Document pBy12y63rRG2zDo84Qdp4v2LE

AR226-3207 DuPont-5991 TRADE SECRET Study Title DevelopmentaHl T-2o4x5i1ci6t:y Study in Rats Laboratory Project ID: DuPont-5991 Test Guidelines: UO.PSP.TESPA87H0.e3a7l0th0EPfrfeencatstaTl eDsetvGeuloidpemliennetsal Toxicity Study OSeEcCtiDonG4u, iNdoel.i4n1es4for the Testing of Chemicals Author: Susan M. Munley, M.A. Study Completed on: December 12, 2001 Performing Laboratory: NEHE.leaIkw.stkodaenurlklPR,LooDanabetdlo,darPewa.tNaOorre.eymB1fooo9ux7rr1Ts54o0a-x0ni0dc5oC0loogmypaanndy Industrial Medicine Company 1Ross not csotvo TSCA CS Page 1 of 165 tCompany Sanitized. Does not enn** to#** H-24516: Developmental Toxicity Study in Rats DuPont-5991 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT TLimhapbisaocrsattuttodhryeyvwPaarlasidcctioitcynedoSuftctahtneeddsaitrnuddcsyoe.mxcpelipatnfcoerwthiethitUem.S.dEocPuAmTenStCedAb(e4l0owC.FRThpearitte7m92l)isGteododdoes not puwTcSuoneeimrdtrshpvtepoirsIclsuSiGeeabs0snos9(cotoRa0edfn0AwtcL2hSeiaitr)sbche,ohsgartraueuanrlgdtaaoouyctnril.toy-aeGtnrPoisLzrr.yaaPtcAgitloiaulcnlbiedooaerSfnlatitdthnaoneesrtdsyaa.a.bnrNiadTllisoyht;ynseheeatosenowsaaftrleeytsvhsueceebros,asntfwtsahoineerdreceeamernepaeadennlryavtfisloaoyelrnssimdeewsdeaedpnarednearatfscloRuyorfsnemfegdisceiuoidwcentnweeatrldeefAroiepnrneiatcrnhlfoyeomtrimcpaleiladnce Applicant / Sponsor: E. I. du Pont de Nemours and Company WU.iSlm.Ai.ngton, Delaware 19898 Applicant / Sponsor: Research Scientist DuPont Representative Date Date G*' -2- H-24516: Developmental Toxicity Study in Rats QUALITY ASSURANCE STATEMENT Haskell Sample Number(s): 24516 DuPont-5991 Dates of Inspections: Protocol: March 21, 2001 Conduct: March 20-21, 2001; April 30, 2001 Records, Reports: October 1,3-5,8-12,15, 2001 Dates Findings Reported to: Study Director: October 10,19, 2001; December 5, 2001 Management: October 15, 2001; November 29, 2001; December 11, 2001 Reported by: _ W tW Id. Wonda K.uK_e_ll_y__________________ Quality Assurance Auditor V L b D*.-ateO tU H-24516: Developmental Toxicity Study in Rats DuPont-5991 CERTIFICATION Wfroem, ththeisunstduedrys.igned, declare that this report provides an accurate evaluation of data obtained Analytical Evaluations ' Janet C. Maslanka, B.S. Staff Scientist Approved by: JL -------- Robert M. Parker, Ph.D., D.A.B.T. Director Developmental, Reproductive, and Neurobehaviorai Toxicology Issued by Study Director: Susan M. Munley, Research Scientist DevNeeluoprombeenhtaavli,oRraeipTroodxuiccotilvoeg,yand oZckS/ Date /2 -a e t- ztib ( Date tZ- e t '2.001 Date S9^ b OO tvO JO c*' CO -4- H-24516: Developmental Toxicity Study in Rats DuPont-5991 TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT...................................2 QUALITY ASSURANCE STATEMENT....................................................................................3 CERTIFICATION.......................................................................................................................... 4 STUDY INFORMATION.............................................................................................................. 7 STUDY PERSONNEL.................................................................................................................... 8 SUMMARY......................................................................................................................................9 OBJECTIVE..................................................................................................................................10 MATERIALS AND METHODS................................................................................................. 10 ABCD.... ATTTeeensssitttmGSSauplubeiHdcsuteiaeslnisbn.ca.e.en.s..d......r.....y...............................................................................................................................................................................................................................................................................................................................................................................................................................................................11111000 EFGHIJK....... 4A2PQR3SSP1....rteaanuuerlniaepadmHFHIrdcmdayeaeooteareniaueDandlmoltsttttinEeihiiaenifnonrzsiuMeogcsndiaat.gf,.otahtWt.oini.DnAna.oo.i.ad.nnbt.ond.ot...aee..s.m.rP....irse.....n.rS...i.i....eg..a.nL..t....t....u.i.P...ee...s......d..rvs...t....o.....rit.e......eag......P..l....d.tr.s......ia.e........o.....m....r.........n...i...........o....,...............d.......a..................n........................d..............................A..................................n....................a.....................l............y.....................s.................i..........s.............................o.........................f.......................T...........................e.....................s.................t.......................S.........................u........................s...................p.....................e......................n.....................s.................i..............o.......................n.......................s................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................1111111111132223441111 LM.. 23CS1...toantPFitIsroentots-iultlcimsfaeoeolsfrOoAtBebfmnsFieaaerOsmlvy.ba.asts.lie.eeo.rs.nsv..s.Sa..t.u.oi..or..fv..nF..i.s.ve...i.om.n...fg..a.F.l..tee..o..ms..S.....a..c..l...h.e...se......d...S..u...u..l...re....v..d....i...vE.....i..un......tg...h.....t.a..o..n......aS.....s..c..i..h..a...e........d......u........l....e.......d...........E..........u........t....h.......a.......n........a......s.....i....a.......................................................................................................................................................................................................................1111155444 RESULTS AND DISCUSSION...................................................................................................16 A. Maternal Findings...............................................................................................................16 4231.... BFBMoooooddrdyytaCWWlioteeynii.sgg.u.hh.m.tt.s.Cp.....th..i...ao...n.n...g.......e.....s..................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................11116666 'zed.1 >n*COri* rn\ 5- H-24516: Developmental Toxicity Study in Rats DuPont-5991 TABLE OF CONTENTS (Continued) Page B. 56F..etaCPlolisFntimicnaodlritOenmbgssFe.r.iv.n.ad..ti.in.o.gn..ss.............................................................................................................................................................................................................................................................................................................................................................................111777 4231.... MVBMoaoadrrilyatfaotWilroimtneyasi.g..t..ih..o...t.n......s...............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................11117777 CONCLUSIONS............................................................................................................................19 RECORDS AND SAMPLE STORAGE.....................................................................................19 REFERENCES...............................................................................................................................20 TABLES..........................................................................................................................................21 TABLE 1MEAN MATERNAL BODY WEIGHTS.................................................................................................... 22 TABLE 2 MEAN MATERNAL BODY WEIGHT CHANGES...................................................................................23 TABLE 3 MEAN MATERNAL FOOD CONSUMPTION.......................................................................................... 24 TABLE 4 CLINICAL OBSERVATIONS.....................................................................................................................25 TABLE 5 REPRODUCTIVE OUTCOME....................................................................................................................26 TABLE 6 INCIDENCE OF FETAL MALFORMATIONS..........................................................................................27 TABLE 7 INCIDENCE OF FETAL VARIATIONS.................................................................................................... 28 APPENDICES............................................................................................................................... 31 APPENDIX A INDIVIDUAL BODY WEIGHTS.........................................................................................................32 APPENDIX B INDIVIDUAL BODY WEIGHT CHANGES......................................................................................46 APPENDIX C INDIVIDUAL FOOD CONSUMPTION.............................................................................................. 56 APPENDIX D INDIVIDUAL CLINICAL OBSERVATIONS....................................................................................66 APPENDIX E GROSS POSTMORTEM FINDINGS...................................................................................................83 APPENDIX F INDIVIDUAL REPRODUCTIVE DATA............................................................................................ 89 APPENDIX G INDIVIDUAL FETAL WEIGHTS AND ALTERATIONS................................................................ 94 APPENDIX H ANALYTICAL REPORT.................................................................................................................... 152 pom pai Sanifttized O oe.'" "'" -6- H-24516: Developmental Toxicity Study in Rats STUDY INFORMATION Hclrpll 'WurriVwar* DuPont-5991 Physical Characteristics: Pale to mediumtan waxy solid Sponsor: WUE..iSIl.m.Adi.ungPtoonnt, dDeeNlaewmaroeur1s9a8n9d8 Company Study Initiated/Completed: March 2, 2001 / (see report cover page) In-Life Initiated/Completed: March 4, 2001 / May 8, 2001 Ulzed. Does_n.,,vostecontain TSCACB DpifPan^ San -7- H-24516: Developmental Toxicity Study in Rats STUDY PERSONNEL ToxicoLloagbyoPArRranietmoaplroaSyyrrttMMytiuVcPdTaaaerylnneteecaaCDprgghaihineenrremmaaeimctrciieeitoaaionnsnnnrttt::::::: WRGMJSSa.uronaaelberngaMyetcndiftaka|ylMyr.M.LkM.LL..KM.WaaPPResuaenloornasnkienltneee,kddryDa,ey,,x.P,MVBthPe....hrMASD..D...,,.DA.JC^*.pLi..TA..M. I 4U I * 4 * * DuPont-5991 i e Ik ACO"A1'" CO^ Sat"VSa* 0s -8- c*' H-24516: Developmental Toxicity Study in Rats DuPont-5991 SUMMARY THgeh-se2ta4pt5uio1rn6p,.oasdemoifntihsitsersetuddbyywgaasvatogeevtoalpuraetgentahnetproattesnftrioaml mthaetetrinmael aonfdimdepvlaenlotaptmioennttoalthtoexeicnidtyooff ttrGlcaieheneolvstremdneoteirstouvlshauspvuitomdisbeoorudsapfonatct0asfaliil.n,onc2ycn5d2aei,0dndt,aiiedinmn2snsda0t0eeib0-.fcc5dm,ilte%oieondamdrit,eca5itwadqno0luea0fpileoegemobvmrhusimgeasesdc/lrikemetv,graeCsea/texdtrixhwaola:eymynCedl.rcDid,eneaDaaletnltuax(uidSroalwioDnmenesxg)oeirIaneGtfmoehucSvdeiotneelgiBrerlnreidRd-onclaseiftrysfeoaelcdsryto.sp6.enox-wOt2Trteeet0nnhirroteenodsna.uafalyotdg,Temfev2rhsuti1ihetssnGacefitoe,siesortftdtaeunuealrsd,aem(eychGdshs,e)swbawpuadoerset,edrprdegayeeannnrweiedaslumyneistoithkdognraeovhsanlsetteo,iedztwffa,eolatdhos;ed UwrifdSnieeibenctmvusidrge.esiellhearaoNstsrpteloahamydnte,tdeo5smcnkx0woteiinanocleledoirimtgtila2otohila0xogtlv0inigccaesmaiarvtiiolyingaldfyt,/weiktoanshganinci/sgsddsencasiioioynntfufni.cccddslrauyTeiednda,vhetsimeunreolesgdoir,dnppartihm2emdet0evraeai0enrnnldrotmeesae-aevlgdoli/tcbdfksoosuekgxemnru/ircdcslvpleaiteotaybyodui.on-fnwneimdnfea-fgsareaetwceneltvdaranlitsepedavdeeolelnbtevlotsfie(xfacNertivbccO5iteots0dEny0weLaimnte)o3cr5sgelfs0u/oiks0dfregiimcemn/danggatai/itryokneengrbddn/auadaasncmaleedyadsd.nwoobdanrovdyy tTwoheterheeNnnOootE-doLebtfseoecrrtvethedid.s-aTsdthuvudesyr,sifeso-erdfetfhfeiicnstesdlteuvadseylt,h(tNeheOhiNAghOEeLEst)Ldaiosssdeeeqafuitnivweadhleibcnyht ttahodevthEeerusNreoOepfeEfaeLnctaUssnadtiteorfniib.n(u,e3td)abblye tthoethUe.Ste.sEt PsuAb(s12t)anacned -9 - Campatii' vtiziid. Docs not contain TSuACC. H-24516: Developmental Toxicity Study in Rats DuPont-5991 OBJECTIVE THh-e24p5u1r6poinseraotfs.this study was to evaluate the potential maternal and developmental toxicity of MATERIALS AND METHODS A. Test Guidelines The study design complies with following test guidelines: UTDonexvitieecldoSpSumtbaestetnastnaEclenTsvoi(xrOoicnPimPtyTeSnStt)auHldPyear(ol1tt9he9cE8tif)of.encAtsgTeensctyG(EuiPdAel)i,nOesf,fiOcePPoTf PSre8v7e0n.3ti7o0n0, PPeresntiactiadles, and OChrgeamniicsaaltsio, nSefoctrioEnco4n(oNmoi.c4C14o)o.pPeararitsio, nFraanndceD(e1v9e8l1o)p.ment. Guidelines for Testing of B. Test Substance wTaJ(HDenhearaCesrsleekyStyeescE.lisols)tn,ALosdEuafur.bbeicdIsost.teeeraDanrdnvttuocibeteryyPys,woRaNcnmaeoutsgpnmdislcoeeuebnpnNoeaptrflerla2tmiAhet4ideno5oau1ntbler6,yyss.tattianhcsTndaeudhlbssesCStpatseoaobprnnmivolsciinpoectsayrew,onsortyah(f,wsRetNhcaADeoseSlwurtl)eePe,asscorJtptknaeos,ctdunkDCbsasisehnobtledanalmenwrLceifaecaotra.abreilo.ntThrSeaeIeodttsolcwtburhstyiaaieusorsHban,asacsstDstaseEkenirgenecinlpzteleeawraLdtpianaorttabheinlsoreye,arsanNetdsoerwy. C. Test Species TdCfLsrpeharoovlbem:neCoCltrDoatahrnptleo:emCro(lySeiDut.nDestr)Tada(IliStGhsutDieSorsae)xssI,BiGetctrR.hiaSteiysnBtstruieRaspsitnarpialnlswitgeowara,csasoascnnrhessdoecidslpoeeermcnertevmebdideeoscnufuaodsiuretssadttehbubiledesyxiesrtteteshulnewadstytiiievvthbseeteiobtcnotaaghcuhekgsaregurcdriiodotimneuilesnipsndaoseupisann.rnfeddofTserihmranretceaiHdtdioaessnnpkceieecslilaoevsfafiolarble ,t coniata TSCACBI Comply SWltliea-O"0' - 10- H-24516: Developmental Toxicity Study in Rats DuPont-5991 wwE2th,ieeig2sirhg0esth0tysu1tu-sdep(oyi2pgn2wlhitetefhdenreemubdl6yalai3lyptehsdate)rhaoyevfurserosnao,mdtltsdoiCmrsu;hhepoda-owrmanlyeeasrd0teeGRcpdeoibvifspeoeitmtrdiavyLanelawedbesewov,irigwedahrteeeotrnsreacirteeraseeno,cigtfIehenicevdcor.ep,fd1ruRo,lomaa2nlt,eiM2ooig2nrah6,3r,dctdNoahayoy21r0s6t(0ho6o6ffgCgrgafaeeermsomsttlsaaia.nttliieaooTs.nn)h.Bea(dnoradadytyMs0fGaorr)c,h D. Animal Husbandry 1. Housing phAt(afrolrnouugivomseiertdaeedelsddicrnreoebdnoleitamvctliaiisdvguuewhsaethe)llrutyoehmneimnidadaasii1tumny2sts-apohiewfnon5eeudd0rree%ldaie,tguhwatnthi1/rdaa0enac%-rimczk.eeepcdAstyhapncb,lrilemsieot(aartaielntpmorlpoepprosoeasmxrrsatisutmteurweiartleetieorcoelnayfg.a02erst60i.0-f2i0Nc6-i1eaCs8llt0yi(n0tigalhlrumgomeuatritesned)ra.itaaeAtld2wn3iamsCan)losatwnderae 2. Feed and Water aPCvMeariItliNafibeuldetriRatidoodnleibnIintttuemCrn.haotiwon)awl,aIsnacv. aCilearbtilfeieaddRliobditeunmt .LaWbDatieetrfr5o0m02U(nfiotermd eWrlaytekrnDowelnawasarPeuwrinaas 3. Identification ntncEhauuaermmcdhs.bbueeapArnrp.silmmiwBeaaraoslspttwhermiratohalsriiesnattosHtaosasiifnghsueknipndeepildwqlinuaaigetnuh.inHmtUihaqaespulkoesnentunlulmrudeamybcneeribemriepcaraton,lardednnasdut.chmihedbaeiemnnritspmiflaiaaennlddtwwncaouistrmhraebsassenpirgoAwnnVededriIneDagruemuncnioiciqrqrudoueecedhHiiompanspikmeleaalpncllthaannctiamgbeyal 4. Health Monitoring Program tAfhosollssoepwetihcnaigftiepwdrooiucnledtdhbuereeHesaxasprkeeeclptleeLdrfaotboromirmaetdpoaprcyetratinhoiedmiscacalilelhynetatioflitcheniansnutdergeerntihtvyaitroocfnotmhneteanmsttauinldaymn:otnleitvoerlisngarperboeglroawm, the Wanadteorthsearmcpolnetsamarienaannatsl.yzed for total bacterial counts, and the presence of coliforms, lead, Feed samples are analyzed for total bacterial, spore and fungal counts. bSyamthpelecsagfreowmasfhreerssh.ly washed cages and cage racks are analyzed to ensure adequate sanitation rCeeqrutiifrieemdeanntismaanldfeneodt tios uesxecde,edgusatraatendtemedaxbiymthuemmcaonnucfeanctrtuatrieorntsoomfekeetyscpoencitfaimedinnaunttrsit,iionncalluding -11 - H-24516: Developmental Toxicity Study in Rats DuPont-5991 pwsproeeuscelidnficenedotohbfeeathveeyxspemececottaenldtsa,tmoafiilnmaatnoptxascinbt ,ethlcoehwlionrtthienegarmtietadyxohimyf dtuhrmeocsacturobdnoycn.esn,traantdioonrgstaantoedphboyspthheatmesa.nuTfhaecturer alTafhbfeeocratanetdiomrtyhaelanhvieamaliladthlitvyaenotdefreitnhnaevrisiratounnd.myE.envtaalul amtioonnitoofritnhgesperodgartaamdidisnaodtminindiisctaetreedanbyyctohnedaitttieonndsinthgat E. Quarantine and Pretest Period aRnadtsthweenrereqleuaasreadntfinoer dthaecsctourddyinugptoonparpopcreodvuarleso fotuhtelinlaebdoirnatHorayskaenlilmLaalbvoertaetorirnarian. F. Study Design The experimental design is shown below: Grout) Dose3 (mg/ke/dav) Co(nmcegn/mtraLtiion TiFmeem-Maleasted IIninV 250050000b 250005...000 22222222 a b V(Sdueashypisceln6es-2ioo0nnGlsy)o(a0ft.H5a%-d2o4as5qa1ug6eeowvuoesrlumemaedtehmoylifcn1eis0lltuemrloeLds/eko)g.n.ce daily, by gavage, over days 6-20 of gestation G. Selection of Dose Levels arwmaataTehlltdhtelcaeemdreotdreearraaiadridntemltnoiy.eixoasssdanltdeIemwnstobrlo.seoeeitanhvdprdgeeeeeytedlrhepsswmeuaifloentioothtiefdrgtacs0htsndta,httaelsusec1tsu,diu2ccbzyfl5rueosa,i,brtdotgar2iedoenra5donnncc0;utedo,ofpsnoe5eftsstun0xtuuohdc0asmeefy,me8sopadwirntdawtieiejio1mrulednye0rse,0etgbb-e0armaywdonsmsaegdemsitagdlgecavy/dhlkota.ieengngfrdieG/encda,maaradsplalayueivfl.sxlreiioiinedgnDtCdangasl,ursntlbdaru:ddinaoCdnayddeygDtsmy(ae1t6)xhwwp-c(aet2eeSoym0iriDngneuidohn-)tcluIetefiGo.rcfdgieltSnleTefepesdohcBtortweawreRtatdueiiinotoi.tryhgenanrhtOeHi(sotnxdsn-wfeta2ewtdyechr4asernoe5eyra6ne1sl2-t6te2u1n0idGntGys,,) Mocactuerrrneadl itnoxraictsityademviidneisntteraesdreddouscaegdesmoafte>rn2a5l0bmodgy/kwg/ediagyh.ts,Owveeirgalhltwgeaiignhs,t avnadlufeosodducroinngsuthmeption ,fSCNC' teatvo\c H-24516: Developmental Toxicity Study in Rats DuPont-5991 ppnropefrvdldf1oeieeareicraoo0ndlsemwotrclssa0dipugiadunietn0eaientneeudnrgirlecsgrdaomecg.uettwnsntihdspomdgsvtT,siaud.er/et,oi,nnhkrorhlnwinioIayefgsnotto2nr.ehhfc/gdeedce5ddoeeefamOa0dtnw(ffwndhcyd,efocvaoieneeca5eiswlsernrtcoyteipc0rhesnttsatsiaht0srtgisnob2loa,d6olioone5rlss(o-onwngda20gsr)ndgieca,1enercuerwr1yoGid5coootimg0suefie0rns,wdh0iprprsb06cmae0tetloie,-ehyvdntg2rrd2ihmoeatjana1oau1orliinegGb1luls.nnf.u1d0e/t0se)klet0c%eev0iefSgdfk0wtrxa0ratov/,i0.toel.dfgerruam3mroearnmTbsef5erymgielsh.pfgtte,/m47ihihekrd/csr%.kpoeregea3uaegsoodsl/%rn,peed/pnsiuwtdornstale,cdomaydrgeyced6adyrat6doiot.tetui,yn5ah6hv,rscr%cnte%eaenw1eterosdltos3dme,yhpilGaoowca.noeeesosnffftcwciediiOhfmdtclnntdehuueeiovgdcvper1drin2etieno3eptstnct5rlhhcudo.eaegy08oieanlrps.d,%spnlnidtdeotei5miaO-fnntoedrr0liehsaoceennn0tte(itealhwa)ees,dhasnlicdtwatoesfeooreoyemrraneedanfmsfntstrn1athteocgdr6wha0itaolmrer/l-i0i5pnoeoelsr2n0.anitsr7vi1gtaidlscahomw%aG,nhoalepnlaitse,glu,fmosnectol/aeo,9sokddoadofbt.nfsgunl3mjdwsososu/rt%iehdrroscsiaroeeoattrfo,vnhcfneyletwnfaadeodm,evttsnmmahicnaufadosteloopmlsnuernt1osesopo4tuhntft.ni2oeod%rn- WTosstibhugisedntehryiref.vricweeagdan.astrdBnreoatdosiuenfcdcetrtioaeonlansfteiihnneidnsmienaegnfaisynn,dccfieoontmmgalspp,wootuuhenniegdddh--ortrees9llea.a8ttle%eeddveaftloenstxdaliilc9seit.t0exyd%teaartfnbotaohrlvis5me0ewa0xl,epfoaroenrsmdusera1elte0iloc0etn0vesedmlofgwro/vrakastghr/liediamatciyouitrnegrsdreontuotpas. H. Randomization rgfDeorasorpmuaeplsclstwgibvreyoeruerlpaoanstssdsthoiogamnnt tewshdaeemtrboepalnlsoiiontsstgosaftfcradoctioamsyrtditc0ihnaGelglrybtaoonddkitfhyefedewirrleeignsigtet.hs(ttpTasth>aioen0ndd.0idas5ast)yrs.ii.bgunTtehidoennto,retchsoeunylttrewodeliranenmrdaeenaxknpeedbrowimdiytehnwitnaelitghheitsr I. Preparation, Administration, and Analysis of Test Suspensions 2wSuiotsrhp3ethnteismivoeenshsipcoelfertwhweeaetsekds,toascnuudbmssettaonnrteecdde riinenftrthhigeeevsrateuthedidcylureen(ct0oil.r5du%ss.eda.quTehoeusmmetehthoydlcoeflmluilxoisneg) wtheeretepstrempaarteerdial rT(e1hc0eommdoLms/ikengng)deswudasbspyebnarsesigeodunlsoatnwotrehyreeamgaedonmsctiinereissctfeeonrrettdbhoibsdytyygwpaeveaioggfhestb.tuedcya.usTehtehevoolruaml reouatdemisintihseterroeudte that is mAcGcSooaprinndmopccudepeeplnlenned,attsrritaaxaonHttiifHdooae.nnseak.,ncedahSlnloatdeLmfssattphtbasleoebursidsalopiwttoseyerin.nyrseg.iFospoTnuerhbrwteimhoeemdirte.steeettdAhca,ooknnsdeahndslyoatasrhnnterlddsyeerotaehftfsiittrmuehdrleetpsssfaroiedmrfpsupttarhlirsineaangstmgieostph,nalenaitnanosglatyutlhasyddeesysde,AsranenraeseadsalpderydrrtteeihchsseaseolebnmdeCteoghdgieneimnnnieinsigttyr,y, -13- Clspa:r-v anIlLcd- t)u no. or, r- ^ H-24516: Developmental Toxicity Study in Rats J. Animal Euthanasia DuPont-5991 ppwFereeonmrcteoeaibelnedasjrienbwcgitteeawrdleibwteheuiftvtohhirsaescnoefidizrxiaeualdmteiboxpynae.mcnaitrnobabotainrobndisitoa; lxt.hidoAesleilntohotahbleaertivfoienstc.uesrFeaseltlauylsseeoxswawmeerireneeiddnejweccaittpehidotauwtteiddthebcseaofpodiriteuamtion K. Parameters to be Studied 1. In-life Observations of Females rBa2en1oldGeday.osnewC;delsiainigygihsnctas6sl-ww2sie1egrGrnee.srreweFccoeoororredddereceddoconoansrtducleeemaddpsaattititolwlyneiaocwsnetapdtswramiyiocserea4tspo,ur5dri,oeodarsnitonodngd2dto1oasGyipnsrago4nv,tdoi6dt,pwer8iod,cvae1ti0add,eaf1oidl2rya,qtoa1un4af,ordar1an6yqt,siun1a6e8r-a,2rne20tl0Gien,a.easen,d 2. Postmortem Observations of Females Surviving to Scheduled Euthanasia tTT2o1hhGpeee.acrbomTdrhipoteomcriaainlntclaauulctletaaantaindocdontuhtohnofetramfecomairctepevratnyicsahculetobervraouadwsryyeowrofeefeeifagxechmahtmadalidaenmjseudwshtgieatrdvhoitsnvosgilaeyabxtlicemlleufmaedsteetudsotihenaseteewpvlyraioasadbfrulteeeccrtfoseertuodutefshdcaw.onnaascseiwapetoiiongnhd.eady rF"enosoronreppartceihognnfsea)mnata"nledfewtmhieathilrevrweislaaibstilsveteaimipnopesdliatwniotiantthsiowanmesrmieteorsne,ciutohmredetsydup.lfeiTsdhoee(f2)iumttoeprdluaesnteotscft(evlaievcrehyaaenpadprladyreeranedstloyfreptutisoenss,.and 3. Fetuses of Females Surviving to Scheduled Euthanasia rlFoeoccroaetridaoecndh,.fseetxu,sa, nthdebfoodllyowweinigghpt.arTamheeteexrtsewrnearlearletecroartdioend:s dideteencttiefidcafotiroenancuhmlibveer,feitnutsrawuteerreinaelso oFaIfnolrotrearasrdeadodatefiictstohiitnogislsnnis.t,e(ut3eea)e.rll,aRtllheitvetearearffdtiiereostdutnsslrie;evsndeaweflceiadtthpueivsmteaaaltnoilodfponmervomeefnarttythiwoeosnatehssefvcrelitasluiisvbsseeliefsfieewadttuaeussxstatihetnertgnhreatehaldfeetiexssraccmhrweeeitmniroeaenteioooxfnfaWmtwhioeenorseetdauendfxdoyarmHdvioiirnsaeecrcde.t(ro4a)rl Awfailxleftarleeitrviorefenicxf,eoatthrtudieoseenadsl.i,inzeEaxBrxcioanluum-sdiintinan'iasgntfietiohdxneasstkfiweveteleae,rltetohhnbeesaahsdweesadefdrioesxneeodxtfhaidemnemcBinaeoeptudhitioaandtn'esddoffsifxkBeateautliresvrteoeasw.l waaletnreedraeTtxiaoaynmlsoirwn.