Document VKxrQrLxLLbZ26N7B3GGNeoK

AR226-2977 FOR DU FONT USE ONLY Study Title Delayed Contact Hypersensitivity Test in Guinea Pigs with H-19173 Study Completed On July 17, 1992 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. 161-92 ^^ Company Sanitized. Does not contain TSCA CBI Amended Final Report Revised Du Font HLO 161-92 COMPLIANCE STATEMENT This study was conducted in compliance with the Principles of Good Laboratory Practice (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 Number: PH 424-DU-012-91 "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 conclusion." A^O^fo - (IA^^I^ Study Director W^ AlJ/^9. bate/ n 2 Company Sanitized. Does not contain TSCA CBI Material Tested: Medical Research No. Synonym; Haskell Test Code No. Pharmakon Study No.; Physical Form; Purity; Composition: GENERAL INFORMATION Test Material Du Font HLO 161-92 H-19173 PH 424-DU-012-91 Slightly yellow liquid dispersion 100% H-19173 contains: Synonym; Submitteds Notebook No. CAS Registry No.; Stability: None availble In the absence of visible evidence to the contrary, the test material was assumed to be stable under the conditions of administration. Material Tested: Purity: Synonyms: Other Codes; Positive Control Material N-Phenyl-1,4-Phenylenediamine 98% 1,4-Benzenediamine p-phenylenediamine (PPD) Aldrich Chemical Co., Lot #05012MK Aldrich Chemical Co., Catalog #24139-3 3 Company Sanitized. Does not contain TSCA CBI GENERAL INFORMATION (CONT.) Du Font HLO 161-92 CAS Registry No.; 101-54-2 Stability; In the absence of visible evidence to the contrary, the test material was assumed to be stable under the conditions of administration. Sponsor: Du Pont Chemicals I. E. du Font de Nemours and Company Wilmington, Delaware Study Initiated - Completed; 10-28-91 - 07-17-92 In-Life Phase Initiated - Completed; 01-28-92 - 03-07-92 Pharmakon Notebook No. 4 - - Company Sanitized. Does not contain TSCA CBI Du Font HLO 161-92 DU FONT CENTRAL RESEARCH AMD DEVELOPMENT HASKELL LABORATORY FOR TOXICOLOGY AND INDUSTRIAL MEDICINE K. D. Dastur Du Font Chemicals Brandywine Building July 17, 1992 Delayed Contact Hypersensitivity Test in Guinea Pigs with H-19173 Attached is a report from Pharmakon Research International, Inc. (PH 424-DU-012-91). Included in the report are test methods, results, and conclusions. H-19173 at topical doses of 100% and 10% (v/v) and an intradermal dose of 1.0% (v/v), was tested on the cl-ipped, intact skin of male and female guinea pigs. p-Phenylenediamine at a topical dose of 35% and an intradermal dose of 1.0% (w/v) was used to demonstrate the ability of the test system to detect a skin sensitizer (positive control group). In addition, a group of male and female guinea pigs was treated with 0.9% saline at induction and distilled water at challenge (vehicle control group). At challenge, a group of previously untreated guinea pigs was treated with H-19173 at topical doses of 100% and 10% (v/v), distilled water, and 35% p-phenylenediamine on separate, intact skin sites (negative control group). One animal died during the course of the study. Necropsy of this animal revealed no visible lesions. The; death of this animal was considered spurious in nature and not related to treatment. During the induction phase, no to slight erythema was observed in the majority of the test article-treated animals. Following the third intradermal injection, a single guinea pig presented with a mild erythema and after the fourth intradermal injection, moderate erythema was noted in another guinea pig. Slight erythema was observed in one vehicle control animal following the third induction. No to severe erythema with/without blanching was observed in the positive control animals. During the challenge phase, no signs of erythema were observed in the test, vehicle, or negative control animals. No to moderate erythema was observed in the positive control group treated with p-phenylenediamine at a 35% concentration. Under the conditions of this study, H-19173 did not produce delayed contact hypersensitivity in guinea pigs. /^3r/c. ~3-y^c^<- Scott E. Loveless, Ph.D. Senior Research Toxicologist Company Sanitized. Does not contain TSCA CBI Amended Final Report Revised Du Pon-fc HLO 161-92 Skin Sensitization Test with H-19,173 in Guinea Pigs PH- 424-DU-012-91 Submitted to E.I. du PNoenwt ardke, NDeemlaowurasre& Company Reason for Amendment: In order to include page number on compliance statement, footnote on page 23, and correct weight range of animals on page 47. F0 t M^JG? - /MfmWjk . Susan E. Armondi, LAT Study Director Lj4c!, Dat^l')^ w'^ \J ( ^ ^ ^ ^ ^ g^st Facility Management Dg^Ce ^^^'. Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 161-92 Skin Sensitization Test with H-19,173 in Guinea Pigs SUMMARY Test Article H-19,173 at topical doses of 100% and 10% (v/v) and an intradermal dose of 1.0% (v/v), was tested on the clipped, intact skin of male and female guinea pigs. p-Phenylenediamine (PPD) at a topical dose of 35% and an intradermal dose of 1.0% (w/v) was used to demonstrate the ability of the test system to detect a skin sensitizer (positive control group). During the primary irritation phase, no signs of erythema were observed in the test, vehicle, or positive control animals. One animal died during the course of the study. Necropsy of this animal revealed no visible lesions. The death of this animal was considered spurious in nature and not related to treatment. During the induction phase, no to moderate erythema was observed in the test article-treated animals. Slight erythema was observed in one vehicle control animal at 24 hours following the third induction. No to severe erythema with/without blanching was observed in the positive control animals. During the challenge phase, no signs of erythema were observed in the test, vehicle, or negative control animals. No to moderate erythema was observed in the positive control group treated with p- phenylenediamine at a 35% concentration. Under the conditions of this study, H-19,173 did not cause delayed contact hypersensitivity in guinea pigs. Work by: Study Director: Al^^Y^ . [//[(^(WC)^ Susan E. Armondi, LAT Reviewed and Approved for Issue: M\L,,'tJ\rfj\Ll^^(/^ ri / I'i (.U(W}ffYJU1' . Susan E. Armondi, LAT Study Director 7 Company Sanitized. Does not contain TSCA CBI Amended Final Report Revised Du Pont HLO 161-92 QUALITY ASSURANCE UNIT STATEMENT Study No.: PH 424-DU-012-91 Study Director: Susan E. Armondi 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 January 30, 1992 Challenge Phase March 5, 1992 Reporting Phase March 30, 1992 June 12, 1992 Amended Final July 8, 1992 Date QAU Report Issued To Study Director To Management March 31, 1992 June 12, 1992 July 8, 1992 Q ^ - ^ ^ y y Quality Assurance March 31, 1992 June 12, 1992 July 8, 1992 7v7 JU ? Date// /??^- Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 INTRODUCTION The purpose of this study was to evaluate the potential of H-19,173 to produce delayed hypersensitivity 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 for its ability to identify compounds that are sensitizers. The sensitivity of the test system and procedures to detect chemical sensitizers was evaluated with p-phenylenediamine. MATERIAL AND METHODS A. Animal Husbandry Young adult male and female Duncan Hartley albino guinea pigs (generally 8 to 10 weeks of age) were received from BuckberG Lab Animals, Tomkins Cove, Mew York. The guinea pigs were housed singly in suspended, stainless steel, ^" wire-mesh cages. Each guinea pig was assigned an identification card on which a unique 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 as 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 study 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. During the study, body weights were recorded weekly. Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 The range-finding test was conducted on 1 male and 2 female guinea pigs ranging in weight from 375 to 417 grams. Aliquots (approximately 0.05 mL) of 1.0%, 10%, 50%, and 100% (v/v) solutions of 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. 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 428 to 512 grams, by applying and lightly rubbing in 1 drop (approximately 0.05 mL) of 100% and 10% (v/v) solutions of the test material in distilled water onto two separate sites of clipped, intact shoulder skin of each animal. In addition, 10 positive control guinea pigs (5 males and 5 females), weighing from 429 to 506 grams, were treated by applying and lightly rubbing in 1 drop of 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 424 to 522 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 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 sacral intradermal injections (1 each week) of 0.1 mL of 1.0% (v/v) solution of H-19,173 in 0.9% saline. A virgin site on the back of each animal was used for each injection. The same injection procedure was followed for the positive control guinea pigs using 0.1 mL of a 1.0% (w/v) suspension of p-phenylenediamine in 0.9% saline. The vehicle control animals were treated with 0.1 mL 0,9% saline. Skin responses were evaluated approximately 24 hours after each induction. One animal died during the course of the study. Necropsy of this animal revealed no visible lesions. The death of this animal was considered spurious in nature and not related to treatment. 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% (v/v) solutions of the test material in distilled water onto two separate sites of clipped, intact shoulder skin. The positive control animals were challenged for sensitization by applying and lightly rubbing in 1 drop (approximately 0.05 mL) of 35% (w/v) solutions of p- phenylenediamine in distilled water onto the clipped intact left shoulder skin. The sites used during challenge were the same used on each animal during the primary irritation phase, respectively. The vehicle control animals were treated with distilled water in the same manner. Also, 2 male and 3 female previously untreated guinea pigs, weighing 415 to 509 grams at study initiation, were treated by applying 1 drop each (approximately 0.05 mL) of 100% and 10 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 10% (v/v) suspensions of the test material in distilled water onto two separate sites of clipped, intact skin and served as negative control animals. These animals also received 0.05 mL of distilled water and 0.05 mL of p-phenylenediamine (35%) in distilled water on separate, intact skin sites. These animals also served as negative control animals for the vehicle and positive control materials. 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. There were no statistically or biologically significant differences observed in the group mean body weight data among the four dose groups. A copy of the original raw data is presented in Appendix C. One test article-treated animal died during the study. Necropsy of this animal revealed no visible lesions. The death of this animal was considered spurious in nature and not related to treatment. In the range-finding test, no signs of erythema were observed at any test site. Based on the results of the range-finding study, 100% and 10% concentrations were used for the main study. During the primary irritation phase, no signs of erythema were observed in any of the test, vehicle, or positive control animals. Individual animal data are presented in Table II. During the induction phase, no to moderate erythema was observed in the test article-treated animals. Slight erythema was observed in one vehicle control animal at 24 hours following the third induction. No to severe erythema with/without blanching was osberved in the positive control animals. Individual animal data are presented in Table III. Individual animal data are presented in Table IV. Dermal responses observed during the challenge phase are summarized in Table V. During the challenge phase, no signs of erythema were observed in the test, vehicle, or negative control animals. No to moderate erythema was observed in the positive control group treated with pphenylenediamine at a 35% concentration. Under the conditions of this study, H-19,173 did not cause delayed contact hypersensitivity in guinea pigs. 11 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pon-fc HLO 161-92 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 codes: ED = Edema N = Necrosis E = Eschar B = Blanching SN = Superficial Necrosis 12 Company Sanitized. Does not contain TSCA CBI Amended Final Report DU. Font HLO 161-92 GUINEA PIG NUMBER 1531 1532 1533 1534 1535 1536 1537 1538 1539 1540 TABLE II PRIM?^RY IRRITATION P:HASE S]KIN RESPONSES OBSERVED IN TEE;T GUINEA PIGS FOLLOWING TC)PICAL EXPOSURE 'TO H-19.173 LEFT FRONT 100% 24 hr . 48 hr. RIGHT FRONT 1 0% 24 hr. 48 hr. 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 0 0 0 0 0 0 0 0 0 0 0 13 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 TABLE II fCont^d) PRIMARY IRRITATION PHASE SKIN RESPONSES OBSERVED IN VEHICLE CONTROL GUINEA PIGS FOLLOWING TOPICAL EXPOSURE TO DISTILLED WATER GUINEA LEFT FRONT PIG Distilled water NUMBER_____________24 hr. 48 hr. 1551 0 0 1552 0 0 1553 1554 00 00 1555 0 0 14 Company Sanitized. Does not contain TSCA CBI Amended Final Report DU Font HLO 161-92 TABLE II fCont^dl PRIMARY IRRITATION PHASE SKIN RES3PONSES OBSERVED IN POSITIVE CONTROL GUINEA PIGS FOLLOWING TOPICAL EXPOSURE TO p-PHENYLENEDIAMINE GUINEA PIG NUMBER 1541 LEFT FRONT 35% 24 hr. 48 hr. 0 0 1542 0 0 1543 0 0 1544 0 0 1545 0 0 1546 0 0 1547 0 0 1548 1549 .0 0 0 0 1550 0 0 15 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 TABLE III TNDUCTION PHARV, SKIN RESPONE;ES OBSERVISD IN TEST GUINEA PIGS 24 HOURS FOLLOWING IV11'RADERMAL lfID) INJECTPIONS OF l.O'ifc H-19.173 GUINEA PIG NUMBER ID1 (LEFT) ID2 (RIGHT) ID3 (LEFT) ID4 (RIGHT) 1531 0 0 1 1 1532 0 0 1 1 1533 0 0 1 1 1534 0 0 2 1 1535 0 0 1 1 1536 1 0 1 1 1537 0 0 1 1 1538 0 0 1 1 1539 0 0 0 3 1540 0 0 1 1 16 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 161-92 TABLE III fcontinued) INDUCTION PHASE SKIM RESPONSES OBSERVED IN VEHICLE CONTROL GUINEA PIGS 24 HOURS FOLLOWING INTRADERMAL (ID) INJECTIONS OF 0.9% SALINE GUINEA NUMBER PIGID1ID2ID3ID4 (LEFT) (RIGHT) (LEFT) (RIGHT) 1551 0 0 1552 0 0 1553 0 0 1554 0 0 1555 0 0 17 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 TABLE III INIAUCTION PHA;W SKIN RESPONSES OBSERVED IN POSITIVE COiNTROL GUINEft. PIGS 24 HOURS FOLLOWING INTRADEISMAL CIDl INJECTIONS OF 1.0% D-P]HENYLENEDIAMINE GUINEA PIG NUMBER ID1 (LEFT) ID2 (RIGHT) ID3 (LEFT) ID4 (RIGHT) 1541 1542 1543 1544 1545 1546 1547 1548 1549 1550 0 1 3 3 0 1 1 3 1 0 1 38 0 0 2 413 0 0 3 3 0 1 1 2 0 0 4B 3B 0 0 2 2 0 0 2B 4 0 0 3 313 B = Blanching 18 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 161-92 Ti^BLE IV CHAH,ENGE PHASE GUINEA PIG NUMBER 1531 SKIN RESPONSES OBSE!RVED IN TEST GIJINEA PIGS FOLLOWING TOPICAL APPLICATION OF H-19,,173 LEFT FRONT 100% 24 hr. 48 hr. RIGHT FRONT 1 0% 24 hr. 48 hr. 0 0 0 0 1532 d d d d 1533 0 0 0 0 1534 0 0 0 0 1535 0 0 0 0 1536 0 0 0 0 1537 0 0 0 0 1538 0 0 0 0 1539 0 0 0 0 -1540 0 0 0 0 d = denotes animal dying on study. 