Document zQZVj9XnZqb9wV6kjYy2XRM2R

AR22G - 3272 454 ARage _ 3274 DuPont9478 --~ `TRADE SECRET Study Title (OY ric Tosicty '90-Day Oral Gavage Study in Rats Volume 1of3 - Laboratory Project ID: DuPont-9478 "Test GUIDELINES: U.S. EPA Health Effects Test Guidelines 'OPPTS 870.3100 (1998) ~ AUTHOR: Gregory S. Ladics, Ph.D STUDY COMPLETED ON: April 1, 2003 PERFORMING LABORATORY: E.L du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 Worx Request Nowse: (JY service Cope Numer: (MY ~ -- Eww Company Santzed. Dossnot contain TSCA CBI U 0-Day Oral GavaY ge Study in RatiscToxics DuPont0478 ~~ GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT `"TLhaibsorsattuodryywParsacctiocneduScttaenddairndcsoemxpcleipatnfcoertwhiethitUe.Sm.dEocPuAmeTnStCedAb(e4l0owC.FRNopnareto7f9t2h)eGiotoemds listed impact the validity of the study. ``TDeesetpswuatbesrt,anNcJe.chNaoranceteorfiztahteioanfowraesmepnetrifoonremdeadnaatlyRseegsiownearle ApnearlfyotircmaeldSuenrdveirceGso(oRdASL)a.boratory rPergaucltaitcieonSst.andAalrldosf;thhoewaenvaelry,setshearaenacloynsseisdweererdevcaolnidduacntdedsuifnficcoimepntlifaornctehewpiuthrpIoSs0es9o0f0t2his study. | utyDror: OS-LadFicso, dPhoD.r SeniorResearch Scientist -=JfhDe0ate03 --~ -- ---- Company Sanitized. Doss not contain TSOA CBI V 90-DayOralR Gavage Sta, y inRts rr QUALITY ASSURANCE STATEMENT Haskell Sample Number(s); 24691 DuPont9478 Dates of Inspections: Protocol: Conduct: February 1,7, 2002 February 12, 2002; March 26, 2002; April 1.2.25, 2002; May Records, Reports: 14.23,2002 October 1-4,7-9,14-15,22-23,25,28, 2002; November 11-13,24-27 2002; December 16-19.22, 2002; January 12-15, 2003 Dates Findings Reported to: . Study Director: October 9.15.28, 2002; November 13,27; January 14,15, 2003 Management: October 9,18, 2002; November 5,27, 2002; December 10, 2002; -- January 14,29, 2003 Reported by: J 3 iy B. Brebner StaffQualityAssuranceAuditor 01- APR-3003 Date -- eet gee ee `Company Sanitized. Does not contain TSCA Cal Un.sonic Toxic -- ~~ CERTIFICATION `We, the undersigned, declare that thisreportprovides an accurate evaluation of data obtained from this study. slic Brahasonsby: [----Evrasi--otny, CleEaatPoansobnyy: AiioPnatso,n (neTeeCtCH.MlaaidheicBh35a.r Seor SafChemie onTeiSn(e)n]oArPRVesieairlPlTLloDyicoDelAogB,is. Hl,io =Ev3es DY Princip)RescDhipCliomeatle aACb.oVoP.gssodManager ostHoPeyoVonwsbY. For SeDiipRleosmesaiecAhPCoVo.git ae MoTkee2002 0= Puein-c0h3 28-MaDure-2003 azatBpiueh-oms ~~ `AnmEovmaiRcsePivaotinheowPlbeoyeg:ry . To DiHplaomea ADNCAVE PD PunoResearch Pathologist Bichonson Bvaunionsby: _pBor/ TRoehosCch0CToomexri3n5s. 23MhDpuaed 2093 BrDueag sir spp floResSseeaosrnchMLiLonvoareoesnkdDiPD.to Sop s Lh GrSeegnoroyrRLesaedseshPToomDe.oDloAgBs T Blbeaned 207 1 Moesdes ~ - | Company Sanitzed. Doss notcontainTSCA G81 C 90O-raDlGaavagyeSR tyinRavtsc oxic DuPont9478 --~ `TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT ....... nnd QUALITY ASSURANCE STATEMENT... wm-------- CERTIICATIOR communes I 4 HIST OF TABLES. chums] LIST OFFIGURES ...... --------------------i] LAST OFALPENDICHS conssmmsmmmmmsrnsns -- wd STUDY INFORMATION... 10 STUDYPERSONNEL ummm 1] IITRODUCTIIN ccnp mmndB OBTECTIVE commission MATEARNIDMAEIALIOSDS sospdsmmmmmmcsgmmnmmmmsmsosmssesnsss 1S A TOA cmmsmmmemmmmemsmmam----------------wk5 BTS mmmmmmmmmmmm--------------------1% FN -- Fo a -- ~ E. QuarantineandPretestPeriod evermore 17 FE G.. ASSIGADE1N0 GIOUDS..rcecerrerersinenenenenmneneronssrnenonenn 18 HL. DOSE SUSPENSION PREPATAION rrr 18 eT 3, "1001 S00 SRRPIG centrist ET --. L. Body Weights......... NR mmgmm--tl M. FoodConSUandmFoopdEtFCiIENoCYn........urmrneremmrsrsmsmmmine2n N. Detailed Clinical Observations and MOLY... 2 O. OphhAIMOIOgical EVANHONS vorrnrrsrsrsremrmrmmenemmrsrsenrsmmrmnrnrson 22 A Q. CHICA] PANOIORY enn 23 R. CollectionofBlood, Urine, Feces, and Tissue (Three-Month ReGOVery )vvevv: 25 8, BIoHmiot] MOSERTAISS woommmmmlmmmnommmmmmnosnindS FS RESULTSAND DISCUSSION mmmdimmmmmnssmmmsmmmbosmmmmmpsngaon 3 ANALYICAL EV SLUATIONS num A TeSt SUDSLANCE SDI vrs 39 B. Chromatography... aw -- ---- C. Homogeneity and Stability Samples... " ed D. Concentration Verification Samples ............... commit BR. GompanySanitized. Doesnot contTSaCAiCnBI 2 E NageSuydiuobnclRharetosniscToxicity DOuDPuoenmtt0i4m78 ~~ E. F. DISCUSOFSRIESOUINS Analytical CONCIUSION cress. ..orresrranasesomnonsmseseosesenen, 36 36 IN-LIFETOXICOLOGY A. DOSE DAE cw ro er st ss ens5131 BC.. MFeoaodnCBoodynWesighutsanamdndFpOBoOdtEyFiWIeCiIoNgChYtn.......G.AcnuS.c.u..r.e..e.r..e.m.crvrcveorce vonrmsosnr ns3738 DE..ICnl-iLniifcaelTOOXIBCOISOZYCCOarNdCVIMOUtTSAIIOOLNYNS.S.ovvcrvoroeersstmssssceeserisco n3938 NEUROBEHAVIORAL TOXICOLOGY A. SensoryFUCHOn EVAIUAHONS ...ccecewve.enrrrtsrtsrseromnsmssmsonesessneenesmnnn.3399 B `C.. MO ACKOc T oors NerobeThOXIaCivtYCiONoCIrUSaIONlS.........rvos costco ones oreme een 39 40 CLINICAL PATHOLOGYwc A. HemalolOgY/CORUIBION ...rvriorrssismsmssreoe 40 40 BC... CUHBIBCHAY]SCISROc IISIY-o ronrrsr mssssr soss e tones s42 ED.. PClIi2nSiIcaalaPnadthUorliongeyFCIONOGGIUESI.ON.S.coevrne..mc.s.s..mrrsemnesvemmsssssommssmesemreerrserernreeooeeoeooenos44o55 BIOCHEMICAL MEASUREMENTS... A. Biochemical MEaSUIOIERIS woven 46 enon 46 B. Biochemical Measurements CONCIUSIONS.........vomomscor errors 47 ~ ANATOMICAL PATHOLOGY crm J BC... GOITOSES OWEBIGSH!CD IVAOa NS..l ovoss ss nt oso son 8878 D. E. MAnatComiIcalOPFAStIhNOCIEOSZYOc COPNCLUISIOCNS r reve erset s e 5088 CONCLUSIONS corners S| REACNDSO AMPR LESD TORS AGE wins S2 FIGURES cosinorsssnssssnnonn268 APPENDICES corres 380 I~ cee CompanySanitized.Doesnot contain TSCA CBI | | O9X O0.DayOD ralGavaw goSyio in Rc ats.w 7coweyiRe Duwroons w:s9478 bom LIOFTSABLTES TABLE I SUMMARYOFDOSINGMIXINGAND STABILITY ANLYSE. Page TABLE 2MEAN DAILYDOSE VOLUMESFORMALERATS TABLE $ MEANDAILYDOSE VOLUMESFOR FEMALERATS coc ccc 6 G6 TABLE 4MEAN BODYWEIGHTS OFMALERATS TABLE SMEAN BODY WEIGHTS OF FEMALERATS coc -- eeeoT TABLE 6MEANBODYWEIGHTGAINS OFMALERATS... TABLE MEAN BODYWEIGHT GAINSOFFEMALERATS 78 coco 71 TABLE MEANDAILYFOOD CONSUMPTION BYMALERATS TABLE 9MEAN DAILYFOODCONSUMPTION BYFEMALERATS wc. ccc 80 3 TABLE TABLE 10 11 MEAN MEAN DALY FOOD DAILY FOOD EFFICIENCY EFFICIENCY OF MALE OFFEMALE RATS RATS... ccc. 86 cd TTAABBLLEE 1132 SSUUMMMMAARRYYOOFFCCLLIINNIICCAALLOOBBSSEERRVVAATTIIOONNSSFFOORRFMEAMLAELREARTAST.S.. ccc on 92 57 TTAABBLLEE 1154SSUUMMMMAARRYYOOFFOOPPHRTTHHAALLMMOOLLOOGGYYOOBBSSEERRVVAATTIIOONNSSFFOORRMFAEMLAELREATS...RATS.. 103 104 TABLE 16 PERCENT SURVIVAL OF MALERATS... TABLE 17PERCENT SURVIVAL OFFEMALE RATS... 105 106 TABLE 15MEANFORELIMEANDHINDLIMBGRIPSTRENGTHFORMALERATS TABLE 19 MEANFORELIMEANDHINDLIMSGRIP STRENGTHFORFEMALERATS TA20BSULMMAERY OF FUNCTIONAL TABLE 21SUMMARYOFFUNCTIONAL OBSERVATION OBSERVATION BATTERY BATTERY FINDINGS FOR MALE RATS FINDINGSFORFEMALE RATS 109 110 TATBLAE2B223 MMLOOTTEOORR AACCTTIIVVIITTYYAASSSSEESSSSEEMMEENNTT::DDUURRAATTIIONONOOFFMMOVEOMEVNTSEFFOMORRMFEAELMENARLAETTSRAST.S..._111112 TATABBLLEE2245MMOOTTOORR AACCTTIIVVIITTYYAASSSSEESSSSEEMMEENNTT::NNUUMMBBEERROFOFMMOVEOMEVNTSEFFOOMRRMFEAELMENALETRASTSR.ATS........1.11143 TABLE 26 TABLE27 SUMMARY SUMMARY OFHEMATOLOGY VALUESFOR OF HEMATOLOGY VALUES FOR MALERATS... FEMALE RATS ccc 115 ooo 119 TTAABBLLEE2S9 SSUUMMMMAARRYYOOFFCCOOAAGGUULLAATTIIOONN VVAALLUUEESSFFOORRFMEAMLAELREATS. RATS. os 123 23 TATABBLLEE3301 SSUUMMMMAARRYYOOFFCCLLIINNIICCAALLCCHHEEMMIISSTTRRYY VVAALLUUEESS FFOORR FMEAMLAELREARTASTScr... os 124 128 _-- CompanySanitzsd. DoesnotconTtSaCAiCanl 0-Day Oral Gavage Study in Rats ici -- LIST OF TABLES (CONTINUED) DuPon9478 Page `TABLE 32 SUMMARY OF URINALYSIS VALUES FORMALERATS ccm 132. `TABLE 33 SUMMARYOFURINALYSIS VALUESFORFEMALERATS... 134 TABLE 34 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE RATS..............136 `TABLE 35 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITYINFEMALE RATS ..........137 TABLE 36 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS... I `TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS ccc 145 `TABLE 38 INCIDENCES OF GROSS OBSERVATIONS INMALERATS... 154 `TABLE 39 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS... 175 `TABLE40 INNCEIDOEPNCLESAOASFNMTDINCIORCNO-SNCEOOPPILCAOSBTSIECRLVEASTIIOONNSSI.N.M.ALE RATS 197 `TABLE 41 INNECOIPDLEANSCTEISCOAFNMDICNROONS-CNOEPOIPCLAOSBTSIECRLVEASTIIOONNSS IN FEMALE Rr ATS on 215 `TABLE 42 INNOCNI-DNEENOCPELSAASNTDICLLEESSIIOONNGSRADESc OF MICROm SCOPIC Oo BSERVATIn ONS IN MAeLsE RATS 231 `TABLE 43 'INNCOIND-ENNECOEPSLAASNTDICLLEESISOIN GORNASDE.S.O.FMICROSCOPIC OBSERVATIONS ImNm FEMAL--E--R--A--TSEl --~ LIST OF FIGURES Page FIGURE | MEAN BODY WEIGHTS OF MALE RATS... 10 FIGURE 2 MEAN BODY WEIGHTS OF FEMALE RATS... 271 FIGURE 3MEANFORELIMBGRIPSTRENGTHFORMALE RATS.. FIGURE 4 MEAN FORELIMB GRIPSTRENGTHFOR FEMALE RATS... 272 273 FIGURESMEAN HINDLIMB GRIP STRENGTH FOR MALE RATS... FIGURE 6 MEANHINDLIMB GRIP STRENGTH FOR FEMALE RATS ccc 274 275 FIGURE 7 MEAN TOTAL DURATION OF MOVEMENT FOR MALE RATS... 276 FIGURE 8 MEANTOTAL DURATION OF MOVEMENT FOR FEMALE RATS ccs 277 FIGURE 9MEAN TOTALNUMBER OF MOVEMENTSFORMALERATS ...c.rcvrrnrenn 278 FIGURE 10 MEAN TOTAL NUMBER OF MOVEMENTS FOR FEMALE RATS coo 270 : |~ -_-- Company Sanitized. Doos not contain TSCA CBI S9ou0omO.riaOlDGnaeavaggeyeSSifhyuibichRkraotnsic Toxicity I~ LIST OFAPPENDICES DDwupmonoe9m47s8 APPAEANANLYTDICAILDAXTA Page ocr 283 APPENDIX BINDIVDOISEDVUOLUAMELS APPENDIX CINDIVBOIDYDWEUIGAHTLS crc. SE ven 376 APPENDIX DINDIFVOODICODNSUUMPATIOLN... APPENDIX EINDIVIDUALCLINICAL OBSERVATIONSAND MORTALITY DATA 11 ror d36 AAPPPPEENNDDIIXXFGIINNDDIIVVIIDDUUAALLFOOPRHETLHIAMLEMGORLIOPGSITCRAELNOGTBHSAENRDHVIANTDLIIOMSNGSRI.P.. oo. 48 STRENGTH.....490 | AAPPPPEENNDDIIXX [HIINDINVIDDUIALMVFOUTNIOCRTDIAOCUNTAIVLAIOTLYB:SEDRVAUTIRONAAOLFBTMATOTIVEREYOMAESNNSETSSSM.E.N.T ....... 511 522. | APPENDIX J INDIVIDUAL MOTORACTIVITY: NUMBER OF MOVEMENTS ranmmimmnnt3S APPENDIX KINDIVIDUALANIMALCLINICAL PATHOLOGY DATA............ SR---- 3 ~ APPENDIXL INDIVIDUALANIMALBIOCHEMDIACATLA. i APPENDIX MINDIVIDUALANIMAL BODYAND ORGANWEIGHTS cc 651 58 APPENDIX APPENDIX N0IINDNIVIDDUAILAAVNNIIMMIAALLGDMRIOCUSROSSAACNODPLIMCIOCBRSOESRCOVPAITCIOONBSSELRIVSATTIINGOINNSDIv VIDU. AL A9 NIMA5LS ~ - CompanySaniized. Doesnot contain TSCA Cal Dbvon0 lomesdyerwees ~~ STUDY INFORMATION th Collcive N( omenclur -- ~ Haskell Num bec: 24691 CAS Registry Numbf er --] Composter: GY) | EY KnownImpuriis: EE | ofthe study. no evidence ofmt wae cbse Sponsor: Telomer Research Program - 1200 South Hayes Street Arlington, Virginia 22202-5050 US.A. Std ntstedCompleted: Februar7y, 2002 (sereportcover page) ~ I-LieIiisedCompleted: February12,2002 August 2, 2002 --"DayO\ ralGavas geStuyic n Rats Tosicity ~~ STUDY PERSONNEL Study Director: Gregory S. Ladics, Ph.D. Management: Scott E. Loveless, Ph.D. Primary Technician: JanicLe. Deborah Connell, A. Vick, M.S., B.S. BA, CLH. Analytical Chemist: Janet C. Maslanka, B.S. Management: S. Mark Kennedy, Ph.D. Clinical Pathologist: Nancy E. Everds, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Neurobehavioral Toxicologist: LindAa. Maley, Ph.D. Management: RoberMt. Parker, Ph.D. Biochemical Toxicologist: John C. O'Connor, M.S. Management: Matthew S. Bogdanffy, Ph.D. Pathologist: G. Tracy Makovec, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. --_ Peer Review Pathologist: Steven R. Frame, D.V.M., Ph.D. `Toxicology Report Preparation: Cecilia R. Kee, B.S. Brenda Tiffin Ophthalmologist: Nancy M. Bromberg, V.M.D., M.S. 6119 Massachusetts Avenue Bethesda, Maryland 20816 Statistical Analysis: John W. Green, Ph.D. Management: Janice L. Connell, M.S., B.A., CLH. Laboratory Veterinarian: Thomas W. Mayer, D.V.M., ACLAM. DuPon.9478 --~ -YYY `Company Sanitized. Does not contain TSCA CBI CDaY y Oral G.avage. Styain.Rats 5c, DDwuoPown.o04a7s8 ~~ SUMMARY i aEpipvreoximgarotupes l. oyf 90youngdays.aduBlbotydmygaalwveeaiaggnehdastf,edfmooasoladegecCsoronlfs:0uCm,Dp*t1,(ioS5n,D,)2I5a,GnSdanBcdlRi1nir2ca5atlsmgwsi/egkrngeas/dwdmeairynefioesrvtaelruaetded aw{nehedokedleuy-.rmionnCgtlhiwnerieecacklov1p3ea.rtyhBopieloroicgohyde.emnidNcpeaoulirnoetvbsaelhwuaeavtriieoorneasvla(lhauesapstaeetsdiscomneonxwtiesdeawktesiroe7,na)1l3sw,oeparenerdfpnoeerrafmroetrdhmpeerdeinord toofdtohseing Aafftteerr1a0pparnodxiampaptreolyxi9m0adtaey9sl0yofdadoyssiongf,do1s0irnagta/nsedxf/odlolsoewwinegrethseactrhirfeiece-dmoanntdhgrievceonveargyorponesrnsioaidn.ld e pemfeifrceicrotosds.,co1Ap0iascunpbiagtrmhooaulpologsifcai5lnretahxteasm/cisonenaxtt/ridooolnsa.enwdeAhrpipegrdhoexdsioimgsanetagetrleodyuatpshrwseaeetremelloeintxteahbmslieanefedtdearfntiohmrearl9es0.c-odvearyydoofsitnogsic efixvpeosaunriematlostsheextiedsotsseubwsetraencdee.signated for hepatic biochemical alysis following An additional a 10-day The 1.210 range of 3.0 ml. mTehaenradnaigley daosdemviolnuimesstotoffe( ermaeldeS rats wS as 0.S t9o 1.6 mI li.i, rc to male rats was oIsbunbsLseitrfavenecTdeo-irxneilctahoteleod1g,2y5tPomaxgri/acokmlegot/gediracsya:lmlyaNlsoeigtaneinsftdicsfauenpmtsatilanenccrdeeo-asrseeelgairtnoeutdphsem.oirntOcailnditetenyscotecdcoaufyrsrt7er7da,tiaenldlttmheeaeltsethudwy.s A test ~ female high fo the teeth, dose animals were There were no test psluabcsetdanocne-grreoluanedd,cthooxwicdouloegitocatlelsyt substance-induced alatnedrations significant alterations in body weight, body weight female dose groups gain, food consumption, or food efficiency observed in any of the male or NineumraolteoxoircfoelmoaglyePraartasmientaernsy:doNsoe adverse group. changes in neurobehavioral parameters were observed BwiaoscshiegmniicfiaclanTtolxyicionlcorgeya:sedTihnefseamtaeloefshaedpmaitincisPt-eorxeidda2t5iomng,/kagm/edaays}ure of males and females administered 125 mg/kg/day peroxisome proliferation, din minomnatlhesreacdomvienriyspteerrieodd.12th5emratoeofehep( atic B-R oxidation was lower but silFsoiglnliofwiicnangtlaytihnrceer-eased had returned to control levels in female rats. rds wit 0133 ngsMAR Oesnes moCnlolinynt)i,hcasalnodPfaprtlehcaooslvomegaryya:nfdSoraumhrpienmleaetsfolwluooergriyed,ecco(lleilnneidcctaoelfdcsahtteummdiiysdat-rnsydt,utduhyrr,ienaeatl-ytmshoienst,ehncdoraeogcufo&lvtaerteriayotpnmeer(nieton,dd)a,nodfasfttuedry three. There were no toricologically signif nical pathology parameters observed in _ mafatgeariatutdhereoef-mcohnatnhgerewcaosvesrmyawlelretrcanosniseindt,eraenddltorreaitnmaendti-rreecltaitoendnbouttansosno-caidavteerdsweibthestaouxisceittyh.e - Company Saritizd. Doss not contain TSCA CBI V9ON0DDaoyOOnraCGoavgageeo Sud.y i.n R.ate s.Toxicity uDoupwomosaa7s8 ~ Tsroemaetmreendt-crelellamtaesdscphaarnagmeesteorbssearlvoendgiwnitrahtsreatdimciunlioscytteorseids>an2d5imngc/rkeags/eddayseirnucmlucdheodledsetcerreoalses in (1f2e5mamlge/skgon/ldya)y. iTnecsltudseudbsttraanncsei-enrtellyatiendcrcehaasnegdesaliknalcilnienipchaolsppahtahtoalsoegy(omfalreastsondloys),edinwcirtehased | auprlhibonusempihkneo,trouinsnec(rcmeoaanlsceeesdntcornaalltyc)ii,oundmsec((frmeeamalaselesedosntloryni)lg.yl)y,cPelirnaicdsermseaa(sfmeladulouerrsiidonenellyve)vo,elliusnmcweree(ramesaesldiegstnoitofanillcypa)nr,tolatyenidinndcaerncedraesaesdeidn mtharleeesamonndthfseomaflreescodvoesreyd.wiUtrhin1e2f5lmuogr/ikdge/edxacyr,etbiuotnrweatsumiendcrteoacsoendtrinolmalelveeslsanfodllfoewmianlge.s dosed cWointthrolSlemvge/lks,g/wdhaiyl.e lAefvteelrstihnrmeaelmeosnwtehrsoefsirgenciofviecarnyt,lyurreidneucfelduorciodmeplaerveeldstiontfheomsaeleatstrheetuernndedofto the exposure period. saminisere 125 mg eR y T Adengaetnoermaitciaonl/dPiastohroglaongiyz:atioTnest soufbestnanace]-roerlgaatend,amteolxoibcloalsogtieclalllsyoscicgunrifriecdanitn male rais wAatsesotbssuebrsvteadncien:rmeallaetseda,damdivneirssteeriendcr2e5asaenidn1t2h5e mingc/ikdge/ndcaey.anAdnseivnecrrietaysoefdfionccaildheenpcaetiacndnescorvoesriisty of chronic considered pardovgerreses.sive nephropathy occurred in the 125 mg/kg/day female group and was ~ pTersets-seunibtnstmaanlceesrealnadtefdeamnadlesstaatdismtiincialsltyersiegdni2f5icoarnt1i2n5cmrega/skegs/idnaylivfeorrwaepipgrhotxipmaartaemleyte9r0sdwaeyrse.. The i1n2c5remags/ekdgl/idvaeyr wmealieghdsosceorgrreoluapt.edLwiivtehrmwiecirgohstcocphiacngheespaatnodcemlilcurloasrchoyppiecrthryoppehrytirnopthhye were cadovnesrisdee.reTdetsot-bseubaspthaynscieorleolgaitceadl aanddapsttiavtiestriecsaplloynsseigtnoifmiectanatboinlcirsemasoefstihnektiedstnesyubwsetiagnhcte and not pkairdanmeeytweerisgohctcsucrorrerdeliantmeadlweisthanmdicfreomsacloepsicadrmeinnailswtbeureldar25hyoprer1t2r5opmgh/ykign/dthaey.25Tahnedincreased e1v2i5demngc/ekogf/dreanyalmatloexigcriotyupwseronelyp.resHeontw.evTehre,renfoorceo,rrkeildantievyewmeiicgrhotsccohpaincgoerscalinndimcailcrpoastchooploigcical sTthpubiousnltcaahrnaehnoygpueesrwftairnsodpnihonytgwiaensrsreoatcsni,aottweacdosnwisinitcdhreeorateshdeedradfivnienirdnsicenigfdsienindncietnhgaesn.dt/hAyolrrtoseierdvegedrlicatonyldlioanindtd,raewaatcesodmamlmasoloennogtroups. considered an adverse finding. sAeefffvteeecrrtistt.yhriTenhetemhoeanm1et2lh5osbmlogaf/srtkeigcc/oddvaeegyreymn,carrlaaettsigodrnoo/usdpe.idsowArilgttahenri1az2tai5toimnosgn/ipknegtr/hsdyiasrtoyeisddhwcooiwlteldho-idtdeecvpererersasiisbseiidleiditniycniodmfeanslocemeera.antsd oIbnscreeravseeddilnivtehrew1e2i5ghmtg/pkarga/mdeatyermsalaendanhdepfaetmoacellelgurloaurphsy.peHrotwreovpheyr,(mtahleeisnocnildye)ncweerofe no longer rnheoectpoaovtbeosrcyee.rllvuIelndacrirnenaeasctersdosskiaiscdriinnfeitychewedea1if2gt5hetrmtgph/arrkeagem/edmtaoeynrtsmhaaslnoedfgrrreeoncauolpvteiurnbycu.rleaIarnshecydopnaetfrrtatesrrto,tphthrhyeee(immnoaclnietdshensocnoelfya)nwdere ~ I Company Sanitizd. Does not contain TSCA GBI U SDeyo Oral Gu c avage Soy inm , Rats OmpedvyeRe wDioon.s e94s75 ~ sfeovlelroiwtiynogftchhrreeonmiocnptrhosgroefsrseicvoevenreyp.hropathy were increased in the 125 mg/kg/day female group In conclusion, the no-observed-effect level (NOEL) for males was 5 moke/daySY 25 mg/kg/day. on the increased incidence of hepatic necrosis The NOEL for females was 25 mg/kg/day] observed in males administered > on the iandcmrienaissetderiendci1d2e5ncmeg/akngd/sdaye.veofrchirotniyc progressive nephropathy Observed in females di`tpeehtfeieTtnhedeted SbsNayOtuetEshseLaEEnfnuvoriworhepoirenseamnseotnUtuardldiyeoitPnsercdo(te1ee9cdn.9te6i)odT,nhuAsg,tehfneocrhyiig1hse9s8tt5yd)o,as tahteowtNhhOiecEhmLtoio-srcciqcblirovgviinecatdlaidmhpveoorrNtfsaOnceEt LenffdectSsGteMfsb)srs 0 - `Company Sanitized. Doss not contain TSCA OBI | Os -- O ey u Oral Gavs C ige Sadlya in Rats O vcmpSebek DwDuepome not9s47s8 I| ~ INTRODUCTION T12h5e mtegs/tksgi/bdsay dose levels for this study were oseleScted based on the toXICity oTMbser|v.ed5.i2n5a,nx8d4. day range finding studies with simil study with 5. 