(ee5d)reaArnefdtceoarrltadelercdaothifooonrl s ComPar>YSanded Does1,0 conl'lnTSC*C' - 14- H-24516: Developmental Toxicity Study in Rats DuPont-5991 L. Control of Bias Ianndadrdemitiaoinnetod rcaonddeodmduarsisniggnthmeecnotltloecgtrioounpos,f palolsftemmoarlteesmwaenrde fceotdaleddabtea.fore scheduled euthanasia M. Statistical Analyses rTSsfeeiehgptqueneusialefeetisenvcdtpaeinlaeultrontdfltriioestltsinengedron-roitesferiisscgtpthanionneinfgcislecietatswenwertlaaemtssrceetdaenaepddntpewlwwciteaaaedsssdpt,duodes<tetaehdt0cae.ta0efds5rdao.t.thmaeFftooehrxrepleiteatotrcpeihmrdppeoaansrrteaaammlgrueeonttueeirtprsfa,wostrahtsasetbeapuxtrilcosaltptuiecoddaretlbidoeeavnlonaowdluf.taahtfIiefofetnace.tsetd Waphpelirceabthlee,deaxtaacwt perveatliueedsawndertehecasltcaunldaaterdd ulasrignegspaemrmpluetavteiorsniomneothfoJdoonlcokghye.ere's test was not Parameter MMMaaattteeerrrnnnaaalll wwfoeeoiidgghhcttocnhsaunmgpetsion LDRIImnieecvspaieoddlarefnpfenetttcaiutoeutsinseooessnfssfetal alterations ICMFEnealcaimrnitldeyiacerldnaneelasclleowimvboiestofrehripretvtrasoealtigtatinyolanrnescsoyrptions FSeetxsaelrxawtrieaoitig(ohC)to(vCaorivaateri:atleistt:erlistitzeer)size, Trend Test Linear contrast of means Jonckheere's test(10) Cochran-Armitage test Linear contrast of least square means(11) pompany Sanitized. Does not eonlam tsc a c -15- H-24516: Developmental Toxicity Study in Rats DuPont-5991 RESULTS AND DISCUSSION A. Maternal Findings 1. Mortality Tschheerdeuwleads snaocrciofimcep.ound-related mortality at any level tested; all rats on study survived to 2. B(ToadbyleW1e,iAghptpsendix A) TT50hh0eerrmee gww/eakrsge/adnamoyi.cnoiMmmeapalo,nucnfoidmn-arpleoblauotnedddy-reweflefaeitgcehtdst rowendamsuc9et6aio%nnmoinafttmehreenaacnlowmnteariotgelhrantnaadltbw5o0adsoyrswt2ae0tii0sgthmictgaal/tlkyg/sdiganyi.ficant. 3. B(ToadbyleW2e,iAghptpCenhdainxgBes) mwwoccTag55oob0va0heeennis00eeiianoggssrrnmmiilehhodddubttvaggweetoeycge//rrkek/eehdrsaarggddayided6n//nadtjda-wcghuyw2adaoeesesy1vyamtsi.Geer6gsweardp-h.A8ss8teoteuf5,rT5tuiael%na08hnt2tsa-ced0ot/m1lh6ost0-f0hwer3ingcse,em%s/eoolkailamigvdmegngtov/eee/dahkpdrrefdgtgaeoal1cn.ldt/ruyo8lodei.ntn-Tcradu2cdeotyuhdar0d-m,ceorleGucetrolpiceuo.lvouaotlfeiwnstaWuoertistnhaenndehlrdiegs,lnegi-slciwtraenmnthehiaoelenatbteaihingacaotoseegnobhtdvdieemstycem,ofargwfpwtllaaehduloatceiyeatesnutieyrsgsne/snwsiahfdmogafdat6-nlnearjs-gcuieblb2flat9lsoio1aitca1sdneGtdean%eydyenw.ddn/wtfwe7Aieirtrane9feeethtifa%digeg5la2suchdh0t0wcotat0t0stntefgigioomoimscagantnoiiigahgnsncndm/t/aktikavatrnlagtogoletty/2/lrmbedcds0ruosaaeaen0isyltyagachii,nnmanluwo2ngilbwpfav0adoitatesc0ehedcraienyagtangolnhotaltdtniannd 4. F(ToaobdleC3o,nAsupmpepntidoinx C) rowccT2oe6eooiv0v-hetd2nne0heerurss1re,eracuueGradcltmmlni.aowooydvfppnneTosetts5rsoiihrie6oo0dadew-nn0mles8lecerGromimoreenervdn.dgeieesmtud/tarrTukhcuanamdghetnclia/fi,tsordpsoyieicnoatoesrsioysnenodu6m.dstnal-ctuta8piAowncon,2onttadf0u8oisso5c0n-uvh10nod9meaa0mr-4dwmn,arpepdlaatangllionsno/ao5fkuddtnno0aegno0o9dd1/dodtd5v0m-rrac%re-ecoeyo1grdonls,2n/auonekGmsbtcsfgeiiout.decmd/iddmeoao,Dpyarnnnspeyaetstwtdfrcasiowoiottpenaoilnioeis,ddgtmt,rnerviheewcceettosaonhrahpvpslnoenlieeeaysctcrrsmuhbcaattsmiaeolmaivwlgtcntpieeefanessltotrutriiyienifodeosc,riadeencsanwlr.alociwefnhtsodtoAteahinosgnsartatsdendadu2saditvicm0fvinugeiso0ecocnptrnriastitaacisafeniongauoidccbndlemnvelaesdy.e,5npcrito0tsatnshlii0vueyogemessnnmirermeeieafgddatifpth/aucnokae5yacogcf0snedot/,tddo,oadny, flcft nllin T S E if - 16' H-24516: Developmental Toxicity Study in Rats DuPont-5991 5. C(Tlianbilcea4l ,OAbpsperevnadtiixonDs) tcSooigmfnupirfoisuctaanindnt-irnceoglmaitnepdothucenlipdne-irrceianllaetoaebldsaecrrleivanaittchiaoalntoswbaastse5rr0veapmtoigort/neksdgw/fdoearrye9./s2e2enanaitm5a0l0s matgt/hkigs/ldeavyela.ndThweererewliemreitneod 6. P(AopstpmenordtiexmE)Findings There were no compound-related gross postmortem findings at any level tested. B. Fetal Findings 1. M(Toarbtlaeli5t,yAppendix F) Tdehaedrefewtuassensoatcoamnyploeuvnedl -treesltaetde.d embryofetal mortality evident as increased resorptions and/or 2. B(ToadbyleW5e,iAghptpendices F and G) nTtw5ho0hee0teiygrsmehwigtgwena/rikatefsgi5cn/a0daonastmyltcilg,gyo/thnkdhtsgieif(/df9vdee7aarr%leyeundewtoawa(fdpscav=eose0qnrs.ust0iregi7ovnb)la).ialfersiWceenaddthnutoitocllneyttihottdhhenieefcifsnmeoernmierntenreidotmaul(napcglt=frieomo0tuna.a0plsg4wvnw)aiewetliuurghedehee.ctroeoaantfss2tihad0et0e2rraee0ndd0ducmco5tmg0io/0pknogm. u/dgMn/adkye-ga,r/enidtlaafweytet;aadsal,t 3. M(Taalbfolerm6,aAtipopnesndix G) There were no compound-related fetal malformations at any level tested. 4. Variations (Table 7, Appendix G) vvofS5iaas0tnasll0duuitfiieemsinsctgfgiaocf/taoarkiotrlgtlnh2ry/ed.e0tsa0aciTygrom.hdnniegicAsfd/uikitcrnsgar2kce/n0rudnte0latlaiynmcsbceo(ogr2nwne/6tkaeragosfsoe/eldsstngusaoiriysnftoe,iucscftpoeahfttnerai(orso7leimndsfwkeea1ertraue4lesedsltpeaiacstrltseoefivsmgrreaosnpnr)miiotfaaeiutpcd7inpaobldnenie-tatstrlreeiowenrlwdsace)trr.iefeendoacR;rosreebpreacsaeiteensrhsnreervpdtereeh,tddcaitutsrhiadteveoteetr2ido:in0ccsa0aikldruaecenllonladncbtietovrnooeellfygthrlooisuwp -17- 4 vfflpanV aft'*'1 0. flO* 'V' iTSCA H-24516: Developmental Toxicity Study in Rats DuPont-5991 Year Study Conducted Reference No. Affected Fetuses No. Affected Litters 1997 1998-01367 19 10 1998 1998-01382 24 11 1998 DuPont-1165 11 8 1998 DuPont-1559 37 13 1999 1998-01500 18 8 1999 DuPont-2287 19 12 1999 DuPont-1454 21 10 1999 DuPont-3378 36 14 2000 DuPont-4177 47 14 2000 DuPont-4341 6 6 2001 DuPont-5676 58 19 rwAeettar5er0da0eldlmcsgok/nukslgli/dbdeoarnyee,dtohcsoesmriefpiwcoaeutrnieodn-s,riegrlneatitafeirdcda.endt pineclvreicasoesssiifnictahteiofno,llaonwdinwgafveytarlibssk.elTethaelsveaoribasteiorvnas:tions Company SanlUte* Does not co'inta*n r.n' -18- H-24516: Developmental Toxicity Study in Rats DuPont-5991 CONCLUSIONS UwirfdSnieeibentcmvusirdge.seiellehaoarNstsrpteloahamydnte,tdeo5smcnkx0woteiiannocleledoirimtgtil2aotohila0xogtlv0inigccaesmaiarvtiiolyignaldfy,t/weiktaonshganincis/gsddsencasiioioynntfufni.cccddsrlauiTyeednad,vhetsimeurneolesdgoir,dnpparti2hmemde0tevraeai0ernnnldrtomeesaea-evlgdoli/ctbdfksooueskgxmenru/ircdclspvleatioeatbyyodui.on-nfwneidmnefa-fgsareaetwcneeltvadranltisepedavdeoelelnbtevltosfie(fxcaNertivbccO5teois0tdEny0weLaimnet)oacr5sgelfs0u/oiks0dfregiimcemn/adnggataii/tyrokneengrbddn/auaadasncmaleedyadsd.nwoodbarnovdyy RECORDS AND SAMPLE STORAGE bLeabreotraaitnoerdy-astptehceififcacoirlitsyitew-hspeerecitfhice rwaworkdawtaassudcohnea.s personnel files and equipment records will ANLCLaahesbbwaaoormaarrraacpktttool,eerrrDyiioez.esafl,tatSihwDopeneaetcerdeeipsam,wttoaesarnutwesab,ritsl,rIltaNarbowneencwedsMtawoJtoearareu,ssdnaectnyaaod.tilnlRtehRecegteeifcodionnfraaodllrsrAeaMprncoaahrnliytavtwgeiceipalmlul ebrSpneeotr,rsveWeitscaieialnsmne(ddiRnraAgetttSoHa)ni,na,seJDkadecealklltaswLoHnaaabrseok.realtlory, TwtoheterheeNnnOootE-doLebtfseoecrrtvetheddi.s-aTsdthuvudesyr,sifeso-edrfetfhfeiicnstesdlteuvadseylt,h(tNeheOhiNAghOEeLEst)Ldaiosssdeeeqafuitnivweadhleibcnyht ttahodevthEeerusNreoOepfeEfaeLnctaUssandtiteorfinibn/ue1t3da' bblye tthoethUe.Ste.sEt PsuAb(1s2t)anacned -19- iffompany Sanitized-poeS not contain tscacbi H-24516: Developmental Toxicity Study in Rats DuPont-5991 REFERENCES 1. DuPont Haskell Laboratory Repo 2. aSmaleUwtsekrui,sEd.e(r1R9a6t4t)e.. FAarrcbheimv.ePthaothd.eEzxupm. Pmhaakrmroaskkoolp.i2sc4h7e:3n6N7.achweis von Implantationstellen 3. 9S(t3ap):lAes3,7R-A.E3.8(.1974). Detection of Visceral Alterations in Mammalian Fetuses. Teratology, 4. DW19eo6v.oe,loDp.Cm.eannt dinHLoaatre, GRe.Msta.t(i1o9n7o2f).RaAtsp:paTrhenetEHffyedcrtoonfepMherothsyisl aSsalaicNyloartme.alTAersapteoclotgoyf,R6e:n1a9l1 5. FBeatrursoews,. MJ..VM.oarnpdh.T, a1y2l7o(r3,)W:29.J1.-(310966.9). A Rapid Method for Detecting Malformations in Rat 6. ASenliwmyanl,SMaf.Ret.y(S1t9u9d5i)e.s.TJhoeuUrnsael ooffTthreenAdmTeersitcsatnoCDoeltleergmeionfeTaoNxioc-oOlobgseyrv14ab(2l)e:-1E5f8fe-1ct68L.evel in 7. HStausdeimesa.n,TJe.rKat.oalongdyH, o1g2a:1n6, 5M-1.D71..(1975). Selection of the Experimental Unit in Teratology 8. PSatatteifsiteilcds,3W1:.3(21-94832.). Exact Tests for Trends in Ordered Contingency Tables. Applied 9. USnneivdeecrsoirt,yGP.rWes.s,aInodwCa,opchpr.a2n4,6W-2.4G8.,(314996-73)5.2S. tatistical Methods, 6th ed. The Iowa State 10. JBoinocmkehtereikrea,4A1:.R13.3(-1194554.). A Distribution-Free K-Sample Test Against Ordered Alternatives. 11. DCSooecmmiepptsyut,teaSrt,ieoArnie.aPsl.,ACSs(epAlewpcpytslnio,edMf MS.Rtiax.t,eiPsdtaiMcteslo),,dC3e3l.M(A2.n),:a2aln0yd3si-Rs2.1o4tTh.h,eAJ.oJ.u(r1n9a8l 4o)f.thSetaRtiosytiaclalStaantdistical 12. WafHol.arazsAUahrnnidnaitglEeytdvosianSsl,utaaDantte.diCsoE.nE,vn2Dav0liui4vra6iost0niio.omnnEe,PonSAfttaSa-l5nuP4dbr0aco/rht9der-ocE8nt5viio-ca0nlau2Ana0dt,gioeJCnunhcnPryeor,on1Oci9cef8fd5Eiuc.xerpeo,ofsTuPorexesitcSiicttuiyddePieoPst.reonPgtairaaylmn:tseG,r,uOid.aEn.ceet 13. (RXisIk/2A83s/s9e4s-sEmNen),tCohfaNpotetirfiIe,dSNecetiwonSsu2b.s2t4anacneds 2T.e2c5h. nical Guidance Document -20- Pompany Sanitized. Does not contain TSCA CBI H-24516: Developmental Toxicity Study in Rats DuPont-5991 TABLES ^Company Sanitized, Doss no omain TSCA CB -21 - H-24516: Developmental Toxicity Study in Rats DuPont-5991 TABLE 1 MEAN MATERNAL BODY WEIGHTS (GRAMS) Group : Days Dose (mg/kg/day): Of Gestation n: I 0 22 II III 50 200 22 22 IV 500 22 0 240 .6 (8..40) a 241 .9 (9. 56) 242 .7 (9. 12) 242 .2 (8.99) 4b 243 .3 (20 .24) 252 .3 (12 .89) 250 .9 (19 .39) 253 .2 (7.46) 6 260 .1 (13 .13) 264 .5 (12 .16) 264 .3 (18 .07) 266 .3 (9.12) 7 265 .8 (14 .03) 264 .3 (14 .51) 265 .2 (15 .61) 264 .4 (9.22) 8 270 .2 (14 .92) 270 .2 (16 .00) 268 .3 (19 .66) 269 .0 (11.55) 9 275 .0 (16 .97) 275 .7 (13 .98) 272 .9 (17 .31) 272 .0 (11.57) 10 281,.6 (19 .01) 281..0 (13 .44) 274 .8 (20 .20) 275 .2 (11.75) 11 289 ,.7 (18 .36) 288 .7 (14 .38) 283 .5 (18 .33) 284 .3 (12.01) 12 296 .7 (18 .54) 296 .0 (15 .22) 291,.0 (18 .26) 290 .0 (12.89) 13 302 .9 (17 .28) 302 .0 (16 .33) 296 ,.5 (17 .71) 298 .1 (13.34) 14 310 ,.7 (17 .98) 307..8 (15 .80) 304 .1 (17 .42) 304 .7 (14.09) 15 318..8 (19 .58) 316 .0 (16 .91) 312 .9 (18 .46) 311..8 (15.11) 16 329..1 (19 .22) 326 .7 (16 .70) 322 .4 (18 .95) 326 ,.4 (14.98) 17 342 .5 (20 .67) 341..3 (18 .97) 337 .2 (20 .95) 339 .8 (17.54) 18 359 .8 (20 .64) 358 .,6 (19 .22) 354 .0 (21 .44) 357 ,.2 (17.65) 19 374 .,9 (23 .64) 373 .,1 (20 .57) 367..9 (22 .91) 369 .7 (20.51) 20 393 .4 (24 .74) 391.,4 (22 .83) 383 .,5 (22 .88) 383 .1 (24.38) 21 416 .,8 (27 .86) 415.,9 (23 .54) 407 ..5 (28 .74) 399 .,4 (28.51) 21c 319.,0 (19 .75) 315 .3 (17 .44) 310 ..9 (21 .05) 303 ..4 (18.99) a Standard deviation is presented in parentheses. b Day 4: Group I - N = 16; Group II - N = 17; Group III - N = 16; Group IV - N = 17. c Body weight calculated using the final body weight minus the weight of the products of conception.* * Significant trend (linear contrast of means); p < 0.05. Company Sanitized. Does not confa8 t<ca CR> -22- H-24516: Developmental Toxicity Study in Rats TABLE 2 MEAN MATERNAL BODY WEIGHT CHANGES (GRAMS) Group : Days Dose (mg/kg/day): Of Gestation n: I 0 22 II III 50 200 22 22 DuPont-5991 IV 500 22 0-4a 4-6a 2 .6 (17'.68)b 15 .3 (11 .33) 10 .2 (11 .03) 13 .4 (10 .61) 7 .9 (17'.39) 13 .4 (6. 76) 11 .2 (10 .88) 12 .9 (9. 10) 6-8 10 .2 (7. 79) 5 .7 (10 .35) 4 ,.0 (8. 52) * 2 .7 (6. 79) * 8-10 11,,4 (5. 82) 10 .8 (8. 31) 6 .5 (9. 60) * 6 .2 (5. 27) * 10-12 15..1 (4. 69) 15 .0 (4 .79) 16 .2 (5. 51) 14 .9 (5. 62) 12-14 14 .0 (6. 42) 11..8 (4. 95) 13 .0 (7. 27) 14 .7 (5. 74) 14-16 18 .4 (4. 50) 18 ,.9 (3. 81) 18 .4 (3. 96) 21 .7 (7. 26) 16-18 30 .7 (4. 77) 31..9 (5. 25) 31..6 (6. 14) 30 .8 (6. 62) 18-20 33 .6 (5. 68) 32..9 (5. 12) 29 ..6 (6. 03) * 25 ,.8 (15 .00) * 20-21 23 .,4 (4. 86) 24 .5 (6. 78) 24 ..0 (7. 44) 16 ,.4 (17 .83) 6-21 156..7 (22 .42) 151..4 (15 .78) 143 .2 (21 .08) * 133 .1 (27 .54) * 6-21c 58 ..9 (14 .88) 50 .8 (12 .39) 46 .6 (15 .74) * 37 .1 (18 .48) * a Day 4: Group I - N = 16; Group II - N = 17; Group III - N = 16; Group IV - N = 17 . b Standard deviation is presented in parentheses. c Body weight calculated using the final body weight minus the weight of the products of conception. * Significant trend (linear contrast of means); p < 0.05. Company Sanitized. Does not contain TSCA CBt -23- H-24516: Developmental Toxicity Study in Rats TABLE 3 MEAN MATERNAL FOOD CONSUMPTION (GRAMS/DAY) Group: Days Dose (mg/kg/day): Of Gestation n: I 0 22 II III 50 200 22 22 4-6 22.7 (5.99)a 23.6 (5.01) 6-8 24.6 (4.21) 20.6 (5.01)* 8-10 25.3 (4.13) 23.5 (2.42) 10-12 27.6 (3.99) 26.4 (3.12) 12-14 27.9 (2.87)-b 26.5 (3.18) 14-16 28.4 (3.44) 26.9 (3.89) 16-18 30.4 (3.09) 29.1 (3.50) 18-20 28.6 (3.95) 28.1 (3.40) 20-21 27.1 (4.68) 26.6 (3.94) 4-21 26.1 (4.12) 25.6 (2.73) 6-21 26.6 (4.71) 25.9 (2.67) a Standard deviation is presented in parentheses. b N=21 * Significant trend (linear contrast of means); p < 0.05. 23.6 (4.89) 20.3 (4.84)* 20.8 (4.32)* 24.5 (2.85)* 26.1 (2.12) 26.9 (2.65) 28.3 (3.05) 27.2 (2.85) 25.5 (4.28) 24.8 (2.18) 24.9 (2.13) IV 500 22 23.1 (2.16) 20.6 (2.94)* 20.8 (3.20)* 24.8 (2.83)* 26.1 (2.89) 27.8 (3.84) 30.2 (3.43) 27.6 (4.81) 24.8 (9.93) 25.1 (1.75) 25.4 (1.91) DuPont-5991 Company Sanitized. Does not contain TSCA CBI -24- H-24516: Developmental Toxicity Study in Rats TABLE 4 CLINICAL OBSERVATIONS DAY OF GESTATION OBSERVATION: GROUP : DOSE (mg/kg/day) : NO. EXAMINED : I 0 22 II 50 22 4- 5 ALOPECIA 6-21 ALOPECIA DEHYDRATED SORE STAINED BOTH SHOULDER STAIN PERINEUM STAIN PERIORAL TEETH MISSING WET PERINEUM * Significant trend (Cochran-Armitage test); p 0.05. 1 6 0 1 0 0 0 1 0 1 11 1 0 1 0 0 0 0 III IV 200 500 22 22 00 11 10 00 10 00 1 9* 01 10 01 DuPont-5991 'Company Sanitized. 6(T Oo 3 i>o03n? H-24516: Developmental Toxicity Study in Rats DuPont-5991 TABLE 5 REPRODUCTIVE OUTCOME Group : Dose (mg/kg/day): N o . Mated N o . Pregnant No. Deaths No. With Total Resorptions No. Litters I 0 22 22 0 0 22 II III IV 50 200 500 22 22 22 22 22 22 0 00 0 00 22 22 22 Means Per Litter Mean Corpora Lutea3 16.7 (1.93)b 16.6 (2.32) 16.6 (3.02) 15.8 (1.77) Implantations 14.2 (1.31) 14.8 (1.82) 14.2 (2.29) 14.4 (1.81) Resorptions : Total Early Late 0.4 (0.58) 0.4 (0.58) 0 0.4 (0.59) 0.3 (0.57) 0.1 (0.29) 0.2 (0.39) 0.2 (0.39) 0 0.4 (0.91) 0.4 (0.91) 0 Dead Fetuses 0 0 00 Live Fetuses0 : Total Males Females 13.9 (1.49) 6.3 (2.29) 7.6 (1.94) 14.4 (1.71) 6.5 (2.22) 8.0 (2.24) 14.0 (2.44) 6.9 (2.31) 7.1 (2.29) 14.0 (2.24) 6.5 (1.79) 7.5 (1.71) Mean Fetal Weight : Total 5.53 (0.30) 5.52 (0.26) 5.36 (0.20) 5.38 (0.44) ' Sex Ratio`S 0.45 (0.14) 0.45 (0.14) 0.49 (0.15) 0.46 (0.09) a Statistical analyses are not conducted on mean corpora lutea data; these data are presented for information only. b Standard deviation is reported in parentheses. c Statistical analyses are only conducted on the mean total number of live fetuses per litter. The mean number of males and females are presented for information only. d Number male fetuses/total number fetuses per litter. * Significant trend; p < 0.05. -26- CotoPatv^ s a la r i Does n0icon'a,nTSC* C' H-24516: Developmental Toxicity Study in Rats TABLE 6 INCIDENCE OF FETAL MALFORMATIONS DuPont-5991 Group: I II III IV Dose (mg/kg/day): 0 50 200 500 EXTERNAL N o . Examined3 Umbilical hernia Micrognathia No. Affected 305 (22) -*...b ------ 317 (22) 1 (1) 1 (1) 2 (2) 309 (22) -. . . -. . . --- 307 (22) -. . . -. . . --- VISCERAL N o . Examined No. Affected 160 (22) 165 (22) 159 (22) --- -. . . -. . . 158 (22) -. . . HEAD N o . Examined Brain - Distended Ventricles No. Affected 160 (22) -. . . --- 164 (22) 1 (1) 1 (1) 159 (22) 1 (1) 1 (1) 158 (22) -. . . -. . . SKELETAL N o . Examined Rib - Fused Micrognathia Vertebra Fused Hemi No. Affected 302 (22) -. . . "-- 316 (22) 1 (1) 1 (1) 306 (22) -. . . --- 303 (22) -. . . --- -. . . 1 (1) -. . . -. . . 1 (1) -. . . --- 2 (2) --- -. . . -. . . -. . . TOTAL NUMBER AFFECTED 0 (0) 4 (4) 1 (1) 0 (0) a Number examined and affected, including the number affected with the listed malformations are expressed as Fetuses (Litters). b For ease of reading, zeros have been replaced with dashes for the listed malformations. No significant trends were detected. Note: Statistical analyses are only conducted on the individual endpoints. The overall total and totals by exam type are presented for information only. -27- Company R?ino' a* Tr * r ' Company Sanitized. Does not contain T3CA CBI H-24516: Developmental Toxicity Study in Rats TABLE 7 INCIDENCE OF FETAL VARIATIONS DuPont-5991 Group: Dose (mg/kg/day): I 0 II III IV 50 200 500 DEVELOPMENTAL VARIATIONS EXTERNAL N o . Examined3 No. Affected 305 (22) 317 (22) 309 (22) 307 (22) ___ b -- -- -- VISCERAL N o . Examined No. Affected 160 (22) 164 (22) 159 (22) 158 (22) -------- HEAD N o . Examined No. Affected 160 (22) 164 (22) 159 (22) 158 (22) -------- SKELETAL N o . Examined Rib - Rudimentary Cervical Rib - Supernumerary Scapula - Misshapen Sternebra - Fused No. Affected TOTAL WITH DEVELOPMENTAL VARIATIONS 302 (22) 1 (1) 16 (5) -- --17 (6) 17 (6) 316 (22) 1 (1) 6 (6) 1 (1) ... 8 (8) 8 (8) 306 (22) 1 (1) 25 (7) -- 1 (1) 26 (7) 26 (7) 303 (22) 1 (1) 16 (6) -- ... 17 (6) 17 (6) Company Sanitized. Does not contain tsca CB1 -28- H-24516: Developmental Toxicity Study in Rats TABLE 7 (Continued) INCIDENCE OF FETAL VARIATIONS DuPont-5991 Group: Dose (mg/kg/day): I 0 II III IV 50 200 500 VARIATIONS DUE TO RETARDED DEVELOPMENT EXTERNAL N o . Examined No. Affected 305 (22) 317 (22) 309 (22) 307 (22) ---- -. . . -. . . -. . . VISCERAL N o . Examined Heart &/or Greater Vessels Patent Ductus Arteriosis Kidney, Papillae Small Papilla - Size 1 Small Papilla - Size 2 Papilla - Size 3 No. Affected 160 (22) 165 (22) 159 (22) 158 (22) ---- 2 (2) --- --- -. . . 12 (12) 16 (12 ) 28 (18) 2 (2) 11 (8) 11 (10) 26 (16) 1 (1) 2 (2) 9 (6) 12 (8) -. . . 2 (2) 12 (11) 14 (12) HEAD N o . Examined No. Affected 160 (22) 164 (22) 159 (22) 158 (22) ---- -. . . -. . . -. . . SKELETAL N o . Examined Femur - Retarded Ossification Pelvis - Retarded Ossification Rib - Wavy Skull - Retarded Ossification Sternebra - Retarded Ossification Vertebra - Retarded Ossification No. Affected 302 (22) ---1 (1) ---7 (7) 1 (1) 110 (21) 116 (21) 316 (22) ----. . . 1 (1) 10 (8) 2 (2) 146 (21) 149 (21) 306 (22) 303 (22) 1 (1) --- 1 (1) 6 (3) * 1 (1) 10 (4) * 26 (14) * 65 (18)* 4 (3) 5 (2) 124 (21) 69 (19) 136 (22) 125 (21) 'fiampaW Sa0lUzed Does t,olcon^nTSCACB1 -29- H-24516: Developmental Toxicity Study in Rats DuPont-5991 TABLE 7 (Continued) INCIDENCE OF FETAL VARIATIONS Group: Dose (mg/kg/day): I 0 II III IV 50 200 500 TOTAL WITH VARIATIONS DUE TO RETARDED DEVELOPMENT 136 (22) 166 (22) 145 (22) 135 (21) TOTAL NUMBER FETUSES WITH VARIATIONS 145 (22) 169 (22) 160 (22) 147 (21) a Number examined and affected, including the number affected with the listed variations, are expressed as Fetuses (Litters). b For ease of reading, zeros have been replaced with dashes for the listed variations. * Significant trend (Jonckheere's test); p < 0.05 Note: Statistical analyses are only conducted on the individual endpoints. The overall total and totals by exam are presented for information only. CompaW Sanitized* Does not contain TSCACBI -30- H-24516: Developmental Toxicity Study in Rats DuPont-5991 APPENDICES 3noicor-!