Document 71YGbbBkv9Br4JK1nboegrGj

R226 _ 327 401 AR2A6 - 3219 Duron 5990 TRADE SECRET Study Title H-24768: Subchronic Toxicity 90-Day Gavage Study in Rats `with One-Generation Reproduction Evaluations Volume 1 of 5 LaboratoryProjectID: DuPont-5990 "TesT GUIDELINES: U.S. EPA Health Effects Test Guidelines 'OPPTS 870.3100 (1998) --_ AUTHOR: Susan A. MacKenzie, V.M.D., Ph.D, D.ABT. STUDY COMPLETED ON: January 18, 2002 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 -- ew CompanySaiizad. Does not contain TSOACBI 1902-4D7a6y8:GaSvuabgcehrSotnuidcyTioxiRcaittsywithOe.Generation Reproduction Evaluations Dupon:5990 -- `GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT "This study was conducted in compliance with U.S. EPA TSCA (40 CFR part 792) Good Laboratory Practice Standards except for the item documented below. Noneofthe items listed impact the validityofthe study. 1. Test substance characterization and stability analyses were performed at Regional Analytical Services (RAS), a non-GLP laboratory. The test substance analyses performed were in compliance with regulatory guidelines. Noneofthe aforementioned analyses were performed under Good Laboratory Practice Standards; however, the analyses were conducted in compliance with ISO9002 regulations. Allofthe analyses are considered valid and sufficient for the purposesofthis study. 2. The original necropsy sheets for 23 rats from the reproductive toxicology subset could not be located. Necropsy sheets for these rats were reprinted from the study electronic database. All information that is normally hand-entered that could be recalled or is documented elsewhere `was added to these reprinted sheets. The namesofthe prosector and recorder for each specific rat could not be reconstructed. ~ Applicant/Sponsor: EL. du Pont de Nemours and Company `Wilmington, Delaware 19898 USA. StudyDirector: S_uSsaenuaAstMnacAKe"nziMe,aLcAIKD,ePRnB. gDAB. SeniorResearch Scientist R-THDNis.s 9002. Applicant/ Sponsor: TDTubontRepresemative Dac -- = -_-- Company Sanitzed. Doss not contain TSCA CBI H02-4D7a6y8;GavSaugbechSrtoundiyciTnoRxaitcistywithOne Generation Reproduction Evaluations QUALITY ASSURANCE STATEMENT Dupont-59%0 Haskell Sample Number(s): 24768 DatesofInspections: Protocol: March 1, 2001 `Conduct: March 15, 2001; May 10, 2001; June 1, 14, 29, 2001; July 11, 2001; August 8, 2001; September 14, 2001 Records, Reports: Sept21e,24m,2b5,e200r1; NOcotvoebmebre3r-51,-28,-162:,9,141-11-51,2,127-01091,;2D2e-c26e,mb2e9-r311,0,20101,1;13, 14, 18, 2001 --_ Dates Findings Reported to: Study Director: DOectcoebmebre1r5,142,2,183,0,20200101; November 5, 9, 2001; Management: ODcetcoebmebre2r2,143,0,2020010;1;JaNnouvareymb11e,r2S0,092, 20, 2001; Reported by: CcJoseph C. Hamill Sr. Quality Assurance Auditor 1b &-Jgm e-200% --~ em `Company Sanitized. Does notcontain TSCA CBI 1.24768: Subehroic Toxicity 30Dey GavagsStudyinRetowith Ono Cenorstion Reproduction Bralvations| DuPont3950 CERTIFICATION f`Wreo,mtthheisunsdteudrys.igned, declare that this report provides an accurate evaluationofdata obtained Aatytcale Asse ent SoiNeaxobrbusvton:t i te"(A*m2iDiac5cCtreem5nitte tTeiorSe)AcVtaRlFesl,iPeLDSriDeiAsBt . T Jp 20e 02, 17 fDuee n BuauationsBRieocphaeimidcbatl oeTRoCenso0rJChSolmnirntMs.S 1:3aBn-a 2003 EvaluaCtliionniscReaploPratbeodlbogyy. 7 2725, 9 T-an-200 NDoiyoBomEiveetAsCDVV.M. Duis Princip ReseachSees _ Buoat[ ions Re-- portsby: Be PD 3-ToBne-2000 eaeSeni Pulogiel Blusions Reporedby: SByiplan-- e ACV, L18f Ven2200002:. PrineReesSlenit rPeubvloigclRBeupnoiosn:s Yossie OF 11 faa 2207 SDeitDoislAoinnmiteosnASiCcYVPuAEe.lPoogy = opr Dfreeis.mGe(inenl TDoJDraiAesB toedbySoy Dior,SSuunngkorVaSQcetKoemniRaeecseHarochmSeaVMD,FlelLDe BAB, 7- Tuane 2002. 18-7uAue:2003. eereese ------ -------------- Company Santized. Doss ot contain TSOA Gel 9H-02.4D7a6y8;GaSvuabgcehrSotnuidcy TinoxRiactistwyith One-Generation Reproduction Evaluations ~ TABLE OF CONTENTS GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT... DuPont5990 Page CERTIFICATION... covcomssmsmmsmssmmmmmmpretassmsssmsssisismmnndy JIST OE TABLES crussssmsssvmommmmsmmssssssompriamsssssmssssns HISTORBIOURES spss 11 UIST OFALPENDICES conmmmmmmssmmmmmmprnssssguommnmasssssssumesseeon1s8 STUDY BIEORMATION mmm STUDY PERSONNEL commons 8 SUMMARY comission lly ITRODUCTION...covcomsmmsmammsmsissmmmmmonsmssssssnons 3 OBIOTIVE ummm MATEARNDIMAETLHSODS... 20 ET ------------ ED.. AQnimUalAHUTSaDnAdANPArLneYte.tsvtPeiEerIvOnsdsesine.s.rcs..n.evmvsonnsrsvromnesnmesssmsmnsosnmssmossonesennsroernor2o2n1. F. G. ASOUSAYSDIESIGGN1A0 vGMroErupNs vasndisSeOsUArYseSsIsAss.svssvmrneenneemmesrmesmmosnsosmmssmssosossennemrsmensn2s324 J I Test Substance AAMiniStration nd SAMPHNG ..........orenorenercrrres 25 L. M. DFeotoadilCeodnCsluimnipctailoOnDSaCnrdvFatOioOnsEaAndFMIOIMEANICtYY...................umwsrcmmmsmrsneosrnrrnro22s71 N. O. NOCpUtThOaHlOOXIIOCHgYiCEaVlAEIVGAHIOENHSONr S e ss rrno 28 28 P. Q. CCloilnlieccatlioPnAoHfOBIlOoRoYd, oUrione,oFercsess, aensd sTissssuse sessssmssmssmsssmsnms 29 R. (Three-Month Recoveryand BiOCHEMical MEQSUICIENNS Fy Genev ration) ......m c.eurnsunnssonsnssn3ne131 S. Anatomic Pathol~oRagtys Designated for 90-Day Exposure T. RAOPIROEGCUOCVHEVLEYAESVSIEUSRSHIOENNNS c rrrrn 32. 33 UV.. SAHnAatSoHmCicAaAlDPBIaYtShEoSl.oc g-y Rr ats Doesigsnats ed foer Res productive EValuations...........3 ....9 . 36 TT Company Sanitized. Doesnotcontain TSCA CBI 92407D6a8y;GaSvuabgcehrSotnudiyciTnoxRiacistywith One Generation Reproduction Evaluations DuPon5990 ~ RECAONDRSADMPSLE STORAGE... 41 RESANDUDISLCUST SIONS ... 42 ANAA.LYTTSIUCSAULBSEAVNCAELUSAATDILOYNS ..cr .cccccersnsmr nnssnsssosssr ninsnsnnnnns 433. B.. C. CUnHiIfOoMrAmIiOtGyoEfAPMhiYxic ng, Conce entratior n Verifics ation and Stability Samples.............4...3.43 D. BE. ACDoAnIcYeHnItCraaltCioOnNVeCriIfiUcaStIioOn NSaSmp.l.es.cDUrrirnog rthne rSsWsAeYs.m.t..m.susrveromsrionoesmesenroerrner44e55 SUBCHRONIC TOXICITY EVALUATIONS. 46 IN-LIFE TOXICOLOGY Ar DOSAGE DE r enes mies s 4466 B. C. FM0e0adnCBOoNdSyUMWPeHiigOhNtsaadndFBOoOdyEIWFeIiIgEhNtCYG.a.i.n.s........c.v.rcm.rro.rvomrvresnorrmerroemnsrenrovmrsemrseinneionrnor 4468 DE.. OCPlihnKicaallOOIbSOEZrYVatEiVoAnIsAanOdNSMOMlty .....v.r.r.e.o.r.s.mosocrsvseennrsmmrseeesrrmrvsemmsreerrroernerrenoseeoenn 00 F. 10-Life TOXICOOgY COMCIUSIONS...rrenrrvcremenersmrenineereer rrr SO NEUAR. OSBenESHOAryVFIUOICRHAOLN TEOVAXIIBCOONLSOG..Y.vv vrve esrvr srenm ssrsiinss osmss msneenss: osonr SS|| Bu C.. NMOeOTuArCHoVIbtYeT-OXhvirGacitryvvCniOsNooCsIrsUSsaIsOelNsSn.s.n.s.svmvnrveennsrsrseonnesnsesonmssemmsseeossooesnornoonss 22 i. CLIAN.ICHAELMBPOAITOHEOYL/OCGOYBGUIIc ON. renr e sonsmn ssmsenseses: enero 5$33 I D.. Clinical PatholOgy CONCIUSIONS .vv.vevrrvenemsmimsmsensrsmsenrenrsosoen63 BIOAC.HBEiMOCIHCCAMILCaMlEMASCUARSEUMIECNITCSN.I.S. cess rssenrssnemssnsosonsossose66r B. Biochemical MCaSurements CONCIUSIONS.........ovrurovrrenemrovsmsonsossnsnr 64 ANAArTOCMIRCAUOLF DPSEAATEDHOc LOGY SUBCHROc NIC TOXICITYn AND RECOVEa RY... 6365 CB.. GOFFOASSNOWBeSiCgIhVtAHDONhS.w.v.ccsrsrmsesneenmemnssmsonmesmmssssmssmosneennssoossooesenrreeeseeroeerennosr6665 ED.. AMnIaCtroOSmGiOcPaIlCPFatIhoIlGogNyGCoSnclusivornssvfroreSeunbeehsrionniscmTsonxisceistyeEnveanlruoatsinoene.s.o..r..e..r.....r..o.n.6760 REPRODUCTIVE TOXICOLOGY EVALUATIONS orcs TL REPRAvODPyUCGTEIEVTREOFNU.N.C.T.I.OcNrrwncrcsorsvrsnrensssmssnssnmesesesmssisennitnmssmsssensesniesoncsrceonssTTLL a D. Reproductive FUICHON CONCIUSIONS ...rrorenrnrorrimrerorerorereororoee 7 ~~ ANATOMICAL PATHOLOGY REPRODUCTIVE TOXICOLOGY EVALUATIONS .........75 mmmemememmmemtee Company Sanitized. Does notcontTSaCAiCnBI 9204-7D6ay8G;aSvuabgcehrSonticiuTonxdRiacyistwyithOne-Generation Reproduction Evaluations DuPont:5990 B. OrganWeight Dat... 19 C. GOSS OBSEIVAHIONS w.ce.covraessesssssesrmsssmenmssmmensmsmsmsmmsensnson 15 D. Microscopic Observations Parental Py AUIS .....c...o.ooeovveemsromsmsnns 15 E. Anatomical PathologyConclusions for Reproductive TOXiCity......... 76 CONCLUSIONS osm TABLES (TH5 1) summons81 HOUT. sossmmmmimsmmmnmmmmmmmmmpmmsmmmsun 357 TABLES (Tables 45-77) cmos 338 FICURES cms 2 APPENDICES (APPENUICES AF)... 440 YOUNES sss APPENDICES (APPENDICES GN)... O10 613 APPENDICES (APPENDICES N-LL) ccs 919 APPENDICES (APPENDICES MM-QQ)..vsssssrisssns: 1198 --_ -_-- Company Saniized.DoesnotconTtSaCAiCanl 9H.02D4s76y6:GaSvuabgcehrSotnuidcyTionrRiactistywith OneGeneration Reproduction Evaluations --~ LI OFTSABLTES Dupont 5990 Page TABLE | SUMMARY OF DOSING SOLUTIONANALYSES... sr $5 TABLE 2MEANDAILYDOSE VOLUMES FORMALERATS. Srmsiasmm--__ `TABLE 3MEANDAILYDOSE VOLUMES FORFEMALERATS... 81 `TABLE 4 MEANBODY WEIGHTS OFMALERATS rss 88 `TABLE S MEANBODYWEIGHTSOF FEMALE RATS.. 91 TABLE 6 MEANBODYWEIGHTGAINS OFMALERATS... 4 TABLE 7MEAN BODYWEIGHTGAINSOF FEMALE RATS... sim--1 TABLE 8 MEANDAILY FOODCONSUMPTION BYMALERATS... 100 `TABLE 9 MEANDAILYFOODCONSUMPTION BY FEMALE RATS... 102 `TABLE 10 MEANDAILY FOODEFFICIENCY OFMALE RATS.. 104 TABLE 11MEANDAILYFOODEFFICIENCY OFFEMALE RATS... 106 TABLE 12 SUMMARY OF CLINICAL OBSERVATIONSFORMALERATS... 108 TABLE 13 SUMMARY OF CLINICALOBSERVFAORTFEIMAOLENRATSS... 14 TABLE14 SUMMARY OF OPHTHALOBMSEROVALTIOONSFGORIMACLEAL RATS... 118 ~ `TABLE 15 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS... 119 `TABLE 16 PERCENTSURVIVAL OFMALERATS ......... A `TABLE 17 PERCENTSURVIVAL OF FEMALE RATS.. pte TABLE 18 MEAN FORELIMBAND HINDLIMB GRIP STRENGTH FOR MALE RATS TABLE 19 MEANFORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS `TABLE 20 SFUOMRMMAARLYEROFAFUTNCTSIO.NAL.OB.SERVATIOtNArL BaATsTEo RY FINDs INGS ---- TABLE 21 SFOURMMFAEMRAYLOEFRAFTUSN..C.T.I..O.N.A..L.OBSERVATIONAeL BsATTsERYmFIN--DIN--GS --------12 TABLE22 MMOETAONRDUACRTAITVIIOTNYASOSFMESSOMENVT:EFMOREMANLETRATSS... 127 TABLE 23MMEOATONRDAUCRTAITVIIOTNY AOSFSMEOSVSMEEMNETN:TS FOR FEMALERATS. cronssmmmnelZS TABLE 24 MMOETAONRNUACMTBIEVIRTYOFASMSESOSMVENTE: FMORMEALNE TS RATS. 129 TABLE 25 MMOETAONRNUACMTBIVEIRTYOFAMSOSEVSESMMEENNTT:S FOR FEMALERATS... 130 `TABLE 26 SUMMARY OF HEMATOLOGY VALUESFORMALERATS... 131 --_ TABLE27 SUMMARY OFHEMATOLOGY VALUESFORFEMALERATS... 137 --_--_--m sr - `CompanySaniized. DoesnotcontTSaCAiCnI H-24768: Subehronic Toxicity 0-Day Gavage Study in Rats withOne Generation Reproduction Evalustions DuPont-5990 ~ `TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE RATS cre 143 `TABLE 29 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS cv 144 `TABLE 30 SUMMARY OF SERUMAND PLASMA CHEMISTRY VALUESFORMALERATS.............. 145 TABLE 31 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALERATS..........150 `TABLE 32 SUMMARY OF URINALYSIS VALUESFORMALERATS... 155 `TABLE 33 SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS wc 157 `TABLE 34 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE RATS...............159 `TABLE 35 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN FEMALE RATS...........160 `TABLE 36 MEAN FINALBODY AND ORGAN WEIGHTS FOR MALE. 161 `TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS... 169 `TABLE 38 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS ....... A `TABLE 39 INCIDENCES OF GROSS OBSERVAITNIFEOMNALSE RATS ccc 189 `TABLE 40 INNECOIPDLEANSCTEISCOAFNMDICNROONS-CNOEPOIPCLAOSBTSIECRVLEASTIIOONNSS .IN.MA.L.EcRAeTSr.ervnrnns 200. `TABLE 1 INNECOIPDLEANSCTEISCOAFNMDICNROONS-CNOEPOIPCLAOSBTSIECRVLAETSIIOONNS1S.I.N.FEMALE RATS - 217 `TABLE 42 INNOCNI-DNEENOCPELSAOSFTILCESLIEOSNIGORNASD.E.S.OF MICROSCOPIC OBSERVsATmIONmS ImN M--AL--E R--AT--S - --_ `TABLE 43 INNOCNI-DNEENOCPELSAOSFTILECSLIESOINONGS.R.A. DES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS nisms 261 `TABLE 44 MAIFCFREOCSTCEODP-INCEOOBPSLEARSVTAICTIAONNDSNIONNM-ANELOEPLRAASTTSICL.I.S.TI.N.G Io NDIVs IDUAc L ANIMALS 284 `TABLE 45 MAIFCFREOCSTCEODP-INCEOOBPSLEASRTVIACTIAONNDSNINOFNE-MNAELOEPRLAATSSTLIISCT.IN.G.I.N.D.IVvIsDsUAL ANIMALS sn 338 `TABLE 46 MICROSCOPIC LISTING OF CAUSE OF DEATH IN MALE RATS ccc 391 `TABLE 47 MAINCDRO1S-CMOOPNITCHLAISNTDIN3G-OMFONCTAHUSREECOOFVDEERAYTAHNIINMFAEMLASL.E.R.ATS FOR 90-DAY EXPOSUR3E9.2. `TABLE 48 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF P, MALE RATS..............393 `TABLE 49 MDEUARNINBGOGDEYSWTEAITGIHOTNS AND Mc EAN BODYr WEIGHT GAIm NS OF P, FEMALE RATS 398 `TABLE 50 MDEUARNINBGOLDAYCTWATEIIOGN.H.T.S AND MEAN BODY WEIGHT GAINS OF P, FEMALE RATS 395 `TABLE 51 MDEUARNINDGAIGLEYSTFAOTOIDONCONv SUMPTIONe AND MEAN Fc OOD EFFICIe ENCY OF P, Fs EMALE RATS396. `TABLE 52 SUMMARY OF CLINICAL OBSERVATIONS IN By RATS cco 397 `TABLE 53 MEAN ESTROUS CYCLE PARAMETERS AND PRECOITAL INTERVAL. `TABLE 54 SUMMARY OF SPERM PARAMETERS IN P, MALE RATS... -- `TABLE 55 SUMMARY OF REPRODUCTIVE INDICES: Py GENERATION... AO --_ `TABLE 56 MEAN PUP NUMBERS AND SURVIVAL: F, GENERATION. cvs 402 _-- rE `Company Sanitized. Doesnotcontain TSCA CBI F-24768: Subchronic Toxicity 20-DayGavageStudyinRatswithOneGeneration Reproduction Evaluations DuPont5990. ~~ `TABLE 57 MEAN PUP WEIGHTS: Fy GENERATION vcs A03 TABLE 58 SUMMARY OF PUP CLINICAL OBSERVATIONS: Fy GENERATION... 404 `TABLE 59 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF F, MALE RATS.............405 `TABLE 60 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINSOFF, FEMALE RATS...........406 `TABLE 61 MEAN DAILY FOOD CONSUMPTION AND MEAN FOOD EFFICIENCY OF F, MALE RATS...407 `TABLE 62 MOEFAFyNFDEAMIALLYEFROOADTCSONScUvMPsTION AND MEAN FOOD EFFICIENCY 08 `TABLE 63 SUMMARY OF CLINICAL OBSERVATIONS IN Fy RATS... 409 `TABLE 64 SUMMARY OF DEVELOPMENTAL LANDMARKS IN Fy RATS ccs 410 `TABLE 65 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS - F; ADULTS. .............411 `TABLE 66 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - Fy ADULTS............414 TABLE 67 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS -- Py ADULTS... 17 `TABLE 68 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS Py ADULTS... 18 `TABLE 69 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - Fy PUPS v.19 `TABLE 70 INCIDENCES OF GROSS OBSERVAITNIFEOMNALSE RAT-S Fy PUPS... 420 TABLE 71 INCIDENCES OF GROSS OBSERVATIONS IN RATS -F, UNSEXABLE PUPS............ocon 2] `TABLE 72 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS ~ Fy WEANLINGS...........0.. 422 `TABLE 73 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS -- Fy WEANLINGS..............423 --~ `TABLE 74 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS ~ Fy ADULTS cv. 428 `TABLE 75 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS -- Fy ADULTS... 425 `TABLE 76 IMNACLIDEERNECPERSOADNUDCTLIEOSINROANTGSRA-DPE;SADOUFLTMSI..C.R.O..S.C.O.P.IC OBSERVATIi ONSm IN ------ `TABLE 77 IFNECMIADLENECREESPARNODDULCETSIIOONNGRRAATDSE-SPyOAFDMUILCTRSOSCc OPIC OBSEc RVATIONS m IN AZ] _-- Company Sanitized. Does not contain TSCA Cal 0H--2D4a76y8;GavSaubgeekSronticiuTnodRxiaycsitwyithOneGeneration Reproduction Evaluations DuPont5990 LIST OF FIGURES FIGURE | MEAN BODY WEIOGFMAHLETS RATS... com FIGURE 2 MEAN BODY WEIGHTS OF FEMALE RATS... FIGURE 3 MEAN FORELIMB GRIP STRENGTH FOR MALE RATS... FIGURE 4 MEAN FORELIMB GRIP STRENGTH FOR FEMALE RATS... FIGURESMEAN HINDLIMB GRIP STRENGTHFORMALE RATS... FIGURE 6 MEAN HINDLIMB GRIP STRENGTH FOR FEMALE RATS... FIGURE 7 MMOETAONRTOACTTAILVDITUYRAATSSIEOSNSOMFENMTO:VEMENT FOR MALE RATS ........ FIGURE 8 MMOETAONRTAOCTTAILVIDTUYRAATSSIEOSNSOMFENMTO:VEMENT FOR FEMALE RATS. FIGURE 9 MMOETAONTROATCATILVNIUTMYBAESRSESOSFMMEONVT:EMENTS FOR MALE RATS... FIGURE 10MMEOATNOTROATCATLIVNIUTMYBAESRSEOSFSMMEONVTE:MENTS FOR FEMALE RATS. Page 30 431 2 433 834 435 436) A 38 439 --~ --~ --_--_-- `Company Sanitized. Does not contain TSCA CBI F9-02-4D7a6y8:GavSaugbcehSrtoundiyc TinoxRiactistywithOne-GenerationReproduction Evaluations --_ LIST OF APPENDICES DuPont-5990 Page APPENDIX A ANALYTICAL DATA w.cccssssssssososssssssmneesmsneseon dd] APPENDIX B INDIVIDUAL DOSE VOLUMES... 49 APPENDIX C INDIVIDUAL BODY WEIGHTS css S15. APPENDIX D INDIVIDUAL FOOD CONSUMPTION... $42 APPENDIX E AINNDDIVMIODRUTAALLCILTIYNIDCAATLAANc D OPHTHALMOLOGs ICAL OBSERVATIs ONS S60 APPFOE PHTN HALMDOLOIGICXAL EXAMINATION REPORT... 610 APPENDIX G INDIVIDUAL FORELIMB AND HINDLIMB GRIP STRENGTH ASSESSMENTS. ...........613 APPENDIX H INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY ASSESSMENTS................624 APPENDIX I INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENT............634 APPENDIJX INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS.............645 APPENDIX K INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA... cirsmmmmmnSh APPENDIX L INDIVIDUAL BIOCHEMICAL MEASUREMENTS... rommmmmnodi9 APPENDIX M INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS... conmmimmmsnlSO ~~ APPENDIX N INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS... 825 APPENDIX O REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS OF Py MALE RATS.....1000 APPENDIX PORFEPPR,OMDALUECRTAITVS.E.T..O.X.I..C.O.LOGY INDIVsIDUeALmBODY WEIrGHTeGAInNS nin B00 APPENDIX Q RDUERPIRNOGDUGCETSITVAETTIOOXNIC.O.LOcGnYsIsNDsIsVIcDvUAsLnBmOsDYmeWEmInGsHTeSsOsFeP,sFsEnMAnLsEnReATS. 012 APPENDIX R RREAPTRSODDUURCITNIGVGEETSOTXAITCIOOLNOGY INcDsIsVIDUAL BODY WEIGHT GAINS OF P, FEMALE 1018 APPENDIX RDEUPRRIONDGULCATCITVATEITOON.X.I.C.OLOGY INr DIVIe DUALnBODt Y WE-- IGHTS O-- F P; FEM-- ALE RATS 0 APPENDIX T RREAPTRSODDUURCITNIGVELATCOTXATIICOONL.O.G.Y INDIVIDUAL BODYEWEIRGHT GAINS OF P, F--EMALE APPENDIX U RBEYPPR,OFDEUMCATLIEVERATTOSXDIUCROILNOGGYGEISNTDAITVIIODNU.AL DAILcY rFOeOD CONSrUMsPTmIONmn035 APPENDIX V RINEPP,RMOADULCETRIAVTES.TOXICOLrOGYmINDIVIDUAL CLINrICAeL OBeSEmRVAmTIOiNS------OA APPENDIX WIRNEPP;RFOEDMUACLTEIVREATTSOXDIUCROINLGOGGYESITNADTIIVOINDU.A.L.CLINICAL OBSERVATIOcNoS mm lOEL APPENDIX X IRNEPP,RFOEDMUACLTEIVREATTSOXDIUCROILNOGGLYAICNTDAITVIIODNU.A.L.CLs INICALs OBSERs VATIONS 1059 -- APPENDIX YIANNDDIVCIODHUAABLITAANTIIMOANLIENSPTyRFOEUMSACLYECRLAETSP..A.RAMETERS DURING PREMATING 067 _-- Ths `Company Sanitized. Does not contain TSCA CBI 9H0--2D47a6y8G:avSaugbechSrtoundiyciTnoRxaitcistwyithOne Generation Reproduction Evaluations DuPont-5990 ~~ APPENDIX Z IANNDDIVCIODHUAABLIATANTIIMOANLIENSPT;RFOEUMSACLYECRLAETSSTAGEcS DrURIeNGePREMATINGsmn d07 APPENDIX AAINRPE;PMRAOLDEUCRTAITVSE TOr XICOLOv GY INDs IVIDUAL ANIMAL SPERM MOTM ILITCY DAATA. APPENDIX BB INDIVIDUAL ANIMAL SPERM MORPHOLOGY DATA IN Py MALE RATS... 1081 APPENDIX CC INDIVIDUAL ANIMAL SPERM AND SPERMATID COUNTS IN P, MALE RATS .........1084 APPENDIX DD`GREESPTRAOTIDOUNCLTEINVGETTHO:XIPyCGOELNOERGAYTIIONND..I.VIDUAL MATING DATAAND 1087 APPENDIX EEIRMEPPLRAONDTUACTTIIOVNEEFTFOICXIIENCCOYL..O.G..Y..I.N.D.IVIDUALtImMPsLaA--NTATION SITE DAiTAnANnD.s 1093 APPENDIX FF REPRODUCTIVE TOXICOLOGY INDIVIDUAL PUP SURVIVAL: F, GENERATION....1099 APPENDIX GG REPRODUCTIVE TOXICOLOGY INDIVIDUAL PUP WEIGHTS: Fy GENERATION...... 125 APPENDIX HHFYRGEEPNREORDAUTCITOINVE TO.XcICcOvLOvGsYsINsDsIVsIDnUnALsLeITsTsERsCnLInNICAL OBA SERVATIONS: APPENDIX Il REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS: Fy GENERATION.....1157 APPENDIX JJFR\EGPERNOEDRUACTTIOINV.E TOXICOLm OGYmIND--IVI-- DUAL--BO--DY W--EIG--HT--GAIN--S: ------ APPENDIX KKF)RGEEPNREORDATUICOTNI.VE TOXICOL-- OGY INDIVIDUAL FOODcCONoSUM-- PTION: -- - APPENDIX LLFyRGEEPNREORDAUTCITOINV.E TOXICOL-- OGY INDIVIDUAL CLINIoCmAL OB-- SERVATIONS: nnd 187 APPENDIX MM INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS - F; ADULTS............1198 APPENDIX NN INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS- Py ADULTS... 1217 APPENDIX 00 INDIVIDUAL ANIMAL GROSS OBSERVATION-S Fy PUPS cv 1377 APPENDIX PP INDIVIDUAL ANIMAL GROSS OBSERVATIONS - F, WEANLINGS 1383 APPENDIX QQ INDIVIDUAL ANIMAL GROSS OBSERVATIONS - Fy ADULTS cv 1399 -_----m--msm$< <m<m--m--m-- Company Sanitized. Doesnotcontain TSCA Cal - STUDY INFORMATION - T grT r HaskellNumber: 24768 CAS Regist Number{ESE pure: QI Koown impure(MSSM\ Physical Characteristics: Tan to light brown paste SEE Sponsor: ming, E. I. du Pont dDeelNaewmaoruer9s8a9n8d Company USA. Study Initiated/Completed: March 14, 2001 /(see reportcoverpage) InLif niedComplete: March15, 2001 / Septem 14, 2001 9H0--2D4a7y6G8:avSaugbechSrtoundiyciTnoxRiactistwyith One-Generation Reproduction Evahations --_ STUDY PERSONNEL Study Director: Management: Susan A. MacKenzie, V.M.D., Ph.D, Judith C. Stadler, Ph.D. NancCy. Chromey, Ph.D. Primary Technician: JNaintiacBe.L.BaCkoenrnell, M.S, BA., C.LH. Analytical Chemist: Management: Janet C. Maslanka, B.S. S. Mark Kennedy, Ph.D. Clinical Pathologist: Nancy E. Everds, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Neurotoxicologist: Linda A. Malley, Ph.D. Management: Robert M. Parker, Ph.D. Biochemical Evaluation: John C. O'Connor, M.S. Management: Matthew S. Bogdanffy, Ph.D. --~ Reproductive Toxicologist: Eve Mylchreest, Ph.D. Management: Robert M. Parker, Ph.D. MaPnaathgoelmoeginstt:: JSothevneFn. RH.anFsreanme,,D.DV..VM..M,.,PhP.hD..D. Peer Review Pathologist: Steven R. Frame, D.V.M., Ph.D. Toxicology Report Preparation: Cecilia R. Kee, B.S. MaryK. LaRoe Maryanne M. Wilford, B.A. Ophthalmologist: Nancy M. Bromberg, V.M.D., M.S. 6Be1t1h9esMdaas,saMcahruysleatntds 2A0v8e1n6ue Laboratory Veterinarians: WWialnldiaamL.SiWnegsltet,oDn.,VD..MV..,M.A,CAL.CA.ML.AM. Dupont 5990 Ee-- Company Sanitized. Doesnotcontain TSCA CBI 0HL-2D4a76y8G:avSaubgeeliSrtoundiyc iTnoxRiactistwyith One-Generaion Reproduction Evaluations DuPont:5990 SUMMARY HFo-u2r47g6r8ouipnsdoefiyooniuznegd awdautletrmbaylegaavnadgefefmoarlaepCprrolx:iCmDat(eSlyD)9I0GdSayBsR, artatdsowsaegreesaodfm0i,ni2s5t,er1e0d0, or t5o0x0icmigt/ykogr/draeyp.rodSueclteicvteeedvaalnuiamtailosnsf.rom each dosage group were designated for subchronic `Iwnetehkleys.ubCclhirnoicnailc psattuhdyo,lobgoydeynwdepiogihnttss,wfeoroed ecvoanlsuuamtpetdidounr,inagndwecleiknsica7lasnidgn1s4woeftreheev9a0l-udataeyd dNeousrionbgephearviiood,raalndasnseeasrsmtehnetesnwdoefrtehaelsoonpee-rmfoonrtmhedanprditohrrteoed-omsoinntgh, rdeucroivnegrwyepeerkio1d3s,. and near the `epnedroffotrmheedoonner-amtosnatfherre1c0ovaenrdyapperpiroodx.imBaitoeclhye9m0icdaalyseovfalduoastiinogn,s a(hnedpaftoilcloBw-ionxgidoantei-onm)onwtehreand rtahtrse/es-emxo/ndotshe(wmearleessaocnrliyf)icreedcoavnedrgyipveernioadgsr.osAsfiaenrdapmpircorxoismcaotpeilcyp9at0hdolaoygsiocfaldoesxianmgi,na1ti0on. One `emxoanmtihnaefdlfeorrtrheec9o0v-edrayyodfotsoixnigcpeefrfieoctds,. 10Arnatasd/dsietxioinnatlhe$ croanttsr/oslexa/nddosheiwgehrdeoesveaglruoatuepdwfeorre.recovery approximately 3 months following the endofthe dosing period. ``TThhee rraannggeeoafdmmienainstedraeidlytdoofseemavloelurmatesswoafsH-1.234-72.648maLd.minAinasltyetriecdaltormesaulletsradtesmwonasstr1a.6tetdo 4th.a6tmtLh.e ~ dteesitosnuibzsetdawnacteewrausndmeirxeredlepvraonptersltyo,rwagaescaotndtihteitoanrsgeutseeddcionnctehnitsrsattuidoy.ns, and was stable in Itno-xLiicfiteyTpoaxritocoflotghey sPtaurdaym.etTeersst:suNbsotatnescte-srueblsattaendcec-lrienilcaatledsidgenastohfstoocxciucrirteydweinrethoebssuebrcvherdoninicmales Tanodw/eorrbfoedmyalweesigdhots,ebdowdiythwe1i0g0htorga5i0n0, amgn/dkfgo/oddaye.ffiCcoimepncayrweedrteoocbosnetrrovle,dsitnatmisatliecaallnydsfigenmiafliecarnatts addovseerdsew.itMhe5a0n0 bmogd/ykgw/ediagyhtanodnitnesmtadlaeyr9a1tswdaosse8d3w%itahnd10904m%go/fkcgo/ndatyr,olanindmwaelree5c0on0saindedred to be f1e0m0amlge/5k0g0/dmagy/kggr/oudpasy,grreosuppe.ctiTvheely.boMdeyawneibgohdtyefwfeeicgthstweorneteastttrdiabyut9e1d pwraisma9ri4l%yotfoctohnetrreodluicnedthe f5o0o0daenfdfic1i0e0ncmyg./kMge/adanyfgoroodupesf,firceisepneccytoivveelry,teastndda8y8s%0o-f91cownatsro7l7i%n 5a0n0d m9g0/%kogf/dcaoyntfreomlaliens.male wAidtvher5s0e0tmegst/ksgu/bdstaayn.ceR-erveelratseadlorfedtuhcetsieonesffienctfsoowdascoonbssuemrpvteidoinnwbeorthe ombasleersvaenddinfemmaalleesrabtys dtohesed end of the three-month recovery observed in any dose group. period. No test substance-related ophthalmologic effects were NTeeustrostuobxsitacnocleo-gryelPaatreadmreetdeurcst:ioNnsoitnesftorseulbsitmabnacen-drehliantdeldinmebugrroilpogsitcraelngetfhfewcetrseweorbseeorbvseedrviend. `5w0e0igmhgt/akngd/dwaeyremaplaretiraaltlsyartetvehreseibnldeo.fthe dosing period, but were associated with reduced body TTT -- `Company Sanitized. Does not contain TSCA GBI 2904-7D6a8y:GavSaugbechSrtoundcy iTnosRiaciistwyithOneGeneration Reproduction Evaluations Dupont5990 ~~ pBieorcohxeimsiocmaelpTroolxiifceorlaotgiyo:n, wReerveerosbisbelerviendcrienasmeasleinrtathse droaseeodfwhietphat1i0c0po-rox5i0d0atmigo/nk,ga/dmaeya.suNroe of biologically significant effects on hepatic oxidation were observed in female ral. CalmiinnioctarlanPsaftehroalsoegya:ndIsnomrbailteosl,daedhvyedrrsoegienncarseea)sewserineloibvesrerevnezdydmueriacntgivtirteiaetsm(eanltanainnde following a atshsroecei-amtoendtwhirtehchoivsetroylopgeirciaoldeivnidraetnscdeoosfedlivweirtchyt5o0t0oxmigci/tkyg./dIanyf;emhaolweesv,eard,vetrhseey,wbeurternevoetrsible, ifninadtisngdsoosfeddewcirtehas5e0d0rmegd/ckegl/ldmaays.sO(thheemrogolbosbeirnv,edhecmhaatnogceristi,nacnldinriceadlcpeallthcooluongty) wpaerraemeotbesresrvweedre caonndsriedderceedlltirnedaitcmeesnti-nremlaalteesd,bruetd ncoelnl-asdhvaepres,eu.reTahneitpraorgaemne,tcerresattihnuisnea,ffiencotregdanwiecrpehroesdphceolrlums,ass cchholloersitdeer,oplo,ttarsisgiluycme,riudreisn,eavlokalluimnee,puhroisnpehactoanscee,ntbrialtiirounb,ina,nadlbuurminien,pHgl.obulin, calcium, sodiurn, (Pmlaalsemsaofnlluyo)r,id1e00c,onocre5nt0r0atmigo/nkgw/adsayi,ncbruetarseetdudrunreidntgotchoendtrooslinlgevpeelrsifoodlilnowriatnsgdtohseetdhrweiet-hm2o5nth irnecmoavleersyapenrdiofde.maUlresindeosfleudorwiidteh(t2o5t,al10f0l,uoorrid5e0e0xcmrge/tkegd/doavye.r tUhreicnoellfelcutoiroindepegrrieoatdl)ywdaescrienacsreedased mduornitnhg rtehecorveecroyvepreyripoedriiond,10b0utanredm5a0i0nemdg/slkigg/hdtlayyambaolveescaonndirfoelmvaallesu,esthatusthiendeincdaotfitnghtehethree--~ continued presenceoffluorinated materia, AdnayastopmriocduPcaetdhoalltoegryat(iSounsbcihnrtohneiclivTeorx,ickiitdyn)e:y,Esxpploeseunr,eantod tthheyrtoeisdt.suIbnsctraenacseedfolrivaeprpwreoixgihmtastealnyd/9o0r mfiecmraolsecsoaptitcheheepnadtoocfetlhlueladroshiynpgerpterrioopdh,yawnedreinp5r0e0semng/inkg2/5,da1y00m,alaensda5n0d0fmegm/aklge/sdaafylemratlhees and orensep-omnosnetthormeectoavebroyl.isTmhoefsea lxievneorbicohtaincg.esInwe1r0e0caonndsi5d0e0remdg/tokgb/edaaynomna-aldvreartss,e,thpehylsivieorlocghiac:nges `hweemraetaospsooiceisaitsedanwditihnctrheeaisneddupcitigomneonft hienptahteicsppl-eoexnidwaetrieonobacsteirvviteyd. inIn1c0re0aasnedd e5x0t0rammge/dkugl/ldaaryy mwaelreescoannsdifdeemraeldetso abned,noinn-faedmvaelresse,, wseerceonadsasroycipahtyesdiowliotghiicnrcersepaosnesderseltaoticvheansgpleeseinnwreeidghcte;lltmhaesys. Iinncfreemaasleeds,chwraosnipcrepsreongtreisns5iv0e0naenpdh/roorpa1t0h0ym,gs/okmge/tdiamyesmaalcecsoamnpdanfieemdalbesy,inacnrdeadsieddnkoitddneemyonwsetirgahtte irneccroevaesreysiinnfuermianleesv.olTuhmee,seashsiosctioaltogeidcwalitfhinrdeidnugcsewdeurreinceonossimdoelraeldittyoabnedasdpveecrisef.ic gNroanvi-tayd,vweerrsee. eobnsdoerfvtehdedounrien-gmotnhethdorseicnogvepreyripoedriiond.500 mg/kg/day males and females, but were reversed by the. `5C0o0mmpogu/nkdg-/rdealyatmeadlehsypaenrdtrfoepmhayloefsfoaltltihceul9a0r-deapyitshaecrliifuimcei,nitnh5e0t0hymrgoi/dkgw/adsayprmeaslenets iannd10f0emaanldes at ctohensoindee-rmedonptohtesnatcirailfliycea,dvaenrdsei.n tNhoen5-0a0dvmegr/skega/ldtaeyramtaiolneosfactolthleoitdhrweaes-mpornestehnstecirnitfihceet,haynrdoiwdsasof ~~ `males and females at all dose levels at all time points. -- CompanySaniized. Doesnot conTtSaCAiC8n1 2-H9L0D2-a4D7ya6y8G:GoavvSaauggbeecShSrutouddiyciiTnnoRsRaiatctsistwwyiitthhOOnneeGGeenneerraattiioonnRReepprroodduuccttiioonnEEvvaaluations DDuuPPoonnt:-5990 ~ Rreepprroodduuccttiiovne:evaTlwueatnitoynsm.alPearaenntdal20raftesm(aPlyegreantesrfatrioomn)ewaechreddoosseegdroduapilwyefroer d7e2sidganyastperdifoorrto cthoehaFbyitoaftfisopnr,indgu.riTnhgethfeolcolhoawbiintgaptairoanmpeetreirosdw(emraetienvga)lauantdedduirniPn,g rlaatcst:atbioond,yunwteiilghthte, wfeooadning of rceopnrsoudmupcttiiovne,pcelrifnoircamlansciegn.s,Rgerporsosdupcatthiovleogoyr,gasnpseorfmanpiarmaamlestewrist,heismtproauisrecdycrliecpirtoyd,uacntidve plaecrtfaotriomnapnecreiwoedrfeorevgarlouwatthedanmdicsruorsvciovpailcaalnldy.giTvehneaF;groofsfssppraitnhgolwoegriecaelveaxluaamtiendatdiuorninagt twheeaning. eAvasluubasteetdoffoFry6gweeneekrast:iobnordaytswweiegrhet,reftoaoindecdoantswuemapntiinogn,,acnlidnitchael fsoilgnlso,wianngdapgareaamtetoenrssetweorfe pvaatghionlaolgoicpaelnienxgamoirnparteipount,iaalnsdepsaerlaetcitoend.reApfrotdeu6rctwieveekosr,gatnhse aF\ndgetnaerrgeattioorngarantssofwteorxeicgiitvyenwaergeross weighed. dTuersitnsgubmsattainncge-arnedlaitnedS0r0edmucgt/ikogn/sdianybPoydfyewmeailgehstdugraiinngwgeersetaotbisone.rvTehdeinf5em0a0lmegb/okdgy/dwaeyigPhtmgaaliens sruebdsuecttoiofnanwiamsaalsssowceiraetesdiwmiiltahrr(e0dtuhcoesdefroeopdoretfefdicfioernctyh.e sCulbicnihcraolniocbsteorxviactiitoynssubisnett.he reproduction Female rats exposed to all doses had 25, 100, and 500 mg/kg/day groups, raesrpeedcutcievedlfye)rtainldityinicnrdeeaxse(d55e%st,ru5s8c%y,claendle6ng5t%ho(f10c9o%nt,rol in ~ e1n1d4p%oi,ntasn,dt1h1e2m%aognfictoundteroofleifnfe2c5,ts10in0,thaendhi5g0h0-dmogs/ekggr/oduapywgarosuspism,irleasrpteocttihvaetlyo)b.seFrovredboitnhthe tlooxwi-cdoolsogeigcraolups.ignTifhiecalnocweeorftfehretiliintcyrienadseexd wesatsrocuosnsciydcleereldenagdtvherisseuinncalelalr.groFuepmsa.leTshdeosed with N50o0amdgv/ekrsge/dtaesyt aslusbosthaandcea-rreeldautcetdioenffiencttsheonnusmpbeerrm opfaurtaemreitneersimoprlaotnhteartiroenprsiotdeusct(i7v0e%ionfdciocnetsrwole)r.e `osbpseerrmvecdo.unGtrso(u8p8s%o,f9m1a%l,e arnadts8e8x%poosfecdonttoraolll dions2e5s,h1a0d0,noann-dad5v0e0rmsge/rkegd/udctaiyongsroiunpse,pididymal sreusbpsetcatnicvee-lrye)l.atTehdehriestwoapsatnhoolaosgsyocwiaatseodbhsiestrovpeatihnotlhoegyreipnrtohdeucttesitvies oorrgeapnisdoifdyPmyisr.atsNwoittehst impaired reproductive performance. bInortnhe(7520%0)m,gn/ukmgb/dearoyfgrpouupps, tbhoemfoallliovewi(n6g6p%a)r,anmuetmebresrwoefrpeuapfsfeacltievde(o%n dcoanytr4o,l)7,: n14u,mabnedr2o1f opfups l8a3ct%atcioonmp(a53r,ed60t,o194,8%10in%otfhecocnonttrroollrgersopuepct.ivLeilvy)e.puTpheweviiagbhitliattybiinrtdhexwa(dsa9y00%-o4fvicaobnitlirtoyl) wanads `lmacetaantipounpinwdeeixgh(tssurwveirvael5t4o%d-ay7121%)ofwtahse1c1o.n4tr%oclommepaanreddurtion1g0la0c%taitniotnhe(dcaoynstr4o-l21g)r.ouTph.eThe litter tshuervnivuamlbwearosfaolfsfosrperdiuncgeidn(t2he5%50c0ommpga/rkge/ddtaoy1g0r0ou%piwnatsheaclornetardoylrgerdouucpe)d. aBtabsiretdh oanndthdeesaethdaotfa, mliovretaolfiftsypriinntghceo5n0t0inmuge/dkdgu/rdianygglraoctuapt,iotnh,emreaiwnalsyaanftienaddaeyqu1a4toefmluacmtbaetiront.o eDvauleuattoetfhuerhthiegrh pup endpoints and the remaining pups in this group were euthanized on postnatal day 33-35. TT -- `Company Sanitized. Does notcontain TSCA C8 9H-02-4D7a6y8G:avSaugbcehSrtoundiyc TinoxRiacsitwyithOneGeneration Reproduction Evaluations DuPont-5990 ~ I1n4;tthhee1n0u0mmbge/rkogf/dliavyegpruoupps,wtahser7e 9w%asanndo 7ap6p%aorefnctoenftfreoclt oatndnaysu1m4 aobnfdpeu2p1r,sruenstpielctliavcetlayt.ionThdeay rlaecdtuacteiodndiunrdienxg wlaacsta7t6io.n1(%8c6o-m9p4a%roefdcotont1ro0l0%meiann)th.e Icnontthreol25grmogu/p.kg/Pduapywgerioguhpt,stwheerreewselirgehtnloy oerffeefcftescotsnopnupmavliaebiolritfye,msaulrevidveavleolroppmuepntwaeilghltasn.dmNarokstewstersuebsotbasnecrev-erdeliante1d00cloirni2ca5lmogb/skegrv/adtaiyons Fy rats. NNOOEELL)f"orfSourbscuhbrcohnriocniTcoxtiocxiitcyi:tyUennddeporitnhtes cionnmdiatlieonasndoftfheimsalseturadtys, wtahes n2o5-ombgs/ekrgv/edda-eyf.feTchtislevel leefvfeilciweancsyb(amsaeledso),ntchliynriociadlfsoilglniscoulfartohxyipceirtty,rodpehcyr,eamnedntcshrionnbiocdpyrowgeriegshstivpearnaempehtreorpsatahnyd food o(bfesmearlveesd),inalmlaolbesseravnedd/oirnftehmea1l0e0s dmogs/ekdg/wdiatyhg5r0o0upmsg./kOgt/hdearyaidnvcerlsued,e cdoemcproeumnedn-trseilnabtoeddyefwfeeicgtsht lpiavrearmeetnezrysmeanadctfiovoitdye(fmfailceise)n,cyre(dfuecmtalieosn)i,ncrherdonbilcoopdrocgerlelsmsaivsesnpeaprharmoeptaetrhsy((fmeamlaeless)),,iancnrdeased trheedudcotsiionngs pienrfioordeldiemmboansntdrhaitneddlfiumllbogrripparstitarlenrgetvher(smaallefso)l.loMwoinsgtoonftehoer etfhfreecetsmoonbtshersovferdedcuorvienrgy. TRheyverrosiadlofofllmicaunlayrehfyfpeecrtstrionpfheym(a5l0e0s mwga/skngo/tdaoybsmearlveesd)uanntidlcahfreornitcheproonger-emssoinvtehnreepchorveorpya.thy (100 and 500 mg/kg/day females) were still present at the endofthe three-month recovery period. ~~ NreOpEroLdufcotrivReepervoalduuacttiiovnes.EvTahluiastwioanss:basUenddoenr trheeduccotnidointsioinnsotfhethfeirstilsittuydiy,ndtehxerienwPyasrantos iNnOalElLdofsoer sgriogunpisf.icaEnscteorofutshicsycclhealnegnegtihs wunacsleparro.loOntgheedriandvPeyrrsaet,scionmaplloudnods-eregrloautpesd,ebfuftectthseotbosxeircvoeldogiincaPly eraftfsicdioesnecdy awnidthr5ed0u0cmegd/nkugm/bdeayroifncilmupdleadnteactrieomnensittsesi.n IbnodF,y