Document 3N80eBB2gXYVJNZQ9yOD54DME

AR A236 3286 as DuPont 11418 AR 426-3286 TRADE SECRET Study Title H-25425: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations Volume 1 of 5 Laboratory Project ID: DuPont-11418 TESTGUIDELINES: U.S. EPA Health Effects Test Guidelines OPPTS 870.3100 (AUG-1998) -- AUTHOR: Susan A. MacKenzie, V.MD., PhD. DAB.T. STUDY COMPLETEDON: August 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 "WORK REQUEST Novo:(guild SERVICE a --\ TT hmiam `Company Saniized. Doos not cantain TSCA CBI $505-4D2a5y:GaSgubechSvtoundiyc TinosRitcstywithOne-GenerationReproduction Evaluations --_ Dupont 11418 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT This study was conducteddarindsc,omwphliicahnacreewciotnhsiUs.tSe.ntE`PwiAthTtSheCOAE(C40DCPFriRncpiaprltes79o2f)GGoooodd Laboratory Practice `Laboratory Practice Stan (as revised in 1997) `published in ENV/MC/CHEM(98)17 and MAFF Japan Good Laboratory Practice Standards (59 NohSan Number 3850) except for the item documented below. The item listed does not impact the validity of the study. purposes of this study. Test substance characterization and stability analyses were performed at Regional Analytical Services (RAS), compliance with a non-GLP regulatory laboratory. guidelines. The test None of substance `analyses the aforementioned performed were in analyses were performed under Good Laboratory Practice Standards; however, the analyses were conducted in compliance with ISO9002 regulations. All of the analyses are considered valid and sufficient for the Applicant/ Sponsor: E.L duPontde Nemours and Company `Wilmington, Delaware 19898 USA. StudyDirector: _ Satin RATS we Susan A. MacKenzie, VM.D., Ph.D. D.AB.T. `Senior Research Toxicologist 0L-AVG-2003 Date Applican/t Sponsor: `DuPont Representative Date --~ - = Company Sanilized. Does notcontain TSCA CBI 02-5D4a2y5:GavSaugbeehSrtoundiyc TinoxRiactistyvithOneGeneration Reproduction Ealusions -- QUALITY ASSURANCESTATEMENT DuPon11418 Haskell Sample Number(s): 25425 Dates of Inspections: Protocol: June 28, 2002; July 2, 2002 Conduct: August 6,29, 2002; September 10,20, 2002; October 7,21,30, 2002; November 14,21,22,29, 2002 Records, Reports: F1e1b,1r4u-a1r5y;2270-0238;, 2M0a0y3;6-M9a,r1c2-h162-,51,91:-210-,142,0170,3;20J0ul3y; 1Ap4r-i1l7,27-080,130- ~~ Dates Findings Reported to: Study Director: July 2, 2002; September 23, 2002; October 8,21,31, 2002; November 22, 2002; March 36,28, 2003; April 11,15, 2003; May 20,2003; July 17, 2003 Management: September 23, 2002; October 18,21,31, 2003; December 3, 2003; March 6,14,27, 2003; April 30, 2003; July 18, 2003 Reportedby: Sob fC [Hefn OTF - "Matthew Frentzel Quality Assurance Auditor 01- Aug - 2003 Date ER Company Saniized. Does not contain TSCA CBI 3H02sD4a2y5G:avSaugbeehSrtondi TinoxRiactistywith One Generation Reproduction Evlustions Dupont1418 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. AnalyticalBvaation by: 4 itTort MWapleanl,an5har "Anlyica Chemist ReproNdeuucrtoibveehEavvailouaaltiaonnds Reported byt _ icles Zbl Lin`dSaeniAorRVeisleea,chPTLoYx,DicAolB.. &folyBr0e 3 HSoiffuudlom-2203 ClinEivcaalluPaattihoonlobgy:y Zz2, `ey=E Ev<er, 4DV. PrincipalReseaDcihpClloimcateAPCa-VtP.holanodMgainasgetr . JoDlay 2603 --~ Anstoic Pathology Evaluation by: Soluets VNeD. 3/ Fb 2603 DiplomateVeAieriaCPry PAaVtChoLloAgiMst, ABT, Anstoic Pathology `Evaluation PeerReviewby: }din C. Mon-- DPiepelroVmiaatne,ADCVVM. Veterinary Pathologist ol AbiwG 2093 Mechanistic Evaluationby: I TTCm s QC ueO r FG eMsTem o. e 31-TuDrye-23 Biochemical Toxicologist Approveaby: (ouSeoE FLoovets,oPhD:. Management a 31-3, 200 sued by Study Director: _ SuSsoaonnA.nMacKenzniee, VcIHoDn.sHdDs. DABT, Seni Research Toxicologit AL:AVDEi-e 2003 --_ _ ER GompanySanitized. Doss notconainTSCACBI 9H02.5D4a2y5G:avSaugbeehSrtoudnyciTnoxRiactistwyith OneGenerationReproductionEvaluations DuPont11418 TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATwEc MENT QUALITY ASSURANCE STATEMENT wssssmsrssssssmmmsmsmmmmssssnd CERTIFICATION ccs LLIISSTT OOFFFTIAGBULREESScro ss rrosioni LIST OF APPENDICES wens STUDYINFORMATION cerns 14 STUDY PERSONNELvcrnssisnrmsmasmmssssssmsmmnsssssssm1n5 SUMMARY corns16 IONBTJREOCDTUIVCETIc ON ro is r s m as )19. STUDY DESIGNrevs19 MATERIALS AND METHODS cvs20. r~ J ed FE ---- D. Ae]HUSDAIALY ccoresmrnnnmmsmssssasmsmmsssssn 2 FR 2 Fob 21 WHEE ---------- worernrenrememrmmmrmnensmsssisisssmsmsmmmssnon 2 E. 4. Animal HeanadEnl virotnmenhtal MOTItOring PrOGFAM crus QUATANiN adPIELESt PEO.crocs 22 22 F. ASSigntomGeronupts and SAY Stat ......wurinssssmmnnirnn 23 1. LRaetvselDeAsnailgynsaitse,dafnodr RtheeprSoudbucchtriovneicETVoxAicNitHy,OONneS-MonthcReocovuerry,rTotialeFlruor:ine 23 G. 2. Rats Designated for 10-Day DOSING SUSPENSION PREPAIUION Biochemical AEIYSIS......crmonsseen rrr 23 23 H. Test 1. Test SUSKANCE SUDSIANCE ACTUSAION vrs 23 SAMPING irre 24 J. ADBIYUCA METhOUS crores 24 J FeA 2 DOSING SUSPENSION THEUME! cr-- es-- s: --25 ~ 3. 4. CHIOMAOGTAPhIC CONGHIONS rrr: Calibration And QUANAGON.....rresmr 25 ns K. Body WEIGHS ceremonies 26 - Eh `Company Sanitized.Doesnotcontain TSCA CBI ~~ Pe 5B02.5D4a2y5:GavSaubgcehSiooniyc TinoxRiacistyith OnGeeneration Reproduction Evalusions Dupont1418 L. Food Consumption and FO0d EFFCIENCY wcccuverrrevevevenessensns 26 M. Detailed Clinical Observations and MOTality ..........wwesessssssssssnsmssnsssnnnn 26. N. OphthalmOIOZY EVAIUAON ..cccvervserssrssssss sss sss 0. Neurobehavioral BVAIMAHONS ......uursssssssssmssms sss sass sss sss sss oes 27 21. 1. 2. Sensory Motor Function EVAIUAtON ....cueeumsmmsesssssssssssssssssssssssisssssssne Motor ACtiVity BVAINAHON vers inl 21 P. Clinical Pathology EVAIBHON errs 28 1. Hematology and COBgUIBHON. cress 28 2. CliniCal CRETMSITY rrr sss 29 Q. Total Fluorine and Perfluorooctancic Acid Level Valuations .......owuursessssssssssssssos 30 1. Total FIUOMNE BVAIUAHONS.....oocoerrorssrsssssssssssmsssmssssssss assassins 30. 2. Perfluorooctanoic Acid Level EVAIAtONS .......owwwsvssssssivssssssssssssssisisins 30 R. BiOCKEMICAl MEBSUICMENLS .cvc.crrrvrvrsrsrssmsmssssssssssssssssssssssssssssssssssssssisss30 S. Anatomic Pathology Evaluationfor Rats Designated for Subchronic Toxicity and Recovery EVANIAONS ....ccovervrmmmmssssssssssmssssssssssssssssssssmssssssssssss13 T. REPIOQUCHVE EVAIUAHONS coroners ssn 3 1. 2. BObosdeyrvWaetiigohntssanfOdrMPoArTtCaDlIiatlyfRoArPSar.ernt.alcRcatos.rsrecooimrsmorn----r----e----n----rrnssresnm--ns3n3 3. Food Consumption and Food Efficiency for Parental RAS... 33 6. GESLANON PIOCEAUIES ..ccrrccrssrsrssssssssssssssssssmsssmssessssesssss assassins 3 7. LACIAHON POCEAUIES...ccvreurssrorrssssssssssssssssmsssimmesssssssssssssssssssssssssssssnsen 3 8. Fj Generation POSt WEANING..........orrrrsrsnsmmmmsmssssssssssssssssssssssssssssssons 39 9. Fy Generation Developmental LANAMATKS ....oewvvsvssssssssssosssssssssssssssins 35 10. Sperm Number, Morphology, and MOUHLY w...ocuversmurssssessssesssivsss sss 36 U. Anatomic Pathology Evaluation for Rats Designated for Reproductive Evaluations........36 FS ---- V. SHASHCAL ABIYSES cvrrrrtmimrmsmnrsmssmmsmsssssssssssse 38 RESULTS AND DISCUSSION commsdl RECORDS AND SAMPLESTORAGE wccovvesssmsssssssssssssssssmsmssssssmssssssssssssssssssssens1d J ------------------ A. Test SUbSLaNCe Stability ANAIYSES .......ccvvrsrsssmssrssssssssssssssssssssssssssssssssssssssss 82. [oR TOIT T1 ECTNY ---------- sss sass eommrnrnnenli2 D. Homogeneity and Stability Samples ..........o..cccccveerers E. Concentration Verification Samples........................ ars a2 rrr -- -- ee -- ---- `CompanySanized. Doasnot contTSaCAiCBnI 9205.4D2a5y:GovSaugbeehSrtoundiyciTnoRxticsityith OneGeneration Reproduction Evaluations DuPont11418 ~ In-Lifle TOUCOI0ZY rrrmmmmmsmmmmsmmmmssssmsmsmsnssmmmmssdnd A. B. DOSE DEE rrr MeanBody Weights and BodyWeight GINS ..ovuvuvvsnininninrnvenin 43 C. Food Consumptionand F0d EEICIENcY ours 45 D. Clinical OBSETVtions and MOMalty......curmwsns sores 46 E. OphhAIMOIORY BYANAONS cress F.In-Life TOXiCOIOgY CONCLUSIONS rrr AT &1 NeuroA.beFhOaTveiloirfbalGEpVASIACONn cose esmsmsmsn msssssnssn mssssssssa ssrassmsi samsmmono4d1 B. HIndlimbGR SENG crn 41 C.SensoryMotorFunction OBSEIVAHONS osama 1 DD. MODEACKVIY.rrrrrnrsmnsmmnmsnrsmmmnssssssssssmmmnsnno4n8 FE -------- Clinical Pathol0gy EVAIIAtON cevererararsasrsaranananssrds B. C.. CClOitUicUalICOHENMIcSoUrYrcorerr rrermsrmsmmsmssmmmmsasmmsmsomnon0 D. UBRBIYSIS rerenemrmmmsmammmmsmssssmmmssssissssssmssssssn 2 E. Urine and PIGSIRFIIOAC. crc 2 ~ F.Clinical PatholOgYCONCIUSIONS rvs S2 FIOHOER] EVAIIAION corrmerermrsmsmomssnsmssssmsisnssnS3 A. BIOCSICAl EVAIIGON rennin:53 B. Biochemical EVAIUAtion CONCIISIONS ress 53 Anatomic Pathology Evaluation EVBIUBHIONS soreness -- Rats Designated for Subchronic Toxicity and Recovery 5 Ae MORBIY. rrr 5 B. Organ Weight Dt ccccoessnnenensansnnssssssssssss 56 C. GOSSODSEIVAONS cress: 55 1D. MICROSCOPIC OBSENVBHONS rns E. Anatomic Pathology Conclusions for the Subchronic Toxicity and Recovery Reproductive TOXICityEVAIURONS vss A. P, Ra-Cltiniscal Observations 3nd MORAY... ST : ST $e 2. T3 Py MFelmalloesrDeUpNrGrGErSoIraOrNagemreomvessmmmmnmnms minss sinsn msmn:31 3. P, Females DUTINGLACAON nrc ST B. Py Ra-MteasnBody Weights nd Body WEIghtGAINS cover FI 2. Py Females DUNG GESAO-- N c --ro A res 58 ~ 3. P, Females During Lactation ....... --r----5 -_ CompanySaritzed. DossnotcontainTSCA C81 5R02.4a2y:GavSaugbcehSroryic TinoxRiaciistywithOneGenerion Reproducion Evaluations Dupont11418 ~ C. Py Rats - Food Consumption and Food EEiCENcY wu... cere 58. 1D. RPyEDFIeOmGaUlCeHsYDEUIMNNGGGIEOSCtSO.N ..or.corvvrerrrsrrsrssrssrsssssssssssssssesssssmsssssssssssssssass .58 58 E. Sperm Count, Morphology, and MOY... 39 A. ORGAN WEIGH DBA cnr 60 L. Litter Size, Sex Ratio and Pup SUMVIVaL.evrrrersmssssssmsnn 39 2. FO Clinical ObSCIVAtONS in Fy PUPS ..ccvvvvrvrsssssssssssnnnsnssssssssssssssssssssnsnsin 39 ---------- H. F, Rats - Clinical Observations and MOMALILY .........ccouwummmmmmsssusssssssssssssese 39 LF, Rats - Mean Body Weightsand Body Weight Gains ......c...oeumsussssssesee cerrenerBO J. F, Rats - FoodConsu andmFOpOt BFfiiCieo nCyn .......cwvwwwmmmmssmmssssssssss ssn 60 K. Fy Rats -Developmental LANMAIKS v.80 L. Reproductive TORICItY CONCIISIONS ents 60. Anatomic Pathology Evaluatio--n Rats Designated for Reproductive Evaluations ........60 C.. MICROSCOPIC OBSEIVALIONS wocerrrsis 61 D. MOTH mirrors E. Anatomical Pathology Conclusions for Reproductive TOXICILY .......everermrnrnsssrnnn 61 CONCLUSIONS covrrsmssssssssssssssssssssmsmssmsssssmssssssssssssssssssssssssssssssssssonn2 REFERENCES cocvsnsrrsssrssssssssssmmmmmmssssssssmsssssssssssssssssssssssssmm63 TABLES cossserssssmsssssssssssmsssssssssmsssssssssssssssssssssssssmss6nS FIGURES cvrrrrrsrsssssssssssssssssssssssmmssmsssssssssssssssssssssssssssssso12s APPENDICES covers 884 sortereeeet-- erS-------- CompanySanitized.Does not contTSaCAiCBnI B25425: Subehronc Toxicity 90-DayGavageStudyi Rats withOne Generation ReproductionEvaluations _ DuPort-11418 LIOF TSABLTES Page TABLE 1 SUMMARY OFDOSING SUSPENSION ANALYSIS... `TABLE 2MEAN DAILYDOSE VOLUMESFORMALERATS ccc 10 7 TA3MBEANLDAE ILYDOSE VOLFOURFEMMALEE S RATS... TABLE 4 MEAN BODYWEIGHTS OFMALE RATS (0). T3 TS TABMEALNBOEDY WEIOFFGEMAHLERTATSS(0) crn TA6BMEALNBOEDYWEIGHT GAINSOFMALERATS (GB). 18 BL T TABLAE 7 B MMEEAAL NN DBAOE IDLYYWFEOIOGDHTCGOAINNSSOUFMFEPMBTAYLIMEOARALNTES((GG)IDAY) 83 ccc) TABLE 9MEAN DAILYFOOD CONSUMPBYTFIEMOALNE (GIDAYcc TABLE10MEAN DAILYFOODEFFICIENCY OF MALE ov 92 wemmn98 TTAABBLLEE1121 MSUEMAMNADRAYILOYFFCOLOIDNIECAFLOFIBCSIOFEEFNERMCAVFLYEOARMTALc IEROATc SN..S. s 98 I) TTAABBLLEE1143 SSUUMMMMAARRYYOOFFOCLINPICAHL OTBSEHRVAATIOLONBSSMFEORRVOAFTEILMOANLSOEFOGRMIALECRRATAS.AT..S L 04 .....c106 -- TABLE TABLE 15SUMMARYOF OPHTHAOBLSERMVATOIONLSFOORFGEMIALECAL 16PERCENT SURVOFIMAVLEARATLS... RATS. 107 -- TABLE17 TABLE 18 PERCENT SUROVFFIEMAVLEAL RATS. MEANFORELIMB ANDHINDLIMB GRIPSTRENGTHFOR MALE RATS (MEANOF 109 THREE TABLE 19MEANFOREANLDHIINDMLIBMBGRIPSTRFEORNFEMGALTERAHTS(MEAN OF TA20BSULMMAERYOFSENSORYMOTORFUNCTION PARAMETERSFORMALERATS. TABLE21 SUMMARYOFSENSORY MOTORFUNCTION PARAMETERSFORFEMALE RATS. . 12 113 TA2B2MLOTEOR ACTIVITY ASSESSMENT: MEAN DUROFMAOVETMENITFOORMN ALE TRAATBSLE(S2E3C)M..OTOR ACTi IVITY ASSESSMENT: eMrEAoN DURATmION--OF M--OVE--MEN--T Fg OR Fr EMALErr 11S TABLE24 MOTORACTIVITYASSESSMENT: MEANNUMBEROFMOVEMFOERMNALETRASTS ..16 TA2B5MLOTEOR ACTIVITY ASSESSMENT: MEANNUMBER OFMOVEMENTS FOR TABLE TABLE 26 27 SUMMARYOFHEMATOLOGY SUMOFMHEAMATROLOYGY VALUES FOR VALUESFOR MALE FEMALE RATS RATS. . . . . smi mmol TABLE 28SUMMARYOFCOAGULATION VALUESFORMALERATS. -- TABLE 29SUMMARYOFCOAGULATION VALUESFORFEMALE RATS... 2? TABLE 30SUMMARY OFCLINICAL CHEMISTRY VALUES FORMALE RATS cv TA31BSULMMAERY OF CLINICAL CHEMISTRY VALUESFORFEMALE RATS.... 128 i2 --_ TABLE 32 SUMMARYOFURINALYSIS VALUES FOR MALE RATS... 136 -_ `CompanySanitized. DossnotcontainTSCACB 0BL-2D5a4y25G:avSaugbecShrtoundiyc TinorRiactistywithOne.Generation Reproduction Evaluations DuPont 11418 ~ `T3A3SBUMLMAREYOFURINVALAUESLFOY R FESMALIERASTS cvs 138 `TABLE 34 SUMMARYOFPEROXISOMAL BETA-OXIDATION ACTIVITY INMALE RATS... 140. `TABLE 35 SUMMARYOFPEROXISOMALBETA-OXIDATION ACTIINFVEMAILETRAYTS ...........141 ``STUABBCLEHR3O6NMIECATNOXFIICNIATLYBEOVDAYLAUNADTIOORNGAcN WErIGvHTS FOR MALE RATS DESIGNATED ---- FOR 142 `TABLE 37 MEAN FINAL BODY AND ORGAN RECOVERY EVALUATION cv WEIGHTSFOR MALE RATS -- DESIGNATED FOR nine 45 ``STUABBCLHER3O6NMIECATNOXFIICNIATLYBEOVDAYLUAANTDIOORNG.A.N. WEIGHTS FOR FsEMsALE RA--TS DESIGNATED FOR 148 TABLE 39 MEAN FINAL BODY AND RECOVERY EVALUATION ccc ORGAN WEIGHTS FOR FEMALE RATS DESIGNATED vorrrdearen FOR 151 T` OXITCI4TA0YIENBVCIADLLEUNCAEETSIOOFNG.ROSS OBSERVATIONSIN MALE RATS DESIGNATEDFOR SUBCHRONIC154 E`TVAABLLUEA4T1IIONNCIDENCEceSssOeFsGROSS OBSERVATIONsSiIN--MA--LE--R--AT--S "DESIGFS ONRARE-- TCOEVE. DRY `TABLE 42 INCIDENCES OF GROSS OBSERVATIONS 'SUBCHRONICTOXICITYEVALUATION... IN FEMALERATS DESIGNATED asm------ FOR nnn 168 `TABLE 43 INCIDENCES EVALUATION cr OFGROSS OBSERVATIONS sme IN FEMALERATS DESIGNATED -------- FOR RECOVER1Y75 N`ETOAPBLLAES4T4IICNCLIEDSEINOCNESSDEOSFIMGINCARTOSECDOFPOIRCSOUBBSCEHRRVOANTIIOCNTSOXIINCMIATLYE RATS NEOPLASEVALUTTION. IC AND NON-AB2 --~ N`ETOAPBLLAES4T5IICNCLIEDSEINOCNESSDOEFSMIIGCNRAOTSECDOFPOIRCROEBCSOEVREVRATYIEOVNASLIUNAMTIAOLNE RAc TS NEo OPLv ASTIe C ANs D NON2-22. `'TNAOBNL-ENE4O6PILNACSITDIECNLCEESSIOOFNSMIDCERSOISGCNOAPTIECDOFBOSRESRUVBACTHIRONOSNIICN FTOEXMIACLIETYRAETVSALNUEAOPTLIAOSNTIC..A..N..D.......261 '`NTOANB-LNEE4O7PILNACSITDIECNLCEESSIOONFSMIDCERSOISGCNOAPTIECDFOOBSRERREVCAOTVIEORNYS IENVFAELMUAALTIEORNATScNcEcOPLASTIC AND 301 VOLUM2Ecc RY sss 304 `TNAONB-LNEE4O8PILNACSITDIECNLCEESSAIONNDSDLEESSIIGONNAGTREADDFEOSROFSUMBICCHRROOSNCIOCPITCOXOIBCSIETRYVATIONSIN MALERATS EVALUATION..............305 `TNAOBNL-ENE4O9PILNACSITDIECNLCEESSAIONNDS DLEESSIIGONNAGTREADDFEOSRORFEMCIOCVREORSYCEOPVIACLUOABTSIEROVNATcIcONSINMALERATS 345 N`TOANB-LNEE5O0PILANSTCICILEDSAIEONNNDSLCDEESESIIOSGNNAGTREADDFEOSROSFUMBICCHRROOSNCIOCPITCOXOIBCSIETRYVEAVTAILOUANTSIOINN.F..E.M.A.L..E..R.A.T.S384 `TNOANB-LNEE5O1PILNACSITDIECNLCEESSIAONNSDDLEESSIIOGNNAGTREADDEFSOROFRMEICCORVOESRCYOEPVIACLOUABTSIEORNV.ATIONSINFEMALE RATS28 `TABLE 52 SUMMARYOFCLINICAL OBSERVATIONSIN Py MALERATS cvs] `TABLE 53 SUMMARY OF CLINICAL OBSERVATIONS IN P, FEMALE RATS DURING GESTATION....428 `TABLE 54 SUMMARYOF CLINICAL OBSERVATIONS IN P; FEMALE RATS DURING LACTATION... 429 `T5A5 MBEANLBOEDYWEIGHTS(GRAMS) OF P, MALE RATS. -- `T5A6 MBEANLBOE DYWEIGHT GAINS(GRAMOSFP)y MALERATS w..corvvv a `T5A7MB EANLBOE DY WEIGHTS (GRAMS)OFP; FEMALERATS DURING GESTATION... 432 `TABLE 58 MEAN BODY WEIGHT GAINS (GRAMS) OF Py FEMALE RATS DURING GESTATION........433 ~~ `TABLE 59 MEAN BODY WEIGHTS (GRAMS) OF Py FEMALE RATS DURING LACTATION. a -- Te `CompanySanitized. Doesnot contain TSCA CBI 0H2-5D4a2y5;GavSaugbcehSrtoundiyc TinoxRiactistywith One-Generation Reproduction Evaluations DuPont-11418 ~~ TABLE 60 MEAN BODY WEIGHT GAINS (GRAMS) OF P; FEMALE RATS DURING LACTATION. ......435 TABLE 61 MEAN DAILYFOODCONSUMPTION (GRAMS) OF P; FEMALE RATS DURING (GESTATION conn -- `FTEAMBALELE62RMAETSANDUFROIONDGEGFEFSITCAITEINOCNY. (GRAMS WEIGHT GAINIGRs AMS FOOD CONs SUMED) OF Py 431 `TABLE 63 SUMMARY OF REPRODUCTIVE INDICES: Py GENERATION... $38 `TABLE 64 SUMMARY OF SPERM PARAMETERS IN Py MALE RATS ccc `TABLE 65 MEANESTROUS CYCLE PARAMETERS AND PRECOITAL INTERVAL IN Py `TABLE 66 MEAN PUP NUMBERS AND SURVIVAL: Fy GENERATION. .c.cvsvrmsmsnnncdl `TABLE 67 SUMMARYOFPUP CLINICAL OBSERVATIONS: F; GENERATION csr 42 `TABLE 68 MEAN PUP WEIGHTS: Fy GENERATION csv a3 TABLE 69 SUMMARY OFCLINICAL OBSERVATIONS IN F; MALE RATS. I TABLE 70SUMMARY OFCLINICAL OBSERVATIONS IN F; FEMALE RATS. nnn 5 TABLE 71 MEANBODY WEIGHTS (GRAMOSFF)yMALERATS. SE -- `TABLE 72 MEAN BODY WEIGHTS GAINS (GRAMS)OF Fi MALE RATS ccs `TABLE 73 MEAN BODY WEIGHTS (GRAMS) OFFy FEMALE RATS... `TABLE 74 MEAN BODY WEIGHTS GAINS (GRAMS)OFF; FEMALE RATS... 49 `TABLE 75 MEAN DAILY FOOD CONSUMPTION (GRAMS)OF Fi MALERATS. -- `FyTAMBALLEE7R6AMTESA.N DAILYFOODEA FFICIENCY (GRAMS WEIGHT GAINA IGRAMS FOOD CONSUMED) OF451 ~~ `TABLE 77 MEAN DAILY FOOD CONSUMPTION (GRAMS) OF Fy FEMALE RATS. ...cvvvon 452 `TABLE 78 MEAN FOOD EFFICIENCY (GRAMS WEIGHT GAIN/GRAMS FOOD CONSUMED) OF Fy `TABLE79 SUMMARYOF DEVELOLAPNDMMAERKNSITNFyARALTS vv S4 `TABLE 80 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS - F; ADULT. 455 `TABLE 81 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - Fy ADULT ..c.ccvv 458 `TABLE 82 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - Py ADULTS... d61 `TABLE 83 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - Py ADULTS ccc 462 `TABLE84 INCIDENCESOF GROSS OBSERVATIONISNMALERATS - Fy ADULTS cvs 463 `TABLE 5 INCIDENCESOFGROSS OBSERVATIONISNFEMALERATS -FyADULTS ccs 464 `TABLE 86 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RAT-S `PTIAABDLUEL8T7SINCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS A `TABLE 85 INCIDENCES OF GROSS OBSERVATIONS IN GENERATION Fy MALE WEANLINGS......... 467 `TABLE 89 INCIDENCES OF GROSS OBSERVATIONS IN GENERATION F, FEMALE WEANLINGS...... 468 `TABLE 90 INCIDENCES OF GROSS OBSERVATIONS IN GENERATION Fy MALEPUPS cc. 469 `TABLE 91 INCIDENCESOF GROSS OBSERVATIONS IN GENERATION Fy FEMALE PUPS... 470 `TABLE 92 INCIDENCESOFGROSS OBSERVATIONS IN GENERATION Fy UNSEXABLE PUPS ......471 --_ _--_--mmm `Company Sanitized. Does not contain TSCA C81 5205.D4a2y5G:avSaugbecShrtoundiyc iTnoxRiatcsitwyithOve Generation Reproduction Evaluations DuPon11415 LIST OF FIGURES Page FIGURE I MEAN BODYWEIGHTSOFMALERATS... wmm------ FIGURE 2MEAN BODYWEIGHTSOFFEMALE RATS.. dT5 FIGURE 3 MEANFORELIMBGRIP STRENGTHFORMALE RATS.. 476 FIGMEAUNFORRELE IMBGRIPSTRFEORNFEMGALTE H RATS.. wn] FIGURE 5 MEANHINDLIMBGRIP STRENGTHFORMALE RATS... " dE FI6GMEAUNHIRNDLE IMBGRIP STRFEORNFEMGALETH RATS.. re BFAIT G7UMORTOER ACTIVITY ASSESsSMsENT: ME--AN-- TOTA--L DU--RAT-- ION -- OF MO--VEM--ENT--FOR--MALy E FFEIMGAURLEER8AMTOS.T.O.R..A.C.TIVITY ASSESSMENT:--ME--ANT--OTA--L --DUR--ATI--ON --OFM--OVEMEFNOTR mnt FFIGrURE --MO--TOR ACTIVITY AA SSESSMENT:M--EAN--TOT--AL -- NUM-- BER--OF M--OVE-- MEN-- TS F-- OR M-- ALE. yl FIGURE 10 MOTORACTIVITYASSESSMENT: MEAN TOTAL NUMBER OFMOVEMENTS FOR LIST OFAPPENDICES Page APPAEANANLYTDICAILDAXTA rvs msAm-- APPENDIX BINDIVIDUALDOSE VOLUMES. swmsmmmm------r APPENDIX CINDIVBOIDYDWEUIGAHTLS v.91 VOLUMES... ms -------------- APPENDIX DINDIFVOODICODNSUUMPATIOLN... en 30 APPENDIX EINDIVIDUAL CLINICAL OBSERVATIONSAND MORTALITY RECORDS vr656 APPENDIX FINDIVIDUALOPHTHALMOLOGY OBSERVATIONS... TIT : APPENDIX GINDIVIDUALFORELIMEANDHINDEIMBGRIPSTRENGTH... nnn 2 APPENDIX H INDIVIDUAL SENSORY MOTORFUNCTION OBSERVATIONS. . 38 APPENDIX 1INDIMVOTIODRACUTIAVITLY: DURAOFTMOIVEOMENNT... 760 APPENDIX JINDIVMOITODRAUCTIAVILTY: NUOMFMOBVEMEENTRS... 161 APPENDIX KINDIVIDUALANIMALCLINICAL PATHOLOGY DATA... N APPENDIX L INDIVIDUALANIMAL BIOCHEMIDCAATAL... en 850 APPENDIX M INDIVIDUAL ANIMAL BODY AND ORGAN WEIGHTS 587 --~ = `Company Sanitized. Does not contain TSCA CBI H902.5D4a2y5G:avSaugbcehSvtoundiyc TinoxRiactistyvith One-Generation Reproduction Evaluations Dupont 11418 ~ VOLUMES... ------------ I APPENDIX N INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS... 09 APPENDIX O INDIVIDUAL ANIMAL MICROSCOPIC OBSERVATIONS LISTING INDIVIDUAL ANIMALS APPENDIX P INDIVIDUALCLINICALOBSERVATIONS AND MORTALITY DATA INP; APPDEUNRDIIXNGQGIENSDTIAVTIIDOUANL CLcoIc NICAL OBSERVATIONS Ai ND MsORTm ALIt TY Ds ATApIN P--;FE-- MAL-- ERATSeh APPDEUNRDIIXNGRLIANCDTIVAITDIUOANLc CLINICAL OBSn ERVATIONS AND MORTALITsY DmAnTA INP; FEMALE RATSBO APPENDIX INDIVIDUAL BODY WEIGHTS OF Py MALE RATS... 1208 APPENDITX INDIVIDUAL BODY WEIGHT GAINS OF Py MALE RATS... 1214 APPENDIX UINDIVIDUAL BODY WEIGHTS OF P,FEMALERATS DURING GESTATION. 1220 APPENDIX V INDIVIDUAL BODY WEIGHT GAINS OF P, FEMALE RATS DURING GESTATION.......1226 APPENDIX W INDIVIDUAL BODY WEIGHTS OFP, FEMALE RATS DURING LACTATION. ...c..v... 1232 APPENDIX X INDIVIDUAL BODY WEIGHT GAINS OF P, FEMALE RATS DURING LACTATION. .....1238 APPENDIX Y INDIVIDUAL FOOD CONSUMPTIONOFP; FEMALE RATS DURING GESTATION....... 1244 APPENDIX Z INDIVIDUAL ANIMAL SPERM MOTILITY DATA IN By MALE RATS... 1250 APPENDIX AA INDIVIDUAL ANIMAL SPERM MORPHOLOGY DATA IN Py MALE RATS... 1252 VOLUMES. min uss sa 1255 ~~ APPENDIBBXINDIVIDUALANIMALSPERMANDSPERMATIDCOUNTSIN Py MALE RATS........1256 APPENDIX CC INDIVIDUAL ANIMAL ESTROUS CYCLE PARAMETERS IN P; FEMALE RATS.........1259 APPENDIX DD INDIVIDUAL ANIMAL ESTROUS CYCLE STAGES IN Py FEMALE RATS... vv 1265 APPENDIXEEINDIVIDUALMATING DATAANDGESTATION LENGTH: Py GENERATION. 1271 APP`EGNEDNIEXRAFTFIIONNDIVIDUAL IsMPoLnANiTATION SITE DATA AND I--MP--LA--NT--AT--IO--N--EF--FICIENCY: Py om APPENDIXGGINDIVPIUPDSURUVIAVALL: F; GENERATION ccc " 1283 APPENDIX HH INDIVIDUAL LITTERCLINICAL OBSERVATIONS: Fy GENERATION... 1309 APPENDIX II INDIVIDUAL PUP WEIGHTS: Fy GENERATION ccs 1314 APPMEONDRITXALJJIITNYDDIVAITDAUAILN FC;LMINAILCEALANODBSFEERMVAALTIEORNASTS,..D.E..VELOPMENTsALwLAnNDmMAmRK--S,--AN--D 0 APPENDIX KK INDIVIDUAL BODY WEIGHTSOF Fy MALE ANDFEMALERATS... 1358 APPELLINNDDIVIIDUXAL BODY WEIGHT GAINS OF F; MALE ANDFEMALERATS. 