19 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 TABLE IV (continued) CHALLENGE PHASE SKIN RESPONi3ES OBSERVED IN POSITIVE CONTROL GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF D-PHENYLENEDIAMINE GUINEA PIG NUMBER 1541 LEFT FRONT 35% 24 hr. 48 hr. 2 3 1542 2 2 1543 1 2 1544 0 0 1545 0 1 1546 0 0 1547 1 1 1548 1 1 1549 1 2 1550 0 1 20 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 161-92 TABLE IV fcontinued^ CHALLENGE PHASE SKIN RESPONSES OBSERVED IN VEHICLE CONTROL GUINEA PIGS FOLLOWING TOPICAL APPLICATION OF DISTILLED WATER VEHICLE GUINEA PIG NUMBER 1551 LEFT FRONT Distilled Water 24 hr. 48 hr. 0 0 1552 0 0 1553 0 0 1554 0 0 1555 0 0 21 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 TABLE n1 rconti nued) CHAI.LENGE PHU^.SE SKIN RESP ONSES OBSERVED 11ST NEGAT3CVE CONTRC)L GUIMEA PIGS FO LLOWING TO PICAL APPLJCATION OF H-19.:1-73. 0-1'TTENYLENEI5IAMINE A]ID DISTI LLED WATER GUINEA PIG NUMBER " 1556 LEFT FRONT H-19.173 100% 24 hr. 48 hr. 0 0 RIGfflV FRONT H-319 ,173 1 0% 24 hr. 48 hr. 0 0 LEFT R]EAR PP'D 35;% 24 hr. 48 hr. 0 0 RIGHT REAR Distill ed Water 24 hr. 48 hr. 0 0 1557 0 0 0 0 0 0 0 0 1558 0 0 0 0 0 0 0 0 1559 0 0 0 0 0 0 0 0 1560 0 0 0 0 0 0 0 0 22 Company Sanitized. Does not contain TSCA CBI Amended Final Report Revised DU Font HLO 161-92 Table V Summary of Skin Responses Challenge Phases Positive Control Test Animals PPD 35% a H-19,173 icm'1 10% b Responses No erythema 24 hr 4/10 48 hr- 2/10 24 hr 9/9 48 hr 9/9 24 hr 9/9 48 hr 9/9 Slight erythema 4/10 4/10 0/9 0/9 0/9 0/9 Mild erythema 2/10 3/10 0/9 0/9 0/9 0/9 Moderate erythema 0/10 1/10 0/9 0/9 0/9 0/9 Responses No erythema H-19,173 100%'^ Negative Control 10% b PPD 35% c 24 hr 5/5 48 hr 5/5 24 hr 48 hr 24 hr 48 hr 5/5 5/5 5/5 5/5 Vehicle Control Distilled Water 24 hr 48 hr Vehicle Control Distilled Water'^ 24 hr 48 hr 5/5 5/5 No erythema 5/5 5/5 left shoulder right shoulder left flank right flank 23 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 APPENDIX A PROTOCOL AND PROTOCOL AMENDMENTS 24 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 161-92 PHARMAKON RESEARCH INTERNATIONAL. INC. WAVERLY. PENNSYLVANIA 18471 Protocol - 424D1 Skin Sensitiza-tion Test in Guinea Pigs PHONE (7171586-2411 FAX (717)586-3450 Sponsor: E.I. du Pont de Henours S Company P.O. Box 50 Elkton Road Newark, DE 19714 Testing Facility; Phannakon Research International, Inc. Waverly, Pennsylvania 18471 Test Facility S.O.P. No.: Study No.; Purpose of the Study: Ownership of the Study: PH-424 PH4^-Ol<L-0^-^l To be assigned upon study initiation. 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. Study Monitor: NSecnootut rsE. 5 LCoovmepleasnsy , Ph.D., E.I. du Pont de Study Director: Susan Armondi, LAT, Phannakon Research . International, Inc. Responsible Personnel,:. Dates of Performance; Good Laboratory Practices Statement; IACUC Statement: 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 in compliance with 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).. Protocol-424D1 has been reviewed by the Institutional Animal Care and Use Committee (IACUC) and complies with acceptable standard animal welfare and humane care. 25 Company Sanitized. Does not contain TSCA CBI -- -Jlil*-'!!-"-'---'.-' Amended Final Report Du Font HLO 161-92 , Protocol-424D1 Delayed Contact Hypersensitivity in Guinea Pigs (Buehler) Tentative Date of Submission of Final Report: Records Maintained: Raw Data; Record Retention; Analytical Chemistry SpeciesStrain; SUPPlJfjT (Sourcg) Acre:_ tWhiethiinn -tlhifreeepwhaeseeksoffotllhoewisntugdyth. e completing of ApArrlocl htoriavcweosl .dwatial,l bfienamlairnetpaionretds, indotchuemePnhtaantnioankonand Amendments to protocol Feed Lot Number Body weights, Compound initial weekly and final preparation Volume administration Observed signs Observed skin reactivity Maintained in a Standard Phannakon Notebook All raw data and completed notebooks. Atensatlyasristicanled/csatarrbieilritymioxtfutrhee istesthte article and trheespsopnosnsiboirl,ityPhoanf ntahkeonsRpoesnesaorrc. h If requested by Inc. will through its International, subcontractor, conduct approp indicat ri e ate the analytical additiona l analy cost sis inv and olve w d i l l receipt and evaluation of the following appropriate analytical method. In the case where a satisfactory method is not provided, Research International, Inc. or its Phannakon sspuobncsoonrt,rawctiollr, daevt ealodpdiatipopnraolpr'ciaotset mtoeththoeds. If the sponsor elects to analyze article/carrier mixtures, the test International, Inc. will appropriate designated Phannakon Research collect the sample at study and transmit the intervals during the samples to the sponsor for analysis. TEST SYSTEM Guinea pig Hartley BuckerG or from lab any Animals, Tomkins Cove, New other U.S.D.A acceptable York source. Male and Female (the sex documented in the study used will be report). records and final Young adult 053191 26 Company Sanitized. Does not contain TSCA CBI -' f'fsSlKV'-'i'-w Amended Final Report Du Pont HLO j Protocol-424D1 Delayed Contact Hypersensitivity in Guinea Pigs (Buehler) 161-92 Weight at Initiation; No. on Study- Method and Justification for Randomization: Acclimation Period^ System of Zdentifjcationj 400 - 650 grains Dose-Range-Finding: 3 Vehicle control: 5 Study Monitor, this (at the discretion group may be of the the study.) excluded from Negative control: 5 (if re-challenge is munseaectcdehs.)esdarny,egaatsiveeconcdonsterot l oafni5mnaalsivwe,ilal gbee- Test article: 10 P os St itive udy c Di ontrol rector : a 1 f 0 te ( r at c the onsu discre ltation t ion with of th th e e Study Monitor, this from the study.) group nay be excluded Treat groups positioning. will Any be housed by vertical animals showing cage clinical signs during eliminated from acclimation evidence will be of is carried out randomization. Randomization by use of a computer generated random number table. Before treatment rcaonmkmeedncaecsc, oardlilnggutioneabopdyigswewigihllt be weighed, and treatment groups using a table of assigned random to anumsibmerislasrodtihsatrtibeuatcihontreaactcmoerdnitnggrotoupbowdiyll have wboediyghwt.eigGhtuinraenagepigwsilbl eynoontdbetheasseixgtnreemd etso,of the tsriegantmifiecnatngt roduifpfse.renIcfethineremeiasn a statistically body between any two groups allocation to the of the same weight sex after substitution from treatment groups, spare animals will be used to correct the situation. Minimum: five (5) days taCanagdggeetsrdem.aatmrkeednt wgirthoupan. aGniuminaela gproigusp anurembeear,r sex Research Facility Registration; Animal Roomc;- HUSBANDRY AUn.Sim.Da.lAW. eRlfeagreistAracttio7n4; NSoC. 22133-R1 -1e0t7 seuqn.der the Separ Light ate cy c i l s e o - l a tio 12 n h o b u y rs t est ligh sy t, s tem. 12 h o u r s Temperature/Humidity made to maintain a Every attempt dark. will be