ ^ ^ ^ ^v Ul ^ Ifl ^ ^ ^ ^ ^ ^ -<-< ^ C 0 ^ ^ w\\ rf z d (V' ^ ^a ^ '3- ^ 69 m 1-1 R3 *"( j U ^ C t-4 Company Sanitized. Does not contain TSCA CBI ^) Amended Final Report i 0 C ( 0 y-t t E o m n ni Ei a; in a- h 01 X <.^ 4 n'\ I Y> >^0~" i^ C-" ^ ^ r^ * s - <^- <^ 0 C: C C (^ ^ ? ^ <N ~^^C: ^? a ^^, ~P 0 ^ C - t4 (U 0) E " in ^HOCQ a) u in c 0 0 Q U 0' c f4 (0 rl 0 0) fr" a U) T h 0) S. "''} \ ^ / ^st ^ ^d^ S -~t^ r^ .^ / ^ '^ ^ J > ^ <^- 0- ^ i Ci^ <$- ^ ^ ^ ^ Q Q^ 0) ^ a 0) o e i" in U -ri 0 0 un E-i Q 1- t- t-i B) U Ul C ^ : a ; a0 0u r^ v^ So f ^ ^ ^ ^ S ^ \ / '0 00 ^ ^ 2^1^^ 0' c f in ? (/" E 'u ra ^ rf o a 6< c; k ? / 'o (?0 c\. a ^r u CM S. ^ 0 ^ 0 0 c ^0 ^ ^ ^ a a) e ^ ^ ^ i ^ ^ ^ y ^ ^ ^3 ^ x 0) 01 ^ 5A rt S ^ ^ ^ E ^> ^ S ^ C 0 ^' . [c ./^ <~^ 1 0 . te ^y^ ^\ |f- . ^ \ k -^'5 k3 ^- ^- ^ n r--4 ^, 10 ^ T- ^ u ^^ ^ ^ ^ c Company Sanitized. Does not contain TSCA CBI D Amended Final Report > -T LW A; 0 0 3E ja 0) (U u cr. 0 (0 Z & 0 ' c 0) iu t e o <n rt aj 6< c; /c\ ' ^, ^ /-' *\, J ^ \r s '.^ (~-\ f ^ ^ u (N 3 01 (U e IM 01 E-^i 00Q r^ ^ \^/ G^'> >n \ ^ -0 C 0 (^ ?;- ^ s^ ^1 ^^ \-^ 's 1s ^'^ / <^ c 0 u -u^ z u M 3 O i5 2 0' 0 C M -^ E-i .M cS 3 Z Q 0; M en H U a n M 0 U B U3 X i-1 < 10 Id E (0 -r4 M C c; a; s - 0 fl ^ 3 < O S ''"1 ca > < -r4 a o n* c ^ ^^ y> ^{SN ^ Q Qs ^1 ^ U 0) A U i a) z ^ s O 3 U P 0 10 i-l ^ -s 0) 0 in e 0 o Q u CP c ^ a) 'o E '*-i in ^ 0 <1) ei o; ^ 0^ ^ T H <M X C Q ^^~^ . 1U ^ <D a> o E >M ro U-ri 0 0 <1 & Q t>0 h (DO 1-< h-1 10 C A >; C Q00U C v O' -rl a) o E ^ la 5?S Oo Q.fcI ^ ^( ^ y'- ^c ^ \ ^ ^ '^^ / <^ ^ os ^1 Q ^ Q Q C Q Q Q ^ \ /s-^. ^a ^ -^ ./i ''no L^ /. ^. T / '^ -3 ^ 0 ^ -s cl^; ^ ^> te ^ ^^ ^-^ ^ 0 1-i U -H w 1-1 0 eS. Ul C U 0 U) & n M E-' -- ^ (M ^ as 1 0 Q ^ a g IM 0) ^ 0 0 f" Q \^ > ^\ Co Q o Q 0 <^ 0 ^ ^ 0 <0 \s 1 ^0 ^ > '? 64 0 U^ 10 C S3 ^ ^ g' M ^ ^ n e <;'- ^ ^ C 0 < 2 ^0 b ^^\& ?