1368 APPENDIX MM INDIVIDUAL FOOD CONSUMPTION OFFy MALE ANDFEMALERATS... 1378 APPENDIX NN INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS ~ Fy ADULTS cc... 1381 APPENDIX 00 INDIVIDUAL ANIMAL PATHOLOGYDATA Py ADULTS cv 113 APPENDIX PP INDIVIDUALANIMALGROSS OBSERVATIONS - FI ADULTS. smd FI8 APPENDIX QQ INDIVIDUAL GROSS OBSERVATIONS IN GENERATION Fi PUPS AND --_ _-- `Company Sanitized. Does not conTtSaCAiCanl DyCag Sy in i OneorrionfeprchionBasins STUDY INFORMATION 9th Collective Nomenclature} prem SonsCodes {E | EEG------ * H-25425 Haskell Number: 25425 CAS Registry Number] rue gulf} Physical Characteristics: Amber-yellow-brown solid Stabilis The est substance speared 0be sale under the over conditions of the study; no evidence of instability was Sponsor: WEiLnidnugiPoonnt,DdeelNaewmaroews19a5n3d8Company USA. . StudyInitiated/Completed: October 3, 20/0(s2ee report cover page) JL nfied/Compied: October 15,2002 Ape 15,2003 9B02sD4a2y5;GavSaugbeehSrtoundiyc iTnosRiaiitywithOGneeneration eprodsection Evasion Dupone11418 STUDY PERSONNEL StMuadnyaDgiermeectnotr:: SScuostatnE.A,LoMvseclKesesn,iPeh,.DV..M.D, PhD. Primary Technician: Robert E. Walker, J. AnalytiMcaanlaCgheemmeinstt:: JSa.nMeatrCk. MKaesnlnaendkya,,PBh..SD.. Neurobehavioral and Reproductive Toxicologist: Linda A. Malley, Ph.D. Management; SRcoobtetrtE.ML.ovPealreksesr,, PPhh.DD.. ClinicalMaPnatahgoelmogeinstt:: SNatnecvyeERn.. EFvrearmdes,, DD.VV.MM,. PhD. Antomic Pathologist: JGorheng FP..HSaynksese,n,VDM.V.M., Ph.D. ~ Peer Review Management: Anatomic Pathologist: PSetteevrenMaRn.nF,raDm.eV,-MD..V.M., Ph.D. Biochemical`TMoaxincaogleomgiesntt:: JGoahrnyCW..OJ'eCposnonno,rP,hM.DS.. StatistMicaanlaAgnealmyesnits:: JJaonhincWe.L. GCroenenne,llP,hM..DS,.,PhBD..A, CLH. Toxicology Report Preparation: CBerceinldiaa TRioffwien Kee, BS. Management: Nancy S. Selzer, M.S. Ophthalmologist: 6N1a19nMcaMys.saBcrhoumsbeetrgs,AVv.enMuDe., MS. Bethesda, MD 20816 : aboratory Veterinarian: Thomas W. Maer, DVM, ACLAM. -_-- Company Sanitzsd. Dosnetcontain TSCA Cal 9205D4a2y5G:avSaugbecShtvoundiyc iTnoxRiactistyvithOneGeneration Reproduction Evaluations DuPont11418 SUMMARY Four groups H-25425 in 0o.f5y%omuentghyaldcueltllmualloeseainnddfeeimoanliezeCdrwla:tCeDrb(ySDg)aIvGaSgeBfRorraaptsprwoexriemaatdemilnyi9st0erdeady.s (92 daanyismailnsmfarloemsaenadch9d3osdaagyes ginrofuepmawleesr)e,daetsdiogsnaatgeeds foofr,eva1l0,ua1t0i0o,noorf1s0ub0c0hmrgo/nkigc/tdoaxyi.citSye,lreecctoevdery from subchronic toxicity, or reproductive toxicity. Iwneetkhley.subCclhirnoicnailc psattuhdyo,lobgoydeynwdepiogihnttss,wfeoroed ecvoanlsuuamtpetdidounr,inagndwecleiknsic6al asnidgn1s4woefretheevdaolsuiantged ppeerrifoodr,maenddpnerarttoihdeooesinndrgo,fdtuhreionngew-emeoknt1h3roefdcoosveirnyg,perainoddn.eaNreutrhoebeenhdaovfitorhael oanssee-smsomnetnhtsrewceorveery p(emrailoed.anBdiofcemhaelmei)c,adluervianlguwateieokns1(4heopfatthiec dfo-soixindgapteiroino)d,wearnedpfeorlfloowrimnegdaononrea-tsmoafnttehr r1e0cdoavyesry period. At the end of the dosing period, 10 rats/sex/dose were sacrificed and given a gross and `imnitchreosccoonptircolpaatnhdolhoiggihcadloseexagmrionuaptsiowne.reOenxeammoinnetdh affotrerretchoeveernydofotfotxhiecdoesffiencgtsp.erAiond,ad1d0itriaotnsa/lse5x droatssi/nsgexp/edroisoed.weTrheehseelrdatwsithhaodutbldooosdincgolfloerctaepdprpeorxiiomdaitceallyly3tmhoronutghhsouftoltlhoewdionsgitnhge aenndd roefctohveery ~~ lpeevreilosd.sTahnedsseelteiscstueedsthisasvueesnoctolbleeecnteadnaatltyhzeedentdo doafter.ecBovleoroydfworaspoaslssioblceolalneacltyesdisforfofmlusourbichnreonic ptoexrifcliutoyraooncdtraneociocvearcyidraltesvaeltst.heTehnesdeofletvheelsdowsililngbeanrdeproerctoevdeirnyapesreipoadrsatfeorreepvoratl.uation of `gTrhoeupr,anagnedo1f.m2-e2a.9nmdaLilfyordotshee v1o0,lu1m0e0,s aandmdi1ni0s0t0ermegd/ktgo/mdaalyegrraotuspsw.asT1h.e2-r3a.n0gmeLoffmoreathnedcaoinltyrol dose volumes administered to female rats was 0.9-1.6 mL for the control group, and 09-15 for the 10, 100, and 1000 mg/kg/day groups. cAonnacleynttircaatliroenssu,ltasnddewmaonsssttraabtleedinthtahtetvheehtiecsltesuunbdsetranrceelewvaasntmsitxoeradgpercoopnedriltyi,ownassusatedthien ttahrigsetsetdu.dy. oInp-hLtihfaelTmooxliocgoilcosgiygPnasroacmceutrerresd:inNroattseisnt seiutbhsetrantchee-sreulbactherdondiecatthosx,iccilitnyiocralrseicgonvse,royrperiods of the cstoundsyu.mpNtoioanv,eorrsef,ootdesetfsfuibcsiteancnycew-erreleaotbedseerfvfeecdtsinoannbyomdaylweeiogrhfte,mbaoledydowseeigghrtougpa.in, food Nsteruernogbthe,hasveinosroraylmPoartaomreftuenrcst:ioNn,ootresmtostuobrstaacntciev-itryelwaetreed eofbfseecrtsveodnifnoarneylimmabloerohrinfdelmiamlbe gdroispe group. aBpiporcohxeimmiactaellTyo9x0icdoalyosgy(:maElxepsoasnudrefetmoal1e0s0)0pmrgo/dkugc/eddamyiolfdHe-l2ev5a4t2i5onfsorin1h0epdaatyisc(Bf-eomxaildeastioonnly) or ~~ apcotiinvti.ty.ActTihviistyelheavdatrieontuwmaesd atsoscoocnitartoeldlweivtehlselienvfaetmeadlleisvebrutweriegmhatiinnedmaelleesvaattetdhien9m0a-ldeasyafttiemrea _ CompanySanitized.Doesnot conTtSaCAiGnBI 9H02-5D4a2y5G;avSaugbeehSrtoundiyc TinoxRaitcstywithOne-GenerationReproduction Evaluations DuPont-11418 ~~ `one-month recovery period. These effects were considered test substance-related but not adverse. Clinical Pathology: No adverse effects were observed on hematology, coagulation, clinical chemistry,orurinalysis parameters in any male or female dose group. Tn male and/or female rats dtroisgeldycweiritdhes1(0a0l0l mmag/lkegd/odsaey,grmoiunpism),altottoalmiprlodteriend,ucatnidonaslbiunmriend wceelrlemoabssserpvaeradmbeulterwse,rbeilniortubin, consideredadversebased on the very slight levelofeffect. All effects except the minimal red cell mass effects in males were reversed by the end of the one-month recovery period. No effects on plasma fluoride concentration were observed in any male or female dose group. Urine fluoride (total fluoride excreted over the collection period) was increased at the end of the dosing period in males and females dosed with 1000 mg/kg/day and in a few males and females dosed with 100 mg/kg/day. Urine fluoride greatly decreased during the one-month recovery period, but remained slightly above control continued presenceoffluorinated material. values in 1000 The increased mg/kg/day males, urine fluoride was thus indicating considered a the markerofexposure to a fluorinated material, and was not considered adverse. Anatomic Pathology (Subchronic Toxicity): Mild increases in absolute and relative liver and kidney weights were observed in male rats dosed with 1000 mg/kg/day at the end of the dosing period. The increased liver weights were associated with minimal hepatocellular hypertrophy and elevated 8-oxidation activity, but no histological correlate to the increased kidney weight was Pe observed. The increased liver weights and histopathology were reversed after a one-month recovery period. These liver and Kidney changes were considered to be non-adverse, pharmacological responses to exposure to a xenobiotic Minimal to mild hypertrophy of thyroid follicular epithelium was present in 1000 mg/kg/day `males andfemales at the end of the dosing period. This effect is indicative of altered thyroid gland homeostasis and, although the follicular cell response observed in this study was within the range of normal physiological response, th effect is potentially adverse. The hypertrophy was sill present inboth males and females at the endofthe one-month recovery period but the incidence and severity were reduced in males and were very low at both time points in females. `Therefore, this one month. lesion is considered reversible, even though full reversal had not occurred after Reproduction: Twenty male and 20 female rats from each dose group were designated for : reproductive evaluations. Parental rats (Py generation) were dosed daily for 74 days prior to . cohabitation, during the cohabitation period (mating) and during lactation, unil the weaning of the F; offspring. The following parameters were evaluated in Py rats: body weight, food consumption, clinical signs, gross pathology, sperm parameters, estrous cyclicity, and reproductive performance. evaluated microscopically. Reproductive organs from animals that did The Fi offspring were evaluated during the not produce liters were lactation period for ``ggernoewrtahtiaonndrastusrvwiavaslraentadingeidveant waegarnoisnsgp,atahnodlotghiecfaollelxoawminignaptairoanmeattewresanwienrge.eAvalsuuabtseedtfoofrF6y --_ weeks: body weight, food consumption, clinical signs, and age at onset of vaginal opening or Company Saritized. Does not contain TSCA C81 910.2-5D4a2y5:GevSaugbeetSrtoundey iTnorRiacistywithOne Generation Reproduction Evaluations DuPont11418 ~~ `epxraempiutniaatlisoenp,araantdiosne.leActfetder6repwreoedukcst,itvheeoFr)gagnesnearnadtitoanrgreattsorwgearnesgoifvteonxaicigtryoswsepraethwoeliogghiecda.l No systemic toxicity was observeidn any dose group in the P, or Fy generation in the. reproduction subset. No test substance-related, adverse effects on any reproductive, sperm, estrus, or pathology endpoint were observed in any dose group in the Py generation. No effects were observed on liter size, Sex ratio, pup survival, or developmental landmark acquisition, nor were any signs of systemic toxicity observed in any dose group in the Fi generation. NOELfor Subchronic Toxiciy: Under the conditionsofthis study, the no-observed-effect level (NOEL) for subchronic toxicity endpoints in male and female rats was 100 mg/kg/day. This level was based on reversible, minimal to mild thyroid follicular hypertrophy observed in the 1000 mg/kg/day male and female groups. Other test substance-related effects observed in males `andlor females dosed with 1000 mg/kg/day include mild alterations in clinical pathology `parameters, increased liver and kidney weights, increased hepatic B-oxidation activity and `minimal hepatocellular hypertrophy; however, these were not considered to be adverse. Most of the effects observed during the dosing period demonstrated full or partial reversal following one: monthofrecovery. Thyroid follicular hypertrophy was still present at the end of the one-month recovery period; however, the incidence and mean severity level in males had decreased by this time and were very low in females at both time points. NOELfor Reproductive Evaluations: Under the conditions of this study, the NOEL for --_ reproductive evaluations was 1000 mg/kg/day, the highest dose tested. This NOEL was based on alack of test substance-related effects on any reproductive parameter in P; or Fy generation animalsdosedup to 1000 mg/kg/day. + tThheeteNstOsEuLbsftoarnctehiswesrteudnyotisddeetefcitneedd.1sThthues,hfioghehstisdosstueady,wthheicNhOtEoxLiciosoegqiuciavlallyenitmp0orhtaentNeOfEfeLctsasadteifbiunteadblbey --~ (thNeOUAnEitLe)dsSstdaetfsinEendvibryontmheenEtuarlopPreoatnecUtsiioonnAg(1e9n9c4)y.(1985) and oth no-observed-advrse-ffct evel Te `Company Sanitized. Doesnotcontain TSCA Cal 0H2-5D4a2y5:GavSaugbechSrwodnyiiTnoxRiactistywithOne-Generation Reproduction Evaluations ~ Dupont 11418 INTRODUCTION `The test substance, H-25425 is sed as a fabric protector. `The dose levels for this study we selectedbasedon the toxicity and an analysis of blood fluorine concentrations from a range-finding study in which rats were dosed by oral gavage with 1, 10, 100, or 1000 mg/kg/day for approximately 45 days." No compound-related effects on body weight, clinical signs of toxicity, organ weights,o gross pathology lesionswere observed in rats in any dose group. Blood fluorine levels appearedto have reached aplateau within 1-2 weeksofdosing with 1000 mg/kg/day, and levels remained very low throughout the entire exposure period. Dose levelsof0, 10, 100, and 1000 mg/kg/day were selected forthis study, based on the results ofthe rangefinder study. OBJECTIVE `The objective of this study was to evaluate the potential subchronic and reproductive toxicity of H-25425 when administered by gavage to male and female rats. Arecovery group was included --_ to investigate the reversibilityofany observed toxicological effects. The oral route of administration was selected as the most efficient way to deliver an accurate dosage. Blood, urine, feces, and tissues were collected for evaluation of total fluorine and/or perfluorooctanoic acid (PFOA), but have not been evaluated. Data from analysisofthese samples willbereported separately. STUDY DESIGN DS mo Group Number/Group. Male Female Male Female Daily Dosage' (mg/kg) 1 I 50 50 0 (Control) mv 4 4 10 SVT a 4 100 VIL VIL 50 50 1000 TT Weietmgb htmomf bodega Concentration" (mg/mL) 0 2 20 200 r`Tahtessfeirxs/td1o0serawtesr/esedxe/sdiogsneawteerdefdorescioglnleactteidonfoorfebvlaoloudatfioornaonfalsyusbicshorfofnliucotroixniec;ittyh;etnheexnte2x0t 5 ratssen/dose were designated for reproductive assessment; the remaining 10 rats/sex/dose (control and high-dosegroupsonly) were designated for one-month recovery assessment. An additional subgroup (S rats/sex/dose) was received as a separate shipment and was added to each ~ dose group approximately 84 days after study start, for evaluation of hepatic beta-oxidation --- CompanySanitized. Doesnot conTtSaCAi0n8 2020-5DD4aa2yy5G:GaavvSaauggbeecShStruuoddiyyciiTnnoRrRaiatctsistwywiitthhOOnneeGGeenneerraattiioonnRReepprroodduuccttiiononEEvvaalluuaattiionosns DDuuPPoonnet1114141188. --_ aacntailvyistiysfaorlelaolwsiongreafe1r0r-eddatyoeaxspotshuerteh,reTe-hmeonratths rdeesciogvneartyesdubfosretcollection of blood for fluorine Study Parameters Frequenc Body Weight Food Consumption Day 0 and weekly thereafier Weekly Detiled Clinical Observations Mortality Moribundity Checks Day 0 and weekly thereafter Twice daily Clinical Pathology Ophthalmoscopic Evaluations Week 6, Week 14, and Week 19 Pretest and Week 13 Neurobehavioral Evaluations Biochemical Analysis Pretest, Week 13, and Week 18 Subchronic Week 14 Recovery Satelite (day 10) Week 17 After 10 daysof dosing Reproductive Assessments Py adults Fy weanlings Week 11-18 Week 13-18 Vaginal Smears (P, Females) Developmental Landmarks (Fy adults) Week 7-9 Week 19-23 Necropsy Subchronic --_ Py adults Week 14 Week 12-18 Weanlings Recovery Week 17-18 Week 18 Fi adults `Blood fluorine animals Week 23.25 Week 26 MATERIALS AND METHODS A. Test Guidelines The study design complies with the following test guideline: + `UTnoixtiecdSSutbastteasnEcnevsi(rOoPnmPeTnSt)alHeParlotthecEtfifoenctAsgTeensctyG(uiEdPeAl)i,neOsf,fiOcPeoPfTPSre8v7e0n.t3i1o0n0, P9e0s-tDicaiydeOsr,aland Toxicity in Rodents (AUG-1998). B. Test Substance Thetest substance, H-25425, was supplied sponsor reported purity of the sample wal bythegponsoras an amber-yellow-brown solid. The stabilityofthe test substance was confirmed by analysis near the beginning and end of the study. --- `Company Sanitized. Doss not contain TSCA CB 29H002-5DD0a2y5GG:eavvSaauggbeceShSrttouunddiyyciTinnoRrRiaacsistywiitthhOOnneeGGeenneerraattiioonnRReepprroodduuccttiioonn EEvvaalluuaattiioonnss ~~ C. Test Species DDuuPpoont1111441188. dOanteOocftoAbuegrus1,t22060,22,010726wmearleeraecnediv1e7d6 ffreommalCehaCrrlle:sCRDiv(eSrDL)aIbGoSraBtoRrireast,s,Inwci.t,hRaanleaisgsh,igNnoerdtbhirth CNaorvoelimnbae.rA2n4,a2d0d0it2i,onwaelre45rercatesiv(e2d3imnaaleseapnadra2t2e sfheimaplmeesn)t, 8w4itdhayasnafatsesrisgtneuddybirsttahrtdaotne of January 7, analysis. 2003. The additional rats were designated for the 10-day hepatic biochemical `The at was selected because it is the species recommended in the subchronic toxicity guidelines and is on con extensively used in sistently acceptable reprod health uction status stud and ioesn.exTtheensCirvle:eCxDper(iSeDn)cIeGwSitBhRthriast was selected bas strain at Haskell ed Laboratory. D. Animal Husbandry 1. Housing sWietehstsheepaerxacteep,tiinonstoafinsleosmsestpeoerlt,iwoinrseo-fmtehsehrceapgreosduscutsipveensdteuddya,baolvleatcsagweebroearhdosu.seAdnoinmealperrocoamgse, pe were 22.4 maintained on a 12-hour light/dark 3C and arelative humidity of 50 = cycle 20%. (fluorescent light) and at a temperature of cRoahtasbditeastiigonnatpeedrifoodr.reDpurroidnugcttihveegteosxtiactiitoynepvearliuoadt,iofnesmawleererahsoudseesdigansatberdeefdoirnrgeppraoidrsucdtuirvientgotxhiceity `emvaatleudatfioenmsawleoerrsah,outsheedeinnddoifvtidhuealcloyhuanbtiitlagteisotnaptieornioddayfo2r0.femBaelgeisnwniitnhgoount egvesitdaetnicoen odfay 20 for lcaocptualtaitoinonp,erfieodm,alaedurlattsfweemarleehroautssewderinedhioviudsueadllwyiitnhptohleyircalritbtoenrsatien ppoalnyscwairtbhonbaetdedipnagn.s. During the `pDeurriiondgftohrePeyntaidrueltisn,-lainfedptehreipoodsftowreraantsinegvapleuraitoeddffoorrFsyubwceharnloinnigcst,oxciacgietyr,atchkes7w4e-rdeayreplroecmaatetding within the animal room each week and cages were repositioned on the racks every 2 weeks. 2. Feed and Water `Tap water was provided ad libitum. All rats were fed PMI Nutrition International, Inc. Certified RinoaddevnetrtLenatblDyiweitth5o0ut02faododlifboirtaupmp.roOxniemaatneilmya2l4inhogurrso.upTVhi(safnaismtailngnwuamsbenro6t6c5o1ns5i0d)ewraeds to have oifmwpeaicgtehdt tahnedsmtoudryeabsytthheerantexltoswteaipgphrodxaiym.atFeulryth3e%rmboroed,ynwoeicglhitn,icbaultsirgengsaiwneerdethniostesdaamfeteartmohuent fasting. -a `Company Sanitized. Does not contain TSOA Gal 02-5D4a2y5G:avSaugbeeShtroundiyc iTnoxRiactistywithOneGenerationReproduction Evaluations DuPont11418 ~ 3. Identification Each rat was assigned a unique 6-digit Haskell number, the last 3 digits of which were tattooed on the tal ofeach rat. The information on the cage labels included the unique 6-digit Haskell animal number and the cage identification number assigned to each rat. F; generation rats retained after lactation were identified by a temporary tail number on postnatal day 21 (weaning), and were tattooed after all litters were weaned. 4. Animal Health and Environmental Monitoring Program `As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impactthescientific integrityofthe study: + Wanadteorthsearmcpolnetsamairneaantnsa.lyzed for total bacterial counts, and the presence of coliforms, lead, + Feed samples are analyzed for total bacterial, spore, and fungal counts. + Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including --_ specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence ofthese contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity of the study. `The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluationofthese data did not indicate any conditions that affected the validity of the study. E. Quarantine and Pretest Period Upon arrival at Haskell Laboratory, the rats were quarantined for 6 days of the 14-day pretest period. The rats were observed daily for any clinically apparent signs of disease or injury, weighed 3 times, and examined by a veterinary ophthalmologist to identify animals with : preexisting ocular lesions - - On the bases of acceptable body weight gains and no clinical observations, all ats were released from quarantine on test day -8 by the laboratory animal veterinarian. Additional male and female rats designated for the 10-day hepatic biochemical analysis were quarantined fo6r days of the 6- and 7-day pretest period, respectively. The rats were observed daily for any clinically apparent signs of disease or injury and weighed three times, then released from quarantine on test day 90 by the laboratory animal veterinarian. --_ TT ---- Company Sanitized. Does not contain TSCA 08 0H2-5D4a2y5;GavSaugbechSrtoundiyciTnoxRiactistywith OnGeeneration Reproduction Evaluations ~ F. Assignment to Groups and Study Start DuPont 11418 1. R`AantaslyDseiss,igannadteRdepfroordtuhcetSiuvebcEhvraolnuiactiToonxsicity, One-Month Recovery, Total Fluorine Level Roapthsthwaelrmeolsoelgeyctaebdnofromrasltiutdiyesuosrecolinnitchaelbasisgenssooffaddiesqeuaasteeobroidnyjurwye,iaghntd gaaibno,dfyrweeeidgohmtfwriotmhianny 2ra2n0do%miozfatthieonmseoanthwaittthhienreawseexr.e nTohestsateilsetcitceadllryastisgwneifriecadnitstdriifbfuetreedncbeyscaommopuntgergirzoeudp,bsotrdaytiwfeieidght means within a sex. Oagrea.l aPdrmiionritsotrtahteisotnaortfoHf-t2h5e4t2es5t bseugbsatnaoncnetaesdtmidniasyt0rawthieonn,t3heferamtaslweerratesawpeprreoxriempaltaecleyd t5o1 adtatyaisnof de2si0r%eodfbotdhye wmeeiagnhtwimtehainn afosreexawcahsgrroeuppl.aceOdn.eOfneemfaelmearlaterwaitthwaasbordeyplwaeciegdbhatstehdatownasaclniontiwciatlhin ofbrsoemrvaantyiocnlionibcsaelrsviegdnsoonfdtiesstedaasye0o.r Rinejpulraycaenmdenatbroadtsywweerieghstel+ec2t0ed%oonftthheebmaesaesnowfitfhrienedaosmex. 2. Rats Designated for 10-Day Biochemical Analysis s`tTahret.raTtshedeyswigenraetehdanfdolretdheth1e0s-adamyebaisotchheemoitchaelr raantasldysuirsinagrrtihveedqusaerpaarnattienley,an8d4pdraeytsesatfpteerrisotdusd,y ~ `ecxocmepputtetrhiezyedd,idstnroattirfeicedeirvaenadnomoipzhatthiaolnmoilntoogisctauldyexgarmoiunpasti(o5n/s.exT/hdoesye)w,ersoetdhiasttrtihbeurteedwebrye no sstuabtsiesttoicfarllaytssiwgnaisficcoanmtpdairfefderaemncoensgatmhoenmgseglrvoeus.p bOordaly wademiignhitstmreaatniosnwoifthHi-n2a54s2e5xtwohmeanltehiasnd afnedma5l1e (raftesmableegsa)ndoanysteosft adgaey.s I9n0-alinfde d9a1t,ar(ebsopedcytiwveeilgyh.tT,hfeoordatcsonwseurmeptaipopnr,oxcilminaitceallyob5s0er(vmaatlieosn)s) `were collected from these animals included in this report. and are in study records. However, these data will not be G. Dosing Suspension Preparation D`moestehysluceslpleunlsoisoen(sinofde0,io2n,i2z0e,dowrat2er0)0. mTghteesdtossuinbgstsaunscpee/nmsLiownesrweeprreepmairxeeddifno0r.a5p%proximately one smtiinrruetreawnidtshtiarpreodlyftorro3n0hmoimnougteensizperri.orTtohednostihnegdaonsdindgursiunsgpednossiinogn.s wDeorseinpglascuesdpoennsaiomnasgnoefttihec. test substance were prepared daily and stored at room temperature until used. H. Test Substance Administration fAlnuiomrainleswdeerseigdnoasteedd dfaoirleyvbalyugataivoangoeffsorub9c2hr(omnailcest)oxaincdity9,3r(efceomvaelreys,)adnadysa.nalAynsiimsaolfsbdleosoidgnfaotred ~ bfiorocrheecmoivcearly oervablluoatoidofnluwoerriendeoasneadlydsaiislwyerbey gdaovsaegdfeofror9110dadyasy.s,Asntairmtainlgs9d0esdiagynsataefdtefrosrtu1d0y-dsatyart --- VY G Company Sanitized. Doesnotcontain TSCA CBI 2H5002-5DD4a2y5;GGaavvSaauggbeeehSSrttouunddiyyciiTnnoRxRitactsistwwyiitthhOOnneeGGeenneerraattiioonnRReepprroodduuccttiioonnEBvraalluuattiioonnss ___ DDuuPPoonntc-1111441188. ~~ A74nidmaayls,s adnesditghneanteddaifloyrdruerpirnogdutchteiv1e4-edvaaylumaattiionnsg wpeerrieodd.osTehdedaPi,lmyablyegraavtsagceonftoirnaupepdrotoxbiemadtoesleyd fwoelelkowgiensgtatthieoncophearbiiotda.tiPornepgenrainotdfuenmtaillessacirniftihcee. prPorceegsnsaonft dfeelmiavleerysowrersehodwoisnegd sdiugrnisngofthdeeltihvreerey- dwaeyre1n8obtoddoysewde.igFhtrso.mLgaecsttaattiinogn fdeamyal1e8sunatnidl dfeelmiavleersy,widtohsenovoelvuimdeesncweeorfecboapsueldatoinonthweegreestdaotsieodn u(n5timlJpkugp)s wwearsebwaeseadneodnotnhepmoostsptarretcuemndtalyyr2e1c.orTdehdebvoodlyuwmeeigohftH.