Document e7BXV8pQ6xN7vX7GKZGGorem

ARRRE_ 3314 4% (r--)....... Toric Study in Rats AR 226 -- 23/4 Dupont 10157 `TRADE SECRET [CJ I Study Title -- Laboratory Project ID: DuPont-10157 TEST GUIDELINES: United States (U. S.) Environmental Protection Agency (EPA), `OfficeofPrevention, Pesticides, and Toxic Substances (OPPTS) ~~ PHreeanlatthalEfDfeevcetsloTpemsetnGtuaildeTloixniecsi.ty(SOtPuPdyT.S 8(7A0u.g3u7s0t01998). O(rOgEaCniDs/aOtCioDnEf)o.rEGcuoindoelmiincesCofoorpeTreasttiinogn andDevelopment ofChemicals, 414, (22nd January 2001). AUTHOR: Susan M. Munley, M.A. ~ STUDY COMPLETED ON: January 30, 2004 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 WsOeRaKvcREsQcUEoSnTNooums )] _ CompanySanhtzed,Does not contain Tsca cay Page 107156 - | (cs Dna GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT "LTahbiosrsattuodryywParsactciocneduSctatneddairndsc,owmphliicahncareewciotnhsiUs.tSe.ntEwPiAthTtSheCOAE(C40DCPFriRncpiaprltes79o2f)GGoooodd Laboratory Practice (as revised in 1997) published inENV/MC/CHEM(98)17. TDPeerseatpswisaeutebesSrtt,aannNcd.eaJr.cdhsaN;roahncotewereoivfzetarht,eiotanhfweoaraesnmapeleynsrtefisoonrwemederdeanacatolRnyedsgeuiscotwneeadrlieAnnpcaeolrymftpoilrcimaalendSceeurnvwdiiectrehsG1o(5oR0Ad9LS0a)0b,o2ratory regulations. All of the analyses axe considered valid and sufficient for the purposesofthis study. uyitor: Fn `Susan M. Munley, MA. `Research Scientist 20-70-2004 Date. ~ [~ [RP ------ eer ; ie [F--)rc. Suty inRus Duponc0157 QUALITY ASSURANCE STATEMENT Haskell Sample Number(s): 24691 Dates of Inspections: CProontdouccolt:: JFaenbruuaarryy302,0,22010,32;0F0e3bruary 3, 2003 `Records, Reports: May 7, 2003; June 3-6,23, 2003; July 29-30, 2003 Dates Findings Reported to: Study Director: January 30, 2003; February 20,26, 2003; May 9, 2003; June 7, 2003, July 30, 2003 Management: February 20,26, 2003; May 9, 2003; August 6, 2003; ~~ January 22, 2004 Reported by: / 7 StaffQuaimberylityAssBu.rance Auditor 3-TeDaate-204 ~~ || _-- `CompanySaniDossinotzconetaidnTS.CA Cal 3 (OO): .c: Toricy Sudyin Ras DuPont10157 ~ CERTIFICATION Wfero,mthhiesunsdteurdss.igned, declare tha this report provides an accurate evaluation of data obtained . Gonct C Wpstardar_ TCVan BS Gu-30- 200% = SeerSfCit Approvedby: fersrre. JandoT2e0% --~ tvs pr) 10SoisVRiumSneltAas/ B= o Ta= -2004 -- -- : Company.Saniized. DDoosss notcontain TSCA Car 7 a ~~ . | |-- (-- pects osc Stdy in Ras DuPon-10157 TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATcoEco MENT QUALITY ASSURANCE|STATEMENT soursnmsursssmssssmsssssssssssssssssssssssssssssssssssssssed. CERTIFICATION covvresssssssssssmsmsmsmsmsssssssssmsssssssssssssssssmmsssod. LIST OF TABLES covvsssssmsmsssssssssssssmsmssssssssssmsssssssssssssssssssssmsssmmmmsss| LIST OF APPENDICES wcvconrnmsisamsmsmmsssssssssmsssssssssamsssns] STUDY INFORMATION cccnnmsmmmmsmsmssssssssmsssssssmsssssssssssssssmsmsssmsssssmsssssssssd STUDYINFORMATION ..coconssssmsmsmmmrmsmssmsssmsssssmssssssmssssis sssss smss sss8s. STUDYPERSONNELwccvvssmsmssssssssssmsmsmssssmsmsssssssssssmssssssssssssssssssmssssmssmmmnd SUMMARY covvrrrrrssssssssssssmssssmsmssssssssss 10 BIECTIVE .ovcrrmsrsrrrsssmsssssssssmsmmsmsmssssmsmsssssssssssssssssssssIs SPONSOR AND TEST FACILITY cocvrnsrrsrsessssssssssssssmssmsmsssssssssssmssssssssssss11s BUIA0ryCOMPHANCE cormslL S109Debimmmmssssssrmenimmmmem--l A. EXDETMENtal DESIG 12 GOI ommmmmmmmam-------------------- VATERIALS AND METHODS sons l2 SS ------ C. DE Preparation, TESUSPEES Ac dministration,o and Analysesr of Dosing FOIm MUIAHONS ..s ......vn 13 1S . E. Anial HOSOI crv |S G.. RENAOMIZAON .ocorrersensesssssssessemessssmssssssssssssssssessemsssesssssssassss mss} 6 TF. TGHEON GE BES corrrreeeeermeenreemrsemeeesessmemsmsmsmssmsmssmsssriren8d XK. SHANSHCAl ANBIYSES voces ere 18 #SULTS AND DISCUSSION pe z e -------- | Company Sanltized. Does not conain TSCA CEL e 3 eee eeeeeeeeee Ec Toxicity Sudy in Rats Dupont10157 --~ ANALYTICAL EVALUATIONS ceva d A. Be CRCHOIVEOTMY BSIEOMPGITEASD.hcYe.vcrsrorsssssssnnnesssees sssnss noosi e d19 C.. D. HOMOEENEiatdy Stability CONCENITAONVELIfiCAtion SSAAIIMPPIIEES Sv ....rr orore css r ieesei1290 E. ADBIYHCA] CONCIUSIONS vrs 21 DEVELOPMENTAL TOXICOLOGYcmon22 A. B. BMoordtyalWity,ePositanMdogrBtoehdmyFWtienidigsnhgts,CHaAnNdGCElSini.c.al.O.B.SS.r.Vartciouncsu.n..e.n.r..e.r.o..r.o..s.o.o..n.s.s..n.2222 C.. D. PFO0S0HdMCOOINISEUDMFPIHNONESc.cr rcvivee vvsnns enemst ssmseso esser ens 22 23 E. Be FReEtParlOAGUUCCHTYBEHOONSUc IaNCr LOee rMDAEAsrs ecessee s enes sse2233 CONCLUSIONS worms25 IECORDS AND SAMPLE STORAGE wns? BEFERENCES cov sssmsmsmsmsssmmmssssssssessssssmssmsmo2n6 ~ J APPENDICES corral | -- |-- `Company Sanitized. Doesnotcontain TSCA CBI [cs i ~ TRADE SECRET (EY 7c: Study Title sic ty in LaboratoryProject ID: DuPont-10157 bums `TESTGUIDELINES: United States (U.S.) Environmental Protection Agency (EPA), Office of Prevention, Pesticides, and Toxic Substances (OPPTS) `Health Effects Test Guidelines. OPPTS 870.3700 ~~ Prenatal Developmental Toxicity Study. (August 1998). Organisation for Economic Cooperation and Development (OECDIOCDE). Guidelines for Testing of Chemicals, 414. (22nd January 2001). AUTHOR: Susan M. Munley, M.A. "7 STUDY COMPLETED ON: January 30, 2004 . EloaRou 70 50x PERFORMING LABORATORY: E.L du Pont de Nemours and Company `Haskell Laboratory for Health and Environmental Sciences Newark, Delaware 19714-0050 WorxRequestNovmex[BRR] SERVICE Cob:rows] -- CompanySanhtized. Does not contain TSCA CBI | ET -- (ccc soi GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT L"TahbiosrsattuodryywPerascctiocneduScttaneddairndsc,omwphliicahnacreewciotnhsiUs.tSe.ntEwPiAthTtSheCOAE(C40DCPEriRncpiaprltes79o2f)GGoooodd Laboratory Practice (as revised in 1997) published in ENV/MC/CHEM(98)17. DTeesetpwsautbesrt,anNc.eJ.chaNroancteeorfitzahteioanfworaesmepnetrifoonremdedanaatlRyesgeisownearleAnpaelryftoircmaledSeurnvdiecresGo(oRdASL)a,boratory rPergaucltaitcieonSst.andAalrldosf;thhoewaenvaelry,setshearaenacloynsseisdewreerdevcaolnidduacntdedsuifnficcoimenptlfioarnctehewpiutrhpIosSe0s90o0f2this study. Study Director; J ? er SusRaenseMa.rcMhunScliecya,tiMstA. 20-780-2c04 Dus --~ --~ CompanySanmtzad.DoesnotcontainTSCA Cai -_-- (I ~ ero iycre QUALITY ASSURANCE STATEMENT `Haskell Sample Number(s): 24691 esos Datesof Inspections: Protocol: January 30, 2003; February 3, 2003 Records,CRoenpdourctts:: MFeabyru7a,r2y02003,;21J,un2e0033-6,23, 2003; July 29-30, 2003 Dates Findings Reported to: - Study Director: January 30, 2003; February 20,26, 2003; May 9, 2003; June 7, 2003, July 30, 2003 -- Management: February 20,26, 2003; May 9, 2003; August 6, 2003; January 22, 2004 Reportedby: / "7 SuffQuimbeay yAsszance Aucior B-TDiee n220= -- Tr---- | Company Sankized. Doss not contain TSCA CBI _ (OO) cs Toxicity Study in Rats CERTIFICATION DuPont10157 `We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. et Bains by: br SoH: Gorct CHptanber JanetC.Maslanks, B.S. u-30 2004 Date. Jan-30- 250% ~ = bys PhD. Date. msn F iisl ZAr a eual )G0TZh-20f _ om sotmena R : :E | i | - ~ . | | _ (-- pecs Tosi Sudy in Rats Dupo 10157 TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT cnn? QUALITY ASSURANCE STATEMENT weccnmmssmsmmsmsssssns3 CERTIFICATION ccs LIST OF TABLES coves] LIST OF APPENDICES woes] STUDY INFORMATION rss STUDYINFORMATION cers STUDYPERSONNEL css) SIMMARY cessssssssssssasmsamsmmmmmmod0 BIECTIVEworms11 FONSOR AND TEST FACILITY womansll PEUIBIONTCOPIES ermal SYDESI rrrssid JS GB ma--------------------------] JATERIALSANDMETHODS ccevcsmsssssssssssnecl2 J -- "DET:ER PrepaSraPtioSn, Acdmrinrisrtrratrioen,raendmAenarleyswesroef DeosnirngmFeorrmuelantiaonnse.n.nomomreeevereod1d3 ------ ge E1L APnairammaelteErustShaUnIas0ia...vore ee s s16 F Fog rr r ------L--s SULTS AND DISCUSSION crn19 a aComptanyaSarniizoed. Does not contain TSCA OBL go 3 ( ee. Toxicity StudyinRats DuPont10157 -- ANALYTICAL EVALUATIONS wonesmmsnsssrsnsssssssssmssssssslnd CB.. RHOoCmOoVgeEnYeiStHyPaInEdSStarbiolirtymSsmAmPmiSremv mnrss ssnsns 19 19 D. E. CAnOaNlCyEtNiMcraAltCiOoNnCVLUESTIiOCNASIOoNvSAeMPrInESrrarrnrenennsssressnssmisssrsrsoss n2201 DEVELOPMENTAL TOXICOLOGY crane22 BA..MBoortdayliWteyi,gPhotsstaMnodrBtoedmyFWinediignhgts,CahndACNliGnEicSal.O.BS.CcTVrAcEOvNvSsnraresurrsosssenin2n22.2 C. D. FP0O0SdICOONENISFUIIPNHEOSN.r rer rer 22 23 E. ReprOuotcdomeuancdLItleriDAvR e curves: 23 F re e ------_ (ONCLUSIONS sss25 RECORDS AND SAMPLE STORAGE wrasse25 REFERENCES corres26 ~ FS PPENDICES sors ~ Company Sanitizod. Doss notcontainTSCA CBI || a = elopmenal Toxicity Sady in Rats Dupont10157 rm LIST OF TABLES TABLE 1 SUMMARYOFDOSINGANALYSES occ nD TALLE 2CLINICAL OBSERVATIONS ccc 30 TABLE 3MEANMATERNBOADLY WEIGHTS... m3] TABLE 4MEANMATERNAL BODY WEIGHTCHANGES crn TABLE 5MEANMATERNALFOODCONSUMPTION cn 36 TABLE 6REPRODUCTIVE OUTCOME 38 TABLE 7INCIDENCEOFFETALMALFORMATIONS s.r 3) TABLE INCOIF FDETALEVARNIATCIONSE... A LIST OFAPPENDICES ATFENDIX AANALYTICALCHEMISTRYREPORT ccc AVFENDIX 3INDIVIDUALCLINICAL OBSERVATIONS... SL APECINNDIVDIDUAILBOXDY WEIGHTS... rcs APENDIX DINDIBOVDYIWEIDGHTUAL CHANGES...) APENDIX EINDIFVOOIDCODNSUUMPTAIONL... 89 _ APENDIX FINDIVIDUAL REPRODUCTIVE DATA. ns 9) APENDIX GGROSSPOSTMOFRINTDIENGMS vcr en 0S APENDIX HINDIVIDUALFETALWEIGHTSANDALTERATIONS 11 |~ |ps | --== | k5e3 CompanySaniized. DoesnotcontainTSCA CBI 7 ~~ STUDY INFORMATION 9th Collectivestm PSe----) I WF ~1 Haskell Number: 24691 CAS Registry Numbe} pcCu) Koon npc. | | `Physical Characteristics: White to yellow wax . `Stability: The test substance appeared to be stable under the. conditions of the study; no evidenceofinstability was 1200 South Hayes Street USA. Study Initiated/Completed: January 30, 2003/(see report cover page) etre Compan Sae nt os econ In-Life Initiated/Completed: February 3, 2003 / February 24, 2003 TSCA GBI (-- Toxicity Study in Rats STUDY PERSONNEL Study Director: Susan M. Munley, M.A. Management: Eve Mylchreest, Ph.D. Supervisor: Deborah L. Tyler Primary Technician: Sandra E. Karr, A.A.S. Analytical Chemist: Janet C. Maslanka, B.S. Management: S. Mark Kennedy, Ph.D. Toxicology Report Preparation: Mary K. LaRoe Management: Nancy S. Selzer, MS. Laboratory Veterinarian: Thomas W. Mayer, D.V.M., ACL AM. DuPont10157 - |~ `Company Sanilzed. Doss not contain TSCA Caf --s _______________ (10.5 inka Dureriots ~~ SUMMARY objective of this say wheansadtmoienviasltuearteedthbey oproatlengtaivalagmeatteorpnraelgnaanndtdreavtesldoapimlyenftraolmtaorxiocuintdy othfe of implantation to the end ofgestation, days 6-20 ofgestation (days 6-20G). Gsurbosutpasncoefi2n20t.i5m%e-amqauteeodusCrmle:thCyDlc(eSllDu)lIoGsSe oBvRerradtasywse6rethardomuignhis2t0eroefdgfesotramtuiloanti(oGn)saotfdatihelytedsotse: cleovneslusmopfti0o,n5,0,a2n0d0c,lionric5a0l0ombgs/ekrvga.tiDounrdiantga wtheereinc-ollfleecptoerdt.ioOnnofdtahye2s1tuGd,y,alblosduyrvwieviignhgtd,afmosodwere: oefuethaacnhizperdegannadntdirsastewctaesd;rethmeoavbeddoamnindadlisasnedcttehdotraocpiecrvmiistceerxaamwienraetieoxnamoifntehde gurtoesrsilnye.coTnhteentust.erus The fetuses were removed, individually identified, weighed, sexed, and examined for external, visceral, head, and skeletal alterations. Uconndseirsttehdeocfonmdaitteimonaslomfortthailsisttyu,ddye,cardevaesresdebmoadtyerwneailgthotxsicaintdy bwoadsypwreoidguhctedgaaitns5,00anmdg/inkcgr/edaasyedand cpleirnsiicsatlenotbsreerdvuacttiioonnss oinfftooxoidcictoy.nsOunmpetliiotneraantdSb0o0dym-gw/ekigg/hdtaygacionnsainsdteidncorfeoasneedccalrilnyicraelsorption; oJibtsteerrvcaotnisoisntsiinngdoifcaatisviengolfeteoaxrilcyitryeswoerrpetiroenpoirtbeedlideuvreidngtothbeessteucdoynfdoarrythtios foveemratlem.atTehrenraelfotroxei,ctihtiys ~~ i(ndetlhiasyeddapme.lvDiecvbeolnoepmosesnitfailcattoixoincaitnydawta5v0y0rmigbs/)k.g/Adtay20c0onasnidstSe0do0fmign/ckrge/adsaeyd, stkheelreetawlervaerinaotni-ons athdevreerswee,rteesstlsiughbtstiannccree-aTseelsatiendt,hteriannsciiednetncreedoufctdieolnasyeind msakutlelrnbaolnefooosdsicfoicnastuimopntaito2n0.0Iannadddition, 5bo0t0hmmga/tkegr/ndaalyatnhdatdewveerleopnomtenctoanlsitdoexriecidtyadwvaerssec.onsTihduesr,etdh2e0n0o-mogb/skegr/vdeady-.effect level (NOEL)' for + TwehroeNnOotEdLetfcotretd.is Tsthuud,y ifsordethfiisnsetaadythtehehiNghOeEstLdiosseeqautivwahliecnht atodvtehresNeOefEfeLctasstdrebfiunteadbblyethetUh.eS.tesEtPsuAbst"anacned -- o the no-obsered-dverse<ffct level (NOAEL)a defined by the European Union. `Gomany Santtized. Doo net cantain TSCA CBI || -_ 0 Ce Toxicity Study in Rats Dupont 10157 ~ OBJECTIVE objective of this studyhewnasadtmoineivasltuearteed tbhyeoproatlengtaivalagmeaotempraelgananndtdaetvseldoapilmyenftraolmtaorxiocuintdy othfe "ime of subst implantation(3%heend of isgaesntatoiorng,adnaoyfsiu6o-r2i0neofcogemsptoautinodn.