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StudyTide PFECE-R14R3: eTwovoYrEiOAvReaOnRewAs.LTomTY-ONCOGSTEUMDYCIRTATYS Anthors PeEterxC.pMameP,atDrhVolMoig.y LmaboresornicstInc.a(EPLl?) `PHOmBdooxn,47V4A 20172.0474 HEaS.skLtedluoRlPL.ovaFnbrtoeadrmaenteo,NreyDfa.ooVr.uMHse,a,sPlnthdhDCso.omdpEaanvyironmeScniteancle ENlekwtaornkR,oDaEd, P1.9701,4B-o0x05500 TestGuideNoltAippnliceab:le DateComplJumea2t5,e20d04 LaboProjrectaID:tDuPoontr15y261 WorkrequestNumber:14459 SerCovdeNiumcbeer: 1243 SubwistedBy: HEalEs.kkLtedolnulRPLoaoabndot,drPaet.oNOre.ymfBooourxrHs5o0aalntdhCsoomdpanvyironmental Sclnco Newark, DE 19714-0050 Authors atMs PeterC.Mann, D.V.M,DiplomAaVtCe. VeterinaryPathologist = 24 Jama_2004 -- len Fis PrincipalResearchPathologist md ResearchManager,Pathology 25 Tune 2009 Date 2 DuPont15261 FC-143:Two YearPOerearlRToexkvoefitOyvea-riOweuscogSteundyitcniRattys Doipnlomdwaetreeo,pfeAeomrmerrteihvceiaevnwCeeodlbslyefgtoowomofvVePet1etre4ir5ni3anraTyrpyvPaathYtoeloehgOisontslPleTntodeoxriScigCio.tvMyieaOnusnRne.,tFoDrgsVaimM:ec,,yDS.Va.My.,a Pohr.igDi,nDaillpyloemxaatmei,neAdmaenrdirceapnoCrotleldebgyeDorf.VeRtoebreirntaGreylPalt(hsotluodgyipsatts.hoTlhoegissltidfeosrwReirkeer La`boprartoroiels,liensficoe,nsr3oMfa(tPthreooijvevacrteyN.uTmhbeerp:e0e2er8e1vCiReOw1pa2t)h.olToghiesptesdeirsrceuvsiseewdfioscsuucsserdeolnated igtnrotaddhiiaengfgnoolsaostwiwicennloglmreeapnocirlnttae.troprreetaatniodncroiftetrhieapanederreeavciheewdfaigndrienegmse.nTtohnisleasigondriaegneiossmreesfealenncdtted MatearndiMaetlhosds rAelviselwi.dTeshleisotvoadrinsessfvariolmablaefbeyw athneismtauldsywpeartheolootgipsrtewsecrtoa mtahdeetaivmaoiolfabtlheefinoirttihael poer d`viaalgunaotsieosna,nedndthtohpeeseesrraemvoioevwacriisogsnwoesreosfnootatvhaeiloavbalrefiosfroprocearcrehviiemw.aTlhareeogriigviennailn AppatpheonldogiixsAt.tIhnepteheorsercovaiseewswdhiaegrnootshiespioselisrteevdaiesw"pAagtrheoel"o.giFsrt gthreepeudrwpiotshestohefstaundayyss, thhoevdeaatnaaimraelssetphaartatdeideidnatfoetrho3sewaeniemsalosnthsattoddiy.eTdohensomribmeaflosrteha5t3dwieeedkosnoonrsbteufdoyr,oen53d ``nwoeneekosfonthsoteosdayniinmcallusdheaddtahonsyepsraoclriiffeircaetdisvtelthieoinntseirnitmhsaecorviafriiceesainndeeiatrhleyrdteheaitnhit.aSlionrco pboeslsorw.oviewevaluations,theywerenotincloded inthereportingoranalysisofdata Criteriafor DiagaoesofProliferstive ChangesfntheOvary