Document nmmkYOXjMk0dmMK3jewrYkpE1

Mars. 3279 oi 7 5125025: Developmen Tosi Sty nats. ~ TRADE SECRET AR226_ 3279 Dwei13 Study Title H-25425: Developmental Toxicity Study in Rats Laboratory Project ID: DuPont-11347 TEST GUIDELINES: U.S. EPA Health Effects Test Guidelines 'OPPTS 870.3700 Prenatal Developmental Toxicity Study ~~ AUTHOR: Susan M. Munley, M.A. STUDY COMPLETED ON: April 21, 2003 PERFORMING LABORATORY: E.L du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 WonkRequest Nowe:GEER SERVICE CODE None AY J H-25425: Developmental Toxicity Study in Rts DuPont-11347 ~~ GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT This studywasconducted in compliance with U.S. EPA TSCA (40 CFR part 792) Good Laboratory Practice Standards, which are consistent with the OECD PrinciplesofGood Laboratory Practice (as revised in 1997) published in ENV/MC/CHEM(98)17, except for the item documented below. `The item listed does not impact the validityofthe study. The bulk test substance characterization and stability analyses were performed at DuPont Regional Analytical Services (RAS), a non-GLP laboratory. These analyses were in compliance with regulatory guidelines. None ofthe aforementioned analyses were performed under Good Laboratory Practice Standards; however, the analyses were conducted in compliance with ISO9002 regulations. All ofthe analyses are considered valid and sufficient for the purposesofthis study. StudyDirector Yer JrA, pr: cts ET Research Scientist ~ ELduPode Nnemotursand Company Applica: "Applicant Representative Date Sponsor: `Sponsor Representative Date --_ 7 -- Company Sanitized. Doesnotcontain TSCA CBI 1.25425: Developmental Toxiity Study in Rats Duont11347 QUALITY ASSURANCE STATEMENT Haskell Sample Number(s) 25425 Dates of Inspections: Protocol: August 23, 2003 Conduct: September 10,11, 2002 Records, Reports: December 17-19, 2002; February 25-28, 2003; March 1, 2003; April 15-16, 2003 Dates Findings Reported to: `Study Director: August 23, 2002; September 11, 2002; March 3, 2003; --_~ April 16,2003 Management: September 11, 2002; December 23, 2003; April 21, 2003 Reportedby: boborfy 8. Breiner StaffQualitiyABs.sBurreabnecre,ABu.dSi.tor 2I-APE-2003 Date ~~ ---s__________________ `Company Sanitized. Does notcontain TSCA CBI 125025. DvlopTximkyeSnyiinRaas Duron 11347 CERTIFICATION `We, the undersigned, declare that this report providaens accurate evaluationofdata obtained from thisstudy. swims: (uemSCCoMSanuiclCthir5ni5t.ar fBeoe ns ~ -- fori: 2hoe 2083 `Manager taser sar [So1n[vinmer,l3 p Al-FTparr3003 ~ _-- Company Sanitzed. Does not contain TSCA Gall H25425: DevelopmentalToxiityStudyinRats --_ TABLE OF CONTENTS DuPont.11347 Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT corns QUALITY ASSURANCE STATEMENT woes CERTIFICATION css LIST OF APPENDICES css STUDY INFORMATION ccs] STUDYPERSONNEL sss OBJECTIVE cvs10 MATERIALS AND METHODS cvs10 ~~ A. To ssn) B. Ton Sanit cnnmnmmnmrrmmmmm--------------------1"0 Br ARIS EAR osama mamm--_-------- | FB -- FSU mmmmmisismmm------------reh G. Selection OfDOSE LEVIS... 12 1. Preparation, Administration, and Analysis OfTest FOTMUIAtONS........vvorveencl3 K. PATAI10MbeESLUEETS crs lS FS -- M, Bt MBER commmmmmmmmm---------- RESULTS ANDDISCUSSION ceramicdT ANALYTICAL EVALUATIONScoon AT Ar CHOPIN mmm ET, C.. Homogeneity and Stability SAMPIES mses 1 D. CONCNITAtion Verification SAMPIES ssc 18 E. Analytical CONCIUSIONS ovr agrmamam---- -- DEVELOPMENTAL TOXICOLOGY crn 20 3 ---- `Company Sanitized. DoesnotconTtSaCAiCBnI H:25425: DeveloToxpicimtyeStnudytinaRalts DuPont11347 --_ A. MBIA FIINGS mss) B. Fetal FIAINES..o rsssss 21 CONCLUSIONS mmission RECORDS AND SAMPLE STORAGE css22 013 33 --. ARPENDICES...onmmmunmmmmimmmmminmmmmsmmmssgomsimmimooty LI OF TSABLTES TABLE | SUMMARY OFDOSINGSOLUTIONANALYSES... 25 `TABLE 2 MEANMATEBORDYNAL WEIGHTS... A I `TA3BMLEAEN MATBOE DYWR EIGN HTCHAANGL ES. smmm--_ `TABLE 4MEANMATERNALFOODCONSUMPTION. . mmmmm--l TABLE CLINICAL OBSERVATIONS... FO TABLE 6REPRODUCTIVE OUTCOME... smmmm-- `TABLE 7INCIDENCEOFFETALMALFORMATIONS. ..... sndmmmnlh --_ `TABLE $ INCOIFFDETAELVNARICATEIONS... " ST APPEAANNALDYTIICXAL DATA LIcSvT OF APPENDICES sassy APPENDIX BINDIVBOIDYDWEUIGAHLTS... mmm] APPENDIX CINDIBOVDYWIEIDGHTUCHA ANGLES .. -- APPENDIX D INDIFVOODICODNSUUMPATILON... smn APPENDIX EINDIVIDUALCLINICALOBSERVATIONS. smi APPENFDGRIOSXS POSTMORTEM FINDINGS... IP. APPENDIX GINDIVIDUALREPRODUCTIVE DATA.... mmm S APPENDIX HINDIVIDUALFETALWEIGHTSANDALTERATIONS... 105 --~ Gg `CompanySanitized. Doas not contTSaCAiCnBI | STUDY INFORMATION SmonmsCocesI _-- ) `Submitter's Notebook Numbers[SIR `Haskell Number: 25425 AS RegistrNyomeRN. ~ rune:fY Piven Carterton Ambros solid J Sit,Th ts substance spesd 0 be sabe unde he -- conditionsofthe study; no evidenceofinstability was Sponsor: E.L du Pont de Nemours and Company `Wilmington, Delaware 19898 USA. `Study Initiated/Completed: August 22, 2002/ (see report cover page) -- F-25425; Developmental Toxicity Sudy in Rats --_ DuPont 11347 STUDY PERSONNEL Study Director: Susan M. Munley, M.A. Management: Eve Mylchreest, Ph.D. Robert M. Parker, Ph.D, DAB. Primary Technician: WilliaPm. Boyer Supervisor: Deborah L. Tyler Analstical Chemist: Janet C. Maslanka, B.S. Management: . Mark Kennedy, Ph.D. Toxicology Report Preparation: Mary K. LaRoe Management: Nancy S. Selzer, M.S. Laboratory Veterinarian: Thomas W. Mayer, D.V.M,, A.CLLAM. William Singleton, D.V.M., A.C.LAM. ~~ --_ 5 CompanySanitized. DoesnotconTtSaCAiCnBI H-25425: Developmental Toxicity Study in Rats DuPont-11347 SUMMARY H-25425 was administered by gavage to groupsof 22 Crl:CD(SD)IGS BR rats once daily at dose levelsof0, 10, 100, or 1000 mg/kg/day. Doses were administered as a suspension in 0.5% aqueous methylcellulose at a volume of5mL/kg/day and dosing took place over days 6 through 20 ofgestation (G). Body weight, food consumption, and clinical sign data were collected during the in-life phase. Onday 21G, dams were euthanizaendd subjected to a gross external and internal examination. Uterine contents were described; all fetuses were removed `and individually weighed, sexed, and examined for external alterations. Approximately one-half ofthe fetuses were subjected to fresh visceral and fixed head evaluations; all fetuses were examinedforskeletal alterations. Under the conditionsofthis study, there was no evidenceofany matemal or developmental toxicity at any level tested. The data for maternal body weight, weight change, food `consumption, clinical observations, survival, and gross postmortem observations did not suggest any toxicity to the dams at either 10, 100, or 1000 mg/kg/day. Data summarizing the reproductive outcomes, embryofetal viability, fetal body weight and sex ratio, and fetal external, visceral, head, and skeletal malformations and variations did not indicate any adverse developmental outcome. The NOEL for maternal and developmental toxicity was, therefore, considered 1000 mg/kg/day. --~ --_ 5 - `Company Sanitized. Doesnotcontain TSCA CBI 1.25425: Developmental Toney Study in Rats DuPont-11347 --_ OBJECTIVE "The purpose ofth study was to evaluate the potential maternal and developmental toxicity of H-25425 in ras. MATERIALS AND METHODS A. Test Guidelines `The study design complies with the following test guidelines: + United States Environmental Protection Agency (EPA), OfficeofPrevention, Pesticides, and Toxic Substances (OPPTS) Health Effects Test Guidelines, OPPTS 870.3700 Prenatal Developmental Toxicity Study (1998). B. Test Substance "The test substance (H-25425) was supplied by the sponsor, the DuPont Chemical Solutions ~~ Enterprise (DCSE), E. I. Du PdoeNnemot urs and Company, Wilmington, Delaware. It was assigned HaskellLaboratory Number 25425. The sponsor was responsible for the characterizationofthe test substance. Test substance characterization was conducted by DuPont Regional Analytical Services (RAS), Jackson Laboratories, Deepwater, New Jersey. A reserve sampleofthe test substance was collected and retained by DuPont Haskell Laboratory. C. Test Species The Crl:CD(SD)IGS BR rat was selected for this study because itis a preferred species for dstervaeilnowpamsencthaolsetonxbiceictayutseesteixntgeanssirveecboamcmkegnrdouenddbiyntfhoermgautiidoenliinsesa.vaiTlhaeblCerflr:oCmDth(eSDli)tIerGaSturBe,Rthe supplier, and previous studies with other compounds at Haskell Laboratory. This strain is also considered suitable relative to hardiness and incidenceofspontaneous disease. --_ Og Company Sanitized. Does not contain TSCA CBI H25425: Developmental Toxicty Study in Rats DuPont-11347 ~~ AEiugghutsyt-e2i3g,ht20nu0l2li(p2a2rofuesmatliemse)-fmraotmedChfaermlaelsesRiwveerre Lraebcoeriavteodrioens,AuIngcu.,stRa2l2e,ig2h0,0N2o(r6t6h fCeamraolleisn)a.and `Bvoenddyorw.eiTghhetsraotns tfhoer tdhaiys sthteudryatwsewreereatmeaittehedr, 1d,a2y, 0oorf3gdeasytsaotfigoens(tdaatyi0oGn)u,pwoenrearrsiuvpapll.ied by the D. Animal Husbandry 1. Housing aAnndimmaalinrtoaoimnesdwaetraenmaacicnetpatianbelde artelaantiavcecheupmtaibdlietyteomfp3er0a%t-ur7e0o%f(1t8arg-e2t6edCat(t4a0r%ge-t6e0d%a)t.22An-i24maCl) (raopopmrsoxwiemraetealrtyif0i6c0ia0l-l1y8i0l0luhmoiunrast)e.d (Afnliumoraelsscewnetrleighhot)usoendain1d2i-vhioduurallliyghitn/sdaurskpecnydcleed, wire-mesh, stainless steel to parturition. cages. Nesting material was not provided because the dams were euthanized prior 2. Feedand Water CPeMrItiNfuitedriRtoidoennItnteCmhatoiwo)nawl,asInac.vaCielratbilfeieaddRloidbietnutm.LaWbaDtieertfr5o0m02Un(iftoerdmeWraltyekrnDoewlnawaasrPeurwiansa available ad libitum. ~~ 3. Identification bEyacthheasnuipmpalliewrparsiaosrstiognsehdipapuinngi.quUepnounmbreecreiapntd, ewaacshiadneintmiafliewdawsiatshsaingnAedVIaDunMiiqcureoHcahsikpeilmlplant raenciomradlenduomnbeera.chBcoatghetchaerdH.asAkemlalsatneirmlasltonfuumnbieqruaendHatshkeelAlVaInDimMailcnruocmhbieprsimapnldanctornruemspboenrdiwnegr.e. unique AVID Microchip implant numbers is maintained with the studyrecords. 4. Health Monitoring Program fAosllspoewciinfgipedroicnetdhuereHsasakreelpleLrafboorrmaetdorpyerainoidimcaalllhyeatlothenasnudreenthvaitrconomnetnatmailnamnotniltevoerlisnagrperboeglroawm, the those that would be expected toimpactthe scientific integrityofthestudy: + `Waantdeorthsearmcpolnetsamairenaanntasl.yzed for total bacterial counts, and the presenceofcoliforms, lead, + Feed samples are analyzed for total bacterial, spore and fungal counts. + Samples from freshly by the cagewashers. washed cagesand cage racks are analyzed to ensure adequate sanitation -- rCeerqtuiifrieemdeanntismaanldfneoetd tios uesxecde,edgusatraatnetdemeadxbiymtuhemmcaonnucfeancttruarteirontsoomfekeetyscpoecnitfaimeidnannuttrsi,tiionncalluding -- -- i `Company Sanitized. Does not contain TSCA C8) $2545: Developmental Toxicity Study in Rats Dupont 11347 --~ pspreecsiefniceedofhtehaevysemectoanlts,amaifnlaantotxsinb,eclholwortihneamteadxhiymdruomcacrobnocnesn,traantdioonrgstaantoepdhbosypthhaetemsa.nufTahceturer would not be expected to impact the integrityofthe study. I`Tahbeoraantiomraylanhieamlatlh vaentedriennavriiarno.nmeEnvtaalluamtoinoinotfotrihnegsperdoagtraadmidisnaodtmiinndiisctaetreeadnbyyctohnediattitoennsditnhgat affected the validityofthe study. E. Quarantine and Pretest Period aRantdstwheenrereqlueaarsaendtfionredthae sctudcy ouptroonpdraopciperdonuvragleosfotuhtelinLeadboirnaHtaosrkyeAllniLmaablorVaettoerrsyinaorianldemsignmee:i F. Study Design The experimental design is shown below: Suspension Dosea Concentration| Time-Mated --_ Group (mg/kglday) (mg/ml) Females 1 ob 0 2 10 2 2 m 100 20 2 Nv 1000 200 2 a vTeosltumseubsotfancmei,kaed.miniired by oral gavage, on ays 6-20ofgestation (G), at dose Vehicle (0.5% aqueous methylceulos in deionized vater) G. SelectionofDose Levels `The dose levels for this study were selected by the Sponsor. H. Randomization rDeasmpescwteivreelaostssiognnethdetboalsoitssofacdcaorydi0nGgtbootdhyeiwregiegshttastiaonnddaasys.iTghneednt,otchoenytwroelraenrdaenxkpeedriwmietnhtianltheir f`gorroaulplsgbryourpasntdhoamtswaemrpelniontgsftraotimstitchaellryadnikfefderleinstt.