(dTahyes 65-0,202G0)0., aTnhde test 500 mg/kgday dose levels were selected for the current study based on findings from two viously conducted in gtwudihes.icThhedofsierstlesvteuldsyowfa5s, 2a5n, 8a4n-dda1y25ramngg/ek-fgi/nddaiyngwesrteudtyes"tewdi.th Evaluation of in-Lifedatafromthe frst few weeks ofthis study indicated that no compound- rsetluadtyedwatosxilciimtiytewdastootbhsaetrwvheidcahtwdaossecsol<le1c2t5edmgd/ukrgi/ndgayt.h fTihste feevawluwaeteikosn ooff ddaotsainfgrboemctahuese84i-ndaay Fdevelopmental toxicity study, time-matedwraastsfarroemonalryatddoesveedlfooprme1Sntcaolnsteocxiuctiitvyesdtauyds.y wiTthhea smil evalubed Matermal ant which dose levels of 50, 200, and 500 mg/kg/day were al toxicity were produced at 500mg/kg/dayand were lsiigmnist,edantod riendcurcetaisoendsfientaml astkeelmeatlalbvoadriyatwieoingsh. t Ngoaitnoaxincdolfoogoidcaclolnyssuimgpntiifoicna,ntinocrraedavseedrscelinical ccoumrrpeonutnsdtusdrye,laatehdigehffdeocstsewleevreel soefe5n0i0nmdga/mksg/odrafyetwuasseseaxtp5e0ctoerd2{000prmogd/kugc/edmaya.temTahuls,anfdor the ~ d`meivneilmoaplmteontnaolttooxxiicciittyy,;atnhdetihnetelromweddioasteeolfev5e0l omfg/2k0g0/mdga/ywkga/sdaeyxpweacsteedxpteocbteetdhteo npor-oodbusceerved- adverse-effect level (NOAEL). SPONSOR AND TEST FACILITY mews cnr IIHS,gn VthiergSipnoian,s2o2r2a0u2t-h5o0r5i0z.ed TthheeWSopronksoAru'thsoarpipzraotviaoln oFfortmhe.proTtohcole studwyaswiclobnseidceornedduceftfeedctaitvDeutPhoendtate Haskell Laboratory for Health and Environmental Sciences, E. 1 du Pontde Nemours and Company, Newark, Delaware. REGULATORY COMPLIANCE The study design complies with the following test guidelines: + PUensittiecdidSetsa,taesnd(UT.oSx.i)cESnuvbisrtoannmceensta(lOPPrPoTtSec)tHioenalAtgheEnfcfyec(tEsPTAe)s,tOGfufiidecleoinfesP.revOenPtiToSn, 870.3700 Prenatal Developmental Toxicity Study. (August 1998). Organisation for Economic Cooperation and Development (OECD/OCDE). Guidelines for Testing of Chemicals, 414. (22nd January 2001). | -- a `Company Sanitizad, Doss nol contain TSCACBI (-- --~ Toxicity Sudy in Rats STUDY DESIGN DuPont 10157 A. Experimental Design : The study design is as follows: Group 1 Dose* (mghg/day) 0 Concentration (mgmLyp 00 Time-Mated Females 2 n 50 100 2 m 200 00 2 w 500 1000 2 = aFdomrimnuilsatteiroendsoofnteesdtaslbysibaynocrealnga0.5v% aagqeuoenoduayss 6m-e2th0yGlacelldoossienwgere b TvoolaucmheieovefStmheiegc.oncentrationsofactive ingredient, the formulations T`hweerceoandjtuosltegdrfoourpsaanmipmlaelspurretcye,ived vlc (0.5% aqueous methylcellulose) onlyat 3dosing value! mL, ~~ MATERIALS AND METHODS A. Test Substance iTheeStpeosntssourb.staTnhcee,teastwsauxbystsaonlcied wwaitshaksnsiogwnnepdutrhe Maskell LaboratcoomrpyoNsiutmiboen,r wHa-s24s6u9p1p.lieTdheb.y Sponsorwas responsible for characterization and analysis of identity, stability, and purityofthe CtaAlSk treesgtissturbystnaunmcbee.r,Avbaaisliacblpehyisnifcoalrmpartoipoenrtoiens,thheazpuarridtsy,, acnomdphoasziatridoonu,scomanttearmiianlanctlass,sisfyincoatniyomns(s,) fsaosrmp.ro`vTihdeeSdpboynstohre aSlpsoonpsroorviadneddisaaCvearitliafbilceatoenofthAenaHlaysskieslltoLatbhoerSattuodryyDSiarmepctloer.EvTalhueatoriiogninal falme pfolretEhveasltuuadtyi.onAFroersmeravnedsathmeplCeerotfiftihceatteesotfsAunbasltyasnicseawraesTectoalilneecdteidnatnhde orfeftiaciinaeldWboyrtkheRequest festing Facility. J. Vehicle cfhoervdeehdicilnetwhaesst0u.d5y%reacqourdeso.us methylcellulose. Lot number(s) and expiration dates) were -- 4 Dos not contain TSCA CBI is um -- (rm--)... Toricity Study in Rats DuPont 10157 |~ 'C. Preparation, Administration, and Analyses of Dosing Formulations Formulationsofthe test substance in the vehicle were prepared daily. The method of mixing the `test substance with the vehicle was documented in the study records. The test substance was administered by oral gavage because this route is recommended by regulatory agencies for this type of study. The volume administered (5 mL/kg) was based on the most recent body weight. Samplesofeach test formulation weretaken 3 times during the study. Analyses addressed concentration, uniformity of mixing, and stability. Samples were submitted shortly after preparation to the Analytical Chemistry Group at Haskell Laboratory. I. Analytical Methods a Recovery Sample Analysis Concurrent with dosing formulation analysis, recovery of the test substance from spiked 0.5% methylcellulose was testedatthe low level (10 mg/mL), at the mid level (40 mg/mL) and at the Highlevel (100 mg/mL) to confirm the analytical method. Thetest substance was weighed (approximately 30 mg, 120 mg, and 330 mg on test days 1 and 11 and approximately 20 mg, 30mg, and 260 mgon test day 20, respectively) and diluted with 3 mL (2mLfor test days 11 and 20)of 0.5% methylcellulose. All recovery samples were then mixed to dispersethetest ~ substance in the methylcellulose. The samples were then processed and analyzed in the same `manneasr the samples at similar concentrations b. Dosing Formulation Treatment Bach dosing sample (3mLfortest day 1; 2mLfortestdays 11 and 20) wasdiluted to 100 mL. vith methanol and mixed to dissolve the test substance in the formulation. The dosing samples | were analyzed without further dilution or were further diluted with the 0 mg/mL sample (initial iilution)toan expected concentration of approximately 0.06 mg/mL (a.i)priorto analysis. efore all final dilutions, the intemal standard diluted solution (refer to Calibration and Quantitation Section) was added to each test sampletogivae final concentration of pproximately 0.09 mg/mL. Each sample (final dilution) was adjusted to have an equivalent mount of matrix (final dilution of the 0.0 mg/mL control) when analyzed. samples submitted foranalysiswere analyzed the day the formulations were received by the esting group. c. Chromatographic Conditions Instrument: Column: 1 Injector: | Detector: I~ Carrier Gas: { Hewlett-Packard Model 6890 GC J&W, DB-1701, 30 m, 0.32 mm ID, 1 um film thickness Split, 250C FID; 250C Helium (2.1 mUmin) CompanySantizod.Goesnotcontain TSCA Caf 5B -_ fh vclopmental Toxicity Study in Rats Dupon-o1s7 Oven Program: Initial Temperature: Initial Time: Level 1 Rate: Level 1 Temperature: Level 1 Time: Total run time: Gradient 100C 1.00 min. 20.0C/min. 260C 0.00 min. 9.00 min. d Calibration and Quantitation A separate sample of the test substance was obtained to use as the analytical reference CS ------ cs standard. A stock solution was prepared in methanol. This stock solution was sonicated to assure that all material was in solution. Before analysis, appropriate aliquotsofthe stock were diluted with the 0 mg/mL sample (initial dilutiotn)o make calibration standards, which bracketed target concentration of the diluted dosing samples. stock solutionof internal standard `calibration standard: Nea. tration of approximately 0.09 mg/mL. The ratioofthe internal staandnthed testasubrstad nce 1peak heights from replicate `GC analysisofthese solutions were sed to constructa calibration curve by least squares regression (see Appendix A, Figure 1 fora representative curve). Measured concentrations for the dosing samples were determined by applying the peak height ratios from replicate injectionsof each ~~ sample to the calibration curve. Test substance homogeneity and uniformity in the vehicle was evaluated by calculating the coefficient of variation (C.V. = standard deviation/mean x 100) of the measured concentrations in the top, middle, and bottom samples (homogeneity) or duplicate samples (concentration verification)foreach dosing level. Acoefficient of variation of less thanorequal to 10% is considered indicativeofacceptable distributionofthe test substance throughout the solution. However, if the test substance has been shown to be difficult to disperse in the vehicle or the `malysis has shown variability, a coeffiofcvairieatniotn greater than 10 may be acceptable. The mean result of the homogeneity samples or concentration verification duplicate samples for tach dosing level was used to determine the concentration of the test substance for the respective dosing levels. Stability was evaluatbeyd using the mean resultofthe homogeneity samples as the baseline for comparing the corresponding stability results. spiked recoveries samples at each level were prepared and monitored to show the effect on the antitation of the study due to sampling into 100 mL volumetric flasks. Based on the spiked ecovery for each level onthedaoftyhe analysis,acorrection was applied toallresults in the study. rm~ rr-- r Company Sanitized. Doesnotcontain TSCA CBI ~ || | [r--. Toxicity Study in Rats DuPont10157 D. Test Species `The Cel:CD(SD)IGS BR rat was selected for this study because itis a preferred species for developmental toxicity testing as recommended by the applicable regulatory guidelines. The strain was selected becausebackgrounddata are available from the literature, the supplier, and previous studies at Haskell Laboratory. Eighty-eight nulliparous, time-mated females were received on January 31, 2003 (66 females) and February 3, 2003 (22 females) from Charles River Laboratories, Inc, Raleigh, North Carolina. Body weights from the day the rats were mated, day 0 of gestation (day 0G), were supplied by the vendor and ranged from 230 to 270 grams. The rats for this study were requested 10 be approximately 63 days old and at ether 1, 2, or 3 days ofgestation upon receipt. Each rat was assigned aunique number and identified with an AVID microchip implant by the supplier prior to shipping. Upon receipt, eachrat was assigned a unique Haskell animal number. Boththe Haskell animal number andthe number provided bythe supplier were recorded on each cage card. A master list of unique Haskell animal numbers and corresponding unique supplierprovided animal numbers was maintained with the study records. E. Animal Husbandry 1. Housing Animal rooms were maintained at an acceptable temperature of 18-26C (targeted at 2224C) and maintained at an acceptable relative humidity of 30%-70% (targeted at 40 %- 60%). Occasional excursions outside the accepted ranges were minor and did not affect the study. Animal rooms were artificially illuminated (fluorescentlight)on a 12-hour light/dark cycle. (approximately 0600-1800 hours). Animals were housed individually in suspended, wire-mesh, stainless steel cages. Nesting material was not provided because the dams were euthanized prior parturition. i 2 Feedand Water PMINutrition International, Inc. Certified Rodent LabDiet 5002 (formerly known as Purina Caevratiilfaibelde RaoddleinbtituCm.how) was availableadlibitum-. Water from United Water Delaware was E 3. Health Monitoring Program Asspecified in the Haskell Laboratory animal healthandenvironmental monitoring program, the following procedures are performed periodicaltloy ensure that contaminant levels are below. hose that would be expected to impact the scientific integrity of the study: Water samples are analyzed for total bacterial counts, and the presenceofcoliforms, lead, and other contaminants. a CCoompamnyeSantizad.Deoesneotce onai" n TSCACBI = FE -.--- ToxicityStudy in Rats DPon10157 -- Feed samples are analyzed for total bacterial, spore and fungal counts. Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. Certified anima feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The. presence of these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrityofthe study. `The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluationofthese data did not indicate any conditions that fected the validityofthe study. F. Quarantine and Pretest Period Rats were quarantined according to procedures outlined in Haskell Laboratory SOP LA003-P, nd then released for the study upon approval ofthe Laboratory Animal Veterinarian designee. 6. Randomization --~ Dams were assigned to lots according to their gestation day. Then, theywereranked within their spective lots onthebasis of d0aGboydy weights and assignedtocontrol and experimental roupsbyrandom sampling fromtheranked list. The distribution resulted inmean body weights or all groups that were not statistically different (p > 0.05). i. Parameters Studied --k In-life ObservationsofFemales a Clinical Observations (Clinical observations were recorded on the dayafterarrival and daily until the endofthe study; dinical observationswere recorded twice daily on days 6-20G. * b. Body Weight fody weights were recorded on the day afte arrival and daily until the endofthe study. c. Food Consumption food consumption was measured on days 4,6, 8, 10, 12, 14, 16, 18, 20, and 21G. --_ Es Company Sankized. Dossnotcontain TSCA CBI (--)- TosicityStady in Rats Dupont10157 -- 2. Postmortem Observations of Females Surviving to Scheduled Euthanasia The abdominal and thoracic viscera were examined grossly immediately after euthanasia on day 21G. The intactandtheempty uterus of each dam having at least one viable fetus was `weighed to permit calculation of maternal body weight adjusted to exclude the products of conception. The corpora lutea count for each ovary of females with viable fetuses was recorded. For each female with visible implantation sites, te types of implants (live and dead fetuses, and sesorptions) andtheirrelative positions were recorded. The uterusofeach apparently "nonpregnant" female was stained with ammonium sulfide to detect very early resorptions. 3. FetusesofFemales Surviving to Scheduled Euthanasia For each fetus, the following parameters were recorded: identification number, intrauterine location, sex, and body weight. The extemal alterations detected for each live fetus were also recorded. For each litter, the first live fetus and every other live fetus thereafter (approximately 50% of the fetuses) were examined for visceral alterations." Retarded renal development was classified euxstienrgnatlheexsacmhienmaeotifonWoweoreaenxdaHmoianre.d)foIrnsaodftdittiisosnu,eaallltleirvaetfieotnsu;sedsecwaiptithamtiaolnfoorfmtahteisoensfevtiussiebslewaats tthe discretionofthestudydireorcadtesiognere. -- Aerfixation in Bouin's fixative, the headsofdecapitated fetuses (fetuses that were decapitated prior to visceral examination; approximately 50% of the fetuses) were examined and alterations fwiexraetiroenc,otrhdeeda.lizEaxrainm-isntaatiineodnsskweelreteobnassweedroen exthaemimneetdhoadnodfskBealretraolwaaltnedraTtaiyonlsorw.e"reArfetceorradlecdohfoolr llive fetuses, excluding the fetal heads fixed in Bouin's fixative. I Animal Euthanasia rfeomcaeleedsinwgerweitehutvhisacneirzaeldebxyamcianrabtoinondsi;oxtihdoeseastpohbyexivaitsicoenr.allFyeteuxsaemsiwneerdewdietchaopuittadteecdapbietfaotrieon vere injected with sodium pentobarbital. All other fetuses also were injected with sodium fentobarbital before fixation. i| A. = > one0 atconsTM 1sCCht8 compe" Tm -- (n----- TosicityStudy in Ras Dupo 0157 ~~ J. ControlofBias Ianndadrdeimtaiionnetdo rcoadneddomduarsisniggtnhmeenctoltloecgtrioounpso,f palolsftemmoarlteesmwaenrde fceotadleddabtae.fore scheduled euthanasia K. Statistical Analyses Descriptive statistics were performed for al quantitative endpoiis listed below. Sequential twotsaiiglneidfitcraenntddtoesset-irnegs"pownasse awpapslideedtetcotetdh,e ddaattaa fforroematchheptaorpadmoesteergarsoutpabwualasteedxcbleulodwe.d aInfdathe test repeated until no significant trend was detected. For liter parameters, the proportion of affected fTehteusleesvepleroflistitegrnoifritchaencleitsteerlemcetaednwwaasspus<e0d.0a5s.the experimental unit for statistical evaluation. Where the data were tied and the standard large sample version of Jonckheere's test was not applicable, exact p values were calculated using permutation methodology." "Parameter Tread Test `MMaatteermnaall wweeiigghhtt changes ~ Maternal food consumption Linear contrastofmeans LDievaedffeettuusseess RImepsloarnpitaitoinosns(total, early, late) Incidenceoffeal alterations Jonckheere' est" | | IClnicniidceanlcoeobsfeprrveagtinoannscy Cochran-Armitage test FMeamtearlneaslwmiotrhatloitatlyresorptions. Early deliveries Fetal weight (Covariates: liter size, sex rati:o) Sex ratio (Covarate: ter size Linear contrast of least square means? | --~ ; -- Company Saniized. Does 1 Em -- (a)... Toncy Sudy in Rats Dupont10157 ~~ RESULTS AND DISCUSSION ANALYTICAL EVALUATIONS A. Chromatography (Appendix A) The test substance eluted from the GC column as resolved peak with 2 retention time of approximately 3.7 minutes. The intemal standard eluted from the GC column as 2resolved peak with a retention time of approximately 4.1 minutes. Representative GC chromatograms are shown in Figures 2(a -d). Test substance was not detected in the 0 mg/mL control B. Recovery Samples (Appendix A) Detailed