gweeniegrhattipoanrraatsm,eatdveaernrdsse,focoodmpound`remleaatnedlietftefrecstiszew,enruemobbesreorfvepdupins 1b0o0ranadn/dorbo5r0n0amlgiv/ek,gp/udpaysugrrvoiuvpals adunrdinigncllaucdteatdirone,duacntdiopnuspin weight at birth and during lactation. Pa * TthheetNetOsEuLbsftoanrcteiswsetrudnyoitsddeetfeictneedd.a Ththues,hifgohretstisdostsudayt,wthheicNhOtEoLxiciaelqouiicvaallyenitmp(o0rtthaenNt fOecEtasLadterfiibnueadbblye to the United Sates Environmental Protection Agency (1985) and tothe no-abserved-adverse<ffet level (NOAEL) as defined by the European Union (1994) - Company Sanitized. Doesnotcontain TSCA Cal R 2H0-2-4D7a6e y8;GavSaugbcehSSrtuouncdiyc iTnoRrRaiactsistwwyiitthhOOnnee-GGeenerationRReepproductionBErvaluaattions --_ DDuuPPoonntt55990. INTRODUCTION clToehnveecletsnetsfrtoarstutibhoisnstsasnftcruedo,ymHwa-e2rr4ae7ng6se8e-l,feicisntdeadinfbglaussoteruidndoaytniendthwoethroigxacinhciircatetystahwnoedxryelaandtoeasnuaesldeysdbiyasosorfaablslugroafovadcatgfaelnutwo.irtiThnhe5e dose 500, or 1000 mg/kg/day for approximately 62 days. 0, 100, bbInooddtyhyewwreeaiinggghhett-fllioosnsssdiaonrngdrsetrdueuddcyut,citroianotssnsienxinbpoobsdoeyddywtewoiegi1hg0th0t0gamgigani/nk(gci/ondmmapayalrewese.drteTorscaaoncnsrtiirefoniltc),edwsteoarnteistteoisbctsadellaryvyes1id8g,niindfmuiacealntto 5a0n0d mfegm/aklge/draatysmeaxlpeosreatds,tome5a00n mbgo/dkygw/ediagyhdtusrrienmgatihneefdirasptpwreoexkimoafetxeplyos1u0r-e1.2%Inbethle.ow control e 4mtohwrsaotsuogfahlotsuhoetsottbhsueedsrytvue(ddnyo.insWtraeattiissgtheitxcasploolfysfseiedgmataoilflecoawrneatrtsddiionfsfetesir,esnbgcuertso)bu.opdRwyeedwreueicsgeihdmtiblpoaardryatmowecetoiengrthsrtoilonvttehhrreostueegtghrodouautypss0tLwooexhriaecivcteoymrwepeaarcrehaeobdblseaetprolvaectodenatiunrowalintoyhvigenrroautpphp.erroeBxslitoomfoatdtehflelyuso2tr-ui3dnyew.eleeNvkeoslsocfiondmoptsohiiusnngdr,-anrgeel-aftienddicnlgisnticuadlysiagpnpseoafred taTbohixeliricetifytooyrfwei,rtatthshoeutthoietgoxhlc-eerdsaostsieevtelheimvsoerdltoafsloeirtiytnh.itshT9eh0er-adlnaogyew-sfdtiounsddeyionofgf2s5t50ud0myg.m/gk/Tgkh/gid/saddyaoywsaewsawseaxsspeeelcxetpcteeedcdttebodabsteeodtphroeondntouh.cee ~ 1ob0steorxviecdi-tayd.verse-effect level, while the 100 mg/kg/day dose was expected to induce minimal or OBJECTIVE t`ToHh-ie2n4voe7bs6jte8icgwtaihtveeeontfhaedtrhmeiivsneirsssttiubediryleiwdtaybosyftagoanveyvaagolebusatetoremvtaehldeetpoaoxtniedcnotflieoamlgaislcueablrcaehtfsrf.oecntAisc.raeTnchdoevreeorpryarlogdrruoocuuttpievweoaftsoxiincciltuydoefd buaurdtimnihen,aivsfteercneasot,tioabnnedewnatsiesvssaeulleuesactwteeedd.reasDcoatlthleaecmftoresodtmfeoafrnfaeilcvyiaselinustaotwfitaohynoetsfoetdheselaimpvphelraerasmnawcaioclckluibrneaettreiecpdooprsrtaoegfdei.lseeopBfalroaHot-de2,l4y.768, MATERIALS AND METHODS A. Test Guidelines `A`TTgehseetnsGcuuybicd(heErlPioAnn)ei,sc,OtfOofxPiiPccieTtoySfsP8tr7ue0dv.ye3nd1te0is0oing9,n0c-PoeDsmatpyilciOierdeassl,wTiaotnxhidtcThieotxyUinicnitSReuodbdseSttnaatntsecse(sAEUn(GvO-iP1rPo9Tn9mS8e))n.HteaaTllhPterhooEtnfeefc.etcitosn ``cgeonmeprlaytiwointrheaprsopdeucciftiicongusitduedliynei.ncludes many endpointsofreproductive function but does nat - `Company Sanitized. Does not contain TSCA CBI 29H00-:2-D4D7aa6yy6G:GaavvSaauggbceehSSvttouunddiyyciTinnoRsRaiatctsistwywiitthhOOnnee-GGeenneerraattiioonnRReepprroodduuccttiioonnEEvvaalluuaattiioonnss DDuupPoonnt55999900 ~ B. Test Substance aSnaamlpylsiessoafndHa-n2a4l7y6z8edwbeyrethseupDpulPioend tneRaergitohenablegAinnanliyntgi,camlidSdelrev,icaensd(ReAnSdo)f.thTeheststuadbyilfiotry satnaabliylsiitys OsfamHp-l2e4v7o6l8uwmea,s tbhaesesdamopnlethseupbhmyistitceadl ncehaarratchteerbiezgaitninoinongfoftthehteessttsuudbystcaonucled.noDtubeetcooimnpsluefftiecliyent analyzed. C. Test Species OdanteMoafJracnhua1,ry20,0215,, 1270601mawleeraenrdec1e7i6vefdefmarloemCCrhiar:lCeDsR(iSvDe)rILGaSboBrRatorartise,s,wiItnhc.a,nRaalsesiigghn,edNobrirtthh bCiarrtohldiantaeofofr uApsreioln8,th2i0s0s1t,udwy.erAenreacdedivietdiionna4as4lepraartast(e2s2hmiaplmeeantnd6322dafyesmaalfetesr),swtiutdhyastnartasosnigned May 17, 2001. The additional rats were designated for the 10-day hepatic biochemical analysis, Tanhde irsatexwtaesnssievleelcyteudsebdecianurseepritodisucttheiosnpesctuideisesr.ecTohmemeCrnld:eCdDin(tShDe)sIuGbSchBrRonistcrtaionxiwcaitsycghuoidseelnines bpreecvaiuosuesesxttuedniseisvaetbHaacskkgerloluLnadboirnaftoorrmya.tiTohniisssapveaciileasb/lsetrfarinomaltshoeilsitceornastuirdee,rtehdessuuiptpalbileer,realnatdive to longevity, hardiness, and low incidenceofspontancous discascs. ~ D. Animal Husbandry 1. Housing Wseixtehs tsheepaerxacteep,tiinonstoafisnloemssestpeoerlt,iwoinrsoe-fmtehseh rceapgreosduscutsipveensdteuddya,blolvertcsagweebroearhdosu.seAdnoinmealperrocoamgse, `2w2er3e maCinatnadinaedreolnatiave12h-uhmoiudritliyoghft/5da0r%k c+yc2l0e%(.flOuocrceasscieonntalligehxtc)uarnsdioantsaotuetmspideeratthueraecocefptable ranges were minor and did not affect the study. Rcoahtasbdietsaitgionnatpeedriofdo.r reDpurroidnugcttihveegteosxtiactiitoynepvearliuoadt,iofnesmawleererahtsoudseesidgansatberdeefdoirnrgeppraiordsucdtuirviengtotxhiecity e`mvaatleudatfieomnaslwese,reorhaotustheedeinnddoifvtidhuealclyohuanbtiitlagteisotnatpieornioddayfo2r0.femBaelgeisnnwiitnhgoount egevsitdaetnicoen odfay 20 for cloapclualtaitoinonp,erfieomd,alaedurlattsfweemraleehroautssewderinedhivoiudsueadllwyiitnhptohleyircalribteornsatien ppoalnyscwairtbhonbaetdedipnagn.s. During the DpeurriiondgftohrePe,ntaidrueltisn,-lainfedptehrei4od0-fdoaryraptossetvwaelaunaitnegd pfeorrisoudbcfhorroFn,iwcetaonxliicnitgys,,tchaeg7e2r-adcakyspwreermeating rweeleokcsa.ted within the animal room each week and cages were repositioned on the racks every 2 --~ --- Company Sanitized. Does not contain TSCA C81 29H0-0-2-D4Da7ay6y8GG:aavvSaauggbceehSSrttouunddiyyciiTnnoRxRaiacttisstwywiitthhOOnnee-GGeenneerraattiioonnRReepprroductionEEvvaaluations DDuuPPoont-5990. ~ 2. Feed and Water Tap water was provided ad libitum. Rodent LabDiet 5002 ad libitum. All rats were fed PMI Nutrition Intemational, Ine. Certified 3. Identification Parbisoernctoe aosfasigcnolmoernetdtotaiglromuaprsk, acnadchcraagtewiadsentteifmipcoartaironi.lySiudbesnetiqfuieendtlbyy,caitnheirndtihveidpuraelseindcenetoifrication unnuimqbueer6w-daisgittaHtatosokeedllonantihmeaalinloufmebaecrhanradt.thTehiendiinvfiodrumaaltiidoenntoinfitchaeticoangneulmabbeelrs aisnscilgundeeddttohecach r2a1t. daFyysgoelnde.ration rats retained aftr lactation were tattooed when they were approximately 4. Health Monitoring Program fAosllspoewciinfgipedroicnetdhuereHsasakreelpleLrafboorrmaetdorpeyrainoidimcaalllhyeatlotehnasnudreetnhvaitrocnomnetnatmailnamnotniltevoerlisngarperboeglraomw, the those that would be expected to impact the scientific integrityofthe study: + `Waantdeorthsearmcpolnetsamairneaanntsa.lyzed for total bacterial counts, and the presenceofcoliforms, lead, --_ + Feedsamplesarc analyzed for total bacterial, spore and fungal counts + Samples from freshly by the cagewashers. washed cagesandcage racks are analyzed to ensure adequate sanitation rCeerqtuiifrieemdeanntismaanldfneoetdtios uesxecde,edgusatraatnetdemeadxbiymtuhemmcaonnucfeancttruarteirontsoomfekeetyscpoecnitfaimeidnannuttrsi,tiionncalluding pspreecsiefniceedofhteahveysemectoanltsa,maifnlaantotxsinb,eclholwortihneatmeadxhiymdruomcacrobnocnesn,traantdioonrgsatnatoepdhobsyphtahetemsa.nuTfahceturer would not be expected to impact the integrityofthe study. Tlahbeoraantiomraylanheiamlatlhvaentdereinnavriiraonn.meEnvtaalluamtoinointoofrtihnegsperdoagtraadmiidsnaodtmiinndiisctaetreedanbyyctohnediattitoennsditnhgat affected the validityofthe study. E. Quarantine and Pretest Period pUeproiond.arrTihvaelraattsHawsekreellobLsaebrovreatdodrayi,lythfeorraatnsyweclrieniqcuaallryanatpipnaerdenftorsi1g2nsdoafydsoifsteahsee 1o4r-idnajyurpyr,etest wpreeiegxhiestdin3gtoicmuelsa,ralnedsieoxnsa.mined by a veterinary ophthalmologist to identify animals with --_ Orenletahseedbafsriosomfqaucacreapnttainbeleonbotdesytwdeaiyg-h2tbgyaitnhsealnadbocrlaitnoircaylaonbismearlvavteitoenrsi,naarlliasnurdvesiivginneger.ats were TTT re Company Sanitized. Does not contain TSCA CBI 292004--7DDa6ayy8G:GaaSvvuaabggceehSrStotunudidycyiTinonxRRiacatisstvywiithOnee-GGeenneerrasttiioonnRReepprroodductionEEvvaallusations ____DDuuPpoonnt-t5990 r~ Additional male and female rats designated for the 10-day `hepatic biochemical analysis were qdauialryanftoirnaendyfcolir6nidcaalylsyoafptphaeren1t1-saignndso1f2d-idsaeyapsreetoerstipnejruiryoda,nrdeswpeeicgtihveedlyt.hrTeehetirmaetss,wtehreenorbesleearsveedd from quarantine on test day 70. F. Study Design Groups Male Female No./ Group Male Female Dosagea (mg/kg/day) 1 1 45 45 m wv 35 35 Vv VI 35 35 vi vi a5 45 0 (Control) 25 100 500 BiochemicalEvaluations atthe10-day TimePoint I-A I-A 5 5 0 (Control) IV-AA IVVI-AA 55 55 12050 a VIW-Ae_ VitIeIstg-sAubhsancte5/koganifmalb5odyweight 500 m~ "The first 10 rats in each group referred to in this reportasthe were designated 90-day exposure for the 90-day animals. The exposure evaluation and next 5 rats in each group are were initially designated for analysis of fluorine in the blood. However, to assess three-month recovery from test substance-related effects, these rats were also evaluated for biochemical (males), clinical, and anatomic pathology endpoints; these rats are reported as the three-month recovery animals. The next 20 animals in each group were designated for reproductive evaluations. The last 10 male andfemale rats in the control and high-dose groups were designated for recovery evaluations and are reported as the one-month recovery animals. An additional 5 rats/sex/dose were received as a separate shipment 63 days after study start for evaluation ofhepatic biochemical analysis following a 10-day exposure. Male and female rats designated for the 90-day exposure evaluation were dosed for 95 (male) and 96 (female)days,and necropsied on test days 95 and 96, respectively. One male control rat was dosed for 96 days and necropsied on test day 96. Male and female rats designated for the one- and three-month recovery evaluations were dosed for 91 days and necropsied 33 (males) or 34 (females) days and 93 days postdosing, respectively. Neurobehavioral evaluations were conducted on male and female animals designated for the 90- dfoarytehxepoonseu-rmeoenvtahluraetcioovne(rpyr(epdroesdeosaen,dwweeeekk 1133,)oanned-moonnctohntprooslt-adnodsch)i.ghC-ldionsiceaalnpiamtahlosldoegsyignated evaluations were conducted on animals designated for the 90-day exposure evaluation on weeks 7 and 14 and on animals designated for the one-month and three-month recovery evaluations immediately prior to necropsy. Biochemical evaluations were conducted on selected animals ~~ designated for the 90-day exposure evaluation, the one-month and three-month recovery Te TTTTe Company Saniized. Does notcontain TSCA CBI H90-0-2-D4D7aa6yy8:GGaavvSaauggbceehSSrttouunddiyyciTinnoRxRaiactsistwywiitthhOOnneeGGeenneerraattiioonnRReepprroodduuccttiioonnEEvvaalluuaattiioonnss DDuuPontt:55990. mm `ewvearleuattriaonnssf,erarnedd ttoheth1e0-redparyoedxupcotsiuonregervoaulpuaotniotne.st Rdaatys7d0e,saingndarteepdrofodrucrteipvreodeuvcatliuoantieovnaslubaetgiaonnson test day 72, when designated male and female rats were cohoused. G. Assignment to Groups and Study Start 1. RReatcsovDeersyigEnvaatleudatfioorntshean9d0-ReDparyoEdxupcotsiuvree,EvOalnuea-tMioonnst.h Recovery, and Three-Month Ropahttshwaelrmoelsoeglieccatledabfnororsmtauldiytiuesse oornctlhineibcaaslissiogfnasdofedqiusaetaesbeoodryiwnjeuirgyh,tagnadina,bfordeyedwoemigfhrtowmitahniyn i2nc0lu%doedfitnhtehmeehainghw-idtohsiengaroseuxp. (rOatne64m6a36l5e)r.atHwoiwtehvaerpr,etiteswtaosphdtehsiaglnmaotleodgifcorotbhseerrveaptrioodnucwtaisve sstubusdeyt,rewsuhlitsc.h wTahse nsoetleecvtaelduraattesdwfeorrepdoisstt-reixbpuotesdurbeyecyoempefufteecrtsi.zeTdh,esrterfaotriefi,edhirsanddiodmnioztataifofnecsto stheaxt there were no statistically significant differences among group body weight means within a aOgrea.l aPdrmiionritsotrtahteisotnaortfofHt-e2s4t7s6u8bsbteagnacneoandmtiensitsdtraayti0o,nw,h2enmatlhee rraattsswwietrhebaopdpyrowxeiimgahtteslyth4at9wdearyes of mnoitcrwoistchoipni+c e2v0al%uoatfitohnse.meRaenplwaictehmiennatsreaxtswweerreerseeplleaccteeddoanndthdeisbcaasridseodffwriteheodutomgrforssomorany --~ craltindiecsaligsniagtnesodffodritshceasreeporroidnujcutriyoannedvaalbuoatdiyonwewiagshtre&pl2ac0e%dobfastehde omneaanclwiintihcialn oabsseexr.vaOtinoenmmaaldee at the timeofdosing on test day 0. 2. Rats Designated for 10-Day Biochemical Analysis `stTahret.raTtshedeyswigenraetehdanfdolretdheth1e0s-adamyebaisotchheemoitchaerl raantaslydsuirsinagrrtihveedqusaerpaanrattienley,an6d3pdraeytesstafpteerrisotdusd,y `ecxocmepputtetrhiezyeddi,dstnroattirfeiceedirvaenadnomoipzhatthiaolnmoilnotogisctauldyexgarmoiunpasti(oSn/s.exT'hdoesye)w,ersoe tdihsttrtihbeurteedwebrye no sstuabtsiesttoicfalrlaytssiwgnaisficcoanmtpadirfefderaenmcoensgatmhoenmgseglrvoesu.p bOordayl waedmiignhitstmreaatniosnwoifthHi-n2a47s6e8x wtohemanltehiasnd cfoenmsaulmeprtaitosnb,egclainniocnaltoesbtsedravyasti7o4nsa)ndwe7r5e, creoslpleeccttievdelfyr.omInt-hleisfee daantiama(lbsodayndweairgehti,n sftouoddy records. However, these data will not be included in this report. H. Dose Solution Preparation wDaotseer.soTlhuteiotensstosfub0,st3a.n3c3e,,1a3.b3r3o,wonr p6a.st6e7, wmagstmesetltseudbsatnadncstei/rmreLdiwenrae7p7repCawraetdewribtahthd.eiTonhiezed adpopsrionpgrisaotluetaiomnosunwteoreftmeisxtesdubfsortaanpcperwoxaismawteeilgyheodneoumti,ntuhteenwdiitshsaolvpeodlyitnrodneihoonmiozgeednwiazteerr.. The Dose -- ssoolluuttiioonnss wweerree prreempoavreedd ftwriocmetahewereefkriagenrdatroerfraingdersattierdreudntwihliulseedt.heyOnwetrheebdraoyuogfhutsteo,rtohoemdose eT Company Sanitie zed. Doee s not cone tain TSCA Cal 209H-:02-D4D7sa6y8y;G:GaavvSaauggbceehSSrtouunddiyyciiTnnoRxRaiacttisstyvwiitthhOOnnee-GGeenneerraattiioonnRReepprroodduuccttiioonnEEvvaalluuaattiioonnss DDuubPoonntt--5990. ~~ treemtpuerrnaetdurtoe.theAreofnreig-edraaytoarl.iqTuhotewdaaislythaelniqrueomtsovweedreanstdirtrheed rpermioarintoinagnddodsuerisnolgudtoisoinnsgw.ere I. Test Substance Administration and Sampling (Afneimmalaelss).desOingenactoendtrfoolrmtahele90i-ndtahyisdsousbisnegtpwearsioddowseerdetdhorsouegdhtthersotudgahyte9s5t.daAyni9m4al(msadleessi)gonrat9e5d dfeorsitghneaotneed-faorndretphrroedeu-cmtoinotnhevraelcuoavteiroynsevwaelrueatdioonssedwetrheroduogshetdhteh7r2o-udgahytpesrtedmaatyi9n0g. peArniiomdaalnsd dduorsiendgdtuhreinmgattihneggepesrtiaotdi.on Ppermioadl.esLcaocntattiinnugedfetmoableesdoasneddfuenmtaillessacwriiftihcen. o Perveigdneanncteoffemcaolpeuslawteiroen s`wteurdey,dwoistehd tuhnetielxpcueppstiwoenorefpwreeagnneadnotnfpeomsatlneastainltdhaeyp2r1o.ceAslsloPrysahnoiwmianlgssiingnthsoefredperloidvuecryt,iownere dosed daily until sacrifice. lTehveeltseostf2s5ub,st1a0n0c,eowra5s00admmginaicsttievreedindgarieldyietontt/hkegsbtouddyy waeniigmhatl/sdbayy,obraalsegdavoangethteomaocshtierveecednotslayge 7r.e5comrLd/ekdgb,otdhyewseaigmhet.dosAellvmoalluemeanudsefdemianloethceorntgrroolupasn.imals were dosed with deionized water at sOtnudtye,stthdearye2w1e,reGrionudipviIdI,uarlatra6t4s6a4c5r8oswsadsosienagdrvoeurptesntthlaytdwoesreed mtiwiscdeo.seDdu;trhiensgetrhaetscoaurreseofthe --~ ddeosccurmiebnedteadboivnestaurdeycroencsoirddesreadndnortetpoorhtaevdeinafAfpepcteenddtihxe Bo.utTchoemeionfctidheencsetsudoyf.misdosing Ainldlidcoasteidngbysotlhuetisotnabsialimtpylaensalwyesries fcoorlltehcetsetduodyn.thTehseasmoeludtaiyonthveehsioclluetiwoanss wdeeiroenipzreedpawraetdero.r as `0S,a3m3p3l,eso13f.d3o3,sianngd s6o6l.u6t7iomngs/comnLtawienriengcoHl-l2e4ct7e6d8atinthdeeiionnitiizaetdiownoaftetrh,eatsttaurdgyet(etedstcodnacyen0t)rafotrions of svtearbiifliictaytsioanmopfluenwifaosrmaintayl,yzceodncteondtreamtoinosnt,raantde sSt-ahboiluirtyroofotmhetetmepstersautbusrteansctaebiilnitdyo.siTnhges5ol-uhtoiuorns coovnecretnhterattiimoensthweearneicmoalllsecwteerdeobnetiensgt ddoasyesd.32,S4a2m,plaensdo9f1dofosricnogncseonltutriaotnisonprveerpiafriecdataitont.heDsoasmieng ssoalmueticoonnscwenetrreatpiroenpsaraesdatbwoivcee,apwreepeakr,edthoenntreesftrdigaeyra3t9e,dwuenrtielcuosleldec(tuepd toon4tedsatyds)a.y 4S3a,mpaflters4atdtahyes ofreffigeration, to verify stability under these storage conditions. oAlnltdhoessianmgesadmapyletsh,e seoxlcuetpitontshowseerfeoprrveeprairfeidc.atiSoanompfl4e-sdasuybrmeiftrtigeedraftoiroannsatlaybsiilsitwy,erweeraenacloylzleecdttehde dunadyetrhe4-sdoaluytrieofnrsigweerrateedreccoenidvietdioonrsrwefarsigaelrsaotesdunpptolrtaendalpyrzieodr.to Tshteudsytasbtialrittby yoftanhaelyttiesctalsurbesstualtnsce. from a developmental toxicity study previously conducted with this test sarc RR -Es `Company Saniized. Does not contain TSCA GBI H9-02-4D7a6y6G:avSaugbcehSrtoundiyc iTnoxRiactistywithOne Generation Reproduction Evahations ~ J. Analytical Methods DuPont:5990 1. Dosing Solution Treatment Pdirliuotretdocaonnatlryosli,s,toeaanchexdpoescitnegdscaomnpcleentwraastidoinluotfed1.w6i7tohrm3e.t3h3anmogl/amnLd(aani)e.quivalent amount of 2. Chromatographic Conditions Instrument: Colum: Hewlett-Packard Model 6890 GC HP-1,30m x0.32mm ID, 025 um film thickness Injector: split, 250C Detector: FID; 300C Carrier Gas: Helium (2.7 mL/min) Split vent: 53.2 mUmin Injection Volume: 1 microliter Oven Program: Gradient Initial Temperature: ~~ 50C Initial Time 0.0 min. Level 1 Rate: 40C/min. Level 1 Temperature: ~~ 300C -- Run Time: 22.25 minutes 3. Calibration and Quantitation rAefsetroecnkces)olwuatsiomnoafdtehein tmeestt hsaunboslt.anAcpep(raosperpiaartaetealsiaqmuoptlseofofthHe-2s4t7o6c8k,weurseeddaisluatneadlywtiitchalthe `wmeertehaunsoeldatnodmaankeeqcuailviablreanttioanmsotuanntdoarfdtshethdaitlubrtaecdkceotnetdrotlhetotamragettcchotnhceenstarmaptlieosn.ofTthheesedisloultuetdions tdooscionngstsraumcptlceasl.ibrPaetaikonhceuirghvtess (b4yrleetaesnttsiqounatriemerse)grfersosmioGn C(seaenaAlpypsiesnodfitxheAs,eFsitgaunrdear1das-w1edrefoursed representative calibration curves). Measured concentrations for dosing solutions were dcaeltiebrrmaitinoendcbuyrvaep.plTyhiengmtehaenpereaskulhteifgrhotms tfhreocmornecpelnitcraatteiionnjsecattiaolnlsoreftetnhteiosnamtipmleesst(on e=a4c)his reported as the concentration for the sample. T(Ce.sVt.su=bssttaanndcaerudndiefvoiramtiitoyni/nmtehaenvxeh1i0c0l)eofwtasheevmaelausatuerdedbycocnaclecnutlraatitnigontsheincodeufpfliicciaetnetosfavmaprlieastifoorn cLaacbhordaotsoirnygfloervaelc.ceAptacbolefefdiicsiternitbouftivoanorifatthieontoefstlessusbstthaannc1e0t%hrioutghheousttatnhdeasrodluctriiotne.rioTnhaet Hmaesaknell trheseultteostfstuhbestdaunpcleicfaotretshaermepslpeesctfiovreeadcohsidnogsilnevgellse.vel was used to determine the concentration of -- aStsatbhileibtayswealisneevfaolrucaotemdpabryiunsgitnhgetchoermreesapnoonfdtinhge5d-uhpoluircartoeosmamtepmlpeesrafotrurceonacnednt4r-adtaiyonrevferriigfeircaatteidon results. eT Tee eet `Company Sanitized. Doesnotcontain TSCA CBI 5HL02-4D7a6y8;GavSaugbechSrtoundcy TinorRiactistywithOne Generation Reproduction Evahations DuPont-5990 ~ K. Body Weights tAhlel rraattss dweesriegnwaetiegdhfeodr onneucreopbeerhawveieorkadluervianlguatthieon9s0,-duanydeerxgpooisnugrefupnhcatsieoonaflthobesesrtvuadty.ionTanlabdadtittieorny, arenpdrmodoutcotrioanctaisvsietyssamsesnets,smmeanltes,rawtesrweewreeiwgehiegdhoend tohneadawyeseokfltyhsocsheedoublseeravnadtifoensm.aleDurratisngwetrhee Pw,eifgehmeadledurartisnwgigtehstnaotieovniodenndcaeyosfc0,op7u,l1a4t,io1n8,,oarntdha2t1,dainddnootndlealcitvaetrioan ldiattyesr, 0c,o7n,ti1n4u,eadntdo2b1e. dwaeyig3h6edfowretehkelyF,. gWeneearnateidonF),. rGatesstwaetrieonwediagyh1e8dbwoedeyklwyeiugnhtitlspwoesrtneatcaollldeactye5d6so(leeqluyivfaolretnhteto test purposeofadjusting dose volumes and are not reported. L. Food Consumption and Food Efficiency `tThhreouagmhoouuntttohfefsotouddy.coEnascuhmefededbeyrewaacsh wraetiogvheerdeaatcthhewebiegghiinnnginigntaenrdvalenwdaofstdheeteirnmtienrevadl and the sfuinbatlrawcetiegdhtforfotmhtehefieneidteiarlafnededtehrewaemioghutn.toFfrsopmiltlhaegseefmreoamsuthreemfeenetdesr,dmuerainngdtahielyinftoeordval was dcaotnas,utmhpetmieonanovdeariltyhefoiondteerfvaflicwiaenscydewtaesrmcianlecdul.atFedr.om the food consumption and body weight -- eMveaalunatdiaoinlsy dfuoroidncgotnhseu9m0p-tdiaoynewxapsosduerteerpmeriinoedd. foFroaoldl acnoinmsaulmspdteisoingnwaatsedalfsoordseutbecrhmrionneidc tfooxricity `naontidmaeltserdmesiingendatfoerdafnoirmoanles-daensdigtnharteeed-mfoorntthhertehcroevee-rmyoenvtahluraetcioovnesrythervoaulguhattieosntsdaayfte1r19te,stbut was day 119. dDeusriignngattehde froerprroedpurcotdiuvcetiavseseassssmeesnstm,enftooadscfoonllsouwmsp:tion was determined for each female rat + Pdraeym7a0t.ing Dosing period ~ individual food consumption was determined weekly, ending test Cohabitation `consumption wpearsiondotbedgeitnernmiinngetde.st day 72 and Py males after the endofcohabitation -- food + Gestation and 21. period ~ individual food consumption was determined on gestation days 0, 7, 14, + + PLaocsttawteiaonnipnegriFoadt--fso--odincdoivnisduumapltfiooondwcaosnsnuomtpdteitoenrmwiansedd.etermined weekly, ending on postnatal day 56 (equivalentto test day 36 for the Fy generation). M. Detailed Clinical Observations and Mortality `Dbuerhianvigotrhaentde/sotrpaerpipoeda,racangcee-saimteonegxarmaitnsawteiroenscotnodduecttecetd maotrlieabsutntdwiocreddeaaidlyr.atAs tanedvearbynwoerimgahling, ~ cclaicnhicraaltowbasserivnadtiivoindsuailnly shtaannddlaerddiazneddeaxraemnainweedrefoarlsaobneovramluaaltebdehoanviroarlsadnedsiagpnpaetaerdanfcoer.thDee9t0a-iled Tr ---------- Company Saniized. Doesnotcontain TSCA CBI 9H02-D4s7y68G:avSaugbechSrtoudiyciTnosRiactitwyithOneGeneration Reproduction Evaluations DuPont 5990 -- wdaeyreexnpotosluirmeitaenddtoo)neev-amlounatthiorneocfovfeurr,yspkeirni,odesy.es,Tmheucdoeutasilmeedmcblrianinceasl,oboscecruvrarteinocnesofinscelcurdeetdio(nbust arensdpierxactroertyiopnast,tearun)t,onchoamnigcenseirnvogauist,spyosstteumrea,ctrievsiptoyn(sleactroimhaatnidolni,ngp,loperreescetnicoeno,fcalnodnuincu,sutoanlic, stereotypical, or bizarre behavior. N. Ophthalmological Evaluations Twewroe oepxhatmhianlemdolboygifcoaclaleixlalmuimniantaitoinosn wanedreincdoinrdecutctoepdhtbhyalamvoestceorpinya.ryTohpehtehxaalmmionlaotgiisotn.s wBeorteh cyes conducted solution. under subdued lighting after mydriasis had been produced with a 1% tropicamide sOenletcetsitodnaayn-d13g,rotuhpeinign.itOialnextaesmtindaatyi8o5n,waallsspuerrvifvoirnmgedratosndaelsirgansatreedcefiovretdhefo9r0t-hdeaysteudxyp,ospurrioeratnod one-month recovery were examined again. 0. Neurotoxicity Evaluations 1. Sensory Function Evaluation -- Padrmiionritsotrtaetstiosnu,bsatnadncfeolaldomwiinnigstarnataipopn,rodxuirmiantgewlyeeonke1-3mo(ntetsht draeycsov8e8ryanpder8i9o)do(ftteeststdasyub1s1t8a)n,ce awshsielsestmheenatsnoimfalrewsaposnisnesa tsotaanpdparrodacahr/etnoa.uchT,hesshaerapsasuedsistmoernytsstwimeurleusc,onadnudcttaeild poinnc1h0waenriemamlasdpeer g1r0oaunpimfoarlsthpeebragsreoliunpedaensdigwneateekd 1f3orervaelcuoavteiroynsc.onTthroelraencodvheirgyhe-vdaolsueatgiroonupwsasonclyo)n.duFcotreed-oanndthe Phuipnidllliamrby gcroinpstsrtircetnigotnhwwaesrememaesausruerdeidmbmyedaiasttrealiynpgraiuogretdoerveimceov(iChnagtitlhleonratsDfigriotmalthFeormcoetograuge). oabctsievrivtiyncghtahmeberersspobnescea.usTehteheprdeasreknecneedorraobosmenicnewohfipcuhpitlhleaarpypcaornastiursicwtaisonlwoacasteadssfeascsielidtaatfetder a `ubneaawmaorfeloifghtthewagsroduipredcetseidgninattoiocnaocfhtehyee.anFimoarl.all these assessments, the experimenter was 2. Motor Activity cFoonldluocwtiendg. thReatesvawleuraetiionndoifvgirduiapllsytrteensgttehd ainnd1osfen3so0rnyofmuinncatlilony,iadesnsteiscsalm,enatuotfommaotteodracatcitviivtiyty was `amcornoistsotrhse(mCoonuiltboorusrnanIdnftriamreoefddMaotyortoAtchteivfiutlyleSstysetxetme)n.t pGosrsoiubple.andThgeenidnefrrawreedremocnoiutnotreirnbgaldaenvciecde menoavbelmeesntmse.asuArecmoenntitnouof2usdmeopevnedmeennttvawraisabcloesu:ntdeudraatsio|nomfovmeomveenmtenretgaarnddlensusmobfedruroaftion. Each wteesltlsaesssfioorn6wsauscc6e0ssmiivneut1e0s-miinnduutreatbiloonc,ksa.nd the results were expressed for the total session as ee eee Company Saniized. Does not contain TSCA CBI H902-4D7a6y8:GavSaugbechSrtouidyciTnorRiactistywith One-Generation Reproduction Evaluations DuPont-5990 ~~ a`Plrseosreencceoordfeddeffeoclaltoiwoinngaenadcuhrimnoattoironacotnivtihtey csaesgseiboona.rds below the motor activity monitor was 3. Test Facility Positive Control Data Data on the effectsofacrylamide, carbaryl, d-amphetamine, and trimethyltin are described in ffoorurthseepianrdaitveidrueaplosrmtas.k"ing juTdhgemseenptossiitnivteheconneturroolbeshtuadviieosraalreatnhdenbeausriosopfattrhaoilnoignygtecsetrst.ifTichaetidoanta also document that the equipment and procedures are capableof detecting effects that may be seen in neurotoxicity studies ofthis type. P. Clinical Pathology `Samples for clinical pathology evaluations were collected from the first 10 male and 10 female rats per group in all groups on test days 39 and 95 (males), or 40 and 96 (females). One control `clgirnoiucpamlaplaethroaltohgaydesvaalmupalteisoncsol(leexcctleuddoinngtecsotadgualyat96i.on)Afwteerreoanlesomoconltlheoctferdefcorvoemry1,0 rseacmopvleersyfroarts preesrpegcrtoiuvpel(yc)o.ntArdodlitainodna5l0l0y,magf/ktge/3rdmayonotnhlyso)fornetceosvtedrayy, 1s2a3mpolres1f2o4r(clmianliecsaolrpfaetmhaolleosg,y evaluations (excluding coagulation and including selected urinalysis tests) were collected from up to'5 satellite recovery rats per group (all groups) on test day 184. ~ `The rats were fasted overnight (approximately 16 hours). During this interval, urine was ccloilnlieccatledchfermoimsteraycmheraatsuirnteomevinatlss cwoenrteaiconlilnegcEteDdTfAr.omBtlhoeoodrbsiatamlplseisnufsoorfheeamcahtoflaostgeydarnatdwsheirluemthe rat was under light carbon dioxide anesthesia. Blood samples for coagulation (endofdosing only) and plasma fluoride were collected from the abdominal vena cava while the rat was under carbon dioxide anesthesia, immediately prior to sacrifice. All blood samples were examined visually and observations recorded. 1. Hematology/Coagulation Cheommaptloeltoegbylaonoadlyczoeurntasnd(idnectleudrimnignerdetficruolmocmyitcers)oswceorpeicdeetvearlumaitnieodnoofntahBeabyleoro"dAsdmveiaar.12W0rightstained blood smears from all rats were examined microscopically for confirmationof automated results and evaluationofcellular morphology. Coagulation times were determined on a BCS `Bceahcrhirnagt uCnodaegrulgaotiinognhAenmaaltyozleorg.yNeveawlumaetitohnylbeuntewbelruee-nsottanineeeddbeldofoodrsemvaelaurastiwoenr.e prepared from --~ --- Company Saniized. Dosnotcontain TSCA CBI H9L02-4D7a6y8G:avSaugbcehSrtoundiyc TinoxRiactistywith One-Generation Reproduction Evaluations DuPont:5990 ~ `The following hematology and coagulation parameters were determined: Red blood cell count (RBC) Hemoglobin (HGB) MHeemaantoccorriptus(cHuClTar)volume (MCV) Mean corpusculr hemoglobin (MCH) M(eMaCnHCco)rpuscular hemoglobin concentration PAcrtoitvhartoemdbipanrttiiamle t(hPrTo)mboplastin time (APTT) Red cell distribution width (RDW) Absolute reticulocyte count (ARET) Platelet count (PLT) `DiWfhfietreenbtlioaoldlceeulkloccoyutnetc(ouWnBtC) Microscopic blood smear examination 2. Clinical Chemistry All clinical chemistry parameters were measured in serum, with the exceptionoffluoride, which `was measured in EDTA plasma. Clinical chemistry parameters were measured or calculated on a Roche Diagnostics (BMC)/Hitachi 917 clinical chemistry analyzer. Plasma fluoride concentration was determined using aphi/12pH meter with a fluoride-selective electrode. `The following clinical chemistry parameters were determined: A`Aslpaanritnaeteamaimniontortarnasnfsefrearsaese(A(LATS)T)~~ AToltbaulmpirnot(eAinLB()TP) `SAolrkbailtionledpehhoysdprhoagteansaes(eA(LSKDPH)) CGlaolbcuiluimn((CGALLOCB)) ~ TUorteaalnbiitlriorgubeinn((BBUILNI)) Inorganic phosphorus (IPHS) Sodium (NA) Creatinine (CREA) Potassium (K) C`Throilgelsytceerroidle((CTHROILG)) CPhllaosrmiadefl(uCorLi)de (PFLU) Glucose (GLUC) 3. Urinalysis `The following urinalysis parameters were determined: VApopleuamrean(cVeO(Lq)uality, clarity, and color) Osmolality (UOSM) pSHpecific gravity (SG) GKleutcoonsees ((KUEGTL)U) BBilloiordub(iBn L(DU)BIL) UUrroibnielfilnuoogreidne((UURFOL)U) Protein (UMTP) Microscopic examination of urine sediment Urine volume and appearance were measured and evaluated visually, respectively. Urine `Cchoenmstiistturenytasnwaelyrzeers.emiU-rqiunaentpirtoatteiivnewlyasmemaesausruerdeodnona BaaRyoecrheClDiinaigtneokstiActsl(aBsMTMCYAHuittoamcahtied 7U1r7ine clinical chemistry analyzer. Urine osmolality was determined using an Advanced Osmometer ~~ 3900. Urine fluorides were determined by multiplicationofmeasured urine volume by urine: - CompanySanitized. DoesnotcontTaSiCnA CBI 2904-7D6a8y:GavSaugbechSrtoundiy TinoxRiactistwyith One-Generation Reproduction Evaluations DuPont-5590 ~~ fluoride concentration (measured using a phi/1 2pH meter with a fluoride selective electrode). Sediments from all urine specimens were evaluated microscopically. Q. CollectionofBlood, Urine, Feces, and Tissue (Three-Month Recovery and Fi Generation) On test day -4 (pre-bleed)andtest days 0, 3,9, 21, 34, 55, 76, and 89, blood (approximately 0.5- 1 mL) was collected from the orbital sinusofdesignated animals (5 rats/sex/dose) while the rat was under light carbon dioxide anesthesia for possible analysisof total fluorine. On the day ofblood collection (except test day --4), blood was collected from the animals 2 hours (+ 30 minutes) aftr dosing. Inadvertently, on test day 34, some rats were bled within 2 hours (= 50 minutes) ofdosing. The blood was collected in plastic tubes containing EDTA while on ice. "Theblood was then separated into plasma and RBCs by centrifugation and stored frozen. For each bleeding, blood was collected at approximately the same timeofday. During the last week ofthe 90-day exposure period and the last weekofthe three-month recovery period, urine and feces were collected daily at 24-hour intervals from each animal. The animals were placed in metabolism cages for collection of feces and urine. The exact time periodofcollectionofurine and feces was documented along with the total volumeofurine obtained. Urine and feces were stored frozen. Blood was also collected for possible analysis at 3,7, 12, 19, 26, 36, 50, 71, and 93 days postdosing for both male and female animalsofeach dose group and stored frozen. Animals were sacrificed at the endofthe three-month recovery period. The testes, fat (1 gram), and ~ aliquots of liver and kidney were collected and frozen for possible analysisoftotal fluorine. On postnatal days 33-35 (F,testdays 13-15), all surviving Fy generationratpups in the 500 mg/kg/day group were euthanized. At the timeof necropsy, approximately 1 mLofblood `was collected from the orbital sinusofeach rat. On the same day as the S00 mg/kg/day group sacrifice and blood collection, 5 Fy male pups and up to $ F female pups (that had demonstrated vaginal patency) from the 0, 25, and 100 mg/kg/day groups had approximately 0.7mLblood collected from the orbital sinus, while the rat was under carbon dioxide anesthesia. This blood `was collected from pups in all groups for possible comparisonof selected parameters among these groups. These blood samples were stored for possible comparisonofthese parameters over time. `The collected blood, urine, feces, and tissues may be evaluated in the future for total fluorine. Resulting data will be reported separately. R. Biochemical Measurements, Following 10 or approximately 90 daysoftest substance administration, or after approximately `one month or three monthsofrecovery, five rats from each group designated for biochemical evaluation were weighed and then euthanized by carbon dioxide anesthesia and exsanguination. `At each time point, the livers were removed, weighed, and then aportion ws homogenized (1 gram tissue/d mL buffer) in homogenization buffer (50 mM Tris-HCI, 50 mM Trizma-base, 0.25 --_ M sucrose, and 5.4 mM EDTA, pH 7.4). Hepatic peroxisomes were prepared using differential CompanySanitized.Does notcontTSaCAiCnBI H902-4D7a6y8:GavSaubgcehSrtoundiyc iTnoxRiactistwyithOne-Generation Reproduction Evaluations DuPon-5990 ~ centrifugation. The resulting peroxisomal pellets were resuspended in the homogenization buffer, aliquoted, and stored between -65 and -85C until analyzed for peroxisomal p-oxidation activity. The peroxisomal suspensions were diluted to a protein concentrationofapproximately 0.25 or 0.5 mg/mL. Peroxisomal B-oxidationactivitywas determinedusing [1"Clpalmitoyl CoA as the substrate.) The protein contentofthe peroxisomes was determined before and after analysis by the Biorad method Final ate calculations were made using the post-assay protein