I`nTthihsegnonoardmaallsargoimngaolvcahreynogfpartes,esnetnsesscsemaatlcolrgploarnads,tleiandeedbveylcoupbionitdoailntoelrlstaitiIanlsgolmaneds. a`cdadsietsi,otnh,eustoceellosemsamybaeycsopmpeemoirnetchoelouvmarniaarnesntdrohmaav.eThaesseeto(llfutoeramlacpeplelsamreanycael.Ison w`haippcehairtsonfootrpmrgelsaenndsi,nibnuttertthietyahlavleanadcsh,aarlatctheocuigshttihcoiloaetgtreacneulllasr,moaymhyaveapapearance `smhaocurolvdeosoitcbueldairavagcnuoosleadracsytporploalsmi.fTehrecsahbatonivgeevsce.hanges aronormaforaging et, and cPlraolsisfiefroatdiavelceistihoernesp(ihtyhpeleirapll,agsoinaaodranlesotprlaosmiaal (isntxrcionrsdi-csttortohmeaolv)aorrygearrmegecneerlailnloyrigin (`ODbisxeorvneeditl,h1e9o9v9;aPreilsufsrooamntdhGeocrudrroenn, 1s9t9ud2y;Awleirseonallfgaola,ad1a9l9s0t).rPormoalliifenraotriivgeilne.sTihoinss `categoryincludeslesionscomposedofgranuloss,thecal tea or sertoli-Hkooclsor 3 Duan 15261 `hmaisxbeodepnopruelcaotmiomnesnodfedthtesheactefolrlttyhpeepsu(rDpioxsoenseotfaal,nal1y9s9i9s;aPnedleuvsaolueantdiGonorodfocna,rc1i99n2o)g.eIntic `iypke,rpalnasoisadneprdeigevoenrdaefvdioaelmws,gthorynopamedaralplaldaesrciiaooamuned,crneeelsolppselbcaetsiicvaoewmleyb(riPenedetidu(asPgoenloanusdseGodoarnsddgooGnno,ardd1ao9l9ns2,t)r.1o9m9a2)l. . 2`G0ontahdealnsotrrmoamafltheyaplecrepllea)sifaoirsprdoissceraettwehoredaitfhfeuisnetaerrsetaistciaolnatnadi/noinrsgeerntloalrifgoerdmccleusltler(sbourt Hy(periplansiacgw:raardseiweitrhainclsreaisinngsigzev). eoneriessiazenoofthe proliferation Tyhpicyallyp,thfeerroemargronnpaodcalllesatrcrayotmoaslloagdiiecnaolafmeaa.tuTrheesrtehfotrdei,sttionaglulioswhfgoonrasdoamlesctornosmiasltenicny sdoiamgenwoshias,tatrhboictrriatreyrfieaeasttuarbloifshtewdof-odrigmoennsaidoanlasltsriozme.alGaodneandoamlasitsrboamsaeladdpreinmoamraislyaornethe `coproressepoinfdthossehdoeutmaesinoglfe fieLledsionusing s thge 10x rmicorosucopeoDbijzecotnive. 1559k). o 1fan animal pbroitmhaacdyecniotemraiaonnddbifyfpereenptliastaingphryepseernp,loasliyatfreosm uormoor,tvhasasrseecsosmredn.toSftiancceiadeencedantea f`goontahdeaslesltersoimonaslliensciloundsed(aconmebvianleudahtyipoenrbpelsaesdioasnnfdeatdoetsnoimnac)i.denceofproliferative Moafnthyissotfuthdeycoovnatraiisndeidvagenroyssemdawlilthrgeaosnoafdparlosltirfeormaatlihoynpwehrpilcahswioaudulrdipnrgotbhaebpleyenrortebveiew Hdoiwaegnvoesre,dtdoureinnsugretrhoauttinnoe esvuabltulaetdioosno(-D<ilxeocntweaaslo,ve19r9l9o;oPkeedl,uaslolapnodssGiobrldeoprno,l1i9f9e2ra)t.ive