analytical resultsofrecovery samples are summarized in Appendix A, Table L The variability of the analytical method was demonstrated by the coefficientsofvariationofthe. recovery results at each targeted dosing concentration (approximately 10, 40, 100 mg/mL) over the courseofthe study. The range of the measured concentrationsofthe test substance for the 10 mg/mL level was 84.5%to92.6%of nominal (mean percent recovery = 88.9% + 3.3, C.V. = 4%). The range of the measured concentrations of the test substance for the 40 mg/mL level was 81.9%, to 93.5%of nominal (mean percent recovery = 85.5% 4.7, C.V. = 5%). The range of the measured concentrationsofthe test substance for the 100 mg/mL level was 76.4% to ~ 9co0r.r2ec%tioofnnwoamsinaaplpl(imeedatno paellrcseanmtprleecroesvueltr=syus8i3n.g0t%he# s5p.1i,keCd.Vr.ec=ov6e%r)y.foBraesaecdh olnevtehlisondatthae, a day of malysis. C. Homogeneity and Stability Samples (Table 1, Appendix A) Analytical results from dosing formulations collected on test day 1 (February 3, 2003) and `malyzed for homogeneity, concentration verification, and stability are shown in Summary Table 1 and Appendix A, Table IL. ||~ | | E santized. Dossnotcontain TSCACBI come 1b -- [--)-- Toric Sudyin Rais Dupont10157 --~ "aTnhdesftoalbilloiwtiynagntaalbylseessummarizes the results for al homogeneity andlor concentration verification SaTmepxlteDiyType| Nmogm/mml Mearmegd/mTMB Me%aNnomTiMnaBl) CV_(%.) _%SNtoabmiilnitayl HoTmeosgteDnaeyit|y 0 ND - -~ 0 849025,,480705,,319080 1502023 71 m55s6 100 965.983.9486 965 21040 b+ DASlaemlaprnleersseihsslucsaofmoherottuehrdsfasonrtalsoypsoiimksteoedfmrtpehecerotavotepur(ry1eb)a.,smediodndtlhee,evaenldanbdodtaoymo(f3)anaslaymple(sReferfo TbD. = MDeenaontreseunloeofdtehtecrtiegdinalanalysisandduplictrealy oftheorga sample. h"TohmeodgaetnaefooursslaymmpliexsedcoilnletchteedveohnicTleesat Dalalyle1veilnsdi(cCa.tVe.s'tsh=a,the1,teasntdsu2,bsrteasnpeccetiwvaesly). The test tshuebsvteahniccelewwahsaetnhheeldtfaorge5tehdocuornsceanttoraotimonteimnpetrhaetsuarem.ples (+ 7.8%of nominal) and was stable in D. Concentration Verification Samples (Table 1, Appendix A) ~ dAanyal2y0tic(aFlebrreusualrtys2f1r,o2m00do3s)ianngdfoarnmaullyazteidonfosrccoolnlceectnetdratteisotndaveyri1f1ic(aFteibonruaarreys1h2,o2w00i3n)Saunmdmtaersty Table 1 and Appendix A, Table I. t`Thheetfesotlsluobwsitnagntcaeblseasmupmlemsafroirzteessttdhaeyrsesu1l1tsafnodr2c0o.ncentration verification analyses of the PrepDayration Nonmgiinola.l HespeoaredTM %TNomeinal O__V% TeDayll "100 HsEWaFAe LL 1T0d05 u2 - TetDy20 10100 10904751,0915978 9959.71 11 - 100 534560,,931798 593120 25 5+ ADulpliecaste csaompmleestecoresvpeilkveedreevbrraytesddsdnshmdv.eC2V.docylofesatytso vtRyesooTurlie.ofmse. RMesanisesolfotfhetshuirs no rndaelmspsldcodlluelctcedefre omthe dy osinghepro aepragrcnilonss.ample. RveersiuflitcsatfironominadniaclaytseidstohfatthteesstasmupblsetsantcheatviwaesrehocmoollgeecntoeudsolnyTmeisxteDday(C1V1 =fo2r,co1)ncaenndtraatttihoen | ~ targeted concentration (s0.5% of nominal) or all samples except for the 10 mg/mL. lpevoenls otcontsn TSAo@ | -_-- % compawTM (--..: Toxicity Study in Rats DuPont10157 -- n(oCmVin=al1)1,in2d2ic.at6e%d tohfatnotmhienoarli)g.inaTlhsea3mp"lsianmgsplheacdolbleeecntecdolflreocmtetdhbee1fo0rmegt/hempLrelpeavrelat(i8on7.w1a%sof adequately mixed and consequently the CV greater than 10 for the replicates and recovery of less than + 20%of nominal forthe level. Results from analysis of the samples that were collected on Test Day 20 for concentration verification indicated that test substance was homogenously mixed (CV = 1,5, 2) and at the targeted concentration (= 9.0% of nominal) for all samples. E. Analytical Conclusions Results from the analysis of the test substance dosing formulations at the start of the study indicated that the test substance was homogeneously mixed, at the targeted concentrations and stable in the vehicle under the conditions of the study. Results from the analysis of the test substance dosing formulations forthe concentration verification indicated that the test substance: was at the targeted concentration during the study except for the 10 mg/mL level on the first sampling for the concentration verification analysis on test day 11. Subsequent sampling of this formulation indicated that the original samples had been collected before the formulation was adequately mixed. ~ CompanySanitized.DoesnotcontainTSCA CBI am -- [r--..... Toxicity Study in Rais ~ DEVELOPMENTAL TOXICOLOGY DuPont10157 A. Mortality, Post Mortem Findings, and Clinical Observations (Table 2, Appendices B and G) Test substance-related mortality was produced at 500 mg/kg/day. Four dams were sacrificed in extremis on either day 10, 11, 12, or 13G andonedam was founddeadon day 16G. Clinical observations preceding death in these animals included hunched-over posture, weakness, diarrhea, and wet and/or stained fur. Twoofthese five dams appeared normal at the gross necropsy whereas three dams had pale kidneys and/or discolored liovrluengrs. There was no `mortality at either 50 or 200 mg/kg/day. Test substance-related clinical observations were produced at 500 mg/kg/day and included increased occurrences of alopecia, diarrhea, hunched-over posture, weakness, and fur-staining. There were no test substance-related clinical observations at either 50 or 200 mg/kg/day. All her clinical observations recorded were considered incidental and unrelated to the test substance. 3. Body Weights and Body Weight Changes (Tables 3 and 4, Appendices C and D) Test substance-related reductions in matemal body weight and weight gain were evident at ~ 500mg/kg/day. Reduicnmtateimaolwneigsht gain occatuthreonrseteoftdhedosingperiod nd persisting for the duration of the study. Mean weight gain over the course of the study (days 21G) was 25% lower than forthecontrol group; when the final body weights were adjusted for fieweightoftheuterinecontents, the meanweightgainoverthe sametimeperiodwas 57% werthan for the control group. These reductions in maternal body weight gain resulted in bwer or significantly lower mean maternal body weights beginning as early as day 7G and fersisting for the duration of the study; mean final body weights were 9% lower than the control foup. There were no test substance-related efforemactetmasl body weightor weight gain at ther S0Gr 200 mg/kg/day; data from these two groups were generally comparable to control foup data. Food Consumption (Table 5, Appendix E) sefeatnemawteerrensalligfhotoadndcooncscuamsipotniaolnlyatst2a0ti0staincadll5y0s0igmngi/fkigc/adntayt.estTshuebsstearnecde-urcetliaotnesdwreerdeucmtoisotns in fonounced over the first few days of dosing but generally were subtle enough such that there fas no appreciable impact on food consumption at these levels when data were averaged over Jecouorfsthee dosing period. Therefore, these slight test substance-related, transient dictions were not considered indicative of adverse toxicity. -- TT = 4. Doss101tainTSCA cal Company Sa -- (-- cc Tonciy Study in Rats DuPont 10157 --~ . Postmortem Findings (Table 6, Appendix F) "`wWeirteh etihteheerxcseapctriifoincoefdtihnoesxetrgermoisssoprofsotumnodrtdeemadf,inthdeirnegswdeersecnrioberdemparrekvsiboluesltyesftorsuabnsitmaancles-trhealtated nsuercvriovpisnygodbasmersvaattiSon0s0.mgO/nkeg/ddaamy farpopematrheed5n0o0rmmagl./kgT/hdearyegwreoruepnhoadrepmaalrekakbildnee,ytse;stalsluobtshtearnceselated necropsy observations at 50 or 200 mg/kg/day. E. Reproductive Outcome and Litter Data (Table 6, Appendices GandH) `There were no test substance-related effects evident in the reproductive outcome and litter data fcoorrpaonriamallustetahaatndsuirmvpilvaendtautnitiolnsccohuentdsu,leldteeurtshiazneass,iianacinddehncaedsloifverelistotreprst.ioLnist,tfeertmalewaenigdhatt,a faonrd sex tio were comparable across all groups on study. `thTihserdeawmassuornveivdedamuntatil5s0c0hmedgu/lkegd/deautyhawnhaossiea,litthtiesr acnoinsmiasltewdaosfionnreeleaatrilvyelryepsooroprticoonn.diAtliotnhobuyghthe end of the study. During the course of the study, ths animal exhibited persistent reductions in food consumption, body-weight loss, and clinical signsoftoxicity. Based on these data, the sorptionofone fetus was considered likely to be secondary to overt matemal toxicity. --_ F. Fetal Alterations (Table7s and 8, Appendix H) 1. Malformations (Table 7, Appendix H) There were no malformed fetuses in the current study. 2. Variations (Table 8, Appendix H) h#e2r0e0awnerde5t0e0stmsgu/bksgt/adncaey-.reAltat5ed00anmdg/sktgat/idsatyic,altlhyerseigwneifriecainntcirnecarseeadsoecsciunrfreetnaclesskeolfetdaellavyareidations felvic bone ossification and wavy ribs. At 200 and S00 mg/kg/day, there were increased sfbcsitdaennccee-sorefladteeldaaynedd asrkeulclonbsoinseteonstsiwfiitcahtisokne.letTahlevsaerifaitnidoinnsgpsrwoedruecealdlbcyonasisidmeirleadrtfoluboertoetsctlomer- sseerdvealdcaoth2o0l0.'mHgo/kwge,vewre,rethneoetfcfoecntssidoenreskdulaldvbeornsee ofsosrisfeivceatriaoln,reiansopnarst.icRuleatra,rdtehed isnkcurlelasbeo,ne sification is arelatively common observation in general and is therefore, not typically nsciledaerrteedstasutbrsetmaenncdeo-uresllaytreedlieafbfleectisndoincaftetoarlobfodedvyewleoipgmhte.ntRaellteovxaincittyhi,setsorpieccailalcloyntirnotlhdeaatbasaernece povided in the table below and ngeofhistorical control data. the incidences for al groups in the current study fall within the -- -- || --= Santtzed. Do nots conts ain Tscacal --_ Historical Control Incidence for Retarded Skull Bone Ossification CI r r Cf em C[CvCe aCmm amimyvv CI T e ) T m m-- m SaA } SCCr e of ee ede ml ) [or wet | ~~ Company Saeitizod. Doss not contain TSCA CBI [---........ Toxicity Study in Rts. DuPont 10157 -- CONCLUSIONS cUonndseirsttehdeocfonmdaitteironnaslofmtorhtiaslisttyu,ddye,cardevaesresdebmoadtyerwneailghtotxsicaintdy bwoadsypwreoidguhctedgaaitns5,00anmdg!/ikncgr/edasaeyd.and clinical observationsoftoxicity. One litter at 500 mg/kg/day consisted of one early resorption; persistent reductions in food consumption and body-weight gain and increasedclini cal observations indicative of toxicity were reported during the study for this female. Therefore, this liter consisting ofa single early resorption is believed to be secondary to overt matemal toxicity in this dam. Developmentaltoxicityat 500 mg/kg/day consoifisnctreeasedd skeletal variations (delayed pelvic bone ossification and wavy ribs). At 200 and 500 mg/kg/day, there were nonadverse, test substance-related, transient reductions in matemal food consumption. In addition, there were slight increases in the incidence of delayed skull bone ossification at 200 and 500 mg/kg/day that were not considered adverse. Thus, the no-observed-effect level (NOEL)' for both maternal and developmental toxicity was considered 200 mg/kg/day. RECORDS AND SAMPLE STORAGE Laboratory-osrspiteec-sipefciificc raw data, such as personnel files and equipment records will be retained by the facility where the work was done. ~~ A sample of the test substance was collected for archive purposes and retained at Haskell Laboratory. Specimens, raw dats, test substance characterization data, and the final reportwill be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware. | | Coro stnoman rch a `TwheereNnOotEdLetfeocrtetdh.is Tshtsa,y ifsordetfhiisnesdtuadsy,ttehehiNgOheEstLdiosseeqautivwahliecnhtatdovtehresNeOefEfeLctassadtefiibnuedabbyltthoetL-S.6EPsuAbsiaannced -- to the no-observed-advrse-<fict level (NOAEL) as defined by the European Union 00 | EE | (-- Tons Sty ns Dupont t0157 ( ~~ C REFERENCES =. 3. Salewski, E. (1964). Farbemethode zum makroskopischen Nachweis von Implantationstellen am Uterus der Ratte. Archiv. Path. Exp. Pharmakol. 247:367. 4. Staples, RE. (1974). Detection of Visceral Alterations in Mammalian Fetuses. Teratology, 93):A3T-A3S. 5. Woo, D.C. and Hoar, RM. (1972). Apparent Hydronephrosis as a Normal Aspect of Renal Development in Late Gestation of Rats: The Effectof Methyl Salicylate. Teratology, 6:191-196. 6. Barrow, M.V. and Taylor, W.J. (1969). A Rapid Method for Detecting Malformations in Rat Feuses. J. Morph., 127(3):291-306. 7. Selwyn, MR. (1995). The UseofTrend Tests to Determine a No-Observable-Exffect Level in Animal Safety Studies. Journal of the American CollegeofToxicology 14(2):1 58-168, ~-- 8. Haseman, JK. and Hogan, M.D. (1975). Selectionofthe Experimental Unit in "Teratology Studies. Teratology, 12:165-171. 9. Patefield, W. (1982). Exact Testsfor Trends in Ordered Contingency Tables. Applied Statistics 31:32.43, 10. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6th ed. The Iowa State | University Press, lowa, pp. 246-248, 349-352. | 11. Jonckheere, AR. (1954). A Distribution-Free K-Sample Test Against Ordered Altematives. Biometrika 41:133-145. 12. Dempster, AP, Selwyn, MR., Patel, CM. and Roth, A.J. (1984). Computational AspectsofMixed Model Analysis. The Jounal of thSetaRtiosytaiclaSltaartdistical Society, Series C (Applied Statistics), 33(2):203-214. 13. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance for Analysis and Evaluation of Subchronic and Chronic Exposure Studies. Paynter, OE. etal. United States Environmental Protection Agency, Office of Pesticide JPrograms, Washington, D.C., 20460. EPA-540/9-85-020, June 1985. | -- 14. Risk Assessment of Notified New Substances Technical Guidance Document 1 | (X1283/94-EN), Chapter 1, Sections 2.24 and 225. Company SanDoiestToticonztaionTSdCAC,B | ~ _ TABLES |~ S ee e . Pb ei --> Toxicity Study in Rats --~ Tables Explanatory Notes Dupont10157 Notes DayC21 = Cutoerrmiencetewdeifgihnatlpmluastetmhealembpotdyyuwteeriigneh=wteifginhatl.maternal body weight minus the gravid Abbreviations ~ = NoDaa SD. = Standard Deviation SE. = Standard Error N= Numberin Group -- ~ -- -- `Company Sanitzod. Doss nco4ontain TSCA CBI x -- Toxicity Study in Rats DuPont 10157 -- TABLE| SUMMARY OF DOSING ANALYSES Dosing Concentrati(omngo/f8m-L2) Telomer B Alcohol HomogNeonmeiintaylS:amples o 100 TestToDpay 1 892 405 965 Middle 2) 013) 063) 873 00 983 Bottom 3) 1000) 83 100 308 948 Average Measured Conc. (1000) ) 922 401 48) 96.5 `A`vSetraagnedaPredrDceevnitatNioomninal 08 2000337) 026138) CoefficientofVariation 7% 1% 2% 5HouSrtaRboiloitmy STaemmppelreasture 956 a1 104 Concentration Verification 56) rer (1040) Test#Day 11 7280 399 100 ~~ @9 8 ) " 7230 @3 39973% 011001, " 871 . aacnziet) 95822) `AAvveerraaggeePMeeracseunrteNdoCmoinnca.l [7274 a0os2) 99)7 CoSeltlaincdiaerndtoDfevViaartiiaotnion* 2108%4 207%6 11%4 Test#Day 20 9.45 350 94.6 45) @3) 46) ." 95577) 03758 . @9199 `AAvveerraaggee PMeeracseunrteNdomCiognacl.' `Standard Deviation" o9s511 31604) 009 +20 532 119 CoefficientofVariation' 1% 5% a Mean esultofthe original analysis and duplicate reanalysisof original sample. 