Document RzL3OmJZgvaXQVxbw4jamq9V

RECEIVED - OPPT NCIC aKAY 12 85 9: 10 FINAL REPORT PROTOCOL 418-028 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 `WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7706.1 FINALREPORTDATE:31 JULY2003 PROTOCOL 418-028- TOORXAILCI(TGYAVSATGUED)YCOOFMTB-I7N70E6DWRIETPHETAHTEED DOSE SRCERPEREONDIUNCGTITEOSNT/DEVELOPMENTAL TOXICITY SPONSOR'S STUDY NUMBER: T-7706.1 TABLE OF CONTENTS SUBJECT PAGE 1. SUMMARY AND CONCLUSION 11 11. Methods 1 12. Results 13 13. Conclusion 16 2. DESCRIPTION OFTEST PROCEDURES 21 21. Conductof Study 21 22. Test Substance Information 24 23. Vehicle Information 24 24. Test Substance Preparation and Storage Conditions 25 25. Test System 26 26. Husbandry 27 27. Methods 210 3. RESULTS- Male Rats 31 3.1. Mortality, Clinical and Necropsy Observations 31 32. TWeerimgihntaltoBToedrymiWneailgBhotsdyanWdeiOgrhgtananWdeiBgrhatins WaenidgRhattios (%) of Organ 32 SUBJECT PAGE 33. Hematology and Clinical Chemistry 32 34. Body Weights and Body Weight Changes 33 3.5. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values 33 36. Mating and Fertility 33 37. Functional Observational Battery 33 38. Motor Activity 34 39. Sperm 34 4. RESULTS - Female Rats 41 4.1. Mortality, Clinical and Necropsy Observations 41 42. Terminal `Terminal Body Body WWeeiigghhtts,anOdrgBraaninWeWiegihgthstaannddRPartiimoosr(d%ia)loFfoOllrigcalenCWoeuingthst~to~ 4-2 43. Hematology and Clinical Chemistry 42 44. Body Weights and Body Weight Changes 43 45 Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values 43 46. Estrous Cycling, Mating and Fertility 44 47. Functional Observational Battery 44 48. Motor Activity 4 49. Natural Delivery and Litter Observations 45 4.10. Pup Clinical and Necropsy Observations 45 4.11. PupLiverWeightandRatioofLiver Weightto TerminalBody Weight 45 REFERENCES 46 APPENDIX A - REPORT FIGURES Figure. Fo Generation Male Rats Al iii SUBJECT Figure2. Figure 3. PAGE Fo Generation Female Rats. A2 Motor Activity - NumberofMovements - Fo Generation Male Rats A-3 Figured. Motor Activit-y Time Spent in Movement - Fo Generation Male Rats A Figure. Figure 6. MotorActivity - Number ofMovements - Fo Generation Female Rats A-S FMeomtaolreARctaitvsity - Time Spent in Movement - Fo Generation Ab APPENDIX B - REPORT TABLES - Fo GENERATION MALE RATS Table BI. Clinical Observations - Summary -Fo Generation Male Rats Bl 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 Fo Generation Male Weight Rats to Terminal Body Weight- Summary - BS Table BS. Ratios (%) of Organ Weight to Brain Weight - Summary - Fo Generation Male Rats B7 Table B6. Hematology - Summary - Fo Generation Male Rats B9 Table BT. Clinical Chemistr-y Summary - Fo Generation Male Rats B12 Table BS. Body Weights- Summary - Fo Generation Male Rats B15 Table BY. Body Weight Changes - Summary - Fo Generation Male Rats B-16 `Table BIO. FAbosGoelnuetreaFteieond MCaolnseuRmapttsion Values (g/day) - Summary - B17 Table BIL. RelativeFeedConsumption Values (g/kg/day) - Summary - Fo Generation Male Rats B18 Table B12. MatingandFertility - Summary -Fo GenerationMaleRats B19 Table BI3. Functional Observational Battery Observations - Summary - Fo Generation Male Rats B20 iv SUBJECT PAGE Table B14. Motor Activity - Summary - Fo Generation Male Rats B26 Table BIS. Sperm Motility, Count and Density - Summary - Fo Generation Male Rats B28 Table B16. Sperm Morphology - Summary - Fo Generation Male Rats B29 Table BI7. Clinical Observations - Individual Data -Fo Generation Male Rats B-30 Table B18. Necropsy Observations - Individual Data - Fo Generation Male Rats B-33 Table BI9. T`WeerimgihntatloBToedrymiWneailgBhotsdaynWdeOirgghatn- WInediigvhitdsuaalnDdatRaat-ios (%) of Organ Fo Generation Male Rats B38 Table B20. Organ Weights and Ratios (%) Of Organ Weigh to Brain Weight - Individual Data - Fo Generation Male Rats B48 Table B21. Body Weights - Individual Data - Fo Generation Male Rats B58 Table B22. MFeaeldeCRoantssumption Values - Individual Data - Fo Generation B-68 Table B23. Matingand Fertility - Individual Data -FoGeneration Male Rats B-71 Table B24. Functional Observational Battery Observation-s Individual Data - Fo Generation Male Rats B74 Table B25. Motor Activity - Individual Data - Fo Generation Male Rats B79 Table B26. Sperm Motility, Count and Density- Individual Data- Fo Generation Male Rats B89 Table B27. Sperm Morpholog-y Individual Data- Fo Generation Male Rats ~~ B-92. APPENDIXC - 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. CTeorumnitn-alSuBmomdayrWyei-gFhotsGeannedraOtrigoannFWeemiaglhetsRaatnsd Primordial Follicle cs v SUBJECT Table C4. Table CS. Table C6. Table C7. Table C8. Table C9. Table C10. Table C11. Table C12. Table C13. Table C14. Table C15. Table C16. Table C17. Table C18. PAGE FRaotGioesne(r%a)tioofnOFregmaanlWeeRiatgsh to Terminal Body Weight - Summary - cr FRaotiGoesne(r%a)tioofnOFregmaanlWeeRiagthst to Brain Weight - Summary - cs Hematology - Summary - Fo Generation Female Rats co Clinical Chemistr-y Summary - Fo Generation Female Rats ci Body WeightsFemale Rats Precohabitation - Summary- Fo Generation cis Body Weight Female Rats Changes - Precohabitation - Summary - Fo Generation ci6 Maternal Body Female Rats Weights- Gestation - Summary - Fo Generation cir FMaotGeernnearlaBtioodnyFWeemiaglhetRCahtasnges - Gestation - Summary - C19 Maternal Body Weights - Lactation - Summary - Fo Generation Female Rats c20 FMoatGeemnaerlaBtioodnyFWeemiaglhetRCahtasnges - Lactation - Summar-y cz `AbSsuomlmuatreyF-eFeod CGeonnesruamtpitoinoFnemVaallueeRsat(sg./day) - Precohabitation - cs RSeulmatmiavreyFe-eFdoCGoennseuramtpitoinonFeVmaallueesRa(tgs/kg/day) - Precohabitation - cos Maternal Absolute Feed Consumption Values (g/day) - Gestation - `Summary - Fo Generation Female Rats cas MSautmemranarlyR-eFlaotiGveeneFreaetdioCnonFseummaplteiRoantsValues (g/kg/day) - Gestation - ca MSautmemranarlyA-bFsoolGuetneeFreateidoCnoFnesmuamlpetiRoatnsValues (g/day) - Lactation - [2 vi SUBJECT Table C19. Table C20. Table C21. Table C22. `Table C23. Table C24. Table C25. Table C26. Table C27. Table C28. Table C29. Table C30. Table C31. Table C32. Table C33. PAGE MSautmemmaarlyR-elFaotiGveeneFreaetdioCnonFseummaplteiRoantsValues (g/kg/day) -Lactation - cs M`aStuimnmgaraynd- FFeortGielniteyr,aEtsitornoFusemCaylceliRnagtsand Days in Cohabitation - C2 FFuonGcteinoenraaltiOobnseFrevmaatiloenRaaltBsatter-y Summary - ca Motor Activity - Summary - Fo Generation Female Rats C37 FNaetmuarlael RDaetlsivery Observations - Summary - Fo Generation C39 Litter Observations (Naturally FI Generation Litters Delivered Pups) - Summary - C40 `ClSiunmicmaalrOyb-sFerIvGaetnieornastfiroonmPBuiprsth to Day 22 Postpartum - C43 Necropsy Observations - Summary - F1 Generation Pups C44 Pup Liver Weights - Summary - FI Generation Pups c45 Clinical Observations - Individual Data- Fo Generation Female Rats C46 Necropsy Observations - Individual Data - Fo Generation Female Rats cst `TWeerimgihntaltoBToedrymiWneailgBhotsdyanWdeiOgrhgta-n IWnediigvhitdusaalnDdaRtaat-ios (%)ofOrgan Fo Generation Female Rats C55 IOnrdgiavnidWuealigDhatts-aanFdoRGaetnieosra(t%i)onOFfeOmragleanRaWtesight to Brain Weight - C60 PFreimmaolrediRaaltsFollicle Count - Individual Data - Fo Generation C65 Body Weights - Precohabitation - Individual Data - Fo Generation Female Rats c61 vii SUBJECT PAGE Table C34. Matemal Body Weights- Presumed Gestation - Individual Data - Fo Generation Female Rats c70 Table C35. Maternal Body Weights - Lactation - Individual Data - Fo Generation Female Rats cs Table C36. FFeoeGdenCeornastuimopntFieomnaV le Raat-s l Precuohabeitatsion - Individual Data - C80 Table C37. MInadtievrindaulalFeDaetdaCo- nFsouGmepnteiroantiVoanlFueesma-lPereRastusmed Gestation - cs Table C38. Maternal Feed Fo Generation Consumption Female Rats Values - Lactation - Individual Data - css Table C39. MInadtiivnigduaanldDaFetrati-liFtoy,GEesnterroautsiCoyncslFienmgaalnedRDaatyss in Cohabitation - C89 Table C40. Functional Observational Battery - Individual Data- Fo Generation Female Rats co Table C41. Motor Activity - Individual Data - Fo Generation Female Rats. cor Table C42. INnadtiuvriadluDaellDiavteray-,FIompGleannetraattiioonnSiFteesm,alaendRaPtusp/FV1iaGbeinlietryatainodnSLeixtte-rs C-107 Table C43. Pup Body Weight Litter Averages from Birth to Day 22 Postpartum - IndividualData -FI Generation Litters. C110 Table C44. Pup Body Weights from Birth toDay22 Postpartu-m Individual Data - FI Generation Pups ci Table C45. Pup Vital Status and Sex from Birth to Day 22 Postpartum - Individual Data - F1 Generation Pups C125 Table C46. Clinical Observations from Birth to Day 22 Postpartum - Individual Data - FI Generation Pups C128 Table C47. Necropsy Observations - Individual Data - F1 Generation Pups ~~ C-130 Table C48. Pup Liver Weights - Individual Date - F1 Generation Pups C136 APPENDIDX- PROATNDOAMECNDO MENLTS D1toD-52 viii SUBJECT APPENDIX E- DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE `TESTING FACILITY PAGE E-1E3 APPENDIX F- CERTIFICATE OF ANALYSIS F-1t0F3 APPENDIX G- ANALYTICAL AND BIOANALYTICAL REPORT ~~ G-1to G-153 APPENDIX H- TEMPERATURE AND RELATIVE HUMIDITY REPORT He APPENDIX I- POSITIVE CONTROL DATA Flol4 APPENDIX J- HISTOPATHOLOGY REPORT J110J-105 APPENIDXK - HEMATOLOGY AND CLINICAL CHEMISTRY REPORTS K1t0K-150 APPENDIX L- STATEMENTOFTHE STUDY DIRECTOR L1 APPENIDIX M - QUALITY ASSURANCE STATEMENT M-1toM2 ix 418-028:PAGE 1-1 TITLE: OOFRAT-L77(0G6AWVIAGTEH)TCHOEMRBEIPNREODDURCETPIEOANT/EDDEDVOESLEOTPOMXEINCTIATLYTSOTXUIDCYITY SCREENING TEST ASPROGNUSSORR'ESSSEATRUCDHY PNRUOMTBEORC:OLTN-7U7M06B.E1R: 418-028 1 SUMMARY AND CONCLUSION LL Methods" `Sgervoeunptsy-(fiGve CrrIlto:hCrDuou(gpShVDs))I,GS15rVaAtFs/pPelrussexpreatrsgpreorupse.xAwnerae dassdigniedtthtroeifeirvoaetsdnopseaarges.lex tpeesrtgsruobsutpanwceer,eTa-s7s7i0g6ne[dPteorfGlruoourposheIxtanheroSuuglhfoVnaftoer PtooxtiacsoskiiunmetSiacltsa(mPpFlHeS)c]o,lloerctvieohni.clTeh,e oanqcueeoduasil0y.b5e%gicnanribnogxy1m4etdhayylscebelflourleosceoh(aCbMitCa)t,iownaasndadcmoinntiisntueirnegd tvhiraoguagvhagtehetdoamyableeforrates asadcmriinfiiscter,aatfitoenr,coamnpdlteotifoenmoalfetrhaetscoohnacbeitdaatiilyonbpeegriinondi,nagft1e4r daamyisnbiefmourme coofh4a2bidtaaytsioonfand pcornetsiunmueindggetshtraotuigohn t(hDeGda2y5,beraftosrethsaatcdriifdicneo,tddaeyli2v1eorfa lliatcetra)t.ioDno(sDaLg2e1s)woerrdea0y,20.53,o1f, t3haenidn1di0vimdgu/aklgb/oddayy.wTeihgehtdsosraecgoerdveodlubmeef,or1e0imntLub/atkiogwn.a,sFa1djguesnteerdadtaiionlypounpsthweebraesinsotof directly administered the test substance or vehicle. rWaitt.hin cach dosage group, rats were assigned to cohabitation, one male rat per female cRlaitnsicwaelrseigonbsosefrevfefdecftosr ovifatbihleitteystatsluebassttatnwciecaenedacdheadtahys wofertehemsatdudey.onOtbhseerfivrasttidoanysoffor ndoorsmaagle watoarpkpirnogxdiamya.telOybsheoruvraltyioinntserfvoarlcslfionrictahlesifgirasst offouerffheocutrssoafntdheattetshteseunbsdtoafncteheand deaths weremade on 60+ 10minutes after subsequent days daily before dosage administrationandon dosage and approximately thedayofsacrifice. Oncebefore the cfiornstdudcotseadgefoarnadllatmalelaestaonndcfeewmaeleeklryatthaesresaifgtneer,d dteottahielemdacilninsitcualdyo.bservations were a. pDertoaviildeedddienstchreipatpipornosoprfiaaltle psercotcieodnusroefstuhsiesdreipnotrhteacnodndinucAtPoPfEthNiDs IstXudDyare (PROTOCOL AND AMENDMENTS). 418-028:PAGE 12 cBoondsyumwpetigihotnsvwaelureesrfeocromradeldedraaitslyasdsuirginnegdtthoe tdhoesamgaeipnerstiuoddyanwderaetrsaeccroirfdieced.weFeekeldy sdtuurdiyngwtehreedroescaogredepderwieode.klFyeteodccoohanbsiutmaptitoino,novnalDueGs f0o,r7f,em10a,le12r,at1s5,as1s8i,g2n0edantod2th5e m(iafin necessary)and on DLs recorded or tabulated. 1, 5, 8 and 15.During cohabitation, individual valueswerenot Evsatgrinoauls ccyytcolilnoggywbaesgeivnanliunagtweidtihntrhaetdsaayssaifgtneerdtthoethfierstmaaidmninsitsutdryabtiyonexaanmdintahteinounntoifl wspaesrombasteorzvoeadwienrseifoubsdeurrivnegd tihneacoshmaebairtaotfiotnhepevraigoidn.alEcsotnrtoeunstscyacnldi/nogrwaacsopeuvlaaltuoartyedpilnug wraetrseasosbisgenrevdedtoitnhae stmoxeiacrookfintehteicvsatguindayldcuornitnegnttsheacnodh/aobriatactoipounlpaetroiroydpulnutgilwsapserombsaetrovzeoda in situ dFuermaatlieonraotfsgweestraetieovna,luliattteerdsfiozresadavnedrpseupclviinaibciallistiygantsboirbtshe.rvMeadtedrunrailngbepahratvuiroirtiwona,s evaluatoend DLs 1,5, 8, 15 and 22. c`Sohnodrutlcytebdefaonrde mscohteodrulacetdivsiatcyriwfiacse,eavafluunactteidonoanl 1ob0smeravlaetiaonndal10bfatetmearlye(rFaOtBsp)ewragsroup. tOhne tdoaxyisco1k4inaentdic4s2aomfplsteucdyo,llbelctoioodnspaomrptlioensofwetrheecsotluldeyctaed fonrnodmdaeyach14moaflseturadtyasasnidgned to sDaGmp2l1e, cbolloloedctsiaonmpploerstiwoenroefctohlelsetcutdeyd.from each female rat assigned to the toxicokinetic cEoaucnhtelidttoernwceasdaeivlya.luCaltiendicfaolr voibasbeirlviatytiaotnlseawsetrtewriecceodradielyd.on`Tcheedpauilpys.inPuepacbholdiytewrewieghrtes wererecorondDeLds 1,8, 15and 22. sMtauldeyaanndd fDeGmal21e,rratesspaescstiigvneleyd.toLitvheertowxeiicgohktisnewteircesrteucdoyrwdeerde. sTahcreifmiecdeidaonnldiaveyr4l2oboefwas. `sahnidpspeedrufmorwaansalsyhsiisp.peBdlfooordansaalmypslise.sTwheerleicvoelrlefcrtoemd feracohmfeeatcuhs fweatsuscaolnldecptoeodl,epdobolyelditpteerr litter and shipped for analysis. The number of implantation sites was recorded. M4a2ldeaaynsodfdfeomsaalgereatasnadssoingDneLd2t2o,threesmpeacitinvsetluy.dyAwegrroessascnreicfricoepdsayoftfetrhaemtihnoriamciucm,of raebcdoormdienda.lGarnodsspellevsiiconvsiswceerraeweaxasmpienrefdorhmiesdt.oloTghicealnluy.mber of implantation sites were tTeesntsrwatesrpeearssseixgnpeedrtgorhoiusptoalsosgiicganledevtaolufautnicotniso.nalThoebsferovlaltoiwoinnaglobragtatnesrywaenrde miondtiovridaucatlilvyity (wceoirgphuesd:andlivcearp,ukt)i,dnseeymsi,naadlrveensailcsl,etsh(ywmiutsh,atnedstwesi,throiguhttfelpuiidd)i,dyprmoisst,atlee,ftsepplieedni,dybmraiisn, heart, ovaries and uterus (with cervix). The following tissues or representative samples 418-028:PAGE 13 s`wteormearceht,aiknieddn:eybrsa,isnp,lsemeanl,ltahnydmluasr,gteraicnhteeas,tiunresi,nalruyngbsl,adldyemr,phspniondaelsc,orpde,rilpihveerr,aladnreernvael,s, uhetaerrtu,s,thvyargoiinda/,pmaraamthmyaroriyd,gblaonnde (mfaermraolwe,rattessotnesl,yp)raosntdateg,rossesmliensailonvse.siHcliesst,oloovgairciaels, `aesxsaimginneadtiteonn roaftsreptearinseedxftirsosumetsh, einccolnutdrionlgarnedprhoidguhctdiovseaogreggarnos,upwsa.sAcoqnudauntcitteadtifvoer the evaluation of primordial follicles was conducted for Fo generation female rats. `Sperm rats in evaluations each dosage (concentration, group. motility and morphology) were performed for 10 male pAetrsgcrhoeudpulaesdsisgacnreidfitcoe,hbelomodasatmpaolnedlscwloienrgiecycaollclhecetmeidstfrryosmatmhpel1e0cmolalleectaionnd. 1T0hfeemale rats hfoelmloogwlionbginh,emmaetaolnocgoircppuasrcaulmaertehresmwogelroebeivna,lumaetaedn:coerrpyutshrcouclyatrehceomuongtl,ohbeimnatcoocnrcietn,tration, cmoeuantn,cmorepaunscpullataerlevtolvuomleu,metaotnaldcleeulklomcyotrephcoolunotg,y.difTfweroentbilaololdesumkoecayrteslcioduesntw,eprleatelet pprreoptahrreodmbfiorn mteimaesuarnedmaecnttisvoaftdeidfpfaerrteinatlitahlrloemubkoopclyatseticnoutnitm.e.PlSearsamasasmapmlpelsesweervealeuvaatleudatfoerd cfhoorlteosttaelrporl,otteoitna,l tbriilgilryucbeirni,duesr,eaalnbiutmroigne,n,glcorbeualtiinn,inael,bcurmeiant/ignlionbeukliinnasrea,tiao,lagnliunceose, samoidnioutmr,anpsoftearsassieu,masapnadrtcahtleoraimdien.otransferase, alkaline phosphatase, calcium, phosphorus, sOinngDleLcr2o2s,sp-suepcstiwoenroef stahcerihfeicaeddaatntdheexlaemvielneofdtfhoerfgrroontsasl-lpeasriioentsa.l Nseutcurroepasnydienxcalumdiendataion of the cross-sectioned brain for apparent hydrocephaly. BlgroooudpssaelmepclteesdfwoerrFeOcoBllaenctdemdfotroormfacitvieviptuypasspseesrssmeexntp,erblliotoedrsfarmopmltehceol1l0ecftioen fmorraatslpeer `haenmalaytsoisl.ogTyhaenldivcelrinfircoalmcehaecmhissterleycatneddphuisptwolaosgiwcaeligehvealdu.ations. Sera was shipped for 12. Results 121. MaleRats A`lwelremacloensriadtesrseudrvuinvreedlattoedscthoetdhueletedstsascurbisftiacnecaen.dallclinical and necropsy observations Body weight gains were significantly `groups on study days (DSs) 29to36. reduced in the 0.3, 3 and 10 Significantly reduced body mg/kg/day dosage weightgainoccurred in wtheeig0h.3t,ga1,in3 waands1a0lsmogs/ikggni/fdiacyandtloysargeedugcreodupfosrotnhsetu1d0ymdga/ykgs/DdaSy2d9ostoagteergmrionuatpifoonr. thBe.ody `enwteirreeudnoafsfaegcetepderbioydd.osAabgseoslouftethaendtersetlastuibvsetfaenecde caosnhsiugmhpatsio1n0 vmagl/ukegs/dfaoyr.the male rats 418-028:PAGE 14 g`Treorumpi.naTlhbeodabysowleuitgehtwseiogfhtthseomfatlheerlaitvserw,etrhee srlaitgihotsloyfrtehdeulcievderinwetihgeh1t0s mtog/tkegrm/idnaayldboosdagye. 3`waeingdht1s0amngd/rkagt/iodsayofdtohseaglievegrrowuepisg.htTshteo rbartaiioonfwtehigehthewaertrewesiigghntisfitcoanbtrlayiinnwcreeiagshetdwiansthe significantly decreased in the 10 mg/kg/day dosage group. dHoesmaoggelogrboiunpscoanncednatvreatriaognesvwaelureesfsoirgnirfeidcabnltoloyddeccelrlesaasnedd hinemtahteo1c,r3itawnedr1e0smiggn/ikfgic/adnatyly dienccrreeaasseedd iinnththee03.3a,n3d a1n0dm1g0/kmgg//dkagy/ddaoysadgoesaggreougprso.upPs.roAtvehrraogembtviaimlneueswafsorscihgonliefsitcearnotlly `awveerreasgiegnviafliuceasntfloyrdtercigrleyacseerdidienstwhaes0.s3i,gn1i,fi3caanntdly10demcgr/ekasge/ddaiyn dthoesa1g0emggr/okugp/sdaanyddothseage agrlobuupm.in/Agllboubmuilni,n rbaltoioodluevreelasnwietrreogseing,nailfkiacalnitnleypihnocsrpehaasteadsei,n ctahelc1i0ummga/nkdg/day dosage group. ``mTarleeartamtesnti.nretlhaete3damnidcr1o0scmogp/ikcg/cdhaayngdeossawgeeregroobuspesr.veTdheinttrheeatlmievenrt-arnedlattheydromiidcrgolsacnodpiocf hcehpaantgoecsytinesthaendliivnertchoentshiysrtoeiddofglmainndiamsaalntionmcroedaesreadtienceindleanrcgeemoefnthyopfceernttrroiplhoybuolfar foklnloicwunlaerfcfeelcltss oafndcohmyppeorupnldassiat.hatThcaeusseemmiiccrrosocsoopmiaclcehnaznygmese airneduccotnisoinstwehnetrweitthhethe thheypraotoicdedluleultaor ihnycpreeratsreodpphlyarsemsualttsuimnovaecromopfetnhsyartoxoirnyehaynpderatsrsoopchiaytaenddsthiympuelraptliaosniaooffthe cthhyarnogieds-sotbimsuelartviinegndhtohremloinveeroifntrhates"F.1 gTehneerreatwieornepnuopstrferaotmmetnhte-rdealamtsedgmiviecnrouspcotpoic 10 mg/kg/dayofthe test substance. hAlilghmaasti1n0gmagn/dkgf/erdtailyi.tyTphaerraemewteerrse nweoroethuenrafsfteatcitsetdicbalylydosisgangiefsicoafntthoer beisotlosguibcsatlalnyce as oibmspeorrvtaatnitondaiflfbeartetnecreys(aFmOoBn)gotrhmeoftoourr dacotsiavgietygornouDpSssin36thtehmreoausguhr3e9s.ofthe functional ``TShpeersmpemrotmilciotuyntwaansdunsapfefremctdeednbsiytdyowseargeescoomfptahreatbelstesaumbostnagncteheasfihviegdhoassag1e0gmrgo/ukpgs/.day. 12.2. Female Rats `Awlelrfeecmoanlseidreartsedsuurnvrievleadtetdotsocthheedutlesetdssaucbrsitfainccee.and all clinicalandnecropsy observations `Bwoedreycwoemipgahtrsa,blbeodayndwediidghntotgadiinfsf,eransidgnaibfsioclaunttelyadnudrirenlgattihveepfreeecdohcaobnistautmipotni,ognesvtaaltuieosn or lactation periods at dosagesofthetest substance up to 10 mg/kg/day. l`iTveerrm,ilneaflt abnoddyriwgehitgkhitds,neaybssoalnudteadarnednarlesl,atsipvleeewne,igthhtysmuofstahnedrheeparrotduocfttihveefoermgaanlse,rabtrsaiwne,re 418-028PAGE 1.5 c1o0mmpga/rkagb/ldeaaymdoonsgagdeosgraoguepgrwoeurpes.coAmvpearraagbeleprtiomtohredcioanltfroollligcrloeucpo.unts for the aNdomitnriesattemernetd-ureplatote1d0mmigc/roksgc/odpaiycocfhtahnegetesstwesurbestoabnsceer.veTdheinreanwyeorfetnhoetrfeeamtamleenrtarteslated. `microscopic changes observed up to 10 mg/kg/dayofthe test siunbsthteanlciev.er of the FI generation pups from the dams given Dosages as high as values evaluated. 10 mg/kg/day did not affect any hematology or clinical chemistry d`Tohseaagveegrraoguepsn.umAblelrmsatoifnegsatrnodusfserttaigleistyppearra1m3etdearyss,wienrcelucdoimnpgatrhaebgleestaamtioonngintdheexf,ive hviiagbhilaisty1i0nmdge/xkagn/ddalya.ctation indices were unaffected by dosagesofthe test substance as `fTihveeredowseargee gnroosutpatsisitnitchalelmyesasiurgesnofitohrfbeiiofulcnocgatiiconanlatllyoibmspeorrvtaatnitondailfbfaetrteenrcyes(aFmOoB)ngorthe. `motor activity on DL 17. dAlalmsprdeeglniavnetridnagmlsittdeerls,ivtehreedduaraltiitoenr ooffgoensetaotriomno,raevelirvaegepsupfso.r iVmaplluaenstaftoirotnhseitneusmpbeerrs of ldeilvievbeorrendpluiptse,r,dtahmesnuwimtbheralslopfudpasmdsyinwgi,thwestriellcboormnpapurpasb,lethaemnounmgbetrhseoffivdeadmossawgietghrnooups. p`Tehrelnituemrbweerroefcpoumppsarsaubrlvievainmgopnegrtlhitetefri,vpeudpossaegxeragtrioousp,sl.itter size and pup body weights dNoocslianiogcfaltehosretneesctrsoupbssytoabnsceeravsahtiiognhsaisn t1h0emFg1/kgge/ndearya.tioFn1pguepnesrwaetrieonamtatrliebuatnadblefteomale b`poudpytewremiignhatlwbeordeycwoemipgahrtas,blaebsaoclruotseslailvlerfiwveeidgohstaagnedgrraotuiposo.f liver weight to terminal 418-028:PAGE 1-6 13. Conclusion On the T-7706 b[aPseisrfolfuotrheosheexdaantea,StuhlefomnaatteernPaoltansos-oibusmerSavlatb]lei-sagdrveeartseer-tehfafenc1t-0lmegve/lkg(/NdOayAE(tLh)e for 10 mg/kg/day dosage caused no deaths, adverse clinical or necropsy/pathology c`ohbesmeirsvattriyonvsa,lucehsantghersouignhbooudtyprweecioghhatb,itfaeteidonc,ongseusmtpattiioonn,or`olrachteamtaiotno.loTghyeopratcleirnniaclal dNiOffAerEeLnceiss lienssbotdhaynw0e.i3ghmtg/gkagin/,dahyem(atthoel0o.g3yanadnd1 cmlgin/ikcgal/dcaheym`idsotsraygevsaclauuesseadndsitghneif3icaanndt. 10 mg/kg/day dosages caused significant changes in absolute and relative organ weights `and microscopic changes in theliver andthyroid gland). e`fTfheecrteopnrotdhuectdiuvreatNioOnAs EofLgeisstgarteiaotnerantdhapnar1t0urmigt/iokngo/rdaanyy(tmhaet1i0ngmga/nkdgf/edratiylidtyospaagraemheatedrnso. `There was no effect on the sperm parameters in the male rats). `The NOAEL for viability and growth in the offspring is also greater than 10 mg/kg/day (dosages of 10 mg/kg/day hadno effect observations or body or liver weights in on perinatal mortality, clinical the F1 generation offspring). ornecropsy Oeil Wr 3 vre3 `Alan M. Hoberman, Ph.D., DABT Date Director of Research Study Director yi ARsoIdate DGi.reYcotr(otamf oR)ebDeaArcBh T Date `Study Director 418-028:PAGE 2-1 2 DESCRIPTION OF TEST PROCEDURES 21. Conductof Study 211. Sponsor 355M14C4o-r1po0r0a0te 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 418-028 214. Sponsor's Study Number T-7706.1 215. Purpose of the Study `mTahye pruersuplotsfeorfotmhriespesattueddyewxapsostuorperoovfiCdreli:nCfDorm(aStDio)nIGoSnBthRe pVoAsFs/ibPlleuhsealmthalheazaanrddsfetmhaalte: raattlseaosta4t2esdtasyusbs(tmaanlceerbatesg)ionrnitnhgrobuegfhorpearctouhraibtiitoantiuontni,ltdharyou2g1homfaltaicntgatainond (cfoenmtailneuirnatgs)f.or t`eTshtistrhaetpecaatnedbedousseedsttuodpyrionvciodrepionriatitaeldianfroerpmraotdiuocntioonn/pdoesvseiblloepemfefnetcatlsotonximciatlyesacnredefneimnagle rdeepvreoldoupcmteinvetopfetrhfeorcmoanncceept(eu.sg.a,ngdonpaardtaulriftuinocnt)i.onT,hmeasttiundgybaelhsaovipolra,cecdonecmepphtaisoins, on naetuersotlsougbisctaalencfef,ecwthsiacshamsapyecwiafricraenntdpfouritnhtearnidn-sdheoputlhdiindveensttiifgayttihoen.neurotoxic potential of Bscerceaeunsiengoftetsthedsiedlnecottivpirtoyvoifdteheeviednednpcoeinftosr adenfdintihteivsehocrltaidumrsaotfionnoorfetphreodsutcutdiyv,et/he d`meavneilfoesptmaetnitoansl oefffpecrtesn.ataIln epaxrptoiscuulraer,oriteoffffeecrtesdthoantlymaliymibteedinmdeuacnesdodfudreitnegcptoisntgnaptoasltnatal exposure. 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 OECD,U.S. Food and Drug Administration (FDA), the Japanese 418-028:PAGE 22 rMeignuilsattriyonosf tHheaatlatfhfeacntdedWethlefaqrueal(itMyHoWr)iTMnt.egrTihtyeroef twheersetnudoyd.evQiuaatliiotnys AfsrsoumrathneceGULnPit afinnddihnagvsedbeereinvepdrfovriodmetdhteoitnhsepeScttuidoynsDdiurreicntgortahendcotnhdeuTcetstoifntghiFsacsitluidtyy Maraendaogceummeenntt.ed 218. Ownershipofthe Study p`TrhoepeSrptoynosforthoewSnpsotnhseosrt.udy. All raw data, analyses, reports and preserved tissues are the 219. Study Monitor John Butenhoff, Ph.D., CIH, DABT 2110. Study Director ARdadyrmeosnsdasGc.itYeodrkp,rePvhi.oDu.s,lyDfAorBTTes(tAisnsgocFiaactileitDyi.rectorof Research) 2111. Technical Performance JJooshenpFh.WB.amLeetcth,,BB..SS..((DSierneicotrorRoefseLaarbcohraAtsosroyciOapteer)ations) JMaacrlyynPS..HFoowxa,rdB.,SB..(SL.ab(oTreaatmorLyeTaedchen-ricGieanne)ral Laboratory) JCohsreitstteoMph.erPrKo.voRsutp,peB.rSt., B(.NSe.cr(oFposrymuLlaabtoiroantLoarbyoTreacthonriyciTaenc/hFniixceidanT)issue Coordinator) 2112. Report Preparation Raymond G. York, Ph.D, DABT JJooAAnnnneFMr.azCeoen,kMl.iSn,. B(.SSt.ud(yDaCtoaorMdainnaatgoerm)ent Specialist) Cristina Petrescu (Report Administrator) 2113. Report Review Valerie A. Sharper, M.S. (Director of Study Management) 2114. Date Protocol Signed 26 March 2002 2115. Dates of Technical Performance 21151. Male Rats Rat Arrival DotshargouegPherai1o4d-(d1a4ydcaoyhasbbietfaotrieoncophearbiiotdautnitoinl and FsaOcBriafnidceMaoftteorratAlcetiavsitt4y2Edvaaylusaotfidonosage) ToDxSic`ok1i4netic Sample Collections Ds 42 `SScchheedduulleedd SSaaccrriiffiiccee --MTaoxiincSotkiundeytic Study 21152. Female Rats Rat Arrival Dosage Period (14 days before cohabitation tChohraobuigtahtiDoLn"P2e1r)iod Male 1 Male 2 Toxicokinetic Sample Collections DS 14 DG"21 DGO DG25 Sacrifice,(Ratsthatdidnotdeliver alitter) FDeOlBivaernyd PMeortioodr"A(ctDiLvi1t)y Evaluation DL22Sacrifice FemaleRatsandPups. 418-028:PAGE 23 26 MAR 02 01APR02- 16 MAY02 06 MAY 02-09 MAY 02 14 APR 02 12MAY 02 12MAY 02 13MAY 02-17MAY02 26MAR 02 01 APR02-JU0N092 14APR 21APR 02 02 PM PM - 21 APR02 28 APR02 AM AM 14 APR 02 06 MAY02-M1AY902 15 APR 02-28 APR 02 10MAY02-23MAY 02 0273MMAAYY0022--2260 MMAAYY 0022 28MAY 02-JU1N002 a DSis an abbreviation used for day of study. b. c. DDLGiissaannaabbbbrreevviiaattiioonn uusseeddffoorrddaayyooffl(apcrteastuimone/dp)osgtepstaarttiuomn.. d. TEhffeedcatsyTeosfbtiGrutihidesldienseisg-naRteepdroldacutcattiioonn danady0Fer(tpiolsittypaErftfuecmtdsa(yOf0f)iicnetohfePrHeevaelntthion, GPeusitdiecliidneesafnordtThoexTiecstSiunbgstoafnCcheesm8i7c0a.l3s80-0C,oAmubgiunsetd, R1e9p98e)ataenddDionsteheToOxEicCitDy NSot.ud4y22w,it2h2tMhearRcephr1o9d6u6c)t.ioTnh/iDsevsealmoepmdeanytiasldTeosxiigcniattyedScdraeyen1ipnogsTtepsatrt(uSemc(tdiaoyn 4|, of lactation) `Throughout in the Standard Operating this study, the dayofbirth Proceduresofthe was designated as Testing Facility. day 1 postpartum (day 1 of lactation) and all subsequent agesofthe lactation period were determined and cited F1 generation accordingly. ratsanddays of the. 418-028:PAGE 24 2116. Records Maintained ve`Thhiecolreigcionmalpornepeonrtts,arraew rdeattaaianneddrienstehrevaercshaimvpelseosfoAfregaucshRleotsoefarbcuhl.kAtensyt spurbesstearnvceed atinsdsubeuslk arfienarletraepionretd, aifnttehrewahricchhivteismoeftthheeSTpeosntsionrg wFialclildietcyifdoertohneeiryfeianraalfdtiesrptohsietimoani.liAnlglofutnhuseeddraft `psruebpsatraendcefworamsulraettiuonnesdwteorethdeiSspconasrodrae.tdthe Testing Facility. Al remaining bulk test 22. Test Substance Information 221. Description `T-7706 [Perfluorohexane Sulfonate Potassium Salt (PFHS)] - a white powder 222. Date ReceivedandStorage Conditions The test substance was received on 11 March 2002 and stored at room temperature. 223. Special Handling Instructions m`Satsakn,dasradfseatfyegtoygpgrleecsauotrisoanfset(yusgeloafsspersotaencdtiavfeaccleo-tshhiinegl,d)glwoevrees,tadkuesnt-dmuirsiynHgEfPoAr-mfuillatteiroend preparation and dosage. A half-face respirator was worn during formulation preparation. 224. Analysis of Purity sItnrfeonrgmtahtiaonndtpourdiotcyoufmetnhtetoerstcesrutibfsytatnhceeidweanstitpyr,ocvoimdpeodbsiyttihone,Smpeotnhsoodr otoftshyentTheesstisi,ng Facility. A Certificate of Analysis is available in APPENDIX F. 23. Vehicle Information 231. Description uAsqiunegocuasrb0o.x5y%mectahryblocxeylmleutlhoyslece(lsloudliousmes(alCt;MmCe)d(isuomdivuimscsoaslitt;ym),edaniuofmf-vwihsciotseiptyo)wdpererp,aarnedd reverse osmosis membrane processed deionized water (R.O. deionized water). 232. Lot Number 120K0252 233. DateReceivaend Storage Conditions o`Tnhe11cSaerbpotxeymmbeethry2l0ee0l1lualnodsestwoaresdraetcreiovoemd tfermopmerSaitugrmea.ChR.eOm.icdaelioCnoiz.eSdt.waLtoeurisi,s Maivsaisloaubrlie, from a continuous sourceatthe Testing Facility and is maintained at room temperature. 418-028:PAGE 2.5 234. Special Handling Instructions mStaasnkd,asradfestayfegtoygpgrleecsaoutisoanfset(yusgelaosfsepsroatnecdtaivfeaccleo-tshhiinegl,d)glwoevrees,tadkuesnt-wmhiesnyHhEaPnAd-lifnigtetrheed vehicle components and prepared vehicle. 235. Analysis of Purity lNiekietlhyterothhaevSepboenesnorprneosretnhteiSntthuedyveDhiircelcetotrhawtawsoauwladrheaovfeainnyteprofteernetdiwalitchonttheamriensaulnttssof this study. The expiration date for the earboxymethylcellulose is September 2005. 24. Test Substance Preparation and Storage Conditions vFeohrimculleaftoiromnuslwateiroenpsrweepraeresdtowreeedklreyfartigtehreatTeeds(t2inCg Facility. to 8C), Prepared test substance and 241. Sample Information mple Typ Bulk Test Substance" Homogeneity DReaitsieoed | CoSntdoirtaigoens ShSihpippepdinTgo Dae Conditions |_ Shipped Room temperature| EAmxbyigeenrt' Reged | Scopnodmistoiro/ns OT APR [oo [eer| res Caonlceenvterla)tion Sabilig Tal 07TUN02 Refigeraed |REexfyiggeerr's/ted Refigeraied | Sponsor | W10VJAUNYO022 01 APR GZ T pr ea [ama] [ReneSe [Te Jone] Ae [TE RVeehsiecrlveeComponents Room temperature|TAerscthiinvgesFacity CuRrOb,oxdyemioentihzyeldwcaltueirose 110053uN0022 11007JuUNNo022 b=. AExsyagmepnleRoesfetahrecht,esSartielCeowllagser,aPiennnesdyolvnantiha.1stdayofweatment4nd sippedForalysis . sQoafumparpedpiuapsrlawtieicroaent.resTtaamwiponlesedasmtwptleeersTfaerskoteimnnfegraFoacmchitlqhiutaydorapusp,blimacicadktdeulpesseaanmwdpelrbeeoss.hoimppoefdefaocrhancaolnycseinst.raTtihoenorematienifnirgst day d. fQTrueoasdmtreiunapgclFhiaccqaitleiustyamaaspblaedcskwurseptseuatwmaepkrpleeesnslfh.irpoipmeedcfaocrhaacnoantlcyesneitsr.atTihoenornetmahienisngtsdaamypolfepsrweeparrearteiaoni.nTedwtostahmeples c. SSaammpplleess ffoorr 0.a0n3,d00..13manyd/m| Lmcgo/nmc.ecnornacteinotnratoinolnys. only. TSsa0wm0op1lsaeesopsofosefsaidcbuhlpdelauipcflaeitrecsparatemepspalereawtsifaorsnosahmniepdapcteehnocdnoantycsehanftdreaartyiotohnfefpwiresertpeatarnaaaktlieyosnnio,snT.thTheheseofsirrestmdasanyiomnwfgepsprrueepmaaplnralaltsieywosene.rdseaO5ne retained at the Testing Fcility as backup samples. 242. Analytical Results 418-028PAGE 2:6 Resultsofthe analytical analysesare available in APPENDIX G. 25. TestSystem 251. Species Rat 252. Strain Crl:CD(SD)IGS VAF/Plus 253. Supplier (Source) Charles River Laboratories, Inc. MaleRats - St. Constant, Quebec, CANADA Female Rats - Raleigh, North Carolina 254. Sex Male and Female 255. Rationale for Test System The Crl:CD(SD)IGS BR VAF/Plus rat was selected as the Test System because: 1) it is one mammalian species accepted for use in toxicity studies and it has been `widely used throughout industry; 2) this strainofrat has been demonstrated to be sensitive to TreepsrtoidnugcFtaivceilanidtyd.evelopmental toxins; and 3) historical data and. experience exist at the 256. Test System Data 25.61. Male Rats Number of Rats AApppprrooxxiimmaattee Daoft Bireth Age at Arrival Weight(g)the DayafterArrival `Weight (g) at Study Assignment 25.62. Female Rats 100 20JAN 02 66 days 277-318 305-348 Number of Rats `Approximate Date of Birth Approximate Age at Arrival Weight(g)theDayafterArrival Weight (g) at Study Assignment 100 21JAN 02 65 days 195-227 207-230 418-028:PAGE 2-7 257. Method of Randomization oUfpcoonmpaurrtievral-,getnheemraatleedarnadndfoemmaulneirtast.swDuerriengasasnigancecdlitmoaitnidoinvpiedurailodhooufsaitnlgeaosnt ftihveebdaasyiss, b`moadlye waenidgfhetmsarleecroartdsewdedruerisnegleacctceldimfoartsitoun.dyTohnethraetbs weareosfaspshiiygsniescdaltoafpipveeadroasnacgeeagnrdoups o(rGdreoruepds) IratnhdroomuigzhaVt)i,on15prroactsedpuerre.seAx npeardgdritoiuopn,alutshirnegearactosmppeurtsere-xgepneerrgarteodup(wweeirgehttahsesiwgeniegdhttovGarrioautpiosnIotfhtrhoeugrahtsVdfiodrntootxiecxockeiendet+ic2s0a%moplfethcoellmeectainonw.eiAgthtstoufdeyaicnhitsiaetxi.on, cLuitltleirnsg wceorueldnhotavceulrleesduldtuerdining ptohteenltaicatlatbiioanspeesriinodpubpecvaiuasbielirtainesdaonmdsbeloedcytiwoeniogfhtpugpasinfsor over this period. Wfiirtshti1n0efaecmhadloesFaogegegnreoruapt,iocnonrsaelcsuttoiavfeuonrcdteironwaalsoubsseerdvtaotiaosnsailgnbatthteerfyir(sFt O1B0)manadamnlodttoehre hacitsitvoiltoygiacsasleesvsamleunatt,iobnlso.od sample collection for clinical chemistry and hematology and Ofonr bDlLoo2d2,saamtpalbeleaonfdrlaivnedrocmolulneicttsiowna.sTuhseesdetpouspeslewcetrfeivoenmlaylseelaencdtefdivferofmemtahlee1p0udpasmpser litter esvealleucatteidofno.r FOB, motor activity, clinical chemistry and hematology and histological 258. SystemofIdentification pMearlmeaannednfteimdaenlteirfaictastiwoenrneuamsbseirgsnewdhteenmpaosrsairgynendutmobethresastturdeycebiepftoarnedadgmiivneisnturnaitiqouneof the `fiBrasntddoasnadgeT.agRCaot.s,wIenrc.e,pNeor.maMnSenPtTly20i1de0n1t)i.fieCdaguseitnaggas Mweorneelmarskeeldf-wpiietrhcitnhge esatrudtyag (Gey ``gnruomubpera,ndpedromsaangeentlevrealt.number, sex, test substance identification, generation, dosage tPeurpmssowfetrehenoltitienrd.ividually identified during lactation; all parameters were evaluated in 26. Husbandry 261. Research Facility Registration USDA Registration No. 14-R-0144 under the Animal Welfare Act, 7 U.S.C. 2131 ef seq. 262. Study Room `aTnhde isntduedpyerndoeonmtlwyassumpapliinetdaiwnietdh uanmdeirnicmonudmoifttieoonnfscphoasnigteisvpeearirhfoluorworfela1t0iv0et%ofraehsahlaliwr ay that had been passed through 99.97% HEPA filters. Room temperature and humidity 418-028:PAGE 2-8 1w0er7e9mFon(i1t8orCedtoc2o6nstCa)n;tlreyltahtirvoeuhguhmoiutditthyewstausdyt.argReoteodmatte3m0p%eratotu7r0e%w.as targeted at 64F 263. Housing `Rcaothsabwietarteioinndainvdidpuoasltlypahrotuusmedpeirniosdtsa.inlDeusrsisntgeecl,ohwaibrieta-tbiootnt,oemaecdhcpaagiersoefxcmeapltedaunrdinfgomale faetmsawlaesrahtsowuesreeidnintdhievimdaulalelryaht'osucsaegde.in Bneegsitinnnginbgoxneos luantteirlthtahenyDeGith2e0r,naFtourgaelnleyrdaetliiovnered cloimtmootrnewnererssetisnagcbriofxicdeudri(nDgGth2e5)p.osEtapcahrtduammpearnidodd.elAilvlerceadgelitstiezrewsaasndhohuosuesdinign a conditions were in compliance with the Guidefor the Care and UseofLaboratory Animals. Argus Research is an AAALAC-accredited facility. 264. Lighting A12n-haouutrosmadtaircka,llwyi-tchonetarcohlldeadrkflpueorrieosdcebnetgliingnhitncgycalte1w9a0s0 hmoauirnstaEiSnTe.d at 12-hours light: 265. Sanitization `Caapgperpoxainmaltienleyrsevweerrye octhhaenrgweedekat.leaBsetdtdhirnege wtaismecshwaenegkeldya.soCfatgeenswaserneececshsaanrgyetdokeep the rats dry and clean. 266. Feed IRnattesrnwaetrioenagli,veInnc.a,dSlt.ibLiotuuimsa,cMciessssotuoriC)eritnifiineddivRiodduealntfeDeideerts.#5F0e0e2d w(aPsMIreNmutorvietdiotnhe `evening prior to the scheduled sacrifice". 267. Feed Analysis Aexncaeleydsiensgwtehreemraoxutiimneulmy pceonrcfeonrtmreadtiboyntfhoer cfeeretdifsiuepdplfieeerd. oNrodecvoinattiaomnisnafnrtosmaetxlpeevcetlesd `fneuetdriatnioanlaylsreesqauriereamveainltasblweerinetdheetercatweddabtya.these analyses. Copiesofthe results of the lNiekietlhyetrothhaevSepobneseonrprneosretnhteinSttuhdeyfeDierdeacttocronwcaenstraawtairoensoftahantywpooutlendthiaalvecoinnttaemrfienraendtwsith the results of this study. a bh. SSeeecAAPPPPEENNDDIIXX EH((DTEVEIMATPIEORNSAFTRAUONRMDETHREELPARTOITVOECHOULMIADNIDTTYHREEPORT). SitTemAN1.DARD OPERATING PROCEDURES OF THE TESTING FACILITY), 418-028:PAGE 2-9 268. Water (LoRcOa.lwwaatteerr)thwaatshaavdaibleaebnleptrooctehsesreadtsbaydplaisbsiatguem tfhrroomugihndaivriedvuearlsewaotsemrobsoitstlmeesmabtrtaacnheed to thecages processed and/or water from an automatic as a bacteriostat. watering access system. Chlorine was added to the 269. Water Analysis (`TLhaencparsotceerssLeadbowraattoerriiess,anLaalnyczaesdtetrw,iPceenannsnyulavlalnyiaf)orapnodssmiobnltehclhyemfoircaploscsoinbtlaembiancatetriioanl rcoentsamuoilnfattthiseonwa(tAenralayntailcyasleLsaabroeraatvoariileasb,leInicn.,thCehraalfwodnat,taP.ennsylvania). Copiesofthe lNiekietlhyterothhaevSepobenesnoprrneosrentthienSttuhdeywDaitreerctthoartwwaosuladwahraevoefiantneyrfpeorteedntwiiatlhctohnetrameinsanuotflstthiss study. 2610. Bedding Material Bed-0cobs as the nesting bmaetdedriinalg.(The Andersons Industrial Products Group, Maumee, Ohi) was used 2611. Bedding Analysis tAhnealbyesdedsinfgorapnoaslsyisbelseacrocnatvaamiilnaabtlieoinnatrheecroanwdudacttae.d semi-annually. Copies of the restults of liNkeeitlhyterohthaevSepboenesnoprrneosrenttheinSttuhdeybDeidrdeicntgorthwaatswoauwlardehoafveaniyntpeortfeenrteidawlictohtnthaemriensaunlttss of this study. 418-028:PAGE 2-10 27. Methods EE 27.1. DosageAdministration Growp_{mghglday] mp/ml) | lVho)erse|[po5er0hSsoe|x|AsMVaaiibnRSuwpds. ei| oMrmaeimb oSruade:s n|| 111999111230269]111999111321555,,, 11199911143131,,11199911131529,.,| 11199900012503,,,11199900051432,,. 111990004g129,,, 11159900286414, T1o9s1ll7oc,vo1ke9i"1n6e119c,1S17u88d1y6:7| | T1o5x070i20o,7k16i9-n017t45e,0S71u98d0y7:5 191191130211V991i102i06,,S11u9911d2698,,119911361,, 119092060,,M11a99i0093n,,S11a30y013:67,1199004138,, 191T3o189s,1i61c49,o13k19i9.n161e59c,1S41t79u1d71y19:153,| 904175,06119,0145,06175,051920711905, Tosicokind Sudy: LE ToMiain S51e81 19101, 19105, 19107 19112, 19003, 11M9500i07n79.S1a155y000:881, 19013, 11991113167,9111799112241169,,111799,11251359,,111799411| 3509,,| 119900121499,,0511799.00311459,,0611099,001317,5.011695400526,, Toriociienei15c184dy: Ma Sudy: Toxc1o00i8n2e-i1c00S8t4udy: Mai Sud 19111991310340,8, 111999111540013,., 111999111540624,,, 11199911146140,.,|11199900050442,,,11199900040858,,,11199940063625,.,111999000563139., T1o5s1e6o2k,i1n9c1t6i3c,Su19d1y6:6 oss 19187 | T1o50x606i, n165e06155s,0S81u750d7:3 v LE 1911911217,,1M199a11218,S7u1,9a11d4y09:,1119291142465,,, 1199000212,,1M1a90i92n5.S110u5900d2170,,1199,002280,, 191T16o95s1c169o81k,51i2,9n1t169c,15S14u9,d1y17:90158,| 190T310o9,0x419i9,0n511e9,0189,0S3t17u9,d0y17:90033, B TThhreteaaddsiitboinaanlcawsaspcsoenxwdeere aTsOsiTgSnpedutroofoxiIceokpnreosIseoaimospfsdloe1s9ca1og9e0lconl.eo 1908 13090 272. RatfiorDoosnageaSellecteion Dsuobssatgaenscwe,etresaeliekcntteoidacbncyoutghnetSppoosnssibolrebdaisfefdeornenprcieevnsiosuesnssittuivdiiteys bceotnwdeuecntperdewgintahntthaentdest onbovniporuesgnsaunftferraitnsg.. TThheedhiegshceesntddoisnaggseewqauesnceexopfetctheedtloocwaerusdeotsaogxeicelfevfeelcstswabsutsenloetctmeodrftoarltihoetry tphuerlpoowseesotfldeevmelo.nstrating any dosage-related response, withnoadverseeffects expected at 418-028:PAGE 2-11 273. Route and Rationale for RouteofAdministration "roTuhteeo,rtahle(gexaavcatged)osraougteecwaanbseselaeccctuerdatfeolryuasdemibneicsatuesree:d;1a)nidn 2c)omitpaisriosnoeonfwtihteh tphoessdiibeltearryoutes for environmental exposure. 274. FrequencyofAdministration 2741. Fo Generation Rats M1a4ldeayrsatbsewfeorreecaodhmaibniitsatteiroend(tmheaxteismt usumbs1t4adnacyeso)ratnhdecvoenhtiicnlueionngctehdraoiulgyhbtehgeidnaniynbgefore saadcmriinfiiscter,aatfitoenr.coFmepmlaelteiornaotsftwehreecaohdambiitnaitsiotneptrehereidodt,esatfstuebrsatamnicneoirmtuhmeofve4h2icdlaeyosnocfe dthaeildyabyegbeifnonriengsa1cr4idfiacyes, bDeLfo2r1e coorhDabGit2at4i(ornat(smtahxatidmiudmno1t4ddealyisv)eraandlictoenr)t.inTuhinegdtohsraoguegh ivnotlubuamteiown.asTahdejursattesdwdearielyiontnubtahetebdasoinscoeftdahielyiantdiavpipdruoaxlibmoadtyelwyetihgehtssarmeectoirmdeedebaecfhodraey. `wTehrefeirnsottdianytuobfadtoedsaungteilwcaosmdpelseitginoanotefdpaarstuDrSiti1.on,Dainmosrdinerthteo pprroeccelsusdoefpodsesliiblvee.ringpups `ddiasmruspwtieorneonfotmaatdemrinnailstbeerheadvioonreadnadi/loyrdcoasnangiebldiuzraitnigonthoefdpeulpisv.eryCopnersieoqdu.enNtloy,dasmommeissed . `more than one daily dosage. 2742. F1 Generation Pups hFa1vgeebneereantipoonsspiubplys ewxeproenseodtdtiortehcetlteystadsmuibnsitsatnecreeodrthveehtiecsltesduuribngsmtaotraevemnhailcclgeees,tabtuitomn a(iyn utero exposure) or via maternal milk during the lactation period. 275. MethodofStudy Performance 2751. Fo Generation Rats ``mWailtehirnatepaecrh fdeomsaalgee rgart.ouTp,hecocnosbeacbuittiavteioonrdpeerriwoadscounsseidstteodaosfsiagnmaraxtsitmoucmoboafbi1t4atdiaoyns,. one `Fceompaullaetorraytspwliutghisnpseifrumawteorzeocaoonbssiedrevreedd1i0nbaesDmeaG0r oafntdheasvsaigginneadl tcoonitnednitvsidaunadl/hooruasing. Fasesmiaglneedraatns naolttemmaatteedmawiltehraattmhaaltehraadt wmiattheind(tshaemfierdstosseavgeengdraoyuspo)fcaonhdarbeimtaaitinoend wienre. cohabitation for a maximumofseven additional days. fRoartsclwineircealoobbsseerrvveadtifoonrsviaanbdilgietnyeartalleaasptpetawircaenceeacwheedkalyyodfutrhiengsttuhdey.acRcalilmsawteiorne peexraimodi.ned Othbesefrirvsattdiaoynsoffodrocslaigneicaalt asipgpnrsoxoifmeaftfeelcytshoofurtlhye tiensttersvuablsstfaonrctehaenfdirdsteaftohusrwheourresmaanddeatonthe `endofthe normal working day. Observations for clinical signs of effectsofthe test 418-028:PAGE 2-12 saupbpsrtoaxnicmeaatnedlyde6a0t+hs10wemrienumtaedseafotnersduobssaegqeueandtmidnaiysstrdaatiiloynbaenfodroendotshaegdeayanodf sacrifice". Once before the first dosage and atleastonce weekly thereafter, detailed clinical `Tdoahbyesseoerfvoacbtosineodnrusvcatwt.eiroEenfsfcowornetdruwecamtsaedmdaefdooreuattlsolimedneasltuehreaecntadhgafteevimanarlaieasttriaaotnnsdsaairsndsitaghreneetndeasttaotctothnhedeimstaaiiomnnessttwiuedmryee"c.ach "mTihneriamtasl waenrdethoabtseobrsveerdvaftorio(nbsutwoebrseercvoantdiuocntsewdebryeonbosterlviemirtseudntaow)atrheeoffotlrleoawitnmgenstiggnrso:ups. acnhdanaguetsoinnomskiicn,acftuirv,ietyye(se,.g.mulcaocursimmateimobnr,apnielsoe,reocctciuornr,epnucpeilofsiszeec,ruetniuosnusaalnrdesepxircarteotriyo.ns cplatotneircno).r tCohnaincgmeosveinmegnaitts,,posstteurreeotaynpidcrbeeshapvoinorsteo(e.hga.,nedxlceisanssgivweeglrloaomtihnegp,rreepseetinticovefe cwiarlckliinngg),bdaicfkfwicaurldtso)rwperroeloanlgseodrpeacrotrudreidt.ion or bizarre behavior (.g., self-mutilation, Bdoosdaygewpeeirgihotdsawnedreatresaccorridfeicde.weFeekeldy cdournisnugmpttheioanccvlailmuaetsiofnorpmearlioed,radtasialyssdiugrniendgttohethe fmeamianlestrautdsy wasesriegnreedcotrodtehdewmeaeiknlystduudryinwgerteherdeocsoradgeedpwereieokdl.yFteoecdohcaobnistautmipotni,oonnvDaGluse0s,for b7e,g1i0n,t1o2,co1n5,su1m8,e2m0aatnedrn2a5lf(eifendeocnesosrarayb)oauntdDoLn 1D5,Lfsee1,d 5c,o8nsaunmdpt15io.nBveacluaeussewpeurpesnot toanbeulfaeteeddjaarf,terreDplLen1i5s.hmDeunrtionfgthcoehafbeietdajtairosn,wawshednoctuwmoernattesdocbcuutpiineddivtihdeuaslavmaelcuaegsewewrieth not recorded or tabulated. Evasgtirnoauls ccyytcolilnoggywbaesgievnanliunagtweidtihntrhaetsdaasysaifgenretdhteothfiermstaaidnmisntiusdtyrabtiyonexaanmdintahteinounntoifl swpaesrombasteorzvoeadwienrseitoubdsuerrivnegd tihneacsohmaebairtoaftitohnepvearigoidn.alEcsotnrtoeunstscyacnldi/nogrwaacsopeuvlaaltuoartyedplinug r`awtesreasosbisgenrevdedtotinheatsomxeiacorokifntehteicvasgtiundaydlucroinntgentthseacohnabidatacto/ipounloapteroriroydpulnutgilwsapserombasterovzeoda insitu. Fduermaatlieonraotfsgweestraetieovnal(uDatGed ftoortahdevdearsyethcleinfiircsatlpsuipgnwsaosbsoebrsverevdeddu)r,ilnigttperarstiuzreisti(oanll, pups d1e5liavnedre2d2). aVnadripautpiovnisabfirliotmy aetxpbeirctthe.dMmaatteerrnnaall bbeheavihorwawearsveervieaclouoradteredd,oinfaDnLdswh1,e5n, 8, present, on all other daysofthe postpartum period. On one occasion durtheiconurgse of the study,a functional observational battery (asFsOeBss)m"e*nt"wwaassccoondnudcutcedtoeshndor1t0lymbaelfeoraensdc1h0edfuelmeadlesarcartisfipceer, gburtouppr.iorFotro mblaoloedrastasm,ptlhies a b. SSeeee AAPPPPEENNDDIIXXEE,, iitteemms4.2 and 3. c. See APPENDIXE, item 5. 418-028:PAGE 2-13 dcuolrliencgtitohnefloarcthaetmioantopelroigoyd,anshdorctlilnyicbaelfocrheemsicshterdyuleevdalsuaactriiofnisce.. Female rats were tested `tThheeraFt.OBTheevafloulaltoiwoinnwgapsarcaomnedtuecrtsedwebryeaanssoebssseerdv:er unawareofthe group assignment of 1. pLuapcitlilmaartyiroena,ctsailoinvattoiloing,htp,alppileoberraelctciloons,urree,sppirroamtiionne,nacnedoufrtihneateiyoen,and defecation (autonomic functions). 2. S(reenascotirviimtoytaonrdresesnpsointisveistyt)o. visual, auditory, tactile and painful stimuli 3. Reactions to handlingand behavior in the open field (excitability). 4. Greaaicttpioanttaenrdilnantdhienogpfeonotfisepldl,ayse(gvaeitraiontdfysgeaintsoarbinmoromtaolrictoioersd,ianiartiroing)h.ting S. Forelimb andhindlimbgrip strength. 6. Aanbdnoorthmearlucnluisniucaallbseihganvsioirn,clhuydpiongtobnuitanoorthlyipmeirtteodnitaoc,oenmvauclisaitoinosn,,tremors dmeohuytdhr.ation, unkempt appearance and deposits around the eyes, nose or "eTshteabalbiislhietyd o(fTtehsitsibnagtFtaecriyltiotydePotseicttivteheCoenfftercotlsDoaftpao)siatnidveiscoanvtariollabsluebisntaAnPcePsEhNaDsIbeXen1 Mbeoftoorre asccthievdiutylewdassaecrviafliucae,tepdrioonr t1o0bmlaoloedasnadmp1l0efceomllaelcetiroant.s pTehregrmoouvpeomnecnet,sshoofretalych rat `bwoetretommoenditcoargeed(4b0y.6a xpa2s5s.i4vexi1n7f.ra8rcemd)s.enEsaocrhmoteusnttseedssoiuotnsiwdaesas1t.a5ihnoluersssisntedeul,rawtiiroen-with tinhteenrvuaml.be`Trheoafpmpoavreamteunstmsonaintdotriemdeasrpenatoifcnumpoktvoem3e2nctagteasbualnatdseednastoeraschdufriivneg-emaincuhte sweesrseiocno,uwnittehrbeaalcahncreatdtaecsrtoesdsintetshteinsgasmeesslioocnastaionndocnagtehse.raDcaktaacdreomsosntsetsrtasteisnsgiotnhsa.t tGhreotuepsst ssuybsstteamncisesca(pTaebslteiongfdFeactielcittiynPgoisintcirveeasCeosnitnroalctDiavittay)pirsoadvuaicleadblbeyipnoAstPiPvEeNcoDnItrXolI. O`mnalDeSrast 1as4saingdne4d2,tobtlhoeodtosxaicmopklienset(iacppsraomxpilmeatceolllyec1tmioLnepaocrthi)onweorfethceolslteucdtyed(ftrhoremeeraatcsh cpoelrlgercotuepd)farnodm eoanchDSfem14alaenrdaDt Gas2si1g,nebdlotoodthseamtpoxliecsok(ianpeptriocxsimaamtpelleyc1olmleLcteiaocnhp)orwteiroen of ttihemesotfudeya(cthhrbeleoroadtscoplelrecgtrioounp)w.asSarmepcolredsedweirnethceolrlaecwtdeadtap. rBltooioddooswaargsecoolnleDcSted14f.roTmhethe oarnbditDalGsi2n1us(foenmaDlSe r1a4ts)o.fthTehsetsuadmypalnedsfwreorme ttrhaensvfeenrarecdaviantoonEDDTSA4-2cooaftsetdud(ypu(rmpalleetorpa)ts) tubes and spun in a centrifuge. The resulting serum was transferred into polypropylene. 418-028PAGE 2-14 t`nuubmebselra,bdeloesdagweitlhevtehle, pdraoytoofcosltunduym,bceorl,leScptoinonsoirntsetrvuadly,nduamteboefrc,olrlatecntuimobne,rs,pesceixc,sg,roup generation `maintained and storage conditions. All samples were frozen (<-70C) until shipmentto Exygen immediately frozen ondry Research, State College, ice and Pennsylvania, for analysis. Resultsoftheseanalysesarc available in APPENDIX G. 2752. FI Generation Pups Donaywh1icofhlaalcltpautiposnin(poasltipttaerrtwuemr)ewiansdidveifdiunaeldlyaswethieghdeady o(fpubpirbtohadnydwewiagshatlsswoetrhee rfeircsotrddaedy afterall pups in alitter were delivered and groomed by the dam). E`caocuhntleidttoenrcweasdaeilvya.luaCltiendicfaolr voibasbeirlviattyiaotnlseawsetrtewirceecodradielyd.onTcheedpauilpys",inPeuapcshwleirteer were toogbestehreveradnifdthneuyrswienrgeorwahradmmainldkcilneasnt,omfoarche.vidEeancchepoupawnfeassteaxnadmiifnpeudpfsorwegerneergarlouspheadpe ofthe head, trunk, limbs, tail DLs 1,8, 15and22 (terminal and presenceofanus. weight). Pup body weights were recorded on 276. Gross Necropsy 27.61. Fo Generation Rats dMiaolxeidaenadsfpehmyaxilaetriaotns oasnsDigSne4d2taontdheDtGoxi2c1,okriensepteicctisvteuldyy.wBelroeosdacsraimfpicleedsbwyercearcboolnlected fanrdomthtehelirvaetrs waesipgrhetviwoausslryecdoersdcerdi.bed`.TheAfmteedrisaancrliifviecre,ltohbee lwiavesr forfozeeanchanradt swtaosreedx(c<i-se2d0C) usnatmipllsehsipwmeernetcoflorleacntaeldysfirs"o.m eTahcehffeettuussesviwaedreecarpeimtaotvieodn.frBolmootdhewuatserpulsacaendd ibnltoootdubes, `tproaonlsefderpreerdliintteor,laablelloewdepdotloypcrlootpyalnednseptuunbeisn.aAclelntsraimfupglee.s wTehreeriesmumletdiinagtseelryufmrowzaesn on dfertyusicweaasndcomllaeicntteadi,npeodoflreodzepner(lSi-tt7e0raCn)dunptlialcsedhiipnmteonltabfeolreadntaulbyesiss.. TThheeslaimvperlefsrowmereeach fwraoszernecaonrddesdt.orCeadr(c<a-s2s0esCw)eurne ldisshciaprdmeedntwiftohroauntalfyusritsh.erTehvealnuuatmiboenr.ofTihmeplliavnetras twieornesites sanhailpypseedstaorEexayvgaielnabRleeseinarAcPh,PEStNatDeICXolGl.ege, Pennsylvania, for analysis. Resuolftthse Maaslpehyaxniadtfioenmafloelrlaotwsiansgstihgenleadsttodtohsaegmeaaidnmsintiusdtyrwaetiroens,aacfrtiefriacemdibnyicmaurmboonf d4i2odxaiydseof dpeolsvaigcevainsdceorna wDaLs 2p2e,rfroersmpeecdt.ivGerlyo.ssAnegcrroosspsnyecirnocplusdyoedftahneintihtioarlacpihcy,siacbadlomexianmailnaantdion coafvietxiteesrnaanldsutrhefiarcecsonatnendtas.lorSipfeiccieasl,aatstewnetlilonaswathsepcariadntiaolt,htehoorrgacaincsaonfdthabedroempirnoadluctive system. The ovariesand the uterus with cervixofeach female rat were weighed, and the a b. SSeece AAPPPEPNDEIXNE,DiitteIemmsX8.6aEnd,7. 418-028:PAGE 2-15 o1v0ar%iefso,rmuatleirnus., `vTahgeinna aund aommfaimmbpmlaanertyatrgiloanndsiwteesrwereerteairneceodirdnedn.eutUrtaelriboufffaeprpeadrently nabosnepnrceegnoafnitmrpaltasnwtaetrieonesxiatmeisnaenddafwteerreberientaginperdesisnendeubtertawlebeunffgelraesds p1l0at%esfotromcaloinnf.irGmrtohse.s lReespiroenssenwtearteivreetpahionteodgirnanpehustroaflgbruofsfselreesdio1n0sa%reforavmaaillianblaenidntexhaemrianweddahtias.tolToigsiscuaelly. tCerritmimfiiendgVaentderhiinsatroypaPtahtohlolooggyiswte.re performed under the supervision of or by a Board "tTesetnsrwatesrepearssseixgnpeedrtgorhoiusptoalsosgiicganledevtaolufautnicotniso.nalThobesfeorlvaltoiwoinnaglobragtatnesrywaenrde mexoctiosreda,ctivity tlirvierm,mkeiddnaenyds,inaddirveindaulasl,ltyhwyemiugsh,etdeasstess,oroinghatseppoisdsiidbylmeisaf,telrefexecpiisdiiodntyomiasvo(icodrpdursyianngd: caanpdutu)t,ersuesmi(nwaitlhvceesrivcilxe)s.(wTihteh faonldlowwiitnhgouttisfsluueisd)o,rprroesptraetsee,ntsaptlieveen,sbarmapilne,shewaerrt,eorveatraiiensed cienrneebuetlrlaulmb,ufpfoenrse)d, s1m0a%llfaonrmdallairng:ebirnatienst(irneepsre(siennctlautdiivnegrPeegyieorn'ss ipnactlchuedsi)n,glcuenrgcsbr(upme,rfused `wpietrhipnheeurtalranlebruvfefe(srceidat1ic0o%rtfiobrimaall)i,ns)t,olmyamchp,h knioddneesys(,ssupblmeaennd,itbhuylmaursa,ntdramcehdeiaa,stuirnianla)r,y btlhaydrdoeird,/psapriantahlyrcooirdd, (bcoenrveicmaal,rrtohowra(csitceramnudm)l,umtebsatre)s,(lfiivxeerd, aindrBeonuailns',shesaorltu,tion for 48 to 9ve6sihcoluerss(bweiftohrceobaegiunlagtrientgaignleadndi)n,ntehuetrraelmbauifnfienrgedpo1rt0i%onfoofrtmhaleinl)e,ftperpoistdaitdey,msiesmi(cnoarlpus `oannldy)caapnutd),grtohsesrliegshitonesp.idHiidsytmoilso,giocvaalrieexsa,muitnearutsi,onvoagfirneat,aminaemdmtaisrsyuesg,lainncdl(ufdeimnagle rats rheipgrhoddousctaigveegorroguapnss., wAasquacnotnidtuacttiveedefvoarltuhaetiaosnsiogfnperditmeonrrdaitaslpfeorllsieclxesfwraosm tchoendcuoncttreodlfaonrd fFoollgicelneesr,awthiionchfewmearleecraotmsb.iEnxeadmiwintahtisomnalilncglruodweidnegnfuomlelircaltesi,onfoorfcnoummpabreirsoofnoprfiomvoarrdiieasl of rwaetrseassshiigpnpeeddttootRreesaeteadrcahndPactohntorloolgygrSoeurpvsi.cesT,isIsnuc.e,sNtheawt wBerriteaienx,aPmeinnnesdylhviasntioal,ogfiocrally evaluation. Results of the histological evaluation are available in APPENDIX J. Tspoearsmseesvsaltuhaetpiootnesntwiearletpoxeircfiotrymoefdthfeorte1s0tmsaulbestraantcseionenatchhedmoaslaegreepgrrooduupc.tiSvpeesrymstem, c(oCnAcSeAn)tr.atMiootnilaintdymwoatislietvyalwuearteedevbaylutahteeHdaumsiilntgocnoTmphuotmere-aIsVsOisStebdyscpoellremctainoanlyosifas espaimdpildeymfirsomfotrheevlaelftuavtaisondebfyertehnes.HaAmihlotmoongTehnoatmeewIaVsOpSrteopadreetderfmrionmetshepelerfmt cauda ceopnicdeindtyrmaitsiowna(ssupseerdmtpoermagnruaamlolfyteivsasluueatweeisgphet)r.m mTohrephroelmoaignyi.ngSppoerrtmiomnoorfphthoelolegfyt cauda einvaalusaatmipolnes oinfcaltudleeadstth2e00f;olalnodwi2n)g:qua1l)itdaettievremeivnaaltuiaotnioofntohfeabpneorcremnatlagseopefrnmo,rimnaclludsipnegrm such categories as abnormal head, abnormal tail, and abnormal headandtail. 418-028PAGE 2-16 Acltinsiccahledcuhleemdisstarcryifsiacme,plteheco1l0lemcatlioenawnedr1e0efxseamnaglueirnaattsepderfrgormoutpheasinsfiegrnieodr tvoenhaemcaatvoalogy and fbolloloodwwinagsscaoclrliefcitceed..TRahtestwuebreesfcaostnetdaionvienrgnitghhetsbaemfpolreesswacerrieficlea"b.elAepdpwriotxhitmhaeteprloyto5cmolL of cnoulmlbeectri,onSpiontnesrovral,stduadtyeonfucmoblelre,ctriaotnn,usmpbeecire,s,segxe,ngerraotuiponnuamnbders,todraogseagceonldeivteilo,nds.ay of study, A`wpeptriocxeiomrarteeflryig1ermatLedoufnbtilloosdhiwpamsenctolfloerctaendaliynstiosEoDfTtAh-ecfooalltoewdintgubheesmaatnodlmoagiinctained on cpoarrpaumsetceurlsa:r heermyotghrloocbyitne c(oMuCnHt)(,RmBCe)a,nhceomraptuosccruiltar(HhCeTm)o,glhoebmionglcoonbciennt(rHaGtBio)n,(mMeCaHnC), `mceouannt,cpolraptueslectulcaorunvtol(uPmLAeT()M,CmVe)a,ntoptlaaltelleeutkvooclytuemeco(uMntPV()WBaCn)d,cedlilffmeorernpthioallolgeyu.kocTytweo. b`mleoaosdusrmeemeanrtssloifddeisfwfeerreentpiraelpalreeudkaotctytheecToeusntti.ng Facility for cach sample for A(0p.p1r2o9xiM)m.atTehley c1o.8ntmenLtosfwbelroeodmiwxaesdaadnddedmationatatiunbeedcoonntwaeitniincge0u.n2timl Lthoeftsuobdesiwuemreci:trate ctreanntsrfiefrurgeeddt(ow2i.th0imnL30pmoilynpurtoepsyolfentehetucoblelsecatnidonimtimmeed)i.atTehley rfersouzletni.ngPpllaassmmaaswaampsles were pr`omatihnrtoaimnbeidnotnidmrey(iPcTe)oarnidn aacftrieveazteerd(pa7rt0ialCt)hrunotmiblosphlaisptmiennttifmoer m(AePaTsTu)r.ement of `ATphperroexsiumltaitneglsye2ramsLamopflebslowoedrewaismmceodllieactteeldyifnrtoozseenrounmdsreypiacreatoarndtumbaeisnatnadinceedntfrriofzuegned. (trSi-g7l0yceCr)iduentsi(lTsRhIi)p,maelnbtumfoirna(n4a)l,ysgilsoboufltihne(fGo)l,laolwbiunmgipna/rgalmoebtuelrisn:Rattotiaol(pAr/oGt)ei,ng(lTuPc)o,se ((GCLRUE)A,T)ch,olcersetaetrionlin(eCkHiOnaLs)e,(tCoKta)l,baillainriubniena(mTiBnIoLtIr)a,nsufreeraasneit(rAoLgeTn),(BasUpNa)r,tactreeatinine `(aPmHiOnSot)r,anssofdeirausme((NAAS)T,),poatlaksalsiinuemp(hKo)spahnadtachsleo(riAdLeK)(C,Lc)a.lcium (CA), phosphorus `LaSbaomrpalteosrifoers,hAemaDitvoilsoigoynoafndCcRlLin-icDaDlSc,heRmeidsftireylda,naAlryksaenssawse.reSsahmipplpeesdwteorReedsfhieilpdpeond dry ice and slides were shipped at available in APPENDIX K. ambient conditions. Resultsofthese analyses are `FeexmaamlienartaitostnhaantddtiidssnuoetrdeetleinvteironalwietrteercwoenrdeucstacerdifaiscdedesocnriDbeGd 2a5b.ovGerofosrsantescraotpsscyh,eduled sfauctruirfeiceev.alGuraotsisonl.esRieopnsrewseernteaptrievseeprhvoetdoignranepuhtsraolfbgurfofsesrleedsi1o0n%s afroermavaaliilnabfloer pinostshieblreaw data. a See APPENDIXE, item 1. 