(pTh>e0d.i05s)t.ribution resulted in mean body weights --~ To Company Sanitized. Does not contain TSCA Cal 125425 Developmental Tricity Sudy in Ras --_ I Preparation, Administration, and Analysis of Test Formulations Dupont11347 I. Test Formulation Preparation wFaotremru)lawteiroensproeftpahreedtedsatisluybasntdanscteorseudspinenadceldosinedthceonvteahiincelrea(t0o.5o%rmettehmyplecrealtluurleosueniln duesiedo.niTzehde methodofmixing the tet substancewiththe vehicle was documented in the study records. 2 Test Formulation Administration "rTehceotmesmtesnudbesdtabnycerewgauslaatdomriynaigsetnecrieedsbyfgoatvhaisgteybpeeocfaussteudtyh.e oral The rvooulteumiestahdemrionuitsetetrhaetd i(s5 mL/kg) was based on the most recent body weight. 3. Test Formulation Sampling SAuagmupsltes26coanntdai2n9i,ng20H0-225f4or25unaitfotrhemictoyn,cceonntcreanttiornastoiofn0v,er2i,f2ic0a,taionnd, 2a0n0d m-gho/umrLrwoeormetceomllpeecrtaetduroen cstoanbcielinttyr.atSiaomnpvleerisfiatcaatlilocnoanncaelnytsirsa.tioAnlslwdeorseincgolfloercmtueldatoinoSnespatmepmlbeesrw4eraendco1l0e,c2t0e0d2onfotrhe same day the formulations were prepared. 4. Analytical Methods ~~ a. Recovery Sample Analysis `0C.o5nc%urmreetnhtylwcietlhlduloossiengwfaosrtmeusltaetdiaotntahneallyoswesl,evreelco(v2emrgyo/fmLH)-,2a5t4t2h5e fmriodmlsepveilke(d20 mg/mL) and at twheeighhigehd l(eavpeplr(o2x0i0mamtgel/ymL1)2 tmogc)oannfdirdmiltuhteedanwailtythi6calmmLoetfh0od..5%Fomertthhyelcleolwlulleovseel., HF-o2r5t4h2e5mwiadsand h3imghLleovfel0,.H5-%2m5e4t2hy5lcwealsluwleoiseg.heAdll(arpepcroovxeirmyatsealmypl6e0sawnedr6e0t0hemnev,orretsepxeecdtifvoerlyd)isapnedrsdiiolnutoefdthweith Hma-n2n5e4r25ainthtehedomsetihnyglcfeolrlmuulloastei.onTshaempslaemsplaetssiwmeirleartchoenncepnrtorcaetsisoends.and analyzed in he same b. Dosing Formulation Treatment 2Eamcgh/dmoLsilnegvefloramnudla3tmioLn sfoarmp2l0eawnads2c0o0llmegct/emdLinleave1l5s)m. LFocrentthreiffiurgsettsuabmep(l5eosrt6cmolLlecftoerd, the tcoulbleesctweedr,e3cmenLtroiffumgeetdhaanndolthweamseathdydlecdeltlouelaocshe rtuebme,ovfeol.loFwoerdtbhyevroermtaeixnidnegrofofrsmaimxpinlge,sts cseunbtsrtiafnucgei,nrgeamnadinrienmgoavsalsoolfitdsh,ewsauspewmaasthanetd.wiAtfhte3rretphleicsautpeemwaatsahnetsw(a3smrLe)moofvemde,thtahenotlestwith vroermtaeixniinngg, acsenstorliifdsu,giwnagsanddrireedumnodvaelronifttrhoegesnu.perTnhaetsaentsoalfitdesr weaecrhewtahsehn.reTcohnesttietstutseudbisntance, ~~ satmetprlaehysdwreofruerarnec(oTnHsFti)tuutseidngtos2o.n5iocrat3mitoLonwaistsuhreTHalEl,mattheer2ia0lmwga/smdLisssaomlvpelde.swTehreer2ecmogn/stmiLtuted Company Sanitized--. Doss not contain T--SCA Cal 25425: Developmental Tricity Study in Rats Dupont11347 ~ f0.1o0 llomwiLngwtiatrhgeTtHcFonacenndttrhateio2n0s0wmegr/emtLhensanaalyzwmede:rp4e.r0eclmogns/etLit,ust6e.d0 tmog1/0m0LmaLnwdi6t.h0 TmHgF/.mLT,he respectively. Samples submitted for analysis were analyzed the day they were received. . Chromatographic Conditions ICnosltruummne:nt: SHteywrlaegtetl-PaHcRka4r;d7M.o8dmelm1x130000HmPmLC(GPC column) FMolboiwlReatPeh:ase 11.000m%L/temtirnahydrofuran (THF) CInojleuctminonTVeompleurmaet:ure: ~~ 3E5rC : Detection: Refractive Index, d Calibration and Quantitation A separate Omi saleof H-25425 test substance was designated as the analytical reference standard stock solutionofH-25425 in tetrahydrofuran (THF) was used to make rceaplliibcraatteiohnisgohlpuetirofnosrtmhaantcberalicqkueitdecdhtrhoematetsotgfroarpmhuyl/agteilonpecronmceeanttiroanticohnrso.maPteoagkrahpehiygh/trseffrraocmive -- cianldiebxradteitoenctcourrv(eHbPyLlCe/asGtP-Cs/qRuaIr)esarneaglryseisssoifoena. cMheacasluirberadticoonncseonlturtaitoinownesrfeoruesaecdhfotecsotnfsotrrmuucltaation were determined by applying respective peak heights to the calibration curve. cToeesftfiscuibesnttaonfcvearhioatmioogn e(Cn.eVi.atn=dystuannidfaorrdmidteyviianttihoenv/emheiacnlxe w1a0s0)eovfatlhuaetemdeabsyucraeldcucloantcienngtrtahteions vienrtihfeictaotpi,onm)idfdorlee,acahnddobsoitntgolmevsealm.plAesco(ehfofimcoigeenntoeiftvya)rioartdiuopnolifcalteesssatmhpanleosr (ecqounaclenotr1at0i%onis `Hcoownesivdeerr,edifitnhdiectaetsitvesoufbsatcacnecpethaabslebdeiestrsihbuotwinonotofbteheditfefsitcuslutbfsotadinscpeetrhseroiungthhoeutvethhieclfeoromrultahteion. analysis has shown variability, 2 coefficicatofvariation greater than 10maybe acceptable. fTohreemacehandorseisnugltloefvetlhewahsomuosgeednteoidteytsearmmpilneesth(en c=on3)ceonrtrcaotnicoenntorfatthieontevsetrisfuibcsattainoncesafomrplthees (a = 2) respective dosing formulations. cStoambpialirtiynwgatsheevcaolruraetsepdobndyiunsgisntgabtihleitmyreesaunltrse.sult ofthe homogeneity samples as the baseline for rBeeccoavuesreyosfatmhpelpersocatedeuacrheulseevedl wtoeriesomlaotneittohreetde.st Asubcsotrarneccteiionntbhaesemdetohnotdhefsoer arneacloyvseirs,y sspaimkpeldes nwoamsianpapllifeodr tthoetlheevesla.mple results,ifthe spiked recovery sample analysis was less than 90% of Ww Company Saniized. Does not contain TSCA Gal 25425: Developmental Toxicty Study in Rats ~ J. Animal Euthanasia DuPont11347 pArdoucletefdeimnaglweistwhevriesceeurtahlaenxiazmeidnbatyicoanrs;botnhodsieoxtiodbeeavsipshcyexriaaltliyone.xaFmeitnuesdeswwitehroeudtedceacpaiptiattaetdiobnefore were injected intraperitoneally with sodium pentobarbital. with sodium pentobarbital before fixation. All other fetuses also were injected K. Parameters to be Studied 1. Inlife ObservationsofFemales Banoddyonwediagyhsts6-w2e1rGe. reFcooorddecdonast ulmeapsttitownicweasprmioerastourdeodsionng dtaoypsro4,vi6d,e8d,a1t0a, f1o2r,q1u4a,ra1n6t,in18e,r2e0le,asaen,d 21G. Clinical signs were recorded at least twice prior to dosing to provide data for quarantine release; signs were recorded once daily on days 4, 5, and 21G and twice daily on days 6-20G. 2. Postmortem Observations of Females Survivintog Scheduled Euthanasia `The abdominal and thoracic viscera were examined grossly immediately after euthanasia on day 21G. The intact and the empty uterusofeach dam having at least one viable fetus was `weighed to permit calculationofmaternal body weight adjusted to exclude the products of ~~ conception. The corpora lutea count for each ovaryoffemales with viable fetuses was recorded. For cach female with visible implantation sites, the typesofimplants (live and dead fetuses, and resorptions) and their relative positions were recorded. The uterusofcach apparently "nonpregnant" female was stained with ammonium sulfide to detect veryearly resorptions. 3. Fetuses of Females Surviving to Scheduled Euthanasia For each fetus, the following parameters were recorded: identification number, intrauterine location, sex,andbody weight. The external alterations detected for each live fetus were also recorded. Foreach liter, the firs live fetusandevery other live fetus thereafier were examined for visceral aInltaedrdaittiioonns,."allRleitvaerfdeetdusreesnawlitdhevmeallofpomremnattiwoanss cvliassisbilfeiaetd euxstienrgnatlheexsacmhienmaetoiofnWwoeoreaenxdaHmoianre.d) for soft tissue alterations. After fixation in Bouin's fixative, the headsofdecapitated fetuses were examined and alterations `fwiexrateirone,cotrhdeedal.izEaxrainm-isntaatinieodnsskweelerteonbsasweedroenexthaemimneetdhoadndofskBealretraolwalatnedraTtaiyonlsorw.e"reArfetceorradlecdohfoolr all live fetuses, excluding the foal heads fixed in Bouin's fixative ~~ _-- --s_ Company Sanitized. Does not contain TSCA C81 H25425: Developmental Toxicity Study in Rats DuPon11347 -- L. Control of Bias aInndadrdeimtaiionnetdo croadneddomduarsisniggtnhmeenctoltloecgtrioounposf,paollstfmemoarlteesmwaenrde fceotadleddabtae.fore scheduled euthanasia M. Statistical Analyses Descriptive statistics were performed for all quantitative endpoints listed below. Sequential two- tailed trend testing was significant dose-response applied to the was detected, data data for each fom the parameter as tabulated below. top dose group was excluded Ifa and the test repeated unil no significant trend was detected. For litter parameters, the proportionofaffected Tfehteusleesvepleorflsititgenriofrictahencleitsteerlmecetaednwwaasspus<e0d.a0s5.the experimental unit for statistical evaluation." Where the data were tied and the standard large sample versionofJonckheere' test was not applicable, exact p values were calculated using permutation methodology. `Parameter Trend Test ~~ MMaatteerrnaall wweeiigghhtt changes Miatemal food consumption Linear contrastofmeans" DLievaedffeettuusseess Resorptions IImnpcliadnetnacteioofnsfetal alterations Jonckheere's est Incidenceofpregnancy MClaitneicmaallobmsoerrtvaaltiitoyns. . EFaermlayldeesliwvietrhietsotal resorptions. Cochran-Armitage test" Fetsaelxweraitgihot) (Covariates: lite size, Sex ratio (Covariate: iter size) Linear contrast of least square means" PN i Company Sanitzed. Does not contain TSCA CI 25425: Developmental Toxicity Study in Rats --~ RESULTS AND DISCUSSION DuPont-11347 ANALYTICAL EVALUATIONS A. Chromatography Appendix A H-25425 eluted from the HPLC/GPC column as a resolved peak over an average retention time of 8.4 108.7 minutes. Representative HPLC/GPC/IR chromatograms are shown in Figure2s (a - ). Test substancewasnot detected in the 0mg/mL control. B. Recovery Samples Appendix A Detailed analytical resultsofrecovery samples are summarized in Appendix A, Table L The variabilityofthe analytical method was demonstrated by the coefficientsofvariationofthe recovery results at each targeted dosing concentration (approximately 2, 20, 200 mg/mL) over the courseofthe study. The measured concentrationsofH-25425 for the 2mg/mL level were 75.7% ~ 10 86.5%of nominal (mean percent recover=y 82.8% 3.8, C.V. = 5%). The measured concentrationsof H-25425 for the 20 mg/mL level were 87.9% to 103.5%ofnominal (mean percent recovery = 96.9% 5.9, C.V. = 6%). The measured concentrationsof H-25425 for the 200 mg/mL level were91.4%to 105.8%ofnominal (mean percent recovery = 97.5% 6.1, C.V.= 6%). Based on this data, a correction was applied to all sample results when the spiked recovery for the concentration had analyzed below 90%ofnominal. C. Homogeneity and Stability Samples `Table 1, Appendix A 2An0a0l2ytaincdalanreasluylztesdfrfoormhdoomsoignegnefiotrym,ulcaotnicoenntsraamtpiloensvceorliflieccatteidonA,uagnudst5-2h6,ou2r0r0o2oamndteAmupgeurasttu2r9e, stabilityare shown in Summary Table 1 and Appendix A, Table IL. --~ To -- `Company Saniized. Does notcontain TSCA Cal H:25425: Developmental Toxicity Sudy in Rats DuPont-11347 -- sTthaebilfiotlylaonwailnygsetasbfloersbuomtmhasraimzpelsitnhgedraeyssuolftsthfoer hHo-m2o5g4e2n5eistaym,pcloencpreenptarraattiioonn.verification, and SampleTyp m 54Nominal 9% Nominal H2o6m-oAguegn2e0i0t2y 0 Np -- --- 213212612 200 144,149,146 60 730 33 6sa5s 20-Aug-2002 20 19,185,204 947 7 960 Homogeneity 0 Np -- --- 2 asm 20 165161173 1100 825 3 1105 4 85 200 189,188,188 940 03 945 ba SMaemapnlerseshuletlsdfo hothuersaantaroloymosftteihmspeetroaptu(r7e), middle (VD) and bio (B) samples. 