concentrations. S. Anatomic Pathology ~ Rats Designated for 90-Day Exposure and Recovery Evaluations After approximately 90 daysofdosing (95 for males; 96 for females and one control male), `groups of 10 male and 10 female rats from the 0, 25, 100, and 500 mg/kg/daygroups were sacrificed and necropsied. Following a recovery periodofapproximately 30 days (one-month recovery), rats from 0 and 500 mg/kg/day groups were sacrificed and necropsied. Male and female animals from a second recovery subset were sacrificed and necropsied following a recovery periodofapproximately 90 days (three-month recovery), where all exposure groups were represented. Rats were euthanatized by carbon dioxide anesthesia and exsanguination. Gross examinations were performed on all male and female rats. In rats sacrificed after three monthsofrecovery, the gross examination was limited to the abdominal and thoracic cavities. `The following tissues were collected from rats designated for the 90-day exposure and one- --~ month recovery. Digestive System Cardiovascular System MusculoskeletalSystem LEisvoeprhagus AHoeratrat FSkeemluertfalinmeuesjcolient Stomach Sterum Duodenum `HematopoieticSystem JTeejuunnum TSphlyemeuns `RepMraodluectiveSystem Cecum Mandibular lymph node: Testes RCeocltounm MBeosneentmearmicowl*ymph node PErpoisdtiadtyemides PSaanlcirvearaysglands `Endocrine System Seminal vesicles Female Pituitary gland Ovaries Urinary System Thyroid gland Uterus KiUdrinneayrysbladder APadrraetnhaylrogildangdlsands Mammary glands RespiratorySystem NervousSystem MisSckelilnaneous Lungs Brain (including cerebrum, Eyes (including optic: TNroascehea Spcienraelbeclolrudm,(cmeerdviuclalla,/mpiodns-) Gnreorsvse)observations Larynx thoracic, lumbar) ~ oPnheamrayrnrxowwascoleciedwSictihatthiec fneemruvreandsternum. -= `Company Saniized. DoesnotcontainTSCA CBI 0H--2D4a7y68G:avSaugbeehSrtoundiyc iTnoxRiactistwyith One-Generation Reproduction Evaluations DuPont:$990 ~~ `The liver, kidneys, adrenal glands, brain, spleen, thymus, heart, ovaries, uterus, epididymides, `and testes were weighed at necropsy, and organ weight/final body weight and organ weightbrain weight ratios were calculated. Thyroid glands were weighed afer fixation. `The following tissues were weighed from rats sacrificed after three-month recovery: liver, Kidney, testes, spleen, thyroid (after fixation), and 1 gramoffat. A sampleofliver was taken for biochemical analysis from control and 500 mg/kg/day males. A sample of liver, kidney, spleen, `and thyroid was taken from all rats for histopathologic evaluation. A sampleoftestes, fat, Kidney, and liver was saved frozen for possible analysisoftotal fluorine. `Gross lesions which were diagnosed at necropsy and for which microscopic examination was not appropriate (e.g, fluid accumulation, ruffled fur, missing anatomic parts) were generally not collected. Gross lesions for which a microscopic diagnosis would not be additive (e.g., osteoarthritis, pododermatitis, chronic dermatitisofthe tail, urinary calculi, and deformoiftthye teeth, toe, tail, or pinna) were saved but were generally not processed for microscopic evaluation. Testes, epididymides, and eyes were fixed in Bouin's solution. All other tissues were fixed in 10% neutral buffered formalin. Processed tissues were embedded in paraffin, cut at a nominal thickness of 5 micrometers, stained with hematoxylin and eosin (H&E), and examined microscopically. All collected tissues from the controlandhigh-doserats sacrificed ontestdays 95 and 96, and all --_ found dead or accidentally killed rats were processed and received a full histopathological examination. Liver, thyroid gland, spleen, and kidneys were processed and examined. microscopically from low- and intermediate-exposure groupsof 90-day rats, and from all rats sacrificed at the one-month and three-month recovery time points. The key to the Pathology Evaluation appendix describes the lesion grading system used in this study. T. Reproductive Assessment 1. Breeding Afr approximately 10 weeksofexposure to the test substance, on test day 72, each female was continually housed on a 1:1 basis with a randomly selected maleofthe same dose level in the `male's cage. On the day copulation was confirmed, the female was transferred back to individual cage housing. Mating pairs were cohoused until evidenceofcopulation was observed (designated as day 0 ofgestation), or until 2 weeks elapsed. The presence ofan intravaginal or extruded copulation plug was considered evidenceofcopulation. Two 500 mg/kg/day males in the reproduction subset died during the premating period. Two surviving males in this group were cohoused with the extra female rats after copulation was confirmed with the original female. Company Sanitized. Doesnot contain TSCA eet CBI 9H0--2D47a6y8G:avSaugbechSrtoundiyc iTnoxRiactistwyithOneGeneration Reproduction Evaluations DuPont:5990 ~ 2. Estrous Cycle Evaluation Vaginal smears were collected from all P; female rats inorder todeterminethe stagesofthe ceoshtarboiutsactyicolne,. aVnadgcionnatlinsumienagrsunwtielrceocpoulllaetcitoend wdaaislycobnefgiirnmneidn,goarptphreoxciomhaatbeitlayt3iownepeekrsiopdrieonrdetdo. dVeatgeirnmailnsemtehaersstwaegeroefaelsstorcooulsleccytcelde.frTohmesalel dPaytapaarreentnaolt fpermeasleentreadtsinattthheertepiomretofbsuatcarriefiicnecltuoded in the study records. 3. Gestation Procedures `eAnfdtoerfbtehiengcothraabnistfaetrrieodn ptoerpiooldycfaorrbfoenmaatleepraantss w(iotnhdoauty 2ev0oifdgeenscetoafticoonpufloartmioant)e,dffeemmaalleersatosrwaetrtehe obsarved at least twice daily for signsofdelivery and pups. The dayofgestation was presumed to have been miscalculated (due to the missed first copulation plug) for one pregnant female in group VIIT-0 (Animal No. 646663) since at delivery pups were much larger than expected for day 16ofgestation and were the size expected for a liter delivered abtotdeyrwme(idgahyt 2a2nodfgfeosotdactioonns)u.mpDtiaotna,fgreosmtatthiiosnalneinmgatlh,weesrteroeuxscclyucdleedpfarroammegtreoruspamnedapnrsec(ogietsatlation interval). --~ 4. Lactation Procedures `The day when delivery was complete was designated day 0 postpartum. At cach examination period, pups were individually handled and examined for abnormal behavior and appearance; any dead, missing, or abnormal pups were recorded. a Day0 Postpartum Live and dead pups in each litter were counted as soon as possible afer delivery was completed. Live pups in each litter were individually weighed. b. Day Postpartum Litters were culled randomly to 8 (4/sex when possible). Extra pups were cuthanatized (by decapitation) and discarded without pathological examination. Litters of8 pupsor less were not reduced. Litter counts were determined prior to and after culling, and individual pup weights were determined prior to culling. c. Days7and 14 Postpartum Pups in each litter were counted by sex and individually weighed. E Company Sanitized. Doesnot contain TSCA Cal H9--2D4a76y6:GavSaubgcehSrtoundiyc TinosRiasistwyithOne-Generation Reproduction Evaluations Dupont. 5990 ~ 4. Day21 Postpartum (Weaning) Psaucprsifiinceedacahndligtrteorswsleyreexcaomuinnteedd boyn speosxtanantdalidndaiyvi2d1u)a.llRyawnedioghmeldy(s3eloefc4t/esdexw/elaintileirngwsere then (loanned/msaerxklsi,tearn)dwweerreepwleaicgehdeidn ainnddivhiadduafloocadgceos,nsmuomnpittioorneddeftoerramtitnaeidnmweenetoklfydeuvnteillodpemveenltoaplmental landmark criteria were met. `Abtehcaavcihoreaxnamdianpapteiaornanpcerei;oad,nyofdfesapdr,inmgiswseirneg,iondriavbidnuoarlmlaylhapnudplsewdearnedreexcoarmdiende.d for abnormal Dweuieghtto,tnhuetrliotiwonnaulm,baenrd ocfli5ni0c0almgob/skegr/vdaatyioFn,srdaattsastairlel anloitvereapfotrertewdeaonnitnhge,spuomstm-awreyandiantag tbaobdleys. Individual animal data are included in the appendices. 5. Post Weaning and Developmental Landmarks O5n00pomsgt/aktga/ldadyaygsro3u3p-3w5er(eFyeutetshtadnaiyzsed1d3u-1e5)t,o ahlilgshupruvipvimonrgtFailigteyneirnatthiiosnrgraotupp.upsThien tmheethod of eMuetthhaondass,iaSeacntdiotnheUe.,ndApnoaitnotmsiecvaalluPaattehdolfoolglyo-weRdatpsroDceesdiugrneastefdofroFryRaedpurlotdsu(cMtaitevreiaElvsalaunadtions, 51.00FymAgd/uklgt/s.dayAtgrtoheuptiamnedobflo5o0d0 wmags/kcgo/ldleacytendecfrroopmsyS, Fbylomoadlweapsupcsolalnecdtuedp ftroo5mFe,afcehmraalteinputphes. --_ a(tnhdatprhoacdedsesmaornesdtersactreidbevdagiinnadeltpaialteinncMya)tefrrioamlsthaen0d,M2e5t,haondds,10S0ecmtgi/okngQ/.daCyolglreocutpiso.noTfhBelomoedt,hods Urine, Feces, and Tissue (Three-Month Recovery and Fi Generation). `Dmeovneiltooprmedenotnala dlaainldymbaarskiss uinnttilhecrFiytegreinoenrawtaisonacmhaileeveadn.dBfoemdayleweriagtsht(oanned/sfeoxloidttceorn)swuemrpteion were determined until postnatal day 56 (Fy test day 36). Animals were weighed on the day the developmental landmark was achieved. a Vaginal Patency Female rats were examined beginning on postnatal day 21. b. Preputial Separation Male rats were examined beginning on postnatal day 35. -- TT------------ Company Sanitized. Does not contain TSCA CBI H9-02.4D7a6y8:GavSaugbcehSrtoundiyciTnoRxiactistywith One Generation Reproduction Evahations ~ U. Anatomical Pathology- Rats Designated for Reproductive Evaluations Sacrifice Schedule Animals Adult Males Pregnant Females Nonpregnant Females Weanlings Fy Adults Schedule After siring liters (at discretion ofreproductive toxicologist) On dayofweaning litters With pregnant females 3 of4 ratssex/liter will be sacrificed on postnatal day 21 Atpostnatal day 60 DuPont 5990 1 PiAdulis AIL Py parental rats were sacrificed by carbon dioxide asphyxiation and exsanguination, and received gross pathological examination, including the females that died and those males and females for which mating did not result in a production ofoffspring. The uteriofall cohabited females were examined for the presence and number of implantation sits. Sperm parameters for the first 10 surviving Py male animals sacrificed by design in each ~ treatment group were evaluated. The right epididymis was removed, and the right cauda. epididymis was weighed. Sperm was collected from the right cauda epididymis and percent `motility and morphology was determined. The left epididymis and testis were frozen in liquid nitrogen and stored between -65C and -85C for sperm and spermatid counts, respectively. `The following table lists tissues that were collected and saved in the appropriate fixative: Tissues Collected from Py Adults Male Female Both Sexes Testes/Testis* Ovaries Thyroid Gland Pr`oEsptidaitdeymides/Epididymis* VaUtgeirnusa(with oviducts) GPirtousistaOrbysGelravnadtions" Seminal Vesicles Coagulating Gland TeosttheestiTsessuetss(nredpreopduicdtiidvyemiadneds/ncop1iedpirdoymdiusctciolvlee)ctceodllfercotmedmfarloemrmaaslweearnedpfleamcaeldeinraBtosuwine'es spollaucteidoni.nAll Gforromaslilne.sions observed at necropsy for which histopathology wasnotappropriate orwouldnt be additive `were generally not collected. --~ -s__Co_mp_ any_San_iti_ zed._Do_esn_otc_ont_ain_TS_CA _ CBI H902-4D7s6y8:GavSaugbechSrtoundeyiTosRiactistwyithOneGeneration Reproduction Evaluations DuPont-5990 ~~ 2. Offspring Offspring that were found dead during the lactation period underwent a gross pathological evaluation. 3. Fi Weanlings TcahrrbeoenF,diwoexaindleiansgpsh/ysxeixaltiitoenra(nrdanudnodmelrywesenltecatgedr)o,ssliptatetrhsoilzoegipcearlmietvtailnuga,tiwoenreonsapcorsitfniacteadlbdyay 21. All surviving Fy generation rats in the 500 mg/kg/day group were euthanized by carbon dioxide `anesthesia and exsanguination on postnatal days 33-35 and received a gross pathological evaluation. Gross leswerieporesnervsed. 4 FiAdils AreIcFei,vegdenaergartosisonparatthsolwoegriecaslacerxiafmiicneadtbiyonc.arSbeolnecdtieodxitdiessausepshaynxdiagtrioosnsalnedsicoxnssawnegurienparteisoenr,vaend.d `The following table lists tissues that were collected and/or weighed: Tissues Collected from Fy Adults Male Female Both Sexes --_ Testes Ovaries `Thyroid Gland EPpriodstiadtyemides* VaUtgeirnusa(with oviducts) PGirtousistaOrbyservations" Seminal Vesicles Coagulating Gland. + Toetshtrest/iTsessuteiss(arnedprcopdiudcitidvyemiadneds/neop1iedpirdoymdiusctciovlelc)tceodlflrecotmemdfaloemamtaslweearnedplfaecmeadlirnaBtouwienr'es lsoaucteodn.inAll Gforromaslilne.sions observed at necropsy for which histopathology was not appropriate or would pot be additive `were generally not collected. Male Testes Epididymides Seminal Vesicles (with Coagulating glands) Prostate `Tissues Weighed from Fi Adults Female Both Sexes Uterus (withoviductsand Thyroid Gland (after fixation) cervix) Liver Brain -- - Company Sanitized. Does not contain TSCA CBI 91.02-4D7a6y8:GavSaubgcehSrtoundiyc TinoxRiactistywith One-Generation Reproduction Evaluations DuPont:5990 ~~ 5. ProcessingofTissues Processed tissues (testes, epididymides, seminal vesicles, prostate, and uterus, ovaries, and vagina) for histopathological examination were embedded in paraffin, cut at a nominal thickness of5 micrometers, and stained with hematoxylin and cosin (H&E). Histopathological examination oftissues was conducted only for Py adults with impaired reproductive performance. Reproductive tissues from some male rats with impaired reproductive performance were saved but inadvertently not processed to slides, and thus not microscopically examined. As these same tissues were microscopically examined in test substance-cxposed rats from the 90-day subchronic toxicity sacrifice, and found to have no test substance-related alterations, the absenceofthese tissues for microscopic evaluation in the reproductive portion of tahlteesrattuidoynsdiwdenroetoibmspearcvtedthienctohnecmlaulsieornastsofwtihteh istmupdayi.reFdurretphreordmuocrtei,vneopetresftosrumbasntcaencteh-artewleartee:d evaluated microscopically. Gross lesions were saved but not evaluated microscopically because they would not have been additive to the interpretationsofthe study. Selected gross observations for which a microscopic. diagnosis would not be additive (e.g., osteoarthritis, pododermatits, tail chronic dermatitis, calculus, and deformitiesofthe teeth, toe, tail, or ear pinnae) were saved, but not processed for `microscopic evaluation. --~ --~ = `Company Sanitized. Does not contain TSCA GBI 9H02.4D7a6y8G:avSaugbelSrooiyciTnoRsaitscywithOne Generation eproducion rations -- V. Statistical Analyses Duron.s590 ind of SeA `Except for Bartlett's test (p < 0.005), significancewas judged at p < 0.05. Separate analyses `were performed onthe data for each gender. [Silldi [-- [ prtmivary Tr et |r SsSiqann er cao n sice" BFFooodooyddWCEoefnicsgiuhertnpGctayoinn I ToTmo-- e trend test" omy malysner -- BOirogcahnemWieciaglhMteasurements sh[omSomgehneWaiitykpeiasnr"d foor |anWeE1folHleowed with | loved FNith _ -- hSeovmheonog'nrine(f5sorand | Re|SpeaSteSdmIeaannes |oSrfebeneaJtorsppiiecTaoopn-e Grip Stags somal boBamrtolegtte'sntiesytof for ve Garrancoe necel enleovredwit l[lyKalwlithaDeuns Terese or pn) Clinical Pathology' homogeneity)a3, and |`vOanrei-awnacyeanfaollylsiosweodfwith |Kfroulslkoawle-dWwailtlihsDteustn"s ~~ Sar `oShrampiro-Wilk test"? for DunoctyWh 3 test IonccOdidepenneceeoorffoCOnlplimcology CochranArmia stforwend InDOcepisediroeofnnFc,OPaeBrameters rey ye oven lowewid Fe oEctet w] + LePsiiorni compasand soneprlminry oswee oly conducted be etfor akof vdwas swtiaghnreinfSeihcdaap. Wilk stvas ot geificantbtLev ttvas igaificant ostversionof Duetscst 3 To ohnednyn abaeinndrdeiba cvloiodrcudaekld(l v10sa-ermvi.antuFiotosenEavPmOapClHce)o,rvdalesduadbbiansgwresepsreepdoartneedcsaerrt0a.i1cn,vr0s.e0vcelseeadnfsorwaenry peeureotmioends Performedih hat blnden . IBfothneiienncoindecnceowanssnoewtisiisgwnoiefdinc.ant, buta significantlackof fitoccurred,then Fisher's Exact test" witah --_ - osCompanySaniized.Doesnot contTSOaAiGBnI `19.02-4D7a6y8:GavSaubgcehSronitciTnuoRxaitcdsitwyiythOne Generation Reproduction Evaluations DuPont5990 ~ `The following table lists the statistical analyses conducted on the indicesofreproductive function that were calculated forthe Py and Fi adults. A -- Body Weight FBoooddy CWoenisguhmtpGtaiionn GOersgtaantiWoeniLgehntgth IImmppllaannttaattiioonn ESiftfeicNiuemncbyers Mean NumberofPups Per LiA tterodie Preliminary Test __|not significant Sequential Test for lack of application"ofthe trend" rJoenncdkhteeesrte-"Terpstra ew gificant [Preliminary tests for |pairwise comparison oLevemne'ns esit forgng | One-wayanalysis of | Kruskal-Wallihs test Precoital Interval SEspterromusPCayracmleetLeernsgth VPraegpiuntailalPaSteepanrcaytion Shapiro-Wilk est for normality" | wVairtihaDnucnenettW'fsoltleoswted" ||Dun"no'lslotweesdtwith 7 rfetrineer|[ee [mem IncOibdseenrcveaotfioCnlsinical MFearttiilnigtyIInnddeexx None GVieasbtialtiitoynIInnddeexx Lactation Index Cochran-Armitage test for trend M(eCaovnarPiuapteWs:eiglhittesr size, [oo Linearcontustof| po sex ratio) least squares means' Sex Ratio 3 sPiaginriufiicsaentc.omparisons sdassociatedpreliminary tess were only conductedifhe tet for lackofwend was btwahs uSshead.piro-Wilk test was not significant but Levens test was significant, a robust versionofDunnett test BIfotnhfeerirnocniidecnocneecwtaisonnowtassigsniefdi.cant, but significant Jackofit occured, thea Fisher's Exact test" witha a: `Company Sanitized. Doesnotcontain TSCA CBI H9-02-4D7a6y8:GavSaugbcehSrtoundiyc TinoxRiactistywith OnGeeneration Reproduction Evaluations DuPont5590 ~~ For cach parameter analyzed with atrendtest,thetest was appliedtothe data sequentially. Ia significant dose-response was detected, data from the top dose group were excluded and the test rafefpeecatteedd fuenttuislensopesriglniitftiercaonrttthreenlidttwear smedaentewcatse"ud"s.'edFaosrtlhiteteerxppaerraimmeetnetrasl,utnhietpfroorpsotrattiisotnicoalf evaluation ) Where the data were tied and the standard large sample versionofJonckheertee'sst was not applicable, exact p values were calculated using permutation methodology. 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. A sample ofthe test substance was collected for archive purposes and retained at Haskell Laboratory. Specimens(if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware. Clinical pathology slides and raw data will be retained at Haskell Laboratory, Newark, Delaware. Characterization data (percent purity, composition, and known impurities) will be stored at Regional Analytical Services (RAS), Jackson Laboratories, Deepwater, New Jersey. Characterization data used to support test substance stability will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, -- Delaware. - `Company Sanitized. Does not contain TSCA G81 9H-02-4D7a6y8:GavSaubgeehSrtoundiyc TinoxRiactistwyith One-Generaion Reproduction Evaluations --_ DuPont-5990 -- RESULTS AND DISCUSSION `Company Sanitized. Does not contain TSCA CBI H9-02-4D7a6y8;GavSaugbcehSrtoundiyc iTnorRiacsitwyithOne Generation Reproduction Evaluations DuPont-5990 ANALYTICAL EVALUATIONS A. Test Substance Stability Analysesof bulk samples ofH-24768 near the beginning, middle, and end ofthe study indicated that the test substance was stable for the durationofthe study. Due to insufficient sample volume, complete analysisofthe sample submitted near the beginning ofthe study could not be: `conducted. However, analysesofsurface tension and density, reported on the certificate of `analysis, dated 29-Jan-2001, support the stability ofthe test substance over the durationofthe study. `The stability of the H-24768 in the samples was based on the physical characterizationofthe test substance. The analyses consistedofthe density at 65 C, the upper cloud point, the surface: tension, the residual ethylene oxide (E.O.) the. ce,andthe percnt fluoride. This wor can be found in| fakell No. H-24768 Analytical Text Table: Analytical Results for Test Substance Stability TypeofAnalyses Sample | Density Upper Cloud Surface Tension Residual CollectiDoany| @65__ Point (C) __(dynesiom) _ Eshylene Oxide_ Appearance %Fluoride TestDay3| 132109 2.0% ND* OK cy ~ Test Day49| 13270 90 20 ND ok 32s Test Day 123 | 13210 91s 210 ND ok 320 b2 VSaalmupelseissuepdparle vatalsuteusdyrespaorrttefdoroanntahlyessispownassoirnssucfefritciifeincattteoopfaenrafloyrsmies diatedbatery oftest. 2N0o.tJdAeNt-e2c0i0e1d. B. Chromatography 'H-24768 eluted from the GC columnasresolved peaks over retention time range of `approximately 5 to 20 minutes. For the purposeof quantitation, the retention times of approximately 7.9, 8.2, 8.5, and 9.0 minutes were determined to be representative ofH-24768 in the dosing matrix. RepresentatiGvCe chromatogramsare shown in Appendix A, Figures 2(a- c). Test substance was not detected in the 0 mg/mL control sample. C. Uniformity ofMixing, Concentration Verification and Stability Samples Analytical results from dosing solutions prepared test day 0, and test day 39 and analyzed for uniformity ofmixing, concentration verification, and stability are shown in Table 1 and Appendix A, Table I. e `Compam ny Sanitizei d. Doesnot tcontainTs SCA CBI H02-4D7a6y8:GavSaugbcelSrtoundiyc TinoxRiactistyithOneGeneration Reproducion Evaluations Dupon5990 ~ Analytical Text Table: Analytical Results for Uniformity, Concentration, and Stability Nmogm/imnla.l Memasgumrled" A%vNeormaigen'al~ CV%__S-%HoNuromStiabinliatyl' 4-D%aNyoSmtaibnilailty * 333 saL28 892 7 88.0 943 133 Le 893 3 87.0 90.0 6667 604551 867 6 87.1 88.3 + SDaumpplliessttcaskaemnpflieosmandaosleyszoeldutionspreparedontestday 0. Sbiltysamplesheld for howsatroomtemperature 4 cSaabmipliitnygsoanmpTleesstpdraeyp3ar9ewdaTsentodasyub0mitaedd.beld for4 days efgerted and sampled. Initial bascline "The results for samples prepared on test day 0, show tht te test substance was uniformly mixed (CVs less than 10), at the targeted levels (target = + 13.3%ofnominal) and stable in the vehicle w4hdeanyshreelfdri5gehroautriosn.atNroooamnatleymspeesrawteurree.coTnhdeucstaemdploenstphreesepasraemdploenst,eostndtahye 3d9aywoefrperespaamrpalteidona,ftteor establish the baseline. However, the results indicated tht the test substance concentrations: following this storage time were simila to those observed in other analyses conducteda the time ofdose solution preparation (ic. test days 32, 42, 91). Furthermore, stability under these storage conditions was demonstrated in previous study (see following paragraph). Test substance was not detected in the 0 mg/mL sample. --~ The following able es results for stability samples from a developmental toxicity study C-- conducted with this test substance. These results indicate that the test substance1the vehicle was stable when held 4 days refrigerated followed by 5 hours at room temperature and support the stabilityofth tet substance under the conditions ofthis study. Thus, dosing solutions could be prepared twice aweek and sored refrigerated until use, and would still provide the targeted dose. This was further confirmed by analysis of samples collected on test day 39 ofthis 90-day study, and held under the same conditions prior to analysis (see above). Analytical Text Table: Analytical Results for Stability g g/mL __%Nominal %_%Nominal % Nominal 50 4m454 926 3 1012 107.4 410000 940326,837859 990859 52 1907502 1907.323 700 2617 891 2 1203 99.6 b DSuapbliilctaytessaammppelseshemldafbore.dys refrigerated. Stability samples held f4odarys refigerted, the5n Boursat oom temperature. - --- Company Sanitzed. Doss not contain TSCA CBI H-24766: Subchronic Toxicity 0-DayGavageStudyinRatswithOneGenerationReproductionEvaluations DuPont:5990 --~ D. Concentration Verification Samples During the Study Analytical results from dosing solutions prepared test day 32, test day 42 and test day 91 and analyzed for concentration verification are shown in Table 1 and Appendix A, Table IL The following table summarizes the results for concentration verification analyses for the test day 32,42, and 91 preparations. Analytical Text Table: Analytical Results for Concentration Preparation Nominal Measured Average CV Da mg/mL mg/mL. 9% Nominal __% Testday32 3.33 3.05,3.08 922 1 13.33 115,116 870 1 66.67 590,617 906 3 Testdayd2 333 13.33 66.67 3.13,3.12 125,125 5838,57.6 93.7 0 9338 0 873 1 Testdayol 3.33 317,318 952 0 1333 124,126 93.8 1 --_ 66.67 587,600 889 2 3 Dupe ampies pe evelwere nayaed CV. called veryanor ofmoxie `The results for samples prepared on test days 32, 42, and 91 indicate that the test substance was adequately mixed (CVs less than 10) and at the targeted levels (target = + 13%of nominal) for all samples. Test substance was not detected in the 0 mg/mL sample. E. Analytical Conclusions Results from the analysisofthe samples collected at study start and during the study indicate that the test substance was mixed uniformly, was at the targeted levels, and was stable under the conditionsofthe study. Test substance was not found in the 0 mg/mL samples. Based on analysesofphysiochemical properties, the test substance was demonstrated to be stable over the courseofthe study. --_ == Company Sanitized. Doesnotcontain TSCA CBI 15.02:4D7a6y8G:avSaubgcehSrtourdiyc iTnorRiactistywithOneGeneration Reproduction Evaluations -- SUBCHRONIC TOXICITY EVALUATIONS DuPont5990 IN-LIFE TOXICOLOGY Rats designated for evaluationofreproductive toxicity were transferred to the reproduction group on test day 70, and were co-housedformating beginning on test day 72. All results reported in this section up to test day 70 (including day 0-70 intervals) include data from both the subchronic. toxicity and reproductive toxicity subsets. All results aftr test day 70 (including day 0-91 intervals) are from subchronic toxicity rats alone. A. Dosage Data (Tables 2-3, Appendix B) Rats were dosed with solutionsof H-24768 in deionized water, prepared at concentrationsof0, 3.33, 13.3, and 6.67 mg/ml, designed to deliver the targeted doseoftest substance at a dosing Volumeof7.5 ml/kg body weight. The quantityof H-24768 administered to each rat was calculated, based on the most recent body weight for each rat, and subsequently rounded by a computer program. - "The rangeofmean daily dose volumes administered to male rats was 1.64.5 ml for the control group, 1.6-4.6 mi for the 25 mg/kg/day group, 1.6-4.1 mi for the 100 mg/kg/day group, and 1.6~ 3.6 ml for the 500 mg/kg/day group. The range ofmean daily dose volumes administered to female rats was 1.3-2.4 ml for the control group, 1.3-2.3 ml for the 25 mg/kg/day group, 1.32.4 mi for the 100 mg/kg/day group, and 1.3-2.3 ml for the 500 mg/kg/day group. B. Mean BodyWeightsand Body Weight Gains (Tables 4-7, Figures 1-2, Appendices C-D) Mean body weight gain in 500 mg/kg/day male rats was lower than control over the entire dosing phase(testday0-91). Mean body weight in this group was 83%ofcontrolontest days 70 and 91, and meanbodyweightgainwas 73% and 72%of control over test days 0-70 and 0-91, respectively. All differences were statistically significant. Inthe S00 mg/kg/day group, mean body weight and mean body weight gain were lower than control on all test days and over all weekly intervalsof the dosing phase except test days 7-14. Differences in mean body weight were statistically significant on all test days and differences in mean body weight gain were statistically significant over all weekly intervals, except over test days 7-14, 56-63, 77-84, or 84-91. Tn 100 mg/kg/day males, mean body weight was lower than control over the entire. dosing phase, but the differences were mild and were only statistically significant on test days 3570. Mean body weight in this group was 95% (statistically significant) and 94% (not statistically significant)of control on test days 70 and 91, respectively. Mean body weight gain was 91% (statistically significant) and 88% (not statistically significant)ofcontrol over test days 0-70 and 0.91, respectively. Although the body weight effect in the 100 mg/kg/day group were mild, they were considered tobecompound relatedandadverse. No compound-related effects on body pe `weight or body weight gain were observed in male rats dosed with 25 mg/kg/day. In this group, - a. Company Saniized. Does not contain TSCA CBI H9-02-4D7a6y8:GavSaugbcehSrtoundiyc TinoxRiactistywith One-Generation Reproduction Evaluations DuPont-5990 ~ `mean body weighton test day 91 and mean body weight gain over test days 0-91 were 105% and 107%ofcontrol, respectively. Neither difference was statistically significant. Mean body weight in 500 mg/kg/day female rats was lower than control over the entire dosing phase. Mean body weight was 95% and 94%ofcontrol (both statistically significant) on test days 70 and 91, respectively. Weekly mean body weight gain in this group was significantly below control over test days 0-7, 28-35, and 63-70 but was significantly higher than control over test days 7-14. Mean body weight gain over other weekly intervals was comparable to control. However, mean body weight gain over test days 0-70 and 0-91 was 87% and 85%ofcontrol, respectively (both statistically significant). Therefore, the body weight effects in this group were considered to be mild, but adverse. No compound-related effects on body weight or body weight gainwereproduced in female rats dosed with 25 or 100 mg/kg/day. Mean body weight on test day 91 was 95% and 99%ofcontrol for the 25 and 100 mg/kg/day groups, respectively. Mean body weight gain over test days 0-91 was 92% and 98%ofcontrol for the 25 and 100 mg/kg/day sgtraotuipstsi,carlelsypesicgtniivfeilcya.nt.NoSnteatoifsttihceaslleydsiifgfneirfeincacnets linowtehre b2o5doyrw1e0i0ghmtg/gkaign/sdawyergerooubpsserwvaesd in the 100 mg/kg/day group over test days 0-7 and 63-70. However, overall body weight gain in this group over the 0-70 and 0-91 test day intervals was 94%and 98%ofcontrol, respectively (neither statistically significant) and there were no statistically significant differences in mean body weight on any day during the dosing phase. Therefore, the body weight effects in the 100 mg/kg/day female group were not considered to be adverse. ~~ Body weight effects were reversible in male rats. In the 500 mg/kg/day group mean body weight gain was 51% higher than control over the first monthof recovery (test days 91-119), due mainly to significantly higher mean body weight gain over test days 91-98 and 98-105. Mean body weight gain was 81% higher than control over the three monthsofrecovery (test days 91-182). Differences in body weight gain were statistically significant over both intervals. Mean body weight in the 500 mg/kg/day group was still lower than in control on test day 119 (90% of control) but was 8% higher than control at the endof the three-month recovery phase (test day 182; not statistically significant). During recovery, muchofthe difference in body weight gain between the control and 500 mg/kg/day male groups reflects a reduction in the control group mean body weight following the 90-day dosing and one-month recovery sacrifices. This reduction is attributed to sampling variability. Although rats were randomly assigned to subsets, and allweretreated the same throughout the dosing and recovery periods, the control rats sacrificed at the endofdosing and one-month recovery periods tended to be heavier than those retained for evaluation after three monthsofrecovery. In the 100 mg/kg/day group mean body weight gain was 19% higher than control over the first month ofrecovery (test days 91-119) and 18% higher than control over the three-month recovery (test days 91-182; neither statistically significant). Mean body weight gain did not differ significantly from control over any weekly intervals during recovery. Mean body weight in the 100 mg/kg/day group was still lower than in control on test day 119 (96%ofcontrol), but was. --~ 6% higher than control on test day 182. Neither difference was statistically significant. Company Sanitized. Does not contain TSCA CBI H9-02-4D7a6y5G:avSaubgcehSrtoundiyc TinoxRiactistywith One-Generation Reproduction Evaluations DuPont:5990 ~ In 500 mg/kg/day females, body weight effects did not demonstrate reversibility over the first `monthofrecovery. In fact, mean body weight gain was below control over 3ofthe 4 weekly intervals (variable statistical significance) and mean body weight gain over test days 91-119 was 26%of control. Mean body weights remained significantly below control over the entire first month ofrecovery. No statistically significant differences in mean body weight or weekly body weight gain were observed over any weekly intervals during these two months, nor over the test day 91-182 interval. Someofthe lossofstatistical significance is attributed to the reduced statistical power due to a reduction in the numberof ats per group. However, mean body weight gainovertestdays 91-182 was 90%of control and mean body weight gain exceeded that of control over many intervals. Therefore, partial recovery was observed over the second and third monthsofrecovery. Overall, adverse, compound-related reductions (compared to control) in mean body weight and body weight