418-028:PAGE 2-17 27.62. F1 Generation Pups lOensDioLns.22N,ecpruoppsswyeirneclsaucdreidfiacseidnbglyeccarrobsosn-sdeicotxiiodnoefatshpheyxhieaatdioatntahnedleevxelamoifntehefforrognrtaols.s Gparroisestallessuitounrsewaenrde epxraemsienravtedioinnofnetuhtrealcrbousfsf-esreecdti1o0n9e%d fborramianlfionr faoprppaorsesnitbhlyedfruotcuerpeheavlayl.uation. Representative photographs of gross lesions are available in the raw data. B1l0ofoedmaslaemprlaesspewregrreocuopllescetleedctferdofmorcaFcOhBsealnedctmedotpourpa(cftiivveitpyearssseexspsemernlitt,tberlofordomsatmhpele cvoelnlaecctaivoan.fo`rThheebmlaotoodlowgaysapnldacceldiniicnatlo cthubeemsi,stproyolaenddpheirstloiltoegr,icaallleovwaelduattoicolnost)afnrdosmptuhne in saacmepnlterisfuwgeer;etihmemreedsiulattienlgysferrouzmenwoasn dtrraynsicfeerarnedd imnationtlaabienleeddfproolzyepnr(op-y7l0enCe)tuubnetsi.l All wsehiigphmtenrtecfoorrdeanda"l.ys`iTsh.e mTehdeilainvelrofbreomweasacfhroszeelneactneddsptuoprewda(s<-e2x0ciCs)edunatnidl sthheipomregnatnfor p1o0ss%ibfloermaanlailynsfiosr. p`oTshseibrleemahiisntionlgogpiocratlioenvoalfueataicohn.liTvehrewlaisverrsetwaeirneedpirnonceeustsreadl abnudffered evaluated histologically as described for the Fo generation rats. vPiutpalsstthaattusdiaetdbibretfho.reThineitliaulngesxawmeirneatrieomnoovfedthaenlditiemrmfeorrspeudpinviwaabtileirt.y wPeurpesewviatlhualtuendgsfor lthiavtesbiornmk,weanrdetiodheanvtiefdiiededassshtoirltllbyoarfnt;eprbuiprsthw.ithPulpusngfstohuantdfdleoaadtwweerree iedxeanmtiifnieedd afsor gross lesions and for the causeofdeath. 27.7. Data Collection and Statistical Analyses A`DragtuagseAnuetroatmeadtdeudrDiantgathCeolcleoctiuoonrfatsnhdiesMasntuadgywemeernetreScyosrtdeemd, teheiVitbvayhrhieaumnrdToermupesriantgutrhee M`aontdoRrelAacttiivveitHyuSmyisdtietmy, MtoheniCtoourlibnoguSrynstIenms,trtuhmeenCtosulAubdoiutronryInSsttarrutlmeenStysstPeams,sitvheeInfrared sCoofutlwbaroeu.rnAlIlnsdtartuamewnetrseStpaabtuilaaltDede,lsauyemdmaArlitzerendatainodn/oSryssttaetmi,staicnadllloyratnhaelypzasesdiuvseinagvotihdeance A`arngduRseAlauttiovmeaHtuemdidDiattyaMCoonlilteocrtiionng aSnysdtMema,naMgicermoesnotftSEyxscteelm,[ptahretoVfivMairciruomsoTfetmpOeffriacteu9re7 (version SR-2)) and/or The SAS System (version 6.12). a Sec APPENDIXE, item 9. 418-028:PAGE 2-18 Afovlelroawgiensg asncdhepmeartciecntraegpersewseenrtesctahlecsutlaattiestdi.calLiatntaelryvsaelsouefstwheerdeatuas:ed where appropriate. The I. Parametric II. Nonparametric commas wo1 e woxsn ay s| vn Sa|ns hoop comune sv|en sap RET Ara area epson ----t nos opoe ne o a R, Snares I J Ial.rTPemnseratBfoieoermpciEoslsDrpoawtrbaiinoDDonaatna. a b. Statistically significant Proportion data are not probabilities are reported included in this category. aseitherp<0.05 or p<0.01. . Test for homogeneity of variance. 418-028:PAGE 2-19 uAdsueldtidnaetvaawlauastieovnoalfuaptuepdwdiattah,thaes aipnpdriovpirdiuaatle.rat as the unit measured. Litter values were cmVoaornisraubmtlpeatsiplwoeirnithvitatilenyurteeswr,vealrlaetoearnncraayltyiazonedsdceaarlsreosdresosfpcemrirebatesrdiuarluensmdceeonrretts,hiesnPuabcrehahamasveitbororidaclyhtweeeasitdgsihnatgns,doffpteeheredcent psrcohbeambaitliict.yBtahrattletthte'sdoTseasgteogfroHupos mhaovegdiefofenfreVenatriivaanrtciaeynscTMes. wAasnouns-esdigtnoifeisctainmtatreestuhlet (in>a0p.p0ro0p1r)iaitned,iacantdedthtehadtataanwaasssucmopmtpiaornoedf huosimnoggethneeiAtnayloyfsivsaroifaVncaerwiaasncnoet.Ifthat test was significant (pS0.05), the groupsgiventh test substance were compared with the cAuonnnadtleryrotslihsgerNooofunVppaaurrsiiaanmngceetDruTniencsethtweta'adssiTnneogosttfa"tp.phreoIspfcrhiBaaertmteal,teitatcn'.ds TtWhehestedanwtaa7sw5sa%isognrainffiacelawyneztre(dopfa<s0t.hd0ee0ss1cc)ro,irbetehsdein all the groups were tied, the Kruskal-Wallis Test" was used to analyze the data, and in gtiheveenvetnhteotfesat ssuigbnsitfainccaentwrietshultthe(pc<o0n.t0r5o)l,gDruounpn.'sWTheesntm"owraesthuasned7t5o%coofmtphaeresctohreegsrionups atineys dinostahegegrgoruopusp. were tied, Fisher's Exact Test"? was used to compare the proportion of Dthartoaufgrhooumttehaemcohttoesrtascetsisviiotny,wteesrte, awintahlymzeeadsuurseimnegantnsArneacloyrsdiesdoaftVianrteiravnacles (wBiltohcRkes)peated (MpeSa0s.u05r)esinTM,thaast tdeesstccroiubledd u havenatphd paetahree eaddir ansgefifnecttheofscChoenmcaetnitcr.atAionsi(gdniifffiecranetncreessualmtong dCoonscaegnetrgartoiuopns ainntdhBeltooctkal(sodiffaflerlemneceassuirnetmheenptasttienrnassoefdsossaigooernag)rsoaunp ivnatleureascatcironosbsetthweeen cmoenatsruolregmreonutp paenrdiotdhse).grIofutphsegCiovnecnentthreatteistonsuebffsetcatncweaswesriegncifoimcpanatr,etdheustiotnaglsDufnonretthte's Test". Ifthe Concentration x Block interaction was significant, an Analysis of Vreasurlit a(pn<c0e.0w5)aswuassedfotloloewveadlubayteatchoemdpaatraiastoenoacfhthmeeadsousraegmeegnrtopueprsiouds,inagndDuansniegtnti'fiscant Test, cVrairtiearbiloensinthaatbehhaadvigorraadletdesotrocroutnhetdscaoyreasd,esvueclhoapmelnitttaerlsliazen,dtmhaerknuampbpeearreodf,tiwaelrseto a `sacnhaelmyazteiduc.singtheproceduresdescribed undertheNonparametric headingofthe CFlOiBni,cawlerobesaenravlaytizoend ianscciodnetnicengdeantca,y atsabwleelslusasitnhgetdheesVcarriiapncteaiTnvedestqufoarntHaolmdoagteanferiotmytohfe the Binomial Distribution, `paSrpaemremmtortiiclmiettyhdoadtsa.were expressaesd percentages and analyzed, as indicated above, by 418-028:PAGE 3-1 3 RESULTS - Male Rats 31 aMonrdtaBl2i;tyI,ndCilviindicuaallaDnadtaNe-Tcarbolpessy BOb1s7earnvdatBi1o8n)s (Summar-Tiabeless BI 311 Mortality All male rats survivteod scheduled sacrifice. 312. Clinical Observations Ainlclicdleinnciecaslwoebrseernvoattidoonssagwee-rdeepceonndseindte;readnudn/roerl2a)tetdhetoobtsheertveasttisounbosctcaunrcreebdecinauosnel:y o1n)etheo.r tmiwsosminagl/ebrraotkseinnoarnmyidsaolsiaggneegdrionucpi.sorTsh,ecsheroombsoedravcartyioornrsheianc,lluadcerdimcahtrioomno,rlhoicnaolrirzeead, afelcoepse,cisacaobnotnheheheaadda,nudnddeerhsyidrdaetoironl.imbs, dry, brown perioral substance, soft or liquid 313. Necropsy Observations Ailnlcindeecnrcoespswyeorbesnerovtadtoisoangsew-edreepecnodnesnitd;eraendd/uonrre2l)attheedotbostehrevattesitonsuobcsctuarnrceedbiencoanulsyeotnhee or tkiwdonemyasl,esrlaitgshtipnealnvyicddoislaagtieongroofupt.helTehfetksiedonbesye,rvsamtailolnsepiindcilduydmeidddeiss,coslmoarleldt/emsottetsalendd diverticulum jejunum. 314. Histopathology (APPENDIX J) Nadomitnriesattemernetd-0r.e3laotred1 mmigc/rkogs/cdopaiycocfhtahnegteesstwseurbestoabnsceer.veTdreiantmaennyto-frtelhaetemdalmeicrraotsscopic c1h0amngg/eksgw/edraeyodbosseargveedgironutphse. lTivheer atrnedattmheynrto-irdelgaltaenddmoifcmraolsecroaptiscicnhtahngee3s ainndthe liver choenpsaitsotceydtoesf.miTnhiemaaflfetcotemdodheerpaattoeceyntleasrwgeermeenetnl(ahrygpeedrtwriotphhya)noifnccernetarsieldobaumloaurntofdense eosinophilic granular cytoplasm. `iTnhceidternecaetmoefntt-hreelmaatleed rmaitcsrionstchoepi3cacnhdan1g0emsgi/nktgh/edtahyydrooisdaggelagnrdoucopnsswiisttehdhoyfpearntirnocprheyased (foelnllicalregse).meAntl)thoofufgohlltihceulianrcciedlelsncaenidnhtyhpeer1p0lamsgi/ak(gi/ndcaryeadsoesdafgoellgircuoluapr wcealslsmainndimsamlallyl aisnscorceiaasteeddowvietrhtthheecloinvterro-lcegllrocuhpanvgaelsu.es, the hypertrophy and hyperplasia could have been 418-028:PAGE 3-2 32. TerBodmyWei ightn sana dOrl gan WeiagndhRattisos (o% fOr) gan TWaebilgehstBt3o TtehrrmoiungahlBSB;odIyndWieviidguhatlaDnadtaBr-aTianbl`eWseiBg1h9ta(nSdumBm2a0r)ies - Tnoetrmsiingnailfibcoandtylyw,eiinghtthseo1f0tmhge/mkagl/edaryatdsowseargee sglrioguhptl,yarsecdoucmepdar(eadppwriotxhimcaotnetrloyl6g%r)o,upalbeit values. T`ahned raabtsioolsuotfe twheeilgihvtesrowfetihgehtlsivteor,brtahienrawteiiogshotfwtehreelisviegrni`fwieciagnhttlsytiontcerremaisneadl(b<o0d.y0w5eiangdh/tosr S001) in the 3 and 10 mg/kg/day dosage groups,as compared with the control group value. in the The ratio of theheartweights 10mg/kg/day dosage group, as tobrain `weight compared with wassignificantly decreased(p<0.05) the control group value. `The absolute and relative (terminal body and brain) `weights of the male reproductive organs (left and right epididymes, left cauda. epididymes, left and right testes, seminal `vsepsliecelne,stwhiytmhuasnadnwdihtehaorutt(felxuciedpatnrdelpartoisvteathee)a,rtbrwaeini,ghlteftasandedsrcirgihbtekdiadbnoevyes)awnedraedrenals, `comparable across dosage groups and did not differ significantly. 33. Hematology and Clinical Chemistry (Summaries - TablesB6and BT; Individual Data - APPENDIX K) Hemoglobin the 1, 3 and concentrations 10 mg/kg/day d (HGB osage ) g were roups significantly and average decreased values for (ps0.05orp<0. red blood cells 01) in (RBC) and hematocrit (HCT) weresignificantlydecreased(p=0.05orp<0.01) inthe 3 and 10 mg/kg/day dosage groups, as compared with the control group values. Prothrombin time(PT) was significantly dosage groups. increased (p<0.05or p<0.01) in the 0.3, 3 and 10 mg/kg/day Dcvooonslcauegmneetsr(oatMfiCtoVhne)(,tMemCsetHaCsnu)b,csotpralpnauctseelceautslsah(riPghLheAmaTos)g1,l0ommbeigan/n(kpMlgCat/He)dled,atimdyveonalonutmcaeofrf(epMcutPsVcmu)el,aanrvohcleoumrmpoeug,slcowubhliiatnre cbellolocdocuonutn(tNsR(BWCB)C,),lyamcpthiovcaytteedsp,arstieaglmtehnrtoemdbonpelutarsotpihtniilsm,eb(anAdPsT,Tm)o,noncuyctleeast,eedorsiendobplhiolosd, basophils and abnormal lymphocytes in male rats. These the four dosage groups and did not differ significantly. values were comparable among. Ainvtehreag0.e3,va1l,u3esafnodr 1c0homlges/tkegr/odla(yCdHoOsLag)ewgerroeupsisgnainfdictahnetlayvedreacgreeavsaeldue(sp<f0o.r0t5roirglpyc<e0r.i0d1es) (TRIG) was significantly Albumin (A), blood urea decreased nitrogen ( (p<0.01) in the10mg/kg/day dosage group. BUN), alkaline phosphatase (ALK), calcium (C A) and albumin/globulin ratio (A/G) levels were significantly increased (p<0.01) in the 10 mg/kg/day dosage group. Clinical chemistry values for total protein (TP), glucose (GLU), total bilirubin(TBILD), creatinine (CREAT), creatinine kinase (CK), alanine aminotransferase. (ALT), aspartate 418-028:PAGE 33 a(mCiLn)otarnadnsgfleorbualsien ((AGS)Ti)n,mpahloesprahtosrwuesr(ePcHoOmSp)a,rsaboldeiuamm(oNnAgY)t,hpeoftoausrsdiousma(gKe),gcrholuoprsidaend did not differ significantly. 34. B(FoidgyurWeei1;ghStusmmaanrdiBeosd-yTWaebliegshBtSChaanndgeBYs; Individual Data - Table B21) B10odmyg/wkegi/gdhatygadionssagweergerosuipgsniofnicsanttuldyyrdeadyusce(dDS(ss)<02.905toor36p.<0A.s01a)rinethseouf0.t3lh,e3tseand r0e3d,uc1t,i3onasn,dsi1g0nimfgic/akngt/lydaryedduocseadge(pg<r0o.u0p5soornps<t0u.d0y1)dabyosdyDSwe2i9ghtto gtaeirnmionactciuonr.rieBndodthye. wfoerigthhetgeantiinrweadsosaalgseopseirginiofdi(cacnatllcyulraetdeudcaesd(DpS<01.t0o1)tferomrintahteio1n0)m.g/kg/day dosage group 35. A(bSsuomlmuatrei(eg/sd-aTya)balneds BRe1l0atainvde B(31/1k;gI/dnadyi)viFdeueadlCDoantsau-mTpatbiloenBV2a2l)ues uAnbasfofleuctteed(gb/ydadyo)saagnedsreolfattihveet(esgt/ksgu/bdsatya)ncfeeeadschoingshuamspt1i0omngv/aklgu/edsayf.or the male rats were 36. Mating and Fertility (Summary - Table B12; Individual Data - Table B23) Afelrltimliattyiinngdeaxn,drfaetrstiwliittyhpcaornafmiertmeerdsm(antuimnbgedrastoefsdaduyrsinign tchoehafbiirsttatainodn,sercatosntdhawtemeakteodf, cuonhaafbfietcatteidobnyadnodstahgeesnuomfbtehreotfesptrseugbnsatnatncreatasspheirgnhuamsb1e0rmogf/rkagt/sdianyc.ohabitation) were 37. F(uSnucmtmioanrayl -ObTsaebrlveaBti1o3n;aIlnBdaivtitdeurayl Data - Table B24) (Ho<m0e.0ca1ig)ne tbheeha3vmigor/okfg/sdlaeyepdionsgaagnedgirmoumpo,bicloem/paawraekdetwoetrhee csiognntirfoilcagnrtoluypd.ifTfhereesnet increases were not considered treatment-related because they were not dosage-dependent, tThheefroeurwedroesangoeotghreorupsstaitnistthicealmleyassiugrniefsoicfanttheorfbuinocltoigoincaallloybsiemrpvoarttiaonntaldibfaftetreernyc(eFsOaBm)o.ng, c`lTohseurreew,eprreomnionaelntcereaotfitonhseineyaeu,tpounpoimlilacryfurnecatcitoinosn(tioaclirgihmta,tpiiolno,esraeicvtiaotni,onr,esppailrpaetbirona,l daenfdecpaaitnifounlasntdimuurliina(trieoanc)t,ivsietnysaonrdimsoetnsoirtifvuintcyt)i]o,nesxc[irteasbpilointsyes(rteoacvtiisounasl,taouhdaintodrlyi,ngtaactnidle `fibeelhda,visoerveirnitthyeoofpgeaint faibenlod)r,maglaiittiaensd, asiernrsiogrhitmiontgorrecaoctoirodninaantdiolnan(dgaiintgpfaotottersnplianyt)haenodpen fliomrietleidmbtoa: ncdohnivunldsliiomnbsg,rtirpesmtorresn,gtuhnuasnudalabbnehoarvmiaolr,clhiynpicoatlonoibsaeorrvahtyipoenrstoinnical,udeimnagcibauttionno,t dehydration, unkempt appearance and deposits around the eyes, nose or mouth. 418-028:PAGE 3-4 `Bwoedreynwoetigsihgtnsifrieccaonrtdlyeddidfufreirenngttthheafnutnhceticoonnatlroolpegrraotuiopnfaolrbtahtetemraylfeorratths.e treated groups 38. IMnodtiovridAucatlivDiattya(-FiTgaubrleesB32a5n)d 4; Summary - Table B14; Tfihveerdeowseargee gnroosutpatsiistnictahlelynsuimgbneifricoafntmoorvbeimoelongtiscaolrltyiimmep(oirntsaenctodnidfsf)ersepnecnetsianmmoonvgemtheent `measures of motor activity on DSs 36 through 39. 39. Sperm Tables B(2S6umamnadrBy27- )Tables B15and B16; Individual Data - 391. Sperm Motility `SGpreorump mmoetainlivtyalwuaesswuenrafefceocmtpedarbaybldoesaagmeosnogftthheeftievsetdsousbasgteangceraosuphsiagnhdarsan1g0emdg/fkrgo/mday. 85.5%t0 93.2%motile sperm. 392. SpermCountand Sperm Density Ttrheeatsmpeentr-mrecloautnetdadinfdfesrpeenrcmesdwenesrietyobwseerrevecdo.mparable among the five dosage groups. No 393. Sperm Morphology dAolsoawgeingcrioduepsn.ceoNfohteraeadtamnedn/to-rrelaaitleadbndoirfmfearleintcieesswwearseoobbsseerrvveedd.forthemale rats in all 418-028 PAGE 4-1 4 RESULTS - Female Rats 41. (MoSrutmamlaitryi,esCl-inTiacballeasnCd1NaencrdoCp2s;y IOnbdsievrivdautailoDnasta - TablesC28and C29) 411 Mortality All female rats survived to scheduled sacrifice. 412. Clinical Observations iAnlcicdleinnciecasl woebrseernvoattidoonssagwee-rdeepceonndseindte;readndu/norre2l)atthteeodobtsheertveasttisounbsotcacnucrerebdecinaounsel:y o1n)ethe ifnemraatlsetrhaatt ianreanaylldoowseadgetogdreoluivpeer.xcTephtesfeorolboscearlviazteidoanlsoipneccliuadwehdibcrhowisnapceroimormaol nsufbisntdainncge, arabldeos,milnocaallidziesdteanltoipone,cieamaocniatthieolni,mcbos,ldbatocktoourchh,easdw,olulreinnen-osstea,insecdaabbodromuilcnearlatfiuor,n moinosbiasc,k or head, dehydration and tipoftal missing. 413. Necropsy Observations iAlnlcindeecnrcoespswyeorbesenrovtadtoisoangsew-edreepecnodnesnitd;eraendd/uonrre2l)attheedotbostehrevattesitonsuobcsctuarnrceedbiencoaunsley:on1e)the ifnecmlaulderedattihenecorateoxcoffththehe1,r3ighatnkdi1d0nemyg/akdgh/erdeady tdootshaegreigghrtoluaptse.rTalhelisveerolbosbeerivnataions 31 mmgg//kkgg//ddaayy ddoossaaggee ggrroouupp ffeemmaallee rraatt ((1199900571)),tshmaatlwlalsefntootvparreigensa(n0t.,0o0u3tge)ricnaopnseule of aspnldetehnealdahregreeadntdostmhaelol minetensttinuiemsndainsottehneterd3wmigth/kgga/s,dasymadlolssapgleegenroaunpdftehmyamlues,ratla(r1g9e063) sadurrefnaacleos,ftanhdeasptpormoaxcihmaitnealy1012mbgl/akcgk/daaryeadso(spaignepogirnottuop0f.e3maclme)raotn(t1h9e02f0u)n.dic mucosal 414. Histopathology (APPENDIX J) aNdomitnriesattemernetd-ureplattoe1d0mmigc/roksgc/odpaiycofcthhanegetesstwesurbestoabnsceer.ved in any of the female rats FThlegreenewrearteionnoputrpesaftrmeonmt-rtehleadtaemd smigcirvoesncuoppictoch1a0nmgge/skog/bdsaeyrovfietnhdettheestlairtiovcfleet.hrTehere. cwoenrseidaefreedw tmoichraovsecoopcciucrcrheadnsgpeosnotbanseeoruvseldyinantdhneovtatroiobues otrregaatnmsenatn-dretliastseude.s whichwere 418-028:PAGE 4-2 42. `TWeerimgihntatloBToedrymiWneailghBtosd,yOWreglagnhWtelagndhtBsraanindWRealtgihost ( andoP% frOimro) gradnial `FToalblilcelseCC3o0utnhtrso(uSguhmmCa32r)ies - Tables C3 through CS; Individual Data- `Terminal not differ body weights significantly. of the female rats were comparableamongdosage groups and did `riTeghphertoakdbuiscdotnlieuvtyeesoaarnngddanraesdlra(eltneiafvtlesa,wnesdipglrhietgehsnt,(ottvohaytremireumssianaannlddbuhoteedarryutsawnewdirtethoccboermravpiianxr)wa,ebiblgreahaitcn),rooflistvsehdre,osfleeafmgtaealned Kigdrnouepystaondthdeibdrnaoitn dwiffeer soifgintihfeigcfaenmth alyle(et rxactsepitnotnheon3emgoc/ckags/idona)y.doTshageeragtrioooufptwhaesleft nssiioggtnndiiffoiisccaaagnnett-lfdyieinpdneicnnrdgeeawnstae;sd a(nnpod<t/0co.or0n52s))iodtveheerreotdbhsteerercavotarmtreienotsn-prwoenaldsaitanegdsicbnoegncltaeruooslcecg:urro1ru)epntchveea.liunec.idTehnicse was A0vethreagcoenptrriomlogrrdoiualp faonldlidcliedcnooutndtisfffeorrstihgeni1f0icmagnt/lkyg./day dosage group were comparable 43. Hematologyand Individual Data -CAliPnPicEaNl DChIeXmiKs)try (Summaries - Tables C6and C7; vDaolsuaegseesvaalsuhatiegdh.asAv1e0rmagg/ekgva/lduaeysdfiodrnroetd abflfoeocdt acenlylshe(mRaBtCo)l,owghyioter cbllionoicdalceclhlesm(iWsBtrCy), (hmeMemCaoHngClc)oo,rbpipunlsacctuoelnlacertesnht(erPmaLotAigToln)o,b(iHmnGeB(a)Mn,CpHhle)amt,ealtmeotecavrniotlcu(omrCepTu()sMc,uPlmVa)er,ahnpermcoootrghplruosobcmiubnliancrotnvicomelenut(mrPaeTt)i(,oMnCV), alcytmipvhaotceydtpeasr,tisalegtmhernomtbeodplnaeusttrionphtiilmse,(bAaPndTsT,),monnuocclyetaetse,d reeosdibnlopohoidlsc,elblacsooupnhitl(s,NRaBbCn)or,mal dflioyfrmfopefrhostcihgyentfiefesimcaianlnetfleryamt(aselxiecnertaphttseo0wn.e3roemngec/ookmcgpc/aadsriaaoybnl)de.osaTamhgoeengcgronotcuheepnftwiravasetidsooingsnaoigffeiWcgaBrnCotlusypsi(nlacynrmdepadhsioedcdyntoets) c2()opnSts0hi.ed0oe5br)seoedvrtevrraetatihtoemnecnwotar-srreealsapstoienndgdlibenegcoaccucosunert:rreo1nl)cget.rhoeupinvcaildueen.ceThwiasssniogtaidfoiscaangte~fdienpdienngdewnats; naontd/or Atkoivtneaalrsabeig(leiCrKvua)bl,iunea(slTafnBoiIrnLetIo)at,malibnlporotoortdaeniusnrfe(eaTrPna)is,terao(lgAbeLunTm)(i,BnUa(NsAp))a,,rtgcarlteueactoaimsnieinn(oetGr(LaUCn)Rsf,EeAcrThaos)le,e.sct(reeAraSotTli)n(,iCnHeOL), salokdailuinme(pNhAo)s,phpaottaassesi(uAmLK(K)),,ccahllcoiruidme((CCAL)),,pghloosbpuhlionru(sG)(PaHnOdSa)l,butmriingl/ygcleorbiudleisn(rTaRtIiGo), s(iAg/nGif)iicnanftelmya(leexcreaptstownertewocomocpcaarsaibonlse).amTohnegctohnecfeinvteradtoisoangoefgGrowuapssasnidgndiifdicnaonttlydiffer dofectrheeafseemda(lpe<0r.a0t1s)iannthde t0h.e3cmogn/ckegnt/rdaatyiodnoosfagAe/Ggrowuapssoivgenriftihceacnotlryrienscproenadsiendg(cpo<nt0r.o0l1)for `group values. These significant findings were not considered treatment-related because: 418-028:PAGE 4-3 o1cctuhrereinncciedfeonrcebsotwherpearnaomtetdeorssa.ge-dependent; and/or 2 the observations were a single: 44. BToabdlyesWeCi8ghtthsroaungdhBCo1d3;yWInediigvhitdCuahlaDngeas-(FtTiagbualrees 2C;3S3utmhmraoruigehsC-35) 441. Precohabitation dBuordiyngwtehieghptrsecaonhdabbiotadtyiowneipgehrtiogdaaitndsowseargeecsoomfptahreabtleset saunbdstdiadncneotupditfofe1r0simggn/ikfgi/cadnatyl.y 442. Gestation Bduordiyngwtehieghgtesstaantidobnopdeyriwoediagthdtogsaaignesswoefrtehceotmesptarsuabbslteanacnedudpidtono1t0dmigf/fkegs/idganyi.ficantly 443. Lactation B10odmyg/wkegi/gdhatygdauirnisnwgelraectnaotitons.ignificantly affected by dosages of the test substance up to 6Btohdyroweuigg8hh,ts11wearned1s3iginniftihcean0t.l3ymrge/dkugc/edda(ypd<o0s.0a5georgrpoSu0.p0,1D)Losn 7daaynsdof8lianctthaetion (DLs) 4, 3grmogu/p.kgT/dhaeysdeossiagngiefigcraonutpf,iDndLisng4s,w6etrhernooutgcho9n,si1d1e,re1d3 atrnedat1m4enitn-trheela1t0edmgb/ekcga/udseaythdeoysage `were not dosage-dependent or they did not persist. 45. A(bSsoulumtem(a-rgTia/bealndesdsRaCe1lay4tti)hvreo(ugg/hkgC/1d9a;y)InFdeievdidCuoanlsDuamtpati-on Values Tables C36 through C38) 451. Precohabitation Aafbfseocltuetdeb(ygd/doasya)geasndofretlhaetitveest(sgu/bkgs/tdaanyc)e fuepedtoco1n0smugm/pktgi/odnayvadluureisnwgetrhee nportecsoihganbiifticaatnitolny period. 452. Gestation Aafbfseocltuetdeb(ygd/doasya)geasnodfrtehlaetitveest(gs/ukbgs/tdaanyc)e fuepedtoco1n0smugm/pktgi/odnavyadluureisnwgetrheengoetstsaitginoinfipcearnitoldy. 453. Lactation sAubbssotlauntceeaunpdtroel1a0timvge/fkege/ddcaoyndsuurmipntgiolanctvaatliuoen.s were not affected by dosagesofthe test 418-028:PAGE 44 DL3Abmssgo/l1ku1gt0/ed5faaeyendddocs8oanogs1eug5mrpiotnuitpohanenv0da.l3DueLmssgw/8ekrgte/ods1ai5ygnidinoftishcaaegnet1gl0yrmorgue/pdk,ugcD/edLdaS(y51d01o.0s0a55gaoenrgdrp<o80u.tpo0.11)3Roeilnnattihve 0f.e3edmgc/okngs/umdpatyiaonndvDalLuSes5wteor8esiingntihfei3camngtl/ykgr/eddauyceddos(a7g<e0.g0r1o)upo.n DThLesse1 stiogniifnitchanet e afinnddtinhgesywdeidrenontotpecrosnissti.deredtreatment related because they were not dosage-dependent 46. EInsdtirvoiudsuaClycDlaintga,-MTaatbilnegaC3n9d) Fertility (Summ-aTarblye C20; cdToohnsesaegacevuetgriravogeuepdnsauyamsnbdoefrdsididoensfotertsustsirogonruisefsistctraaungstelsdyipddeirfnfo1etr3.ddifaTfyheser wsniegruneifmcicoabmonpftealryra.artbslweiatmhosnixgotrhmeofrieve cfAeolrhltaimbliaitttyaiftnnigdoenaxna,dnrdfaettrshtiweliinttuyhmpcbaoernarfmioerftmeperrdsegm(nanatunimtnbgreardtsasotpefesdrdanuyursimnbigen rtchooehfafbirriastttsataiinnodcn,osheracabotinttdahtawiteonme)aktweoedfr,e unaffected by dosagesofthe test substance as high as 10 mg/kg/day. 47. Functional Observational Battery (Summary - Table C21; Individual Data - Table C40) f`iTwvheeerredeonswoaeagrleetengrroatosiutopantssisiitnnicthaholelmymeesaicgsanugirefeibcseoahnftatvohiroerb,ifoualnuoctgtioiconanolamlliycoibmfsupenorcrvttaitaoinnotsnda(illbfaafcetrrtieemnracytei(soFna,OmBso)anl.igvaTtthhieeorn,e arpeuasdlpipiterobarrtyai,lontc,alcdotseiulfereeca,antpdiroponamiainnnfduelnucrsietnioamtfuiltoihne)(,reeysaeec,tnispvouirptiiylmalonatrdoyrsrefenusanicctttiiivoiontnyst)o}[,lrieegxshctpi,otnpasibelisoleitrtoyecv(tiriseouanac,lt,ions to sihnpalntadhyle)iaonnpgdeannffdoirebeledlh,iamsvbeiavoenrrdiithnyitnohfdelgoiapimtebnagbfrniioeprlsmdt)ar,leigntaiigtetsha,anandirdsraeinbgsnhootririnmmgaolrtceolaricntciiooconaraldniondbalstaeirnovdnait(ngigaoifntospoatttem n`ihonyscpleeurodtrionnmigoabu,utethm.naoctialtiimoint,eddetho:ydrcaotnivounl,siuonnsk,emtpretmoarpsp,eaurnaunscuealanbedhdaevpioosri,thsyaprootuonndiathoereyes, `Bwoedreynwoetisgihgtnsifrieccaonrtdlyeddidfufreirenngttthheafnutnhceticoonnatlroolpegrraotuiopnfaolrbtahtetefreyfmaolrethraetst.reated groups 48. IMnodtiovridAucatlivDiattya(-FTiagbulreeCs4a1n)d 6; Summary - Table C22; fTihveerdeowseargee ngorosutpastisitnitcahlelymesiagsnuirfeiscoanft onrumbiboelrogoifcamlloy vimepomrtaeonrtntdtiimfsefer(einncseescaomndosn)gstpheeat in `movement motor activity on DL 17. pe --------------,. i 418-028:PAGE 4-5 49. CNa2t4u;rIanldDievliidvuearlyDaantda -LiTtatbelreOsbsCe4r2vatthiroonusgh(SCu45m)mary - Tables C23 and P31r0megmg/gnk/agkn/gcd/yadoyacydcodusorarsgeaedgeignrgoraulolpusp1.5s A(aln1ld00p1r%3e)gr(na8ta8sn.t7ad%s)asoimgfsntedhdeetloirtvaethsreeadsas(liVigetnheeirdctlooeft),hone0e.13oraannmddore l p(cuaplsc.ulVaatledueisn fdoaryst)h,eanvuemrbaegerssoffordiammplsantthaattidoenlisvietersedpeirtdeesl,ivtehreeddulriattteir,ontohfegneusmtbaetiriosvneobfom sddiyagimnnisgfiwdciaatnyhtslsy1i1d0l.i4lffbeor.amnpdTuh5pes0,ntu2hm2e,bnewuremrobefecriosvmeopbfaodrraanmbplsuewpisa,tmhothnnegontluhimevbefebiorvreondfpopusupaspg,sedfgaormuonsudpwsdietaahnddadolripdunpso cpormepsaurmaebdlceaannmiobnaglitzheedfoinveddaoys1a,gaendgrdoauypss an2d10d.8i,d9ntoot 1si5gnainfdic1a6nt0ly2d2iffpeors.tpartum were oTpnrheeDgngLaens1tt)artaaintosdn),liavncidtaeabxtiil(ointnyuiimnnbddeeexrxo(f(nduuammbmbeesrrwoioftflhliivovenepepuouprpssmooonrneDDLlLiv28e2bpoperernrnpnuuumpmbsbeeprerroofnfullmiivbveeebbroomfpups n DL 8) were comparedtothe control group valueanddid not differ significantloyr.n pups pnTeohrtelsniigunmtibfoietncraDenoLtfrlsypud1ip,f8sf,esru.1r5vainvidn2g2pweerrlietcero,mppuaprasbexleraatmioosn,gltihteefsiivzee adnosdapguepgrbooudpyswaenidgdhtisd 410. (PuSpumCmlianriyca-lTaanbdleNsecCr2o5psayndObCs2e6r;vaItnidiovnisdual Data - TablesC46and C47) ndNoootsadcgloiesnsaiogcfeal-todhreepneetnecsdrteosnptus;bysaontbdasn2e)acrsetvhahetiogibhosineanrssvta1ht0eimoFgnI/okgcgeu/nredrraaeytdiboeinncaopunuslpeys:woen1r)eetthaoetttirwniocbiuldtietatnbeclrsee,stwToere dcilisncioclaolroebdspeurrvpaltei,onsscainbccloudleddt:ontootucnhu,rslienfg,eyeemadciisactoiloonr,eddephuyrdprlaet,ioing,htwheoyleeenbloadryged,hese fLoiapvcaeecriratetysipooenfctoriinvgehrtidgeohytsea.hgienNdeglcriromoubpp,ssbyorunoibspseoesrotvnaptabiraoctnkus,mondfoaty2s2n8eS,sta2in0nd3g,,2p21aw9l6ee,irn1e7a2lpiapmneitdaer2da1nt1coepmouadpnesdriganotretahceal dilation of the renal pelvis of one pup from a 0.3 mg/kg/day dosage group liter, 411. P(SuupmLmiavreryW-eTiagbhlteaCn2d7;RaItnidoivoifduLailveDraWteai-gThatbtloeTCe4r8m)inal Body Weight daFonlsdgareganeteigroarotofiuoplnsivmeaarnldweediaigdnhdtntofotetmdeairflfmeeirpnusaiplgtnbieforidmciyannwatellybi.gohdty(bwyesieghxt)s,wearbseocloutmepalriavebrlweeaicgrhots(sbayllsefixv)e -- -------------- 418-028:PAGE 4-6 REFERENCES 1. (S1a9n8d8e)r:s,ThJyEr.oiEdigaenndbelrivge,rDt.rAo.p,hiBcrcahcahtn,geLsJi,nWraatnsgs,ecWo.nRd.a,ryantdo lZiwvieertmeinc,rMoJso.mal `eTnozxyimcoeloignyduacntdioPnhcaarumsaecdolboygayn, 9e5x:pe3r7i8m-e3n8t7a.l leukotriene antagonist (L-649,923). 2. GOrugiadneilsianteifoonrfToersEticnognoofmiChceCmoi-coaplesr.atSieocntiaonnd4D,eNvoe.l4o2p2m:enCto(m1b9i9n6)e.d ROeEpCeaDted TDeosste, aTdooxipctietdy2S2tuMdayrcwhith19t9h6e.Reproduction/Developmental Toxicity Screening 3. `OrOgEaCniDsaPtrioin nfocrioEcfpoGlnooeomsidcLCaob-oorpaetroartyioPrnaacntdicDeesv[eCl(9o7p)m1e86n/tFi(1n9a9l8l). The Revised 4. U.S. Food and Final Rule. 21 Drug CFR APdamrtin5i8s.tration. Good Laboratory Practice Regulations; 5. Japanese Ministry of Health and Welfare (1997).GoodLaboratory Practice St1a99n7d.ard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 6. CThersitss.tiaEnn,vMi.rSon.maenntdaVloyPrtoetke,ctPi.oEn. A(g19e8n2c)y.,IWnasVhiivnogRteopnr,odDu.cCt.ivNaetainodnaMluTteacghenniiccailty Information Service, U.S. Department of Commerce, Springfield, VA 22161. 7. nCharlitsrteixaonn,e,M.(SP.ro(c1e9e84d)i.ngsReopfrNoadlutcrteixvoenteoxSiycmitpyosanidumt,erNateowloYgyorevkaAlucaatdioenmsyofof Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10. 8. LCoanntgroPl.DL.at(a19i8n8)t.heEChamrlbesaRrnidvyFeertCoarllD:eCvDeloBpRmeRnatt.alCThoaxrilceistyRi(vTeerraLtaobloorgayt)ories, Inc, Wilmington, MA Laboratories, Inc.) 01887-0630. (Data base provided by Argus Research 9. Institute of Laboratory Animal Resources (1996). Guidefor the Care and Use of LaboratoryAnimals. National Academy Press, Washington, D.C. 10. cHaapgagbeirltityi,esG.fCor.i(n1c9o8r9p)o.raDtieonvnetolpoivpootmaflTerinoedrteIntnesuafreotbyehaasvsieosrsamlentetssttiundgies. J. Amer. Col. Toxicol. 8:53-70. 11. qIurawnitni,tSa.ti(v1e9p68r)o.ceCduormeprfeorheanssseisvseinogbstehrevbaethiaovniaolraaslsaesnsdmpehnyts:ioal.ogAicssytastteemoifcthe `mouse. Psychopharmacologia (Berlin) 13:222-257. 12. oMbosseerrv,atVi.oCn.al(1ba9t8t9e)r.y.ScJ.reAemneirn.g Caoplp.roTaocxhiecoslt.o8n:e8u5r-o9t4o.xicity: A functional 418-028PAGE 47 13. bOaDsoendoegxhaumei,naJtLi.on(a1n9d89n)e.urSocpraetehnoilnoggyfo.r Jn.euArmoetro.xicCoilt.y Tusoixnigcoaln.e8u:r9o7l-o1g1i6c.ally 14. vSaorkiaaln,cResR..BiaonmedtRroyh,lWf,.HF..J.F(r1e9e6m9a).n aBnardtlCeot.t,'StaenstoFrfahncoimsocgoe,npepi.t3y70o-f371. 15. MSentedheocdosr,,6Gt:hWE.ditainodn,CoIcohwraanS,taWt.eGU.ni(v1e9r6s7i)t.y PArneaslsy,sAimsoesf,Vaprp.ia2n5c8e-.27S5t.atistical 16. Dtruenantemtetn,tsC.wWi.th(a19c5o5n)t.rolA. mJu.lAtmipelre.cSotmatp.arAisssoocn.p5r0o:c1e0d9u6r-ef1o12r1c.omparing several 17. S'oWk.aHl.,FRrRee.maanndaRnodhClfo,.,F.SJa.n(1F9r6a9n)c.iscKor,uspkpa.l3-8W8a-l3l8i9s.Test. Biometry, 18. Dunn, OJ. (1964). 6(3):241-252. Multiple comparisons usingrank sums. Technometrics 19. Siegel, Exact. SM.cG(1r9a5w6-)H.iNlolnCpoa.r,aNmeetwriYcorSkta,tipspt.ic9s6f-o1r05t.he Behavioral Sciences. Fisher's 20. SUsAeSr'IsnsGtuiitdutee,,RIencl.ea(s1e9868.)0.3 REedipteiaotne,dCamreya,suNrCe,spapn.al6y0s2i-s6o0f9.variance. SAS/STATTM 21. bSinneodmeicaolr,diGs.tWri.buatniodn.CSotcahfriasnt,icWa.lGM.et(h1o9d6s7,).6tVhaErdiiatnicoen,telsotwfaorShtaotmeoUgneinveeirtsyitoyf the Press, Ames, pp. 240-241. APPENDIX A REPORT FIGURES 418-028:PAGE A-1 ;CPo oLS rilridaE delded. ]aol : | / hg | BfeEtd | .. ifrgs8tg | It | 92 Q2 2 l P| ` b r 3 & ory a : 3 38 418-028:PAGE A-2 EARN bss i| g Ho2 wIz 8P| :| ioe Eg 085,| i 5" iieoge | i | !| i s % od5 Rg I 3 : 5 et -- ny, 2 i "B 8 H = - Ra i. Ei LI Bo ss FE I (9)1HoIaM 418-028:PAAG-E3 pe: 0wn 2 |I y 3 3 dd)82 81% ] iz | CL g g ,----_---------- 8 2 i ol fe \ 5Po2 | I" ig Cs 2 zg 55 | |: BEE | = 8 i | i it j re g bo e LAL. WO J . 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[resem [I Pdia p IIe I e | Ba c K i i gir ress P#nmannaanss] i it i a Poon i i { LN : i-- k 418-028:PAGEC-108 ir a gr nner eel ene een Bat Be ee ee | dH gi inode ee ly TTT EH fd be TTI TT gi id i il (BE leans omnes mann (Besser Bassas] 5 gE in 3 ; fyi Few PLE wm i EE Lonetesessons foomsalbnseen i i !a|p ;| loagmgazeansnesssrier!| {3mssmassrsasssaras1i 418-028:PAGE C-109 Loa | oy jrm-- f[FSrFEE ;i soft Proreareserazged dBih e ye n! 8 led fsaazaaazansians] lh bn TT :IfHhaeie{GEEilsafsanfeaanuzanagiin d ET i : : Al rns 418-028:PAGE C-110 B1 EEEE ME P]i : xX PiEERE 5|! i: bPeh mmmIam i Pa ee : || JIC jE Reem CL rnanens HH sREREEE dL Bl bans mms mann amma df mmm mmmmnng BIC mmm Ey HELe ! ii o msm fn i p dH HERI | nnn 418-028:PAGE C-111 P[EHL o ILl :i soa mamma nm ramp BEL Ln seen] lesen saeseiHs BoEHEp RLe ,eI n I p e suwmpaea seamyi sexsi ff Bann un an Bain fn ammo nn nam Bs 5 i +E HELEN GEE gag spb ose anaae sas j230ens gs ie : po she fff f Fai. iFe ! ] | Ba a 418-028:PAGE C-112 inAE NE I5 id EEE ki e if bo mmommn PE dm 5 i dE Be E Plo df iy on EEE Bp. moment B10 mmammmnd mmamnuaBn i jIRRszEAgRIRIARY E Lm E fm m mn Ppgjom ng f i wy | nm Uo me i 2 I E 5 pn 5 serzsan suai sf BE femme Er ssn) Eg ie llmaszmaaonsassned ois sammasanniiil 6 fy fmm an Hi mann EE 10 mmm mp EE mes Eerie 0H dd ghy 0 | Jr 418-028:PAGE C-114 EL ii ; Plo mmm iiaim PIL Laie i Bo Chnni wees gi "eens Pog ial Boner ammne sumed Bonne iy ERASE g ssn EEE Ime f i Li fur 3333 sz) i sgeic sash E EP PfEoeGhjmumma2 aginmal a l inreeese ssvmesamsenidl i il BEE fon mam sn Baum muni fr Bi 8 oi IE Blovie savas nese! Rlaswens amwnenid oooIbo gh fLf TE sk iv HEE ns 23s TEE gh iesuaiz FE HEE Jasna gen Lapa sfit Fili il fog ie Eim fennnERnnananly 418-028:PAGE C-115 Eola in os | {ole : E ErLinfa. ad i* ul . we " we ig ial Bi saEEnebiEIaane DoE g Bia [lRmEmCmERmEeRsEgIuYeseeessi i: fo msg] gl BiFEi ii. o Slm eccam naam ganaananin i2 Bg tll lsomsosnennnennif LEER ams : il!i= hEi: rn mmrensensenml i pr EEE 418-028:PAGEC-116 Foal os: ia [BVo lR a ls m simis omomsow i Cn mm PR Bp mma mmm Gono ply mmm an [op na jEiC m DEm ER E STl E fh dm | je mmm am IHooonp m Em Rm R g Es Em E gl Po. 151g ; hem sr is 1 2g fia si: tn foam een DEL inmommam apn BL mania mem BEE mmo am Damn TEE Eman Caen ait ll oman onmng B ny ] gio Emma moa jio mam ames hil GEEEE IER EE EE Ton: teen Duane Banani] 8g itl ieEE EEE GEE fia EERE Fa dE j lf f pin EERE pein Bo PFE ammachnan al Fol ia Pleas say : H iE Hi EE Pe mmm |] BE gE |i i HE , reg BL ml Bi mmm $wy i Dg smm s g ll FjiE,LLB,ELoEaniRoif EioE mEy EEL maaan aan aa BE EERE ma wai fl 0 fc Bhp | reemeeesten a ji ToSamah HBEEL c mam i diay | | Poo mess | Eni m H[Flooildimlsmshinloaam PE mmm am mEn Ble smmman mem BEE Emm am pamn as, JaE) mami aun] mung HED onl Sia phd a dfbo E ERhR aDElE GlE e Popham HERE 418-028:PAGE C-121 017 2 Pye iw | PEE inl I ome Ey a mal | Pia dR EEEG g fy Haag Pop Po i i [3] Epc Hi BET i el BBE hiEE lil PHo N| Emal qe Ee 32 8 [ai rem i EEN iRARdedRRadRANAd of Panning go am pf EEmREELH ss inant ZHinninacnannananas CofE fiance SER Lo = ih in gi hBoea ii | f Si n : bfD ft E e E a walh fifi Em En m rm y| | ; ym pam i! Li nasell Porno gomm Gen Pie puma nn | ome ss | BE onEE aman ammo ama Bi Lamon fume nl; HBEi 0 Hoo j mmn fffa eaesili ENE smn ann 1 418-028:PAGE C-124 TRhIePEth E5Ei il i SEE E1ERh) tSaenlsy,] i bi ph iffc m Em n m fe. smnnn ii sm a ahi i | [mHE iInReSllA f: EIiLn m EEEi il ia pin | he he sd Had bd EA | Pl : BP x face PR i fmm Jrmp =i om 2 BL , er BoE foo m deen i Bo Sen d He | sem n EEE i ii Pri Jia frm [i Sm E | sssE EERE B pin Ed iE LH IEEE bProibool lfooo mmr men) taarnm aasmadgl gf ECan oe lay $80 Ht Borers sn jms ras pone pai gf) Ey 1 m Eshm imlm in |pserses sprover pid i Pld ioc sm Ble sini of BE fms fF gl RENE i i BEE iBgigco psmnmmmmmnnniay | Emm Pog gFES, 418-028:PAGE C-128 frPoe he o Elool i , PS ocEaL niEnN anHEiE FEOLEEHEEIBEg Ll $383 ne ii Bef Dl.f 2g Eo ii AlI iE,E..E. Hfyi: eg CUlas i sed i PE fEraEcRE53d Hiiz LiEglgi OE li HOE in fEEob HITEE. PPeEodiEppd glpi h Spell: hia flo iEbI PAE RHE REE Bg Bi i Bead Tanna2.d fr 1] Hse sanr el i is aR iI FiHlHl :tL 418-028:PAGE C-129 CE HED PiE g m i 85m ag 45 9y 8g ii HFBPolEREd ESETHEIL iiix B5el8 nen ene kn nA EE 88 {361 8 NR8 v8 3'an 8 8 88 a Rigs i i fil i fy 4 fig Hi, 8I8E Cedi 3iB Fill i Lo hhh he bo doa ah | Pog HE cally Po HEEEEEREILm Og iid RENE eR <onomoaog Be il : 3 3352 8 3 5 fdo ig F1ilhl al E 33% 3 ir iI iHl [oe PPP gooo dd iL ad Bl oy Pog hai Hanan | HHBeafEerek Heel i!deg! Lrg iBi : Fpeigll #5 Po Pog Lg Hin) CLoI Lo 2 ig: Hl IC o Pimil 2Fj rumamam an a i i i ERUEIEEEERCE pn 5 BBe, Eid ih0o 00 ir nang sae ia o11f hy HEE sid it BbEoErRETggE P ElginriEn THgELn Poop aE DrojMimtimmaegi TN pr #83 0 oR anmRy on - eng iu HE i bill Hh Foor coo morron g L Po o E Eocn if hg pos Ril : in ggatite Ep ojlmiHt Em] EE Thgf gE TE i a asa :an Faoilf Ii Fill v -| | : BN o ll al 1 | S NN I. . | rr APPENDIX D PROTOCOL AND AMENDMENTS 418-028:PADG-E1 isSeyors A Telephone:(215)4438710 Telefiuc (215)443-8587 ~~ ARGUSRESEARCH ChRa iver r Lal borae tors ies Discovery andDevelopmentServices PROTOCOL418.028 SPONSTSUDOYNRUM'BESR: T-7706.1 STUDYTITLE: PURPOSE: IESTING EACILITY: t`hOreaRlDe(pGraoevdaugcetv)iCoonmebinledRaepeapteTdemDroiseeToSxcnirceietnayiSntguyldoyoofT-7706with `Thepurposeofthisstudyi to provideinformationon thepossiblehealth hVaAzFar/dPsltuhsatmmaayeraensudlftefmoamlerreaptesatoeadteexsptossuubrsetoanfcCerbleg:iCnDni(nSgDbe)fIoGrSeBR. s`efeacporsohee)catbnoeiirtodnantdrgimtoooanuss,lgtehhhprandotadyucrgaithnnmbicaeloetvpienonurrdgnsaetln0cpdacrpoyrnooptv2ruii1noadcuefciiinatgvtfiloaoernipaeftero(lfnetla(aoosostp5m4mmo.2senandapsotaoynn)ssp.cto(ansemosiaitlsye function,matingbehavior,conception, developmentof to conch nd Ssppuaebrctsiutrcaintcioenn,)w.hTidhcehsaptaduydswiyhaalorsuraolapdnltaetfcmueristfheyemriphhenadnseiepsarooninoeiuerpoloogriacallveganefofesctosats a Buecya,usteeosf trheeetcetiwivllithotycproooviifdnesvsixdehefsoodriurvatieonpoif tehse of nmaoetrameparoyofdbudeceittnieodcnui/ncdgeepdvoedlsuortpimaneglnptoamlseaftfiaeclstseo.xInpnpoaorsfteicrulear,liteofxferpsonalynlimsiteed ArgusResearch 905ShDre ivee , Buih ldiny gA Horsham,Pennsylvania 19044-1297 Telephone: (215)443-8710 Telefax: (215)443-8587 DSITRUDEYCTOR SIONSOR: RayG. Yomrk,oPD.nDAdBT AAsEsdnorsclei:astexDciiretrcetmsorhoooovfedReysoeroaTkrec@hac.iinvgeFoccoim 3MCorporate Toxicology 3MCenter, Building220-2E-02 St. Paul,Minnesota 55144-1000 418-028:PADG-E2 . Procolaiasazs STUDY MONITOR: J33ohMMMnCeB odripucoaralttDeeepToaPn xrhit.cmDho.el,noo DgtyAf BT,fC, IH TTeellepeh:one: ((665511))7733334-1797632 Email. jluenhof@mmmcom REGULATORYCITATIONS: oOrfgCahneimsiactailosn.foSrEeconco4mt,iNcioC.oo4-2o2np:erCaotimobninaneddDReevpeelaotpemdeDnots(e1T9o9x6)i.ciOtEySCtuDdGy wuitihtdheef.olr Tiesntieng ReproductionDevelopmental ToxicityScreening Test,adopted 22March 1996. `PrOirngcainpilseastioofnfGooroEdcLoanboomraitcoCro-yPorpearcattiicoensa[Cn(d97D)e1v8e6l/Foipnmaeln]t (1998). TheRevisedOECD U20SC,FFoRoPdaartnd58D.rugAdrmisistratin. GoodLaborstoryPracticeRegulatiinoalnRusle;. `SItsupdainecsseoMniDnriusgtsr,yoMfHHeWaOlrthdainnadnWceelfNaurmeb(e1r92971),.MGaorochd2L6a,bo1r9a9t7o.ryPractice StandardforSafety REGULATORYCOMPLIANCE: "ThisstudywillbeconductedincompliancewiththeGoodLaboratoryPractice (GLP) `regulationscitedsbove. AblelScphoannsgoers,odrarteevdisainodnmsoaifntthaiisnperdowtoictohltshheaplrlbooecdoolc.umented,signedbytheStudyDirector and t"hFTaheceirTleietpsytoirinn,gaaFncaccwoiirldlialtnyicneswQpuieatclthicttihyeiASastslaunprdhaaansrcedeOsUopnefirtatht(oisQneAgpUoPr)rtwoicioelndlsusruoefistthotefhtsetepurdoTytecsootcinonldg,uFtcahteceirdlasywtd.haetaTeenstding "aTchceufraitneallyrerpeofrltecwtisltlhienrcaluwddeataacoobmtpaliinaendcdeurtiantgethse pesrifgonremdbanyctehoefStthudsytDidryeactnodtthhaatatlhlereport applicableGLPregulationswerefollowedintheconductof thestudy. Shouldsignificant ddeevviiaattiioonnsmfirgohtmaGffLePcrtetghuelqautailointsyoocrciunrt,egeraicthy woifltlhbeestduedsycr.ibedindetail,together withhowthe `Shouldanyportionofthestudy be conductedby asubcontractororbytheSponsor,theStudy Directorwillensurethat aqualifiedPrincipalInvestigatorisidentifiedbythefacilityconducting tshuadtpreospercotiftvtehrieessuotlutdn sys.oTdhreepoQrAtUsffoorrtthhaitssftaucidlyiptoyrwtiiolnlcoacncdourcdticnrgittioctalhpehSaOsPesinosfptehctaitofancsailnyd. Ps`rSuiubncmchiiscprsaiitloiIncsalwnpihlvalsbeeeiinnssacponerctdptotiirohaneStrgetedpuioadnryttDotsiarneoQdctArroeUrp.oSTrtthasetueddmiaettnsetwgoielfnltebhreeasituenbdmbsiytptteheadtbcyattinhidlerofyeapcnaionlsrdittpyrtoovtihdeed 418-028:PADG-E3 Procol 41P8a.g00e83 staiottehnmeeTcaestitloniftnuGghFLeasfcPiicnlaoiilmtrpyeoflpiooarrnnitnc.cel,uasisodneiscnrtihbeedianbaolvreep,osritg.nIendbdyittihoenP,ritnhciispfacliIlntvyeswtiilglaptroorvfoirdea SCHEMATICOFSTUDYDESIGNANDSTUDYSCHEDULE: Sec ATTACHMEN1Ttotheprotocol. `STESUT BSTAANDNVEHCICLEE: Identification: `TestSubstance: Td-7o70c6 u[miPnetehnerratwfdeatldSau.lufonoatrePootashsiuemSxaltaPFnHSe))Lot identificawitlilobne ``cTohmepSopsoitnisoonr,wmieltlhpordovoifdseynttohtehseiTse,ssttirnegnFgatchialnitdyacdtoicvuimtye/nptuarittiyonooftrhceertteitfiscuabtsitoanoncfet.heThiidesntity, docuwmil ebeinnclutdedaintthefiinaloreponrt. Vehicle: `A`oSqsuumpepolsoiiuesrsmw0ie.lm5lbb%recadneaoprorcceusbsemidodneetixhoneniyatzweddme(watCadaetM.eCr)t((Rm.he0d.dileuimoyvniiszccoesdiwetayt)elprr).elpLaoruteidudlseinnotgifrseivceaertsaienodn NopertiebtseherenttrhitanhntetShhpeovosenehmsieocnrltneitoohrnatethwdeioSnuttluhddiiysnDtpierrrofetecortceoowrliiwtsihaltwbhaeercreoosnufdlaunscotyepfdot.theinstsitauldcyo.ntTamhineanrtselnifkoealonyatrloyebsee,s `SafetyPrecautions: ``Galwoovtmedsut,rdtiauonstgcthfmeiphosrotetHroEcdoPmlA.p(fruAielpTtalerTraeAtdamiCaonsHtkaM,niEsdpdNp2oorT)soa.pgnreis.tTehyeeMpartoetreicaltiSoanfaentdy uDnaitfaoSrhmeyeltab(cMoStDSto)bies Storage: `BBuullkkVTeehsitcSluebsCtoamnpcoen:ents: P`anrd VeehTipcelseatFSourrbmsuetlaantdcieons: RRoooomm tteemmppeerraattuurree,. Refige(2rCa1t0 8eCd). AFlolrmteusltastuibosntLaanbcoersahtoirpym,entttshsehopruelvdiboeuaaldydrceitsesdeTdetsottihneg tFiaceinliiotnyaodfdrJeuslsizannGdutleblienpshkoi,neMmaunmabgeerr.of 418-028PADG-4E ProcolatPsaaczts b`Sehliapbmeenltesdasphporuolpdriiantcelluyd.eiTnhfeorremcaitpiioennctosnhcoeurlndibnegnosttiorfaigeedcionnaddivtainoncseaonfdsshhiippmpeinntg.cartonsshould FORMULATION: EreqoufPreepanractioyn: Formulations (suspensions) will be prepared weeklya theTesting Facility. Detiledpreparationprocedureswllbeattachedtothisprotocol (ATTACHMENT3). AdiustfomrPeunrit: `Thetestsubstancewillbeconsidered 100%pureforthepurpose ofdosagecalculations. `TestingFacility ReserveSamples `aTnhdebTuelsktivneghiFcalceicliotmywpiolnlernetsser(vaeppasroaxmipmlaetoelfyea1cgholot5omfLb)ulsteeddtusurbisntgatnhceec(opurrosexoifmtahteesltyud1yg.) `Sampleswill bestoredunderthepreviously citedconditions. ANALYSES: Results ofrequire report analyseswill be provide tothe Testing Facility forinclusion inthestudy. o`Sfatmhpelsetsuaddyd.itAiodndailttoontahloasneadleysscersi,bifedrbeqeuliorwedm,waiylblbeetdaokceunmifedneteedmbedynpercoetsoscaorlyadmuernindmtehnetc.ourse `Bulk TestSubstanceSampling: aAnsdasmepnlt eaomfbaipepnrtocxoinmadtietliyo1ntgsoo):fthetestsubstancewilbe takenonthelast dayof treatment P3riMnEcipnalInvvesitigartTore:ochLnionslaoCgmyleamenednSnafetty Searvilces BuSitlPdaiunl,gM2i-a3n8e-s0o9ta 55133-3331 TTeelleepxho:ne: ((665511))777788--56516786 Email: laclenco@mmm.com "Therecipientwillbenotifiedin advanceofsampleshipment. 418-028:PAGE p.5 ------ri--ses AatviesofPreparedFormsiations: `ConcaendnHormogaenosint o`fCtohnciesnsttruadtyi.onQaunaddrhupolmiocgaetnesiatyuopfltshe(prneLp.araecdhf)owrimulllabteitoanksewnfilrobmevtheetopr,dmuiirdidfnlgetiahendceoburodsoem ``ioflelabcehscohnicpepnetdrfaotriaonnaolynstihse;fhiresrtedmaayionfipnrgespaamrpalteisonw.i`lTlwboesratmpalneesdfraotmheeaTceshtqiunagdrFuapililcatae0set `prbprearemcevukpiiuaonpruistsnloagynsm.cpailmTteepwdslc.oeo`ssnQwaduimaildptrliluobepneslsrfiaercntaoatdmiedcnsieaasdcmacphaslrqbdeuaesacdwdakniuultplphlsbeiaecmtTaapetklseseteeinstnf.wgBriFaolccmlikcblaeutcpyhhsiuacppmoponpecnledetnsfteworrriaeatlqilnuoebnyesotantoe;tfrhettehdhleueaSnsptddoeanrystoohref `Stability: pdSrtueapbpliailrciatatyioofsna.tmOhpelnpeerses(pa2ammrpelLdefocoafrcmehua)lcfahtodiumopnlcsiawcciahltcelobsneecdteowmcriualmtbieeonnthweiidpldpluerbdieontgnatkthheinsdsoatnuytdohyef.fpTrewperodasaseyisooofn,f These bsaeacnmkpdulaepyssaawfmieplrlltbeesha.nBfaailrcsytkzauenpdasltyatsmihpsel.eTfsohwleliorlwelimbnaegistnoiirmneegpsouanimdspe:lretsshweipslorloebnveirfoeuetsalpiynercditeaedpcheonadTeiarststipiaonongsstaFinabicdlieoimtyanads discardedatteTesting Facilty upon the requestoftheSponsor. ShinolagInstractions: Samplestoboanalyzed willbeshipped(efigeaidto): BuP3irilMndEciipnegnI2n3vvEe.st0ii9gatrToer:cohLniosalaoCgmlyeamneednSanfetty Searvilces StTe.lPeapuhlo,neM:inne(s6o5t1a)7557183.35-5363831 ETemlsi: (6l5a1c)le77m8e6n1@7m6mmcom "Thercipictwill benotifiedinadvanceofspleshipment. DISPOSITION: Prsepuarebdfwsoirlmtlulbaeatrieontnusmwceildlteboe:discardedattheTestingFacility. Allremaibnuliktnegst D3aMnEHHaSkRes- Auto &Chern Grp 3StM. PCaeunlt,eMri,nBnuoisloditnag 3253164-41-B1-01000 Telephone: (651) 733-2392 418-028:PAGE D-6 TESTSYSTEM: Procs 16I.0d28 `SoecaindeReuasSontforrSealecitionn: `TheCHCDBSD)IGSBR VAF/Plus atwasselectedssth TestSystembecause: 1)isiotne `idmneadvmuesmltaorlpymi;ea2nn)tsaphleisctsiotexrisanaisnc,ocnefpdrtaet3d)hfaiossrbuoesieecniadnlemdtoosxnaiscatirntaydstteeuxdpitee0rsbiaeennscdceaesitxihitasitsvaebteterneewpTiredosedtulicyntguisFveaedactnhdroughout Namber: InPiotpiuailsptoipounlsaetlieocntesdcfloirmmaatiend:study: 7150m0amlaleeaanndd7150v0ivgiirngfienfmeamlaleatrt(1,5persexper Population selectedfortoxicokinesttuidyc:do1s5maagleegrnoudp)1.5femal ras (repersexpr dosagegroup). BWodey ignhdAtse: Macxlpheecraittorsde1cw0iiblpel,baaetocrwsdhteirc6eh0did0mywsetioghfhyawgfieol.lmFbe2m7e5axlpeerc0atte3adw0i0ol.bleebaaocrlhdeaetartreecd6eitdptaw,yesaiogwfhhgfierco.mtA2imc0eh0thgebyy 5wyi2l5l bo ``awweteiigwghihtltslrwaninolgleesbwxicrleelecbdo2er2die0nd%ctlohuedfdetadhieymfteheeenfriwenecaleiigrpehtpaoorntfdc. awAiclhtlsbxeyd.oicnuimteinotne,dtihnewheeieghwtdvaitas.ioThneofthe sa: Bothmaleandfemaleratswillbe evaluated. Soares: Charles River LaboratorieInsc,. "LTaobeorraattsowriielsl,beIsnh.itpoptehdeinTfesetrinegFdaccarltyon.sbysi freightandlortruckfromCharlesRiver Identification: RIniacvt.esnNuronei.pqMeurSemPpaenTremn2t0a1ln0ye1in)d.teinMdteainlftiiefaiuncsaditinfogenMmnauolmenbreeirsssawrlhespniiesgrsncieignngteeeadmrpttotarhgaser(syGtmuemdybyBbeaernfsdoarstndardoTmaiansgitCsoai.r,tion boeefvfitrsatdhoislnaegteue.mPsauopfsttwhieelllintdeort.beodividully identified duringlactation;allpasmeerswill 418-028:PAGE D-7 ANIMAL HUSPANDRY: Protocol 18r.a0e28? Allcagesizesandbusingconditionsar incompliancewiththeGuideor theCareandUseof Laboratory AnimalsTM. Argus Researchisan AAALAC-accredfaicitleitdy. `Housing dFuroignegnetrhaetcionorathswiallbbeaniidnpdoitvsitdpauaarlttluymipeurosieodndisn.sDauirnilnsgcsstoe twirue-bboctaiicohmapeidrtcoagfiersaetosxwcnieplt,be `T`shieoenuresnewuditiilnotnbhefeehmmoaaullseeerrdaaittsn'wsiclcalgobem.imBnoedgniinvniendsutiainlnglgbynoohlxoaudtseierdntihgnantnehdseatpiyon2sg0tbpooaxfreptsru.empEseuarmciehodddg.easmtaatnidodne,lFiovered Nesting Material: Nestingmaterial (bed-o'wilclboepbrosvide)d. Bpeodssdiibnlgewcoinltlabmeicnhaatnigonedarsscoonfdtucatsendesceemsis-aanrnyualkleyeapntdhedaonciummaelnstderdyimnhecrlaeawnd.atAsn.alysesfor ETeoemAlmr, perastndHuumirditey: {6"hT4ahteFah1an0sibm7ea9elrnpo(ao1ms8sCtiontd2her6poeuCngd)he9an9nt.dl9ym7sou%npiHptlEoirPeedAdwfciiolnttsehtraastn.tlRleyao.sottRmontocemhrabpnegreaustpa rmwiwhiloillulrbooldfsmoa1bi0ien0im%aoontfeirdetoayrseid constanlysodmaintsta30i% nto e10d%. Lint At`mhnaeiSanutttauoidmnyaeDtdii.rcBeaacltlcoyhcrdooanrtrdrkeopsleilrgeindoed1w2ii-fbldoleubeselmgiegidhntan:e1c12e-9sh0so0uarrhydotuaorksaEcTSocToo.rmemTsochdeeanlttielgsihcgthhcteydccyulclelemedawliyalbbloebreaa:tdojryustebdy activites. Anysuchadjustmentwillbedocumentedintherawdata. Dar Raisabtcisrtiwufiimclfel.obemgiinvdeinvCiedrutailffioeeddReosd.enFteDediweitll#b5e0r0e2m(oPvMedINtuhteerivteinoinnIgntperrinoarttioontahlo)asvcahieldaublleedad Water: `raWouavtteoremsrawtoiislcmlwboaestiaevsramiinlgeaabclmceeasbdsslbryiebsfitaoterumnem.ufAresol.mliwCnahdtlieovrriwidniuelawllibbleolfttrbleoeamsdadtlteoadccah0letsdthoueorptcrheoeaccnaesgdsepesadoswsraeftdretorhmraasonu3gh `bpaaocnsatsleiyrsbiiloses.ctWahtae;mtpiercroacilescsoaenldtwaymazitenedarmtioisonnte.xhpleycftoerdptooscsoinbtlaeibnacntoemrioarlceotnhtaanmi1n.a2tpiponmcahnldotrwiinceeaatnthaeltliymefoofr 418-028:PAGE D- Frowcol eF1u5se0s Contaminants: NipenrtieesbrefenertreitwnhiettShhpectoehnrestioefrinsedolrdtoihftetihSnitstuhsdetyuDddiryri.encTkthioenrrgeiwfsaoatrweea,ornfeiooanfntaahlneyynsepesosttoietnthgiemaralttechroainnattlahmoiasntlarneotvusetllisinkteehllayywtoobueld performedbyth feesupplierorthose mentionedinthisprotocolwillbeconducted. DAYNUMBERINGSYSTEM: . cGoenstteanttisonadnadyor0iscdoepfuilnaetodraystplhuegdoabysesrpveermiantsoiztoea.ar observedin smearofthevaginal STGuuhbiesddalaniycnoeefss8b-i7Rr0et.ph3ri8osdd0eu0sc,itgAinuoagntuaesndtd,laF1ce9t9ra8ti)iloatnyndEdafifynetc0ht(sepoO(sOEtfCfpiaDcretGouufmiPddraeeylv0ienn)etiifnootrnth,hePHeeseTtaeilscttiihdnEegfsofaefncCdthsTTeomexisictcals p`oCSsoetmrpbeacinrnitenudgmTRee(spdtae(yaSte1oectdfiDooancs4tea,TtNioooxn.i)4c2int2ty,hSet2S2utMdaaynwrdicathrhdtO19ph6e6rR)ae.tpTirhnogidPusrcsotacimeoodnd/uDraeeyvseoilfdoetpshmeiegTnnetasatlteidnTdogxaFiyacc1iitliyty. blTaehcrtdaotuigeohno)utatntdheailsoplrdsrouctbmiostceeodqilu,cetcnnhoterddgeiaensygooldyff.tbhiertFhwIilglenbeerdateisoingnraattseadnddadyay1spoosftpthaerltaucatat(idoany p1eorfiodwil RANDOMIANDZCOAHATBITIATOIONN: s`reUalpneodcntoemrduinvoiartlss,t.uDadtuyrowinintlghlabenebasascsscislgomnafetpdihoynsipincedarilivoiaddpoupaeflaaroaunescaiesaatgnfoidvnebdotadhyyesb,waesmiiagslhoetfascnrodemfcpoeurmtdaeeldregrraetnisenwrgialtlebde orsdceclriemda)tiroann.dTohmiezraattisownilprlobcoedausrseisg.nedtodosage groupsbased oncomputer generated (weight- `waWiitttphheiprnfeemeamcxahntdoaozlsaoateag.oTebghsroeorcuovphe,adciboinntasatesiceountapiervreooifodtdehwerivwlailgliclnonabselicusostneotdfetnotmssasaxinidgmonuram8otcfotpou1lc4oadbtaaoybrsiy.tpatlFiuoengm,oaoblnseereramtvaselde ihnoesuirsninsngw.imFlaleblmeeaclaotnessrtiahtdasetrnheoadtmvtaebmteeadatwteidtah(yisna0tnhoeefdpofrsierassgtuesmgeervdeognuedpsat)ay1t0sidoonwficalonblaeabnsistaaitginoeinwdcitolohlaibbndioitavasitsdiiuoganlnfeodra maoxfsei ven amdditounaldmays. pDuapyai1noflliatctteartiaorn(ipnodsitvipdauratlulmy)weidgehfeind(edpauptbhoeddyawyeiogfbhtestwhinlldbieraelcoortdheedfaifresrtdaalylopnuwpshiinch all litteraredeliveredandgroomedbyth dam). Licatlelirnsg cwoilullndortebseulctuilnlpeodteunrtiinagl btihaesleasctiantpiuonppveiraiboidl,tebsecaanudsebroadnywdeoimgsheltegctiinonsoofvepeutphssfopreriod. 418-028:PAGE D-9 Procol 41P8a.g0e2s8 1s`aW0imftpehlmieanclocelalcrehacdtsoitosona.fgofegrucnrlcoitunipio,cncaaolloncbshseeecmruivtsaittvrieyooanrnaddlebrhawtetimealrtybo(leFouOgsyeBd)(aConCad&smHso)it,gaonrntahcehtfiiisvrtisottlyo1ag0simscaeasllsevsaaenlndutta,thbielofonisor.ds.t `Odeanpmdssaspyeel2el2cipttoeesdrftfopoarrrbFtlOuomBo,,dmsotaatmbolperlaoecaftnirvdailntiydv,oeCmrcuConl&iltHescawtinioldnlh;bitsehteuossleeopgdiutcpoasleewlvieallclutoafntilivyoebmn,easleelaenctdefdifvrefometmhaelteen ADMINISTRATION: . `Route and Reason forChoice: etTnhhveioroeoxnnalmct(edgnoatsvaaalggeeex)pcroaosnuubtreeea.wcacsusrealteecltyeaddfmoinruissteebreecda;ausned:21))iitnisconeoofmtheppowsiastihbtrlheedriioeuttseasryoorroutne, MeatndFhreqouendcy: t`iDmoseagaecshidalyl.bTeahdejufsirtsetdddaaiyloyffodrobsoadgeyiwsediegshitgcnhataendgaessdaanydg1oivfesntautdysp.proximatelythe same sM`apcaerlriiefoirdcutesh,aawtitcleolrnbcseiosgmtpislveoetfniaotnmheaotxfeitshtmesuucmbohsat1b4aidntacayetsoi.noncDpeodesaraiigoledywb,iealgftilecnronanimtniignnu1ie4mtdhuarymosoubfgehf4to2hrdeedayaacsyoobhfaebfiotraetion administration. `psFecerhmieadoullteehadatssaccworinislfiisbcteesog(ifdvaeaymn2at1hxoiftemsautctmsauotbfosnt1)a4.ndcaeyosn.cDeodsaialgyebweiglilncnoinntgin1u4etdrayosubgehftorheedacyobbaebfiotraetion `RationaleforDossgeSelection: : DDsouosbnsaptgraeengcsaew,atenatrrkeitsnslg.eicnTttheoedahbciycgtohuehnsettSpdpooossnsasigboelrwebidalislfebfdeeraeennxcppereseicvtniesodeunstsosicttauivudiisteeysbtcoeoxtniwdceeufecfnteepcdtrswobigutnthattohaetmdteersttalityor `TOpobuwvreipsootsuesloseuvfefdlf.eemroinnsgt.Trahteindgeasnceynddoisangges-erqeuleantceedorefstphoenlseo,wweirtdhosnaogaedlveevreslesweifflelcbtes seexlpeecctteeddaotrhteh. 418-028:PAGE D-10 DCessogenLevceles ntratanidVoolnumess: Frowcol P18a0t2o8 FI I or2S S STY S TT o = sC nasom~um~ are--] ER 1 IEE ee | `TM `ESVTSE .iA-NaMAA aLlbYeaSinS EdSFlAeNmU iaDletRR ayts: EME- FoN GENETRATS ION: AllPeriods: At leasttwice daily. `ClsicalObservationsandlorGeneralAppearance-MaleandFemale Rats: Acclimation Period: Weekly. DosagePeriod: MaternalBebavior: Dailybefore dosage.Onthe firstday of dosage, `p`bowoirosltmludabyoelsirwanogtoeerorkorvibdasnelegsdrdfavaotaytri.intoSteneusfvbiwarsilseltsqldfuboeueeernrmhteeopcduoosrrspdsdpeorndosadpartgiaaeaptotphbeersboexyorivtdmahateotifeotlnhyse toSxtiucdoylDoigrieceoffreocrtdse.sign aferdeterminaotfipoank Dbaehyasvi1o,r5,r8e,co1r5deadndadi2lyp.ostpartum.Observed abnormal Clinicalobservations mayberecordedmore frequentlythancitedabove, `by the StudyDirector and/orStudyMonitor. ifdeemedsppropriate Danaatlayczoeldlscutteistfiocralayt. assignedtotricokinetcsamplecollectionwillnotbosummarizedor DOetailbed Csllleesl rva-MtaliandoFemanleRsaty: Oncebeforsthe firtdosageandateastonceweeklythereafes, detailed clinicalobservations iv``awnirlilsabntteiaoncnodoasanfrditdurvtcaehtraeeettmandeefantotarcragotrnlhodleiusemtpamislo.eenSsaatinrigdmenfemsecnimaoanctliehedmdrsaa)htysono.udfTlchdtohienansdtceouhbcousdbtees.r,eEbvrfauvftatoitnroiotnowtsnibaslwelilblceloibnemedaudmdcatetdoetreodocbeuhyntasosunbirgedeectestrhvahetesrcksaing,e ureyes, mucousmermbranes,occurrenceofsecretionssndexcretions aod ulanomicactivity (eg, Incrimation,pilocrection, pupilsize, unusualrespiratorypattern). Chainngaig t,pe osts ure 418-028:PAGE D-11 Procsairstis baehavrieosrpo(ns3et,oexbcaensdsiinvgegar5ooemlinlga.trheepeptrietsievencciercolfincgl)o,ndiicfofrictuolntiocrmporvoelmoenngtedsp,usseeoitinyepocr `bizarre behavior (c.g,self-mutilation, walking backwards)shouldalso be recorded. BodyWeights-MaleandFemale Rats: AcclimationPeriod: Weekly. DosagePeriod: Daily. Sacrifice: Terminalweight. sedConsnmutionValues-MaleRate (recordedsodtabulate): DosagePeriod: Weekly. `esd ConmmptionValues-FemaleRats (recorded and tabulated): DosagePeriod: Weteocohkabiltatiyon. GestationPeriod: PostpartumPeriod: Days 0,7,10,12, 15, 18,20and25 (ifnecessary). Daya1,5,8and15, F0eceodncsounsmuemmpattioenmanlotfotoadbu.lated afterday15postpartum, whenitisexpectedthat pupswillbegin `FCeed onsa Valumss-MoaletandiFemaoleRnaty: rrFoeodepcolnpestuhnmelpiftoosifeeoh.nthvDnauflrouoieidnsmgcaaosrhysabwbhieitlarbtemiecodonore,cdwuedhmmneeonnrttteewdfo.reIrqnautdesionvtcilcdyuuatplhyavtnahcleiusteeadtswbialoclvanegoetibwioittriheacnmoerecdeoessdda0rJyrt,o tabulated `ToxicSoamkplleoColeletctiiocn: `Onday14 nd42oftudy,bloodspies (epproximately 1mL.cachwill be collectedfom `cachmalerat assignedtothetoxicolineticsamplecollectionportion ofthestudy(3pen group). tOhinelsldtbaueydcyo1(l4l3oepfcetsertdufgdrryooaumpn)d.edaSacahym2pfe1lmeaoslfwepirluetlmsbaoimcegodnlgleeedscttaettdipeorni,tobrolioocdoodokssianamegpteleoesnsdoacpyi1o4ofssyt.eT1omseemacphsea)r ofeachbloodcollectionwillbe recorded ithe rawca. 418-028:PAGE D-12 Pro1Pasctz arBlloolsotedelwreeisdliitbn;ecioofElsDl0,eTcAtth-eecdaohfaretommeadtt(hpsuoirrpbtilwteail0lps)bnteudusob.ecIsufamnneednctessepsduanriyi,nhbealocaeondwtmdraiafytubegee.TTcohhlelsreceutseetdfisrnogwsmicatonbnos `oufimlbcloeblrlee,cratainaoinsm,fsaeplreencduiimebt,eorg,eonsleyxrpa,trgioorpnoyuiapcnnnsuimtobubemergs,ecdaoobnsldaiegtdiwloeinvseh.lAt,dhlealpyaromoftpolscetousldwya,imclbolleblreec:itSimopnomnetseodrrvihaalsn.bessealacey `ondryice andmaintainedfrozen (s-70C)untilshipmentforanalysis. Acofllrecttehdflaosrtabnlaloyosdissa.mplecolection,ratswillbe sacrificedan samples ofthe ive wilbe `ShioploeInstructions: `Samplestobeanalyzedwillbe hippedondy ceto: Pr3iMnEcipnalInvvesitigartToerc:oLhinosnlaoCgmlyeamenedSnanftty Searvilces SBtu.iPladuiln,g2Mi3nn-e0so9ta 55133-3331 TTeelleepxho:ne: ((665511))777788-.56516786 Email: laclemen@mmm.com "Therecipientwillbenotifiediaadvanceofspl stipment. `EstronsClingand Mating: acEosfntreontuthsseacfyincrdlslitonargdwmaiicnloilpsbutelraattoiovoranyhpaulntueddgtbihsyenebxusacnmriivnepaedtrinmosanitoofzdvouanrgiirnngeadltbhstecoorlhvoaegbdyibitneatgiimonncipanegewodif.tthhtehveadgaayl Cassarean-Sectioning-ToxicoklasticStudy: dOensidganyat2e1dfoofrptroosuxmeidgecstoastakimonpi,lbenlcooeloldteacnitdioclni.versampleswillbecollct from al femal ats: fioBoflzcoaeocndhasrnaamdpswltieolsrlwebidol(el<xb2ci0csoelCdl)euncntdteitdlhfsrhloiimpvmeterhwnetifagoihrstpawosipslrilobvblieeormuescaloyyrddeaesd,c.rTibheedm.Aedfiearnsliavecrlroitfwhieilflcvbeeer. "vTihaedfeectaupsictsawtiionl.bBelroeomdowvieldlfbreopmltacheedutnetroutsuabneds,bplooooldesadpmeprlelsiwtei,lalblecoowleld1ec0tceldoftroanmdesapcuhnfetus centrifuge;the resultingserum willbetransfereditolabeledpolypropylenetubes.Allsamples `awnialllbyseiis.mmediatelyfrozenondryice andmaintainedfrozen (<-70C)untilshipmentfor 418-028:PAGE D-13 ProcPatunccziss "sTahmepllievserwfirlolmbeefarcohzfeentausdwistlorbeecdo(l<l-e2c0teCd),punotoillesdphieprmelnitefroanadnpalalcye.d ntolabeledtubes.The Spleswillbeshippedon ry ice toLisa Clemena thepreviously citedadress. Natura)Delivery: Female rats willbe evaluatfeod: `Adverse Clinical SignsObservedDuringParturition. DurationofGestation (day 0ofpresumedgestation to thetimethefirspupisobserved). Litter Size (definedas allpupsdelivered). PupViabialt iBitrtyh, FunctionalObservations)Battery: bcOoenncodonuncedtouecdccisabdsooirotnnlyd1bu0ermfiaonlrgetehsaecncdhod1ua0slfeeedomfsaatlchereirfasitcseup,deybr,utgaprfournuctpt.tiooFnobarllmooaobdlsseearrmavtapstl,ieotcnhaailslbseascteiiesorsynr(fcoFaOtwB)il bweill hpemoadt,olsohogrytalnybdecfloirneiscalcchhemeisdtrsuyaeclrviaefliucdaet.ion.Femaleratsshouldbe estedduringtheIacation `tThheefFoOllBo,witnogbpoacroamnedtuecrtse:dbyancbecrvrunaware ofthegroupassignmentofthe at,will assess 1. Lacrimation,saivaion,palpebral closure,prominenceoftheeye, pupillary `reaction tolight, piloerection,respiration, and urinationanddefecation (autonomic functions). 