Document zmXq5GEqjwM4jQD0VMbVZJoa

ee | ARAR6 -- 3234 | || | | | 416 || | | 1502-4D5u1y6:GavSaugbechSriodnyi iTnoRxsicihOneGenero Repoducion alton "TRADE SECRET Study Tie 1:24516: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations Revision No. 1 Volume 1 of5 AR226 _ 3234 DuRreovnd 3Pa8g5e "TEST GUIDELINES: U.S. EPA Health Effects Test Guidelines OPPTS 870.3100 (1998) . AUTHOR: Gregory S. Ladics, Ph.D., D.A.B.T. ORIGINAL COMPLETED ON: December 3, 2001 REVISION NO. 1 COMPLETED ON: April 5, 2002 PERFORMING LABORATORY: EL du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 won sues Novae {ED suvice Cove Nuv[sSIen} sronson sro Nowner:(ENE) Company Sanized. Doss rot contain TSCA CB TT ee T 9204.5D1s6y;GaSgbeehrSotnuidcy iTn Rotsyvith OneGeneration Reproduction alsions Duron: 386 : `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. The item listed does not impact the validityofthe study. 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. Applicant/ Sponsor: WE.iI.lmdiungPtoonnt,dDeeNleawmaoruers19a8n9d8Company USA. Study Director: GH regos ry Lad5en,ZFDh, D,AB. Senior Research Semis 3-DeBca-e 2001 Applicant / Sponsor: __ DuPont Representative Date Company Sanftizc. Docs nc: contain TSCA CEI --- 9102-4D5a1y6:GavSaubgcehSruondiyc iTnoxRicaittyvith OneGeneration Reproduction Evaluations QUALITY ASSURANCE STATEMENT Dupont Haskell Sample Number(s): 24516 Dates of Inspections: Protocol: Conduct: Records, Reports: December 5, 2000 January 15,30, 2001; February 13,14,28, 2001; March 1,8,13,26,29, 2001; April 25, 2001 June 19,29, 2001; July 2-3,9, 2001; August 8-10,13-17,20-24,27-31, 2001; September 4-9,17-21,23-28, 2001; October 15-19,22-27, 2001 Dates Findings Reported to: Study Director: January 15, 2001; March 1,14, 2001; July 5.6,13,9, 2001; --- August 29, 2001; September 25,27, 2001; October 23,27, 2001 Management: February 6, 2001; March 5,14, 2001; July 5,6,13, 2001; August 29, 2001; September 27, 2001; October 17,23, 2001; November 18, 2001 Reported by: BimEbery8. Brebneyr Qty Assurance Auditor 3-DECDa-te00. vipany Saniized. Docs nctSontain TSCA CBI -_-- 152045a16GaSnubaehSrotnaiyc iTnoRxaiscithOneGeneraion Reproduction valuions Duron 38g CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluationofdata obtained from this study. Sons Rescaony: (oat C. EE TiSCatVeisiion 55 a EniNewtephownitond oaFo 7.)ViMseoelDAE reEoee, tCuliniPathology Seo7n"here Sn 3lec am D tueicDtaRee aArCgeYtht Sar soar [He I 8 Evaluations Reported by: JohnC. O'Connor, M.S. 3-Dec- 20g Date ~ EutsionRseSprpoodurcetbivye epi envgv 3-D2ee00 UNOP.a.to.n ) rR i ST Feian onr Puclogicd Evtsions I.D..one A"CV? PeerReviewReportedbB y: ayDiot ne ACYT 3-Qec-a00; Approved rDeeC rnS comente Tos2itoy 3-prae-t200 onbySdindy Divo GetooirT Se.eua PhSDeSmZk e iFn T 3-Deoce= 200 "smpany Sanlizer. Des: vf sani TSCA Cal -_-- 124516: Subchronic Toxicity 20-Duy GuvageStudyinRatswith OneGenerwionReproductionvaluations DuPore-5386 `TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT occ QUALITY ASSURANCE STATEMENT ccs d MATAE. RTIeAsLGS AUNDEMETHODS csessssnneIrIeI cee 18is BCTTeswSSpuebcstiasnce CII is DE. AQniumalaHruasanbdPanrnetidsritPyen.ri.eod.. CII CII 00 -- FG.. SAUdsy DsES itoGrgounpsamndSeudnsSttart. CII BE 2 11. DTeossteSSuubsspaennscieoAndPmrienpiasrtanrtdaSiatmopilnio.nng.. . III Im2 JK.. BoAndalyytiWceailMgehtthso.d.s. BE ER Tm2 LM.. DFeotoaidlCedoClinnicasl OuabnmdsFpeoordtEvfaifiancdoitMenoincry.otanlisty... SE Le2 0N.. NOeuprioatlomxoilcoigtiycEavalEuvatailonastons..... CII CII Tn7 QP.. CCloilnlieccatioPnaothfolBolgoyo.d, Urine,andSE Feces (TheeMonth Recovery)... III So SR.. RAenpartoodmuicctiPvaetAhsolsoegsymeRnatt.s.D.esignated for Subchronic Toxicity and REGovery .....-....... 320 TU.. BAinoacthoemmiiccaallPMatChAolroegmye- nRttsDesignatedfocrrR.eprodsctiveEviltions CII S--Yis V. Statistica Analyses CLI Tae RECORDS AND SAMPLE STORAGE crv 3 RESULTS ANDDISCUSSION cress 39 ANAAL" YTTeIsCtASLubsEtVanAceLSUtaAbTilIitOyNS ssesssscnsvsnenesonenrnenrneroAano) C5.. CHohmroogmeanteoigtrya,phCyoncentration Verificationmand aStabilmity Samples for nial Ming ProcedureC s and w D.. MCoinxcienngtrnadtioSntsabiBlaisteydStoundDyofsoer CVhoalnugmeeionfF1r0eqmuenLcy o(fTDeostsiDnagy 0Pr1epTaersattioDna(y241i)me cek) and Done 0 E. VHoolmuogmeenCehiatnygaen(dComnLceKnEtra0t.i7o.n5VmerLiKfigc)ation Spiceosefor.Fin Mixing Procedures and Concentration nA] - F. ACnhaalnygteiBcaalCsoendcolnuDsoisone.V.o.lume of7.5 mg (Tes Day TI 42). a@ "mPaNnyY 5:Sanilzed.Doos nt conTtSaCAiCn1 --- = -- H9-02-4D5a1y6;GinSaugbeehSrtoundiyc iTnoxRiactistywithOne-Generation Reproduction Evaluations DuPont $386 TABLE OF CONTENTS (CONTINUED) SUBCHRONIC TOXICITY EVALUATIONS cssvssnsssnssnmsssssssssssssssidS AB.. DoMseaangeBoDdaytaWeighisand BodyWeighGa ain. d-- -- as| CD... FCloionidcaCl Oobsenrvatsionuasn,OdmFopopdhEiFctioehncnyaE.v.a.ll.u.a.tmi.o.no.s.,.la.n.d.o.S.u.rg.vi.v.ya.l.......... 6 -- E In-LifeToxicologyConclusions. A---- a NEUAR. OSBenEsHoAryVIFuOncRtAioLnETvaOluXaItiConOsLOGY vs --------s A}a8 CBL. MNOOeTuArCoY.beTohxiacivtyCionoclrusiaonls. Aa AB.. ClHienmiactaollCohgeymiCosatgyu.lation... emoo A 51 CD.. PUlrainsamlyasiasn.dUrine Fluoride Measurementsmr---- rene-------- _--3 E. ClinicalPathologyConclusions eem------ ss ARA`AT. OSMubIeChrHoLniTcAToTxiHciOtLy OnCdYRescoonvsermymmmmmmmins-- sssasassmmsmmmmmenssormerrmerrmred5l6 REPRODUCTIVE TOXICOLOGY EVALUATIONSwos BECAR. OPD,UGCeTneIrVatEioFnUNCTION maem e----m -- al6 --- B,L OFTrEmDah gmrosamonoroossomoooon rem-- ----s b. ReproFudnctuiocn Ctonciluvsioens A @ REPAR.ODOUrgCaTnIWVeEigThODXaIaCOLOGY EVALUATIONSA ANATOMICAL PATHOLOGY cr664 C. Microscopic Observations. -- . A----nt DE.. AMnorattaolmitiyc.alPathology Conclusionsfo ReproductiveA Toxicity venmm----ros L A. Biochemical Measurements..L . A--6 B. Biochemical Measurements Conclusions... rs ampany Sanilized. Docs not contain TSCA Cai i-- 0H--2D4a51y6:GavSaugbeehSrtoundiyc iTnoxRiactistywith One-Generation Reproduction Evaluations ReDvuiPsoendtp5a38g6e LIST OF TABLES Page TABLE | SUMMARY OF DOSING ANALYSES... i T6 TABLE 2 MEAN DAILY DOSE VOLUMES FOR MALE RATS. SR 19 TABLE 3 MEAN DAILY DOSE VOLUMES FOR FEMALE RATS ccc 50 TABL4E MEAN BODY WEIGHTS OF MALE RATS. co---- 81 TABLESMEAN BODY WEIGOFHFETMASLERATS ........ sm-- 2 TABLE 6 MEAN BODY WEIGHT GAINS OF MALE RATS.... SE 57 TABLE 7 MEAN BODY WEIGHT GAINS OF FEMALE RATS .......... nnn 90 TABMLEAEN DAILY FOODCONSUMPTIOONF MALE RATS... BE TABLE 9 MEAN DAILY FOOD CONSUMPTION BY FEMALE RATS. -- 9% `TABLE 10 MEAN DAILY FOOD EFFICIENCY OF MALE RATS. constr? TABLE 11 MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS ........... nn 102 `TABLE12 SUMMARY OFCLINICAL OBSERVATIONS FOR MALE RATS........... -- TABLE 13 SUMMARY OF CLINICAL OBSERVATIONS FOR FEMALE RATS. ccc. na TABLE 14 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR MALE RATS... 21 `TABLE 15 SUMMARY OF OPHTHALMOLOGICAL OBSERVATIONS FOR FEMALE RATS....... et} TABLE 16 PERCENT SURVIVAL OF MALE RATS... 123 TABLE 17 PERCENT SURVIVAL OF FEMALE RATS SE er 120 --- TABLE18 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR MALE RATS....... 12s `TABLE 19 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS. ....... 126 `TABLE 20 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS..... 127 TABLE 21 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS. 129 TABLE 22 MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS FOR MALE RATS......... 131 TABLE 23 MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS FOR FEMALE RATS...... 132 TABLE 24 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR MALE RATS 133 TABLE 25 MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS FOR FEMALE RATS........ 134 TABLE 26 SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS. -- 13s `TABLE 27 SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS.d.... B--. `TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE RATS... es M3 `TABLE 20 SUMMARY OF COAGULATION VALUES FOR FEMALE RATS. SE 193 TABLE 30 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS... 144 TABLE 31 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS... 145 TABLE 32 SUMMARY OF URINALYSIS VALUES FOR MALE RATS... 152 TABLE 33 SUMMARY OF URINALYSIS VALUESFOR FEMALE RATS co 154 TABLE 34 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE RATS ccc. 156 TABLE 35 SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN FEMALE RATS............157 TABLE 36 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS . 15% `TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS. enn 166 "ompany Sanltized. Doss not contain TSCA CEI 7 9H:02D4a51y6:GavSaugbcelSrtoundiyc iTnoxRiacittywithOneGeneration Reproduction Ealustions DuRePvoisnetd5P3a8g6e - LIST OF TABLES (CONTINUED) Page TABLE 38 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS... wo TABLE TABLE 39 40 INCIDENCES INCIDENCES OF OF GMIRCORSOSSOCBOSPEIRCVOABTSIEORNVSAITNIFOENSMAILNEMARLAETRAST.S-.NE.OPLASTIC AND 191 NON- TABLE 41 NEOPLASTIC INCIDENCES LESIONS... OF MICROSCOPIC OBSERVATIONS IN rossi FEMALE RATS - NEOPLASTIC --e AND NON-NEOPLASTIC LESIONS... mm TABLE 42 INCIDENCES OF LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS - 1 TABLE 43 NON-NEOPLASTIC LESIONS... INCIDENCEOFS LESION GRADES OF MICROSCOPIC . OBSERVATIONS IN on FEMALE RATS 258 - NON-NEOPLASTIC LESIONS... -- enn TABLE 4 MICROSCOPIC OBSERVATIONS IN MALE RATS LISTING INDIVIDUAL ANIMALS 381 AFFECTED- NEOPLASTIC AND NON-NEOPLASTIC f-- TABLE #5 MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS 318 TABLE 46 AFFECTED. NEOPLASTIC AND NON-NEOPLASTIC. MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS OF P; . MALE --1 RATS... 434 TABLE 47 DMUERAINNGBOGDEYSTWAETIIGOHNTS AND MJEAN--BODY WEIGHT GAINSiOF P, FEMALE RATnS n 35 TABLE 48 DMUERAINNGBOLDAYCTWAETIIGOHNTS AND .M..E..A.N BODY WEIGHT GAINS. OF P, FEMALE RA.TS 3 - TABLE 49 DMUERAINNGDAGIELSYTAFTOIOODNCONSUMPToIOoN.AND MEAN FOO-- D EFFICIENCY OF P, FEMALE RnAnT3S1 TABLE TABLE $0 SI SUMMARY OF CLINICAL OBSERVATIONS IN P, RATS... MEAN ESTROUS CYCLE PARAMETERS AND PRECOITAL INTERVAL IN P, FEMALE en 38 RATS440 TTAABBLLEE 5523 SSUUMMMMAARRYY OOFF SRPEEPRRMODPUACRTAIMVEETIENRDISCEISN:P,P,MAGLEENERRAATTISON. - aa -- ww TTAABBLLEE 5554 MMEEAANN PPUUPP WNEUIMGBHETSR:SFA,NGDENSEURRAVTIIVOANL.:..F, GENERATIONS--.. i. an wm TTAABBLLEE 5576 MSEUAMNMABROYDYOFWEPUIPGHCTLSINAINCDALMOEBASNERBVOADTYIOWNESI:GFH, TGEGNAEIRNASTIOOFN.F;..MALE RATSe.r.n. 8 446 TABLE TABLE 5% 59 MEAN BODY WEIGHTS AND MEAN BODY SUMMARY OF CLINICAL OBSERVATIONS WEIGHT GAINS OF Fy IN Fy RATS... FEMALE RATS... 447 en8 TTAABBLLEE 6610 MSUEMAMNARFIYNAOLFBDOEDVYEALNODPMOERNGTAANLWLEAINGDHMTASRFKRSOMINMFyALRAETSR.A..T.S..-.P.y.ADULTS en 49 .............450 TABLE TABLE 62 63 MEAN MEAN FINAL FINAL BODY BODY AND AND ORGAN ORGAN WEIGHTS WEIGHTS FROM FROM FEMALE RATS MALE RATS - F; P, ADULTS... ADULTS... 451 452 _--mmm`mpam ny Sanilized. D-- oes not contain TSCA CBI V 9H0--2D45a1y6G:avSaugbcehSrtoundiyc TinoxRiactistywithOneGeneration Reproduction Evaluations DuPont-5386 - LIST OF TABLES (CONTINUED) Page TABLE 64 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - F; ADULTS. as6 `TABLE 65 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - P; ADULTS............. 459 TABLE 66 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS ~ P, ADULTS... 460 `TABLE 67 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - Fy PUPS... 461 `TABLE 68 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS-Fy PUPS... 462 `TABLE 69 INCIDENCES OF GROSS OBSERVATIONS IN RATS - F; UNSEXABLE PUPS ccc 463 `TABLE 70 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - F, WEANLING. -- TABLE 71 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - F, WEANLINGS. 465 TABLE 72 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS- F; ADULTS... 466. TABLE 73 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS- F, ADULTS -- TABLE 74 RIENCPIRDOEDNUCCETSIAONNDRLESA -IOPNyGATDRUALDS TESS OF MICROSCOPIC OBSERVATIONS INe MALE.n 68 TABLE 75 RIENCPIRDOEDNUCCETSIAONNDRALTESSI-OPN, GADRUALDTSE.S..OF MICROSCOPIC OBSERSVRATIONS IN FEMALE. 469 LIST OF FIGURES Page FIGURE | MEAN BODY WEIGHTS OF MALE RATS. nnn STE - FIGURE 2 MEAN BODY WEIGHTS OF FEMALE RATS............. ATS FIGURE 3 MEAN FORELIMB GRIP STRENGTH FOR MALE RATS.......... Ah FIGURE 4 MEAN FORELIMB GRIP STRENGTH FOR FEMALE RATS... 13 FIGURE S MEAN HINDLIMB GRIP STRENGTH FOR MALE RATS... 76 FIGURE 6 MEAN HINDLIMB GRIP STRENGTH FOR FEMALE RATS... an FIGURE 7 MFOORTOMRALAECTRIAVTIS.T.Y..A.S.S..E.S.S.MENT: MEAN DURATION OF M- OVEMENT-S. an FIGURE MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS FOR FEMALE RATS.......... SE an FIGURE 9 MFOORTOMRALAECTRIAVTISTY ASSESSMENT: MEAN NUMBER OcFsMOVEMENTS 450 FIGURE 10FMOORTFOERMAALCETIRVAITTSY. ASSESSMENT: MEAN NUBEMBER OF MOVEMENTS -- LIST OF APPENDICES Page APPENDIX A ANALYTICAL DATA. SE -- APPENDIX B INDIVIDUAL DOSE VOLUMES (ML). IE 1 APPECINNDDIVIIDUXAL BODY WEIGHTS............ " i S69 APPENDIX DINDIVIDUAL FOOD CONSUMPTION SE 03 - APPENDIX E INADNIDVIMDOURALTACLLIITNYICDAATLAA..N..D. OPHTHALMOLOGICAL OBSERVATIONS SE 0 APPENDIX F OPHTHALMOLOGY EXAMINATION REPORTS, en 6T2 -_--kmsm<TMm--m--m<Sm--m--=m mTM ~~ "mpany Sanitized. Doos not contain TSCA C81 9H0-2-4D5a1y6:GaSvuabgcehrSotnuidcy TinoxRiactistywith One Generation Reproduction Evaluations DuPont5386 - LIST OF APPENDICES (CONTINUED) Page APPENDIX G INDIVIDUAL FORELIMB GRIP STRENGTH AND HINDLIMB GRIP STRENGTH. 15 APPENDIX H INDIVIDUAL FUNCTIONAL OBSERVATIONAL BATTERY ASSESSMENT. 96 APPENDIX | INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: DURATION OF MOVEMENTS. .........706 APPENDIX J INDIVIDUAL MOTOR ACTIVITY ASSESSMENT: NUMBER OF MOVEMENTS... 717 APPENDIX K INDIVIDUAL CLINICAL PATHOLOGYDATA vec TK APPENDIX L INDIVIDUAL HEPATIC BETA-OXIDATION ACTIVITY ..... sis APPENDIX M INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS ccc. use APPENDIX N INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS... 871 APPENDIX O REPRODUCTIVE TOXICOLOGY INDIVIDUAL BODY WEIGHTS OF P; MALE RATS....1063 APPENDIX P ROEPFROP,DUMCATLIEVREATTSO.XICOLOGY INDIVIDSEUAL BODY WEIGHT GAINS -- APPENDIX Q RE`POFROP,DFUECMTAILVEE RTAOTXSICDOULROIGNYG IGNEDSITVAITDIUOANL BODY WEIGHTS S-- APPENDIX R REOPFROP,DUFCETMIAVLEE TROAXTISCDOULROIGNYG IGNEDSITVAITDIUOANL BODY WEIGHT BR GAINS 1081 APPENDIX $ REOPFROP,DUFCETMIAVLEETROAXTISCDOULROIGNYGILNADCITVAITDIUOANL.BODY WEIGHTSSE . 1087 APPENDIX T REOPFROP,DUFCETMIAVLEETROAXTISCDOULROIGNYGILNADCITVAITIDOUNA.L..BODY WEIGHFRT GAINS. 1093 _ APPENDIX U REBPYROP,DUFCETMIAVLEETROAXTISCODULROIGNYGIGNEDSIVTIADTUIAOLNDAILY FOO-- D CONSUMPTION 1099 APPENDIX V REIPNRP,ODMUACLTEIVREATTSO.XICOLOGY INDIVIDUAL CLINICA--L--O--BSERVATIONS Hos APPENDIX W REIPNPR,ODFUECMTAILVEERTAOTXSICDOULROIGNYG GIENSDTIAVTIIDOUNA.L CL..I..N..I..C.AL OBSERVATIONS re 14 APPENDIX X REIPNRPO,DFUECMTAILVEERTAOTXSICDOULROIGNYGILNADCITVAITDIOUNA.L CLINICAL OBSEJRVA--TIONS N20 APPENDIX Y INADNIDVICDOUHAALBAINTIAMTAILONESITNRPO,UFSEMCAYLCELERAPTASRAMETERS DnURIaNG PREMATING nr APPENDIX Z INADINVDICDUOAHLABAINTIAMTAILONESITNRPO,UFSECMYACLLEERSATTASGES DURIFNE G PREMATING nx APPENDIX AA RIENPPRyOMDAULCETRIAVTES.TOXICOLOGY INDIVIDUALrANItMAL--SPERM MOTILITY DATA 139 APPENDIX BB INDIVIDUAL ANIMAL SPERM MORPHOLOGY DATA IN P, MALE RATS. nat APPENDIX CC INDIVIDUAL ANIMAL SPERM AND SPERMATID COUNTS IN P, MALE RATS. . 1144 APPENDIX DD RAENPDROGDEUSCTTAITVIEONTOLXEINGCTOHL:OGPY; GIENNDEIRVIADTUIAOLNMATING DATA . nar APPENDIX EE RAENPDROIDMUPCLTAINVTEATTOIXONICEOFLFIOCGIYENICNY.DIVIDUAL IMPLANTATION SITE :DATA ss APPENDIX FF REPRODUCTIVE TOXICOLOGY INDIVIDUAL PUP SURVIVAL: F, GENERATION. ....1159 APPENDIX GG REPRODUCTIVE TOXICOLOGY INDIVIDUAL PUP WEIGHTS: F; GENERATION..... 155 _ APPENDIX HH RFLEPGREONDEURCATTIIVOENTOXIo COLOGe Y INDIVIDUAL LITTERcoCnLmImN--I--C--AL OBSERVATIONS: 1235 Company Sanitized. Docs not contain TSCA CB 0 9H.02D4a51y6:GavSaugbcehSrtoundiyc iTnoxRiactistywith One-Generaion Reproduction Evaluations DReuvPiosnetd 5P3a8g6e LIST OF APPENDICES (CONTINUED) Page APPENDIX II REFPGREONDEURCATTIIVOENT.OXICOLOGY INDII VIDUAL BODY WEIGHTS: nn 241 APPENDIJXJ REF,PRGOEDNUECRTAITVIEONTOXICOLOGYFIND--IVIDUAL BODY WEIGHT A GAINS: 151 APPENDIX KK RFE.PGREONDERUACTTIOINV.E..TOXICOLOGY INDIVIDUAL FOODfo CONSUMPTION: 1261 APPENDIX LL RFE,PGROEDNUCETIRVAE TTOIXIOCNOL.O.GY.INDIVIDUACLLINcICAoL nOBSERVATIONS: n APPENDIX MM AINNDDFI,VIADUDAULLATNSIM.A.L.FINAL BODY AND ORGABN--WEIGHTS- P; ADULTS 20 APPENDIX NN APPENDIXOO INDIVIDUAL INDIVIDUAL ANIMAL ANIMAL GROSS GROSS AND MICROSCOPIC OBSERVATIONS - P; ADULTS OBSERVATIONFSy PUPS... 1209 1459 APPENDIX PP INDIVIDUAL ANIMALGROSS OBSERVATIONS - Fy WEANLINGS cv... APPENDIXQQ INDIVIDUAL ANIMAL GROSS OBSERVATION-FS{ADULTS... 16s 91 APPENDIX RR REASON FOR REVISIONNO. | S-- 1501 "ompany Saniized. Doos not contain TSCA CBI -- vo 20H9-0-2DD4aa5y1y6:GovvSaauggbecShSartdonyyiiTinnxRRiaakteywviithhOOnnecGGeenneerarttiioonnRReperopdcrioon Evvaabliioonnss - STUDY INFORMATION Substanc( e Tested: --) DDuurpanosinsst or Hha-- isie -- HaskellNumber, 24516 || Puri = ) Physical Characters ] Sponsor: WE.il1midnugtPoonn,t dDeelNaewmaoruer1s9a8n9d5 Company USh Study Inated Completed December 12, 2000 (sereport cove page) - In-Life Initiated Completed: December TT 12, 2000 / June 11,S2e00m;pany Saniized. Does ottecog Ts opr 910.2.4D5a1y6:GavSaugbeehSrtoundiyc iTnoxRaitcstywith One-Generaton Reproduction Evaluations STUDY PERSONNEL Study Director: GregorSy. Ladics, Ph.D. Management: Judith C. Stadler, Ph.D. Nancy C. Chromey, Ph.D. Janice L. Connell, M.S., B.A, C.LH PrimaryTechnician: Janine A. Britton, B.S. Analytical Chemist: Janet C. Maslanka, B.S. Management: S. Mark Kennedy, Ph.D. Reproductive Toxicologist: Eve Mylchreest, Ph.D, Management: Robert M. Parker, Ph.D. Clinical Pathologist: Nancy E. Everds, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Pathologist: G. Tracy Makovee, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Peer Review Pathologist: Steven R. Frame, D.V.M., Ph.D. - Neurotoxicologist: Linda A. Malley, Ph.D. Management: Robert M. Parker, Ph.D. Biochemical Evaluation John C. 0*Connor, M.S. Management: Matthew S. Bogdanfty, Ph.D. Toxicology Report Preparation: Cecilia R. Kee, B.S. Mary K. LaRoc Ophthalmologist: Nancy M. Bromberg, V.M.D., MS. 6119 Massachusetts Avenue Bethesda, Maryland 20816 Laboratory Veterinarians: William Singleton, D.V.M., A.C.LAM. Wanda L. West, D.V.M, ACLAM DuPont5386 Company Sanitized. Docs not contain TSCA CBI vo H9-02-4D5a1y6G:aSvuabgcehrSotnuidcy TinoxRiactistywith One-Generation Reproduction Ealuations DuPons 5386 SUMMARY Four groupsofyoung adult male and female Crl:CD(SD)IGS BR rats were administered H-24516 by gavage at dosagesof0, 25, 100, and 250 mg/kg/day. Selected animals from cach dosage group were designated for subchronic toxicity of reproductive evaluations. In the subchronic study, body weights, food consumption, and clinicalsignswere evaluated weekly. Clinical pathology endpoints were evaluated on weeks 7, 13, and near the endofthe one-month recovery period. Neurobehavioral assessments were also performed prior to dosing, during week 13, and near the endofthe one-month recovery period. Biochemical evaluations (hepatic f-oxidation) were performed on animals after 10 and approximately 90 daysofdosing and following one- and three-month recovery periods. After approximately 90 daysofdosing, 10 rats/scx/dose were sacrificed and given a gross and microscopic pathological examination. Approximately one month after the 90-day dosing period, 10 animals/sex in the control and high dose group were examined for recoveryof toxic effects. An additional five animals/sex/dose were evaluatedfor recovery approximately 3 months following the end of the dosing period. "The range of mean daily dose volumesofH-24516 administered to male rats was 2.5 10 4.6 ml. The range administered to female rats was 1.9.0 2.8 mi. In-Life Toxicology Parameters: No test substance-related mortality occurred in the study. A test --~ substance-related, toxicologically significant increase in the incidence of broken (males) and absent teeth (males and females) was observed in the 250 mg/kg/day dose group. Test substance- related, toxicologically significant decrements in body weight, body weight gain, and food efficiency occurred in males dosed with 100 and 250 mg/kg/day H-24516. Statistically significant decrements in mean body weight parameters and food consumption occurred for the female groups dosed with 100or 250 mg/kg/day. The mean body weight and body weight gain decrements observed for the 100 and 250 mg/kg/day female groups, however, were of small magnitude. They were associated with decreased food consumption, but not with any alterations in food efficiency, and, therefore, were not considered to be toxicologically significant. Furthermore, the decrements in body weight parameters observed for both males and females appear to be related in part o test substance-induced toxicity to the tecth and subsequent decreased abilityof the animals to eat the pelleted chow. Neurotoxicology Parameters: No adverse changes in neurobchavioral parameters were observed in male or female rats in any dose group. Biochemical Toxicology: The rateof hepatic B-oxidation, a measureofperoxisome proliferation, was increased in a dose-dependent manner with statistical significance occurring in males and females administered 100 or 250 mg/kg/day H-24516. Following a one- or three-month recovery period, the rate of hepatic B-oxidation was still significantly increased in males and females administered 250 mg/kg/day. `Company Sanitized. Docs not contain TSCA Cal 0 9H0-2-4D5a1y6;GaSvuabgcehrSotnuidyc TinoxRiactistywith One-Generation Reproduction Exalations DuPont5386 ~ Clinical Pathology: Samples were collected at mid-study, at the end of treatment, and after one monthofrecovery for hematology, clinical chemistry, urinalysis, coagulation (endofstudy only), and plasma and urine fluoride (endofstudy and endofone- and three-month recovery) Males and females dosed with 250 mg/kg/day had decreased red cell mass parameters, along with correlative changes in other hematology parameters and in red cell morphology. After one month ofrecovery, mean red cell mass of female rats was similar to the control group, although some changes were sill present in other hematologic parameters. Male rats still had decreased red cell mass effects, and associated alterations in other hematologic parameters. Oretchoevrercyh,anwgeerseicnonclsiindiecraledpattrehaotlmoegnyt-praerlaamteetdebrust, dnuorni-nagdvterresaetmbeenctaourseafttheer amaognnei-tourdetohfreceh-maonngteh was small, transient, and/or in a direction not associated with toxicity. The serum parameters thus affected included serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, cholesterol, triglycerides, total protein and albumin, calcium, phosphorus, sodium, chloride, and potassium. Affected plasma parameters were activated partial thromboplastin time and plasma fluoride. Affected urinalysis parameters were urine volume, osmolality, specific gravity, and fluoride. Anatomical Pathology (Subchronic Toxicity): Test substance related, toxicologically significant degeneration/disorganizationof enamel organ ameloblast cells occurred in male and female rats administered 100or 250 mg/kg/day H-24516. Test substance related, potentially adverse - increases in thyroid hypertrophy were observed in the 100 and 250 mg/kg/day male and 250 mekg/day female dose groups. In addition, alterations in thyroid colloid were observed in male and female rats at all dose levels, but were not considered 10 be toxicologically significant Test-substance related and statistically significant increases in liver weight parameters were pTrheeseinntcrienamsaeldelsivaenrdwefiegmhatlsescoardrmeilnaitsedtewrietdh2m5i,c1r0o0s,coopri2c5c0enmtgr/iklogb/udlaayr hfeorpaatpopcreolxluilmaartehlyype9r0trdoaypsh.y ainntdhset1at0i0stiacnadlly25si0gnmigf/ickagn/tdianycrmeaalseesanindk2i5d0nemyg/wkegi/gdhtaypafreammaelteergsroaulpss.o ocTceusrtr-esdubisntamnacleesrealnatded fomales administered 25, 100, or 250 mg/kg/day. The increased kidney weights correlated with microscopic renal tubular hypertrophy in the 100 (1 of 10 rats) and 250 mg/kg/day male groups only. The liver and kidney alterations, however, were considered to be a pharmacologically adaptive response by these organs to the test-substance and therefore, not considered toxicologically significant. After one monthofrecovery, rats dosed with 250 mg/kg/day showed reversibilityofsome effects. The ameloblastic degeneration/disorganization persisted with decreased incidence and severity in the 250 mg/kg/day male and female groups. Thyroid hypertrophy was no longer observed. Alterations in thyroid colloid persisted in both male and female rats. Increased liver weight parameters persisted in the 250 mg/kg/day male and female groups, although their `magnitude was decreased relative to that observed at the end of the 90 day exposure period. Hepatocellular hypertrophy was no longer observe in female rats bu persisted with decreased -- severity in male rats. Renal tubular hypertrophy persisted with decreased incidence and severity in males, while some kidney weight parameters remained increased in both male and female rats. - C<mpany Sanitized. Docs not contain TSCA cai 01.-2D4a51y6:GaSvuabgcehrSotnuidyc TinoxRiactistywith One-Generation Reproduction Evaluations DuPon-5386 - `pArfetseernttheintthhreee1-0m0onmtgh/krge/cdovaeyrmyapleeriaondd, a2m5e0lombgl/aksgti/cdadyegmeanleeraatnidonf/edimsaolregdanoiszeatgiroonupwsabsusttialtl a lower incidence and severity relative to the one-month-recovery animals. Alterations in thyroid cthoell2o5id0pmegr/siksgt/eddaiynmbaolteh manadlefseamanldefgemraoluepss., aLlitvheorugwheitghheitrpmaarganmiettuedres rweamsaidencerdeaisncerderaesleadtiivnebtooth t2h5a0t ombgs/ekrgv/eddayafmtearlethger9o0u-pda(1y opefr5iorda.ts)H.epAalttoecrealtliuolnsarinhyKpiedrnteryopwheyigwhatspoabrsaemrevteedrsonorlyreinnalthteubular hypertrophy were not observed at any dose level. Reproduction: Twenty male and female rats from cach dose group were designated for reproductive evaluations. Parental rats (P; generation) were dosed daily for 74 days prior to cthoehawbeitaantiinongo,fdutrhiengF,thoeffcsophraibnigt.atTihoen pfeorliloodwi(nmgatpianrga)m,edtuerrisnwgegreestcaotinodnu,catnedd odnurPiyngraltasc:tabtioodny, until weights, food consumption, clinical signs, gross pathology. sperm parameters, estrous cyclicity and reproductive performance. The Fy offspring were evaluated during the lactation period for growth and survival and given a gross pathological examination at weaning. A subset ofF, rats (Fy generation) were retained at weaning, and the following parameters evaluated for 6 weeks: body weights, food consumption, clinical signs, and age at onsetof vaginal opening and preputial separation. After 6 weeks, the F selected reproductive organs and generation rats were given a gross pathological target organsoftoxicity were weighed. examination, There were no toxicologically significant pathology findings in the P, or F, generation rats. No --- test substunce-related mortality occurred in the study. There was statistically significant reduction in body weight in Py male rats during and afer the cohabitation period. Although this finding was test substance-related, it was not considered toxicologically significant. There was a statistically significant increase in testicular spermatid numbers in Py male rats administered 100 or 250 mg/kg/day. This finding was not considered test substance-related. Implantation efficiency was significantly reduced at 100 and 250 mg/kg/day and reflects a reduction in the number of pups born, There were statistically significant reductions in the number of pups born, the numberof pups bom alive and the numobfepuprs alive on da4y of lactation in the 250 mg/kg/day group. Reductionsofsimilar magnitude as in the 250 mg/kg/day group were also observed for the `singunmibfeicraonft,ptuhpessebocrhnanagnedsbwoerrneacloivnesiidnetrheed 1te0s0t msugb/sktga/ndcea-yregrloautpe.d aAnldtthooxuigcholnoogticsatlaltyisstiigcanlilfyicant, as was the significant reduction in the numberof pups alive on day 4 of lactation in the 100 mg/kg/day group. days 4,7, 14 and 21 in tThheer2e50wemrge/ksgta/tdiastyicgarloluyps.ignificant reductions in pup weights on lactation On the dayofweaning, mean body weights were significantly lower than control in both F, males and females in the 250 mg/kg/day group. However, mean body weights in these groups progressively returned to control values during the post-weaning period. These findings were not _ considered toxicologically significant. 2mpany Sanitized. Docs not contain TSCA cay 910.2-4D5a1y6:GavSaugbeehSrtoundiyc TinoxRiactistywith One-Generation Reproduction Exalutions DuPont-5386 - N25OEmgL/fkogr/dSauybcHh-r2o4n5i1c6Tobxaisceitdy:on Tahdevenros-eobdseecrrveemde-netfsfeicntbloevdeylw(eNiOghEtLp)arfaormemtaelressawnadsfood efficiency, increased hepatic peroxisomal B-oxidation, and the degeneration and/or disorganizationofenamel organ ameloblast cells in males administered 100 mg/kg/day. The NOEL for females was 25 mg/kg/day H-24516 based on increased hepatic peroxisomal B- oxidation and the degeneration and/or disorganization of enamel organ ameloblast cells in females administered 100 mg/kg/day. NOELfor Reproductive Evaluations: The NOEL for the reproductive toxicity parameters evaluated under the conditionsofthis study was 25 mg/kg/day based on decreases in the number of pups born, born alive, and the number ofpups alive on day 4 of lactation at the 100 mg/kg/day dose level, _ * ThheeteNstOsEuLbsftoarnctheiswesrteudnyoisddeetfecitneedd.asTthhueshifgohresthtisdosstuedayt,wthheicNhOEtLxiicoslocaguiicvlallyenitmportthaentNcOfEfeLctassatdreifbiunteadblbey10 t(hNeOUAnEiLte)daSstadteefsinEendvibryonthmeenEtuarlopPreoatnecUtniioonnA(g1e9n9c4)y.