Document Jv8DXnawDDGZDrnNpQ6r3dExK

AR226-1307-5 @ Summary - APFO reproductive effects, 8/23/2002 CSCrooaetsotBoyutansyS SezMFeaoRrnmGm1a0/tG0ao7n/m2T0oo02urs8io1o0Pg1ry2od7Tue8cstisng Kaos ras NanSSeupon A680Repro etocssammy A fl = ym sa stom atoms criasarn 000050 21P0r6o1s3060708830 DuPont Sum-Amuguast2r3,2y002 Oral (Gavage) Two`-AGmemnoernaituimonPe(rOfnlueoLcoiotcttaPneoartGee(nAerPaFtOi)onl)aRReaptrsoduction Study of 3MstudyconductedatArgus (ArgusStudy #T-6889.6) tThheesmuudlyigiesnreerpaotritoendrbeeplroowdu,citnioanddsittiuodnywtistohmAePFcoOmhmeanstbseoenrpoeevaiteiwaeldaennddoDcuriPnoenetf'fsepcotssiotfon on ASoPtFeOdb.eTlnogwe.neArfaelr,wreevaigerweienwgtithhetrhepeocrotn,cHlausskieolnlscsoantteadcitendtthheestArugduysrepSoturdtwyDiitrhetchteor2oenxcMepatyi3on1s, 2002todiscussourdifferences adatainterpretation. Thestudydirector wasinagreementwith stthuedryiellusctratoethmacthtmahnegepeasrsentmattadeldabneeilmaodlws.aOrveemroarle,stehveedrielayfarfofemctthedetmhualnttihgeeoafefrseptiroinngr,eapnroddhuecntcieo,n AiPnFcOreasiesdnoptup mroeraplritoyd,ualcttteoriexvdieaes.tHroouwsevceyrc,icthteyr,edaerleaeyfefdecptusbe(rity.)tdheactrceoauselddpbuepswuegiggehsttsi,ve of barseperdodouncttihveeefefffeeccttss,oabnsder3v0edmign/tkhge/rdeapyrocdouucltdiorn esdpyr.tIheenbpseagretiincnnuilantrg,otfhteheefdfoestes-ornesppuopnsecurve: vairabeisluigtgye,setsitvreo,aulstcyheoluicgihtny,oatinnddaitcaatiiovmee,oaftorfeppruobdeurcttyiv(eveafgfiencatlso.peAnsin&greasnudltporfetphuetsiamlaslelparation) aslitgenriaftiicoannscienoftthheeseeefnfdepcotisnitssu,nwchleiacrh.wCelreaerolnyl,ytohbesserevfefdecattsd3o0 mnogt/ckogm/dparyo,mtihseebitohlorgeipcraolductive scucocens d(Leio.ftmtaihtisiosntgnuadnsy.dDfueeltto)thoefttohxeiacnitiymaolfsAaPtFdoOstaogtehseomfal<es3,0mtges/tkigng/fdoaryurenpdreordtuhcetive effects tdosageshigherthan 30mg/kg/daymaybeproblematic. `Thesummaryofthefindingsofth studyaresummarizedbelow: PGIenerTahteipoant:ernalno-observablo-adve(rNOsAeEL-)<fofrfAePFcOti-sllesestvhaenl| ``wmegr/okogb/sdeayrbvaesdeedto|nmtghes/igknifgiacn/andtdaibnaocrvyeea.sesi organweights(liverandkidney)that ThematernalNOAELis 10mg/kg/daybasedonthesignificantdecreasesin idoey `weightsthatweeobserveda130mg/kg/day. The reproductiveNOAELinmalesisgreaterthan30mg/kg/daysincethrewere00 affectsonmatingorfertilityat 30mg/kg/day. `TwheeigrhetpsraonddupctuipvesuNrOviAvEalLaitn3f0emmga/lkegs/idsa1y0(msgee/dkigs/cduasysbiaonsbeedloonwt)h.e decreasedpup EGleneThe ratiopant:ernal no-observable-adv(eNrOAsEeL)-feorfAfPeFOci-sllesestvhaenl| ombgs/ekrgv/eddaaytba|smedgon/thkegsiagn/ndidfaibcaoavneyt.alterationsinbodyandorganweightstha were 000051 E21TDD6B1O360709B3L The `weimghattsetrhnaatwleNrOeAoEbsLeirsve|damgt/3kmgg//dakygb/adsaeydeonndstbhoevsieg.nificantdecreases in pituitary + `Tvheerere2p0raofdfueccttsivoenNmOaAtiEnLg,ifnermtialliteys,aonrdmfateemamldsealgirveleartyeperatrhasamnet3e0rsmag/tk3g0/dmagy/skign/cdeatyh.ere 000052 EPITDD6B10360800832 PotenIntial ebnodtohcmrianlee-raenldatfeedmeaflfeecFts1wweeanrlaeisngfosl,ltohwesr:ewer alterationsinataiamentof puberty de(dlealyaeydedaaggeeaotfvapgrienpaulsioaplesnepiaarga(tiVoOn;(ePPsS;tanrdrooggeendnep-enpdrdoeecnetpspsr)eoicnnefsdes)meailnnesta]l.esWahinlde