and a humidity of temperature 30 to 70%. of 22'C 3'c 053191 27 Company Sanitized. Does not contain TSCA CBI ;;;n:;J -;-. Amended Final Report Du Font HLO 161-92 Protocol-424D1 Delayed Contact Housing- Sanitication- Food : Food Analym'j Water Analysigj- Hypersensitivity in Guinea Pigs (Buehler) Gui cag n e e a in pig st s a i are nles h s ou s sed tee l i n h d " i vidu wire a l l y or two per Size in and Use accordance with of Laboratory the nesh cages. "Guide for the Care Roef sLeaarbcohraCtooruyncAinl.imal RAesnoimuraclse"s, oNf atthioenIanl stitute Waste material will and feeders will be be removed sanitized daily. Cages every two weeks. aPcucreinpataCbleertsifuibesdtiGtuutienewa iPlligbeChpowro^vi#d5e0d26 or libitum. soiling, Feeders are designed bridging, and to ad reduce potential been effects of scattering. The dietary contaminants have considered, and manufacturer's data, based on the contaminant believed to be within acceptable levels are limits. pTrheesreenat rein ntohecodniteamtairnyanmtsateexrpiaecl ted to be capable .conduct of of interfering the with the known to be purpose or study. Fresh tap water, ad libitum. Winatteerrvaislsmaocnciotordreindg fotor contaminants Standard at periodic Procedure PH-018. Operating Rationale fmTest System- Rationale for Pose Selection; Justification for Test System: Compounr} Preparation^ METHODS This study is on the health intended to provide information exposure to route; skin thehatzeasrdtsmlaikteerliyal tobyatrhiseedefrrommal consumer contact is a exposure route. possible worker and sBtausdeyd uapnodn/otrheat rethseulstspoonfsotrh'se rdeoqsuee-rsatn. ge According EPA to EPA Health 560/6-82-001. The Effect Test Guidelines historically been used chemicals for dermal guinea in the pig has evaluation of sensitization. Liquids wLhiqeunidsspewciiflilc beinsatprpulcietidonass received, except mixing. The be described use of in the a vehicrleequfoerstddiliulutitoionnwoirll report. study records and final 053191 28 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 Protocol--4 2 4 D Delayed Contact Hypersensitivity in Guinea Pigs (Buehler) The test material appropriate. The will test mbeatpeurlivael rmizaeydbeif moistened with distilled water vehicle to ensure good contact or a with suitable the skin. When a vehicle is used, the influence vehicle on penetration of the skin by of the the test substance will be considered. Absorption of thp Test MaterialVehicle; Semi-Solids Extremely viscous liquids may approximately 50*C to dosing, be heated to with the approval of be the Study Monitor. The documented in the study procedure used will records and included in the final report. For the purpose of this material applied to the study, all test sites of is the test assumed to be absorbed by the test system. calculations and the evaluation of All effects will be based on the applied dose. The choice of vehicle varies, nature of the test substance. depending Commonly on the vehicles are distilled water, saline, used ethanol: distilled water (80:20, v/v) , phthalate, acetone:dimethyl phthalate dimethyl (1:9, v/v) will or be propylene glycol. documented in the The vehicle used study records' and the final report. Volume Administration Approximately 0.05 ml/dose Route of Administration Bationale for Route of Administration- tTohpe itceasllty aandndc/oorntirnojlecmteadteriinatlrsadweirlml ablely,aptpoliethde clipped, intact shoulder skin. Sexkpinoscuorentraocut teis. a possible worker and consumer No. and Description of Animals per Dose Group: Dose-Range-Finding: 3 Vehi the cle Stu co dy nt D rol ire : c t 5 o r ( , at th t i h s e g disc roup re m tio ay n b e o f excluded from the study). Negative control: 5 (if re-challenge is necessa matched ry, ne a ga seco tive nd co set ntro l of a 5 ni nai mals v e, w i l a l ge- be used.) Test article: 10 P ositive Study control Director : 1 af 0 te ( r at c the onsu discre ltation t ion with o f the Study Monitor, this group may be the excluded from the study.) 053191 29 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 6 Protocol-42401 Delayed Contact Hypersensitivity in Guinea Pigs (Buehler) Method of Study Performance: PL/ruisoer-Ktaonqien-iFtiinadtiniocrnSotufdtyhe main torharedhegre-tfoindeivnaglusattuedythewiilrlribteatpioernfosrtmudedy., a dose- In to test material, 3 animals preliminary studies will pboetesnutbiajelctoefd bacAk naimndalssidweisl.l be as follows: closely clipped The over the concentrations of the test will test material be based on the solubility the maximum compound soluble (solids will concentration be tested at lower concentrations). at 100% (as received Liquids w an ill d b a e t t 2 e s or ted 3 Sponsor's or instructions) concentrations. as prepared and at 2 or per the 3 lower wit dif h fe up to rent 4 si t di es f Each feren (1 t guinea conce pig ntra t may ions be a t d o s e d some cases where it common solvent, thecosnocleidntirsatinoont /ssiotelu).ble Inin will be a by topical application. tested as received , conOcneentdrraotpion(awppilrloxbiemaatpeplylie0d.05 ml) of each tahpepreonpdrioatfethteesdt ossiinteg and directly on the rubbed gently with of approximately Observations 25 mmsiynrindgiaemteotecro. ver an area will be for recorded signs at 24 of dermal and 48 irritation, ' application. sites will be At each observatihoonu,rsaallftetrreated scored according to Table I. Primary For the Irritation Phase test guinea pigs there will per the animal middle in of the the area between the be 2 sites shoulder and cthoencheingthreastitonslightbtaockn. onO-nierrsitiatetinwgill receive range-finding as determined study. The from the dose- receive one-tenth site will receive of 1 that second site will concentration. Each ml) of the drop appropriate (approximately 0.05 gently into the dosing the clipped csoknicnenwtirtahtiothne, syringe to rubbed end of approximately 25 control guinea mm in cdoivaemr eatner.areaThe vehicle if at 1 site positive as abopvige su, sing utsheed, vewhiilcl lebe treated 1 site witchontthreolpgousiinteivae pigs will be only. The treated at tchoentcrhoal llgeunigneeaphpaigsse. will rceomnatirnolu. ntrTehaetendeguantitviel hdoeurmrsalaifrterirtaatpiopnlicwatiilolnO.bbeserrevcaotridoends for signs at 24 and of 48 053191 30 Company Sanitized. Does not contain TSCA CBI Amended Final Report 7 Protocol-424D1 Delayed Contact Hypersensitivity in Guinea Du Font HLO Pigs (Buehler) 161-92 If Sensitization Phase fInduction) The first after the induction application will 48-hour dermal observation be is made made for the primary irritation phase. material is soluble in an appropriate the test vehicle, e.g., 0.9% saline induction will be or dimethyl phthalate, performed by intrademal i i n n j ecti the on. com m If onl y t he us e te d st'ma vehicl ter es i a a l t is op i ins cal o l u b l e induction procedure will be used. The hair at the will be clipped appropriate application site on the day prior to each application or, if a topical induction procedure is employed, at least induction. After clipping, the weekly during area to be otrfeaatneddamt atyhebeddiseclirneetaiotendoffotrhethestucdoynvdenirieencctoe r or the experimenter. The hair will be clipped as needed during the study the dermal irritation. for evaluation of A total 1 of 4 intradermal injections will be made, per week at 1 