gain were observed in male and female rats dosed with 500 mg/kg/day, and in male rats dosed with 100 mg/kg/day. The effects in 500 mg/kg/day females and in 100 mg/kg/day males were considered to be mild. Weight effects were more readily reversible in males than in females. C. Food Consumption and Food Efficiency (Tables 8-11, Appendix E) In 500 mg/kg/day male rats, mean food consumption was lower than control through test day 63. --~ `The differences were statistically significant through test day 56. No statistically significant differences in food consumption were observed over the restofthe dosing phase. However, `mean food consumption over test days 0-70 and 0-91 was 90% and 93% ofcontrol, respectively (both statistically significant). Food consumption in 100 mg/kg/day male rats was generally comparable to control. Mean food consumption in this group was 96%of control over test days 0-70 (statistically significant) and was significantly below control over test days 49-56. These differences in the 100 mg/kg/day group were not considered adverse as the differences were small and the differences in food consumptionovermost weekly intervals and over test days 0- 91 (98%of control) were not statistically significant. No compound-related effects on food consumption were observed in male rats dosed with 25 mg/kg/day. No adverse effects on food consumption were observed in female rat in any dose group. Statistically significant reductions compared to control were observed in the 500 mg/kg/day group over test days 0-7, 7-14, 21-28, and 35-42, and statistically significant increases in food consumption were observed over test days 77-84 and 84-91. However, food consumption over the 0-70 and 0-91 test day intervals was 95% and 97%ofcontrol (neither statistically significant). No compound-related effects on food consumption were observed in female rats dosed with 25 or 100 mg/kg/day. In the 100 mg/kg/day group, mean food consumption was significantly below control over test days 0-7. However, mean food consumption over test days 0-70 and 0-91 was 100%ofcontrol, therefore the isolated interval ofreduced food consumption was not considered to be adverse or a compound-related effect. --_ Food consumption effects were reversible in 500 mg/kg/day male rats. Mean food consumption over the first two weeksofrecovery was significantly higher than control and overall mean food - oo. `Company Sanitized. Doesnotcontain TSCA CBI H9-02-4D7a6y6:GavSaubgcehSrtoundiyc iTnorRiacittywith One-Generation Reproduction Evahations DuPont:5990 ~ `consumption over test days 91-119 was 112%ofcontrol (not statistically significant). Mean food consumption in $00 mg/kg/day female rats was also significantly higher than control over test days 91-98, but was comparable to control over the restofthe one-month recovery phase. Mean food efficiency in 500 mg/kg/day male rats was lower than control over the entire dosing. `phase (test day 0-91). Mean food efficiencyinthis group was 79% and 77%ofcontrol over test days 0-70 and 0-91, respectively (both statistically significant). Mean food efficiency was lower than control over all weekly intervals during the dosing phase. All differences were statistically significant through test day 56 and over test days 63-70. In the 100 mg/kg/day male group, mean food efficiency over test days 0-70 and 0-91 were 95% and 90%ofcontrol, respectively (both statistically significant). Differences in weekly mean food efficiency were only statistically significant over test days 0-7, 14-21, 28-35, and 49-56. However, the effects in this group were considered adverse because they were associated with adverse reductions in body weight gain. No compound-related effects on food efficiency were observed in male rats dosed with 25 mg/kg/day. Compound-related adverse reductions in mean food efficiency were observed in female rats dosed with 500 mg/kg/day. Mean food efficiency was 929% and 88%ofcontrol over test days 070 and 0-91, respectively. The differences in weekly mean food efficiency were only sporadically statistically significant but the effects on food efficiency were considered adverse based on the magnitudeofthe overall effect, and because they were associated with reductions in body weight gain. Mean food efficiency in the 100 mg/kg/day female group was significantly -- lower than control over test days 0-7 and 63-70 and over the 0-70 test day interval (94% of control). However, the effects on food efficiency in this group were not considered to be adverse: as they wereof small magnitude, were not associated with adverse reductions in body weight gain. Furthermore, mean food efficiency over test days 0-91 was 97%ofcontrol (not statistically significant) and weekly mean food efficiency exceeded thatof control over numerous weekly intervals (none statistically significant). The recovery in food efficiency was similar to that observed for body weight gain. In 500 mg/kg/day males, food efficiency over the first month ofrecovery was 27% higher than in control (statistically significant), mainly due to significantly higher food efficiency over the first 2 weeksofrecovery. In 500 mg/kg/day females, food efficiency over the first monthofrecovery remained significantly below control, although weekly food efficiency was only significantly Tower than control over test days 91-98. Food consumption data were not collected after test day 119; therefore, food efficiency was not calculated after that day. Mild but adverse, compound-related reductions in mean food consumption were observed in `male rats dosed with 500 mg/kg/day. Adverse, compound-reductions in mean food efficiency were observed in male and female rats dosed with 500 mg/kg/adndaiyn mal rats dosed with 100 mg/kg/day. Reductions in food efficiency indicate that test substance exposure at these: dosages reduced the rats' ability to convert feed into increased body mass, resulting in lower body weight gain in these groups. Although the effects on food consumption in 100 mg/kg/day `males and 500 mg/kg/day females were not considered to be adverse, they were likely compound. related, and may have contributed to the reduced body weight gain observed in these groups. EE `Company Sanitized. Donotecontsain TSCA CBI H902-4D7a6y8:GavSaugbcehSrtoundiyc TinoxRiacistywith OneGeneration Reproduction Evahations Dupont-5990 ~ D. (ClTianbilceasl 1O2b,s1e3r,v1a6t,i1o7,nsApanpdenMdoirtxaFl)ity Trehlearteedwianscrneoasceosmipnouclnidn-icraelloabtseedrvefafteicotnosnwemorretaolbisteyrivnedeiitnhetrhema5l0e0 omrg/fekmga/ldeayramtsa.leCoamnpdofuenmadl-e `groups. In both sexes, there was a statistically significant increase in the incidenceofwet fur (chin/perineum), clear discharge fromthe mouth, hair loss, and stained fur/skin. The hair loss was observed in many sites including side, perineum, abdomen, ventral body, sacral region, and/or hindlimb. The hair loss was due to ras chewing, possibly in response to general toxicity and discomfort. Therefore, the hair loss was considered indicative ofan adverse effect. "The stained fur/skin was also observed in many locations, but most notably in the perineum in `both males and females. The perineum staining is likely related to staining with urine,sincean increase in the volumeofurine production was observed in both sexes (sce Clinical Pathology section). The increased urination was considered to be a non-adverse, transient pharmacologic aefdfveecrtsoef. tSetsattsisutbisctaallnycesiagdnmiifniicsatnrtaitnicorne.asTehserineftohree,intchiedestnacienoefdclpeearrindeiusmchwaargsecfornsoimdtehreedmonuont-h (males and females) and in hair loss over the dorsal body (females only) were also observed in rats dosed with 100 mg/kg/day, and were considered compound related because they were similar to those observed in the 500 mg/kg/day group. The clear dischargefromthe mouth was observed `most often when rats were handledpriorto dosing, and it was consideredlikelyto be a behavioral response to dosing with the test substance. -- E. Ophthalmology Evaluations (Tables 14-15, Appendix F) No compound-related ophthalmological lesions were observed in male or female rats examined near the endofthe dosing phase ofthe study. Three rats were observed to have unilateral, focal retinal degeneration (one each in the 25 mg/kg/day male, 500 mg/kg/day male, and 500 mg/kg/day female groups) and one rat had phthisis bulbi ofthe globe (one 500 mg/kg/day male). Noneofthese lesions was attributed to dosing with the test substance. F. InLife Toxicology Conclusions Under the conditionsofthi study, the no-observed-effect level (NOEL) for in-life parameters was 25 mg/kg/dayfor males and females. The NOEL was based on clinical signsoftoxicity observed in males and females dosed with 100 and 500 mg/kg/day, and reductions in body weight and nutritional parameters observed in males dosed with 100 and 500 mg/kg/day. In females, compound-related reductions in body weight and nutritional parameters were observed in rats dosed with 500 mg/kg/day. -- - = `Company Sanitized. Does not contain TSCA Cal H9-02-4D7a6y6G;avSaubgcehSrtoundiyc iTnorRiasittywithOne-Generation Reproduction Evaluations --~ NEUROBEHAVIORAL TOXICOLOGY DuPont:5990 A. Sensory Function Evaluations 1. Forelimb Grip Strength (Table 18-19, Figures 3-4, Appendix G) Males administered 500 mg/kg/day H-24768 had significantly lower forelimb grip strength during the week 13 evaluation (25% lower compared to control). In addition, forelimb grip strength in males administered 500 mg/kg/day was 10% lower than the control value during the recovery evaluation (not statistically significant). The decreased forelimb grip strength observed in 500 mg/kg/day males correlates with decreased hindlimb grip strength, and may be secondary to reduced body weight (17% and 10% lower than control values for week 13 and week 17, respectively). Forelimb grip strength for 500 mg/kg/day females was slightly lower (11%)(not statistically significant) compared to the control value for the recovery (week 17) evaluation, which correlated witha slightly lower (10%) body weight, compared to the control value. `There were no test substance-related effects on forelimb grip strength in males or females administered 100 mg/kg/day or below. 2. Hindlimb Grip Strength ~ (Table 18-19, Figures 5-6, Appendix G) Males administered 500 mg/kg/day H-24768 had significantly lower hindlimb grip strength during the week 13 evaluation (18% compared to control), and recovery evaluation (15% compared to control). The lower hindlimb grip strength for 500 mg/kg/day males correlated with the lower forelimb grip strength and may be secondary to the lower body weights. Hindlimb grip strength was also slightly lower in 500 mg/kg/day females during the recovery evaluation (13% compared to control), which may be secondary to the slightly lower body weight during recovery (week 17). `There were no test substance-related effects on hindlimb grip strength in males or females administered 100 mg/kg/day or below. 3. Sensory Function Observation (Table 20-21, Appendix H) `There were no test substance-related changes in sensory function parameters in males or females `administered any dosage ofH-24768. However, male and female rats administered 500 mg/kg/day had higher incidencesofstained perineum (4/10 males and 5/10 females compared to 0/10 control males or females) during the week 13 evaluation. The increased incidences ofstained perineum in S00 mg/kg/day males and females were considered to be test substance-related. --_ Male rat 646373 (100 mg/kg/day group) had abnormal gait during the week 13 evaluation. `However, since this observation did not occur in any male administered 500 mg/kg/day or in any TTI Company Sanitized. Does not conta-- in TSCA CBI H9-02.4D7a6y8:GavSaugbcehSrtoundiyc TinoxRiacistwyithOne.Generation Reproduction Evaluations DuPont:5990 ~ females administered 100 or 500 mg/kg/day, it was not considered to be test substance-related. A higher incidence of an exaggerated reaction to tail pinch (3/10) was observed in males. administered 25 mg/kg/day. However, the incidences were not increased in the 100or 500 mg/kg/day groups, and therefore, the incidence in 25 mg/kg/day males was not considered to be test substance-related. B. Motor Activity (Tables 22-25, Figures 7-10, Appendices 1-7) `There were no test substance-related effects on durationof movement or number ofmovements for males or females for any dosage concentration tested. Females in the 25, 100, and 500 mg/kg/day groups had significantly higher mean number ofmovements during the sixth 10-minute intervalofthe week 13 evaluation. However, a dose-response relationship was not present, and the total number ofmovements was similarto the control value. Therefore, the increased numberof movements inthe sixth 10-minute interval for females administered 25, 200, or 500 mg/kg/day was not considered to be test substance-related. C. Neurobehavioral Toxicity Conclusions Under the conditionsofthe study, the no-observed-effect level (NOEL) for neurobehavioral `parameters was 100 mg/kg/day in males and females. The NOEL isbasedon the significantly decreased forelimb and hindlimb grip strength in 500 mg/kg/day males, and the increased ~ incidences of stained perineum in 500 mg/kg/day males and females. The reductions in grip strength were attributed to reduced body weight and were not considered evidence of neurotoxicity. Although the slightly lower forelimb and hindlimb grip strength was also observed in 500 mg/kg/day females, the minor differences were not considered to be biologically significant. `Company Sanitized. Doesneotceontaein TSCA CBI 1902-4D7a6y8:GavSaugbechSrtouidcy iTnoxRiactistywithOne.Generation Reproduction Evaluations Dupo 5990 CLINICAL PATHOLOGY A. H(Teambalteoslo26g-y2/9C,oaAgpupleantdiioxn K) Males and females dosed with 100 or 500 mg/kg/day had minimal to mild decreases in some or all parameters indicating red cell mass (hemoglobin, hematoerit, and/or red cell count) (Clinical Pathology Text Table 1). In males dosed with 100 or 500 mg/kg/day, minimal decreases in hemoglobin and hematocrit, but not red cell counts, were associated with small red cell. These changes were indicated by decreases in both MCV and MCH, and increased RDW. Increased inciodfmeicrnoccytees and anisocytosis were also present in males dosed with 500 mg/kg/day. Male ats dosed with 5M0C0HmCg,/kign/cdraeyasaeldsorehtaicdulaocccyetleesr,ataenddpprooldyucchtrioomnaosifra;edinccerlelsas(erdegreenteircualtoicoynt,esinadnidcaptoeldybcyhrdoemcarseiaased were also observed in fow rats dosed with 100 mg/kg/day. Several minortreatmentrelated red cell microscopic changes were observed on blood smeoafmarless dosed with 100 or 500 mg/kg/day only. Histologically, males dosed with 500 mg/kg/day had minimally increased splenic extramedullary hematopoiesis (see Anatomic Pathology section). Hematology changes aptremsiedn-tstatudtyh.e end ofdosing were generally ofgreater magnitude or incidence than those present ~~ Freocromvaelrye (raDtas,yh1e2m3a/t1o2l4oR)g,y cahnadnwgeersewceormepliemtpreolvyirnegv,eraslbeeditafntoert 3commopnletthesloyf,raefcteorveornye m(Doanyth18o3fR). `After one monthofrecovery, males previously dosed with 500 mg/kg/day still had minimally decreased hemoglobin and hematocrit, but red cell mass was recovering. However, RDW was increased to a greater magnitude compared to the endofdosing, and was consistent with the microscopic changesof increased nisocytosis, microcytes, and macrocytes. Reticulocyes, polychromatophilic ces, and acanthocyes were increased. After 3 months ofrecovery, red cell parameters in rats were similar o control values in rats previously dosed with test substance. Compared to males, females dosed with 100 or 500 mg/kg/day had similar decrements in red cell mass, however, the relative decrease in red cell mass (compared to control values) was greater, and the responseofthe bone marrow (accelerated production ofred cells indicaling regeneration) was more marked. Female rats dosed with 100or 500 mg/kg/day had decreased red cell mass phaermaamteotleorgsic(dpeacrraemaesteedrsreidndceilclatcionugnta,ccheelmeorgatleodbipnro,dauncdtihoenma(tionccrrieta)s,edanrdetailctuelroactyitoenss, iRnDW, and polychromasia, and decreased MCHC). MCH was decreased (500 mg/kg/day only); in some animals, this decrease comrelated with decreased MCV, suggesting the presence of smaller cells woibtsherlveesds hienmfoegmlaolbeisnd.osOetdhewritmhin1o0r0raenadtm5e0n0t.mrge/lkagt/eddayr.ed Hcielsltomliocgriocaslcloyp,icfecmhaalnegsedsowseerdewith 500 mg/kg/day had minimally increased splenic extramedullary hematopoiesis (see Anatomic gPraetahtoelromgaygsneicttiuodn)e.orRiendcicdeellnccehtahnagnesthtohsate pwreerseenptreastemnitda-sttuhdeye.ndofdosing were generally of ------------------------------------------ Company Sanitied. Dossnot contain TSCA Cal 9H02D4a76y8G:avSaugbecShtruodnyiiTnoxRiactitwyithOne Generation Reproduction Evahations DuPont5990 ~~ rIencfoevmearly,e arantds,wheermeactoomlpolgeytcelhyanrgeevserwseerdeafiimeprr3ovmionngt,haslobefirtencootvecroym.pleAtfetleyr,oanfetemroonntehmoofnth of recovery, females previously dosed with 500 mg/kg/day still had minimally decreased hematocrit (not statistically significant), but red cell mass was recovering. However, RDW, echinocytes, and acanthocytes were sill increased compared to control values. After 3 monthsofrecovery, red cell parameters in rats were similar to control values in rats previously dosed with test substance. `The red cell mass changes, during dosing, in female rats dosed with 500 mg/kg/daywere: considered adverse due to the magnitudeofthe change. Similar typesof changes occurred in `males during dosing, but these changes were not considered adverse because the magnitude of change was not expected to have an adverse impact on functionofred cells. Clinical Pathology Text Table 1: Red cell mass parameters T "MalT es TT Females | a tm [CRBC T3970 |""08% | 99% | 102% || To1% |93%| 93%| [1 osm6 | 100% | o8% | 103% || o7% | 91% | 89%| [I snzaR TNT ITNT [Tor |[NT |NT | 08% | [e oo% |o8% | om |R |100% |99% | 101% | ~~ [THGB| 3oia0 "00% | 09% | 96% | | 101% |94% | 91%| [T |oo%o | os% | 9m 2% ||o7% |e 90%| 85%| [T TN o T[NT n | 95% e [| | NT _|Nr T|97% | [ et [0s 1%e | 98% |n 99% |R |1e 01% | 94%y |97%| [CHCT "30 "00% | oo% | 96% || 102% |95%|94%| [T | 0%o | 96% | 9m 4% ||o8% |e 01% | 87% | [CT snzaR [NT NT | 96% || NT |NT| 07% | C Re recover1 y ime-poins t. R[00% | 99% |100% || 104% |96% | 100%| * Riensduilctastperdbesyebntoeldaaslpcerzceednttoyfcpeoncurrent control group mean. Siatsial significance is NT: Not taken -- ee ---- `CompanySanitized. Donotecontsain TSCA CBI H9.02-4D7a6y8:GavSaugbcehSrtoundiyc iTnoxRiacsitwyithOneGeneration Reproduction Evaluations DuPont-5990 ~ All other statistically significant changes in hematology or coagulation parameters were considered unrelated to treatment and/or non-adverse (not toxicologically significant). These changes are detailed below. Females dosed with 500 mg/kg/day had mildly increased platelets at Day 96. Increased platelets were likely secondary to increased erythropoietin production in response to the red cell changes. Mildly increased platelets are not associated with adverse effects. After one `monthofrecovery, platelet counts were similar to control values in rats previously dosed with 500 mg/kg/day. Males dosed with 25, 100, or 500 mg/kg/day had minimally increased monocytes at Day 39. `This change is possibly related to treatment. However,becausethere was arelatively flat dose response, no peripheral need for increased monocytes (no inflammation observed in clinical or anatomic pathology results), and because the change was minimal and transient, this change was not considered adverse. Females dosed with 500 mg/kg/day had minimally increased white blood cells and lymphocytes at Day 40 only. This change is possibly related to treatment. However, because this change was minimal and transient, it was not considered adverse. Atthe endofdosing (Day 95/96), males dosed with 100 or 500 mg/kg/day had minimally shortened activated partial thromboplastin time, and females dosed with 500 mg/kg/day had -~ `minimally shortened activated partial thromboplastin time and prothrombin time. Afier one `monthofrecovery, coagulation times were similar to control values in rats previously dosed with 500 mg/kg/day. The coagulationtimechanges were likely related to treatment, but were not considered adverse, because shortened coagulation times are not associated with adverse effects. `The following statistically significant changes in hematology or coagulation parameters were considered to be unrelated to treatment because they did notoccur in a dose-related manner, or occurred only after one or three monthsofrecovery: Increased neutrophils in males dosed with 500 mg/kg/day after one monthofrecovery Increased neutrophilsand monocytes infemalesdosed with 25 mg/kg/day at Day40 Increased platelets in one female previously dosed with 500 mg/kg/day, after 3 months of recovery. This change was considered to be unrelated to treatment because subjective evaluation ofplatelet counts on blood smears from 2 other rats in the group did not indicate: increased platelet counts. In addition, increased platelets occurred after 3 months but not one month ofrecovery. -- - mg Company Sanitized. Dossnotcontain TSCA Cal H902-4D7a6y8:GavSaugbcehSrtoundiyc TinorRiacsitywith OneGeneration Reproduction Evahations -- B. Clinical Chemistry (Tables 30-31, Appendix K) Dupont. 5950 LiverTests dMuarliensg dtohseeddoswiintgh p5e0r0imogd/(kCgl/indiacyalhPaadthmoilnoigmyalTleyxttoTambilldel2y).inAcrneiamsaeldsAwLiTthamnodrSeDpHroancotuivnicteieds cwihtahngleesss(pRraotmNiunmebnetres.nz6y4m6e3c4h6anagneds.64C6h4a75n)gehsadinsAimLiTlaranhidstSoDloHgiacctcihvaitnigeesswceormepoafrseidmitloatrhose magnitude at both time-points, and persisted during one and three monthsof recovery. In contrast, females dosed with 500 mg/kg/day had transiently (Day 40 only) increased ALT activity, without an associated increase in other time-points. Therefore, this change SDH. ALT activities were similar to conrol was considered to be unrelated to treatment. values at `The minimally to mildly increased ALT and SDH activities in male rats suggest hepatocellular injury. Histologic changes (see Anatomic Pathology section) did not indicate cellular damage, only hypertrophy. In individual animals, the magnitudeofenzyme increase did not correlate with degreeofhypertrophy. However, dueto the consistency and persistence ofthe enzyme changes, the increases in ALT and SDH in male rats were considered potentially adverse. Males and females dosed with 500 mg/kg/day had minimally increased ALKP activity and bilirubin concentration during the dosing period. (Clinical Pathology Text Table 2). Compared ~ to control values, the change was similar at both time-points. There was only occasional correlation between ALKP activities and bilirubin concentrations, suggestingthat a mechanism other than cholestasismightbe involvedin ALKP or bilirubin increases. Males and females dosed with 500 mg/kg/day had increased liver weights and liver hypertrophy, changes that normally are associated with enzyme induction (see Anatomic Pathology section). Enzyme induction is consistent with the ALKP changes, but wouldnotbe expected to result in increased bilirubin unless cholestasis occurred secondary to hypertrophy. Therefore, the cause for increased bilirubin is unknown. `These minimal changes in ALKP and bilirubin were not present aftr one or three months of recovery in rats previously dosed with test substance. The changes in ALKP and bilirubin were considered non-adverse because they were minimal and were reversible on cessationofdosing. PS Terme Company Saniized. Doss not contain TSCA CBI H9-02-4D7a6y8:GavSaugbechSrtoundiy iTnonRiactistywith One-Gencration Reproduction Evaluations DuPont5990 ~ Clinical Pathology Text Table 2: Changes in hepatic parameters for males and females T "MalT es TT Females | |Doi se(o mgkgtdayA) R| 25 | tS1.00 [500 |B| E 25 |J100 [500 | Sl eb [ALT | 30 92% | 106% | 64% || 11%|125%|764% | [1owe 1 ioow | wiose| 75206 |[76%[61% |73% | [ t [ 1 myT erp | | NseTwi || Narr |"7re 9od%s e |||[mNnT[|r Nvy aTs ||t55o%v|] [spi| somo 1" io | toa | 137% |[102% [00% | 92%| [ [1 1 wo5pma6 [|"w1ir3% | | 1woat%T | a 130% |[[8w9t% || 6n8%t |7i 5% | t [1 sr | 157% | 16p 0% |E22R1%||R 86%[e 120%|y 131% | [ALKP| 30 "02% |ow | 125% |[108% | 101%| 174% | [ [C1 T wospma6 [|w89r% [|Noar%T|o14s% |[[1n02t%|[11n3r%||2o0o7%|| [ t 1 srp | 124% | 13%|106% || t 109% | s2%y |133% | [CBr| somo "75% | tise | 250% |[100% [100% | 129% | [1 osm6 |" 90% | 1as% | 200% || 88% |oa% |124% | [TT moyiaR [NT[NT[00% || NT |NT|8%| ~ C Ri recove1 ry tme-point.ex J wow | son |emJ] sm]sw]so] Ni"aRTle:iscuNilztoesdtpreesnented as perofcconecunrretnt control group mean. Statistical significance s indicatedbybold Renal and Electrolyte Changes Males dosed with 100 or 500 mg/kg/day had either no change or minimal increases in parameters. that measure glomerular filtration (urea nitrogen, creatinine, and inorganic phosphorus) during the dosing period (Clinical Pathology Text Table 3). Concentrations were similar at both timepoints for urea nitrogen and creatinine. After one monthofrecovery, creatinine was decreased, `whereas urea nitrogen and inorganic phosphorus were increased in males previously dosed with 500 mg/kg/day. Histologically, there was no correlation between individual rats with chronic progressive nephropathy and rats with increased urea nitrogen and inorganic phosphorus. After three monthsofrecovery,a few rats previously dosed with 500 mg/kg/day had increased inorganic phosphorus; again, this change did not correlate with rats that had chronic progressive nephropathy. Females dosed with 500 mg/kg/day also had minimal increases in urea nitrogen, creatinine, and inorganic phosphorus during the dosing period (Clinical Pathology Text Table 3). In addition, females dosed with 25 or 100 mg/kg/day had minimally increased urea nitrogen, without changes in creatinine or inorganic phosphorus, but only at the endofdosing. In females previously dosed with 500 mg/kg/day, these changes were not present after one monthofrecovery. After three ~~ `monthsofrecovery, inorganic phosphorus was increased (not statistically significant) in females aBlea `Company Sanitized. Does ne ot contae in TSCAe CBI 0H--2D4a76y8;GavSaubgeelSrtoundiyc iTnoxRiactistywithOne-Generation Reproduction Evaluations DuPont-5990 ~ ptrreeavtimoeunstlybdeocsauesdewtihtehre1w00asorn5o0e0ffmegc/tkogb/sdearyv;edthaisftcehraonngeemwoansthcoofnrseicdeorveedryt.o be unrelated to `aTnhde imnionrigmaanilcipnhcoresapsheosruisn)pawrearmeetgeernserraelfllyecctoinnsgigdleormeedrturleaartmfeilnttr-arteiloant(eudreian mniatlreosgeann,dcrfeeamtailniense, dmoesaesdurweidthi1n0t0his(msatluedsy wonoluyl)donro5t0b0e,mgin/kigs/oldaatyi.on,Fcoorntshiedseerepdaraadmveetresres., cChhaannggeessoofftthheismamgangintiutduede aevnidbeencoebosferrveendaliinnjtuhreyawbasesncoebosferrveendalinhimsatloelosgaicndalfteermaatlieosnsd.osHeodwewvietrh,50in0tmhgis/ksgt/uddya,y.histologic Twheerreefnoortec,oanlstihdoeurgehd tahdevecrhsaen,gtehseiynwuerreea snuiptproogretni,vecorfeaatdivnienres,eafnidndpihnogssphionrhuiss,toblyogtyh.emselves, dSeocmreeamsaedlesoradtisu(m50a0ndmgc/hlkogr/iddaey)duarnidngatfheewdofseimnagleperraitosd(.10T0heore5ff0e0ctmwg/aksg/sidmaiyl)arhaatdbmoitnhifmiamlel-y phooiwnetvs.er,Eftfheectpsososnibclhelocrhiadnegweerinecshtillolrpiodsesaitblthyipsrteismeen-tpaofitnetroocnceurmroendtihnotfhreeacbosveenrcyeoifncmhaalnegreatss;in ottrheeartmpeanrtambeetcearuss.e Ithnicsrecahsaendgesowdaisumnoatftperrestehrneteafmtoenrtohnseofmroenctohovefryrewcaovsercyo.nsidered unrelated to Decreased sodium and chloride during dosing indicate lossoffluid containing these two electrolytes. Becauseofthe marked increase in urine volume in individual rat, loss through the ~ urinary tract ofchange is most likely. This change was not considered adverse du to the minimal degree Males dosed with 100 or 500 mg/kg/day had minimally increased potassium during the dosing period. A few femaleratsat the same doses had similar changes. The effects were similar at btootchonttirmoel-pvoailnutess. inAfrtaetsr porneevioorutshlryeedomsoendtwhistohfrteesctosvuebrsyt,anpcoe.tasTshieumrecaosnocennftorratailtoenrsedweproetassismiiluamr was not determined, but was likely related to treatment dueto the consistencyofchange across. time-points, groups, and sexes. The magnitudeofincrease in potassium was always minimal and was not considered adverse. -- -_-- Company Sanitized. Does not contain TSCA CBI 0H--2D4a7y68G:avSaubgcehSrtoundiyciTnoxRiactitwyith One-Generaion Reproduction Evaluations DuPont:5990 ~ Clinical Pathology Text Table 3: Parameters indicating glomerular filtration rate T "MalT es Temas] Dose mafky/da) | 25 100 50 [35 T100 [500 | [Rt ammer[Day |t | [t T_T 1 1 [BT ON|e 590T1o [o0||6 ia0r7s% 9 ||12435%%|||rteo0%]|[i1o169%|%|112315%%|| [NT "NT "106%| e[ e eee 8 T %e|e2e % |toise% |R |toi m |120% |120% | [CREA| soo 1"7i06% | 113%|125% || os |os |173% | [1 osio6 1 108% |124% |11% | | os% [105% | 114% | [o NTTNTw | 08% [|Ne T|NT|om | [ tp"0W u3i% | S88e% ||I 109W% |R |O0W2% J|OtoMa%]|o98s% || [PHS| 39740 ["i00% |106% |101% || 105% |105% |122% | [1 smeTome| 7a |11% | | or [115%|125% | [| DyerTNTTNT "776% || NT | NT |106%| L Ri covery time-pornt. io0% | 109R % | 129% || 104% |136%|136% J * Rietsaulilctiszepdretsyepneted as percent ofconcurrent control group mean. Satistical significance is indicated by bold NT: Not taken ~~ Protein Maleand female rats dosed with 25 (males only), 100, or 500 mg/kg/day had dose-dependant, mildly increased albumin, which generally resulted in increased total protein during the dosing period (Clinical Pathology Text Table 4). This effect was slightly more pronounced at the end of dosing compared to mid-study. Changes in albumin were still present after one month of recovery in male rats previously dosed with 500 mg/kg/day. In addition, after one month of treatment, globulin concentration was mildly increased in bothmalesand females. The albumin and globulin increases after one monthofrecovery could not be definitively attributed to treatment; however, the consistencyofthe result and the continued presence ofcompound (as indicated by urine fluoride measurements) makes this changeofuncertain relationship to treatment. Afier three monthsofrecovery, females previously dosed with 100 or 500 mg/kg/day had minimally treatment increased globulins (no dose response); this change may or may not be related to Increased albumin causing increased total protein indicates alterations in albumin synthesis, distribution, or metabolism. Minimally increased globulin in the presenceofincreased albumin is interpreted similarly. Although the changes in albumin and globulin concentrations were considered related to treatment, they were not considered adverse because mild increases in these `parameters have no known adverse effects. EE `Company Sanitzed. Does not contain TSCA CBI 29H0-0-2-D4Da7a6yy8G:GaavvSaaugbgceehSSrttouunddiyyciiTnnoRxRaiatctsistwwyiitthhOOnnee-GGeenneerraattiioonnRReepprroodduuccttiioonnEEvvaalluuaattiioonnss ~ Clinical Pathology Text Table 4: Protein parameters DDuuPPoonntt:59590. pete) |3 Two sw[1 To[50| FT1 Wels TT Temas] [Rammer| Day [1 11 [| soso Too | josw |112% || oo% | om |104% | [oT sm TToNmTo [|NsaTr%||amv roaw[| || ioNsT ||a N1aT1s|| 111010%%|| [ er ToT mp | e 101% | 1R 01% g |R | 1J0O1%|1J0O4% |T1I01N%] [A somo [osm | os% | grow | orm [iow| 124% || 128% | | 102% | 114%|110% | ow |1asw| aisw| [ p [ ee [ TToN T y wT| |oNsp m t% ||og ims%% R a || ||e N1oTa%| |IoNR eTK %||oIj50Ns%%|)| [GrobTomo T"i00% | 00% | 100% | | Too% | 96%|96% | [ [ 1 oT sm6 T1NomT%o [|N10r 0% | | 9y 035%% |||| tNoaT||e 1N0T8%||1a0r4s%%|| [ Recovery ime-porn. Tos w | tom | 03% |R |or |14% |14% | * Raelsiuclitzsepdryepseent as percent ofconcurrent onirol group mean. Statistical significance i indicted by bold NT: Not taken ~ Calcium dMoasliensgapnedrifoed.malTehsedeofsfeecdtwwiatsh s1i0m0iolarr5a0t0bomtgh/ktigm/ed-apyoihnatsd.miCladllcyiiunmcrweaassesdticllamlicniiummadlulryinignctrheeased ifnemmaallees.s pArfetveiroutshlreyedmoosendthwsiotfh r5e0c0ovmegr/yk,gc/adlacyiuafmtecronocneentmroanttiohnosfwreecroevseirmyi,labruttohcaodntrreoclovvaelrueedsin cinhaanlgsepsrdeivsicouusssleyddaobsoevde.witChaltcesitusmubesxtiastnscei.n sTehreumcailnctiwumocfhoarnmsg,esitpharearllbeoluenddthteoaallbbuummiinn or ruengbuolautnedd.