Document 7xy8w51EG05G37d6qVeyQzK6

A&M6-IHAO DuPont-13788 Review op Proliferative Lesions of t h e Exocrine Pancreas in Two Chronic Feeding Studies in Rats w ith A mmonium Perfluorooctanoate . Authors Steven R. Frame, D.VJM, Ph.D, DACVF Ernest E. McConnell, D.V.M., M.S. (Pathology), DACVP, DABT Date October 16,2003 Laboratory Location NEHEle.akIws.tkoDaenrulklRP,LooDaanebdtlo,darPwea.tNaOorer.eymB1foo9oxu7rr1H5s40ea-0an0ldt5hC0aonmdpEannvyironmental Sciences . Laboratory ProjectIdentification DuPont-13788 Page 1of 8 DuPont-13788 Page Reserved STATEMENT OF CONFIDENTIALITY This document is the property ofE l. du Pont de Nemours and Company and atdconoodncauntCamioonuemsntscptioadsnnhefyopiudoalerrdntiynttiswoaaltifbatfhneilodipautattrerattshdi,aeeolplsryre(iocioirr)reMwut sirneiyfdtote(brinm)ycpaaohtirnooestngoe.incsoEttropxaiftceiEeodpJnot.aradursuethrlePeoqaorusinteiytrdedtodeinbNsauyenpmlypawoofour,trrimtsbhies registrationofany otherproduct without the prior written consent ofBJ, du Pont de Nemours and Companyor its affiliates. 2. S ignature Page DuPont-13788 Author Signature: Author Name: Author Position: A uthor Address: ______ Date: b / ~ a 3 Steven R. Frame, D,V.M., Eh.D., DACVP Principal Research Pathologist and Research Manager NEHleafcwstkoaenrlklR,LoDaaebdlo,arPwa.ta0orr.eyB1fo9ox7r1H540e-0a0lt5h0and Environmental Sciences Author Signature: A uthor Nam e: Author Position: A uthor Address: _ Bate: W @ 0 $ Ernest E. McConnell, D.V.M., M.S. (Pathology), DACVP, DABT President, Tox Path, Inc. RTaolxeiPgaht,hN, Ionrct.h Carolina 3 17 DuPont-13788 Table of Contents Tide Page................................................................................................ 1 Statement of Confidentiality......................................................................................2 Signature Page.......................... 3 Table ofContents.............................................................................. ..................... 4 1.0 Introduction and Methods........... ................................. 5 2.0 Results and Discussion......................................................................................6 '3.0 Conclusions.....................................................................................................7 4.0 References............................................ 8 DuPont-13788 Review of proliferative Lesions of the exocrine Pancreas in Two Chronic Feeding Studies in Rats with Ammonium Perfluorooctanoate 1.0 Introduction and Methods Acosmppaorut nodfsstaunddytiunmveosrtiiggeantiensgistihnetrheelartoiodnesnhtilpivbeert,wteesetnis,pearnodxpisaonmcree-apsr,omlifaeleraCtinDg rats were exposed to ammonium perQuoiooctaaoate (APFO) for 2-years at dietary concentrations o f300 ppm (Biegel et al., 2001). This study was conducted at DuPont's Haskell laboratory during 1991 and 1992. Among the findings in that