Document dQ54wyL0Gr1gzwGJXynz9XLd0

AR RRC _ 1228 FINAL REPORT PROTOCOL 418-027 O`WRIATLH (TGHAEVRAEGPE)ROCDOUMCBTIINOEND/DREEVPEELAOTPEMDEDNOTSAELTTOOXXIICCIITTYYSSTCURDEYENOIFNTG7T5E99S.T7 SPONSOR'S STUDY NUMBER: T-7599 FINAL REPORT DATE: 25 MARCH 2003 PROTOCOL 418-027 - ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDYOF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7599 SUBJECT TABLE OF CONTENTS L SUMMARY AND CONCLUSION Ll. Methods 12. Results - Males 13. Results - Females 14. Conclusion 2 DESCRIPTION OF TEST PROCEDURES 2.1. Conduct of Study 22. Test Substance Information 23. Vehicle Information 24. Test Substance Preparation and Storage Conditions 25. Test System 26. Husbandry 27. Methods 3. RESULTS - Male Rats 3.1. Mortality, Clinical and Necropsy Observations PAGE 1-1 1-1 13 1-3 1-5 2-1 21 23 24 25 2-6 8 2-10 3-1 31 SUBJECT PAGE 32. Terminal Body Weights and Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight and Brain Weight 32 33. Hematology and Clinical Chemistry 32 34. Body Weights and Body Weight Changes 32 35. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values 33 3.6. Mating and Fertility 33 37. Functional Observational Battery 33 38. Motor Activity 33 4. RESULTS - Female Rats 41 4.1. Mortality, Clinical and Necropsy Observations 41 4.2. Terminal Body Weights and Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight and Brain Weight 42 43. Hematology and Clinical Chemistry 42 44. Body Weights and Body Weight Changes 42 45. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values 43 46. Estrous Cycling, Mating and Fertility 43 47. Functional Observational Battery 44 48. Motor Activity 44 49. Natural Delivery and Litter Observations 4 4.10. Pup Clinical and Necropsy Observations 45 REFERENCES 46 APPENDIX A- REPORT FIGURES Figure I. Body Weights - Male Rats Al SUBJECT PAGE Figure2. Body Weights - Female Rats A2 Figure 3. Motor Activity - Number of Movements- Male Rats a3 Figured. Motor Activity - Time Spent in Movement - Male Rats. Ad Figure 5. Motor Activity - Number of Movements - Female Rats AS Figure 6. Motor Activity - Time Spent in Movement - Female Rats As APPENDIX B- REPORT TABLES - Fo GENERATION MALE RATS Table BI. Clinical Observations - Summary - Fo Generation Male Rats BI Table B2. Necropsy Observations - Summary - Fo Generation Male Rats. B2 Table B3. Terminal Body Weights and Organ Weights - Summary - Fo Generation Male Rats B3 Table B4. Ratios (%) of Organ Weight to Terminal Body Weight - Summary - Fo Generation Male Rats B4 Table BS. Ratios (%)of Organ Weight to Brain Weight - Summary - Fo Generation Male Rats BS Table B6. Hematology - Summary - Fo Generation Male Rats B-6 Table B7. Clinical Chemistry - Summary - Fo Generation Male Rats B-9 Table BS. Body Weights - Summary - Fo Generation Male Rats B12 Table B. Body Weight Changes - Summary - Fo Generation Male Rats B13 Table BIO. Absolute Feed Consumption Values (g/day) - Summary - Fo Generation Male Rats B14 Table BIL Relative Feed Consumption Values (g/kg/day) - Summary - Fo Generation Male Rats B15 Table B12. Mating and Fertility - Summary - Fo Generation Male Rats B16 Table B13. Functional Observational Battery - Summary - Male Rats B17 Table B14. Motor Activity - Summary - Fo Generation Male Rats B23 iv SUBJECT PAGE Table BIS. Clinical Observations - Individual Data - Fo Generation Male Rats B-25 Table BI6. Necropsy Observations - Individual Data - Fo Generation Male Rats B-30 Table B17. Terminal Body Weights, Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight - Individual Data - Fo Generation Male Rats B34 Table BIS. BBrraaiinn WWeeiigghhtts,- IOnrdgiavnidWuaeligDhattsa a-nFdoRGaetnieorsa(t%i)onofMaOlregaRnatWseight to B46 Table BIS. Body Weights - Individual Data - Fo Generation Male Rats B-54 Table B20. Feed Consumption Values - Individual Data - Fo Generation Male Rats B-66 Table B21. Mating and Fertilit-y Individual Data - Fo Generation Male Rats ~~ B-70 Table B22. Functional Observational Battery - Individual Dat-a Male Rats B74 Table B23. Motor Activity - Individual Data - Fo Generation Male Rats B78 APPENDIX C- REPORT TABLES - Fo GENERATION FEMALE RATS Table C1. Clinical Observations - Summary - Fo Generation Female Rats cl Table C2. Necropsy Observations - Summary - Fo Generation Female Rats ~~ C4 Table C3. Terminal Body Weights and Organ Weights - Summary - Fo Generation Female Rats cs Table C4. Ratios (%)ofOrgan Weight to Terminal Body Weight - Summar-y Fo Generation Female Rats C6 Table CS. Ratios (%) of Organ Weight to Brain Weight - Summary - Fo Generation Female Rats c7 Table C6. Hematology - Summary - Fo Generation Female Rats cs Table C7. Clinical Chemistry - Summary - Fo Generation Female Rats cli Table C8. Body Weights - Precohabitation - Summary - Fo Generation Female Rats C4 v SUBJECT Table C9. Table C10. Table CI1. Table C12. Table C13. Table C14. Table C15. Table C16. Table C17. Table C18. Table C19. Table C20. Table C21. Table C22. Table C23. PAGE Body Weight Changes - Precohabitation - Summary - Fo Generation Female Rats [SH Maternal Body Weights- Gestation - Summary - Fo Generation Female Rats C16 Maternal Body Weight Changes -Gestation - Summary - Fo Generation Female Rats cis Maternal Body Weights- Lactation - Summary - Fo Generation Female Rats C19 Maternal Body Weight Changes - Lactation - Summary - Fo Generation Female Rats c20 Absolute Feed Consumption Values (g/day) - Precohabitation - `Summary - Fo Generation Female Rats cai Relative Feed Consumption Values (/kg/day) - Precohabitation - Summary - Fo Generation Female Rats cn Maternal Absolute Feed Consumption Values (g/day) - Gestation - Summary - Fo Generation Female Rats C2 Maternal Relative Feed Consumption Values (g/kg/day) - Gestation - `Summary - Fo Generation Female Rats cu Maternal Absolute Feed Consumption Values (g/day) - Lactation - `Summary - Fo Generation Female Rats cas Matemal Relative Feed Consumption Values (/kg/day) - Lactation - Summary - Fo Generation Female Rats C26 Mating and Fertility, Estrous Cycling and Days in Cohabitation - Summary - Fo Generation Female Rats c21 Functional Observational Battery - Summary - Female Rats C29 Motor Activity - Summary - Fo Generation Female Rats C35 Natural Delivery Observations - Summary - Fo Generation Female Rats C37 vi SUBJECT Table C24. Table C25. Table C26. Table C27. Table C28. Table C29. Table C30. Table C31. Table C32. Table C33. Table C34. Table C35. Table C36. Table C37. Table C38. PAGE Litter Observations (Naturally Delivered Pups) - Summary - Fl Generation Litters C38 Clinical Observations from Birth to Day 5 Postpartum - Summary - Fl Generation Pups C41 Necropsy Observations - Summary - FI Generation Pups ca Clinical Observations - Individual Data - Fo Generation Female Rats c43 NFeecmraolpesRyatOsbservations - Individual Data - Fo Generation cas Terminal Body Weights and Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight- Fo Generation Female Rats csi Organ Weights and Ratios (%) of Organ Weight to Brain Weight - Individual Data - Fo Generation Female Rats C59 Body Weights - Precohabitation - Individual Data - Fo Generation Female Rats C63 Maternal Body Weights - Presumed Gestation - Individual Data - Fo Generation Female Rats C61 Maternal Body Female Rats Weights - Lactation - Individual Data - Fo Generation cn Feed Consumption Values - Precohabitation - Individual Data - Fo Generation Female Rats cs Maternal Feed Consumption Values - Presumed Gestation - Individual Data - Fo Generation Female Rats C79 Maternal Feed Consumption Values - Lactation - Individual Data - Fo Generation Female Rats C83 Mating and Fertility, Estrous Cycling and Days in Cohabitation - Individual Data - Fo Generation Female Rats. [=4 Functional Observational Battery -Individual Data - Female Rats ~~ C-89. vii SUBJECT PAGE Table C39. Motor Activity - Individual Data - Fo Generation Female Rats C9 `Table C40. Natural Delivery, Implantation Sites, and Pup Viability and Sex Individual Data - Fo Generation Female Rats/FI Generation Litters C-101 Table C41. Pup Body Weight Litter Averages from Birth to Day 5 Postpartum - Individual Data - FI Generation Litters C103 Table C42. Pup Body Weights from Birth to Day 5 Postpartum - Individual Data - Fi Generation Pups. C105 Table C43. Pup Vital Data - FI Status and Sex from Generation Pups Birth to Day 5 Postpartum - Individual ca Table C44. Clinical Observations from Birth to Day $ Postpartu-m Individual Data - FI Generation Pups. cur Table C45. Necropsy Observations - Individual Data - Fl Generation Pups ~~ C-118 APPENDIX D- PROTOCOLAND AMENDMENTS D-loD42 APPENDIX E- DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY E-lt0E2 APPENDIX F- CERTIFICATE OF ANALYSIS Fl APPENDIX G- ANALYTICAL REPORT G1 APPENDIX H- TEMPERATURE AND RELATIVE HUMIDITY REPORT ~~ H-1 APPENDIX I- POSITIVE CONTROL DATA Holk4 APPENDIX - HISTOPATHOLOGY REPORT FloJ-110 APPENDIX K- HEMTOLOGY AND CLINICAL CHEMISTRY REPORTS K-1oK-51 APPENDIX L- STATEMENT OF THE STUDY DIRECTOR Li APPENDIX M- QUALITY ASSURANCE STATEMENT M-1toM-2 418-027:PAGE 1-1 TITLE: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST ARGUS RESEARCH PROTOCOL NUMBER: 418-027 SPONSOR'S STUDY NUMBER: T-7599 1 SUMMARY AND CONCLUSION LL Methods' Sixty male and sixty female Crl:CD(SD)IGS VAF/PIus rats were assigned to four dosage groups (Groups I through IV), 15 rats per sex per group. The test substance was TT7h5e909..57%aCndMtChewvaeshiucsleedwfaosr tahqeuefiorustsf0ou.r5d%ayors 1o.f0t%hecasrtbuodxyyamnetdhtyhlece1l.l0u%loCseM(CCMwCa)s.used for the remainder of the study. The test substance or vehicle was administered to the male rats beginning 14 days before cohabitation and continuing until sacrifice, after `fceommaplleetriaotsn boefgtihnencionhgab1i4tadtaiyosnbpeefroiroed,coahfatebritaatmiionniamnudmcoonft2i8nudianygsuonftidlodsaayge$ aofndlatcotatthieon (DL'S). Dosages were 0 (Vehicle), 10, 50 and 250 mg/kg/day. The dosage volume was adjusted daily `Within each dosage group, consecutive order was be usedtoassign the first five male and the first five female rats to a functional observational battery (FOB) and motor activity assessment. The next five rats per sex in each group were assigned to hematology and clinical biochemistry evaluations. The last five ratspersex in each group were assigned to metabolite analysis. Histological evaluations were performed on the last ten rats per sex in cach group. Rats were observed for viability at least twice each day of the study. Observations for clinical signsofeffects of the test substance, abortions, premature deliveries and deaths were made daily before dosage. Postdosage observations were recorded approximately 60 + 10 minutes after dosage administration and on the day of sacrifice. Once before the first dosage and at least once weekly thereafter, detailed clinical observations were conducted for all male and female rats. Body weights for male and female rats were recorded daily during the dosage period and at sacrifice. Feed consumption values for male rats were recorded weekly during the dosage period. Feed consumption values for female rats were recorded weekly to cohabitation and on gestation days (DGS) 0, 7, 10, 12, 15, 18, 20 and 25 (ifnecessary) and on lactation days (DLs) 1 and 5. a. Detailed descriptions of all procedures used in the conduct of this study are provided in the appropriate sections of his report and in APPENDIX D (PROTOCOL AND AMENDMENTS). 418-027:PAGE 1-2 Eafstterrotuhsecfyicrlstinagdmwiansisetvraaltuiaotneadnbdytheexnamuinntialtisopneromfavtaogzionaalwecryetoolbosgeyrbveegdininniangsmweiatrh otfhethdeay vaginal contents and/ora copulatory plug was observed in sifu during the cohabitation period. Female rats were evaluated for adverse clinical signs observed during parturition, duration of gestation, litte sizes and pup viability at birth. Maternal behavior was evaluated on DLs I and 5. Motor activity was evaluated on five male and five female rats per group once during the coofubrisrethoafntdhewsatsudayl,sobetfhoerfeirsstchdeadyuloendwshacircihfiaclel.pDupasyi1n oafliltatcetrawteiornewiansdidveifduianleldyawsetihgehedda.y Each liter was cvaluated for viability at least twice daily. The pups in each litter were counted twice daily. Clinical observations were recorded once daily. Pup body weights were recorded on DLs on DL 6, all surviving 1 and 5. After 36 days of dosage, all female rats were sacrificed. A gross male rats necropsy were sacrificed was performed. and Tsehmeinteasltevsesaincdlecspwiidtihdycmoiadguelsaotfinagllgmlaalned arantds wpreorsetawteeiwgehreed,raetnadintehde. teTshtees,oveapriideisdyamniddetshe, uterus with cervix of each female rat were weighed,and ovaries, uterus, vagina and a `mammary gland were retained. "The following organs were individually weighed: liver, kidneys, adrenals, thymus, estes, epididymides, spleen, brain, heart, ovaries and uterus. The following tissues or representative samples were retained: brain, small and large intestines, lungs, lymph nteosdteess,, eppeirdiiphdeyrmaildense,rvsee,msitnoamlavcehs,ickliedsn,epyrso,stsaptlee,ens,pitnhalymcuosr,d,trliavcehre,a,adurreinnaalrsy, bhleaardtd,er, thyroid/parathyroid, uterus, bone marrow, ovaries, uterus, vagina, mammary gland (female rats only) and gross lesions. Histological examination was conducted for the assigned ten rats per sex from the control and high dosage groups. Histological evaluations were performed on the livers of ten male and ten female rats, the thymuses of ten female rats and the stomachsof ten male rats in the 10 and 50 mg/kg/day dosage groups. At scheduled sacrifice, blood was collected from the five male and five female rats per group assigned to hematology and clinical chemistry sample collection. One aliquot was analyzed for hematologic parameters. Two blood smear slides were prepared for each sample for measurements of differential leukocyte count. Plasma from another aliquot was measured for prothrombin time and activated partial thromboplastin time. Serum from a third aliquot was analyzed for clinical chemistry parameters. Blood samples were collected from the five rats per sex per group assigned to metabolite analysis. The liver was excised and the organ weight recorded. On DL 5, pups were sacrificed and examined for gross lesions. Pups found dead on DLs 2 to 4 were examined for gross lesions and for possible causeofdeath. 418-027:PAGE 13 12. Results - Males Apelrliomraallesruabtsstsaunrcveiavendd tuorisnceh-esdtuailneeddsaacbrdiofmicien.alSfiugnriofciccuanrtreidncirneatshees2i5n0exmcge/sksg/sadlaiyvadtoiosna,ge group. All other clinical observations unrelated 10 the test substance. and all necropsy observations were considered Body weight gains were significantly reduced in the 250 mg/kg/day dosage group on DthSes5011m0g8/,kg1/tdoay15doasnadge1 tgoro36u.p oBnodDySswe1igtoht36g.ainBsodweyrweeailgshotssiwgenirfeicsaingtnliyfidceacnrtleyasreedduinced ownerDeSsi2g9niafincdan3t6lyinretdhuec2e5d0inmgt/hkeg5/0daaynddo2s5a0gemgg/rkogu/p.dayAbdsooslaugtee gfreoeudpcsoonnsuDmSpsti1on10va8launeds sRieglnaitfiivceanfteleydrceodnuscuemdpitnitohnev2a5l0uemsgw/ekrge/dsaiygndifoiscaagnetlgyrroeudpuscoedn oDnSsDS1sto11105 8anidn t1hteo5306.and 250 mg/kg/day dosage groups. `dToesramgienaglrobuopd.y Awbesioglhuttsoefwetihgehmtasloefrtahtes lweeftreansdigrniigfhitcaknitdlnyeryesdwuecreed sinigtnhiefi2c5an0tlmyg/ikncgr/edaasyed in the 50 and 250 mg/kg/day dosage groups and the absolute weightof the liver was significantly increased in the 250 mg/kg/day dosage group. The ratios of the weights of t2h5e0semgo/rkgagn/sdatyo tdeorsmaignealgrbooudpsy.weRieglhattsivwee(r0etshiegnbirfaiicnanwteliyghitn,croenalsyedthien ltihveer50weaingdht in the 250 mg/kg/day dosage group was significantly increased. Treatment-related microscopic cgrhoaunpgsesanwderien otbhesesrtvoemdacinhtohfemlailveerroaftsmainlethreat2s5i0nmtghe/k5g0/daanyd d2o5s0amgge/gkrgo/udpa.y dosage Dosages of the test substance as high as 250 mg/kg/day did not affect any hematoloogyr clinical chemistry values evaluated. All mating and fertility parameters were unaffected by dosages of the test substance as high as 250 mg/kg/day. There were no statistically significant or biologically important differences among the four dosage groups in the measures of the functional observational battery (FOB). Body weights recorded during the functional operational battery for the treated groups were not ssiiggnniiffiiccaannttloyrdbiifofleorgeintcatlhlaynitmhpeorctoanntrtodligfrfeoruepncfeosr tahmeomnagltehreatfso.urTdhoesraegweegrreonuopsstiantitshet.ically `measures of motor activity on DS 86. 13. Res-uFlemtalses Al female rats survived to scheduled sacrifice. All clinical and necropsy observations were considered unrelated to the test substance. Body weight gains were significantly reduced during the precohabitation period in the 250 mg/kg/day dosage group on DSs 1 to8and 110 15. Body weights and body weight gains were not significantly affected by dosages of the test substance during gestation or lactation. Terminal body weights of the female rats were reduced in the 250 mg/kg/day dosage group. Absolute liver weight was significantly increased in the 250 mg/kg/day dosage `group. The ratios of the weight of this organ and the weight of the right kidney to 418-027:PAGE 14 Otenrlmyintahle braotdiyo owfeitghhetlsivweerrweeisigghntiftiocbarntaliyn iwnecirgehatseidn itnheth2e5205m0g/mkgg//kdga/ydadyosdaogseaggerogruopupw.as significantly increased. Treatment-related liver and thymus of female rats in the 250 microscopic changes were mg/kg/day dosage group. observed in the vDaolsuaegseesvaalsuhaitegdh.asA2bs5o0lmutge/kagn/ddareyladtiidvenofteeadffceoctnsaunmypthieomnatvoallougeys owrercleinnioctalsicghneimfiicsatnrtyly apefrfieocdtse.d bAylldoesstargoeuss,omfatthientgesatnsdubfesrttainlictey dpuarrianmgettehrespwreecroehaubniatfafteicotne,dgbeystdatoisoangeosr olafctthateion tbeisotlosguibcsatlalnyciemapsorhtiagnhtadsif2f5e0remngc/eksg/admaoyn.gTthheerfeouwredroesnaogestgartoisutpiscailnlytshiegmniefaiscuanrtesorof the. `FgOrBo.upsBwoedrye wnoetigshitgsnirfeiccaonrtdleydddiuffreirnegntthtehafnuntchteiocnoanltrooplergartoiuopnaflorbatthteerfyemfaorlethreatst.reaTtheedre were no statistically significant dosage groups in the measures oofrmboitoolorgaicctailvliytyimopnorDtSan8t6d.ifferences among the four `The number significantly of liveborn pups increased in the was 250 significantly reduced and mg/kg/day dosage group. number of sillborn pups was The number of pups found idnecardeaosrepdrienstuhmee2d5c0anmngi/bkagl/idzeadyodnosdaagye 1garnoudpdsa.yTshe2 vtioab5ilpiotsytipnadretxumanwdasnusmigbneirfiocafnptluyps dsoursvaigveinggropuepr. liPtuerpobnodpyoswtepiagrhttusmpdearyli5ttweerrweerseiganlisfoicraendtluycerdediunctehdei2n5t0hemg2/5k0g/mdg/akyg/day dosage group on postpartum days 1 and 5. iVmaplluaenstaftoirotnhesinteusmpbeerrsdeolfivdearmedsldietleri,vegreisntgatliiotnerisn,ddeuxr,atniuomnboefrsgeosftadtaiomns, awvietrhasgteisllfboorrn d`pauyps,1 daandmspuwpitshexallraptuiposswdeyriengc,osmtpialrlabbolrepuapmso,nsgurtvhievifnogurpduopssapgeerglriottueprso.n Npoosctlpianritcaulmor necropsy observations in the FI generation pups were attributable to dosages of the test substance as high as 250 mg/kg/day. 418.027:PAGE 1-5 14. Conclusion On the basisofthese data, the paternal no-observable-adverse-effect-level (NOAEL) for T 7599.7 is 10 mg/kg/day (the 50 mg/kg/day dosage caused reduced weight gain during precohabitation, reduced absolute and relative feed consumption values, increased absolute and relative liver and kidney weight, and liver histopathology). The maternal NOAEL is 50 mg/kg/day (the 250 mg/kg/day dosage caused reduced weight gain during precohabitation, reduced terminal body weights, increased absolute and relative liver weight, and histopathology of the liver and thymus). The reproductive NOAEL is greater than 250 mg/kg/day (all estrous, mating and fertility parameters were unaffected by dosagesofthe test substance as high as 250 mg/kg/day). The NOAEL for viability and `growth in the offspring is SO mg/kg/day (dosages of 250 mg/kg/day caused postnatal mortality and decreased pup body weights). Dolled Alan M. Hoberman, Ph.D., DABT Director of Research 3 Date ond G. York DABT Date Associate Director `search Study Director 418.027:PAGE 2-1 2. DESCRIPTION OF TEST PROCEDURES 21. ConductofStudy 211 Sponsor 3M Corporate 55144-1000 Toxicology, 3M Center, Building 220-2E-02, St. Paul, Minnesota 212. Testing Facility Argus Research, 905 Sheehy Drive, Building A, Horsham, Pennsylvania 19044-1297 213. Study Number 418-027 214. Sponsor's Study Number T7599 215. Purpose of the Study `The purposeofthis study was to provide information on the possible health hazards that `may result from repeated exposure of Crl:CD(SD)IGS BR VAF/Plus male and female rats (0a test substance beginning before cohabitation, through mating and continuing for at least 28 days (male rats)or through parturition until day 5 of lactation (female rats). "This repeated dose study incorporated a reproduction/developmental toxicity screening test to provide initial information on possible effects on male and female reproductive performance (e.g, gonadal function, mating behavior, conception, development of the conceptus and parturition). The study also placed emphasis on neurological effects as a specific endpoint and was designed to identify the neurotoxic potential of test substance, which may warrant further in-depth investigation. 216. Study Design "The requirements of the Organisation for Economic Co-operation and Development (OECD) were used as the basis for study design. 217. Regulatory Compliance "This study was conducted in compliance with Good Laboratory Practice (GLP) regulations of the Organisation for Economic Co-operation and Development (OECD), WUe.Sl.faFroeo(dMaHnWd)Dr.ug TAhdemrieniwsetrraetnioonde(vFiaDtiAo)nsafnrdomthtehJeaGpaLnPesreegMuilnaitsitornys otfhaHteaaflftehctaenddthe quality or integrity of the study. Quality Assurance Unit findings derived from the inspections during the conduct of this study are documented and have been provided to the Study Director and the Testing Facility Management. 418-027:PAGE 22 218. Ownership of the Study `The Sponsor owns the study. property of the Sponsor. Al raw data, analyses, reports and preserved tissues are the 219. Study Monitor Paul H, Lieder, Ph.D., DABT 2110. Study Director Raymond G. York, Ph.D., DABT, Associate Director of Research Address as cited above for Testing Facility 2111. Technical Performance John F. Bamett, B.S. (Director of Laboratory Operations) Christine A. O'Brien (Research Associate) Loma A. Sinotte, B.S. (Laboratory Technician) Stephanie M. Dorizio, B.A. (Necropsy Laboratory Technician) Christopher K. Ruppert, B.S. (Formulation Laboratory Technician) 2112. Report Preparation Raymond G. York, Ph.D., DABT Jo Ann Frazee, M.S. (Study Coordinator) JoAnne M. Conklin, B.S. (Data Management Specialist) Jennifer M. Hughes (Report Administrator) 2113. Report Review AMilladnrMe.d SH.oCbherrimstaina,n,PPh.hD..D,,DFAelBlTow(,DAirTeSct(oErxoefcuRteisveearDcihr)ector of Research) 21.14. Date Protocol Signed 15 February 2002 2115. Dates of Technical Performance 2.1151. Male Rats Rat Arrival Dosage Period (14days before cohabitation and through a 14-day cohabitation period until sacrificeafterat least 28 days of dosage) FOB and Motor Activity Evaluation Scheduled Sacrifice: 12 FEB 02 18 FEB 02 - 25 MAR 02 19 MAR 02-20 MAR 02 26 MAR 02 418.027:PAGE 2:3 2.1152. Female Rats Rat Arrival 12 FEB 02 Dosage Period (14 days before cohabitation through DL* 5) 18 FEB 02 - 12 APR 02 Dosage Period Estrous Cycle Evaluation 19 FEB 02 - 04 MAR 02 Cohabitation Period Male | 04 MAR02 PM - 11 MAR 02 AM Male 2 11 MAR02 PM- 18 MAR 02 AM DG"0 05 MAR02-17 MAR 02 Delivery Period" (DL 1) 27 MAR 02 - 08 APR 02 DG 25 Sacrifice (Rats that id not delivear liter) 30 MAR 02 - 12 APR 02 FOB Evaluation and Motor Activity Evaluation 31 MAR 02 - 12 APR 02 Pup Sacrifice (DL 5) 31 MAR 02- 12 APR 02 Scheduled Sacrifice (DL 6) O01 APR 02-13 APR02 2116. Records Maintained "The original report, raw data and reserve samplesofeach lot of bulk test substance and bulk vehicle components are retained in the archives of Argus Research. Any preserved tissues are retained in the archives of the Testing Facility for one year aftr the mailing of the draft final report, after which time the Sponsor will decide their final disposition. All unused prepared formulations were discarded at the Testing Facility. Unused bulk test substance will be returned to the Sponsor. 22. Test Substance Information 221. Description T 7599.7 - amber waxy solid a. DLisan abbreviation for day of lactation. b. DG is an abbreviation used for day of (presumed) gestation. Cc. The day of birth is designated lactation day 0 (postpartum day 0) in the Health Effects Test Guidelines- Reproduction and Fertility Effects (Office of Prevention, Pesticides and Toxic Substances 870.3800, August, 1998) and in the OECD. `Guideline for the Testing of Chemicals - Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (Section 4, No. 422, 22 March 1966). Thissameday is designated day 1 postpartum (day | of lactation) in the Standard Operating Procedures of the Testing Facility. "Throughout this study, the day of birth was designated day 1 postpartum (day 1 of lactation) and all subsequent ages of the FI generation rats and days of the lactation period were determined and cited accordingly. 418-027:PAGE 24 222. Lot Number 6 223. Date Received and Storage Conditions The test substance was received on 18 February 2002 and stored at room temperature, protected from light. 224. Special Handling Instructions `Standard safety precautions (use of protective clothing, gloves, dust-misVHEPA-filtercd `mask, safety goggles or safety glasses and a face-shield) were worn during formulation preparation and dosage. A half-face respirator was worn when the bulk test substance was not being used in a chemical fume hood. 225. AnalysisofPurity Information to document or certify the identity, composition, method of synthesis, strength and purity of the test substance was provided by the Sponsor to the Testing Facility. A Certificate of Analysis is available in APPENDIX F. 23. Vehicle Information 234. Description Aqueous 0.5% or 1.0% carboxymethyleellulose (CMC) (medium viscosity) prepared carboxymethylcellulose, an off-white powder, and reverse osmosis membrane processed water. The 0.5% CMC was used for the first four days of the study. Beginning 22 February 2002, the 1.0% CMC was used for the remainder of the study. 232. Lot Number 120K0252 233. Date Received and Storage Conditions The carboxymethylcellulose was received on 11 September 2001 from Sigma Chemical Co, St. Louis, Missouri, and stored at room temperature. R.O. deionized water is available from a continuous source at the Testing Facility and is maintained at room temperature. 418-027:PAGE 2-5 234. Special Handling Instructions Standard safety precautions (use of protective clothing, gloves, dust-misyHEPA-filtered mask, safety gogeles or safety glasses and a face-shield) were taken when handling the vehicle components and prepared vehicle. 235. Analysis of Purity Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the vehicle that would have interfered with the results of this study. The expiration date of the carboxymethyleellulose is September 2005. 24. Test Substance Preparation and Storage Conditions Formulations were prepared weekly at the Testing Facility. Prepared test substance and vehicle formulations were stored refrigerated, protected from light. 418-027:PA2G-E6 ETE 24.1. Sample Information `BulkTest Substance `Concentration' Gall levels) [3]26FEB 02 | Room temperature, g | 12APR02" | protected from light 03APR02 | Refrigerated, 2mL_| 04 APR02' | protected from light Te] 26FEB02 15 APR02 03 APR02 04 APR02 oin me | 1: |e 2 og 242. Analytical Results Results of the analytical analyses are available in APPENDIX G. 25. Test System 25.1. Species Rat 25.2. Strain Crl:CD(SD)IGS BR VAF/Plus 413-027:PAGE 27 253. Supplier (Source) Charles River Laboratories, Inc., Raleigh, North Carolina 254. Sex Male and Female 255. Rationale for Test System The Crl:CD@(SD)IGS BR VAF/Plus rat was selected astheTest System because: 1) it is one mammalian species accepted for use in toxicity studies and it has been widely used throughout industry; 2) this strain of rat has been demonstrated to be sensitive to reproductive and developmental toxins; and 3) historical data and experience exista the Testing Facility" 256. Test System Data 2561. Male Rats Number of Rats Approximate Date of Birth Approximate Age at Arrival Weight (g) the Day after Arrival Weight (g) at Study Assignment 0 04 DEC O01 71 days 282-333 303-354 2562. Female Rats Number of Rats Approximate Date of Birth Approximate Age at Arrival Weight (g) the Day after Arrival Weight (g) at Study Assignment 10 D7EC OI 65 days 185-226 210-230 257. Method of Randomization Upon arrival, the male and female rats were assigned to individual housing on the basis of computer-generated random units. Afteran acclimation period of at least five days, `male and female rats were selected for study on the basis of physical appearance and body weights recorded during acclimation. The rats were assigned to four dosage groups (Groups I through IV), 15 rats per sex per group, using 2 computer-gencrated (weightordered) randomization procedure. Within each dosage group, consecutive order was usedto assign the first five male and the first five female rats to a functional observational battery (FOB) and motor activity assessment. The next five rats per sex in each group were assigned to hematology and clinical biochemistry evaluations. The last five rats per sex in each group were assigned 413-027:PAGE 2-8 to metabolite analysis. Histological evaluations were performed on the last ten rats per sex in each group. 258. System of Identification Male and female rats assigned temporary numbers at receipt and given unique permanent identification numbers when assigned 10 the study. Rats were permanently identified using Monel self piercing ear tags (Gey Band and Tag Co, Inc., No. MSPT 20101). Cage tags were marked with the study number, permanent rat number, sex, test substance identification, generation and dosage level Pups were not individually identified during lactation; all parameters were evaluated in termsofthe litter. 26. Husbandry 261. Research Facility Registration USDA Registration No. 14-R-0144 under the Animal Welfare Act, 7 U.S.C. 2131 ef seg. 262. Study Room `The study room was maintained under conditionsofpositive airflow relative to a hallway and independently supplied with a minimum of ten changes per hour of 100% fresh air that had been passed through 99.97% HEPA filters. Room temperature and humidity were monitored constantly throughout the study. Room temperature was targeted at 66F 10 77F (19C to 25C); relative humidity was targeted at 30% to 70%". 263. Housing Fo generation rats were individually housed in stainless steel wire-bottomed cages except during cohabitation period and postpartum periods. During cohabitation, cach pair of male and female rats was housed in the male rats cage. Beginning no later than DG 20, Fo generation female rats were individually housed in nesting boxes. Each dam and delivered litter was housed in a common nesting boxduringthe postpartum period. All cage sizes and housing conditions were in compliance with the Guidefor the Care and Use ofLaboratory Animals. 264. Lighting An automatically-controlled fluorescent light cycle was maintained at 12-hours light: 12-hours dark, with each dark period beginning at 1900 hours EST. a See APPENDIX H (TEMPERATURE AND RELATIVE HUMIDITY REPORT). 418-027:PAGE 29 265. Sanitization Cage pan liners were changed at least three times weekly. Cages were changed approximately every other week. Bedding was changed as often as necessary to keep the rats dry and clean. 266. Feed Rats were given ad libitum access to Certified Rodent Diet#5002 (PMI Nutrition International, Inc., St. Louis, Missouri) in individual feeders. Rats were fasted overnight before sacrifice. 267. Feed Analysis Analyses were routinely performed by the feed supplier. No contaminants at levels exceeding the maximum concentration for certified feed or deviations from expected nutitional requirements were detected by these analyses. Copiesofthe resultsofthe feed analyses are available in the raw data. Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the feed that would have interfered with the results of this study. 268. Water Local water that had been processed by passage through a reverse osmosis membrane (RO. water) was available to the rats ad libitum from an automatic watering access system and/or individual water bottles attached to the cages. Chlorine was added to the processed water as a bacteriostat 269. Water Analysis `The processed water is analyzed twice annually for possible chemical contamination (Lancaster Laboratories, Lancaster, Pennsylvania) and monthly for possible bacterial contamination (Analytical Laboratories, Inc., Chalfont, Pennsylvania). Copiesofthe results of the water analyses are available in the raw data. Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the water that would have interfered with the results of this study. 2610. Bedding Material Bed-0'cobs bedding (The Andersons Industrial Products Group, Maumee, Ohio) was used as the nesting material. 418-027:PAGE 2-10 26.11. Bedding Analysis Analyses for possible contamination are conducted semi-annually. of the bedding analyses are available in the raw data. Copies of the results Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the bedding that would have interfered with the results of this study. 27. Methods 27.0. Dosage Administration elmlm[EF DGoogpe|| oDhooe)|| omoeegmoion|| tVohamye|| RaSsop"er | mers | remem | J TT76eR0 71T77666000298, 171677136880 1177676063%,0||| 17T77086,T076r782, 17177607083.,17T70sT0 Tiss rss vi Tie 137 11s " w Toe aR ascone TOE 0 a 11770629sl776645754,6115745s15.7577s06%5, || 117706701%,.71766071.. 