-2M5a4l2e5agnidvefnemtaoleeaccohntrraotl animals were similarlytreated other groups. with 0.5% methylcellulose a the same dose volume as used in the Oonnlytersetcdeaivye2d2,apaornteiaalnidmoasle.inOgnrotuepstVIdIay(a6n9i,moanlenaunmibmaelr i6n6g5r1o1u8p)VsItr(uagngliemdaldunruimnbgedros6i6n5g26a2n)d dwealsivoebrsede.rvTehdewsiethpadrotisaelsduosspeesnswieorneonnottcheonlsiipsdefroeldlotwoihnagvdeosiimnpga.ctTehdertehfeosrteu,dayfausllthdeoysewewraes not isolated dose. incidents, the rats were notinthesame group, and they received mostofthe intended Otanrgteetsetdddaoyse69v,oolnuemaen(i2m.a5lmiLn).groTuhpisVIsIin(galneiimnaclidneuntmboefr26m5i0sd8o4s)e rweacseinvoetd c0.o4nsmidLeorvedertohihsave: wiemrpeacotbesdetrhveedstiundtyhiassrtahtesruatbrseecqeiuveetndotthtehitsamrigsedtoedsidnogs,e thereafter and no adverse clinical signs 1. Test Substance Sampling `coDlolseicntgesdufsoprehnosmioognesnaetictoyn/cceonntcreanttiroantsioofn 2v,er2i0f,icaantdio2n0a0ndmgst/abmiLliotyfaHn-a2ly5s4i2s5(5w-ehroeurprreopoamred and tvaermipaetriaotnu(rCe.)Vo.n) otenstthdeaylo2w(lOecvteolbfeorr1t7e,st2d00a2y).2 sBaemcpaleuss,eosfaampnleusnewxepreectcoeldlehcitgehdcfooerfftihceielnotwolfevel fverroifmictaetsiotnd."ay O8ndotseset pdraeypa4r2at(iNoonv(eOmcbteobre2r62,32,020020)2a)nfdortetshtedhaoymo8g6e(nJeaintuya/rcyon9c,e2n0t0r3a)t,iodnosing sadudsipteinosni,o0nsmagt/amllLl(ecvoelnstrwoel)resacmopllleecstewdefroersuunbimfiotrtmeidtyf/ocronacneanlytsriastiwointhvetrhiefiecaactihonseatnoalfyssaimsp.leIsn. "ATlhledsoussipnegnssiaomnplveeshiwcelreewacosll0e.c5te%dmaenthdyalncealllyuzleodseo.n the s-ame day the suspensions were prepared. J. Analytical Methods 1. Recovery Sample Analysis mCeotnhcyulrcreelnltulwoistehwdaossitnegstseudsaptentsheiolnoswalneavleylse(s2,mrge/comvLe)r,yaotftHhe-2m5i4d2l5evferlo(m2s0pmikge/dm0L.)5 a%nd at the high level (200 mg/mL) to confirm the analytical method. For the low level, H-25425 was. ~~ `weighed (approximately 12 mg) and diluted with 6mL of 0.5% methylcellulose. For the mid and - `Company Sanitized. Does not contain TSCA GBI 2012-.5D4a2y5G:GravSagugceehSvSoteniyciiTnRRoatsivithOneeGGeenneerartaioonnRReepprrooddusccttiion EBvvlaubsions DDuuPpoonntt111441188 --~ 3himgLh loevfel0,.5H%-2m5e4th2y5lcweallsulwoesieg.heAdll(arpepcroovxeirmyastealmypl6e0sanwedre60t0hemngv,orretsepxeecdtifvoerldyi)sapnedrsdiiolnutoefdtwhieth `Hm-a2n5n4e2r5asinthtehedomsetihnyglscealmlpulleossea.tsiTmhielasracmopnlceesntwreartieotnhse.n processed and analyzed in the same 2. Dosing Suspension Treatment Each dosing sample was collected in a 15mLcentrifuge tube (6mL for 2 mg/mL level and v3omrLtefxoirng2f0oramnidx2in0g0,mcgen/tmriLfulegvienlgs)a.ndMertehmaonvoall (3 of tmhLe)suwpaesmaatdadnetd.toAeftaecrhtthuebes,upfeorlnlaotwanetdbwyas s`rumbeestthmaannocoelv,twherieettdmheas,vitonristnuegbxsiatnsagn,scocel,iednrs,terwmiaafsiundgriiainaendsgdgusnrodeliemdrosv,naiwltaorosfgtewnha.eshTseuhdpeeswreintashtoal3nitdrseapfwlteiecrraeeteatchwheanswrhaesechso.n(s3tTimhtLeut)teedosftin 1ste0atmmrpaLlheywsdirwtoehfruTerHarnFec(aoTnnHsdFtti)htuuets2eid0ng0tosm3ognmi/cLmatLwiiostnahmtopTlHaesFss,uwrteehreael2lr0meacmtogenrs/itmailtLuwtsaeasdm.ptdolies1ss0o0wlevmerdLe.rweTichtohensT2tHimtFgu,t/emdTLht.eo rfeoslpleoctwiivneglyt:arget concentrations were then analyzed: 4.0 mg/mL, 6.0 mg/mL and 6.0mg/mL, 3. Chromatographic Conditions Instrument: HewletPackardModel 1100 HPLC --_ CFMoollbouiwmlRnea:tPeh:ase. 1LSt0Oy0rn%aLgtenelitrnHahRyd4r;of7u.r8amn m(TxHF3)00 mm (GPCcolumn) CInojleuctminonTVemopleurmaet:ure; E35MC Detection: Refractive Index 4. Calibration and Quantitation [ A separate -- sagloesftoHc-k2s5o4lu2t5itoenostfsHu-b2s5ta4n2c5e iwnatsedtreashiygdnraotfeudraans (thTeHaFn)alwyatiscaulseredfteoremnackee.standard `calibration solutions that bracketed the test solutions. Peak heightsfromreplicate HPLC/GPC/RI analysisofeach calibration solution were used to construct acalibration curve by least-squares regression. Measured concentrations for each test solution were determined by applying respective peak heightstothe calibration curve. - est substance homogeneity/uniformity inthe vehicle was evaluated by calculating the. icnoetfhfeictioepn,tomifdvdalrei,atainodn b(oCt.tV.om=ssatmapnldeasrd(dhevoiamtioong/meeoanrnedxuip1l0ti0c)yaot)fetshaemmpelaessu(rceodncceonntcreanttiroantions tsvthearrinofduiagcrhadotuicotrnit)tfheoerrisoeonlauactthiHoadns.okseHilnolgweLlvaevbeeorlr.,aitAfotrchyoefftofersitacicsecunebtpstotafabnlvcaeerdihiaasttsirobinbeuoetfniolsenshsooftwhtnahnetootrebseetqdsuiuafblfsitctauolntc1et0o%diissptehrese ~ aincctehpetavbelhei.cle or the analysis has shown variability, a coefficient greater than10 may be - -- Company Sanitzed. Doos not contain TSCA Gal 0H2-5D4a2y5;GavSaugbechSrtoudnyi TinoxRitcstywithOneGeneration Reproduction Evaluations DuPont11418 - f`oTrheemacehandorseisnugltloefvtelhewahsomuosgeednteoidteytsearmmpilneesth(en c=on3c)oenrtrcaotnicoenntorfattihoentevsetrsifuibcsattainoncesafomrplthees (n = 2) respective dosing levels. cStoambpialirtiynwgatsheevcaolruraetsepdonbdyiunsgisntgabtihleitmyeraesnulrtess.ultofthe homogeneity samples as the baseline for Because recovery of the procedure samples at each used level to isolate the test were monitored. substance in A correction the method for based on these analysis, recovery spiked samples was than 90% of applied nominal to the sample for the level. result,if the spiked recovery sample analysis was less K. Body Weights sAtluldyr.atsInweardediwtieoing,htehde ornatcsedpeesrigwneaetekddfuorrinngeutrhoebeshuabvcihorroanlicevtaolxuiactitiyonasn,durnedceorvgeoriyngpefruinocdtsioonfalthe observational observations. battery and motor activity assessments, were weighed on the days of those L. Food Consumption and Food Efficiency ,~ `The amount of throughout the food consumed by each study. Each feeder was wraetiogvheerdeaatchthewebiegghiinnnginigntaenrdvaelnwdaosftdheeteirnmtienrveadl and the sfuinbatlrawcetiegdhftroofmtthheefieneidteiarl and the feeder waemigohutn.toFfsrpoimlltahgeseefmreoamsutrheemfeenetdser, during the interval mean daily food was dcaotnas,utmhpetmieonanovdeariltyhfeoiondteerfvfailcwieanscydewtaesrmcianlecdu.latFerd.omFothoedfcooondscuomnpstuimopntfioorntahendrabtsodthyatwewiogreh:t sampled for blood fluorine was only collectedduringthe exposure period. M. Detailed Clinical Observations and Mortality bDeuhraivnigorthaendte/sotrpaerpipoeda,racangcee-saimtoenegxarmaitnsawteiroenscotondduectetcetdmatorlieabsutntdwiocreddeaaidlyr.atOs nanfdivaeboncocramsailons, Tduheesteomiinscslemdecnatgew-esaittheeerxaomritneacthinoicnisandiedrnrort, acfafgeec-tsittheeevxalaimdiintaytoifontsewsetruedyonalsytdheorneewoenrceenaoday. `animals found dead or sacrificed in extrem a the nex cage-site examination. aAptpeeavrearnycew,eigDheitnagi,leedacclhinriactawl aosbsienrdviavtiidounalsliynhanstdalneddaardnidzeedxaamriennaedwefrore aablsnooremvaallubaetheadvoinorraatnsd cdleisniigcanlatoebdsefrovratthieonssubicnhcrloundiecdt(obxuitciwteyreexpnootsulriemiatnedd toon)ee-vmaolnuatthiornecoofvefrury,psekriino,dse.yesT,hmeudceotauisled. ~~ (mleamcbrirmaanteison,,opcicluorerreecntcieoon,fsaencdreutniuosnusalanrdesepxicrraettoiroynsp,atatuetm)o,nocmhiacngneesrvionugsaist,ysptoestmuarcet,irvietsyponse to handling, presence ofclonic, tonic, stereotypical, or bizarre behavior. T Te T e CompanySanitized. Doesnotcontain TSCA CBI 2092:05:D0De2ay5y:GGaavSagugbeeeShSrttouunddiyyciiTnnoRxRitacsistwywiitthhOOnnee-GGeenneerraattiioonnRReepprroodduuccttiioonn EEvvaalluuasttoornss ~ N. Ophthalmology Evaluation DDuuPPoonmt1111441188 `wTewroe oepxhatmhianlemdolboygfyoceaxlamiilnluamtiinoantsiowneraendcoinnddiurcetctedopbhythaavlemtoesrcionpayry.opThhthealemxoalmoigniastti.onBsowtehreeyes `conducted solution. under subdue lighting after mydriasis had been produced with a 1% tropicamide: sOenletcetsitondaaynd-1g1r,otuphiningi.tiaOlnextaesmtindaatyi8o7n, walalsspuerrvifvoirnmgedratosndaelslirgantatreedcefiorvetdhefo9r0t-hdeaysteuxdpy,ospurrieoratnod one-month recovery were examined again. 0. Neurobehavioral Evaluations 1. Sensory Motor Function Evaluation Pthereintdootoefsrtthseurbesctoavnecreyapdemriinoids,traastsieosns,mdeunrtisnogfwreesepkon1s3eosftteosatpspurbosatcahn/cteouacdhm,insihsatrrpataiuodni,toaryn.d near 0stmigmu/lkugs/,daanydatnadil 1p0i0n0chmwge/rkeg/mdaadyegrwohuiplse,tthheeabnaisemlailnew,awseienka 1s3t,anadnadrdreacroevnear.yFoasrsetshsements were canodnd10u0cmtgoe/ndkgt/hdea1y0graonuipmsa,lsthpeerbasseexlipneeragnrdouwpeedeksi1g3naastesdesfsomrernetcsovweerrye. Fcoonrdtuhcete1d0omngt/hkeg/1d0ay ~~ caonnidmaulcstepderonsetxhepe1r0gorrou1p00demsgi/gknga/teddayfogrrosuupbsc.hronic toxicity. Recovery assessments were not FFoorrec-e agnaudghei)n.dlPuipmibllgrairpy scotnrsetnrgitchtwioenrewamseamseuarseudrebdy iamsmterdaiinatgealuygeprdieovritcoer(eCmhoavtiilnlgontheDirgaitstaflrom tahpepamroattuosr wacatsivliotcyactheadmfbaecirlsit(atSeed cotbise2orn.vibneglothwe) rbeescpaonussee.thTehdearpkreenseedncreooormaibnsewnhciechoftphuepillary caosnssetsrsimcetnitosn,wtahse eaxspseesrsiemdenatfetreawrabseaunmaowfarleighotfwthaesgdrioruepctdeedsiingtnoateiaocnhoefyet.heFaonrimalall.these 2. Motor Activity Evaluation F(oMlAl)owwiansg ctohnedeuvcatleuda.tioRnatosfwgerirpesitnrdeinvgitdhuaalnldysteesntseodryinfu1noctfi3o0n,naosmsienaslslmyeindteonftimcoatlo,rauacttoimvaittyed . cacotuinvtietrybmaolnaintcoerdsa(cCroosuslbtohuermnoniIntforrasreadnMdottiomse AocftdiaviyttyoStyhsetefmul)l.estGrexotuepntanpodssgiebnldee.rTwheereinfrared . monitoring device enables `number of movements. A measurement of 2 dependent variables: continuous movement was counted as 1 duration of movement and movement regardless of dtoutraaltisoens.sioEna,cahstweesltlseasssfioonr6wassuc6ce0smsiivneut1e0s-mininduutraetbiloonc,kasn.d the results were expressed for the aPlrseosernecceorodfeddeffoelclaotwiionngaenadcuhrimnoattoiornacotnivtihteycasegsesiobno.ards below the motor activity monitor were -- --- Company Sanitized. Does not contain TSCA CBI 0-Day Gavage Study in Ras withOneGeneration Reproducion Evaluations ~ P. Clinical Pathology Evaluation Dupont 11418 Calpipnriocxailmpaattehloyl6ogaynedva1l4uawteieoknss awfeerreicnointidautciotnedofotnhethsetruadtys,daensdigonnatreatdsfdoerssiugbncahtreodnfiocrtroexciocviteyry (ocfosnatrmoplleasndfohritghhedcolsineiocanllyp)atahftoelroagpypervoaxliumaattioenlsy,5thweeaenkismoaflsrewceorveeryp.lacTehdeindamyetbaebfoolreiscmolclaegcetsi.on `aTnhiemsael.anOimnaltshewmeoremifansgteadftaefrtetrhe3 fpa.smt,. b(latooldeasstam1p5lehosufrosr)haenmdautroilnoegwyaasndcocllliencitceald cfhreommisetarcyh mecaarsbuornedmieonxtisdwe eanreesthceoslilae.cteBdlforoodmstahmeploerbsitfaolr spilnaussomafeflaucohriadeniamnadl cwohaigluelatthieoannpiamraalmewtaesrsunwdeerre cuonldleerctceadrbatonsadciroifxiicdeeoannleystfhreosima.theAdadbidtoimoinnaallblvoeonda ccoalvlaecotfedeafcrhomantihmeavlewnhaicleavtahewaansipmlaalcweadsin a dsiesrcuamrdteudbew,itphrooucetsasneadltyosissebreucma,usaenfdurftrhoezrenteastts-8w0eCr.e nSoetrrueqmuciorlelde{c0tesdupfproormttehxepevreinmaecnatavla was mfianrdrinogws.smBeoanrse wmearreroswtasinmeedarwistwheWrreipgrhetp'asrseadinat,sbcuhteadnualleydsissacwraifsicneotfrnoemceaslslaarnyimtaolss,uppBoortne experimental findings. 1. Hematology and Coagulation Blood samples were evaluated for quality by visual examination prior to analysis. Complete abnlaoloydzecrouonrtsd,etienrclmuidniendgfrreotimcumlioccryotsesc,opwiecreevdaeltueatrimoinnoefdtohneabBlaoyodersmeAadrv.iaWr1i2g0hhte.m-asationleodgbylood ~~ apsrnmedepaearvrsaeldfurfaotrmioomanlolefaaccnehilmalanulilsamrawlemrouernpdehexoralgomogiiynn.gedaBmhlieocmoraodtsscomolepoaigrcysal,elvsyatlafuoiarnteicdoonnw,fiitbrhumtnawteeiwornemeontfohtayunlteeoenmedaebtdlefudo,rrewseulrtes `examination. Coagulation times were determined on a Sysmex CA-1000 CoagulationAnalyzer. `The following hematology and coagulation parameters were determined: red blood cell count hemoglobin hematocrit `mean corpuscular volume `mmeeaann ccoorrppuussccuullaarr hheemmoogglloobbiinn concentration raebdsocleultledriesttirciublutoicoyntewciodutnht platelet count white blood cell count `dmififcerroesnctoipalicwhbiltoeodblsomoedarceelxlacmoiunnattion apcrtoitvhartoemdbpianrtitailmethromboplastin: time: -Y ------------ `Company Sanitized. Doesnotcontain TSCA CBI 5102-5D4a2y5:GavSuabgeehrSotnuidcy TinoxRiactistywithOneGeneration Reproduction Evaluations DuPont11418 ~~ 2. Clinical Chemistry 7`S1e7rculmincilcianliccahlecmhiesmtirsytarnyaplayrzearm.etPerlsaswmearefldueotriedremicnonecdeontnraatRioocnsheweDrieagdneotsetrimcisn(eBdMuCs)i/nHgi&tachi Beckman model 12 digital pH/ISE meter and a fluoride-selective electrode. `The following clinical chemistry parameters were determined: aspartate aminotransferase alanine aminotransferase: sorbitol dehydrogenase: alkaline phosphatase: total bilirubin urea nitrogen creatinine cholesterol iglycerides glucose total protein albumin globulin calcium inorganic phosphorus sodium potassium fclhuloorriiddee (sacrifice only) 3. Urinalysis Urine volume and appearance (quality, color, and clarity) were measured and evaluated visually, respectively. Urine constituents were semi-quantitatively measured on a Bayer Clinitek AtlasTM ~~ (ABuMtCo)m/aHtietdaUcrhiine7C1h7ecmliisnticrayl acnhaelmyizesrt.ryUarnianleyzperro.teUirniwnaesosmmeoalsaulriteydwoansadReotcerhmeinDieadgunsoisntgicasn ``mAoddvealnc1ed2Odsimgiotmael tpeHr/I3S9E00m.etUerrianendflaufolruiodreicdoen-sceelnetcrtaitvieoneslewcterroeded,etaenrdmtionteald uursiinnegfaluBoericdkemsawnere calculated (volume x concentration). Sediments from all urine specimens were evaluated microscopically. The following urinalysis parameters were determined: quality color ketone bilirubin clarity volume blood urobilinogen "osmolality fluoride (sacrifice only)* + pH glucose `prmoitcerionscopic urine sediment examination --~ b FFlluuoorriiddee ddeetteerrmmiinnaattiioonn wwaass aannaallyyzzeedd fornoEmDuTriAnepwliatshiEa DTA added. -- E] -- `CompanySanitized. Doesnot contain TSCA C81 01-25D4a2y5G:avSaugbecShrtoundiyc iTnoxRiactistywithOneGeneration Reproduction Evaustions DuPont. 11418 ~ Q. Total Fluorine and Perfluorooctancic Acid Level Evaluations 1. Total Fluorine Evaluations 0O.n6 mteLst)dwaays4co(lplreec-tbeldeefdr)o,matnhdetoersbtidtaaylssi3n,u9s,of22d,es3i4,gn5a5t,e7d6,anainmdal8s9,(5blroaotsd/s(eaxpipdroosxe)i,mawtheillye the Oannimtahlesdwaeyorefbulnodoedr lcioglhltecctairobnon(edxicoexpitdteesatnedsatyhe4s)i,a,bflooropdoswsaisblceoltloteacltebdlofordomfltuhoerianneiamnaallsys2ish.ours (3,273,01m1i,nu1t8e,s2)5,af3t6e,r d5o0s,in7g1., aBnldo9o2ddwaayssaplossotcdoolsliencgte(daffeorr tphoessliabsltedtoostea)lfbolroboodtfhlumoarlieneaanndalfyesmiaslaet animals of each dose group. Animals were sacrificed after the 3-month recovery period (test day 182). TDhureibnlgotohdewlaasstcwoelelekctoefdtihne palpapsrtiocxitmuabteeslcyo9nt0a-idnaiyngexEpDosTuArewpheirlieodonaniicmeaalnsdwsetroerepdlfarcoezdeni.n `hmoeutraibnotleirsvmalcsagfersofmoredaacihlaynicmoallle.ctUiroinnoefafnedcefsecaensdwuerirnee.frUozreinneanadndstfoerceeds. wBelroeocdolflleucotriendeat 24analysis has not yet been performed butmaybe analyzed at a later date. 2. Perfluorocctanoic Acid Level Evaluations sBulbocohdrownaiscctoolxlieccitteydevinalEuaDtTioAn farnodmftrhoemvlelnaatcsavdaesaitgnneactreodpfsoyrfrreocomvaelrlyaetvsaldueastiiognn.atePdlafosrma was ~ prepared and stored frozen at ~80 to ~20C until analyzed for concentrationofperfluorooctanoic acid (PFOA). Pdaltaaswmiallhabse nroetpyoerttbedeeinn aansaulpypzleedm.enPtlaarsymraepwoirltl. bTehaenadleycziseidofnrtoomecvoanlturaotle alnodw-hiagnhd-idnotseerrmaetdsi,aatned-. odrogsaengircosuoplsvewnitllprboetebianseprdeocinpirteasutlitosn iunstihnegahipgrho-tdeoisneprgercoiuppi.tatPiloanscmoalsuammnplaensdwtihlelnbaenaexltyrzaecdtefdorby PFOA by LC-MS-MS. R. Biochemical Measurements Fadomlilnoiwsitnrgat1i0ondoarysaf(tmearloensea-nmdonftehmaolfesr)ecoorve9r2yd(atyesst(dmaayle1s2)7orfo9r3madlaeyss a(fnedmafleemsal)oesf)t,efsitvessuabtsstafnrcoem eanaecshthgersoiuapadnedsicgxnsaatnegduifnoartiboino.cheAmticeaalchevtailmueaptoiionnt,wetrhee wlieviegrshewderaendretmhoevneedu,thwaeniigzhedd,byanCdOt;hen a HpoCrt,io5n0wmasMhTormiozgmean-biazseed,(01.2g5raMm stiuscsruoes/ed,maLndb5u.f4femr)MinEhDoTmAog,enpiHza7t.4i)o.n Hbeupfafetric(5p0ermoMxisTorimse-s were prepared using differential centrifugation. The resulting peroxisomal pellets were raneasluyszpeedndfeodr pinertohxeihsoommoaglenB-iozxaitdiaotniobnufafcetri,viatly.iquTohteed,pearnodxisstoomraedl bseutswpeenesnio-n6s5 wanedre-d8i5luCteudnttiol2 7 dpreotteerimnicnoendceunstirnagt[i*o*nColfpaalpmpirtooxylimCatoeAlyas0.t5hemgsu/bmsLt.ratPee.r)oxTihseomparlotBe-ionxciodnatteinotn oafcttihveitpyewraoxsisomes Too Company Sanitized. Doesnotcontain TSCA CBI 9102.5D4a2y5:GavSaugbcehSrtoundiyc TinorRitcistyithOGneeneration Reprodcion Evaluations Dupont 11418 -- was determined before and after analysis by the Biorad method.) Final rate calculations were made using the post-assay protein concentrations. S. Anatomic Pathology Evaluation for Rats Designated for Subchronic Toxicity and OneMonth Recovery Evaluations fAfetmearleasp,prreosxpiemcatitveellyy)9,0gdraoyuspsofofex1p0omsuarleetaontdhe10tefsetmsaulbestraatnscfer(otmestthdeay0s,9120,a1n0d0,93anfdor males and 11000f0emmagl/ekgra/tdsafyrgormouthpes0wearneds1a0cr0i0fimcge/dkagn/ddanyecgrroopsuipesdw.erAeddsiatciroinfiacledgraonudpsneocfro1p0smiaelde and faipnpdrionxgis,magtreoluypsonseacmroinfitchedaafftteerrtahepplraostxiemxaptoesluyre90(tdesatydsaayre12r7e)f.errIendtthoeadsistchuesssuibocnhorfonpiacthtoolxoicgiyty rgersopuepcst,ivaenldy.grRoautpssdseascirginfaicteedd ofnortpeostssdiabyle1e2v7alarueatrieofnerorfedbltoooadsftlhueoroinnee-lmeovneltshdriedcnoovterryecgeriovuepsa, gross or microscopic pathology evaluation. SRaactrsifiscceh.edTuhleedofrodrersaocfrisfaiccreifwiecreefofrasstcehdeodvuelrendidgehattohns wthaesarfatnedmooomnabmeofnorgeatllhetirresacthmeednutlgerdoups. Rats were euthanized by carbon dioxide anesthesia and exsanguination. Gross examinations. were performed on all male and female rats. --~ ar CompanySanitized. DoesnotconTtSaCAiCnBI 9H62.5D4a2y5:GavSaubgcehSrtoundiyc TinorRiactistywithOGneeneration Reproducion Evaluations Dione 1418 ~~ `sTahceriffoilcleodwbiyngdetsiisgsnu,esawnedrfercoomlloenceterdatftrhoamt swuabscharccoindiecnttaolxlicyiktiyllaendd. one-month recovery group rats Digestie System iver Cardiovascular System heart Musculoskeletal System skeletal muscle esophagus aorta stomach femur/knee joint stermam duodenum jejunum Hematopoietic System spleen ReproductiveSystem ilceeucmum th`myamnudisbular lymph node Matelsetes rceocltounm b`moenseenmtearricrolywmph node: epididymides prostate salivary glands pancreas EndocrineSystem seminal vesicles `pituitary gland Female UriKniadrnyeSyysstem urinary bladder ptahryartohiydrgoliadndglands adrenal glands `uotvearruises `mammary glands gross observations RespilrunagtsorySystem Nberraivnou(isnScylsudtiengmcerebrum, Miscellaneous trachea nose: cerebellum, medulla/pons) spinal cord (3 levels: cervical, esykiens (including retina and _ larynx pharynx `mid thoraci, lumbar) sciatic nerve. optic nerve) gross observations" b. BGoronsosmoabrsreorvwawtaiosncsmoaldleeacttnweeictdrhotphesyfefromriwhaincdhihirstoompa.thology was 10k appropriate (6. fluid, uffled fr, nd missing anatomic pars) vere generally no collected. "gTrhoeufpoalnlodwtihnegotniess-umeosnwtehrerewceoivegrhyedgrforuopsm:raltisvesra,crKiifdinceeydsb,yaddreesniagln gilnatnhdes,sutbhcyhmraosn,ibcrtaionx,icsiptlyeen, wheeairgth,t/tfhiynraolidbo(dweyiwgehiegdhtafatenrdfoixragtainonw)e,iogvhatr/ibersa,iuntewreuisg,hetpirdatiidoysmwiederse,caalncdultaetsteeds.. Organ Gaprporsosprlieastieon(se.wgh.icflhuiwdearcecduimualgantoisoend,artunfeflcerdopfusry, amnidssfionrgwahniacthommiiccrpoasrctos)piwcereexagmeinneartailolynnwoats not c(oel.lge.cotsetde.oaGrtrhorsistils,espioondsodfoerrmwahiitcih,acmhircornoisccdoeprimcatdiitaigsnoosfitshewotaull,dunroitnabrey cadadlictuilvie,:and deformity ofthe teeth, toe, tal, or pinna) were saved but were generally not processed for microscopic evaluation. T1e0st%esn,euetpriadlibduyfmfiedreesd,faonrmdaeliyne.s wPerroecefsisxeedd tinisBsouueisnw'esrseoleumtbioend.deAldliontphaerrafifsisnu,ecsutweatreafnioxmeidnianl thickness of 5 micrometers, stained with hematoxylin and cosin (H&E), and examined `microscopically. En CompanySaritized. Doesnotcontain TSCACB 9102D54a2y5a;vSaugbechSvotnuiyc iTnorRiactistwyithOeGeneration Reproduction Evlustions DuPont 11418 ~~ eAlvlalcuoaltleedctmeidcrtiossscuoepsifcarlolmysfurbocmhrcoonnitcrotloxaincdit1y0g0r0oumpg/rkatgs/dsaacyrirfatisc.edLoinvetresatnddaytshy9r2o/i9d3glwaenrdewere Tpartoscaenssdefdraonmdoenvea-lmuoatnetdh mrieccroovsecroypiractasl.lyAlflrocomll1e0ctaenddt1is0s0uemsg/wkegr/edparyocseusbseehdroannidc rteocxieciivteyd garfouulpl histopathological examination from one control male rat in the recovery subset that was accidentally killed. T. Reproductive Evaluations 1. Observations and Mortality for Parental Rats tCahgreo-usgihtoeutextahmeipnraetmiaotnisngw,ercoehcaobintdautcitoen,d gtewsitcaetidoani,lyantdhrloaucgthatoiuotntpheerisotdusd,y.caActh loefasttheonPycepawreeenktlaly rats were individually handled and carefully examined for abnormal behavior and/or appearance. 2. Body Weights for Parental Rats a. Cohabitation Period tAhlelrePayftmearl.esFeamnadlfeermaatlsewsiwtheoruetweeviigdheendceoonfctohepufliasttidoanywoefrteheweciohgahbeidtawteieoknlpyeruinotidl, daenldivweereykolry until sacrifice. ~ b. Gestation and Lactation Periods `Pg,esfteamtiaolnedraayts1w8ewreaswceoillgechteoeddnindaoyrsde0r,7t,o a1d4j,uastndth2e1doofseaagcehdupreirinogdt.hiIsnpaedrdiiotdioonf,rbaopiddywweeiigghhtt on gain. However, these weights are not included inthefinal report. 