4 RDeepnoortteesdnroensueltdsetceocrtrede.ctedfo recovery ofthe spiked sample atthe level refer to Table ). `The results for H-25425 samples prepared on August 26, 2002 show that the test substance was sTtoawbelre tihnatnheexvpeehcictleedwfohretnhehe2ldan5dh2o0urmsga/tmrLoolmevteelmspbeurtataudreeq.uaTteesltysmuibxsetdan(cCeVw'asslnesosttdheatnec1t0e)dainnd ~~ the 0 mg/mL samples. a`tThteheretsaurlgtsetfeodrcHo-n2ce5n4t2r5atsioanmsp,leasdepqrueaptaerleydmoinxeAdug(uCsVts29l,es2s00th2asnh1o0w) athnadtstthaeblteesitnstuhbestvaenhcieclweas when held $ hours at room temperature. Test substance was not detected in the 0 mg/mL samples. D. Concentration Verification Samples `Table I, Appendix A Analytical results from dosing formulation samples prepared September 4, 2002 and September 10,2002 and analyzed for concentration verification (uniformitayre) shown in Appendix A, Table ITI and Summary Table 1. is -- Company Sanitized. Does not contain TSCA CI H:25425: Developmental Toxicity Study in Rats Dupont11347 --~ TsahmepfloilnlgodwaiynsgotfatbhleesHu-m2m5a4ri2z5essatmhpelerespurletpsarfaotriocno.ncentration verification analyses for both PrDepaaration Nominal Messuinrle.d %ANveormiigneal o%v asepr2002 2 210659,,211713 1805450 22 200 10-5ept2002 2 190, 191 202,179 955 04 955 8 2200 2198,7,211947 1090 955 1 3 ab DRuepploirctaetderseasmulptlsecsoprerrecltoevdeowrerreecaonvaelryyzeodf.theC.sVp.ikceadlscaumlpalteteaodtvteherflyevuenli(froerfmeirt0yoTfambixlteuIr).e. aRneaployrstiesdforestuhltssaamreplaevser(a7g6e.o0f%alalndan7alys1esoo.fnnot5hmeind%aols,inrgesfpoercmtaivlealtyi)o.ns. CV reported based on the original `The results for samples prepared on September 4, 2002 indicate that the test substance was at the targeted levels (target =: 14.5%of nominal) and adequately mixed H-25425 samples. Test substance was not detected in the 0 mg/mL (CVs less samples. than 10) for all `The results for samples prepared on September 10, 2002 indicate that the test substance was at tFh-e2t5a4r2g5etsedamlpelveesl.s (Ttahregerte=port9e.d0r%eosufltsnofmoirntahle)2amndg/admeLquaantdel2y0mmigx/edmL(ClVev'eslsleasrsetbhaasned10o)nfoarnall --_ average from 3 samplings from both dosing formulations. The inital sampling was lower than `epxrpeepcatraetdio(n76at.0bo%tahnldev7e1l.sw5a%sofrneo-msianmapll,edrebsuptecntoitveplryo)p,etrhleyrerfeo-rdei,sptehresredembaeifnodreetroakfitnhgethdeo.sing nsoammpilneasl.) aTnhdishiagnahleyrstihsawnaesxpleocwteerdtfhoarntthhee2o0rimgign/almrLessualmtpfloer t(h1e223.m5g%o/fmLnosmaimnpalle).(2T2h.e2%doosfing seuxsppeecntseidodnusewteorethaegparienvdiiosupseproseodr asnadmprlei-nsgasmp(l1e8d8.fo0r%aananldys1i3s.2.T0h%eosfenroemsiulntasl,werreespheicgtihveerlyt)h.anAll rTeessutltssubfsortatnhcee3wsaasmpnloitndgestewcetreed tinhetnheav0ermagg/emdLansdamrpelpeosr.tedasthe concentrations for the levels. E. Analytical Conclusions Rtheesutletstssfurbosmtatnhceeawnaalsysmiisoxfedthperotpeesrtlsy,ubasttathnecetadrogseitnegd lfeovremlusleatxicoenpst dfuorritnhgetihnietisatlusdaymipnldiicnagtoeftthhaet 2and 20 mg/mL levels and stable found in the 0 mg/mL samples. under the conditionsofthe study. Test substance was not 3 -- -- Company Saniized. Does notcontain TSCA Cal H-25425: Developmental Toxicity Study in Rats -- DEVELOPMENTAL TOXICOLOGY DuPont-11347 A. Maternal Findings 1. Mortality (Table 6) `sTchheerdeuwlaedssnaocrcifoimcpe.ound-related mortality at any level tested; al animals on study survived to 2. Body Weights and Body Weight Changes (Tables 2.and 3, Appendices B and C) `MTehaerne bwoedrye wneoicgohmtpgoauinnd-orveerlattheeddeofsfiencgtspoerniboodd(ydawyesig6h-t21oGr)wewiagsht91c,h1a0n2g,esanadt a9n4y%loefvtelhteesctoendt.rol gwreoruep96v.a5l,ue99a.t8,10a,n1d009,7.a2nd%o1f0t0h0emcgo/nktgr/odlagyr,oruepspveacltuievealty.theMesaamnearbessopleuctteivfeinallevbelosd.y weights Dovuerrindgaytshe4p-r6eGdoasti1n0g0paernidod1,0m00eamngb/kogd/ydawye.igThhtecsheainngsetsanwceersoesflsitgahttilsytbicuatl ssiiggnniiffiiccaanntcleyalreo:wer considered to have occurred by chance and clearly are not indicativeofany compound-related ~~ effect. 3. Food Consumption (Table 4, Appendix D) `cTohmepraerwaabslenoaccroomsspoaullndg-rorueplsa.teMdeefafnecftooond mcaotnesrunmapltfiooondocvoenrstuhmeptdioosni;ngdpaetraiwoedr(edagyesne6r-a2ll1yG) was 97.8, 98.9, and 97.8%ofthe control group value at 10, 100, and 1000 mg/kg/day, respectively. 4. Clinical Observations (Table 5, Appendix E) `oTchceurrerewnecreesnoofacloomppeocuinad-wreerlearteepdorctliendicfaolroalblsegrrvoautpisonosnasttaudnyy.level tested. Occasional 5. Postmortem Findings (Appendix F) ``TOhcecruerrweenrceesnoofacloomppeocuinad-greenleartaleldymcaotnseimsatlengtrwoissthpothsetmcloirnticeaml oobbsseerrvvaattiioonnssawtearneyrelepvoerltetdesftoedr.all ~~ groups on study. 0 Company Sanitized. Does not contain TSCA CBI 25425; Developmental Toxicity Stdy in Rts DuPont-11347 B. Fetal Findings 1 Mortality (Table 6, Appendix G) `There was no compound-related in incidencesofresorption were low utero embryofetal mortality. across al groups on study. There were no dead fetuses and 2. Body Weight and Sex Ratio (Table 6, Appendices G and H) `aTchreorseswaellrgernooupcsomopnosutnudd-yr.elated effects on mean fetal weight or sex ratio; data were comparable: 3. Malformations (Table 7, Appendix H) ~ "There were no compound-related fetal malformations. Two fetuses from two liters at 1000 mg/kg/day had malformations; one fetus was affected with gastroschisis and a kidney was afbisndeinntgfsroamreonnoet cfoentussi.dDeersepdictoemtphoeundfa-crtetlhaattetdh.eseBoftehtoufsetshearseeimnatlhfeor1m0a0t0iomngs/kogc/cduarryeldevaesl,sitnhgelsee incidences and no dose-response relationship was evident. 4. Variations (Table 8, Appendix H) ``gTehneerreawlleyrceonmopacroambploeunadc-rorseslattheedstfeutdayl gvraroiuaptsioanns;d ithnecriedewnacse dnaotastfatoirstalilcaslpseicgifniicfiecnadnpcoeidnettsecwteerde for any endpoint. -- --T a `Company Sanitized. Does not contain TSCA C8 H:25425; Developmental Toxicity Stdy in Rats -- DuPont-11347 CONCLUSIONS tUonxdiceirtythaet aconnydiltevieolnstoefsttehd.isTshteudNy,OtEheLrefowramsantoerenvaildaenndceodefvaenloypmmeantteamlatloxoircditeyvewlaosp,metnhetraelfore, considered 1000 mg/kg/day. RECORDS AND SAMPLE STORAGE Laboratory-specific or retained by the facility site-specific raw data, such where the work was done. as personnel files and equipment records were ALabsoarmaptolreyo.ftShpeectiesmtesnusb,srtaanwcdeawtaa,sacnodlltehcetefdinfaolrraerpocrhtivweiplubreporseetsaiannedd ratetHaaisnkeedlalt LHaabsokrealtlory, NCheawraarckte,rDizealtaiwoanreda,toar(apterIcreonntMpouurinttya,icnomRpeocsoirtdisonM,aannadgekmneonwtn, Wimiplumriintigetso)n,wilDlelbaewasrteo,red at a JSeprosenys.orCfhaacrialicttye,rRiezgatiioonnaldaAtnaaluysteidcatlo sSeurpvpiocerste(sRtAsSu)b,stJaancckesostnabLialbiotryawtaorsierse,taDieneepdwaattHears,keNlelw LDaebloarwaatroer.y, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, --~ -- - ~ El i ---- Company Sanitized. DoesnotconTtSaCAiCanl no25s0e5speovsgeattToiss Sys oowmse C-- onREFERENCES ------) 2. Salewski, E. (1964). am Utederr Ruattse. Farbemethode zum makroskopischen Nachweis Archiv. Path. Exp. Pharmakol. 247:367. von Implantationstellen 3. Staples, R.E. (1974). Detection ofVisceral Alterations in Mammalian Fetuses.Teratology, 9(3):A37-A38. 4. Woo, D.C. and Hoar, R.M. (1972). Apparent Hydronephrosis as a Normal Aspect of Renal Development in Late Gestation ofRats: The Effect ofMethyl Salicylate. Teratology, 6:191-196. 5. Barrow, Fetuses. MJ.. VM.oarnphd.T,ay1l2o7(r3,):W2.9J1.-3(10966.9). A Rapid Method for Detecting Malformations in Rat 6. Selwyn, MR. (1995). The Useof Trend Teststo Determine a No-Observable-Effect Level in Animal Safety Studies. Journal ofthe American Collegeof Toxicology 14(2):158-168. 7. Haseman, JK. and Hogan, M.D. (1975). Selection ofthe Experimental Unitin Teratology ~~ Studies. Teratology, 12:165-171. 8. Patefield, W. (1982). Exact Tests for Trends in Ordered Contingency Tables. Applied `Statistics 31:32-43. 9. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6th ed. The TowaState University Press, lowa, pp. 246-248, 349-352. 10. Jonckheere, A.R. (1954). A Distribution-Free K-Sample Test Against Ordered Alternatives. Biometrika 41:133-145. 11. Dempster, A.P., Selwyn, M.R., Patel, C.M., and Roth, A.J. (1984). Statistical and `Computational Aspects of Mixed Model Analysis. The Journalofthe Royal Statistical Society, Series C (Applied Statistics), 33(2):203-214. 12. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance for Analysis and Evaluationof Subchronic and Chronic Exposure Studies. Paynter, `OWEa.shietnaglt.onU,nDi.tCe.d, S2t0a4t6es0.EnEvPiAr-o5n4m0e/n9t-a8l5-Pr0o2t0e,ctJiounn.eA1g9e8n5c.y, Office ofPesticide Programs, 13. (RXiUs/k2A8s3s/e9s4-sEmNe)n,toCfhaNpotteirfiI,edSeNcetiwonSsu2b.s2t4anacneds Technical 2.25. Guidance Document reeset CompanySasso otctin304 1 H:25425: Developmental Toxicity Study in Rats DuPont-11347 TABLES --_ -_-- % Company Sanitized. Does not contain TSCA Cal B2H:32454325::DoDevvleolpompmeennttalTTooxicity StuoddyyininRaRtasts_ ~~ TABLE1 DuDpuPeomnetn1i1s34a7 SUMMARY OF DOSING SOLUTION ANALYSES Sample Type/Date Dosing Concentrations and Stability ofH25425 (mg/mL) Homogeneity 26:Aug2002 Norma 200 200 200 Top P13r2 1a03) 1 3) Middle 1260 4s 185 [) 745) `Bottom 1264 @14.06% 022004) AAvveerraaggee PMeeracseunrteNdoCmionnael. [C1228] u0s 041839) Standard Deviation 2004 2040 13 Coefficient ofVariation EA 3% % Subiliy26Aug2002 S-hour Room Temperature Los ge 192 G49) 60) HomogeneitsT2o5p:Aug-2002 2110 161 189 --_ Middle (10535) @05) 45) 2250 161 158 Bottom aizs) 09) 40) 2am 173 188 ails 3) 40) AAvveerraaggee PMeeracseunrteNdoCmionnael. a2t0o 21565) 014808) Standard Deviation 007 2069 058 SCtobeifliicne/n2t9:oAfuVga:r2i0a0t2iont 0 % 03% Shour Room Temperature pn 1s 15 aios) 5) ) ConceSnetprra2t0io0n2Verification 208 171 191 10-Sep-2002 00) 53) 055) 1918 2188 1 055 090) 53) 3 NAlulmrbpeorrseidn presaultrscoameactteehtdboearseessdpsocirsevcopverey rofoctfhesesopnnikiteadevmapls eeetoAppendixA. Table). T`hearavaertoaigfeomoepna,smuireddi,coannodebttriiomn., average perocfneomnintal (in preheses, standard devistion, and coefcen of -- 4 M2Deu0ap0lnmceufeu.sfaomr1pil5cla%snuabflmyistoiesdoi.fs.Maempslaeo.repOsulritgrsepaorataenmda.lyisinswaosflhoewdeortsianngexppeectaedn2.s0myg/smLs=d76.0g% odf nvoiminahleandgi ee----------------------------te= eeeeeegeeieesmm---- `Company Saniized. Does not contain TSCA CBI ~i g2 3 g 7| 8s 84 828 &F ggd -- a8 B5g"B-| | 282% 44%%: ga8% RfSig = EI : 3 3=Z |v | 4g1. 5gs 38 me9s. gRat iv w2y8, gR2o8n =oa 0 g 3 35 o|2R%e2 5Ra3% 8FaT iReN g2 3 i 1 53 4 =88 CompanySaitzed. Dossnotcontain TSCA Cat ~ z 5 -- z 2 g {2i| 8 "~ 3 gi } T2 EZ8H. | oe, vm. ce', cd. & ~ | Ad a E28 EgF 5 2 28 EBg fa in ee es am a24l%s s2als 5229% 2 = z= |9] 2233,8% 2225,8 728:,8 408 L | 53, A 8Fa0%% 18, 5358%8 55, B24%a 95 25ssF 839. a83 38 " 5 E 2 CompinySantized.Doss otcont75a0AiGnai ~3 33 33 3 Z Z 5 g1 3 g a | o3o83g Iw3e q m3a84 2mo% 32 i $Bg| 7] ht3W 88 H 2Sf2,8Eg25inRditi}s $3i ,4 oToB2 y0a lEitTe oRtsT1T3 0AE% i25:: fi il 38 3 | 7 | 8s% 55 828 48 2% 2 = zI I a Iiid iz 07 i ERE aR at Bad 55 ugog L0% s0% og ||Esigiiniil FdEarEaigdl Blv un 1 = 8 EE 2azaal g if% :i E33s% I a2 CompanySaitzsc. Bos ot contain T50A G81 ~ 3g :g8 |s9l| a2g.3g wg3.5g w2s.84 m2e%) Z |S | ast 248 ass agq cB -- o 5 8 g gla | 25. dle | 8eY 18. 24% Ea 847 m3 25 g 38 2 3 g23&7| 2a%R 1%SR: 33G08s odSTe i] S< |, | ag. an. sa. be Z [4 | 24% 238 438 43R 3 J 7I &I 8- 5 :88 CC ~1 IEEE 2 8 " Company Sanitzed. Dossnotcontain TSCA G1 ~3 < a | z 3 3 AI] | 8288%g o5R8,8 #a4d8, eg38, oi 2 sor 3, ii I 2 3P|R8aEf T3E4E8N475d8s 2 3 5 & 88 EEE Ha asl en. es wz 2i 3. _ BE FHzI ||85af28 3842%8 goad 8 gaugs i8t s 52 37 = 38 2 zag, 15] 23% n8, gg' ex. 428 oa. =2R 3a gis ii: g ud sz 7 dis |B Fs :2 3 3 gl $2i5s8i9q8d 3 Z a gl . EB = 658 y frieyd i i si1i10R5E3T PE fH F| ioi%di 3 ~3 : 382 EF ean Company Saitzed. Doss no contain TSCA a1 ~ 3 i _ 3 2 Zi| 7i :4 ~ 3 i3 [3[3% Rls 30s Jie Zz |8i|| ene%fs 3ad8m%: 2as5ta fa g Zs 38 228zgBgEiIa | |aanse,ks a4af%.: ee3s3lxf g3d8g = E 2 8o | ap. 9% | sl% es. 238 wn. 438 ox 3s gg gZ Z o358[4s38 a23385 1a35g% 2g2I = + | &a gI8 QR 43% I 28 ss 8 El. F5 OEow CompanySaniizsd. Dono scontsain 750A C1 ~ 3 ~ 343 zg zga ~3 EE 2 : z zz _ 2 ga | nse 28. ang oz, : = 34 3 8058 875% 5 gt 2% 3: || AE -A Egl E z3 AEA 3$iii 3gT udEg4 Fs EF2 8og [E5F8I iB1dE2 z 5|. = g 5" a 3[5Hifls a53i8%t. 2s%e,di84s 262 4% LE , z3g @5%% & "2 CompanySanitized. Doesnot contain TSCA CBI ~ i 3 } 2 aial --_ | z ~& S .3 WF E oft 5: ogE 32@a ...i 28oa lB3aEii na i8 f3 s z i3H8 |g:f Ei 3 ii is Li iz Ugi R8 NS% SEER agi le 2 [ES ------ H-25425: Developmental ToxicityStudyinRats DuPort-11347 ~~ TABL6E REPRODUCTIVE OUTCOME Group: x Dose (mg/kg/day): No. vated =n No. pregnant 20 No Delivered sarly Yo. Deaths No. With Total Resorptions Yo. Litters 20 u Ee w 10 100 1000 2 2 2 20 2 20 o o o o o 20 Ed FY Hean Corpora Lutead Implantations Resorptions: Total Barly Lace 15.8 GB Ha 08 0.2 0.8) 0.2 0.4) 0.0 150 0.0 13 6) 0.2 (0.4) 0.2 (0.8) 0.0 155 18) 15 M8) 0.3 (0.4) 0.1 (0.4) 0.0 15.5 (0.3) 135 6.3) 0.3 (0.6) 0.2 (0.5) 0.1 0.3) ~ Deaadd FesFetuses, 0.0 0.0 0.0 0.0 Live fetuses: Tomal | 142 (L8) Males 7.4 @8) 13.2 Gu) 164 5) 13.3 @.) 