-ainTSCACBl -31 - H-24516: Developmental Toxicity Study in Rats DuPont-5991 APPENDIX A Individual Body Weights (Company Sanitized. Does not contain TSCA CB! -32- H-24516: Developmental Toxicity Study in Rats DuPont-5991 Individual Body Weights Explanatory Notes Footnotes a b oDMnaalyyteOrrenGcaolbrobdodedydywtoweie3gihgsithgstnamirfeiicnpaurnsotvtfhiidegeuwdreebsigyahtnthdeoafvrteehnerdepoprroo;rdttheuedctvisneontfhdicosor-naspcuepppeptnilodienixd. abcocdoyrdwineigglhyt data are Abbreviations --- =No Data Corntr -33 - ij'js; ji conta; SCACBl H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP I : 0 MG/KG/DAY ANIMAL NUMBER 0<a 646224 646225 646226 646230 646236 646241 646251 646252 646256 646257 646261 646265 646272 646276 646278 646282 646284 646288 646290 646292 646294 646308 247 230 260 252 230 245 246 235 250 244 235 234 235 243 235 252 242 236 226 236 240 240 INDIVIDUAL BODY WEIGHTS (grams) 4 255.6 237.3 271.6 241.0 252.1 259.9 259.9 246.5 258.6 246.9 228.8 -- -- -- -- -- -- 260.7 227.4 195.4 243.2 208.6 DAYS OF GESTATION 678 261.9 249.2 291.2 265.0 268.7 271.4 267.6 255.2 257.4 259.0 261.0 250.6 263.8 276.8 260.4 274.3 258.2 264.9 240.3 238.8 252.4 233.7 275.7 254.0 294.7 273.2 267.9 282.3 272.7 265.3 269.4 264.0 266.4 254.9 266.7 272.2 265.6 275.9 268.4 275.2 243.7 225.7 261.4 251.9 279.7 258.1 297.7 285.4 275.2 290.4 275.5 266.5 278.8 264.9 269.2 257.5 271.3 274.7 268.4 282.8 270.9 280.4 247.2 228.8 263.1 258.8 9 288.7 262.6 305.4 289.5 283.4 296.4 276.9 270.3 281.8 268.6 276.9 261.7 276.7 287.5 272.4 288.2 274.3 286.1 249.2 226.8 264.3 261.6 10 298.0 268.0 313.0 293.0 291.3 305.8 289.5 284.7 286.2 272.5 282.2 267.6 281.9 294.1 280.0 292.9 280.1 294.4 252.5 222.8 267.9 276.9 Company Sanitized. Does not contain TSCA CBT -34- H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP I : 0 MG/KG/DAY ANIMAL NUMBER 11 646224 646225 646226 646230 646236 646241 646251 646252 646256 646257 646261 646265 646272 646276 646278 646282 646284 646288 646290 646292 646294 646308 301.1 278.8 324.4 301.5 299.6 312.5 294.1 292.4 301.4 281.0 286.4 273.4 286.2 299.7 288.2 302.3 285.9 303.8 263.5 235.5 274.2 287.6 INDIVIDUAL BODY WEIGHTS (grams) 12 309.1 282.7 326.0 307.6 305.4 319.1 295.0 297.5 302.0 283.9 293.9 280.7 305.9 315.1 298.4 313.4 303.0 308.5 265.9 245.5 277.3 291.7 DAYS OF GESTATION 13 14 15 313.9 285.4 337.9 313.4 309.0 320.5 303.7 305.9 318.6 294.3 303.6 284.5 304.0 314.5 302.2 314.6 301.1 318.6 273.9 261.0 283.9 299.5 327.0 295.2 350.4 323.2 321.4 332.0 310.6 312.6 316.9 297.2 304.6 289.6 307.7 321.8 308.2 320.9 306.7 329.9 280.2 273.9 291.8 313.4 330.5 302.1 361.8 327.9 323.2 348.9 315.9 316.0 325.2 302.2 309.0 299.8 313.0 341.1 319.3 333.3 319.1 333.5 285.6 279.8 300.1 326.5 16 340.5 313.9 376.0 338.4 334.0 352.5 326.8 329.2 340.3 313.7 315.2 302.5 327.0 347.6 334.0 340.0 329.2 345.8 299.9 296.2 305.6 332.7 17 357.3 326.6 394.3 352.0 349.6 365.6 331.8 343.9 348.1 322.9 324.2 314.9 326.9 359.9 343.4 360.6 347.9 364.3 318.2 311.9 319.3 350.8 *ift '5 Ck C&l -35 - H-24516: Developmental Toxicity Study in Rats GROUP I : 0 MG/KG/DAY ANIMAL NUMBER 18 646224 646225 646226 646230 646236 646241 646251 646252 646256 646257 646261 646265 646272 646276 646278 646282 646284 646288 646290 646292 646294 646308 373.9 340.3 409.7 368.7 362.0 384.1 354.0 358.5 368.8 340.4 339.1 334.9 347.5 381.2 360.4 376.2 360.0 382.8 331.2 334.1 335.4 373.2 INDIVIDUAL BODY WEIGHTS (grams) DAYS OF GESTATION 19 20 21 386.1 350.5 424.1 388.9 378.3 405.1 365.7 379.4 381.3 354.1 348.4 344.0 364.1 403.8 377.4 393.9 380.2 402.3 342.4 345.0 343.4 388.9 405.3 372.2 448.0 402.9 394.2 429.5 385.0 401.7 398.8 368.3 365.3 361.2 385.5 417.7 389.5 413.2 397.1 420.0 358.6 365.8 360.8 414.5 432.6 395.0 471.4 419.2 418.5 459.1 404.4 430.8 427.8 391.5 382.2 383.5 409.0 444.8 417.2 440.7 420.8 443.1 369.3 387.1 378.6 442.4 21* 335.6 301.4 353.0 321.0 321.0 342.8 307.8 325.7 339.4 306.6 305.8 302.8 312.5 342.5 328.9 327.4 325.1 331.3 276.5 283.2 296.3 330.5 DuPont-5991 not contain TSCACBI Company Sanitized. Does -36- H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP II: 50 MG/KG/DAY ANIMAL NUMBER 0a INDIVIDUAL BODY WEIGHTS (grams) DAYS OF GESTATION 46 7 8 646227 646229 646231 646235 646242 646245 646246 646249 646250 646253 646264 646267 646274 646279 646280 646286 646291 646296 646297 646298 646300 646306 252 267.3 285.6 285.5 286.5 230 237.6 257.1 258.8 266.4 255 263.2 282.3 284.9 285.3 246 260.6 272.6 278.5 273.5 251 256.5 264.1 265.7 267.2 235 250.9 252.4 247.2 259.3 253 266.7 279.5 268.1 283.0 233 218.6 252.1 253.0 262.3 239 259.3 272.9 278.1 288.6 245 258.9 272.6 272.0 283.4 257 238.3 277.1 274.9 289.2 248 -- 270.6 275.2 278.6 232 -- 253.1 253.8 261.2 233 -- 247.8 249.3 252.1 258 -- 256.7 227.0 220.1 235 -- 273.9 276.5 278.4 230 243.0 244.2 249.5 254.5 230 246.5 253.3 257.0 263.8 243 251.7 256.5 259.6 266.8 233 248.1 264.7 269.4 280.8 238 254.2 254.7 255.9 263.1 245 267.7 274.9 275.7 280.8 9 296.4 272.7 295.9 287.0 271.7 263.4 296.5 261.3 285.6 288.7 291.3 277.9 262.5 262.0 248.3 282.4 256.8 267.1 267.7 279.8 266.9 283.7 10 301.2 277.6 298.6 287.4 272.1 266.2 293.0 268.3 296.7 292.9 298.6 282.8 270.5 260.2 264.5 293.6 261.4 272.1 268.6 288.6 277.7 288.8 'gim pinyBKm tszea. Doe; ;'not contain TSCA CBi -37- H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP II: 50 MG/KG/DAY ANIMAL NUMBER 11 INDIVIDUAL BODY WEIGHTS (grams) DAYS OF GESTATION 12 13 14 15 646227 646229 646231 646235 646242 646245 646246 646249 646250 646253 646264 646267 646274 646279 646280 646286 646291 646296 646297 646298 646300 646306 312.8 284.2 307.6 294.8 280.2 268.5 307.4 274.3 305.1 299.2 300.6 289.6 276.6 271.4 273.4 301.2 268.0 277.0 276.3 298.7 284.5 299.3 320.7 292.3 308.1 302.2 282.3 277.7 320.1 283.6 315.0 308.8 314.9 296.7 283.9 279.6 289.4 305.1 269.5 282.9 278.6 306.7 290.8 303 .4 327.8 302.2 318.1 309.8 286.3 286.7 323.8 294.8 321.7 320.6 320.7 298.5 295.9 273.7 292.3 311.2 270.8 290.9 286.3 310.0 294.7 307.6 335.4 313.3 327.1 320.3 295.1 287.0 323.3 296.6 327.8 321.6 321.2 302.1 301.8 285.5 299.2 318.0 276.5 297.3 290.0 313.1 307.5 311.5 340.5 328.1 330.6 325.4 295.9 292.2 337.8 302.7 336.2 330.5 335.7 315.5 306.1 293.3 309.0 330.1 286.7 310.0 294.6 325.1 310.5 315.0 16 353.9 335.3 339.9 334.6 306.0 306.4 348.5 316.5 346.0 344.8 344.1 322.1 322.0 304.2 315.1 337.2 296.8 320.1 304.2 336.6 321.5 331.3 17 368.9 355.3 359.3 357.0 321.8 310.7 361.4 330.3 361.9 361.1 360.1 337.0 332.7 310.6 330.0 349.9 305.4 333.8 324.2 351.4 338.9 347.1 D09S not contain TSCACB CcmpaV SanWied -38- H-24516: Developmental Toxicity Study in Rats GROUP II: 50 MG/KG/DAY ANIMAL NUMBER 18 INDIVIDUAL BODY WEIGHTS (grams) DAYS OF GESTATION 19 20 21 21* 646227 646229 646231 646235 646242 646245 646246 646249 646250 646253 646264 646267 646274 646279 646280 646286 646291 646296 646297 646298 646300 646306 390.5 377.8 368.2 371.7 338.1 324.0 379.8 347.9 376.4 375.4 377.7 352.9 352.5 329.4 350.8 371.8 321.4 356.2 341.6 369.4 355.9 359.4 402.3 391.6 382.9 385.7 348.8 338.7 394.4 357.1 395.5 392.5 397.1 367.6 373.0 350.0 369.4 388.7 328.4 364.9 349.6 380.1 374.4 375.8 423.2 411.1 406.5 406.9 362.8 357.0 421.0 377.2 411.6 413.1 418.3 380.2 387.1 361.0 384.7 410.0 345.4 380.6 368.0 404.0 392.1 389.9 447.1 438.5 437.3 435.2 385.2 379.0 450.2 404.4 432.5 430.8 443.6 404.3 393.1 396.1 408.8 432.7 364.5 417.4 399.3 424.3 407.5 418.4 348.5 340.8 333.3 331.0 296.3 295.8 332.0 314.1 319.4 319.9 336.2 307.9 295.5 301.8 303.5 310.4 284.8 326.6 292.7 316.1 304.8 325.4 DuPont-5991 nv;cmpa' -39- . b~ ,, s''*co n ta' nTSC/VCb H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP III: 200 MG/KG/DAY ANIMAL NUMBER 0a INDIVIDUAL BODY WEIGHTS (grams) DAYS OF GESTATION 4 678 646222 646228 646232 646234 646237 646238 646243 646248 646254 646258 646259 646266 646268 646269 646271 646273 646285 646299 646302 646303 646305 646307 252 252.8 264.3 263.8 272.8 257 273.6 291.4 292.0 301.2 236 248.4 259.4 239.5 228.3 251 252.8 268.0 270.0 270.3 246 255.3 265.5 269.5 272.3 239 246.2 260.2 260.8 266.1 243 257.9 269.2 261.7 266.1 260 242.8 278.8 284.8 285.5 234 249.9 264.1 261.3 270.1 241 260.9 271.5 278.6 275.6 250 256.3 272.2 270.8 279.5 255 -- 278.0 275.9 280.5 230 -- 248.4 242.9 251.4 245 -- 265.8 270.1 274.9 244 -- 263.9 264.6 273.8 242 -- 268.9 268.5 272.5 236 -- 261.3 269.5 272.1 230 255.6 262.7 266.0 267.9 230 186.7 195.5 221.0 205.4 249 276.8 285.8 283.6 287.7 231 250.1 257.9 255.7 262.8 238 247.7 262.2 263.8 266.7 9 268.6 307.4 249.6 278.0 281.9 269.1 263.0 294.9 267.9 275.7 282.4 289.4 254.5 275.8 275.6 274.6 276.1 276.9 235.4 299.7 263.5 243.8 10 270.6 306.7 260.5 282.5 266.4 273.9 271.9 295.7 270.1 280.2 286.9 292.0 265.1 279.2 282.8 278.8 281.6 275.5 209.9 304.7 264.0 246.6 Company Sanllteed. Doe not con'" TSC* nRI -40- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL BODY WEIGHTS (grams) GROUP III: 200 MG/KG/DAY ANIMAL NUMBER DAYS OF GESTATION 11 12 13 14 15 646222 646228 646232 646234 646237 646238 646243 646248 646254 646258 646259 646266 646268 646269 646271 646273 646285 646299 646302 646303 646305 646307 276.0 315.9 261.1 290.3 275.0 277.2 281.7 305.6 275.9 289.0 298.4 300.3 267.8 287.8 289.0 284.6 288.1 289.2 244.3 316.3 274.6 249.4 288.0 319.7 273.3 298.8 287.8 283.3 292.5 315.2 278.8 295.9 302.9 310.3 277.1 298.3 300.3 295.1 298.5 293.1 244.7 315.0 276.7 257.6 291.0 327.7 279.9 303.5 301.0 288.8 301.4 323.7 287.6 306.3 317.2 303.8 279.4 302.4 299.7 295.0 293.8 296.1 250.9 319.9 281.4 272.9 302.6 337.8 288.7 312.7 315.8 298.6 305.8 329.6 290.2 309.7 319.6 320.2 289.7 306.3 302.4 301.3 292.8 303.7 265.3 330.0 283.3 283.6 304.7 347.3 292.7 311.2 320.8 305.1 311.7 336.1 301.2 319.9 326.1 333.4 297.3 321.1 311.0 312.1 310.4 320.9 273.1 346.5 290.4 291.8 16 314.5 358.7 301.2 328.6 335.4 311.7 325.9 351.4 313.9 333.5 336.6 339.1 310.4 329.9 317.5 322.5 312.5 321.2 282.4 349.5 293.0 304.1 17 335.9 376.0 316.4 344.4 346.7 327.3 336.1 366.8 325.0 345.1 351.5 352.4 319.6 344.1 339.1 336.8 324.2 337.8 289.7 375.0 303.3 325.0 Does nocontain r?.c&f'Bt Company SanV -41 - H-24516: Developmental Toxicity Study in Rats INDIVIDUAL BODY WEIGHTS (grams) GROUP III: 200 MG/KG/DAY ANIMAL NUMBER DAYS OF GESTATION 18 19 20 21 21* 646222 646228 646232 646234 646237 646238 646243 646248 646254 646258 646259 646266 646268 646269 646271 646273 646285 646299 646302 646303 646305 646307 349.2 394.8 333.9 360.0 359.5 344.7 353.3 389.5 349.4 360.0 368.1 368.4 336.1 352.1 350.1 357.2 336.1 354.7 316.5 398.3 316.0 339.9 360.9 411.0 346.3 373.0 371.0 355.3 367.3 407.7 367.7 377.4 386.3 382.5 354.8 371.5 368.0 370.6 350.3 365.7 325.5 407.8 322.4 351.6 381.0 425.2 358.6 393.2 383.2 367.2 381.8 426.9 387.9 387.2 402.5 397.4 375.4 393.2 377.9 388.7 365.1 373.4 343.9 420.3 338.5 369.6 403.6 460.9 371.3 414.8 416.3 389.0 394.9 460.2 407.0 407.1 438.7 424.1 403.0 423.2 403.8 410.9 389.8 397.2 363.8 449.3 345.3 391.1 318.7 358.2 289.7 314.8 304.3 311.1 306.9 355.4 288.4 314.9 338.3 330.3 296.8 304.3 306.6 300.4 310.0 302.3 279.8 331.5 291.8 285.5 DuPont-5991 Company Sanitized. Doe* not contain TSCACB1 -42- H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP IV: 500 MG/KG/DAY ANIMAL NUMBER 0a INDIVIDUAL BODY WEIGHTS (grams) DAYS OF GESTATION 4678 646221 646223 646233 646239 646240 646244 646247 646255 646260 646262 646263 646270 646275 646277 646281 646283 646287 646289 646293 646295 646301 646304 245 255.5 273.0 264.8 277.6 257 262.4 280.9 272.0 286.5 253 246.6 269.9 270.6 280.1 248 260.8 273.3 264.9 278.8 239 258.8 271.1 263.0 275.2 250 251.1 261.5 263.1 261.7 239 257.5 257.6 272.2 276.4 243 260.7 275.4 270.5 266.3 255 241.3 279.9 282.5 285.4 226 248.4 261.1 264.9 268.0 243 253.7 271.8 264.0 262.8 229 -- 255.2 254.5 257.3 236 -- 266.4 264.5 260.0 250 -- 277.8 276.3 280.5 250 -- 271.5 272.3 280.5 250 -- 264.2 263.8 277.2 236 252.4 255.7 252.0 252.2 233 253.5 263.1 261.7 260.4 240 242.4 255.0 246.5 254.6 231 260.2 267.4 268.2 268.9 246 259.9 261.2 260.8 262.2 230 238.6 245.9 243.2 244.9 9 280.0 293.3 288.0 278.7 274.7 263.4 281.4 274.1 282.2 269.3 261.0 263.8 267.9 284.9 276.9 275.3 256.5 266.6 254.4 277.1 268.9 245.8 10 275.6 290.6 283.4 285.6 272.7 264.9 288.3 272.6 289.4 273.1 255.5 273.1 268.6 292.4 287.4 284.0 259.7 271.3 261.1 279.0 273.5 251.5 Company SaniHied. Doe*:, not contair SCA CQt -43 - H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP IV: 500 MG/KG/DAY ANIMAL NUMBER 11 INDIVIDUAL BODY WEIGHTS (grams) DAYS OF GESTATION 12 13 14 15 646221 646223 646233 646239 646240 646244 646247 646255 646260 646262 646263 646270 646275 646277 646281 646283 646287 646289 646293 646295 646301 646304 286.1 300.1 289.1 297.0 283.1 271.0 292.5 275.7 301.4 280.2 260.4 284.0 283.2 293.9 298.1 296.7 265.1 286.0 277.4 290.4 281.8 262.1 285.9 310.4 293.4 302.6 288.2 273.8 301.7 281.9 297.6 290.4 275.9 280.7 295.8 309.0 312.7 301.8 275.4 288.8 280.0 289.0 280.3 265.2 291.5 316.2 308.1 313.8 302.4 282.5 310.1 292.4 313.9 298.6 288.2 288.9 297.5 310.0 316.2 310.4 281.3 287.9 296.5 297.2 288.6 265.7 298.0 322.9 317.5 328.8 306.2 280.5 313.9 295.1 317.1 304.7 296.7 294.1 298.4 317.1 325.9 316.3 289.0 300.2 303.6 304.4 298.1 275.3 299.4 325.4 329.6 332.9 318.2 285.2 310.4 304.7 328.6 313.9 306.2 300.6 308.9 330.5 338.1 317.4 295.0 308.5 313.0 313.6 296.6 282.8 16 312.8 336.9 335.4 347.7 333.9 298.7 314.1 319.1 342.8 330.5 329.4 315.4 319.4 341.5 351.7 338.0 312.7 323.7 337.7 330.9 310.0 298.6 17 330.6 351.6 356.5 361.1 351.1 302.4 333.0 331.6 360.8 346.0 346.2 310.2 339.3 338.9 364.4 354.8 324.0 348.5 349.2 342.4 324.8 308.3 Company SanHized-Does notconta1*1TSCA CBl -44- H-24516: Developmental Toxicity Study in Rats GROUP IV: 500 MG/KG/DAY ANIMAL NUMBER 18 INDIVIDUAL BODY WEIGHTS (grams) DAYS OF GESTATION 19 20 21 21* 646221 646223 646233 646239 646240 646244 646247 646255 646260 646262 646263 646270 646275 646277 646281 646283 646287 646289 646293 646295 646301 646304 341.3 364.8 370.6 383.8 361.1 315.8 349.9 350.4 381.6 359.2 365.2 351.4 359.3 361.0 377.1 369.1 337.7 367.9 369.5 362.6 335.7 323.7 344.4 380.9 386.6 395.0 372.9 321.3 367.4 366.4 391.2 367.5 388.8 371.0 363.8 379.3 395.8 383.5 346.3 374.6 389.1 371.3 343.4 333.7 362.4 401.4 407.1 416.2 382.1 336.4 376.8 376.3 411.8 322.6 401.9 388.0 378.9 393.4 399.0 398.8 363.4 396.1 403.2 393.2 365.6 352.7 377.1 428.6 432.4 441.4 390.4 357.4 397.0 400.8 430.6 353.6 421.1 414.4 396.0 363.3 358.3 421.2 376.2 423.0 426.4 426.0 384.6 367.5 303.8 327.4 330.4 340.2 282.9 301.4 297.5 307.6 313.9 276.1 309.0 303.0 297.3 276.2 272.6 326.4 280.0 309.4 305.2 324.5 303.3 286.9 DuPont-5991 |3gwpa^ SanUiz -45 - -tscacbi H-24516: Developmental Toxicity Study in Rats DuPont-5991 APPENDIX B Individual Body Weight Changes Company Ss-5*5'! n* en**5 '**'' * ^Rl Company Sanitized. Does not contain TSCA C8 -46- H-24516: Developmental Toxicity Study in Rats Individual Body Weight Changes Explanatory Notes Footnotes a Maternal body weight minus the weight of the products of conception. Abbreviations --- =No Data DuPont-5991 1is -tWK -47- H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP I : 0 MG/KG/DAY ANIMAL NUMBER 0 -4 INDIVIDUAL BODY WEIGHT CHANGES (grams) DAYS OF GESTATION 4 -6 6--8 8-10 10-12 12-14 646224 646225 646226 646230 646236 646241 646251 646252 646256 646257 646261 646265 646272 646276 646278 646282 646284 646288 646290 646292 646294 646308 8 .6 7 .3 11 .6 -11 .0 22 .1 14 .9 13 .9 11 .5 8 .6 2 .9 -6 .2 --- -- 24 .7 1 .4 -40 .6 3 .2 -31 .4 6 .3 11 .9 19 .6 24 .0 16 .6 11 .5 7 .7 8 .7 -1 .2 12 .1 32 .2 --- 4 .2 12 .9 43 .4 9 .2 25 .1 17 .8 8 .9 6 .5 20 .4 6 ,.5 19..0 7 ,.9 11..3 21..4 5 .9 8 .2 6 .9 7 ,.5 -2 .1 8 ,.0 8 .5 12 .7 15 .5 6 ,.9 -10 .0 10 .7 25 .1 18 .3 9..9 15 .3 7..6 16 ,.1 15 ,.4 14 ,.0 18..2 7 .4 7 .6 13 .0 10..1 10 .6 19 ,.4 11,.6 10..1 9 .2 14 .0 5 .3 -6 .0 4 .8 18..1 11..1 14 .7 13 .0 14 .6 14 .1 13 .3 5 .5 12 .8 15 .8 11..4 11 .7 13 .1 24 .0 21..0 18 .4 20..5 22 .9 14 .1 13 .4 22 .7 9 .4 14 .8 17..9 12 .5 24 .4 15 .6 16 .0 12 .9 15 .6 15 .1 14 .9 13 .3 10 .7 8 .9 1..8 6 .7 9..8 7 ,.5 3 ,.7 21..4 14 .3 28 ,.4 14 ,.5 21..7 14-16 13 ,.5 18 ,.7 25 ,.6 15 .2 12 .6 20..5 16..2 16,.6 23..4 16 .5 10 .6 12 .9 19..3 25 .8 25..8 19..1 22 .5 15 .9 19..7 22 .3 13 .8 19..3 Como"' iTftd nnem'n'0r-,'vcnolfniltnaiTnfiTfSACOABCIB. CSSpany s a n i l i - D" -48- H-24516: Developmental Toxicity Study in Rats GROUP I : 0 MG/KG/DAY ANIMAL NUMBER 16-18 646224 646225 646226 646230 646236 646241 646251 646252 646256 646257 646261 646265 646272 646276 646278 646282 646284 646288 646290 646292 646294 646308 33 .4 26 .4 33 .7 30 .3 28 .0 31 .6 27..2 29..3 28..5 26 .7 23 .9 32 .4 20 .5 33 .6 26 .4 36 .2 30 .8 37 .0 31..3 37..9 29..8 40 .5 INDIVIDUAL BODY WEIGHT CHANGES (grams) DAYS OF GESTATION 18-20 20-21 6-21 31 .4 31 .9 38 .3 34 .2 32 .2 45 .4 31 .0 43 .2 30 .0 27 .9 26 .2 26..3 38 .0 36 .5 29 .1 37..0 37..1 37 .2 27 .4 31..7 25..4 41..3 27 .3 22 .8 23 .4 16 .3 24 .3 29 .6 19 .4 29 .1 29..0 23 .2 16 .9 22 ,.3 23 ,.5 27..1 27 .7 27 .5 23 .7 23.,1 10..7 21..3 17 ..8 27 ..9 170 .7 145 .8 180 .2 154 .2 149 .8 187 .7 136 .8 175 .6 170 .4 132 .5 121 .2 132 .9 145 .2 168 .0 156 .8 166 .4 162 ,.6 178 ,.2 129..0 148 .3 126 .2 208 .7 6-21a 73 .7 52 .2 61 .8 56 .1 52 .3 71 .4 40 ,.2 70 ,.5 82 .0 47 .6 44 .8 52 ,.2 48 .7 65..7 68.,5 53 .1 66 .9 66 ..4 36 .,2 44 .,4 43 .,9 96 .,8 DuPont-5991 Company S a n i t i Doesno*coniata TSCA0 & -49- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL BODY WEIGHT CHANGES (grams) GROUP II: 50 MG/KG/DAY ANIMAL NUMBER DAYS OF GESTATION 0-4 4-6 6-8 8-10 10-12 12-14 646227 646229 646231 646235 646242 646245 646246 646249 646250 646253 646264 646267 646274 646279 646280 646286 646291 646296 646297 646298 646300 646306 15.3 7.6 8.2 14.6 5.5 15.9 13.7 -14.4 20.3 13.9 -18.7 -- -- -- -- -- 13.0 16.5 8.7 15.1 16.2 22.7 18.3 19.5 19.1 12.0 7.6 1.5 12.8 33.5 13.6 13.7 38.8 -- -- -- -- -- 1.2 6.8 4.8 16.6 0.5 7.2 0.9 9.3 3.0 0.9 3.1 6.9 3.5 10.2 15.7 10.8 12.1 8.0 8.1 4.3 -36.6 4.5 10.3 10.5 10.3 16.1 8.4 5.9 14.7 11.2 13.3 13.9 4.9 6.9 10.0 6.0 8.1 9.5 9.4 4.2 9.3 8.1 44.4 15.2 6.9 8.3 1.8 7.8 14.6 8.0 19.5 14.7 9.5 14.8 10.2 11.5 27.1 15.3 18.3 15.9 16.3 13.9 13.4 19.4 24.9 11.5 8.1 10.8 10.0 18.1 13.1 14.6 14.7 21.0 19.0 18.1 12.8 9.3 3.2 13.0 12.8 12.8 6.3 5.4 17.9 5.9 9.8 12.9 7.0 14.4 11.4 6.4 16.7 8.1 14-16 18.5 22.0 12.8 14.3 10.9 19.4 25.2 19.9 18.2 23.2 22.9 20.0 20.2 18.7 15.9 19.2 20.3 22.8 14.2 23.5 14.0 19.8 Oss -50- H-24516: Developmental Toxicity Study in Rats INDIVIDUAL BODY WEIGHT CHANGES (grams) GROUP II: 50 MG/KG/DAY ANIMAL NUMBER 16-18 DAYS OF GESTATION 18-20 20-21 6-21 6-21a 646227 646229 646231 646235 646242 646245 646246 646249 646250 646253 646264 646267 646274 646279 646280 646286 646291 646296 646297 646298 646300 646306 36 .6 42 .5 28 .3 37 .1 32 .1 17 .6 31 .3 31 .4 30 .4 30 .6 33 .6 30 .8 30 .5 25 .2 35 .7 34 .6 24 .6 36 .1 37 .4 32 .8 34 .4 28 .1 32 ,.7 33 ,.3 38 .3 35 ,.2 24 ,.7 33 .0 41,.2 29..3 35 .2 37 ,.7 40 ,.6 27 .3 34 .6 31..6 33 ,.9 38 ,.2 24 ,.0 24 .4 26 ,.4 34 .6 36 ,.2 30 ,.5 23 .9 27 .4 30 .8 28 .3 22 .4 22 .0 29 .2 27 .2 20 .9 17 .7 25 .3 24 .1 6 .0 35 .1 24 .1 22 .7 19 .1 36 .8 31 .3 20 ,.3 15 .4 28 .5 161,.5 181 .4 155 ,.0 162 .6 121,.1 126 ,.6 170 .7 152 ,.3 159 .6 158 ,.2 166 .5 133 ,.7 140 ,.0 148 ,.3 152 ,.1 158 ,.8 120 ,.3 164 ,.1 142 ,.8 159,.6 152 .8 143 ,.5 62 .9 83 ,.7 51,.0 58..4 32 .2 43 .4 52 .5 62 .0 46 .5 47,.3 59 .1 37 .3 42 .4 54 ,.0 46 .8 36 .5 40 .6 73 .3 36 .2 51,.4 50 ,.1 50 ,.5 DuPont-5991 Sanded. Do**not conta' TSCACM Company -51 - H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL BODY WEIGHT CHANGES (grams) GROUP III: 200 MG/KG/DAY ANIMAL NUMBER DAYS OF GESTATION 0-4 4-6 6-8 8-10 10-12 12-14 646222 646228 646232 646234 646237 646238 646243 646248 646254 646258 646259 646266 646268 646269 646271 646273 646285 646299 646302 646303 646305 646307 0.8 16.6 12.4 1.8 9.3 7.2 14.9 -17.2 15.9 19.9 6.3 -- -- -- -- -- -- 25.6 -43.3 27.8 19.1 9.7 11.5 17.8 11.0 15.2 10.2 14.0 11.3 36.0 14.2 10.6 15.9 -- -- -- -- -- -- 7.1 8.8 9.0 7.8 14.5 8.5 9.8 -31.1 2.3 6.8 5.9 -3.1 6.7 6.0 4.1 7.3 2.5 3.0 9.1 9.9 3.6 10.8 5.2 9.9 1.9 4.9 4.5 -2.2 5.5 32.2 12.2 -5.9 7.8 5.8 10.2 0.0 4.6 7.4 11.5 13.7 4.3 9.0 6.3 9.5 7.6 4.5 17.0 1.2 -20.1 17.4 13.0 12.8 16.3 21.4 9.4 20.6 19.5 8.7 15.7 16.0 18.3 12.0 19.1 17.5 16.3 16.9 17.6 34.8 10.3 12.7 11.0 14.6 18.1 15.4 13.9 28.0 15.3 13.3 14.4 11.4 13.8 16.7 9.9 12.6 8.0 2.1 6.2 -5.7 10.6 20.6 15.0 6.6 26.0 14-16 11.9 20.9 12.5 15.9 19.6 13.1 20.1 21.8 23.7 23.8 17.0 18.9 20.7 23.6 15.1 21.2 19.7 17.5 17.1 19.5 9.7 20.5 pOTiipa'VSanitize p^PoVconlatn -52- H-24516: Developmental Toxicity Study in Rats INDIVIDUAL BODY WEIGHT CHANGES (grams) GROUP III: 200 MG/KG/DAY ANIMAL NUMBER 16-18 DAYS OF GESTATION 18-20 20-21 6-21 6-21a 646222 646228 646232 646234 646237 646238 646243 646248 646254 646258 646259 646266 646268 646269 646271 646273 646285 646299 646302 646303 646305 646307 34.7 36.1 32.7 31.4 24.1 33.0 27.4 38.1 35.5 26.5 31.5 29.3 25.7 22.2 32.6 34.7 23.6 33.5 34.1 48.8 23.0 35.8 31.8 30.4 24.7 33.2 23.7 22.5 28.5 37.4 38.5 27.2 34.4 29.0 39.3 41.1 27.8 31.5 29.0 18.7 27.4 22.0 22.5 29.7 22.6 35.7 12.7 21.6 33.1 21.8 13.1 33.3 19.1 19.9 36.2 26.7 27.6 30.0 25.9 22.2 24.7 23.8 19.9 29.0 6.8 21.5 139.3 169.5 111.9 146.8 150.8 128.8 125.7 181.4 142.9 135.6 166.5 146.1 154.6 157.4 139.9 142.0 128.5 134.5 168.3 163.5 87.4 128.9 54.4 66.8 30.3 46.8 38.8 50.9 37.7 76.6 24.3 43.4 66.1 52.3 48.4 38.5 42.7 31.5 48.7 39.6 84.3 45.7 33.9 23.3 DuPont-5991 ComPanVSanHired. Do*noto"*"''tqCAC' -53 ani no,\co>ti^n H-24516: Developmental Toxicity Study in Rats INDIVIDUAL BODY WEIGHT CHANGES (grams) GROUP IV: 500 MG/KG/DAY ANIMAL NUMBER DAYS OF GESTATION 0-4 4-6 6-8 8-10 10-12 12-14 646221 646223 646233 646239 646240 646244 646247 646255 646260 646262 646263 646270 646275 646277 646281 646283 646287 646289 646293 646295 646301 646304 10.5 5.4 -6.4 12.8 19.8 1.1 18.5 17.7 -13.7 22.4 10.7 -- -- -- -- -- 16.4 20.5 2.4 29.2 13.9 8.6 17.5 18.5 23.3 12.5 12.3 10.4 0.1 14.7 38.6 12.7 18.1 -- -- -- -- -- 3.3 9.6 12.6 7.2 1.3 7.3 4.6 5.6 10.2 5.5 4.1 0.2 18.8 -9.1 5.5 6.9 -9.0 2.1 -6.4 2.7 9.0 13.0 -3.5 -2.7 -0.4 1.5 1.0 -1.0 -2.0 4.1 3.3 6.8 -2.5 3.2 11.9 6.3 4.0 5.1 -7.3 15.8 8.6 11.9 6.9 6.8 7.5 10.9 6.5 10.1 11.3 6.6 10.3 19.8 10.0 17.0 15.5 8.9 13.4 9.3 8.2 17.3 20.4 7.6 27.2 16.6 25.3 17.8 15.7 17.5 18.9 10.0 6.8 13.7 12.1 12.5 24.1 26.2 18.0 6.7 12.2 13.2 19.5 14.3 20.8 13.4 2.6 8.1 13.2 14.5 13.6 11.4 23.6 15.4 17.8 10.1 DuPont-5991 14-16 14.8 14.0 17.9 18.9 27.7 18.2 0.2 24.0 25.7 25.8 32.7 21.3 21.0 24.4 25.8 21.7 23.7 23.5 34.1 26.5 11.9 23.3 -54- H-24516: Developmental Toxicity Study in Rats INDIVIDUAL BODY WEIGHT CHANGES (grams) GROUP IV: 500 MG/KG/DAY ANIMAL NUMBER 16-18 DAYS OF GESTATION 18-20 20-21 6-21 6-21a 646221 646223 646233 646239 646240 646244 646247 646255 646260 646262 646263 646270 646275 646277 646281 646283 646287 646289 646293 646295 646301 646304 28 .5 27 .9 35 .2 36 .1 27 .2 17 .1 35 .8 31..3 38 .8 28 .7 35 .8 36 .0 39 ,.9 19..5 25..4 31..1 25 .0 44 .2 31..8 31..7 25 .7 25 .1 21 .1 36 .6 36 .5 32 .4 21 .0 20 .6 26 .9 25 .9 30..2 -36 ,.6 36 .7 36 ,.6 19 ,.6 32 ,.4 21..9 29..7 25 .7 28..2 33 .7 30.,6 29.,9 29.,0 14 .7 27 .2 25 .3 25 .2 8 .3 21 .0 20 .2 24 .5 18 ,.8 31..0 19 ,.2 26 ,.4 17 ,.1 -30..1 -40 .7 22 .4 12 .,8 26 .9 23..2 32.,8 19..0 14 .,8 104 .1 147 .7 162 .5 168 .1 119 .3 95 .9 139 .4 125 .4 150 .7 92 .5 149 ,.3 159 .2 129 .6 85 ,.5 86 ,.8 157 ,.0 120 .5 159 .9 171..4 158 .6 123 ..4 121..6 30 .8 46 .5 60 .5 66 .9 11 .8 39 .9 39,.9 32 .2 34 .0 15 ,.0 37,.2 47 ,.8 30..9 -1..6 11..1 62 . 