3. Food Consumption and Food Efficiency for Parental Rats a. Cohabitation Food consumption was not determined during cohabitation. b. Gestation Period 2I1n.divBiadcuahlffeoeoddercwoanssuwmepitgihoendoaftptrheegbneagnitnPninfgemaanldesenwdaosfrtehceoridnteedrvoanl gaensdtatthieonfidnaalyswe0i,g7h,t1o4,f tahned ifneietdiaelrfaeneddetrheweaimgohtu.ntForfopmiltlhaegfeoofdrocmontsheumfpetedieorndaunrdinbgodthyewienitgerhvtaldawtaa,stshuebtmreaactneddafirlyomfotohde efficiency was calculated. `Food consumption was not measured for females without evidenceofcopulation or for males following the cohabitation period. -- e--------------B-- e --------e-- si --s-- : `Company Sanitized. Does not contain TSCA CBI 5102.5D4a2y5G:avSaubgeehSrtoundiyc TinoxRiactistywithOneGeneration Reproduction Evaluations DuPont 11418 --_ c. Lactation Period Food consumption was not measured during lactation. 4. Estrous Cycle Evaluation tVhaegiensatlrosumsecayrclse.weVraegcionlallecstmeedadrasilwyefrreocmolalllecPtyedfebmeagliennriantsg i3n woeredekrstporidoertetormcionheabtihteatsitoang,esaonfd continuing until copulation was confirmed or until the cohabitation period ended. dVeatgeirnmailnsemtehaersstwageereofalessotrcooulsleccytcelde.frHoomwealvlePry,tpahreesnetdaaltfaemwaelreernaotst natetehdeedtfiomredoaftsaacrifice to interpretation, and will not be included inthefinal report. These data are maintained with the study records. 5. Breeding a. Start of Cohabitation Each female was the same dosage continually level, in the housed on a male's cage. 1:1 basis with Cohabitation a randomly selected, nonsibling was initiated on test day 74. male of b. Duration of Cohabitation Period -- gCeoshtaabtiitoan)t,ioon2rcownetienkusedhaudntillapesveidd.encOenofthceopdualyatcoipounlwataisonobwsaesrvceodnf(idremsiegdn,attheedfaesmdaalye 0waosf transferred back to individual cage housing. c. Evidenceof Copulation Each female was examined once daily for the presence ofan intravaginal copulation plug or sperm in the vaginal lavage sample. 6. Gestation Procedures tAhfeteernbdeoifngthteracnoshfaebrirteadtiinotnoppeorliyocdafrobronfaetmealpeasnswi(tohnoudtayev2i0deonfcgeoesftactoipounlaftoiromna)t,efdemfaelmaelreast,s owrerate observed at leat twice daily for signsofdelivery and offspring. ' 7. Lactation Procedures The day when delivery period, offspring were iwnadisvicdoumapllleytheanwdalseddeasnidgneaxtaedmidnaeyd0fpoorsatbpnarotrumma.l At each examination behavior and appearance; any dead, missing, or abnormal pups were recorded. --~ -_-- oe CompanySanitized. Doesnot conTtSaCAiCn81 9H02.5D4a2y5:GovSaugbcehSrotnidc TinorRiactistyith OneGeneration Reproduction Evlustons DuPont11418 ~~ a. Day 0 Postpartum Live and dead pups in each liter were counted as soon as possible after delivery was completed. Live pups in each litter were individually weighed. b. Day 4 Postpartum dLietctaepristawteiroen caunldleddisrcaanrddoemdlwyittoho8ut(4p/astehxolwohgeicnalpoessxiabmlien).atiEoxnt.raLoifttfesrpsrionfg8 woefrfesperuitnhgaonrizfeedwbery were not reduced. Litter counts were determined prior to and after culling. Individual pup weights were determined prior to culling. c. Days 7and 14 Postpartum Pups in each litter were counted by sex and individually weighed. d. Day 21 Postpartum (Weaning) (Pounpeslseixn/eliatctherl)itweerrweeprleaccoeudnitneidndbiyvsideuxalancdagiensdiavniddumalolnyitwoerieghdefdo.r aRtatanidnommenltyosfeldeecvteeldowpemaennltianlgs landmarks. Three of 4 pups/sexlitter were then sacrificed and subjected to a gross pathological examination. --_ 8. F, Generation Post Weaning a. Clinical Observations Ciangdiev-isdiutaelelyxahmainndalteidonasndwecrareefcuolnldyuecxtaemdianteldeafsotroanbcneordamialyl. beAhtavleiaosrtaonndc/eorweaeppkelayreaancceh.rat was b. Body Weight Measurements All ras were weighed weekly until termination (approximately postnatal day 60). Rats were also weighed onthedayofpreputial separation or vaginal opening. c. Food Consumption and Food Efficiency Idnadyiv60i)d.ualEafcohodfceeodnesruwmpatsiwoeniwgahseddeattetrhmeibneegdinwneienkglyanudnteilndteorfmtihneatiinotner(vaaplparnodxitmhaetfeilnyalpowsetingahttal othfethineitfieaeldfeereadenrdwtehiegahtm.ouFnrtoofmstphielsleadgeetferrmoimntahteiofnesedaenrddbuoridnygwtehiegihnttedravtaal, winadsivsiudbuiarlacdtaeidlyffrooomd consumption and food efficiency were calculated. 9. Fy Generation Developmental Landmarks a. Vaginal Patency -- pFoesmtanlatealradtsaywe4r3,e wehxiacmhineevderocncaemedafiilrsytb.egBiondnyinwgeoinghtpowsatnsatraelcodradye2d1onunttihle adcahyioefveamcehnite,veomrent, = `Company Sanitized. Does not contain TSCA CBI 9H02.5D4a2y5:GavSaugbeehSrtoundiyc iTnoxRiactistywithOneGeneration Reproduction Evaluations DuPont 11418 --~ b. Preputial Separation wMhailcehraetvsewrecraemeexfairmsit.neBdobdeygiwneniignhgtownasporstencaotradleddaoyn3t5heundtaiyl oafchaicehvieemveenmte,nto.r postnatal day 5, 10. Sperm Number, Morphology, and Motility T`iSgphetremppiadriadmyemtiesrswwaesrreeemvoavleuadtferdofmoretahceh dfiersstig1n0atseudrvriatv,inagndPythmealriegshtincaeuadcah edpoisdaigdeygmriosupw.asThe `wmeoirgphheodl.ogSypweerrmewdaestecromlilneecdt.ed Tfhreomletfhteerpiigdhitdcyamuidsaaenpdidteisdtyims iwse,raenfdrothzeenpeinrcleinqtuimdotniiltirtoygeanndand stored between --65" and 85 C until sperm and spermatid counts were determined. U. Anatomic Pathology Evaluation for Rats Designated for Reproductive Evaluations 1. PyAdults oArIfPo,unpdardeenatda.l rRaattssrewceerievesdacarigfriocsesdpbaythcoalrobgoincadlioexxiadmeinaanteisotnh,esiinaclaunddinegxsraantgsusiancartiifoicne.d Tbhyedeustiergin ofall cohabited females were examined for the presence and number of implantation sites. ~~ F`Soplelromwipnagracmoeltleecrtsiofnorotfhseafmirpslte1s0fPoyr smpaelrems ppaerragmreotueprweevarleuaetviaolnu,attehde raisgdhetstcersitibsedanadboevpei.didymis from these 10 ras were saved and placed in fixative for histopathological evaluation. "aTnhyetfiomlelporwiionrgttoatbhlee lscshtedtuislseudessatchraitfiwceer)eancodlplreectseedrvferdoimnaallppPryopadruilattse(fiinxcatliuvdeinfgorthpoossesitbhlaetfduiteudre: histopathological examination: Tissues Collected from Py Adults Male Female Both Sexes E`pTiedsitedsy/mTiesdteiss/"Epididymis* Ovaries Uterus (with ovi ducts) ~~ `Thyro Gross id Ob Gland" servati o n s Prostate . Seminal Vesicles Vagina Pituitary 3 TCeosatgeuslTaesttiinsganGdleapniddidymidesepiddymis colcied om mal atswere paced in Bouin's solution. Al other b GTishrsyourseosilde(srlieaopnnrsdossduewcterirvveeewaeniadtghnneeodcmrraoepfpseryoffdioxuractwtihovine.c)hchoilslteocptaetdhoflroogmymwaasenaotndapfpermoaplreiartaetsorwewroeulpdloatcebiedn afdordmiavlien.were generally ot collected. 2. Offspring P= Offspring that were found dead during the lactation period underwent a gross pathological evaluation. FE Te ------ `Company Saniized. Doos not cantain TSCA Cal 9102.5D4a2y5:GovSaugbcehSrtoundiyc TinosRiacstywithOne.Generation Reproduction Evaluations Dupont 11418 -- 3. Fy Weanlings TcahrrbeoenF,diwoexaindleinagnse/sstehxe/sliiataenrd(urannddeormwleyntsaelegcrtoesds),palitthtoerlosgiizceapleervmailttuiantgi,onweornepsoasctraiaftiacleddabyy21. Gross lesions were preserved. 4. Fy Adults SAulbljFeyctgeednetroaatigornosastspawtheorleogsiaccarilfeicxeadmibnyatciaornb.onSdeiloexcitdeed atnisessutehsesainadagnrdosesxslaensgiuoinnsawteiroen,parensderved. "The following table lists tissues that were collected and/or weighed: Tissues Collected from Fy Adults Mie Female `Both Sexes. `ETpeisdtiedsymides* OvUatreriuess(with oviducts) TGhryorsosiOdb"servations Prostate Vagina Piitary Seminal Vesicles TCeosatgeuslTeasttiinsgaGndlapinddidymdesleididymis coleted rom male ras were placed n Bouin's solution. All oer --~ b Tihsysruoeisd(rgelparnoddsuwcteirveewaenidgnhoedmarfeeprroidautcotinv.e) collected from male and female rats were placed in formalin. gGernoersallleysinoontscooblsleercvteedd at necropsyfo which histopathology was not spproprie or would not be additive were : Organs Weighed from Fy Adults Male Female Both Sexes Testes Epididymides `Seminal Vesicles (with coagulating glands) Prostate Uterus (with oviducts and Thyroid (afer fixation) cervix) Liver Brain Pthriocckensessesdotfis5sumeiscrfoormehtiesrtsop,aathnodlsotgaiicnaeldewxiatmhinhaetmiaotnoxwyelrieneamnbdeedodseidn (inH&paEr)a.ffiHni,sctuotpaatthaolnoogmiicnalal reexparmoidnuacttiiovneopferrfeporromdaunccteiv(e3 opraigrasnsofwPaysrcatosn)d.ucGtreodssonlleysifoonrsPwyermealneostaenvadlfueamtaeldemsicwriotshcoipmipcaailrleyd. ~ -- `Company Sanitized. Does notcontain TSCA CBI S-- e--Tot on tonpoimnis oo V. Statistical Analyses `pEexrcfeoprtmfeodr oBanrttlheettd'astatecstol(lpec<te0d.0f0o5r)e,ascihgnsiefxi.cance was judged at p < 0.05. Separate. analyses was Cen Ete [om [ted emer Body weigh FBoooddyCWoenisguhmtpGtaiionn `Statistical Methods for Subchronic SS Toxicity Parameters rime |Scoonn me rsforckofwend? |heJonkbsie Top | imo(5fo re , re trend test a1 5-Oxidation Sor Shapiro-Wilk esfor | pene" BIE |con ia-- y irsn oronsis IncidenceofOphthalmology|None: Cochran-Armitage test for trendTM Activity CTE ar Wik ronth [Roce [Suni t | analysis of variance | he Jonckheere-Terpstza ---- somality peste foe followed by contrasts" [| tfireend tserswt nDans cir [ TRa WET mogencity Sho br |Sc[`DunrnetvtCS'seteEsgtm'mz iro||tesEt"na: rvfa3 farr [ee] +A founvtescompatonsdsipein ve lo;aneieosw rDoast-- speed vs r E en me ei e , ta 0i0o8 wnaettd Ifthe incidence was not significant, but a significant lack of fit occurred,then Fisher's Exact testTM with a - lorspermed wih BinidnaHeen oes sos eonemFetatbbgopeont --ep ee----eeniees ee e Comps, CA 9H02.5D4a2y5G:evSaugbeehSrtouidyc iTnoxRiactistywith One. Generation Reproduction Evalutions Dupont 11418 - `The following table lists the indices of reproductive function that were calculated for the Py and Fy adults. Mating Index (%) = NNuummbbeerrCCoophualbsitteedd? x100 Ferily Index (%) = NumberPregnan x100 `Number Copulated? Gestion Index (%) = NatuLmebasetrOonfLeiLtievres Pwuitph x100 NumberofLiters IEfmfpilcainetnactyio(n1 = NupbePurps oBofm x100 Number of Implantation Sites Pups Bom Alive (5 = NumobfPeuprs Bom Alive x100 Number of Pups Bom ViabilityIndex (9)d = NNuummbbeerrooffpupPuspsAbloimveaDliavey: 4 Preculling x 100 Numberof pups alive Lactation Index (9)0d = awNtumbeeroafp(uDpansy a2l1iipvoesDtnapyar4tguPmo)steuling x100 ~~ Litter Survival (%)d = N Numbuerom offlvib stberiseewleiater nresddelivered x100 b Dpnerctgheauradmnii,nneoprdrdefeoglrniaevnsetcrhaynloimefaa.les Mtrhesatnweanrdfsotuannddadredaddevdiuartiinogngfeosrtactaiconh.dos eve wer calculated Excluding liters scrifced due o death ofdam durin lactation. -- Te Company Saritzed. Doesnotcontain TSCA C8 910..2D54a2y5a:vSaugbechSvtoundiyeiTnoRxaictistwyithOneGeneration Reproduction Evalustions DuPont11418 Fe gi ~~ Statistical Methods for Reproductive Toxicity Parameters [TehT odorSuselAmys] PaBroadmyeWteeirght Preliminary Tes Sequentsiiaglniafpipclainctation" .significant. Cr FoBooddy CWoenisguhmtpGtaiionn Testor lackofwend| ToefrtpshterJaoencnkdbeeesre,| | PPATE remacoemssfor GFoeosdatEfofnicLI ieenngctyh IOmrpglaanntWaetiiognhtSit Numbers MIimaplnanNtautmiboenrEofffiPciuepnscPyerLiter Leven"s est for PFronsyBVoisabsilAitye ShahpoimrooogWenimelikttye?standfor|||4O12T0Ne2snnd ueof | uaankdaDl-uWnaststetset'st VaagcitnialonPaItnednecxy [PErsetpruotuisalCyScelpearPaatriaomneters iSnpceirdmenPcaeroafmeCtleirniscal FMearttiilnigtyIInnddeexx Cochran.Armitagetetfo rend" GLeisnteartSiuornviIvnadlex (Covariates: litersizsexerat,io) quaresmeans opclo | Now | Nw | + sPiaginriwfiicsaentc.omparisons and sssociated preliminary tests were only conducted i th test for lack of wend was IvfatsheusSehdapiro Wilk test ws notsignificantbut Levene' tet ws significant, robust verofsDiunoens test BIfotnhfeerirnocniidecnocneecwtaisonnowtassigunsiefdic.ant, but significant lackof it occurred, then Fisher's Exact test with a Fsoirgneiaficchanptadroasmee-treerspaonnasleyzweadswidetthecatterde,nddatteastf,rtohme ttehsettwoapsdoapspelgierdoutpotwheeredaetxacsleuqdueendtaianldlyt.heItefast arfefpeecatteedd fuenttuislonsopesriglniitfeircaonrttthreenlidttwear smedaetnewcteerde.u"seFdoraslitttheer epxaprearmiemteenrst,althueniptrofpororsttaitoinstoifcal evaluation." The level of significance selected was p < 0.05. --~ wo" CompanySanitized. Doesnot containTSCA Cal 9205-4D2ay5:GavSaubgeehSvtoundiyciTnoRxitcstywithOneGeneration Reproduction Evaluations DuPont 11418 --~ RECORDS AND SAMPLE STORAGE Laboratory-specific or site-specific raw data, such as personnel files and equipment records will be retained by the facility where the work was done. LAabsoarmaptloeroy.ftShpeecteismtesnusb(sitfanacpeplwicaasblceo)l,lercatweddaftoar,aarnchditvheepfuirnpalosreespoarntdwrieltlabineerdeattaiHnaesdkaetlHlaskell LDaebloarwaatroer.y,CNhearwaacrtke,riDzealtaiownardea,taor(paetrIcreonnt Mpuoruintyt,aicnomRpeocsiotridosnM,aannadgkemneonwtn,iWmipulrmiitnigets)onw,ill be: sCthoarreadctaetriRzeagtiioonnaldaAtnaaluysteidctaol Sseurpvpiocretste(sRtAsSu)b,stJaancckessotnabLialbiotryawtiolrliebse,rDeeteapinweadteatr,HaNsekewllJersey. Laboratory, Newark, Delaware, or at ron Mountain Records Management, Wilmington, Delaware. ~~ -- EE -- Company Sanitized. Doss not contain TSCA C81 0s-aDsaezy:GavSaugcetSroyn iLnoRxeitnywith One-Generation eproducion Evaluations PN RESULTS AND DISCUSSION Dupont 11418 Analytical Evaluation A. Test Substance Stability Analyses `SaanmalpylseessoifntdihceatteedsttshuatbstthaenHc-e2w5e4r2e5awnaalsyzsetadnbleearovetrhetbheegcionunrisnegoafntdheenstdoudfyt.he study. These The average ofth active ingredient v--- samples analyzed October15,2002 and Feb , 2003. This work is reported in analytical _ Cm iH.25425 was reported by the spocnosotro fognd in Haskell `LTahbeordaitffoerryencce bretwfeen the sponsor reported purity and the experimental data represent analytical variability. B. Chromatography . oH-f2584.521059e.l0utmeidnuftreos.m RtheeprHePsLenCt/aGtiPvCeHcPoLlCu/mnGP1CsIaIrResoclhvreodmpaetaokgroavmesr aarneasvheorawgneirnetAepnpteinonditximAe, Figures 2 (a- d). Test substance was not detected in the 0 mg/mL control. C. Recovery Samples DvaertiaaiblielidtaynoaflytthiecaalnarleystuilctaslomfertehcoovdewrayssadmepmloensstarraetseudmbmyarthiezecdoeifnfiAcpiepnetnsdoifxAva,riTaatbiolneoIf. tThhee croeucrosveeroyfrtehseulsttsudayt.eaTchhetamregaesteudreddoscionngcecnotnrcaetnitornastioofnH(-a2p5p4r2ox5ifmoartetlhey 22,m2g0/,m2L0.0lmevge/lmwLe)reov6e8r.t5h%e `1c0o7nc8e.n4tr%atoifonnsomoifnHa-l2(5me4a2nfpoerrtcheen2t0remcgo/vmeLr.y =le7ve4l.2we%re48.24,.1C%.Vt.o =886.%1)%.oTfhneommienaaslur(emdean p2e0r0cemngt/rmeLc.ovleevreyl=we8r6e.08%9.192%.0t,o 9C.6V..5=% o2f%)n.omTinhaelm(emaesaunrepderccoennctenrtercaotvieornys=of9H2-.285%4+253.f7o,rCt.hVe. r=4e9c%o)v.eryBfaosretdheoncotnhciesndtartaat,iaocnorarneacltyizoend bwealsoawpp9l0i9e%dotfonaollmisnaamlp.le results when the spiked D. Homogeneity and Stability Samples Aannaallyytziecdalforreshuolmtosgfernoeimtdyo/scionngcesnutsrpaetnisoinonvsercioflilceatcitoendaonndSte-shtoduaryr2o(oOmcttoebmeprer1a7t,u2r0es0t2a)bialnidty and tienstApdpaeyndi(xOcAt,obTearbl2e3I,T2a0n02d)SaunmdmaanraylyTzaebdlfeor| homogeneity/conceniration verification are shown -- a -- Company Sanitzed. Doss not contain TSCA GBI 9F02.5Da5y:GavSaugbeehSrtoundiyc TinoxRiactistywith OnGeeneration Reproduction Evaluations DuPon 11418 --_ `The following table summarizes the results for homogeneity/concentration verification and stability analyses for these samplingdays of the H-25425 sample preparation. Sample Day Nominal Measured TMB' Mean (TMB) CV. Stbiliy SampleTyp gin mg/mL %Nominal _(%) _%Nominal Testday 2 Homogeneity 0 ND --- -- - a2 113960,,128078,,220103 18072.00 196 1901855 Testday 8 00 187,188,191 945 1 980 `Homogeneity 0 ND 2 187.197.191 -- 90 --2 --= b MSaemapnlerseshuletslTdohotuhersanaatloysoismotfetmhpeertaotpur(1e).. middle (V) and boiom (B) samples. RDeepnoortteesdnroenseuldtesteccotrerde.cted or recovery of th spiked sample at the level (reer 0 Table I). `The results for H-25425 samples prepared and collected on test day 2 show that the test substance was at the targeted concentrations for al levels (x 13.0% of nominal), adequately mixed except for the 2.0 mg/mL level (CV = 19) and stable in the vehicle when held 5 hours at room temperature for all levels. Test substance was not detected in the 0 mg/mL samples. "The results for H-25425 samples (2.0 mg/mL level) prepared and collected on test day 8 show ~ that the test substance was at the targeted concentration (4.0% of nominal), and adequately mixed (CV =2). Test substance was not detected in the 0 mg/mL samples. E. Concentration Verification Samples Analytical results from dosing suspensions collected on test day 42 (November 26, 2002) and test day 86 (January 9, 2003) and analyzed for concentration verification (uniformity) are shown in Appendix A, Table Ill and Summary Table 1. `The following table summarizes the results for concentration verification analyses for both sampling daysofthe H-25425 sample preparation. Preparation Nominal Day mg/mL Measured" mg/mL Average CV %Nominal __% Test day 42 2 235,236 118.0 04 2 205,208 1035 1 200 190, 193 96.0 1 Test day 86 2 203,204 1020 05 20 196,218 103.5 7 200 209,203 1030 2 --~ =b Duplcae samples per levelwere analyzed. C.V. cleulaed verity uniformity ofmute. Reported resus corrected fo recovery ofthe spiked sample at the level (refer to Table I). Company Sanitized. Does not contain TSCA CBI 2905-4D2a5y;GavSaugbechSrtoudnyi TinoxRiactistywith One-Generation Reproduction Evaluations DuPont. 11418 --~ "The results for samples prepared and collected on test day 42 indicate that the test substance was at the targeted levels (+ 4.0%of nominal) except for the 2.0 mg/mL level that was marginally higher than expected (+ 18.0% of nominal) and adequately mixed (CV's less than 10) for all 'H-25425 samples. Test substance was not detected in the 0 mg/mL samples. `The results for samples prepared and collected on test day 86 indicatethatthe test substance was at the targeted levels (target = + 3.5% of nominal) and adequately mixed (CV's less than 10) for all H-25425 samples. Test substance was not detected in th0e mg/mL samples. F. Analytical Conclusion Results from the analysis of the test substance dosing suspensions during the study indicate that the test substance was mixed properly except for the inital sampling of the 2 mg/m level, at the targeted levels and stable under the conditions of the study. Test substance was not found in the 0 mg/mL samples. In-Life Toxicology Rats designated for evaluation of reproductive toxicity were transferred to the reproduction group -~ othnistessetctdiaoyn7u2p,toandtewsterdaeyc7o-2h(oiunsceldudfionrgmdaatyin0g-7b0egiintnenrivnaglso)nintecsltuddeayda7t4a. fArlolmrbeosutlhtsthreepsourbtcehdroinnic toxicity and reproductive toxicity subsets. All results after test day 72 (including day 0-91 intervals) ae from subchronic toxicity ras alone. A. Dosage Data (Tables 2:3, Appendix B) Ra0t,s w2,er20e,doorse2d00wimtgh sHo-l2u5ti4o2n5s/omfLH,-d2e5s4i2g5neidnt0o.d5e%limveetrhtyhlecetlalrugleotseed,dporseepaofretdesattscuobnscteanntcreataitoans dosing volume of 5.0 mL/kg body weight. The quantity of H-25425 administered to each rat was `ccalocmupluatteerd,prboagsreadmo.n the most recent body weight for each rat, and subsequently rounded by a `gTrhoeupr,anagnedo1f.m2e2a9nmdLaifloyrdotsheev1o0l,u1m0e0,saadnmdin1i0s0t0ermegd/ktgo/mdaalyegrraotuspws.asT1h.e2-r3a.n0gmeoLfmfoeratnhedcaoinltyrol dose volumes administered to female ratswas 0.91.6 mL for the control group, and 0.9-L.5 for the 10, 100, and 1000 mg/kg/day groups. --Company Sanitized. Does notconTtSaCAiCn8 H902-5D4a2y5:GavSaugbeehSrounidc TinorRiactistywithOneGeneration Reproduction Evalutions Dupont11418 --~ B. Mean Body Weights and Body Weight Gains (Tables 4-7, Figures 1-2, Appendices C) No any adverse, male or test substance-related female dose group. effects on body weight or body weight gain were observed in Ninomastlaetrisattiscaollnyasingynitefsitcadnaty.difMfeearenncbeosdiyn wmeeiagnhtboindythweei1g0h0t0,mcgo/mkpga/rdeadytgorocounpirwoals, w9e7r%eoofbcsoenrtvreodl o9n0%tesotfdcaoynstr7o0l aandth9e1e,n9d6o%fotfhectonhtrreoel-matontthhe reencdoovfetrhye(toesnted-amyon1t8h2;reflcuoovreirnye(atnesatlydsaiys s1u2b6g),roaunpd). `Nboondyeowfetighhetdgiafifnerweenrceesowbassersvteadtiisntitcahlelymasilgeni1fi0c0a0nmt.g/kStga/tdisatyicgarlloyuspigonviefrictaenstt draedyusc0t-i7o,ns7-i1n4m,e2a1n- 2t8h,ey49w-e5r6e,n7o0t-7c7o,nsaindder1e0d5-a1d1v2e.rseAleftfheocutgshasthmeesaenrebdoudctyiwonesigmhatygahianveinbteheins gtersotuspubwsatsanccoem-rpealraatbedl,e `tmoecaonntbroodl yovweerigmhotsgtawineeokvleyr itnetsetrdvaalyss; 0t-h7e0roe rw0a-s9n1o(s9ta4t%istoifcaclolnytsriogln)i;faicnadntmdeiafnfebroendcyewieniogvhetraglalin eIaxtcteeretdewdocwoenetkrolly(innottersvtaaltsisotciccaulrlryesdigdnuirfiincagntt)heorveecronvuermyerpoeruisodw.eeSktlatyisitnitcearvlallyss.igFniufritchaenrtmore, the r1e0d0ucmtgi/okngs/idnamyegarnoubpoadnydwoeviegrhtesgtaidnawyser7e-1a4lsionotbhseer1v0emdgo/vkegr/tdeasyt gdraoyusp7.