2 wdsesitvity). `Sensorimotor responsestovisual,auditory,tactile andpainfulstimuli(reactivity 3 Reactionstohandling andbehaviorintheopenfield(excitability). 4 ``Gmaditlpaantdtienmgifnootthespolpayen(gfaiieltad,nsdesveenrsitoyroimfogtaoirtcaobnoorrdmianlaittiieosn,.airrightingreaction, 5 Forelimb and hindgrlipsitremngtbh. 6. o`tAuhbnevkroerummnpautslaupcapllienbaierchaaanvcsiieogran,sndhdycepphootusonintgisaaborurothunynpodetrihteotniyess,d,etmoacscoienveouolnms,ioodnuesbt,yherieaatnoirosna,nd -- emm 418-028:PAGE D-14 ProccaaPtusts pEirnvotievdrieodbnescedervToeefrstthrielnaigbaFibalicilititylyoiitffytmPhooisrsiebttaihtveaernCoyonu1tedroeobtlseDecatrtsvt)eh.reiDfsafitcntavoswloivflepdoissniottbhieevepcesotnritnrogo.lvsiubisdtadensceeesowdi,ll be: Motor ActivityTest: Mobofltlohoodersasatcmutdipyvl.ietTcyohwliilselclatbsiseoenes.vsamelnutawtieolndlbe1c0omnadluecatedds1h0ofretmyableefroarts psechegdruoluepd osaerduer,inogthpercoosurse s`Ttdmhuairiensnumtltioeeovnseswtsmeirettvnhlatlhws.eoTfnhiueamacebphpearra-otaftwmuibsoclvawlgeiboemelmel(om4ntn0ot.ins6taitoxo2rxre5otd.ab4rmyxamc1s7pop.eea8nsctimidvn).imEnofavrceahrmeetdnessttetnsasebosurilmoaotneuwdnistltelcbdaeocuh1t.s3Birdpe.orae in secssioon,uwinth tcacaehcatrosstbtesetdaiinngltsheesassiaonmnseaclnodcceaatgodenos.nktfher0ac3k2acrcoasgsetseatnsdssseomonrss,dGaosriegseaaclhlbe . Daicttiaviitylplrboedpurcoevdibdyepdtosodiedmvoecnosnttrraotlestuhbastttahencteess(tTseysstingFaccialpiatbyPloesoiftidveeteGcotimngeirncDreaase in HEMAANTD CLO INICLAL COHEMG ISTY RY: s`d`xceAamsttcspbrcolihnbdeecidoduobllxleeoilcddotseiwaaoc.nsrpiDwfheiiytlcxeelir,bamtetihineeoaxrntaa.tisAsoapgn(pusfriaanosdatxdetiidamt)daaofstnsoeaillmgynoSethdehmtioonshfoeeedrfmeibasolrtcorovoiledboowegidcyblaaelnvlbdaeofwccolmolilnaliloycrwabilicoenhdgscesmnoiedsnrptriruoyocs(ebHsysA1eCtdCses) (ccmhsool.winncespatrleoirpauesmret,)i.pehsoosfpthahtetesutssiubnsgtraingcleymcearyi,deosraanrdfsuusspiencgtgeldu1c0o,sle,fspcecriefliactheodrmmeotnsebso,iweptrocs Hematology: Aipcperoorxriomfagtoerlayto1dmuLnolfsbhliopomdewnitlflorbancaollylseicstoedftnhteofEoDlTlToAwi-ncgoahteemdafluobleospaenpdamarinetanin:edonwet EHxeyntahtroocctyiite(CHoCuTn)t(RBC) Hemoglobin (HGB) MLLeaeenCuaokCkgrooupognuc,DoTiVsofyoftylecarulte(muntetWiel(BaelMCaC)Vr) MeanCorpuscularHemoglobin (MCH) Me`CaonncCeontrrpautsicounla(rMHCeHmCo)globin PlateletCount(PLAT) CMeelalnMPolraptheloeltoVgoylume(MPV) c``oTnwdoimtbilooneosd)swmaieolalfrbdreisiffhdeieerpespnwtemiidallobelReeepudrkfaeoipceayltrtdeecLoaausbnottrh,seAToelrslitssianamgptlFhaeecsif(loioltnlywofwoeingceaaedc)dhrasenasmdspl.leefsor(smbient Ap(p0r1o2x9im4a.tTelhye1c.o8nmtcLtosfwibllloobedmwiilslebdsaadnddmeaditnota8tinbeedcoonnwtaeitniindg 0.i2mtLheoafesosdsieuemciarmapttfeigad -- 418-028:PAGED-15 Procol 4P1a8g.0e2s8 `lP(voilteyhpirdnvoap3yyo0elmfeinsnletututud,ebyse,ocsolflatlbeheceltcieoodnwliinlttehesrcvttaulidi,mydoeann)tu.emTobehfrec,roeSlslpeuoclnttsiioonrng',psslpsaetsiucmdsay,wngiuelmnlbeberera,ttiroaanntsafnneudrmrbseetd2ro,r.a0dgoems,La.Aglel. ``tsoavhmepmrliegsohwmticlboluorbiepetfrirlfmooeazr(esmAneoPtaTnsiTur)rn.yeimceenatonfdpmraoitnhtraoimnebdinftroizmeen((P<T-)7a0ndCa)cutnitvialtsehdippamretaitalon iyi by `Clinical Chemistry: uArtpeispurllotsxihniigmpsameteeanltsyfaom2rpmalnLeaslwoyfisblillsoobfoedtiwhmiemlefldobilealcotowelillnyegfcptoaerzdaeimnnettooensrdser:ryuimcseeapanrdamtaorinttuabienseadnfdrceenntr(i<fu7g0ed.C)The TTroitgalycPreortiediens((TTRPI)) ACrleaantiinneinAemKiinnaoster(aCnKs)fe(rAaLsTe) AlGlboubmuliinn((AG)) A`sAplkaarltiantePehAomsipnhoattraanssef(erAaLsKe)(AST) GlAubcousme i(GnL/U)GlRoabtiuo(lViGn)~~CPaholscpihuomr(uCsA()PHOS) ``TCohtoalesBtielriorlub(iCnH(OTBLI)LI) PSootdaissuimu(mN(AK)) UCrreeaatNiintirnoeg(eCnR(EBAUTN)) Chloride (CL) `Sampleswil beshipped(ondryice)toRedfieldLaboratoriesa th followingaddress. `Shipolag Instructions: d`eSsacmrpilbeesdwialblobveestoh:ippedtoamiveonMondaythroughFridayaccordingtotheconditions `RPerdifniceipladlILnavbeosrtaitgoartioers:Ms.Phyllis Powell 1AD00EiasvtBoioofnseCRiSLtr-oeDeDtnS P.O. Box308 ReTdefleipehlodn,eA:rkan(s5a0s1)7329173-22540 Telefax: (501) 397-2002 `Therecipientwilbenotifiedin advanceofsampleshipment. URINALYSIS: teUsrtisnaulbysstiasnwciel.l notbeconductedunlessindicatedbasedon expectedorobservedtoxicityofthe -------------- 418-028PAGE D-16 METOFHSACROIFIDCE: [--p--ad Fogeneration rats willbe sacrificed by carbon dioxide asphyxiation. `H GROSI SNECSROPT SYAO ND PATH-O FoGL ENEROATIG ONRAYTS `ScheduledSacrifice -ToxicokinSteutdyi: f`eScmhaeldeulaetdsswaiclrilfbiececoonfdmuaclteedatonwialylb2e1ocofnpdruecstuemdeodngdoaayt42oonf:study. Scheduled sacrificeof ofBfrloeozaoecndhsaranamtdpwslioelrslwebidel(le2xbce0icsoCeldl)enuctndtihafeirlopimvretorhweeetiafgtohtaswpairllevybieo.ruesFcleotyraddleessdpc.riTiehbesedm.weAidflitlaemnr savcecrloibsofthaiefclienve,rr previouslydescribed Carcasswillbediscardedwithou furtherevaluation. Secnpeswillbeshippedondry oLis Clemen tthepreviouslycitedaddres. `ScheduledSacrifice -MaoStudy: sScdchmeiodiuslrnetdicsdoancndr,iaaafiyc2eec2oofmfmiaialcenetaiaidsomnwoifl4l2bodcaoynsdoufctdoesdaognet.Secdhaedyufloeldloswiangctih ouftfdaomsaagnetswillbe ceoGxnrttoeesmnantlc.srSoupperecfiyaoslfnaltdtleamnltaliloonreiafniildcfe,beaempsawaleieldrltosatthwihlorcgacalniusndo,eftthhoerrnaeicpiarclsodpehuycstaiibcvdaeolsmyeixnaamlinaaTvtioioenn omafedmtbheire implaniation itsandcorpora tewillberecoded. Mbpaeurllffeorrsemmdedd1fu0en%mdaeflroerrtmhaatlesiwuniplearldvbieesxiaaomnmoiinfneoedrhdbisfytoor&lgBorogiotcsda-llGyse:iroTtnisis.fsiGudreoVsietsnelnreiisninaogrnyswsPoiudlhlHoblieoropetpaainhedoitwnoiegiyl t"vaeaTpghiepaonabvssareeranidceesnasoomfpdarmpotmlhgeaaaunrtateynartuilasoatnwsnswidiitwtlehisllc,ealbronbvcedixrxraeeotmtfaiaicinnaneeecdddhaiifinntmeeearvbluteriianaaltgbbwpuarlffellsrebsereodddwbe11ei00tg%%wheeffedoon,rmgamanaaadsnt.svalrUaioctss,ueotfecornufsi,rm 418-028:PAGED-17 `ESpevalustofiMaolenRatss: ProsocolP4a1g8.e01278 H{ihtoessbceslsotwhwipoltlebneteiavlalouxaitcetdyroofmthehtesftirasrtt1i0clmeaolthaetmsilneexrcephrdoodsuactgiegversoyuspt.e, the endpoints t`e`Osrtgswa,neWifetiitgpdhi)tdhsai:ndydTomphrieosusft(oawtlthelo.olweianngodrgcaaundssw)i,lrligbhetienpdiidviiddyumaillsy,sweemiignhaeldv:ersiigchletses(twsi,thaefntd IsspVsOismStbedyEvscapolelurlametcaitnoianolsnysoSifpsea(srCamAmSpcAlo)necf.ernMotomrtaittlhiioetnyewaRinvdlamsobtedieelvfiaetlryuewaaitsle.ldbbAeyhevotahmleuHoaatmgeidleisnowinniagTltchoemopmuster. SSpphreietrtpemaermlmeiednogrfcprsahopumoedtrlamhoecilondecifedcnytamruiadstawieoipnlil(dsibepdeuyrsmmeidpstfeororgmervaaammluoufaattliiyosensvbuaoylutwahetiegeshHtap)me.irTlmtmhoonrrpTehhmooalimonegiyn1.gVpOoSsttioon p`eArbcneonrtmaalgsepoefrnmo,rigmnyacellvsuadplieunargtsiiuoncnshwacsiaaltmelgpionlrceiloeufsdeaathaeebafnotol2rl0mow0ai;lnhageu:da12d),)daebqtuneaorlrimtmianatalitvaieoten,vaaolfnua.ntrion of `sbnhoeamdamndatalil. SpeeregrAoTuTpaAsCsiHgMnEedNtTohi4fsotorlsoigticiaolnsamtpilsescuoelslecbtieowneaingdheevdaalunadtiroent.ainedfomthe tenratsper sex Al othertissueswillbediscarded. `s`eRcoahtepsdteuhlyaet.ddseoaxncaromitifdnieaclteii.ovnerasnldtteirsswuielrlebteesntaicorniwfiilcledboencodnadyu2c5toefdparedessucmreidbgeedsptraetviioonu.sGlryofossrat at `SDamuswrithvNoivinPupgs: pderesecnsrsuimbweeiddtachbanonovneisbufraovlriivzrieandsg.apGturspocsshwseindluellcebredosspaayccr,riieffixicaceme.idnaatteironthneldasitpssuupeiestfeoatuinodndweialdl,mbeicsosnidnugoctred as 418-028:PAGE D-18 [--p--e] BatsFoundDeadorMoribund: bReTaexhtceeisxsaaehsmdaaitwndieilpedlarfbieorareetdexhsaeocrmcgiraaniunefswdioeofoifdrbgdgehroasotwsshioelrslmbiooeformrnioeb.cruoiTrnbedduveincdood.ncdaTionhtndieotenipnia,isahbedoidreiyidotohoyfdmlprmlapyebtmeeianrnteudsnrweeadelosivery will obitauibonl frdei1fcn0onrl %eeduetfdror.ramAleabbluoidfrnft.eerTdehdfee1tt0uess%etsoesmawanidllliolnrb,odfePilrixevegedrnieandnBpcuoypusstawsrislonbuedicoxwnifieoinn4ecd1o00m56imepnmgisresdmsiaeou,tsed 10% formalin. ``cUotnefriromftshpepaabrcsaetnlcyenoonfpirmeplgannatnattriaotnsswiitlesl.bOeveaxraimeisnaenddaufteerribweiilnlgbperreestsaeidnbeedtiwneneeuntgrlaalsbsupflfaetersedto Viability: PrevesaingPecod: LPiuptsinwcialclhbleiotbesweirlvlebdoocroduentsepduopnessdlalays: wicedaily.The CO linib cal serv anda /or Gt enei ralAo ppean rans ce: PreveaningPeriod: Once daily. Ptuogpesthweirlslnbde oubrsienrgveodrifhaevyemairlkwianrsmtaomdachl.oEssa,cfhopeuvidielnlceboeefxsniesnteddfiofrppunpstaegprevoprod thehead,trunk,limbs,tailand presenceofanus. ColyitniecaSltoubdsyeDrivraetcitoonrsmaanyobretrheecSohdaeddyMmoonrietfoerquenlythan sited abv, ideemedspproprite BodyWeights: PreweaningPeriod: Days 1(birth), 8, 15and22postpartum. Sacrifice: `Terminalweight. CesdonsuValumes(rpecortdednid aoblned: PrewesaingPeriod: Notrecorded F1 generation pups willbe sacrificedby carbon dioxide asphyxiation. 418-028:PAGED-19 ProceP4a1g8e.02189 NEC-RFIO GENPERASTIOYN: UGnrloesssslsepseicoinfiswcaillllybceirteetdabienleodwi,nnaleutotrhaelrbtuifsfseureosdw1i0lb%efodrimsaclairndfeodr.possible tureevaluation. `PupsFound Dead onDav1Postpartum: iPdbieurnpttshi.tfThieahdtedilseuibnleglfsbwooirrlsmelb;xpaeumrpiesnmwaotiviteohdnhaoufnntgdhsietmhlmaiettrefrslfoeoadrtwipinulwplabvtieesirbd.iePnlttuiypfwsiiewldilatbshelleiuvvnaeglbsutoahrta,etdafnsoidrnvtkoiwhtiaallvlseptodatiuesdat fsuhtourrtleyvaatleuratbiiornt.h.Pupswithgrosslesionswillbepreservedin Bouin'ssolution forpossible. tBPhoueupicsnaf'uosssueonlodufdtdieeoaandtfohoorrrpstoahscrseiimfboilcreefidubbteuucnradeuceosvneadoliuftaimtoionor.ni.Pbuunpdsiwtiywtihlglrobseselxeasmiionnsewdiflorlgbrporseslseesrivoendissnadfor `Scheduled Sacrifice: sl`eeOcsntiiodonansyow2if2ltplhobesotphperaaerdstaeutrmtv,hepediulnpesavewcliuolrflatbhobewufifrlfolenbrteaelds-ap1car0ri%ifeiftcoaresmduaatlnuidrnee.xaN anmdienxeeamdfioncwraitglirloornnsosulfedo tsehion8cp sr;oisgnsrg.s loesscryoss. `sectionedbrainforapparenthydrocephaly. BenlxdogohrdisostauomplposlgeielcesacwlteieldlvfboeracFoOlllBeuacfatareddofmmtrototihmoercovaaecctmnhiavcsisaetlvye)aacs.tseeTdsphstueubpcla(to5,opdbewlriosloeldxsbaepmeprplllaiectceeodrliflnretcootmitoutnhbfeeo,1pr0oHfoeAlmCeadClpe,esr `(pio7tle0y,praCol)pluyonlwteeindletstoucbhelso.tiaAnpldlfsomsrapamuennpaillnyenssaiwtsc.ienlTtrbhieefilumigvmeee;rtdfhireaortemeselualytcfirhnosgzeseleneorctunemddwrpiyulipclebwoiatlnrldabmneascifoneltrlaeeicdnftoeetddoefnaatgnsses.nd caisntdetdhhaododirregfsaospnr.pwoTsemhsiiegbrheletemraaennciaonlriytdsneigsdp..orTFthriooenzmeoenfdseiaamacpnhlleoisbveweiwrlwillibllbelesbfehrrieoptzpaeoindnateondLdiisntsnoerCuetldre(am<leb2un0fafteCrt)heudnptr1ie0lv%iously hfiAosrtTomTlaolAgiinCcfaHolrlMpyaoEsssNdi4ebTs.lcerhiibesdftorotlheoFegvoaigluecanteairoalnt.iTonhreatlsiivenrHsiwsitlollbogeipcarlocEevsasleudamtidoneivnaluated 418-028:PAGE D-20 EROPOSEDSTATISTICALTESTSTM': Thefollowingschematicreprecots statisticalanalyses ofthedata Procol 11 8.028 1. Paramattic A wwii TE | nae dm taro 1 Memes aso | oapmctvans a Soman Msg oe1 r --, ow1er 8 pestren mm, [ ---- moss x Ot EINER consi OmerI Tee orm IVl.fTPeeisrB tTfoooiargtoi oarHratrmm aitsoDeonatna b=. G. PTrSoosptotrotriohin odasmtaoatrgneoiotnfipvencarcrloiiuabdtaneacdeybi.lnltehirlsocraetyepgrotrsoyd. gitaerip0f.05ocrpo00t1, ------------ 418-028:PAGE D-21 ProcaPtusttn Tpleaysteset,sinwtehelFaOs Bbuosdiynwgeiingthertvdaaltcale,fsoocd hcosnmtuempgtriiopnsviureenswtielsltbenndalheypleading fox dVeasrcirainbecdesundweilrltbhesuPasreadmoetcrticmhaetaedithnegoprfotbhaebislcihteymtahtaict.hBeagrtrloeutpt'sshTaedstdoifffeHroemntogveinseainteyaon,fA `t{`noohottensiicinsogawnpmgiprpfriloicpfgarirnioctaunrtpetesu(,uapsl=nit0dn(.tpg0hD>5e0)d.,u0at0th1enag)wwriinollTullbpeeiesntedc'"ixocp.maoIptseafetrhdBeaatduratsinhiaenstgsTteuhtemeptrtAiidnsocanteliyomgsfuiibfshoscoaafmnonVtgc(aeeprnwi<eai0inl.tcl0yeb0e1oTcfevosatmrhopei)aaAnIrvcfaeaitlhsmyatth NoofmpVaarriaamnceetrTceshteiasdniontgaopfprtohperisacthee,maatnidct.heWdhaetsnw7i5l%lbo efaneawleyrzoefdtahdesecsorpeainvaaldtehretgoreoupeare tied,theKruskal-WallisTest)wil bousedt result(p<0.05), Dua Test"?willbeusedto acnoamlpyazreetthhoedgartou,psnedxipnotshedetvo etnhteotfestSgaitiouns atritdi,clFei/sshuebrsstEanxcaecwtitThetahe"cwoinltlroblegruosupd.`toWchoempnamroertehtehparnop7or5t%ioofn tohfetsceornesihnaprny groupare (DissefcahftergmefarnetnoicAcme.nbtaAhleseytimswgiooaseoionfrfgcaracVontauirpvisifatnifyncetetcewhtei(,t0twho.itR0atel5hpsr)ecpareitosesttsdheaMdtlelmemaeetasascusuaurrnreesemmp)eeensnatstdsrsewaisisnctrohiifbnetdsueonsfsdCieoron,thwnaittlhlebiaedaninnagloyzsed bgpeietvriweonedetsh)n.CIoefnstctheanertCtroianltcliesonuntbarsnattdaiBnoclneowocifklflc(tabedciofgmfprioacrfoebdtetitwnehegonDuganrnoeuftoptrsstaTheesctpsoee.nscItiirfoonhlT)geraCeou4psoaansnnd atoheginroounps cBalcohcmkeiantseurarcetmioenntipeirgiaoidf,iacnndt, saingAnniaflicyasnitsroefsVulatr(i5a<n0c.e05T)eswtiwlil lblebfoulslodwetdobeyva8luoammpahceideunsroaf `the groupsusing DunnetTte'sts. est temsintheFOBbavinggradedo coun score willbeanalyzedusingthoprocedures describedundertheNonpar heaadinmgoe f thte scrhei matc ic. Cilinbicaloabsleyrzveadtaiosncionnctiidnegnecnecdyttsa,basswuseilnshtehVdaersicarnicpetTiveetaafdorquHaonmtoaglednaetiatfyoomf thho FBOiBs,el Distribution, Al' eoraddmitioanalstatiseical evaluationsmayboperiffdeoemerdnemcesesrydor rr---- Ee-------- Co 418-028:PAGE D-22 Proce h41e8e.0z2z8 DATAACQUISITION.VERIFICATIONANDSTORAGE: DHAuuamttiodmigatetynecdMrDounaoitdtdaouCrroiilnnlgegStcythsieotcneoamu,ntrdhseeMoaCfnotuahlgbieosmnsuetrndntIySnsywtsirtluebmmee,rnttehsceoVPriadvseaidreviieutmhIneTfrermbapyrheedarManotdtuoorreruaAscnitdniRgvetilhyatAvers `sDuesmltmaeaymre,itdAzhletdeCaronnuadltboioornusStrayntsiIsttneismcia,lraluynmaden/naossltyAhzuedepidatusosrsiyinSvgeatahrveoliAdSraygnsutcseesAmou,fttthowemaaCrteoe.udlADblaolturadCantIoanlwslitclrtluibmoeentnaatbnsuSdlp.aatteida,l MMai(vcnerarasgsieoonmf6te.E1nx2tc)S.eylstpeamr,tohfeMiVcirvoasroiufmtOTffeimcpee9rat(uvreresainondRSeRl.a2t)i)veaHnidolnoirdTithyeMSoAniStSotrienmgSystem, `2RFe1acsdialariytdyss.awAfiellrlbogereinrgeeirvnaaitliedowanet.dabwAiylltllohrbeieSgbitnouauldnyrDedcisornreddcsitwnoidrlealxnbededo.sroArpcpeordopipynrotihsftoaealrmlcaahniwavdgeaseotmafewntithlpelebTreessotsniunpnpeglliweidtthoin tdnheteeeSyremaipnreaoftdehurnpmioainsslrieoqpnugeoosrft.toshPfertdiehrseaestremvfaieitndeaorliirsasenlupseo,srw,ialfebrewshtoircehdtaifmtehtehTeeSsptoinngsFoacriwliiltlybaetcnonotGaucatregdeffoor KPEEYRSONNEL: EDxeicutrivoeefDcRierestcetaoorrcorh:fRAelsaeanrMc.h:HMioldbreedS.PrCh.mhDa,DrnAiB,PThs.Dt,Fiellaow,nAT,S DAisrseocctiaotroeDfiOrepctoer orfRaeasnctdaCroicmhpaolnidanSntcseu:dyBDireactorJr.:PabRttearsaonr,BGyaA.Y.omrk,o Ph.Dn,DAdBT Di`DreMcitaornooroffafSLAetagnubiodemrcyaarMtloatOrmpyOaeporgeseriamortneis:o:nDsVe:JnaoahCn.lAFL..eSeBbhoaar,rmpVeer.i,MtB.Mt.D.eS.,S.. ``CCohnasiurlptearnsto,n,VeItnsetriitnuatriyonPaaltAhnoilmoagly:CWa.rsRaanydBUrsoewCno,mDm.iVt.eMe:.PDhD.o, AuCBV,gPL.ealrn,aPh.sD. 418-028:PAGE D-23 RECTO O BEMR AINTDAINS ED: A"TPneistmraSulobAsactnqatudnicAseoim,tVeiencohdnim.coelnetlsan.d/orReagentReceipt,PreparationandUse. MRaatnidnogmiHizsattoiroyn.Schedles. GTerneeartamlenCtomimfpernetssc.ribedby StaffVeterinarian). BCloidniycWaelOighbtssearndvor aGenterailApopeanransce. FeNaetdurCaolnDseulmipvteiroyOnbsVearluveast.ion. `FBGOlrooBsosadNSneadcmrMpoolptesoCyrAObcosteirvlviattyliOPboroneocsrc.veasctsiiontngsa.nidSohipnme,nt. POrhgaon Wteioghg(tsir.raequpirheds). FSeteuddyaMnadinWtaetnearnAncael(yrsoeosm. andenvironmental records). PaacndokrShiipmenntLigsts. ProcolsP1u.e2s8 EINAL REPORT: ```TasnuhaneliSymtsauecsdywytiDaliblrleenoscottofberpuwniealrulfdpoirrtoemvdeicddooepmneprutiehoersd-eiricenuctpoderardtneeddsadtaoaft.satumdayyparocgcroemspsatnoytthheesSepuopndsaotre.sD. rStaatistical iAncloimzperdehfeolnlsoiwviendgcraotinalsruepolwritttwhiatlhltebSipproeoopanrr,eTdohnecroemppolrettiwoinl ocfltuhdeestthuedfyaolnldowwiinlgl:be E`xSpuaemndrmDCeomsnaiclgeurnsaoinoydnt.Meathold. PrAEoptpvoencadoilclaensoud:fFAaTisesgsotuctriReisesis,eouSdlutnAsm.mmeanrdymaenodtIsndnivdiDdeuvailaTtaibolness,SStumdmyaDriirzeicntogrt'hseGALboPvCoemDpaltis,nce Statement,Reportsof SupportingDta(ifappropriand QAU Statement. aD`nTadhtleaoSrwpioalnplspbroeorpwhraiinlsdtl-ermaenacdnilavogerecaomnmeecpnuottppeeyrrsorofentncheolrddwreiadft.thRireencp2oo1rrdtdaasnywdsitalflwbeecrogrepeniveeirseawtoeifdotbnh.yefAtilhnleaoSlrrtiegapioynratDl.irreeccotrodrs ``iwilnidllelbxbeeedss.ttooArrceeddoaiptnyhtoheefTaaerlscthaiinvwgedsoaFatfcaitwlhiietlylTaebtsetnsiouncpghFpaalciriegldeit1fyo.rtoAhnelSepyooernagrsioanrfauelprdomaanairwleiiqlnulgebosetfb,toPhreudensrdcaratneddintaislsues mpaoterrti,aalfs.erwhichimeth Sponsorwilbecontacted determinethedisposition ofhese 418-028:PAGE D-24 Iiioal AnalCare 2 UsComite. Ardcotanetroa ProtaPsest INSTITUTIONAL ANIMALCARY. AND USECOMMITTEESTATEMENT: `TheproceduresdescribedinthisprotocolhavebeenreviewedbytheTestingFacil inpvolavestnthueadtyimanaoilm.alswillbeconductedin amannertoavoidorminimize discomfort,distressor co"TnhdeucStpionngstohrissisgtnuadtyuarenbdetlhoefwadcotctuhma enthtisstihsnott hanauntneicnefsosramraitliyodnucpolnicceartniivensgthye nmecaeyssbiety for obtfraomtihenSpoensodr. Noallemative inviro)procedures wereavilableformeeting the `stated purpofothse steudsy. REFERENCES: 1. Christian, M.S.andVoytek,P.E. (1982). InVivoReproductive andMutagenicity Tests. Environmental Protection Agency, Washington,D.C. NationalTechnicalInformation Service, U.S. DeparotfCmomemenrcet, SpringfieVldA, 22161. 2. `CNaooarlvireseimxabonen,erM(7PS,r.o1c9e(81e39d)8i4Jn.)g.CsioRfnNPeaylchoipxaotn.er4toS5xy9imoc0ip7toy1sd0ia,nudm,uteNretcewloYgtoyrekvAiacaatdvoenmyseooffSciences, 3. Lianntgh.eCPhLa.rl(e1s9R88i)v.erECmbrrlyo-anCdDFRBeataRt.DClearivsReivleroLTapaximcbiyeoTnerrattnoaeal.oWtglyi)oCkoinrtnrgoil,Data MA 01887-0630.(Database provided byArgus Research Laboratories,Inc.) 4. ILnasbtoitruatteoorfyLAabiomrast.orNyAatniiomnaallARcesaoduermcyesP(r1e9ss9,6)W.GausiideofgoirtoDh.neC,C.areandUseof S. Hian7cg0o.greprotrayt,ioG.nC.nt(o19p8i9v)t.alDervoedelnotpsmaelnttyofssTsicearsImenntesuuirs.oJb. Aetmeeshrt.ianCgocvla.piaTboioxliitroile.asf8ol:r53 6 pIPrroecveiydnuS,rc.e(bf1o9o6r8ps)s.chCsosaimnpmgr(eBtmhheeiabnnecs)hi1aovv3ei2loo2braso-lc3arg5nv7daat,pihoynslioalssoegsiscmseantte:oaf. Asmyosutsee. quanitve 7. Mboatteey,.V.J.CA.m(e1r9,89C).oSleTxoexincionl.gs:p5r5os4c.hes oneurotic: Afunctional observational 5. OeDxoanmoaigLdLnh.nu(ea1u9re8to9p,)ai.thSoocloegnsyi.nJg: Afomren.erCvool.xiTcotxiycuoslin8g97-n1e1u6rologicbaalsleyd 9. SWo.kHa.l,FRrRoc.aaanndaRdobCi,,,FSJa.n(F1r9a65n)c.Biasrcipot.,ts37t0e.s5t7o1fh. omogeonfveariiatnceys, Biometry, 418-028:PAGE D-25 Proce 4P1a8.g0e28s 10. 6StnheEddeictoiro,nG,.lWo.waaSntdatCeoUchnrainv,eW.rGsP.rie(ts1s9y,67A)m.eAsn,alysis ofVariance.StatisticalMethods, Pp. 258-275. 11. tDuranee,aCtw:iWm.the(a1c9no5n5t)t.rsoA.Jm.ulAtmieprle.cStoamtp.aArsissoocn.p5r0o:c1e0d9u6r-e1f1o2r1c.omparing several 12. CSoo,kalS,aRnRF.raancnidscRoo,hplf.F3J8.8-(318996.9). KruskalWallis Test. Biometry, W.H. Freeman and 13. Dum,0.3. (1964).Multiple compausrinigrsanoksnumss.Technometrics6(3)241-252. 14. NSieegwelY,orS.k,(1p9p5.6)9.6-1N0o4n,parametric StatisfotritchseBehavioralSciences, McGraw-Hill, 1S. SGAuSidIen,sRietluetae,sen6c..0(319Ed8i8t)i.onR,eCpaerayt,eNdCm, ppe. 60a2a-n6as0l9y.suisorfvaeriansce. SASSTATTMUser's 16. bSAinmneeodsme,icaoplrpd.,iG2s.4tr0Wi..b2au4tn1i.donC.oScthartainst,icWa.lGM.et(h1o9d6s7),.6VtahrEidiatnicoent,elsotfwoarShtoatmeoUgseinveeoifrPttirheyetssy, [EROTOCOLAPPROVAL: FORTHETESTING FACILITY `Alea M_RobPerno,Plh.Do, DABT DiofrRestor p(meeJ 2i Yotd pGv.eYork rP{oD.,oDkA StuyDieter ShooLib f=MeinbeeCro,Hm.nmWisotosdiartdA,unimialD.VIM.Coarneaand FORTHE SPONSOR Felon. Bulerleldy SSJtpouobdmayoBrMu'ocsnhRiotefoprlrs,eads5ta,vDeABT,CI 418-028:PAGE D-26 [-- i 2mm Due bow260m 2002. Mw ama Date ' April, 2002 Due 418-028:PAGE D-27 ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE 418-028:PAGE D-28 ATTACHMENT! STUDY SCHEMATIC ProTcaolgae s1osf3 COMBINED REPEAT DOSE AND REFSRCORDEUECTIVE/DEVELOFMENTAL TOXICITY FinkDayofTest LatDayofTet NAD MaeDosePronatog| CotabiatDoonsage" Ra LastpDDraoeytgoefedTest 2WeleM|et,2Wes Neuen Deva AciviyFoB . Femme Geen Pored Ra Wes | 2veds 3 Weeks AMcoaro Iorn b&. FMFaOolrBaedardnaidstmsoaonctaroilfdrieactceatiilavsfitseyereecv"aoTlmeupsalttesit,oAinnsocanlooynfsdaeutsclatenaesddtMo4e2ndtsaeunyraseolmefesndtopsse"asgeegc:rtnoieuocpn,roofptshyeapnrorteotceonlt.ion & ocfolmlcatle rferproomdutcetnimvaeolregraantss.peHregmrmoauopl.ogy,cleabiochemisey sad isologessamples TenfemaleratspergroupassignedtoFOBevaluationand motor activityevaluation. hTieesttenonlfioeogmniacolaeflasfaetmmppalleeesrgecropolulrpeaoctndeddu.tcRoeetrmigialaivinntseiensgsHafcermeiaflimceerdaoasnscltdaiacnyii2ocfa2cleplbdoiosonocthpdeaamgriyts2uty2,pnoen,sctrdpoapratyuamnd and discarded. ATTACHMENT 1 418-028:PAGE D-29 ProcoPlag1e2z.o0r2s8 SCHEDULE 26MARQ2 AnimalReceipt -AcclimaBtegiionsn. 01 APR 02 pSe`trairtocodufnoDtiolshaatghneeaddPtaehrybribooeufdigo-hrMestas1al4cer-aRidfaaittcysecoa(hfi1at4bediroaatayttsinbloeenafsotre2: daofdyosagse). OLAPR02-12TUN G2 DocsaogehPeraitohdbroFuiegmhaDtlaeRyaa22tto(f1il4adcatoaytsibnoen)f.ore I241AAPPRROO2ZPPMM--2218AAPPRROGZZAAMM M`alCe o1(7bdaPyaesr)ibod(iMatxiamumtof1i4odayns). Ma2 (l7daeys) 14APR02 Day14 ToxicoSakmpilneCoellteciticon 218SAAPPRRO2 LFairssttPPoossssiibblleeDDaayy00ooffPPrreessuummeeddGGeessttaattiioonn.. : 05MAY02 FTirstoPosxsibileDScaamyp2ol1eoCkfoPllrieecstuinmonedeaGnedstStacarsiiifoicnce - 19MAY02 LaTTsotoPoxsxsiibicleDSSocatauymkdpo2yli1FeoeCknfomPlaerllieeecsttRuinamoctnesadenGedsSttacartiiifoincce - ToxicoStkudiy nFemealteiRatcs 06MAY 02-07MAY 02 FpOerBGraonduMpotorActivityEvaluation -10 MaleRats &b ITTahhcrteoatuigothno)dauuntedthaoilfsltsshcuehbessdueulqeu,enshtehadgeaeysdaoffytbhhierSFth1igsyedneeDsriiartgeincoatntoerasdtiasgyan|ntdhdoaspyprsaoorcfnctehe,(ay1atocf "pDeariyodNwuimlblebreidnegteSrymsitneemd.a"nd citedsccordingy,asdescribedsbovetheproto!section, ATTACHMENT 1 06 MAY02 2BMAY02 10MAY02 BMAY 02 12MAY 2 13MAY02 23MAY 02-09 JUN02 27MAY02-13 JUNG2 24sEP02 418-028:PAGE D-30 ProtePsatg4e138o.0r238 FigressttaPtioosns)i.bleDelivery(Day21ofpresumed gLeassttatPioons)s.ibleDelivery(Day 25ofpresumed. FFiermsatlPoesSsaicrbilfeiDcae.y25ofPresumed Gestation LFaesmtaPloesSsaicbrliefDicaey.25ofPresumedGestation ``RSDacathyse4d2ulTedoSacxrifiicec- aSTaomkpxliieCcnololekecSitttinuoidneyaMtcnadilce GSacihtoecdihuenlmeipsdStoarscyarlinefdidcHaeistt-oM)loagHiicenamlSatiunSdiayomMgpyal,leCeClRoilanltiescctaionof SelectedMale Rats, RFaOtBspaeordGMrootuopr.ActivityEvaluation -10 Female: P`uHDipasstyo2.l2oHgPiocsaetlpaSmretmupamleC-tSlCaiocnloriliecfcalitlicCoehnoeoFmefnmgSiaesllryeeyRcaat,netddsaFenmdale. RandtPupss. Draft FinalReport 418-028:PAGE D-31 ATTACHMENT 2 MATERIAL SAFETY DATA SHEET : 418-028:PAGE D-32 OWATTEARISAHLEETSAFETY 3am Genter (Experimental) sS5t.1aaP-a1u0l,00Minnesota . 1-800-384-3577 or (851) 737-8501 (26 hours) ACLoLpyrriioghhtt,s r1e9s6e9r,veMdi.nneCsooptyainWginainndg/oarnddoMwanniuotaadcitnugrinofg Csoimspany. - 21ii))snfnBtaoerhlriielmtooahriwteeniradfogontprrhermfesoaoatvrceiionodttpnehydei1nsstpohurocarbotpt:tpohaiseiaendoeordifingTPirfrnouoanlplleSrhtwl:siytarhuentsgnioollidczhianngge3sM products unless G1StribuTed witn the intention of earning & porrovoetrheiruriosen. MDAITLVE-IR0S0II5AO1LN::DEV3EMLOSPPMEECNITAALLTYPRMOADTUECRTIALS DSIOUSGPSUEUMREESDN:ETD:EDSe:c0e4Rm-ab8ye4r71070,.7, 1919900.0 mete TTT TT veman TT RPEOSTIADSUSAILUMORPGEAANFILCUDFRLOUHOERXOACNHEENSTUGLAFLOSM.TE-.-......... hi38s7t1o.r9y9-6 U1n0k0n.o0wn sfTuohpriesrrvmeiassteiaeorrncihaolfaniads tdneeocvthenlLioicpsaetleenldty oqpnuuartlphioefsieTesSdCoAnilnidynlvseuinnddteeorer"ly:thaenddsihroeucld be used . "a pwvateal cara : Te BOLLINGPOINT: ............... WIA sEvovAaPuPosonrorLaITsTIyONsTmwa:TAeT:1E1R:11111111111 lMWaRegueiginae sree Gaem..LLL Ca Pe atures PHEiRCENTVOLATILE:............... Ne(gBlulikg)ible wveaLsTeIaNsGirpyo:iL nt: LII TT NwDp APPOEfAf-RwAhNiCtEeANcDry0s0tOaRl:line solid, sharp odor. : Abbreviations: WD - Not Detereined WIA - Not Apiicubis EA Aoproxiastely 418-028:PAGE D-33 #O5e0c5e:stLe-r90075,1 D1E9V9E5LOPMENTAL PRODUCT Pace 2 3. FIREANDEXPLONSAZAIRDODANTA Crm HASH POINI FLAMMABLE LIMITS - LEL:........ N>/SAe2t1a2tlFasShetCaltolsaesdh Cup AFULTAOMIMGABNLTETIOLNINTTTESMP- GEeRL:A.TU|l.Rl.E.l.:] WN/AD EXMTaItNeGrU,ISCHaIrNbGonMEDdiIoAx:ide, Dry chesieal, Foam SPWPEOeCBaILrALLLuVFleIlRpErperFsoIstGueHrcTetIiNovGrePcRplOrCoeEtsDhsUiuRnrEgeS,:deisnacnldudbinrgethheilnagst,appsaerlaft-ucso,ntbauinnekde,r coat . . parndotpeacnttisv,e bcoavnedrsinagrofuonrd aerxepso,iedMaairsetasanodfletghse,heTaadc.e mask, and UWeSeUALHaFzaIrRdEouAsNDDeEcXoPmLpOoSsIiOtNioHnAZAsReDcSt:ion for products of combustion. 4. REACTIVITY DATA } Tree STABILITY: Stable INNCoOnMe.PAkTnIoBwInL.ITY - MATERIALS/CONOITIONS TO AVOID: HAZARDOUS POLYERIZATION: Hazardous polymerization ill nat ocour. HAHZ(aAoyvReDprOrU3oS0d0DuEcGCe)O.MfPlOuSoIroTcIaOrNboPnRODgUaCsTeSs:if exposed to vary high teeperatures Ts. BWIROWENTAL INFORMATION - Cm SPIOULsbLesewRrevEteSPOspNwrSeeEec:paiuntgiocnosmpforuondotohrewratseecrtitoonsa.voidCodlulsetcitngs.pilClleedanmatueprial. residue. Place in a closed container. REC2IOncMcoMisEnbeNurDsaEttDeibDlIieSnPOmaSanAteLir:nidauls.triCaolabourstcioomnerpcrioadluctfsacwiilliltyinicnlutdhee pHFr.esence of Opiesrpmoistatledatloterancacteipvte:chemDiicsapolsemasotfs.waste product ina facility Abbreviations: NID - Net Deterwined WIA Not Applicable GA Appronisstely 418-028:PAGED-34 2 Pe -- os ---- oe 3 Einar Tarn fons nonr --n--,"oa: seoVseiatmese dperoeaUTmSIsN:ats,ewin, PE BBETnstEaen Since regulations Ee lite vary, consult applicable racions or regulations or wr"ens authorities ats-- PE rossere -- og omTee-- Heaaene Spsrreaorngige TTihesrreshmtonte chat ory sehcns FETIRE MAE: Wo mERSRE: Wo REACTIVITY Yo CUTE ven coments evf acceocnimsataerA sly rlush ayes with Lage sins of rater. Get megiate saEFnalchoopveeiinnn:witsh1Laarge amounts of ster.1 rritation persist, got. --Siiim--misatairsiyoantsonssoacrers, rrespove rpersonto ea ai 17 i"SrPhrsrUwferreAuece:t,silooncnae3ts?4 sEnyeisettien.t`snaslatteetly.oonyytLrnadensvovmoittiinngg at RATIO TT JrTTotoo-- etTeabylonnlioSonnrgtaScemti.aasdebbleedoorornmeascnoonnotasarctrtSohacutvdiapeor,ssoprraay,, oorrmaiist,t, ASSristions Nia Lr oeareiond WA Wo ices ox hepsineniy : 418-028:PAGE D-35 MOSeDcSe:nseLr-90057,1 1D9E8V8ELOPMENTAL PRODUCT PAGE 4 7 PRECAUTIONARY NORATION | fosmiegy Tes SKAIvNoiPdROsTkEiCnTIcOoNntact. Wear appropriate gloves when handling this Gimr(otSaeveatcemreorsarmanimle1aelx3lns).d..need:cAPeUrssposebatauierotrcynyteloitfvoorerugpblrmboeeovvrree,esntospfaosldktyeihsnetfhrcTyooolmnletlntaaehcx/etip:nfogollyhplveeoirrwnsdiyonlnsgiaeldv.ewenarsetiernrcoeih,ralolo(rssii)dceare echiltohreirdeof(tShaeranfeoxl)l.owinggmaartmeernitasls(:otheroltyhsanthgylloveenss)sspmooluyrvyi'ibeoeresmade of "RECOMMENDED VENTILATION: gi1VUsroesicnensatoawlitiiloeatanxthdsheeadaqbupueaspalrtrteooeswvp,.errniuetasPitcerleooampvtleiirondocodenapelrdsaiuteefaxxfthtpiraeocausinsurestrenfestevpreiv1nieptnnioitlitiansit.tsiaioino.InfUse1Pex0rhosasvnuiaosdtbewewaeaprlnpttriolpartiiaotne - vreenctoimlmaetnidoend eaxdpeoqsuuartee t1ioaictosntarnodl/ovrapcoorntcrroaontlcoernsytprrpaartyoitooencrst.iaoornve.isoe'Breri aLeoscalairebxohranues.t ventilation is recossended where the material beco REAHcSovIPnoOItiBRadHAnTiabOnprRapeYnratotPsvhReiOadnTngEdCroTeiIfsnOpNia:aricarctbooorrrdsnaenbcmaeasteeidrtiohanl.OaiSrAbSoerrlneeegcutlcaootnniseoennosifretrheiorfollowing supplied air respirator, full-face supplies air res:pireasrr task PRDaEroVeEanNsoTtITOhsNoatrO,oFugAdhrCliCynIkDwEioNtrThALssmooIakNpeGEwaShnTeIdOnNw:autseirn.g before eating. tNhaisshphraondudcst.siWeanshheesxgpvoiseeed and REScCltOooMsrEeeNdDawEthDernoSoTnOmoRtAtGeEmi:pneruaset:ure. Kes container dry. Keep container FIRNoEtAdNoDteErXaPiLnOeSdI.ON AVOIDANCE: : ExrosuRe Linirs INGREDIENT VALE WIT TYE Ame sane RPEOSSTIAWDSFUSOAILMUMTOERPGEARNFILCUGo FRLOURGERX. OACNHEEo NICALo S.... 001.11 mMaOmNeS nTaA oan ny SKIN NOTATION: Listed substances indicated Mith *Y* under SKIN refer to Abbreviations: NiO hot Deterained WA - hot opiiossie Gn Approxinately 418-028:PAGE D-36 MDSeDcSe:neLr-90057,1 D1E9V98ELOPMENTAL PRODUCT PAGE 5 EXPOSURE LINITS (cont inusd) INGREDIENT VALUE WNIT TIE AUTH skzwe btiyhnecdliuprdoeitcnetgntmciouancltoauccsotnmtwerimitbbhruatntiheoenasnLudubsettyhaeen,coeev.ietrhaVelerlnibecyxlpeoassiurrcbaeonrnbeaylottreh,re mcourteanpsaorssticreleasrlty,e skin absorption. `SSOURMCE OMF EXRPeOScUoRmEenLdIeMdITExDpAoTAs:ure Guidelines . eveWocionafcorrs:ation was found regarding effects from eye contact. Single exposure may cause: WswielldliEnyge, Iprariint,atiaonnd:tesairginnsg/.sysptoas can include redness, SKWIoN iconwfToArCmTa:tion was found regarding effects from skin contact. eMxatyenbdeedabtsionreb.ed through the skin and persist in the body for an Single exposure may cause: x Mswoedlelriantge,SkiitnchiInrgr,itaatnidond:rynseisgsn.s/sysptoas can include redness, IeNAoLAiTnIfOoNr:astion was found regarding effects froa inhalation exposure. Htianye.be absorbed by inhalation and persist in the body for an extended Single overexposure, above recomended guidelines, ssy cause: SIorreeinteastsioonf (tuhpepenrosreespainrdattohrryo)a:t,sciognueg/hsiynsgptaonsdssnceaenziinngc,lude 1FIsnugaeLsLtoiwoenD:is not a Likely route of exposure to this product. No information was found regarding effects from swallowing. wApernieigsmheatnltlsoitsnusd,itehislsoscspornoodfduucctatpepdeitnoidntieco,artgelaentsihctarrefgciyut,osroiacnnhdcslaunideciuarnelglsolgwiivhceiarclh,dsipasyatnubcrerbeaantciecs,, adrenal and' hematologic effects. There are no know human healih Abbreviations: WO - Not Deterained WIA- Not Applicable Ga Aspreriastaly : 418-028:PAGE D-37 OMSeDcSe:nteLr-90075,1 D1E9V95ELOPMENTAL PRODUCT 0. WEALTH WAZARD DATA (eontinusd) PAGE 6 Cm Wehfefnecutssedfraosn ainntteincdiepdataenddeixnpsotsruurcetetdo. these organic fluorochemicals OTphTHeahErviRiesoHdtpEshrAeoLodTfupHcotttHieAsnmZetaA,iyRaDelcioItntNhtoFeaOribRneMaAsToaInbtOeshNoe:robrpesadraerannetdomrrogelasenicinucleifnlourtohraeo5cbhRoeedsyicfaolrs ltohnegt Th2leauayolrtAohccchueefsnfuielccaattlseskfWrihotenhnarunestpeiedcaitapesadtieendxtpeoensxdupreoedssu.arnedTthioenrstethreausrceetenodor.gaknntoaswbnoLhiutseesn: ang wgPToahortepkiuenplrgrasetbsiiaeoncnndkcieactnaoodtfetsshuoebrnpgoo1ap9nu7ail0do'avsteT.irlosuneuosr',eosfcfsheeuecpcstihisdc.eaansltsowolironkgeitrohsne,lbshltaousoddybeooaffntihpteusosgoieuannmeernal SECGuTa IDOATNES TTT PRECAUTIONARY INFO. SECTION CHANGED SINGE May 17, 1969 1s8e Abbreviations: NID Net Deterained WAL Not Appiissbis" A Approximately bIIeMnPecLoIriEnrDfe,ocrtImaNaCtsLiUooDnfINtiGnh,etdBhUiaTsteNMOaLTtaesLruIieNadIl.TES3DafHTeOM t,y ADNA aYtaNIOWSKPhWLeAIeREtE RDAN(WTMASIS RDERSS)A,NTiYEsXObPreRliEeSvSedEOnDto MUEHPshEReaRCrtFH'hOAsaRKrMTmAAeNtBtChIhEeLoIdOSTRHYofOUprSRuoAsdGFeuEIcTotONrFiEasTSpRSpATFlDtOiERc.aftoAirUPosAn&e.RrTpIaiGCrsiUtvLireAcenRuslpPtaoUhrnResPpiOvubSarlrEpeOioesfRteoyrCaOondUfdeRtSTesaErucaoiitiFeenrsisinsgthfeor tuGhnBeiDquuPseaelryctweviattlhhuieantuetsheethaeunsde3rMa'pspprlokidncuoacwttlieodtnogeodfeatnaedrImcMionnpterroowdlhu,ectt,hietrsoiLsutseiaossfeniWthtiisclfhortahraaetr particular purposs and suitable for user's sethod of use or applicution. rdO3ne4uprepertrsroooavrntisthd,aeetsoiraoeiinsnssofstoiearosanpsstotosiosoriintbsaiillnctioetesrylpaelttceihttoarentonsnseislcisnecfottorhrriomsanciaccsiunrtafarocasrynem.srafvteiifrcnoe'naaatdSyoaMihitamtivasoeknecsrusetnsooumletresd. iinnffoorrmmaattiioonn ionbtatihneedMSOfrSonavaaildaabtlaebadsierescytlynotfrobme 3as.current as tn:e 418-028:PAGE D-38 ATTACHMENT 3 TEST SUBSTANCE PREPARATION PROCEDURE 418-028:PAGE D-39 ATATAGCHHMENT 3 Version: a1g7T2000 418.028 TEST SUBSTANCE PREPARATION PROCEDURE rsp) VeTheisctlSeu:bstance: AT-q7u7e0o6us 0.5% CMC (medium viscosity) A. Purpose: TdRheoesseapagurercpshousSsetpoeufndsytihnoiunsmspbroeforcTe4-d17u87r-0e062fi8os.trooprraolv(igdaevaagmee)tahdomdifnoisrttrhaetiporneptoarraattisoonnoAfrgus B. General Information: 1. sAnpluelmcsbiuefsryp,tehnceosnipcorenonttcorocanottliaoninun,emrdbseorswi,altlgeebsetlselvuaeblb,seltpeardnepcaaenrdaitdcieonoltnoifrdi-actcaeot,dieoendx,.pAiErraagctuihsonlbadabtaectlhewill and storage conditions. 2. --SuspeDnaslyiownilslbeXpr_epareWde:ekly _For_doafuysse Approximately every ten days __ BySponsor 3. Suspensions wil be administered ata final dosage volumeof10. mL/kg. 4. Safety: X_ Glshoiveledss.,uniformfiabcoat,gogglesorsafetyglasseswith side X-- _ _ HDaFuulslftk---FFmaaiccseetRReHesEsppPiiArraafttiootrre/rIPefodnsoiMttiauvssekePdreisnsaucreheHmoiocadl fume hood TyvekSultortyvek apron and sleeves 5. --DosageYessuspensions adjustXe_d fNo5or% A(ciCvitay/lPucrtuyboalrCsaoerdtreoicntoi1o0nn0Fs%ac)ior: Activity _%Pury _ Commection Factor 6. Sampling requirements: Cited in protocol 7. Storage: Cited in protocol -- -- ------ ET -- 418-028:PAGE D40 Le ATTACHMENTS Y Version: 41Pr8o.to0c2nM84A1(0R.1002920) TEST SUBSTANCE PREPARATION PROCEDURE Page2of2 NOTE: Pri to o ter st substance preparation accurately measure the required amouofnthte forcalibration appropriate vehicle (R.O. purposes) in a graduated deionized water should be cylinder,pourthe required used amountofvehicle into a beaker. Carefully mark eachbeakeratthe meniscus. This mark will be used duringthe preparation to bring the test substance slurry up to volume. C. Dosage Suspension Preparation: 1. Weigh the required amount of test substance on a piece of weighpaperor into an appropriately sized mortar (see PREPARATION CALCULATIONS). 2. If weigh paper is used, transfer the testsubstanceto an appropriately sized mortar. If necessary, grind the test substance into a fine powder. Slowly add a small amoofuven hict le and grind. Contintuoe add vehicle slowly and grind the vehicle and the test substance togethetor form a fine slurry. Transferthe vehicle/test substance slumy to a marked beaker. ' 3. rReimnaslentihneg mteosrttasrubasntdanpcees.tleTrwaintshfaedrdirtiinosneatlovebheiackleert.o remove any 4. oAnddmaagdndiettiiocnasltivrephaictleeatnodthaegbiteaatkeeprrtioor btroianngdvodluruimneg uspatmopltihneg,maalrlkq.uoPtltiancge and/or administration. witen sy. HiJ dfl0Berus]ss 5. Repeat steps (1) through (4) for each concentration. ApA proved h Date: 26 prnoz Clarification: ro -- Yes [see attached clarification form] niieUDate: CQ 7/51)03 418-028:PAGE D-41 ATTACHMENT 4 TISSUES TO BE WEIGHED, RETAINED AND EXAMINED HISTOLOGICALLY 418-028:PAGE D-43 Aacamrs ProcPeagaen2n03a Histological Examination: Hfiosrttohleoagsisciaglenexdatmeinnartaitsopneorfsreextafirnoedmttihsseuceosn,tirnocllaundidnhgirgehpdroodsuacgteigvreoourpgsaansn,dwfirlolbmetchoen.ducted {ecFssoIuntgceseeusnnbetwsrritaalattlniiobconene.aperuSxcphaosomb(iuslenlirvedevdrrefesds)ouiflmnrttsowhmhaeetrshrreaaetcnsotenetcxdrpxooatslmeeaidnnotdrtoathtosihnpgoehehdfiosgsheheaxtlgeeeoxsptwgsoreousrubedpsost.tafonIgcfheelecgeorsnoiocwouenpnestsrwaatsetritiobcsnu,etotebhdreteesmostasshmee quntitiveevaluation, scheduledreportdateand priceswillbe dus soompi cTpcohnedorupcrotiseptdmafocooioloroiFfcnrolallageceotpdtnvoaeapterriuiaylotssaniah.toioHnoulinlsi.tdmoaAcpolaqntutbaaniotlsnio;ptgairthaieilvmueeemexvdabamleiaunartadoitofginornootmsfwa,ipynorvgdmaerootreldcietsqsuaoallsliiawcieevsle 3dtetfphraegseof the isnarcmolpvulidneegseinzouemiwelirlastl,iboenosrotafctoitsmhtpieacmarluilmsybosnepspoofrofopvrpirrsiemeosfroodrfiartlaheflovlalsiliculgaenst,eiwdohtniporcoehcicaeaandsnduberceentcsdooremsdsbo.inEtnxeosdmpnmmiaasnnadcscosnaeclotuiron Stiopio Instructions: Tissues10beexaminedhistologically willbeshipped (ambientconditions)to: PVrointcriapaalryIPnavetshtoilgoagori:stW.RayBrows, D.V.M.PhD,ACVP R4e3s8eEa. BcuhtPlaebroAlvogeynSeervice,nc. NTeelweBprhiotnaei:n, P2e1nn5a)y3l4v5a-i7a07108501 TEemlaeiflo.r: (2W1R5B)RP3S4@5e4o3n2o6caticaet "Therecipient willbemoteinadvacceofsep shipment. ` 418-028:PAGE D-44 905Sal Dt, igA STodkn1p(21hu5)4ot34n71e0 Toofax 215)43.8587 ARGU~ S RES~ EARCH CharlesRiver Laboratories Discovery andDevelopmentServices PROTOCOL 418-028 ORAOLF(TG-A77V0A6WGEI)TCHOTMHBEINREEPDRROEDPUECATTIEODND/ODSEEVTEOLXOIPCMIETNYTSATLUDY TOXICITY SCREENINGTEST SPONSOR'S STUDYNUMBER:T-7706.1 -_-- Amendment 1 -17April2002 000 1+ Detaled ClinicalObservations - MalesndFenaloRats page 10oftheprotocol): r[eBcfofrecdteidvfeoDratmea:le1aApnrdfielm2a0l0e2]rDaesatsasiilgendecdltinoitcoaxliocboskeirnveattiicosnasmwpillilnngo,tbe ReaforsChoangne: Tohbissecrvhaatinognswwaislmbaedaevabielcaabulesefrsuofmftihcieernttdsaatssifogrneevdatluatthiemonaoifndsettuaidlye.dclinical # Ee Consumption Values-MaleRats andFemaleRats(age 1 oftheprotocol: [EtfafbeulcattievdefDoartmea:le1Aapnrdiflem2a0l0e2r]atFseesdgaedto ttion ovaolunesswilslamnpoltibnegr. ecordoerd ReaforsChoangne: `Twhililsbcehaavnagislawblaesfmraodmetbheecraautssaesssufifginceidetnotdtahteamfaoirnesvtauhduayt.ion offeed consumption Any revisions madetothisfinalized amendment`mustbe madebysubsequent amendment. 418-028:PAGE D-45 . 3 trons Couingan Mating(pogo 12ofthoproto: Pro"cAorlc1=8a.t0Ha2|8 a(esxBtirfoobcussicevyrecvDleidaintgnwaie1lAmlepbaoerelvoa2fl0tu0hae2t)evdFagodiurartaihlnecgrotinhtsoecnsothisaagbnnidetoartitaoconopipeurcliaootdokurniyplnhpeytpiecsoampling p `Observedinsity, butnotduringthedosageperiod,prior to cohabitor. BesforsChoangne: wTihlilbcshaanvgaielwbalesfmoamdotbhecaausseaseusfgfinceidefntodtahtaofmoaresvaslyua.tion of estrouscycling 4 ScheduledSacrifice -Toxicokinatic Study (page 16oftheprotocol): Ju[tEeffewcitilvlebDartce:on5dAopdr.iCla2r0c0a2s]eTshwielnlubmebdeirsocfaridmepdlwainttahtoiuotnfsiattessanrdcioreporra.. RessonofGrange: {Tohxiicsicthyaonfgtshewtaesmtasdubesitnanacnediearrepgrooavaitdetmsa.rsinformation aboutpossible 5. S[rcEcehfocefonedrdcdusteldide,v,derDSaaatchcreir:ft2ihc7aenM-taMhraecimhnmS2bt0eu0rd2)yo(fTphaepglmea1un6tbaoetfitoohnfespiirtoemstospcaodllc)a:onrpstoea.stwciilaolrbnso be RosofsChoangne: Thraepniudmrabteearnodfcarorpoortacoiucnatweidollnottudbeesreactoredaetdbiencga:use corporate regres at 6. ScheduledSacrifice(page19ofth protocol: b(EeoffcdoetlchlteeiocvtreegDdaaentxewc:ei4siegAdhparrniedlc2otr0hde0oe2dr),gTraahntewheelriighvaehnrtfrrtehocmoervadeecrdhf.soelmecetaecdphesplwoitllsbpeeexcgiased `Anyrevisionsmadetothsfiaalzed amendment mustbemadebysubsequentamendment, . a ---------- 418-028PAGE D-46 . [-- RenfrtChoangne: ed Thi changecriesthprotocolbyremoving anextraneouswerd, DAirlect.o oHfRoesebarechrPAmD,iDzAB,T De AssociateDGi.rYeocrk10,DABT Due Study Director 1 M2T0e0Uehse,CH.ooesWniontorsediossn[ esADnVismMa.S Cae P Dute. SJtoBudFyMuLoni.ttortBncFdiLDob,DlAoRaT,GfhaDl. SpontorsRepresenative Anyrevions made toti nls amendment mstbemdeby sbssquent sendin, - er ------------ 418-028:PAGE D-47 90S5.oc Ostg. A TeTleepfhoocne(:2(1251)54)344835887710 ~~ ARGUS RESEARCH `DC iah sndDRca eivveoelr roLpvaml beonertaSe terrovris iyceess PROTOCOL 418-028 ORA`LOF(TG-A7V70A6GWE)ITCHOTMHBEINREEDPRROEDPUECATTIEODND/ODSEEVTEOLXOIPCMIETNYTSATLUDY `TOXICITY SCREENING TEST SPONSOR'S STUDYNUMBER: T-7706.1 Amendmen2t- 15 July 2002 -_-- 1. SathfeeptryoPtorceocla)u:tions(page 3of theprotocolandAttachment 3page 1of [gElfofveecst,iavpepDraoptrei:at2e9eAyperpirlot2e0c0t2i]onAahnadlfafuancifroersmyp/ilraabtcoorwaitldlubreiwngofronrimunlaadtdiiotnionto preparationofthe bulk test substance. `RefaorCshaongne: ``TwhiitshcinhatnhegeMawtaersimaladSaefteotymDaattcahtShheebetu.lktestsubstancetextwith thetextlocated 2. StudySchedule (Attachment 1 page2ofthe protocol): [eEvfafleucattiivoenDshataev:eb2e9enAperxitle2n0d0e2d)toTfhoeurdadtaeysfso(r0F6 OMBAYan0d2mo-t0o9rMaActYivi0t2y )rather thantwodays (06MAY02 -07MAY02). Any revisions to this finalized amendment mustbe made by subsequent amendment. 418-028:PAGE D-48 rTonecs= Rhie schaafnos greCho waansgnoe:tebsemore ied to eval ils 10 FOB andmotor activity evaluations. Eat Mfbofeman i PLD. DAST Duis.Rfiont0.. Soro)oR iam re Ret fevaslingd bc x sinigins BGoanddial7anufsoe. #MUee|HC.oWhmooidaoernd,ArDYo.M.,Car DateSJoS ohnnoBsuy RoterpePeh.naD,thDABoT,fCIHfDa,te Rayrvitons hl lcd medicamabemadebysubsguntsendin ' ` 305Shes rh,Bi 4 JToelrepahomne: (215) #438710 Tofex: ahs 438587 418-028:PAGE D-49 ARGUS RESEARCH Charles River Laboratories Discovery and Development Services PROTOCOL418-028 ORAOLF(TG-A7V70A6GWEI)TCHOTMHBEINREEDPRROEDPUECATTIEODND/ODSEEVETLOXOIPCMIETNYTSATLUDY "TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7706.1 Amendmen3t - 17July 2002 _-- 8 ------mmm Shivving Instsructions, Stalin, `Study,and ScheduledSacrifice, protocol) (page4s, 5, 12, 13, 16 and 19, respectiovfetlhye a[nEaflfyescitsisvheiDpapteed:t2o9LiMsaayCl2e00m2e]naStam3pMlEensvfiorropnermfelnutoarloTheexcahnncosluolfgoynaantdeS(aPfFetHyS) SCelrevmiceensawnildlhbaevreensohtiypeptebdeaenndsrheimpapiendi,nwgislalmbpelsehsi,ptpheadttwoe:retobeshippedtoLisa John Flzherty, Ph.D. (Principal Investigator) Exygen Research 3058 Research Drive: State College, Pennsylvania 16801 Telephone: (814) 272-1039, ext. 122 Telefax: (814) 231-1580 `Email: john.flaherty@exygen.com Any revisionstothis finalized amendment must be made by subsequent amendment. 418-028:PAGE D-50 Hoofia=si] LL ------ Bulk testsubstancesampling(page 4oftheprotocol) Concentrationand homogeneity (page $of theprotocol) Pi`aaSmvaPtlo(apa eargebcSsroi aafitslhstsei,pi preotlotthogcsoy aglxg)ues1c21rsdi1s126aponnidrnpsaegwpe1or6soasfthe protce) PPFooollleed pttpallssveruecsxkioiannntssamlpplss(Gpaaaggges113 5aonad t1 o6efothprrfoln) Pp vr coin ples(ae 19 of rowan) ATahsietamyraeeepUsancwttililovrboxesysuebsnRnedesteearrt wEsixcyogoreinnnbgytheiShaepoSdnssvorsidpnhaenteQeuayTt roofdhtfs ly. Such sl hse peck pars dma ports `dwaitlelbofestuhbemiintstpeecdtbiyontshaatnfdacrielpiotyrttsoutbhmeiSstsuidoynsDwiirlecltboeri,nRcaorypmoorantdeGd.inYtoorakQ.TAhUe F5ro038. statementgencratedbyExygenResearchforinclusioninthefinalreportfor ReaforsChoangne: Tchoimspclheangheewoas mdiest thetryequwt oifthhe Spoenssor bwecaguse Motsl JoliDirectorofRessPAD.DASTeDaate KyiAeEDYilovk7oef4Dr.fGoesp rnusee SyDito BlotQl sll GB e il 0czon +Minise,|HCI.oWomoomdiaesrsd,oAniiD.mVa.Mol. Cnas Date SSJpoahenyaBrosu oRet nprne sPsmh.an Di.v,h DeABoT,f CIf HDa, te Any revisions 0 isfianlesrendment mastbe madeby subsequent amendment 418-028:PAGE D-51 205 SveesSg A Ie e710 Teac 215) 1433587 ARGUSRESEARCH DiscoreC ry anhd DRa ievver reLalbl oorpaSe mteorevris niceetss PROTOCOL 418-028 `ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITHTHE REPRODUCTION/DEVELOPMENTAL "TOXICITYSCREENING TEST `SPONSOR'S STUDY NUMBER: T-7706.1 _-- `Ame4n-d 20mMae rchn20t 03 oamleTest Sabstance SamalSmpling, Shippi5ng Insti ructioins ons Shi . p`rSotutdoyc,oalnadnScdi hpAemdauenlneddmSeancrti3f,ice",m(pa1g;eBsu4l,k5T,es1t2S,Se1u3cb,stt1as6nacnedS1a9m,prleisnpge,.cSthivieoplpylinofgthe. ScheduledSacrifice -ToxicokineticStudy, andScheduledSacrifice(page 1of Amendmen3t) [Effective Date: 27 February 2003] `TheanalysesperformedbyExygenResearch `will be doneaccordingto ExygenMethod ExM-023-071Revision1,entitled "Method ofAnalysisforthe Determinationof Perfluorobexancsulfonate(PFHS), Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serumand Urine Revision 1". Anyrevisions tothis finalizedamendmentmustbemade by subsequentamendment. . ReaforsChoangne: 418-028:PAGE D-52 Proto"cAomlca4d1m8e.n0t2s8 as Thischangewas madeatthe equestofthe Exygen Researchin ordertoclarify the methodofanalysis. Alan M. Hoberman, Ph.D., DABT Directorff Research Date G. Yo ASstsoidcyiDaitreectDisor .D., DABT Date NE . Learn, Ph.D. = Chair, Institutional Animal Care and Use Committee phnEBS 30 pane John Butenhoff, Ph.D., DABT, CIH Date `Study Monitor and Sponsor's Representative Anyrevisions tothisfinalizedamendmentmustbemadebysubsequentamendment. APPENDIX E DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 418-028: PAGE E-1 DEVIATIONS FPRROOMCETDHUERPERSOOTFOTCHOEL ATENSDTTINHGEFSATCAINLDIATRYD OPERATING 1. The following rats were not fasted overnight prior to necropsy. | eprom|n|e so | Group| (mefkgiday) | Necrops | Rat Numbers [oo I" SE me Le 1904T75,00199,05129,01169,05159,03169,06119,04139.071 [2OMAYO2| Female [28MAYO2| Female | |o " o o0i8.r 19037 ]| [Tv[5 [29MMaAYv0e2| Fremealee|mms1901i3,1o 9029s,190i80 on| [ MAY02 | Female| 19030,19063.19060 | IC BE le19049, 19059, 19070 Tbheicsaudseevisautfifoicnidenitddnaottaawdevreresaevlayialfafbelcetttoheevoaluaute ttohirsicpnatreoarmpreetmtearteiaonndofthtehreewsetruedyno. indications of toxicity in clinical chemistry parameters for the female rats. 2. Posidosage observations following dates. were performed outof the range of 60 + 10 minutes on the [om gh | pe oii somes]= tm Dosage `RangeofTime Deviated [ro [Pomme + [ogqoNeeT------ FT . TT vee | 71u-- g -- Lv IT TowweTT 7 | `bTehceasuesdeetvhieateixotnesntdiodftnhoetdaedvvieartsieolnywaaffselcetstshtehoauntc1o0mmeinourtienst.erpretation of the study 3. Orencdoradye3d9foorfosnteudmyal(eDSrat39i)n (t9heM0a.y3 m2g0/0k2g),/daapyosdtodsoasgaeggercoluipni(c1al91o5b3s)e.rvTahtiisondewvaisatniootn ddaitdanwoteraedvaevrasiellayblaeffteocetvtahleuaotuettchoimsepaorraimnetteerrp.retationofthe study because sufficient 4. 3OnmDg/Sk4g/4da(y14doMsaayge20g0r2o)u,pd(o1s9a15g6e)v.olTuhmisewdeavsiantoitornedciodrdneotd afdovreornseelmyaalfefecratttihen.the eovuatlcuoatmeetohrisinptaerrapmreettearti.on of the study because sufficient data were available to 418-028: PAGEE-2 5. OnontDreSco4r6d(e1d6foMratywo20m0a2l)e,rpaotsstidnotshaege0cmlgi/nikcga/ldoabysdeorsvagaetigaroonudsp d(o1s9a1g6e1vaonldum1e91s6w7e).re bTehceasuesdeesvuifaftiicoinesntdiddatnaowteardevearvsaeillyabalfefetcotetvhaeluoauttectohmisepoarrianmteetreprr.etationofthe study 6. Detailed clinical observations were not recorded weekly for the following rats. Dosage [I CI-- T0 --TOOMMAAYY02 ||FeFemmaalel| e|o 1902o 3, io0ar. 190] 50 | [or [ CVV T 3 00 TToOMMAAYY0R| | Female | Female | To0s6.19002 io020.1900 | b`Tehceasuesdeesvuifaftiicoinesntddiadtnaotweardevearvsaeillyabalfefetcotetvhaeluoauttectohmisepoarrianmteetreprr.etation of the study 7. wOenreDpSla1c3ed(i1n3tAopcroihla2b0i0t2at)i,ofne.edTlheifst dveavliuaetsiwonerdeidnontotraedvceroserflodyarefafldelctatthsbeefoourtecotmheeyor pinatrearmperteetra.tion of the study because sufficient data were available to evaluate this 8. rOenspdeacytisve1lay)n,do2noefpluapcinttahte(i0DoLmgsn/g1a/dnady2d)os(a1g0eMgaryo2u0p0(l2iattnerd191015M0a)ywa2s00r2e,corded as dhiadvinnogt aandvaedrvseerlsyeacflfiencitcatlheobosuetrcvoamtieoonrwiinttheoruptretthaetisoenoxfbtehinegsrteucdoyrdbeedc.auTsheissudffeivciiaetniton data were available to evaluate this parameter. 9. OntnDreLco3rd(e1d2aMsahya2v0i0n2g)b,eoenneolbisteerrveidn.thAell10pmugp/skagp/pdeaayrdeodsnaogremgarloounpD(L1490.22T)hiwsas sduefvfiiactiieonnt ddiadtanwoteraedvaevrasiellayblaeffteoctevtahleuaotuetcthoimsepaorraimnetteerrp.retation of the study because 10. 0O.n3DmLg/5kg(/1d2aMyadoys2a0g0e2g)r,omuapte(r1n9a0l18o)b.seMrvaatteironnalwabsehnaovtiorrecoonrdDeLdf8orwoansenroartmainlthfoer this braetc.auTsheissudfefviicaiteinotnddaitda nwoetreadavvearislealbyleaftfoeectvatlhueatoeutthciosmpearoarmientteerr.pretationofthe study 11. dOante1o9fMmaatyi2n0g02in,tthhee0frmogz/ekngli/vdearysdaomspalgeefogrroounpe(f1e9m0a7l7e) wraatswilotshtabenfoonr-ecosnafmiprlmeed ssthuidpymebnetc.auTsheissudfefviicaitenitondadtiadwneorteadavvearilsaebllyeatfofeecvtaltuheatoeutthciosmpearoarmeitnetrer.pretation of the 418-028: PAGE E-3 12. gOrnouDpL(p2u2p(931inMlaiytie2r010920)2t4h)ewlaisvernowteriegchotrdoefdo.neThpiuspdienvitahteio|nmdgi/dkngo/tdaaydvdeorssaegley affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. All deviations are documented in the raw data. 2 0 Uh NO--3tauc2001. RayKibnd G. Coif. haa Date Associate Director of-Resef Study Director APPENDIX F CERTIFICATE OF ANALYSIS 418-028:PAGE F-1 Certificate of Analysis `NominalProduct; Potassium perfluorohexanesulfonte: C1350; K(* `ProductCode: PFHS; 127498-50 April 15, 2002 "Tom Kestaer and Joel Miller aTTnhhaeelsyoasvemesrpaallrleeoqsfuuaml1im2ta7ar4tii9vz8e-ea8dn0bdPeqlFuoHawnStiiwntaaTtsAivaBenLacElo-ymz1peodsiutsiionngalLCreMsSul,tsFth-atNwMerReadnedri'veHd-fNrMoRm tahnealsyescisotemcbhinnieqdues. `Sample:T1A27B49L8.E80: PFHS Overall QuantitativeCompositional Results b "*F-NMR, and 'H-NMR Analyses T n --TFe--ao--re mi m--e ||w mwaem ] FrSae aletialmeamurements, ee xcludinganywater) _ | [o we u [Se amoCR.SO K loomers | e toioxoapomy) | L_ LTra_ ce moS us oo f term asio gedcfomK petn v| ere so sSw odnlo mmpeurits Paget FleReferee: Colp_PFHS_127498.80d0c 418-028 PAGE F-2 3M SPECIALTYMATERIALS MANUFACTURING DIVISION ANALYTICAL LABORATORY In From: DanHakes -(3.2392) ~ EHSR -Auto &ChemGroup ~ 236-1B-10 RoNgo,uGIDe:328s37 TomKester- (5633) -SMMDAnalyticalLab.236.2B.11 Sublet; Dae ChemicalCharacterization Apil1s,2002 of PFS(12749880)by "H-NMR & PF-NMRSpectroscopy _ S+AM12P7L45E8DEaS1CERISPTmIONy; GongsMoor nd bev ilogin sing Nominalproduct=Cof-S0,"KTM)(white powder). p"rOTohBidJsusEcaCtmTapInldVetEwo:achsasruabcjteecrtiezdetao m"aHn-yNiMmRpaunridty*cFom:pNoMnResnptesct1rsaploasnsailbylse.estJooed)eMtielrlmeirnaesthoepeprufroriyoftsheenLomgienal analysisandhisresultswer reported youpreviously. thEAepXonPrttEhieRosnIoolMfuEttNiheoTnsAwaaLmsp:lsepi(k4ed0w0imtgh) wmaasltoltaamlloyudnitosof1l,e4d-biinsd(eiuftleuroartoedmedtihmyetbhyelnezuelnfoex(iHdeE(XD)MSfoOr-NdA)Ra.nd Ta3hn2ae5l3yps7i.sG.-1ADw.44aH00s01u)MFwehedrzeXasaHac-q'uNi1Mr/RedFsa-tpNercMotRormcurmtoe(sm+sphei3rn2ae5tg3ur7ra.iGuoIsnDi.snAtgDaaInV)daaarrniddaton Up3eN7rT6mTiMYtitplhsucsPr4Fo0s-0sNcFMoTRr-selNpaoMtsRorsnpuoefctt(r4aometer. relative 'Hand PFsignalitensiticsfor valuationoftheoveal samplecompotion. RESULTS: Tnh[oemMiCcno]amlwbiaisnsoemadeNrsiMpsRrous1dpucmebtcemeiKxtdd.ursTer,iaCcnoeFd-olinercv-eelSshoOef?spnMropUb,abwlohefeal1ri2ep1h`an5t'8wi8cah0symdcaroionnscilasyrtboanioofmdpawurhiiegtryspcatorhtemmypeftooarsmctaotwfietorene alsocbsaendrquvanteifided. ``bTeh0eesnpiqnurateleisgteraattitivineoetnnhnedsalqayumsapinlsiaearwieavsseuicmgomnmaoprroieszdifetdriiocnnaalTlcrAuelBasLtuiElo-tn1tphouarntpwtoheseersef.doelTrlhioevweirdneglfpaoatigmveetw.heeAisngihyntwgplaeetrreioatlha'tcrHo/anePya-hnNatMvtieRo.ns bsoehfoontwehneedireundniTidnAeaBnntLiEoff:ifersdtihmoopuaulsrdsibitegyvncoeorrmyqpuocanlnoetsnitfsyotwthehereurnaarlsesssopdieegctnteeivcdetiaembdpsironilttuhiteeewN,eMigRhstppeecrtrcae,nbtvuatlaudeist.iTornaaclewomrok waould C`oqpueisetsionosfatbhoeuNtMthResserpeescuilrtas,reaiaf acyfuwtihtehrtwhoerpakp1esrnceeodpeydo,fptlheisreIepermtefokrynoouwr.reference. Ifouhavesay Tom Keser RGdooacdebgtieteMeorre: tr 357.00) Peeters 418-028:PAGE F-3 [e-- e [ w r eme oemmer e--ma -- c --m w e H-- w m ES g -- ) ww] wmeeT s e--] SEes tn IdentifiedComponents * F/'H-NMR Relative Wt%Concentrations oman i APPENDIX G ANALYTICAL AND BIOANALYTICAL REPORT 418-028:PAGE G-1 ANALYTICALPHASE Oral (GavaRgeep)rCoodmubctiinoend/DReevSpeeTlaotUpemDdeYDntoTasleITTTooxLxiiEcciittyySScretenoiufngT-Tde7s7ty06 with the `OECD PriUn.cSi.plFesooodnDaGnoAdoDTdrLAuagRbAoEdrmaQitUonrIiysRPtrEracMattEiciNe2o.T1nESCNFVR/MPCa/rtCH5E8,M(98)17, MHWGoodLaboratoryPraNcutimcbeeSrta2n1d,aMradrfcohrS2a6f,e1t9yS9t7udies onDrugsOrdinance STRUaDymYoDnIdRG.EYCoTrOk R ANAL REJPuY lOy R21TT ,C20O0MI 3PLEC TIOA N DAL TE PERFOREMxIygNeGnLReAseBaOrcRhATORY St3at0e5C8oRlelesgeea,rcPhADr1i6v8e01 Phone: 814-272-1039 TESTArIgNusGFReAsCeaIrLchITY 90H5oSrshheaemh,y DPrAive1,90B4u4i-ld1i2n9g7A Phone: 215-443-8710 3SMTCUorDpoYraStPe OToNxiScOolRogy St.