24 .,3 46 ..3 50 ..2 57..1 42 ..1 41..0 DuPont-5991 Company Sanitized. Does not contain TSCA CB -55 - H-24516: Developmental Toxicity Study in Rats DuPont-5991 APPENDIX C Individual Food Consumption company Sanitized Does not contain TSCA CBi -56- H-24516: Developmental Toxicity Study in Rats Individual Food Consumption Explanatory Notes Abbreviations --- = No Data DuPont-5991 Company Sanitized. Does notcontain TSCA CBi -57- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FOOD CONSUMPTION (grams/day) GROUP I: 0 MG/KG/DAY ANIMAL NUMBER 4-6 DAYS OF GESTATION 6-8 8-10 10-12 12-14 14-16 646224 646225 646226 646230 646236 646241 646251 646252 646256 646257 646261 646265 646272 646276 646278 646282 646284 646288 646290 646292 646294 646308 20 .1 23 ,.2 23 ,.2 15 ,.1 27 ,.7 24 .0 22 .0 40 ,.4 8 ,.4 23 .3 26..6 20..3 23 .5 26 .8 23 ,.2 23 ,.7 24 .2 26 ,.0 19,.5 23 ,.7 21,.5 13 ,.9 36 .1 24 .4 27 .6 28 .0 22 .9 28 .0 21 .8 24 .7 24 .1 21 .0 22 .2 19 .9 23 .8 26 .7 22 .6 23 .3 27 .7 28 .3 20 .8 14 .6 24 .4 27 .3 29 ,.7 22 .6 28 .2 25 .3 24 .5 29 ,.3 23 .5 28 .0 27 .0 21..4 23 .9 23 .2 24 .9 30 .2 24 .3 25 .7 28 .7 31..0 20..3 12 .4 23 .9 28 .3 30..9 27 .4 32 .5 30 ,.9 28 .1 31..2 24 .1 28 .9 30 ,.9 24 .4 25..2 22 .1 29..3 31..4 26 .4 26 ,.3 31..6 29 ,.2 20 .8 18 .6 23 ,.7 32..4 29 .7 25 .3 33 .5 30 .6 28 .0 31 .0 23 ,.8 28 .9 29 .8 24 ,.7 24 .4 24 .8 27 ,.4 -- 26 ,.6 29 .1 27 .6 31..9 22 .9 29 .5 25 .8 31..1 29 ,.0 30 .3 34..7 29..5 27 .9 34 ,.1 23 .3 26..0 29..7 25 .6 23 ,.8 23 .9 29 ,.9 32 .5 29..3 25..8 31,.4 31..1 23 .2 26 .3 26..4 31..6 16-18 31 .6 29 .7 35 .9 29 .6 28 .7 34 .0 26 .8 31 .6 33 .2 26 .1 25 .4 26 .9 28 .9 34 .5 29 .7 30 .4 33 .5 35 .2 25 .8 30 .6 30 .0 31 .3 Company contain TSCA, CB* Sanifeed. Does not -58- H-24516: Developmental Toxicity Study in Rats INDIVIDUAL FOOD CONSUMPTION (grams/day) GROUP I: 0 MG/KG/DAY ANIMAL NUMBER 18-20 DAYS OF GESTATION 20-21 4-21 6-21 646224 646225 646226 646230 646236 646241 646251 646252 646256 646257 646261 646265 646272 646276 646278 646282 646284 646288 646290 646292 646294 646308 31.6 28.7 30.7 29.2 29.8 34.3 25.9 29.9 32.0 27.9 23.8 26.9 31.1 36.3 28.3 31.6 30.5 30.6 22.6 22.4 24.2 21.1 31.1 25.5 32.0 24.4 26.7 32.9 22.9 28.6 30.8 22.9 19.9 24.5 26.9 26.9 32.6 32.5 34.2 28.6 17.8 24.8 19.9 30.3 29.9 26.4 30.8 27.1 27.2 30.9 23.8 29.7 27.1 24.2 24.1 23.6 27.3 12.3 26.7 27.3 29.7 30.3 21.7 22.4 24.7 27.3 31.2 26.8 31.9 28.7 27.1 31.8 24.1 28.3 29.6 24.4 23.8 24.0 27.8 10.4 27.1 27.8 30.4 30.9 22.0 22.2 25.1 29.1 DuPont-5991 -59- rC6Tt'PanV i\cowiia1 H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FOOD CONSUMPTION (grams/day) GROUP II: 50 MG/KG/DAY ANIMAL NUMBER 4-6 6-8 DAYS OF GESTATION 8-10 10-12 12-14 14-16 646227 646229 646231 646235 646242 646245 646246 646249 646250 646253 646264 646267 646274 646279 646280 646286 646291 646296 646297 646298 646300 646306 26 .5 26 .1 25 .0 23 .6 20 .3 20 .6 22 .4 24 .6 29 .6 21 .4 25 .1 22 .0 24 .0 18 .4 12 .,6 26 .9 21..5 23 ,.6 20 ,.9 21..9 39,.9 22 ,.1 22 .3 23 .9 19 .9 20 .2 17 .9 17 .3 15 .6 22 .9 27 .0 23 .1 23 .9 20 .4 23 .8 17 .1 2 .1 23 .6 19 .9 24 .1 20 .9 24 .0 23 ,.4 20 ,.8 25 .1 22 .8 21 .9 22 .3 20 .7 20 .9 23 .8 24 .4 28 ,.6 24 .7 23 ,.0 21,.4 24 ,.4 19 ,.1 24 ,.4 27 ,.4 21.,2 24 ,.3 21..1 24 .0 28,.0 22 ,9 29 .9 29 .0 24 .5 25 .8 22 .9 24 .9 28,.7 27 ,.5 33 ,.6 29 .4 28 ,.3 23 ,.0 25 ,.0 23 ,.2 31,.8 26 ,.4 21,.7 25..8 22,.3 25 ,.4 26 ,.6 24 .6 29 .1 31 .3 25 .7 26 .9 22 .0 25 .6 26 .1 29,.7 31,.3 30,.1 27,.6 24 ,.2 27 ,.6 22 ,.2 30 ,.9 28 .7 20..7 25 ,.2 23 .3 24 ,.3 27 ,.4 23 .,0 30 .7 34 .7 25 .7 28 .6 17 .1 23 .3 28 .5 31 .9 30 .3 29 .9 27 .3 27 .0 27 .2 21 .8 27 .6 28 .6 22 .9 29 .7 22 .2 24 .6 26 .4 26 .1 16-18 33 .8 37 ,.8 27 .9 30..4 23 .1 25 .0 28 .1 30 .,9 32 ,.8 32 .,5 31,,2 28 ,.8 28 .8 23 .2 28 .8 28 .,0 24 .,8 28,,6 27 .9 28 .8 32 .,3 27 .,6 Company Sanitized. Does not contain TSCA -60- H-24516: Developmental Toxicity Study in Rats INDIVIDUAL FOOD CONSUMPTION (grams/day) GROUP II: 50 MG/KG/DAY ANIMAL NUMBER 18-20 DAYS OF GESTATION 20-21 4-21 6-21 646227 646229 646231 646235 646242 646245 646246 646249 646250 646253 646264 646267 646274 646279 646280 646286 646291 646296 646297 646298 646300 646306 30 .4 33 .4 27 .3 29 .0 23 .0 25 .8 30 .3 31 .8 31 .1 32 .0 32..4 26 .4 30 .1 23 .4 28 .6 29 ,.4 22 .6 25 .0 23 .5 26 .2 31..8 25 .6 27 .4 31 .6 30 .4 30 .2 22 .5 21 .9 126 .7 30 . 28..7 23 .1 27 .0 25 .2 19 ,.2 28 .3 23 .0 30..7 19 .3 31..2 28 .7 25 .8 22 .7 31..2 28 .4 30 .0 25 .1 26 .1 20 .9 22 .8 25 .5 28..1 30..4 27 .6 27 .3 24 ,.2 25 .9 21..5 23 .3 27 .6 21..8 26 .1 23 .,1 24 ..9 29..1 24 ..5 28 .7 130 .5 25 . 26 .4 21 .0 23 .1 25 .9 28..6 30..5 28 ,.5 27 .6 24 ,.5 26 .2 21..9 24 .8 27..7 21..8 26 .,4 23 .,4 25 ..3 27..6 24 ..8 DuPont-5991 .uortalnTSCAC Comp a n v S " * * a ' DOM'' -61 - H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FOOD CONSUMPTION (grams/day) GROUP III: 200 MG/KG/DAY ANIMAL NUMBER 4-6 6-8 DAYS OF GESTATION 8-10 10-12 12-14 14-16 646222 646228 646232 646234 646237 646238 646243 646248 646254 646258 646259 646266 646268 646269 646271 646273 646285 646299 646302 646303 646305 646307 20.8 26.4 21.0 22.4 23.3 19.9 20.4 27.4 22.3 26.1 26.6 23.1 21.1 22 22.. 29 36.0 30.1 24.9 10.1 22.1 20.9 28.6 17.8 23.4 1.3 19.3 21.9 19.9 17.8 24.7 20.1 21.4 21.6 21.0 19.2 24.0 20.6 20.4 25.5 22.7 17.5 20.7 20.6 25.5 16.7 23.3 19.3 21.4 15.6 18.3 18.1 25.7 18.5 21.3 25.0 23.1 21.8 22.6 22.9 23.9 25.3 24.1 15.1 26.7 20.1 8.3 23.8 25.3 21.7 24.8 22.7 22.7 25.1 29.1 21.6 26.4 29.1 26.6 22.9 25.9 25.6 26.1 24.8 26.1 25.3 26.2 22.4 15.7 25.3 26.6 27.2 25.8 28.1 23.7 26.1 29.2 23.9 28.3 31.3 27.9 23.7 26.8 24.8 27.9 24.9 25.4 24.9 25.1 22.6 23.8 27.4 30.4 26.2 26.0 27.6 25.5 24.7 29.0 22.2 27.7 28.1 29.6 26.2 25.9 25.2 29.3 23.3 26.7 33.9 27.3 22.6 27.4 16-18 29.2 31.9 26.3 28.4 27.6 29.4 25.1 31.9 24.4 27.9 30.7 32.3 25.5 24.7 28.4 29.6 26.8 31.9 21.5 33.8 26.9 28.4 -62- H-24516: Developmental Toxicity Study in Rats INDIVIDUAL FOOD CONSUMPTION (grams/day) GROUP III: 200 MG/KG/DAY ANIMAL NUMBER DAYS OF GESTATION 18-20 20-21 4-21 6-21 646222 646228 646232 646234 646237 646238 646243 646248 646254 646258 646259 646266 646268 646269 646271 646273 646285 646299 646302 646303 646305 646307 29.1 29.8 25.1 28.3 20.7 27.8 26.5 31.3 27.1 29.4 32.4 31.0 26.3 27.7 27.5 28.6 26.2 22.4 26.7 26.3 23.0 25.7 27.2 32.7 20.4 24.1 25.9 24.7 17.2 35.3 24.8 21.7 32.3 28.2 25.3 26.5 23.4 24.0 27.8 24.5 24.5 27.7 18.6 25.1 24.0 27.5 21.0 24.5 23.6 23.5 22.6 28.9 22.7 25.8 28.3 26.9 23.5 25.1 24.6 27.5 26.0 25.5 22.0 26.1 22.2 23.1 24.4 27.6 21.0 24.8 23.6 24.0 22.9 29.1 22.7 25.8 28.6 27.4 23.8 25.4 24.9 26.4 25.4 25.5 23.6 26.7 22.3 22.3 DuPont-5991 t contain TSCACB1 Company Sanded. Doesno' -63 - H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FOOD CONSUMPTION (grams/day) GROUP IV: 500 MG/KG/DAY ANIMAL NUMBER 4--6 6--8 DAYS OF GESTATION 8-10 10-12 12-14 14-16 646221 646223 646233 646239 646240 646244 646247 646255 646260 646262 646263 646270 646275 646277 646281 646283 646287 646289 646293 646295 646301 646304 23 .4 24 ,.3 20 ,.1 24 ,.3 26 ,.8 20 .7 18..4 24 .8 24 ,.9 25 .5 24 .8 22 .0 24 .0 24 ,.7 24 ,.3 20 .0 21..6 24 ,.8 22 ,.2 22 ,.3 20 .8 24 .6 19 ,.8 21..4 23 ,.8 20 ,.6 21,.3 16 ,.8 25 ,.0 17 ,.1 27 ,.3 22 ,.2 16 ,.8 19 ,.2 17..7 22 ,.8 21..8 21..1 16 .3 22 .4 16 .4 22 .7 19..8 20..7 18 .7 22 .7 22 .1 21 .8 20 .9 15 .6 24 .8 16 .9 22 .9 23 .9 11..8 23 .9 19..4 24 .9 21..3 21..4 18 ,.1 22 .0 18..1 23 ,.3 20 ,.8 21..4 20 ,.8 26 ,.8 24 ,.3 27 ,.3 25 ,.6 19..2 26 ,.8 20..0 28 ,.4 28 ,.0 19 ,.6 25 .3 26 .0 26 .7 28 .4 24 .7 26 .1 26 .2 24 .4 25 .3 21..6 24 .6 21..4 25 .9 27 .4 32 .1 25..8 22 .1 27..9 23 .2 29..3 30..9 27..3 23 .5 26 .4 28 .1 30 .3 25 .5 24 .6 23 .8 26 .6 25 .4 22 ,.6 24 ,.2 26 .2 27 ,.3 30 ,.5 30 ,.6 30 ,.3 22 .6 18 .1 25 .9 30 ,.3 32 ,.7 34 .9 25 ,.6 27..2 29..7 32 .3 25 .0 25 .9 28 .1 29 .5 28 .9 21..9 27 .1 16-18 27..3 27..2 32 .8 34 .7 29..0 24 .6 29..2 28 .4 32 .8 35..4 35 .6 28 .3 32 .3 24 .0 31..8 28 .0 27 .6 34 .1 33 .8 31..5 27 .0 28 ,.7 ' Company -64- H-24516: Developmental Toxicity Study in Rats INDIVIDUAL FOOD CONSUMPTION (grams/day) GROUP IV: 500 MG/KG/DAY ANIMAL NUMBER DAYS OF GESTATION 18-20 20-21 4-21 6-21 646221 646223 646233 646239 646240 646244 646247 646255 646260 646262 646263 646270 646275 646277 646281 646283 646287 646289 646293 646295 646301 646304 25.1 27.7 31.9 32.4 24.4 22.9 28.2 25.1 27.8 16.1 31.8 29.6 26.2 30.1 30.9 26.0 28.1 22.7 34.1 22.4 38.8 25.3 24.5 28.6 31.0 31.4 19.3 26.0 25.4 24.2 24.5 50.6 25.0 30.8 18.1 0.7 ' 1.6 24.1 24.1 29.7 24.7 31.8 24.4 24.6 22.9 25.6 26.9 28.2 25.1 20.9 24.8 22.8 27.7 28.2 25.3 25.0 24.5 24.9 26.1 24.0 23.6 25.7 25.6 25.6 24.2 24.6 22.9 25.8 27.8 28.7 24.9 20.9 25.7 22.5 28.1 28.6 25.4 25.4 24.6 24.9 26.3 24.5 23.8 25.9 26.0 26.1 24.6 24.6 DuPont-5991 Company Sanitized. Does not contain T*CA**M -65- H-24516: Developmental Toxicity Study in Rats DuPont-5991 APPENDIX D Individual Clinical Observations DOSStiot COHtS'T-TSCA KR* -66- H-24516: Developmental Toxicity Study in Rats DuPont-5991 Individual Clinical Observations Explanatory Notes Footnotes a weTxheaermefiimnrsaattdioeobntswse,ritvcheaetdi"oabnil"yreeocnnotrrdideaesydaser6ea-co2hm0Gdiat.tyeIdifsfnironodmsiicgtahntesedwprbeiynret"ooaub"t.;sethrveesdecdounridnbgyth"eb"st.uOdybservations Company Sanitized. Does not contain TSCA CBI -67- H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP I: 0 MG/KG/DAY ANIMAL OBSERVATION NUMBER : 646224 ALOPECIA LEFT FRONT PAW ALOPECIA BOTH FRONT PAW ALOPECIA BOTH FRONT LEG SACRIFICED BY DESIGN 03/19/01 646225 SACRIFICED BY DESIGN 03/19/01 646226 SACRIFICED BY DESIGN 03/19/01 646230 SACRIFICED BY DESIGN 03/19/01 646236 SACRIFICED BY DESIGN 03/19/01 646241 ALOPECIA RIGHT FRONT LEG ALOPECIA BOTH FRONT LEG SACRIFICED BY DESIGN 03/19/01 646251 SACRIFICED BY DESIGN 03/20/01 646252 SACRIFICED BY DESIGN 03/20/01 INDIVIDUAL CLINICAL OBSERVATIONS3 DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 a : /13,14 , , , , , , , / b: ,13 ,14 , , , , , , , r a : , , ,15,16,17,18,19,20,21, b: , , ,15,16,17,18,19,20, a : , , ,15,16,17,18,19,20,21, b: , , ,15,16,17,18,19,20, a: , , / / ,t t I t t 21 , 21, t t t i r r / f / /. ,2 1 , 71, , , , , , / / / / ! / f t / / / / / / " , / / / / / / / / / / / /71J*f a: , , / / / / / / / b: , t i l t t t t / a: I l II I t II ! b: I l I I I I I I ! a: ! I l II II t! ,15, ,17,18,19,20, , , , ,17,18,19,20, , , ,16, , , , ,21, ,3.5,16, , , , , , , , / , / # /21, 21/ / / / / ' / ' ' ' i<c`-i`t / I ! ! t I I t f t ' 71 "Company Sanitized. Does notcontain tsca ori -68- H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP I: 0 MG/KG/DAY ANIMAL NUMBER: OBSERVATION INDIVIDUAL CLINICAL OBSERVATIONS3 DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 646256 SACRIFICED BY DESIGN 03/20/01 646257 SACRIFICED BY DESIGN 03/20/01 646261 SACRIFICED BY DESIGN 03/20/01 646265 SACRIFICED BY DESIGN 3/21/01 J 646272 ALOPECIA LEFT HIND QUARTERS SACRIFICED BY DESIGN 3/21/01 a*O. 646276 SACRIFICED BY DESIGN 3/21/01 GlN. 646278 SACRIFICED BY DESIGN 3/21/01 ns 646282 toSi ALOPECIA BOTH FRONT PAW o SORE NOSE '3 SACRIFICED BY DESIGN 3/21/01 75 646284 >5- SACRIFICED BY DESIGN 3/21/01 a 646288 SACRIFICED BY DESIGN 3/22/01 a: t i t i l l i l i ,,I I I t f a: a: a: I I , 21, , 21, , 21, , 21, b: 21a: / l I I I t I I I I I ,13,14,15,16,17,18,19,20,21, I I I I I I I I I ! / ,13,14,15,16,17,18,19,20, , a: i i i t t i i i r i i / t i i t i i , / / a: t i t i l l i l i I I I f 1 , 21, a: I l t I I ! , 21, a: Il II II II ! tI !> 1 ,16,17,18,19,20,21, b : I l I I I I I I ! , / ! I I ,16,17,18,19,20, , , r I ,20,21,a : I I I I t I I t I I I I t ' b : ! I l I I I I I ! ! I I f t i i i i ,20, , a: I t it ti it i i i i f r i i t ii ,21, a: i i i itili t , , , i iiii i i21, a: i i i i iiii i it t i i i , , ,21, -69- H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP I: 0 MG/KG/DAY ANIMAL OBSERVATION NUMBER: INDIVIDUAL CLINICAL OBSERVATIONS3 DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 646290 SACRIFICED BY DESIGN 03/22/01 a 646292 TOP TEETH MISSING ba , , , , , ,9,10,11,12,13,14,15, ,8,9,10,11,12,13,14, ALOPECIA ABDOMINAL ba , , , , , , ,14,15,16, , , , , , , ,14,15,16, cot SACRIFICED BY DESIGN 03/22/01 a i i i i 646294 SACRIFICED BY DESIGN 03/22/01 a: 3roM 646308 3 ALOPECIA ABDOMINAL b :SB a: 3" SACRIFICED BY DESIGN 03/22/01 a: C>Oo ,5, ,7,8,9,10,11,12, , , ,7,8,9,10,11,12, , 21, III ,I I I , 21, , 21, // , 21, I m-. g 83. -70-fy8i. % H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP II: 50 MG/KG/DAY ANIMAL OBSERVATION NUMBER: INDIVIDUAL CLINICAL OBSERVATIONS3 DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 OEtohpanySanitized. Does not contain TSOA rni 646227 ALOPECIA RIGHT HIND QUARTERS b : , , , ,a: , , , , / t l t 3*^ / l ,14,15, ,r / / 1 / / ! / t t / 1 0 / H / / ,14,15, ,f i i / f / SACRIFICED BY DESIGN 03/19/01 a: , , , , / / r f i t / / / / / t / / / ,21, 646229 SACRIFICED BY DESIGN 03/19/01 a: , , , , / / / / / r r r I I I , t t i / ,21, 646231 SACRIFICED BY DESIGN 03/19/01 a: , , , , / r t / r / t / I I I 1 ! t / ,21, 646235 SACRIFICED BY DESIGN 03/19/01 a: , 21, 646242 SACRIFICED BY DESIGN 03/19/01 a: , 21, 646245 SACRIFICED BY DESIGN 03/20/01 a , 21, 646246 ALOPECIA BOTH FRONT LEG ALOPECIA BOTH FRONT PAW SACRIFICED BY DESIGN 03/20/01 / / i / r r r / / / r , ,14,15,16,17,18,19,20,21, , ,14, ,16,17,18,19,20, , , , , ,16,17,18,19,20,21, ,, ,, ,, 15,, 16,,17,,18,,19,,20,,21,, 646249 ALOPECIA BOTH FRONT PAW ALOPECIA BOTH FRONT LEG SACRIFICED BY DESIGN 03/20/01 ba:: ba:: a: 3 ,9,10,11,12,13,14,15,16,17,18,19,20,21, ,9,10,11,12,13,14,15,16,17,18,19,20, , ,, ,, , ,, it i ,, , ,, ,, ,, , ,, ,1 ,9 , iiii,,, 2,,190,'2,0,2211,, -71 -  H-24516: Developmental Toxicity Study in Rats w DuPont-5991 GROUP II: 50 MG/KG/DAY ANIMAL NUMBER: OBSERVATION INDIVIDUAL CLINICAL OBSERVATIONS3 DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 646250 SACRIFICED BY DESIGN 03/20/01 646253 ALOPECIA RIGHT FRONT PAW STAIN BOTH SHOULDER YELLOW STAIN BOTH SHOULDER BROWN SACRIFICED BY DESIGN 03/20/01 646264 ALOPECIA ABDOM-INAL SACRIFICED BY DESIGN 03/20/01 646267 SACRIFICED BY DESIGN 3/21/01 646274 ALOPECIA RIGHT FRONT PAW SACRIFICED BY DESIGN 3/21/01 646279 SACRIFICED BY DESIGN 3/21/01 646280 DEHYDRATED SACRIFICED BY DESIGN 3/21/01 a: , 21, ba:: r r t / t i t r t r / / / / / / ,18, t / r / r r t r r r r t t t t / ,18, ba I I t I I I l l f i i r i t t t rr / / r r t i t i r t f r r t b :a: I f I I I I I t I t I / /I I/ II I I I l I I I / / / I / / / 19, , , 19, , , ,,2200,,21,, a / / / t t / / / r i i i / / l / / / , ,21, ab:: ,,5,,68,,77,, ,,9,,1100,,1111,, a: ,,, 2 2 0 0 ,,,2211,,, a , 21, b : , , ,21,a: ,19,20,21, ,19,20, , a: a , 21, a: , , , , , , , 8 , a: , , , , , , , , , 21, 't' SSpMy B a rttfe e i Coes no! contain TSCA 'CBS -72- H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP II: 50 MG/KG/DAY ANIMAL OBSERVATION NUMBER: INDIVIDUAL CLINICAL OBSERVATIONS3 DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 646286 ALOPECIA LEFT FRONT PAW ALOPECIA LEFT FRONT LEG SACRIFICED BY DESIGN 3/21/01 646291 SACRIFICED BY DESIGN 03/22/01 646296 SACRIFICED BY DESIGN 03/22/01 646297 ALOPECIA BOTH FRONT LEG ALOPECIA ABDOMINAL ALOPECIA BASE TAIL SACRIFICED BY DESIGN 03/22/01 646298 ALOPECIA BOTH FRONT PAW ALOPECIA BOTH FRONT LEG SACRIFICED BY DESIGN 03/22/01 ba:: ,, ,, ,, ,, ,, ,, ,, La:: ,, ,, ,, ,, ,, ,, ,, a: , , , , , , , a: , , ,13,14,15,16,17,18,19,20,21, , ,12,13,14,15,16,17,18,19,20, , , ,13,14,15,16,17,18,19,20,21, , , ,13,14,15,16,17,18,19,20, , , , , , , , , , / ,21, ,21, a: , 2 1 , I t i l i I ,12,13,14,15,16,17,18,19,20,21, I t i t i I ,12,13,14,15,16-,17,18,19,20, / I I I 1 ,18,19,20,21 Il II ! ! 1 1 ! I 1 ,18,19,20, Itili I 1 1 1 1 1 ,18,19,20,21 Ititi / 1 1 I 1 1 ,18,19,20, Itili I 1 I 1 1 1 , , , ,21 a: / / b: / / a: / 1 b: l 1 a: 1 1 , ,, , ,9,10,11,12,13,14,15,16,17,18,19,20,21, , ,, , ,9,10,11,12,13,14,15,16,17,18,19,20,, / , , , , ,10,11,12,13,14,15,16,17,18,19,20,21, , ,, , , ,10,11,12,13,14,15,16,17,18,19,20,, , , , , , , , , , / / / / ' ' ' I21 Company Sanitized. Doesnot contain TSCCSI -73- H-24516: Developmental Toxicity Study in Rats _ DuPont-5991 GROUP II: 50 MG/KG/DAY ANIMAL OBSERVATION NUMBER: INDIVIDUAL CLINICAL OBSERVATIONS3 DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 646300 ALOPECIA BOTH FRONT PAW ALOPECIA RIGHT FRONT LEG ALOPECIA BOTH FRONT LEG SACRIFICED BY DESIGN 03/22/01 646306 ALOPECIA RIGHT FRONT PAW ALOPECIA BOTH FRONT PAW SACRIFICED BY DESIGN 03/22/01 a: / / t' t i' t i l t b: i / i' r tf t i i i a : / / i' t if i l l ! b: t / i' t jf i l l i a: / f i' t tf i l l i b: i t r if i l l i a: t t i r tf i l l i , ,12, 14, 15, 16, 17, 18,19, 20,21, i /3-2/13, 14, 15, 16, 17, 18,19, 20, , i i t / / I ! 1 1 / / t iti iti iti ili , /15, / / ! ! / ! / / 116, 17, 18,19, 20,21, / 1 , 16, 17, 18,19, 20, , / 1 ! / 1 ! ! /2X / a : / / i' ! Jf i l l i a : / / i' t jf i l l i a: r i i' / tf l i t ! ill iii iii ! 115, / 1 1 l / / / / t / 1 t / ,21, ! / / / / / / ,21, 'pazmugs AusdiH.f%| U) DooI*ocn** o>Ow- -74- H-24516: Developmental Toxiciiy Study in Rats DuPont-5991 GROUP III: 200 MG/KG/DAY ANIMAL NUMBER: OBSERVATION INDIVIDUAL CLINICAL OBSERVATIONS9 DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 646222 SACRIFICED BY DESIGN 03/19/01 646228 ALOPECIA LEFT FRONT PAW ALOPECIA BOTH FRONT PAW SACRIFICED BY DESIGN 03/19/01 a: I f I I t l ! bbaaa::::: till t I I I I I , 21, ,,,,, ,,,,,1188,,,,,1199,,,,,2200,,,,,2211,,,,, 646232 ALOPECIA BOTH FRONT PAW ALOPECIA BOTH FRONT LEG ,14,15,16,17,18,19,20,21, ,14,15,16,17,18,19,20, , , , ,16,17,18,19,20,21, , , ,16,17,18,19,20, ALOPECIA ABDOMINAL , , , , ,18,19,20,21, i i i i i 18,19,20, , SACRIFICED BY DESIGN 03/19/01 O 646234 -O30o) SACRIFICED BY DESIGN 03/19/01 9- i t t i iitt / t i l l / / t t 21, tn a:*3S 646237 SACRIFICED BY DESIGN 03/19/01 I I I t i l l It I IIIII I 1 . 1 I 21, MOaboo<n3 646238 ALOPECIA RIGHT SIDE SACRIFICED BY DESIGN 03/19/01 baa::: ,15,16,17,18,19,20,21, 71,15,16,17,18,19,20, / I I I I ! /**/ 646243 ALOPECIA BOTH FRONT PAW SACRIFICED BY DESIGN 03/20/01 a : t / / t t t ! / / f / / ,14,15,16,17,18,19,20,21, b : / / i i / / / / / / / / ,14,15,16,17,18,19,20, a / / t i i i i i / / / / , , , / / / * ,21, UtfUX s^ uuuu -75- 3 H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP III: 200 MG/KG/DAY ANIMAL OBSERVATION NUMBER : .