-1T4heasnedd7i0f-f7e7reinncetshewere dnaoytsco7n0s-i7d7e,raenddtensot ssutabtsitsatniccael-lryelsiagtneidfiacsatnhtedyifwfeerreenicseoslaitneodvienrtaelrlvamles,anratbsowdeyrweeniogthtdogsaiend woenrteest --~ observed recovery in these periods. groups over the test day 0-70 or 0-91 dosing periods or the one- or three-month Nobosesrtavteidstiincaallnyysfiegnmiafliecadnotsdeifgfreoruepncoens iannymeteasntbdoadyyorwoeviegrhtaonry mweeeaknlyboidnytewrveailgohfttghaeinstwuedyr.e M70eaanndb9o1d,yrwesepiegchttiveinlyt.heMfeeamanlebo1d0y00wemigg/hktgg/adianyignrtohuispgwraosup99wa%sa1nd009%6%aondfc9o3nt%roolf coonnttreostl days otovecronttersotlda(y9s5%0)-7o0vearndth0e-o91n,e-rmesopnetchtirveelcyo.veMrey aanndbeoxdcyeweediegdhctongtarionlin(1th3i1s%gorfocuopntwraosl)coomvpearratbhlee. tbhordeyew-emiongthht raencdovbeordyy. wNeoinghetofgtaihnesine oitntheerrvfalemdailfefedroesnceegsrwoauspsstwaetirsetiaclaslloycsoimgpniafricaabnlt.e tMo ecoanntrol throughout the dosing and recovery periods. C. F(ToaobdleCson8-s1u1i,nApptpioenndainxdDF)ood Efficiency : . Ninoanadyvmearlsee,otresftesmuablsetadnocsee-rgerloautpe.d effects on food consumption or food efficiency were observed oInbsmearlveedraitns,annoysdtoastiestgircoalulpytshigrnoiufgihcoanuttdtihfefderoesnicnegsoirnrweeceokvleyryorpeorvieordaslloffotohde cstoundsy.umpMteiaonn wfoeorde --_ consumption in the male 1000 mg/kg/day group was 99% and 97% of conirol over the testday0- -es `Company Sanitized. Does notcontain TSCA CBI 5205-4D2a5y:GavSaugbeShrtoundiyc iTnorRiactistyithOne Generation Reproduction Evaluations Dupont 11418 --_ 70 and 0-91 intervals, respectively (neither statistically significant). Mean food consumption in this group was 101% of control during recovery (test days 91-126). In female rats, no adverse effects on food consumption were observed in any dose group throughout the dosing or recovery periods. Statistically significant reductions in mean food consumption were observed in the 1000 mg/kg/day group over test days 21-28, 28-35, 84-91, and 112-119. Statistically significant reductions in meanfood consumption were observed in the 100 mg/kg/day group over test days 84-91. These differences were not considered adverse as mean food consumption in these groups was comparable to control over most weekly intervals, there was no statistically significant difference in overall mean food consumption, and rats were not dosed during the test day 112-119 interval. Mean food consumption in the 1000 mg/kg/day female group was 99% and 97%ofcontrol over test days 0-70 and 0-91, respectively and 94% of control during recovery (test days 91-126) In 1000 mg/kg/day male rats, statistically significant reductions in mean food efficiency were ionbsmeeravnedfoovoedretfefsitcdieanycsy0w-e7r,e7-o1b4s,er2v1e-2d8o,v4e9r-t5e6s,t adanyds7208-7-73,5aannddsta1t1i9s-t1i2c6a.llyAsfigenwifsitcaatnitstiinccalrleyases significant decreases and increases in mean food efficiency, comparedto control, were also observed in the 10 and 100 mg/kg/day groups over one or more intervals. It is questionable. `whether these effects were test substance related, and they were not considered adverse as the differences included increases and decreases, a dose-response was not always evident, and orveecroavlelrmyepaerniofdoso.dMefefaicnieonvceyrailnlaflloomdalefefidcoiseencgyroinup1s0d0i0dmngo/tkdgi/fdfearyfmraolmescownatrsol96d%u,ri9n7g%d,osainndg or ~ 95% of control over test days 0-70, 0-91, and 91-126, respectively (none statistically significant). No statistically significant differences from control in mean food efficiency were observed in any female dose group throughout the study, except for a single weekly interval (est day 91-98), in which mean food efficiency in the 1000 mg/kg/day group was significantly higher than in control. Mean overall food efficiency in 1000 mg/kg/day females was 102%, 97%, and 97% of control over test days 0-70, 0-91, and 91-126, respectively (none statistically significant). D. Clinical Observatioansd Mortality (Tables 12-13, 16-17, Appendix E) `cTohnetrreolwraast wnoasteasctcsiudbesnttaanlcley-krielllaetdedduerfifnegcttohenbmloeretdailnitgypnroceietdhuerremoanleteosrt dfaeyma1l2e7.ratOs.neAmmaallee.rat in ftohre p1o0s0simbgl/ekfgl/udoraiynegreovualpuwataisonfoaunnddddiedandootnretceestivdeaya p1a0t8h.oloTghiicsalraetvwalausatpiaornt.ofThtehreesfuobrsee,ttbhel.ed causeofdeath is unknown. No early deaths occurred in any female dose group. No increases in any clinical observations occurred that were attributed to test substance exposure. --_ EE Company Sanitized. Does not contain TSCA 81 B902-5D4a2y5:GavSaugbcehSrtoundiyciTnoxRiactistywithOne Generation Reproduction Evaluations DuPon11418 --_ E. Ophthalmology Evaluations (Tables 14-15, Appendix F) Nneoarctohmepoeunnddo-frtehleatdeodsoipnhgtphhaalsmeoolfotgihcealstluedsyi.onUsnwilearteeroablseforcvaeldrientimnaalledeogrenfeermaatlieonrawtsaesxoabmsienrevded in one male and one female were in the control group. rat. This observation was not test substance related as these rats. F. In-Life Toxicology Conclusions Under the conditions ofthis study, the no-observed-effect level (NOEL) for in-lfe parameters was 1000 mg/kg/day for males and females. The NOEL was based on a lack of adverse effects on any in-life parameters in rats dosed up to 1000 mg/kg/day, the highest dose tested. Neurobehavioral Evaluation A. F(Toarbelleismb18G-r19i,pFSitgruernegsth3-4, Appendix G) `There were no test substance-related effects or statistically significant differences on forelimb ~~ galrlipgrsoturpensgwtherien msiamlielsarortofethmealceosntardomlivnailsuteesrefdorabnoytdhomsaalgeesofatnhdefetemsatlessu.bstance. Mean values for B. Hindlimb Grip Strength (Tables 18-19, Figures 5-6, Appendix G) `gTrhieprsetwreenrgethnointemsatlseusbsotranfceem-arleelsataeddmienfifescttesreodr satnaytidsotiscaaglleyosfigtnhiefitceasnttsduibfsftearnecnec.esMfeoarnhivnadlluiemsbfor all groups were similar to the control values for both males and females C. Sensory Motor Function Observations (Tables 20-21, Appendix H) . T`mhoetroer wfeunrcetinoontpeastrasmuebtsetarnscien-reeiltahteredmeaflfeesctosrofresmtaaltiesstiacdamlliynisisgtneirfeidcaanntydidfofseargeencoefstfhoerttehset sensory wsuebesktan1c3e.andOnreecfoevemrayleevianlutahteio1n0s0.0 mAlgt/hkogu/gdhaythgirsooubpsewravsatoibosnerisvesudgtgoesbteivcieroclfinnegudruortoixnigctithye, snioncoetohnerlyclionniecaalnsiimganls aodrmcihnainsgteerseidn 1g0ri0p0smtgr/enkggt/hdoarymwoatsoorbascetrivvietdywwietrhetehvisidbeenhtaviinoarn,yadnodssaignece aglrlogupr,outphsewcierrcelisnigmbileahravtiootrhewavsalnuoets cfoornstihdeecroendtrtoolbveaelsutessfubosrtbaontche-rmeallaetseda.ndTfheemailnecsi.dences for -- = Company Saritized. Does not contain TSCA GBI 2S504D2a5y:GavSaubgcehSrtoundiyc TinoxRitcistywith One-Genertion Reproduction Evaluations DuPont 11418 ~~ D. Motor Activity (Tables 22-25, Figures 7-9, Appendices I-J) Tfohrermealweesroernfoemteasltessubasdtmainncies-treerleadteadnyefdfeocstasgoenofdutrhaetiteosnt osfubmsotvanecmee.ntDuorrinngumtbheerweofekmo1v3ements evaluation, males administered 1000 mg/kg/day had significantly increased duration of `vamlouvee.meTnhteasntadtinsutimcbalerdiofffemroenvceemsemnatys bdeursiungggetsheti6v"e o1f0a-mdienluatyeeidnhtaebrviatluactoimonpairnetdhetomatlheescontrol administered 1000 mg/kg/day compared to control. However, the range of individual duration of `almlo3vewmeeanttmevnatlugersoduuprsi(n4g5t-h3e666,*7100--3m7i0n,u4t1e-i3n2t0ersvaelcofnodrsthfeor1t3h-ewe10c,k1e0v0a,luaantdio1n0w0e0rmegs/ikmgi/ldaaryfor males, respectively), and were higher compared to the range of individual control values during the 6 10-minute interval (10-207 sec). In addition, the rangeof individual number of `grmoouvpesme(n1t4s-1f5o3r,t3h6e-61*511,0-5m9-i1n5u2t,e 3in7t-e1r6v0alfdourrtihneg0t,he10,131-0w0e,eaknedva1l0u0a0timogn/kwga/sdsaiymimlaalresf,or all respectively). Therefore, these statistical differences were not consideredto be test substance- related for the following reasons: 1) a dose-response relationship is not evident for the range of i`nmdeiavniadunadlrduraatoinofnnougfmmbeoevreomfemnotvveamlueenst; 2va)lauedso;sea-nrdes3p)otnhsee-mreelaantidounrsahtiiponisonfomtoevveidmeennttfoarndthe number of movement values for 1000 mg/kg/day females were similar to control values. Therefore, these statistical differences were not considered to betreatmentrelated. Mean values ~. for all `males other groups and females. and time intervals were similar o the values for the control groups for both E. Neurobehavioral Conclusions Under the conditions of the study, the NOEL for grip strength, sensory motor function observations, and motor activity, was 1000 mg/kg/day, the highest dosage tested. Clinical Pathology Evaluation A. Hematology (Tables 26-27, Appendix K) ' Tsthaetrisetiwcealrley nsiognaidfviecrasntecchhaannggeess iinn mheemaantohleomgaitcolpoagriacmeptaerrasmeitnemraslewoerrefneomtaaldevreartss.e oTrhneotforlelloawtiedng 10 exposure to compound: Rdeecdreacesleldmiansmsalpearsadmoesteerdsw(irtehd 1ce0l0l0cmogu/tk,gh/edmaoygaltoebsitn,daaynsd3h7emaantdoc9r2i,t)anwderaeftemrinoinmeamlolynth of creelclovmearsys(pvaarraiambelteersstatwiesrtieca9l5s-i9gn7i%fiocafrneces)p.ectAitvethceosnectuhrrreeentticmoen-tprooilntgsr,omuepamneavnaslu.esThfoerrerewdere. ~ no correlative changes in other numeric or microscopic red cell parameters. = -_-- Company Sanitized. Does notcontain TSCA CBI 9102-5D4a2y5G:avSaugbehSotnuidyc iTnoRxaitcstywithOne-Generation Reproduction Evsustons Dupont 11418 -- Rdeecdrecaelsledmaisn sfepmaarlaemsetdeorssed(hweimtohgl1o0b0i0nmagn/dkgh/edmaatyoactritets)t wdearye9m3i(n9i7maalnldy 9bu5t%stoafticsotnitcraolllygroup `cemlelanpsa,rarmeestpeecrtsi.veAlyf)t.erTohneeremownetrhe onforceocrorveelrayt,ivreecdhcaenllgemsasinsoptahrearmneutmeerrsiicn ofremmailcersospcroepviicourseldy dosed with 1000mg/kg/day were similar to control values. `1T0h0e0ambgo/vkegc/hdaanygewserien rperdobcaeblllymadsuse ptoartarmeeattemrenstindumealtoetahnedcfoenmsaislteernactysdoofscehdawnigtehbetween osfexceosntarnodl agcrroouspsmteiamen-sp,oiwnhtesr.eaHsowceonvterro,l bgercoauupsmeetahneschcaanngveasrwyebrye1s0opmeirnciemnatlag(ealplowiinttshin 95% bpeertswiesteendsitnutdoietsh)e,rtehceoyvweeryrepecroinosdi,dtehreedvetroybeminnoinm-aaldvneartsue.re oAfltthheouegffhectthsescuhgagnegsetsedinthmaatltehse changes were non-adverse. * tPelsattedlaeyts3w7e(re91t%raonsficeonntltyroalngdrmoiunpimmeaalnl)y.deActretahseeednidnomfatlheessdtousdeyd(tweistthda1y00902)mga/nkdga/fdtaeryoante mdeocnrtehasoefirnepcloavteerleyt(steastttedsatyd1a2y7)3,7pwlaatselpeotssswieblryedsuiemitloartrteoactomnetnrto.l Hgroowuepvecro,untthse. rTanhgee of aidnddiitviiodnu,alalclovuanltusesinwmearleewsedllosweidthwiinthth1e0h0i0stmorgi/ckalg/rdeafyerweancsesriamniglearftoortihnadtiovfidoutahlerangirmoaulps. In ``Tvhaelrueesfofroer,tahlisthpoaurgahmethtiesrc(h7a2n9g-e14w1a5s xp1o0s*s/iubLl.yfdourematoletsreaaptpmrenotx,imitatwealsyc1o9nswiedeekrsedoltdo).be non- ~~ adverse. `0Thbeefounlrleolwaitnegdsttoattirsetiactamlelnytsiagnndifniocann-tadcvhearnsgeesbeicnamuesaenthheeymdaitdolnootgyocpcaurramientaerdsoswee-rreelcatoendsipdaetrteedm, or occurred only after one month of recovery: + Increased red cell distribution width in males dosed with 100mg/kg/adttaesyt day 37 * Increased neutrophils and monocytes in males dosed with 100 mg/kg/day at test day 37 * Increased neutrophils in females dosed with 10 mg/kg/day at test day 93 Ipnrcerveiaosuesdlywhdiotseedblwoiotdh c1el0l0s0, mlgym/pkhgo/cdyatyesa,ftmeronoonceymteosn,thanodflraercgoeveurnyst(atiensteddaceyll1s27in) males * D`oencermeoansetdhreofdcreelclovdeirsytr(iebsuttidoanywi1d2t7h) in females previously dosed with 1000mg/kg/day after - B. Coagulation (Tables 28-29, Appendix K) `stTahteirsetiwcealrley nsiognaidfviecrasnte cchhaannggeess iinn cmoeaagnulcaotaigounlaptairoanmeptaerrasmeitnemrs waoerreflecmonaesliederratesd. tTohbee fuonlrelloawtiendg 1 treatment and non-adverse because they did not occur in a dose-related pattem: --_ --- CompanySanitized. Does notcontain TSCACBI 9H02-5D4a2y5G:avSaugbeehSrtoundiyc iTnoxRiactistywith OneGeneration Reproduction Evaluations DuPont11418 --~ + Activated partial thromboplastin time was minimally decreased in males dosed with 100 mg/kg/day at test day 92. This change was considered to beunrelatedto treatment because there was no dose-relationship in the response; activated partial thromboplastin times were similar in groups dosed with 10, 100, or 1000 mg/kg/day. In addition, minimally decreased activated partial thromboplastin time has no toxicologic significance. Activated partial thromboplastin times were similar to control group times in males previously dosed with 1000 mg/kg/day after one monthofrecovery. C. Clinical Chemistry (Tables 30-31, Appendix K) `There were no adverse changes in clinical chemistry parameters in male or female rats. The following statistically significant changes in mean clinical chemistry parameters were not adverse or not related to exposure to compound: Alanine aminotransferase activity was decreased in female rats dosed with 100 or u1n0u0s0uamlgl/ykhgi/gdhayacattivtietsitedsoafyb9o3th(noatspsatrattaitsteiacanldlyasliagnniinfeicaamnti)n.otAratntshfiesrtaismeeinpooinnte,ftehmearleewere (#665221) dosed with 0 (vehicle) and in one female (#665332) dosed with 10 mg/kg/day. `These two rats had alanine aminotransferase activities of 223 and 165 UL, respectively (individual age-matched historical control activities range from 25-122 UL). These changes -- wapepraerceonntsdiedcerreeadsteobinemdeuaentaolsapnionnetaanmeionuostrlaenssifoenrsausnerreelsautletdedtoftrroematsmepnotn.taTnheeoruesfolresei,otnhsein wcointthro1l00a0ndmgl/okwg/ddoasye.fAefmtaleerso,nreatmhoerntthhanoffrreocmovterreya,tmaelnatn-irneelaatmeidnocthraanngsefseriansfeeamcatlievistideossiend females previously dosed with 1000 mg/kg/day were similar to control values. Bilirubin was minimally decreased in males and females dosed with 1000 mg/kg/day at test day 92 and 93, respectively (variable statistical significance). In males, there was histologic eDveicdreenacseedofbielnizruybminewiandsulcitkeiloynt(ocenbterisloebulcarohnytpoedertnarzoryphmyye),iandnudctliiovenr,waesiaghrtessuwlteroef ia.ncreased. bpheynsoino-laodgviecrrsees.poAnfsteertoondeosmionngtohf aofxreneocboivoetriyc.(esTthedraeyfo1r2e7,),thbeisleircuhbainngceosncweenrteractoinosnisdienrerdattso previously dosed with 1000 mg/kg/day were similar to control group values. Triglyceride was mildly decreased in malesdosedwith 10, 100, or 1000 mg/kg/day at test d1a0y0092m.g(/70k,g/7d6a,yanondly5).8%Thofesceoncthraolnggersouwpermeealnikse;lystraetliastteicdatlolytsriegantimfeincte.ntHaotw1e0vearn,d mildly `dneocnr-aedavseersde.t"rigAlfycteerridoensehmaovnetnhoofardevecrosveeerfyfe(cetsst; dthaeyre1f2o7r)e,,ttrhiigslcyhcearnigdee cwoanscecnotnrsaitdieornesdintombaeles previously dosed with 1000 mg/kg/day were similar to control group values. T1o0t0a0l mpgro/tkegi/ndwaaysatmitelsdtldyadyec92r.easMeedadnusewteordeec9r6eaansedd8g3l%obuolficnonintrmoallgersoduopsmeedawnist,h respectively. `means of 7.1 These changes and 2.4 mg/dL were considered to be due to for total protein and globulin, treatment. However, the group respectively, were within the ~~ historical range of means for age-matched control animals (6.87.5 and 1.9-2.6 mg/dL, = Company Sanitized. Does not contain TSCA G81 2025:05-D4Da2ayy5G:GaavvSaaugbgecehSSrttouunddiyyciTinnoRxRiaactsistwywiitthhOOnnee- GGeenneerraattiioonnRReepprroodduuccttiioonn BEvvaalluaattoiornss DDuuPpoont 11418 --_ raensdpe1c.t9i-v2e.l7y)m.g/IndLadfdoirtigolno,biunldiinvwiedurael waintihmianltcheoinrcernetsrpaecttiiovnes hoisftor6.i8c-a7l.4rmefge/rdeLncfeorratnogtaelsp(r6o.t2e-in 8tr.e2amtmge/ndt-Lrefloartteodt,alwaprsotceoinnsaindde1r.te5od-3.b3emngon/-daLdvfeorrsgel.obuAlfitne)r.onTheemreofnotrheo,ftrheiscocvhaenrgye,(teasltthough d1a0y0012m7g)/,ktgo/tadlayprwoeteriensainmdilgalrotboulcionntcroonlcegnrtoruaptivoanlsueisn.males previously dosed with Ca(l1c0i4%uomfcwoanstrmoilnigmraolulpymienacnr)e.aseTdhiencfheamnagleesindocsaeldciwuimthwa1s00d0uemtgo/tkhge/dmaiynatitmeastidnacyrea3s8e in aallbbuummiinn (onroutnsbtaotuinstdic(a"lliyosniigzniefdiccaanltc).iumC)a.lcTionuimzeexdisctaslciniusmersutmheinpthywsoiofloorgmisc,alelityhaecrtbivoeunfodrtmo, aapnpdroisprtiiagthteliynrcergeualsaetdedb.ouInncdrecaaslecsiuimn,awlhbiucmhinreasrueltnseciensisnacrrielaysaesdstooctialatecdalwciituhm.phyHsoiwoelvogeirc,ally iAofntiezreodnceamlocinutmhoifsruenacfofveectreyd.(teTshtedraeyfo1r2e7,)t,hcisalcchiaunmgecownacesnctorantsiiodnesreidn tfoembaelneosnp-raedvveirosues.ly dosed with 1000 mg/kg/day were similar to control group values. * Inorganic and 1000 mpgh/oksgp/hdoaryusatwtaesstmdianyim3a8ll(1y0a8n,d1t0r7a,nsainednt1ly14in%corfeacsoendtrionlfegmraoluepsmdeoasne,dnwoitth 10, 100, saltlattihsrteicealglryosuipgsnidfoisceandtwaitt1h0t0hemgt/esktg/sduabys)t.ancIenddievsipdiutaeltphheo1s0p0h-ofroulsd vdiaflfueersewnecereinsdiomsilea.rIancross acrdedaittiinoinn,et)hoerreinwehrisetnopoacthhaonloggeys tihnatcosrurgegleastitvtehcaltintihceaslecphheomsipshtorryupsacrhaamentgeerssa(ruerteraenaittmreongte-n, ~ related. Therefore, these changes were considered to be unrelated to treatment and non- adverse. Ch(l1o0r2i%doefwcaosntmroilnigmraolulpymienacnr)e.ase`Tdhiisn cfheamanlgeesidsopsoesdsiwbiltyhre1l0a0te0dmtgo/tkrge/adtamyentat. teHsotwdeavyer9,3 the `1m0e3a.n4cmomnoclen/tLr)atwieorne(w1e0l0l.5wimtmhoiln/tLh)e ahinsdtoirnidcialvirdaunagleanfoirmaalgec-omnactencthreadtihoisntsor(i9c7a.l9-data (historical is 91-105. rangeofmeans is 95-102 mmol/L Therefore, although this change is and historical rangeof individual animal values possibly related to treatment, it was considered 1s0imbielanrotno-acdovnetrrosle.grAofutpervaolnueesmoinntfheomaflreescopvreevriyou(stelsytddoasyed12w7i)t,hch1l0o0r0idmegc/okngc/ednatyr.ations were `cTohnesifdoelrleodwitnogbsetautnirsetilcaatleldy tsoigtnriefiactamnetntchaanndgensoni-namdveearnseclbieniccaaulscehtehmeiystdriyd pnoatraomcectuerrsinwaedroese- "related pattem, or occurred only after one month of recovery: = Increased alanine aminotransferase in males dosed with 100 mg/kg/day at test day 37 Decreased alanine aminotransferase in females dosed with 100 mg/kg/day at test day 38 + Iprnecvrieoausseldyadspoasretdatweitahmin1o0t0r0anmsgf/ekrgas/ed,ayalaafntienreoanmeinmootnrtahnosfferreacseo,vearnyd (atlesbtudmaiyn i1n27m)ales Decreased triglycerides in females dosed with 10 mg/kg/day at test day 93. PN --= -- `Company Sanitized. Doss not contain TSCA Call 92-5D4a2y5:GavSaugbeehSrtoundiyciTnoRxaitcistywithOne-Generation Reproduction Evaluations DuPonc11418 --_ D. Urinalysis (Tables 32-33, Appendix K) `bTeheunfroelllaotweidntgosttrateiasttmiecanltlyansidgnniofni-caadntvecrhsaengbeescaiunsmeetahenyuorcicnaulryrseidsopnalryamaeftteerrsonweermeonctonhsoifdered to recovery: Decreased urine protein and osmolality, and increased urine volume in males previously dosed with 1000 mg/kg/day after one month of recovery (test day 127) Decreased urine volume and pH, and increased urine protein and urobilinogen in females previously dosed with 1000 mg/kg/day after one month of recovery (test day 127) E. Urine and Plasma Fluoride (Tables 30-33, Appendix K) `There were no treatment-relatedorstatistically significant changes in plasma fluoride in males or females dosed with up to 1000 mg/kg/day. Urine fluoride was increased (statistically significant) in males and females dosed with 1000 mg/kg/day (see text table below). Urine fluoride was also increased in most males and a few females dosed with 100 mg/kg/day at test day 92/93 (statistically significant in males only). After one month of recovery, urine fluoride was statistically increased in males previously dosed with 1000 mg/kg/day; this change was probably related to treatment based on the individual ~~ animal data. Increased urine fluoride indicates exposure to and metabolism of a fluoride-containing. compound. Dose(mgiPgldaasyma and 0 Urine Fluoride 10 100 Measurements* 1000 0 100 1000 WI WIV VM VIVE WAV VAT viv FlaMales Days2 or or or ol 00% 100% 100% (ugiml) FE 100% Females Day93 oor oo 100% 100% 100% Py 01 - - wu 100% Une Vale Dw 95 92 5 54 91% 18% Sa% Dayii 77 ~~ 108 Tam Females Day93 6s 55 98 286 85% 151% 0% Dl? 63-48 76% "Roeybsuolltdsixtalpicirzedefoassntasctudal values or 4 percent ofcontrol group mean. Statistical significance is indicted F. Clinical Pathology Conclusions ~ `Imnacsosnpcalrusaimoent,ermsal(reesdacneldlfceomuanlte,shdeomsoegdlowbiitnh,1a0n0d0hmegm/atkogc/rdiaty) haandd mmiinniimmaallllyyddeeccrreeaasseedd rseedrcuemll -- = -- ~ Company Sanitized. Does not contain TSCA 08 H902-5D4a2y5G;avSaugbcehSvtoundiyc TinosRiactistywithOneGeneration Reproduction Evalutions DuPont 11418 --~ bilirubin. In addition, male rats dosed for 90 days with the test substance had mildly decreased triglycerides (10, 100, and 1000 mg/kg/day), and mildly decreased total protein due to decreased `globulin (1000 mg/kg/day males only). Urinefluoridewas increased in males and females dosed with 100 or 1000mg/kg/day. After one month of recovery,redcell mass parameters were still `minimally decreased and urine fluoride was sill increased in males previously dosed with 1000 mg/kg/day. Noneofthese effects were considered to be adverse. `Therefore, under the conditions of this study and for the clinical pathology parameters measured, the NOEL was 1000 mg/kg/day for males and females, based on the lack of adverse effects at any dose. Biochemical Evaluation A. Biochemical Evaluation (Tables 34-35, Appendix L) Idnecmraelaeserdatastaadtotsheag10e-doafy1t0i0m0empgo/inktg,/tdhaeya(t9e1o%fohfepcoanttircolB)-.oxTihdiatsidon weescswtraatissectiocnaaslliysdseirgeendifiacantly swpiutrhitohueseffifnedcitnsgoabsnedrwvaesd natotthceon9s2i-ddearyedantdo obneet-esmtosnutbhstraenccoev-erreylattiemdedpuoeinttso.a lAatckthoef9c2o-ndcaoyrdaanndce --~ `siognnei-fmiocnantthlyreicnocvreeraysetdiamte apodionstasgien omfal1e00r0atsm,gt/hkeg/rdataeyo(f1h5e9p%atiacndf-1ox4i9d%aotifocnonwtarsols,tarteisstpieccatlilvyely). A1t0t0h0em9g2/-kdga/ydatyimweaspoainctc,otmhpeainnicerdeabsye ainnhienpcarteiacseB-ionxaibdsaotliuotneaacntidvirteylaatitavedloisveargweeoifght in all subchronic toxicity point in male rat. male rats. Liver weights were not affected at the one-month recovery time At the 10-day and 93-day time points in female rats, the rate of hepatic B-oxidation was rsetsatpiescttiicvaelllyy)s.igAnitfitchaentolnyei-nmcornetahsreedcaotvaerdyotsiamgee opfoi1n0t,00hempga/tkigc/Bd-aoyxi(d1a2t0ioannadct1i2vi5t%y hoafdcroenttruomle,dto control levels in female rats. B. Bjochemical Evaluation Conclusions . Uinnmdaelrethaendcofnedmiatlioenrsatosf. tAhitsastcuodnyc,enFt-r2a5t4io2n5oifs a10m0i0ldmgi/nkdgu/cderayo,fchheapantgiecspienrtohxeisraotmeaolfBh-eopxaitdiaction pweerroexniostocmoenpsriodleirfeedraatdivonerasrec.coAntstihdeeroende-tomobnetthesrtescuobvsetraynctei-mreelpaotiendt,eftfheectrsa.teoHfohweepvaetri,cthe effects peroxisome proliferation returned to control levels was stil increased in female rats. at a dosage of 1000 mg/kg/day in males, but