117760712,711770760s8 11T760s21s5,., 17166120601117757661021,5,5170s66.7,15||| 1177067610.11776.60077,.11177763960%79,5,1177076767086. T76061.615706017,65177,6121.76157067. | T7664i,707507. 176787, 017653 1029i7.11,7663261o,,i11776027726s11t766245,.|| 1177698T, 1L17769635m.. 7768e, 1177659,. Ge Sos 272. Rationale for Dosage Selection Dosages were selected by the Sponsor based on previous studies conducted with the test substance, taking into account possible differences in sensitivity between pregnant and nonpregnant rats. The highest dosage was expected to cause toxic effects but not `mortality or obvious suffering. The descending sequence of the lower dosage levels were selected for the purposeofdemonstrating any dosage-related response, with no adverse. effects expected at the lowest level, 273. Route and Rationale for Route of Administration `The oral (gavage) route was selected for use because: 1) in comparison with the dietary route, the exact dosage can be accurately administered; and 2) it is one possible route of human exposure. 418-027:PAGE 2-11 274. Method and Frequencyof Administration 274.1. Fo Generation Rats Male rats were administered the test substance and/or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuing until sacrifice, after `completion of the cohabitation period, after a minimum of 28 days of dosage. Female rats were administered the test substance and/or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuing until DL5. The dosage volume was adjusted daily on the basis of the individual body weights recorded before intubation'. The rats were intubated once daily at approximately the same time cach day. 2742. Fl Generation Pups F1 generation pups were not directly administered the test substance and/or vehicle, but may have been possibly exposed to test substance and/or vehicle during maternal `gestation (in utero exposuroer) via maternal milk during the lactation period. 275. Method of Study Performance 275.1. Fo Generation Rats Within cach dosage group, consecutive order was used to assign rats to cohabitation, one male rat per female rat. The cohabitation period consisted ofa maximum of 14 days. Female rats with spermatozoa observed in a smear of the vaginal contents and/or a copulatory plug in sifu were considered to be DG 0 and assigned to individual housing. Female rats that were not mated with a male rat within the first seven days of cohabitation were assigned an alternate male rat that had mated (same dosage group) and remained in cohabitation for a maximum of seven additional days. Rats were observed for viability at least twice each day of the study. Rats were examined for clinical observations and general appearanceweekly during the acclimation period. Observations for clinical signsofeffects of the test substance, abortions, premature deliveries and deaths were made daily before dosage. On the first dayofdosage, postdosage observations were recorded at approximately hourly intervals for the first four hours after administration. The observation at four hours after administration was at the end of the normal working day. Postdosage observations for subsequent daysofdosage were recorded approximately 60+ 10 minutes after dosage administration and on the day of sacrifice'. Once before the first dosage and at least once weekly thereafter, detailed clinical observations were conducted for all male and female rats. These observations were made a Sec APPENDIX E (DEVIATIONS FROM THE PROTOCOL AND THE. STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY), item 1. b. Sec APPENDIX E, items 2 and 3. 418-027PAGE 2-12 omuatdseidteotehnescuargeethiantavsatriaantdiaorndsairnetnhaeattestthecosnadmietitoinmseweearcehmdianyiomfalcoanndductth.at oEbffsoerrtvawtaisons `wweerree cnootndluicmtiteeddbtyo:obcshearnvgeerss iunnsakwianr,efuorf, teryeeas,tmmenutcogruosupmse.mbSriagnnessn,ootcecduirnrcelnucdeedo,fbut ssiezcer,etuinounssuaalndreesxpcirreattioornyspaatntderanu)t.onCohmaincgeasctiinvigtayit(,e.pgo.,stluarceriamnadtiroens.ppoinlsoeertcocthiaonnd,lpiunpgilas well as the presence ofclonic or tonic movements, stereotypic behavior (c.g., excessive `grooming, repetitive circling), difficult or prolonged parturition or bizarre behavior (e.g. self-mutilation, walking backwards) were also recorded. Bpeordioyd,wediagihltysdufrorinmgaltheeadnodsafgeemapleeriroadtsawnedraetrseaccroirfdiceed. weFeekeldycdounrsiunmgptthieonacvcalliumeastifoonr male rats were recorded weekly during the dosage period. Feed left was recorded on the day before sacrifice. Feed consumption values for female rats were recorded weekly to c5.ohaFbeietdatliefotnwaansd roencoDrGdsed0o,n7,th1e0,da1y2,b1e5f,or1e8,sa2c0rifaincde.2D5u(rifinnegcecsoshaarbyi)taatinodn,onwDheLns tIwaond rats occupied the same cage with one feed jar, replenishment of feed jars was documented but individual values were not recorded or tabulated. Male and female rats were fasted overnight before sacrifice. Estrous cycling was evaluated by examination of vaginal cytology beginning with the day after the first administration and then until spermatozoa were observed in a smearof the vaginal contents and/ora copulatory plug was observed in sifu during the cohabitation period. Female rats were evaluated for adverse clinical signs observed during parturition, duration of gestation (DG 0to the day the first pup was observed), litte sizes (all pups delivered) and pup viability at birth. Maternal behavior was evaluated on DLs 1 and 5. Variations from expected maternal behavior were recorded, if and when present, on all other days of the postpartum period. On one occasion during the course of the study, shortly before scheduled sacrifice, a functional observational rats per group. For male braattst,erhyi(sFaOsBs)essm2'enwtawsacsoncdouncdtuecdteodnafpipvreomxailmeataenldy foinvee fweemeakle before scheduled sacrifice. Female rats were tested during the lactation period, the day before scheduled sacrifice. To avoid hyperthermia of pups, dams were separated from their litters for no longer than 30 to 40 minutes. `The FOB evaluation was conducted by an observer unaware of the group assignment of the rat. The following parameters were assessed: 1. Lacrimation, salivation, palpebral closure, prominence of the eye, pupillary reaction to light, piloerection, respiration, and urination and defecation (autonomic functions). 418-027PAGE 2-13 2. Sensorimotor responses to visual, auditory, tactile and painful stimuli (reactivity and sensitivity). 3. Reactions to handling and behavior in the open field (excitability). 4. Gait pattern in the open field, severity of gait abnormalities, air righting reaction, visual placing response and landing foot splay (gait and sensorimotor coordination). 5. Forelimb and hindlimb grip strength. 6. Abnormal clinical signs including but not limited to convulsions, tremors and other unusual behavior, hypotonia or hypertonia, emaciation, dehydration, unkempt appearance and deposits around the eyes, nose or mouth. "The abilityof this battery to detect the effects of positive control substances has been established (Testing Facility Positive Control Data) and is available in APPENDIX L. Motor activity was evaluated on five male and five female rats per group once during the course of the study. For male rats, this assessment was conducted approximately one: week before scheduled sacrifice. Female rats were tested during the lactation period, the: day before scheduled sacrifice. `The movementsofeach rat were monitored by a passive infrared sensor mounted outside a stainless steel, wire-bottomed cage (40.6 x 25.4 x 17.8 cm). Each test session was 1.5 hours in duration with the number of movements and time spent in movement tabulated at each five-minute interval. The apparatus monitored a rack of up to 32 cages and sensors during each session, with each rat ested in the same location on the rack. across test sessions. Groups were counterbalanced across testing sessions and cages. Data demonstrating that the test system is capable of detecting increases in activity produced by positive control substances (Testing Facility Positive Control Data) is available in APPENDIX I 27.52. Fl Generation Pups Day I of lactation (postpartum) was defined as the day of birth and was also the first day on which all pups in a litter were individually weighed (pup body weights were recorded after all pups in a litter were delivered and groomed by the dam). Each litter was evaluated for viability at least twice daily. The pups in each litter were: counted once daily. Clinical observations were recorded once daily. Pup body weights were recorded on DLs 1 and $ (terminal weight). 418-027:PAGE 2-14 27.6. Gross Necropsy 27.61. Fo Generation Rats Adfotsearge3,6ddaayys37ofofdosstaugdey,(aDllSm3a7l)earnadtsownerDeLs6a,crailfliscuerdvoinvitnhgefdeamyalfeolrlatoswiwnegrethseaclrasitficed. tRhaotrsacwiecr,eabsadcormiifnicaeldabnydcpaerlbvoinc dviisocxeirdaewaaspshpyexiraftoiromne,d.andGraosgsronsescnreocprsoyopsfyoalfl tmhaele and afsemwaellel raaststhienccrlaundieadl,anthionriatciailcpahnydsiacbadloemxianmailnacatviiotnieosfaenxdtetrhneailr scuornftaecnetss.anSdpeaclilaolrifices, asittteesntainodn cwoarspopraaidluttoeathweeorregarnecsorodfetdh.e rTeipsrsoudeucttriivmemsiynsgteamn.d hTihsetonpuamthboelroogfy wiamsplantation pGreorsfsorlmeesdiounnsdweerrteherestuapienrevdiisnionneuotfraolr bbuyffaeBroedar1d-0C%erftofrimaeldiVneatnerdienaxraymiPnatehdologist histologically. Representative photographs ofgross lesions are available in the raw data. `sTehmeinteasltevsesaincdleespwiidtihdycmoiadgeuslaotfinagllgmlaalned raantds wpreorsetawteeiwgehreed,reatnadintehde itnesnteeus,treaplibduifdfyemrieddes, 10% formalin. The testes were fixed in Bouin's solution for 48 to 96 hours before being retained in neutral buffered 10% formalin. The ovaries and the uterus with cervixofeach female rat were weighed, and ovaries, uterus, vagina and a mammary gland were retained in neutral buffered 10% formalin. Uteri of apparently nonpregnant ras were examined after being pressed between glass plates to confirm the absence of implantation sites, and retained in neutral buffered 10% formalin. "Ten rats per sex per group not assigned to functional observational battery and motor activity tests were assigned to histological evaluations. The following organs were excised, trimmed and individually weighed as soon as possible after excision to avoid drying: liver, Kidneys, adrenals, thymus, testes, epididymides, spleen, brain, heart, ovaries. and uterus (with cervix)". The following tissues or representative samples were retained in neutral buffered 10% formalin: brain (representative regions including cerebrum, cerebellum, pons), small and large intestines (including Peyer's patches), lungs (perfused with neutral buffered 10% formalin), lymph nodes (submandibular and mediastinal), peripheral nerve (sciatic), stomach, kidneys, spleen, thymus, trachea, urinary bladder, testes (fixed in Bouin's solution for 48 to 96 hours before being retained in neutral bpruofsftearteed, s1p0in%alfocromradli(nc)e,rveipciadl,idtyhmoirdaecsic, asnedmilnuamlbavre)si,cllievser(,waidtrhecnoaalsg,ulhaetairtn,g gland), thyroid/parathyroid, uterus, bone marrow, ovaries, uterus, vagina, mammary gland (female rats only) and gross lesions. Histological examination of retained tissues, including reproductive organs, was conducted for the assigned ten rats per sex from the. control and high dosage groups. Histological evaluations were performed on the livers of ten male and ten female rats, the thymuses of ten female rats and the stomachs of ten male rats in the 10 and 50 mg/kg/day dosage groups. Tissues to be examined a Sec APPENDIX E, item 4. 418-027:PAGE 2-15 histologically were shipped to Research Pathology Services, Inc. New Britain, Pennsylvania for evaluation. Results of the histological evaluation are available in APPENDIX J. At scheduled sacrifice, the five male and five female rats per group assigned to hematology and clinical chemistry sample collection were exsanguinated from the inferior vena cava following sacrifice. Rats were fasted overnight before sacrifice. Approximately 5 mL of blood was collected. The tubes containing the samples were labeled with the protocol number, Sponsor study number, animal number, group number, dosage level, day of study, collection interval, date of collection, species, generation and storage conditions. Approximately 1 mL of blood was collected into EDTA-coated tubes and maintained on wet ice or refrigerated until shipment for analysis of the following hematologic parameters: erythrocyte count (RBC), hematocrit (HCT), hemoglobin (HGB), mean cmoerapnusccourlpaurshcuelmaorglvoobliunme(M(CMHC)V,),metoatnalcloerupkuosccyutlearcohuenmtog(lWoBbCi)n,cdoinfcfeenrterntaitailonle(uMkoCcHytCe):, count, platelet count (PLAT), mean platelet volume (MPV) and cell morphology. Two blood smear slides were prepared at the Testing Facility for each sample for measurements of differential leukocyte count. Approximately 1.8 mLof blood was addedto a tube containing 0.2 mL of sodium citrate (0.129 M). `The contents were mixed and maintained on wet ice until the tubes were centrifuged (within 30 minutes of the collection time). The resulting plasma was transferred to a transport tube and immediately frozen. Plasma samples were maintained on dry ice or in a freezer (< 70C) until shipped for measurement of prothrombin time. (PT) and activated partial thromboplastin time (APTT). Approximately 2 mL of blood was collected into serum separator tubes and centrifuged. `The resulting sera samples were immediately frozen on dry ice and maintained frozen (570C) until shipment for analysisof the following parameters: total protein (TP), triglycerides (TRI), albumin (A), globulin (G), albumin/globulin Ratio (A/G), glucose (GLU), cholesterol (CHOL), total bilirubin (TBILI), ureanitrogen (BUN), creatinine (CREAT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALK), calcium (CA), phosphorus (PHOS), sodium (NA), potassium (K) and chloride (CL) `Samples for hematology and clinical chemistry analyses were shipped to Redfield Laboratories, A DivisionofCRL-DDS, Redfield, Arkansas. Results of these analyses are available in APPENDIX K. Blood samples (approximately 3 mL) were collected from the five rats per sex per group assigned to metabolite analysis. Blood was collected from the vena cava. Each sample was divided into two aliquots. One aliquot of2 mL was transferred into an EDTA-coated (purple top) tube and refrigerated. The second aliquot (approximately 1 mL) was a See APPENDIX E, item 5, 418-027:PAGE 2-16 strearnusmfewrraesd tirnatnosafesrererduminttuobpe.olaylplroowpeydletnoecltoutbeasndlasbpeulnedinwiatchentthreifpurgoet.ocoTlhneurmebseurl,ting cSoplolnesctoironstiundtyernvaulm,bdeart,eaonficmoalllencutimobne,rs,pegcrioeusp, ngeunmebreart,iodnoasnadgestleovrealg,edcaoyndoiftisotnusd.y,All samples were immediately shipment for analysis. frozen on dry ice and maintained frozen (<-70C) until Tinhea cloinviercawlaswbeexcainsdedfalansdhtfhreozoerngainn awneiigchet/arleccoohrodlebda.th.OnLeivleorbes(armipglhetslawteerrael)mwaainstpalianceedd. frozen (<-70C) until shipment for analysis. Liver and serum packs. Samples samples were to be analyzed shipped on dry ice and whole blood were shipped to Southern Research will be shipped Institute, on ice: Birmingham, Alabama, APPENDIX K. for analysis. Results of these analyses are available in Female rats that did not delivear liter were sacrificed on DG 25. Gross necropsy, examination and tissu retention were conducted as described above for rats at scheduled sacrifice. Dams with no surviving pups were sacrificed after the last pup was found dead, missing or presumed cannibalized. Gross necropsy, examination and tissue retention was conducted as described above for rats at scheduled sacrifice. Gross lesions were preserved in neutral buffered 10% formalin for possible future evaluation. Representative photographs of gross lesions are available in the raw data. 27.62. FI Generation Pups On DL5, pups were sacrificed by carbon dioxide asphyxiation and examined for gross lesions. Necropsy included a single cross-section of the head at the level of the frontalparietal suture and examination of the cross-sectioned brain for apparent hydrocephaly. Gross lesions were preserved in neutral buffered 10% formalin for possible future evaluation. Representative photographs ofgross lesions are available in the raw data. Pups that died before initial examination of the liter for pup viability were evaluated for vital status at birth. The lungs were removed and immersed in water. Pups with lungs that sank were identified as stillborn; pups with lungs that floated were identified as liveborn, and to have died shortly after birth. Pups found dead on DLs 2 to 4 were: `examined for gross lesions and for the causeofdeath. 418-027:PAGE 2-17 27.7. Data Collection and Statistical Analyses Data generated during the course of this study were recorded either by hand or using the Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Hunidity Monitoring System, the Coulbourn Instruments Passive Infrared Motor Activity System, the Coulbourn Instruments Auditory Startle System, the Coulbourn Instruments Spatial Delayed Alternation System, and/or the passive avoidance software. All data were tabulated, summarized and/or statistically analyzed using the Argus Automated Data Collection andManagement System, the Vivarium Temperature and Relative Humidity Monitoring System. Microsoft Excel [part of Microsoft Office 97 (version SR-2)) and/or The SAS System (version 6.12). 418-027:PAGE 2-18 Averages and percentages were calculated. Litter values were used where appropriate. The following schematic represents the statistical analysesof the data: I. Parametric TyofpTeset" I. Nonparametric spn | pn | Sern | woman ---- wopo-- | AE 5: sop oss apse A --A. co-- h -- a Sumanrisos | wpa IIS. aTPessrktrfiooearpnEousrpartiainDDoaatsna. a Statistically significant probabilities are reported as either p<0.05 or p<0.001. b. Proportion data are not included in this category. Cc. Test for homogeneity of variance. 418-027:PAGE 2-19 Adult data was evaluated with the individual rat as the unit measured. Litter values were used in evaluation of pup data, as appropriate. Variables with interval or ratio scales of measurement, such as body weights, feed consumption values, latency and errors per trial scores in behavioral tests and percent mortality per ltr were analyzed as described under the Parametric heading of the schematic. Bartlett's Test of Homogeneity of Variances' was used to estimate the probability that the dosage groups have different variances. A non-significant result (p>0.001) indicated that an assumptionof homogeneity of variance was not iwnaasppsriogpnriifaitcea,ntan(pd<0t.he05d)a,tathwagsrocuopmspgairveednutshiengtetsthesuAbnaslaynscies woefrVeacroimapnacree"d, wIiftthhatthetest cAonnatlryoslisgroofuVpaursiianngceDuTnensettwt'assTneostt"a.pproIpfriBaatrtel,eattn'ds Ttehsetdawtaaswsaisgnainfiaclaynzte(dpa<s0.d0e0s1c)r,ibtehde under the Nonparametric heading of the schematic. When 75% or fewer of the scores in all the groups were tied, the Kruskal-Wallis Test was used to analyze the data, and in gtiheveenvetnhte otefast ssuigbnsitfainccaentwrietshultthe(pc<o0n.t0r5o)l,gDruonupn.'sWTheesntm"owraestuhsaend7t5o%coomfptahreesctohreegsroinups. any ties dosage group in the groups. were tied, Fisher's Exact Test" was used to compare the proportion of Data from the motor activity test, with measurements recorded at intervals (Blocks) throughout cach test session, were analyzed using an Analysis of Variance with Repeated M(pe=a0s.u05r)esin",thaats dteesstccroiubledd uhnadveeratphpaetahreeaddaisnegffiencttheofscDhoesmaagtiec(.diAffseirgennicfeiscaanmtornegsuldtosage: `groups in the totals of all measurements in a session)oras an interaction between Dosage: and Block (differences in the pattemsof dosage group values across the measurement periods). If the Dosage effect was significant, the totals for the control group and the groups given the test substance were compared using Dunnett's Test". Ifthe Dosage x dBaltoackaticnatcerhacmteiaosnuwraesmesnigtnipfeirciaondt,, aanndAnaasliygsniifsicoafntVarresiualtnc(pe<"0.w0a5s) uwsaesd ftoolelvoawleudatbeytahe comparison of the dosage groups using Dunnett's test". Variables that had graded or count scores, such as litter size, the number of trials to a criterion in abehavioral test or the day a developmental landmark appeared, were analyzed using the procedures described under the Nonparametric headingofthe. schematic. Clinical observation incidence data were analyzed using the Variance Test for `Homogeneity of the Binomial Distribution. 418-027:PAGE 3-1 3 RESULTS - MALE RATS 31 Mortality, Clinical and Necropsy Observations (Summaries - Tables B1 and B2; Individual Data - Tables B15 and B16) 311 Mortality All male rats survived to scheduled sacrifice. 312. Clinical Observations Significant increases (p<0.01) in the incidencesofexcess salivation, perioral substance and urine-stained abdominal fur occurred in the 250 mg/kg/day dosage group. `1A)lthoethienrccildiennicceals owbesreervnaottidoonssawgeer-edecpoennsdiednetr;edanudn/roerla2t)edthteootbhseertevsattisounbsotcacnucrerbeedcianusoen:ly one or two male rats in any dosage group. These observations included chromorhinorrea, Soft or liquid feces, missing/broken incisors, chromodacryorrhea, scabs on right forelimb, red substance on the penis and ulceration on right forelimb. 313. Necropsy Observations All necropsy observations were considered unrelatedtothe test substance because: 1) the incidences were not dosage-dependent; and/or 2) the observation occurred in only one `male rat (17636) in the 250 mg/kg/day dosage group. These observations included a tan, firm, lobular mass (2.8 cm x 0.9 cm x 0.7 cm) on the right hemisphere of the prostate and ared ventral sideof the same prostate gland. A cut surfaceof the mass revealed a tan smooth surface. Histomorphologic diagnosis was suppurative prostatitis 3.14. Histopathology Treatment-related microscopic changes were observed in the liver of male rats in the 50 and 250 mg/kg/day dosage groups and in the stomach of male rats in the 250 mg/kg/day dosage group. "The treatment-elated microscopic changes in the liver consisted of minimal or mild enlargement (hypertrophy)ofcentrilobular hepatocytes in most of the male rats in the 250 mg/kg/day dosage group and 4 out of 10 in the 50 mg/kg/day dosage group. The enlargement was due 10 an increased amount of finely granular, dense eosinophilic cytoplasm. Also, in three of the affected rats in the 250 mg/kg/day dosage group, necrosis of individual enlarged hepatocytes was seen in the centrilobular areas. Microscopic examination of the stomach revealed focal erosions in the pyloric glandular `mucosa of two rats in the 250 mg/kg/day dosage group. No treatment-related microscopic changes were observed in any of the male rats given 10 mg/kg/day of the test substance. 418-027:PAGE 3-2 32. `TWeerimgihntatloBToedrymiWneailghBtosdyanWdeiOgrhgtananWdeiBgrahitns WaenidgRhatti(oSsum(m%a)roifeOsr-gan Tables B3 through BS; Individual Data - Tables B17 and B18) `2T5e0rmmign/aklgb/oddayy wdeoisgahgtesgorfouthpe, masalceomraptasrweedrweistihgnciofnitcraonltlgyrroeudpuvcaeldue(sp.<0.01) in the Absolute weights of the left and right kidneys were significantly increased (p<0.05 or S001) in the 50 and 250 mg/kg/day dosage groups and the absolute weightofthe liver wwiatshstihgenicfoinctarnotllygrioncurpevaasleude(.p<T0h.e01r)atiinosthoef2t5he0 wmegi/gkhgt/sdoafytdhoessaegoerggarnosupt,o atsercmoimnpalarbeoddy dwoesiaghgtesgwroeurpes.sigRneilfaitciavnteltyoitnhcerebarsaeidn (wpe<i0gh.t0,5 oonrlpy<0t.h0e1)liveirn wtheeig5h0tainndth2e5025m0g/mkgg//kdga/yday dosage group was significantly increased (p<0.01). 33. Hematology and Clinical Chemistry (Summaries- Tables B6 through B7) Dcloisnaicgaelsochfetmhisettreystvasluubesstaenvcaeluaastehdi.ghAavse2r5a0gemgva/lkuge/sdafoyrdrieddnboltooafdfeccetllasn(yRBhCe)ma,twohliotgey or blood cells (WBC), hemoglobin concentration (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular thhermoomgbloopblianstcionncteinmter(atPiTonan(dMACPHTCT)),,pmlaetaelnetpsl.atveolleutmveo,lpurmoeth(rMoPmVb)i,n nauncdleaactteidvarteedd bpalrotoidal cell count (NRBC), lymphocytes, segmented neutrophils, bands, monocytes, eosinophils, `basophils and dosage groups aabnndordmidalnoltymdipfhfoecrystiegnsifiincamnatllye. rats were comparable among the four tAovtealrabigleirvuabliunes(TfBoIrLIto)t,albplroootdeiunre(aTPn)i.traolgbeunm(inBU(NA)),, gcrleuactoisnein(eGL(UC)R,EAchTo)l,esatlearnoilne(:CHOL), aminotransferase (ALT), aspartate aminotransferase (AST). alkaline phosphatase (ALK), calcium (CA), phosphorus (PHOS), triglycerides (TRIG), sodium (NA), potassium (K). chloride (CL), globulin (G) and albumin/globulin ratio (A/G) in male rats were `comparable among the four dosage groups and did not differ significantly. 34. Body Weights and Body Weight Changes (Figure 1; Summaries - Tables BS and BY; Individual Data - Table B19) Body weight gains were significantly reduced (p<0.01) in the 250 mg/kg/day dosage group on study days (DSs) 1108, 110 15 and 1 to 36. Body weight gains were also significantly decreased (p<0.05) in the 50 mg/kg/day dosage group on DSs 1 to 36. Body weights were significantly reduced (p<0.01) on DS 29 and 36 in the 250 mg/kg/day dosage group. Body weights and body weight gainsofthe male rats were unaffected by dosages of the test substance as high as 10 mg/kg/day. 418-027PAGE 3:3 35. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values (Summaries - Tables B10 and B11; Individual Data - Table B20) Absolute (g/day) feed consumption values were significantly reduced (p<0.05 orp<0.01) in the 50 and 250 mg/kg/day dosage groups on DS I to 8 and significantly reduced (pS0.01) in the 250 mg/kg/day dosage groups on DSs 110 15 and 1 to 36. Absolute feed consumption values during the recovery period were comparable between the 0 (Vehicle) and 10 mg/kg/day dosage groups. Relative (g/kg/day) feed consumption values were significantly reduced (p<0.05 or P<0.01) on DSs 1108 in the 50 and 250 mg/kg/day dosage groups. Relative feed consumption values of the male rats were unaffected by dosages of the test substance as high as 10 mg/kg/day. 36. Mating and Fertility (Summary - Table B12; Individual Data - Table B21) All mating and fertility parameters (numbers of days in cohabitation, rats that mated, fertility index, ras with confirmed mating dates during the first and second week of cohabitation, rats pregnant per rats in cohabitation and the number ofpregnant rats per number of rats in cohabitation) were unaffected by dosagesofthe test substance as high as 250 mg/kg/day. 37. Functional Observational Battery (Summary - Table B13; Individual Data - Table B22) `There were no statistically significant or biologically important differences among the four dosage groups in the measures of the functional observational battery (FOB). There pwaelrpeebnroalalctleorsautrieo,nsprinomhionmeencceagoef tbheehaevyieo,r,puapuiltloanroymriecacftuinocntitoonlsig(hlta,cpriilmoaetrieocnt,isoanl,ivation, respiration, defecation and urination), sensorimotor functions [responses to visual, auditory, tactile and painful stimuli (reactivity and sensitivity)], excitability (reactions to handling and behavior in the open field), gait and sensorimotor coordination (gait pattern in the open field, severity of gait abnormalities, air righting reaction and landing foot splay) and forelimb and hindlimb grip strength and abnormal clinical observations including but not limited to: convulsions, tremors, unusual behavior, hypotonia or hypertonia, emaciation, dehydration, unkempt appearance and deposits around the eyes, nose or mouth. Body weights recorded during the functional operational battery for the treated groups were not significantly different than the control group for the male ras. 38. Motor Activity (Figure 3 and 4; Summary - Table B14; Individual Data - Table B23) There were no statistically significant or biologically important differences among the four dosage groups in the measures of motor activity on DS 8. 413-027:PAGE 4-1 4 RESULTS - Female Rats 41 Mortality, Clinical and Necropsy Observations (Summaries - Tables C1 and C2; Individual Data - Tables C27 and C28) 411. Mortality All female rats survived to scheduled sacrifice. 412. Clinical Observations All clinical observations were considered unrelated to the test substance because: 1) the incidences were not dosage-dependent; and/or 2) the observation occurred in only one or two female rats in any dosage group. These observations included perioral substance, excess salivation, bent ail, chromodacryorrhea, comeal opacity of ight eye, localized alopecia on the limbs, underside or head, urine-stained abdominal fur, red perivaginal substance, soft or liquid feces, missing/broken incisors and dehydration. 413. Necropsy Observations Al necropsy observations were considered unrelated to the test substance because: 1) the incidences were not dosage-dependent; and/or 2) the observation occurred in only one female rat in the 50 mg/kg/day dosage group and one female rat in the 250 mg/kg/day dosage group. These observations included an absent right kidney in one 50 mg/kg/day dosage group female rat (17706) and a small thymus in one 250 mg/kg/day dosage group female rat (17696). The small thymus was not available for histomorphologic diagnosis. 414. Histopathology Treatmentrelated microscopic changes were observed in the liver and thymus of female rats in the 250 mg/kg/day dosage group. `The treatment-related microscopic changes in the liver consisted of minimal or mild enlargement (hypertrophy) of centrilobular hepatocytes in most of the female rats in the 250 mg/kg/day dosage group. The enlargement was due to an increased amount of finely granular, dense eosinophilic cytoplasm. Microscopic examination of the thymus revealed an increased incidence and severity of atrophy of the thymic lobules in female rats in the 250 mg/kg/day dosage group. No treatment-related microscopic changes were observed in any of the female rats given 10mg/kg/dayof the test substance. 413-027:PAGE 42 42. Terminal Body Weights and Organ Weights and Ratios (%) of Organ Weightto Terminal Body Weight and Brain Weight (Summaries- Tables C3 through CS; Individual Data - Tables C29 and C30) `inTetrhmein2a5l0bmogd/ykgwe/idgahytsdoofstagheegfreomuapl,easractsomwperaererdedwuictehdco(n4t.r8o%l)g,raolubpeivtalnuoetss.ignificantly, Absolute weights of the liver was significantly increased (p<0.01) in the 250 mg/kg/day dosage group, as compared with the control group value. The ratios of the weight of this organ and the weight of the right kidney 10 terminal body weights were significantly increased (p<0.01) in the 250 mg/kg/day dosage group. Only the ratio of the liver weight 10 brain weight in the 250 mg/kg/day dosage group was significantly increased (p<0.01) was considered treatment-related; the significantly increased (p<0.05) ratioof the liver weight to brain weight in the 10 mg/kg/day dosage group was not considered treatmentrelated because it was not dosage dependent. 43. Hematology and Clinical Chemistry (Summaries - Tables C6 and C7) Dosages as high as 250 mg/kg/day did not affect any hematology or clinical chemistry values evaluated. Average values for red blood cells (RBC), white blood cells (WBC), hemoglobin concentration (HGB), hematocrit (HCT),meancorpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelets, prothrombin and activated partial thromboplastin time (PT and APTT), mean Iymphocytes, spelagtmeelenttevdolnuemutero(pMhPilVs),,bannudclse,amtoendorceydtebsl,ooedoscielnlopchoiulnst, (baNsRoBphCi)l,s, abnormal lymphocytes in female rats were comparable among the four dosage groups and did not differ significantly. tAovtealrabgileirvuabliune(sTfBoIrLIto)t,albplroootdeiunre(aTPn)i,traolgbeunm(iBnU(NA)),, gclreuactoisnein(eGL(UC)R,EAcTho)l,esatlearnoilne(CHOL), aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALK), calcium (CA), phosphorus (PHOS), triglycerides (TRIG), sodium (NAY), potassium (K), chloride (CL), globulin (G) and albumin/globulin ratio (A/G) in female rats were: comparable among the four dosage groups and did not differ significantly. 44. Body Weights and Body Weight Changes (Figure 1; Summaries - Tables C8 through C13; Individual Data - Tables C31 through C33) 441. Precohabitation Body weight gains were significantly reduced (p<0.05) during the precohabitation period inthe 250 mg/kg/day dosage group on DSs 1 10.8 and 1to 15. Body weights were not significantly affected by dosages of the test substance on any weight day during precohabitation. 418-027:PAGE 4-3 442. Gestation Body weights and body weight gains were not significantly affected by dosages of the test substance during gestation. Body weights gains were significantly reduced (<0.05 orp<0.01) during gestation on dDaGySssof1g2.e1s0ta1t5ioinn(tDheGs1)00m1g0/k3g/adnady1d2o1s0ag1e5 ginrotuhpe.50Thmegs/ekgsi/gdnaiyfidcaonstagreedgurctoiuopnsanidn obnody weight gain were not considered treatmentrelated because they were not dosagedependent. 443. Lactation Body weight gains were not significantly affected by dosages of the test substance during lactation. Body weights were significantly reduced (p<0.05) during lactation on day of lactation (DL) 1 in the 250 mg/kg/day dosage group but was not considered treatmenrelated because it did not persist. 45. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values (Summaries - Tables C14 through C19; Individual Data - Tables C34 through C36) 451. Precohabitation Absolute (g/day) and relative (g/kg/day) feed consumption values were not significantly affected by dosages of the test substance during the precohabitation period. 