*m53' *WKtN0 oo QOo1S2T >3 > 646248 SACRIFICED BY DESIGN 03/20/01 646254 ALOPECIA BOTH FRONT PAW SACRIFICED BY DESIGN 03/20/01 646258 SORE MOUTH SACRIFICED BY DESIGN 03/20/01 646259 SACRIFICED BY DESIGN 03/20/01 646266 ALOPECIA ABDOMINAL ALOPECIA RIGHT HIND QUARTERS ALOPECIA RIGHT SIDE ALOPECIA BOTH FRONT PAW SACRIFICED BY DESIGN 3/21/01 646268 SACRIFICED BY DESIGN 3/21/01 646269 ALOPECIA BOTH FRONT LEG SACRIFICED BY DESIGN 3/21/01 INDIVIDUAL CLINICAL OBSERVATIONS3 DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 a: i t i t i / ! ! I I I I l I I ! ! !2 1 , ba:: a: a: t i i t i i i i i / , , ,15,16,17,18,19,20,21, , , ,15,16,17,18,19,20, , / , t / t i t /21/ ,,,2200,,,2211,,, iii iiii ,! !2 1 ,11,12,13,14,15,16,17,18,19, , , ,11,12,13,14,15,16,17,18,19, ,11,12,13,14,15,16,17,18,19,20,21, ,11,12,13,14,15,16,17,18,19,20, , , , , , , / ,17,18,19,20,21, , , , , , ,16,17,18,19,20, , , , / / ti / ! t I II Itili t t i ,20,21, I l I i t li I 70 f, 21,, a: i i i i tilt / , i i i iiii ,21, a: i i I t i l i ! I ! , ,13,14,15,16,17,18,19,20,21, b: ! I l I I ! , , , , , ,13,14,15,16,17,18,19,20, a: , , , , , , t i t , , / , , , , , , , ,21, H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP III: 200 MG/KG/DAY ANIMAL OBSERVATION NUMBER: INDIVIDUAL CLINICAL OBSERVATIONS3 DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 646271 ALOPECIA BOTH FRONT LEG SACRIFICED BY DESIGN 3/21/01 ab:: a: 646273 ALOPECIA BOTH FRONT PAW SACRIFICED BY DESIGN 3/21/01 ab:: a: 646285 SACRIFICED BY DESIGN 3/21/01 a 646299 ALOPECIA BOTH FRONT PAW a: STAIN PERINEUM YELLOW a: e SACRIFICED BY DESIGN 03/22/01 a: 3 646302 ALOPECIA BOTH FRONT LEG ALOPECIA BOTH FRONT PAW ALOPECIA LEFT FRONT LEG SACRIFICED BY DESIGN 03/22/01 646303 SACRIFICED BY DESIGN 03/22/01 a: 646305 SACRIFICED BY DESIGN 03/22/01 a: ,17,18,19,20,21, ,, 17,, 18,i19,i20,,21, ,, 2200,, 21,, , ,21, , 21, , 21, ,21, , 21, , ,14, ,16,17,18,19,20,21, , ,14, ,16,17,18,19,20, , , ,15,16,17,18,19,20,21, , , ,15,16,17,18,19,20, , , 21, , 21, ,2 1 , 1 8 0 VOSjLUjBjuoo}0Usaoa -77- H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP III: 200 MG/KG/DAY ANIMAL NUMBER: OBSERVATION 646307 TOP TEETH MISSING SACRIFICED BY DESIGN 03/22/01 INDIVIDUAL CLINICAL OBSERVATIONS3 DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 a: , i i i t t , ,9,10,,11,12,13,14,15, /I I 1 b: t t r I r , ,9,10,,11,12,13,14, , , 1 1 1 1 a: i i i i i III 1 / I l 1 / / I 1 , ,21 CompanySanitized, Does notconi; >3 -78- H-24516: Developmental Toxicity Study in Rats Hf DuPont-5991 GROUP IV: 500 MG/KG/DAY ANIMAL OBSERVATION NUMBER: INDIVIDUAL CLINICAL OBSERVATIONS3 DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 646221 STAIN PERINEUM YELLOW SACRIFICED BY DESIGN 03/19/01 646223 STAIN PERINEUM YELLOW SACRIFICED BY DESIGN 03/19/01 646233 ALOPECIA BOTH FRONT PAW SACRIFICED BY DESIGN 03/19/01 646239 SACRIFICED BY DESIGN 03/19/01 646240 ALOPECIA BOTH FRONT PAW STAIN PERINEUM YELLOW SACRIFICED BY DESIGN 03/19/01 646244 SACRIFICED BY DESIGN 03/20/01 646247 SACRIFICED BY DESIGN 03/20/01 646255 SACRIFICED BY DESIGN 03/20/01 a: i t i I I I ! 1 t 1 I l l / / ,17, 1 1 1 1 b: / / ! 1 / / / ! / ! t i l 1 t ,17, f 1 1 1 a : I l l / / / / / / ! I I t ! I I / 1 , ,21, a: I I I l 1 / ! / 1 ! I I I 1 I 1 1 ,19 ,20,21, b: I I I 1 / / t 1 1 / I I I ! ! 1 1 ,19 ,20, , a: I I I / / 1 1 1 / 1 t I 1 1 1 l / 1 , ,21, a: I I I b: I I I a: I I I / / / / ,9, 10, 11,12,13,14 ,15, 16,17,18 ,19 ,20,21, / I 1 1 , 9 , 10, 11,12,13,14 ,15, 16,17,18 ,19 ,20, , 1I 1I 1! ! I I I I 1 / 1 I , ,21, a: I I I 1 ! 1 1 1 1 I I I I 1 I 1 1 / , ,21, a: I I I ! / I 1 1 1 1 / ! 1 ,15, / / 1 / / b: I I I / t 1 I 1 I l 1 1 l ,15, / I ! t I a: / ! ! I 1 1 t l I l 1 1 1 / / / / ! t ,2X a : I l l 1 1 / l I 1 1 t 1 1 / / 1 1 I I / 21 a : I I I ! 1 1 1 l ! 1 1 1 t / / I 1 1 , ,21 a: I I I 1 I 1 1 ! / ! I I I 1 1 I 1 I , ,21 a: I I I 1 1 1 1 / / ! I I I 1 I I 1 ! , ,21 Company Sanitized. Does notcontain TSCACBI -79- H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP IV: 500 MG/KG/DAY ANIMAL NUMBER: OBSERVATION INDIVIDUAL CLINICAL OBSERVATIONS^ DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 twdmoff. ALOPECIA BOTH FRONT LEG ALOPECIA BOTH FRONT PAW SACRIFICED BY DESIGN 03/20/01 646262 ALOPECIA BOTH FRONT PAW STAIN PERINEUM YELLOW WET PERINEUM SACRIFICED BY DESIGN 03/20/01 646263 SACRIFICED BY DESIGN 03/20/01 646270 ALOPECIA BOTH FRONT PAW SACRIFICED BY DESIGN 3/21/01 646275 STAIN PERINEUM YELLOW SACRIFICED BY DESIGN 3/21/01 646277 STAIN PERINEUM YELLOW STAIN PERIORAL RED SACRIFICED BY DESIGN 3/21/01 a: t t i t i i t 8,9,10,11, 12,13,14, 15,16, 17,18,19,20,21 b: t t i i i i^ i ,9,10,11, 12,13,14, 15,16, 17,18,19,20, a: , i i t i t i ,9,10,11, 12,13,14, 15,16, 17,18,19,20,21 b: t t I l I I !8,9,10,11, 12,13,14, 15,16, 17,18,19,20, a: , t I t i l i I l / I I I , / / / , , ,21 a: i t Il II ! It b: i i I l I I ! I l a: i i I l I I t I l b: / / f i l l i I l a: / , I t i l i Il b: / / I t i l i I l a: , , I l ! ! ! I l f 112,13,14, 15,16, 17,18,19,20,21 ! 112,13,14, 15,16, 17,18,19,20, ! I I I I 15, , / ,19,20,21 ! I I I I ! ! / , ,20, ! / , , , ! 1 I , /20, / / , , / 1 1 ! , ,20, t / I I I I ! ! , , ,21 a : , i I t i l i I l 1 I I I I / / ! , , ,21 a: / / t t ,6,71 8,9,10,11, 12,13,14, 15,16, 17,18,19,20,21 b: / , , , ,6,7, 8,9,10,11, 12,13,14, 15,16, 17,18,19,20, a: , t i i r t t t i i t I I I / ! / , , ,21 a: i t i t t i . t i b: / / i t i l i t i a: / t i i i i i t i t i III i i III i i III ! 1 1 , ,20,21 ! / 1 , ,20, / / ! , , ,21 a: f r i t i l i i , ,11, 12, , ,15, , / ,19,20,21 b: t t i t i l i , , ,11, 12,13, ,15, , 1 ,19,20, a: t f i i i i i t i i , I I I l ! 1 , , ,21 a : t / i i i i i t i t i I I I ! / I , , ,21 -80- .tfUJOOlou sao_a jyy H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL CLINICAL OBSERVATIONS3 GROUP IV: 500 MG/KG/DAY ANIMAL OBSERVATION DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED NUMBER: 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 sssssssssssss:==:ss=====:=s===:s=====:=:s:ss=:==s============= ======== === 646281 ALOPECIA BOTH FRONT PAW ALOPECIA RIGHT FRONT PAW ALOPECIA BOTH FRONT LEG STAIN PERINEUM YELLOW SACRIFICED BY DESIGN 3/21/01 646283 SACRIFICED BY DESIGN 3/21/01 646287 ALOPECIA RIGHT FRONT PAW ALOPECIA BOTH FRONT PAW STAIN PERINEUM YELLOW SACRIFICED BY DESIGN 03/22/01 646289 ALOPECIA RIGHT SHOULDER STAIN PERINEUM YELLOW SACRIFICED BY DESIGN 03/22/01 a / / t i l l ,8, b t / t i l l ,8, a / / III! ! ! b t t till 1 1 a / t lilt I t b f t till ! / a t/1I11// b / / till / 1 a: / > III 1 I 1 a / / t i l l 1 ! ,13,14,15,16,17,18,19,20,21, ,13,14,15,16,17,18,19,20, ,,1111,,1122,, , ,17,18,19,20,21, ,16,17,18,19,20, ,, ,, ,, ,,1199,, 21,, 21 , 21, a / / t i l l b * it t i l l a il t i l l b / t i l l a / ! t i l l a * /,/ t i l l // /! // !! /! !I ,15, ,16,17,18,19, ,16,17,18,19, , 21, ,,, 2 2 11,,, a* / / t i l l b 11 t i l l a II l i l t b / t i l l a II I I I ! 11 ! ! ! !/ ,,2200,,21,, , , 21, 646293 ALOPECIA LEFT FRONT PAW SACRIFICED BY DESIGN 03/22/01 a It I I I ! / b II t i l l I a* It l i l t ! / ,18,19,20,21, ,, 18,,19,,20,,21,, 103 VOSI IMBUIOS10USSO<| *R9Z|li*fS.^MS-diUO^ -81 - H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP IV: 500 MG/KG/DAY ANIMAL NUMBER: OBSERVATION 646295 ALOPECIA BOTH FRONT PAW SACRIFICED BY DESIGN 03/22/01 646301 SACRIFICED BY DESIGN 03/22/01 646304 SACRIFICED BY DESIGN 03/22/01 INDIVIDUAL CLINICAL OBSERVATIONS9 DAYS OF GESTATION ON WHICH SIGN WAS OBSERVED 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 a: I l I I I I I I ! ! ! ! I I ,16,17,18,19, b: a: IIIIIIIlI //////// / I / I / / / / / I ,16,17,18,19, IIIII , 21, a: I II I I II ! I t I I I I I I , 21, a: I I I I I I I I I I I / / / t I / / , 21, -82- H-24516: Developmental Toxicity Study in Rats DuPont-5991 APPENDIX E Gross Postmortem Findings CoWoan^ San -83- H-24516: Developmental Toxicity Study in Rats Gross Postmortem Findings ' ExplanatoryNotes Abbreviations NAD = No Abnormalities Detected DuPont-5991 2) contain TSCA -84- H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROSS POSTMORTEM FINDINGS Group I: 0 mg/kg/day NAunmimbaelr Dam Code Structureis) Findinefs') 666666666666666666666644444444444444444444446666666666666666666666222222322222222222222264576072555788939923821118585626722826046044 442442236355557888117213113860109206242742 Perineum MassNNNNNNNNNNNNNNNNNNNNN2AAAAAAAAAAAAAAAAAAAAAxDDDDDDDDDDDDDDDDDDDDD1.5 cm Company Sanitized. Does not cwW" T*CA' -85- H-24516: Developmental Toxicity Study in Rats GROSS POSTMORTEM FINDINGS Group II: 50 mg/kg/day NAunmimbaelr Dam Code Structure(s) 666666666666666666666644444444444444444444446666666666666666666666222222222222222222223332324454459667788999001579523691074490667806 22322211656558887848565833747638412536850 DuPont-5991 Finding(s) NNNNNNNNNNNNNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAADDDDDDDDDDDDDDDDDDDDDD -86- H-24516: Developmental Toxicity Study in Rats GROSS POSTMORTEM FINDINGS DuPont-5991 Group HI: 200 mg/kg/day NAunmimbaelr Dam Code 666666666666666666666644444444444444444444446666666666666666666666222222222222222223233322343733455657686090008322184788983465939527 244434113554614768679312452913600775980786 Structureis') Findinefs) NNNNNNNNNNNNNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAADDDDDDDDDDDDDDDDDDDDDD Company Sanitized. Uoes fttrf contain TSC GBI -87- H-24516: Developmental Toxicity Study in Rats GROSS POSTMORTEM FINDINGS Group IV: 500 mg/kg/day NAunmimbaelr Dam Code- Structurefs) 666666666666666666666644444444444444444444446666664666666666666666222222222222222232222322353446468767780998801335903417052107335794 333332615661167777778187685295944910635749 ' DuPont-5991 Findineis) NNNNNNNNNNNNNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAADDDDDDDDDDDDDDDDDDDDDD H-24516: Developmental Toxicity Study in Rats DuPont-5991 APPENDIX F Individual Reproductive Data Company Sanitizes. Does not contatoTorn m l -89- H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP I: 0 MG/KG/DAY ANIMAL CORPORA NIDA NUMBER LUTEA TIONS INDIVIDUAL REPRODUCTIVE DATA RESORPTIONS TOTAL EARLY LATE DEAD LIVE FETUSES MEAN FETAL FETUSES TOTAL FEMALE MALE WEIGHT (G) 646224 17 14 1 1 0 0 13 6 7 5.70 646225 15 14 1 1 0 0 13 9 4 5.69 646226 18 17 0 0 0 0 17 7 10 5.59 646230 23 15 0 0 0 0 15 9 6 5.28 646236 15 13 0 0 0 0 13 8 5 5.94 646241 17 16 0 0 0 0 16 7 9 5.68 646251 19 14 0 0 0 0 14 11 3 5.51 646252 16 15 0 0 0 0 15 5 10 5.26 646256 13 13 1 1 0 0 12 6 6 5.79 646257 16 14 2 2 0 0 12 5 7 5.67 646261 16 12 1 1 0 0 11 8 3 5.63 646265 18 12 0 0 0 0 12 6 6 5.13 646272 15 13 0 0 0 0 13 8 5 5.80 646276 17 . 15 0 0 0 0 15 6 9 5.29 646278 15 13 0 0 0 0 13 11 2 5.52 646282 17 15 0 0 0 0 15 11 4 5.91 646284 18 13 0 0 0 0 13 7 6 5.76 646288 17 15 0 0 0 0 15 8 7 5.55 646290 16 14 0 0 0 0 14 6 8 5.30 646292 17 15 0 0 0 0 15 8 7 5.25 646294 16 15 1 1 0 0 14 5 9 4.67 646308 17 16 1 1 0 0 15 10 5 5.82 'Company Sanitized. Does not conta* H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP II : 50 MG/KG/DAY ANIMAL CORPORA NIDA NUMBER LUTEA TIONS INDIVIDUAL REPRODUCTIVE DATA RESORPTIONS TOTAL EARLY LATE DEAD LIVE FETUSES MEAN FETAL FETUSES TOTAL FEMALE MALE WEIGHT (G) 646227 17 16 1 1 0 0 15 12 3 5.13 646229 16 14 0 0 0 0 14 11 3 5.53 646231 20 18 2 2 0 0 16 12 4 5.28 646235 17 14 0 0 0 0 14 9 5 5.69 646242 14 14 1 1 0 0 13 6 7 5.21 646245 14 12 0 0 0 0 12 8 4 5.30 646246 17 16 0 0 0 0 16 8 8 5.66 646249 12 12 0 0 0 0 12 6 6 5.78 646250 20 18 1 0 1 0 17 10 7 5.28 646253 16 15 0 0 0 0 15 7 8 5.78 646264 17 15 0 0 0 0 15 10 5 5.40 646267 17 16 1 1 0 0 15 7 8 5.11 646274 17 14 0 0 0 0 14 5 9 5.46 646279 18 15 0 0 0 0 15 7 8 5.41 646280 16 15 0 0 0 0 15 9 6 5.61 646286 17 17 0 0 0 0 17 7 10 5.83 646291 14 11 1 1 0 0 10 6 4 6.27 646296 15 13 0 0 0 0 13 5 8 5.46 646297 16 16 1 1 0 0 15 5 10 5.71 646298 17 16 0 0 0 0 16 7 9 5.31 646300 16 15 0 0 0 0 15 11 4 5.41 646306 23 14 1 0 1 0 13 7 6 5.57 ' m m m 'Sanitized. Does HotcontainTSCCBi H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP III: 200 MG/KG/DAY ANIMAL CORPORA NIDA NUMBER LUTEA TIONS INDIVIDUAL REPRODUCTIVE DATA RESORPTIONS TOTAL EARLY LATE DEAD LIVE FETUSES MEAN FETAL FETUSES TOTAL FEMALE MALE WEIGHT (G) 646222 13 12 0 0 0 0 12 6 6 5.40 646228 14 14 0 0 0 0 14 8 6 5.90 646232 19 12 0 0 0 0 12 7 5 5.27 646234 17 15 0 0 0 0 15 10 5 5.14 646237 21 17 0 0 0 0 17 9 8 5.20 646238 12 11 0 0 0 0 11 3 8 5.52 646243 20 14 0 0 0 0 14 7 7 5.20 646248 16 15 0 0 0 0 15 5 10 5.52 646254 19 18 0 0 0 0 18 10 8 5.11 646258 17 14 0 0 0 0 14 8 6 5.19 646259 22 14 0 0 0 0 14 8 6 5.50 646266 18 15 1 1 0 0 14 8 6 5.25 646268 18 15 0 0 0 0 15 3 12 5.35 646269 21 18 0 0 0 0 18 10 8 5.29 646271 15 13 0 0 0 0 13 7 6 5.49 646273 16 15 0 0 0 0 15 8 7 5.40 646285 14 12 1 1 0 0 11 5 6 5.56 646299 15 15 1 1 0 0 14 5 9 5.38 646302 12 12 0 0 0 0 12 11 1 5.46 646303 17 17 0 0 0 0 17 9 8 5.40 646305 12 9 1 1 0 0 8 44 4.99 646307 17 16 0 0 0 0 16 6 10 5.26 Company Sanitized. Does not contain TSCACB -92- H-24516: Developmental Toxicity Study in Rats DuPont-5991 GROUP IV: 500 MG/KG/DAY ANIMAL CORPORA NIDA- NUMBER LUTEA TIONS INDIVIDUAL REPRODUCTIVE DATA RESORPTIONS TOTAL EAR] LATE DEAD LIVE FETUSES MEAN FETAL FETUSES TOTAL FEMALE MALE WEIGHT (G) 646221 13 11 1 1 0 0 10 6 4 5.46 646223 16 14 0 0 0 0 14 8 6 5.65 646233 16 15 0 0 0 0 15 10 5 5.40 646239 16 15 1 1 0 0 14 6 8 5.70 646240 18 15 0 0 0 0 15 9 6 5.66 646244 15 12 4 4 0 0 8 5 3 5.54 646247 18 15 0 0 0 0 15 7 8 5.13 646255 16 13 0 0 0 0 13 5 8 5.88 646260 19 18 0 0 0 0 18 10 8 5.02 646262 15 14 1 1 0 0 13 6 7 4.51 646263 17 17 1 1 0 0 16 7 9 5.36 646270 15 15 0 0 0 0 15 9 6 5.58 646275 16 15 1 1 0 0 14 7 7 5.48 646277 15 . 15 0 0 0 0 15 7 8 4.61 646281 15 15 0 0 0 0 15 11 4 4.29 646283 14 12 0 0 0 0 12 7 5 6.15 646287 14 14 0 0 0 0 14 8 6 5.42 646289 18 16 0 0 0 0 16 6 10 5.69 646293 19 17 0 0 0 0 17 10 7 5.57 l l 646295 15 14 0 0 0 0 14 6 8 5.59 s 646301 14 12 0 0 0 0 12 7 5 5.35 at. 646304 13 12 0 0 0 0 12 7 5 5.26 HC&, al does Wei contain 1 6CA r-'' -93- H-24516: Developmental Toxicity Study in Rats DuPont-5991 APPENDIX G Individual Fetal Weights and Alterations BTdmpaftySanitized. Does not contain TSCACBI -94- H-24516: Developmental Toxicity Study in Rats DuPont-5991 Individual Fetal Weights and Alterations Explanatory Notes a mNaorksekdelwetiatlhetvhaislufaotoiotnnowteaws deroenedifsoarrttihceuslaetfeedt.uses; due to technical error, the fetal skeletons For ease ofrecording, many ofthe findings have been abbreviated or coded, as listed below: bacNIlrtuhttreiAlnD -- ========= baNrtNcllheuireigofolcomnathhrttADbatr(euecabrasimarntc)aloormr caelnittireas Detected * Subcutaneous hemorrhage that was not present in utero. Renal papillary sizes refer to papillary development using the scheme ofWoo and Hoar. Alterations are classed as: NVMDVR ==== DVMNoeaavrtleifeasoltorimopnmatdeiuonentastloVaRrieattaiordnesd Development Numbers are used to: IIRSndpedeefniecctriaiffttyyoessrskepkuneelacllelifbtpiaocalnpspeitoleslsmaairtceyicobosnrirazdfeoinrgritbostohrevfeorltleobwraing key: 4235671....... INPFPMZnarryatoaeregsimxnraeopitltmaalaallxalraiileltaal 981111..0132.... TBEHSSqyuxayumsopoiacriopemdccaoicponciisicptcaiaipltlaaintlanlulus *xx0t VIts c -95- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KG/DAY DAM NO./ FETUS NO,. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646224 1 2 3 4 5 6 7 8 9 10 11 12 13 5.60 5.60 5.83 5.74 5.90 5.43 5.79 5.96 5.61 5.31 5.63 5.59 6.12 Vertebra Vertebra Sternebra Vertebra Kidney Vertebra Vertebra Vertebra Vertebra Vertebra Retarded Ossification (cen thll,12} Retarded Ossification (cen thll,12) Retarded Ossification (4) Retarded Ossification (cen thl2) Papilla - Size 3 (rt) Retarded Ossification (cen thl2) NAD Retarded Ossification (cen thll) NAD Retarded Ossification (cen thl2) NAD Retarded Ossification (cen thll) Retarded Ossification (cen th8,ll) VR VR VR VR VR VR VR VR VR VR 646225 1 2 3 4 5 6 7 8 6.01 5.69 5.76 5.94 5.77 5.64 6.21 5.48 Vertebra Vertebra Vertebra Vertebra Vertebra NAD Retarded Ossification (cen thl2) NAD Retarded Ossification (cen thl2) NAD Retarded Ossification (cen thl3) Retarded Ossification (cen thll-12) Retarded Ossification (cen thll-12) VR VR VR VR VR CotnpaannVvSanWzed' D08S -96- .,,Tcr H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KG/DAY ' DAM NO./ FETUS NO. FETUS WT . STRUCTURE FINDING(S) CLASSIFICATION 646225 (Cont.) 9 5.34 10 5.79 11 5.70 12 4.74 13 5.94 Vertebra Vertebra Kidney Vertebra Retarded Ossification (cen thl2) NAD Retarded Ossification (cen thll) NAD Small Papilla - Size 2 (bilateral) Retarded Ossification (cen thlO,11) VR VR VR VR ' 646226 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 5.63 5.33 5.54 5.66 5.43 4.68 5.67 5.45 5.25 5.55 6.10 5.87 5.70 5.73 5.62 5.98 5.85 Vertebra Rib Kidney Vertebra Vertebra Vertebra Rib Rib NAD NAD NAD Retarded Ossification (cen thll) NAD Supernumerary (site thl4 bil) Small Papilla - Size 2 (bil) Retarded Ossification (cen thl2) NAD NAD NAD Retarded Ossification (cen thlO,12) NAD Retarded Ossification (cen thl2) NAD Supernumerary (site thl4 It) Supernumerary (site thl4 It) NAD VR DV VR VR VR VR DV DV 646230 1 5.61 NAD Sanitized,boss ,,0l=0l.taiWC B C B ` ffnpany -97- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) ______ CLASSIFICATION 646230 (Cont.) 2 5.36 3 5.15 4 5.28 5 5.15 6 5.43 7 5.31 8 4.96 9 5.14 10 5.26 11 5.94 12 5.01 13 5.25 14 4.90 15 5.48 Vertebra Vertebra Kidney Vertebra Kidney Vertebra 646236 1 2 3 4 5 6 7 8 9 10 11 12 13 5.88 6.20 5.97 5.83 5.67 5.57 5.81 6.25 5.31 6.15 6.36 6.34 5.83 Vertebra Vertebra Kidney Rib Kidney Retarded Ossification (cen th8,10-12) NAD NAD Retarded Ossification (cen thlO) NAD NAD NAD NAD NAD Papilla - Size 3 (left) Retarded Ossification (cen thlO) NAD NAD Papilla - Size 3 (bilateral) Retarded Ossification (cen thlO) VR VR VR VR VR VR NAD NAD NAD NAD NAD Retarded Ossification (cen thll) * Retarded Ossification (cen th9) NAD Papilla - Size 3 (bil) Rudimentary Cervical (7 rt) NAD NAD NAD Papilla - Size 3 (bil) VR VR VR DV VR SanS*ed oiop**^ -98- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646236 (Cont.) Vertebra Retarded Ossification (cen thll) VR 646241 1 2 5.53 Rib 5.39 Vertebra 3 5.35 4 5.78 Vertebra 5 5.85 Rib Vertebra 6 5.63 7 6.25 8 6.24 Vertebra 9 5.54 10 5.53 11 5.70 Vertebra 12 5.76 13 5.75 14 5.42 15 5.19 Vertebra ') 16 6.02 Vertebra Supernumerary (thl4 site bil) Retarded Ossification (cen thll) NAD Retarded Ossification (cen thlO) Supernumerary (thl4 site It) Retarded Ossification (cen thlO-12) NAD NAD Retarded Ossification (cen thll-12) NAD NAD Retarded Ossification (cen thl2) NAD NAD NAD Retarded Ossification (cen thll) Retarded Ossification (cen thll) DV VR VR DV VR VR VR VR VR 646251 1 2 3 4 5 6 7 5.12 5.51 5.61 5.98 5.49 5.21 5.80 Subcutis Vertebra NAD NAD Hemorrhage (back*) NAD NAD Retarded Ossification (cen thl2) NAD N VR a, BOSS Sanftfe3l W- -99- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S)___________ CLASSIFICATION 646251 (Cont.) 8 5.18 9 5.25 10 5.26 11 5.59 12 5.99 13 5.81 14 5.32 Skull Vertebra Retarded Ossification (6 bil) NAD NAD NAD NAD NAD Retarded Ossification (cen thl3) VR VR 646252 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 646256 1 2 3 4 5.15 5.33 5.59 4.90 Vertebra 5.62 5.86 4.92 5.05 Kidney Vertebra 5.70 5.67 Vertebra 5.24 Vertebra 4.41 4.76 5.48 Skull Vertebra 5.19 5.85 6.28 5.73 5.79 Vertebra Vertebra Kidney NAD NAD NAD Retarded Ossification (cen thl2) Papilla - Size 3 (rt) NAD NAD Retarded Ossification (cen thl2-13) NAD Retarded Ossification (cen thll) Retarded Ossification (cen thll) Retarded Ossification (2 bil) NAD Retarded Ossification (cen thl2) NAD VR VR VR VR VR VR VR Retarded Ossification (cen thll,12,13) Retarded Ossification (cen thl2,13) Small Papilla - Size :2 (bil) NAD VR VR VR Company -100 con,a'nTSCAC H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) ______CLASSIFICATION 646256 (Cont.) 5 6.00 6 5.79 7 5.61 8 6.20 9 5.74 10 5.01 11 5.77 12 5.72 Vertebra Vertebra Vertebra Vertebra Vertebra Vertebra Vertebra Vertebra Retarded Ossification (cen thll,12) Retarded Ossification (cen thll) Retarded Ossification (cen thlO,11,12,13) Retarded Ossification (cen thll) Retarded Ossification (cen thl3) Retarded Ossification (cen thl2) Retarded Ossification (cen thl2,13) Retarded Ossification (cen thlO,13) VR VR VR VR VR VR VR VR 646257 1 2 3 4 5 .6 7 8 9 10 11 12 5.61 5.94 6.12 6.02 5.43 6.44 5.03 5.46 5.42 5.52 5.20 5.90 Kidney Vertebra Vertebra Vertebra Vertebra Kidney Vertebra NAD NAD Papilla - Size 3 (bil) Retarded Ossification (cen thll) NAD Retarded Ossification (cen thll) Retarded Ossification (cen thll) NAD NAD Retarded Ossification (cen thll-12) Small Papilla - Size2 (left) Retarded Ossification (cen thll) VR VR VR VR VR VR VR 646261 1 5.56 NAD - 101 - H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646261 (Cont.) 2 5.94 3 5.74 4 5.78 5 5.12 6 6.09 7 5.81 8 5.36 9 5.30 10 5.61 11 5.60 Vertebra Skull Vertebra Kidney Vertebra NAD NAD Retarded Ossification (cen thll-13) NAD Retarded Ossification (6bil) NAD Retarded Ossification (cen thl2) Papilla - Size 3 (bil) Retarded Ossification (cen thl2) NAD VR VR VR VR VR 646265 1 2 3 4 5 6 7 8 9 10 11 12 646272 1 5.62 5.18 4.67 5.28 5.19 4.85 5.08 5.22 5.13 5.42 4.82 5.11 Vertebra Kidney Vertebra Vertebra Vertebra Vertebra 5.66 Rib NAD Retarded Ossification (cen thlO) Small Papilla - Size 2 (bilateral) NAD Retarded Ossification (cen thll) Retarded Ossification (cen thll-13) NAD Retarded Ossification (cen thl2) NAD NAD NAD Retarded Ossification (cen thll) VR VR VR VR ' VR VR Supernumerary (thl4 site bil) DV empany Sanitized- $ oes not contain TSCA CB1 -102- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646272 (Cont..) 2 5.07 Vertebra 3 6.14 Vertebra 4 5.20 Vertebra 5 5.51 6 5.60 Rib Vertebra 7 5.67 8 5.94 Rib Vertebra 9 5.97 KidneyRib 10 5.92 Rib 11 6.06 Kidney 12 6.06 Rib Vertebra 13 6.63 Kidney 646276 1 2 3 4 5 5.54 5.47 5.18 5.36 4.41 Vertebra 6 5.47 Vertebra 7 5.54 Rib 8 5.46 9 4.50 10 5.64 Rib Retarded Ossification (cen thll-12) Retarded Ossification (cen thl3) Retarded Ossification (cen thlO) NAD _ Supernumerary (thl4 site rt) ,Retarded Ossification (cen thll) NAD 'Supernumerary (thl4 site It) Retarded Ossification (cen thl2) Papilla - Size 3 (It) Supernumerary (thl4 site rt short It) Supernumerary (thl4 site It) Papilla - Size 3 (bil) _ Supernumerary (thl4 site bil) Retarded Ossification (cen thll) Small Papilla - Size 2 (bil) VR VR VR DV VR DV VR VR DV DV VR DV VR VR NAD NAD . ' NAD NAD Retarded Ossification (cen thll,lul) ' Retarded Ossification (cen thll) Supernumerary (th site 14rt) NAD NAD _ Supernumerary (th site 14bil) VR VR DV DV ontalnTSCACBl ted. iJoBSftOi - 103- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646276 (Cont.) 11 12 13 14 15 646278 1 2 3 4 5 6 7 5.42 5.38 5.16 5.28 5.54 6.31 5.70 5.34 5.70 5.38 5.28 5.40 8 9 10 11 12 13 646282 1 5.56 5.53 5.81 5.22 5.06 5.45 5.71 2 6.27 3 5.98 4 5.43 5 6.12 6 6.25 7 5.64 Vertebra Vertebra Kidney Vertebra Vertebra Vertebra Kidney Vertebra Kidney Retarded Ossification (cen thl2) NAD NAD NAD NAD NAD VR NAD NAD NAD Retarded Ossification (cen thll-12) NAD NAD Papilla - Size 3 (bil) Retarded Ossification (cen thll) NAD Retarded Ossification (cen thll-12) NAD Retarded Ossification (cen thl2) NAD NAD VR VR VR VR VR Papilla - Size 3 (bil) Retarded Ossification (cen thll) NAD NAD NAD Small Papilla - Size 2 (left) NAD NAD VR VR VR ^CompanySanitized. Does not contain TSC CPU - 104 H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646282 (Cont.) 8 6.01 9 6.10 Vertebra 10 5.24 Skull Vertebra 11 5.93 Vertebra 12 5.46 Vertebra 13 6.10 Vertebra 14 6.48 15 5.98 646284 1 2 5.66 5.59 Kidney Skull Vertebra 3 5.61 Vertebra 4 5.14 Vertebra 5 5.45 Kidney Vertebra 6 6.14 Vertebra 7 5.69 Vertebra 8 6.48 Vertebra 9 5.44 Kidney Vertebra NAD Retarded Ossification (cen thll,12) Retarded Ossification (2 bil) Retarded Ossification {cen thl2) Retarded Ossification (cen thlO) Retarded Ossification (cen thl2) Retarded Ossification (cen thll) NAD NAD VR VR VR VR VR VR Papilla - Size 3 (bil) Retarded Ossification (6 bil) Retarded Ossification (cen thlO-ll) Retarded Ossification (cen thl2) Retarded Ossification (cen thll-12) Papilla - Size 3 (bil) Retarded Ossification (cen thll) Retarded Ossification (cen thl3) Retarded Ossification (cen thl2) . Retarded Ossification (cen thl3) Small Papilla - Size 2 (bil) Retarded Ossification (cen thlO-12) VR VR VR VR VR VR VR VR VR VR VR VR ULii -105- :o n i a ? n T S C A < ^ fJo H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT.. STRUCTURE FINDING(S) CLASSIFICATION 646284 (Cont..) 10 5.87 Vertebra 11 5.57 12 6.26 Vertebra 13 5.94 646288 1 2 3 4 5.47 5.84 5.65 5.61 Kidney Kidney Vertebra 5 4.87 6 5.33 Vertebra 7 5.63 Vertebra 8 5.65 Vertebra 9 5.73 Vertebra 10 5.58 11 5.17 Vertebra V\ 12 5.42 13 5.46 14 5.94 Skull 15 5.85 Vertebra Retarded Ossification (cen thll-12) NAD Retarded Ossification (cen thll-13) NAD VR VR Small Papilla - Size 2 (left) NAD Papilla - Size 3 (bil) Retarded Ossification (cen thll) NAD Retarded Ossification (cen thlO) Retarded Ossification (cen thl0,ll) Retarded Ossification (cen thl2) Retarded Ossification (cen thlO,12) NAD Retarded Ossification (cen thlO,12) NAD NAD Retarded Ossification (6 It) Retarded Ossification (cen thll) VR VR VR VR VR VR VR VR VR VR 646290 1 2 3 5.41 5.66 5.27 Kidney Vertebra Small Papilla - Size 2 (bil) Retarded Ossification (cen thl2) NAD VR VR CompanySanitized. Does not contain TSCCBt - 106- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646290 (Cont,.) 