`PBauuill,diMngN22550124.4-012000 SponsPorort'oscSoltPuNRduyOmNJbueEmrCb:eT4r1:8T--0727806.1 `Exygen Study Number: 023-072 Total Pages: 153 Exygen41St8u-d0y2N8o::PA02G3E.0G7-22 D Te TI A by Exygen Research, Exgyen Toxicity Study Study Number 023-072, of T-7706 with entitled "Oral (Gavage) Combined Repeated theReproduction/Developmental `ToxicityS Dose Test," conducted for 3M Corporate Toxicology, FoodandDrugAdministration GoodLabor was performed in creening compliance with U.S. `OECD Principles on Good Laboratory atoryPracticeRegulations21CFRPart58, Practice. ENV/MC/CHEM(98)17 and MHW Good Laboratory Practice StandardsforSafetyStudieson DrugsOrdinance Number21 JProihnnciFplaalheIrnvteystigator [Exygen Research Ra} |G. York St r Argus Research gi Felon L. Kilt John Butenhoff Study Monitor 3M Corporate Toxicology 2s Date 2Jue 2003 Date: 28 pr zoo Date = ExygenResearch Page20f 153 Boyan41S8-y02N8o:wPA0G2E30G7-23 QUALITYASSURANCESTATEMENT Exygen Research's Quality Assurance Unit reviewed Exygen entitled, "Oral (Gavage) Combined Repeated Dose Toxic Study Number023-072, Reproduction/Developmental Toxicity Screening ity Study of T-7706 withthe Test". All reviewed phases were intsehpereeScrtteuepddoyfrtPoerrodttcooocnotdlhu,ceatEnaxdcyacglolerandpiPpnrlgiitnccaoibplEaexlGyIognoevdnesRLteaisgbeaotarorarctaohr'nysdPSrMtaaacnntdiaacgreedSmOtepannedrtaeartndisdn.tgPoArltolhfceiednSudtriuendsgy,s Director. LPR 2. Extraction, EE Fortification FialteAril T mao ma Due nz 09/24/02 DE Duclos DateReportetdoDateReportedto netie nom umm arom 121/02 12/18/02 01/20/03 mOBION Gam mes ovens omms ones ome ome 2 Lydje Assurance Audi gaffes Date Beppe Resear Pago3eriss Exygen41St8u-d0y2N8o:.PA0G23E.0G742 CERTIFI OFC AUA THT ENI TIO CIN TY `This report, for Exygen Study the raw dataforthe study. Number 023-072, is a true andcomplete representation of `Submitted by: Exygen Research 3058 Research Drive State College, PA 16801 (814) 272-1039 Principal Investigator, Exygen: i 4 V) ls Viochen FPrleashiedretnyt Exygen Research 24s Date Exygen Research Facility Management: thoi Richard President Exygen Research Hut -03 Date `Study Digpctor, Argus Research: Hy . York: Director of Re Argus Research <y ut ses Date Study Monitor, 3M: Rl 2. Bilater ff John Butenhoff 3M Corporate Toxicology 28 TUL 2003 Date Exygen Research Pagedof 153 418-028:PAGE G-5 Exygen Study No.: 023.072 Oral (GavagRee)prCoodmucbtiinoend/DReevpeelaotpemdenDtoasleTToaxrixciciittyySSctruedeynoinfgTT-e7s7t06 with the PROTOCOL NUMBER: 418-028 SPONSOR'S STUDY NUMBER: T-7706.1 EXYGENSTUDY NUMBER: 023-072 TYPE OF STUDY: Residue SAMPLE MATRIX: TEST SUBSTANCE: SPONSOR: STUDY DIRECTOR: `TESTING FACILITY: Rat Liver, Serum, and Plasma Perfluorohexencsulfonate (PFHS) 3BuMilCdoirnpgo2r2at0e-2To6x0i2cology St.Paul,MN 55144-1000 RAragyumsoRnedseGa.rcYhork H9o0r5sShhaeme,hPyADri1v9e0,44B-ui1l2d9i7ng A A9r05guSshReeesheyaDrrcihve, Building A Horsham, PA 19044-1297 STUDY MONITOR: J3oMhnCoBruptoernahtoeffToxicology SBtu.iPladuiln,gM22N0525-10424-1000 PERFORMING LABORATORY: 3E0x5y8geRnesReeasrecahrcDhrive State College, PA 16801 TIAMNEATLYATBILCEA:L PHASE SAntauldyytiIcnaitliaSttiaornt DDaattee:: 0093/71266//0022 AAnnaallyyttiiccaall TReenpmoirntaCtoimopnlDeattieo:n Date: 0171//2113//0032 Exygen Research Page Sof 153 418-028:PAGE G-6 Exygen Study No.: 023.072 PROJECTPERSONNEL Tfsohtleuldoyw:SitnugdypDeirrseocntnoerlffroormthEixsypgreojneRcetswcaasrcRhawyemroenasdsGo.ciaYtoerdkwaitthAvragruiosuRsepsheaasrecsho.ftThhee Name John Flaherty Karen Risha Paul Connolly Xiaoming Zhu Lawrence Ord Rickey Kelley Amy Sheehan Emily Decker Mark Necley Title Vice President Scieatist `Technical Lead-LC/MS Technician Sample Custodian Sample Custodian Technician Scieatist Scientist ExygenResearch PageGof 153 418-028:PAGE G-7 Exygen Study No.: 023-072 TAOFB CONL TENE TS TGQIUOTAOLLDEIPLTAYAGBAE.OS.RS.AUTROANRCYEPRSATCATITCEEMCEONMPTL.IANcCE.ScTvATrEsMsEeNT..Pa.ge CSPERTROUTJDIEYFCIITDCPEANETTRIISOFNOINCONAFTEAILOUwNT..HcE.N.T.cIccCcIocTrcYr.or.os.mcssss osmmmesmoo ssomsosees ossso sism8 TLEIAESBTLOEFOTFACBOLNETSE.N.TcSocc.o.ccm.soeescecscsosnoesmsmsmssmsssnmossoessnseeneseeonnessseeseesegge LF IST OF APPENDICES......T voccsvommmmmsmneoee1e0 3200 40 IAONNBTAJRLEOYCDTTUIICCVTAIELO.TN.Ec.ST ScAMPoLcEcSe.o.m.m.m.so.s.o.soennmeossosreosoem1s111s12 56:060.1DR.EEBSFXCUERRRCIEHPNOTCDIEPOINMOGOEAFIUTAIENEARLYITcAICLoA.LMc.E.ToHOoD..n. scover 1133 66:32 6:4 CPHrIeOpMarBaItOiGoTnEoPfhSYtao ndards and Forts ification SOIUEOs S..........................r-.INSU SESIVY eos 13 1144 7.066::56EDQXuePasncEtrRiitpIatMtiioEonoNn fTanALdLCE/DXMSESISI/IDMIGESNCaIclncsut.lrautcmieoncnt.acnd.cOp.ser.amti.sng.sCossndsitsioei nms.m.n .msns119145 T 9100.0CROENTCELNUTSIIOONNSOF.D.A.TAoAcNsD ScAcMPcLT EeSo_.s.m..m..m_.mmseoossoseooessen11ss8 .. roo 18 Exygen Research C------------------ Page 7of153 418-028:PAGE G-8 Exygen Study No: 023.072 LI OFS TABT LES Table Table Summaryof PFHS in ControlRatPlasma Sample.....................P.a3g1e Summary ofPFHS in Control Rat Serum Samples...21 Table IIL. TeblelV. Summary ofPFHS in Conirol Rat Liver Samples...21 Summaryof PFHS Fortification Recoverics in Rat Pasha...22 Table V.. Table VI. Summaryof PFHS Fortification Recoveries in Rat Ser... 22 Summary ofPFHS Fortification Recoveries in Rat Liver.............2.3. Table Table VIL VII. SummaryofPFHS SummoafPrFHyS Residues Residues in in Rat Rat Plasma Samples....................2.4. Serum Satple...................2..6 TebleIX. Table X. Summaryof PFHS Residues in Rat Liver SAmpIEs............2.8 SummaryofPFHS Residucs in Dosing SOluions....................d.o. Table XL. Table XII. Summary ofPFHS Summary ofPFHS Residues in Stability Sample...4] Residues in Homogeneity Samples...................4.2. Exygen Research rere eee eee----ee Page 8of 153 a 418-028:PAGE G-9 ExygenStudyNo: 023-072 LI OF FS IGUT RES Figure 1. Typical Calibration CUrVe fOr PFHS ..c.cocvcvonrrrmomsnenPsan4gsde Figure 2. Chromatogram Representing a 0.1 ng/mL standard for PFHS..............4.5. Figure 3. C(EhxryogmeantIoDgr0a2m0R2e9p1r3esCeonnttirnolg,aDCaotnatrSoelt:R0at91Pl6a0s2ma8S)a.m.p.le for PFHoS vr46 Figure. C(EhxryogmeantoIgD:ra0m20R2ep9r8e7seCnonttirnogl,a CDoanttarSoelt:Ra0t91S9e0r2uBm)Sc amplv e for . PFHS..47 Figure 5. (CEhxryogmeantoIDg:ra0m20R2ep8r7e7sCeonnttirnogla,CDoanttaroSletR:at10L0i2ve0r24S)amcpvlveevfoonrvPrFvHrSm,mssosoro48r Figure 6. Cwihtrhom1a0tpopgbroafmPRFepHrSes(eEnxtyinggenCoInDt:ro0l20R2a9t1P3laSspmkaAS,aDmaptlaeSFeotr:t0if9i1e6d02B).....49 Figure 7. `Cwhitrhom1a0ptopgbroafmPRFepHrSes(eEnxtyigngenCoInDt:r0ol20R2a9t8S7eSrpukmAS,amDpaltea FSoert:ti0f9ie1d902B).....50 Figure 8. Cwihtrhom1a0tpopgbroafmPRFepHrSe(sEenxtyignegnCIoDnt:ro0l20R2a8t7L7iSvepr SAa,mDpalteaFSoertt:ifi1e0d02024).....51 Figure 9. C(EhxryogmeantoIDg:ra0m20R1e8p1r6e,seSnptoinnsgoRraItDP:l1a9s1m7a6SGamRpOlUePAnIa,lDyazteadSfeotr:P0F91H6S028) .52 Figure 10. ChromatogramRepreseatingRatSerumSampleAnalyzedfor PDiFtHaS,SetD:F0=91109(0E2ZxByRg)ec n ID: 0201o 863, Sponsoo r ID: 1907r 9 GROUP s II, $3 Figure 11. C(hErxoymgaetnoIgDr:a0m2R0e2p0r5e0s,eSnptoiunsgoRraItDL:iv1e9r0S18amGpRleOAUnPalIyfzMeadlfeor1,PDFaHtaS Set: 1002028) rssicon$4 Exygen Research Page9of 153 418-028:PAGE G-10 Exygen Study No.: 023.072 Appendix A AppendiBx LIST OF APPENDICES Page ASmtuedaydmPeronttosc,olD4e1vi8a-t0i2o8n(aEnxdyNgoetneS1t0udFyIlNeo....023-072) and 35 APPneearnlftylatudioecrcaoalbfelMxueaotnrheoosoudclt:faMonnoeaittcheAo(cdPoiFdfH(ASnP)a,FlOPyAesr)ifslifnuooRrratotohceLtiaDvneecrts,ueSlrfemorinuanmtaeat(nioPdoFfUnOrSi)neand Revisio1n (ExygenMethod No. EXM-023-071 Revision 1) ..........110 Exygen Research Page 100153 418-028:PAGE G-11 Exygea Study No.: 023.072 1.0 SUMMARY ExdeytgeremninaRteisoanrcohfepxetrrfalcutoerdohaenxdanaensaullyfozneadtreat(lPiFvHeSr),saecrcuomrd,ianngdtpolEaxsymgaesnaMmeptlheosfdoErxtMh.e. 023-071 Revision 1 (Appendix B). `ppTleharesflmoiarm.mietdTofhatqeuEaLxnytOgiteQantfi(ooEnrxfyeogarecPnhFSmHtaSutidryniNrxoawt:lai02vs3ed-r0ew7ta3es)r.m1i0nnegd/igannda1m0en thodgvianlir/ daattsiem ornusmtL audnyd PPPFFFHSHSSiininntththeheerrartaalttisvpeelrrasusammmaspalsemaspmlprlaeenssgreadranfngrgeoedmdfnrforono-mmdneotnneo-cndt-eeddtetelececvtteeeldsd tlloeevv6ee7ll5ss,t0to0o021n38g79/,g,,000000nngg//mmLL.. lTihveeravsearmapgleespweercreen8tr4e%cov+er7i%e,s 9+5s%ta+nd1ardd2eavnida%t8i6o,%ns+for13P%F,rHeSspiencrtaitvpellay.sma,serum,and aPlFl HwiSthriensi7d0ue%stiont1h2e5d%oosfitnhgeisrolkuntoiownns,csotnacbeinltitryatsiaomnps.les and homogeneity samples were. 2.0 OBJECTIVE Tpherefolbuojreochteixvaencosuflftohneatae (nPFaHSl)yipntasrpiteoccifmteanhsliosfsrtautdylivwera,ssetroumdaendtpelarsmmlaeivsneamlepsleso,f abuclckortdeisntgstuobPsrtoatnocec,olco4n1c8e-n0t2r8at(ioAnppaennddhioxmAo)g.eneity formulations, and stability solutions 3.0 INTRODUCTION `sTehirsurmepoarntddeptalialssmtahersaemspulletss,ofbtuhlekantaelsytsissufbosrttanhceed,etceornmciennattraitoinonofPaFndHShionmroagetnleiivetry, Afuomrmluylsaitsions,foarnd stthaebilityDestoelrutmiionnastiuosning the of anaPleyrtficlaulormoehetxhaondeseunltfiolneadt,e "Method of (PFE), LPievrefrl,uoSreoorcutmanaensudlUforniantee.Rev(iPsFiOoSn)1.a"nd Pentadecafluorooctancic Acid (PFOA) in Rat n`Tuhmebsetrud4y18w-a02s8.iniTtihaetedanoalnytMiacarlcshta2r6t,da2t0e02w,aswhSeenpttehmebesrtu1d6y, 2di0r0e2c,toarnsdigthneedanparloyttoiccoall termdiatnewaastNoiveombenr 13, 2002. Exygen Research Page 110f153 418-028:PAGE G-12 ExygenStudyNo.: 023.072 4.0 ANALYTT ESI TSC AMA PLL ES TfBhoierotlicofogiincctaatrliosol,nsrRawotgalesirsvr,eercA(eriEkvxaeyndgsaefsnr.IozDenTh0oe2n0c2do8nr7ty7r)ouilcsereadtonfpolArautsgmhuaestm(aE7tx,ryig2xe0nb0l2IaDnfkr0so2ma0n2Pd9em1l2-aFtrareneidyx s0ie2cr0eu2om9n(13A)uEugsuesxdtf8Ioy,Drt20gh020e02me2a9ft8rrno7imx)buPlsealen-dkFsfraeoenrztdhBmieaomlroaigtixrcfiaolxrstb,ilfRaiocnagktesiroasn,nswdAamraksatrnresicaxesif.voertdTifhfreioczacetoinnotnrosonldwrraaysr rAerckeainvseads.frozen on dry ice on August 15, 2002 from Pel-Freez Biologicals, Rogers, msDeooflsiugateginoean/tsseoudlsupateitnosniE/osnxuyssagpemenpnsliefosno(EsmxamypgAleernsgIDu(sE0x2Ry0eg1se7n5e7a-Ir0Dc2h001o27n5081)7w5Me3ar0ye2re0c12e79i,5v)e2d0w0ree2rf,reigDrereoacsteeaidvgeaetd ExExyyggeennfprerosmonAnregluansdRpeselarciahnorencfrJiuegenread1te1d,st2o0r0a2ge.. Thesesamwerpe lolggee d insby iBRnuelrekfsiTieAge/oarSanrteJsdcaumsnhtpeol1rea1g,(eE.2x0y0g2e.nThIiDss02a0m1p7l5e6)wawsalsogregceediivnedbaymEbxiyegntenapteErxsyognenenlfarnodmplAragcuesd M0I2De0d01i27a08n188-l60i12v-0e01r2800l10o8)b7,e4p)(l,Eaxpsoymogaleen(dExIpyDugpe0ns2eI0r1Du7m0529(0-E10x82y00g11e-7n0827I0)D1,0826p00o1)o8,l7ep5do-o0lf2ee0tda1l9fe2tl4ai)lv,esraenr(duEmxpyu(gpEexlnyivgeIernDs (Exygen Research ID on 0J2u0n1e92158-,022000224.08)Thweesreesraemcpelievsewdefrreozelnogogneddriyn ice by aEtxEyxgyegnepnerfsroonmneAlrganuds placed in frozen storage. `Mweerdeiraenceliivveerdflroobzee(noExnydgreynicIDea0t2E0x3y6g5e0n)farnodmpAorogluesdRfeetsaelalricvheor n(ESxeypgteenmbIeDr 0121,023065012) and loggedinbyExygenpersonnelandplacedinfrozenstorage. PSreepptaermebderfo1r9m,ul2a0t0i2oannsd(ElxoygggeedniInDby02E0x3y9g2e3n-0p2e0rs3o9n6n2e)lwaenrdeprleacceeidviednffrroozzeennstforroamge3.M on S`amaplsesloogw-icitnhiathnaidstcshteauiddny.ofStcoursatgoedryecionrfdosrmwaitlliboneckaenpbtaetfEoxuyngdeinnRtehseearracwh.datapackage Exygen Research Page 120f153 418-028:PAGE G-13 Exygen StudyNo.: 023-072 5.0 REFERENCEMATERIAL Theanalytical standard PFHSwas receivedat Environmental TechnologyandServices. Exygen on January 26, 2000from 3M The availableinformation forthereferencematerial is `mawtase storrei d fraozeln. listed below. The reference PFHS SP244 SE036 `The molecular structures oftestsubsistgiaven n bc eloew: Name: PFHS Chemical Name:Perfluorohexanesulfonate Molecular Weight: 399 99.99 E FlF|F F FFF 01/01/10 6.0 DESCOR FAI NALP YTIT CAI LMEO THN OD `TheanalyticalmethodExM-023-071Revision 1 was used forthis study. 6.1. ExtractionProcedure procedureforthe aboratory controlsandfortifications. Duetoinsuffsiamcplieseizne,t A 1mLaliquotof the serumandplasmaand 1 gof liver wereusedforthe extraction 100 uL aliquotof theserumand plasmaand0.1 gof theliverwereusedfortheextraction procedureforthe study samples. After fortificatioon fappropriate samples, the serum sampleswerebroughtupto 20 mLwith Type | Waterand theliversamples were brought up 10 10 mLwithType I Water. Theserum samples were vortexedfor ~ 1`minuteand theliversamples werehomogenizedwith atissuemizerfor ~ 1 minute.Analiquotof one `milliliterwastransferredfromeach sampleand 5mL ofacetonitrilewasaddedandthe sampleswereshaken for ~20minutes. The samples werecentrifugedand the `` withs2mu Lop wfamese tdheacr naonltn .edEoaa ncthost aacmoa pnldein twiaost neadnaSPlEyzceboldyumLnC./TMhSe/nMtSheesleacmtprolsepsrwaye.reeluted Anextraction procedure wasnot necessary for thebulk testsubstance, concentration and `homogeneity formulations, and the stability solutions. 10 mg of the bulk test substance `was weighedandbrought to volume with methanolin a 100-mL volumetric flask. The ExygenResearch Page 13 of 153 418-028:PAGE G-14 ExStyudy Ngo. e023.n072 cfsouarrmmvpuelleaatnwidaosntasnhaaelnnydzdteihdleubtsyetadbLi1Cl0i/0ty0M0sS0o/ltuMitSmioenseslwweicettrrheomsapelrtalhyda.inlouTlthtedeoafcipotpnriconeptnrthiraeatrteailonyngweiaotnfhdtmhheoetmahonaagnleoynlteiaicntaiyl analyzed byLCMS/MS electrospray. 62 PrepaorfaSttanidaordns andFortification Solutions E`AxscytogoneccnkemsnetattnhrdooaadftrEdi1so0xon0lMuptg-i/omn0Lo.2fb3RyPeF-vdHiiSss0siwoo7lanv11sin.pgTr1eh0peasmrtegodocokfnestaAacunhgduasrstdatsno2dl0aur,tdi2o(0nc0ow2rareascsptserpdefepcoairrfpeiuderadiittyna proenlpya)reindbmeythtaankoiln.g methanol. F1 rmoLmothfisthsoelsuttioocnk, aan1d.0bruign/gminlgtfohrteivfioclatuimoneustpantdaord1s0o0lmutLi.own iwtahs foArti0f.i1catpigo/nmlst.anfodratridfiacnatdibon rstaindantrhdegwvaoislupnmreepugapretdo1b0y0tmaLkinwgit1h0memtLhaonfotlh, e 1.0 pg/mL vAarisoetuosfcasltiabnrdatairodnssconotainliinngtuhPeFftHoSllwioawisongpmrnaepnanrseerd:via dilutionofthe 0.1pg/mLand Total Conoer. (ug/ml) 0.011 0.005 00.000012 'of PFHS Volumse (mL) 2 1 10 1100 Dilu1t0et0do (mL) 100 110000 110000 Final Co0n.c0.05(ug/ml) 0.002 00..0000015 0.0002 0.0001 `The stock stored in standard solution arefrigerator (4 and all fortification +2C) whennot and in ucsaeli.bratDioon cstuanmdaerdnsootlfuatistotnasinwdoearrned `preperationcanbe foundintherawdataassociatedwiththisreport. 63 Chromatography tQiumaenotifficPaFtHioSn owfasPF~H8S.3wmaisn.acPceoamkplsiasbhoedvebtyhLeCL/OMQSw/eMrSeenloecttdreostpercatye.diTnhaenryeotefnttihoen `control samples corretsotpheaonanlytdereitenntigon time. 64InstrumentSensitivity Tchonecsenmtarlalteiosntofst0a.n00d0a1rdpamgouon/tfiPmnFjHeLSc.ted duringthe chromatographic runhad a Exygen Research Page 1407153 418-028PAGE G-15 Exygea StudyNo. 023.072 65DescriptionInosftrLuCm/enMtS:/MSMIincsrotmrausmseQnutaatntrdoOUpletriamtai(nMgiCcornodmiatsiso)ns Interface: Electrospray (Micromass) Computer: COMPAQ Professional Workstation AP200 Software: Windows NT, Masslynx 3.3 HPLC: HewlettHPPacQkuaartdP(uHPm)pSeries 1100 HHPP VAuatcousuammpDleegrasser HP Column Oven HPLCColum:Genesis Column Temp.: 35C C, (Jones Chromatography), 2.1 mum x 50 mm, 4 MoInbjieclteioPnhVaosle.:(1A)5:pL2.mM AmmAo cetan teinitypeuIwamter Mobile Phase (B): Methanol Ti0m0e %9A0 2500 %100 9.0 9.5 10 0 140 145 0 9 200 %0 Tons monitored: PHS Negative %1B0 %10 % 110000 1100 i, 399580 F(lomw LRai/0e3min) 0033 03 0033 0033 RaAppreoximate ~83 min. 6.6 Quantitation and Example Calculation TFhieftpeeenakmaicrreoaliwtearssmoefassuarmepdleanodrtchaelsitbarantdiaorndsctuarnvdearwdawsegreeneirnajtecetded(uisnitnog t1h/exLfCt/wMeiSg/hMtSe.d cloinnecaerntrreagtrieosnsiwoans) dbeyteMramisnseldynfxrosmotfhteweaqruautsiionngs bseilxowc.oncentrations of standards. ~The Ethqeuasttainodan|rcdalccuurlvaete(dltihneeaar mroegurnetsosifoannaplaryatmeeftoeurns)d(giennnegr/atmeLd,bbaystehdeoMnapsesalkyanrxesao)futswianrge. Exygen Research Page 15 of 153 418-028:PAGE G-16 Exygen StudyNo: 023.072 npgr/omgrLafmo.rTsehreunmEqaunadptliaosnm2ac.alculatedthe amountofanalytefound inng/gfor liverand Equation1: Analyte found (ng/mL) =(Peak area-interceptx) DF x AF `Where: ADFF ==DAilliuqtuiootnFaFcatcotorr slope AnEaqluyatteifo2onu:nd(ppb,ng/gforliverandng/mLforserum and plasma) = Where:FV =Final Voslaummpea( lnaelvyotnelfuomug en(dmL/)orm samxpL FleVw(e) milgh)t(g) cForasalmplctehseupfeolrrtciefanietdrtewcioetvhedrky.nown amounts of PFHS prior to extraction, Equation 3 Recovery(%) = (analytefound`(apmpobu)n-taadndaleydte(ipnpbc)ontrol(ppb) 100% To findthetotalanalytefoundcorrectedforthesaltconteatEquation 4 wasused. Equation 4; "TotalAnalyte FoundCorrected(ppb) =analytefound(ppb) xsaltcorrectionfactor `Wherethesaltcorrectionfactor= 0.91. AneRWxhaaetmrepl:ilveeorfsaamcpallceulEaxtyiogneunsiInDga0n20a2c8tu7a7lsSapmkplAef(oSlelt:ows1:002024), fortified at 10 ng/g pientaekrcaerpeta == aannsos sdliolpuet.ionfactor == a1 men papvbga,damdteidnc(ofnotrtrloelvsel|) == 01(0NotDetected) failniaqluovtoflaucmtoer == 210m sample weight - 10g ExygenResearch Page 1601153 418-028:PAGE G-17 `Exygen Study No.: 023-072 Fromequation 1: Analytefound (ng/mL) = [2"12i5z-41.0x316x51]0 Fromeq`uAanatliyoten f2o:und (ppb) Fromequation%3:Recovery AFnraloymteequFaotuinodnC4o: mect(oeptd) = 441 ng/mL = @alngnlx2nl) (10g) = 882ppb = (8T8o=2m0p0oh)0x 100% = 88% = 8.ppb8x0291 = 8.03ppb 7.0 EXPERIMENTALDESIGN E`ablcahnksseftorotfifsiaemdaplteksn(oliwvnecro,nsceernutmroatriopnlsa,samnad)c~o2ns0isstaemdpolefso.nEeamcahtrsiaxmpbllaenwka, tsewxotmraatcrtiexd `usingthe methodandthen analyzed induplicate. ExygenResearch Page 1701153 418-028:PAGE G-18 ExygenStudy No.: 023-072 8.0 RESULTS TMchIeLoPFrHPSefraokusentwdoeitsrnheetphnaenoatoclodynettnterreoecdttreeandttipiilonannstaimnmg,yeso.cfrSutomh,meeacnpodenltairkvoeslrswpaelrmaepsdlmeeatseaocrrteelsdiesirtnuetdmhienscTaomanpbtllreeossl l`iwveerre aslalmbpelleoswctohrereLspOoQnodifng10tpoptbh.e analyteretention time; however, thepeaks detected FiopnrltaTisfamibacl,aetssieoIrnVru-emc,VoLvaeTnrdhieelsifavevorerrsPaagFmeHppSleiersncetwnheterrreeact8ovp4el%raise+ms,7+s%se,traun9md5,aa%rnddd+elvi1iv2aet%ri,sonaasnfdomr8aP6prF%eHldS+eitean1i3rls%ea,dt respectively. `PInnoFdnHidvSeitdeuinactltherdeesrluaelvttespllsaatrosml1ia8ss9te,ad0m0ip0nlnTegas/brmlaLen.gVeIIdnLfdirvPoiFdmuHnaoSlnr-iendsteuhltteesrcaatretedsllieesrtvueedmlisnstaToma2pbl3le7es,V0raI0nL0g.edn.Pg/fFmrHLoS.m reisnultthsearraetlilsitveerdisnamTpalbelserIaXn.ged from non-detected levels to 675,000 ng/g. Individual P`cFonHcSentrreatsiiodnusc.sThinetrheesudlotssairneglsiolsutteiiodnnTsarbalnegXe.dfrom 88% to 125% of their known PFcoHncSerntersaitdiuocnss.fTohuenrdeisnultthseasrteabliisltietdyisnamTpalbelserXaIn.gedfrom91%to 122% oftheirknown PkFnHoSwrnecsoindcuenetsrfaotiuonnds.iTnhtehreeshuolmtsogareenleiitsytseaidmnpTlaebslreaXnIgIe.dfrom 70%to 11of6th%eir 90 CONCLUSIONS `PcTohFneHcreSanttalrciactvoierordn,insgaerntudoma,nhaaolnmydtopigcleaanlsemimetatyshaomdfpoErlxmeuMsl-aw0te2iro3ne-s0s,7uc1caeRnsedsvfiussltilaoybnielx1i.ttyrTahcsetobelduutlainkodtnesasntawsleuyrbzesetdanafcloesr,o sI.uccessfully analyzed for PFHS according to analytical method ExM-023-071 Revision Exygen Research ------------ Page 180f153 418-028:PAGE G-19 ExStyudyg No.:e023.a072 10.0 RETOE FDN ATAT ANI DSAO MPLN ES `sRWuehcsehenaatrschihewfniilnlasbl aentsahloyirftpitpceeuamdlptremoerptaohtereutrsiepnsloocnogtsmospr.l.EextTaeh,citsldcloooperiisgenisonotafilpnaaclllpueadrweddafatatacag,iealnseirwtaeytle-ldsabpsyeraEcasxwiiygfganiseetcnda rce3ot8pa,iyOnoeEfdCitDnhteEhfNeiVEn/xaMylCagn/eaCnlHRyetEisMce(aa9lr8rc)ehp1ao7rrc,thaainnvdedsMafloHlrWotrhiOegrpideniranilaofndacociefltiNtiuym-mesbpseepcreicf2ii1fc.irReaediwtdani2ant1ead,CsFwaiRmlPpllabetes ofreferencesubstancesarearchivedby the sponsor. Exygen Research Page 19.0153 418-028:PAGE G-20 `Exygen Study No.: 023-072 Exygen Research EE-------------- Page 200f 153 418-028:PAGE G-21 ExygenStudyNo.: 023-072 Tablel. Summaryof PFHS in Control Rat PlasmaSamples TeD me Enm E NumbT er FE oud C LOTIT 0202913 n Control 916028 ND G --_--LLOOTTIO7ES4I_2_6_ L T00h 2200225911o 32CCoonntE tmrrooll 009911A 98002244 N NNDD TableIl. Summaryof PFHS in Control Rat SerumSamples SomDer EDve NNuCmber Found Tm E361193 0202987 ContG rol 0920024 a ND 363161118933 00220022998877 CCoonnttrrooll 00992230002284 -- 36183 2o02w9w87iCconotrwosl. _lO10U11O02A4. NnDD NNDD Table III. Summary of PFHS in Control Rat Liver Samples TheDme LToOraTi2ma4s LLOOTT22188244 LLOOTT22Ei2R64 LLOOTT2208I244 LLOOTT221U824 LLOOTT212244 LLOTO2ET4 LLOOTT221E82244 EmDm 00220022887777CConomoml A 0200220807877C7oCnotnrtorlolA 00220022887777CCoonnttrrooll 00220022887777 CCoontnrotl 00220022887777CCoonnttrrooll 00220022887777CCoonutrroll 002008287777CCoonntmrooll 0022002288777)CCoonnttrrooll m NumbermFoum nd (ppb) 00992268002244 NNDD 00592276002284. 32382409000) 01902072002284 385ND(VQ) 11000013002244 ND ND 11000044002284 200N0D90) 110000990022B4R 2309150NNQQ)) 11001100002284 319855((NNQQ)) 11001114002244R A33T1O00)) NINQD ==NNoottQDueatnetcitfeids(beA(rAarlceasistgheansttheetlhoawne0s.tc1onngc/emnLt.rbautitolneosfstthheacnaLliObrQa(ti1o0nsntga/nmdLa)r)ds(0.1 ng/mL) `ExygenResearch Page21 of 153 418-028:PAGE G-22 Exygen Study No.: 023.072 Table IV. Summary of PFHS Fortification Recoveries in Rat Plasma Swmer m Enmgm TsNuember Admdeed w a 1SLIO7T6GIRTOEUAP1 020x1o00913Sa SkCB 9o196c0o2a4A e E50Y 7u LLOOTTIITZAA BoIt3SsiAB 00991166002288 5100 19I76GROUPT 20I8I6SHC 0916028 5000 8 78 LLOOTTOONS224 N29B2SAkB 00991188002244 5010 ISVI6GROUPI G0IS46SkcC 0918024 5000 88 8 LLOOTTIITMN GGaSao3iS3skiBA 00991199002244 10 50 16GROUP _ 0201831 Spc 0919024 3000 7 98% Standard DeAvvieatriaogne: 84 7 Relative Standard Deviation: ~~ 8 Table V. Summary of PFHS Fortification Recoveries in Rat Serum SoDmer 3i6i11s9s3 I3T661G1R9O3UPT I031621G1R9O3UPI 3366111199:33 I6C36R1O1U53PII IS03S6G1R1O9U3PIV 336611115933 BDow oCmT98S75AB C02001986E1 ISSPAC C0I87SISSpBC oo0s9eIsSkAB O0001E1I90SSPpkAC 00S20E15T0S5SKpkBC CC0R0S8ETTSIpSRA sNuamberA_Am dded (pm b) _r Racove-- ry 00991155002288 T5o0 92% 009921000282.4 E10d 1o06 00592200002244 550000 1%05 00992200002288 5100 707 009922300022B4R 501000 1%20 10091213002244 20050000 101 8 11001111002244 10 5 7 n Standard DeAvvieartaigoen:: 9152 Relative Standard Deviation: 12 Exygen Research Page 220f 153 Table VI. 418-028:PAGE G-23 ExygenStudy No.: 023-072 Summary of PFHS Fortification Recoveries in Rat Liver Spouis)er BDow NSumeber AAddmed gph) 1T0o7t2z1i0m2a6r TTTSISBpA o92s8a0m2aA ISEGROPT onmsKC oos2a T5o0 00 LLoorT2z1m8240 ITEGROUPL BCISKBA o09s2a60m2a0 oiTMSKC on2e2A 100 S00 LLoorta21i8a24 nTsSeA oomeenms I6GROUPI @OIESKC oasean 500 00 LoLorr2211882246 ccoomssa oommaa 1902GROUP LMue1 20I2SSpKC 027020 5100 00 wLoorT2211m8s4 n wnniS ske 19021GRLOMaUeP1 0IMSSpkC oozuss 0927028 00 s000 LLoorr22i1s8a4e cwmnsa 1SOIBGIRLOMaUleP] 0202050SpkC lloommmmsa tomar 500 S000 LLoorT22i1m8z2e4 mmsssA 190410ROUP LMue | 0016SSpkC lo000i0mAa 1001024 500 00 LLooTt2izs ocoamSSAB 1036CRI,OMUaeP1 C2200 l0o0oam 1003024 E1F0] 5000 LLoorT2218i2s4 CCTTSSA 19003GROIL,UMalPe| 0202119SKC oi0mMmaA 1004024 500 S000 1L0o7r2121882244 Cmsusa il0ooouuzzsERR ISO0RGIRLOMaUleP 02IBSKC 100i2BR 500 5000 LLoorraain UUTTEA IOISGROUPILMule] MZISDSHC 110000s00AARR 100902AR 5100 5000 LLoorr2iigeze cCxAmTnISSiBA IOSGROUPIMuVl.e! GHZZ9SHC ilooosaramk looSo2BR 100 500 LLOoTT22i1882244 aooomnsskisa 1900CRIVOMUalPe? QOBSKC 1o0m0aA I0I00AR so10 5000 LLooTrzaisin cousmSsks o10t0om 5100 1906LGoRrO2iUsPMaYl,e Gc3m0nSspikAC lIo0InOe2BrR 150000 INMOLRoOrU2P1V82,4Male2 C0uDnMSOKSBC l100lM0O2AARR 250000 LLoorr2211ma224s cuunnska 15025GROUPV, Mule_can360 pC 1i0ow4aA __io1do2aRR 010 000 Bogen Sundard DeAvviaetniogne: RelateStandurdDeviation: _Recomey 55 192%s 1n0o0 1"4 m7s 54 1500 1=0"5 3n 77% a= 7n a n an n n n9% 0" 7n %" 7 9ns 10 813 16 p00 153 Eva418S-0t2y8N:oPAsG0E23.G0-7224 Table VII. Summaryof PFHS Residues in Rat Plasma Samples E R RmmeaEslm sTGmET TE.T m BRiEvm Ees m ISEE D ooomm ammmmiaeaansssnts (S-EoEmDnSEeeD DBBBIIIINDESEE MMGSERRR aomoanmmna Om2eS mmaams W=SEhDe SBIENEE ESa oDmed = mmmaaenmmse =L--EEmDR.e BBDIEINEEE MEGRR ooommSaEr OaXEZ mmeEm LLEEED.C BBMMEE ZHEooomsm == mmEaNmiL .enmnble DHIEEE HGR oNmE = mEaEmE OmCyDeE MBEMEE SOEE =osE == mWaEsEs eompi.s EBSELE MBRE oiSEE 3 apemaeeamrmemriik mE(wwENmhEbaiDT DBBBBEIoEOANMSAMS aMMMLR2RE ooooomnSmR= O==o mmaacts mami =LEEe. SBIEMRE LED. BEE RORE OE onomm oOmE EOE mmmmeaeaemzn WGSwEERHRN EBBHEEEMRLR MmOEmmE Oo2SEnEa 2aoOmmB wmaan .WSEfN. BEEhE EEoOmE =EB HmEaTy memL. BBOERMA MGRE oSa=mm =om A AlbyEheied ndalnowci mheens allehbuems wwiegigh mnddal eekpens EvgaResear Pag 2s0r153 418-028 PAGEG-25 ExStyudyNgo.:e 023.n072 Table VII (contd). SummaryofPFS Residues in RatPlasmaSamples T r 5 E B H e Se mh ee m l npmmgooooorRn mmo cCCeoobouDsnew oGoonurnsanea omDew DARA iwmneee hm oeowmnees een 3 pmaorn Toone mime we eee mDMaOn CaooismDemm SuirrABeA 4eme owe a Se ImDReGGgOarTnn Goa Tuemwti emouunnrnaammaaa dimememe eoowmaees F-=E nn TToCwIn Taiwmae EARIATMMA fam mameews srod MDpaOCoOrOIy pwacnn oawTiieiaDseen GoGrnraaamnma Tw Guna awWme em ooeneaes owes mG aa-n - O pmaacO rye oniTkeaDseww GOooRnnRmmAiANsMAaA oun murama eeamme osoemamen mRGOrY aoe umama sasoam TmTOsmGaoOoorrTyyY GeaoimmDsew GGDaiAmrRmmAaa wwhmee ae ooowwmsea oe 3SSom im TGmmoOaoonnWts WG DTmaeeinrwd DmmuuuTrnSaeA omiDew ura peemmmo im geoueeees es pant 3nIe " EDmAoTowSn oeCTSooinnneeu DTRuuurmraeaaa vvaieees ooowmemenn -wwo Tmeegarn Teomrmta BDUUSSAK UdEm gSeEeYs io1 mPI eCOn eoumDoe DROHWrUAeEoNniiSviEew So oEeRs is=e mann emi BUSA LE SEM a OHmoTCoTOr noTudoiDuema MuTMRrRASaMA ioudmEs ooa wweesn iiimoo mena emi TRUS GE mh 2m G DuucdtG oOrryY pwaony aoruoiooDDeeww oTRuWumRnAaaMasAa Toon Dunas vsvuemems es oooesos oes poorevmt oo RiDmooOotwoYryy GaeaemonuiDseewN mTToouWuvnriAaeBmsAa uuviumsm eoowmaee ppSeems *DuplicatoInjction ND =NotDotted (Are lesthanlowestcalibration standard of 0.1ng/ml) ExygenResearch Page 250f153 418-028:PAGE G-26 `Exygen Study No.: 023-072 ------------------ Table VIII. Summaryof PFHS Residues in Rat Serum Samples TmeEm mmmmaaaamm oOEecEEeEEDeEIEEEEEEEEEREEEEE 2BE BBOoOEOsIR e =22OS mmmmmmeaaaasmmesrmnis OEOcccBEhenEeEEIEEEEEEEEEEEERREERR WEE EER O22=2mE ooOIOOmBI=EREE Bo 2===0X = mmm= mer mmEn GGEEEELER.E}EELEERREEEEEEEEE 22BoOOEEE EE=== E2 OoEm OIE mBEmaaEEnn EEoEIehLImEgEEEEEEREZE OB2REE oI=EOIEE =O2OXE mmmmmmmeoaeeaEnmm EWaEjEEpRnnEDmeIe.. mn BESEBEEEREEEEEEEEE ERE EE m OOEEE OOE EEEOOEE 2= ioIm EEEmmoeoEEmnm mam eGGECEEEnIbREL EEEEBRRREIEEEEE En ERE g= OE2EE o=m=OOEE EE =O3E EmEmmBaaeamfEmmnio.WceEcEnEaREneEE. EEEDEEREEREEEEE ERE OBBO2EZEE OOOO=SEEEm22O=23OEE mEHeemnm EoEcREbR ESEEEEEEE OOEEZ OO=EE O2ZE e e ARgEsn Te n"Sed0TostSeoTteI (A lbelsvcgtsa mbbetof ty ExygenResearch Page 26 of 153 -- 418-028:PAGE G-27 ExStyudyNgo.:e023.n072 `TVa IIIb (col nt'e d). SummaroyfPFHSResiduesinRatSerumSamples wu WmnoGmEowTsE al CDeM a hedryiem odEe "omnia wa e ooemme WORT comDen e emen OomeBamorIrsEy GmeouDomme|N mhhaudrrniiie lusriem aaimmma wm AGATE oomDeN hudrgiem am oeeeamnm i--m i HmpommoOmwrrEam IGATE GoeCmuaDmwew rhdddrrrivieeessm camDew Mdriem bwwesne hem emeemem am EiJeed na UmmmooGorGrnnE WIORE CoeComwmbm e eambew MMMaaeadddrrvarr itieesmmseoai ame neoeeammm -ioon =Sou WsmoOoonTn WICH cowomsmmie Gombe Mndarmdiriieensm raarviem imhiema an osoenemm enw pmo wm --sfvd a pPTmCoGoITnEE ocoommwiwbieew Mhhdaardymdieernm iamanem Mries ma aeeammm ome Ptrn "eos Madris ee o-sonn oo IPpAeBGaGKrIEsE moon biCmeimDnel rMhaaaddmrryeiiotsm am Mdretem weimmm mia eeommeen mmeea -oie ed SI maCaO rTy Toramry iamCmieDmiseew Fhneaedddrrreeiiieeesmm Tow hadries oiovmma me eewsmea ome -S=am oien pmemeooTncYe eGmmmDmeaw MSMiaddIbrytiDess hmmeEwe mwweeEaa okFdd TOpmGaGISnEOYy:. eGow"mmeebwe MFhaaeddrmryiiieeTsm mmiemm emeesmne nooeen ApmeoGooTnr eomm"ibeDmeewy PmmeAarrSzEiieTn Diimmm omommaeenn niineee mAeOGaGIgAATeTYrY. Deomy vGCoonoe itDel hdaedrmreeiieins "mw hdres mnmmeG be oobmmeeea ese nnseao a mDmmmOamonK:y mov caonTmieiibne "awn rrhaeairddeerioesrns iwhweewm nnoeomsmeeeea Ffadnd som WdDmeOaGMcTeEYy mmanny mcobanneiesi hhhieadddrrreiiieeensn Toy Ain imaumm hm eseeseeea ome PEON. eumiDen Mamie ooEnym ord WPmeaEeernTyy ciTToamwwin m hhhaauddrreriteeenss eiwnsE om wok: Gmibew Medries im eeeanase eesseea Soaoe Ed A pmmmaoG mrnyyATT"oE oa hrhedidrregetnse eT: Gime hedretes wwmasameoe maan AG weak FiFooYw ovoww moo me Omi An mew i *DuplicateInjection Exygen Research Pa27gof1e53 418-028:PAGE G28 Exygen StudyNo. 023.072 TableIX. Summary of PFHSResiduesin RatLiver Samples T e T e BIGGDROPE DEonmke NMedsT iieeiT anT e e "sDmuee e p Memberepoun) d BBinIraGnOoorT1 a0s60d MMreodsaimnatent IIMGRORE GOI Dp MotaLive Ssiamm sm oownnaaannn onan 2nm6 2m6 P5o17IocGaarOooTunT1. G00I766D MaMetoti tLitvieLoen suomm nsmm BIGOT OOD MetaLiaiote ooomaannn e53m5 om on Sam BBoiIIRRMcrGGoOIuWpTI GDaOToOHnDp|R MNMaeattteetLiieeiLooow ssmm ssamm DIREOPT uD Med Lone moan me o[nar n a] PBPInMDGGGOOTnW Doesl ating MMMeetetaLmtietioLewe ssamm msamm ooaA waza seewn iw oon im BIBIUSGSGOOPUT CGOGIIoGTrDDap MMaett Med LLLeeieb sssaammm BGG Gory| Medline sna a onan oan einw iw oon ow BBBIUNISGOOGPUN 0ITw7eDiDrseDl MMMaaedtteLLLeeooee aamm sm sinscrourv Go Mei tLone sam owmaann oan a laommo oma om DPiIISaDGRoGOOrUPTyYYS GTOIoTDmpD MMaeMLtdeiesnEsvoeirnwioa sSnoom nm ior v 07 etmLomLoe sam oowoaannn eso e eo ou DCrIsNGGaoRuOOrPtV ioranor 1 GGQOITIETN MMMeetteimnlLtivieevLroee QS Metmticlone sSoam saoum woawnn oooem oan o WOITHmIGOoRrOoRPurIEtY GCOQOSTNDEuDpe MMaMekkianLtLeaoaeie ssommm pGwoonnn wan naaw woo 1108TsCGRROOoUUrPPouFFreenem}1+ C25Go0D0mp|MMcetihLiieLele SSsnooomm INPGROPT QTD Mek Lee som wmoannn oa@e mom iRE swoGrm o0Rrn Ta0Io7sD eMMeetddmieaeal SsSououmt EGOS oop Medina som mmmaaanm nens oan ow HGRORRGGOOUWRIT GGmooIoimm]OsDw MMMeeedttasiLiieeeiiionateee sssooommne MGT GoD Madeira som vwwaannn oomm om mam OOSORGTI PHCROPY GwOTmO omy MeedsLLienleea Mek Llane ssoemm sm 10SGROUPV0 pty tnie he som ooawnn ae wc an m rF"eosAbplbotnahssoenusoagthebtehweiemtnhveiatlnhtiohddeautceaeldidbarlatlioownscuforvaelltimzimtast,csthaempprelceivsoiolnumoerstohrewe0i.1gmhtLsaord0.a1lltsheapmepalkessbeeslow100 *Duplicatenjecion ND =NotDetected (Are lessthen lowestcalibration siaadardof0.1 nginL) ExygenResearch Pa28gof 1e53 418-028:PAGE G-29 ExSty udyg No.:e 023.n072 Table IX. (cont'd). Summary of PFHS Residueisn Rat Liver Samples Er E m Fy Due ay Nembee pound C1901R3GoOw Pv 1I9R0S5RGROoUwPrVvS GCOUmTGTODSUDupMMleeLLiiiivvedd LLnoebe e sswomoo eemnaanns eaC 0woe Y 06 iOsoTaROourPYy PONGROVPE CGOOTTD MMedeaLdiceLoabe MetaLib COUTDp MihmLvLu spseo svomx foeoaraar isi mm ean e InSsGaTouOm 1 i907 GRour TED T Gms | PpoeoedFreetliir Pedi ssonoon ps TORU oniTODup hosed eatin ooneems oem aipsei saoge 19O08N1GGRROOUUPP Iemmi? 150m ror 200G51SDTep @0i%0 | PPbooooddedFFFeaealllliLiiinvneer sasmva Ssinorn owaeem oensmen xo aae P19U0P0GGrRoOPT1 UOCRORT CLIoD COSI Dek hePaolonettreeraltlieimvs S"aamnan om Iso Gorm 01% PedFeLi soma foosrma a om mo C190RrOovPe IDGROUPI IGOQIIMoIDDLpy pPoeddFFaeddLLivve FoodFeatLv ssmamaa sma 5004GRouRII GOSH Pus FedL ooamn one a2i wo om as ITNoUsOcRaOoUUPRIIIv USCROUPIV D015p 5| PFoodoFlkvv O15Dep FoldFnLv innonna SSinnrz ooopmm wan daios a ome nm 19Is0Io8Sn7sCGaRrmOooUuPwrIIVv 0G1o6ing oT PFodePtvivr efi swaemr or PONCROPIV GOI Dep PedPadi som aoemm mum aasoio so am 1B9To0r5CscGooRwrnPyv VG@Co0i%D rppoesaedtFteelieLLiidve sSsanoz az PCRVE COD reedreiive soo moooannmmee ozmioo IImIasNGoORCaORRUPoULuPMrVay:e CoGl00D0epl ems PPenodFasdLLeivv PepLiven ssmon pe oomman m0o io aman wo IGCCRRROOPPLLLMeeSz RoSieD IAD ICOM ci fPeprLieveds PPoelii paem saasvm owaann oman wwo wo oman GIRCROPULPeSs CROPLMS GRcInTDR DAD gPptt i Faplives ssa aoma omomaann oman wwo w 19I100N22GCGORRORPOLLLFUMeemPSsi? ICI015D m0 Ppplli Po 102CROUPLFee 0D plies soamv ssmm omoann oan ww mw 119I90M0222CGGRRROOOUUUPPPLLTFeeemmmei" I03S0190D7 tn3 PppLtiivvens rot poemt sm oamemaannn oman 3w w 12003GROUPFic 4_oimpy mpi mu oman =o `rpebsAplohtanhssoneuogathrbetewheiemtnhveaitlnhitdohadetceuadsl.eidbraaltlioownscfuorrvaelltiemaiattsetshaempprelceivsoilounmfeosrtohrew0e.i1gmhtLsaord0a.1lthsetpaepalkesabreealow 100 Duplicatenjection ND =NotDetected(Arealesthanlowestcalibrationstandardof0.1ngfmL) Exygen Research Pa29gof1e53 418-028:PAGE G-30 Exygen Study No: 023.072 Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples T 102GREOPnETene 1 CFSSSD plies S Dnuoem Nouambner Founda 119900022GGRORUPLOPFUmemaP1664 IIOP Ler COGUM0D8ILS ois fPrpleivdes Pati ssamma oommaann ww wo sam oan w 10SCGRROO OTRO LLeMz LMT S0D20iN CRIADRE 1009 CROPLhde3 oni PPoltiies PPoetpiin pnoom sonov oonmaann oman w wo 101 GRROOUUTPLLMaes?Y CROPLMT OcIoteD XH 10sGROUPLies C01 mPoptii Ppoltiier ssoouw nom mmoAa ma gaee mse ma om 191091099GGRROPO,LFMUmaP1 1019CRLOTeUmeP1* C3I01S000D C010Dlwy feParyleidn pln ppnd ssnoow amaann man wwoo w aman w 111900111999GGGRORRUPOOLFPaeeUUmmniePP1?2+ CCIotIoD i013 Pppitven Pte 109CROP Femi + CISD piven snoomm nom oommaann woo mom som 1911900011959GGCRORURP OLOLFPanUUmdeePP1 OCS15S03D 21544 frreaplmiees frie oomm omaAn oon eweoe w pd fren w 1190001GRGORUOPU,PLPaeaes 15+ CROP Lie CIoSioUesDII omISSDh Pohtpii PepLive ppet sao poeam oman ww w 119900022011GGGRRROOOUUUPPPLLLahuiseizs Xo02I0n18d0D7 fPappirleid pmom ov wwanz wen ww wo 19I02I1CGCRROUPRPLLLMaP icGes IMoTtoOO omISADuh 19001 ROPLhe ois PMoatples fPrepebidve poeva smanv owamn ww wwann ww 1199100900112GG1R RORUPOOLLLFeeUmP mdPe11"* C6I303S51D SSID 19021 GROUP Femi 12 0157 PPioppliive PMoptlis oovva ooon om om www asm os 11199900200111GGGRRORUPLOOFpTeUeUmnsPP1e137% COCNaSnoInDsOlps OISSDulps Ppolties plies savvm py mamaann wwo wo in w 11990011GGRRLOOPemUUm PP1 1003GROUP Lair RICS1S05D4DE oi foPprld Poti DROPLM SD Ppl soamm om oroom wwo omm sme sim om sem i CIO LM: 1GRO Les WNrDtBE oi Ppetile Pp ppdy som ommam eMoem wm sen CCRRGROOUPOPLLLM MPdSeCSR21I5H T5 I PPpelpi Paptive soomm wm womn awe oan o 1903GGRROOW LleerT+_ n0i01s95 Pppttm ovmm mommm oewvee `repsbAplobtnahssoenusogathrbteehweeinmtvehaitlahitdohadetuceasdle.idbraaltlioownscfuorrvaelltiemmiatst,esthaempprelceivsoihonusfoerstohrew0e.i1gmhtLsosro0d.l1ltghsapmeplaeksbreolnow100 *DuplicateInjection ND =NotDetecid (Areales thanlowestcalibrationstandard of0.1ng/mL) Exygen Research Page300f153 418-028:PAGE G-31 Exygen Study No.: 023-072 a Table IX. (contd). Summary of PFHS Residues in Rat Liver Samples a D n Due Numbe-- r _ F-- ound -- 11I990D23)GRGRROOUPOLULFFeeUPemmiePLa 1O020D19N81 D 0201961 Dupla PppLiivver FopLiv 1903GROUP Peni t0 Can Papin sasmaaa sau oossaammzzss.. onan. T wo Y ww 111999G0023GGRRORUOPLLOLFTUeeUFmmiaP]P161 C021059066021DD0uu3ppllesii PogLLiver PapLive ssmanz soz oossaammaa oman ww w soz oss. wo 119910001GGRROORUUPPLOLLFFeeUamemePet20 iG09a6n141D953uplPPaootpLLhiivveeerrss 1901GRLOFeUmiP0 G01 DuploLiven ssaamnez ssozmomaz oossaammaa om wwoo wo T 1901 RO OU LLe 190 GROUP bez N63S0106D5 02018 PPoaptLihves PopLiven ssammae mime m10u010m24 1001024 nw> OA 2am 1P1900T00GOGRRUOOUPUPPLLLMMe2Sd ON00I1566D7 w COINTDNp PPoolpiosv PapLives 1901GROUP Les C1008 Poti sosomie:z ssoomz ooAA 000A 226606mm 247m 1001024 11C99011OGRRROUOOPLULMMaPbP leesL5 X02I016D CISD PPaep pLiivens PpLiven 1901GROUP Feet Cai Pole ssmainn sisninae 1100o1i00224A 1"3 w 1001024 w 111999090001GGORROROUPOL FTFeeUemmimeePests G2I015a7101DDuuTppllasi PPopLLive PopLvs ssoimma sain io1o0t10022a4 oA wno soem OIA ow 111999000011GGGRORRUPLOOLLFeeeUUmmtiPP1sl5+ G01G0a3001D17u93pls} PooplLiiven PpLiver sasinnz sim 1901 ROUP LFemi 16 01mDupin PoplLiv soma 11000011002244 w 101024 w 1199000M0)1CGGRRORUPOLFFeeUeml?P177 C0I201S974D 2a PPpoLpLhievenn PpLives snaimz: sim iio0oi10z2A ww o10a102r4 zwp I1NUO0ACGORORUUPOLIMUMeePSs 2G00a2ESmDteDp PPPooopLpiLLiivvveeesrs sosimnaa me ICRUTbe tar Pathe sau: O00A4R% oA 11610) 1120 o2AR I10AMGGGROORUPOIMMUMoeiPeSs OaTmaTnO ID PPouplLiivses Pop Lives ssaaum sie o1010R248 22000 160 oR 160 191I9004OMGCURRGRIOOITOLMPMUUUieaemPPPs"a 202a2m5aDuspl 00 PPyoplLives Pole ssmonm: sim OUCRIO,FUeeP3 OODls PpLives sim OoAAR I0l02AR 220mm em 100% 1191900044CGGRORRUPIIOOFeeUUemmlPP1115C20003001200D331p7 PPppLLiivver PapLiver sssuno smo 0OAAR iae io 0A low 1119900044GCCRRRIIIOOOLFaFUmUUemmiePPP15166+ C20E203023D30bpy COO PoPppLLiivveens PpLives 104GRIOFUeeP17 0020 Plier psiame ssnaian II00II02AARR aiow ;oOAAR ises 5904ROIeUlY7 wimp plies Fires join on r`"epAsblphtoanhssoeusogathbtewheienmthevitanlhtiodhdaetucesadle.idbraaltlioownsfcourrvaeltliemrintast,estahempprleceivsoilounmfoersothrew0e.i1gmhtLsoanrd0a.l1ltshaemppelaeksabreelaow100 *DuplicateInjection ND =NotDetected (Arealesthen owes calibrationstandardof0.1ng/L) Exygen Research Page 31 of 153 418-028:PAGE G-32 ExSty udy Ng o.:e 023-n 072 Table IX. (cont'd). Summary ofPFHS Residues in Rat Liver Samples Ea T EGRU>P Cie e CToTBTD e Poplin , pl eoe Nem) o red UGDoGRoULriPsdeert onosryyo pPpolplliiin ORR Ties CoD piven SSooaommm So wwwaaass oomo wns OGUKOUGOMiieReetr 0oo5mmoydD ICR Laker CD FvPelipeet pki Soam SSooom wwwoanssa was om IoORlIlNAGCKOrP GPrreeeess roosnys GRO Lee0 ESD hphpatttieien Rpts SSSoooonmmes fe mmwaaonss was IGTokGRCRroOInUrereeeeTts TtGroEOn Ppmeptttih OILGROUP ree cD pki SSooooowmas wwwmoaas om mas a IGRROOs U LTro eeeeess EaSomwnD pFTaetpltireen GRP Mies OOD Pepin SSSoomea oa wmwmaaans om mar IOCGRROORUPLUTie)llt ooGtnasss PpPeelppiitn GRO Lies ck pli oomm wwwmnas"a om niimm wn IORORLOO iUTeeTrr CooomtyD CRO Lie cies hPpoltpilehes pti iinoamm nm [orroaor ee C I[CR rR r OrPer enPz sGspali pPolpileirn IWGRIOreUeT+ Duy Pept poimea Sam owro.vne og wn GGRTRKOOrU erTeenes0 CEoGNuuTst)OS PPPeppptlt onimm wo jrnosone nim mas io OGKRROOOUUP rTreeeet5 ACcDDRyHH hrhepppiis Imo Love revive sooammm Fe wnwnana iino won IGOGACROUPOLTieTetr o CtmD O PPpoeplpliienn ROU Met Gu pie SSaovummmss sa wwmaasnarele wax wm [ OGdROWeLessA HNoTmOyGN rpPeeiepedt IROLes amy het ff"oeeven po wmmamasas a mas a IOOCUTCreTse: acrsD ppltieis LNOOPNIerowoipel teum onimm woanns ww wor *DuplicateInjection ND =NotDetected(Arealessthanlowestcalibrationstandardof0.1 ng/mL) ExygenResearch Page 320f153 418-028:PAGE G-33 ExSty udy g No.:e 023.n072 Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples TT1a 96E CeReDIOFUeP COTSm DC opls PapLia vn m "Dua is y e Humbe _ FoundTC) 1C 9I03U6GR RRO IIO O,FFFeUeimP P aeP112+COiaTsm2Du,pls Ppotlis frre smamm sam fTroemoens "st0 on so py omen a C 119606CGRRORUPO IO,PFFeUeP eePs123 CCTU0AD2D0De%epllpsi 10 GROUPLM Cor PPoaptliiven pplrieesd Spaym ssaavm oomweens rn wIa by 11990I0077CGCRRRUOPIOUL,FFMUPmAeIP1eL5+ CIHORiUS0S2De5Dpt 1900GROILU2P uring PPaotple PapLiv ssoowm svn ommoenn tomes wBo 95 ron "5 TITRGRUOUPLLMs OciD PPoelpits Pp ICRU LMS IDp hive ssoamva sav wmaasas mas eemn om ooo 1199005C77GCRRORO OTIIUaMyPeT CaIioD ction fePerpLeivedr pti pi e saver momonaaasnn aamm 191007GCRROIOL, PMUUeimiPePe10 1907GROUFePe,104 CaMnotsD C2ASDelpy 19057GRIO,FUeP1 30200 PPpetpin PPaplLiievnr spoy o9m0a owonna im omosan la 19110500071R7CGRROOIIOL,UUPFFeUeeamPkePePl1T1s3% CGO0iOU32T06D7ei5p PpopiLivves apLiven 1907COI,UFmP oo20s saavmaa oan ie was ao so was lem 19100703GGRRIOOPUUemePaPt4* CzIanyD PPoatpLiive Poli 0CROI MUakP1 OSD plies m9mm ssnnooww ooooon am 0i wo waa mo C 9003GR ROIWLLU MUbPee 1903CROP Mises O30D2120D ian CROP Mies ND Ppoles Ppplli 0no2m noma owwans oan aann wo sno oan 1910003CGGRRROOOUUPPPILWMeaT? Ti1D 23 2022) mpigvt Plier smnoomw nam wmaam asoo ons sa 119901000)3GGCRRROPIIOOMLPFUUeememaiPP R0D81%O cami Dupls 19003GRIO.PUePe 02133 Ppelptiievrer Pgotiin soowmna ssnnoow o omaanmnetaimo ma 11199900000)32GGGRRRIIILOOO,L,,FFFUeeUUemmmaiPPP1110% 7X21C1S06D21Du3uppl PPpiven Plies 19003GRIOL,PUmP15. C0317 Poli snoomm isn0o0w0 omaann aaom ane 111999000003)3GCRRROIIIOO,,.UFFFeeUUmmnaPPP154+C02E0C202D21Du1u2ppiin paPgtlirvmas Piven soooomm om oomwaansn ewsonoo wa 60 19I0TC0ORGROURPPOMMWL UMesPeez1+ I21D 2s imo Pppllies Poti 1900GROUP2+ _onaodupts pte snoomm s"nnoonw: eoaann oan mmoo amo jes *Duplicate Injection ND =NotDetected(Arelessthanlowestcalibrationstandardof0.1ng/L) Exygen Research Pa33gof1e53 418-028:PAGEG-34 Exygen Study No: 023-072 Table IX. (cont'd). Summary of PFHS Residues in Rat LiverSamples T a 1900GRnOILMU3P C2FyDuplee s aplivn De.] Number _ sou, 119I000)GGCRORUPROIIWLLMUMUaeseP6? CcLaiD ams PPeeppLiivens pti osoww sooomm noouxns oa aua a a 191I00077IGRRROOITIlLU,FFUMiePPTse CGSaitD 0134Dwpli PPepii gives 1907GRIO,rUiP 32133 Pptiv onoamm nom norn owas mGio ow 111999000777GGGRRRIIILOOO,..FFPUUUeemaseiPPPe12112 1CI60S30D2D13;uplPgliioser sooow psoom ooaar oar omoo oan 30 1199100000777GGCRROIIOOT,,UFFPeUUneePiPPs1s3+ CHeS22T31D33u78pl PoPteipi Poin snoomm mm 19007GRIO.FUm P16 INSDupli piven sa oowanrs eax iGon smo 1199900000080CGHROORUURPITWOLMppiPk1+ EaIwayD coa14y PuoptLiivs Prive "aa m Fr eonmn 0 vzanm wwoo 1I0N0O0COGORORUUPPIOTMLMUeaeePs TaOnD C21Dupe 100CROP Ts 216) PPeopLiives PoPetpiin spozt S"ooi wovooonmm samm 119C 900000GGRRORUPO OIIpLLMMUeP aP6?7+ TIoilDvsp CHI Dupla 190CROP,Fey Cut PPoetpLiives PepLives opmd owaonm a om ao oa vom wo 119900000GGRRIIOO.,FFUUeemmaiPP10 201GM02A14D3ep Ppoitvien Pptive 19500ORILO.FeUmaleP10 2214SDws gives "aam om wwwooowme Saiss om Pr ova am 1119990000000GRGRROIIIOO,,UFPPUUeeePnPP1e CXG322aU1tS4eD7suip Pppiven Lie 900GRILO,FUm P24 021701 plies oomm ai vwoomm wom 00 mo aim 119900080CGRRIILOOL.,PFUUemePP1133.+ 19003 GROUP Mp1 2100021400 s aay pptli s Pati oamm oweomm oz u0e ne mm wom is 119I900D01CGCRRUOOPPIIaLMMd4+ C62O0130D C010 PoPatpLiives PapLives 19013GROUP Tes sy fared omma ism a wwmm imo oem 191I0000D33GGRRRUOOPI UUIPeMP6ss+ CIoseDsupe CUZ APPeppoLpilvees momm mm ooovma mamoe vosomn 33000 190C[ 13GR rRIOO eIL.LFMUt eP9eP1 CtCI2n1S5g8D PPoppLives Piven 1901)GRIO,FUemaP14 OiS4Dupe) plies ssaovm awwm ovoemm vom dmo0 aus oom 11199900001)13C3GRRRIO OOII,L,,FFFUUeeeP mmeiiPP1 C214653352211D55u50ly ppltiies pti 1501) GROUP I,Fema 13+ R156Dl piven ssmm som [ [Cr 1--30 oem ao on joven imo *DuplcatoInjection ND = NotDetected (Arealesthan owes calibrationstandardof0.1ng/mL) ExygenResearch Page 34.0f153 418-028:PAGE G35 Exygen Study No.: 023072 TableIX. (cont'd). Summary of PFHS Residues in Rat LiverSamples 1Ti m 9T 0T03Ge GRnILOr.r FUaT eP14 0Ea 157eDupe egiTv l R Der ) Number 1199100900031)G5OGRRRIIOOOILFFUUweUmmPaePP1155% 21c2Su2Ha115D5sulps Ppoltiiven Pot sFoem pepees SOILR Mak1+ C osonm wow 0om amo oan ve 01ISSCRROOUPIMLMa3) C2zt1Ta6tOlDeIpollps PPPreeippLviievne 19015GROUP Mes cater Poti nooiiuee pn ooawaaaannan aaaamepo I0II1SSSOOGRRORUUPPOIILLLMMUeiAGP?T" C0I03G163D CIGD 19015GROMLUePt a301e3 PPoetpiin PPoetpilive ssomm mimm a oaann eaam 11990011I33CGSTRRPIIOO.I,FFeUMUmealmTePPi10 OtOa1esD GIADuplei rpiovten pis snez: woaaxn a aaow en mm moan 111999000111333GGGRRRIIILOOO,L.FPPeUUUmmaelePPP1132. C01226025211D44u58plsi 1901SGRIOLFUemaP3+ 22166Dep PPoptliives PPootpLiivs oimm ez wo mooaan rsoawm mz 111999000111355GCOURRPIIIOOL,L,.FFpeUUmmaleePP1154. E01006237001D166o87pe 1901SORIOLPUemaP1 2IGSDuply PPotpis PoMppLlin ponu "ova ioowaa ew mooaann seem 1I90S0SCGRROOUIV.PMUaaIePe1V+ OXzZtID Potiives Peplive 0SCRI OMP3 d20220 Peptive ppre psrom a wos oan snae oa oa C 1U0SOSRGROURPIOOIVV.MMUPkP32es 22002)D 21D Peoptliive PepLives psaoma soma 1900SGROUPVs 020223 Poti som owaana [ror ogms oa P1ISUUCSSCRCRROIIIVVOO,.MMMUaUUikeePnPPs6* C1H20R23D EDDM PPoeptLiive pLives 1900SGROIV,FUmPd cae P s"oovm pa woaann onwe yi aan owe 19I0O5SGCRROIVU,OFPeePmnPa,B* 0Z43U0D22I5 D plii Poli 1905CRIO,FeUm P10 020225Dupe pis spodm oomm ooAA AR itlma i oan ue 111990000005CS3GGRRORUPIOIOVV,.,FFPUUeim1anPP171 C020020362022D3387 opPPatip ie 1905GRIVO. ReUmiP2 C2270 opin prpt pmmd oaann on ian0 0 oan ow 119900S05SCCRRROIIOO.V.,FFUUee)meiPP15 022a3208z2zD3zu8yplai ISCRIO.MUkP1* CIID Ppotlivs Ppoltiies momm py aoaann t0e om so aim om I1U9SSCGRORUPOIIVpMUikkP?2 11SOROUP Maes O02N023O0 nt PPoapiin Poplin soomm som mn on aoomm tmaoo 11I9305O CSROUPR RIIVV.,MMR O aakes CHtIaiDnsol dei PPoepin peti ppat om owoas ea er *DuplicateInjection ND =NotDetoted (Are essthanlowes calibrationstandardof0.1ng) Exygen Research Page 35 0f 153 418-028:PAGE G-36 Exygen Study No.: 023.072 Table IX. (cont'd). SummaryofPHS Residues in Rat Liver Samples TeD FEye T1IHOSSGGGRROROUPVOIs VFMUebmePdls* R RcEaiIneD 1I 50058GGRMORUPIVG OV,FFTUee, elP1m0 CCO0Hs2DA3e5pD 19100033553GCRROORUUPOIVVUFFPePemmVis,1t1+ 20aa0sD0inup 1I0033S3SCRGORPPRIIVV,..OFFeeeUmeTs713+ CXT3A0DD3u0pplf IARCGRROO NNVaYeak)s EaGIzyD IIIDNCGRGROURPIVVOVMeeUiserPr MTcIDerDR GIINGRSROOURUVMt aOkPeesd HaesZ y R IR GGORROOUUPU IPYV.,,eMFmT eeisdt Dtsp CHAT 19150093GGGRROOUURPPVVFOeriUeeePy13 TeaS322Du8pls 101089GGCRRROIIOVV.UFOFeeUmPemePrP,42++ TE3mT3p0Bl G10T39ORCROORIIVVTUOFFeemePTd1s5+ HG2Desyi O IOOCGRYVV,iO MeiSses CROOGarDDisEE OIOOCCUTRRMe, aesdst dcSIiDyyipl IRIOOGOROOCGUIRVVKV,AOek7OT7S CIStIiiD sDeyp OI1OOCGCRRRIPIV.VOOeFeeUUemisR1T XIG2A22DId0SN I5100UK RGOOUGRPIRIVOV,eFFOUmeeUePs1T23 GOcSSDeepts OTST O11500R0CGORROOGUUPPIVRVV,FeOFentUs11P55 023205027D23%7p 50GROU IV em6* TAD Rm PPootTpil Ppotlii PPPootppiess rPPootteiipi roPTptpliitve JPaPoiotrpies PpPoitpvieln PPoPapttliiives PPopltpiiels rPoMottpils juPPateppreiennd PPhaatpiiin PaPhtppi si PPapotltiiies rPoetpi PgPoatlpiiin Ppatpiin rPopattiiiv ppt aDEu soTuar sssomoum soaoumm aooium sssoooon sssoovmm isomm ssoaemmn psoeomem osoammm imvm Smsaonmn soomm ssoomomm Snnoom ssnoao SSnonoamn ssoooo ssSoooeommn snooom T[ Suommbeara _pee] ndTospnt) w[lorowoasem io lomo lnEaoEmwR ulono an wooommm i ines wooowums ine a wm[roaemme GGie owvoveeos aseey woomm eu va voommmo0 wwwooommm siee den aoovomumm ie o[aoarmna an olooaaannn isiee oooooan me ooloaauns itiiooi woioosaawax liiomnmeoo owaonu ow rlaow te loooooonrrs linommeoo *DuplicateInjection. ND = NotDetecied (Arealesthanlowestcalibrationstandard of0.1ng/L) Exygen Research Page 36 of 153 -- E4x18S-ty0u2d8yg:NoP.A:Ge0E23G.n-03772 Table IX. (contd). SummaryofPHS ResiduesinRat Liver Samples TE e> E5e a `Dur Mem-- b p-- ou -- IOf[ osSGrTr ReNRiikr er D cr iow onell phe Reem mSawmm am for aTE Jfirroo G DSoAmAO oT NNT aktss TosChores ciuamnaeDtel a hrhepptiie ete IRANi CoD SFpmed Fd a eparsoS ne a ae TTOORo NT Tu rreeeikr altmimnstgn phRbbo hob [opertig J oapmt mn a aesa wan o7nan on oSTosHRORoTPr.rrFiaters1s0. itsieeri SOUNr 1 TI hehvmb pb ipaemm Sma a waan oe oe fn ron o S[ ToR orr Oous. t t0 cs mm yel oR ons ibe hhRoabbi iSoamomm om faornomeSo om TTeConAoeTroVovasks DO Vk cxmmimDrmen woe RhRapottb pti Tonos am Fooemm om llvooommm sllooonw om zo OTTNoGseoVVoo aeuss enirgDrgsN rRhoiitme Rete SFoomsm ped im m oeSose nm iNTmsocRauorTVvfareleset Coaumyep Prsicheh0n cig hhhippmii hpi Toon reais my Sooommm am amemmm neon lo I[ROrT.o,aeFkme1 cTitAIDewDillhopeieinensd Toro reais iy hopkins ooammm Saomm noemmn lr3oeaw nm ide SoCCnIRoTOVUvaeiTmeitY icebDnwyN Toco oe or RrRpptmts mim oomm feirmma iimm m moe m lTIoNooGnOeTnvvaeenes onGo sas ocsooiDrmeeN ay hprpiiim ae Siiimmm Sim wnoimmmm oe l IToRGoRo Vosakee cwnmmimdeDgenl hRhpoptitvse I on rGon rveetsy eantyi rRoem aiiimmm m lwooommlej1oan im om 2m im tem se *DuplicateInjection ND =NotDetected (Arelstha lowesclbration standardof0.1 fal) ExygenResearch Page3701153 418-028:PAGE G-38 Exygen Study No.: 023-072 Table IX. (cont'd). SummaryofPFHS Residues in Rat Liver.Samples T1E T e 901T1GGe RDVO,PreaUkP10e CHm 2F33y6Dupf e m Dl ue e amb) er _ ound 11919000011111RGGOROURUPVOV.,,RPFUeeeP1z1 CG00Ha2n33nO7 Ppolvi PPpetpiivnes waiimm psrum oommaa [rrr a20m00 om 2100 11919000011111GGRRORUVOVO,FFPeUeUmnVmeaPP,3213+0.CC0200H13D3eD7pt PPpetpin PapLivn GROUPVe 2020 Pole ssooimns som owomos on nows a ICCGR RROUUPOVVV.biMPeeEs DtOrierD BAD PhDoeippllviivene s"oomm pamrm wwwaaRaa iiseee oan om PIIGMCRRRVV.MbMPeeSs? D0D2303S Gey ICRV MP ie BOD Photeili PPeeppiinn ssoomm ssoaimn: owoenn ons wmea 19I10R00RGGORRROUPPOVVV,.,eUbiMdnlePstt D02M054D4 03158 IOCROUPVTeme CDMSDUP PPptl e Poti ssomme ooAoR oa saom pw som oA jw G 1IG9NIRROOGVU VV,R,,TFmUOeeeP UeP1P110% CMi2S233D2o00pe PPaotpilin PoPteipi soamm ssoomua mooos wooAn iiome ia loan tam II 1OGGC RORU OR VUFFeeePmP ie,12120COOTtTMgDDsupMls hpotpiin Poplin ssoomm pr ICRP,Fame 3 00230 Poli AwoRr oA osewm ise IINGORROUPOVFPeemdYe)1,* ROU Vie HtOasteD COD rPoetli Pepin momm poam ooaAn wos oama i PAR om B1I0CRGRRGOPUYRVVMbeeesds UB2cSo0nI3s5De3rwL ECUVMS OBSD PMpoettivin hopin "noum Sou AoRA oA aam0o awe "om PIIRCCRRROUUPVVV,MMdeeTt BwaSnssDy ooatsy goltii patra ssoomm som oolaan pm ooAA 119I22R2CG0RRORO OVUFMeaPmamikVe1,1r1 MCH2025D BSSDp 19002GRVO,FeUm P12. 001350 PMoplrs Ppplties porme sim AoRA AR alae ita 11G9922ORGROROVVVO..,FUeeUemeePP1323"+ CHD3S2ED7epl CXOBSTDUBI PPhoopplmiin somm om owaAs sao0 oloAR am sim OAR i 191R022CG2ROO0UPVR,FFe 0ee0ee3Pd160 0C2O002TD3u8pAls PPPeopilivvnes 192CROFePm ,15COBHDupla Piven soomm soomm ooweaosnn iasoo Lae 1I1UoSSsCGCRRROOUOUPPPVVV.Meieez BGaEoserD Oise Phoitvie pti nnoomm soo ooaxn oR iimaom dime aan a IscRoiue mie mpi sum jouer so *DuplicateInjection ND =NotDetected(Are es thenlowestcalibrationstandardof0.1 ngs) ExygenResearch Pa38gof1e53 ---------------- 418-028:PAGE G-39 ExygenStudy No.: 023.072 TableIX. (cont'd). Summary of PHS Residues in Rat Liver Samples Te T T ee Em m Duis Mum-- be --Foum nd -- 119C 902SSGGR RROVOV.UMMU iUPekeT1P,s3 DdOashD OSA 19005 GROUPV. Pm PPpetpe y oamm uaaxa miooe pli nom oan in 199002SSGGRRVVOO.,PFUUreP1 PU1e C5MC3S31D8u5pe PAaplLiiv Ppt PESCRFOemUi 1P5+ asp pti nnaomm "naz ooaarn Ax iism 20 "oe oan 2m 111999000022555GGGRRORUOPVO..UFFFeUmmPePI,14F. CH020T23D8up 0338 193GRVO.TUeeP15+ 02hDupli PPoapLives PepptLiive pnoym "om ooaanr oA i0e ie som wa 190IT23sCGGRRROOVOU,UFFePUPmmY.P2.00 OtiOatssD Peppt i Pv ICRP Vets amish give ssooom mm oaaann iime i WAR i som tonne *Duplicatelnjection ND =NotDetected(Are ssthanlowestcalibrationsundardof0.1ng) Exygen Research Page 39 of 153 418-028:PAGE G40 ExygenStudyNo.: 023-072 Table X. Summary of PFHS Residues in Dosing Solutions TE TB T ADGL G eTecnrTDeeOOeI A RnAeLC lTootrst Noiombemor_Kccaern m Consmovatinant) FemWocnt) Beve5 ry BBB 4IILLLDDGGQI AAUMeMIrED0OOLSrC meggallo1offett 1T1o0n2eC loc BAILRAQCU0) m1ot4 i 0000000 asso mm ". 5 ooo am BBB ALDA D OIMI amySL 0mmmgditStT1o0sr4s HhoiomiaCe Tl0aCR So0o0mo0 wom asmisoommw "a 0000 wo BBbAtiA TAvSiSmgoL nt5ivgerE l]Lots tLniioommaaccR soooooomo froieooo inIHs) ND =NotDette (Arealossthanlowes calibrationstandardof0.1ngimL) ExygenRescarch Page d00f153 418-028:PAGE G41 ExSty udyNg o.:e 023-n 072 Table XI. Summaryof PFHS Residues in Stability Samples o SN rBDHoy EaImR e eTTnIhnTe. i omLaimmmsmm--mmeammnmTho edIo B Bi Ra OD SETE mF 5o rl SBSSEBiHEIIlIEiEDE:i WeeTTTTnnooInenonTse... MMDMGMiimiSmimEmiimowmmEEommmoseRmutdmThmoAieiernnd BBBiEEEoOOOELEmO=S BE = =O2O=oEEm :8I7 OE ESSEEDoIonrnfiEvi eTeTTnmEooenvse.N. mlmMGmiEmmmmSemIEmEmesESSntiIiimhEIrEEEE EBBBEEREROE==O=E =Oi===mR I x Bmp CET HERIEE OE OE OE: Duplin ND otDet (Ar motcronsir aint) Exygen Research Page41of 153 418-028:PAGE G42 ExSty udyg No.:e 023-n 072 Table XIL. SummaryofPFHS Residues in Homogeneity Samples m oPre. sem a EmSeEl GomDel AENEATGMEt OISRTrBoA n5t ost) ReTemEs OT mmmooonnwes moll coawmnnbntosC consben pADAitImiaaAAAAGeGuGwewmoummWmaitLoiamadUiimen looomewas Den 555 Doe onl pilok 2 D 19 C 1D mmmoeelwne Eases cGooovmnebeen DcSiLiLGaGIiaGoAAwwGGmmaoMemoemDLsoeoeoeamwrirmsmm Coon| pmawemiwaiodin lllooowwas Mlooewn 555 5 2NSB C DC m m moE wan moi Goooamnbnoeyeln wow b MpBIoLOstDLaG GhmAeee mmGoonmHmmnnaStioo |ai dLTT hoooomena lon mG conebes oo5m Ba aSny 0D9 18 mmooltets: mel Gwoonn]e b r MHIILIDo CGGMuenDr n foa Ornimoests siiinTe GoraDeiy BAILDIDChin eon Noien aawayyn J D Some EX3 Em DNao Ou)L IEG |Gcoowepmnline BABB AiLlG IeI sCGGhr aeeL noD Oi neL wmeat n sS oseuuorri3l NoioonEna Nloion Zon y heoyw o D NM eeyn alon 8 m mmoaewl oun Gwooanwneabudlell BC MaiI mrca aaO LmMen mToommwn M L aeta1a ts C oarr omy BAIS Gee lNooowoonnn hi enoyay loss 0BD2 on 1 Ie mmoEIun NGsE IO CcooompomosnbbdeenDBBBAILALAICLICLGmLehTLi)niCIennrcGpeonnCnntmsssssauoo)orallidnsd oH TiNomooAnen y leaoyo on 00 J3I mEDOooIwnNGn:T Smeei.n camaoemebteen aml BBpS AAiLNtLIai CLsCGoMnOnuMk eoeInnls0)0me smneaotml0s soiain3n8 open Holoeww Hoo oa lye bRU mn 41 easy arhe Immoomwnone mol GoonoEl |Bb B B AA Da GeGI N MMaoDL b a rnotE I ua T osicDiTon lHhooooonn loots Gooey MLLDGO a aSee ey MMSo 23 nD mmmooonoaa moO: |nomeommnsedl n| M MAILLDDL GGGMMNDu DommaoD sosuaioiie Gosek BIDem 1D Nlaoowses lloosts daeyym ooms a oan 2 Emmm eoui mol Goooroodey GTDe D BBA aaGaIIGmMvei aLLnOIa mmngatdLr|os losDaDt iD BALESCMD |mek [oT rlooeowt NR mow edye oSaoes le oon o le 1 EEmClaMn:: cSooaopme Gobo DAp D ALIG LLEa I oGGvvMerDn L n |pmopsnlis L sasooulnii IllIolDns ls mae ome DAIL oven ljooeonss enrnnes lon Lo 7 11 mI EoolOn: Imo wCmeGalbD ons BA B AILL Coa IvwDe)nL |mooays knE essreriDite BACoiI e iL me lS e lo1owDos lioosts loaooy mn oo 1 11 mocue: eonabee DGU hee yeH rout los aeye hLol% I *DuplicateIjcion ND =No Detected(re es he owes cabrio sandr of 0. n/n) ExygenResearch Page 420f153 ct e ---------- 418-028:PAGE G43 Exygen Study No: 023.072 Bogs Reser Page 430r153 Figure 1. TypicalCalibCruravetfoirPoFHnS 418-028:PAGEG44 ExSty udyNg o.:e 023-n 072 EEE Coe ofee: 99484 ee tr On Ex,Wolghtng: 1. ve an: hore |_-- 00 0s 10 15 20 25 30 35 45 45 sooTM Exygen Research Page44of 153 Figure 2. Exyg4en18S-tu0d2y8N:oP.AG0E23G.04752 CPhFrHoSmatogram Representinag 0.1 ng/mL standard for cT or1o rm irs = emEmEeE Exygen Research Page 45 of 153 Figure3. 418-028:PAGE G46 `Exygen Study No.: 023-072 foCrhProFmHaSto(gErxaymgeRnepIrDe0s2e0n2t9i1n3agCCoonntrtorlo,l DRaattaPSleat:sm0a91S6a0m2p8l)e -- anima 21 | i | || PN "T ay [arr ET Ge Ee e a ExygenResearch Page460f 153 418-028:PAGE G47 `Exygen Study No.: 023-072 Figured. foCrhProFmHaSto(gErxaymgeRnepIrDe:s0e2n0ti2n9g87a CCoonnttrrooll,RDaattaSeSertu.m Sample 091902B) m------ WAL oT [tn 1. Exygen Research Page47 of 153 Figure. 418-028:PAGE G-48 Exygen Study No.: 023-072 CfohrrPoFmHaSt,og(rEaxymgReenpIrDe:se0n2t0i2n8g7a7CCoonnttrroollR, aDtatLaivSeert:Sample 1002024) rot min omg TE Exygen Research Page 480f153 Figure. Exyg4en18S-tu0d2y8N:oP.AG0E23G.04792 FoCrhtriofimeadtwoigtrham10RpepprbeosfenPtFiHngSC(oEnxtyrgoelnRIaDt:P0l2a0s2m9a1S3aSmppkle4, Data Set: 0916028) avenmn a= mma go = ol ME aaa TEE Exygen Research Page 49.0153 Figure 7. 418-028:PAGE G-50 `Exygen Study No.: 023-072 FoCrhtriofimeadtwoigtrham10RpepprbeosfenPtFiHngSC(oEnxtyrgoelnRIaDt:S0e2r0u2m98S7amSpplkeA, Data Set: 091902B) priest po | Exygen Research Page 50 of 153 418-028:PAGE G-51 `Exygen Study No.: 023-072 ) Figures. DFCoahrtrtaiofmSieaetdt:ow1gi0tr0ha2m1002R4pe)pprbeosefnPtFiHnSg C(oEnxtyrgoelnRIaDt:L0i2ve0r28S7a7mpSlpek A, w= ma . wEonEg | BoygenResarch Page 51 of153 Figured. [ Exyg4e1n8S-tu0d2y8N:oP.A: G0E23G.