site will be used for week each intervals. injection. A virgin A 0.1 ml aliquot of a 1% solution in an acceptable solvent of the (e.g., test 0.9% material saline, dimethyl by intrad pht erm ha al lat in e, je c etc.) tion t w o ill the be c l admin ipped- istered sacral area of each test guinea pig. water is used as a vehicle in If the distilled primary tihrreitianttiroadnerpmhaasl ei,nj0e.9c%tiosnasli.neTwheilvl ebheiculesed for control guinea pigs will be treated as above guusiinngea thpeigsvewhiiclllebeontlrye.ateTdheaspoasbiotviveeucsoinngtrtohle positive control material. Topical Administration A total of 9 applications will be made to the sacral weeks. area, 3 applications per One drop (approximately week 0.05 for ml) 3 of a minimally irritating concentration material in the acceptable solvent of the test dimethyl phthalate, applied directly to 0.9% saline, the skin and etc(.e.wg.i,ll be . rubbed in with the end of the then gently syringe, to cover an area approximately test guinea pig. The 25 mm in diameter on each vehicle control guinea vpeighsicwleilol nrleyc. eivTehe spimosiliatirvetrecaotmnternotlsguuisnineag the will receive similar treatments using the pigs positive control article. 053191 31 Company Sanitized. Does not contain TSCA CBI Amended Final Report o Protocol-424D1 Delayed Contact Hypersensitivity in Guinea Du Pont HLO Pigs (Buehler) 161-92 Method Validation/ Positive Control; Evaluation of Dennal Response: Challenge Phase App trea r t oxima ment, t ely the 1 4 c days hallen af ge t er tre t a he tm la ent st w in ill d uc be t i o n administered. administered The test in the same material manner will as in be the primary irritation phase, treating with the sFaomlleowcoinngcetnhetr'astaimonesparotcethdeuresamthee sniteegsa.tive control animals will'be treated with the same concentrations of the test material, and may be treated with material (up the vehicle and positive control to 4 separate test sites). The vehicle control animals will be the vehicle only. The positive treated control with animals will receive the the test results paroesictiovneclucsoinvteroalndartthice lete. st If material has either sensitization or is clearly caused allergic not a sensitizer, the test is terminated and the guinea pigs are euthanized. If the reactions are less than conclusive, a second challenge nay be performed approximately (rechallenge) 1 week after the initial challenge using the same test guinea Tphigesveanhdicaleddaintdionpaolsintiavieveccoonntrtorol langiuminaelsa pigs. not be rechallenged. may The procedures and test system will be ceovanlfuiramtedthewivthalaidkintyowon fdtehrme atlesste.nsiEtvizaelur attoion of the test system with a known dermal sensitizer with every may not be study, but conducted concurrently testing with a known dermal sensitizer will be performed periodically. Dermal evaluations hours and/or 47-49 will be made between hours following 23-25 but the data will be reported as treatment, the 24- or 48- our evaluations. Intervals; a. Primary 1 I r r i t a t i o_ , n-- T-- es ------ t-- - DWWeJr.Am1LCaIJl. ev <a^r 24 aal a un->a4t-i-So--n**<s'nd 48 h .w-;ill ours b-e- m after ade the appr tes o t ximately materia l application. Induction - Dermal made approximately evaluations will be 24 hours after each induction treatment. Challenge and Rechallenge Dermal evaluations will be (if required) made approximately test material 24 and 48 hours applications. after the 053191 32 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 Protocol-4240 Delayed Contact Hypersensitivity in Guinea Pigs (Buehler) Interpretation of Results; All test sites will to 4 as follows: be graded on a scale of 0. TABLE I Score 0 1 2 Skin Reaction No erythema or edema Slight erythema (barely perceptible, usually nonconfluent) Mild erythema (well defined, usually confluent) Sensitization Ratincr: Score 3 4 Skin Reaction Moderate erythema Severe erythema (beet redness, with or without edena, eschar formation or necrosis) If edema, blanching, necrosis, superficial nalescorobseis inodriceastcehdarusfoinrmg atthioen foolclcouwri,ngthecyodwe;ill ED = Edema H = Necrosis E = Eschar B = Blanching SH = Superficial Necrosis Sensitization is increase (e.g., defined from 0 to as 2, a 2-or-nore from 1 fco step in dermal irritation scores in the 3, etc.) test animals over those challenge. obs Wh er en v ed the i n te th st e a ne nd gat ne ive gat i co ve ntrols contr a ol t tahneimtaelssthmavaetesriimalilwarildl enrmotalbeirrciotnastiidoenredscores, sensitizer. follows: a The rating of a sensitizer is as Ratio of Responsers 1 to 2/10 3 to 4/10 Ratio of Responsers 5 to 6/10 7 and above Degree of Sensitizatjoi Weak Sensitizer Mild Sensitizer Degree of Sensitizatii Moderate Sensitizer Strong Sensitizer 053191 33 Company Sanitized. Does not contain TSCA CBI Amended Final Report 10 Protocol-4 24D1 Delayed Contact Hypersensitivity in Guinea Du Font HLO Pigs (Buehler) 161-92 Necropsy: Euthanasia: Statistical Analysis; Rechallencre: Positive Control Article; Supplier (Source): Special Handling Instructions: Analysis of Purity: How Supplied; Rationale for Positive Control Article: This rating scale is not Scientific evaluation of fixed rigidly. the data and will be used to decide whether a judgement material will be classified as a weak, mild, etc. sensitizer. Pathological evaluations of test animals not ordinarily be performed. Exceptions will will be noted in the study records and final report. Animals that survive euthanized according the test period will be 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 for considered sensitized. Verbal instructions rechallenge nay be given by the sponsor, aforltliocwleedabnyimwalrsit, teanloncgonwfiirtmh aatniona.ddiAtilolntaelsgt roup of four six (6) naive guinea pigs, days after primary can be rechallenged challenge, but not before groups . w Th ill e ne not gat be i ve rec and hall posit enged i . v e control POSITIVE CONTROL ARTICLE H'-Phenyl-i,4 phenylenediamine (PPD) Aldrich Chemical Company, Milwaukee, Wisconsin Standard precautions The purity is the responsibility of the manufacturer. 100 ga bottle As per sponsor's request. ACT/PT3 053191 34 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 ll Protocol-424 D1 Delayed Contact Hypersensitivity in Guinea Pigs (Buehler) Test Article (Name or Code); ^ H0 J 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 -X Dispose of Test Article Carrier Mixtures Person to whom carrier mixtures should be sent: Shipping Instructions: Government Acrency Submission: AMENDMENTS PDA EEC % TSCA OECD FIFRA MHW Other Date l0/^-^^! Date /O/PJV*^/ APPROVAL OF PROTOCOL Study Monitor Jff^^z - dr-^-^ Study Director AUl^Q^ ^/2^<W07)^Zo 053191 35 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 161-92 12 Protocol-424D1 Delayed Contact Hypersensitivity in Guinea Pigs (Buehler) APPENDIX A Test Article Information I Identification: loo-^o'0" Test Article (Name or Code) : |-4 I'll'Q_______________ Lot or Sample No.: Physical Description: 5\r<l^, ^aXbiw ^c,.^) A:i/i^jT,n^ Puurr-iittyv:; ____________loo'-?? EDexjpaiSrSatEiyo/nSpDecaiftiec:_G_r_a_vi_t_y:_____y_-o?' Solubility (check one) : Water Pijr^r^bie- Acetone Ethanol Corn Oil DMSO Other (please specify)_ Chemical Classification: Flammable___Corrosive II Storage Information; Other_______ __ ___ Material Storage (check one): Room Temperature )C ; Refrigerator Freezer _____; Other (specify)____ III Handlincr Information: Known Hazards: fnoMApA^-tio-^vV^y ?