thesealterationscanbeatributedtoperturbationsinendocrinehomeostasis, thepattern othfatthweielflfaetctseinusaitnecaonsnisdtenrtwloietvgehlkseniolnwlednedloacyrPiPnSe wmheiclheanoitsmafsf.ectTiynpgicValOl,y,wchoemrtpaosunds cgeonmeproaulnddesltayhiantbaotttehacuaatneoesctcruorgien lceasveeslosfwiblrlodaedlasyterVoOiwd hdeiplleentiootnawfhfeercteibnogtPhPeSs.trAogens andandraoegatieenunatesd.Whilethre sevidencethatAPFOhasthepotential 0 in0duecveidaernocmeatthaasteAiaPrFoOdpenotss(stheeesbnsrzoeyamsdesttheartoicdonbvieorstysattehsetsoisitnehriobniettioonesptrroapdieorlt)istthhearte is ouldaccountfortheeffectsthatwereobserved.Generaldelays in PPSand VOcan also cboencatlruidbeudttehdtatotnhoezd-eslpaecyisfiinc seefxfeucatlsmoantbuoradtyiwoneiingmhta.lIeannthdefceumraelaertasttsumdya,yitbweadsu.etothe decreasedgestaionalageintheanimalsatpuberty. Forthisreason,itinotsuggestive ofanendocrinemediated effect In verFs1usfe5.m4aslteasgtehse)r,ewwhaicshaisloiughttsiindcereofatsheeihnitsthoeriocuaalmcboenrotrfolefsotrrotuhsctyecslteinsgpelarb2o1radtaoyrsy.(4.7 `rWehpirlodetuchtiisvmeasyucrceepsrses.eat acompound-relatedeffect, i doesnotmanifestinaltered D`iTrheecftoolrlowwaisnigmnoadgirfeiecamteiaotnwsitohtHhaeskoerlilg'isnarlerceopmomretnwdearteidoinssc:ussedwithArgusandthe Study L. The P1generation MaternalReproducNtOAiEvLe:Thestudyreportstatesthatthe aPnIdge8nienratthieo3nf0emmga/lkeg'/sdoafyfdsoprsianggehgarvoeudpe.cYreeastsehdeprueppobrotsdaytewseitghhetsPo1gnenleacrtaattiioonndMaaytsem1,a5l ReprNOAoEL disgruestecrthatn30img/vkg/deay. Inaddithtesiignioficnant,ly Diinrcercetaosredtnoubmebuenrreolfsipeuptdoetshtehseisntatrhtei3cl0ebmegc/akugs/edtahyewdaeastchosndsiiddenroetdabfyfetchtethStiunddyicesof `dpeucprveiaabsieldit(ys,aalctohnosuigdhetrheedlbacyttahteioSntiunddyeDxivraecltuoeritnotbhee 30melga/tkegd/tdoatyhewatessstiagritficilceabnetclayuse: thevaluewaswithin historical oatrollis). Weagree tha while00othermeasuresof p`wuaps vnioabtielditays weceasuasfefoefctdeeda,tthhfeodescerveearsaeldopfutphebsoedayniwmeaiglhstwsoaunlddtlheeafdauisl1ur0etcoontchlruidveetthhaatt thiswaspossibly atreatmentrelatedeffect. lAalcltaftaicotno,rtshteaskemnatolgreetdhuecrt,iionncihnumdienagnthpeuspliwgehtilgy thiognhdearyssu1m,b5e,reonfdF81 p(aupppdreoaxt9hs0d%uorfing cSouagtgreols)t,taantdtthherepewosats-waecaonmipnogFu1ndpurepldaeteadtehfsfe(cdtuoento f1aipluurpetgroowrtihvaen)dastu3r0vimvga/lk.gT/hdaey sciognnsiifsitceannttwrietduhctthieoinnicnrelaascetadtoiovnerianldlepxuipsamlosroalpirtoybiebnltyhceoFm1pogeuonedr-atrieoante8ds3i0ncmeg/iktigs/day. 000053 EITDo6B10306081833 Thi streagens thedeterminationtorevisedow th P1 generationMitermal ReproductiveNOAEL fromgreaterthan 30mg/kg/day to 10 mg/kg/day. A comprehensive evaluation of pupmortalityisnotmadeinthereport,whichis whythis conclusionmayhavebeen overlooked.Thedataforthe F1pupsaresummarizedbelow. E[ TTIC -- oTw o[1r [3[0a %] [beipiyzs [or[40| 0|wo[Tor] [[eDeisinpsonpioenn-zwzossigadem || s3n||50[|u+w[[o3w[ma0r|r] [eT speposweming r ws) r|y 3[5[3[2 [|| [G EoTpepy omw ir on_ C _ |7_ [1_ C [1|[0| [[ls oodmopwpgospepo 1 |n 16|| a1||] 71| || [oowosr Tosal[wea[a95l[0e3[sas]] [[woiwss [Tu0s[[wwirelnas[[onuso[umro]| [CNomomo