452. Gestation Absolute (g/day) feed consumption values were not significantly affected by dosages of the test substance during the gestation period. Relative (g/kg/day) feed consumption values were significantly increased (p<0.01) during gestation on DG 15 to 18 in the 250 mg/kg/day dosage group but was not considered treatment-related because it did not persist. 453. Lactation Absolute and relative feed consumption values were not significantly affected by dosages of the test substance during lactation. 46. Estrous Cycling, Mating and Fertility (Summary - Table C20; Individual Data - Table C37) `The average numbers of estrous stages per 14 days were comparable among the four dosage groups and did not significantly differ. The number of rats with six or more consecutive daysofdiestrus or estrus did not differ significantly. 413-027:PAGE 44 All mating and fertility parameters (numbers of days in cohabitation, ras that mated, Fertility Index, rats with confirmed mating dates during the frst and second week of cohabitation, rats pregnant per rats in cohabitation and the number of pregnant rats per number of rats in cohabitation) were unaffected by dosages of the test substance as high as 250 mg/kg/day. 47. Functional Observational Battery (Summary - Table C21; Individual Data - Table C38) There were no statistically significant or biologically important differences among the four dosage groups in the measuresofthe functional observational battery (FOB). There were no alterations in home cage behavior, autonomic functions (lacrimation, salivation, palpebral closure, prominence of the eye, pupillary reaction to light, piloerection, raeusdpiitroartyi,ont,acdteilfeecaantdiopnaiannfdulursitniamtuiloin)(,resaecntisvoirtiymaontdorsefnusnicttiivointsy)[,reexscpiotnasbeislittoy v(irseuaaclt,ions to handling and behavior in the open field). gait and sensorimotor coordination (gait patter in the open field, severity of gait abnormalities, air righting reaction and landing foot splay) and forelimb and hindlimb grip strength and abnormal clinical observations including but not limited to: convulsions, tremors, unusual behavior, hypotonia or hypertonia, emaciation, dehydration, unkempt appearance and deposits around the eyes, nose or mouth. Body weights recorded during the functional operational battery for the treated groups were not significantly different than the control group for the female ras. 48. Motor Activity (Figures S and 6; Summary - Table C22; Individual Data - Table C39) There were no statistically significant or biologically important differences among the fourdosage groups in the measures of motor activity on DS 6. 49. Natural Delivery and Litter Observations (Summary - Tables C23 and C24; Individual Data - Tables C40 through C43) dPorseaggneangcryouopcsc,ur1r4ed(9i3n.a3l%l)1o5f(t1h0e0r%a)tsraastssiagsnseidgnteodthtoe t1h0em0g/(Vkegh/idcalye)doasnadg5e0gmrgo/ukpga/ndday 13 (86.7%) of the rats assigned to the 250 mg/kg/day dosage group. All pregnant dams delivered a litter of one or more liveborn pups. The number of liveborn pups was significantly reduced (p<0.01) in the 250 mg/kg/day dosage group. The number of stillborn pups was significantly increased (7<0.01) in the 250 mg/kg/day dosage group. `The number of pups found dead or presumed cannibalized on day 1 and days 2 to 5 postpartum was significantly increased (p<0.01) in the 250 mg/kg/day dosage groups. `The viability index (81.5%) was significantly reduced (p<0.01) in the 250 mg/kg/day dosage group, compared to the control group value (99.19). The number of pups surviving per litter on postpartum day 5 was significantly reduced (p<0.05) in the 250 mg/kg/day dosage group. Pup body weights per litter were also reduced, albeit not significantly, in the 250 mg/kg/day dosage group on postpartum days 1 and 5. These 418-027:PAGE 4-5 findings at 250 mg/kg/day were considered related to the test substance because they were dosage dependent Values for the numbersofdams delivering litters, the duration of gestation, averages for implantation sites per delivered litter, the gestation index (numberofdams with one or `mdoarmes lwiivtehboalrlnppuuppssd/yniunmgb,esrtiolflbporrengpnuapnst,rastusr)v,itvhiengnupmubpesrpserolfitdtaermosnwiptohstsptialrltbuomrndpauyps1, and pup sex ratios were comparable among the four dosage groups and did not significantly differ. 410. Pup Clinical and Necropsy Observations (Summary - Tables C25 and C26; Individual Data - Tables C44 and C4s) No clinical or necropsy observations in the F1 generation pups were attributable to dosages of the test substance as high as 250 mg/kg/day because: 1) the incidences were not dosage-dependent; and 2) the observation occurred in only one to three litters. These clinical observations included: not nursing, not nesting, pale and bruise on head, back, `mouth, lower midline, chest and/or neck. Necropsy observations on postpartum day 5 was limited to slight dilation of the renal pelvis of one pup from a 10 mg/kg/day dosage group litter. 418-02TPAGE 4-6 REFERENCES 1. Organisation for Economic Co-operation and Development (1996). OECD Guidelinefor Testingof Chemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996. 2. Organisation for Economic Co-operation and Development (1998). The Revised `OECD Principles of Good Laboratory Practices [C(97)186/Final]. 3. US. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. 4. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice S1t99a7n.dardfor Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 5. Christian, M.S. and Voytck, PE. (1982). In Vivo Reproductive and Mutagenicity Tests. Environmental Protection Agency, Washington, D.C. National Technical Information Service, U.S. Department of Commerce, Springfield, VA 22161. 6. Chistian, M.S. (1984). Reproductive toxicity and teratology evaluations of naltrexone (Proceedings of Naltrexone Symposium, New York Academy of Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10. 7. Lang, P.L.(1988). Embryo and Fetal Developmental Toxicity (Teratology) Control Data in the Charles River Crl:CDBR Rat. Charles River Laboratories, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.) 8. Institute of Laboratory Animal Resources (1996). Guidefor the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C. 9. Haggerty, G.C. (1989). Development of Tier I neurobehavioral testing capabilities for incorporation into pivotal rodent safety assessment studies. J. Amer. Col. Toxicol. 8:53-70. 10. Trwin, S. (1968). Comprehensive observational assessment: Ia. A systemic quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia (Berlin) 13:222-257. 11. Moser, V.C. (1989). Screening approaches to neurotoxicity: A functional observational battery. J. Amer, Col. Toxicol. 8:85-94. 12. O'Donoghue, JL. (1989). Screening for neurotoxicity using a neurologically based examination and neuropathology. J. Amer. Col. Toxicol. 8:97-116. 418-027:PAGE 47 13. SBoikoamle,trRyR,.WaHn.d RForhelefm,aFnJ.an(d19C6o9.),.SaBnarFtrlaentctistcesot,opfp.ho3m70o-g3e7n1e.ity of variances. 14. Snedecor, GW. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition, lowa State University Press, Ames, pp. 258-275. 1s. tDruenantemtetn,tsC.wWi.th(a19c5o5n)tr.olA. mJ.ulAtmipelre.cSotmatp.arAisssoocn.pr50o:c1e0d9u6r-e11f2or1.comparing several 16. Sokal, RR. and Rohlf, F.J. (1969). Kruskal-Wallis Test. Biometry, 'W.H. Freeman and Co., San Francisco, pp. 388-389. 17. Dunn, 0.J. (1964). Multiple comparisons using rank sums. Technometrics 63241252. 18. Siegel, Exact. S. (1956). Nonparametric Statisticsfor the McGraw-Hill Co., New York, pp. 96-105. Behavioral Sciences. Fisher's 19. SAS Institute, Inc. (1988). Repeated measures analysis of variance. SAS/STATTM User's Guide, Release 6.03 Edition, Cary, NC, pp. 602-609. 20. Sbniendoemcioarl,diGs.trWi.buatniodn.CSotatcisthicWa.rlGM.eat(h1no96d7s,),.6tVhaErdiiatnicoen,teTsotfwoarShtaotmeoUgneinveeirtsyiotyf the Press, Ames, pp. 240-241. APPENDIX A REPORT FIGURES or --- :-] re arr om CET BODY WEIGFHoTuSer- MALE RATS ee . eT "|=Ima || GF - || somoncnr " Fa " | Z7 wl & eas [E ELr Ca wl BT E d----n -- 35 z5 a ---------- wy 85 F}an | ! my ~ BODY WEIGHTFiSgu-r2FeEMALE RATS --e = ---- -- ipmram "7 fo | /x || sommesmmarcon | po I Hn Xow acae" . | svanesonr | aSlTE ||e oo A| ra= | em EoaEvEorstuoEEREEEREoEarEoTr oEesTTaETONE ET EAR EEEER) oavor ueTATON z z A 7RA MOTOR ACTIVITY - NFUoMrBeEsR OF MOVEMENTS - MALE RATS - A- | msn " at \ ON g, 1| \\& AR i &i PARYAN a ani || - | nanan :1 - wl,as oA Lo NT em g . AR : - y "a | wo - - 7 x a TT a ve i TIME (MINUTES) 2 xz a RT TTRPHHARPS MOTOR ACTIVITY - Fue TIME SPENT IN MOVEMENT- MALE RATS fs ia v"i i waHe Jn | g at E. \ =- mail aorw a 3: : " w-e uures" - - - 55 I OT MOTOR ACTIVITY - NFUigMuBrEesR OF MOVEMENTS - FEMALE RATS mms . | . g = a .- ToMaxGDAY J 2g, A { \m nt : {n Vm X | 1 = dAf) ma ul I oo k k comarenTM - A i g orca torSx ae concn at Jo TH RRO TONSA TOT MOTOR ACTIVITY - TIME SPENT IN MOVEMENT- FEMALE RATS Figur6e g= 2a $ zw = 5 = A om 2Bo | 2. a Aa<a. g8 oe -wJa - Na - io Ly mn omnes To-uonaoRr sounaon | : "ne mares)" - - i z APPENDIX B REPORT TABLES - Fo GENERATION MALE RATS [Er ---- oe we we won ma.easerosso.sn oe we vo woe sso ronson, senna) oe oe oe wo sor ronson, cman oe oe we va TELL lfefremtromtvhenicin Chsaecvheoe s he0.01 3 Z8 2 : i or "Tbe Nh ht Eh -- eFieg HoiSd BWhle iSlhe J I i Tid Tada Tibia" "Pion = z EESE e EreteEThiEc akaSS eothee SacIomed Tone attested z:2 we mpi mii wii meio on mihiiwe LombidiLe Lsehnesne Tmheie i LiTihheee C oabbi i.l Co BhEatL J(CToheraidrlom E FI TEE E REEEDreiutof ve iasrtmia 53g } EEE WEE ENE ES 2 Eien Stfaren hen the seni cone pees ie oh z : r rt ant --vn-- mwoawwa maivevnn maawwn sweiamn rSemarrmrsn mmann arvewen vmaetemm amneeemn awann 5 = prvluihaptonint -z oenrocepa tenr t---- - sense o--o-- rreeemeen 2 Tan mm elena een ane g zg  - tro-- p re trie jon. . an 8 E BEE eee BETTE g E 5 z 8 i EEEEr a BEREAN MA%2D Hay ter g : EEE re g i 2 Popes, . . , 1 g i nm :: : : : 1 (2) + Score assigned to Graded test items; mean score was Caicuiated by weLCIFiyiny each score by the ember of rate with that score Ss EeSEeB EI : : i ie SI I TT e: ens :ary on so:me : ewe ot oe tue orn 2: ieeEB ee wlll BO E-I 3bESPrui.ear a:: a i3 :3 : i3 g:3 5 TE ry Le eepsrne cad iyo enh ss by ma of a ih ht srs 8: fe CTE = z el [I : : : 8 en 3 : : : : EA SCORE . a8.nos a r28.t re oe 428e.s E2 i : i = wn &Smeemnmttn cmacs %:te :: -:: -:: 5:: z2z A Sr irs re on ct Ct sere cece yd ee te ett of 1 in errr g g ---- ee Z z 3 3 : 2 3 5 zz m EB Em g E memes Zz ek Te ona Fo WoahSpy OF 77 WTRmemes sem, ies 5 z z Z 3 2i  3z  t rh A S + f ne err PEERS Sm Em & J a aAB Ca To oma Np TERSNABOLY WREHT) X300. : 2 Z : g Zz 2 8 z2 z : z : : i:  g i : : : : Porat 30637, Ab (A) Ca SRSTATED 06 TRICET EEE GT 749.7 ITH RETTIG VEO, TOIT me 1 aT TLremewinoheaAtttactnS8 ivis sobiosed13mgeen Siatape oksvtiotiont amtien 1 5 5ig  t  2zE : : : z 2 : gt : g a g 2 z : :g 8 2 3s  2 : i  5 g : 5 z g riers z g zg : 5 g 32g : g gg 8 g zi ZZ 25 & BT Fate aon Tt wow omom am z ELeinrocaresaTeyst142 sHE om oe mAs am z2 Ee Til tacosnr sabes Sri cues hai foo iy tosis, Farina our rin 2 wowonow ow z framed now oan oan on 8 pil Bots i be Famiva cir ue 13 noma we 5 hoi orran Wom own 8 ---- EEE : Poymr Linz : _----Tmw ee we 5g  g z2 ee ew ee ee oe I : z : 38 i Eb HH 5 z8 & g zz 2  zg: & APPENDIX C REPORT TABLES - Fo GENERATION FEMALE RATS pmoe -- co -- ave MuYl o_e noee 3 g EEE on o vein 3 5 2 J con e--sa es o. wn wr we or i vz ii ve ai nS te en 8 g 8 nJ n we - we a EB. i gi i ii 3 2 2 z J po mneadpan RpDe gDeenl Iepe obi. oi IMD DWT I Jo H dI L R -- TH Ee ERY 3 2 g cn mitm ewgie omiioc ougie fm Tes e emg tape reanma g l owe 88 bESo g EERE a a en BrSBE BE : 2z mt hs gpsom sya a .W ------ mn ro wa gyn ene J ies a v4 3058 J J seri ees man, on rt SEE So EE rpeonbolga ie cen ene rirern rn g 2 =z ------ -- p Jump -- orts) seemeenr . g2  g 2 %g g 3 z: Fsr m, o" fEei : so 2 z 82 RE Jp. i i i g e a an awn mama mien rien & a prow g g 2 freee g e 2 DIETITID, rs resrsgusrs ior ant Trans se Bentsen arses senses ens ses 3 ass wees 3 ase wanes pase areas . passe es ws SE as os SE ---- sas es aaa aos ss aa ee was as nos se ss 9 a whe ale wii niente sah 3 z 22 wn an wm mm mei We z8 2&  2 e 8 8 gg hg tm wi es : 2 2 3 g Z & BTher g g 2 me wes ass sas on ats ve rasoe z 22g  z 23 a ; en mene . . . (R=. Po : : i Z EEEIIII ITI ii a z 3 tome : i : Ply ali : : : : 3 ig A en z i i D3 REte heErEeTeErDe: grgerel:eereeeee:tbeeeere:eeerrese:rmenmermmee | 8 RRELL CS haat Mang wo er vf fon oar 0 tr ev wt 2| ts omen J i i FA = : : : Co 10amet . s . in.scien oy eSriten v. :: :` aEEy pre: m : . s g :: :: 28 : r : ns 2 sect marian, omg H i a [I : : : : me nies i Wh de : wsSo aL, ren cibyeis i ah sor by the hr of rc veh rs ser semen oom i x. se :: g --- 3 z 22 E 5 2 aie Ta i Gi id een iosei een ii 1sdn0 4 BIauer af fataa vith hiveEofSinEprinRa/mTmbecSof pEregeRant ace pon ie 13au) g 2 : g22 ST Thar ie aay es wien eg oe g g 2 me mn TY Waa or atimeaves g mmpnoo nnwo oonn uu= nuo uu. Zi i : i: EL = g 8 z82 & Be BREE : 7 "ammervationcontiraesat secre rine : & et vanemsatoavarin iv wiv Z FERFTE cormois a oeg s senso sis wee g g g i 2 dEaimtese EAE SEBRE zz 2 g : i SB BR rar ra si ww z & g TL : HI ET iti us g3 &g 2 FERS 3:2 8 BT Ra oFa bB E E ETT ErMTTSEiey otcocto ies eh nr srs sd tio g i a P EET i aSLLIUeT I +o snes ites Tmmm---- eas smgr re sn stiri 0. EAR'TSESE nad a sma1t Shyma. Sen the dividual secre chesrvsticns table (Table C30). i g BBEAR SENR GE OM Um duROME WEF IEEEEE ae FT : z 2 2 2 EEMauh i RS m GmWo s G ouE Ae ER O3F mmm mm m---- 3E & 3 BRILLTILAL Jf ravi secre chaeraticas table (ale can) 2 8 BHI HOT ommoI imo oR oom NPuL NPSRTEL RNTWENPR+NEOTCPRIOEGRNGAUNDNTGE(V(AD6L)UE.S EXCLAUbeD.EDWPER.ON+GAhVOEARANGEW S) EIRGEL.H\TO. N + (onan NER MATH EI X 106- 8oe EE eats: ius eit om sey ass 1 ssicint s . SanThE% had 8 small thyma. See the dmdividunt necropey cheervacicns able (Table CH i Z Z g er ch gt,ca a eyro a sO 2 : :: Z 282 Fler Roulaial : bEEE es g z 22 83 z 3 : Ree z z 3 g gg  z 8 2 E 5 2 g BC CO FC SL. 2 g 5 Z2 : i: g: BEERSCTT : a & ERmI s 8 8 z ; g : :  :: = i ; i : s a : i i : 2 HL 5 ii i i ; Z ETE REE : EET 2 ff 4 Ts Shea hors bem 2 TRS hEGE ERSha. ASEEOn RE SHE Fo AT BR 2 EEE oh o& 4 of oS Z EEE fans 8 Fania ars ue 13 momma g precept mol on mun 2 "Sia nsidbainTdHaGlApRaTcEaR. FCiAeTSfNorWeOeRs1E1e5GI8RxL1Rt.En6S0T1OR1Oi.niSSSSocMlkssCrEes T(O6N0A6NxT3R6IcuRsdWiRg Bihinh 2.0cn2.0n 2 2 Zg Fosse :Z S 2 g z 22 g : : : 8 i f 3 g IIE fa I = iid 21 FE 11d 133i : z g mm nc ny con rs ss nc wn. mem Bi~1 11 Zz: iid 21 iid sept isco tees setters sesso un sd 11%: : Pha 3 2 hoe Sassen Bosse TB EERIE z LR h E CERB P LN. & opupaun g BORE ERR g Ni WhkarrsYaka FROOROED ICu(0s1 WEA LIVES VERO CLI Shey VRIobSOvRe YS 5 Z 28 g 3& 2  z22 2 5i : 2 5 :g g g: 3 : 2 : 2 z8  & 2 z 22 2OERRRp mea none Cn rm mmara 3 z RRR a AEE Cr z z  2 2 ERR EAR FRE EREERE z APPENDIX D| PROTOCOL AND AMENDMENTS Hao 905 SheehyDrei.A TTeelkefpohorne(:2(152)15#)4434835887710 418-027:PAGE D-1 : ; ~~ ARGUS RESEARCH y CharlesRiverLaboratories Discovery and Development Services PROTOCOL 418.027 SPONSOR'S STUDY NUMBER: 7-759 STUDY TITLE: PURPOSE: SFATCIILNITGY: stupy DIRECTOR: OthrealRe(pGraovadguec)tiCoonm/bDienveeldoRpempeenattaeTdoDvoisteyToSxcirceietnyinSgtuTdeyrofT 7599.7 with `The purposeofthis study is to provide information onthepossible health `hazards that may result from repeated exposureofCrl:CD(SD)IGS BR 'coVhAaFb/itPaltuison,mtahlreouagnhd mfaetmianlge arantds ctooamtmesitnsgubfsotranatceebaegi2n8niinggsbe(fmoaree TrSaectpsre)esoterondtihdnrogosusegshhtptuadraytunirnibctoiropnvoeurnaettiel1s0dparyreo4pvrioorddu5icntoiiftoanllacdfteoavtreimloanotp(imfeeonmnatloaeln rpwatosi).stTehis effects on male and female reproductive performance (e.g., gonadal function, mating behavior, conception, developmentofthe conceptus and psapretcuirfiitcioenn).dpoTihnet satnuddsyhaoluslodpdlaecneisteymhpheasnieswroonlnoewuiroplotoegnitciaalleofffecetstas a `substance, which may warrant further in-depth investigation. SBteucdayu,stehofstchreeesneilnegcteivsitwyiolfl tnhetepnrdopvoiidnetesvainddentchee fsohrodtefdiunriattiivoencofathme of hmnaoetarnesparoyofdbdueecttneidcotuni/endegesvpoeGsltuonpiamtneanltPamolanneiftffeeecsttsea.xtpiIoonsnpiaorfrsptiecunlaar,liteofxfeprsoosnloy lsimeitsed A50r5guSshReecsheyaDrcihve, BuildinAg THeolresphhaomn,e:bean(s1y3va)n4i4a3-189701404-1297 Telefax: (215) 443-8587 Raymond G. York, Ph.D., DABT A`A AsdsdorceisasteciDitreecdtoarobofveRefsoeraTrecshting Facil SPONSOR: 3M Corporate Toxicology 3M Center, Building 220-2E-02 St. Paul, Minnesota 55144-1000 418-027:PAGE D-2 Protocol 418.027 Page2 STUDY MONITOR: Paul H. Lieder, Ph.D., DABT 3M Corporate Toxicology 3TeMleMpehdoincea:l De(p6a5r1t)m7e3n7t-2678 Telefax: (651) 733-1773 Email: phlicder]@mmm com REGULATORY CITATIONS: Organisation for Economic Co-operation and Development (1996). OECD Guidelinefor Testing ofChemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996. Organisation for Economic Co-operation and Development (1998). The Revised OECD PrinciplesofGood Laboratory Practices [C(97)186/Final]. US. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. Japanese Ministryof Health and Welfare (1997).GoodLaboratory PracticeStandardfor Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. REGULATORY COMPLIANCE: "This study will be conducted in compliance with the Good Laboratory Practice (GLP) regulations cited above with the exceptionofanalysisofblood and liver samples sent to `Souther Research Institute for metabolite analysis. All changes or revisionsofthis protocol shall be documented, signed by the Study Director and the Sponsor, dated and maintained with the protocol. `The Testing Facility's Quality Assurance Unit (QAU) will audit the protocol, the raw data and the report, and will inspect critical phasesofthose portionsofthe study conducted at the Testing Facility in accordance with the Standard Operating Proceduresofthe Testing Facility. The final report will include a compliance statement signed by the Study Director thatthereport accurately reflects the raw data obtained during the performance ofthe study and that all applicable GLP regulations were followed in the conductofthestudy. Should significant deviations from GLP regulations occur, each willbe described in detail, together with how the: deviation might affect the quality or integrityofthe study. 418-027:PAGE D3 Protocol 41P5a-g0e237 SDihroeucltdoranwiyllpoerntsiuornoeftthahteasqtuuadlyifbieedcPornidnuccitpeald Ibnyveastsiugbactoonrtrisacitdoerntoirfibeyd bthyetShpeofnascoirli,tythceonSdtuucdtying athuadtitporretsipoencotfivtehreessutlutdsy.anTdhreepQorAtsUfofrorthtahtatstfuacdiyliptoyrwtiilolncaocncdourcdtincgrittoictalhephSaOsPesionfstpheacttiofancsilaitnyd. P`SruicnhcicprailtiIcnavlepshtaigsaetionrsapnedcttihoenSretpuodrytsDiarnedctorre.porTthaeuddiattseswoilfltbheesiunbsmpietctteidonbsyatnhdatrefpaocriltity to the soutbhmeisTseisotnisngwiFlacbileitiyncfoorrpionrcaltuesdioinntionathQeAfiUnalStraeptoermte.ntIngeandedriatitoend,btyhatthaftacfialciitlyiwtiylalnpdropvriodveidaed statement inclusion of GLP compliance, in the final report. as described above, signed by the Principal Investigator for SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE: See ATTACHMENT 1 to the protocol. `TEST SUBSTANCE AND VEHICLE: Identification: Test Substance: T 7599.7. Lot identification to be documented in the raw data. "The Sponsor will provide to the Testing Facility documentation or certificationof the identity, `dcoocmupmoesnittiaotni,omnewtihllodboefisnycnltuhdeesdisi,n stthreefnigntahl arenpdoratc.tivity/purityofthe test substance. This Vehicle: o`Asqmuoesoiussm0e.m5b%racanrebopxryomceetshsyeldcedleilounliozseed(wCaMteCr)((Rm.Oe.didueimonviiszceodsiwtayt)erp)r.epLaortediduesnitnifgirceavteirosne.to be documented in the raw data. Neither the Sponsor nor the Study Director is aware of any potential contaminants likely to be present in the vehicle that would interfere with the resultsofthis study. Therefore, no analyses other than those mentioned in this protocol will be conducted. Safety Precautions: G`lwoovmesd,udriunsgt-fomrimsuVlHaEtiPoAn-fpirletpearreadtmioanska,ndapdporsoapgrei.atTeheeyeMaptreotreicatliSoanfaentdy DuantiafoSrhme/eatb(cMoSatDSto)bweill be included in the raw data. Storage: 418-027:PAGE D-4 Protocol 41P8a.g0e27 Bulk Test Substance: Bulk Vehicle Components: PrVeeplaircelde TFeosrmtuSluatbisotnasn:ce and Room Room temperature, temperature. protected from light. Room temperature, protected from light, `AGlullbteisntsksiu,bsMtaannacgeesrhoifpmFeonrtmsultoattihoenTeLsatbiornagtFoarcyi,liattytshheopurledvbieouasdldyrceistseeddadtodrtehsesaattnednttieolneopfhoJnuelian `number. bSehilpambeenletdsasphporuolpdriiantcellyu.deTihneforremcaitpiioenntcosnhocuelrdnibnegnsottoirfaigeed cionnaddivtaionncseoafndshsihpimpepnitn.g cartons should FORMULATION: Frequency of Preparation: Formulations (suspensions) will be prepared weekly at the Testing Facility. Detailed preparation procedures are attached to this protocol (ATTACHMENT 2). Adiustment for Purity: `The test substance will be considered 100% pure for the purposeofdosage calculations. Testing Facility Reserve Samples: `"aTnhde bTuelsktivneghiFcalcielciotympwiolnlernetsseruvseeda dsuarmipnlget(haeppcroouxrismeoatfetlhye 1stgu)doyf. aScahmplloetosfwiblullkbetessttosruebdsutnadnecre the previously cited conditions. ANALYSES: Rreepsourlttsofrequired analyses will be provided to the Testing Facility for inclusion in the study o`fStahmpelesstuadyd.ditAidodniatlitoonatlhoasnealdyessecsr,iibfedrebqeuliroewd,mwaiyllbbeetdakoecnuimfendteeedmebdynpercoetsoscaorlyadmuernidnmgetnhte.course Bulk Test Substance Sampling: 418-027:PAGE D-5 Protocol 418.027 Pages sAensta(mapmlbei(eanptpcroonxdiimtaitonesl,yp1rogt)oecfttehdeftreosmt sliugbhstt)atnocethweilSlpobnestoarkefnoroannatlhyesilsa.st dThaiyosfsatmrpealtewmienltlbaen:d sentto: Principal Investigator: Gregory S. Gorman, Ph.D. Staff Chemist Bioanalytical Chemistry Group. Southern Research Institute 2000 Ninth Avenue South Birmingham, Alabama 35255-5305 Telephone: (205) 581-2725 Telefax: (205) 581-2044 Email: goman@sorrig `The recipient will be notified in advanceofsample shipment. Analyses of Prepared Formulations: Concentration and Homogeneity: `Concentration and homogeneityofthe prepared formulations will be verified during the course: ofthis study. Quadruplicate samples (2 mL each) will be taken from the top, middle and bottom of each concentration on the first day ofpreparation. Two samples from cach quadruplicate set will be shipped for analysis; the remaining samples wil be retained at the Testing Facility as pbraecpkeruaptisoanm.pleTsw. oQsuaamdprlueplsifcraotem seaamcphlqeusadwriulplbliecattaekesnetwfirlolmbceacshhicpopnecdenftorratainoalnyosins;thtehelat day of remaining sampleswillbe retainedas backup samples. Backup samples wibesltorledunderthe previously cited conditions and discarded at the Testing Facility upon the requestofthe Sponsor. Stability: Stability of the prepared formulations will be documented during this study. Two sets of duplicate samples (2 mL each) from cach concentration will be taken on the first day of preparation. One samopfleaceh duplicate set willbeshipped on the dayof preparation. These `samples will be analyzed at the following time points: a soon after preparation as possible and ten days afer the first analysis. The remaining samples will be retained at the Testing Facility as bdaiscckaurpdesdamaptltehse.TeBsatcikngupFascailmiptlyeuspwoinlltbhee rsetqoureesdtounfdtehrethSepopnrseovri.ously cited conditions and `ShippingInstructions: 413-027:PAGE D-6 Protocol 41P8a.g0e27 Samples to be analyzed will be shipped (ambient conditions) to: Gregory S. Gorman, Ph.D. StaffChemist Bioanalytical Chemistry Group. Southem Research Institute 2000 Ninth Avenue South Birmingham, Alabama 35255-5305 Telephone: (205) 581-2725 Telefax: (205) 581-2044 Email: goman@sri.org "The recipient will be notified in advance of sample shipment. DISPOSITION: PsurbesptaarnecdefwoirlmlulbaetrieotnusrwnieldltboetdheisScpaorndsedoratathteheTepsrteivnigouFsalciylictiyt.edAaldldrreesmsa.ining bulk test TEST SYSTEM: `Species/Strain and Reason for Selection: ``TmhaemCmarlli:aCnDsp(eScDi)esIGaSccBepRteVdAfFo/rPulsuesin rtaotxiwcaitsyssetluedciteesdaansdtihtehTaesstbeSeynswtiedmebleycauusseed:th1r)oiutgihsooutne dinedvuesltorpy;me2n)ttahlistosxtirnasi;noafndrat3)hhaisstboereincadledmaotnastarnadteexdpteoribeencseenesxiitsitveattothreeTperosdtuicntgiFvaecainldity Number: Initial population acclimated: Population selected for study: 70 male and 70 virgin female rats. 60 male and 60 virgin female rats (15 per sex per dosage group). Body Weight and Age: Male rats will be ordered to weigh from 300g to 325 g each at receipt, at which time they wil be: expectedtobeatleast 60 daysof age. Female rats willbeordered to weigh from 200 g to 225 ach at receipt, at which time they will be expected to be at least 60 daysofage. Actual body weights will be recorded the day after receipt and willbe documentedinthe raw data. The weight ranges will be included in the final report. At study initiation, the weight variationofthe rats will not exceed 20%of the mean weightofeach sex. 418-027:PAGE D7 Protocol 41P8a-g0e27 Sex: Both male and female rats will be evaluated. Source: Charles River Laboratories, Inc. "The rats will be shipped in filtered cartons by air freight and/or truck from Charles River Laboratories, Inc, to the Testing Facility. Identification: RInac.t,sNaor.e pMerSmPaTne2n0t1l0y1)i.denMtiaflieedaunsdinfgemMaolneerlas saerlefa-psiseirgcniendgteeamrptoargasr(yGneuymBbaenrdsaatnrdecTeaigptCaon,d. ogfivtheen ufnristqudeospaegrem.anPeunptsiwdielnltinfoitcabteioinndniuvmibdeuarlslywhideenntiafsiseidgndeudri(n0gtlhaectsattuidoyn;bealflorpearaadmmeitneirsstrwaitlilon be evaluated in termsofthe litter. ANIMAL HUSBANDRY: All cage sizes and housing conditions are in compliance with the Guidefor the Care and Use of Laboratory Animals". Housing: Fduorgienngetrhaeticoonharbaittsawtiilolnbaendinpdoisvitdpuaarltluymhpoeursieoddsi.n sDtuariinlnegsscoshtaebeli,tawtiiroen-,beoatcihompeadirocafgeast,sewxiclelpbte housed in the male rat's cage. Beginning no later than day 20ofpresumed gestation, Fo generation female rats will be individually housed in nesting boxes. Each dam and delivered litter will be housed in a common nesting box during the postpartum period. Nesting Material: Nesting material (bed-0'cobs) willbe provided. `poBsesdidbilnegcwontbiameicnlhaatnigolnedaraescoofntdeuncatsednesceemsis-aarnynutaolkleyepantdhedaonciummaelnsdterdyianntdheclreaanw.datAan.alyses for Room Air, Temperature and Humidity: "tThhatehaansibmeaelnropoamssiesditnhdreopuegnhde9n9tl.y9s7u%ppHlEiePdAwfiitltheras.t leRaostotmentecmhpaenrgaetsurpeerwihlolubroefma1i0n0ta%inferedsahtair 66F to 77F (19C to 25C) and monitored constantly. Roomhumiditywil also be monitored constantly and maintained at 30% to 70% 418-027:PAGE D-8 Protocol 41P8a-g0e27 Light: An automatically controlled 12-hour light:12-hour dark fluorescent light cycle will be `tmhaeiSnttauidnyedD.irEeactcohrdoarrdkepseirginoedeiwfildlebeemgiendantec1e9s0s0arhyoutrosaEcScTo.mmTohdeatleighstchceydculleemdalyabboeraatdojruysted by activites. Any such adjustment will be documented in the raw data. Diet: Rats will be given Certified Rodent Diet #5002 (PMI Nutrition International), available ad libitum from individual feeders except during fasting. Water: `aWuattoemratwiilclwbaetearvianiglaabclceeasds lsiybsitteumm.fArlolmwiantdeirviwdiulallbbeotftrloesmaattloaccahledsotuortcheeacnadgepsasosrefdrtohmraonugh a rbaecvteerrsoesotsamt;ospirsocmeesmsebdrawnaelebeifsoerxepuesce.tedCh(l0ocroinnteaiwnilnlobemoardedetdhatno 1t.h2epprpomcecshsleodriwnaetaetrt3hseatime of apnoaslsyisbilse.chWeamtiecrail caonnatlaymziendatmioonnt.hly for possible bacterial contamination and twice annually for Contaminants: Neither the Sponsor nor the Study Director is awareofany potential contaminants likely to be pirnteesrefnetreinwitthhe ctehretirfeiseudltdsioeftt,hiinsthsetuddryi.nkTihngerwaetfeorronero,inantahleynseesstoitnhgemrattehrainatlhsoastelreovuetlisntehlayt would performed by the feed supplier or those mentioned in this protocol will be conducted. DAY NUMBERING SYSTEM: Gcoenstteanttisonandda/yor0aiscdoepfuilnaetdoraysptlhuegdoabyssepreverdmaitnosztoua.are observed in a smearofthe vaginal `The dayofbirth is designated lactation day 0 (postpartum day 0) in the Health Effects Test Guidelines - Reproduction and Fertility Effects (OfficeofPrevention, Pesticides and Toxic Substances 870.3800, August, 1998) and in the OECD Guideline for the TestingofChemicals Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (Section 4, No. 422, 22 March 1966). This same day is designated day | postpartum (day 1of lactation) in the Standard Operating Proceduresofthe Testing Facility. Throughout this protocol, the dayofbirth will be designated day 1 postpartum (day 1 of lactation) and all subsequent agesof the F1 generation rats and daysofthe lactation period will be determined and cited accordingly. RANDOMIZATION AND COHABITATION: 418-027:PAGE D9 Protocol 41P8a.ge0s27 r`Uapnodnoamrruinviatls,.aAtfstewirlalnbeacacslsiimganteidontopeirnidoidvoidfuaalt hleoausstifnigveondatyhse,bmaasliesoafndcofmpeutemrr-aagteslnweirelaltebde selected for study on the basisofphysical appearance and body weights recorded during acclimation. The rats will be assigned to dosage groups based on computer-generated (weightordered) randomization procedures. `Within each dosage group, consecutive order will be used to assign rats to cohabitation, one male rat per female rat. The cohabitation period will consist ofa maximumof 14 days. Female rats `with spermatozoa observed in a smear ofthe vaginal contents and/or a copulatory plug observed in situ will be considered 10 be at day 0of presumed gestation and assigned to individual housing. Female rats not mated within the first seven daysof cohabitation will be assigned a`lmtaexrniamtuemmoaflseervaetsnthaadtdihtaivoneamladtaeyds.(same dosage group) and will remain in cohabitation for a Day 1oflactation (postpartum) is defined as the dayofbirth and is also the first day on which all `lpitutpesrianreadleiltitveearreediannddivgirduoaolmleydwebiygthheedd(apmu)p.body weights will be recorded after all pups in 2 `Within each dosage group, consecutive order will be used to assign the first five male and the first five female rats to a functional observational battery (FOB) and motor activity assessment. "The next ive rats per sex in each group willbe assigned to hematology and clinical biochemistry evaluations, The last five ats per sex in each groupwillbeassigned to metabolite analysis. Histological evaluations will be performed on the last ten atsper sex in each group. ADMINISTRATION: Route and Reason for Choice: The oral (gavage) route was selected for use because: 1) in comparison with the dietary route, the exact dosage can be accurately administered; and 2) it is one possible route ofhuman exposure. Method and Frequency: Dosages will be adjusted daily for body weight changes and given at approximately the same time each day. Male rats will be given the est substance and/or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuing until sacrifice, after completionofthe cohabitation period, after a minimum of 28 daysofdosage. rotaetne 418-027:PAGE D-10 p`eForemvealiecdroartbspbwtimliliobnneygmivaenntiheates1t4suabsytanscnedacndo/omr tihenvewhiiclleioncceadavily beeginninng 14 wdayos s Pup wilotbediy given he et btn theveilbotmaybepsyxpd 0 tehestemstmsupbsitatnce during maternal gestation (in utero exposure) or via maternal milk during the Rationse for Dosage Seieton `Dsousbastgaenscew,itllabkiensgelinetcoteadccboyuntthepoSspsoinbsleordibfafseerdenocnespirnevsienosuistisvtiutdyiebsectownedeuncptreedgnwaintth the and test `nonpregnant rats. The highest dosage will beaEexpected to ees cause toxic effects bbuutt otnot mmoorratlaitlyity or peurtpoaseioftdemonstrating any dosage-related response, with no adverse effects expected at the Dense Levels,Concemraions and Volumes: pl SiSeolml] | Ppove0| coimnmd ] STEE JR o or i Tot0a[[00s | iloo [[saEsammsosnvmaayrmaan] CH w vTs osa TTsmo0[ r |55|r itoo [[vpaassoarnocoomnmvamvaarne]] TESTS, ANALYSES AND MEASUREMENTS - Fo GENERATION: Villy Mleand Female Rats All Periods: At least twice daily. Clots Observations norGenera Ampessanes:Mle and Female te Acclimation Period: Weekly. Dosage Period: 418-027:PAGE D-11 Protocol 4P1a8g.e02171 Daily before dosage. On the first dayofdosage, phoousrtldyosiangteerovbaslseravfatteiroandsmiwniilsltbreatrieocnofrodredthaet farpsptrfooxuirmahtoeulrys aobnsderavtatthieoennsdofofrtshuebsneoqrumenatl wdaoyrskoifndgodsaya.gePwoisltldboesage rDierceocrtdoerd aantdi/notrerSvtaulsdydeMtoenrimtionredafatprprdoeptreiramtienbatyitohneofStthudey onsetofpeak pharmacologic/toxicologic effects. Postdosage Period: Before sacrifice Matemal Behavior: Dreacyosrd1edanddai5lyp.ostpartum. Observed abnormal behavior bClyintihceaSltoubdsyerDviarteicotnosrmaandy/obreSrteucdoyrdMeodnmitoorre. frequently than cited above,if deemed appropriate Detailed Clinical Observation-s Male and Female Rats: Owinlclebebecfoonrdeutchteedfirfsotrdaollsamgaeleanadndatfleemasatleonrcaet.weTehkelsyetohbesreerafvtaetri,ondestwaiillledbcelminaidcael ooubtsseirdveattihoencsage vinaraiasttiaonndsairnd tahreenteastatctohnedistaiomnestairmeemeiancihmadlayaonfdctohnadtuocbts.erEvfaftoirotnswialrlebceonmdaudcetetdo ebnysoubrseetrhvaetrs `fuurn,aweyaerseo,fmturceoautsmemnetmbgrroaunpes.s,Soicgcnusrrneontceedosfhosuelcrdeitnicolnusdae,ndbuetxcnroettiboensliamnidteadutto:oncohmaincgaecstiivnitsykin, (aen.dg,relsapcorinmsaettioonh,anpidlloienrgetasiowne,llpuapsilthseizper,eusneunscueaolfrcelsopniircatoorrytopantitcermno).vemCehnatnsg,esstienregoatity,pipcosture behavior (e.g. excessive grooming, repetitive circling), difficult or prolonged parturition or bizare behavior (.8., self-mutilation, walking backwards) should also be recorded. Body Weights - Male and Female Rats: Acclimation Period: Weekly. Dosage Period: Daily. Sacrifice: Terminal weight. Feed Consumption Values - Male Rats (recorded and tabulated): Dosage Period: `Weekly. Feed let recorded on the day before sacrifice Rats will be fasted overnight before sacrifice. Feed Consumption Values - Female Rats (recorded and tabulated): Dosage Period: `Weekly to cohabitation. 