("Ifnocnriezaesde"scianlcailubmu)m.inonariezenedcecsaslacriiulmy iassstohceipahtyesdiwoiltoghipchaylsliyoalcotgiivcealfloyrmap,paronpdriiasttei.ghtly iunnacfrfeeacsteedd.boCuhnadncgaelsciiunmc,awlictihumreasrueltsaenctoinndcarreyasteodcthoatnalgecsalicniuaml.bumHionw,evaendra,rieocnoinzseiddcearlecdium is `physiologically insignificant, and therefore non-adverse. Lipids `Mmaoldeesraatneldyfdeemcarleeasseddosterdigwliyctehri1d0e0coonrc5e0nt0rmatgi/okngs/dduaryihnagdthmeilddolsyinigncpreeraisoedd. cThohleesetfefreocltsawnedre isinmcirleaarseadt (bnootthsttiamteis-tpiocianltlsy.siIgnnriaftiscapnrteviniomuaslleysd)oasfetderwointehm5o0n0tmhgo/fkrge/cdoavye,ryc.holAefstteerrotlhwreaesmsotinltl hs opfrreevcioouvselryy,docsheoldeswtietrholteastndsutbrsitgalnyccee.ridIenccornecaesnetdrcahtoiloensstewreorleasnidmidleacrretaosceodnttrroilglvyacleureidsesinirnadtiscate malatgenriattiuodnes iwnalsipsimdalmletaanbdolwiassm.noCtheaxnpgeecsteidntloipriedssulwteirnetcoxoincsiitdy.ered non-adverse because the. Te `Company Sanite ized. Doeesn--ot--con--tabinmTSmCAtCeBIt H902-4D7a6y8:GavSaugbechSrtoundyc iTnorRiactistwyith One-Generation Reproduction Evaluations DuPont-59%0 ~ ``Tbheecafuosleltohweiyngoccchuarnrgeedsaifntcehtehmriesetmroynptahrsa,mebtuetrnsotweorneecmoonnstihd,eorefdretcoobveeruyn.related to treatment Irneccroevaesreyd sodium in males previously dosed with 500 mg/kg/day after three months of Increased inorganic phosphorus three monthsofrecovery in females previously dosed with 100 or 500 mg/kg/dayafter C. Urinalysis (Tables 32-33, Appendix K) Mgraalveistyalnodsmfoleamlailteysadnodseidncwrietahse5d0u0rimnge/kvgo/lduamyehdaudrimnigldtlhey tdoosmianrgkpeedrlioydd.ecTrheiasseedffuercitnweasspesciimfiilcar oatfbiontchretaismeed-pvooilnutmsedsuorfidniglduotseinugr,inbeuctawnabsendouteprteospeonltyaufrtiear(oinnecrmeoasnetdholofsrseocfowvaetrey.r tPhrrooduugchttihoen `rweansalnotrtacdte)toerrmpionleydd.ipsHioawe(ivnecrr,eassoedmedrriantksidnogsoefdwawtietrh)5.00Inmtgh/iskgs/tdudayy,htahde csamualsleovfodliulmuetse ourfine cproenvcieonutsrlayteddosureidnew.itIhn5a0dd0itmigo/nk,gt/hdiasyc.haInt gfeolwlaowssrtehvaetrsdiibllueteafutreirnoenweamsonnotthcoafurseecdobvyerreynianl rats impairment, but was a transient pharmacologic effectoftest substance administration. ~ Males and females dosed with 500 mg/kg/day had moderately decreased urine pH only at the end. o5f00thmegd/oksgi/ndgapyearfitoedr.onTehemsoencthhaonfgreescwoeverreyn.otDepcrerseeanstedinumrailneespoHrifsegmeanleersalplryevtihoeurselsyuldtoosfed with physiological renal compensation for excess acids physiologic rather than a toxicologic response. in blood. This change was considered to be a (Mmaalleessaantdthfeemeanldeosfdtohseedstwuidt,h a5n0d0fmegm/aklge/sdaatymhida-dsmtiulddy)l.y dTehcirseacsheadngureiwneasprcoatuesinedcobnyceinntcrraetaisoend urine volume, which diluted the protein present in urine. has no toxicologic significance. Decreased urine protein concentration Atlrleaottmheenrtsatnatdi/sotricnaollny-asidgvneirfsieca(nntocthtaonxgiecsoliongiucrailnlaylyssiigsnipfaircaanmte)t.erTshweeserechcaonnsgiedsearreedduentraeillaetdebdetloow. pArtevtihoeuesnldy dofosoende-wmiothnt5h00remcgov.erTyh,iusriinnecrperaosteeiwnascodncuenttoratthieopnrweasesnicneocrfebasleododinifneumrailneerats (incidental finding), to treatment. rather than glomerular or tubular injury, and thus was not considered related --~ TT Company Sanitizede . Does e notcontae inTSCA CBI 9H204D7a6y8:GavSaugbechSrtouidcy TinoxRiactistwyithOne.Generation Reproduction Evaluations Dupont5990 ~ Plasma and urine fluoride Males (25, 100, or 500 mg/kg/day) and females (100 or 500 mg/kg/day) had increased plasma fluoride concentrations during the dosing period (Clinical Pathology Text Table 5-6). After one. `monthofrecovery, plasma fluoride concentrations were decreased, relative to endofstudy `values, in males and females previously dosed with 500 mg/kg/day. However, in females, plasmafluorideswere still minimally increased compared to controls at this time-point. After three monthsofrecovery, plasma fluoride concentrations were similar to control values in all rats previously dosed with test substance. Males and females dosed with 25, 100, or 500 mg/kg/day had increased urine fluorides (total `urine fluoride excreted during urine collection period) (Clinical Pathology Text Table 5-6). Increased urine fluorides were still present after one monthofrecovery in males and females previously dosed with 500 mg/kg/day, although the magnitudeofthe effect had decreased substantially. After three monthsofrecovery, urine fluorides were further decreased relative to end-of-study and one-month recovery values in rats previously dosed with 500 mg/kg/day. However, urine fluorides were clearly increased compared to concurrent control values in both `males and females previously dosed with 100or 500mg/kg/day. Urine fluorides in females previously dosed with 25 mg/kg/day were also slightly increased compared to control values, although this change was not statistically significant. `The presenceofincreased plasma and urine fluoride indicates exposure to a fluoride-containing ~ ccoonmtpaoiuninndg.cTohmepopurnedsesnacreoe fsfllouwolryibdeeiinng urreilneeas3edmofnrtohmstiasfstueer esixtpeso.sure suggests that fluoride- Clinical Pathology Text Table 5: Fluoride parameters (absolute values) T MalesT | Females | |Doe semgm hgidp ay))| 0 |25 | 100 [5000 | 0 |B 25 [0 100 |0 500| [Parameter |" Day | 1 [PFLU ugmD) 95/9 |01|02 | 02 |05 | 01| 01 |02 |a5 | [ [momar [or[NT[NT[or[ 0 [NT|Nr | os| [ ee1E RTor[or[or|e oi[of[ot |oi |or] [OFLUGee) | 3970 ND[ND |ND|ND[ND|Nb|Nb|Nb| [1 9osw6 [121[506 |740.8| 6326]55 | 23.7| 50.4|291.7| C [ Re recoverT y mepotet rRs [T1e0d2[[1N3T5|[2Na 2.T5[[948638 [[a529||r N86T ||0N9T||13507|| N=TS:ttNsottiacakesnignificance is indicated by bold licized ype ND: Not done ~~ -_-- Company Sanitized. Does not contain TSCA Cal 9204D7a6y8:GaSvuabgcehrSotnuidcyTionsRicaistywithOGneneration Reproduction Evaluations Dupont 5990 r~ Clinical Pathology Text Table 6: Fluoride parameters (compared to concurrent control values) T Males T -- T emals _] ey o | Parae meter | Day |0 | 25 | 100o | 500y [0 | D 25 |D 100 |s00| [FLU | 95/06 |NA| 200% |200%|500% | NA |100% |200% | 500% | [ [i23/a2aR NATNT|NT|100% |NA| NT[NT |"Na_| [1 18p R |Np A|100%|100% |100%|NA | 100% |100% |100%| [1 o3s9m4e0 |NATN18D%||1N6D4%| | 5N22D8%[NA[ND |1N03b0%| | 5N29D5| % [ [msnar 1214% 714% [ recoveryiC me po1ints3R1 [NA [130%| 207%| 459% |NA|146% |168%| 266% * Rieasluilctszepdretsyepneted as percent ofconcurrentcontrol group mean. Siatstical igaificance is indicated by bold NA: dNeontomapipnlaitcoarblwea(sei2t2h1e0r)because the calculation would be 100%-dividing number by tel, o because the NNTD:: NNoottadkoneen D. Clinical Pathology Conclusions --_ Under the conditionsofthis study and for the parameters measured, the no adverse effect level for males was 100 mg/kg/day, based on the presenceofincreased ALT and SDH during treatment, which persisted into recovery. The no adverse effect level for female rats was 100 mg/kg/day, based on the presenceofmild decrements in red cell mass parameters (hemoglobin, hematocrit, and red cell counts), associated with regeneration. There were no adverse findings for coagulation or urinalysis parameters for either sex. --_ - eComp_ any S_ aniize_ d. Doe_ s notc_ ontain_ TSCA -- CBI 01.-2D4a76y8:GavSaugbechSrtoundiyciTnoxRiactitwyithOneGeneration Reproduction Evaluations -- BIOCHEMICAL MEASUREMENTS DuPont:5990 A. Biochemical Measurements (Table 34-35, Appendix L) `The rateofhepatic B-oxidation, a measureofperoxisome proliferation, was determined in a subchronic oral toxicity study with H-24768 in male and female rats after 10 days or 95 days (males) or 96 days (females)oftet substance administration or following 2 one-month or three`month (male only) recovery period. `At the 10-day time point in male rats, the rate ofhepatic p-oxidation was increased in adosedependent manner and was statistically significantly increased in rats dosed with 100 and 500 mg/kg/day (171 and 286%ofconirol, respectively). At the 90-day time point, the rate of hepatic B-oxidation was statistically significantly increased in rats dosed with 500 mg/kg/day (181% ofcontrol). At the one-month recovery time point, the rateofhepatic p-oxidation was statistically significantly increased in rats dosed with 500 mg/kg/day (195%ofcontrol). At the three-month recovery time point, the rate of hepatic B-oxidation had retured to control levels. At the 10-day, 90-day, and one-month recovery time points, the increases in hepatic B-oxidation activity were accompanied by increases in liver weights In female rats, the rate ofhepatic B-oxidation was reduced at the 90-day time point in rats dosed ~~ with 25 mg/kg/day. This decrease was not considered a compound-related effect due to a lack of a dose-response and lackofconcordant changes in anyofthe other dose groups at any of the sampling time points. At the one-month recovery time point, the rateofhepatic B-oxidation was increased in rats dosed with 500 mg/kg/day (131%of control). Dueto the small magnitude of the increase (131%ofcontrol), the increase at the one-month recovery time point was not considered tobebiologically significant. Hepatic B-oxidation was not evaluated at the three- `month recovery time point in female rats. In-life data (body weight, nutritional and clinical observation parameters) collected for the rats evaluated for 10-day biochemical evaluations will not be included in this report but are in study records. B. Biochemical Measurements Conclusions Under the conditions ofthis study, H-24768 was a mild inducer ofhepatic peroxisomal oxidation in male rats. At dosages of 100 mg/kg/day and greater, changes in the rateofhepatic peroxisome proliferation were considered to be biologically significant effects. At the one`ramtosndthosreedcowvietrhy5t0i0memgpo/ikngt/,dtahye,rbautteohfahdepreattuircnepdertooxciosnotrmoelplreovleilfserbaytitohnewtahsreien-cmroenatshedriencomvaelrey time point - `Company Sanitized. Does not contain TSCA CBI F9-02-4D7a6y6:GavSaugbcehSrtoundiyc iTnoxRiactistywithOGneeneration Reproduction Evaluations DuPont-5990 ANATOMICAL PATHOLOGY 'SUBCHRONIC TOXICITY AND RECOVERY A. Causeof Death (Tables 46-47, Appendix N) Nreocouvnesrcyhgerdouulpesd.deOantehsmoaclceurrarteddoisneadnwyiftehm1al0e0 mragt/skign/tdhaey9d0i-eddoayfetxrpaousmuaresoercoonndea-rmyotnotthhe bilnefeldaimnmgatprioocneadnurde/.or oObnsetrcuocnttiroonl. mNaolneeaonfdth2emsaeledseadtohssewdawsictohn5si0d0emregd/ktges/tdsauybdsiteadnocfekreildatneedy. Oprnoecescso.ntrTohlefreemwaelereinntohceotmhproeuen-dm-ornetlharteecdodveeartyhgsraotuapndyidedooseftlervaelu.ma secondary to the bleeding B. Organ Weight Data (Tables 36-37, Appendix M) Liver: Mean liver weights (absolute and relative to body and to brain) were significantly higher in all dheopsaetogcreolulpuslaarthtyhpee9r0t-rdoapyhysa(csreiefidciesicnumsasiloensunadnedrfMeimaclreoss,coapnidccFoirnrdeilnagtse)d.wiLtihvemricwreoisgchoptisca:t the. ~~ one-month recovery sacrifice were significantly higher in the 500 mg/kg/day males and females than in controls. There were no intermediate groups evaluated at the one-month recovery sacrifice. Mean absolute and relative (to body) liver weights were higher, compared to controls, in the 500 mg/kg/day males and in the 100and 500 mg/kg/day females at the three-month recovery. Higher liver weights were considered compound-related and correlated with microscopic hepatocellular hypertrophy diagnosed in animals from the 90-day and one-month recovery sacrifices. Kidney: `At the 90-day sacrifice, mean kidney weights (absolute and relative to body and to brain) were significantly higher than controls in 500 and 100 mg/kg/day females. The mean relative (to body) kidney weight was significantly higher in 500 mg/kg/day females at the one-month croencsoivdeerryeadncdotmhproeuen-dm-ornetlhatreedcoavnedryposascsriibfliyceass.soHciigahteedr wmietahninkcirdenaesyedwecihgrhotnsicinprfoegmraelsessivweere nephropathy detected microscopically. M10e0anmgr/eklagt/idvaey(1m0abloedsya)t ktihedn9e0y-wdeaiygshatcsriwfeicreeasnidgniinfi5c0a0ntmlyg/hkiggh/edraythmaanlienscaotntrhoelosnien-5m0o0ntahnd rreefcloevctesrythseacrreifdiuccee.dbTohedyinwceriegahset iinn rtehleasteivaen(itmoalbso,dybu)t,kiidnntehyew5e0i0ghmtg/inkgt/hdesaeyggrroouupps, wpraismaarlisloy possibly associated with increased chronic progressive nephropathy detected microscopically. `Compar ny Saneitizee d. Doee snotce ontain TSCA CBI 9102-4D7a6y8:GavSaugbcehSrtoundiyc iTnorRiactistwyith One-Generaion Reproduction Evaluations ~ Spleen DuPont:5990 R5e0l0atmigv/ek(gt/odbaoydfyemaanlde/sorattothbera9i0n-) dsapyleseancrwifeiicgeh(trselwaetriveeitnocbreoadsyedatco5m0p0amrge/dkgto/dcaoyntarnodlsrienla1ti0v0e atnod cbornatirnoalts 1at00thaenodn5e0-0momngt/hkgr/edcaoyv)e.ryMseaacrnifsipcleebeuntwreeilgathitvsew(etorebondoyt)ssipglniefeincawnetilgyhdtisffienretnhte from 5hi0g0hemrg/skplge/ednaywefiegmhatlseswewreerecohnisgihdeerrtehdacnocmopnoturnodls-raetltahteetdharnede-cmoornrtehlarteedcowvietrhyisnaccrriefaiscee.d The extramedullary hematopoiesis detected microscopically. o`Trhgearne wweeirgehtnochoatnhegrescoimnptohuensdu-brcehlraotneidcoarngdanrewceoivgehrtyegfrfoecutpss. wAelreostehecronsdtaatriysttiocadlelcyrseiagsneifsiicnanbtody `weight or were spurious. C. Gross Observations (Tables 38-39, Appendix N) 5La0r0gmegl/ikvger/sdwaeyrfeemoablseesr.veTdhiats tohbese9r0v-adtaiyonsaccorrirfeilcaetiend5w0i0thahnedpa1t0o0cemlgl/ulkagr/dhayypemratlreosphaynddiiangnosed microscopically and was considered to be compound-related. There were no compound-related gross observations in one-month or three-month recovery animals. --_ Other gross observations noted at any time point were sporadic across groups and were not considered to be compound-related. D. Microscopic Findings (Tables 40-47, Appendix N) Liver: `aTnhderfeewmaalsesmi(n1i0m0aalntdo5m0i0ldmgd/ikffgu/sdeayh)ep,aatnocdeilnlu5l0a0r hmygp/ekrgt/rdoapyhymainle9s0-adnadyfmeamlaelses(aalt tdhoeseonger-omuopsn)th `rmeocnotvherryectoivmeeryp.oinMti.crTohsecropeiwcaalsly1,0hheeppaattoocceelllluullaarrhhyyppeerrttrroopphhyywiansmaclhearsaocrtefreimzaeldebsyatanthienctrhereaes-ed ahimsotuonmtoorpfhfoilnoegliycgervaniudleanrceeoosfinhoepphaitloiccelclyutloaprldaasmmawgiet.hiTnhheepsaetvoecryitteyos.f Thehpearteocwealslunloar hypertrophy `rawtass. leTshsusin,ocnoem-plmeotnethrreevecrosviebrilyirtaytosftthhaenmiincr9o0s-cdoapyircathsepaantdocwealslualbasrehnytpienrttrhorpehey-mwoansthesrteacbolvisehreyd, ahelptahtooucgehllluilvaerr wheyipgehrttsrorpehmyaainneddtheeleavsastoecdiattherdouignchrtehaesetihnrelei-vemronwtehigrhetcsovweerryepceorniosdi.derTehdea compound-related physiologic response to a xenobiotic and not toxicologically adverse. ?2429 PN TT -- Company Saniized. Does not contain TSCA CBI _ E nmT inis arn [EI TPeaa-- sorn]|IEo+Nn[[Eo5wNeJTa[ EwrE[[oowNe|[o [NoEwNoT{no EooaweYTeLEoo]vmY bm Li Hyipertirmophy]m w|o|[we [on [oe]w [os|] Kidney: "The incidenceof chronic progressive nephropathy, a spontaneously occurring lesion in rats, was increased (compared with controls) in 500 mg/kg/day males and in 100 and 500 mg/kg/day femalesatthe 90-day sacrifice. The incidenceofthis lesion was also increasedinmales and females at the one-month recovery (500 mg/kg/day) and in 100 and 500 mg/kg/day females at the ~ three-month recovery. This lesion was considered compound related and adverse. TT "Males [Females| momienn]+T[o5JToww [on[|ooo[oonT[o]r Diepehropathy To Tor Tor To ToaLe [Nephropathy sn | 20 | smu | mae| 210 > sox| sox -r a ee m aT Tor Toe Toe Tor Tor] oe a Apoundsign(#) indiancefafecttleevsel. An increased incidenceofextramedullary hematopoiesis was observed in 25, 100, and 500 mg/kg/day males and females at the 90-day sacrifice, in 500 mg/kg/day males and females at `the one-month recovery, and was not observed in any exposure group at the three-month A ---- recovery. Thus, reversibility of increased extramedullary hematopoiesis was established. The --_ occurrence of a single incidence in some groupsofextramedullary hematopoiesis (25 mg/kg/day `males and females at the 90-day sacrifice and 25 and 100 mg/kg/day males at the three-month Br A io .20S ~~ recovery sacrifice) was not considered a compound-related effect, as this can occur `asspeocnotanndeaoruyslpyhyisniaonloogciccasrieosnpaolnsaenitmoaclh.anIgnecsreianserdedexcetlrlammeadsusllaanrdynhoetmaatporpiomiaersyisadwvaesrsceonefsfiedcet.red Hematological this report, findings and interpretations are discussed within the clinical pathology portion of I5n0c0remags/ekdgp/idgamyefnetmainletsheatsptlheee9n0w-adasoybssacerrivfiecdei, nin150000anmgd/5k0g/0dmagy/mkagl/edsayatmathleesonaen-dmonth recoveryand in 100 and 500 mg/kg/day females at the three-month recovery. The pigment observed tumover. was As consistent with hemosiderin and could with extramedullary hematopoiesis, the be an indication ofincreased red cel presenceof increased pigment was l not considered aprimary adverse finding. BpEreerloNn+E[o=nNMatl[esown1[EvYs|E1 N[|EonFoNem[aEloewswN[E]|| ~ Ebr[Hemratoepoiesi]s oon w[ow[Low[oow[onw[woo [oono[o]n bP=sim]ToonoonoL[oooe w LToor[oonwToev]| Bian]oxLoLo[on [ow[50]ow] Thyroid: Follicular hypertrophy was present in thyroid glands in all male dosagegroups and in 100 and 500 mg/kg/day female groups at the 90-day sacrifice and in 500 mg/kg/day males and females at the one-month recovery. Follicular hypertrophy was present in 500 mg/kg/day males at the three- nn `month recovery, but not in females. Follicular hypertrophy was characterized by tall columnar follicular epithelium with a finely granular or vacuolated cytoplasm. The occurrence ofasingle incidenceof follicular considered compound hypertrophy in related because a 25 this mg/kg/day male at the 90-day lesion can occasionally occur sacrifice was not spontaneously. --_ Hanypienrdticraotpihoynofotafhyprhoyisdiofloolgliicculraerseppointsheealnidumnoist, naesciessshayrpielrytardovpehryseof.otHhoewreveenrdo,cirninteheoragbasnesn,ceofotefn' H9.02-4D7a6y8:GavSaubgcehSrtoundiyc TinoxRiactistwyith One-Generation Reproduction Evaluations DuPont-5990 ~ hormonal data to demonstrate maintenanceof normal hormonal levels, the thyroid hypertrophy was considered potentially adverse. Follicles containing altered colloid were found in thyroids fromcontrolsas wellas in treated 90day, one-month recovery and three-month recovery rats. An increase in incidence and/or in Severity gradeof this lesion was present in all exposure groups at all ime points and was c`gornasniuldaerr,ecdlcuommppeodu,nda-nrde/loartdeidf.fusTehley bdaisaogpnhoisliisc "caolltleoriadt.ioAn,4collelvoeildg"rwaadsinugssecdhteomdeiawgansosapepsltiiepdpled, based on an estimate ofthe percentage of follicles that contained altered colloid. A grade of 1 was applied when up to about 25%ofthe follicles were involved; with grades 2, 3, and 4 applied for each 25% increase in follicular involvement. The size, density, or staining intensity of stipples, granules, clumps, or diffuse basophilia within individual follicles did not impact the grading. Although follicular hypertrophy was usually accompanied by altered colloid, the reverse was not necessarily the case, as altered colloid was observed in the absenceoffollicular hypertrophy. Altered colloid described as lumped or granular has been reported to occur spontaneously in cSoplrlaogidueo-cDcuarwslesypornattsanweiotuhsilnycirneahseianlgthiyncSipdreangceuec-orDraewllaetiynrgattso,ianncdresaisnicneg iangce.r"easesBeicnaiutssgeraaldtienrged score occurred in some groups without morphologic alterations in the thyroid, altered colloid was interpreted in the present study as not biologically adverse. ~ All ther microscopic observations noted are known to occur spontaneously in ratsofthis strain and age and were not present in adose response fashion in either incidence or severity. min] + 5 0[| 5 ow | [AHpypoertrophy Males TT ont | vio | one| une Females | 2n0 | sox ES a [wars a [fr [mHyperterophy]2[owv |wnTeJom[wn| so Jor| [Hypertroophyver ws | om oa Emin) Alteration, Colloid] 0| | xn Toei[un| vo Jno] eration, Colloid a Apoundsign (#) indicates an effect level. b NA indicated tissues wer not availble. -_-- Company Sanitized. Does not contain TSCA CBI H-24766: Subchronic Toxicity 20-DayGavageStudyinRatswithOne Generation ReproductionEvaluations DuPont-5990 ~ E. Anatomical Pathology Conclusions for Subehronic Toxicity Evaluation Ekixdpnoesyu,rsepltooctnh,eatnedsttshuybrositda.ncIenfcorreaaspepdrolxiviemrawteeilgyh9t0s adnady/soprrmoidcurcoesdcoapltiecrahteipoantsocienltlhuelalriver, f`heympaelretsroapth9y0w-edaryes,praensdenitni5n0205,mg1/0k0,g/adnady5m0a0lemsg/akngd/dfeamyamlaelseastatnhde oinne1-0m0onatnhd r5e0c0ovmegr/yk.g/Tdhaeyse liver changes were considered to representa and thus were not considered to be adverse. physiologic response to metabolism ofa xenobiotic iInncfreemaasleeds,chwraosnipcrpesreongtreisnsi5v0e0nmegp/hkrgo/padtahyym,asloemseatnidme1s00acacnodmp5a0n0imegd/bkyg/idnacyrefaesmeadlkeisdantetyhweeight 9500-0dmagy/skagcr/idfaicye,feimna5l0es0 matgt/hkeg/thdraeyem-amloensthasnadcrfiefmicael.esTahtisthfeiondnien-gmwoansthcornesciodveerrye,d atondbeinad1v0e0rsaen.d tAlitmeeraptoiinotnso.fcTolhleosiedvewraitsyporfeasletnetreind tchoelltohiydroiindtshoyfromiadlgelsanadnsdifnecmraelaessedatbealyloenxdpocosnutrreollelveevleslsataasll talhteedraotsieonisncarnedasweads, hnootwecvoensriidtewraesd bniootloagsiscoaclilayteaddvweirtshe.any adverse cellular morphologic 5Co0m0pmogu/nkdg-/rdealyatmeadlehsypaenrdtrfoepmhayloefsfoatlltihceu9l0ar-deapyitshaecrliifuimcei,nitnhe50t0hymrgo/idkgw/adsayprmeaslenetsiannd10f0emaanldes at tsahceriofniece-.moTnhtyhroriedcogvlearnydsfaoclrliifciuclea,rahnydpeirnttrhoeph5y0,0imngt/hkega/bdsaeyncmeaolfeshoatrmtohenathlrdeaet-am,ownaths rceocnosviedreyred -- potentially adverse. t`Tohxeicnool-oogbiscearlvleydi-mcpfofretcatnlteveeflfe(ctNsOaEtLtr)ibfuotrabtlheistsottuhdeytiesstdesfuibnsetdanacsetwheerheignhoetstdedteocsteeda.t wUhnidcehr the `cTohnedsietiNoOnsEoLfSthwiesrsetubdays,etdhoenNmOiEcrLosfcoorppiacthcohlroongiycwparsog2r5esmsgi/vkegn/edpahyroinpamtahlyeiannmdalfeesmaalnedraftesm.ales dosed with 500 mg/kg/day hypertrophyofthe thyroid and in in 100 females dosed with and 500 mg/kg/day 100 mg/kg/day, and males and females. on follicular -- a a`Company Sanitized. e Does not contad in TSCA CBI 9H02-4D7a6y8:GavSaubgcehSrtoundiyciTnoRxiacsitywith One-Genertion Reproduction Evaluations DuPont5990 REPRODUCTIVE TOXICOLOGY EVALUATIONS REPRODUCTIVE FUNCTION A. Py Generation 1. Mean Body Weights and Body Weight Gains (Table 48-50, Appendices O-T) Mean body weights 500 mg/kg/day. and body weight gains in the P, generation rats were lower than control at Mean body weight gain was significantly lower than control (68%ofconirol) in Py male rats wdeuirgihntgsanwderaeftaelrstohseicgonhifaibciatnattliyonlopweerriotdha(ntesctondtaryosl 7(78-39%8)-8at4%5o0f0cmogn/tkrgo/ld)ayin.thWiesegkrlouypm.eWaenebkoldyy mean body weights were statistically significantly lowerthan control ontestdays 77-98 in Py male rats at 100 mg/kg/day. This change was not considered toxicologically significant because it was small (93%-94%ofcontrol) and was not associated with lower body weight gain in this group. ~ dMuerainngbgoedsytawteiiongh(tdagyasin0-w2a1sG)siagtni5f0ic0anmtgl/ykgl/odwaeyr.thWaeneckonltyromle(a7n2b%oodfycwoentirgohlt)siwnerPye aflesmoales rats significantly lower than control (85%-92%ofcontrol) in this group. Reductions in mean body `weights and body weight gains occurred during gestation in P, female rats at 25 and 100 mg/kg/day. These changes were not considered toxicologically significant because they rweedruectsimoanllin(o9v0e%ra-l9l5b%oodfy cwoenitgrholt),gasipnoriandtihce,saengdrowueprse. not associated with any significant Statistically significant differences (both higher and lower than control) in mean body weight gain were observed in Py female rats during lactation at all dose levels. These changes were not considered test substance-related due to their sporadic and inconsistent nature, and lackofeffect soingnoivfeircaalnltlbyoldoywweeritghhatngcaoinntraotlainnyPdyosfeemlaelveel.ratWsedeukrlinygmleaactnatbioondyatwe1i0g0hatnsdwe5r0e0 mstga/tkisgt/idcaalyl.y `These changes were not considered toxicologically significant because they were small (87% 97%of control) and were not associated with lower body weight gain in these groups. 2. Food Consumption and Food Efficiency During Gestation (Table 51, Appendix U) eFfofoidciceoncnysuwmapstlioownewratshannotcoanftfreoclte(d7i3n%oPyffceomnatlreolr)atisndPu;rifnegmagleestraattisodnuartianngygedsotsaetiloenve(ld.ayFso0o-d 2ob1s6e)rvated50d0urmign/gkgge/sdtaayt.ionThiinsthcihsagnrgoeupi.s consistent with the lower mean body weight gain - a Company Sanitized.Doesnotcontain TSCA CBI 2904-7D6ay8:GavSaugbechSztoundcy TinoxRiactistywith One-Generation Reproduction Evaluations Dupont 5990 ~ 3. Clinical Observations (Tables 52, Appendices V-X) `There was no test substance-related mortality. Salivationatthe timeofdaily dosing was observed in male rats at all dose levels and in female rats during gestation at > 100 mg/kg/day. Stainingofthe perineal or inguinal area was observed in a few animals at 500 mg/kg/day. The toxicological significanceof salivation in Py males at 25 mg/kg/day is uncertain due to its low. incidence and sporadic occurrence. 4. Reproductive Indices (Tables 53-55, Appendices Y-EE) `There were no test substance-related effects on percent days in estrus, diestrus, or proestrus. Individual animals displayed persistent or prolonged estrus or diestrus during the evaluation period. These abnormal cycling pattems were not considered test substance-related since they occurred toasimilar degree in the control and treated groups. Mean cycle length was similar at 25, 100, and 500 mg/kg/day (4.7, 4.9, and 4.8 days, respectively) but was significantly greater than the control group (4.3 days), however, mean values were within the historical control range for Haskell Laboratory. The toxicological significanceofthese changes is unclear. `There were no test substance-related effects on sperm motility, morphology or testicular spermatid counts. The mean numberofepididymal sperm per cauda was similar at 25, 100, and 500 mg/kg/day (278.8, 291.1, and 279.4 million sperm, respectively) but was significantly lower ~ than the control group (318.4 million sperm). Although not statistically significant, a change of similar magnitude was observed in the mean number ofepididymal sperm per gram cauda at 25, 100, and 500 mg/kg/day (979.2, 969.0, and 1062.1 million sperm, respectively) compared to the control group (1180.2 million sperm). These changes were not considered toxicologically significant because they were small (82%-91%ofcontrol), mean values were within the: historical control range for Haskell Laboratory,* and were not associated with any histopathological changes in the tests or epididymis. The mean number of testicular spermatids per tests was statistically significantly higher than control at 500 mg/kg/day (126.5 vs. 137.0 million spermatids). This change was not considered test substance-related since the mean numberofspermatids per gram testis at 500 mg/kg/day was similar to the control group. `There was no test substance-related effect on the lengthofthe precoital interval or on the mating index (number of females with evidence ofcopulation/ numberof females cohabited x 100) or gestation length. The fertility index (numberoffemales delivering aliter/numberoffemales with evidenceofcopulation x 100) was similar at 25, 100, and S00 mg/kg/day (55%, 58%, and 65% at 25, 100, and 500 mg/kg/day, respectively) but was lower than the control group (85%). `This change was considered test substance-related. The number of uterine implantation sites was significantly reduced at 500mg/kg/day (10.7 vs.15.3 for the control group). There was no effect on implantation efficiency (number of pups born/number of implantation sites x 100) at any dose level, indicating no post-implantation loss (no resorptions). --~ * FotrhseecvoenntsotludgireosucposnrdaunctgeeddfatoHmask4e.l2l4.L9adboaryastotrhyembeetawneeenpi1d9i9d9ymaanlds2p0e0r1mthneummbeearnamesotnrogutshceyccolntloelnggtrhoaumposng ranged rom 274.3-345.5 millon sperm. - a `Company Sanitized. Doesnotcontain TSCA CBI 2904-7D6a8y:GavSaugbcehSrtoundiyc iTnoxRiactistwyith One-Generation Reproduction Evaluations Dupont 5950 ~ B. Offspring Data 1. Litter Size, and Pup Weights, Clinical Observations, and Survival (Table 56-58; Appendices FF-HH) Mean litter size was lower than control at 500 mg/kg/day. Sex ratio and gestation index (percent litters having at least one live pup) were unaffected in F; litters at any dose level. The numbers of pups bom and born alive were significantly lower than control at 500 mg/kg/day (72% and 66%ofcontrol, respectively). As a result, the mean percent pups bom alive was significantly Tower than control at 500 mg/kg/day (86.5% compared to 100% in the control group). Pup survival during lactation was lower than control at 100 and 500 mg/kg/day. The mean `numberofpups per litter on day 4 preculling, day 7, 14, and 21oflactation were significantly lower than control at 500 mg/kg/day (53%, 60%, 14%, 10%ofcontrol respectively). The mean `numberof pups per liter was similar to control on day 4 and 7oflactation at 100 mg/kg/day. `The mean numberof pups alive at day 14 and 21 was significantly lower than control at 100mg/kg/day (79% and 76%of control, respectively). As a result, the lactation index (survival from day 4 postculling to day 21) was significantly lower than control at 100 and 500 mg/kg/day (76.1% and 11.4% compared to 100% in the control group). The litter survival index (percent liters born with at least on live pup on day 21) was significantly lower than control at 500 mg/kg/day (25% compared to 100% in the control group). Pup weights at birth and during lactation were lower than control at 100 and 500 mg/kg/day. ~~ Mean pup weight at birth was significantly lower than control at 500 mg/kg/day (90% of control). Mean pup weights during lactation were lower than control at 100 and 500 mg/kg/day. Mean pup weights were significantly lower than control at 500 mg/kg/day on days 4, 7, 14, and 21oflactation (71%, 54%, 56%, 57%ofcontrol, respectively). Mean pup weights were significantly lower than control at 100 mg/kg/day on days 4, 7, 14, and 21 (94%, 86%, 94%, 94% of control, respectively). `There were no test substance-related clinical signs in pups during lactation at any dose level. C. Fi Generation Due to poor survival in 500 mg/kg/day Fy generation rats, there are insufficient data available to evaluate post-weaning in-life parameters. Therefore, results from this group will not be: discussed. 1. Mean Body Weights and Body Weight Gains (Table 59-60, Appendices 11-11) `There were no test substance-related effects on body weight and body weight gain in Fy male and female rats during the post-weaning period at 25 or 100 mg/kg/day. --_ . -a `CompanySaniized. DoesnotconTtSaCAiCnBI H9-02-4D7a6y6:GavSaugbcehSrtoundiyc TinoxRiactistwyithOne-Generation Reproduction Evaluations DuPont-5990 ~ 2. Food Consumption and Food Efficiency (Tables 61-62, Appendix KK) There were no test substance-related effects on food consumption and food efficiency in Fy male `and female rats during the post-weaning period at 25 or 100 mg/kg/day. 3. Clinical Observations (Tables 63, Appendix LL) `The few pups in the 500 mg/kg/day groupthat survived to weaning on postatalday21 either died soon after weaning or were sacrificed on postnatal day 33-35. There were no test substancerelated clinical signs in Fy maleand female rats during the post-weaning period at 25 and 100 mg/kg/day. 4. Developmental Landmarks (Tables 64, Appendix LL) `There were no test substance-related effects on the age at onsetof vaginal opening in Fy female rats orofpreputial separation in Fy male rats at 25 and 100 mg/kg/day. D. Reproductive Function Conclusions `There was no NOEL for the reproductive toxicity parameters evaluated under the conditions of --~ this study; this was based on effects at all dose levels on the fertility index in the Py generation. - = Company Sanitized. Doesnotcontain TSCA CBI H9L02-4D7a6y8G:avSaugbcehSrtoundiyc TinoxRiacistywithOneGeneration Reproduction Evaluations --~ ANATOMICAL PATHOLOGY REPRODUCTIVE TOXICOLOGY EVALUATIONS DuPont.5990 A. Mortality Fy Adults (Appendix NN) Donuepotsotneaxtcaelssdiavye3t3o-x3i5c.ityT,htehree5w0e0rmegn/okgc/odmapyouFnyda-nriemlaaltsedreetfafiencetds aofnteprowseta-nweianngiwnegrmeorstaaclriitfyicfeodr the other groups. B. Organ Weight Date Fy Adults (Tables 65-66; Appendix MM) Organ weight data was not collected on the 500 mg/kg Fy animals retained after weaning because they were sacrificed early. ~~ `wTihtehre25weorre1n0o0cmogm/pkog/udnady-.relAatseidgneifffieccatnstodnectrheeasoergiannmweeainghltisveorfwFeiigahdtuslt(mabasloelsutoerafnedmarleelsatdivoesetdo body and to brain), and an increase in mean brain weight (relative to bods) in 100 mg/kg males `were considered to be secondary to lower body weight in that group. C. Gross Observations Parental Py Adults (Tables 67-68, Appendix NN) Fy Adults and Weanlings (Tables 69-75, Appendices 00-QQ) Tinheprareewntearleonrowceoamnploiunngdr-artesloactceudrrgerdosisnolboswerivnactiidoennsceisn apanrdenwtearleorrawnedaonmlliyngdirsattsr.ibuOtbesdearcvraotsisons control and treatment groups. Olebssieornvsatthiaotnasriencpoumpmsoonfllyunsgesennoitn eaxllppanudpesdt,haatnadrenobomimlkdesapdo,t ainndthtehusstoamreacnho,t acroennsoinsdpeercietfodicbe compound-related. Pup viability and mortality are discussed elsewhere in this report. D. Microscopic Observations Parental Py Adults (Tables 76-77, Appendix NN) There were no compound-related microscopic findings in anyofthe Py males or females that received microscopic evaluation. Lesions occurred in low incidences withouta relevant doseresponse relationship and were considered incidental occurrencesofspontaneous lesions in rats ~ of this strain and age. ~ = Company Sanitized. Doesnotcontain TSCA CEI 29H0-0-2-D4D7aa6yy8G:GaavvSaauggbecehSSrtountdiyciuiTnnodRRxaaiyttcisstwywiitthhOOnnee-GGeenneerraattioonnRReepprroodduuccttiioonnEEvvaalluuaattiioonnss DDuuPPoonntt-5$999900. ~~ E. Anatomical Pathology Conclusions for Reproductive Toxicity t`Tohxeicnool-oogbiscearlvleydi-mepfofretcatnlteveeflfe(ctNsOaEtLtr)ibfuotrabtlheistsottuhdeytiesstdesfuibnsetdanacsetwheerheignhoetstdedtoecsteeda.t wUhnidcehr the conditionsofthis study, the NOEL for pathology was 100 mg/kg/day for males highest F) adult dosage group evaluated for reproductive anatomic pathology. and females, the --_ eee erect Company Sanitized. Doesnot contain TSCA CBI 910.