/k's C^)g 5^^ ir/'tfev-^ 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: Sc^ L<3vJ^______of ^^-A- (J^^9 (person) (company/division) at ^J2- A-T\ -^5o(- (phone number) IV Disposition: 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. Name: Address: V Signature: A^^L J-"^-\______ Date:_____U-'Z-^'n 053191 36 Company Sanitized. Does not contain TSCA CBI Amended Final Report Protocol Amendments Skin Sensitization Test in Guinea Pigs PH 424-DU-012-91 Test Article: H-19,173 Du Font HLO 161-92 Records Maintained: (page 2 of protocol, line 8) Reason for Amendment: Evaluation of Dermal Response: (page 8 of protocol) Reason for Amendment: Compound Preparation: (page 5 of protocol) Original Statement Body weights, initial weekly and final Corrected Statement Body weights, initial, weekly and final (including means and standard deviations) As per sponsor''s request. Original Statement Dermal evaluations will be made between 23-35 hours and/or 47-49 hours following treatment, but the data will be reported as the 24- or 48- our evaluations. Corrected Statement 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 evaluation. Typographical error. Original Statement 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. 37 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 161-92 Protocol Amendments Skin Sensitization Test in Guinea Pigs PH 424-DU-012-91 Test Article: H-19,173 Corrected Statement Semi-Solids Extremely viscous liquids may be heated to approximately 50C to facilitate dosing, with the approval of the Study Monitor. The procedure used will be documented in the study records and included in the final report. Reason for Amendment: Method and Justification for Randomization: (page 3 of protocol) Typographical error. Original Statement Treat groups will be housed by vertical cage positioning. Corrected Statement Treatment groups will be housed by vertical cage positioning. Reason for Amendment: Typographical error ^ m)QM: An^ar'i Susan E. Armondi, LAT Study Director Pharmakon Research International, Inc. ^//^/^'/^- Date \J 38 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 161-92 APPENDIX B WEEKLY BODY WEIGHTS (as) 39 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 Animal Number Sex Initial Test Group 1531 M 452 1532 M 512 1533 M 482 1534 M 483 1535 M 507 WEEKLY BODY WEIGHTS fG) Week II Week III Week IV Week V 481 539 579 612 572 648 719 783 573 638 621 717 558 612 675 719 555 613 658 702 Week VI 670 d 788 692 757 Final 680 748* 797 732 766 Mean S.D. N 487 548 24 38 5 5 610 650 707 727 744 . 43 53 61 55 50 5 5 5 4 4 1536 F 446 506 1537 F 466 509 1538 F 428 448 1539 F 496 548 1540 F 452 489 Mean S.D. N 458 500 25 36 5 '5 537 572 625 654 683 558 574 634 648 668 492 534 558 583 579 593 610 669 710 713 509 549 588 620 641 538 568 615 643 657 40 29 43 47 51 5 5 5 5 5 d = denotes animal dying on study * = weight upon death, data not included in statistical analysis 40 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 WEEKLY BODY WEIGHTS (G) Animal Number Sex Initial Week II Vehicle Control Group 1551 M 519 576 1552 M 461 518 1553 M 522 593 Week III 642 581 668 Week IV 710 613 713 Week V 772 668 780 Week VI 825 712 830 Final 840 739 845 Mean 501 562 3 3 S.D. N 34 39 1554 F 424 457 1555 F 465 525 630 679 3 3 45 57 506 524 557 597 740 789 808 3 3 3 62 67 60 568 605 608 624 666 694 Mean 445 491 532 561 596 636 651 22 222 S.D. N 29 48 36 52 40 43 61 2 2 41 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 WEEKLY BODY WEIGHTS (G) Animal Number Sex Initial Week II Positive Control Group 1541 M 506 557 1542 M 503 532 1543 M 494 544 1544 M 464 511 1545 M 499 548 Week III 616 584 588 571 602 Week IV 666 617 637 611 647 Week V 714 668 677 674 653 Week VI 746 691 721 710 683 Final 776 710 746 732 697 5 5 Mean 493 S.D. 17 N 1546 F 429 538 18 460 1547 F 462 533 1548 F 471 534 1549 F 457 488 1550 F 499 542 592 636 677 710 732 5 5 5 17 22 23 25 31 5 5 522 526 591 594 633 558 592 627 657 679 590 618 694 744 753 534 536 585 608 599 589 642 683 723 744 Mean 464 511 559 583 636 665 682 S.D. N 5 5 25 36 5 5 5 5 5 31 51 51 67 67 42 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 WEEKLY BODY WEIGHTS (G) Animal Number Sex Initial Week II Negative Control Group 1556 M 482 546 1557 M 509 575 Week III 619 636 Week IV 663 679 Week V 742 761 Week VI 801 826 Final 812 839 Mean 496 561 628 671 752 814 826 22 222 S.D. N 19 21 2 1558 F 415 454 12 11 13 18 19 2 485 497 530 556 571 1559 F 486 548 592 650 664 725 754 1560 F 447 468 525 526 587 563 608 Mean 449 490 534 558 594 615 644 33 333 S.D. N 36 51 54 81 67 96 97 3 3 43 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 161-92 APPENDIX C COPY OF RAW DATA 44 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Font HLO 161-92 PHARMAKOS RESEARCH INTERNATIONAL, INC. ^fc} Skin Sensitization Test in Guinea Pigs Dose-Range-Finding Study Sponsor: i^ ,'J^. j^^r ^/e. /l^e^y^v^s s- <S>-_______ Purpose fT^c/fT'c^M.'^'e. y^- li^.e^t. y^oT*^-* ?.7<^?7.<g. ^/>^f-e- TfsV /fit7'iet<. '/^> <^wW /3^j Study Ho.; P//-ysV-'b^-0/^-9/_______________________________ ' / / ^ i>> Method i/'e^og. /o 7'^r'e^. -yff.-^"b f__________________________ Date of Initiation; //^l6/?^. Date of Termination; / Test Article^-- /^ /'73 Descriptioni S/f'^rt-y vtif SM l/'Wtt_ ye ^>/iv^,'^ ^J^r/tji'i-r Amount Received; l^e^ i A^ q, {(sinaS^) Date Submitted; /o/y.jS/'if Vehicle .)>/f'y,^.eec/ <^>Te^t._____________ Dose Levels: /-6 /o ^> ^^f yooZ, ^r ^ Route of Administration; ?><"-e-^<_ Animal P.O. f: ^11-0(03^^ & ' < / Species: ^^/^g^ /? Food Lot #; /P^3^1 M Ko. of Animals on Study; 3 Strain:_/^^/<^ Identification; &^e <%</- /{aiiM<- ^uo. --T-------------------- Sex; Male / Female p^. Scaleff: 5) (^'- L ) 3,?<.^,, ^^/^Tie ) Light Cycle Checked -.__/^_fy^j^_ Animals Clipped: ///S/ft-X^_____________ Compound preparation; fp^ffs 2'-- 'bytt^ o^^-zs^in^e^ ^o-ifS^-i/^& ) ^^^-. /ys~z>^ ^_^_^^-^-^r^ ^^.<^/ /p /.^, - ^./^ i. zzr^tg^. -/- 'y;7^,i. v.^(^.^&, \ /g /.^^ -r z?. /^,Z .-//^ ^-^ fe -"^^ ^ ^<-^-e-^ -^ s^L^cee^ ^v^-t. -r^s^ ^, ^-^f ^^L^ 7^T~^Z<J2^. j-^K^^.-&^ ^__ ..^GL-^, ^;93^. P^^^ ^y^,^. y^L ,y----^ ^^.^^S^^^^^,,^. - " "'"' -- ^ ^ f . . A^~g-^e- -^^^^^"^ ^ ^^w^ ATABL3(1) ^MInve^sti.ga^to.r ^^/y^^^ /]iuuAA^^}^h..LUiffwwr^^^r^ . Study Director D-ate6^& Da^e 45 Company Sanitized. Does not contain TSCA CBI Amended Final Report DU Pont HLO 161-92 PHARMAKON RESEASCH INTERNATIONAL, IHC. M.B.ff P^a^^K-Ol^-^ ~t3Kj SKin Sensitization Test in Guinea Piers Page //^/T2^) Dose-Range-Finding Study c^ff^ -r // In this test, both sides of the animal are sh&ved and^xposefedd tt'oo/^ffoouurr .,$:$?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 C Figure D Site 1 = /, o % Site 2 = /O 7o Site 3 = r^> Site 4 v^% ^"^c^, w( iDisa^w^Ai^1^" Q^ 1-4; Test Sites Animal No. / 5L 3 24 Hour Scores / . Test article Sex and dose Initial Tine of Site Site Site Wt. (gins; Dose 1 2 3 375^ / 0^ >/-/?/73 Y/7 / ^ /-c? /o. s^? / ^ AjJcf /cro 7c, - S ^ /Ay/y'1-^ ^^ .7^, y OIP^ 0 ^ / 0 ^: a/pPn 0 t//V/1-i- ^ /^? 0 D 0 0 0 0 / /-/ ^ Site Finaa: 4 Wt. (gfos) 0 0 a 48 Hour Scores 0 0 0 0 c> 0 6 0 0 /r/^ ^ 0 0 0 %4^S ^y y^y/^ ^^->^ ^i^S ATABL3(2) ^^^ ^/^^^g^C Investigator v (lu-'irv^C /Mn-n.