418-02TPAGE D-12 Protocol 4P1a8g.e0i227 Dapryessu0m,e7d,g1e0s,ta1t2i,on15a,nd18d,a2y0san| da2nd55(ifpnoestcpearstsuam.royFf)eed loft will be recorded on thedaybefore fasted overnight before sacrifice. sacrifice. Rats will be: Feed Consumption Values-Male and Female Rats: rFeepeldenciosnhstuhmeptfeieodn. vDaulruiesngmcaoyhabbeitraetcioorn,dewdhmeonrtewforerqatusenotclcyutphyanthceitseadmaebocvageeifiwtitihsonneecefseseadrjyatr,o traebpulleantiesd.hmentofthe feed jars will be documented. Individual values willnotbe recorded or Estrous Cveling and Mating: afEtsetrrotuhse cfyicrlstinagdmwiinlilsbteraetviaolnuaantdedtbheyneuxnaimilinsapteiromnaotfozvoaagianraelocbysteorlvoegdyibnegaisnmneianrgowfitthhethveagdianyal contents and/or a copulatory plug is observed in stu during the cohabitation period. Natural Delivery: Female rats will be evaluated for: Adverse Clinical Signs Observed During Parturition. `DurationofGestation (day 0ofpresumed gestation to the time the frst pupi observed). Litter Size (defined as all pups delivered). Pup Viability at Birth, Functional Observational Battery: Obencoonneduocctceadsioonn fdiuvreimngalteheacnodurfisveeoffetmhaelesrtautdys,paerfgurnocutpi.onaFloorbsmearlveatriaotsn,althbiastatsersyes(smFeOntBw)illwiblel conducted shortly before scheduled sacrifice. Female rats should be tested during the lactation period, shorly before scheduled sacrifice. To avoid hyperthermiaofpups, dams will be separated from their litters for no longer than 30 to 40 minutes. "The FOB, to be conducted by an observer unawareof the group assignmentofthe at, will assess: the following parameters: 418-027:PAGE D-13 Protocol 4P1a8g-e02173 1. Lreaaccrtiimoantitoonl,igshatl,ipvaitliooenr,ecptailopne,brreaslpicrlaotsiuorne,,apnrdomuriinneantcieonofatnhdedeefyeec,aptuipoinllary (autonomic functions). 2. aSnendssoernisimtoitvoitry)r.esponses to visual, auditory, tactile and painful stimuli (reactivity 3. Reactions to handling and behavior in the open field (excitability). 4. Gviasiutaplaptltaecminignrtehsepoopnseen afniedldl,asnedvienrgitfyoooftgsapiltayab(ngaoirtmaalnidtiseesn,saoirrirmiogthotring reaction, coordination). 5. Forelimb and hindlimb grip strength. 6. Aotbhneorrumnaulsucallinbiechalavsiiogrn,shiynpcoltuodinnigabourthnyopterltiomniitae,detmoaccoinavtuilosni,odnesh,ytdrreatmioorns,and unkempt appearance and deposits around the eyes, nose or mouth. pErvoivdiednecdeo(fTetshteinagbiFlaictiyloiftytPhiossibtaitvteerCyonttordoelteDcattat)h.e eDfaftecatswoilflpaolssiotibveepcroonvtirdoeldsutobsdtoacnucemsenwitll be interobserver reliability ifmore than one observer is involved in the testing. Motor Activity Test: Mcooutrosreoafcttihveitystwuidlyl.beFoervamlaulaeterdatos,ntfhiivseamsasleessamnedntfiwviellfebmeacloenrdautcstpeedrsghroorutlpyobnecfeodrursicnhgedtuhleed sacrifice. sacrifice. Female rats should be tested during the lactation period, shortly before scheduled `The movements of each rat will be monitored by a passive infrared sensor mounted outside a sdtuariantlieosns wstietehl,twheirneu-mbbotetroomfedmocvaegeme(n40t.s6axnd25t.i4mxe s1p7e.n8tcmi)n.moEvaecmhetnestt tsaebsusliaotnedwialtlcbaech1.5 hours in efaicveh-smeisnsuitoen,inwtiertvhale.acThhreatatpepsatreadtuins twhiellsammoe nloicaattrioaocnrkoonftuheprtaock32accraogsessteasntdsessesnisoonrss. dGurrionugps will be counterbalanced across testing sessions and cages. Dacattiaviwtiylplrboedupcroevdibdyedpotsoidteivmeoncsotntrraotlestuhbastttahnecetesst(TseyssttienmgiFsaccialpiatbylPeosofidteitveecCtoinntgroilncDraetaas)es in 418-027:PAGE D-14 Protocol 4P1a8g.e02174 HEMATOLOGY AND CLINICAL CHEMISTRY: Acltinsicchaledcuhleemdisstacrryifsiacem,pltehecfoilvleecmtailonewainldl bfieveexfseamnaglueinraattsedpefrrgormotuhpeaisnsfierginoerdvteonhaecmaavtaolfooglyloawnidng sAapcprrifoixciembayteclayrb5omn Ldioofxbildeooadsp(hfyaxsitaetdi)owni.llRabtescwoilllebcteedfaasntdedproovecrensisgehdtabsedfeosrcersiabcerdifbiecel.ow. `hDeetteersmtisnuabtsitoannscaedmdiatyi,onoarl atroetshuosspeedcetsecdritob,edafbfeecltorwelmaateydbmeetcaobnodluicctperdioffitlhese(ken.go,wcnalpcriopuemr,ties of Tphhoespthuabtees,cofansttaiinngirniggtlhyecesraimdpelseasnwdilflasbteinlgabgelluecdoswei,tshptehciefpircohtoorcomlonneusm,bearn,d Schpoolnisneosrtesrtausdey). `number, animal number, group umber, dosage level, dayofstudy, collection interval, date of collection, species, generation and storage conditions. Hematology. Acpeporroxriefmraitgeelrayte1dmuLntoilfsbhliopomdenwitllfobreancaollylseicstoefdtihnteo fEoDlTlAo-wicnogahteemdattoulbeosgiacndpamraaimnettaeirnse:d on wet Erythrocyte Count (RBC) Hematocrit (HCT) Hemoglobin (HGB) MMeeaann CCoorrppuussccuullaarr HHeemmoogglloobbiinn (MCH) Concentration (MCHC) LMeeuaknocCyotrepuCsocuunlta,rTVootallum(eWB(CM)CV) Leukocyte Count, Differential PMleaatenlePtlCatoeulnett V(oPlLuAmTe) (MPV) Cell Morphology T`mweoasbulroeomdenstmseoafrdisflfiedreesnwtiilallbleeupkroecpyatreedcoautntt.he ATlelstsianmgplFaecsil(iotny wfoertciacce)hasnadmpslleidfeosr(ambient conditions) will be shipped on the dayof collection to Redfield Laboratories at the following. address. A(0p.p1r2o9xiM)m.ateTlhye1c.o8nmteLnotsfbwillolobdemwiilxlebde aandddemdaitnotaaitnuebdeocnonwteaitniicnegu0n.t2ilmtLheoftsuobedsiaurme cceinttrartiefuged (twuibtehainnd30immmienduitaetseolfytfhreozceonl.lePcltiaosnmtaimsea)m.plTehsewrilelsubletimnagipnltaasimnaedwiolnl dbreytircaensofrerirnead tforeaezterransport `(m7e0asuCr)emuennitol fshpirpoptehdroonmbdirnytiicmeeto(PRTe)dfainedldacLtaibvoartaetdorpairetsiaalt tthhreofmoblolpolwaisntginadtdirmeess(,APfoTrT). 418-027PAGED-15 Protocol 4P1a8g.e02175 Clinical Chemistry: Arepspurloixnigmsaetrealysa2mmplLeosfwibllloboediwmimledbieatcoelllyecftreodzeinntoonsderryumicseeapnardamtaorinttuabienseadnfdroceznetnr(if7u0gedC. )The until shipment for analysis ofthe following parameters: TTroitgallyPcreortiediens ((TTPR)) ACrleaantiinneinAemi(nCoRtrEaAnTs)ferase (ALT) AGllobbuumliinn ((GA)) `AAlskpaalritnaetePAhmoisnpohtartaanssef(erAaLsKe)(AST) AGllbuucmoisne/(GGlLobUu)lin Ratio (A/G) ~~ CPhaolscpihuomr(uCsA()PHOS) CThootlaelsBtielriorlub(iCnH(OTLB)ILY) PSootdaisusmiu(mN(AK)) Urea Nitrogen (BUN) Chioride (CL) L`aSbaomrpalteosrwiielslabetshehifpopleldow(ionngdardydriecses).to arive on Monday through Friday at Redfield Shipping Instructions: `Samples will be shipped according to the conditions described above to: PRreidnfciiepladlLIanbvoesrtaitgoartioers: Ms. Phyllis Powell A Division ofCRL-DDS 100 East Boone Street P.0. Box Redfield, 308 Arkansas 72132 Telephone: Telefax: ((550011)) 339977--22504002 The recipient will be notified in advanceofsample shipment. URINALYSIS: Urinalysis will not be conducted unless indicated based on expected or observed toxicityof the test substance. METHOD OF SACRIFICE: Fo generation rats will be sacrificed by carbon dioxide asphyxiation 418-027:PAGE D-16 Protocol 4P1a8g.e02176 GROSS NECROPSY AND HISTOPATHOLOGY - Fo GENERATION RATS: Scheduled Sacrifice: aSdcmhiendiuslterdatsiaocnr,ifaifcteeor fammailneirmautsmowifll28bedacyosnodufcdtoesdaogen.thSecdhaeydufloeldloswacirnigfitcheeolfafstemdoaslaegreas will be: conducted on day 6 of lactation. Gerxotsesmanlecsurrofpascyeosfaanldl amlalloeriafincdesf,eamsalweelrlatas wtihlelicnrcalniuadle,atnhoriancitiaclapnhdysaibcdaolmeixnaamlicnaavtiitoinesoafnd their contents. Special implantation sites aatntdenctoiropnowrialllubteeapawiidlltboethreecoorrgdaends.ofthe reproductive system. The number of Mbuaflfeeraendd1f0e%mafloerrmaatlsiwnilalndbeexeaxmaimniendedhifsotrolgorgoiscsallleys.ionTsi.ssGureotsrsimlemsiinognsawnidllhbisetroeptaatihnoeldogiyn wnielultrbael: `Tpheerftoersmteesd aunnddeerpitdhiedsyumpiedrevsisoifoanllofmoarlebyraatsBowialrldb-eCewretifgiheeddV,eatnedritnhaerytePsatetsh,oleopgiidsitd.ymides, sfoermmianlailn.vesTihceletseswtietshwcilolagbuelaftiixnegd ginlaBnoduiann'dspsroolsuttaitoenwiflorlb4e8rteota9i6nheoduirnsnbeeuftorrael bbeufifnegrreedta1i0ne%d in wneeuitgrhaeldb,ufafnedreovdar1i0es%,fuotremraulsi,n.vagTihneaoavnadriaesmaanmdmathreyutgelraunsdwwiitlhl bceerrveitxaoifneeadcihnfneeumtarlaelrbautfwfielrlebde b1e0t%wefeonrmgallaisns.plUatteesrtoofacpopnafriernmttlhyenaobnspernecgenoafntimrpatlsanwtialtiboen esixtaesm,ianneddraefttarinbeediningnperuetsrsaeld buffered 10% formalin. Balssoiogdnesdamtoplmeesta(baoplpirtoexainmaaltyeslisy.3BmlLo)odwiwlilllbebecoclollelcetcetdedfrformomthtehefivveenraacsapvear. sEeaxcphersagmrpoluep will be divided into two aliquots. One aliquot of2 mL will be transferred into an EDTA-coated (inptuoraplesetropu)mttuubbee,analdlroewferdigteoractleodt.aTndhespsuencoinndaacleinqturoitfu(gaep.prTohxiemraetseullyti1ngmsLe)ruwimllwiblel tber:ansferred transferred into polypropylene tubes labeled with the protocol number, Sponsor study number, animal number, group number, dosage level, dayofstudy, collection interval, dateofcollection, species, generation and storage conditions. All samples will be immediately frozenondry ice `and maintained frozen (<-70C) until shipment for analysis. `Theliverwill be excised and the organ weight recorded. One lobe (right lateral) wl be placed inaconical tube and flash frozen in an ice/alcohol bath. Liver sampleswillbemaintained frozen (S-70C) until shipment for analysis. `Shipping Instructions: 418-027:PAGE D-17 Protocol 4P1a8g.e02177 Liver and serum samples will be shipped on dry ice and whole blood willbe shipped on ice packs. Samples tobe analyzed will be shipped to: Principal Investigator: Gregory S. Gorman, Ph.D. Staff Chemist Bioanalytical Chemistry Group Southern Research Institute 200 Ninth Avenue South Birmingham, Alabama 35255-5305 Telephone: (205) 581-2725 Telefax: (205) 581-2044 Email: gorman@sri.org "The recipient will be notified in advance ofsample shipment. p`SeeregAroTuTpAaCssHigMnEedNtTo h3ifsotrolaodgdiictailosnaalmptilsesuceosltloebcteionweaingdheevdalaunadtiroentained fromthetenratsper sex All other tissues will be discarded. `Scheduled Sacrificeof Female Rats that Do Not Deliver Litters: Rnaectrsotphsayt,deoxanomtindaetliiovenraandlittitseswuiellrebteenstaicorniwfiicleldboencodnadyu2c5toedfparsedseuscmreidbegdesatbaotivoen.forGrroatsssat scheduled sacrifice. Dams with No Surviving Pups: Dams with no surviving pups will be sacrificed after the last pup is found dead, missing or presumed cannibalized. Gross necropsy, examination and tissue retention will be conducted as described above for rats at scheduled sacrifice. RatsFoundDeadorMoribund: Rats that die or are sacrificed becauseof moribund condition, abortionorpremature delivery will be examined for the causeofdeath or moribund condition on the day the observation is made. "The rats will be examined for gross lesions. Testes and epididymidesofmale rats will be: excised and paired organ weights will be recorded. The epididymides willberetained in neutral buffered 10% formalin. The testes will be fixed in Bouin's solution for 48 to 96 hours and then retained in neutral buffered 10% formalin. Pregnancy status and uterine contents of female rals will be recorded. Aborted fetuses and/or delivered pups will be examined to the extent possible. Uteriofapparently nonpregnant rats will be examined aftr being pressed between glass plates to confirm the absenceofimplantation sites. Ovaries and uteri will be retained in neutral buffered 10% formalin 418-027:PAGE D-18 Protocol 4P1a8g-0e2s7 `TESTS, ANALYSES AND MEASUREMENTS - FI GENERATION: Viability: Preweaning Period: Litters will be observed for dead pups at least twice daily. The `pups in each litter will be counted once daly. Clinical Observations and/or General Appearance: Preweaning Period: Once daily. Clinical observations may be recorded more frequently than cited above, ifdeemed appropriate by the Study Director and/or the Study Monitor. BodyWeights: Preweaning Period: Days 1 (birth) and 5 postpartum. Sacrifice: Terminal weight Feed Consumption Values (recorded and tabulated): Preweaning Period: Not recorded. METHOD OF SACRIFICE - FI GENERATION PUPS: F1 generation pups will be sacrificed by carbon dioxide asphyxiation. NECROPSY - Fl GENERATION: Gross lesions will be retained in neutral buffered 10% formalin for possible future evaluation. Unless specifically cited below, all other tissues will be discarded. Pups Found Dead on Day 1 Postpartum: Pups that die before examinationofthe liter for pup viability wil be evaluated for vial status at birth. The lungs will be removed and immersed in water. Pups with lungs that sink will be identified as stllbom; pups with lungs that float will be identified as liveborn, and to have died shortly aftr birth. Pups with gross lesions will be preserved in Bouin's solution for possible future evaluation. Pups Found Dead or Moribund on Davs 2 to 4 Postpartum: tPhuepscafuosueondfddeeaatdhororsatchreifmiocreidbbuencdaucsoenodiftimoonr.ibPuunpdsitwyitwhilglrboesselxeasmiionnsedwiflolrbgeropsrsesleersvieodnsinand for Bouin's solution for possible future evaluation. 418-027:PAGE D-19 Protocol 4P1a8g.e02179 ScheduledSacrifice: On day 5 postpartum, pups will be will be sacrificed and examined for gross lesions; gross lesions will be preserved in neutral buffered 10% formalin. Necropsy will include a single crosssectionofthe head at the levelofthe frontal-parietal suture and examinationofthe crosssectioned brain for apparent hydrocephaly. PROPOSED STATISTICAL TESTS: `When possible results will be evaluated by appropriate and acceptable statistical methods. sBiegcnaiufsiecoanfctehaereolifmiltiemditdeidmevnasliuoenfsoorfmtahneysteunddyp,oisnttatsi,stpiacratliacnualalrylsyisreipnrtohdeucftoirvmeofantedsntesurfoorlogical ceenndtproailnttse.ndSenocmye,oafretihneapmporsotprwiiadtee.lIyfussetadtimsettichaoldasn,alesypseecsiaarlely10pabreamceotnrdiucctteesdt,stfhoer mmeetahsuordess of sperloetcotceodlwpirlilorbetoafpipnraolpirziaattioenfoorr tbhyeadmisetnrdibmuetniotnofthe variable examined and added to the DATA ACQUISITION, VERIFICATION AND STORAGE: AuDattoamagetneedraDtaetdaduCroilnlgectthieoncoaunrdseMoafntahigsemsetundtySwyisltlebme, rtehceoVridevdareiiutmheTrebmypehraantduorreuasnidnRgetlhaetiAvregus Hunidity Monitoring System, the Coulbourn Instruments Passive InfraredMotorActivity System, the Coulbourn Instruments Auditory Startle System, the Coulbourn Instruments Spatial DesluammyaerdizAeltderannadt/ioornstSaytsitsteimc,alalnydalnoarltyhzeedpausssiinvgetahveoAirdagnucseAsuotfotmwaartee.d ADlaltdaaCtoalwliecltliboentaanbudlated, Management System, the Vivarium Temperature andRelative Humidity Monitoring System, (Mviecrrsoisoonft6.E1x2c)e.l [part ofMicrosoft Office 97 (version SR-2)] and/or The SAS System Records wil be reviewed by the Study Director and/or appropriate management personnel within 21 days after generation. All original records will be stored in the archivesofthe Testing Facility. All original data will be bound and indexed. A copyofll raw data ill be supplied to the Sponsor upon request. Preserved tissues will be stored at the Testing Facility at no charge for one year after mailingof the draft final report, after which time the Sponsor wil be contacted to detemmine the dispositionofthese materials. KEY PERSONNEL: 418-027:PAGE D-20 Protocol 4P1a8g.e02207 EDixreeccuttoirvoefDiRreescetaorrcohf: RAelsaeanrMc.h:HoMbielrdrmeadn,S.PhC.hrDi.s,tDiaAn,BPTh.D., Fellow, ATS ADsisroecctioartoefDOipreecrtaotrioofnRseasnedarCocmhpalnidanScteu:dyBDairrbeacrtaorJ:. PRaattyemrsoonnd, BG..A.York, Ph.D., DABT DDiirreeccttoorrooffLSatbuodryaMtoarnyagOepmereantti:onsV:aleJroihenAF.. BShaamreptetr,, BM..SS.. ManagerofAnimal Operations: Dena C. Lebo, V.M.D. CCohnasiurlptearnsto,n,VeItnestriitnuatriyonPaaltAhnoilomgayl:CWa.reRaanyd UBrsoewCno,mDm.iVt-tMe.e,: PDho.uD.g,laAsCBV.PLear, Ph.D. RECORDS TO BE MAINTAINED: Protocol and Amendments. ATensitmaSulbAsctqaunicsei,tiVoenh.icle and/or Reagent Receipt, Preparation and Use. RMaantdionmgiHziasttioroyn.Schedules. - TGerneeartamlenCto(mimfpernetssc.ribed by StaffVeterinarian). Clinical Observations and/or General Appearance. Body Weights Feed Consumption Values. `Natural Delivery Observations. FOB and Motor Activity Observations. Blood Sample Collection, Processing and Shipment. OGrrogsasnNWeecirgohpss.y Observations. Photographs(ifrequired). FSteueddyaMnadiWnatteenarnAcneal(yrsoeosm. and environmental records). Packing and/or Shipment Lists. FINAL REPORT: 418-027:PAGE D-21 Protocol 4P1a8g.0e2l7 ``TshuemSmtaurdyytDabilreescotforunwialuldiptroevdicdoemppeurtieord-irceucpodradteedsodfastatumdayyparcocgroemspsatnoytthheeSspeounpsdoart.es.DraStfattistical analyses will not be performed on these interim data. AfincaolmizperdehfeolnlsoiwviengdrcaofnsfuilntaaltrieopnowrtitwhitlhebeSppornespoarr.eTdhonerceopmoprltetwiiolln iofntchluedesttuhdeyfaolnldowwiilnlg:be Summary and Conclusion. Experimental Design and Method. EvaluationofTest Results, APrpopteoncdoilceasn:d AFsisgourceisa,teSduAmmmeanrdymeanndtsInadnivdiDdeuvailaTtaibolness, SStuumdmyarDiirzeicntogrt'hseGALbPovCeomDpaltia,ance Statement, Reportsof Supporting Data (if appropriate) and QAU Statement DTahteaSwpiolnlsboerhwainldl-reacnedi/voerocnoempcuotpeyro-rfetchoerdderda.ft RreepcoorrtdasnwdiltlwboecropeiveiseowfetdhbeyftihnealSrteupdoyrtD.irector awinldllobreasptporroepdriianttehemaarncahgievmeseonfttpheersToensnteilngwiFatchiilnit2y1. dAalylsoarifgtirnaglendeartaatiwoinl.l bAellboourngdinaanldrecords wiinldlexbeed.stoArecdoaptyothfe TlelsrtianwgdFaatcailwiitlylabtensoucphpaliregde tfoorthoeneSpyoenasroarftuepromnairleqiunegsotf.thPeredsraefrtvfeintailssues mreaptoerrta,lsa.fter which time the Sponsor will be contacted to determine the dispositionofthese. INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMENT: `ITnhsteipturtoicoendalurAensidmeaslcrCiabreed ainndthUisseprCootmocmoilttheaev.e bAelelnprroecveideuwreedsbdyestchreiTbeesdtiinngthFiasciplriottyo'csol that ipnavionltvoetshteuadnyiamnalism.als will be conducted in & manner to avoid or minimize discomfort, distress or `cTohneduScptoinsnogrt'hsissisgtnuadtyuraendbetlhoewfadcotctuhmatenthtisstihsenoflacatnthuantneicnefsosramraitliyonducpolnicceartinviengsttuhdeynmecaeyssbiety for ostbattaeidnepdurfproosmestohfetShpeonsstourd.y. No altemative (in vitro) procedures were available for meeting the REFERENCES: 418-027:PAGE D-22 Protocol 4P1a8g.e02272 1. ECnhrviisrtoinanm,enMtSa.l ParnodteVcotyitoenkA,gPe.nEc.y,(1W98a2s)h.inIgntoVni,voD.RCe.prNoadtuicotniavleTaencdhnMiuctaalgeInnifocrimtaytTieosnts. Service, U.S. DepartmentofCommerce, Springfield, VA 22161. 2. Cnharlitsrteixaonn,eM(.PSr.oc(e1e9d8i4n)g.soRfepNraoldturcetxiovneetSoxyimcpitoysainudm,teNraetwolYogoyrkevAalcuaadtieomnysooffSciences, November 7, 193)J,.Clin. Psychiat. 45(9):7-10. 3. Linatnhge PCh.aLr.l(e1s98R8i)v.erEmCbrrly:oCDanBdRFeRtaatl.DeCvhealrolepsmeRnivtearlLTaobsoircaittoyri(eTse,raItnocl.,ogWyi)lCmoinntgrtoolnD,ata MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.) 4. LaIbnsotriattueoorfyLAanbiomraaltso.ryNaAtniiomnaall ARecsaoduercmeysP(r1e9s9s,6)W.asGhuiindgelfoonr,tDh.eC.Care and Use of 5. iHnacgogrepnorya,tiGo.nC.in(t1o9p8i9v)o.talDervoedlenotpmseafnettoyfaTsiseerssImennetursotbuedhiaesv.ioJr.aAlmteerst.inCgolca.pTaboixliictoile.s 8f:o5r30. 6. Iprrwoicne,duS.re(1f9o6r8)a.sseCsosmipngrethheenbeshiavveioorbasleravnadtipohnyasliaoslsoegsiscmsetnatt:e oIfat.hAe msoyusstee.mic quantitative Psychopharmacologia (Berlin) 13:222-257. 7. Mbaotsteerry,. V.J.C.Am(e1r9.89C)o.l.ScTroexiecnoiln.g 8a:p8p5r-o9a4c.hes to neurotoxicity: A functional observational 8. OexDaomniongathiuoen,aJn.dL.n(e1u9r8o9p)a.thSoclrogeye.ninJ.gAfmorerne.uCroolt.oxTiocxiitcyoul.si8n:g9a7-n1e1u6r.ologically based PROTOCOL APPROVAL: FOR THE TESTING FACILITY Fo lA tr recMo.roffRioebseeramarnc,hPh.D, DABT Ra7f2pbn- d G.~YorvPh.EDY|DABrTmmsvesies ASstsuidcyaDtierDeicrteocrtor of Refearch bhuno0 oll MReebmebcecra,AIlntsmtaitnunt-iRoenialllAyn,iMm.aSl.Care and Use Committee FORTHE SPONSOR 2 SPatuuldyH.MoLniietdeorr,aPnhdD, DABT Sponsors Representative. 418-027:PAGE D-23 Protocol 1Pa8g-e02237 SEA Date DaAteSAE 202 is Feb.doen Date ATf2h 200n Date 418-027:PAGE D-24 ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE ATTACHMENT 1 STUDY SCHEMATIC 418:027PAGE D25 ProtocoPlag4e18.001237 COMBINED REPEAT DOSE AND REPRODUCTIVE/DEVELOPMENTAL TOXICITY SCREEN" FirstSDvayaorf Test LaDyoores Dosswe Dosage: Premating| Cohabitation LastSuDbastyaonfcTeest MRaalise Dosage 2Wedks | 2 Weeks Natural ActiviMtoytoFrOB Delivery PGreestsautmioend PosPterpiaordtum FeRmatasle Weds | 2 Weeks 3 Weeks 7 T6 ActivMiottyoFrOB J voce ic ab. FFoOrBadadnidtimoonatlordeatcatiilvsistyeeev"aTelsutast,ioAnnsacloynsdeuscatnedd Moenafsiuvreemmaelnetssp"esregcrtoiuopn.ofthe protocol. ce. Male rats sacrificed after completionofat least 28 daysofdosage; necropsy and retention ofmale reproductive organs. Hematology and clinical biochemistry samples (five male and five female rats per group) and histological samples (ten male and ten female rats per group) collected. d. Five female rats per group assigned to FOB evaluation on day S postpartum and motor activity evaluation on day 6 postpartum. e. Last dayof dosage for female rats is day 5 postpartum. Pups sacrificed on day 5 postpartum. Female rats sacrificed on day 6 postpartum; necropsy and retention of fcoelmlaeclteedr.eproductive organs. Hematology, clinical biochemistry and histological samples ATTACHMENT | 418-027:PAGE D-26 ProtocPoalg4e182.001237 SCHEDULE" 12FEB 02 IS FEB 02 18FEB02- 16 APR02 19 FEB 02 - 04 MAR 02 014IMMAARROO22PPMM-- 1118MMAARR22AAMM 05 MAR 02 18 MAR 02 19 MAR02 - 22 MAR 02 25 MAR 02 Animal Receipt - Acclimation Begins. SctoahratboiftaDtioosnaganedPetrhiroodug-hMaal1e4-Rdaatysc(o1h4abdiatyastiboenfore: pdoesraigoed)u.ntil theofsacrifice after at least 28 days of Dosage Per-iFeomaldeRats (14 days before cohabitation through Day 4 or Day 5 of lactation). Dosage Period Estrous Cycle Evaluation. Cohabitation Period (Maximum of 14 days). MMala12e((l77ddaaeyyss)) First Possible Day 0ofPresumed Gestation. LastPossible Day 0ofPresumedGestation. FOB and Motor Activity Evaluation - Five Male Rats per Group Scheduled Sacrifice - Male Rats (Earliest possible dHaitset).oloHgiecmaaltoSlaomgpyl,eCCloilnlieccatlioBni.ochemistry and a The start dateofthe study is the day the Study Director signs the protocol. b. Throughout this schedule, the dayofbith is designated day 1 postpartum (day 1 of lactation) and all subsequent agesofthe F1 generation rats and daysofthe lactation period wil be determined and cited accordingly, as described above the protocol section, "Day Numbering System." ATTACHMENT 1 26 MAR 02 12 APR 02 30 MAR 02 12APRO2 30MAR02 - 16APR 02 30MA0R2- 16APR 02 31 MAR 02-17 APR 02 31 MAR 02- 17 APR 02 01 AUG 02 418-027:PAGE D-27 ProtocoPlag4e183.o0f237 FgierssttatPioosns)i.ble Delivery (Day 21ofpresumed Last Possible Delivery (Day 25ofpresumed gestation). First Possible Day 25ofPresumed Gestation Female Sacrifice. LFaesmtaPloessSaicbrliefiDcae.y 25ofPresumed Gestation FOB Evaluat-iFiovne FeRmatsaperlGroeup. Day 5 Post-pPuapsrSactrifuicemd. Motor Activity Evaluation - Five Female Rats per Group. HDeama6ytoPloosgtyp,arCtluinmic-aSlacBriiofcihceemoifstFreymaanlde Rats Histological Sample Collection. Draft Final Report 418-027:PAGE D-28 ATTACHMENT 2 TEST SUBSTANCE PREPARATION PROCEDURE 418-027PAGE D-29 ATTACHMENT 2 Protocol 416-027 Version: 418.0Pa2Fg7eE(Bf0o1f242) TEST SUBSTANCE PREPARATION PROCEDURE Test Substance: T7559.7 Vehicle: `Aqueous 0.5% CMC (medium viscosity) A Purpose: `The purpose of this procedure is to provide a method for the preparation of dosage suspensions ofT 7559.7 for oral (gavage) administration to rats on Argus Research Study number 418-027. 8. General Information: 4. All suspension containers will be labeled and color-coded. Each label wil specify the protocol number, test substance identification, Argus batch a`nnudmbsetro,racgoencceonntdriattioinosn., dosage level, preparation date, expiration date 2. Suspensions will be prepared: _ ADpaiplryoximatelyXe_veryWteeenkdlayys _For_daysoBfyusSeponsor 3. Suspensions will be administered at a final dosage volume of 10. mL/kg 4. safety: X_ Gloves, uniform/lab coat, goggles or safety glasses with side shields X_ DustmisyHEPAfittered Mask ____ FHaullfl-FFaacceeRReessppiirraattoorr/PiofsniottivuesePdreisnsaurceheHmoiocdal fume hood Tyvek Suit or tyvek apron and sleeves 5. Dosage suspensions adjusted for % Activity/Purity or Correction Factor: _ Yes _X_ No (Calculations based on 100%) Z %Aciviy _%Puity _ Correction Factor 6. Sampling requirements: Cited in protocol 7. Storage: Cited in protocol 418.027:PAGE D-30 ATTACHMENT 2 Version: 418P.r0o2t7o(c1o4l F41E8B.00227 TEST SUBSTANCE PREPARATION PROCEDURE Page 2012 NOTE: Parmioourntto toefstthseubaspptraonpcreiaptreepvaerhaitciloen(aRc.cOu.rdaetieolnyimzeeadswuarteerthsehoruelqduibreedused faomrocuanlitborfatvieohnipculrepionsteosa)bienaakegrr.adCuaarteefdulclyylimnaderrk, epaocuhr tbheeakreerquaitretdhe smeunbisstcaunsc.e sTlhuirsrymuaprktowivlollubmee.used during the preparation to bring the test C. Dosage Suspension Preparation: 1. Winetiogahn tahpeprroepqruiiarteedlyamsiozuendtmoofrttaesrt(ssuebesPtaRnEcPeAoRnAaTpIiOeNce of weigh paper or CALCULATIONS). 2. Isfiwzeedigmhorptaapre.rIifsnuesceeds,satrrya,nsgfreirntdhtehteesttesstusbusbtsatnacnecteoiantnoaappfrioneprpioawtedleyr. SSlloowwllyyaandddgarisnmdaltlheamveohuinclteoafnvdehtihceleteasntdsugrbisntda.nCcoenttoigneutehetro taodfdovremhiaclfiene: slurry. Transfer the vehicie/test substance slury to a marked beaker 3. rReimnasientihnegmtoersttasrubasntdanpcees.tleTrwaintshfaedrdriitnosnealtovbeheiackleer.to remove any 4. Aonddmaagddnietliiocnaslivephliactleeatnodthaegibteaatekeprritoor borianngdvodluruimneg uapliqtuootthtiengm,ark. Place administration and/or sampling 5. Repeat steps (1) through (4) or each concentration. wiiten By: [Zia 0, 4 4 Approved by; ols Date: 15 Fea zen? Clarification: No _ Yes [see attached clarification form] InitialiDate : __g< / 319-63 418-027:PAGE D-31 ATTACHMENT 3 `TISSUES TO BE WEIGHED, RETAINED AND EXAMINED HISTOLOGICALLY ATTACHMENT3 418-027:PAGE D-32 Protocol 415.027 Page 10f2 TISSUES TO WEIGHED AND RETAINED FOR POSSIBLE EXAMINATION FROM TEN RATS PER SEX PER GROUP "Ten rats per sex per group not assigned to functional observational battery and motor activity tests will be assigned to histological evaluations. Tissues to be Weighed: "The following organs will be excised, trimmed and individually weighed as soon as possible after excision to avoid drying. liver aKdirdenneaylss thymus testes epididymides spleen hberaairnt ovaries uterus (with cervix) TistobseRuetaeinesd: The following tissues or representative samples will be retained in neutral buffered 10% formalin. brain (representative regions including cercbrum, cerebellum, pons) small and large intestines (including Peyer's patches) lungs (perfused with neutral buffered 10% formalin) Ipeyrmipphhenraoldenser(vseub(smcainatdiicb)ular and mediastinal) gross lesions spinal cord (cervical, thoracic and lumbar) stomach liver Kisdplneeenys ahedarretnals thymus thyroid/parathyroid trachea uterus. urinary bladder bone marrow testes" ovaries epididymides uterus seminal vesicles (with coagulating gland) vagina prostate mammary gland (female rats only) * Testes will be fixed in Bouin's solution for 48 to 96 hours before being retained in neutral buffered 10% formalin. ATTACHMENT 3 `Histological Examination: 418-027:PAGE D-33 ProtocPoalg4e182-001227 Histological examinationofretained tissues, including reproductive organs, will be conducted for the assigned ten ratspersex from the control and high dosage groups. Iflesions attributed to the test substance are observed in the rats exposed to the high test substance dosage, the same tissues will be examined from the assigned five ras per sex exposed to the lower test substance dosages. Should results warrant examinationofthe lower dosage groups and conduct of quanitative evaluation, scheduled report date and prices will be adjusted accordingly. `Shipping Instructions: Tissues to be examined histologically will be shipped (ambient conditions) to: Principal Investigator: W. Ray Brown, D.V.M., Ph.D, ACVP Veterinary Pathologist 4R3e8seEa.rcBhutPlaetrhAovloegnyueServices, Inc. New Britain, Pennsylvania 18901 Telephone: ~~(215) 345-7070 "The recipient will be notified in advanceof sample shipment. 418-027:PAGE D-34 05 SheyDv,i4 TTeelkepfhoone2:1(52)15#)4434835887710 ~~ ARGUS RESEARCH Charles River Laboratories Discovery and Development Services PROTOCOL 418-027 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY `OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7599 Amendment 1 - 15 March 2002 1. Purpose (page 1 ofthe protocol): [iEnfffoercmtaitvieoDnatoen:th1e Mpoasrscihbl2e0h0e2a]lthThhaezpaurrdpsotsheaotfmtahiysresstuuldtyfirsotmo prerpoevaitdeed exposure ofCrl:CD(SD)IGS BR VAF/Plus male and female rat toatest substance beginning before cohabitation, through mating and continuing fora least 28 days (male rats), or through parturition nil day 5, rather than day 4 or 5,of lactation (female rats). Reason for Change: "This change corrects the protocol and is consistent with the method and frequency ofadministration to female ras on page 10of the protocol. 2. Vehicle (page3ofthe protocol): [Effective Date: 22 February 2002] The vehicle will be aqueous 1.0% carboxymethyleellulose (CMC) (medium viscosity), rather than aqueous 0.5% carboxymethlycellulose. Reason for Change: "This change was made because the test substance is precipitating out of suspension during shipment for analysis and cannot be analyzed. Any revisions to this finalized amendment must be made by subsequent amendment. 418-027:PAGE D-35 Prot"oAcmoeln4d1m6e.n0t27| Page? 3. Safety Precautions (page 3oftheprotocol): b[uEflfketcetsitvesuDbasttea:nc1e8isFenbortubaeriyn2g0u0s2e]d iAn haaclhfe-mfaiccealresfpuimraethoroowdi.ll be wom when the `Reason for Change: "This addition was made so that safety precautions are consistent with the MSDS. 4. Storage (page 4ofthe protocol): [Effective Date: 18 February 2002) The prepared test substance and vehicle formulations will be stored refrigerated, protected from light, rather thanatroom temperature, protected from light RefaorsChoangne: `This change was made at the requestof the Sponsor based on the stabilityofthe test substance. 5. Analyses (page 4oftheprotocol): Additional analyses for concentration and homogeneity andstabilitywill be p1e.r0f%orcamrebdoxoynmsetahmipylceeslltualkoesne.froTmhetshee sseacmopnldestewsitlslubbesttaankceenparnedpaarnaatliyozneudsaisng described in the protocol. Reason for Change: `This change was made to provide an analysisof samples prepared using 1.0% carboxymethylcellulose as the vehicle. 6. Bulk Test Substance Sampling (page $ofthe protocol) [Effective Date: 25 February 2002] The 1 g sampleofthe test substance taken on the last dayof treatment will be sent directly to Souther Research Institute at the address in the protocol, rather than to the Sponsor, for analysis. Reason for Change: `This change corrects the protocol to indicate that the sample will be sent to Southern Research Institut, rather than to the Sponsor. Any revisions to this finalized amendment must be made by subsequent amendment. 418-027:PAGE D-36 7. Bulk Test Substance Sampling (page 5ofthe protocol) Prot"oAcmoeln4d1m8e.n0t271 Page3 [Effective Date: 25 February 2002) A sample (approximately $ g)ofthe test substance will be taken and sent (ambient conditions, protected from light) for use. in the preparationofanalytical standards and for possible spectrophotometric: analysis. The sample will be sent to: Principal Investigator, Gregory S. Gorman, Ph.D. StaffChemist BSioouatnhaelryntiRceasleCahrecmhiIsntsrtiytGutreoup 2000 Ninth Avenue South Birmingham, Alabama 35255-5305 Telephone: (205) 581-2725 Telefax (205) 581-2044 Email: `gorman@sri.org 8. Shipping Instructions (page 6ofthe protocol): [Effective Date: 18 February 2002]The samplestobe analyzed will be shipped refrigerated, protected from light, rather than at ambient conditions. ReaforsChoangne: `This change was made at the request of the Sponsor based on the stabilityofthe test substance. 9. Schedule (Page 2ofAttachment 1 to the protocol): (Effective Date: 25 February 2002) The dosage period for female rats will be 14 days before cohabitation through Day 5oflactation, rather than through Day 4 or 5oflactation. Reason for Change: `This change corrects the protocol and is consistent with the method and frequency of administration to female rats on page 10ofthe protocol. 10. Safety (Page 1 ofAttachment2tothe protocol): [Effective Date: 18 February 2002] There should bean "X" before "Half-Face Respiratorifnot used in a chemical fume hood" to indicate an additional safety. precaution. Any revisions to this finalized amendment must be made by subsequent amendment. ReafosrChoangne: 418-027:PAGE D-37 I uyneat) `This addition was made so that safety precautions are consistent with the MSDS. nm ped Sa (eden ommen Aged KIC _ssmmo, `Alan M. Hoberman, Ph.D., DABT Date Raymdnd G. Yor, Ph.D., DABT Date Study Director WeaveWA Ade Nah ett Rebecca Altmann-Reilly, M.S. Member, Institutional Animal Care Date _(Blllid 12m ee Paul H. Lieder, Study Monitor naive Ph.D., DABT Date NBA OAT REA IBHE HSR HARAI 418-027:PAGE D-38 9SHoroo0rSsShhaeme,hBPyA.JDri1Tv9e,0r4B4idig. Ae Tekfar (215) 4438587 ~~ CharlAeRs GRiU"vSer RLaEbSorEaAtoRrCieHs Discovery and Development Services PROTOCOL 418-027 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OFT 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7599 Amendment 2 - 5 September 2002 1. Proposed Statistical Tests (page 19 of the protocol): [Effective Date: 25 June 2002); Attachment 1 to this amendment describes the proposed statistical methods. Body weight data, feed consumption values and organ weights will be analyzed as described under the Parametric headingofthe schematic. Bartlett's Test of `HgormouopgsenhaeditdyifofferVeantrivaarnicaensce"s.willAbneonussiegdnitfoiceasnttimraetseultthe(>p0ro.b0a0b1i)litwiyllthiatndtihceate that an assumption of homogeneity of variance is not inappropriate, and the data will be compared using the Analysis of Variance Test". If that test is significant (p=0.05), the groups exposed to the test substance will be compared with the control group using Dunnett's Test". If Bartlett's Test is significant (p<0.001), the Analysis of Variance Test is not appropriate, and the data will be analyzed as described under the Nonparametric headinofg the schematic. When 75% or fewer of the scores in all the groups are tied, the Kruskal-Wallis Test will be used to analyze the data. and in the event ofa significant result (p<0.05). Dunn's cToenstrto"l gwirlolupb.e Wusheedtnomcoormeptahraen t7h5e %groofutphseesxcpoorseesdintoatnhyegtresotuspuabrsetatniecde. wFiisthhert'hse `Exact Test" will be usedtocompare the proportion of ties in the groups. Data from the motor activity test, with repeated measurements within a session, will be analyzed using an Analysis of Variance with Repeated Measures", as described under that heading in the schematic. A significant effect (pS0.05) in that test canappearas effect of Concentration (a difference between groups in the total across all measurements in a session) or as an interaction between Any revisions to this finalized amendment must be made by subsequent amendment. 