2% b SNtuamsbierssbianspeadrocntthheesesaavreeratghemreesspseucrteidvecopnecrecnetrnattoifonnoofmtihaelovpa,lmueisd.dle an bottom of exchdosing eve. aeSRtesaulttosftbhaesaenaolnystihsfaovretrheatgheirmdeassaumrpeldeccoonlcleencttreadtiroonomftwhrpdliocsaitnegpsarmepplaersifoonsthe dosing level. | f Statistcsbasedontheaveragemeasuredconcentration of duplicatesamplesforthedosinglevel ~ Company Sanitizod.Dossnot contsin TSCACBI | " 3 | | gi Ed is 13 TEEHH thee veececeeoelHt . i } { 5 i pe 2 ig 2 if i oor 1 iI gIf og Lopj2 : J igf ggiieds 3EgEa0og2SuEmEm3n3E.8EHtfSiF) [~ FH | if Company Sanitized, Doesnotcontain TRCA CRI mmm---- om oc sn DuPont-10157 r TABL3E MEANMATERNAL BODY WEIGHTS (grams)* DAYO DAY4 DDAAYSSOF GESDTAAYTGION Dav DAY oars GROUP IT: 0 MG/KG/DAY G5.R2O.UP MEAN sz! 214093.64 2.15 216.56.87 2.48 217103.72 2,02 21727..353 283 218.43.75 2,50 21819..898 2.5 21960.s9 2.48 22 2 22 EE 2 2 El GROUP II: 50 G/KG/DAY GsRpO.UP MEY 2w09s.6 sel 2,51 21646.6 2.53 21721..80 281 21726..93 2.80 2128.13.85 2.70 2118.74.59 2,43 2109.03.36 2.26 : 2 3 a a 2 2 a ROUP IIT: 200 MG/KG/DAY. O5.U0.P MEANY siz! 2i0193.88 - 215692.01 2.83 345 216398.12 2.90 21730..068 278 21728..221 2.60 21283.4.5.5088 21817..570 250 --~ x E) 22 iz 22 ES 22 22 GROUP IV: 500 MG/KG/DAY. 5O.0U.P MEAN 21029..072 se 3.00 21663.5.75 eae 2d6e0e.r8 4.20 2l7e7.d8 408 21s7.18.09% 2207.8939+ 2228.44.02% 497 5.20 5.60 6 is is is i6 ic ic ~ `Company SenitizedD.oesnotconte in TSCA CBI 0 [I]. oi DuPont10157 --_ TA3B(ConLtinuEed) MEANMATERNAL BODY WEIGHTS (grams) mri mwa moeuasnor aamsmwatazon mw owas owe GRowe 1: 0 w/xa/mRY aeGsorm 2PT sa.o6 eWl 26h8 W3ONwE WmuWee mHueWno BaWmhRs eiNaeE B i i 5 ia i ii i GRour 13: 50 e/xa/ORY ioGoow W2T9a7ROOW3I6ee3 WaEseE LdNeuys Bmiehnn Ban mmes um Wowa H i 31 i 3 i Fi i - amoup 111: 200 wo/xG/oRY ~ Gaoz5vewmw 2DT2EEs ORaIE3E wWTamy mHueuar EmN0mR mBCeNha aWussw B i i i 32 ii 32 ES Group 1v: 500 Ye/xG/DRY iG5ouramPiCaseOEHsSeWRe O2R6B0HN0 BdWwae LaWmuma BeuWne BwAaEEe B it ie f ie it ie id ~~ | --- `CompanySanilizod. DDoosessnRoottcontainTSCACE [ro DuPont10157 --~ `T3A(CBontLinuEed) MEAN MATERNAL BODY WEIGHTS (grams) DAY 17 DAY1s DDAAYYSSOF GEDSATYAT2I0ON DAY 21 Dav can GROUP I: 0 WG/KG/DAY Gsroo.ve Ew 1358s.2 m34d.e5 23095121 2410.90.10 2483.39.58 23300..307 sz 3327 n2e a23 a2ss s2is a2s GROUP 11: 50 MG/KG/DAY r3o.ve wsay 13255.81 1365a.5 13e99.62 41051.s8 1n8a.4 31342..847 Hsz 22718 320 p3i2t8 33316 aise 33 GROUP IX: 200 MG/KG/DAY. cSbo.ve may 3W56i.8 m33a.o2 326.02: 0259..33 e322.6955 332500 ~ sz E2ss s2or s2ss e32r e3s2e a3s2s GROUP 1: 500 MG/KG/DAY GsRoo.vPMEAN 324560.611 236m0..5 2378a9lc 2386.4.72 339058.71 23090..409 5SE sias.o iesss i7s1s imsoa isses 1is7 a eDaxttaremwiesr,e oefxchlauddedlitftreormsfecmoanlseisstitnhgatenwetrierenloytofprergensaonrtp,tiofnosu.nd dead, sacrificed in statistically significant trend (linear contrast of means); p < 0.05. | --_ CompanySankized. Doo nokcontain TSCACBI 5 7 (-- oe Toscity Stdyin Rats DuPont10157 TABL4E MEAN MATERNAL BODY WEIGHT CHANGES (grams)* es as DatCsesor czsmEadzezon wm as 1s aaove 1: 0 worxo/mAY pGoe5ve amw IF2E3BC1 TemmHso tS 1a4 SE S5s7e IxMm9M o v oame oW1s6He2 i FA i 8 2 i ia 52 amour 1x: 50 Mo/o/TRY imeEsov e23n67od:ee nSmhms oow sma Tdaeaas iS1ama 160 Ln i 3 i 52 3 i Fy i Grou 11x: 200 a/KG/AY m5SoEve wm 2Im0ho8e 1I5.nu4s mdf2am ms7nu0 Iassnas meIneE 2ii0an8 ~ 3 i 32 i FY F 3 5 wove 1v: 500 varxa/oAY i5moEve vmw ZF2oes i314ms2 zsokass as5mase aAlesmaer aamcsaeme aaissso i is is is is ie i is ~ CompanySaniizad,Dog hotcontainTeacay | -- --= CE - Toicity Sudy in Rats DuPont10157 --~ `TA4(CBontLinuEed) MEAN MATERNAL BODY WEIGHT CHANGES (grams) . 16-18 move 1: 0 Mo/KG/DAY GSoo.w ma 3Q0G3e 5ix o2s asa Days oeratcEsTaTIeoan l $o9.s3 a1n8d6s8 e5d2s9 z32n ais s22a OUP I: 50 MO/XG/DAY moevse wmw G29e.4 a$1s.6 115.058 n56e1 i3E. T31a u3n e3m z2s; ROUP XIE: 200 G/KG/DAY ~ m5SboE.ve aEw 71301s28 a2saaa mmed9nr sasddisel 2 12 i 32 ROP IV: 500 G/EG/TAY m5ppeo.ve umwy T129hs.o3 aeeeszee aesdnesa snnoeeer | is is ie is Deaxttarewnesr,e eorxchlauddedlitftreornsfceomnasliesstitnhgatewnetrierelnoytofprergensaonrtp,tiofno.und dead, sacrificed in + statistically significant trend (Linear contrast of means); p < 0.05 --_ CompanySentient. Doopos,containTs cg; 3 (-- lopment Tosicity Stay in Rs DuPont 10157 ~ TABLES MEAN MATFE OODRCONNSUMAPTIL ON (grams/day)* ws 68 aes0op GESTTaATzION 1216 lel 16-18 Rowe 1: 0 Ho/KG/DAY m5oe wmw m25e8 2s:a3r a231s 2as5a 22.6418 2242s 3269s3 s e io2s io2m ons oiez goHs o3s2e o2s GROUP 11: 50 HO/KG/DAY mio.ve wmn 2m3e6 22.452 zmsa 22517 2246s4 s2e6e8 d30a.z2 ix 023 0353 EoAsa E0h3 0is 028 0371s OUP TIX: 200 MG/KG/DAY msoo.ve wma 223.,355 22.30+ m2a2r 2366.s6 23.6501 230348 L2.o56e --_ iiz G325 o3s oiw or)s o32e 020 o32e @OUP Tv: 500 HO/XG/DAY siiDzo.vedew 2S0307.367 si1u9s.s8 3o2sma ei20ne.e6 aL25go.er8 24t9dn 3sio1mns i is is is is is is is --_ CompanySanitizeq Does,motcontainTSCAcg E3 -- cc `Tosicity Study in Rats DuPont.10157 --~ `TABLE 5 (Continued) MEAN MATERNAL FOOD CONSUMPTION (grams/day) DArYiScaoF GESTA#T1ION GROUP 1: 0 MG/KG/DAY c5o.ve mw 238ha 226.,64 s z o32s o2se GROUP II: 50 MG/KG/DAY aapm5eo.sur vmwy 2208d5.r2 220.6402d0 hH 3a GROUP III: 200 MG/KG/DAY --_ m5.o0v.e Mew 2305.84 226..83 SE. os os 2 32 GROVE TV: 500 Ma/KG/DAY mS5oE.ve Mew 2S1533.5%4 o22.0m60m 5 is is Doaxttarenviesr,e eofxchlauddedlitftreormsfceomnasliesstitnhgatenwteirreelnyotOfprergensaonrtp,riofnosu.nd desd, sacrificed in + statistically significant trend (linear contrast of means); p < 0.05. | --~ `Comoanv Sen#Doiesznootcodnta.inTSCACBI 57 -- OY ccc oc sty ns DuPont 10157 - TABLE6 REPRODUCTIVE OUTCOME Group: 1 Dose (mg/kg/day): o zn ux wv 0 200 500 Yo. Hated Yo. Pregnant No Delivered Early No. Deaths Yo. With Total Resorptions Yo. Litters Mean Corpora Lutead 2 2 2 15.7 (L6UP 2 zn o 2 16.0 (3.08) zn = o o 2 16.0 (3.40) 2 2 5 1 6 16.1 (2.51) plantations (Nidations) 16.7 (1.62) 13.9 (1.56) 13.9 (1.64) 13.4 (3.87) Resorptions: Total 0.0 021) 0.7 (1.06) 0.4 (0.99) 0.4 (0.81) Barly 0.0 (021) 0.7 (1.06) 0.4 (0.79) 0.4 (0.81) Late 0.0 0.0 0.0 0.1 (0.28) Dead Fetuses 0.0 0.0 0.0 0.0 Live Fetuses: Total | 14-6 (136) Males 7.2 (173) Females 7.5 (174) 13.2 (1.81) 13.5 (LIM) 13.8 (1.59) 6.0 (158) 6.9 (2.16) 7.1 (1.68) 7.2 (1.6) 6.8 (1.97) 6.7 (1.89) Mean Fotal weight: Total Males Females 5.55 (0.31) 5.68 (0.33) 5.43 (0.32) 5.65 (0.29) 5.77 (0.39) 5.40 (0.44) 5.83 (0.30) 5.94 (0.40) 5.57 (0.47) 5.51 (0.26) 5.59 (0.42) 5.20 (0.39) Sex natiod 0.49 0.11) 0.45 (011) 0.50 (0.10) 0.51 0.1m) a b pSStrtaeanstdeiasnrttdiecdadlefvoiraantaiilnoyfnsoersimsatarireoepnonroonttleydc.onindupcatreedntohnesmees.an corpora lutea daca; these data are DSprteaazsteilsnitttietcdearlfaonradnailtnoyftsoaerlsmasntreieaonnoonfnelltyya.lcownediugchtte.d onThehememanesanfotrotmaallensumbaenrd offemallievse afzeetuses 4 Runber male fetuses total number fetuses per litter. NotG"eae:.tkaeThs(eteaxptcrieepsgttniacfnaocrlylyfraaattanelaldwyaeztieagd,htuasdiaunnlgdt stmehoxertCraoaltciihtor)yandw-aeAtrmaem,itaaanpgadelytscheoesdt.tuostianAllglrJeolsnioctrktpheterieormnee:adsnate sCoqsuta.re m`Feeatnasl.weight and sex ratio were analyzed using a linear contrast of least statistically significant trend; p < 0.05. ~ CompanySanitized.Does notcontain TSCACBI --Jortpmns Tosicity Study in Rats DuPont 10157 " TABLE 7 INCIDENCE OF FETAL MALFORMATIONS croup: 1 n mr TM ose (maka): s0 200 500 ExrERL No. Examine" No. Aftected apn an sea) 2006) oto) oror oro ot 0) viscem No. Examined No. Affected 6702) we@ ass2) 1306 ote oro) ore or 0) No. Examined Yo. Attected 67022) 1221) 1ssi22) 1306 ool orol oro) ot oy cmon --~ Yo. Examined No. Affected a2) 2 29702) 220016) oto) oral oro oro 20m yonmERapECTED oo oo oo oto) a b FHmoaurlmfboecrarmsaeetxioaofnnisrneeaaddrieanngde,xpasrfaefresocstseeddh,aavseiFnbecetleuunsdeisrn(egLpilttahtceeerdnsu)wmibteohrr dFaaofscfhueescsetsedfo(rwLiitttthheertshl)eistleidsted 2alformations. No significant trends were detected (Jonckheers-Terpstra Trend test); p < 0.05. Note: Sotvaetriasltlictaoltaalnaalnydsetsotaarles obnylyexcaomndtuycpteedaroen ptrheeseinntdeidvifdouralinefnodrpmoaitnitosn. onTlhye -- CompanyGanitizad.DossnotcontainTSCACBI || (--h- co Tonic StudyinRats Dupont10157 TABL8E INCIDENCE OF FETAL VARIATIONS evEzomemm, vARzATIONS perme Yo. Examined" Ho. atectaa visemm Yo. Branine No. Attocted Grow: x = m TY so 200 322022] oo wa) oto 277021) ote aan ote 297022) oto stn oto w s00 220(16) oro; 106 eto =Yo.oBantned No. Attected we ae ssn wns oem ote oto oro -- No. Banine --~ a - Rustnentary Cervical - supernumerary So - ruse wo. Attectea men man wom ane ean uw san pan nas ao -- 10D san pan Mae san TnL wi DEvEORENL viRIATIONs 2501) 2003) 406) sun) anzazzons pum $0 RETAXDED DEVELOMERNT Yo. Buanineas No. Affected viserm Ho. Buamined Kidney" Smal papila - Size 1 Seal) peptala - size 2 [A Yo. Attocted ~ | --- | men wan wen one oor ota opm oo) wa wa am se 2m es ween sen sae wn ww 2m unm wn sts am an mm osm sia CompanySanltesd. DoesnotcontainTSAcay Gem -- opmentalTonciyStudy in Ras `TABLE 8 (Continued) INCOIF FD ETAE L VANRIACTIOENS DuPont.10157 VARIATIONS DUE TO RETARDED DEVELOPMENT (Continued) =Yo.oExamined 16102) deen spn sue Yo. Affected oor oto ote oro Yo. Examined * elvis - Retarded ossification Rib - avy Skul - Retarded casi fication Sternebra - Retarded Ossitication Vextebra - Retarded Ossification No. Attocted sat) aan e702 2006 wn -- ses - - -- sea 20s nan sao sane 503) 202) 3(2) 80% san sce man ue sens sens ape) B04) om".DEwimRaETsAzRaDrEIDONDSEVELOPMENT sun esas ean sas ToT WNmER FETUSES WITH VARIATIONS 89(21) 80019) 9920) 106015) --~ b NVSautrmaibtaeitrsicoiencxsaa,lminaaerndealyaesnxedpsraefsafrseeecdtceaodsn,duFcoitcneucdsleusod(niLnitgthtetehrceso)nmubomirbneerdFoatinufcsfieedscetne(cdLeiswtittoefhrs)ts.phaelllisrteneadl Papilles; the details for each size are prasenced for information only. significant trend (Fonckheere's test) < 0.05 Note`:oversatlaltitsottiaclalanadnatloytsaelss abryeeoxnalmyacroendpurcetseedntcend tfhoer iinndfiovrimdautailonenodnlpyo.ints. The preg || ~ CompanySanitized. DossnotcontTSaCAiCBnI ~ - APPENDICES ~ --- Company Sanitized. Does not contain TSCACBI CORY ccorocomonne -- ews APPENDIX A Analytical Chemistry Report --_---- Company Sanitized. Does not contain TSCACBI (--...c.. `Toicity SudyinRats DuPont-10157 Table. SRaemcpolwe to Dating Vebicle Percent Not Nominal Toe 105 937 892 RReeccoovveeRryy 110458 915357 9012.60 RecovERY 148 25 845 RReeccoovvEeRryY" 1n4s8 110276 2850.71 Mean: 3c8v9.33, RReeccoovvEERRyy 450838 3a302 881290 RReeccoovveerRyy" 558888 550000 885500 RecovERY wy 20Mean: 8525254, cv.s% RReeccoovveerRyy 101099 99370 885630 RReeccoovveErRyy! 114444 1ns0 764 9 - ~ RReeccoovveeRryy" 14 15 99 132 19 202 Mean: 8C3v..0251, (A)Pcroolcleecstseeddownittheshtodmaoyge| n(eFiebtryuaanryd c3,on2c0e0n3t).rationverificationsamples (B)coPlrloeccetsesdeodnwietshthdoamyog1e(neFiteybanrd3uc,o2an0cer0n3ty)r.ationverificationre-analysis samples ()Processedwithconcentrationverificationsamples collctedontestday 11 (0) P(rFoecberusasreyd w12i,t2h0c0o3n)c.entrationveificaionduplicate re-analysisofthe original samples (E)coPlrloeccetsesdedtweisttdhacyonc1e1n(tFreabtriounarveyri1f2i,c2a0t0i3o)n.analysis for re-samplingof theoriginal formulations (F)prPeropcaersesdetdeswitdhaycon1c1e(ntFreabtriuoanryv1e2ri,f2i0ca0t3i)o.n samples collected on test day 20 (Febrary 21,2009. + --~ CompanySanitized.DoesnotcontainTSCACBI | = | [| Toxicity StiundRatys DuPont 10157 ~ Table IL.SaHmopmloegeneity end -- po --fois Formation:Percent Type Nominal TebyiGE `CHoomnoTgeenoeLity 000 NDB) -- Tor 110010 s9.1a3 ws 913 102 ls. ous MDL 100Mean(: 58972 0.2% 09 110012 88672 886727 Boron 10 Mean): 180730 71.0300% Mean); 9222069 22% crm MTL or aa0 000s 11001030 Borrow " Mean: 28 4012037 995 03%) cri Tor 100 963 %5 ~~ Mooie 11000001 21002 1902200 1002 101 1010 Boru 100 Mean: 8438 08.3%) 945 Mean): 9c6v5.z1%8 96.5%) 5StHaboilRity 10 956 956 1a00 a1014 11002680 (A) B) ADlelnoetesssnocodrertcteecdedfo spikedrecoverybasedonthelevel anddayofalysis(Refer 0 Table. ((CD)) MTheeanavreersaulgteomfetahseororeidgicnoanlceanntalryastiison(,-0a)vearadgeduppelricceantteorfeannoamliynsaislo(fiorpiagriennatlhessaemsp),lest(a-1n,dar2)d.deviation, and ) Sctoaefbfiilciyesnatomfplveasrihaetlidono5fhotuorps, mirdodloem,taemdpebraituore.. = `Company Sanitized, Donotceontsain TSCA CBI = | ~ | ~~ . ~~ || | Tc power ableIL"PreCpoanrcaetnitornaDtaioyn Verification" Sample Type `Nominal Test Day 11 (12-Feb-2003) ConcentraCtoionntVreoslifcation) 00 110011A 101M8ean): 1100224 1028 10M3ean): Mean):; DoAsi)ng Soluions= Me Nominal ND - 676532 3652 171208 77308 673828 @7828 147283 77338 871 7742084 282.1) cv.% 0011a 30889 1001230 i018 29 Mean): 399 99338 4400224 30880 1505200 "028 Mean): 02 37 190305 03 411 1026 Mean), 4c0r2a076 (1005) 110000-114 91072 1908270 100.18 Mean): 21020 190200 110000224 71012 190120 100M28ean): 11001 11001500 100M3ean): -99m72214 0998.2) . cvs A8)) ADulpllriecastuesscaonrprleecste1d o,r2sppikredlerveeclowveerreyabnaasleydzeodn.thMeelaenve,lSa.nDd. daanydoCf.aVm.aclaylsesul(iReedfetrotoveTraifbyleunDi.formity of 5))TDheenoatveesrangoet dmeetacstuerd.ed concentration, average percent ofnominal or duplicate samples (-1, and 2), and. ) dTuhpelivceartesgreeamnaelayssuisreadnacloynsciesnotfrtathionc,riagvinearlagseampperlcee(ntLAof,no-m1iBnaanld -(2i4p,ar2eBn)t.heses), standard deviation, and ceorsgtiincailednotsoifngvaprrieaptairoantfioornd(u3p)l.icate samples based on foomote (D) an CtohmpanaanlyysiSsaonfitttihze3dr.d Dsaomspslneoftocm ohentTSaCAiCBnI --- ss (mmm-- cr Tosi sty n Ras Dupont10157 ~ Table IPreCpoarnacteinotnraDtaioyn Verification mL Sample Type Nomi DosiAng Soluions conPteirncueendt) Me Nominal TestDay20 (21-Feb-2003) `Concentrati`oCnonVterroilfieation() 00 DO -- 110021 295475 094557 Mean(P): 951c20v.0s9 51) "w0z1 73580 9w4s5 Mean). 364c5v2.0s% L0) 11000021 92416s 9p4t6) Mean: c93o2%m19 32) ((38)) ADlulplcioclattesscaommpleect(1feo2d sppeikrelreevcelovweerryebaansaelyozend.thMleeavne,l SaInDd.daanydoCfVa.nalcysails (cuRletoatvfoteTreeiafbdyrle ~ uniformityofmixture. ((C)) DTceohnseotativeiesernnatogotefdmveeataresicuatterdie.odncoorncdeunptlriactaitoen,saamvpelreasge perocf eminnatl in parentheses), standard deviaion, nd | a. | --_-- win TSCACBL sized. Does Po! Company Se ---- Toxicity Suwdy in Rats ~ Representative AnalyFtiicgaulreC1alibration Curve DuPonc10157 - 1.2 Equation for the fitted line: Y=0.012673 + 11.0931 *X 10 R-Square=d 0.9995 g 08 & E os g=os & 02 ~ 00 000 002 004 006 00 010 Concentration, mg/mL. Figure 1: Calibration curve showing linear fit line) to replic rai `measurements (squares)forcalibration solutions of] || dilutedoveraconcentratrianogneof 0.0155 t0 0.0937 mg/mLwiththe 0 mg/mL. control diluted sample was used as the zero. rNrm --_-- || | ossnatcontrseacBl Comps sanitized: -- Developmental Toxicity Study in Rats DuPont10157 --~ Figure 2 Representative High Performance Liuid Chromatography Chromatograms FITS, (OZER SCOZREDT ] | |! 