7.0 2) TS @&) 7.2 (2.2) Females 6.3 (22) 6.2 2.3) 65 G8) 61 (24) Mean Fetal Weight: Total 5.55 (0.34) 5.53 (0.23) 5.48 (0.20) 5.50 (0.31) sox maniod 0.52 0.15) 0.52 (0.13) 0.51 (010) 0.52 (0.37) a pSrteasteisnttiecdalforanailnyfsoersmaatrieonnoontlyc.onducted on bean corpora lutea data; these data are b SSDettraatnidlsaittrtidecrad.leviaanTtahileoynsmeesaisnarnreuempobonerlrtyedofcoinnmdapulacertseendatnhodensfetesmh.aelmeesanaretotparlesennutmebderfoofr liinvfeormfaettuisoens 4 oNanmyb.er male fetuses/total number fetuses per litter. Note"l:earteaThsletoanpccrieespgttniacfnaocrlylyfreatatanelalduyaeztieagd,htuasdiaunnldgt tsmheoexrtCraaoltciihtor)yandw-aeAtrraew,itaaanngadelytstheeesdtt.uostiaAnllglrJeolsnioctrktpheterieormnae'adsnata CSoqsuta.re mFeeatnasl. weiNgohtsiagnndifisceaxntrattiroanwdesreveraenadleytzeecdteUds;ingp a< l0.i0n5e.ar contrast of least -- 3% `CompanySanitized. DossnotconTtSaCAiCnBI F-25425: DeveloToxpicimtyeStnudytinaRalts DuPont-11347 ~~ TABLE 7 INCIDENCE OF FETAL MALFORMATIONS Grow: 1 un 1x w Dose (sg/kg/day): 10 100 1000 `Exe No. Bxaninedd Gastroschisis Yo. Affected 263 (201 263 [200 316 (22) EP i. ol ot) ot) 265 (20) 110 1m viscemy No. Examined Kidney - Absent No. Affected 17 (20) 136 (200 164 (22) -- - -ot) oe) of 138 (20) fey 1m EAD Yo. Examined ~ Yo. Affected 147 (200 136 [200 168 (22) 138 (20) ow) ot) ot oto) sme Yo. Examined No. Affected 263 (200 263 (200 316 (22) 265 (20) ot) ow ol oto) TOTAL NBER AvEECTED se ow om 202 a Cuaslfboerrmaetxiaomnisnedareanedxapfrfeescsteedd,AsinFactluusdeisng(Ltihteternsu)mbeorr aFfefteuscetsed(wLiitthtertsh)e. listed b Pmoarlfoeramsaetioofnsr.eading, zeros have been replaced with dashes for the listed Note:GverSatlaltitsottiaclalanadnatloytsaelss abryeeoxnalmytcyopneduacrteedproensetnhteedinfdoirviidnufaolrmeantdipooninotnsl.y. ThNeo Significant trends were detected. --~ 3 `CompanySanitized. Doesnot conTtSaCAiCBnI H:25425: Developmental ToxicityStudy in Rats DuPont11347 TABL8E INCIDENCE OF FETAL VARIATIONS Grow: 1 un Dose (mafxs/aan: 0 DEVELOPMENTAL VARIATIONS `Ere No. Bxamineds No. Affected 203 1200 263 (200 ow) oto) x 100 316 122) oto) TM 1000 265 (200 oto) Yo. Examined No. Attected 147 (200 136 [201 164 (22) 138 (20 ol oll ofa) oto) Yo. Examined Yo. Attected rere Yo. Examined ~ Rib - Rudimentary Cervical Rib - Supernuserary No. Affected 147 1200 136 1200 164 122) 130 (200 or oto oto) ot01 263 (200 263 (200 316 (22) 265 [22] 1a ep -- ws se sa ue sl sm om nie TOTAL WITH DEVELOPMENTAL VARIATIONS sm s@ cm 1@ -- _--m 36 Company Sanitized. Does not contain TSCA CBI 25425: Developmental Tonicity StudiynRats DuPont-11347 -- `TA8(CBontLinuEed) INCIDENCE OF FETAL VARIATIONS Grow: 1 1 ES TM Dose (ng/kg/aap: 10 100 1000 VARIATIONS DUE TO RETARDED DEVELOPMENT xremnL Yo. sxamined No. Atfected 283 (200 263 (20) 36 (22) 265 (20) oto) oto) oto} oto) `viscoRnL Yo. Examined Kidney Small papilla - size 2 Papilla - size 3 Yo. Atfectea 107 (20) -- sw sw 136 20) 1a cm osm 164 22] . sm sm 138 (20) ae 2 2 Yo. Examined ~ Yo. Attected 17 200 136 (20) 168 220 139 (20) oto} oto) oto) oto) sxmLETAL Yo. Examined Wavy xib(s) Skull - Retarded Ossitication Sternebra - Retarded ossification Vertebra - RetardedOssiication Yo. Affected 203 120) 1m wm Tw 100 G8) 107 08 263 200 --ww iw 14 (9) 17 09) 326 (221 es wa z@ 125 G2) 15 (221 265 (20) as um ae 98 (9) 103 Gas 37 -- Company Sanitized.Dossnot conTtSaCAiC8n1 H25425: DeveloToxpicimtyeStnudytinaRalts Dupont11347 ~~ `TABL8E (Continued) INCIDENCE OF FETAL VARIATIONS Grow: 1 un Dose (sg/ka/aans 10 m TM 200 1000 TOTA7L0 WRIETTHARVDEADRIDAETVIEOLNSOPDMUEENT 108 G8) 1m a9) 1s G2 105 Gs) TOTAL NUMBER FETUSES WITH VARIATIONS 1 ae as 09) us ea we as a b VFNaourrmibaeetarisoeenxsoa,fmianrecedeadieannxgdp,reasfzfseeercdotseadsh,avFeeitnubcaeleeusndiLrnigetptlteahrecse)dnuomwrbietrhFeadtfaufssehecestse(dfLoiwrtittetrhhse)t:hleistleidsted NoteG:verSatlaltitsottiaclalanadnatloytsaelss abrye ooxnalnyacroendpursetseedntoend tfhoer iinndfiovrimdautailonenodmpyoi.ntNso. siTghneificant Erends vere detected PS --~ 3 Company Saniized. Does not contain TSCA C81 H-25425: Developmental Toxicity Study in Rats ~~ DuPont 11347 APPENDICES --~ -------- 3 Company Sanitized.Dossnot conTtSaCAiCanl H:25425: Developmental Toxicty Study in Rats --~ DuPont-11347 APPENDIX A Analytical Data --~ _-- 0 `Company Sanitized. Does not contain TSCA CBI H-25425: DeveloTopxicmtyeStnudytinaRalts Dion 11347 ~~ TableS.amRepcloevery of H-25425 Amgd/dmeldHt2o5D4o2si5ng Vehicle Percent T Nominal Measured __ Nominal RTeCeoovERY) 211969 116748 R82244 Recovery) 28 215 757 RREECCOOVVEERRY?Y) 226666 223207 386553 RecovERY? 298 252Mean 528844635, CV. 5% RREeCcoOvVeErRyY?) 119908 RREeCCOoVvEERRYY?) 201084 RREeCcOOVVEERRYY" 119954 210657 1807.395 119912 9919..80 119907 1901.145 Mean 9c6v9.2o59%, --~ RReeccoovveerRyy") 118879 2m00 1901548 RREeCcOoVvEerRyY?) 118980 181 953 183 23 Mean 9c75v2.6%1, ((A)) PPrroocceessseeddwwiittshboommoggeennievyveerryiiflfiicc/aatctiioocnnsosaamomnppllenescffrocoemmddoenossiinntngg pprrrteeppaaarrreeddAtAauuggiuaissttn22o96,,22n000022. (()) PPrroocceesssseeddwwiitthhccoonncceennttrraattiioonnvveerriiffiiccaattiioonnssaammpplleessfrroommddoossiinoggpprreeppaarreeddSSeeppteemmbbeerr41,0,22000202 (8) PSroecpeetdew1im0,br2ee0s0ra2mplingofconceiraionverificationsamplesfomdosingprepared () SPerptoecmobsedrwi1t0h,s2e0c0o2ndro-samplingofconcnttionvrifctonsamplesfomdosiogprepard ~~ a -- Company Saniized. Does not contain TSCA CB F-25425: Developmental Toxicity Sudy in Rats DuPont-11347 ~~ "Table I Homogeneity/Concentraron Verification and StablcofH-25425 in Dosing Suspensions SaTmipplee omar"mani. 125425Siezed N= ominal 6A 2007 HomCoogmsnmcoi.es: 000 NDA) - Tor 2008) 132 ao MBoororosw 22000088)) 121266 00 Mean(): 1c2v80s04 0% MoToors 2200008)) 114415 0uss Borrow 200 Mean(): 1164660.40 onmo Tor 20 c17rn ws BMooriosn 00 128050 1902250 Mean): 1c8r9213 6% SHour) 220000@8)) 110555 ss5 29-Aug2002 20 102 %0 ~ HoCmoomgson.siy 0% Noh) -- MTootre 22000088)) 22215 11025s5 Borrow 2008) Mean(% 2a20n2007 a1nosn Tor 00 cv161 05 BoMrorootw 2000 112631 08655 Mean() 1c6v50.69 as MTooor 2200 11888 o94s0 Borrow 0 Mean(): 11888+8058 o54n0 SHo() 2008) cr2o21ss 10s 2000 1817s 89145s A(B)) ADlelnoetpeosrreodt rdeecsisdc.omet based on recovery fhespikedsmple (fe to Table). (C) Tvahieasivoenaogfemoep,smuriedceonncdenbraottioomn. sverage percentof pominal (parentheses), sandr deviation, and coefficieonft ) Sbily samples ek hours room tempera --~ 2 Company Saniized. Donotecontsain TSCA CBI H25425: Developmental Toxicity Study in Rats Dupont 11347 ~~ "Table I. Concentration Verificationof B-25425 in Dosing suspensions Preparation Day Sample Type mgm H:25425 Nominal Measured Fen Nominal Sepra002 `ConcentratCioonntVreorlification(A) 00 ND - 20010) 205 1025 2.002M0e)ar): 211 208% 0.05 105.5 ao) cr.a% 2001 169 ss 2002 13 865 Mean): 17c.1r+m028 @s.5) 2200021 119900 995550 Mean): 1c9r12o07n1 5.5) Concentrat1i0o-nSeVpe-r2i0fi0ifc2caattiioonn(") Control 00 ND) - 20010) 2008) 1010 20020) L796) 507 Mean: 1912016 cra 059 2001 2196) 1095 2002 212) 1085 Mean): 2c1v8.410%14 09.9) 22000012 191847 955 97.0 Mean(): 9c1y5s4%9 5.3 B(A)) DDuepnloitceastenostadmeptleecstepde.r evel wee snalyzed. Me, 5.0. 3d CV. clued foverywnforiyofmins. ()) MAelalnpsoarttroressnsacloymcoesntdubpalscetodnarmepcolveeryofthe spiked sample fet Table (E) M0eanmemsl.fo7a6.l0a%naolypsoimsionfaslam1plde.2O0r0igmingalman.aly7s1i.s5w%aosfnloiwenrth.anexpects Duplicate sampling ofth dosing suspension azad and averaged wihe torighinal ays. --_ -- = -- -- Company Sanitized. Does not contain TSCA Cal 125425: Developmental Toxicity Study in Rats DuPont-11347 Figure 1 Representative Analytical Calibration Curves 3000 Equation for the fitted line: Y =-17.970907 + 333.0798 * X 2500{ R-Squared = 0.9996 Z22 200 25 1500 32 1000. --_ 50 zs 1 ss 71 5 Concentration, mg/mL Figure la: Calibration curve showing linear fit (line) to replicate peak height `measurements (squares) for calibration solutionsof H-25425 diluted with "THFovera concentration rangeof2.1411 to 8.0886 mg/mL. --_ - a Company Saniized. Does not contain TSCA Gal H:25425: Developmental Toxichy Sudy in Rats Dubont-11347 -- Figure 2 Representative HPLC/GPC/RI Chromatography Chromatograms [TT ROTARIOARafeci(veRdEo0rS2oSmTG0E02020) | Ri | |\ | z i 5 5 0 % En Figure 2a: Representative HPLC/GPC/RI chromatogramof 0.00 mg/mL. dosing suspensionof H-25425. ~~ oR TTA RID. Racivs dexSpal 062O8OS0T520250) | ! | | | z 1 E 0 z EA) Figure 2b: RoefprHe2s5en4t2a5t.ive HPLC/GPC/RI chromatogramof 5.9475 mg/mL analytical reference solution --_ -- -- = Company Sanitized. Does notcontain TSCA CBI H:25425; Developmental Toxicity Stdy in Rats ~~ Representative HPLC/GPCF/iRgIurCeh2ro(cmoanttoignureadp)hy Chromatograms [RITA RIARefacivOs GdeZxSRoUlESTOTE B70) |g |g DuPont11347 x] 2 | { z 1 5 ; To i a Figure 2c: RnepormeisneanltactoinvceenHtPrLatCi/oGnoPfC/6R.0I0cmhgro/mmaLtoofgrHa-m25o4f2250.0Tmhge/mmeLasdousriendgcsounscpeentnrsaitoinodniolfuttheed:to ~~ representative solution is 190 mg/m. a 57 RIO Rifacivs iesSnelOBZ90ZSTOTE21C3 | | |: s | |7 0 z z 5 | | To = En Figure 2d: RdeiplruetseednttoatniovmeinHaPlLCco/nGcPenCt/rRatIiocnhorfom6a.t0o0gmrga/mmoLf.o1f89H-m2g5/4m2L5.spTihkeedmdeoassiunrgesducsopnecnesnitornation ofthe representative solution is 199 mg/mL. --~ -- -- % -- -- `Company Sanitized. Doesnotcontain TSCA CBI H:25425: Developmental Toxicity Sudy in Rats ~ DuPont-11347 APPENDIX B Individual Body Weights -- -- a ~ `Company Sanitized. Does not contain TSCA Cal 12125542255:DeDevveellooppmmeennt) TTooxniicicty SSutuddyyiinnRRaattss ~~ Individual Body Weights DDuuoponnet-n1i13y4r7 Explanatory Notes Note dRaepyo0rtainndgdoafybo4dGybweeciaguhstedwaetiaghthtadtawtearaerecoalvlaeicltaebdleprfioroatlol satnuidmyalsstarotn(tdhaeyse6Gda)yas.reAlinmyitoetdhetro bavoadiylawbeliegihnttdhaetraafwordatthae.scparate breeding lotsofanimals collected on days prior to day 6G are Footnote `a Maternal body weight minus the weightofthe productsof conception. Abbreviations N"-P- ==NNooDtaPtreagnant -- =-- `Company Sanitized. Donotecontsain TSCA Cal H25425: DevelopmentalToxicity Studyin Rats Dupont11347 ~ INDIVIDUAL BODY WEIGHTS (grams) GROUP 1: 0 MG/KG/DAY ammoesn OAYO DAYs DavDeAYS OFDAGEYS?TATIONDare DAYS DAY 10 -_-- 7 ses6e333333s88256 Gm) 2m2.l0 2sl0 a2a5e1l3s els 22662140 mle 22609.43 ass aZsee.s4 293.2 23669150 ass 227670.87 3030 seSesseiosn se3309 2a6s1l0o alo aeslelon 2elz r25e5l0a7 2se7 aem7i1s5 aels 228376.03 seas a30a3as aes 33o030s% 201s s66633440068 Gs3a1a 2auleloo ilo a2660slls7 207i 22873sl2s esis 22736437 aa 22as89l75l3ss dssesansas 92ze99n9.28 sGes33a0z51 se3a30 2232l000 malo 226037011s asa 2260601 s 2602 aseelss 261 2e3n0d4 sls sseosss deed 7290027 2e80 Ss66334337 G63439 a2s5l00o 20l0 226612lse aisle 221757133 asco aasllyo assis 22meev2s dees aasseis ana a9ss0o amo ssee3saaasas prin aasslloo 200 2ass3is as3ls 2am:i2e ale e26l1s 2601 2s6e0o3 2772 2aase0ss0o a2s0er4sass SSe436ic3a (np) Gauss a24s0llo0ilo e25e0l3s 230 227e27l8e aera 2s7o5.s0 a0i2 2a27s6ses aase0sssa.6 zs16e2ee7ss S646 27lo amis 2:2ls 2980s 001 30a 31a --_ --~ _-- E `Company Sanitized.DoesnotcontainTSCA CBI H:25425: DevelopmentalToxicity StudyinRats DuPont-11347 ~ INDIVIDUAL BODY WEIGHTS (grams) GROUP 1: 0 MG/Ka/DAY anmosss -_ DAY Il DATI2 DAY Iavs oDrAYca1s4TaTIODNAY 1S mv 1s oar 17 7 s6e3a3z8e5z te) 22706.i7 S338e 3052 227915ms 7 2z6e1es dale 23606231 345 3de:e0s7 ma 23260h2 sss ademalos aes sss6ee3se3s9er9s 2d30m072.l64e 32031s60l7s 3alss 2:02 d3eaals 054 332000 3s. d3ss3er2s veeelys av sSs6e6333i41200a88 332009068200 aa310m0slllss ai3sz4il3se 33l226e0s3 adesraes cdisaearsno ddsaeeree psreoivnesd se3i30 2s15l00 2708 a3s0i7n 302ls a3s2siss sole a29l2s3 3131 m2s9i 4 died a3orass 32 nasee see se8363i43317 S63035 jaeislao 2072 aswlls 2%12 s3ao0llss as2ls ojalsios 2037 3d7e3d 30a 3ads3ai0sn0 eaaaesls s sseessaaiias se3icz a2s7l9o5 2911 2290970046 