418-027PAGE D-39 ProtAomceolnd4m1e8n0t272 Pag2e Concentration and Block (a difference between groups at specific measurement periods). If the Concentration effect is significant, the totals for the control group and the groups given the test substance will be compared using Dunnett's Test. If the Concentration x Block interaction is significant, an Analysis of Variance Test `will be used to evaluate the data at each measurement period, and a significant result (p<0.05) will he followed hy a comparison of the groups using Dunnett's Test. Test items in the FOB having gradedor count scores will be analyzed using the procedures described under the Nonparametric heading of the schematic. Clinical observation incidence data will be analyzed as contingency tables using the Variance Test for Homogeneity of the Binomial Distribution". Altemate or additional statistical evaluations may be performed if deemed necessary or appropriate. Reason for Change `The statistical methods were to be added by amendment. 2. References (page22ofthe protocol); [Effective Date: 25 June 2002): The following references are added to the protocol. 9. Sokal, RR. and Rohlf, F.J. (1969). Bartlett's test of homogeneity of variances. Biometry, WH. Freeman and Co., San Francisco, pp. 370-371 10. Snedecor, G.W. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition, Towa State University Press, Ames, pp. 258-275.11. Dunnet,, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1121. 11. Dunnet, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1129. 12. Sokal, RR. and Rohlf, FJ. (1969). Kruskal-Wallis Test. Biometry, WH. Freeman and Co., San Francisco, pp. 388-389. Any revisions to this finalized amendment must be made by subsequent amendment. 418-027:PAGE D-40 Pro`toAcmoeln4d1m8e.n0t272 13. Dunn, OJ. (1964). Multiple comparisons using rank sums. Page3 Technometrics 6(3):241-252. 14. MSiceGgrealw,-S.Hi(l1l95,6)N.ewNoYnoprakr,apmpe.t9r6i-c1S0t5a.tisticsfor the Behavioral Sciences, 1S. SSAASS/ISnTsiAtTutTMe,UsInecr.'s(1G9u8i8d)e., RReelpeeaasteed6.m0e3asEduirteisona,naClayrsyi,sNoCf,vaprpi.an6c0e2.-609. 16. Shnoemdoegceonre,iGty.Wo.f tahnedbCioncohmriaanl,diWs.tGri.but(i1o9n6.7).StaVtaisrtiiacnacleMetetshtofdosr, 6th Edition, lowa State University Press, Ames, pp. 240-241. ReaforsChoangne: `The proposed statistical tests cite these references. 3. Histological Examination (page 2 of Atachment 3 of the protocol): [oEbfsfeercvteidveinDatthee:r4atJsuenxepo2s00e2d)t:o tIfhelehsiigohnsteastttrsiubbustteadntocetdhoesategset,stuhbestsaanmcee tarics:sues 1w0iltlhbeeleowxearmitensetdsufbrsotmantchee adosssaiggense.d ten rats, rather than five rats, per sex exposed. ReaforsChoangne: `cTohhiasbicthaatnigoen wseacstimoandoefttohecoprrroetcotcotlh,eppargoteoc9,ols.ta`teTshethRaatnhdiosmtiolzoagtiicaolneavnadluations will be performed on the test substance dosages. last ten rats per sex in each group exposed (0 the lower 4. Histological Examination (page 2 of Attachment 3ofthe protocol): [Effective Date: 4 livers of ten male aJnudnete2n00f2e]m:alHeirsattosl,otghiecatlheyvmaulsueastioofntsewnilflembaeleperraftsoramneddtohne the stomachs of ten male rats exposed to eachofthe lower test substance dosages. Any revisions to this finalized amendment must be made by subsequent amendment. Reafosr Choangne: 18027:PAGE D-41 Pro"toAcmoeln4d1m8e.n0t27 [5 "pTehrisfocrhmaendgebewcaasusmealdeesitoonscolfatrihfey tlhiavterasd,ditthiyomnuaslehsisatnodlosgticoamlaecvhaslwuaetrieonfowuonudldinbe `male and/or female rats assigned to the 250 mg/kg/day dosage group. Gerdes, i= Alan M. Hoberman, Ph.D., DABT Date Ra G. York, Director of Research ASstudy DireDctiorrector cn assez Rh.D.,JDABT Date oRResarch bleu go bold ofl Rebecca Altmann-Reilly, M.S. Member, Institutional Animal Care Date and Use Committee ~ Dal _Slifre Paul H. Lieder, Ph.D., DABT Study Monitor `Sponsor's Representative Date Any revisions to this finalized amendment must be made by subsequent amendment. PROPOSED STATISTICAL TESTS*'%: 418-027:PAGE D-42 Auschment 1PtrootAomceonld4m1e8n.0t227 Page | The following schematic represents statistical analyses of the data. _ Tyofe Tese t* Sontcrmpotr orsuImene vrsancam I nor vanes Sweats 1 vorSgtoen Sae00s 1 onsen or Sontennt ERE 5 ra Vance ms ganna anna Soman-- asost-- Noxon 0Spa prmmS eoaeses ymI ss sopscannpeaos | or teat IV.aoTifPaehnsecrteBfoiFonroopmsiaotl Dr Hoit rsaipobDo niantnna a Sutistically significant probabilities are reported as either p<0.05 or p<0.001. bc.. TPersotpofrotriohnomdoatgaeanreeitnyotofinvcalriuadnecde.in this category. Any revisions to this finalized amendment must be made by subsequent amendment. APPENDIX E DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILTY 418-027:PAGE E-1 DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 1. On 25 March 2002, day 36 of study (DS 36), male rat 17632 in the 10 mg/kg/day dosage group refluxed approximately |mL of the 4.9 mL test substance that was administered. This deviation did not adversely affect the outcome or interpretation of the study because the rat was administered mostofthedosage. 2. On3March 2002, DS 14, and on 26 March 2002, day 19 of presumed gestation (DG 19), the postdosage observations for female rats 17716 in the 0 (Vehicle) mg/kg/day dosage group and 17683 in the 250 mg/kg/day dosage `group were performed one minute early from the rangeof60% 10 minutes. These deviations did not adversely affect the outcome or interpretation of the study because the extentofthe deviation was minimal. 3. On3 March 2002, DS 14, the postdosage observation for male rat 17630 in the 0 (Vehicle) mg/kg/day dosage group was not performed. This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available for evaluation of this parameter and it was a single event. 4. On30 March 2002, DG 25, ovaries of female rat 17686 in the 250 mg/kg/day dosage group were not retained after necropsy. This deviation did not adversely affect the outcome or interpretation of the study because sufficient tissues were saved from other rats in this dosage group to evaluate ovaries 5. On4 April 2002, plasma and serum samples from the followingrats were processed and immediately frozen on dry ice. On 5 April 2002, these samples were found in astyrofoambox after they had thawed because of insufficient dry ice to keep the samples frozen. Samples were immediately refrozen and transferred to a -70 C chest freezer for storage. [oDosage cGormousp] piiggi | mRaot Nuvmbere| sSaumppleeTyrpe | rT o 1mms 1 Sewm | |" Eee [me Sem B= = = 418-027:PAGE E22 `This deviation did not adversely affect the outcome or interpretationofthe study because sufficient samples were available for evaluation. All deviationsaredocumented in the raw data. an ir 0 Lo AS02003 Raymond G. Yo(r mi. DABT Date Associate Directorof Research Study Director APPENDIX F CERTIFICATE OF ANALYSIS 418-027:PAGE F-1 Certificate of Analysis N-MeFBSE [C4FsSO,N(CHs)CHzCH,OH] 41-2601-1878-5 Lot 6 30 January 2002 Gibbes Bailie Sample puri - 95.55% t`Tehcihsnisqaumepsl.e Twhaes raensaullyszeodf tushiensge tGeCs,tsGsCh/oMwS,thaLCs/aMmSp,la"tHo-cNoMnRt,aianntdh 'fFol-lNoMwRinagncaloymspesosi: [ GHRSONCHH | oe3% | [ [ [ C CF C FS F SO S ON O NC N CH C | | HI H |J C IC H CH N H ooofoC sC O ase%%H H CO Y HH , H| || [c --r [ e <soppmo| CC Ghhso, | doppm | `Additionally, the isomer distribution of the C4 alcohol (C.FySO;N(Me)-CH,CH,OH) was `determined using '*F-NMR techniques and found to contain the following relative composition: [CFLCFCFLCFSONCHICH,CRORTinea | branch (CF3):CFCF;SO;N(CH,)CH,CH.OH [iso- 88% branch Gibbes Bailie APPENDIX G ANALYTICAL REPORT 418-027:PAGE G-1 FINAL REPORT AFNOALRYSSPIOSNSOOFRD'OSSSITNUGDSYONLUUTMIBOENRS TU-S75E9D9.A7 T(AARRGGUUSSRREESSEEAARRCCHHLLAABBOORRAATTOORRYY PROTOCOL NUMBER: 418-027), SOUTHERN AS362 RESEARCH INSTITUTE STUDY STUDY ID: A5362 SPONSOR STUDY NO. T-7599.7 (ARGUS RESEARCH NUMBER: 418-027) LABORATORY PROTOCOL Southern Research Institute 2000 Ninth Avenue South P.O. Box 55305 Birmingham, AL 35255-5305 Study Initiation Date: 3/15/02 Study Completion Date: 2/12/2003 Experimental Initiation Date: 3/11/02 Experimental Completion Date: 6/14/02 1 418-027:PAGE G-2 SUMMARY dAlolsesasmapmlpelsesweirncelaudnianlgyzveedhiacclceosrrdainnggitnogainnalcyotnicceanltrmaettihoondfrBoAmCG0-t3o52952.mgA/mtLotawleorfeanfaolrymzueldatteod determine the 10 day stabilityof1-Butanesulfonamide. 1,1.2,2.3,3,4,4,4-nonafluoro-n-(2hsyadmrpolxeyseitnhcyllu)d-iNn-gmveethhiyclle(sT-r7a5n9g9i.n7g)ininctohnecefnotrrmautliaotnefdrmoimxt0urteo.25Amtgo/tamllowf8erefoarnmaullyazteedd tdoose: dfeotremrulmaitnieocnoancteontatlraotfi2o4noffoTr-mu7l5a9t9e.d7dionsethseafmoprlmeuslaitnecdlumdiixntgurvee.hicTloestersatnfgoirnhgoimnocgoennceeinttryaotfiodnose bfortotmo0motfo t2h5emfgo/rmmlulwaetreed aminxatluyrzee.dtSoadmeptleersmiwneerecosntcoernetdrartefiroingeorfaTte-d75a9s9p.e7risnpotnhseotro'ps, smhiidpdpliengand recommendations. For the 10-day stability, study samples were found to be within 11%of the dcoanyce1nvtarlauteisonexbcuetpttwifcoret(h2e054%mga/nmdL19sa6m%polfesDwahyic1 hvwaelureesw)itthhatinfo+un1d5o%nofdtahye1.exFpoercttehde ddoossee analysis, | mg/ml dose formulation samples were found to be within 15%ofthe reported c6o9n%ceonfttrahteioenxspebcuttetdheva5luae.nd F2o5rmtghe/hmoLmosgaemnpeliestywesarmeplloewsetrhteh|anmegx/pemcLteadn,dr5anmggin/gmfLrsoamm5pl5e%s to were lowerthan their expected concentrations ranging from 55% to 70%, but values between top, middle,andbottom samples differed by less tha+n 16%. The 25 mg/mL dose samples were within 16%ofexpected values for both concentration and homogencity between top, middle, `and bottom samples. 2 KEY PERSONNEL Raymond G. York, Ph.D., D.AB.T. Study Director Argus Research Laboratories Gregory S. Gorman, Ph.D. Manager Bioanalytical Chemistry Group Lara Cook, M.S. Research Associate IT Bioanalytical Chemistry Group 418-027:PAGE G3 3 418-027:PAGE G4 1.0 Objective o`fThdeoosbejefcotrimvueloafttihoinss s(ttoupd,ymwiadsdlteo adnetdebromtitnoemthseamsptalbeisl)ityo,fd1o-sBeutcaonnceesnutlrfaotniaomni,daen,d homogeneity s1o,l1u,t2i,o2n,s3,r3e,c4e,i4v,e4d-nfornoamfltuhoersop-onn-s(o2-rhaynddroxtoyectohnyfli)r-mN-tmheethiydeln(tiTt-y75of9t9h.7e)tiensttshoelsuutipopnl.ied dosing 2.0 Safety tAhlel MnaetceersisaalrySapfreotcyedaunrdesDattoaeSnhseuertes,sapfreotvyoifdedthbeyantahleypstrsodwuecreerbofatshedeotnestinafrtoircmlaetainodn ctohentsatiundeyd in director. 3.0 Compliance "LTahbeosrtautdoyrydePrsaccrtiibceediSnttahnidsarfdisna(l2r1epCoFrtRwPaasrtc5o8n)d,uOctEeCd DinParcicnocirpdlaenscoefwGiothodtheLaFbDorAatGooroydPractices [C(97)186/Final], March 26, 1997). and The JfaipnaalnersepeoMritnaicscturryaotfelyHeraelftlehctasndthWeerlafwardeat(aMobEtWaiOnerddidnuarnincge Number the 21, performanceofthe study. integrityofthe study. There were no adverse circumstances that affected the quality or 4.0 Experimental 4.1 Analytical Procedures `BTAheCGsa-m3p5l9e2prweepraeraetmiponloayneddafnoarlyaslilsanparloycseedsu.reFsorastdheessctraibibleidtyinsttuhdeyaenaalcyhtiscaamlpmleetwhaosd avolrltoewxeeddtwoewlal rbmeftoorerobeoimngtesmapmeprlaetdu.reA, nwaaslisqouonticwaatsedtfaokrenabforuotm1c5amcihnauntdesdialnudtewdaass then dheosmcorgiebneediitnytshteudmiectsh,osda.mpFloersswaemrpeleaslltohawtedwetroecoanmaelytzoerdofoomr ttheempdeorsaetuarnealaynsidssaonndicated faonrd1s5onmiicnautteeds,fubrutthewrobuultdwnooutlgdonointtgoosoilnuttoiosno.luStiaomnpalneds rweemraeitnheednirnusnteuanddaersuhsoptenwsaitoenr. aTnhaelsyesissasmhpeletess. weMruletqiupalnetictaaltiibvrealtyiotnracnusrfveersrewdearnedprdielpuatreeddaosvdeerscarciobnecdenitnrtahteiocnhermaincgaelof 5T0h0e 0cor1r0el,a0t0i0onngco/emffLicainedntanfaorlyezaecdhacluornvgewwiatsh tehqeuaslatmoploersgraesadteesrctrhiabned0.i9n9t9h1e method. 42 Results The resultsofthe identity testing confirmed that the found spectra (LC/MS, FT-IR and "C the fNoMrmRularetsiuolntsa)nawleyrseescoanrseisptreenstenwtietdh (tThaebsluebsmIit- tVeIdI)sucbosrtraenscpeo,nTd-i7n5g99to.7t.hTe hspeornessourl'tss of study number at the endofthe report. 4 418-027:PAGE G-5 43 Calculations CthaelcduillauttieodndsowseerfeorpmeurlfaotrimoendsuasmipnlgeTsu(rnbgo/QmuLa)nwa(Vsebrsaicoknca1.l0c)u.laTthedeuasmionugnatcoafliabnraaltyitoen in ccuarrvbeoxgyenmeertahtyeld cferlolumalosseet(oCfcMaCl)ibarsatiinotnhestdainlduatreddssacmopnlteaisn.inTghtehecaelqiubirvaatlieonntcuarmvoeunwtasof egtecn.e)raantdedabmyouanrteogfrewsesiigohntiannagl.ysAisqtuoadderatteircmifnitewtihtehb1e/stX fwiet icguhrtvien(ge.wga.,sldienetaerr,mqiunaeddrattoicb,e the best fit: where: year+ bx +c = Peak area responseoftest article x= Concentrationofthe test article in standards. a,b, c = Constants derived from the regression analysis. 5.0 Storage A copy of archives. the final report and all raw data will be stored in the Souther Research Institute 6.0 Conclusion Awertoetaalnoafly4z0edT-u7s5i9n9g.m7edtohsoedfBoArmCuGl-a3ti5o9n2s.amFpolretshera1n0g-idnagyisntacboinlcietnytsrtautdiyo,nsfarmopmle0s1w0e2r5emfgou/nmdLto obfetwhietheixnpe+ct1e1d%doofstehceonDcaeyntr1avtailounebsuextcweipctef(or20th4e%5amndg/1m9L6%soafmpDleasyw1hviaclhuewse)rtehawtitfhoiunnd+ o1n5% (D5a2y%o1.fTehxipsecmtaeyd hcaovnceebntereantidoune)t.oFtohretlhoewdvoasleuaensalfyosuinsd, tfohre t1hmeg5/mmgl/dmosLesfaomrpmluelsatoinonDasaymp1les wweerree lfoowuenrd ttohabneewxpietchtie%dn, 1ra5n%goifntghferormep5o5rt%edtoco6n9ce%notfrtathieonesxbpuetcttehde v5alauned. 2F5omrgth/emL samples hcoonmcoegnetrnaetiitoynss,armapnlgeisngthfer1ommg5/5m%Ltoan7d05%mbgu/tmvLa.luseasmbpeltesweweenretopl,owmeirddtlhea,n atnhedirboetxtpoecmtseadmples differed for both by less than + concentration 15%. The 25 mg/mL dose and homogeneity between samples were within top, middle, and bottom 16%ofexpected samples. The values svaursipaetnisoinoinnreaxtpheercttehdancoinncseonlturtaitoinonasndmaiynstheaavdeobfeaesnsidsutiengtointhseolfuabcitlithtayttshaempprleessenwceeoreftinhea 1% CMC made the samples very viscous and quantitative transfer difficult to perform. DreaptraodpurceisbelnetebdasinedTaobnlersouIntdherdounguhmbVeIIrsardeisbpalsaeydedo.nVnaolnu-tersunfocrateeadchnummebaesrusreadndcomnaceyntnroattiboen are based on the averageoftwo replicates per sample. 5 418-027:PAGE G-6 Table I Day 1ofthe 10-Day Stability Study faoDor se Formulation Containing T-7599.7 1% CMC Sponsor Study Number T-7599.7 (Argus Research Laboratory Protocol Number:418-027) [Nominal| Targel | MeDaasyur1ed| Dose | Dose Dilution onc. |Conc.(mg/mL) % of concentration | (ug/ml) (ug/ml) Theoretical (Smagm/pmlLe) & [[T0@oorraa) | | NWAA [[NNoortddsetteedcitesed------ || --|| [(T@oo&r)) || 3300 || 2235 || 00s8 || 75 || Store) | 30 | 17 | 2s | & | 52 of 4) 25(of4) Fe |30| ara] [28o2 T E | 3r 0 | zs | aa % "Table I Day 10ofthe 10-Day Stability Study for a Dose Formulation Containing T-7599.7 1% CMC Sponsor Study Number T-7599.7 (Argus Research Laboratory Protocol Number: 418-027) [Nominal | Target|WessurDeda|y 10Dose | - Dose Dilution Conc. [Conc(mg/mL) % of %of Day 1 co(nScmaemgnptmlr)aet#i&on| (ug/ml) (ug/ml) `Theoretical [[0O@Toofr4s)) | | NWAA |[NNoottddestteecdlsead)---- -- ||-- || ---- (TTeorodr) | [[2232[[oo r ||7 s 75 || wm | [loa[3 30 [|30 s0a | | ss0e ||i foi || afme || Feo | 3300 |[2800 | |amar | | sm || toorr | 6 418-027:PAGE G-7 `Table ITI Dose Formulation Analysis ofT-7599.7 in 1% CMC Sponsor Study Number T-7599.7 (Argus Research Laboratory Protocol Number:418-027) Ey|| ER NoDmoisnsal ||TDiaon"|rMCgoensceosneradlon|ConcDeonstaeion|| oT | concentration| (ug/mL) (ug/ml) (mg/mL) Theoretical [roSatmaple.|NA_| nordetecied|=|=| Eriaerns | NmsA |[ notte o | w |ow | sTteroahy 3I 0 [E zr--| sa |e|| sae sors [30 |_| mr |e Sponsor Tables IV, V, VI and VII `Homogeneity Dose Formulation AnalysisofT-7599.7 in 1% CMC Stu dy N umber (In the T-7599.7 (Argus Resea sample ID, T =top, M rch Laboratory P = middle, and B rotocol Number: = bottom) "Table IV. Normal Veasued | Controls (0 mg/ml) Dose concensation Dilution | om) | maim)" Concentration|Concentration| Teo9%roeftca DorS(miagm/zmpLn)o.& | NA |rordetoced_| | CofatT sotra A--o"ranrcr o--nci|es|| t |e ] [0001 28) | NA |noTtdaobtloVeced| | =a| [NBoosem|iTnaDriagoentl|| CoM1nemcaegsn/utmraelldon|CDanucsensvain|| of 41: 8-027) S(mag/mmLp).& [ftror330z0n 2708 CC [Tor|s 30 om |[res 05 J LEA ; 418-027:PAGE G-8 Smgm Table VI [No|mTorgiel|nMeaasurels| Dose | coonDceonmstreaa'tion| gm) Dilution | Smelt. om) | moms oncentration |Concentration| [Th%eaorefrcal|| [B@loofizznn[[3200| | 7 r | 2288[| |wsms || [[SSoGroirzw[[3300 || Soare [30| 1189 20 || 29s2 || 8& || | se | er | toes) [30 | is | sz|e | `TableVII [NomiDnosael || TDairogno"l|| 2CWo5onscmesgnu/roamatlon| CDaoncseentv|sion|o7| cSohnocoromenvloant8.on| gm)| Geom) | amg [Thomrercal| fB(s@oorriznn|[3500 ]| 03 | 25G@oorriiaaM)[|2890 | | 237a || z2ss | Twios | [wseswooroe r|[ a503 || 250 90 | as | 0wms Calculated valuesare based upon non-truncated numbersand may not be reproducible basedonrounded numbers displayiend tables I through VII. ` 7.0 Approvals natch Lara Cook, M.S. Research Associate IT Bioanalytical Chemistry Group C Gregor an, Ph.D. Manager Bioanalytical Chemistry Group 418-027:PAGE G9 2-11-03 Date 2/11/03 Date Charles D. Hbert, Ph.D, D.AB.T. DSiarfeecytoArssessment Deparment Acom, A J RSaoydmbjDidreGc.toYrork, Ph.6.) BT. Argus Research Laboratories Date _(2-FeB-2002 Date , , 418-027:PAGE G-10 rQuaecor cityPFma,ssed occu. FRC (007 QUALITY ASSURANCE STATEMENT Final Report On: Analysisof Dosing Solutions Used at Argus Research Laboratory For Sponsor's Study Number T-7599.7 (Argus Research Laboratory Protocol Number: 418-027), SRI Study A536.2 Study No.: A536.2 LauidsietdedbbeylotwheaQeuatlhietyphAassseusraanncedrUniptrodcuerdiurnesthepesrtfuodrymdeedscbryibSeoduitnhetrhne rReeposreta.rcFhinIdnisnigstewetrheatrewperrteeidns(ptehcteedstaundyd iretorand management periodically Test Substance Characterization: Liquid Trspecion' | Date Management| DareoSyeDirecior me me Final (raf) Reort Review 1703-1903: 2303 12403 em | 3] we | oe "The resus presentedinthis final report accurately reflect the rw data. lCricy k. ACoQualo ity Assurance Hos APPENDIX Hl TEMPERATURE AND RELATIVE HUMIDITY REPORT 418-027:PAGE H-1 ARGUS TemperatureLoacnadtiRoenl:atRioveoHmu0m1idity Report | Protocol Number: 418-027 Rangoef Dates: 12-Feb-2002 13:35 to 13-Apr-2002 09:59 EE -- | TTTSEpaorotgoietetstE R:taoRnagntte:tEobon. 1| o%f 66F to77F ohole 30%to 70% |i | NjptEuy--n: m7niste win| wa2#s wen | efRBmRatyRes 0l oA ErR aAtl we um oprGoer: 2-20 18 we CalA= one 6/55 umulative by Location (vMay-21-1999) APPENDIX I POSITIVE CONTROL DATA 418-027:PAGE 11 Historical Control Data `This Functional Observation Battery Standard Operating Procedure and Studies cAcotnidvuicttyeNdetgoatdiovceumCoennttrotlheDtartaainainngdaPnosdictiovmepeCotnetnrcoyloDfatthaeatreecahvnaiiclaalsbtlaefaft atnhde TMeosttoirng Facility. Page | 418-027:PAGE 1-2 Summary Information StudyNumber Tie for bl Ter Functional ObservationBattery Sat Subsunce ngDryogeoieformation NO0o1r2m00vs6 iVnagaPdtooersFTiotnrosAnt.v 19 bmi 0 17 pone 075 15 1 oor woo 0P1c20h14ao CmNonoVesti ASerTiSn gERariol wom 6 1s one wm 1s whom 5 oor woos a mn m0 51 D0o12r01h5ciNcoomRnAErrieoRne 2 oor wa 0PE120DC07NRaeVsSAToSosrocsiinyo C01o20i02nNCeLCrOSyR AEPvPiSlas R0C1ro2c0i3D1oCmoNmneVoASiaIabrBRaiaon of m2 aowme on ant oor omnis 10% eet Wome one oor opm 0 1 wm 1s ws so a 00 1 mos 1 8 1 ow wo a wo a + 11 Page2 . P0Co1s2Ci0e56CD-oNnVeBeuArRSBoPunbaRicsnyevsRatans io of Po01i2i0v7e5CNoenottSusbsaceEsvilnionof CHCDOBR VAPPIs Ras F0o1rt2i0n8e1C-oNnetvSounbcnyeEtvasion of CCDOBR VAPPIS Rots 418-027:PAGE 13 wes wobmie as 1 0 on ma s att 0 1 oor no 1 donphcamine 401 1 ws some 0 1 n vinhin 81 ' Meson 0s | ES | oor wo 2 1 wo somme 0 1 0 ex ma ' Pe |' abot ws ' oor w 2 s Page3 418-027:PAGE 1-4 Summary Information Suu for wSiari MotorActivity ShTewr e rDyogsnmyomen aSSootpmeeer res. : "sm amas 1 c-- 14 s BAimrty woe wa om 3 wns w--or--- os w s3 a y i pLa , Amphetamine (PositiveControlStudy) dein Sunghdanise s1i241! ' m SSs i mn E n [-- eo +1 Pag4e , APPENDIX J HISTOPATHOLOGY REPORT 413-027:PAGE 1 RESEARCH PATHOLOGY SERVICES, INC. 438 EPahsotneB:ull2e1r5A.3v4e5n.e7,07N0e+wFBaxr.a2n1,6.P3A451.84930216 ORAOLFT(G7A5V99A.G7EW)ICTOHMTBHIENERDEPRREOPDEUACTTEIDODNO/SDEEVTEOLXOICPIMTEYNTSATLUDY TOXICITY SCEENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7509 HISTOPATHOLOGY REPORT RaymondSUG.BMYoIrTkT, EPDh.TD.O,: DAB.T. 9A0r5guSsheReehsyeaDrrcihve Horsham, PA 10044 SUBMITTED BY: W RWy. RBay pBrowon,eDVM,FPih.lD.ing sen Veterinary Pathologist February 25, 2003 418027:PAGE 1-2 `ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSORP'RSOTSOTUCDOYL 4N1U8M-0B2E7R T7599 HISTOPATHOLOGY REPORT TAOFBCONLTENETS REPORT Page MSHI ssmmmmtsmm-------- RESUS mm------ Quality ASSUTANCE UNit SLBEMENL ccs TABLE 1. Incidence and Degree of Severity of Histomorphologic OBSerVations................7 APPENDIX I. Histomorphologic Observations........................... nsssssmrnnsssenn 1 10 13 Key 10 HiStOMOIPNOIOGic OBSEIVANIONS cvs Tables 1-1.Histomorphologic Observation-s Group | Male RaS........................2 1-2.Histomorphologic ODSerVations - Group If Male RS.........................14 1-3.Histomorphologic Observation-s Group lll Male Rats........................1-5 14.Histomorphologic Observation-s Group IV Male Rats .......................6 1-6.Histomorphologic Observations - Group | Female Rats ..............cccccwuuuuernnn. 1-8 11--67..HHiissttoommoorrpphhoollooggiicc OObbsseerrvvaattiioonnss -- GGrroouupp IIlll FFeemmaalleeRRaattss ..............................................l.-11-110 1-8.Histomorphologic Observation-s Group IV Female Rats......................-12 Il. Individual Animal Gross and Histomorphology Data......................I1- TO 11-80 413-027:PAGE 1-3 OWRIATLH (TGHAEVRAGEEP)ROCDOUMCBTIINOEND/RDEEPVEEALTOEPDMEDNOTSAELTTOOXXIICCIITTYYSSTCURDEYENOIFNTG7T5E0S9.T7 PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT METHOD 40 Microscopic examination was made of the specified female CH:CD(SD)IGS BR VAF/Plus rats in an tissues from 40 male and oral (gavage) combined repeated dose toxicity study of T 7599.7 with the reproduction/developmental toxicity screening test. A brief outline of the study design showing the dose group identifica: tion, dosage levels of the test and control substances and number of male and female rats examined group are shown below. CT eee [ew 0GoRsOAUGPE|| POEFRRSAETXS DOghSgAiGdaE | CONCENgTiRnATION | VO(mLiUgME [[ov eTe e ] [[oo e Jee [we] [[v = [| =o [| | TG ost SubSTanca Was cansdared be TOUS: Sevefor1purpessofdosage CAouaLons. The rats were given the test substance and/or vehicle beginning before cohabitation, through mating and continued for at least 28 days (male rats), or through parturition until Day 5 of lactation (female rats). Dosages were adjusted daily for body weight changes and given at approximately the same time each day. Scheduled sacrifice of male rats was on the day following the last dosage administration, aftear minimum of 28 days of dosage. Scheduled sacrifice of female rats was on Day 6 of lactation Al rats were necropsied and the specified tissues were collected and placed in 10% neutral buffered formalin for fixation. The testes were fixed in Bouin's solution for 48 to 96 hours and then retained in 10% neutral buffered formalin. The in-life portion of the study, necropsies, and recording of the gross necropsy observations were performed by the staff of Argus Research, Horsham, PA. The tissue processing, microscopic slide preparation and histopathologic evaluation were performed by Research Pathology Services, Inc. Research Pathology Services, Inc. a 418-027:PAGE 1-4 OWRIATLH (TGHAEVRAGEEP)ROCDOUMCBTIINOEND/RDEEPVEEALTOPEMDEDNOTSAELTTOOXXIICCIITTYYSSTCURDEYENOIFNTG7T5E9S9.T7 PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT rats of GTrhoeuptsis|suaensdspIeVciifniceldudfeodr: mbircarions,cdopuiocdeenvaulmu,atjieojnufnurmo,m the male and female ileum, cecum, colon, rectum, Peyer's patch, lung, submandibular and mediastinal lymph nodes, sciatic nerve, stomach, kidneys, spleen, thymus, trachea, urinary bladder, testes, epididy- mides, seminal vesicles, coagulating gland, prostate, spinal cord (cervical, lumbar and thoracic), liver, adrenal glands, heart, thyroid, parathyroid, uterus, bone marrow (sternum), ovaries, uterus, vagina, mammary gland (female rats) and all other tissues with gross changes. In addition, the liver of male and female rats, stomach of male rats and thymus of female rats were examined from the intermediate dosage groups. Representative samples of these tissues were routinely processed, embed- ded in paraffin, evaluation. sectioned, and stained with hematoxylin and eosin for microscopic Upon completion of the project, all raw data (remaining wet tissue, paraffin blocks, microscopic slides and histology records) will be returned to Argus Research for archiving. Research Pathology Senices, Inc. 2 418-02T:PAGE J-5 OWRIATLH (TGHAEVARGEEP)ROCDOUMCBTIINOEND/RDEEPVEEALTOEPDMEDNOTSAELTTOOXXIICCIITTYYSSTCURDEYENOIFNTG 7T5E9S9.T7 PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT RESULTS The type, incidence and degree of severity of the histomorphologic changes in the specified tissues for the male and female rats are presented in Table 1. The `microscopic observations in each rat are summarized in tabular form in Appendix | (Tables I-1 to 1-8). A key to the histomorphologic observations precedes Table I-1. The gross necropsy observations, detailed descriptions of the microscopic observations, and a correlation of the microscopic findings with the gross changes in these rats, when applicable, are contained in Appendix Il. No treatment-related microscopic changes were observed in any of the male rats given 10 mg/kg/day or in female rats given 10 or 50 mg/kg/day of the test substance. Treatment-related microscopic changes were observed in the liver of male rats of the 50 and 250 mg/kg/day dosage groups and female rats of the 250 mglkg/day dosage group, thymusof female ratsof the 250 mg/kg/day dosage group and stomach of the male rats of the 250 mg/kg/day dosage group. The treatment-related microscopic change in the liver consisted of minimal or mild enlargement (hypertrophy) of centrilobular hepatocytes in most male and female rats of the 250 mg/kg/day dosage group and in 4/10 male rats of the 50 mglkglday dosage group. The enlargement was due to an increased amount of finely granular, dense eosinophilic cytoplasm. The incidence and severity of the change occurred in a dose-related manner. Also, in three of the affected high dose male rats, necrosis of individual enlarged hepatocytes was seen in centrilobular areas (Table 1). The treatment-related effect in the thymus consisted of an increased incidence and severity of atrophy of the thymic lobules in female rats of the 250 mg/kg/day dosage group. Single incidences of thymic atrophy occurred in female rats of the control and lower dosage groups, but the increased incidence and severity of this effect in the high dosage group was considered to be treatment. related. Microscopic examination of the stomach revealed focal erosions in the pyloric glandular mucosa of two high dose male rats. Although the incidence was low, this Research Pathology Services, Inc. 3 418-02TPAGE 6 OWRIATLH (TGHAEVRAGEEP)ROCDOUMCBTIINOEND/RDEEPVEEALTOEPDMEDNOTSAELTTOOXXIICCIITTYYSSTCURDEYENOIFNTG7T5E09S.T7 PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T7599 HISTOPATHOLOGY REPORT change may be treatment-related. Other changes observed in the stomach which occurred at a somewhat varied and sporadic incidence in the control and compoundtreated male rats included edema with or without inflammation (infiltrations of polymorphonuclear inflammatory cells) in the submucosa of the glandular and nonglandular (forestomach) areas. The very slight increased incidence and severity (Table 1)of these changes in these areas of the stomach of the high dose male rats may also be treatment-related. However, these changes were not clearly associated with the erosions. All other microscopic changes were considered to have occurred spontaneously and to be incidental and unrelated to compound administration. The type, incidence and severity of these changes were not influenced by compound administration. These changes also are listed in the attached histomorphology tables. One high dosage group male rat had early lymphosarcoma in the spleen only. There was no evidence of disseminated involvement. Although this is a Group IV rat, it is still considered to have been incidental and a spontaneously-occurring effect. Research Pathology Services, Inc. + 418.027:PAGE 1-7 `ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 `SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT SUMMARY Microscopic examination was made of the specified tissues from four groups of 10 male and 10 female Cri:CD(SD)IGS BR VAF/Plus rats used in an oral (gavage) combined repeated dose toxicity study of T 7599.7 with the reproduc- tion/developmental toxicity screening test. The four groups of rats had been given 0 (vehicle), or 10, 50 or 250 mg/kg/dayof T 7599.7, orally by gavage, once daily for the protocol-specified numberof days. given 1N0omgt/rkeagt/mdeanyt-orrelfaetmeadlemircatrsosgciovpeinc10choarn5g0esmgw/ekrge/doabysoefrtvheedteinsttshuebsmtaalnece.rats rats ofTrtehaetm5e0nt-arnedlat2e5d0 mmigc/rkosgc/odpaiyc dcohsaanggeesgrwoeurpes oabnsdervfeedmaline trhaetsliovefr tohfe m2a5l0e mg/kg/day dosage group, thymus of female rats given 250 mg/kg/day and stomach of male rats given 250 mg/kg/dayof the test substance. The treatment-related effect in the liver consisted of minimal to mid hypertrophy of centrilobular hepatocytes in the mid and high dosage group male rats and in the high dosage group female rats. A low incidence of high dose male rats had individual-cell necrosisofaffected centrilobular hepatocytes. severitTyhoef tarteraotpmheynto-fretlhaetetdhycmhiacngloebuinletsheinthfyemmaulsewraastsaonf itnhcerehaisgehd dionscaigdeencgeroaupn.d There were single incidences of atrophy in each of the control and lower dosage groups, but this increased incidence in the 250 mg/kg/day dosage group was con- sidered to be treatment-related. The treatment-related change in the stomach in male rats of the high dosage group consisted of a low incidence of focal erosions of the pyloric glandular mucosa. A varied incidence of edema and inflammation of the submucosa of the nonglandular and glandular areas also was observed in a few rats at a slightly higher incidence and severity in Group 4 and this may also be related to compound-related. All other changes were considered to be spontaneous in origin and not treatmentrelated. The type, incidence or severity of these changes were not considered to be influenced by administrationof T 7599.7. Resoarch Pathology Senicos, inc. s 418-027:PAGE J-8 `ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT QA UALS ITYSURUA NITN STAC TEME ENT All aspects of the tissue processing, microscopic slide preparation, histopathologic evaluation and report preparation for the study listed above have been performed according to the Standard Operating Procedures of Research Pathology Services, Inc. and were audited in accordance with the procedures established by the Quality Assurance Unit of Research Pathology Services, Inc. in compliance with the regulations as specified in the protocol. Quality Assurance inspections were performed on 04/08/02, 04/12/02, 04/18/02, 04/19/02, 04/23/02, 04/24/02, 05/22/02, 06/05/02, 06/07/02, 07/10/02, 07/11/02, 07/12/02, and 02/25/03 and findings were reported to management on 04/30/02, 05/31/02, 06/28/02 and 02/25/03. There were no deviations from the protocol, Standard Operating Procedures and/or appropriate Good Laboratory Practice regulations noted during the conduct of the study that had an impact on study integrity. The summary report of QA inspections is included in the final report submitted to the Study Director on February 25, 2003. Tr ---- Karen W. Harkins, BS Quality Assurance Unit ses Date 418-027:PAGE J-9 ORWAILTH(GATVHAEGER)EPRCOODMUBCITNIEODNPRDREEOPVTEEOALCTOOEPLDHE4DN1OT6SA-EL02T7OTXOIXCIICTIYTYSTSUCDRYEENOIFNGT 71658375.7 SPONSOR'S STUY WMGER 1-759 ee 1 Incidence and Degree of Severity of Histamorphologic Observations seNxita of snimalaforon W0 owlo lo P0 ETo Elo A fo A30.ENOL "ipnfiiltgration,monomuclear-cell, "viiacnuoelation, cortex S00..00hBwoaawsawlous (sre s0i.anBy unnie o00..meSNoRniAeLs "innifllammation, mucosa, chronic S00a. tNsOoaRMnnALge avo: 0c0..oonMG, RaLne o00u..oohEpuoim;men 0NO.p. r0OOfmRoimLteesd "innfiilmtration, sononuclear-cell, p080..agoiwenAsle: deirmeatitis, ulcerative, focal matifocs] focal oo0o 00sow (A 0) [0] (0 0] P Toebowwoy wEEoRoE 0 1 ooo6 00 ooww ooo0 00 oomm wToooe o0 o 00000 00 oxm 00000 00 11 Boooo 0oo ooww oo0o 00 1 22) 9[0 (R0) h(1) S0 50 00 01 ow o9@ o0n $oo0o 0o ooww [ToAoOR9N9] CeRNoO5RNOaoRNoC]0 wooo 0o o1w 0o0o0o 00 o1w w0o0o0 00 xom ooon 0 000oo o0o 1ow Bwoooo 0o m1. oeeo 59 00 00 O o0 o0 o E0. eovanl $oo0o 00 8om TT otaT Trerdence of specified Testor, aM grades ooo5 9a om a 418.02:PA1G-1E0 ORAULT(GTAVEAGREb)soCnOiMBINED RRSEEePVEtLToaEDmE1ONaST-EdLeT)OONCAITLY STSUeDYmen1 T7e5o6r8.7 SPONIR'S Tir NER T7538 TLE 1 (contin Incidence and Degree of Severity of Wstomorshalogic Observations SNBooereofsfoim1ofiroe: PT 0 EmfAfmm PT0 TrGo oIimo io SET (Contam): p"iInffailsaem)ation, sibscte, focs/mititeen 0vT1 eeo@ e(0 0) Wa w Pbeeoom peSrinciarrditis, chronic, focal w? oeeeno WHoEme pRo. eNonmae woo88oo 8ow w5o8o 0o owwn TasofBowile 6o0 oo0ow ooso0 o0w rT6. orNanoe oo8 o ow do0o 0oo ow eps), meta 0 oo oe 00o ~diiatation, pelvis wPweeesoo ERPC ey edmen.apapiiary wPoem eooo voq e oo "infniilntartation, oneal, foPul) e e [w0 WCE we oo --sinmerraltzation, multifocal WLRw ww w ?Rm 9RY neiphr)itis, chrntc, foul w e Pen Pwweyo Fimyeti, crane WPme eooy w wveeyow ~acuaglation, cortical tular within 07 PR Y(0) wvmeeoe ow ivehen EvR ow pow EonEoEw ow p"hremiteopdotesis, extramedullary, satifeen (0 ee(0) s1 wPowym TT Tora revdeee ofsperfied Toston, aT gradi 418-027:PAGE I-11 RAILTH(GTAHVEAGER) CEOUBPNESODONTRDDEEPRVEAOELTLETIDWEEObNTSTeAEL)TOTKOICRIITYISTSUCDRYEEGNFINTG 17655978.7 SPONSIR'S Sub Kaen 17598 THLE 1 (contin) ctdinc and Degree of Severity of Wstamsrpolaaic Observations SEWoatreof oimnlyGro PTotTEo Emlo F P 0 TE fo iT fo mdo LIVER (Continued): "phepietrstryoshy. hepatocellular, cantrilobatar 1T o[o w(00 s(0) w CTCseoe2 "ipnlfalianmga]tion, chronic, foat/mitifonsl 0T?1 o@gde(8 d6) 9Tboewne6os "ptdonts, tenon, focal 1 oa 00 ecirnovsetnst, foes) W ww meoyo wPoew ewsw crioarsase. dividual hepatocytes R o0C o0dm w w95 eQ0 Qoo acenlaitaion, hepatocellular, mati Po[0] y(0) wPeeee oo ~wacwvoelnattion, hepatocellular, periportsl 1P) e e(0) 01 WTmeooyow wlRoo. o:obmae S0o 8ow 0ooo ow nflraimoantion, interstitial, mati (PE @eu01 w Pewee s macroophnages.alveoli focal WT w eoyw wPweee om TToov.rosomwoan scorssri: sP00 00 ow 5$80 80s ~cponigasoti)on/erythropagecytasis wyoeboeoo i WePo e0e0m2e ptpesrtasia, hooperplammer HEE [0 wPweew oyo eip -- w Em E 0 CPECPE R N fTop.iooobmoats, Susman se EoEoE o ow wroooo e ow TT Tor Trerdenes oF speed Teton a grades a 418-027:PAGE J-12 ORWAILTH(GTAHVEAGREE)PRCOODVUBCITNIEODNDPRREEOPVTEEOALCTOOEPLDHE4DN1OT8SA-E0L2T7OTXOIXCIICTIYTYSTSUCORYEENOIFNGT T7e558T8.7 SPONSOR'S STUDY NUMBER 17-7599 THBLE 1 (Continued) Incidence and Degree of Severity of Wistamorpholosic Observations TSHweixmieesoofwAnimala/6roup: W1 o0wkmWoN 0 lo lo do TForOn Jo do 15H NODE, SUBMANDIBULAR (Continue) "hmyiplnedripallasia, Impocytic/lumentic (38 2 (00 0 [00 0 (96) 1 vo 30 Poderate 50 0 i :0 mN0O..aNyOiR6NAam: Loo0 "hyperplasia,physiological woo "ihnfalamation, subacute wToooo N0R.EB, iscdiac; Xo. MoRL wBoooo o9o 11 oo o0NO..weENsoOR.mMAL woooo Np0oa..aTnOIvoWRNOlIEDD: owoooo 0osos ooo WNpoOE..vBERO'AsRpAaDLrce wooooo 00 8ow wBoooo "minenriaallization o o0 o0 n1 NpoR.ostEaxTmei.nED Xo. hol 5woo0 0oo 6ow p"atirop]hy. focal wTooooo0 o1w "infnlaimemtation, chronic, mutifocel wToooooot "pFroorskteatditis, suppurative W o0 o0 o1 Na0o:s.cnBo.owenrled soo o0o 81 00oo moEWE lo 10 0 1 00 s 0o 0ow oo ow E90 w oo 1ow 0os9 0o o1w ooo w1 0 00 o1w TT ToT Treidence of spectied Tesvon, aT grades 0 418-027:PA1-G1E3 GRVAILTH(GTAHVEAGER)EPCOOUDBEITNIEDONOROEEPTVEAOETLELIDWE3ON1TS5AE-L62T7OTKOIXCIICTIYTYSSTUcDRYEE0NFIN1G 17655978.7 SPONSOR'S STUDY WBE T-7588 THLE 1 (Contined) Incidence and Degree of Severity of Mistosorshalagic Observations Eee TT Wm TT mT SHeiximeoofPsnteu1s/6ran: HobOMTo NDo N F0 OFfo Ffo Ffo RECTIM(Continued): -edemraa/inneflammation, submucosa parastte(s) sa.uaoemacvestues: m Po eeOo r 00 oe 0 woo50oo 0wm o?m eR e 000 SP00.INAfELoiCaOnRleDs,CERVICAL: Sfloo.omomncaosm, mess [6a. ooEauapiies isaa ufBeoealo v05 00 ow vo6 o5 o8w wWooooo0 o1w 8 noo0odw woosoo0 ow vo8 8ow0 RwIoEo o ow Bo5o 0 ow atTroaphy om To u @ 90wm heamanetiopmoiesis, extramedullary, increased "ympossrecns Yo. homyea ~Smpliiantoaitmton, reo stands aadrreemienlflammstion, submcoss, glandular maodaerate (L0) A[0] DECI [Q0] u[1] EvoElAo ow FCOoUoiewni wFPI oeew 00 2 W 3P0O eem 0 Boa 000 Soo50own wP EAwoeyo @TCE woo 50 50 TT TouT TrevdeneosFsperFied Tesen, aT grader - 418-027PAGE I-14 ORWAILTH(GATVHAEGER)EPRCOODMUBCITNIEODNRDEEPVEEALTGEPDWEUtNTSAELeTOTXOIXCIICTIYTYSTSUCORYEEONFIN1G 17650979.7 SHNSOR'S STUDY WAGER 17-7599 THLE 1 (Contin) Incidence and Degree of Severity of Mistamarghalogic Observations Sort mew PI EIT EIm WTETA m Meberoffmlyes lo lo lo lo jo do lo fo STOMCH (Continued): edAFenmtyaesi]nfomation, submicoss, nonglandlarwpoow ooo YoE Rnoidlearate @oe 10 00 di O o0 oi 0 o0 e000 p-eeraoisiid)on(s), glandular micosa p00"reybAagmone m6Ho. shEsonwnlo 5B0o0y@1 80 00 00 00 0no5o 0oo 1ow ooo0m 9o 0 0o0 S 0 00 00 11 T020..vsMB:oivnnaey 006oo 05 1ow 8 no.8odns aStiiortnoetprheayte m030..oMsEo:iannae "Ehyipertrophy, follicular epithelium tisbranchial bady/eyst 20j0:. eMEonnae e [OI C0 0 0om Fooeo s0 ow [PICe ICw I] soo 0 3 @00000 onwo meovo ooomyew o0o o2ai BPooee0 sow OCCwe oo 50 0s 6no5o 0o ooww ipnfiltaamsma)tion, chronic, focal 1106s..euohsomswnoleusst; r00.esih:annae w Pmeoewow woo550 iow vw Ew 0v6o 50 o1w wo0o 0o ow TT = Tort rerdenes of speetFied Tester. grader EY 418-027:PAGEJ-15 OREALTH(GTAHVEAGER)EPCROONDLICNTEIDONPR/REDOPETEVOAECTLOEOLDPED4NO1TS8AE.L62T7OTXOIXCIICTIYTYSSTCURDEYEONFINTG T7E550T8.7 SPONSOR'S STUDY NMGER 1-7598 TLE 1 (Continued) Incidence and Degree of Severity of Histamorphologic Observations sNoixmberGeofeAnimsls/Groun: W1ooTwTlo oWWJo WokTo F10 oEIjooEIlo Wlo UTERUS (Continued): "dPmioisdnteiemrnaatltioen, Tumen "hmenoerrhage, endometrium "inaflammation, endonstrium, diffuse "eaaclnrdoipehages. pigmented Foderste ~thronbus w0HO..imOE,RuALn "imnofdlearmamtaetion, acute "ePouadcrtekfrieacdtaetion w roooooo0 ooo1 ooooo o0 oo1 o5 o0 m0 ow1 CeTIooCoIC00IO]22 Too o os 200 8 0o 0 We5o0O 0oo 81 0 o1m o00 e01 TT=TotalTrctdenceofspectfiedToston, 3M grades 2 418-027:PAGE J-16 OWRIATLH (TGHAEVRAGEEP)ROCDOUMCBTIINOEND/RDEEPVEEALTOEPDMEDNOTSAELTTOOXXIICCIITTYYSSTCURDEYENOIFNTG7T6E9S9.T7 PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT APPENDIX | HISTOMORPHOLOGIC OBSERVATIONS 418.027PAGE 1-17 PROTOCOL 418-027 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT - = * = <> = <> = XM = P= 1= 2 = 3= 4= SS = KEY TO HISTOMORPHOLOGIC OBSERVATIONS cNhoacnhgaenngoet (pnroetsernetm)a.rkable, within normal histologic limits or indicated Tissue not available (specified tissue missing, insufficient tissue in plane of section, artifact precludes evaluation, or specified tissue not present in section). Microscopic finding(s) in tissue(s) with gross observations). Within normal limits [no microscopic changes) to correlate with the gross observation(s)]. Primary malignant neoplasm present. Indicated change or lesion present Minimal degree or amount of indicated change or lesion. Mild degree or amount of indicated change or lesion. Moderate degree or amount of indicated change or lesion. Marked degree or amount of indicated change or lesion. Scheduled Sacrifice 1 418-027:PAGE I-18 ORVALTi(GTAEVER)ERCGOBMLBCINTEIDONREPDPERELAOOTPTEWDOE0Nd0T1AEaLc0T2OT)NBIICEIITTYYSTSUCDRYER0IFNG1 T7E5S8T8.7 SPOUSO'S STUY Wrath 17599 Tale 11 Wstamarpralogic Ghservations SSoarree)EtReudnoar: Death upe ELDosETLis S% TT130TTrest % TTresesTraTsa 1rsssee J1Ts7essTLeeTsss 1r6s0 0% 58S 5 sEone om to. 1 oo. S008 wag (sremu; me ee ees... mam Se aL fimation, mon, chrome Se ee ee... coun es L s"feirlotormaotiso.n, meonclear-cell, focal sSofr mt, ate, fesmttieest en ean aSeadteelanst:atipoanp,itfpoerlyvis BE "uCvnualmcm:aattiioonn,,hecphsrtoonciecl, affaore,al/paetriipfooreisall wSineflamtion, fnterstitiol, matifoeal "Coonrgesotoki,oneorytnhropimagscytosts Lsopnueeeinmoannen,,pioatuiucsiel.esmetic agave, scare paaarivaon: - - - - 1 - oq. . - - -o oa LLL Se es eee es. 0 2 ee ee aoe a D eoe ntenonoee. 1 o2 o1 p1-o 1foto1 =.Tt4 1 - - ooo oo. Se ee << <2 1 z= 1-1 - ee... fs ete eee eo stmrosoTpre. focal rv 2c eee os os 2 418-027:PAGE J-19 ORVAILTH(GTAHVEAGER)EPRCOODMLBCITNIEODN/RDEFEPRVEoEArLToEOcDoPlWEDNO4TS1AE8L-0T2OT7KOIXCIICTIYTYSTSUCDRYEENOIFNTG T7E5S9T8.7 SPONSOR'S SOY NNGER 1-758 soBaxma)edNbeer: Bath Tee. P"RiOnSfTlAaTmEmati(oCno,nticnhureo)nic, sultifocsl aSceErE nramation, simucoss Sou vesicLes SPINAL como, csv Seu con, yous: THBLE 1-1 (Continued) Histosorpholeaic Observations 7I 608 T1761T8 17630 T 17831T178T39 17648 J1eT765T2 17e6s5e6 eT1se65T8 17650 $05 0% 0% SoS SS + 2 + 2 oe oe aq os oa Sea a =e LLL. 2 ee sae ee os = + 2 2 2 a aoe oso seueen "S"edtdioelmawtaea,itinofnl,ammaotisosn), Sgulbamnudcsoss. glandular "erndoeenmsgaliannfdluatmamratairoena, submucosa, estes: -- e"ulEtinaybra.nchiaftolbloidcyu/leayrsteithetiin Riinfgleanm.mation, chronic, focal RINARY BLA00ER: EE Sore oa See oo LL sx bee os ioe eo 2 =e 2 ee a ws ex 2 s+ a x oa oe oo PSoosllszRIaT.T .n . 2 + = + + = + ow oa = 2 + + sox aoe oe os =) 418-027:PAGE 120 ORWAILTH(GTAHVEAGREE)PRCOODIUBCITNIEODNRDEPERPVOEETALOTOCEPODNLEON4ST1EA8-L0T2OT7XOIXCIICTIYTYSTSUCDRYEENOIFNG1 7Te5o9T9.7 SPONSOR'S STUOY NBER 1-759 Tae 12 Histonorphalogic Observations wSAonxi.moal Nmumber: H N 17634 1H T 7635 1H 7638 N1784N2 17843 T 17645T1764T9 17651 1T7653i17655 Besih Type: SS sos Ss Ss SS & 8 Ss i"ltiupniedasfis,ltenacshiromonn,iacf,ocftaolcail/moiltnifo,csl s1 o1--s2o 2 1 T 1 - d = 1 "vacuolation, hepatecellular,periportal 1 Lo 0-1 s""eaodioTonanst/a,itnifolna,mmmuactoiuosn),glSiabnmdcsoss, Se ee eo TongTandutar ares See eos 4 418-027:PAGE 1-21 ORWAILTH(GTAHVEAGER)EPCROONDBLICNTEIDONR/REDEPOVEEATLTOOEPD!NEDNO4TS1AE6L-0T2OT7XOIXCIICTIYTYSTSUCRDEYEONFINTG T7E5S8T8.7 SPONSOR'S STUOY NBER 1-7599 TLE 1-3 Histosorprologic Observations soTAnxiomaSl Nasser: Besin Tune F1I7C62A0 R1T7T62A3 1AT762E7LA17828 a1M783I3 a17T640T17646 17650 1T7657T17659 SS Ss S55 55 5% % 8 q"ueeimr:tnropfhy.lhcehopartomonciecal,lfuotlcaarli,/cmeointtirnfiolco,sbuilar =1 =1 11 =11 -- 11`. oi i "pe"adieTmaotaatiinofnl,ammmautcioosna,lglsaunbdmseos, glandular Pose eo oo ares To. - ee oe 5 418-027:PAGE 1-22 ORWAILTH(GTAHVEAGER)EPCROOMDBUICNTEIDONRDPEERPVOEETALOTOCEPODMLEONsST1EA6L-0T2OT7KOIXCIICTIYTYSSTCURYEEONFINTG T7e560T9.7 SPONSOR'S STUDY MUMGER T-7598 THLE 1-4 Histemorphologic Observations sAenximalGeNummber: Death Te: F7T6A21WA17622 $05 5W 12s%W162Ws a 17636 1W7637Wa 176sWL $1as6aLWearT%tress ASavcuoalatqiuona,:cortex Toe oa oa On aE (STERN: ses aso. oa. a ce aks aa... eSiIn0f1ioltmrianteison:, mnomclesr-cell, focal oSarnmaetistis:. ulcerative, focal sianfrl.ation, subacute, focal/miltifocsl fu = =~ =. +. . 1 @ = = oo... oj es 2 ee ae ea. r""eerisrtrelrsa]t,izmaetdiuolnlamtsfocs) Tepneicia, chronic. Toca uTinyfpelearmtartoihoyn,, hcehpraotnoicce,llfueleasrl/cmeinttiefiolesotbl|ar HCnieptlrodaotnst,sfoteesn!sion, Toca] "hecroata, individual hepatocytes wC"ansfsclreompmsatsieosn.,ativnetsetr1s.titfioatla,t ition "Co1ng4esOtOiKo,n eMrEyDtIhArSoTpImNaAgLe:cytosts LseTypneuroslpka,tsp, blmmeecti;chlesmetic NERVE, sciatic: SSooeoLe oo ebnoopbar.noo. nn . 22T =o2 ooo 2 o2oo b1cn2 p b23 r22o0 ? n2 1 Sos Inne tot = o- o<r1 =.on.o . se ee 2 ea ee. 13 1 2 =. 1 1. 2 + es oe ee ow 5 1 418-027:PAGE J-23 ORVAILTH(GTAHVAEGER)EPRCOODMUBCITNIEDONRDEPEPRVEOENTLTOOECPDOHLEON1ITS8AEL-0T2OT7XOIXCIICTIYTYSTSUCORYEENOIFNGT 71250975.7 SPONSOR'S STU hGH T7599 TABLE 1-4 (Continued) Histanorshologic Observations ESenx:teGeWimr: HW1762a1W1762z TWeesWLesW17636 W17637WT 17641 W1764R sWWea Lisse Death Tipe: 5 6 0% 5% 0% 5 SNE easarwaorD: Se SseSniErwe'rsariazvaotni:on See eee SeSritonrsfTiaaaprmE:a,tifoonc,alchronic, mltifocs] o. s4lo2 2 xIos. on 3 2 = "prostatitis, suppurative Tobe on bn fSaraesrite(s) [ Sou vesicuss: + = 2 2s + = 2 ow a sTThhpeemsothnoopsoatrecsaimss, extramedullary, fneressed "esSdaoeamtwaat;iinofno,mamtucioosna,l gsluabnmdcsoss, glandular ~eoadenrngeats/ainndfuotmaartairoena, submcoss. ~erasion(s). glandular moss a= = I <=I=I= = b1 on- o:- Soe ss 2 - Se ss ss. Spoose 1 oon2b 1. n.. rn `Si0TEmimabranchian badyfeyst ae; ET 2 = x eae a rr 418-027:PAGE 1:24 ORAVLITH(GTAHVEAGER)EPRCOODMUBCITNEIDONRDEPEPRVEOEATLTOOECPDOHLE0N01TS8AEL-0T2OT7XOIXCIICTIYTYSSTCURYEENOIFNG1 7Te5s9t9.7 SPONSOR'S STUOY INGER T-7599 THLE 1-5 Histanorshologic Observations isenxi:eatToNamber: p T76_81T1769T 0 1T763T4 17685 1T770T3 1eg7713 1Tm71sTs gIe me gTdm rmTrms Death Tine: Sos Ss SseosoS5%osos ASnRiAiLtnatoiaon., mrenelear-cell, matifocal =~ - - o-oo 1 oo Bn ww (STERN): aL, a te eee ee. s"poearri,carditis, chronic, focal an pSeuhnsera;tization, mtifocs) "Snievfcefreoismits,ionfo,calwoe, osetia "vacuolation, hepatocellular, maltifecsl ri"onafyclraompmmaatgieon,n,ativnetsetr1s:titfioacla,l mtifocsl "comnegsesntoipoe,ierwyetohirasoTpinnagacytosis h"epaecrloaphsatsees,. Bblmoonsenttiecdlploseeytic Serxia hewotms:ete s"SiynpfemlrasmtaaGtsuitaoann,:, phsyusbisocliotgeical ase, scraric fm pews paron: Se ee eee. "2 es se 2 oa oa toe. ere eee. o31 C2- 211 o 1o -Ct 1 1 : . IC P= r= y=.To= r. on. to. : Soo-aoo onoCnon0 on1 on1o1n 3 1 z= 3 1 2 1 2 a Pr roprpr p rp r ppgp "ee rss see. x + 2 + + + oa os = Ce ee ee eee rs 418-027:PAGE 25 ASnoixmGaleNmbr: Datnlee ORVAILTH(GTAHVEAGER)EPRCOODMUBCITNIEDONRDEFEPRVEoEATLTGOECPD0WE01N01TSE6A-L0T2OT7XOIXCIICTIYTYSTSUCDRYEEN0IFNG1 T7e5s9t9.7 SPONSOR'S STIOY MNGER T-7509 TABLE 1-5 (Continued) Histomorshologic Observations TE1768T 1E176E3T 0 17634 eT1768p5T177T03 E1771E3 1T71Ts T1e s T1mTma 5% 55sos sosososo os Sen com, cavicaL: Sei com, Less Sela com, Tomcic: sFeamsot;ipotests, ectromedillary, Sasitatoant;ion.mecosal glands m"tsro:phy HSiaEiom:osranchia sadyfeyst oe: isinaay uso: "omacersoaghstag.ees.in,pilgemnented hronous "pmcoietication foereased Ls... ALL, ere ee eee oe. 2 <2 2-1 oo "3 + ea xe. oe. EE TET LE tee ee ae a. =r eee eee oe. S DsIsIr 2ss s2op 3s 23 s ss oa Sse eee. BS) 418-027:PAGE 126 ORVAILTH(GTAHVEAGER)EPCROONDBLICNTEIDONR/REDPEOEVATETLCEOD,PEDNO1TS8AE-L0T2OT7XOIXCIICTIYTYSSTCURDEYEONFINTG T7E5S3T8.7 SPONSOR'S STIOY NNER 1-799 Tete 1-5 Histomorphologic Observations SSeoxm.aG)eNmeer: 1[M76A75TR17E679AN 17684 AsN ss 1A7T 698 1A7702 1N7708H1A7707 H1770T8 17730 Death Troe: Sos oS SS Ss Ss 6 Gs Gs "Srevecisr.omnre,ffolccalharonmfea,foteoli/moltinfoc,sl =S= o=o= n = 1 1.not "aTtoruosph,y See eee 0 418-027:PAGE J-27 ORWAILTH(GTAHVEAGER)EPRCOODBUICNTEIDON/RDEEPVEEALTOEPDWEDNOTSAELTOTXOIXCIICTIYTYSTSUCORYEENOIFNGT T7E5S6T8.7 SPONSOR'PSROTSOTCUOOLY 4N1U6M-B0E2R71-753 Tete 17 Histomorphologic Observations SSReaetnwa eNnrber: T[17L88A7 I1A768A3 I17C607 AN 17700TA17701 A1T770T5 T17a 706 17708 A a17718T1720 Bath Tee: 6S 8 & Sos oS wSeinflcharonmfca,fotcali/muoltinfoe,sl = 1 = 1 1 1 1 = = 1 ostsr:ay Se ee eee [= 418-027:PAGE 1-28 SeAextna)mgNumpber: Benth Tie: ORAILTH(GTAHVEAGER)EPRCOODMUBCITNIEODNRDEPEPRVEOEATLTOOECPDOMLEDNO1TSA6EL-0T2OT7XOIXCIICTIYTYSTSUCDRYEEONFINTG T7E5S9T9.7 SPONSOR'S STUDY MNGER T-7599 Hate 18 Histomorsholosic Observations 7AW68AsW17686 1AW758sWA1761 1W7632WA1769W6 17699 1Wa 71W172 17716 S05 8% 0&5 Ss & 0 & & & & sont wssow (sre sun EE 2 + % 2 5 a 9s + = oon So sCanflamation, suscute, focal/mltifocsl = = = = 1 = =. = ean Saienser:afization, multifocal Soiyceuioiltaitsi:onc,hrocnoirctical tutor epithelin p"i1enfrlaimmpathio,n, hcehpraotnoicce,llufleaera,l/cmeinttirfiolcsotblar HCwpaltcueotsattsi,on,tanhsetpoant,oceftoicsallar, periportal : ~YCoenpgehsOtOiE,oteErOyLtAhSroTpImNaAgecytosts LSTepeturpgioaomski,aN, DhrIeyUtRic:iplameytic wuapearasyTgasipa,;physiological see aL, SFE oaoC sss oC 1 2 IC =p1 o=1 o11 11o 1=o-o 1o1 2:o1b1 o2% Co 1 C1 IC So See 2 ee 33 2 13 2 3-2 Poe or ppp pp bop eaaaTHYROID SEtER's parc = a sos 2 oa os = a Cee ee eee IY A18.027:PAGE 1-29 ORAiLrk(GTUAEGER)E COMBINEODVREErPVEiENTcLEODoMESRiTEcALkTOTyXOIACISTTYYSSTeORYeeGvFng T7e5o8r8.7 Srovon'S STA Nae 17538 TLE 1-8 (ontined) Htomarshotesic Oservations T rfSrnyteeer: TFFs asETreW sW as JSse W sEreessEDWeoseeWLE {es rssE[LWrs ysWEfpri raE{niiEz 11a [p---- - s+. -- sou com, nescrc Co a JsyATR NOE stougs . onwse, faa.ction sores pr ---- uFSoriutso:hnas, etuanterion mmeearaotuos,nsaomnmiest, diffuse FE SS : o Co on FE Chee cee FE PE SS sooeo E2sC 3 a3 zs nr EPEid s TEs as BBiulttton. acute T Ceyeoe ee a. ws 418-027:PAGE J-30 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T 7599.7 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-027 SPONSOR'S STUDY NUMBER T-7599 HISTOPATHOLOGY REPORT APPENDIX II INDIVIDUAL ANIMAL GROSS AND HISTOMORPHOLOGY DATA 413-027:PAGE 1-31 ORAVLITH(GTAHVEAGREE)FRCOODMLBCITNIEODNRRDEEOPVEETALTOCEPDME04N100TS-AE0L0T7OTXOIXCIICTIYTYSTSUCDRYECOHFNG1 7T5E9T9.7 SPONSOR'S STUDY NONBER 1-750 Individual neal Grsoospsenadnis M11stomorghalosy Data 5Axa ner: W17508 DoEsAeTHsToYoP:E, S1 acr Fice-Scheduled S055 sERATIONS): SEEBAL: No gross changes. HISTOMRPIOLOSICOBSERVATIONS): Nat applicable HisTouRproL 061 osscruaTion J{AuiRvsEerAL GLANDS: TTRiARCoKmER viianncflulaoamlmaaatttiiiooonnn,,:co`Scrnhttreeoxrnsict(.imtiilfador)c:al/mualuttiffooccaall ((maiinmiesa)l) USinEfilmaombartainocnh.iachrboanciyc/.eysftocs) (minimal) HE FOLLGUING TISSUES) VERE wT noun, Liu: cjoSolinoe]nARR (STERN) fDrsl0oAoTEHvun LPSUPRMIOPNSYATLATOCEDOER,O, SUBMANDIBULAR LMBAR NSREEPRCIVTNEA,L SEIATIC CORD, THORACIC TESTES Ths End of Record 17608 EKceIpcOiuNnnEiToSmioes PSSPERLAREIAENTNAHLROVIEDSICLES Rika suisoer - FCLoOisRvaUerLAoTeIN,G GLAND weoTASTINAL SPSEtHVoIEmRRaL'cShCPOART.CHCERVICAL oT 1 418-027:PAGE 1-32 ORVAILTH(GTAHVEAGER)EPRCOODMUBCITNIEDONPRDREEOPVTEEOALCTOOEPLDHE4ON1UT6SA-EL02T7OTXOIXCIICTIYTYSTSUCORYEEGNFING1 7T5o9T8.7 SPONSOR'S STUOY WAGER 1-7509 Individual Aniral Grsoospsenadnid H11istomorpholooy Data sAeMx:AL we: W17618 DooEsAeTHroTYvPeE:, S1acr ice-Scheduled 80S QRSCRIATIONS): GENERALS No gross changes. HISTORPHOLOSICOBSERVATIONS): ot appl cable HISTORRPIOLOSICOBSERVATIONS: fcSieTvcoeuarmc:: iidinnlffalltaaammtaaittoiinoo,nn,,mucmcohesrsaolnai.cg.iacnhfdrosocnail(cjamrum(niatnfia1fld]o)cs] (aid) edemainflamation, Submcose, Slandslar sre (sinimal) IHE FOLLGUING TISSUC(S) VERE wITHINnoma, us cAfoelRowE Guns FDSEoUnDeEoNMw (STEON) KiE9oBwianetrosmioes SLFIEPNTIGEMYRL'SMCOODpREa,Dt,cMhCEEDRIVAISCTIANLAL SPLPYRDWOIPSAHTLAMTOCEDOER,, SLUBVWGAAORIBULARRESNEPCRITVNEUA,L SCTATIC COW, THORACIC GTeRstAesY sLAsoER Ths Thoin End of Record T7618 CHieOoaUrRTING GLAND SSFAEpRMTtIAROVIeDsices Trier 12 418-027:PAGE 1-33 ORVAILTH(GTAHVEAGER)EPRCOODMUBCITNIEODNRPDEREOPVTEEOALCTOOEPLDHE1DNOT8SA-EL62T7TOOXXIICCIITTYYSTSUCDRYEENOIFNTG T7E559T9.7 SPONSOR'S STLOY WMGER T7599 Individus) Anima) GAroospsenadnid M11istosorphalgy Data SA or: ve: W1763 DooEsAeTHcToYuPEr.: 1Sacrifice-Scheduled 8058opsTRIATIONS): SENERAL: Mo gross changes. HISTONORPHOL0SICOBSERATIONGS): hot applicable HisTovosproLos1c opscruaTions: LASiTovoennrc:ew cus: vdIianlcfautslalatatitioinoo.nn,,ruccocorhstraeolxmeg(,lnafinnodicsnasll()mmiunlitmaflo)cal (minieal) edema inflmation, submucosa, noralandilar ares (sinimal) IME FOLLGUING TISSUC(S) VERE WITHIN gua, Ls cSofOleNoEmMou (STERN) JfBREiAIrNNm KiEcevBoiedrisomoes HLSPRIIONSNATLATOECEOR,D, SULUBWMBAANRDIBULARRENSEPCRITVNUEAM,L SCIATIC CORD, THORICIC SFSPaoLgEavETNaiROvIDes Ths THrRoiD TRACHEA CHiOErAReRUTLATING GLAND SPTPeEIsVNtEAeRLs'sCOpRaDr,cHCERVICAL GRINARY BLADDER ISSUE(S) MOT AVALLABLEFOR EvALATION: LINN NODE, HEOTASTINAL End of Racers 17630 1s 418-027:PAGE 1:34 ORVAILTH(GTAHVEAGER)EPCROOMDBLICNTEIDOVRF/ROEOEPTVEOEACLTOOELPDWE6DNUTS2AEL7TOTXOIXCIICTIYTYSTSUCDRYEEoNFINTG T7E560T8.7 SPONSOR'S STUDY NUMBER T7538 Individual imal Gsroonpsenadnid H11istororshalaay Data sRexU:A WHER: W17631 DoEsAeTHcToIvEe.: Sa1 crFice-Scheduled R085 GESERATIONS): SEAEBAL: No gross changes HISTONORPHOLOG1C OBSERVATIONS): Not applicable HisTovoRPiL0gIC oBscRuATION: tKiivoenwe:rs: TPLHRvHORSeOTALTDNEO:DE, SUBMANDIBULAR vdIianlcfaultooalmtaaittoiinoo,nn,,pheeclphvraiotsnoic(cea,lflluf)loacra,l puenrtigfaorctaall ((msiniinmail)) sGPtyirptoeTprrnpoylb.arsaifnaoc,ahli"mnp(rBaaiocmydimtiaielc)s/piasmcrtic (mila) Papertroghy. fonticular epithelium (sila) HEFOLLOUINGTISSUE(S) VEREWITHINbom, Lowi. AC0OkRaGErUMLAALTIGNuGavGoLsAND clloenoemnwou (STON) SBSEuAnDIEvum LRSEPoCITNnUAMLpCoOeR,O,METDHIOARSATCIINCAL sSNPEeRLnVEEEn,NasVce1saiTcicles SPSPAtIRoNAmAcTLRCOOIRDD, CERVICAL Thws TACHA URINARY BLA00ER End of Recor. 17631 hcEbosiwolommocs BTSePEsIEtWeARsLSCOpRaDr.cLAR 1 418-027:PAGE J-35 ORWAILTH(GTAHVEAGER)EPRCOOMDBUICNTEIDON/RDEEPVEEALTEODPHEDNOTSAELTTOOXKIICCIITTYYSSTCROEENOIFNGT T7E5S6T9.7 SPONSORP'RSOTOSCTOULDY41N8U-M0B2E7R 1-759 Individual Anes] GArpopsesnadnidx H1i1stamorshology Data sAeNx:AL WER: W17639 DooEsAeTHGToYwRE:: S1ecfice-Scheduled 4055 OBSERVATIONS): GENERAL: No gross changes. HISTOMORP10L0G1C OBSERVATION(S): Not applicable HISTOMORPHOL0GIC OBSERVATIONS: eLLIIpNNtPPoHHtoNNmOOiDDnEEe,,s.MSEUDBHIAANSOTIIBNUALLA:R: cionnfgiletsrtaitaino/ne,ryntohnreonpuhcalgooacry-tcoeslal,"(afioncialssl()ainim1) Pyperplasia, Tymgrocytic/plasmacytic (sini) THE FOLLONING TISSUE(S)WEREWITHINNORMALLIMITS: ACLOReAEGwUALLATLINaGaGsLAD BcOaNtEowNARROW (STERN) Jesu DBRuAIeN Kiers FLROgSTATE RENCERTVUEH, sciatic PSAERHAITNHAYLROVIEDSICLES STPeIsNtAeLs CORD, LNBAR URINARY BLADER TShPIsNA.L CORD, THORACIC STPHLiEgEoNi0 End of Record- 17639 cHEeAeRmT SLPPIEIVYNEEARRL'SCOPRADT,CHCERVICAL STRoAuCHcEyA 1s 418-027:PAGE 1-36 ORIALTH(GATVHAEGER)EPRCOODMUBCITNIEODNRFDEREPOVETEAOLTCGEOPDLWED1NO8TS-AE0L2T7OTXOIXCIICTIYTYSTSUCDRYEEONFINTG 7TE503T5.7 SPONSOR'S STUOY NUMBER 7-759 Individual neal GArpopsesnadnisx W11stomorsnalogy Data sAexna oaER: W17648 oDEsAeTHcToYvPeE:. S1 ace ice-Scheduled 05s opsTmATIONs): GENERAL: Yo gross changes. HISTOMORPHOLOS1COBSERVATIONS): Not applicable HisTOEBrOLGsIC osscRuATion: K{iiHoEvAneReeTr::s: SLToInhGH1:0, SUounOIBULA IIInnnffflilaTamEmmraaatttiiiooonnn,. Smsouobnanocneuet,le,saarfco-accaileml/ilmtttfssofcfaoolccaal(lai(nm(iiamnfa1ii6e))al) Paiafpaecraatiiaosnt,o,mIeowy!mglpacn/dosoa(cmmmianyimail) (x10) HEFOLLOUING TISSUES) WERE WITHINNomuAL Liu: ACeOReAESnUALLATGILNaGNDGSLAND SBcOooNloEonnwoeow (STERN) pBtrnAeTH RENSEPCRITVNUEAM,L scraTic CORD, THORACIC SSPPaLArEaELmNROVIeDsts SPTeePsvIteeVwsL'sCOaRr,cCERVICAL THiRDID TRACHEA URIMARY 614008 End of Record 17648 ceLYpeMiPopHioNmOiDoE,tsHEOTASTINAL SFTPRhIOVSsATLATECORD, LVOAR 1s 418-027PAGE 1.37 ORAILTH(GTAHVEAGER)EFCROOMDBCITNIEODNoRDErEPVEeEALoTOE,PDMEsSNiTaEAcLeTrOTXOIXCIICTIYTYSTSUCORYECOHFNG1 1765597.7 SPONSOR'S STUDY NABER 1-599 bpiea wae: 1V7652 divide) est Grsepssenants M11stamorphology Data cSoEsTeHcoTvPeE:, 1cri frcs-Schaculed `GROSSOBSERVATION(S): SEMA No gross changes. HISTOMRPHOLOGIC OBSERVATION(S): tot op cable HISTOORPOLOSICOBSERVATIONS: iuteiso:n: STOMACH: aninfilaamatiaono,ttcohrnonics,bfmoccots/m(lntoidfeoratle) (minimal) edema/inflammation, submucosa, glandular area (mild) HE FOLLOUING TISSUES) ACovHreGnA,TIcGumGs o ERlSiAPnITeNHAYLRCOOIR0D, CERVICAL GTesatetsa suisoen End of Record. 17650 WERE WITHIN vom LINTS CfcooetnoennWow (STUN) SFLPEIIVINEARLSOCDPOEhR,,CHNEUONTGAASRTIWAL Tos Sa Seioonn cKEireoinoeetrosnmoes SBLPoTDTWHAALTNEOCDoEm,, SUOMANOIBULAR THORACIC SNSEEeRVEaEN,t SCVIeAsTiIcCtes Toro Trach ur 418-027:PAGE J-38 ORWAILTH(GTAHVEAGER)EPCROOMDBUICNTEIDONPROREEOPVTEEOALCTOOEPLDWE08NO6TSAE2LT7OTKOIXCIICTIYTYSSTCURDEYEONFINTG T7e5s9T9.7 SPONSOR'S STUDY NABER T7508 Individua Anim Gsroospsenadnis 1W1istomorshology Data Asex:L NBER: v17656 DoOuAsTtHcToYuEr.: S1acr Fice-Schediled cassopsERMTIONS): GENERAL No gross changes HISTOMRPIOUGGICCBSCRMATION(S): Not applicable HISTOORPIOLGGIC GassrATION eKLiIpoHtvPoeHrrsoO:mEo,es:SUBMANDIBULAR: PROSTATE: ayipdnfeeirmls:tlraapstatipaoi,nr.iTasyeoeynponTnoauccymltaaraner/)-pclealslm,acyftociacl ((maiinniimnas)l) TnFiamation, Chronic, mitfocal (sinimal) THEFOLLONING TISSVERUE WEIT(HINSNo)a, Lins. CAtoOeRAemSuUAATsIaGveGsLAND ScOeoNlaEonnow (STERN) oLSiuAveTtr RSLEPCIWTMALoc0oEm,,NETOiTowAiScTiIcNAL NSSEPeRLVEnEE,NaSCveTsAtTcIiCes, PSSAPAtITNoAHLoTRCOOIRDD, CERVICAL Ths THRol TRACER End of Record 17655 cRLoeEncAeuRn TFSePesIvtMeeARsL'sCOwRrDe,nLNGAR Ria sLisoER 1s 418-027PAGE 1.39 ORVAILTH(GTAHVAGREE)PCOODMEBITNIEODNRRDEEPOVEEATLTOEOPDME04N1SToAE-LteT7OTXOIXCIICTIYTYSTSUCDRYEEONFINTG 17655879.7 SPouSOR'S STUDY Nec T-7500 Individual Ania) GArionspeamnd W11stomrprlony Data Sahnia wags: V17658 sSEeATcToI:E S1 ariice-chadited 6205S QBSERVATION(S): SEL: No gross changes. HISTOMORPHOLOGICOBSERVATION(S): totapp cable STORRSHOLOG1CoaseavATIONS: on: itimabranchial body/eyst HEFOLLOUINGTISVSEREUWIET Sno)ua LIT ACeRrOEAAL cGuGsMD SGfovtleowwwo (STEON) pJsereaoton Af{RveIeEx), sciatic SrPosMTa Ovisices FDSEIVPPERCSNOCDPE.A,THKECOoTAvSoTILVAL STPoINmAsL com, Tomiie SToeatchhn SRoimv une of Record. 176% KcEireoikebetrsomoes HLSIPoPCsaNOCDOER,D, SLUBeWaANrIBULLR Tas ws 413-027:PAGE J-40 ORAVLITH(GTAHVEAGER)EPRCOODMUBCITNEIDONRPOREEOPVTEEOALCTOOEPLDHE01N06TS-AE0L2T7TOOXXIICCIITTYYTSOCRYEEoNFIN1G 7Te5s9t9.7 SPONSOR'S STUDY NWBER 1-750 Individal Anes) Grsoospsenadnis i11stomaranalogy Data sAeNx:AL NNER: W17660 DooEsAeTHcToYvPeE:, Sa1 ce ice-Schedsled S055 psERuATIONS): SEAEBAL: No gross changes. HISTORRPHOL001C SERIATIONS): hot applicable HISTOMRBHOLOGIC gsERuATIONS: Lvievse:oe, suemavorBuLRR: Piynpfelrapmimaasttiao.n, Tocmhprmoenciycb,icf/opcisas)musletritfico.ca(]mi(mmmianli)ral) IHCFOLLOUING TISSUE(S) ERE WITHINNowa Liu. ACHOEoARRSnTUeATIsNuGwoGsLAD cBLoOeNuwEnow (STERN) ouEBoRooAeTvmun {SiPPenIveNEARL'sCOpaRrDoHCERVICAL RSLOPYITVNPAAHLTNEOCDOER,O, NELOIVTGAASRTINAL RNSEEPRCIVTNEA,L SCIATIC CORD, THORACIC STRtAoCwHEA UTeRsItNeAsRY BLAOOER jit Ed of Record 17660 EcKiveoivooeirosmioes SSFPALRoEAETuNIROvIeDsices THrRoro 1-10 418-027:PAGE J-41 ORVAILTH(GTAHVEAGER)EPCROONDBLICNTEIDONRR/EDOPEETVAECTLE.ODPE1DNO8TS-AE6L2T7OTXOIXCIICTIYTYSSTCURDEYEONIFNGT T7E5S0T9.7 SPONSOR'S STIOY NNER 17-7599 Individual Anima] GArpopsesnadnidx H1i1stamorpholagy Data ASex;L NER: W17634 DDoEsAeTHgToYwPE:: S1a1crifice-Scheduled 8055OBSTRUATIONS): SHIERAL: No gross changes HISTOMIRPHOLOGICOBSERVATION(S):| Not applicable HISTOMRPHOL0GIC OBSERVATIONS. ve: inflammation, chronic,focal/mutifocal (minimal) THE FOLLOUINGYISSUE(S) WEREWITHINNoRAAL INIT: stoucH End of Record. 17634 1 418-027:PAGE 1-42 on. chuEe)ScooTmnSysVEraeSTebntostselTT|Oorrrgseyy0or 1175.7 sess sts SjS-- Bom a =J wfe ofe -- 10 -- `GGROSS.OEBStEoRVLAgTrIoOsN(Sc)h:es. HoIStTOpNOcRPHrOLe0SICOBSERVATIONS): je'HISTOMRPHOLOGICOBSERVATIONS: or re STOMACH: Fp -- mie "rene herie) (Sal) dilatation, mcosal glands (minimal) wie 418-027PAGE 1-43 ORVAILTH(GTAHVEAGER) CEOMPBINREODWORHDREEOPVDTEEOALCTOUOEPLDMCED4NOT-STA0EL2T7OTKOIXCIICTIYTYSSTCUROEYEONFINGT 17250979.7 SPONSOR'S STUDY NURBER T7599 Individual Animal Gsrooepsenadnid H11istororphalaay Data nSex:a wen: v176% DooEsAeTHrToYvPeE:. S11ace ice-Scheduled 805s gasERATIONS): GENERALS Mo gross changes. Towois au Not applicable stove uation uve Mipidosts, tension, focal HEFOLLOUING TISSUES) wERE wITHIN opus LIN: srowck End of Record 768 CTT 1 418-027:PAGE J-44 ORAVLITH(GTAHVEAGER)EPCROOMOBLICNTEIDONRPOERRPOVETAEOTCLEOODLOU4001TS5A-L02T7OTXOIXCIICTIYTYSTSUCDRYEEONFIN1G 7E55979.7 SPONSOR'S STOO NNER T7500 Individusl Anieal GrAoospsenadnid H11istamorsholooy Gata sAixL Nee: W162 DoEsAtTHoToYrPE:: S1a1ceice-Schedsled 05s OoscavTIONS): SEUEBAL: Wo gross changes. HISTONIRBHOLOGICOBSERVATIONS): Not apace HISTOORPHOLOGICOBSERIATIONS: uve inflamation, chronic, focsl/mutifoca) (ai10) IH FOLLOUING TISSUES) WERE WITHIN omen,LWT: stow End of Record 17642 Tr "- EY 418-027:PAGE J-45 ORIALTH(GTAHVEAGER)EPCROONDBUICNTEIDONR/DEEPVEEALTOEPDHEDNOTSAELTOTKOIXCIICTIYTYSTSUCDRYEEONFINGT T7E5S0T9.7 SPONSORP'RSOTSOCTOULDY41N8U-M0B2E7R T-7599 Individual Animal Grsaospsendainxd H11istomorgholosy Data. AseNx:AL BER: 1W7845 DDoEsAeTHcrToIuPpE:: S11acrifice-Schaduled 6055 OBSERUATION(S): SENERAL: No gross changes HISTOIORPHOL0G1COBSERVATIONS): Not applicable HILSTOMORPHOL0SICOBSERVATIONS: SLTiovueAsC:H: 1d of Racor 17643 idinlfaltaamtmiaotni,on,muccohsraolnicg,lanfdoscal(/aeiuild)tifocal (sild) A 1s 418-027:PAGE J-46 ORWAILTH(GTAHVEAGER)EPCROOWDBUICNTEIDONRF/ERDPOETEVOAECTLOEOLDPES4N1TE8A-L02TT7OOXXIICCIITTYYSTSUCORYEEONFIN1G 71655979.7 SPONSOR'S STUDY NBER 1-759 Individual Animal GrAopspsenadnidx H11istamorsholagy ata SAoxL NNER: W17645 DooEsAeTHGTaIoPE:. S11acrifice-Scheduled 805s OBSERUATIONS): SEMERAL: ho gross changes. HISTOMORPHO0G1C OBSERVATION(S): Net applicable HISTONRPHOL0G1C OBSERVATIONS: uve: inflammation, chronic,foes]fmtfocal (ain) THE EOLLOVINGTISSUE(S) WERE WITHINNoRuaL Lu. stoucH 111s 418-027:PAGE 1-47 ORWAILTH(GTAHVEARGEE)PRCOODVUBCITNIEODNDRREEOPVEETALTOCEDPE4DNO1TS8AE-L02T7OTKOIXCIICTIYTYSTSUCORYEEONFINTG T7E5S0T9.7 SPONSOR'S STUOY NNER 1-759 Individual Animal GrAopspsenadnidx H1i1stamorsholesy Data AseNx:AL NBER: 17649 oDEoAsTeHGToIwPE:: S11acrifice-Scheduled 58055 OBSERVATIONS): SEIEBAL: No gross changes HISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMORPHOLOGICOBSERVATIONS: SvToeusc:H: Ed of Record 17688 eidnefmlaamimnaftiloanm,atcihorno,nics,ifbmoiccso)ssm,ulntoinfgolcaanldul(amrinairmeaa) (moderate) na 418-027:PAGE 43 ORVAILTH(GTAHVEAGER)EPRCOODMUBCITNIEODNRFDEREPOVTEEOALCTOOEPLDH1E0N60TS-AE0L2T7TOOXXIICCIITTYYSTSUCORYEEONFIN1G T7e5o9r9.7 SPONSOR'S STUDY MBER T-7598 Individual Animal Grsoospsenadnid H11istosorpholy Data sAexM:L wc: W17651 oDoEsAeTHrToYwPE:, S11ac ice-Scheduled O80RSSCRATIONS): SEERA No gross changes. HISTOMORPROLOSIC OBSERVATIONS): ot applicable THEFOLLONING TISSUE(S) ERE WITHNoIN Lin. uve stoucn End of Record 17681 11s 418-027:PAGE J-49 ORAVLITH(GTAHVEAGER)EPRCOODVLBCITNIEODN/RDEEPVEEALTEODPHEDNOTSAELTTOOXXIICCIITTYYSTSUCDRYEEONFINGT 7TE5S9T9.7 SPONSORP'RSOTOSCTOULOY4N1U8M-0B2E7R 1-759 Individus) Anima] GArpospsenadnidx H1i1stosarphology Data AseNx:AL rE: W17653 DDoEsAeTHGrToYuPpE:: S1a1cri Fice-Schedvled E055 SERVATIONS): GENERAL No gross changes. HISTOMRPIOLGSIC OSSERATION(S):| Not applicable HISTOMAPAOLOSICOBSERVATIONS: Lives: vaculation, hepatocellular, periportal (ainisal) IHGFOLLOUINGTISSUES) VEREWITHINNORMAL LIWITS: sown End of Record- 17653 or or or te 418-027:PAGE 1-50 ORVALir(GTAViAGER)EPCAOGMDBLICNTEIDONFRREDPOEETVAoETcLOEoPDLWB40N10T.SA0L2T7OTKOICCIITTYYSTSUDCY ROFE1 17655979.7 SPONSOR'S STUOY KNBR 1-759 Todividual nies] rsopspsenanise M11istamorphalosy Gata pfyu wae: 1v765s ScoEsNeNcThIoPE:, S11ari ice-schaduied Sa0ssopsemnIONs): SEMERAL: No gross changes. HISTOLOGICossERATIONS): -- HisToPHOLOGIC coscaTions: uve: Inflamation. chronic,focalmitsfocal (minimal) HEFOLLOWING ISSUR(S)VERE ITHINbom Lins: stow 04 of Record 17655 - - A 12 418-027:PAGE J-51 ORWAILTH(GTAHVEARGEE)PRCOODNUBCITNIEDONPRDREEOPVTEEOALCTOOELPDME4DNO1TS8AE-L02T7OTXOIXCIICTIYTYSTSUCDRYEEONFINGT 7TE5S0T9.7 SPOISOR'S STUOY NUMBER 1-7508 Individual Animal GrAopspsendainxd H11istemarpholosy Data ASNexI:MAL NBER: "17620 DouEsAeTHGrToIuPpE:: S1a11crifice-Schaduled 8055 OBSERVATIONS) SEAEBAL: No gross changes. HISTOMORPHONOGIC OBSERVATIONS):| Hot applicable HISTOURPHOLOSIC GBSERUATIONS: uSTvoec:n: End of Record 17620 d ihylpaetrattrnioofpnhlm ,ya.mmauhtceioposanat,olcegsllulabunmludacsro,s(am.cienngt1iramin)ldoublualraarre(sa(iminni)mal) na 418-027:PAGE -52 ORAVLITH(GTAHVEAGER)EPRCOODMUBCINTEIDON/RPDREEOPVTEEOALCTOOEPLDHE04N10T0SA-L02T7OTXOIXCIICTIYTYSTSUCDRYEEONFING1 7T5e0t9.7 SPONSOR'S STOOY WAGER 1-7508 Indivicunl Aniral Grsoospsenadnid H11istomorphology Data Asex:L Noe: "17623 DooEsAeTHroTYvPEe,: S11a1ri ice-Scheduled R055 OBSERIATIONS): SEERAL: No gross changes. HISTOMRPHOLOSICOBSCRVATION(S): tot a1cable HISTOORPHOLOGIC opsERITIONS: Lives: inflamation, chronic, focs)/mtfocal (minimal) HEFOLLOWINGTISSUES)WERE WITHINoma,LWT: stowch Ed of Record fees Te na 418-027:PAGE 1-53 ORAVLITH(GTAHVEAGER)EFCROOMDBLICNTEIDONROEPREVAETLEODMOISTAELTOTXOIXCIICTIYTYSTSUCDRYEEONFING1 17655979.7 SPONSORP'RSOTSOCTOULOY41N0N-0E2R7 1-7508 Individual Bnfeal GArpaspeanndd H11istomorphalony Sata Asoe:L Neer: 17627 DooEsAeTHoTwYP:E, S11a1ri fice-Schaduled HOSS BSERIATIONS): SEERA; ho gross changes. HISTOMRPHOLOSICOBSERVATIONS): Not apolicasle HISTOPHOUGSICOBSERVATIONS: ues iPynpfelraimraotgihoyn,, hecphruotnoicce,iTuftoacra.lc/aeunttirfaTcaamlula(rain(issianli)sal) HEFOLLOUING TISSUES) vERE WITHIN opin, Liu: stowc Ed of Record 17627 - TTT nas 418-027:PAGE J-54 ORAVLITH(GTAHVEAGREE)FRCOODMLBCITNIEODNRFOREROPVTEEOALCTOOEPLDHO04N01TS.AE0L2T7OTXOIXCIICTIYTYSTSUCORYECOHFNG1 71655079.7 SPONSOR'S STUY WMGER T-7508 Individual Aafeal Gorapseranad H11istamarphalosy Gata SAoL vee: W128 SvoTstNcThIoFwE:, 1S11acriice-scheduied GROSS OBSERVATIONS): SEMEBAL No gross changes HISTOMRPHOLGEICCESERUATION(S): Not applicable HISTOORPOLOGIC opsERATIONS: we Inflomation, chronic. focalfmtface) (nfes]) HEOLOMING TISSUES)VEREWTIbom,LINTS: stowscn wa 418-027PAGE 1-55 ORAWLITH(GTAHVEAGER)EPRCOODVUBCINTEIDONR/EOEPVEEALTOEPDHE0N0TSALTOTXOIXCIICTIYTYSTSUCDRYEEONFINGT 7E55010.7 SPOVSORP'RSOTOSCTOULDY41N8U-M0B2E7R 1-759 Individual aioe] GrAopspsendainxd W11istanorshalogy Data sAeNxIMAL NER: 17653 DoEsAeTHoTwIP:E. Sa1c1rifice-Scheduled 8055 OBSERVATIONS): GENERAL: No gross changes. HISTOMRPHOLOGIC OBSERVATIONS): Wotapfeable HISTOMRPHOLOGIC CaseRwATIONS: uve: hypertrophy. hepatocellular, centrilobular (ainima)) IH FOLLOUING TISSUE(S) VERE WITHIN woman LINITs: stouch zs 418-027:PAGE J-56 ORWAILTH(GTAHVEAGER)EFCROOMDBLICITEODW/FRDREEOPVTEEOALCTOOEPLDME4SN0TE-A0L2T7OTXOIXCIICTIYTYSTSUCDRYECOHFIGT 7TE58979.7 SPONSOR'S STUDY NABER T7599 Individual neal GAropspseanndd H11istororphalasy Data ASomx a nen: v17600 oDEsAeTHcTrYoPEw:: S11o1cifice-Scheduled 05s oastmAnIONs): SEUERAL: No gross changes. HISTOMEPHOLOSICOBSERUATION(S): Not appl cable HEFOLLOUING TISSUE(S) ERE WITHIN Nom uve srouck End of Record 17640 " Lin. J 12s 418-027:PAGE J-57 ORAVLITH(GTAHVEAGREE)PRCOODMUBCITNIEODNRDEEPVEEALTOEPDME0NOTSAELTOTXOIKCIICTIYTYSTSUCDRYEEONFINGT T7E5S0T9.7 SPONSORP'RSOTSOCTOULY41N8U-M0B2E7R 1-753 Individual Anima GrAoospsendainnd H11istomorgholosy Data AsNeIx:MAL NOUBER: X17645 DouEsAeTHGrToYuPpE:: S1a11crifice-Schaduled 5055 OBSERVATIONS): SENERAL No gross changes. HLSTONORPHOL0GICOBSERVATION(S): Wot applicable HISTOMRPHOLGSIC OBSERVATIONS: ver: snflamation, chronic,focalmultifocal (minimal) THE FOLLOUINGTISSUE(S) VERE WITHIN NORMAL LIWITS: stoucn nar 418-027:PAGE J-58 ORWAILTH(GATVHAEGREE)PRCOODMUBCITNIEODNRRDEoEPTVEoEAcLToOELDPED4NO1TS8AE-L02T7OTXOIXCIICTIYTYSSTCURDEYEONFINTG T7E5S9T9.7 SPONSOR'S STUDY NMGER 1-759 Individual Animal GArpospsenadnidx H11istamorshology Osta SAtN;AL NER: W17650 DoEoAsTeHGTrIoPEw.: S1a1crifice-Scheduled 58055 OBSERVATIONS): SEUEBAL: No gross changes. HISTOMRPHOLOGICOBSERVATIONSS):| Not applicable HISTOMRPHO06ICOBSERVATIONS: STvoewi:cn: End of Recora- 17650 ddhiyelpametrsatitrnioopfnhl.ya.msauhtceioposanat,locgesllulabunmlidacsors,(em,cienngimtlaralin)ldoublualraarre(sni(mniani)mal) zs 418-027:PAGE J-59 OREALTH(GTAHVEARGEE)PRCOODUUBCLTNIEODNRDEEPVEEALTOEPDMEDNOTSAELTOTKOIXCIICTIYTYSTSUCDRYEEONFINGT T7E5S0T9.7 SPONSORP'RSOTOSCTOULDY41N8U-M0B2E7R 1-759 Individual Animal GrAoospsendeinxd H11istomorgholosy Data ASeIxN:AL NONBER: W17657 DooEsAeTHGiToYwPpE:: S1a11crifice-Schaduled 05S ORSERUATION(S): SEVERAL: Yo gross changes. HISTOMRPIOLGSICOBSERVATION(S):| Not applicable HISTOMRPHOI061C OBSERATIONS: Liver: Inflammation, chronic,focal utifocal (minim) THEFOLLOUING TISSUE(S)WEREWITAINNout,LIMITS: srouch na 418-027:PAGE J-60 ORAVLITH(GTAHVEAGREE)PRCOODMUBCITNIEODNRDEEPVEEALTOERDMEDNOTSAELTOTXOIKCIICTIYTYSTSUCDRYEEONFINGT T7E5S9T9.7 SPONSORP'RSOTSOCTOULDY41N8U-H0G2E7R 1-759 Individual Anime] GrAoospsendainxd H11istamorphology Dota AseVxI:NL NONGER: W17655 oDoEsAeTHcoTYuPpE:: S1a11crifice-Schaduled 055OBSERIATIONSS): SENERAL: Yo gross changes. HISTOMAPIOLGSIC OBSERVATIONS):| ot applicable HLSTOMRPIOLOGICOBSERVATIONS: Liver: inflammation, chrontc, focal/mtifocal (mini) HE EOLLONING TISSUE(S) WEREWITHINNORMAL LIMITS: stouck End of Record- 17658 " or or Tr 1-30 418-027:PAGE J-61 ORAVLITH(GTAHVEAGER)EPRCOODMLBCINTEIDON/FROREFoPVTEEGALCTaOELPDHE4SN1TE9A-L02T7OTXOIXCIICTIYTYSTSUCDRYEEONFIN1G 7TE5S9T9.7 SPONSOR'S STUDY NNGER 1-7500 Individual Anim) GrAopspsendainxd W11istonorshology Data AseNx AL ge: W17521 oDoEsAeTHcTrYoPwE:, SIavceice-Schedsled S053opsgRuATIONS): SPLEEN: Nodule, 0.3m (triming observation) HISTOMRPHOLCGICGRSCRUATION(S): Iymghosarcona HISTORRPHLO61C sERATIONS: AveRr:E cua: faLRtIENCeET:NGO, SUBKMOISULAR STOMACH vPiaancpfseleraltmaratetipiononyn,., cheocprhurttoenoxicca(,islfiuontcioamrl,a)c/omunttiifoTcaolu(rai(ln)11d) pTSorirpraaosrniscttsaoatsrstc)so,ns.Tymmaplhiogcnyatnite/pssmacyeie (minima) ereston(s), siandulor mesa (sinimal) HEFOLLONING TISSUE(S) VERE WITHIN Nosy cBotOliNoEnWAH (STERNUM) farSaiAuTnt PSLRPOIISNNTAALTHEOCOOFR,DMETDHIORAASCTIICNAL TSNEEeRSaVTEEn,SaSCvIeAsTtIcCies TRACHEA URINARY BLAOOER Luis: Kceiereiworisomioes FSPaIgNaATLiRCOOIRDD, Tis CERVICAL HCLiEOnAReRUTLATING GLAND jFSPeiIvtVetAReL'nsCOaRr,chLR Neopuass: spueen End of Record 17621 Iywhosarcons, malignant 1s 418-027:PAGE 1-62 ORAALTH(GTAHVEAGER)EPRCOODVUBCITNIEODNRRBEEOPVEETALTGCEWDENO4T1S6AE-L00TT7OOXXIICCIITTYYSTSUCDYREOFENT T7e5a9r9.7 SPONSOR'S STUDY Wve 1-7508 aSoxna woven: W17622 Tnsvidial Anes) csreoapsenadnis M11stomrphalogy ta BoEsReTHcoTYvPeE:: S1vuri fie-Scheduled GROSSOBSERVATION(S): NREMIIES: Right front leg- scab. 