(1985) and 0 the no-observed-adverse-effec evel 7 Company Sanitized. Doss not contain TscA car 29H00-2D-4Ds5a1yy6G:GaaSvvuaabggceehrSSottnuuiddcyyiTinnoRxRaiatctisstwywiitthhOOnnee-GGeenneerraattiioonn RReepprroodduuccttiioonn EEvvaalluuaattiioonnss DDuuPPoonn-t55338866 - INTRODUCTION The test substance, H-24516. is 100, and 250 mg/kg/day dose levels for this study were selected based on the toxicity 25, nd pH-h2a4r5m1a6c.okiInnetriacsaenxaployssiesdotfop2l0a0smmag/fklgu/ordianye Hco-n2c4e5n1ir6atfioron3s5fdraoyms,atroaxincgiet-yfi(in.dci.,ngbosdtuydwyewiigthht epfrfeevcitosusolryclfionuicnadlwohbseenrvaantiimoanlss) wwearseneoxtpoobsseerdvetod.dosPalgaessmathaftluionridnueceldevleeltshaalpitpyr.oaTchheedhilgehve-ldsose mloervtealloifty2.50`Tmhge/lkogw/ddaoysefoofr 2th5ism9g0/-kdga/ydastyuwdyaswaesxpeexcpteecdtetodbteo pthreodnuoc-eobtsoexrivceidt-yewfiftehcotulteveexlc,ewshsiilvee the 100 mg/kg/day dose was expected to induce minimal or no toxicity. OBJECTIVE THh-e24o5b1j6ecwtihveenofatdhmiisnissttuedryedwabsytgoaevvaagleuattoemtahleepaotnedntfieamlasluebrcahtsr.onRicecaonvderryepervoadluucattiivoenstowxiecriety of aidnmcilnuidsetdrattoiionnvewsatsigsaetleetchteedreavsertshiebimloistytoefffaincyieontbswearyvetdo toxicological effects. The oral deliver an accurate dosage. route of - MATERIALS AND METHODS A. Test Guidelines ATgheenscuybc(hErPoAn)i,c OtfofxiiccietyofstPurdeyvednetsiiognn, cPoemstpilciiedses,wiatnhdthTeoxUincitSeudbsSttaantecsesEn(vOiProTnSm)entHaeallPtrhotEefcfetcitosn `TgeesnterGautiidoenlrienpesr,odOucPtPiTonSs8t7u0d.y3i1n0c0lu9d0es-DmaaynOyraelndTpooxiinctistyofinreRpordoednutctsi(vAeUfGu-n1c9t9io8n).butTdhoeesonneo-t comply witha specific guidelinc. B. Test Substance aSnaamlpysliessoafndthaenaHl-y2ze4d51b6ywtehereDusPupopnltieRdegnieoanratlheAnbaelgyitnincianlgSaenrvdiecensd (oRfAtSh)e,sJtaucdyksfoonr sLtaabboirlaittyories, Deepwater, NJ. documented in Methods and study records. results for the stability analysis ofthe test substance are C. Test Species bOinrthNodavteemobfeOrct1o6,be2r00205,, 1270600m,awleeraendrec1e7i6vefdemfarloemCCrhlar:lCeDs(RSiDv)eIrGLSabBorRatroartis,esw,itInhc.,anRaaslseiigghn,ed North Carolina for use on this study. -_-- Company Sanitized. Does no contain Tse oar 0 2904-5D1a6y;GavSaugbcehSrtoundiyc iTnosRiactistywith One-Generaion Reproduction Evaluations Dupont5386 - a`Tnhde irsatexwtaesnssievleelcyteudsebdecianurseepritodisuctthieosnpesctuideisesr.ecTohmemeCrnld:eCdDin(tShDe)sIuGbSchBroRnistcrationxiwcaitsycghuoisdeelnines because extensive background information is available from the literature, the suppl, and previous studies at Haskell Laboratory. This species/strain also is considered suitable relative to longevity, hardiness, and low incidenceof spontaneous diseases. D. Animal Husbandry I. Housing sWeixtehs tsheepaerxacteep,tiinonsotafinsloesmsestpeoerlt,iwoinrsoe-fmtehsehrceapgreosduscutsipveensdteuddya,baollveractasgweerboearhdosu.seAdnoinmeaplerrocaogmes, were maintained on a 12-hour light/dark cycle (fluorescent light) and at a temperature of 22+ 3C and a relative humidity of 50%+ 20%. ranges were minor and did not affect the study. Occasional excursions outside the accepted cRoahtasbidteastiigonnatpeedrifoodr. reDpurroidnugcttihveegteosxtiactiitoynepvearliuoadt,iofnesmawleererahtsoudseesidgansatberdeefdorinrgeppraoirdsucdtuirviengtotxhiecity emvaatleudatfieomnaslewse,reorhaotutsheedeinnddiovfidtuhaelcloyhuanbtiitlagteisotnatpieornioddayfo2r0.femBaelgeisnwniitnhgoount egevsitdaetnicoen odfay 20 for cloacptualtaitoinonp,erfieomd,alaedurlattsfweemraleehroautssewderinedhivoiudsueadllwyiitnhptohleyircalribtoernsatien pans with bedding. polycarbonate pans. During the Cage racks racks every were relocated 2 weeks within the animal room each weck and cages were repositioned on the for animals periods. designated for the 90-day exposure period and one- and three-month recovery during the 74-day premating period for animals designated for reproductive assessment, and the 40-day post-weaning period for F, generation rats 2 Feed and Water "Tap water was provided ad libitum. All rats were fed PMI Nutrition Intemational, Inc. Certified oRnodteensttdLaaybD57i,etaTMni5m0a0l2s eaxdhliibbiittiunm.g efnfietcitaslltyo, tahlel traetesthwewreerefepdlapceeldleotnedgcrhoouwn,d hcohwoewv.erO,nbetegsitnning edvaaylu7a4t,iaolnlsrawtesrienptlhaec2e5d0onmgg/rkogu/nddaychdoows.e gOrnoutpestthdataywe7r7,e adlelsoitghnearterdatsfoirnrtehpero2d5u0ctmigv/ektgo/xdiaciyty dose group were placed on ground chow. 3 Identification aPbrisoernctoe aosfasigcnomleornetdtotagilromuaprsk, eaancdhcraagtewiadsenttiefmipcoatriaorni.lyAifdieenrtiafsisedigbnymecnitthetro tghreoupprse,seannceinodrividual ~ identification number was tattooed on the tail of each rat. The information on the cage labels `Company Sanitized. Docs not contain TSCA CBI vo 0H--2D4a51y6:GavSaugbeehSrtoundiyc iTnoxRiactistywith One-Generation Reproduction Evaluations DuPont-5386 ~ included the unique 6-digit Haskell animal number and the individual identification number assigned to each rat 4. Health Monitoring Program fAosllspoewciinfgiepdroicnetdhuereHsasakreelpleLrafboorrmaetdorpyerainoidmicaalllhyeatlothenasnudreenthvaitrocnomnetnatmailnamnotniltevoerlisnagrperboeglroawm, the those that would be expected to impact the scientific integrityof the study: + Water samples are analyzed and other contaminants. for total bacterial counts, and the presenceofcoliforms, lead, + Feed samples are analyzed for total bacterial, spore and fungal counts. + Sbyamtphleecsagferwoamshfreersshly washed cages and cage racks are analyzed to ensure adequate sanitation Creerqtuiifrieemdeanntismaanldfneoetd tios uesxecde,egdusatraatnetdemedaxbiymtuhemmcaonnucfeancttruarteirontsoofmkeeetyscpoencitfaimeidnannuttrsi,tiionncalluding sppreecsiefniceedohfeathveysemectoanltsa,maifnlaantotxsinb,eclholwortihneamteadxhiymdruomcacrobnocnesn,traantdioonrgstaantoepdhboyspthhaetmea.nufTahceturer would not be expected to impact the integrity ofthe study. = `The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluationof affected the validityofthe study. these data did not indicate any conditions that E. Quarantine and Pretest Period Upeproiond.arrTihvaelraattsHawsekreellobLsaeborrvaetodrayi,lythfeorraatnsywcelrieniqcuaallryanatpipnaerdenftorsi1g1nsdoafysdoifsctahsee2o6r-idnajyurpyr,etest weighed 4 times, and examined preexisting ocular lesions. bya veterinary ophthalmologist to identifyanimals with Prior to without grouping, necropsy. one male rat animal no. 643168) One male rat (animal no.643186) was and accidentally killed and discarded 2 female rats (animal nos. 643355 and 643469) found. were found dead and necropsied to check for the presence of disease. No discase was Orenletahseedbafsriosomfqaucacreapnttainbeleonbotedsyt wdeaiyg-h1t5gabiynsthaenldabcolrianitcoarlyoabnsiemravlatvieotnesr,inaallrisaunrvdievsiinggner.ats were >mpany Sanitized. Doss not contain TCA oof N -- -- 219002-D5Da1ay6y:GGaavvSaauggbceehSSrttouunddiyyciiTnnoRxRaiacttisstwywiitthhOOnnee-GGeenneerartaiioonnRReeprrooddiuccttiioonn EEvaalluusaitioonnss F. Study Design Groups. No Male Female Male 1 nas m wv 35 v Vv ivvi a3s5 Group Female as 35 d3s5 Dietary Dosaged (mg/kg/day) 0 (Control) 25 215000 DDuuPPoonn:55338866 BiochemicalEvaluationsatthel0-dayTimePoint I-A I-A 5 5 0 (Control) I-A IV-A 5 5 25 V-A VI-A 5 5 100 VILA VILA Ss s 250 a Waneiimgahltobfotdeystwesiugbhsttance (adjusted fof ] tive ingredient)kg `The first ten rats in each group were designated for the 90-day exposure evaluation. The next five rats in each group were initially designated as a satellite subset for serial blood collection in the event findings warranted analytical evaluations. Due to findings after the one-month recovery period, these rats were designated for evaluationofselected tissues following a three- month recovery period; 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 and female rats in the control and high dose groups were designated for recovery evaluations and are reported as the one-month recovery animals. An additional $ rats/sex/dose were received as a separate shipment 65 days after study start for the biochemical evaluations (hepatic B-oxidation) following a 10-day exposure. Male and female rats designated for the 90-day exposure evaluation were dosedfor 90 and 92 days, and necropsied on test days 91 and 93, respectively. Male and female rats designated for the one- and three-month recovery evaluations were dosed for 90 days and necropsied 36 days and 92 days postdosing, respectively. Neurobehavioral evaluations were conducted on male and female animals designated for the 90day exposure evaluation (predose and week 13) and on control and high dose animalsdesignated for the one-month recovery (predose, week 13, one-month post dose). Biochemical evaluations (hepatic B-oxidation) were performed on animals afier 10 and approximately 90 daysof dosing. and following one- and three-month recovery periods. Clinical pathology evaluations were conducted on animals designated for the 90-day exposure evaluation on weeks 7 and 13 and on animals designated for the one-month recovery evaluation immediately prior to necropsy. Reproductive evaluations began on test day 74 when designated male and female rats were cohoused. `Company Sanitized. Docs nct contain TSCA Cal - 1902-4D5a1y6:GaSgubechSrtoundiyc iTnoxRiactistywith One-Generaton Reproduction Evahations DuPont5386 - G. Assignment to Groups and Study Start 1. RRaetcsovDeersyigEnvaatleudatfioorntshean9d0-RDeapryoEdxupcotsiuvreeE,vOalnuea-tiMoonnst.h Recovery, and Three-Month Ropahttshwaelrmeolsoeglieccatledabfonrorsmtauldiytiuesse oorncltihneicbaalsissiogfnsaodfedqiusaetaesbeoodryiwnejuirgyh.tagnadina,bfordeyedwoemigfhrtowmiathniyn ra2nd0o%moizfatthieonmesoanthwaittthhienreawseexr.e nTohestsateilsetcitceadllryatssigwneifriecadnitstdriifbfuetreedncbeyscaommopuntgergirzoeudp,bsotrdaytiwfeieidght means within a sex. `oOnratlesatdmdianyis0.traPtriioonr otoftHh-e2s4t5ar1t6obfetghaenteosnt stuesbtsdtaanc0ye.adTmhienirsattrsatwieorne, arpatpsrowxiithmabtoedlyy 4we9idgahytss otfhaatge w`meirceronsoctopwiictheivnalua2ti0on%so.f tRheeplmaecaenmewnitthriantsawseerxe, wseelreectreedploancetdheabnadsidsiosfcfarrdeecddwoimthforutomgraonsys or clinical signsof disease or injury and a body weight = 20% of the mean within a sex. 6O4n33te1s5t d(a2y500,mgtlwkog/mdaalye))r.atsInhcalduscilionniocfaltshiegsnesaonfimhaailrsloonsst(heansitmuadlynduomebsenrost6i4m3p2ac3t2 t(hceonoturtolc)omaned ofthe study. 2. Rats Designated for 10-Day Biochemical Analysis - sTtharet.raTtshedeysiwgenraetehdanfdolretdheth1e0s-adamyebaisocthheemoitchaelr raantaslydsuirsinagrrtihveedqusaerpaanrattienley,an6d5pdraeytsesatftpeerrisotdusd,y `ecxocmepputtetrhiezyedd,idstnroattirfeiceedirvaenadnomoipzhatthiaolnmoilnotgoisctauldyexgarmoiunpasti(oSn/.sexT/hdoesye)w,ersoe tdhiasttrtihbeurteedwebrye no sstuabtsiesttiocafllryatssiigsnicfoimcapnatrdeidffaemreonncgestahmemosneglvgers.oupOrbaoldaydmwieniigshttramteiaonnosfwiHt-h2i4n7a68sebxewghanenonthtiesst day 76. H. Dose Suspension Preparation D0o.s5e% smuetshpyelncseilolnusloosfe.0, 2M.e5t,hy1l0c,eolrlu2l5osmeewtaesstsseulebcstteadnacse/tmheL vweehrieclperebpeacraeudsewiitthis the vehicle of dcahoyi0cethforrourgehprtoedstucdtaiyve37stuwdiitehs.a dDoosseevsoulsupemnesoifon1s0wmeUrkegp.repHaorweedvdeari,lyipnroirodretrotdooasidnmginfirsotmeatrest dfoesmealveorlautsmewausnddeercr$eamsLe.dtofrcoommp1l0ymwLi/tkhglta0bo7r.a5tomrLy/pkrgocoendutrees,t dtaheyd3o8s,ianngdvtohleusmuespfeornsmiaolne and concentrations were increased to 0, 3.33, 13.33, and the endofthe dosing period, these dose suspensions 33.33 were mg/mL. prepared Starting on test twice a week. day 42 until aTlhiequtoetsetdm,attheerinamliwxaesd mweiltthemdedthoywlncetlolualpopsreoxfiomraotneelymi9n0utCe, tmoimxaekdefotrheapdporsoexismusapteenlsyio3n0s.minWuhteesn, - tdhaeydtohseesussupsepnesnisoinosn wwearseptrheepnarheodmtowgiecneiazewdeefko,r othneesmuisnpuetnesiaonndwtahsenrsetfirrirgeedraftoerd3u0ntmiilnuustede.s Each Company Sanitzad. Dosnotcontain TSCA Cay -- 7 -- -- H9-02-4D5a1y6G:avSaugbeelSrtoundiyc iTnoxRiactistywithOne-Generation Reproduction Evaluations DuPont 5386 =~ breeffroirgeeratthoer.dayT'hseadlioqsueotssuswpeernesiroenmsovweedr.e sRteirmraeidnpirniogrdtoosaensdusdpuernisnigodnossiwnegr.e returned to the I. Test Substance Administration and Sampling Animals designated for the 90-day exposure period and one- and three-month recovery periods were dosed for up to 92 days. Animals designated for reproductive evaluations, were dosed for the 74-day premating period and during the mating period. Py male rats continued to be dosed until sacrifice. Pregnant female rats were dosed during the gestation period. Lactating females and females with no evidenceof copulation were dosed until pups were weaned on day 21 "The test substance was administered daily to the study animals by oral gavage to achieve dosage levels of25, 100,or 250 mg active ingredientkg body weightday, based on the most recently recorded body weight. All male and female control animals were treated with 0.5% aqueous methylcellulose at the same dose volume as that used for the high dose group. On test day 3, five male rats in the 25 mg/kg/day group were dosed with vehicle only. On test day 18, all male rats and the first 11 female rats in the 25 mg/kg/day groups received 37-39 mg/kg/day. There were individual rats across dose groups that were misdosed; these rats are documented in study records and reported in Appendix B. The incidences of misdosing described above arc considered not to have affected the outcomeofthe study. -~ Al Py animals in showing signsof the reproduction study with the exception delivery were dosed daily until sacrifice. of pregnant females in the process or At the initiationofthe study (est day 0), samplesofthe dosing suspensions containing H-24516 at the concentrationsof0, 25, 10, and, 25 mg/mL were collected. On test day 6, to verify that the 10.0 mg/m. level was mixed homogencously, samplesof the dosing suspensions containing H-24516 at the concentrations of0 and 10 mg/mL were collected. These samples. were analyzed to verify homogeneity/concentrationofthe test substance in the vehicle and 5hour room temperature stability to verify the test substance stability while the animals were being dosed. sPtraiboirlittoyt(h4edianyist)iatainoanlyosifas wchaasnrgeequiinrefdr.eqAulesnoc,yo2fndeoesdintogcphraenpagreatdioosne. vaolluomneg:term refrigerated (10 mg to 7.5 mlkg) was identified and a subsequent change in the concentrations of the. "sTuhsepesnasmipolnesswcaosllencetceedssdaurryi.ngThtehirsefaodrdei,tiaonnaalddsittuidoynawlemriexniontgaadnmdinsitsatbeirlietdy tsotutdhye wanaismaplesrfbourtmed. addressed the mixing, rangeof concentrations and the stability parameters that would be needed after the frequencyof mixing and dose volume changes were made in the study. In this separate 5st0udmyg, /smaLmp(lbeassoefddoonsian5g msuLskpegnsdioosnes vcoolnutmaien)inwgerHe-2c4o5l1l6ecatetd. thTehceosnecesnatmrpalteisonwsoerfe0,an5a,l2y0z,edantdo, verify homogeneity, concentration and S-hour room temperature stability. On subsequent days 2, 3..and Verify 4 afte this preparation, samples concentration after re-dispersion from the same preparation were collected and of the test substance and refrigerated stability analyzed (4 days) to ~ astluodnyg,twoitshat5i-shfoyutrherodoosmetveomlpeurmaetucrheanstgaebiolif5ty (mld/ak4yg staom7p.l5esm,L/oknlgy,).saLmaptleersoinfthtehe9d0o-sdianyggavage BE Company Sanitizad. Des not contain TSCA C1 0H--2D4a51y6:GavSaugbeehSrtoundiyc iTnoxRitcsitywith One-Generation Reproduction Evaluations DuPont5386 - suspensions containing H-24516 at the concentrations of0 and 3.33 mg/mL were collected and alantaelr,yzseadmptloevserfirfoymhotmheogseanmeeitpyr,epcaornacteinotnrawteiroen caonldle5c-theoduarnrdoaonmaltyezmepdertaotvuerreifsytacboilnictey.ntFroatuirondays after re-dispersionofthe temperature stability. test substance and refrigerated stability (4 days) along with 5-hour room Oconncteensttrdaatyio3n8,raanfgtee,r tthhee mmiixxiinngg afnrdeqsuteanbcilyitaynwdadsoseestvaoblliusmheedcfhoarntghee(s1t0ormaLge/kcogntdoit7i.o5nmsLaknde)thewas 2in4i5ti1a6teadtitnhethceonsctuednyt.ratTihoenrsefoofr0e,o3n.3t3e,st1d3a.3y34,9a,nsdam33p.l3e3s mofg/thmeLdowseirnegcsoulslpeecntsedioannsdcaonnatlaiynziendgtoHVerify homogeneity and concentration. On test day 91, samplesof the dosing suspensions containing H-24516 at the same concentrations were collected. The 3.33 mg/mL samples were analyzed to verify homogeneity and concentration while the remaining levels were analyzed for concentration verification. All dosing suspension samples were collected on the same day the suspensions were prepared or at the prescribed protocol time for analysis. They were analyzed when received or were frozen until analyzed. J. Analytical Methods - 1. Dosing Suspension Treatment Each dosing sample was diluted to 100 mL with methanol and sonicated to dissolve the H-24516 in the suspension. The dosing samples were further diluted with the 0 mg/mL sample initial dilution) to an expected concentrationof approximately 0.05, 0.06, 0.075 or 0.09 mg/mL (@.) prior to analysis. An internal standard (refer to Calibration and Quaniitation Section) at an equivalent amount was added 10 cach sample before the final analysis dilution. Samples submitted for analysis were analyzed the day the suspensions were received or stored frozen until analyzed by the testing group. ~>mpany Sanitized. Doos nocontain TSCACBI EI 5 12D6e51y6G:CoSgvhaSoodynyniToeaittwiihOneGGeeeirns ReeppodicoionnEEshssitioonns p-- urer sits - rC-- oetcoonr 2 Chromatographic ConditJHiooWnwsi,eDPBack1a7r01d,M5o0dme.l Si 350 0659930 GC 0, um i ticks Dees Fi 250 OSrCaveroecrniiveoPraneGagVs:oal.ume: SCH2eer3lirmauiimnnm(2ie.1 mL/min) ITInontvtl TTeRrmoepeerature: 0L1o00n0mmiinn LTLoovaevt n| TTeimmpeerate: 0S260o0moiCmn 3. Calibration and Quantitation A separate sample of H-24516 (-3) was obtained to use as the analytical reference standard LC ii vs prepares mn Te ston cots "assure that all material was in solution. Before analysis, appropriate aliquotsof the stock were tdihleudtieldutweidthdomsientghansaomlplteosm.akAe sctaolcikbrsaotliuotniosntoafntdahrdes,intwehrinaclhsbroarckeeted the target concentration of - -- prepared in methanol and added tc ch aration stn test for sample intemal to give an equivalent inal concentration standard and H-24516 at three retention in all times dilutions. (3.5, 4.17, The and rato 4.77 of the peak heights minutes) from replicate GC analysisofthese suspensions were squares regression (see Appendix A, Figure la, used to Ib, and construct calibration curves by lc foar representative curves). least Measured concentrations for the dosing samples replicate injectionsofcach sample to were determined by applying the the respective calibration curve. peak height ratios from Test substance homogeneity in the dosing suspensions was evaluated by calculating the cinoesfafimcpileenstoofbvtaariinaetdifonro(mC.tVh.e t=ops,tamniddadrlde,deavnidatbiootnt/ommea(nT,xM1,00a)nodf the measured concentrations B) ofthe dosing preparation or the meanofduplicate samples for each concentration. A coefficientofvariation of less than 10% is the standard throughout the criterion at Haskell dosing suspension. LTahbeormaetoarnyrfeosrulatccoefptthaeblteopd,imstirdidbluet,ioanondftbhoetttoemsthsoumbosgteanneceity samples or duplicate concentration verification samples for each dosing level was used to determine the concentrationofthe test substance for the respective dosing levels. Stability was evaluated duplicate concentration by using the verification mean of samples the top, middle, and bottom homogeneity (0-day room temperature) as the baseline samples for or comparing the corresponding room temperature and refrigerated results. _---- ComPany Sanlized, Docs mot contain 7504 cy 9H0.2-4D5u1y6:GaSvuabgcehrSotundiyc iTnoxRiactistywith One-Generarion Reproduction Exalations DuPon-5386 -~ K. Body Weights tAhlel rraattss dweesriegnwaetiegdhfeodr onnecureopbeerhawveieorkadluervianlguatthieo9ns0,-duanydeerxgpooisnugrefupnhcatsieoonafltohbesesrtuvdayt.ionIanlabdadtittieorny, and motor activity assessments, were weighed on the daysof reproduction substudy, male rats were weighed on a weekly those observations. schedule and female During the rats were wPieifgehmeadledurratisngwigtehstnaotieovniodenndcaeyosf0c,o7p,ul1a4t,i1o8n,oarntdha2t1,diadndnoltadctealtiivoenrdaalyistt0er, c7o,n1t4i,nuaendd t2o1.be weighed weekly. Weaned F; ras were weighed weekly until postnatal day 56 (test day 36). L. Food Consumption and Food Efficiency `The amount of food consumed by each rat over each weighing interval was determined tfihnraoluwgehioguhtttohfe stthuedyf.eedEearcahndfetehdeeramwoausnwteoifghsepidlaltagtehefrboemgitnhneifnegeadenrddeunrdionfgtthhee iinntteerrvvaall waansd the subtracted from the inital feeder weight. From these measurements, mean daily food consumption over the interval was determined. From data, the mean daily food efficiency was calculated. the food consumption and body weight eMveaalunatdiaoinlsy fduoroidncgotnhseu9m0p-tdiaoyn ewxapsosduerteerpmeirinoedd.foFroaold acnoinmsaulmspdteisoingnwaatsedalfsoor dseutbecrhmrionneidc tfooxricity - animals designated for one- and three-month recovery evaluations. The only exception is that food constmption was not determined for animals designated for three-month recovery during the urine and feces collection period on test days 83-89. During the reproductive assessment, food consumption was determined for rats designated for reproductive assessment as follows: + Premating Dosing period individual food consumption was determined weekly, ending test day 74 + Cohabitation period, beginning test day 74 food consumption was not determine. + + FGeosltlaotwiionngptehreioedn-doifndciovhiadbuiatlatfiooondpceornisoudmptfiooond cwoanssduemtpetrimoinnewdasonnogtesdteatteiornmidnaeydsf0o,r7m,al1e4,s. and 21 + Lactation period ~ food consumption was ot determined. + sPpoisltlwageeanniotngreF,corradtesd~diunrdiinvgidtuhaelpfoosotdwecaonnisnugmppteirioondwfaosrmiannadyvearntiemnatllsy.noAtscoallreescutletd, oarvailable food consumption data are not presented in the report but are included in the stud records. M. Detailed Clinical Observations and Mortality bDeuhraivnigorthaendte/sotrpaepripoeda,racnagcee-saimteonegxarmaitnsawteiroenscotnodduectetcetd matorlieabsutntdwiocreddeaaidlyratthsraonudghaobuntotrhmealstudy. --- aAptpeevarearnycew.eigDheitnagi,lecdacclhinriatcawlaosbsienrdviavtiidounaslliynahasntdalneddaradnidzeedxaamriennaedwefrore aablnsooremvaallubaetheadvoinorraatnsd designated for the 90-day exposure and one-month recovery periods. The detailed clinical `Company Sanitized. Does nol contain TSCA CBI 3 -- -- 1902-4D5a1y6;GSaugbcehrSotnuidyc TinoxRiactistywithOne-Generation Reproduction Evaluations DuPont5386 - oobcsccurrvraetnicoeonsfisnecclruedteidon(sbuatndweerxecrneottiolnism,itaeudttoon)oemviaclunaetrivoonusofsfyusrt,esmkianc,tievyietsy,(mluaccroiumastimoenm,branes, pilocrcetion, and unusual respiratory patter), changes in gait, posture, response to handling, presenceof clonic, tonic, stereotypical, or bizarre behavior. N. Ophthalmological Evaluations Teyherseeweorpehtehxaalmmoilnoegdicbaylfeoxcaalmiinlaltuimoinnastiwoenreancdonidnduicrteecdt bopyhathvaeltmeroisncaorpyy.ophTthhaelmeoxlaomgiinsatt.ioBnostwhere conducted solution. under subdued lighting after mydriasis had been produced with a 1% tropicamide On test day -11, the initial examination was performed on all rats received for the study, prior to selection and grouping. On test day 80, all surviving rats designated for the 90-day exposure and one-month recovery were examined again. On test day 122, all surviving rats designated for the one-month recovery evaluation were given a final examination. 0. Neurotoxicity Evaluations 1. Sensory Function Evaluation - oPfrtieosrtto sutbessttasnucbestaadnmcieniasdtmriantiisotnr,aatinodnf(otlesltowdianygsa~n6aapnpdro7x)i,madtuerliyngonwee-emkon1t3h(treesctodvaeyrsy 8p6erainodd (8t7e)st day 120), assessmentsofresponses to approachitouch, sharp auditory stimulus, and tail pinch were made while the animal was in a standard arena. These assessments were conducted on 10:animals per group for the baseline and week 13 evaluations. The recovery evaluation was conducted on the 10 animals per group designated for the one-month recovery (control and high- dose groups only). Forc- and hindlimb grip strength were measured by a strain gauge device (Chatillon" Digital Force gauge). Pupillary constriction was measured immediately prior to rapepmaorvaitnusg twhaesraltoscaftreodmfatchielimtoatteodroabcsteivrivtiyncghtahmebreersspobnesec.ausDeutchetodtahreketnecehdnircoaolmdiifnfiwchuiltcyhotfhe evaluating pupil size in albino rats under ambient light conditions. pupil size was evaluated by assessment of pupillary response. The presence or absence of pupillary constriction was assessed after a beam of light was directed into each eye. unawareofthe group designationofthe animal. For all these assessments, the experimenter was 2. Motor Activity Following the evaluation of grip strength and sensory function during week 13, assessment of `motor activity was conducted. Rats were individually tested in | of 30 nominally identical, automated activity monitors (Coulbourn Infrared Motor Activity System). Group and gender were counterbalanced across the monitors and timeofday to the fullest extent possible. The infrared monitoring device enables measurement of 2 dependent variables: durationof movement - and number of duration. Each movements. test session A continuous movement was counted as | was 60 minutes in duration, and the results movement regardless of were expressed for the total session as well as for 6 successive 10-minute blocks. `Sompany Sanilzed. Does not contain TSCA CBI 7 91.02D4a51y6:GavSaubgcehSrtoundiyc iTnoxRiacistywith One-Generaton Reproduction Evalutions DuPont5386 - Presenceofdefecation and urination on the cageboards below the motor activity monitor were also recorded following each motor activity session. 3. TestFacility Positive Control Data Data on the effects of acrylamide, carbaryl, d-amphetamine, and trimethyltin are described in ffoorurthseepianrdaitveidruepaolrstsm.a*ki*n*g juTdhgemseenptossiitnivteheconneturroolbeshtaudviieosraalreanthde nbeausrisoopfattrhaoilnoignygtecsetrst.ifTichaetidoanta asleseondioncnuemureonttoxtihcaitttyhesteuqduieispmoefntthiasntdypper.ocedures are capableofdetecting effects that may be P. Clinical Pathology oAnctleisnticdaalypsa4t4hoalnodgy91ev(amlaulaetsi)onorwatsestcodnadyusc4t5edanodn 9t3he(ffiermsat l1e0s)m.alTeheanrdats10wefreemaflaestreadtsovpeerrngirgohutp (approximately 16 hours) and urine was collected during this interval. Blood samples for hematology and clinical chemistry measurements were collected from the orbital sinusof each fasted rat while the rat was under light carbon dioxide anesthesia. Blood samples for coagulation parameters and plasma fluoride were collected from the abdominal vena cava while the rat was under carbon dioxide anesthesia, immediately prior to sacrifice (days 91 and 93 in males and cfleimnailceasl,paretshpoelctoigvyeleyv)a.luAatlilobnl(ohoedmastaomlpolgeys,wcelrineiceaxlacmhienmeidsvtirys,uaalnldyuarnidnaolbysseisrvoantliyo)nswarsecaolrsdeod. A - conducted on all one-month recovery rats from blood and urine collected on the day of necropsy (test day 125). In addition, urine samples were collected from three-month recovery ras for urine fluoride analysis only. 1. Hematology/Coagulation Cheommaptloeltoegbylaonoadlyczoeurntasnd(idnectleudrimnignerdetficruolmocmyitcers)oswceorpeicdeetvealrumaitnieodnoofntahBeabyleoro"dAsdmveiaar.12W0rightstained blood smears from all rats were examined microscopically for confirmation of automated results and evaluationofcellular morphology. Coagulation times were determined on a BCS. Behring Coagulation Analyzer. New methylene blue-stained blood smears were prepared from cach rat undergoing hematology evaluation but were not needed for evaluation. --_--m-m A eo o `Company Sanitized. Does nok contain TSCA CBI 1902-4D5a1y6:GavSaugbechSvtoundyc iTnorRiatcsiywithOne-Generation Reproduction Evaluations DuPon5386 - "The following hematology and coagulation parameters were determined: Erythrocyte count (RBC) Hemoglobin concentration (HGB) Hematocrit (HCT) `MMeeaann ccoorrppuussccuullaarr vheomlougmleo(biMnC(VM)CH) Mean corpuscular hemoglobin concentration MCHO) ARbesdolcueltledriesttirciubluotciyontewciodutnhts(R(DAWRE)T) "Total leukocyte count (WBC) Differential leukocyte count PMliactreolsetcocpoiucntbl(oPoLdT)smear examination PAcrtoitvhartoemdbipanrttiiamlet(hPrTo)mboplastin time (APTT) 2. Clinical Chemistry Clinical chemistry parameters were measured or calculated on a Roche Diagnostics (usBiMngCa)pHhii/tI a2pcHh9i1me7tecrlinwiictahlachfelmuiorsitdrey-saenlaelcytzievre.elPelcatrsomdae.fluPolraisdemacofnlcueonrtirdeastiwoenrweadsetdeertmeirnmeidneadt the endof treatment and at the end ofa one-month recovery period. The following serum chemistry parameters were determined: ~ AAslpaanritnaeteamaimniontortarnasnfsefrearsaese(A(LATS)T) TAoltbaulmpirnot(eAinLB()TP) ASlokrabliitnoelpdheohsypdhraotgaesneas(eA(LSKDPH)) Globulin (GLOB) Calcium (CALC) "Total bilirubin (BILI) Inorganicphosphorus (IPHS) Urea nitrogen (BUN) Sodium (NA) CChroelaetsitneirnoel((CCRHEOAL)) Poassium (K) Chloride (CL) Triglyceride (TRIG) Glucose (GLUC) Plasma fluoride (PLU) 3. Urinalysis "The following urinalysis parameters were determined: Appearance (quality, clarity, and color) Volume (VOL) Osmolality (OSMO) Specificgravity (SG) pH Glucose (UGLU) Ketones (KET) Bilirubin (UBIL) Blood (BLD) Urobilinogen (URO) Urinefluoride (UFLU) Protein (UMTP) Microscopic urine examination Urine volume and appearance were measured and evaluated visually, respectively. Urine - cCohnesmtiisttuernytsanwaleyrzeers.emUir-iqnueanvtiotlautmievealnydmeaapspeuarreadncoen waeBraeyemreaCsluirnietdeka"ndAtelvaalsuTMatAeudtvoimsauatleldy,Urine Company Saniized. Docs notcontainTSCA C1 Fa 01.