2msl7 2i0:0330 298la 2a9s1a1 03a 0di6s0s Joss msssi diez ad2aele sels se6334a6a3 Gm) Geaies 32181011 20 mmelien 2:21 3easlios ols 2a8i6.s0 081 ldeassaa 317 Jaessa 330 aammees ae Ee Ms 3:3 aml rie ea ses ama Pa -_-- 50 `Company Sanitized. Doss not contain TSCA CBI H-25425: DevelopmentalToxicity Study in Rats ~ INDIVIDUAL BODY WEIGHTS (grams) GROUP: 0 Ma/KG/DAY ANonHBaEsR DAY1e DAY 1S DAYSDAovF20GESTADTaIvON21 Day 218 -_ 8c6e3a3s8e5 WP) pe 3266735 m7 3262823 desis 2se6372 sels adoenar 30.0 3s0o0l3 asa Gsee33339e10 563395 l30ss ale a3amly 3807 a39l9s0 smi aarseo 33 d3e3ed ders sseeS33eaai00ne86 e33l6sas ssdeeoaillnss aairslae als aadeesn a4 a3se8 anes sesss3a0115 s6330 3i7s0 3s a3sssila7 Imi daso a: asseasesoss a3nna3elsss G8s66633344a333971 233909003i mdelles 313 assssn aml asale 3923 dmasse joes ssees3aaias seca 33630'is 3sals 33540072 36s edeall e sess sdeorss dose ndeaa 03.7 d6s36ic3a mB) sesaes s20l21ss 3sels a29n6l3o ole zaelnsy ssl asesnsio aie ssoaisls ams Sesser BL desis axa asia sar ~ DuPont11347 ~~ 51 `CompanySanitized. DoesnotconTtSaCAiCBnI H:25425: DeveloToxpicimtyeStnudytinaRalts Dupont-11347 r INDIVIDUAL 30DY WEIGHTS (grams) GROUP 11: 10 M/Ka/DAY waaS -m_n--EeR DAYO DAY4 DavDeAT YS oFDRGYasTATIONbars T oarsTmR ayo sSe6s3s2 G63393 223436.000 aslo a24e7.s4 amis s26l0.s0 assis 2e6r0.s8 2330 a2m2i.s7 asco 2d6osno 296 2307090.0 3094 s666333333999856 0m) 2223370s00l00o 226a00llss 26s 22:12520 aasls 228662.37 2563 2aeesd4 256.0 saeee1n7 ase m20e6lse ees ss6633140057 2a3llo0 63013 aw milo asorlss 2001 e26l5e6 2501 2ze5s9a7 za6i2 aaane asi aaseos asso eaenless 633 ses3e2442137 se3i2a 22s0s0l00 slo e26l1ss 263.4 aammias 2190 2m3l0s5 mals 2e279vs0l.es5 dsaeoselass asaeooans sese33ai2278 s63i20 a20l0o0 rio aassilao asia 226635052 amis 22668880 ae d2e7s3e ea a21m5as sees azemnes asa se8s63a4i3s3 sesaar 220206l00 slo 2a6a1ys 260i aemlier 2msls daannya 2901 aanviea eed masssso sess seelnys sons ssaeeei3iissss 2a2330s5l00o 2aassssias 22e6el4s anil a27m0l7 292s aamniae dees 2ar0am dens eseaasn ses Geaice 20lo 28s 2e6le mls mo seas zee --_ -_-- 2 Company Sanitized. Doesnotcontain TSCA Cal H:25425: Developmental Toxicity StudyinRats DuPont11347 ~~ INDIVIDUAL BODY WEIGHTS (grams) GROUP II: 10 MG/KG/DAY amMBoEsR -_-- DAY 11 DAY12 DAY DI3AYS oDFAYGa1s4TATIODNAY 15 DAY 16 oar 17 TTTEmw Gs6eaa3z9e2s sess 3806023 3090 S395 WB) 2152 a2es a3m3i6ss 32100.i8 2aelsle0 a29s2a9 23639.a3 323m30 323e1rs7 d30e2n.e7 saamss daoer s sdeeesse s6d363339968 6G633i40057 a2685.8 2227.4 maalan 229171 odaasiiss 2a03s0l0s e28l1a5 ssellss 233ss s3u2i4 3s0a3s0 sssiss sneeees ddaelse 6ss6633340i112373 (WP) 22u6997s0.44 e63020 Jos s3e0l7s 3d1e6en a3s0ssll2e aailles aaissehlas osaaeillzs 323si24 a33m60l8 Zmeinsa sseees dseeresn eaaln Ssee3aa2s7 SS6633442353 2208020l5s 2900 2a9m7i0es 3022 o29i10es 006 0091ss 323 3deo0eos 33362s 3204 sspaee saa 6 213 30007 281 siz dinz ame sese33aaa4s7 SS6e3i4ssz1 2269782 207% 2390s303 2:0 3m0o3 20815 730711 08s 3e3lse 3003 ejens 3230 s3aen ses 263 29907 306i 3127 3:03 3a ml sessezaacsss 23987.058 2397902 m0l8e1 aullse ddasro d3sso sdaense --_ --~ 5 = `CompanySanitized.DoesnotcontainTSCA C81 H:25425: Development] Toricity Study in Rats ~ INDIVIDUAL BODY WEIGHTS (grams) GROUP 11: 10 Ma/ka/DAY wmnaan DAY 1s -_-- sess36633z33s99s32 a330m0.i04s s56e3039s6 mB) se33s8 236251112 397 s866e3334i100375 (wp) s326es8ll1s73 ssee33aa2137 336ssallos SS6633a43247 a63i28 smilee 366s sef3rae3n3 Se3aas 332a02 373 sSe6a3easa17 e3lso SSea3iiss2 a36i6lis Se3ise als DAY 1SDAYSDOAFY2G0ESTATDIaOvN 21 3m2isls eslz onaesias amis 3an0i2a 436s 23s7a4l7e 339i a269110 als s2o6l9e3 sees 2ss5ee8s0zs3 2aa6mm5id3s 4a29is3s0 33m03 amis aseosss aes atzoelee aso 3sm3a0 esis ssoallsa sez saes: sora 337611 aslo esrsaa 39001 aasmlao a1rle eselles 330 msellss als aa;olae ase serie dose asl AY 218 3s0e6d3 oaosl s28a6.a0 a3o0oa0on0 a17e.0 asdraaesas ian0sae dziesss 3d332o20.d00 -- DuPont11347 --_ -_-- El Company Sanitized. Doesnotcontain TSCA CBI H25425: Developmental Toxicity StudyinRats DuPont11347 ~ INDIVIDUAL BODY WEIGHTS (grams) GROUP TIX: 100 MG/KG/DAY AnBnEaRn -_ AYO DAr4 DatDsAYS OFDAGETS7TATIONDAYS mars oar 10 TT FR mw ses3633308a7 se633335907 2253050.00 2600 aamsias 6sl2 a26m2i.s0 2m s2elms eed 2a9m1es asi a2moe aoe daessceo ens 2300 asia 260 247 3938 200.8 sS66311002 as3it0 223326.00 23000 waallse ase easeod 26 2sa6l6a0 alo azemaie daar a2a6:s as daemnes esleye SSs633012 sse63a42s0 2350000 22461.00 2a7s0sli0s 2a6l5s2 22363017s s26l31ss 2273542 v2a0lss 2se9s50 adesllee 3200a87 22562902 edeiisn aeensa) Gass3sii2s6 pS6r34e4d0 22000000 2300 2255:0005 assla e260s1 261 2a7m4iss 260le Z3a7l5e8 163 a2e0s5s 2156 dseeaelss seals Bio aelz a0 ele am ame see GS66344a13 ssees3a4sss0 23500000 2300 a25e002 a1sls a28l6oi amis 2266147s amis a26l5e6 sens aamees 293 asewees sess 210 2423 adele as0s 3532 sees seve GGee3iisss7 Seaee1 22420.000 2700 32650712 aslo emslizs 2601 asllss 2645 aaess 301s aaeeses aan saeeeniyn dere ~ ~~ 5 Company Sanitized.Doesnot containTSCA CBI SH:Z254:25: DoDevvleoloppmmeenntaallTTooxxiicciltyySSudtyiinunRRaayttss DDuuPopnotw.n1d13e4r7 ~ INDIVIDUAL BODY WEIGHTS (grams) GROUP 111: 100 MG/KG/DAY vsaeL" -_-- sesse6s33m3385c70 ss6e333a9072 GS6633440230 sesse3e3aaa11n06 sS6633aa2z0s SsG666333444423068 sSee3sa43 seS633aas409 GG6e2i4sss7 Seal DAY 1 DAY 12 DAY1D3AYS oDpAYGES14TATIODNAYIS DAY 16 mv a7 TE xu aa2s3ll.a3 23a39l3.0s5 33320m89l13s5 3asemll.ss 33314s03.a06 33das2sa3as aa3s8em73 22221'3s 27 2207913s 20s 230:s0l2e 02lo 20999l0ss 305.7 sa3il1ess 3331a0 zee 3veae ns 2S:0l7s als 233:23174 30002 330304i melo 3 3063 3s issdle 3:93 aesos ses asmeelns aes 2s7l5os 2001 d3o0e0s2 2s niusslles sols a3:zls sls 3333721s ass 3ca4e3s seta 3esvass aes 22200097200s70 2209070s3 30sls a30s2l.s4 sla 33017334 340 amisrae 3303 dsaairs dass daaaass eas e2s2i0s4 3007 229831031 desis 320080573 mls o0a8d siz a31s4a4 asls 3d2i3rs3 aos eaaelse oasis 236s90 ala 3a0m7i4s aris 2aml0ies sels 230as dala 23344.6 daa a30s03 ses Iansde m0 2217 assis oss ula 3200 30a aise --_ --~ _-- 5% `Company Sanitized. Does not contain TSCA Cai H-25425: Developmental Toxicity StiundRayts --~ INDIVIDUAL BODY WEIGHTS (grams) GROUP III: 100 MG/KG/DAY waoumBaERn DAY ie DAY15DAYS ODFAYG20ESTATDIAOYN 21 av 21a _-- ssee863n33z3aa970 m3302l.0e63 a36z5l.70 assis 3de.l7s sols aasossis sala 3d2a0.r0 330 sGe633a39072 se3403 a3sssis assis w3isae sez aamsias als aesre s 3s s32090e3s ses36a31102 Se3416 3a8060113 mz aerlisa amie sdaelly aoa aaczeos ana 23964s sie see33a1280 sesazs 3ami0s 3708 33:m2sllas 332 aaiwa als a43rs a does saeis 30 SSg666333a4a23a680 3336s9e25l3s a3m9ll70es7 asSel2lso adaoawana 3a380s05e02 sseeS3s63aaasa43n5 33s0 alo sIemlis sein s3esl0s3 als saomslo asne 3s0a7i3n 3a seSei3z4se0 S347 3a2l60s1 32ls 3sa306l23 dosla asiosllse aslo aasles sss 32301043 daar seser sen sls amr ase ames ~ DuPont-11347 --_ _-- 5 `Company Sanitized. Does not contain TSCA GBI H:25425: DeveloTospicmityeStnudytinaRalts DuPons-11347 r INDIVIDUAL BODY WEIGHTS (grams) GROUP IV: 1000 M/K/DRY rmt E DAC O DAr4 DATDEAYS opDGAEYS?TATIONDAYS Dav oar 10 -_-- 7 Sae3333e88 WB) Gea30a 2a6s.l0o 20500 2264030.s2 2684 mssss 2633 2m6i2.o3 2nals e2216l960.e70 a2aa6s21.i6 22aes7ses0 sGe633a40000 S63a0 maalloo 26l0 aacrle sila assilso els eseios 2a daeesaar 277 aeerss gens aemsre aad sS6e3aa0n9 as319 223390000 alo 2262sls 2ssia 2amac 220s5 e227 z2eisis2 dele aaels e ails 2309391s 2033 GsE3303222 WP) 2laeolo s63a34 20000 2a5m5i0s3 28901 2a3s2i2a ols 2zi0e9l8o amis d2e1v1o mes esedes assa ss2e6ae2er5 SS663aaa335e S63442 2206l00 aslo s26s21n3 20707 e2essls 2a eamlise 260 d2e9n3e elo a9s5e3ls szameeasnssy GeSe33iissss Ge3asa a2es0llo0 20700 2a5m8i1s1 26512 aammiise asic azelar 2034 d2e7nse ees eaeess aso 2s30e07e73s0 SSG66e33344a65s09s 2m2m2allloo0 aassse 2sel2 s2aiz 262 e2necllss amie m20l1e3 solo aamei)s as0s sseeaar sess Geiss 2700 26813 2m mele 2931 des doz ~~ --~ _-- 5 eee `Company Sanitized. Does not contain TSCA CBI H-25425:Developmental Toxicity StiunRdatys DuPont11347 ~ INDIVIDUAL BODY WEIGHTS (geams) GROUP Iv: 1000 MG/KG/DAY WmawoEsR DAY II, DAY 12 DAY ID>AYS oDFAYca1s4TA|TIODNAYS DAY 36 DAY 17 _-- seG3ezesne Gm) 20713.40 S63394 2002 236006.10 28801 32164424 30ols 236290.31 ails 2da6v.i5s de 2367a.8 se 2660s.6 3390 seG6s3a4000 sesi0 a21m9ils7 3212 misllsa 3083 22:02s2 364 asioes avis 02162 pag dooinss mss 33204800 sis ssee33aa0n9 s63a1 3a0ss7'0s7 20707 230s esis aansn 2912 2sesd 081 3oi3s mo dsiaass dine aamsas 33000 s6e33003222 (261302732 Ge3i3a 2970s 324080s7 300i 3248737 290 3300011 0sls e2sl2s5 dea 323se02 mrs 325s80 ser seeG3e3aau3a362s 23200s66l11s22 332010340220 a31n8e0 2914 a32o30l5 0sle a33i00e5 3123 ssss sa 33s9 sel sesd36e33i4ii5ss3a 333006520.0136 333080512s 33300s88ss 33s19l900ss 3332318.2 33s3a36r5sa sadasesese Geaae3uissse e360 3i0l60s7 2202 aosssliss 2:70 u30l2a2 ols 3d0a3l1e dalo mdea a0 3ddaeaas 33agds print 30703 ale aslo 32208 3:13 Mew 3s ~~ ~~ -_-- 5 `Company Sanitized. Does not contain TSCA CBI H25425: Developmental Toxicity Study in Rats ~ INDIVIDUAL BODY WEIGHTS (grams) GROUP IV: 1000 Ma/KG/DAY nsear Ds oarsDAYSDOaFY2G0ESTATIDOaNv: pay 21a -_-- se3G36033391808 0B 3am2a 355s ammelz els e2l2e1 me ooassess as oeenns aus seSes3aa00n0 S63408 330ss 3207 33m0 312 33200s4 a2 a3bels ane ateerea sae sSe63aan09 sesa10 3a9m2l sls 3s0i1 n 361 aavlno eels eaasrase 33291990.s70 se632a4z322 P2533628s G63a34 30 23 843 amis asnelsz den aZseleo ans oaoels oss eG6a3ae3s sesaiz 3am6i0e 3a 3emllys 36h admoilne Selo aaaeas allo aalsse 295.0 SS6e33ia5d3s Seas 3a2l2s 3677 0de0l7s dees aavleas 0's 4a3assls oes a33e4 04s sesse3aas8e0 sesa60 aMm2a2 sls 33sssla ela a3lao sen maselzo aoe osried darn sesaes als 343 anki aes so Po DuPont 11347 --~ -_-- w `CompanySanitized. Doesnot conTtSCaAiCnBI H-25425: Developmental Toxicity Study in Rats DuPont-11347 -- APPENDIX C Individual Body Weight Changes. --~ - o Compny Sanitized. Does not contain TSCA CB H:25425: Developmental Toxicity Study i Rats -- Individual Body Weight Changes Explanatory Notes Footnote a Matemal body weight minus the weightofthe productsofconception. Abbreviations | NP = Not Pregnant ----=No Data Dupont-11347 ees Company Sanitized. Does not contain TSCA Cal H-25425: Developmental Toricity SudyinRats Dupont-11347 ~~ INDIVIDUAL BODY WEIGHT CHANGES (grams) GROUP I: 0 MG/KG/ORY unMBiEnR os ws eDCAYS op GeEdSeTATION10-2 12a 1416 cGeaaszeesz tw 17.63 G6336 ule 15778 elo s0o as mfai ss 2ls2h 07 saz2 a2 1aan iso SSSe6ea33233e98s19 L2es0 2 11m nls 0zso so ms2 12 aiso Ss assaa 17 zass 202 GSSe66333a44100s88 22275 8 u15s4 me m5a3 ws malss ass am2e ai a5s2 ss 2a0 2s SSeeaaazsn 63430 1ss az o1w2l2s a0 p1is] 87 2s8a azn Masss als wsae wl m11is2 SGeesaa3n7 pri lfeee ls 11s27 1002 0a0ls als 73s8 sa 1177as 12 oiwlss 3s amlls ma GeGS6e33a4ueaesaz 3 mF E v uosa a15 ils as313li m52 32 m5l5s ar 1nl0s ul GGeeee6sa ew Seuss 220035 2sl3s Luis 3iz 10 oawlles Sia s8l3s $2 m7a3 eo Ssoi 1s pared #200 72 nls 5a wi wis ~ --~ `Company Sanitized. Doesnot contain TSCA CBI 125425: DevelToxoiciptySmtudeyinnRatts --~ INDIVIDUAL BODY WEIGHT CHANGES (grams) GROUP 1: 0 MG/KG/DAY sAomnsaER fr DAYS OF GESTATION sseesa3ez3ee8sz6 me) 6-01'6 38 26.0.27 sen 1703 ala 39.3 sos s6e3a3z9e1s 2233 mwsa a1mal ssans SS6633330096 Seaa08 3Te621 3a assoo eoasnes eos aes ssias EE66204145 G63ia1 230hs 203 esooss aaeess ssa mes aasdo sas EG66a443301 S63437 2Z3i smsaa aross aasnss 3 ses sea ms SSe633s4a3s9 Seaads f 20soea:ls b10e0s5 a3ess HE sls ae sels Sr See3ia6s2 r. 2 als os2s ls amma als oma sed pSe3nas7 H3E2 elzz aasse l ssanss Dupont-11347 --~ @ `Company Sanitized. Does not contain TSCA Cal H-25425: Developmental Toxicity Study inRats DuPont-11347 --~ INDIVIDUAL BODY WEIGHT CHANGES (grams) GROUP IT: 10 MG/KG/DAY. anBeEsR ous 3 eDBAYS oF GBE1S0TATION10-12 12le 14-16 6G6e63363333899323 w0a fs 1a2s6s ba 1u2l7 Sa 5G.a7 ul a5z.2 7 aalss 197.s8 ss mis GGeeaar1osn6 te) aSls G63398 als awiaa 5s muaz 10s m5z5 12 iaslis ss wsass owls a2e.2 i SG6633440075 mmlles 1 ls a3 om 121 i saes mmol mwlls ua7l1s 2m.a0 1s ils 53 oa os SG66330273 Se3524 nallss 1owl6s wa 160 sS1s0 m0l2s sallss 