-2D4a76y8:GavSaugbechSrtoundiyc TinoxRiactistwyithOne.Generation Reproduction Evaluations --~ CONCLUSIONS DuPont5990 Under the conditionsofthis study, the no-observed-effect level (NOEL)* for H-24768 for the 90day exposure in male and female rats was 25 mg/kg/day. This level wasbasedon clinical signs oftoxicity, decrements in body weight parameters and food efficiency (males), thyroid follicular hypertrophy, and chronic progressive nephropathy (females), al observed in the 100 mg/kg/day groups. Other adverse, compound-related effects observed in males and/orfemalesdosed with 500 mg/kg/day include decrements in body weight parameters and food efficiency (females), chronic progressive nephropathy (males), increased liver enzyme activities (males), reduction in redblood cell mass parameters (females), and reductions in forelimb and hindlimb grip strength (males). The reductions in grip strength were considered secondary to body weight effects and `were not considered evidence ofneurotoxicity. Other compound-related effects were observed that were not considered adverse, but were cither physiologic responses to exposure to the test substance or markersofexposure. Increased liver `weight and hepatocellular hypertrophy were observed in all dosed male groups and in 100 and 500 mg/kg/day female groups. These effects were considered non-adverse physiologic responses. In 100 and 500 mg/kg/day males, the liver effects were associated with reversible inductionofhepatic p-oxidation. Microscopic changes in the spleen, including extramedullary `hematopoiesis and pigment, sometimes associated with increased spleen weigh (in females) `were considered non-adverse and secondary to effects on red cell mass. Clinical observations --_ attributed to increased urination were observed in male and female 100 and/or 500 mg/kg/day groups, and were associated with changes in clinical chemistry and urinalysis that were attributed to a physiological effect on kidney function. An increase in altered colloid was observed in the thyroidsofall dosed male and female groups. This lesion was also observed in some control rats `and was not considered adverse. Mostofthe effects observed during the dosing period demonstrated full or partial reversal following one or three months of recovery. Reversal ofmany effects in females was not `ombasleersvaendduncthirlonafitcerprtohgeroenssei-vmeonntephhrreocpoavterhyy.inT1h0y0roainddfo5l0l0icmugla/rkhgy/pdearytrfoepmhayleisn w5e0r0esmtgi/lklpgr/edasyent at the endofthe three-month recovery period. `Under the conditionsofthis study, there was io NOEL for reproductive parameters. This was based on reductions in the fertility index in all dose groups. Prolongationofestrous cycle length was also observed in Py rats in all dose groups but the toxicological significanceofths effect is unclear. Other adverse, compound-related effects observed in Py rats dosed with 500 mg/kg/day include decrements in body weight parameters and food efficiency and reduced number of implantation sites. A reduction in epididymal sperm counts was observed in all male groups dosed with test substance, but this effect was not considered adverse. * TthheteNstOEsuLbsftoarncheiswesrteudnyoiddeetfecitneedd.a Tthhues,hifgohresthtidsossteudayt,wthhiecNhOtEoxLiciosleoqguiciavlallyenitmpoortthaentNfOfEcLtsssatdreifbiuntesdbibeyto --~ tdheefiUnneidtbeydtShteatEeusrEonpveiarnonUmseinotnalP.rotection Agency and fo the no-observed-adverse-effect level (NOAEL) as: TT Company Sanitized. Does not contain TSCA CBI 9H0-2-4D7a6y8:GavSaubgcehSrtoundiyc TinoxRiactistywithOne-Generation Reproduction Evaluations DuPont 5990 ~~ Adverse, compound-related effects observed in 100 and/or 500 mg/kg/day group Fi rats included reductions in mean liter size, number ofpups bor and bom alive, pup survival during lactation, and pup weight at birth and during lactation. In the S00 mg/kg/day Fr group high mortality, during lactation and post-weaning, resulting in early sacrificeofthis group, precluded evaluation ofpost-weaning parameters (body weight and nutritional parameters, clinical observations, developmental landmarks). No compound-related cffects on any post-weaning parameters were observed in the 100 or 25 mg/kg/day Fi groups. --_ ~~ - = Company Sanitized. Doesnotcontain TSCA CBI H0.-2D47a6y8:GavSaugbcehSrtoundiyc iTnoxRiacsitywith One.Generation Reproduction Evaluations DuPon-5990 REFERENCES 1. DuPont (1995). Neurotoxicity EvaluationofTrimethyltin in Rats (Positive Control Study). 2. DuPont = Neurotoxicity Evaluation ofAmphetamine in Rats (Positive Control Study). 3 DuPont (1997). Neurotoxicity Evaluationof Carbaryl in Rats (Positive Control Study). ci ---- of Acrylamide in Rats (Positive Control Study). 5. Lazarow, P.B. (1981). Assayof Peroxisomal Beta-Oxidationof Fatty Acids. Methods in Enzymology 72, 315-319. 6. Bradford, MM. (1976). A Rapid and Sensitive Method for the Quantitationof Microgram QuantitiesofProtein Utilizing the PrincipleofProtein-Dye Binding. Anal. Biochem. 72, 248-254. 7. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Statist. Assoc. 50, 1096-1121. 8. Dunn, O.J. (1964). Multiple contrasts using rank sums. Technometrics 6, 241-252. ~ 9. Draper, NR. and Smith, H. (1981). Applied Regression Analysis, 2" edition,pp 266-273. Wiley, New York. 10. Selwyn, MR. (1995). The useoftrend tests to determine a no-observable-effect level in animal safety studies. Journalofthe American College ofToxicology 14(2), 158-168. 11. Jonckheere, AR. (1954).A distribution-free K-sample test against ordered altematives. Biometrika 41, 133-145. 12. Levene, H. (1960). Robust test for equalityof variances. Contributions to Probability and Statistics (1. Olkin, ed.), pp 278-292. Stanford University Press, Palo Alto. 13. Shapiro, S.S. and Wilk, MB. (1965). An analysisof variance test for normality (complete: samples). Biometrika 52, 591-611 14. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6 edition, pp 246-248 and. 349-352. The lowa State University Press, Ames. 15. Kruskal, W.H. and Wallis, W.A. (1952). Useofranks in one-criterion analysisofvariance. J. Amer, Statist. Assoc. 47, 583-621. 16. Milliken, G.A. and Johnson, D.A. (1984). Analysisof Messy Data, Volume 1.; Designed Experiments. Lifetime Learning Publications, Belmont. 17. Hocking, R.A. (1985). The AnalysisofLinear Models. Brooks/Cole, Monterey. 18. Bartlett, M.S. (1937). Some examplesofstatistical methodsofresearch in agriculture and ~ applied biology. J. Royal. Statis. Soc. Suppl. 4, 137-170. = Company Sanitized. Does not contain TSCA CBI H24768: Subchronc 90-Day Gavage Study Tosicity in Ras withOne Generation Reproduction Evaluations DuPont-5590 ~ 19. Fishier, R.A. (1985). Statistical Methods for Research Workers, 13" edition. Haffner, New York. 20. Dempster, AP., Selwyn, MR., Patel, CM. and Roth, A.J. (1984). Statistical and computational aspects ofmixed model analysis. The Journalof the Royal Statistical Society, Series C (Applied Statistics) 33(2), 203-214. 21. Haseman, JK. and Hogan, M.D. (1975). Selectionofthe experimental unit in teratology studies. Teratology, 12, 165-171. 22. Pateficld, W. (1982). Exact tests for trends in ordered contingency tables. Applied Statistics 31,3243. 23. Sipes, G. I, and Gandolfi, A. J. (1991). InBiotransformationofToxicants. In Casarettand Doull's Toxicology: The Basic Scienceof Poisons (Amdur, M. O., Doll J, and Klaassen, C.D, Ed.), Pergamon Press, New York, pp 88-126. 24. Paynter, O.E., Harris, J.E., Burin, G.J,, and Jaeger, R.B. (1985). Guidance for Analysis of Evaluationof Subchronic Exposure Studies. United States Environmental Protection Agency, EPA-540/9-85-020. 25. Greaves, P. (1990). Digestive System 2. In HistopathologyofPreclinical Toxicity Studies: Interpretation and Relevance in Drug Safety Evaluation (P. Greaves, Ed), Elsvier, Amsterdam, pp 393-496. 26. Rao-Rupanagudi, S., Heywood, R., and Gopinah, C. (1991). "Age-related Changes in ~~ Thyroid Structures and Function in Sprague-Dawley Rats," Vet. Pathol., Vol. 29, No. 4, pp. 278-287. 27. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance for Analysis and Evaluationof Subchronic and Chronic Exposure Studies Paynter, O. E. et al, United States Environmental Protection Agency, OfficeofPesticide Programs, `Washington, D.C., 20406. EPA-540/9-85-020. (June 1985). 28. Risk Assessmentof Notified New Substances. Technical Guidance Document (XI/283/94EN), Chapter ,Sections 2.24 and 2.25. 1994. = --_-- `Company Sanitized.Doesnotcontain TSCA CBI H9-02-4D7a6y8G:avSaugbeehSrtoundiyc iTnoRxiactistywithOne-Generation Reproduction Evaluations DuPon-5990 TABLES --~ --~ wn Company Sanitized. Doesnotcontain TSCA CBI H9-02-4D7a6y6:GavSaubgcehSrtoundiyc TinoxRiacistywith One-Generation Reproduction Evaluations ~ TABLES DuPont-5990 EXPLANATORY NOTES Critical Dates Day 70 Last day data from the male and female rats designated for reproduction evaluations were reported with the subchronic toxicity animals. Body `weights and clinical observations collected during the cohabitation and postmating periods are reported in the Reproductive Toxicology section; Dose volumes administered during the cohabitation and post-mating periods are documented in study records. Day 90 Last dayoftest substance administration for male and female rats designated for one-month and three-month recovery periods. Day 91 Last day ofbody weight and food consumption data collection for male and female rats designated for the 91-day exposure period. Day 94 Last dayof test substance administration for male rats designated for the 91-day exposure period. Day95 Male rats designated for the 91-day exposure periodwere sacrificed. Last day of test substance administration for female rats designated for -- the 91-day exposure period. Day 96 Female rats designated for 91-day exposure period were sacrificed. Day119 Last dayofbody 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 123 Male rats designated for the one-month recovery were sacrificed. Day 124 Female rats designated for the one-month recovery were sacrificed. Day 182 Last dayof non-fasted body weight data collection for rats designated for the three-month recovery period. Day 183 Male and female rats designated for the three-month recovery period were sacrificed. Note: Group I, Male Rat No. was dosed through test day 95, and bled for clinical pathology and necropsied on test day 96. `Thisratsclinical and anatomical pathology data are reported with the other males from test day 95. - = Company Sanitized. Doesnotcontain TSCA CBI 9H0--2D47a6y8;GavSaugbceShrtoundiyciTnoRriassitwyithOneGeneration ReproductionEvaluations ~ TABLES ABBREVIATIONS: EXPLANATORYNOTES Summary of Hematology Values RBC - redblcoellocoudnt HGB - hemoglobin HCT - hematocrit MCV - meancorpuscularvolume MCH - meancorpuscular hemoglobin MCHC - meancorpuscular hemoglobin concentration RDW - redcelldistribuwtiidotnh ARET - absolutereticulocytecount PLT - platelet count WBC - whiteblcoellocoudnt ANEU - absoluteneutrophil (all forms) ANPR - absoluteneutrophil precursor ALYM - absolute lymphocyte AMON - absolutemonocyte AEOS - absoluteeosinophil ABAS - absolute basophil -- ALUC - absolute largeunstainceldl ABLT - absbolasltleuuktocyete AMSC - absolutemiscellaneous leukocyte AHSN - absolutehypersegmented neutrophil ABAN - absolute neutrophilband AMET - absolute neutrophil metamyelocyte AMYE - absolute neutrophil myelocyte APRO - absolute neutrophil promyelocyte AMYB. - absolute neutrophilmyeloblast ARL - absolutereactive lymphocyte AAL - absoluteatypical lymphocyte AIL ACL -- aabbssoolluutteecilmefmtaetdurleymlpyhmopchyotceyte ABLB - absolute lymphoblast AIE - absolute immatureeosinophil AIM - absoluteimmaturemonocyte APLA - absolute plasmacell count NC - notcalcournlotacaltcuelabdle `Summary of Coagulation Values PT - prothrombin time APTT - activated partialthromboplasttiimne ~ DuPont-5990 --- Company Sanitized. Does not containTSCA CBI F9-02-4D7a6y8;GavSaugbcehSvtoundiyc TinosRiacistwyithOne-Generation Reproduction Evaluations -- TABLES DuPont:5990 ABBREVIATIONS: EXPLANATORY NOTES Summary of Serum and Plasma Chemistry Values AST - aspartate aminotransferase ALT - alanine aminotransferase SDH - sorbitol dehydrogenase ALKP - alkaline phosphatase BILI - total bilirubin BUN - urea nitrogen CREA - creatinine CHOL - cholesterol TRIG - triglycerides GLUC - glucose TP - total protein ALB - albumin GLOB - globulin CALC - calcium PHS - inorganic phosphorous --~ NA - sodium K - potassium CL - chloride PFLU - plasma fluoride SOSM - serum osmolality `Summary of Urinalysis Values VOL - volume UOSM - urine osmolality SG - specific gravity pH. - the logarithmofthe reciprocalofthe hydrogen ion concentration URO - urobilinogen UFLU - urine fluoride UMTP - urine protein `Notes for Clinical Pathology data: `When an individual observation was recorded as being less than a certain value, calculations were performed onhalfthe recorded value. For example, ifbilirubin was reported as <0.1, 0.05 was used for any calculations performed with that bilirubin data. `When an individual observation was recorded as being greater than a certain value, calculations -- w1e.r08e3pwearsfoursmeeddfoonr tahneyrceaclocurldaetdiovnaslupee.rfFoorrmeexdawmiptlhe,thiaftspsepceicfifiiccggrraavviittyywdaastar.eported as >1.083, - - Company Sanitized. Does not contain TSCA C81 H902-4D7a6y8:GavSaugbeehSrtoundcy iTnorRaitcsiywith One-Generation Reproduction Evaluations DuPon-5990 TABLE 1 SUMMARY OF DOSING SOLUTION ANALYSES Semple Type DosingConcentratiaonds Silof Ht-24y768 (mg/ml) TesDay0 Nominal: 3% 133 ss67 ConcenraionVeriicaion n o340m 08) r w00e6) 282 ne sab 7 610) `AAvveerraaggee MPeeracseunrteNdoCmoianlc 298 119 S18 3) 3) 67) SCtoaenfdiacridntDoefviVtairoination prTMe 033%5 2A37 Sabie 203 inet sad 63104) @1200)8 ss. 04) 00) 3) CoTnecseDnamyt3i2onVerification 32027) 16 ws 0) 06) --_ Tes Day 42 312 12s s52 @n 5 a3) Test Day91 `ConcentionVerifieaton `AAvveerraaggeePMeeracseunrteNdoCmoinnca.l SCtoaenfdiacridnDteovf aVtaorintion a7 12s 593 52) 5 a9) oanr 936 0w05z) a022) ase 875 389 a7 608) @5) an "a 505 396 24 2061 0054) 8"90)9 1 11 EN % % 2% Stabile wsoye e90n0 0a5r2e) aa3z saanhh oomm aav3y 0o6m) b MTeoamnerrcsuTlncpofaalrleanmtabsyerse he repeeepsretoma & SaMmepaln,es5(.0T.eatnDdaCyV.0)fhoedduplircoaotme scammppleerstcraelfolriSehoourvse.rity unifoorfmmiixtturye DSaomppllieasie(sTaemtpDleasys3u9b)mihteeldd.efgeratd fnoyr day nd sampled. ~ 5R SSuampplless hbeolmdprreferviigeorwastesdufdoyr 4fdoarysfollowed by how a roomtemperature. ET `CompanySanitized. DoesnotcontTSaCAiCnBI H0--2D4a76y8:GaSvuabgcehrSotnuidcyTionxRiactistywith One-Generaton Reproduction Evaluations --~ TABL2E DuPont-5990 MEAN DAILY DOSE VOLUMES (mL) FORMALERATS G0rmogu/pkgT/day G2r5oumpg/kTgIT/day G1r0o0umpg/vkg/day G5r00oumpgV/IkIg/day DAY 0-DAY 6 10..61145) 10.16 s) 10.161035) 1o.i6 s) DAY 7 - DAY 13 0.2.20045) 2i.0135) 20.101035) 10.18 s) DAY 14 - DAY 20 20.34045) 20l.21035) 201.22035) 20.220a5) DAY 21 - DAY 27 0.2.380a5) 201.59035) 20..72035) 20.25145) DAY 28 - DAY 34 0.3.31045) 30.11333) 20..92035) 20.370a5) DAY 35 - DAY 41 3l.a3ws) 30.3438) 30..22035) 201.38343) DAY 42 - DAY 48 3o.l5awas) 30.16368) 30.23035) 301.30143) ~ DAY 49 -DAY 55 3l.a7gs) . 3.8las) 30..53035) 30.113143) DAY 56 - DAY 62 30.58145) 3l.9as) 30..6360) 301.32143) DAY 63 - DAY 69 40.50044) al1as) 30.3760) 30.33343) DAY 70 40.51044) 40..24035) 30.39030) 3o.l4aa3) DAY 71 - DAY 76 40.50024) aol2aus) 0.3.38014) 30.3308) DAY 7-7 DAY 83 4i.1sa) 40..3aa1s) o3.l9aaa 3.4 03025) DAY 84 - DAY 90 4i.2624) a0.a415) 40..04014) 031.35028) DAY 91 - DAY 94 4i.5410) ai6410) a04110) 3l.6do Data summarized as: MSetaanndard Deviation (n) - _% Company Sanitized. Dno otcons tain TSCA CBI H-24768: SubchronicToxicity 90-Day GavageStudyin Rats with One-GeneratonReproduction Evaluations --~ TABL3E DuPont-5990 MEAN DAILY DOSE VOLUMES (mL) FORFEMALERATS G0rmogu/pkgT/Tday G2r5oumpg/kIvg/day G1r0o0umpg/vrkg/day GSr00oumpg/VIkIgI/day DAY 0-DAY 6 o1.l3ism) 10.l313s) 10.13 s) 1l.i3as) DAY 7-DAY 13 l1.i5es) 10.l513s) 10151635) 10.14 s) DAY 14 -DAY 20 1l.i6es) 1o.l6 i) 10.16165) 1ol.16aas) DAY 21 - DAY 27 10.28045) 10.l82(35) 10.181035) 10.174s) DAY 28 - DAY 34 1i.9203) 01.192035) 0119165) 01.28345) DAY 35 - DAY 41 20.20045) 201.20035) 10..91035) 10.2945) DAY 42 - DAY 48 2i.1203) 021.20035) 02..02035) 02.20045) ~~ DAY 4-D9AY 55 20.122045) 20..12035) 021.12035) 20..21325) DAY 56 - DAY 62 2i.2203) 02.122635) 20.122035) 201.21385) DAY 63 - DAY 69 20.122025) 20.122035) 20..22035) 201.21345) DAY 70 20.2305) 20.122035) 20..22035) 201.22345) DAY 71 - DAY 76 20.132025) 20..2305) 20..32115) 201.22025) DAY 77 - DAY 83 20.132028) 20.320s) 20.l32as) 202.22028) DAY 84 -DAY 51 20.112028) 20.l33as) 20..42115) 20..22025) DAY 9-D1AY 95 20.3400) 20..33010) Data summarized as: MSetaanndard Deviation (a) 02.2400) 20.23010) --~ `Company Sanitized. Doesnot contain TSCA G81 H-24768:Subchronic Toxicity 90-Day Gavage StudyinRats with One-Generation Reproduction Evaluations --_ TABL4E MEAN BODY WEIGHTS (g) OF MALE RATS DuPont-5990 0 mGgr/okugp/d1ay 25 Gmgr/okugp/dTaIyT 100Grmogu/pkgv/day 500Grmogu/pkgV/IdIay Dosing Period for Subchronic Toxicity and Reproduction Evaluations ay 0 bay 7 Day 14 bay 21 DAY 28 Day 35 --~ DAY 42 DAY 49 ay 56 DAY 63 Day 700 21154.73s) 27211.81s) 32311.26s) 37308.25045) 10a92.l7aas) 4a18.l3swas) 46552..10045) 8595..94045) 51610..1315) 52663l.67(aa) 54615..66040) 21163.050035) 27138.176035) 32285..32035) 37360..75035) 413950.90035) 454120.40035) 47464..35035) 54061..42035) 55203..40035) 54502..25035) 55594..29035) 21183..31035) 26177..09035) 31145.196035) 35275.170035) 39330..72035) 423021.490835) 3332..648035) 45363..730835) 8323.189004) 49395..020834) 51357..52064) 21152.2205) 23176.680845) 282721.770045) 32288..79%45) 35392..798345) 37366..440843) 39420.17043) 41402..75%03) 42173.290043) 44423.55043) 45425..15043) --~ -_-- CompanySanitized. Doesnotcontain TSCA Cal 9H-02-4D7a6y6:GaSvuabgcehrSotnuidcyTionxRiactistwyithOGneen-eration Reproduction Evaluations -- TA4B(ConLtinuEed) DuPont-5990 MEAN BODY WEI(g)GOF MHALT ERASTS 0 mGor/okugp/day 25Gmrao/kwg/IdIaIy 100Grmoaw/kgV/day S00Grmogup/kv/idzay Dosing Period for Subchronic Toxicity Evaluation (continued) ay 77 54775..84 (20) 55753..10015) 52501..08010) 45422..06(425) DAY 84 57587..7802) 55639..56015) 53512..55014) 6414..808025) DAY 91 56787..02028) 5s941.1805) 53523..1004) 47404..45(825) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 98 55#11.53010) 54692..1905) 52534..2700) 49412..08805) DAY 105 s6826..30 (14) 57406..0705) 54537..0006) 51430..660815) ~ DAY 112 578162..80(14) 5860..2505) 5565..8800) 51188..860015) DAY 119 57876..35 (14) 56422..2105) 56576..4800) 52526..100815) I Company Saniized. Doesnotcontain TSCA CBI H9-02.4D7a6y8G:avSaugbcehSrtoundiyc iTnoxRiactistywith One-Generation Reproduction Evaluations DuPont5990 `T4A(CBontLinuEed) MEANBODY WEIGHTS (g) OF MALE RATS 0 mGgr/okuap/d1ay 25 Gmrao/ukpa/1d1a1y 100Gmrgo/ukpa/vday S00Grmogu/pkgV/IdIay Three-Nonth Recovery Period for Subchronic Toxicity Evaluation DAY 126 53994..3806) 59432..79(5) 57671.110 53330..27(5) bay 133 59590..1204) 60474..0105) 5772..4000) 53525..6505) DAY 140 561001.1350) 61461..3205) 57845..2904) 53629..8805) AY 154 55987..4200) 62455.06605) 59655..2300) 53983..9605) AY 147 59573..1406) 62428.6905) 56875..3900) 53778..2605) ay 161 1051131.1204) 63405..18(5) 559990.4900) 64048..9705) ~~ DAY 168 1s0a511.2604) 64532..0405) 611l.a0t) 64154..0805) ay 175 517082..0704) 64477..2505) 61658..23 (4) 63252..6305) DAY 182 5T8o8a.l0s (a) 65553..1305) 67212..3400) 64340..0035) Data sumaarsi:zMeeStadanndard Deviation (n) a. oRnatstesdtesdiagynat70e;d sfuobrserqeupernotdudcattiaonareevarleuaptoirotned (a2s0 rpaatrst/gorfoutph)e wreerperodcuochtoiuosned evaluation. # Sttraetnidsttiecsatl.ly significant difference at p < 0.05 by Jonckheere-Terpstra -- -_-- Company Saniized. Does not contain TSCA CBI H-24768: SubchronicToxicity 90-Day Gavage Study in Rats withOneGeneration Reproduction Evaluations --~ TABLE5 DuPont-5990 MEAN BODY WEIG(HgT)OSF FEMALE RATS 0 mGgr/okugp/dIaTy 25 Gmrgo/ukpg/TdV.ay 100Grmogu/pkgV/Iday 5G0r0oumpg/vkIgI/Xday Dosing Period for Subchronic Toxicity and Reproduction Evaluations AY 11751.56345) 17172..16035) 110..38035) 17162..6405) av 7 119371.50045) 19164.148035) 19131.940s) 18155.0000045) AY 14 21167..95045) 21157..16035) 211440..2205) 20186..91045) ay 21 23260..5845) 23240..12035) 23145.56035) 22197.650s) Day 28 25222.150045) 25222.148035) 25107..05035) 24169..81045) ay 35 26255.133045) 26253..53035) 21588..09035) 25250.230445) -- bay 42 27265.9.45) 27235..4405) 27200..8135) 22605..253845) DAY 48 22687..53045) 28247..42035) 28232.140035) 27252..190845) DAY 56 20228..74045) 29218.100035) 28283..52035) 28202..770845) DAY 63 22707..91045) 29330.195035) 202451.32035) 28252..2545) Day 70 23605..33145) 30300.120035) 29294..28035) 28293..260045) --~ Se `Company Sanitizes. Does notcontain TSCA CBI 9H0--2D4a7y68G;avSaugbcehSrtoundiyciTnoRxaitciswtyith One-Generation Reproduction Evaluations -- TABLE 5 (Continued) DuPont-5990 MEAN BODY WEIGHTS (g) OF FEMALE RATS 0 mGgr/okugp/d1a1y 25 mGor/okuap/d1avy 100Grmoou/pkgv/1day 500Grmogu/pkev/IdIaTy Dosing Period for Subchronic Toxicity Evaluation (continued oat 77 31320..10025) 23986..33035) 3300.7.55015) 29252..81025) DAY 80 33106..53025) 33081..64015) 31362..0108 29291..89025) oar 91 32301.'0204) 30355..5205) 31372..3005) 30109..80(825) One-Month Recovery Period for Subchronic Toxicity Evaluation oaY 98 32267..53040 30486..9205) 31467..0405) 29198..170815) AY 105 32278..68014) 30691..2605) 324372.8905) 29281..70405) --_ oy 112 340.9 321.0 332.2 312.08 31404) 51.205) 12.505) 221405) AY 119 30313.02004) 32564..5405) 32477..5205) 30249..610415) --~ --_-- Company Sanitzed. Doesnotcontain TSCA CBI H-24768; SubchronicToxicity 90-DayGavageStudyin RatswithOne-GenerationReproductionEvaluations ~~ `TA 5(CBontL inuE ed) DuPont-5990 MEAN BODY WEIGHTS () OF FEMALE RATS 0 Gmrgo/ukpg/1d1ay Group Iv. Group VI Group VIII 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 126 33398..384) 33505..68(5) 43345..38 5) 31208..44(5) DAY 133 33399..2104) 33515..39(5) 34367..78(5) 31344..305) DAY 140 33493.07004) 33558..49(5) 35404..14(5) 32309..805) DAY 147 34363..3604) 33642..51(5) 34456..41(5) 32312..69(5) DAY 154 34359..694) 33650..77(5) 34426..01(5) 32336..00(5) DAY 161 35328..6404) 34611..37(5) 36459..17(5) 33309..1005) fo DAY 168 43521..8504) 34653..80(5) 34561..42(5) 32490..91(5) DAY 175 35379..7504) 36426..41(5) 34555..07(5) 32482..01(5) DAY 182 34566..2000) 34694..29(5) 35554..38(5) 33455..96(5) Data summarized as: lSetaanndard Deviation (n) a. oRnatstesdtesdiagynat70e;d fsourbserqeupernotdudcattiaonareevarleupaotritoned (a2s0 praartts/gorfoutph)e rweeprreodcuochtoiuosned evaluation. #trSetndatitsestti.cally significant differences at p < 0.05 by Jonckheere-Terpstra --_~ -- `Company Sanitized.Doesnot conTtSaCAiCBnI 9H0--2D4a76y8G:avSaugbecShrtoundiyciTnoRxaitciswtyithOne-Generation Reproduction Evaluations --_ TABL6E DuPont-5990 MEAN BODY WEIGHT GAINS () OF MALE RATS 0 Gmrgo/ukpg/day G2r5omugp/kTgI/Tday G1r00oumpg/V.ka/day Group vIz 500 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0- DAY 7 DAY 7 - DAY 14 DAY 14 - DAY 21 565..120a5) 204..04045) 4192..3205) 577.133035) 548.155035) 88.147035) 88..780035) 4170.09035) 28.1848035) 2521.250845) 1500..06045) 209.1970%45) DAY 21 - DAY 28 398.12245) 2.93 5035) 365.108035) 317..601045) DAY 28 - DAY 35 315..62045) 3821.08035) 276.1720035) 186..500843) DAY 35 - DAY 42 238..75045) 258.151035) 2120.272035) 1106..420043) --~ DAY 42 - DAY 49 206..82045) 207..71085) 22i.7605) 188..160043) DAY 49 - DAY 56 2811.27045) 226..38035) 16s.3l8a) 177..420643) DAY 56 - DAY 63 16l.8ac) 169..85035) 165..57034) 18.162043) DAY 63 - DAY 70 16..81044) 196.172035) 165.136034) 69l.a708a3) DAY 0 - DAY 70 | 32566..26044) 34473..30035) 293621.690%34) 23470..070043) -- -_-- Company Sanitized. Does not contain TSCA CBI 90H--2D4a7y68G:avSaubgeehSrtoundiyciTnoRxaitciswtyithOneGeneration Reproduction Evaluations --~ `TA6 (CBontLinuEed) DuPont 5990 MEAN BODY WEIGHT GAINS () OFMALE RATS 0 Gmrgo/ukpg/Iday 25Grmogu/pkgI/IdIay 10G0romugp/kV.g/day 5G0r0oumpg/VkIgI/day Dosing period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 91 125.55020) 106..80024) 79..73020) 12a.l7aas) 105.167015) 15.135015) 9s.i8204) 1a1.l4 sa 06.3604) 8.20 105025) 9.2 815025) 881.36025) DAY 0 - DAY 51 354.0 377.9 67.8020) 54.8015) 312.6 48.104) 255.60 41.208) One-Month Recovery Period for Subchronic Toxicity Evaluation DAY 91 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 u6s.700) 170..7100 103.l0saa) 55.l350a) 82.0405) 67..7805) 9a.s8s) 155705) u8sl0w) 139.230 12l.s8t) 1315 2861.700815) 1222.3200 8) 2651.22015) a3l.i3as) DAY 91 - DAY 119 375.15704) 277..7505) a97l9(a) 5a6l.o60ns) -_-- CompanySanitized.Doesnot conTtSaCAiCBnI H9-02-4D7a6y8G;avSaubgcehSrtoundiyc Toxicity in Rats withOneGeneration Reproduction Evaluations --~ `TABLE 6 (Continued) DuPont 5990 MEAN BODY WEIGHT GAINS (g) OF MALE RATS 0 mGor/okugp/dIay 25 Gmrgo/ukpg/IdIaTy 100Grmogu/pkgV/day Group VII 500 mg/kg/day Three-tonth Recovery Period for Subchronic Toxicity Evaluation DAY 119 - DAY 126 147..0206) 16..5505) 106.:324) DAY 126 - DAY 133 141.s0 138.l30(5) 4a.8a DAY 133 - DAY 140 130.014) 96..22(5) 184l.4004) DAY 140 - DAY 147 717..0708) a6l.s7(s) 010.01004) DAY 147 - DAY 154 7a.8000) 26..6905) 93.320 DAY 154 - DAY 161 154.20 81.5605) a6.754) - DAY 161 - DAY 168 88.74 ) 88..8005) 11als.0 DAY 168 - DAY 175 -531.6704) 46..2705) 65.3504) DAY 175 - DAY 182 104.0a 87..80(5) 66..2100) 2271..4805) 227..3365) 145..2905) 128..19165) 135..90(85) 135..7165) 1160.4105) 1271.4505) 126..0005) DAY 91-DAY182 4922..300) 110501.1605) 10194..1204) 16474.142045) Data sumarized as: MSetaanndard Deviation (n) a. oRnatstesdtesidganyat7e0;d fsourbserqeupernotducdtaitaonareevarleuaptoirotned (a20s praartts/gorfoutph)e wreerperocdouhcotuiosned evaluation. # sttraetnidsttiecsatl.ly significant difference at p < 0.05 by Jonckheere-Terpstra --~ - `CompanySanitized. Does notcontainTSCA CBI 'H9-02-4D7a6y8G;avSuabgcehSrtoundiyciTonxRiactistwyithOOrnie-GennereatoionnRReepprroodduuccttiioonnBEvaalluautiaonts ions_______DDuuPPoonntt55999900. TABL7E MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS 0 Gmrgo/wkpg/IdIay 25Grmogu/pkgI/Vday 100Grmogu/pkgV/Iday S0G0romugp/kVgI/IdIay Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 216..47045) 196..32035) 165..530835) 180..39%45) DAY 7 - DAY 14 719..9945) 186..75(35) 205..32(35) 24.9% 6.9(as) DAY 14 - DAY 21 198..68(45) 619..60035) 520..14035) 19.6 5.6(45) DAY 21 - DAY 28 158..95045) 168..74035) 157..31035) 17.3 6.7045) DAY 28 - DAY 35 127..98045) 125..84035) 8.86.0935) 8.68 6.1045) DAY 35 - DAY 42 ~ DAY 42 - DAY 49 17..6145) 160..84045) 86..10035) 16..0735) 18..97035) 127..66(35) 10.2 5.9(45) 5.5 7.0045) DAY49 -DAY 56 56..45045) 66..06(35) 5a.84035) 5.7 6.2(a5) DAY 56 - DAY 63 a5.46045) 42.a9 s) 66..01035) 4s 5.0(45) DAY 63 - DAY 70 85..29045) 66..43035) 65..544035) 4.08 6.2(45) DAY 0 - DAY 70 12290..7945) 12213..71035) 12129..74035) 112.68 18.a(45) ~~ _-- To: Company Sanitized. Doesnotcontain TSCA CBI 9H-02-4D7a6y8:GaSvuabgcehrSotnuidcy iTnoxRiactistywith One-Generation Reproduction Evaluations ~~ TA7B (ConL tinuEed) DuPont-5990 MEAN BODY WEIGHT GAINS(g) OF FEMALE RATS 0 mGgr/okugp/dIaTy 2G5romugp/kIgV/.day 10G0romugp/kvgi/day S5G00romugp/kVgI/IdIay Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 DAY 77 - DAY 84 DAY84 -DAY 91 a6119025) a6.36025) s2l.82c2a) 64..64015) 45.l2sas) a6111015) s2.a3 a) a5.l4os) a1.s4us a512505) 5a182025) 601.50025) DAY 0 - DAY 91 14225..90024) 13320..13015) 21640..62015) One-onth Recovery Period for Subchronic Toxicity Evaluation 12113.870825) DAY 91 - DAY 98 78.l25014) 23.66s) s3.l4s) ~~ DAY 98 - DAY 105 82.l250a) 18.0.9805) 47.15305) DAY 105 - DAY 112 DAY 112 - DAY 119 127..2300) 06.3300) 111.240s 55..5405) 108..7405) 55.1010s) l0.i4a8s) 105..5105) 1132.230s) 177..42805) DAY 91 - DAY 119 2110.097040 20u.1s 1147..245) 235l.86081s) --~ -_-- oe CompanySanitized. Doesnot conTtSaCAiCBnI 29H0-0-2-D4Da7ay6y8GG:aavvSaauggbecehSSrttouunddiyyciiTnnoRRxaaittcisstwwyiitthhOOnnee-GGeenneerraattioonnRReepprroodduuccttiioonnEvvaalluuaattiioonnss --_ TABLE 7 (Continued) DDuuPPoonntt--55999500. MEAN BODY WEIGHT GAINS () OF FEMALE RATS 0 Gmrgo/ukpg/IdIay 2G5romugp/kIgV/.day 100Grmogu/pkgV/Iday 50G0romugp/kVgI/IdIay Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 119 - DAY 126 a613500) ala3s) 75.1615) 3191.1365) DAY 126 - DAY 133 08.l150a) a0l.s6es) 24.30s) 37.3935 DAY 133 - DAY 140 1201.570) a7.0165) 105..7645) DAY 140 - DAY 147 61.28600) 07..9405) 801.1705) DAY 154 - DAY 161 7E.0R) 5i.0605) a3.l5ses) DAY 161 - DAY 168 110124) 4a3s6s 70..515) ~~ DAY 147 - DAY 154 0s.l7i s1l3s) 25.19905) DAY 168 - DAY 175 s6.i2s) 10.3s) 06..5305) DAY 175 - DAY 182 1117a) 32.695) 96.1680s) 76..0565) 71.1505) s7.l0es) 06.18505) 511.8105) "4181s) 170.06505) DAY 91 - DAY 182 424.2020) 203..56(5) 4321.12s) 3289..4815) Data sumarized as: MSetaanndard Deviation (n) --- a. Roantstesdtesdiagnyat70e;d evaluation. fsourbserqeupernotducdtaitoan areevalrueaptoirotned (a2s0 praartts/gorfoutph)e wreerperocdouhcotiuosned # Sttraetnidsttiescta.lly significant difference atp < 0.05 by Jonckheere-Terpstra --~ _----o-- e ---- CompanySanitized. Doosnot contain TSCACBI H:24768: Subehronic Toxicity Z920:-DDaayyGGaavvaaggeeSSttuuddyyiinRRaatsswwiitthhOOnnee-GGeenneerraattiioonnRReepprroodduuccttiioonnEEvvaalluuaattiioonnss --~ TABLE DuDPuoPonutt--55999900. MEAN DAILY FOOD CONSUMPTION (g) BY MALE RATS 0 mGgr/okugp/dTay 25 Gmrao/ukpa/IdIaTy 100Grmogu/pkgv/day S00Grmogu/pkgV/IdIay Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 DAY 7 - DAY 14 DAY 14 - DAY 21 DAY 21 - DAY 28 DAY 28 - DAY 35 ~ DAY 35 - DAY 42 DAY 42 - DAY 49 DAY 49 - DAY 56 DAY 56 - DAY 63 DAY 63 - DAY 70 263.323045) 283.702040) 293.137085) 303.1870s) 303.5604s) 331l130as) 313.1478s) 341.l830s) 341.31 0 293.178044) 263.8403s) 282.139035) 303.20205) 331196035) 313.l8603s) 313.670s) 313.l9603s) 323.5160s) 304.194035) 313.149035) 252.124035) 262.175035) 2281.61035) 293.l5603s) 292.68035) 292.188035) 302.147035) 292..32803) 292.19364) 292.28200) 1281.260045) 262.810445) 237.102005) 283.l0a8as) 273.15d80a3) 237.87483) 283..788043) 293.56403) 340.23203) 293.9843) BAY - DAY 70 303.50043) 303.16208) 282.191803) 237l.0100a3) --~ _--_-- Ti00CompanySanitized. Doesnot conTtSaCAiCnBI H9-02-4D7a6y8G:avSaugbcehSrtoundiyc Toxicity in Rats with One Generation Reproduction Evaluations -- `TA(CBontLinuE ed) DuPont-5990 MEAN DAILY FOOD CONSUMPTION (g) BY MALE RATS Gmrgo/ukpg/Iday 2G5romugp/kIgI/Tday 100Grmogu/pkg/day 50G0romugp/kVgI/Xday Dosing Period for Subchronic Toxicity Evaluation (continued) Day 70 - pay 77 Day 77 - Day 84 Day 84 - Day 91 284.2620) 248.1802e 284.183020) 294.l1aas) 303..5805) 340.21 a) 282..7304) 282..8500) 272..3800) 238l.84025) 293.1208) 233.162025) DAY 0 - DAY 91 253.029020) 303.3408) 282..6304) One-Month Recovery Period for Subchronic Toxicity Evaluation 2371.410425) Day 91 - Day 98 284.6004) 28E.R5IE 292..734) ~~ Day 98 - Day 105 28s.1aa 272..76(5) 311.3600 Day 105 - pay 112 274.3200 271.36305) 302.:220 Day 112 - Day 119 274.27 00 261..6765) 282..7000) 334..41805) 333.03%s) 295..26015) 