-nC^ /0-A . Study Cirecror l-^-^ llltfll^ Date ' 46 Company Sanitized. Does not contain TSCA CBI Amended Final Report Revised Du Pont HLO 161-92 PHARMAKON RESEARCH INTERNATIONAL, INC. Skin Sensitization Test in Guinea Pigs Ij--------------f ^^SBBCj ^ Title; r^fec^. SA-^SI 4i'^-^&x_ (^^J" .^t/i ^Uu'lmLrt r^'y0 Sponsor: cLi PO-Y^ pi)!- D (' MA Pi i \ ^ -*- C.f-v^a^Li ,I. purpose :"?o t^U^h^^i fic^-M^. SSwSi. \\ ^^icn^J^M^liiHt/^UL Usi- O^WL,^ Mu.^i ftLy Study No.: P^ ^^.4-^-0^-^1^_o_J_'T_F____"____________ 9 Method = ReLA 4-0 ^O^C^f ^13 ^^.ti^.^^. Technical Ihitiation: ////Scl.Ki/'/JfS.L^.. ' Test Article: H - TTeecchnical Termination:___^_/7/^? /'ppb/' Positive Control .w .^e^i.-i Lot Hmnber= ^nf. QoffU^iO Lot Hmnber-.gj-g/a^,^: qij^ ,I,^L ^. Description; 1 ' ^JU^-i-(u ujuAC/*Icn;^Ai. m'(j otJspinge^rfplfon^'^*'/^^^^&-A^- ^- Vehicle: ft,.57, /1^/ ^,,,Tu._____________ Amount Submitted: /^pZ. /J? Receipt Date: /^/-iS/fl Vehicles 'h.^.UcJI ^rus_ Boute of Administration: cu^rmw^, ,WifilWyiial Animal P.O. ff: SDtt-O/CQ 9o? C- Toxicology Lab. Ho.s_ ia_ ^ , r - ^^- 9-^^^s' Species: f6t!::J;'l,,'wc|.,nt//>'y^ty>AWf_e._e_^_rw__->/_m^')t-r-, Strain; 4n . -.. ... 4--^i,,___________ Weight Range 6 Food Lot #: 0/67^/&fff 0793. /A u . , /0' Ho. of Animals on Study: 30_______ Sex; Male Female /^f } -^^^- Scale #; 3/^,'^c) 3 ^^<<':g3A ^&^ I-ight Cycle Checked ^g/ya-s,, , - ^J^^//^<^!^^ Anin.als Clipped. ^A^^^z.^ ^4.^ WfSL'&U/ Format for Primary Irritation, Induction and Challenge Phases w^-/^^W" ' JlQ/9^-lajthen CMf ' 1. ^ aA^, ccnL . . ^^\^^adow^ (rm i^c^ of^ Ja^- 5^ 1-2 Primary Irritation and Challenge 3-6 Sensitization Phase (Induction) BT^DT T--) / / investigator / /f 'f r ^ (}{u\i\w f, . i^w.^ri. Study Director ^/^'^ Date ' 5/''////r'f^V Date 47 Company Sanitized. Does not contain TSCA CBI Du Pont HLO 161-92 Amended Final Report Notebo. Page PHARMAKON RESEARCH IHTEENATIOHAL, INC. Skin Sensitization Test in Guinea Pigs GEMERAL OBSERVATIOHS f^h Study Ho.: PHystrf-tiU-O/St Sponsor: gLZ". oLn djL // -f/ Test Article: - / g/ 7 s7_________________________/J^vyierui^ *- (lawjs'a^< = (appears D a t e A N nonnal'5^I.n^itialsQ //3L!'/f>._____'b.sr.LL^ '^<fTe.^-/-o'^"tt-^o|^^ yA^fr^ t> s^.^ ^. /^:l//^, ^ ^-y -r^ _________^r^^^ /A?/^ 0.77.^^1----&^^JiM. ^zgfc 7?^i^^________ r^ ^/<r^ _______^^.-^^ 2>^^.^' 3r^ ^or^^^S^^/ ^ ^7^/ / Mi'.'^Z^fr '^'"il^'W z ^: Z: Z .z- ^ A. z ^ Y /I^- / /_ / / / / / ATABL3(7) 48 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLotel-gi. PHAEHAKON RESEARCH INTERNATIONAL, INC. Skin Sensitization Test in Guines Pigs Test Article Preparation Study No.; P\^Vi- taU- 0 >5 -^ I ^,-T. d^ ^cr^J- C<A. Test Article: H ~ H-H 3_____________Sponsor;______/Ucwtu^.s -4- (1^. Primary Irritation Phase (Week I) .(S/cro'Z. -^^aA u-^CL^-^ ^jt^i^-iP ,\j ^e.<-sL^/> ^'"^'^i^}- ;.,,/--/.*/,<- / p^ -/^ 75^^ Q/e?. -= O.T^t.'&g A^Z^-4. s-^*-^-^^ L ?'P^ @ ss-Z -> JT/. ??2> ^ ^ ^ ^j.3^ y^, //,t/f^~----------------------------------f------------------y .CP^^- VjtJi^jS^-^- M^iCs^ i^-lX^. 7?t> ^^.gji^j!^, ./.r^r^fS^c^eJ ^J-^i -- j y - y - y - r p ( . ^). A^ ^-A/"^,/'1..n7^r^^ r/t<^^Lr---, --/--^^f-f^^-y *--cr ^Mmi^-fj^^^^Q, ^^^.^^<^y^^-i---, ---h--^^.'^1 f^f'^^--u. t<"-.--w1> ,^^^^^^^,^^y. "T^y ^___^ ..J> Thf- ^d&^ ^ss^-s^^^ ^ .7' ^ . ^ Q' y : -^''T--- ^^^^^^^^A.. ^mT^^i /^ff^/Ut^' ^o^^^ / //^/ft.-J^^'' Induction (Week I):/? />?,, --5>' iJ./wi.~K^7~ia^ZZ^- ^ ^- 9^^ i^L-L^.. ____________t/c^i^, - ^- ^^ ^^^,^-;__________________ ^^5^e- C^tw-^> ^2? (p /: /> ^ --' /^t>,^ pra ^.s . 7b ^^ Uf^ p 7 --.^ ________________9-^^. ^ - Induction (Week II) :^) /'-0 '7. --* ___________^<M<,8'. -^ l ^ ^ e ^ , - g , -- -- -- -- ---&>^-^/--/2--^e-----^<----!^y^--\rjl---n^--g--^n---^t.^--t^ ,^J>A, fT-i.__________//Se/j^r^, ^ /,. /^, i '~hj^~^L^7^^-^ T- ? ?^ c ^^^e^. ,_____ o-?^ ^^p^ ______________ f'^ 'pt^S^e. ('^CSwJ' 'T7>Dl0/->7c-^t/0V^v. ^ s th/e^iL . / ^ ^ , ------------------------------------------7y------------__------------^ i^f y ^ ^ ^f^y ^ A^^-u>^i.,. lyf). -^--^--^ a^ZL4. - ________-e^!^c^ 1'^ ^^ZZ^^ /^^<,^.___________^AA?-^7<gg induction (Week III) : /^'; 1.0 ^-==7 H. t^Buf T^.^^C^Ut^^^ ^ ^^/^/ r^^/^ ^J^PJ lU^-^O.^AAS^. ^^^/2w^/^/?Z^"^~ /(?Q, ^<; a^' ^Uf1 4y. j. /^ ^i?/^r /fo ^d QAfc^^ f c t^.'^. t^^ hw^.sMMvi^/ T/^^.^^-, ./^^ l gAsht^ ^ ,.)/^') r ' ^ //^^?. j^^i ATABL3(3) 49 Company Sanitized. Does not contain TSCA CBI Amended Final Report . Du pont HLO 161-92 PHARMAKOH HESEARCH INTERNATIONAL, INC. I I------ ^1 HofcebooM----------| --| page ^-f^^HT Skin Sensitization Test in Guinea Pigs GENERAL OBSERVATIONS Study No.; /377Vg^/-^>4-<7/g-<y/ Test Article: Sponsor; igj". db^ftn^h {h, ^/-/g/7>7_________________________^^WIITIA,^ "-- = (appears (law^a-^i g' D a t e A N normal)Initials s^^ //AS/f^______b.sT. i Le^ ^Area. - /" ^^.1^ 0/3. ^/L^T^ jb in^,.^ ^?. __________________e^h^^M. 'p/f -Xp ///^Ll I^L J^- ^ ^ ^ / / 3 o h ^ 0.77. ^^^4- ^t^zgt^ '^-^-AzfiC.- - ^ :-^y ^ -- ^-f^L,--2>f^-.^> --n, ^ ----^ . ^ ^---- ^ / / / / / X / ,Z- / x / / / / / / / ATABL3(7) 50 Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 161-92 K.B Page PHABMAKOM RESEARCH INTERNATIONAL, INC. Skin Sensitization Test in Guinea Pigs Test Article Preparation (Continued) Study.Ho.: PM^-'blA-Oig--^ Test Article i \\ - 1^1'73 Induction (Week IV) : ^D/. 0 7o --> 0. A? L ~tS^ 6.1:.<5liA Pev^oGC ------^^^m^As -t- C^'' rirs--jK^- e^Kwf. ^PP'2)g> -/-o? J-^A'p.^c ppt) y^ ^.s. -4 "7" ^o^c . Challenge (Week VI) :'Z^'^ZI^./g>/g'% --^7^ ^^J^^^ ^^ui^ew^/ff-0^^/^}. /g /g ^ - <g. S^C'Gta^S^&L. -f- y.S'^L ' -Pi^S^e. 6->Cfc^ >/>^ /O^^-^ -a 3.^u^ ^2L^^^a^; /^gf^, --------y------??--^--'--^--.f.---A--,--^--0--w--ty.----' --1^^_&__<^L - ^eJU> . ~J?------^------------ ^ -- -- -- - y -- -- t e -- ^/.f-W^-gje^t^JL, ^i)- / (y ol.7^ J^ ^'7^^p^./^^^(..yi Rechallenge (Week VII): 1-^0-^ a-m^t^^~ ^/Ct^^tt--^-e^v r t^tM I/ J/s-hi ^ ^ /---.i" ATABL3(4) Company Sanitized. Does not contain TSCA CBI Amended Final Report DU Font HLO 161-92 PHARMAKOH RESEARCH INTERMAIOMAL, INC. Kotebo Page S Skin Sensi-tization Test in Guinea Pigs Body Weights (grains) Sponsor;C.T-oluPpTj-o(f. Dg-tWK/IS-^-C^ Test Article: l4->q.l-73 ^/^ J^ Animal Initial Sex Week I Week II /531 ^ y^z. ^/- /5"^ ^ /^33 (? y^A ^5 57 /^ ^3 &r /535" d7 <fo7 ^^ 1^ -? yy^ ^^ l53~? ^ m ^ 153^ ^ y^ ^ /539 ^ yy^ ^ /5'VO v^ ^ 'ffi //^S/f-i. ^.-^-99- c^ty /U^ Week III ^ l^<l /^ ^fff biS ^ ^ ^;a ^ ^ > -/' - ^b w^6 S L tu ot dy N Numbe umber: r : ^p pM- ^ ^ - b L t - 0 1 " 3 - "^1 il U.^Urn^i.^. .. . Week IV ^ 7/^ ^S>1 ^76 ^ ^ S-7 ^ ^0 ^ ^/9-y's ffa^Si Week V G12 70 7/7 7/7 103. (f3^ ^4 ss^ ^ 5^ ^/sS-/^ f^tf KnfcodoSic. VV TJ- ^ Final ^) ci w ^ //7-?x>7( /^y Lyc" '^,T- ,{,//r<n? 7^ 7^ 7^? ^f,JV\ /7|M/y> ^/^-/)?^j i/^/khft ^^>iifs<Q? 6r7~r1ja ^ 7/? 3/^ W W/'y/jli ^s'-^ ,,., /%/<^ ^ ^U Ua Ce-!'Cr /^/ ^7 r^i ^ ^ 7/Q ^'6 ^D ^^ /5.5"c3 ^ y^/ 7^ /-5"JJ ^ ^^ ^6 ^3 /^"5"^ i ^ ^ ^5 ^s bb7 ^7 ^^y&/^^ 6^ J^/ j^4^ ^7 ^ /1^) <-/ 0 ' ^V - cr ffi-^-^' ^te' ^y >-" c^^ ^^-& d-^. ^^J^ A-t ^r l, cr^,,^ W IJ i^ .^'y^ ^'y^'^ r/^^^lA.' ^/.^^ ^'i^.^J-U.^-n 5 c6-a^L ^13-c^ (U^(^^ ^W ATABEL3(5) ^ y ^ - (>Ji^4/^_ -inve^iqator '- /4 C f] _//!A/.^U/?M..^k)L/;__. study Director 772. (^? '71 // "^? 7f^ 6'fc? 6^ -- ^/"L/7'--1^' ^p7//6<- ^ ?^^ ^ /' <?(/ '-' - tA^t^/^.^v^.' fc7// ^iM-Fi^ /7 ,/' 1?3^^/Ww^er^s> 'lSi.''-'^S ^/gy.?