25, and 125 m/e R d perflR uorooctaR noic aci} d (PFOA)5.cIhnrotnhiclll cmoenatnrolbowdeyreweoibgshetrsvecdomigpneamrfaeilndedetroratcsstounadtdyrm,oilnsiiwgsentrieferiecadalns1tol2yo5blmsogew/rekvrge/dmdeaiany.nrabsSoiadmdiylmawirenliiygs,httessirgecndiof1mi0pc0aanrmtegldy/kltgoo/wdeary oinr mgarelaetserdoosfesdimwiiltahr f1l2u5ormoet/eklgo/mdeory-G based alcoN hols. SigniI ficaintl:y incwreeiagshetdslwiveerrewaelisgohts occurred -- msiagyniafciccuamn- utrlayt incrienlaoasenwdiamcsaol1ms0p0daormsgee/ddkgtwo/idctaohyn.tt roFluirnthreatrsmoardem,iM ndiasttaerseudggdeosstethlearvteeltsph.etoPfdSFoONsAsmeetsab,oliBtEeOA at doses of 10 mg/kg/day or lower increased hepatic cell proliferation produced and beta the following oxidation, and effects: altered increased liver serum hormone weights, levels, 123 | qTheuhiighd-adsoiwsneecllrlesavseseltdohelfiav1be2ir5liwmteygi/ogkfhgtr/sadtosabytsoefrtoorvletedhriasitnesmtauad1ly0s0wadmsogs/sekedgl/ewdcitateyhdd1bo2as5seemdlegoven/ltgihnesrueSbdcuShcrtRoinoNniscRisntRubdoYidesy with similar The 125 mg/kg/day dose was expected to produce --~ toxicity without excessive mortality. `ombisneirmvaeld-cff1e0cttolxeivceilty(.NOEL), while The the 5 low and d2o5semgo/fk1g/`dmagy/kdgo/sdeaylewvaeslsewxpeerceteexdpteocbteedthteo no- induce: | OBJECTIVE | Rectve gts sty is 0 evaluat the potential subchronic toxicity and reversibility offi Ec `administered by gavage to male and female rats. The oral route of administration was Selected as the most efficient way to deliver an accurate dosage. MATERIALS AND METHODS A. Test Guidelines `The subchronic Agency (EPA), toxicit Office ys of tudy design Prevention, cPoesmtpilciiedsesw,iatnhdtTheoxUincitSeudbsSttaatnecs.esEn(vOiPrPoTnmSe)nHteaallPtrhotEefcfetcitosn `Test Guidelines, OPPTS 870.3100 90-Day Oral Toxicity in Rodents (Aug-1998). B. Test Substance Tkhneowtnestpusruibstty; d composition. A rweasesrvseupspalmipeldbeyotfhtehestpesotnssuboasrsta|ncSe RwasNcRollecite:d --~ `and retained by Haskell Laboratory. = -- `Company Sanitized. Does not contain TSCA CBI U9R 0-DayOral Gavage Stay in RtisTcorii wDeupmo w47n8 [om C. Test Species i| | raOenncde2i19v0-e5Jdaffne-rm2oa0ml0eC2h,raaCtrselewlse:rCReiDv(reeSrcDeL)iaIbvoeGrdSaftBoorrRitehrsea,tmsIanwici.nt,hsRtaaunldeayisgashn,idgNn2oe8rdtmbhairlCtaehrdaolanitdneoa2.f8 fO3en1m-eaDlheeucn-d2r0e0d1 fwievreemale received for the 10-day biochemical evaluation, rats were `aTTvhhaeeilCraarbtllew:aCfsrDo*sm(elSteDhc)etIeldGtSebaeBtcuRaruess,tertaihiteniswsutaphseplcsihpeoercsieaennsdbrepecrcaeouvsmieomueesxntsdetenusddiivieens.tabhtaeHcasksugkbrecolhulrnondiicnftooxrimcaittiyognuiidselines, dsipseecaiseess./taain is considered suitable relative 0 longevity and low incidencLeaobforsaptoonrtya.neoTuhsi.s D. Animal Husbandry 1. Housing apfbobosrviaettiscoawngeeerdeboohanrodutshs.eedrCaoacnkgesepereavrceckars2gywee,wreseeekxrsee.sloscAeanptaiermdaatwlei,trhioinonsmttsahiewnaleenrsiesmsmataleiernl,otaowiminreaedn-dmecsahgecsagweesresuspended `cOyccclaesi(ofnluaolreexscceunrtsiloinghst)ouatnsdidaet theteamcpceerpattaubrleeorfan2g2es+w3erCeamnidnoarrealnadtidveidhnuomotindaaiftf1ey2cto-fhtoh3ue0rs%ltia=gyh,2td0a%rk I~ 2. Fed and Water Tap water was provided ad bir. All rts C1e2r5timfgi/ekdgR/oddaeyntgrLoaubpDsiweetr"e5p0l0a2caeddloinbigtruomu.n were fed pellet dOcnhtoewstbdeacyau7s7e, ed PMI all rats of test Nutrition Internationa, siunbtshteanmcael-einadnudfceedmale Inc. tothe teeth. alterations 3. Identification `Acnanugmeibnledaribveailsdssuiiagnlnceildduedtnoetdieftaihcceahtuirnoanitqnuuem6b-edirgiwtaHsatsaktetloloeadniomnalthneutmableorfeaancdhtrhaet.inTdihveiduianlfoirdmeanttiiofnicoantitohne 4. Health Monitoring Program hfthosolslseopwteihcnatigfwpiroioeuncdleddthubereeHesaxsapkreeecltpleeLdraftoboroimrmepadatpcoetrrityohdeainscimcaaillelhnyetatioftcheniasnnutdergeerintthvyaitorfcoontnmhteeansmttiaunldmayon:ntilteovrelisngaprboegjroanm., the + aWnadteorthsearmcpolnetsamairnaanntasl.yzed for total bacterial counts, andth presenceof coliforms, lead, ~ + Feed samples are analyzed for total bacterial, sporeandfungal counts. - `Company Sanitized. Does not containTSCACBI O. 90R-Day . Oral Gava. ge Sty: iRn Reates 7:.c: DDwuPoonn.0e47n8 Po + Sbyatmhpelecsagferwoamshferressh.ly washed cages and cage racks are analyzed to ensure adequate sanitation || rCeerqtuiifrieemdeanntismaanldfneoetd 1i0s eusxecde,edgusatraatnetdemedaxbiytmhuemmacnouncfeancttruarteiorntsoomfekeetyscpeocnitfaimeidnannuttrsi,tiionncalluding psrpeecsiefniceedofhtehaevys:mectoanltsa,maifnlaantotxsinb,eclholwortihneamteadxhiymdruomcacrobnocnesn,traantdioonrgsatantoepdhobsyphthaetemsa.nufTahceturer `would not be expected to impact the integrity of the study. Tlahbeoraantiomraylahneiamlatlh vaentdereinnavriiraonn.meEnvtaalluamtoinointoofritnhgesperdoagtraadmiids naodtmiinndiisctaetreeadnbyyctohnediattitoennsditnhgat affected the validity of the study. E. Quarantine and Pretest Period cUlpinoincaalrlryiavaplpaarteHnatsksieglnlsLoafbodriasteoarsye,oarllinrjautrsy,wearnedqwueairgahnetidn4edtifmoers,7 days, observed daily for any Rblaetesddsewseirgneaatlesdofeoxratmheinseudbcbhyroanviectteorxiincairtyyoapnhdthtahlrmeoel-omgoinstthoreicdoevnetriyfyeavanliumaatlisonwsi,tahnpdreseaxtielsltiitneg `woecruleargilveseinonas.basRealtisnedenseiugrnoabteehdavfioorrtahleesvuablcuhartoionni.c toxicity and three-month recovery evaluations ~~ `aOtnstwheerbeasriesleoafseadccferpotambqlueabraondtyinweeibgyhtthgealianbsoarnatdocrlyianinciamlaolbsveetrevraitniaornisa,nadllessiugrnveievionng tmeasindasytudy 11; rats designated for the 10-day biochemical analysis were released on test day --. F. Study Design . Group Male Female Number/Group, Male Female Dosage' T mM I IV 30 20 30 20 Omgkgday (Control) 1mgkgday v VI VIL VID 20 20 20 Smgkgday 20 25mgkglday 8 xX Weightneight of est 30 substance 30 (djusted 125 mgkgday forsponsor supplied purty of active ingredient). = cEoancshisgtreoduopfotfhsrteuedsyubagnriomuaplss:, ethxecefpirtstth1o0seradtess/isgenx/adtoesdefwoerrtehede1s0i-gdnaaytebdifoocrheemviaclaulatainoanlyosifs, Lsausbtc1h0rornaitcs/tsoexxi/cdiotys;e t(hceonnterxotl a5nrdaihsi/gshe-xd/odosseegwreoruepsdeosnilgy)nawteerdeasdessatieglnlaitteedblaesetdharneiem-amlosn;tahnd the |~ rbeicoocvheermyiacnailmaanlasl.ysiAsnfoadldliotwiionngala s1u0b-gdraoyuepxpoofsurraesto/setxhe/dtoessteswuebrsetadnecsei.gnated for hepatic EE `Company Saniized. Doesnot contain TSCA CBI O S9e0DmaN yoOrnaCG. aevageS. Syeink. Rts. oc DwDuepwonets94n7s8 --_ fdMeaamylasel9ea2nrd(amsfaeldmeea)sliaegnnrdaat9se3dde(ffsoerimgtanhlaeet)se,adtaefnlodirttnehebelcseruebdocsphwrieooenrnidecdttoeossxteiddcaittyhysre9ov3uaglahunatdteis9to4nd,awryeers9pe0ecdtaoinsvdeeldnye.tchrrMoopaustgeh atneds.t etvesatludaatyio1n7s5w(e8r5eddaoyssepdostthrdoousginhgt)e.stMdaalye9a0nadnfdenmaelcerroapssideeosndigtneastteddafyo1r8t3ht(9h3redeamysonpotsht rdieoecdsoiovnnegr,y sNuebucrhorbocnhiacvitoorxiacliteyvaelvuaaltuiaotnisonwearned ctohnrdeue-cmtoendtohnremcaolveerayndevfaelmuaalteioann(ipmraeldsodseesaingdnaetecdkfor13t)he aeAvnadclluiunariticniaeolnfpdlauutorhriiondlgeowgwyeeereevkan7louatantdideotwnewrkmaisn1ce3odn(odpnuricwotereed0kon7ne.crraPotlspasdyse)ms.aigaCnnoadatgeuudrlfiaontteihfolenuposrauirbdaecmhewrteoernreiscdaetntodxeirpcmilitanyenda for the three-month recovery animals on week 26. ItBonix-oiiccfhieteydmaietvcaaall(ubaeotvdiayolnuw,aettiihogenhts,hwrfeeoreoe-dmccooonnntdshuurcmetpcetodivooenrn,ysceelvliaenlciutcaaetldioaobnnssie,mraavlnastdidtoehnsesi)g1nf0ao-trderadayftoserxdpetoshsieagrnsaeutbeecvdharlfouonarittcihoen. H1o0w-edavyerb,iotchheesmeidcaatlaaanraelynsoitsiwnecrleudceodllientchtiesdrferpoormt.these animals and are in study records. G. Assignment to Groups _ 1. aRantdsSDateeslilgitneatBeldeefdosr the Subchronic Toxicity and Three-Month Recovery Evaluations, 2oRpa0htts%hwaoelrmfoetlhsoeeglimecceatalendabfwnoirotrhsmitanuldiaytsiueexss.eoorTnhclteihnesiecblaaelscistseoidgfrasadtoesfdqwiuesareteaesdbieosotdryiibnwujetuierdgyh,btyagncadoimnap,ubftorederyeizdweoedmi.gfhsrttorwamtiitafhniieynd `rmaenadnosmiwziatthiionnassoexthat there were no statistically significant differences among group body weight rwOeinptlhtaecoseutdt.doafyRae0pn,lgparecieobmroetdnoytthwreeatissgahwrttesr,oefscletilenseitccstaulebdssoitgnannst,cheoerabdnamesiuinrsiosobtferhfatariveoienod,roa3mlmfafrilnoedmrianatgnssydacunlridinin3cfgaelpmrseaitlgenesstraowtfesre mdiasleeasceonotrroilnjruartywaintdh aabnooduty-owfe-irgahntge=b2o0d%y woeftighhetmewaasnuwsietdhionnastsuedxy.. Due to technician eror, one H. Dose Suspension Preparation (rtehemaO tiesntdesR urbosftaY tnhceedow)seirneg. ppreerpiao1rde.dctwi.ce per0w.e5e%kauupcooudsayme4t8h,yltcheelnlpurleopsaereDdodsaiinlgy tshursopuegnhsihoens of --~ ere Company Sanitized. Does not contain TSCA CBI C 90-Day OraO l Gavage St, ey ineRats 7c, bDuePone.4n78 L Test Substance Administration wJheevieeglhtste.sotfDs1uo.bs5se,ta2vno5cleuorwmea1ss25faodmrmaielnlikgstrbeorouedpdsy dwwaeeiirlygeht5todmtaLhyle,ksgbt.ausdeyMdaalnoienmaatlnhesd mbfoyesmotarlrleeccgeoannvttalrygoelreatcotosarcdwheeidreebveosdidymoislaage htiregaht-eddowsiatghe 0gr.o5u%p.aqueous methylcellulose at the same dose volume as used i their respectiverly arBanatdss e4ad8t.lolnSudtbhoseserqelsueuevlnetltssaomnfaaalynyatnliyoctatilhcaaanlvaealnyraselicysesoiivsneoadfdadaif4tu-loldnadaylosddeoossoeef ptperrseetppasarurabatstitiooannnscoeb(inoaontintaeedsdtmoidnnaiystsetse4tr5de,ad4yt6o,45r4,a7t,s indicated that the test day 45 results were duteo a sampling error ) 1. aRanidsSDateesliigtneaBtleedfeodsrthe Subchronic Toxicity and Three-Month Recovery Evaluations, taOhprrpaorluoagxdhimmitanetsitesltdyraay5t0i9o2dnao(ymsaloefsa)goer. 3Rat(sfedmeaslieg)na.tedRafsorgdtaenhseiognsnuatbtecsethdrdfoaonyrict0,htewotxhihecrineteyt-hemevoarnlatuthsatrwieeocrnoevweerrye dosed seavtaelluiatteiobnleaendds sdaitdelnloitterbeiceeaidvse tweesrtesudbossteadnctehrdouurgihngtetshtedraeyc9o0v.eryRaptesridode.signated for recovery and 2. Rats Designated for 10-Day Biochemical Analysis wOerraeaapdpmroixsismaitoelnyo4fN 2 days of age anN d ended o<n tnest d7adye2y. pio to sty ia when the rs J. Test Substance Sampling smDuoissxpietnnogsbiseounsupspeerndespeiaiortanhtseirfoofnrowrtah3issocrsht4audndyagyewsdero0fedoapsrsiempnaaglr.ledvSaoulbusthemqeubmeenigtxilnyin,oiboneng udosfaeytdh4ef9oostfu1dtdhayeyaosstfudldyao,rsgitenhegv.odlousmien.g mSagdm/epmtlelersmwcieonrneethcioonmliloengceS tnecditoynlN teeosntcdeanR ytr--a6ti(ol: narvgeeriVfoilcruacmtieco/on3n-ac4neddnat5ry-amthiioxo)un.szoofToh0me,st0ee2m,spae1mr.pa0l,teu5sr0ew,seatranbodilai2nt5ay..l0yzed daSfiatsmeprpelr7seidsoanfy/srcooofmncrteehfnertirsgaaetmriaeotniporvneo.rpiafTriahcteaitsoienonsaatamntpdhleer0es.f2rwiemgreger/aatmenLdalslytezavbeeidlliottnoyldyae,ltowenergrmwieincteohlrel5.c-ehtoeudrornootmest day 0, ttheempoetrhaetrulreevesltasbihlaitdy.beeTnheesrteafbrliigsehreadteddurrei-ncgitshpeer`smiixoinn/gc/osntcentation verification and stability for ability study for a previous study.) esOsantmtpedlsaetysdsaf4yo2rs,a44l58,,le65v32e,,lsa5n6w,der578e3,c(6o35l-,l4eacdtnaedyd.9m1iTx(h)se,mactleolsntcdveaonlytur4ma8et/i1pornedvpaeayrriamftiiixco)an,tiwcoonansscaenmnopttrldaeotsisofenodrvtaeolrliaflnieicvmaeatllisso,nsoOn collected. evaluation Toefstthedalyar6ge3 and 73 volume pmriexpar(a3t-i4odnasy)w.ere not used for dosing the animals but for rs -YY Company Sanitized. Does not contain TSCA Cal O 0-Day OraR Gavage Sy..in:Raitsc Toviciy Dupom. 476 ~ afArnlolizmdeaonlssuionntrgialstaunstaphleeynezsseitdoa.nblsiasmhpedlsetsabwielirteytciolmleecftoerd aonnalytshies.dayThteheyswuesrpeenasniaolnyszewderwehdeonsreedcetoivtehde or K. Analytical Methods 1. Dosing Solution Treatment `Emaecthhadnooslianngdsammipxleed t(o1d0imssLolfvoer 0t.h2 mg/mL; 3 mL for other levetlhse)swuaspsendsiilount.ed 1T0h1e0d0osmiLngwith samples were analyzed without further dilution (initial dilution) to an expected concentration of or were furtherdiluted with the 0 `mg/mL sample Before all final dilutions,the intemal standard approximately 0.03mg/mL (a. i.) prior diluted solution (refer to Calibration and to analysis. Quantitation 0.04 mg/mL. Section) was added Each sample (final except the 0.2 mg/mL (10%). to d each ilutio test. `sample to give a n) had an equivalent final con amount cmeanttrriaxti(o3n%o)f`wahppernoxainmaalytzeeldy, t`eSsatmipnlgegsrsouubpmiotrtferdozfoern anniallysainsalwyezreed.analyzed the day the suspensions were received by the 2. Chromatographic Conditions Instrument: ~~ Hewlett-Packard Model 6890Gc --~ Column: Injector: J &W, DB-1701, Split, 250C 30 m, 0.32 mm ID, 1 um film thickness Detector: FID; 250C Carrier Gas: Helium (2.1ml/min) Split vent: 22.3 mL/min Injection Volume: 2 microliter Oven Program: Gradient Initial Temperature: 100C Initial Time: 1.00 min. Level 1 Rate: 20.0C/min. Level 1 Temperature: 260C Level 1 Time: 0.00 min. `Total run time: 9.00 min. 3. Calibration and Quantitation - stasnedpaardr.ateAsasmtopclkesoofS lution wR as prepN ared in R metha<n5oln. Thdis stfoockussoeluutsiotnhewaasnaslyotniiccaalterdeference dfaiselsuuttraeerdgtewhtiattchoanltlchemenat0treamrtigia/olnmwoLafsstahimenpdsloielluu(ttiienodinti.daolsBdieinflgoutrsieaomna)pnlateloyssm.iasA,keasptcpaorlcoikpbrrsiaoalttuietoinao`lnsitqaunodtasrdosf, twhhesitcohcbkrwatecokreeted ~~ calibration standard and test sample to give 4 was prepared in metohfainonltaenldsatdadneddartdo[eJiafch final concentrationof approximate ly 0.04 mg/mL. - Company Saniized. Does not contain TSCA O81 O X 0-DaD y OraluGavaY O ge Sinn dy in RG aits i Toxiciv ty geSudyinRDuDue oPwoonats 0r4s78 [a A`aTnphapeleyrnsaditsiioxofoAft,hteFhseiegiunsrtoeelrun1taifloonsrstaawnradeasprrdue.ssA eednttaoticvoenscturruvcet).a McieasureidonccounrcveenhtberiyagtlhietoasnsstfrsfqoourmatrrheeepsldirocesagitrenegsGssiCaomnp(lseese were determined calibration curve. by applying the peak height ratios rom replicate injections of each sample to the icTnoeestfthfeiscutiobepsn,ttamonifcdedvlahero,imaaotginoednnbe(oiCtt.ytV/o.um=nsisaftmoaprnmldieatsryd(ihdnoemtvhoiegaetvnieeohnii/tclmyee)awonarxsdue1pv0la0il)cuaoatfteetsdhaebmympelcaeasslcu(urcleoadntcicenongntctrehanettiroantions svetrainfdiacradticorni)tefroironeaacthHadsokseilnlgLlaevbeolr.atAocroyeffforicaicecnetptoafbvlaerdiiasttiroinboutfiloenssofthtahne otersteqsuuablsttaonc1e0% is the itnhrtohuegvheohuitclteheorsotlhuetiaonna.lyHsioswehvasers,hiofwtnh vatreisatbsiluibtsyt,aancceoehfafsicbieenetngrsehaotwerntthobane1d0ifmfaiycubletot disperse acceptable. eTahcehmdeoasinnrgelsuelvtelofwathseuhsoemdotgoedneetietrymsianmeptlheescoorncceonntcreanttiroantioofntvheertiefsitcastuibosntdaunpcleicfaortethseamrpeslpeesctfiovre dosing levels. sStaambpilleitsyrwoasm etvhaelcuoantceednbtyrautsiionngvterhiefmiceaatinonreassultthoeftbhaseelhionmeofgoernceoimtpyarsiamnpgltehse ocrortrheesdpuopnldiicantge stability results. ~ L. Body Weights 1. aRnatdsSaDteeslilgitneaBteldeefdosr the Subchronic Toxicity and Three-Month Recovery Evaluations, iaRnnatdasdmdwoiettriooern,awcettihiegvihrteaydsaosdnsecessiesgpmneearntwteesd)efokwredrnueeruiwrneogbiegthhhaeevdaioporpnarltohxeeivmdaalatuyeasltoyifo9nt0sh-o(dsfaeuynocebtxsipeoornvaslautroiebosnpeshr.avsaetoifontahle bastttuedryy. 2. Rats Designated for 10-Day Biochemical Analysis Rats were weighed on the first, eighth, and tenthdayoftest substance administration. M. Food Consumption and Food Efficiency ftTihhnraeoluawgmehoiougunhttttoohffe stfthoueoddyf.ecedoEinearscuahmnfededtehdbeeyracmwaoacushnwrtaetioofgvhseepridlelaaatcghtehfewreboiemgghitinhnnegifneignetadeenrrdvadelunrwdianosgfdttehheteeiirnnmttieernrvevaadllwaansd the csuobntsruamcpttediofnroovmertthehiniitniatlefrevaeldewraswediegthet.rmiFnredo.m tFhreosme mteheasfuoroedmceonntssummpetainondaailnydfboooddy weight data the mean daily food efficiency was calculated. ~ -YY Fy Company Sanitized. Does not contain TSCA CBI | A 90-Day Oral Gava. ge Stay in Rats 7 DuPon.9478 --_ N. Detailed Clinical Observations and Mortality Dobunerlhiyanvoginoterhceaangtdeelssotirtpeaeprepixeodaamrciaanngacete-siaiotmneowenaxgsamrcaiotnnsadtwuiecortneesdc.toonMddoeutrceitcebtdumnaodtlrreiaassbtuwtenowridrecedseadcaaridilfyri,acteesdxacnedptabonnotremstalday 46 tDDhecetiagsiuhlbiecndhgcrleoiannciihccatrlaotbxiswceairstyviaanniddoivntishdruiaenleal-ymsohtnaatnnhddalreddiazendd aerxeanmaiwneerdefaolrsaobenvoarlmuaaltebdeohnavai.tosrAdatneedsvieargpypneeadrafnocre. not evaluated on rats designated for satelrietceobvleeroydsp.eriods. Detailed clinical obsorvations sors Ucahoeeruidtesmtaamiiloeenmd,bcprliailnnoeeisreel,ctooibcoscneu,rrvraaentndicouennsoufsiunsaeclclruredetesidpoin(rsbautatonrwdyrepxeactrneeottrio,lnismc,ihtaaenudgte1osn)oiemnviagclautna,etrivoonusofsfyrs,tesminac,tievyietsy, handling, presence of clonic, tonic, stereotypical, or unusual behavior. posture, response tc O. Ophthalmological Evaluations cwwoenordeuoecpxtheatdmhiaunlnemdodelrbosyguifcboadclualeedxialllmiuigmnhitinitanitgoainofnsteawrnemdryedirncidoianrsdeicustctohepadhdtbbhyaeleamnovpestrceoordpiuyn.caerydTohpehtehxaalmmionlaotgiiosnts. wBooret.h eyes Solution. with a 19 tropicamde I~ smOuanbicnthsersttoudndiaycyrt-oax1si,crpiertcyioearinvtdeodtfhsoerrleeetc-htmioosnnttuahdnyr.degcOronovuetpreiysntegvd,aaltyhuea8t7ii,noiatnlislalsuerxvaimviinnagtiraotns wdaessigpneartfeodrmfoerdtohne all were examined again. P. Neurotoxicity Evaluations | 1. Sensory Motor Function Evaluation | | { waPhrsiisloeersttsohmeetneatsnstisomufablrsetwsaapnoscneisnaedsamtisontiaasnptdprararotdaicaohrnieatnaon.udcTdhhu,erssihneagrawpsseaeeuskdsimt1eo3nrotyfsswtteeismrtuelsuucsb,ostnaadnnducectaatidlmepidniinscthrwaetiroens,ade. ppeerrggrroouupp ddeessiiggnnaatteedd ffoorr sruebccohvreornyifcrtoomxitchietycofnrtormoltahendlohwi-gdho-sceosaengdrmouipds-,doasnedogonrnotuthphese.1100aanniimmaalls tfFhooerrecm-eotagonaurdgahec)it.nidvPilutipymibclhglarrmiypbcesortnsrset(nrgSitechcitwoienornwe2a.msbemealesoauwsr)uerdbeebdcyaiuamsmseetrdtaihiaentdgeaalruykgpeenededrvriocieorem(moCiohnavtwirihnliglcothnhetDhrieagtistralom acaospnspseatsrrsaimtceutnsitoswn,awstahlseoecaaxstpseeedsrsifemadceinaltifettaret&werdabosbeusanemraovwfialnrigegthothf wtrhaeesspgdoritorsueepc.tdeTedshiiengtnpoartecisaoecnnhceeyeo.r Faobrseanllceheofspsupillary of the animal 2. Motor Activity (FoMbAa)wwiansg ctohnedeuvcatleuda.tioRnatosfwgerirpesiznednigvitdhuaalnldysteesntseodryinfu1noctfi3o0n,naosmsiensaslmleynitdoenftmicoatlo,raavcttiovmitayd a Company Sanitized. Dossnot contain TSCA CBI `Oral Gavage StudsyuibnctRvaosn:ic Toriciy Dupont.9i78 ~ caoctuinvtietrybmaolnaintcoerdsa(cCroouslsbtohuermnonIintforrasreadnMdottiomre AocftdivaiytytoStyhsetefmu)l.lestGrexotuepntapnodsssiebxlew.erTehe infrared ``mnounmibteorrionfgmdoevveimceenetnsa.bleAs cmoenatsiunrueotuhsenmtoovfem2ednetpewnadsenctouvanrtieadbleass:1dmuoravteimoennotfrmeogvaredmleensstoafnd tdoutraaltisoens.sioEnacash wteestlsaesssfioorn6wsausc6ce0smsiivneut1e0s-miinnduutreatbiloonc,ksa.nd the results were expressed for the aPlrseosernecceorodfeddeffoelclaotiwoinngaenadcuhrimnoattoironacotnivtihteycsaesgseiboon.ards below the motor activity monitor were 3. Test Facility Positive Control Data Dataon the effects of aerylamide, casbary, d-amphetamine, and trimethyltin are described in ffoorurthseepianrdaitveidruealpsormtaksi.n"g juTdhgemseenptossiitnitvheecnoenturroolbeshtauvdiieosraalreatnhdenbeausriospoaftthroaliongiyngtecsetrst.ifTichaetidoanta saleseondioncnuemureonttoxtihcaitttyhseteuqdiueispmoefntthiasntdyppe.rocedures are capableofdetecting effects that may be. Q Clinical Pathology tAesctldinaiycsal48p/a4t9hoalnodgy93e/va9l4uiantimoanlwesasancdonfdeumcatleesd,ornesapelcrtaitvsedley.sigTnhaeteddayfobresfuobrcehcroolnlieccttiooxnicoifty on - `sTahmepsleeasnifomraltshewcelrienicfaalstpeadtohvoelrongiyghetva(laupaptrioonxitmhaetaenliym1a5l-s1w7ehroeurpsl)acaenddiunrimneetawbaoslicsolmleccatgeeds.from feraochm atnhiemoarlb.itaBllsoiondussoafmcplaecshfaonrimhaelmawthoilloegythaenadnicmlailnicw]aschuenmdiesrtrlyigmhetacsaurrbeomnednitosxiwdeereanceoslthleescitae.d tBhleooabddsoammipnlaelsvfeonracocaagvualoafteioancpharanaimmeatlerwshainlde ftlhueoarniidemaalnawlyassisunwdeerreccaorlbloenctdeidoaxtisdaecrainfeisctehefsrioa.m a`Andddiftrioozneanlabtl-o8o0dcCo.lSleecrtuemd frwoams tdhiescvaerndaedcawviathwoaust apnlaalcyesdisi,nhosweevreurm,tbubeec,aupsreocfeusrstehedrttoesstesruwme,re | not requiretod support experimental sacrifice from all surviving animals. Bfionndiengmsa.rrBoownesmmeaarrrsowwersmeesatrasinweedrweitprheWprairgehdta'tstshteaifninaalnd coverslipped, but analysis was not necesszry to support experimental fincings. a`Antdthpelaesnmdaoafnad3u-rmionentfhluroericdoevewreyrpeecroilolde,cstaedmpalneds afnoarlhyezmeadtforloogmyr,atcslidneiscialgncahteemdisftorryr,ecuorvinearlyy.sis, 1. Hematology and Coagulation - Blood samples were evaluated for quality by visual xamination prior to analysis. Complete. abnlaoloydzceoruonrtsd,etienrclmuidniendgfrreotimcumlioccryotsesc,opwiecreevdaeltueartimoinneodftohneabBlaoyoedrsmeAadrv.iaWr1i2g0hth-esmtaationleodgbylood asnmdeaervsalfuraotmioanllofanciemlallulsarwemroerpehxoalmogiyn.edBmliocorodscsompeiacrasl,lsytfaoirnecdonwfiitrhmnateiwonmeotfhayulteonmeabtleude,rewseulrtes prepared from cach animal undergoing a hematology evaluation but were not needed for ~ examination. Coagulation times were determined on a Sysmex CA-1000 Coagulation Analyzer. --e ---- =:e Company Sanitized. Docs not contain TSCA CBI U X0D-DuaOymOrCalaGgeveaY gteuSykiyninRReatiss Toxicity 0DDuuopomnoo478 -- The following hematology and coagulation parameters were determined: red blood cell count hemoglobin absolute reticulocyte count platelet count hematocrit `mean corpuscular volume white blood cell count differential white blood cell count `mmeeaann ccoorrppuussccuullaarr hheemmoogglloobbiinn concentration microscopic blood smear examination red cell distribution width pacrtoitvhartoemdbpianrttiailmethromboplastin time 2. Clinical Chemistry S7fl4eu7rourcimldienc-ilscieanlliecccahtliecvmheiesemltiercsyttraronydaelp.yazrearm.etPerlsaswmeareflduoertiedremsiwneedreondeateRromcihneedDiuasginnogs2tipchsi(lB2MpCH/mHeittearcahnid a The following clinical chemistry parameters were determined: aspartate aminotransferase: asolrabniitnoel admeihnyodtrroagnesnfearsaese alkaline phosphatase total bilirubin urea nitrogen creatinine cholesterol | triglycerides glucose total protein albumin globulin calcium inorganic phosphorus sodium potassium cflhuloorriiddee! 3. Urinalysis rAUeursitpnoeecmtavitoveellduym.UerUiarnniednCeahpcepomenisastrtiartnuyceenant(asqluwyazelerirte.y,sUecmroilio-nrqe,uapanrntodittecailtnairwvietayls)y wmmeeeraaessuumrreeeaddsouonrneaadRBaoancydheerevCaDlliiaungainttoeesdktviicAssutallalys,TM f(AlBduMvoCrai)nd/ceH-eisdetlOaecschmtiiovmee7e1tl7eecrctlr3io9ndi0ec.0a.lScUehrdeiimnmieesntftrlsyuoafrniradolemyszawelre.ruerUidrneitnseeproemsicmnioemldeanlusistiwynegwraaespevdhaielltu2earptmeHidnmeedtuesrianngdana microscopically. * Fluoride determination was snlyzed on EDTA plasma. -Y Company Sanitized. Doss not contain TSCA Cal C A"DaY yD Oral Gu . avageO . Sbdyn in. Ratsncg y estdyinke Dwuepowns o04s78s The following urinalysis parameters were determined: quality color clarity volume osmolality gplHucose ketone. bilirubin blood urobilinogen fluoride* mpiroctreoisncopic urine sediment examination R. Collection of Blood and Tissue (Three-Month Recover)y B90l-odoadywdaossicnogllpeecrtieoddfarnodmraenciomvaelrsy(p5erainoidmaalnsd/ssetxo/rgerdofuopr)pdoesssiigbnlaetaendalaysssiasteolfliptaerbelnetecdsomdpuroiunngdthe `and metabolites. Blood collection time points were: prior to dosing (test day -7), and days 0, 4, 10, 21, 35, 56,77, 90, orbi 94, tal 98, 105, sinus of 119, desig 133, nated 154, and animals 175. while Blood under (approximately 0.6 mL) was col light carbon dioxide anesthesia. lect On ed f the rom day the of `blood after d collection, osing. For blood was collected from each bleeding, blood was the col animals lected at `approximately approximately 2 hours (< 30 minutes) the same time of day. The `blood wa was then s collected in plastic tubes separated into plasma and containing EDTA while red blood cells. The sep on ice. The blood from each animal arated plasma samples were stored ~~ frozen at -80C and red blood cells were discarded. Afterthe final bleeding (day 175), all aeniemaclsawgeerde,euwtehiagnhateidz,end dbysctaorrbeodnatdi8o0xiCd.e aTshpheyxpihaatsimonicaonidn`eixcsapngruionaftiooJn anEd lNiverNandYfat --- be evaluated in the future and resulting data reported separately. S. Biochemical Measurements. Following 10, 93 (males) or 94 (females) daysoftest substance administration or afterthree- `months (test day 183 for males and females) of recovery, five rats from each group designated for ebxisoacnhgeumiincaatlioenv.alAuatteioanchwetrimeewpeoiignth,edthaenldivtehresnweeurteharneimzoevdedb,y CO; anesthesia and weighed, and then aportion was homogenized Trizamabase, (1 gram tissue/4 0.25 M sucrose, mL buffer) and5.4 mM in homogenization buffer EDTA, pH 7.4). Hepatic (50 mM Tris-HCI, peroxisomes were 50 mM prepared using differential centrifugation. The resulting peroxisomal pellets were resuspended in the homogenization buffer, a peroxisomal B-oxidation liquoted, activity. and The stored between -65 and -85C uniil analyzed for peroxisomal suspensions were diluted to a prote in `concentration of approximately 0.5 mg/mL. Peroxisomal p-oxidation activity was determined using [14Clpalmitoyl CoA as the substrate.