-2D4a51y6:GvSaugbechSrtoundiyc TinorRiactistywith One-Generation Reproduction Exaluations DuPont5386 i rAeustpoecmtaitveeldy.UrUirnienCehceomnissttirtuyeanntaslwyezerre. sUermiin-equparnottietiantiwvaeslymmeeaassuurreeddoonnaaRBoacyheerDCialginnoistteikcsAtlasTM (AdBvMaCn)cHeidtaOchsimom7e1t7ecrlin3i9c0a0l.cheSmeidsitmreynatnsalyfzreor.m aUllriunrienoessmpoelacliimteynswawserdeeteevramliunaetdedusing an muriicnreosfcloupoirciadlelyc.oncUernitnreatfilounor(imdeeawsausreddeutseirnmginaedphbi/ylm2upltHipmleitceartiaonndofamfelausoruirdeedseulreicnteivveolume by electrode). Urine fluorides were determined at the end of reatment and at the endofthe one- `and three-month recovery periods Q. Collection of Blood, Urine, and Feces (Three-Month Recovery) On test day -4 (pre-bleed) and test days 0, 3, 9, 21, 34, 55, 76, and 89 blood (approximately 0ra.t 5wa1smuLn)dewralsigchotlclaecrtbeodnfdrioomxitdheeaonrebsitthaelssiian.usOonfdtehseidganyaotfedblaonoimdaclosll(e5ctriaotns/(seexxc/deopstc)teswthidlaeyt--he 4), blood collected was collected from the animals 2 in plastic tubes containing EDTA hours while (+ on 30 minutes) afer dosing. ice. The blood was then The blood was separated into plasma and RBCs by centrifugation and store frozen. For each bleeding, blood was collected at approximately the same timeof day. During the last weekof the 90-day exposure period urine and feces were collected daily at 24-hour intervals from cach animal. The animals were placed in amnedtafbeocleisswmacsadgeoscufmoer nctoleldecatlioonngowfiftehcetsheantodtaulrivnoe.luTmheeofexuarcitnetiombetapienreido.doUfricnoellaencdtifoenocefsuwreirnee stored frozen. Blood was also collected for analysis at 3,7, 12, 19, 26, 36, 50, 71, and 92 days - w`peorsetdsoascirnigfifcoerdbaottthhemaelned aonfdthfeemtahlreeea-nmiomnatlhs roefceoavcehrydpoesreiogdr.ouTphaencdolslteocrteeddfbrlozoeond., uArniniem,aalnsd feces may be evaluated in the future for the test substance and/or possible metabolites. data will be reported separately. Resulting R. Anatomic Pathology -- Rats Designated for Subchronic Toxicity and Recovery Affetmealreasp,prreosxpiemcatitveellyy)9,0gdraoyusposfofex1p0omsaurlee 1a0ndthe10tefstemsaulbestraatnscefr(toemsttdheay0s, 9215,a1n0d0,93anfdor males and 21500fmemga/lkeg/rdatasyfgrroomup0sawnedr2e5s0acmrgi/fikcge/ddaanydgnreocurpospswieedr.e sAacdrdiiftiicoendaalngdronuecprsoopfsi1c0dmaaplperoaxnidmately ofnreommoalnltghroaufpesrdtehseilgansatteexdpfoosrutrhee(ttehsrtedea-myon12t5h).recInovaedrdyitpieorni,ogdrwoeurpse osafc5rimfiacleedaanndd Snefcermoaplseierdatosn tdeasytsdaarye [r8e1f.errIendtthoeadsistchues9s0io-ndaoyfpeaxtphoosluorgeygrfoiunpdsin.gsa,ndgrgoruopuspssascarcirfiifciecdedafotenrtaepstprdoaxyisma1t2e5lyan9d0 181 are referred to as one-month and three-month recovery groups, respectively. sRaactrsifiscceh.edTuhleedorfodrersoacfrisfaiccreifwiecreefofrasstcehdeodvuelrendidgehattohns wtheereafrtaenrndooomn abemfoonrge talhleitrrsecathmeednutlegdroups. Rats were euthanatized by carbon dioxide anesthesia were performed on all male and female rats and exsanguination. Gross examinations `Company Sanitized: Does not contain TSCA CB] -- a -- - 9H0-2-4D5a1y6;GavSaugbeehSrtoundiyc TinoxRiactistywith One-Generation Reproduction Evaluations DuPont-5386 - `The following tissues were sacrificed by design, or rats collected that were from 90-day found dead oerxapcocsiudreentaanldlyokniel-lemdonth recovery group rats Digestive System liver esophagus sdtuoomdaecnhum jejunum ileum cecum creocltoumn salivary glands pancreas Urinary System Kidneys urinary bladder Cardiovascular System heart aorta Hemsaptloepeonietic System tmhaynmduisbular lymph node `bmoenseenmtaerrircowl'ymph node EndopcirtuiintaerSyygsltaenmd thyroid gland parathyroid glands adrenal glands Musculoskeletal System skeletal muscle sftemeumrukmnee joint* mandible RepMroadluective System testes epididymides prostate Fesmeamlineal vesicles ovaries uterus `mammary gland Respiratory System lungs Nervous System brain (including cerebrum, Miscellaneous skin ntorascehea spicnearlecbeolrldu(m3, lmeevedlusl:lac/eprovnicsa)l, egryoesss(oibnscelruvdaitnigoonpstic nerve) - larynx `mid-thoracic, lumbar) pharynx sciatic nerve a. oBtohtehrfpermoucresksneedeajsodientsscrwibeerd abekleonw:fom 90-day exposure ats. One femurkncejoint was frozen and the b. Tmahnedimbalnediwbalse wfraoszeankaenndftrhoemot9h0e-rdhaaylfepxrpoocseusrseeadndasodnees-cmroinbtedh breelcoowv.ery animals. One-hoaflthfe . Bone marrow was collcted with the femur and sternum, "liTvheer,foklildonweyisn,g tthiyssruoeisdwgelraned,conlolseec,tetdesftreso,matnhdrefaet-m(oanptphrorxeicmoavteerlyyg1rogurapmr)a.tsTshaceritfesitceesd,bfyatdaensdig portions of tissues may the be liver and evaluated Kidney in the were future placed in for total plastic freezer fluorine levels bags and stored frozen; to study the distribution these of the test substance. Resulting data will be reported separately. `Tahned tfhoelloonwei-nmgotnitshsureescwoevreerywgerioguphse:d flriovemr,raktisdnseacyrsi,fiacderdenbayl dgelsaingdsn,inbrtahien,9s0p-ldeaeyn,extphoysmuurse, ghreoaurtp,. owveairgihets',bruateirnusw,eicgphitdirdaytmioisdewse,reancdaltceuslteast.ed.OrTghaen twheyirgohitd/fgilnaanldb(oadfyterwefiigxahttioann)dwoarsgaanlso weighed dinestihgenPayfaedrultthsr.eeLmivoenrt,hksidrneecyosv,ertyhywreoridegwleaingdh(eadfiaerndfioxragtiaonn)w,eiagnhdt/tfeisntaels bfroodm rwaetsigsahcrriaftiicoesdwbeyre calculated. Organ weight'brain weight ratios were not determined for three-month sacrifice rai. _ aGprporsosprlieastieon(sc.wgh.,icflhuiwdearcecudmiualgantoisoend,artunffelcerdopfsury, amnidssfionrgwahniacthommiiccrpoasrctos)piwcereexagmeinneartaliloyn nwoats not `Contpany Sanitzed. Does notcontain TSCA CBI -- -- - 29H0-02-D4D5a1y6:GGiavSgaubgecehSSrttoaunddiyyciTinnoRxRaiacttiestwywiitthhOOnnee-GGeenneerraatiioonnRReepprroodduuccttiioonnBEvvaalluuaatiioonnss DDuuPPoonntt:55338866 = c(oel.lge.ctoesdt.eoaGrtrhorsistisl,espioodnsodfeorrmwahiitcihs,acmhircornoisccdoeprimcatdiitaigsnoosfitshewotauill,dunroitnabrey caadldciutliiv,eand deformity of the teeth, toe, tail, or pina) were saved but were generally nol processed formicroscopic evaluation. Testes, epididymides, and eyes were fixed in Bouin's solution. All other tissues were fixed in t1h0i%cknneeustsroalf$bumfifcerroemdeftoerrmsa,lisnt.ainPerdocweistshehdetmiastsouexsylwienreanedmbcoesdidne(dHi&nE)pa,raafnfdine, xcautmianteadnominal microscopically. A25l0cmogl/lekcgt/eddatyisrastuse,safnrdomallexfpoousnudredegardouopr arcatcsidseanctrailfliycekdilolnedtersattsdawyesre91p/r9o3cefsrsoemdcaonndtrroelceainvded a pfurlolcheisssteodpaftrhoomlo2g5icaalndex1a0m0inmagt/iokng./daLyiv9e0r,-dkaiydneexypso,stuhryerogirdouglparnadt,s naonsde,farnodm omnaen-dimbolnethwerreecovery rfaetms.aleLsivsearc,rkiifdicneedysa,fttehrytrhoeidthgrleaned-,moanntdhnroesceovferroympmeariloedswaenrdetphyrroociedssgeldanfdroamndalnlogsreoufprso.m Tissues were microscopically examined in descending order ofdose until a no-cflect level was reached. S. Reproductive Assessment I. Breeding - Afier approximately 10 weeksof exposure (0 the test substance, on test day 74, cach female was continually level in the housed on a male's cage. 1:1 On basis witha randomly selected maleofthe same dose concentration the day copulation was confirmed, the female was transferred back otobsienrdvievidd(uadlesciaggneatheodusaisndg.ay M0aotfignegstpaatiirosn)w,eroer ucnothiol2usewdeeukntsileleavpisedde.nceTohfecoppruelseantcieoonfwaans intravaginal or extruded copulation plug was considered evidenceofcopulation. 2. Estrous Cycle Evaluation eVsatgrionuaslcyscmlee.arsVawgeirnealcoslmleecatresd wfreorm caollllPe,ctfeedmdaalielyrabtesgiinnonridnegr3towedeetkesrpmriinoer tthoemsattaignegs,oafntdhe continuing until copulation was confirmed, or the cohabitation period ended. Vaginal smears were also collected determine the stageofestrous cycle. from all Py This data parental female is not presented rats at in the the time of sacrifice to report but is included in the study records. 3. Gestation Procedures aFtetmhaeleenrdaotsftwhereecothraanbsifteartrieodntpoeproiloydcfaorrbofneamtaeleparantss (wointhdoauyt 2e0viodfegnecsetaotficoonpfuolratmiaotn)e,d afnedmawleerseor observed at least twice daily for signsofdelivery and pups. `Company Sanitized. Docs rot contain TSCA CBI = -- -- 9102-4D5a1y6:GavSaugbcehSrtoundiyc iTnoxRictistywithOneGeneration Reproduction Evalutions Dupont386 - 4. Lactation Procedures "pTehreiodda,ypwuphsenwedreelivinedriyvwidausalcloymhpalnedtleewdaasnddeesxiagmnaitneedddfaoyr 0abpnoosrtmpaalrtbuemh.avAitorcaacnhdeaxpapmeianraatncieo;n any dead, missing, or abnormal pups were recorded. a DayO Postpartum Live and dead pups in each litter were counted as soon as possible afer delivery was completed. Live pups in cach litter were individually weighed. b. Day Postpartum Litters were culled randomlyto 8 (4/sex when possible). Extra pups were euthanized (by decapitation) and discarded without pathological examination. Litters of8 pups or less were not reduced. Litter counts were recorded prior 0 and afer culling, and individual pup weights were recorded prior to culling. c. Days7and 14 Postpartum Pups in each liter were counted by sex and individually weighed. 4. Day?! Postpartum (Weaning) - Psaucprsifiinceedacahnlditgtreorsswleyreexcaomuinnteedd bony speoxstannatdalinddaiyvi2d1u)a.llyRawnediogmheldy (s3eolefc4t/esdexw/elainttleirngwsere then (onelsex/lter) were placed in individual cages, monitored for attainmentof developmental landmarks. bAetheaavcihoreaxnadmianpapteiaornanpceer;ioadn,yofdfesapdr,inmgiswseirneg,iondriavbidnuoarlmlaylhapnudplsedwearnedreecxoarmdiedn.ed for abnormal 5. Post Weaning and Developmental Landmarks Dmoenvietloorpemdenotnala dlaainldymbaarskiss iunnttilhecrFi,tegreinoenrawtaisonacmhaileeveadn.dOfnecmaeldeervaetslo(pomneen/tsaelnllitaenrd)mawrekrecriterion was achieved, the animals were weighed. Body weight and food consumption were also determined weekly until postnatal day S6 (test day 36). a Vaginal Patency Female rats were examined beginning on postpartumday 21. b. Preputial Separation Male rats were examined beginning on postpartum day 35. Company Sanitizad. Does 10t contain TSCA CBI -- --- 91.02D4a51y6:GavSaugbcehSrtoundiyc TinoxRiactistywithOne-Generation Reproduction Ealusions Dupont-5386 T. Anatomical Pathology - Rats Designated for Reproductive Evaluations LP Adulls Aulnlderratwsenftouandgrdoesasda,nadccmiidcernotaslcloypikcilelevda,luoartisoanc.rifTihceed tiinsseuxeisrceomlilsepcrtieodraore tthhee csoahmabeitaasttihoonspeefroirod ats designated for the 90-day exposure period. sAuLbPje,ctpeadretnotaglrorsastspawtehroelosgaiccrailfiecxeadmbiynactairobno,nidnicolxuiddiengastphheyfxeimaatlieosn athnadt eixesdanagnuidntahtoisoen,foarnwdhich meaxtaimnigneddidfnorotthreespurltesiennacepraondducntuimobnoerfoofffismpprilnagn.tatTihoen uteriofall sites cohabited females were eSvpaelruamtepda.raTmheeterrisghftocratuhdeafierpstid1i0dyoumtisofwa2s0 wPe;igmhaelde.anSipmaelrsmiwacsaccholtlreecattemdefnrtogmrothueprwiegrhtecauda ewpeirdeidfyrmoizesnainndlpieqruicdenntitmrootgielnitaynadnsdtomroerdpbheotlwoegeynw--a6s5daentedrm~i8n5ed.C The lef epididymis and for sperm and spermatid tests counts, respectively. fixative, The right testis and epididymis from these 10 ats were saved and placed in "The following table lst issues that were collected: - "Tissues Collected from Py Adults Male Female Both Sexes `TEepsitdesi/dyTemsitdiess"/Epididymis' OvUtaerriuess(with oviducts) TGhryorsosiOdbsGelravnadt"ions Prostate Seminal Vesicles Vagina Pituitary Gland Coagulating Gland a ToatshtretsiTsessueis formalin, (aenpdroediudciidvyemidaensdineopnidtiedpyrmoidsuccoilvleec)tceodlfeotemdmfaloemrmataslewesrnedlfacaedlinatBsowwelrse psoaacteiodn.in All b GThryorsosisdiloanndsobwseerrevewdeiatghneedcrfopesy vfaortiwohni.ch hisopathlogy was not propriate o would not be adiive were generally not collected. 2 Offspring Offspring evaluation. that were found dead during the lactation period underwenat gross pathological 3 F Weanlings i cTahrrbeoenFydiwoexaindleiansgpsh/ysxeinaltiitoenra(nrdanudnodmelrywesnetleactgerd)o,sslpiattehsoilzoegipcearlmietvtailnuga,tiwoenreonsapcorsitfniacteadlbdyay 21. Gross lesions were preserved. ompany Sanitzed. Does iocontain TSCA Ca - 910.2-6D5a1y6:GavSaugbcehSvtoundiyc TinoxRiactistywith One-Generation Reproduction Evaluations Dubont5386 - 4. Fy Adults All Fy generation rats were sacrificed by carbon dioxide asphyxiation and exsanguination, and subjected to a gross pathological examination. Selected tissues and gross lesions were preserved. `The following table lists tissues that were collectedand/orweighed: Male Testes EpPriodsitadtyemides Seminal Vesicles Coagulating Gland _-- Male Tissues Collected fromF Adults Female Both Sexes Ovaries VUtaegriunsa(with oviducts) Thyroid Gland GPirtousistaOrybservations Liver Kidney New `Tissues Weighed from F Adults Female Both Sexes Testes Epididymides Uterus (with oviducts and cervix) Thyroid Gland (after fixation) Liver - Seminal Vesicles (with coagulating glands) Brain Kidney Prostate Processed tissuesforhistopathological examination were embedded in paraffin, cut at a nominal thickness of5 micrometers, and stained with hematoxylin and eosin (H&E). Histopathological `examination of reproductive organs was conducted only for P, males and females with impaired reproductive performance. Selected gross lesions were evaluated microscopically. Gross lesions observed at necropsy for which histopathology was not appropriateorwould not be additive were generally not collected. U. Biochemical Measurements Following 10 or approximately 90 daysoftest substance administration, after 36 days on recovery,orafter 92 days on recovery (control and high-dose only), five rats from cach group designated for biochemical evaluation were weighed and then sacrificed by CO; anesthesia and exsanguination. Rats were fasted overnight on the afternoon before their sacrifice. The livers were removed, weighed, and then homogenized (1 gram tissuc/4 mL buffer). Hepatic peroxisomes were prepared using differential centrifugation. The resulting peroxisomal pellets were resuspended in the homogenization buffer, aliquoted, and stored between -65 and -85C until analyzed for peroxisomal B-oxidation activity. The peroxisomal suspensions were diluted _ toa protein concentrationofapproximately 0.25 mg/mL. Peroxisomal B-oxidation activity was - `Company Sanitized. Does not contain TSCA CB 9H0-:24D5a1y6G:avSaugbesSontiycTion rRiact with OneGeneration Reproduction xaos Duron - determined using ['"C]palmitoyl CoA as the substrate.) The protein content ofthe peroxisomes `was determined before and after analysis by the Biorad method. V. Statistical Analyses Except for Bartlett's test (p <0.005), significancewas judged at p < 0.05. were performed on the data for each gender. Separate analyses Parmer BBooddyy WWeeiigghht Gin Primm Tes Ton orkafend"o ||aSfEenhpqiurmJeon:clikersenptTsco"osta|rsriegleniimlainamtryae7s ox is donghe"ere Tem | iise comparison OFFroagoeadnECfWofesiiwcigaephnscyien FLmH aevrretneeo 's testg for | iODnienm-ewcrasyeaenasflo"ylslioswoefd with|wKlrutwskall-wWiahllDsutensst" Mtoe aie revern'res orng | Repcoamesrurest | Soerqueentoialmppliicattion-s Stair Wik ef" 0 Coy commas | vend st -- Grip Strength Fe con eeances|OVranncee! fosllowoedf with | RoulslkawedWwailtihsDuns Clic Paology* Le omgoensy ly a |D[uOvnrniectnwt'cyseaterslato"ywieodl ith|| tKleosatvTMleld wwailhlDsaents" orn a Dunnett's test" testTM Sncn urvival of Ciel | InOcbDiessdecerrnvicapottiifvoFenOsPRarameters None || Cochran-Armitage test for trend" I- Biochemical Messrements | Nore GA rey myEvRara alonewid necdns rsa [rome None 1 4 PShaiiernwiiSscenhcoimpaWriilskonsstndwsasootiastiedgpnrilnmibrurLyeevesne'ersstaways csiognndini, et or ack o rnd was obs versionofDunes st CTwWashsendaaynadidvildoucakl(o1b0s-emrivnauttieonEvPaOsCrHe)cwoarsduededbainpeoast hnme1sucreritovrisl,e, clclatons were performed opernfoarmeld wrietchortdtedbvallu.iFnordample, bili is reported <0.. 0.03 was uedfot ay ations BIfotnhieeimnocnitdecncoe wmassnowtessigwnifdicant, but a significant lackoffit occurred, then Fisher's Exact test" with a CompanySantzed. Does not contain TSCA CB) --- 1502-4D5a1y6GvSaugbeelSvotniycTionxRisc with One Generation Reprdicion Evaunions Duron 5386 `FyThaedfuoltl.lowing table lists the indicesof reproductive function that were calculated for the Py and r Parameter Body Weight Body Weight Gain GOFerosgotadantCiWooennisLguehmntpgttihon Implanation Site Numbers IMmipclaantNatiaonbEofffeicPiruenscyPer Be emis Prcotal Inirvl VESaspgteirronmuaslPCaPyrecmlreecteyLren.gth Preputal Separation Preliminary Test Test for lack of trend TrelmMentahordyoftestSs at|seWaplrlAiTmiInary G0 Sein not significant application"ofthe Jonckheere-Terpstra trend test" significant | Preliminary tests for | pairwise comparison gg Shupro-Wilktent for normality" | | One-way analysis of |Kruskal Wallis st |Votan followed |Pfollowweitdh umnet Food Efficiency I Nore One-way analysis ofvariance" followed with Dunnett's test" || IantcOiibdnseegnrcvIeanotdfieCoxlnisnical V|iGFaeberistlitilitityoynIInnIddnedexexx None Lactation Index | Cochran-Armitage test for trend |( V(iCaonvarPiuapteWse:ieghrs sice, Linearconisor |p SosxexRraattiioo) None least squares means" Dans et + be PSaiirwSrisheoacoimpWarkonss anad aooctiseidgnrimnbautnLeveesne'wesretowlasyscoindgucnteid,1ohusstt ForioanckooffDorennedtwse st od BIfothneiinnciidecnocneewcaisonnowtasrigmniefdicant, but a significant lackoffit occurred, then Fisher's Exact test" with a Company Sanitzsd. Docsnotcontain TSCA CB _-- 9H0-2-4D5a1y6:GavSaugbcehSrtoundiyc iTnoxRiactistywith OneGeneration Reproduction Evaluations DuPont5386 ~~ sFiogrniefaicchanptadroasmee-treerspaonnasleyzweadswidetthecatterd,enddatteastf,rtohme ttehsettwoapsdaopspelgierdoutpo wtheeredaetxacsleuqdueedntaianldlyt.heItfeast repeated until no significant trend was detected." For litter parameters, the proportion of affected fetuses per liter or the litter mean was used as the experimental unit for statistical evaluation.) Where the data are tied and the standard large sample versionof Jonckheere's test is 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 sampleofthe test substance was collected for archive purposes and retained at Haskell Laboratory. Specimens (ifapplicable), raw data, and the final report will be retained at Haskell LDaebloarwaatroer.y,CNlienwiacralk,paDtehloalwoagrye,sloirdeast aInrdonrMaowudnattaaiwnilRlebceorrdestaMianendagatemHeasnkte,llWiLlambionrgattoorny,, Newark, Jackson Delaware. Characterization data will Laboratories, Deepwater, New Jersey. be stored at Regional Analytical Services (RAS), -- Sompany Sanitized. Docs notcontain TSCA CBI ow --- 9H0.2-4D5a1y6:GavSaugbeehrSotnuidcy TinoRxiactistwyith One-Generation Reproduction Evalustions DuPont5386 -- RESULTS AND DISCUSSION `Company Sanitized. Does not contain TSCA CBI -- 209H:0.2-D4Du5a1yy6G:GaaSvvuaabggeeehSrSotunuiddcyiTinnorRRiacaitttsy wwiitthhOOnnee. GGeenneerraattiioonn RReepprroodduuccttiioonnEEvvaalluuaattiioonnss - ANALYTICAL EVALUATIONS DDuuPpoonntt55338866 A. Test Substance Stability Analysesofbulk samplesofH-24516 near the beginning and endof the study for stability indicated that the test substance was stable for the durationofthe study. The average percent of H-24516 in the sample submitted near the beginningof the study (test day 7) and analyzed (test day 23) was `The average percent of H-2456in the sample submitted at theeng of the study (fest day90) and analyzed (test day 105) we This work cgn be found i in valies 2b4e5t1w6e}e the sponsor 'reeppourritteyd wpuarsitryepaorntedd thbeyextpheerismpeonntsaolr dtaotbae represent anaileytdiicfaflerences variability and not instability of the test substance. B. Chromatography H-24516 eluted approximately from the GC column as resolved peaks with 6.0 minutes. For the purposeof quantitation, retention resolved times peaks from at {be 2.9 minutes retention ti to ofapproximately 3.5, 4.17, and 4.77 minutes were used. The internal stan EE: as a resolved peak at approximately 3.99 minutes." RepresentativeUC chromatograms are shown in Appendix A, Figures 2(-a). Test substance was not detected in the 0 mg/mLcontrol, C. Homogeneity, Concentration Verification and Stability Samples for Initial Mixing Procedures and Concentrations Based on Dose Volume of 10 mL/kg (Test Day 0 to Test Day 4l) Analytical results from dosing suspensions collected on test day 0 and test day 6 and analyzed for homogencity/concentration verification and 5-hour room temperature stability are shown in Table 1 and Appendix A, TableI. The following table summarizes the results for homogeneity, concentration verification and stability analyses. PrepDaartaetion NomimnaLl | TeaDay0 205 0 23 Measumrge/dmlT. MB NDF 829370,214072214400 ususBs Me%anNo(mTinMaBl) CV0.0%SuNboimliinya'l . -~ 91560 23 08849 | 1000 7 ses | || Temas 00 9269No5892 96 e2s ws || a SVaiemapnlerseahellsdorhohuersanaatlrysoiosmoftetmpeefroatur(e1)., dle (V0 a0 bio (3) samples Denote none decid. Company Saniized. Doss nat contain TSCA CB EE -- H5-02:4D5a1y6:GavSaubgcehSrtoundiyc iTnorRiactistywithOne-Generation Reproduction Evaluations DuPont5386 - `The data for samples collected on test day 0 indicates that the test substance was homogeneously mixed in the vehicle except for the 10 mg/mL. level (C.V. = 24). The test substance was at the targeted concentration in the samples (= 11%of nominal) and was stable in the vehicle when held 5 hours at room temperature. The 10 mg/mL. level samples were collected again on test day 610 show that the mixing and the room temperature stability was acceptable. The data indicated that the test substance was homogeneously mixed in the vehicle (C.V. = 2%), at the targeted concentration in the samples (+ 6.4% ofnominal) and stable in the vehicle when held 5 hours at room temperature. "The lower than expected result for the 2.5 mg/mL (82.4% of nominal) for the S-hour sample was within the targeted rangeofthe study (& 20%of nominal) and is due to sampling and analytical variabilityofthe method and not stabilityofthe test material in the vehicle. This was concluded based on the data from the remainderofthe levels in this study, which were stable for the S-hour room temperature period. Test substance was not found in the 0 mg/mL samples D.Mixingand Stability Study for Change in Frequency of Dosing Preparation (2 times/week) and Dose Volume Change (5 mL/Kg to 7.5 mL/Kg) "This work was done prior to initiating any mixing or storage condition changes in the study. ~ Analytical results from dosing suspensions collected for the special mixing study and analyzed to verify homogeneity and/or concentration with stability are shown in Table 1 and Appendix A, Table Il `Company Sanitized. Does not contain TSCA C -- = -- 9H0.2-4D5a1y6:GaSvuabgcehrSotnuidyc TinoxRicaittsywith One-Generation Reproduction Ealuations DuPont-5386 - The following table summarizes the results for homogeneity/concentration verification and stability analyses. DSoasmeplVeolTyupmee. S0mLig Homogeneity" 2-Day ReSftraibgielriatyted' 3-Day Refrigerated' 4-Day Refrigerated Nomgiinla.l Measgurned 0 Nb: 500 20 as425.439 199,177,186 so $34,526,540 5500 4a7m4a,4z4e8 50 a Mean 4 Nominal = 878 935 1066 995242 96.1 cv8. )__%suNobmiilnayl - ~ 3 920 6 860 ' 9%.6 042 =- -- 71 2-Day Refigerated 2 187, 180 D3-aDayy RReeffrriiggeerraatteedd'" 2 2 393,19.6 106 91.5 3 ~ 1470 a -- 075 - 82 23--DDaayy RReeffrriiggeerraatteedd" 500 441635,,448649 4-Day Refrigerated' 50 9 9on5s5 21 -- | 078 -- 057 | - 2.5 mig Homogeneity 0 pf > -- " Stability AB 2825426 sit o 9 4-Day Refrigerated a 294,288 84 | 83 a SMaemapnlersesuhltesdfSorhothuersaantaroloymosfitimhpseetroapu(rTe), middle (M) and bot (B) samples. 0 DMeenaontersesnounseodfdeutepcltiecd.ate concentration verification samples, Othreigoirniaglinaanlalsyasmipslneotrerpoerptoerdt.ed because ofapparent aliquot error. Mean result ofduplicate re-analysis (12) of Msteabainlitrye.sultofsingle sumple for concentration verification aanindgle sample for -hous room temperature & sMaebainlye . os fdupll icate samples fo concentration verification ansindgle samplefo S-hour oom temperature `The data for samples collected initially (5.0 mL/kg dose volume change) indicate that the test snuobmsitnaanlc)eawnadswhaosmsotgaebnleeoiunstlhye vmeihxiecldeiwnhtehenvheehlidcl4e,daaysthreeftrairggeertaetdedcofnoclelnotwreadtiboyn $(+ho1u2r.s2a%torfoom t2e0mpmegra/tmurLe.levTelhe(1h4i7g.he0r%tohfannoemxipneaclt,eCd.rVe.su=lt4f7o%r)thein3di-cDaatyesrtehfartigtehreatteedstssaumbpslteasncaet twhaes not pbreocpaeursley druep-ldiicsapteersseadmpinletshewveerheiccloellaefceterdraefnidigaenraaltiyoznedanwditbhefoonree osfamtphleinsga.mplTehsishawvaisngcoanhcilguhdeerd - sthuapnpoerxtpeedcttehed druepslulitca(t3e9.r3epmogrt/emdLa)nailnystihse.anTahliyssisd.ataTahleosngamwpilteh wthaesrreesaulntaslyfzreodmatnhde tlhasetrseasumlptlsing time at this level (4-day refrigerated/97.8%of nominal) supporied this conclusion. --_-- `Company Sanitized. Does not contain TSCA CBI 910:"24D5a1y6G:avSaugbechSrtoundiy TinoxRiactistywithOneGeneration Reproduction Evaluators Duponc5386 a s"Tuhbesidaantcaefworassahmopmloesgecnoelloeucstleyd mfoirxtehde i7n.5thmeLvekhgicdleosfeorvtohleu3m.e33chmagn/gmeL.indliecvealte thatthe test (C.V.=6) was lower and stable in the vehicle than expected (81.1%of when held 5 hours a room nominal) but was probably temperature. duc to initial The concentration samplingof the mixture before adequate mixing. The results from the 4-day refrigerated samples from the same perledpa4radtaiyosn rienfdriicgaetreadtetdhefomaltleorwieadlbwya$s hatoutrhse attarrgoetoemdtleemvpeelr(a2tu1re2..6% of nominal) and stable when "The results from this mixing and stability study indicated that the mixing time for preparation of the suspensions before use with the animals would have to be monitored for both the initial sprheopwanrat{0iobneasnadbltheeirnet-hdeisvpeehrisciloenoofvterhethseucsopnecnesnitornastiaofntrrarnegfreigneereatdieodn.forThtheetdesotsesuvbostlaunmcee cwhaasnge wanedeku)nodferthtehedostsoirnaggesucsopnednistiioonnss.for the change in frequency ofpreparation (3 or4 days twice a CE.oncHeonmtoragteinoenitCyhaanngdeCoBnacseendtroantiDoonseVeVroifliucmateioofn S7a.5mpmlge/skfgo(rTFeisntalDaMyix4i2n)g Procedures and fAonralhyotmiocaglenrcesiutlytsafnrdoomrdcoosnicnegntsruastpieonnsiveornisficcoaltlieocntaerdeosnhtoeswtndianyT4a9blaend1 taenstddAapype91ndainxdAa,nalyzed Table IIL nn "The following table summarizes the results or homogeneity and concentration verification analyses. PrepDauraetion NmompimnLal Measumrge/dmlT.,MB* Me%anNo(miTnMaBl) C_V(%). Test Day 49. 3303 271,N2D99.34 9-13 12 | 1333 108,127,128 908 9 3033 310,324,334 98 4 TestDayol 0 NDP -- -- 333 305,300,301 90.7 1 133 28122 98 3 333 327.323 97.5 ! b3 DVeanontersesnuosnTodeheeda.naly ote top (1. middle (9) and tors (8) saris. Duplicate samples submited. C.V. forthe duplicate samples used 10 confem uniformityofmire "The data for samples collected on test day 49 indicates that the test substance was homogencously mixed in the vehicle except for the 3.33 mg/m level (C.V. = 12). The test substance was at the targeted concentration in the samples (+ 9.2%ofnominal). - "The data for samples collected on test day 91 show that the 3.33 mg/m. level was homogeneously mixed, indicated tht he fst substance was properly mixed in the vehicle = `Company Sanitized. Doos nt contain TSCA ca 20012--4DD5aa1yy6G:GiaSvvuaabggceehSrStotunudidcyyiTinnoRxRiaacttisstwywiitthhOOnnee GGeenneerraattiioonnRReepprroodduuccttiioonnEEvvaalluuaattiioonnss DDuuPPoonntt:55338866 = (thCe.dVu.p=li1ca%t)eacnodncaetntthreattiaorngevteerdifciocnacteinontrsaatmipolneisn ftohretshaemrpelmeasi(ni9n.g3le%voelfsnionmdiincaalt)e.d tThahtetdhaettaesftor substance was respectively). at the targeted level (& 6.2%of nominal) and mixed properly (C.V.'s = 3 and 1%, Test substance was not found in the 0 mg/mL samples F. Analytical Conclusions Dinatthaefvreohmictlheewaanaslymsiixsoefdthhoemosgaemnpcloeussalty,thewaisniattiatthieonotfartgheteedstluedveylisnadincdatweatshasttatbhleetfeosrt s5uhbostuarnscea:t room temperature. Dteasttasufborsttahnecaenainlytshiesvoefhitchleeswaamsplmeisxaefdterhotmheogmeinxeionugsalnydadnodseatvtohleutmaergcehteadngleevselisn.diAclaltesdtatbhialtittyhe cveohnidcilteiohnasdwbeereenasddhroewsnsetdo ibnetshteabaldediatfitoenra4l dsaaybsioliftrye/fmriixgienrgatsitoundfyoalnldowtehde bteystSshuobusrtsanacterionotmhe tneecmepsesraartyurfeorovteher itnhieticaolnmciexntirnagtiaonndrraendgies.peTrshieondoaftatahlestoesitndsiucbastteadntcheatincotnhtervoelhliecdlmeiaxfitenrg was refrigeration Test substance was not found in the 0 mg/mL samples. Analysisofthe test H-24516 was stable substance near the during the study. beginning and the end of the study indicates that the _-- Company Sanitized. Does otcontain TSCA CBI w 9H0.