-05722 Chromatogram Representing Rat Plasma Sample Analyzed for PFHS (Exygen ID: 0201816, Sponsor ID: 19176 GROUP, Data Set:091602B) [rr aut Exygen Research Page 520f 153 418-028:PAGE G-53 Exygen Study No.: 023-072 Figure 10. CGfohRrrOPoFUmHaPSt,Io,gDrDFaa=tm1a0ReS(eptEr:xeys0ge9en1tn9i0In2Dg:BRR0a)2t01S8e6r3u,mSpSoanmspolreIADn:al1y9z0e7d9 aysiorn siomr os [Exygen Research Page 53 0f 153 418-028:PAGE G-54 Exygen Study No.: 023-072 Figure 11. CfohrrPoFmaHtSo(gErxaymgeRnepIrDe:s0e2n0t2i0n5g0R,aStpLoinvseorrSIaDm:p1l9e0A1n8alyzed GROUP IT Male 1, Data Set: 1002024) en -) Exygen Research Page 54 of 153 418-028:PAGE G-55 Exygen Study No.: 023-072 APPENDIX A Study Protocol 418-028 (Exygen Study No. 023-072) and Amendments, Deviation and Note to File Bega Researet Page SSf153 418-028:PAGE G-56 `Exygen Study No.: 023-072 "NEE eSa R isa aClAhRGRo Uv~ eSrLRraEboSrk~ EaAtoRrsCieHs rRorocoL asa SPOSTNUDYNSUMBOER:RTrS STRYIITLE: GuelR Gerae )obieRes ptoDoywe TSseerty 7.770wi6t FuRROSK: BTCehopreeoptsaofytieeihym is oprop vidTeaod iImecCn he o pb idhoi ei tronago rmn eint sodpo , eto erpbATps a Ey Ee o : eTe T ee r ype ot Be RE Sanewrotoiopotentialof a est BE etlSi, pel foe diostoriopaeai epeeeeee toe `Becaouf sthee scotivy of theendpoints mn theshort duration of the me agp paren R TTiac E GGISi07S n8 BR SPOOR s ABm vrexhnes ,nosasr aT 3f MPCeupb r ra Tiem 5e1t 201000 tee em---- ExygenResearch ------------ Page 56.0153 CL Ex41S8ty-u0d2yN8g:oP:AeG02E3.Gn0-7527 ~ [ my oScO o toni -- mitwse f[a rliie u Gicn . (651) 733-1962 e BEGiUiLee AnTtOBRYCIeTTATeIOpNeSo:indpDre tme (090,0058DGeCotlteerre pinion Prac Boni CocpenionmiDevin 19). Te Re0v3 15:plsodfGosod LAabbosekrryPiracnticGeo[t00eb0r8ommP.csRion Pete. pAecMm ere y itOhu Vol 799, oocetebrr rc Soir ry BEGUtdLAyTwiOReYcCOMtPLIsAcoNntiocCEpp:t vi GdLCaesrtetrsPPrirn07 0 mn vnof theSponsor,da et bn me,pySty Dice P eT PiteodsndQmoaintaiASnedmwditchCtUhyee pkrotQocAoeLlY.haatsty erreortse ,t ,ts n 4 des mo=g F The rce toi mprle eS nTote pse dtyhn SstsSyDDlictettrseeet iy SE SimoperonoodfBi TyAbE ioeoteayyyebe niece Shheybpe0rmmteyoeneyty P beltwi benpr i GACSe etpem nedyi eect ----e-------- ExygenResearch Pa57gof1e53 Ex41S8t-yu0d2y8Ng:oP:Ae0G2E3.Gn0-7528 7 preeTrt iGPL tncy ochomndihp dfolnpee,onmdbiyn, taIs~] tity iLErv ad SeeATTAC1HtoMhEeNpT. TaESTRTAANNDVGEmCELE: Liman: TSo m: p7r0l6idPiehvriarbsernrmeiSyulePuesS (PPE)Lot deninionwith TCoimpSeptiooTnrmiltsrdiofda shie erientPhmryew dspoo c=riBmofe hei, Covel SSAeopmnoseew5irtbc emonca dbkirt(b UC) 0.to hdocsest Tper sing erm NrrteneebSacsimmcosnhrtdheoSt5nyr Driotwrwvbe sypots cannisSiy, ate rations: fooermestdoogtee sEPA Sl hermrk,a ydprgo.pTihi oMpieltSisn yd ailee ce ot sone DP BAlkTVoar tiTSleeusSCed aon:vmpet hRooom tarpeers:. = aFoes: RigidGC 50, AF tt bco eicsm hponrebitayi caoddTookien Fstmyionofe liaOui, ,MMeeneg of ExygenResearch PaSBgof1e53 Ex41S8ty-u0dy2g N8:oP:Ae0G2E3.nG0-7529 7 ilmle tcoitiy.Ttoesmca tcoebnotgisdcoandvossed art pigcusdo IoRMULATION Zoot Presson: DFoermdalr in (me pi)vils lbo prosprct ehweeklyi rheoTesntiv nAgTPTreAiCtyH.e MENT 5, Adm Pre: The mewillnnd100 esfnponofdongction. TataPaci ReesStr: San4gmiknoeviglilPboycrodmwpnionrlspeesoepiyemoyfch cha 1o. kwtdt bgtem pEinnt-1 Je rp fremr il eri Tenety choo ty SoSarFiatuTotbr y.tAdeoo nstt dm:in,eFde ebeit tmwahybbnedndteeodseome ing8 re AAsp tt ayan1to8t 9totnmbt il be nk nh Dr -- PIriE el ovr TeeLiinsnt Co:maerStl ySavin ETToalphham: (G6Ss)Ds7s3s5i6n8e een Theepi illbooidavinof leimc. _-- Exygen Research Page S90153 418-028:PAGE G-60 ExygenStudy No.:023-072 ~ Susi of ProaretPrmatons: Prnaes ComsomdHoomosne: CooefnanscehtrcisonoGmanusoihesreatodftcyhoetpfepphrpideyviorne ,mTwiosaspwiilo leboovnny eegsdudaiengephoiceomuo rieicplkaoerpadieiepmnp.pTeldwf.orQseryupisfononeerxicehipnrwimlplllbcaecktelwfaiolllobeosrcshpecspsonf3mcreTareznwyohspPhieoteyk ary of eFviionnlysipesowdililobenraeidndecardacdk sTprieis.gBcaypspoonpeewrilltbefdotSepre. sit `pSpirbilisoonftpGlopreparpecdlcohocanchtdopcwihlboeemtdcwoilolbmiepdiedlidbnognim o unyyo.fTdpwrootsnes,of Toe Epn iswild lbo ly mifo linggsepi ot: 4oee 1 pe respossie ame yay1 nos Stunts aeration: `Spotbesuyond willbe tippedeign) BPSuHriiBdceeev3a8ev05lsT:aLicmCtlaandnSalty Svcs 5TT:oePdeuops:eM:i(m(6s31H)$T53S13336T38331 Bek enon Torcptwillbepif mda ofsplsige. Dmrosmoy: Popeffoomnstsins wi ibedcareteedd TioPal,3ALeningkt - 3DS MaCetnM a,-BAruiE n&gCBh6S 1m5G.1y0 STtPoth,oMi(sc5 $T51S0-T1000 Exygen Research Page600f153 418-028:PAGE G-61 Exygen StudyNo.: 023-072 ~ meses a pi SnecsdoRamSontroSfaotinon: n`TmahaeyClH,iLCn2D)sl(pSeeDcs)ieiIGcnSoBpfRtutVhAaoPxsPealeandreatiwccakysiedclioetbsomasdthiiehTvessebteSeyrwpkiredosedbalcyciwvaeed:71o)ucghoe evecare;od)bialdtmdexpr eitthTesting ay Number: Pntolipolah tionsch limant: ty 71S00lmaldoendS100ivirgii nmlers.3pm Population selectedfr erenantdy:do1o3nmwaeslgegarrnood)u)1.5 cal rt(Bonprsxpr BWorertArs: Macphlecaetfeetdi0wtibl,lobse ewdhetirce6d0t1iyewweohlefgyahwgoil.mlFbee7et5xpe3e1cm0ts3ed0w0i.lblobouocchJdetrr5edc6tidopaw,yesioghhfi$acg0h.tA2cc0tti0h]y4b2owid2ly5lb5e ~ `eweiseghwgitlrlwaoigkleclsrwcrilcbod1i2d0c%tehofddayMoteheorfrwueclipgpthomroftd.nwAiLhlslbaoydocutmienite,tnhehwegohwdveins.tiTheofhe = Bothaes femalertwil be vated. Po CreRiver LabsI. 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Ponnteiy = Ws10iiielcaecliecdsongfi rhroeu lch sohmapyirlebbwerlaybgGo)wOe(d)OCA gsamhdtfoyots1e0mmeomnvd hoe rdt Onedopy2 prroePpOo,mobaeopfseiys,CEliAitowwniklslsommi pdegmwwiicevnye"balbeddrBsfm e apmusTRATION: BetndEe forCooker -- ie csdos a o-- e rm s-- me d-- h oF P-- bre Mt adPoh esy itRh uetdyLBdrty ri memmdgpern ema ame ~ 3pcp ednodn,tichocngotpvoiamoiofmboe toTarbee.iDpomrestwbsohhg ie1o4eodvai4 decryhin PFeimoalhetscwiolnalebooyifveiotmromo,c1 seso.cDdaygbwegimn 14dBoynbgeliecoybs te forDon ne t ctor miir enke igng Toefh-- oomteedpoogeeB -- n ees-- iabee -- pgai esro ty porsi ofderingmy sg ipn wnhd ExygenResearch Page640f153 418-028:PAGE G-65 ExSty udyg No.:e 023.n 072 = DoesCocoa stVem Patafn=i] E E r aers a an me e eae] ee TRMSTHELANAALYSSESAUNDREMENPeGTRNESRAT.ION: ral dFema Rt: Aid: tit nay. `lalOrationsad GoraAuman -MaesdPenalBa: Aen Pio est. - Dome: DPu-- n loymboetcsdmeegr.eOry nrwtieofbeeoeeasy otafonsne,ecerirmaty SgoyDeiorsdp hsee ne [er Di are 1,e n5im,ddy28,p.p1m5Ohare soemat bCylicSsidDhecaeynobrSetyiMoo.r uy tldho, end pelts Dfunnr cnprs igntimlsion il ctbe it DetaledlnklCherratons Make Po Ra: = TTeiamrsomhdettfro1ciie fohmIla n--dT--f S o c--Be o--oS--obohb--ids-- eei--ege oldpeSp tetho ce tpi Se, re, esmei,orsoset (e8,lacrimation,piloarecton,pupilsize,uousualrespiratorypatters). 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[A -- Exygen Research Page 1060153 418-028:PAGE G-107 ExSty udyNg o.:e 023-n 072 : : me= Protocol418.028 |i fo-- rt fd y "This change wasmade attherequestof theExygen Researchinonderto clarify || S fe E fleSe es a | : ALon amFAD. on e _SS adlBesa BoibPLai D.DASl T,tCaT,mDea pram Soar ptr || | Aieisoe tnd emit kb mi by bentmet i Exygen Research Page 107 of 153 418-028:PAGEG-108 ExygenStudyNo.: 023-072 Exygen.. oa \ \ \ me m Re ea e se \ PROTOCOLDEVIATION + ou omensSR \ vient, \ ; \ gy [RN oe:t7liSh3 (gal a (noel2. N77 [OT] 72720 m(ussPei y2. Soff \ Eonr/tre1/rses0.s stems yp OAL etw b:r 7/16/03 + THIS IBAATODISBEINGFE-ISSUEN TO SPECTER LOSS of CRIEINARL .ise ss Roms NP, Exygen Research Page 108 of 153 418-028:PAGEG-109 `ESx tudy yNog .:0e 23-n 072 AN, E EtEe. mmausnsee NoToTPELE ownous rroaroecous ne Surs e_arz ore S C m ct vaom tSEer tsn ot crrw y oretE etolbeincedormserosTf tr, me = pbvaluefoundby0.91. Chali ge e-- e ---------------- soya ExygenR Page 109of 153 Exy4ge1n8-S028t:NPouA.GE0dG23-.1y01720 Analytical Method: Method of Analysis for the Determination of Perfluorohexanesulfonate (PFHS), Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serum and Urine Revision 1 (Exygen Method No. ExM-023-071 Revision 1) ExygenResearch Page 11007153 418-028:PAGE G-111 ExygenStudyNo.: 023-072 me Er MeethofAonsdys e fLoitvehDSeteerrmninwatdioUe nroofePReecvihsio1n mr olslPeFS) AuraoRs Jokaler,KarenRiba,andBlyDeck DATEISSURD Noveaber20,2002 seosoR 3M MediIcMaSlCteDnPtaerle,BMaNlpdi$C5n1ogar721p0r02s050T.et0n0olsogy PERFORMING LABORATORY. S3t0Be5oC8yRoeelsRleaPseAeDga1ic6ev8he0,1 METHODNUMBER BO Revision 1 `NTOTAUL MBOE FPAR GES a Exygen Research Page 1110f153 418-028:PAGE G-112 ExSty udy g No.:e 023-n 072 Bor ed B5e7nt MANAGEMENTAPPROVAL CFn aabFa=a b,er g Abe er 7L m2. 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CHEMIANCDSUAPPLLISES 1Cmacus M-- tf J hooe lOGnM -- tHPmLC EMTSRk-- SoOeT AeVsorcite HAC EEMugSens AXDISL Tfypme wLaabeonccoiWaatelrpro awiavkiz,atcmnomof 16.67iim35C, 32TSr teamos aee nw we FFeereosc)scaioss =sDa1t msiCg ghachin APdradaorcotmroocmcic oGLiaadkeo: % ACien 33.E y Bouvomsuamse e e T`TuDmiepsseCorhtussaceoBpiees(0-008 1000) Dru"NmTaesngVa R) S5io0rs.aadcReoCpnChospeetrpslCyepneatpoiesecesifg shes Bur"loDuSpRcointntic aLdp ir mis vn saoeRsveta tpun t AT ClnelcAlprHePLsCdvvilKmit f45e18n13400) HecvoenrPpalctss pSuansdobpeapaadFcluo odhnle dersput KeyuomoSceenic aHEPhLpoCePrsaapp0iC-n1p0AdD)sm Gr meut Koes Shima LJ CMSMSsod PLC pss --- Asedciroin d43i.n Pe) mses FoyprPoth Page 1190 153 Bop sty 007 418-028:PAGEG-120 mssmsn -Tin r Es ett eeoe, (1EET E E E TL e TIen TRR ---- ETE Tr : 3043.StoEE E uomeonmshomtE m aveyger Tytrpsttbeyva ae EEEemRE aEn e ESe me =S FPeT t ce, t RS ------ Ee I in eEn y T ATy a RTSTE s FEA e eisE eT n ----sr eye rnofSo teme ret in. i ee -- i Exygen Research Page 1200f153 418-028:PAGE G-121 `ESxtudyy Nog.: 0e23.a072 Eo Ne 230n 7Ren FPR2r3O1e.AsSbioynwcdeikivlgihdoiunanglscouck1sc0ogtoonfsecmh 1s00bpig).soex PdRES,aPFrOtS smd. 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TiFdhogsenocdkxc k10o0fCrt.spe vaigsrnmaSio eyneyn - 2&5P2Pr,FoFUp,oePrR4mOaiSs1nenSddoftoPsiFifOoaAntbsiyonmsiangd10..1.0ofg/acmhLof10h0n0a08fpleo.f ckobonsok 4 1002.veeflaksndinpt em 5fTPTrorIpSie.ePsRnmOSisScxlteaodtdPRO0c1b0ny0dnmiclnwnight10t00hm01cL1 yoipgthv.1.e110p000epatcFfmykieof ESSxpal)ivafelor:nooiocm| micld.roef dsmreurmrliionofequ0i1viytp0.4s1e07os(0oatgoesn1 Sertteoprleynai)lon.i7cNaottoti6osnls ftohtadede nr)pciioeonoefvd oeonnymoGynbb1ee2i 5predpLaiDPfE LC25Mp3S.aICMdaSc0r1aa.n0nt2S,ou0nn3d,e1dr0,t20s1cdo50liheP.FiSn ,etOiScsvmidcPiFnOAsonf 0.1 pol isc rican lon(cio35.25 TM Flloningbmon8 pcexe dona concatatonsmmay be TRICE Vas Died aie I530] 00b0o mw 2eis0m os 2i0s w wo wiw oaiz Thelewa)nwdhuredns raydbrewepdrfeo (pFcC1o06fc0oeyeuGn125ml.LDPE rts reiio -- Page 121of 153 Exy4ge1n8S-t0u2d8y:NPoA.GE02G5-017222 re tt pes Memon 44.PowDucat eo doftn nmd1 gnbo, ond bydt `description ofeachsep. > Mato ncn : J ST I Ava fo fsp hot 10 e we rv ies Ror ta. a1 ---- et megsirn etme Lonpnd [rP---- e oireeeTa lecos 3o Ca sbltemsi iaabaordepoe emamnde,on oopweomsinvin e aTh LS mpie,106 , peep elo ps ry s JN r--ien Exygen Resarch Page 122of 153 418-028:PAGE G-123 ExStyudyg No.:e123n .072 Br ed Ke 27 ten. Burrs Abn of piesthn stcontinmeethem20 idspe. oe riccnh)ebuvascitnhngk ysocf(osppuuirrmaelemaea1anr0e)1ecnovdderry0twtso/bsimanfhtoti.evceoorrotsepnfecrm ointaGt mBuoiootd i AodAirots]closeei kpdcuhmplaehiencadcahbyeuchnbeacoeofaa foliid ws Allcps idepictions. 4 SuuBermacron 441. Lier Beracion & `AJa mdeeagnwhree1dgrd1eopfsetadviineomnltoee ololLe1vi3i0bnal.roldifoOntLa.wCecmo.potimye,vbeemmdd THoiamnmeosbrpim ie"ecsopfolstiw hienivgedigeee.hmitoiSg Fi tAmiHp lateneros 13a. . frstber a 30r00Erm far- h$ mi,Ro Po] 1. E a Lowthev52 pd Sli PsEocfocmieoI td hcuanc oalo.iCdoolSoso722ncmoLhsofchi ik pads 15 Rcadeicapgetein copLOMySS 442.Sram ndUrineBracsion &Mm1ei1g|mbiolo.noadfyrbeetr,mcoapriontapepseeamipnlNeoiottont4ph le0smsLa edevpboet ntlfooerf Brats reno `ExygenResearch Page 1230f153 418-028:PAGE G-124 ExStyudyNgo.:e023-n072 Br MedHB2571Bren Afodr-Tw iranTa icofir s wvihnssp of2s0i.Cropslondvyor 445. SPECoenContin A SSPEcn oyus byl pe epi g1o0hr5toofeetgrneyebs eShlooeennSt,eoCspSpoeenionste 45.Quan 43.1. LOMSASSytemadOpersing onions ManSpec McQur oUsoaDcroe man) S"Coompar, HW CrOMdPAi aQWPoWTrMsn taenpduys pasG3l3tioiAFi n eon,g HPLC BowePcQua Gm1pSo.p e 1100 Note:{cbAon4 ri1e0n1msmvdpe1araCeyeodrn tosoeepe idccJierdait cFphPLyCfeekter HCPi oLtCsCTVm ooelmeem33a555n. CyGosCoresto1 psremin NVaiklePThoues((58) 2h00edA t rAmai Tyea wate Tw o m RSAS)ii Belaaem o 55b0000 woo i% i 00a a m u= e io aa3 PR reuse ExygenResearch Page 1240f153 E41x8-S0ty2u8dy:PNgoA.G0Ee2G3-.n102725 rneet 8 23 tin Ioimvmrrymb tcaCcop omymwihelbe KhyePyeLsCBpisto(fn5e3b 1copioo ps Comm AHTwOESw TOA Nrheeem,p TooenMoott SKSSeeaobniaaTimi mow Sem - TS e hi on iE imyve,inE eysh yo oN apeeinbobec of i Nok a iveLCMSASpr maybeod neecmene 8 Ttihiredm0c0pilcciint1N0onw+ts0d%hpiogrtsechsakknm oOEbayFeyt ai o1g - o1: 0s nl. P=a inro d ee 5 be e CToosto 1re t eh peimnd 452.CaltCrvartcosn Dfcgoau2nameaootesb10103B 011ofe echcobra Srdrt ST= peedSefr ehmmiyn by dointcmpaoimT gie1MLn-- otySt parh t08ayceooae aCmtBeecrdieSsiltrs Tocoltoncote ( fo liaoavesprotco be m er ep a e n ih or eT. 209925 (R*20965). Ifcalibration.results faloutsidetheseHamit, then Bates reise ExygenResearch Page 1250f 153 Bos ays05.07 418-028:PAGEG-126 rmtes btnce 7, Focep. 05m steot tmm1m 0 chi S fSEe S e EErSEoetT e er S r ot R e e tcr E E rE er Te ee =S S E eonutr e nttE E t T m rT Eh e e E E S is e n n E +FPRS S S S-- t c -- om -- mc -- m --s -- eeee eeren SA Seim LTeE ReT E S=B n E p rE e ares es pores FT -- 418-028:PAGE G-127 Exygen Study No.: 023-072 rn etdMe 7 on 4h4efAclcmairraanccseCtamraatnbn tt nm thprecofPPS,PROSmt 1 Te 59 cm forPROSe,tmnTtshdomwgBpmkpof 8369tr Perey dn8+e0pegaemmrfnoamt . 2BMSaatkhkoedclHaoeniksrcamthbtoewacchioonnitemadomtyhmprrsvseilt pt1brgta heaenhe e. LQe, 1 3mBapnaasclleoleovnfctc,ouetdose7ro0Tp-iek1e30eamt8odtefmhcaiadtmbT popoeitanhosnfte)bdrbeyt tbebsi bene tmi esrconsd mir. 4Hoptwaeyvtcelst,ca5tciodntsa2al0mn0atonafotrfhoofdc0anbboensroiefcnadlscsdrftshBjbcbyyouiidnbne hcorfone 5T2h00o9d9cci2ora5msisnc2ois2oe0np5ce8l5eo,v sbIoectaotlafBek)netinooincrshastsnhenlasidrnbcacmuiarsdegednpsreBeitc:stabe 6. Rieb4ta8ivnisttiianmmenbasetyrweee:hsdta.ndaort1dmmdtabiloneteiomnc4t.netveintsmessstam 47. PravomunsCarman iTt hofolbowcingt wofocrrmeeimF u.tboE pectrmL edcoea 1yi ty =. 2R(l140ecahCafngeEiicrocmeupnaieutodnpreronernmLigMpieeSgrno i0cso mo(osmxpaeenfec hte mnflcbsiyonnit sFtei 1y0 somo). [--. [ Fog Reon Page 1270153 E4x18S-ty 0u2dy8N:goP.A:Ge 0E23G.-n017228 [ER ------ Ceolmicito0fla hideeacsmMiinchtmioonecaom1c)ernoefnicornflsotvet0d5ebeforohcehrs ombn e hris tions oe, pinaybe ydwih andr en. 42ToaReva ronAare . 015pmprielodi.iimn|camcoalanysak)bowiemkl.,oTke3o2pW0LbrCopMimSreIyMicSomcm1ns4itbtsioyohioneefBnseo| pmrCeopmo reiosn3pocres 5. CALCULATIONS UFPeakuBniceoen))nwr1oi1agrceadhebnylahehMdeaadcsoccaosvtseofs(eUyxspwfeoniugnh:de(d3ogef,eepsidocn Eun: a Rri o 1-- 0oe30 a BiFoonpl3s10fcriieadnwithpXroewtrmonomyofsysp7ce 0ccc pe [ST sameaan -dmegt mr)t ce mtd] NotasSU ubernwygodhpiscioodm(e n0g0/L)fcmyood(fa Bor rein Exygen Research Page 128.0153 418-028:PAGE G-129 ExygenStudyNo.: 023-072 eee 87 tm . Un to31clesBsmt ye dn Bin; Arbr sis Fett t tcep peweg(0)or mplvee(mL) . CsSxoEoraaggpivpesrcap,neidwahhhe pii o pels ndnpeeeyrte 0 se rry mSfem oeTdmenietemtn ECTegnlypoannarydaecSrptaetbe dfinase he nitto Breet Exygen Research ovo Page 129of 153 418-028:PAGE G-130 ExStyudygNo.:e023.n072 ErmMetHB 2307 prin. Tabl1e. RecoverySummaryof PFHSfnRatLiverandSerazm PacovcySumofmPFSaIn rak Lyiver = mw 2eBm=e ? = w rtSon o e sEmRm Ss peonge 2 y RecoverySummaryofPHSIn aSeren EES tye) reominemny| mt in gs a axe aIH Siri Boras ExygenRescarch reso Page 1300f 153 Boge Sty aco 418-028:PAGE G-131 op; Tule.Rorr ySoone ofPOSoRim mBiov Smadre =me ------s a : == : 5 Er. Ea -------- = EE 5 : Re Ee ee------ rs ta-- i Fh 2 BEE == Bip Sevsee Pagp2iota Soros A 418-028:PAGE G-132 ExSty udyNg o.:e 023-n 072 opr Tule.Reo Suman oPROMiatLie,Sr adre tStront EE mmm = : = cone mae = ---------- r EE ee i = I I ==`RecaverySummary ofPFOAinRatUrine: eEEpE et------n == Si Panos Exygen Research Page 1320f 153 418-028:PAGE G-133 ExSty udyNg o.:e 023-n 072 rBt k Figur1e. CalibCarrvaetforiPoFEnS STEERER Rae ExygenResearch Peete Page 133of 153 418-028:PAGE G-134 ExygenStudy No.: 023.072 Sqr: Pein. Ctra Carnet 0S SEEEERorE , ern rr ExygenResearch rs Page 1340153 B418S-0to 2y8:NPoAsGn E02G3-.017325 EE-- Peres. CulbCsatvuicPorOnA S S SpriE meR sTneE mre Co a8 STS 3638 WWE aed SS ExygenResearch J Page 135 of153 418-028:PAGE G-136 `Exygen StudyNo.:023.072 Er kos ns Fred Rete Qronstogam ofs 01 gf. Standard Figures. Reprssttive Chromatogr of 01ng.Standard -- sug -- Exygen Research ronan Page 136 of153 418-028:PAGE G-137 Exygen Study No.: 023-072 rmMe NeB7d1 tn Figure 6. RRepaetspresentatihvre semtogrcooffa0.0.1, gf. Stdard Flgure7. CoRneptraeisneintnagtPivFe SChromatogorafam 0.5;wll.Standard -- TEE Botan a J Exygen Research Page 137of 153 Exyg4e1n8S-t0u2d8y:NPoA.G0E2G3-.103728 Ar B 7e ts `gure 8. CoRneptraeisneintnagtFivFeOCShromatogramof a05 allStandard CL Piss9.. Reps Crotognof800.55nggia.. Standard omeRoush Exygen Research Pag otas Page 138.0153 418-028PAGE G-139 `ExygenStudy No.: 023-072 EL -- Figure 10.CRoenptraeisneintnagtiPvFeECShromatogramof 50gin,Standard 1 Figure11.SReporesrenttatieve Chromatogramof 50 g/m.Standard Forte -- ExygenResearch Pesan Page 1390153 418-028PAGE G-140 ExygenStudyNo: 023.072 eBOe 257 ten Figure12. RReperestentaativeCrotonotfa$s0e aL.Sands 1 Figure13.ARneaprleyszeentdattoirvPeRCEhrSomatogramofa* ReagentBlackSemple me Fmt reso Exygen Research Page 1400f153 418-028:PAGEG-141 Exygen Study No.: 023-072 Breet Bsrpes Figure 14. Representoaative Chromatogramooff ReagentBlank Sample |---- mEg= Figure 1S. Representative Chromatogroafm Aualyzedfor PFOA `ReagentBlankSemple Lk Bowe Pdtotas - ExygenResearch Page 141 of 153 E4x18S-ty0u2d8yNaPoAG:eE02G3-.n104722 Eb Bp Figs 16.ARneaplryezseetfaotriPeFCEhromtogramof Contre verSua -- Eg Figs 17. Representatieve Croatoaof ConLitverr Seomplle --------" veg Erte ExyienResearch ---- ronao Page 14207153 Esyg4e1n8S-t0u2d8y:NPoA.GE02G3-.017423 [EE Figure18. RepresentativeChromatogram oa Analyzed for PFOA ControlLiverSample LI Figure1. RAepnreasenltayftoirzvPeeFChdSrocuatogrammofaControlSerumSample Fon: TRE rm -- Exygen Research Penuo Page 143 of 153 418-028:PAGEG-144 `Exygen Study No: 023-072 odKo B2h7 in Figure20.R`eApnraelsyeznetdaftoirvPeFCOhSromatogracofaControlSerum Sample: -------- = Figure21.ARneaplreyszeendtaftoirvePFChOrAomatogram ofaControlSerumSample LN F-- ort_e ---- resco _ BrypaBuenet -- EE ---- Page 144of 153 418-028:PAGE G-145 ExSty udy Ng o.:e 023-n 072 Eo MedNeBz ain Figure 2. RepresenaattiyvCehroratogramooft+ConUtrinrsSaomplle T= 5 TER Figure23.ARneaprleyszeendtaftoirvePFChOrAomatogramof a-Control Urine Sample Tom Em Sota `Exygen Research oss Page 145of153 418-028PAGE G-146 Exygen Study No: 023.072 [EP Figure 24. RepresentativeChromatogramof ControlLiver Foratt10ing/fgwiihePPdS Sample Figure25. FReoprrienseendtaatti1v0enhwihPROS.ofaControlLiver Beenie Te-- EE Borba ExygenResearch _ Page 14601153 418-028:PAGEG-147 ExSty udyNg o.:e 023-n 072 Spiers Fis28. FRoretipfioedsatt 10nCg/ghwitrhPoFOmAaof oCgort Laivme `Sample To-- bu: LL | Figur 27. RepresmiativeChromatogr ofaContraLive Semple Fortifiedat50 ng/gwithPFES rer ep R-- ExygenResearch Pe Totes Page 147 of 153 418-028: PAGEG-148 `Exygen Study No.: 023-072 BeeeE37Brn Figure8,RepresentativeCaromatogorf aCme Fortified at 30 ng/gwith PFOS LiverSample = em Figure 29. RFoerptriefsieendtaatt5iv0enCgh/rgowmiatthPogFrOamAof a Control Liver Seple =I . TEE re ExygenResearch ao Page 14801153 418-028:PAGE G-149 Exygen Study No.: 023-072 EnMet NB 23071 ren. Figure 30. FRoerptriefsieendtaatti1v0enCg/hmrlo,mwaittohgPrEamSo.fa ControlSerum:Sale -- fo] a Fm mg Figu1r. FRoretpirfieecdtaatt1v0enCgormwaiithogPeFsOoSfContr Sum Semple Berar Exygen Research LL reas Page 149of153 418-028:PAGE G-150 `Exygen StNou .: 0d 23-y 072 CR. Figure32.FoRerptriefsieendtaatti1v0enCgh/mrLo.mwaittoghPraFmOoAf ContrSerumSample Figure33.FoRretpriefsieendtaatti0venCghr/oLmawtiotghrPaFmEmoSfControlServsSample rps Exygen Research ron Page 150of 153 418-028:PAGE G-151 ExStyudyNgo.:e023.n072 Bm eddMeB3r7n Figure34. BReperesrenttat:ive CorsesCottoSrgoSemaple IC Figure 35. REeprmesemntateiveregaltesContr SernSage mi | -_ Fr-- 0[ BorgenResearch Page 151of 153 418-028PAGE G-152 ExStyudy Ngo:0e23.n072 Be8ke7pts Figure36.FRoerptrifelseedntaatti1v0eCghirno.mawtitosgPraOmSofa UoeSele -- =z Figure37.FoRretpirfieesdtaattv10snCghr/oLmawtiotghrPFOAof Control UrenSle -- J Fortes BaygeaRessecs a reauo Page 1520153 418-028PAGE G-153 ExStyudy Ngo.: e 023.n072 er etdoc 2071Brn. Figure38.PRTeprieespeentsaiteivseCoremooft atConotragUrtrosSaemmis ---- Eg Figure35. RFepreosentar attSivnetgChhruf olmmwaic tiogrPadFmOoAfa ne forme A Pesds ExygenRescarch Page 153of 153 APPENDIX H TEMPERATURE AND RELATIVE HUMIDITY REPORTS 418-028:PAGE H-1 _ _ ARGUS i i Temperature and Relative Humidity Report Location: Room 05 i Protocol Number: 418-028 alr ota: noo a 3 E-- RangeofDates: 26-Mar-2002 14:20 to 10-Jun-2002 08:59 TaTarrsgettRange:Range: wer | ad TTooaa NNomoaroomffpBooaonrt: ww is o| w owls | Mean(SD): Y`MMiaanxmiimmsuumm:: | fm po NimbofeortoLot 050 Report Generated: 103 20022 328 692 (207) | S46 e7a1o20 | [i 6&435 wr ame | wr ood (244) | | | axe 6 -co_mments: SESS e R-- EVIe Ee WEDBr mY: m{eyfe--pen(eLeeeeeeeOATEe : foe i0.0e 3 APPENDIX I POSITIVE CONTROL DATA 418-028:PAGE I-1 Historical Control Data `ThchcotinisdvuiFctutynecNdtetigooantdaiolvcOeubmCsoeennrtvtratohtleiotDnraaBtiaantiatnengrdyaPnoSdstiactnoidmvaepreCdtoOenptnercroyalotDfianttghPaertaoercceehadnviuacrialealabnsltedafaStatunhdediMeTsotor Facility. esting Page | 418-028PAGE 1-2 s InformationforFunctional ObservatiBon: StudyNumber Tite oSalrti SubTseaxnce TOa be serBrvayaa-- tiioroAcntivsity MosUngoirTaSes. 1209 omits Bosigmoe 0P120o14Cs-oNnatirotSiobmeveBserakioonf oor CACDOBR VATPsRan om men extent oor D0D1T2015CrNieCrDoOoOiRcAyRBTonInSihne of wm wadiosts oor "DosagelormaNtiaomnba of msan eg 30) , 0715 15 \ sa ' PE . mw 3 ns ' ns ' 20s ' sa \ FCo0As1Ci2Dv01eO7CBNoRveVeASwoTwSoBRaiat edyof Pose 0 . El wm 3 aren os ' " oor Ba ' Gombe 40 ' Co01t2e022bNGLeCtDSiER BVrAaIosPihonOoRfit 102 abet doa 5 \ C0P H1C20D31o OCE-oRnNs teVarsAoSnuiTimcaeSyne ERvaabationof W emte a ES ma cavert os ' oor wa ' --_--_-- eomsphceamioe 4 4 1 ' | Page2 C0P1A2C05DoICE-oNRss etVoARSsPuibItmSceeBhartsattoonf PCAoLCmDOcBmR eVFRRas FCLCoDOBrR VeAPTcIaSaRatst _ 418-028PAGE 1-3 WS mite 4s 1 0 Ed = s ett ' oor sa ' upbamios 401 1 Waite 0 " vod 8 ' wo 0 1 whet 0 4 ' oor wo 2 ' I 1 en = ' Gombe 0 1 ' whet 0 4 ' poorr wwm 2 a s s Page3 --_--ee 418-028:PA1G4E Inforfomr MaottoriAcotin vit Soy Tae prEIT dip In-Life Test Beene Eo. DosageInformation omise HL S osl T s S 21e i6 y s ins et. hlorpromazioe 124 1 1 - . -on mm4s wwaoma os ---- nae fromTmT sanr - . oe - --wm-- owma -- Pag4e APPENDIX J HISTOPATHOLOGY REPORT -- ---- -- ----E-- E -------------------------- 4 418-028:PAGE J-1 RERESSEEAARRCCHH PATHOLOGYSSEERRVVIICCEESS,,IINNCC,. 458 EaanteBurrenAvaeea, onw,raPA T30500071 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCEENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT SUBMITTED TO: Raymond G. York, Ph.D., D.AB.T. Argus Research 905 Sheehy Drive Horsham, PA 19044 SUBMITTED BY: U-ReBrnn v8 32002 W. RVaeyteBrrionawrny,PaDt.hVo.lMo.g,isPtHD. July 3, 2003 418-028PAGE J-2 WOIRTAHLT(HGEAVRAEGPER)OCDOUMCBTIINOEND/DREEVPEELAOTPEMDENDTOASLE TTOOXXIICCIITTYY SSCTRUEDEYNOIFNGT7T7E0S6T SPONSORP'RSOSTTOUCDOYLN4U1M8-B0E2R8 T-7706.1 --_-- HISTOPATHOLOGY REPORT MEHNOcDco RESUS TABLE OF CONTENTS REPORT Page | ssid Quality ASSUTBNGE Ut SLAEMENt cc. Good Laboratory Practice COmMPHiance SIZMEMENt............................T TABLE 1. Incidence and Degree of Severityof Histomorphologic Observations................8 APPENDICES 1. HiSOMOIPOIOGIC OBSEIVANIONS.......c.ccrrrrn 10 142 Key 10HiStomorphoIOgGic ODSEIVEONS..............wevcsmn1 Tables 1-1. 12. HiHsitstoommoorrpphhoollooggiiccOObbsseerrvvaattioinosns-- GGrroouupp I|lMMaalleeRRatas .t...s................"..1.142 1-3. 146. HHiissttoommoorrpphhoollooggiicc OObbsseerrvvaatt--iiGGoorroonnuussppIIVllMMaallee RRaattss.............................................--65 1165.. HHiissttoommoorrpphhoollooggiicc OObbsseerrvvaattiioonnss -- GGrroouupp V| FMeamlaeleRtRSa.ts....................................7-9 1-7. Histomorphologic Observations - Group V/ Female Rats...................1-11 11. Individual Animal Gross and HistomorphoIOgy Data... to 170 Il. Histomorphologic Observations in the Liv-eFr1 Generation Pups......ll- to lIl2 Tables il-1.HFi1stGoOmNoGrIphRoUlOoNgiPUcPS.O.b.servations in the Live--r Group | - 2 ll-2. FHi1sGtEoNmOorIpAhHoOlNogPicUObsPerSva.tio.ns.in the Live--r GrouVp - 13 418-028:PAGEJ-3 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/PDREOVTEOLCOOPLME4N18T-A0L28TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER T-7706.1 -_-- HISTOPATHOLOGY REPORT METHOD male anMidc2ro0sacodpuitcfeexmaamlienCartii:onCDw(aSsD)mIaGdSeBRofVtAhFe/Psipuecsifireadtstfirsosmuefsivfergormou5p0s aindualnt norraeatpliroon(dguwacvataisgoenm)/addcevoeemlbooifpnmteehdnetarllievpeteroaxoitfceidt1y0dsocpsrueepesntoiixnnigciettaeyscths.tuoIdfnytahodefdicTtoi-no7tn7r,o0lm6iac(nrPodFsHchSoip)gihcwdietoxhsaatmghiee ggrroouuppsidoefnttihfeicaFt1ionG,enneurmabtieorno.frAatbsripeefrosuetlxinpeerofgrtohuep,staunddy ddeossiaggneslheovwelisngoftthheedcoons-e. trol and test substances are shown below. [J 0 Te T Ts e DOSAGE| ONFUMRABTESR GROUP PER SEX" DOSAGE | CONGENTRATION'| (mg/kg/day) g/mL) VODLoUsMeE (mLkg) [|vvy [[ooovr|Teow T |e + | wwoe | "TThfheornteemsaatlesdanuddtiebrnfaitewssmpaoaeslrtcensorenaaastxispdolnerfrGeddrcoosuoabopgseo|g1arn0odu0p%Vwacweterirsveeaafsssosiigghnneeedpdu1foprtohsxiecsooftdkoosipaansgateemchtpaeolvceealulaocutoagtoteniicostcn.o.n. a cohabMiatlateiornatspewreirode tghiavtencotnhseistetsetdsoufbsatamnacxeiomnucme odfai1ly4bdeagyisn.ninDgos1i4ngdacyosntbienfuoerde mthirnoiumguhmthoef d4a2ydabeyfsoroef asdacmriinfiiscter,ataifotne.r cFomepmlaelteiornatosfwaerceohgaibvietnattihoen tpeesrtiosdu,bsafttaenrcea omnucme odafi1ly4 bdeagyisn.niDnogsi1n4gdcaoynstibneufeodretharocouhgahbitthaetdiaony pbeerfioorde tshcahtecdounlseidstseadcroiffiacem(aDxaiyg2i2veonf altacataptpiroon)x.imaDtoeslaygtehse swaermee atdijmuesetaedchdadialyy.foTrhbeodfiyrstwediagyhtofcdhoasnignegswaansddewseirge- Research Patnlogy Services, nc. o 418-028:PAGE 14 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/PDREOVTEOLCOOPLME4N18T-A0L28TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER T-7706.1 eee HISrTOePeATrHOLOGY REPORT eter nated as Day 1 of the study. Pups were sacrificed and necropsied on Day 22 post- partum. in 10%Alnleurtartaslwbeurfefenreecdrfooprsmiaeldinanfodr tfihxeatsipoenc.ifTiehdettiessstueesswweerreefcioxleldecitnedBoaunind'splsaocleudtion for 48 to 96 hours and then retained in 10% neutral buffered formalin. The in-ife wpoerrteiopneorffotrhmeesdtubdyy,thneecstraofpfsiofesA,rgaunsd Rreesceoarrdicnhg, oHfotrhsehagmr,osPsA.necTrhoepstyisosbuseerpvraotcieosnss. ing, microscopic slide preparation and histopathologic evaluation were performed by Research Pathology Services, Inc. rats of G`rThoeuptisss|ueasndspVeciifniceldudfoerd:mibcrraoisn,codpuicodeevanluuma,tijoenjfurnoumm,10ilmeauml,e and 10 female cecum, colon, rectum, Peyer's nerve, stomach, pkaitdcnhe,ys,lunsgp,leseun,bmtahnydmiubsu,latrracahneda,meudriiansatryinballadldyemrp,htensotdese,s,epsicdiiadtyi-c mainddesth,orsaecmici)n,allivVeers,iacdlerse,nacloagglualnadts,inhgeagrlta,ndt,hyrporiods,taptaer,atshpyirnoaild,courtderu(sc,ervbiocnale, mlaurmrboawr (ssuteesmwuimt)h,grovoasrsiecsh,anugteersu.s,Invaagdidintai,onm,atmhemalirveyr aglnadntdhy(rfoeimdaolfe 1r0atms)alaendanadll1o0thfeermatlise- rpautpssinFe1acghenoefratthieoinntpeurpmsedifartoem deoascahgeofgrtohueps10wesreeleecxtaedmicnoendt.rolThaendlivheirgohf d9oosrag1e0 froeumtailneelyraptrsocweesrseeda,lseomebxeadmdiendedi.n paRreapffriens,ensteacttiiovneeds,amapnldesstaoifnetdhewsiethtihsesmuaetsoxwyelrine aconndtreolosianndforhimgihcrdoosscaogpiec gervoaulupatmiaonl.e rIantsadwdietrieon,stsaeicnteidonwsitohf the testes from the periodic acid-Schiff (PAS) reaction and examined. Upon The study was initiated on June completionofthe project, all raw 24, data 2(0r0em2aiannidngcowmeptlteitsesdue,onpaJrauflfyin3,bl2o0c0k3s., amricchrivoisncgo.pic slides and histology records) will be retumed to Argus Research for r---- 2 418-028PAGE J-5 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/PDREOVTEOLCOOPLME4N18T-A0L28TOXICITY SCREENING TEST `SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT RESULTS in the sTpheceiftiyepde,tiisnscuiedsenfcoretahnedmdaelgeraenedoffesmeavelreitryatosfatrheephriessteonmtoerdphionlToagbilcech1.anTghees microscopic observations in each rat are summarized intabularform in Appendix | tT(iThoanebs,lgerasonsIds-1anteoccor1r-or7)ep.lsaytAioobnkseeoyrfvttaohteitohmneisc,hridosesttcoaomipolirecdphfdoielnsodcgirniigcpstoiwboisnteshrvotfahtetihgoernsomsipscrrceochseacdonepgisecsToaibbnslteehrevI-sa1e:. traitosn,s wihn etnheaplipvleircaobflteh,earFe1 cGoenntearianteidoinn pAupppseonfditxhIel. coTnhtreolhiasntdomhoirgphhodloosgiacgeobgsreoruvpashairsetsoumomrmpahroilzoegdicionbtsaebruvlaatriofnosrmisininAcplpuedenddioxn lTllab(lTeasblIeisl-1lia-n1dalnIdl-2l.l-2). A key to the rats giNveontr0e.a3tmoernt1-remlga/tkegd/dmaiycroosfctohpeictecshtansguebsstwaenrcee observed in any of the male or in female rats given 10 mg/kg/day of T-7706. roid glaTnrdeaotfmmeanlte-rrealtastoefdthmeic3roasncdop1i0c mcgh/akngg/edsaywedroesaogbesegrrovuepds.in the liver and thy- modera"tTeheetnrleaartgmeenmte-nrtel(ahtyepdemrtircorpohsyc)opoifc ccehnatrnigleobiunlatrhehelipvaetroccoyntseisst(eTdaboflemi1n)i.maTlhteo affected granular hceyptaotploacsymt.es were enlarged with an increased amount of dense eosinophilic incidenTcheeoftrmeaaltmeenrta-tsroelfattehde e3ffaenctd i1n0thmeg/tkhgy/rodiady gdloasnadgceongsriosutpesd woifthanhyipnecrrteraospehdy (enlargement) of follicles) in male follicular cells rats (Table 1). and hyperplasia (increased Although the incidence in follicular cells Group IV was and small minimally cionuclrdeahsaevdeobveeernthaesscoocnitartoelsd,witthhethhyepelvretrr-oceplhlycahnadngheysp.erplasia in this group of rats known These microscopic changes in the effects of compounds that cause mliicverrosaonmdalthyernozidymaereicndouncstiisotnenwthweirteh the the hepatocellular hypertrophy results in a compensatory hypertrophy and hyperplasia of Research Pathology Services, Inc. 3 418-028:PAGE 1-6 WOIRTAHLT(HGEAVRAEGPER)OCDOUMCBTIINOEND/DREEVPEELAOTPEMDEDNTOASLETTOOXXIICCIITTYY SSCTRUEDEYNOIFNGT-T7E7S0T6 PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 r--H-- ISTOPATHOL-- OGY REPOr RT-- tee the thyroid due to increased plasma tumover of thyroxine and an associated stimulation of thyroid-stimulating hormone in rats." of the FT1hegreenewreartieonnopucposmpforuonmdt-hreeldaatmesd microscopic changes observed in the liver given 10 mg/kg/dayofthe test substance. and There were tissues which a few were other microscopic changes observed in the considered to have occurred spontaneously various and to organs be inci- odefntthaelsaencdhaunnrgeelsatweedrteo ncootmipnofluunedncaeddmibnyisctoramtpioonu.ndTahdemitnyipset,raitnicoind.enTcheeasned csheavnergietsy also are listed in the attached histomorphology tables. * TSraonpdheircs,ChJaEn,geEsigiennRbaetrgs,SeDcAo.ndBarraycthot,LLiveJr MWiacnrgo,soWm.aRl.,EnaznydmveanInZdwuicettoenn,CMa.uJs.,eTdhbyyroaind EaxnpdeLriiver mental Leukotriene Antagonist (L-649,923), Toxicology and Pharmacology 95, 378-387 (188) Research Pathology Services, Inc. + 418-028:PAGE J7 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/PDREOVTEOLCOOPLME4N18T-A0L28TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER T-7706.1 _--_-- HISTOPATHOLOGY REePOsRT SUMMARY of Microscopic examination was made of the specified tissues male and female Cri:CD%SD)IGS BR VAF/Plus rats used in from five groups an oral (gavage) tcioomnb/idneevedloprmeepnetaaltetdoxicditoysescreteoxniicnigtytesst.tudTyhe of five Tg-r7o7u0p6s with of rats the had bereenprgoidvuecn: tTh7e70ve8h,icolreal(layqbuyeoguasva0g.e5,%ocnacrebodxaylmeythfoyrlctehleluplroosteo)c,olo-rsp0e.c3i,fi1e,d3nourmb1e0rmgof/kdga/ysd.ay of In aedrdaittiioonnf,rtohme 1l0ivderawmasseaecxhaomfitnheed cmoinctrrooslcaopnidcahlilgyh fdroosmag9eogrro1u0psp.ups of the F1 gen- given 1N0omgt/rkega/tdmaeyntorfeTla-t7e7d06moircrinosmcaolpeicractshaginvgeens0.w3erore1ombgs/ekrgv/eddayinoffTe-m7a7l0e6.rats of maleTrreatastomfentth-ere3laatnedd 1m0icmrgo/skcgo/pdiacychdaonsgaegse wgeroruepso.bserved in the liver and thyroid The treatment.related change in the liver consisted of minimal to moderate thchyrepeeafrosltelrdiocuiplnhacyriedopefintccheeenltoirfiumlmoabilnueltahrreatshseewpgiarttohoucapystceoosfmpmaeannldseatrthaotesr.yefhfyecpteritnrotphhey tahnyrdoihdypwearpslaasniaion-f F1 geneNroattiroenatpmuepnst-frreolmatdeadmmsicgriovsecnop1i0cmcgh/akngg/deasyowefrTe-7o7b0s6e.rved in the liver of the and notAltroetahtemrenmti-rcerloastceodp.icTchheantgypees, wienrciedecnocnesiodrerseevdertiotyboefstphoensteancehoaunsgeins origin were not considered to be influenced by administrationofthe test substance. Resechve.panokgysonics5 s 418-028PAGE 1-8 WOIRTAHLT(HGEAVRAEGPER)OCDOUMCBTIINOEND/DREEVPEELAOTPEMDENDTOASLE TTOOXXIICCIITTYY SSCTRUEDEYNOIFNGT-T7E7S06T SPONSORP'RSOSTTOUCDOYLN4U1M8-B0E28R T-7706.1 T _-- He ISTOPATHOLOGY REPORTs QUALITY ASSURANCE UNIT STATEMENT b`eyptoarhtedGpurouAeafpllaRtrreayassAtaepiseaoscnrsutcfsrhoaronPtfahctethhUoesnloittgtiyysosSfuieesrRveepidsrceoeacasebr,socsIvhnicPen.agaR,tanhmvodielwcorobgoroyseec,Snoesppunilcietcrsesidm.deeIdnapcraicocnopcracdoaoatimnoncpngei,wa1iHnictIseloioepiSatpathhcnoeeougdsiraeeOosvdpaseluaoracaitrnoFanrsnsed Pracicaroquiaions pectedi he prtoc QCuoamnbiianteonRfoopEerdncikCToptatSoknyaihehveepnatc(1i9o6n),DoErCoOpGtuaildTii TSoatvoerof leas,maa,oSdcioon,oNo,5228 OrrinCanoricCoprtinandDevnet 1556),TheRidOECDPrisofGordaotrcs [ US FCoo1d88 6anFidn7aDlr.ugdition. GoodakakryPract RitFaol:.21 CFRPant, Npabsesr21M,iHiachof2,e6a7andWer 157).GoodLarson rcsSando forSetSto ngs, WNrnc oiontlsddfrdo0umQttnhuhgeeashtyperuaocstooscnduordlroiaccinstotcorafenoutdnnhaortJdttoypuuey3r.-.a2bt0Tai0hns0ge.pdrsioncsuepdeumcrteimosrnenspaworertrroafppyeGrArfoaormpeepdsGsoseohdo8wmHcnsordbelletooswy.soroTaecfnheowsesoramnrpo dietevi: Cates ct Datos Reporedto Date Reported I1ins2epe6ec0tei2on 07s Ma`PSstrtuodeyrsPSthcahosendee Timing Man11a23g31e10m0se2nt ost toSctcuaadrnyDeeinsrector Garam OoOuUiITgnGSs MEmiSbcaerdondoigmnyg oooimms [a[e7r7a OO0U1U1S3RTsS3 OrganHiiDzsasoiipaoaEntn'hstRoyeovmiew O01r/127n103 [aGuarrreayas G0G2R4RI0SN03SG RODeuupaoabrVrioPorrcoecpsaesrtiaiinnogn 002022a27211001033 GETS Prowbmisonudt GTS Gccaeerrreees cerns aToBnAscTs | FDraatrelpoert cGamraesss ooaets Ee Research Pathology Sova, inc. feWe_ HarkiJns, BYSing Bd Quality Assurance Unit s7.69D.a0t3o 5 418-028PAGE 19 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODSUPCOTNISOONR/P'DRSEOVSTETOLUCODOPYLMNE4UN1M8T-BA0EL2R8TOTX-7I7C0I6T.Y1 SCREENING TEST --_-- HISTOPATHOOLyOGYRReEpPORT GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT All aspects of the above-referenced study performed by Research Pathology Services, Inc. were conducted according to: OCamntainndPeoprEs rDisCToodapyaStnynidDevFaetnob1t5o0nboOErCpDnGetuTlodfTSaolroiofnCermaasoSeainv'o,nNo 142222 misonoErr apart xDevaar 156).TosOECDPic GostironPrckns (UCSOTF)oo1d86aFidnarl).gAdan Gon tortorrcsRoun: Fd ul.21 CR an NrisaeMeMsaoh 25.e1s5t8rdWear (1957),GodLatoProceScStySudoon rg We roar No deviations were noted that had any significant impact on the validity of the`study. Bey W. Ray Veterinary Bre ), DVM, PhD, DACVP Pathologist 07-03~53 Date Research PatySovios ne 7 418.028:PAGEJ-10 ORVAiLn(TGUeAGRE)CIA VBIERDTOESRErPEEIALWTEhoDem0OyeS.10TT.oO0x3UI5CIITTYYSTSUDoY i0 770a6 SP STNWO BATS -5706.1 mete1 Incidence and Degree of Severity of Histamorsholote Ghservations NTiomewraofprim1o/Grom: F6: haa vaa.nes. dewgeeneration cystic, corte, sultifocal -pyperrtrosptyvacslation,cortex, altifoca crBioHss. cortex. focal aaccoolantion,corte, dhthuse Ei) acwaelatiozonm, omsratess sR0oENoavwaw STE:: 1B6. ul" noe 5E c:anT.oe fLiinLlamation, meoss hroe wobowbhomowBoo%B FbTb P BooEo0L0Eow pwodw P ewoRm eooyo mooww wWowW wom emoem wmmoa mRme o e me ogny PDWomm omoyw wmoow isos o0 ft 0 meomRomewoe 9g Boososo0 0dHwm BwoBw 6 Boo0oo00 BoRm BwoEw geE s E Pn mdgmsesmew8n8n moi oam 6S.:lE a E $ Doo0000 8ow 0. uOmALe R ne T ---- Soo st 0 ow wBoRw mPmRRo mYoRm o@gm ToB .MLe TpeHRsiEty:: TT Ter rere oF spetFie TesfonMT rade BBo5oo80 30 8ow e woooy 1m BwoRw . ee 418-028 PAGE I-11 ORIATLH(TGUEAGREE)MCDOLBETIIEFODRUODTREECVPLEELWAOTRERoDEENTnSAEL1T5TO-RU1II5CC8IHTYYSSTWORYoEF 1T-h7a0r6 SPOSTURDYWTAGERR '770S6.1 TH1 (CLontEd) E&ww Incidence and Decree of Severity of Histomrphologic Observations TIWoTw Wow Tow Tow TfT T Kimberof soges)s/rog, ob BB Boh bh [---- exoorlaftateed spersaogenccells ovweewmeqom ppoiseecreadta Tewew mom inifnlirtatton, onaractesr-call. focal wTwPRw oRm Yom Bo.uRRnLe naifavemeartion, chronic focal oeBeRune 00 0 0AB miPooeow5eew0 Yw0 ooooF B00EE 8BREB]H To0..Bkian:en rn YBo.oisWi:en Sbo iorsiophmidegereration, cortical tubules, antes). sella dawiilantiaatrion pelvis fiireatt, sovonclear-cal, falimitifosl sirwertal zation, sltifecal B69 09 89 1 1noRp 0001 00 P Bosio0e0sow Pwodw mCPoweeeyn owoa 100 02 0 oo p moa1m g0ow e0m5omg oo8w dq 1PR0) Y WRmY QQ mPPomYewew mom9 TT Tom eras of serie TestoTT gre 9 E-- E ---- ye 418-028:PAJ-G1E2 i RESEOSSheISetYWorWeeansaTsFC6E.1Shr$T0 LE 1 (Contin) Incidence and Bere of Severity of Histomrptogtc hsrvtians RSeixb:erof :inlsfro: IDES (Corti: npr. crn, foc re`winimal 0NO.EXAMINED hyperpterrotpohpyy., SEi e `hepatocellbpusltcaerlu,tar, cceennttrrlautaar Sn2hfle3meation, crane, fosmtifoa) Mptast, test, focal --a--t---- En ---- amtiulldaactctattoi0om:n,hebpoaptheatocelta, tits] R W0he ipnetreiatsioni. /ppoelrRimborpshoncier ronchia) Snfnmaation, iterstita, focal scrataes, swt, foal 0w:ii nWionala--ate-- comensenion hHOoObKo hOH hKhN FhOhF Wm wom 0 P o P wa PP PEERY 1 10 10 10 10 p0 y10 @omo 0 om oonm owmo @ ssopheo ddb bs S gywPoosewseoh w4wgm oz 0 0 0 0 o mFwPoP w wmR ofm v mew em wm 0 www 3 ro 0 on 0 on wo 7? io cs TY 8 Boeoos0so0 now pmooyw 0ow 9ww4 omm w0 OPwReRwme Wome ow @ 0 ? 0 0mo9m wwym moo 0P F sp e0 r 0 om rwoyw T moR w ewoew Ywm mvo9o OTST aR oT FR eso eee a 418-028PA1GE3 RiALh(TOeWRAP)SHCES TBIOIOUTDP RCISEPETEIUAMMTYEEAWDO NBeTEnAtxL8TTT.S o-E65rI55i0Tc6Yy.1SST EPof 72-0706 THLE 1 Canine) cider and Degree of Severity of Wistasorsholgtc Ohserations HToierofwAwveslo/Groun: hoboEEE Bh Lhp0yipHerMpOaEst,aV,EDIIyApStTIcMiLc/(pCloanstemso)t:ic dRoweeeRoo --en-- Wrmewgee e 10.aWAL muse BSooeo0r0row "hRyipoe)rrltasta, Iprecyticrplasmantic Te BedPvme0e0mo0 8wbeoeedr ToT.!NoArL e e San-- weB,Waane soc: BB5o8o d0 Row Tof.aeeine 2cyst), t`ntraourtan R0:UlBoa.E fi saegssyou mi--rra--ttzation, foca 5o:lhioa.h, BBsooos d0 Hwm Bo5o0p800 Pom mRmemewmY g ooo e 0 ow fh mgogm wmoo owr o @4o8g 3 B0 3ow wm wqfm Bwoes Enlo]w ie BmoRw BwoBw m9gm T= Tom ede o period Tester, aT rater ------------------------------------ a ---------- 4I8-028:PAIG-1E4 ORiAnLi(BGeAGR)eTCIOSUOBIVNPOOEDETELROEoSPTEmAOAETNKrERDWaT0anRA5gL10TT'T.oO-6x5U5I3CSI0H6TY.Y1SSThoYe0l117006 T1ECaLniEne Ictdence and Degree of Severity of istamrspologic Observations Soxerof OPrin /Gro: PROSTATE (Contre: atroph--y. _--foal mntocat rie Ii nflammation. cheontc,focal /mltifocan ToE.WiAnLe Annfmltoiomna.tion,mmaossas, chrome ne f3o: toma. fso0a.noa sion: ddermmi.s, cocnrotne, foc we os0H.w RfL o T 0. Noay ee YToo.2 Wdif. ee:, B0.lionva aHtrioty NbooHoo %oBowobowh PfohE wmmooo oooo sc o0o0 8 i OFmROow wRYw S Pooeo2r0r nmoouw Pnmommew nw owoo i000 os of o0 6 00 0308m $s 3 9d 0 0 1i a ww o oomme owono e000 8 1d BBoeoes 0dHwm mBoBw wosooos 0dRow wBoEw BB5o8o 80 How BwoRw Bwoeo o0o 00 oX w Bmow FRLweRmRom mguy om B1%. ihoeo TT ToRT gee oT peed TestaoT grades SFR88 yr a2 418-028PAIG-1E5 RWAITLH (TGHUEAGREE)PCROOSVOPBOIFINCNRSTEOUIRDTOR'CSUEEEPLSVEETAENUTLMYEOGDEANETRSEAEL1RT6TO.TOX0-XI27IC7C8I0IT6T.YY1SSTUHDYAONFG7T.r7a0n6 T1H(CLontaEnt) Incidence and Degree of Severity of Histasorphologic Observations MabweraofpmlsGops wAoEw do dodfPofro STO (Contin): Nwaintiantgi!on, masa) glands mTewmBmRoEm wTohm edweimdainflammation, submcosa, forestomach WToemBoR nm o0 m0 edcemea rnefl amstion, submucosa, galandulararea Raeidiedrate m1 wWmomemoo e w2 o 0000 1s `dereorsaiotnes.). glandlarmucosa 100 0 1s W oommoFeg oo o T0E.ShTNISaRL ga): B90 90 10 8ow Edeigenedration, multifocal P0mow ewomy 1B 0. NRI L 0o0 oo 01 Bow deerratioant.ion, mitmit focal mWwow m omw o. HNiALe airony he Eire B10.BML "yHyppeeretrponpyty/pyprersslasta, folcercularepithe fim aBiodaerate "ultimbranchial body/cyst 0. MRL T= TewaT Tretdaesof specified TestonIT grades. wooooop 9oo Bow 05wow3 mooeeemo wmmma 00 0 01 EDERoP Oo wow8 moMm m@ eWono om oo ez6z001 6d3 [03 0 3442 Bry s 2 os ss wow @000 03 FY -------- 418-028PA1G-1E6 RAL (GHARRE) CUOEITNRODUTDEEPVEEARLTOREMDEBNOTSAEL18TT.OH0NIC0IGTHY SSTUeDYmcir 7.T7h7a06 Soo STUYMOREAT06.1 TLE 1 Cantina Incidence and Deore of Severity of Histamorholagc Observations Nxoer of Ewe Mrimlo/irop: T0 TBE H hr oE b T hETohTh -- IRpnifltleat]ion, chon, focal wFPweEweR dmOw w0ow g fsNtoa ini flamation. chronic. foal oeo0o880 oBw s3oBm mTmEmPwe mBgo 5iNoel Pno ow dihsteerntaieon, Ten Ww @a mwcroipthease.s.pipgimetnsted w0 w = arate J i FI To. hivae BaB) SE a 418-028:PAGE J-17 WOIRTAHLT(HGEAVRAEGPER)OCDOUMCBTIINOEND/DREEVPEELAOTPEMDENDTOASLE TTOOXXIICCIITTYY SSCTRUEDEYNOIFNGT-T7E7S06T PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT APPENDIX | HISTOMORPHOLOGIC OBSERVATIONS 418-028:PAGE J-18 WOIRTAHLT(HGEAVRAEGPER)OCDOUMCBTIINOEND/DREEVPEELAOTPEMDENDTOASLE TTOOXXIICCIITTYY SSCTRUEDEYNOIFNGT-T7E7S06T SPONSORP'RSOSTTOUCDOYLN4U1M8-B0E28R T-7706.1 HISTOPATHOLOGY REPORT -= .= <> = <> = P= 1= 2= 3= 4= SS = KEY TO HISTOMORPHOLOGIC OBSERVATIONS No change change not (pnroetsernetm)a.rkable, within normal histologic limits or indicated Tissue not available (specified tissue missing, insufficient tissue ninotplparneesoefntseinctsieocnt,ioanr)t.ifact precludes evaluation,or specified tissue Microscopic finding(s) in tissue(s) with gross observation(s). Within normal limits [no microscopic change(s) to correlate with the gross observation(s)]. Indicated change or lesion present Minimal degree or amount of indicated change or lesion. Mid 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 418-028:PAGE 1-19 SoAnxima)BeRumban: Bthlee OVRA1L (TGhAEVAGREE)PROCDOUMCBTIIPNORENODTDORECEVOPELELAOTNEMNDEENDRTOASL4E18TT-OO0KX2II8CCLITTYY SSTCUROEYENOIFNG1-E787706 SPONSOR'S STUOY NUMGER 7706.1 LE 1-1 Histamorsholoofc Observations ETis10ET9 1911s aaTntTs a15119 1T912T2 a19125 a1T913T1 Io1sz 191s fT_ s1zs 550% 5 8% 8os50% 8% AREne, arrrse Sr EfEimation, mon, chrome P---- wSionfnlamation, mucosa, chronic C3 HE1 ects, tet fHiemation, chronte, focal Ses ea a. "ee eee a a. a Seer oo <1 oo 4 oa Lg. Se eee pSSCiynsafcilT,at]r,atimoend, imanonuclear-cell, focalmi focut Simtion, awonte, fcstmttitosn wsesetcoconyoinuee,iTrs ing. aDemet Cee eae Ce ee eo oy <1 1 2 4 1 2 2. Loe ee oe 3-2-1 a 2. - - ERR focamatiocat Se ee ee ee I) 418-028:PAGE 20 OVRATL (TGAEVAGREE)PRCOODMUBCITNPIERODONTOROEECPOVELEALATOEWBDEENBTROASL4E1TT3OO-XX0II2CCIHTYY SSCTRUEDEYNIONFG1T-E7S0T8 SPONSER'S STUDY MBER T07706.1 THLE 1-1 (Gantinaes) Wistamarpralegic Gssarvations ASooixeal EgEoer: 3T10T8 EJSous fTouTs aIons lTorzzTalonTzs aleous aJTarseTaLssaTae)Jes [St SOinSflaEmit(iCoonn,tcanetn)t,s, foal/mitifossl 1 - =. - - 1 . y iSuticn, mots, chronic Se ee ee. So. vuoi: $e setae. os E"ea EdemoaAninn,falmamttiiooonns,, sSstbtmmaconossss,, 3fToraamsdtteamrach =ss ee r= Se I5s11s (mg) LLL Em ee. 1ee1 e1 Ie}g. eos ses. `"ompatenrtgthf,eophy/hperplasta, follicular ~iebrarchtel boa/eyst Bion. chronte, fot EE EEE Ses sa. 2a 3 418-028:PA1G-2E1 GTBA T(GAVAGRE) COEMBINPoERP NDOSTORCEEOPR LELAoTNEmBDeE ENSTRAEL418TT-o0Ox2I8IITTY SSTgUDiYnioFnTT77s08 SPONSE' STUDY WAGER T1081 oe 1-2 Hatamorghologtc Obersations T oESorclneWer: A 13102 1T 9106 510T 0 1a31T 0 1a31T 9 a16120 JTatzTsTa13198 oss piso pHhrb.on, petvis - @ a SWpaiahfatitssiti,oonn,v,irescptheorontn:otte,fiooctfeorcs,timmnittittoesnnt nTptorp:ny/hperstesta, folicater EA mt prarehte) ibgod/eyst 2tr22 yL1 D1boo1 pyPT11 . Spoors sz o bpa gt 1 418-028:PAJ-G2E2 SAnwal Nbr: sox OIRATLH(TGHAEVARGEEP)ROCDOUNCBTIINPORENODTDORECEVOPELELAOTKPENHDGEENORTSAEL41TT8GO.KX0II2CC5IITTYY SSTCURDEYENOINFG1T-E7S0T6 SPONSOR'S STUDY NHGER T-7706.1 Tete 1-3 Wistemorpholosic Observations I19101 DR 19105 a1W8107T1911I 2 18114 1T 8121T19123T19130 1T91T37 T1914s. SvHfvaiamctcuiwoonll,aattiioonn,, hheeappvaatotooncceeel,llluulflaoarar,,tmmiimiditetioifntaooteotn - +1- =-1 =1- =1- o=1z o1- 1ao.II 23 I"hmySpptoetrh:tertopthoym/hyperplasta, follicular -ulTimabranchial body/eyst SSoosS or ho opoe D 2 TI a C 5 418-028:PAGE 1-23 fonin GRear: Deathlwoe: GVOiAL (TGhAeVARGEEP)ROCDOUMCBTIIFNORENODTBROEECVPOEEMALTOEaMDENe0T0AS4L16TT-GO0AX2IIC6CHITTYY SSTcURDcYaiOnFe1-T7E87T08 SPONSOR'S STUDY NKOER T-7706.1 ue1 Histomorgholastc Observations F 1W3100W9N 10s WIsiorW13s a13W153T19141 1N 912 1a914sT Lovee 150 55 55 5 55 55 55 58S S5 R TeforR raermtogeie tccellcons a@3 LSppvtEiRe:rmopihya,heprsotmoec,ellear,ceontrn ilowler 101 E2 b11Lr1 p 1 =p1t1 THERE avin BEE wren @ THpviieRirOmtItrtOao:thnya/hhtyaplarbploodsytes,tfolltculor VoLssoonyos ono oe t rs 418-028:PAGE 1-24. OVRIATLH(TGHAEVARGEEP)ROCDOUMCBTIIFNORENODTDORECEVOPELELAONTPENMDEENDRTOASL4E18TT-OO0XI2I6CC.IITTYY SSCTAUCOEYNOIFRG1T-E7S7T0 SPONSOR'S STUDY NAGE 777061 me 1-5 Histemorphoogt Gbservations sBeAeoxintal eRuoer: TPIsiiV Et 911V 7 IsiV 24 191T 26 19127V 19128 a YoT us Isne) T s lousT dsise bates 0s sowowoso8%%0&0 aSqoaacuuclsetiosn,:Gortex, diffuse ce eee ee. Hifimation, meses, chronic oUATING cL: Se ee eee a. av re ews soa a lSfipltrmati:on, meewclar-cell, fel ESionfsTamation, chronic, focal << 1... LL se ee eee ey a"dgivoer;ticulum eee eo. f eTrosctoe)m.itmtodT fuolcaal ---------- pFO oop ""niTepoprchiarTiimtriastl,tonc,hfroomcnaoilrce,nucfloacaalr-call, tToro IIIT oo b"inrflaomat,ion,tcehsrotnoisc,llfioeesri/cmiattirfiocosblier 21 1= 2 21s: 12 11 f2 l1 } LMSDiEstDecI0y0iAEo,iSnsTINAL: mente 3 3 + + + oe oe oa oa 1 so 1 a oa a Eien, oon EEE -------------- 418-028:PAGE 125 SeAxie:a)EENaEber: Daihiwe OVRIATLH(TSHAEVARGEEP)ROCDOUVCBTIINPOERNDOTODRCEEOPVLEEALNTOEPDEpNDTOASL4E13TT-GO0XK2II0CCHITTYY SSTCURDYEEONFG11-6707706 SPONSOR'S STUDY NUAGER 1-7706.1 THBLE 1-5 (Contraed) Wistamrpralogic Ghsarvations H IT sis tT ou dsizH e dTsizVe 15127 V1912V8 19140 T19e14SsTlowTes eLSoree 5 505 ossowo80% 0% 0% E"inEflRemEatfieonc,amchurtoniitc,otfoeal/mitifoest E 1 = CE 1 C1 I TI Hatton, mess, chontc Se ee ee aa. 5inflation, submcoss, forestameh = 2 ~~... . . `HZSuppoieotrnhtner;togthuyn/hperplasta, follicular uitimcbranchia) body/eyst oEtton, crente, foes $3i oF - zsr 23y s oe 3 2 Cee ooo ---- eee---------------------- ts ee BnSooixr:neaGrhiesbor: Er 418-028:P1A2G6E OARATLH(TSHAEVAGRE)ECOMPBI[NPRREOODWTDOCRECEVOPELEDLAONTEMCADEGNOETTOASL4E16TT-OO0XN2II8CCHITTYY SSTOUDRYEofN7.T7E7N0T5 SPONSGR'S STLOY WNGER 777051 Thee 1-6 Histemorphlagic Observations E15012E190E19 JTso21TE190T2p3 19041 p1e5042 E1Ts304T4 1103050 J1os3053 1T3085 ee ee aa. Hfimation, mea, conte saa Sees, ee eee ee. FE n"ipenefr:iilvtarsactuilona,rpagrolyrmeonreprneinactiear, wLdecpneewgrelnpwteoisouaottrt,eas, sbmTteIct:ic/plemerte tnmete See ooo S Sos0 oLn Csoo Cr obnoIn. oTn C 2 oa. 5 4. SSE. ntrsonrion See oe oo S -_-- EER @ To SAenxi:malelNeabmer: 418-028:PAGE J-27 OVRIATLH(TGHAEVAGREE)PROCDOUMCBTIPINROEONDTDORECEVOPELELAOKTPIEWNDEGNDETROASL4E18TT-OO0KK2II8ECLITTYY SSCTRUOEYENOIFNG11-673770 SPONSOR'S STIOY NBER 777061 THBLE 1-6 (Continued) Histamorpralogic Observations [1T5A01TA2R1501s TA1302T1 A13023 A1T5041TA190T42 A19044 1aT9050T130T53 13085 s""ateaotwadt;itneofni,nmamtcaioos/na,l gslbamncdsoss, glandular er Sy Rreaho:naa) soayeyst FE See [I so. eo... ee ee as SREnt, fect e"esscr:ophages, pigmented se re ee. Ly sz 3 13 ss 3a a 10 418-028:PAJ-G2E8 OURAILT(TGhAeVARGEEP)ROCDOUMCBTIINPOERNODTORDCECOPVLEEALTNOEMMDGEENDTROASL4E13TT-OO0XX2II5CCIITTYY SSCOREYENOIFNG1-T7E07T06 SPONSOR'S STIOY WAGER T-7706.1 ae 17 Histomorpholagic Observations ASnoixn:alwwNoegber: isco TiTscos FAA TisoTn 18020 AA T1802T2 15025 AA T1302T7 13028 A T1903V0 19051 DthTwe somsomSo%5808os A"RSueEppeernterrLoaptohiyosfni.:accuyssttaitci,onc,ortceoxr,texm,itifee) = = @ - - - - - - "necrosifso,calcortex, focal ISIasfs tr aoan.: hRefprtrziatitsi,ocnhr,onimci,tiffooocealt wS"rimancfr:loaamtast,iofno,calchronic, focal/miltifocsl e"eifcraompartagieosn,,alnvteasrts,itfioaels, focal aoeoeoee ebe on. =Don= on= = 1 = =. pE o EEo EEr E i motte 2-2 2 ozs + 2 mn 418-028:PAGE J-29 ORVAALT(TGHAEVAGREE)PRCOODMUBCITNIPEORDNOTDORECEVOPELELAOTNPENMDEENDRTOASLE41T6TO-OX0KI2IC0CIITTYY SSTCIROEYEKOIFNG1T-E7S0T6 SPONSOR'S STLOY NUMBER 177081 THBLE 1-7 (Continued) Histonorpholosfc Observations Sonxi:m)TeNumsbr: ET1500V1E190E06 T 15011 E1902V E0 13022 E 19025E1T30E2V7 19028 TE1903TE0 19051 Dsthe ss0% 50S SNS 8% 88 SSnGerm(agtriotisss.Lecshiroonni)c:, focal a RE S"edaodAimnifnloinl,meammtatoiiuoonnn),, gwsluhabmnoeccoeosrss,. "earrcesaion(s). glandular meosa WS `"iotnimeos:ranchial body/cyat Toren, crane, foes footreensdtioamrsch Ce se eee S= e.e @ - a - ooe 1 BE I Ce sw eo Sk oh op or FS e"eRactrvopohange,s, tpeignmented 52: :03 z4o2: 3:z >tazsz 8os 12 418-028:PAGE 1-30 WOIRTAHLT(HGEAVRAEGPER)OCDOUMCBTIINOEND/DREEVPEELAOTPEMDENDTOASLE TTOOXXIICCIITTYYSSCTRUEDEYNOIFNGT-T7E7S06T PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT APPENDIX Il INDIVIDUAL ANIMAL GROSS AND HISTOMORPHOLOGY DATA 418-028:PAGE J-31 OVRAILTH(TGHAEVARGEEP)ROCDOUMCBTIIPNREOODNTDORECEVOPELELAOTNPEVMDEGNEDTROASL4E16TT-OO0XX2II5CCILTTYY SSTCURDEYENOIFNG1-1075710"6 SPONSOR'S STUDY NNGER T-7706.1 Individual Ante) GrAopspsenednidx H1i1stamorphalogy Dats AsNexI:HAL NRGER: 19109 DDoEsAeTHgToYwPE:: Sa1 criice-Scheduled 4055 BSERIATIONSS): SEIERAL: No gross changes. HISTONRPIDL01C OBSERVATIONS): Not applicable HISTOMRPHOLOGIC OBSERVATIONS: PLLRIOWNSPPTYATONEOO:DFE,. MSEUDBIKAOSTIIBNUALLR:: Tho: pTnaofspltsaermcpytaattsoitnoatn,s, (Tcymhmirpnahnioicmcy),tfico/cpallasmmuulctyitfiocca(lsod(earisntiema)]) hypertrophy/hyperplasia, follicular epithelium (ni1d) `THEFOLLOUINGTISSUES) VEREWITHIN NORMALLINITS: AHCDEORAGERUNTLAALTIGNLGANDSSLD CBjOoNldEonWARGO (STERN) o0BRoAIENNM JEW SFLiPEvIVeNEARL'SCOARTD.HLUMBAR RrSePcyINAL CORD, THORACIC SNSPOeLNvEIeEN,NALscVEiSaItCiLcES TREISATIRSY(BlLeA)DDER TESTIS (pas) Ths 0d of Record. 19100 pcieoeimomIoEs PKIADAITEIYTSROID SsPtIoNuAcLHCORD, CERVICAL TRACHEA 1 418-028:PAGE 1-32 ONRATLH(TGHAEVRAGEEP)ROCDOCMBTIIPNORENODTDORECEVOPELELAONTPOEMNDEGNEDTROASLE410TT-GO0AU2II0CCLITTYY SSCTRUEDEYNIoNFG1E-757706 SPONSOR'S STUDY UNGER T-7706.1 sA ex: WER: 19115 Individual Anime) Grsoospsenadni H1i1stamorghology Oats DooEsAeTHhoTYuPrE:. S1ucrfice-Schadsled 8085 GESRVATION(S): SENEBAL: No gross changes. HISTOMRPHOLOGICOSSERIATIONS): Not pp fable HISTOMRPHOLOGICOBSERVATIONS: AHEEPRAiRDETI?AOmIGoLtAsS:: TlTRiiAvaCeoHriEoA: ViiinncffuilsTaltmaratatttioionon,n., coscrhotrneooxnn,iice,ldeiaffrfo-urcsteenl((.smiifnnoiicmmaaalll)) (mine) aIIlnntfrillnaacmmbmaratatinioconnh,,ialcchhrrbooonndiiycc/,:eysfftaoccea)l/(msi1t1idf)oca) (sina) "TIE FOLLOMINGTISSUC(S)VEREWITHINNORMALLIWITS: cKioBoOlNwoEenrMsow (STERN) LrBoRAIyN cLLeIoePw NO0E MEDIASTINAL SRNEPERICVNTEAU,Ll SCIATIC com, Tiowicic SFSAPERLEAADTKLIRVODTE SSPPErIVoNEuARL'cShCOPRADT,CHCERVICAL Testis (bas) THIS GRINGY BLADER End of Record 19115 LSCoIsePuLdANTOIEN,G GLAND SUBHMIOISULAR SPPRIONSATLATCEORD LUMBAR Testis (ae) nz 418-028:PAGE 1-33 ORWAILTH(TGHAEVRAGEEP)ROCDOUMCBTIINPOERDNOOTREOECVPOEELLAOTNPEKDEENRDTOASL4E1T8TO-OK0KI2IC6CIITTYY SSLTRUEDDYHOINFGTT7E740T6 SPONSGR'S STUDY NMBER T-7706.1 Individual Ante GArpopsesnadnidx H11istanorphalogy Data AseNx:AL NER: 19115 DDEoAsTeHGTaIoPE:: Sa crifico-Schedulad `S055 OBSERVATION(S): KIDNEYS: Yottled tan and red, bilateral. HISTOMRPHOL0GICOBSERVATIONS): No microscopte change to correlate HISTOMRPHOLOGIC OBSERVATIONS: rLaLiIpvHeGeHs::NODE, SUBANOIBULAR: WhIyonpfmeTiracpmrlaaotssiicoaon,p,icIcycehhaprnghoeomcey,ttfcoo/pocltoarsfrmemalctay:tteficoa(lmt(da)nise) `THEFOLLOHINGTISSUE(S)WEREWITHIN ORALL1WITS: ACHeORsNEsSUALLATGINuG sGLO BaLOlENoE'WARROU (STERN) rSBRoAEINN SLPPEIVGNEARL'SCOpRaOr,enCERVICAL PSLRPIOISNVTKAALTNEOCDORED,, MEDIASTINAL LINBAR RENSEPCRITVNEA,L SCIATIC CORD, THORACIC THSRoouIcoy TTERSATCIHSEA (1a) TUERSITNIASRY(BpaLsA)DER End of Record- 19116 KEcpoiiweDosmIDES SSPPEALNREIAEMTNAILYRVOEISDICLES THINS ns 418-028:PAGE J-34. ORVAELT(GTAHVERAGEEP)ROCDOUNCSTIINPEORDNO/TDORECEVOPELELAONTPEMRDGEEDNROTSA4EL18TT-OO0XI2IC6CIITTYY SSTCURDEYENIONFG1-T7E7ST06 SPONSOR'S STUDY NUMBER 7706.1 Individual Animal GrAoosspeannd H1i1stamorphalogy Data IseMx:AL NrER: W15119 DoOESAETHGRTOYuPpE:: Sa1orifice-Schedulad A055OBSERITIONSS): SEAEBAL; Ho gross changes. HIST0O5IMC OBRSEPRVAHTIOON(S1): Not applicable HISTOORPIRLOIC OBSERUATIONS: cACooElRCoeu::AL suas: KLReiiCDvTweOe:Nr:s: vIianncffulloaalmmammtaaittoiinoo,nn,,comsruutcceoexss,ss,, dcichhfrrfoounnsiiecs. (m((immnodidae)sr)a)te) iiInnnffflilalamtmmrmaaatttiiiooonnn.,, cmmihocrnooosnnaiu,cc,lecfahorrc-ocenaillc/lm.(fatioi1cf6a)olca/lmul(tniifloa)ce] (sininal) `THE EOLLOVINGTISSUE(S) VEREVITHINNORMALLINITS: BiEPIylEoIWomaIDuES.