(9 The protein content of the peroxisomes was determined before andafter analysis by the `using the post-assay protein concentrations. Biorad method.0" Final rate calculations were made ~~" Fivoridedetermination was analyzed from wiv with EDTA added. -Y Company Sanitzed. Doss not contain TSCA Cal (S-- 0-Day Ora-- l SyuibnctRvaotnsic Toriciy DuPont9478 pm T. Anatomic Pathology fAefmtaelreasp,prreosxpiemctaitveellyy)9,0gdraoyuspsofofex1p0omsaurleetaondthe10esftemsaulbestraatnscefr(toemsttdhaey0s, 913, 5a,n2d5,94anfdor males and f1e2m5amlge/rkagts/dfaryomgrtohuep0s awnedre12s5acmrigf/ikcge/ddaanydgnreocurpospswieedr.e Asdadcriitfiiocneadlagnrdounpescroofps1i0emdaalpepraonxdim1a0tely atdhdrieteimono,ntghrosaufpiserotfh5emlaalsteeaxnpdos5ufreema(tleestrdatasyf1r8o3m)atlol egvraoluupastederseicgonvaetreydoffortohxeipcatefifcecbtiso.chIenmical danaayly1s8i3s).were sacrificed and necropsied approximately three months after the lat exposure (test wRaetrsewpeerrefcourtmheadnaotniazleldmbaylecaarnbdfonemdaiolxeirdaetsa.nTeshtehefsoilalaownidnegxtsiasnsguueisnwateiroen.colGlreocstsedefxraomimnations ascucbicdhernotnailclyekxiplolsedu.re and 3-month recovery group rats sacrificed by design, orratsthat were. Digelsivteirve System essotpomhaacghus dujeojduenunmum ileum cecum rceocltounm salivary glands pancreas UriKniadrnyeSyysstem urinary bladder CarhdeiaovratscularSystem aorta HemasptloepeonieticSvstem th`myamnudisbular lymph node. bmoesneentmearrircowl*ymph node. `EndpoictruiitnaerSyygsltaendm tphayrraotihdyrgoliadngdlands adrenal glands RespiTnunagtsorySystem Nerbvroaiuns(Siynsctleudming cerebrum. tnroascehea spicnearlecboerlldu(m3, lmeveedlsu:llcpeorvnisc)al, laryax pharynx `smciidattihcornearcviec., mbar) Bonomarrowwascoleiedwit tefemur andserum MuscuslicolsektaellemtuaslcSleystem fesmtuerm/ukmnes joint ReprMoadulcetiveSystem testes eprpoisdtiadtyemides seminal vesicles Feomvaarliees umtaemrumsary gland Miscskeilnlaneous eyes (including optic gnreorsvseo)bservations g"Trhoeufpoalnldowtihneg3t-imssounetshwererceowveeriyghgerodufpsr:omlirvaetrs, skaicdrniefyisc,edadbryendaelsigglnanidnst,htehsyurobicdhr(owneiicgehxepdoasfutreer wfiexiagthito/nf)i,nbarlaibno,dsypwleeeing,htthaynmduso,rghaenarwt,eiogvhatr/ibers,aiuntewreuisg,hetpiradtiidoysmwiederse,caanlcdultaestteeds.. Organ a`Gprporsosprlieastieon(se.wgh.icflhuiwdearcecudmiualgantoisoend,artunfeflcerdopfusry,amnidssfionrgwahniacthommiiccrpoasrctso)piwcereexagmeinneartailolyn nwoats not collected. Gross lesions for which a microscopic diagnosis would not be additive -- % `Company Sanitized. Does not contain TSCA CBI (O"9M-Day Oral Gavage Stdcy iniRacs Tosicry DuPont9478 re | (e.g, osteoarthritis, pododermatitis, I~ of the teeth, toe, tail, or pinna) were chronic dermatitisofthe saved but were generally tai, not urinary calculi, and deformity processed for microscopic Testes, epididymides, and eyes were fixed in Bouin's solution. All other tissues were fixed in 10% neutral buffered formalin. Processed tissues were embedded in paraffin, cut at a nominal thickness of S micrometers, stained with hematoxylin and eosin (H&E), and examined `microscopically. All collected tissues from 90-day exposure group control and 125 mg/kg/day rats, and all accidentally killed rats were processed and received a full histopathological examination. Liver and kidneys were processed from 1, 5, and 25 mg/kg/day 90-day exposure group andfromall 3month recovery group male and female rats. In addition, thymus, thyroid gland, and nose from 1, 5, and 25 mg/kg/day subchronic exposure group and all 3-month recovery group male rats were: processed and examined microscopically. ~ ~ --- Company Sanitized. Doss not contain TSCA Cal C 50O.R rDGavaagY eySy: inRas 7c DuPone7s ~ U. Statistical Analyses `Except for Bartlett's test (p < 0.005), significance was judged at p < 0.05. Separate analyses `were performed on the data for each sex. [-- Prliminry Test Tsiognrien n testioot |Isfgpmirneelanitminary Baty wig vie Teor kof end Sow efqpeue FelmsapreaTorpe |piirvmiize c:omspasr o FFooooddECofncsiuennpesyion Tense ew " LOrOgnadnuWieoinght Shhoapmiorog-Wei"nlkceiasndtfor|| pvOeriencenaer-iwaanyceafneaflolyllslioswoefd with | Kferoulsslkoawle-dWwailtlhisDtuesnt"s || Motor Activiy Levene's efnlor Repeatedmeasures |Sequential pplication o Step ah | fnoa loblfyvy aocroawnnrs eaeessd |oefnhde eJsontcas Terps FocooSepnagyin Bhaotmeos: gneonfrveariiatncyes|YeSeeay"aollyleodf wit | thigegedwiahliDons Teves ior Clinica Pathology ity.eh fr ||Ovnea-nwacyeanafloylslioswoedf vith| Klrouswkeald-WwailtlhisDuteasnt'" |~ Sarl a apie: DumettstesTM + |test IncOibdseenrcveatofioCnlsinical Icidenceof wd None CochranArmitage estforrnd- | IncOidlencseoef nFOB TiDdeesnccreispiovfeGrPoasspaenrds Microssopic Lesions + Pasiipriwfiisceacno.mparison adsociatedpreliminaryetswer onlyconductedi hetetfo nckof wendwas bth wSthwaedp(DiurpWielokTatmetbawnaesDoutnseig)ni,ficant but Levene' est vas significa, a robust version ofDuet est 4 pTWoeerhnsfeetolndrfaamyehdieannrvddiibetvlhicodhcuaokatlrb(void1bal0siel-ermerudiv.bnaiFutnodtioearnEaevPx.aaOsmCprHlee)c,woraifdsbuisasebdoeainsnrgweaJpse:sarteephdoa-rnmteedaosru.tr<ea0.if1na,cvt0oa.rl0s5.,waslcuulastdionosrwaenrycpuelraftorimoends IBfontfheerirnocniidecncoecwiaosnnovtassigenidfi.cant, but a significant lackofft occurred, then Fisher's Exact testTM with a ~ e-- e -------- =ee-- s ----ir-- reeeee] eiecs Company Sanitzed. DossnotconTtSaCAiCnBI A 50-Day Oral GavaY ge Say in Raits oxic --~ RESULTS AND DISCUSSION DuPont9478 ANALYTICAL EVALUATIONS Dosing suspensions for this study were prepared at the beginning of the study as large volume `mixes to be used either fo3r or 4 daysofdosing. Samples con the concentrations of 0, 02, 1.0, 5.0, and 25.0 mg/mL. were collected at the initiation ofthe day study (test day 6 for large volume/3-4 day mix). These samples were analyzed to determine. `shaommeogperneepiatrya/tcioonnceatnttrhaet0i.o2nmvegr/ifmiLcatlieovnelaonndly5-wheoruercroololemctteedmpoenrattesutredasytab0i,liatfyt.erS7admapylsesoffrom the. refrigeration. These samples were analyzed to determine re-dispersion/concentration verification and refrigerated stability along with 5-hour room temperature stability. The refrigerated redispersion/concentration verification and stability for the other levels had been established during the mixing/stabilty study foar previous study. These data indicated that the test substance was. homogeneously mixed, could be re-dispersed after reffigeration to the expected concentration, and was stable in the vehicle for 5 hours afer refrigeration. On test days 42 and 45 (3-4 day mix), concentration verification samples for all levels were collected. Results from analysis of the dosing suspensions collected near the mid-point ofthe study (ist day 42) for concentration verification indicated that test substance was marginally at the targeted concentration (+ 20%of nominal). In order to investigate these results, a new large volume preparation of the dosing suspensions was made and sampled on test day 45. The results for these samples were lower than expected (range: -33.4% 10 66.0%of nominal) indicating a sampling problem. Investigation of the study records showed that the correct amount of test material was contained in the preparations but that a possible technicianerror had occurred with the re-dispersing and sampling ofthetestmaterial o the analytical group. Du to the length of time needed for evaluation of the samples, the preparations had already been dosed to the animals and further sampling could not be done to define the problem with the sampling of this mix. Therefore, due to the unexpected analytical results observed on test dy 45, the following study changeswere implemented: 1) on test day 49 of the study, the dosing suspension preparation was. changed to smal volume mix to be used for 1 day of dosing and concentration verification samples for all levels werecollectedon test days 48 (notdosedto animals), 52, 56, 58, 65, and 91 (small volume] day mix); and 2) on test day 63 and 73 large volume mixes (3-4 day) vere prepared and sampleswerecollected from all levels for evaluation of the mixing and sampling for the study before test day 45. These preparations were not used for dosing the animals A. Test Substance Stability Samplesoftest substance wereanalyzednear the beginning and the end of the study. These analyses indicated that the test substance was stable over the course of the study. The average percent of active ingredient was 99.1% 0.81 and 101.8% 2.9forthe samples analyzed on February 15, 2002, and May 30, 2002, respectively. (-------- reported by = --- Company Sanitized. Does not contain TSCA C8 (ccc, 0-Day Oral Gavage Sul in Rats DuPont9478 -~ the sponsor to have 99.2% active ingredient. The differences in values betwee the sponsor reported purity and the experimental data represent analytical variability. B. Chromatography CORY) ox th GC column as resolved pk with eenton ime of `approximately 3.5 minutes. The internal standard eluted from the GCcolumn as a resolved peak. witha retention time of approximately 3.9 minutes: Representative GC chromatogeams are shown in Appendix A, Figures 2(a -). Test substance was not detected in thOe mg/mL control. C. Homogeneity and Stability Samples Analytical results from dosing suspensions collected on test day -6andtest da0y and analyzed for homogeneity and/or and Summary Table 1. concentration verification and stability are shown in Appendix A, Table I `The and following table summarizes stability analyses. the results for all homogeneity and/or concentration verification TestDay Nominal Measured TMB Mean (IMB) CV' Stabiliy" Sample Type mg/mL mg/mL. %Nominal __(%) _% Nominal Test Day 6 -- Homogeneity 0 ND -- 02 0.163,0164,0.161 LS --- -- 1 85 10 0803,0857,080 850 5 818 50 455480461 9.0 3 82.8 Test Day 0 2 19.9%,219,22.9 86.4 7 872 Stability 7Day Refrigerated ~~ 0 ND* -- - -- = Memrestsfor thesnlysis0of2thetopCT),m0id.d1l6e1M,)0,.a1n7d3bio 835 (3)sples. 5 790 < CSVu.mp=eCs heold ehiooesfcVaanraoitoontemper. && DDuepnliecsencoen-eadaeytsecsto.ftecipalsimplesupports heoriginalres and arenoteoried. Mean el for temasofdpc concent verification sles. m`Tihxeeddatian ftohresvaemhipclleesactoallllelcetveedlosn(Ct.esVt.'dsa=y -16,i5n,d3icaatneds7t,hraetstpheecttievsetlsy)u.bsTtahnecetewstassuhbosmtaongceenewoaussalty the targeted `when held 5 concentration in the samples hours at room temperature. (+ 18.5%of nominal) and was stable in the vehicle t`Thheetdesattasufbosrt0a.n2cemgwa/smLhosmaomgpelneecooulslleyctreed-osnustpeestnddeadyi0n atfhteerve7hidcalyes(oCf.Vr.efr=ig5e)r.atTihoneitnedsitcsautbessttahnacte ~ wreafsriagtertahteedtafrgoert7eddacyosncfeonltlroawteidonby(+51h6o.u5r%s oatfrnoomoimnatelm)paernadtustraeb.leTihneth5e-hvoeuhricslaemwphleenanhaellydzed at - Company Sanitized. Dossnot contain TSCA GBI (D-- ayOralGavage StSuuibncdRhartyosnc Toriciy DuPont9478 Lo 79.0% of nominal appeared to be lower than expected but this can be attributed to sampling and. analytical variability and not stability of the test material in the vehicle. All other concentrations in the study had been shown to be homogeneously mixed and stable in the vehicleafter 7 days of refrigeration followed by 5 hours at 100m temperature in the `mixing/stability study." The following table from this study is included. TestDay Nominal Measured TMB Mean (IMB) CV. Stability" Sample Type mg/ml. mg/ml % Nominal __ (%) __% Nominal Test Day 4 Homogeneity 0 ND -- --- 10 0.944,0.884,0.836" 88.8 6 85.4 50 443,437,472 902 4 950 235 2227242 920 5 96.0 Test Day 11 Stability 7 Day Refrigerated' 100 0900,N0D86*4,0859 87--.4 - -- 3 904 50 446,444 890 0 8428 25 242,239 964 1 sat = MSamcplresehetldfohrthuesslrosrsoefptheertaore(.1,idle(Vandbao 8)samples d MDeenaontreeosnioefdlesstea.ys ported. DuMMeepaalnnirnesullcttoooncffednlturaantpailoeynsveees.srfceeupsmotrpitloenndgsxafcmperlpoefshmoearononryiegadiun)peldxiicceetpdteosptpshees.a1m.0 pm Olrewiinc)/ hanewavalesysl i(lsohwwmdaasuge. eotnwoeeayrl)ihqunotecxpoercted doe0 icuot mrsnoreported. So Company Saniized. Does not contain TSCA CBI S 90-Dayo Orral Goau vage So ty in Rm ats OmpeSeiRe DwuPoons w047s8 ~ D. Concentration Verification Samples || Aannadlyatniaclaylzerdesfuolrtscofnrcoemntdroastiinognsvuesrpiefincsaitoinosnparreepsarheodwtnesitn Adpaypsen4d2,ix45A,,4T8a,b5l2e, I5l6a,n5d8,Su65m,maanrdy91 Table 1. | [ lhe folE lowing E table summarizesprtehpearreastuilotnssffoorrcotnheceanbtorvateitoenstvedraiyfsic4a2tiaonndan4a5ly(s3e/s4 were dosed to the animals. of th -day e. mix), that Preparation Day. Nominal natal Measured" mg/mL. Averge % Nominal CV __% TetDa4y2 0. 10 016,069 07490776 SLs 763 6 3 25500 3198.47,139.01 1 78 m2 1 1 TeswDayas 02 10 00.607666,,00.605863 315 666 13 2 25500 283240,,82631 452 340 4 3 =b MaeMliaeqnunotrreeessruurlloDtturpolofifntedstadpmhpileensooiplrtecieragvietnoearlleadsnw:aaemlrpyesliiwsngnlfdoddumpltihCceVaot.reigceilnaeslltaliiseedodfstvhpeeery.glaOaopmiren.aaoflmytsoisyswas lower tha expected duet --_~ TvRheeresirufeliftcosartfei,ronotmoinaidnnivacelasyttseiidgsatothfeattthhteeessdteosrsueisbnusglttassnu,csaepenwneaswsiolmnaasrrgcgeoilvnlaoellclutyemdaecopcnreeptpteasatrbaldteaiy(o-n422(33.f/7o4r%-odcfaoynncmoeimnxti)rnaaotlfi)o.tnhe doowseirngthsaunspeexnpseicotnesdw(arsanmgea:de-3a3n.d4%satmop~l6e6d.o0n%toefstnaomyin4a5.l)Tbhaeserdesoulntsprfeovritohuessley asnaamlpylzeesdwere samples for the study. Atshduedsipsteainmospnilaoilnnswg(of3ro-kr4 twdhaaeysamntiahlxeyentsid)coaonlnegrttoeoustpi.ndvaey`sTsthii6gs3atiaennvwdohle7vt3ehdteorthbteehpeurrseeepsdaurolanstlifyoonfrooftretasnwadolayylsai4rs5gteowvevoreleruiufmnyeiqduoeseto mnoitxidnogseadndtostahmeplaniinmgaplsr.oceOdnurteesstodfatyh4e9latrhgeedvoosleusmuespdeonsseipornespawrearteiopnrse.paTrheedsdeaisluyspfeonrstihoetnhsewere remainder of the study. 4 -- 7 ~ Company Sanitizod. Does not contain TSCA CBI || --9o0-mDaoymOrOalmGaavgagee bStiSdyubkicnteRraossnic Tosiciy DDuwPeonwto.s94n7s8 -- ic following table summaarmipzleesprtehpearreastuilotnssffoorrctohnecetnetstradtaiyosn4v8er(infioctadtioosnedantaolyasneismaolfs)t,heand 52, 56, 58, 65,and 91 (1-day mixes) that were dosed to the animals. PrDepaaryation Nmogm/imnlal Memags/umrLed %ANvoemriagneal CV __% TestDa48y 02 10 0.0816957,,00.291498 1040 907 7 6 50 250 239139,,32950 783 888 1 2 TestDay 52 02 10 00:.187445,,00.81985 895 870 a 4 25500 48252124136 98186 41 Test Day 56 02 10 00.916647,,00..915809 8959.07 91 25500 42481,423114 887.24 42 TestDay58 02 10 00..91475,4,00913570 810 94.1 10 1 50 250 422458,42.2117 86.5 892 5 1 -- Test Day 65 02 10 50 00.185392,,00185980 75 865 4 5 432,440 872 1 250 TestDay91 02 208,205 826 0.162,0.165 820 1 1 5100 0.3769063, .098063 788162 1 `+b DSuupslpiecnastieonss anotmdpops2ele5rd0eetvoesalnwimrales.ana199lC,.1yV8.7czaeeulded1.ver7if2yifortof4mire, Mean resultofthe original analysis and duplicate reanalysis ofthe original sample. coBfoencfcoaeuunrstersaaotmfipoltnheeso,rnereesssuutlstdsfaryfor4mo8mt(etsnhtoetdsdaeoyasn4ea5dl,tyssoeasamnpiilnmedasilcswa)et,erd5e2tc,hoa5lt6l,etch5tee,ddo6fs5ri,onamgntsdhues91pd.eanisWliyiotmnhisxtwehesertceoxacvtoeprtthiiefoyn tvleaavrseglemtwaeradgscionmnaaclrelgnyitnaracalctleiypotnaascbc(leept2aat0b7l%e8.oaf3t %n7o7om.ifn5na%olom)if.nanloO.mnintOaelns.ttdeaOstynd4at8e,ystt6dh5e,ayrte9hse1u,rltetsfhuolertretfshouerl5tt.hf0eorm0t.gh2/0emmLg/lmevLe.l `5n0omimngal/,mrLesapnedcttihveel2y5..0 mg/mL levels were marginally acceptable at 78.6% and 77.20% of --~ -Y Company Sanitized. Doesnotcontain TSCA C81 O Z0D-oDOayY uOGrealaG. paveaSgeu. Sdtvuiynin. RRetss cy 0DDuuPmonst0a47s8 -- BBeasceodncolnudtheedstthaattistthiecsd(osmienagns%uspoefnnsoimoinnsaclo)nftoarinaleldstahmeptlaersgeatneadlayzmeodunfotrthOedRaily mixing, it can T5 he following tatbhleepsehrioowdsftrhoemmteeastnd%ayof48no(nmoitnadlosfeodrtlolaanniamlaylzse)dusnalmptlheeseantdeafocrhtchoencsteundtyr.ation forthe daily preparations based on this average for and the average of the ll the levels analyzed. mean % of nominal, with the SD, and the CV StaNtoismtiicnsaflor all Samples AnalyzeMdeafonr Small Volume Mix (1-day) mg/mL 0 %po Nominal 020 872 10 892 50 836 | 2s Mean: 886636 sD 23 --_-- 3% Ovenritfeisctatdiaoyn 6of3 mainxdi7n3g,adnodsesapmrpeplairnagtipornosc(e3-d4udraoeynfslatrhgeelvarogleumveo)lwuemreedporseepparreepdarbatuitouns.edTohnelsye for suspensions were not dosed to the animals. = pTrheepafraotliloonwsi.ng table summarizes the results for concentration verification analysis for these Preparation Nominal Day mg/mL Measured mg/mL Aversge CV. % Nominal __% | TestDay63 02 0.190,0.192 955 1 10 50 0.784,0.792 788 412,408 820 1 1 250 230,214 8838 5 TestDay73 . 02 10 0.176,0.155 0.980,1.03 8238 1010 9 4 Dolssamplesp2r5l5ev00elwer mye24C53V73.,,e4264c04 gveyS9n9o15r86e 04 ofme 3 `sWuistphentshieoenxscewpetrieonatotfheontearsgaemtpeldec,onrceesunlttrsatfiroonmst(h=e2se0a%naolfysneosmiinnadli)c.ateOdnthtaetsttdheaydo6s3i,ntghe result fporreptahreat1i.o0nmsgw/emreLdloesveeldwtaosthmearagniinmaalllsybauctctehpetarbelsuelatts 7w8e.r8e%usoefdnoamsisntaalt.istiNceailtdhaetraofaltohnegsewith the trheastultthsefdroosmintghesupsrepveinosuisolnysdcoosnetdailnaerdgethveotlaurmgeetperdeapamroautnitonosf(teesstt dsuabysst6an,ce42b,efaonrde4t5es)ttdasyh4o5w - `Company Sanitized. Does notcontain TSCA C81 e C0-DO ae y Ora. l Gara. geSl. yinRRaets Toric Duwpoonmta9n4s78 ~ and that group. the results for that day were due to technician error while samplingfor the Analytical Bzazseed voonltuhmeos)taitticstaincsbe(mceoanncl%udoefdntohmaitntahle)dfoosrianlgl ssuasmppelnessioannsalcyoznetdaifnoerdat3h-e4t-adragyetperdepaamroatuinotnof eunatcihlr cteosntcednr atyra45t.ion"Tahned ftohleloawvienrgtahtgeaebploeefristohhdeowmfsreoatmnhet%hmeoeiafninntio%amliosnfaamlnp,olmwiiinntgahl(tthefseotrSdaDla,lyaa-nn6ad)ltyfhzoeredtChsVeamsbptalusedeysdaotn tthhiast awveerreagneotfdorosaeldthteo laenvielmslsanbaultyzperde.paIrnecdloundleyd taoreevtahleutawteo tphreepmairxaitinognasn(dtesstamdpalyin6g3 parnodce7s3s). The table includes results (x) with test day 45 and (b) excluding test day 45. Statistics for Nominal all Samples Analyzed for Large Volume Mean Mix (34-day) mg/mL. % Nominal @0 -- 020 10 758 sL5 50 25 780 764 --~ Mean: 79 SD 26 | cv 3% | 0) -- | 020 10 853 83 50 25 862 0 Mean: 859 sp 20.8 E cv E 1% TtahhnaedtatshtCaetVissatomifcpsl1ef%os.rwtAehlretealhatortugghehevotthlaerugmsetetatedidsotcsioecnspcbreeanpstareradattoiiononanslshwaliavtrihgnegthvaeomleexucamlenusp%irooenpfaornfaottmihioenntsaelsatr8ed5am.ya9r4%g45i.ni0an.ld8li.ycate aschcoeupltdanbolte bweitchonthseidienrceldusaisonpaorftotfetsthdeaydo4s5e(v7er7i.f9i%caotifonnosmainmapll)e,stfhoerttehte sctauyd4y5ansdamsphloeuladnableysis sepurxbocsbltluaednmec;de2fw)raotsmheptrshetesusedenytstnaaotttieseatbicochsokbdeodcsoaisunesgepl:reev1pe)laprfraoetrvioitnohuessphreaeenptaalsryahstoiiswoson,ntahlnaadrgt3eh)evscouolbrursmeeceqtumeainmtxoleuys,nittnohdafittceianstetd no --~ tshaemptelsitnmgataenrdiaalnawlayszidnigsptehrestedwoprloapregerlvyoalnudmaetptrheepatraartgieotnesd acfotnecrentterstataioyns4.5 (test days 63 and 73), -Y Es `Company Sanitized. Does not contain TSCA Cal C X9D0y.DOany iOrGaR lrGaagvaegSeuSda, dy.yi.innR.Raatss 0 7: DuDurpeonmto94s7s8 - Test substance was not found in the 0 mg/mL. samples. E. Discussionof Results | 0Bastheedaonnimtahles,stiatticsatnicsbe(mceoanncl%udoefd ntohamtintahel)dfoosrianlglssuasmppenlseisoentss caonnatlayizneedd fmoarrtghienasltluydythaentdardgoesteedd amount (& 20% of nominal)o amount (+ 20% of nominal)o iitthh tteesstt ddaayy 4455 eixncclluuddeedd.anTdhethefotlalrogweitnegd atavbelreasgehoowfstthheemmeeaann%%ofofnonmoimnianla,lwfiotrhatllheanSaDl,yzaenddstahmepCleVsbaatseeadchoncotnhciesnatvreartaigoen faonrdatlhethe levels analyzed (a) including test day 45 and (b) excluding test day 45. NStoatmiistnicaslfor all Samples AnalyzMeedaannd Dosed to Animals mg/mL. % Nominal @0 -- 020 10 774 841 50 25 799 783 MeaSnD: 799 29 =~ oa 0) -- 020 10 83.1 865 520 849 849 Mean: 848 SD il4 ov 2% F. Analytical Conclusion tsRtheaesruta,ldtadstittfihroeonaimlnittlhiaeartgaienoanvloyolsfiutsmheoefdtsohtsuedey,prfeopratrhaetidoaniloyndotesset pdraeypsaor6a3itiaonndss:7ap3fet(nensoeitsodtnosdspaerydio4tr5ot,toahentdhaeniinsmctaluludsdy)ing sitnadbilceatiendtthheatvethhieclteestunsduebrsttahnecceowndaistihoonmsoogftenheeoustsuldyy.miFxuerdt,heartmtohreet,artgheestetdudcyornceecnotrrdastiionndsicaantde `tThaatketnhetocgoertrheecrt,atmhoesuentdaotfatpeositnstutbostaapnrcoebwleaisncnoinqtauienetdo itnhethaenatleysttidcaalys4a5mpdloessintghastuswpeernesicoonlsl.ected on test day 45. ~ . _-- -- Company Saniized. Doss not contain TSCA CBI U 90-r DayOrale Gavac gey Study in Re ats Toxicity ~~ IN-LIFE TOXICOLOGY Dwuopomnta. n67s8 A. Dosage Data (Tables 2-3, Appendix B) | ipRraeettpsaawrieergdeaatndcocosnecdeanwtidrtoahstiisnougnsspveonofsli0,oen0s.2oo,fS1,m5i, kangdb25ymgw/emiLgh,.dTehsq0i.u5tgoa%dneyalqeiuoveGedorustEhmeetRthayrlgRceeteldYludloovsee,of rat, and Subsiequeentsly rtoouenadcehd rat by waacsomcpaluctuelratperdo,gbraasme,d on the most recent body weight for cach | fogTrrhoteuhpre,a2n15g.e2mo-gf2/.m8kemea/Lndfaodyragirtlohyuedpo|,smaeg/nvkodgl/u1dmaeys2gaTrdo-mluipfn,2iosr1t.t82e-hr3e.e01dm2t5oLmmafglo/erkrtga/htdseaSwyamgsrgo/1uk.p2g.