2 | | | |o z T i PR Figure 2a: RepresentativeHRLC cho (control) saggple with intemal stan mm Retention time fo s approximately 3-1 minutes. . Retentiontimefor internal standard is approximately 4.1 minutes. aEmm] } | 5 | ---- 1 z Ie Figure 2b: Representative HPLC chromatogramof40.0 mgr 7 | dosing solution diluted to a nominal concentration 870.06 mg/mL. The | measured concentration of the representative solution is 41.1 mg/mL -- Company Senitzed. Doss not contain TECACE! -- Tw | (cc Toxicity Sudy in Rats DuPont10157 [~ `Representative High PerforFmiagnucreeL2iq(cuoindtiCnhureodm)atography Chromatograms FOYE, (EES SORSFOR0 0) 7 o z 1 Figure 2: tative HPLC chromatogramof 0.0618 mgs alytical reference solution. -- E5a SOTTn O] ; i | |= - i | | c z Z T 7 Figure 2d: sRpeipkreedsernetcaotvievreyHsPolLutCiocnhrdiolmuattedogtoraamonofm4i0n.a3l mes concentration of 0.06 mg/mL `The measured concentration of the representative solution is 33.0 mg/mL. --~ Company Sanitzed. Doss nt containTSCACS! -- To -- | ~ ~ APPENDIX B Individual Clinical Observations ~~ --- | Compan Sri orsotcnnTAGE (--: `Toxicity StudyinRats ~ Individual Clinical Observations DuPont10157 Explanatory Notes Note `The first observation recorded each day i indicated by "a" the secondby "b". Observations were made twice daily on days 6-20G. If no abnormal signs were observed during the study examinations, the "b" entries are omitted from the report. -- `Company Sanitzed. Doesnotcontain TSCA CBI -- 2 | | g i grrr Bl. 4H Eogsi oso ~ gogho ono nnd ? J: BB EE D o oo no s n fF Ec ooo H fo 5 sss 5 5 8 5 was 5 aa a g & isi3:88 _32 i8:s8 o8 :3 igg : igdg P5085 3s S85 8738 38 8 :idg1 868 6fdq:1f1 Soagied of oF 853280 oiF 30908 0 ~ FEE Ee fp ggg tid | `CompanySanttead. oes notcontain TSAcay z} ES Bf 0D oEdl DooD aAAl Pog cE CT | ES SN % PoE NDI J 80 2 fo 5 #35 #8 3 4 3 & 3% 3 : | | ~ ls 8 ss 3323538: PfgEgE gBtE gg1i8of803515858:525 7 5oC gait ite fii idiiid fl fefi eae 3818s 3;: gfiE iE BE FE FE BE EE EE OE EE OE EE EE EE EK EE Sogiiaf 5823 8 08 5% oF oF 58 52 50 40 ERE f 8f FFEfof Comony Saniized, Donotscontsain TSCA Cay Bat cc, oT g E DDE TO n PE ~ FE - dBc LIEEE EE E 3 feos ss as wos sos aoa EEEEEEEEEEREEE] 8ix i998 55 98 5 5 2 EE BE OB BE OB 8888%88%868 FHC EI 0 | Company Semen. boss comin SEACH! ~3 i 3 i PoE EEE PoRjLED OD Em - Popp rn ps ; ii trees te 4 amit oI HEE IEE HE 3 i FEET LE 5 & & sdcdeds 5 i " Ek & : i 3 38 38 3 5 i gd 8 3 88 3883 32233 : |do.s fgie ii gpsEER gs 8 8 ggge EREiEgniigii iE EioFio& og3 : EifEz Fox or FpEs zoo: o5o: sf 8i 882z 223Z 838g 3;s | Dgiiaf 5958 0 58 28530 68 50 50500 |~ jit EE fg EE CompanySutend ose mote TSCACH! Ba TT atR Pogson FEET IA N N N N - C eees -- 8 ERbai on TE --~ 3J = Joos nnn FFE ooo z fess @ @ 5 3 3 3 IEIES 5 8 a 2 H i m mm 2 = 2 8 32 8 8 8 giigr BoEioi3Eb oogii 3l 3 HI EEE RRLR ERE sr EAE ~ |X 8s 8 8 8 8 8 emia S m t i i i 3 filme TOT Toa UD low goBdEDoEnEEeT o HEEmSs CoMnowB Po Bisson o cd DDB ~ i Bian o ED Co nod CPPEod tnnononorohinonooonn R | 3 "f sashEas a s = iias : : isis 58 J } ; 32 8 8 8 zg 8 3i Spppidbipr iby fiEg5f5sox ghz 5 285 |i siirrre iin o i HB OE HE BRE EE gz au 38 company Santas oss otcara SGACS! | | i BY Le daddd Poa Hoan DoE amaE ; BR oss ali dom 5 Ci isssssiains bo Ho 5 HH i ER spi Pig fgniibeaangag ~ Rs EgEhiz3d | $144f8 | : Company Sanitized. Doesnot contain TSCA C51 foe HEE Eo Bai ei 0 EES i Hn "ct dat TTT ogg IIIT El ceeeee BRO Gada Ctaettes EET eee amt od ooooAR 00 fF gc oon on PoE onnnoonnomn on PN 8FEEETdi CHvE oddddd C0 TTT T ETEE eeEeOEee I HR GT Sn h : dois pining lpe dyer: | SaiId Npf B R RR IN E NIT InIT IT |~ Hid HN | Company Sanitized. Does not contain TSCA CBI poo EER ND EL mm aaa Eon III ED In aa CF gE ]okpsnnn i: gif ceili 3 "f fAiisdee I i g N i a ommnonns tries reeen rE os Bann 3 Iirrires: fdasaE 3 Sheds El 83 SAcAsAcAEAE 2 Es g 8 8 iz 8 Bldp EE EEL HHI EEFE EEE EEE EERE | sag IE IH I~ iE g HE Bde 000 if dn Adaa lel IID DD PORES on ~ |] palimmeess a PORlmLEAILL OL Ioagf moi tii no IE gs coon noo SpE ERED i : phe pled i fy i of Bi Prd : $ Hr o 8 ] Ei CEB: bzoa Ex oz oz PDaCgiIadRE3E3B3E3E3E3E8: ham 5800068 ok 48 02 ~ Hi Eg g 5 | Gg E o n sinht iedd Co Pogo oi Eos i noe ~ 8 Bp Em : g BREESE IEE JF 5 connn nnn 3 | osssasaiana GEsiiBsAiAEERAs 8 :i Pg : os 3 i .8 gg : 1,1i 11g H33 pfix D2 oe by riteeily Ph eEoy Pagid BREE 3E3R3B3d3E3R8E4os8s ~~ ZEIGE H g CompanySanttized. Doss notcontain TSCACSE lamps fol cooaceaa "Tas rrEereas - g BS mmmmmsssTTTTT0 0 TTTTTTT0 onimmnmL SE Poa ELA ~~ 3 Bi gdaTa TTs TTT 3 Eo FabdEddTIIIIIIIIIID ii : gi Satin ig SE Eg Soonnnnnn mmm 2 i fhndcisBsAshAEhshe fisdciesaE 5 i 5 i oi 9 g zs 3 3 3 i 8' 8 sFieilzfiecbie 3B5i5g8s 5g:o3o, 38 8x PA ld S TERIEREF ERNR eEdNad ~ gis | i se i p TIEAS [--.-..... Toxicity Study in Rats DuPont 10157 -- APPENDIX C Individual Body Weights - comps m------ ----------eee---- | (-- rox ToricityStudy in Rats Individual Body Weights DuPont10157 Explanatory Notes Notes DayC21 = Corrected final maternal body weigh=t final matemal body weight minus the gravid uterine weight plus the empty uterine weight. dReapyo0r,t4inGg,oafnbdo5dGy bweeciaguhstedawteaigthhtatdwaetraeacroellaevacitleadblperifoorrtaollsatnuidmyasltsarotn(dtahyes6eGd)aayrs.eliAmniyted to additional body weight data collectedforthe separate breeding lots of animals on days priotro day 6Gare available in the raw data. Abbreviations -- = NoDaa SD. SE. = = Standard Deviation StandardError N= Numberin Group l~ NP = Not Pregnant | FD = Found Dead SE = Sacrificed in extremis R = Liter totally resorbed |lL. | -- CompanySantizod.Dossnatcontain TSGACSL w -- I sr 50 DuPon-10157 INDIVIDUAL ADULT BODY WEIGHTS GROUP I: 0 MG/KG/DAY prroeny oaro oa DAYSDoFSGESTATIDOANG DAT DACS DAYS 7700997801 s70985 aZsiee.l Zislo 2266773 2633 22.600 2008 22as ama m2a933m3 230s07 ze a308z.8 esio 7700998867 70989 Siilvo0 a0 s3e%re 28s aaneess0 2624 m2o6l3s6 zee 2260m7 2:27 2291371s9 2m 228968161 2:ln 7700999908 670999 3Z3a0s0l0o is. aessed 61s aevss ass 2enss zee 2202m05 20 2201037 262 a30m00o2 ams 661721000027 71015 3Z5u3o0 Iolo aamsal 2eals aamoee 200 aanmey 2ssls 2a0ma8 2ssla 230:00s 29918 2m9l0d 30sl0 s77n11000133731 ZZaoo 3500 aama daz saemniss amy a207 elo 22906933 222 330068s0 20307 3301313 2936 E77111100033259 33460.0 Jil asslio sss 2s7s3s ase szeel7 ae masso amis a20mls mlz 229m86 amr 77212000485858 Z3si3ls1l0o0o 20e3033 asa 22e005 as 2a0s.u1s amie asmeolss aor. 22e6l5s3 0s 2e8e30d0 29912 71085 Zao 2767 202 ass 2970 3030 3032 ~~ c5o.ve ww sz f20o9.e4 23s d26r5.e7 24s 2103.72 2a 217273.35 2 s1a7s 2s 2a8e.s9 2s 2d9i3e.s9 2s 2 FH 2 32 222 --~ Company' `SanitDoieszAoOKdCO."tain TSCACB & (-- coe Toxicty Sudy in Rats Dupont10157 Group 1: 0 O/KG/TAY froem Dario noIvIon ASTLE SoDY WEIGHTS . mara oavsBAoYp 1oesmTBIAOYN1) DAY DAYS DAY 16 Ee77000955878s aBZmoeae daaemnoan d3aeemas awdslso 3sa0oa iegasTlas 33a20m.0r9 E77700099988875 B3S0400285 M2das9ls3aa dojaeoezss damesaoss pissralsse ssasenad e3a3ls6s2 777000955395984 Jr0o3ie mdameeesns jddeeessa 1maseme dwiesssa smsealoiss amellao 777111000100327 HBSeoUdrE sBdeBhrS d3 WlSs mEmlSls mswlless 3mssas aedmwnls f77r11i00o0531317 B33305008 dBaoellloes daaammeas aadesmnsse da saesas jsaeess mm30als a7711i00o3335 Z3Bo9ee5l3 Dnmeaests ad0msea Bajaemsss dssmwhi wmm0nrse a03l06ss0 7711000i 71058 3B3i4e Sh ddMmemas aamywl amdmeeian ooBaeesedss jwsloan sd3uieslss 71055 3 Mes amis aoa sme ela mls ~ m5SE,ore 23F95.a06 3lA a6k8e E3 TasHsO aDmaas MsJeaeoe asFmdCes 364.4837 5 i i 32 ii3i --~ Company' Saritizad.Doos atcontain contain TSCACBI @ | locTosicity Study in Rats DuPont10157 -- DDIVIDUL ADULT BODY WEIGHTS GROUP I: 0 WO/KG/DRY wmmEoRn SAY 17 DAY 1s DAYSDAoYF1SGESTATDIAOYN20 DAY 21 DAY C21 6200998710 3si.s6 1es4s 2el3o adso.e0s aasssa 3a82s 5&777000999888567 3334307s 3dsmeelllss aamomzel amvlizs 2s sareoz a2 d3u3a8lss ns 7700998990 330823 e3s2a sdazs aseoalrs eamlaz sdsel 7&77010909909528 33l70a00s0sss 33s07al0la4e aaaemulsss sa0els aazis aamlso asa 33222513 3ssls 777111000101775 333s37a0l70s m3a60ll1 ss mmamlsalss assllesod aaoanzsllesss ddseaei ss 171003313 a 553 a3l7sa mml2s a3a3 aasilso msamas 7e77111000383255 33J2a60ss e3s2seaee mdseelsnz1 edossoe 2m23 sens | asl2 3332662 32s 777111000485580 S339l30s00 3ia8lllsss eaesnliass ess2ee0al3 saasesl2iss 3233099160818 1085 367s 3es7 alo ale sla 301 --~ sGpo.ve ME 2 358.2 e37d4.d5 230812 a40t9e.r0 4253..585 2303.00.73 e s 327a a32m a21 a2ss s3s2s a32s ~ Company Sanitized. DoesnotcontTSaCAiCBnI | | (> ose ns Duron10157 ~ arcup 13: 30 v/KG/ORY SpsviouN, sou sony HEIGHTS soiana sro owe aavsComr cSzsEmoss mer mye ms eGoroonmsmenes ppfiroetn]e jGaCiiooae8e] we Baaaiiooe faiiioeed i aaiieo aaaiiioss mnMeoSe Med mmdeedds den mmmeisa me aamE eel Ba amammias mel mBE ao B maemde RD Bed HhMeeeos BS dddeeedsr ded dmadaegdmomIEssSd hI Iomni mRBmedSbs BBBBNGns MBE mieee maddeeed ddd e mmmieles EbBdienZel mdEdmitaomREdewesn BmBBiidssd BhBeeSss me ammmandd dd m mdomdoedomm BmsRS RBB ReDStoa BBIs WeBandndd enweses RIS admmeydd dma dImmmsns ddE mnns B BmmideloB mB BdSo B WomSe Mmees mmeld mmn3 Wd EWdn R WM R WS --_ co3roven v ae dse uI assa Su mBuWen aWameno RW aW umss W aumea amumdde wm Wu { | - . ~ `CompanSenizsd.DoesRtconianTSCACE! | = (res Toy yin DuPont10157 ~~ INDIVIDUAL ADULT BODY WEIGHTS GROUP 11: 50 MG/KG/DAY jomros oar DAYI1 oarsBAoYF1G2esTADTIAOYN13 DAY 1a DAY 35 DAY 36 s7700997756 &70978 aJo7a.o Jed 2l1s4 3093 239.1 ams 3m9e.a5 ms maaa3as 2a 3398. 4 aslo malLs so 887700988880 570950 230000.04 2061 s0a asa o0e7s amy a3n0o sls 133s 32 a3ml3leae adall asia 5&7701909030 71008 3a0s6l0o 3s esoss see aso2s ms 33037s as 33020a 33s asllas ml aa3sa3ansd rsE77i100c11o62 em) 3J1e3.1 $e salsess 325 m30a67 men 3a6ss aes 33038s7 ass 3m0e9lla9 ae ndussls ans 7577111000212850 32070055 $62 moesa mz aami7s owe aienss asl samils aes swelld ela 33sa ami s7&77111000632308 s339e03l03s5 o03a00s0e50s 30s03e0 30300661d2 33311000600s73 snelessa 3da3sisedls 7711008580 671052 rSo0.3 287.4 soesa 02s seaas aula 3a0m0a7 dele smeizs 323i 1m2lss ml aals Iss 671086 383 mela mols als sal sls sels --~ GSovEe vews 2l17e5.s78 3g0243e.88 3w2e5mra d02e.2d66 312.300386 3a28i.sa62 31a23.9e3.70 2 32 FH Fl 2 2 32 --~ fe CompanySankized.DoesnotcontainTSCA CBI ----lstan 7pres streetree [ms osu on INDIVIDUAL ADULT BODY WEXGHTS GROUP I: 50 MG/KG/DAY Aonmoer DY 17 mays DAYSDAOYFASGESTADTAIYON20 DAY 21 67700997756 70978 3s7sss 3635 d3ssoe7 Isao a3sssi.s does a39i5s.e5 dels saanlsa sas 7&700988840 870930 33861330 370 mellss ss aaswila7 asa odsoleon sas aoassiss az &87701909030 871003 e3s3i%s 307 aeamss 3s 3sseiso elo saonaar se saallso mn sG7100102 ow 33137.72 13016 3643 d32e0n7 30 mdiless awe saeo aes aaaasn aazls 77002105 7028 33202 3584 deenlos ess eas1 | d3o98e3n des seo aaniaz api e771100326 s71043 338073 Pes e3sze7 sso 3332 sml7 a3smal2 sez admeins as 8si7701100858208 3366166 ss dweeess 27 eslen all asls m3 sdeoo ses 7056 Jel dels aoas saws aan ~~ SiGnr.ove vey sz 3f2l.e4 330 d36e6i9 Se 2320.02 em m3asn ew; zaead ses 2 2 32 2 32 DAY C21 3s47a00 3a4s6ei22 ddoaess 3ssiSsL 333832360001 a3a6d7 33u0slse 33a660s7 ddaasses a3d2r sEate DuPont 10157 --~ `Company SanDkoesi notcz ontaeinTSdCA. Cay 7 (5 Ras Dupont 10157 ~ INDIVIDUAL ADULT BODY WEIGHTS Gaoup Tx: 200 Yo/RG/ON . TR sommo sro mya oE esSormE ceR smarzhowns mys os os EE610008831750 0a03 nusiseeo nee bmmzeo7 me faPmsases dD eGaelms Men bJaeamnee damn maa9mso ome aaassmeaa ans EGGo0oa5ns0en8 ped BBWeSSe IoMmmyg3 BEND mime3dd Bhs i0 dane Gawd BBBnns amo ddmwwennn aes aaammmioas 0 Spieooelsdo 02a mmMeee mameeedss mem immmyli RED adReeenl Be BBdIemsL Bil eaGsenne dan adswmean aes ESirioionoans i020 E n3e0eSE BwEsY WS ded BdsEmddi m3 dpBieels dan m2aeis deh cdsoeessna as ddaemmeine ase GGiliooosss gem mBWLSeY meeIvsee Ie IBS dmMaaEs dme mmdeedlsns deameSs BE maselmi aml aazemmnl ama E piheoes mIMee8n3 eRsHE eRimeNsDOEseSd Gseens waasno --~ B5GoHon vmw B waEsarsr i wmFaaJ ii Ha2R i BmlJes ia Be3 EaRtsBehJs 32 ia i2s ii | --~ || FE CompanySanitized. DoesmnootcontainTSCACH 75 --- J:::-:-: Toit Study in Rats Dupont10157 ~ oTVIDONL ADULT 300 WarGHTS Group 231: 200 WGKA soomeos Dwi owaavs sop aesTaBTAIYON my ori oars eSo0oa8ar0s SaBoveos smmeasns aaabmmlsae aadsehiea maasmbaad pmRaEosS 2eN46sSd Grrrooossseessse RB 9i5e0sn fdeana madoieE3 nBdkaeoda WamEegDs eMNaidsn aEeE pGSrriooatssss ISBoe6w7ia deamawds dmwimil aBeamSns dnNeeEssDe ddmeiEso aamlliss GErroiiioozena oFIiEesE mdreioe aaB mmean TedaossEA aammean IdeoEso domao iiricootars SSMeeoao GsdySee ddmmmna addemedad amaem3ro ddaeaedns Esdneois iiooosse IBDomisa Gddeeaao mddaeinas adeewmeass agaembdaa sodeelles 0aam8aa3an iii0oozse 0 SBoetsa dddaemss aaemmdys odamemass addmaeoss maalmleoe mdieessne ficis Bod des ams des and he Ed ~ oG5oave aMnsees aBhsaee dWuonmea mBdeWEs aaa NR 3RU0aa2 aLUuSYs 3 ia F 32 22 ia ES i ~~ Sota | 7 ey, car [m-- Toxicity Sudy in Rats ~ KNDIVIDUAL ADULE BODY WEIGHTS Group 131: 200 MO/KG/ORY moomw Moay r 17 ois oavsBAoYpdcsesTATPIAOYN20 ee ee Dawn maven S6$710000997770 1098 3 Jseeels ddsemmsaa dededsd msmeoelnes mdasasiiss 2mo.om9 3% dma wa ms ass an &717000900895852 10098 FJSoaek mBdianon aasmems aasleesn aaanaes na0eo0os 3 de Dor sls amb ames n10o090t00e7 ni02 $DBoeIsfe 385 SwSissn den Maaammas des waaesas ass aasoeess ae mmaoe2ds wns i710n072o78 sno JP3aeie #3 deddEn me esGedns a GsmsEllss Ee aadwmeahn sel deeoselsn amen ni71en0s5o2s Enos PJ HeoEE mdama 3S mI mddoe7ms des dmseaaseys see aademmlles msl omdwenens aoe 7e0d0s0 fee BEee wes Edand Idmeee WH 4 4 gSeelss aase aumns ~~ cfsoszve imu u 3B5T6e.8 HaBBmha 32 i 3die2me 32 faTsueasm i amTxaiesms i smuasgos i DuPont 10157 I~ CompanySanzed.Docsnotcontain TSCAC5 | SSS | 7s | DG > Toy sty nse DuPont 10157 --~ IVIDUAL ABIL BODY WEIGHTS crow TV: 500 O/KG/DRY om mmoesn ovo A wa aovsaeomFsaew sTaTIYONe wl Dae DWO O60790O9m77 em saBsEoeS Gro0e2 BES mddsaeean dmc aamsmeaas dma easmesaa ess 1 assaoe ams 7s2e224n a2 mm24e26n0 300 617710009005181 0 0 ime OI em elo dededEd pan iddmeesas ass ammmeaird sas ssaaeesrs asa aaammoao mia d2a0am0as ad iGi00o00n8 01 BDMEeoSp nee BdBmaEas Hed dadmweass Rs dhreseass des maamlmisln als aaanomhne ash sa1u0ie8s es GO7i11o0282 en 3dm0ee0o Gi0zs 0 adBeRneEs Bas dadaewsssa dae msmaooso mae aeamewa: geo a2am6mise als 22o4:2s8 2s O{7r10i0o48u7s ee #dma0el 8 wm dae JdHmedan sea aGdmewaon ders gssseeesnr aisls aaamesasl aes aaassmssbo 