4 5.67 Vertebra 5 5.50 6 4.91 Subcutis Vertebra 7 5.27 8 5.33 9 4.81 Vertebra 10 4.94 11 5.56 12 5.14 13 5.42 14 5.26 646292 1 2 3 4 5 6 7 8 9 10 11 12a 13 14 15 5.15 5.43 5.43 5.56 5.52 5.21 5.05 4.74 5.37 5.37 5.05 5.29 5.13 5.48 4.96 Kidney Rib Rib Kidney Rib 646294 1 4.89 Retarded Ossification (cen thl2) NAD Hemorrhage (back*) Retarded Ossification (cen thll) NAD NAD Retarded Ossification (cen thll) NAD NAD NAD NAD NAD VR N VR VR Small Papilla - Size 2 (bil) Supernumerary (thl4 site It) NAD NAD Supernumerary (thl4 site bil) NAD NAD NAD NAD Papilla - Size 3 (bilateral) NAD NAD NAD NAD NAD Supernumerary (thl4 site It) VR DV DV VR DV NAD impany Sanitized. Does not contain r<5\ps*~*\V - 107- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE ___________ FINDING(S)__________ CLASSIFICATION 2 3 4 5 6 7 8 9 10 11 12 13 14 646308 1 2a 3 4 5 ea 7 8 9 10 11 12 13 14 4.92 Vertebra 4.02 4.48 5.25 4.61 Vertebra 4.57 4.44 4.82 4.85 Vertebra 4.75 Vertebra 4.79 4.26 Vertebra 4.69 Pelvis Skull 5.59 6.02 6.49 5.65 5.80 5.96 5.85 5.71 5.37 5.85 5.97 5.92 5.60 5.65 Subcutis Vertebra Retarded Ossification (cen thll-12) NAD NAD NAD Retarded Ossification (cen thl2) NAD NAD NAD Retarded Ossification (cen thl0-ll) Retarded Ossification (cen thl2) NAD Retarded Ossification (cen thl2) Retarded Ossification (pubis bil) Retarded Ossification (2 bil) VR VR VR VR VR VR VR NAD NAD NAD NAD Hemorrhage (nose*) NAD NAD NAD NAD NAD NAD NAD NAD Retarded Ossification (cen thll) N . VR Company Sanitized. Goes not contain TSCA CF H-24516: Developmental Toxicity Study in Rats DuPont-5991 , INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE _____________FINDING(S)__________ CLASSIFICATION 646308 (Cont.) 15 5.82 Kidney Small Papilla - Size 2 (bil) VR 'andzeS. Woes ft'e? co-*ar TfCft CF H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP II: 50 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT.. STRUCTURE FINDING(S) CLASSIFICATION 646227 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 646229 1 2 3 4 5 6 7 8 9 5.38 Vertebra 5.17 5.23 5.42 5.48 5.03 5.35 Vertebra 3.18 5.36 5.31 Skull Sternebra Vertebra 5.01 5.33 4.91 5.35 5.40 Brain 5.53 5.88 5.67 5.58 5.49 5.78 5.17 4.96 5.40 Vertebra Vertebra Vertebra Kidney vertebra Vertebra Vertebra Retarded Ossification (cen thlO) NAD NAD NAD NAD NAD Retarded Ossification (cen thll) Retarded Ossification (3 bil) Retarded Ossification (1,4,6) NAD Retarded Ossification (cen thll,13) NAD NAD NAD NAD Distended (ventricles) VR VR VR VR VR M Retarded Ossification (cen thll-12) Retarded Ossification (cen thl0-12) Retarded Ossification (cen thll) NAD Small Papilla - Size 2 (left) Retarded Ossification (cen th7,9-12) Retarded Ossification (cen thlO-12) Retarded Ossification (cen thll) NAD VR VR VR VR VR VR VR Company Sanitized. Does not contain TSCA or H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP II: 50 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646229 (Cont.) 10 5.45 11 5.65 12 5.48 13 5.26 14 6.14 Vertebra Skull Vertebra Vertebra Rib Skull Retarded Ossification (cen thl2) NAD Retarded Ossification (12(6bil) Retarded Ossification (cen thll-12) Retarded Ossification (cen thlO-11) Supernumerary (th site 141t) Retarded Ossification (6bil) VR VR VR VR DV VR 646231 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 5.46 5.79 5.48 5.24 5.77 5.43 5.46 4.68 5.13 5.48 4.95 4.77 5.57 - 5.13 4.93 5.26 Rib Vertebra NAD NAD NAD NAD NAD NAD NAD NAD NAD NAD NAD Supernumerary (th short 13rt) NAD Retarded Ossification (cen th9) NAD NAD DV VR 646235 1 2 3 4 5 5.89 5.71 5.26 5.44 5.39 Vertebra NAD NAD Retarded Ossification (cen th4) NAD NAD VR liofttpar-y ized :d?33 'fio! contain TSCft r-' - Ill - H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP II: 50 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING (S)__________ CLASSIFICATION 645235 (Cont.) 6 5.81 7 5.99 8 5.55 9 5.95 10 5.81 11 5.38 12 5.95 13 5.62 14 5.94 Skull' Kidney Vertebra Vertebra Vertebra Vertebra Retarded Ossification (2 bil) Papilla - Size 3 (It) NAD NAD NAD Retarded Ossification (cen thll) Retarded Ossification (cen thl2) Retarded Ossification (cen thll) Retarded Ossification (cen thll,12) VR VR VR VR VR VR 646242 1 2 3 4 5 6 7 8 5.93 5.04 5.76 5.35 5.01 5.53 4.79 4.23 Kidney Vertebra Vertebra Kidney Vertebra Vertebra Scapula Rib Skull Vertebra Kidney Vertebra Small Papilla - Size 2 (bil) Retarded Ossification (cen thl2) Retarded Ossification (cen thlO) Papilla - Size 3 (bil) Retarded Ossification (cen thll) Retarded Ossification (cen thll) NAD Misshapen (bil) Wavy (5-13 bil) ' Retarded Ossification (1,12 bil) Retarded Ossification (cen thl3) Papilla - Size 3 (bil) Retarded Ossification (cen thll) NAD VR VR VR VR VR VR DV VR VR VR VR VR Company Sanitized. Does no! contain TSCA CB? H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP II: 50 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646242 (Cont.) 9 5.63 Vertebra 10 5.15 11 5.21 12 5.55 Skull Vertebra 13 4.52 646245 1 ,5.00 Kidney Vertebra 2 5.55 3 5.28 Kidney 4 5.46 5 5.77 Kidney 6 5.66 7 5.51 Vertebra 8 3.02 Rib Vertebra j)X Vertebra Skull Sternebra Vertebra 9 6.34 Vertebra 10 5.04 Rib Vertebra 11 5.43 Retarded Ossification (cen th!2) NAD NAD Retarded Ossification (1,6 bil) Retarded Ossification (cen thl2) NAD VR Small Papilla - Size 2 (lt;size 3rt) Retarded Ossification (cen thl2) NAD Small Papilla - Size 2 (rt) NAD Papilla - Size 3 (It) NAD Retarded Ossification (cen thl2) Fused (th3-5 It) Fused (th3-5 arch It) Hemi (cen th3,7) Retarded Ossification (3 bil) Retarded Ossification (1,3-4,6) Retarded Ossification (cen th9~l0,12) Retarded Ossification (cen thlO) Supernumerary (thl4 site rt) Retarded Ossification (cen thl2) NAD VR VR VR VR VR M M M VR VR VR VR DV VR V z T m z * * - tfces Wo!cut,lain TSCA'CBI vSormwr -113- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP II: 50 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646245 (Cont.) 12 5.59 Vertebra Retarded Ossification (cen thll) VR 646246 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 5.77 Vertebra 5.83 Vertebra 5.72 Sternebra Vertebra 5.80 Vertebra 5.36 Vertebra 5.66 Vertebra 5.52 Vertebra 5.62 Vertebra 5.23 Heart &/or Greater Vessels Vertebra 5.04 Vertebra 5.79 Vertebra 5.60 Vertebra 5.90 Subcutis 5.43 Vertebra 6.06 Vertebra 6.31 Skull Retarded Ossification (cen thll) Retarded Ossification (cen thlO-12) Retarded Ossification (3) Retarded Ossification (cen thl0,ll) Retarded Ossification (cen thll) Retarded Ossification (cen thll,13) Retarded Ossification (cen thl2) Retarded Ossification (cen thl0-13) Retarded Ossification (cen thl2) Patent Ductus Arteriosis Retarded Ossification (cen thlO) Retarded Ossification (cen thlO-13) Retarded Ossification (cen thll,12) Retarded Ossification (cen thl2) Hemorrhage (chin*) Retarded Ossification (cen thll-13) Retarded Ossification (cen thll-13) Retarded Ossification (6 It) VR VR VR VR VR VR VR VR VR VR VR VR VR VR N VR VR VR ! CompanySanitized. Does not contain TSCACB |r -114- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP II: 50 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT.. STRUCTURE FINDING(S) CLASSIFICATION 646246 (Cont..) Vertebra Retarded Ossification (cen th.12-13) VR 646249 1 2 3 4 5 6 7 8 9 10 11 12 4.25 Vertebra 6.50 5.80 5.47 Vertebra 5.79 5.73 6.14 Kidney Vertebra 6.30 6.39 Vertebra 5.61 Vertebra 5.90 5.47 Vertebra Retarded Ossification (cen thl2) NAD NAD Retarded Ossification (cen thll-12) Papilla - Size 3 (left) NAD Retarded Ossification (cen thl2) NAD Retarded Ossification (cen thll) Retarded Ossification (cen thll-12) NAD Retarded Ossification (cen thll) VR VR VR VR VR VR VR 646250 1 2 3 4 5 6 7 8 4.90 5.08 5.16 5.66 5.36 5.43 4.99 5.20 Vertebra ' Vertebra Vertebra Vertebra Retarded Ossification (cen thl2) NAD Retarded Ossification (cen thl2) NAD NAD NAD Retarded Ossification (cen thll) Retarded Ossification (cen thll-12) VR VR VR VR WlSpM Sanitoal. * <**O" * * 'TSCA * -115- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP II: 50 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) ________ CLASSIFICATION 646250 (Cont.) 9 5.34 10 4.99 11 5.42 12 5.79 13 5.34 14 5.24 15 5.13 16 5.65 17 5.08 Vertebra Vertebra Vertebra Rib Vertebra Retarded Ossification (cen thl2) Retarded Ossification (cen thl2) NAD NAD NAD Retarded Ossification (cen thll) NAD Supernumerary (site 14rt) Retarded Ossification (cen thl2) VR VR VR DV VR 646253 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 5.45 5.71 6.31 6.03 5.94 5.89 5.35 5.40 5.65 5.72 6.22 5.57 5.73 5.82 5.85 Vertebra Vertebra Vertebra Vertebra Vertebra Vertebra Vertebra NAD NAD Retarded Ossification (cen thll,12) NAD NAD Retarded Ossification (cen thll) Retarded Ossification (cen thll) NAD NAD Retarded Ossification (cen thl2) Retarded Ossification (cen thll) NAD Retarded Ossification (cen thll) Retarded Ossification (cen thl2) NAD VR VR VR VR VR VR VR Igmpriy Sanitized. D oes Hot conan TSCC81 -116- H-24516: Developmental Toxicity Study in Rats DuPont-5991 . INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP II: 50 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT.. STRUCTURE FINDING(S) CLASSIFICATION 646264 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 5.51 5.60 Vertebra 5.96 Kidney Vertebra 5.46 5.15 Vertebra 5.27 Rib Vertebra 5.21 5.18 5.16 5.31 Kidney Vertebra 5.50 5.62 Vertebra 5.17 5.34 5.53 Vertebra NAD Retarded Ossification (cen thl2) Papilla - Size 3 (bil) Retarded Ossification (cen thll,12) NAD Retarded Ossification (cen thll) Supernumerary (thl3 site rt) Retarded Ossification (cen thl2) NAD NAD Small Papilla - Size 2 (It) Retarded Ossification (cen thll) NAD Retarded Ossification (cen thll) NAD NAD Retarded Ossification (cen thll) VR VR VR VR DV VR VR VR VR VR . 646267 1 2 3 4 5 6 7 8 5.26 5.11 4.92 5.30 4.64 5.27 5.16 5.01 Vertebra Vertebra Vertebra Skull Retarded Ossification (cen thll) NAD Retarded Ossification (cen thll-12) NAD . Retarded Ossification (cen thlO) NAD NAD Retarded Ossification (6 bil) VR VR VR VR fcompanySanitized- Ses not contain TSO cRl H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP II: 50 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE ' T FINDING(S)___________CLASSIFICATION 646267 (Cont.) 9 4.71 10 5.29 11 5.50 12 5.29 13 4.86 14 4.91 15 5.37 Kidney Vertebra Vertebra Vertebra Vertebra Vertebra Vertebra Small Papilla - Size 1 (left) Retarded Ossification (cen thl2-13) Retarded Ossification (cen thl0,12) Retarded Ossification (cen thl0,ll) Retarded Ossification (cen thl2) Retarded Ossification (cen thl0,13) NAD Retarded Ossification (cen thll) VR VR VR VR VR VR VR 646274 1 2 3 4 5 6 7 8 9 10 11 12 13 14 5.55 5.46 5.35 5.33 5.33 5.50 6.06 5.35 5.50 5.05 5.24 6.02 5.13 5.53 Vertebra Vertebra Vertebra Kidney Vertebra Vertebra Vertebra NAD NAD NAD Retarded Ossification .(cen thll) NAD NAD Retarded Ossification (cen thlO) NAD NAD Retarded Ossification (cen thl2) Papilla - Size 3 (bil) Retarded Ossification (cen thl2) Retarded Ossification (cen thll-12) Retarded Ossification (cen thl2) NAD VR VR VR VR VR VR VR sani*.Zittii''fSCACQ^ nnlCflS 118- Company S a n $ s` H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP II: 50 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT.. STRUCTURE FINDING(S) CLASSIFICATION 646279 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 5.17 5.71 5.24 Vertebra 5.36 5.53 Vertebra 4.99 5.25 5.56 5.31 Vertebra 5.54 5.89 5.38 5.44 5.61 5.19 Heart &/or Greater Vessels Vertebra Vertebra NAD NAD Retarded Ossification (cen thll) NAD Retarded Ossification (cen thl2) NAD NAD NAD Retarded Ossification (cen thll) NAD NAD NAD Patent Ductus Arteriosis NAD Retarded Ossification (cen thll,13) Retarded Ossification (cen thl2) VR VR VR VR VR VR 646280 1 2 3 4 5 6 5.55 5.77 5.83 5.76 5.67 5.53 Kidney Vertebra Vertebra Vertebra Vertebra Vertebra Vertebra Small Papilla - Size 2 (rt) Retarded Ossification -(cen thll) Retarded Ossification (cen thl2) Retarded Ossification (cen thl2) Retarded Ossification (cen thl2) Retarded Ossification (cen thll-13) Retarded Ossification (cen thl2) VR VR VR VR VR VR VR Company -119- xed. <.,^,11^1W* *<*cntain Tisr.a H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP II: 50 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 7 8 9 10 11 12 13 14 15 646286 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 5.79 6.08 5.61 5.40 5.95 4.99 5.45 5.53 5.19 Vertebra Vertebra Vertebra Vertebra Vertebra Vertebra Vertebra Vertebra Kidney 6.30 5.91 6.21 6.01 5.70 5.51 5.77 6.08 5.43 5.84 5.58 5.81 6.06 5.75 5.74 6.13 5.24 Kidney Rib Retarded Ossification (cen thll-12) Retarded Ossification (cen thl2) Retarded Ossification (cen thl2) Retarded Ossification (cen thl3) Retarded Ossification (cen thl2) Retarded Ossification (cen thl2) Retarded Ossification (cen thlO-12) Retarded Ossification (cen thll-12) Papilla - Size 3 (bil) NAD NAD NAD NAD NAD NAD NAD NAD NAD NAD NAD NAD NAD NAD Papilla - Size 3 (rt) NAD Supernumerary (site 14 It) VR VR VR VR VR VR VR VR VR VR DV CompanySanlifee'd. DoesTM " 1'" " TM '" r " H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AN D ALTERATIONS GROUP II: 50 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT.. STRUCTURE FINDING(S) CLASSIFICATION 646291 1 2 3 4 5 6 7 8 9 10 6.01 6.09 Vertebra Vertebra 6.42 6.32 Vertebra 6.21 Vertebra 6.16 Vertebra 6.36 Vertebra Vertebra 6.34 Vertebra 6.51 Vertebra 6.26 Vertebra NAD Retarded Ossification (cen thll) Retarded Ossification (cen thl2) NAD Retarded Ossification (cen thl2-13) Retarded Ossification (cen thll) Retarded Ossification (cen thll-12) Retarded Ossification (cen thll) Retarded Ossification (cen thl2) Retarded Ossification (cen thll) Retarded Ossification (cen thll) Retarded Ossification (cen thll-12) VR VR VR VR VR VR VR VR VR VR 646296 1 2 3 4 5 6 7 5.17 5.31 5.67 5.72 5.61 5.39 5.28 Vertebra Vertebra Vertebra Vertebra Vertebra Vertebra . Retarded Ossification (cen thl2) Retarded Ossification (cen thll) Retarded Ossification (cen thl0-12) NAD Retarded Ossification (cen thl2-13) Retarded Ossification (cen thlO-13) Retarded Ossification (cen thll) VR VR VR VR VR VR - 121 - Ji' notantiss7 Does cdntatn i s c kCoi H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP II: 50 MG/KG/DAY ' DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646296 (Cont.) 8 5.05 Vertebra 9 5.65 Kidney Vertebra 10 5.34 11 5.55 Vertebra 12 5.57 Vertebra 13 5.68 Rib Vertebra Retarded Ossification (cen thlO) Papilla - Size 3 (bil) Retarded Ossification (cen thll-12) NAD Retarded Ossification (cen thll-12) Retarded Ossification (cen thlO-13) Rudimentary Cervical (7 It) Retarded Ossification (cen thlO) VR VR VR VR VR DV VR 646297 1 2a 3 4 5 6 7 8 9 10 11 12 13 14 15 5.67 5.63 5.80 5.95 5.71 6.25 5.68 Kidney Vertebra 5.89 Vertebra 5.73 5.61 5.82 5.75 5.69 Kidney Abdomen Vertebra 4.69 Vertebra 5.71 Vertebra Small Papilla - Size 2 (rt) NAD NAD NAD NAD NAD Retarded Ossification (cen thl2) Retarded Ossification (cen thll-12) Small Papilla - Size 2 (bil) NAD NAD ' NAD Malformation (umbilical hernia) Retarded Ossification (cen th.9-12) Retarded Ossification (cen thll-12) Retarded Ossification (cen thll-12) VR VR VR VR M VR VR VR fSCA CBl ComPanYSanttzed-0oeS notconta*0 - 122- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) A ND ALTERATIONS GROUP II: 50 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT.. STRUCTURE FINDING(S) CLASSIFICATION 646298 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 5.29 5.33 5.00 5.65 5.28 5.06 5.71 5.28 5.28 5.19 5.51 5.64 5.10 4.96 5.01 5.60 Kidney Vertebra Vertebra Kidney Vertebra Vertebra Vertebra Vertebra Small Papilla - Size 2 (right) NAD Retarded Ossification (cen thll) NAD Retarded Ossification (cen thlO) NAD Papilla - Size 3 (bil) Retarded Ossification (cen thlO-13) Retarded Ossification (cen thll) Retarded Ossification (cen thll) NAD NAD NAD NAD NAD NAD Retarded Ossification (cen thlO-13) VR VR VR VR VR VR VR VR 646300 1 2 3 4 5 6 7 8 9 10 11 12 5.70 5.58 5.45 5.58 5.79 5.16 5.03 5.55 5.14 5.47 5.32 5.37 Skull Vertebra NAD Retarded Ossification (2 bil) NAD NAD NAD Retarded Ossification (cen thlO) NAD NAD NAD NAD NAD NAD VR VR - 123- ICoropany ' alnTSCA'C ^ H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP II: 50 MG/KG/DAY ' DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S CLASSIFICATION 646300 (Cont.) 13 5.37 14 5.32 15 5.39 Vertebra Chin Skull NAD Retarded Ossification (cen thll-12) Micrognathia Micrognathia VR M M 646306 1 2 3 4 5 6 7 8 9 10 11 12 13 5.50 6.08 5.54 5.86 5.25 5.51 6.00 5.53 5.69 5.53 5.30 5.27 5.41 Kidney Skull Vertebra Vertebra Vertebra Vertebra Vertebra Kidney Kidney Small Papilla - Size 2 (It) Retarded Ossification (2 bil) Retarded Ossification (cen thl2) Retarded Ossification (cen thl2) Retarded Ossification (cen thll-13) Retarded Ossification (cen thll) NAD Retarded Ossification (cen thll) Small Papilla - Size 2 (It;size 3rt) NAD Small Papilla - Size 1 (left) NAD NAD VR VR VR VR VR VR VR VR VR - 124- gompany D o.no,con,ainTSCACB, DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 250 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646222 1 2 3 4 5 6 7 8 9 10 11 12 4.85 Vertebra 5.06 Vertebra 5.94 5.30 Skull Vertebra 5.05 Rib Vertebra 4.08 Sternebra Vertebra 5.67 Vertebra 6.30 Rib Sternebra Vertebra 5.95 Rib Vertebra 5.66 5.83 5.09 Kidney Rib Sternebra Vertebra Retarded Ossification (cen thll, lu2) Retarded Ossification (cen thll-13) NAD Retarded Ossification (6rt) Retarded Ossification (cen thl0-ll) Supernumerary (thl3 short rt) Retarded Ossification (cen thl0-12) Retarded Ossification (6) Retarded Ossification (cen thlO-13, lui) Retarded Ossification (cen thl2) Supernumerary (thl3 short rt) Fused (1,2) Retarded Ossification (cen thl0-13) Rudimentary Cervical (7rt) Retarded Ossification (cen thl3) NAD Small Papilla - Size 1 (bil) Supernumerary (thl3 short It) Retarded Ossification (6) Retarded Ossification (cen th9-13) VR VR VR VR DV VR VR VR VR DV DV VR DV VR VR DV VR VR 646228 1 2 3 . 