286.:835) DAY 91 - DAY 119 2a7.9aa 272.:25(5) 301.4004) 331l.26015) Data sumarized as: SMteaanndard Deviation (n) a. ocRnoahtsatbedsitetsatidigaoynnat70ae;nddffpooorosdtrmceaoptnrisonudgmupcttpieioroinnodedsavtaaluwaetrieonno(t20coraltlse/cgtreodupd)uriwnegretcheohoused # sttraetnidsttiecsta.lly significant difference at p < 0.05 by Jonckheere-Terpstra _--_-- Tor `CompanySanitized.Does not conTtSaCAiCnBI F9-02-4D7a6y8;GaSvuabgcehrSotnuidcyTionxRiactistywith One-Generaton Reproduction Evaluations Dupont5990 TABLE MEANDAILY FOOD CONSUMPTI(OgN) BY FEMALE RATS 0 Gmrgo/ukpg/1d1ay 25Grmoau/pkgT/vday 10G0romugp/kVgI/day 5G0r0oumpg/vkigI/zday Dosing Period for Subchronic Toxicity and Reproduction Evaluations Day 0 - pay 7 191.5004s) 181.185035) 171.1558035) 132l.0500as) Day 7 - Day 14 191.97(as) 220..00035) 191.175035) 172..140%45) Day 14 - pay 21 1291.71045) 202.174035) 201.73605) 129.1000s) bay 21 - Day 28 202.27015) 202.181035) 201.7508) 129.4748s) Day 28 - Day 35 231.l80ws) 212.164035) 22.1310385) 212.470s) Day 35 - Day 42 212.1740s) 212.15505) 2201.29035) 202.580%45) ~ Day 42 - Day 43 22.2.82045) 22.135035) 222.172035) 212..98045) Day 49 - Day 56 2221.17035) 212.185035) 222.115035) 22.117045) Day 56 - Day 63 22.1.84045) 220.196035) 222.137035) 222.634s) Day 63 - Day 70 2211.28045) 202.165035) 212.162035) 212..95045) DAY 0 - DAY 70 212.0004s) 220.191035) 201.7808) 1291.91045) --~ _-- TTozCompanySanitized. Doesnot contain TSCACai F0--2D4a76y8;GaSvuabgcehrSotnuidcyTionxRiactistywith One-Generaton Reproduction Evaluations --_ TABLE 9 (Continued) DuPont$990 MEANDAILY FOOD CONSUMPTION (g) BY FEMALE RATS 0 Gmrgo/ukpg/1d1ay 25Grmogu/pkgT/vday 10G0romugp/kVgI/day 5G0r0oumpa/vkI/zdzay Dosing Period for Subchronic Toxicity Evaluation (continued) Day 70 - Day 77 Day 77 - Day 84 bay 84 - Day 91 212.196025) 212.202025) 192.195020) 203.2908) 202.19305) 203.220s) 22.115015) 23.12a) 2l.o3us) 2221.74025) 223.l000825) 222..118025) DAY 0 ~ DAY 91) 212.010024) 220.165015) 22.1220) One-tonth Recovery Period for Subchronic Toxicity Evaluation 201.155028) Day 91 - Day 98 222..1104 ~~ Day 98 - Day 105 212.l6004) Day 105 - Day 112 223.25 00 Day 112 - Day 119 221..4704) 223.5165) 25..2605) 2E.R5I) 23.45s) 233.09s) 222.1945) 232.5905) 22.1245) 224.132005) 223.32 a) 202.l1aas) 2a1.l2sa) DAY 91 - DAY 119 212.192014) 2311.3805) Data summarized as: MSetaanndard Deviation (n) 232..245) 222..9705) - a. oRFnaotosdtedsctoenssidugamynpat7t0ie;odndfdaoatratarweepcrroeoldlnueoccttteicdoonldlueervciatnlgeudatgdieuosrntiant(gi2o0nthraeartesc/oghrraeobpuioprt)taetwdieoransepecpraoirhetodu.osfed the reproduction evaluation. # Sttraetnidsttiecsta.lly significant difference at p < 0.05 by Jonckheere-Terpstra --_ EE TosCompanySanitized. DoesnotcontTSaCAiCanl 0H--2D47a6y8:GavSaubgsehSrtoundiyciTnoxRiactistwyithOneGeneration Reproduction Evaluations -- TABLE 10 DuPont-5990 MEAN D(AgIbLodYyFwOeiOgDhtEgFaFinI/CgfIoEoNdCcYonOsFumMeAdL)E RATS 0 Gmrgo/ukpg/1day 25Grmoau/pkgI/dxay 10G0romugp/kVvg. /day S0G0romugp/kvgI/zday Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 00..30036545) 00.l301a33(35) 00..0237750035) 00.013668(0a5) DAY 7 - DAY 14 0.00.22694(44) 0.0.20720735) 00..024586(35) 00..024920(8as) DAY 14 - DAY 21 00..025430145) 0.01203209035) 00..023147(835) 00.0231750845) DAY 21 - DAY 28 00..108219(45) 00..10838135) 00..107432(35) 00..0125970845) DAY 28 - DAY 35 00..104361145) 001.012802035) 00..1033008(35) 00..002902(443) r~ DAY 35 - DAY 42 0.0.100371145) 00.0101340035) 00..10047535) o0l.o0s811(8a3) DAY 42 - DAY 49 00.01211285) 00.1101217035) 0.0.100264035) 00l.004809(%43) DAY 49 - DAY 56 0.000393345) 0.000928535) 00..0027590834) 00..0038738(43) DAY 56 - DAY 63 00..007264144) 00.l007s40(3s) 00..007297(34) 00..00638643) DAY 63 - DAY 70 00.00277044) 0ol.o02970(35) 00.l007275(30) 00..003406(843) DAY 0 - DAY 70 o0l.o11528(a3) 0o.l1o5l9o(3s) 00..1041618034) 00..011222(043) --_ _-- Te `CompanySanitized.Doesnotcontain TSCA C81 9H0--2D4a7y6G8:avSaugbeeShtroundiyeiTnoRxaitcistwyithOne-GenerstionReproductionEvaluations --~ `TABLE 10 (Continued) DuPont5990 MEAN DAILY FOOD EFFICIENCY OF MALE RATS (gbody weight gain/g food consumed) Dosing Period for DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 91 DAY 0 - DAY 91 0 mGgr/okugp/dIay 25Grmogu/pkgI/dxay 10G0romugp/kvg/day Subchronic Toxicity Evaluation (continued 00.00362124) 00..005227024) 0o.l0o4a6i(2a) 0.0l006350(1s) 0o.l0o4a83us) 0.o0lo5a3rts) 0.0.00447314) 00..005274014) 00..0003214) ol0.o113i2za) 0.0.10306815) 00l.011129(814) 50G0romugp/kVgI/Iday 0.0.006338(25) -00..00440625) 00..004400(25) 00l.011022(025) One-tonth Recovery Period for Subchronic Toxicity Evaluation ~ DAY 91 - DAY 98 o0l.002575014) 00..004023(5) 0.0.005335(4) 00..0131410815) DAY 98 - DAY 105 00.l005337114) 0.0.003393(5) 0.0.008173(4) 00.0059440815) DAY 105 - DAY 112 00.l005135(14) 00.l005224(5) 00.0035694) 00.201058015) DAY 112 - DAY 115 00..002380014) 0.00.03120(5) o0l.002015(a) 00..000657(15) DAY 91 - DAY 119 00..00089(14) 0.0l003162(5) 0.0.005130(4) o0l.00d6s1(415) D_a--ta summarized as: Mean Standard Deviation (n) a. Ropnaotssttmesdatteisnidggaynpae7t0re;idoddfsao.trarweeprreodnuocttiocnolelveacltueadtidounrin(g20trhaetsc/oghraobuipt)atiwoenreancdohoused # Sttraetnidsttiecsta.lly significant difference atp < 0.05 by Jonckheere-Terpstra ~~ -_-- 105 Company Sanitized. Doesnotcontain TSCA Cal 9H-02-4D7a6y8:GavSaugbcehSrtoundiyc iTnoxRiactistwyith One-Generation Reproduction Evaluations --~ TABLE 11 DuPont-5950 MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) 0 Gmrao/ukpg/IdTay 25Grmogu/pkgT/vday 10G0romugp/kvgx/day S0G0romugp/kVgI/IdIay Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 DAY 7 00.01d680(as5) 00.010435935) 00..103349835) 00..215189(845) DAY 7 - DAY 14 00..014432(45) 00:.018302(35) 00.1104363135) 00..025045(845) DAY 14 - DAY 21 0.00.15481145) 00l.01a310(35) 00..013432035) 00.l104481(a5) DAY 21 - DAY 28 00.l100593(45) 00l.10285335) 00..10045335) 00..014275(as) DAY 28 - DAY 35 00..00841545) 00.100835635) 0.0.005665(35) 00l.003556(845) --_ DAY 35 - DAY 42 00.l007a6s(as) 00.1005329035) 0.0.007596(35) 00..007318(45) DAY 42 - DAY 49 0.ol006d5o(as) 0.0.00639935) 00..004748(35) 00.00365045) DAY 49 - DAY 56 00..003451(4s) 00.1008333035) 00..003259035) 00..003396(a5) DAY 56 - DAY 63 00.l002386(a5) 00..001289035) 00..003386(35) 00..002393(45) DAY 63 - DAY 70 0.00.03855(a5) 0.0100445535) 00..0043474(35) 00.004206(8as) DAY 0 - DAY 70 0.0.000898 (45) 00.000814035) 00..000893(835) 00..001801(%45) R Te T -------- CompanySanitized. Doesnotcontain TSCA Cal 9H0--2D4a7y68G:avSaugbechSrtoundiyciTnoRxaitciswtyith One-GenerationReproduction Evaluations --_ `TABLE 11 (Continued) DuPont-5990 MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) Dosing DAY 70 DAY 77 DAY 84 Period for - DAY 77 - DAY 84 - DAY 91 0 Gmrgo/wkpg/IdIay 2G5romugp/kIgv/day Subchronic Toxicity Evaluation 0.0.002463(25) 0ol.o0a227(1s) 00.00423925) 0.0.003377115) 00..001433(24) 0o.l0o2a8sas) DAY 0 - DAY 91 00.00079224) 0.000710115) 10G0romugp/kVgI/day (continued) 00.004153015) 00..005205015) 0.000039115) 00..007028(15) S0G0romugp/kVgI/IdIay 00.003256025) 00..003327(25) 00.00403125) 0.0.0006558(25) One-tonth Recovery Period for Subchronic Toxicity Evaluation DAY 91 - DAY 98 00.005476014) 00l.002137(5) 0.0.001398(5) 00l.00a071(815) ~ DAY 98 - DAY 105 00.005182(14) 00..013934(5) 00l.002836(5) 00.105281015) DAY 105 - DAY 112 00..004703(14) 00.l008937(5) 00..006530(5) 00.007717015) DAY 112 - DAY 119 o0l.o0a0a0(1a) 00..00330(5) 00.l003a6d(s) -00..130188015) DAY 91 - DAY 119 ----___ 000.l.000113665(a144)) 0.000l.10013332((55)) 0.000..00222771((55)) 0.00..0004403360001155)) Data sumnarized as: MSetaanndard Deviation (a) a. Roantstedstesdiagynat70e;d Food efficiency ddfaaottraarwefeprrroeomdutncohtteiocgneosltleaevtcaitlouenadtdpiueorrniino(dg20atrhreeatscr/eogphroaorbutipet)datwiaeosrnepapercrtoihooodfuss.etdhe reproduction evaluation. # Sttraetnidsttiecsatl.ly significant difference at p < 0.05 by Jonckheere-Terpstra --_~ -_-- Tos `Company Sanitized. Does not contain TSCA GBI ~~ Z| 3 s zie ss g gz 4 A TE B:E EY) | iro --_ 2z E 2 :g 3 CE : 4 Fn a ap ge gop oe go: > : : 3 7 5 eer er er er ar er ay 32 PEo3E3pdf 8oF 3B1i 8R3ET3ROR0% ii Bs y Behptaploi.iidhiighiegdnog ~ ix3 a ii ofh F b cosi CompSante. Bosc5o0hm01 - z .4 giBE ser ou -eFETS- a on or : - E 2= L 3 . oo ea a --~ S2 EB = Y SZ 52 2 ji {I i 253 ii7 i2 ~ i4z Fg gg r: a er mi er er eee a gL Sag en z co: os yo BdLO oogp A Hst cI b oH3 , LE 5 4 5 h idEfg1 oIF een a. sls = a fsid igoeop opo HEHE 3s 5 5 3u Fi OF# { f CompanySoca. BossnotconTasonn ca ~8 i g "3 x 3 =a ht] "3 "& fs i : 3 3 & 38 cep mg lg en er en ~ | s83! 4 5 23 pos 35 25g i 3 g E| = = "8 nr or * ov Boo jpop pop ogg LH22 28 ~ 343 cB- O2F P= OF= FF a = 2 jlgt ut #08 # HM, H pFEE H o g obPFA 3 F23 ood8 Company Saiizad. Does ntcontain780A OBI ~ i | 5 Be "8 vt ng - . cg em va ag ng : 5<s E ~ iE :. s 1 8 gs 2 3 liBol ee er er ag ee 8$ i i2: : 0:0: f3F 0F%F : P3 3OGTOG3 Bo Bigg ~ 23 swieoHCEb H LH b Hyd e Hu HH GompanySantzad. Dootconstain 750A cr ~8 i 3 ] EI gle ax eg re ey Tx wg ong ~ | g" Haa 3 zr : : ii i . go: i 1 If d 2: z ; & "+ or ag g - 4 i4 or ii Cie. =2 5 i= i2s cFeEEs os r a orib.s ii3 L go y fooggso ogi gg ga tiiagg oodg ~if Meo Fd coretases momen ~$ 2 i . gp er ex fz ng i ii x PE _: 3 ; hy i FREY rE Is Bpobob Bel : : ih ~ i Ec8iE: BITh iEndEd 2. idl fzzEa3 n. ow JiHtdA i8 ggE *F ie #2 i G18 : z= H5 IfIp0 :| i 54 ir pe i Si 8 em er ex eof0F GRE 33 CHsfE5 H 53 szL lsiufsH . u8%s2 ~ 5 m fetooL gfT df T Hug CompanySanitized. Does not contain TSCA CBI a z4 - : iF 2 08 oy oR I. B g Z sie ng 125 , er er on CRY CL ~g 2 | g c:ii 33g 5 og 8 : Bowlgs oo eg eg omy er en ag : a i 3 2 z& ph3e: osrs alea R5N ~8 13 HL fPg. Lp 38,a E20g 8 I.giNH sd H Lgaid H sa hii _&5 i ff ply 8 #4 ff: FF H Fk ConanSento, Bvt cr3ci ~5 3 2 zg 4 - :i 2 - - $ % v8 32 en -g 3 - gifs . 14:3, 3g |23 ag i55 a4 ~ iFi 5 id= Bal1BeE axe eg er en en er a nd SEHR EE P i F3 5 og8i o3F F F P E OE3 g8i sfgs gi8 1g8 ggfi 4fH iSieedFoToE r oEf TEd,oTds Company Sanitized. Does not contain TSCA C81 ~ : 2pn 33 Fi . J 3 a3 28 5 s "8 *8 8 78 : Br r er ng g cg eg mg ep Pe! ) ~ SE $ ii 0853g 3 i iF : pfs or or or eg weg ag ero E| g =B -- 2 $i 2 ud3e r= =r eg mg4 wgte ngce mgox i i3a ~8 ii ibid Pogo FF} ,gHs8i dsd HgsEf HiT iai $p5i, 8 gf 58 8g8f 8gd Company Sanitzad. Donotecontsain 150A G31 i ~ g Er3CE gi - ECE TE i El dal | g TEgs s4k oo x oe i, oe eg oo 3fiai d1: Fl - Hj IER= g fii gy 8 iGdn i ' i 2 g oe "& er mg mg ep i Eid i L]I it PnE ig3 lai- i Spies : Eh Cline i p08 ky FORD Biaids i5 Pbiygeig1hio1 n!knii hian fiid ng ~i mE OFF F fg iE CoanSaie.oos omaT5cAn -- it i3 3pos Efd Ely 28 i ) 8I 0sy |i 3% 2X 9 s= 57% ig g8 iE e =EBE d32 .g 2i o 5i :: ~ =3 2 gv ET os z i IE": g aif 3 ZE i 1 TH i:2 i3 d ~ 3g 3 5 fF go | E : 3i 3 3 11 + 3 fi 2 i 5Pooogrif!s F oiob E 4 Ui|g tiHv L zz Edfgf is 11328% 85| | A3%E CompanySantee,Dosnotcont0aAiGn1 ~ i8 {8 3 5 zs 3 i gi zg =3 i} gs EzR 23 2 | ii2 sf 2 3 IEE if Eso 33 i5hos8b ~~ 2 8 nrw o cl 8gn2 83 | FM 2 ~ 2 3 wd > I5%E : 5 HE 2 | 8 ii Pia Po iE [A 52 2 | 1: L$E1I 5 |S2 LoL Lee ~if HENS IC Company Santzed. Does ot contain TSCA GBI 0H:-2D4aa7yy68GC:aovvSaauggbeechSSrhtoucndiyycniTnoRxRaiacttisstwwyiitthhOOnnee-GGeenneerraattiioonnRReepprroodduuccttiioonnEEvvaalluuaattiioonnss --~ TABLE 16 DDuubPoonntt:-55999900 PERCENT SURVIVAL OF MALE RATS DTorseeatm(emngt/kGg/rdoauyp) Animal Count at Study Start 4H5H0 2x5 100v v5i0z0 3s 35 as DAYS ON TEST 0 7 100 100 100 100 100 100 100 200 1 21 100 100 100 100 100 100 100 100 28 3s 100 100 100 100 100 100 100 960 2 a 100 100 100 9% 100 100 100 9% s6 6 100 100 98 100 ES 9% 97 9% 70 7" 98 100 97 9% 96 100 93 9 8a 01 96 100 93 03 96 100 93 93 9% 0 100 80 88 105 12 9 100 80 88 93 100 80 3 r------eee11e9 eeeeeee93 te100ens80 ree88ee SNuamcbreirfiactedstinudyexsttraermtis 4s1 35 35o as1 RFoeumnodveDdeafdrom study | 200 200 201 1 18 Aslaicvreifioncedtesbty ddaeysig1n19 11a0 105 10 4 10 15 PercNeunmtbeSrurovfivraalts= rom study - a(tNurmibsekr =ofNurmabtesraaltivset/uNduymbsetrarotf number sacrificed by design. -rantusmbaetr roifsk)ra+t1s00removed b2.l RRaatt sfaocurnidfidceeadd diunrienxgtretmhiesprdeuvriionugstwheeekp.revious week. . R(actoshoudseesdi)gnaontedtesftordaryep7r0o.duction evaluation were removed from study 4.. RRaetcsovdeersyigpneartieodd test days 95 fbeograntheon91t-edstaydaexypo91sure period were sacrificed on CTohcehrreanv-eArremintoagsetattirsetnidcatleslty significant decreases in survival at p < 0.05 by --_~ Niontcel:udedRaotsn atdhidsedtafbolre.evaluation of 10-day hepatic biochemical evaluations mot _-- 120- Company Sanitized. Does not contain TSCA Gal 29H--0D2-4aD7ay6y8;GGaaSvvuaabggceehSrStotunudidycyiTinonxRRiaacttisstwywiitthhOOnnee-GGeenneerraattiioonnRReepprroodduuccttiioonnEEvvaalluuaattiioonnss -- TABLE 17 DDuuPPoonntt:-55999900 PERCENT SURVIVAL OF FEMALE RATS DTorseeatm(emngt/kgG/rdoauyp) n0 Animal Count at Study Start 4s 2w5 35 1v0i0 v5i0z0 35 as DAYS ON TEST 100 100 100 100 7 100 100 100 100 1 100 100 100 100 21 100 100 100 100 2 3s 100 100 100 100 100 100 100 100 a 100 100 100 100 as 100 100 100 100 56 100 100 100 100 63 70 100 100 100 100 100 100 100 100 _ " 100 100 100 100 oe 100 100 100 100 oe 9% 100 100 100 100 100 100 100 100 105 100 100 100 100 12 100 100 100 100 _m -- 119 100 W 100 100 1W0w0 ANucmcbiedrentatalsltyudkyillsetdart as1 350 350 as0 RSaecmroivfeidcefdrobmysdteusdyign 1200 2100 1200 2100 A APleirvcl eentoni Sutrevsv tivadlaye =11(9No umben r oft r1a1t4sv 5 alie ve/Ns umb5ert s of d ratsa a5t y risk 1 *1101055s Numfbreorn osfturdayts- antumrbiesrks=acNruimfbiecredatbystduedsyigsnta-rtnu-mbneurmbaecrciodfenrtaatlslyrekmiolvleedd. a. R(actoshoudseesdi)gnaontedtesftordaryepr70o.duction evaluation were removed from study b.. RRaetcsovedreysipgenraitoedd test day 56. bfeograntheon91te-sdtaydaeyxpo91s.ure period were sacrificed on d. Rat accidentally killed during the previous week. TChoocrheranw-erAermintoagsetattirsetnidcatlelsty significant decreases in survival at p < 0.05 by ~~ Niontcel:udedRatosn atdhdiesdtafbolre.evaluation of 10-day hepatic biochemical evaluations not -_-- Tis Company Sanitized. Does not contain TSCA Cal 292004:-7DD6ea8yy:GSaavvSauagbgceehSSrttouunddiyyciiTnnoRxRaiatctsistvywiitthhOOnnee-GGeennesrrattiioonnRReepprroodduuccttiioonnEEvvaalluuaattiioonnss ~ TABLE 18 DDuuPPoonntt:-55999900 MEAN FORELIMB AN(DMHEIANNDOLFIMTBHGRREIEPTSRTIARLESN)GTH FOR MALE RATS Assessment Dosage Period Group (mg/kg/day) Forelimb Grip Strength (kg) Hindlimb Grip Strength (kg) Baseline 1 0 m 25 v 100 vi 500 0.53 (0.09) 0.55 0.07) 0520.10) 0.54 (0.09) 0.33 (0.06) 0.33 (0.05) 0300.06) 031 (0.04) Week 13 1 0 m 25 v 100 -- vi 500 153030) 137024) 133029) 115 032)% 0.85 (0.10) 0740.11) 0740.15) 0.70013) Recovery 1 0 142033) 0820.13) vi 500 1.28038) 0.70 (0.10) Data aranged as: Mean (Standard Deviation) + pSu<i0s0tsi.call significant differencesfromcontrolbyOne-wayanalysisof variance followed by Duets test; --~ TTT -------- Company Sanitized. Does not contain TSCA CBI 9H0L2-4D7a6y8;GavSaugbechSrtoundcy TinoxRiacsitywithOGneneration Reproduction Evahations --~ TABLE 19 Dupont 5990 MEAN FORELIMB AND(HMIENADNLOIFMBTHGRRIEPESTTRRIAELNSG)TH FOR FEMALE RATS Assessment Period Group Dosage (mg/kg/day) Baseline u 0 v 25 vi 100 vi 500 Forelimb Grip Strength (kg) 0.52(0.11) 0.54 (0.11) 0.56 (0.08) 0.53 (0.06) Hindlimb Grip Strength (kg) 0.33 (0.06) 0330.07) 0320.06) 0.33 0.05) Week13 n 0 nv 25 VI 100 -- vin 500 098 0.17) 097 (0.16) 1160.24) 097023) 0.68 0.14) 0.62 0.07) 0620.13) 0610.10) Recovery n 0 1.04033) 0.71 (0.09) vin 500 0.93 0218 0.62 (0.11) Data arangedas: Mean (Standard Deviation) @ sRtaattis6t4ic6s.540 was uncooperative during forelimb grip strength. Data were omittedfom summary tables nd `DTuhmenreetw'esreesntospta<tis0t.0i5c.allysignificant differences from control by one-way analysisofvariance followed by -- - Tm Company Saniized. Donotecontsain TSCA CBI 292204-7DD6a8y:GGaaSvvuaabggceehSrStotunudidycyiTionnxRRiaactiistywviitthhOOnneeGGeenneerraattiioonnRReepprroodduuccttiioonn EEvvaalluuaattiioonnss --~ TABLE 20 DDuuopmontt5-9599%00 SUMMARY OF FUNCTIONAL OBSERVATIONAL BATTERYFINDINGS FOR MALE RATS Dosgo(mkgiGdonp: NumberExamined: DAorePactPionRO&TAOUCCHH: inscormeaasledreaction Gunps awayoratacks) Baseline 0Tm25 10v0 vSi00 10 102 10 10 0 0 0 000 0000 Week 13 0Tm25 10v0 o5i00 10 lo 10 10 Recovery 0or50i0 10 10 100000 00 00 1o0g 1o0 0 0 0 `oo A0UrDesIctTiOonRYSTIMULUS: nolreaction (ratfinches orficksean) 10 100 100 100 100 91 100 91 1o0 o10 exaggerated reaction (at jumps,fips) 0 0 0 0 0 0 0 oo 2T0ArIeLspPonIsNeCH: somal(rs towardsie) ~~ `exaggerated response 00 100090 000 100 07 09 90 100 10o - 001 0 03 1 00 IDNEMFEOCTAOTIROANC:TIVITYMONITOR: abpsreesnetnt diahes SSs473s0s 8200ss 64 82 4gss 000 0000 00 prUeRseInNtATION: absent S5018.28000 91 91 91 00 10o0p prPeUsePnItLLARYRESPONSE: sbaent 001000100 100 100000 00 00 1o0 o10 --_ ee TT -------- CompanySaniized. Doesnot conTtSaCAiCani 9HL02-4D7a6y8:GaSvuabgcehrSotnuidcyTionxRiactistywithOneGeneration Reproduction Evaluations ~ Dupont5990 TABLE 20 (Continued) SUMMARY OF FUNCTIONAL `OBSERVATIONAL BATTERY FINDINGS FORMALE RATS Dossge(mGghooyw: Baseline TH vvi Week Tm 0 25 100 S00 25 13 10v0 ov50e0 Recovery 0or30n0 NumberBramined: 10 104 10 10 10 lo fo 10 10 go ADDITIONAL OBSERVATIONSNOTED Soreleh forelimb: Sore forelimbtoes. 000 000 0 0 01 oo 0 0 2 1 oo Stainedperineum Abvormlgit 000 0000 0004 oo 0 0 1 oo o a* FStotrsttheicbaalysesingniefviaclaunattiifonf,erienncaeisbonyCanoddeafencaAtrimonitwageetneosttfcorowrdeednFpo<rdo0.n:05a.nalinGroup Il --_ -- - ------------ ms CompanySanitized. Doesnot conTtSaCAiCna 2504.7D6a8y:GaSvuabgeehrSotnuidyTionxRiactstywithOneGeneration Reproducion Evausions --_ TABLE 21 Duront5990 SUMMARY OF FUNCTIONAL OBSERVATIONAL BATTERY FINDINGS FOR FEMALE RATS Baseline Gop I IV Viv DosNaumgbee(rmEgxkagm/idanye)d:: 100 2150 10100 50100 Week13 0 Iv Vivi 100 2150 10100 50100 Recovery IVI 100 50100 DAorePactPionRO&TAOUCCHH: somal 0 100 100 010 10 000 00 100 100100 rreasedreaction Gumpsavayoratack) | 0 0 0 0 0 0 0 0 0 0 hAoUDeaIcTtOonRY STIMULUS: Hom eacion (catflschesorflicksea) 10 100 100 100 100 100 10 0 010 100100 cxaggersedreaction(ratjumps, ps) 0 0 0 0 0 0 0 0 0 nToArIeLspPoInsNeCH: normal (ramstowardsic) ~ `exaggeratedresponse. ooo 0 00 90 0001 100 100 100 100 0000 100100 00 IN MOTORACTIVITY MONITOR: prDeEsFenEtCATION: Sheet 3700ss 28 037 31 64 7337 64ss danbea 0 0 00 0 0 0 0 0 0 prUeRsIeNntATION: sent 9137 82037 28100 51 100 100100 pPrUePseInLtLARYRESPONSE: Sosent oo 0 00 00 100 00 00 00 10 0 ADDITIONALOBSERVATIONS NOTED Stinedperineum 000 0 0 0 st 0 0 + Sutistialy significant difbfyCoechsrannArcmiteage est fo rend: <0.05 --~ ----------------Ti-- e -------------- CompanySaniized.DoesnotconTtSaCAiCanl ~ 5 sges gaze if i g 4fSi88s8i55s88 F233828i8d gies F94d2% gi KH is : WERE? "5388 "ER 1% . 5 fgse ess se i 2 5| vE55% -EEE v3 52 . 22 8 "Z2I8 THERE "RR < 3 ~ |f zBED2 7| "sReEsREs gser "E3dE st "ER 41 iH 8 iIg5 $g3g3e8s g8f58es H3H8. 3H1I% | 4] cnn eau 5] i ki: :5 2 gg mss mss -a1s1i0 di io kor 1 iii 781 i 3 3a7 Commi Santos. Berta ~8 zH . WsEeEgEa WSB85E8 W5i8 iih : Z| "2E3F "REAR TER) 12 ag Z g2gzg RARE 88 Hi |. [esas REEL ER fg | i Z Be i gk gg z Z 3 g i ii. 21 ~3i5 SZ5g 5358 TEEEE "Ez2: 558g CIERE . "8: fs gs 1p i CERLTL I sig N _ _ g =zs =z5 oB0 eidg ; 885 2 iii IEE = = diz 2 ; i 11 i or com ~ 2 - 888 35538 48 w2x5EsEc2 $538 wFEFS whe i i 3 Zz s58 Bo iz 1 <3 El ages sss: as i 28 EB oo. od I 3ag f%|| me5E838sg ESES8E8 "E2Y9 i1pf . . ~ 3= Z| sees eoss ms iE k 8 q HEc "55e3r% ~gamEeEs 3oo3 IE41, HG1 i 8s F255 "EEES 5g $1 : 5: 333 ner oem od]$iis i PRE Rk 2 g -g>5 -E>EF ~= ti 3 g& . 230 8 ~Hi 1 B i 1E 9H : ail i E9L] Company Saritaad.DoonotonTSaCA nCl ~8 i 285% 49558 38s o| "EF F233 -i i ER ICl woe ge 2888 588 .8Y _ a iz ` 23g TMzzzs "83 i . 1J 052e: | "BgEeEeF ~EgEsEaEm CgEgE ipr : i PE ga8ss S58 8% gs L 1= Pi | Z E3 E ong az 83i s1,s $1 < ie 8 asp asx ong A110 i 9 ~| 9] 1367 H902.4D7a6y8:GavSaugbechSrtoundey iTnosRiactistywith OnGeeneration Reproduction Evaluations DuPont:5990 TABLE 26 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group1 Omgkgdsy GroupI 25 mgkg/day Group V 100 mgkgiday Group VII S00 mg/kg/day RBC (x10%4L) DAY 39 8.11 794 8.04 825 DAY 95 035(10) 863 032(10) 8.60 021(10) 8.50 03310) 885 DAY 123 04310) 862 0.40(10) : 0.49(10) * 038(10) 833 DAY 183 0.420) 879 871 8.59 0.40(10) 850 0.62) 02165) 0.434) 0.534) HGB (g/dL) DAY 39 149 148 147 143 DAY95 0.510) 154 0.4(10) 153 05(10) 147% 03(10) 142% -- DAY 123 0.6(10) 153 0.6(10) E 0.610) + 03(10) 145 DAY 183 069) 154 155 151 0.4(10) 152 0.4) 0.75) 0.6(4) 074) HCT (%) DAY 39 419 476 412 459" DAY 95 1.7010) 474 12(10) 46.8 1.4010) 457 12(10) aaa DAY 123 2.0(10) 459 17010) ? 2.0010) # 1.1010) 442% DAY 183 1.40) 46.7 469 464 18(10) 468 0.403) 176) 3.004) 3.164) Mev @) DAY 39 59.1 60.1 587 55.7 DAY 95 1.4(10) 549 1.010) 545 2.110) 539 16(10) 503+ DAY 123 13010) 534 14010) 18010) 2.1(10) : 53.1 DAY 183 2009) 532 539 540 22010) 552 340) 26(5) 1.064) 374) -- _-- TE `Company Sanitized. Does notcontainTSCA CBI H9-02-4D7a6y68G;avSaubgcehSwtoundiyc iTnoxRiactistywithOne Generation Reproduction Evaluations --~ `TABLE 26 (Continued) DuPont:5990 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group1 Omgkg/dsy Group II 25 mgkgday Group V 100 mghkg/day Group VII 500 mg/kg/day MCH (pg) DAY 39 183 18.6 184 17.4% DAY 95 0.510) 179 0.610) 178 0.7010) 173 0.6(10) 160% DAY 123 0.4(10) 178 04010) 3 0.5010) 0.710) LS 175 DAY 183 0.709) 17.7 178 17.6 0.7010) 179 176) 1165) 0.504) 1364) MCHC (g/dL) DAY39 310 310 313 312 DAY 95 0.4(10) 325 0.610) 27 04(10) 322 0.4(10) 319 ~ DAY 123 0.4(10) 04 03(10) : 04010) 0.7010) 3 330 DAY 183 0.49) 3.1 30 26 0.610) 325 1.063) 0.95) 114) 114) RDW (%) DAY 39 11 1s 1s 121% DAY 95 0510) 134 0.8010) 137 03010) 143% 0.710) 150% 0.910) 09(10) 0.5010) 05810) DAY 123 127 0.409) : 2 165% 13(10) DAY 183 137 020) 136 0.6(5) 147 084) 13.6 054) ARET (x10) DAY 39 200 28 212 20 DAY 95 29(10) 191 96(10) 32(10) 184 235 53(10) 252@ DAY 123 34(10) 187 33010) 4810) 48(10) = m* 389) DAY 183 151 170 181 33(10) 187 30) 3565) 20) 2904) --~ s-- o ----------------T--e------------------ Compiny Saniized. Does not contain TSCA CBI H9-02.4D7a6y8:GavSaubgcehSrtoundiyc TionxRiacittywithOne GenerationReproduction Evaluations DuPont5990 ~~ TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group 1 Omgkg/day Group Il 25 mg/kg/day Group V 100 mglkg/day Group VII 500 mg/kg/day PLT (x10%4L) DAY 39 1013 1084 1024 1028 DAY95 146(10) 121 162(8) 1099 93(8) 1163 1339) 1246 DAY 123 201(5) 1097 17168) : 1220) 158(8) : 1209 764) DAY 183 1047 1084 1164 127(7) 1105 19403) 695) 2052) 11064) WBC (x104L) DAY 39 13.82 16.15 15.42 16.14 DAY 95 2.18(10) 1276 337(10) 1237 1.74(10) 11.66 23810) 1231 ~ DAY 123 681(10) 11.46 3.15010) E 187010) * 18910) 1176 DAY 183 4479) 936 9.11 1032 2.43(10) 1145 1396) 13005) 1.90(4) 33164) ANEU (x104L) DAY 39 150 188 179 155 DAY 95 04210) 333 0.56(10) 199 0.5010) 179 03010) 193 DAY 123 5.64010) 199 0.40(10) 3 0.45(10) 043(10) 200@ DAY 183 1800) 190 1.64 233 0.49(10) 201 0.1403) 0.63(5) 0214) 0.534) ANPR (x10/4L) DAY 39 hy DAY 95 DAY 123 B : . > ------ Te ---- `Company Sanitized. Does notcontain TSCA CBI 2904.7D6ay8:GavSaugbechSrtoundcy iTnorRiactistwyithOne-Generation Reproduction Evaluations --_ TABLE 26 (Continued) Dupont 3990 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group1 Omgkg/day Group Il 25 mg/kg/day Group V Group VII 100 mgkg/day 500 mghkg/day ALYM (xI0/uL) DAY 39 1161 1338 12.67 13.60 DAY 95 2.30010) 869 3.1210) 9.68 1.43(10) 9.18 220010) 9.63 DAY 123 24510) 8.86 273(10) : 1.74010) # 177010) 9.14 DAY 183 3.0609) 673 7.02 749 221(10) 887 1290) 13265) 1934) 33004) AMON (x104L) DAY 39 030 043+ 0.50% 052+ DAY 95 0.0810) 030 0.08(10) 029 0.12(10) 029 0.16(10) 028 --_ DAY 123 023(10) 030 0.1110) : 0.06(10) # 0.08(10) 028 DAY 183 0159) 032 0.16 020 0.1010) 030 0.106) 0.0465) 0.054) 0.144) AEOS (x104L) DAY39 012 oll 013 01s DAY95 0.06(10) 014 0.04(10) 0.15 007010) 0.16 0.05(10) 017 DAY 123 0.05(10) ol 0.08(10) # 0.06(10) 3 0.06(10) 012 DAY 183 0.069) 013 [3] ol 0.0710) 009 0.0403) 0.045) 0.024) 0.064) ABAS (10/41) DAY39 0.16 017 016 0.16 DAY95 0.04(10) oll 0.02(10) 0.10 0.05(10) 009 0.0510) 0.12 DAY 123 0.06(10) 0.10 0.05(10) : 0.0310) * 0.07(10) 0.09 DAY 183 0.069) 013 0.08 009 005(10) 0.10 0.1103) 0.0405) 0.028) 0.10) -- EE Tos ---- `Company Sanitized. Does not contain TSCA CBI 9H-62.4D7a6y6:GavSaubgcehSrtoundiyc TinoxRiactistywithOGneneration Reproduction Evaluations DuPont:5990 TABLE 26 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group Omgkg/day Group II 25 mg/kg/day Group V 100 mg/kg/day Group VII 500 mg/kg/day ALUC (x10) DAY 39 014 018 017 DAY 95 0.04(10) 020 0.05(10) 017 0.05(10) 016 DAY 123 0.14(10) 010 0.05(10) : 0.06(10) : DAY 183 0.099) 01s oll 010 00503) 0.02(5) 0.064) ABLT (x10%4L) DAY 39 DAY 95 > * > DAY 123 > : : DAY 183 . -- AMSC (x104L) DAY 39 DAY 95 v > v > DAY 123 > : : 017 0.03(10) 018 0.05(10) 0.10 0.04(10) 009 0.064) v5 ` AHSN (x10%/4L) DAY 183 * ABAN (x10/4L) DAY 183 Md 5 AMET (x10/uL) DAY 183 B uy AMYE (x10%4L) DAY 183 * v v APRO (x10/uL) DAY 183 2 v v ` AMYB (x10%4L) . -- DAY 183 . . _-- TC Company Sanitized. Does notcontain TSCA CBI 9H02.4D7a6y8G:avSaugbechSrtoundiyciTnoRxiactitwyith One-Generation Reproduction Evahations --_ TABLE 26 (Continued) DuPont5990 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS Group1 Omgkg/day Group Il Group V Group VII 25 mgkgday 100 mgkg/day 500 mg/kg/day ARL (x104L) DAY 183 AAL (x10%4L) DAY 183 * AIL (x10/4L) DAY 183 b ACL (x10) DAY 183 * ABLB (x104L) DAY 183 . . --~ ATE (x10%4L) DAY 183 v AIM (1041) DAY 183 b APLA (x10%4L) DAY 183 v Daa amngedss; MSteaanndarddeviation (Number of values included incalultion) a MMeeaassuurreemmeennttssffoorrtthhiessgrcolulpasrchdiestteirmmeiponiendtcwietreernboytitnaskternumoefnntootrmpiecrfroorsmceodp.ic examination. Microscopic `slwiadsepreerfvoiremwedi.ndiIcnatdeidvindouacleldsoaftatahrisretpyopret;etdheinretfoereC,litnhieicnalstPrautmheonltogcyoaupnptenwdaisx.accepted and no manual count Wohmenthtihsissmanaalllyssiasmpwlse spiezrfdoirdmendo,k avadldidvamleuaesfuoretmiesnstusmwmearreytatakbelne.onInodnilvyid1uaalnidmaatla afrreomretphoertgerdouipn.thDeita Clinica Pathology appendix. @+ SSattsitsiticcaallllyy ssiiggnniiffiiccaanntt ddiiffffeerreennccee ffrroomm ccoonnttrrooll aattpp<< 00..0055 bbyy pnaornapmaertarmiectrfiesctt(esDtun(pDeuts/)Ta.mbane-Dunnet). -- e`Company Sanitized.Doesnotcontain TSCA CBI 19.02.4D7a6y8G:avSaugbcehSrtoundiyc TioxRiactistwyithOne.Generation Reprodustion Evlustions _ TABLE27 Dupont59%0 PTEERSIT/OD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS OmGgrkogu/pdIaI y 25GmrgohukpgIdVay 100GrmogukpgiVIday 50G0rmogupkgV/IIdIay RBCDA(xY104704L) 781 786 7300 7.26% DAY 9 053010) 791 03010) 7.66 073280(100) 7030539@) DAY 124 076010) 03709) 817 : 049(10) : 061010) 804 DAY 183 0.4510) 799 797 789 05210) 806 0.160) 0.434) 0382) 0260) HGB (g/dL) DAY 40 147 148 138+ 133+ DAY 9 0610) 150 0.6(10) 145 0.6(10) 135% 079) 127% - DAY 124 05(10) 15.1 070) $ 1.000) : 11010) 147 DAY 183 07(10) 153 155 144 05(10) 149 0.40) 0.64) 012) 050) HCTDA(%Y) 40 456 463 a 26 DAY 96 2.0010) 446 1.6(10) 46 1.9010) 406+ 2709) 387 DAY 124 27(10) 460 189) 2700) : 3.4010) 4s DAY 183 23010) 447 463 27 29(10) 447 0203) 176) 030) 190) MeV (@) DAY 40 586 589 592 586 DAY 96 2.6(10) 1.510) 566 569 1.4(10) 564 1.96) 551 DAY 124 3.0010) 200) 563 : 20010) : 1.710) 555 DAY 183 23(10) 559 582 54.1 55L.55(10) 140) 1664) 160) 200) ~~ Tre A ---- `Company Sanitized. Does not contain TSCA CBI 19.02.4D7a6y8G:avSaugbeehSrtoundey TinorRiactistwyith One-Generation Reproduction Evaluations -- TABLE 27 (Continued) DuPont-5990 TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group TT Group IV Group VI Group VIII Omgkglday 25 mg/kg/day 100 mg/kg/day S00 mg/kg/day MCH (pg) DAY 40 189 189 189 183 0.710) 06(10) 0.610) 0.60) DAY 96 19.1 1.0010) 190 089) 188 05010) 180@ 0.5(10) DAY 124 185 % 0.4(10) 3 183 0.510) DAY 183 19.1 195 182 18.5 0803) 0.44) 082) 0.903) MCHC (g/dL) DAY40 322 321 319 313% 0.510) 0.5(10) 0.5(10) 0.809) DAY 96 37 33 03(10) 030) 33 0710) 27+ 0.4(10) --_ DAY 124 29 0.7010) s 7 330 0.7(10) DAY 183 342 0.603) 31s 034) 37 052) 334 0.503) RDW (%) DAY40 13 11 1n7 126@ 1.0(10) 0.4(10) 0.6(10) 0.709) DAY 96 ns 18 129Q 145@ 1.0010) 049) 09(10) 1.2(10) DAY 124 120 3 3 13.0% 0.4(10) 0(10) DAY 183 125 050) 122 121 0.74) 022) 125 0.503) ARET (x10/4L) DAY 40 199 19 240 252% 3710) 35(10) 55(10) 379) DAY 96 168 24(10) 168 2509) 187 3200) 25% 43(10) DAY 124 164 E 148 26(10) DAY 183 156 155 152 12687(10) 266) 15(4) 20) 183) --_ Ee `Company Sanitzed. Does not contain TSCA CBI H902.4D7a6y8:GavSaugbelrSotnuidcy TinoxRiactistywithOneGeneration Reproduction Evahations DuPont-5990 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group IT Group IV Group VI Group VIII Omgkg/day 25 mg/kg/day 100 mghkg/day S500 mg/kg/day PLT (x104L) DAY 40 my 1242 117s 1291 DAY 96 1139) 904 154(7) 1094 126(6) 1180 160(5) 1326@ 3547) DAY 124 932 154(7) 179(8) 165(6) : * 1025 188(5) 183(6) DAY 183 1084 920 1308 1708* WBC (x104L) 13003) 24Q) 320) NC(1) DAY 40 1078 2.70010) 13.12 3.36(10) 13.74 2.52(10) 14.52@ 2.1609) DAY 96 897 136010) 1013 3300) 1002 1.6510) 10.54 1.69(10) --_ DAY 124 8.68 * 241010) : 7.43 1.82(10) DAY 183 8.14 0.603) 7.13 1.054) 648 2432) 8.83 29303) ANEU (x10%4L) DAY40 12 176@ 151 135 0.49(10) 0.59(10) 0.66(10) 02609) DAY 9 099 140 028(10) 05409) 117 04710) 122 052(10) DAY 124 115 3 035(10) : 131 0.58(10) DAY 183 158 0.430) 123 0394) 147 0810) 195 02903) ANPR (x10%4L) DAY 40 DAY 9 DAY 124 > * * --_ ~ TE -- `Company Sanitized. Does not contain TSCA CBI H9-02-4D7a6y8G:avSaugbeelSztoundiyc TinoxRiacsitwyithOneGeneration Reproduction Evaluations DuPont-5990 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group Il Omgkgday Group IV 25 mgkg/day Group V1 Group VIII 100mghkg/day S500 mg/kg/day ALYM (x10%4L) DAY 40 9.02 1055 1141 1235@ DAY 96 2.48(10) 736 2.8410) 798 2.06(10) 8.17 21109) 8.67 DAY 124 144(10) 2680) 707 : 158010) # 1.44010) 565 DAY 183 227010) 601 541 466 1.42(10) 626 0230) 1.0564) 1462) 3010) AMON (x10%4L) DAY 40 026 0.40 036 039 DAY 96 0.10010) 029 01710) 037 0.09(10) 029 0.079) 027 ~~ DAY 124 0.1910) 0239) 021 : 0.08(10) : 0.06(10) 023 DAY 183 0.06(10) 022 018 018 0.13(10) 026 0.020) 0.06(4) 0012) 0.09) AEOS (x104L) DAY40 oll 013 013 012 0.06(10) 0.08(10) 0.06(10) 0.0509) DAY 96 0.10 0.06(10) 011 0.059) 014 0.06(10) 013 0.05(10) DAY 124 0.09 0.0410) : 0.09 0.0310) DAY 183 016 [3 0.0603) 0.044) 0.09 0.062) 014 0.020) ABAS (x10/uL) DAY40 0.10 012 01s 012 DAY 9 0.0410) oll 0.04(10) 0.12 0.06(10) 0.08 0.049) 0.08 DAY 124 0.0410) 0.10 0.0409) : 0.04(10) . 