^ .3A/<? Date- l- / I' -,/,/ 52 Company Sanitized. Does not contain TSCA CBI Amended Final Report DU Font HLO 161-92 PHARMAKOH RESEARCH INTERMAIONAL, IMC. Skin Sensitization Test in Guinea Pigs ' ^ ^ 3 ^>fcebo(M------------B "' Body Heights (grains) -/-^-" r- Sponsor; 6. ~^ ofnhrnT ^ iJ^ttLW^'^. Study number; /^/^Z-^-^Z - {>j/3- -^j "Te-s-t A--r--tic--le--: /^ -/ <?/ 73 Lot ^er= fp.Lip^rr.hU7 II III Animal Enitiai dumber 3ex ^eek I ^eek Week lrfeek IV Week V I?eek VI Final /%>/T^ ^ /S^/ ^ /^%z ^ /S^3 <r' /^// ^ /^T /' /^(p ^ /^^7 ? 0 ^^ ^ /S~5~0 ? ATC^'-- r ^ . ^^ 6^ ^3 ^39. -^^ ^y y^/ j?/ y^^ ^ ^/^^ i-^ ^^ ^2 ^/ ^ ^r7 ^ ^//X^/TZ. J^? ^ s> ^<s' /a^-s - ^ ^/ ^7? ^7/ ^ ^^ ^^ .?% J^/ ^ ^-^^ ^^-W <i>^'^ 7H ^/7 ^^ ^7 Ll7 ^/f W ^7 I.S3 ^ ^>/ ^3 ^/S7 ^3^ ^y^ ^^//^^r 6^7 ^ ^ W .i/sr/'cfs^(-l. ^y^ 77^ /.f/ 7/^ 7^1 7^. 7/'? 7-^ /,fJ c.n ^Y ^33 ^7 ^ 7-// 7^ ^^ W. ^ J'.sr^ C^^fJ AI^ ^) ^ ^ AJ^L( ^i/ ?, <^7^ /s'si ^ ^<?^ ^ /^~7 /sy //^^6 ^r 5^7 ^ ^^ ^ ^ y ^^^ j^y -^y 0 /- y^r ^.;4/y^- ?--/-%? J^7 ^^ ^ ^ W ^ 5'^ a'// -^ ^J<fl ^f^3 ^ 7fo/ yf7 .^o ^-^ U4 ^^ S'?7 ^-/.F-?;?! ^f/'i^. ^-^ t-^/ f0/ <f^ f^ ^?f J ^ ^-<--^-- 7^^ 7fy ^^ W j-^-^ 3C^& ^j^' ATABL3(5) ^WS .^^/ ^a.^ ^/r/^ M^stiqacor^ yDa^e /JU^OG. Li^frn^ ^]^hy SCudy Director Date 53 Comparty Sanitized. Does not contain TSCA CBI < PHABMAKON RESEARCH INTERNATIONAL, INC. ! ^ Individual Animal Scores During Primary Irritation Phase Sponsor yf.Z^. Mp,Jr ^e/^^ues e ^ Study Number; T'^'S^^-^^-P^ -y/_________ ^bt.djb^icnihjh_____ Test Articles ^-/J'/^J___________ Lot Number; i}bt^iU)p\JLCQ^U Noteboo: Page 8 animal No. Sex y^3/ ^ 7^39^ ^ /^33 ^ /^3-/ ^ /<-35- r /'r^c. ^ y6"3 / ^ xO-s ^ /^7 /r^o ^ ^ Dose Cone. Left Shoulder -K\ ^ ^ ^ ? ^ ^' --M- ^.' r- \ i k ^ ^Y" ^ --------------^i-- Dose Cone. Right Shoulder ----------------^4- ----------?-^- (& ^ s ^ K^- r>- r~\ .,,. ,,,,,,,,,,, ,, ,,.<',- 6/ ,,.',,"(- f ------s^^'i'u 's>,j 0->"J' Time of Dose //.35"^ \ / //:y:r^ //^ 3/f Z- ->>? 4f^S' 24 (iHours^ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 > //.2 Time of Reading //3^^ 4 //'3\S~^-w y/^ ^ 48 A-HoursA 0 0 0 L? Tim Re // 0 0 Jl 0 j2- 0 A- 0 JL- 0 0 -e0 - 0 -QL 0 // 7 /J< Yf^ /c.^'c<L e- ^'/ ^7^'C y<5-^ ^ ^ ,/J'Tc?. ^ /S^ ^6^ ^ ^ /.5-^T ^ ^ S"Si .-1 . ^1 '. ^I -(^ ' ^^ - / / / / / Initials "^l- ^^r'fs-'*la-Jwc'eir<' .sbfc.-^sc/^ei/'Syf//fiyT^^^hvofL^Jd^f/,' ATABL30) </3~Z /h-^, ' 0 0 //V/ ^ 0 \ / ^ ^ L //yA^ //^^ 0 \// 0 : //^ 1/^SL , I Cf-tf 0 0 0 0 <9 ^ //:r" //:5~ oli-i- PHARMRKOH RESEARCH INTERMATIOHAI., IHC. Individual Animal Scores During Primary Irritation Phase Sponsor; jg.X. alv P'^'^e^eMe^/t. v- C.s> Study Number; p^/^(/-t>U-o/X-cf/__________ Test Article; //-/'/,/ 73___________ Lot number; f\ pL /IfiDq^gL^^ ____ Notebook Page ff Animal No. Sex '^/^rr/. /-e^ /<-^ ^ /5"^3 ^ /<yy ^ /r^r ^ /<^ ^ /^y? -r /<^ ^ /<^ ^ /<^ ^ Dose Cone. Left Shoulder <:''a^T^L. ^ ^ 0 ^ ----?r-^- ^ ^ ^ ^ <- ^ Dose Cone. Right Shoulder / Time of Dose --------^ //,V5^, / -i--/ - -/ f-- / ^ / //-^O/M //SL/?Z- ^*7 MfS> 24 Hours Time of Reading , 0 11'-3^ Aw 0 0 0 0 0 0 6 0 \ v 0 //^ ^"w^, ^ 48 Tim Hours Re 0 //- 0 0 0 0 D V 0 0 0 //: /^ ^/fi 2^---- ^-^ /^'^^ Tiv-e^ (,ie>^t~ft-aC /? ^ /^'7 ^ /<'^ ^' /^r? f /<?^' ^ Initials ATABL3(9) PHARMAKOH RESEARCH INTERNATIONAL, INC. Individual Animal Scores During Induction lit73____ iP^^'t^ Sponsor. P.TcLiPniAf- l4i /J&vM.M^^-Study Number! no-i/)jpDlirr^U^ Test Article: <4- Lot Hunger; -01?- -) { Notebook Page S Aniroal No. /S3/ /AJ^ /^33 /^J-V ^5" /^% /537 /6'3? /6'^ /s^o Sex 0^ <? CT7 O7 (7' A ^ ^ =?^ ^ ?? ^ :>? ^ p? Dose Cone. ^:--u? ^^ r p> PS v ->--^ t" <., ^'^ Time of Dose Week I 24 Hrs. /ff.-S'O^, d 0 0 0 0 . 1 0 Time of. Reading . Time of Dose /(3.-5-y^ //^ 0 -i\\ t-/- 0 \j7^- \1(/ /cr. ^f^ ,/JV,1t. r-i (UJSt 0 i'o' '>""/ *->. . -7 ^ . 3 yy y) z - it:,i^ -t/l./IZS.^^3 Week 24 Hrs. :I Time of Reading (? I0'-35'^ tf 0 0 6 ^ 0 "^ ^) 0 / G /O'-lg.^ ah/ ^ ^// W Time of Dose f/.ID \ /-7^ ^'k ek III 24 Hrs. Time of Reading Time of Dose ,z^ ^ --^/-/f------3---P------ / / 2- ( / / / c? \// 1 ^//// ^J/'-^97? ^^\,/ /J V^K ^r< ^ ' /5-51 /S59 ^ l55^ ^ ISSH ? /5Sf $. Initial; ^d ( 0 ^ sn ^k -. O^ ^L^ .f P A <--'? - r^n:6^ 0 0 4 0 / 0 '/>i if"! ff '/S'/ft- .... ^ r^Ot-U- -K // :ti^'^< V / //(?5^, /^ -i //S^ \ / /i-iU^ t/<l/" ^(^ 0 /^ '^- 0 0 \/ 0 / 0 /^^"^ o2/7/^5 ^// A-i ^3/ -//Y^ (Q-SAI & (9 / 0 -0O-/r^ f/:^ \ / Y/^ 1} .7 "7 ^ /.'// \ / /.'y ^^'/^y) ATAnL3(10) 180 VaSI UIBILIOO lou.saoQ pazinuBS Auedluoo Amended Final report Du Pent HLO 161-92 g 57 PHARHAKOM RESE.-.-H INTERNATIONAL, INC. Individual Animal Scores after Challenge ^oi^hrct^bj Sponsor." S,T. ^u ^nJ- Al ^WLW^^G^. Study Number; Tost Ar tide l-f-1^112 t of Numbe r, ^^2^- Z><!/-<3/3. -<?/ page M &i.H ~O^LtU-S^MJiv ^,<if^ ' ' Challenge Recha ,b^yy /^"}D.o^se^ ID'oose Animal Cone. Cone. Time Scores Time Time Dose Cone. Dose Cone. Time Scor Time Ho. Sex /S31 a" /S3 3. ^ IS'32 df /W ^ /'3^S' ^ /S'3L, -f /S3~l $. Left Shoulder ^ ^1 ^ Q P '-S l^y --?A? -i^[- <ri" r S-^ Right ^ Shoulder " ?" A .,-,.,(\.--.-1. ^^ ^^\ },> ^.^> ^ of Dose ff.'t<^ 24 Hrs6 ? ? c6 P f) D. 0 a t) Q. b ^ 0 of Reading /o'Ty^ ^.0 r> <s 0 a f? 0 (-> 0 n P LL D of Beading A^ Left Shoulder Right or Shoulder Dose - 24- of. Hrs Readi -7 / / ^ /^3S ^ /.S3'? ^ Xt ^VO f \1 ^ / 0 0 -JL. \ Q0 / f^? Pc \(/ ^6S /D:^ ^ //"'4, 0 3/7- f^CS D H:03f^ ^ ft ^ hsoQ / / / / / VA^U 'AL 'l^-l"^hn& ^. /P:^ /^6-/ o7 r\^.-^/ --------ir-/rif^ D 0 //^ ^'^l WS. (f /^5~3 ff7 ^ w / & 0 0 <? ^4 ^^ H \f IS / ^ / 0 N^ P / ^k ^ /^>r -? fl:llM 0, //i/UW 0 /0:3fM / / yr^jGSSe '9Q-6S ^/ 7^C& / --7"--" / / / / Initials ^~ *----------' -- -----"------IJ_J- ^-^"^s^.n^i. 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S ^ f- / ^- It 0 g^3- r0f fcat <& yaM ^| \ s & "' n 3 < Po, 3i3 Z C P< 01 III < .^ ^>---o--^ Ifs ? ^ 1. n i-" (D 0 1-' M i^ >o H fl> ID 3 jj B) ifl s III " ^^ f / ^. ' 0 S^' ---- ---- ---- ---- ---- ---- ---- ^ ^3 n- " !0 ^3 B> m 3 Q. It ^| i N \ ^ ^1 \ \\ ?- | \ mf n o ^!;,?- ;r (B o o U (1 Ml 3 0 " i; rr o (C i s " * > A fcj ^ in ; n o ^Fr016 ^ ? ^=fc w 8 ^^ H -p^ <1! ui Cr'--7/ DJ R, &-' 9 S- " rt <B ( M >^ o ? & r t-' l ID fcO r"N a Sg " 3 ^ M 2 > i-3 - gs - M 2 n r i ^a ^ .X\- 'i? ^ 0 P- in MI 3 (B a ^ \ , a o s 2 P C - r . \ 3- \ (Mn iMt> >0 fl Dr . \ ^ 0 r^ \\ 00-, \t \ \ 3 3C C } (B o t-B l-ft 3 0. 1B h-- 3 ifl in o 0 S 0 f 1M1 1-' 1 v(D> *-' 01 (B tfl &. (B 1-1 0 l ' (n k L1J \a s i \ S ^ \ "i , Bl 0 -" 0. 3 \i m Z6-T9I 01H ^-uod na a-ioday: -[BUT^ pspuswY Company Sanitized. Does not contain TSCA CBI Amended Final Report Du Pont HLO 161-92 PHARMAKON <" RESEARCH INTERNATIONAL. tWAHAlV>*EER"'l.y" . P----E-NNSyLVA INC. Individual Necropsy Sheet '"one H>7) SS6-2* Stu^dy^^-^U-W^-fl No.__________Species; , . (ju/njta roiQ. Animal g; /5'3ff, \Eax Tag ffi i/ .^-l Sex: <?____Wgeeiicghht: 7^f< n Compound; V'f^/j^S /.f3^-_____(RReeaassoonn**; (l\) 32 3 4 (circle one) Tissue .B--r.--a--in----_--iww Eli7t7(Ti\Dsosseu: e^|^E((hl^C1 Study Director; }}.iUrf)']C>r}cL^ --"' ^------|----r--L--- HC..(TissueT~^~'';"7:: Sp.cord Liver Ipituitir^" Eyes Icholecvst: Sal.glands _Subinn.i.noQe _Thyroic ^Parathyroig Thyrous Pancreas jurocys Testes Epididyais Esophaous iTrachea 'Lung Uterus ISternebrae lesxons);';I E= examine _N_e_c_r_o_p_s_y__O_b_s_erva-.---cionwcj(-NijVinI-. , /./ tgin)___*1 = = no visible dead 2 = tegm sac3 == sac morib 4 = sac weak) " tlocobook J^^f pac^^ 2^__ 60 Company Sanitized. Does not contain TSCA CBI