-/2d.Ta9hymegLrroaufnpogr,eto1h.fe2m.3c.eo0namtnrLol. | | dailydose volumes forthe 1 mg/kg/day adminis group, tered 0.9-L. tofemalerats 5mLfor the 5 was 0.9-1.5mL for mg/kg/day group, thecontrol group, 0.9-1.6mLfor the 0.9.1.5 mL. 25 mg/kg/day group, and 0.9-1.6mifor the 125 mg/kg/day group. B. M(TeaabnleBso4-d7y,WFeiigugrhetss 1a-n2d, ABpopdeynWdeiixgCh)t Gains --~ 0ohr1e4br0oedaywnedwre5ei1gn%hot,tgreaetsispnueocbtbsistveaenrlcvyee,:doeiclncaatuenrdy,roeitfdnotxhtiehcemomaleloaeginocrabfloedsmiyaglnweiefdiiocgashnetggaarlioenurpoasft.itohneSsi2gi5nniamfniecdaann1t2b5doemdcgyr/ewkmegei/ngdthasty im1na2c5lreemaggs/reoksugip/nsdmadeyuarminanlbgeotdghyerow6ue3pi-g7dh0utrtiegnsagtidntahweye7irn-et1eo4rbvdasale,yrvwienhtdielrfveoalra.tshiegFnoirfaitnchdaen2t459i-nm5cg6r/edkasage/ydoiacnytceumrrvaralele,d gsfriogornutiphfsie,canOtn mcteahslotewdsabiyenc7ta7h,uesa1eiol2f5anmtiegms/atklssgu/bndsattyahnegcrheoi-ugiphn-dhduaocdseeda maslaitgleneriafatinicodannsftetimonacthlreeadsteoeestihen.gmrOeonaucpnsebwpoeldrayceewpdelioagnchetgdrgooanuinngdrfoocruhtnohdwe, rh8eo4cw-oe9v1veertrey,stpwedaraisyodsi,inmtsiearltvaairlts.tocaTclohlneytrsooivlgenraiacflrilocsa(sn0t-a9li1lncddroaesyaesielnsetveierlnvsa.mle)aOmnveebarotndhbyeocwdoeyuirgwsheetiogghfatitnhgeaoicntchuorrfemreea-dlmfoeonrrtahtths,e f1o2r5tmheg/1k2g5/dmagy/kmga/ldeaygrmouapl.e gOrvoeurpalwlamsesaingnbifoidcyanwtelyigihntcrgeaaisnedfo3r6t%hectohmrpeae-rmeodnttohcroenctorv]e.ry period iiDnnutcrerrievnaagslet(hi0ne-9m717e-ad8any4sbt)o,edstyhdewaeymieignahtntergbvaaoild,nyffweoemlialglohewtsiniggnatithnheeifro1rp2fl5eammcagelm/eeksngt/wdaoasnysgdiromosiuelnagdrftcoohuocpwo.nhtardFoloarascitrghoneisofsvielcralanltdlose mglerevoaeulnsp.bdouAdriysniwggentiihgfehict1a5ngt4a-ii1nn6ca1rlestaoessoetcidcnaasymieionantanelrvlbayol.doyccSwutearitrigeshdttiocgvaaleliryntsohicegcntuihrfrrieceeadn-tmfooirnnttchhreera2es5ecsomvagen/rdkygdp/eedcrariyaoadfsefemosarlftenh.e -- w1e2s5 smigm/iklga/rdtaoycofnetmraollefgorrotuhpe;ohvoewraelvlerre,ctohveermyeainntebrvoadl.y weight gin fo ll female dose groups -_-- Company Sanitized. Doss not contain TSCA C81 X0D-oDOaynlOrGaleGvaavgaegSewddyySiuibnncRkiaratosnsic Toxicity 0Doupwoonwts04s78s --_ C. (FToaobdleCso8n-s1u1m,pAtpipoennadnidxFDo)od Efficiency oTbhseerrevweedrien naonytoesfttshuebsmtaalnceeo-rrefleatmeadl,etdooxsiceoglrooguipcsa.llyFosritgnhiefi9ca8n-t1a0l5tearnadtio1n0s5-in11f2otoedstcodnasyumption Tinotweerrvaflso,odmacloenssuinmptthieo1n2o5fm9g/akngd/d1a0y%,thrreesepemcotinvtehly.recOovveerrayllgr(o9u1p-1h8a2ddsatyatiisnttiecravlally),sihgonwiefivcearn,t and food consumption control. for the 125 mg/kg/day male three-month recovery group was similar to e`Tfhfeirceiewnecryeobnsoertevsetdsiunbsatnaynocef-trheleamtaedl,etoorxifceomloagliecdaolslyesgirgoniufpisc.anMtaalleterraattsioinns tihnem1e2a5nmdga/iklgy/fdoaoyd c`ognrtourpolhaovdesrevtehreacloiunrcsiedoefntcheseosftsuidgyniefxicceapnttldyurhiingghetrheme6a3-n7d0aidlayyfionotderevfafliicniewnhciycchomsipganrifeidcatnotly 2l5owmegr/(k5g/9d%acyodmopsaergerdotuopcaolnstorohla)dmaeasingndiafiilcyanftoloydleofwfeircimeenacynwdaasilyobfsoeordveedf.fiMciaelnecsy oifn 4th2e% cduhroiwngonthetes6t3-d7a0y t7e7stfdoraythient1er2v5alm. g/Fkogl/ldoawyinmgaltehegrreopulpa,caemseingntifoifcpanetlllyetheidgchehrowmewainthdagirloyufnodod `emfefiacniednaciylywfaosodobesfefrivcieedncfyorftohrema84l-e9r1atdsawyaisntserivmaill.arFtoorctonhter0ol-,91whdialyesftourdtyhienotevrevraall,lhtohwreevee-rm,onth croenctorvoelrfyoirnttehreva1l2,5mmega/nkgd/aidlayyfmoaoldeegfrfoiucpi.ency was significantly increased 26% compared to --~ i Fduermianlgetrhaei6s3in-7t0heda1y25inmiegr/vkalg./dFaoylglroowuipnghtahdesriegnpilfaicceamnetlnytloofwpeerll(e6t0ed%)chmoewanwidtahilgyrfoouonddecffhiocwieoncny test day 77 for the 125 mg/kg/day female group, a significantly higher mean daily food efficiency || t`wraesatoebdsfeermvaeldefogrrtouhpes,77h-o8w4evdeary,iwneterrevasli.miOlvaerrtaollcomnteraoln. daDiulryifnogodtheefftihcrieeenc-imeosnftohrrteecsot-vseurbyst(atnecste, | defafyisci1e5n4cy-;16h1o)w,evfeemra,lfeosritnhethoeve1r2a5llmtgh/rkege/mdoanytghroruepcohvaedryaisnitgenrivfail,camnteainncrdeaaisley ifnomodeaefnfdiaciileyncyfood was similar to control. D. (CTlainbilceasl1O2b-s1e7r,vaAtpipoennsdainxdEM-oFr)tality oAbsteesrtvseudbsitnatnhcee.1r2e5lmagte/dk,go/xdiacyolmoagliecalalnyd sfiegmnaifliecadnotsiengcrroeuapsse.inItnhaedidnitciiodne,ncteheorfe swtarisataend itneccrtheawsaes in tooth clipping required for both males and females in the 125 mg/kgldaydose group. No test substance-related ophthalmological signsoftoxicity or effects on survival were observed. ~ EE Company Sanitized. Does not contain TSCA Cal O S 0-Dayo OraY u GavagO e St: dm inRatO s _ Toxu icityageSbyioRDuDe uepommge 94e7n8 ~~ E. In-Life Toxicology Conclusions || bUonddyerwetiheghctongdaiitni,ofnosoodfctohnissusmtpudtyi,ont,hefNooOdEeLffifcoireninc-yl,ifaentdocxliicnoilcoalgysipganrsamoeftteorxsic(ibtyo)dywawseight, || o2b5smegr/vekdg/idnamyafloer abnodthfmeamlaelse raantds afdemmianliesstbearesded1o25n tmhge/kign/cdraeya.sed incidence of striated teeth NEUROBEHAVIORAL TOXICOLOGY A. Sensory Function Evaluations 1. Forelimb Grip Strength (Table 18-19, Figures 3-4, Appendix G) f`Tehmearleewseardeminnoisttesetrseudbastnayndcoe-sraegleat-- ed effects on forelimb grip s tr e ngth in x the males or baseline e v a l u a t i on, sfienmcaeleasdmiinnitshter5atmigo/nkogf/tdhaeytgesrtoumaptheraidalsihganidfincoatntbleyemneirneitaisaetedd,fotrheislismtbatigsrtiipcasltrdeinfgftehr.enHceowweavserno,t atensyt sduobssatgaencoef rtehleatteedst. maTtheerriael.were no statistically significant differences for males administered 2. Hindlimb Grip Strength rm (Table 18-19, Figures 5-6, Appendix G) 7Therestwreenrgethnoortesittshuebsmtaanlcees-roerlfaetmedaleefsfeacdtsmionrissttaetriesdticaanlylydsoisgangifeicoafnt differences in hindliGmYb 3. (STeanbsloery20F-u2n1c,tiAopnpeOnbdsiexrvHat)ion There were no test `neurobebavioral pa substance rameters -related changes or in malesor females statistically administere significant differences d any dosage oA in B. Motor Activity (Tables 22-25, Figures 7-10, Appendices 1-7) . ifTnohtreermrveaallweesfrooerrtnfhoeemtbaeaslsteessluifbnoserteaavnnacyleu-darotesiloaantg,eedmoaefS flfeesctisn otnhR edu1rmagti/oknR go/fdmayovgreomDuepinhtnadortshnieguntmihbfiiercdran1ot0fl-ymmhoiivnguehimeeernts dbausrealtiinoeneovfalmuoavtieomne,nmtalceosmpinartehed t1,o5t,he25c,onatnrdol1v2a5lumeg./kDgu/rdianyggtrhoeufposurhtahd1s0i-gmniifniuctaentilnytehrivgahlerof the bdausrealtiinoenoefvamlouvateimone,nmtalceosmpianrtehde 5tomtgh/ekcgo/ndtaryolgvraoluupe.haDdusriignngiftihceanftilfythhi1g0h-emrinduutraetiinotnerovfal of the -YY T Company Sanitized. Does not contain TSCA Cal U X0D-yDOauyOlB rGaalvigavB eagSeudStyyi: innRRaatss 70 0 DDuupoonms9o478 --_ mnootvbeemeennitnictoiamtpead,retdhesteotshteaticsotnitcraloldivfafleuer.encHeoswweevreern,otstinecset administration of the substance related. test material had D2u5rmign/gktgh/edafiyftmha1l0e-smwinaustseiignntiefrivcaalntfloyrltohweer13c-owmepeakreevdaltuoatthieonc,ondturroaltivoanluoe.f mHoovweemveenrt,fsoirnce | durationofmovement was for the 25 mg/kg/day males similar to control for 125 was not considered to be mg/kg/males, test substance the statistically related. lower value || aDnudri2n5gmtgh/ekfgo/udratyhm1a0l-meisnuwtaesisnitgenrivfailcafnotrltyhheibgahseerltihneanevtahleuactointorno,lnvuamlubee.r oInf madodvietimoenn,tdsurfionrg1t,h5e, | fwiafsths1i0g-nimfiincuatnetliynhtiergvhaelrotrhanthtehbeacsoenltirnoelevvaalluuea.tioHno,wenvuemrb,ersionfcemoadvmeimneinsttrsatfioorn5omfgt/hkegt/edstay males `material had not been initiated, these statistical differences were not tet substance related. Tthoeta1l3n-uwmebekerevoaflmuaotvieomnewnetrse asnigdnitfhiecnanutmlybelrowoefrmfoorve2m5emngt/skdgu/rdianygmtahleefsifcthom1p0a-rmeidnuttoetihnetecrovnatlroolf vtahleusee.stHatoiwsteivcaelrd,ifsfienrceenncuesmbweerreofnomtocvoenmseindetrsedfotro1b2e5tmesgt/skugb/sdtaayncmealreelsatweda.s sNiummilbaerrtoofcontrol, `evmaolvueamteinotnswfaosrs1i2g5nimfigc/akngt/lydalyowmearlecsomdpuarrinegdtthoetfhoeurctohntr1o0l-mvianluuet.e iHnotewrevvaelrf,orsitnhece1t3h-ewteoetakl n12u5mbmegr/kogf/mdoavyemmaelnetsswwaassnostimciolnars1idetrheedctoonbtreotlesvtalsuueb,sttahencsetarteilsattiecda.lly lower value for Tmahteerriealw.ere no statistically significant differences for females administered any dosageofthe test C. Neurobehavioral ToxicityConclusions Under of the conditionsofthe study, the NOEL for `males and females, neurobehavioral parameters was the highest concentration tested. 125 mg/kg/day CLINICAL PATHOLOGY A. Hematology/Coagulation (Tables 26-29, Appendix K) `pTohienrtedwuerriengntoreaadtvmeernste. cThhanegfeosllinowhienmgatstoaltoigstiiccaplalyrasmigentiefriscainntmcahlaengoersfienmamleearnathseamtateiotlhoegritcime parameters were considered to be non-adverse. + aRneddfceolmlalmeasssdo(sreedd wceiltlhc1ou2n5t,mgh/ekmgo/gdlaoybi(nat,bhoetmhattoicmreitp)oiwnatss dmuirniinmgaltlreyadtmeecnrte,asveadriianblmeales wstaastisatsiscoalcisaitgendifwiictahncreegfeonremraalteiosn) o(fClriendiccaelllPsat(ihnoclroegayseTdexrettiTcaublloecyt1)e.s)Diencrmeaalseesd(srteadticsotlilcamlalyss I~ significant only at 125 mg/kg/day, test days 48 and 93) and females (statistically significant at |! -_-- Mm Comers, StsnTEOR CY... icy O 0-DaD y Oralw GavagO e Stm y in RO ats uageSud 0 yinRDDuua oPownot.s a9r47s8 --_ `temsetadnacye9ll4vonollyu)m.e (Ivnacrrieaabsleedsrtaettiisctuilcoalcystiegsnirfeiscualntceed).inHionwcreevaesre,d hriesdtocellolgidciasltlryi,btuthieorne wwiadsthnoand increase in extramedullary hematopoiesis. Red cell counts (males) and hematocrits (females) were minimally but statistically decreased | iinncrraetassdesosiendrewditchel2l5dimsgt/rkigb/utdiaoyn.wiTdhtehseancdhamnegaens were sometimes associated with cell volume (variable statistical minimal significance). iInn madadlietsiodno,smeidnwiimtahll2y5ionrcr1e2a5semdgc/hkagn/gdeasyaitnbroetdhcetlilmmeo-propihnotlsodguyri(nagcatnrtehaotcmyetnets.) were present i`nTdhiecaabteovmeincihmaanlgleysiinncrreeadsceedllrepdarcaemleltuemrosvweerr.e cHoonwseivdeerre,ddtuoebteo rtehleamtiednitomatrleantmaentto,ufartnhdee crleidancgelsls,mdaesys wpaerraemectoenrssi,dreerteidcu{loocbyeteiso,n-raeddvceerlsled.istArfitbeurtiaopnprwiodxtihm,ataenldy m9e0adnaycseollfrveoclouvmeery, | were similar to control group valuesofras previously dosed with 125 mg/kg/day. + tMeisntidmaayll9y3 iwnacsrecaosnesdimdeeraend tcoobrpeuspcouslsairblhyermeolgaltoedbitno tirnematamleenst,dobsutedwawistcho1n2si5dmegr/edkgt/odbaeynaotn- aaddvveerrssee befefcecatuss.e mAfiineirmaalppirnocxriemaasteesliyn9m0eadanyscoorfpurseccuovlearryh,emmeoaglnocboirnpuasrecunloatrahsesmoocigaltoebdiwnith I~ c1o2n5cemngt/rkagt/idoanys.were similar to control group values of ras previously dosed with cTohnesifdoelrleodwitnogbsetantoinst-iacdalvleyrssiegnbiefciacuanste cthhaenygweesrien umnerealnatceldintiocadlocsheeamnidsltorry opcacruarmreetderosnlwyerate three `months post dosing: + Minimally day 49. and transientlydecreased reticulocytes infemalesdosed with 25 mg/kg/day attest + Minimally increased basophils in females approximately 90 days of recovery. previously dosed with 125 mg/kg/day after ~ - -- -- a `Company Sanitized. Does notcontain TSCA CBI r 9ou-OODrnar il aOGnavayapgeeoSntdyyiinReaRtess wDuoPoonss478 --_ Clinical Red cell PmaatshsolpoagryamTeetxetrsTaabnlde 1 reticulocytes (expressed as a percentofcontrol group mean)* i Mies Females | Dossge(mghgday: 1 5 25 125 Test Day 1s as ns RBC 4gag 99% 98% 95% 93% oye 100% 91% 95% 91% 8H 98% 9% 9% 100% 102% 95% 93% B= - - 9% HGB gag 101% 100% 98% 96% = 0% 9% 99% 96% 91% . 904 100% 98% 98% 94% 102% 102% 95% 94% HOT gJuy 10E 0% 100E % 97% 1 96% "= iw 9%% 99% 96% 91% oes 101% 9% 08% 95% 101% 102% 9% 94% ARET gB gg =97% = 1% = 113% a 123% = o-oo 8% 9% as% 94% 394 92% 108% 112% 126% 9%% 110% 99% 125% Saisie sig8nificance di~ cated~ byS~ WTaiaedb10e5% - = - 0m I~ B. Clinical Chemistry (Tables 30-31, Appendix K) Tfhoelrloewwienrgestnatoisatdivcaelrlsyesicghnainfgiceasntincchlainngiecaslicnhmeemiasntcrlyinpiacraalmectheermsisitnrmypaalreaomretfeermsalweerraets.noTthe toxicologically significant (i. not adverse) or not related to exposure to test substance: + A1l2k5almign/ekpgho/sdpahyatttaessetdaacytiv4i8t.y wAattshmeineinmdaolfldyoasnidngtr(atnessitednatlyy9i3n)c,reaalskealdiinnempahloesspdhoatsaesdewith astcattiivsittiycawlalyssmigonrifeicsanit).mItniocrceolanstaerodalrsl,kaallitnheopuhgohsipthwaatsasseticllamninbiemdaulel(yi0nicnrdeuacsteidon(nboyt a ixetnhobi1o2t5imcgc/okmgp/doauyndhoardcbaonthbiencdrueeasteodliinvcreerawseeidgbhitlsiarayndprheissstuorleo.giIcnetvhiidsesntcuedyo,fmhaylpeesrtdroospehdy, aabccutttiivvniiottyyewwaavss cpiornoosdbifadbceelhroyelnddeustetcoatsboieesi.nnodnuT-chatedirovenfeorbrsyee,tbhieencttaheuissstessutmbuisdnyti,amniacnlecl.ryeIiannsccerdreeaadlsskeeaddliaanllekkaapllhiionneseppphhhaootssappshheaattaassee iPshonsopthaastsaosceiaatcetdivwiititehsawdveerresseefifemctitso.Alcfonatterrrolagproputpovaxliuemsai9nt0redaaltyysporefviroeucsolvyerdyo,sealdkawliitnhe 125 mg/kg/day. -YY Company Sanitized. Doesnot contain TSCA CBI ( 50.D-- ayOral GavageStySiubncRhartosnic Toxicity DuPon: 9478 + Cholesterol was mildly increased in females dosed with 25 or 125 mg/kg/day (variable statistical significance) at testdays49 and 94 (group means were 136% to 139%ofcontrol `group means). Although this change was likely due to treatment, mildly increased cholesterol does not result in adverse events. Therefore, this change was consideredtobe non-adverse. After approximately 90 days of recovery, cholesterol concentrations were similar to control `group values in females previously dosed with 125 mg/kg/day. + Triglycerides were mildly decreased in males dosed with 125 mg/kg/day attest days 48 and 93 (49 and 48% of control groupmeans,respectively). Mildly decreased triglycerides were considered to be related to treatment; however, mildly decreased triglycerides are not associated with adverse effects, and therefore were considered non-adverse. After approximately 90 days of recovery, triglyceride concentrations were similar to control group `values in males previously dosed with 125 mg/kg/day. + Total protein was mildly increased due to increased albumin in males and females dosed with 125 mg/kg/day at days 48/49 and 93/94. Mildly increased total protein and albumin concentrations were likely due to treatment, but were considered to be non-adverse because `ampiplrdoixnicmraetaeslesy i9n0tdhaeysse poafrraemceotveerrsy,arperontoetinascsoonccieantterdatwiiotnhsawdevreersseimeiflfeacrtts.o cAofntteorl group values in rats previously dosed with 125 mg/kg/day. | + Calcium was increased in females dosed with 125 mg/kg/day at test day 94. The increased calcium was consideredtobe secondary to increased albumin. Calcium exists in serum in ~~ two forms, either bound to albumin or unbound ("ionized" calcium). Ionized calcium is the `physiologically active form and is tightly regulated. Increases in albumin are necessarily associated with physiologically appropriate increased bound calcium, with resultant increased total calcium. However, ionized calcium is unaffected. Therefore, this change was considered to be non-adverse. After approximate9l0y days of recovery, calcium `concentrations weresimilarto control group values in rats previously dosed with 125 mg/kg/day. + Phosphorus was minimally increased in males dosed with 125 mg/kg/day at testday48 and 93, and at the end of recovery (test day 183). Increased phosphorus was possibly due to treatmenattestday48and 93, butwas likely to be unrelated to treatment attestday 183 (after three monthsofrecovery). Increased phosphorus is of toxicologic significance when it is associated with evidenceofdecreased glomerular filtration rate,but may also be affected by extrarenal factors. In this study, other indicators of glomerular filtration rate (urea nitrogen and creatinine) were uriaffected by treatment. Anatomic pathology changes included increased kidney weights associated with renal tubular hypertrophy; these changes were not `present after three months of recovery. However, these anatomic pathology changes are not expected to result in decreased glomerular filtration rates. Therefore, the minimally increased phosphorus was considered to be non-adverse. EE Company Sanitized. Doesnotcontain TSCA CBI e 50-D.ay Or.al Ga.vage.Stu. y in R.ats o., e oDuwpone.94n78 ~~ The following statistically significant considered to be non-adverse because changes in mean clinical chemistry they were unrelated to dose parameters were `monthspost.dosing: andlor `occurred only at three | + + DDeeccrreeaasseedd cbihloilreusbtienroiln imnamlaelsedsosdeodsewditwhit1hm2g5/mkgg//kdga/ydaayteasttedsatysday484a8nd 93 + + DIenccrreeaasseedduurreeaanniittrrooggeenniannmdalcreesatdionsiende recovery test day 183 winitmhal2e5smpgr/ekvgi/odusalyyadtotseestd day 93 with 125 mg/day at + Decreased cholesterol in males dosed with 1 mg/kg/day at test day 93 C. Urinalysis (Tables 32-33, Appendix K) . AMcloItmShpTolOueSgtCehOdPnIo0Etnarerdaaityame9Sn4Vt,a.lsieoaltmaietonefdehmcaahldaenlsgoehwsaedrvpeirnriseourfpifrtieycsiteehnnattniuonrtithnheeerfsuoarrmimnpielcetrseosstescv.oaplAuifactteeordbo,stehrevratitoesnt.s were || 9Soi3pg,enctihifiemcreaennstwectroheamnnagokeesadiuvnneemrqseueaincvohocaranlgienddseitivenirdumuriainlnaautlriyiosnniassl.ypaFroamrehteersr. tiTmhee-pfooilnltsowainndg fstoarttimhsatelirceeaslawletyrteesttoodafyew adverse. sis parameters were considered to be pon. --~ + uiUrhrieinrneeeavsvoeodlluwumameteecrwaacnosbnisenudcmurpeetaitsooendp.riniTmmhaarelyecisanudcsoreseoaefsdeidwniuctrrhiena1es2ep5drmoudgru/icnktegi/podnra,odyouracttctaenstbdeasye9c3o.ndIanrcyretoased dwdieesticegurhsmtsisinoaenndd.unrTdehenaerlsMetiuccbrhuoalsnacrgoehpsyipcceorFritrnerdloiapnthgeysd)ww.hiitchhanwaetroemciocnpsaitdteiroeldogtyo fbiendniioonnng-sioadftvheiirnsscserte(uasdseyaodKwiadsnneoty ahlitsetroaltoigoincscihnaontgheesrirnentahlepkairdanmeeyt)iersc(osnesriduIemnrcuerrdeetaaosnebidetrunoroginenn-e,apdsrveoerdruuscemt.ciAroefnattieinrntianhpeep,raoobrxsiaemndactveeeolrfy 90 d witha o1f2r5y emcgo/veksrgy/,dauyr.ine volumes were similar to conrol group values in ats previously dosed + ctDeoesnctsrdiedaaeysre9e3dd.w(0iThnheeesnkeoentd-oeacndreveceaorsnsecese.nwteArrfaetteilroinkaseplpwyresorexeciompnardteaerlsyyen9tio0tnimdnaaclyrseeasosdfeodrseucerodinweivtohl1u2me5sm,/sknggdayaeyseat e1o2n5cmegn/tkagt/idoanys.were similar to control group values in ats previousvleyrdyo,suerdinweitkhetone . --~ - `Company Sanitized. Does not contain TSCA C81 y - | l~ | | | | --- E I ovo e.. twToty wetetaotwRee Tn D. Plasma and Urine Fluoride (Tables 30-33, Appendix K) Plasma fluoride was increased in males dosed with 125 mg/kg/day, and in females dosed with 25 25 omgr/k1g2/5damyg)/.kg/Adfateyraatptperstoxdiamya9t3el/y9490(ndoatysstaotfisrtieccaolvleyrsyi,gnpilfaiscamnat in females dosed with fluoride concentrations were. simtioclonatrr ol concentrations for males and females previously dosed with 125 mg/kg/day. Urine fluoride day 93/94 (not was increased in males statistically significant and females dosed with in females dosed with 5 5, 25, and 125 mg/kg/day at test mg/kg/day). After`approximately 90 daysofrecovery, total urine fluoride amounts were approximately 3 times greater than cinonftermoallsesi.n males previously dosed with 125 `mg/kg/day, but only `minimally greater than controls Increased plasma and containing compound. urine The fplrueosreindceeionfdifclautoersideexpaofsteurre90todaaynsdomferteacboovleirsymoifndi2caftleuosrcioden-tinued `metabolism of the test substance. Clinical Pathology Text Table 2: Plasma fluoride (expressed as mean and as percentofcontrol group mean)* Parameter Sex TestDay im mv. p7a%3 viv XX PFLU (ug/ml) Males PFLU (ug/mL) Females 0 mglkelday wo 93 01 94 0.1 - 1 mefkg/day 0.1 5 mg/kg/day 0.1 25 mg/kg/day 0.1 WT e R 0% EwAn 01 100% 0.1 02 100% 200% 125 mg/kg/day da0e4 05 500% - Foe ws sw>D TamenLaosMwma e neeamme 2F0E2 UFLU (ug) Females 94 6 - - - 100% 57 14.1 88 702.6 TR B. Clea ahologyConclusions 12% doseviRI cscs vy 153 mo. ie210 In conclusion, here were no adverse effects, measured by clinical pathology `parameters, in rats rats dosed with > 25 mg/kg/day included decreases in someredcell mass parameters along with ee eA! ( X0D-uDaOynS OGraelvGaavgaY geesSotiddyy: iinRRaatss oii 0DDwuoPomn:o0w47s8 ~ rseegreunmerpahtoisopnh(oirnucsre(amsaeldersetoincluyl).ocytAedsd)i,tiionncarleatsreedatsmeerntu.mreclhaotleesdtcehroalng(efsemianleclsinoinclayl)cahnedmiisntcrryeased (ombasleersveodnliyn),radtescdroesaesdedwiwtighly1c2e5rimdge/sk,gi/ndcaryeaisnecdlutodteadl tprraontseiienntalnydianlcrbeuamsiend,aalnkdaliinncerpehaosesdphcaatlacsieum (vfoelmuamleesaonndlyd)e.crFeoarseudriunrailnyesikseptaornaemceotnecresn,trmaatlioens.dosed with 125 mg/kg/day had increased urine dToresaetdmewnitt-hre1l2a5temdg/ckhga/ndgaeys,iannfdluionrfiedemamleeassduorseemdenwtisthin>c2lu5dmedg/ikngc/redaasye(dvparliaasbmlae fsltautoirsitdiecailn males 2si5gnimfgi/ckagnc/ed)a.yU(rviarnieabflleuosrtiatdiesteixccarletsiigonnifwiacasncien)c,reased in males and females dosed with `Nsmtoaunldeeysoaafnntddhfefoeramatbhloeevsec,lcibnhaiascnaegldepsoaantrhteohelexolpgaeycckpotaferadadmtevoteebrressaemdevefeafrsesucert.sedaT,theatrhneeyfNodroOsee,E.Lundwearsth1e25comngd/iktgi/odnasyoffotrhis BIOCHEMICAL MEASUREMENTS A. (BTiaobclheem3i4c-a35l,MAepapseunrdeimxenLt)s | --~ `sTuhbechrratoeniocf horeaplattiocxiBc-iotxyisdtautdiyonw,itasmeasureofperoxisome approximately 10 or 90 days of test substance administration p`rmolailfeeraatinond, fweamsaldeetreatrsmianfteedr or following a three-month in a recovery period. Aoxtidtahteio10n-wdaays, s9t0a-tdisatyi,caallnyds3ig-nmiofnictahntrleycoivncerreyatsiedmeatpo1i2n5tsmign/kmga/ldeaayts(,16t3h,e 1a6t6eoafndhe1p3a3ti%c opfac(co1tn3it3vrioatlny,darte1s15p2e25c%tomivgfe/clkyog)n./trdAoatly,tihrneesm1pae0lc-tediavryealtays)nw.der9Ae0t-adtcahceyottmhiprmaeeneip-eomidonntbtsyh, itrnhececroievnaecsrreyesatisniemsreeilnpaothiienvptea,tltiihvceeprr-weolexaitigidvhaett.sion liver weights had returned to control levels. hAseitpgtnahitfeiicc1aB0n--todlxyaiyidnatctirimeoeanspweoadinsattsit1na2tf5iesmtmgiac/lakleglry/asdtisag,yntih(fei1c3raa1nt%teloyofficnhocenrptearatosilce)d.Ba-toAx2ti5dthaaetnid9o0n1-2wd5aaysmgts/itamktegi/sptdoiaicnyatl,l(y1t1h6e arantde of re1c5o2v%eroyftciomnetroplo,inrte.spAecttitvheely1)0.