52 ss mi 7s7s 1a8laa ss 203 GGS6e633344a222789 L20a0 nz osmles ua 2is3 s1 m5i2a wa 1w2s0s sa aoloneu:s wa 17a GS66334443s3 863447 20755 nls ssh: alo a nls 2s 5s3 als as6l 53 uFlEa 1 w16na SSeeaiss Ge3ass nnlhs 11s6 ws mn a$35 nwliss a2s1 11s 120d0 24 as2 ws nls als Se3a66 als ul Bh ma we asl 2s --~ & CompanySantized. DoosnotconTtSaCAiC8n1 F-25425: DeveloTopicimtyeStnudytinaRalts -- INDIVIDUAL BODY WEIGHT CHANGES (rans) GROUP II: 10 MG/KG/DAY wna unpER 618 em emDAYS OFeGEmSTATION ss6e33338932 22a7 e2oss amsi2a s4e3s es6a3%39s3 me) 060.37 eal1s oa asis snelns ses6s333s9s0 1a637 aseslas niesllse daoiss SSe6a3aa0075 3alse asslop aweasn asasa eS63314137 mB) 310ss a0ls a2m8s9 ai2 sp6a3rae2n3 2a6l0s5 smeai 1m6lss 0e7n GS6633442278 2a0l0s wailss sseezs s1l7y GeSS3e64u4as3ss B23l01o ss esalr7esi1;eas aaseczleos SS6e3a4u4s71 s36l0s5 2002 a1s4l8o aarains Gassee3eriassess sBlws01 amse2oz aaasmssiss ssazlsis ss --~ DuPont11347 ~~ `CompanySanitized. Dossnot conTtSaCAiCanl H-25425: DeveloToxpicimtyeStundytinaRalts ~ INDIVIDUAL BODY WEIGHT CHANGES (grams) GROUP 111: 100 MG/KG/DAY jvAL ous as cDAYSaoF o GESTATION10-12 ale Gse6a3z3e8a7 220.54 152.h 5a52 1i2a17a6ss a13a0 s86633333907 Seas0z 2W2h Te anehs ws aael a2 S5s5 aso a102s Sl w5s7 a2 5S6633440130 Se3a12 Bwhe nalbe Ne 2s T5e1 Ze a5e7 123 010s mn wal2 wl Ss6e3u86 S63420 $258 az n1ua2n mmoo Ss wanle ls mai1s 21 oswsl asi Gsee3u4z2e5 Se3a38 useo 2508 wwli S27 s2l3s wl d2s% Ge aam2o aol aaras wo ssGe663334aa441310 3302 2502 ubel G2 s7i1s ma aam2o ass m3sls5 aSe1s0 wm Ge633i45400 Seaise nnise sslos 12 al 3ils 7 Be ass ara s7e3 120 a5783 sS6e3a4s5e71 2B1o aaia 7a5 eolise dSes 1as1s --~ DuPons-11347 ee a18l7 aaare2ss ma a2le a Cals 1a2s3a a1l2 asllss aa1sl0iss mwlbe -_ Cl Company Sanitized.Doesnot conTtSaCAiCnBI 125425: Development TrichyStudy in Ras Dupore1347 -- NDIVIDUNL BODY WEIGHT CHANGES (srans) Group 13: 100 WE/KG/OAY soisneo was wen emoars oFesaseTATION pi pGrets wBWoEiooesGedns wmdeann mamlole prfeeat2neodn feaao nwE osee SENeG3inommaeEemonawahn ffaaiiniz team BB B7E0 enwown imaesEs Tao Ba aed mBwlbn ais ffaeaiiazzse pr] eBRerEoOoEEGLSn aWesssd ose ami uwslkds an ofpaiHse iis n RIeoo enBmIr EE Hn Ewawsse mi aisens al pairieed F wFCIeanC me an ~~ --_ J & Company Sanitized. Dossnotcontain TSCA GBI 125425: Developmenal Toxicity Stdy in Rats Dupont11347 --~ INDIVIDUAL 300 WEIGHT CHANGES (gran) nove TV: 1000 WO/KO/DAY . aoEsR F-E-oaa. rs oF i GastaTION SScem6ee0sr am SB73i20 E6300 Peo 1W2aS 1wB0nDa 5H wesessr sl mwsahns mE nw2hi1 oan uwsss3 an 6SG3eo4ra0o5 Sam BB WE3i oWaB 4S% 0 BM3s3 ME8B5o Bi OMi 3 gs o5mwehir mh wvahlek ss oasmlla na SSNeeaiiZzsz am 2Bb3ie BwOEass Gru S50 as ai3s iEenrs mmo3hn whaeaa ooeuwnn se sn ash ar ale SGooeaaaan2ressz Seria RB1F30ooasOwH0eS aWMrGI Tio di a3 s&8@sns mwDisEs awsllne a2ea0s SE ml aa as Gperreuasssesot Gras R WBPi 38 OBB3E0 nod aDfnpD wwNuiEn DOES wnmkas mh aesllnee wl aawlon wa G6irei6s0 2H3 ie B00 osaer 8B1E mTEk nukk a=sk -- -- [L------ ------`Company Saniized. Does not containTSCA CBI H-25425: DeveloToxpicmityeStnudytinaRalts --~ INDIVIDOAL BODY WEIGHT CARNGES (grams) GROUP 1V: 1000 MG/KG/DAY nn WER I DAYS op GESTATION psreeer wm) 2030s1 s5l2 masmss 0eeae Ssee33389040 2[903 ssnl asllso saaslse ssee33aa0041 3512 1elss mm23 assoo see3344018 220708 aslsss m1e9zs weas seses3aai2s2 3a0l8s 3s9e0n0 1s2s0s1 3siss SS6e3aa33zs we) d6o'0s dsels a3z2o4 9o-aoo seS3eaaa33s6 229077 sselo 11e7ls2 eesls Spsreeia3aaaszs 22290sa1 sssllssrl s1aemlss amis a3lse sols pSreaaese 32520 saesllso 11220s1 2a0s1s ssGeee3s34aa8sc0s0 3232a18 lssllsos a1s2lalss aaslso2 --~ DuPont-11347 7" Company Sanitized. DoesnotcontTSaCAiCnBI H25425: Developmental Toxiety Study in Rats -- DuPont11347 --~ APPENDIX D Individual Food Consumption --~ 7 `Gompany Sanitized. Does not contain TSCA CBI H:25425: Developmental Toxiity Study in Rats --~ Individual Food Consumption Explanatory Notes Abbreviation NP = Not Pregnant DuPont-11347 --_ --~ -_-- = -- `Company Sanitized. Does not contain TSCA CBI 125425; DeveloToxpicimtyeStnudytinaRalts DuPont-11347 --~ INDIVIDUAL FOOD CONSUMPTION (grams) GROUP 1: 0 MG/KG/DAY omuseEsR as ss edDoAYS OFdGoEaSrTATIONaaas wens 16-18 i s3a9n2e wm Ge3zee aai2e Re a6e1s Bo s2e2s he 2amss wma 1msa aa 2l6m1s oar 2a8e8 a SGeea3r3o8n0 se3ass 2250 #E dBeE BBES Bd3a7 GEeh asmsllsse wmls aanhsna ase u2ss 2 21 dgweaeez ne GGee33ii0068 SSee3ae1ss FRed 22s0 Haa BL BhIa ds mmeh ah amlee mh aase ame m3a0 ze mls ma ms ae SSee33aa3z0 GSe633403371 3 RS HBoy daeess EMBEs lsie E2S 2m6l0e mle 2amsa ah 2a6s7 xa 333a ae Speaurzs Sean 3#59 2B2e Zdoee dBois amlss 2E3Sa mmllss aRoh amlse aamna 2ma5 mmas 3a6es a3e8s3 SSesMaeE2 ae GSee3iecss mAsi ME 2333 ms aBess B30 waissi mmies 2m0l9e amlse s0s8 a2ss m390 ase Sesser Re Rd NE ~~ -- - 7CompannySanitized. DoesnotcontainTSCA CBI 25425:Developmental Toxicity StiunRdatys DuPont11347 --_ INDIVIDUAL FOOD CONSUMPTION (grams) GROUP 1: 0 MG/KG/DAY To aounsen wen DAYe_ SmoF GESTATION o seGsesaeszs om) Geazse 12814 30 2m020 ao SGeea3z3ess1 s63399 32930s s2lo 1 sis prSei3na06 se3a1s f20s3 aare Zo aslo pSSreeia3uunsa01 n3ss0l am2sl7ss SeSS36e3aa433ns7 2 #3 32 w2ihs als SeSae3saa4s0 Seais2 22015 oaasiss Bs als SGee3aia6eas aw Seaaes 91035s Er 229007 Se3a67 21 3 PS -- - 7 `CompanySanitized. DoesnotconTtSaCAiCanl F-25425: DevelopmentalToxicityStudyinRats DuPont-11347 --_~ INDIVIDUAL FOOD CONSUMPTION (grams) GROUP 11: 10 MO/KG/DAY aunBER a Ge edDoAYS OFAG0E1S2TATION12a 616 262 Gcee333zse23 563393 32.56 201 s2e2n8 se 2se3s ss m24a ze m2672 ass a2e4s asin 20982 dala GSGeeias3ss0e8 mm) 312923.060 - aarusa 33 msiess 3 2209.a4 2s 3105a6 2a 2m3sa 223 n1l4s0 ms GGeea3aao0s7 32a0 Sa: am dele s2a5sa ie 2as6a3 soa 22e6s0 mls. 226r0a 184 230s ase 3al3s 2200 S8e6a3a4z137 Seize Jeoes 34 2z 4s e; 2a 3a Bs z23s mo 22ss als m2633 a7 2n9a9 2s SeS363aaz2s7 Seaa29 $3e6 Bo 3auas a4 mslss sen 2m7a0 ma 3aa0 awa 2a3s60l7so siaase S6e234a3a3s G63447 335::35 30 aa10 sae saeann mie amsas as oaalsiss aes 2aaa 261 0 29% 24s SSee33iess21 Seuss 2200%8 3s 3da3s1 aa szeha aes malssa 29 2oaa6sei3s 0262s 3s 32l9ssa pared 225 34 asa 201 268 2a 32 ~~ --~ -_ 7 Company Sanitized. Does not contain TSCA CBI F-25425: Developmental Toxicity StudyinRats --~ INDIVIDUAL F00D CONSUMPTION (grams) GROUP II: 10 amBiEnR ee Ss6e33a8s3 Se3a3s9s wm eSG63630340808 SG6a3i4n0s7 am SsSee6a33a11z27s3 GeSe33642278 SSe6a3u13239 Spei3naad7 Gpeisnas2 GSeearsases MG/KG/DAY wen E2XsE 13s 23005 n2l1 1672 23653 23s5 2B8E2 BPso 2F3R aas5 DAYeSaOF GESTATION 2s 1a8s6s 229a04 2s1l0s a12s83is aaess a30s00 aahe as 22aasl --~ DuPont-11347 --~ -_ 7 CompanySanitizad.Doesnot containTSCA C81 125425: Developmental Toicty StdyinRats DuPont-11347 GROUP II: 200 annGEaR ----- GGs6se3nn32e50r06 prS6io23rn0a7n pGpaaitisia]] SGGeuraiaazsz0 GCGoeerrruausaz0s SSeearraeitda SSeeaautisssey Grae IOTVITAL MG/KG/DAY 6 en 3#2035s mdBsoh o2Be3i iBdelan B3 BSy MdBsEs P#B33p0 aBa3so aBmaeoR3kian 5 2 #3 ammasi fR7se dMSeee noms 200D CONSUMPTION (grams) edDoaa ys oFaGoaSrTATIONdae hmdanen wm3aes moaweoe HBBIyI B3BLI5 aaalkss mmB3aE zBBLns 3 saeon maBens 3BkIas awmslsao E2W3DE REhGEi mmglins BBGaIos aaBsl5a3 aaomsmssa EnBswL kdmass i Ealos RD OED EE ede 6s mmmaba aannl amalhhs mmaeso mmahaa oa3a0a maasela wwaklea ammlehe aaaaon aaalsoss aaweel zmalsls asaeoss wa an --~ -- FE -- 7 -- CompaannyySanSianized. Does notcontinTSCA CB H:25425; DeveloTospicmityeStnudytinaRatls ~ INDIVIDUAL POOD CONSUMPTION (grams) GROUP III: 100 MG/KG/DAY wosaELR wn DAYeSnoF GESTATION se86n3n38a7 G6S363339370 GGee334i0032 sep3rai1n2t seSse3iai1s8 ssS6e6333aia2226s0 seS6i34z4e0 pS866a340n441 GeG6e3s45e0 pS6i3irs7 a0.77 d2o6s1 a0073 2a:a0 1 az s2e6 aal1a m3 a233 wmao nn2la2s mem7sa 3slss 2297% 620a00 2o3a4s0iss 08a8 2210s 7Fr2 ls --_ DuPont11347 -- 7 Company Sanitized.Dossnotcontain TSCA C81 25425: Developmental Toxicity StudyinRats Dupont-11347 INDIVIDUAL FOOD CONSUMPTION (game) GROUP IV: 1000 MG/KG/DAY WaoMnBER as G8 80DAYS OF1G0E-S2TATION121 lls es sseaxsees1 Gwe2.08 226.40 220841 220927 2815 2168a7 1299.02s ee330080 2247 aml1s 0:03 mm7s mzlse 222ss 91sm psree34t0y8 223s ams1s amlss 226s0 226as 2a1lse 2ansa pSreiannt 2 3s am2a 2e7 a; ws m26ss 223s k9h8 ppSeiiatt32 me) 22100335 mm2l11ss ma22a0. m22a11 2aml4so a2m9ll0ss3 2209000 sSeea3aa33s 2310s8 22033 2zesa aaseos 22041 220s5 n3l3ss peer33i34e66d 2226000%45e 222007a1a a226s09 2e268s3 22wm3aa 22z4aa 33a46ds sGeea3sass3 2B50e7 2a6s2 2maa 2m7s1 mmlas amsal 3w00a3 SSGeee33saaessoe9 22258151s3 ms2l0lss a2286sas 222406328 mz2sa7 a 2 26a m3al0ss3e Seases Hs a1 a3 alo sa sa se --_ --_ 7 `CompanySanitized. DoesnotconTtSaCAiCanl H25425: Developmental Toxicity Study in Rats --~ INDIVIDUAL FOOD CONSUMPTION (grams) GROUP IV: 1000 MG/KG/DAY oamneor wn DAeYSmoF GESTATION sesseazseosn mp) SSee333a9040 Ss66344000 GeGae3e41015 ssseeeaaaazz1z5 me) S6e3a4a33s sesS36633aa03ia6s2 SG6e3e48s3a SSee33iiss9e GeGeaaies0e 6210.0 2201.1 0 20 a2s6lho 3m32 2 ae F6E2S 2502 2S2o3:s m2si7a 33s7 22960s9 33310a 2339900%17 H8ie a2aa F 00 ET 245 32635 3as2i ~~ DuPont 11347 --~ Company Sanitized. Does not contain TSCA CBI H:25425: Developmental Toxicity Study in Rats -- DuPont-11347 APPENDIX E Individual Clinical Observations ~ a Company Sanitized. Does not contain TSCA C81 H-25425: Developmental Toxicity Stdy in Rats --~ Individual Clinical Observations DuPont-11347 Explanatory Notes Footnote: a `Twheerefimrastdoebstewrivcaetdiaoinlyroecnorddaeydse6a-c2h0Gd.ayIifsniondsiicgantsedwebrye"oa"b;setrhveesdedcuornidngbyth"eb"s.tuOdbyservations examinations,the "b" entries are omitted from the prinout. 8 -- -- Company Sanitized. Does not contain TSCA CB ~5 : 3 i 2 ii Bligme. a al add LEIET RRR + RE Eb , BBoRfoEmaEmsDl TT0 TTDD amwmamssnl omTgTT ofdamnesd EOgEd EEEE...... Loom m aEdn oomdiagann oo The ee EER ~ E|g EESEED D D DID D I looNsI enE 8 sii eiiea v2 ID INI in ae : Bf Illini g i EFETE a 5 EL] Wasa s SAEAE BAGAE : Poise 3 3 iggs ff fo zg: EEE ogz;illeEBiBfmoF B5hgeozpfiiEisi J|| oop2i diiBsEs:foEDoEBogEE do; EEG PEE oBcEg:f BRE c[cEf pcist BEG PEC 5 safigfiiigdadiisgddagdii ~ i 3s gE Company Sz. Gos ocr 5A 0 z i EgsoiI TT 9 9 sang Bi. EE 3:4J 2 %-8 % 5 = ooo I2 I -- 1 LE NN 28 wFea$ll00T co0oonoii niimo norornoron g Ps i AsAs i a 8 5 05 3 3 fe ge $8 gee oe ~ pyre EEE 3 i283 3 {8 3FJ opfgEEgiiif:f g:i8 SJl os ciiEg % gies BB 58=:F8 88 v2 8EEwd BE ggg o:g% EFzEEzEd C28 o EBEEEE2 23 3 3 8 3 BOE OEE OEE 82:0:82o:82oE8:o&#;8og8 8 8 88 8 8 EEOEE EEEE OEEEE 28 42 rd 02 $2 oF 2 g ZBi8 8 8588 CompanySantize.Doss ot contTSaCAiGanll --~ 5 3 3 i z i u i si adad| sdrdRs. | | aii rit. ag >-, Fob ooooanono ~ 8 Esl ois = E Bal "To NN : - N g Boi lllllolniniiionolo E00 Fqf Illiloniiiiiionoloo g | savas ssaEeds 3 5 a i g ss 8 og Jogpilbitiin oe 32 2 i fgdl ~ ifggs8 g58s gE 2 5 3 8 3 i 2 sEf: 8 2 ggifi; EEE of o&o% f di{sEsEdE sBsEsEs: BE fEEo p apiF e SiFiLg3i 85i8iLg E LgEsE Z| ZBIS $ e88 GompanySaitzed,Doss notcontaSiGnA G1 ~3 ; 2 ii gi 0 0 0 0 ail Sai CooololEEl Dn gE OBEIC OCC DTT EDD 8 ogi oct dE SOE EE DE dogs on noon i B40 oon ononoronnororon 2 is a a i < a 5 sas 5 & a a 3 j2 2 822% 32 $2 5 3 3 J Egig og fz 8&8 $148 8 1 HE iz % 5 5 % 5 % EEF OB OE ET FLEE EE EER ELE : 4B EE EE EE FE OE OE EE 2 i 8 8B 8 & & 8 & & g Il gEpiE EB gE 8 8 CompanySaitzad. Dos rtcontainTSGG1 ~5 : 3 | a| i: FE Bai cc dct ~ . cc . - JJ ] css. gaa. - ~ . . ean. . BLOOD Ln EO o.oo oo oD ll 8 gal c cee AE EE = g Bab0 0 0 Dll E a SE 4sh To oT Tolono NN g id a 5 a a 5 5 a sisas a #4 i ,, 1% F BF 8 EEE ogpE oB Eid BE 8 8 f # 8 8 FE4 8 I] fE5iw os ox o5 oz ozo o EEE o& d file 2 8 8 8 8 88 "493 3 a3d gSz 8& iiFg 2FE FEB EBH OoH BOB o;8B RoBF g Es Eo E oOfE fd sais 58 38 38 38 33 34 gd 3338 of [ET S---- --~ . z i 3 gif cc LOBE CL ee DL Dl ~ le Ek EoEg2i3H loolononoE roronononn BoE&l occa ee 2 Pi dd 8s os soo&s oawos JBl S giig g g_ i1i1d&88 3 Os5 iE &B58 082B 8 B&&& #g8 gg2p 88g @B82E 5 BoB OF ox o OE #8@@8 #B4 XE g884828 &x C3 Rn5 oE.1TP8EEE& ET8EI EELEEEgELEIEEIP EIFEIg EE Company Saiz. Sos otcr5nG1 ~3 ; & i , EEL DODOUIDD Do Poko ooo ~ L5E EedSi D ee A EEo8gasi i1TToDoTnennonToonTonniTnnToninTnooo : g Bad 10D IID oronninonnito 2 PoE 5 aaa 5 5 