(STERN) PARATITROID LBHREIAANIRPNTH JOOE, NEDIASTINAL CLLOeYMKPUHLANTOIDEN,G GLAD SUBMANDIBULAR oSEuIoNE NERVE. SCIATIC PEVER'S PATCH PROSTATE SENDA VESICLES TSSHPTYIoRNmOAILcDCORD, CERVICAL TSTREPASICTNHIAESLA C(OiRnDe.) LIMGAR RTSIPTINRASARLYC(OBpRLaDA),DETRHORACIC TSPiLEESN Ed of Record 19119 11s 418-028:PAGE J-35 ORVAILTH(TGHAEVARGEE)PRCOODVUBCITNPIERODONTOROEECVPOEELLANTOEPMDENRDTOASL4E1TT8OO-KX0II2CC5IITTYY SSCTRIEOYENIONFG1-TE7S7T08 SPONSOR'S STUDY MMGER 7-7706.1 Individual Anim) GrAoospsenadnid W11stomorshology ata sA ex ER: W19122 DooEsAeTHshToYvPeE:, Sa1 ceice-Schedaled R035 OBSERVATIONS): SENERAL: Mo gross changes. HISTOMORPHOLOICOBSCRIATIONS): Kot aplicable HISTOMRPHOLOGIC.OBSERVATIONS: {eLipIvieoPwi:oNmOaDoEe,s:SUBMANDIBULAR: Taker: IPiunnpffeilrlastmlraaastttiiaon,n,, lmcyhomrnpoehnonicucyc,tliefcs/orpc-lecaetsl/m,cmyttfiioccfa.ola(lw(ian(innniienlli))m1) inflamation, chronic, foc (anime) THEFOLLOUINGTISSUE(S)VEREWITHINbolLIMITS: ACeORAwESAUALTIGNLGavGsLAND CESoolnmoenmaww (STEOH) fBrAI KIONErS RENSECPRITVNEA,L SCIATIC CORD, THORACIC SSPPORERHEAARTLHRVOeDstcLes SSFPETIVoNEuARcLSHCOpRaDT,cHCERVICAL Testis (oa) Ths oid HLceeoaor TSpPERISoNTsAITLSATCE(OaReD), LINGAR URINARY BLADOER TAISSUVR(S)AMOTILAFORBEVALLUATEION: LHeH NODE, NEDTASTINAL End of Record 19122 1s 418-028PAGE 1-36 ORVALT(TGHAEVAGREE)PROCDIUNCBTIFINROEONDTDGREEEVDPELELAONTPCEMMDEGNEDOTRSAEL4.1T6T-OOCRU2II8ECLITTYY SSCTRUEDEYNONFG7E-97770 SPONSOR'S STLOY WINGER 777081 Individual Avimal GrAoopsasnadnidx H11itoorshology ta sAox L woSER: 19125 DoEsAeTHsrToYvPeE:. S1acrice-Schadiled SA0ss casTRIATIONS): SDMA No gross changes. HISTOHRPHOLOSICOBSERVATIONS): Net appiscatle HsToRvHoLeeopsenvaTION: c(LeiIvoVerE::NOE, SUSMAADIBULR: ThBRoOSlToAT:E: aI{itannrpffoellpraahgmmylma.eatsftiiioosocn,na,,lYccmahopirtseoenaiic,cfy,otccfiahaclrc/oepn()timcoi/nmmiuc(mTsyaeotlidi)facorsast()es)ad(esrfantien)al) Uitieabranchi bady/eyat THEFOLLOVINGTISSUG(S)VERE WITHINNome,LIMITS: coAelRomEnAL Gunos E0So0noe0wu (STERN) eSipoAlwIoelrosmioes RESLCPIITNMLNcOoEm,o.MTEHDOIRAASCTIICNAL SSNEPeRLhVElEEM,NALSVCEISAITcILCEs FSSAPtAIoNTwAhLRC0OIR0D, CERVICAL TESTIS (pis) Thikis TRACHEA End of Record 19125 CHlOeoMaUrLATING GLAND TSPePesIttNeAirLs'sCGOpRaaDr:cLivaAR URINARY BLACOER 1s 418-028:PAGE 1.37 OVRIATLH(TGHAEVARGEEP)ROCDOINTBINPOERNDOTDORECEVOPELELAOTWEWADEGNEDTROASL4E1T5TG-OH0XI2IC6CHITTYY SSTCURDEYNONFG11-070076 SPONSOR'S STUDY MMGER T-7706.1 Individual Ania) GrAeospsenadnid i11stmorphology data Asex:a wees: 19131 DDoEAsTeHcaTYoPuEr:: S1acrifice-Scheduled 8085GESERATIONS) SERA:No gross changes. HISTOMRPHOLOGIC.OBSERVATIONS): hat appl cable HISTORRPHOLOSICOBSERVATIONS: HEAePRaTOrEI:OAMMILOaEwSs:: BLiRvIOeSNrT:ATOED:E, SUBMANDIBULAR: TRACHEA: vIianncffuiolTltaarttaiitoionon,n,,cscohcrrntooenxn,iicc,ldeiaffrfa-cucese]eil((.3a1i11f9ao))cal (atninal) iIInynfpflaoarmmsmiaaattsiitooann,,, Tccyhhmrrpoohnnoiicccy,,bifcfo/ocpcaialst/s/mmmeitctiyiftfoiocccaeerlil((ena)itnlt)eal) inflammation, chronic, focal (ni1a) THEEOLLONINGTISSUC(S)WEREWITHINNODALLIWITS: KciBooOlNwoEenrNsOV (STERN) LirBRvAeIyN PARATHROID PETERS patch cLieTtoHePmY NODE, NEDIASTINAL RECT TSSPTRIoNuOAcLDkCORD CERVICAL UTSEPRSIITNNIAASLRYC(OBiRLaDA),DOELRKR TSEPSITNIASL C(OPRADS.) THORACIC End of Record 19131 pCYOEaNRVrUEA,mTSICNIGATIGCUND TSSPHLoEsEuN VEsIcLes 1 418-08:PAGE 1-38 OWRIATLH(TGHAEVARGEEP)ROCDOIMCBTIINPOERNDOTDORECEVOPELELAONTPEAMDEGNOETSAEL416TT-OG0AK2II8CCIITTYY SSTCURDEYENoINFG1E-707705 SPONSOR'S STUOY NABER T-7706.1 Individual nim GrAoospsenadnid H11istmorphology Data Asex:L BER: 10132 DoEoAsTeHoTIwPE:. S1acefice-Schedulod 8053oBsTRATIONS): SENEBAL: No gross charges. HISTOARPHOLO61C.OBSERVATIONS): Net app cate HISTOMAPHOLOSICOBSERMTIONS: THSvietRsoo:ioD:: ieStdniofmnlseabm/ranatfnilcoahnmi,aotlcihohrnoo,dniycls,eiybemftuoccoalsfe,mGtlfaoncaaelr (aar1e16s) (soderate) 14 EQLLONINGTISSUC(S)VEREWITHINNORAL1WITS: ACnORArEGUALLATIGNuGnGsLAND ine cStoOelNioGnnHsu (STERN) olSBEosSATeNn LIN 100, SUBMMOIBULAR YER, SCIATIC TSpePEvISEVRAT'CsCGOPRaADT).CHCERVICAL TSPEPRSIOTNSIATSLATCE(OPRiO), LNBAR TREiSCPmTIVsAL CORD, THORACIC URINARY BLATOER KcEpeIiboTiSomaoes SSPAOTRLAAETARHLNRVOEISDICLES TrkcheA IASSUVE(S)ANOTILAFOB REVALLATIEON: LIYE, HEDIASTINAL End of Record 19137 ns 418-028:PAGE 139 OVRIATLH(TGHAEVRAEGEP)ROCDOUWCBTIIPNORENODTDORECEVOPLEELAONTPEBMDEENORTSAEL418TT-OO0XX2II6CCIITTYY SSCTRUEOEYNIONFG7T-E7S7T0 SPONSGR'S STLOY NBER 7.77061 Individual Aniral Grsooppsenadnid H11istomorphology Data sAex:v rer: 1913 nDEoAsTeHcaToYuPrE:: S1acrifice-Schadsled SA0sS pscRATIONS): SENERALS Mo gross changes. HISIOHRPHOLOSIC OBSERUATIONS): hat appl cable HISTORRPHOLGSICOBSERVATIONS: SKetIpootuvioecmrnso::moes: TTRRACOHDE:A dairhnsiftsi(tlsat]tr.iaotnim:oend,mutemlooasnoolnucglleaanrd-sce(lwli,nizfao1c)al (minimal) esdocepeemnraetrionpftlayimahmayaptteioronpn,l,asSsiiuabb,rmufecooostsss,i,cugfllaoarrnedssuptlraaimrhceha]reu(anni (9n()fninlian)al) inflammation, chronic, focal (minieat} `Ti EOLLONINGTISSUE(S)VEREWITHINMORALLIMITS: CAeORAwSEUAATIGNLGavGDLsAND LINPH JOE, MEDIASTINAL SBlOeNosEntWo V (STERN) LoiS0ava0eT0rnBN LTAPH MODE, SUSHMADIBULAR NERVE, SCIATIC TSFeEPsVItEMiRAs'LSC(POaARTeDCHCERVICAL FTSREPOSISTNTIAASLTCE(O7RaO), LWGAR TREShCPTINOsAHL CORD, THORACIC End of Record 19134 rHceeeayot SSEEAPNRILMiARLOvIeDces URINARY LroER 1s 418-028:PAGE J-40 OVRAALT(TGHAEVAGREE)PROCDOLMCBTIIPNORENODTDORECEVOPELELAONTPOEMMDEEENDRTO,ASL4E16TT-GO0HXI2IC5CLITTYY SSTCURDEYENI0N1G-77675076 SPONSOR'S STLOY NUMBER 7706.1 Individual Anime) GrAeospsennddi W1i1stamorghology Data a sex recs: W19135 DooEsAeTHcTrYoPwE:: S1acrice-Schadiled R05 OBSCRUATIONSS): SEMBALL No gross changes. HISTOMRPHOLO61C.OBSCRUATIONS): Not ppfcable HISTONRPHOLOSICOBSERMATIONS: PLKRiiOvoSevTeArTsE:: IIInnnfffllatamrmmaaatttiiioconnn,,, ccmohhnrrooomnncl,,eaffroo-occeaalltl//,mmfttoitcffaoolcc/samul((tmntiifnnoiicmmaaa]ll))(ainisal) HEFOLLOVINGTISSUES)VEREWITHIN ow,LINTS: sCAeoORNrEUMAALTIGNLGAN0S D LYMPH NODE, NEOIASTINAL GoBTOleNoEnJew (STERN) LINPH MODE, SUBMANDIBULAR SDBRoEAIESN H NERVE, SCIATIC TSBePEIsTNtEAiRLs'SC(OPaRAeDT).CHLUMBAR RETSEPCSITTNIIAMSL C(OPRaOs,) THORACIC TSSPLosEEuN VESIcLEs TRACHEA UriuaR 50088 End of Record 19135 chErioieomlonuioes SSPPTAIRoNAuATcLHHYGROORIDD, CERVICAL THR 11 418-028:PAGE I-41 GBVAiLt(TGIAEVARSE)PGCDILMEBTIIFNEOODNDTREEYOPEELTIMEMBDEEN0RT0ASL41T8TO-OX0UI2CC8IITTYY SSCTRUCYENOIFns1T-e70o8 SPONSOR'S STUDY NpoER 1-7708.1 Indika) Anise) Gsropmearr H11istomrshotogy Duta Sa o wreck: n15102 DwsEeTTgoEr,: S1ar Fic-Scheduled 8058GascRTIONS); ONES: Bitatera- mottled HISOBCT OBSERO UATIORNS): Dr -- His081tessorTIlON: TLhixvioeoiesrn:s:: tiionmfmlraiamrmroasctcihaoipnt,eclchcrbhoaonndtgyeei,ytefootccaolr/rmeultattiefacal (a11d) HEFOLLOUINGTISSUR(S) WEREWITHINMun LIITS: xiokers Ed of Rona Tolez - TTT 1 418-028:PAGE J-42 OVRAILTH(TGHAEVARGEE)PROCDOUMCBTIINPOERNDOTDORECEVOPELELAOTNPEOHDNEGNEDTROASLE416TT-GO0RK2II5CCIITTYY SSTCURDEYENOINFG1T-E7S7T06 SPONSOR'S STUDY NUMBER 7-7706.1 Individun) nine] GrAoospsenadinx H11istamorpalogy Date AsNeIx:MAL NBER: 19106 DooEsAETHGToYwP:E S11acrifice-Schaduled `SAUSSOBSERVATION(S): SEMERAL Wo gross changes. HISTOORPHOLOIC OBSERVATIONS): Not applicable HISTOORPHOL0IC OBSERVATIONS: TivRoei:o: End of Record 19106 uIlntfliacmhmraatnicohni,alchrboondiyc/,efysotcal/multifocal (mid) ee 418-028:PAGE 1-43 OVRiAL (TGIAEVAGRE)ECPOMBRIFNOREIDDTDGREEECVOPLEETLAoNTImEAeDAGoTGEASnLE.416TO-OA0KI2IC8CHITTYY SSTOURDEYNIoRFG1-T1E7R0T5 SPONSGR'S STLOY WINGER T-7706.1 Individual ies] Gdrosospanes H11istomorshology Data Asenx:na woeER: 19108 DoEsAeTHgToYwE:, S11uc fie-Schedulad HOSS BSTRUATIONS): SEMA No gross charges. HISTONRPOLO0IC ORSERATIONS): tot apcatle STOO BCosM tRvATP IONS: uve: pitndPaomnattei,ont,enSsihoonn,ief,ocfaolce mitface) (siiaal) THEEOLLOINGTISSUR(S)WEREWITHINMgUALLIMITS: Ro EE) EE ey 418-028:PAGE 1-44 OVRAILTH(TGHAEVRAEGEP)ROCDOUMCBTIIPNORENODTOORECEVOPELELAOTWMENNDGEENDRTOASL4E18TT-OO0XX2IIC8CIITTYY SSCTRUEYCROIFNG1T-E7S0T6 SPONSOR'S STIOY NBER T-7706.1 Individual Antes Grdoespseanndd H1i1stamorshology Data sAexI:C Ng: 19110 DDEoAsTeHsToYuPrE:: S1a1crFice-Schedaled S803 ORSERIATIONS): SEMERAL: No gross changes. HISTORRPHOLOGIC ORSCRUATIONS): hot applicable HISTOMRPHOLOGICOBSERVATIONS: TLiikvedsi.o: End of Rocore- 19110 PIynpfalretmraotpihoyn/.ypcahrrpolnaisci,a,ffooclalc/umlatrfoecpailth(eatsniimnala)i10) nu 418-028PAGE 1-45 OVRIATLH(TGHAEVRAEGEP)ROCDOUNCBTNIPERODONTOORECEVOPELELAONTPEWYDESNDETOAS4LE16TT-OO1KX2II8CCIITTYY SSTCURDEYENIONFG11-675075 SPONSOR'S STUDY MIMGER T-7706.1 Individual An) GrAopspseanndd W1i1stcmorphotogy ta asex:L nega: x9113 oDEuAsTtHGrTYoPuEp:: S11acrifice-Schaduled S805 QESTRUATION(s): KIDNEYS: Left pelvis, shight dilation. HISTORRPHOL081C QRSTRATIONS): anatation, pelvis HISTORRPHOLOGICOBsERvATIONS: woes: dlatation, pelvis (ai1d) IA EOLLOUINGTISSUC(S)VERE WITHINNBO LpurTs: uve THRO Ed of Record 10113 TTT ---- 1s 418-028:PAGE J-46 OVRIATLH(TGHAEVAGREE)PRCOODMUBCIFNTAEIODOTUOROCEEOPVLEEARTLIEODNEGNEDTROASL4E18TT-OO0XL2II6CC.IITTYY SSCTRUEYENI0NFG7T-E740T6 SPONSOR'S STUDY NNSER T-7706.1 Individual Anima) GrAooepnenadnid i11stonorphology Data SABL MBER: 19120 DDEoAsTeHsToYuPrE:: S1a1crifice-Scheduled S055 QOSERUATION(S): SEUEBALL No gross changes. HISTOHORPH01061C OBSERVATIONS): ot spplfcable HISTOMSRPHOLOSICOBSERVATIONS: Lives: Tiinpfildaomamtast,iont,encshirono,nicf,ocaftocal/miltifocel (sintesl) HEFOLLOWINGTISSUE(S)VEREWITHIN nomaLLIMITS: THrROID E03 of Record: 19120 Tr 11s 418-028:PAGE 147 OVRIATLH(TGHAEVARGEEP)ROCDOUMCBTIIPNORENODTDORECEVOPELELAGNTRENNDEENDRTOASL4E18TT-OO0XX2II5CC.IITTYY SSCTRUEYENIONFG1T-E7S7T06 SPONSOR'S STLOY NNGER 7706.1 Individual Animal GrAopppseanndd H11istororphology Data 5Av ner: W19120 DoEosAtTHsToYwPE:: S1a1crifice-Schediled 8085 QBSERATIONSS): SEERA: Wo gross changes HISTORRPHOLO8IC 0BSCRATIONS): Not appceble HISTOORPIOLOGICOBSERVATIONS: Tiuevoei:o: End of Record 19120 einrfilraompattiyohny,pechrrpoinaics,i,fofcoalll/imciutliafroceap)ith(ealtintuemsl()anise) " wy --_-- LL 418-028:PAGE 1-48 OVRIATLH(GTAHVEAGREE)PRCOODNIBCTNPIERODONTORDCEEOPVLEEALNTOEPMDMERNDTOAS4LE10TT-OO3XK2II8CCIITTYY SSTCURDEYENOIFNG1E-32106 SPONSOR'S STUOY NNBER T-1706.1 Indivicual imal GrAoospsenadnid H11istororphalogy Data sAxNAL WoER: W19136 DoEsAeTHcTaIPoE.: S11ucr fca-Scheduled 8085 OBSERVATION): KIDNEYS: BfTateral- mottled. HISTOMRPHDL001C.ORSERIATIONS): anatation, pelvis HISTOMORPHOLOGICOBSERVATIONS: TLwaiiovRwideairso: End of Record 19136 eivtaaictmuasotbliraoatnnic,ohnipehelelpvaibtsoodcy(eyaletyTnaaittnaarl,) multifocal (stnimal) ns a ---- ------ 418-028:PAGE J-49 OVRAILTH (TGHAEVARGEE)PRCOODMUDCITNIPEORDNO/TDORECEVOPELELAUOTPENHDGEEDNROTSA4EL18TT-OO0XX2II8CCIITTYY SSTCURDEYCNOINFG1T-E7S0T5 SPONSOR'S STUDY NNER T-7706.1 Individual Anima) GArpopsenadnidx H1i1stamorphology Data MseIx:NA NrgER: W19138 0D0EsAETHGrToYvPeE:: S1a1riflce-Scheduled `SROSSOBSERVATION(S): SEUEBALS ho gross changes. HISTONRPI0L061C OBSERIATIONS): Not applicable 'HISIOMRPHOLOGICOBSERVATIONS: `Toro: ttesbranchis) body/eyst IHCFOLLONINGTISSUE(S)VERE WITHIN MORAL LIMITS: ve End of Recor- 18138. " Tr ne ---- EE ---- -- ------ -- 418-028:PAGE J-50 GRVAILTH(TGAEVARGEEP)ROCDOUMCBTIINPORENODTOORECEVOPLEELAOWTIEANDGEENGROTSAEL41TT8OO-KX0II2CC6IITTYY SSTCURDEYDNOTFHS1-T7ES7T05 SPONSOR'S STUDY NNGER T-7706.1 Individual tna] GAreospsenadnid H11istomorphatosy ote MsexA:L WER: 19135 DooEsAeTHcrTYoPwE:. Su11ce ice-Schadsled 8055 OBSCRATIONS): SEMERALS Wo gross changes. HISTORRPHOLOGIC ORSERUATIONS): hot applicable HISTONRPHOLOGICOBSERVATIONS: movi: hypertrophy/hyparslasta, follicular epithelium (n11d) HEFOLLOWINGTISSUE(S)VCREWITHIN go.LINITS: ve 1 418-028:PAGE 1-51 OWRIALTH(TGHAVERAGEEP)ROCDOUNCSTIINPOERNDOTDORECEVOPELELAOTNPENHDGEENDTROASLE41TT6OO-RX0II2CC5IITTYY SSCTRUDEYENOIFNG1T-E7S7T0 SPONSOR'S STUDY NBER T-7706.1 Individual Anime] GArpopsesndainxd 1H1istamorphalogy Data ASNeIx:NAL NoMBER: 19101 DooEsAeTHGTaYoPE:. S1a11crifice-Scheduled 05SOBSERVATIONS): GENERAL Ho gross changes. HISTOMRPIOLOGIC OBSERUATIONIS): hot applicable `THE FOLLOVINGTISSUE(S) VEREWITHINNORMALLIWITS: uve ao10 End of Record 18101 Cm na 418-028:PAGE 1-52 O`RWAILTH(TGHAEVARGEEP)ROCDOUMCBTIINOENDDREEVPEELAOTPEMDENDTOASEL. TTOOXXIICCIITTYY SSTCURDEYENOIFNG1-T7E7S0T6 SPONSPORRO'TSOCOSLTUDNYUMBNEURKBE4R16-7-0727808.1 Individus) Antes) GrAopspsendainxd H11istomorphology Data seANxI:MAL NOVBER:[)15105 DDOESAETHGRTOYUPPE:: Sa11o1rifice-Scheduled `5805SOBSERVATIONS): GENERAL; Ho gross changes. HISIOHORPHOLOICOBSERVATIONIS): Not. applicable 'HISTOHORPHOLOSICOBSERVATIONS: ves: inflammation, chronic, focal /mltifoca) (minimal) IH FOLLOVINGTISSUE(S)VEREWITHINNORMALLINITS:. THYROID. End of Record: 19105 TT "2 418-028:PAGE J-53 ORUALT(TGHAEVAGREE)PROCDOUWCSTIINOENDDREEVPEELAOTPEMDENOTASLE TTOOXXIICCIITTYY SSCTRUEDEYNIONFG.1-T7E7S0T6 SPONSFORRD'TSOCOSLTUDNYONBNENRE4R18-T-0727506.1 Indivicun) Antes] GrAoosspeannd H1i1stonorphology Date seAxNI:MAL NOER: 19107 DDEoAsTeHgToYwPE:: S1a1c1ri ice-Scheduled 8055OBSERIATIONS):. SEVERAL: to gross changes. HISTOMRPIOI0G1C OBSERVATION(S): Not splfcable HISTOORPIOLOGIC OBSERVATION: Tuvoei:: End of Record 19107 WIIyinpfralarabemrrmaaotnpihcoyhn,i,haytpcahrrbaoolndatyse/,icay,sftofcoalll/imclutliafrocpa1lthe(lanfimmal()ainiel) ns 418-028:PAGE J-54 OURAILT(TGHAEVAGREE)PROCDOUNCBTIINOEND DREEVPEELAOTPEMDENOTSAEL TTOGXRIICCIITTYY SSTCURDEYENOIFNG1-T7E7S0T6 SPONSPORRO'TSOCOSLTIONYMGNENRGE4R16-7-0727506.1 Individual Ante) GArpopsesndeinxd 1H1istamorphalogy Data IseAx:L NBER: 10112 DoEuAsTtHcrToYuPpE:: Sc11r1 fice-Scheduled 8055OBSERITIONS): SENEBAL: Yo gross changes. HISTOMRPIOLOSICOBSERVATION(S): ot applicable HISTOMRPHOL051C OBSERVATIONS: THRvoerio: End of Record. 19112 uinlftliaamombartainocnh,ialchrboondiyc/,eysftocal/mltifocal (minim) nea 418-028:PAGE J-55 ORWAILTH(TGHAEVARGEEP)ROCDOUVCBTIINEODN RDEEPVEEALTOEPDKEDNOTSAEL TTOOXXIICCIITTYY SSTCURDEYENOIFNG1.T7E7ST08 SPOISPORRO'TSOCSOTLUDNYMGNERER4167--0727808.1 Individual Ante GrAopspsenadnidx H1i1stamorphalogy Data AsNxI;MAL WER: h19114 oDoEsAeTHgToYwP:E: Sa11c1riice-Scheduled 8055OBSERVATIONS): SEAEBAL:Yo gross changes. HISTOMRPHOLGGICOBSERVATIONIS): Not appease HISTOMRPIOLOGIC OBSERVATIONS: TuHveD:: End of Record 19114 tiinfnlaabmrmaatnicohni,alchrboondiycs,eyaftocal/mult1focal (atntna) FE 12s 418-028:PAGE J-56 OVRIATLH(GTAHVEAGREE)PRCOODMUBCITNPIERODONTOOREEEDPVLEEALNTOEOEDMNOTSSAEL18TT-OO0KK2II8CCIITTYY SSTCUROEYENIONFG1T-E7S7T08 SPONSOR'S STUOY MMBER T-7706.1 Individual Anima GrAoospsenadnid M11itoorshology ata a sex: woes: W19121 DoEsAeTHiToYwPE:. S1u1c1rfice-Schadsled A058 BSTRUATIONS): SEURAL: No gross changes HISTORRPHOLOGICOBSERVATIONS): Not pple HISTOMRPHOLOGICOBSERVATIONS: uve: mio: Ed of focord- 10121 VUIainctfuilsnaigmabmtraiatoninco,nh,ihaalcphurbtooondciyeccl,yfusottcra.lfmmilltttiffooccae)l ((RmIiTEn)al) -- 1s 418-028:PAGE J-57 OIRATLH(TGHAEVAGREE)PROCDOUMCBTIINOEND/DREEVPEELAOTEPDHENDTOASLE TTOOXAIICCIITTYY SSTCURDEYENOIFNG17TE7S0T6.. SPONSPORRO'TSOCOSLTUDNYMGNELRHBE4R18-10-276706.1 Individual Antes GAroospsenadnidx H11istomorphlogy Data seAxI:NA MOSER: W19123 DDEoAsTeHtToYuPpE:: S1a11crifice-Scheculed `HOSSCRSERVATION(S): SEMERAL: No gross changes. HISTONRPHOLOGICOBSERVATIONS): Notappl cable HISTOMRPHONOSICOBSERVATIONS: ver: inflammation, chrontc, focal/mtifocal (mintnal) THEFOLLOWINGTISSUE(S)VERE WITHIN MORAL LIMITS: THYROID. End of Record 18123 TT nz 418-028:PAGE I-58 OIRATLH(TGHAEVARGEEP)ROCDIUNCGTIINPOERNDOTOORECEVOPELELAOTNPEMRDGEENDRTOAS4LE1T6TO-GX0KI2IC5EIITTYY SSTCURDEYENOIFNG1-TE7S7T0. SPONSOR'S STUDY NMSER 7-7708.1 Individual Antes] GArpospsenadnidx H11istoorsholosy Dota ASNBI:MAL NORBER: 019130 oDoEsAeTHoTwYePE:: S11cr ice-Schodulad 8055 OBSERVATIONS): SEUEBAL: No gross changes. HISTON8PH0L061C OBSERVATIONS): Wot applicable HISTORPHOLOIC OBSERVATIONS: TvieRosi:o: End of Record. 19130 hiynpfalratmraotpihoyn/,iycpherropnliaca,af,ocfaoll/leiuclutl1afroscpailne(mliniiummal()af1d) - i= 418-028:PAGE 1-59 OURAILT(TGAeVARGEEP)ROCDOUVEBTIINPEORDNOTORDCEEOPVLEEALTNOEHDEGNEDTROASLE41T0TO-OK0XI2IC8EILTTYY SSTCUROEYENONFG17-678076 SPONSOR'S STIOY NUMBER T7706.1 Individual Anima) GrAooppsenadnidx 1H1istomorphalosy Osta AsexL HpER: W19157 oDoEsAtTHsToYuPEr:: 1Sa1crifice-Scheduled SAOSSOBSERVATIONS): SEERA: No gross changes. HISTOMORPHOLOSICOBSERVATIONS): Not ppl tcable HEFOLLOUINGTISSUE(S)VERE WITHINMRLLINITS: uve THRO End of Record 19137 TTT ns 418-028:PAGE J-60 ORIATLH(TGHAEVAGREE)PROCDOUMCBTIINPORENODTDORECEVOPELELAONTPEMRDGEENDRTOASLE418TT-GO0AK2II6CCIITTYY SSCTRUEYENOINFG71T-E7S7T08 SPONSOR'S STUOY NHGER 7-7706.1 Individual Anina] GArpopsesnadnidx H1i1stomorsholosy Dota sAeNxAL WABER: W19146 DooEsAeTHaTaIoPwE:. S1a1c1ri fice-Scheduled S055OBSERVATIONS): SEMERAL: Ko gross changes HISTORRPIOLOGIC QASERVATIONS): Not pplteate HISTORRPIOLOSIC GASERVATIONS: uve: vacuolation, hepatocellular, midzons] (af1d) THE EOLLOVINGTISSUC(S) VEREVITHINNORMALLIWITS: THvRo0 End of Recora- 19146 11-3 418-028:PAGE I-61 GiRAT(TGHE1AGR E) COME OIFNGRDOTE REEEAPREELAoTRmERT DEGNRSTRAEL1-TT0ORK0II8CCIHTYY SSThUYeopF 1E-07078 SPONIR'S STUY RGER 7105.1 dividual Anis) Gsrpeeancd H11stamrspolosy bata iJHr -- W SoEsAcNGTaIrPE:, S1vhri ice-Schoduled `GSROESAS 0LBSENRoVAgTrIoOsNs(Sc)ha:nges. HISTORICCesEIvTION: ues: THYROID: rd of Racors 0100 'HoItSTOpMOiRPtHOtLOaGIC QBSERVATION(S): rreaptt,, Pebsatoella ular, Eceontrolar (ninioat) hypertrophy/hyperplasia, follicularepithe] fum (minimal) wa 418-028 PAGE 1-62 OVRAALTH(TGHAEVRAEGEP)ROCDOUMCBITNIPERODONTOROEECVPOEELLAOTNPEYDMENCDTOASL4E18TT-OG0KK2II5CCIITTYY SSTCURDEYENIONFGTE-787706 SPONSGR'S STUDY WNGER T-7708.1 Asex:L Woes: x19103 Individual Ania) GrAopspsendainxd H1i1stomorshology ata DoEoAsTeHaToYePE:: S1uvcrifice-Scheduled S055OBSERUATIONS): EUEALS Wo gross changes. HISTOMEPAOLOGIC ORSERIATIONS): Not applicable HISTORRPHOLOGIC OBsERvATIONS: Lives: hypertrophy, hepatocellular, centrilobular (aintesl) HEFOLLOVINGTISSUES)WARE WITH Hom,LTS: THrROID End of Record 19103 TTT ---- nx 418-028:PAGE J-63 OVRIATLH(GTAHVEAGREE)PRCOODMUBCITNIPEORDNO/TDORCEEOVPLEELAMOTEPMDHSENDETOAS4LE16TT-OO0KK2II6CCIITTYY SSTCURDEYENIONFG71T-E7S7T06 SPONSOR'S STUDY KMBER T-7706.1 Individual Aten) GrAoosspeannd H1i1stamorphetogy Data AsNexI:MAL NBER: 19106 DDEoAsTeHGrToYuPpE:! SIvacrifice-Scheduled 8055 OBSERVATIONS): SEMERAL: Mo gross changes. HISTONRPHOL1C OBSERVATIONS): Not opplteable HISTOHRPIOLOGIC GRSERVATIONS: Liver: hiynpfelratmrmoapthiyo.n,hecphraotnoicce,llufloacra,lc/eeunlttriifoocbsu)lar(stn(iasrsal)) THE FOLLOUINGTISSUES)VEREWITHIN NORMAL LIMITS: THROID End of Record. 19104 1-3 418-028:PAGE J-64 ORVAELT(GTAHVEAGREE)PRCOODMUBCITNIPEORDNO/TDORCEEOVPLEELAOTNEPMDHGEENDRTOAS4LE16TT-OO0XK2II6CCIITTYY SSTCURDEYENOIFNG1T-E7S7T06 SPONSOR'S STUDY MBER 7-7708.1 Individual nine] GrAoosspeanns H1i1stamorphotogy Data Asex:L WogER: W19118 0DoEsAETHsTaYoP:E SIavcrifice-Schaduled 05SOBSERVATIONS): SENERAL: Yo gross changes. HISTOHORPIONOGIC ORSERUATIONIS): Not applfcable HISTOWAPIOLOGIC OBSERVATIONS: Lives: hiynpfelratmrmoapthiyo,n, hecphraotnoicce,iluftoecra,l/cmelntt1rfiolcoablula(rnt(nmiisnai)nsl) `L4EFOLLOVINGTISSUE(S)VEREWITHINNORMAL LIMITS: THRoID End of Record- 19118 es 418-028:PAGE 1-65 ORAL (GAVAGR E) CONIHNE FoERnDOSTROvECPeLEAaE MTmEBDeEHDRTOaS4EL15TT-OO0XU8I8GCIHTTY SSToUaDiYnOiFn1-T7r708 SPONEIR'S STUY WBER T1081 Individual Anima rsepps ann H11istory tata pae o we: 16133 GosEcNGTaIrP:E, S1vwi tca-Schoditad sassosemuATIONE): SOUSA Ho grons changes HISTOMRPOL0G1C BSERUATIONS): ot aplscable HISTOMEPIOL0GTC BsERVATIONS: wHesri:n: Edo aan 19138 R TTpEiermtarE noeptnyt.ey bhaeptaateocye:llulaar1, coentrrilosbulare(wfat(ear] f) nas 418-028:PAGE 1-66 OBA (GAVAGE) CSOEPfMOIHNNRrEISDR'eSSREeSPTEy vLAeBTYErDRneOBaGo.EsReTTToe7xit0cc8hY1SSeTaivonri1o-17e06 dividual Anim rtonospeas H11isomorpTosy Bute iAw wae: 1016s SosEeAaPorE: So1vriice-schadulod sasomsETIOus): SEMEL No ross changes STORIEGssRUTIOS): [p---- HISTORICorsTITION: Hrieveso: opp ipagrstoapttyi.ohgsvtoicsiel)ta,cent lablar (aife ! - ------ nse I_ 418-028:PAGE J-67 OIRATLH(TGHAEVAGREE)PROCDOUMCBTIINOEND/OREEVPEELAGTPEHDENDTOASLE TTGORXIICCIITTYY PROTOCOL MNGER 416-025 SSCTRUEDEYNOIFNGTT7E7S0T8 SPONSOR'S STUDY NUMBER 7-7706.1 Individual Animal GrAoospsenadnidx H1i1stamorphology Data IsaMx:AL ges: W15162 DDoEsAeTHRoTYwPeE:: SaIovriflce-Schaduled A055QBSERITIONSS): ETEISeDTfEItSO,:MsImBOaiEllSla:,teBraill-atmeorlall. smal): coud epidichmis, HISTORPHOLGGICOBSERVATIONS): sdheeogfpeoonlseparetartaaistoans,pemrmaslttogefonctacl, ceTlElSsTIS (PAS) degenaration, mittifocal, TESTIS (HSE) HLSTOMORPIOLOGIC GRSERVATIONS: eporomines: Lv: TTEESSTTIISS ((PmAeS)):: eixPnyffpololasmfpmaeatrteaidioans;p(ercrahmrrkeoetndoi)gce,ntfcoccaell/lesul(1wofdoacraa!te)(stnina) dhdyeepggeeernnteerrroaaptthiiyoo,nn,, hmmeaiplstttiioffcooscciasll]ula((raw.iii1d3c))entriTcbular (aintesl) `LYEFOLLOVINGTISSUE(S)VERE WITHIN MORAL LINITS: THo1o 0d of Racore- 19142 or nes -------------------- OVRIATLH(TGHAEVARGEEP)ROCDOUMCBTIINPOERNDOTDORECEVOPELELAOMTPUEHNDEGNOETRSAEL41T8TO-OK0KI2IC8CIITTYY SSTCURDEYENOINFGT-T7E7S0T8 SPONSOR'S STUDY MUMGER T-7706.1 sMaI:NA WOBER: W19144 Individua) Ania] GrAopspsenadnidx H1i1stomorphaloy Data DDOESAETHGRTOYUPPE:: SaIvorifice-Schaduled 05S CBSERVATION(S): GENERAL: Mo gross changes. 'HISTQHRPHOLOGICOBSERVATION(S): Not applicable HISTORPHOLOGICOBSERVATIONS: Ler: inflammation, chronic, focal/mtifocal (minimal) THE FOLLOING TISSUE(S)WEREWITHINNORMAL LIMITS: THYROID. End of Recor- 15144 TT 418-028:PAGE J-69 OWRAILTH(TGHAEVARGEEP)ROCDOUVCBTIINPOERNDOOTROECEVOPELELAONTPUEWHDEGNEDTROASL4E18TTO-OX0XI2IC8CIITTYY SSCTURDEYENOIFNGT1-6787706 SPONSGR'S STUDY NBER 7-7706.1 Individual Antea GrAoopsesnadnidx H1i1stamorphology Data sAeNAL NRGER: W19148 DDoEsAeTHsToIuPpE:: SIvucrifice-Scheduled `HOSSOBSERMATION(S): GENERAL: Yo gross changes. HISTORPHOLOSIC OBSERVATIONS): Not appltcable HISTOKRPHOL01C OBSERVATIONS: ver: THYROID: Ed of Record: 19148 hniyynppfeelrrettmrraootppihhoyy,n/,nhyepcseharrtpoolncatesci,ilau,flfoaocria,ll/ccmeulnltatirrfiolecopabilutlha(ernti(inmiminnai()mmail1)d) ns 418-028:PA1G-7E0 OVRIATLH(TGHAEVARGEEP)RGCBOUMCBTIIFNORENODTDGREEEVOPELELAOTNPEAHDGEENDRTOAS4LE13TT-OO0XX2II8CCIITTYY SSETAUCDOYNoTFNS1-T7E7S0T6 SPONSOR'S STIOY INGER T-7706.1 Individual Anima) Gsroospsenadnid H1i1stonorshology Data AsexL NBER: W19150 DoEsAeTHsToYuPrE:: S1avceflce-Schadiled `05SogsTRATIONS): SENEBAL: No gross charges. HISTOORPHOLOSIC OBSERUATIONS): Not ppcable HISTOORPHOL001C oBsRIATIONS: TLiiRvdeir:o: End of Record 19150 IIyppaerrttrroopphtyyi,myppeepraptlaacsatlal,ulfaori,licceunltarrielpoibutlhaerl u(amfni(nna1]1)4) " 1140 418-028:PAGE J-71 OVRIATLH(TGHAEVRAEGEP)ROCDOUMCBTIINPOERNDOTDROEECVPOEELLAONTPENMDGEENDRTOASL1E8TT-OO0XX2II8CCIITTYY SSETAUCDDYNOIFNG1-T7E7S0T5 SPONSOR'S STUDY MRGER 1.77061 Asenx a ees: W19111 Individual nies) Gsroopsesndainxd H11istomorphalosy Data DoEsAeTHcToYoPrE:: Sacrifice-Scheduled 8055OISTRATION(S): a Jesu diverticulum, HISTOMEP/OLOSIC OBSERVATIONS): anverticulin, JIN HISTORRPROL0ECopsERATION: KiJoEwaenrws:: LLiWvei r: MODE, SUBMANDIBUoLAeR: PTPRiEOrVSREToRAt'oTS:EPATCH: Baavasenrcitmhiaclu)ludnegeneration, cortical tubules,focal/mtifocal onufpaiet1rsit)rrao,tnitmoyen.d,ilhmleoapnaotnouccelleaa1ra-rc:e1lc,antfroiciso)bumlualrt.if(onc1e1]0) (miniea1) aFltemrrotatsatt.si.onye,phocyt chfoiccal, i(cf s/ppliasno ea)tcyetie ce.el(miTniimatlel} uhIlyntpfielnragimbrarotasinhocynh/.ihayltphebrroopdnlbeai,stfy,soscfaolllmiiceuliafrocaapilth(elsfiusnt()suerte) HEFOLLOUINGTISSUE(S)VEREWITHIN boatLTS: ACHOemAaGerULxATIcNuGwoGsLAND icBtoOleNoEmnHos (STERN) jBriAsTHn NSSEPTRIoVNuEAc,LHsCcOuRADTICCERVICAL TRACHER STPPeAIsRNtAAiTLsHICR(OOaIReD,) LNGAR GRAY SLASoER RETSePCsITtNiALs C(OoRDa. THORACIC End of Record 19111 EcLpeuiomolohomeo,esMEDIASTINAL TSSPHLSEUENT VESICLES a 418-028PAGE J-T2 OVRIATLA(TGHAEVAGREE)PRCOODMUBCITNPIERODONTROOECEPOVELEALWTOEAMDGEENSTRAEL415TT-OO0XX2II5CCIITTYY SSOTRUEYPHOIFG1T7E730T6 SPOOR STUDY NMGER To7706.1 Individual Animal GrAopspseanndd H1i1stonorpholosy Data sAexL weer: 10117 DoEsAeTHcrToIwEe:: Sacrfice-Scheduled 05s ossravTIONs): SEUEBAL: Wo gross charges. HISTOHORPHOLOGIC.OBSERVATIONS): Not applicable HISTORPHOL031C oBsavATIONS: TLEuIovHuePrHc:hMO,DE, wSUBoMAmNDIeBUnLAR: mhR hyyppeearrptlrR aotspihay,,oTBo,eghheeopcaytaotcitecll/oupllarra,ssmcsecTnyttiroci.lrob:e(umlonadrer1(astei))ninal) `THEEDLLOUINGTISSUE(S)VEREWITHINNORMALLIMITS: HCsOeoNrmUAeTIsNGosSAD coLBOleNoEnnWow (STERN) rSBAeTaHmn LPSiRPnOIgSNTAALTECORD, LUGAR SRNPEEICRNTVEAU,LH SCIATIC CORD THORACIC FSSAPELAaEITEMNARLOIVDESTS RTEISNTAIRSY(BpLkA)DDER Ths THikolo End of Record. 16117 " KcEreRieolYommics TFSEPESITRAILSSG(OpiRaDTa.cHCERVICAL TRACHEA " na 418-028:PAGE J-73 OVRIATLH(TGHAEVAGREE)PROCDOUUCBTIIPNORENOD/TODRCEEOVPLEELAONTPOEHMDEGNEDTROAS4LE18TT-OO0XX2II8CCIITTYY SSCTRUEDEYNIONFG1T-E7S0T6 SPONSOR'S STUDY NMGER 7-7706.1 Individual Animal GrAopspsenadnidx H11istamorphalogy Data MseIxH:AL NER: 19126 DDoEsAeTHgToPwE:: Sacrifca-Schedvied 8055OBSERUATION(S): SEMEL Wo gross changes. HISTONORPI0L061C OBSERVATIONS): Not apicable HISTOHORPIOLOS1C OBSERVATIONS: KeIpDRtEoTmSm!ioes: TLweHHrI::NODE, MEDIASTINAL: cnientpfhisrl)ittr,iatsi,roendC,uhtrolmnaoinco,nucfloecaanr-c(emliln,imafloc)s] (mininal) FymFpyaepsrattrotcrryootppohhsyyt,/shyh(pemepriapntloiacmse)ilal,ulafro,llfcceunltarrielopbtutlhaerl t(1m1d()mil) `THE FOLLOUINGTISSUES)VEREWITHIN NORMAL LINITS: CALOReAEGwUALLATGILNGANDGSLAND cBOoNlEonWARRON (STERNON) fr) DBUAOTEHMM ae: SRNEPeRIcVNtEA,L scrATIC CORO, THORACIC SSPPAELRNEAIETANILTRVOEISDICLES SPSPETIYONEuARCL'HSCOpRaDT,CHCERVICAL TESTIS (pas) THIS TRACKER End of Record. 19124 H=en PSLRYPONISPNHTAALNTOECDomEo,, SLUBAMARNDIBULAR UTERSITNIASRY (BvaLcA)DDER 1a 418-028:PJA-G7E4 oC) cBomrsAsrReoEos vcs sm or oe rin ot E--E --mrs st asm oeoo: pos EwRaEn b1 esaaie 01; 10 gous or. GROSSOOSERVATION(S): ot wmiene 'HISTOMORPHOLOGICOBSERVATION(S): maee 'HISTOMORPHOLOGICOBSERVATIONS: t aent cci rme, ce n oSmeise , Bpiyny taFmaorwcreyust THEFOLLOVING TISSUE(S) sforsowose mGirnn, VEREWITHINNORMALLINITS: SERcoven omen Sor5senmo, sumonfbsaeonmcaSsncH ceo er pFi s joyycm; io e,m, 5 arm he 418-028:PAGE 175 ORVAILTH(TGHAEVARGEE)PRCOODMEBTIINPEODRNOROEEVPDEELAOTMEMADEGNE0TR0ASLE41T8TO-OX0UI7C5CIHTYY SSTEUYEONF T-T7H7O0T8 SPONSOR'S STIOY MRR 7.77081 Idhviduel Anes] Gtroospseannig M11stamorsialony Data sAoa woes: w15127 SsoEsTeHcThIoEw,: Svocifce-schduted SA0sSopsTRIATIONS): SENEBAL No gross chones HISTOAPHOL051COOSERIATIONS): ot episcatle HISTORPHOLOGICoasERvATION: fT(DHhoeeRreOeo:nae,nss:uomworBuLR fIoopppearaertprrloaprlshiysy.;tyTcppeobrephtctepeyasttotitcaec,l/tluplfaTtora:lslimcecouyntttarircs(pariTniabuilanrmst(Tsmyode(raaltled)) THE EOLLOUINGTISSUC(S)VEREWITHINNALLIMITS: CoSetNeoEndsou (STEN) fBDrloyyE LIN oe, MeDTASTIL NERVE, Scric EKrceOieNoelToSmies Pinson FTSREOPSSTTII C(OhRaDe,) LIGA uit sdoen RETSCEPTSITNIASL C(OpRaDs,) THORACIC TSShmhAeA VEStcues 04 of Record 16127 cfioorresuATIG euuie SSpTePvoIEmMRcL'nsCOpRaDT,CHCRIA re ins 418-028:PAGE I-76 OVRAATLH(TGHAEVAGREE)PRCOODMUBCITNPIERODONTOORCEEOPVLEEALNTOENPDEENDRTOASL4E15TT-OO0XL2II6CCIITTYY SSTCUROEYENIONFG1E-37706 SPOKOR'S STIDY NNGER T-7706.1 Individual isa) GAroospsenadnid i11stosorphatogy Data Asexn:a eee: 1912 DoEoAsTtHcTaYPoE:: Sacrifice-Schecilod E055OBSCRATION(S): SENERAL: No gross changes. HISTOMEPHOLOGIC OBSERVATIONS): ot apicable HISTOREPHOLOGICOBSERVATIONS: Gsievceorn:: TFhLRoeOsoTHArTO:E:E, SUBMMOIBULR: pIonefrlrtarmomeapthiymo.n, hemSpclastssoes,,eilcfuhetraiorn,notcie(inattfr1egi)elonbulmarr(imil)d IaPtyyrppoeaprrhptylr.aoafsthoayc,/ahlyTpymemraapntloacfysottciac,/fpoll(uss)emicacacurytatatirec). ep(irtohdeelrsituem) (moderate) iE FOLLOUINGTISSUC(S)WIREWITHINNORA LIMITS: cjAiotRloEnAL GLANDS SSBONEUE NHNsu (STERN) LIRPH NODE, NEDIASTINAL NERVE, SCIATIC KEBIpAnlThoHetrsomoes FARATIROID TSREePCsITtNiAsL C(OpRiDs,) THORACIC TSSPEhLMEIsENNAL VESICLES STSPRtIAoNCAHLERCORD, CERVICAL End of Record 19125 CjeOosAyrUATING GLU TSFEPESIVTNEIARSL'C(OpiRaDT),oHLivaaR URINARY BLACOER = 418-028:PAGE J-77 OVRIATLA(TGHAEVAGREE)PRCOODITNIPEORDOTOORECEVOPLEEALTNOEAMDEBNEDTROASL4E18TT-OO0XX2II8CCIITTYY SSTEURDEYNTORFG1-TE107T06 SPONSOR'S STUDY WAGER 1-770.1 Individual Anima Grfoospseannid W1atomorshology data Asox:a ne: x19140 DoEsAeTHoTIrPE:. vSaceice-Schedulod 05s omsTRvATIONS): SEERA:No gross changes. HIS08CT OosERO ATIOR NS): ot apical HISTOHRPHOLOGIC SERVATIONS: we: aon: IIIoonppfeelrrattmrraootppithoyyn,/,yhpceephreprsioeancsa,tiafl,ouctfaeolriclfeimenuttlarrfioieocpbaii)ltehr(e niiemmnmai()amesld)arate) HEFOLLOWING ISSURLS)WERE WITHINMga,LINTS: AeCOoArGnULeATIsNuGoSsLD {ne CBfoOteNoEnnWARE (STEORN) pDaBlAonTotHEy cKEieroieuomElrosmuoes LOW MODE, MEDIASTINAL LIN MODE, SUSHMIOIULAR NERVE SCIATIC SHrSaEeNmIyMaARL oVEnSICLES kis SSBTPEoIYmEMaRLcSnCOPRADT,CHCERVICAL TSFPReIONSsATLATEGCOaReDj. LUMBAR HOG Uns BuABoER TRSPEeINCsATL CGooms.h TIGRACIC End of Record 19100 [= 418-028:PAGE J-78 OWRIALTH(TGHAEVAGREE)PROCDOUMCBTIIPNORENODTOORECEVOPELELADNTPEHHDGEENDRTOASL4E15TT-GO0UX2II8CCIITTYY SSTCURDEYENI0NG1E-707706 SPONSOR'S STUDY NUMBER T-7706.1 Individual Anima) Grsooepsenadnis i11stomorphotogy Data fANyIMAL WoBER: 19145 oDoEsAeTHhToYwPeE:, Sacrice-Schadated R053 ORSCRITIONS): SEERA No gross changes. HISTOORPH\GSIC OBSERUATIONS):| Net applicaie HISTOMRPHOLOSIC OpsERIATIONS: fLKiiIovwNeer:s:00, SUBMOIBULAR: TRREACCTHEA IIi{ppnnffeelrr1apttmlrrmaoaaspttihiiayoo..nn,, Thmeysspoecanpotehsomoscuc,ecyllticeiuah/trrpa-olrcna,eis1cmlmc,eu(yn<ttifirnociic.sfaaolib(/)arelouadlretris(ft1oe1c)6l) (atnimal) inflammation, chronic, face] (e110) THE EOLLOUINGTISSUE(S)VCRE THIN Noms,LIMITS: eCAORaSErUAALTIGNLGANGSLAD cosiotoneenmWow (STERN) HSLRPOIISNNTAALTMECOOER,D,MTEHDOIRAASCTIICNAL SsNEPeRLuVEiEE,NviSVceIsATtIcCes Testis (ous Tims End of Racord- 19145 SBrEAS Im SSPPAtIRNAoATLoIRCOOIRDD, CERVICAL TROD EicpneieDoiomioes TSPePEsITtNEiARsL'SC(OPaRADT):CHLuna GRibARY BLADER Hess 418-028:PAGE I-79 oa save) come cpa ose Toc stor or 170s SPONFIRRO'TSOCSOTUaY EWeE4R15-T0o81808.1 Ivica) Anim) Grteospsncaimx H11istomorploay tuts AeNyDO eG: 10145 DosTeHcToVeEE:, vSacrfios-Schodled 03s SEATON): SEAEBAL: Ho gross changes. HISTORRPHLOGICGRSERATIONS): tot appltcable HSIAO CesErvATION: Twireere:ios FEyrerot rshiy.rPpeerepshetphaartsoycael.lufloarl, centrilobular (minimal) cular eptthlm (sudrate) HEOLOUING TISSUES)VEBE WIT oma rss hseorrde rcusssao bloinkknonn iiGP ioion L L010, MEDIASTINAL Da--oby Xcieoilooonmocs LSP HOO, SUBKADIBULAR NERV, SCTATIC BEYER pate rks SiTSlEesnMnA ViStcuss STSPtIoMnuLtCO, CIC iTSaPrsI C(sogmtyoaLnom TiRekackonen coo, TORIC eppeeyrry a 418-028:PAGE J-80 OIRATLH(TGHAEVAGRE)ECPSOPMOBRNISPNOORERODD'TDSORECECSVOPTLEETLLAOoTWIYmEAeDGWMOETMDRaOONLSR4.ER16TT-O7O0AR72II78CC0HITT8YY1SSTuepYnonF 7T-E7R0T6 Individual Ania) Gtroospeansd W1stomorshotogy Data sAoa we: "10152 oDEsAeTHgToYwE:, Svucrifice-Scheuted S55opsERALIONs); SEMA Yo gross changes. HISTOHORPH0L051C BSCRUATIONS): tat ap catle HISTORRPIOLOGIC coscRmTIONs: (weoku:: RLOToAToEe, sussMOTBULIR: Roto: ITiIpnefRrrltaIermoaEpttti,oy,n,,YDeScephrastreoeoceneo!,,iuGfoloatcrEai,)scAo(enayftnriiieTsa1b)(ueildaorrasr{teor)ginal hs{tynrpoeaprrmtyra,opihfoyon/e,haytp/Gemrrioptnlitasfs,otcaa,fl fa(onnflimmcciulnaa)(tclaeprith(eellmuint()nile) HEFOLLOUINGTISSUR(S)VERE THINNOLLIMITS: CAeOmwGeUnATGIuNanGos00 LY OE, WEDIASTIAL SCSoNelEoinnsu (STEN) NERVE Sci KIBsOaoRrEyeYsm Bannon TSREECSHTTIIS c(roims,) occ TiSSaomteusent bTies TSSaoPhmIerCORD, CERvION. End of Record T0152 fEcoseiootonuoes STBPEeSIeTRrIA'SLsCGpOea.T)cHLiven kikat Soe 1s 418-028:PAGE J-81 OVRAATLH(TGHAEVAGREE)PROCDOUMCBTIIPNORENODTDORECEVOPELELAONTPENMDEENDRTOASL1E8TT-GO3AX2II8CCIITTYY SSTCUROEYENOIFNG1-16737106 SPONSOR'S STUOY NUMBER T-7706.1 Individual Anima) GrAopspseanndd H11istomorphelogy Data aML ser: F19012 oDEsAeTHsToYwE:! S1acrfice-Schuciled 8085GRSERVATION): SEHERALS No gross changes. HISTOMRPHOLOSIC OBSERUATIONSS): Not app cable HISTOMAPHOLOGICOBSERVATIONS: uTTseHtRRouOmsLo:Dn aWmaitctiramotcpabhtraiagonencs,h,imauplicgomsbeaon)dtyefdo.glyas(ntmdosde(raattnet)eal) THEFOLLOVINGTISSUE(S)VERE WITHIYnome,LINTS: cSoAReoEinAnL Guanes KIUSOvEEOisow (STERNUM) HisEovAaeRTrTn oSLvIPNIPiNYALsOCOOR,D, WCEEDRIVAISCTAILNAL THIS SFLYPAMIRPNTHAILRNCOOODIREDD,, TRACHEA SUBMANDIBULAR LWA NSFPOEIDVNAEARRLY'COPGRALDTA.NCDHTHORACIC RINARY BLADER 03 of Record 19012 tcHneeewo RSNEhERiCVtETe, SCIATIC AGI 1s 418-028:PAGE J-82 RWAILTH(TGHAEVAGREE)PRCOODMUBCITNIPEORDNOTDORECEVOPELELAOTKPENMDGEENORTSAEL418TT-OO0XK2II5CCIITTYY SSTCURDEYENIOFNG1T-7E7T05 SPONSOR'S STUDY NUMBER T-7706.1 Individual Anima GrAoospsenadnid H11iatomorshology ta A sox: weg: F19019 DcEoAsTeHciToIuEr.: S1 ucriica-Schedulod A058 QRSCRUATIONS): SENERAL: Mo gross changes. HISTORPHOLOSICOBSERVATIONS): Not applicable HISTOMRBHOLOGIEOBSERVATIONS: nLoinesNOE, SuBMANDIBULR: ePoEpreerpphlaesstea., pIlymapmhnoecsydttc(/1p8la)smscytic (are) HEFOLLOUINGTISSUR(5)VCREWITHIN sootyLIMITS: CASaRleoEanAnL GLANDS HrBOINNEeEHSRV (STERN) LIN OOF, MEDIASTINAL WAMARY LD HlsiaovAeTtrH NERVE, STATIC TSBAPiRIAMsTLHTCRODRLDD, LbeAR BTSPEaIVNEiARL'oSCOPRADT,CHTHORACIC RjESiCHTEN haa E03 of Record 19019 ictnrhemw aSSktPtioIeosCoro, CERVICAL Ribas" suo ws 418-028:PAGE J-83 ORVAILTH(TGHAEVAGREE)PRCGODVUBCITNPIREOODNT/GROEEEDPVLEEALNTOEBMDEENORTSAEL41TT8OO-KX0II2CC8IITTYY SSTCUROEYEROInFG1E-147708 SPONSOR'S STUDY NMGER T-7706.1 A sex: ser: 19021 Individunl Animal Grsoospsenadnid H1i1stosorphalogy Data DoEsAeTHgaToYuPrE:, S1acri fice-Schoduled 805s GBsERATION(): HEAD: Hed scab, 0.200. dem HISTORPHOLOGIC OBSERVATIONS: uLSKvIINeN(o60e5,% MLEEDSIIAONS)TINAL: urTeHRrkuost:d: HISTOORPHOL0G1C OOSCRATIONS): dermatitis, chronic, focsl, SKIN (6R0SS LESION) dcieonrnfmglaeatsmitmtiaitosin,on(,cahircnohinraioecn),ic,focfaolca(ls/mtult)ifocal (aintnal) muaicErtoapshbargaensc,hiepligbmoecnyt/ecdys(tmdsrate) HEFOLLOUINGTISSUE(S)VEREVITHINMORALLIMITS: cSoAelRoaEnAnL GLANDS KIBOOOuwNoEEdresWN,aHdi (STERN) tHiBernaagIrn HFSPEIVRNEARYLSCOGPRAuDTa,CrHTHORACIC RSNPEELCRETVE,N sciatic ouSSPaTIoiNMAecLsHCORD, CERVICAL TRACHEA Asi cLSrotoweeww none, suamavoIBULIR FSTPAhIRNAsATLRCOOIROD, Livan LLSSUE(S)MOTAALUABLE FOREVALATION: RIN BLADER End of Racord- 19021 1s 418-028:PAGE J-84 OVRIATLH(TGHAEVRAEGEP)ROCDOUMCBTIINPORENODTOORECEVOPLEELAOTWMEIMNDEGNEDTORSAEL4.10TT-OO0KX2II5CC.IITTYY SSOTRUEYPHONFG1T-E7R7T0 SPONSOR'S STIOY MRGER 1.77061 Individual Animal Grdoevpeeanndd H11istosorphalogy Data AftL neh: 19023 DsEAeTHoTwYeP:E. S1ucrFice-Schadulod R085GESERVATIONS): SENERALS Mo gross changes. HISTOMRPHOLOSICOBSERIATIONGS): Hot pp fcable HISTOMIPH0I061C SERVATIONS: we: inSLeIktlNos:oNOE, MEDIASTINAL: sIanosfitiolctyrtaotinotns,(aptonliynmae]rphoucies,perivascular peribronchial me acrophagen s. pigmntecdo(mnini,esl}glandular ares (a116) LIE EOLLOUINGTISSUC(S)WEREWITHINMORALLDWITS: SAelRoaEnAnL GLANS hau cua DSKUIODMDNEEEYWS,ARY (STEDN) LiHBvAeTeaHr NeRiE, scuaTic dinates SFTPREIAVNCEAHRLE'ACOPRADT,CHTHORACIC REGSPCRLTiEUERMNY suiooeR TSVPAHIGNIIANSLA CORD, CERVICAL End of Record 15023 cLnIeeMowP OE. SUBNANTBULAR TFSPAhIRoNAAiLTnICROORDD, LukaAn 1s -------------------------------- 418-028:PAGE J-85 OARATLH(TSHAEVAGRE) ECOMPBILNFRREOODWTDOGREEEVOPELEDLAOTNEMRIDEGNEGTTROASCE413TT-OO0XK2II8CCIITTYY SSTcUnDtYinonFe1T-H73075 SPONSGR'S STUDY WAGER 7-7705.1 Individual Anim 6s1p0%enadns H11atomorshology ata sAex:a wove: 1;9001 DoEsAeTHciToPuEr.: S1 acefice-Schedulod 8053oBSTRUATIONS: SUBALS No gross changes. HISTOMGRPHOL061C OBSERVATIONS): hot applicable HISTOMEPHOLOSIC OBSERVATIONS: STLtIHoNRGOu.tNODE, SUBMANDIBULAR: GTeRUs: UIllyotpTeerapblnraasantcah,tiaTleymb:pahoyc/Syctuyibucmt/tpolassemaScytteinct(omrodaareatse)lderate) mcropnages, pigmented (radarate) THEFOLLOVINGTISSUES)VERE VITHIY ORLLINTS: coASelRsotEnnLos DSoUNnDEeEWs Y (STEW) LHBiAevTaeHrn PLShPIRIAMNTPAHLTKROCODOERI,DD,MELDUIMABSATRINAL WFSAPeIReNAA'RLsYCOGPRLADAT,NCDHTHORACIC TRACHEA URINARY BLAGOER RNSEEHCRLTVEEE,N sciATIC si End of Record 1800 ciJLereem oSTPuiIiMmeAisLesCom, cemvicaL A = 418-028:PAGE 1-86 OIRATLH(TGHAEVARGEEP)ROCDOIUCBTIINFOERNDOTDGRVEEEOPLLEAOWTMEAEDGNEDTROASL1E6TT-OO0XX2II8CCIITTYY SSTUODYROEF 7T-H7T70 SPONSOR'S STUOY NUMBER T-7706.1 Individual Anim] GrAopspsendainxd H11istasorphotogy ata Asax:L eer: 19082 DoEsAeTHgToYPpE:: S1acrifice-Scheduled 805s opsTRvATIONs): SEUEBAL: Mo gross changes. HISTOMRPHOLOS1C OBSERVATIONS): Not ppcable HISTORRHOUOSIC BsERvATIONS: TuHroeRmRaDirIseDs;:: mWaarlcstrtio(mpsbh)ra,agneicsnh,tiropaliogwmbreoindatynefdcys(tadarate) THEEDLLOUINGTISSUE(S)WEREWITHINMORON,LWT: SAetRdoEinoAnL GLANDS LIHPY HOOF, MEDIASTINAL CKBUODONREdEHNMw (STERN) tHiBeavaaeTrn LTAPH. HOO, SUBMANDIBULAR NAWKARY GLAND ThSEmRTRiIAsTLHICROORIDS, LEAR FTSREHAVICEHMRESACOPRhDi,CHThoRiCIc RUSRehICeNTAdRNY BLASER Ed of Record 19002 rcjeiyeg SNSEtRPoVEAw,eCsOcrRa,TICcervical Ae ness ------------i 418-028:PAGE J-87 OVRIATLH(TGHAEVRAEGEP)ROCDOUMCBTIIFNORENODTOGREEEVDPLEELAOMTREBNDEENDRTOASL4E1T8TO-OX5LI4IC5CIITTYY SSOTRUEOPYHIONFG71.6747706 SPONSOR'S STIOY NUMBER 7708.1 Individual Anime] GrAoospsenadnid H1i1stamorshology Data MsexA:L NBER: F19084 oDoEAsTeHcrToYwPeE:: Sa1orifice-Schediled SAOSSOBSERVATIONS): SERA:No gross changes HISTOMEPHLO0ICOSSERVATIONS):. ot apicabie HISTOORPHOLOSICoBstRMTIONS: LKihoveersho, meoASTIMAL iTLEIRNPlHs:ODE, SUBMANDIBULAR: cBneooppnhegrreisstltiaisso,tna,c{harTtonyniminhceo,lc)yftoicca/lpl(amsimneicmyatli)c DRL Sel ((21i16i)a) eacrophages, pigmented (mderate THEEOLLOUINGTISSUE(S)VEREWITHINMORON,LWT: cEAoRlooEnnAL GLANDS NERVE, ScuaTic tDiBOvONeEENw (STERN) cuales HsLroeavTern PARATHYROID RETtCRATyCOHREA SRSiPtNIAoMRLoYCOBRLDA.oECR oC TVSPhiIdNsiK CORD, LWGAR End of Recor 19044 cHiotRoenmY SLND TSPPEhIViNEARlL'oSCoPmAbT.CHToRacic } ns ---------------- ------------------ 418-028:PAGE J-88 OWRIALTH(TGHAEVRAGEEP)ROCDOUWCBTIINPOERNDOTOORECEVOPELELAONTPEMHDBEENDRTOASL4E18TT-OO0RX2II5CCIITTYY SSTCURDEYENIONFG1T-E7S70T6 SPONSOR'S STUDY KKGER 7-7706.1 Individual Raina] GrAoospsenadnidx H1i1stomorphology Data sAeNx:AL NBER: F19050 DDoEsAeTHaToIePE:: Sa1orifice-Scheduled 8055OBSERVATIONS): GENERAL: Yo gross changes. HIS 061CT QRSERO UATIOR NS): Not appltcable HISTOMRPHOLOGICOBSERVATIONS: uLAroeeriosA:LNODsE,usS:UBKADIBULA: mvRaacceruooiplhanatgiseosn,,, zpSiognuarntgeleda.neer(umladoiasramate(e]11id) (simi) THEFOLLOVINGTISSUE(S)VEREVITHIN NORMAL LIWITS: DKBuIOoDNNoEEEYHNSARROW (STERN) LiHBeRvAAegIsTN ceLLaegEw.W SPHPEAIYNESARL'TSCOLPRADTD,CHTHORACIC RESNCEPRLTVEED,N SCIATIC oSSnPIoeNAcsL CORD, CERVICAL in) TRACHEA URINARY sLA00ER 0d of Record- 19050 LEcioakogenanNooe, weomaSTINL TSFPALIRNASATLITCROORDL, LUMEAR isINA ns ---- --a ---- es 418-028:PAGE 1-89 OiRALT(TGoAeVAGRE) ECOMBPIiNPEoRDonOoTREEOvuP.EELAoTMeEmBDeEdSTRtaE,416TT-Oo0XI2I8CCIHTYY SSTeOYiOnF 1T-E7R06 SPORORS STUDY WER 177081 Tovidual Anim) rtecossaned H1i1stomorshotasy Data wiyna wre: 15053 ScoEsNeNcTrPuEe,: 1cri ica-Schwdiled S058CRSERVTION'S): Pr -- HISTOLOGICCRSERATIONS): tat aplscable HISTONORPHOLOGICOBSERVATIONS: cACehcouonnkneovseu,assusmmioIBuL: ThTEomRnst:: ovTFoarppcaewtrmlpyaalttaisiooioonain,,a,rzIkmoyenmosebt)ogsely,mteisrchu/ploionanessms((omsy1at1diea)cat(e1)1d) nSacirbophreagrech.iapligmseandteedys(tmoderate) TsrHoEnyeFOwLLaOVsING(TTIESSNUNE)(S)WERBHEaeWrIwyTHINNORMALLIMITS: coi on RRtEEeCETx, scare pit tSruPnIyMeLsCOR, CERIO. SLpPIlNiALHoC)nOeR,D,WELUDMLBAASRTIAL Some TaAcnEn iain 3 of Recara. 10050 WKrIAORREeYYS SLD RSPPEIYIREARML'SCSoBAtAToCRHTEHORKIC us --_-- 418-028PAGE J-90 OVRAiLt(TGAiVAGREE)PRCOOOMCBTIIPNOERNDOORTEEPOEATTMEADAB0E,0418TT-OO0XX2II8CIITTYY SSTeUYionf 1a-7r08 SPOVKIR' STUDY WNGER 7705.1 Indtvical Anim Gsrepsoan H11istomorstoay Bate EinsL wn: ;19065 DsEoNeTHiToIwPE:: _ S1uciice-schodtad GROSSOBSERVATIONS): GENERAL: Mo gross changes. HISTONORPHOLOGICOBSERVATION(S): Not applicable ciee: HISTOMORPHOLOGICOBSERVATIONS: Va{incoeetsn:oorS, obas:ussaorsiu: TIiofmetausrmtsaitaoitonrn,, SSmeoeoton,,n 1ccfroocanaltlmicean(taxti1a6c)) oim1are) Sicroages, pigmented (10) sIKsEin reFoOsLLOGVuINnGsTISSUE(S)WlERiHBEOoeNVErITa HIN NOR(MSALTLEINM)ITS: ejBRAddIN hot, MEDIASTINAL RiEAtTve sciatic Todi SuSoaPrmIecOsCO, CovIc. iy PTSoPmReIs CDO, WB End of Record- 19065 REcmonYon Lino TSeeaiNikALoncome. THORCIC " or ia ---------------------------- 418-028:PAGE J-91 OVRILTH(TGHAEVRAEGEP)ROCDOUNCBTINIPERODONTDORCEEOVPLEELAOTNPENMDGEENDRTOASL4E1T6TO.OX0KI2IC6CIITTYY SSOTRUEOEYNIONFG1E-37706 SPONSOR'S STIOY MOGER 7.77061 Individual Anime) GrAoospsenadnid H1i1stamorsholony Data sAeNxI:MAL wns: v15001 oDoEsAeTHcToYoPEr:: Sacri fice-Scheduled shossopscRvnOns): SENERALS Mo gross changes. HISTORRPHOLOSICOOSCRATIONS): Hot applicable HISTOMRPHOL061C opsERvTIONS: ne: urTeRAhClHsE:A: mIianmcfraolptahtiaigoeonsn,,,slcnvhersotnrti.c, gffooccialf(o(aaci)mmiin(ail)ves) sGiisctreonpttiaoen,s, Tpuingemnen(tae11d0)(moderate) THEEDLACNINGTISSUE(S)VEREWITHINMORON, LIMITS: coSAlReoEawAnL GLa KDBOUINBESIMNOU (STERNUM) {BHiRveAeItN TSBLPRHIAsNeTAHLIHRCOOOOIR,D, SULUBMMBAANRDIBULARTHMFSrPAeRIMvNMEoAARiLR'DYsCOLPRAoDT,CDHTHORACIC RENSCEPRLTVEOEE,RN SciATIC URINARY BLsooER Ed of Record 19001 LcfUeeMcPmnY MODE, NEDTASTINAL SoSPutIaoNlAueLrscoo, CERVICAL VAGINA - a -------------- 418-028:PAGE 1-92 OVRIATLHSTAHVEARGEEP)ROCDOUNCITNIPERODONTDORECEVOPELELAOMTRENADEGN0TE0ASLE415TT-CO0RK2II8CCHITTYY SSTEUEDYINOFG1T-7706 SPONSOR'S STIOY MOE 7-7708.1 SiANxI:MAL WER: v15006 Individun Anima GrAopspseanndd H11itomorshoTosy Data DouEsAtTHGToIpPE:: Svarfice-Schedalod 8058OpSERIATIONS): SIMBA bo gross charges. HISTOORPHOLO8IC ORSERATIONS): ot applicable HISTOORRHL08IC oasavATION: TTeRas;: slIspFceirrmopaslbhaarsgatenasc,,hipyaimghmbeeconytdteiidce/(spxl1a0s)mmcytic (si1d) HEFOLLOVINGTISSUG(S)WEREWITHINhome LikTs: cpoAliRoEvnAL Guavos LO NOE, MEDIASTINAL KoBilOoaNnEErMsATRON (STERNN) WABARY LAND se{SaeoArxTH NERVE, SciATIC TSBPRhAITMsHLIRCOOLRDS, Li TSFPRRIAYNCEAHRLESACOPRADT,CHTiomiCIC ReRSpcIeeAn aLioocR Er of Racord 15008 Lctiaekemn SoSuPtaIoiNueAtscomo, cenviea VAGIMA 12 418-028:PAGE 1-93 GOVAILTH(TGAHVRAGEER)GBCSOLIPCBOTIRIFNSGORODNROSOTREEOVSPCETEILADMTIYEWaDEWNe0AT0AG8LE4R15TT-1OO0X7U2I78HC0ITT8YY1SSETAUEYENoHFGTT-7H7O06 sA o woes: 19001 divide) Ania) Grtooaspeonsd H1stomersmiony Data DsEeAsToHw,: vSacrfic-schediled `RS05E5OBBSEYRoVAgTrIoOsNs(Sch)a:rges. 'HtLoStTaOpMsOcRPaHbOLlOeGICOBSERVATION(S): HAIaSmIeOnHO.RPcHvOLsOG:ICOBSERVATIONS: reas: cmToartcororspeshma,igseasc,notretpeixg,mnftoecda ((saotdirca)te) `TDSHNEEFEOA LLONING(TSITSESRUNE)(S)VEReiEnWyITHINNORMALLIMITS: Kone fry LcfIceNmw OE, MEDIASTINAL SFRPEIVANEARYLSCOBsRAuDC,oHTioeicic Troi SRvEiCeTe,h sciatic Titi auSSRPoIiuNAecLsyCORD, CERVICAL RIA suo End of Record- 19011 JLcSoeAoPdnHiMOE, SUBMADIBULAL STBPoInNTkAsLRC)o, Lv ii " ne 418-028:PAGE 1-94 ORrALt(TGAEVAGR E) COMBTIE NIOERNDGDREYESEPLELAO OTRMEMEDNST0E0ASLE18TT-OR0XI5IC6CIITTYY SSTEUYEORF 1-E787708 SPoNioN'S STUDY WER 1.1706.1 Inivicut Anima rsompeonodn H11istmorptogy Beta biasn wes: 1h0020 oSAoTNaTIrZ:E Savoritca-scheiled sass pseRmATIONS): \ roe and ol B-iinetteseinnrecsotnaortigaseii.ndaetdstawnithiong,is. sSaRsooRruo,xtsmFmtienln.yi1c7oSnhasckuarrfecseracnognitnaginsin size iTtTrpinponk to 0.3cn In tamer HISTONPOL0G1C GRSERUATIONS): dKNoonpeHeIrncorresatcciooopinlcscthyhasantng,gs 55c5orcctooere,rreamlatltete,i:foDScAHaROENN K3Koo SlSiieccrrreoossscccooonnnses:.. ccchhhaaannnggge tttooa cccooorrrrrreeelllaaattteee,, CC1OhUimNm SsNeormmiocaronscmopaitcicohna.ngesutmiccoorsr,elagtlea,ndRulEaCr Tarea SSSirromseetoyintnsf)l.amaatrioina:ssumsamcsceoss, Jorestomsch HISTORICoxservToN: oimnte anes: lo aw : LWoEu one,: morn: RESoTaaIntN:h:: pTThoirsgh:: dmarEartoisocnp,lcohpnigeh c50orctoer,armatsts (a10) NYoo mmiiccrroossccooppiec cchangehangs ttoa ccoorarlmatse XYoo lBiecrroossccootiec cchhaanrggee t1o0 coorraattatee RPpEreEraorntatiassiteT:aect n(teatoepm)eytiaovpeleatsetteic .(x16)! rSC toroaye nt.aiteSn )hindlarmmoossn(srodarstta)e ar (410) SiStetamrdor\yinnfrelaahmriaeat)iobno,dyS/emyiactoss, forestameh 118) Secrotuses, pigmented rarked) THE FLLONING ISSUES)WERE MITHDN ORALLIT: SoS0oookneceusshow (STERN) {BioRaAenIN fcLieeIm MODE, WEOLASTINAL TNREiSRTe,nseuaric dSGHiIerMsCCoSrL,ANcE ic PiPaInaAeL lCosb, LAGIR of Racor 13030 cSMoeAolAniRmY SLD SFPoIReALscpomaToute nes 418-028:PAGE J-95 ORVAILTH(TGHAEVARGEEP)ROCDOUWCSTIINPOERNDODTROEECVPOEELLAOTNPENKDSEENDTROASLE41TT8O-O0XX2II5CCIITTYY SSTCURDEYENOIFNG1T-E70T6 SPONSOR'S STUDY KNGER T-7706.1 Individual Animal GrAoospsenadnidx H11istamorphalogy Gata ASeNx:AL WownER: 1P9022 DDoEsAeTHGTaIoPE:: Svacrifice-Schedvled 055OBSERVATIONS): GENERAL: o gross changes. HISTONRPIOLOGIC OBSERUATIONS): Net applicable HISTOMORPHOLOGICOBSERVATIONS: LHvIOVeAI:RYNODGEL,ANDS:UBUADIBULAR: TuirgEoRUlso:: InIeyncpfreloraspmilmsaa,sttiaof,no,caTlycherp(ohanonicicym,tafilco)/cpalla[smmualctyitfiocca(la11(dm)inimal) mUalctriorpbhraignecsh,iapligmbeondtye/dcys(ta116) `THEFOLLOVINGTISSUES) VEREWITHIN NORMALLINITS: AcDoRlEoNnAL GLANDS. DBuOoN0EEWNHOU (STERN) BHREAAIRNT NEEaR, ScATIC oKwIOeHETsS LPuAeRATHYROID sREpClTeen sSPtIoNuALcnCORD, CERVICAL TSHPINKAL CORD, LUGAR GRINARY BLADDER iG Ed of Record 19022 cToLwE PLEYYENR'SNODPEA,TCMHEDIASTINAL TSPRIANCAHLEACORD, THORACIC 11-85 418-028:PAGE J-96 ORVAiL (GTAHVEAGREE)PRCOODNUBCITNIPEORDNOTDORECEVOPELELAONTPENMDEENDRTOASL4E18TT-OG0KA2II5CCIITTYY SSTCUROEYENIONFG1-T7E7ST08 SFONSGR'S STLOY WAGER T-7706.1 Individual Ania) Grsoospsenadnidx 1H1istomorphalony Dots Asex:L wrcR: v19025 DoEoAsTeHrToYvPeE::_ Sucrifice-Scheduled 805 QRSERVATION(S): SEARAL:No gross changes. HISTOHRPHOLOGIC ORSERUATIONS): hat applicable HISTOMORPHOLOSIC ORSERIATIONS: KaiSwtoeorews:: Gus: ureRus: hdnyeeppenhrartirtnoifpsl,haymcvohrtaoicnoainct,,iosfnuob,mcuccoo(sreatt,emxi,mgalnam)ntdiufloarcarlea(s1(1adf)1d) Sacrophages, pigmented (moderate) TH FOLLOMING TISSUE(S)WEREWITHINNORMALLIMITS: LDiBUOvDNeDErENJRO (STERNN) HBERAARITN Lhe citoewm LYNPH NODE, NEOTASTINAL SHPPEAITNEAARL'RSCOPGRALDT,COHTHORACIC SRNEPERLCVETEEU,RM SCIATIC oTSvPiIamNlAsLeCORD, CERVICAL TRACHEA URINARY BLAOER "Rai End of Record 19025 cSoeonnn SPLPAYIRNNAPATHLHMTOCRDOOREID,D, SULBiMWMAORIBULAR ThRoio 1-6 418-028:PAGE 1-97 ORVAELT(TGEYARGEEPRCOOUMEBTIINPEORDONTDROEECLPOEELLAOMTEMADEGN0TE0A8L41T6TO-GX0HI2IC5CILTTYY SSTEUYEoNf 1E-87708 SPONTR'S STUY RGR T-7706.1 Individual Ania) Gfroopenadnis H11istomorolosy Data A so wo: 19027 BwENeTHcTaIrPE:: _ Svucrice-schodlad 205OpsERATIONS): SEMEL bo ross changes. HISTORIAOxsERALINS): tot applica 'xHi{IoSieTOrMsOk:RiPeH,OLOsGICuOBnSERsVA:TIONS: TSiTnOoMAiCnH:: sRiyrpaerraslliazsatta,ionT,ompmhioteiyfoec/ap)ls(mneicnyei)e (ila) ebdremaa/nincfhlaema)tiosno,syseuybemtucosa, glandular ares (si1d) cS`oTselHoEooFrnOnLeLOGWIoNGsTISSUE(S)WERI5SEOhW0EIeTWHIONHNOR(MSATLELRINM)ITS: iBoaayarn SHRiAEtCTe 60 TdSPuoIkMseLsCom, CERVICAL TESoPuIonNAmtLiaCOiDo, LN res vist chiemee oot, weOTASTIML SFiPIeWnAvL chSoeomitnTsosctc LwIeSSvUeE,(Ss)cNaOrTeAVAILABLE FOR EVALUATION: End of Record- 19027 " TT TT or ie 418-028:PAGE J-98 OTRAHL (TGAHVARGEEP)ROCDOUNCBTIIPNORENODTDORECEVOPELELAONTPENHDGEENDRTOASLE418TT-OO0RX2II8CCIITTYY SSCTRUEDEYNIoNFG1-T7E7S0T6 SPONSGR'S STUOY NMGER 7-7706.1 sAeMx:AL WogER: F19028 SA053 OBSCRIATION(S): SEUEBALL No gross changes. Individual Animal Grsoospsenadnid H1i1stamorshology Data DDoEsAeTHGrToYuPpE:: Svacrifice-Schaduled HISTOMAPIONOGIC OBSERVATIONIS): Net applicable HISTONRPIOL0G1C QBSERVATIONS: rSLTeoaIvlcsH:N:ODE, SUBKANDIBULAR: mpocrori pphlaagsetr sa,, pye ihgomceyntted idc/(pmloa adsermaatc] ey)tic (sodarate) THEFOLLOVINGTISSUE(S) VEREWITHIN MORAL LIMITS: EcARoEnnAL Gus DKBIODUENEYWHSARY (STERN) H{BieRvAseIrtN PLAiSkAeTIVNOROOEI,D MEDIASTINAL SPINAL CORD, LUNAR SMPPAEIMVNAEAARLR'YSCO6PRA0DT,CDHTHORACIC RSNEEPRCLVTEEE,N SCIATIC THrRor TRACHEA URINARY BLAO0ER End of Record 19025 " " LucLeeeww SoTPnIhaNrsAeLsCOR, CERVICAL SIN EE ees 418-028:PAGE J-99 ORVAILTH(TGAHVRAEGEP)RGCBOUMCBTIIPNORENODTDORECEVOPELELAONTPENMDGEENDRTOASL4E18TT-OO0XL2II6CC.IITTYY SSETAOEYPNONFG1T-E7S0T8 SPONSOR'S STUDY NMGER 7706.1 MsexA:L ER: 19030 Individual Antnel Grsoospsenadnid H1i1stamorshology Duta DoEuAsTtHaToYePE:: Saorifice-Scheduled S055 oRSERUATIONGS): HAD: Hoss scab, 0.3m x 0.3m. HISTORRPHOLOGICopseRvATIONS: TSLKiRIveNOrD:(s:hoss Lesion): TERS: HISTORRPHO\GSICOBSERVATIONS):| darmatitts, chronic, focal, SKIN (6205S LESION) dUNeoirtEmTarmteaimbtariraskn,acbhcliheeronbiacd,y/cfyoactal (wtntnal) macrophages, pigmented. (raderate) `TE FOLLOUINGTISSUE(S)VEREWITHINNORALIMITS: ScAoeRlaoEnAnL GLANDS HiARY GL KoIBuoOnvNeDErEsNH, O (STERN) LiBHAneTetH NERVE, Sciaric ouates TSFeRPvAIeCMRHL'EsACOpRADT,OHTRACI GSRPERLCICTNERHY suaoER SSVPAtIGoINmNAoALnCORD, CERVICAL cLiHetRoeH NOE, NEOTASTINAL TSFPAiIRmNAATsLAICROOLS, LivaAR `LASSUEV(S)ADOTILAFORBEvLLLATIEON: LINPH NODE, SUBMANDIBULAR Ed of Record 180% " Tr we 418-028:PAGE J-100 ORWAILTH(TGHAEVAGREE)PRCOODMUBCITNIPEORDNO/TRODECEPOVELEALRTOEPMDHGEEDNROTSA4EL16TT-OO0XX2II6CCIITTYY SSTCURDEYENOIFNGTT7E7S0T6 SPONSOR'S STUDY NBER 7-7706.1 Individus) Antes] GAroospsenadnidx H11istororphology Data AsoNxAL NNER: F19051 DoEoAsTeHgToYPwE:: Saori fice-Scheduled ISSOBSERUATION(S): SEARLS Ko gross changes. MISTONRPHOLOGIC OBSERVATIONS): Not appitcable HISTOMRPHOLOSIC OBSERVATIONS: rLveIseuV:s:MODE, SUBKROIBULAR: pdhoiycsprteoersnpttlsia,osni,af.oc1auTlryemnp(hmoi(cnsytatediaetcr)/aptel)asmucytic (ai1d) I4E FOLLOUING VISSUE(S)VEREWITHINNORMALLIMITS: cASoDeRoaEmnNaAnL GLANDS KDIBDONUEEYESWAY (STERN) HeBtsRnAaeIrN RPESVAERR'YS GPLAATNCDH RNEERCVTE, SCIATIC SPINAL CORD, THORACIC SPLEEN oSPwIeNAsL CoRo, Soucy CERVICAL ThoID TRACHEA URINARY BLADDER End of Record 19031 cLeeow SHLESTPAIMHIRPNANEHATLITNROCDOOEIR,DD, NELDIWIGAASRTINAL 11-10 418-028:PAGE J-101 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT APPENDIX Ill HISTOMORPHOLOGIC OBSERVATIONS IN THE LIVER F1 GENERATION PUPS. 418-028:PAGE J-102 `ORAL (GAVAGE) COMBINED REPEATED DOSE STUDYOF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 Table llI-1 HistomorphologicObservations n theLiver - Group | - F1Generation Pups. DBamwNuembeGr:wm "Po Number T 11 9012 T1901T2 1T 9012 19012 19012 190T 12 1T 90T 12 19012 1T90_72T19012 2 3 4 5 7 8 woos DBemmNuembegr:wm `PugNuber 15019 T1_ 5019 T190_19T19019 T1901T9 19019 1T901T9 19010 1T901T9 15010 +2 3 7 8 nop wou GDmameNGuwmbmer: PpNombec TT9021T100T21 19021 1T90_21T19021 1T9021T190T21 19021 T190_21T16021 1 2 68 8 0 WH 11 BDoem Neumbper: FupNumber: 11 9023 1T002T8 19023 +2 3 1T902T3 19023 87 T1902T3 19023 89 119023 wo 11023 1T 9_023 wow DDowmGNuombemr: PwMomber T1004T1 10041 11 9041 1T904T1 10041 1T004T1 19081 1T0041T190T41 19041 12 34 5 8 0 45 6 uy n-1 418-028:PAGE J-103 (ORAL (GAVAGE) COMBINED REPEATED DOSE STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1 `Table lll-1 (Continued) Histomorphologic ObservationsintheLi-vGre oupr |- F1 Generation Pups DeGm mNumbGer:om Pup uber: 11 9002 1T908T2 19042 24 1T904T2 19042 55 11 9042 1 1T904T2 19042 81 1T904T2 16042 1 ig ----e ----e ------------------------ DbowmeNGumobwer: Pup umber T 1T004T421004451T9046 T4 197 044 1T904T4 1s0044n1T904T4 n190o84 i1T904T4 To0M4 cers------------------------------ Dom NSuemGbwemr: Pup Naber: 1T60_50T19050 2 1T905T0 19050 34 1T8050T190T50 19050 557 1T9050T190T50 19050 8 43m DbewmeGNoumwbmer: Po Nunber 1T905T3 19053 3 1T9059T190T53 19063 45 5 1Tw9o05T3 n190o59no1T9080T190T53 10053 DbawmGNoumrber: Botmber Wer 1T50_55T19065 1T906T5 19065 1T908T5 10065 1T006T5 {9085 1T908T5 19065 3 4 5 7 8 00 0#ow 1% uw se a er oe se oe oa "2 418-028:PAGE J-104 ORAL (GAVAGE) COMBINED REPEATED DOSE STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENINGTEST PROTOCOL NUMBER 418-028 `SPONSOR'S STUDY NUMBER T-7706.1 Table ll-2 HistomorphologicObservationsintheLiver ~Group V ~F1GenerationPups DDawmeNuGmobemr: BoNwer 1V500V1 15001 1V9001 V19001V19001 V1900V1 15001 V1900v1 19001 1 2 3405 & 79 yo r-- wR-- : ----ee - rSrmeoreseeeeeeeemeemssm - reese DPDouospmeuNGrumombubpee:rr. V11v50026 V1v9006 V31v6006 V41v9006 V51v5006 1V98v006 Vm1v900u6 v1o900g6 oo1v9008 1v0006 --_-- Db"owPmpeNGNouommbwbeemrr: V21901V1139011 V1901V1 19011 45 V1901V1 16011 59 V1901V1 19011 1 1v9011vTo0t1 21 ee we e ee e eee e m, irr-- PDubeomtouNmumprbeerr: V1902V0 190V 20 1902V 0 19020 2451 V1502V0 16020 89 V1902V0 19020 1v902v0 19020 Ww op 4 e ee ee DtewmNGumwberr: Bomber V1002V2 19022 1V902V19022 V1902V2 1022 V102V2 19022 1T902v2 19022 1 4 5 7 8#1opou 3 418-028:PAGE J-105 ORAL (GAVAGE) COMBINED REPEATED DOSE STUDY OF T-77068 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENINGTEST PROTOCOL NUMBER 418-028 `SPONSOR'S STUDY NUMBER T-7706.1 DPDeuwmpNeuNGunmwhbeemrr: re `Tablelll-2 (Continued) HistomorphologicObservationsin the Liver ~ GroupV/~F1GenerationPups 1Vt902oV5 150V 25 7190V 25 819025V1vn90o25 w1V902V5 15025 V1902y5 1902T5 v19025 wa eeeSee eee DDPouwmpGNNuuommbbemerr:: 1V10022V7 100V 27 1300V 27 419027 1V5902V7 15 9027 1V902vg77 19n027u719027 --_--_------ DDommeNGumobemr: Boobs Wer --_--_-- V19026V. 190V 28 190V 28 19028 1V902V8 15028 1V902V8 19028 V1902v8 1o0z8 1 2 345 5 7 yop Ce DDPouwmpeNNGuummwbbeerrr: 1V603V0.12903V 40 1903V 0 51s6030 81V8030V189030 19V9030V1n90o30 p1V903V0 10D --_--_--m--m---- DDommeNGumobepr: Botmber 1V903V1 1000V 1 1803V 1 19091 1V9031V10031 1V9031V19091 1V0091vfaust 12 3 5 6 8#1 og ---- 4 ------------------ APPENDIX K HEMATOLOGY AND CLINICAL CHEMISTRY REPORTS ------------------------------------------------------ --_-- ------ STUY Sov 10: Mo: 0A6R0G-u0s69418-028. Study Report for Hematology INDIVIDUALPEARINOIDM:ALTERREMPOIRNTALBY GROUP --n_i--nal 10 CUwc MLLnomcM. Gasoelo Groue: 1-0 1199111050 555s 87.5180 504 1911169 5217 p7.e16 1166.23 w191z2s 16.60 7s.6m1 61527 31 1s wr ws nar as 63 13 13 0135 50 ws a7.n43 181.526 913 9151 - ~ = - 19157 we - - - wer - - - nea n5e3 o7s.5s1 11.6356 [ 0 0 wer Xo wv micaons pico cuaonns 7TOT w50.e0 537.2 2a1r 221s asas a2.s4 "wass s5e5s 2 23 ae a3 56.5 a1 21 as er Ss7a5 2E0Y = - - = - - - = - - - wssa s5ts o20r 0 0 418-028:PAGEK-1 sex: mie none x miscnmr I Tewam 3.9 30 2 wn w3s3 19664 7 1 107 52 2 36 ws 1264 36.s6 a1269 = ~ z ~ = z - - 03..303 0w.r9 0 10 Fe---- (= = bata Unavailable LABCAT uet.43 -------------------------- 27-202 418-028:PAGEK-2 Study Report for Hematology ---- INDIVIDUALPERAINOIDM:ALTERREMPIONRATLBY GROUP -- ssttuonr w1o:: w06u0-s069re-iza sex: mae a ml ec mc wo wer, ev wo oc nr TW MLM Gunso x won pico caus x move m a1r9o1u0r2: 20 09 7.55 62 we sr as 52 15106 wo em 15.2 6 1 2s se s2m6 111559111101083 217 o2z3 5619 ws5 sssse =4e w2o B57 em 1 0 as zz ws u5e5s9 nm 1199112290 19136 w1r rrem w10s4 pewsa wsss zzas 3e6s5 05 Tm wa as se a0 ws n13o8e2 es 1159115389 wwoe TTsm wwess a@r2 0swe aasm wmas 1P0e69 w15a15r3 ~- -- -= -= -= == =- -= 15911665 -- -- -- -- -- -- -- -- ort - - - - - - - - now swes o7mm o5.e9 w5z7 2227 awss waas w=rn 0 0 1 0 (= - tata vatiabie oT vet.3 EE------------------------------ -- 7-2 --_-- Study Report for Hematology ------ INDIVIDUALPEARINOIDM:ALTERREMPIONRATLBY GROUP SsTuuovY b1o0:: 0A6R0eu-s064918-028 --_-------- --_A--oost 10 TOWac ALnMc Gums/woLs werXu mIch"nesv picoGwaomsn Group: 30 TTR 1199110051 19107 Ex] no 73 na 11663.0 au az 7.4 93 2s 7.59 61 wl sas az 2.4 212 w11z4 war n5a3 n72r0 2 ra 155.74 w2is ssss2 2234 15.4 ws 560 a3 2s 9130 1s wa 55 22 so 76 150 16.4 1 as sa. sso 2.4 20.6 7.60 63 0 9.2 a 919110565 k~n 65-0 wr- a~ En~ 2s~ 1i91n59 - - - - - - 73 017 - - - - - - en [] 25ms 0.74.4312 0155.57 0 2202 E1n.7 0 0 207ss 0 418-028:PAGEK-3 sex: mee wee x miseamer ITowem 2.7 77 ose 60 m3e 09032 6 30 3124503 4 7.4 ns nas 3.25 61046 - - - - - - 5osm wmo.s2 0 10 _--_-- (=) = bata nmmitabte ABCATbe 43 ------------------ -- 27-anv-2002 418-028:PAGE K-4 -- Study o Repoo rt fo or Hematology -------- INDIVIDUAPLERAINOIDM:ALTERREMPIONRATLBY GROUP SSTTUUDDYY 010:: A0R6G0U-S069418-028 sex: mae e Animal 10 THOvUec WILLe nc GRawns/ooL werxe cmcev pico Gaonsn . nonex THsw/cuPmre T --G_r--oup: 4on T Tewem 1199110080 9106 2.6 20 639 67 18.1 pe we 15.0 15.6 2 0 57.9 8.0 32 22 23 2 2s =a 7 wr Tes 1029 o1e3 wa 22.00 4 7o.s5s0 7.07 6w8s 5.5 w3s4 so6r2 ws 57.0 2a.74 2s 63s9 = an naask 12 1991048 es 195..66 oar 7s3r7 5.0 16.1 Ex ak se Es 15.6 ws sz as 224s 7.6 3340 98 s9s62 9150 w15e6 na ~ oe - - - 15.-0 31- 76- 27- - - - - 4- ne-r - me we es - - - = - = = - - - - - en w 6so2 o6.s5s8 10 015..64 w22z9 E1n3s 0 o2s2 o3.m4 os EX 10 --m-- (=) - data Unavailable. BcATbet.43 ---------------- 27-2002 Study Report for Hematology INDIVIDUALPEARINOIDM:ALTREERPMOINRATLBY GROUP SSToUyY H1o0:: A06v0o-u0s69418-028 ot TSCvem c Lsc Gunws/aoL wer3 mieonv Pico onosn aoom: 54 57 7.20 161 az 5.9 2.4 o91n26 1038 opry 5157.0 w.a0 5sa2 254 191r2e8r n25o a66o1r w3r powes) 555.60 2242 19941208 152.2 T7.o05 516s.2 ""wis 55550 a0s 1195110055 237 7o3e 5w.s7 awks s5a9..8 22.20 9125 Bs~ c-e w=s EY~ E-X 2=2 911568s -- -- -- -- -- -- 919117609 -- -- -- -- -- -- nea wsro o6s5e9 o15n.6 war 5r3e 02.536 n wo 0 418-028 PAGE K-S sex: me novex memnr ne4 1n0e1r3 3s0 1n26e9. 