-24D5a1y6G:avSaugbeehvSotnuidcy TinoxRiactistywith One-Generation Reproduction Evaluations DuPont5386 SUBCHRONIC TOXICITY EVALUATIONS IN-LIFE TOXICOLOGY A. Dosage Data (Tables 2-3, Appendix B) Rats were dosed with suspensions of H-24516 in 0.5% aqueous methylcellulose, prepared at concentrationsof0, 2.5, 10, and 25 mg/ml, designed to deliver the targeted doseoftest substance ata dosing volume of 10 ml/kg body weight. However, in order to administer a dose volume under mL to comply with animal welfare guidelines, the dosing volume for male and female rats was decreased from 10mL/kg to 7.5 mL/kg and the suspension concentrations were increased 103.33, 13.33, and 33.33 mg/mL on test day 38. The quantityof H-24516 administered to cach rat was calculated, based on the most recent body weight for cach rat, and subsequently rounded by a computer program. `The rangeofmeandailydose volumes administered to male rats was 2.5-4.6 mL for the control group, 2.5-4.6 mL for the 25 mg/kg/day group, 2.5-4.6 mL for the 100 mg/kg/day group, and 2.5.4.6 mL for the 250 mg/kg/day group. The rangeof mean daily dose volumes administered to female rats was 1.9-2.8 mL for the control group, 1.9-2.8 mL for the 25 mg/kg/day group, 1.9- - 2.6 mL for the 100 mg/kg/day group, and 1.9-2.8 mL for the 250 mg/kg/day group. B. Mean Body Weights and Body Weight Gains (Tables 4-7, Figures 1-2, Appendices C-D) Statistically significant decrements in body weight compared to control were observed in males inthe 100 mg/kg/day dose group afler day 77 (7-8%) and in the 250 mg/kg/day group after test day 56 (6-14%). Statistically significant decrements in body weight in females compared to control were observed in the 100 mg/kg/day dose group after day 77 (67%) and in the 250 mg/kg/day group after test day 56 (6-12%). These weight gain differences appear to be directly related to test-substance induced adverse effects to the teeth (see Section C and Anatomic Pathology Report) and subsequent decreases in food consumption in the 100 mg/kg/day female and 250 mg/kg/day male and female groups (see Section C). `The 250 mg/kg/day male group had significantly lower mean body weight gains compared to control over the courseofthe study. Significantly lower mean body weight gains were observed for the 100 mg/kg/day male group during the 35-42 and 49-56 day intervals. A significantly Tower mean body weight gain also occurred for the 25 mg/kg/day male group during the 35-42 day interval. The mean body weight gainof the 250 mg/kg/day male group was significantly higher than the mean weight gainofmale controls during the first weekofthe study and during the 77-84 and 84-90 day intervals. The increased mean body weight gains observed after test day 77 appear to be associated with an increase in food consumption and food efficiency after both - the male and female rats in the 250 mg/kg/day dosage group were placed on ground chow becauseof adverse effects to the teeth. Overall (0-90 day interval), significantly lower mean `Company Sanitized. Doss nt contain TSCA CBI = H9-02.4D5a1y6:GaSvuabgeehrSotnuidcy TinoxRicaittsywith OnGeeneration Reproduction Evalustions DuPont5386 - body weight gains of 13% and 16% compared to control occurred in the 100 and 250 mg/kg/day `male groups. This reduction in body weight gain was considered test substance-related and toxicologically significant. `The 250 mg/kg/day female group had significantly lower mean body weight gains compared to the control group over the courseof the studs. Significantly lower mean body weight gains also occurred for the 100 mg/kg/day female group during the 28-35 day interval and for both the 25 and 100 mg/kg/day groups during the 42-49 day interval. The mean body weight gain of the 250 ghkg/day group was significantly higher than control during the second weekof the study and during the 77-84 day interval. As with males, the increased body weight gain occurring after test day 77 appears to be associated with an increase in food consumption and food efficiency (see Section B) after the animals were placed on ground chow. Overall (0-91 day interval), significantly lower mean body weight gains of 12% occurred in both the 100 and 250 mg/kg/day female groups. The mean body weight and body weight gain decrements observed for the 100 gkg/day and 250 mg/kg/day female groups, however, were of small magnitude and were associated with decreased food consumption but not with any alterations in food efficiency (see Section B). Therefore, the statistically significant mean body weight and body weight gain decrements for the 100 mg/kg/day and 250 mg/kg/day females were considered to be test substance-related but not toxicologically significant. Furthermore, the decrements in body weight parameters observed for both males and females appear to be related to test substanceinduced adverse effects t0 the teeth (see Section D and Pathology Section) and subsequent decreased abilityofthe animals 10 eat the pelleted chow. Following a one-month recovery period, the mean body weight and body weight gain ofboth male and female rats that received 250 mg/kg/day approached control. For the overall one-month recovery period (90-119 day interval), a statistically significant decrement in mean body weight gain occurred for the 100 mg/kg/day group. The lower mean body weight gain did not oceur in a dose-dependent manner and appeared to be due to test substance-induced adverse effects to the teeth anda subsequent large decrease in food consumption for one male in the 100 mg/kg/day group. Therefore, this effect was not considered toxicologically significant. Following the threemonth recovery period, the mean body weight (females only) and body weight gain ofboth males and females exceeded control levels C. Food Consumption and Food Efficiency (Tables 8-11, Appendix E) Male rats in the 250 mg/kg/day group had statistically significant and lower food consumption `compared to control over the courseofthe study. Overall (0-90 day interval), a significantly Tower food consumptionof7% compared to control occurred in the 250 mg/kg/day male group. Females in the 100 and 250 mg/kg/day had statistically significant and lower food consumption compared to control over the course of the study. Overall (0-91 day interval), significantly lower food consumptionof 9% and 8% occurred in the 100 and 250 mg/kg/day female groups. However, after the rats received ground chow as a resultof tooth toxicity, their food consumption immediately increased and began to approach or exceed (female 77-84 day interval) control `Company Sanitized. Docs mat eontain TSCA Cal --. 910.2-4D5a1y6:GavSaugbcehSrtoundiyc TinoxRiactistywith OneGeneration Reproduction Evaluations DuPon-5386 --- levels. Test-substance related and statistically significant effects on food consumption were observed in the 100 mg/kg/day female and 250 mg/kg/day male and female groups. Male rats in the 250 mg/kg/day group had significantly lower mean food efficiency compared to control over the courseofthe study except during the first and third week of the study and test days 77-84 and 84-91 in whichsignificantlyhigher food efficiencies were observed. The 100 mg/kg/day male group had significantly lower mean food efficiency during test days 35-42 and 49-56. For the entire study interval, significantly lower food efficienciesof 8% and 9%, respectively, were observed for the 100 and 250 mg/kg/day male groups. With the exceptionofthe first two weeks of the study and test days 77-84 in which a significantly higher mean food efficiency occurred, female rats in the 250 mg/kg/day group had significantly lower mean food efficiency compared to control over the courseofthe study. A significantly lower mean food efficiency was also observed for the 100 mg/kg/day female group during test days 28-35, 42-49, and 49-56, while a significant increase occurred during test days 35-42. During test days 42-49, the 25 mg/kg/day female group had significantly lower mean food efficiency. These differences were not considered to be of toxicological significance as overall mean food efficiencies for est-substance treated female groups were similar to control. "The decreased mean food efficiency in the 250 mg/kg/day male group appears to be directly related to test substance-induced toxicityof the teeth. Following the replacementofpelleted chow with ground chow on test day 77 for the 250 mg/kg/day male and female groups, a significantly higher mean food efficiency was observed for the 77-84 and 84-90 (males only) day - intervals. Nevertheless, based on the parallel reduction in body weight parameters observed in the 100 and 250 mg/kg/day male groups, this reduction in food efficiency is considered to be toxicologically significant. Aftera one-month recovery period, mean food consumption in the 250 mg/kg/day male group was still significantly lower, while mean food efficiency was the same as that observed in control rats. For females, lower food consumption was also observed following the one-month recovery period. For the overall one-month recovery period (90-119 day interval)a statistically significant decrement in mean food efficiency occurred for the 100 mg/kg/day male and female groups. The lower mean food efficiency did not occur in a dose-dependant manner and therefore was not considered to be toxicologically significant. Following three months of recovery, mean food consumption for males and females was similar to control levels, while mean food efficiency for the 250 mg/kg/day males exceeded control levels. D. Clinical Observations, Ophthalmology Evaluations, and Survival (Tables 12-17, Appendix F) A test substance-related, toxicologically significant increase in the incidence ofbroken (males) and absent teeth (males and females) was observed in the 250 mg/kg/day dose group. In addition, there was an increase in tooth clipping required for both males and females in the 250 gkgday dose group. There was also a statistically significant increase compared to control in the incidence of stained red perineum and clear discharge from the mouth in the 250 g/ke/day - male dose group. The increased incidence of stained red perineum and clear discharge from the `mouth was considered to be test substance-related. Company Sanitized. Does sotcontain TSCA CBI 7 9H-02-4D5a1y6:GaSvuabgcehrSotnuidcy iTnoxRicaittsywith One-Generaton Reproduction Evaluations DuPonc5386 ~ No test substance-related ophthalmological signs of toxicity or effects on survival were observed. E. In-Life Toxicology Conclusions Under the conditionsof this study, the no-observed-effect-level (NOEL) for in-lfe toxicology parameters (body weight, body weight gain, food consumption, food efficiency, and clinical signs oftoxicity) was 25 mg/kg/day for males and 100 mg/kg/day for females. NEUROBEHAVIORAL TOXICOLOGY A. Sensory Function Evaluations 1. Forelimb Grip Strength (Table 18-19, Figures 3-4, Appendix G) There were no test substance-related effects or statistically significant differences on forelimb grip strength in males or females administered any dosage of H-24516. Females administered 100 or 250 mg/kg/day had slightly lower (12% and 14% lower than the control value, respectively) forelimb grip strength at week 13, however, a linear dose response-relationship was not present, and the values were within the range of normal variation for this measurement. In addition, the forelimb grip strength in the control group during the recovery evaluation was - similar to the valuesofthe 100 and 250 mg/kg/day female groups during the week 13 evaluation demonstrating the degreeofvariability in this typeof measurement. Therefore, the slightly lower forelimb grip strength in 100 and 250 mg/kg/day females was not considered to be test substance-related. 2. Hindlimb Grip Strength (Table 18-19, Figures 5-6, Appendix G) There were no test substance-related effects or statistically significant differences in hindlimb grip strength for either males or females administered any dosage of H-24516. 3. Sensory Function Observation (Table 20-21, Appendix H) `There were no test substance-related changes in neurobehavioral parameters in males or females administered any dosageof H-24516. B. Motor Activity (Tables 22-25, Figures 7-10, Appendices 1-1) There were no test substance-related effects on duration of movement or number of movements for males or females for any dosage tested. Males assigned to the 100 and 250 mg/kg/day group --- had significantly lower mean durationofmovement during the third 10-minute interval for the baseline evaluation. In addition, mean duration ofmovements was significantly lower for 25, `Company Sanitized. Doesnot contain TSCA CBI - 910.2-4D5a1y6:GaSvuabgcehrSotnuidyc TinoxRiactistywith One-Generation Reproduction Evaluations DuPon5386 - 100, and 250 mg/kg/day males comparedtocontrol during the fourth 10-minute interval ofthe baseline evaluation. However, test substance administration had not been initiated, and therefore, these statistical differences were not considered to be test substance related. Females in the 250 mg/kg/day group had significantly lower total duration of movement and number ofmovements during the recovery evaluation. The total duration of movements for both the control females and 250 mg/kg/day females was lower relative to the baseline and week 13 evaluations. However, the number of movements for both control and the 250 mg/kg/day fomales were within the rangeofbaseline values for females in this study. Since there was no increase or decrease from the rangeofbaseline values with respect to numberofmovements, and since there were no changes in motor activity observed at week 13 or in any other neurobehavioral parameter, the statistically significant differences compared to control were not considered to be test substance related. C. Neurobehavioral Toxicity Conclusions Under the conditions ofthe study, the no-observable-effect level (NOEL) for neurobehavioral parameters was 250 mg/kg/day in males and females, the highest concentration tested. Company Sanitized. Docs not contain TSCA CBI ss 5102:4D5a1y6:GavSaugbcehSrtoundiyc TinoxRiactistywith One-Generaton Reproduction Evaluations DuPont5386 CLINICAL PATHOLOGY A. Hematology/Coagulation (Tables 26-29, Appendix K) Rats dosed with 250 mg/kg/day had minimally decreased RBC mass parameters (RBC, hemoglobin, hematocrit; variable statistical significance) (Clinical Pathology Text Table 1). These decrements were associated with minimally increased RDW in both sexes, anisocytosis, `microcytes, and increased reticulocytes in males, and poikilocytosis in females. Following the approximately one-month recovery period, male ats previously dosed with 250 mg/kg/day stil had minimally to mildly decreased red cell mass parameters, and decreased reticulocytes compared to conirol group rats. Female rats previously dosed with 250 mg/kg/day had red call mass parameters similar to controls by day 125, although MCV, MCH, RDW and reticulocytes were decreased. The minimal red cell effects discussed above are not expected to affect red cell function or the health of the animal. Nevertheless, based on the progressive natureof the effects during treatment and the persistenceofmany effects into the recovery period, the red cell changes noted at 250 mg/kg/day were considered toxicologically adverse. Clinical Pathology Tex! Table | Red cell mass parameters as a percentofcontrol group mean - Parameter |I [ nt M 2e5[r1a 00v[2a 5l T 0]lT | 2e 5Fe[1m0a0]ls es250| CLTT ITT[7 RBC [4Da4y /43[017%0[918%%| ] [05%99%]94%| pm 96% [Day12s | T89%| [Tio1%] ETTIT]] 1 HGB [Day44/45[101% 100%|98%| [96% 98%| 94% 99%| 98% [93%] __|98%|97%| 92% [Da1 yrToaols| HCT [E 4D4ay/45[101%L [100%]98%|[96%|[ 97%T |94T %|| [oDaayytasl91/| 93] 97%|97% J[o9r3%]||96%[9L79o2%m%]| * Statistica significance indicated by bold alcized ype Females dosed with 250 mg/kg/day had shortened APTTs at day 93. This change was not considered to be treatment related because there was no clear dose-related response. Similar APTTs were present in all treated groups. Additionally, shortened coagulation times are not considered adverse; prolonged, rather than shortened, coagulation times are toxicologically. seingdnoifficdaonsti.ngB,eccoaaugsuelatthieoren wpearraementoetrrseawtemreentn-ortelmaetaedsuarletedraattitohnes einndcooaftguhleatoinoen-pmaornatmhetreercsoavtertyhe - (Day 125). `Company Sanitized. Does nc contain TSCA CBI ED 910.2-4D5a1y6:GaSvuabgcehrSotnuidyc TinoxRicaistywithOneGeneration Reproduction Evaluations Dupont.5386 = "The following minimal but statistically significant changes in hematology parameters were considered to be unrelated to treatment because theydid not occur in a dose related manner: Decreased hemoglobin and hematocrit in females dosed with 25 mg/kg/day at Day 45 Increased MCH in males dosed with 100 mg/kg/day, and increased MCHC in males dosed with 25 mg/kg/day at Day 91 Increased cosinophils in males dosed with 25 mg/kg/day at Day 44, and decreased eosinophils in females dosed with 25 mg/kg/day at day 45. "The following minimal but statistically significant changes in hematology parameters were considered to be unrelated to treatment because they only occurred after one monthofrecovery: Increased neutrophils in females dosed with 100 (day 93) or 250 mg/kg/day (day 125; recovery) Increased cosinophils in females dosed with 250 mg/kg/day (day 125 recovery) Decreased APTT in males dosed with 25 or 100 mg/kg/day at day 91 was not considered adverse because decreases in coagulation times are not associated with toxicity. Red cell counts were statistically deceased at test day 91 in males dosed with 100 mg/kg/day. "This change was small, was not associated with changes in other red cell mass parameters, and did not appear to follow a dose response; and thus was considered unrelated to treatment. B. Clinical Chemistry (Tables 30-31, Appendix K) There were no toxicologically significant changes in clinical chemistry parameters in rats dosed with 25, 100 or 250 mg/kg/day. All statistically significant changes in clinical chemistry parameters were considered non-adverse (not toxicologically significant) or unrelated to treatment. These changes are detailed below. Alkaline phosphatase was minimally increased in male rats dosed with 100 (day 91 only) or 250 mg/kg/day (days44 and 91). Toxicologically important increased ALKP activity generally occurs as a resultofcholestasis, but may also be due to direct enzyme induction by a xorenhoibstiooltoigciTMc.evIindetnhicseosftucdhyo,letshtearteswisa)s. noTheevriedewnacseohficshtoolloegsitcaseivsid(ebnicleiroufbiennezmiyam,ebiilnudruucbtiinounri(as,ee Anatomic Pathology report). Therefore, the ALKP changes were most likely due to direct enzyme induction and therefore were considered non-adverse. After one monthofrecovery, alkaline phosphatase activity in 250 mg/kg/day males was similar to control values. Company Sanitized. Does not contain TSCA Cat = 0H--2D4a51y6:GovSaugbcehSrtoundiyc TinoxRiactistyvith One-Generation Reproduction Evaltons Dupont 386 - Clinical Pathology Text Table 2: Alkaline phosphatase as a percentof control group mean Males [T 2 TT 10 [2% [D | 1a 07% |y11a 6% | 138% 192% [+DaSayiisaise]sT gnicanc indT icated by bod95a%lc|zadtype Cholesterol and triglycerides were mildly decreased in males dosed with 100 or 250 mg/kg/day at days 44 and 91 (variable statistical significance). In females dosed with 100 or 250 mg/kg/day, triglycerides only were decreased at days 45 and93 (variable statistical significance). After one `monthofrecovery, both cholesterol and triglycerides were still statistically decreased in 250 mg/kg/day males. For females, triglycerides in most rats were still minimally decreased after one monthofrecovery, although there was much variability among individual rats, and values from some previously treated rats were higher than any control rat. Therefore, the relevance of the effect in recovery females is equivocal. The changes in cholesterol and triglycerides were treatment-related and indicate altered lipid metabolism, but were not considered adverse because mild decreases in cholesterol and triglycerides do not have any known adverse effects. Males and females dosed with 100 or 250 mg/kg/day had alterations in serum proteins. The _ primary change was mildly increased total protein in rats dosed with 100 (females only) or 250 mg/kg/day (variable statistical significance). The increased total protein was generally due to increased albumin; increased albumin also occurred in males dosed with 100 mg/kg/day (day 91), but this change did not affect total protein concentration. Globulin changes were minimal and variable between sexes; at day 91, 250 mg/kg/day males had decreased globulins, while c2o5n0cemngt/rkagt/iodnasy ifneamtalsepsrhevaidouisnlcyredaossededglwoibtuhli2n5s.0 mAgf/tkerg/odnaeymwoenrtehosifmrielcaorvteorcyo,ntprrooltevianlues. The increases in serum protein noted above were primarily due to increased serum albumin. Mildly increased serum albumin is not known to have any adverse consequences, so these protein changes were considered non-adverse. Increased serum albumin in females dosed with 100 or 250 mg/kg/day caused secondary hypercalcemia. Calcium exists in serum in two forms, either bound to albumin or unbound (In"ciroenaiszeesd"incaallcbiuumm)i.n aIroeninzeecedscsaarlicliyumassisocthieatpehdyswiiotlhogpihcyasliloyloagcitciavlelyfoarpmp,roapnrdiaitsetiignhctrleyarseegdulbaotuend.d calcium, with resultant increased total calcium. However, ionized calcium is unaffected. Thus, increased calcium in association with increased albumin is considered physiologically a2p5p0rompgrliaktgedaanyd ftehmuaslensonw-aedrveerssiem.ilaArftioercoonnteromlovnatlhueso.f recovery, calcium concentrations in Inorganic phosphorus was minimally and statistically increased in females dosed with 100 or 250 mg/kg/day at day 93 only. After one monthof recovery, inorganic phosphorus values in 250 mg/kg/day females were similar to control values. Increased inorganic phosphorus was not ~ associated with other changes that would indicate toxicity (such as increased urea nitrogen or Company Sanitzed. Docs mot contain TSCA CBI = --_-- 51.02-4D5a1y6:GovSaugbeehSrtoundiyc TinoRxaitcsitwyith One-Generaion Reproduction Evaluations DuPont5386 -~ creatinine, or histologic changes indicativeofrenal damage). In addition, rats with the highest inorganic phosphorus concentration were those dosed with 100 rather than 250 mg/kg/day. Therefore, this minimal change, although possibly related to treatment, was not considered adverse. Sodium and chloride were minimally decreased in males dosed with 250 mg/kg/day at day 91 `The magnitudeofchange in these parameters was very small, and in individual rats there was no consistent relationship between sodium and chloride concentrations. Therefore, these changes, although possibly relatedttoreatment, were considered non-adverse. Potassium was minimally increased in females dosed with 250 mg/kg/day at days 45 and 93. The `magnitudeofchange was small compared to the normal variability of the parameter, and was not associated with changes that might indicate toxicity. Therefore, this change was considered nonadverse. At day 125 (one-month recovery), potassium in 250 mg/kg/day females was similar to control group values. `The following minimal but statistically significant changes in clinical chemistry parameters were considered to be unrelated to treatment because they did not occur in a dose-related manner. Transiently increased phosphorus in males dosed with 100 mg/kg/day at Day 44 Decreased creatinine in females dosed with 25 or 100 mg/kg/day at Day 45 (in addition, decreases in creatinine are not toxicologically significant) - Increased glucose in females dosed with 25 mg/kg/day at Day 45 Decreased sodium in males dosed with 250 mg/kg/day `The following minimal but statistically significant changes in clinical chemistry parameters were considered to be unrelated to treatment because they only occurred afler one monthofrecovery Decreased SDH in males dosed with 250 mg/kg/day (in addition, decreases in SDH are not toxicologically significant) Increased urea nitrogen in males dosed with 250 mg/kg/day Decreased calcium in males dosed with 250 mg/kg/day Decreased sodium in females dosed with 250 mg/kg/day Decreased AST and ALT in females dosed with 250 mg/kg/day at day 45 were considered to be `non-adverse because decreases in transaminase activity are not considered toxicologically adverse. C. Urinalysis (Tables 32-33, Appendix K) Urine volume was increased in males and females dosed with 250 mg/kg/day at days 44 (males equivocal) and 91 (variable statistical significance). Urine osmolality and specific gravity were correspondingly decreased at these same time-points with statistical significance occurring only - for males at 91 days. In addition, in males dosed with 250 mg/kg/day, urine total protein was decreased at day 91. Increased urine volume and decreased urine concentration can oceur duc to "ompany Sanitized. Doss =i centain TSCA CBI E-- E 91.02-4D5a1y6:GaSvuabgcehrSotruidyc TinoxRiactistywith One-Generation Reproduction Evaluations DuPont5386 ~ decreased renal function or secondary to increased water consumption. Effects on urine volume and concentration in the 250 mg/kg/day groups were not associated with changes in other clinical pathology parameters (creatinine, BUN, phosphorus) indicative of primary renal toxicity. Furthermore, although renal tubular hypertrophy and increased renal weights were present in male rats, there was no evidenceofcytotoxic effects in the kidney. Therefore, these urinalysis changes were considered non-adverse. At day 125 (one-month recovery), urine volumeofmales previously dosed with 250 mg/kg/day was decreased, compared to control and end-of-study results. Urine concentration (measured by osmolality and specific gravity) was correspondingly increased at this time-point. These changes were not considered adverse because production of low levelsof concentrated urine is considered normal for ats. The urine volume and concentration of female ras after recovery were similar to controls. D. Plasma and Urine Fluoride Measurements (Tables 30-33, Appendix K) Plasma fluoride was mildly increased in males and females dosed with 100 or 250 mg/kg/day at day 91/93. At day 125 (one-month recovery), plasma fluoride in 250 mg/kg/day rats was similar to control group values. At the end ofthe exposure phaseofthe study, urine fluoride (as determined by total fluoride - excreted over the collection period) was increased in a dose-related manner in males and females dosed with 25, 100, or 250 mg/kg/day (Clinical Pathology Text Table 3) At day 125 (one-month recovery), daily urine fluoride excretion was increased in males and females previously treated with 250 mg/kg/day, although levels were markedly reduced relative 0 those present at the endofexposure. Thus increased urine fluoride showed evidence of reversibility, albeit incomplete, following the one-month recovery period. `Additional urine was collected from males and females designated for three months of recovery, to determine whether or not further recovery had occurred. For rats previously dosed with 250 mg/kg/day, urine samples collected at day 181 still contained significant amounts of fluoride, although the total fluoride was less than at day 125. In addition, urine fluoride at Day 181 was still increased over control group values for males and females previously dosed with 100 mg/kg/day (males statistically significant). Urine fluoride was also probably increased in males and possibly females dosed with 25 mg/kg/day; but the change in females was equivocal due to the low numbersofvalues and the variability of the data. Increases in plasma and urine fluoride were considered to be secondary to the administrationof a mixture containing fluorinated compounds and/or free fluoride. The presence of fluoride in urine three months after exposure suggests that fluoride containing compounds are slowly being released from tissue sites Company Sanitized. Dos ct containTSCA CBI = 19.02-0D5a1y6:GavSaugbesoStnuidcy TinoxRiactistyith One-Generaton Reproduction Evaluations DuPon5386 -- Clinical Pathology Text Table 3: Daily urine fluoride (ng)* [Mae [| |IT| [1 payor 202]2130]662.7 1473.6] | 1054%|3281%|725%] [| Dayi2s| 142] ND ND|#4 | ND[ NDI6I5% [Toayisies 121] 228] 307] 600] | 188% 323%] 571%) eb [TTT 1 [Fema [|| Fm]iq_ad sei]sien | Spd arsedse NDI ND|509%] {ND GrouDp anoyt su1n8pl0e+da]thi 8i8me p1oi5.9] 200] 20.3] | iBi%]227%]333%) + DBootladparleisceinzteedd fasonabisnodliucttveaslhueash(e1cc)anhdawsaapsersncaetnigtstocfaeclolnytrsoiglngifriocuapntmean (igh. ++ Data collected from at designatedfo biochemical analysis E. ClinicalPathology Conclusions Under the conditionsofthis study, the NOEL for males and females was 100 mg/kg/day. These were based on the findings ofminimal decreased red cell mass parameters in males and females --- dosed with 250 mg/kg/day. After one monthofrecovery,red cell mass parameters were still decreased in males previously dosed with 250 mg/kg/day, and some hematologic parameters `were still altered in femalespreviously dosed with 250 mg/kg/day. There were no adverse findings for coagulation, clinical chemistry, or urinalysis parameters at any dos. Company Saniized. Does not conanTSCACB a 0H--2D4a51y6:GavSaubgeehSrtoundiyc TinoxRiactistywithOne-Generation Reproduction Evaluations DuPont 5386 ANATOMICAL PATHOLOGY A. Subchronic Toxicity and Recovery 1. Organ Weight Data (Tables 36-37, Appendix L) Test substance-related and/or statistically significant increases, compared to controls, in liver weight parameters were present in 25, 100, and 250 mg/kg/day males and females sacrificed at the endofthe approximately 90-day exposure period. At the 250 mg/kg/day dose level, liver weight parameters remained increased in the one- and three-month recovery group males and females, although the magnitudeof these effects was decreased relative to that observed in the 250 mg/kg/day exposure group. Nostatisticallysignificant liver weight effects were present in the three-month recovery groups previously dosed with 25 or 100 mg/kg/day (organ weights were not evaluated in these groups at one-month recovery). In 100and 250 mg/kg/day exposure group. male rats and 250 mg/kg/day one- and three-month recovery male rats and in 250 mg/kg/day `exposure group females, increased liver weights correlated with microscopic hepatocellular hypertrophy (see discussion under Microscopic Findings). Test substance-related and/orstatisticallysignificant increases, compared to controls, in one or more kidney weight parameters occurred in male and female rats at all exposure concentrations. - Some kidney weight parameters remained increased in males and females in the 250 mg/kg/day `one-month recovery groups. However, there were no statistically significant kidney weight changes in any dosed group following three monthsofrecovery. In male rats, increased kidney weights correlated with microscopic tubular hypertrophy in the 100 and 250 mg/kg/day groups sacrificed at the end of the exposure period and in the 250 mg/kg/day group sacrificed following, 2 one-month recovery period (sec discussion under Microscopic Findings). There were no microscopic correlates to kidney weight changes in females. `There were no other test substance-related organ weight effects. All otherstatisticallysignificant organ weight changes in exposure and recovery groups were secondaryto decreases in body weight. In 100 and 250 mg/kg/day male rats sacrificed at the endofthe exposure period, organ weight changes included: decreases in absolute organ weight and/or organ weight relative to brain weight for heart and epididymides and increased brain weights relative to body weight. `There were no weight changes in heart and epididymides when adjusted to final body weight. In 250 mekg/day males sacrificed at the endof the exposure period, testes weight relative to body weight was increased, however, absolute testes weight was notstatistically different from control testes weight. In addition, no test substance-related microscopic changes were present. In female `one-month recovery rats brain and adrenal gland weights relative to body weight were increased a1 250 mg/kg/day. There were no correlative effects in other weight paramelers or microscopic changes in these organs. Weights for these latter organs are generally maintained despite body weight loss, and thus this patternoforgan weight change is also consistent with effets occurring secondary to decrements in body weight. `Company Sanitized. Does rot cortain TSCA CBE 3 0H--2D4a51y6:GaSvuabgcehvSotnuidcy TinosRiacsiywith One-Generation Reproduction Evaluations DuPon-5386 = 2. Gross Observations (Tables 38-39, Appendix M) Gross observations noted were sporadic across groups and were not test substance-related. 