'HISTOHORPHOLOICOBSERVATIONS): dermatitis, ulcerative, foes) HisTooRmOL0G1C oBsErvTIONS: oonies: BLISOLVoEAImR:T0, SUBMOTBULAR armas, ulcerative, focal (eile) SEFhroyeppepeesrrthptoirynooispethf)aye;,ia)lhTaeynpBmaaoiuthotnococeriylimt)uiolcas/rss,smc(eesyn1t1ti9rc)i.lob(usloadrors(tmei)ld) HE FOLLGMING TISSUE(S) VEREWITHnoIN LIMITS ACeRnEAOL GGumsN ciolEon Re SSlEoeoritn tiSFenvIgERA'sRpa,tchWe RSCECNPTPOMOcDoEn,,WTEiOoTmAiScTiIcNL NSSEAeRVLnEE,tSEVIeAsTiIcCies Tams Titolo Trick End of Record. 17522 EcKiFeoiewnmelrosmines STBeasPttkeIstsCoRrDn, camvion. hay uoee wa 418-027:PAGE 1-63 ORAVLET(GTAIVEAGER)EPRCOODMUBCITNIEDONPROREEOPVTEEOALCTOOEPLDHE4DNO1TS6AE-L02T7OTXOICRIITYCSTSUCORYEEGNFING1 7E50978.7 SPONSOR'S STUOY KMGER T7599 Individual Animal GrAopspseanndd H11istomorpholooy Data MseAx:L BER: "17625 DooEsAeTHGToVwPE:: S1voci ice-Schaduled R055 OBSERUATIONS): GENERAL ho gross changes HISTOMAPrOLCSICCoSERMTION(S): rot applicable HISTONRPH0,061COBSERVATION: Aedem Laws: Ln Na, SuBMAOIBUUR: hrTyoeppteerrrettarrtaossphhyyf.voaehcseupoaTltaaotcmieionnmi.u)laz,onacgolnotmielroubluolsasr((ani1d1)d) Paperstasta. Tyeonocytic/pnasmseytic. (mmmaT) HE FOLLOUING TISSUE(S) WEREWITHINNom Lin. CjiBoOlNoEnHaRROw (STERN) fSBreAiTn PRSLOPIISNNPTAHALTNEOCDOER,D, MELOUTGAASRTINAL NSREPeRIcVNrEAu,Li SCIATIC CORD, THORACIC TGeRsItAeRsY sL0ER Ths 0d of Record 17625 " scEipooviemorlsomioes SSPPaHtLaEIENA VESCLES Talo " CeLooanRgrBUATING GLAND FSSPetIvoNenAwaL'csHCOpRaDr,enCERVICAL THacHeR 1s 418-027:PA1G-6E4 ORiALT(4T1h4E66R ) COMBINE EODVpRSEEPVEiEATLO EODMeEONSTEA)LTTOXAICSITTYYSSTeOnYtei0ng.T 17653878.7 SPONIR'S STU WAGER T7530 Indtvicat Ani) Gsroonpd W11istamropotony Daa a 5 we; "1762s sSEsNcTsTrIP:E S1evriice-schdilod 6805S OBSERVATIONS): SEMEBA: No ross changes HtIoStTOaMpOpRlPiHcOaLbOlGeICOBSERVATION(S): HISTORICoEsehvATIoNs: xpitionvee:rs Len noe, stsuwo -_ TPRoOSwTeATrE: avon: EHaRrertriiEscr)i,aoRmhneylaleAopmatoecrel lfnuoleasr,S(cenntiHri)lobulear (ns110) aSDcTPontimlanatesoiniomana,mtleiTreoasstnnoacSi.ylmtaeuSnctgeioinis:nsttspe]sann()gsains(icaeaiaildr) ares (minieal) itimreninar hodioms HEFOLLOMINGTISSUES)WERE ITH owLibr: GAaavrleiceuomsme NEE, scune Sctooirnwo (STRUM) SSeBiAooTnn ann FERS owen SRSooatnri Viele suaoee STEeAL Co, coon STeolsa con Was cECFeinnDlo:mneseons SRTeisinncor, Tome comets: stoucn of Reena 75 TThoe inflamation 13 est prominent at the initing nese 418-027:PAGE 1-65 ORAWLITH(GATVHAEGER)EPCROOMDBLICNTEIDONRR/EoDPTEEOVACETLOEOLDPED4NO1TS8AE-L02TT7OOXXIICCIITTYYSTSUCDRYEEONFINTG 7TE5S8T9.7 SPONSOR'S STUOY NMGER 1-759 Individual Ansa] GArpospsenadnidx H11istamrshology Data ASexI: L NNER: u17636 DooEsAeTHGToIwPE:. SaIvcriFice-Scheduled 4055 OBSERVATIONS): PRGtOuaStnTAsiTunE:rfcaoclRoeirg,hrtemvaehsaeslmusirsitpnahnge,r2es6mcofmoirtmhx, 0su.lr6of6bamuclexa,r0.m7aesms,, Ventral right side red in calor HISTOMORPHOL0GIC OBSERVATIONS): prostatitis, suppurative HISTONRPHOLOGIC OBSERVATIONS: GAKiDIvReDEsNS:A.L GLANDS: RLPREIONCSTKTAT:NEO:DE, MEDIASTINAL SToucH: roo: vciaanctfusoll)aa.ttiiosonan,d,uciolchrartoenxic(,afinoicnaall)/mtifocal (minim) pCyroponesgrtetasrttoioptnhi/yse..rysthuheprppoauptrohacategilovleueyltao(rsm,tasr.kceadn()tsiri1dt)ahular (sininsl) `eeBddaeermmaaastiitnanf(lfsa)lmmaatmioaonnt,, sSuubbmmuiccoossas,, grloanngdlualnadruloarreasr(erod(enria1td)e) Wltimbranchial body/cyat IHEFOLLOVING TISSUE(S) ERE WITHINnoma Lins coBLOeoNwEnWARROH (STERN) [BJEArTHm SMTPEIRsNEA,L CscOiDa,tiLc MG STPPERIYANECARKL'ESRCOaRrDe,nTHORACIC ctEepeIeDmIOMIOES SSGAROLIHENEAAMRLY vesicLes BLADER CLeOIsRSMaULANTODIEN,G GLAND SUBMANDIBULAR TSePsItNeALs CORD, CERVICAL LAISSUVE(S)ANOTILAFORBEVAL LUATE ION: PARATHYROID 04 of Record. 176%. 113s 418.027:PAGE 1-66 ORAVLITH(GATVHEAGER)EFCROOMDBCITNIEODNRRDEEPOEVATETLECODM40N1T06AE-L02T7OTXOIXCIICTIYTYSSTCURYECNOIFNG1 7165597.7 SFONSGR'S STUY RMR T7599 Sa ort noes: W17607 Individual fea] Grseopsesraatne H11istomoranalony Oats DsEeATHoTvYePE:: S1vuri fie-Scheduled R055OBSERVATIONS): SEER: No gross chnges. HISTOMORPHOLOGICOBSERVATIONS): tot appl esble sTovoL061coasERvATION: we: Sseovnei'cs oat hwoI0: sToenpceerrrotasrsta.pinyio.nndhiavpi(adatuioacmlaelaelTp)aattaarc:ytceosnt(alionbiuelsal)t (x16) cSTacaemntsetiionnnff,lloommmttoiinooonn]., sgslwuabbnmmdccsooss(ssn;,innGiolmnaog)lrainadlaarresare(ss11(0s)iniasl) itimcbranchial bodyleyat HE0LLOUINGTISSUE(S) WEREWITH om, LIT: SeaCOaAmGrUeLATIcNGuGsLAD Csalolenoeonnwou (sTEON) DsJeuedidanen EcKireoiweoetrsomoes S{PoRPnAeITIOCOIR0, CERIO Testes LSHRIoPMsaDCEo,, MELDAIARSTINAL SSLEiWCTaPnROcDoEr.o, SLBWMIBULAR TRAGIC SSNEAoRVLhEE,nSVCEASTIIeCies Tiwis Toda iy suiooce End of fncord- 17657 13s 418-027:PAGE 1-67 ORAILTH(GTAHVEAGER)EPCROOMDBLICNTEIDONRR/EoDPTEEoVAcETaLEOlDPE4DNO1TS8AE-L02T7OTXOIXCIICTIYTYSTSCURDEYEONFINTG T7E5S9T9.7 SPONSOR'S STUOY NNER 1-759 Individual Animal GArpopsesndainxd H1i1stanorsholegy Data sAeNxIMAL NBER: 17641 oDoEsAeTHGTrIoPwE:: SIavcrifice-Scheduled 8055 OBSERVATIONS): SEUEBAL: No gross changes HISTOMIRPHOLOGICOBSERVATIONS): Not applicable HISTOMRPHOL0GIC OBSERVATIONS Lwiavneess: SLLItONoHOw:NNOODDEE,, SWEUDBINARSDTIIBNUAXLA:R: mIinnfelraamlmiaztaitoni,on,chmruolntici,focfaoles](mmuilntiimfao)cal (minimal) Chneyocpnregorestsirtsai,gohny/J.airdyhitveihpdaritoaoplchealghloeucplyaattroo,sctycsteens(tnri(innliinonabilnu)alla)r (mid) dPiylgaetraptliaosnt,a,suTcyomepahlocgyltaincd/spta(smmileay)tic. (minim) IHE FOLLONINGTISSUE(S) VERE WITHINMORAL LIMITS ACeODsARaGEUNLAALTIGNLGANGDSLAD oBOoNEnKatROH (STERN) ite RNEECRTVUES, SCIATIC SPINAL CORD, THORACIC SpOraHaATLROVIEDSICLES SPLEEN THROIO' TRACHEA End of Record 17641 BoRUADIDNEKM SSPPeeIvoNenARL'sGOpRaDr,enCERVICAL QTREISNTAERSY BLADER ecvoiomiomioes LfSPReIONSATLATECORD, LIVEAR THIS nw 418-02TPAGE 1-68 ORAVLITH(GTAHVEAGREE)FRCOOBMLBCITNIEODNFRDREEoPVTEEoALcTOoEPLDME04N108TS-A0L2T7OTXOIXCLICTLYTYSTSUCDRYEEN0IFNG1 17655979.7 SPONSOR'S STUDY RABER 1.7509 Tndvidus) Anima) GSr5o5speonrs W11stamorprlogy Data ASoMr:AL WER: "17644 BoEsNeTHGrToYvPeE:, S1cvrifice-Scheduled 8058 psRATIONS): GENERAL No gross changes HISIOHRPHOLOGICopsERATIONS): tot a1 cable HISTORRBrOLOGIC OnsERATIONS: Avmem:en Guns LSeOHeeSn:EN:OE, SUSWAOIBULR: IyTTyaoepcpreuersretlssraietsipisnotynor:,, ahcToeyvrpetoaetiexoyct(eesitiplcnau/ittmpoeatrlca)ymcteeeny(ttroiiicl1o6b(]uMlianrima(ls)110) PTeanfsiecmpaotiieosnt,s,Seoxtmreo,msdmnilairfyo.cs{]ncr(omssiemsi()mins) HE FOLLOVING TISSUELS) VERE wii gous, Luis. aSftNeoEo wash (STERN) SJsaEosAinn LTH Noe, WEDIASTIMAL NERVE. SCIATIC ccEorrviademlrosmises HERES owen STSRtEAoCAuHtELAs VESIELES TRSePisIutNeaAsRLYCOaRuDtoCnERIO. TSoOTsA COR, LUMBAR cetanrnesuaTNG amo SiTPHeIRtNdiAimLoCom, TORIC ISSUE(S) HOTAVAILABLE08EVALUATION eraTROID End of Record. 17644 TT oT 13s 413-027:PAGEJ-69 ORAWLITH(GTAHVEAGREE)PRCOODNUBCITNIEODNRPDEREOPVTEEOALCTOOEPLDHE40NO1TS8AE-L02T7OTXOIKCIICTIYTYSTSUCDRYEENOIFNGT 7TE5S6T9.7 SPONSOR'S STO NUMBER 1-759 Individual nine] GrAopspsendainxd H11istamorphelogy Data AsNeIx:MAL NBER: w17647 DoEsAeTHgToPwE!: Sa1vcrifice-Schaduled 8055 OBSERVATIONS): SEMEBAL: No gross changes. HISTOMORPHOLOGICOBSERVATION(S):| Not applicable HISTOMRPHO1061C OBSERVATIONS: SLTievpoteuosCm:oHmines: dhiynepfmeirlttirraangthifyo.n,lhseaipooanmtnoo,ncuesclullbeumlauarcr-o,csea,lc,enntefroncigallloabnu(dlnualrirn(anari)e1a0.) (moderate) demsinflammation, submcose, glandular ares (roderate) THEFOLLOMING TISSUE(S) VERE WITHvoImN Limits ACORREUALALTILNAGNDGSLAD Hew iSON)E aR (STERN) fro UBR0AIENwM RIONETS LPIEMVPEHR'NSODpE,aiMEDIASTINAL SPINAL CORD, CERVICAL PLRYOMSPTHATNEODE, SPINAL CORD, SUBUADIBULAR LWBAR RNEERCVTE, SPINAL SCIATIC CORD, THORACIC TEGSRTINEASRY BLADDER Ths Throio 0d of Record: 17647 ceaorm wPAiRsATHTROLD SSTPERLHAEICEHMNEAAL VESICLES ns 418:027:PAGE 1-70 ORIALTH(GTAHVAEGER)EPRCOODMUBCITNIEODNPROREEOPVTEEOALCTOOEPLDWED1NO-TS6AEL2T7OTOXXIICCIITTYYSTSUCDRYEEONFINTG 7TE5o9T8.7 SPONSOR'S STUY MNBER 1-750 Individual isa) Gsroonpsenadnid H11istororphalaay Dats Asexna wae: W17654 DoEsAeTHcThYoPwE:. S1uvcrifice-Scheduled 8055 GESERATIONGS): SEAERAL: No gross charges HISTOMRPHOLOSICOBSERVATIONS): ot applicable HISTOORPHOLO01COBSERIATIONS: seK{IvaDeNsrEYS: irTinapfipldahomseait.ai:onCt,hernossniuiobcna,.cutffeoo.caallfoc(amli/mmeualtt)ifocs] (nisl) PiynpFelraimraotpihoyn,, hcahpraotnoicce,ifloucasr),cfeenlttrsifoocballa(rain(iaemamli)nal) IHC FOLLGUING TISSUE(S) WERE WITHYoImN LNT CAeOReREnUAALTIGNuGanGeLsAND SsloEnoaeonuwnow (STUN) fFBirnAe PSLRPIOIHSNPTAHALTNOECDOER,D, SUBMANDIBULAR LAR RSNEPERICVNTEAU,LM SCIATIC CORD, THORACIC SSPRLowEAuDTlHROvIeDsteLes TGeRsItNeRsY sLAER Tims TiRot end of Racord- 17654 ECcpeoioudioAmOoEesWEOTASTINL SSFPETIToNEmARcL'HSCaOtRc,hCERVICAL TRACHER 10 418-027:PAGE 1-71 ORAALTH(GTAHVEAGER) CEOMBIoNEODWDrROErIPoVuETENoLTcIEEoMDESSNiTTEaA-LteT)OTXOINCEIITTYYSTSUDeY nOFnT E758879.7 SPONSGR'S STUOY NER 1-753 Individual Ania) Gsropgpsenadnis W11stomrsvalony Dats SA o ves: 17681 BtoEsReTHcToIeE:, S1arifice-Schasuled saosscesERVATIOS): SEAL: Wo gross changes HISTORMOAISICOBSERATION(): ot applicabie HIsTOORPOLOGIE GRSERATIONS: KiCaoHvmrPasaYo:tLei,o:suowmorouLR ShTPeLhEiiEoNl: sTBiionppeeerrrpotllaaissztitsai;,on,pThmypmshitotociifygoiicccaaltpl(maisnimmas) (saderate) mhUceimitaTltaioccpbaortiaiensocinhsi.raaexBdtoardayrmiseedy)ualtlary, increased (mild) HE 0L0INGTISSUES)VERE WITHINbom, pus: casStcvoanen suis AER, scaric fIsornRe eagaow (ste sliaannep Dinkies Bitkrmsonn ReSeCinTouosehn TSPsA CORD, COMICAL ToStPhI CORD, Lar dof Record. 1701 cCcaeomn OE, EOIASTIIAL {SBnPYiOaRncBopmai.cnhTkiaRACIC wa 418-027:PAGE J-72 ORAVLITH(GTAHVEAGREE)PRCOODNUBCITNIEODNPRDREEOPVTEEOALCTOOEPLDHED4NO1TS0AE-L02T7OTXOIXCIICTIYTYSTSUCDRYEENOIFNGT 71655619.7 SPONSOR'S STUOY NUMBER 1-759 Individual Animal GrAopspsendainxd M11istamorpholony Data sAex:L eR: 17650 DDoEsAeTHGrToIuPpE: S1acrdfice-Schedaled 055 BSERUATIONS): GENERAL: Yo gross changes. HISTOMRPIOLGSICOSSERVATION(S):| Not applicable HISTOMRPYOL0SICOBSERVATIONS: YNLiMvHAerRYNODSEL,NDS:UBMNDIBULAR: VSATGoIuNAc:H: IPiypnpfeelrrapgmllmaaasstiiiaao..n, pIhcyyherspoihnooilccoy,tgiiccf/aoplclsa)s/mmauclyttiifco.ca(lmin(immianli)mal) GmicTiaftiactaitoin.onmu(cmoosdaelratgel)ands (minimal) IHEFOLLOUING TISSUE(S) WERE WITHIN soma Limits cSAoeRlosEnAL Laws BKIIoEONEEMrwsai (STERN) NREeRcVtEo, ScIATIC spLeen owSPeIiNAeLsCORD, Ths CERVICAL RINE BLI0OER TERS End of Record. 17600 BwLRieAnaIsnN SPPAIRNAATLHYCROORIDD, Tsoi UNGAR cIfeNeoHw NODE, MEDIASTINAL SPPEIVNEARL'SCOpRaDc,hTHORACIC THACHER 1 418-027:PAGE 1-713 ORWAILTH(GATVHAEGER)EPRCOODMUBCITNIEODNFRDEREPVoEEvALcTGcEPoDHED4NO1TSA-EL02T7OTXOIXCIICTIYTYSSTUCDRYECONFIGT 17658978.7 SPONSOR'S STUY NUMBER 1-759 Individual Am! Gsroospsenadnid i11stororshalagy Data Asox a ees: v17694 DoEoAsTeHcToIoPEr.: S1ucrifice-Schadulad S055 oseRuATIONS): SEERA: Yo gross changes HISTONRPHOLGGICOBSERUATIONSS): Not applicable HISTOOIOUGGICOBSERVATIONS: Lwnsi: oo, wenTASTINAL HULnIAeNRaGsHReYNODSEL,IDS:UENANDIBULAR: CPmoaanccgrreoosppthhaatggoeenss/..arapylltvohenroeolnpith,eadgofoc(cynatilonsitm(osnli]n(ianianli)es]) IEEuhppreeorrnppblluaasssitaa.. Tpyhmypsnieoclyotigci/cptasmacstic (m6) macrophages. pigmented (minima) HEFOLLOWINGTISSUE(S) VERE WITHINNOBUAL LINITS: cSAoReuEinAnL Guus KiUOnNDwEeOrHsagsow (STERN) LHBieAveaTrrH, oSSutnPaamIMeesyCORD, CERVICAL TFShPAIRNAsATLIRCOORIDD, LWGAR TFSPehIvoNeARiL'nsCOpRaDt,chTHORACIC GRINARY oLA00ER Vagina End of Record 17604 " } cNfEeeRcVumEn, ScuaTIC TRSEPhCLiTEUEcNNh na 418-027:PAGE J-74 ORAWLITH(GTAHVEAGER)EPRCOODMUBCITNIEODNRPDEREPOVETEAOLTCOEOPDLHE40N01TS0AE-L02TT7OOXXIICCIITTYYSTSUCORYEEoNFIN1G T7e5s9t.7 SPONSOR'S STUDY NUMBER T7599 Individual Animal Grsoonpsenadnid H11istororpholaay Data SAoxL NNER: v17695 DooEsAeTHcToYvPEe:: S1acrice-Schedsled 05s psERwATIONS): SEMEBAL: ho gross chores. HISTOHRPHOL0GICOBSERIATION(S): Not applicable HISTONRPHOL0GICOBSERVATIONS: LHe Hove, MEDIASTINAL: uWSrpaleweseRn:Y oh: TrIyaypcpereroroppthlaaascsteissa;., ppThhyyomscpiehonoltcosygdtiicc(a/mlpilnaismamla)cytic (sinima)) Pmaecmraoipohpaogteess,ts.pigauxetnrtaemded(tsloadreyr,otei)ncreased (ni1d) THEFOLLOUING TISSUE(S) VERE WITHINNom Lins. cASoRleoEonAnL GLANDS BiOOoNEEnKsMARO (STERN) tiBHEAvATeRHT LFSIPEHIVPNEHARLSNCOODoREkD.i,cnSUTBHOMRAANCDIICBULARRSENETCRoVTwEa,cwSCIATIC OSiPnIaNiAeLs Thmis GORD, CERVICAL Trach GRINARY suacoeR VAGINA End of Record 17685 cjLeeio SPPAIRNAATLHTCROORIDD, Thoin LVR tra 418-027:PAGE 175 ORAWLITH(GTAHVEAGREE)PRCOODNUBCITNIEODNRDEEPVEEALTOEPDHEDNOTSAELTOTXOIRCIICTIYTYSTSUCDRYEENOIFNGT 7TE5S6T9.7 SPONSORP'RSOTSOTCUOOLY41N8B-0E2R7 1-750 Individua Animal GrAoospsendainxd H11istomorsholagy Data AsNeIx:MAL NBER: 1F7703 oDuEsAeTHGrToYuPpE:: S1acrifice-Scheduled 8055 OBSERVATIONS): SEIEBAL: No gross changes HISTOMRPHOL0GIC OBSERIATION(S):| Not applicable HISTONRPHOLOGIC OBSERVATIONS: KGLaiTpvHieGesHr:s.NODE, SUBMANDIBULAR: NTSpHAivMERAeOnRI:YD:GLAND: ures: oIIyinpnfeelrrapamllmaiasztiaiato,ni,onI,cyhmrmpolhnoticicyf,toficcos/c]palla(snmmiuenlyittniiafc1o.)ca(nrod(earfsntei)m) uhIeylmptaeitrsopoplboarisaeinsaci;hsi.pahaybxsteirdoaclmyodgsulitlcary, incressed (si1d) Racrophages. pigmented (sodarate) HE FOLLONING TISSUE(S) WEREWITHINNORMAL LIMITS. AJcoReuEsnAuL LS BLBOONsEDEANRAM (STERNN) HBaRaAIrN LINPH NODE, MEDIASTINAL oSPiINlALsCORD, CERVICAL THs PSPAIRNAATLHYCROORIDD, TRACKER LWGAR PSUPERIVINENARAL'RSYCOBpRLDAa,DiDETR.WIRACIC End of Record 17703 cLeeewm NRSETeROVcMEAt,CHSCIATIC I 114s 418-027:PAGE 1-76 ORWAILTH(GTAHVEARGEE)PRCOODNUBCLTIIEODNDREEPVEEALTOEPDMEDNOTSAELTOTKOIXCIICTIYTYSTSUCDRYEEONFINTG 7T5E0S9T.7 SPONSORP'RSOTOSCTOULOY41N8N.0E2R7 1-799 Individual Anima GrAoospsenadnid H11istomorgholosy Data. AseNx:AL NBER: v17713 DooEsAeTHcrToIuPpE:. S1acriflce-Schaduled R055OBSERITION(S): SENERALL Yo gross changes. HISTOMRPHOLGSICOBSERVATION(S):| Not applicable HISTONORPHOL061CoBSERATIONS: lrLieHvaePr:10DE, SUBMANDIBULAR uJroemsa! Gin: pTaecruisctaartdiiotni,s, Toperoasia. hDecyphmraaotnnooicccye,tlilcuf/looaclras,lsmm(auemlyittinifcio.sc)a(lmi(nmeisnli)mal) mdTiayscptreeornppthliaaogsnei,sa.. lppuhimyegnarteon(ttaoeigdniics(aasllo)derate) THEFOLLOVING TISSUE(S) cAKoDiRoiEnENrAsL GLANDS ouSSPtiIoNeAwLseCORD, CERVICAL RINRY BLADDER Ed of Record 17713 ERE WITHINMORAL LIMITS. DtSUOOsNEDEaNUtMROw (STERN) STPPAaIRNAsATLHYCROORIDD, UNGAR visi BHReAIN LPSIPENIVPNEHARL'NSOCDOPERA,DT.CMHETDHIOGAASCTIICNAL Thos ceaamm NREERVCET, SCIATIC STPRLaEcEkNen 14s 418-027PAGE I-77 ORVAILTH(GTAHVEAGREE)PRCOODMLBCITNIEODNFROREEPOVETEAOTCLEOODLMN1OTU-SA0EL2T7OTXOIXCIICTIYTYSTSUCORYECHOIFNGT E755919.7 SPONSOR'S STUOY NMBER T-7509 Individual Animal Grsoospsenadnid H1i1stosorpholaay Data SAx.a ges: v17715 sDEeATHGToIwEr.: Sa1 crce-Schedsled S055opsERATIONS): SEERA Yo gross changes. HISTOMORPHOLOSICOBSERVATIONS): Not applicable HISTOORPrOLOSICcoscRMTIONS: JALiRIEeMALOOGFL,ANSS:UBMANDIBULAR: ShHTeeaaeAnsR::Y GLA: iiTunnpffeilr1aptmlraaatstiiioaon,n., lryComhnprohoonncuiycct,liacaf/rg-icoaeslfmmlac.cymtsuiflcot.1ciaf(lois1s{a]a)in(immianli)ma) btmepmheartrpclpeaostieas,is,phayxstiroalnoegdiasltary. increased (sininal) macrophages, pigmented (moderate) IHCFOLLOING TISVSERUE WEIT(HINSNo)y, Luis: ofCuONi0E 0nHNaw (STERN) HLBeiAnaTerH cLTeIeWowPH NODE, MEDIASTINAL ToSiPaIMstALsCORD, CERVICAL FTSAPhRIrANRTAoLiIoRCOOIRDD, LWGAR STPPREIAENCAHRLESACOPRADT.CHTHORACIC VAG End of Record 17715 SNcEoeRuVanE,nSCIATIC RSRTEOoCmAkTcRn SLATER ny 418-027:PAGE J.78 ORAWLITH(GTAHVEAGER)EPCROONDBLICNTEIDOWRPDEREPOVETEOALCTOOEPLDHE4DNO1ST8EA-.L02T7OTXOIXCIICTIYTYSTSUCDRYEEONFINGT E750819.7 SPONSOR'S STUDY NUMBER 1-759 Individual aime] GrAoospsendainxd 1H1istamorsbology Data AseMx:AL NBER: v17716 oOoBsAeTHGToYwP:E. Sa1 crifice-Scheduled 58055 OBSERVATIONS): SEUEBAL: No gross changes HISTOMORPHOLOGIC OBSERIATION(S):| Not applicable HISTOMORPHOL0SICOBSERVATIONS: JvLOeYOrMN:ARYNODGEL, :SUBMANDIBULAR ures: phPeyycppreeorrsspillaaa.sstiaaf..ocapylheyps(hiaooiclnyoiegmiatclca)/lplasmeytic (minimal) macrophages. pigmented (soderate) HE FOLLONING TISSUE(S) VERE WITHIN NoORIAL LIMITS. AEcoRdlEoonAmL Glas KBDOUINDEDDEWSNAMRROM (STERN) RNEeRcVoEn, SCIATIC Shien oSuPIRNiAeLsCORD, CERVICAL Sion TRACKER ARDIARY BLA0OER 0d of Recora- 17716 BwwReeAaIrN BSPAIRNAATLHYCROORIDD, LUMBAR VTAiGmINsA. cLjIeMedPwH NODE, HEDIASTINAL SFPeIvNeArLsCOaRtDo,nTHORACIC TiRoio 11-8 418-027:PAGE J79 ORAWLITH(GTAHVEAGREE)PRCOODNUBCITNEIDONREDEPVEEALTOEPDHE0N0TSAELTOTXOIKCIICTIYTYSTSUCDRYEEONFINGT 7TE5S0T9.7 SPONSORP'RSOTOSCTUOOLY41N8U-M0B2E7R 1-750 Individial Animal GrAopspsendainxd i11stomorpholasy Dota SAex:L NER: 17717 DDoEsAeTHGrToIuPpE:: 1Sacrifice-Scheduled O0B5S5ERIATION(S): SEUSRAL: Yo gross changes. HISTOMORPHOLOGICOBSERVATION(S):| Not applicable HISTO05M1COOBRSEPRIAHTIOONSI: HLuMnTAsHRYODSEL,R:SUBMANDIBULAR: uTTherRoUlso:: iTPyynppfeelrroppmllaaatssiiioaan,;, plryimyngtshetorosstytctiiitccis/aptll,asmmualctyitfiocc.al(sl(imdi)nias]) mualcErionpohbargaensc,hiapligebeondtye/dcys(tsoderste) HEEOLLOUINGTISSVEUREWEIT(HINSMO)RAL LIMITS. AcSDoReEnNnAL GLANDS BoKOuINDEDDaSRtMROM (STERN) LiHBeRvdAeeIrrN NREERCVOEN, SCIATIC Shien oSwPIeMAsL CORD, CERVICAL Soucy SPPAIRNAATLHYCROORIDD, LWGAR Ths. URINARY BLADDER AGI End of Record 17717 cLjeYedNw NODE, MEDIASTINAL SpTPERIYANECARHL'ESACOpRaDc,hTHORACIC i 418-027:PAGE 1-80 ORIALTH(GTAHVEAGER)EPCROOMDBUICNTEIDOWFROREEOPVTEEOALCTOOEPLDWEDNOTSAEL2T7OTKOIXCIICTIYTYSSTCURYEEoNfING1 T7E559T8.7 SPONSOR'S STLOY NMGER T7599 sinL ser: l1i719 Individual nm) GrAopspsenadnidx i11stororshalasy Data DoEoAsTeHcoTYoPrE:: Sa1 criice-Schediled S058opsERUATIONS): SEMEBAL: No gross changes HISTONRPHOLGGICOBSERVATIONS): Not applicable HISToMORPIOLOSIC opseRvATIONS: LHIAMPAODGEL,AS:UBHANDIBULAR: TUHes:: PITyynppFeeirrcpsmtlaaatssitioean,.,IphySyomsbpiehacotucotygetiiccne/ilp1laa)smecytic (mini) sJcrriopchtagaeis,tipoigdnenteedd (mderate) HEFOLLOUINGTISSUES)WEREWITHIN omuALLiNITS: AcSoEuRdnEum Guus KIBSONuNnEEdTEHSNaMgRow (STERN) LHSiEAvAeRTrT RENECRTVE, SciATIC spieen SvSTPiOIeMLsCOR, CERVICAL TSEhAPrRRALoTiIDNCROORIDD, LUNAR URINARY L00ER Vad cLLieeneew TSpPeRIvANeCAaHL'EsACOpRaDt.cnTHORACIC IASSUEV(S)ANOTILAFORBEVALLUATE ION: wen nao, weoiASTINAL End of Record 17719 ns 418-027:PAGE J-81 ORWAILTH(GTAHVEAGREE)PRCOODMUBCITNIEODNRDEEPVEEALTOEPDHE0N0TSAELTOTXOIXCIICTIYTYSSTCURDEYENOIFNG.T 7T5E9S9T.7 SPONSORp'RSoTOSCTOULDY41N8U-M0B2E7R T-7589 Individual Animal GrAoosspeannd 1H1istamorphology Data AsNxAL NER: 1F7675 DoEoAsTeHgToYPwE:: S11cr fice-Scheduled 62055 OBSERVATIONS): SENEBIL: No gross changes HISTOMRMOLOGIC OBSERIATION(S):| Not applicable IUEFOLLOUINGTISSUE(S) WEREWITHINNORMAL LIMITS. ve Hows End of Record- 17575 or Cr est 413-027:PAGE J-82 ORWAILTH(GTAHVeAGER)EPCROOMDBUICNTEIDOWRPOEREPOVETEOALCTOOEPLDWE04N01TS8AE-L02T7OTKOIXCIICTIYTYSTSUCORYEEONFINTG 71E55919.7 SPONSOR'S STOO NMGER T7599 Individual Anim GrAoospsenadnid i11stcmorshology Data MseAx:L NBER: ;17678 DooEsAeTHgrToPwE:, S11oci ice-Scheduled R058 OBSERITIONS): GENERALS No gross changes. HISTORPHOUGGICOBSERVATIONS): Netspp cable HEFOLLOUING TISSUE(S) WERE WITHIN No LIMITS: uve THs End of Record 17678 1s 418-027:PJA-G8E3 OREALTH(GTAHVEARGEE)PRCOODWUBCITNIEODNRRDEEPOVEAETTLECODPED4NO1TS8AE.L62T7OTKOIXCIICTIYTYSTSUCDRYEEONFINTG T7E5S9T8.7 SPONSOR'S STUDY NMGER 1-759 Individual Anil GAroopsesnadnidx W11stamorsholagy Data ASNoAL NNER: 1;7684 DoEsAeTHGTaIoPE:. S11acrifice-Scheduled 2055 OBSTRUATIONS): GENERAL: ho gross changes. HISTOMORPHOLOGIC OBSERVATION(S) Not applicable THE FOLLOUING YISSUE(S) WERE WITHIN NORMAL LIMITS. uve THs. End of Record 17684 11s 413-027:PAGE J-84 ORWAILTH(GTAHVEARGEE)PRCOODMUBCITNIEODNDRPEERPOVETEOALCTOOEPLDME4DNO1TS8AE.L2T7OTKOIXCIICTIYTYSTSUCDRYEEONFINGT 7T5E0S9T.7 SPONSOR'S STUOY NNER 1-759 Individual Ansel GArpopsesnadnidx i11stamorsholagy ta sAeL WER: 17688 nDoEsAeTHGTaYoP:E Sa11crifice-Scheduled 2055 OBSTRVATIONS): SEMERAL: Yo gross changes. HISTOMRPHOL0GICOBSERVATION(S): Notapi cable THEFOLLOMING TISSUE(S) ERE WITHINMORAL LIMITS. uve Hs. End of Record 17608 ese 418-027:P1A-G8E5 ORMAELTH(GTAHVEAGER)EPCROOMDBLICNTEIDONRR/EODPTEEOVACETOLEOLDPED4NO1TS6AE.L62T7OTKOIXCIICTIYTYSTSUCDRYEEONFINTG T7E5S0T9.7 SPONSOR'S STIOY NNER 1-759 Individual Animal GArpopsesndainxd H1i1stamorsholagy Data sAeL wen: ;17608 DDoEsAeTHGTrIoPwE:: S11acrifice-Scheduled 2053 OBSTRUATIONS): GENERAL: No gross changes. HISTOMORPHOLOGIC OBSERVATIONS) Net applicable HISTO0MG1COOBRSEPRVAHTIOONSI: THs: atrophy (minimal) HE EOLLONING TISSUE(S)VEREWITHINNORMALLIMITS: we End of Resora-Tass mm ss 418-027:PAGE J-86 ORAVLITH(GTAHVEAGREE)PRCOODNUBCITNIEODNRPDEREPOVETEOALCTOOELPDHE4DNO1TS9AE-L02T7OTXOIKCIICTIYTYSSTCURYECOKFINGT T7E5S0T9.7 SPONSOR'S STUOY NABER 1-7599 Individual Animal GrAaosspeannd H11istomorsholosy Data HseAx:L NogER: 1;7702 DoEuASTEHGhToIuPpE:! S1a1crifico-Scheduled 8055OBSERATIONS): SENEBAL: No gross changes. HISTOMRPHOL0GIC OBSERIATION(S):| Wotapplfeable IMFEOLLOUING TISSUE(S) ERE WITHINNORA LIMITS: ver THs. End of Record. 17702 11-56 418-027:PAGE J-87 ORWAILTH(GTAHVEAGER)EPRCOOMDBUICNTEIDOW/RDEEPVEEALTEODPMDEONSTEALTOTXOIKCIICTIYTYSTSUCDRYEENOIFNGT T7E5S3T9.7 SPONSORP'RSOTOSCTOULOY41N8U-M0B2E7R 1-759 Individus) Animal GAroopsesndainxd H11istosorphology Data DsexAL vg: F17704 DDoEsAeTHGrTIoPuEp:: S1a1crifice-Schaduled SR055OBSERVATIONS): GENERAL: No gross changes. HISTOIORPHOI0G1COBSERVATIONS): hotap cable HISTOIORPHO0G1COBSERVATIONS: uve: inflammation, chronic, focal/multifocal (minimal) THE FOLLOMINGTISSUE(S) WEREWITHIN NORMAL LIMITS: Tons End of Recora- 17704 " or CTT es 418-027:PAGE J-88 ORAWLITH(GTAHVEAGER)EPRCOOVDBUICNTEIDOW/RDEEPVEEALTEODPMEDNOTSAELTOTXOIXCIICTIYTYSTSUCORYEENOIFNGT 7TE5S9T9.7 SPONSORP'RSOTOSCTOULDY31N8M-G0E2R7 1-758 Individus) Anima] GArpospsenadnidx H1i1stomarphalogy Data MsxAL WER: F17707 DDoEsAeTHGrTIoPuEp:: Su11crifice-Scheduled 2055OBSERVATIONS): SEMERAL: No gross changes. HISTOHORPHOLOGICOBSERVATION(S):. Notapicsble HISTONORPH\0G1C OBSERVATIONS: Le: niencfrloasmimsa,tiofno,calchr(omniicn,aflo)cal /mtifocal (minima) THE FOLLOVINGTISSUE(S) VERE WITHIN WORMAL LIWITS: THs. 1d of Record- 17707 - or Tm tess 418-027:PAGE J-89 ORWALET(GTAHVEAGER)EPCROOMDBLICNTEIDONER/REDOPETEVOAECTLOEOLDPEDhNOaTSAEiLTrOTKOIXCIICTIYTYSTSUCDRYEEONFINTG 7T5E0S9T.7 SPOISOR'S STIOY NNER T-7599 Individual teal GrAoospsendainxd H11istanorpbolody Data Asex:L NBER: F17708 oDuEsAeTHcoTYuPpE:: S11acrifice-Scheduled R053 OBSERITIONS): GENERAL: Yo gross changes. HISTORPIOUGGICOBSERVATIONS): Not spolicale THEFOLLONINGTISSUE(S) VERE WITHIN MRL LIMITS ver ws End of Record 17708 or or 11s 418-027:PAGE 1.90 ORAVLITH(GTAHVEAGER)EPRCOODNUBCINTEIDON/PRDREEOPVTEEOALCTOOEPLDWE4DN1OT8SA-EL02T7OTXOIRCIICTIYTYSTSUCDRYEENOIFNGT T7E5S8T0.7 SPOVSOR'S STUY NUMBER 1-750 Individual Anima GrAapspsendainxd H11istomorsholosy Data AsNeIx:MAL NBER: F17710 Do0ESAETHGrToYuPpE:. S11acrfice-Schaduled 58055 OBSERVATIONS): GENERAL: No gross changes. HISTOMORPHOLOGICOBSERVATION(S):| Hot applicable HE FOLLONING TISSUS(S) WEREWITHINNORUAL LTS: uve THs End of Record 17710 11-80 418-027:PAGE 1-91 ORWAILTH(GTAHVEAGREE)PRCOODMUBCITNIEDONRPDErEPoVEtEAoLcTOoEPlDWE04N01TSA9EL-02T7OTXOIXCIICTIYTYSSTCURYECOKFIYTG 7TE58978.7 SPONSOR'S STUDY NNER 1-7500 Individual Anim GrAopspsendainxd H11istororphalasy Data SAona ees: v17687 oDEsAeTHoTuYrP:E. Sa11c1eFice-Schedsled GSS scRuATIONS): SEARLS No gross changes. HISTOMRPHOLOGICOBSERVATIONS): Nat applicable THEFOLLOUING TISSUE(S) ERE WITHINNowy Luis. ven ns End of Record 17687 tt 418-02T:PAGE 192 ORAILTH(GTAHVEAGER) CEOMPBINREODWORDPEREPOVDETEOALCTOUOEPLDMCE01NU5TSTA.EL52T7OTXOIXCIICTIYTYSTSUCORYEEONFIN1G T75E9T9.7 SPONSOR'S STOO NMGER 17590 Individual Anim) rteaospeonsg H1istorica ta Asox:a woes: li17693 DoEoAsTeHGToPwE:. S1a1c1rFice-Schadalad sassopseRmTIONS): GENERAL No gross changes. HISTORPUGGICpESERATIONS): hot applicable HISTOMRPrOLGSIC CRSERATIONS: vers Inflation, conicfocalmtface ainieal) HEFOLLOVINGTISSUE(S)VEREWITHINNoRAL LIT: Ths ns 418-027:PAGE 1.93 ORWAILTH(GTAHVEARGEE)PRCOODMUBCITNIEODNDREEPVEEALTOEDPEDNOTSAELTOTKOIXCIICTIYTYSSTCURDEYENOIFNGT T7E5S0T9.7 SPONSORR'SOTSTCIOY41N8-M62R7 1-759 Individual Ania) GArpopsesnadnidx W11istamorsholagy Data sAeL eR: 1;7667 Ga0ss oasemuATIONS): SEMERAL: ho gross changes DooEsAeTHgaTIoPwE:. Sa11c1rifice-Scheduled HISTOMRPHOLOGIC OBSERVATIONS) Wot appl fcable HISTONRPHOLOGIC OBSERVATIONS: THs: Jp ne) THEEOLLOUING TISSUE(S)WEREWITHINNOBUALLIMITS: we Ed of Record wes Tm es 418-027:PAGE J-94 OREALTH(GTAHVEARGEE)PRCOODNULCNTEIODNOREEPVEEALTOEPDEDNOTSAELTOTKOIXCIICTIYTYSTSUCDRYEEONFINTG T75E0S9T.7 SPONSORP'RSOTOSCTOULGY41N5N-0E2R7 1-759 Individual Animal GrAaospsenadnid H11istomorsholoay Data AsNexI:MAL NONBER: F17700 DoOESAETHGhToYwPpE: S1a11crifice-Schadaled R055OBSERIATION(S): GENERALS No gross changes. HISTOMRPHOIGGIC OBSERVATION(S):| Not applicable HISTOMRPHOL0SICOBSERVATIONS: uve inflammation, chronic, focs)/multifocal (minimal) THEEOLLOUING TISSUE(S) WEREWITHIN NORuAL LMS: Tovas ns 418-02TPAGE 1.95 ORLALTH(GTAHVEAGER)EOCDONUBAITNIEDONRRDEPEOEVTAETLCEODMES4N1TE0A-L02T7OTROIXCILCTIYTYSTSUCDRYEE0NFING1 7165597.7 SPONSOR'S STOO NNER T7599 Individual Anim GrSoosspeanrd 1i1stomorshology Data Aeya wes: li17701 DooEsNeTGrTYoPwE:, S11c1r fice-scheduled stsoostRIONs): SEMERAL: No gross changes. HISTOLOGICapsERATIONS): Not sppltcable HISTORRPHOLOSIC OBSERVATIONS: uve inflomation, chronic. focalfmtfocal (snfes]) IMEFOLLGUING TISSUR(S) VERE WITHIN noun, LTS hws End of Record- 17701 CTT ss 418-027:PAGE 1-96 ORWAILTH(GTAHVEAGER)EPCROOMDBUICNTEIDOVR/FEOREPoVETEaALcTaOELPDWE04N1ST0EA-L02T7OTXOIXCIICTIYTYSTSUCDRYEEONFIN1G 7TE5S9T9.7 SPONSOR'S STUDY NABER T7599 Individual Anim GrAopspseanndd H11istoorphaosy Data Asex:L BER: 17705 DoOoAsTeHoTeYP:E: S1a11criice-Schediled 8055 QRsERATIONS): SEMEBAL: ho gross charges. HISTONRPIOUGGIC BSERATION(S): Not applicable HISTOMRPHOLOSIC OBSERVATIONS: uve: Inflomation, chronic,focal mitsfocal (ainieal) IH FOLLOUINGTISSUES) VERE WITHIN omuALLiu: Ths dof Record10s 11-66 418-027:PAGE 1.97 ORVAELTH(GTAHVEAGER)EPRCOODMUBCITNIEDONPROREEOPVTEEONLCTOOEPLDHEO4N1ST8AE-L02T7OTXOIXCIICTIYTYSSOCRYEENOIFNG1 7E50975.7 SPONSOR'S STOO KMGER 17599 Individusl Anieal GrAopspseanndd H11istomorpholooy Data MsexA:L BER: 1;706 oDuEsAeTHrToYwPE:. S11a1ri fice-Schedsled R053 OBSERIATIONS): GENERAL No gross changes. HISTONRPHOLGGICOBSERVATIONS): Not apoticale HISTONRH0\GGICOBSERVATIONS: uv: Inflammation, chronic,focal fmtfoal (ainieal) HEFOLLOUING TISSUE(S) weRE wITHIN oma, LiwrTs: THs Ed of Record Tos Tse ne 418-027:PAGE J-98 GRAWLITH(GTAHVEAGER)EPRCOODMUBCITNIEDONFROREEOPVETEAOLTCOEOPDLHE4ONU1TS5AE.L02T7OTXOIXCIICTIYTYSTSUCORYEEONFING1 T7E509T8.7 SPONSOR'S STUOY WAGER 1-7500 Indivicus] Animal GrAoospsenadnid H11istamorsholooy Oats AeyL Weer: ;1708 DooEsNeTrToYwE:, S1a11crifice-schadulad A058OpsERATIONS): SENERAL to gross changes. HISTOORPrOLGSIC coscRMTION(S): tet sppicable HEFOLLOUING TISSUES) uERE uITHIN omuAL Luis: uve ws 0d of Record 17708 CTT = 418-027:PAGE 1-99 ORVAILTH(GTAHVEAGREE)PRCOODMUBCITNIEODNPRDREEOPVTEEOALCTOOEPLDH4ED1NU5TS-AE0L2T7TOOXXIICCIITTYYSTSUCDRYEENOIFNGT 71650979.7 SPONSOR'S STLOY WMGER 17599 Individual Anima) Gsroonpsenadnid H11istomorphalaay Data ASenx:na wer: v1718 DoEsAeTHsThYoEw,: S1a11crice-Schedulod S055 sERwATIONS): SEHEBAL: No gross charges HISTONRPHOL0GICOBSERIATIONS): hot applicable HISTOORPHLOC sERIATIONS: Liver: hematopotests, extramedullary, mitifocal (sininsl) HEFol0uING TISSUE(S) VERE WITHIN onus, LIN: ns E03 oF Record 7716 TTT 1s 418-027:PAGE J-100 ORIALTH(GTAHVEAGREE)PRCOODMUBCITNIEODN/RDEEPVEEALTOEPDME0N0TSAELTOTXOIXCIICTIYTYSTSUCDRYEEONFINGT 7TE5S9T9.7 SPONSORP'RSOTSOCTOULOY41N8U-M0B2E7R 1-759 Individual Animal GrAopspsendainxd H11istomorphology Data asex:L ree: F17720 DDoEsAeTHcrToYPuEp:: S1a1o1ri Fice-Scheduled GR0SS OBSERVATIONS): SENERAL: Yo gross changes. HISTOMORPHOLOSICOBSERVATIONS): Not applicable HISTOHORPHOLOGICOBSERVATIONS: uve: inflammation, chronic. focal /mtifocal (minima) THE FOLLOVING TISSUE(S) WERE WITHIN NORMAL LINTS. THs. 14 of Record: 17720 - oT TT wn 418-027:PAGE 1-101 ORAWLITH(GATVHAEGER) CEOMPBINREODMORRDEEOPVDETEALETGLEPLDWCE04N1T00TAS-L02T7OTXOIXCIICTIYTYSSTUCYREOEF N1 1750878.7 SPONSOR'S STUDY NR 1-758 SoAna wre: 1768s Individual Ani) rAecospeanns W11stomrpralony Data DmsEeNoToEr,: Si1vrs fce-Schadiled `GROSSOBSERVATIONS): SEMEBAL No gross changes. HISTOMRPHOLOGIC QBSERVATION(S): Pr HISTOMRPHOLOGIC OBSERVATIONS: pcionses HLreansm0kS,csuoumOISULA: pFriepliictoirst,, chTroomnaitco,(sfoicnats) RNRrppeeerrtrpalaapastrtyea.,, RpTehpveaittooeretgiiucleaorrr, icesnterislobautlearr (tien)iesl) sacroprases, pigmented (minim) HEOLOMING TISSUES) WERE wT soma, LTS ASCeoRstEonAL Guns SlSoonegeninow (STON) SdSPtuIoNeALsCOW, CERIO. fTSPhrIMsALeCOU. eA IY auio0cR rs of Recora. 17085 LwBIAoNNrP ODE, WEOLASTIMAL STFPEmIVoNEAiRLoSCoPmhoCHTHORACIC cNtEieRoVnEn, SCIATIC SfTPoeLaErEc)Nn wn 418-027:PAGE J-102 ORVAILTH(GTAHVEAGER)EPCROOMDBUICNTEIDONRREDOPETEVOAECTLOOELPDHEO4NU1TS.RE0L2T7OTXOIXCIICTIYTYSTSICORYEEONFINTG T75o9T9.7 SPONSOR'S STUOY WAGER 1-7500 Individual Animal Grsopspsendained H11istamorpholoy Data Asexn:a wre: F17508 oDoEsAeTHGrTYoPwE:, SIvari ice-Scheduled R053 QRSCRUTIONS): SEAERAL: No gross changes. HISTORRPIOUGSIC OBSERVATIONS): fat applicable HISTONORPROLOGIC OBSERVATIONS HLLiAvoeRs:ToeGL,ADs:ueunOIsUL iTUHTsTREiDSI:D:: TIIupnpeferlrpoplmiaaatssiitoaan;,, Ipchyhymrspoinncaiiccay,gtificoca/clpailasmmuslctyitfiocca()mod(eariantiee)sl) SmUclrEieipeeDhbargtaensec,hiapfliegsnbzeoandrtyaertdec.)ya(tnininal) HEFOLLOWINGTISSUES)WERE WITHINomuALLINITS: AGJoelRoowEn GLANS KBiSUoODNvEEerNHsogeow (STERN) LiBrAnTeyH NSSEPTRIoVNmEAa,LcHsCOcRuDa,TicCERVICAL TBSHPAIRNAsATLHRCOOIRDD, LWGAR FSTPeRIvANeCARHLE'RsCOaRrDe,nTHORKCIC TISSUE(S) NOT AALLABLEFOR EVALUATION. owtes End of Record 17685 cLLIeeNomE NODE, NEOTASTINAL SSGREtiCiRTY suasoeR nr 418-027:PAGE 1-103 ORAVLiTH(GTAVHAGER)EPCOIDNCBITNIEODNDROVETPEELOAOTPLEWDE40N10T0AS-L0T2TO7XOIXCEIITTYYSSTcURYEE0NFNG1 17655878.7 SPONSORS STUDY NBER 1-7589 Idividuo) Anos! Grteosspeanss M11stamorphalogy Data Snoa recs: 1;7ees cGoEsAeTHcTrPoE:S S1vri lcs-Schacutod anos onsemuTions): I-- HISTOMORBHOLGGIC OBSERVATIONS): totapiscavle HisTosOLCEIeoastavATIONs: uve: HpLiooawlwooik,inwepuASTIOAL Siiees: ICironpnfeglreaesmrtmearstyhiyot.nh,nreocphpertmoonacigecol,feltoanec.sifcsump(timHf0ot)cG)oo(nainoimeail)t) TRorperenersrpTploiapnseitsasi;.ahsyhpbvrxeetctryoatrmitacii/inolttaarsym,accyrtolcss(end11d()sinial) eropneses, pigmented (m9) HEFOLLOMINGTISVSEREUWITEHISNNoo)uAL LIMITS CASaeRtdEoonAmLn cos fJsiornre iiwn (STEN) pTSiPoIreNAsL Con, CERIO BTSiPhIarNtAoLnoCOlRoD, LummiR wha En of Record. 