had ~~ Ee `Company Sanitized. Does not contain TSCA CBI 9H025D4a2y5G:avSaugbechSruodnyc TinoxRiactistywithOne.Generation Reproduction Evaltions DuPont11418 ~~ Anatomic Pathology Evaluation -- Rats Designated for Subchronic Toxicity and Recovery Evaluations A. Mortality (Tables 16-17, Appendix N) `aTchceirdeenwtearlleynkoiltleesdtdsuurbisntagnbcleo-roedlcaotleldedcetaitohns.onOtnheelcaosnttdraolyomfatlheeraotne(A-nmiomnatlhNroe.co6v6er5y04p2e)riwoda.s The. wgreoisgshtasndwemriecrnoostctoapkienc.pathology data for this rat were included in the incidence tables; organ B. OrganWeightData (Tables 36-39, Appendix M) iInnctrheeasseusbcinhrmoenaicntloixviecriatyndgrkoiudpnse,ytwheeiognhltystienstmsaulbestraantcseg.irveleante1d00o0rgmagn/kwge/idgahyt,eafsfecctosmpwearreed to cmoanlteroslsf.ollMoawlienglitvheerowneei-gmhotnptahrarmeectoevresryrepemraiiodn.ed increased, to aleer extent, in the high-dose iMnecarenasaebdsol1u9t%e,, 2re3l%at,ivaend(l2iv2e%r,/broedsypewcetiigvhetl)y,,ainndthreel1at0i0v0e m(lgi/vkerg//bdraaiynmwaelieghrta)tsiavsercowmepiaghrtesdtwoetrhee ~ `cownetirgohltss.coArlrleltahtreedewiintchretahseesmiwcerroescsotaptiicstoicbaslelryvsaitginoinfiocfanmtibnyimtahle htreepnadtotceeslt.luTlahrehiynpcerretarsoepihnyliinvearll tMeincrmoaslceopraitcs Ofboslelrovwaitniogntsh)e. suIbncthhreonoince-tomxoinctithyreexcpoovseurrye1p0e0r0iomdg(/skege/ddiasycumsaslieonrautns,demrean ianbcsorleuatsee,dr1el0a%t,ive11(9l%i,vaern/dbo1d1y%w,eirgehstp)e,ctaivnedlyr,elaaltitvheou(glihveorn/lbyratihnewmeeiaghnt)reilvateirvewe(ilgihvetxs/wboedryewsetiilglht) wreacsovsteartyismtailcaelsl.y sIingnfiefmicaalnet.raMt,icirnocsrceoapseiscihnepaabtsoocleultleulaanrdhryepleatritvreo(pthoybwraaisn)noltiveevriwdeeintghitn these `pgarroaumpestweerrsethcaotnwsiedreereodbsteorbveedbiionltohgeicsaulblcyhirnosniignciftiocxaincti.ty exposure and one-month recovery wMeeraenianbcsroelausteed, 1re2l%a,tiv1e6%(,Kiadnndey1/4bo%d,yrweesipgehctti)v,ealyn,dirneltahteiv1e0(0k0idmnge/yk/gb/radianywmeailgehtr)atksiadsnceyomwpeaigrhetds tothe control rats. All three increases were statistically no microscopic morphological correlate to the increase significant bythetrend test. There in kidney weights in this study (see was - rdaitssc,uksisdinoenyuwnediegrhMticparroasmceotpeircsOwbeserrevastiimoinlsa)r.to Icnontthreolonreat-mvaolnutesh.reTceosvtersyub1s0ta0n0cem-gr/eklga/tdedaykimdanleey weight effects were one-month recovery not observed groups. in female rats at any dose level in the subchronic toxicity or Aunlreoltahteerd itnodtievsitdsuaulbsatnadncmeeaadnmionirsgtarnatwieoin.ghtAdlitfhfoeurgenhcessomweerfeecmoanlseitdheyrreoditdowbeeigshpturpiaoruasmeatnedrs in -- the subchronic study were increased in al treated groups (variable statistical significance), there TTT------ Company Saniized. Does not contain TSCA CBI 2F9002:-5DD4aa2yy5GG:aavvSaauggbecehSSvouunddiyciTinnoRxRaitctisstwywiitthhOOnnee:GGeenneerraattiioonnRReepprroodduuccttiioonnBEvvaabluustiioonnss DuDuPPoonntt1114141188 yy wanadsnnootdtoosaetreesstpsounbses.tanTcheerseelaitnecdreefafseecst.were attributed to a spuriously low control group mean, C. Gross Observations (Tables 40-43, Appendix N) `iTnhteerreprweeterdetnoobteesntatsuurbasltlayncoec-cruerlraitnegdbgarcokssgroobusenrdvalteisioonnss. tAhaltlagrreostyspoicbasleorfvartaitosnsofatthniescargoepsayndwere strain. D. Microscopic Observations (Tables 44-51, Appendices N and 0) Tgelsatndsuobfsmtaanlcee-arnedlafteemdamliecrraotss.copic findings were present in the liver of male rats and the thyroid Incidences and Average LesionIGnrMadaelseoafnTdesFtemSaulbsetRaantcse-Related Microscopic Findings Dwemghgly 0 ew Males: Subchronie Toxicity ~ HLyipveerr:trophy, hepatocyte, entilobelar 0/10 (00) 01000) 010000) 91009) HTyhpyerrotlrodphgyl.anfdo:lliclecll 11002 mo) no. 1010016 Males: One-Month Recovery THyhpyerrotirdopghlya.nfdo:llicular cll no@1 NA NA 1009) Females: Subchronic Toxicity THyhpyerrosiodpghlya.nfdo:llicular cll 01000 21000) 010000) 21002) Females: One-Month Recovery THyhpyerrotirdopghlya.ndf:ollicula-r cell. 01000) NA -NA 21002) + NNuummebreartoirn pianrdiecnattheessensuimnbdeircaotfesagsrowuipthavmeircargoescsopeicvleeosirfonli.estiDoeynn.ominator indicates numberofrs n group. NA Tissue not available. H(y1p0e0r0tmrgo/pkhgy/doafyc)enmtarlielosbualnadrwheapsatgorcaydteedsmwiansimoablseirnvaeldl ciansmeso.stS(i9n/c1e0)hehpiagtho-cdeolsleu.lar hypertrophy --_ Hweapsatnooctelolbuslearrvehdypienratnryopohfytwhaesonnoet-moobnstehrvreedcoinvearnyymfaelmeas,lethriastsefffoelcltowwainsgctlheear9l3y-rdeavyerseixbploes.ure. -_-- =e Company Sanitized. Does notcontain TSCA O81 292005D-0Da2ay5y:GGeavvSaauggbeeehSSvttouunddiyyciTinnoRxRitactsistwywiitthhOOnnee-GGeenneerraattiioonnRReepprroodduuccttiioonn EEvvaalluuaattiioonnss DDuuPPoonntt1114141188 -- opfefriionde.lyMgircarnouslcaorpiecoaslilnyo,phhielpiactcocyetlolpullaasrmhywpiethritnrocpehnytrwialosbuclhaarrahcetpeartiozcyetdebs.y aTnhienrcerewaassednaomount ehliesvtaotmeodrp(hseoeloCgliicniecavlidPeantcheoloofghyepsaecttoicoenl)l.ulTarhudsa,mahgepea,toacnedllhuelpaartihcypeenrztyrmopehlye(vaenlsd wtheereasnsootciated tihnecrmeeatsaebionlliisvmerowfeaigxhetnso)biwoatsiccoannsdidneorteaddvaetresset.substance-related pharmacological response to aAdnmiinnicsrteearseedd 1in0c0i0demngc/ekgo/fdtahyyrfooirdafpopllriocxuilmaratceelllyh9y0pedratysr.ophFyolwliacsulparresceelnlthiynpmearltersopahnydwafse.males. cchyatroapcltaesrmi.zeFdoblyiclloews cwoelruemdneacrrefaoslleidcuilnasriezpe,itihreelgiuulmawriitnhsahafpien,elayngdrcanounltaarinoerdvdaeccuroelaasteedd amounts soefvneorirtmyalofpfionlkliccoulllaorihdy.peFrotlrloopwhiyngwatshedoencere-amsoendthinrtehceovmearlyepaetrsi.od,Inboftehmatlhee riantcs,idtehnecienacinddence: (th2e12p0e)rsainsdtesnecveeorfittyh(emiefnfiemcatlf)owllaoswithneg sthaemoenien-bmootnhththreeecxopveorsyu,rethaenodverreaclolvdeercyrgeraosuepsin. tDhee.spite incidence and severity demonstrates the reversibility of follicular cell hypertrophy in this study. Aalnteirnecdrtehaysreoiind tghleanidnchiodmeenocsetaasnids.sevAelrtihtyooufghthtyhreofiodllfioclulliacrulcalrlcerlelshpyopnesretorbospehryviesdininditchaitsivsetuodfy i(smpiontiemnatliatlolympirlodlihfyeprearttivreopahnyd)awdavserwsiet,heisnpetchiearllayngien otfhenroart.maSlipnhcyesifoollloigciuclaalr creelslphonyspee,rttrhoepehfyfeicst ccoanussiestoefntthweihtyhpeservterroaplhidcifrfeesrpenotnsmeecinhathniisssmtsudoyfiaslnteortedclteahry.roIind graltas,ndahcoommeomsotanscisa,usteheofsptehcyirfoiicd ~~ follicular cell hypertrophy is an increase in the rate of hepatic thyroxine (Ts) glucuronidation and lseuvbeslesqwuhenitchbitlriiagrgyeersxcarnetiinocnr.e*as"e Ainntihnecrreelaesaesde roaftepiotfiTtyareyx-cdreertiivoend rtehsyurlotisdinstliomwuelratTisngblhooordmone '(PT4S5H0)i,sroeesnuzltyimnegsinintthhyeroriadt faorlelikcnuloawrncetlol sheycpoenrdtarroiplhyy.caMusaentyhyirnodiudcefrolsloicfuhlaerpacteillc hcyypteorcthrroopmhey by tinhitshmeehcihgahn-idsoms.e mIanltehsisdesmtuodnys,trtahteepsrethsaetncheepoaftotceestllsuulbasrteannczey-meelastyesdtheempsathoacveellbueleanr hiynpdeurcterdoapnhdy tthhaytroTgyleoxbcurleitniboinnmdianyg,haanvde tbheeencasseecoonfdUaDrPi-lgyliunccurreoanseydl.-trDaunesftoeradisfefienrdeunccetsioinn,Trsathsaalfr-elimfue,ch more susceptible than humans to secondary thyroid follicular cell hypertrophy." iMnamleeaanndrefleamtiavlee(kkiiddnneeyysbrdaiidnn)oktiddenmeoynwsetirgahttesainny tmhoerp1h0o0l0omggic/aklg/cdhaayngmealdeesrpaitts,e aas1c4om%pianrcerdeatsoe "thkeidncoenytrwoelisg.htAplatrhaomuegthertsubiunlatrhecehlilghhy-pdeorstermoaplheyswiassinndoitcaaptpiavereonft,a intoins-alickveelrysteh,atsltihgehti,ncrease in : wphaasrmnoatcoplroegsiecnatlforlelsopwoinnsge tbhyetohneek-imdonnetyhtroexceonvoebriyotpiecrieoxdp,otshueree.ffeScitnwcaesanreovrergsainblwee.ight increase aAlnldoatgheeranmdicwreorseconpoitcporbesseernvtaitnioandsoisnethriesspsotnusdey afraeshkinonowinnetiothoecrciunrcniadteunrcaelloyrisnevreartistoyf. this strain ~~ 5 `Company Saniized. Does not contain TSCA CBI 2505-4D2ay5:GavSaubgeehSrtoundiye iTnoxRiactistywithOne.Generation Reproduction Evaluations --_ E. Anatomic Pathology Conclusions for the Subehronic Toxicity and Recovery Evaluations Duponc11415 Etoxpmoisludrtehytrooi1d0f0o0llmigc/ulkagr/cdealyl ohfyptehrettreospthsyubinstmaanlcee faonrdafpepmraolxeimraatse,lmyi9n0imdaalyscepnrtordiluocbeudlamrinimal hFeoplaltoowcienlglulaornhey-pmeornttrhoprheycoinvemraylpeerriatosd,,atnhdyrionicdrfeoalsleidculliavrerelalndhykpiedrnteryowpehiygahntds oinrgmaanlweeriagthst ewfefreectisndwiecraetidveecorfeaasepdhaarnmdachoelpoagtioccealllruleasrpohnyspeerttoraopxheynowbaisotnioctapnrdesewnetr.e nLoitvecronasniddekrieddnetyoebfefects bpoitoelnotgiiaclallylyadavdevresres.e. The thyroid effect, although mild and reversible, was regarded to be U1n00demrgt/hkeg/cdonadyibtaiosnesdoofntthhisyrsotiuddye,fftehcetsNaOt EthLe f1o0r0p0atmhgo/lkogg/ydafyordmoasleeleavneld. female rats was Reproductive Toxicity Evaluations A. Py Rats - Clinical Observations and Mortality 1. Py Males --_ (Table 52, Appendix P) No test clinical soubbssetravnactei-orneslawteerdeefofbescetrsvoerdsitnatmiastliecsallaydmsiignniisftiecraentd differences any dosage in the of the incidences of test substance. One `mgaalveagaeterirnort,hean1d00w0asmgn/oktgc/odnasyidgerroeudptwoabseftoesutndsudbsetaadncoen-rteelsattdeady. 89. The death maybeduc to a 2. Py Females During Gestation (Tables 53, Appendices Q) cNloinitcesatl soubbssetravnactei-orneslawteerdeefofbescetrsvoerdsitnatfiestmiaclalelsyasdimgininfiisctaenrteddiaffneyrednocseasgienotfhethientceisdtesnucbesstoafnce during gestation. Mortality did not occur in female rats during gestation. 3. Py Females During Lactation (Tables 54, Appendices R) - cNloinitceaslt soubbssetravnactei-orneslawteerdeefofbescetrsvoerdsitnatfiestmiaclaellsyasdimgininfiisctaenrteddifafneyrednocseasgienotfhethientceisdtesnucbesstoafnce during lactation. One female in the 10 mg/kg/day group was founddeadon lactation day 10. -- eTTee ee Company Sanitized. Does not contain TSCA GBI $H02-5D4a2y5G;aSvuabgcehrSotnuidcy iTnoxRiactistywith OneGeneration Reproduction Evaluations -_ B. P, Rats - Mean Body Weights and Body Weight Gains DuPont 11418 1. Pi Males (Tables 55 and 56, Appendices S and T) gNaointewsetrseubosbtsaenrcvee-rdeilnatmeadleefsfeacdtmsionrissttaetriesdtiacanlylydsoisgangiefiocfantthdeitfefsetrseunbcesstaonncebodudryiwnegitghhet or weight reproductive portion of the study. 2. Py Females During Gestation (Tables 57 and 58, Appendices U and V) gNaoitneswterseubosbtsaenrcve-erdelinatfeedmeaflfeesctasdomrinsitsattiesrteidcalalnyysdigonsiafgiceaontf dtihfefteersetnscuebssitnanbcoedyduwreiingghgtesotratwieoin.ght 3. Py Females During Lactation (Tables 59 and 60, AppendiceWs and X) fNeomaaldevserasdemitnesitstseurbesdtaanncey-dreolsaatgeedoeffftehcetsteosnt sbuobdsytawnecieghdutroirngweliacgthattigoani.nFweemraeleosbsaedrmviendisitnered c1o0m0p0amrge/dkgto/dtaheychoandtrsoilgnviafliuceas.ntlyVairnicarbeialsiteyd iwneiwgehitghgtaignaidnurdiunrginlgacltaacttiaotniodnayissc0o-7mmaonnd,0-a2n1d the increased weigh gain was not considered to be tes substance-related or adverse. C. Py Rats - Food Consumption and Food Efficiency Py Females During Gestation (Tables 61 and 62, Appendix Y) fNoootdesetffsiucbisetnacnycwee-rreelaotbesderefvfeedctisn ofremsatalteisstaicdamlilnyissitgenrifeidcaanntyddiofsfeargeencoefstihne fteosotdscuobnsstaunmcpetidournionrg gestation. D. Reproductive Indices (Table 63, Appendices EE and FF) iNnodetxe,stgessutbasttiaonncei-nrdeelxa,teodr egesftatifoornseltaetncigstthticwaeslrlye soibgsneirfivceadntindiPfyfemraelnecsesainndmfaetmianlgesinaddemxi,nifesrtteirlietdy any dosage of the test substance. -- - = = - Company Sanitized. Does not contain TSCA CBI -- Ee -------- SH02-5D4a2y5:GavSaubgeehSrtoundiyc TinoxRiactistywithOneGeneration Reproduction Evaluations DuPonc11418 ~~ E. Sperm Count, Morphology, and Motility (Table 64, Appendices Z-BB) mNoorptehsotlsougbys,taonrcen-urmeblaetredweefrfeecotbssoerrvsteadtiisntipcaarlelnytsailgnmiafliecasntaddmiifnfiesrteenrceesdiannyspdeorsmagmeotoiflitthye, test substance. F. Estrous Cycle (Table 65, Appendices CC and DD) pNeorcteensttosfubdsatyasncien-reesltarutse,d peefrfcecetnst oofrdsataytsistiincadlileystsriugsn,ifpiecracnetndtifoffedraeyncseisnwperroeesotbrusse,rvmeedaonncytchele length, or the mean number of days in the precoital interval in females administered any dosage of the test substance. G. Fy Offspring Data 1. Litter Size, Sex Ratio and Pup Survival (Table 66, Appendix GG) No test substance-related effects or statistically significant differences were observed on the -- number of pups born, number of pups bom alive, sex ratio, lactation index, or litter survival in offspring from any dosage group. 2. Clinical Observations in Fi Pups (Table 67, Appendix HH) No test substance-related effectsor statistically significant differences in the incidenceofclinical observations were observed in offspring from any dosage group. 3. Pup Weights (Table 68, Appendix I) No test substance-related effects or statistically significant differences in body weight of pups during the lactation period were observed in offspring from any dosage group. H. Fy Rats - Clinical Observations and Mortality (Tables 69 and 70, Appendix JJ) No test substance-related effects or statistically significant differences in the incidence of clinical observations were observed in Fy male or female rats from any dosage group. Test substancerelated mortality did not occur in Fy maleorfemale rats from any dosage group. ~~ PE `CompanySaniized. DossnotcantainTSCACal 01.-2D5a4y25G:avSaugbeehSrtoundiyc TinorRiactistywithOneGeneration Reproduction Evaluations DuPont 11418 --_ I Fy Rats - Mean Body Weights and Body Weight Gains (Tables 71-74, Appendices KK and LL) No test substance-related effects or statistically significant differences in body weights or weight gain were observed in Fy male or female rats from any dosage group. J. Fy Rats- Food Consumption and Food Efficiency (Tables 75-78, Appendix MM) No test substance-related effects or statistically significant differences in food consumption or food efficiency were observed in Fy male or female rats from any dosage group. K. Fy Rats- Developmental Landmarks (Table 79, Appendix JJ) No test substance-related effects or statistically significant differences in the development of preputial separation or vaginal patency were observed in Fi male or female rats from any dosage: group. L. Reproductive Toxicity Conclusions ~ The no-observed-cffect-level (NOEL) for reproductive parameters was 1000 mg/kg/day in parental males and females. In addition, no systemic toxicity was observed in parental males, parental females, or offspring from any dosage group. Anatomic Pathology Evaluation -- Rats Designated for Reproductive Evaluations A. Organ Weight Data Fy Adults (Tables 0 and 81, Appendix NN) There were no test substance-related effects on organ weights in the Fi adults. Minimal differences in some weight parameter means in the high-dose (1000 mg/kg/day) maie testes (increased relative to brain weight) and female livers (decreased absolute and relative to body weight and to brain weight) were statistically significant by the trend test. These differences were considered to be spurious and nottest substance related. w Company Sanitized. Does not contin TSCA CBI 9H02.5D4a2y5:GavSaugbeehSvtodnyi Ti oxRiactistyith OnGeeneration Reproduction Evaluations DuPone-11418 ~~ B. Gross Observations FPayrAednutalltsP,yWAedaunlltisng(sT,abalneds P8u2pasn(dT8a3b,leAsp8p4enadnidx805,0)Appendices PP and QQ) oInbsPeyrvaadtuilotnss,.FyObadsuelrtvsa,tFiyonwseaonclciunrgrse,dainndlFoywpiunpcsi,dtehnecreeswaenrdewneroeerstansduobmstlayncdei-strreilbautteeddgarcorsosss control and treatment groups. C. Microscopic Observations 1. (PaTraebnlteasl8P6yaAnddult7s, Appendix 00) MInictrhoesPcyopaidculetxgaemnienraattiioonn,otfhePryeawdeurltesnwoatsesltimsiutbesdtatnocet-hererleaptreoddmuicctriovesctoipsisucefsoifndtihnges.two found dfaeialdurreast)s. (TsheeeMmoarltaeliatnyd)faenmdalteheratthsretehaptaidrisdonfotraptrsotdhuactedildittneorts pwreordeuicnetlhiet0esmg(/ik,g/rdeapyrogdruocutpive 6(6A5n2i9m8a,l rNeossp.ec6t6iv5e0l6y)9,aanndd6t6h5e218090,0remsgp/ekctgi/vdealyy),gr1o0u0pm(gA/nkigm/adlaNyogs.ro6u6p5(1A3n3imaanldN6o6s5.22646,5114 and respectively). -- 2. Fy Adults In the F; adult generation, there was no histopathology conducted since there was no mortality. D. Mortality * Parental Py Adults and Fy Adults (Appendices 00 and PP) PIyn trhaes,Pyonaedul1t00g0enmegra/tkigo/nd,atyhemraelwee(rAenniomatlesNtos.ub6s6t5an0c5e0-)realnadteodneeff1e0ctmsgo/nkgm/odrtaaylifteym.alOef(1A6n0imaadullt No. 665248) were found dead. The causes of death were undetermined. nInotdheeatFhysaadumlotnggentehreat1i5o2n,atdhuelrteFyweartes.no test substance-elated effects . on mortality. There were E. Anatomical Pathology Conclusions for Reproductive Toxicity For pathology, the NOEL was 1000 mg/kg/day (the highest dose level) for both male and female ras. --_ - or `Company Santized. Does not contain TSCA CBI 9205.4D2a5y:GavSaubgcehSrtoundiyc iTnoxRiactistywithOneGeneration Reproduction Evaluations DuPont 1418 --~ CONCLUSIONS N(NOOEELL)f*ofroSrubscuhbrcohnriocniTcoxtiocxiitcyi:tyUennddeporitnhtescionndmiatlieonasndofftehmiaslseturdayts, wtheesn1o0-o0bmsge/rkvegd/-deafyf.ecTthilesvel l1e0v0el0 wmag/skbga/sdeadyomnarleevearnsdibflee,mamliengirmoaulpst.o mOitlhderthtyersotisdubfosltlainccuel-arrehlyapteerdterfofpehcyt,s oobbsseerrvveedd iinn tmhaeles apnadlroar fmeematalneedsridsnosheedpawtiitchB1-o0x0i0damtgi/oknga/cdtaivyiityn;clhuodweemveirl,d atlhteesreatwieornes innotclcionnicsaildepraetdhotloobgey adverse. Mfoolsltowoifntghoeneeffmeoctnstohbosferrveecdovdeurryi.ngThtyhreodiodsifnolglpiceurliaordhdyepmeorntsrtorpahtyewdafsulsltiolrl ppraretsaeltraetvetrhseaelnd of the one-month recovery period; however, the incidence and mean severity level in males had decreased by this time. NreOpEroLdufcotrivReepervoadluucattiiovnesEwvaalsua1t0i0o0nsm:g/Ukng/ddearyt,htehceohnidgihteisotnsdoofstehitesstsetdu.dyT,htihsewNaOsEbLasfeodron a lack of test substance-related effects on any reproductive parameter in Py or Fy generation animals dosed up to 1000 mg/kg/day. --_ = T{hheeteNsOt sEuLbsftoarnctheiwsesrteudnyoitsddeetfeictneedd.asThthues,hifgohrestthidsosstuedayt,wthheicNhOtEoxLicisolcoqugiivcaallenitmpoortahentNeOfEeLcsastdbefuitneadbbeyto ~ d{ehefiUnneidtbedyStaheteEsurEonpveiarnonUmnenitoanl.Protection Agency" and fo th no-observed-adverse-ffet evel (NOAEL) 3s _-- @ `Company Sanitized. Does not contain TSCA CBI 9B02.5D4a2y5;GavSaugbeelSoundiyc iTnoxRaitcstywithOneGenerationReproduction Evalutions Dion 11418 --_ REFERENCES 1. DuPont Haskell Laboratory. H-25334: RepeatedRose Oral Toxicity Gavage Range-Finding Study in Rats. Unpublished 2. Lazarow, P.B. (1981). AssayofPeroxisomal Beta-Oxidation of Fatty Acids. Methods in Enzymology 72, 315-319. 3. QBuraandtfiotride,sMofMP.ro(t1e9i7n6U)t.ilAiziRnagptihdeaPnrdinSceinpslietoivfePrMoettehion-dfDoyertBhiendQiunagn.tiAtnaatli.onBioofcMhiecmr.o7g2r,am 248254. 4. Draper, NR. and Smith, HL. (1981). Applied Regression Analysis, 2* edition, pp 266-273. Wiley, New York. 5. Selwyn, MR. (1995). animal safety studies. JTohuernuasleoofftthreenAdmetersitcsatno dCeotlelremgienoefTaonxoi-ocbosleorgvyab1l4e(-2c)f,f1e5ct8-l1e6v8el. in 6. Jonckheere, AR. (1954).A distribution-free K-sample test against ordered altematives. `Biometrika 41, 133-145. 7. SLteavteinstei,csH(.3.(1O9l6k0i)n., eRdo.)b,upspt 2te7s8t-f2o9r2e.quSatlaintfyoofrdvUanriivaenrcseis.tyCPornetssr,ibPuatlioonAlsttoo.Probabilityand 8. Shapiro, 5.5. and Wilk, MB. (1965). An analysis of variance test for normality (complete ~ samples). Biometrika 52, 591-611 9. 3S4n9e.d3e5c2o.r, TGh.eW.foawnadSCtoactherUanni,veWr.sGi.ty (P1r9e6s7s),.AmSetsat.istical Methods, 6edition,pp 246-248 and 10. Dunnett, C.W. (1964). New tables for multiple comparisons with a control. Biometrics 20, 482491 11, Dunnett, C:W. (1980). Pairwise multiple comparisons in the unequal variance case. J. Amer. Statist. Assoc. 75, 796-800. 12. Tamhane, A.C. (1979). A comparisonofprocedures for multiple comparison of means with unequal variances. J. Amer. Statist. Assoc. 74, 471-480. 13. Kruskal, J. Amer. WH. and Wallis, Staiist. Assoc. 41, W.A. (1952). 583-621. Useofranks in one-citerion analysis . of variance. 14. Dunn, 0.3. (1964). Multiple contrasts using rank sums. Technometrics 6, 241-252. 15. Milliken, G.A. and Johnson, D.A. (1984). AnaloyfsMeisssy Data, Volume L.; Designed Experiments. Lifetime Learning Publications, Belmont. 16. Hocking, R.A. (1985). The Analysis of Linear Models. Brooks/Cole, Monterey. 17. Bartlet, M.S. (1937). Some examples of statistical methodsofresearch in agriculture and applied biology. J. Royal. Stati. Soc. Suppl. 4, 137-170. --_ _--m `Company Saniized. Doss notcontainTSCA CBI 9205.4D2ay5:GavSaugbcehSrtoundiyc TnoxRiactistywithOne-Generation Reproduction Evaluations Dupont 11418 -- 18. Fisher, R.A. (1985). Statistical Methods for Research Workers, 13" edition. Haffner, New York. 19. cDoemmppusttaetri,onAa.Pl.,asSpeelcwtsyno,fMmRix.e,dPmaotdeell,anC:aMl.y,sains.d RTohteh,JoAu.rJ.na(l1o98f4t)h.e RStoaytiasltiSctaaltiasntdical Society, Series C (Applied Statistics) 33(2), 203-214. 20. Haseman, JK. and Hogan, M.D. (1975). Selection of the experimental unit in teratology studies. Teratology, 12, 165-171. 