3. Microscopic Findings (Tables 40-45, Appendix M) Test substance-related microscopic findings were present in teeth, thyroid gland, and liver from male and female rats and in kidneys from male rats. Incidences and Average Lesion Gradesof Test Substance-Related Microscopic Findings In Male and Female Rats oem 0 3 iw am Males: Exposure TDeegeetnhe:ration, ameloblasts (nose) 010 00 01000) S005 1111Q0) Degeneration, ameloblasts (mandible) 10000) 01000) 19ED) 1010018) THyhpyerrotirdopghlya,ndf:ollicular 01000) 01000 21003 1011015) Aleation, colloid 911009) 9004 MEH IEE -- LHiyvpeerr:trophy, hepatocyte, centrilobular 01000) 000 91009) 1A) KHyipdenretyrso:phy,tubular 01000) 01000 1000 man TDeeegetnhe:ration, ameloblasts (nose) Thyroid gland: Aleation, colloid LHiyvpeerr:trophy, hepatocyte, centrilobular Ktiiydpneerytsro:phy, tubular TDeeegetnhe:ration, ameloblasts (nose) Thyroid gland: Altraton, colloid _iLyipveerrt:rophy, hepatocyte, centrilobular Males: One-Month Recovery 01000) Na 1010012) NA 01000) Na 01000) NA Males: Three Month Recovery 0500) 0500) 5506 5506) oso) NE NA 910013) Na 101027) Na 1010016) Na 21002) USE) 2506) ss@o) $502) 0500) 1502 `Company Sanitized. Does notcontain TSCACBI Es 910..24D5a1y6G:avSaugbeehSvtoundiye TinoxRiactistywith One-Generation Reproduction Evaluations DuPont-5386 Dose mghgday 0 3 Females: Exposure io 30 TDeegeetnhe:ration, ameloblasts (nose) Degeneration,ameloblasts (mandible) 001100000000)) 0019000.00)) 6011000006 17180190 THhypyerrottrdopghlya,ndf:ollicular Aleation, colloid 001100000000)) 06110000006)) 000E0n 6M11E05H) LHiyvpeerr:trophy,hepatocyte centrilobular DeTgeeentehr:ation,ameloblasts (nose) TAlheyartoiiodn,glcaonldl:oid 01000) 01000). Females: One-Month Recovery. 01000) Na 1003) Na 01000) nia Na 7100.1) NA ono. Females: Three-Month Recovery TDeegeetnhe:ration, ameloblasts (nose) 0500) NE 0500) 2504) - TAlhtyerraotiidong,lcaonldo:id 550.2 405) 50.0 52 * Numerator indicates incidence ofras with microscopic lesion. Denominator indicates umber of rats in group. > Number in parentheses indicates group average severity of lesion. NA Tinsotsavauilaebe NE Tissue not examined. `Test substance-related tooth lesions in male and female rats administered 100 or 250 mg/kg/day consistedofdegeneration and/or disorganization of enamel organ ameloblast cells. This lesion was most evident in the upper incisors of the level I (anterior) nose section.A similar lesion was present in cross sectionsofmandibular teeth, however, the frequencyofoccurrence and severity were generally less than the ameloblastic degeneration/disorganization observed in the nose sections. Followinag one-month recovery, ameloblastic degeneration/disorganization was still present in male and female ras previously dosed with 250 mg/kg/day; following three months of recovery this lesion was present in males previously dosed with 100 and 250 mg/kg/day and in females previously dosed with 250 mg/kg/day. This tooth lesion is consistent with fluoride toxicosis and is considered adverse. Thyroid follicular hypertrophy was present in males administered 100 and 250 mg/kg/day and females administered 250 mg/kg/day. Follicular hypertrophy was characterized by low columnar follicular epithelium witha finely granular or vacuolated cytoplasm. Hypertrophy was reversible in both male and female rats, as this change was not present in dosed rats following the one- and three-month recovery periods. Thyroid hypertrophy was minimal and unassociated with - proliferative thyroid lesions. However, this hypertrophy indicates possible disruptionof thyroid homeostasis and thus was considered "potentiallyY adverse. Company Sanitized. Docs not contain TSCA CBI - 9H0.2-4D5a1y6:GaSvuabgcehvSotnuidcy TinoxRitcistywithOne.Generation Reproduction Evalustions DuPont5386 - Inthe thyroid gland, the relative degree (and in females, the incidence)ofaltered colloid was increased in males and females in al dosed groups a the end of the exposure period. Following the one- and/or three-month recovery periods, severity grades for colloid clumping were increased in males at all dose levels and in females al the 250 mg/kg/day level only. The diagnosisof "alteration, colloid" was used for colloid changes characterized by stippled, `granular, clumped, and/or diffusely basophilic colloid. A 4-level grading scheme was applied based on an estimate of the percentageoffollicles that contained altered colloid. A grade of 1 was applied when 1 follicle to about 25%ofthe follicles were involved, with grades 2, 3, and 4 applied for each 25% increase in follicular involvement. The size, density,o staining intensity ofstipples, granules, clumps, or diffuse basophilia within individual follicles did not impact the grading. There was no consistent association between the presence or absence ofaltered colloid and the presenceof hypertrophyof thyroid follicular cell. lier colloid described as clumped or granular has been reported to occur spontaneously in cSoplrlaogidueo-cDcauwrslesypornattsanweiotuhsilnycirneahseianlgthiyncSipdreancgeuec-orDraewllaetiyngrattso, ianncdresaisnicneg iangcer.e*a"sesBeincaiutssgeraaldtienrged score did not consistently correlate with other morphologic alterations in the thyroid gland, altered colloid was interpreted as not biologically meaningful and not adverse. Hypertrophyofcentrilobular hepatocytes was present in 100 and 250 mg/kg/day males and 250 mekg/day females sacrificed at the end of the exposure period. In male rats previously dosed with 250 mg/kg/day, hepatocellular hypertrophy was present, but was less severe, after a - one-month recovery period and was present in only one of $rats sacrificed after a three-month recovery period. Microscopic hepatocellular hypertrophy was not observed in male rats in the 100 mg/kg/day three-month recovery group or in any female rat recovery group. Taken together, these findings suggest that microscopic hepatocellular hypertrophy was mostly reversible in males following three-month recovery and in females within one monthofrecovery. Microscopically, hepatocellular hypertrophy was characterized by an increased amountoffinely `granular eosinophilic cytoplasm within hepatocytes. There was no histomorphologic evidence of hepatocellular damage, and hepatic enzyme levels were not elevated (see clinical pathology section). Thus, hepatocellular hypertrophy (and the associated increase in liver weights) was considered a test substance-related physiologic response to metabolism ofa xenobiotic and not toxicologically adverse. %27%) Renal tubular hypertrophy was present in 250 mg/kg/day male rats sacrificed at the end ofthe exposure period. In addition, hypertrophy was seen in oneoften ras in the 100 mg/kg/day male exposure group. Following the one-month recovery period, minimal hyperlrophy was present in 20F 10 male ats, but ths change was not observed in rats sacrificed afler the three-month recovery period. Thus, hypertrophy decreased in incidence and severity after one-month recovery and appeared to be reversible by three-months recovery. Microscopically, tubular hypertrophy was characterized by increased eosinophilic staiofncoirtnicgal tubule epithelium and a slight increase in cell height. Cortical tubule epithelial cells appeared to contain more granular cytoplasmic material then cortical tubulesof control ats. Tubular lumina of hypertrophied tbules were slightly smaller then those in control rat kidneys. There was no --- histomorphologic evidenceofrenal damage, and renal clinical pathology parameters were not indicativeofadverse effects (see clinical pathology section). Thus, the renal tubular hypertrophy `Company Sanftized. Dos ot contain TSCA CBI = 9204:5D1ay6:GavSaugbechSrtoundiy TinoxRiactistywith One-Generton Reproduction Exalutions Dupont5386 - (and the associated increase in kidney weights) was considered a test substance-related phhyypseirotlroogpihcyrweassponnsoeotbosaerxveendobiinotfiecmaalnedrnatost attoxaincyoldoogsiecallelveyl.adverse."" Renal tubular All other microscopic observations noted are known to occur spontaneously in rats of his strain and age and were not present in a dose response fashion in either incidence or severity: 4 CauseofDeath There were no test substance-related deaths. One 25 mg/kg/day female rat (Animal No. 643411) was accidentally killedduringblood collection. One male rat in the 100 mg/kg/day group (Animal No. 643175) and one male rat and one female rat in the 250 mg/kg/day groups (Animal Nos. 643309 and 643368, respectively) died from dosing injuries. Two female rat in the control (Animal No. 643336) and 25 mg/kg/day (Animal No. 643321) groups died from urogenital inflammation/obstruction/calculi complications. A causeof death was not determined foar 250 mg/kg/day female subchronic toxicity rat (Animal No. 643340) that was found dead on test day 69. 5. Anatomical Pathology Conclusions for Subchronic Toxicity Evaluation Exposure to 100 or 250 mg/kg/dayofthe test substance for approximately 90 days produced degeneration/disorganizationof enamel organ ameloblast cell in male and female rats. -- Ameloblastic degeneration/disorganization was not reversible afer three-month recovery in 100 mg/kg/day males and in 250 mg/kg/day males and females. Thyroid gland hypertrophy observed in 100 and 250 mg/kg/day males and in 250 mg/kg/day females was reversible at one `month and was considered to be potentially adverse. The severityofaltered colloid in thyroid glands increased beyond control level a the dose increased, however, it was not consistently associated with any other morphologic alteration and was not considered biologically adverse. Increased liver weights were present in males and females at 25, 100, and 250 mg/kg/day. The increased liver weights correlated with microscopic centrilobular hepatocellular hypertrophy in males at 100 and 250 mg/kg/day and in females at 250 mg/kg/day groups. Hepatocellular hypertrophy was mostly reversible in males following three-month recovery and in females within one monthof ecovery. Increased kidney weights were present in 25, 100 and 250 mg/kg/day males and females. In mals, these kidney weight changes correlated with microscopic renal tubular hypertrophy. The increased kidney weights and male renal twbular hypertrophy appeared to be reversible by three months of recovery. These liver and kidney changes were considered to represent physiologic responses to administration ofa xenobiotic and thus were not considered to be toxicologically significant. Under the conditions ofthis study, the NOEL for pathology for male and female rats was 25 mg/kg/day based on tooth lesions at the 100 and 250 mg/kg/day dose levels. Company Sanitzed. Does fat containTSCA CE! -_-- 9H0--24D5a1y6G:aSvuabgcehrSotnuidyc TinoRxaictistwyith One-Generation Reproduction Evaluations DuPon-5386 REPRODUCTIVE TOXICOLOGY EVALUATIONS REPRODUCTIVE FUNCTION A. Py Generation 1. Mean Body Weights and Body Weight Gains (Table 44-46, Appendices O-T) "There was a statistically significant reduction (89-91%ofcontrol mean) in body weight in P; male rats at 250 mg/kg/day during and after the cohabitation period. Although this finding was test substance-related, it was not considered toxicologically significant sinc there was no concomitant reduction in body weight gain in Py males during that period. There were no test substance-related effects on body weight or body weight gain in P, female rats during gestion or lactation. 2. Food Consumption and Food Efficiency During Gestation (Table 47, Appendix U) There were no test substance-related effects on food consumption and food efficiency in Py = female rats during gestation. 3. Clinical Observations (Tables 48, Appendices V-X) There were no toxicologically significant clinical observations in male and female rats at any dose level. There was an increase in tooth clipping required in male rats administered 250 mg/kg/day. Two females in the 250 mg/kg/day dose group also required teeth clipping. (Animal No. 643429 on Day 0G and 643417 on Lactation Day 7). One P, female rat (Animal No. 643429) in the 250 mg/kg/day group and her 16 pups were found dead on Lactation Da0y, Prior to death this animal exhibited weakness, diarrhea, wet underbody, facial staining on Gestation Day 21; this animal also had teeth clipped on Gestation Day 0. The causeofdeath was determined to be dystocia and was not considered test substance-related due to the single occurrenceof this finding and the occasional occurrenceofthis condition in control animals of the strain of rat used in this study. One Py female rat (Animal No. 643454) in the 100 mg/kg/day group died on gestation day 22. The causeofdeath was undetermined but was not considered test substance-related due to the absenceofsignsoftoxicity or gross lesions in this animal. 4. Reproductive Indices (Tables 49-51, Appendices Y-EE) "There were no test substance-related effects on estrous cycle parameters, sperm morphology, - amosttialtiitsyt,icoarlleypsiidgindifyimcaalntspiencrrmeacsoeunintsteisntitchuelaPrysgpeenremraattiiodn.numAbter10s0(a1n2d32%5a0nmdg/1k1g3/%doayf,ctohnetrreolw,as respectively) in Py male rats. This finding was not considered test substance-related since the. Company Sanitized. Does al contain TSCA CBI a -- 01.-2D4a51y6:GavSaugbeehSrtoundiyc TinoxRiactistywith One-Generation Reproduction Evaluations DuPont5386 - means for these groups were within the historical control range for previous studies and the increase appeared to be duc to a slightly lower than usual mean in the control group. There were no test substance-related effects on mating or fertility indices, gestation length or number of implantation sites. Implantation efficiency (number of pups bom + uterine implantation sites x 100) was significantly reduced at 100 and 250 mg/kg/day (83.4% and 84.5%, respectively, compared to 96.6% in the control group), and reflects the reduction in the number of pups born (see section B.1.). B. Offspring Data I. Liter Size, and Pup Weights, Clinical Observations, and Survival (Table 52-54; Appendix FF-HH) At 250 mg/kg/day, there were statistically significant reductions in the number of pups born, the number of pups born alive and the number of pups alive on day 4 of lactation (85%, 83% and 81%of control mean, respectively). At 100 mg/kg/day, reductionsof similar magnitude as in the 250 meke/day group were observe for the numberofpups born and born alive (84% and 77% of control, respectively). Although not statistically significant these changes were considered test substance-related, as was the significant reduction in the numberof pups alive on Day 4 of lactation (68%ofcontrol) at 100 mg/kg/day. - "There were no significant reductions in gestation index, mean % born alive, 0-4 day viability, lactation index or liter survival. At 250 me/kg/day, there were statistically significant reductions in pup weights on lactation days 4,7, 14, and 21 (89%, 85%, 78%, and 75%of control mean, respectively). `There were no test substance-related clinical signs in pups during lactation at any dose level. C. Fy Generation Mean Body Weights and Body Weight Gains (Table 55-56, Appendices 11-1) On the dayofweaning (Lactation Day 21 = test day 1) mean body weights were significantly lower than control (74%-78%of control mean) in both Fy males and females at 250 mg/kg/day. Subsequently, weekly mean body weights in F: males were significantly lower than control throughout the post-weaning period (81%-93%of control) in this group. For F\ females weekly mean body weights were significantly lower than control for test days 8 and 15 (85%-92% of control) and were similar to control thereafter. Thus mean body weights in these groups progressively retuned to control values during the post-weaning period. Because the lower body weights in the F generation at 250 mg/kg/day appeared to be due to a test substance-related effect on pup weight during the lactation period (see section B.1.) and there was no concomitant - reduction in body weight gain in F; males or females during the post-weaning period these findings were not considered toxicologically significant Company Sanitized. Dos notcontain TSCA CBI = 2904-5D1a6y:GavSaugbeehSrtoundiyc TinoxRiactistywith One-Generaton Reproduction Evaluations DuPont $386 - I. Clinical Observations (Tables 57, Appendices LL) "There were no test substance-related clinical signs during the post-weaning period. 2. Developmental Landmarks (Tables 58, Appendices LL) The age at onsetofvaginal opening in F, female rats was similar across groups. The age at onset ofpreputial separation in F\ male rats was similar across groups. D. Reproductive Function Conclusions For the reproductive toxicity parameters evaluated under the condition of this study, the NOEL was 25 mg/kg/day. `Company Sanitized. Does not contain TSCA CBI . 19.02-4D5a1y6:GavSaugbcehSrtoundiyc iTnoxRiactistywithOneGeneration Reproduction Evaluations DuPont5386 REPRODUCTIVE TOXICOLOGY EVALUATIONS ANATOMICAL PATHOLOGY A. Organ Weight Data Parental Py Adults and Fy Adults (Tables 59-62; Appendix MM) `There was astatistically significant increase in thyroid gland weight relative to body weight in Py males at 250 mg/kg/day, however, thyroid absolute weight was not significantly different from thyroid control weights. The increased thyroid weight was secondary to decreased final body weight in the 250 mg/kg/day Py males. In F; males at 250 mg/kg/day there were statistically significant decreases in liver and testes absolute weights and in epididymide absolute and relative to brain weights. There were no weight changes in these organs when adjusted to final body weight. These statistically significant organ weight changes were secondary to decreased final body weight in the 250 mg/kg/day Fi males. In F, females there were statistically significant increases in liver weight relative to final body _ weight and relative to brain weight at 250 mg/kg/day and in kidney weight relative to brain weight at 100 and 250 mg/kg/day dose levels. Neither liver nor kidney absolute weights were statistically different from control weights. The kidney to brain weight changes were not dose dependent. Noneofthe organ weight changes were considered to be toxicologically or biologically adverse. B. Gross Observations. Parental P; Adults (Tables 63-64, Appendix NN) Fy Adults and Weanlings (Tables 65-71, Appendix 00-QQ) `There were no test substance-related gross observations. Observations occurred in low. incidences and were randomly distributed across control and treatment groups. C. Microscopic Observations Parental P; Adults (Tables 72-73, Appendix NN) There were no test substance-related microscopic findings. Lesions occurred in low incidences without a relevant dose-response relationship and were considered incidental occurrences of spontaneous lesions in ratsofthis strain and age. - Company Sanitized, Does nc? contain TSCA CBI 9H0-2-4D5a1y6:GavSaugbcehrSotnuidcy TinoRxaitcsitwyith One Generation Reproduction Evaluations DuPont 5386 - D. Mortality Parental Py Adults and Fy Adults (Appendices NN and QQ) `There were no test substance-related effects on mortality. Two P female rats were found dead. Causeofdeath appeared to be dystocia for rat Animal No. 643429 (250 mg/kg/day) and was undetermined for rat Animal No. 643454 (100 mg/kg/day). One 250 mg/kg/day P: female rat (Animal No. 643346) was sacrificed in extremis afler sustaining an injury in its cage; the fate of this animal is reported as accidentally killed. E. Anatomical Pathology Conclusions for Reproductive Toxicity For pathology, the NOEL was 250 mg/kg/day (the highest dose level) for both male and female as. Company Sanitized. Bocs not contain Tso ca - 9204-5D1a6y:GavSaubgcehSrtoundiyc iTnorRiactistywith One-Generation Reproduction Evaluations RDeuvPiosnetd5P3a8g6e BIOCHEMICAL MEASUREMENTS A. Biochemical Measurements (Table 34-35, Appendix L) The rateofhepatic -oxidation, a measure ofperoxisome proliferation, was determined in a subchronic oral toxicity studywith H-24516 in rats following 10 or 90 (males) and 92 (females) daysoftest substance administration or following a one- or three-month recovery period. Dose-dependent increases in the rate of hepatic -oxidation were observed at the 10-day time point with statistical significance occurring for rats administered 100 or 250 mg/kg/day (223 and 349%ofcontrol, respectively, in the males and 170 and 260%ofcontrol, respectively. in the females). Dose-dependent increases in the rateof hepatic B-oxidation were also observed at the 90-day time point with statistical significance occurring for rats administered 100 or 250 mg/kg/day (398 and 856%of control, respectively, in the males and 345 and 381% of control, respectively, in the females). At both time points, the increases in hepatic B-oxidation activity were accompanied by increases in liver weights. Following a one-month recovery period, statistically significant increases in the rateofhepatic Broxidation persisted in rats administered 250mg/kg/day (353 and 207%ofcontrol, respectively, - pinermsailsteesdaanfdterfetmhaeletsh)r.eeS-tmaotnitsthicraelcloyvseirgynipfeircianotd ifnocrrtehaese2s50inmtgh/ekrga/tdeaoyfdhoepsaetgicroBu-pox(i3d0a2tiaonndal1s7o2% ofcontrol, respectively, in males and females). At the one-month recovery time point, the increase in hepatic B-oxidation activity was accompanied by increased liver weights in the males, but not the females. B. Biochemical Measurements Conclusions Under the conditionsofthis study, H-24516 is an inducer of hepatic peroxisomal B-oxidation. At dosages of 100 mg/kg/day and greater, changes in the rateofhepatic peroxisome proliferation were considered to be biologically significant effects. After three monthsofrecovery, the rate of hepatic peroxisome proliferation was stil increased in rats administered 250 mg/kg/day. `Company Sanitized. Doss not contain TSCA CBI ww -- 91.02D4a51y6:GavSaugbcehSvtoundiyc TinoxRiactistywith One- Generation Reproduction Evalations Dupont 5386 CONCLUSIONS No test substance-related mortality or alterations in neurobehavioral parameters were observed in male or female rats. Test substance-related and toxicologically significant decrements in mean body weight, body weight gain, and food efficiency were observed in male rats administered 100 and 250 mg/kg/day compared to controls. Food consumption was also significantly lower in male rats administered 250 mg/kg/day. Aftear one- and/or three-month recovery period, these parameters were similar to or exceeded control. Test substance-related, toxicologically significant increases in the incidence of broken (males) and absent tecth (males and females) occurred in the 250 mg/kg/day dose group. Statistically significant decrements in mean body weight parameters and food consumption occurred for females administered 100 or 250 mg/kg/day. The decrements in female body weight parameters wer not considered to be toxicologically significant. Furthermore, the decrements in body weight parameters appear tobe relatedto test substance-induced adverse effects (0 the teeth and decreased ability of the animals to cat pelleted chow. Toxicologically adverse findingsofminimally decreased red cell mass parameters (RBC, hemoglobin, and hematocrit), along with correlative changes in other hematology parameters and in red cell morphology were observed after the 90-day exposure period in males and females administered 250 mg/kg/day H-24516. After a one-month recovery period, the 250 mg/kg/day male dose group still had minimally to mild decreased red cell mass parameters as well as - decreased reticulocytes compared to control. Red cell mass parameters for the 250 mg/kg/day female group returned to contol levels, however, some hematological parameters (MCV. MCH, RDW, and reticulocytes) were still decreased. A statistically significant rateofhepatic B-oxidation occurred in males and females administered 100 or 250 mg/kg/day H-24516. The increased rate persisted in the 250 mg/kg/day groups after one and three months. Test substance related, toxicologically significant degeneration/disorganization of enamel organ ameloblasts cells occurred in male and female rats dosed with 100 or 250 mg/kg/day H-24516. `This tooth lesion is consistent with fluoride toxicosis. After three months, the degeneration/disorganizationofameloblasts persisted, at a lower incidence and severity. Test substance related, potentially adverse increases in thyroid hypertrophy were observed in the 100 and 250 mg/kg/day male and 250 mg/kg/day female dose groups after the 90-day exposure period. Afr the one-month recovery period, thyroid hypertrophy was not observed in any dose group. Increased liver weights and/or hepatocellular hypertrophy were observed in male and female rats atall dose levels. Similarly, increased kidney weights and/or renal tubular hypertrophy ware observed in male and female rats at all dose levels. These latter changes were considered to be a _ pwheairgmhatcsorleomgaiicanleldyiandcarpetaisveed, innotnh-ead2v5e0rsmeg/rkegsp/odnasye.maAlfelearndthfeetmharleeeg-rmoounptsh, rwehciolveerhyeppaetroicoedl,lullivaerr Company Saniized. Does not contain TSCA CBI & -- 910.2-4D5a1y6:GaSvuabgcehrSotnuidyc TinoxRiactistywith One-Generaton Reproduction Evaluations DuPon-5386 ~ hypertrophy was observed only in the 250 mg/kg/day male group (1of $ rats). Alterations in Kidneys were not observed at any dose level after the three-month recovery period. There were no toxicologically significant pathology findings in the Py and Fy generation rats. A statistically significant increase in testicular spermatid numbers in P, male rats was not considered test substance-related. Implantation efficiency wassignificantly reduced at 100 and 250 mg/kg/day and reflects the reduction in the number of pups born. `There were statistically significant reductions in the numberof pups born, the number of pups born alive and the number of pups alive on day 4 of lactation in the 250 mg/kg/day group. Reductionsof similar magnitude were also observed for the number of pups bor and born alive in the 100 mg/kg/day group. Although not statistically significant, these changes were: considered test substance-related and toxicologically significant, as was the significant reduction in the number of pups alive on day4oflactation in the 100 mg/kg/day group. There were statistically significant reductions in pup weights on lactation days 4,7, 14and 21 in the 250 mg/kg/day groups. On the day of weaning mean body weights were significantly lower than control in both F; males and females in the 250 mg/kg/day group. Fy generation body weights at 250 mg/kg/day progressively returned to control values during the post-weaning period indicating that the test -- substance-related effect on pup weight during the lactation period was reversed following cessationof exposure and therefore, were not considered toxicologically significant. "The no-observed-effect level NOEL)" for H-24516 for the 90-day exposure period was 25 mg/kg/day based on adverse decrements in body weight parameters and food efficiency, increased hepatic peroxisomal f-oxidation, and the degeneration andor disorganization of enamel organ ameloblast cells in males administered 100 mg/kg/day. The NOEL for females was 25 mg/kg/day H-24516 based on increased hepatic peroxisomal oxidation and the degeneration and/or disorganization of enamel organ ameloblast cells in females administered 100 mg/kg/day. The NOEL for reproductive evaluations was 25 mg/kg/day based on decreases in the numberofpups born, bor alive, and the number of pups alive on da4y of lactation at the 100 mg/kg/day dose level --~ * hTheeeNstOsEuLbsftoarnctehswesrteudnyotisddeetfecitneedd.asThtuhes,hifgohresthtidsosstuedayt,wthheicNhOtEoxLiciosleoqguiicvlallyenitmptoortthaentNOeEffLecatsssdterfibnuedtabybtlo hdeefiUnneidtebdy StthaeteEsurEonpveiarnonUmenntiaol nProtection Agenc'TMy and othe o-obse`rCvoemdp-aandvyeSrasnei<tfilzcetd.leDveole(sNOnoAtEcLo)ntaasin TSCA CBI 3 -- 25H00.:2:D4D5ea1yy6G:GaovvSaauggbeecShSvtotunudiyyciinTnoRxRaiatctsistwywiitthhOOnnee-GGeenneerraattiioonnRReepprroodduuccttiioonn EEvvaalluuaattiioonnss DDuuPPoonnt55338866 - REFERENCES i DuPont (1995). Neurotoxicity oi of Trimethyliin in Rats (Positive Control Study). t DuPont (1997). Neurotoxicity aof Amphetamine in Rats (Positive Control Stud). 3. DuPont (1997). Neurotoxicity Evaluationof Carbaryl in Rats (Positive Control Study). DuPont a) Neurotoxicity iof Acrylamide in Rats (Positive Control Study). 5. LEanzzayrmoowl,ogP-yB.72(,1938115)-.319A. sofs Peroaxisoymal Beta-Oxidation of Fatty Acids. Methods in 6. QBuraandtfiotride,soMfMP.rot(e1i9n76)Ut.ilAiziRnagptihdeaPndrSeinsinotifvcPeriMoettepihnol-dDeyfeorBtihnedQiunga.ntiAtnaatli.onBoifocMhiecmr.og7r2,am 248.254. -- 7. Dumett, C.W. with a control. (1955). A multiple comparison procedure J. Amer. Statist. Assoc. 50, 1096-1121 for comparing several treatments 8. Dunn, 0.1. (1964). Multiple contrasts usingrank sums. Technomerics 6, 241-252. 9. Draper, N.R. Wiley, New Yaornkd. SmithH,. (1981). Applied Regression Analysis, 2* edition,pp 266-273. 10. Selwyn, M.R. (1995). animal safety studies. JTohuernuaslcooffttrheenAdmetersitscatno dCeotlelremgienoefaTonox-iocbosleorgvyab1l4o(-2e)f,fe1c5t8-l1e6ve8l in 11. Jonckheere, AR. (1954). Biomerrika 41, 133-145. A distribution-free K-sample test against ordered alternatives. 12. LeveneH,. (1960). Statistics1. Olkin, Robust ed), pp t2e7s8t-f2o9r2e.quaSltiatnyfoorfdvaUrniiavnecressi.ty CPornestsr,ibPuatlioonAslot.o Probability and 13. Shapiro, S.S. andWilk, M.B. (1965). samples). Biometrika 52, 591-611 An analofyvasriiancse testfor normality (complete 14. 3S4n9e-d3e5c2o.r, TGh.eW.loawnadSCtoactehrUanni,veWr.sGi.ty (P1r9e6s7s),. AmSetsat.istical Methods, 6" edition, pp 246-248 and _ 15. Kruskal, W.H. and Wallis, W.A. (1952). J. Amer. Statist. Assoc. 41, 583-621. Useof ranks in one-criterion analysisofvariance. - Sompsny Sanlized. Does nt contain TSCACBH 9H0.2-0D5a1y6:GaSvuabgcehrSotnuidcy TinosRicaistywith One-Generation Reproduction Evaluations DuPont5386 - 16. Milliken, G.A. and Johnson, D.A. (1984). Analysis of Messy Data, Volume L.: Designed Experiments. Lifetime Learning Publications, Belmont. 17. Hocking, R.A. (1985). The Analysis of Linear Models. Brooks/Cole, Monterey. 18. Bartlet, M.S. (1937). Some examplesofstatistical methodsofresearch in agricultureand applied biology. .. Royal. Stati. Soc. Suppl. 4, 137-170. 19. NFieshwerY,oRr.kA. (1985). Statistical Methods for Research Workers, 13" edition. Haffner, 20. Dempster, A.P., Selwyn, M.R., Patel, C.M., and Roth, A.J. (1984). Statistical and computational aspectsofmixed model analysis. The Journal of the Royal Statistical Society. Series C(Applied Statistics) 33(2), 203-214. 21. Haseman, JK. and Hogan, M.D. (1975). Selectionof the experimental unit in teratology studies. Teratology, 12, 165-171. 