17000 wsleooarn SbTPeaIvNEtAreL'srCommpc, THORACIC cNTEieReeVn, sciatic RSRiIeaGcnH suooex nn 418-027:PAGE J-104 ORAWLITH(GATVHAEGER)EPRCOODMUBCITNIEDONRPDEREPOVETEAOLTCOEOPDLHEO4N1UT3SA-EL02T7OTXOIXCIICTIYTYSTSICORYEENOIFNGT 7TE5S9T9.7 SPONSOR'S STUOY NNER 1-7508 Indivicus) Animal GrAoospsenadnid H11istomorpholaoy Data Asex:L oe: 1F7691 oDoEsAeTHgrToYvPeE:, S1vari ice-Scheduled R053oBsCRITIONS): SEERA No gross changes. HISTOHRPHOLGGIC SERVATIONS): Not applicable HISTORRPHOUGSICOBSERVATIONS: Live: LHTRIaoPanDgO: GELADS:UBMANDIBULAR: ureRus: PgIrnepfreltrarpmioaaotshiiyoa.n., hTceyhpmrahootncoiyccte.ilfcuo/tpcalaral,smmcauoclnytttirifico.Tocn()uilna(sraein(tit)enailp)al) Iaylpteirmpolbarsainac;hiaothybeodryoiiceysatt macropnages. pigmented (soderate) HEFOLLOUING TISSUE(S) WERE WITHIN oma Liu. AElRooEnAnL GLANDS KBiOo0NnEe0rsMaw (STERN) jHAiELAsRNT sReREERCeVTEn, SCTATIC oSSPtaIoNrAmLscCORD, CERVICAL TPSPRiIRWAsATLHTCROORIDD, (GAR RIARY sLasoER VAGINA End of Record 17681 - cLtIeeMomP DO0E, NEOIASTINAL FTSPERIVANECARHL'ESRCOPRaDt.chTHORACIC nn 418-027:PAGE J-105 ORAWLITH(GATVHAEGREE)PRCOODMUBCITNIEODNRDREEDPVTEEOALCTOaEPLDNED4NO1TS6AE-L62TT7OOXXIICCIITTYYSTSUCORYEEONFIN1G 7TE5S9T9.7 SPONSOR'S STIOY NMGER 1-759 Individual Animal GrAoospsenadnia 1H1istamorshology Osta AsiNx;AL NNER: V17652 DoEoAsTeHGTaEo.: Sa1crifice-Scheduled 58085 OBSERVATIONS): SEIEBAL: No gross changes. HISTOMIRPHOLOGICOBSERIATION(S): Hot applicable HISTONRPHOLOGIC OBSERVATIONS: GLKiIivHpeEeRHr:sN:ODE, MEDIASTINAL MLoATnHRs:YNOCDEL,AD:SUBMANDIBULAR: mcPyiopnneegrretasrltoiipzohanyt/.ieornyh,tehprmauotlpothcieaflgolocucalylatro,s(imscienn(immtiarli1d)l)obular (mines) FPuappeerrppliaassitaa;, pThyymaptroatcoyatircca/lptasmacytic (soderate) atrophy (atid) HE FOLLONING TISSUE(S) VEREWITHINNOBUAL LIMITS. AcSoRelEoanAmL GLaos ThPSPAaIRNAoATLHYCROORIDD, LIBAR VATA BDLOuUNnDEgDEARRNRON (STERN) TPSRPEAITCNEHARELSACOpRaDr.esTHORACIC 0d of Record: 17632 eNBERaRAVIrEN, SCIATIC RSEPCLTEEN GRINRY BLADER coLeveewiws SSPtIoUAwLeComo, CERVICAL ores 117s 413-027:PAGE 1-106 ORWAILTH(GATVHAEGER)EPRCOODMUBCITNIEODNRPDEREPOVETEAOLTCOEOPDLMED4NO1TS0AE-L02T7OTXOXIICCIITTYYSTSUCDRYECOHFNGT 7T5E9T9.7 SPONSOR'S STUDY NABER T-7599 Individual Aisa) Grsoospsenadnid H11istororphalaay Data Asexna ees: v17636 DsEeATHoTuYrPE:, S1avcrice-Schedsled S058 psERUATIONS): ms: smn HISTOHRPHOL0GICOBSERIATIONS): Tissue rat avatlable HISTOMEPIOLGGIC asscRuATION HHLeAIaMMrAP:RYODSEL,DS:UBMANDIBULAR: uTTeRilos:: IIiypnpeferlrpaplmlaaaststitaoan;,, Ipyshueybpsanicaoucitysetg,iicfc/oapctaels/memcuyttifcoe(s]m1()minima) nunilfcilrmaoompranatoniocoehnsi,opleingdmboeomndetyterrdyisu(mtr,oddeirfautes)e (nile) distention, Toman (moderate) HE 0LLOUINGTISSUE(S) WERE WITHIN ou, LINTS: KciAobRlvoEenArLs GLANDS sRhENECeRTeVUEn, SCIATIC Aci fJrBiOeNEieHnAO (STERN) BLeoRnAweIN cSSuPtaIoNlAceLksCORD CERVICAL TePSPAcIRhNAATeLHRGOOIODD LVGAR LcSeIecMunPmnO0E, WEOIASTINAL FSUPREIIVNNEAARLRSYCOoSRLADAT.CcOHETRHORACIC IASSUEV(S)ANOTILA08BEVALLATIEON: THs End of Record 766 ws 418-027:PAGE 1-107 ORAVLITH(GTAHVEARGEE)PRCOODMUBCITNIEODNRPDEREPOVETEOALCTOOEPLDHE04N10T8SA-L02T7OTXOIXCIICTIYTYSTSUCDRYEENOIFNG1 7Te5s9t9.7 SPONSOR'S STUDY NNER 1-7508 Individual Animal GrAoospsenadnid H11istamorpholooy Oats ASoxa wees: l1i 99 DooEsAeTHoTwYePE:. S1avcri Fice-Scheduled 8053 opsERUTIONS): SEARLS Yo gross changes. HISTOORIOUGICOBSERUATIONSS): Not spoicabe HISTONRRHOUGICOBSERVATIONS: tKiiovwee:rs: HLSaIeANnRY10G0EL,ADS:UBHMOTBULR flTTHihrRiosID:: mIToinpnfeelrrutamrlaoitpzihaoytn.i,onh,ierpmoaintliotcci,eflofucoteca)arl.(cmseinnlitnrailb)caulla(rain(smemsnli)aal) RIIoeopmpeaertrpoplplaoastsietasa;i.s.pIhayymxsntiaroclayontgaiidcca/alslalrays,mseiyntcirceas(erdode(rssirnei)mal) maUaticrEroiopmpohhbyarga(enasci,hniianplailg)Beaednyi/ecdys(tsoderate) TIE EOLLOUINGTISSUE(S) VCREWITHINNORMAL LIMITS: AcSoelRoinEn sos DtBUoOnONeDEENHUAMRRY (STERN) pSTrPRIAaVCAHLE CORD, CERVICAL SGPRPAIIRNMAAATRLHYYCROSORLIDAD.BoEURNGAR End of Record 17660 LHBIERNAABRIHTN MODE, NEOTASTINAL SsPPEiITNnEARgL'SCOPRaDrcTHORACIC NciEteReVeEm, SCIATIC SRTeOcMAtCH nn 418-027:PAGE J-108 ORAWLITH(GTAHVEAGREE)PRCOODNUBCITNIEODNPDRREEPOVETEAOLTCOEOPDLWED4NO1TS8AE-L02T7OTXOIRCIICTIYTYSTSUCDRYEENOIFNGT 7TE5S6T9.7 SPONSOR'S STUOY NUMBER 1-759 Individual Animal GArpopsesndainxd M11istamorpholosy Dota ASexD:L NER: F17711 oDoEsAeTHGeToIuPeE:: ISvacrifice-Scheduled GOROBSSERVATIONS): GENERALS Yo gross changes. HISTOMORPHOLOGICOBSERVATION(S): Not applicable HISTOMRPHOL0GIC OBSERUATIONS wGiavres: : MTSeAiskRe:nY: GLAND: ures: vista: vvTaaycGpuuooorlltaarttoiipoohnny,.. chhoeerpptaaittcooaccleelllltuuullbaaurrl..arecpeparniittprhoierltaabulamta(rs(inni(i1aim4s)1i0)) Tatorpoeprhiyas(taai;id)physiological SPtaercnoroporhpryhiaagg(eems,o.deenprdiatogemm)eetnrtieudm(m(os1d1edr)ate) miuncfilfaimcmaattiioonn, (craurtkeed)(moderate) HE FOLLONING TISSUE(S) VEREVITHIN MORAL LMT caJAteRsoEowAuLm suas SRNEETRCoVTwEc,HSciatic End of Record 17711 LBSiOUnNDeEDAERNRON (STERN) oTSPhuIRmNOAeILsoCORD, CERVICAL LwBIRNArIGNH NODE, MEDIASTINAL TESPRALARICAAKTLEHRICRODRIDD, LWAR cLfYeeMePwwY NODE, SUBMANDIBULAR GpSPREIIYNENARAL'RSYCOaBRLtDAc,DhDETRHORACIC ns 418-027:PAGE J-109 OREALTH(GTAHVEARGEE)PRCOODNUICNTEIODNRDREEoPVTEEOALCTOOEPLDME4DNO1TS8AE-L02T7OTKOIXCIICTIYTYSSTCURYEEONFINGT 7TE5S0T9.7 SPONSOR'S STIOY NNER 1-759 Individual Anton] GArpopsesndainxd H11istamorshology Data AsexL; WER: 1V7712 DooEsAeTHGTaIoPE:. SaIvcrifice-Scheduled 9055 QASTRATIONS): TAIL Bent. HISTOMRPHOL0GICOBSERVATION(S): No microscopic change to correlate HISTOMRPIOL0GICOBSERVATIONS: Liver: HLIAMRATODCEL,ANS:UBMANDIBULAR uTTrIieLnss!. IIynpfelratmrmoapthiyo.n,hecphraotnoicce,llfuolcaarl. mcuelnttirfioicoahlula(rmi(nsiisn)a) INToooppmeerrippcllraaosssiicaa.;opepThycymhpsantonocglyeotgiticoc/apcloarsrseslcaytteic. (aii) raatcrroopphhyag(emsi.nimpailg)mented (aid) HE FOLLOMING TISSUE(S) ERE WITHIN NoORUAL LiMITS. SAcoDelRaoEnnNAL GLANDS KDBIOUDNDNEDEYEASIMRH (STERN) teBiRnAysIN NRsEpEClRTeVOeEHn, SCIATIC oSSwPoIeuUAtsLhCOR, CERVICAL TSPHPAIRNAATLHYCROORIDD. LMGAR TRACHEA URINARY BuA00ER isin 0d of Record 17712 ciUIoNePmY YO0E, MEDIASTINAL SPTPEsIYNEoARL'iSCOPRADT.CHTHORACIC 117s 418-027:PAGE J-110 ORAILTH(GTAHVEAGER)EPCROOMDBUICNTEIDONRRDEOEPTVEEOALCTOOEPLDMEND2TOASLE7TOTXOIXCIICTIYTYSTSUCDRYEEONFINGT 7Te5s9t9.7 SPONSOR'S STUDY NABER T7509 Individual Anim) Gsroospsenadnid 1i1stomorshology Data Asex:L BER: 1v714 oDuEsAtTHcTaYoE:. SIavcrFice-Schedsled 8058 QRSERIATIONS): GENERAL No gross changes. HISTOORIOUGIC 0BSCRUATIONSS): Not spplicasle HISTORRPHOLOGICOBSERVATIONS: HSLpilvAeee.Rn GLAND: TTTiERmROSsD FhPuoeppmeatrrotpprloaopsthieyas.,l:hpehpeyaxstitaorclaeomlgaliducolaallra,y,cenitcrrielsosbeudlar(i(ni1eds)l) stSLthTrrReobprma(nncinai)a bodyfat macrophages, pigmented (soderate) HEFOLLOUING TISSUES) VERE WITHIN opuAL Low: AScoeldoamm Las KSDIOUNDTEESHai (STERN) wBLeoAanTerH SNREEiRCoVTwEUc,MH`sciatic DTSiPRAIARNCIAHELESRCORD, CERVICAL FSUPRAIIRNNAAATLRHYICROOSRILDDA,COELRUNAR ctLTeHePeY MODE, SUBMANDIBULAR VSPPEAIVNEGARL'SCOARDT.HTHORACIC A TISSUA(S)HIOT LAFB OREVL ALUATEION: LWP NODE, NEOTASTINAL End of Record. 17714 . " 16 APPENDIX K| HEMATOLOGY AND CLINICAL CHEMISTRY REPORTS 418-027:PAGE K-1 Study Report for Hematology INDIVIDUALPERAINOTDM:ALTERREMPIONRATLBY GROUP SSuunann v1o:: 0a6n0u0s63rear sex na owee m mmTe oseoo wer manwer rico auon rox suesnmr arrn, 10 ws re wr ws sma me 1 jeem wwee sraem ewsr wess swess mmsa wuss wome jroes rxro ew wr E ae aE e ma wo nm ve " swers oouwsss owmes aemrs am;ss 1mso: owwss mnsws wSoer, on wa ss es wo ss ma m2 mn joes wWse rrew mess ewno sms2 mmsi wsoe wiwm ereiz wmse rrem mwse amss swss mmsa wwee m1am new wiwe onwsse owme aasm somms mare owne snom " s s s s s s s 5 arer, 30 we ww we ws ses ms ws ts jeest mWrarmrm wwes aase mwer mmir wmee iimme rreesn wBrso eTmm ws awes wWen mBey mwhe owwm no awks orma omad waem sssm woem maem wuemr " s s s s s 5 s 5 Gackt eas rez Study Report for Hematology 418-027:PAGE K-2 INDIVIDUALPERAINOIDN:ALTERREMPOIRNTALBY GROUP Sruonrn v1o0: a060s-064310-027 sexe cswmc mieasc onas wr manser po ouon we myewmr Gaonon on wa ws er es sr me we ws eesz WWos e7mm wwrs amoe ssmze mmoa mm1a uumm reess wDs3 oermm wowss mwae wowse mmes wmse uumm nea Twese aamw owas vwse tsees oaam waem muems s s s s 5 5 s 5 ent a. is zoe Study Report for Hematology INDIVIDUALPEARNIOIDM:ALTERREMPIORNTALBY GROUP SStruunnt v1o0:: 0a6r0o-u0s65K1E-G2T jevaWc oooc GRAeSe er+ moonnese pico unwsn oounr: 1-6 ws sn wa ow ss ws r7e0n3 =we esisss wnhs m3e 0er 221 nneeso 25@ se we we e2 us@ new xa2m osuas owe mTas 8208 m"asn 418-027:PAGEK-3 sex: ree oc5 myewmr sr1 1567150 wsse n05e @ oowrs wwew ourrs: 2-1 ws ers wi e6x0 wr1 owwes aa29 2213 E3n o25n9 npeo0ss w8s 2s s0m sm w2r E2n we 7 wwss 3 ssrowsws us EX rzsn = new 3] wvsm oeums 5 s owkss mp2y s eamss mTee5 woew msor s s pmers wer w"o3 ssans wnea 351.3 awss 515 E3n zerme mo0n ar a02 22 osawn 519 mwee wr aw0nz w@uo wo numsse wowss ws owwwn on m9 ne ss 20 0 us En os nem nwnz ossmm norm 023m sraor s2ss wnso avmws . o . . . . e = ctoreed Ue vee.3 2-202 Study Report for Hematology INDIVIDUALPERAINOIDM:ALTERERPMOIRNTALBY GROUP Stoo Suny v1o0:: 0A4s0u-s063Rete-027 to wee Thom WLCwcmeanwse wr= cmonne pico cunmosn rreesss 2ws6 5s.9s1 225 5s.s3 5w.s8 223 wwween 2E0n8 sons 2wsa 308s s7u.s 237 nFeyw) 22m6 osme oB5s2 22as 328 209s 418-027:PAGE K-4 sex: rome nore= mewnmr s2e 11650750 swmee 253000 v7e e15s47 [rr 2-202 sStuupy w10o:: a0n6o0u-s06#3a18-027 neat 10 Secondosr Grow: 10 r7e6r0es wwss ree n 5wso es ws ne 0i.66 " 5 Study Report for Hematology INDIVIDUALPERAINOIDM:ALTERREMPIORNTALBY GROUP secownodns CUMICROwNnS 5216 55..00 z5s3 09.58 2s as 5T.e4 00%2 5 5 C0ONT LTymRocyCtmMe THSSeHg/mCeUntMeNd oo n5as T2e0 oo 0w3s 2us0 we 22 00o s2as 01..69 s 5 5 418-027:PAGE K-5 sex mic THSWG/aCnmUdE THHSoHo/cCyUtmens o0o0 0011 0o0o oorz oo 00 0.0000 0.0.017 s s Groeosn: 20 5 2. oe rreessss 33 aa'rs 0935 prteee wwrr 22s0 n9i1 oo w7o 9a 0o0o 0020 oo w5e 2215 oooo 002s o as 29 oo 00 now 50379 52.359 05.17 00o 5sa8 o2s8 o0x.0 0002 " s s 5 s 5 s s s arenon: 30 0s 21 89 reeaars wwas 2a2s n5o7 eeesns 5a9 EEnX 0517 nFe)m owrm 22382 9058 s s s o wnee 2230 o0o0 oooo 0155.0 we 2 oo 00 oo oz 05 Wr oo 01 00o 5s3a o1i8 00%0 00.019 s s s 5 5 [a a Study Report for Hematology INDIVIDUALPEARINOIDM:ALTERREMPIORNTALBY GROUP SStuuneyr w1o0:: 0a6r0-u06R3eTe-G2T antest 10 iocontosr secowndrs CUNICROwNyS CWONcT TmRSeH/CrUMeA TWSSeMg/mCeHntMeAd Geoaor: in 16.0 07 05 mreeazsz nwss 2a1s s95e rreesss wwoe 220 oe8 0 5o.8r 10 20 o 5046 ns 23 o ni 2 oan 0w3e 2750 o5.s1 oo wwoa 530s x s s 5 5 5 s 418-027:PAGE K-6 sex mus TNSW/CSUandNsG TNHoSocUy/tCeUs 00 00 03 00 00 oo 00 00 oo oo 00005 001s Linear vee.43 2-20 sSttoorr 010:: 0A4r0-s063Hete-2T todm ecors Grronw: 1-5 ws 7e7n03 wwse weso wwsa ew wols w s Study Report for Hematology INDIVIDUALPERAINOIDM:ALTERREMPIONRATLBY GROUP secoendms COMCROwNvS wwoe Troo aa2e eTss ws aaam oomr s . CONT TUHmmote TSIOeNmG 0 mmoe saa oomwee ssae a~~ eo0` umms. asms` 418-02TPAGEK-T sox rome THCSas TemHoUteYs 0000 o03z o0o0 ooos == o0m0. o0m3. aearas: 2 we ws 52 as9ss wwee mowse maa re8s wae we "s ew wosx wiem 2osm 3] . . s 0owewe 2227 0o0o 0o3o oomems 2os6 0000 o0o3 owe To oo os oo[E 2m o2m0 o0m0 o0u2 s s s s s rrers ws as es wmeor wwee awre Toss ke7 wwys awrrs 832 1109 @ BY 0omwe 52ss 0000 ooro wwzr s2s3 0000 oooz o0 weten ssne 0I0 o0o2 new " omei s2w0 a0e.0 s s . 000 awsw a"x o0m0 o0x2 . . . . . = oats tmnt user ees -- 2 "rroorr v10o:: aanu0s RE18-027 ow seconds aSars or we rraen wwas rem ws vous owze Study Report for Hematology INDIVIDUALPERAINOIDM:ALTERREMPIONRATLBY GROUP secwonmd Commw s eoN GTmemororme esewmiems mwas n5m 0 ommae eToo 0omemo Ios 00 eamsa 32ss amme a0s2m oo0 uwwe aomr 418-027:PAGE K-83 ex ree ENtaEIns Dtearnceyimens oosz wvss oooo ooss o0.m1 o0m5 resem Zain Study Report for Hematology INDIVIDUALPERAINOIDM:ALTERERPMOIRNTALBY GROUP SSruuopw n1o0:: 0a6r0-s06#318027 imal 10 T EosinoOphil TSosCopnUits TAbHnoOrmUa1l HSGtUher rraesn 0011 o0o0 0o0o 0000 eresso 0o1o o0o0 0000 0000 res 00 oo oo 00 no 00015 00.0 00.00 o0x0 " s s s 5 aso: 20 res 02 00 00 00 rreessss o0s0 0000 0000 0o0o rreee 0022 0o0o 0o0o 0000 neao o0n2 0.0000 B0y0 00000 ] s s s 5 r-- reo 01 00 00 00 reeasr 002 0000 0000 o0o0 rmeeasss 0o2o 0oo0 o0o0 0oo0 ew o0s2 0.0000 0.0 0.00 00 0% s s s s 418-027:PAGE K-9 sox me Ucn wee6.3 2mv-2002 Study Report for Hematology INDIVIDUALPERAINOIDM:ALTERREMPOIRNTALBY GROUP SStnuon v1o:: 0a6r0-s065rE-G27 Inisal 10 CTonHfroCnt TBasHephCits ATmoHrsDal THOtUher omuerr: on 00 00 00 00 wees 0a3o 0000 0000 aaoo measzee oozo 0000 0000 0o0o new" o0w1s o0w0s o0m0s o0m05 418-027PAGE K-10 TT sex: me Geantwe 43 22m Study Report for Hematology INDIVIDUAL ANTMAL REPORT BY GROUP PERIOD: TERMINAL sSttuubn w1o0:: 0A6R0o-us063Rite-027 Anieal 10 ETosCinUophil TBHasOopUhils SAbNeorCmal L TRSGener woop: 1-8 r77e0n5 o02o 0000 0o2o 0000 arreemso o02o 0o0o 0000 0o0o res ~ - - - naan 0.0. 00.000 00.. 0 00.02 [] " " " . weors: 2 00 00 00 00 ers oo 00 00 00 rreene o00o 0000 oooo 0000 nem [XoSo 00m0 0.0000 0000 " 5 s s s wreoans: 3 00 00 oo 00 wen 00 00 00 oo r7e0s0 0000 0000 0000 oooo 709 02 oo 00 00 oaFy o0n1 o0x0 o0x0 0000 418-027:PAGE K-11 sex: rome (2- bate Unsvtabe ear vets 2-20 Study Report for Hematology INDIVIDUALPEARINOTDH:ALTERREMPOIRNTALBY GROUP Snonr r1o0:: a06u0s065aro-cer real 18 SaNonTin HbeEts SRoaDr LoTH hr aresr or a he oo eooo eozo oooo oonn a0s0 waoo ooso oooo re owwo oomo oosn oaw0 418-027PAGE K-12 so ro prep moe Study Report for Hematology `PSEURMIMOADR:Y RTEEPROMRITNAL rSruy v1e0:: c0i0s63ere-c27 Twearesr mewme mmme Gawoe wa+c menmoes po cawnes fworw wr ows me wr sme mo wo" ses ouss oms ms ams ams praren: 20 ws ass me as ss mr o" 2%s owes oms aws oms oes nnowp Ba rm ma ae sms me " Tis oms oks im5 ams oms areroen: on wa nw ma ws sms aa Tes oms oss ams tws oms 418-027:PAGE K-13 nkSoenr om3n wwsr ss wokss xmoe5 Lwves wwrss w1em uwmems :: sox mie secownm oweu 5 omkrs owmrs wose3 Gear vee. a 418-027:PAGE K-14 Study Report for Hematology SPEURMIMOADR:Y RTEEPRONRITNAL Ssnro v10o:: 0A6t0o-s063#027 sex: mae Twesst:er: SecWonTds CU MICROmNvS CWOUeNT mTHoOnUteA TSHeSgNm/eCnUceTs NCBandTsH THHScHy/CcUe8s ETosHinUophiPlH TSHasEopNnils n[ere sa 02 0 we 1s 00 e101 ao Tss oms oos ses oxs oms oo5 0%s oms rneowu: 2-0 s9 er o ms 28 00 oz 02 00 " am3 om5 005 sa5 om3 o5 om3 on5 oms nGorou: 3 wz es 0 ms 1s 00 01 oz ao " wes wm5 a0s sas ois oms 0ms oss ow5 nGerionu: 40 w2%r oeea ss ooo w4rm 7sBo ooo 0031 sss5 5 0e% 10000 ss Gent wee. i3 mraz Ssttuun w1o0:: 0a6v0u-s06W5 027 Study Report for Hematology SPEURMIMOADR:Y RTEEPROMRITNAL wTaErsT,: MToreoromatmLoTner nw o0m05 oowos naerwo: 20 oo oo oms oxs anreowm: 30 00 oo oms ows nen3 o0m0s oomos 418-027:PAGE K-15 sex: mae Gicat we43 rez Study Report for Hematology SPEURMIMOADR:Y TREERPMOIRTNAL Ssrtuuoyyw1o0:: a06s0u-s083#iT8-027 Testo. we bec we UTS HSHLLU GRRL wr nv wn cu moans pico cans ne 2m720 oswee omee tMes 2e%o 1mas " ". .. Gnronup: 27 ws em ws m2 es me Py" 2s ome5 ods aes ams Les Gnreomw: 37 22 sm wr %3 ao ms " an. osme om. zm. vw. 1%0 nGoroup: or ae sw m2 ma m2 @s w 28 osm oe zie 13 ode 418-027:PAGE K-16 sex: rome nec mr on Xuemn seconds wome" wwaw. omkss woer smsow mo3m s 5" ws wm Ba eBg as. omes m1r3 mweae onma [rr 2-202 Study Report for Hematology 418-027:PAGE K-17 SPEURMIMOADR:Y RTEEPROMRITNAL Stun Sup 1100:: 0av6o0u-s08s3e1e-027 wTaersst: LocWonTds CU HICROWNYS sex: rome CWONCT LTyHsSoHh/oCcUytie THSSeNg/mCeUnteHdt THSN/BCUand1s THMSoNn/oCcUyte1s TEoHsSiHn/oCsUh1il TBaHsoUphit4s pnen---- an 1a 2: om ooo wims 11%s oemo oax3 o0r1 o0w0 " 5 ..".." " . Gnerao: 2 w1e% 2se ooo 2wem ozmo o00 o0l2 0omo o0m0 " " ss ssss 5 s Group: 3 non zSom aseo ooo mzse a4sc o0w0 o0x2 o0w1 000 " s .0 . 0.o. Grow: now Owse o8s2 000 e4w 11s o0w1 00%5 o0w0 o0m0 wana vet.43 2-200 Ssutnuyb v1o:: 0a6s0u-s063RETE-027 Study Report for Hematology SPEURMIMOADR:Y RTEERPMOIRNTAL TwaErsS:T: AToenoyrast TewLovemre Gnrooup: 1-7 01 00 ow om cnreoup: 25 00 00 w" oos ow5 Gnreoww: 37 00 00 w] oo. omBf Gnreomm: 01 oo on om 418-027:PAGE K-18 rr [---- 2onar-zonz rsuonrv010:: A06r0-s083#16027 = Study Report for Hematology WHITE DIFFERENTIAL DATA anor: 10 ets uLcmtieoseterdesned celts faSeigusented etrosnite Corimpnits pSoavoranat Lymhocyies woemer ete u[ctiested fed ells pSoeygre Netrepnits Ereanocrriness pHroenasrlmae.yLymphocytes omer anes 8o ne uos oo20 Toaono o oooo 5s ao se w osoo T1 onoa o0 oooo ooo 0 wUemloecsreetdesae colts tSoegmsented Nestropnits nceonsoienyatneists Bsasooprnistsysracyies aomear &o ws 6 o2o0 [TaEnS 0o oooo aoso 418-027:PAGE K-19 oT sex: mae Gocar nek 63 Zora Study Report for Hematology WHITE DIFFERENTIAL DATA sSmunoyro10:: A06n0u-s063#61627 mis 10 cour: 100 Tenia. Te ctested fed celts Lymoertes pSeeguented Neutrophils Croesctnyetpenists BaJsencoprnsiatlsLymphocytes omer vac ess clested Red cells uSemqeucenyctesesNeutrophils rooniacsytes Coesaisnoeplnsits Aonarsal. Lymphocytes Iosmer oo ws 5 ooso 1oooee oooooo ooToes o ws n oozo o0 oooo oooooo o 2000 418-027:PAGE K-20 TT - sex: mae Lisear wes6.3 22-nar-zo0e Study Report for Hematology WHITE DIFFERENTIAL DATA stub 10: agous 418-027 stor no: 060-063 sow: 20 animal 10 renin ek cLytmeerpotceydtesfed colts aSaengmented Neuerephits Eoprsinepnits BaJ sopnits -- woether Ts cLytmeennotceydiested colts Speogmyented Neutrophits_ Enoesnioncoypsheisls BsaesnoosrnaistteLyspocytes o wo o1os o1 oo02 o0 oooo oo1o no or x ooo 1ooo02 oooooo 6 uLycsteennotceydtesneg colts aSaenguenced Neutrophils nEeonsotcnyospensits BaAsoenpornsiatlsLyppocytes wc o ws w anoo v2 ezos oooooo 6s 418-027:PAGE K-21 sex mus nar vee.3 22 Study Report for Hematology WHITE DIFFERENTIAL DATA rSTUoY r100:: A0R6G0U0S634418-027 = a To aroun: 20 Uantproancyeiesea ott oSemsened Nestrets roCeorrireenste smoonratlsUyssrortes awrlr Jeutaernss1 celts Soeprend messes rCowoemrmeists soerepssLymieertes wler o= nes o ws ooozs 3Dooo:s oooooo 0 woso wo we %ooozo oi oooz 0ooooo ooao5 418-027:PAGE K-22 TT so: ue- [ 2m Study Report for Hematology WHITE DIFFERENTIAL DATA Cstruub o1s0:: Anus 118-027 060-083 Gro: 30 = renin 620 uLycmteersatceydieesd ets aSenqsuence Neutrophils Eorsanisnceyptneisls BJ asesny ite r-- woewer TES eLytmersotceyidesRed celts aSengusented Neutrophils rEoosniancayptneiste BAaosnooprnsiattsLymphocytes waoteher er eLytmepanotceydtesved colts peseegmented Neuerophite Eroesctonceyptneiste aHnosnoaprnaiattsLymphocytes omer wc "o ne isooo20 oTonoo oooooo oowoe o we noooeos 1 eozo oooooo oo2o7 5o 0s wooooos 5 oooe FE oo oo5o1 418-027:PAGE K-23 sexs mais wear bes.43 2m Study Report for Hematology WHITE DIFFERENTIAL DATA Srtoorrvo10:: a4c0t0sspre-cer aro: 30 nt 10 Temi Te tLymeroecydeesto colts aSerueed Restrshits Eroemoacrniietss sRooanrts Lyemocyies wolr VE Ueecptreanceyidesne cette Swormes vesepnits rCeooenyatenst aIrmainssprees opsr no wo T ooao TTeer: oooooo oo6os wo s Booto T0 enao oooooo oowor 418-027:PAGEK-24 sex: mu sor ess neva Study Report for Hematology WHITE DIFFERENTIAL DATA srSuupayw1o0:: A06s0-s083Rra-027 animal 1 Gaon: on Teena 2 uctested Red colts Lymenacyies pSeeeguented Neutrophils reaonsoicnyetpensits BsaesneoprnsiatteLymphocytes other wo us 0 10oo o2 oo03 oooooo oo 2 uctested ved celts LSyemgeuneonctyeidesNeutropnite rSeannotceytes BEaosnotprnoiptnsite otRhoneorrast Lymphocytes we 2s uetested hed cells LySmepqnueenecyetsesNestronits roannaceytes pcoostnepnits Aoeenorrsal Lympocytes wc nw er20 oooooo 5 ooso oo oooo no 0o wa ooo1s oooooo oooooo oowos 418-027:PAGE K-25 sex mus Usenr vet.43 2-20 Study Report for Hematology WHITE DIFFERENTIAL DATA Sstmuoerr1o0:: 0A6R0-s06#5415-027 aro: on intent 10 anTaemeis T29 Lmwoectyetnessfed cells JSeegmented Hevtropnits Creovrciysnensa aHnosnaoprnsiatlsLymhocytes owtheer o we noooeos 01 oooe oooooo oo2o3 se [ wee--d ed colts nsegrmented Netrepnits EHoosriomeoyntietss BfaosocrpnsiatteLymhocytes Joeer @o ma sowoeo oooooo ooooao 0 EoNo 418-027:PAGE K-26 sex: mae fr-- Zam Study Report for Hematology WHITE DIFFERENTIAL DATA Ssrryvo15:: 0c0u-s063seat Grow: 106 nim 10 arTemias Terk [treastes fd calls pSoemen hesrenits roeCorriimoeonsits prRerseanstsmpocries owveer no oe 6oooer zooooos o1 ooee oowos TS wUneenotcrtieesfed colts Saeegre Netra reCoorciymosneists aswcsonrietdsLymbocyies no wo sososo J bee [oa oo we zs Te UcneomnoctystesBed ells Saegsments eset o sa FE oo connate aJmosooriatast Lympocytes oooooo ooo 418-027:PAGEK-27 sox: romeBb Lor eis Z2vame Ssttuunr1o0:: 0a6n0o-s063Kere-G2T Study Report for Hematology WHITE DIFFERENTIAL DATA are: 1 Teo testes ed cells UmSpeqoneenrtiedesNestropnits vJoroyeytes SCasoopsniitnse Sonarsat. tysocytes uonmcer ers tUpeoactytsesed celts eSatgtmsentad Netrophits raCroonctymtheists pSronaoranat tysphacytes oer anes w o e woaoao oToooe oooooo oo2o5 o0 00 -0=0o -0- 418-027:PAGE K-28 or sex: remus [-- Use 3 22-202 PE Stun wo: 060-063 Study Report for Hematology WHITE DIFFERENTIAL DATA = Ts cow: 2:7 etested ed Celts uSyemgeuneonctyetdesNeucrephite Haennocsytes pEosiniophils Aotehneorreat Lysppocytes renin on ws o 5EE we 2 ooos oooooo oooooo WS cLytmepsatceytdesved colts aSenqeuences Newtroshits rEoosntancayptneiste Bjnsopenils-- woewer Me t[ent-- ed hed colts peSegeuented Neutrophils rEoonsatcnyotgensits BsaesnooprmaistteLymocytes owmcer o 0s 2 aoro oooooo oo oooo oo3o =o ns woooo2s oooooo oooooo oowos 418-027:PAGE K-29 sex: rome [pp 2-202 rSuoarn v1o0,: 0a0c-t0s88se-c27 Study Report for Hematology WHITE DIFFERENTIAL DATA car: 25 418-027:PAGE K-30 sex ree on Ltmemnotcreedessea tts vbrpaoaessriteys EoSrenraopmintists oorral typracyes pe os utemanctreeesed celts Sei NestrpniLs raoorerees sCeoirsps caamrrat ympracyies pe 5o we ososoo ioooso oooooo oobor so e nooeo :ooooa oooooo oonos ear vee 43 vi Study Report for Hematology WHITE DIFFERENTIAL DATA Ssttoror100:: a04s0u-s063He18-c27 arr; 31 nie 10 Temi. Ts Uwerloecaytieedsrd celts aSegsmented Nestrshits Croesciynioneists psroeras ymphacyies ovr no oms a soso soooro oooooo o oo WT eUarceynitesned cetts aSeigmsented Netrepnits reoasicpenists snfsioconriatteLymocytes wocmer 0 tLyemsrotceydtesred cols aSepsmened ewtrepnits rcoesiymoenists assosresnatt Usghacyies owmcer wo we w aeoo oooooo oooooo oo3o ao we PEooo ozoooe 00 oooo oowoo 418-027:PAGE K-31 sex rene Lect vee 43 Za Study Report for Hematology WHITE DIFFERENTIAL DATA SSrTuuopyy v100:: 0a6n0u-s06s3u18-c27 sow: 3 ansest 15 rena on aes TO eLytmeesnotceydtesRed ces pSeegmented Neutropnite fr BEaossoipnnoipthiels Aoomneorrsat Lyphocytes vac o wr noaoso 1 oz oooooo oooooo 22 Te etested hed celts LySmepgruaenctyeidesNevtrophits raannaceytes [Eoastnopnite Hoomnearraat Lymphocytes we no en xooosa oooooo oooooo ooaoz TD eLytmehsotceydtesred celts pSeoquyences Neutrophils Enoosnioncayptneiste BAoanosrsiatsLymphocytes voathcer no oe 7oooss 11 eeez o oooo oo2o6 418-027:PAGE K-32 sex: rome [---- 2-20 Study Report for Hematology WHITE DIFFERENTIAL DATA Ssutnuyb v1o0:: 0a6r0o-u0s63#18027 antent 10 Geo: ier Teena on aes rs Ltyemnentoecydteshed cells oSnegamented Neutrophils roCnoascinyotpensits SaHsocnpornaisttsLymocytes wocmer we Ncteoted hed cells LSyemgpmmeonctyetdesNewtrophits oronnascytes eaossciennotpsh.ils Aoomneorrast Lymphocytes wc o Bo =102es 6oooas o1 oo02 oo2o6 0 n waes 1ssee oooooo oooo 8.6 re cterted Res celts LSyemgeupeonctyetdesNeutrophils repnoocyytes Eosinopnits BAoanosraealsLymphocytes owtcher o wwo anas o2 ooos o oooo o1 ooos sa 418-027:PAGE K-33 sex rome [-- 2-2 Study Report for Hematology ) WHITE DIFFERENTIAL DATA rioer 010:: 0p6r0-s06p3iv-ger aro: it et 1 Temi Ton eLetmemres tes cots Sneimsened Nessie CoFroenynieists psroreaatt Lymhocyies wcetr ao ee w asoo I o ao oooooo ooPoH 418-027:PAGE K-34 sex rena Lect vee is neva run 10: agus 110-027 stun wo: 060-083 Jntent 10 ara p60r8 66 ers 59 rreesso o6s wes oz nen 06239 " s Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL 418-027:PAGE K-35 sox mae Gnae mlawe moeo meni siwe on sje ar wn 5wz5 a56 @n 0011 03 03 " ss 5wa5 276s 2 0011 w5o 0022 5FY wa @ 5 oa 5 03 0w6o n1o59 nsse 00.010 2FS 0.0035 233 s s 5 5 s s 5 craeosun: 20 oz 59 w0 0 01 1 03 us reessss 6o7r "was wa5s a0 o0r1 n" 0033 @@ TTreess 660 w"o@ 1a50 5@ 0o1a Te o03z @py now 0033 0a31s anse 5532 00.010 23 o0x3 6" " s s s 5 s 5 s 5 crreoup: 30 6 wz 5 Pl 01 n 03 0 reaars osns "5a7 iss a 0011 P"e o0u3 P-Y rezsss eeso wwaz w15s1 sPsY 0o1r " 0033 neom 0522 ownr 1156 5"5 0.0010 "53 0o.0s "a2 n s 5 5 5 s 5 s s wear ccs 22002 Srtourb 1:0: s04e0s-s061318-027 nwaa wmeen 661s rezs eeze ss oz neww o6t3e " s Study Report for Clinical Chemistry INDIVIDUALPERAINOIDM:ALTERREMPIORNTALBY GROUP nGea miwe ow mie wrae wiweo oose "% = 0011 ""e ppe s 056 5 0011 a5 se no x 01 02 n0s e>z o0w1 s"e s 5 5 5 5 418-027PAGE K-36 sex: mae waao uwre 00 6st oIz spey ou = o0.m oos s 5 near cco 43 2-202 sSttuubb w1o0:: a0t6o0u-s06a3ete-car niet 10 ara Study Report for Clinical Chemistry INDIVIDUALPERAINOIDM:ALTERREMPIORNTALBY GROUP us aw oo ren a da me sje ma me rreesn 6sss 573 w9o a 0011 1x6 r77e0s o2r3 os2 m16 a" 0012 =i" reo 63 "a 2 oz 2 newn ooss 0230 229s FnYs 0.0.018 s2e x 5 s 5 s s s weoros: 2-5 7s os 5s n 02 reerns ossz w3z8 1wse 5& 0011 " nese os wa 2 5 01 = ress os "2 1s @ 01 w no 0o6s 0"52 s6s 7@s [x041 353 s s s s 5 5 rroeos:s 55 62 wo 5s wrreesnt 66s0 538 "12 m77o0n0 6o9z wuas E1Ss 09 se 6 ss w 0011 i2 so = 01 01 11s a= 0011 22 wom o6u2 0w3as ar2e wsss 0001 3139 " . . . . . 418-027:PAGEK-37 sex: rome aon nr se we 003 ss ooxu @ ou @ o0.o Po s s oosz a 0o3x " ou 5s 00.03 550 s 5 0033 =@ 00x3 nsz 0033 5& o0o3 5@s . wear ects 2mv-2002 Sruunny w1o0:: 0a6r0-s08A3LTE-GET nieat 10 w ara s`aosws: 6s meeeren psee en os new 0393 Study Report for Clinical Chemistry INDIVIDUALPERAINOIDM:ALTERREMPIORNTALBY GROUP we Ge aw mia oo md mrea moew "w2z 20005 o 0012 2" 3wn5 59%6 @5 0011 22 0a1 2m1e 2s9v 0001s 225 418-027:PAGE K-38 sox: rome saofn nurn oosu 5 0o3s 0a2 00..08 4 wear cct.i3 a stStuobp w1o0:: a06u0-s06s3ete-czr o--n ro: 10 rece w rere wren % eesss == nesao 3a4 I] 5 Study Report for Clinical Chemistry INDIVIDUALPERAINOIDM:ALTERREMPOIRNTALBY GROUP nOen mio miose mijee eli 10a6 n0.e6 7a3 oos wr 50 2 nnea 5556 1076 uas 106 05 " o us E0X 0n3a7 oass 22" w1ss 5 5 s 5 5 areosune: 20 0 " ns 8 we reessse PyPy nae nnos 8523 w1r mreeiszs " Hnes wnoe wIs o5 a" nesa 02 068 n03e8 27s 1551 2wr5 5 s 5 s s s pr reo ww I ns 92 Py wr eeeers 2- 5Ee nnos Ios Py2 uasr reeesss w9% 2= nnaa 0039 s0os uPse no 597% ETne 0n.e [X9. 2"2 ouss " s s 5 s 5 s 418-027:PAGE K-39 sex: mu a mel self ss = 6w0s " 5692 %" o5s7 %s 5 s 02 50 os 5% o5s9 P0e0 "s a 1201 259 s s sosr 0707 6750 o10n3 os oots 0202 s s usar cct.43 2-202 Sstuupy w10o:: a06u0-s063#ets-car PT or Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL ne I CoE rLoEs C we e- reeezr 105 weeeess 110089 ress os m1w0 nnsa 053 115030 "n3s woss 155 ns 02 x 1u5r1 x@ w150 = ww newn 0a3 220s 0ns 11.0501 055 w2s8 ] s s s s s s 418-027:PAGE K-40 sex: me x @ 539 0w0 703s 150ss 61 % 06.s0 29 s s Ucar cca. 2-202 SSrtuuonr w1o0:: 0u60s-06w3ir8-c27 to wAsnt prr ene 2 1r7e7s0s3 " eemo B%A nean 19010 s anor: 2-5 ners 107 wreeree E2 reeesnn 7 non 18o8e " s croeos: 3 5s wreeenr 0107 7770000 TM2 ron 50 new s Ie 2.0 . Study Report for Clinical Chemistry INDIVIDUALPERAINOIDM:ALTERREMPIORNTALBY GROUP UILY sioe mraes sofie me-l 5 nwss 995 55 nnse 0022 a ne 93 "5 wIw "o 0s ws 7w 3&5 0n1e5 003s 2s56s w21ss 5" n24s 30 2= ww@@ s@o wnse o7s0 "@ 1wa 5 nr ns 5 as 0531 0nr5 o8s1s 22s 012 5 s 5 5 s 9 nnee 1005 = ww x 2n1z wosr FA5 6uss py nnsa 815 n2u wi@ se 20 ns on as as 2:2 ws 10 . . . . 418-027:PAGE K-41 sex: rome sellx self 700 0%1 61 6s 55 or oorr 0" s 5 aeo %5% 65s 95 os oores 1E2Y5 6os2 11 671 0E2Y 7eo xw or 051 0 18 3 6 [--p-- 2-202 Srruuany w1o0:: 0a6u0-s06B3i1E-027 mo oAnST sreosws: er 53 rreese w0r wren i oan a08 Study Report for Clinical Chemistry INDIVIDUALPERAINOIDM:ALTERREMPIORNTALBY GROUP I wr o ros we " o n2e 09.:50 wTM 2na6 56 se wwo ame wso 0n.o 09550 10o.6 2w1w 418-027:PAGE K-42 sex: rome opre 55% oous P=S oozr 2E9Y waar ccs 222 stub 10: aru Ru1e-G2T sruoy wo: 060-063 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL [EE are nwonee rreetse 2200 1280 emeos 2203 bJuid es 21 20 nea o2e2 083s " s s aoesne: 20 23 nr eessse 226 6ne rreecsz 2200 2210 no 0.2236 0821 s 5 prezno 9 22 reeeasr 2213 wnss reeass 2Ws3 I22 nan 021 0.2202 " 5 5 418-027:PAGE K-43 sex: mus usar ci.d3 2-202 Srmuuony1100:: a06r0-s06w3i18-C2T Study Report for Clinical Chemistry INDIVIDUALPERAINOIDM:ALTERREMPIORNTALBY GROUP m0 ooea se one eezn 2T1s 2210 rreezs 121s 220 ress 28 2 wean o2i1 o2i0s " 5 s 418-027:PAGE K-44 sex: mie [pr 2-mr-zone Stun 10: ars #i18-ceT srupy wo: 060-063 Study Report for Clinical Chemistry INDIVIDUALPERAINOIDM:ALTERREMPIORNTALBY GROUP to oe we I none eeses 2212 210. 7re0sst 225s wsr 0 22 pis nem 23 8 " s s aerrrs: 2-5 28 16 reers 2T1e 2200 Trreeaose 2237 wree nww 0230 0.820 1] s 5 ro eessrr 2222 2w0r mon 24 5 7709 20 Ts nem 02.23 09.2 " . 418-027:PAGE K-45 sex: rome [ep ane oT esrrro w10o:: 0A4r0-s06318-027 - Study Report for Clinical Chemistry INDIVIDUALPEARNIOIDM:ALTERREMPOIRNTALBY GROUP Animal 10 cdoae rAeGe GeRosvwPs: ef 22s3 wwsr ween T2s 2ps nPoBw o2i2s o2w0 418-027:PAGE K-46 sox rene sar cee.is Zane 418-027:PAGE K-47 Study Report for Clinical Chemistry PSEURMIMOADR:Y TREERPMOIRTNAL stub 10: ARGUS 18-027 STUDY No: 060-063 sex: mie Tweasrtses vo awe ow oo ew Bw om AT a EE EE EC Gnreowup: 10 63 wow son wos 3 a w] 025 0%5 mos mss o5 tes 08s 235 3 s Gnreonup: 20 63 a1 ow 0w ox5 oas ass 523 0on 5 5 2w3 oo0s% s3 t"e 1-2 55 Groups 30 ea 62 er we " 0s oms wrs 53 oa om s5 1B3 esoe 55 @ 9% e5 287s ow 63 0% 42 os ws ms on sz o woe 53 0m ww es 83 " 5 5 s 5 5 s s s s saat cce.43 2-202 r stubvop : 060-06--5 -- waTresst:o UneL wGoronw: 10 wo " ass Gnreomw: 21 ws " m6` nGeronup: 30 we w] Zes nen = " mo5 Study Report for Clinical Chemistry SUMMARY REPORT PERIOD: TERMINAL 418-027:PAGE K-48 sex me mie mmjees mmjee moll meltx melt aega oanee oomma oems m27 5s5 1osw ossmz s5 18 o2m2 oass sss onxe aas7 sw ma 29 ez a ss 5 s5 sas as 25s oxs oas moem oswa m2 sss woes oess 5s o2w2 o2n1 o2z0 sss ms we nw es 21 20 ow5 asms 9ss ass om5 29s oas odss Uenr coa.i Z-ro Sruny 10: srupy vo: waTressta Study ARs #18-027 060-083 oawowgsla Report for Clinical Chemistry PSEURMIMOADR:Y RTEERPMOIRNTAL av oe Tew ea ser fe mjd me me md 418-027:PAGE K-49 sex: some AT as UL UL rea o6iss oekz awss m2s 0o%a 3EsE oo 7a monw ] s5 s s 5s s 5 5 Gnraonw: 2: 6s wz om a on wo 03 5 oe " oe5 0xs ess 7ss os5 335 oms mo5 mes Group: 3-4 nen 62 wr wm ss on wo 03 wm " ow. om mPes ws3 oo. 33. 0%3 ws m0P ne= 06%3 oemr mwam =Ee E)oes 2ns oeom rw i wms ear cc. 2-2 Study sgtor e 10 sn us sre waTresr:o: w Ea E apreo: 1 wss meoy 55 naerwn: 2 snr o\ 553 oss naerwom: 1 o mso owosn .. neop ome o ms ow Report for Clinical Chemistry PSEURMIMOADR:Y RTEERPMOIRNTAL mIe me wm Ca osms wsswa1 oewr 3w0m s5s55 osmn mzwm oa1w oeme 1o2w s:5s: usse mw e w10 aem rmae ..... 0ss ww e wa1 oemr 2o5w 418-027:PAGE K-50 sex remne aA m Aowe oams5 oamss o2mc oam s: o2m2. oaws. o2k2 o2n0 sor css pr 418-027:PAGE K-51 QUALITY ASSURANCE STATEMENT ReSdtsyaNuymbevro: n16,.032070063 TistryhysbeFernapc sacLtaPndptiaonuosrSdoohme suStloeyttAyasoeap0:ni3. UFenoknd,O3andaAOa riomTihbn ydhe ee eso moopen er porerd pore Bo OAL. i haree Drmp osamcn ApPROVEDBY: SP een a ha5s5aon Austr WDne (f\Bpo>-- APPENDIX L STATEMENT OF THE STUDY DIRECTOR 905 ShenDre,Bg A He Tekfox: (215) #438587 418-027:PAGE L-1 hate ARGUS RESEARCH Charles River Laboratories Discovery and Development Services PROTOCOL 418-027: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OFT 7599.7 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7599 STATEMENT OF THE STUDY DIRECTOR "This final report accurately reflects the raw data obtained during the performanceofthe study. No deviations from the U.S. Food and Drug Administration (FDA) Good Laboratory Practice Regulations; Final Rule", the Japanese Ministry of Health and Welfare (MHW) Good `LCaob-oorpaetroartyioPnraacntdicDeeSvtealnodpamrednftor(SOaEfCeDt)y,SttuhdeiReesvoinseDdruOgsE"C, DthePrOirncgiapnliessatoifoGnofoord ELcaobnooramtiocry Practices" and the Organisation for Economic Co-operation and Development (OECD), The `stOuEdyC.D Guideline for Testing of Chemicals' occurred that affected the quality or integrity of the (ese CH ON jond G. Yorkf, i) DABT Date Associate Director ofRedearch Study Director `Argus Research a US. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. b. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance No. 21, March 26, 1997. c. Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final]. 4. Organisation for Economic Co-operation and Development (1996). OECD Guideline for Testing of Chemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996. APPENDIX M QUALITY ASSURANCE STATEMENT 905. sy i Sp A Telephone 215) 443.8710 Telefax: (215) 443-8587 418-027:PAGE M-1 ~~ ARGUS RESEARCH Charles River Laboratories Discovery and Development Services QUALITY ASSURANCE STATEMENT Argus Protocol: 418-027 `Sponsor's Study Number: T-7599 Study Director: Raymond G. York, Ph.D., DABT A`TshseuprraontcoecoUlr,ictri(tiQcAal)p,hatsoesa,ssruarwe cdaotnafoarnmdafnicnaelwrietpo:rt were inspected by the Quality Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final]. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. Quality Assurance Unit `The undersigned indicate that the report is an accurate representation of the raw data. Data provided by the Sponsor or a subcontractor were not audited by the Argus Research `The QAU inspection and report audit dates are listed below: Inspection Phase Protocol `TS Administration TS Preparation Motor Activity FNOaBtu!ral Delivery/ Litter Observations DaNBliLoloiedvSCueoelrrlieSecuteei.ornfice Raw Data Check In-Life Data Necropsy Data FRoerpmourltaTtaibolness,Data Report Text Inspection Date(s) 12FEB02 15FEB02 22 FEB 02 28 FEB 02 20 MAR 02 20 MAR 02 27 MAR 02 0044AAPPRR0022 01 AUG 02 17-19, 22-24 JUL 02 18,22 JUL 02 0263:,3301JJUULL0022 25-26 JUL02 30JUL 02 01 AUG 02 Date(s) Findings Submitted to Study Director 12 FEB 02 15FEB 02 22 FEB 02 28 FEB 02 20 MAR 02 01 APR 02 27 MAR 02 1199AAbPRR 0022 01 AUG 02 24 JUL02 23 JUL 02 3301JJUULL0022 26 JUL 02 30JUL 02 01 AUG 02 418-027:PAGE M-2 Date(s) Findings Submitted to Management 12FEB02 15FEB02 22 FEB 02 28 FEB 02 20 MAR 02 01 APR 02 27 MAR 02 1199 AAPPRR 0022 01 AUG 02 24 JUL 02 23 JUL 02 3310JJUULL0022 26 JUL 02 30 JUL02 01 AUG 02 "Functional Observational Battery Cristy. >ManiaOB.35meos [op Matthew J. Vaneman, B.S. Date Maureen O'Brien, B.S. Date Manager of Regulatory Compliance Quality Assurance Associate and 0 Principal Auditor