F r Eo sa[6 |37[ma [357] 2.gTenheeraFtIigoennecraatilocnMhaatveerdnoaclrNeOaAsdELa:bTolhaeesatnuddyrreelpiovretfpuirtthiearrsytwateeistghhasttahte3Fm1g/kg/day andhigher. The StudyDirectormayhaveoverlookedthisfindingwhensettingthe sF1gehneboreatrueivoinlsMeadtdetorn1amlgN/kOgA/EdLaya[tth3emg3/mkgg//kdga/yd.aTyhaendFh1iggehneerrdaotsieosncMaautseerdndaelcNrOeaAsEedL (30mg/day), deceased prweaningbodyweight adginG0mya, desessed `absoluteandrelativepituitaryweight (3mg/kg/dayandhigher),postweaningmortality feedconsumption(30mg/kg/day),increasednumberofestrous cyclesper21days (30 mg/kg/day), anddelayed sexualmaturationpossibly due todecreased gestational age: at quis(3i0 mtg/kig/odayn). 000054 06Pr1o3n6o602s3s "Thefollowingtsblesscrmarizethestatisticallysignificantresus oftisstudy. y/Kg/day (md) APFO_ [ Pammeer [7[3 [ 10 TT 350 [MoCrlianliciatlyO(bsTerrevaattmieonntsRelated) |0 [0 | 0 | 1 TT 7] [BodyWegOuis |- |=[=[= | [FeedConsumption(Absolwe) |[~ [~ = | [[N1 FecerolptsyOb-- servat- ions [1 = |~ - ~ 1 [|1] TemminaiBody Weign || =| = | = | [OrganWeighs Abeohay [| | p`rosEtaptei, pditiuitdasreyy,mimandairlecvdaelsesi,csle,s, [o ve o To | = | [[OK rgaa nWeiyghts (RelsiveioBody)[|To|[ oo [ oo | [ = | a -- wal TT][=| [T Ban T ToTo | [Kae ToToTo | o | [[AO| rdgaenaWeaiglhts (RelsivetoBraim) ||| -- [ Te | ] re | | | | =| [ve Tol oo | o| o | omer| -| | | Gene Toxiclly NOARSIL mEB [[ TOAEL T 1Ad1 enalT | Adrenal || 000055 EIPDB601306088335 Femmes TT 5VTigoAP[O wm [[MClooriacallObeTrrveastmieonntselie [ 1 >[0 = 0__0 [__0__| [EFeFeeeeddCCoornnssuumamppttiiioonn((RReelseiov)e)||----- -| | - E[NecTropsyObervaioms-- [~ ES |E ~ E|-- [OE rganWeights(bolo-- Bday) | ----o --| ------. = --| -- [[O[ EragraonWweGiugehisc(yRelaiveridony)| | ~~ |=| [HlisopaoologygOferoOss)n||=]|__]| 7|]_"_| [[ Gover Toxely | ___[NokeL |__| 000056 ETp0r6o103c6o84s3s [ (FlGmmtoPnrVmacaaBas-- |T[5Wiggaa0 yAFR[O _w || [[VCohrlaOlbyeGrovtiieowsnison como| )|5 &|3o[|2=| =1 || [[BFoededyCWonesugmptGiounsRbsohay ||=| |--- |= = |==| [[FPereodpwCionasSuemppatriaotnionQReaive)|| =[ |= || o ~ |o elayed || [[NPeecriolpsyyObservations || =|= | = [[TOemninnaWeliBgohdtysWbeogol) |[ =| =| | = | |< CT e oo = [ = [o Ray o [=| [Prosate inode |[| =] [[Seo meinmalvesicles, verBiloo eys| | =|o =|=|| [O[ rganS Weighe s(Rem live m Boii y||v =| | e=i [ |c=s|i | v =e| [([ TSepem [=|| = |eooT| ==o logy certs| = 1 [[| [Geoer Toxicity NOAEL I mi [TOABL| | -- 000057 =iporeo1mso6oe0sss? CVio ral Gosptehpeemosono |T2T|1 3Ni|g1 n;loAPE[|O 6 ! | r[[BFoeedr dyCWonseur mpgtioanGbso--li--y| I~ _ --=--| ~ -- | =-- |--==--|| [NFe[ egedmCiopnsuummpetiyon GResive) [ = =| [| == || aw- l M[ ehoaotpleyyObsavaoms T [= [|= T ] -] [OTregamniWeBioghgsWGhawgobepic)||~| |=- | - = |-=| fe | 1 e MEoowGiay | --[- [ - = | [[HGiseteopnatThooloxgeyOyb--erO--ngassy |R_oa|RL] = = |[|| 000058 Eieoreoimsosoa0ssas E[Vo abmonpauimya |T- T3-|- 0 | [. | [o[[ CelsireaslOebservations [ | -~ | ~ | Eee [NecrropsyoObservations--|[I =| -- | nope dines | [= = |] ummary of F2 pup mortality [[oDeoiippmmoaamnats [eotpomapmzsz [ T2 o[[5os5[[5#[15] [ [5 7[[+5[5w][5e[]s|] Document Revision Originaldocument: August 19,2002 1%Revision: August23, 2002 000059 2TP0r6o1s3o6o8o7sas