5.69 5.81 6.13 Vertebra Vertebra Vertebra Retarded Ossification (cen thll,12) Retarded Ossification (cen thl2) Retarded Ossification (cen thll) VR VR VR /ontalh TSCA P-' 1 / ,,.,,,,rt `OoSS'UOt gompany Sani^- -125- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) A ND ALTERATIONS GROUP III: 250 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT . STRUCTURE FINDING(S) CLASSIFICATION 646228 (Cont.) 4 6.10 Vertebra 5 5.84 6 5.69 Vertebra Vertebra 7 5.86 Vertebra 8 5.17 Sternebra Vertebra Vertebra 9 5.93 10 5.93 Vertebra 11 5.92 Vertebra 12 6.06 Vertebra 13 6.11 Vertebra 14 6.30 Skull Vertebra Retarded Ossification (cen thll) NAD Retarded Ossification (cen thl2) Retarded Ossification (cen th5) Retarded Ossification (cen thl2) Retarded Ossification (5) Retarded Ossification (arches cel It) Retarded Ossification (cen thll lui) NAD Retarded Ossification (cen thll,12) Retarded Ossification (cen thll) Retarded Ossification (cen thll) Retarded Ossification (cen thl2) Retarded Ossification (8,2 bil) Retarded Ossification (cen thl2) VR VR VR VR VR VR VR VR VR VR VR VR VR 646232 1 2 3 4 5 6 5.13 5.20 5.26 4.69 5.14 5.35 Skull Vertebra Skull Vertebra NAD Retarded Ossification (2 bil) Retarded Ossification (cen thll-12) Retarded Ossification (6 bil) Retarded Ossification (cen thl0,12) NAD VR VR VR VR . CompanySanitized- Doessot " '' S*0' - 126- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 25 MG/KG/DAY ' DAM NO./ FETUS NO. FETUS WT,. STRUCTURE FINDING(S) CLASSIFICATION 64G232 (Cont..) 7 5.33 8 5.42 9 5.64 10 5.59 11 5.42 12 5.05 Vertebra Vertebra Vertebra Vertebra Retarded Ossification (cen thll-12) NAD NAD Retarded Ossification (cen th.11,13) Retarded Ossification (cen thl0-ll) Retarded Ossification (cen thll-12) VR VR VR VR 646234 1 2 3 4 5 6 7 8 9 Y\ 10 /.) 11 T 12 13 14 15 646237 1 2 3 4 5 5.23 5.39 4.46 5.22 5.16 5.01 4.94 5.28 4.93 5.26 5.63 5.31 4.84 5.19 5.28 Vertebra Vertebra Vertebra 5.25 5.36 5.07 5.59 5.46 Vertebra NAD NAD Retarded Ossification (cen thll) NAD NAD Retarded Ossification (cen thl2,13) Retarded Ossification (cen thlO) NAD NAD NAD NAD NAD NAD NAD NAD NAD NAD Retarded Ossification (cen thl2) NAD NAD VR VR VR VR - 127- no'tcontatn xenlsed.'P ;a c B* H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 250 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646237 6 7 8 9 10 11 12 13 14 15 (Cont.) 4.91 4.84 5.45 4.60 5.38 5.46 5.21 5.33 4.74 5.53 16 5.06 17 5.24 646238 1 2 3 4 5.41 5.10 5.56 5.81 5 5.94 6 5.96 7 5.73 8 5.05 9 5.26 10 5.68 11 5.24 * Vertebra Kidney Rib Rib Rib Skull Rib Rib Rib Rib Skull Rib NAD NAD NAD NAD NAD NAD NAD NAD NAD Retarded Ossification (cen thll) NAD Papilla - Size 3 (bil) VR VR Supernumerary (thl4 site bil) Supernumerary (th.14 site bil) NAD Supernumerary (thl4 site bil) Retarded Ossification (6bil) Supernumerary (thl4 site bil) Supernumerary (thl4 site bil) NAD Supernumerary (thl4 site bil) Supernumerary (thl4 site bil) Retarded Ossification (61t) Supernumerary (thl4 site rt;short It) DV DV DV VR DV DV DV DV VR DV 646243 1 2 3 4.73 5.34 5.61 Vertebra Skull Vertebra Retarded Ossification (cen thll) Retarded Ossification (2,6 bil) Retarded Ossification (cen thll) NAD VR VR VR )J Company S a n ity . M no!conta,n - 128- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 250 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING (S) CLASSIFICATION 646243 (Cont.) 4 5.71 Vertebra 5 5.30 Vertebra 6 5.43 Skull Vertebra 7 5.54 8 4.19 Skull Vertebra 9 6.26 10 5.95 11 4.60 12 4.88 13 4.71 Vertebra 14 4.59 Skull Retarded Ossification (cen thll) Retarded Ossification (cen thl0-ll) Retarded Ossification (6 bil) Retarded Ossification (cen thl0-ll) NAD Retarded Ossification (2 bil) Retarded Ossification (cen thll-12) NAD NAD NAD NAD Retarded Ossification (cen thl2) Retarded Ossification (6 bil) VR VR VR VR VR VR VR VR 646248 1 2 3 4 5 6 7 8 9 10 11 12 13 5.52 5.33 5.95 5.74- Kidney Vertebra 5.69 5.20 Vertebra 5.68 5.56 5.51 5.61 Skull Vertebra 4.99 Vertebra 5.20 Skull 6.16 NAD NAD Papilla - Size 3 (bilateral) Retarded Ossification (cen thl0,13) NAD Retarded Ossification (cen thl2) NAD NAD NAD Retarded Ossification (6bil) Retarded Ossification (cen thl3) Retarded Ossification (cen thl2) Retarded Ossification (6bil) NAD VR VR VR VR VR VR VR -129- contain f S 'CA'CBl H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 250 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S)___________ CLASSIFICATION 646248 (Cont.) 14 5.43 15 5.20 646254 1 2 3 4 5.20 4.37 4.43 4.69 Vertebra Vertebra Vertebra Skull Vertebra 5 4.38 6 5.82 7 5.53 8 4.99 Skull Vertebra 9 5.32 10 5.04 Vertebra 11 4.73 12 5.82 13 5.62 14 5.61 Skull 15 5.43 16 5.16 17 4.87 Vertebra 18 4.95 Skull NAD NAD Retarded Ossification (cen thl0-ll) Retarded Ossification (cen thll) Retarded Ossification (cen thl2) Retarded Ossification (l,12,6bil) Retarded Ossification (cen thl0-ll,lul) NAD NAD NAD Retarded Ossification (1,12 ;2,6-8bil) Retarded Ossification (cen thll) NAD Retarded Ossification (cen thl2) NAD NAD NAD Retarded Ossification (6bil) NAD NAD Retarded Ossification (cen thl2) Retarded Ossification (12 ;6bil) VR VR VR VR VR VR VR VR VR VR VR 646258 1 4.97 Kidney Papilla - Size 3 (bil) VR -130- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) A ND ALTERATIONS GROUP III: 250 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646258 (Cont.) 2 5.00 Vertebra 3 5.18 Vertebra 4 5.32 Vertebra 5 5.10 Vertebra 6 4.60 Skull Vertebra 7 4.75 Vertebra 8 5.19 Vertebra 9 5.18 Vertebra 10 5.26 Vertebra 11 6.38 12 5.83 Vertebra 13 4.54 14 5.38 Vertebra Retarded Ossification (cen thl0-ll) Retarded Ossification (cen th9-10,12) Retarded Ossification (cen thl2-l3) Retarded Ossification (cen thl2) Retarded Ossification (2 bil) Retarded Ossification (cen thll,13) Retarded Ossification (cen thll-12) Retarded Ossification (cen thll-12) Retarded Ossification (cen thl2) Retarded Ossification (cen thll-12) NAD Retarded Ossification (cen thl2) NAD Retarded Ossification (cen thll-12) VR VR VR VR VR VR VR VR VR VR VR VR 646259 1 2 3 4 5 6 7 8 9 4.84 5.19 4.83 5.59 5.58 5.72 5.53 5.69 6.08 Subcutis Vertebra Vertebra Hemorrhage (back*) NAD Retarded Ossification (cen thll) NAD NAD Retarded Ossification (cen thll) NAD NAD NAD N VR VR ( Ifp p p iy Silflzed. Usfol contain TSCAC1 -131 - H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) A ND ALTERATIONS GROUP III: 250* MG/KG/DAY DAM NO./ FETUS NO. FETUS W T . STRUCTURE FINDING(S) CLASSIFICATION 646259 (Cont.) 10 5.75 11 5.55 12 5.65 13 5.82 14 5.16 Subcutis Subcutis Vertebra Skull Hemorrhage (back*) Hemorrhage (back*) Retarded Ossification (cen thl3) NAD NAD Retarded Ossification (6bil,7rt) ST N VR VR 646266 1 2 3 4 5 6 7 8 9 10 11 12 13 14 4.56 5.00 Vertebra 5.32 Vertebra 4.97 5.29 6.01 5.61 5.14 5.41 5.29 Vertebra 5.50 Vertebra 4.91 5.04 5.46 Subcutis Vertebra NAD Retarded Ossification (cen thll) Retarded Ossification (cen thl2) NAD NAD NAD NAD NAD NAD Retarded Ossification (cen thll) Retarded Ossification (cen thlO) NAD Hemorrhage (head*) Retarded Ossification (cen thll) VR VR VR VR N VR 646268 1 2 3 4 5 4.95 5.46 4.70 6.58 4.45 Vertebra Vertebra NAD Retarded Ossification (cen thll) Retarded Ossification (cen thll) NAD NAD VR VR Doesuo'Acorta'"TMTM''" Cmpany Sand -132- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 250 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646268 (Cont.) 6 5.40 7 5.64 8 4.83 9 5.83 10 5.24 11 5.49 12 5.09 13 6.98 14 4.58 15 5.07 Rib Subcutis Rib Kidney Rib Kidney Vertebra Vertebra Vertebra 646269 1 2 3 4 5 6 7 8 9 10 5.97 5.13 5.12 5.24 5.42 5.01 5.35 5.19 5.13 4.71 Rib Vertebra Skull Kidney Rib Vertebra Vertebra Vertebra Rib Vertebra Supernumerary (site thl4 It) NAD Hemorrhage (chin*) Supernumerary (site thl4 bil) Papilla - Size 3 (bil) Supernumerary (short thl3 It) NAD Small Papilla - Size 2 (bil) Retarded Ossification (cen thll) NAD NAD Retarded Ossification . (cen thl2) Retarded Ossification (cen thl2) DV N DV VR DV VR VR VR VR Supernumerary (thl4 site rt) Retarded Ossification (cen thll) Retarded Ossification (2 bil) Small Papilla - Size 2 (bilateral) Supernumerary (thl4 site bil) NAD NAD Retarded Ossification (cen thl2-13) Retarded Ossification (cen thll-12) Retarded Ossification (cen thl2) Supernumerary (thl4 site bil) Retarded Ossification (cen thll) DV VR VR VR DV VR VR VR DV VR p l f any SitnlffKcf- 'Doss fltoot1contain T3CCBI -133- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 250 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 546269 (Cont.) 11 5.36 12 6.06 13 5.87 14 5.35 15 5.22 16 5.34 17 4.81 18 4.99 Vertebra Vertebra Vertebra Vertebra Rib Vertebra Rib Vertebra Vertebra Retarded Ossification (cen thll-12) Retarded Ossification (cen thl2) Retarded Ossification (cen thll) Retarded Ossification (cen thl2) Supernumerary (thl4 site It) Retarded Ossification (cen thl3) Supernumerary (thl4 site It) Retarded Ossification (cen thlO-12) Retarded Ossification (cen thll-12) NAD VR VR VR VR DV VR DV VR VR 646271 1 2 3 4 5 6 7 8 9 10 11 12 13 5.52 5.67 5.62 5.83 - 5.20 Brain Vertebra Kidney Vertebra 5.53 5.50 5.36 Vertebra 5.15 5.57 5.45 Kidney Vertebra 5.40 5.61 Kidney Distended (ventricles) NAD NAD Retarded Ossification (cen thll) Papilla - Size 3 (It) Retarded Ossification (cen thll-12) NAD NAD Retarded Ossification (cen thll) Papilla - Size 3 (bil) NAD Retarded Ossification (cen thlO) NAD Papilla - Size 3 (It) M VR VR VR VR VR VR VR 'Compaq - 134- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 250 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646273 I 2 3 4 5 6 7 8 9 10 11 12 13 14 15 646285 1 2 3 4 5 6 7 5.32 5.41 5.11 Vertebra 5.42 Skull 5.61 Vertebra 5.27 6.07 Rib Kidney Vertebra 5.61 Skull Vertebra 5.45 5.50 Kidney Rib Vertebra 5.14 5.45 4.83 5.32 Rib Rib Skull Vertebra 5.56 5.77 5.50 6.11 5.51 5.41 5.54 5.72 Vertebra Skull Vertebra NAD NAD Retarded Ossification (cen thll) Retarded Ossification (12 ;6bil) Retarded Ossification (cen thl0-ll) Supernumerary (th site 14bil) Papilla - Size 3 (It) Retarded Ossification (cen thll) Retarded Ossification (6rt) Retarded Ossification (cen thll-13) Papilla - Size 3 (right) Supernumerary (th site 14lt) Retarded Ossification (cen thlO) Supernumerary (th site 141t) NAD Supernumerary (th site 14rt) Retarded Ossification (6bil) Retarded Ossification (cen thl2) NAD VR VR VR DV VR VR VR VR VR DV VR DV DV VR VR Retarded Ossification (cen thl2) Retarded Ossification (6 bil) NAD NAD Retarded Ossification (cen thll,12) NAD NAD VR VR VR . .. vic!1. IS'IU g S S p A y S m * "1-'D 0 8 S *C W -135- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 250 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646285 (Cont.) 8 5.40 9 4.78 Rib Femur Pelvis Rib Vertebra 10 5.40 11 6.00 646299 1 5.46 Vertebra 2 6.07 3 5.49 4 5.63 5 5.38 6 5.23 Vertebra 7 5.40 8 4.94 Vertebra 9 5.02 10 5.31 11 5.31 Vertebra 12 . 5.12 Skull Vertebra 13 5.27 Vertebra 14 5.64 Skull 646302 1 5.19 Vertebra Supernumerary (thl4 site rt) Retarded Ossification (bil) Retarded Ossification (pubis,bil) Wavy (7-llbil;6rt) Retarded Ossification (cen thll) NAD NAD DV VR VR VR VR Retarded Ossification (cen thll) NAD NAD NAD NAD Retarded Ossification (cen thll) NAD Retarded Ossification (cen thl2) NAD NAD Retarded Ossification (cen thll) Retarded Ossification (2 bil) Retarded Ossification (cen thll) Retarded Ossification (cent thll-12) Retarded Ossification (6 left) VR VR VR VR VR VR VR VR Retarded Ossification (cen thl2) VR C o m pa w S - ^ ' '- " ,oon,a,nTSCA -136- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 250 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646302 (Cont.) 2 5.70 Vertebra 3 5.43 Vertebra 4 5.87 5 5.54 Rib 6 5.61 7 5.36 8 5.37 9 5.36 Sternebra Vertebra 10 5.67 Vertebra 11 5.25 12 5.16 Retarded Ossification (cen thll,13) Retarded Ossification (cen thll) NAD Supernumerary (thl4 site It) NAD NAD NAD _ Retarded Ossification (5) Retarded Ossification (cen thll) Retarded Ossification (cen thlO,12) NAD NAD VR VR DV VR VR VR 646303 1 2 5.52 5.57 Vertebra 3 3.25 4 5.60 5 5.71 $6 7 6.08 5.75 Vertebra 8 5.14 9 5.19 10 . 5.17 11 5.73 Vertebra 12 5.10 13 5.48 Vertebra 14 5.59 Vertebra 15 5.91 NAD Retarded Ossification (cen thll) NAD NAD NAD Retarded Ossification (cen thll-12) NAD NAD ' NAD NAD Retarded Ossification (cen thll) NAD Retarded Ossification (cen thll) Retarded Ossification (cen thlO) NAD VR VR VR VR VR ytilized. Does not contain TSCA CB, |ftpa.n - 137- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 250 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S)___________ CLASSIFICATION 646303 (Cont.) 16 5.36 17 5.71 646305 1 2 5.28 4.35 3 5.19 4 4.91 5 5.13 6 4.70 7 4.87 8 5.45 Vertebra Vertebra Vertebra Vertebra Vertebra NAD NAD NAD Retarded Ossification (cen thll-12) Retarded Ossification (cen thlO-13) Retarded Ossification (cen thll) NAD NAD Retarded Ossification (cen thlO) Retarded Ossification (cen thll-12) VR VR VR VR VR 646307 1 2 3 4 5 6 7 8a 9 10 11 12 13 14 15a 16a 5.34 5.13 5.19 5.23 5.44 5.32 5.65 5.27 5.21 5.69 5.29 5.02 5.09 4.90 5.39 4.99 Skull Vertebra Vertebra NAD Retarded Ossification (6 It) NAD NAD Retarded Ossification (cen thl2-13) NAD . NAD NAD NAD NAD Retarded Ossification (cen thlO) NAD NAD NAD NAD NAD VR VR VR - 138- tioes tiotcox**i%r* iltize'd f*Vn H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL PETAL WEIGHTS (grams) AND ALTERATIONS GROUP IV: 500 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S ) CLASSIFICATION 646221 1 2 3 4 5 6 7 8 9 10 !) 5.03 Vertebra 6.16 Skull Vertebra 4.84 Vertebra 5.34 Skull 5.78 4.99 Skull Vertebra 5.93 4.86 Vertebra 6.07 Pelvis Rib Vertebra 5.61 Pelvis Rib Skull Retarded Ossification (cen thll) Retarded Ossification (6,7,2 bil) Retarded Ossification (cen thll) Retarded Ossification (cen thl2) Retarded Ossification (2,6 bil) NAD Retarded Ossification (6 bil) Retarded Ossification (cen thl2) NAD Retarded Ossification (cen thl2) Retarded Ossification (pubis bil) Wavy (10-11 rt) Retarded Ossification (cen thl2) Retarded Ossification (pubis bil) Wavy (9-12 bil,-5-8 rt) Retarded Ossification (1,2,6 bil) VR VR VR VR VR VR VR VR VR VR VR VR VR VR 646223 1 2 3 4 5 6 5.78 5.74 5.61 5.91 5.38 5.56 Skull Vertebra Vertebra Rib NAD Retarded Ossification (1;6 It) Retarded Ossification (cen thl3) Retarded Ossification (cen thlO,12) NAD Supernumerary (thl4 site It) NAD VR VR VR DV - 139- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP IV: 500 MG/KG/DAY ' DAM NO./ FETUS NO. FETUS WT. STRUCTURE ________ FINDING(S)___________ CLASSIFICATION 646223 (Cont.) 7 5.55 8 5.68 Vertebra 9 5.71 10 5.90 11 5.30 12 5.75 Skull 13 5.56 Rib 14 5.67 646233 1 2 3 4 5 6 4.87 5.20 5.82 5.72 4.79 4.94 Vertebra 7 5.29 8 5.62 9 6.07 10 5.24 11 5.14 Rib 12 5.93 13 5.93 Kidney 14 5.43 15 4.99 646239 1 2 6.07 . 5.54 Skull 3 5.45 4 6.18 Skull Vertebra NAD Retarded Ossification (cen thl2) NAD NAD NAD Retarded Ossification (1;2,6 bil;7-8 It) Supernumerary (thl4 site It) NAD VR VR DV NAD NAD NAD NAD NAD Retarded Ossification (cen thl2) NAD NAD NAD NAD Wavy (th8-lllt, 6-9 rt) NAD Papilla - Size 3 (bilateral) NAD NAD VR VR VR NAD Retarded Ossification (2,6 bil) NAD Retarded Ossification (6 bil) Retarded Ossification (cen thlO,12) VR VR VR - 140- onlalnTSCi.fi> not Sanitize^063 H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP IV: 500MG/KG/DAY ' DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646239 (Cont.) 5 5.45 6 5.87 7 5.51 8 5.74 9 5.95 10 5.19 11 5.87 12 5.70 13 5.53 14 5.68 Vertebra Vertebra Vertebra Skull Kidney Skull Vertebra Skull Vertebra Retarded Ossification (cen thlO) NAD NAD Retarded Ossification (cen thll-12) Retarded Ossification (cen thll-12) Retarded Ossification Papilla - Size 3 (It) Retarded Ossification Retarded Ossification (cen thll) NAD Retarded Ossification (2,6 bil) Retarded Ossification (cen thll) (6bil) (2bil) VR VR VR VR VR VR VR VR VR 646240 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 6.01 5.50 5.52 5.97 5.12 5.78 5.90 5.89 5.31 5.48 5.57 5.78 5.59 5.82 5.59 Vertebra Skull Vertebra Vertebra Skull Kidney Retarded Ossification (cen thll) Retarded Ossification (6 It) NAD NAD NAD NAD Retarded Ossification ` (cen thll) NAD Retarded Ossification (cen thll) NAD NAD Retarded Ossification (6 It) Papilla - Size 3 (bil) NAD NAD VR VR VR VR VR VR _-esU*cont ' E S S 5'"' -141 - H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP IV: 500 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S)___________CLASSIFICATION 646244 1 2 3 4 5 6 7 8 646247 1 2 3 4 5 6 7 8 9 / ) 10 VW 11 12 13 14 15 5.48 5.42 5.79 5.37 5.68 5.43 5.44 5.73 Vertebra Skull Vertebra 4.71 4.98 4.80 5.27 5.05 5.21 4.92 4.89 5.26 5.43 4.86 5.41 5.19 5.35 5.62 Rib Skull Skull Vertebra Skull Vertebra Skull Skull Vertebra Kidney Vertebra Retarded Ossification (cen thll-13) Retarded Ossification (6 bil) Retarded Ossification (cen thl2) NAD NAD NAD NAD NAD VR VR VR Supernumerary (thl3 site It) NAD NAD NAD NAD Retarded Ossification (2,6 bil) NAD Retarded Ossification (7,8 bil) Retarded Ossification (cen thll) Retarded Ossification (6 bil) Retarded Ossification (cen thll) NAD ' Retarded Ossification (6 It) NAD Retarded Ossification (8 It) Retarded Ossification (cen thl2) Papilla - Size 3 (rt) Retarded Ossification DV VR VR VR VR VR VR VR VR VR -142- 'CptiVPan^ t S C M ' 1' H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP IV: 500 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT.. STRUCTURE FINDING(S) CLASSIFICATION 646255 1 2 3 4 5 6 7 8 9 10 11 12 13 5.45 6.15 7.05 5.47 5.62 5.81 5.81 5.64 5.49 5.87 6.05 5.41 6.57 Skull Vertebra Skull Vertebra Skull Vertebra Vertebra Skull NAD Retarded Ossification (61t) NAD NAD NAD Retarded Ossification (cen thl0-ll) NAD Retarded Ossification (6bil) Retarded Ossification (cen thll) Retarded Ossification (6bil) Retarded Ossification (cen thll) Retarded Ossification (cen thll) Retarded Ossification (6bil) NAD VR VR VR VR VR VR VR VR 646260 1 2 3 4 5 6 7 8 9 4.94 5.15 5.08 4.66 5.66 5.47 5.44 4.28 4.85 Skull Skull Rib Skull Rib Vertebra Pelvis Rib Skull Vertebra NAD Retarded Ossification (2 bil) NAD Retarded Ossification (6 bil) Supernumerary (thl3 site lt) Retarded Ossification (6,8,2 bil) Wavy (th7,9-11 rt) Retarded Ossification (cen thl2) Retarded Ossification (pubis bil) Wavy (th9-ll bil,thl-8i rt) Retarded Ossification (6 bil) Retarded Ossification (cen thll) VR VR DV VR VR VR VR VR VR VR - - 143- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP IV: 500 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S) CLASSIFICATION 646260 (Cont..) 10 5.01 Vertebra 11 4.99 Kidney Pelvis 12 4.86 13 5.35 Rib 14 5.18 Skull 15 4.55 Rib 16 4.94 Skull Vertebra 17 4.52 Rib 18 5.48 Rib Skull Retarded Ossification (cen thll) Papilla - Size 3 (right) Retarded Ossification (pubis bil,ischium bil) NAD Wavy (th7-12 rt) Retarded Ossification (2,3,6 bil) Wavy (th.6-11 rt) Retarded Ossification (2,6 bil) Retarded Ossification (cen thll-I3) Wavy (th.8-12 bil) Wavy (thlO-12 bil,th8-9 rt) Retarded Ossification (3,6 bil) VR VR VR VR VR VR VR VR VR VR VR 646262 1 2 3 4. 5 6 7 4.60 Kidney Pelvis - Sternebra Vertebra 4.64 Skull 4.69 4.81 Skull Sternebra 4.51 Vertebra 4.70 Skull 5.01 Sternebra Papilla - Size 3 (It) Retarded Ossification (ischium,pubis bil) Retarded Ossification (3-4) Retarded Ossification (cen thl2,13) Retarded Ossification (2,3,7 bil) NAD Retarded Ossification (2,3 bil) Retarded Ossification (3,4) Retarded Ossification (cen thll) Retarded Ossification (2,6,7,8 bil) Retarded Ossification (3-4) VR VR VR VR VR VR VR VR VR VR not contain TSCA^pI e o m p a > y san',tted,DBS -144- H-24516; Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP IV: 500 MG/KG/DAY ' DAM NO./ FETUS NO. FETUS WT.. STRUCTURE FINDING(S) CLASSIFICATION 646262 (Cont..) 8 4.32 Skull Vertebra 9 4.28 Pelvis Vertebra 10 4.34 Skull 11 4.12 Vertebra 12 4.30 Skull Vertebra 13 4.33 Sternebra 646263 1 2 3 4 5.50 5.27 5.10 5.21 Kidney Vertebra 5 5.21 6 4.81 Skull 7 5.36 8 5.17 9 5.90 Vertebra 10 5.15 11 5.77 Vertebra 12 5.23 Skull 13 5.20 14 5.24 Vertebra 15 5.94 Retarded Ossification (2,3,7,8 bil) Retarded Ossification (cen thl3) Retarded Ossification (pubis bil) Retarded Ossification (cen thlO,11,12) Retarded Ossification (2,3,8 bil) Retarded Ossification (cen thl2) Retarded Ossification (2,3 bil;12) Retarded Ossification (cen th3) Retarded Ossification (4-5) VR VR VR VR VR VR VR VR VR Papilla - Size 3 (bilateral) NAD NAD Retarded Ossification (cen thll,12) NAD Retarded Ossification (2 bil) NAD NAD Retarded Ossification (cen thl2) NAD Retarded Ossification (cen thll) Retarded Ossification (2 bil) NAD Retarded Ossification (cen thl2) NAD VR VR VR VR VR VR VR . H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP IV: 50O' MG/KG/DAY ' DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING(S)___________ CLASSIFICATION 646263 (Cont.) 16 5.72 646270 1 2 5.79 5.74 Vertebra- 3 5.33 Rib Vertebra 4 5.60 Vertebra 5 5.54 6 5.78 7 5.27 8 5.50 Skull 9 5.87 Rib 10 5.57 11 5.35 Kidney Rib 12 5.16 Vertebra 13 5.94 Rib 14 5.62 Rib Skull Vertebra 15 5.57 646275 1 2 3 5.40 5.47 5.65 Vertebra 4 5.83 5 5.53 NAD NAD Retarded Ossification (cen thll) Rudimentary Cervical (71t) Retarded Ossification (cen thl0-ll) Retarded Ossification (cen thll) NAD NAD NAD _ Retarded Ossification (6bil) Supernumerary (th site 141t) NAD Small Papilla - Size 2 (bil) Supernumerary (th site 14bil) Retarded Ossification (cen thl3) Supernumerary (th short 141t;site rt) Wavy (3-13M1) Retarded Ossification (1,2;6-8bil) Retarded Ossification ' (cen thll-12) ' NAD VR DV VR VR VR DV VR DV VR DV VR VR VR NAD NAD Retarded Ossification (cen thll) NAD NAD VR -146- Saw T S C A CBl H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS | GROUP IV: 500 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT.. STRUCTURE FINDING(S) CLASSIFICATION 546275 (Cont..) 6 5.54 Skull ' Vertebra 7 5.25 8 5.66 9 5.11 10 5.15 Vertebra 11 5.56 12 6.06 13 5.24 14 5.29 646277 1 2 3 4 5 6 4.34 5.09 5.19 4.08 4.76 3.68 Skull Kidney Skull 7 4.49 8 4.24 Skull 9 4.31 10 4.79 Skull 11 4.77 12 4.89 Skull 13 4.84 Kidney 14 4.78 Skull 15 4.85 646281 1 2 3 4.15 4.17 4.70 Skull Retarded Ossification (6 bil) Retarded Ossification (cen thl2) NAD NAD NAD Retarded Ossification (cen thl2-13) NAD NAD NAD NAD VR VR VR NAD Retarded Ossification (6bil) NAD NAD Papilla - Size 3 (bil) Retarded Ossification .