22. Patefield, W. (1982). Exact tests for trends in ordered contingency tables. AppliedStatistics 31,3243 23. Hoffinan, W.E. and Solter, P.F. (1999). Clinical Enzymology. The Clinical Chemistry of Laboratory Animals (WF. Loeb and F.W. Quimby, eds.), Taylor and Francis, Philadelphia, -- PA. pp399-454. 24. Reddy, C.S., and Hayes, A.W. (1089). Food Borne Toxicants. In Principles and Methods of Toxicology (A. W. Hayes, Ed), Raven Press, New York, pp67-110. 25. 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. 26. Sipes, Gi. 1, and Gandolfi, A. J. (1991). In BiotransformationofToxicanis. In Casearett and Doull's Toxicology: The Basic ScienceofPoisons (Amdur, M. O., Doull,., and Klaassen, C.D, Ed), Pergamon Press, New York, pp 88-126. 27.Paynter,O.E., Harris, 1.E., Burin, G.J.,and Jaeger, R.B. (1985). Guidance for Analysis of Evaluation of Subchronic Exposure Studies. United States Environmental Protection Agency, EPA-540/9-85-020, 28. Greaves, P. (1990). Digestive System 2. In HistopatofhPorelcloingicyal Toxicity Studies: Interpretation and Relevance Amsterdam, pp 393-496. in Drug Safety Evaluation (P. Greaves, Ed), Elsvier, 29. Greaves, P. (1990). Urinary Tract. In HistopathologyofPreclinical Toxicity Studics: Interpretation and Relevance in Drug Safety Evaluation (P. Greaves, Ed.), Elsvier, - Amsterdam, pp 497-583. Company Sanilized. Docs ot contain TSCA CBI -- = 91.02D4a51y6;GoSvuabgcehrSotnuidyc TinoxRicaittsywith One-Generation Reproduction Evaluations DuPont5386 ~ 30. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance for Analysis and EvaluationofSubehronic and Chronic Exposure Studies Paynter, O. E. ot al, United States Environmental Protection Agency, Office of Pesticide Programs, Washington, D.C., 20406. EPA-540/9-85-020. (June 1985). 31. Risk Assessmentof Notified New Substances. EN), Chapter I, Sections 2.24 and 2.25. 1994. Technical Guidance Document (X1/283/94- _--_-- Company Sanilized. Does nai contain TSCACBU H9-02.4D5a1y6G:avSaugbcehSrtoundiyc iTnoxRiactistywith OneGeneration Reproduction Evaluations DuPont-5386 TABLES "ompany Sanitized. Does not contain TSCA CB -- = -- H9-02-4D5a1y6:GoSvuabgcehrSotnuidcy TinoxRicaittsywith One-Generaton Reproduction Evaluations - TABLES EXPLANATORY NOTES Critical Dates DuPont5386 Day 74 Male and female rats designated for reproduction evaluations were co- housed. Body weights and clinical observations collected during the cToohxaibciotlaotgiyonsaecntdiopno;stD-omsaetivnoglupemreisodasdmairneirsetpeorretdeddurinintghetRheepcroohdaubcittiavteion and post-mating periods are documented in study records. Days 83-89. Rmaettsabdoelsiisgnmactaegdefsorfotrheur3i-nemoanntdhfreeccesovceorlylepcetriiono.d wFeoroedtceompnosruamrpitliyohnoduasteadwians not collected for these animalsduring this period. Day 89 Last day of test substance administration for male and for one-month and 3-month recovery periods. female rats designated Day90 * Last dayoftest substance 90-day exposure period. administration for male rats designated for the Lafsortmadlaey roaftsnodne-sfiagsntaetdedbofdorytwheei9g0h-tdaanydefxopoodsucroenspeurmipodt.ion data collection - Day91 * Lfoarstfedmaayloefrantosn-dfeassitgendatbeoddyfowretihgeh9t0a-nddayfeoxopdocsounrseupmeprtioido.n data collection * Male rats designated for the 90-day exposure period were sacrificed. Day 92 Last day of test substance administration 90-day exposure period. for female rats designated for the Day 93 Female rats designated for 90-day exposure period were sacrificed. Day 119. Lraatsstddeasyiognfantoend-ffoarsttehed obnoed-ymwoenitghhtreacnodvefroyodpercioonds.umption data collection for Day 125 Male and female rats designated for the one-month recovery were sacrificed. Day 175 rLaatsstddeasyigonfatneodn-ffoarsttheed 3b-omdoynwtehigrhetcoavnedryfpoeordiocdo.nsumption data collection for Day 181 Male and sacrificed. fomale rats designated for the 3-month recovery period were Note On test day 18, 38 mgkgiday. all male rats and the first 11 female ras in the 25 mg/kg/day group received ~ -- Company Sanitized. Does not contain TSCACB -- -- 01.-2D4a51y6:GaSvuabgcehrSotnuidyc iTnoxRiactistywith One-Generation Reproduction Exalutions = TABLES ABBREVIATIONS: EXPLANATORY NOTES Summary of Hematology Values RBC - redbloodcell count HGB - hemoglobin HCT - hematocrit MCV - mean corpuscular volume MCH mean corpuscular hemoglobin MCHC - mean corpuscular hemoglobinconcentration RDW redcell distribution width ARET - absolute reticulocyte count WBC - whiteblcoellocoudnt ANEU - absolute neutrophil (all forms) ANPR absoluteneutrophilprecursor ALYM -absolute lymphocyte AMON - absolute monocyte AEOS - absolute eosinophil ABAS absolute basophil ALUC - absolute large unstained cell ~ ABLT - absbolasltleuuktocyete AMSC - absolutemiscellaneous leukocyte PLT - platelet count Summary of Coagulation Values PT - prothrombin time APTT - activated partial thromboplastin time Dupont 5386 Company Sanitizsd. Does aot coatain TSCA CBI = 910.2-4D5a1y6:GaSvuabgcehrSotruidyc iTnoxRiactistywith One-Generation Reproduction Exaluations - TABLES DuPon-5386 ABBREVIATIONS: EXPLANATORY NOTES Summary of Serum and Plasma Chemistry Values AST - aspartate aminotransferase ALT - alanine aminotransferase SDH - sorbitol dehydrogenase ALKP - alkalinephosphatase BILI - totalbilirubin BUN - ureanitrogen CREA - creatinine CHOL - cholesterol TRIG - triglycerides GLUC - glucose TP - total protein ALB - albumin GLOB - globulin CALC - calcium IPHS - inorganic phosphorous NA - sodium = K - potassium CL - chloride PFLU - plasma fluoride Summary of Urinalysis Values VOL - volume UOSM urineosmolality SG - specificgravity PH the logarithm of the reciprocalof the hydrogen ion concentration URO - urobilinogen UFLU - urine fluoride UMTP urine protein Notes for Clinical Pathology data: wWehreenpearnfionrdmievdidouanlhaolbfstehrevartieocnorwdaesd vraelcuoer.deFdoarsebxeaimnpglel,esisftbhialniraubcienrtwaaisn vraelpuoer,tecdalacsul<a0t.i1o,ns0.05 was used for any calculations performed with that bilirubin data Company Sanitized. Docs not contain TSCA CBI -- 7 -- 292004."5DD1aa6yyG:GaovvSaauggbeecShStotunudidycyiTinnrRiRaacttisstywwiitthhOOnnee-GGeenreerrattiioonnReRepprroodduucsttiioonnEvvaalsuttioonnss DDuupPoonntt5338866 TABLE | SUMMARY OF DOSING ANALYSES Homogeneity SNaommpilnesa: "esTtonDay 0 Midd Bottom 5 Dosing Concenenio0n0of 124516 (mginL) 30 22300 @59n7 0228) o2n47) (100220) 022x) 026400) (#10500) 024505) AAvveerraaggee MPeeracseunrteNdoCmoinnca.l" (293569) aniio a205.0) `Standard Deviation * 0.08 26 16 Coefficient of Variation * 3% 24% 1% HoSutrabRioliotmy STaemmppleerasture 206 550 201 24) 9) G64) Homogeneity Samples -- Test Day 6 Top ul 90.26206) -- Middie wr 005598) - Bottom we 02)3 we A`vAevreraaggeeMPeearsceunrtedNoCmoinnca.l" -= 093.636) =- Co`eSftcaindeanrtdoDfeVvairaitaitoino*n =- 20.19 == 5 HoSutraRboiolymSTaemmppleerasture we 503 = 03) R SSablios beimedgoos ntehefgwrreeymepeeaed cponrtean (pm) oh 0, mle and boofosch dosing cl. Company Sanized. Doss not contain TSCACR --r-- e ------7---------- H9-02-4D5a1y6:GaSvuabgherSotnuidcy TinoxRiactistywith One Generation Reproduction Evaluations DuPont-5386 TABLE | (CONTINUED) SUMMARY OF DOSING ANALYSES Homogeneity SNaommpilneasl: "Test Day 49 Top Middle Bottom AAvveerraaggeeMPeearsceunrteNdoCmoinna.l" `Standard Deviation Coefficient of Variation * Dosing Concentration of H-24516 3 53 271 108 19 10) 209 127 08) 053) (1304223) 128 63) o30y0 010281) 04 11 2% 0% (mymL) Eke] 310 29) 324 7) 134 (1003) 63823) 212 % Test Day 91 Top 3.L065) 28 60) 327 81) Middle 300 122 23 - ) 15) 66) Bottom 03.041) . -- Average Measured Cone." 302 125 32s Av`eSrtaagnedaPredrcDeenvtiaNtoimoinn"al 0070)3 020084) 27053) CNoeufmfbiceirentinofpaVraenrtiheasteisorns*te Tspesive1e%rectof rorrna vio 3% 1% hSotmatoigsetincesibtaydsamopnltehseoatvehragaevemraegesoftdupcloinccaenttersataipoine(pfomr)coonftcehnetroapti,onmivedrieficaantdiobn sopiroefosca(nc1h.3d3omsigng.eealndfor S3a3m3p3lemsgn/omtlresquubimriedtefdorcsstdd.ay 9) Company Sanitized. Does notcontain TSCA CBI --_--_---- 9102-4D5a1y6:GaSvuabgcehrSotnuidcy TinoxRicaittywith One-Generation Reproduction Evalstons DuPont5386 TABLE | (CONTINUED) SUMMARY OF DOSING ANALYSES _ Dosing ConcenratonofH-24516 (mg/mL) Homogenciy SaNmopmliensal: 333 so wo* S00 Top Middie Bottom 238 4s) 199 sa 865)" (90.6) 99.5) (106.8) 625)4 54025) 573) (502s6) 02267) a43)9 156 540 0) (1080) AAvveerraaggeeMPeearsceunrtedNoCmoinnca.l* 2(.817.01) 74.839) 0138.57 `Standard Deviatio*n +02 20.14 11 Coefficient of Variation * 6% 3% 6% 1056336) +07 1% Stability Samples ODay Room Tenperaturet G2170 74939) 1879) (1s06s8) Hour Room Temperature 266 460 "2 453 (199) 2-Day Refigerted wt 92.0) 47 (8168.30) (4961.96) 54) 15) 58) 3-Day Refrigerated 3 461 27940 4674) 4-Day Refigerted f2e9e1) 6a.s1i) 1189)6 aso 1% 4-Day Refigerated i. 12243) oanss 81726 a059. Seis propelSeov 7S mG dos 4 SSNaumumpblieersssprmseppaaraetodncbahtseeesad oavrneet5.0hremarLe/sgpKeecgtsidvoeospeenvrcoelnuctmoe.fonommin)al vfalhs.fo mii nd bot f ach dosing eel. Tshdemeaanbmesassurfeodrcloomspaftoomnnihyheoefshpoemcoigeensctaybaimpalees (.considered Fresh. oom epersrssamples) wre * Samplesnotrequired for study. Company Sanitized. Doos not contain TSCA CBI - = H9-02-4D5a1y6:GavSaubgeehSrtoundiyc iTnoxRiactistywithOneGeneration Reproduction Evaluations DuPont5386 TABL2E MEAN DAILY DOSE VOLUMES (mL) FOR MALE RATS Grmogu/pkaT/day G2r5oumpg/x1a1/2day G1r00oupma/vkg/day o0aoar6 02.2505) 02520s) 2.0.52035) b7aDyAY 13 03.21 05) 03..0205) 30..21035 ) DAY 14 DA2Y0 03.3605) 30630s) 05.16305) bay 21 DAY 27 04.0 .3045) 50..93035) a0103038) DAY 20 DAY 34 o4.l3atas ) a0.34035 ) a033035) DAY 35 DAaY1 40.l5aas ) a016405) 0a36035) DAY 42 DAY 48 03.36 05) 05.3605) 30..63035) DAY 49 DAY 55 03..83645) 03.37035) 0.3.3035) DAY 56 -DAY 62 o3.l9awss ) 05.84035) 30.830s) DAY 63 DAY 69 40.04s) 3.0.94035) 05..03038) DAY 70 -DAY 76 4l.a1 ws) 40..04035 ) 40.30035) AY 77 DAY 83 40.25s) 0a.14015) 03.3904) DAY 8 DAY 8 04..35025 ) a0.2415) 03s304) DAY 90 a0s400) 4053010) 40.200 Group vit 250 mg/ka/day 20..5205) 30.12085) 30.36085) a0.0305) aa3s) oalaws ) 036305) 30.36045) 03.3604s) l3.a7ws) 3o6lds) 03..64026) 03..8425) 40..03610 ) Data summarized as: MSetaanndard Deviation (n) -- Contpany Sanilized, Does nol contain TSCACBI -- H9-02-4D5a1y6:GavSaugbeehSrtoundiyc TinoxRiactistywith OneGeneration Reproduction Evaluations DuPont 5386 TABL3E MEAN DAILY DOSE VOLUMES (mL) FOR FEMALE RATS Grmogu/pkg1/1day G2r5oumpg/kTgv/day G1r00oupma/vIkg/day G2r5o0umpg/VIkIgI/day DAY 0-DAY6 10.2945) 10.92035 ) 10.l913s) 10.2914s) D7A-DYAY 13 20.210s) 20.2204) 20.112035) 20.22 1s) DAY 14 - DAY 20 20.230s) 20..3204) 20.23035) 20..42045) DAY 2-D1AY 27 2o.l52tas) 2.2.6200) 20.25 3s) 20.25045 ) DAY 2-8 DAY 34 20.l62eas) 2.07204) 20.l62635) 2o.6la) DAY 3-D5AY 41 20.l83us) 20.2803) 20.l72035) 2.8i205) DAY42 -DAY 48 20.21 08) 20.22 33) 20.l12035) 20.1 l205) DAY49 -DAY 55 20.l22aas) 20.22033) 20.l12035) i2.21 05) DAY56 -DA6Y2 20.l32tas) 20.23033) 20.122035) 2i.21 00) DAY 63 DAY 69 2o.l32aas) 20.23 03) 20.122035) 20..1204) AY 70 -DAY76 02.2314s) 20.24 03) 2.22205) 20..12143) DAY 77 - DAY 83 02.333025) 02.23 13) 20.22s) 20.1 2024) DAY 84 -DAY 90 20.34025) 02.l32a3) 2o.l22as) 2.2 012024) DAY 50 - DAY 92 20.330) 02.2409) Data surnarized as: MSetaanndard Deviation (n) 2.2i200) 2.2 01209 ) Company Sanitized. Doss notcontain TSCA CBI 0 -- H-24516: Subchronic Toxicity 90.Day Gavage Study in Rats with One-Generation Reproduction Evaluations DuPont-5386 TABL4E MEAN BODY WEIGHTS (g) OF MALE RATS. 0 mGgr/okugp/dTay 25 Gmrgo/ukpa/1d1a1y 100Grmoau/pkaV/day 250Grmoau/pkaV/IdLay Dosing Period for Subchronic Toxicity and Reproduction Evaluations oY 0 25108.51045 ) 22070.070035 ) 25108.04035) 25117..6205) AY 7 32035..62045 ) 30244.13205 ) 30271.088035) 32122.092045) AY 14 32569.22045 ) 35268..65035) 32567.113035) 326601.01045 ) bay 21 39383.037085) 33922..8205) 39288.183035) 40340.90045 ) Day 28 1382.7005) 42385.010035) a30108035) 43327.6005 ) -- AY 35 5a7t.i5aus 45369.06405) 5358.1305) 5399..35045) ov 2 8433.21025) a0n.n605) 47366.020035 ) 4105..97045) AY 49 s5o11.55035) 9403.28205) 49337.51035) 8[3.E0RIE DAY 56 51590..04045) 50570..01035 ) 50389.81035) 48466..60805 ) DAY 63 53553.045045 ) 552131.65035 ) 52150.3505) 887..670045 ) ay 70 55516..17045 ) 553281.65035 ) 51373.108035) 47538.280045 ) av 720 55680.81020 ) 55483.13820 ) 55389..57020) 4799..160019) Company Saniized. Doss not contain TSCA C81 El) 9H0-2-4D5a1y6:GavSaugbcehSrtoundiyc TinoxRiactistywith One-Generaton Reproduction Evaluations DuPont.5386 TABLE 4 (CONTINUED) MEAN BODY WEIGHTS (g) OF MALE RATS 0 mGgr/okugp/d1ay 25 Gmrgo/ukpg/TdIaTy Group Vv Group VII 100 mg/kg/day 250 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) oay 77 56550..5425 ) 54535.079015 ) 51530..770015 ) 41597..250025 ) DAY 84 56579..56025 ) 5595..27015 ) 52338.23004) 50582..828025 ) oY 90 56730..5025 ) 56602.17015) 53317..140014) 552121.188025) One-Month Recovery Period for Subchronic Toxicity Evaluation oY 98 57683.026015 ) 5399.3605 ) 52379.091s 55268..29415 ) AY 105 58763.82015) 54592..5905) 56163..50405 ) 56320..730815 ) - av 112 59780.157015 ) 55563.890s) 56256..4485 ) 56470..684015 ) ay 119 59773.54015 ) s6s20..5605 ) 53518.17905 ) 54884.06 1s) Company Sanflized. Doss no! contain TSCACB - w 9H-02-4D5a1y6:GaSvuabgeehrSotnuidcy iTnoxRiactistywithOne-Generation Reproduction Evaluations DuPont-5386 TABLE 4 (CONTINUED) MEAN BODY WEIGHTS (g) OF MALE RATS 0 mGgr/okugp/day 25 Gmrgo/ukpg/1d1a1y 100Grmogu/pkgv/day Group VII 250 mg/kg/day hree-tonth Recovery Period for Subchronic Toxicity Evaluation AY 126 56370.3405) 5455.03 s) 53612.01905 ) 153009.1075 ) Day 133 53826.03 10) s6415.130s) 54s5d.l1ors ) 1sa163..1305 ) DAY 140 53929.06565) 56594.5305) 56508.5205) 515067..69(5 ) DAY 147 598.3265) se516..975 ) 57650..0765) 157130..63(5 DAY 150 60i6s.9is) 58569..5705 ) 56873.1.45) 518028..46(5 ) DAY 161 61s4l.4ots) 5S921.105) 59647..6505) 519036..90(5 ) DAY 168 61a9.s1 a) 60s2.1s) 6078.0075) 16017.374s) DAY 175 63553.5805) 60s9a.7is) 61B8i.6las) 611102.8605 ) Tata summarized asi SWteamndard Deviation (n) # Sttraetnidsttiecsatl.ly significant difference at p < 0.05 by Jonckheere-Terpstra a. Ronatstedstesidganyat7e4;d sfuorbserqeupernotducdtatiaonareevalrueaptoirotned (a2s0 praartts/gorfoutph)e rweeprreodcuocntoiuosned evaluation Company Sanitized. Dossnotcontain TSCA CBI ws H-24516: Subchronic Toxicity 0-Day Gavage Study in Rats withOne-Generation Reproduction Ealuations DuPont5386 TABLE MEAN BODY WEIGHTS (g) OF FEMALE RATS mGgr/okugp/d1a1y 25 Gmrgo/ukpg/1dvay 100Grmogu/pkgV/Iday 2G5r0oumpg/IkgI/Dday Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 19115.01505 ) 19125.04205) 18174.605) 19a0.l3 s) oy 7 21149.032085 ) 21159.04504) 21115.194035) 21158.560s) ov 14 23220.155045 ) 23139..9004) 23118.66035 ) 23270.153045) oa 21 24291.128045) 25202.18106) 20179.181035 ) 25212.196045) Day 28 26226.165045) 26273.164034) 26202.109035) 26243.111s) DAY 35 27266.103045) 28202.157033) 26283.177035) 27243..94045) - DAY 42 28237.00805) 29206.177033) 272149.101035) 28233..60045) DAY 49 20238.109045 ) 20278.173033) 28262..00035 ) 28278.60045 ) ay 56 30209.050045 ) 30210.59033) 28280.167035) 28332.0730044) oY 63 30280.038045 ) 30271.189033) 20221.7205) 28219..520044 oa 70 31300.14315) 32137..89033) 29189.82035 ) 28302..068003) ay 740 30390.12220 ) 31381.52020) 30126.282020 ) 28327..23009) Company Sanitized. Doesnotcontain TSCA CBI w -- H9-02-4D5a1y6:GaSvuabgeehrSotnudiyc TinoxRiactistywithOne-Generation Reproduction Evaluations DuPont 5386 TABLE 5 (CONTINUED) MEAN BODY WEIGHTS (g) OF FEMALE RATS mGgr/okugp/d1ay 25 mGrgo/ukpg/dTavy 100Grmoaulpka/VIday Group VIII 250 mg/kg/day Dosing Period for SubchronicToxicity Bvaluation (continued) oy 77 1311s9025) 30255..74013) 20221.820015) 27246..570024) DAY 84 31373.019025) 30295.54013) 29230.660015) 29265..578024 ) DAY 91 308.01025 ) 32100.04503) 29252.1838015) 29298.940824) One-onth Recovery Period for Subchronic Toxicity Evaluation oAY 98 3a322.l1aas) 30158.650) 26260.6805) 30280..84015) --- DAY 105 3s37l.0101s) 30270.07800) 2911.86305) 31303.24015) DAY 212 38471.38 04) 31271.100) 26389.04205) 338a.86015) bay 119 35080.135014 ) 32200.27 0 24626..2905) 32a2.s5 s) Company Sanitized. Does notcontainTSCACBY 910.2-4D5a1y6:GaSvuabgcehrSotnuidcy TinorRiactistywith One-Genertion Reproduction Evaluations Dupont 5386 TABLE (CONTINUED) MEAN BODY WEIGHTS (g) OF FEMALE RATS 0 G'rwoau/pka/1d1ay 25Grmoa/wkgI/vday 1G00romwa/VkIa/dey 2G5r0oupma/VkIIaI/day Three-Honth Recovery Period for Subchronic Toxicity Svalustion DAY 126 29D 2.6 s 5m17.i7a 20S3e.2as 0 3s25.i0s DAY 133 3018.7470) 32215.04064) 3012.7456) 3S32.900 DAY 140 3017.68a 33239.05504) 30w3.a1 s) 3s38.s0 s) oar 147 31155.i380s 33289.07306 3130.29 6) 30590.405 oa 154 32160.53 5 0 3426.33070) 31068.10s 35S6i.l7as Day 161 3322.9s 0 32449.03 90) 319.8ses 3S626.126 ) oay 168 32291.60s 34.6ae) 32S22.020 3$591.2.20) oay 175 32Z8.1s 0 sas ie) 32365.05665) 36S1a.7las) Tata sumeTEed as WSetaamndard Deviation (n) 4trSetndatitsestti.cally significant differences at p < 0.05 by Jonckheere-Terpstra a. oRnatstesd:esdiagynat7e4;d sfuorbserqeupernotdudcattiaonareevalrueaptoirotned (a2s0 praartes/gorfoutph)e wreerperodouhcotuisoend - Company Sanitized. Does notcontainTSCACB wo 9204.5D1a6y;GoSvbaegherSotniacy TinoxRas with OneGeneon Reproduction Ealions Duron 386 TABL6 E MEAN BODY WEIGHT GAINS (g) OF MALE RATS oGarloaws1ny c5roump/k1a1r1day GSoroowma/ka/day G3r50oumpalvkizg/day Dosing period for subchronic Toxicity and Reproduction Evaluations Davo - oar 7 owas ow ie maean ow a oars one ae or 3s oa ss ora sTshsasy sSosous) ah2:s) 3s30 y 2S6o3us) aTsshus) seh. ous) 523.30s) 36H.2H 3h.3as 3s0.o5 ns) 1i0.b50s) 5(.0RI 0S.2os) aaas 52T.i3 es) 2S.0os) aSiies, oTais) EYsles caaslees 2G9i.0l1es) 25o.3us) 1165.0h - DAY 42 - DAY 49 1S8.h4 as) 1T3.o7 es) 316.39 s) a7b.s8%us) owas oar ss 1W19u) 163Bes) 15.0k0es) assaus) arse owe iTshous) 1T6.95Zes) 1T.2hasy aslabeus) ont es ov 0 iSsous) 1S5.e0es) d1esms) "iss.ets) oh 70 <p er S36eor eosae 2S3huey siesas) SRS TER TE soim.co) 30H0.e5 o) 3B01.a9 er 22S5.h00e (Company Sanitized. Does not containTSCA CB --_-- 19.02-6D5a1y6:vSaubgchrSotniyc iTnoRsts ith OneGeneration Reproduction Evssins Duron "TABLE 6 (CONTINUED) MEAN BODY WEIGHT GAINS (g) OF MALE RATS 0 FGoroNwart1ny 25Gmrooxwar1d1ny 10G0r0o/wkaVsany Dosing Period for subchronic Toxicity Evaluation (continued) owe 70 - owe 71 w2i:ses) rosecs) m2aas) one 77 - ony 8 1T2.a0es) 12e.s0as) l1e2as) oar 84 - nv 90 66070s) 1s2a05) a7c.9 e) SRE 0 To 5D 2W22i.s7 es) asa.e0as) maiweiae) 3r56ow23/viar/day oasses) 2a.o60s) nas tes) am4naz0s) One-Month Recovery Period forSubchronicToxicityEvaluation on 90 - ony 98 50.02 s) 1e02ss 0 maans) oar 99 - ony 10s wii)ns) 10s.2os) csaeas) oar tos cow 1T2sausy 7.w06 rnses) oy uz owns 1Waas) gwaales w=as) 12. seas) 6a0es) a6us s) aaous) oar 90 - oar 119 w0a.us) nwaas) aolese) 2t5r.1ees) CompanySanilzed, DossnotcoTnSCAnCE! --_-- `H9-02-4D5a1y6:GaSvuabgcehrSotnuidcyTionxRiactistywithOneGeneration Reproduction Evaluations DuPont-5386 TABLE 6 (CONTINUED) MEAN BODY WEIGHT GAINS (g) OF MALE RATS mGgrrokugp/dTay 25 Gmrao/ukpg/IdIaIy 100Grmogu/pkgV/day Group VII 250 mg/kg/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 119 - DAY 126 0.6 1.2 0.6 7.9 14.205 0) 10705) 26.405 7.065 DAY 126 - DAY 133 15.0 6.005 ) 15.8 15.205 1) 14.0 18.765 ) 16.1 6.205 ) DAY 133 - DAY 140 10.2 0.745) 8.8 10.85 ) 15.4 9.305) 10.5 5.805) DAY 140 - DAY 147 5. 18.405) 12.1 3.60) 1.4 3.5(5 ) 17.0 7.305) DAY 147 - DAY 154 6.6 as 12.1 8.7 --- 2.905 ) 7.005) 1.305) 5.605 ) DAY 154 - DAY 161 7.5 5.6 7.005 ) 1.96 7.5 7.05) 11.5 6.705 DAY 161 - DAY 168 4.7 8.3(s ) 10.0 3.605) 13.4 10.7(5 13.9 9.005 DAY 168 - DAY 175 16.4 6.05) 7.6 6.9(5 ) 10.7 6.205 2.9% 7.205 1) DAY 115- DAY 175 68.7 37.465) 57.2 13.365) 85.9 29.105) 88.68 14.9(5 ) Tota summarized asi WSetaanndard Deviation (n) # Sttraetnidsttiescta.lly significant difference at p < 0.05 by Jonckheere-Terpstra * Statistically significant difference at p < 0.05 by Dunnett's test. a. oRnatstesdtesdiagynat7e4;d sfuorbserqeupernotdudcattiaonareevalrueaptoirotned (a2s0 praartts/gorfoutph)e wreerperodcuochtoiuosned evaluation. Company Sanitized. Does not contain TSCA CBI 0H--2D4a51y6:GaSvuabgcehrSotnuidcy iTonxRicaittsywithOne Generation Reproduction Evaluations DuPont:5386 TABLE7 MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS 0 Gmrgo/ukpg/1d1ay 25 Gmrgo/ukpg/IdVay 100Grmogu/pkgV/Iday Group VIIT 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 23.3 8.6045) 22.5 7.504) 26.3 6.1035) 25.3 6.5045) DAY 7 - DAY 14 18.0 7.1045 ) 18.4 19.7 8.104) 6.905) 22.08 5.8045) DAY 14 - DAY 21 16.8 6.9045) 21.0 6.0034) 16.2 6.4035) 14.48 6.7045 ) DAY 21 - DAY 28 13.4 7.305) 12.7 12.2 7.6036) 10.9035 ) 12.2 6.7045) --_ DAY 28 - DAY 35 1.4 12.0 8.78 10.8% 7.205 ) 6.2033) 9.2035) 6.1065) DAY 35 - DAY a2 7.1 6.3045) 10.2 10.3 6.603) 8.305) 8.7 5.705 ) DAY 42 - DAY 49 19.0 5.6045 ) 7.08 7.8031 7.00 10.8035) 3.0 14.1045) DAY 49 - DAY 56 7.4 7.8045) ar 11.6033) 2.78 5.6035) 4.5% 14.5044) DAY 56 - DAY 63 3.8 7.2045) 6.0 9.7033) a0 6.505) -2.2 22.2044) DAY 63 - DAY 70 6.1 6.1045) 5.9 6.4033) 5.5 7.305) 1.7% 22.4043) DAY 70 - DAY 74 1.0 4.220) 1.7 11.2020) 1.7 10.0020) 4.4 31.9019) AY 0- DAY 74 115.5 120.3 ms 20.120) 21.520) 15.2(20) 85.98 32.1019) Company Sanitized. Does not contain TSCA CBI 50 -- H9-02-4D5a1y6:GaSvuabgcehrSoundicy TinoxRicaistywithOne Generation Reproduction Evaluations Dupont5386 - TABLE 7 (CONTINUED) MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS 0 mGgr/okgw/dIaTy 25Grnoau/pkaI/vday 10G0romugp/kva1/day 25G0rowuap/kVaI/IdIay Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 13 450s) 14 e203) 2.2 7.28 saus) 16.3024) DAY 77 - DAY 84 5. 5.605) 3.6 3.903) 1a 22.00 6.0us) 12.9028) DAY 84 -DAY 91 1.0 Be@s) 10 2.2 5303) was) 2.8 87024) DAY 0- DAY 91 129.1 125.1 13.10 1a. 2.5025) 200803) esas) 20.2024) One-tonth RecoveryPeriod for subchronic Toxicity Evaluation - DAY 91 - DAY 98 10.8 7.9 0.3 5.4 BsEs) 7) sles 0 10205) DAY 98 - DAY 105 5.0 2.0 70s) 62) 5.0 4065) 5.5 5.905) DAY 105 - DAY 112 10.0 mse) 9.4 32 ew) 2.006) 8.2 6205) DAY 112 - DAY 119 0.5 Tea) 5.6 6.2 3200 2836) 5.9 580s) DAY 91 DAY 119 21.6 2.9 a1 2.2 Baca) S06) 2am) 19.105) -- ZompanySanfized. Does not containTSCACB = -- H-24516: Subchronic Toxicity 90-Day Gavage Study inRatswith One Generation Reproduction Evaluations DuPont-5386 TABLE 7 (CONTINUED) MEAN BODY WEIGHT GAINS (g) OF FEMALE RATS 0 Gnrao/ukpg/1d1ay 25Grmogu/pkgI/vday 100Grmogu/pkgv/Iday 25G0romugp/kVgI/dLay Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 115 - DAY 126 5.9 7.965) -3.0 2.04) 11.08 18.905) 3.28 5.365 ) DAY 126 - DAY 133 15.8 3505) 9.7 8.2 2.84) 12.105) 8.9 sas) DAY 133 - DAY 140 0.6 4905 0 6.1 70) 17 7.205) aa 8.805 ) DAY 130 - DAY 147 7.5 2.85 1) 5.2 7.806) 7.8 11.4 5.105) 4205) DAY 147 - DAY 156 1.0 5.5 5.2 7.3 -- 10.005 ) 7.608) 8.905) as) DAY 154 - DAY 161 6.6 7.65 0 0.1 7.006) 3.7 7.005) 5.4 465) DAY 161 - DAY 168 DAY 168 - DAY 175 5.7 7.605 1 15 3.265 ) a3 2.266) 2.3 a6 2.28 0.905 1 a5 5.305) 2.98 1.465 ) 2.5 4205) DAY 119- DAY 175 29.6 30.3 a2 39.9 16.505 ) 8.364) 18.905 1) 15.15 ) Tata summarized mer WSetaasndard Deviation (n) # Sttraetnidsttiecsatlly significant difference at p < 0.05 by Jonckheere-Terpsira a. Roantstesdtesdiagynat74e;d sfuorbserqeupernotdudcattiaonaerevalrueaptoirotned (a2s0 praartts/gorfoutph)e wreerperodcuochtoiuosned evaluation. Company Sanitized. Does not contain TSCA CB! 5 9H0--2D45a1y6G:avSaugbcehSrtoundiyc iTnoxRiactistywith One-Generation Reproduction Evaluations DuPont5386 TABLE MEAN DAILY FOOD CONSUMPTION (g) OF MALE RATS mGgr/okugp/d1ay 25Gmrgo/ukpg/TdIaTy 100Grmogu/pka/day Group VIT 250 mg/kg/day Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 25.8 25.8 26.1 26.5 2.205) 2.5035) 2.2035) 2.805) DAY 7 - DAY 14 DAY 14 - DAY 21 DAY 21 - DAY 28 27.4 2.905 ) 26.3 2.6085 ) 28.2 2.805) 27.7 2.8035 ) 28.1 3.205) 28.2 3.205) 28.1 2.7035) 28.1 2.305) 28.9 2.605) 28.58 2.405) 28.2 2.6045 ) 28.6 3.70) ~ DAY 28 - DAY 35 28.5 2.705 ) 29.2 3.408) 30.0 5.6035) 29.2 2.905) DAY 35 - DAY 42 28.7 2.705 ) 28.8 3.108) 29.1 2.605) 20.5 3.605) DAY 42 - DAY 49 29.2 2.6045) 27.6 4.005) 28.6 3.605) 26.26 3.305) DAY 49 - DAY 56 DAY 56 - DAY 63 DAY 63 - DAY 70 DAY 70 - DAY 74% 29.2 3.005) 28.9 4.2025) 28.9 3.3085) na 4.1020) 29.1 4.1035) 28.9 3.405) 28.8 3.405) 30.1 3.2020) 29.4 2.505) 29.5 2.9035 ) 28.8 4.5035) 28.8 3.7020 ) 26.08 4.805) 24.50 sas) 21.80 7.905 ) 25.20 7.5019 ) DAY 0 - DAY 74 28.4 2.5020) 28.4 3.2020) 20.5 2.0020 27. Los) Company Sanitized. Doesnotcontain TSCACB 5 -- 9H0--24D5a1y6G:avSaugbcehrSotnuidcy TinoxRiacttsywithOneGeneration Reproduction Evaluations DuPont 5386 TABLE 8 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY MALE RATS. Gnrao/ukpa/Tday 25Grnoau/pkaT/dIay 100Grmogu/pkgv/day 25G0romugp/kVgI/Iday Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 28.2 27.4 25.7 2.20 3.5025) 3505) 5.8015) 5.9025 ) DAY 77 - DAY 84 20.0 27.9 25.0 26.8 3.6025) 310s) 3.504) 3.505) DAY 84 - DAY 90 21.0 2.9025 ) 26.3 3.5015) 20.7 2.9014) 25.3 3.705) DAY 0 - DAY 90 28.2 27.9 27.1 26.20 2.4025) 2.605) 2.004) 2.4025) -- One-onth Recovery Period for Subchronic Toxicity Evaluation DAY 90 - DAY 98 28.4 26.8 25.08 25.48 2.708) 2.405 ) 3.605) 2.9015) DAY 98 - DAY 105 28.0 5.0015 ) 27.7 2.605 ) 22.4 12.305 ) 25.60 3.505) DAY 105 - DAY 112 DAY 112 - DAY 119 28.7 2.8015 ) 26.2 5.0015 ) 27.7 2.265 ) 25.9 4.25) 25.0 5.505 ) 25.5 440s) 20.70 3.805) 25.4 3.305) DAY 90 - DAY 119 27.8 310s) 27.0 2.405) 2.6 416) 25.38 3.1018) Company Sanitized. Does not contain TSCA CBI % -- H-24516:Subehronic Toxicity 90-Dey Gavage Study in Rats with OneGeneration Reproduction Evaluations DuPont-5386 TABLE 8 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY MALE RATS Gmrgo/ukpg/day 25 Gmrgo/ukpg/1d1a1y 10G0romugp/kva/day 2G5r0oumpa/IkaI/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 119 - DAY 126 27.3 26.2 25.5 25.1 0.565 ) 0.965 ) 6.365 ) FRTE DAY 126 - DAY 133 27.5 26.5 27.3 25.8 1706) 6.205) 1.965) PRTC DAY 133 - DAY 140 DAY 140 - DAY 247 27.9 4305) 26.0 7.005) 26.7 2.705) 29.5 2.365) 26.5 7.805) 37 3.005 ) 26.9 2.505 ) 20.8 2.865 ) DAY 147 - DAY 154 30.4 30.6 sz 29.5 - 2.265) 18s) 3.205 2.965 ) DAY 154 - DAY 161 32.4 2.405 ) 25.8 30.9 1.805) 3.605) 30.7 3.96) DAY 161 - DAY 168 29.5 29.2 11s) 1.905 3.6 30.9 5.205) 3.365 DAY 168 - DAY 175 30.8 29.0 30.7 28.9 5 2.905 ) 2.005 ) 4.205) 3.45) DAY 119 - DAY 175 29.0 28.6 29.5 28.3 2.265 ) 170s) 2.805 ) 3.205) Data suarized asi WSetaanndard Deviation (n) # Sttraetnidsttiecsatl.ly significant difference at p < 0.05 by Jonckheere-Terpstra a. oRnatstesdtesdiagynat74e;d ffoorodrceopnrsoudmupcttiioonn deavtaaluwaetrieonno(t20corlaltes/cgtreodupd)urwinegrethceohoused cohabitation and postmating periods. Company Sanitized. Docs not contain TSCA BY -- 55 9H-02D4a51y6:GaSvuabgcehrSotnuidcy TinorRiatcsiywith OnGeeneration Reproduction Evaluations DuPont 5386 TABLE9 MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS 0mGarlokupg/d1ay 25Srmoaw/pkgI/vday 10G0romugp/kvgI/day 2G5r0oumpg/vkgi/rday Dosing Period for SubchronicToxicity and Reproduction Evaluations bar o-Dav7 DAY 7-DAY 10 DAY 14 - DAY 21 18T.7os) 220.21 05) 129.0920s) 18l.9od) 194.09 04) 203.90a) 117.590s) 18T.i50ss) 191.69 0s) 1s.0a0s) 191.6484s ) 202.380s) DAY 21 - DAY 28 129.0730s) 204.0604) 129.88035) 202.0000s ) DAY 26 - DAY 35 212.0030s) 23.3503) 129.4305) 202.l620s ) -- DAY 35 - DAY 42 202.04205) 231s0) 182.4880s ) 192.06200s ) DAY 42 - DAY 49 20l.8as) 21W.3003) 202.40 0s) 19S.l0a0ts) DAY 69 - Dav 56 DAY 56 - DAY 63 AY 63 - DAY 70 DAY 70 - Dav Tat 212.1s) 212.l10ws 202.0920s) 221.0900) 2lsoess) 20T.9s03) 202.53303) 213.73020) 201.75 0s) 129.15005) 191.1090035 ) 202.02 00) 92.30a 147.590844) 156.270843) 1201.3400s) DAY 0-DAY 76 201.15920 ) 231500) 201.00a) 129.08009) Company Sanitized. Docs not contain TSCA CBI -- ~~ 0H--2D4a51y6:GavSaugbeehSrtoundiyc iTnoxRiactistywith One-Generation Reproduction Evaluations DuPont 5386 TABLE 9 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS 0 Gmrgo/ukpg/1d1ay 25Grmogu/pkgT/vday 10G0romugp/kvgI/day Group VIII 250 mg/kg/day Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 DAY 77 -DA8Y4 DAY 84 - DAY 91 212.016025) 213.64025) 193.10s) 202.09703) 203.81a) 192.30303) 19F.2R8YE 181.9880s) 127.0300s) 146.163004) 223.60a) 183.82a) DAY 0 - DAY 81 201.740s) 201.13) 8T.6i0ss) One-Month Recovery Period for Subchronic Toxicity Evaluation 16l.8a0a) DAY 91 - DAY 98 DAY 98 - DAY 105 DAY 105 - DAY 112 DAY 112 - DAY 119 203.24 05) 211.310s) 212.l6s04) 213.54304) 15.07a 201.0 ) 201.750) 20L.4a) 171.71 6s) 181.3a) 17a.l9as) 16s.a9 s 1l9.a7cs) 203.l36u)s 129.015805) 9.3 3s) DAY 91 - DAY 119 212.02504) 201.030) 1m2.l965 ) 129.l6801)s Company Sanilized. Does notcontalnTSCACB 5 -- -- H9-02-4D5a1y6:GavSaubgcehSrtoundiyc iTnoxRiactistywith OneGeneration Reproduction Evaluations DuPont 5386 TABLE 9 (CONTINUED) MEAN DAILY FOOD CONSUMPTION (g) BY FEMALE RATS 0 Gmrgo/ukpg/IdTay 25 Gmrao/ukpa/Idvay 10G0romugp/kIa/day Group VIII 250 ma/ka/day Three-Month Recovery Period for Subchronic Toxicity Evaluation DAY 119 - DAY 126 DAY 126 - DAY 133 DAY 133 - DAY 140 DAY 140 - DAY 147 DAY 147 - DAY 156 DAY 154 - DAY 161 DAY 161 - DAY 168 DAY 168 - DAY 175 129.04265) 211.2a) 220.11265) 211.97s) 233.2k) 2240.206s 223.55 06) 201.965) 201.6a) 201.4a) 22T.0aw) 221.33 04) 231.120) 2i.3e 21T.a7 w 221106 202..6865 ) 202.0316s 22a.8s) 24l.a5 s 212.0316s) 222.06565) 212.l3a5 213.0s) 18.5 20665 ) 182.042805) 203.24 05) 222.0346s 222.0976s 222.05665 221.28s) 20.6 20265) DAY 119 - DAY 175 212..7165) 21.6s) 212.080s) 211.9065) Tata summarized asi WSteaandard Deviation (n) # Sttraetnidsttiecsatl.ly significant difference at p < 0.05 by Jonckheere-Terpstra 4 Statistically significant difference at p < 0.05 by Dunn's test. a oRnatstedstesidganyat7e4;d afotrarweeprreodunocttiocnolleevcatleudatidounrin(g20threatsc/oghraobuipt)atiwoenreancdohoused postrating periods. Sompany Sanitized. Does not contain TSCA CBI x -- 0H--2D4a51y6:GaSvuabgcehrSotnuidyc TinoxRiactlstywithOneGeneration Reproduction Evaluations DuPont 5386 TABLE 10 MEAN DAILY FOOD EFFICIENCY OF MALE RATS (g body weight gain/g food consumed) 0 Grroo/ukpa/day 25Grmoau/pkaI/IdIay 10G0romaw/kva/day 25s0romuap/kvai/tday Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 00..300276045) 00..30134235) 00..30130335) 00..3033128045) DAY 7 - DAY 14 00..206227(45 ) 0.02.70028(35) 00..200295035) 00..2032548(45 ) DAY 14 - DAY 21 00..201218(45) 0.01.80425(35) 00..201238(35) 00..202252%045) AY 21 - DAY 28 00..106268(85) 00..107288035) 00..105392035) 00..113259%045) DAY 28 - DAY 35 00.012391(45 1 00..104381(35) 00..101259035) 