-dHaeypattiimce Bpo-ionxti,dtahteioinncrreetausmeeidn thoepcaotnitcroP-eoxviedsataionthaecttihvriteye-amtonth ta1hc2ec5o9mm0gp-/adknagyi/etddiambyeywpiaoniscnrtae,cactshoeesmpiiannncriereleadtaisbviyeenslainhveeiprnacwtreieicagsBhe-toisxni(rd1ea1lt2aitoainvnedalc1itvi4ev5rit%wyeoaiftghc2ot5n(tar1no3dl,21%r2e5ospfmecgcot/niktvgreo/llyd))a.,yAAwtetre the three-month recovery time point, the relative liver weights had retumed to control levels. --~ -Y Company Sanitized. Dos not contain TSCA CBI XS 9DDoaOynS OlrOalnGga) veaSgeuSdtuydsiyionnRRnaaitssc0 Toricity DDuuPoowno9w4n7s8 --~ B. Biochemical Measurements Conclusions p`Uenrdoexristohmeaclonfd-iotxiiodnastioofnthiinsmsaulce a( nd femaI le rats. At concentraatmiiolndsionfdu1c2e5rmogf/hkegp/adtaicy in males caonndsi2d5emregd/ktg0/bdeayteistn fsuebmsatlaensc,ec-rhealnagteesd ienfftechtsr.atAetofthheeptahtriece-pmeornotxhisroemcoevperroylitfiemreatpiooinntw,etrhee rate. hofidherpeattiucmepdertooxciosnotrmoelplreovleilfseriantifoenmawlaesrsattsi.l slightly increased at 125 mg/kg/day in males, but - ANATOMICAL PATHOLOGY A. Mortality (Appendix N) | fT1eh8me3aralenewdaet1r9e,(anrnoeismtpeaesclttnisvuuebmlsbyt.earnc6e5-5e0l7at1e)dfdreoamthtsh.e Oconnetrmolalgeroruatp(waenriemaalccniudmebntearl6ly54ki9l4l9ed)aonndsotundey days B. (OTragbalnesWe36i-g3h7t,DAaptpaendix M) ~ wTeesitghstubpsatraanmceet-ererlsawteedreanpdr/eosrensttaitnis2ti5caalnldy s1i2g5nimfigc/akngt/idnacryemasaelse,scaonmdpafremeadlteoscsoanctrrioflisc,edinatitvheerend of the exposure period. Liver weight parameters were not significantly increased in males or cifonertmreaerllmeaestdeiidantwteidhteohs1me2id5cgrmrogos/uckpogsp)/i.dcahyIenptah1tr2oe5cee-mlmglo/unlktaghr/rdheaycypoeevrxetprroyospguhrryoeug(spreoe(tudhpiesrmceauwlseesrioeantnsu,onridneeccrroMeviaescrerydogslrciovoueprpiswceiinght Findings). mTeosrteskuibdstnaenycew-erieglhattpeadraanmde/toerrsstawteisrteicparlleysesnigtniinfi2c5anatnidnc1r2e5asmesg,/kcgo/mdpaayremadlteoscaonntdroflesm,ailnesone or isnaccrriefaisceeddiantmtahleeesnodroffemthaeleexspionsuthree 1pe2r5iomdg./kKgi/ddnaeyytwheriegeh-tmopnatrhamreetceorvserwyegrreonuopt(stihgenriefwiecarnetl3y0 o`rwfeictthohvemeiercxyrpgoorssocuuorppesipcientrwiibonudtlea(rrsmeehedydipiaestrceturdsoospishoeyndiugnnrotdhueeprs2M)5.icaIrnnodsmc1ao2lp5eicmrgaFt/iskndgii/nndcgrasey)a.gsreodukpisdnsaecyrwifeiicgehdtsatctohrereelnadted oTrhgearne wweeirgehtnochoatnhgeresteisnt esxubpsotsaunrcee-arnedlarteecdoovregrayngrwoeuipgshtweefrfeectcso.nsAildleroetdhesrpusrtaitoiusstiacanldlynsoitgnificant hwbeieaoirlgtohgtwieciiangllh1ytmsrgie/glknaigtfi/ivdceaantytob.foe"mdTayhleweseeriacgthshatsnagciernsitfihiencce1ld2ua5dtemtdghde/ekecgnr/dedaoasfyetdthhaerdeerexe-pnmoaolsnugtrlheanrpdeecrwoievoidegrahyntgdrredoleuactprievfaeestmeaodlb.eos.dy cbIrnhaa1inn2g5ewsemigwg/ehkrtge/tpdhrayeysmeutnsth.rweeei-gmhotnsthwerreecoivnecrryeamsaelde;sH,oawbesvoelru,t,noretleasttivseubtsotbanocdey-rweeliagthetd,maincdrorselcaotpiivce to -- -YY Company Saniized. Doesnotcontain TSCA CBI |. | S0-R DayOral Gavage ShSaduy ibRncRveoansic Toricity C. Gross Observations (Tables 38-39, Appendix N) DwuoPowns.478 Gross observations noted were sporadic across groups and were not est substance related. D. Microscopic Findings (Tables 40-45, Appendix N) tTeeestthsfurbsotmanmaclee-eraltasteadnmdiicnroksicdonpeiycs findings werepresent from female rats. in iver, kidneys, thyroid gland, and Anatomical Pathology Text Table: Dose (mg/day: HLyipveerrt:rophy, hepatocellular Necrosis. focal HKyipdenretryosp:hy, tubular ATlheaytriooind,cgollalnodi:d DTeepeetohc:iuion. ameloblasts 0) MTinccriodesnccoepsicanFdinAdvienrgsagIen LMeaslieonanGdraFdeemsaolfeTReasttssubstanceRelated 0 1 5 2 5 Males: 90-Day Exposure V0I0C0EO0' 0M1000000)) M01O0A0)0 0511000000)) 10V10006) 0000) 01000 0000 9000) 101000 MOCO WOMH MOM) 100000) M003 010000) 010 00) M1000) 01000 10016) NeLcirvoers:s,focal way ATlheyrraotiind,gcloalnlodi:d mos TDeegeetnhe:ration, ameloblass bose) ~~ 010000) Kidneys: -- Coronicprogesivencphiopatty 21110) Males: Three-Month Recovery Na Na NA Na NA NA NA NA NA Females: 90-Day Exposure 2100.0) MOO) ~ 3000 0a wae 21000) 010) Kidneys: Females: Three-Month Recovery bC+.hrNoNunuimmcebpreraortgoirnrepsnasirieavnettenheespsheirsonipncadtiihcydateeosfnacvieesr5aw/gi9eths1.me0i)cvroesocrfopiiictoNlnyea.sion. DenrsinaNtaorindictsuNmbAerof NA Tissue not available because there were no termediaterecovery groups. 100.4 i rv. -Y `Company Sanitized. Doesnotcontain TSCA C8 -- 90-D. ayOra.l Ga. vageS.ly.inRa.ts Toxicity | | --_ F2o5caalndhe1p2a5tomcge/lklgul/adraynemcraolseis90a-cdcaoympexapnoiseudrebygr&oumpisn.imIanlaidndfiltiaomnm,atthoeryinresponse wasDpurpesoenntti9n478 | | oODoScLrmoskiesGirynoup1n:2o5Ttmehgset/kssguib/nsdgtaaeynoctech:crueerelea-tnmeocdnetoshfirnhececpotavhteorcyelmlaulleasr nweacsroisnicsreinasmeadlweshceaintd$ecnmcogem/opkfhagerdpeaatytoocwreael.slular a25nianmdal1s25.mFgo/ckagl/dliavyermnaelcerorsaitss was consideresdlteosiboen ocoann.ocscuubrstsapnocnet-raenleaotuesdlyadivnecrosnetfiinnding in FhHeeeppmaattmooecceselllplueulrlaiarorhdh.yyppeIenrrttthrrrooeppehhymyowwnaastshnpoertcepsorevenestreinyntm1aa2nl5demargpa/ptkeagpr/rsedvatiyoombueasllryesdossaecrdifwiictehd 1at25thmege/nkdgiodfatyhe ceSoeaspiasntooepcheilillniuclliacvryehrtyowppeeliragtshrtmospw)ihwtyhawisanschoecnphsaaitrodaccytteers.izeTdhbuys,anheipnactroecaesleldulaaemrveohruysnpitbelroet.fMriofcipnrheoylsy(csaonprditachatlelays,sociated `metabolism oaf xenobiotic and not beiroelodgaictaelsltysaudbvsetrasnec,e6.t7e2l5a2t9ed physiologie responses dieedsgetennseturbaistntiatonhnceeau-nrpdeplleoarrteidndicstioosroogtrahsnilozefasttihioeonnseivonfeel1n2a15m(meanglt/ekorgri/ogrda)anynaoemsxeeplosoesbcutlraesgcrlolu.p mTahliesaltessicononwsaisstesdoroyf aSdnosoed twithet1o2b5lmaes/tkigc/ddaeyg.enTehriatsitono/odtisloersgiaonniizatsiimoinlwaras10illelsiipoornnes.sseneFteonlilnwoimwtaihlnefglauatiorsriepnereeosvsivojeuensalcys d is considered adverse." --~ mTIenactoheveetirnhyyaprleolrididoogds,leadsnedgv,rerotiuhtepysiananctditdhieenncceienddaeonncdelotohfrrae9ll0ta-etirdveaedycdeoexlpgorseurofealpetreiroed.d cFoollloliodwwiangstihnectrheeasseedsaionnth f13l5oemveekclheagdnraagdeyisnwcghhsaercnahccetomemreipwzaeardebdytsotciopnptlreodl,s.grTahnueladri,agcnlloousimidpsewdoef,re"aanildtnlecorraretaidsoienf,dfucisnaelmlyallboeacssowaptahsilussodfifonrc, oimrienienvdolavetde,rewditcohllgoriadd.esA2s3gr,aapdapenldioef4d1abpwapaslseideadoppnfloairneedeaswcthhiem2na5t1%efoiofnlctrlheieacsplteeoericnbeofnotulatlgie2cu5olfaf%r opofvntchehe foggoieies indhivsiidzuea,ldfeonlsliictlyesordisdtaniontinigmpinaecntstihteyogrfasdiipngp,ls, granules, clumps, or diffuse basophilsrmunesn `Altered colloid described `Sprague-Dawley rats with as clumped or granular has increasing incidence com been reported to occur spontaneously in orceeollaeltroeoidsd,cowocpacisucrnasolttsepcrooannttisaoinndseeoriuensdtlhayedvitnehryhsreeoa.ildthgylaSnpdr,aaglutee-reDdaewclolalteliyonirgda,ttsoa,liatnnhcodruesgaihsniclniegkhealegyretee.sw":esrBeuebcyasyutssaengaliered {{Tnxchproesiaunsrceeiddfienenmc1ae2lo5efsmcgwh/hrkeognn/icdcaopymropfgaerrmeesadslitevoeactnotentphrhrorelosmp.oantIhntcyhiswdaersneccieonvacernredassweevdeirnit1y2o5fmtghi/sklge/sdiaoyn9w0e-rdeay Jeslon appears to progressafer cessationof test material expyosiheenancdomi pacroensdidtoerceodnsaqnua,reTshis -- - Company Saniized. Doesnotcontain TSCA CBI ( 0-Day-- Oral Gavage Sadycin RacsToxicity DuPon7.V947S8 -- Rrtheeecnoaevlxeprtoyusbpuuerlreairpohedryiaponedrd.tarpTophpeihasyrcswhatasonbgpereerwseeavnsetrsniionbtl2eo5.basMenirdcvr1eo2ds5cinompgmi/acklagel/lryda,atys smaaclreifriactesdsaafctreirftihceetdhrateet.hemeonndtof icnhcarreaacsteeriinzecedllbyheiingchtr.easCeodrteiocsailnotpuhbiulliecesptiathienliinaglocfelclosrtaipcpaleatruebdultteuobecupolinattrhaheiylnpimeumrotrarenodpgrhaaynswuialgashrt | atcusybstuoolcpeilsaatswemedirwceimtsahltioegrthihialelyrsthmihaseltlocemorortrtiphcheanollttohugobisuceleeisvnicdoecnntctreooorfartreakntisa.dlnedTyasum.bauglTeau,rbuallnuadmrirnheanyapolefrchtlyirpnoiepcrhatylrowpahsiendot Ipnacrraemaesteedrskiidnndeicyatwieviegohftrseoncaclurtroixnigciatbysweenrteconrortelparteisveentev(isdeeenccleionficraelnpaalthtoolxiocgiytysecctoimonmp)o.anthloyloogcycur in toxicology studies and may represenat physiological response to high doses of test rV`eimpkaertleeysretnietsatal"s.utebTsshttuassnuc,besi.trnaecnlrcaeeta-esrdee;dlahktoiewddenvpeheyyrsw,ieoitlhgoehgstiesccarhneadsnpgtoehnesseaw.sesroecinaottedcornensaildetruebdulaadrvehryspeerbturtopmhoystwelriekely Aalnldoatgheeranmdicwreorseconpoitcporbesseernvtaitnioandsosnoerteedsaproenksenofwasnhitoonoicnceurthsepronitnacniedoenucselyorinsreavtesriotfy.this strain E. Anatomical Pathology Conclusions dEexgpeonseruarteiotnoy/1d2i5somreg/aknigz/adtaiyonofoftheenatemsetlsuobrsgtaanncaemefloorbalpapsrtocxeilmlsatienlmya9l0edraatyss. pArmoedluocbeldastic cadoenngdseniseedvreearrteiidtoytne/osdftcihssrourbogsnatinacinzcpaertorigeorlneatswesadisvaennodntebpriehovrleoorpgsiaictbalhleylayfitnaed1v2te5hrsrmeeg.e/kmFgoo/cndatlahyshefrpeeamctaoivlceernryee.ccrooIsvniecsrryewaarsasetdsprwioanssc.eindtence 9Th0i-sdalyesmiaolnewsaastc2o5nsaindder1e2d5tmesgt/sukbgst/adncaaenydreilnattehdreaen-dmaodnvtehrsree.coTvehreyimnacliedsenacte1a2n5dlmogr/ksge/vedraiyt.y ofin niaolnttcercreoeadnssecido;dlelhrooeiwddeiavndevrteh,ryssreio.nicdegtlhaenrdeswoefrmeanloeortathserinmcirceraossecdobpiecyoanltdecroatnitornoslplreevseelnatsttihsefdionsed.ing was iI1nn2cc5rrmeeaagss/eekddg/lLdiivaveeyrr.wweeHiieggphhatttssoccweoelrrlrueellpaarrteehsdyepwneittrihtnrmomipachlryeosswcaaosnpdircefveehmreaspliaebtsloecaetiln2lmu5laaalrnedhsy1fpo2el5rltmorgwo/ipknhggyt/hdirnaeyme.a.mlTeohsnetaht s e`rmeicegothvaetbrosyl.wiseTmrheoefpsraeexsleeinnvotebriicnoht2ai5ncgaaennsddw1te2hr5uesmcwgoe/nkrsgei/dnedorateycdmotanolsierdseeparrneeddseftoenamtbaelpehasyd.svieorIlsnoemg.ailcIenrsce,rsetpahosenessdeekKtiio.ddnneeyy cahnadnrgeensalcotrurbeullaatrehdywpietrhtrmoipchryosacpoppeiacrerdentaolbbeurleaverrshiybpleertbryotphhyr.eeT-mhoentihnscrreeacsoevderKyi.dnIenycwreeaisgewhdetisght fkmiiondrdnpiehngyoslw.oegiigchtosr aclnidnimciaclrpoastchoopliocgitcuablulcahranhgyepseratnrdopthhyuswewreerenontotascsooncsiiadteerdewdittohbceorardevleartsiev.e `2Uo5nn dmhegepr/akttghi/ecdcnaoeyncdrbioatssiieosdnasoot nfthtaenh2ii5nscatrnueddays1,e2dt5hiemngcNi/OdkeEgn/Lcdeafayonrddpoassteehvelorelvioetglyysofafonrndempfaholrreofpaeatmtsahlwyeaarstat15s2mw5ga/msgk/gk/gd/adyaby.ased - Company Sanitized. Does not contain TSCA Cal o | 9--0.De ay.Oral. m Gavag.e NS.otinRm. ya.eToney --_ CONCLUSIONS bDurponetssa8 || | No test male or sfuebmsatlaencrea-tsr.elaNtoedtemsotrtsaulbisttyanocrea-lsteelraateidondsecinrenmeeunrtosbeihnamvieoarnalbopadryawmeeitgehrts, were observed body`weight in g0a1in3,5fomoodhcoo nsumption,or R food efficiency T were observs ed in maleortoxfiecmoalloegisaetaslyadsmiignniisfteircead up rinoctrsea.ses in the incidenceofstriated teeth occurred in the 125 mg/kg/day male and female dose ir`anTthtsehrdeeorwsaeetdreeowfinthohetpuoapxtiitccoolB1o-2go5ixcmiadgla/ltkyieos/indgonaicyfciucrarnetdcE ihnantghes obE served in Aclisntiacvailstpiactahloylsoiggynipfaircaanmtetmeerrseainse aatanrdefdeumacleedgrloeuvpesl.coAmfptaerretdhetoretchoev9e0r-ydpaeyritoidm,etpehoe2in5itn,mcgrine/aktsghe/edd1raa2yt5efmeogmfaBl-eoxainddat1i2o5n `pmergs/iksgt/edda,yamlbaeliet /kg/dzy malegroup. Testsubstance elated,toxicologically significant degeneration disorganization of enamel organ ameloblasts tooth lesion, caellolsngocwciutrhrethdeiinnmcarelaesreadtsindcoisdeedncweitohf 125 mg/kg/day striated teeth, is consistent with [ol This | ltooxwiecroisnics.i*d"encAeftaenrdthsreeveerimtoyn.ths, the degeneration/disorganization of ameloblasts persisted, at a ~ wAatsesotbssuebrsvteandcien. mreallaetseda,damdivneirssteeriendcr2e5asaenidn1t2h5e imngc/ikdge/ndcaey.anAdnseivnecrrietyasoefdfionccaild`ehnecpeataicndnescervoesriisty of chronic progre considered ssive nephropathy occurred in the 125 mg/kg/day female adverse. After three months of recovery, both the incidenc of group that was. in the 125 mg/k nephropathy in g/day m the 125 ale group and the mg/kg/day female incidence and severityof group were increased co e chronic mpared hepatocellul progressive to control, a r necrosis pTreesste-nstubisntmaanlceesrealnadtefdeamnadlesstaatdismtiinciaslltyersiegdni2f5icoarnt12in5cmrgea/skegs/idnaylifveorr weight parameters were approximately 90 days. The 1in2c5remags/ekdgl/idvaeyr wmeailgehtdsosceorgrreoluapt.edLwiivtehrmwiecirgohstcocphiacngheespaatnocdemliluclraorschoyppiecrt`rhoyppheyrtirnopthhey. were considered to be a physiological adverse. Test-substance related adaptive response to metabolismofthe and statistically signif test substance and not Kpiadrnameeytweerisghoctcsucrorrerdeliantmedalweisthanmdicfreomsacloepsicadrmeinnailsttuebruelidacr2an5htyopirnecr1rt2er5aospmehgsy/ikingn/ktdihadeyn.2e5yTawheneidgihntcreased e1v2i5demngc/ekgo/fdraeynamlatloexigcriotyupwseronelyp.resHenotw.evTehre,renfoorceo,rrkeildantievyewmeiicgrhotsccohpaincgeosr calnid`nimciaclrpoasthcoolpoigcical stpubounltaarnheyopuesrftirnodpihnyg winerreatsn,otwacosnisnicdreeraesdedadivneirnsceifdienndciengasn.d/Aolrtseerveedrictoyllionidt,reaatceodmmmaloen.groups. pc`Toahnrisasimcdehetreaerndsgeaannwdaadshveneporattsoeacsfesilonlcduiilanatgr.edhyAwpfiettrehrtrotothhpeehrtyhf(rimenaedl-iemnsognsotnihlnyrt)ehcweotvheyrryoipdergiloadn,diancnrdewasaesdallisvoerwnoetight 125 mg/kg/day male and female groups. Similarly, ere increased no longer observed in the kidney weight `parameters and renal --~ rteucbouvlearryh.ypertrophy (males only) were not observed in rats sacrificed after three months of - { a | Company Sanitzed. Does net contain TSCA Cel ["L90-DayOral GavageStySuibnchRvaotnsi:c Toxicity ~ The was 5nom-go/bksge/rdvaeyd]:effect lovel (NOEL)' for DuPon.9478 or the 90-day exposure period ( Qaen ciO n malcs sY diuisired nephropathy obs > 2=5 imgn/kcgr/adseaeydc.ohnTohtheceNoinOcsEreiLassfeeodvreifrneicmtiaydloeefnsccewhrooosfnhi3ec2ppamrtgoilgckrgnee/scdsraiovyseis erved in females administered 125 mg/kg/day. RECORDS AND SAMPLE STORAGE bLearbeotraationreyd.sbpyectihfeifcacoilistiytew-hseperceiftihcerwaowrdkatwaa,ssudocnhe.as personnel files and equipment records will L2abbosoraramatptoolrreyy,.ofNtSehpweactreiksmt,esDnuesblsfatwaanarcpeepl,wiocaarsbalcteo)ol,lnercatMweodcufanottr,aaiarnncdhRietvhceeoprfudirnsaplosreespoarntdwirleltabieneed att HaaskeHlalskell DDeellaawwaarree.,orTeasttISruobnsMtoauncnetacihnarRacetceorridzsatMioannadagteamewinltl,bWeirlemtianignMetadonnaat,gHDeaemslekanewlta].rWeLi.albmoirantgotroyn,,Newark, ~ ~ "mdfoeevefiuonnNepidOtebeEytsdheLhESsfauatorentsociEwxsevriyonnsomtedndteeafclindPer.dotaesTcththuiso,nigAfohgrsettoidsyosseayaa,nwdthh1iecNthOeoEocLc-ogceiqucbiavlaslyeaenivtmerproviroetfindfcsfsoscamt(risbustabbiye to pean Union NOAEL) as. - `Company Sanitzed. DoesnotconTtSaCAiCBnI S e 50-Day Orals Gavage St. y in Rats e oDeupomnt9478 REFERENCES 1. pCeorvfalnucoerosotcutdayneNos.ulf6o3n2i9c-a1c8i3d p(1o9t9a8s)s.iu"m1s0a4lt-(wPeeFkOSd{ ietar4y camrcinorgaetnsi.c"ity study with 2 eSIktueoddca,htnrT;o,mFFeauhPki-um4di5a0,HDaK.n,,dSMpoiererio,Hx,Li, sedoEsm.neoPmpeorrotlooir,fieMsr.oa,tmieoKsnoiimnnaBirai,toTll.io,vgeSyruabgnyad,pMeTr.efd(li1uc9oi8rn7i)n.ateIdndouccttainoensaolffonic New York, pp 304-308. e. Springer Verlag, 3 oSPtoehhrelfrelnuaiocutrisov,oictAtiKaesn,ekEsnruoilwfkonsnsitocona,bceiAdaMfif,ecatHpeoodtgbesnyttrpioenmrd,ouxCc.i,esrKoiomfmelppaerrnooldxi,fiesMro.amt,aorlDsefpiaintetrmyroeau,csiIdeWb.eta(-1o9x9i3d)ation and Toxicol. 72: 90-93. iver. Pharmacol 4. pBHeiaroufcglhuheoomr.mo,oBciBto.ap,nhoSyipscy.daAeccvitodal.(d,P,F10O1.2A8)(:,196p95e2-r)7f.2l.uTohreoomcetacnheansuilspmhounnidceralcyiidn(gPtFhOeShAy)poalnidpcelmoifiebfrfiecctacoidf. 5. ADnuaPlogtnitcaHlasRkeeplolrLaboratory 6. Dupont 2) a Evaluation of Trimethyltinin Rats (Positive Control Study), 7: luPont (1997). [HL-1997-00686. Neurotoxicity Evaluation (MRID 44628703)] of Amphetamine in Rats (Positive Control Suds), 8 [H(LD-u1P9o9n7t.(01093967)1.. (NeMuRroItDox4i4c6it2y8E7v0a2lu)g)tion of Carbaryl in Rats (Positive Control Study). 9: [fHDuRban2t93(.19959.6).(MNReIurDot4o4r6i6c0it6y0E1v)a)luation of Acrylamide in Rats (Positive Control Studs), 10. ELnazzayrmoowl,oPg.yB.72(,1938115)-.31A9s.say of Peroxisomal Beta-OxidationofFatty Acids. Methods in 11. 2BQ4ur8aa-nd2tfi5ot4ri.de,sMofMP.rot(e1i9n76U)l.iAziRnagptihdeaPnrdinSceinpsleitoifvePrMoettehiond-DfyoerBtihnedQiunagn.tiAtnaatli.onBioofcMhiecmr.og72r,am 12. WDirlaepye,r,NNeRw. and York. Smith, H. (1981). Applied Regression Analysis, 2 edition, PP 266-273, 13. Saneilmwayln,saMfeRt.y s(t1u9di9e5s).. JTohuernuasleoofftthreeAndmetresitcsatno dCeotlelremgienoefTaonxoi-cooblsofgvyab1l4e(-2)e,ff1e5c8t-l1e6v5e,l in 14. `JBoinocmkehtereirkea,4A1,R.133(-1195445).. A distribution-free K-sample test against ordered alternatives, 15: SLteavreisntei,csH.(1.(1O9l6k0i)n., eRdo.b)upspt e27s8t-f2o9r2.equSatlaintfyoorfdvUanriivaenrcseis.ty PCroenstsr,ibPuatlioonAlsttoo,Probability and ---- TT----in--r -- Company Sanitized. Does not contain TSCA Cal | A X 9-DaD y O. rau l GavO a. ge Sm uidy. C in Rata s Toxv icita y geSuityinkDwua opomnte9s4n7s8 ~~ 16. Shapiro, S.5. and Wilk, MB. (1965). An analysis of variance test for normality (complete samples). Biometrika 52, 591-611 17. 3S4n9e-d3e5c2o.r, TGh.eW.IoawnadSCtoactehUrnainv,eWrs.iGt.yP(r1e9s67s),.AmSetsat,istical Methods, 6 edition, pp 246-248 and 18. Dunnett, C.W. with a control. (J1.9A55m)e.r.AStmatuilstt.ipAlsescooc.mp5a0r,i1s0o9n6p-r1o1c2e1d.ure for comparing several treatments 19. KJ.ruAsmkearl., WSt.atHis.t.anAdssWoacl.li4s7,,W5.8A3-.62(119.52). Useof ranks in one-criterion analysis of variance. 20. Dunn, 0.J. (1964). Multiple contrasts using rank sums. Technometrics 6, 241-252. 21. Milliken, G.A. `Experiments. LiafnedtJiomhenLseoanr,nDi.nAg.Pu(b1l9i8c4a).tioAnsn,alByeslimsoonft.Messy Data, Volume 1.: Designed 22. Hocking, R A. (1985). The AnalysisofLinear Models. Brooks/Cole, Monterey. 23. Baaprptllieetd,bMiLoSl.ogy(.193J.7)R.oyaSlo.mSetaetixsa.mSpolce.soSufpsptla.ti4s,ti1c3a7l-m1e7t0h.ods of research in agriculture and 24. FNieshwerY,orRk..A. (1985). Statistical Methods for Research Workers, 13 edition. Haffner, i -- -- 26. Greaves, P. (2000). Amsterdam, pp 453. In HistopathologyofPreclinical Drug Safety Evaluation, Elsvier, 27. Sipes, G. I, and Gandolfi, A. J. `Doull's Toxicology: The Basic (S1c9i9e1n)c.eoInfPBiooitsroannssf(oArmmautrio,noMf.TOosx,iDcoaunltls,.1.I,naCnadsaKrleatatssaennd, C.D,Ed), Pergamon Press, New York, pp 85-126. 28. EPavyanltueart,ioOnLEof,SHuabrcrihsr,onJiEc,EBxuproisnu,rGe.JS.t,udaineds.JaUegneirt,edR.SBt.at(e1s98E5n)v.irGounimednatnaclePfroortAencatliyosnis of Agency, EPA-540/9-85-020. 29. IGnrteearvperse,taPt.io(n1a99n0d)R.eDliegveastnicveeiSnyDsrteumg 2S.afIentyHiEsvtaolpuaatthioolno(gPy.oGfrPeraevcelsi,niBcd.a)l,TEolxsivciietry,Studies: Amsterdam, pp 393-496. 30. Reddy, C.S., and Hayes, AW. Toxicology (A.W. Hayes, EQ.), R(a19v8e9n).PrFesoso,dNBeowrnYeoTrokx,icpapn6ts7.-11I0n.Principlesand Methods of 31. RThayor-oRiudpaSntarugcutduir,esS.,aHndeyFwunocotdio,nRi.n,SapnrdaGgoupei-nDaahw,leC.y R(1a9t9s1,)".Ve"tA.gPea-trheolla,teVdoCl.ha2n9g,eNso.in4, pp. 278-287. 