287 22a801a3s 2668 O10N87E, om Mmee wel dMe0r eA? aNens oC aamns oo gaelns wswealse asoms ~ o5euSr mw : w2n5a.e4 i 2B6O3p.S3 i i3N9.E4 22 2WB7eSa i 2W6B9ia.n9 32 2wG4am3m ES 2as1s5es8 i anDosi sP01 d rscaCs! --~ || 7% ---- (5inka Duron 10157 ~~ oTvIDRAL 00 BODY WEIGHTS Shove 19+ 500 E/RGITRY sRT EmREN wa EoRwn oaBVorIcr assBiYaDL mY pis ows cOGrooOan:n em Grae Mee NnSe R eHeess B my d ds gdMeeSs3 Tdndd maBmeaa hReSs maawowsen Mdeess eaiash m8ld uasnossl dwanl piGGTriiIoosNs rine mmdelroo deNeld 2 et BBdahEe ES dOHeoasn wes d3e8ml3r mn kWMneh ams awiws awa fiiioocnkns ios mpBedrOoRn EonEebs omdMWgenS MHdeESdE Ms Wamahend mE m3 med Bn amanies San mmiiooeanns, rio dm BWmtae Oa mMPen BEL sq smeadn gmPsu ammealor meEsm 7 owMnr weWeL aWmPnsn amWaL Nehhsn mie Tfioeee w,, Eee] mdEnSemMdeeT) meONn ddamnae MND BBasieonl edmmrs OEROM ddomead BE aanhedn aah ~~ pPrB iwhyEoerwvw emmTeaseeHON aRmsed aSmRaW A aBSmuEs TJ8eoTRs 3Wuasm -- N6aE2 ; 2 RE ws ie wn poss natcontainTS cacal CompanySeniized: e een e 7 mee eeeee (2 SuwdyinRas Dupont10157 --_ IHDIVIDUL ADULT BODY WEIGHTS up 3: 500 HO/RO/DAY . aomomn rir owe DavsaoiFsGESTATBI2ON0 mar: owen EPr0o9o7ma7 m rse8els BS aasmWao FmaDmea Bei men wwaoORasL ass aanmCase ass 3301o00e70 ma Gi0r00o0s8s12 T1h00t8 em HHTeeelll CTS NIdeeEsd WES SWeeoenn en owaess RL asameelens Te 22wee0nos ae ai3oo0rr0ts 101 wm3eAa 5 PsMeeEe en a mahs hel sdaemlles Sah aaamnwyoh awls aaasmse oe wa aed ma0ioosee a 1033 sWiOsoORseWsL wer WI HweePialn WML djesRnsLs deRnL mamaeeren Cee maeassn qi7100o4478 moo, swoeonens m3 WaoB ds PBsRIsE BEd BS dmaeolhse szaesase ELLOS aaamassns wT goosnt mow mwasezis eee seBOaL sea wnt A ars amr 30a ~ iomEoovevmw #0aTia0s7 i W392u3 i 3eH6aEas Fo fsaemnsos ES) ns3obo6ss i n2n9s6e9e it CompanySanitzea,DoesnotconttainTSCACa1 --~ 7 S-- see Toxcity Sy in Rats ~ DuPont10157 APPENDIX D -- Individual Body Weight Changes | ---- CompanyrizedSaniizeg, Doss mot contain scacay a --~ Individual Body Weight Changes Explanatory Notes DePont10157 Notes 6C21 = Comected final matemal body gravid uterine weight plus the weight = final empty uterine matemal weight. body weight minus the Abbreviations -- = NoDam SD. = Standard Deviation SE. = N= Standard Ermor Numberin Group NP FD = = NotPregnant Found Dead SRE = = SLaictreirfTicoetdalilnyeRxetsroemribsed --~ | -- Company sanitized.DocsPO!contain TSCACB! J % | [ccststn ss DuPont 10157 -- INDIVIDUAL ADULT BODY WEIGHT CHANGES Grove 1: 0 o/RO/DAY mfmesym eefs as oavs vs ofTORcSesmaT- IoN wee meu ee Gon009e07s pied # soa 5g8s4 Bios aWrsEee 3S BmBes30 81 ai5as5 ws w1Be6sn5 nh oLme oeas ma G00o35s65r50 pie Bm BOe eWd mS #0oWd EBHEEI dE B3B3r0 33 wwWhnE wn pwssle ws aaend a: sh wa 1000500872 phd $mfPioWWBysS BloON3 BamSE WE aIUdsSn sn Gamhsn Ee oseenb wmmnda as owls ul Giroooanyl 2033 afZre1 0 WD Wnes BaWE II aWnS 3 83 bbBhhe aaeslss wumnol NE al mh bs Ei10o04a32ss aoa 2 oB20o4Mg Nr30 aoe m HWEi eIn H Bs esale aaBessnoalaashh Be oan wweald as Eahos oss Z2:e me on ee? WWPI ES 83 Sh al ~~ mafosvemw i 2# $m3:3 03 dams LBsemEre i 33 ia eJssaoe i 3S1ah 3 aomeme 22 oadsdesed i [~| oman Santiend Anadspanets TSOACE! eae (7:5 Ras ~ VIDAL CLE 30D VEIGHS CHES ancun 2: 0 worro/oRY omwos oata s oa n ceemariion SEE oaoroso3mre ass B3wsiok8Bnoa3n weowndmo 0=mwanis Bios ues m3 oaaaoos8 ake R RBB33100 iaohfndsnoa aawmes 3awEHnd Bao ome as Ed paaoi isooeis wBmBifioiooosan BnosaWwwsEs Ew8BIn9d Bio dn wd fiGiiisotkwe iss BBFiEieR8oo6mIkI5oe an aE dE1i3nn8 Ri Bias BR jpii os BF Baro owBeR aese of ~ mipoEoan i owaEoodopoaam wa AGueW Ese aaNaE Duron10157 _ . `Company' anitized D00s 201" rscacel || _ = | rc oi DuPont 10157 ~~ NUDIVIDURL ADVL BODY WEIGHT CHIGES GRoup 151 50 G/EG/DNY . wTsooonow [EoL ws of GESTATION TE sGGrrroooaannss Grosso msnee edommoe aooW3 B mBsS 33wBaI B30 Bi ommWsS wn BmGDan mE aaasdhee oun EEGrrrooosassso rine #m nwee eoon wae qm Ban3sS BS BBN3DD0 oslaeen mE HBBEaS HE aaann an Cir0iIo0tS3s we riots Z aBvereoadddhe Baad aBBn5Is0 wl 88317a Ba3n1IOaSsTass wDo0n sn oaaaanl Eh Earrioioonnn rio R WrioE oooBS Ess w5ooEE am Wsd ioS3330 33 i BBHnIS awn wsjin imahuann i mn Gtarrioieosss 10% Rm#3oe0ow08ms3 naooWs aoEdimiowaoE2o ad fp mEBEnoasaae Bn Ein ownwnhn un Fr iB0oRs%rePneodee OeEDO%B330r 8d0n aBne omwnrer ann --~ mieoEsver : mTaazo 3 omdgRw i mBI7dm 2 Jdsnma 32 Mdtssk 3 nEIomR 32 osiwee i || --FE compa5nyJwized.Does not scacel ps ---- cs Toricty Study in Ras |~ INDIVIDUAL ADU? BODY WEIGHT CHANGES Grove Tx: 50 MG/KG/DAY Tfrmon wamm reas sean Dave oeanGestatisoena ews we eH 6G0r09o93777s58 E0980 mffeeo Be mGSaaln wmaemosa wa mo sselssd ss p$77i0099e550 4000 SnB3es0 3 EBssIa dwaesmihs Bs men eaalln ws lirroiaoootnss om BA2ias iors B30 mBsI se wdso ame @e wn sae amso {araiooozsas ions #HB5ee WsEeSnn walehee asalelsz nr HE hee mi {{{TiT1oa0ou3ss4 1050 BnBidE B8BS3E auBemisas aeallbs Wy Es ime es P{irraso0s8e2e B3e5 wo WWSE ee Gleor MW wwihs HS -- d5SoEve mw V 2Fi1Ea. i at $u5.s5 Ca1n6e5As4 ia i w36a1 a Dupont10157 |~ || _-- Company Sanitized.DoesnotcontTSaCAiCEnI Ww | noi ~ ie. es so ss cus fh so gsm Comm Sunkenoo etcmaincca | resent5 ments al; sco sn Duron 10157 ~ INDIVIDUAL ADVLT B0DY WEIGHT CHANGES aroun 333: 200 wo/RO/ORY A t = emo eas ee n oars oT r cesman nzan e Gaor0oronmnn0 n Bwgpo ro@mBifs BmmmhSee a3Bms6so Gaoooornnsne F FBwERoinsRSsiR CiBnYBTEsnd ppiiaiooednn wa#a1riioomoRnoeduii d Eomm3ig Boosnfs aoGiiiioonn noBioatonkooeBd:d5 l#E1tsn BaBBuSs oaaiiiioooen BmM#2y0ryoooomnmEse iEom mEGniosuWBdoS oaiicoe ie w$r3 w0HoEepm: w8#e33 eWBfer - 3mow or : mmf2 iaroumsa me ma hW l WUn -- + SanteDDooeessnot cont Tscaces | J 2 -- --) soc Toxicity Sod i Rats Dupont 10157 ~ INDIVIDUAL ADULT BODY, WEIGHT CHANGES rove xv: 500 /xG/ORY ommos os as oats opecesetaTIl on 1092 14 ues Go0os5s7ms7 em mmM2sioo0mane1 aGHmeees s4oTlassr 0ahisrlo 3aw0sn6 36 as E77001090850211 33Ba5% mmmaEs adsdeh 8dee7eo ma2lsss apalllee 1aaslsas Gi71oi0n0os8 om W 2aa an dleeel oBHinss a8mh8sn amTehilss mos ahn n awssl aiiooonns BBasoaa1sM%s ewmsis oEsw3zn0 nBenys as7al 2E a1w0an2 Gr7i1io0t2ns2 em BjBl0so0 1wM2ss eETsone 0sssnr aaiSnro wBosEn aaalens 7T711o0020a38 em S2WaoEwEdss eaTames aeaBsnn unTnion uS Chen T hsaa G010s%87 wemm Hm2i33 mgsaee 83e6s aammers daBerssaa aasasa7k asles 105 #3 an wn 35 HE Wh wo --~ m5pso,veumw 2TIos7n 1sTa:aa8 u22s3.e08 wieoassr aCoeoesss aa13ae9 1aaslsss EF 3 ia 3 io is' 17 ~~ Company Saniized. Does hot contain TSCA Cal | 5 Son v1 Torii Study in Ras ~ INDIVIDUAL ADULT BODY WEIGHT CHANGES anos v.50 w/Ka/RY . osmao wre wn os oeraqesmamieonn eGG0oo0san en F mfn sar nnssea Er0i00o05ns1 m5w30eeaaGlly GGalonongss em wWcieoe moTiweoe ioonnis Swmeeeo Bm3a3 fiGi0oa oi en wwoinooedC53m en: 2 iGirciooeags waiB$330 sWSaSE Fi0sr wean armD es Ra eEddss 5addds wWMase amTssR ohhmsaa bwkdni asmMms2a 8 as oowims oa ss mWnS aBas wh se ~ pmpesom um v w2P6ees amtnddss saBamRna wT saaie i Duron 10157 -- CompanySanlited.Does notcontainTSCACaf I FOIA crocr Ts sty ns -- Dupont1015) APPENDIX E -- Individual Food Consumption -- CompanySanitized. Does notcontain Tscacar | UUM |~ Individual Food Consumption Explanatory Notes Abbreviations ~= SD. = SNNEP.=== FD = SE = R= NoData Standard Deviation SNNtouatmnPbdreaerrgdinnaErnGrtorroup Found Dead Sacrificed in extremis Litter totally resorbed [~ | EE CompanySer "ized. 5% DossnotcontainTscaogy -- (--) a Tony Sty in Rats. DuPone10157 ~ SprvIDON yan DATE PEED CoRSTIPEIGS croup x. 0 vo/xo/mRY fesrmeant eo es avs oTrUEcasmaszon na wes em ESeroranunessna mBm2eoaomnra RomDaBiomEsdts BoamDed EEommypa moa3d GSGriooasssne 3Bm30onRBedi EEmddi HHnfDi RHnDid Eamnnl 0BRdid GEorraoemnsesa mFpEiRooan mmeSiSmBOiD kI mdb Cmk3D nd ad SGiiionnaess mBmeeiOBofmTnoi imRsDi imBni3 Hmkipn ERBDds 3Nndd GGiiiontn H#Bie3o 0onEsn HaRsn E3End BBBSsE oBB3im0 ioRnB3ed pGGiieoo BBmeooknmsio EmmDiiOo Bmib BknDiD BREsly 3RRdd aiaoiisii mEaeommRod mBBbDn EESI REBDpD BEEEiDS naadd Si miOH Rs Bs EDS |I~ iG5ow mGmnes Ramgna oambma Bempms damaam dNmdRa mo om 2 al wt ue uw wt ComanySani, | ~~ ot contaiTn scacay ST i --:.-:- Tosicity StudyinRats ~ INDIVIDUAL MEAN DAILY FEED CONSUMPTION ROU 1: 0 MG/KG/DAY farneno wn en DAYS OF GESTATION s67700998710 m260e9 23500.04 s&7700998865 7 sls aslls 777000999988475 22388778 2226a009 7700999385 2321 asllss &7711000027 a30018 226008 67711001175 3Bl2e a3ls 7711003313 2206008 22850020 &777111000833255 5 2365 s2284l74s 67711008405 226015 oaalsiss &s7711008845 2F0C1 oasis --~ 5c.o0v.e mn 3 281 226.0 SH E ois oise DuPont 10157 ~~ aTI"00comin, scace |2 I cr oc sy ns DuPont-10157 ~ INDIVIDUAL MEAN DAILY PEED CONSUMPTION GROUP II: 50 MO/KG/DAY aMmBEoRn. 4-6 6-8 DAYS OF20GESTATI1O0N-2 12-4 14-16 16-18 557700997765 2232.080 2232.83 2230.84 2256.47 2260.92 1274.53 239.30 67700998708 2260140 18220.s8 262018 22653a 23'1s0 234063 336001s 557700959804 21090053 129100s 2a2e4 22300035 224167 2 22'8s9 2n0x1 57702909030 223818 225164 220862 2273192 226822 22933l59 3u0s2 757210200038 (mp) 2242104s 22140s7 223200s 2270..17 220664 2186051 2n2l8 7721001126 71019 2234s1 226684 n25l0s3 2223.74 22461177 224668 2380033 224 26.3 25.8 298 279 301 n3 7122002250 s72026 22267183 222433 a27'3s 22..32 229310s5 236264 330281 216 202 a's 2008 2s 253 2801 772200433 22'2s4 1903ls 220052 228101 2252.d4 226170 6 2266.36 s7722008580 2226393 212.171 128035 22626a a2l%o6 2265086 22830072 771005862 2205085 2s2l5o 2211ss E27X8 2267.26 236006 2320.24 ~~ 5G.R0O.UP MER 22.35.08 2.224.30 22:.430 22.55.66 22.63.52 4266.a4 32.96.88 sxie 0253 0252 0252 0.2527 0.2520 0.286 0279 Comp,1Sanitygg, Does --_ "ronanrc,car EB [---. TosicityStudyinRats ~ INDIVIDUAL MEAN DATLY FEED CONSUMPTION GROUP I: 50 MO/KG/DAY rAommoEsR wn en DAYS oF GESTATION 7700937765 a6l3s a25l.s9 E77000939887408 22a900132 220680 7700993903 1315 7as7h i7711000000830 aw) 12297.521 2221663 7i11000111692 38 603 232607010 E771002205 0do7s 2259.043 7711003288 227s n2ls 7711006883 #613 naas | 7711005820 230a5 aalao 71036 Wz 200 f im.ouse a27b.s8 a26i.s0 isz o3ss 03427 DuPont-10157 CompanySanitized.Doesnotcontain TSCACBI I~ | o% - coi pom ~ oe gts i FE I ---- oo Dew wt 2 pr THETA wn wn ww ~ || ee % Sr E Dae"nPTSSCgAy | i (cc i en rm INDIVIDUAL MEAN DAILY PEED CONSUMPTION Gove 111: 200 wo/KO/AY nimnoE wa en oars op Gestion 7700050977708 3 x3: m526as 56777000990858823 35 53 23aa6s 6777000900595785 ouwals #3o3ss i7r3oi0o0t9 F ma H a03s E77r31a0002237 aenss am26si2 i7i1100033306 siBenas e2Bdu i72110003078 3 B0350 a2ee2us 10a #3 63 --~ i5mpoE.ve V b28Xe4s a2l6s3 i3 Duponc10157 |~ Company Santizec. Doss notcontain TSCA Cay % PO) occ sci cy es DuPont10157 --~ INDIVIDUAL NERY DALLY PEED CONSUMPTION GROUP 1v: 500 Ma/Ko/DAY annEoR as es DAYS osFaoGESTATIlOoNz 121 16 161s G&6700099573m7 51 m2a00o2 s14s9 nls 2111 aa 120:.19 p2o84 p3 ris ow x7 es m2s2 wi &6717100099069121 22051 32 02a0ss1 20m1z mzail3ss 32m3l20e wazase 3 i4i &0771100000s88 sm) 2 ;273s3 w4ss als m2a00 aie 2o1's 283 bia as a2s2o 303 ssie 3s e76710200111238 a2a30l5s aw5li7s waamisss 12a2sss m2il2ns7o 1 zea ams anlos aed eo0a1n8 sm s71022 236s2 alo 3apa ale 20o0s1 mle 12s 103 moless paod 262 mo spads aia 7i1000213 sm 61006 B2l0alo iliro als 1a31lo 2 1=7 pBjasie pmdeas eaa2d 8 01180837 (m 282230900s 2 1125s8 a;1less bosalisz 20e9:ss2 a20e11s sa2s n1057 33 wh Bi wi awe mn 60 = mrosvedmw iz 323000 oes e1d.s am a1dsn 13s s1a2s 20s smdas Las 26.d0z lea 3e0d.s9 es ' 22 32 Ei 0 is ia ir ~ `Company Sanitized.Does notnoctontain TSCACBI --m--mm8 | ~ [ =riR saR sssti hy woyrsanbst DuPont- 0157 nh I ~ Soar etsSe | . | | (r --~ cssososuoyors pews APPENDIX F Individual Reproductive Data | - | ---------------- Company Saniized. Doss mat anntain TSA CBE erties frum--...~. Toso Sud in Ras -- Individual Reproductive Data Explanatory Notes Note Nidations = Implantations Abbreviations ~ = NoData SE. = StandardError N = Numib n Ge ror up NP = NotPregnant FD = FoundDead SE = Sacriifneixtcreemids R= Littertotallyresorbed -- DuPore-10157 ~~ |-- Tw porent con"ay 1a 78cATS ~ B2| sgnsesnnasazsaannanngs a3 | i anounssgansageesargeee Foy ) 5 5999299%99223053 325355 Fo8 lf : Eel oe 38 :g ; Lo | SNNETNANANSNINNIINIING ~w3e : i samsageagsieiagsagases don i i2E8o mEnamIMGImMEEMMMR ORM, | revere ionmennenenne 3 8| ceemrernr mamnngnerens Hy mE enim 2 : 8 2 gasnassen ingeanansneey SS ] 3 | | e=ccccccc icoccccaasaasn % 52 i =] 3 5 HH RE EA < B| coennoonn oonceccanncs 38, 1 a 2 2 i 8| 238998350 insannnnganes 359 : i Fas mma a nyse00087 8 1 45R273233524a0E0aRT 2 i ; Ed| ezomccorvonsmaovanance Sig | k anannisidsnsnansaaIIany Pe ~~ g4 2 5 a] : BE Egl z | 3 sosssosasanesssnspeene og Bi EgE,| eenomeencoccocecnose J5ig 3 .2 i ZEnangRILAIRLEIINIANIL E09 | || ta careers" 2 siemens mnnns inninxg 53 | civevacigenegine ones Hoy b = inomon {woman Ign famfeo So mE eerie : & izanen inu innsinng n ix 2 7 | i o fovans Inno jou fone is Tog }: HE i : i FE | oy er -- APPENDIX G Gross Postmortem Findings | Company Sanitized. Does:notcontain TSCA CBI ~ rm------------------ reerer eer [m--)-~ Toxicity Study in Rats Gross Postmortem Findings `Explanatory Notes Abbreviations ~~ = NoDaa NAD = No Abnormalities Detected NP = NotPregnant FD = FoundDead SE = Sacrificed in extremis R= Liter totally resorbed DuPont10157 -- |~ --_-- | `Company Sanitzed.Dossnot conTtSaCAiCnBE em]-- or Toxicity Study in Rats ~ GROSS POSTMORTEM FINDINGS Dupont 10157 Group I: 0 mg/kg/day Animal Number `Structure(s) 670074. - 670981 - 676700998856 --- 670987 = 670989 - 670994 - 670998 - 670999 - 671002 --- 676711001057 ------ 671017 - 671031 - 671033 - fr 671035 - 667711000329 -- 671044 - 671045 - 671054 - 671055 - Finding(s) NAD NAD NNAADD NAD NAD NAD NAD NAD NAD NNAADD NAD NAD NAD NAD NNAADD NAD NAD NAD NAD -- Company" Saniized Boos not containTscacay --mmmmmYFYPPP------------------ | [r-- --~ ToxicitySudy in Rats GROSS POSTMORTEM FINDINGS DuPont 10157 Group I: 50 mg/kg/day Animal Number Structure(s) 670975 - 670976 - 670978 - 670980 - 670984. - 670990 - 670993 - 671000 - 671003 - 671008 (NP) - 671012 - 671016 - 671019 --- 671020 - 671025 - -- 671026 - 671034 - 671043 - 671048 - 671050 - 671052 - 671056 - `Einding(s) NAD NAD NAD NAD NAD NAD NaD NAD NAD NAD NAD NAD NAD NAD NAD NAD NAD - NAD NAD NAD NAD NAD | CompanySeniized. DoesnotcontTSaCAiCBaU || ---------------- aTsE -- ------ ------ ------ ------ ---- -- ---- -- || (--)...: ~ Group Il: 200 mg/kg/day Animal Number 670970 670972 670979 670983 676700999828 670995 670996 | 670997 671009 671010 676711002274 671028 ~ 671029 671030 671032 667711003376 671038 | 671040 671049 Toxicity StudyinRats GROSS POSTMORTEM FINDINGS Structure(s) -------- Finding(s) NAD NAD NAD NAD NNAADD NAD NAD NAD NAD NAD NNAADD NAD NAD NNAADD NNAADD NAD NAD NAD DuPont 10157 | --~ |- | company Tw. ized. Dossroto cat ek (Oi Resi ~ GROSS POSTMORTEM FINDINGS Group IV: 500 mg/kg/day . Number Structue(s) Finding(s) 670971 -- NAD 67073 (SE) Lungs DiBslcaoclko,rartaiiosend-, 1s-e5vemraml adricaamseter 670077 --- NAD 670982 --- NAD 670991 --- NAD 671001 -- NAD 671004 Kidney Pale, bilateral 671005 (SE) LLuinvgesr DDiissccoolloorraattiioonn ddaarrkk, diffuse Kidney Pale, bilateral 671006 --- NAD 671011 --- NAD 671013 --- NAD ~ 676711001148 ----- NNAADD 671021 (SE) - NAD 671022 = NAD 671023 -- NAD 671041 (SE) Kidney Pale, bilateral | 667711004476 ------ NNAADD 671051 ) --- NAD 671053 (FD) - NAD 671057 --- NAD ~~. Companydi Sanizea, Does motcontainTscacay | --_---- | (roc sic susines I~ Duponei01s7 APPENDIX H Individual Fetal Weights and Alterations |-- || -- | Comp,any Santizag, D0not0cont8ain sc og, ww -- TosilySudy in Rats Duponc10157 ~ Individual Fetal Weights and Alterations Explanatory Notes For case of recording, many ofthe findings have been abbreviated or coded, as listed below: a = arches) cbeln == cbielnatreurmalorcentra WIo == lleufmtbar NroAD == NrioghtAbnommaliies Detected --@~ == NthooDmcuiac + Subcutaneous hemorrhage that was not present in ero. `Renal papillary sizes refer to papillary development using the scheme of Woo and Hoar Alterations are classed a: NDV == DNeovweslopmental Variations VR = Variation duteo Retarded Development M = Malformations | `Numbers are used to: | IIdnednitciaftye srpeencailfipcapsitlleamreybrsiaze + RSpeefceirftyosskkuellletbaolnpeossiatcicoonrdfoirngibtostohrevfeorltleobwriang key: 21 IPnatseirepualrieal 95.. TSyqmupamaonsiaclannulus 34. FNraosnatlal 1101. BEaxsoicocciepiiptiatlal . 