21. Capen, C.C., DeLellis, R.A., Yarrington, J.T. (2002). Endocrine system. Handbook of eTdosx)i,coppl.og7i3c7P-a7t4h0o.lAogcya,de2m*icedPitrieosns., N(eWw.MY.orHka.schek, C.G. Rousseaux, and M.A. Wallig, 22. HfoarzAanradlEyvsailsuaantidoEnvaDlivuiastiioonn,oSftSaunbdcahrrdoEnviacluaantdioCnhrPornoiccedEuxrpeo,sTuorxeicSittuydiPoetsePntaiyanlt:erG,uOi.dEa.nce eWtaaslh.,inUgntiotne,dDSt.aCt.es2E0n4v0i6r.onEmPeAn-t5a4l0/Pr9o-te5c-t0i2on0.Ag(eJnucnye,1O9f85f)i.ce of Pesticide Programs, 23. ERiNs)k, ACshsaeptsesrme,ntSoecftNiootnisf2i.e2d4Naenwd 2S.u2b5s.tan1c9e94s.. Technical Guidance Document (XI/283/94- -- ---------------- - -- Ey t --e --t --e --r pa r `Company Saniized. Doesnotcontain TSCA CBI 9205.4D2a5y;GavSaugbcehSrtoundiyc TinoxRiactistyithOne.Generation Reproduction Evaluations DuPont11418 TABLES --_ rg Company Sanitized. Does not contain TSCA CBI 9205.4D2ay5:GavSaugbeehSvtoundiyc TinoxRiactistywith OneGeneration Reproduction Evaluations --_ TABLES DuPont 11418 EXPLANATORY NOTES CriticalDates Day 72 eLvaasltudaatiyodnastwaefrreomretphoertmeadlewiathndthfeemsaulbechrraotsnidcestiogxnicaitteydafnoirmraelpsr.odBuocdtiyon weights and post-mating clinical periods observations collected during the cohabitation and are reported in the Reproductive Toxicology section; Dose volumes administered during the cohabitation and post-mating periods are documented in study records. Day 90 dLaesstigdnaayteodfftoerstonsueb-smtoanntche aadnmditnhisrterea-tmioonnthforremcaolveeraynpderfieomdasl.e rats Day] Last day of body weight and food consumption data collection for male and female rats designated for the subchronic toxicity evaluation. Last day of test substance administration for male rats designated for the subchronic toxicity evaluation. Day92 Male rats designated for the subchronic toxicity evaluation were sacrificed. --~ Last day of test substance administration for female rats designated for the subchronic toxicity evaluation. Day 93 Female rats designated for the subchronic toxicity evaluation were sacrificed. Day 126 Last day of body weight and food consumption data collection for rats designated for the one-month recovery period. Last day of food consumption data collection for rats designated for the three-month recovery period. Day 127 Male and female rats designated for the one-month recovery were sacrificed. Day 182 Male and female rats designated for blood fluorine level evaluation were sacrificed. -- --- Company Sanitized. Does not contain TSCA GBI 9205-4D2a5y:GaSvuabgeehrSotnuidcyTionxRiactistywithOneGeneration Reproduction Evaluations ~~ TABLES Abbreviations EXPLANATORY NOTES mg=/mg/k kg/dgay ganmida=y grams/animaliday in=ciinciddenece `SuofmHemm atolaogyrValyues RBC - redblcoellocoudnt HGB - hemoglobin HCT - hematocrit MCV - mean corpuscularvolume MCH - mean corpuscularhemoglobin MCHC - meancorpuscular hemoglobin concentration RDW - redcelldistributionwidth ~ ARET - absolutereticulocytecount PLT -plateletcount WBC - whitebloodcell count ANEU - absoluteneutrophil (ll forms) ALYM - absolute lymphocyte AMON - absolutemonocyte AEOS -absoluteeosinophil ABAS -absolutebasophil ALUC - abslarogeulnstuaintedceell ~ - nodata Summary of Coagulation Values . PT- prothrombintime i APTT - activatedpartial thromboplasttiimen. ~ - nodata DuPont-11418 : -- --- Company Sanitized. Does notcontain TSCA Gal 5H02-5D4a2y5:GavSaugbechSrtoundyc TinoxRiactistwyithOne Generation Reproduction Evaluations DuPont. 11418 --~ TABLES EXPLANATORY NOTES Abbreviations: (Continued) `SumAmaSrTy o-faCslpianrictaalteCahmeimniostrtarnysVfaerlausees ALT - alanineaminotransferase SDH - sorbitoldehydrogenase: ALKP - alkaline phosphatase BILI - totalbilirubin BUN -ureanitrogen CCHROELA - creatinine cholesterol TRIG - triglycerides GLUC - glucose TP - total protein ALB - albumin GLOB - globulin -- CALC TPHS - icnaolrcgiaunmicphosphorous NA - sodium K - potassium CL - chloride . PFLU - plasmafluoride ~ - nodaa `Summary of Urinalysis Values VOL - volume UOSM PH - urineosmolality the logarithmofthe reciopftrheohycdraogeln ion concentration URO - urobilinogen UFLU - urinefluoride UMTP - urineprotein . ~ - nodata -- ee--------------------------------- Company Sanitized. Does notconTtSaCAiCn8 2905-4D2ay5:GaSuvbaeghrStoundcyTion rRitcsywith OneGeneration Reproduction Evalustions --~ TABLES DuPont11418 EXPLANATORY NOTES Notes: `Summary of Hematology Values Summary of Coagulation Values `Summary of Clinical Chemistry Values `Summary of Urinalysis Values `When an individual observation was recorded as being less than a certain value, calculations wwearseupseerdffoorrmaendyocnahlaclufltathieonrsecpoerrdfeodrmvealduew.ithFotrhaetxbaimlpilrueb,inifdbaitlai.rubin was reported as <0.1,0.05 RTeesptrDodauyct1ifoonr FTIabmlaelses and fem=aPolstenatsal Day 21 --~ = Company Saritized. Does not contain TSCA CBI 9H02.5D4a2y5:GevSaugbcehSrtoundiyc iTnoxRiactistywith One-Genertion Reproduction Evaluations DuPont 11418 r TABL1E SUMMARY OF DOSING SUSPENSION ANALYSIS Sample Type Dosing ConcentrantdiStaobinlisty ofB-25425 (mg/ml) Nomina: 200 200 20 THeosmtodgaeyne2ityTop 1368 1908 187 Middle (63.0 187 50) 35) 2088 188 Botom 2030)8 2o1t3o8) 1091, 100) 1063) 55) `AAvveerraaggee PMeeracseunrteNdoCmionnale 1074 a2n0o4) 189 015 CSoteafnfdiacriedntDoefvViaariioantion 21093%4 2o12 212%1 SSuhboiulrtyRoom Temperature --~ THeosmtodgaeyne8ityTop Middle Boom `AAvveerraaggee PMeeracseunrteNdoCmionnale CSotefafnidcairedntDoefvViaartioantion 611853)0 2(0a8m3) 018906) Lem 9 a 35) Lom 4 4 Lo ) 4 4 055) 016902) 220%05 `TCoencsetntdraaty2ion Verification 1213860) 020s70) 152 060) Testday 86 : a2c00o a2o0s7) 0230060) : TNThueembspereisadin peearlsensstheecdseocsoeanrcdntchieastreoesnp,eocnatievvecrpgoerncpeeonrbtfcoefnetnofspipnohamsvarlse.p(aere0eTn)RrEsa.ndr deviation, nd coeficenotf DvDauerpilnaittciaeotnesoasfmtapmolp,elsemsoidstdulbuemb,irtnetdde.bdMo(ema).n esl epored --_ os Company Sanitized. Doesnotcontain TSCA CBI ~3 5 a > om om wm a a wm @ B 8 gorditas gE NENE : --_ 3 O:F Fe ee dss ne need ne ke |: fg Fz i z HS HO HO HO NG NO NO NO NC NG NO 3 i3 1 24 ~ Eg 3 PH2I% 8 I2 3T3T8E 3 8O 4 2 fF FFE EE EEOEOEE CompanySanitzes. omsotcasrtanTSCA GBI 3 I 5S g en 8 oF 2.8 8 2% 8 nn ay 3z BS dS dS ds Ws we ae i 5 i 58&3 i : i s2 Co a a oad zi ~ | EE i : : : He o 5 5 "5 a = i || 5: css az od 74 13 3 id HO JS dS 6 a8 ao mo 34 : IE : 183 5 ji i3 ii3y EH ~ 33 ia 3E 8 fs 28 8/4bHe0y 583 2 3 2 3 4 Hi iifH: iE... Company Saiz. Donotecontsain TSCAGSI ~3 Hl ggess 23333233 33oioloadoloload ~ 33 : Co BwmmmammEuaa :g 8"A @52 @82 8 2 @2 @8 @& @8 @2 &3 f2 | 8, 1: |i a7 ed a af ad af ed ed wd wd wd 3: i 5 . i2s 5E8dE4E03E08ER80E8%ER% EfoEg Eog it gg 5 &# 5 8 & 8 8 8 & & 4 23 48! ~ Company Santen.Soe ron5a0nGB ~i eee : 5 A: ii 2 2 oF 3 ed wd : 3 ~ | 88 ! : LB ft% EE 5 323 oo i i i8 i8 i ooo.| F5E4 | bs i2 3 g% ncie d979i8ioaf wddl | a g t EE 5 3 +32 3cs iy ~ f55f8s 58 % | ff ih B5 18 55 2% 83 5 ||3di: i: ie Compo Seten.Doe conanT3001 ~3 5 fl 8 3 8 & & & @& 8 @a BO OnNHHEHBEERS GEREN ERSuR 8 87 2% BR BR 3B 38 ER 89 8% g% g: 2 22 5 8 88 & 8 7 3 ~ iE : 9 & [7 8" [VY 5M 3 2 g 5 3 3 n | gl z 8c 2 27 a3 a3 of of 3 wh 4s o3 ox |iz F1$% 89 g4 58 4 $4 g8 9 ge ge 3 I i i 24 ~ 8 4 Bf FF FEE EEE: : 3 CompanySais, onstats1 ~3 3 & - #8 = a -~ nan == & n - nunnH > 15 2 a 2 oS wd oF a" 8 a2 4% 03 43 eS 8" 8% 8 8 8 : : ri yfididis4s ~ gE 4 3 yd 5 8 ' 2: 0. .3 : I yc i a g 3 8 833 53 5 58 3 2 So wn 5 on wn ar J 3% 5 wo oa wma 4H Bz vo 34%s 3J BoYn o5%% Bss o|f eEcS B5S $3%8 ogs9 o3s 2 3 3 9 3 5 & 4 1 34 8 5 3 3 53 8: 8: zg f3 8 3 it 8% 3% F FE $i E F F % ~ 388 38 8i CompanySanitzed. Dossnot conTtSaCAiGanll i 2 3 oo] % BEd nne i ~ 1J 3JFH 5 ]fg 5 i so GELS EEEE 2 " 8i% d3i8i3 r83d3d3 d2 44 gg g : i I 83E3ErI Fm8Fo82En88&F8o@8&Fn@8En@8Psa5Ey3ga i i i 8E i : 88 &8 43 133:2 25-] P i IzEzTzER ossg # 14 oe 4 f Flee EEange JL 3 i: iEK: Hi ig2 12 a3 ~ i2g LRA f i i [I i CompanySania, con recont5aAiGn1 < ko FE EEEE ES Lf REBEBEnoDE s Polsagrreaaac -- E2 l5 FTFH d53 gAsT R csEsAd RgSF R8N8 E8R4 2R 8 $R 2 as : | 28 3 ' i g ~ 5 32 if EH 3 54 Hy i88. 88 Ji 2 8 g : 78 85 33 33og 22Z23 %3 3 Company Satizad. Dossnot conTtSaCAiOnBI ~ 3 5 A = aa a Fr TS HE HIE BEBLE :g ~ zEE8 ops os5ig2 RsFio3i8 i8r8og3 gBtTor57oi8o7an8oa8r A SE5 3 3 7 %3 g ia : Zg i17 = 15 s 5 2 2 43 ~ 4 Esyd 5 58 S 584 2 32 33 52 5 385 3 3 me 238dZ| B3F 28% H3R34 428 AIEa88sR5E3 a3:3 1 ! g3 i3 3 33 3&5 8: 8ogc 0:8: 333 88 8 3 8 BE F ji i E E Z z 1 : 3 8 CompanySantiza. DossnotconTtSaCAiOnBI f x a 5 ug2 5%Eg 988 4%8 88 28 188 1%& oF 2i Fogsaareee | i g 8 8 & 8 8 & 39 : 3 fi.qad00000 ~~ & z aT 87 2% 37 8% 3% 3% 7 2 % g c5 E8 2 5: id=: 3 it 58i fzP Seod4pen gg. E 8n EgE a f R8m E2 E u 8Sr 8 i1fs] F] t4 4 & 1 : 3 8 3: i5y3 <4 iil Is 1 Fi iFN c if i253 2 H2E4 ~3 : Pal 5883 835%8 8 3s 2 5s 2 3 8 g 8 & 8 3 s|,.3688: 3|3%3 38570% % 3 5 L3il 7 iL: CompanySanizsd. Doosnot conTStCAiGnBI ~ 2 8 && & @ @ @ #2 DNs agbha :8 pilgigargioig g5H.55.5A.R2N.E88ER 28F 88E2E 8 } ~ is 3 #8 13 ] 5 8 = 8 sss 03 oF af of3swfgooFzoof zoFozoF 3 g 87tgf 7 57 $0 #9 87 2g ge of : g3 i & i2% P3os 8 iiEi85 % % ii3&i5 g8 Bt B28 1 1 3 oz fooodg 2 88 gy 2 2 FZ F i Zz 3 3 % 23 5 CompanySantas. Dons ot tainTAGo ~ 33 &] a8 gain Boog 2s 2 i 2 52d az 5 i:2 ue a33 =3 oF <588a5 o8F of 3g 22: . od 5: qos :j ZSe gRE iz dial a g 4 i &| od 5}2 Fi pEf q ag E ozEc oEa || ! ii BFEEE FLA 5I : 83 CompanySorts. Doere conSoaACno ~F <2 sf ocrgmiiaag sms 2 Wag fn 2 2 g EY Y J8 ge di 4d G0 gg ge ae . ~ cd z - & 2 58 2 il 28g 3 5 3 8Z 3 a a & & 7 3& - = 33 S5 eg2nWdIeRf Eof oEf EoF oEF YY E oF EoF 1 of : 3 25 <135 22] 24 #6) ~ 8 2ds 5 /8 43% = OE REN 8E 8EE 8 EEE 8 EN1E 2 pE a & 83889%Ss 22 E50F% 2| 4553 32 = |3 8 3 8 Gompany Santzed. Doss otcontain TSCA CBI 3; 2 | i EIe g 8 8 i 8 8 8 @ 2 g i a8 W g $8E 5 5E 5 3 if z TEE 2 z a8% 85 :.:::3538 i| 2g iue575 0433 n3%S 4483 aGYs 4445 8ad egyi : 2og . rr 83 3 - [3 2 I 3 7 EH SE I 28 of 93 278 af at8 =e8 en& ey8 F5%E: I gon oi ge dS ge $a gd 17 v 2 is sPfg:E ozioFz og3 2 f 2 |B d 58 H4E8 i gf EEE E ERs 3 z id CompanySnns, Doss contin3AG1 ~z 5 % EE B 3 oa aq PE 3 ox 0s 0s 3 PH 8 Cae d 3 aT Eigda d i a } ~ 3% 8 3 gg 7 ! of pgFE e E22E 4% oS Y oF R of EoF gof aof sof 3 z 2 $ og & iy. . =| 54 i 3 42% 548%: iz Company Santas. Dos rtcotTSCiAGn1 ~3 g 8 = = go TMno = mars =am agi g? an gs murspe 3gd :f Rl omg BNE ynns ~ | 8% 3 2 : c 2 g : i 5 : : 2 &2 ==z 2$ 2 4yg 38 2 83 28343& &3 8& Bowe SIogi od oatanoziodanoaiu gl 2 aN a 2g on &| A g3 5:Ba2 2 13 ~ Eg& 5 PiLR]E eo 57 Z 58% 3 [I { 4 SEREIN:E " PE 5 7 &9 z 55 &7 " 34 2 5 [2 yi F Is &Bl 88 Company Sac. GoesconTSonACo ~3 g A a a om BN muaNEs B : ondR90 m 853u 83ons: z g: t reilly Wags ~ 3 : 8 | SE 2] | i i S| gz Be bY i ~i 5 " wg Ae ee 3 <4 fF S SF gg nw 3 3 3 2a oe TH mg soz 8 8 * FEE IE 2 22 2 7% 8 a a TO es 2 2 & 2 oo 3 FF 4% FFiF o: lg f CompanSans, DosscontT30iAGn1 ~i 3 3 :2 Hg 8g ma8 a3 zi 88 33 34 4 z i I3 s ior i 2 i 3 ~3 : B2 eilalo3gBEga i| --- ; 3 1 # 3 gz 8 3 4g 8Zone 333323 i $3 g 23] i! i 4 i 3 g iid i: = if 5 d2e5 5 ls H | : i29 2 _ ds 32 Hef 8% 3 kgs h 2ia 3B%F22 Pi LINE io. 2 CompanySantized. DossnotcontTSa0AiGant ~i a 8 3 & @& @ @ @&a 3 8 88 88 8888 3 1: Sdffsdsded 2 g :ZIBeo 8 88 8 8 8 8 8 8 8 V J 2%Raf B a3 R@ R48 B48 E0]AaE3 aEn Rna ~ wi:QO 49 ~ : | 25 f f 5 8 4 3 5 3 5 5 5 58 5 8 & 3: f8 o g 2F3 oEF E 23 R 0% E oI Rod R02 EesEafSon | iiz 34 $3 HE 28 ~ #4 =8 gas 88 88 3 8 3 & fFi 52 i 8 ff gg 8 8 38 3 FE F 3 F E 3 [EE ---- ~ iZ & a 83 338 = FES 5 8 5 8 HFEER E I R,E0 F GE0E8L 22: :Pa E58% ed2a graf3r3ehaey3ig32 =E =E = Co ~ 3d = 523 2g 3 & # sil F2 g LEgYd a8ma8n 8ed B g43 3R 3a 3:a3E i g EEEIEE AF EE EE i i 3 8 31E i 35 _& 23 z 2 4 g5 g Ek H T $1 d: ozE EosR| EgI4 E EgsE8 3E32 gl B80 f4F0 1 5 Ez oaJ0i gigigi IE lg 8 9 & 8 CompanySiz. ConscorTsSCAoGo ~~ : SL 58 2 qd ! 1 gs: |3{g = s& S| 8 g TF 2 5 1 ~ Egz e og si io : i; i 32 i 38 i: sos 18% i 2a 8 wo nzaa 2%JZ 318ds i8 | = > See 1 if > 3 5 z 2 z i FE 1f 5588: i EI IHRiE bE3 3i4 3% ~ #3 838%3 85 ||g] 3F 3 | 1: iB11i% f 331 i. . CompanySaitzsd, Doss notcontainTSA Gl ~ 33g B oprrrikibidses g2 sf 3% aa oonoof oy aiozlogl al a3 = a) sr rrr ags BA o & 8 8 8 8 85 85 3 8 3 -~ iE 8 RT RT RY RY AT RY 8% 87 RY 2 3 1 3 2z 13 2dg. 8 4Y .2 2223268 23053 23853 23 i E2 5 Y =r og Av dA as gt a5 ge 80 gt z& 2 ii 2 EL 49 aT 4 54 Sa5 38 3 i g &a :. 5455 83:3 84 234588F&2 ComporySass, ous coma 50m G1 ~f 3 4: z 8 an 8.8~~ = ated dd Ad a a =88= digian we 33 3 g 2 3gi 238.8% s<2teas 33 a3 3:33 . Co : B pg own og oR ZH async rH gs 7 : eT : 12 8 8 9 3 4 8 i: 23 sds il le Bc 88 :|[g3 83888 82 3 502 %% gi efi iEdll: : 4i BiE"oogfZ 2 2 I :Bi FEE ~ #3 3 g 59] tod =& al &l Company Sanitized. Doesnot containTSCA CBI ~ : Co. gg i iat : 3 EP 3 : i 2 2 g 5 & Eo Hy a gS ~~ 3 LH 4 az 3dE2 g5 | Q 1 1a: :} 32 ii i g 33 i2%| 22g3f ~ 3453 58 i BE 5s 2 LiEi so +. i Loo fit oFgE e=512z giLd Fe ge ge 3 83 2 FI ills PE iz fgaigg 28 81|i2 if8l53 Pid cif | Pil id | [8303E5y%:3&3 i isdi PHELEL : . CompanySaritzs. DootecotsainTSAG1 ~ : A gs BESNEEZERZ 28 .8 58 , @ 8 2 8@., 83 8 3 & 3@&8 gtd SRE ILEERE g g 3z algy a @8 &8 8 B 88 8 @8 @8 &8 2 3 22 35 38 5% 38 38 38 8% 22 88 cg 4x SS 33 43 33 35 58 SS Ss as a 8 . ~ i: g & ] 3 i g JH 2% 98 3% 35 3% 3% 38 38 38 33 : =e 8 3333333335 35334333 38 i Z i55 HiE ~i g$id.fs3 ii 3g 8 2 8 ii8 a 3 8 r% E % 8ad 82% 8 2 & % CompanySaitized. Does not contTSaAiGnBI ~3 3 $803 EERE REE pes 33 FEE E = | : : - gg : : : i5 82 3283 83 83 5 one 93 S38 8B 8% 33 le ss 3 Ss Ss Ss ss 3gs 55 338 38 To 1 38 gg 8 283338 i3 & 2= we 33344 332%33338 383% S253347 383% 358 33883283 2 z l 4 2 3 3 g : 3 l pb 3: :3,| P4 LL odies 5i23 EBs1ig2g B24e8% f2Eo2Es |gf8 4d4 2:8o2g% f7 d2% :2 Gr[o.gs FEE JEG 28 Id Ig 5 2 3 ~ Eg 8 & Gompany Saritized. DoesntcotainTSOA Gl ~3 3z zo: ; gg 33 33 i EE ` ngi ag 2 a& gE i ~ |i bi = 33 = 1 : i 12 828 :=:[11EI } HIER i] di o s22i3a3)] 1118:424 Z 1388 4ig i i 33) ~ gg Hi EEg NNEdRHS]: Lda i it 2 gE +. ~i BR Sc oo oo oo oo oO SO 6 86 o6 23 35 85 33 33 38 33 33 33S 48 6s = b2 e 45z 3232533 38%305%3853 502 38%5528 8% 8% . ~ it E = E0 g 5 @& & 8 & @ Bo orlpiiEiiito 1 He gf S538 8 85 33 88 dd dS dd 23 2: El 3 54 : i Ws oe os ok : 3 2g 8 8 8 % 88 8 13: fHlE4F88E5E 85E3E5E3R8E3E:E5+ 253 7 ~ 3 (Company Sanitized. Does not contain TSCA CBI ~3 =: 2a EE Ss a 8& 8@ 8a 6c so oo oo 3Ss 28 83 =s3 8s S66 se oo gg. 32 HEIE oe 5 85 i ssiasa, 5 oa2 22g 323238 %g .. 1:8 0....1.... OBS gid aisisi:oeocz : 5Eoae 324: 3535330 354: 55353 f3 zg EEi2 ag: 3] i 5 4 E & E i5% H S E IE EERI A EREIN EEE i CLEARER IRR E2E 8 || 5g Fi g 9g 124 38 8 CompanySanitized. Doesnot contain TSCA C81 gs 3 uo 58 33 5 iE go od 3 z : if ~ | Ei= 1 1H 55 : 3 iig gd 2= E giE:gfg ' 3 38 5 3 ing |: 15 1 5.8% 3 :Z | 2 EiPF ih:23 8i . 33 ii3h:: . i2 53 T28IE: 1r6y1e HERE HE 2 id 88 EF st Pole ig ~i HI CompanySento,Does atc TaERCB! ~3 :I5 ge =e hs s c. 3 z 2 2 g 38 - "3 "Fe ~~ a s & ? E i ff ~ i23 28] Por oror omnlahBE DOLL SEE fix Hi odMH h BOM HO mar Borou bong 82 & i& i i ComaSntis, oe cron ~3 g5 oy "2 v3 "3 :i. 85.8 5 ow oo oo oo - FEE z ~~] gi 5 a Oo | a Ham = 28 Batis IS ds 3$ 224: i4 3 ~ i3 : < 5. $P1 r3ob1 o% r 'b% g 3 d3g BFHoTppsf BsiodEad Posi Sif HLH GEgElocc oEH i mefqoF f FOF OE OFF CompanySatins. Does otcontain5AGt ~% i: ge ., . 2 n 23 ; 8g2 u ow of 33 : 48 --_ gE ii 5 gl = 8 iq 3 IE iE = i 2 : as cp eel GE os | I i : ig3 | ]: itd 2: 32 coa3l g|HIlTsEii : EH7 if JHLE BoH ad 5 ~ 3% Ig 2g | 11 Bi 3 FF | Ed [EP ------ ~1 353 2 ue 3 ge "% "= tz "F " "8 := 2 g2si8x2 - - wys wg$ wg% wg 22 ; ~ | 25 : fg 8 38 % 8 |1 8 2 54 52 4 ~ i2s4 3: mot : 3 1:i FdH 3888 3 gHii ad 5 - - El ss: fP r F odoF iiez ggky 83% 33 if 88i HH] TREE i i d Company Saritzed. Doesnotcontain TSCA CBI ~ fi 8 Ee ow wo a oe LB% 588 cw mz m3 :i val og ~ &= 5 5 i. il 8 2 BES J1 2 oZz am owe he omg ox onAg E$s 2od 3 s: ir i 5 3Z iE q BH v2 3 x -x -~g| .% 3% i55 5s8igi 58d3 h3b d3 a31d4 H942o] ~ ig BfBreodaPhAi3 hTRHhOIeFh Led tes 1 5| diet fF FF 7 iid CompanySaiz. Dossnot contain TSGA Gl ~3 3 2 - #2 8 gi ii z fs 22.Ego | 3i% ~ EE 7 22 giig Sgz Md &Txa =+ g 82 i: i . fis 2 | &2 2 I Fg i 1i: 58 2 3% 33 E A= R8H : 2S 3 -| 8as8 & 2 &g LE 1 iz - zis2 2 #5o11i3i2 ogii:i i $508: bode: 3) 2544) 8% gd & gf. % Igf iF;v 72 %|(13} --_E3H HiH ii:is 3i%i Company Sanizsa. Does notcontainTSCA Cal ~3 2 . .% 0" i8 it :3 o g osE = FP 2 2 sg 552% -| 3% 5:be) gE Hi 8 -- 38 29 23 = a a8t2 5: =8 is 13 58 E 2 7 Fiua HEN 5 uw. = Ifa% $S3 zSs FtEF gE 3 31J3] . 233 cf 2 5-gs383 48i%i of i fg 3 g2ih: iofd|0, a78f fPED e0gf) |B ~ Eg 28 i: if CompanySaid.DoesnotcontTSaOAiCnt 9H02.5D4a2y5G:avSaugbechSrtoundiyciToRxaitcstywithOneGeneration Reproduction Evalustions Dupone11418 TABLE 16 PERCENT SURVIVAL OF MALE RATS DAYS O0N TEST OmGgrhoguipday 100 10GmrgoukpgdIsy 100 Group V 100 mykgiday 100 Grow VI 1000 melkg/cay 100 17 110000 100 100 100 100 100 100 21 100 100 100 100 32s 110000 110000 110000 110000 2 4 100 100 100 100 100 100 100 100 56 100 100 100 100 @i) 110000 110000 110000 110000 La 100 100 100 100 8ort 101000 110000 110000 110000 9% 105 110000 101000 110000 110000 ~ 12 119 110000 110000 s00 110000 126 100 100 5 100 FNouumnbderdeaatdstudy start 40 3s 0 3s | 5 0 RSaecmriofvieceddfbryomdesstiugdny'* 2100 0 20 10 10 20 10 Alointevstdeay 126 is 5 4 1s PNerucemntboSufervairtvaal =i(sNku=mbNeurmobfeRratatssAtluidyves/taNrutm-bneurmobfeRrartsemaotRviesdfkr)o1m0s0tudy - number sacrificedbydesign Raonttsesdtesdiagyna7t2.ed for reproduction evaluation (20 ras/group) were transferred fo reproductive assessment +b RRaetcsovdeersyigpneraitoedd fboergtahneosnubtcehsrtodnaiyc 9o1x.icity evaluation were sacrificed on test day 92. : 4 Rat found dead during previous week. Ther wer no saisically significant decreases in survival st < 0.05 byCochran Ariag rend test Note: Rats designated for evaluation of 10-day hepatic biochemical evaluations are not included in this table. ios `CompanySaniized. DoesnotconTtSaCAiCBnI `H9205-4D2a5y;GavSaugbcehSrtoundiyc iTnoxRiactistywith One-Generation Reproduction Evaluations --~ TABLE 17 DuPont 11418 DAYS ON TEST 0 PERCENT SURVIVAL OF FEMALE RATS Group IT Omgkgday 100 Group IV 10mgkg/day 100 Group VI 100 mgkglday 100 Group VII 1000 mg/kg/day 100 7 1" 100 100 100 100 100 100 100 100 21 2% 100 100 100 100 100 100 100 100 35 100 100 100 100 42 49 100 100 100 100 100 100 100 100 56 100 100 100 100 63 100 100 100 100 70 La 100 100 100 100 100 100 100 100 84 100 100 100 100 91% 100 100 100 100 9 100 100 100 100 105 12 100 100 100 100 100 100 100 100 ~~ 119 100 100 100 100 126 100 100 100 100 Numbeart study start 45 35 35 45 Removed from study' 20 2 2 20 `Sacrificed by design Alionvteest day 126 10 15 10 5 10 s 10 15 Percent Survival = (NumberofRats Alive/Number of Rats at Risk)* 100 Number of rats at isk = Number at study start ~number removed from study - number sacrificed by design a Rats designated on test day 72. for reproduction evaluation (20 rats/group) were transferred for reproductive assessment b Recovery period began on test day 91. Rats designatedforthe subchronic toxicity evaluation were sacrificed on test day 93. `There were no statistically significant decreases in survival at p < 0.05 by Cochran-Armitage trend test. Note: Rats designated for evaluation of 10-day hepatic biochemical evaluations are not included in this table. ~~ Ter -- `Company Sanitized. Doesnotcontain TSCA CBI Z9F20---2DD5a4ay2y5DG;savvSaauggbecehSSrutouunddiyyciiTnnoRnRaiatctsistwywiitthhOOnnee-GGeenneerraattiioonnRReepprroodduuccttiivveeEEvvaalluuaattiioonnss DDuupPoonntt1111441188 TABLE 18 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR MALE RATS (MEAN OF THREE TRIALS) Assessment Dosage Forelimb Period Group (mg/kg/day) _ Grip Strength (kg) Hindlimb Grip Strength (kg) Baseline 1 0 m 10 v 100 vi 1000 061 (007) 062007) 0.64 (0.09) 0.56 (0.08) 0380.07) 038 (0.05) 033007) 0.37 (0.06) Week 13 1 0 m 10 v 100 vi 1000 -- Recovery 1 0 vi 1000 154033) 1.64 036) 1540.40) 149 (0.14) 164035) 140 0.40) 0.74 (0.08) 081 (0.15) 0750.17) 0.71 (0.09) 0.68 (0.14) 0.62 0.09) DStattiasiacrarlanMgeetdhaosd:s:MeaBnar(Stt?an'datresdtDfeovrihaotimoong)eneity followed by analysisofvariance and Dument's test. "There were no satisealysignificantdifferences from conrol at p<0.05. --~ EE -- `Company Sanitized. Dos not contain TSCA Cal 51025D0a2y5G:avSaugbechSrtodniyciTnoxRiacittyithOne-Geersion ReprodsciveEvaluations --_ TABLE 19 Dupont1418 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS (MEAN OF THREE TRIALS) Assessment Period Group Dosage (mg/kg/day) Forelimb Grip Strength (kg) Hindlimb Grip Strength (kg) Baseline 1s 0 wv 10 vi 100 vi 1000 0.46 (0.08) 0.47 (0.05) 0.47 (0.15) 0.49 (0.07) 0.35 (0.03) 0.34 (0.06) 0.32 (0.06) 0.34 (0.08) Week 13 on 0 1.18 (0.28) 0.65 (0.08) mv 10 vi 100 -- vim Recovery 1000 0.99 (0.21) 1.24 (0.31) 1.16 (0.31) 0.65 (0.10) 0.61 (0.09) 0.63 (0.10) on 0 0.97 (0.29) 0.63 (0.09) vi 1000 1.06 (0.37) 0.61 (0.14) DSDaautiansrinaaenlgMeesetdt.haod:s:MeaBna(rStea'ndacrsdtDfeovrihsotimoong)eneity followed by analysisofvise and There were no saisticly significant ifrencesfom cotrol a 0.0 by Dunn's st. _ --_-- Company Santzed. Doss not contain TSCA Cal 29H002--5DD4aa2yy5GG:eavvSaaugbgeeeShSrttouunddiyyciiTnnoRxRaiatctisswtwyiitthhOOnnee.GGeenneerraattiioonnRReepprroodduuccttiivveeBEvvaaulusattiioonnss DDuuPpoont 11418. TABLE20 SUMMARY OF SENSORY MOTOR FUNCTION PARAMETERS FORMALE RATS BASELINE 13. WEEK Recovery Dosage (mgfkgGiodawy:: 01m10 1V0v010V0I0 0Im10o1v00o1v00e0 0110v0i0 Numberexamined: 10 10 10 10 10 10 10 10 0 10 MAANPIPPULRATO&IOTANOSUC:CHH: ppoormeaacltion 0001000010 100 100 100 100 100 00 100 increasedreactionGumpsavayoratacks) 0 0 0 0 0 0 0 0 0 0 nAoUrDeIacTtOiRoYn STIMULUS: 0 0 0 0 0 0 00 0 0 epxoargmgaelraretaecdtrioenairoant frintchjeuson,ffliipcsks)ea) 10 100 100 100 100 010 100 010 0[3]10 nToArIeLspPoInNsCeH: 0 00 0 0 0 0 0 12 ~ enxaogrgmearlat(terdmrsetsopwoanrsdeste) 0010 10 10 10 9 10 10 9 8 Gocalizaaptidonensin,g) 0 0 0 0 1 0 0 [3 IPNUPMIOLTLOARRYARCETISVPIOTNYSMEO.NITOR: prabesseenntt 00100 100 100 100 010 100 100 0[I 10 DabEsFenEtCATION dpiraemsehneta 5s 46 64 082 460055 13 46 55 06a 0 0 0 0000 oo UabRsIeNnAtTION: present - 46 28 91s5 9L1o0on9 9 73 82 ADVDOITCIOANALLOIBWSZHEREAVNATTHIAIONNDOSLNENODTED parbesseenntt 00 000 100 00 100 100 100 100 9Io10 "There were no satisically significant differencesbyCochran Armitage tetfo trend atp < 0.05. --~ er ---- ees `Company Sanitized.DoesnotcontainTSCA C81 9F0--2D5a4y25G;avSaugbecShrtoundiyc iTnoRxaitcistwyithOne-GenerationReproductive Evaluations --_ TABLE21 Dupont-11418 SUMMARY OF SENSORY MOTOR FUNCTION PARAMETERS FOR FEMALE RATS. BASELINE 13-WEEK. Dosage (mkgiGdaoy)w: I0 I1V010V0I1V00E0 Numberexamined: 10 10 10 10 I0 I1V0 V1I001V0I00 10 10 10 10 Recovery n01v00m0 0 10 MAANPIPPULRATO&IOTANOSUC:CHH: npoorrmeaalction 0000 0000 00 0010 10 0 101010 10 0 10 increasedreacton jumps awayoratacks) 0 0 0 0 0 0 0 0 oo AUDITORY STIMULUS: npoorremaacltrieoanction (ratfinchesor flicksean) 100 100 100 100 90 100 90 100 00 9 `exaggeratedreaction (atjumps,fips) 0 0 0 0 1010 01 TAIL PINCH: pnoorrmeaslpo(nusres toward site) 00 100 100 100 100 100 100 100 0[3 9 ~ exaggeratedresponse. (vocalizrpaitdwiarominngs) ~~ 0 0 0 0 0 0 0 0 0 1 PIUNPMILOLTAORRYARCETSIPVOINTSYMEONITOR: praebsseenntt 010 10 10 1010 10 10 0 10 0 0 0 0 0 0 0 oo ab'sDeEnFtECATION pdrieasmehneta 52 0505 46 13 55 064 28 82 6446 0 0 0 0 0 0 0 0 oo abUsReInNtATION: present 28 64 82s5 9L1o0o 9o1 91 6437 - CADDIITIRONCA-LCLLOOBICSKENWRIVGSAETIONS NOTED absent present 010 10 10 000 - 101010 9 00 0 1 0 01 MaAbsSenSt - SUBCUTANELEOFTUSSID,E 010 10 10 101 10 I 0 present 0 0 o_o 0 0 0 0 0 1 ~~ "There were no statistically significant differencesbyCochran-Armitage test for trend atp < 0.5. EE Company Sanitized. Does not contain TSCA Cal ~3 fo esr sl IE o o JE 5zB: "ERES FEFg if i 2% 5 TEEE EExd RE] if gz oe i 8 2 4 538% gges gg . jg C i :z ii z 2 aii:PF ses gegs ag BFL i 83 PH < 23 -288 oe88 85 Efi 53 EE 1%: i5 g5 ~E>s ~=_=>.Fx "F_sdl3 dsRi:d ~ i83 2358 2 ifFs. d1s?s cmpgstat tromson ~3 iz CRESE ZFXE E% HE - i Log gf8f gesz gg ii | "ssf: {8% & 53 iz it HE 5| "ggg 538% Az ii ~ 3gzEasffEBll mioEe9E2d2 g28Frsasf ogfg5 1ifsg =a 33 2 28 = 2328 4ILgz SERRE ERIE FE 33 HE 5i 2Z:l E5E5 HL2 ~ i) z g T5E3E $35 iF). i%% gis : 2233 o=88 o-e88 8|f fIFE g = py werF- = o-eeE: i B2iE3 e.Bz|f Cfpil3 g8 d |:B i33i:: i2s g f3132f:f Company Santis. Goesre con5taAiGnt ~3 :i 4B5a85i8 fHpEzg i22 : 5-5 Ecos oe ii RED s8s88 MEE $888 BY 288s 38382 53 3 .0 oo 1 fF EZ :5 E8z 3 "sEgXoEg: FgseE38 agfs iItf ; ER 5 2i s2a8s "ERE3 ce5s8s2 iEEE 8a338m iH 3: E3 gi 9% eg -ezz ogIait . 