0.03(10) 0.07 DAY 183 0.0710) 008 0.09 003 0.04(10) 010 0.06%) 0.05(4) 0.042) 0.083) -- "Hao-Company Saniized. Doesnotcontain TSCA CBI 9H0-2D4a76y8G:avSaugbechSntoundiyc TionxRiactistywith One-Generstion Reproduction Evaluations DuPont5990 -- TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group IT Omgkg/day Group IV 25 mg/kg/day Group VI 100 mg/kg/day Group VIII S00 mg/kg/day ALUC (x10%4L) DAY40 DAY 96 DAY 124 DAY 183 ABLT (x10%4L) DAY 40 DAY 96 DAY 124 DAY 183 017 0.10010) 0.13 0.05(10) 007 0.03(10) 0.09 0.033) by b 0.16 0.05(10) 01s 0.059) : 0.10 0.034) > 5 : * 018 0.06(10) 0.18 0.05(10) : 0.06 0.082) : > : 019 0.060) 017 0.06(10) 007 0.03(10) 0.1 0.0663) > > ~~ AMSC (x10%uL) DAY 40 : . * DAY 9 DAY 124 ` s > > 4 v AHSN (x10%4L) DAY 183 * b ABAN (x10%4L) DAY 183 > : AMET (x10%4L) DAY 183 v v AMYE (x104L) DAY 183 * APRO (x104L) DAY 183 AMYB (x104L) --_ DAY 183 e------------------Ta-- n ------------------ `Company Sanitized. Does not contain TSCA CBI H9-02-4D7a6y8G;avSaubgcehSrtoundiyciTRoaritcsitywithOne Generation Reproduction Evaluations DuPont:5990 TABLE 27 (Continued) TEST/ PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group I Omgkg/dsy Group IV 25 mgkgday Group VI 100 mg/kg/day Group VIII S00 mg/kg/day ARL (x10%4L) DAY 183 v > . AAL (x1074L) DAY 183 * AIL (x10%4L) DAY 183 > v . ACL (1041) DAY 183 v ABLB (x104L) DAY 183 * v > ~ AIE (x10/uL) DAY 183 * AIM (x10) DAY 183 . v . . APLA (x104L) DAY 183 hs * J Danaranged ss: MSteaanndard deviation (Numofbvaelures included in calculation) ab MMsleeiaadsenurrreeevmmieeennwttissnffdooirctahhtieesdgsnrocoeculelplsasarotefitdsiettsiemtreymppieon;iendtthcewiretfreoerrneb,fythiteanksientnsroturfumnmeoeonntrttpmceoirucfnrotorsmwceaodsp.iaccccexpatmeidnaainodnn.oMmiacnruoaslcocpoiucnt Wrwhoaesmnptehtriifsossrammneaadll.lyssiaIsnmwdpilavesisdpuieaerlfddoairtdmaenado,txavradeldpiodvrmatleeuaedsitunortethhmeiesCnlstiusnmwicmeaarlerPytatatahkboeleln.oognyIoanpnpyen1ddiax.idantvaafrioeimrmedtphoeargutreodluaipn.tlheData ClinicalPathology appendix. +@ SSttaitsitsitciaclalllyyssiiggnniiffiiccaannttddiiffffeerreenncceeffrroomm ccoonnttrroollatpp<<00,.0055 bbyy pnaornapmaertarmiectrfisct(fDesutn(nDeutnatsT)a.mhane-Dunnet). -- S-- e -------------- Ta ----r---- e-- er e `Company Sanitized. Does not contain TSCA CBI 9H0--2D47a6y6G:avSuabgcehvSotnuidcyTionrRiactistywith One-Genersion Reproduction Evaluations ~~ TABLE 28 Dupont5990 TEST/ PERIOD SUMMARY OF COAGULATION VALUES FOR MALE RATS Group Omgkg/day Group Il 25 mgkgday Group V 100 mgkgiday Group VII S00 mg/kg/day PT (seconds) DAY 95 DAY 123 APTT (seconds) DAY 95 DAY 123 157 120) 149 0.910) 201 2.19) 20.1 23(10) 153 0.510) : 186 22010) 148 0.810) : 165% 19310) # 152 12(10) 148 0.810) 156% 1.8010) 197 17010) - Dasmangedss: M`Setaanndard deviation (Numbofvalues included in calculation) ~ 2 Measurementsfo thisgroup a thsimepointwere nottakeno notperformed. + Satisically significant difference from control at < 0.05 by parametric tet(Dunnet Tamhane-Dunner). - Tie: `Company Sanitized. Doesnotcontain TSCA CBI 9H0--2D4a7y66G:avSaugbechSronticiuTnodRxaicytistywithOne-Generation Reproduction Evaluations DuPont:5990 TABLE 29 TEST/ PERIOD SUMMARY OF COAGULATION VALUES FOR FEMALE RATS Group TI Omgkg/day Group IV 25 mgkg/day Group VI 100 mgkg/day Group VIII S00 mg/kg/day PT (seconds) DAY 96 146 145 142 Br DAY 124 0.709) 139 0.6(10) : 0.410) : 0.4(10) 138 0.509) 03(10) APTT (seconds) DAY 9 184 178 172 15.0@ 1.609) DAY 124 1.7 16(10) 19010) 2510) * LJ 181 180) 2700) - Dats amanged as: M`Setaanndard deviation (Number ofvalues included in calculation) ~ a Measurementsfor thisgroup a hisGimepointwere nottaken ornotperformed. @+ SSttaattissttiiccaallllyy ssiiggnniiffiiccaanntt ddiiffffeerreennccee ffrroomm ccoonnttrrooll asttpp << 00..0055bbyy pnaornapmaertarmiectrteisctt(eDstun(nDeutntsT)a.mbane-Dunnet). --~ --------------------T--as-------------------- Company Saniized. Doesnotcontain TSCA CBI H9-02.4D7a6y6:GavSaubgcehSrtoundiyc iTnoxRiactistywithOneGeneration Reproduction Evaluations --_ TABLE 30 DuPont-5990 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I Omgkgday Group Il Group V Group VII 25 mg/kg/day 100 mg/kg/day 500 mg/kg/day AST (UL) DAY 39 8 8 7 7 DAY 95 822(10) 9106(10) 890(10) I910) 710) 14010) DAY 123 103 # 810) 13010) # 108 37(10) DAY 183 101 100 28(10) 9 118 184) 2505) 144) 46) ALT (UL) DAY 39 36 33 38 59 DAY 95 6(10) 3(10) 8(10) 33 36 37 14010) 50@ ~ 610) 13010) DAY 123 4 # 410) . 8(10) 53+ 14010) DAY 183 34 53 50 10010) 66@ 64) 316) 2049) 3165) SDHDA(UYL)39 197 201 205 269 DAY 95 5310) 23 33010) 253 2.4(10) 277 115010) 2.1@ DAY 123 63(10) 194 7.1(10) * 5.7010) : 4.5(10) as 6.2(10) DAY 183 1.5 181 184 9.2(10) 254+ 5204) 476) 299) 62(5) ALKP (UL) DAY 39 139 128 126 174 DAY 95 34(10) 9 25(10) 80 17010) 85 48(10) 128 DAY 123 16010) 80 13010) # 15010) # 46(10) 75 DAY 183 1410) 7 9% 89 1200) 84 184) 2165) 1804) 165) _ Ties `Company Sanitized. Does not contain TSCA CBI H-24768: Subchronic Toxicity 90.DayGavageStyinRaswithOne GenerationReproductionEvaiaions --_~ TABLE 30 (Continued) DuPont399% SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group Omgkgiday Group I 25 mgkgiday Group V 100 mgkg/day 50G0rmogukpgV/IdIay BILI (mgdL) DAY 39 0.08 0.06 0.09 020@ DAY95 0.0310) 0.12 0.03(10) 011 0.04(10) 0.15 0.05(10) 024% DAY 123 0.03(10) 014 0.05(10) : 0.06(10) + 0.05(10) 014 DAY 183 0.03(10) 0.10 0.08 005 0.02010) 0.06 0.034) 0.0465) 0.004) 002(5) BUN (mg/dL) DAY 39 1 14 1s 200 DAY 95 130) 16 210) 2(10) 17 19@ 3(10) 20@ ~ 3(10) DAY 123 16 210) : 3(10) # 2(10) 20 2(10) DAY 183 17 15 14 5(10) 18 24) 36) 1@ 16) CREA (mg/dL) DAY 39 032 034 036 0.40 DAY 95 0.04(10) 038 0.0310) 0.41 0.06(10) 047% 0.06(10) 042 DAY 123 0.06(10) 043 0.0410) ' 0.05(10) : 0.05(10) 0.42 DAY 183 0.04(10) 0.43 0.40 038 0.04(10) 047 0.08(4) 0.06(5) 0.064) 0.08(5) CHOL (mg/dL) DAY 39 6 66 100@ 102@ DAY 95 9(10) 7 14010) 85 12(10) 2 36(10) 109 DAY 123 12(10) 7 2210) * 29(10) # 30010) 87 1010) DAY 183 91 80 8 20010) 80 374) 36(5) 22(4) 25(5) FTiS e: -- `Company Sanitized. Does notcontain TSCA CBI 01.-2D4a76y8G:avSaugbeetSotnuidcy TinoxRiactistywithOneGeneration Reproduction Evaluations DuPont:5990 `TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group1 Omgkg/day GroupI 25 mg/kg/day Group V 100 mgkg/day S0G0rmogu/pkgV/IdIay TRIG (mg/dL) DAY 39 63 7 33@ 2@ DAY 95 22(10) 85 3210) 9 10010) 45 6(10) 2@ DAY 123 39(10) 7 48010) 17010) * # 5(10) 7 DAY 183 32(10) 7 115 125 35(10) 8 3764) 3365) 5604) 235) GLUC (mg/dL) DAY 39 101 810) 102 5(10) 9% 8(10) 97 710) DAY 95 9% 12010) 9% 810) 102 13010) 95 5(10) --_ DAY 123 17 2510) : : 12 24(10) DAY 183 93 74) 100 108 209) 124) 116 2165) TP (DdALY)39 DAY 95 DAY 123 DAY 183 ALB (g/dL) DAY39 DAY 95 DAY 123 DAY 183 65 0310) 72 0310) 6029(10) 74 0.4(4) 41 0210) 4033(10) 41 02(10) 45 0204) 66 0310) 73 0310) : 72 035) 43 0.1010) 46 02(10) # 42 04(5) 7.0 0.410) 8.0% 0310) > 75 0364) 46 02010) s1* 02(10) 3 44 0204 73 0.4(10) 82+ 0310) 76 02(10) 75 0365) sax 02010) 5.5% 03(10) 47 02(10) 44 03(5) --~ J Tie ---- `Company Sanitized. Does not contain TSCA CBI 9H0..24D7a6y6:GavSaugbcehSrtoundiyc iTnoiRactistywith OneGenersion Reproduction Evaluations DuPont:5990 `TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST! PERIOD Group I Omgkg/dey Group II 25 mgkgday Group V Group VII 100 mg/kg/day 500 mg/kg/day GLOB (#dL) DAY 39 23 23 25 23 DAY 95 02010) 29 02(10) 27 0310) 29 02(10) 27 DAY 123 0.410) 27 0.110) = 02010) 3 0.1010) 29 DAY 183 0.1010) 30 30 32 0.1010) 31 034) 03(5) 0204) 02(5) CALC (mg/dL) DAY 39 11 12 7 nm DAY 95 0.4(10) 107 0.4(10) 109 0.510) Ey 04(10) 1.5% ~ DAY 123 0.4(10) 109 05(10) : 04(10) 0.4010) : 13+ DAY 183 0310) 101 103 104 03(10) 106 0.564) 0205) 044) 0365) IPHS (mg/dL) DAY 39 89 89 94 90 DAY 95 07010) 72 0310) 77 0610) 8.1% 0410) 80% DAY 123 0.510) 0.6(10) 80 : 0.8(10) 7 0.8(10) 9.3 0.610) DAY 183 69 69 75 09(10) 89 0.44) 06(5) 0.9(4) 205) NA (mmol/L) DAY 39 146.4 1462 145.6 1433@ DAY 95 1.1010) 149.1 13(10) 148.7 0.9(10) 1485 12(10) 1462* DAY 123 0.7(10) 14638 11010) : 1310) 13(10) * 146.6 DAY 183 1.6(10) 146.7 1482 148.1 1.7(10) 150.1% 144) 096) 2.404) 2165) --~ = -_-- Company Sanitized. Does not contain TSCA CBI H:24768: Subcronic Toxicity 90-DsyGavageStudyiaRatswithOne Generation ReproductionEvaluations --_ "TABLE 30 (Continued) DuPont-5990 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group I 0 mg/kg/day Group III 25 mg/kg/day Group V/ 100 mg/kg/day Group VII 500 mg/kg/day K (mmol/L) DAY 39 DAY 95 DAY 123 DAY 183 6.01 0.27(10) 5.88 0.18(10) 6.37 0.48(10) 6.17 037(4) 6.07 0.35(10) 6.06 032(10) * 6.03 0.24(5) 6.62% 0.51(10) 6.66@ 0.48(10) : 6.52 0.46(4) 6.75% 0.33(10) 657@ 0.55(10) 6.61 0.68(10) 6.47 0.44(5) CL (mmol/L) DAY 39 DAY 95 = DAY 123 DAY 183 97.8 1.2(10) 99.0 1.7(10) 102.8 1.410) 99.6 1.6(4) 98.1 1.9(10) 99.9 2.010) : 100.8 1.505) 97.0 1.8(10) 98.7 2.010) : 101.8 234) 95.8% 1.5(10) 97.7 1.510) 101.2% 1.6(10) 103.6 3.8(5) PFLU (g/mL) DAY 39 DAY 95 DAY 123 DAY 183 - : 01 0.0(10) 0.1 0.1(10) 0.1 0.064) * 02 0.1(10) * 0.1 0.0(5) * 0.2@ 0.0(10) : 0.1 0064) : 05@ 0.1(10) 0.1 0.0(10) 0.1 0.065) Dat smnged as: Men `Standard deviation (Numberof values included in calculation) a Measurements forthisgroupa tistmepointwerenottakenornotperformed. @+ SStuwtiisitciaclllyyssiiggnniiffiiccaannttddiiffffereennccee ffrroomm ccoonnttrooll aat pp<< 00..0055 bbyy npoanrpaamreamreetrteisct(eDsutn(nDetutsT)abaneDunner). ee Ties ee ee Company Saniized. Does not contain TSCA CB 9H.02.4D7a6y8:GavSaubgeelSrtoundiyc iTnoxRiactistywithOneGeneration Reproduction Evaluations DuPont5990 TABLE 31 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II Omgkgday Group IV 25 mghkg/day Group VI Group VIII 100 mg/kg/day S500 mg/kg/day AST (UL) DAY 40 84 9 7 75 DAY 9% 1510) 128 17010) 106 16(10) 75 13010) 79 DAY 124 85(10) 7 65(10) : 20010) + 29(10) 9 56(10) DAY 183 110 79 92 18010) 118 3) 205) 26) 3565) ALT (UL) DAY 40 36 a 45 59@ DAY 96 7(10) 66 11010) 50 11010) 4 13(10) 3 -- DAY 124 63(10) 34010) 62 700) 9(10) 1@ 37(10) DAY 183 47 39 a" 8(10) 51 26(4) 86) 16(5) 26(5) SDH (UL) DAY 40 24 208 183 188 DAY 96 28(10) 247 5.4(10) 219 1.9(10) 167 2.6(10) 186 DAY 124 16.1(10) 25.1 11410) : 35010) 3 48(10) 281 DAY 183 62(10) 139 1.9 167 135(10) 182 4.6(4) 265) 3.90) 7.56) ALKP (UL) DAY 40 85 92 86 14s@ DAY 96 18010) 45 20010) 4 21010) 51 6210) %@ DAY 124 1210) 39 910) 18010) 42(10) # # 36 DAY 183 10010) 33 36 27 1200) a a) 14(5) 65) 145) PN _-- T1s0-Company Sanitized. Does notcontain TSCA CBI H9-02-4D7a6y8:GavSaubgcehSrtoundiyc TinoxRiactistywith One-Generstion Reproduction Evaluations -- TABLE 31 (Continued) DuPont:5990 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group Tt Omgkg/day Group IV 25 mg/kg/day Group VI 100 mg/kg/day Group VII 500 mg/kg/day BIL (mgAlL) DAY40 014 014 014 018 DAY96 0.04(10) 017 0.02(10) 0.15 0.04(10) 016 003010) 021 DAY 124 0.03(10) 019 0.03(10) 0.04(10) * L 0.05(10) 0.16 DAY 183 0.0410) 01s 012 0.08 0.03(10) 012 0.03) 0.06(5) 0.035) 0.02(5) BUN (mg/dL) DAY 40 16 16 1" n@ DAY 9 2(10) 16 310) 19% 310) 19% 4(10) 2 ~ DAY 124 210) 2010) 1 : 200) 210) * 18 DAY 183 135(10) 16 18 183(10) CREA (mg/dL) 44) 25) 45) 25) DAY 40 039 0.05(10) 037 0.0410) 037 0.02010) 0.44 0.0310) DAY 96 0.44 0.06(10) 043 0.05(10) 0.46 0.05(10) 0.50% 0.05(10) DAY 124 051 0.05(10) : = 0.50 0.06(10) DAY 183 051 0.084) 047 0.05(5) 053 0.085) 0.50 0.045) CHOL (mg/dL) DAY 40 84 2 123 120 19(10) 11010) 22(10) 1810) DAY 96 98 2310) 109 19010) 154+ 39010) 148+ 44(10) DAY 124 97 : 138 28(10) DAY 183 103 129 142 13303010) 214) 2965) 625) 39(5) Ist A-------- `Company Sanitized. Does not contain TSCA CBI H9-02.4D7a6y8:GavSaubgcehSrtoundiyc TinoxRiactistywithOGneenerationReproduction Evaluations DuPont 5990 TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group I Omgkglday Group IV Group VI Group VIII 25 mgkg/day 100 mgkg/day 500 mg/kg/day TRIG (mg/dL) DAY 40 45 2 37 2@ DAY 96 1910) 13010) 13010) 74 46 39 4(10) 2@ DAY 124 54(10) 9% 13010) 3 15(10) # 4(10) 78 DAY 183 366(10) 132 148 12068(10) 394) 3805) 154(5) 595) GLUC (mg/dL) DAY40 101 100 101 104 8(10) 8(10) 710) 9(10) DAY 9 103 6010) 102 610) 9 1200) 100 6(10) --_ DAY 124 106 9(10) > 4 92+ 6(10) DAY 183 9 9 102 106 94) 1005) 25) 1065) TP (DgALY)40 74 73 79 77 DAY 96 0.5010) 0.510) 79 83 0.6(10) 88 03(10) 88 DAY 124 05(10) 0.7010) 0.410) 82 : : 0.5(10) 89+ 0.4(10) 0.510) DAY 183 84 85 87 85 0.34) 04(5) 0.65) 05(5) ALDBA(Ygd4L0) 50 5.1 57+ 55 DAY 96 03(10) 54 0.4(10) 0.510) 57 62 03(10) 61 0.410) 0.4010) 03010) 0.410) DAY 124 56 : 0.4(10) 59 0.4(10) DAY 183 55 57 54 52 039) 035) 03(5) 0565) PN -_-- = Company Sanitized. Doesnot contain TSCA CEI H9-02-4D7a6y8:GavSaugbcehSrtoundiyc TinoxRiacsitywithOpe Generation Reproduction Evaluations --~ TABLE 31 (Continued) DuPont-5990 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group I Group IV Group VI Group VIII Omgkg/dey 25 mgkgday 100 mghkg/day 500 mg/kg/day GLOB (gL) DAY 40 23 23 22 22 02(10) 02(10) 02(10) 0.1010) DAY 96 25 02(10) 26 27 0310) 0.110) 26 0210) DAY 124 26 z 02010) ? 300 02010) DAY 183 29 28 33+ 33% 024) 0.15) 0305) 0.15) CALC (mg/dL) DAY 40 12 12 18 118@ 0.410) 0.4(10) 0.6(10) 0.510) DAY 9 13 0.5(10) 15 0.4(10) 21 03(10) 122% 03010) --_ DAY 124 15 0.4(10) * > 16 0.5010) DAY 183 107 024) 11 0.15) 13 0.765) 12 075) IPHDS A(mYg/4d0L) DAY 96 DAY 124 DAY 183 NA (mmol/L) DAY 40 DAY 9 DAY 124 DAY 183 73 0.6010) 55 0.5010) 64 08(10) 53 034) 1459 1.0(10) 145.8 1.0010) 1438 2310) 1449 2.004) 75 0.510) 59 05(10) : 55 055) 145.4 14010) 145.6 1.010) : 1464 1465) 77 1.0010) 63 10010) x 72 245) 1446 14(10) 1453 1310) 147.6 3.76) 89 11010) 69 0510) 68 0.7010) 72 3305) 1435 1.4(10) 1452 1.6010) 1443 11(10) 1456 2.75) --_ Tiss `Company Sanitized. Donotecontsain TSCA Cal F9-02.4D7a6y8:GevSaugbechSrtoundcy iTnoRictistywith OneGeneration Reproduction Evaluations ~ TABLE 31 (Continued) Duont5990 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0 mg/kg/day Group IV 25 mg/kg/day Group VI 100 mg/kg/day Group VIII 500 mg/kg/day K (mmol/L) DAY 40 DAY 96 DAY 124 DAY 183 5.63 0.37(10) 5.50 0.38(10) 5.90 0.72010) 5.36 0.30(4) 5.85 0.30(10) 5.47 0.39(10) * 5.57 0.35(5) 5.99 0.38(10) 5.53 0.56(10) : 5.87 0.89(5) 6.34@ 0.50(10) 5.95 0.50(10) 5.84 0.76(10) 6.12 1.20(5) CL (mmol/L) DAY 40 98.9 1.010) 99.2 1.2(10) 97.6 22(10) 96.3% 1.310) DAY 96 101.0 99.5 98.5% 97.5% 1.8(10) 1.6(10) 1.8(10) 2.5(10) -- DAY 124 98.4 : 22(10) * 98.2 2.0(10) DAY 183 101.4 100.5 102.1 102.1 2.44) 0.8(5) 3.6(5) 3.4(5) PFLU (g/mL) DAY 40 DAY 96 : 01 : 0.1 * 02 : 05@ DAY 124 0.0(10) 00 0.0(10) 3 0.0(10) E 0.1(10) 0.1@ 0.0(10) 0.1(10) DAY 183 0.1 0.1 01 01 0.14) 0.005) 0.14) 0.0(4) eeeeee eee Dus smanged ss: Mean `Standard deviation (Numberofvalues includedincalculation) a Measurmentsfortisgroup siimepoiatwerenotken otperfomed. @+ SSuttiissticcalallyyssiiggnniiffiiccaanntt diiffrfeernencceeffroommccoonnttrrooll aatt pp<< 00..0085 bbyy pHoaprpaamrearmeettresit(tDesutn(nDeutntsT)a.mbane-Dunner). -- TE A -- `Company Sanitized. DoesnotcontainTSCA CBI H9-02.4D7a6y8:GavSaugbcehSrtoundiyc iTnoxRiactistywithOne Generation Reproduction Evaluations --~ TABLE 32 DuPont 5990 TEST/ PERIOD SUMMARY OF URINALYSIS VALUESFORMALE RATS Group T Omgkgdsy Group TI 25 mgkgday Group V 100 mg/kg/day Group VII 500 mg/kg/day VOL (mL) DAY 39 141 148 13.0 296 DAY 95 6.8(10) 101 10.0010) 13.5 108(10) 86 17.1010) 372@ DAY 123 6.0(10) 80 10.0010) : 4.5010) : 17.1010) 98 DAY 183 5910) 14 88 5.0010) 89 127 7.404) 4305) 574) 46(5) UOSM (mOsm) DAY 39 757 843 1002 655 DAY 95 283(10) 1230 540(10) 1046 606(10) 1222 650(10) 506% ~~ DAY 123 583(10) 1465 394(10) bd 415010) * 195(10) 1262 714(10) DAY 183 1089 1452 1419 474010) 955 4224) 663(5) 396(4) 206(5) SG DAY 39 1.024 1.026 1.031 1.020 DAY 95 0.008(10) 1.038 0.015(10) 1.034 0.018(10) 1.039 0.01910) 1.018% DAY 123 0.016(10) 1.045 0011010) 0.012(10) # 0.006(10) 1.040 DAY 183 0.020010) 1.031 1.042 1.039 001410) 1027 0.0114) 0.019(5) 0.0094) 0.004(5) pH DAY 39 72 71 69 71 DAY 95 02010) 66 0310) 0.4010) 65 62 03010) 53@ DAY 123 0.8(10) 0.7010) 65 x 0.5010) # 0310) 65 03010) 0410) DAY 183 : * ~ ---- e ie n CompanySaritized. DoesnotconTtSaCAiCBnI H9L02-4D7a6y8G:avSaugbcehSrtoundiyc iTnoxRiacsitywith One Generation Reproduction Evaluations -- `TABLE 32 (Continued) DuPont 5990 TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group Omgkgday Group III 25 mgkgday Group V 100 mgkg/day Group VII 500 mg/kg/day URO (U/L) DAY 39 02 02 02 02 DAY 95 0.010) 02 0.010) 02 0.010) 02 0.0(10) 02 DAY 123 0.010) 02 0.0010) * 0.0010) % 0.010) 02 0.0(10) DAY 183 * . 0.0010) . UFLU (ug) DAY 39 3 + : : DAY 95 121 5.4(10) 506 11.5010) 1405@ 392(10) 6326@ 89.0(10) ~ DAY 123 81 : 2.50) J 9%83@ 30.010) DAY 183 102 29(4) 135 3.005) 215 439) 468+ 4505) UMTP (mg/dL) DAY 39 60 59 3 37 41010) 55(10) 69(10) 56(10) DAY 95 101 64(10) 69 45(10) 91 52(10) 38@ 53(10) DAY 123 27 # : 125 DAY 183 7631(10) 263 123 4849(10) S004) 468(5) 70(4) 27(5) Duaamngedss: MSteaanndard deviation (Numberof values included in calculation) 4 Measurementsfor thisgroup a thi tmepointwerenottakeno notperformed. @ SSttaaiissttiiaallllyyssiiggnniiffiiccaanntt ddiiffffeerrennccee ffrroomm ccoonnttrrooll aatt pp<< 00..0055 bbyy npaornapmaertarmiectrtiect(tDeutn(nDeutnt)T.ambane-Dunner). _-- Company Sanitized. Doesnot contain TSCA CBI 9H02-4D7a6y8:GavSaubgcehSrtoundiyciToxRiaciistywithOne.Generation Reproduction Evaluations DuPont:5990 TABLE 33 TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS Group TI Omgkg/day Group IV 25 mgkgday Group VI Group VIII 100 mgkg/day 500 mg/kg/day VOL (mL) DAY 40 75 72 102 2.00 DAY 96 4.609) 47 38010) 4.5010) 13.4010) 91 78 165@ DAY 124 27(10) 620) al : 7.410) : 5.6(10) 26 DAY 183 2.4(10) 54 75 73 1809) 7.1 1.664) 215) 3.00) 376) UOSM (mOsm) DAY 40 1046 1028 826 487@ DAY96 58209) 178 493(10) 923 270010) 1166 264(10) 595% 4379) 38109) 44310) 17310) ~ DAY 124 11384700) : : 1834 762(7) DAY 183 on 1024) 1018 266(5) 935 296(5) 934 31765) SG DAY 40 1.030 1.029 1.025 1016@ DAY 96 0.0159) 1.040 0013(10) 1.028 0.008(10) 1.038 0.008(10) 1021+ DAY 124 001810) 1.040 0.011) 0.01410) * 0.007(10) 1.054 DAY 183 00139) 1027 1027 1.027 0.02009) 1.027 0.0024) 0.006(5) 0.01005) 0.009(5) pH DAY 40 69 67 66 61 DAY 9 0.509) 60 03010) 58 02(10) 58 03(10) 54@ DAY 124 0.7010) 0.99) 57 3 0.510) 1.0010) = 55 DAY 183 0.4(. 10) . . 0.541g 0) e--m ------------------i--S-------------------- Company Saniized. Does not contain TSCA CBI H9-02.4D7a6y8:GaSvuabgcehrSotnuidcyiTnoRxaictistywith One Generation Reproduction Evaluations DuPont:5990 `TABLE 33 (Continued) TEST/ PERIOD SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS Group IT Omgkgday Group IV 25 mgkg/day Group VI 100 mghkg/day Group VIII S00 mg/kg/day URO (EU/L) DAY 40 02 02 02 02 DAY 9 0.09) 02 0.0010) 0.0010) 0.0010) 02 02 03 DAY 124 0.010) 02 0.09) = 0.0(10) : 03(10) 02 0.010) DAY 183 3 : 0.010) * UFLU (ug) DAY 40 * . * * DAY 9 51580) --~ DAY 124 413207) DAY 183 59 1164) UMTP (mg/dL) DAY 40 25 1909) DAY 96 4425010) DAY 124 a 20) DAY 183 45 5004) EE 237 7.80) s 86 1665) 2 18010) 34 3609) : 30 185) 594@ 16.0(10) = 99 206) 2 14(10) 278 513(10) * 333 477165) 2912@ 9350.50(@10) 10.604) 157@ 7.16) 20@ 41(10) 165 422(10) 538@ 7938) 157 165(5) Duamngedas: `MSetaanndard deviation (Numberofvalues includedincalculation) + Measurementsfothisgroup a thisimepointwerenottakeno notperformed. @+ StSaattissttiiccaalllyyssiiggnniiffiiccaannttddiiffffeerreennccee ffroomm ccoonnttrooll aatt pp<< 00..0055 bbyy npaornapmaertarmiectrtiecse(sDtun(Dnuentn'Tsa).rhane-Dunoet). -_-- ise `Company Sanitized. Does not contain TSCA CB ~ 3g| 4H = 3 8 % | 1 oz g |Bg 12 3 2 5@ LoE3 4 4 HE z | 3 i:3 3E18%] z BE . se ~ 2 E18g) gis 22 03 3= i 2; 1| FEpEb El8|48 %$s 42 == g2 , iz25 : i 25 HI 81% 4 EY 5 &4:z 5i 2 3 i24 ~ 52 EERE 3| S$ S|; fk Eg 53 Fy BH3 - 8 8 liET EZ 8 5 g- = s|181L80i LoL 3 corp Sats, Gowtoma TEATS ~~f 8 2 218 1Elg 2 tl : |5|4 B E 4= EE|EE... 5 oz, 3 5 i a EEEo g ig o e a Ee _ "1a %8 || 22 $i33zz 3: HqER2: | g i85os z 22 15(E8E 2= 53 53 2S||l&Esi i 2 2 5 ElE mons aoe aFa2 |7L%ge | :gHI% dii1Ef: SI3 EE a & EEE igi:zl 2i5 fg == 5 52s3i2i 3 a ~~ 33 atm, BE H9-02.4D7a6y8G:avSaugbeehSrtoundiyciTnoRxaitciswtyith One-Generation Reproduction Evaluations DuPout-5990 ~ TABLE 36 MEAN FINAL(B9O0-DDYAYAENXDPOORSGURAENEWVEAILGUHATTSIFOON)R MALE RATS MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) rSioauTiiiasy r35oewarkxaixrcay g10r0owmavlkslasy aS0z0oma/vkia/day Laver 1S.6e33o1s0ao 0.020a6s0o0s0ne 2726s2i9i0onn 2481.245600000) ames aE.am n S3a11b00an o4.2m091a0 n o4.0l00s00un =) 1F.e2a560e 1E.02a220n S17i2s02i0zen 1.o39w86s00to sruem 30.5i03%80ae 0.S87f5i40San 0.S79I7B80San 0.o6l51o1s0m0ae Ba S2.i13d20e0an 2o.o2s6s0oan 2.o0lno5s0esno 2.o07o9i70o0no mows i0.03a800n S0.4i54i40San 0S.2i96s30t1 o 0o.l26s9m50e0am ons uvos S0.i0b87s0e0sao 0.c0d58w1s0sae 0o.l0o5b0r6e0suor 0.o0l4o8070m0ste ~ vom quo 0S.0301600 0O.S02m00s0ao 0S.l0wmmmrao 0.o0l33e7s0sno estes 3.63B0i00a0 3.o6i01n0t0ian 3.S61E0s50san 3.o5l05e2r0zce srromomos sFimloan o1570f00S oLhaeisesan 1caosw0m0eno how sony weir SSeeiomao n sSsee.siionno e sda.aasos00ne| 44s36.7a03408017400) - Tier-Company Sanitized. Does not contain TSCA CBI H9-02.4D7a6y8:GSauvbaegherSotnuidcy TinoxRiactistywith One-Generation Reproduction Evaluations DuPon-5990 --~ `TABLE 36 (Continued) MEAN FINAL(B9O0-DDYAYAENXDPOORSGURAENEWVEAILGUHATTSIOFNO)R MALE RATS : MEAN RELATIVE ORGAN WEIGHTS (3 of body weight) gSroaotuxarcay G35romwork1ax1iday G10r0owmalvkoscay r$0o0umavlikxalcay LFahvaecnoor + 200 2i.82a741n 3.o1l90e0e0i1ne soelmsainsan soalmdmmesn Frc moo + 200 S0.072i9%09oan 0C.7o20o13ns o0l.a1a3i3no 0.o5l8o0e88s1sze FRC sor + 100 S0.a31e26h8an 0.G32o07ean 0.S33o3a09sne 0o.3c06e14an hac soo + 200 S0.i15e35e8an 0.o1d41t2m5eun 0.o1l52o7i3iao 0o.l1o0i3n2oce) FIL soo + 100 0i.36a601n 0G.3l680a7 n 0S.l40d02e2uo 0.o4l6o0d3s5s0eco -- Fhe ooy + 100 0S.0h136a7 n 0C.o01l50m9es 0o.l05G7o03s1te 0.o0l59o1i6s1uo PAhounsoGbuns100 0o.0a09n 0o.f00u02i4am 0.o0l09o8o2ouo o0.01o079o zFruavcorBouoyno+ s100 0S.00036a7 n 9.o0d0o34s6euor 0.00l00801s9sao) 0o.l0o0o8i2s8e1nio) Pshrass,soo + 100 0S.i62s0s53ean 0C.f6mmasan 0.o70000e6an 0.o7l93o6s9s8en FsehromooDves+/100 0S.i26t7s46aan o0.l26e77a5e) 0o.l2o9w2s68suo) 00.0294818620) --_ _-- "162 Company Sanitized. Does not contain TSCA CBI H9L02.4D7a6y8:GavSaugbcehSrtoundiyc iTnoxRiactistywith OnGeeneration Reproduction Evahations --~ TABLE 36 (Continued) DuPont5990 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (8 organ to brain weight ratio) cCouep 1 Gfroupe1x G(rBowhv.s aSxoorupRaivinxs cEaNve.) je emsaesn aeoasseensan 1eso5ase0us0 3m0o.u5s0ym00 MaNoESe eSsinoan sDismnene sseemsessao |i1:9.esnemun wEaars + 100 sSscie SanN.EoaSmhs e 6T2.e3w66e0an Ters.onau7o0 sSeuamne 100 aT.iman 4T.45i05a0 n 28N.i47099Ean a1. 2T8E9G00R0Le ma ows; 100 2C0.42H08a 20i.9R885e8 e wTsEGe 1H2.9E500E sore Gus Pp pa Ponan Sis EBae SEMlan SBNHI moommo o50o P101h56a3 n o0.l90a3k88hae o1.08s501e 1.o13s83s0ao Tae Eitrios) wWoiule 7S.1i16h08ae weTedsEieeE 3E.0l02b0 e uTReBsian 3S.1S00T98ae 17s2.e35s9i6 an 6.7U9i9R0i21dhe -- - Ties`Company Sanitized. Doesnotcontain TSCA CBI 9H02-4D7a6y8:GaSvuabgcehSutoundiyc iTnoRxaictistwyithOne-GenerationReproduction Evaluations --_~ `TABLE 36 (Continued) DuPont:5990 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) G0romuap/ka1/day G50r0oumpa/vikzg/day Liver 152..9611956870(10) 129..92962834038(10) KiowEvs 041.6031048100(10) 40.11526169706(10) HEART 1.0.8216178004(10) 10.:7202174%5(10) sereay 0.0.7172328106(10) 00.17153206402(10) BRAIN 2.o1lo776a1z02(100 20.10081627300810) THOUS 0.03029768901(10) 00..3016777905(10) ~ ADRENAL GLANDS 00.1005122700610) 00..0004992680(10) THYROID GLAND. 0.00.020654103(10) 00.10020631801(20) Testes 3.047308s0 ) 031.4634314670010) EPIDIDYMIDES 1.0:5126881501(10) 10..4178139000(10) FINAL BODY WEIGHT57768.100021070210) 55077..963739949(10) -- -_ BTR `CompanySanitized. DoesnotconTtSaCAiCnBI H9-02.4D7a6y8G:avSaugbechSrotniyciTnoRxiactistwyith One-GenertionReproduction Evaations ~~ `TABLE 36 (Continued) DuPont5990 MEANFIN(AOLNBEO-MDOYNATNHDROECROGVAENRWYEEIVGAHLTUSAFTOIROMN)ALE RATS MEAN RELATIVE ORGAN WEIGHTS (8 of body weight) Gromugp/kg G5r0o0upmgv/kig IFIvNeALrBODY * 100 021.1755379076(10) 30..7390710013(10) KFIIDNNAELYSB)ODY * 100 00..0649053971(10) 0.0.80151472588(10) FHIENAARLTBODY * 100 00..3013548550(10) 00..3032920367(10) FSpILNEAELN/BODY * 100 00..0113547509(10) 00..1042805332(10) ~~ BFRIANIANL/BODY * 100 _ 00l.0338e2a2s7(10) 00.044105063310) FTIRNASL,BODY * 100 00..0051774424(10) 0.0.0016325836(10) AFDIRNEANLALBOGDLYAN*D1S0/0 001.0000198188(10) 00..0000928074(10) TFHIYNRAOLIDBOGDLYAN*D,100 00.1000040622(10) 00..0000501785(10) FT8ISNTAELS/BODY * 100 00..0650057920(10) 00..70270994828(10) EFPIINDAILDYBMOIDDYES*/ 100 00..2062616678(10) 00..2093113222(10) -_-- Ties Company Sanitized.Dossnot conTtSaCAiCBnI 9204-7Da6y5G:aSvuabgcehrSotnudiyciToRxaictistywithOne Generation Reproduction Evaluations DuPont5990 ~ TABLE 36 (Continued) MEANFINA(OLNBEO-DMOYNATNHDROECROGVAENRWYEEIVGAHLTUSAFTOIROMN)ALERATS MEAN RELATIVE ORGAN WEIGKTS (% organ to brain weight ratio) G0romuaplkg G5r00oumpavkier LBiRvAeIrNs + 100 712090.02297383610) 912191.83308681120(10) KBuRoAwIENYS+/ 100 12844.20000016320) 129473.54343715020) BBREAAIRNT+ 100 8T3o.l1a9z820300) 210.14301168890020) sBeRuAsIaNN/+ 100 3S5.a50s5s2o) 366.001759412000) --_ TBRoAnINs,+ 100 1L5.0a86s21sa 135l29s11475600) ABDRRAEINNAL+ G10L0ANDS TBHRYARIONID+ G1L0A0ND! 2.D4s1175208910) 1.V2a1n0e1s2ao) 2.0.3471437530(10) 10./2158391152010) eBRsAtIeNs)+ 100 159T.4l3s90563029(10) 17144..1515752885(20) EBpRxAoNIDY+MI1D0E0S/ 706.21737508110) 706..4528835082(10) -- -_ Tee `CompanySanitizad.DoesnotconTtSaCAiCBnI H9:02.4D7a6y8:GavSaugbeehSotnuidcyiTnoRxaitciswtyith One-Generation Reproduction Evaluations DuPont-5990 ~ `TABLE 36 (Continued) MEAN FI(NTAHLRBEOED-MYOANNTDH ROERCGOAVNEWREYIEGVHATLSUFAOTRIOMNA)LE RATS MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) aeroh GHoawna111 GGrooowTavna r90o0upavrikzs Loven 1R 5.108e 5 16.1E65B20s 1S7.a70a28aw 10.2o59e8m00e ames 3.V57i50k0a o4.0d520e0 s 4o.0s69e25w 4o.20d080s sees 0.7t070w0 0o.8b59e6s0 e 0O.l79a60m0 w 0o.8l50e40n momom uve 0C.0h265i0 e S0.0o25m20e 0.o02l00e0s 00.002076m0 ) mses P5.h74H8k00bw 3o.5l20d00e 3o.d52m85e0 w o3.6b20s20) now soo wEIGHT sSevcaoorn 6C0e.i0a4o00as) sssveesomnoe 64029..77502000005) --~ --~ -_ i67Company Sanitized. Donotecontsain TSCA CBI H9.02.4D7a6y8:GaSvuabgcehrSotnuidcy iTnoxRiactistywith One-Generation Reproduction Evaluations ~~ `TABLE 36 (Continued) DuPont5990 MEAN FI(NTAHLRBEOED-MYOANNTDH ORERCGOAVNEWREYIEGVHATLSUFAOTRIOMNA)LERATS MEAN RELATIVE ORGAN WEIGHTS (8 of body weight) Sgiroouipiubiaay GSSromwarkTaiirdey G10r0owbav/ka/day GS0r0owBalvikzarcay had movie xFeoovrarsm)oro sPheausori TeargmsoGov-L10 zPeEeM 0N.6R333W 0S .138w 08 S0.0i06b32 i 2.A56e50s G0.6h45P10Ee C0.a1i36m1es o0.d00o39m7as 2O.9d09i19 e 0S.6o80l10 e 0o.1o320o 0.l0o03c4o0enw 3o.0l02e851n 0o.l6o9s0e8s0cs) o0.l13e9a59e) 0o.l0o0m4i5e5ies) Thad mori 0S.6i10w c0.o60s76e0ts 0.o5o9m3i3sw o0.55m769a Data summarized as: MSetaanndard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). + statistically significant difference at p < 0.05. ~~ _-- Tes CompanySanitized. Doesnot conTtSaCAiCnBI H-24768:Subchronic Toxicity 90-Day Gavage StudyinRatswithOne-GeRenproedurctiaonEtvailuaotionns --~ TABLE 37 Dupont5990 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) GSreoawna11 Grorwak1e GTrooourpaunra g50r0owmarvkarss Loven 8T.9e68m10as 01.4309000s 1f68i2d9s2s0e0an 1z5.0e601a00e xaos 2S.3a08sa0 2S.0mm00a 2S.a74s89s00an 2.o72s8e00u00o wear LGiaisssiosan 11o3l5s5e0suo 1.o27a8s60Tan Loaasssiosno sruame 0S.5o20s0 a 0o.l5g6m7a70iae) 0.O5l9e5e1i0ssan 0o.5.785o0 o sa 1S.9a565s0 a 1o.l9d85n3o0zae 1.o9l52m0s0oun o0l1o3a8s0suo mvs 0O.l206s6s3s0za0) 0o.l2o1s3s2i0sno) 00..2c6a5s6e0ann) 0.02.0o0z8s00n) Jorma Gums 0S.0o67l70on 0O.l0oml0s0iao 0.o0.6o8n3e0aan 00..00m800 --~ mom GAD 0O.i01s66t80enn 0.o0l17a9m0ean 0.o0l1o0o4w0zan 00..00190030000 oszes 0G.o13i3s90za0 0.o2l0t0e00suo) 0.O1l1o9s9s0isao 00..101058200) remus S0.5i830a0 n o0.1m41a0 n o0.a50S99m0an 2.o19m68m0an sS073.006%0600n0) 206e.o0s00e0nae 30256.s9m0s0u0) 2692.1073s0e0sn0 --~ 165`Company Sanitized. Doesnot contain TSCA CBI H-24768:Subchronic Toxicity 90-DayGavage StinuRatdswiythOne-Generation Reproduction Evaluations -- `TABLE 37 (Continued) DuPont-5990 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) gSroolwii1a1sy g35romwarkTavicay G10r0owmavkia/day g50r0owmav/kiazsday ohvaecnssoo + 100 2S.a92l20i0ne 3o.l54n0R00on soalSvaEesae s.oslmSreann0e Pharceesoo + 100 0S.7s86o22nn 0.o0l37i5zman poelederi)sno 0o.53v0200e aL sony + 100 0S.3a75d87ao 0o.28u600n 0o.l4d1a6m6a30ao) 0.02.0006m7mae Fra oor + 200 0Sl.a1emae) 0c.1l90o31wn 0o.l1s9i0s8i9iuo) 0.o2o00i5z2s1no ePIdL soo + 100 0S.e68n4i21ian 0.o6l6o0m1o6san 0.o6l0s1s5sao) 00.l6o8s6i0esno ~~ mPehnaussop + 100 0.0802) Soldano 0o.m0s1i9nm 0.o0l0o6l8s7zae o.d0laeosm1mae PAoamcmw,Socotu+s)300 0l.0o0- 2o15s) 00.o0020e2s6ae) 00.l0000232aec0) 00..0026a0e71ci0) mFeAvLRomBouotno+ s100 0S.a00o5477an 0o.0m061e6 n 0.0o0n60s9en 0o..00o6m69sae Fr por + 100 rPehsaussopy + 100 0S.l06a3n85ian 0S.l29o84an 0.o0l0i70ean 0o.f20n2e09san 0o.l0d3l0owmruo) 0.S2l62d0s8ean 0.o0o0B0s2s4zior 0.o4l0z8z3m0man ~~ Tm `Company Sanitized. Dosnot contain TSCA CBI H-24768: SubehronicToxicity 90-DayGavageStudyinRatswithOne-GeneratonReproduction Evaluations DuPont-5990 `TABLE 37 (Continued) MEANFINAL BODYAND ORGAN WEIGHTSFORFEMALE RATS (90-DAY EXPOSURE EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (% organ to brain weight ratio) Grnoawra11 grorwa1rv oTroouRp avrk g50r0owparvkanst Em TI eS5a47s60e10) Gsesiwsssolrer 11se7.3sa6se0s) 137994a.7s40e9im0 BAI 100 mBaars + 200 sBruasmy+ 100 Tmanes, 100 u1s5e3s500 S58l.92i00t 2S.s1m09ian 1T2.i58s55ao 1B25o.9s93m0an d5a8m15o0o4n9o) 5.30S0s7m0s7euor 1.9e0s6e15san u20s.ssme00|) 5.s4s7m3s01ao 230..5s03e7s8o0 ao 1B3.0e23e6 n a226..a000m030700 587..2s6n06ao 320.s28e6o52s0no 12L.a78s9s6 en ~ sian oemsao oldman amen oan +100 0S.i85t20s0an 0o.0b105e8 n 0o.a94p20m7an 1o.m01e98ns Sa + 100 rBeasus+ 200 6T.o05i1l26ian 5f.19a756n 5.o5l0m1e50suar 2S6.i20l7m7 an 6l.20e228an 1e.e32s00t0or 5i.o01s0r9oo Sa2i.5s708i8 an ~ TI CompanySanitized. Does notconTtSaCAiC8n1 9H02-4D7a6y8G:aSvuabgcehSrtoundcyiTnoxRiactistywithOneGenerationReproduction Evaluations --~ TABLE 37 (Continued) Dupont 5990 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) G0ronugp/ka1/1day 5G0r0oumpav/ikI/rday L1vER 51.36478250000) 11.186056076068010) KiowEvs 2.04274698030010) 20..2652269110(10) Hear 1.ol2i2z8e6s03c0) 10.1254202810010) seuey 00.1505709700010) 00..0552337080(10) RAT 1.09065224000010) 10..0957515630(10) pe 00.0222556770010) 00..0242800100(10) ~~ ADRENAL GLANDS 00.007995867010) 00..0070684606(10) THYROTD GLAND 00.0002202760010) 00..0001299430(10) ouaRzEs 0.01001588400010) 00.0121703420110) ures 00.1718513720810) 00..3981342630(10) FINAL B0DY wErGHT330.86000 254.550008 34133764010) 23134041(10) --~ -_-- `Company Sanitized. Doesnotcontain TSCA CBI 9H02.4D7a6y8G:avSuabgcehrSotnuidyTionxRiactistywith One-Generation Reproduction Evahations DuPont.5990 ~ `T3A7 (BContLionuEed) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (8 of body weight) G0romuap/ka1/1day G5r00oumpa/VkIaI/day LFIIVNEARL,BODY * 100 2.92561 0.18109(10) 30..9392570675%(10) KFIIoNNAELYsB/ODY * 100 0.74132 0.05681(10) 00..80941762184(10) HFEIANRATL,BODY * 100 0.37328 0.04081(10) 00.042290863810) sFeILNeAeLN/BODY + 100 0.16646 0.02663(10) 00..1071758914(10) ~ BFRIANIANL,BODY + 100 0.59523 0.05966(10) 00..06571258458(10) TFIvNAsL)BODY * 100 0.06887 001061(10) 00..0071456565(10) AFIDNRAELNALBOGDLYAN+DS1/00 00..0022280567(10) 00..0002257959 (10) TFHIYNRALOIDBOGDLYAN+D/100 0.00628 0.00067(10) 00..0000160651 (10) oFIvNaARLzEsB/ODY * 100 0.03334 0.00565(10) 00.0003979625(10) uFrIeNRAuLs/BODY * 100 0.23659 00428810) 00..1321319878(10) --~ ES `Company Sanitized. Does not contain TSCA C8 9H0--2D47a6y6G:aSvuabgcehSrtoundiycTionxRiactistywithOne-GenerationReproduction Evaluations DuPont5990 --~ `T3A7(BContLinuEed) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (8 of organ to brain weight ratio) G0romugp/kg1/1day 5G0r0oumpg/VkIgI/day aBRvAeIrNs* 100 45965..894079978(10) 59789..132688318(10) KBIRDANIENYS*) 100 1251.21388671605810) 11333.0265960230(10) EBRRAYIN, * 100 626..9567307864(10) 672..599448819(20) sBeRLAEIENN/* 100 28.53240720509110) 262..5529170921(10) --_ TBRiAISN)+ 100 1158511 1.14676 118346010) 2135367010) ABDRRAEINNAL+ G1L0A0NDS/ 4.87004 309999310) 30..4847166339(10) TBHRYARIONTD+ G1L0A0ND/ 1.0.0160083603(10) 00..1958958045 (10) oBvRaARIzNss+/ 100 50..6522273046(10) 51..5380270528(10) rBReARIuNs/* 100 407..0855340627(10) 620.17409105961(10) --~ EE Company Sanitized. Doesnot contain TSCA CBI 9H0.-2D4a7y68G:avSaugbecShrotnicuiTndoRxaiytcistwyithOne-Generation Reproduction Evaluations _~ `TABLE 37 (Continued) DuPont-5990 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHT (grams) Sgrroiuipi1i1asy g3romwarkxgviasy 1g0r0owmarvxkascay g5r0o0uspalvkiansday uve T8.50o150w 9T.3h16o0s a2oaseomorew 1L0.i77e35s aon 2.3l26i78e S2.35N700e o2.83m000e m2.60s075m seus S0.l5o09m5i0sw o0.4s75s00) o0.l5o14d0e0m@ o0.60a150n Too GD S0.01o878w o0.l02m05m0 w 0.C01o7o78mw o0.01o025d FI BOU UES dFioR.gErEs0II33R 6.00000TR nt e6.s75O 00 309.6003010) ~~ --_~ m=`CompanySanitized.Dossnot conTtSaCAiC8n1 9H0L-2D4a76yG8:avSuabgcehrSotnuidcyTionxRiactistywith One-Generaion Reproduction Evahations Po TABLE 37 (Continued) Dupont5990 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (THREE-MONTH RECOVERY EVALUATION) KEAN RELATIVE. ORGAN WEIGHTS (8 of body weight) Chiara SS mviany S00Ralsasday S00Palko/dey Foal soovei00 2S.5H82E6 S 2S.00m527a 3o.2d08i300e 3o.d45o90i0n Fon Borrio0 seem mFiOvsComDBoopru-1s00 0C.eme n A CBee 0O.000h8a50aw 0G.l70e26n0 s 0o1o0imss 0.G0o0o6m22gow 0o.i01m59mw 0.S15o0v98ew 0O.l0o0nd8sw) o.o0oussmsrie 0c.o1m05e7s 0o.-0o0o8i0e5ace Data summarized as: MSetaanndard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). --- # Statistically significant difference at p < 0.05. --~ eS `CompanySanitized. DoesnotcontTSaCAiCnBI ~ : ETRE gs 3F%s 89n 8:v =v | 2 ------ Eww) E8 i ini,= iz H 3~ 3S ~~ 3x a 32 a3a n=4 $ Sm E] r ie Bi m : rnerv- ERLE i| Jig yic i oh BE ;iii3s}t ; |B |!5 Ei i o || ] gi haiti | iH |: 8 gh 2 1H i pi oei ogfioH i gli EE | ih og 1 lp ] || | i FO iI bE fi af ifii gi : {get Edis is 8 ge i i 24 FI .: `CompanySanitized. Doesnotcontain TSCACBI 1 f ~ : z : 8c 1i3j111528ul 88s2 38%x 481% 5Guu 48s9 88%0 5fan | 0 inigl 8.1 gn gn 3 frp lesSS g8it ER g= $= On = 82 = gn gs 8s 8s 8s i JEsiiR Bllim. mEaEeEaEaEa E--a iyi Ig 0 i ~ | fg 5 ir 152 Ef 11 2Egeo |i IiH 2 sf jig | 2 k gz | ist I ZZ | | i | | g EH goofy Mg Ling 3 : i : PEER BEE Eig PEE ER BEE OE 2 gi PE ih i : < 4 Eigoy gi i ii i L ge i igid 4 gi 1288 BFE Ein ~ CI z 3 : 8131 |. ol as v Ge 3 3% 8% 8% &% | HAR EEEEEEEE) 2 g {E17 n qpi 82082 82 8T 2 83S82 T 32 T 8s if i2t3 E8}T |. .f T3% o3 3 32a31 a82 82a32 iEaFd 3 : en $2 fEE =! ig8s || ils PEE ~ |] E xEE| LiI." S83 31| edi 1i9E5 = 1 1 rtrd iy$ WooEop ddd iif 3 ~ % gE i Zi i iis O= | i ied 2g:i [Ds8E EFEFE EBEE EBE EOuk 25 : B 5EsEpkT e PIEPEEOSE gi =Ft F Fi CompanySanitze. 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