BAE4E LEET] a H i808 388 2 8 pg zg: 3 d sl zI &,ii%g 8%R E B g5f EER OI BE EE EgBE og1p EBDEB 3 Boi: oso pps for BE opp: og df ig df ogEisd 5 HEE e388 FF Efi EEG Efi ~ 3 5 EE:z 3 3% 33 2 3 3 Z| ZBi8 3 88 2 @ [ET SP ---- ~3 ; 3 i BgEiEf BAR if dies Bip onn ae Eada ~ | EEE 8 pei oLiililon a SogOdFf IvIellrlel . gE iio g {| szssge 4 24 , P1sE8E2E5 3OC &3 g stpf EEg 13iJ| 93:cfffiiiigf:8g.fEicEE:fzg o48z os EE HERR EL ~ E EEE : Company Sniizsd. Doss not contain 0A Cai ~~ 3 : 3 i g| ii EF Et SA Bpo000 0 DD ssT l gos o-o Ho e PoEb oon goss Pi & 0&8 & nnn & a s&ss 8 3 3 PS 5 8 8 58% 8 gg 8 3 g gEid 4 4 & 4 & 4&2 FRE OE od I Efi or oxo: 5 Box oi opr oxox RE IER ELE ERP I FU 8 EEIE 8 og o& og og og o& gE Gompany Sana. Dos nacontain SoA G1 3 i 2 i gsi 4 ]" Ad NS NN AN Bpasl 00D DDT DT : PLL LD nnn --~ gOEH ce BE OBajoiinononononolololorl : Bef iit oC oro g fas 5 & 5 sas & 3 3 8 8 3 3 | 27 2% gp2 2 2 2 3 3 32 J EZ. is? fF FB gf 2 2 OE OE OE OB Fo ogEicf d fF #f 68 4 & & % # 3 g5ifs 5 5 3 EEE 4 ~~ i3 = gizd 8 58 38 38 $338 28 33 24 38 8 gd 8 EzREiig3 2gE 8 2 8 3 38 8 8& 3 3% Company Saitzad. Does nt conan TSCA CB 25425: Developmental Toxicity Study in Rats --~ DuPont-11347 -- APPENDIX F Gross Postmortem Findings - BE ~ `Company Sanitized. Does not contain TSCA CBI 125425: Developmental Toricity Study in Rats ~ Gross Postmortem Findings Explanatory Notes Abbreviations --. =NoData NAD =No Abnormalities Detected NP =Not Pregnant DuPont11347 -- oa `Company Saniized. Does not contain TSCA CBI H:25425: DevelopmentalToxicity StiundRatys DuPont11347 GROSS POSTMORTEM FINDINGS Group I: 0 mg/kg/day HAunmibmearl Structure(s) Finding(s) 663382 skin Alopeciaanbdothlegfsront paws s6ce3a3s8e6s wp o-C- NnaDp 6c6633335819 Sskkiinn AAllooppeeccitaa bloeftth psaiwdse 666633319096 Skin aAnldoperciighat rifgrhotnt sildeeg Skin Alopecia both front legs 6s6633440184 = - Nb RD 66663342115 --=--- aNApD 666633443310 --- NNaaoo 666633443375 5= NNoo se6633444480 js --- No NAD -- s6633136623 we SSkkiinn AAllooppeecciiaa bbootthh ffrroonntt ppaawwss s6346a -- and leftwDfront leg 6s6633416657 =--_ Nnaap _-- 55 Company Sanitized. Doesnotcontain TSCA CBI B:25425: Developmental Toxicity Study in Rats --_ GROSS POSTMORTEM FINDINGS DuPont-11347 Group II: 10 mg/ke/day NAunnibmealr Structure(s) Finding(s) s6633338932 ------ Nwoa 666633339935 we ----- NNDD 666633339986 =oC wwDD 666633440075 Sk--in AlopeciNaDabdomen se6633441173 we po-- nNaDp 666633442243 jooC n5aD 666633442287 -= nNDD 666633443239 ---- nx>D s56633444457 o-C- wnoD 656633345521 skain Alopecia boNtDh front paws ~ 663455 se3a66 sk--i-n AlopeciaanbdowtDhlegfsront paws % CompanySanitized. Doesnot contTSaCAiC8n1 F-25425: Developmental Toxicity StiundRayts --~ GROSS POSTMORTEM FINDINGS DuPont-11347 Group III: 100 mg/kg/day HAnuimmbaelr Structure(s) Finding(s) 666633330874 666633339570 666633440023 s66633a41120 656633341186 666633442250 s66633443286 s63a40 66633444413 666633445409 ~~ se5633a45567 s63a61 J--jy NwwoDpo ----- xAaD Sk--in Alopecia boNtahp front paws =pn js o5r)t Nao --- anDD o=o wMDD skin Alopeciaanbdothlegfsront paws ---- xWDD Sskkiinn AAllooppeecciiaa bbootthh ffrroonntt ppaawwss sk-i-n Alopecia boAtDh front paws = ) -- 57 CompanySanitized. Doesnot conTtSaCAiG8n1 H-25425: Developmental Toxicity Study in Rats --~ GROSS POSTMORTEM FINDINGS DuPont-11347 Group Iv: 1000 mg/kg/day `NAunmibmearl structure (s) Finding(s) c56e3a3s8e8 np ---- NwApD 666633430904 ski=n AlopecNiDa chest 666633440014 jo--s-s NwDD 566633440191 -=- NNDD 563419 skin Alopecia`abnodthlegfsront paws s6e330a2z2z we a-- NNADD s6633443345 Skoivn AlopeciaNArDight side 566633443426 ------ NNaApD 66663344563 jo--- NNADD cGee33aassss ----- nNDa --~ 666633445690 ---- Nnaapp s63468 -- nap % `CompanySanitized. Doesnot conTtSaCAiCBnI H-25425: Developments] Tonicity Study in Rats --~ Dupont. 11347 --~ APPENDIX G Individual Reproductive Data --_ % Company Sanitzed. Does not contain TSCA Cal H25425: Developmental Toxicity Study in Rats ~~ Individual Reproductive Data Explanatory Notes Abbreviations NP = Not Pregnant +. =No Data DuPon-11347 --_ --_ --- Ti, -- -- Company Sanitized. Does not contain TSCA CBI ~ 2 25| 4 ursssrsassasssnoes i Jw imamenegeneeneingeesg Ef|r imrmrmaeazeennionanne ~ | oH i 2 i& iE 4iAggsangsasnaninnnngs g i lcccccccoo0000000 lose ] 2 loccecccccccccslosos H ig 3 E 4 ~ 3 58| otonenococoenosons toon i Zg| oienoncosssonoocianse 3 a | 2 iassanssanzananns ina 5 g gs | 2 msmannnasnsnann as <BR = p8 i55||SEEEGnCUEnEERaIInIERnEEnEEEgEE Company Sanitzsd. Does no contin TSCA Cat ~ 3 i g are igegr lavnergareroas 5 g | v=niszazissgssscanaess 8 2 200 loco locsccssssssso g&l g `El i" i 3 EH | 52 i i Bo: 3 3 80| c0 lodoo lcomnco0000000 000 lonoo lconnsososases 2a iazas nnsnzaennnaa 5 "83% iaxag iaznzgaasianag Eszazszsanzasasazsaags J egrruravvegacanassegye g "3 48eIanaTIINanIagnsnans 2 g g 000000000000000000000 2 4600000040000 H00000000 4 F ese Pansss Eines es ees 3 5 i Ee | AGLI NnpwaTEInRNYESaonD ] : i | senggyseNEnInANANSNEny = 95| 35358555555500%0088se ~3 i | eerepmensinnanaannzes i loarduarne lvoasaroonny 5 agE| isssssaaainzzEassnsAsIaNsEaasNs -_ i E 2 g Pog loooconoco looooo00oro0 g g | feeeeenoeciooncoononce i 3i A. 8 E8E8 | izzs~anans ixnssspaasas i1 z 354 .| inravaazas .iazaanazanze 2 52| szugsiggcioceesaggcess Company Sanitized. Doesnotcontain TSCA CBI H:25425: Developmental Toxicity Study in Rats DuPont-11347 -- APPENDIX H Individual Fetal Weights and Alterations 3 Company Sanitized. Does not contain TSCA C81 H-25425; Developmental Toricity Study in Rats -- Individual Fetal Weights and Alterations Dupont-11347 Explanatory Notes For easeofrecording, manyofthe findings have been abbreviated or coded, as listed below: ar = bil = cen = It = n= NAD = nt = th = --= arch(es) bilateral centrum or centra left lumbar No Abnormalities Detected right thoracic NoDaa * Subcutaneous hemorrhage that was not present in utero. Renal papillary sizes refer to papillary development using the scheme of Woo and Hoar.@ Alterations are classed as: N= Notes --~ DV = Developmental Variations VR = Variation due to Retarded Development M = Malformations Numbers are used to: + Indicate renal papillary size Identify specific stemebra Refer to skeletal position for ribs or vertebra Specify skull bones according tothe following key: 1. Interparietal 2. Parietal 3. Frontal 4. Nasal 5. Premaxilla 6. Maxilla 7. Zygoma 8. Squamosal 9. Tympanic annulus 10. Basioccipital 11. Exocipital 12. Supreoccipital 13. Hyoid --_ a LWaotoe,GDes.tCa.tiaonndoHfoRaari,:RTMh.e1E9f7f2)e.t oAfpMpeatrheynltSHayldicryolnateep.hrToesirsaatsolaoNgoyr,m6a1l91A-s1p9e6ctofRenalDevelopment in 3 `Company Sanitized. Does not containTSCA C81 H-25425: DeveloToxpicimtyeSundytinaRatls ~ gi `TERATOGENICITY STUDY OF -25425 IN THE RAT DuPons-11347 ALTERATIONS IN INDIVIDUAL PETUSES GROUP 1: 0 MG/KG/DAY oFonr#s7' PTUs wr. stRucroRE FnmniG(s) cuTaesRsTtIrO-N sea1zen 5.33 23 sSa0s4 vertebra .5 350.6106 vertebra `7 51.268 verter 10.5 7 5s.n08 21 S36705 vmeartebra ~ 5 B4a5s Vveerrsed: un 1 5.45 vertebra 11 Ss3a4 my se323186 S5.2408 vertebsa 3 5.54 vertebra 5s S5.8958 vertebra s 5.89 Vsekrtaelbra nmwo Ret(acrednedthaots)sification = 0Retarded Ossitication wo(cen tho) = Ret(acrednedth1O1s)sitication w wwwooo RSueptearrnduemderoasrsyifi(csaittielosn bil) DV RetTaerended1O0s)sification w RetfaermdedthOsasiytication = wo(een tn2011) w Suppeirnnpuonienrtarysite 14 bi) wv RweotardedOssification Ret(acrednedeho0s-s1i3f)ication w Rweot(acrednedthaOzs)sitication = Ret(acrednedthaO1s-s1i2f)ication (12) wVR Retcaernd'edthOss,s2i0t-i1c2a)tion w PS 107 Confpany Sanitized. Does not contain TSCA Cai 125425: DeveloTopvicmiyeStundytinaRalts Dupont 11347 ~~ = HN-25422 TERATOGENICITY STUDY OF H-25425 DN THE RAT [E------ AuTERATIONS Tn DIVIDONL PETUSES GROUP 1: Wo/KG/DRY rs0ss mes wr. smoorome rns) cuTaosnszieo- -- 3 5.43 vertebra . s25 Temsitpanra 5 4.73 vertebra 0 5.89 vertenra un 613 VKeirdtneebyea eaz23es 5.500 --_ ::3 [ $a5 ---- . 60 vertenra 5:- 52 s1.5m0 2 HH -- n 5.51 vertebra 2 5.74 vertebra 0 5.02 VKeirdtneebyra i1 5se8e vertenma sRueptTeaerrenndcusmhdearozasrs2yi3f)i(csaitteionthla bil) Dwv RReetteaaerrndaeedtdhoGsns)ssilfeiiccaattiioonn = Retc(aeczne'dnsanehaiOsos))sitscation w w PRaepfciaeirnldandthoasS)siizfeic3at(iboidn) = w xwwno kReetaxded ossification Ret{(acCreednnedetahaOasr))sitication = w nowooo RReett(aacrzeddneeddthooass)ssiifiiccaattiioonn = ReTtceaeeanneacnhiaotns))sification w Rpeatp(aiCrtednleadon-oisS)siizfeic3at(ieo)n = RwewtTaesdeend ao)ssiscation = 3 `Company Sanitzed. Donotecontsain TSCA CBI 1425025 DolomerTxiyStynats ~ [------ EE -- = sermons (cont JU ---- one 12 ersanns --_1. J rama Ton ve : im OsEm ve 7 eee ee I B0 EEem em B 2 Esm wen wom e-- 2 wp men 1iFP I aiiz= FHP1OI oEiz ; IE o[ s to-- ny P=uL rsesae osisicaion reBTasiehcnrion ree Eedso Sit enion a-Prrpseesrss occsutnssiiccaasiionn r.oaeohnBastcaron arrseesgciosticarion =2=we 2=== ours aoserir. - --_ --_-- CompanySenza bos otarainTsoCaA 22H:324542255: DeDveelovpmeentlaloToTxopixciicmttyyeSStunuddytyiinaRnaRtlsas ~~ aai_2542 Clin TERATOGENICITY STUDY OF -25425 IN THE RAT APPENDIX (continued) DDuuPPoownlti1s1a34r7 ALTERATIONS IN INDIVIDUAL PETUSES GROUP T: MG/KG/DAY aFETUS4& EeTUS Wr. srrvcTRE FomNG(S) cTueaasTsIro-n 61630399 (cont.)57 1n2 slseise 6634106 5.74 2 5.71 vertenra vertebra 3 5.66 vertebra a s 6.03 sSaenm) 5.74 Vertebra ~~ 52 65..308 s 503 sam Vertabra 5 5.67 vereebra 1n0 55.2289 vertebra 112 550.7500 vertebra 1 5.50 vertebra is 5.71 vertebra s63e108 5.56 2 S28 saan F>y wo Ret(acrednedthaozs)sification Retarded Ossitication w Ret((accreednnedttOhhast1s)1izi)cation w = RRseeetttaaarrrdddeeedddOOOssssssiiiffiiicccaaatttiiiooonnn ((12)x0) wVR ap(cen th12) = xRentarded Retarded OOssssiittiiccaattiioonn (1) = Ret(acrednedtr1O1s)sitication = wo(cen th10,12) w 0Ret(acrendedth1oos,s1i2f)ication = RReett(aacrreddneeddchOaostss)siifiiccaattiioonn w Ret(acrednedth1O2s)sification w (cen th10,12) w wReotarded Ossitication (6 Bil) VR --_ _-- To `Company Sanitized. Does not contain TSCA CI 255 DevTostotynss --~ BT sores meses smarions min. ens F wBes rE m, ore ems pe" conird r ] mHE em semIE ween 4iHvIeEmiomf --~ 55: BBiOEEEEoeahme 2 Pg OmRif Tooym ;i 1EI mioIgZ 3 iwDoOrE2m ee EuEsreeygdiaspeseeion = wi =tA necrc 0B= 2==A 2 , B=eiseotid tis 1 -irere sn ase on 1we 8===I: u=BLtrAn -- CV ---- ass - -- SN iia orm (cmon [-- i By-- ms seme -- -- aEssesr. 