^^ ^ ^Ft) ^^^ ^. ^^ ^ m ^ ^:^^E~^r;^^-& 1 ^'\ ^s^ ^ ^ '^s t- ^^?:^ r~ ^NS 71 Du Pont HLO 19-91 / ^ ^^ i ^' f tn '- i-^ ^ (0 -^i U ^s)- Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 19-91 Y cr c \ E .. a) -rf "-i o >< 0 10 KS.'SJoC> \U) co ^ W T S \ CP C ' 11) 01 CP ^ (1) C rt \ --131 0U 0) r4 - \ '0 , U g m <T3 u in ^ o <u 0 (!) 6- \s 0 ^i: 0: ft \ a (U n 0' 0 'O T U) r^j ^i s 2 & s <U 0) e 4^ in -e<^00Q N \ i-i 0) \ ^ <u CP ^ ^ u c ^ z ai ^ ir 4-1 .-1 a) u .a a Ul C 0' 0 0 0 .C - Q CJ K Ul \ . u 0) N o 4 ^ ^ ^ Qi ^ .-4 ai o sJ p 01 C v-i 0 o o a) . QU ^ W \ i ^ cr. \p ^ c 0 ^ ^-) ^ in a) ^ o CT: g u-i ia ^ r ^ 6- o a) tC 0 =h 0 <3- .^ ^ ^ 0 0 <J 0 0 0 0) o' oi i-i C (U CO )- \J u o 0 0 0 0 . z O E M IB i-l 0 o) 3 lJ & a. - ^ 4-1 0 0 0 0 ^J 0 -.s 0 <3- 01 ^ '0 %' , -Q- 01' <^ <J -0 '< ^<J\ -Q ^ 0 0 <T H 3s ^ ^ ^1 ^ ^ Q C ^ Q ss, Q (? 0E) v-i t<oU 1-~ S o o H Q ^ \ 5^ T^ ^ VS- 3 1 (\ ^ 0) c . A t-1 fl) U C, 3 in c o> 0 0 Q 0 U -C^; CO, 1 C/ n \ 01 ^ O ^ 7 ^ (-( y ov f-t x U (U ^, -^ Ul U w <^ !-1 U 1 5 ^ ^ ^ (> ^ 0 < 1-1 -^ ra in It) (^ c JJ r^ ^ ^ ^^ ^ 0 U) ^ St- 4-) ^ ^ n ^ Q. a) C 0 C Ul E- < z 72 Company Sanitized. Does not contain TSCA CBI 1<\ Amended Final Report c: \ (U ^ e u-i o ^ 0 ra , E- 0) a- \ " \ 5 ^ a) CP ' (D U) vx^ ^ 0 ,-1 H 13 0 ^'E -s .C U U t/1 v 0 (D S^ 0 3= & A 0) 0) u cr> ^ 0 m <4?^ a- Ut ^ CM Ll z Q- (u ^ E u-i in -rf 0 0 E-" Q JU \ 't' ^^- < ^-' ^ ^ u ^ ^^- 4 ' '3 ^: ! ^ s ^ <^ -)- _6 ~^. < 00-^4: a u j:-^ 01 c o' -v Q L> 0; 03 w . ji tti u in c 0 0 Q U y^i <u./<. >l3U"7; ; ^ \ ^/ ^ \ \ <:^' c' c: .r< ai 'o E u-i (u -6-1' 00a. ^~ ^ \ c\ ^ ^~ 'Q 0- ^S- 0 0 0 0 U <a 0 01 o' <n ->^ in -<: 'CT U )-< c (U CG - k~ K ^ E v-i <a t (^ --1 0 0 e< (.1; 0) 1-1 ^ Jr- in (- ^J <^ ^<J <J T 1-1 <M 3: 0 <; Q e ^Q ^ ^ n 0 in c: 0 Q. 01 ^ ^ ^' ^ 01 73 ^ 4-1 Ll < AJ U) CI E" ^ t) a) B 1-1 ui Ct) -< 0 0 6< 0 t ^). ^ iS- fc^. (U Io JJ r-1 <a u c 3 in c o> 0 0 0 '1 .C Q L> B; 01 V? V ) ^m ^ ? B) 0 U ^(i) o, -f 3 000^: j Ul C "-1 0 Q U ^ 03 ^ v- ^ 7 L^ ^ ^ ^ I X 01 ^ to ^ s^ ^4- VI ^ ia ^ ^ C 0 < ^ 1 ^^Q m 1 Du Font HLO 19-91 ^ :?