32. IGnrteearvperse,taPt.io(n1a99n0d).ReUlreivnaanrcyeTriancDt.ruIgnSHaifsettoypEavtahloulaotgiyoonf(PPr.ecGlrienaivceasl,TEodx.i)c,iEtlysSvtieurd,ies: Amsterdam, pp 497-583. ~ --_-- TTT rT Company Sanitized. Does not contain TSCA Cal D 9-Dao y Oralu GavaO ge Sud mubinshRO raosricv Toricii ty geoutvinkDDuue Poonmte 9o478 ~~ 33. fHoar.zAanradlyEvsailsuaantdioEnvaDlivuiastiioonn,oSftSaunbdcahrrdoEnviacluaantdioCnhrPornoiccedEuxrpeo,sTuorxeicSittuydiPeotsePntaiyanlt:er,Gu0i.dEa.ncete `aWl,asUhniintgetdonS,taDt.eCs.,En2v0i4r0o6n.meEnPtAa-l54P0r/ot9e-c8t5i-o0n2A0g.en(cTyu,neOf19f8i5c)e.of Pesticide Programs, 34. ERNi)sk, ACshsaeptsesrme,ntSeocftiNoontsif2i2ed4Naendw2S.u2b5.stan1c9e94s,. Technical Guidance Document (XJ283/94- | -- ~ Ten. Company Sanitized. Does not contain TSCA CBI || O 20DayOr Gavageo Sty ne || - Drona `TABLES ~~ ~ C290DDayOrcalGGauvaaggeeSSyyitinntRRatnss Tost 000 -- TABLES EXPLANATORY NOTES DDwuoPownss9n47s8 Critical Dates: Day91 + Lblaesetddsaaynodf3t-esmtosnutbhstreacnocveerayd.ministration for rats designated for satellite Lafosrtradtsaydeosfingonna-tfeadsftoerdtbhoed9y0w-ediagyhetxaponsdufroeopdercioonds.umption data collection Lsaatsetllditaeyoblfefeodosdinctohnesu1,mp5,tiaonndd2a5tamgco/lklge/cdtiaoyndfoosreragtrsoudpess.ignated for Day 92 9L0a-stdadyayeoxfpotseusrtesupebrsitoadn.ce administration for male rats designated for the. Day93 Lathset90d-adyaoyfetxepstossuurbestpaenrcieoda.dministration for female rats designated for Male rats designated forthe 90-day exposure period were sacrificed. ~ Day 94 Female rats designated for 90-day exposure period were sacrificed. Day 175 Rats designated for satelite bleeds were sacrificed Day 182 rLaatsstddeasyigonfatneodn-ffoarsttheed3b-omdoynwtehirgehctoavnerdyfpoeordiocdo.nsumption data collection for Day 183 Msaaclriefiacnedd.female rats designated for the 3-month recovery period were Note mg/kg = mg/kg/day Notes for Clinical Pathology data: ``wWerheepnearnfoirndmievdidouanlhoablsfetrhveatrieocnorwdaesd rvaelcuoer.deFdoarsebxeaimnpglel,esisbitlhiarnuabcienrtwaains vraelpuoer,tecdalacsul<a0t.i1o,ns0.05 was used for any calculations performed with that bilirubin data. -- T ee r me-- `CompanySanitized. Dossnot conTtSaCAiCnBI Cy omy m}.P.E. occ --_ |. (Em TABLES ma EXPLANATORY NOTES (CONTINUED) ABBREVIATIONS: . Summary of Hematology Values RBC - redbloodcell count HTHGB - hheemmoagoloonbtin MCV - mean corpuscularvolume MCH MCHC -- mmeeaannccoorrppuussccuullaarrhheemmoogglloobbiinnconcentration WBC hit boodcecolunlt RDW - redcelldistribuwtiidotnh ARET - absolutereticulocyte count PLT - platelet count ANEU - absolute neutrophil (allforms) ALYM - absolute lymphocyte AMON - absolute monocyte I AEOS - absoluteeosinophil ABAS -- absolute basophil ALUC - abslarogeulnstuaint ed ceell - - nodata Sum ofCom agula atior nValy ues PT - prothrombintime APTT - activatedpartialthromboplasttiimne - - nodata CompanySuits. Docs rotonanTSGA G1 C 20DayOT-- E StyinRati os --~ `TABLES EXPLANATORY NOTES (CONTINUED) ABBREVIATIONS: (Continued) S ummAAaLSrTTy of - aCllaisapnnaiircntaaeltaeCmhianemomitinrosattnrrasynfseVfraealrsuaesees SDH - sorbitol dehydrogenase ALBIKLPL :- taoltkaallibnielipuhboisnphatase CBRUENA -- ucrreeaatniintirnoegen CHOL - cholesterol TRIG - triglycerides TP GLUC -- tgoltuaclopsreoein ALB - albumin GLOB - globulin CALC - calcium --~ PHS - inorganicphosphorous NA - sodium K - potassium CL - chloride ~~ PFLU - nodata plasmafluoride SummarofyUrinalysisValues VOL - volume UOSM - urine osmolality pH - the logarithmofthereciprocalofthehydrogen ion concentration URO - urobilinogen UFLU - urinefluoride ~~ UMTP - nodua urineprotein Dupont9e78 -- Ex CompanySanitzed. Does notcontain TSCA Col L C 50.Day Oral GaY v Sty in Rats Dupont 478 TABLE | SUMMARY OF DOSING MIXING AND STABILITY ANALYSES _oi concn v0 Homo"NgTeoenmteiDinatayylS1:a1m6ples 020 10 50 25.0 | Top 0163 os ass 109 Made 8o1@t50t) 0(n 8s0s.37) e 431.00) (2191.96) @9 Bosom 0ot5e) om0 s@a) o29l AverageMessured Cone. ie oso des 216 Average Percent Nominal 81.5) fan 93.0) (86.4) Coe`SltcanednatrdoDfeVvairaiattiioonn 1%0,002 5%0.04 30%13 m1ns $HouStraRiolotmy STaemmppleersate 9 0167 osiys p@ny w21n8 `TestbDaaseyli1n-e6 faonrdsTteasbtlDya)y 4 06 oss 4st 20 | " Bam 7-Day Reotrigeatea 81.5) (88.8) 902) 2.0) ie 00 as ax 9 o een | o6r5m GosHs @as9 025399) 1 859) 1 AAvveerraaggee PMeeracseunrteNdomCionnca.l 5 0.167 Go 0.874 @440s o24u1" Co`eSftiacnideanrtdofDeVvairaitaitoinon +0s0a1t" aw 0.02 e0a.0m1 1% +021" 5 HourRoom Temperature 0158 0.904% ant 22 + altar oie] quo. Doamlp (19o.f0r)e gal p(l9e0s4u)ppor oi(e84n2)ays ao o(t84.e8)por. * NSumbei rsbianspn eadreonnthe heeseasvaes rreatgheeTreesgpeectliveopermcenteofneofmihmnealrovpal.iumesi.ole od b- otcaochdmosiong lefvel. #SSaampilessbaanasleydzoendtineprsevvrioaugsesteudyset oesof apt samp rhe dsig evel Meanresultsofduplicatere-analysisofthe originalsample. Originalresultswerelow due 0aliquot ror -------- Company Sanitzea. Doss not contain TSCA CBI Do--.IEcvocs vo _ `TABLE 1 (CONTINUED) pions SUMMARY OF DOSING MIXING AND STABILITY ANALYSES copno Lass so Coron SRE. Nominal: 020 10 50 25.0 # 0.156 0.749% 3.87 194 wnt 80* (74.9) (773) (71.6) Wwny 0.169 Wwem0.776 aah391 a1o9eh1 Average Percent Nominal aTein 5 `StandardDeviation # a815) +001 0.066% 33.0) RS (76.3) 0.02 (77.8) 0.03 0.676 (67.6) 220 (44.0) 77.2) +021 834" (33.4) " 0.083% 0.656% 232 864 ~ t pRen Etns 5(w Wa41h.5) oe5 (W6a5m.s6) 8(a4m a6.s4) a9(3a42.6) | | 2X `Test Day 48 Gw9n wasss aame 8us " ous asm as ms MT Er ans et O m wm n m ww n mwm (109.5) (94.8) (78.0) =5me90.0) ntT CoefficientofVariation * cAoenp nenes Standard Deviatio*n 7% 6% wwiet wdsm Yonw aOWmm wo m wWn 0.01 hk0.04 1% 3% ah me m Ss m a4m mma sn0.04 i+0.85 * Numbersinparenthesesaretherespectivepercentofnominal values. *MSetaatnistriecssbulatsoefdtohneotrhiegianvaelraangaelmyesaissaunredddcuopnlciecnattreraetainoanloyfsidsuoplfitchaetoersiagmipnlaelssfaomrptlheerdeopsoirtnegdl.evel Meanresultsof duplicate re-analysisofthe original sample. Original results were low due 0aliquotemor ~~ * Suspnoetdn oses dti oano iman ls. | CompanySz, oss ton TOGA SH C oDa--r r.l G.re.e W.e cace roi ~. "TABLE 1 (CONTINUED) Domus SUMMARY OF DOSING MIXING AND STABILITY ANALYSES ess connor NY =) || ConNotmtiaDnheanrle:5t6eaton @0o2i50 1so0eses 5wa0an o2m5sn0 | 0 0.189 0950 431 214 AvergeMeasuredCone. os0435) os(95.0) ax(862) mi(85.6) | CAvSeoraegreiPerocDfenSoteNitomnoinna"l p(r8o9.dr0) WW rW v 5.7) #72) (88.4) TetDay $8 Gamoe ooses aes easo basyo Bohw eanh eome AE Co we esa am ms Co`AtvSetrtoaagnertPseorfceevnvtietNrioaomonin"na*l ST1o.e0) S4.a1) (8SN 65a) ERf9.a2) `TeaDay es # " o0WW1s5no9o m@o0.m8en3e2 eG443oe02 @m20os28 A tao "a GBosmSs Sokw8es0 Swawxm Semaea Coentof vasation? Ve whee "Numbers mne swanes yar rar s gepli eglergngl inparenthesesaretherespectivepercentofnominalvalues. | a CompanySanlad. ossnat containTSCA CBI [ 90.DayOral Gavi age StidnRayts ois Dupont9478 -- `TABLE 1 (CONTINUED) SUMMARY OF DOSING MIXING AND STABILITY ANALYSES || Nominal: Dos0in2g0Concentrati1on0J-- 250 Concent"rTaetstioDnayVer9i1fication # 0162 619 oarss0ot m396n a19s9s n o5es G036y3 03900 i18s7 A`vAeverraaggeeMPeearcseunrtedNoCmoinnca.l" 0512604) o@syu o3s93e 01293) | CoScttalnidciaerndoDfevViaartiiaotni"on o1o% s9o% m s1om%4 053s || Test"Day 63 01% 0784 an 230 50 my @9 0 n 0516902) 0mn 4@08n 62514 A`vAevrearaggeePMeeracseunrteNdomCionnca.l" 001515 amrys @4100 6282H ~ CoeSftfaincdieanrtdoDfevViaartiiaotnion o1o%n f1o%ol 010%3 +51%1 TestaDay 73 ous 0980 457 23 680 0 ol n a01rss a1s03o e560016244 { A"vAevreraaggeeMPeearscuernteNdoCmoinnca.l" 021866 wLoy e4ls9y e2s39e CoeSftfaincdieanrtdoDfeVvairaitaitoinon" 090%1 fo5o%d s4o%m t3o%n MNeuambneersilnporftchnebesigeisnaalrantahlyrseisspaecdtivdeuppleiccatteroofanyomsinsalofvthoers.ial samplereported. * Stsbased ontheaveragemeasuredconcenation of uplictssamplesfrth dosingevel -- ET -- Company Saritzed. DoesnotcontainTSCA GBI ~ i x8 97 97 m7 ad 43 ad v8 es ex en en 2 g2 he 9%8 9%8 5%883% 9%88 0% 3988oS8e3n 8en38 as : 2 ~ | gf, 221221888183 4 Ze2 8 2 a #2 = = 8 = 82 = 2 = @ z 2g 3 < is: i?E 05: F.4508%3%FF345 7%8 :3 Gif 8 8 8% fii` 3 . g td Company Santis. Goss ot aanTSGAGH! ~~ 2 3 & 8 55 ea ed 2 g zz 3 2, an an on 8] Z2 e 5 8-33 33 3 a353 gg 5 gg 3g g2Z< we 7 332% aa z g iZ ~ : | EE3 EN 3 F B11 H 58 & i 2 2 g =| wl : Company Saitzad. Dos notconTaSCnA CBI ~3 5 # T g 8E8E8R8E8E8E8E8R2E8 xg 23 97 77 a7 an ad wd es as as an | | | E| =| 2# & 8: w 2 g a aa ss om om os os = iS rudd d2AT & &8 8 & 8 7 L 2 8 8 A ZT ET EE BE E 5 H SS de HG WS Ho we HS we wo no mo 5 so $4883 $ T 48 Fs 5 8 s582g 5 4 4 88 5 & & ww 3 9 @ = 52% 8433 358 3 53 3% 8 82 83 3 2 8 8 5 5 5 & & & 3& Company Sritze. Doss no contTSaCAiG8n1 ~ | xg 5% 33 33 3 EEE | 2 533 | og se 3L 3033E 3333 EE es so ~ | BE aia : 33 g2 2ga xe 5s335& 333333333 ` i2 $235 i: 83 38 - 25 HA 5 i4 8B 2% 5 32 8c 33 $ -- Company Santzsd. Goes no contain THEA 031 ~~3 Z " ||| $8 G 8 8i 88 s88 oee8 si8 s8i8 n%: Eo fnduniutnes 2 RF B 3 B% 9 3 3% 3% gR 4% : st FE & 8 BE F BE 28 0 & df + mpmEDOssEgsEgs : gg on 3 ZL 802 3#0 #o8f a5S8 gofn 907 493 gadf 8o9F 9ea o8bgeof IE&| # & | Bz& - izi3gi BEd. 48 38 2 28 . cozosos 85 5 5 5 18s os og og 5 &&&&2 CompanySaiz. oss rotcontinTSCA Gr ~ | 3 o5 su g 5= 2 8% zioiar 58 8% 8% sso: 335838 88s oa3anoanoes B ER BR BF goo%f ogarn o$o8 CL. gf 2 2x 8 7 2Z cI37 pga i 93 22h 2% 8 2&@ 2& 2& fgg @ @& @ i ii i - 5 3 3 i 3 3 5 54 4 : is 7 58| B22$l8y9 F3zF2 J$#F82 8F 8 E8% E3 :8 3%%%3 2 p : & 4 # El al l -d CompanySantos. Gov ton90i021 ~ : 1838383 g2 : i 8 ue Bf Wf LE .E NEY SE elddaang 3: 8: a8 3 SEFFE tg :;3 = 28 7 3 x i i BSiHe. LiLe.ifa fia;ld &8 Ls I 3B ~ : 4 HERE REESEE a so 5 & & d & 3 3% 8 & 5230 GE 39 35 ge fe 44 E048 ge 8 2387 HERuEEFnRoRmRoRmB mSaRRAmBnAaRR T CHER RPREREERE &54 EE 2g e. z -d 34 i id H33E8E: ii . - E2E5E8EE8 R E8ER8 E E8 CompanySanit. ongretemai TSG  REICH Et S 2 8 24388 8 8 8 8 8 o sc 1 3 "8 fi: siszzoszzosos CE FE EEE E iES iE :5 1 2id3 i83 - iE 3d pr s88: 3 3 93 88 3 88 %% i Gi4% 2 2% 2 3% 51 i: % 2 pf | ; 3 1] CompanySantis.Doss eterTEAGE! ~ |Ls3 5 i28s2d .3n: Sg ow aaa| _ Tog BS RY BS ES : g8 & "182 f Zz 6 agd m 8 8 a 8 8 8 :z 1: 2w 88 3: #8 BR 3% 28 gz 3 2a 3 8 iss 3 3 2 3g 22228 gz PriERERE 5d FETA AEA ay 5 3 iz 2 ul Fl I=3s 8 3Pa3 i= 2 2 a 5| B: d 3i H 3 23 i3 ES2 ~K - 88 zf9&4 & & 5 & iPiis2 i ii GompanySates.DosnotTSCAeGH! ~ g [g fe pngdpggaraia 32 gg se cs sos os somso oss= 97g 9%8 2238 oF2 m02 va2 o@8.2I8 n32q8 ew3 en3 8=i 885 5 Bill 08t88888 i -- e2 2g 2 2 m= = & Bm = = = = = 8 8 8 2 8 2.8 8 2 3 88 3% 97 4 2 8] {ET R a B 3 9% 5 8 8 8 5 8 8 8 8 8 2 Hod uf RawSf oS 5822S iZz He F4 a3c 8EF 4gf adu< 2saa aag8 d$d4 Sa4 4$6 88 aw : S 25 58 2 --:4 w 3 54 48 52 iH8E2F8 i4 5858383403384 EREes E4ER=EEwoRoEa EEa oRwER=E! 24 8 83 23 Company Sanitzed. Doss no contain TSCA CI --~ 23 s | Bair om oo. mamas g 88 53.33.83 oe. zion pumopuma . El I~ 8% 22 a28a gage a2 gs 1 odpm 888a 8= 3= 4 R : Ca REECE ELIE LR 2g 8 p gon2 gz _3Jq .8eu .88f8 pfm82Eol .gg2Pg.a2g.Ea8n.ag2zs8 7 g 2i 38 : 5 ! i4 B$U4F: F51F5 fBsE 5 E F% F2 5 g ~wB: figf i : i | 13 id f # Company Sanlzad, Dos no contain TSOACRI 2 fi S| :Cfdg mg+ aaad =tg i4 J ERI 5 = 3 =e iC REBEEE BH) gu z _8 33 : H $94 833 5.583 53 i gir rrisil|i G : BF FE iiii i|i }H 2 f Ii 5 g PE Con Sti, otoTi son8 ~~ 2 3 A x 2% UF 7483 va ay a8 3 ee an on g33 53 5 3333% 333 i 23 45 4% a3 45 03 a5 of a3 oF oF : i P5Eg o,. EfE4.E.0s0f0.E0a.E0g.0a.n0d0 % | "5 P ga e3j4b3E.ra3 2n3 FE 5 Es 3 E3nE3i5E3sE3eE3aE3 . LE :g 3: i3 $5445: i 55 8 3 38 4 4 5-88 % 3 Co 2 5 288. 583i cz 55 533% 5iii $oso iz 2 3 3 H 28 2 3 8 & w Company Sanco. Dosrotcontain TSCAGt ~ : 2 eb if E 2523E3E3E33g3e | 2 3 2S8%5 28% 3so3s 8s 8383s 5883 gp 3H OZ OFFI LRL i 2 J . ~~ 52 aga2i2 F 2gR2E .2I .2I.E28E .8 &~ zgge8 Za Z2 3 ggdd = = RTE3 2% ma : Td 7 - 82 age6 P5 A0E3 - 2 amAam 2 2 2 3= aA m ne A em ma Td :S| Fd: : i Hs: 2 la 2 38 3 2.85 3 Z| 3438 252 |32 95% 8 3 2 | ER ' E ! t 2 E8 Ts E3 |I e E EEE EEE E] 3 i RE i |2 ol CompanySabin Doss contin TEATS! | 2 i | Esz os ugsfgiedgSg ae d HEE]F 3I gi i Cf - E Zz 2ZS EEE VgN o=o 82 EERE a8 3@ 8i -z8 88 83 1i ?\ 2 2g35 j 3 izz flat225 2 edu HNNl HE] z 3 i EEdl L3 EDO8 3 8 8 8 & 8 3 3 54 ::F :i%|8:|}4 2: :] I5f!: J CompanySantas, oes conanTSAO ~~ og z gy 24222202000 3 s gE y | ir BEERFESESASS zz --~ = 12 szg s2238383333834588383338 FEERppEn@gges 3: Zz8 g JREEREEF REA i 3 2ail 2 | le H td i 3f4l. P48 $88. S833 2 3 5s 53i 545r 83e 835s 333 . z5 333% 3 8g 2 2 3 3 :z & i i Z [---- ~g |e2 E gg22 8.82383 #8 333 & JAE digigi at ;: fff ::zzczosos a= ~ g: gang #40000000 = g3 g 3 g eg 83333: :33:3 8> "f3 anis sen 5as dsNG gwnm g5s0ca m5m Agms #o9e : i i ls EER aaiE e 3 iE. EE 5 5 BEd oz |: HEE] 3 go 98 5 fi: 58& i % 2 : oJ ~~gz : 8 mnfsis Fd : ; 2 ss 8838 8 88 3 . 2 = 3] i ~ |S ge ,iq 2 c sied : !385888 "CH g 8 8 s a0ge 3 mY 8| RY | H5% By |EEJrErE E E EE RR EE LiE ~~ ; "J li! npn imma ~~ 3 5 533383833 | LB FErdsassgass | 3 | 2 z xz & I is oE3r3a3S3S3S3r3n3Eg3s 8 . 2 Z3Z8 g Some dm5a5i5si:usasa3a3n3as 3 2 Fd ad dg dS 49 4d d9 gg 8 z z 23 2i 8 52 4 2 ~B aFifgs iis 2 3 i FfF85 82 83 53258 % +:& FE FFE FPF: Company Saritind. DossrecorTStCAOiB | | |g 3: % . S8SF 2 F3E8E3 E38E3%E8 0 BEE HE 2 2: S88 . s:33 33s Fc ~ |8 Ez LuLSgEF FoFosgd os os osos sos rss H; : JE Ag 28 3 a gl 3 8 4 503 FY 2a 2 2 8 8 & gE 8 gE d7 RY 8d EC A a : E 3 i: EiYL.IE EJ EeEI2 5 ons 5s [22 H53i8t, i& js fsg.e2 f8 8i5 3f8i3 |5 i: :i IS & & J [~ g< 8 8s 8zs 25 85 35 38 wigan | 5833| ag 2 : g 5 sg 3535353538 3838 =3 2 z 3 ~ 5 gE jg 85s 83 g 338 g 88 g 8 3 3 83 23 5: . 5i i. [25H | le - 28Z i 1; 8 d oo i FoR ga IEERE FE] 3 2 2 gg iEiRd g 51 oHf E PI AEEIEEEEEEE Rg EEERE LE 8 irF 3 8 E3 F:8s 3:8 g |g(E2 R|%I.}% g Pi : gi Company Saniized. Does ot contain TSOA G1 ~g A x8 33% 58 58 8 a8 48 83 2% 38 83% 33 g zs = 5 & :it HEN HHNHERENE 2 ~~ 2 gs added Su ddedd & g22E3SE HEHEHE EE ' |( |i 5 23 ~~ i2 H ~Q: 5% 3883355335f 8% 0h 8d af ada g B3S 5 853S 3 G8 33 48 43 d8 dd dd ;g 54 I1gE0E : E 1 = 83 R 38 3E 8 33332382 82 3= Bg28f. F. i:fi35 f8 i8 g3% i3 i3 i8t2 i 3 -d GompanySanized. Doss ot conTtSaCAi0n81 ~8 a 5 $582 352 gE ES SE SE 8% 4% 32 | 2 | 2 228 & 3333333 :3 | i EEE 52 iEE g 8 5 35 3 35 3 35 3 La 88. sss oy CC CC T 5 <> Ag 22 22 qd . "vo. . . v zg 8: E =F 8 2 5 52 54 3 8sz 85 85 85 85 85 3= i Hadad gid :5 ,9 3 i:: I id. leR 3. E2 E3RN 5E8E3E E Hiss qssiiiit p 3 & 4 3 5 8 | Company Saniized Doesnot contain TSCA CBI | I~ 3 ia sv 5.2 5 & IgEg gr8a8 zz s8i&e8 3& l8g & 8 z zs 5 5 8 8 58 8 8 : 582& ilcci oss 5 ~ 8 0-0 0" 3 2 5 8% 2 x 32 Yi :33f 333r 3: fzlozg : : -o of 88 88 83 8S 85 88 85) 4 z : i 2: if S .. 3 . $8: 505 88 3 [53 g$ r 59 orov:ov% Fod : [538] s5idEe 3EF3 OE 3 8 i% E |:[838 3 : ig i | PE |3BEEZ3 ii i | mga eats BonarISORSRS ~~ = k 5 83gd 9%& 33 838 33& 8% 38%& 68 48 5838388 H5 2 stoma ' 25 A0 z eoSEs3Sm85HE35g96uSssgsEssgssasogss | 88%: n3 ds 5 5 5 35 5 5 3 3 3 3 5 TIER : 9 iiy iFfis ff 3e2e EPOeTxOEOREssGE ; d4 85 542 33384: 14 H55 o8 rs i3 i5 i f53 i3 i8 i i8ge z : g 2 | El Sd CompanySantis. Sous ot conTSaE Cn1 ~= 3 | g8 z 5 53 3 5 5 5 3 LEE BEE 553% oo ~ | Eog, dd dgrreeeee ZoSz EERBAERT YlsE3 Ees Hs i:sf LLL : $87 i : SE dL. ge 32% 8 ne 4 2% 8% @ se oo Ld 8f% a4 rBE e83 3e% z33o88o8e% e82 Ss J oS Ss 85 SS 85 Ss Ss i : 3 5 Fd. 1.0%. fe sosoxooms isE pFda: F88 |g(8 f38 8 8F8F EB 3 2 3 uf 2 8 a =e = 2 B2l3o 3ele ds8 s& i2 i i l8 s2 ed CompanSantis. boss cont TSCA ~~ 2 GEL 22 E 2 Spe oT gs aa 5Egg 33 ioi - 8: Je=zzszsz zz | . = 2 3 Lo . . . i i gF8EfE dL... sos : :2% l a Es RRa Rt EA sa fl iis FBi0r5a 5 a5 a5 d a |r-a3 |i 2 g ~ d [IE | i: Company Sizes. GoesconTsSOAiCa ~ [I | al : : g5 &g s zz = =2 2 z SE Ee : 5 ~ 54 22 zzg #2g . : 3 _ | 5: ; :g gz gg gz gz i ax s PU7 5 -.-. g: g :g g: a2 2 2 aa bd " B 3 3 B 3 golf 7 38 1] 1 1 B2r3, .BF 223:5 081 BREED, 55:8o BEG, L55a6%8:5 1os AREER, 485 EE Be pi 8H BF HE i$3i5 E2F 58 & a & CompanySaad, Dosre conanTSAGo 2 ~~ g &| : g3 =g =g g& gs 3Ean z . 2 g >0f :. z rz r -e ts. 8 =2 Z . ~ aCI g| s5 &g gg gz 2 322338+. I: I I = 5: g g22g dz 4 gy3 & z1 3i- 4| 3 op hsdfedof faf oogd sp AREA GEM f 5 68% 2 3 ud FC -- I~ 4 a :g fe z 2 I I IL g=s 8= z =2 g= s z z z z ~ | 2Ent ag omg oem - - S2 : zz I 2 2 5zS83og5e. Is: 32I 2 Ln gI 3g=: g5 z$g).z-*= =o.z z = z3= 5 4 if B 3i 3i iB 5 [ETE HE HE HE LP 1 : Id 3 1 gid ~ HR =f Fd [=] msriSae, SvsetemEIAIS ~g a 23 en : i. 2H " g oC : oz: z 2 a 5 gg 2 PO ; : zz oz z g of "3 ~ S8 ig z: 2oz z zzzz 2 38a I c So 3g :Ewer A zzVzEC. E 5 7 : Won : i TF 3 0% 3 :|5 B 4o hi 2 i8 gos E8opall Cu d4igou eif 8B i fe & F LfEe] HH3 32 M2 EEE 22 i 8 CompanSanten. OsertcoriSGAG81 ~g 32 " = 8 g ss | g Pig 2a - PPE | g Ess a2 g 2 $s ~| &&gfe S8 H HEES HER 5 EREE g & g2 " x 2 wel EE + = - 8% 0 5s8gta - ~ lv --g LEE MH 2:J 2s0% gfx gSiElEl : lfe,l 4H 0 4 yd ~~ 2 Bfsisds 5HO L[FciEs =) Sompepsmn, Bons 4 : SOR ~g 3: 2 g: 5 g= =z =z =g &25 =g z=g z= =Z =z F8E wan =a : a E s: : ~ q|= 2 z| z 8: = s: : Ban Tw oy os 5 :s2 foioant pr 2 z 2> izg8 :Ae 33% 2H 3# 2H ~igE - 5%7.5 8. 25 faaffdy,f ii 8 if i i5 ` 5i8f s8ir3 5s5i%r 5gf5 4 15 33 3S%z 8 Sof82 23: EF 83: gf HsHHOdHAEEA, GompanySanlzed. DossnocontTSaOAiCni ~~ 2 z | 2. : : gz zz = BE ~ & 2 =g =2 z=g FoH> * 5sa I I, I I = : I~ |e & 5 5 5 gz = gEEg : a oSco : o : l SI & FS FE] g gg Z> ron "g p-o -ag y - e- i038 IE 3 N23) 2 aB i oe ee ow fF 8 bd 5 a8 9% 03 FY H23d ,I3RE82203 f28 iEIg3pI 4d8lF0R i8 fp EEE 38%3 2 ConnySons, bons caraTSCA ~8 3 8 . LL 2 8 2 E g 5822 : Err o z D E 3 f3 zz Sgza ~ | g= fg :E gszg 3 gz s: 83 2Sa,m. < :ES< :z a=x "3 | 5 3 g zg 2 : Z Hem po - - z az i i i3 cr. a _ _ fFpi f0 obfg; i d% S SEE 8 3g 38 38, BY, ii 32 f$8s2: 4si3 3Fiiz 3:5 =| 8% & i & i= ed Company Santen. Doero tan TSCA Go ~i 2 | . 2 % < 2g 23 - sg 3z fs EE & 52 2 g 2 g zg "8Z 25an : - pe -- zz : -- cs= g22 5g zg 2 zgE E t2z g 23 23 8. - x3 ag2 -- &5 z zg g& Z Hot : - he 20g . pe 1gi4: " &2g f 5g F52 isFR o:os Hf : 553, #i0f g sd giH 2 3; 1 33 fsf isgd $13 1s lS5 Gfo eo,FF iE LdLEE Li E PREFE H &= 5582% 8% i3 =5 zEH82 38 3 ERE 2 2 - CompanySanitiza. DoesnotcontTSaCAiCBnI --g : 2 2 2 EE fT 3 z z 2 fe cg eg eo ng = : z8 gg 8 & Eos wm om 7 Ca C -- ~ | % i: & & : 8EoI g3|p 8Ez2 g z g g I. oT. I = - = v czog z 2z z 2= 2= gzs Ele Sp mg mg on : - 2, 4 |7 gJ S: ~F - 2Pr8 of3 3FBgE o3% p3iogdg ofF S af58 of555g%b BgEf zgpf o2gsgt LBB 2J 4BE gLR. EQ0Eff oa Ef0glfEiiYs iI:re:3 Lg fiHnHI iE: 0% FF 8 $ Gompany Santzed. Doesnocontain TSOA Gal : ~ gl 3 8 2 sz 5 2 | g 2 J. So | Es o g g 2 g g 8 ggaa -- - "-2 -- -- ||. g8z3 : Bit ~2 gzfer _I I-g _I2, I_2 CIgE RE[(8EA0l% ~ | 8 %= LHLE -= 82 g gz 2 g fErsax : daa ei oo jE & 5g ~ M8Ev 5 2 g2 2 g EET Enos 2 "] ay > Ss Fes :z i . - F35u; 2 osei dog upd ogy gr fad i4 sfrv, DyEfE gBE aInAEgG iERf iOEFE pan :J H firEF5, G f 0 F5 Fop fBEsE -d CompanSantas oe ot cnnTSAOB a g 5 2 ws 2 <4 I H z goz|if55 z fag < a = z ie >EBso sez - ~pb3E3R --- F x 8N z 2] 53sa g5 | Ba SE 7 53% a - '- cS| l8s% z os Ho & - 2%@ 3 & 3 bE = 73 sobs 8$388s 258 Loe 33 3|4:; : gy 83 2 FV g5| BSeEyL ofog Fo2z3 gef 25 HHEEE 3 EgEd] -- CompanySaized.Dossnot contTSaOAiGnBI ~t iA ii 3 g| 8g fas -i : les g |8 Zc End tH ~ | 2% 253 gsES i : z as : Hi : :| 3% 5.oma Ic"lEHig 5 : Z 3 iB . 3: iol: 2 ii - 0 Ina B J HEIA H 3 12 TE id SE -t CompanySans, oss et ceraTSCAG1 [ m Or Gogo Sm ud ncaisc7c ~ `TABLE 16 Duron oa PERCENT SURV OFI MAV LEA RAL TS PTreaentiTaantiagamay ;rmi vy wE m B pas ou H Emest Eeae w+e aS0S 1BIm odemmee 1d10e mdaeem dm 1o0 emoooo 5o 0 kde ak 0 kde wame am 6w & healoe adee adaoee s d1e0 ooio Swaoo ddtemm dda0ee adawmm d dieo eo10 So dm dm dm me ~ wWm9so8 %o > l1a d0m0 pm 1a0e0 m1a10o0 10m 00 e11000 | TBBoe oomadoo ddaemm adaemm 1dm e o100 Wo ddmm dmoe dlmm aM b mme B 1s dddme dpdeee 1dawm id0om ae RE : ? Pw wsber at study stare 25 1s 1s 1s et Sacrificed by oodesign TM 215 315 :15 315 1Hi5 Moermcbear ofSuTravtievalat=riuskbe+rNumobferTavast BsTtIuvdey estmaerer-oFmimTbeas sRCacT eificTed ny deaicn. I b. HTaacetadestignattoensefoaraych5e5. 90-day exposure pa eriod werea sa:crificed on a: an BTe0s8t BdaEyS3t0rum ton msi Wiewts wets sweatin on sais do $15 TDit e ps p 70 SASIRLIARIAY SSHIA Cant Sensesui. Un HUSTINGS 81 ot GI PP | ioe Gompany Saiized. Doss not contain TSGA Bt - 90DayOnlGavageSiudyinRats _ TABLE17 DuPom7s Emo, 1-1 tT 8% PERCENT SURVIVAL OF FEMALE RATS | bass on ges 175 100 100 100 100 100 Smmmrimnaenanel lo44. 00971 29 9 .217.0%% DT E EE RE nra Dasyay ~ number sacrificed by design. ctopmae iessicod eassesa.crecticstonm on ~ TDiarE as oR digi Hip HER SE 5 FEE #23070 ow Compan Sota. ss ti sh C S0DayOral Ga --~ iubncRtartosnic Toricty TABLE 1 DuPont9478 1 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR MALE RATS (MEAN OF THREE TRIALS) | Assessment Dosage Period Group (mg/kg/day) Forelimb Grip Strength (kg) Hindlimb Grip Strength (kg) Baseline 1 0 m 1 v 5 vr 25 x 125 Week 13 I 0 m 1 v 5 --~ VI 2 x 125 0.53008) 0580.11) 0570.11) 0600.11) 0580.11) 113031) 117017) 122021) 1270.18) 114029) 030006) 031006) 0280.05) 0290.06) 027007) 0530.15) 0580.12) 0.53 (0.10) 0580.16) 049014) `Data sranged as: Mean (Standard Deviation) `Sttistical Methods: Bares es or homogeneity followed by analysis of variance and Dummer' test. There were nostaticallysignificant differences from contol a pe0.. --_ - ee Company Sanitized. Doosnotcontain TSCA CBI C 9-- 0.DayO.nl .Cavage .yin- Rts. Toxiy ~ TABLE 19 Dupont9478 | MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS | (MEAN OF THREE TRIALS) | Assessment Dosage Forelimb Hindlimb | Period Group _ (mg/kg/day) Grip Strength (kg) Grip Strength (kg) Baseline bi 0 0.56 (0.08) 0.37 (0.07) wv 1 0.63 (0.09) 0.35 (0.05) vi 5 0.65 (0.09) * 0.36 (0.03) | vi 25 0.60 (0.09) 0.35 (0.09) | Xx 125 0.60 (0.10) 033 (0.06) Week 13 o 0 wv 1 vi H ~~ vi 25 X 125 0.88021) 1.03 (0.19) 1.05 (0.15) 0990.19) 0.97 (0.13) 0.50 0.10) 0.40 (0.09) 0.49 (0.09) 0.47 (0.13) 0.46 (0.07) 0Da2t9a adrreantgoeudnassc:hedMuelaend d(Settan.dard Deviation) | Ssical Methods: Batts for homogeneityolowedbyalysisof vain andDuetsts. | *Stal igafcnt diffrence romcontol ape0.0 byDunne'test. -- = Company Sanitzad. Doss not contain TSCA CBI LC e 90.DayOram l GavageSm tdyinRatsy | --~ rete TABLE20 Duont478 -- SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FORMALERATS BASELINE 13WEEK Dosge(mghgGaoypy 01 m1 V5 V2I5 1I5X Numberexamined: 10 10 10 110 10 0 m1 ov5 o3I5 oowsX 0 0 0 0 10 AMANPUPPULRATO&IOTANOSUC:CHH: ssoomraealcton 00 09 10 00 0 creasedreaction Gumpawayorstacks) 0 1 0 0 0 DAoUrDeaIcTtiOoRnYSTIMULUS: 00000 Deormxa sreacgtiroegnsctieaotnfr(lrsactshjeusmipors,efiicdgks)ca) 100 100 100 100 100 pToArIeLsPpIonNsCsH: -- nenoargmgaelr(suimdsretsopwoanrsdesic) 90 09 100 100 10 11 0 0 0 00 00 00 00 100 00000 00 00 00 00 100 00000 000100 00 00 100 00000 PIUNPMIOLTLOARRYARCETSIVPIOTNYSMEONITOR: psrbeiseenntt 00 00 00 00 100 00 00 00 00 100 pDrEeFsEeCtATION daherehnea $6 73 28 73 64 00000 6 37 731 13 64 00000 prUeRsIeNnAtTION: sheen 00 91 0o_o0 91 259119 371 91 "Theewerenosatsiallysignificant ifrencesby Cochran-Armitagetestfor eat p<0. -- wm CompanySaritzed.Dossnot conTtSaCAiGBnI 15m0.uDanyOalGavageSynRatvsic Toxics ~~ TABLE 21 Dwremsers SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS BASEN FORFEMALE RATS 1am DNosoamgeiospahgmiGiinnpg 1I00 N1V10 W 150 31VX105 m100 v10TvN10iSv10 X 10 TaMNrAeNeaUcPPiUoLRnAoT&ITAONoCSv:H: Jodi w0 oo0 increased scion Gps sway orsnack) | 0 AooUrrDcaIiTrOeRsYoSnTOaAtUfLiUnSch:esrkscx) 160 100 Cegracaion ejarpdip m ToArLepPooImsNeCsHm ovea rs) 00 00 ron a0 w00 o00w00 1000 1000 100 00 00000 5% S0 100 00 100 100 a0 he S0 1000 %00 10 100 05 00 100 00 100 oo oo FjIUrNoPeMIOLmLTAORRYAKCETSIFVOINTSYMEONITOR: a E 0E% R 5 0N0 n 0 ow rTDEoeFBsCATION ames s66s0737a 4062s0 PS5E0E107soaos rReAeTION: et 08deorch dest. s 79 r wog w oe p E1E1E - There ersnosassy giantiffocesbyCochran Aria st for end tp<005. --~ -- = Company Saniized. Docsnot conTtSaCAiCBnI ||Co 2 i | BJLRaiEsErsEaE sEgEeRanisgs Ps - 33 fo ead RENE ERERE 52 c88s58 gigh8 2: gH iH EE 888% s33el i oc dl Ip fg f| .gee28 gsesd i 5 iy = gs z sssee ssess| I=3 "23383 G5EES iE gsgEs 888 ig i . oii 4 z o-ng8 o-wn8l% iF EE: isffst Ve2 g8 msE5x -EoLEmE x|i| 3 iiHt] 5 g i : i138 - Compras Serta TSOAH rTM nu z ss5888 98838 "5S38T5E%5Rg5E% gglsEsEEzEeggsl ii& ~|g z 7: :8 5B i| ar = 2:5 78] Bgfz | | "52EE3E8:8 amsst "iEEER Z"s3eiisagf "SqeEgaEgsg sess gazsg sees: sased RcfaRsass E$8aEsgee : 3: Is 2 i i iz 4 Iz - 1id: i : : I : ::2 ~KBH o R28% 88358 1 i 83 29 g o-nmn agr =zsEx i3 ] o-wng| EasEk| g FH 31H 22 3 p$iii a 1 i2:i3dk Gongs, Samp ~~ 2 | Bets REgEE 3 EEE 88858 : "SIER pEE3s dese gpm A . a I 3gf El o223s EEE cease :i: 52 EX3 Zf|| ".Sg3gE8E2Rs sFaEsEs Fti:] a as ge= 3i 2 29568 2g898 . zi 2gs2 = 5 | "s3g3s3c5s IsIsEsaszg iig ig sggag esses Ha oi g3 2gg o=nmQ8 o-wgB i i : if .. H g -E>5x 1 EE TI hess] dal} 2 8 3 = ig 2 ~H 8 181352 corpses, bmn | 3og "28i533e8s 3g2SE8I8fE :: I~ | gf of -EREEE HME ; dEO O nEEdRE i: g EE | 3 .sgsse Td5Hs3 g5assEsEess i i sg 8 3g : | gE i, | zz ge J8EE88 | "s585F s8sgg EEEE: HE Hi Ei SF +i2 i55 ~&i Eg3Eg ---en e-wmn. lzI y Ei H i 2-4 5E : PL g =zs Ex EzsEk i i ! 