4omy gH 1 os een w=o BE esraseoxciasin L fH o ee _ a == Des ve Se 2EE R aH m wm am Fo. arPCaseseenosession - Eapnmesonainnadess 8oR m sietea - Ca ETTE u=s hy 2scone wo CompanySent, toseTSCACot FE ~ , stv cen ot ete ee Ci) omen cine -------- coBoysm5. m0 veor omen na J weer, i PoHPoEo o TC L I H o ao Ti eo oim, I ii EiiooR oEn Bi E o0 o o Pi nHH oE L., Poi 2&2wmIuBs;fese cosiccin " fase I: w=&o =2=&8 2i=&8 28u2weo 8 Company ents, boes tirs SR Gri --_ ~ A J-- coBYmyr:5 0vars mow. oe J, J nr, 7 P o E an iBa 0o4oi3mn o ES , ~ cen vwhn ne P;LOeEw en a en 2BwEoFiasegcesrinron iuIeG eS - i. Ee m E rR tae l En- uBwFir osopnoen C feite E -- ~ - nnn Conansentis, dncosns eToont 25605 DolgTrims eSynits Dupen11307 ~ _ FeOICET se oF as4as mi an Cay [---- A ---- aru 11 fwyo 0 wororony To TT room EEne ewe EER 2 ser vee ses vem RE en gm ee SsEeEm een RRlefSSotersEeceSaiemnteoisennn 2) 1-2 Sotiris o seein -vtaesuttesoonnnteicntion = ~ B1 ows5.e31 oanme Vertebra P[P rIl OnE [I F i Si= iwsi=ois E RRehtteiansrenddeeod grOsS esitfitcaitinon ino) = 220ue ES w&e EwoSed Company Santzad. Boe ot contain TSGA GBH 425625 DevToirtSnayien - oe ---- Omi) eo FO iao sh5s0ee sirnis smi P i Tpr oEm . on 3. IE ~ 12 6.09 se I Le iHmime a. i;LTirnaiHEm re xBI=E. odren w=s NnADEesns en ogegoon A ue Ee) iEee oZ ---- -- wn - Composant. sos otsama 756AG1 52255005,5DDoenvieaTTlossocypSsomytyneiatness ~ -- secs soe 9p eashns z-w om Ur) sian oir SEN-- JO-- oBuYv,f nw. omons som HEaElaRs) eae 2Bioi uimd FF R N FII ea IE iene --_ IF H:I E1m an 8 ELaT. Rm.oemm Bom FHR I.ieEn FI : giE w2o2, spigptioe ==% EwSo ="BD,vesycsetiiten ="=ron 1 op reise ==3tare = 2 =EEwSSo =22 oDwureine cwssrna. " w --_ CompanySante. Boentcontain 50Gr 1505 tyTop tssye -- ~ A ---- xen 3. erro stron 1 ois sos hS2yUA I mew ew ones aWennE, yieinyemyiE i8uie" vo I;Fa - re erscotionion PT o ooi i HE in 2uwk i Ei 0Pio Eni iE i&=i #= ~ costo, sommm-- 12305. DrTioitpSpisna Ps oo smsrotes s or ass 0 eo Cosi sort (ets sorters 1 svi, ese hcBorYon,1.w20ws.ons eos some Ln o nome Sio EI i ~ f :IH .im en g 33. iiiai=mnm E IF OI a A iIii:so em#BoiBm Bwoore otgiotion 41 uhve; -- Issuweeee Boog rtm oo s5umeea te - f2a CompanySard. Bost omanToncB $2525 Drop ToySty has ~_ [ew] ssncmvcrse smn o wascas 0 wa [------ sama 1 rv, reese FA oBmlee -- mow. smocrne samme wToLs vaca F5I sm we P1Iso EsRniE wea P I E vee 35war31m ven EEE me Bsa vera soensrasets asicicasion 5an m=:Eurshoptics P;reEessnipicicrion =wrs TShrscastn Poise 3 a0 ICy E-- re ras aorsoin: " -- ~ CamrySantas, DoortconnTSCAGol 125425Dovlpmenl Toity Syins --_ _ Swsiasstns ovum se mass Hon [=] IEEE final Arms TEN to wow 1: 10 wersorane EyEs roo) Dane ciesns. LD awwFE a sFIo fmm nA Ssteasems oo t e0 - -HE - =Pomp nny ~~ PiE E1E II oE Hu=5.16 an sTeEa se EaS 2 en a sw FBE oiES =2wNEAsSD EB tot ouitioston (1) wm =BoBohoenggienee l5n, 2 BhRoponrgtsgrr - o=r Pp CompanySanitead, DocsnocanaSGAiGn1 ass: Bet ote nse ~ [" oy JE ms caine I B--Y ---- mw, aon rn DLo EErr vn en E fiarreon tbt PC Lo OnH ame ~ B. omET E-rESrLreveasn mB -= r oi HET i yoouoo B=AL iiPP:ooo oaim 2hFiwvS=; bres cr ;. a . ~ -_-- hmm sitintSmmssgn 525025 DevToiitSntne ~ -- Sassomcres or or mates mm a Camsinn rect tensity smrions x sis. sss S BaatyI1: r20Tvsnmeernw e--s-- s cWaenr T pe T zoo WER F waEa z BPE ois werao " "oan he; en --_ FHEFOERI ep Iuwpeoe S si ;HoE i oiEEE gi hBipBxeere be iu u2e sw - e nts - ~ Company Sats. Doss tani5aG G1 a125s02s5 DDeveinveopToumsseesSundyaintalotse ~ a seamoamzcrny sor op n-aseas ae [CA [Rn ---- J ---- avo 53: 30 wo/rcrone roadrs ssw omoonns ramos) sw ssw Bose vem Base een --~ E PEI , ween PR, I 1 msas 5J $ PE ain , wsfoarte we ReoetiBaticaetidon ReteitrhoadsBearttsencson wPadupraaes onitscacson a 2=fst wwwsw wdEke Doupwo e13s67 cufnrsiorerd. P w - - Company Santee, Doss nt conan TSCA Cal H:25425: Developmental -- ToxiSctudiyintRayts Fr-------- DE DuPont-D 11347 auramaTions 1 TorvioEa seveses ww 130 18 mene mYys mri. een I --_-- aiipo = wo I t!I! aHmgz oem ME PBOE oE tm n 72 onuimf T" 2.% wn tv woe PI iE fz $a wad + ser vere .==Ee w =A C faried gene ie - ImParnesi iSeset wits w n=d : opi- ogAoce--n " juwew: CCPCCo oh P -- metri-- c ------ GompanySartzad. Dosnot conta7i50nA G1 52505 Developme Toit Styms _ ile msrscmcirs swt or 2542s 50 mn ar Io--y J ---- FE om 52. owfees 19 waren -- T_T emw oses -- om e WS wm 1FV se , ven PE ER an se ven --~ TDwo oImE van PE TD P{E IE:iz van ?oemiz 2a2 ia=m otEs w SE evsiatitesuC todcoaxntiC cavion " - C-L marCtes sy-- st SfasdeHd cErei = "C 2wRT---- w w=2eFate sit " 2-L-hlS-- w b"Ygs w --~ Compl Santee. Goes rot containTSACot ~ 125025 DogmeeTiacsyeinsen or asst 1 im Cog sermons (cnsins rseions sam, ress sWrrieolsh0n9mvtamnt swe -- 1iDA O7Hmi s 1i aom ~ . it eae en oem oL Lm se T1PaEm J =woeobon are -zsew he;ant om v:ihEsE pe i. he;SE hr:En =z" pn coaes. " w" -- CompanySates. bossnotcrTsonnca E 255 Dra Tysons t --_-- ~ aid FE ---- [ai sR sions emis a ovis rene aBJEeY sma, sens -- -- em, my wo 2La -- - D LeEa em o : ei -- wm Eonh FP, 2 rm -- m w eetrstnca m rs -" - tad Ss n BNGeFEematcnesston - m rn m pEhiaeli.as wR mp EeTt prren " ~ CompeStnd oe ots3AG8 sss: pmentoySin setestee vem et ern [S-- orm cin ------" oBolmye15m20mv,rs omen mee PTT i orooen me =&2wt iis ses I cPo e.n &iI; Booig u Fs : . Loon Lo E EE ssEoS T teE E EfeeeEb nE dg -- aunen, 00m . -. . ~ Compan Soritin, esos cmaiecm 12505 DonTogitSeeyn ~ smc sm or mass us ae [si y F---- J ---- BmaweY11m10 amr omens ees Iusm van Bem vem --- C tnE ag ~ te50 -- oi ~ CompanySn. Does econo scr H25425 DovlooscpSmtyenaos / a eae ek eres Cpl posmmnn msi SR, ens 222: 100 verses Bwvy esr sues rome) Hi P E o eos TFJ 1E oeB I i eis a ae --_ :P Pr oooI ER. =2wwo =ES B2RSngogppiesbinn =wH"S BRpgvnErrit ssine bear vee 2 ir verse FA]. INC CT Sete] Bi oC 2 w EN u 2-%prs ---- anngeres. w w w Pe CampinSized. Doe rot cortTSaCAiCnl D1o42s5e05sDpooipe TtorsytySsyyioaise oowrne ~ S------ [Coy | J---- S---- wBBiynYprereooms ovens sm -- wan "ET emne vn -ecto osticsin FRI EE, P we a T :}saneEi,f,h, f=wvsieitoantitconieon 1m ~~ IiA,iiE i"=HAE - Fay I oem ="&Sa I. i oi 2& T EPo L H3wSe i: an xrI g bi I. -_-- Company Sasso net crin 3A G81 142505 DogmeTicSyio a ~ i remomncre sr cr ssi 4 mm mr oir iisen Cmmnll JR sraarions 10 vr, ans T1 F or, -- Timm owes ew --ww -- HeEnR S. EYiw ve Bwoeoep 85 oemn ee - ; i T oE Emow i iH E iFwOPeEnia -- HI iH iiPoIf omi oo -C I"SFoA t -- - ue fN s C uswzweeeeo sgeE taesi on d 22u4e 2w"se Sen - -_-- como, Stn SER 128025 DovlpneneToySaynas ~ asi mercy sre 0 n3sezs on sae Duro sursarions w otras, remsss SoBdrres5722r100evera omens roomate aswsesss. 1 1 vera J SE oem 2 ar ven sa ven - en ve :Po1m mSn 7. wr o FE e enn B iB$Ii i EiE see wen Boueme o---- 2o nd SoE aEvtnseioypE ssicmion - oEnEpeEh mien w BBuroaogs ogstcmicncsion 01 wn =-EwiTn earrin - i=eE=S skcixsnsticasion w o= a --_ --- Company Sates. Dosrt contTSaCAin1 12525Deven Tortias pe - i msmcire on or asks vm a Teli} sermons somone [ES ------ nwBcyes520m1e00wroma omens ve -- oi Tul E ween Pf :1I oiEeIm en I seEw ee EO nen ~ be vee xromim 2 se ven se vee sen wpea. PSO se vena !FP s I H mI -<A 2=nD=osrriscsiticntion 610 [ oyi-- - EuErcsriicuion - =E":yEesorn on -- [ T WFEokh)a-- E s wenn -w8 jE eEreenErstsooulRE iesl eeenn - mz=w ~ ses ------5 Coe mpanyrSanties, Dsost--a50n4a81 1.25025 Dovlopmenl ToySay nats. ~ izes Cony J FeRoGaCITY stub op 25425 Tn wan J ---- Jp -- oTarnolely s mms. smucrme cers (cone) 33u i5p3xd0 enone) =bwsson Dwani3e) cTanos. w 33:1 iBEsAsEa vere :s EsRm vertenma ~ :5y H[srie . -- 0 a1 verona u38 iEsioB versanen cor vertenra 2 636 vertebra s: 5m.m0 ILwjiootA-- Rwusp ocaedeoe usisicarion w - SeKwetsfouncaedtatcearsnisiocateion 1) wn = Rareesdf(ienendhS;optetcation RoIbSahrtednommictcation w RReatthnaarndteSidovsoipspgiieeiactatiioonn w =wsfahin w ~ Tee GompanySaizsd. Dossnot contTSaCAiCn1 m RT mcim rm or as 5 m -- (db) orm csi) irs el eS . wBoYn,55owsenr, n sens aon csner, s voim E BA oHo a wm =utns one - =uEtCaese consis tases os ~~ Ere 663425 en LT eum P1vF o ao mom . 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I" C Dn n eeen oe WCEEHsEAED ETEi E DE reon B 2m terse cweer " - rmpa ees n ere CompanySanz. bons tts36 BHSEEprerpe TTeostsecso ~ -- FE -- Cums oraz arson rans 3 a Foe LWcsvs15i3w00 ,von simon wm ooween cose 1 Ph HE ES Grs it ton hm wan L EE va wm =iz som BsuE. oe Jwn oErHe vn ba ve -:..Tr - he:preen " wwo Sos HpeEmedda oenlis oun wRw - " JpOCAantee nFw Z he;ffeecreesdoSeeT id - AEAin ~ CompanyStes, DsarateaaTOR BHa-25s425s: DDeevevlooprmeentalTTooxiicciytysSntuddyyiinnRhatess ~ oi F---- o`DwuPonat-11s347 surmarions 1% orvroun semess FE mBAyY rms. emocmns rman aengeres. 1 im :LE g+u J. iF| E Bom --~ 2 am vem W em re ween 3 =. em ven {izEiEE a ot en os testes on o2Edtretsneosicsorssetinctasisoonn 6x00 1-m Etacteedmi oooss n w @2teres ot w Revardos usietcation Simi sition ozCdraXze oI u w Drrted cotstension --_ -- CompanySantos. Doss ot araTSCAGBI Loses DodomaToieysuyiakes [H:25425: Developmental ToxiStucdyiintRayts wesw DuPont-11347 Pa occ Femmes smo or ass me mar Collis1 rermos (continues) sermons ox moro, raves sBouresyr1550me100mweernerone omocns rome) aesserse. Sess comer sBr le Ten van rEEorta taeeerssr bciitrntirchenansenitoosnn 01) = en osm eSeinetne 8= R 35 nism mamn. PE --. e BxEEhp snrtooessttice ation 0 vm = rete besheation Pp BEsm an wPsctfieeeancssopsticasion " - PPPPoEooeRsn Poi cen Iw =Bute oniticntion FRsF5I isam =w=nh = I i 3 FFEO m BE an LF==IES -- sm nd ns - ~ _-- Company Satz. 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[= ~ saa Bsa veman vee B usHs ene B usH m venan E 5 Rsw aw vs Ewfoucaes osicicntion 610 RaeeendnoanSianteiihscaosidon " w RRoetSaeEettRihneodsStShsnsssiccaartiioonn w Ep) pRoeltaifkteriinheesdtshoSenonrttlsteincinoins retsthodSpmticacion 1Bw w wresteSEResieSnpain Ps w wWA asestensom-- nscicarion w Fwfsuecaasdsomyniticacion 41 w ~Eat w I 5 osas iastn n - [TS---- Bp5a2s56eo2s5 vDle opTlomito eSyansaisToiciySadriDonwuehsrnr ~ ess mssomcrrt smn or wasias mw me ae [ow 3 sepa (comics) J-- com 32: pfo o 300 w/ncrone room cfaseo ce1C r coE me)un venan wwLo A D I E vena sa feet wPsaeteyusseicacion = = FB3FRO omik =E=erenase nine ~ --- Compa Sata. 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C 2s cvE isinion -- _o--i "- -_-- RA HL25025 DevlToogitnSaeynnals Dupuis _ _ SoC sve or ascss mm sae Com 1 [---- NrEATION HorvEouN FEROS [A -- -- mByy 0 mew. mse vcm erw one wWi nEsE. i [II B3am FI 2wm:o HP f i I o o i 2w22e F2E iH 2=2 tere on - ~ 663IF4PI 34 oenw tere =wo - iIiEmE w3wee 18PIsiaanioBm =w2o=n 2 HPIE =- an J. --_ CompanySunitesd.Does otTSOa A GBI sespeso cysts H-25425: Developmental ToxiStucdyiintRayts ~~ mss ess i 5 tees 7 Cow] sere (mie) rion x mors ree Wasrresis3n1e83m.taps oie sions p7ie H ido C is E mi2iE 8ig &= a Pa van ~~ oe 3 5.23 Vertebra IcmI vee dPE 2 on a a woeame vee buweeo isBw"eee s=9e -started nviicasion oRetarded Ossification a mTn Ihe;farers oets Em >SoSkyn png DuPont-11347 cuonsser -- --~ CompingSat.boss otonTaSAnGa 125025: DeveTeopitmSeyinntls. --_ aa Cue) SematoomcITy spy os masazs mmm man Aor (continued) Dwani13e) AuTERTIONS Ix orvIDUN pervs 0a 11: 1000 v/v srlys res. smuerme p-- ctuosns.i worvfez 31 versebea :: BsIn wRestasdedhcaasizicarion =. .: sEaH vereame wERlopeErnusheseucy (has shore bit) ov Refezaed ausitication .SEsas omHea . 5.30 E SupC eermeuT neh )rtey L (has shore p11) ws BwY w ii3$; BxiEeoNw So S=SSibippeeerrrmmmennnaeecresatccyyy (sha ((s3ha2s shore sBehroere 313) p11) ow o2y sittien REReeeattiiaiteeddseSoSmnumitifiaicratriisoon 4[h hoyon I ces3s13es xsie : in wfwoeod :: EaE versanen ;- Rwiesbuxdeshceasstication ws w : 5 Caeatnin s wos vercanea RRReeittseoanrraadreeesdd]bogamsiistmisccaattaiioonn 121 vn A ss sam RetE hriod E Cnsiticacion 1) wUm ~ - Tm Gompany Saitzad.DossnotconTtSaCAiG8n1 $2502 DvclToogitmSueninals ~_ Ua) reoomcry ston op nezsezs 1 me mr Aer (contsouey NurEATIONS 0 morvEBn FETs [r---- Beyr mre emo re Dwam1130 _iv--i 2FI8A sa #8 um wen BimB. 8 em =.wa :" STWaTasEtmeRsooLmmtamsinocantieon l1m), o1wm w # se omvm) = 2 moa Ws T 3. Eum ven P5 ERse sso 3 1sommIf wm 3 ser vere B 2 ooo F-- rito WN oS WSeey n i pin ws 3 w Bos grisisoasion Fzoimge ae trom 10 n R=ootteretreat,cesttsention (6 bits wm 2RzeosTaseotBnaltication ww -- Gompany Saniized, Doss ot contain SGA G1 1125025 Developmen Toi Sy aRas ~_ C) FeARoaBretry sry op wessezs on ms ae [---- wore sursmaions mm mor seroses [EO -- mBydsmmT Tome oornsw erm ome s aareunn,e. 1 sn wpm sm .SeyessmteotnSsqpsascation w +! eEmven Paugi rseas ossstescarion w 1I 2a mae 5 sae verse P"ifrracaieeseedodonomsfiicarion EC - ~ B 2yoz EioFh 2[ziyee w = = ew S T!:3 oE mIiosEFm vena 8 am vee 28 riuHmB - 2Jae.ir ho " RA 5etRetaiesBohecaion w =oz Company Sanitzed. ows rt contain TSGA OB! 2505DolpmeneToy Sy ---- ~~ maisys | esses st 8 3485 0 en sre test smsrions svi, sess o-- Buonye 19.= m1000ewremn oe mensm esw omes cgosee s EER om Ssese vveenenn D so a cm ope ~ osm veNOn 2, IE.Biren F5PE O.m,,oie T I seen ho": -r ResveraiesndSecipE itteteusion a w Bofrrseedm osteica, rion on mCS EEme nfeo wn - oB-limsisyneyestee is si ov "EA ".Rp pEen stine w- wuotsareescortscnsion a --_ - CompanySantas.BostconanTso Co 142505. Dern Toitey me pera ~~ me -------- Cow) [---- saris sion, rans UB[ yysrTmr-- me. mesewr s esaemmews -- WCEoG C TL ree veen I LH e ee r -- tects osm Ne IHC I eBoe BoImsFse ropn st i an Fron ~ om a PE E E ge , !EIR 2a. . ie oo zoi gl m mA =sFrom - a ht - wt --~ Cons Sots. sscconan750A 61 525625 DeveTlosot pStmyen PCS omm | ORR soo 3sezs mm men sores (contin sermons sori remase fo[=u 0a)J --. Tm e-- Ue[= we SSpeprmmmerearyn(sitoe ia 10 2 ra " rg tin Dito HweErnR oy " _ -- ---------------- = ===------ CompanySata. Dos rtcontainTSCAGBI