00..102246(45 ) - DAY 35 - DAY 42 00.012257(45 ) 0.00.901286(35) 0.1.003246(35) 00..0172260045 ) DAY 42 - DAY 49 00.00389845) 00..006386(35) 00..00798535) 00..0036874045 ) DAY 49 - DAY 56 00..008560(45) 00.l0072B1(35) 00..0073258035) -00..0214968(45 ) DAY 56 - DAY 63 00..007458(45) 00.1008510035) 00..00833335) -0.00.110386(45) DAY 63 - DAY 70 00.l007266(as) 00.l002771035) 00.102311735) -00..3961890(45 ) DAY 70 - DAY 78% 00..002483(20 ) 0.00.50361(20) 0.001l704220) 0.00.74736(19 ) DAY 0 - DAY 74 00.011416(20) 00..104131(20) 00..10401920) 00..101145819 ) -- `Company Sanitzed. Doesnotcontain TSCA CBI -- 910.2:4D5a1y6:GavSaugbcehSrtoundiyc iTnoxRitcistywith One-Generaton Reproduction Evaluations Dupont 5386 TABLE 10 (CONTINUED) MEAN D(AgIbLodYyFwOeiOgDhtEgFaFinI/CgIfEoNodCYcoOnFsuMmeAdL)E RATS 0 mGgr/okwg/dIay 25Grmoau/pkaI/dIay 10G0romugp/kvo/day 25G0romuap/kvai/zday Dosing Period for subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 90 00.00297s) o0.l0o6d3s(zs ) 00.00835525) 0o.l08o5sis) l0.0o59s) 00.l002784(15) -00.3042805) -00.10808914) 00..00580914) 0-.03.03237(25) 00..711506385) 0.00.604802365 1 DAY 0 - DAY 90 00.01126225) 0o.l1o2l42as) 0.01010690(14) One-onth Recovery Periodfor Subchronic Toxicity Evaluation 0.0.611105285) - DAY 90 - DAY 98 00.004828015) 00.0026605 ) 00..0018930(s ) 00..004632(145 ) DAY 98 - Dav 105 00.01243s) 00.005213s) 25..335952(5 ) 0.00.40540115 ) DAY 105 - DAY 112 00.003871015) 00.l0o376a(s 1) 00.l017z5a(s 1 0.00.70301015) DAY 12 - DAY 119 00.101221015) -00l.003830(5 1 00.l0l2a8s(s 1 0.00.40434(81s) DAY 90 - DAY 119 00.00147715) 0.000330s ) 00.l000279(s ) 00..603437(15 ) - Tw. `Company Sanilized. Does not contain TSCA cay 1902-4D3a1y6:GavSaugbcehSrtoundiycTionxRiactistywith One-Generaton Reproduction Evaluations Dupont5386 TABLE 10 (CONTINUED) MEAN D(A8IbLoYdyFwOeiOgDhtEgFaiFnI/CgIfEoNodCYcoOnFsuMmeAdL)E RATS 0'Gnrgo/uipg/Iday 2G5romuap/kIgI/Iday G1r00oumpa/Vka/day G3r50oumpe/vikza/day Three-Month Recovery Period for Subchronic Toxicity valuation oaY 119 - DY 126 00.0007225) 00.l003996(s 1) "00..028015(5 ) 00..00348(65 ) oAY 126 - DAY 133 00.007381s) 00l.o0B780(s 1 00..009m(s ) 00..00381(95 ) DAY 133 - DAY 140 0o.l0o4a9ss 1 00.l0040ss ) 0.00l9o2vis 1 0.06.3045185 DAY 140 - DAY 147 -o0l.100s0e(s ) 0o.l0o5w8(s ) 0o.0l66i 1 00..00(83s ) DAY 147 - DAY 154 0o.l0o4l1as ) 0o.l0o1k2s ) 0o.0l56s 1 0.00.030735 - oaY 154 - Dav 161 0o.o03z1es) o0l.o0o28R(s 1 00.l0o3a3s(s 1 0.00.035055 av 161 - OAY 168 Day 168 - DAY 175 0o.l0o2a1sts 1 00.007251s) o0.l0o8w9is ) 00.00337 s) 0o.l0o5a6acs 1 02.l004283(s ) 0.2.0036025 00..003155(50 ) DAY 115 - Dav 175 00.00240105 1 00.l0o376(s ) 0.o0l5o2las 1 0.06.0055(56 ) -- EE Standazd Deviation (n) + STtraetnidsttiecaatlly significant difference at p < 0.05 by Jonckheere-Terpstra + Statistically significant difference at p < 0.05 by Dunnett's test 4 oPRnoaststtreasdtteisnidggaynapte74er;idoddfsaotrarweeprreoduncottiocnolelveacltueadtidounrin(g20threatCs/ognraopuipi)atiwoerneancdohoused - mpany Sanitized. Does notcontainTSCA CE H9-02-4D5a1y6G:aSvuabgcehrSotnuidcy TinoxRiactistywith One-Generaton Reproduction Evaluations DuPont-5386 TABL1E1 MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g bodyweight gain/g food consumed) 0 Gmro/okwg/1d1ay 25Grmoau/pkaI/vday 10G0romugp/kvaI/day 25G0romuap/kveI/Idzay Dosing Period for Subchronic Toxicity and Reproduction Evaluations DAY 0 - DAY 7 0.0.107660(45) 00..10740834) 00..10943335) 00..013979(%45) DAY 7 - DAY 14 00..102488(45) 00..103547034) 0.01.50047(35) 0.0.014622405) DAY 14 - DAY 21 0.0.102405045) 00.110436934) 00..101476(35) 00..004948(8d5 ) DAY 21 - DAY 28 00.l0o9a58(ss ) 00.00588034) 00..017506(35) 0.00.0485745 ) DAY 26 - DAY 35 00.1008493(45) 00.1008316033) 00..0066198(35) 0.00.308714485 ) ~ DAY 35 - DAY 42 o0.l0o0a82(45) 00.l006475(33) 0.00l702786(35) 0.00.40060345 ) DAY 42 - DAY 49 00..006374(45) 0.00.400887(33) 00..0048608(35) ~00..109010(8a5) DAY 49 - DAY 56 00..006583(45) 00..002906(33) 00..0013898035) -00..513220(844) DAY 56 - DAY 63 0.0.002433045) 0.01000723033) 00.004288(35) -00..305674(844) DAY 63 - DAY 70 00..004318(45) 00..004413033) 0.0.003580035) 0~.05.222900843) DAY 70 - DAY 74 -00..001540(20 ) -0.00.62269(20) -0.00.82834(20) 0_.o7.31838019) DAY 0 - DAY 740 00.100706720) 00..007183(20) 00..00716020) 0.00.200508189 ) Jompany Sanilized. Does nct contain TSCA CBI 0 -- 91.02D4a51y6:GaSvuabgcehrSotnuidcy TinoxRicaittsywith One-Generation Reproduction Evaluations DuPon5386 TABLE 11 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (g body weight gain/g food consumed) 0 Gmrao/ukpa/IdTay 2G5romuap/kIgv/day 10G0romugp/kvg1/day 25G0romuap/kVaI/IdTay Dosing Period for Subchronic Toxicity Evaluation (continued) DAY 70 - DAY 77 DAY 77 - DAY 84 DAY 84 - DAY 91 00.0000125) 0.0.003346(25) -00.02200825) -00l.o000l2(s 1) 00.1002236013) 00..000482013) 00..000014(s ) 00..000495(15) 00.1001379015) -00..000191(54 ) 0.0.01739620 4) 00..006175(24) DAY 0 - DAY 91 00.00169325) 00..006087013) 0.00.60705(25) 00..000686(24 ) One-tonth Recovery Period for Subchronic Toxicity Evaluation ~ DAY 91 - DAY 98 0o.0i77ls) 0.o0le5d7ne 00.00017s) 0.06.7043015 ) DAY 98 - DAY 105 00.10018515) 00..001446(4 1 0.0.004303(s ) 0.00.30397015) DAY 105 - DAY 112 o0l.0o6s4iiie) 00.00062434 1 -00..028739(s ) 0.00.40250915 ) DAY 112 - DAY 119 -0o.l0o0e0o(ia) 00.l002241(s ) 0o.1l5d9s ) 0.00.30296015) DAY 91 - DAY 119 00.l004440(4 ) 00.l004104t4 1 -00..001555+(5 ) 0.00.20399015) [CH ompany Sanitized. Does not containTSCACBU -- 910.-24D5a1y6G:aSvuabgcehrSotnuidyc TinoxRiactistywith One-Genertion Reproduction Evaluations DuPont5386 TABLE 11 (CONTINUED) MEAN DAILY FOOD EFFICIENCY OF FEMALE RATS (body weight gain/g food consumed) 0 Gmrgo/wkpg/1d1ay 25Grwoau/pkaI/v.day 10G0romugp/kvg1/day 25G0romugp/kVgI/IdIay Three-tonth Recovery Period for Subchronic Toxicity Evaluation DAY 119 - DAY 126 00.l004888(5 ) -00.0.2021714) 0.0.0161958(s ) 00..004223(54 ) DAY 126 - DAY 133 00.l100278(s ) 0.00l6081B4 1 00..006804(s ) 09..006637(5 ) DAY 133 - DAY 140 -00.00073s) 00.l0o3a8Ts ) 00..0010885) 0.00.5082(35 ) DAY 140 - DAY 147 00.001590(s 1) 0i.005324 ) 00..008268(5 ) 00..60277(45 ) DAY 147 - DAY 154 00..0006115 ) 0.00l3os56w4 1 00.l003548(s ) 00..00342(55 ) - DAY 156 - DAY 161 00.l004417(s ) -00.l000a16(4 1 00..0014935 ) 00..00237(3s ) DAY 161 - DAY 168 000.006430(5 ) 001.00122864 1 00..0010558(5 ) -00..007139(58 ) DAY 168 - DAY 175 00.l000291(s ) 00.10013444 J 00..002289(5 ) 00..00310(65 ) DAY 119 - DAY 175 o0l.o0l2a6(s ) 00.l002055(4 1 O0.i03l6s ) 0.00.1023045 ) -- EE Standard Deviation (n) # sttraetnidsttiecsatlly significant difference at p < 0.05 by Jonckheere-Terpstra @+ SSttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt ddiiffffeerreannccee aatt pp << 00..0055 bbyy DDuunnnne'tst'Lsestt.est. a poRnaotssttmeasdtteisndigagynapet74re;idoddfsao.trarweeprreodnuocttiocnolleevcatleudatidournin(g20threatsc/ognraobuipt)atiwoenreancdohoused CompanySanitized.Dossnotcontain TSCA CBI -- To -- - BH i 8 3 i y3e . - wg eg ox :2J 3 Z:g| z 335 g : 3 5 3 ~ 34 z8 : i en. sEzE FF 2 =z 22 3 s=g E3, a 200HER 4 38 2 <z2 gs 3 r Z 5 f n3 : |8 ~g -g ce2 myz ap& 8 or ee8 aez en eo = ok - wy wy ey %&: i s7z1g 3i8: %g83 i3I i3 4 TEE EI EI EI ET LF B.TE EE OGD Rg PD REZ oRE i kg Bg gf" 3% i i2 a g - : 3 : : 33 fs i :eg3i : zdFe eyeeeea2 i SZztf . 8g - z|B 5=Ea2 EI1E42EE23 11352; 2| |5 i %zErBe }i ce. qin i Dota i fy 4 853 ou:, g. ooPgi 44 4 1 5 #i -5 i B3 . 5 Enqs se 3 oar te ove ce 2i g ) i8 5 g3 LB: 23 8 Z=z 2 2E4EE 22 - Zg zZz untis gl =ScS z28 "a 3F=E EC z 1 g 8cS i 7 E is op om we wg me - ai I - - 2 ng en ot o "_ o |2 5$ i5s3 i7t ~ 44 2 i& , g-is:5 f33 F3 i@3 3i?& i73% i5 gp,2 S 38osf #o2g OofH goHd o oid ggsd S781 0L % $5 E 3s OR3E 3 OiHy O4%3 OK0% 1 PiaIC TIE EEI I I 1] B8 i i 3 -4 iz #338 wg8 me2 en nge epr naygB 2 8 3 zz L2k aEI Tg 85 er mg wg ce ag on 3 == 5 22 g8z 3 ~ ZEE =2 Rui2, "ger en EPR os fg 8 18: s| Fg 3Z zcg o4 4: F2E ps oer en " ~z on 3 32 g ~2 i2z bE 3 228g - &54 EH 2 - =zt i i> r g 3g i3 g3 3i i5 iM8T c I= T]: sf i= ot +P FH OH OH 8 i ii Ed 8 3; ff i i EM ;1:3 757S131. MHi, i 8 "| iH fE3yf iI:Z 3g i 285 iFl a82 & 8 - E3E3 5 22 PELHE 2 * g2 g Lis 8Z 8 =Z JO2 N zz ~~ 8Z = ufFas fl 8 3|] 22 yz 55 2= pe yd = i 5$ 72 io3f] E84%0a a3 35 3 "gy` or wga s=g mg= wmig3 5 3 5 at vr st ng e I 2 wg8 wgs we= en o 2N i : 3 on or eg Zag eg er 3 g& 3& Tof: 33 2 33 3Ai5ggy dRs8dg f4s5 iG s5 sE uEeg5 E 2dE:3% i3 ~ us =5g 3a35l z1 ra on x "yng 2: #4 F g8 2" I ep 2 22 =z 5%2 3 g3g2 32 ~ &gEs& 13 H.% gg o. oe = gl = 8 33 42 =Qz 3 2 i3 S 5 z3 gZ23]| xz %EI WBBEa or ol .. g : $ g: @ f3g o. 3 33 z iad ~2 i i3 3@ --~ i354 f iE ed Ef RPEt Bl + | Be i3 :22 - oH I: iz ;3 wixae o -g ws3 8 ~ I& gl 3i&5 : 52| i2 5i zE g i h... g2q 8 28= %Z 3 ZE2z Z2=& oi.isn Sz ag me es & a O sz Zz Zz "3 5> g ' & Ba 2i :: 3 " afi 8ifg fi 3 efo sf ABE gg IE] ga 58g ae 2 3Z 8 3i & o.oo. 8i ms a .2 eee i 1 i3 sf" si2 ggar of2 ~ Eia z2%e g g.u8 ef zPY 3m4E i5s i5% HsEaHg - 6 & & ~3 iz : i5%a -' on ~e ~e 3i 3 8 gE 3 Nbs op2 pe- o i. i 42 x= 2 2 _ J &Zg %ZBE Een ou on on on " 3| 98 2 ) 9 Foz2 3 3 g32: [Z:ZzZoIr. ohpee Io hy t on g2 s 3 if i i iz ig @ 3 5 s : ii 3: | og 48 FR PERL fy gE ga 87 gi ic * & -x i33 gi. 53 "re "2 on : i ii |3 & eli o. : LE B 2 or i3iFgT 8 i: 4i 85 i 22 s28 s1 i$E:i3dd3 fil ~ ir 5 | gg oreo | EF g 1 3% 8 - ;1172iE :8Po ;g s: 3: | iHH g3rI2 l 2i8 F3 5{ S3s -2 % ou on on on i 2i p 8 : : ] 2% 3 & 3 5 wP y o o do.5 3 | wisifs i Bik : . : if ! SHC Ei OE Eg 8 ti -H i 32 ;3 gERgE 8 1 gf 5 sf 22 i= 2 ZEz d3= 2 : -g or a ng g g = 2 &3 :2 % fg: C J 23 = E2:H Sz$ o 5 3 5 I us 4i 2s s a . "3 - fo. 3 3 3 z 22 2 48 of ef. st it ~ i2z EEN EER Is id gg HE H f1y1Iagd:8 ii3%ed 11 3a53 I. $8 2 a 3: g> = i 23 sEjie, e 3 Az aa3 r ef3 fi ! 2 33 3z 3v 52 gbFg, ng ng aeg 2 olen =2 2 == Ee2 & F868 ~ z& EZF=F*, ar es o . ar wg 8 g "a8 i =2 cE iiyq 22 z i53 s 2z z2 i I] !s Zgeysi ne ap "E "28 or on i 3 i2it:g < - ? i 7 z 3 B 8 3 : . 33 o Z2 E LiEE TI4 R MEIE8 EZMAC OEMIE3 4RE] E28Dog4 E i#.f ,E,IE:E 1: 3 4 i 1 5 $1 2 i 3 23 iia | 3 - J 2 ig i 53 H i $2 23 5g FfiEe 2 ] 55 33 e2s 32 a= piFg, = 3 =gz 5 28 3 &EZgzzEE xwia23,n 52 =ERE Fz3 5zfuok.3i% . z v 2 i, e y8 f 5% ai : o Ag oe F cs cm veg a i3 i5 3"3 on on on on ag8 er er er er ug2 . er ere `ee er a 33 %113 %3 T._ %3 a 3 a 8 8% & - = - - 2= HH2 Sf8 EE L, RR EYSE iE BEER 8OEE EEEEGoEi is9 idyogiE fF1 4i i i i --~ 35g 3 :8 i z 3 38 Hie ~g SE a: = "8 oe "2 ~5 3 . i 5% 3 g 3 2ZER vi4B z8 = 8g5 EzZz z2 53 - Z z% z=2i2 gi oa= 22 i| zFsz 3 7 5gFs i2 3 z fe or Cn age wg mm2 an en * ng eg 5 eo or ere 2 ot ot $:$ g 27s iyi 5 1TE3 5T 33 3 5g 5:3 Sig28202Le PE 8 12 i. 32 2 ffaFg S38 8H OBgEHOgE 5 ij is is 8iHF] i t is H sip A Eg EF OBE EEK ag2g EH 8Efggl5:i81s2 433 ai5,8 o3 22i3s 5i358 --~ 33 31f3 iz fl 3 il 1 4 55 g 2 ry 13 3 i35e *e 5 . go:$ 5 Fg =2 = g= 2 2gg%gc: 5&Zz z=on = 38 82 2g ~2 g :SEs isFfe zz = 8 3 ii I: or oa 2 oes wgg em 4 3: 3: 53 g te orfg 8 1 8z 2 8 as en g#e "a2 ||e= or er en a ~ z 7 4 zd: i: i: i: cH g - x = 2i4 ni3e t tg 7s "% ~g 53 EH 2i a 3 i . 2 i 22 whe or s2 =g= 2 log zg 2 -- ZgE gz= 20?s na8 on or or or 2 3gooa303 i 23 1g ~z &: &3 = aiGee a on or on i Pio 3058 fg 8 &: :zy 2%S2| % 285 3g3 g3 i33 3gg 33 3 # = e 3 2 sf 5d gd gd i 2it% ScEs:F sEpLBM E VE EELAERL Y E ef.posai} EM fy if 3 i sit iF 13s5 iddd::3yy -+E i 22| : FF v ::a 3 E Co. 3:&:: sog 0|;5 oJsif1== , ] gPLs 1 1341;8i 8g23 8iss i@ 25.0 iH fIoE gl 3= & ou i1H 8 o 3i1s 13 2 E 1 8r:z iHyE52t j | ;: |4 a |i ] 8 3 3] Zz euri2 : | isd . HE on eo i `i ES ig ii yGd og4 g4 |b5d.4 iif i 8d pIs a$e Vi 8 Bgiac i"i :& HiE : 3 --s iz 235 523 2 i 3 3i 2 sio4r, 3 od .| 3 E os8 2g gE. zi EH] _ NE 4 : 4% ig3g 2Fgg8 @5 2=z 33 EEg3 FE 2 BF 3| x3 a 18 3 3 3i =}LI 8y 38 gc 1 H32 | : gd ei i a33 iil i 2f4y -~ E5 OB Bp, S PEoDds EHHle 8, i: i 8 3 : - gy 2 # 3 z 2 iE35zH E5uHl 0% :z 2 i igE . : i - zis th ' 3 3 8: - i g : i 8 2 2 - o 8 2E 5=] - - 2: o 2 g= Z2 gg; , : ) PEB 23 23 5to:8 { 23 ENE - 3 3 CEE { &g 2 $g 23 3 53 id -~ 2i4s3 EO z gEg F2 o - Z .8 2z I3 `@ 3 3% 5 1 EI og82 POE i 8is H: B8f: i I2E03 A085 fl8388 TELE g 3/483 3IEElifdz NEAR EAR EE g;r;i|ll%e; pif H e5i |383i2ks 9H02D5a1y6:GaSvuabgcehrSotnuidcy TinoxRicaittsywithOneGeneration Reproduction Evaluations Dupont 5386 TABLE 16 PERCENT SURVIVAL OF MALE RATS TDorseea.tm(ennat/xaG/rdoauyp) 1 12x5 100v v2i5r0 Animal Count at Study Start as 5 3 is Days on TEST 0 100 100 100 100 7 100 100 100 100 1 100 100 100 100 2 100 100 100 100 2 100 100 100 100 3s 100 100 100 100 a 100 100 100 100 as 100 100 100 100 56 100 100 100 100 & 100 100 100 100 7 100 100 100 100 "e 100 100 100 100 8 100 100 100 100 - sree 100 100 100 100 9 100 100 100 200 105 100 100 100 100 12 100 100 100 100 19 100 100 100 100 ANcucmbiedrentatallsytudKyillsteadrt RSaecmroivfeidcefdronbysdteusdiygn* Alive on test day 119 aso 35o 351 1s1 2i0o 2100 205 f1n0 15 5 5 is `PercNeunmtbSeurrvoifvarlat=s (aNcumrbieskro=frNuamtbseralaitves/tNuudmybsetraorftr-atnsusabterriOsfk)r:at1s00reroved from study - nunber sacrificed by design - accidentally killed. a. R(actoshoudseesdi)gnaotnedtesftordaryep7rdo.duction evaluation were removed fron study b.. ROneecovreartywapsezaiocdcidbeengatnallony Lkeisltleddaydur5i0ng the previous week. al Rtaetsst ddaeysig51n.ated for the 30-day exposure period were sacrificed on "Choecrheranw-erAermintoagsetattirsetnidcatleslty. significant decreases in survival at p < 0.05 by `Company Senilzed. Dossnotcontain TSCA CB -- = 0H--2D4a5y16G:avSaugbcehSrtoundiyc TinoxRiactistywith One-Generation Reproduction Evaluations DuPont 5386 TABLE 17 PERCENT SURVIVAL OF FEMALE RATS. TDroesaetm(enngt/kGgrdoauyp) Fe o 2w5v 1v010 v2i5r0 Number Animals at Study Start 5 35 35 is DAYS on TST! 100 100 100 100 7 100 100 100 100 1 100 100 100 100 21 100 100 100 100 28 100 100 100 100 35 100 97 200 100 a 100 97 100 100 a9 100 97 100 100 56 100 9 100 100 6 100 9 100 100 7 100 9 100 98 77 100 03 100 6 84 100 93 100 9% - 910 100 9 00 9% 98 100 80 100 9% 105 100 80 100 9% 12 93 80 100 9% 119 9 0 100 % NAucmcbiedrentatallsytudkyillsteadrt a5o 3 1 35 0 5 1 sFaocurnidfidceeadd in extremis o1 o1 o o 1 0 SReamcorviefdicefdrobmystduesdiygn * 20 10 20 20 s 10 1 5 Alive on test day 119 10 < 5 1s PercNeunmtbeSrurovfivaralts= a(tNarmibsekr =ofNursabtesraaltivset/uNduymbsetrarotf -rantusmbaetr roifsk)ra+t1s00removed fxon study - nunber sacrificed by design - accidentally killed. abl. OOnree rraatt wwaass aacccciiddeennttaallllyy kkiilllleedd dounritnegstthdeaypr0eavnidousrewpeleakc.ed day 0. a. OOnnee rraatt wwaass sfaocurndifidceeadd diunrienxgtretmheisprdeuvriinogustwheeekp.revious week. ! R(actoshoduseesdi)gnaontedtesftordaryep7rdoduction evaluation were removed from study . 6. RRaetcsovdereysigpneartieodd bfeogrartheon90te-sdtaydaeyxpo9s0ure period were sacrificed on test day 93. - CThoecrheranw-erAerninotagsetattirsetnidcatleslty. significant decreases in survival at p < 0.05 by `Company Senifized. Does not confain TSCA CB 3 ~ 2010.--2DD4a5a1yy6G:GaovvSaauggbeehSrStotunudidycyiTinnoRxRiaactsistyvwiitthhOOnneeGGeenneerraattiioonnRReepprroodduuccttiioonnEEvlaulusattiioonnss DDuuPpoonntt-55338866. TABLE 18 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR MALE RATS (MEAN OF THREE TRIALS) Assessment Period Baseline Week 13 Group 1 m v vi ju]1 v vi Dosage (mg/kg/day) 0 25 100 250 250 100 250 Forelimb Grip Strength (kg) 0.51 (0.08) 0.52(0.10) 0.54 (0.08) 0.54 (0.09) 1.133850(02.934)) 1380.32) 1.31 (0.23) Hindlimb Grip Strength (kg) 0.40 (0.06) 0.38 (0.07) 0.36 (0.03) 0.40 (0.06) 00.58040(0..0175)) 0500.13) 0.73 (0.11) Recovery 1 0 vi 250 127(0.31) 1.03 (0.32) 0.74(0.14) 0.75 (0.09) Dua arranged as Mean (Standard Deviation) Satisical Methods, Bart's est for homogeneity followed by analysisofvariance and Duets est "There were nostatisticallysignificantdifferences from control at p<0.05 `Company Sanitized. Does not contain TSCA CBI =-- -- 9102-4D5a1y6:GaSvuabgcehrSotnuidyc TinoxRiactistywithOneGeneration Reproduction Evaluations DuPont5386 TABLE 19 MEAN FORELIMB AND HINDLIMB GRIP STRENGTH FOR FEMALE RATS (MEAN OF THREE TRIALS) Assessment Dosage Forelimb Period Group _(mghglday) Grip Strength (kg Hindlimb Grip Strength (kg) Baseline n 0 wv 25 vi 100 vin 250 0.58 (0.08) 054(0.12) 054(0.12) 0590.14) 0.37 (0.04) 0.39 (0.06) 0360.05) 0.36 0.04) Week 13 n 0 wv 25 vi 100 vin 250 1.18025) 122021) 1.04021) 1.01022) 0730.10) 0720.12) 065 (0.10) 0.64(0.14) Recovery 0 vin 250 1.07027) 1.13035) 0.69 (0.09) 0.66 (0.11) Data arranged as: Mean (Standard Deviation) Statistical Methods: Bart's test for homogeneity followed by analysis of variance and Dumnet's es. "Therewere no stistically significant differences from control at p<0.05 Sompany Sanitized. Does <i contain TSCA CBI -- = -- H9-02-4D5a1y6:GaSgubechSrtoundiyc TinosRaitcsiywith One- Generation Reproduction Evaluations DuPont5386 TABLE 20 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS Baseline Dosage (mgkgG/rdoauyp:: 0| 2151 10V0v 2v5i0i Number Examined: 10 10 10 10 Wek 0Cm25ov10 2o5w0e 10 10 9 10 Recovery 0 2v5i0 10 10 AnoPrPeaRcOtiAonCH & TOUCH: 0000 0010 00 ninocrrmeaalsed reaction Gumps away oratiacks) 0 100 100 100 91 00 x0 100 10 100 AnoUrDeIacTtiOonRY STIMULUS: 0000 0000 00 nexoargmgaelrarteaecdtrieoanc(triaotnf(irnacthjeusmoprs,flNiicpkss)ear) 100 100 100 100 100 100 90 100 100 100 TnoAIreLspPoInsNeCH: --- nexoargmgaelra(tteudmsretsopwoanrsde sic) 09 91 09 100 100 09 90 o0w 09 o0w Loo 0 0 to 0 10 IN MOTOR ACTIVITY MONITOR: prDeEsFenEtCATION 70 8 8 3 6 0s 1 8 6 adbisaernhtea 300020 2 0 7 44 3 0000 2a 00 prUeRseInNtATION: absent 7328037 46 46 73 63 73 73ss prPeUsPenItLLARY RESPONSE absent 00100 100 100 00 100 90 00 100 100 Sempany Saniized. Does rn: sontain TSCA CBI -- wm -- -- 9H0-2-4D5a1y6:GavSaugbeehSrtoundiyc iTnoxRiactistywith One-GenerationReproduction Evaluations DuPon-5386 TABLE 20 (CONTINUED) SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR MALE RATS Baseline Dosage (mg/kgGirdoauyp):: 0| 2W5 V100 2V5II0 Number Examined: 10 10 10 10 Week 13 0Cm25 10v0 o2w50 10 10 5 10 Recovery 0 2v5i0 10 10 ADDITIONAL OBSERVATIONS NOTED SPorrees,enrtight axilla Absent 000100 100 00 100 100 81 00 100 100 pPrueosseisnt absent 000 W100 0 10 0 10 0 10 0 9 00 010 1 9 "There were no statistically significant differences by Cochran-Armitage tet for trend atp < 0.05. Company Sanitized. Doss nol contain TSCA CBI 3 -- -- H9-02-4D5a1y6:GavSaugbcehSrtonuidcyTionriRcaittsywithOneGeneration Reproduction Evaluations DuPont-5386 TABLE 21 SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS Groups DNousamgbeer(mEg/xkagm/idnaeyd):: Baseline II IV VIVO 100 2150 10100 25100 Week 13 Recovery 10 W2V5 1v00 i2v50ian0 v2i5l0 10 9 10 10 9 10 AnoPrPeaRcOtiAonCH & TOUCH: 0000 0000 00 normal increasedreaction (jumps away oratack) 000 000 10 0 109 00 0 0 10 0 9 10 00 pAoUrDeaIcTtiOonRY STIMULUS: 0000 0010 00 enxoargmgaelrarteeacdtiroenac(taiotnf(riat jnumcopsrh,felNiicspkss)a) ~~ 10 10 0 10 0 10 0 10 0 9 0 9 0 10 0 9 10 00 TnoAIreLspPoInsNeCH: --- pormal (tums toward site) exaggerated response 00 00 09 100 00 09 00 09 09 a00 0010 0001 00 IN MOTOR ACTIVITY MONITOR: DEFECATION praebsseenntt 2x 64 82 a6 7 0a 96 5s 3 69 diarthes 000 0000 00 prUeRsIenNtATION: absent 76 3a 0s so 9 223 x17 a 6 63 37 PUPILLARY RESPONSE praebsseenntt 00 100 100 00 00 90 100 00 90 100 `Company Sanitized. Does not contain TSCA CBI 3 H9-02-4D5a1y6:GavSaugbeehSrtoundiyc iTnoxRiactistywith One.Generation Reproduction Evaluations DuPont-5386 TABLE 21 (CONTINUED) SUMMARY OF FUNCTIONAL OBSERVATION BATTERY FINDINGS FOR FEMALE RATS Dosage (mghkgGirdoauypy:: Number Examined: Baseline I0I IV 25 VI VIL 100 250 10 10 10 10 Week 13 WIV viv 100 259 10100 25100 Recovery avin 09 25100 ADDITIONAL OBSERVATIONS NOTED Prosis present absent 0 0 0 0 000 00 90 00 91 09 91 prSecsraetncth, right comer ofeye absent 00 100 100 0 00 90 100 00 09 2 Chromodacryorthea present absent 00 100 100 10 100 09 100 10 090 91 - "There were no satistically significant differences by Cochran-Armitage test for trend a p< 0.05 Company Sanitized. Doss not contain TSCA To -- ~ ui2s: i:: 8 2588 4SE5E 45 ; BEEd EH E ff i: 3 "s2e5e8 ZEEsEcEs EsYs i2 i gZ, i E| WwBsEEzEIeGSsEE EiEE coat AI 1IE LEE ww2EI3EfsZf:Eg EgfaIg5 "isgg ii3E2f YHif viz Lf ~ I 8g 5 k E8 E2H 225F% IseE ef R5s 3iEF o fp G| TRAEE "AZAR "EE i |z 22 8 2E2z iH3 EER2igHz a 5553:: 2gggzzzz- 3o2T% BZAEBRHEEE L"EREREEEE "E"E5EY3 izg iifEf:: 2 z= : 7i ggkzfs W$EI5E89gF8E L-gE5sBEsEzzLE FFEsEEaR.AEF Ii4IFE%f:Of : TI 1 i RB Y -sgg -nsg 8gl/3 552, i; :: Co g: 35233% 3 3 -=-3 -zs: _2 #32 &5:4 zg5l laF; g8$3i73 2F i3 E EE E 3g g2f 4 if:i i g g 8 2%E -3 = | a ~ 83: iz : BPEeReZrE BgRiSHsEtE EHlER pg0 i | "g2RE5E38T58 -:Z3=zE2egisEzg Sgfgg IH i i .23 &FZ|E w8EsE2ss8sE% essf.=Z=is wigfg 5i:f2 BgZfE3w fiZEf| w2zeiZssEszfe iv8TiiT2zg2sif8s - vg5igs iIii:ffI3 g 22 g:| fgeef3s: gses@fs gg 3E4 _ 2% -E3EF Raf: ~EE i} iioJ z=a52 :22 E 38273 LJ$goEo3gE5Eg:E ~2Zg3Ei2Eer%E TT hEfpFE Is5% i 2~ 3 g RHE RZ 52 5 3: 22g 8 LsFEEeE3sE%sE Fs"EHzEeEEsL EagsER;iIsfe Gb OB : 5| if :g3 g Sog2sy 288 n8%- f#F3L 3L,fI . i$ . F$ 5E3238:5 RK &3 =z:> =z2s2z2 5=5%7% 7FErEd: i z| 5 33 2 cg a T 232 31 2% 8 gd |F g:7% 529 } Bhi 5 ~ 3 ig EH 5a s 2 2 45S2ES5E8 L48E28E2 2g3l e : =f i $222885 32g8@8s% gs3a Giff 35 2 WIRTRAI waIIE URE 5Egg 2 , EB wESEE FREE wfy if 22 Z5z sgss ass=es = L5i2f 3 22 Bl... io. od EH 2bgg f5| 38238S% ~g2E8I2F3 ms2sg Igif % = fJg Ea=Z Z52z28 g| "888g5g%c ~fgzciEy5 5g8g 2 EipF 1= k2 5 22 =a=2omeIn TRS 2p of 23s g2sa= sggesae czesae:dz &=| i=2z $&f $g Bg g ~8gSEEHFE ~ETE3RzREE ~E"5EMT: iPgE H = S ud : zi 8 EZ 3 3H " 2z283 oz8s2s8 R"EsRg F2lZJ E5gy &% 28 31:3 8 &| o 3 EE% 2 255$2 g3 58 -=5 -=ex -5[F3 2033%2 3% |g 2H33H3 3 gy Z [3 $i: oe 3 2LE2 222g9% 33 54 33 ||:|&& 3E55E5%E% 22 27 ~~ id 3 -- 53 : Hi: / $s32i83e58 e4FaS8sE828tz3 E pFefo g i gait 8258 gi: FH i |2 oBEge LeERdE wzggy - g 22 sins sass se in f g Bzl .I25F0A8 LIWEEARBEER "gLEsE iift i 9wo iI3 L3R3EzEg .E$zE3EE8Ef5 L588% wid i2:3 i: 2 tl ssaz 3s _ LZ | n3zzs 385% zy If 413| 5z 58%sg8z 7 WE=sEmEsE wsgBsEsR HSE8 2s3n "Eg ogEE2fe z- 33 EH> SSsEe8gSs f2azfsEz ZTz.a f3y :: 3 gg 2282 TEEES TERE 3: OB <g0 EZ E]2333 ong8 -a8E%R 3eR%gi=ifl:, z&: g g g 2:5 % zig: 32] i3% ~ #49 z 8] gl =25% H7 P 7g 4 28 =25% =52 22% % F4T 3 3a3h3s% 2 gtd 3 g 14ii38i% 7 202904D-5Da1uyy6G:GoavvSaauggbeeelSSrttouunddiyyciTinnoRxRaiatctisstwywiitthhOOnnee-GGeenneerraattiioonn RReepprroodduuccttiioonnEEvvaalluuaattiioonnss DDRuuePPvooinsnettd-35P33a88g66e. TABLE 26 SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS TEST/ PERIOD Group 1 Omgkg Group Ill 25 mg Group V 100 mg/kg Group VII 250 mg/kg RBC (x10/uL) DAY 44 822 0.4110) 834 0.23(10) 796 036(10) 806 0.3210) DAY 91 888 0.569) 8.57 0.3809) 827 03509) 7.99 0.43(10) DAY 125 893 : 0.3810) : 797 031010) HGB (g/dL) DAY 44 15.1 0.510) 153 0.4(10) 151 0.6(10) 148 0.410) DAY 91 153 151 0.709) 059) 150 0509) 143+ 0.10) DAY 125 156 : - HCT (%) 0.5010) : 143+ 0.8(10) DAY 44 460 1.710) 466 1.5(10) 458 2.110) 42 1.410) DAY91 489 279) 474 2909) 472 2109) 45.4 2.5(10) DAY 125 483 : 18(10) Mev (fi) : 39 27010) DAY44 560 1.8010) 559 1.5010) 57.6 1410) 56.1 1.3(10) DAY 91 552 553 57.0 568 DAY 125 2509) 542 1.709) 120) * 525.01010) MCH (pg) 1.810) 21010) DAY 44 184 0.6010) 184 0.4(10) 190 0510) 183 0.510) DAY91 173 17.7 0.69) 0.49) 18.1 0.49) 178 0.5(10) DAY 125 175 : z 179 0.610) 0.7(10) Company Sanitized. Does not contain TSCA CBI -- -- -- EE H9-02-4D5a1y6:GavSaugbechSvtoundiyc TinorRitcsiywithOne-Generation Reproduction Evaluations RDeuvPiosnetd5P3a8g6e TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS TEST/ PERIOD Group 1 0mgkg Group il 25 kg Group V 100 mg/kg Group Vil 250 mg/kg MCHC (gL) DAY 44 329 0.510) 329 0.710) 29 0.5(10) 326 0.5010) DAY 91 313 0.609) 319 0.409) 317 0.609) 314 0.4(10) DAY 125 22 # RDW (%) 0.510) : 326 0.4(10) DAY 44 122 0.510) 12.1 0.510) 19 0.6(10) 126 04(10) DAY 91 132 0.79) 129 0.39) 135 0.59) 1si@ 1.3(10) DAY 125 136 : - ARET (x1071L) 0.810) * 127 13010) DAY 44 200 40(10) 185 179 32(10) 21(10) 17 25(10) DAY91 181 179 4909) 239) 196 218 3609) 46(10) DAY 125 188 : WBC (x10%L) 31010) : 150 200) DAY 44 17.36 217(10) 1634 4.10010) 17.97 383(10) 1929 3.11010) DAY 91 1437 2089) 1215 3.1409) 14.04 3.059) 15.25 3.14010) DAY 125 B10 : ANEU (x10) 383(10) : 1323 345010) DAY 44 232 10110) 231 0.76(10) 250 0.7510) 248 0.9700) DAY91 214 0.4709) 1.92 0.479) 1.75 0.759) 234 0.66(10) DAY 125 1.79 . 0.9710) : 1.94 0.74(10) Company Santized. Doos not contain TscA cor -- -- ow 01.-2D4a51y6:GavSaugbcehSrtoundiyc TinoxRiactistywith One-Generation Reproduction Evaluations DuReovinsetd 5P3a8g6e `TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS TEST/ PERIOD Group | 0 mg/kg Group Ill 25 mg/kg Group V 100 mg Group Vil 250 mg/kg ALYM (x10%uL) DAY 44 14.19 13.03 1465 1586 DAY91 191(10) 1154 40700) 9.57 3.82010) 1156 1225152(10) 1.599) 3.1609) 3239) 2.80010) DAY 125 1060 : : 10.62 AMON (x10%uL) 336(10) 298(10) DAY 44 034 040 039 044 0.10010) 0.10010) 0.1710) 0.13(10) DAY 91 045 038 037 040 0.200) 02109) 0219) 0.16(10) DAY 125 034 : 0.19(10) : 028 0.11310) - AEOS (+10) DAY 44 0.16 023+ 01s 0s DAY91 0.04(10) 01s 0.05(10) 020 00.1075(10) 00.2017(10) 0.079) 0.159) 0.1009) 0.13010) DAY 125 014 : ; 013 ABAS (x01) 0.08(10) 0.13(10) DAY44 on 0.10 oll 0.10 0.03(10) 0.0410) 0.0710) 0.0510) DAY 91 003 0.03 0.04 004 DAY 125 0.049) 007 0.039) = 0.0249) 00..008410) 0.03(10) 00510) 2ampany Saniized.Dossnot contain TSCA CBI -- -- H9-02-4D5a1y6:GavSaugbeelSrtoundiyc iTnoxRiactistywith One Generation Reproduction Evaluations DReuvPiosnetd-5P3a8g6e TABLE 26 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR MALE RATS TEST/ PERIOD Group | 0 mgkg Group lll 25 mgkg Group V 100 mg/kg Group VII 250 mg/kg ALUC (x10uL) DAY 44 DAY91 DAY 125 PLT (x10%L) DAY 44 DAY91 DAY 125 024 0.06010) 007 0.099) 017 0.12010) 141 1039) ns 153(7) 1059 126(7) 027 0.1910) 007 0.079) # 1077 92(9) 1055 12209) : 0.18 00..1105010) 0.1709) > 1069 1202952(8) 155(8). 026 00.1134(10) 0.1310) 018 0.06(10) 1008 H1i02(8) 109810(7) 789) Duta arranged as: SMteaanndard deviation (Numberof values included i calulaton) Group not sampleda ths timeport. @+ SSuuttiissiiccallllyy ssiiggnniiffiiccaanntt ddiiffffeerreennccee ffrroomm ccoonntrrollaattpp<< 00..0053 bbyy npoanrpaamreatmiectrtiesctt(eDtun(Dnuenn'Ts)a,shan. Dunnct), Company Sanitized. Does not contain TSCA CBI I 9H0.2:4D5a1y6:GavSaugbeehSrtoundiyc TinoRxiacsitwyith One-Generaton Reproduction Evaluations RDeuvPiosnetd 5P3a8g6e TABLE27 TEST! PERIOD SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group It 0mgkg Group IV 25 mgkg Group VI 100 mg Group Vill 250 mg/kg RBC (x10%4L) DAY 45 826 7.85 814 775% DAY 93 0.17(10) 8.41 03009) 808 08.1475010) 07.8425+10) DAY 125 027(10) 0.289) 795 = 0.62:(10) 0.030209) HGB (g/dL) 0.389) 0.5009) DAY 45 154 148+ 151 145% 0.5010) 0.39) 0.4(10) 0.710) DAY 93 155 152 15.1 142% 0.5(10) 0.69) 05(10) 059) DAY 125 15.1 : : 148 - HCT (%) 0.79) 089) DAY 45 469 4490 456 443+ 11310) 189) 1.7010) 2.1(10) DAY 93 476 457 462 440" DAY 125 1.9010) 2009) 4.7 : 2.410) 441.359) Mev (1) 2009) 230) DAY45 568 572 560 57.1 DAY 93 1.2(10) 179) 56.6 566 561.86(10) 5613200) 15010) 190) 39010) 119) DAY 125 575 < 159) : 555% 2109) MCH (pg) DAY 45 187 189 185 18.7 0.5(10) 0.69) 0.6(10) 0.710) DAY 93 185 188 185 182 0.4(10) 079) 0810) 0.509) DAY 125 19.1 : : 18.5% 030) 0.709) EE Company Sanilized. Does rotcontain TSCA CBY H9-02-4D5a1y6G:avSaugbeehSrtoundiyc iTnoxRitcsitywithOne Generation Reproduction Evaluations DReuvPiosnedt5P3a8g6e TABLE 27 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS TEST/ PERIOD Group Il 0mgkg Group IV 25 mg/kg Group VI 100 mg/kg Group Vill 250 mg/kg MCHC (g/dL) DAY 45 29 30 31 27 0.8(10) 0.99) 0.510) 05(10) DAY 93 27 32 326 23 0.5(10) 1.409) 12010) 0.49) DAY 125 32 ` 3 34 RDW (%) 089) 050) DAY45 ny 19 nr 122 0.510) 0.59) 0.7010) 0.4(10) DAY93 13 ns 123 123@ 0.510) 0.49) 25(10) 1009) DAY 125 124 : 0.79) 3 ni@ 0309) - ARET (x10%L) DAY 45 208 216 201 210 25(10) 3509) 37010) 39010) DAY93 151 157 219 2 35(10) 0.0369) 181010) 289) DAY 125 71 : : 145@ 249) WBC (x10%L) 3909) DAY 45 13.67 12.83 13.42 13.59 DAY 93 3.13(10) 9.96 2.999) 9.86 1033.612(10) 101..5903(10) 1.6(10) 1.769) 227010) 1.98(9) DAY 125 798 : 17609) 8.12 1.4709) ANEU (x10%L) DAY 45 177 1.62 1.69 181 0.70(10) 0.489) 0.54(10) 0.67010) DAY 93 Lis 1.46 231@ 1.65 032010) 0.4909) 0.94(10) 0.789) DAY 125 L13 : 1.58% 0279) 0.54(9) `Company Sanitized. Does nc: contain TSCA CB Tan 910.2-4D5a1y6:GavSaugbcehSrtoundiyc TinosRiactistywith OneGeneration Reproduction Evaluations RDeuvpiosnetd 5P3a8g6e TABLE 27 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS TEST/ PERIOD Group It 0 mg/kg Group IV 25 mg/kg Group VI 100 mg Group VIII 250 mg/kg ALYM (xI0/uL) DAY45 11.10 10.52 1091 1099 243(10) 28709) 257010) 1.67(10) DAY 93 82 783 739 819 1.50010) 1.700) 229010) 1.669) DAY 125 641 # 1779) * 594 1519) AMON (x1074L) DAY 45 030 025 031 029 0.09(10) 0.089) 0.08(10) 0.10(10) DAY 93 021 024 026 029 0.07(10) 0.1009) 0.08010) 0.1709) DAY 125 021 * * 029 0.0709) 0.1409) - AEODSAY(4x1507uL) 0.19 0.10 018 0.18 0.07(10) 0.059) 0.09(10) 0.04(10) DAY 93 0.18 014 022 0.18 DAY 125 0.0910) 0.069) 0.10 * 0.09:(10) 00..016059) ABAS (x107uL) 0.0409) 0.039) DAY45 0.10 009 on 0.10 007(10) 0.059) 0.05(10) 0.03(10) DAY 93 0.08 007 0.07 005 0.02(10) 0.049) 0.03(10) 0.039) DAY 125 004 : : 0.04 0.039) 0.029) Company Saniized. Does ot contain sca cp Tr 9H0.