1] s i Fd i ] la i i i l I frit `Company Sanitized. Donote contsain TSCA C81 C --90-D)ay Ora.l Gava.ge Sudy.in.Rats Tony --_ TABLE 26 Dupon0478 | SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS | TEST/ Growpl ~~ Groupll ~~ GrowpV Group VII Group IX PERIOD 0 1 5 25 125 | mekydey mekefday mgkeday mg/kg/day mgkgday RBC (x10/uL) DAY 48 8.33 8.26 8.18 7.90% 7.78% 0.38(10) 0.35(10) 0.13(9) 0.20(10) 0.42(10) DAY 93 8.57 03200) 8.55 037010) 832 022010) 8.12% 0.22(10) 7.76% 0.44(10) DAY 183 084721(10) - - - 80437907) HGB (g/dL) DAY 48 15.1 152 15.1 14.8 145 0.6(10) 0.710) 0.409) 0.5(10) 0.7(10) DAY 93 159 159 156 156 15.0% 0.6(10) 0.610) 0.5(10) 0.710) 0.7(10) DAY 183 154 - - - 15.1 ~~ 0.610) 03(7) HCT (%) DAY 48 483 483 484 470 46.4 1.7(10) 2.2(10) 1.2(9) 1.410) 24(10) DAY 93 417 480 1.7(10) 1.6(10) 47.0 1.5(10) 46.8 1.9(10) 45.5% 25(10) DAY 183 47.8 - - - 46.6 1.8(10) 16(7) MCV (@) DAY 48 580 58.5 59.1 59.5 59.7 1.4(10) 1.8(10) 1.2(9) 1.7(10) 2.010) DAY 93 55.7 56.2 56.5 57.5% 58.7% 0.9(10) 1.8(10) 1.0010) 1.4(10) 2.4(10) DAY 183 MCH (pg) DAY 48 5419600) - 182 184 - - - 185 187 551.4607) 187 0.5(10) 0.7(10) 0.49) 0.6(10) 0.5(10) DAY 93 1085610) 1087600) 180.5710) 109.5110) 190.64(10) DAY 183 17.7 - - = 18.1 07(10) [X0) -- --_-- Company Sanited. Does not contain TSCA CBI ~ | | | | -- | ~ C90.o Dsy Ol n Ga. ve S. oy in. Rat roy Dapone9478 `TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS PTEERSITOD _ Gro0wl Gow1pIl Gro5wpV G2ro5wpVIl mg/kg/day mg/kg/day mg/kelday mefkelday MCHC (gat) DAY48 313 315 313 315 DAY 93 DAY 183 RDW (%) DAY 48 DAY93 DAY 183 3330.5(10) 0.6(10) 30273010) 11.9 0.4(10) 128 0.6(10) 135 3510.5(10) 0.5(10) - 15 0.5(10) 122 0.5(10) - 310.49) 0.8(10) - 11.9 0.6(9) 126 0.7(10) - 330.7(10) 0.6(10) - 122 0.8(10) 127 0.5(10) - ARET (x10%uL) DAY 48 DAY 93 DAY 183 PLT (10%1) DAY 48 DAY 93 DAY 183 `WBC (x10%uL) DAY48 DAY 93 DAY 183 0.5(10) 2126 en16.7(10) 22.7(10) 179.0 24.2(10) 10115016) 1221 1329) 11148556) 14.18 2.1810) 12.19 1347 3.55(10) 3.28(10) 206.0 159225.6(10) 21.2(10) - 10908 0 1227 109(7) - 15.67 3.75(10) 1245 =1.99(10) 235.8 4145.7509) 30.8(10) - 1054 11190947) 1288) - 15.12 3.70(9) 11.77 z2.58(10) 2396 192643.2(10) 31.210) - 1012 nsa2s 126(8) - 15.46 3.13(10) 13.36 =3.59(10) Gro1u2p5 X mg/kg/day 313 300.5(10) 0.7(10) 325 0.6(7) 12.9% 0.9(10) 13.6 1.8(10) 133 0.6(7) 262.0% 22166.80+10) 53.6(10) 188.4 229(7) 950 11217586) 209(9) 10176457) 16.29 4.01(10) 13.89 13973.97010) 2.30(7) EE Gompany Sanitzsd. Dono ocontsain TSCA CBI ~ | | 1 ~~ - -- [ mm--]....e.e.n.ic pe "TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALERATS TEST/ PERIOD ANE 0D) DAY 48 DAY 93 DAY 183 ALYM (x10uL) DAY 48 DAY 93 DAY 183 AMON (x10%uL) DAY 48 DAY 93 DAY 183 AEOS (x10%/uL) DAY 48 Daves DAY 183 ABAS (x10%L) DAY 48 DAY 93 DAY 183 Group I 0 mg/kg/day Groupll = GrowpV ~~ Group VI 1 5 25 mg/kg/day mg/kg/day mg/kg/day 1.63 0.55(10) 1.86 0.68(10) 213775(10) 11.97 1.60(10) 9.89 3.01(10) 9.99 2.56(10) 0.30 0.13(10) 0.21 0.06(10) 0.40 0.14(10) oa"0.12 0.08(10) 0.07(10) 0.17 0.06(10) 0.09 0.05(10) 0.04 0.03(10) 0.11 0.05(10) 1.61 0.7910) 145 0.33(10) - 13.50 3.21(10) 10.55 1.99(10) - 024 0.1010) 0.24 0.14(10) - on?0.11 0.05(10) 0.06(10) - 014 0.09(10) 0.04 0.03(10) - 1.96 0.66(9) 1.81 1.04(10) - 2.00 0.68(10) 248 1.13(10) - 12.50 3.119) 9.49 1.45(10) - 12.84 2.95(10) 10.34 2.79(10) - 038 0.1509) 024 0.12(10) - 0.29 0.10010) 0.26 0.10(10) - on0.10 0.0509) 0.1210) - 0.10 0.05(9) 0.04 0.01(10) - oa"0.11 0.04(10) 0.14(10) - - 0.14 0.05(10) 0.04 0.02(10) - Group IX 125 mg/kg/day 2.04 0.90(10) 217 0.7910) 249 0.56(7) 13.69 3.35(10) 11.26 3.21(10) 10.67 L74(T) 0.27 0.11(10) 021 0.0610) 043 0.13(7) on0.12 0.04(10) 0.04(10) 0.18 0.05(7) 0.11 0.07(10) 0.04 0.0110) 0.14 0.08(7) CompanSenta. coetoraTSAGBI Lo CR on- b}, n ..-- o.u rorGweSeeD nDw res `TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group] ~~ GrowpIl ~~ GrowpV ~~ Group VII 0 1 5 25 mg/kg/day mg/kg/day mg/kg/day mg/kg/day GroupIX 125 mg/kg/day ALUC (x10%/uL) DAY 48 DAY 93 DAY 183 0.08 0.03(10) 0.06 0.03(10) 0.05 0.02(10) 0.07 0.04(10) 0.05 0.04(10) - 0.08 0.0209) 0.05 0.01(10) - 0.09 0.02(10) 0.06 0.03(10) - 0.07 0.04(10) 0.06 0.02(10) 0.07 0.02(7) sr ts dvi(Nerflsclini) - + ilypiifnomconol <0. byDun ahsDees. ~ { TIE -- -- | CompanySanitzsd. Donotscontsain TSCACal | | ~~ ~ UR o... 10 r 0-Day Oral Gavage Sy in Rats DuPont-9478 `TABLE 27 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Growl 0 mg/kg/day GrowplV 1 mg/kg/day GroupVI 5 mg/kg/day Group VII 25 mg/kg/day Group X 125 me/kg/day RBC (x10%4L) DAY 49 prDAY 94 HGB (g/dL) DAY 49 DAY94 JDAY 183 DAY 49 DAY 94 poDAY 183 DAY 49 DAY 9%4 DAY 183 MCH (pg) DAY 49 DAY 94 DAY 183 828 0.29(10) eo8.24 0.26(10) 0.369) 8.09 0.2909) 028.28 0.25(10) 8.14 0.36(10) :838 0.31(10) 8.00 0.41(10) 48.07 0.46(10) 7.50% 0.43(10) oe7.66% 0.34(10) 0.30(10) 156 0.5(10) 16.1 0.5(10) 147 0.6(9) 154 0.509) 16.4 0.4(10) - 155 0.6(10) 16.5 0.4010) - 149 0.6(10) 157 0.7(10) - 14.2% 0.7(10) 15.1% 0.7(10) 15.1 0.5(10) 490 48.1 483 46.8* 44.5% . 1.7(10) 1.709) 1.7(10) 2.2(10) 2.5(10) 472 419 483 458 44.6% 1.5(10) 1.4(10) 1.8(10) 2.410) 2.1(10) 44.0 - - - 45.1 1.709) 1.9(10y 59.2 0.9(10) 572 0.9(10) 56.8 1.809) 01.84810) 196 0.3(10) 190 0.79) 59.5 1.19) 57.8 0.9(10) --- 190.3109) 19.8 0.310) - 594 1.6(10) 517 1.3010) - 01.94010) 197 0.5(10) - 585 1.2(10) 56.8 0.8(10) - - 108.7410) 19.5 0.5(10) - 59.4 1.4(10) 58.3 1.6(10) 582 1.1010) 109..60(10) 19.8 0.6(10) 19.4 0.3(10) --_-- copys, por C-- 90-Day Or-- a Gavage Sty in Rats: Toxicity --~ `TABLE 27 (Continued) DuPone0478 SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS TEST/ Growl GroplV GrowpVI Group VII Group X PERIOD 0 1 5 25 125 | mg/kg/day mglkelday mefkglday mefke/day mg/kglday MCHC (g/dL) DAY 49 318 321 320 320 320 0410) 030) 0410) 0510) 0.5(10) DAY 94 343 343 42 344 310 04010) 04010) 0510) 08010) 0300) DAY 183 334 ~ - ~ 334 RDW (%) 030) 0.6010) DAY 49 17 1.6 1s 18 120 DAY94 0610) 0409) 109 11.0 1015010) 1004810) i0L46*00) DAY 183 0510) 18 0410) ~ 04010) - 0-310) 102.51010) ~ ARET (x10%4L) 050) 0010) DAY 49 2566 254 2490 a71@ 2406 447010) 2690) 51410) 3120) 180010) DAY 94 1414 1390 155.1 1406 176.6 314010) 160(10) 284010) 19310) 39.0010) DAY 183 1535 - ~ - 1644 3340) 27.0010) PLT (x10%L) DAY 49 973 835 1095 952 978 46(7) 175(7) 185(8) 1818) 160(5) DAY 94 1083 1025 1158 1026 1068 13000) 17409) 8807) 1907) 859) DAY 183 1059 - - - 957 1947) 2316) WBC (x10Y4L) DAY49 13.02 1183 13.25 1256 1L10 41110) 2630) 33810) 27310) 3.04010) DAY 94 1084 959 1057 9.86 1026 3910) 25700) 24700) 26100) 13810) DAY 183 729 - - - 8.19 19709) 173(10) --_ -= `Company Sanitized. Does not contain TSCA C8 --~ C 5D0.Dyay OOo rlaGGuavvaggeeSSu. tddyyiinnRRaetss oxi DuPont9478 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Giowpl 0 mgkgldsy GrowplV 1 GroupVI Group VI 5 25 _meg/kgldny _ me/kgiday mg/kglday GrowpX mek1g2l5day | ANEDUAY(x41904L) 136 066010) 094 0369) 150 05610) 143 08210) 1.40 0.56(10) DAY 01427800) 01831210) 01541510) 11272610) 107.648(10) DAY 183 133 - 0490) - ~ 143 0.47010) ALYM (x10%41) DAY 49 118 10.50 1.23 1060 925 DAY 94 34700) 2400) 207 785 325010) 870 27910) 761 267010) 801 DAY 183 33010) 555 22700) - 24810) - 21200) - 6L1247(10) ~ 1659) 167010) AMON (x10%uL) DAY 49 022 020 023 025 022 DAY94 015010) 018 0079) 018 01000) 015 0.1310) 023 002068(10) DAY 183 007010) 025 00910) - 00810) ~ 02110) - 0.09(10) 029 0119) 0.13010) AEOS (x10%L) DAY49 on 009 oz ou 010 DAY94 006010) 018 0039) 013 00410) 017 00510) 0.15 001035(10) DAY 183 007010) 009 00310) - 00610) ~ 0.0610) ~ 005(10) 011 0039) _ 00510) ABAS (10%) DAY 49 009 005 0.10 008 006 DAY 00510) 006 0029) 006 00810) 005 00510) 006 000064(i0) DAY 183 00210) 004 00310) - 00510) - 00410) - 0.0210) 0.06@ -- 004) 001(10) ------------------------or --------eesieo ere `Company Sanitized. Doss not contain TSCA GBI oh --_ S0Dsy cc os in Rats DuPont.9478 | TABLE 27 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS TEST/ PERIOD Growl 0 mgkg/day GrowplV GroupVI 1 5 mefkg/day - mefkglday Growp VII Group X 25 125 meglkelday mg/kg/day ALUC (x10%4L) DAY 49 DAY 94 DAY 183 007 00300) 006 00410) 003 0019) 005 0020) 005 0030) ~ 007 00310) 004 00310) - 008 00310) 005 0.0410) ~ 007 0.04(10) 005 002010) 003 001010) Daa amnged ss: SMteaandnarddevition(Numberofvaluesincludedin calulation) ~~ +@SuSitsiisctiaclallyyssiiggnniiffiiccaannttddiiffffeerreenncceefrroommccoonnttrroollaatt p<< 00..0055bbyyDDuunnnnettTesatm.bane-Dunnet fest. --~ Ee Company Sanitized. Doss not contain TSCA CBI - C-- a--.... prs TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE RATS TEST/ rt PERIOD DAY93 APTT (seconds) Group 0 mg/kg/day GroupIll 1 mg/kg/day GroupV ~~ Group VII 5 25 mg/kg/day mg/kg/day 159 0.809) 16.1 0.6(10) 159 1109) 155 0.5(10) Group IX 125 mg/kg/day 159 1709) | F 2509E ) 2.1(10) 1609) , 1710) 210) | -- i `Standard deviation (Numberofvalues included in calculation) - smnsam------------ TABLE 29 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS TEST/ PERIOD Group IT 0 mg/kg/day GroupIV ~~ GroupVI 1 5 mg/kg/day mg/kg/day Group VII 25 mg/kg/day GrouXp. 125 mg/kg/day PT (seconds) DAY 94 APTT (seconds) DAY 94 153 0.5(10) 158 1.8010) 149 0.6(10) 162 2.0010) 153 0.6(10) 150 1.6(10) 152 0.6(10) 154 1.7(10) 149 1.0010) 14.1 2.0010) reesesome itor Data amangedas: Mean `Standard deviation (Numberofvalues included in : calculation) ~ [ o50.Damy Or]Gava.ge .Sly in R.at I Dwromsers | TABLE30 | SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALERATS PTEERSIT/OD Gro0wl Go1wll Gr5owpV G2ro5wpVI Gr1o2w5pIX mglgiey _mg/kg/dsy _mglkglisy _mekgdsy _mgkgiday ASTDAUYL)88 0 n DAY 93 18010) 5510) 146010) 185610) po610) DAY 183 7ao 13-0) G0-0) 12-00 1314700) 13410) S110) | ALTDUALY)48 54010) ES5010) 25010) 55010) E7n(10) DAY 93 365010) 259) 4a0) M8 0 "1600) --~ DAY 183 91700) - - - 26010) SDHDA(UYL4)8 141 132 126 132 133 DAY 93 18375010) 1268900) 12s400) a3ls000 1385400) DAY 183 2437100 4-500) 16=300) 38=200 2616010) ALKP UI) 18010) 65010) DAY 48 11310) 121400 121670) 1B35 a 13695*00) DAY 93 103900 51750) o1sao 112000) 1336500) DAY 183 20800) - - - 286010 BILID(AmYgl4d8L) oat oor 010 - 010 007 DAY S3 00014010) 0o0o3s0e0) 00013000) 00009410) 00003910) DAY 183 00104310) 0-029) 005010) 0-0410) 0-0510) 00013210) 00410) ~~ eee pee ete Gompany Sanitzed. Does not contin TSCA CBI | -- | |~ 1 | Cooby]on.ly..Shae -- pis `TABLE 30 (Continued) TEST/ PERIOD SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS Group 0 mg/kg/day Group ~~ GrowpV ~~ Group VIL 1 5 25 mg/kg/day mg/kg/day mg/kg/day Group IX 125 mg/kg/day BUN (mg/dL) DAY 48 DAY 93 DAY 183 CREA (mg/dL) DAY 48 DAY 93 DAY 183 CHOL (mg/dL) DAY 48 DAY 93 DAY 183 TRIG (mg/dL) DAY 48 DAY 93 DAY 183 GLUC (mg/dL) DAY48 DAY 93 DAY 183 14 2(10) 13 2(10) 18 2(10) 025 0.06(10) 0.42 0.06(10) 0.46 0.03(10) 66 9(10) 80 16(10) 76 28(10) 87 24(10) nm 32(10) 81 33(10) 119 (10) 109 28(10) 129 40(10) 14 1(10) 14 2(10) a 14 2(10) 13 2(10) - 0.27 0.04(10) 039 0.08(10) - 0.28 0.04(10) 0.36 0.04(10) - 53 11(10) 57% 9(10) - 62 12(10) 74 19(10) - 74 27(10) 67 239) - 95 50(10) 7 28(10) - 115 9(10) 17 32(10) - 122 10(10) 114 24(10) - 14 1(10) 15% 2(10) - 0.26 0.02(10) 037 0.06(10) ~ 52% 15(10) 66 17(10) - 83 42(10) 64 26(10) - 118 9(10) 110 29(10) - 13 1(10) 13 2(10) 16* 2(10) 0.26 0.04(10) 0.37 0.04(10) 0.41% 0.04(10) 57 11(10) 65 15(10) 9 17(10) 43% 21(10) 3m 18(10) 95 59(10) 122 20(10) 105 22(10) 127 3110) eeeeenreeee--------eenseeet -125CompanySanit, Does otcotanTSCAGE! | |~ | ~~ | | Cworg. 705 Drees `TABLE 30 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group 0 mg/kg/day Groupll 1 mg/kg/day GroupV ~~ Group VII 5 `25 mg/kg/day mg/kg/day Group IX 125 mg/kg/day TP (g/dL) DAY 48 DAY 93 DAY 183 ALB (g/dL) DAY 48 DAY 93 DAY 183 GLODBAV(gi/dSL) DAY 93 DAY 183 CALC (mg/dL) DAY 48 DAY 93 DAY 183 PHS (mg/dL) DAY 48 DAY 93 DAY 183 6.5 03(10) 72 0.4(10) 69 0.210) 42 0.2(10) 44 0.2(10) 42 0.210) 2 0.3(10) 28 270.3(10) 0.2(10) 10.8 0.4(10) 113 0.410) 114 0.5(10)- 83 0.6(10) 81 0.6(10) 85 0.8(10) 6.6 04(10) 7.0 0.3(9) - 4.1 0.3(10) 43 0.209) - 24 0.210) 26 z0.209) 10.8 0.2(10) 13 0.6(10) - 79 0.5(10) 89 1.409) - 6.6 0.4(10) 70 0.5(10) - 65 03010) 70 0.4(10) - 42 0.210) 43 0.210) - 2s 0.3(10) 27 =0.3(10) 42 0.2(10) 44 0.3(10) - 2 0.2(10) 26 z0.2(10) 10.8 0.5(10) 112 0.6(10) - 84 0.7(10) 87 0.9(10) - 10.5 0.4(10) 111 0.2(10) - - 84 1.0010) 92 1.3(10) - 7.0% 0.4(10) 76* 0.1(10) 6.8 0.1(10) 47% 0.2(10) s0@ 0.210) 42 0.1(10) 2 0.3(10) 26 270.210) 0.1(10) 10.8 0.4(10) 114 0.4(10) Hs 0.3(10) 9.2% 0.9(10) 9.5% 1.2(10) 92 1.0(10) " mon Si, So eA TEES _. Cb ooo s --o . ccd 0 wedemDPe woew `TABLE 30 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD [i Groupll ~~ GroupV ~~ Group VIL Group IX. gl0 y mafi1gtsy _moh5eidey_maf2i5gley _me1g25tay | i --~ NA (mmol/L) DAY 48 DAY 93 DAY 183 K (mmol/L) DAY 48 DAY 93 DAY 183 CL matty DAY 48 DAY 93 DAY 183 1482 1.3(10) 1484 1.3(10) 1479 1.4(10) 5.87 0.53(10) 6.15 0.51(10) 6.17 0.45(10) 1022 2.1(10) 100.7 1.910) 1023 2.2(10) 149.5 4.7(10) 149.4 2.2010) - 5.68 0.47(10) 6.16 0.479) - 103.2 3.7(10) 101.8 1.8(10) - 1482 23(10) 1483 3.0010) - 5.76 0.62(10) 6.31 0.52(10) - 101.5 2.2(10) 1001 1.5010) - 1483 1.2(10) 1483 2.5(10) - 5.52 0.43(10) 6.32 0.71(10) - 101.0 2.1(10) 101.2 1.7(10) - 147.7 1.6(10) 148.1 2.4(10) 1484 22(10) 574 0.3410) 631 0.59(10) 6.29 0.54(10) 101.1 2.0(10) 100.1 1.5(10) 104.1 1.9(10) e e e rmineeee PFLU (ug/ml) DAY 93 DAY 183 0.1 0.0010) 0.1 0.19) 0.1 0.0010) - 0.1 0.0(10) - 01 0.0(10) - 04@ 0.0010) 0.1 0.0(10) ne Data: as: Mt Mean oii rfle lied clo n) Suita esifs rmcrota<0CotyeDbaikoceoeseDoes ~ | | SS comporySatins, Does ot eranTSCA CO20D Ort vag Sy nevi vic Demis ~~ rime `TABLE 31 SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD asDtAmY) DAY 94 DAY 183 - ALT (UL) DAY 49 DAY 9% DAY 183 ~~ DAY 4 SDH (U/L) DAY %4 DAY 183 DAY 19 ALKP (UL) DAY 94 DAY 183 * BILI (mg/dL) DAY 49 DAY 9% DAY 183 _ Groupll ~~ GrowpIV ~~ GrowpVI Group VII Group X meal0ies _mofk1gltay meal5ies _me2k5giay _ mol12t5ay n 11(10) 85 17(10) 177 176(9) " 15(10) 119 51(10) - os 6(10) 82 18(10) - or 89(10) 176 285(10) - a 9(10) 93 40(10) 103 54(10) 34 8(10) 40 0617(10) 90(9) 103 2.7(10) 16.7 4.410) 292 27.509) 816(10) 51 11(10) 34 89) 0.15 0.04(10) 0.15 0.01(10) 0.17 0.079) 35 7(10) 64 z 46(10) 29 4(10) 37 10(10) 44 41010) 75 106(10) 105 4.0(10) 215 8.2(10) - 19(10) 52 13(10) - 29 0.9(10) 13.6 2.710) - - 24(10) 54 19(10) - 0.15 0.03(10) 0.15 0.03(10) - 0.13 0.0310) 0.12 0.0310) - as 412(10) 44.4 84.1(10) - n28(10) 49 19(10) - - . 0.14 0.04(10) 0.14 0.0410) - 32 5(10) 45 5816(10) 41010) 100 22(10) 19.0 10.4(10) 17.5 10.4(10) 7s 14(10) 53 10(10) 38 10010) 0.16 0.03(10) 0.17 0.04(10) 0.15 0.04(10) SompanySarton. Bowsrotconan TSEASEH --~ Co prem m m].Aerlos Tioxiic -- Dipont9478 TABLE 31 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS | PTEESRTI/OD Growl 0 mgkgdey GrowpIV 1 mg/kg/day GroupVI 5 me/kgday Group VI 25 mgkgiday Group X 125 mekglday BUNDA(mYg/4d9L) 15 2(10) 162010) 12610) 125(10) 125010) DAY 94 1 17 2010) 210) 1m 100) 17 410) 7 2010) DAY 183 1 29) - - - 16 3010) || CREA (mg/dL) DAY 49 033 00510) 035 00610) 034 00610) 033 00710) 031 0.03(i0) DAY 94 047 00610) 049 00310) 044 00610) 048 0.10010) 046 006(10) ~ DAY 183 052 --~ 0059) - - 048 0.06(10) CHOL (mg/dL) DAY 49 7 19010) 86 1610) 7 14(10) 12085(10) w21e10) DAY 94 8 19010) 07 1510) 18010) 125 45010) 123 39010) DAY 183 134 - 260) - - 147 67010) TRIG (mg/dL) DAY 49 "4 20010) 50 20010) 37 12(10) 43 200) 55 46(10) DAY 94 51 26(10) 66 53010) 39 a 1100) 1300) 2 47010) DAY 183 78 146) - ~ - 89 63010) GLUC (mg/dL) DAY 49 115 t 2 116 13 m DAY 94 10010) 101 13010) 13010) 104 104 5010) 106 510) 100 DAY 183 9310) 121 1200) - 9(10) 16010) - - 5010) 104 ~~ 329) 6(10) |- | i 19 Company Saritized. Does notcontainTSCA CBI C o 90Daym Oral Ga] vage S. ty inR. ats 7.: Dupont 9478 | ~ |--~ `TABLE 31 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD _ Groupll ~~ GrowpIV 0 1 mg/kg/day mg/kg/day Group VI 5 mg/kg/day Group VII 25 mefkg/day Group X 125 mg/kg/day TP (g/dL) DAY 49 DAY 94 DAY 183 ALB (g/dL) DAY 49 DAY 9% DAY 183 GLOB (g/dL) DAY 49 DAY 94 DAY 183 CALC (mg/dL) DAY 49 DAY %4 DAY 183 PHS (mg/dL) DAY 49 DAY 94 DAY 183 13 03(10) 78 0.3(10) 85 0.39) 49 0.210) 52 0.3(10) 50730) 24 0.2(10) 26 0.2(10) 28 0.109) 13 0.2(10) 17 0.4(10) 124 0.3(9) 70 1.3010) 6.8 711.7010) 1.309) 73 0.3(10) 8.0 0.3(10) - 7.0 0.5(10) 76 0.510) - 76 0.5(10) 83 0.7(10) - 49 02(10) 54 0.3(10) - 46 0.4(10) 50 0.3(10) - 50 0.4(10) 55 0.5(10) - 24 0.210) 26 0.1010) = 25 0.3(10) 27 0.3(10) - 26 0.3(10) 27 0.4(10) - 113 0.4(10) 115 02(10) - 74 1.210) 59 =0.8(10) 110 0.310) 113 0.4(10) - 68 0.710) 68 -0.9(10) 11.4 0.4(10) 18 0.5(10) - 69 0.5(10) 67 -0.9(10) 7.9% 0.4(10) 8.6% 0.6(10) 84 0.4(10) 55@ 0.3(10) 5.8% 0.3(10) 50.4410) 24 0.210) 28 0.3(10) 29 0.4(10) 116 0.5(10) 122% 0.4(10) 122 0.3(10) 16 1.0(10) 73 740.5(10) 1.0(10) e--e ----------------BE-- E ---------------- GompanySaniized. Doosnotcontain TSCA CBI LC e oe }cc050 pn | 1 | --_ ~ `TABLE 31 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALERATS TEST/ PERIOD Growpll ~~ GrowplV ~~ GroupVI 0 1 5 mg/kg/day mg/kg/day mg/kgday Group VII 25 me/ke/day Group X 125 megkg/day NA (mmol/L) DAY 49 DAY 94 DAY 183 K (mmol/L) DAY 49 DAY %4 DAY 183 1452 1.4(10) 1456 2.1(10) 148.7 1.5(9) 574 0.70(10) 5.74 0.67(10) 5.80 0.55(9) 145.1 1.7(10) 145.7 1.3010) - 5.59 0.48(10) 5.54 0.39(10) - 145.1 1.6(10) 145.9 1.6(10) - 5.50 0.38(10) 5.96 0.36(10) - 144.1 2.4(10) 145.5 1.2(10) - 5.36 0.27(10) 5.40 0.31(10) - 144.5 1.8(10) 146.3 2.5(10) 149.6 1.5(10) 5.55 0.38(10) 595 0.31(10) 594 0.53(10) CL (mmol/L) DAY 49 DAY 94 DAY 183 101.2 1.6(10) 101.1 too) 3.0010) 104.1 101.6 1.3(10) 101.1 1.8(10) - 101.9 1.110) 1024 1.5(10) - 100.7 2.0010) 100.5 2.0010) - 100.9 1.0(10) 100.5 2300 1.9(10) 103.9 ee. PFLU (pg/mL) DAY9% DAY 183 0.1 0.0010) 0.1 0.00) 0.1 0.1(10) - 0.1 0.0010) - 02 0.0(10) - 05@ 0.1(10) 0.1 0.00) Data arranged as: ~~ Mean ion of . es din ci- n Se utennsdilffomsr tp <005bybDo oT Det J a Com Sa ROA -- C -- 90D1y Ol G] vage Fy metbsro Toxic DuPont9478 TABLE 32 TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR MALE RATS Gowpl ~ GrowIl 0 1 mg/kg/day _mykgday GroupV 5 mgkg/day Group VII 25 mg/kg/day Group TX 125 mg/kg/day VOL (mL) DAY 48 144 109 nr 130 1.2 DAY 93 10510) 68 5610) 63 6010) 76 7910) 56010) 78 2110 DAY 183 25100 75 1810) - 4200) - 56010) 13400) - 77 65(10) 41010) OSM (mOsm) DAY 48 79 841 913 840 605 DAY 93 42000) 34100) 31300) 36510) 1321 1324 1203 1549 16210) 703 ~ DAY 183 45700) 1400 32300) - 593010) - 85410) 45200) - 1322 8089) 590(10) pH DAY 48 73 7.1 71 71 74 DAY 93 0310) 63 0200) 68 0200) 68 0410) 68 03(10) 70 07010) 0400) 0400) 0310) 04010) || DAY 183 66 - 0.6010) - - 66 0410) URO (EUAL) DAY 48 02 02 02 02 02 DAY 93 0000) 02 0000) 02 0010) 02 0010) 03 00(10) 02 DAY 183 0009) 04 0000) 0000) 0310) 00(10) - ~ - 03 03(10) _ 03(10) UFLU (ug) DAY 93 107 130 88@ 4@ WI2@ DAY 183 4400) 99 1900) 1010) - - S790) 2463(10) - 27.6% 310) 5.1010) I~ -_ 1 BER `Company Sanitized. Does not containTSCA CBI Co _ C -- --) pron | `TABLE 32 (Continued) | SUMMARY OF URINALYSIS VALUES FOR MALERATS TEST/ PERIOD Group I 0 mg/kg/day GroupIl ~~ GroupV ~~ Group VII 1 5 25 mg/kg/day mg/kg/day mg/kg/day Group IX 125 mg/kg/day 'UMTP (mg/dL) DAY 48 " 5s a " DAY 93 -- e A m DAY 183 3410) 108 87(10) 161 164(10) 26(10) 9% 47(10) - 34010) 81 49(10) - 33(10) 89 53(10) - 34(10) 67 91(10) 95 91(10) Data arranged as: MHeoandin Cm les din bin) + ftye fonie fn lie p<<0003b5y DouonTabaneDic. --_ 1 | mE i ree | onsen, CORES Co}... Tos 0-Day Oral GavagSty in Rats Dupo 9478 R --~ e E rcossr e msg SERR2 TABLE 33 SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS TEST/ PERIOD Growpll 0 me/kgidsy GroupIV Group VI Group VII 1 5 25 mglkglday _ mg/kgday mg/kglday Group X 125 me/ke/day | VOL (mL) DAY 49 72 75 82 144 82 | DAY 94 3310) 5810) 6200) 13310) 5200) 50 28 42 48 77 DAY 183 4500) 180) 82 ~ 25100 - 3100 - 4300) 49 14107) 4410) UOSM (mOsm) DAY 49 882 985 1050 63 954 28110) 49010) 5090) 25700) 569(10) DAY94 1336 1519 61510) 5988) B17 1231 1051 52810) 49310) 71410) | ~~ DAY 183 1477 ~ 11047) ~ - 1445 868010) || pH DAY 49 71 70 68 70 69 | DAY94 0200) 0610) 60 6.1 0310) 59 0310) 64 0400) 62 03310) 040) 0410) 0310) 03010) DAY 183 51 - 05) ~ - 6.1 0.5010) `URO (UAL) DAY 49 02 02 02 02 02 DAY 9% 00010) 02 0010) 02 0010) 02 0010) 02 0.0010) 02 0010) 000) 00010) 00010) 0000) DAY 183 02 - - - 03 0.07)- 03010) UFLDUA(Ykg9)4 DAY 183 60 23) 119 1246) 51 141 - 8800 70260 146) 33) 2900) 25589) ~ - - 157 320) --_ | 1 { --------------------------------T--e------------------------------ | `Company Sanitized. Does not contain TSCA CBI _ Cm c -- o --o: o coc od c meleekpi0e pms `TABLE 33 (Continued) SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS i TEST/ | PERIOD Group ~~ GrouwpIV ~~ Group VI 0 1 5 mg/kg/day mg/kg/day mg kg/day Group VII 25 mg/kg/day GroupX 125 mg/kg day i 'UMTP (mg/dL) DAY 49 2 34 26 13 46 | Days 5 # a 2 | 7(10) 24(10) 18(10) 6(10) 35(10) i 83 21372(10) 370-9) 15(-10) 147(-~-10) 31538(810) i DAY 1 --_-- i 278(7) 1031(10) | Dats arranged as: dMeanion Caf es ncn) --_ Sis pinioc oman <0by0De 8 | a at i Company Sanitized. Does notcontainTSCA CBI C Ie o .t-- nocsro ioweMbwDrpiioe enns TABLE 34 er SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE RATS Hepatic Peroxisomal Beta-Oxidation Activity Group Dossge (mg/kg/day) 10-Day Timepoint (nmol/min/mg protein) 90-Day Time point Monts Recovery "Time point 1 0 148+ 10" 12412 11218 m 1 140217 136%15 -- vt 5 15921 13.63.0 -- vi 25 147%11 13421 -- xX 125 24.13.7# 20.6+2.8# 14920% r x e Smaty spin de iTfeaoe mweewn<]yw<0019)m bbyyDckA ahesr'Os TenRd st. SampleswerenotprepfoararnaleysdisfromgroIIu L, p V as nd VIIat the 90-dayrecotv imeepor intys. ~ etee e e eeee-: reri: ma CATIONS C90-oDay Ormal Gav.age S.tdinR.ats ic -- | TABLE 35 DuPont 9478 | SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN FEMALE RATS Hepatic Peroxisomal Beta-Oxidation ACtivily (--_-- wmoUmin/meprotein) Dosage 3-Month Recovery | Group (mg/kg/day) _10-Day Time point __90-Day Time point Time point | u 0 5222 256433 28513 | mw 1 22415 25414 -- | rr 5 23845 2713%2.1 -- | vm 25 22422 29733# -- x 125 255444 3915474 270456 ~ >Mican Sample=sswtaenrdeanrdodperveipaatiroend.fTorheannal=ysifsorroemacghrgoruposuT.V, V1an VIIatthe 0-day recovery timepoo. # Stadscallysignificantdifference fromcontol (-< 0.09) by Tonekbee's Tend test. --~ {i { C137 `Company Saniized. 