(1,12 ;6bil) NAD Retarded Ossification (6bil) NAD Retarded Ossification (6bil) NAD Retarded Ossification (6bil) Papilla - Size 3 (b'il) Retarded Ossification (12 ;6bil) NAD VR VR VR VR VR VR VR VR NAD Retarded Ossification (6 bil) NAD VR - 147- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP IV: 506 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT.. STRUCTURE FINDING(S) CLASSIFICATION 646281 (Cont..) 4 4.50 Vertebra 5 4.45 6 4.91 Skull Vertebra 7 4.42 Vertebra 8 4.07 9 4.68 10 4.14 Vertebra 11 4.05 12 3.90 Skull Vertebra 13 4.27 14 3.97 Sternebra 15 3.92 646283 1 5.90 Vertebra 2 5.87 3 6.16 4 6.19 Vertebra 5 6.36 Kidney 6 6.04 Vertebra 7 6.03 8 5.86 9 6.43 Vertebra 10 6.27 11 6.56 Kidney Retarded Ossification (cen thll) NAD Retarded Ossification (6 rt) Retarded Ossification (cen thl2) Retarded Ossification (cen thll) NAD NAD Retarded Ossification (arches ce4 rt) NAD Retarded Ossification (7 bil) Retarded Ossification (cen thll) NAD Retarded Ossification (4) NAD VR VR VR VR VR VR VR VR Retarded Ossification (cen thll) NAD NAD Retarded Ossification (cen th9,ll) Small Papilla - Size 2 (rt) Retarded Ossification (cen thll) NAD NAD Retarded Ossification (cen thll) NAD Papilla - Size 3 (right) VR VR VR VR VR VR - - 148- H-24516: Developmental Toxieity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP IV: 500 MG/KG/DAY DAM NO./ FETUS NO. FETUS WT. STRUCTURE FINDING (S) CLASSIFICATION 646283 (Cont.) 12 6.11 Vertebra Vertebra Retarded Ossification (cen thl2) Retarded Ossification (cen thll) VR VR 646287 1 2 3 4 5 6 7 8 9 10 11 12 13 14 5.19 5.47 5.65 5.77 5.55 5.38 5.21 5.54 5.09 5.14 Rib Rib Skull Rib Rib Skull Subcutis Rib Skull Vertebra 5.72 5.29 5.50 5.43' Rib Skull Rib Skull Supernumerary (th site 14bil) Supernumerary (th site 14lt) Retarded Ossification (6bil) Supernumerary (th site 14rt) Supernumerary (th site 14bil) NAD Retarded Ossification (6bil) NAD Hemorrhage (right, limb*) NAD Supernumerary (th site 141t) Retarded Ossification (61t) Retarded Ossification (cen thl2) Supernumerary (th site 14lt) Retarded Ossification (61t) NAD Supernumerary (th short 14rt;site 141t) Retarded Ossification (6bil) DV DV VR DV DV VR N DV VR VR DV VR DV VR 646289 1 2a . 34 5 6 7 8 9 10 6.10 5.26 5.89 5.75 5.98 5.94 6.30 5.04 5.50 5.55 NAD NAD NAD NAD NAD NAD NAD NAD NAD NAD TSCACW S a * ze.V^*<*coni* n Company -149- H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP IV: 500 MG/KG/DAY ' DAM NO./ FETUS NO. FETUS WT.. STRUCTURE FINDING(S) CLASSIFICATION 646289 (Cont.) 11 5.65 12 5.87 13 5.58 14a 5.30 15 5.55 16 5.78 646293 1 6.04 Vertebra 2 5.66 Skull 3 5.53 4 5.61 5 5.07 6 5.54 Skull 7 5.79 8 5.11 Skull 9 4.80 10 5.70 11 5.70 12 5.98 13 5.75 Kidney 14 5.86 15 5.25 16 5.56 Skull 17 5.66 646295 1 2 3 4 5 6 7 8 9 10 5.88 5.92 5.80 5.37 5.38 5.47 5.25 5.59 5.94 5.40 Rib Rib Skull NAD NAD NAD NAD NAD NAD Retarded Ossification (cen thll) Retarded Ossification (6 rt) NAD NAD NAD Retarded Ossification (6 It) NAD Retarded Ossification (6 bil) NAD NAD NAD NAD Papilla - Size 3 (bil) NAD NAD Retarded Ossification (6 It) NAD VR VR VR VR VR VR NAD NAD NAD NAD Supernumerary (th site 141t) NAD Supernumerary (th site 14bil) Retarded Ossification (12) NAD NAD DV DV VR H-24516: Developmental Toxicity Study in Rats DuPont-5991 INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP IV: 500 MG/KG/DAY ' DAM NO./ FETUS NO. FETUS WT.. STRUCTURE FINDING(S) CLASSIFICATION 646295 (Cont .) 11 5.42 12 5.52 13 5.66 14a 5.69 Skull NAD Retarded Ossification (61t) NAD NAD VR 646301 1 2 3 4 5 6 7 8 9 10 11 12 5.49 5.50 5.44 5.74 5.35 5.00 5.06 5.63 5.30 5.50 4.91 5.30 Vertebra Vertebra Vertebra Vertebra NAD Retarded Ossification (cen thl2) NAD NAD NAD Retarded Ossification (cen thlO) NAD Retarded Ossification (cen thl3) NAD Retarded Ossification (cen thl2) NAD NAD TO TO TO TO 646304 1 2 3 4 5 6 7 8 9 10 11 12 5.38 6.05 5.60 5.83 4.84 5.06 5.05 5.14 5.17 4.85 4.66 5.45 Skull Kidney Skull Vertebra Skull Skull NAD Retarded Ossification (6bil) Papilla - Size 3 (bil) Retarded Ossification (6bil) NAD Retarded Ossification (cen thlO) NAD Retarded Ossification (611) NAD NAD NAD Retarded Ossification (6bil) TO TO TO TO TO TO CowpanySar.!t^ed-t3oesKolcontai TSCft - 151 - H-24516: Developmental Toxicity Study in Rats DuPont-5991 APPENDIX H Analytical Report - 152- ^ovcio'ntam ,,-.'--tTides ft H-24516: Developmental Toxicity Study in Rats DuPont-5991 A. SAMPLE SUBMITTAL hTo5SSn.ouah0umbeMrcrpmhrealorfergorocsi/nmhgmcieco2Ltr,neaTw2tmtaoe0iedxpn0rie1iescnrwt.iacagttyobiTutHlih9rhlleei-e0Ht2csysDt4et-eaf25adosb41yario65mltGin1htapy6aetMl.*vtelh1aesaSegvrwaceecmhleoSsrp5neilt,cneaue2sntn0hdVfat0rirl--so1yyamtzstiSteooudtnBhdvsteyeooHrhsivfafaye0mHdr,tiehbf5Byeep.0ehrm,neHo2pimex0asfir.otn0laagHgtbaieolhnninHsodehima5teyBt0do,t.hg0icHneeomnncaHeocgipent/rymnHcetefvLrona.iH.ortwt.ri.utoa.heH.stn.rii.seo,.BanlcensovdHloele5lf.cV-teJdi oSnamMpalercshco9n,2ta0i0n1inagnHd-M24a5r1c6h a2t0t,h2e00co1n. cTenhterastaiomnpsleosfw0,e5re.0a,n2a0ly.0zeadndto5v0e.0rimfygc/omnLcewnterraeticoonl.lected TAhlledyowsienrge saunsaplyeznesdiownhseanmrpelceesiwveedreocrowlleercetefdrooznenthuenstialmaneadlyazyetdh.e suspensions were prepared. The suspension vehicle was 0.5% aqueous methylcellulose. B. METHODS 1. Analytical Methods a. Dosing Suspension Treatment eH([Eiaqna-.ui2ci.tih]4iv)a5adlp1loedr6sinioilitnunragttitmoohsnaeoam)unstnaupoltslyepwasenwiasnse.asxisaAopddnendi.cleuitdnTetetdhtedoercntoedoaanolcc1sshei0tnna0sgntarmmdasaatLpirmodlwenp(bilorteeehfsffameowprreeepttorrhteohaCxfenuaiomfrliiltnbhaaartenealrdltayidonsi0lnoau.ln0yatie9nscdidamstwQedgdii/utlmhutaotnLtihodtie(nitasa.0sctiotomilvnvgeeS/imtnehcgLetrieosadnmi)eanptltean Company Sanitized. Does not contain a -153- H-24516: Developmental Toxicity Study in Rats b. Chromatographic Conditions DuPont-5991 ICIDCISOnnnpoaevsjjeelrltteiuerrcctnuicmttevomTiIILLLtProonnenreeeor:enrnGii:ovvvtt:tntiiaVagee:eaatls:lllrllo:ra11T1TulmuneiTTRmm:mieatmieemtpme:ee:pe:re:artautruer:e: HJFH22SG2209112.6.0I.0p&0e0emr0D.0.0lal3w0000iid;itWuc,CClmmmmi2Cmere25,otnLiii/5tnnnm0Dl-t(0i/P...2mtBieC.an1Cric-.n1km7a0Lrd1/m,M3in0o)dmel, 608.3920mGmC ID, 1um film thickness c. Calibration and Quantitation *1hcrAdafsdaerqoseniiopllsuinsduumguleacittthrpcreeeeeertaddanssesttrttpehwdarfrsaloteaoiiaeitncgrtstimhojarsiaienenatnplmcelsmts^letsemieGraipfotonotrhaClnonaerrstaselrtgtano(ohorossnioifcvteealfaalkHeeeleldnty^woas-aFods2Aocnasiamih4glsirsuendu5asosqtigr1ktinaafuoeo6mesnwticnsahvld(cokpaam-ewaal3lsH,suslelpae)eioptl-bslnitbwl2reoosrutep,s4oanatpftr5atil.whiseiouann1oepronteBad6nieabrrolodeereasltncefacsfttidoosdapinatnernnfwheneiotmecdnceredreiaeatrnemirnnmearvfettdtahoeeerrrisulraeerantynchsntpttueseiheaaaorodisndllasneleint,btsbositaaetbaooyilrnan.snaprnndacattptaTdiapothcoariltapkhnomeldinrvleispdddyaseetcterirneisluiscuncuadatr!(cgutotlv3etiyttrcooeht.vta5hka.nieeecl,ecsissaatq4.aao)pcl.u.lrlhe1irTguobeaM7cethtfrki,saetaeoearlhtconiairenoeboafsndwinrtnutgciahcor4aehtceeesi.tuo7donsssrrt7ntftaavorottnaesnmhicttdsoiieakcioasbnnaprnwyudftdeertaoeaolederrkfmsdeat)tohste micdfTcnoooieisrnetdsthefrctdfieaesblicencutuh,oitbetrapisadnont,totanidmonsooinbcifnde.ofvgdtthaAhtlloroeeeim,vmcataoeteionhlesogdotwfnfemsiban(ucCosoeibetigu.sttVnoytesatemn.inodne=cif(tettTsovyhtta,aehdsrMnareidoadmtoe,tuaisrparogmidlnnnhedgiodsnoueBsoefvtur)ltitsehoahspslaeefseimotncdthnhospoe/ianlmsoendicnsneues1gaonp0wnrtls%riutcaxahssatieip1toseee0mnvcn0caooeso)lniaunfoonsatcnfihtedo.teenhedfTtertdreebhamusdytetpieiocsmlnainuacdselbauvciacstureentaearltadisnrifetvaiciccsmneeouagnopftlitocltfoehoeransenftchftsctroheaearmeptietotpaoanlbcpeslh,se respective dosing levels. coSoftamtbhpielaidtryiunwpglaitchsaeetvecaoclruoraentscepedonnbtrdyaituniosginnrogvoetmhrieftiemcmaetpiaoennroastfuatmrheepaltneodsp(r,0emf-rdiidagydelrreao,toeadmnrdetebsmuolttptsoe.mrathuorem) oagsethneeibtyassealminpelfeosror - 154- ' &<* >oniatn H-24516: Developmental Toxieity Study in Rats DuPont-5991 C. ANALYTICAL RESULTS 1. Chromatography ,noHaopfi-npta2urdp4otep5extr1esiom6.cxteieRamldtueeatplieyntrede6tlshyf.e0re3onm0.mt5aimt,ni4tvhug.ee1t/em7GGs,.LCCaFcnccoodhonrrl4toutr.hn7moer7lan.pmtouasgrinprrauoefmetsseelousslotvwaeferdeedqrausepshaeunoaastwkeritesdnas.twoiionlTivntFhhe,eidrrgeeipunstereotenealsvrktnie2oaad(ntlapast-ieptmacpak)ern.sosdxTafirtaenotsrMmht^esef2urlle.byH9tse3tmnaH.9ntii9ncoHuentHwetisma^stoeVs | 2. Homogeneity, Concentration, and Stability Verification A(s5hn.o0awlmyntgiic/nmalALrnelaseulvylettsilc)faarlonTmdaabdnloeaslIiynazgneddsufAsopnreahnloysmitoiconagslecSnouelmilteymc,tecadorynoTcneanMbtlreaart1cio.hn2,,a2n0d0s1taabnidlitMy varecrhifi5c,a2ti0o0n1are Tvehreiffiocalltoiowni.ng table summarizes the results for homogeneity, concentration, and stability I I) PrepDaartaetion 2-Maf-2001 Nmogm/minLal 255000..0.00 Measmurge/dmTL,M,Ba 4713.79..667,,,442N4.0D4..716C,,,4324.09..199 M%eaNno(Tm,Mina,Bl ) 1980--887..37.6 i C(%.V). %StNaboimlitiyn1a'l 4--911 798--497...572 i 5-Mar-2001 5.0 4.96, 5.06, 5.07 100.7 1 _d abcd MD5S-aeehmanonoputrlreeersssounholoetmsnldeftoe5dmrehttphoeeeucrtraaesntduaa,rtleyrossioasmmopftletehmenpoteotrpcaot(ulTlree)c,,tmedid. dle (M) and bottom (B) samples, sissbucmhiTsnnautouseoahdmibencbmtbxeihdsacscpeiteuotdllaadlfauisgiattonvnndiyebtenrtecageienrtghdeahefeftatoiohoswteoecnhsurarldudiesaealtnssatsbtntatsglwmhhytyamo.hfeehtptmotepTehtlitsrhelnhntieuhetxeesiehssehrtsewpiteetsedcaafestoleorsliaudnignurrlnsbslmeleiba5teiitsttomlsicchueiahtnotftdaellpyoeralnowdllsuvctoieciamnroeoaocemfsghnsntnttewa.ihcpshacdtMeelaedlTairnesanerotashtefegqehroartisaxcuseomsm(tthrtca7miwisopetrf4t3uenolroape.e,lbe7smrgtysid2sm%nenfth0pcoancouo0toenreohotl1mrlcaotnelacfheetuttooinies.uicnosgnnoatrldn5eeTuysmemi.din.opc0hdmpieaurniMeTlmoestisearexpuhlescalgsye)asedor/(drtcmdrndh5atehouciuta1Lfnmirlt5rlo1huieitn,tlgnna.shche7g2/vi.gvteemo%0etedunT0vthLloeas1eheoi(esdsshleCti.mfevfnnisrnsvc.ego,uVTiuloerxmetpbshslm.hieposni(w=esltCtoigyahniafrf4t.neoatiiVsa1erniclrfsrs)id).mdefena.era=igbmswenucnTuuyatgl1daeeaflhst)safdtwohpe.wiirconreitatTateihnaesyerspebhssenaoteslstasertluftraayuettlbtohtdisloeeynof ,talnTSCACBl - 155 - CompaW H-24516: Developmental Toxicity Study in Rats DuPont-5991 tsshutuebdssyttaadnbocilneietwyfaosasr'mnthopetlefSsouufboncrdhtrihonentoihctehT0eormxleigcv/iemtylsL9i0nsaDtmhaepylseGtsu.advyaagned by the data from the referencTeedssttability 3. Stability Study H"tTcJeaomm|nenupcmfaeoerrylnaUloth1uwj5urHe,itn.i2ogh0^0toaa1mbn)lgaeoneigds^teitnhsnceulemu4id-mtdeyaad/yrcifzrooeerfsnraitcghreeeefrneraertteserundaclttseistoaifnbonirtlhviStieyusrbiasfnctiuchadalryotyisnoteionsct(fThJoaoellnxoruiewcafirretiyydge89br,0ya2tD50ed0ah1yostuGaarqbasdivlriaotgyoemfoSrtuthdey PrSeapmarpalteioTnyDpeate Ho8m-Jaong-e2n0e0i1ty a Stability 4-Day Refrigerated" Nominal mg/mL 0 5.0 2500 5.0 Mmega/smurLed 4.53,4N.D25b,4.39 19.9, 17.7,18.6 53.4, 52.6, 54.0 4.81 % NMoemaninal 98--37..58 106.8 96.1 C.V. (%) . --63 1 -- %SNtaobmiliitnyal 92--.0C 86.0 96.6C 97.1 4-Day Refrigerated" 20 19.6 97.8 -- 88.2 4-Day Refrigerated" 50 48.9 97.8 -- 95.7 bdac MdMDSaaeeeymananropnetrlfereeresssisgunhueloeltrtnlaosdetfef5dodseir/hn5ttoeghuchleetroesausdnaar,amtrlorypooslomiesmfotoetfremtm4hp-epdeertaorayatputruer(reTfer)s.i,gtamebriiadltidetydle./c(oMnc)eanntdrabtiootntovmer(iBfi)castaimonplaensd, a single sample for 4- rTssouthoobermsadtgaatenetcamceofpnwredoraiaisttiruosJtrna^esbHfoloefrHittnhh^eethHtceeosHvtniecn|h|eg|inBcstlryeaaswmttieohmnpenrldaeuhnsregilniedsgo4itnfhdctihalsuyesdstseurtdueddfywry.igi.tehTrtahhtieissddsaatnutaddysfuotopllposowhroetswdthbtheyam5t thihxoeiuntrgessatantd ffrnpaw - 156- H-24516: Developmental Toxicity Study in Rats DuPont-5991 4. Concentration Verification AannaalylyzteicdaflorrescuolntscefrnotrmatidoonsivnegrisfuicsapteionnsioarnesschoolwlecnteindToanbMleaErHchan9d,2S0u0m1 manadryMTaarbclhe 21.0,&2ar001 and The following table sujhmarizes the results for concentration verification analyses. PrepDaartaetion 9-Mar-2001 Nmogm/minLal 2500..00 50.0 Mmeags/umrLed3 148.4.N04d,D,41C.488.5 44.6,46.0 % NMoemaninal -- 89.2 91.3 90.7 C.Vb. (%) -- 1 2 2 20-Mar-2001 0 5.0 2500..00 NDC 4.33,4.38 17.6,17.7 46.7,46.1 ____ ____ 87.0 1 88.3 1 92.8 1 abcd MaCDMn.eeeVdnaa.ownnftieorrleeslrssnntuuhoolletttnsboedfeufdopdrereluttiepphccoaletirteceatdeansd.taea.lmyresp-ilsseaosmfuptshleiedngdtoufprcoloimcnafttihermesaoumrnigpifiloensra,ml sitaymopflem. ixOturirgei,nal analysis was lower than expected ttTmshaahreimgxeteepedtdlseaetditsnagc(uft+oohbnres1cts0avean.en8mcht%eripacwltloeieosafansnctoouianmnlllieltfihcnoleetarevmlsd)ea.llmosyT.nmphMTleeihxsadeer(adcttehaisn19ft3ot,s.hr0u2e%s0ba0vsmt1eoahpnfiinnlccedeolseimwccaaoiatntsleaalealltl)cht.tlateehtdvetehotleasn.rtgMeTesatthersedcuhtcbeo2ssttn0as,cnue2cbn0est0rtw1aatnaiioscnenduinwicniaafottsehrametthltayhte Test substance was not found in the 0 mg/mL samples. 5. Conclusions hDstouamdtayo.fgroeTnmeesotthusesulbaynsmtaalinyxcseeidsw,oaaftstthnheoesttaafmorgupenltdeesdindleitnvhieenlg0s atmhnegd/smwtuaLdsyssatimanbdplielceaust.nedtherataltlhceotnesdtitsiuobnsstaunsecde winatshe \i > - 157- H-24516: Developmental Toxieity Study in Rats ANALYTICAL SUMMARY TABLE 1 DuPont-5991 SUMMARY OF DOSING ANALYSES Homo3g-MenTaeroit-p2y0S0a1Nmopmleisnal: Middle Bottom AACvvoSeeerrtfaaafnggicedeieaMPnredteraocDsfeuenVrvtaeiaNdrtioiaComtnoioin1n1nca1.*lb Dos5inJg) Concentrati2on0.o0f H-24516 (mg/mL) 50.0 (175.99.63)a (84.84.11) (739.9.79) (145012.73%..826) ' (8187..57) (12003..62) (12004..93) ` (919189%...778) (4837..63) (4849..73) (4848..12) (4848..13) 0.5 1% 5-HoSutraRbioliotmy STaemmppleersature (734.7.37) (9199..59) (4837..62) Homo5g-MenTaeroit-py20S0a1mples 4.96 C C (99.3) Middle 5.06 C (101.3) c Bottom (150.10.75) c c AACvvoSeeerrtfaaafnggicedeieaMPnredteraocDsfeuenVvrtaeiNadrtioiaComtnoioin1n*nca1.*lb (1500..000.376) 1% a Numbers in parentheses are the respective percent of nominal values, b Statistics based on the average measured .concentration (ppm) of the top, middle, c aSnadmbpolettsonmotorfeeqaucihreddosfionrgstluevdeyl., Company Sanded. Oo*' -158- .. -----Does PO' C-wmpanU H-24516: Developmental Toxicity Study in Rats ANALYTICAL SUMMARY TABLE 1 (Continued) SUMMARY OF DOSING ANALYSES Concent9r-aMtioa#nr1-2V0e0r1iNficoamtiionnal"1: /0o0o '""tu 00 Dos5inJ)g Concentratio2n0.o0f H-24516 (m50g./0mL) 4.44 (90.0) (4849..63) #2 (48.94.86) (9128..55) (4962..01) AACvvoSeeerrtfaaafggniceedieaMPnredteroacDsefuenVvrteaiNadrtioiaComtniooi0nnnea0.l0 (4801.9%.40.263) (+91218%0...334) (492150%...370) 20-M#a1r-2001 #2 (48.63.35) (8177..86) (4963..74) (48.73.85) (8187..77) (4962..13) AACvvoSeeerrtfaaafggniceedieaMPnredteroacDsefuenVvrteaiNadritoiaComtinooin0nnea0.l0 (4810.7%3.0.504) (811087%...371) (941026%...844) DuPont-5991 ba Numbers in parentheses are the respective percent o f nominal values. Mean result o f duplicate re-sampling o f the original sample. Original analysis was lower than expected and w ill not be reported. C Statistics based on the average measured concentration (ppm) o f duplicate samples. Company Sanitized. Does not conta'" t s o a rc!! - 159- H-24516: Developmental Toxicity Study in Rats ANALYTICAL SUMMARY TABLE 1(Continued) DuPont-5991 SUMMARY OF DOSING ANALYSES HomStoagbeilniteyityStSuadNmyop3mleisnal: Dosing Concentration ofH-24516 (mg/mL) 20.0 50.0 Top (940.5.63)b (9199..59) (15036.4.8) Middle (84.52.50) (8187..57) (15025.6.2) Bottom AACvvoSeeerrtfaaafggniceedieaMPnredteroacDsefueVnvrteaiNadritoaiComtinooin0nnea0.l0 ((484830.7.7%3.31..98984)) ((9911613388%.....50716)) ((1155100034%86...40..708)) Stability Samples 0-Day Room Temperature*1 (48.73.98) (9138..57) (15036.4.8) 4-Day Refrigerated (49.68.11) (9179..86) (9478..98) 4-Day Refrigerated/5 hr. (49.78.51) (8187..26) (9457..97) .Samples prepared January 8,2001 for Subchronic Toxicity 90 Day Gavage Study bc NStuamtisbteicrss binaspeadreonnththeseeasvaerreagtheemreesapseucretidvecopnecrceenntrtaotifonno(mppinma)l voafltuhees,top, middle, and bottom ofeach dosing level. d The mean measured values from analysis of homogeneity samples (considered fresh/O-day rsotaobmilitteymsapmerpalteusr.e samples) were used as baselines for comparison with the respective -160- Sanded: Oses notcontatnTS^w H-24516: Developmental Toxicity Study in Rats DuPont-5991 Analytical Table I. Homogeneity and Stability of H-24516 in Dosing Suspensions Sample mg/mL H-24516 Percent Type Nominal Measured Nominal 2-Mar-2001 H om ogeneity Control 0.00 n d (a ) -- Top M id d le B ottom 55..00 47..4916 5.0 3.99 Meanf): 5.38+2.2 C.V.41% ' (1107857899...617.3%,) Top M id d le B ottom 222000...000 221007...697 Mean(); 19.7+1.8 C.V. 9% 118(0098438.5...327%) Top M id d le B ottom 555000...000 444434...167 Mean(): 44.1+0.5 C.V.1%0 (88888978....3332%) S tability^ ii 25500.0..00 431.397..369 798974...527 5-Mar-2001 Top M id d le Bottom 555...000 455...900667 Mean(): 5.03+0.06 (11109000911..73..35%,) , C.V.1%0 ((BA)) DTheenoatveesrnagoet dmeeteacstuerde.d concentration, average percent of nominal (in parentheses), standard deviation, and coefficient of variation of top, middle, and bottom are (C) bSatasbediliotyn smameapsluersedheclodn5cehnoturarstioatnrfooormeatecmh lpeevrealt.ure. C o m p a n y Sanitized. Does not contain TSCA CBI - 161 - H-24516: Developmental Toxicity Study in Rats DuPont-5991 Analytical Table H Stability Study ofH-24516 in Dosing Suspensions Preparation Date Sample Type mg/mL H-24516 Nominal Measured Percent Nominal 8-Jan-200l(A> 0-Day Room 5.0 4.39 87.8 44-D-DTaeaymyRpReeefrfraritgiugererera^atte)edd/5 Hour RT 55..00 44..8815 96.1 97.1 0-Day Room 44-D-DTaeaymyRHpReeoefrufrarritgiRugerTerera(atbte)edd/5 20.0 2200..00 18.7 93.5 1197..66 97.8 88.2 0-Day Room 50.0 53.4 106.8 44-D-DTaeaymyRHpReeoefrufrarritgiRugereTrera(atbte)edd/5 50.0 50.0 4487..99 97.8 95.7 % (A) Samples from Subchronic Toxicity 90 Day Gavage Stud]! (B) The average measured concentration of top, middle, and bottom for the homogenfeitty samples (0-Day Room Temperature) used as baseline for stability comparison. Does not con TS - 162- H-24516: Developmental Toxicity Study in Rats DuPont-5991 Analytical Table in. Concentration Verification ofH-24516 in Dosing Suspensions Sample mg/mL H-24516 Percent Type Nominal Measured Nominal 9-Mar-2001 C o n t r o l 0.00 n d (a ) -- ##12 #1 #2 ##12 20-Mar-2001 C ontrol 55..00 44..4484 M eanf): 4.46+0.03 20.0 20.0 C.V.1%0 1188..05(C) M eanf): 18.3+0.4 5500..00 44C64.V..06.2%> Meanff): 45.3+1.0 C.V.2%o 0.00 nd(a ) 8889..76 (89.2%) 90.0 92.5 (91.3%) 9829..13 (90.7%) -- ##12 55..00 44..3338 , 8867..f5r Mean(): 4.35+0.04 (87.0%) - ##12 2200..00 C1177.V..76 1 % 8878..87 Mean(): 17.7+0.1 (88.3%) ##12 5500..00 44C66.V..17.l%o 9932..34 M eanf): 46.4+0.4 (92.8%) C.V. l%o (A) Denotes not detected. (B) The average measured concentration, average percent of nominal (in parentheses), standard deviation, and coefficient of variation of duplicate samples are based on measured concentration for each level and reported to verify uniformity of mixing. (C) Mean result of duplicate re-sampling from the original sample. Original analysis was lower than expected and will not be reported. Company Sanitized. Does no! contain TfiCA cr* -163- H-24516: Developmental Toxicity Study in Rats Representative AnalFyitgicuarleC1alibration Curve DuPont-5991 (a) (b) (c) Figure 1: Calibration curve showing linear fit (line) to replicate peak height ratio measurements (squares) for calibration solutions of H-24516 diluted over a concentration range of 0.0525 to 0.1576 mg/mL. [(a) Retention time = 3.5 minutes, (b) Retention = 4.17 minutes, (c) Retention time = 4.77 minutes.] -164- Iiy ; n o i contai -1 H-24516: Developmental Toxicity Study in Rats DuPont-5991 Representative High PerformanceFLigiquuried2Chromatography Chromatograms Figure 2a: ^3a.p9pmroixniumteast.ely 5?tndimtdreoedlf).osrRaimenttpeenlretniwaolnitshttiaminnedteafrrondraiHlss-at2ap4np5droa1xr6diims ately FIDI B, (010309SR\009F0902.D) pA1 45 40 35 ; 30 - 25 -j 20 -i 15 -i 10 Va_A 5-; Figure 2b: Recspoorlneucsteieonnnttraiatsitvi4oe.n4G8oCfm0cg.h0/mr9oLmm.agt/omgLra.mTohef 5a.v0emragg/emmLeHas-u2r4e5d1c6odnocesinntgrastioolnutoiofnthdeilruetperdestoenatantoivmeinal FIDI B, (010309SRW05F0502.D) ueco3*ri>> -i tOcCvo)O gtcoo. O) j ] 11 __ 1. J1 1 . --- ,--- .--- .--- 1--- .--- --- *--- J--- --- ---- --- 1--- *--- --- --- 1--- --- Figure 2c: Representative GC chromatogram of 0.1051 mg/mL H-24516 analytical reference solution. -165- y '- - -- Company Sanffizsa. Does noi contain TSCACBi