3 i5S3dd5 8 83 s2s-s5 -m-p FORRES -z| 4s:i5r1: 2 g H HERE:S fEiRi $25 2 ~i FE |83 4382 CompanySatis.Does otcontTSaCAiGBnI ~1 i Five hf Be . "3s8s3s% EsEsEs 3H8 U 2828 9EEE :i f i : 52 35 2 Cems seid 2d qf a = z ~ i8 E28 8 "s5e8s8s sazz FEEE as HY i if E 2 gE * i IH crs sere s i 4 Eg ~$385 888 iE k i 3 $8 2 2 1a g z .gges sgssz zy if og i EEEE SIRE 8 1 $ i 3% qoS 83 oc eg coges g i CEH252 Hee 255 1 3% #9z) ~ i4 gg5l =2s5E5 =25F5s =3==3;i 443":5223i31 5 a 5 Es oajig2 2g8 24 3 ise_i I3i%d g:: copys, onset 91205D4a2y5:GavSaugbcehSrtoundiyc iTnoRxaitcstywithOneGeneration Reproduction Evaluations -- TABLE26 Dupont 11415 SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group Group II Group V/ Group VII [A 10 mg/kg 100mgkg 1000 mg/kg RBCDA(xY103%74L) 782 7.70 7.66 7.51 0.18010) 0.40010) 0.39(10) 021(10) DAY 92 858 853 851 822 DAY 127 031010) 0420) 856 ~ 029--~010) 083224(10) HGB (g/dL) 03910) 0300) DAY 37 158 155 153 150 03(10) 056(10) 0.6(10) 0.5(10) DAY 92 158 157 155 152 DAY 127 0.5(10) 060) 15.1 - 0.510) - 104..54(10) HCT (%) 0.710) 050) ~ DAY37 463 454 48 446 DAY 92 0.6(10) 476 24(10) 476 241.21(10) 46130(10) 2.0(10) 2509) DAY 127 486 - 1610) - 42647(10) Mev @) 24(10) 200) DAY37 592 590 585 594 13(10) 1.8010) 1.6(10) 16010) DAY 92 554 558 555 560 1410) 189) 17010) 20(10) DAY 127 568 - - 567 17010) 1769) MCHDA(Y9)37 201 201 : 200 200 : DAY92 0.5(10) 185 0.8(10) 18.4 108.37(10) 108.5810) DAY 127 0.5(10) m1 05-0) 0.6(-10) 107.48(10) 0.510) 0.60) A -------- Tree `Company Sanitized. Does not conTtSaCAiCBnI 0-2D5a42y5:GavSaugbechSrtoundiyc TinoxRiaciistywith One Generation Reproduction Evaluations --_ DuPont 11418 `TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group Group I Group V Group VII 0 mg/kg 10 mg/kg 100mgk 1000 mg/kg MCHC (g/dL) DAY 37 340 341 12 37 DAY 92 0.4(10) 33 0.810) 29 0.510) 29 30340(10) DAY 127 0.710) 311 05809) - 0.(10) - 300.8710) RDW (%) 0.2(10) 0.50) DAY 37 12 13 16+ n2 DAY 92 0.2010) 126 0.410) 128 03010) 127 10224(10) 0.5(10) 0.709) 0.510) 0.8(10) DAY 127 130 - --_ 0.9010) - 136 0.60) ARET (x10%4L) DAY 37 1774 1628 1790 169.9 DAY 92 19.8(10) 155.6 213(10) m7 22.9010) 1617 12717..17(10) DAY 127 34.2(10) 1844 29309) - 307010) - 13900.80(10) PLT (x10%4L) 26710) 3279) DAY 37 1207 1237 1189 1o1+ DAY 92 999) 1063 548) 192 116(10) 1109 13874(10) DAY 127 166(6) 3s 1743) - 127(7) - 273753) WBC (x10%4L) 1236) 13565) DAY 37 13.87 1601 15.68 16.08 DAY 92 197010) 1228 4.18(10) 13.99 336(10) 13.18 4.03(10) 13.32 DAY 127 234010) 1028 33909) - 371010) - 4.96(10) 14.16% 182010) 3.6409) -- - Company Sanitized. Doesnotcontain TSCA Cal 5H02-5D4a2y5;GavSaugbsehSrotnuiyc iTnoxRiactistwyith OnGeeneration Reproduction Evaluations --~ DuPont 11418 TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group I Omg Group II 10 mg/kg Group V 100mgkg Group VII 1000 mg/kg ANEU (x10%uL) DAY 37 143 193 201@ 208 033(10) 0.8110) 037(10) 1.09(10) DAY 92 1.66 275 203 187 035(10) 23109) 0.54(10) 0.73010) DAY 127 187 ~ - 226 ALYM (x104L) 0.62(10) 0.690) DAY 37 1.79 13.39 1279 13.28 176(10) 3.47(10) 3.07010) 3.1610) DAY 92 9.99 10.60 1041 108 191010) 2039) 33100) 4.5310) DAY 127 791 ~ --- 17510) - 121+ 3.100) AMON (x10%uL) DAY 37 027 0.28 042 029 0.05(10) 0.06(10) 0.12(10) 0.10010) DAY92 035 031 040 029 0.08(10) 0.1309) 0.19(10) 0.12(10) DAY 127 026 - - 037+ AEOS (1041) 0.09(10) 0.109) DAY 37 0.13 0.15 012 [373 0.05(10) 0.08(10) 0.03(10) 0,04(10) DAY92 012 014 0.14 013 005(10) 0.049) 005(10) 0.0710) DAY 127 012 - .- 016 003010) 0.079) ABAS (x10%4L) DAY 37 010 010 on 012 005(10) 0.04(10) 005(10) 0.06(10) DAY 92 007 007 008 005 0.04(10) 0.050) 0.0410) 0.02(10) DAY 127 008 ~ ~ 009 0.05010) 0039) ~~ eet ---- ------------p eee Company Saritized. Does not contain TSCA C81 55025D0a2y5:GavSaugbeehSrotraiyc Tin Riatcs vith One-Generstion Reroducton Evaluations Dupont 1418 TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Gr0mogulpkg Glr0omugpkIg G1r0o0umpgkVg 1G0r0o0ump eVIeI ALUC (x10%uL) DAY 37 DAY92 DAY 127 0.15 0.06(10) 0.10 0.04(10) 0.05 0.0210) 0.15 0.05(10) 0.13 0.079) - 0.22 0.20(10) 0.13 0.07(10) - 0.19 0.15(10) 0.11 0.07(10) 0.07% 0.039) Duaarangeds: MSieaanndard devision (oerof values cluded in cleo) + SSuuttisttaalllyy ssiiggnniiffiiccaanntt idiffffrrenncceeffoommcoonntrlol satpp<<00..0055 bbyyDDuumnnseteTsta.mhaneDomest. --_ -- --_-- Company Sanitized. Doosnotcontain TSCA GBI 9H025D4a2y5G:avSaugbcehSrtoundiyciTnonRiacsitywithOneGeneration Reproduction Evaluations DuPont 11418 --~ TABLE27 SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II 0 mg/kg Group IV 10 mg/kg Group VI 100mgkg Group VIII 1000 mg/kg RBC (1091) DAY 38 795 794 787 7.87 033010) 048(10) 0.29(10) 034010) DAY 93 821 8.19 8.17 7.96 023(10) 0.38010) 021010) 0.42(10) DAY 127 8.14 - 022010) - 8.12 0.36(10) HGB (g/dL) DAY 38 159 159 158 157 07(10) 0.(10) 0.4(10) 0.4010) DAY 93 158 157 158 153@ 06(10) 04010) 0.410) 0.5(10) DAY 127 153 - - 151 0.510) 0.710) ~ HCTDA(%Y) 38 45.1 454 "9 445 19(10) 2.5(10) 1.0(10) 1.3(10) DAY 93 465 46.1 46.4 444 1.6(10) 15010) 12010) 18(10) DAY 127 483 ~ -- 485 13010) 3.100) MevDA(Y@) 38 67 572 S71 566 09(10) 1.3(10) 14(10) 19(10) DAY 93 566 563 569 559 16(10) 14010) 20010) 2.2(10) DAY 127 594 - 1610) ~ 59.7 2.110) : MCH (pg) : : DAY 38 201 200 201 200 0.5(10) 0.510) 0.6(10) 0.610) DAY93 193 192 193 193 06(10) 06(10) 0.710) 0.7(10) DAY 127 187 - - 187 0.510) 0.510) -_-- CompanySanitized. Doesnot conTtSaCAiCBnI 5102-5D4a2y5G:evSaugbechSvotnuidcy TinoxRiacistyithOne Generation Reproiction Evaluations - Duponc11418 TABLE 27 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II Group IV GroupVI Group VII Omplkg 10 mek 100mgks 1000 mek MCHC (g/dL) DAY 38 354 350 352 353 0610) 0.5(10) 05(10) 0.4(10) DAY 93 341 340 340 345 DAY 127 05(10) 316 050-10) 040-10) 30153(10) ROW (%) 05(10) 03(10) DAY38 106 108 106 107 0310) 0.4(10) 0.5(10) 0.4(10) DAY93 110 13 110 110 0.4(10) 03010) 04010) 0.4010) DAY 127 17 - --- 115@ 03010) 05(10) rm AREDTA(Yx3180%L) 1346 1547 1500 1683 DAY 93 333010) 1227 15246.26(10) 3184460410) 12466.7710) DAY 127 1381029(10) 4870-10) 32.1-00) 148.571(10) 352010) 43.6010) PLTD(AxY103%84L) 183 1366 178 1254 DAY 93 101644409) 11165576) 1192049) 9197116) 1748) DAY 127 1148 510)~ 574)- 12001804) WBC (x10%L) 134(5) 820) DAY 38 1375 1220 1446 1436 DAY 93 293849(10) 22010) 947 331(10) 936 260010) 896 DAY 127 72.2926(10) 1.5-0010) 25=9~010) 826233(10) 273(10) 1.50(10) -- e--------e -- er-- er-- at Company Saniizsd. Does not contain TSCA CBI 9205.0D2a5y:GavSaugbcehSrtoundiyc TinoxRaitcstywithOne Generation Reproduction Evaluations -- Dupo 11418 `TABLE 27 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group TI 0mykg Group IV 10 mg/kg Group VI 100mgkg Group VIII 1000 mg/kg ANEU (x10%L) DAY 38 116 120 128 156 038(10) 0.55(10) 051010) 0.94(10) DAY 93 11s 161@ 126 156 0.58(10) 037010) 0.55(10) 1.0010) DAY 127 117 - 0.44010) - 133 047(10) ALYM (x10%4L) DAY 38 1189 1042 1251 12.10 1.99(10) 175(10) 280010) 205(10) DAY 93 814 721 761 696 181010) 1.55010) 209(10) 191(10) DAY 127 643 - - 650 ~ AMON (x10%4L) 234010) 137010) DAY 38 032 029 029 034 0.13(10) 0.09(10) 0.18010) 0.15(10) DAY 93 028 027 021 019 0.18(10) 0.12(10) 0.09(10) 0.13010) DAY 127 016 - 0.09(10) ~ 019 0.07(10) AEOS (x10%4L) DAY38 oll 013 012 010 DAY93 003010) 011 0,05(10) 011 0.o0u4t010) 00..0103(10) 002010) 0.05(10) 0.06(10) 0.06(10) DAY 127 0.10 - - 013 ABAS (x10Y4L) 0.03(10) : 0.08(10) DAY 38 012 012 012 on 0.03(10) 0.05(10) 0.03(10) 0.06(10) DAY 93 008 010 0.08 006 DAY 127 0.03(10) 005 0.06(10) - 0.0-4(10) 00.0054(10) 003(10) 0.0210) -- --------------------r-------------- `Company Sanitized. Does not contain TSCA CBI 0H-25D4a2y5G;avSaugbcehSrowndiyciToxRiactistywith OnGeeneration Reproducion Evalustions -- DuPont 11418 TABLE 27 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group II Omgkg Group IV 10 mg/kg Group VI 100mgkg Group VIII 1000 mg/kg ALUC (x10%4L) DAY 38 DAY 93 DAY 127 015 002010) 0.13 0.07(10) 005 00310) 014 004(10) oll 0.0410) - 016 0.09010) 009 0.04(10) ~ 01s 0.06010) 008 00510) 004 0.01(10) Dataamngedas: M`Setaanndard deviation (Number of values included incleuton) *@ SSttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt ddiifffferreenncceeffrroommccoonnttrrooll attpp << 00..0055 bbyyDDuunnnest/eTs.amhareDunne test. --~ ~~ -_-- Tm Company Sanitized. Doesnot conTtSaCAiC8n1 9H02-5D4a2y5;GavSaugbcehSrtoundiyc iTnoxRiactistywith One-Generation Reproduction Evaluations DuPont 11418 ~~ TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE RATS Group 1 0 mg/kg Group I 10 mg/kg Group V/ 100mgks Group VII 1000 mgkg PT (seconds) DAY92 DAY 127 APTT (seconds) DAY92 DAY 127 160 0.910) 160 0.909) 26 1.4(10) 207 160) 159 1.0-010) 194 140-10) 154 03(-10) 189% 201-0) 157 105.5610) 0.5010) 190 21161(10) 18010) Daa amamged as: MSteaanndard deviation (Number of values included in calculation) ~ = Statistically significant difference from control at p-< 0.05 byDunnet/TamhaneDummett test. --~ = -_-- Company Sanitized. Doesnotcontain TSCA CBI 01-25D4a2y5G;avSuabgeehvSotruidcy iTnoxRiaciistywith One-Generation Reproduction Evaluations --~ TABLE29 DuPont 11418 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS Group II Omg/kg Group IV 10 mg/kg Group VI 100mgkg Group VIII 1000 mg/kg PT (DsAecYo9nd3s) DAY 127 APTT (seconds) DAY 93 DAY 127 150 040) 149 07(10) 180 160) 175 19010) 155 0.510) 187 0810) - 155 04(10) ~ 176 20010) - 151 0.89) 153 0.610) 192 1178769) 25(10) Dutsaranged ss: MSteaanndard deviation (Numberofvalues included incalculation) ~ Therewereno satisicallysignificantdifferencesfromconattpr<o0.l5. ~~ -_-- `Company Sanitized. Doesnotcontain TSCA CB 5205-4D2a5y:GavSaubgcehSrtoundiyc TinoxRiactistywithOneGeneration Reproduction Ealusions DuPont11418 --_ TABLE 30 SUMMARY OF CLINICALCHEMISTRY VALUES FOR MALE RATS Group! 0mgkg Group TIL 10 mg/kg Group V 100mgke Group VII 1000 mg/kg AST (UL) DAY 37 7 (10) 7 6(10) 75 910) 0 6(10) DAY 92 80 11010) 2 EK) 2700) 8(10) 6 910) DAY 127 9 13010) - - 920 22(10) ALT (UL) DAY 37 2 2(10) 31 4(10) 34+ 4(10) 31 510) DAY 92 3 410) 48 30010) 38 6(10) 35 7310) DAY 127 3 - 910) ~ 450 1100) SDH (UL) a) DAY37 126 13(10) 116 20(10) ns 1200) 125 23(10) DAY 92 192 19(10) 208 106010) 163 34010) 15 4.7010) DAY 127 172 54(10) - - 186 9.410) ALKP (UL) DAY 37 156 4(10) 164 4510) 159 25(10) 150 31010) DAY 92 9% 26(10) 103 28(10) 07 1510) ut 1700) DAY 127 8 - 15010) -- 9(10) BILI (mg/dL) DAY 37 : 008 007 006 . 006 DAY 92 003(10) 0.11 00310) 0.10 0.03(10) 009 0.02(10) 007@ DAY 127 0.03(10) 0.12 0.03(10) - 0.04010) - 0.03(10) 0.10 0.04010) 003010) --_ ee TES Gompany Saritized. Does not contain TSCA C81 9H02D54a2y5:GavSaugbeehSvtoundiyiTnoxRiactistywithOne Generation Reproduction Evalustions Dupont 11418 TABLE 30 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS Group 0mg/kg Group I 10 mg/kg Group V 100mghg Group VII 1000 mg/kg BUN (mg/dL) DAY 37 1 100) 1 100) 1 1(10) 14 100) DAY 92 15 210) 15 2010) 16 2(10) 16 2(10) DAY 127 1 210) - - 1s 210) CREA (mg/dL) DAY 37 036 0.05(10) 033 0.03(10) 033 0.04(10) 031 00510) DAY 92 047 0.07(10) 045 0.07(10) 041 005010) 044 0.06(10) DAY 127 035 - ~ 0.05(10) - 034 0.0410) CHOL (mg/dL) DAY 37 64 1100) 65 18(10) 55 8(10) 53 1100) DAY 92 68 14010) 6 23(10) 52 810) 51 13(10) DAY 127 0 - 1510) ~ 60 12010) TRIG (mg/dL) DAY 37 48 37 59 45 DAY 92 22(10) 7 1200) 55+ 2110) 6 27(10) 46 DAY 127 20010) 7 23(10) 23(10) - - 19010) 6 29010) 32(10) GLUC (mg/dL) DAY 37 9 105 9% 9 DAY 92 1010) 107 710) 135 8(10) 128 7010) 127 DAY 127 2510) 3 34010) - 48(10) 4110) ~ 144 20010) 45010) --~ JE--"--"-- Be `"-"-" `Company Sanitized. Does not containTSCA GBI 1502.5D4a2y5:GavSaugbeehSrtoundeyTionxiRcaittsywithOne-GenerstionReproduction Evaluators Dupont 11418 --~ `TABLE 30 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS Group 0mg/kg Group I 10 mg/kg Group V 100mgkg Group VII 1000 meg TP (gL) DAY 37 DAY 92 DAY 127 68 03(10) 67 61 03(10) 0.4(10) 66 04(10) 74 03010) 73 03010) 72 03010) 7.0 02010) 71 ~ 03010) - 72 04010) ALBDA(gY/dL3)7 44 02(10) 43 02(10) 43 03(10) 44 02(10) DAY 92 45 02(10) 44 02010) 45 02(10) 47 0110) --_ DAY 127 45 02(10) - - a7 02(10) GLOB (g/dL) DAY 37 25 01(10) 24 0310) 24 02(10) 22 0310) DAY 92 29 02(10) 28 03010) 27 0210) 24@ 02(10) DAY 127 21 - 02(10) - 25 03010) CALC (mg/dL) DAY37 109 03(10) 11 0.5(10) 109 03(10) 11 03(10) DAY92 13 0.610) 17 0.5010) 114 0710) 110 05(10) DAY 127 ni - 0.4(10) - 14 04(10) IPHS (mg/dL) DAY 37 84 85 88 89 DAY 92 0510) 96 07(10) 0310) 99 98 0510) 104 DAY 127 09(10) 80 110-10) 150~10) 91600010) 05010) 09010) -- - BE Company Saritized. Does not contain TSCA CBI H502-5D4a2y5G:avSaugbeehSrtoundcy iTnoxRitcistywith One-Geneation Reproduction Evaluations DuPont 1418 ~~ TABLE 30 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR MALE RATS Group Omglkg. Group Il 10 mg/kg. Group V 100mgke Group VII 1000 mg/kg NA (mmol/L) DAY37 1516 32010) 1508 3200) 1512 26010) 1516 28(10) DAY92 1505 29(10) 1516 30010) 1513 35010) 1509 25(10) DAY 127 1495 2000) ~ - 1499 18010) K (mmolfL) DAY 37 062084010) 066079010) 602 026(10) 614 039010) DAY 92 647 052(10) 669 07700) 6.46 063010) 676 1.10010) DAY 127 60325200) - - 639 063010) rm CL D(AmmYo3l7) 1032.60010) 1029 20010) 1022 28010) 1035 27(10) DAY 92 1069 : 39(10) 1072 35010) 1073 2910) 1090 3.4(10) DAY 127 103168010) - ~- 1043 13010) PFLDUA(Ypg9/2mL) [30]0010) 01 00010) 01 00(10) ot 0.0(10) DAY 127 ol 0009) - - ol 0.0(10) LE Dus sranged as: MSteaanndard deviation (umber ofvalues included in calculation) + Sttaniisstteiaalllyy ssiiggnniiffiiccaanntt ddiifffereennccee ffrroomm ccoonnttrrooll satpp <<00..0055 bbyyDDuunesteTsta.bane Duet cst. --~ _ TT CompanySaritzed. DoesnotcontTSaCAiCn81 9H025D4a2y5:GavSaugbechSrtoundiy iTnoxRiacittywithOGneeeraion Reproduction Balustions DuPont11418 --~ TABLE 31 SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS Group TI Omg/kg Group IV 10 mg/kg Group VI 100mgke Group VIII 1000 mg/kg ASTD(AUYL)38 5 11010) 75 7 1010) 10010) 7 11010) DAY 93 102 64010) 101 40(10) 84 18010) 84 19(10) DAY 127 101 16(10) - - 105 31010) ALT (UL) DAY 38 3 32 28% 3 DAY 93 5010) 6 6(10) 57 410) a 610) 37 DAY 127 58(10) 58 40010) - 20(10) - 1000) 57 13(10) 35010) SDH (UL) ~ DAY38 14246(10) 139 38(10) 138 32010) 14.8 32010) DAY 93 22 13.8010) 23 121010) 198 65(10) 14.1 3.8(10) DAY 127 20 - 67(10) - 209 12.200) ALKP (UL) DAY 38 120 1 12 18 DAY 93 28(10) 58 32(10) 60 24(10) 60 637310) DAY 127 9010) 18010) 51 - 8010) 19(10) - 49 : BILI (mg/dL) 2500) t 14(10) ) DAY 38 010 0.03(10) on 001(10) 0.10 0.03(10) 010 0.04(10) DAY 93 009 00410) 0.1 0.04(10) 009 0.04(10) 0.05 0.00(10) DAY 127 0.15 - 003010) - 013 00210) -- _-- CompanySanitzed. Doesnot contTSaCAiCnBI 9H0aDsasy:GavSaugbechSvtouidcy iTnrRiactistyith OnGeeneration Reproduction Evalusions Dupont11418 --_ TABLE 31 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS Group TI GroupIV Omgkg 10 mle Group VI 100mgks Group VII 1000 me/ke BUNDA(mYg/3d8L) 7 3310) 16 2010) 16 2010) 16 2310) DAY 93 7 2310) 16 100) 7 200) 13 2010) DAY 127 16 2010) - po 18 200) CREA (mg/dL) DAY 38 047 045 045 044 DAY 93 006(10) 054 005(10) 0.49 005(10) 052 0.0410) 050 DAY 127 005010) 049 005(10) - 00310) - 004010) 0.46 006010) 005010) ~~ CHODLAY(mg3/8dL) 6 65 6 0 DAY 93 1310) 76 13010) 7 10010) 71 1410) 7 DAY 127 8100010) 1801-0) 15010-) 9310) 7% 1610) 9310) TRIDGA(Ymg/38dL) a 34 39 37 DAY 93 11010) 53 15010) 3@ 14010) a2 200) 2 12010) DAYLI | 45 11010) - 1110) - 19(10) 3 16(10) 1110) GLUC (mg/dL) DAY 38 100 100 100 100 DAY 93 5(10) 102 9310) 94 957010) 10160010) DAY 127 2161(s10) 801-0) 400-) 12104(10) 17(10) 25010) _--_--m GompanySanized. Doasnot contTSaCAiGBnI 5205D4a2y5:GaSvuabgehSioundise TinoxRitcistywih OnGeenertion Reproduction Bvalustions --_ TABLE 31 (Continued) Dupont11418 SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS GOrmogulpkIg G1r0omupeIgV 1G0ro0umpgVkIg 1G0r0o0upmVeIIkl TP (DgAaYl)38 72 74 74 76 DAY 93 0.4010) 77 03010) 78 03010) 76 02010) 75 DAY 127 05(10) 83 0.4010) - 0.4010) - 02010) 83 0510) 0.410) ALBDA(gYdL3)8 49 50 50 52 DAY 93 0300) 52 03010) 52 03010) 52 0200) 52 DAY 127 5036(10) 040-10) 050-10) 0536010) 03010) 05(10) ~~ GLODBAY(g/3d8L) 23 02010) 24 0200) 24 03010) 0234010) DAY 93 24 02010) 25 02010) 25 0200) 022300) DAY 127 26 04(10) - ~ 27 02010) CALC (mg/dL) DAY38 12 1s us 16+ DAY 93 1023(10) 03010) 11 0130110) 0.4(10) 110 . pavw 0.4010) 17 03010) - 0.4010) - 0.4(10) 17 0.4(10) 0.4010) TPHDS A(mYg/3d8L) 7063010) 07590010) 78 03010) 830 0610) DAY 93 616510) 6150010) 63 09010) 70 1.0010) DAY 127 62 - 09010) - 74 19010) --_ er -- ee -- ee -- `Company Sanitized. Doesnotcontain TSCA CBI 3502.5D4a2y5GavSaugbeehSroeriyc iTnoxRiacistywith Ono-Generaton Reproduction Evaltons Dupon11418 -- TABLE 31 (Continued) SUMMARY OF CLINICAL CHEMISTRY VALUES FOR FEMALE RATS G0rmougpsII G1r0omuppkIgV 1Gr0o0umpgVkIe 1G0r0o0upmVeIIgI NAD(mAmYol3f8L) 1457 1472 1468 1464 DAY 93 20010) 1449 2.4(10) 1456 14157810) 1441.45010) DAY 127 1.2010) 1519 1500) ~ 201-0) 15125210) 14010) 2000) K (mDmAolY/L3)8 575 604 589 597 DAY93 036(10) 530 039010) 554 052635010) 053745(10) DAY 127 0.48010) 574 052010) - 038-010) 053975010) 049010) 039(10) ~~ CL D(mAmYol/3L8) 1010.6710) 1011.88010) 101133010) 10118410) DAY 93 9815610) 991.9700) 9919700) 101090510) DAY 127 105266010) ~ - 101699010) PFLDUA(Yug9/3ml) 01 01 01 01 DAY 127 00106) 000-10) 000-10) 001000) 00(10) 0.100) Duasmanged ss SMteaanndard deviation (Number of values included in caleuaion) + SStutiissttcaally ssiiggnniiffiiccaanntt idiffrfeernenccee ffroomm ccoonntrtool astpp<< 00..0055 bbyy DDuumnTsaestm. barDuene- 5 --_ e oe eee------T=------en-- erge yp--sr Gompany Saniized. Dogsnot contain TSOA Cll 9H02-5D4a2y5G:avSaugbechSrtoundiyc iTnoxRiactistyvith One-Generion Reproduction Evaluations DuPont.11418 TABLE32 SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group! 0mghkg GroupI 10 mg/kg. Group V 100mgkg Group VII 1000 mg/kg VOL (mL) DAY 37 86 16 95 102 DAY 92 4.1(10) 87 12.110) 85 35010) 61 57(10) 90 DAY 127 62(10) 48 5.1010) - 25010) - 38010) 89% 1700) 350) UOSM (mOsm) DAY 37 1043 896 1014 12719 316(10) 4250) 353(10) 537(10) DAY 92 1194 383(10) 1070 34210) 153 655(10) 1155 407(10) DAY 127 2092 ~ ~ 12280 669(10) 46409) pH ~ DAY 37 0360810) 063709) 69 02010) 69 03010) DAY 92 61 05(10) 66 03010) 68 04(10) 66 03010) DAY 127 64 - 0.5(10) ~ 67 060) URO (EU/L) DAY 37 02 02 02 02 DAY92 010) 009) 02 02 0.010) 0.0(10) 04 03 0.010) 0.0(10) 04(10) 03(10) DAY 127 0s 0.4010) - - 03 0309) UFLU (ig) DAY 92 95 92 17.5% 53.4% 39010) 26(10) 35010) 9.0(10) DAY 127 77 ~ 16010) ~ 108* 150) ---- I-- Company Sanitized. Does not contain TSCA Cal 9205.4D2ay5:GavSaugbcehSrtoundiyc TinoxRiactistywith OneGeneration Reproduction Evaluations --_ TABLE 32 (Continued) DuPont 1418 SUMMARY OF URINALYSIS VALUES FOR MALE RATS GroupI 0 mg/kg GroupII 10 me/kg. Group V 100mg/kg Group VII 1000 mg/kg UMTP (mg/dL) DAY 37 76 ke 58 51 DAY 92 34(10) 4909) 11 75 421010) 361510) DAY 127 50(10) 143 40010) - 55010-) 74150010) 36(10) 599) Dua amnged ss: SMteanadnarddevition (Number of values included in calulation) @+ SSuutiissiiccaallllyy ssiiggnniiffiiccaan:: ddiiffffeerreenncceeffrroommccoonnttrrooll aatt pp<< 00..0055 bbyyDDuunnnsettTesat.baneDunnet test. -- ~~ _-- `Company Sanitized. Does not contain TSCA CBI 025-4D2a5y:GavSaugbeehSrtoundiyc iTnoRxaitkywith OneGeneration Reproduction Evaluations DuPont 11418 ~~ TABLE 33 SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS Group Il 0mgkg Group IV 10 mg/kg Group VI 100mg/kg Group VIII 1000 mg/kg VOL (mL) DAY 38 104 71 75 71 DAY 93 66(10) 6.1 3.6010) 41 3200) 45 8.1(10) 58 DAY 127 56(10) 86 25010) - 35010) - 4709) 34@ 47010) 19(10) UOSM (mOsm) DAY 38 839 952 868 1219 DAY 93 486(10) 1120 497(10) 1339 340(10) 132% 659(10) 1744 DAY 127 538(10) 1035 549(10) - 55210) 13419) - 1388 342010) 4436) ~~ pH DAY 38 73 71 69 70 DAY 93 07(10) 60 0.4010) 61 04010) 59 02010) 60 DAY 127 05(10) 62 0.6(10) - 04(10) - 030) s7@ 0310) 0.510) URO (EU/L) DAY 38 02 02 02 02 DAY 93 0.0(10) 03 0.0010) 03 0.0010) 02 00(10) 02 DAY 127 03010) 02 03010) - 0.010) ~ 000) 05@ 0.010) 04(10) UFLU (9) DAY 93 65 55 98 : 286" DAY 127 33(10) 189) 63 - 328) - 9.107) 48 25(10) 120) --_ _-- = Company Sanitized. Does not contain TSCA Cal 9205.4D2ay5:GavSaubgeehSrtoundiyc TinoxRitcistywith One GenerationReproduction Evaluations -- `TABLE 33 (Continued) DuPont 11418 SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS Group Il Omgkg Group IV 10 mg/kg. Group VI 100mgkg Group VIII 1000 mg/kg UMIP (mg/dL) DAY 38 2 28 19 32 DAY 93 13(10) 21010) 32 38 7(10) 32 4149(10) DAY 127 21010) 19 2310) ~ 22(10) - 4335%0) 910) 19(10) Dutaamngedss: MSteaanndard deviation (Numberofvalues included in calculation) +@ SSaattiissiiccaallllyy ssiiggnniiffiiccaanntt ddiiffffeerreennccee rroommccoonnttrooll aatt pp<< 00..0055 bbyyDDuannn'es eTstabaneDunnet test. -- --~ i `Company Sanitized. Doesnotcontain TSCA CBI ~3 Z a 3 S| g 188 zo. 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