65. PMraemiaxlilla 1123. SHuyporiadoccipital 7. Zygoma ~ & WLouoe,GeDs.tCa.tiaonndoHfouRrt,s:RMT.h(E19f72c)t. ofApMpeatrheynltSHyldryoe.phvToesssolsso.gyN, 6o1m911A9s6p.ctofRenal Development in | Company Sanfized, Does | mn CA car (7055 ~ wa 5. 0 moms srs ts sn aBY mv, omens a Dios -- HiIi PT Eo oHE3n F g iA PPo oi i E .E 5i :i ii i ii43 g&iiI pErEnE a 2ET H8emEmmAusR h, .# &iii8 - LPCioEoi iSnn wee $ aPi o. i i a"PREa p a p #iii 5iii gi _ A anTsonce | Tw [---..- Toric Study in Rats DuPont 10157 I~ ALTERATIONS I TNDIVIDONL FETUSES GROUP I: Wa/KG/DRY FmEsS4'7s mms we. smuore rooms) cuTnesasttiro-n S03:2 0 s5.i20 533 5sH2En3 : $5 sn 5:7 SlS5ei.ea1 2 $2 sen n 3 Sssia ai | e0:33 6 S5.8327 vertebra 3 5.03 vertebra -- . 5.68 vertebra s 575 vertebra :7s S6i1r01s 115 pid3s un SE servis Ea u1 SPams 0xwoo Rn0eo0tarded ossification m0o(6708 nity w= Raeot6ard7ed0ossification w mn0oop RmeotGaerednedtaio0s)sification w RReett(aaerreddneeddenOOss5se.1id2ft)iiccaattiioonn w Ret(TaeeredneednastOs))eitication wn ew2do0 n2io0o RReett(oaprruddnaetdds Oo26rs)ssiiftiiccaattiioonn w wxo060708 oi) = `Company Seniized. Does not contain TSCA Cat ~~ Ti on oc sy es DuPonc 10157 ~ Ausmanzons ov monvioNs Ferusss sxowe x: 0 wa/ro/one . arnt0s. nsw. smn rons) cTuernsmoirosn 615i0386 (cont.)8to sn roi3m 5580 san 5i: Hisaie ;:: HiiE neo -- : i HB$ee3 verve i= sioee aman ~ ro3s3 a sioon : $8 verses `:: 5i.8o0 semen pie , 5.43 sssesrmennea .SESisens ae wNeoeazdaag onsitication w wReotfarxadted oasitication w wo3Ss FRSoatpareodrosmsitiicaationS(Y6 bil 0ve wRieetaziad ossisicasion n=otyatanod opriiteation (6 01 =Th kRwedotarded onsitication 5ws hin w nRReeotvtEaaatrraexoeedds ]Soomamsisisisificicaaatrtiiiooonnn (61 (6) w5 wRescoaranas ioasitiacion w S5permmerary Gite 1410) by | --~ -_=s Company Santize, Does not containTSCAcy [--}.......al TricitySy in Rts Deport10157 [-- amove 3: 0 woxa/ony ALTERATIONS IN INDIVIDUAL FETUSES arwosers sews. smoorons eno s) cTuearrsioen 67H0iS989 (cont)555 ridney E3iS DHie8n] sremenea ero:s3se g 6.09 y xidney Tervanea > 590 vertebra . 5.571 san s 5.01 vertebra . 613 vertebra - 5.43 Txeirdtneetyea -- 3. 3s8s Vseerneen 2ii0 2si8nr san aan i5 50r9 iVKeisrdtneenyes 1s ss; aos:3se p5.e0:0 nRPeastpairidiead-osssiizfeic3at(i4o1n) (6) w wm EwSo RRSeeittaalrradeemsdepooiemlsslaiitiii-ccaesttiiizooenns (b3i1)h wWmh Roteeeoernnaadeenaioirtop1i3i)cation nw RReettraarrdaieedd oonrsaiiftiiccaattiioonn w ReteEaerrndedtenOieeooaiiat)ication n RFeefpEairttaiseaeonrseiiz)feic3at1i6o)n w w RReettTaaerredndeeddthiOoommrsaiiiaft)iicceatsiioonn @ bid) w wRReoottaesrddsedn orsitlestion ossitication (2 bin) A RRseomttaHaalrlrdaEeeEddpTooimmmesiiftii=nceasttiiizooennd (3mibni)d) AwWm EYyt = wwoo --~ | -- | Com,SESDo, mmt py ha TSCAcg [---..cc. Toxicity Study in Rats DuPont 10157 ~~ rRaTIons In nDIVIDUAL Peruse Gove 1: 0 worxa/aY oFEwTS4s+ remus wn smaoeruns noms) cTaosnsriiosn 703i98 (cont.)e6t 7s: & S5aai Py5: $H5H63 sem Fo12] s555o6 aKidhey uii fl5h7ae an 6703999 88 vertebra i23 si6en ~~ 5: $S5s2e sen ::7 S2S155610 xicmey vertebra 1a20 o2sioi | F3nuS asi5aa e0702 as wmnooo anon o7Rewtarded ossification (210) VR FSStaSpielrnFuampeirialrsy (ssiitzee161G6)O pwmv 5kSew)permunerery (site 16 1) ov Rxe0t(acxednedwios)sification nnfooses RraeptGiaearidnaeid nossxisezi)efic3 atzito)n w= nRopc(acxendadeniozs)sification w 10n0o waa0oo wo --~ --- CompanySentizecDoesnotcontain sca cay ww (-- rc 1c ~ JE eras oss ress I3 I -- -- awpos gF o Tmd en CsRaEm FET ?1 mEowmw EIta ren HuEe -- i aH roa a, ona ve imsts gs lrpeie 0 e iEp E J iN TaE ELreEsyerrncntoinionn o5Epl2a rimtfh atren -B BBSoees2v orioon in- omnw 1.2 :fomie 052 i 3"2: ns I~ | _-- | : CompanySeized Dos ete 5g cr vc vcs si oe Dupont10157 ~ ALTERATIONS 13 INDIVIDUAL FETUSES GROUP 1: 0 MG/KG/DAY oFneerosas# FETUS Wr. smrvcTRE FoDDG(S) cuTaCsAsTtIrO-N 72007 cont.)3.10 stemebra Vertebra 05 53.2590 sternebra F1e12 slsaeilass1o 111 ssslieees no21s a4l.s9 3 378 vertenra 5` i5.s3s8 7: aSllsoee 5s 5a1l3s0 - fr0e 5i3i2s iu113 isllost Sle 11s aaless sm0717 5.35 Kidney 32 5s7e :5i ss&llesass RReettaarrddeeddOOssssiifiiccaattiioonn (6) = Ret(acrodnedth1Ozs)sitication (6) == wwoo rmyn wm0oo wwoo Ret(acrendedth1O2s)sification = w0o wwoo aI>g wwoo Fm<n 3x=oo aaPanppilla - size 3 (re) w wm0oo CompanySentizad. Doesnotcontain TSCA CBI | 9 [-- v0 5 ~~ ALTERATIONS IN INDIVIDUAL FETUSES GROUP I: 0 MG/KG/DAY . FoEnTsUS#78 PTUs Wn. stavcTuRe FooIG(S) 6727017 (Cont.}5.17 H8 55191 1p0t 665..1587 52 5s1l9e2s 1 633 710131 5.5 32 55.719 53 55..8068 7: a5.l7s8a 58 5s.l5e3s 10 55..7198 152 ssis lse ~ 120133 s.62 32 553375 mip 53 5s.i7s8 7` 6.5.1768 | 58 ssiss0 1101 5s6o2 Kidney 1 ss Rib 0wo afeny wmDp wono mmoo nmpo mjooey wapD mopo wmoo wo mSuopermumerary (site 14 bil) nmapp mwoo nwaDn mnoo SPuappeirllnaume-raSziyze (3sit(ebil1) 1t) DuPont 10157 cuTaesasTiieo-n DV Ekaa --_ Company Sanitized.Does notcontainTSCA CBI | 120 | [--) Toit Sudy in ats Durontt01s7 ~ surearzons mv TIvION reruses cao 1: 0 xo/xa/oaY rPoyss mews wr. smocns sams) cTunrsiszorn- er3os iwoas mm :i3 ieiays :i 3ipei] scemern irl: HiHieH i3i iI3E aw ersio3ns isa :i3 iiiaso | _ :: iiodag ird5 iia5e it2i ii3n a srn0:az 536 vertebra | 3: sa8 vercaoma ` sa wFsweopermmerssy (site 14 x8) ov EiFSeA FRweSetarded omsification 6) SuEpeSermumerary (site 1470) ov =5 awweo FEnSSe nBiee 5oFeS SEoSrermmerary (site 14 biD) ov wRestoaorndednao)ssification = wFisRoaxcais osesiication = CompanySenseB,ess ot,contain Toca cay mm (--} ..... ToicityStudy in Rats DuPont10157 GRoUR 1: 0 uo/KG/DAY oFEaTUS07 ETUS wr. ALTERATIONS IN INDIVIDUAL FETUSES structure FmonG(s) cuTaesasTtIro-n 710s62 (cont.)5.60 Lung 575 55a..l22s08 15 sl5o233 vertenea un 4.2966 n 538 7087 4 5.2 233 s5si5ie8a a 75` sSSe7eo5s RRiibn :5 speen ~~ 1u0 3s5i5a0n ip 2 sls 0s1 5.26 23i sHirs Ss aw 75` 5sa3so2s Rin 0s5 slp1se0 n sls cot(oxr<ealove, tan, 1m dia) x wwwowo R0etarded ossification a(con thil) w wwoo a0 wSuopernumerary (shore 14 bil) DV SSNAuuDpp.eerrnnuummeerraarryy ((ssiittee 1144 bBiill)) DDVV o0s Swuopernuserary (site 14 Bi) DV by e0Suspernumerary (site 14 18) Dv S5Suuppoerrnnuumseerraarryy ((ssiittee 1164 b1i8)l) DDvV emny Iwo ws `Company'sanitized.DoesHot ontain TSCACBI --_ | 22 - (e-- z= ToxiitySudy in Rats DuPon.10157 ~ surmarions mm morvION: FETUses anove 1: 0 worxarmay hPoyls msur smocmons non cuonrsiszorn- ensi#ous cont.)15a5 i3 ens3oHse 5s6e versa >i s8a vercabea 3s: isiss a:: iIprRny ae iiiP HHoeaEr i Si versansa -- i see jmn=. 13 sa mHeie enso3ss PHre | 3i: asi3as : U5 sen Tertabea , sa ww5eo wwResosfaezndesentoenrsiication w w8Restfaxdeed tossitication ES FawSpSoermumerasy (site 1410 ov ES5pSermmerasy (site 4 r0 ov eRsowrtefurermdeusomdetrociaaenstyietii(ocsaaitttieioonn1418) w30 sSweeernnmnentnan)ty (RteEi E30 BRwy wwoceod RwFReeoStkaarxddeedd oSnmstiriicaatniiosn (2 16) VR 0eon ain) w |-- _--_-- | ain TSCACE companysaniuzed.D0081! [---. Tovey Study in Rats -- ALTERATIONS TN DDIVIOUAS FETUSES Grove x: 0 wa/xa/aY oPuro0sse remus wr smmvcrone Pownce) en:5s (cone.)tS3a0s nwoo 31FS op5eh6t wn0oo 3ii p5 pens wnoo wo 18 peS3d0 ewSo | DePont-10157 cuiansistoen- --_ - | CompanySaniized.DoesnotcontainTSCA CBI Tm F130 ~ srs rere oe reenter --By me, smoens oe hn wHErS PP7moo oE5, a HLLPPE IooO.omHL i iE a a w =mrI i.FeEvon"," E&owBFS otionton 0 w _ P ir To eE na ve Loo C Po o ig iii in 8-wEs iin o-Fens - BEiES [| ~ emilym----A ee SO} cx ris DuPout-10157 --~ ALTERATIONS IN INDIVIDUAL FETUSES GROUP IX: 50 MG/KG/DAY oFEnTUS#7 FETUS WE smRucTURE POING(S) cLTaesasTzIeo-n 6709178 5.67 23 5si7a2n .5 sslleaz 75 ssliesd 58 sleirs 110 5512274 23 5.2377 1ry ssosrs 6 523 6709180 5.83 23 55.18579 Rib 5 66.11120 Rib --~ 57 551:5207 smal 85 sl53e3s6 1u0 sslies 132 ssieas 6703180 5.38 23 ssliee7 45 5sl.e3s6 oxpD mnoD wnpp wxoo naDD wxoD wxoD naaD naapp wSuDpernumerary (site 14 bil) DV SReutpaerrdneudmeOrsasriyfi(csaittieon14 (b6ilr)t) VDRV wwpD WaDD wwpp aD mmpo wwop wo aniDtoesznoetcodnta.iTM TSCACBI -- CompanSy | 126 Prnmm-- Toxicity Sudy in Rats Dupont 10157 ~ ALTERATIONS TN INDIVIDUAL FETUSES GRouR 11: 50 Wo/KG/DAY Boeers's remus we. strucTone FroiGs) cuTnosasstiro-n 709s84 (cont)6.11 `7 $85 a 5 05 Vertebra 110 55.7762 i2 p8e2s0 er027950 s5l.a59 :35 1 [8647 xine : HEE 1: 65.43 15 si5s sku rT E1S 6.3580 am r09393 5.47 33 Es3i1 vertenra :5s s55.i55e2 :7 SSi7s6 xSiednney 5 5.79 awno RSeutpaerrdneudmeOrsasriyfi(csaittieon14 rt) Dv n0o(cen chit) w wnoo wPmawopilla - size 3 (bi1) = Rf0ee5tyarded ossification noopfree w xReotarded ossification IGre pid) = Supernuserary (short 14 Bil) Dv wwoo 1Re0t(acrednedtn1o2s)sification w aap0 RPeatp2airldbleaidt-io)nssizfeiscat(ixot)n w w 0 `CompanySanitized.Doesnotcontain TscATSCACH! | 7 (Fl cc sic st nee Dupone10157 ~ JuERATIONS TN IDIVIDON: FETUSES [Ep aonl0s1 mes wr. scone Faas) cTuerasnioorn 5ii ----1s5ea Pl sen 5i s5amBm erao2300 sies 3i: : iHiEi $8 semen :: Haie n iii iiDn5 sen -- 8ii iiiise i ia enoi30s 5HH0 3i FiiHna] :5: hii aEH ii5 ii0hG wPwaoordes ossttication ER w rsur peecnae mtseersyy lri(ziatteion10 Bl V w wfiod Pi=utas Ousitication ) Ww nnFooo AonRaeorded Ossitication (610) EhnSoo we wnnoeo wnkee wfodoo Woeo --_ | || --_-- come*TM sch ae 08-0 = Sm---- cco Toxicity Sudy in Rats DuPont 10157 ~~ ALTERATIONS IN INDIVIDUAL FETUSES Grove 13: 50 WO/KO/DAY oFawroe4sse pees wr. smavcroRe noms) cuTenxsrsieo-n 122003 (cont)3 en3o3 n 5l.1e5 i5: Sai55a 7:: sliseeos 0a5 SsSiaoG a riamey 2 io en:3o l5.a22 3i5 a&Heon ~ ::: sHl7aE 015 eesletst 2 8 oan PYu [p=ed en07:19 5.655 sen no wnnooo 5nnoo naSuoopernumerary (site 16 bil) DV xF5abpitta - size 3 (bil) w 0nnoo enndoo Snobpermmerazy (site 143) BY fnnieood 1RetBardeRd ossification w ao 0Retarded ossification (2 bil) VR | CompanySankieed!poavetcontsitvscACsl |-- J------ 3 ------ ---- Toxicity Study in Ras Dupont10157 ~ ALTERATIONS TN DDIVIOUAL FETUSES Group 11: 50 Ya/KG/DAY oPnreo4'7s wesw smocroms noms) cuTnossnterr- sm019 (cont) Vestenza 5 sso vertebra . 61 vertebra s s0 vertebra 5. HsaEE, . sco vertebra Ret(acxednedehoi0s-s1i2f)ication * w RReotteaaerxnddeeddemOoas0rs-ai1if2fi)iccaattiioonn = Ret(eacorendnedesaaOt0s)1s3i)ication Rwost(acxednedeho0s-s1i3t)ication w Reteaernd'edehsi0s,i1f2i)cation w em0z20 S5.e01 i:5 iS5en5o i;: DSei9te ae ~ i15 ipfenart 132 o55n0 eno:3zs 5s8a sen 35i ps$e3nd5 xiney :;: pv5ed8 wwWooo nSwtoopermmerary (site 14 70) OV n5nos ~owwooo wTwaootarded ossification (6 p11) WR eSWeo),e papilla - size 2 (uy WR rness 4. Doss onanTSCA ~~ comps. J.)-M || (-- 5 Done10157 --~ ALTERATIONS IN INDIVIDUAL FETUSES GRouR TI: 50 MG/KG/DAY oToerus0' + remus wr. smmocTRE noms) crunsesey- snt0l5a5 (cont)s5.i7s6 3hFtS 5p35e80 eno7z6 s.66 vertebra 2 sas seal Vestenza 2i 6&.05 sam s 52.580 sn Vestenea . s.6a versenra ~ 5 sea san 5 5.39 vertebra fo smbSen n 5.67 vestenra 2 sas seal Vertenze xwwnwoeoo RReettTaaexradmdeeddehooitssossaii2tf)iiccaattiioonn w Ret2 (acrende)dnaO.r1s1i3f7i)cation w w R0obEargneahos)sitication w 0Re0s[axdsrd oessification . RReettTaaerreddneeddehoaoabas-si1i3tH)fccaattiioonn w Retr(aciraasnesaeaonatbs)iid)ication PS = SReutp(aecrredmneudmeenorasa)sriyfi(csaitteion16 16) wDV RReetc5aorr7ddeehdd.6oosssa1ii8tf,2ii0cc)aactiioonn Retl7aerandaede)mOisa1i2t)ication Rotatedetontsi)sication w ontai TSCACE! f-- -- -- 1 iv sic su Dupon10157 ~ ALTERATIONS TN INDIVIDUAL FETUSES Grove 13: 50 vo/xO/EAY oTrwoeis mews. smocrons samo(s) cTuorasrioorn 613026 (cont)bos vestanee 03: o6n6 :ii iHaaH :;: ii$an8 sents i15 pFSa th mn Fi Ha en7on 8 vertebra i32 osa8no seal sen ~~ s 58 vertebra . a7 vertebra :. 35.800 sen irl5 iI5.an6 rBaanre Fi I sn RotTserednadiiosasi)fication kWweoo EnHeSsporshage. (backs) f wfSioapermumerary (site 1 Bil DV nDSevsrimmmmoerraarryy (sive (site 1416 14 BD) ov nRootc(eaerzoddneadderoorsipsiitiiccaettiioonn (2 bi) wWR Rnootsasasea oessification = RReotteeaaoortnndeeddeeornorirte)piiFiccaattiioonn ww Nweotrardsed)ossitication seadi mapilia - sire? rr WwR RnSetotasstaeedd oasitication ossiication (LID TE ww CompanySenttz22. Does not contain Tsca cay -- errr g-------- = emseieemeresesese Fg sss DuPont10157 ~ ALTERATIONS IN INDIVIDUAL FETUSES GROUP II: 50 MG/KG/DAY ornus s87s eros wr. strucTuRE FIvOIG(S) cusaosasTizro-n n081 8 3 i5.s4s5 mb i3 ssis s 7s5 aiasm sie 58 1 ssalaisrse F1y spiesrtt 5 pe no7o 2 56.2335 i5 slpoet 7i5 psseiiess 58 sgioas min ~ br110 e6Gl4s00 Kidney sm01s2 3 s5i.a9n5 Rib { 533 sslleess sol me | 87s ss55s0ss mip s se msuppernumerary (site 1418) DV ww>oo wooo 4waoo wwoowo wooo wwoo wwoD wSuopernumerary (site 14 18) OV mwop Papilla - size 3 (41) w a5 oSuDpernumerary (site 141) DV mxo Supernumerary (site 1418) Sbmiodpyermumerary (site 1418) DV E53 in TSSACE! `Does note" --_ compsanyS01 ---- e -- e E e ------ [cr sis se Duroni0is7 ~ [ON -- srmastons morvIDAL FESR BeEyYy ms. omoomns remote cuwnsaaie. oi3fnys (cont)uL3ii we Sii 3 EEdRFoaH ono ong3|se b5.a0c0J verter s sutt Tosopien ` ses sas seceivet :s B 2.0 wSou _ J. T' ERse sen ' 35.0 on 5 ae vem uw ere st sa ==zgy ww ==rhage sniass rwroaReedEdoNsstnEicarsEion - reEeehySpbticaion - C CpE ErH aTR D - eE ;EveTryn Icit)e 1201 - v-a rasahoepsicaion - oea te cixsttsteasion rSeeFelmeleaOyStTtaToionn - > oe = | | [3 (crc sci nye Dupont10157 ~ AueEATIONS TH DDIVIDN PERUSES J ---- Boes0) res we. sero [-- cTasesriiee ferriose cont.)Los afsey msupeErnumerary (sitet 1W6) e Rov ~~ = [ r oo Tw [5:1 Dupmtorsy ~ ALTERATIONS I INDIVIDUAL FETUSES Grove TI: 200 HG/KG/DRY rEsYs mmsw. smuonme pre cuTnesasriiro-n s03170 5.95 vertenea 2 437 san TSeerecmaebbrzaa :i3 sS6i 1a4 ::8 $5565 san a Sen 5 5.98 vertebra 0 see sen u32 Sa1Ez0 sen --_ ii 0580 Tseortnavra sr09:3m2 H6.e3s5t :i3 sS5i2ie :5: i 5a5e frie5 e3i85 RReett(aacrreddneeddenoOass)ssiitfiiccaattiioonn w RReett1aa6rr.daee7dd.8oorrbasiiittii0cc)aattiioonn (6) VwR mIo(een aaa) w BR5oocarded ossification (6 bil) VR RSeibpoaerrmamsuiamteoreasrryetsi(cssa)hcoiroen1370) BY RReett(aacrrddaeeddneoOrs)ssiitfiiccaattiioonn 0Retard5e0d.o0ssification (6 Bil) w VR RR5eetcaorrddeedd oossseiiffiiccaatciioonn (6 16) WR Teen 10) = nnwooo n0eos wwnooo 0wo TsCACE! companygantized.00087" -- | E | [FT 1: inka DuPont.10157 ~ AurERATIONS I TOEVIOUAL F2TUSES asoum 333: 200W/O RY Bswoe tvss mmswn smocr sno) cuTesasrziro-n ro=iam conc.)