isntuAdyPFwOer-etreinacterdearsaetsd.inTchideesencreessuoltfspwanecrereiantiacpapcainreanrtcceol!nhtryapset troplaaspiraeavnioduasdenoma scahmroenidciefteaerdyincognsctuendtyrawtiiothnAofP3F0O0ipnpwmh(i3cMh t,h1e9s8a7m),e Irnatthstarat isntuwdyas, neoxpcoosmepdotounthderelated proliferative lesions ofthe exocrine pancreas were identified. This latter s1t9u8d3y. was sponsored by the 3M company and was conducted between 1981 and In an effort to address the apparent discrepancies between fire two studies, the following activities were undertaken sequentially: * aFDSnrluaiddPm3eose0n,0otaSfpvttphuemedteypr()iah.nniagTcrhryhediapsosarstfeehrv)ooimgelorwogthuifspeotsc3auoMtsDfetsduhtPueodon3ynMstlwi(dstehteruesedfsryrteou.vmdieywmpeaadtlheborylaotDgsiris.ntStfhtoeervtechnoenRtr,ol * pAstauttdhthyoelworegeqriseutreesvtioefw3eMd,bpyaDncrr.eEasrnselisdteEs. (McocnCtroonlnaenldl, tarecaotnesdu)lftirnogmvfeilteerDinuaPryont Dr. McConnell then reviewed all pancreas slides from the 3M study, tibDhnocertsrhD.eaFtuhsrPeeaodm3nMcetesaltalnunpdddryMoDlsicfutaCePironaonetnidnotenswlt.luijtdohiien5st-.lbyrTorhemvisoier-e2wv'e-idedewsoexilneyccultureidddeipndaepn(acBnrercdarUesas)sltisodleiddseeftsreofcmrtom gtdArrTheeeeePvhnleaieFemtetwriOwsvaelol.iedsd.csntTeotoeuThrncpdeehcevaisulesnueissessc,a.rwirenroTeyvsonahitotsteeoiauwcorltaelflassivtscnwshilieeeienedswdsarseeerais-anbcrnnfgeeorodvolvptli,mceaelhoetwwhomsasoiwelolplr(noeegassvgerrceoeeiiosnrutRtn,hpstddheeswueseweusceftitlrefwgeteesrdneociaenttesdncoxhdaoahagrnsDeomrleentiphiexsinccmehceulafdeeaesuxnrsebsioitdftuocriyivnetnrigtoegnhbanpeeesrlalydtpofutiihatwnndhnodgi)oecl.iossrtnheeggwaeyssiptihneer 5 DuPont-13788 2,0 Results and Discussion piacBinnsoacacnnaisrdcfceeireiardenmnsaaoecserndedictino.ehnfSlmeclhpirndayeeeelpcveonieifprceriaeplwcatsalssal.ooilsayfifDa,D(parcia.rdnhn.MerAMconrcnPoecCmiaFCctoOiaoecnxn-oneanprexceolcipllsnalocu,arsocrtreheincndefteoiorcrlamlmo3thsna0e.y)c0d.plupaeHslprlipemoalnaacAlssisinooaPaFfarctOnochdenewlfalDidralmeuessnPaeioosodmsnnaostancsditoiaiunaftdcegtyrhdneeowwasseieetrdhde B3ctue0aml0lseohpdrypigpmoeennrApthilPnaeFsjtiohOaeinbin3tuMrtdenivesoite3tuwMaddybe.syntuoDdmyrsaw.oMafsccaaCrsocsionncnoieamltleaad.nwdTihFtuhrasam, AselP,igFehxOtpiownscaursreenasooetfiamnpaaalcenicnraraetrsattioc hIdu1tHpeIsnhyTi9nxtasodoup9ktoitwehcudie2ncneogirr)eoredgpe.gihvwsn,uvlTeteaaesiinntorsseroo,peihewimaadsnaehcimsnitxsemehoyco-ioaipalrseodifnretuekvesebadarteteshsopsllcdcoioilstomrahahinoriafsssobgmgtieithhloeahnsaaeaed,enrofvcurao3tosrooehnntnMafimnadicumtfptnositacranyaePordnrdulpmdigriidetugsioetrcnismeneDltraiioyrsiamfalmumsenoliiyPnrietofsalaosaanhtdtsht(nrciyauiHvoeiawtbpcnesrrgalheetahrinnulrsreeeaaposhdgsncrsesleiiereaneeochdelsnssonylseifoansalsitpoeni,csaoeocsrdairridtynpfodiop,cettrseanlohoars1anlesletlos9oleoidia(f9nagamGtebi5cghinraoe;airaatnnserEthtata!hadaianuvttvrefhoatdseepeerdcctasaiilcooesterenauaennnssecrnrs,oittcetroieuddmniesanxnliauFtlatsotas.shua,gotmooomaacn1ffucrtfao9teitcsh.its9nhhslet0eeiei,ca).trwlyo. dtdBfacheiidrfomeaifeottenedeurrronimreaiemsangaioconhnaenoaf,,svaats1weline9nssdo9bibo-z0etdihef)eoi,ehnmoloyTcefegprsahniiettucsareriasapbro,lnillnoaifpdsoasnoohliratmmesmedianzosnatteseoindatcoycdlat.fioiadoftmcefhneinenmrtohealmoernrosntcaiiuloaeyrgtlneelehfpm(latHerhcopceailtlnnioslfaseyearesercndiadoetieifnilofstlernhatarhslyet.,he,pnteec1hsrreo9eptm9ihdln5aaie;sftnwfihEaekehurfneatrswonottiawcmsorena-bbnitedrtawryeen tplatTcfopolaBshsoeootehbbrsesuatronoeseoirdsdtolceesncrehiiieenrafeitedaivaeintsstssarotsreotteelwarqaudrniaditgrusadeiewtetveiawirstnhoenheenqe.ue'nsieertuptasImiethwtoaterimcacoqlbiisfetcisndoioutedArovaaueemsrarntePrtxicniocfsveclFepdttoiifieseddkOeidtnvslalecewiyldciatfrtln(iloufreayis3veeitrdtcitah0seirmdhftobie,ai0etaeonhnnlcitdnenlphDascttascoospaaetrieuprtmt,esotthhPpiiadirfins)aesornsae,tfotsinhstalAmneacxuptepsnoiPetittsopmpetoiruntFemraamuaelecaOidrundnaitetpanescywlc.npnoelrghoytOcerodroutonalotahOoflssldtsmfaratebauatiurityobalpnngcddlteneuadeoeipibardftedrseoeeoflrrsaofesdysirttomnircheso,asetciacsoiepbsnatnnturotiatelrttoucolehearatpildtnstnuestfrdkiaaaecoodse3innlcditflsifdMrtviofnd.toafieehawgneirirnTrnnrecssenidcat,hianauDd.editbeaecindsievuHltefdddyen,ofePsiise.oacfdffoaorsewffwiTnceeebsewientrreshtn,oeeavetraeeannrefernlyrrvclcrde,eceeaades3ssil.Mnol n 6 DuPcrat-13788 c(cpifnLeoerceolmolidlndihifgoenyennigprlceaerbectariyskpvwegolearasfsaaovaicnaaycidgniadneanMiaredcrtciosaclelmdeaolellrprl,nladeho1rsiyme9eipod9tasen0trsdo;wp,MelreafaVricsectiGsaiaiernnuinaoocintnurtidensngaenfascsoeveshrodamoepgfltlesiianavdoslee.i(f,,aEfda1oiurin9leesd8tttkaih0isrnn)ey.aopcnTmwoadhnnnaeBncttrroiioonpeolmcaumrislmdoaoaetdailfnoeenrcrn,oFae,1dts3ei9en4o8ntc4hf5tlseuag).cdiviinneangr 2kfApcoaa(toIrdo0hnGldhonnfboiPr0oeesaddtmsrfFch0twnreeemiiomMheO)naoarnn.nvitvacmtea,ai,,isejetoxlcpttoliiadlsehnydoetarr.oheaueicriidatns,ynadrrtyTniiiiv1dunfcnnhpdhofe9acogueFreefsl9eotbmrsarpteih0ebhegpecwawua)naeeencn.inmtbsonriiihcnosdffTlrnirar.puytxieceorh,normliuaWadmoyys1pknesooda9utanchmniduht9nsnenouicua2elrocemwoeheed)ctrt.lpdutfretnoeihiuIopnrmanrvineaoldntsadaaisahlnehcaironisrncufncdienocnfeassmrtdtece.ttertesotheoiaiTouaaotabletpinptamoihtofiyoilselcguoancaa,onxasisnac,sarcsmo,mipninscuabnncwaciuasclesarnnetmhrihttrohanayrwecicerarfhelbprteeeesectyaeeplhelaieotzrptlvanhoehtlaohiifnleeecfcrpttyrpcfhdath.pahaurpcrleeenrTofyclomesyeoacilpdmrhecnisrrpoofdueeiacepmhlsrlsecaaorireouersptssamcouiuemmiiivteasdanelnipeaoltraneecdlaeodrcnnmclhsniuoutrsshfnyydwanmdriai(pcportdnenGnhheememaseiirerrsigc(oaaopenmLharetnpnalosnc,raovdlldaoiyatlsanen;ittseixkfgussaaine,eanmratnecinioncosedrktltslehsre, 3.0 Conclusions Mstuidcrieosscinopriactsl,escioonndoubcsteedrvbeyd3inMthaendexDoucrPionnetpraenspcreecatsivienlytw, woecrherroenviicewfeeeddibnyg two