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S gig 5| He 8 5588 | 3 | 285974 --i: TB HH :D. oE ig :z 2 ~B 3 [TM) nd it st || d| o LiL Eid i : E HH pl Cob 3 i i:jii gi hPyE i IRN NNN E enEE EE Gompany Sized, Doss net conTtSaCAiCBnI ~ : z 2 Zgbagf i ez r . 2 888FBPEgNE: Ez1Hl ITonTle age a ETnT oF ~ | ESEaEig lA TTETT Tgih i: gie8i5d8ZEAL i-- iE | i0iz | 1 HH g5 i i| 35 i5 iEaE ! | 3 if WoT buF g8E ~8 | u3 tia i E EEd E] yyo 122 organ iBT h Poor i pe ge I ii EF Fi a n Corps an. tr5ic ~ 55 } g a 3= fpe------ SHI a E Lak g Bie 08g: i | Bogan i { 37) HH TT i | EERE TT Eee -- gg2ge9g PT j i jed l e | STt E ieH g 4i geie S558 i 5 Hi gi | ids 8i i igs Wo: iy : i Popes i: 8sg | FERSEiEi Ri :iH g Lobe fiig H ' i E io |I ow : ConnySas,oss canTSA i ~ og 3 | z SN I py RrEIER eSHg b p Eri ; BSEd idiliTe i2 FERREIRA 13, glEeRpagd yi | ooTn i feo irsie. 8igs 3 ! g S58: fF 5 888 | 15 i 2813 -- iiHt io:27 iih z i | oi oi iy gCF Pooli, hiheliiid PC ohatkeit ~K - = ed Somes, ovpannesn ~~ | 3 | 3 3 ee g = gTTTme 7 Frae.fi| Z gi : bE | :a2,8 E i Blnf e| ie--lis 3564 i i 3, Ede TT aa. ~ | Egle rity ; g:8 3 888 | fre -- Fl | 28 4 ; |: g | 5 2| i Z 5i PE iIE i IH 1ii3s iss it 2 i: Ho: dil EI I = rEI I HE I i or peffijelchii 2 -- 2 g p27 Fl nE Sl 2g kh ? ofp ad i Co gi id aS i i| Bigilf igHp 51a1% 2| | i: Bk 6 fF, BE ui | {isin iE Lod HEE i KE i [iE if : TM] ~~ goZg EE : oI g Y EJm Er --Br Ee PRES iy = E 3 ggg # ilk TET i fF Ee iE CTH . $F Ef 5838 1 2 3 85gz83g | fF | -- ify HH z 2Z28 e i: id 1g]k Wgl oof2 oo 4g : g Z| 5 -) Co EdgrER ofr En lp ffi Eg Pi i g iPEE sgaigne G5E2L 0 0IH: Cb IE eh al i PE gig -- iE ComprSori. bons coma sco | ~ g3:l 3 i B g lahf z= TN Bp9 EiELp E ilif go54fg gr1 iTofud i _ g gg fem Fig ; SEE yk ; gg 528Fd 1 i53 gEaz8581 --: iHHRH iS "i :| iig N: za i |i ii%is : go HH 2 | Pork i Ely - i= i i eit PE IH z:S| i1 i 5 8 | I % HN0iis CompanySentins. Gorateconstin TSA GH ~ 53 g3 E =gE T flEimT Er i 2eaB s E | Eglis i Bp8 i iyi if cil i :z $i |gd 8 ~KH gf 5 : BEEN TE iE 3: g588 y i-- F | 75 HJ EI i | ; ! EiHE 5 iiRnL gE gz i| Pi ET2ER 0H%E]iar 2 & i LP(rE EBogpecEiAhEnS i PF iz EgetTE if PoEiepgezeee i2 hig wEH | CompanySw, oseotcomTsacAGn81 --| 5 z : g2 5 tg Bil E al #1 i fits i : - god298 | | iii , 2 HH i i 5 El | | FER ETER | ii; ihi i E| | i sg o5 8 og ifsf g | i iin i 2g | | gBoEygig dkE 2 2 | :8 |Le dBnOEER i g2, i PE Riialpaeduldi idB: ~E:: |E i iI ts af Fs Sih wo CompanySaiz. cons cnnTsoACo ~ =| 23 g2 gh gm g Ta EE EETTT ow i gE--, ZEoou if | i4 gata | i, g PT 15 ~ gi gigaa | i|| 0iidx $; 20E0ER ;i 5i273 2 gz i i 6 S325"8 i (igsk Wo5 gq ` : Eg EI oS gg | g i LE S PB $ ! Eadie :| ffLailae11a 110a { Pada1: POEHEET LH Lipg jHEegenianine 5i8 di f f sf 12 Eel BoE Eid (EE if = [=] rg : Cd : EE TT T g 280 i ZEg B fai i r Eei.i ggo Ei,i 22 i ig is Si = | ~ gi | EL 5 q52858 | } ! its ify Hi i i g | | a | | 1g gif iE FE ; Cb ETT i : iLo i | f[HiEi 5igo: i 3 8| :ifoAa38 l 8B8 iEF l[a0 os, pli if kK : i| oiigdFCC | Compa antes, rasraTorons --_ :i _ lo of3 3 $ | 3BE || Z2 [igLiIgIifIER LF s [HELO I ii, 9 1 g ogg HE | i z 888 EER | iE i S 82g! i ih sq: 3 i353 Eg 8F5144d1 i : :8 |i iE }| i] lH ii |IHH 8 1d g i 0 bE {8 Fig 2i ig iH POE ie i sf P i od E Ee ih $ 3? : ---- --_ 2]a 3 TTT HiT ooo H imo | it f fG.l00 F1o ii, g 824 i * 58H --_ 82g |i |i {52 1i3s5i 2 a Sg om =9 |i ii iingg 5 i Woe kia is a:| Cpl 5 ~F 1 aZgz ii zg g i: |i 0 i| 5 iiizfd ii iu Eid Poe 1 Lod PE, dds gs Pf Eoegee g I| ) [------ Zz {TM~ a |3 3 ggTg TTE| geen gi en g fa gg, Bggoog qgiiles i 5EA8E gf Hiz Ek=T| an ees, iy | ~ | 2 88 8 EF imiem ETETTEE EH i. fed = Po i :| Wo 5 oofF 3 i: gE g | "|: z ; S2 i 2& fw} a iH i ifs |: EgEfE yiiEn kJprue:te ifgiili HiO B BfLh EREoh i1 e ELEEA EeaiEgiagt i iEEd 0&8 if geETTF2 Ti i2 yi338 CompanySanizes. oss ot tainTc Gt ~x 2 i i] | g&E 4 PiRlELl zs H zfraezeeezal | hae || hEl gil iH "EET i ~ lsEeglss fyl1yeh] fe --Ezgu30 if iH } gBoargde 0iL iHH 2i i iaf Hoi8 | Bo: 2 g! Sf | ;i EERE | Td i | B I lah55 Ebi Ceomd IRE iT por |op llF h `CompanySanitized. Doesnot contain TSCA C8I | |~ :| g " E 0aE : g2g hgiidEgiT |i g 8Dou8fnd 5By iB ini ii% Eg m--o ~ SaseeidisS A1EE iiE iazaR zaz1 a ; dsiagisd -- 0 i0 58g! i i5k g2 | A 2 : i ig i Pog [ i P1a: i:sI oF EHfgEI REIFEIE EHgEB] bd omtrtatins, mpsmenronnce 3 g Shi I fgJ ESI 1 5 880 LiL ie is ~ ieggagg 3 iigi lii e --N E S ERTify i 1 1 gag 1 i gg | if gz 2 | |i gi5, 3513% 4y10i : : iCLCi opjppiie iuEEnE anpfiulinllgdy iWf o8og 0 PoBdEddderd Bfed s 4 gZ i g || f [ Lii lia f3 i t i ~2 |CoE sgEpd8 0 iE 7 lora gEsk 3 |=) RI - g 32 Ep. F838) Bo gdi 0e ~ 3Sgggi3dEg lj I 4 E=Eaiaiisg 82 8; Eggs -- 0 ii :: i Z pos 3 3: g g g op LHLLE i i5n | | i | !i PFs |i opr Pa pH i i 3 EE 8 bd Company Santas.SescominGo ~ CgZ| | Ep hE | :3 I g& iigTi 1Bghi| gEF eaem= gal L EgEg RB IN ETi _ BsleggeEL=T Eee z ge PLE 5 2E280iifF i 9 5880 0 CE83 iE ' 2938 -- 227 } ig 15k g4 3| { i i i | } i 13 fl 8 ro TEE EEE EN #4 z i yf pl BEIH 5 iPEO EE fHhe EE 5 Pie=F iE l| u | Coan Sates.SenecTsomAGB I~ | | gg E yh4 la eat | le4 SEig i bh R oF g gi I po TELE | ~ pL 1 E i ib] ibd Hi j p i apfg F e fr Fs is ed ~ f 2: | goggles gag29d8 iEmi NF ~ sgages e 1 3858 1 is if i 8 Eil 2] i i 5] of, HE : : : niy o! : ~ KH2: i ! Li y A od 1h i | i Pyle a B 1833 "EE ise Cio E iE EEF e F HE ed ~ |B g ; --_---- To 2. | A Z igi | --i gsaggd Lo------iiy : gif iH 1] 2838: --i yo: osg 2 g gl g i i FEg 1 g i1i| thyioy i 1h olb{ilpo1g0i = | Company Sanitized. Doesnot contain TSCA CBI ` ~ g g 0 i :: | 2soggITeT.| PgTe-T--E3TzgEzT! FRE 2p 8 EE 2 FH Elm: gsedf 1 ih a iggy -- E ai 5 Hor g ooff , ~ ;S; iF ud pgdil E JEd E eT2k pl IM i3 | gg PE :8 TE zceezr eicl| z RELA | Lik on g88Bdg8 Bg ITE m 21 TO : EEB RE eh1 i g 588 if | IE Z8 ; ii | ig i i Ey :0 EHR yRIS fl "J Come. ttTn S ~ ar A Eb B08 hfit E------12i | lglg a gaia i | ~ gzESgEggeH4d 81-- 8 3eTmTii gSLTEN hEHb &g Zz Phe Pg =e] -- | gi i i%s LE| 333 ~K | gs ; fI g T Fae LE 5; pg 1 I Pod EgE e EigE Company Sanitized. Doesnot contain TSCA CBI |: 2 erp B0g5gd iT gil ~ | g sld =on --1i : gag Zgzg -- Hii Fgi ygq || (iliiiisn fl 2 i] o Sosf piiEde gy PoErpiel ck g : ite Ea ~~ -- |w mers mmeemnocnen --_ |3 I 5z TTT | zg fem T PT E I 5,20 1 g 28 i i ~ | Eggdeigg Hi ; i gs = | i 121 Tei 2i i i . 5 iH z EoIg 3Bo 2 gs ~5 2 td EEE | guEpEiii[layH | i 0 HEpEiE gi | g Lirf Biafnpainaal:a 4 i p i iss iE Pe : |2 ied i : | ~ : : 5I e Me rm gz ElTETT eee | T BalEe1o n C y:i g gggid -- iiad 8| | iE $828. i252826284a 5g29 { z| :| |i | i| || g Lf 5iiiB H1i% 8p0%iniE y eid Wot :2 2 zg , i i| 0 BELW wHh.indenad ii=i k KE gJ I ip.ie iPiE r HE g 5 iE%ee3 CompanySid. Sons contain SOAR --~ g 3 3 ------ || 2goa ETiT iis ~8 Bo2389 ii ii3s ~ E fe842d4d | |!: I3 ih 3; c B25 i Io: ly gd 458 4 i : 1 ! if Woo8 i [A bob i git doc HE HE f| Eg Lf dr osidifg 3 i {EB F iim ~~ Ri x Somes, Domi ~ g 2 -- E2E opBeE lT3 TTa Z Fi | it 8 HH] PE i Bog i S3 g5i5f7 5580 |! 1i%g i gal Hi #4 iH] : Pa =f g |: | iEkis . J ! Pie ;4 _ IEEE gi, oF i i: EEE ore LEER tRF iE 2| Ld Sempsoind BonsATIT ~ CC Xo Dy mo mu. CwgElRymR Dions 9418 | | FIGURES | | {- Gompany Sanitzsd. Does not contTSaCAiC8n1 C ners ~~ 90.DayOnl Gavag Sady in Rats DuPont0478 FIGURES || EXPLANATORY NOTES CriticalDates Day1 Last dayoftest substance administration for rat designated for satellite bleeds and 3-month recovery. Lfaosrtradtasydeosfingonna-tfeadsftoerdtbhoed9y0w-ediagyhetxapnosdufroeopdecrioonds.umption data collection | Lassattellditaeyboifefedosodinctohnesu1m,p5t,iaonndd2a5tamcgo/lklge/ctdiaoyndfoorseragtrsoudpess.ignated for ! Day 92 Last day of test substance administration for male rats designated or the 90-day exposure period. Day93 + Last day of test substance administration for female rats designated for + tMhael9e0r-adtasydeesxipgonsautreedpfeorriotdh.e 90-day exposure period were sacrificed. ~ Day 94 Female rats designated for 90-day exposure period were sacrificed. Day Day 175 182 Rats designated for satelite bleeds were sacrificed Last dayofnon-fated body weight and food consumption data collection for rats designated for the 3-month recovery period. Day 183 Male and female ras designated for the 3-month recovery period were sacrificed. | --~ | ee | `Company Sanitized. Doss not contain TSCA Cal ~ g = 3) jest 5 pe ttx a 1h | i% | iCI 1 1s\ zg 4 3 --~ BS pi)3 8g A g =5 LB: gg X) 2H 125 2 lesd &X 58 13= & & 5 3 . : : 1 & id2 ._ | WN 2 AN s Ry : Ah 5 Ne a N = :# ~ RK 2 J 1 ER en EEE CompanySenitized.DoesnotconTtSaCAiCBnI 3 [EY i HitiH i. o [sa nN is 891 8 % TW List s Uh Fost --~ ||| 5 gE z 3E 1 R7 Rue : XS i i, 5 iA 3gEE o&h El 2 2 28 3: 23 3 ii } i xX % i x fpeo Loa Len w lo = 663 * nw i w os " s w ii2 s 3> - "= ) " y > 0 %g & 2 2 @ wo Apo m EI ~~ i= = || ed Company Sankized, Dosnot contain TSCA Bll --_ | 23 | g g =4 : | : ~ . g2 E2R gg : | 2 z | E< ~ KEE 52 | WJ Geeid 182233 Gagan a3 2 : rodi i i : 1 32i ------ 333 5+ 1} TE teres i corpse, onc --- | | | g3: : cg --_ z& 3El g E& : 5 zgZ 2 | 4i ig ~ KE 2 I)g Eee [Beaan . 2 |3 & |3 : iIEt 2 gE gg i " i HiEi id 1 3 ia -sput2esdo3 rons38 21] Company Sante, Dons otcota TSEACE! ~ i 2g3 5 ~~ gw EB ?E iz: te |8 |S ~E5 [I~] Hil 25233 EEE Eos E-EwniSRQ _-- Capes 3EB 3 3 8 gi 2 i2i Company Sand, Doesrtcontin TSGAG1 3 | | 2 3 || 83e --~ E i: | gELg B & 5 :2 | 4 {| 3 ~ KE 2 | 1 = l1mmE33e3 32d:dd 2 = i 1 & 22 8 5 33 1 i 5 [ 33 | ii CompanySanitized. Does not contain TSCA C8 : || 2<3 | g8 :g - : ~8 gE sz ggg 3 i # g =E w HE2535= 33 123832= 33 Eaanal [ . z 3 . 5i 2 i 2 2s 3 g 8 con m8eer &g 8 i Company Santzd. Does no contain TSCA Cal z : E 2 --_ .& zg 8 En Eg z 5:&< z g 5g > S| z 2] 3 2 |) [EEEeESaanl 3 = 3 : g & PB i2 ! , fo 3 i 8 m@peg & -- 2 | | 7 { --_ 2 | | gsZ y ~ Eg s2z E: { 22 g -- [3381 lsaadal -2 L3i iF1 ii --z io 2Zzg] RB ~F 5 lw8 | -- -- -- 88--5---- 8888 ig1s sno Jo SGN 52 CompanySanitized. Does not conTtSaCAiCBnI ~~ |4 | 3z [FERES CERRN a | fs Ez : | 2 IE3 |;i IE =) i g io | : | I | Escerrersenac- i; | | Corrinne ~~ Cm90-m DayOm ralG] avag. e$y.inRa. ts ic DuPont. 9478 APPENDICES | | | --~ | | ee | 20+ Company Sanitized. Does not contain TSCA Cal --- C -- Day Oral G) avage 08 isntRaotns Tovicky DuPont: 9478 APPENDICES Critical Dates EXPLANATORY NOTES Day91 + Last day of test substance administration for rats designated for satellite bleeds and 3-month recovery. Last day of non-fasted body weight and food consumption data collection for ats designated for the 90-day exposure period. Last day of food consumption data collection for rats designated for satelite bleeds in the 1, 5, and 25 mg/kg/day dose groups. Day 92 Last day of test substance administration for male rats designated for the 90-day exposure period. Day93 + Last day of test substance administration for female rats designated for the 90-day exposure period. Male rats designated for the 90-day exposure period were sacrificed. --_ Day 94 Female rats designated for 90-day exposure period were sacrificed. 1 Day 175 Rats designated for satellite bleds were sacrificed Day 182 Last day of non-fasted body weight and food consumption data collection for rats designated for the 3-month recovery period. Day 183 Male and female rats designated for the 3-month recovery period were sacrificed. Note mg/kg = mg/kg/day | --~ = Company Sanitized. Does not contain TSCA CBI Cd... ~ '90-DayOralGavageSudyinRats I ||| APPENDIX A ANALYTICAL DATA -- || [~ | J { ENCompany Sanitized. Doss not contain TSCA CBI | C -- ee ]hcarco Dros pss S2omat]5 ---- | Cy A boooom op.ty joi~s | bed = a a or 1 opstci Mean): 0.16330.002 (81.5%) 2 Lyoouius iin afmeed =5 || Mean(): a 0850:0.04 (85.0%) vpToosrz I"i= ji2oa "bx --_ Tor rSsloa-- ig b=5393+25 oya a=namies aw=2nusei 5 Hour) 250 020 Mean): 4.6530.13 199) Mean: 216315 0.167 (93.0%) 796 (86.4%) 85 Mean): uy0.16730.01 (83.5%) gr 5TDa HouErr(eL) eL er e0Pt2m ----0T.158--) ----C1--0 mporererter -- ---- B 5 Ems iemtm ottritin,sem atet i FRE | EI -- Company Sanitized. Doesnotcontain TSCA C81 | _ C oonon-- oh} re ioc pmo T-- ae -- DoinSupeios cTonoe a a gn e oo ow s I. woms 1 oa bo BoTTOM 10 0836 () 86 Mean(B): fi0.588+0.05 (88.8%) | yaTmors 550 3443 o886 || BoTToM 50 Me: 4431na3019 o9r4e.4s ||| SNTooormrs 2F25t0 F22A2 4+88HH8 Men: 730510 rom) sng SH 1|| ~ 5 Hour) 10 50 30.854(G) 475 %85.4 950 | DayRveToomsar 1i0 oosrm 5p0o0o hid i ii F4 A Mean(B): 0.874:0.02 (87.4%) a 4 Men:er4"453001 wwoi "" 220 H5e s5s5 Men) 2102 06%) Ar 5 Hour() n10 "a09040) - 904 P J Sra 2E50E toE mate21e.20t0)m rit-- tern-- o8t4.i8 note, GR E re T -- PR oJJgU iarse I .SYt coinetiht ets | (| OS = , | Company Sanitized. Does not contain TSCA CBI _ Co).Et .ar.es ric --; A et Concentration Verification(4) | `Control 00 NDB) i. 02-1(0) 0.153 765 0352200 o-bosee b8in8e mean(): 0.156 78.0 mean(): 0.169 845 fisn ioo nnsl Mean(D): 0.163 0.01 (81.5) mean(): 0.749 749 ~~ 1020) 0784 784 mean): 0.776 7.6 Mean(D): 0.763 + 0.02 (76.3) 00 =32 wEH so mean): 3287 f7F3 5.02) ea 39 is786 Mean(D); 3.89 20.03 (77.8) snowd25.0102) mean: oia119944 m777ss6 R , a Mmeeaann)::S119o9312021 7262 ||| JJ S EEEEr a oy merrea e Die or eets itmon trentetree : 1| os Gompany Saniized. Doss not contTSaCAiCBnI ~ TU9-- 0DayOnlv GavageShi y inRais 05 Dupont478 Table I.Cones Vedficiono mi sia n SolutiFoonsre(nconned) | Sampplee lTye lNoeminal `Measured `Nominal ConcentrationVerification") 00 NDB) = Control 02-100) 0.065 325 020-21110)) 000.06s7 3n3s5 00222200)) mean): 0o0.00o8663 0220) 00s i"303ss0 20 mean): 0.083 as `Mean): 1010) c0v.0.0670520.01 1010) oer 37.5) 2a8 10-12) 1020) m ean : 000.7658667 a66864.67 ~~ 11002200)) 008665s7 657 6s mean(): 0.656 65.6 | | Mean): 55001100)) c0v.26.1636% 0.01 an (66.6) iasse ! 5.012) 5020) mean: 222222160 5020) 236 44202 a2 5.022) 233 466 mean(): 232 464. Mean): 25010) v25a.321m60.09 5.2) 52 25012) 836 ~ 34 25020)mean(): 853746 35340 25.022) 852 341 mean(): 8.64 346 |! --~ De EE Ce ee i Mean): We SB Cc8Vv.c .4o9%021 a r(o3d 4.0) [r= { Em REICest nt | () Meanrub of the crginl alysis (0),3dduplicatereanalysisofheaig sample (1) @) itramicn hecot mit spc (1). Odin sonsnckpt 185e otror | J eeGampanySaniized. Does not conTtSaCAiC8n1 -- 90-DayS Oral Gavagem Sy ivRiat-- cs 1557 Dupont9478 `TableIL Concentration Vecification SPraemppalreaTtiyopneDiy Nngomi! "Test Day 460) Dosing Solutions conned) Measrid N= omina! C`oConntceanltration Verification(A) 00 ND) pe 002212 2011979 o18955 Mean): 0c2v0.872%002 aot) | 101 036s 65 |{! --_ TesDa5y2 MeantD): 0c.v07.+o0%06 007) 550012 3r%e 778860 Mean): 3c92r20m02 83 22550012 22s19 %5706 Mean): 2e2.v2a0.n42 58) CoCnocnevnotlration Verification") 00 o) -- i 002212 oose 25700 Mean): 0c.v1.7a9%001 .9 110021 0088945s 5ws Mean): 0c7v0..a2%004 0 550012 aprss 842 Mean): 4c19v20s04 @8r 2550021 22351 220 Mean): 2c2v9.2085 oo ~~ &DOTO DtDepoa emogieen,vevag SdCpercot fori pressed rte e det, odcsocf ssion fo So dustn ins. | --_-- Company Saritized. Does notcontTSaCAiCnBI (mi... ~ 90-Day Oral GevageShy inRats DuPont. 478 Table IL.Concentration Veifcaton Preparation Day myn Dosing Solutions (continued) Forcen Simple T Norina Messur Nominal E.R ConcentuaCtoonntVreorlification) 00 NDB) -- 021 022 0167 018 85 045 Mean: 0.1c7v8.09.0%2 0) 110012 00995630 996540 MeanD): 09c57v2.010%1 sn) S50012 saanl 85622 Mean: 43c6v2.020%7 72) 22550012 22s8 185256 1 Mean) 2.c1v5.0i9n9 89) TestDay 58 `ConcentratCioonnVterroilfication) 00 NDB) -- 021 022 owns 0150 #0 750 Mean): 01c6v2.01.00%2 610 110012 09093415 954357 Mean): 0.c94v1.0i0%1 ou) 550012 asa1s w9m6a Mean): 43c3v2.0s2%2 69 22550012 221s 288040 CR Dee ams Cer ve MeanD: weesad 22c30i03s8 Mean SD. 8CV. ) Gleuna to vofme ixture ~ O aDeo e pfnootroddeutn peelcitseceda.de scaomnpcleeassaion vers erentofpominl (i parenbess),sandeddeviation, odosfcint of { | - Te Company Sanitized. Does not contain TSCA CB --_ TC DmemymOr Cava Sy in Rcartsi vic DuPont9478 Tal ILP.SrCaoemnppcleoennTtyipBoeyn Verficion S Nongmimld.MesDsoesding Solutions coNFnotmieinnumaeld) TeaDay 65 `ConcentratiCoon nVeciafiation() 00 xo -- 00221100)) aoissee 00 || 0210) oi mean: 0159 s10 7s 0220) Gia 740 | 0220) oie Po | 0222) mean: MeanlP: 0011530 0155 2000 076.5 79) 101 aosvn 102 oss 0023 ~ Mean(D): so1 v0pi.r8s6y5a0.05 502 120 (86.5) s5s8s0 Mean(D); 4360.06 2501 a2v0isn 22 2502 205 (87.2) 820 Mean(D): DP e CL Tek Ve 55.cnv2d0.C7V=.02G1 lee (82.6) vey Soofmye. nDebsedni.issyis (0v)e,gaedpdolncfsemoiihetienlsasmaplned(r1d) evmdoconli,n of | --~ | EE ER Company Saniizsd. Does not contain TS--CA--GBI lan 1commun sic Ts '90-Day Oral Gavage StudyinRats DuPont-9478 TableIL. Concentration Frepaatan Day Viconof gin] Sample Type Noma! jn Dogg Solutions (continued) Misr NFoormein A eS RR ET ConcentratCioonmVeertification) 00 Po) i. 002212 001166s2 061s0 | Mean): c0v1.6r4%20002 0 11001100)) 0077841 778414 ||| 10-12) mean: 07053460 775640 102 0563 63 | Mean(D); cv0..8o1%220.07 81.2) 55001.00)) 39o0n 5014 50-102) 39 782 ~~ 55002200)) mean): 33.8916 398 776922 6 5.0202) 0 780 mean(): 390 78.0 Mean(D): c3v..93i2e0.04 25010) 191 (78.6) 764 25010) 03 a2 250-12) 202 808 2255002200)) mean(): 111889399 777556264 25.020) mean: 118847 8 736 Mea: c1v933085 (72) CR OS DDDueapsnesavoosfendaC1i5acammrlvaiesown.(ei0r)n, g20apde lisofrseSaallDyGoCn.fptVreceragslislol)edssaoinvcdwr(1d.ao 0i)n,r sodfciot nsfi. of etaion ondoi ss. ~~ `\ - Ho: Company Sanitzsd. Doss not contain TSCA CB -- CoDemOr]mGav}age.Sty.in R.as Toxicity Dupont9478 |i Table Co cts FSetpasmton Boy mg goal cp Soluions (coFntoionured a Norm -- ee -- | ConcentrationVerification) Control 00 NDB) ps 002212 0012 306500 Meal: v0i19e120001 059 110012 or0m7s 2me Meal: a0v7i88n2001 a ssoo1z aao2 s0e: Mean(C): 2501 2v4.0i10n20.03 202 214 (82.0) 582506 ~ Meanl): c2v2s2a11 (888) TeaDay 72 ConcentratCioonVnertification) 0 NO) - 002212 oosrss mssso Meal: cau16m6 2000 8 110012 1005830 1508300 s01 Mear: c1us0m12008 oa14o) 502MeanlD): dscp40v6002s "9e2r0) 25250012 234 s5i3s2 Mean: cv2.392078 50 ~ Pe DDepetnordtce.CDconT,w sp Vi55.Clie fs nes). veryweofmys. dri oe piety ering - 1 En Company Sanitized. Does not contain TSCA C81 ~ tT -- 90-Day Ora Gavage SuSdyuibncRhactosic Toxicity Figure 1 Representative Analytical Calibration Curve DuPont9478 | 10] Equation for the fitted line: Y=0.006840-+21.23095 * X 08 R-Squared = 09980 Fos 2Soa { = 02. -- ao. 0 | oot ox 0; 0% 008 Concentration, mg/ml Figure 1: C(saqluiabrreast)iofnorcucralviebsrahtoiwoinnsgolluitnieoanrsfoit ine) to replicatepeak eilguhtterdatoivoemreaasurements. csamoplenwacs eurseandngatseotfhre0.za201005t.0tio0o.04n53mg/mLwiththe 0mg/m.contol diluted --~ 5 Company Sanitized. Does not contain TSCA CBI ~ {mOrm Covm eSBicncac sty Figur2e Duron5i78 | Representative High Performance Liquid Chromatograj phv Chromatograms || : i i R l a FC a omigng, ! a0cms LRe(ocrio)onsnigVib ealsandy 3 mm ma andar sprasttly 5. minuS s. s i | # | | " 3 FieairdsRbeompimrFlPecLCoscnhrocofrm0ea.t0ano%mgrepatalofi.o0oThnemessed cOpERTLOonfBY reprLesieonn: E| ASolu4t5o5mnyias = i |. : = [mori regmt tome] i { erence sin { -- eee ------ ee-- ------ ---- Company Sanitzd. oss not contain TSCA G31