<cr ^O 0 O 0 ^5 c"i 0- ^ ^* 0 .'^-'i Q \ ^- '^-3- ^ / 0- 0 ^T 00 0 0 0 0 0- K \ ^ rv / -^ ^ ^ ^ Yr^J ,^\ I-S^ ^^ r~^ 'c<\J \ 2 1 ^ -> /- ''d 7<: d i 22^ 1 w / ir ^ 3 /' ^ \ ^r ^ : r ~i~ (0 <^- o -C 0 (j o 0 0 ', } 0 0 0 --) r > < ^ <3- ^ 1 2^. 0 r^ >>. ^ ^ Cl^. O Q> ij '>-> Q ^ c ^ O (=) -Q 0 (Si^' ->^ ?> ^Y '&- fe \ <v> r ; "/ Q/ ^ ^ i ^ ^i / i /-. 'i \-) P w, ^ 1/ /- ^ 0^ /V P'' -DC ^ ^ 0()i.- ^^ ^ ^ ^ ^ ^ ^ ^ rch ^ CT) L j ^ --c ^ ^ /c ? 0 <- ~^ ^ -0 c-^ ^ ^ ? ^ I) 0' i;. c tn -4 <o (- ^ AJ s p4 < C <r- -;.'N 73 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 19-91 Y CP c ai ^ \ E u-i o '<d 0 " ^N^0 q^ 1 ^ 0 0 ! .c (U a) 4J 0' 0 a z A (U cr d) ) ^i ill ^1 Vl a o S.c u u in 11 m ^ <r a CP c tt> T g i*-i (0 ^ 0 (U ^ 0; a' u) IN ^ a (D t) gm M -5 o o < Q '? ^ (U tr u z t-1 c U tt) O -U r-1 .C 3 CP 0 ^ (S .0=1 n O) t 0) U ^-> ; -; in c IM o 0 0 <D Q t-> i-l U3 C' C 0) T g U-< (fl H 0 0) E-l Q: '\ \^ '>. ^ ^ <^ y^- > ^ ^ / '^^ < ( ^y ,\ \ )^ ^ C.>- / i ? ^ ^r =r ^ v) / O cr cr <3- \ \ \ ^--Stn (u CP U) n c a) CG 1-1 ^tc E u-i ifl ^ 0 01 fr< OS 4-1 0 0 0 0 0 0 0 c^ o 0 ~2 0 0 n 0 <--\ 0 0 c^ 0 o~ ^ C) ^ ^ 6x . \^ Q^- (-4 01 f) ^ ^CS K ^ .0 0 0 ^ ^---- 0 0 <; ^ 0 ^ '0 ^ ^^. .0 Q> 1 ^ t ^ 1 ^ ( 7c/c s , ^0 ^ > ^ ^ ^ ^^ 0- ^ <s i-4 ^ ^ ^ U ^ ^ ^ ^ ^ ^ 4J ^ 0 < ri ^, Ul 1 .^ ^^ ^ ^ c 4-1 ^ -^ 0 U) ^ ^) 0, 0) U3 E-i 0) 1) e '-i in rv- -E-.*-10Q0 .a-' 6-- . l-i r-1 0) U .: 3 in C CP 0 0 0 -rl .C Q U Oi 03 u (O 'o r-1 a) u AJ 3 in c: in o o o ai s Q U >-) 01 >^ \ >; w ^ ( 03 "^ ^ ^ ^ / Q /. / / 7/ ^ / ^ ^~ r-1 C 0 < z 0 ^ ^ ^ w ^- ^ ^ r^ ^< ^ ^ IT) ) 0- S^ <s^- 11 ==??-^^ S' Ul r~1 r-l n n ^ ^-1 u a ^ < E: n Company Sanitized. Does not contain TSCA CBI