-24D5a1y6G:avSaugbcehSvtoundiye iTnoxRiactistywith OneGeneration Reproduction Evaluations RDeuvPiosnetd 5P3a8g6e TEST/ PERIOD TABLE 27 (Continued) SUMMARY OF HEMATOLOGY VALUES FOR FEMALE RATS Group Il 0mg/kg Group IV 25 mg Group VI 100 mg/kg Group VIII 250 mg/kg ALUDCAY(x14507pL) DAY93 DAY }125 PLT (x10/4L) DAY 45 DAY 93 DAY 125 021 0.08(10) 0.12 00510) 0.09 0.039) 186 1106) 1025 144(10) 1043 2179) 024 0.189) 012 0.089) : 1081 202(9) 1004 102(8) : 02 0.0910) 012 0.06(10) * 1084 i10s8(8) 105(6) : 022 0.0610) 014 0.079) oll 0.0409) 1068 11020969) u1n436) 159(5) Dus arranged as: MSteaanndarddeviation (Numberofvalues included in calculation) a Group not sampled at this tmepoint. = Statistically significant diffrence from control at p< 0.05 by parametric est (Dunner TamhaneDunne). @ Statistically significant difference rom contol at p-< 0.05 by nonparametric est (Dunn's). `Company Sanitized. Doss not contain TSCA CBI wo 910.2-4D5a1y6:GavSaugbcehSrtoundiyc TinoxRiactistywith One-Generation Reproduction Evaluations DRuePviosnetd$P3a8g6e TABLE 28 SUMMARY OF COAGULATION VALUES FOR MALE RATS TEST/ PERIOD Group 1 0 mgkg Group ill 25 mg Group V 100 mg/kg Group VII 250 mg/kg PT (seconds) DAY91 152 147 152 APTT (seconds) 0.810) 0.410) 0.909) DAY91 187 163% 158 25010) 22010) 2109) 155 0.7010) 168 0.8(10) Dawamanged as: MSteaanndard deviation (Numberofvalues included in calculation) + Suusically significant difference fiom control at <0.05 by parametric est (Dunne Tabane:Dunne). TABLE 29 - SUMMARY OF COAGULATION VALUES FOR FEMALE RATS TEST/ PERIOD Group Il 0 mgkg Group IV 25 mykg Group VI 100 mg/kg Group Vill 250 mg/kg PT (seconds) DAY 93 145 144 1s 14.1 050) 0.309) 05010) 050) APTT (seconds) DAY 93 17.1 158 154 15.00 1.49) 149) 17010) 1.59) Duta arranged as: MSteaanndard devinion (Numberof values included in calculation) + Statistically significant difference from control tp < 0.05 by parametric test (DunnettTamhane-Dunne). `CompanySanitized. Does not contain TSCA CBI wo 9204-5D1a6y:GavSaugbcehSrtoundiye iTnorRiactistywith One-Generation Reproduction Evaluations DReuvPiosnetd.5P3a8g6e TABLE 30 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group | 0 mgkg Group Ill 25 mg/kg Group V 100 mg/kg Group Vii 250 mg/kg AST (UL) DAY 44 3 84 6 82 10010) 13(10) 78) 149) DAY 91 9 87 80 9% 29(10) 18010) 159) 30010) DAY 125 7 * 010) = 7 1010) ALT (UL) DAY 44 30 3 3 3 4(10) 5(10) 68) 30) DAY 91 36 36 43 810) 8(10) 50) 22(10) DAY 125 3 : 7010) : 36 14(10) - SDH (U/L) DAY 44 188 179 182 174 4.2(10) 4.6(10) 26(10) 6.3(10) DAY 91 286 233 24 2538 8.1(10) 62(10) 580) 9.110) DAY 125 215 * 2 14.0% ALKP (UL) 6.510) 3.4010) DAY 44 134 144 156 185 3110) 35(10) 2168) 3009) DAY 91 97 95 139 186+ 2210) 20010) 200) 32010) DAY 125 81 : : " 1810) 14(10) BILI (mg/dL) DAY44 009 0.09 0.08 0.06 0.0310) 0.04(10) 0.04(8) 0.029) DAY 91 007 0.06 0.05 005 0.03(10) 0.02(10) 0.009) 0.00(10) DAY 125 0.06 : - 005 0.02010) 0.00(10) `Company Sanitized. Docs rot contain TSCA CBI Ta 9H-02-4D5a1y6G:avSaugbcehSrtoundiyc iTnoxRiactistywith One-Generation Reproduction Evaluations DReuvPiosne-d5P3a8g6e TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group1 Omgkg Group lil 25 mg/kg Group V 100 mgkg. Group VII 250 mg/kg BUN (mg/dL) DAY 44 14 14 15 14 2010) 210) 210) 2(10) DAY 91 1s is 16 15 2010) 200) 29) 110) DAY 125 15 : 18 CREA (mg/dL) 1010) 200) DAY44 034 031 030 034 0.05(10) 0.05(10) 0.04(10) 0.07010) DAY 91 0.42 0.40 039 0.45 0.0710) 0.09(10) 0.059) 0.0610) DAY 125 0.40 : * 0.40 - CHOL (mg/dL) 0.06(10) 0.06(10) DAY 44 84 65 56+ sar 22(10) 1010) 16(10) 1810) DAY 91 78 65 48a 1@ 27010) 13010) 1609) 15(10) DAY 125 7s 2 1310) : 56+ 10010) TRIG (mg/dL) DAY 44 97 90 75 53 5810) 30010) 388) 399) DAY 91 127 98 49 39 5110) 3910) 2409) 2710) DAY 125 95 ` : ss@ 37(10) 3710) GLUC (mg/dL) DAY 44 110 104 108 m2 1700) 1200) 1310) 16(10) DAY 91 125 102 02 16 38010) 14010) 2709) 30010) DAY 125 127 : : 106 37310) 16(10) Company Sanitized. Does rc: contain TSCA CBI Tw 910.2-4D5a1y6:GavSaugbcehSrtoundiyc iTnorRiaciistywith OneGeneraion Reproduction Evaluations RDeuvPiosnetd5P3a8g6e `TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group | 0 mgkg Group Ill 25 make Group V 100 mgkg Group VII 250 mg/kg TP (g/dL) DAY 44 66 66 61 73 0310) 0310) 038) 0409) DAY 91 69 68 7.1 7.7% 0:4(10) 03310) 040) 04(10) DAY 125 70 : 0310) 67 0.3(10) ALB (g/dL) DAY 44 al 42 43 50@ 0.210) 0.210) 0.5(8) 0.39) DAY91 43 44 a sar 02010) 02(10) 0209) 03010) DAY 125 44 > 43 0200) 0.3(10) - GLOB (dL) DAY 44 24 24 25 23 02(10) 02(10) 04(8) 029) DAY 91 26 24 24 23 0.2010) 0.2(10) 0309) 0.1010) DAY 125 26 * 03010) 24 0.210) CALC (mg/dL) DAY44 108 109 108 n2 0.4(10) 0.4(10) 0.5(10) 0310) DAY 91 no 10.6 10.5 109 0.710) 0.410) 0.59) 0.510) DAY 125 10.6 * : 102 IPHS (mg/dL) 0310) 0310) DAY 44 86 91 9.5% 9.4 0.7(10) 0.510) 08(8) 0909) DAY 91 92 87 89 9.1 DAY 125 22(10) 81 1.510) : 1.0039) 71.84(10) 1.510) 0.8010) `Company Sanitized. Does r=: contain TSCA cat Ti 91.02-4D5a1y6:GavSaubgcehSrtoundiyc iTnoxRiactistywithOneGeneration Reproduction Evaluations RDeuvPiosnetd$P3a8g6e TABLE 30 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR MALE RATS TEST/ PERIOD Group| 0 mgkg Group Ill 25 mgkg Group V 100 mg/kg Group Vil 250 mg/kg NA (mmol/L) DAY 44 1445 1435 1444 1439 1.910) 1.0(10) 0.9(10) 1.200) DAY 91 1472 145.9 146.1 1452 22(10) L4(10) 1509) 20010) DAY 125 146.4 & 0.810) " 1466 1.510) K (mmol/L) DAY 44 602 605 624 598 0.40(10) 0.23(10) 0.408) 04709) DAY 91 633 607 624 625 0.60(10) 0.42(10) 0399) 0.56(10) DAY 125 641 b . 6.05 - CL (mmol/L) 0.63010) 0.41010) DAY44 1005 99.4 99.5 99.3 15010) 2.110) 23(10) 1.610) DAY 91 100.7 100.1 100.5 9B" 1.7(10) 1.8(10) 139) 1.3010) DAY 125 103.4 * 09(10) # 103.4 1.6(10) PFLU (pg/mL) DAY 44 : * : * DAY 91 0.1 02 04@ 07@ DAY 125 0.0(10) 0.000) 0.1) ol : : 00.1110) 0.0(10) 0.19) Data armanged as: SMteaanndard deviation (Numberofvalues included in calculation) a Group not sampled at his imepoint. @+ SStaattiissiticcaallllyy ssiiggnniiffiiccaanntt ddiifffferreennccee ffroomm ccoonnttoel attpp<<0.00.055 bbyy pnaornapmaertarmiectreisctt(eDstun(Dnuenrn'Ts)a,ran Dunner). Company Sanitized. Does --: contain TSCA CB - 91.02D4a5y16G:avSaugbcehSrtoundiyc iTnoxRiacsitywithOne-Generation Reproduction Evaluations RDeuvPiosnetd P$a3g8e6 TABLE 31 SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group Il 0mgkg Group IV 25 mg/kg Group VI 100mgkg Group Vill 250 mg/kg AST (UL) DAY 45 87 76 7 69" 1410) 1509) 17(10) 8(10) DAY 93 90 79 89 87 27(10) 160) 10010) 1909) DAY 125 124 : " 152 ALT UL) 619) 198(10) DAY 45 37 31 3 20+ 6(10) 7) 5(10) 8010) DAY 93 3 3 3 38 8(10) 79) 410) 169) DAY 125 65 : 6 409) 72010) - SDH (U/L) DAY 45 182 183 163 158 DAY93 5.4(10) 4.69) 189 164 138.3810) 147.2610) DAY 125 7.510) 380) 258 3 4.2(10) 255.000) ALKP (UIL) 12.009) 27.600) DAY 45 66 7 3 81 1810) 229) 18(10) 18010) DAY 93 a2 a 55 52 1010) 179) 15(10) 1509) DAY 125 33 : 38 1309) 1410) BILI (mg/dL) DAY 45 013 ol 01 0.09 0.04(10) 0.059) 0.04(10) 0.04(10) DAY 93 0.13 0.10 0.10 0.11 DAY 125 0.0610) 0.10 0.049) : 0.05>(10) 00..00949) 0.049) 0.0610) Company Sanitized. Doss not contain TSZA Cal ww -- 910.2-4D5a1y6:GavSaugbcehSrtoundiyc iTnoxRaitcstywith One-Generation Reproduction Evaluations DuRePvoinse:d 5P3a8g6e TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group Il 0 mglke Group IV 25 mg/kg Group VI 100 mg Group VIII 250 mg/kg BUN (mg/dL) DAY 45 16 15 16 16 2010) 29) 210) 2010) DAY 93 17 16 16 16 210) 29) 3310) 19) DAY 125 16 * $ 16 39) 2010) CREA (mg/dL) DAY 45 040 035+ 035 037 0.04(10) 0.039) 0.05(10) 0.0710) DAY 93 047 044 051 0.50 0.05(10) 0.049) 0.0810) 0.069) DAY 125 048 = 0.0609) + 0.48 0.04(10) - CHOL (mg/dL) DAY 45 83 89 82 2 12(10) 199) 13(10) 15(10) DAY 93 I 90 76 95 14010) 199) 13010) 2009) DAY 125 106 - : 98 3609) 51010) TRIG (mg/dL) DAY 45 6 8 a 2 26(10) 419) 18010) 1300) DAY 93 160 87 5@ 54@ 136(10) 4509) 24(10) 209) DAY 125 136 + = 102 720) 96(10) GLUC (mg/dL) DAY 45 97 109 9% 101 910) 1309) 5(10) 710) DAY 93 92 97 100 9 810) 50) 17010) 59) DAY 125 107 : 104 200) 14010) `Company Sanitized. Does fet contain TSCA CBI .- 2504:5D1ay6:GavSaubgcehSrtoundiyc TinorRiactistywith One-Generation Reproduction Evaluations DReuvPiosnetd5P3a8g6e TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group Il 0 mgkg Group IV 25 mg/kg Group VI 100 mg/kg Group Vill 250 mg/kg TP (g/dL) DAY 45 73 74 77 82 0.510) 0.409) 03010) 0.4(10) DAY 93 75 78 83+ 86% 0.5010) 0.409) 0.4010) 0.49) DAY 125 82 $ 050) * 82 0.5010) ALB (g/dL) DAY 45 50 50 54 57 0.510) 049) 0.2010) 0310) DAY 93 52 54 6.0 6.0 0.510) 0.409) 0.3010) 030) DAY 125 57 * 039) : 5.8 03010) - GLOB (dL) DAY 45 23 24 23 24 02(10) 029) 02(10) 0.210) DAY 93 23 24 24 26 0210) 0.109) 0210) 0.209) DAY 125 25 * 039) : 27 03010) CALC (mg/dL) DAY 45 10 na n2 nr 0.4(10) 0.49) 0.3(10) 0.4(10) DAY 93 108 10 13% 1s 0.3010) 0.5(9) 0.4(10) 0309) DAY 125 ni : 0.59) = 109 0.3(10) IPHS (mg/dL) DAY 45 75 76 79 78 0.7010) 120) 0.6010) 0.510) DAY 93 56 60 61 6.6% 0.710) 0.509) 1.310) 0.79) DAY 125 57 : * 64 0.99) 09(10) Company Sanitized. Does noi contain TSCACBI TS 19.02-4D5a1y6:GavSaugbechSrtoundcy TinoxRiatcslywith One-Generation Reproduction Evahations RDeuvpiosnedt 5P3ag8e6 TABLE 31 (Continued) SUMMARY OF SERUM AND PLASMA CHEMISTRY VALUES FOR FEMALE RATS TEST/ PERIOD Group II 0mgkg Group IV 25 mg/kg Group VI 100mg/kg Group VIII 250 mg/kg NA (mmol/L) DAY45 1435 143.5 1425 1433 DAY 93 2.4(10) 1437 2709) 1428 144.11.610) 141332010) 16(10) 1.69) 22(10) 139) DAY 125 1455 : 1439+ K (mmol/L) 130) 15010) DAY45 566 573 588 632 DAY 93 021(10) 0.4009) 529 529 052682(10) 063.20(510) 036(10) 0.269) 0.40(10) 0.4009) DAY 125 531 > 4 5.45 - CL (mmol/L) 0.440) 0.48(10) DAY 45 1008 9.9 99.7 9.5 09(10) 1.6(9) 1.210) 1.0(10) DAY 93 99.2 989 993 979 22(10) 239) 2100) 149) DAY 125 1026 3 14) : 103.2 18010) PLU (ng/ml) DAY 45 2 = : : DAY 93 ol 02 04@ 03@ 0.1(10) 0109) 0.110) 0209) DAY 125 ol : i 01 0.009) 0.010) Dats amnged us: SMteaanndard deviation (Numberof values included in calculation) a Group not sampled at this timepaint. @+ SSuuttiisstiiccaallllyy ssiiggnniiffiiccaanntt ddiiffffrreennccee ffrroomm ccoonnttrrooll aatt pp<< 00..0055 bbyy pnaornapmaertarmiectrtiescte(sDtun(Dnuenn'Tsa).shan. Duct). Company Sanitized. Docs :1contain TSCA CBU To 9204:5D1ay6:GavSaugbcehSrtoundiye TinoxRiactistywithOne.Generation Reproduction Evaluations DReuvPiosnetd5P3a8g6e TABLE 32 TEST PERIOD SUMMARY OF URINALYSIS VALUES FOR MALE RATS Group 0 mg/kg Group Il 25 mg/kg Group V 100 mg/kg Group VII 250 mg/kg VOL (mL) DAY 44 8.6 10.0 8.0 17.1 DAY91 DAY 125 5.6(10) 75.14610) 152.04(10) 5.3(10) 100 689) : 5.6(10) 100 9.009) i 1165.74(@10) 70010) 12@ 6.110) UOSM (mOsm) DAY 44 138436(10) 1407149(10) 135392309) 96388510) DAY 91 1330 1158 1315 793 474(7) 473(10) 556(9) 297(10) DAY 125 952 : : 1759* 364(10) 932(10) -- SG DAY 44 DAY 91 01..00137110) 1.048 10..00312410) 1.036 01..00145910) 1.040 01..001299(10) 1027+ 0.017(9) 0.013(10) 0.016(9) 0.009(10) DAY 125 pH 01.001311 10) . : 10s1* 0.023(10) DAY 44 72 73 70 75 DAY 91 0.667(10) 06.98(10) 07.61(10) 06.6710) 0.4(10) 0.7(10) 0.8(9) 0.5(10) DAY 125 68 : : 6.6 0.5(10) 0.5(10) URO (EU/L) DAY 44 DAY 91 00.20010) 0033(10) 0002010) 02 0.0(10) 02 03 02 02 DAY 125 0.010) 02 0.3(10) . 0.009) . 0.0(10) 02 0.0(10) 0.0(10) EE `Company Sanitized. Doss not contain TSCA CBI H5-02:4D5a1y6:GovSaugbcehSrtoundiyc TinosRiactistywith One-Generaion Reproduction Evaluations RDeuvPiosnetd5P3a8g6e TABLE 32 (Continued) SUMMARY OF URINALYSIS VALUES FOR MALE RATS TEST/ PERIOD Group | 0 mgkg Group lll 25 mkg Group V 100 mg Group VII 250 mg/kg UFLDUA(Yug4)4 : : : : DAY 91 202 2130 602.70 1473.6@ DAY 125 53(7) 142 3680) 3 188.5d9) 31837..040%10) 29(10) 228010) DAY 181 121 28 30.10 6. 4805) 3.265) 1.55) 6.6(5) UMTP (mg/dL) DAY 44 7 6 103 66 37010) 47010) 5310) 60(10) DAY 91 119 7% ol 00 7110) 64(10) 5009) 20010) DAY 125 66 : : 121 - 49010) 7310) Du amanged as: SMteaanndard deviation (Numberofvalues included in calculation) a Group not sampleadt this imepoint. + Sutisically significant diffrence from control at p< 0.08 by parametric test (Dunne Taare.Dunc). @ Statistically significant ifernce from contol tp< 0.05 by nonparametric test (Duns) Company Sanitzed. Doss rc: contain scca -= 2904:5D1a6y:GovSaugbeehSrtoundyc TinoxRiactistywith One-Generaion Reproduction Evaluations RDeuvpiosnedt5P3a8g6e TABLE 33 SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS TEST/ PERIOD Group Il 0mgkg Group IV 25 mg/kg Group VI 100 mgkg Group Vill 250 mg/kg VOL (ml) DAY 45 58 69 82 126 DAY 93 420) 31 369) 49 3460(10) 140.67(@10) DAY 125 3.107) 52 2668) : 3.00*10) 76820) 479) 3.107) UOSM (mOsm) DAY 45 1271 m7 786 589 960(8) 7119) 249(10) 197(10) DAY 93 ns 1204 1541 764 464(3) 37207) 62209) 269(9) DAY 125 976 = * 983 - SG 3807) 1207) DAY 45 1.035 1.033 1.024 1018 DAY 93 0.0218) 1.044 0.01709) 1.042 01..00408710) 01..000264(10) DAY 125 0.0214) 1.040 0.019(8) * 0.01:7010) 01..0030189) pH 0.0219) 0.0147) DAY 45 7.1 69 72 77 DAY 93 0.89) 65 039) 64 06.2610) 06.24(10) DAY 125 09) 57 078) : 04(310) 05380) URO (EUAIL) 0.409) 057) DAY 45 02 02 02 02 0.009) 0.009) 0.0010) 0.0010) DAY 93 02 02 02 02 DAY 125 0.0) 0.068) 02 : 0.0(:10) 00209) 0.09) 0.07) Company Sanitized. Docs roicontain TSCACB wm 910.2-4D5a1y6:GavSaugbcehSrtourdiyc iTnoxRitcistywith One-Generation Reproduction Evaluations Revised Page Dupont 5386 TABLE 33 (Continued) SUMMARY OF URINALYSIS VALUES FOR FEMALE RATS TEST/ PERIOD Group Il 0 mg/kg Group IV 25 mg/kg Group VI 100 mgkg. Group Vill 250 mgkg UFLU (ug) DAY 45 4 . : : DAY 93 167 992 4603 9147@ DAY 125 382) 86 32166) = 127.00d4) 63183.1@9) 517) 14.907) DAY181 88 159 200 203+ UMTP (mg/dL) 38(5) 693) 5.6(5) 13.164) DAY 45 a 2 18 21 3409) DAY 93 84 220) 49 5010) 57 5141310) 56(6) 4) 31010) 2609) --- DAY 125 109 13009) * 2) 767) Datwornged as: MSteaanndard deviation (Numberof values included in calelaton) a Group not samattpisltimeepoidnt. @+ SStuattiisstticcaallllyy ssiiggnniiffiiccaanntt ddiiffffeerreennccee frroomm ccoonnttrroollattpp<< 00..0058 bbyy pnaornapmaertarmiectrtiescte(sDt(uDnunnent'sT)a.mbane-Duet). `Company Sanitized. Docs ict contain TSCA CBI iw 8a ~ zFH i: z 24 2 3 5 2 5 i |W 204 a i 2if|B] i 2 lg 3 oz HE3 2 2i z E04 9 1 1 IT2 E214 = gl & Z |2x 3 ciz sf 22 Ez E & g33:gZ 3:1 3Bl8:I g3i%ig2% - 25 (31g x 8 alg Za 8 d 2|5]48 7% 8 IE Ez EiH 7% 2[5 fics SgEV VY giz gs52S i:2 |2|43S= oz f.F 5obl|zZEEfEiEgE & EF ow 8 NEN gg 4ig &S 2g=dF 2 22 Elf=FEE 21$i82i%1i8u;8: #| z2 3 EEfEfREz]z 07 | Hoe ose alii 52 =2 E33E:R2E2 2% ~ Eg4H a g - .BE > =F|8225483Z32 S56.= "= ~ 3252 -J 3 HI322 & |H5 3 I 52 14] ~ "983 iz 8) ER 205 00 04 = a z:g ||egl g : |? <i zz z= = ||% &SOE 5 z z 1z8 g 5 2H|2 AE z5 == =zorF = =|g = E , =9 lz2 Poo|l:e 8 E=za zfF i 53 EE $id E a285 2 ou & Fa <Q |[g23|g3E E(I2S2 [E] aR lg oz #232 03% 05@% Oz=l]S||E 2243 = 2 8 algE zEz Z Fez 2 5 PEE 222 |ZE||l gg8 a3 -9 8.3 3.|2|235E38FEE3E dlzasd g S08 9|E2y 5=8 g3l 2 Rf 22 &Zls$i5=g%88e3 = = $558 x2 SE E5TE& ? a5 - og g"l1E2i2i2e8 g 5252 &g5 = 2 &> FES (E8|2325EaE:a3 "sda 5 2 fz 8 3 3 8 I 8g 5 : 9H0-.2D45a1y6:GaSvuabgeehvSotnuidcy iTnorRicaistywith One-GenerationReproduction Evaluations RDeuvPisoend5P3a8g6e TABLE 36 MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) cCroaupr1an GSrokwatilr a gS0r8owTvalrany 5G5r6ouRpasvik:arday Laven E5.R61E0H00ITE 16.0I 710 momHenH aGsHsu)r waoers T3.8amn 4S.o16m07a0 er oomeenm 40.s2s6s0e0s0co nee C10l00an S17i1e0mun cshmeae esltoinym seve 0C.0l23e00an 0S.h12S4e00uor 0o.7d303e1 s 0ol.o0m0esao - 2T.o11d00ao 2S.1a60l00en 2oda .0m 2a.l0o98m0i0ean os 0T.4h400a0 o 0Sommmenn oolmmmor 0s.3e59m67e Jone cus 0C.o05o56r0ao 0C.o05s02t0co 0o.o05m161 0o.l0o54o5m0eco - nesnes 2C.Sc2o0mr0ao 2.a20m6e0cn o2.5d526a o3.l56e0m10eco enoronioes i+ 0S3R70ao 1o5l0u0ean dLaoveosen olceorremrio FC SOD gGg lgai00co sCeamainm:an suLesasseserm sos.aausnocss o - `Company Sanitized. Does sot contain TSCA CBU TS --- 9H-02-4D5a1y6G:avSaubgcehSrtoundiyc TinosRiacsiywithOneGeneration Reproduction Evaluations RDeuvPiosnedt 5P3ag8e6 `TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (90-DAY EXPOSURE EVALUATION) NEAN RELATIVE ORGAN WEIGHTS (3 of body weight) CGruowll1 y 3GroSuipae1rier G0r0oow vra G3r5o8uSpauosxcay Fivesony + 100 S2.a72b7S02ieo 3.o0M2G9a0e0no pSr2oen)ti 5 o0leamsmsan Fnov 100 0C.o6mmbmine 0So.d7e0r7ne oo.0dtaiearn 0e.s9s10e0s0t0io Ra soon + 00 T0d3l0bmimsan 23O0S96d2ace 0S.e9lmsem 0.o29l7e51wan Fas som + 200 0C.1a05l09ta 0C. oisan 0.o55a12em 0o.l10d5m0an Fimoor + 100 S0.I16B6an aCammban 0Sosmoeers 0ol.d0mmeto - Ther + 100 0C.h0a7nce o2.S06l5ue 00.003a7m 0.e075l: a Foor +l 0C.o0mam n aS.0t10am n 0S.a01m00er 0s.e0mdman Finsor + 100 0.6a8020n oCsHtGS oCoamle So.goEmenB Fito CA Callan S0.G27B06tan oChmeeam s0.e0l2be . I Company Saniized. Docs not contain TscA car -- TABLE 36 (CONTINUED) - MEAN FINAL B(O90D-YDAAYNEDXPOORSGURAENEWVEAILGUAHTTISOFN)OR MALE RATS MEAN RELATIVE ORGAN WEIGHTS (8 organ to brain weight ratio) oGrdoupy Srowa11 ek Growo y 2cr0ow mvi:g Bm ain+ 200 MATa 5S.70a333n 0a .1752e 0 0H105E28R60G 1S21.0700060 0 mSeanesa aB mesR aNsL i aRssIeEsL Mm mCaaman miaaoan aTsEiRe EosNm E BRAIN+ 100 3h8.93e490n 3S3.9h40a3 e 38C.L56E39Be 6C.01H72E2 E BA 0 2S1.0o06t6 a 1L7.2i08a0 n 8U .0008e6 1T7.1i300e WEE sFaenn 2d.a7mmmes pSEoENe 23E33mae Bam 100 LLieina sB 6.067e 0 2.T02H3E08R. 62 9.0001a : -- sArroTtomEoss/ mCoiman eTeee eTsHeEI waEsRe - --- Te `Company Sanitized.DaesnotconTtsacAicnI H-24516: Subehronic Toxicity 90-Day Gavage Study in Rats withOne-Generation Reproduction Evaluations Revised Page DuPont5386 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) 0G'rmogu/pkg/day G2r50oumpg/VIkIg/day LIVER 1251.0360767500010) 128..4919358830(810) KIDNEYS 30.l9a2313850910) 40..54256102038(10) HEART 011.2728867970(10) 10..7009331502(10) sevgen 0.017195006507(10) 00..8122725602(10) BRAT 2.0l1150140508(10) 20..1046823307(10) - Tvs 0.013200307100020) 00..0289052080(10) ADRENAL GLANDS 001.0005953090(20) 00.10050379603(10) TESTES 30l.44s0E3s9S0 (10) 03..5365731620(10) EPIDIDYMIDES 01.15211055301010) 11..2859589660(10) FINAL BODY WEIGHT 590.65000 537.98000 8253324(10) 37055428(10) `Company Sanitized. Does not contain TSCACBI Tor -- 9H0:-2D45a1y6G:avSuabgcehrStoundiyc TinoRxaictistwyith One.Generation Reproduction Evaluations RDeuvPiosnedtP5a3g8e6 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (3 of body weight) GOr'omuaprka/day G2r5o0upmav/ikzo/day LFiIvNeArLsBODY + 100 2.59628 ollasas(i0) 30.l52282375840010) KFiIoNNAELvSB/ODY + 100 0.67037 0107651010) 00..0854405804(410) sFIeNrALeB0DY + 100 0.30689 olos2ssi0) 00..30177126610) sFIeNAuLsB0DY + 100 0.13384 001870010) 00..1052444870(10) - sPRIANIANL/BODY + 100 0.37046 0.401048 olos3sacio) 002098010) mFINaALsBODY * 100 0.05128 ololeso) 00.l0o5t4s9olco AFIDNRAELNALBODGYLAN+DS1/00 0.00943 olo0ie7(10) 00 .001001045510) eFIsNaALs,BooY + 100 0.56528 olfzicor 0o.6l249s0 ) eFIpNoArLoMBIODDYES+/ 100 0.25949 olos3r10) 00.2325102288010) `Company Sanilized. Doo not contain TSCACB1 -- wo 9H-02-4D5a1y6:GaSvuabgcehrSotnuidcy iTnoxRiactistywith OnGeeneration Reproduction Evaluations RDeuvPiosneid-5P3a8g6e `TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS (3 organ to brain weight ratio) Gromugp/kg1/day G2r5o0umpg/VIkIg/day BLRiAvIeNr* 100 BKIRDANIENYS*/ 100 71818..3549050745(10) 1621.8.3444262752(10) 818146..91181871124(10) 21200..7632665248(810) BHReARITN/* 100 1831.7233607754010) 7591.7368980431 (10) BseRuAEIENN/* 100 376.1811438608210) 358..951665103(10) -- BTRvAIsN,* 100 144.203177680620) 1331.773228518020) BADRRAEINNAL* G1L00ANDS/ 20.15345724556(10) 20..5317106602(10) BERSATIENS)* 100 1589.l1a92868570(10) 125550.995839332010) BERPAIIDNIDY*HI1D0E0S/ 09.12304090955(10) 58882.027670833(10) Company Sanitized. Doo- olc=atainTSCACBI & 9H-02-4D5a1y6:GavSaubgeehSrtoundiyc TinoxRiaciistywith One Generation Reproduction Evaluations ReDvuiPosnetd-P5a3g8e6 TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS (THREE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Laven p-- wrRom GLb ress OGrraoknasiday 1T 6.063e 60 S1.2h20e20 s O0l.o0o2a6m6s0isy l1ims0se FEN SOUT gBga2s0s00e) 25GrsoawjxaTrridey 1T09E20s Sczhsom0ws 0o.l0tmis2s0isy o3.l7a1s8d00ers seelsaoeoenecs) 1c00romwa/kvasday 1T7.2E006E o4.l20e20a0 e a0.l02b68a0 ) 2.d7l6s06s0isy seevoameanosois) 25G0roumpe/vkiaz/day 185d37e60se o4.42s080e 00..00360036 o3.7e068s0 ) Lsieasi.ooonsosois: `Company Sanitized. Dec: not contain TSCACBI Tor -- 025Das1y6G:vorSggsuecSSlryeytToRriihc Oovre GenrecrrioonRepprotsciionfEoitnoss DhRoocvoaruese TABLE 36 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR MALE RATS HEA ERELATyIVE ORRBWELEGHTSR(4 oEf hyTweigh)EE (THREE-MONTH RECOVERY EVALUATION) - Data summarized as: Mean S Seti Neta icTmSstacrndscary GdsDoevriaet0si0onT5(en)e) Tw 0 `Company Sanilized. Does notcontain TSCA CB H-24516: Subchronic Toxicity 90-Day Gavage Study in Rats with OneGeneration Reproduction Evaluations Revised Page DuPon-5386 TABLE 37 MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) Onarkaldar 2malady 100m/karday 250rrkaday Lave aS.ia2d89o0un 9L.e20o98n9e 1S0.o29a61m08es 12s50o1w10s GENan Odtean oamwsan oem Sian omens estan oles sna 0S.5l08i00an 0o.50s611e 0o.l0i0t7i10soam 00..520516700 a Oslsesna o19lm eae o1l9m1s2z0enn 0s.a0r98 ns 0S.2i978a0 n 0o.3s12e 2l.a28e5s00ian 0o.2s88l08o AomEAL GLaDs 0S.o06l4o90eae 00.006e5r67s: 0o.l0a6b5e5s0enn) 0.00.60809isw - ownes 0S.1e15m50an 00.1022m11m 0S.a1i20s7i0sun 0.o1.1i1i2sm wens 0S.o57s2m0an 0o.m61e22ns 0o.u58o07m0an 0.06l8s8e6so I aSgeaiibnenn aCveaessee a2sea.amloonoan aam.naeedssa `CompanySanitized. DoesnotcontainTSCACBI 3 -- 9H-02-4D5a1y6:GaSvuabgeehrSotnuidcy iTnoxRiactistywith One-Generaton Reproduction Evaluations DReuvPiosnetd-$P3a8g6e TABLE 37 (CONTINUED) MEAN FINAL BO(9D0Y-DAANY DEXOPROGSUARNEWEEVIAGLHUATTSIFONO)R FEMALE RATS MEAN RELATIVE ORGAN WEIGHTS (% of body weight) OGrrooiukpa1/2ey 25Gramsapika1lday 1c06rosupo/vtday 2G9r0oumpo/vkaorrsaay FOALsony + 100 S2.84N006e N2.0e608m a2.5i03s00e so.aass06e0 Coy + 100 S0.S60M73s6an Gomnoess booswemcor o0.l2i68s5m Fina wor + 00 So.aaatannee S0.o3m74me o0.e35b29m0an S0.3e67e5m FIsoo + 100 S0.o16E38T0an 0.S3o6t3w1mm 0o.13a678n S0os.10508 Fimoor + 100 C0.6h409a9 n C0.o6m5mm 0.o67o0s35man o 0.692e5 --_ FoInNeshoo + 100 T0.S09mmeeno G0.1o02n82e o0l.o0a5s9i8cor o0.b09s98e3 r I hoy 00 oPIAvLeBoor + 100 S0.%02a1aan 0O.0m209a7 n 0.G0C21o7m0sr 00.00042s 0.o0l1o3i0e:scor 0S.o0mmeruo 0ol.bs0iiaie o0.0l09o4 r Patsor + 100 B0.1i970e0 n C0.2o190m0 m c0.20a335mcod0.2e380r CompanySanitized. Does notconTtSaCAiCnBI -- Tor ~ 5sta:nSesSey ToResi reGers Berton Eins RDeoinsie TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (90-DAY EXPOSURE EVALUATION) i Ed Ele SET BRAT + 100 109.9013 117.94230 21675618 133.952474 BRAIN - 100 26.8370: as.51771 6.45901 27.051 Fim, Ue Ue HHS. Company Sanitized. Does rot contain TSCA CBI 9H0--24D5a1y6G:avSaugbcehSrtoundiyc iTnoxRiactistywith One-Generation Reproduction Evaluations ReDvuiPosnetd-P5a3g8e6 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN FINAL BODY AND ABSOLUTE ORGAN WEIGHTS (grams) OGrvogu/pkg1/1day 2G5r0oumpa/vkiaz/day LIver 101.1069782404609) 1.9.3989837370(10) KIDNEYS 02..24a3168798(9) 0.24.500674330 (20) HEART 0.11.107540353 (9) 01..0088629780(10) spreen 00..0586470333(9) 001.1533775470(10) BRAN o1l.o9n228103019) 01..099151:800(10) - mvs 00.027688139309) 00..0222974960(10) ADRENAL GLANDS ol0o.103662516(9) 00..0017045460(10) ovaries 00..0121953494(9) 0.11770 0.01938 (10) ureRUS 00..6195227984(9) 00..2608294150(10) FINAL BODY WEIGHT 353.1111 78324409) 33028.57830304008(10) _--_--m CompanySanitized. Does ret contain TSCA CBY 9H0--24D5a1y6G:avSaugbcehSrtoundiyc iTnoxRiactistywith OneGeneration Reproduction Evaluations RevisedPage DuPont-5386 TABLE 37 (CONTINUED) MEAN FINAL BODY AND (ONE-MONTH ORGAN WEIGHTS FOR FEMALE RECOVERY EVALUATION) RATS MEAN RELATIVE ORGAN WEIGHTS ( of body weight) Grmogup/kg1/1day 25G0romugp/kvIgT/Tday FLaIvNeArL)BODY * 100 02..2895158142(9) 03..3294572350(10) FKIINDANLEYSB/ODY * 100 00..0669934914 (9) 00..1821454994(810) FHEIANRATL,BODY + 100 00l.03a3051079(9) 0.35335 0.03687(20) FspIrNeAaLn/BODY + 100 o0l.01z6614838(9) 00..0147750204(10) --- BFRIANIANL/BODY * 100 0.55117 0.625278 0.05678(9) 0.06535(10) FTHIYNMAULS)BODY * 100 0.07543 0.01729(9) 00l.0017741350110) AFDIRNEALNAL30GDYLAN*DS1/00 0.01885 0.00301 (9) 00..00024464854(10) uFrIENRAULS/BODY * 100 00.014977282309) 00..0252126509(20) oFvIaNrAzLssB/ODY * 200 00..0003824758(9) 00..0003688399 (10) .mpanySanitized. DoesnotcostTSaCAiCBnI -- ~ 0 -- H-24516: Subchronic Tonicity 0-Day Gavage Study in Rats with One-Generation Reproduction Evaluations Revised Page DuPont5386 TABLE 37 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FOR FEMALE RATS (ONE-MONTH RECOVERY EVALUATION) MEAN RELATIVE ORGAN WEIGHTS ( of organ to brain weight ratio) Gromugp/kg1/1day 2G50roumpg/VkIaI/Iday LBaRvAeIrN) * 100 KBRIADINNEYS+ ) 100 52940..8531726454(9) 12162.045608755079) 55291..788621193(10) 13106..7457674626(10) HBERAARITN, * 100 sBpRrAsIeNn/+ 100 661..7096184791) 294..8521358340(9) 5461.2626390635(10) 62.8.800553478) (10) TBaRvAMIUNS/+ 100 13.319165313089(9) 12.3898185016(10) ABDRRAEINNAL+ G1L0A0NDS/ 031.645489223309) 30..85955053)7 (10) oBvRaARIINzs+ / 100 51.3975420530(9) 06..1958041516(10) uBrREARIUNS/+ 100 3751.484923068009) 036..8194875837(10) CompanySanitized. Doesnot contTSaCAiCBnU id i25y1:GSgrScyashiecioeGoro erosion Eins RDeset rie TABLE 37 (CONTINUED) MEAN FINA(LTBHROEDEYMOANNTDHORREGCAONVEWREYIGEHVTALSUFAOTRIOFNE)MALE RATS SIRE WT Te Be ne Ee SEI FIN BODY WIGHT 2 e200 334.42501 315.18001 347.5600 Company Santa Doe continTSCACDI 910.-24D5u1y6G:avSaugbechSrtoundcy iTnoxRiactistywith One-Generation Reproduction Ealutions RDeuvPiosnetd5P3a8g6e TABLE 37 (CONTINUED) MEAN FINA(LTBHOREDEY-MAONNDTHORREGCAONVEWREYIGEHVTALSUFAOTRIOFNE)MALE RATS VERY RECATIVE GROAN WESGTS (4 of body weight) CGrrooupl1ey 2SGrmasapkavnday 0G6rosuo/mva1sdny 2G%ouep v/ita Firatsony + 100 i2.3s07l80e S2.6i178e o1csimon e o20ise Fer i S0aomke S0o.w7s0en 0.o1l86a3m7ms c0l.a8s2s3es) Tha oor loo T0.00o332s C0.l0a05c5h6ew o0.0l06e20n 0.0o05i74 e Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend tet (Jonckhere- Terps). # Satstically significant difference at p = 0.05. `Company'0any SanitSanitized. Doss . contin Tsca cay = i8 - 53 5 i reeees i 2 8EZz ii1= 35f] iJg nji8g%e~T~TT8Hxa 3ga G42mT 842T Si5s4T Gfaal 322 Zoigigid aif 32 3% 22 38 2 3 g E| i3Tif s mi E Ee 82 90 82 gFoe ald8 B$E2 0s igi mf ae an as an as sa|iBdg gs PRED idee mwyIT i TT on TT oS EoonTToan RgTEisy yg iH ~ | = E i z=t iHEfYogs i 258% | iE3E21 EE | HX SE g 24 85%5 | ii 3z 2g22 | |i 53 | } 2 2Z | i 1I iEEM iE {33 15: {3% i{3r2 F 1155%2 53 iyd &i E2gZERo PPiBgEgsogE B2O8B O2E O8B O3B 8OBIiTHi=Y 2 2pis 32 ~ 2i8: gi (EEE OE OE BE OE OR iif 2Bo!o, aPEEs dEOdE iESEE dOE iEinEC so EHREEE EIN i HE!REINi i 233 R02 F2 E2 28 _ g2i7 fo IHRAAGF 3%gE G8 ER 5% ce _% H | 3i 15 i : 2 222%: ~ 38 zs f8 3 ----------, } sli SZio3Tf!i TjifoTTiBT 5I3ET4RT 3EqF E3%m 57+ 3E2F 544 349 5Fa%l zg fly,ig 82 8282 32 822s gi ia Hig= 82 82 gs 8s B= 82% i 8 ig) ii --------------i.3 S5E5 l8a]i jo -ji22%q 33%9 E3R9 SEgR ESmg 8E9R SEeRlEE EG i: 58 gzEZE;| f1188p8d || 1EI2HH8 2z E SeXi| 2 zi! TERRE fi j5s1 3 EE : 15 5 = 5%! | ig 28 3E5z i: 12 (53 3313! }i Hisc a28 i i: I-28 EE 22 | iig o8 8 s 8 8 gl3a gzii Pii EEEEEBE 84 E fFEF EHEEBE BBHiiigEdyf Ei s dod 38 3 4 Fit 5 &]| EG0E0{L228 0LG%Oe sfLdoOf3]4F ESosHipe gH2te 2g24id1d zsli ooo 187 87 BP 3 RZHF HEEZI7S 3 5gg g g ziiisyi o iIRg giTg"Tr Ta= SuT Sx ST g- 3FzT 32 5~32ii 3 g SFEi iiafiiiR e laE gs aenE 3 nn BE FE s i e wlEiigniif(iBgRpEiTga=ges82 S8E2 -- 33 33 8s sof fF 2 if I 53 14; 1. is? S82e 333g 3333 3333 3 8s p 8s t sisd dg 22m Et (EFsi EN TTTTTEE is ZZ | 5 28%5.: 18g3 HEI {23 ;i(g5s8 --- g2 sE$E5:!1 g %s jiEi | 133 183 aER0%E :j r jg8 f liz H i EZF R8E 8!: ]i; 15% jet 3 Af 3 2S%z i i i i Lug 5 1 gE : 23Zi f] ap oe 88OE L8B g i143 gist i Jf gFi : PPEEEE E EELHE fH iigdE i: gl E [HI Ppl id diy i: _ 34 z 2!| liHhg2 oEgFe E i8lglEegLgeen. 5gR8eELfLBe a2ifE geig _id --E__E 823 5 3 34 oSz IiTeT gR ran gd T Eo Zn ds Gn dese-- ll i oY Ee SESiiag siLei 32 22Ca as Se --RE i SE gig jsRifo e uma 3: 3c it 3 Is S E5 E {a3 8= 38 CgErHits 3s 5 EE 2 83 3U2 B2T2 E3L2i1E35 8 2z2z!! gi Ti a EE 1i 18% i1i5sd ~ Z|z% EEEE! (FE ed is i iiiHgi . gl = o83i i: iEHk 5 Hi1IE z 2g3g1 ii {2 {3s i z5 z z! O i i igd it | f gt | =BE Z| i| 808 PEEE 8E8g8 B&PEE8 R8 EEIEEHs Ln d 522 fgEoiHz H HEBEEReGEofdss 3so RE3PEiEaHEHgiiitse Bof ozi! is3 i 1i5s%g ._iEgR EER E2S ga gHaefEIiR2eEgE8e2s% EH] #aEtiiang Rfe ~ i=| _E -~ : =i Co 3 g :2E1i13d3171l;,g 4yliqigaen~nagasm dg2n E 4Gsn 5n E19237% 3ga 3g1a1) 5 E2 ilE iip j5gs2 389a33 a3rs a33na BB gai 8 igiyid ME i :EEi Tes nite gm2 o8= mSs E82 m83 E8:= Egail FZ BEE Ei DLCa LL E 3=8%2 223%2 33%32 E83 2RE%F =@ aa s Ee Ri E thn 2: EF = E1 z i2 1 Zx idii fl 2 2% i fir in ii Eio i is 38 188 i%r l2e: Z= 8 z! || 3 143:4 i:gi ggi g2Efz3!! P|||17EE828od 13P4i8 di8 sq8 128 gBI iaif 3 ! Z| {Bg BE BB rat i : g! Pedop dr Er ox S80 8E i: :Ey E dRaElERFEEER R i : EE 98 2% 4 BEigd i Si Ehiegr iii -- HE zs 8 - 3: 3i 2 BBgiiis l o1g ig giuidds oE v gaa i: : 2 ff ea} g ilgi, Eiaz ii8T30 EB i} Elif nige ald g8 ig Ti hE | 8sSBgEigiRlfl jleL miigie.s aElaia isd ZF ies | TTT BH {Be ER HEggE E . Ep--ii i5i3s2H% g =S ios 52z%3k || j1&o : ii os= og25 j EiH 12 2823 i }} FiEe 2i: 33:i ii4 iHi ii: z88% eZ%!l i:|i a gligiaidd EEzZgSilii IiPii E]g gBEgiiiiEndtff Zg2i: ,o |DiroHnf,F EiiiEEsY z5zi f ggE 00o i Fe oFsE aBiEgs a |fi--fie igEo% EBEEE3 BRgieiZlEd% 8 g t 2 8 gree B {{811,1l8o n5i8S%e S30o 38g2 8 22 580 88o5 8E9m SEeel) 4; BIE. 5. 5e 3s 4 fen de 2al 8 ~ i 3I3 x :Z: 5 g g ioER i gE5 5 Ze! a 25! zE2=5& = 2gz3! aogz gggbzg! = 28 zog-ge! ai 9| FE | | | ;: : i|| i ii| i i : 2i i 12 IE 115858 EH |e {1i3aE8g {8% 1ii3a: ioe 12 3: || 1PBEEBB EB OEB EB E8 EE REE] 24 i ife fe Ee gs fe ged 5e gs in sg --- 2 i i iRfT 1,iTgTTgT ide 22 T = 3s T = 2 , 3s 3a 2: 2 2o || gl 5 gB5E!! 8 oz - EZg CZ3EHz2Z!! f| = 83! iHE 2 E gE g5 & Z8Z8!! 3g 2P%H! i5 8ge i Z| EEEn Bd 18% i| : }||i ii | j! |i || is 8 8 838 8@g |i i i |ii i5iiz%d `j1i ez 3i1i3s iigE iEEswH 5 al: < 52: =43 a ~~ 5 } : i PPoF Fg | PE EOE OE EEE RI PEE EEE ROE BIH ipg%iE8 EaF faEk ELF f EFafEF koE:! : Bgiiba: {5% Fe 2 ue fe ge ge gail! --------igf 5 B 2 FlTig EiEee Em ae ia i eT iss o Cao si e | a 3 i fIEeE i| ] i E S:Ez!) |i fol] oy 4j9d4d 1E25:P% Z1 5ihE2 i||; J 5 881 i|i| <= EH H;gE2fe] |i | ii : 2%! || ia1523 i ji 1iie5% | dyf ia de feiBs l ee UE z : bie 2 i2y --i 8| i i i223 En iM :i EE i ArBEyhbore :Fogigy Ek zn iiC PoE4 h giiEe25E52Se %xEi iioE Eii E T dH H i ~: gi | 1H Cid 8 r TVis? Tennnnnnnn8 n8 yg$ii i E e T .j2% 8 82 82 22g Ze gal i | led AAA RAI 5 30PoiiiE [i1i33 iz i I ~ g 8~f%2S i2:ss1i |}i||| ii ii1fii]s 3| 5= gz8! 3i 2E8 R5 ggg=%Ez:! i: oggf eg! | Z| i i: :| || Lee a 5 H TgiHtz & ii IiitEtE: iad i iid : Pi og CE 0L2E ReBeodrOF oFBrgEEabH SE oonBH ig id Geol ii _ i8 PP8oy3 Di o lEE[iHe2f3a8edne8 dS2e Hg3e0 Ef2e0 Eioef fiiig gil! i _EEBZ RE BF B=i%z 8 : =g E fpTeE ee ow "REFlag 4 isd 5 VEE iz! [J zg ] 5i2L5 | li2s5! | _ iH zi ! i i: E|1 ERi 4 3 E3 | | BEr-- EbrE i | | | |i |is i;i 158 5i1Pia3o%d {5 2% 2 252] _ 7i4#::9 Zz |i is 8 8 : I | i P iE 1E11}8iB:: E: i Lii i : .yg [8.8 | 33 8Bdie gard rH if Egd giipl | CREE iE i; I ifefgEa,Td Ho gs je5d5i hel HEE di ik HE 8 ~ 3 Ti : 3 ETT [18g1igl]g nBi2S7e 8BFe 8 2% |4 3 LLEE EE gL i: i| if18% 2iad ZE| i Ix 8 53 i is _ 2F AC2EEE3S!1 ii| iiEiaE : i) =S o23g:! i| f4xd R i 2g ; i i5 oF Hcge. i i pe ik 1 gg : is 5 Zz : fof 2 e } 153 i z| feos og ia %i i |ERR ied | | pes 8 isk 22 | PEE OBE IES 33 | PEE igs icg ]PFgE isd fPF alFoiiln: ~ Hii4Y IE LL LELH 8] ~3 %: FE |g3 5 i831 Io oiGe Ge Ge Go Go Ge Ge Eo) i HIREI EA a ied EE 15 2age Go Go 0 Ge an iH i ig Fz 5 gig] mig 2g igEige d jGl go Bw Si v 3 8 } Bs Zwu1l5R3 S5e3l idein iie. z8 z8z3 1835 4 iizi3 - ZED ; ik y gf S2 S28E1 ii I8E g = if os 8g; !: Eie 3 5g } {ug Z3l 3 : 53:3 5s3 - 5:4 BSeE! i| 4 1 8Y 71 ! 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