(aRVR FH3 Et3 sn cre:7as i5o0e i3: i&5n :5: RiHonea ii5 iifr8] Vseennte 8u isBe --~ ro3:se 3 iisaanr ::i $ii3an een s;: i oan5 ae He 3ii poEias era3ge cos 3RsouRpaexrenuamderoasrsyii(csaittieon142(201D1) BY WR ES nEwSoo onBeeo Pemmezazy (site 103 5 twnasorced ssigication 0x) WR wRostEarates ]onaiticacion = Ed nnwoeo RnFeoStarded ossstication (2351) wEPseSmmerssy (site 1010) + iwnnooo ES FS te --~ ores Eg --....-: Toxicity Study in Rats DuPont 10157 ~~ ALTERATIONS IN DIDIVIDON. FETUSES Grou IZ: 200 Ya/KG/DAY oroesss rewswr. smuome owns) cuTnesvsrriro-n 670:2988 (cont.)Gtsa i 53 :5 8s5n .: ea0 5 6.30 0 6st 1n $sa8o n 620 san son vertebra sem son vertebra vertansa verteba sem vertama --_ sr07952 37 zi5 3h8n Saen :: 3i0s sen :;: 85i.08 a Vereanza 0RReettaazrddeead ossification ossification (6 bil WR Rot((ae5re,na6s,as7.to8osb)siilfisc1a1t2i)on = wRestGarrdeedeosmsiinfication w mResc5a:z6dedpido)ssification RReettTaaerredndeeddehOaOds3)asiistiiccaattiioonn w Ret((acerendnedehhoio0s..s1123t))ication w xRetGarr6d.e7d.9osbsiif)ication Ret(acrdoendesos)sification nRwuoodimentary cervical (1 56) Dv aRReettaarrddeedd Grsificacion ossification (6.716) WA wwoo69% RRoetd(aicrnenceendesanGrayy)sicfeirsviacrailon (1x6) Dv w (ainTSCACS | comooySaneDoes Tot! || ~ 5s [---e Toxic Sudy in Rats Duponc10157 ~ ATERATIONS IN TDIVIDUAL FaTOSES Grove 113: 200 v/xG/ONY fP=Y --_-- smocrme -- cu"nesnsrziro-n 6i102o592 (cont)5Lo sucutis e092 9 5.65 vertebra 2 59 sen 5 5.90 vertebra . so swan :5 5.390 san . PrVe-- reetea :. e5s Tsoente |~ 10 i 9eernt sn vertebra 2 5.2 vertebra 1 50 sen 1is 6.086 san 61083396 55.a90 i fi =Hemorrhage (chine) x RReettGaaerrenddeeddmiooopssisiistt)iiccaattiioonn ww RetTraereindnedtahiossi)sidica1t0i)on wReotfarrded ossification - Rsoavprairaidimeadi=o)sSsizteic3at(izot)n ww RToettTaaerreddneeddmiootss)ssiiffiiccaattiioonn (1) VwR wReotfarrrdeed orsitication w Tfeotraradeed )ossitication RReotteaaartndaeoddthdoiesobrsiiisft)iccaattiioonn = Retreaorndeedsapoaste)itication = Rweotarded ossification (6 76) WR eweod Company' atDom s rote,vscacs! --_ || w | (-- Toxicity Study in Rats DuPont10157 ~~ ALTERATIONS IN INDIVIDUAL FETUSES GROUP IIT: 200 MG/KG/DAY Eonreos47' penUs wr. strveruRE FIGS) cuTaosRsTtIrO-N 6708s95 (cont.5.33 55 s3s7a mb 3@ Px 27 1105 s&elameoe 1 88.3240 san u sr 67097237 5s.e9s mp | 33 Sssiee 55 SE2t3 78 sSl8s1 skal ~~, u1n05 sssiaisrz s7120709 ssearn ska 33 8s3n1 skin 5` s3ie 77 s7 8s:1a2sr0 1ry 85307 am wmSuoppernumerary (site 14 x6) DV exS mmxoo 0Retarded Ossification (6 bil) VR wo wSumpernumerary (site 14 bil) DV woob wwoo IReetarded ossification (2 Bil) VR bmmypn mReotarded Ossification (6 bil) VR Rweptarded ossification (1) w wFoY wwmooo xSuDpernumerary (site 14 x) DV CompanySanhized.Does not containcontain TSCACBI --~ 10 Sey) Toxicity Study in Rats DuPont10157 ~~ ALTERNTIONS TN INDIVIDUAL FETUSES GROUP II: 200 HO/KG/DAY Foewro0s pens wn. smmocToRe FnomG(s) cuTnosasTtIeo-n 67112009 (cont)6.29 mid 13 S5.7278 Swat sen 1178 5Ea.54206 mip n0211 0 s6l.e0s5 i3 8a1i2os 5: p8e7s1 vertebra 7:5 5iSz.4a3 10 628 ~ m221 35.8351 subeuris Sail :3 s5.a21 75` SSsi3lee8 a 1:5 slsseams a HH SReutpaerrdneudmeorsasriyfi(csaittieon14 (b1)il) D=v RBeStG adedn oss ication = oPSupepermumerary (site 14 38) Dv rJwieeoyd 0FReStarded ossification I)(cen ent) w wwJoooel mHeomorrhage (backs) mReot(a6r.de7d26o5s3si2f)ication w mmoo wfSuwypernusorary (short 13 b1) DV w0woo > Company Sanizad, Does not contain Tsca cg | an | wr csc osssu ne Dronei0157 --~ ausmATIONS 10 IOIVIDUAL PeTuSes anoue 133: 200 wo/x/mRY PPtYs mms. smc saomee) cTaosnsiteo Eir Loe san 3in oL53na0 Rriaenrey enio n isan :i: Bisess :;: iBBene | : i HiBE r 3i aiiB oa ne3a siaar subeutis ~ i:: B33e3a8 :$: HHBiE H 5 i H3Ber3 | iH5 p5iead ii sneecaratzeic`arsiaporinisalitnicasviizoen2 rm) Wwm FReoteraed oasitication (65) Wwweeo 5S0lpermimerasy (site 1 2) wwnooo S5Slppeerrmmuummeerzaassyy (site (site 1b) 11 ov Dv ES HFneoomorchage (cight shouidezn) n mn5oo wniooo mwneoo ww5eo --_ Companyganized.DoesTLE gw on = fu} opmental Toxicity Study in Rats Dupont10157 ~~ ALTERATIONS I DDVIOUNS FETUSES GROUP T11: 200 MG/KG/DAY Fouotrsyye remus wa. smvcrone nos) cuTnesnsrrieo-n e03729 isno si3 SSi5Es1 Kaimdney H` ssies Rib 15: p$$5d68 am i1 $p2t vertebra en037%0 s5.i57 5:5 HSse1i3s :5: Hp2Ee8 sen = Pe5 S035 Samepan || Vertansa n 5.59 an0732 s.00 vertebra i5: sol5a .n37 s Sse nwwooo SSSiiippeelrrmnuPuammpeeirriaalrrayy ((ssShhioorzrtet 11144 G5bri1)l)) BuoVmv Swwuobpernunerary (short 14 bil) Dv a0anb Roc(aexedne"edaiozs)sification wn 0xwoo wwfeowd 5Raontazded ossification (6 B11) WR RRSeelttpaaerrrddmeeuddmeoOrrsaasriiyttii(ccsaaitttiieoonn14 (z6t)bil) ov 2(can eniz) w 0Ret(acrodnedeao)ssification = =nnooo | |~ CompanySanitzeq,Does not contain Tsca cay | ia [5 fon ~ e =BY en r somran sy iCC PPeoonii w=e iiii iiidiHiB EE&&B I omg git. 3 PPPCDIPooooleoiHkBm, E=&B2gBemo mumu im, og ~ BL4 ooeHy,=, =B B Brm n y = i 2 Skull 2Retarded Ossification TiPoioHHHw EE&goe | OMPanySanfized.Dogs,Poteontain Tsca,car | [--..... Toxicity StudyinRats DuPont10157 --~ ALTERATIONS TN INDIVIDUAL FETUSES Group 111: 200 arxG/ORY oFweeras0'ss remus wr smverme roms) cuTnosnsriro- 720;`97 (cont)5o.n08 pd:5 pa$5ea i23 SpSeeaot n Be mo!e 5.06 Vsetrecmaebneeaa 23: $6i.E501 qE-- s see mVebrtenra ` 6.35 vestenra --_ :7 $6.3058 Vmienrena s 5.67 vertebra i30 PSSi1a5E2 Ts.temenes Verronra 5 sas mo:w p6.H08 xnwooo nwnooo nn0oo RReettaarrddeedd oosrsaiiftiiccaatciioonn (6) (een emt) vm w wwReostaxded ossification SRuepf(ecarernnausmeearonas)rsyiti(csaittieon14181 wby Ret((acCreadnnedewnhodar))sitication w w sReufp(aecrreannsusmoenroiar)rsyiti(csairtieon14 18) Ov w Rsuept(eaGrrannduemdtheirO,arra2yi0t.i1(c1s,ai0tt3eionT16ut)161 Dv nRReepttaarrddeedd oossssiiffiiccaattiioonn (6) vm 8(ean eni3) = wwwo CompanySanitzeq1 Does not, --~ containTSCACay | ws [m--) re Toric Study in Ras Dupont10157 --~ AutmRATIONS I IDRVIDUAL FETUSES anove 712: 200 W/KG/ORY oBwre i0ss memsw. smocrme roma) cuTnesrsizoen- 671i0S80 (cont.)iboo min :55 iHswEa :5 EH5e0 Tneersonea 1ii0 HsSHoe mRmE 3i eno7:ne so0 aRwm 5:5 o5i.nB0 sen : 8 sn --_ vertanea ||| ,: 5$.850 sen | 5 6.00 vertebra 0 ss smal n 5.59 vertebra n se smn n er wm nwSwsopermmezary (site 1610 ov Rwneootarded ossification (6 BD RSelfpeaeerrnameunmmerorire)artyei(csairteion14 bl ov w 5SSwepmemrmemreeranryy ((ssiitvee 11461B6h o5v ES RseutpIoerranseuameoreraariyeni(cssaittibeaonhnd) bi) Dv w EwReSstarded ossification (2 bi) W RReott[aarTtdeeedd goosrssTiiftiircsaattiioonn w wResteaorndedenotsssification = RotT(aerieniinrath2is,or)3at0i76c.,a8tiboinl) = = RRoettaarrtdieezdd,oosnpoppbiiitiaicccaeattiioo0nn = RetTiareridaeeeadn.aoas)essifibacha)tion = w speimmeraty (sitels 1) 30 Company Saniized.DossnotconkeinTSCACB 3 ee Toricity Study in Rats DuPont10157 --~ ALTERATIONS IN INDIVIDUAL FETUSES GROUP TIT: 200 MG/KG/DAY ooruos4'7s reros wr. staucTons Fons) cuTaesastzieo-n 1114009 (cont.)5.55 mip Skt vertebra Rseutp(ae3rr1dn2eu,dm2eO,rs3as,ri5y,f7i(,cs8aictiBeiollnd) xt) w = Ret(acrednedeh1G0a)siication = --_ | --~ --_-- `Company Sanitized. Doesnotcontain TSCACal Sm-- cmc rir 100 DuPonc10157 ~ ALTERATIONS IN INDIVIDUAL FETUSES GROUP TV: 500 Ma/KG/DRY FoEaTSby8 FETS wr smocToRe Fons) cuTaosasriiro-n 1097 m s.e0 33 sle8s0 sen :i 15862 sen 5s7 6 52576 sen 1Pe $5h8 san f32y $52i86s san san i Sse 1097 m 5.00 :32 35S5i8ss swan san --- 7`s S$5le.7030 swan 5: slim 1n0 SSis 1554 F1o l7o0 e0391 8 S5.l6ed san 3 Sa am Rweotarded ossification (6 18) VR mJIeos 5Retarded ossification (6 Bl) VR RIReeSttaarrddeedd Omsitication ossification (6 (6 bil) 6) VR VR xR5etarded Ossitication (6 x6) VR EReStarded ossification (6 15) VR Fwuosed (1 to 12) w RIet(a6.rde5d23o7s.s5iti1c0)ation = mRweontarded Ossitication (2 bil) VR n0o 2a=00 wwon RRweuotdairmdeendtarOyssCietrivciactailon ((1210b)il) DVvR --~ CompanySanized.Docsmetcontain TSCACat ww | [a]Development Toviciy Study in Rats DuPont 10157 --~ ALTERATIONS TH INDIVIDUAL FETUSES Grove v: 500 wa/Ka/AY . Fooryos's remus wr smrocToRe noma) cuTnesnszriro-n e058 (cant) . sao Saienan :`: EH33E3 aSnen 1s: o5a5 Sen sen bnFiSt E$i5He0 i in 1 er0:3391 SsEa sen vertebra i3 55.800 sen --~ vertabra s 5.9 : 5% san , sor Vmenreenra . s son s.47 DSmemolnia 0 sa sen 21 sa.01 SRSueuptpeaerrrnanueumsmeeroraascrsyyifi((cssaiittteieon1148 (p3116)2b)il) 2VDAVv RSReouttpaeerrrddneeuddnosOrssasrliytfii(ccsaahttoiirootnn14((22bibblii)lb) WDUmVA nRneootarded Osaification (2 bil) WR oSniEopernumerary (site 14 1) ov Rneot5a7z6d0e7d Bosasiifinc,ation w PReYt(Caarnedniodn)sitication w RRoett(aa5rz.ad6se.ad7.O5osssBsitLft;itcc3a3a)ttiioonn w Rxet(acrednedenosis0if.i1c53a,)tion w RSeutp(ae6rr:an7ei5dmoO5rra1er)lyti(csaittieon14 bi) Iwnv RSeutpTaeorrodmneudm3a1Or,sas1rly3f)i(csaittieon16 (x6t)Bi) VDwRv RReett{haprruddnetesad oboisslss)iiffiiccaattiioonn w wweores. SL w CompanySani od. Does ot contain Tsca cay |~ iW [ccrs ss pr ~~ corn 10: 500 vorneroneALTERATIONS IN INDIVIDUAL FETUSES nByY eve. om roan PEye ra ent [F-AI REJ. MEs P E SE TiE am a 1 ass vem osm en 2sani swuon P J 2ERE00ErJomom, || 2SANSmoIm aos enoonl a. seossepngiratsspissen = BwoDiptrarrtinn - I Er ESig ft ifi I spsessesro aiiC idn - oBrrBefaneredrt osgt ai y . BoDEseocosrstatioion, 308 12 E fUmTCmiSsCe fI oe - i wfhairsesoSocealetben w 2A irepsitiene aRCo ~ pe yi 150 [-----~: Toxicity Study in Rats DuPont-10157 ~ susmacions mn IoTVIDORL rErusss ano 3: 500 verze oTwho1)s meme wr. smocross samme) cuTnesrsnziro-n er30S06 (cont.)Lae saws ` ese SsteErnebea :s SsEo afy ): Isa sane sal is 3saHe sane saz u wo ovis 2 Pr |~ 1 sa revi ori:?on o$aa 3i: HiErs0 ridney :: eiirt ne i#d3 HioHnF nRoectToriruabdeteedd. ooferscsihititioiencraBii1oo0nn (6 wVR wfseAarRoRnt)o w Htaonat1a-10brl,5i1ibinn) " = wMourrandtos oLaoscihtiiocnasBiAoDn 5netEorEseEs cIoeTttiEoaTtioSn = FReettooouirbideeesss. oonucsshiitfiiimccaatcBiiioo)nn w RetBearroaennSsosEbsiinF)lontion = w SReotlraatraeisss ecoeisaithtEiiiceatsiioonn - outs. Sechium BET w weSdo01 rapiita - size bib we onSeeermumerary (site 14 501 ov EFFSaS wFeS sor oe | san | cone | fo | (rc sce Deron 1015 ~ RH Tr 90 TEENsusmrgEns 35 mE, Tomas wByY me em Frm fi re Rfi2R tnFiLads ny :: [ sIon iam f::: ii1E2y] pn 22:$ I55E8] ow re 21 in IiB" on 52 12 ---- wz2o wBLoonoonusuncitntaeigonatogn ywsots 3 BE]>Brct oettonsion wits 7B tBhotutnthe -- ssaiizeen 33tmtoinsy " = -hwoendeA dompith-- " T PC SH ~~ | i7:671013 I"LBe en :`: i1i1"42 3:3 ionen @=BfDrogts ien = F=z>S 522 ac otoo | | -- I~ | ------------------= ---------------- I cc ici sy ss DuPont 10157 --~ ALTERATIONS IN TNDIVIDUAL FETUSES GROUP TV: 500 MG/KG/DAY Foewrus4+ Feros wr. sucTone Fan(s) cuTeaasTsieo-n n013 4 5.62 2 3 36 sa Saan :i5 i5s3 aaSinen . 4.37 StKiodrnmeyer 5o 4si7s8t subeuria 11n i2 SssinoReme noz7s 35.827 vertenra i5 pseie r. :5 siixa | | : i Paelvis Py55 Fs3RIR TSSan 31a2 5Sl10o370 vertenea be11]s 5i$.3s028 aSan 7 ies RwSetotpaerrdneudmeGreasriyti(csaittieon14 (618)1) WoRv ISuSpernuserary (site 16 bil) Dv RSReuetptaearrrdndeuedmdeorosassrsiyiffii(ccsaaitttiieoonn14 ((766))Bil) V=DRV HSewmazoielr,havg"asepi.iziesl(ab1a5-c)ks)ize 1 w Saunpernumerary (site 14 ro) DV SSuippeerrmmummeerraarryy ((ssihtoert141415B)il) DDvv mReotarded ossification Iopleon ent) w oeyy RSuept(eaprrundbuiesmdero1a6s)zeyiti(csahcoiroen14 16) OV w RSsueuptpeaerrrndnueumdmeeroresarsryiyfi((cssaihttoierotn1414(6161)t1)8) DADVv Rnwepotarded ossitication wSupp(ecrennumtehraza)ry (site 14 bil) w ov wReotarded ossitication (6 70) VR he a oe" [~~ | 3 {-- ee Toricity Study in Rats Dupont10157 ~ AuTERATIONS 13 TOTVIDU PeTSES Grou xv: 500 Wosxa/DAY . Foewrtos'0s eros wr smvcrone noms) cuTnesxsmriro-n soza H5.i6 =steimenra i5 85.08 san :s 1s.5050 -- servis sen :, 0so5r stermebsa sen 1s 5568 san 2n S pe aSen || ~ 11 1w8n swan | 1s 5.05 subcusis | so7z wer elvis i2 1435 Stmmesmrmebra :s` 13o56n1 SSteernmence ;:: pioei} san RReettraarrddeeeddeoOnsasiifsiiccaattiioonn (6) WR - RRoe1tt5aa7rz6id0ee7dd.8Sosssbsiiitf1iircc1aa,tt)iioonn (6) vwn Rfoeit)paurbdiesd boists)isication RReottG ahrrddeeds h Sosspsiittiiccaattiioonn (6) Aw IRfestazdod ossification (6 311) VR wRestrardeednossification w IRSettpaerrdmeusmeoreasriyei(csaittieon3 (z6t)BI Any HReemt5oa7tz6zd,he7ad.g8eosbs(iiht1aic5ck:a)1t2i)on Nw SRuopt(epaurdnmetmdsero1a6sr)syifi(csaittieon14 51) Dwy RRSeeittpaaerrrdameeuddmeooresaasrilyfeii(ccsaaitttiieoonn14 ((626))10) VWbmny bnReeostarded Cositicacion (61 VR nReotarded ossification (6 B11) VR 1 : . Lo | || I} [Roc sss os Duron t0is7 -- ALTERATIONS IN DOIVIOUAL PETUSES aaoue 1v: 500 verxa/oAY oruos0ss eeros we. smocrme noms) cTuenxstsizorn- 110i023 (cont)iLan 3i1 1$335 aSseunn noz7us Soon nn San 31 ss8o vercanra :s isna maSeben :, 55.98 sternebra a |-- 25 psemt San F3d $S8e san 5.50 sn02767 seie :i3 2Seo5o :: iaek nRmeootarded ossification (6 bil x SReifpEaerraaneuamweornrassiyti(csaittieon1410 Dv w aRwevotyard(e6d-1o0ss=i)fication = Rwesteardead osshifiicnat)ion w sVaav(yycen((62e2n31e)7B,i1)0,11 16) =wnw RReett(aa2r1z6dd.ee7dd. 8bo5esaisi1itf,ii5cc:aa3rt2ii)oonn (6) ww R0Waevtyard(e5d-13osbsii1f)ication (6 xt1) VwA a=wno PReYtGarededeosmsiitnication w nwwooo awwWsees a ~~ | = [-- Toricty Sudy in Ras Dupont10157 ~ AummasIons 1 nov ErusEs | Grou? 19: 500 wxTAY eBryos ssn. swore Ee cuTnesmsiro-n 7205:87 (cone)He00 0a e0573 7 ssaeiamn ii3 a 6in aAanm ::5 iS3EH6 we 1i: S5ona aamm ii H5O aw Vereanea 2 sas wWwooo SSSiiwpeeerrrmmmumummeeerrraearsryyy (((sssiiittteee 111444 bbbiiil))) bbByyy SSFiisppeerrmmmmeerraaryy ((rriivvee 1144 31501 BByY nSSiloppeerrmnuummeerraarryy ((rsiictee 11443508) obvy BSSilSppeerrmnaummeerseanryy (site 14 BD (short 14 bl) bv ov RSeifpEaerraaneuamteorsrearly)ei(craitcieon10 zh By ws' ~ . . ee oe l~ APr F r-- TE ie -- eees-- ses