3s6r 1100600 w7o 0155293 25 20631% = = -- -- -- -- o8m3 nuse 0 (=) - tote tvaitabte Lamar ek 43 2-awz00e 418-028:PAGEK-6 EE STUDY STUDY w1o0:: 0AR6c0u-s06198-028. Study Report for Heimai toltogyA INDIVIDUALPEARINOIDM:ALTERREMPIONRATLBY GROUP ee sex: rome -- Animal 10 TCvec. ML_ mMac Gaswoal we-- rTc nich"oonsv pico caonns -- T onex T movermr G1r5o0u1p0: 1-5 -- - - - ~ -- -- - 1502 15019 5 66 65.3605 *6.o4 a5.s2 @as 5E.n0 n36a w0n 19021 19028 7.4 73 7.10 se 67 63 "wr au 0 1 as 26 7.4 34 ne 2 15041 02 80 68 68 ods 62 5.1 wu wz as a3 En 34 22 37.6 1529 1225 19044 19050 10.6 82 s60s9 1630 e57z.6 aazs a2.s1 3570.9 416329 19083 19065. 6s 12.5 608 61 wr 57 37s wz as "2 22 zs 2 1 52 6 19088 19072 ~ - - - = - = - - ~ - - 19074 19075 - - = = - - - - - new s5.m0 o6d5e1 015.55 w25s3 e1z9 a0.595 0 or 19 0 [] 0 0 0 10 0 -_-- (= -bata tnavettabte BeAT He.43 27-uav-2002 Study Report for Hematology INDIVIDUALPERAINOIDM:ALTERREMPIORNTALBY GROUP sSrtuuoby w1o:: 0a6v0-s06910-028 il meewmc jerm c cwe werEu mcronnesv pico uwnosr 19a0r04: 2 78 ror we ws 0 zs 159001069 wwoe 65530 wwes ssss wwss =51e 129500286 55:31 6se3 wwsr w3s eao 2=s 155003376 w2o3 ssmz wwss m2s awrs #z0s 91500437 wnas ssss wwrs E3x aa7s =a2s 59005420 a= c-a w=o as~ s=s wz= 1159006515 -- -- -- -- -- - 155007671 -- -- -- -- -- -- new swne oedms momo 23m a2031 20726 " wo 0 o 0 418-028:PAGEK-7 sex: rows werex movenmr m9e 5s1r0 wmo7 s52r9 33 weass wsae 20st P7a r20a0s1t z= -- -- -- - - 5a3s a2e0 B) - outa tnavatiable sont ves.3 27-202 Study Report for Hematology --_-- Stuov STUY b1o0:: A06u0-s069418-028 INDIVIDUALPEARINOIDM:ALTERREMPIONRATLBY GROUP animal 10 TSUac WLUsamc GRS/eoLs wer Xo micwsv pico Gwuosn Group: 3-5 15005 15007 na 7s oss on 15.7 154 wo 9 2 Pe 26 24 19008 013 7.0 16.6 re 53 55s7 w=sa "9.39 5B0u 550015 7.~4 sa-n 54- na- a- 36- 07 19024 2s ws 6re08 w15e.6 2@10 awos 3as9 15029 9034 2s 21 5.6 st wo 161 3.6 ws a6 1 26 2% 2199003586 wr~ 73-m 16.-6 "2- 9.-9 2s~ 19057 19060 ~ - - - - - = - 9084 - - - - - - em0 2na o6s.s0 o15n.2 5S20 a1580 2os5 0 0 0 418-028: PAGE K-8 sex: rome none ur x Tew m 3 86 nes ws0 awzs n3e1r9 El~ 16--1 E37.X1 w2e0 3 4 1082 = 37.--6 0-- = ~ - - - - aErl 2a6n3 0 =) - ata toavaitable ABCAT 43 27-aw2002 418-028:PAGEK-9 Study Reopoort for Hematology INDIVIDUALPERAINOIDM:ALTERREMPOIRNTALBY GROUP e Sor 10: ARous 418-028 e ---- sex: roms STUor wo: 060-069 animal 10 THON/wCUc LLUnoc Ganwsau a90o0r2: ar - - - 1199000355 0:5 9.6 651 oan 58 162 1199000%0 210..80 epea 1w5a8 1199004065 0=.7 sm- 57~ 1199005541 ws-- 7-5 15.-7 199006528 157 62 si 86 2 57 1199006636 29 71 se so wo 157 1199007639 ~ - - - nea 31105.8 63 0.52 5.2 050 0 wer nv Tc niches en pico Guns. 20 as %3 4 9 a3 Py 38 8 a673 rren 2a67 ~ - - "1- wz- 24- 2.2 ext @6 aa as 25 52 w3 as ao 2s 1 - - - "i 32 as 2.04 zs us 0 0 none nr x Hu me -- 7.6 ~ 169 2 0 27 1086 m33 5E5r3 = - 5.-6 17-- sz 33 1094 199. na 0 5% 506 - - 3.8 12 2173.025 0 (=) = bats Unavailable. eeAT hee. 43 ee 2-aw202 418-028:PAGE K-10 mm StuedyeReepoertefeortHetmoateologymereseeemsmeemeeemseeeeeeee e INDIVe IDUALPERAINOIDM:ALTERREMPIONRATLBY Ge ROUP sStTuin r1e0:: a06u0-s06r5e-ces sex: ree resem ---- rrr etme imp mc rac we wer emeer 4554$neEFSP ae nev nen nore nr r eew/c m mj m Gunso r Emons I rico ons Rx TmwRm a9r0oun: 5-5 5a 19006 7s 5635 50 wBse 5m3o eazs uuzs m3s 25 1155001210 19022 opta pn 7u4s em w8o7 we wdess ao @wsr a4 uass me isaes wma 125s0t9 wan 1195002257 2733 ccaor m5.s1 w7z arn3 azss mwor nan6 1159002880 2a1 se7e6 mmas maaa eezs am0e wmsr arars 1o9s0521 23- 5?~ wr~ s-e i~ 5-7 ws= 099 1199003489 -- -- -- -- -- -- -~ -- 1155005790 -- -- -- -- -- -- -- -- now" sae5 os2m 0 0 o5m30 nass aroo B) maees 0 mIe muesss 0 ] [EE ------ ABTwee 3 21-202 -------- sSuTeiy w1o0:: A0n6u0-s06916-028 --_-- iwi COMCwHvN G19a1o09: on 0 110911516 8702 w19i11z9 672s 9911321s 88.32 1112 a50 19914338 s~s 1199115517 ~- 9116617 -- eam 08512 n Study Report for Hematology INDIVIDUAPLERAINOIDM:ALTERREMPIONRATLBY GROUP secondosr secwoendrst cMoOnCt LTpmhUocMyte TSegWmenOted 55.32 5as2 oo m5e7 2207 567 22.04 oo 19s1 022 56a 2w.e 15.2 8 oo w3a vjo s o 1 27 55.72 2z8s oo 207 35s 5=2 =~ -o 22~ 6= -- -- -- -- -- -- -- -- -- -- 03.x4 23.1000 00o n17s o2n2 0 0 EK wo 0 418-028:PAGE K-11 sex: me TG Bands mReenoecytes 00..00 16 00.00 033 00.00 012 00.00 01.6 00.00 o0s3 -~ ~- -- -- - - 00..000 0o.5s6 0 _-- (= = ota unmvatiabte wea vee43 2r-smzocz --_-- STUDY Sor 10: wo: A06R0-S069418-028 minal 10 CUNICwRNv Group: 2-1 02 19106 5 76 19108 a m0 m3 In 72 912209 77.26 1191%38 s81s 9139 i our 9153 ~ - 9164 9165 - om - em 7.9 0.54 Setuedy Report for Hematology INDIVIDUALPERAINOIDM:ALTREERPMIONRATLBY GROUP secoondrs secwonrdts 0 wo 21 20 6 2% 2 we 22.02 6u3e EwsY "527 11.636 ws ne - - -- -- -- -- "2 2.1 oa0r wa0 CWOSNCT LTyHmSpWhCoUcytRen TSHeSgWm/eCnUtemdE o 65 o 21 27 25 o 10.9 10.0 in 20 oo 5naa 53a6 o o 9.4 56 wo pn o na o 163 52 2s - ~ - - - - - - - - 00o 2n6o8 12398 0 0 418-028:PAGE K-12 sex: mae THSW/Bcuands TMoHnoUcytes 0.0 0.0 10 14 00 0.0 or or 0.0 00 os 1s 0.0 oo or 03 oo oo 02 02 - = -- -- - - 00.m0 0o.5r0 0 =) - bata Unaveitabte ear hee.43, 27-uwzon2 TSuuoov K1o0:: 0a6v0-s069418-028 inl CUMIwNv G5r1o0u1r: 30 so 1195110057 spno worna 8535 w151z21 aa13 159113370 7ess 1199115456 v=e 1199117529 -- wones -- new osmz " Study Report for Hematology INDIVIDUAPLERAINOIDM:ALTERREMPIONRATLBY GROUP second"s secwoendrst w7y xwes wwss 2210 wwasz w2s2 w7r 213 wwao ewre -= -= -- -- - - wozs w23e8 0 CWOBNCT TUpHhSoMcCyUiMe TSHeEgmWeCntUeMd o0 0o.s T21s o n5o8 o3s w8a w2o1 oo 0n4r 5I4e 0na6 1Iu -- -- -= -- -- -- - - - 00o 0w8e a2m0 o 418-028:PAGE K-13 sex: mae THSNG/aCnHtMs HMoSnocCyt)es 0000 0o2s 0o1o o1s5 oooo ovss oooo 0o1s a0o0 203 -= -- -- -- - ~ oomo 00st6 0 3 - tata tnmmtiabie BT bes.3 -------- 2am 418-028:PAGE K-14 Study Report for Hematology --_-- INDIVIDUALPERAINOIDM:ALTREERPMOINRATLBY GROUP -- SSToUrY w1o0:: A0R6G0U-S065418-028 sex: mie --i_n--al 10 UMwNv secon"ds secroenmdsy CWONCT TyHsShWo/CcUytmeM 7 THSSeWg/eCmUntMeMd THSW/CBUasMsN TTT Tham TMHoSnWo/cCyUtemsa ewes Gr9o1u0p: in 71 5s 9.8 1 52 we 23 77 16.4 "0 23 0.0 00 06 17 11911084 9133 873 %5.0 a30e 7.6 0 9.1 25.14 i3an 00 oo 22 os 0 4 23 00 07 9w1u0z1 87s4 556 a2s8 9 3 39 as oo 2a7s 2327 o01o o1.s0 o 55 27 0.0 oe 915s0 156 a537 nEes 80.67 = ~ - oo 2a33 32a4 oo oo - - = = oo 0=2 wi6e0 we -- -- -- -- -- - - - - - - - - - - 16 - - = = - - - - nen 8.2 06 ns 0.60 22 2.20 o 00 32517 o2r8 o0m0 0o.6s7 [] 10 0 10 0 0 ---_-- (=> = bata tnavaitable. ABCAT 43, ---------------------- 27-aov-2002 Co 418-028:PAGE K-15 emer StmudeyeRepeoret efoeree Heemeaetologyereseeeeemeeeeeeeeeemesses INDIVIDUAPLERAINOIDM:ALTERREMPIONRATLBY GROUP SSToUDrY 1e0o:: A0R6G0U-S064918-028 sex: me Pe UMNwv seconodrs secownidsr. Gormoup: 50 7.7 01127 77s3 0126 zr 5.0 ss 128 10 ss 80 ous 99 7s 78 152 9154 52 - 1199115688 -- 191m609 -- 5 3.4 5w.e1 323 57 a wwis 22067 5wss a19s.6 w5s7 2905 - - - - -- -- CWMCT LTyHmpOocNytGe TSeHgmUenteMdm THU[H-- SH 5n0s 1a.74 o0.o0 0o6s w01z 013 0000 0o2s 2540 244 o0o0 0032 oo 222 22s1 00.00 oozs o 6311 2024 o0.o0 0o0e - - - ~ - - - - - = - -- -- -- -= -- em 085.90 wo 0.47 a3 ns 00 2a 275 1.6 om 0.0 0.00 os 03 x 0 10 0 0 _-- (=) = data Unmaitable. ocAT hei 43 ------------ 27-am-2002 ---- STO ST r1o0:: 0A6R0-s069418-028 _-- --i_--m CNwNv 1a5r0o0: 1-1 ~ 11550092 7as 1199002251 77ss w0o62n 94 1155005804 aa2s 1199008635 8815 1199007628 -- 1950075 -- nen o8is " 0 Study Report foor oHematology INDIe VIDUe APLERAe INOIDM:Ae LTREERe PMOINRATLe BY GROUP secoondrs T secorndrs T CMOONCT TTpToWrtTOe TSSh egCmenmMted 9~ 2.-6 508 2.202.4 24s 9a.s3 2288 2ws 3531 2255 2-s 2-6 -- -- - - -o 26- 2~7 oo spzo T2e0 oo 5610 20s5 oo 573 3 5Ts oo 6w1r 1188 - a~e s-a -- -- -- - - - 50..62 a2%r 00o 2.646 025.02 0 o 418-028:PAGE K-16 sex: remus TheNvHBaendms mTMeeoonomeceytmemsn 0.-0 0~s 0000 0002 o0o0 0011 0000 00.10 00..00 o0.o2 0-0 o-r -- -- - - 00..000 o0s1 0 _--mm--m-- - bata tnavitatie wBcAT Hee.43 Ea 418-028:PAGEK-17 fit Sittudiy Rept ort for Heme atology st INDIVIDUALPERAINOIDM:ALTERREMPIONRATLBY GROUP sro 10: avs 418-028 sex: rome e suo wo: 060-089 e isl QM secon"ds secLondEs CONT TOMO TNSWCOM TH-- U THSN/G) mm a1r9o0u0n8: 2. se 119900196 o7s2 1159001285 5o2e 125500567 8r1e o90u0r3 s69o 115900528 r~o 2155006815 -- 199007617 -- new osmo " wx3 aass 73 2zs ouwss x33 wnzs 2x80 uwas E3x ~- -~ -- -- - - ow>a 3539 0 o wsrs 260 0000 0011 o om we s 2313 0o0o 0o0o oo 5717 212% 0o0o Ioo oo n5o n5rs 0o0o 6o3 oo s2e Twee 0o0o 0o2o --~ - ~ - = - = - = - -- -- =- == -- - - - = - 00o s5i8 636 o0.w0 00.439 wo 0 0 [EE ------ seat 43 21-sama2 ----- Sor 10: ARGUS 418-028 STe uov bo: e 060-069 imal 10 wv CUmcRN Group: 35 19008 25007 72 73 19008 013 93 ss 129900156 9-.0 99001276 s78s 19029 19034 7.4 a 198 9056 ~ 93 057 29060 - 9064 - neFEw) o8x3 ] Study Report for Hematology INDIVIDUAPLEARINOIDM:ALTREERPMIONRATLBY GROUP or wrt seconds seconds 2s 2s 2277 1n2r8 a216 n--e an~s 235 221s 3 21 2224 ~ Be ~ as - - - - 50327 2as3 0 Wc CMT Lywhocyte THSW/CU MN Segmented THSW/CU MN 65s7 2wo0 oo 25.30 319s - 5~7 ~ 16 o 7.84 26 26 oo 00s3 2110 - 10--.2 2~2 - - - - - - 0.0 se 260 24 om 0 0 418-028:PAGE K-18 sex: rome Sands Kenocytes THSW/CUJ THSW/CU o0o0 o03z 00..00 o00s ~ 0.0 ~ 01 00 00 01 oz 00..00 oooa 0--0 0~s - - - - 0.0 0.0 02 0.13 0 --- (date Unavailable. ear Hk43 2r-avaonz 418-028: PAGEK-19 Study Report for Hematology INDIVIDUALPERAINOIDM:ALTREERPMIONRATLBY GROUP Sruor 10: ARs 418-028 sex: fom - suo wo: 060-069 Anil 10 mcRwnv secondosr seco=nds CMOBNCT TLIySmHp/hCoUcyMtNe THSSeNg/mCeUntMeNd THSN[ /ICU -- THSW/-- CUHn swoop: 4oF 9002 - -- - - - ~ -- - 19005 19035 7.8 5.0 5a 4 24 2s o o 77 7 16 23 00 00 01 on 1159000309 8718 2s4 5a7s oo 57.76 2282 0000 0013 005 19046. 7.6 3.0 29 - - - - sh - 38 - 03 = 02 - 19051 19086. 7.5 16.1 an.-- -o 2-2 1-9 0-0 0-4 199006528 571s 55s9 E2X o wwss 3s 14 00 00 oz 01 19063 190686 as 7.4 %o ws %225 60.08 206 0o0o 0013 19089 19073 = - - - - - - - - ow 0.5.0 0w.s2 2345 00o 25%2 0.29.64 00.009 oonz [] 0 0 0 (=) = oate Unavailable. seat ves.43 2-22 418-028:PAGE K-20 er----StudyaReep=oereeteeefsoer tHemrateoloegyrer ests ome INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL Smo 10: ARs 418-028 -- Stuor wo: 060-069 sainal 10 wy Omron or seconds wer seconds MBC CONT TLHySmNp/rCoUcyMtGe THSSHe/gaCeUntWeNd THSWB/aInCdUs THmSoWn/oCcUytRers Group: 5-1 19001 6s 5a 0.4 04 2 00 os 1199000161 75.02 22.98 2213 oo wwea 21 "8 oo 0.0 02 01 9020 19022 70 7.6 6.8 57 z2ss o2 322 2109 00.00 0012 19025 19027 83 73 ws 52 Ex as 52 o 02 20 20 oo 0.0 01 0 19028 19030 a 75 En 5 2ns2 o 752 2283 00..00 0I3 9005321 o~s w-s a=e - 2- 3-7 o~o o=o 119900393 -- -- -- -- -- - - - 19059 5070 - - - - - - - - new 7.1 on 5a ne 538.12 0.6 26m0 02x.6 00..000 00.2 [] 0 (=> = bata Unavaitable. eatHes 45 7-202 sStourb 110:: a06v0-s069418-28 study Report for Hematology INDIVIDUALPEARINOIDM:ALTERREMPIONRATLBY GROUP Animal 10 TEoHsOiWn/oCphil a19r1o09: 1h 07 119911165 00.22 1921129 0012 pnaas o0s2 w1i3z 00.20 1193s5 0-3 199115517 -- 9916617 -- rea 0023 n TBasHcpnUils 0000 00..00 00..00 0000 oooo --00..000 0 AThoSmWo/rCUsamLln 00.00 0000 oose 0023 0000 --00210 wo THCOther 00.00 00..00 00..00 00..00 00..00 --00..000 418-028 PAGEK-21 sex: me (=) - outa tnwvitabte weeaT wes.43 21-2002 418-028:PAGE K-22 Study Report for Hematology INDIVIDUALPERAINOIDM:ALTERREMPIONRATLBY GROUP Susy Suny H1o0:: 0u60s-069618-028 sex: mae Arial 10 TEHoSsNr/oCpUniWlN THBSaWs/cCpUhils TAbnHorUmalnnL Thco)thePrn. e-- r ---- Group:-- 2-0 ------T-- Lr-- eper-- SS-- R we 19106 03 os 00 00 03 02 00 0.0 19108 1910 0.0 03 0.0 00 03 03 0.0 I om20 0042 0.0 00 oo oo oo oo 29 9136 0.6 02 00 0.0 00 00 00 00 w0w139 ooso 00..00 o0o0 00 0.0 wr - - = = 53 wish - - - - 6s wn -- -- -= =- ow 03 oz 00 om 0.1 0. 0.0 0.00 ] 0 0 10 ee (r=)e- ata Unavaile able. rs ------------t --------See UABCAT et. 2raw2002 Study Report for Hematology INDIVIDUALPEARINOIDM:ALTREERPMOIRNTALBY GROUP SSooyr 1r0o:: 0A6n0e-v0s64918-028 Jotsal 10 CTosHtnOopNhiGl THBaSsWop/nCilUs ATbooHrsaUlL THSWO/thCeUr c5r1u0e1: 30 03 00 01 00 1o9n1o05 o0s0 00.00 0010 00..00 w1om2 0031 00..00 0010 00.00 w12s1 o0l.0 00.00 00.12 0000 15115370 00.12 00..00 00..00 00.00 1946 06 00 00 00 11915559 -~ -- -- -- 97723 -- -- -- -- ws - - - - now 0.0213 0.00.00 00.017 00..000 wo 0 418-028PAGEK-23 sex: ue [EE ---- LABCAT et. 2-amacez Study Report for Hematology INDIVIDUALPEARINOTDM:ALTERREMPIONRATLBY GROUP stun sup w1o0:: 0Av6e0u-s064918-028 Jntsal 10 EHori/oopCiL HmsSpnNilOs TMHorCmmln THLoOner cao: 40 19100 01 00 01 00 1199110084 000s 0000 ooee 0000 om3e 0025 o0o0 oosz 0000 wweae 0013 0000 ao1z oooo t9o1u0s4 oosz o0o0 0000 0000 1199115506 0~1 0=0 0=0 oo w91e60 -- -- -- -- w51e6s6 -- -- -- -- nw 00236 o0m0 oozz o0x0 " By 418-028PAGE K-24 sex: mus - toca nvatiable wer vee.43 r-azo sstmuon v1o0:: 0A6v0s-06618-28 Study Report for Hematology INDIVIDUALPERAINOIDM:ALTREERPMOINRATLBY GROUP Intent 10 ETosHfooCsil a5r1oun: 50 02 w19o1r2z o01t 1w9i12r6 o01u 199170208 0013 ou0s5 0002 912st o=o 5t1s6es -- 9w16m9 -- nea 00125 " 0 THBSoWs/hCUita 0000 0o0o oooo 0000 o0o0 =-o0w0 ATovoHrsaCl L_ 00s 0 0000 o02o o0s0 o0o0 =~ = -o0a1 THNouher 0000 0000 0oo0 0o0o 0000 ps -0000 6 418-028:PAGE K-25 aes WE (= sats tnavatiable seat v.43 ama Study Report for Hematology INDIVIDUALPERAINOIDM:ALTREERPMOINRATLBY GROUP ssummoe 1r0o:: a06v0-s069418-28 Mrinal 10 Eeoscinoophiml THBoaWscCpLhimls eAownormaml THeLochmer coroowon: 1+ -- - ~ _ 1e001129 oozo o0o0 0o0o 0o0o 000123 0013 0000 o01o Ioo k0e 2 o0o0 o0o0 0o0o oooo o900s40 0011 oooo aaoo oooo 199008535 ooao oooo 0011 oooo wosr2s -- =- Z - 2 Z oorrs -- =- z- zz new 00:10 o0m0 o0s0s o0m0 " 0 o o 418-008:PAGE K-26 sex: rem [------ ven e.43 2r-am-zone ssTtuoppy n1o0:: 0a6n0-s069416-028 Study Report for Hematology INDIVIDUALPERAINOIDM:ALTERREMPIONRATLBY GROUP Animal 10 TEosHinCophil 1ar5o0u0n0: 25 00 1199001069 0013 159001286 0010 o15s08s7 ooou 1199004475 0011 155004582 0~1 1159006515 -- 155007617 -- nea o0n1 n TBoHsoCpnils 0000 0o0o 0o0o oooo 0o0o ~-o0.m0 0 nTorHastUL_ 0000 o0o0 0o0o o0o0 0000 ~-o0x0 HSUoxher o0o0 o00o 0000 oooo 0o0o -~ -~ 00..000 0 418028:PAGE K-27 - sex: rene [ER -- LaBeat bee.3 2r-amz2 Sor STUor 10: to: 0A6G0U-S064518-028. Study Report for Hematology INDIVIDUALPERAINOIDM:ALTERREMPIORNTALBY GROUP Animal 10 TEoOsOivNe/phICiUl Group: 3-5 1199000078 0010 10901038 0000 195001156 0.~0 19017 04 1199002269 0012 1199003348 0--1 19056 00 1199005670 -~ 19084 - new 0011 ] THOBWa/soCpUhiWlYs TAHborUaalRYL 0000 0011 0000 o01z 0--0 0~0 00 00 00.00 0010 00 oo 0--0 o-o -- -- - - 0.0000 00.017 0 0 other THSH]CU 00.00 o0.o0 0~0 00 oooo 00 0-0 -~ 00..000 418-028:PAGE K-28 sex: rows (=) - bata available eAT He.43 2-22 Study Report for Hematology INDIVIDUALPERAINOIDM:ALTERREMPIONRATLBY GROUP Stor Sor 10: 0: A06R0-s069418-028 Animal 10 HEosiMnopChil TBHesSoHp/hiIClUs TAHbSor/mCeUlmnL Other HSU G1r9o0u0p2: 4or - - ~ - 19005 01 00 oo 00 19035 oo 0.0 01 00 1199004309 o01o 00 0.0 oo 00 00 0.0 19085. oo 00 00 00 1199004561 --- -- --- --- 1519008848 0020 0.0 oo 03 00 00 0.0 1199006823 0030 oo 00 00 00 00 0.0 19088 oo 00 01 00 2199007639 -- -~ -- -= ow o0n1 00..000 0.0110 0o.o0 0 0 418-028:PAGE K-29 sex: rome =) - tata tnavaitabie oeaT vee. 43 27-uw2002 Study Report for Hematology INDIVIDUAPLERAINOIDM:ALTERREMPIONRATLBY GROUP ssttuonp w1o0:: A06v0-s064918-028 Animal 10 EHos/inCophil TBHaSsWc/sChUils ATbHvNor)mlmLn THeother a1r9o0u0n7:5 03 00 00 00 15900m06 00.00 0000 00.10 o0o0 0502220 00.10 00.00 0o.o0 o0o0 55002257 00.00 o0o0 0010 oooo 1910903208 00.00 0o0o 0010 0000 9150251 0~4 o-o 0~0 0~0 159003453 ~- ~- -- -~ 1155005790 -- -- -- ~- nen 0.0115 00..000 000.s0 00.000 " wo 418-028:PAGE K-30 . sex: roe (= - bata unmeiladte User ves.3 27-2002 418-028:PAGE K-31 Study Report for Hematology SUMMARY REPORT PERIOD: TERMINAL suo 10: AReus 418-028 suo wo: 060-069 MALYSIS OF VARIANCE FOLLOVED BY DUWKETT"S. PROCEDURE sex: me TesTear: wc noc a ITS THC RILL/CU WY GRAS) wr ww woo nr wv % cu nicRonS PICO Guns Hswco mn cu micon nGreonup: 11 B37: es @s se =o mo wm 0 [1 16 oe0s 16 ae u10 om os ms0 0s eGrwoup: 2-1 ws 7m we @2 wz as wr wm 7.9 ss ome oe sw 2x 1a LB we 0s 00 Group: 30 nen ws 7m w7 Ro ss as ws ws 82 2m ow om 22 1m on om Wwe om " 0 10 10 10 0 3 Group: 40 new 2 ssw Bam La se 22 Be Me 2 " 3% oxs oe0 220 115 ods om0 As oz0 nGerowup: 5-1 wr em me em m3 23 B3 ee so 07 owe om 1m x os om 195 05 " 00 a-signiticant 03tterence from Control P< .05 AT ee.43 significant Difference from Control P< .01 27-sav200z 418-028:PAGE K-32 --_-- Study Report for Hematology PSEURMIMOADR:Y TREEPROMRITNAL B Stuov 10: ARsus 418-028e . ses e y sex: me SToY Ho: 060-069 ANALYSIS OF VARLANCE FOLLOVED BY DUWNETT'S PROCEDURE ee ------ wTaesst:a: PT seconds APT seconds WBC CONT TLHySmWh/oCcUyIte THSSeHg/mCeUntMend THSW/BCUanIdNs TMHoSnNo/cCyU1tes TEHoSsNi/nCoUphiRlN TShasycp.himtme nGerowup: 1m Be 20 o ms 22 0.0 os 03 oo " 0x "0 x 00 1m o0n od 03% 0x ow eGrowup: 20 " woazn 2wi4 0 00o m2o8 00 12m5 0omo 0 oosr o0x3 oowo 0 Gnraonup: 30 [] Be 26 oz 23 0 00 18 2@ 20 1k 00 om 06 os 035 on 00 om wo 0 0 0 nGeroww: 40 we 22 oma 28 00 os 03 0.0 os 22 0 00 o Lx 0 om 1 om o& 0 0% 10 oc 10 nGerowup: son wom 213 ome ae oo os 02 oo 0407 1s0 00 2m0 om ow 030 03 00 A-ignificant Oifference from Control P< .05 BeAT Hei. 43 significant oifterence from control P< .01 27-sm-2002 418-028:PAGE K-33 --St-- udy Reepeort for Hematolog-- y I PSEURMIMOADR:Y REPORT TERMINAL tisha STO STuor w1o0:: 0AR6G0U-S064918-028. sex: mie --_-- ANALYSIS OF VARIANCE FOLLOVED BY DUWNETT'S PROCEDURE --_ vTaEtSsT:): ATbnHorMm-- al L THCothemrn -- neGraoup: 10 0.1 0.0 om om 00 nGerowup: 20 0.1 0.0 ou om 10 Group: 30 ean 01 0.0 oo oc " 0 Group: an own 02 0.0 oz ow ] 00 neGraoup: Son 01 0.0 . " 02 os1 LcAT he.43 27-aaw2002 418-028:PAGE K-34 Study Report for Hematology PESRUIMOMDA:RYTERREMPIONRATL Ssutnuyn w1o0:: 0a6n0u-s064918-028 NALYSIS OF VARINNCE FOLLONED BY BUANETT"S PROCEDURE pr White Blood Countsa. omerr's Duwerr's ees Gow N Tol Mem ow. tf LOIN 0-9 ML Sarce DegFrnee mSaowrtes Smaenme =n 0Ww oomwaz B ws 31SW om ms WT Ma Ws memeonwse 4s2waes oaa0 an on owmoez W2a 2Sms 1o1e Mmes Wwrr MMA1 9w5s e om 4 T eee sn ues wr 30 ou ms wr ma ws Gooft. Worra.tiXoes 2.0.0560 oCeFnetraeb'lse v7alutesblewtos PrOoss Sa1m2 roroessee a23s)m Red Blood Count =nn w 0 T mn TTeB oomees 0% =n To Te TR OM 0% on wo Sn Ge3m. eesm oomse 228x 70 8% 68 8% mememres 44 924s ooeart 70 BE 68 816 mm TTwm ssmme 6ew sai wm 6 mae Goett.Faur.roXrn 62838 DCirnewri'es v7astblewoes rPoOss s3m2 rreossse a25s)m Eemoglobin oonn wWow wmez wwss 1oe Lm m7 we Wa we monmetes72a7m voews onn wo w0s mwre aose L2s8 77 Wwaee MBea Mveem m Tw 6 e as pe 0 ss se 08 ar 7 me 4 me Gott.Farra.tXe=r A3EM DUEembelte vTivetsblewles rPOoIes u30m2 rPo0sSee 22:s1 e+--ssiiggnniittiiccaannttbOiitfffeerreenncceeffrroommCoCnotnrtorlol PP<< 0051 Srrorvithin groups Lane ek43 Tsoruersctea-esnotusrbceetwoefenvagrrioavteiosn 7-amzo2 418-028:PAGE K-35 --_-- Study Report for Hematology --_---- PESRUIMOMDA:RYTERREMPIONRATL sstorth1o0::u0A6n0a-n0s69418-028 ee AALYiSISiOF sVARLAsKGE FOLLOVD BYBANETT'S ROGEBURE --G_o--p Hematocrit W Tem MenTbstwi.. T ommT err's TW TSawF Mer'sOpmesTMN trsreee brrreeee =nn o0 w 2 eee a@s2 oes 0 suams LW 2m 1 0W8s 141 w0z2 ks mamownosr 64 ds i sonn TBo oawrT wsz umam azme w8s wseanrs 2wz kess om wo sex: moe mSeweorrtme sswheeeme meesae rvaes O00 soe PO Cott. VFarratXe=r _-- S36.7066 otwablmevTaleuesrbl'ess TT PrOoTe 3s1m2o roroesse OCR Me aats ----M-- ean Cor-- puscular Volume = 0 0 ssmeas Bo wa ssos ma u2mm om Am os 0360 w9o msmss wws3 --mavemnas 6cmoee De otew 3 seh no0 ssmme msm3s UusW oodms s6m0o smse smss @s3s wm @ en e --G_--ofFVuafnt.To.=n 3.00036 ourmettte's vTatlbelevees RrOe oTe. 3s1m2o nraesses aasam -_-- Mean Corpuscular Hemoglobin 2In 223m zaos ozs2 as oumm om om nu 2a1a 2z5e mmse mman mommemnms 6 moe@ a1e0 0 oo 0 sennoww mm23 2232 oosk oosm maa1 m2ss mmey mm1i wm @ mer Cott. FVarr.toTs= --_-- L1S7T owtelsevTalwvebslevaes prooee TT TT 2mo rseee aams NRee R significant pifference from Control 1 T < 05 Source-osfovaurdratcT ioen Errorvitnin groves Trentmnta-setveen groupe userves. ama 418-028:PAGEK-36 Study Report for Hematology PESRUIMOMDA:RYTREERPMOINRATL Ssttoorr r10o:: 0A6w0o-u0s69416-028 NALYSIS OF VARIMKCE FOLLOUED BY BUNNETT'S PROCEDURE sex: mie Mean Corpuscular Hsted.m.oCwoensc. owes ws Gop KN Tol Mem dw. Ct WSEM L0-M Swe Degfreee SSamroes Shaeummre n an 0 ws mo Ww m2 wr os AB 0m Wo BO es 3 memes www 44sB?a 1oam Sonn 0To Mwsy7 ws 34 0m 1B 0% 08 Wo BO 8 $I ee Wo Bo %8 3 ow ea sn 0 1 m3 om oe Wo os 3 Gott.Fveert. eTse 21.381 DCeFsetrabtlse v'aTluetsblevalves FPo01ee s3m2 rPoossee a25s1m Platelets I 2x w wm ws mMHm 1M079 on Ws ms ws mm memeonmse 4sussasms zewn P- WMS MS MP2 OS WIS IMS TT osnn dToo mmeews TTeOs 1S9e9 L0kMr ootss Nmss oerss mmmm om 4 sew Cott. vrr.atiXoes E0.B40 m7ettabsle v'Taluebs less rPoOeT s3m2o rP0msse a25s)m MEAN PLATELET VOLUME -on 00 mm2e 7a19 ooss 0% 74 88 72 90 Temeenwse 44 woem oozk onn 1 @@13 e8z2 oOmr o0x% 1744 8888 7T2Z 99.00 m wm e ew sn m4 so om om 74 ss 72 90 Goff. Fvhaar.tixoxs T0E5S6 oCwFnecrab'lse vTalauesbles FPoOrVe= 332m prGesSse 2z:s1 ESraruorrc--ev-istohuirncegorfoupVsariation LaBcAT Het.3 [------ 27-am-2002 418-028:PAGE K-37 Study Report for Hematology PSERUIMOMDA:RYTREERPMOINRATL rereer ee eee eee SSTUDTYh1oU0:; 0A6DR0S-u0Ys65418-028. ry WALYSIS OF VARIANCE FOLLOUED BY OUWIETT"S PROCEDURE Prothrombin Grp M Toml Men su. owes om. tT W09oSw-Mes LeeSs m Saree Degfrdaee mSeoets Seaeaenre n an 0 ms Ba 0 wes we o02x7 se BO ms 29 Wem moneewte 4 osnu ovme > 0 Tes 16 025 166 0 BE R29 1B me PoYn ws ws awo ooeer 2Lmm B0o WBee 21299 WToyw Tm 0 sas Cott.Fvrara.tTosx 29..40458 uCFmtehlse v7aluebslevaes rPoOtVse 332m proossse a2sse Act. Part. Thromboplastin Time oxn 0wo woz0ss 2210 3460 08 7 2 WO 20 memmeese snawsw 82%m 3 ws? M6 2B OR WT M2 WO 80 me osnn wo mFers mAz3126m 00%3 WwTT 22 MW0o 5500 Tom 4 ew Contr.Fvrart.iXoxs T0L3D5 D6eecra'blse v7aluetsbleveles fPOoIes s3m2 proesses a2ssm Nucleated Red Cells =-n wwo0 o0 0o0o ow 0 oo TeAMEeNw'eS 445 o0.0o00d00 0o.o00m0 3on w 0 ooo o oo ow 00 ow 6 8 8 8 -------- oo om oom sn woo 00 ow a oo Cott.vFarra.tixo=s 00..00000 uCFmetacbltev'Tasluetsablevelves rPoOvIes 332m rpoossee a2sstm 4-significant 0itference from Control P<05 sErirgonr-iufiitchianngtrodwifsference from Control P< .01 Beatnes.43 Source-osfvaaruiratcioen Trestaents-betveengrows Z-am2002 418-028:PAGE K-38 Study Report for Hematology PESRUIMOMDA:RYTERREMPIONRATL ~ Stae y10:Atous 41e 8-028e mma Pp ST0U: 06o0-0Y69 --_-- WALTSI-- S OF VARIANCE F-- OLLOVED BY DUW-- ETT'S PROCEDUR-- E -- Lymphocytes Grow N Tewl Men so. Dw. oumeU rr's, LoM wesRWamseIs M Sars Degfranee Ssmeomfe emeeme 2T-- nn 09m72 mMs0 126m8 -- 08 7 50 We T83TT 6-- T memE memsoTR54 Smewamrzs Seeeaoe 30 on 0 1 08 Ta 2a 20 0% IF 0% 50 ts 50 ws 83 te --0 0 4% 83 we om 4 mse sn ws 24 275 ow so we a3 14 Cooff.FVaar.teXs= 2.06.1790 DCwFmettatb'lse vUaTlvelsevels PPOOls= 330m2 rpoossee 2asst Segmented Neutrophils Tn 20 0 21 as 22 2s om 1m le 12 32 09 3s memes mot 6s 27 wa 3a om on on 22 14 20 28 106 os om is 12 32 os 3s -- iz 32 os 3s a 6 soe 0% sn 1s te om oe 12 32 os 3s Cooff. FVrara.tiTo== 379 9.85 mCFetwabsle vTaulubelsevalves ros POV _-- _--mBanndms n o=n 0000 0000 o0m 00 00 00 o30n 0011 0000 0ome 1122 o0o0 oo 00 sn 00 00 om oo 00 00 sm 312 ress pos. 2s 25 00 00 TemEems 44 0o00o0 0o00o0 -- rom 6 oo.o0>mm2 O0o.F0o03 oom Cooff. FVrara. iXs --_-- O75 50.000 6 table Oumert's vatues 'T' table valves ros POV= 3m 32 rose Pos. 2s 25 SEorurrocre--vsiotuhricnegorfouVpasriation LABCAT et.43 Treataents-betveen groves. 2r-aaw2002 418-028PAGE K-39 e -- rrr --St-- udy ReSpUoMrMtARYg f-- orREPHOeRmO TatologFy-- rere ae -- ra PERIOD: TERMINAL Ssunmb1ou0::0a6p0r-0sy65era-azs vm ae e ANALeYSe IeS rOF VARIANCE eFOeLLOeVEeD BYeDETeT'SerPeRrOCtEoe DtUmRpE etreesees Monocytes sta. oomerr's somes maces Degree Smof men op MN Tol Men be ULM LWW Sree re Smee See ann an 0 eecy 0o7s ooss 0s ss oe om am 0022 6ae 0o1r te memmees 41wme oomz ne --0oF 0% osnn wowsso ooss oo@m otwe 0022 1t4e oorr tase wom 6 mie Cott.Faar.te+s Z0Z55 bFeleres valvewsblevales rPoOeL s3m2 pmosee a2sst Eosinophils a-n w 23s8 0033 ooam; 0 00 os oo os manoerwse 6omtm ooow oann w Ww 227s a033 ooaa oomm 0000 ooss 0000 aoss -- wm 0 6 12c0 0% Sn To 1s oz om os oo as oo os Contr. vFarra.tTeor 8.00%drbeeaetbtl'esva7lvebsleiben PrOoLe. 3sm2o oess.e 2a4s1s Basophils . onn 1Ww 0o0o oooo oowc 0 06 oo 00 00 memtowsa 44 oo.ocomm o0.w00e0 oan 00 0000 0000 ooxx 00m 0000 oooo 0000 Gooo ----rom 6 0 owe "0 on 00 00 om am 00 00 00 00 Contr.vFerratie=r 00.0m0 btruebtltev'7asluetsmlevwewes PrOoLe: s3m2 Peosse. 2a5s1m So[ urces-- ource -- of variation sear wee43 Treataents-betueen groves 1-2 418-028:PAGE K-40 Study Report for Hematology PESRUIMOMDA:RYTREERPMOIRNATL SSTUDTYh1o0U::0AD6R0G-UY0S69416-028 sox: nue --_-- AWALYSIS OF VARIANCE FOLLOVED BY DUNWETT'S PROCEDURE Abnormal Lymphocytsue.s ouwerr's Gow NW Teal mem Dew. CT WIsMawspW nces W arse sefgareee mseomle smeeme on ee Wr1 0011 om TT TTT Tm TR Sate See momers 4 ox og om 03-1 03-1 ok ewe 4s 0 oa 3r sn M0 2106 12 o0z1 01 oozr 0to8-1<1 oa; em oa 03 a1 0os3-1oa ooosdc --0 --tom sam 0% --C_--otE FVrerta.ce .os I055 mramaebctl'esvTawlesevalu 0F0os= 337m2 rhoossee saaste --_-- Other e o=n 3 0000 0000 0oWm 00 W000 00 0m 00 0000 0000 00 00 TAOfmSm 445 00 00 ---- 00.00000x00 00o.000o0M00 sn W 00 00 0000 0000 000% 0o0o 0000 0000 0o0o tom 45 oom Ce ott.PVarr.atXox 00..00000 bFweatbtl'esvaTle vees ves ProOvLe 332mLTproossT.e aaas r -- Errorvithin groups _-- Treatmenta-betv-- een groups -- Source-source of Variation LABCAT hee.43 27am 418-028:PAGE K-41 --_-- --_-- SSTouorr w1o0:: A0R6G0U-S065418-028 Study Report for Hematology PSEURMIMOADR:Y TREERPMOIRNTAL ANALYSIS OF VARIANCE FOLLOUED BY OUNETTS PROCEDURE sex: rome r TeWTsSt:a: THSN/CUveWcN NILL/CUnoc r GRwAe oN ewXe ce u Wicy hows Pico cuamnnr s woeexemTeHmSent/cunpmrnremcu micRwoyn ten Groups 1-F now 3s.0 0es4t m09s5 2k:s 1 @2 0B%y 0m%4 uw 110 83 ods ] 0 0 10 0 10 10 nGerowup: 207 Be ez 130 3&3 az B30 5.0 ] s0eas0 om10 2m 20 om os0 wea om Grow: 37 new ) na 2% ew oss 12 om Ws 3% es 150 ms om m7 1 um 263 83 0m [] 0 0 0 0 10 10 neGraoup: 4ot ws em m2 wa es ms ws 1s 0 sa0 os0 0% le am 130 12 wr0e oe Group: 5-1 ea ) sy se ea oss 13 om 4 31 0 le ms 105 we 1% ss mes 71 on 0 0 10 0 10 significant oitterence from control < .05 CAT he.43 27-awa2 STUY Stuer 10: wo: 0A6R0G-US064918-028 Twess:: PI seconds Group: 1+ new 0B4z1 " 0 Grow: 2-7 nem oBme ] 0 Group: 3-5 ow wa [ ox Gra: oF nea Bs oie eGrowup: 5-5 Bs wz n Study Report for Hematology PSEURMIMOADR:Y TREERPMOIRNTAL 418-028:PAGE K-42 WALYSIS OF VARIANCE FOLLOVED BY OUWNETT'S PROCEDURE sex: rome APT seconds MC COUNT TLHySmNp/hCoUcytMeY TSHeSgNm/eCnUteWdH Bands THSH/CU HA THMSoHno/cCyUtIeNs TEHoSsHi/nCoUphiMlN TBHaSNs/cCpUhile 2a3r6 00o ss 22 00 oa 24 0% 00 oi 0.1 010 0.0 0.00 0 0 0 10 10 3Bom o 00 em 36 4 36 00 00 03 0 0.1 013 0.0 000 00 0 0 0 ams 23 00os2e60 24 0% 00 02 0m 0 01 01 0.0 0m 0 10 10 0 0 10 #3 oo s2 24 00 oz oa 00 245 00 2% 0%0 0m om0 om0 000 x2 o 60 26 00 02 0.1 00 ose 06 2m om om om ois om 0 10 significant Offference froa Control P< .05 AThk.43 27-awzo2 418-028:PAGE K-43 -- er --St-- udy RepSoretnfe-- ort HS ematEoloRg-- y S eS ssen SPEURMIMOADR:Y RTEERPMOIRNTAL sStTuUoDyY b1o0:: A06n0u-s06198-028 ANALYSIS OF VARIAKCE FOLLOVED BY DUMKETT'S PROCEDURE sex: rene aTErSsT:): TAeHmoCrmYelmYLTHON CoUther nreoaw: 1-1 00 oo " 0s ow nGeraow: 2-7 00 00 0o om Geraonw: 3F 01 00 [] or0 om Geraounp: 7 01 oo n 00 omwo nGreowve: 37 00 00 " 0% ow waBcAT Het.3 Ea 418-028:PAGE K-44 -_ Study Report for Hematology SUMMARY REPORT PERIOD: TERMINAL SsTtuuooYy v1o0:: A06u0-s069418-028 WALYSIS OF VARIANCE FOLLOVED BY OUWETT'S PROCEDURE sex: rome White Blood Count Gop W Tol Mem std. owerr's Oe. LOSDUSMEITS RLa0kG9ES7 MI Soc DegFriene SSmuorfe SMqeuaanre +r ar ms 0 3 ms BE ST 280 47 BI memes 4 36 3 mes 6 1842 esi2 me es w>r To t0e7s ma WE 2s. 12 315 18 47 133 36 U3 eee 47 33 ke 3 rom 4 ewse sr 0 ms 8s 34 00 47 B36 3 Fratiox 270 Fable values ros 3m rose ass Cooff. var. X= 35.721 emett's T table vals POV 302 nOSe 25 Red Blood Count 5 0 eo es oss 2>5 010 e6ms e64z0 004S3 O1429 s5%% TToOrT wr sr 1 es em ose 055 to ex: ek OS OX ssws 77.0077 Frater 0.4 TF ble values Fos Coeff. Vor. X= 7.9 mmett's 'T tablevalves P.OVe omens 4 ous om sSm 7T2a m mor 4s e M4 om sswm 772a oa 4 me 3m rss 2s 32 pose 251 Hemoglobin wr 25 wo se 04 s8s0 0097s 1B 6 165 W367 eammeasm 44 B13e6 o0rxs 35 Ww B24 152 0% OT WE 65 WI 6] p= 10 Le 2 0% 0% the les W317 Tow 4 3498 sr fo M26 m3 07 om te 165 WI ter Cooff. Fvhaar.ti1o=s 5.064669 DCmFmettatb'lse v'aTluetsable values mPOeT s31m2 rpeOsss= a2ms significant Difference from Control P< .05 Error-vithin groups LABCAT et. Source-saurce of Variation Treatments-betveen grove 27-nov-2002 418-028:PAGE K-45 --_-- ---- stu 1-- : aus 4-- 18-028 stu vo:060-069 _-- Hematocrit --Gap_-- NW T-- oul --Men =wrr W omwes Ww3s o>r o wowss 1ws pa ws se Study Report for Hematology PESRUIMOMDA:RYTREERPMIONRATL NALYSIS OF VARIANCE FOLLONED BY OOWETT'S PROCEDURE pr" dseewd.. om0ens 2amm om 3L@x 0o2m% 3 oes WOouHmerr's wWussN TF CTT Sure brteee Ln IR ssmmeotSeee Seem see Wwaa Gw5s 3ms wr momemres 6+ ammosl aan7 wr eMo 0 0 Zwaa sass %M3s wwrr wm 6 ao. C-- ortt. FVrara.tXe=r _ 703300 'oFweteatbtl'esvaTl-- uubeslevaes rP-- oOlss 332m pr-- oesses asasrm -- s Mean Corpusculae r Volume tt ="rr r 0ome3s eaz3 ez es 120 1 1s 0% 0@33 1ea ms9s eess --nummemnms 6+ 0wwee0e 4sse%ns ppea wooeer e@so 2100 0oy @@33 &a11 mw5e seee wm 6 es Cott Vraart.iXoes 21.730 s'eF wtaeblresvaluuebslevalws proolse 331m2 proossee 22ss) -- r Mean Cmoropusczulsar Hoesmso-- globin -- memes 4 1m ox >ar pe w oemess muzs 0 ms ms oomm oomw 1m om 2299 wwss 2zse m322 -- mw 5 2s ws =e mz wm 6 m0m0 0o%a wm pa Tes ms ves om ms ws ze m2 = --C_ot--t. Fwrra.ttXosn 3083%7 bweettatb'lseTvaulubesleves rroolee 332m ProGs.e 228s1 _-- esroruorrc--ev-istohuirncegorfovsariation Lane ve 43 Treataena-bocueen grape Z-ama02 418-028:PAGE K-46 _-- Study Report for Hematology --_---- PESRUIMOMDA:RYTERREMPIONRATL SSTUTY M100U:: 0A6oR0G-U0YS64518-028 sex: roms _-- WALYSISOFVARLINCE FOLLOVEDBYDIAWETT'SPROCEDURE Mean Corpuscular Hsteam. .ouCweornr'cs. Sue's Rakes Degree Sumof Mem -- "rGrom NwHo Tomta2l mmeme_ oow.m 'T LSXM-- L LOMT TeSomuR rece-- s fd4a TSun5m e%s sSeeaaresm ar > 1To 3M2e5 mw37 01%m 0oa2r Wwaa B m778 es 0wo0 --0 owe 4s 0 ses 1s wsrt wwwes wwss u1m2 11%6 wwaa wwrr MMss kwoo ee Cooff. VFarra.tiXo=s _-- 219.075 'Fbtaublen'vTaeltueatsbltev'aluses PFOOVIe. 330m2 proossee 2s 25 _-- Platelets r or Te EE0E) Wer 205 Mw ew ms ter EmeBTosr 4s19m6i5e7 sseeesrs w>r 0To eemes amsm 263 Wrz te 10 mw te Mm 16 ws tm ---- ms te To 9 oo MF wen sr ms ms wes or 1% ew ms te Cooff.FVarra.teXr= 8 1.29 eeettatb'lseTvaalvbeslevaloes rPoOle= _--m --_-- MEAN PLATELET VOLUME "r or 1 me 20 a3 80 ow om 106 7S 91 3 wr mr w3 8&3 80 om oz oe ow rs 1 75 91 sr ws rT om 23 75 ea 331m2 rPoossee a25s)s 73 93 Temeems 4 45 255 mu om on 73 73 93 93 -- To-- 49 O 26.06 % 73 93 Goff. FVrara.tiXo=s _-- 1.46 0.8% Dunertta'bsle Tvtalaubelsevalves rote P.Ol= 3m 32 proossee 2s 281 -_-- ESorurrocre--vsiotuhricnegorfowVsariation BT hek.43 Treataents-betveen grows 2-aw2002 418-028:PAGE K-47 ee Se tude y Ree port feorre Hreeemmmaetmeomlemoe gy meee eeeemmmeeremeeeee, --_-- PESRUIMOMDA:RYTERREMPIONRATL SToY Sor 1M0o:: A0n60u-s064918-028 sex: remus e MALYSIS OF VARIANCE Fe OLLOVED BY DIWETT'S. PROCEDURE emer Prothrombin su. ower' DuesRaces Degree Smo hewn -- Gop NW Tol Nem Dw. tC LOSHE LM TSaTreTe TfdRa TSearmms tSeeree 2-r > fo mmes mm24 mr m2 o0s2 08 ox oo 225s Wwee w12s3 wo memBeoosr 4 4s 2: eis oss 03 we --0 OF r 5 00 ewss Bwmsa 012 21mm 2rss WwSe 112233 ttoo om 6 we Cooff. VFahra.tiKo+s 158 4521 bCuFmettatb'lse v'aTalbvelsevslves rROiVsE _-- _-- Act. Part. Thromboplastin Time r ar 1 ars me a7 zs 2% uw an ws mo r w ms ms 23 1B ws zo srlr mmas #z3z 2u4ms 2zme wwss mmooee 33m2 hroossee a2s wr ms Tenens oon 4 4s wr ms -- wwrr mmss WL 4 sso wes 21s ex 0 OF 0.7 Conf. vFarra.tXexr eee 122.05831 oCuFmettatb'lse v'aTlvetsblevales PPOoTl:s 331m2 meee renee --_----Nu--cl--e--at--ed Red Cells = 25 o oo ooo o0o0 om oo w>r o oo o oo ow oo ow o oo o oo sr 2 o oe ss oo proossee 22s51 eee eee eeeeens 0 Temewrosr 4s4 3002 aocoe oo -- 7% o0o om 4 se --Cooff-- . FVraar-- .tiXo=r--T-- OL1A.G0-- T0 -- 'DFumet-- tatb'lse -- v'aT'luueb-- slev-- alves---- PrOoTs----33-- 2m --hroe-- sses ---- 2as8mee--e ------S-- e rme *m-eSieonete efiecaenet e1tefmereeenceeefereomeCeonetreole?ee<e.e0e5meeeeemeeeSeoeuermcmeee-oesfmvoaeureiraetcsioeeneeeeeeeeeeeeseeemmsnnes Error-uithin grows Treataenta-betuen grows AT hee.43, 27-a0n-2002 418-028:PKA-G4E8 Study Report for Hematology _-- PESRUIMOMDA:RYTERREMPIONRATL ~ SstuoTvH1oU0:: m0D6u0-sY085410-28 sox: rome ANALYSIS OFVARLAKCEFOLLOVEDBY AWETT"S PROCEDURE Lymphocytes, Gap MTL me bseea. oomTerr'Ws EENerrsa0ve9s H sare beagree smoete oeem a-rr Sr Tomeos me esse se z3Mu 26 ze a6 33a0 asrm 2a7r mjua TM amoewTmes 6o0 ssme znomem pser o soews eszo zzmm oUwD S3i4 ssrr 2277 ados me een Cott. FwurtXo=n --_-- 3625m% otwlen7waeitvebrslev'alses BROoLs. 332m roroees oans re eo --- Segmented Neutrophils arr > Maos 3262 3o6m Lm m8 2s om om 0011 4433 a4 auss m-- ememnes 6wn UwVmiPm 3asna py mmss z2e6 0osm o0e 0a11 4a33 44 t4sp rm 6 sew C-- -- ott.vFaBrraa.tnxidoss 5055 m-- teabeleve7aluttebsltev'alosns hroo-- vtes 3s9m2 hraossee -- saamn aarr o0o0 0o0o 00 oo o0c0 0 om om 0000 0000-11 0o1n -- namoowres 6oo OocoFmmo 0os0ememem psr 0a30 0o0o oomm 1ow 0oo0 o0o0 11 0of1 rom 4 oom Coot. VFerra.tXexr --_-- TO1A0D0 dtaa blev'm aT ltbeleevas lus EhOeTe 332m rroesses saestm TEee _-- E4-rSriogrnviifthhcianntgrooiutptserence from Control F< .05 seat wet.43 Tsraostuaerntcs-ebe-otvsfeeonVuagtrraotvcieosen 7-an22 --_-- oo 418-028:PAGE K-49 ere eee --_-- Ssrupyub1o0::n0A6n0u-y0s64918-028 Stm udyeRepe ortrfor Hematoeleogyeres meee eeeneeemre PESRUIMOMDA:RYTREERPIONRATL AAALTSIS OF VARLAKCE FOLLOVED 8 DOWETT"S PRocEbORe sex: rene Monocytes Gop NM Tew Mem bseea.. owCUes 09sawMerr'smW ustsW Sarce befgrnes smeowles Sheeewnr awrr 2173 0013 ooum 12-1 04-2 os mammenes 64 2omm ooom p3l uas7 0o2z oomm aox% ooaa ok ou 2 -z os 0s m tom 0 2m 0% =r 7 oz om o% 1 04 -z os Contr.vFeur.toXse TS04E5 wCF etableev7arstebstle'velsos ProOeT 3s2m Pneosmee 2asms Eosinophils =-rr x 0 aozs 0011 w os 01 0o3w os om ow 0000 0022 -11 0033 --m--emm--ees 6+ 0 ooomk 0o0.%o0s0 wprs wwozos 0011 oomm o0w% 0000 o0z2 -11 0033 wm som Cott.Fverr.oTn= 1.602836 mtebltevs'aTluets la PrOoex 3s0m2 hrossse 2a5m0 Basophils >r 0000 0000 oomw 0 00 00 00 00 TAOS 4 o0.0o00o00 o0.0o00o00 p> 0000 0000 00m 0OmW 0000 00 oo 00 00 me 00 00 mm 4 ooo sr oo 00 om o 00 00 oo 00 Contr. vFerr.oXne 000.000 oCFtweboevw7aluttebstle'vases rPoOVee 332m Rroesee 225s1 SEorurrocrev-istohuirncegorfaVsariation LABeATbet.43 [------ Z-amzmz 418-028:PAGE K-50 -- Studye Repoe rt fe or Hematology _--m PSERUIMOMDA:RTYERREMPIONRATL S STOwo 1o0:: 0A4Rr 0G-U0S69418-028. sex: rem --_-- ANALYSIS OF VARIANCE FOLLOVED BY DMETT'S PROKEDURE Abnormal Lymphocytsue.s bowers Doerr" aavses --_G--ow NW Towl Men bev. CY LN LEM Saree Degree fn Smo sueres ean Sere 2r5 0003 o0o0 o0s 19 TTT rm TR Geers swe 00 01 -a on memomrost 4 4s 01 oan oc oom 3 " 06 01 0s 01 o@ 109 om 07 00 01 00 01 -1 01 OO -1 01 WL 0am sr 03 00 06s om 00 01-1 oa Goff. VFehra.tiToxs _-- --_--Ot--her 1 2 pu wr 5 1 181.133056 DUF teabmlev'eaTltuteasbclev'alvses PrOos= or 00 00 00 00 om 0M 000 00 00 00 00 0 00 0m 00 00 00 om 00 0000 0000 0000 oooo 330m2 proosses aasste 00 00 TEmOTS Emr 4 45 00.0000000 00..00000000 00 00 00 00 ML 0.000000 O00 00 00 Goff. VFerra.tXioes 00..00000 --_--m e'Fettatb'lse v'aTltueasblevawes mmmam rPi0isx 33m2 rpeossse 224s1 --_--_-- SEorurrocre--vsiotuhricnegroofupVsariation cAT he.43 fe---- EE ------------------ ee 27-am22 Study Report for Hematology WHITE DIPPERENTIAL DATA srupy 10: Ansus 618-028 stub vo: 060-069 our: 1 minal 10 arTemes 0 cLyomsbtocerdtesRed Colle saSevqiuennted Neutrophils EoHsenicncoyptheisls SAoansoorpsnaillsLyshocytes ovtehcer "o er Bo2o0o ssaoar oooooo oonos 915 etested Red colts LySmepghueonctyetdesNeutroghils penoenocyes SCaocriennepimsits otAhievarrm. Lymhocytes vec 7o na woaoro 1 o02s oooooo oo9o WME wLycmtpohnotcyetdesRed Cette sSaergcuented Neutrophils snoosntcneoyptheists pAemnorsat Lymbocytes ovtehcer 7o ns ooox0 2Tez03 oo oooo oo5o1 418-028:PAGE K-51 sex: me [---- 7-am2o2 Study Report for Hematology WHITE DIFFERENTIAL DATA stun 10: Avous 418-028 Soy ho: 060-069 oon: 1 Jotmat 10 orTERIAaLs 1919 LywbcloecsrtiedenRed calls BSengeented Meutropnita nEoonsoicnyoepehsils BAeesnoorhsiettsLymphocytes ovteheer 7o ea woaozo w 1 aaa oooooo oo2o7 92 Leytmoprhotceydtehsed cotls aSengmented Neutrophils rEoorsoicnyotpehsits BaAsocnoprhmiatlsLymphocytes oweer s o w o5 oo1s 11 0202 o3 ooos oo6o4 W125 WLeylmensoctyetdesRed Coll BSeagnueented Neutrophils reEnooscinyotpehsils BsoarsocrpshailtsLymphocytes oweer ao us ooo1 65 1o1s o2 ooox oo6o 418-028:PAGE K-52 sex: me BAT Hee.3 2-smac02 418-028:PAGE K-53 --_-- Study Report for Hematology -- Sto 10: ARG-- S 418-028 -- WHI-- TE DIFFER-- ENTIAL DA-- TA ---- r-- rSrTUY-- bo: 0-- 60-06------------rowp-- : 1-0---------------- 0 -- ee Animal 10 Tema e-- r ------W-- I -- Wucle-- sted Red-- Cells -- ER------ o--ro-- -- aee s -- ta--e-- eeeee-- tettn Lymhocytes Segmented Neutrophils 5nom2a7 Bonds Monocytes 5 oo 1s BeEsocspinhoiplhsils o1 oooz otAbhneorrmal Lyshocytes 1 oz oo ee kad 912 LyWsucblaecsytetdesRed Colle BaSengdmesnted Neutrophils EPoosrtarcayptheisls ABbansocrpmhaillsLymphocytes other ec 5o 27 1s 3 ooso oooooo 2oooos ws WH wucteated hed Colts LySmepqhueonctyetdesNeutrophils oy Enoosntorcayptheists BAarscoprnai.tsLymphocytes other Py o 3nonsos 3oooos 1 02 oooooo ooo 15.0 e BAT He..43 ect SEs SS27-ame-e2e0e02t$. Study Report for Hematology WHITE DIFFERENTIAL DATA suo 10: Aus 416-028 STUDY bo: 060-069 cour: Ton anit 10 onTemaes 9135 cleoted Red calls LySmepghueonctyetdeNseutrophils nfoonndoscyes BEacsscienncietnsile Hoobneorra. Lymphocytes wc o 5nonez o2 oo03 2 03 oooooo ooo3 US Wclested Red cells SapghueonctyetdesNeutrophils Pfoonnodcsrtes Eosincphits BAaersorimall.eLymphocytes ovveecr. o --= 0r = oo 0I-- 5 WI elented Red colts LySmepghmeonctyetdesNeutrophils Wsoarnodceytes BeEsocspinhciplhsils ouHhoenorra. Lymphocytes py o0 -- o o -- 0-- 0o -= 418-028:PAGE K-54 sex: wae [RE---- eeaT Hes.43 amaze Study Report for Hematology WEITE DIFFERENTIAL DATA SSoovv K1o0:: a06n0u-s069418-028 or: 10 nist 1 arTemses 957 uclented Red cells LySmehguoecnytetdesNautrhits sPaonniocaytes EBoussicnpohpihtists ostohmeorrsat Lyshocytes vec o0 oo == o = Fa -- o0 =--- We cLytmebnotceytdeshed cells oseagrmesnted Ntrophits Eornertorcerptnesits BaHsoncoprnsiatlsLymphocytes oethser oo 0o == oo == oo == : z= 96 Wcleated Bud Colla LSeygmupehnotceydtesNeutrophils sHaonncdcsytes EBasvcpihintas otAhoveorrml. Lymphocytes wc oo oo -oo =Fa o -- 418-028:PAGE K-55 sex: me - sate tnmettante Lane bee.3 2-am202 418-028:PAGEK-56 SreeestereeorerS--------S--t--u--d--yAReeponrtefor HeCmeatMolAoDgy A eee stASeen ercen eWrHoImTeEt DIFFEt Re ENTIAL O DATA s eSat reereeseast sstmuon w1o:: 0a6u0-s064916-028 ar: 20 2 we ------ ES------NS------------------ tetramer IE minal 10 oTresm WE Welested ted lls LySmepghueonctyetdesNewtrophita sreanncdesyten BEaosxcipnheiptnsita otAhoreorrsat. Lyshocytes we o 6s soaozo 35 1o0s o3 ooos oo0o5 906 MLuycmlpeheotceydtehsed calls sSaengdeented Meutrophite HEoorrcicryetpehsits BtoamsocrpsiallsLymhocytes ovtehcer no aa woo oo2s s 5 uos 1 ooeo oowoo 9108 uteehnotceytdesRd colts oSaenguented Neutrophils REoonscicnyotpehisls BsasocaphristaLymphocytes ovtahcer o ws nooo oo o1 oooa o2 ooos oo2o7 [--_ a Study Report for Hematology WEITE DIFFERENTIAL DATA ssumoo v1o0:: 0A6n0u-s06198-028 ar: 20 nina 10 orTemeis WHO Welested hed Calls LySmepghueonctyetdesNeutrophite nsoanncdcsyten EBoassienponpihtisls toboemrar yshocries wc o %B2w0o osoooz ozoooos 2ooo03 wa WB LboWectsraiteed sfed Colts saSnegdusented Meutraphila PEoonsoicryptheists SaHosvcoprsiatleLyshocytes oatcher no aa 3 3oso s1 osez oooooo oo5o7 20 WLyemtpehnotceydteRsed Colts Spegymented Neutropnita Cnoonntaocrpiheists SsaoscnpanirtsLysghocyies ovtehcer Bo oas wvooo3a s FE s 00 oooo oowoe 418-028:PAGE K-57 sex: mae [r-- 21-20 418-028:PAGE K-58 Study Report for Hematology --_-- WHITE DIFFERENTIAL DATA Sor --s_Tu--oY 10: Ho: ARGls 418-028 060-069 croup: 2-0 niet 10 Tem _--mm ors 19129 LWycmlbeaactyetdesRed Cells "o su BSaengdmsented Neutrophils 7ooowo noEnoosicnratpehsils sooer - BeAsecoporhmiallsLymphocytes oooooo wotcher. woro Esm ex: mse 96 LyWscblaeectyetdeshed Cells peSeogmented Neutrophils NEoorsotcnyctpehsils BaAsbcnoprnmiatlsLymphocytes woteher 2o as Boooao 3 2 os oz o oooo o ao 105 19138 LWuycslbeoactyetdesRed Cells odSegsmented Neutrophils EPoosntoncoyptheists BoAsbonoprnmiatlsLymphocytes woteher. 6o me ooosz 1 3 ez os oooooo ooo 2 _-- LseAT ek.43 ar-az _--mmmm --_--m SSoovv w1o0:: 0AR6G0U-S069418-028 --_--m _-- Joinal 10 919 Study Report for Hematology WHITE DIFFERENTIAL DATA orowp: 20 Muclested Red Cells LySmepghmeonctyetdesNeutrophils Bets ERoosnicneoyptheisls ABabsncoprnsiatlsLymphocytes otehcer orTemas o Bsass 1ooooz ooooo ooooo 0.0 UT LyMmupchteosctyetdesRed calls BSaengdmeented Neutrophils HEoorsotcryotpehsile pAroreorsaaliLymphocytes wotcher. oo o oo -- oo -- z- 915 mctested hed Colle LySsepgbmeonctyetdesNeutrophils BPoonndcsytes EBoanstonpchpihtists otAhbreorraal Lymphocytes we o o = o = o o oo - 418-028:PAGE K-59 Tsex:m me _-- =) - bata Unsvaiable LABcaT e.3 2-22 Study Report for Hematology WHITE DIFFERENTIAL DATA StuoY 10: Aus 618-028 STuoY bo: 060-069 howe: 2-0 imal 18 Tem ar aes 6 clested Red Cells LSeygsmbeonctyetdesNeutrophils MBoannodcsytes EBoessionponpihlisls Aencrast. Lymphocytes woteher o oo - o == o = = FR = z 9165 clested Red cells LySsegpmoecnytetdesNeutrophils BHoennodcsytes EBaossoipnnoiplhsils otAhbreorrsal. Lymphocytes wc o = o -- -- = oo =-- o -- - WI eleated Red Colts LySmepghmeonctyetdesNeutrophils MBoannodcsytes Eosinophils BeAsionpornsialls Lymhocytes other we oo - - o - -- o -- 413-028:PAGE K-60 sex: me (=) = bats tnavaitable scat hee 43 27-22 418-028:PAGE K-61 Study Report for Hematology T mmr ------e--r--ve ea me oree rmT mr enaesae m serer-- sTrorv 1100:: 0A6r0o-s06910-628 aor: 3a _-- ot 10 Tem Tm reser------------oi r -- fass re-- eesteee-- mseess---- ---- 01 ipsrtaoenreednhed cele 7o wa aSreeman reps Neocron 6 2aao as Cposnompaists priry-- :aTooaoso oTer oonoi 05 mUeytmennetredenhad colts o es frSeegomennted Notre w ovoeo CHoormeyiietne o2 oooz Sapsrcomviite Toeoao anmer oonoo J Croracrin-- no oes oSegrmnted Ntrehts P5 ooos ToCeorrireise nPR as aAoierormt Lyehocytes oooooo tner 0 woso -- [reesmp-- s T---- ee o-- es---------- ----------e ----------r r--o--a--m 418-028:PAGE K-62 arts r------------Study RepA ort A for HematGoeloSgeyve rametereseronstoen artisteseiitenireereereWrHIeTEeDrIFFEeRrEeNeTeIiAenLr Dp ATAees tara SSTtuupeyr w1o0:: 0Av6e0u-s069418-028 aroun: 30 _-- re ee ---- ETTetmsmeese restesssstmsrprriie NE -- ee-- r -- Mninal-- 10 ------orsT-- pree maees e-- r --Eemee-- eea as WZ Leylmebnotcertdeshod colle 5o no oSuengdeented Mewtrophita 0ooo1s Eroesnicncoyptheisls 2+ ooss BAaosrcorpenailt.eLymhocytes oToono woeber oonos WE cLytmepnhotceydteshed cotta SSaengdeented Nestrophila Enooaniomcoytneists BAaesncoprhaialls Lympocytes oveer n o s uoooar 15 ooas oooooo oonoa WE Lyemtpeheotcyetdeshed colts peseegmsented Nserophita EPoosntcncoyptneiste psoa rorsa Lyehocyces ovtehcer o w noo us vasoo o2 ooou o1 oooz 29 LAscAT Het 3 E-- --_-- -s8 Study Report for Hematology --_-- m---W-- HITE DIFFERENTIAL DATA Sov suo 10: wo: ARsus 418-28. 060-069 _-- cour: 30 animal 10 Tema _-- or aes WB Welested Red Calle o LySmepghmeonctyetdesNeutrophils nao 04 3 ands Horocytes 1oooon Eosinaphils Bescphits oooooo otAhoreorr.mal Lyshacytes 1ooooa we wa 10 Wcleated fed Colts LySmepghmeonctyetdesNeutrophils Bands. EHoosntroocptneists BAerscrpansit.sLymphocytes other I uo nr w oroo 3 1 ou on o oo oo oonos 7 Lcytmehaoctyetdeshed colts BSoengdusented Neutrophils Enoosntorcayptneists BAarsoorpshailt.sLymphocytes woteher 7o we 5a 2ooooz o2 oooz ooooo wz 418-028:PAGE K-63 sEexm: mmee -_-- AT Het..43 -- EE ---- ------ -- ---- 27-auv-2002 418-028:PAGE K-64 _-- Study Report for Hematology WHITE DIFFERENTIAL DATA _ SSTTUoDYY b1o0:: A06R0G-U0S-- 69418-028 meem row: 30 --m| msexm: mee inal 10 Tema -- or as WUE LyumcplhoonctyetdesRed Calls BSoengdusented Neutrophils PEoosnioncoyptheisls BAabsvcoprnsiallsLymphocytes woteher o 55 maa 2 oo os osao oo oo 15.4 19155 LyWuhcotcesyttedesRed cells BSaengdmsented Neutrophils EPoosricnyoptheisls ABbensocrpahait.lsLymphocytes otwheer o ooo =-- oo oo ---- oo = oo =-- z W159 closed Red Calle LySehgomcenyttedesNeutrophils [pry-- ESoassionpohpihtisls OtAhreorra. Lymphocytes poy oo oo oo -- -- o -- o o --z =) = vata tnevestabte LBeAT ee.43 -- EE -- rE-- ---------------- 27-am2002 418-028:PAGE K-65 --_-- Study Report for Hematology e WHITE DIFFERe ENTIALemDATAeeemmeresmeen eeeeemeeesmmmeen -- SSTUToY-- M1o0:: A0R6G0-- U-S069418--- 28. --r----erou-- p: 30------ en -- rt-- ------ tt--sex:-- mNeEe somal 10 Tew teen eects ------E or st ass peeeretSESE WIR Wuctested Red Cells Lymphocytes o -- BSaengdmsented Neutrophils oo - HEoorsoicnyotpehsils -- BAabsnooprmnaill.sLymhocytes o - woteher. o 2 WITS Lywsuechtoosctyetdesfed calls SSaengdmented Neutraghils EPoosvtarcoyptheinte BaAsbcooprnmiatlsLymphocytes wotcher oo o = o -- oo -- --= z TE LywmupchteonctyetdesRed cells SSaenqdusented Neutrophils ENoosrtoncoyptneists BAabsccoprnaiallsLymphocytes wotcher o o -- oo -- o o -= oooo =-- - -- r)e- bea-- ta stnsaeitab-- ile ------------Sott-- oeeeeeenntE s SSS useAThee.45 ar-az --------------Ee---------- a Study Report for Hematology 418-028:PAGE K-66 --_--m WHITE DIFFERENTIAL DATA _ ssttuunn r1o5:: 0m6o0u-s069413-028 -- cao: on -- sex:mmues Joieat 10 orTenes WO LyumcptheosctyetdesRed ells saSengtmaented Nsrophile EPoonntancayptheists BHoansacrpsnaillaLympocytes ovtahcer WI WUeytheosctyetdesRed cotta Bsaengdusented Neutrophita rEoosnianceyptheinta SRaosnccprsnaillaLympcytes poetsher ao 77 =ooo4 5Toaos [oEoro oo2o6 no ee noaoso soaozo o3 ooos oo2o10 WI LyMmapchteosctyetdesRed Calls soSnegiuented astroshils nEoorncicnaypehsits BHoensocrosnailtaLyebocytes owteheer @o a woaoao 2 2o2s ozooou oowoi _--_-- near v.43 ---------------- i---------- Z-aonzoz Study Report for Hematology --_--_-- TStoovr w1o0:: A0w6S0U-S064978-025 WHITE DIFFERENTIAL DATA croup: eon somal 10 Tem _-- or aes TIE cLylsepsbotceydtesRed cells o neu pSeeeguented Meutrophila w aoo REoovsotcryotpensits 2os02 BeAsrcorpshaill.sLymphocytes s osoo ovtehcer oo 12.0 IIB wclested hed Colla LphSeogcmeyntteed sNeutrophils prHoerosytes BaEsocrptrhoiplhsits otAheenrormt Lymphocytes we m o e Boaoso 3 oosr o1 oooz ooo 20 WH Lywmehteosctyetdetsed Colts BSaengdmsented Neutrophils HEoorsatcnyotpehsite BAabsocoprhsiatlsLymphocytes ovtehcer LEo aooosz 3 2 os 03 o1 oooe oo4o 418-028:PAGE K-67 sex: mae --_-- BAT 43 e-------------------- 27-2002 Study Report for Hematology WHITE DIFFERENTIAL DATA suo 10: ARsus 418-028. Sor wo: 060-069 orowp: ion Jamal 10 Tema ar aes WIR Wcleated Red Colle SepgaheonctyetdeNseutrophils Bands EMoonsotcnyotpehsite BAeosoorpmnaitt.sLymphocytes other I o a se 21 o2na 50 1 on 1 oono 2o8o 196 LyNmupchteoactyetdesRed Cells BSoengdusanted Neutrophils PEoonsatcryatpehsits BAarsoorpmahli.teLymphocytes ovtahcer o a wo wooooar 3 oe o2 ooos oo 9o.o6 WIE clested Red Colle LySmepghmeonctyetdesNeutrophils Bans PEoorsaicnyotpehsils BaAseomporhmialtsLymphocytes ovtehcer o n2 us31 oooooo 1 ez ooooo oo 5.6 418-008:PAGE K-68 sex: me BAT He.43 27-2002 --_-- --_--m--mm stay STuoY 10: bo: Rus 418-028 060-069 --_--_-- --_-- Aoimat 10 amo 150 19156 19160 Study Report for Hematology WHITE DIFFERENTIAL DATA ctoup: 4 LyWmchloesctyetdesRed cells aSnegdmsented Neutrophils EPoorsatcnyotpehsite BaAsocmoprnaiatlsLymphocytes other vac cleated Rod Calls LSyemgpuheonctyetdeNseutrophits Bonds ERoonscterratpehsils ABbansoorpshail.lsLysphocytes otphser Welseted hed Calls LySehgomcenyttedesNeutrophils Bands HEoorsotcryatpensits BaAsorcoprhsialleLymphocytes wotcher orTemses o nas 2 ak oo 2 1 02 en oooooo oo na o ooo --- o -- 0oo =ooo =-- z o o o -- ooo ---- z-- 418-028:PAGE K-69 Msemx: meie . (=) - bata Unavasable BAT ee.3 27-aw2002 Study Report for Hematology WHITE DIFFERENTIAL DATA suo 10: ans 618-028 Sor wo: 060-069 anor: in anim 10 orTEeRs. WE Wcteeted Red Cells UnSepghmoecntyetdesMeutrophils oPonnoscytes SEeosscipnohpihtials Aooenorrmat Lymphocytes vec o 0 - r0a 0- 0o MI E = WE mLcmlpareoctyetdesRed colts BSegsmented Meutrophils Enoostoncoyptneists BoAepnohrsaat Lymphocytes o-er oo o oo -0o -a o - 6s mLcymtpehsotceydteRsed Colts oSaegnuented Meutroshls HEoonnoicnyoteensta BessenaonrisatlsLymphocytes wotcher 0o -- oo = 00 -00 -o -- 418-028:PAGE K-10 sex: mie (=> ~ outa inevitable BAT Het.3 27-2002 Study Report for Hematology WHITE DIFFERENTIAL DATA Stupy 10: Anus 418-028 Sor Ho: 060-069 nour: sn animal 10 TRL or ses WM cLyosambtoecydteRsed Calls Segmented Heutrophils Band HEoroeacpyhteisls BAoansocrpmhaillsLymphocytes other vee 8o wo FR ooo 1 osez o3 ooos ooo 57 WIT ucteated Red Colts Lysebocytes Segmented Neutrophils HBoarnodcsytes Eosinophils BAaosncoprhmitlsLysphocytes ot=her. o ns waz 6oooos 3 os oooooo oo3o 1992 Wclested Red cols LySmepghmeonctyetdesNeutrophils Bonds Honocytes Eosinophils BAbansocrpshaill.sLymphocytes other vec o 102 5oooos 2 02 hen oooooo 00 10.8 418-028:PAGE K-71 sex: me aT hk.43 27-aaw-2002 418-028:PAGE K-72 -- Study Report for Hematology _-- WHITE DIFFERENTIAL DATA --ss_tt--uu h1o0:: 0A6n0u-s06910-028 aw: sn sex: mie Ininat 10 Tem Teme B reer n on aes 9126 LycmlpehsotcyetdesRed alls Co EE aSegsmented Neserophits o[oESo NCoroareyitnesna 5[a]oe BsavsaeprnmiatsLymhocytes oooooo oothcer 2oso WE WLyemtbeosctyetdesRed Calls Jsregmented ostrophits Eocnterrrthsits ASeansocrpsmailt.aysphocytes ovtehcer no so 2oooaa 12 o0a2 FoE oo oonoo WI Lyemtpehsotcyetdesned colts seSnegtmsented Mevtrophits Eroesaicryeipehinte KSoamsacrhimtasLympocytes woteher 70 ua 0ooo 12 0o1s oooooo oowoz ---- neat ve 43 7a Study Report for Hematology WHITE DIFFERENTIAL DATA sup 10: aus 618-028 STupy wo: 060-069 Gow: 50 animal 1 aTresm 0 ctested Red Cells LySmepghueonctyetdesNeutrophils nBoantoscrtes BEoessicnpohpihlisls otAohneorrsal. Lyphocytes vec o 0 22 Wow ooo2a 21 0032 o5 ooos 1o2o US LyMmupchleonccyetdesRd Calls BSaengmiented Meutropnils nEocnsoincoyeensts BaAsoncoprhsailt.sLymhocytes woucher 8o a2 ooo2s 1+ 0o2s o0 oooo ooEoX US mUcmtreomctyetdesRed cells BSaegnesented Neutrophils PEoonsoicnyotpehnils BtosvrohrsialtsLymhocytes ovtehcer 8o ten 2ooo22 ooooao oooooo oo8o.3 418-028PAGEK-T3 sex: mie BT Hee.43 a-amaoee 4I18-028:PAGE K-74 _-- Study Report fT or Heme atology --_-- WHITE DIFFERENTIAL DATA Ssrrtuueonyeh1o0r:: 0a6r0-s06961e8-e02e8 reeeeeeerreeem eem eesaamre:emesmenmmamseeeeeteeeeeemmmmsenx: emaeee aninal 10 _-- arTemises rs W152 Lcytmebsotcertdesfed Colle o ma sSaegieesnted Neutrophil soooeo Eowveriomcoynteists F0E oo BAiamosrsialsLymhocytes oooooo owecr oowos WS Lycmlpehsotceytdesfed Calls Siegesented Newtrophita EMoosntoncoyptneiste Sassocnoprhsiatl Lyghocytes voeveer 0 -- o =-- o = 0o =-- 0o --2 WIS eLycmtheonctyetdeRsed Cotte oSaegrusented Neutrophite Enoovnicreeyptheisls ABeanosrscaal.lLyghocytes ovtehcer 0o ooo == 0= oo == 0o == - _-- <5 = sate tnmaitable uscaT vek 43 7-202 Study Report for Hematology --_-- SSTUoov 10: bo: A06n0u-s06198-028 WHITE DIFFERENTIAL DATA orp: 50 visa 10 Tem --_--_-- or aes 19168 MLuycmtpehooctyetdesRed cells o -- BaSnogdusented heutrephils o o ERoosntorcayptheists oo =-- BAabsrcoprhsiatlsLymphocytes oo -- ovtheecr. oo =z 19169 Wuclested Red calle LySsosghueonctyetdesNeutrophils BWoantocsytes EBoasstcrponpintists Aerorsal oer. Lysphocytes wc oo oo o Io -- o= oooo --= z 170 WLuycmtheosctyetdesRed calle BSaengdusented Neutrophils ERoosntorcoyptneists BeAseocoprhsialtsLymphocytes wotcher oo =-- oo =-- o oo =-- - 418-08:PAGE K-75 sex: mie UO -- (=) - bata Unavastable LABCaTnet.43 27-aav2002 Study Report for Hematology WHITE DIFFERENTIAL DATA Suv STuov 10: bo: ARGUS 418-28. 060-069 --_-- animal 10 _-- OD swoop: 1-5 Mcleated had Cells LSyemgmmbeonctyetdesNeutrophits PBoannodcsytes BuEsxcnpinhoiplheits otAhoreorrmal Lyspiocytes - Tem or aes o oo oo ooo ---- z 02 LWyimcplheosctyetdesfad Cells BSaengdmsented Neutrophils nEoonsoicnyotpehsils BuAsrcopmhailtsLymphocytes owtehr. Lao w aroo 31 oosz oo oooo oo5o9 1019 LWycmlhoosctyetdesfed Colts BSaengdmsented Hautrophils HEoosnioncayptneisls BKeansocrpmhaillsLymphocytes woteher. PoE no 20 oo o3 oooz oooooo ooo6s 418-028:PAGE K-76 sex:rreowes -_-- LABcar ee.3 -------------- 2r-aw2002 _Ssto--uovy w--1o0:: 0An6o0u-s084518-028 animal 1 2 WO WOM Study Report for Hematology WHITE DIFFERENTIAL DATA aor: 1 UWyeeleetoactyetdesRed coll oSaengmented Meutrophits EHoesnicneoyptheisls BeAsocnoprhsiattsLymphocytes wocther Lywmcptheosctyetdeshed Cotte sSaengdmsented Neutrophils EHoosnioncoyptheisls BAeosrooprheiattsLymphocytes ovtehcer LmpMcttoecsyttedeshed calls BSoegnmtented Mautrophite HEoonnctcryptneista BeHsocnoprnsiattsLymphocytes wotcher orTeaames 7o sz E RYoo `oooso oo ooao ooo7. 8o en oooy 22 oona 1 aoao 3oo 8o so ooo2s o1 ooos o oooo o80o 418-028PAGE K-77 ssexr : rews ie Ucar bee.a3 a ------ ---------------- Z-ana2 --_-- Study Report for Hematology WHITE DIFFERENTIAL DATA STUoY 10: ARGUS 418-028. STuov wo: 060-069 ono: 1-5 animal 10 TERIAL on aes 1902 uLcymlpehaotceydtesRed Cells aSengdmesnted Neutrophils PEoorsaicnyotpehsils BaAsocrpohrislaal.Lymphocytes other vec o no oss 2 as oooooo ooooo o oooo 68 WO Lyumchtoeoctyetdeshed Cells BSoengdmsented Neutrophils ERoonsatcryotpehsits BAaosrcoprnsiallsLymhocytes other I o 73 ooo31 1 oa o1 oooa oooooo 0. 