adevlxielfotfseectrurrieindnnayecryeapsnapinbamcethrtaweolsalesowe;gnhaissothtwnse.oetvtTwcehoore,nssadetuufrdoceirtveemisdea.rwleTplsaahwttiehveroereelstoocugolcytnsopdmoeufepctrtoheruedenvttdwoie-orwcelslaaotrutifefdtdyhieleaesppswpiaoanenrrceesrneostaifmsthfirleoarm pilisdwidnenantiiuscfenetifdthrrocteheeaiernreaareelsyDstsianmeAaptccuidnroceiPPotdsnieFoandcdngOnbcueorititcnnedoptseeataetrrdsudrtnoaeldhcdqtibrigyyeuouethsepcnaicnnteelosoiigddrtnmfopaehcqptlnfpiaryur3vceaospa0yearilnaee0lisfyfdtreaoiepptsnsxtralpoiadairmpmnt.isivtraivhioa.aedleecga-eaIMirr3nlnnneerModtasesghmrsisahoeipcsdoaent3oeeunrsilnMndnoloosoyhvetffmh.yesspltSrepeaiuaanseirdnlwnirlaoytcpcithenr,neliereatsscetrasphietitodooaaiaecfeb.nttadmnesacdIiecncrnfeereefivannnetsaheotrisro-edeem,rinfn.efwDplacleabTireuwctotohhePtbltieudihooetfrhstenencsw,erhtttoaouheasbtfdteeniusvnisgeedeeersyvs,aetd pcskldrvaiotaenkiuarfmnsboerdfucieiwlmiatyrlerrbteensasooalnrenwtposycos,efteidocrtmtthhahiohabtaoebaAigotvdrstnaetPeewuhocxrFlivotastinOehstetisrettdec.ithbzutci3hDeeedsrMedtiidwentepbseiosfeapryrftenoiaieaktnfrdlreionee(ftDosctnehihinwarcezuealmeePrnstpse)ie)o,vraiaonandesAnlotinirddfsfnlefuteteeashnumrgprboodaerolbutietneienngeevcscsrheee.oeoocstlfn,ehoefrcstsevefasoistaoarbhrpgrrndaeioieasaslnytaibnossoclcbeefifreinsgopos,agaareleroinntevshpgncepeeairnfecienfnqcaaectuihltcrtaiaheeptclsnealoeyatsotixtectwdnipainnintoeettihiirrvt,aaci,eemlwhta,srreteoehanrnneetiadclare 7 DuPont-13788 4.0 References BMCDieecgrhaealtsnL.iBsTm,oHsxioucfoiteltSxMctriEa.h,$eF0pr:4aatm4ic-e5t5uS.mR,oOri'nCdouncntioornJChy, apnedroCxoisookmJeCp(r2o0li0f1er)a. tors in male FMEiusasccthkisee,rnSRzLiaea,t ne(GddsAB.)o.BoAormocraamdnea,mnG,iAcSLP(1rEe9su9ss0,t)iIs.n,8cM.,,ERSxaoSncwDrineieellg,poaC,npAcprMe9a5os-n.1tIg0no8:m.PeartyhoJlor,gaynodfWtheF IrEneulsastttii7os5nS:s1Lh0iap6n7tdo-7Bc3oo. mormoialngGavAag(e19in85th).ePNroaltiifoenraaltiTveoxleicsoiolongsyoPf rtoi egreaxmo.cJrinNeaptlanCcarneaces:r AHGmirsetsaotveperads,tahmPo(,b2pg0py0.o04f)9P.0Cr-eh5ca1Up4nt.eircValHT,oDxiicgietystSivtuedsiyesst,eSme.co1n. EdxEodcitriionne,pEalnscerveiaesr., In: HGirsetaovpeast,hPobangdy,FSaecccorinnd, JEMdit(i1o9n9,2E)l.sDevigieers,tAivme ssytesrtdeamm. ,Ppapn.c1r1e8as-1. 2In6: Rat HPGrauonildisfeeesnrf,aoJtirFv,TeRoaoxnisdcso,obPthgEei,rcMPseaaletkhcootvebedgcl,yeG.sSiToTn,PEs/ouAsfRttihsPe,/ASeLxFo,IPacn,riWdneSa'pisgahlniencrg,reRtoaEns,i(Dn19rCa9.t5s)..GI-6, In: L(oLVycfSorTonuTg,mnupeoipucr.kss2oei4rny,1LDa-n2aSd4bJa9oCn.rJadMtMoorihyllrAa,rne,idPmsM)a.lIsn(.1teV9r9on0lau)t.mioTenuIam-l AoTuguremsnoocfuytrhfsoeorpfRtahneescerReaaarcst,h, SfoeeuncPoCnaadtnhEcoedbri,tgioyn pMWancocGirmeuaisnslen,yeSsKcsaGEn,Ed(,J1M9G8oa0rs)gt.arTno,ehRnetGeefr,foLelc,etv1si5so:o4fn9lo7Dn-A5g0-,t2eF.rrmapfeeDedLin, gHoopf swooyoadfDlo,uarnodn the rat R3Mats(.1R98ic7k).eTr EwxopYeeriamr eOnrtaNlo(D. 0ie2t8)1TCoRxi0c0it1y2/C. arcinogenicity Study ofFC-143 in 8 O jD