changeswerodiagdurninogthsereeviedw. `ihnycpiedrepnlcaessiosf/pardoelniofmearactoimvbelienseido)nws(egroeneavdaallusattreodmbaylthyhpeeCropclahsriaan,-aAdremniotmaeg,torrendtestand theFisher'scxacttest.StatisticalsigniwafsjuidgcedsatPn<c0.0e5. Results A`pTphoepnrdeisxenAc.eTohfelilnpcriodliefnecreaotifvgeolneasidoanlssitrtohmoaolvhayrpieerspolafsiinadainvdi/douraalrdaetnsiosmparienstehneteodviarnies ``oTfaablller1a.tRaontssstaucdryibfeicyeodnadtthheeoonneo--yyeeaari(nSt3e-rwimoeskac)irinftiecrei,massawcerliflcosirastsshtohwatniinedTperxitorto rehfolienctteerdiimnstahcerfiaficctet,hwaettrheneomtucmobnesridoefraendi"maatluri/sgkr"ofuopr,tasugmiovredneivselToapbmlee1n,t.iTslheisssithsen 50 o(fa8daepaptehasrisnienatchhegorrioguipntahlarteopocrutr)raenddbveafroiersetlhiegihntltyeaimmosancgrgifriocue.psTbhaosneduomnbetrhoeftaunmibmaelrs Ienxcaimdeinnceedspoefrogvraoruiapnallsesoireofnlsebcetssaendiomnatlhsfeoarriwghiincalhm0i0croovsacroypwicaesvaavlauialtaibolnefcoarnbreevfioeuwn.d intheoriginalstudyreport (Sibinski,1987) 4 Dias Tabl1e Incidence of Gonadal StromalHyperplasia andAdenoma In Rats [DNoeBeemioed 1T 3o 5 T|w--o7 T3405 ]| [ [Hyperplasia(T--oetaoi)si| 6 8[ | 7 16 |5 15 | [ CC GGuaaa5 l0 5 1 1 Gatasl 0 113 (Mmems-- 4 05 liAspaelmcan idry yo |rs5k)| tin6| uw | `Therewere 0o statisticallysignificantincreasesinhyperplasia (totalnumber),adenomas, `or hyperplasia/sdenomacombined intrested groups compared to controls.Some `evidenceofincreased lesion grade forproliferativelesions was observedi the 300ppm. group.For example,incidences ofproliferative lesions diagnosedwith a gradeof 3 or `more(thatis,grade3,4,oradenoma)was4/45, 6/47and 11/46inthe0,30, and300ppm groups,respectively.Theinciofdleseionnsoc fgreads e3 andsbweo restv atiste ical significant at300ppm (P = 0.046and0.048fortheCochranArmitageandFisher'stest, `Tespectively). However,trestment-relatedprogression ofproliferativelesionstothesize criteriaestablished for adenoma didnotoccur,as incidencesof adenomawerehighestin controls. DiscaundsCosnci lusoionns eviewswih aghast obese Ks of hoe. Lio Sagoho `Theslidesofovariesofratsfrom with FC-143 ``pceoerrrreosvpioendwepdattohtolhoegdiisatgsnaossgeosnoafdtaulbsutlraormhaylpheyrppelrapsliaasoiratourbguolanraaddaelsntormoambalyatdheensotmuad.y `pathologist (onegranulosacelltumor- typeofgonadalstromaltumor-wasalso diabyg then stao dypas thole ogisd t). Thediagnostictermsusedbythepeerreview | i oh Si a LL er pe gt ofgonadal stromal lesions| reflected he orm ofmpei g `nuormteancceleaptiutrhee,ltiuubmulraerhehyrptehrplfasoiamorovaadreiannomsatworulodslulggestanoriginfromovarian 1`E0xc8e4p0t80foorfdtihfefoerriegnicneaslisntdoidaygfnoorstthioc3n0om0epnpclmatgurroeu,rpe.sMuoltrsoofdthie peserprreesvuailteswrowcecrauersetidmfieolarr thecontroland 30 ppmgroupswheremorehyperplasticlesions (irrespectiveofthe 5 DoPoce15261 onftoopomr eevuesnwe,d)cwheerrlsoveoabrssertavedusbyhtroheoptoerevfielwaptacetnhaol3Bagosonegadoinsthrotoemsast.s hcyopnetrrpolla.siSao,amdaeenvoimdae,ncoeroafdeinncormoaasaenldehsyipoerngplraasdiea,wchoimbcihnweoduilndtcroesrtreedsgproonudtpoe rsenlative to iancdreenaosmeaisnosciczuerorfesdtirnogmraelelteesriionncsi,dweancseosbisnetrhveecdoinnttrholeg3r0o0uppptmhagnrionuept.hHeorwoefvtehre,treated Foups. Referencss SALl,isEolnwReEll,MMoRr,gMeonntKgTo,maenrdyMJor.nCtgAo,mtenrdyMJarc.kCeAn(z1i9eW90F),.O(veadrsy)P.aItnhBooloorgymoefntGhAe,FiEsuhsetris `Rat.AcademicPress,SanDiogo, ppaz9-442 D`iPrxoloinfeDr,atLievielneisnigoenrsJoRf,tVhaelOevrairoyM,GU,terJuosh,nVsaogniAnNa,,CSasrbviinxssknidLOGvaindudcFtriintRhCatHs.(U1R99G9S).. i:GuidesforToxicologioPatboiogy.STP/ARP/AFTP, Washington, DC. PIeol:uMsaokJeJaUn,DdoGagorrerdtLoRD(in1s99a2o)d.CaNnto(mbyeaenbdooNetotp pilagssltiocCfahangsesnitngtm hieOvv acry. ILIPress, WashiDnC,gppt35o1-n364,. friLlJ(lP 1987I ). TwAo YoAurOnl(Die)hToixicnity BAiOnoroogrenstiodcyAioyf Inc/3M Company. 6 Dupo 1261 IndAinAimpvaplePnieedriARdxe:viuew aResullts 7 0ppm (Group1) Dist fI [onsnsseaoT TT oT1wwi hee rn e n thers | er asoanreexs e--|| IT TT I CT A JIT Lmao Tz1 TT AT 7 wma om aes-- sons | fe] oo |woenome | sis ewer s s| I I TTT ----- I TT zlammaTEE mas [a snus | ro I [nn-scse7e|108s||w= irTHeIN tNORhciamrmesi,haves|| OS [inioe |ME Casco | oprses |re somw es s| 8 0ppm (G1r )-o contu inup ed Diai26t ex[|---- ; a [FEiEE ART 9 ee DuPont-15261 [irae Ti| winsUMo TS| me somes | 10 30prem Groep 6) Dare 15261 m |I moore LEA [maneleIwnmonesisers1gm] Pos Two aTne oe paFmRR | aan| EE1 un 30ppm (G6r)-coontuinnped DuPont-15261 rE [mooos | wommomsuu|rs soem| (Boel wT woeomeiuer | s sam| ToL. AT, esLal mTm iere . | 2 300pen (Group5) Dw26l Ia C IT a T a|e=m| * (men 7 | worowsspm|es ses esy| TN-- TT. = [owl @|womuomu| wr sones| [meer] os|wiomsim | m somes s | [masse sos |wieomwu|wsr oems| [inasso | vos|wev |e somes | Pies tos | eam ore rar hone--s]| (meee jos |wmevomswu | ssor ne s| 13 iT sale|mm|s 300ppm(Gr9) -oconutinuped. Dubs 15261 a HN|en |= CemTve|rtr a eason| 15