19050 LyWmucbtoecsytetdeshed Calls Segmented Meutrophits sHoornoscytes BaEsoosptrhaipthsits otAhbenro.rmal Lymphocytes wc o 2nenaa 3ooooz 1 oa oooooo oo 52 418-028:PAGEK-T8 sex: row LaBeAT Het.43 27-10-2002 Study Report for Hematology Sener ----------s45S stupy 10: Avous 418-028 STUDY ho: 00-069 WHIoTmE eDIS FFEA RENR TIAE L DE ATAcee Group: 1-1 Jost 10 orTemsies 19055 cLytmetnotcertdesRed coll pSegyuented Neutrophils PeEnoscicnyotpehsils BAoavsccrpshaillsLymbocytes ovtahcer no ar ooo1s oooooo o1 oooa ooope 106 eLylmepahotceydteshed Colle oSaegnmented Neutrophils raEroasicnyotpehsils ASbarsocromhaillsLymphocytes ovtehcer. @0 ee 0 3s o1 ooan 1 on 01 aono ooo 2s 19068 cteated Red cells LSeygmmpehnotceydtesNeutrophils onc nEoomsoicnyotpehsils ssAoonponrimatlsLymphocytes ovtehcer oo oo 0o -- -- ---- - 418-028:PAGE K-79 ----et sex: rene (= = ata Unavailable LABCAT HeG.63 2-azec2 Study Report for Hematology sstmuon v1o0:: A08s0c-u0s69418-028 --_-- intent 10 WHITE DIFFERENTIAL DATA car: 17 aTreems WO Lycmlbeosctyetdested celts soSengimented ptroshite ncoonncieryetneists BsaoscrphailsLympocytes over oo 00 == oo *o == o = 1 wLyemtpehsotceydteshed colts Seeepuented Newtroghita EHoornicecysemeists sHaosncoprnmiatlsLymhocytes opthser OTS wLyumcpthaonctyetdesBed colts sSaecgusented Ntrophits nCoonnciemyotpehsits BAaosnccprmsiatlaLymphocytes woteher 0o 0o == o0 =0o == o =z -- o Z 0o == 0 =-- oo == - 418-028:PAGE K-80 msex:rroe e [EE ------ BT het.43 sma 418-028:PAGE K-81 --Study Report for Y Hematole ogy e m-- SeTr-- 1e0: AsRG-- US 418--- 028 ----WH-- ITE -- DIFF-- EREN-- TIAeLA -- SDeATtA-- tee-- e -- ---------- eeeee ss --t -- mSTeuoeY swo:te06r0-s069emesterereeeerercereosuepo:mm2e-s5ptr eeereseresesemmmreesssmemmmmeeeeesex: rome antnal 10 Tem e oom --------190-- 06 --Wcle-- stedeRe-- eedeCeelle s eoe reoeee aes ee ee eeeme eesse emmee LySpehgmoecnytetdesNeutrophils 3nse20 ond Horocytes 1ooooa EoBsaisnopohpihlisls ooooo oAtehneorrast. ysphocytes ooooo we 78 1009 Muctented had Colts LySmepgmheonctyetdeNseutrophils PBoorodcsytes BEoesstorpohpinliels otAhbenro.rsal Lymphocytes wc o n7 ower 1 oono o1 oooa 0 oooo e 106 LWyehlaecstyetdesRed Colts BSaegnmsented Neutrophils EPoonntorcayptheists BAaesnooprhmiallsLysphocytes ovtehcer o me wooooos 2 oo 03 oooooo ooo 0 AT He43 2-am2002 --_----m Sor STUY 10: bo: ARGUS 418-028 060-069 _--m animal 10 08 1026 10% Study Report for Hematology WHITE DIFFERENTIAL DATA orp: 2p Melested fed Colts SLeygsmheonctyetdeNseutrophils BHoarnodcsytes EBoasstorpahpintiets otAheerro.rsat Lymphocytes wc MLcymlpehaotceydtesfed Cells eSeogmnented Neutrophils EHoosnioncoyptheisls BAabsncoprhmiatlsLymphocytes ovtohecr. LMyemlpehoactyetdeshed Colts BaSengmsented Neutrophils EMoosnioncoyptheisls BAabsocoprnsiatlsLymphocytes otwheer. oremuaes o w2 a1s0s o oooo o1 ooon oooooo 53 5o 77 Boaoko oo oo o oooo ooo01 uo sa 2ooo22 2 2 os ou oooooo oo 8.0 418-028: PAGE K-82 sex: rows --- LAAT het.43 27-aw-2002 Study Report for Hematology ~ _-- emommmemom SsrruupoYy --_-- 1bo0:: 0an6c0u-s069419-28 sow: 2 animal 10 arTemaes OT WLycmlbeonctyetdesRed Colts sSaepnueented ectropnits reEroavciyrtpehsits BAaosneoprhsiattsLymphocytes woucner @o no 2[I wr o6 oous oooooo oo2o3 KS J ctontad hed colle prSeeguyentad hatrshits toconsaicnroepehsita saMsocrmailt.aLycos woteher nooose xooo3s 2Ios oooooo oo5os 7 WLcmlbeonctyetdeshed Colts ssaegsmented Nstrils Eowreriamceynteists ABeensocrpanaitlaLymphocytes ovtehcer o ez aooous T2 eaoz oooooo oonoa 418-028:PAGE K-83 sex:rreows _-- [rr azz 418-028:PAGE K-84 --_---- Study Report for Hematology --_-- WEITE DIFFERENTIAL DATA -- SsTtUuYb b1o0:: 0A6n0u-s069418-028 -- aroup: 2% -- Msex:mreem Animal 10 Tem --_-- or ass 08 Mucleotad Red Cells o SLeygmmpehnotceydtesNeutrophils % sa 1.6 RBoonnodcsytes oooooo BEeosscipnnoiplhsils o1 ooon otAhoerro.rsal Lyshocytes oooooo vec 7 19052 MLycslbeoactyetdesRed Cells BSoengdmsented Neutrophils HEoonsatcoyptneists BAaosrcorpmnailt.s Lymphocytes other .c o oo o --oo --- o o -- 1055 LyWmcplheosctyetdesRed Cells BSoongdasented Neutrophils EMoosnioncoyptheisls ABeansoorpsnailtsLymphocytes ovtohcer o -- oo = o 0 o z- ---- =) = bate Unavailable. BATHes.45 2-22 Study Report for Hematology sSTTUuDsYY w1o0:: A06n0o-u0s69418-028 --_--_-- pr WHi ITE i DIFFEi RENTIeAsLtiDATA oor: 2-1 orTEeRs WO LMyumcptheosctyetdesRed colts BSaenqdusented Neutrophils HEeonsaicnycteehsits BsAoorponrisatlsLyshocytes wccoher oo -- 0o --- 0 o o :c ==-~ - 067 UcnopahotceydtenRed Colle nSegsuented Neutrophils ERoosrioncoyptheisls BeKoanocrosant.sLyshocytes owteheer. 0o 0 00 -- 0oo-- o = WON LWycmtpehnotceydtesRed colts aSengusented Neutrophils Enoosnioncoyptheisls BAeosmooprhmiatlsLymphocytes ovtohcer o 0 --= 000 ----= 0 ---oo2 418-028:PAGE K-85 sex:rreomes -_-- (=) ~ tata Unavailable LBcaT hes.43 Za 418-028:PAGEK-86 Study Reepoeret for Hemat0olOogYy BE stun 10: aus are-czniitYyWiHIsTEsDaIFtFbERsENiTIiALsiDAsTAmimaiiiiiluiad stub ro: 060-09 mmm ow: 3 sex:PreE e --_-------- Jntent 15 orTemes 00 Umweatcesytteedsfed colle 5o es prSeegeented Ntrophite PE oo nEoonroiceyptmeists 5Tonos BKaosncaornaisttsLymhecytes Toaon pchser oonoa WOT Lymmcbteenctretdeshed calls Sfepnuented hstropnits EWoorotceyrtheists BRmosncoprmeiattaymcytes owmwer o sa 5ooo20 2 oozo 1 ooao ooo" 1908 Lymmcotheosctyecdesed Colle nSaegneceenced hetrsnite ncoonncteyrtoelss BseicaocrosanlsLyshocyses wateer 7o so =ooo1s oo oooo oToaao o0o tS r[eeyeepeeret4e 458SS ne eee SSr S------7---am2--00--2 Study Report for Hematology SSTouorv 10: wo: AvGus 418-028 060-069 WHITE DIFFERENTIAL DATA our: 3-1 Animal 10 _-- orTemaes OS Muctented Red colts o LySmeghuoecnytetdesNeutrophils 3nos3a BHeonndoscytes 2 oo 03 BEaossoipnnopihtisls o oooo otAhbreorr.eat Lymphocytes o1o0o2 vec 16.6 OU Mucleated Red Cells LySmepghmeonctyetdesNeutrophils BRoonndoscytes EBoasstorpahpihtiets otAhreorrast Lymphocytes . I oo = o oo oo --= -- 19015 LycslbeosctyetdesRed calls BSoengdmsented Neutrophils REoonsoicnyotpehsils BeAsroorpshailt.sLymphocytes owtaheer 7o sr 2 o1 oooa oooooo oooooo 7.4 418-028:PAGE K-87 sex: rome - _-- (=) - bata Unavailable seATHet.43 2-aavaoee 418-028:PAGE K-88 _--m StWuHdIyTEReDpm IoFrtFERfEoNrTIHAe-- LmaDtAoTlAogy ---- TSTouBrY Io: wo: Amsus 416-028 060-069. --_-- Animal 10 --_--m 7 croup: 3-5 UWyumcetheasctyetdesRed Cells BoSnedgmsented Neutrophils HEoonrotcnyotpensits BaAseonporhsiallsLymphocytes owteher orTemaaes o LEEETN 1 ooao o3 ooos o oooo 2s -- re 102 LWycmlpehnoctyetdesRed Calls BSdegemented Neutrophils MEoonsotcryetpehsils BeAsocrpshailt.eLymphocytes otTMher noo 7a 5 26 [2 EYo]z 2ooooz 1 oa oo 10.5 2 uctested Red Calls LySehgomcenyttedesNeutrophils BHoannoscytes SEaosscipnnoipthsils otAhoerrsat Lymphocytes wc o 2wowzs ooooo 1ooooa oooooo 25 _-- wBeAT Hed. 43 27-am-2002 _-- Study Report for Hematology WHITE DIFFERENTIAL DATA ST SY 10: wo: ARGus 418-028 060-069 Group: 3+ Animal 10 orTemes WO LywmupchteoactyetdesRed Cells frSeeogmnented Neutrophils ENoosntorcoyptneists BAaesnooprnsiallsLymphocytes ovtohecr. o 0 ws osoaoo 1 1 on on o oooo oo 2. 108 Mcleated Red cells LySmepgmheonctyetdesNeutrophils [ Enoosnioncoyptheisls ABbensocrpmiatlsLymphocytes obtoher. o o oo ---- o o --- z 1056 cteated ted Calls LySmepghmeonctyetdeNseutrophils MBoannodcsytes EoBsaisnooppihlisls otAheneorrmel Lymphocytes wc o 02 voo ooo22 3 ou oo oooooo ooo 27 418-028:PAGE K-89 sex: rene -------- =) = bata avaiable uBcAT ee.43 -------- 27-am-2002 418-028:PAGE K-90 --_-- Study Report for Hematology e Sov 10: ARIS 418-028 e WHITE DIFFERENTIAL DATA e --STu_oY --bo: m060---069 animal 10 hour: 3-5 Tem esex:erens e --_---- a 107 MLuycmlheoactyetdesRed cells o o SSaengdmsented Neutrophils o -- oo = PEoosnicnyotpehsils + o - BAaesncoprnsistlsLymphocytes or = o ovtheecr. =z 19000 MLuycsteehaotceydtesRed Cells BSoengdusented Neutrophits NEoorsoicnyotpehsils BeAseonpornsiatlsLymphocytes Ovtecher oo o --- o o -- - oo = - -z 106 MLuycmlheosctyetdesRed Calls BSeegnmsented Neutrophils WEoonsotcryatpehsile BaAsbocoprhaiattsLymphocytes owtheer o o - o - o = o - o -- -_ =) - data avaiable Bear ee. --E--r ---------- cca 27-am202 Study Report for Hematology WHITE DIFFERENTIAL DATA sstmuob --_-- v1o0:: a08s0u-s069418-028 aor: or inal 10 orTemaies 2 mLyumcptheonctyetdeshed colle F o -- ssaegcusented Reutrophits oo == rEonoocyntess 0oe == aAaosncaprmsiatleLysprocytes 00 == owmear =- 05 uLcymtpehnotceydtesRed cette tSaegusented Neutrophils vEoorractystmeists seAsocrparnaiatls Lymphocytes opthser ao ar woooeo 1[a ea ooooo 5oo 95 LymemtcesytteedsRed Cells sSaergimennted Neutrophils cRooonctyrteiste BAiavsocrpmhaillaLympacytes woteher wo on oooas oToooon oTeono ooove 418-028:PAGE K-91 sox: roms me -- sor e.43 a -------- Study Report for Hematology sStoovr 10: wo: A06v0e-u0s654.18-028. WHITE DIFFERENTIAL DATA hour: 4s animal 10 orTemes VO LmycmlpehsotceydteRsed Calls fSeenqdusented Neutrophils rs EBoasstcnpanpintists OAtehmeorrmal Lymphocytes we o 2nos2e 2 oo os [)oo oo oooo 2s 00 JMcl--eate--d Red Cells BoSengduesnted Neutrophils NEoorsotcryotmensits BAabsrcoprhsiatlsLymphocytes opthser 7 o 7 2ooo22 o1 oooa ooooo 0o.o0 05 LyWhcloecsyttedesRed Calls Segmented Bonds Neutrophils Honccytes EoBsaiscnpohpihtisls otAhcoerrsal. Lymphocytes we o sa 3s 32 oozs oooooo o oooo 51 418-028:PAGE K-92 sex: rome -_-- ) = tata Unavailable sear es.43 27-am2002 418-028:PAGE K-93 ---- Study Report f-- or Hematology -- e tore re eer WHITE -- DIFFER-- ENTIAL-- DCAeTA --r-- ees-- eSS-- sstuunn r1o0:: 0a6r0t-s069re-tza wr: ar sex: rene es inals1p p0 ot e SSSA r orTtetatamesea ratesr Sime. Toe uUchtoecnytetdened cells 0o - sseagmsented Neutrophils oo = 0-- ENoovriamesrtneiste oo = sseosrcpanrimtas Lympocytes o == omnecr oo =- 9051 wUcptheosctretdeRsed calls pSegymented Nstrophite Enoaramcpynteiste aAnosncoprsneilt.sLymphocytes ontemr o -- oo -o o C-- oo =o -- 905k LboacctyentteedsRed alls sseagmsented hautrophits TEeorciyotrensite HsoansocrpsnailtsLymphocytes avteecr &o uae noooso 3oooos o: oo03 oouos > - outa tnmarisnle seat et.3 2r-ama02 --_-- -------- STuoY STUoY 10: bo: Anus 418-028 060-069 ----mm teat 10 --_-- 108 1902 1068 Study Report for Hematology WHITE DIFFERENTIAL DATA orowp: oer MLuycmlpehaotceydteshed Colle BSaengmdeanted Neutrophils EHoosnioncoyptheisls ABoarsoorpmhailtsLymphocytes wotcher. LwycmlpehaotceydtesRed Colle BoSnedgmsented Neutrophils EMoosnioncayptheisls BaAsocoprhaialteLymphocytes owteher LcytmepahotceydtesRed Colts pSeognuented Neutrophils ERoosntorcayptheists BaAseomoprhsiatleLymphocytes woetheer orTeaams o Bons 3ooo3 1 1 02 az oooooo ooo 15.7 L o R E oomo o1 oooa oooooo ooo 62 %o ea E ooEo 2 2 os os ooooo oo 29 418-028:PAGE K-94 Esrex: erowss _--_-- BATbet.43 2-202 418-028PAGEK.95 --_-- Study Report for Hematology WHITE DIFFERENTIAL DATA er rr[ nrov--woE ; -- 00-06-- -- 9 ------------arr-- : orS--S---------------------- se --sor x: IroEe ws. niet 1 errrrere terme or=aes eerie eemmpeseee 066 UeWheolecsyteedeshed Cols "o eo sSoegcmnced Neutrophils price woooo Ton sFmosrests Jocorat tymbecyies oooooo Ton ptsr ooo7 106 Lehmeotcerntteedshd colts JeSegymented estrephits Ewoeroecpytneints Bsesscoorhmitt.eLymhocytes cptsr 0 [ o --= [0a = oo -= o z= Bors LehmoectyaesesRed colts SSoegmnced Narophila Cnoerriomcoypineists pSrievsoirnmttiyLymbocrtes pcstr 0oo =o == oo oo z mesht~acautteeettenmnetiorte ste [rene EEE PFEeeeeeerereesese ssrmerpsmmrtee ena --_-------- Study Report for Hematology 418-028:PAGE K-96 er ee SteerWeHITeErDeIFpFeERENTIAL SsTuuppy rer w1o0:: 0o6u0-s069ere-czn Toriesrearrsr inet 10 err ------------ 19001 SS ---- cLylmopsoecsyttesfea cols ascegemrented estrophils nEeorrcicnyazneiste BAaosrcoernmitaeLympocytes owveer DAATAreerotSSSoS eerie orTemes o o a oao2 z soos oooooo oo5o1 eratemma L sex: reE ne eee eeeset. 1006 wetosted ted colts LySmepgheeonctyetdesheutrophita ooirorertes BaEsocrptnmirtnsita ovAoenorrsal. Lymphocytes we ao ws EaYr) o3 oooz o0 oooo 0 eoo WON Lcylmobonceydeestad colle feseqyuent Nestropnits rCooancytteessts BHaosnocrpsnaill.s Lymphocytes oethcer o o a o1os 2 aoao 1ooooa 0 4oo sctasreatati4s3reenmere-- stre ------------ee-- tSie-- m ---- eeeee-- Zreaetm-- eaery ---------- Stor Sov 10: wo: 0A4R0-s0694.18-028. animal 10 1020 19022 19025 Study Report for Hematology WHITE DIFFERENTIAL DATA Rowe: 5-5 Muclested Red cells Lymphocytes BSoengdmsented Neutrophils EHoosnioncoyptheisls ABbemsocrpshailtsLymphocytes wocther LmyimclpehaotceydteRsed Colts BSoengdmsented Neutrophils HEoorsotcnyetpehists AbnvsocrpmnailtsLymphocytes wotcher Wiclested fed Colle LySmepghmeonctyetdeNseutrophils Bands HEoonsoicnyotpehisls ABaosrcaphaillsLymphocytes other. ec orTemaes 2 2ws22 2ooooa o oooo o oooo pe o ss 3a 20 3 oo 02 L2 Y)on oo oo 5.4 nooosa 7 20 oo o1 ooon 1o0oao oo 73 418-028:PAGE K-97 sex: rene --_-- oeAT Het. 43 27-ao2002 418-028:PAGE K-98 --_ Study Report f-- or Hematology -- WHITE DIFFERENTIAL DATA Ssuoeyy w1o0:: 0A6n0u-s069618-028 wo: 5p sex rows Ininal 10 arTemaies 90 Leytmehnotceytdehsod ella peSegruented Neutrophita Eroosrimncoyptheisls Sa[acremiatslog-- ovtahcer o 8 w2e0 oToono oooooo oooooo 23 0 LcymleohnoceydtesRed colin pSreqeuyented hutrophila nEeorsoicnyetpehists sa[soprhitas yr-- ovtehcer noo 7a 7oooas 3oooos oooooo oo0o2 BD WLyemlpehnotceydteshed Calls sSaengdmented Nestrophita Eroornioncoyptneista pAornaermaal Lymphocytes otwheer o sz uon oo2s I ooo oTaono oooa1 eeUesrrereeweee.r43------------------------re------------tereeeesessssesamaE eea t---- Study Report for Hematology ssttoorr v1o0:: 0A6n0t-s069418-028 WHITE DIFFERENTIAL DATA Grown: 5 Inia 10 arTemeis 01 LwuocleesrtiedeRed cotta psnegmented Neutrophils fEorsinapnita BAeosncoprnsiatlaLyshocytes oeacr oR metseted hed [-- colts sSaegimnented Meutrophits fErcninepnite saKocnasrmal Lypocytes pomser ao sa 0oooa7 3oooos oooooo 3oo oo o = 0o =-- [oao o == - 053 mctented hed olla UrSeegbmeecntyetdesMewtrophita nsoannoieaytes EoBrasisehrimlists omAoenorrsal Lysphocytes ne 0 00 == oo -= oo = 0 z= 418-028 PAGE K-99 sex: row _-- ) - outa tnavettasie saat vet. 3 Zama Study Report for Hematology moTm TT maoom Ssttuobr v1o:: 0m6r0-s064918-028 aor: 5 ima 1 arTenimae 109 MLremtpeosctyetdeshed Cote peseeprented Nestrophits roCnoarciymtpenists sJooerasstsLyshocytes ov--er 0o 0o o === 00 == oo C= = 059 Upcotceyntteedsed cole sSoegsmented Wares RCoooryeine sesisonrisetteLymhocyten othr 0o o == oo =Z [oa = o = WOO Lymmeptoenctyetdesed cote aScegmaented ptrophits NCaorrimehnits pRoa orst Lymhocytes patser 0 0 == 0o = oo = =z 418-028:PAGE K-100 sox rows --_-- 3 ~ taen toavtante sentvee. 3 Zone em ---- SSooyv p1o0:: A0R6G0u-s065418-028 418-028:PAGE K-101 StudyeeReeport for Clinical CheY mistry e INDIVIDUAPLERAINOTDM:ALTERREMPIONRATLBY GROUP sex: me nial 10 ar nE s E ww .oo ---- ano: 10 ---- 1199110195 65s9 w3e9 11665 "@ 1195111165 s6s0 wo1 1TM9 "a 1w9i12z8 6652 opess 6"0 s@e o1s3e1 665 "pe2 2wn 55 r913n5 6730 "w3r 0153 5n 919105s1 -- - ~ - - ors 19161 - - - - 5167 - - - - now 63 0.3 0=.]2 16w.s8 s3r " 0 o o ren a oor o Eh un 0012 "1e 0034 6265 0012 1" 0033 310%5 0013 15 0034 2w0m 0011 11s 0033 2350 0o2z 1s" 0033 == = - - 2 -- -- >- -- = = = - - - - - 00.027 1.5 o0x3 m2e8 wo 0 (= = dota tnaveitable earcee 43 amaze SSTouoyv w1o:: A06v0-s064918-028 ------- animal 1 IS ara 1o9o1o02: 2-0 61 1199710086 sesz 11911130 6s1e 1199112290 sesz 1199113386 6632 911037 6- 919716563 -- w19o16n5 -- em o6z1 w wo 418-028:PAGE K-102 Study Report for Clinical Chemistry INDIVIDUALPERAINOIDM:ALTERREMPIONRATLBY GROUP sx: me us i aw I ao ren = ar un "wr0 1n66 35 152 "" 0012 01 w* 0033 "1659 03 a5 w3a5 057 ws ns 0011 02 166 0033 0=7 " 04 350 o3s5 2ws "i 108 552 0011 @ 0.2 "" 0033 b2a% 04 wn "-2 - r-es s-s - - 0~2 - 6- 0= - - a= - -- -- -- -- -- -- -- 0.wr9 3 2.010 0 na" 00s1 0 1oss [ 0003 a2s06 EF] (=) = Duta Unmastabte Baar cce.a3 27-202 418-028PAGE K-103 Study Report for Clinical Chemistry -- INDIVIDUALPEARINOIDM:ALTERREMPIONRATLBY GROUP sSTtuubeyr w1o0:: A0v6e0u-s0619-028 ---- sex: me --_-- P --a_ni--mal 10 aeTM ngsh T maaw moeo rmaen momewa awr sea o vn 1c9o1u0r1: 19105 6612h ohsow 2sw R 2an 0o1sm 1wh 0o3an wn o19m10e7 916 6s3s w"r3 63 ws w198 sPoy 0011 " 0033 w os 01 1s 03 i32 2220s a23 19130 662 wwes a156 57 "a 5 "s 0011 PY 01 " 00.42 " 03 22 0 919115476 9155 667 "" PE158 = - ~ 35- 0011 1sw ~ = 00=33 2ns0 ~ b15d9 173 -- -- -- -- - - = - - - - = -- 9176 - - - - - - - - ow x 0633 0oss 8.22 ne" 0.0016 0 [) 1s8 0003 m2s o 0 _-- = = bata aetiabte weeaT ces.3 W= Hesotyzed 21-2002 sstuop v1o0:: 0A6n0u-s06018-028 nat 10 ola a0r0: on 0 1o9n104 5557 oosrsn 6630 mwaer a62 wuese oosz m19s15s0 o--a mweo =- mees -- new o5m2 " 0 418-028 PAGE K-104 Study Report for Clinical Chemistry INDIVIDUAPLERAINOIDM:ALTERREMPIONRATLBY GROUP sex mie ue ola aw [i ja w/o wo w/a w/o aor oat ue wwoo BwSs wpez; 61 o"sa wTMr 4"a n0e pwoas TM1s =- -- -- -- - - o2n =22 0 o @= o0n4 e 0o1r 0o1z 5=6 0012 0o1z ~- -- -- -- - - naa o0es1 PB) 0 1=s 0033 ums 2 o0u3 e9r6 w 0033 wwee " 0033 2m0n2 s. 0033 B2Y ~- -- == -- -- -- - - - 6" o0m3 565 3 0 --- = outa thmatiabte sear cen.a3 ------------ sma --_-- SSTouovv H1o0:: 0A6R0G-u0s69418-028 Ininal 10 olTM Goromup: 5-1 sen oz sin 1912266 6664 n2z7 6636 00 60 459 6634 w1zst 5~8 9115688 -- 9169 - wim - ew 06m3 [ 418-028:PAGE K-105 Study Report for Clinical Chemistry INDIVIDUALPEARINOIDM:ALTERREMPOIRNTALBY GROUP sex: me ns ow oo Tn ow oer oa sa wld w/a ls aL a wen "3m ma mn wh 7 02m 03h wwse 2 es > > 01 01 wwse 156 1 a pb 02 02 "3 0 x 02 w"oss 3% 5 2 oz 02 "~2 2- =-n 0-2 -- - - - - - - - - - - - 04.2s0 =65 E7l2 00.026 10 0 2m 06m anu z2n 003h E5a 22 0033 E56a 28 0043 w30n0 w 03 2 0033 s2 - = - - - - -- -- -- - - - 224 00.035 wr2e 10 ) - tate Unavailable. seAT ch 43 W- Hemolyzed 2-202 SSTTuoOr M1o0:: A0R6G0U-S064918-028 Ioimat 10 TM ola o1r9o0u1e0: 1-5 - 59001129 5643 9021 71 1199006213 6519 91900424 66s3 15050 sa 19083 5s 1+5900685 5-1 072 5074 - 29075. - om 61 " 052 418-028:PAGE K-106 Study Report for Clinical Chemistry INDIVIDUALPEARINOIDM:ALTERREMPOIRNTALBY GROUP sex: rowie ns aw oot pr ole mie a m/s -- -- - -- 3w7s 9uo. 2o 002 ws ps 157 156 ws = or 02 ws 65 "3 55 @ 02 01 paes 8we Eln] 0023 57 35 108 163 FY " 01 01 ~ - - - - - - - - - - - - wr 0.2 152 7 0.8 are 0.2 0.07 0 a crear ja mje uo - - - = 00.34 1a%n = 0s 20 22 00.34 = a> 0044 3n2 x 2 03 03 98 2 -1 0=3 wzs - = - 2 - - - - 2 04 x "0 0.05 S61 =) - ata Unavailable. wBeAT cck.43 Z-sm2002 JE SSTTuuooYy w1o0:: 0a6v0-s068418-028 anu 10 da c19o0o0r: 2-5 59 119500069 5557 +159001286 s5se +9500337 5s0o 199004678 sots 1159005828 5~9 1155006515 -- 1155006m7 -- nen o5k5o ] 418-028:PAGE K-107 SttudfyaRepAort foerli Clint ical e ChemniastryA INDIVIDUALPERAINOIDM:ALTREERPMIONRATLBY GROUP sex: rem ndea maew woam wreaw maf wooar wn o3s9 1m0s s@o oozz w2z "152 n 0022 329 amsTM =" 0012 s3ss 35 s2t o0z2 3"32 1w5e n7 0022 =- - - = - -- -- -- -- - - - - owuo 0re w7o o0m2 0 o wo 22 [05 m" 2z 0o3s 5z=1 2 0o3u zann =2 003 2Py 1 = o0s3 = =ao6 -- -- -- -- -- -- o2r 00.. 8 5260 (= - beta tnaitable [rng 1-2 . TSoOvY r1o0:: A06u0-s064518-028 nit 10 TM os oor: 3+ 1159000073 5536 2159001038 s57s 1159005% 5~6 9900127 s6s7 1199002%9 5o8t 1159003586. 6~ 1199005670 ~- 19064 - new o5n9 " wo 418-028:PAGEK-108 Study Report for Clinical Chemistry INDIVIDUALPEARINOIDM:ALTERREMPIORNTALBY GROUP sex: reme us sa ow mia oo mje Taw mje mae mcoer un 3s9s =TM "se 0011 wwoa wns s56 0012 5~7 -- 5s - = @ 02 wuas 6wo 9o% 0022 wwos w51 10I5 00.12 "=2 TM-- -s 0~1 -- -- - - - - - - 00.21 8.5s7 2.n0 00.0.52 0 [3 0 o 0033 9159 x= 0034 2660 - = . 2a 00.3 20 =2 0043 2225 == 0=4 E~S 2- 0=3 w~r -- z- -= o=r 0003s a5z2 0 0 (= - oota inevitable wecAT cot.43 7am SSroupyy b1o0:: animal 10 a5a0ou0r2: 1195003055 119900309 1199008456 1199005514 1199008528. 2199006636 1159006793 nen" 0a6n0-s064918-28 ar 6--~ s57s ssse --~~ oses s02 5=5 0538 418-028:PAGE K-10 Study Report for Clinical Chemistry INDIVIDUAPLERAINOIDM:ALTERREMPIORNTALBY GROUP sex: rome ouas moew wGeo wTeen wwao aor wae o~s w-- w-o 0~2 - 0~4 =- w"o0 1"6 n@ 0o1z 22 o0s 10630 33s7 a0r s" 0012 => 0o3s -~ --- -- --~ =- =: - - o3s5 =150 a" 0011 == 0034 =I p3os wurs @ 0011 = 0o3a ni "= 2- -a 0-1 -2 0-2 w-r - - - - - - - o0m 6u2e 2@ 00.015 "= o0.m6 0a.n4 0 o o = - bata ravatioble usar ech.43 Zam a02 418-028:PAGEK-110 eer eeeeeSteudyA Repoe rt for r ClineieceaeelreCrheermmiesrterys INDIVIDUALPEARINOIDM:ALTERREMPIONRATLBY GROUP eens eeeneeeen SsTuuooY 1p0o:: a06t0-s069618-028 sex: remit nina 10 TM sla ns aw EE oo Ten wo oor a un a19n0o0r1: 5 5s wo 10s 55 01 = os a 115900101 5578 w"o3 59 ss 0011 0043 7uo 99002202 5586 "sas 255 5 0012 = 00.32 w1o8 002275 s5s5 5378 1152 n 0011 z2 003 2w2s 10950208 6539 "wo5 1059 sns 00.12 2= 0033 260 0251 6=3 w=s 5-7 0-8 0=2 == 0=3 21-0 99000393 -- -- -- -- -- -- -- -- 1195005790 -- -- -- -- -- -- -- -- rea 0ss 0w3o1 5w5o 0.@8 0.0015 54 0003 m2s2 [ 0 0 0 (= = dota naveiabte LancaT cc6.43 7-20 Ssmouovy v1o0:: 0A6t0o-s069410-028 mtn wwre o19o1r09: 10 3% 1199111156 3 1wi9z 55 es w1r3e1 3@ 1191%3 " 910513 -- 9915671 -- wer - ren 6@0 n 418-028:PAGEK+111 Study Report for Clinical Chemistry INDIVIDUALPERAINOIDM:ALTERREMPIORNTALBY GROUP sox: mie oonr nWee mew wmos me ma M mol x me "7 n10a.6 2n0e z u0s6 01035 = 0ne2 00.38 0775 "3 uwsr 6ass B*Y s03 1n0s6 9ar wuss ssss ne o%r naa 2938 FY uuss Pies wose 1n2o6 0n4e ossz 33% www ssst -- - ~ - ~ - - - ~ - -- -- -- -- -- -- -- - - - - - - - 2%4 1053 00.5 19405 a5s2 w1s 26.60 wo 3 ) - outa tnavatiaste wo ch.43 7-am22 Estrun vo: p 060-069-- nAon noouen: 2 5 mi1c0e6 == o91s10 5a 119011220 "" 9o3m8e 2n1 1e9n1e3r9 5- oeshs -- wwers -- new" o 418-028PAGEK-112 Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL sex: mee oanst nWrU mioe moes mmiide mel"t eel =" oTMn n0se 2030 2w wast oono n=e at 0033 9I1) "e wase esoe m =7 0n7z 0535 =a wero sssz 0=0 = 0067 5o3s nz wIs opez} =o w5 owsna oas saw wr ssss -- -- =- ~- -- -- =- -- -- -- -- -- -- -- - - - - - - - w=e m%9 0os.s7 a5m0 wIes u3e o6m1 o 0 no o 0 vata tomatiabie saat cca.3 Fa 418-028 PAGEK-113 --_-- Study Report for Clinical Chemistry INDIVIDUALPERAINOIDM:ALTERREMPOIRNTALBY GROUP SsTtUuBb 1b0o:: n06u0-s06918-28 sex: mie eee ttn TOURER AwTeSsawsetFR.YnwLP.maoO,mjS oes O. wmied comolo"l s mell ar1o0u1n: 30 @w wn ww onshore 2 ww ssw 199110075 53 w 057 nwss k5n5 5 waw 5oe6 1o9r12 ias wr w2o 002s 5s9 F5 uwsr o7s0 w12z3 o2n "2 = 0n1z 59..0 25 wuer s1s 1w9n13s0 s"s wwo =1 wnsr 90.3 P2l uuso ssez 1i9sss @- =- 5=% n=s a=s =5 u--e- s=e w15r9 -- -- -- -- -- -- -- -- w151r73 -- -- -- -- -- -- -- -- no ne wese vwe maok 2509 neBy w1r6 a6z5 ] ) - beta rmattabie User cca.d3 [-- 2-ama00z 418-028 PAGEK-114 Se ae 555538 SterumdyemRtepoerrte foetrEClT iniA cal ChemiSsEtery res INDIVIDUALPEARINOIDM:ALTERREMPIONRATLBY GROUP SStoorr h1o0:: 0A6n0u-s069410-028 sex: me it uAiT aswnt wVrL meo woise mijed moll meltx ao0r0: on 5 7 2 10.9 83 " we 55 110086 05 0=7 E7l nnso 5o3s 51 wwsr 65s6 pa13 w=FY 10a8 1526 n0.r8 o9s3 2= wwrs 563s poer i"s 108 550s 00.77 0a7s n5s wuws 5o3s 9w14s8 3i anno n2e nmz2 9o.s2 2 wwrr 6ss 115%0 -Ps 0-7 >- ns~ ~3 =- "= 3= we60 -- -- -- -- -- -- -- -- 1199116663 -- -- -- -- -- -- =- -- ean 5s wa u5r8 =nas m0.a3 ir5.]7 aPsY w1r0 06500 0 0 (= - beta Unavaiaste Baar ch. 21-2002 --_-- --_-- STuov suo 2100:: 0A6R0o-u0s69418-028 _-- J --_-- aure roup: 5-0 womr oEYn 1226 E2Y wr 128 s0 1910 1945 ry 5 1905 sz " @ 115548 -- wees -- om - ow Cl 7.0 ] 0 418-028:PAGEK-115 Study Report for Clinical Chemistry INDIVIDUALPEARINOIDM:ALTERREMPIONRATLBY GROUP se: mae ausLt wueL jao oods. WEAY TTR mil" mW melx men msewun TWSHH nnTow saeww w7nH wn 040 rw son 1=3 5a9 nnss 50..86 04 "2 na na "2 wr us 2 wr ss Pr 71 255 1=6 n0e5 5s.e0 12s ia ns 08 2" 1 was ws ssso 70 7 7- "w 1n2a0 0ns2 1sn - - ~ - wus - s7a ~ - - = - - - - - - - - - - - - 7 5.6 ws 3s ns 03 02 13 " so us 22 65 15 0 10 ST -- (= = batatwalable uaBeAT cck.43 We Hemolyzed 27-aav-2002 418-028:PAGEK-116 _-- Study Report for Clinical Chemistry --_-- INDIVIDUALPEARINOIDM:ALTREERPMOINRATLBY GROUP STUoY STUoY 010:: A06R0G-U0S69418-028 _-- Ininat 10 mmr aorp auset nure L o yios eeeeeetereee meme Tmijee mol"l etter eee r5o0u1p0: 1-5 - ~ - - - - -- 9012 5019 we x I 2 a 7 10.5 10.5 8 ne n & uw w@ 5021 9023 id ns a ne us " ns 03 3 se a 0 59 0 19041 902 we 0 184 2 mn = 9.9 102 0.2 87 " " 0 138 119900540 5563 1987 0=0 nwrs 0843 TM = us 10 19053 19085 o 123 33 2 n 5.6 01 7.6 82 " FY 160 ws 19088 0072 - - - ~ - - - = - = - 1007 5075 - - - - - - - sex: rem x molleee 60 5s4a 5652 w5s7 7.4 57 5-6 - nem 2 nr "2 28 us 7 10.6 or ss 3 se 5 3 63 58 0a [] 10 3 0 0 0 --_-- (=) ~ Data tnavaitable. BAT ck. 43 -am-2002 418-028PAGE K+117 --_-- mm Study Report for Clinical Chemistry ------ INDIVIDUALPEARINOIDM:ALTERREMPIONRATLBY GROUP smo STUDY 10: bo: A06v0-s06918-028 sex: row E mimi AT 1 T wr os . is " x _-- un UL mf TwmFf Tjed mmem lt ewen f 1p90r06 19009 657 5no 153 nnsr 7a6 P1r 5539 19001186 15026 31506 ws 0102 2%0 nnee or8 2 ws 10.7 96 P@y P w0r at ssuo so 199003%7 7ns6 128s1 03 n0.o9 o5s3 19068 150 1 = ws a3 a= 5 wuss ssez w@ 6 199006678 15052 21 - w11r w3 010..40 n5s3 s2s - - - - = w0e 65s6 - - 519006515 19087 -- -- -- - - -- -- - - =- -- -- 190m - - - - - - - - nen x 21.303 a365 1759 0n.a6e3 17%9 10.02 0 0 2030 o5s6 0 -_-- (= = bata Unmvasable scar cct.3 2r-s2002 smuoy SOY J10o:: Er 1o9u0r03: 3 1195000087 915001163 19015 1199001270 fr1e9029 119900368 1195006507 15064 rem [] a06n0u-s069ere-cas 7 10. E0d7 "-- 2166 129% 0-- -522 wo 418-028:PAGEK-118 Study Report for Clinical Chemistry INDIVIDUAPLERAINOIDM:ALTERREMPIONRATLBY GROUP sex: rem swonr nYeL mMo wrois mTMae me met TM3 us 101 o 09:36 5.7 s0z7 "2 73 El 12--5 wr 5= 0.~6 5=6 57 3 ws &-- ne 1353 151 we n"s3 n5s9 90 ns 61 b"Y 5 "~0 1-08 "n~o 10~5 Ee m 0.7 9.9 =7 = -- -- -- -- -- - - - - - n1e57 [3 or1s% wo o10.r6 25.m0 EX E) [] 1w s5ss w1e5 5547 w--w w~s wuse 6s0i "war ssse w~e 5~5 -- -~ - - 225 05x62 0 0 (=) = tate Unavailable [rer Z-am2ce 418-028:PAGEK-119 e SItNuDdIyVe IRDeUpAoLrtANfIoMrALClRiEnPicOaRlT BCYheGmO e RiOsUtY Pry -------- PERIOD: TERMINAL -- SSTtuoorY w1o0:: a06R0o-u0s6-- 5418-028 ---------- sex: rene --i_--tn aunr awnst nVeL miod wPmroas FT miie me" ER Om seyP) me 1a9o00r2: oot ~ -- 19005 TM rar 1--08 10-.6 9-.6 - 1-2 6-2 1195003359 19060 mms 112285 2or n10o0 i92 TM 2 % 5.7 08 @@ wwr n3 s5s5 7.0 119900885 5- I- -- na- s-e E=S u=s 5=5 1910905541 *- 7-- n-o 10.-0 10-1 19058. Ey nr m 0.7 5.4 =- 1-- 6~s "2 53 199006623 n5o8 p2n sa10s2 0073 05..70 wwws 5711 199006669 19073 6- n-e - -= 03= 52- - - - 5 -- we -- 6s -- ean " 1E2x7 21a2% 07 00..66 2a87 wo 0 0 5 2w6e 06.01 0 -- (=a) p=-- oputart-- neavita-- bte --re-- --eseet-- estee-- ns------eaees-- weet cct.3 2r-am-2002 Sor STUBY h1o0:: A06R0-s069418-028 minal 10 aurL ao: 5-5 1199000016. 6n0e 190m 19020 32 51 1199002252 n3s 1159002287 ius 11990091% 1u5s6 919003323 -- 199004599 - 500 - ea 2u.s0 [] 418-028:PAGE K-120 Study Report for Clinical Chemistry INDIVIDUALPEARINOIDM:ALTERREMPIONRATLBY GROUP sex: owe ausnt wure w/aa H Pros w mie ml" mlx 3us ans 010..11 w5r.0 3 1 El 3 10.3 5.8 8.2 57 s 7 wur 0we 093.6 05..04 1287 258 25..06 150:.26 PY" 5wm mwn wnes nses 757 -- -- -- -- - - = = - = = - - - = = w1r56 "iwer] o0.e4 0.4 16 " ws 10 10 wn 38 os 6s we uw 52 65 wuse. spao wurn 6sa 3us 6sa3 - - - - = - - w@ 26 62 050 0 -_---- =) data tnavaiteble weaAT cck.43 27-2002 Sov SOY b1o0:: 0A6v0e-0s694.18-028 418-028PAGEK-121 Study Report for Clinical Chemistry INDIVIDUALPERAINOIDM:ALTERREMPIONRATLBY GROUP sox: mie animal 10 @ --tt oafoae ownee o19v10:9 on 03 20 20 1191516 1580 281 2212 119112125 0F0e 159 2223 01321s E%Y 2223 2108 91133%2 5 280 2224 90133s =5 2=3 2A0 919115517 -- -- -- 919116617 -- -- -- neFwy E2e7) x20 02.118 10 0 1] -_-- ) - beta tnevattate wear cee.a3 2-202 418-028:PAGEK-122 --_--StI-_ uNm-dDmIy_-V-IRweDWpU-- oAmrLtANfIo- MrALCliRnEiPm cOaRlT BCYh- eGmRiOsUtPrym-m --_-- PERIOD: TERMINAL Sov So w1o0:: 0A6R0-s069418-028 sex: mu --_--mn _--mmm vAmnimal 10 --La aPny Sr we = none. s19o1u0p2: 2-0 20 21 1199110086 % 01 22 i 18 21 110 13 01 270 2213 0120 2 % % 22 1 20 22 91% 9138 % v1s9 2233 R191d39 - 1s ~ 22 - w15e3 -- -- -- 9w1o6m5 -- -- = nea % 5 20 0.16 21 0.16 1] 10 -_-- (=) - bata tnavastable eat cee.43 ava sStouprY b1o0:: 0a6n0o-u0s65418-028 418-028PAGE K-123 Study Report for Clinical Chemistry INDIVIDUAPLERAINOIDM:ALTREERMPIONRATLBY GROUP - sex: mie animal 10 -- @ aaosn nownee. a9r1o0u1n: 3 We 22k aw 1199110075 150%5 "T7s 2244 19911124 P10Y0 2200 2222 122s1 0I 282 2240 1199115370 10E0Y 1236 256 19114565 - 2~2 20 ~ 159117529 -- -- -- 99117743 -- -- -- rea 2030 02.0 02.226 " 0 To --- (=) = tote Unavailable Baa cce.3 ---------- = Hemolyzed 2-szsez --_-- _ss--ttuunb h1o:: 0a6u0-s0694re-czn 418-028:PAGE K-124 Study Report for CTlinUicalTCehemeisntryy INDIVIDUALPEARINOIDM:ALTERREMPOIRNTALBY GROUP sex: ue om 10 --iao aErra nownee w15a1r00: on 0 20 20 0063 1000 aar 2243 o13s3 E5sS "85 2233 1w91e01 0% 2125 2z3o E191m48 15150 5 2211 2210 20 22 w1i6s0e = - = - 2 - w9i16e8 -- -- -- wes - - - new 2w7 02.06 o2s2 " 0 0 --_--_-- (= - batetna sear cek.43 Zaman 418-028:PAGEK-125 C _-- Study Report for Cy linical Chemistry --_-- INDIVIDUAPLERAINOIDM:ALTERREMPIONRATLBY GROUP SSmOoY --_-- w1o0:: A0R6G0U-S064918-028 sex: mur _-- Joa 10 ol@ oaas nwonee = = onomr: sn ww 208 23m 19m1274 mK 1v8eM 227am 1199112276 100 2108 2236 119914208 "% WWrr 22ss 9 19s 05% s9 22s4 1191552 - 6~ 2~6 1199116588 -- -- -- 919117609 -- -- -- new 1020 0.813 o2r5 [ 0 --_-- (= - bata Unavaiiabe ABT ch.45 ee W= Homolyzed 2-sm-202 SSTTuUoYY b1o0:: A0v6a0l-s064918-028 -_-- 418-028:PAGE K-126 Study Report for Clinical Chemistry INDIVIDUALPEARINOIDM:ALTERREMPIONRATLBY GROUP sex: femur nit 10 @ tL wooa nownoe o5o0r0: or - 9012 5% 1--7- 2-2 11500092.1 1200 2220 2222 10940213 =7 16s 2274 119900024 %2 2220 2202 1199005530 I 158 2211 1199006885 072 -- 2=2 Te = - - = 155007754 -= -- -- wean 55%4 0129 0222s [] wo o (=> = sata tnavaitante Baa cce.43 -- A-- -- Hr ------ Ea. _-- SSrTuUoowY b1o0:: A0n8e0u-s089418-028 --_--_-- 418-028:PAGEK-127 Study Report for Clinical Chemistry INDIVIDUAPLERAINOIDM:ALTERREMPIORNTALBY GROUP sex: row nimi 10 --iLo aooee nwonee r5o0w04: 27 1.6 27 1155000196 %5 1a3 3222 15900286 75% I6n 23.40 1199005376 95% "57 2253 1199004678 5nn 110s 3230 1199000582 5-5 7~ 2=s 1195008651 -= -= -- 1159006m7 -- -- -- nea 2*7 0.12.66 02s6 [] 0 0 _-- =) = bate unavailable sear cco.3 ------ 7-uw2002 _-- Stor SOY b1o0:: 0An6o0u-s084916-02e _--_-- . 418-028:PAGE K-128 Study Report for Clinical Chemistry INDIVIDUALPEARINOIDM:ALTERREMPIONRATLBY GROUP sex: rowe soit 10 tja san nwonee 1a9u0r03: 3 2 17 23 915000087 97% 17s 2245 15500143 a~ 7~ 2~4 15001157 " W9r 294 1199002249 051 2128 2220 95003386 -~ 2=1 2~0 1105005576 5- 9= 2=2 1T99006604 -- -- -- rea s5s 012.18 022.12 0 0 wo _-- (= = beta nmmstable ABT ch43 ---------- -am20z C 418-028:PAGE K-129 -- Smtumdy mR_epmort for Clinical Chemistry INDIVIDUAPLEARINOIDM:ALTERREMPIONRATLBY GROUP SSTTUUoYY b1o0:: A06n0u-s064918-028 sex: rewLe animal 10 o@ ott oloae ws none o19u00r2: oor - -- - 1199003055 PF) 9% 18 ar 2.4 24 1199006309 oEnl 1Ws s 2217 919004856 a- 5 - bey - 1159005516 *- 1--.8 2-s 910906528 7 5% Ix 6 23 28 1906 19086 7 El 16 Te 23 23 1199007839 -- =- ~ - nea 5s4 0.1173 02..24 x 0 0 = = vata tnavedtable LaBeaT cet. 27-2002 SSuOnYy r1o0:: a06n0u-s064918-028 418-028PAGEK-130 Study Report for Clinical Chemistry INDIVIDUALPERAINOIDM:ALTERREMPIONRATLBY GROUP anil 10 tL@ aPra noIne 1o9v0r01: 5-1 " 19006 5 715 2247 1e9e020 5"2 2115 "275 10902252 15027 1E00Y 9% 2w1r wr 12s4 22 51900208 55 11s5 2251 155005312 - 1~9 2=3 1195000593 =~ -z z- 1159007509 -- -- -- new 5510 o1an8 0253 " "0 0 sex: rome (= = vata tnavailable asc cce.3 Co Tanz 418-028PAGE K-131 Study Report for Clinical Chemistry SPEURMIMOADR:Y RTEEPROMRITNAL SSoorr 010:: A06n0u-s064516-028 ANALYSIS OF VARIANCE FOLLOVED BY OUWETT'S PROCEDURE sex: mae Twaersst:o: Gavowose moaw moioa Twean makm ommekr UL wrwn nGerow: 11 63 43 ws sz 02 6 03 am @ ~ 030% oz0 88 83 o@wo 105 0% ms[) 600 neGraoup: 2 0621 oam1 0ow MAamoons 0W8w 00035 mase es 3 3 0 0 0 [) 0 Gneraoru: 30 63 43 ow 6 oa 03 aw @ w" 03wo ois sm2 m[e3 006 18 00w6o M2o9 Ma nGeraow: 0 62 42 iw CR] 02 oa 32 WA 0s n 0 [) o 0 1v6 es0 [3 masw a= o Gnreoaup: 50 63 asm 1s sm 02 am 03 us n om om m7wo 112 om[3 2w4o 0065 we 0 70 [3 significant bitterence from Control P< .05 LAB cc6.63 significant offference from control P< .01 2-am-2002 418-028:PAGEK-132 --_------ --_--_-- SSTUTY H1o0:: A0R6e0u-s064518-028 Study Report for Clinical Chemistry SPEURMIMOADR:Y RTEEPROMRITNAL ANALYSIS OF VARIANCE FOLLOVED BY OUMNETT'S PROCEDURE sex: me Twearsst:: w UL owUL wm a fmees mmjee el"f moltx mela) gla nGeroww: 1-1 % ws ws 9s 2 " 24 w3 08 tk0 28[3 w1ss zews 0 10 27 o2a0 00 nreoww: 2-0 wm er se a " 6 %3 os Am wz0 w 13 enom 1s o2a0 0 nGeroaup: 30 wow ma 9s % " ws0 we os 20 ms 1w6 es1m 0 2o3w o2m0 o eGrwo: on wom ma sr Ww 60 wm 20 we0r mA 0M 18 Z"s 100 oe0) 2o7 oa nGerow: 51 7 we nse 02 we w0s om 1B 8m0 us22 1esy 0 00 o12w o1iss 0 [3 significant Difference from control P< .01 ABAT ch43 2-an20 418-028:PAGEK-133 ---- Study Repor-- t for Clinical-- Chemistry -- STMOORY REPORT eer meres sruor 1: vs 0-028 ----PE--RI--O--D:--T--ERtMeINeAL rE ---------------------- so me smo vo: 060-069 MALTSIS OF VARLAKCE FOLLOVED BY DUWETT'S PROCEDURE mTaersst:a: nwee n[ew---- 21 " oe anreowup: 20 21 w" 01T6o Gnroowup: 30 22 " 00 nreowu: 22 0s naerowun: 50 25m w" oir o-signtticant ottference from Control P < 01 uasearech. 43 mama 418-028PAGE K-134 Study Report for Clinical Chemistry --S_o--r_10--: mAn--eums --41m8---02--8 sTwou: 0o60-Y069 --_--m Total Protein --_G--ap P3= psn WN Toul Mem @ees 6613 Wmeess 6623 e363 PESRUIMOMDA:RYTERREMPIONRATL ANALYSISOFVARIANCE FOLLOUEDBYDUNNETT" pROCEORE sex: nue osd. wcatverns 002% Le oomm o0m2 om ox WoSeNr RO avesM TT Tsan re borrees SSsemaromfsn ssahneewene 5599 6e6s 59 er mommeenn 45 59 er -- 0 ocsm ooemr 0 0% 5ss5 6e6s 5s9o 6er7 tom erm Cott. Varra.tiXoxs _-- 41186 DeFnearbt'lseTvualbuelsevalvss PrOoItss -_-- Albumin on woeAsT 4Ll3 o0z9 Le 40 45 3on W@2r3 43 42 0s 0a 07 02% 40 45 40 45 sn Wo ez &5 02 32 40 4s 330m2 hroosses 2asst Tee 44b0 a4ss e menmeTes 0e os0TmrWen 00oe%ze 4400 4assm vom ea -- CI oott.FWur.toXns 663395 Dw'eFetttu'bsleTvaalubeslevetoes Pr0o1ex 330m2 proesses asast --_-- Glucose =onn bY WW ws Wws ows oe i2e0s 02 sz 23 6toe Mwss % wm memmews 4s4 som aammse ose aw ---- srn W0 etsee dtee mm27 o1m 106s wwss k % m1% om 4 som Cott VFahra.tiXoxs --_-- 202.2968 n'mFeitta'blse vTawlubeslevalves rPOoIes 3s2m proossee aasas ---------- SsiiggnniiffiiccaannttdDiiffffeerreenncceefrformoncCoonnttrrooll PP<<..0051 Errorvithingros weet cce.3 TSoruersctea-esnetusr-cbeetovfeevnargiraoctpison ER 418-028:PAGE K-135 e Studye ReportSUMfMoArRYCliRnEiPcOaRlT Chemie stry r STUDY 10: Aves 616-028 m PERIOD: TERMINAeLee s memeeeeeeeeseme eemerresesxe:eemssee STHoU:0D60-Y089 ANALOFYVASRIIANSCE FOLBLYOBAVWEETTD'S PROCEDURE ee Cholesterol eee Grow NW Toml Men std. Ow. oawerr's Ct L0So-uMrsLa0e9s9 ML Sarse DeFgraee mSweorte Smeeaens a=n Wwass asw Ma13 IR 6 ere me memmeRs 44 saemme Ttouas bo=n 0woeww8 ne 2% Wa M is & oe nome 6 en 2 or om TON mmm sn wom om rz sw es em mm Cott. Fwear.teTs= 25687569 oUwFertatb'lse v7aluuesblewsles rPoO1e= 330m2 hrossse 2a5s1 Total Bilirubin onn 3 we 12 0o1z 01 0o0osr 07 0 1S 01 02 01 02 omeonmse 64 oomme oo.oomo 01 02 01 02 mee OO on Pa w 1153 0012 000s6 A1s 0011 0o2z 0011 0o2z rom 4 ous eCott.rFe wrre .atXos =s B5227r 5 beFeewtbtl'es vTn aulwuebslewalues m rROoVsE 33e 2meeeeebrmooesesestetn eema2:s1e eee oet eeeeeeemeemen mmBmloodemUereeeearerNeiteroegeenaoe eeeeee ereeeneeemeem ee oonn ooem oe 0ass 0m Ww Bw memmees 44 wwmza aesrs oann w mwe wtme a1es ozms w woww on ow nw ome mae PY Ww A ak els wm 3 em Conf.PVerra. tXs= 91.18221 uCFmetnetblse vTaluetsable welwes rPoOtVs= 330m2 proossee 22sst -s-sSiigonnitfiiccaannttDoifffffeerreenncceeffrroommCocnatnrtorlol P#<<..0051 Errorvithin grows wee ech43 TSreoatuaerntca-ebe-sousfeeanVaugrrfroavtceisoen Zam az 418-028:PAGE K-136 e Y ee e Study Report for Ce linical Chemistry , cr memPe eSERUsIMOMtDAe:ReYeTeREEReePMeeOIeNRemATsmLsm eeeeeeeeeeee eeee seemmeemeemeeeemsmm S Sorro 1o0::0A5R0r G-U0S65418-28 sex: mae em ANALYSIS OF VARIANCE FOLLOVED BY SUMNETT"S PROCEDURE creatinine std. oweerr's DwETTsrues Degree Smof mem Gop NW Tol Mem dw. Ct WSK 099M Sowce Fe Sars Sere o-n B w 3332 0033 o06o od 31 03 006 0M 0033 004h 03 04 Temmeask 445 03 04 me o00oM 0.o0o01e0 OO sonn Wo 3313 0033 o06ms ooke 0033 0o4k 0033 0o4c wm 6 om Coeff.Fvarr.ieXsx 1.0.44%7 oIwFnebrl'es v7aluetsableveles ---------- oo rPoO1es 330m2 hroesses a28m1 =--Cr-- ewatinmeeme-- Ksinawsse e ms eeee Teme es 0 e ase set 2 P woo wzew us MmSs Oomm Wwmm @22 wwm asas eme or 5 0 uss WaRm sonn o Tw e u6s wBas om s m @2 wwmm a4ss om 4 sees ee mGeooetrt.eePtVarr.artXeox et0.e 037813 e b'uFmebrtl'e es vTae wlubelsevslses rPoOVss 332m erepe oosseee ee 2a5se1eeeenseemeee ee eAe lanine Aminotransferase " 2n I w We w TW 0 o8e eeso om 0 M4 06 cm We 0 me Tomaemsr 4mswsm aanw 2 Mes Me ee D0 osnn W we w m6o m7a0 otem 2 2 Mwe ssoo m1em tom 6 owe GoottFVrara.toXnx 1071.5095 o'wFneturb'lse v7aluetsblevaloes ProOvVe 3sm2 hroossee 2a5s0 --_-- err rrerTe~eereiemeasearostserem--a--a------S SEorurrocre---vsiatuhricnegorfouVpasriation [I------ eTcc.3 SSeS Zama 418-028PAGE K-137 emSte udy Report r feoreeCleeieenmimecae s l Chee mistryro reeerseemsn eee PSERUIMOMDA:RYTREERPMIONRATL ee eee S sTuovro10::r 0A60v-s069618-028 sex: mae commerreeset enAoALrISmISeOF VARIeANeCEsFOLeLeOeVEDreBsYeeDtUWoEmTTe'SrePeROoCnENUREeterseesmsomeeeeeeeeessmenn Aspartate Aminotrasend.sfoevraesres Dow's Races Grow N Towle dw. CLONE Saree begKrees Ssemmeetn Seeane --_--_-- nr wk za TT mT mR mem an nomeTs 4 ee as =In oowTnm om mwes 0ol 0wmBmmma 0 men ess TrOise sonn o wemwwe wweer otme o0w m mm m aawm ome reen Ce ott. FVraratZeer B1.S20 m Fable ev7alr utt eesblevs aloes PrOosex ee1s2m eePre ovsGeeeee2a4s1seeeeememeremmeeeemeease ememeeeeArleekraelimnerPhe osprhaetasmeeses eee eeeneeeeemeester eeeeesemmmereesemeeeme 2-n 3 m owmws Wm wo wMss 0s mo 16 Re 0% 1% #7 ws memeeTws 44s snems zresr Ws eee sonn Lo E w wo CwEs uw A om me & ue eCer otrt. FVarr.eoXn= Z3T3e ou'mFewrbtl'sevaTlbvlesevalm ves rPoOLss 330e m2 hroossseeeem22ss1e m eetemseenemmerre meeecaelceiuemees ee ene eresema ereeemems 2b W ALmIe 7ws Mor ma o0us Lm os oe 110055 Mmee 04 Ns mameeTwss 54 r3e4r5 oormse we ms m0 OT osnn WMMO3 MMas 003%% o3s 10055 Mmeer dtooks nmsse tom 6 ma Ce oet.FVlara.tc eXt nx 34880 mmetratb'lsevaTlwubeslevse les rPo0lVee 330m2 rpoossAeeo z21s --_---------------- +a--SStiognntiifciacnatntdiofiffefreernecnecefrformomCoCnotnrtorlol P#<< ..0051 TSrouersctea-esnatursc-ebeotfemvargtraotwison Error-uithin groups eaAT cc6.43 2-202 418-028:PAGE K-138 Study Report for Clinical Chemistry SPEURMIMOADR:YTREERPMOIRNTAL Ssuoub1o0::n0a6n0-uy0s69616-028 rye ELE ,Pihosiphoiruss tA bsMALYiSISsOF ViARINKtCE FiOLLONiED BnY OUiMETTi'S PRiOCEObREBuE itibiii -- Gop KW Tol R-- en bste. oom0errs -- WRoEwT eNrT'sTRW acTesH -- TSamree e trteee w msermesotseee aonn sn wmrr 9ssk Itna 0s wa ss a0 oss Tree mm22 rrea mnee --mO ameorwse 6 o wm es 1 EaFo pson To @w3a tszr uusm 0un% 7rse mm2e 7rae mnes wm oe som --Co-- rFVtrear.ttt%.oxn -- 150.45833 bwabelevw'Tatcslte's _-- Triglycerides 2 w wss eows zwaz os B Pon w oo ww% amwee taem 0ow sn ww 80 40 2 PrOoVe= 332m B nomx nTmm 33 pooessee aaas om ammete ksrweok ear owmo 1 om we M mem me Co_n--tt.vFarra.tXe=r 0455%8 D'F teablemvTalvewesblrewises rPOoe= 33m2 rpeeses aaem Ee _-- sodium ann B 0Bowus 0 wes wUe es13 0m wr te om W we Wwe we ue namBems 6+ ws we 0 msde 2e4e0 00 BO sonn omoewe uWew 202 k ow wwuwe w ww uue om 6 new Corff. FVaar.tXe=s _-- L1O0R0 CDF wblweT ve7aluresbclm e'wlses rPOoVe. s3m2 rpeGee lOEe a28s1m eM -- a-signiticane oitterence from control < .05 S-- ource-osfoVauriratcioen E+ir-rsoirgvniitthiicnangtraBmfserence from Control < .01 Trestaente-betvem grape Brcce.3 7-22 418-028:PAGE K-139 _--mmmm BT SSTUDTYv1oU0:: 0AD6R0c-uY0s64918-28 Potassium Gap _---- W Toml en -. an er 60 e61s = on W 0 7es606s sn eo es Study 8M Report for Clinical Chemistry PESRUIMOMDA:RYTERREMPIONRATL tisha sant ANALYSIS OF VARIANCE FOLLOVED BY nnn DUNETT'S PROCEDURE su. bowers, bw o21m 07% ta 01 01s8 00%s LSDWEMTT'sRL akes M sarc Degfraeee SSmeoefs 7 Tm 5so0 8811 4s as memwess4 4s as -- m5526 or 5s0o 8811 44ss aass EET sx: me seeane ee 1qmm M Cooff. FVarr.toXs= --_--_-- ZEO7B5 o'uFmettatb'lse vTaTluewsblevalies FPoOVs= 331m2 hroossee a2as) E Chloride T a,n p w 0 wwe os Wm ow 217s oe 23 as %swmses Tamemrosr 4 is ezwe am -- Ce ss 44Bm on 50 10 0 0 ee aw 2172 ttees x% m os s 11;; Tw 8 zeso Cooff. Fveora.tXo=s --_--_-- 2112950 owCnFerttab'lse v'aTlvuebslevives RnOOIsx _-- Globulin = on 23 ws 20 20 ow ot ow 1s 22 0 on ws ws 20 20 ox 0 016 om 1s 22 1s 22 sn 1s om 27 1s 22 330m2 proossee 2s a1 1s 23 Teams mon 4 4s 18 235 -- 118s 2233 tom 4 om 6 om om = O% C-- oeff._FVhear.-- tXioxs-s 92.2.5036MmD'mnFettatb'lseva'Tl'vteislevalves Fpo01e= 33m2 hRoossee 2s 21 _------ sEirrgonri-fuiitchainntgrDoiufpfserence from control P < 05 BeAr cch.43 STreoatuuerntcs-ebe-tovsfeeovnaurgirraotucpisoe.n 27-22 418-028PAGE K-140 _-- _--_-- SSovTH1oU0::0A6Dn0e-u0Ys6d9re-cze. Study Report for Clinical Chemistry PESRUIMOMDA:RYTERREMPIONRATL ANALYSISOF VARIANCEFOLLOVEDBYGUWETT'S PROCEDURE sex: mae Albumin/Globulin Ratio op NM Toml mem msted. oomerr's WowMer r0 acesM -- src Degrreee Stemeos smeeaen P=Yn o A22 Bae 22212 0o%m 0A ox om 11ss 2233 1a9s zaeu ne ammenes Ows4 MT voew eozn 00 spn WB2A922as o0kv eorm 119s 223m a1ss 2s4um rm se om CoffeFrr.aiXnx --_-- a733h Dweettatb'lseTvatlulesevams 0Os1-332m rroossee sasas --_---- *Soi-gsniigfniifciacnatntoDiiffffeerreenncceeffrroonmccoonnttrrooll # << ..0051 Error--vithingroups Laat cch.43 TSraesutarmtcs-ebe-tousfeveaanrugirraotvcieose.n am az 418-028PAGE K-141 --_-- Study Report for Clinical Che emisty ry --_-------- SPEIRMIMOADR:Y RTEERPMOIRNTAL Tsoovx v1i0:: 0a6n0e-s064916-28 sox: rome teTetstr:aI mersvowAsNALYSIS oF wVARIoAKE mFOLLOED BYrDeOnWETT'SIPReOwCEORE earewesreeereaeressamaesrseen _--UaNIrTSo: 11 ofa 7 ola 7 ofl Sg/FdL OSfEd wmo/deL. wafmd m we w un row 061 ow k mws oo 0 2smezom 4okm www oomh Cw soam Cw aaa Tw naeroonm: 21 0s0s 0wM owmo wmoo o0mx oorm oome moem oasm oe wow wm ow Tw Te a nroowm: 3-5 0s4e o4x wwrm 2n0m 0asr ear oams 2wsm uwse " oe ww we we Te To e worowm: it osRe o4m0 2we w@z o0s 1mcc ootxe mm a may " oe we we wm Tw tw naeronm: 5-1 osme ow n wms m&s o0m1 wex ooms wm e wame " oe ow ow ee Tw Te Te een cee.s Em 418-028:PAGE K-142 Study Report for Clinical Chemistry -- PSEURMIMOADR:Y -- TREERPMOIRNTAL sSuunny 1b0o:: 0a6u0-s069ate-czn sex: rome --_-- WALYSISOF VARIMACE FOLLOVED BY COMETS PRoceoune --_-- wTaersst:e: YwL weUL wia T mmas B sm/eh OmTol"l OmTel @ mmon i am egee r[o---- 2w8e wwTs 00m6 AaBs 95x 6o3w os&a 3%4 oams [] To o wo 0 rnoenw: 2% awe omm7 0m82 a7xs 02ow26 osses an 7 eomm ] 1) 3 0 wo o weGraonw: 3-5 nweo wt3e 0o4m 2s0o m4 2o5w oske 35 a som o 0 o 0 wo nGerowup: der 2w 1 m mo 0odss aam7 wsswe26 oemr 3s4 aron ~ 0 (3 ) 0 wo eGrwow: 5+ s7e wr o0m4 twae ws"we26 oemz 3w1 asom [] 0 o 0 13 o 0 0 o _--_------m significant Difference from contrat P< .01 eat cce.3 azz Co 418-028:PAGE K-143 re Study ReporStUMMfAoRrYCr RlEiPnOicRaTl ChemT istY ry e RN aPEiRIiOD: TERMINAL SSTTU w1o0:: a06n0u-s065418-028 sex: rome ---- ANALYSIS OF VATRIeANsoCtEeoF:OoLLON-- ED BY OwUeWETT"S PROCEDURE -- --_-- as: none n[ew---- 22 ] 028 naerwos: 2 2.60 " ois3 neGraoup: 3-1 2.2 [] oz eGrmoup: oF 24 02s 0 nGerwow: 5-5 23 [] 0w3o -- #-Signiticant Differen_ ce from Control P< .05------ weet ccs.3 Z-a-2002 418-028:PAGEK-144 -- eSteudy Report for C-- linical Chemistry ee PSEURMIMOADR:YTREREMPIONRATL SSovTb1oU0::0AD6n0e-uY0s69418-028 e sex: ree ------ AWLe YSIS OFe VARIAKGEFOLLOVED BY OUANETT"S PROCEDURE Total Protein Gp W Towle sed. be. owerr's CU WowM erT'sR0 akesM Saree Omrgernes ssemrofe Seherane --_-- ar Wmeor esrs o0ms 30% TTTTTm TR Germ seen se 65 ss er monmeet s s 1mTe ooaw 3 osrr ses wos 59 5B 0& 1m 0% Le sez ss om 1m se es ssee 6e5s ss ss er er --0 --om 4 se O% 5s ar Cn --o_t--t. FVeur.toXnx 72..2402 CFDtwableev7atluteetsble'vslsoes PFOoss 332m rpoossee a25s1 -_-- Albumin n orr > W Was 4wr0 0oMe 1H 0 ws 41 ox ou 3388 445s 37 4s mommemnm 4ovom oomo 37 ae --0 0OT p sr To 0w3s 4400 00Mm 00@6 3x8s 44ss 3377 4c6e rom 4 em Gott. Fvuera.tToas _-- 80.03599 bmFeatbtl'sevaTlwvbeslealoes Prooltss s31m2 proossee 228s1 _-- Glucose orr > wwna wdme 0 se as mw0e os wr ox emwm wm omeonwst 44s ow wm aam0s eemw poar wuee wweo te5z 1o2x awmmwom otmw tom zee Goff. vParr.atXox 151..22858 --_---- CFDtwabele e7valttueasebl'ess PrOoIss 3m1o2 proossee 2a1s ---- *-Siniti-- cant Dif-- ference fron control P<.05 Error-uithin grows BcaTcce.63 TSreoatuaerntce-ebe-otusfeeavnaurgdrraotvcieosen a-amzue ee 418-028:PAGE K-145 Study Report for Clinical Chemistry PESRUIMOMDA:RYTERREMPIONRATL SStoonvy v1o0::a06v0-s069418-028 sex: rome ANALYSIS OF VARIANCE FOLLOVED BY DUETS PROCEDURE Cholesterol --G_ro--w MTR Mem sea. be omwerr's WEDaNwerT's 0 watsM sare Deagres sSmeemte sheeen orr Sr o om7 oom on oaws 02 mo om ssow FT Im Ik Sem Sane 6 wm mOmmeTes s4 mwee gs prss L ooe @ E uz le swEE a ow 6 os n om O owT e W Cooff.FVaort. eXsn 8.1398 nCeFeettetb'se v'aTluteablets PBOOs+ 33m2 rhoossee aosms Total Bilirubin 2r > P LP16 os 0022 02 0ooBr 1B 06 08 0011 0022 0011 0022 Tomoewse 64 oorwes oooom O em O 00m sotr 1313 0101 0oss 11H% 0011 0o2z 0011 0o2s rm eons Coeff. Fvetr.ioXse BL235 bFeaesbtlt'es v'aTltuaesblewsives POOex 331m2 proosses saests Blood Urea Nitrogen >r > o ooo m ma aa7 as oom Ber om m mw y pwer owoomm 33% wk o0ms B ww w _Coe--ff. FVrart.iIo=s 0.06.7729 DCwFoettatb'lse v'aTluetsable vetoes 7 PBOOVss w ow wog o momemTes os4 n P u2mmWem easwmr 7ow ow om 6 mee 332m proossee zasrm EME SSorurrocre--vsiatuhricnegorfovvesariation wea ech.43 ------------ p-- 2-anzeez 418-028:PAGE K-146 e Study e Report for Ce linical ChemiY stry e ------PSEURM-- IMOAD:RYTREERPMOIRN-- TAL ---- SsTTupYr1o0:: 0a6n0-u0s89618-028 a ro AWALYSIS OF VARIAKCE e FOLLOUED BY DNe WKETT'S PROCEDURE eee. Creatinine ap W Toul en sta. be oum0err's LBoMwer rL acesM ScerDegeree Ssmeoefs sheeme 21 33ss 0o4k oosm 0m 03 06 sli nil 03 ok momemrms 65 ootse eoeoem pesr sr W 0336% 31 0034 03 008ms 0 om 00 1&0 03 04 0033 0o4k 03 03 04 04 m tom 4 o OomTe O00 03 oc Ce --o_ot--.VFohra.tTo=s T718.1030 D'umFetcte'bsle'vTalwubeslevawes PrOose 33:m2 prooss.e aase EE Creatine Kinase e 2r5 > Wawr mme0 www smae 14 a7 0% mvBs wwss some 3wss Temmeese 4s4 Sa0smoe0es Bs7eess rPea wwo ozza oa3m tmoee o12x mmee awss sswe Xwss om 4 mew C-- ott.-- VFerr.ae -- tekr= --BA13T5 ouFmetttab'lse vTalbvlesevales rPootlss o 331m2 proossee z2ss _-- Alanine Aminotransferase 2-r > W omw%w Wow m wo mowr om Ww we M2 ow ow 9 tw memoewse s 4 ease ow ow aw 8 swrr owwse wusm 07 o 1% mow 0wwmw wm mee Goff. FVhara.tiXo=s --_--_-- 2.00.8%5 D'F etablse 7vaeluwebrsletvavses PROoIlse s30m2 pressas aaas Tm. -- [a -- fe t---- Source-saurce of variation wBeaT cet. 3 Ea --_-- 418-028:PAGE K-147 Study Report for Clinical Chemistry PESRUIMOMDA:RYTERREMPIONRATL SSTrn1ou0:: 0Ap6v0e-uy0s69418-028 ANALYSIS OF VARIANCE FOLLOVED BY DINNETT'S PROCEMRE sex: rem Aspartate Aminotrasdn.sfoeurwearsr'es ours pues Gop MN Towl Mem ow Ct WCHL 0M sree Segre re sSmeonfs ohneme =orr sr 0 wom ws we az6e og oo me oy ms 0m mwss ww e e5 me memmees as4 me asmsew Co a resr W Wow me mwem mw1r o13t%e m1s we w we mme om se se CottFvrare. tXss 7.24325 --_---- meeittab'lse vTaluvebs e valves rPOoIs. 330m2 rpoesee aoamr --- Alkaline Phosphatase Io=r > no uwmss ome muse mmr7 oom me wns 0d 33 moem row oaamp mO mmsenna4 P esee awe pser W0 omaew ouwm m4o7 o om kBmmw2 aamm rem a sm --Co_nt--t.--Fwaert. iXoss G0T4 s'rweteatblse vTablulTesewTaiToms BhT Ools- OE 331m2 rhsase Te 2sas _--_-- calcium a*r > omses wMe2 o0m8 um oI 06 om ox 5s7r mNae sess me mammeTes 64 me -- m3n% ON e10m0 0% resr WE wa 0044 0oms oOMx 5sr7 Mma4 s9ss mmee tom 0 zm Cot FarartiXoxs --_-- 617650 m'eFttta'blse vTawlubelsevalves RPoOt1se 330m2 proesses aass ---- SEorurrocre---vsiotuhricnegorfovsariation weeaT cct.3 Treatuents-beteen groups 2-an2002 418-028:PAGE K-148 Study Report for Clinical Chemistry PESRUIMOMDA:RYTERREMPIONRATL S STUDYTn1o0::U0A6R0G-Y U0S65418-028 --_-- Phosphorus Gop MN Twl Me Ia=r B WeIms 7sss sr wr Boeoeo 50 ar sr ome 1 WUALYSISOFVARIANCE FOLLOUEDBYDUWETT'SPROCEDURE sex: rem std. bv ouwU err's W owMes WeeWs M saree begfrees sSemmofe sneeemn 1umm om 2 02 6633 mm2z 5s7r oma HOMI ES 4 E ass me -- S00 ers 4 2vme 0wr 6es3 Mm2z s5r7 miEe ome sem Coeff.VFerra.tXe=r 2.18.0236 --_---- b'Fumteatbtl'esva'Tl'uwebslevalwes RPoOlVe= -_-- Triglycerides rr >ar ooess ks0 we 0B2s 00sm R Rm m "r 5 vom& s 4 wm3 o0r %RTom 330m2 rroesses aasas aoa wg m Temmo ees 4 o Te3eMnG"are6s) oxx oogm ome ames Coeff. Farra.tXo=s --_-- 20.S42 W'eFmettatb'lsevTawlbuelsevsives FP0sVe 332m -_-- Sodium r > B ouwk ws W es 24 08 WW me w>r sr oowwzk woo wwe as26 om 0@ ww me 1H Wm we ae ow wr me proossee ase aa uoee m amcomre 6s4 n 0 s0i%e BraSer uuss wm 6 mem Coff.vFarra.tXo=s 021 25% b'Fumeblretv'aslue'sTtebleveles Fs POV 3m 32 proossee ase 2st --- SErorour-rvicthein-ogsrfoouVpeusriratcioen ABeATcet.3 p-- 2r-am2002 418-028:PAGEK-149 Y rrr Study Report for Ce linical Chemistry BEETS TOR PESRUIMOMDA:RYTREERPMIONRATL onthe S STUYTM100::oA06R0G-UY0S64918-028 sex: rome --_-- AALYSIS OF VARLAKCE FOLLOVED BY DMETT'S PROCEDURE Potassium Grow W Tol em sud. om. owet rr's M DUETS wLaveHs L Saree Degfrdaee smeoets SMeeme a"-- r 10 ssmsa ssse ooes 0m 51 -- 6s 4s 67 T memR oensTR4s4 flw3ee3e Seeoomw > or sr ss 1 60 se 61 ox: os Om 0s st 51 es 66 4s 4s er 67 --0 -- OH om 4 250 ee 62 0% 1 S166 4s 67 Cott. FWrera.tTexr _-- 18 132 oFwanberl'es v'aTluwebslevalus Role ROVe _-- Chloride or w wwse %os 4 27 um % ow > or W e ws s 38 oer 34 om = wm om wm sr me os 31 am 2 3m 312 Proossee ase 21 aom mw namEemosn 45mo53s00 170.2.7 0 ----0 -- 10% o9m o1w ow sz Cooff. vFarr.eeXs= _-- 0.66 3% 'F table oumett's v'Talvewsblevalus Fos POV _-- Globulin 2 Bwes 169 0022 42 17 220 pe p= wz ws 1s a7 o0xn 2t2z a177 2222 5 ws 1s 0; am 17 22 3m 312 Proosses 25s 281 16 22m memeemso 44s ttee 2222 -- ow te 22 o22e oooz am 0% T --Cof_f.--FVrara--.tiXo=s TO43R56 D'uFettetb'lse vTa'lwuebslevalwes rPoOtVsx 3m 3:2 proossee ase 28) e _--m-- #--sSiiggnnfiifciacnatntDDiiffffeerreenncceeffrroommCConotnrtorlol P< P< .05 .01 Error-vithingrows BeAT cet.43 TSreoatuaerntca-ebe-otvsfeeVoneurgtrraotuciposen 2-202 418-028:PAGEK-150 Study Report for Clinical Chemistry PESRUIMOMDA:RYTERREMPIONRATL STuToh1o0:: 0A6n0e-us064910-028 sex: roms MALYSLS OF VARIANCE FOLLOVEDBYDUWKETT'S PROCEDURE Albunin/Globulin Rsda.tiooomerr's rom NW Tew Mw be VW 0M DawerTs 0 ravesm -- E-- sarc Sergere mSemeoe smeemane 2-r > B ooBar Jooo23 o2z2e_ 0o8a we -- amT17Fas lTommm-- es r6e4 eL1m 0e6 sogndo 22 swrr BmmTo 2243 0a 02% oR A ox om us a5 11ss 225s 17 11 26 2s enO46 wm 6 sm 00 17 a4 Coeff. vFarr.aiXs= T2S8T5 bFettatblee vTaUluetsablevalus rP01ee am32 hroossee o2ns SEirrgonri--fviitchainntgDroiufpfserence from control P< .05 saat ccs.3 TSreastuaerntca-ebe-ocusfeevanaurgdrartocisoen Z-ama0z APPENDIX L STATEMENT OF THE STUDY DIRECTOR -- a --------a ---- 905ShooBio Sop A Telephone: (215)443.8710 Telefax: (215) 443-0587 418-028PAGEL-1 ~~ ARGUS RESEARCH Charles River Laboratories Disanc dDeo velovpmee ntSr erviy ces PROTOCOL 418-028: SOTRUADLY(OGFATV-A7G7E0)6CWOIMTBHITNHEEDRREEPPREOADTUECDTIDOONS/E TOXICITY DEVELOPMENTAL TOXICITY SCREENING TEST SPONSOR'S STUDY NUMBER: T-7706.1 STA OF study. N`TohidsefviinaatliroenpsofrrtoamctcuhreatUe.lSy. rFefoloecdtsantdheDrrauwgdAadtmaionbitsatirnaetdiodnur( ing F thGeopoeD drfLoarA bmoarnac) teoorfythe Practice Regulations; Final Rule",the Japanese Ministry of Health and Welfare (MHW) Good PCLroaa-bcootprieacretsao*triyaonPndraatnchdteiDOceregvSaetnlaionspadmtaierondntfof(orOrSEEaCfcDeot)ny.oSmt`iuTcdhieCeRose-ovonipseDerradutgOisoE"n,CatDnhdePrODirengvcaeinlpilosepasmtoiefonntGfo(ooOrdEECcLDoa)bn,oormTaihtceory sOtEudCy.D Guideline for TestingofChemicals occurred that affected the quality or integrityofthe AS prow J J aneocdh Ys203 ayG.Yn ork, PHD, PABT Associate Director of ReS&arch Date Study Director Argus Research a US. Food and Drug 21 CFR Part 58. Administration. Good Laboratory Practice Regulations; Final Rule. b. fJoarpaSnafeesteyMSitnuidsitersyoonfDHreuaglst,h aMnEd WWelOfradriena(1n9c9e7)N.o.G2o1o,dMLaarbcohra2t6,or1y99P7r.actice Standard c. POrrignacniipslaetsioonfGfooroEdcLoanboomriactoCroy-oPprearcattiicoens a[nC(d9D7)e1v8e6l/oFipnmaeln]t. (1998). The Revised OECD d. TOersgtainnigsoaftiCohnefmoircaElcso.noSmeicctiCoon-4o,peNroa.ti4o2n2:anCdDoemvbienleodpmReenpeta(t1e9d96D)o.seOTEoCxiDciGtuyidSetluidnyefor with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996. ee APPENDIX M QUALITY ASSURANCE STATEMENT ------------------ -- -- -------------- ------------i ---- To 219 38710 905Sed?nb A Telefe: oy #438587 418-028:PAGE M-1 ~~ ARGUS RESEARCH Charles River Laboratories Discovery and Development Services QUALITY ASSURANCE STATEMENT Argus Protocol: 418-028 Sponsor's Study Number: T-7706.1 Study Director: Raymond G. York, Ph.D., DABT A`TshseuprraontcoecoUln,ictri(tQicAaUl)p,hatsoesa,ssruarwe cdoatnafoarnmdadnrcaeftwfiitnha:l report were inspectedbytheQuality 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). GoodLaboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26,1997. `The undersigned indicatethatthereportis an accurate representationoftherawdata. Data provided by the Sponsor Quality Assurance Unit. or a subcontractor were not audited by the Argus Research --- "The QAU inspection and report audit dates are listed below: Inspection Phase Protocol `Test Substance Administration `Test Substance Preparation Motor Activity Blood Collection FetalBloodCollection Fetal LiverCollection Satellite CaesareanSectioning Male Sacrifice Male Blood Collection Sperm Evaluation Litter Observations Functional Observational Battery Blood Collection Dam/Litter Sacrifice In-Life Data Necropsy Data Formulation Data Report Tables Report Text Revised Report Inspection Date(s) 22 MAR02 04 APR02 05 APR 02 08 MAY 02 09 MAY 02 09 MAY02 09 MAY02 09 MAY02 14 MAY02 14 MAY 02 14 MAY 02 17 MAY 02 24 MAY02 30 MAY 02 30 MAY02 11-20 SEP02 13-20 SEP02 17 SEP02 16-23 SEP 02 24 SEP02 19,2223 SEP02 25 SEP 02 06 NOV02 Date(s) Findings Submitted to Study Director 22 MAR 02 05 APR02 06 APR 02 16 MAY 02 10 MAY 02 13 MAY02 13 MAY02 13 MAY02 14 MAY02 14 MAY 02 14 MAY 02 17 MAY 02 24 MAY 02 04JUN 02 04JUN02 23 SEP02 20 SEP02 17 SEP02 23 SEP 02 24 SEP 02 23 SEP02 25 SEP 02 06 NOV 02 418-028:PAGE M-2 Date(s) Findings Submitted to Management 22 MAR 02 05APR 02 06 APR 02 16 MAY 02 10 MAY 02 13 MAY 02 13 MAY 02 13 MAY 02 14 MAY02 14 MAY 02 14 MAY 02 17 MAY 02 24 MAY 02 04 JUN 02 04JUN 02 23 SEP02 20 SEP02 17 SEP02 23 SEP 02 24 SEP02 23 SEP 02 25 SEP 02 06 NOV02 sz MMaatntahgeewr Jo.fVRaengeulmaatno,ryB.CSo.mpliance Date _ l