Document 6R73XBLmGEobj5eXXyKDQKqo9

#R226 -- 326] 443 H25231: Developmen Tsiiy SdinRyas ~ `TRADE SECRET ARR26 - 326] Duron 10209 Study Title H-25231: Developmental Toxicity Study in Rats Laboratory Project ID: DuPont-10309 TEST GUIDELINES: U.S. EPA Health Effects Test Guidelines 'OPPTS 870.3700 Prenatal Developmental Toxicity Study --~ AUTHOR: Susan M. Munley, M.A. STUDY COMPLETED ON: November 19, 2002. PERFORMING LABORATORY: ELL du Pont de Nemours and Company `Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 WonRaquesrNownen:JE SERVICE Cope EE --~ --_-- Company Santtize 068 notconti Tc cay ees --~ GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT "This study was conductedincompliance with U.S. EPA TSCA (40CFRpart 792) Good Laboratory Practice Standards, which are consistent with the OECD PrinciplesofGood Laboratory Practice (as revised in 1997) published in ENVIMC/CHEM(98)17, except for the item documented below. The item listed does not impact the validityofthe study. The bulk test substance characterization and stability analyses were performed at DuPont Regional Analytical Services (RAS), 2 non-GLP laboratory. These analyses were in `ucnodmeprliGaonocedwLiatbhorraetgourlaytPorrayctguiicdeelSitnaensd.ardNso;nheoowfetvheer,afthoereamneanlytsieosnewdearnealcyosnedsucwteerdeipnerformed compliance with IS09002 regulations. Allofthe analyses are considered valid and sufficient for the purposesofthis study. Applic Sponsor:E`WLildnuiaPgoonnt,dDeeNlearwoawrres9a5n5d8Company USA -- sovy en Shu Susan Mi. Vacnle 13:100D1e-sdeo Research cient Applicant Sponsor: DupontRepreemaive Bie _ Company Sanitizad. Does not contain TSCA CBI --~ r 25231: DeveloTripcimtyeStnudytinaRalts DuPont-10309 QUALITY ASSURANCE STATEMENT `Haskell Sample Number(s): 25231 Dates of Inspections: Protocol: March 20, 2002; April 17, 2002 Conduct: April 17,30 2002; May 1, 2002 Records, Reports: September 26,30, 2002; October 9-11,13-14,27-30, 2002 Dates Findings Reported to: Study Director: October 2,14, 2002; November 1, 2002 Management: October 9, 2002; November 13,19, 2002 repose, _ onSbendti Qui>myhAestBy.suBBrrreeumAleumrdeirtor 12-NoDuvc-3602 --~ `Company Sanitized. Doesnotcontain TSCA CBI --- 1.25231: Developmental Toxicity Study in Rats Dupont10309 -- CERTIFICATION `We, the undersigned, declare that this report provides an accurate evaluationof data obained. from this study. . ye ot ( Hester tg tors 2002 T`oSeeniioCr MSatCnhrisBt35.. ow Approvedby: R>obeAMU..PeA te Pu 5, DABT. Manager Mue2Tiaen ~ Study eso Sasa. Manly, 19: 000-GooR Tow Reseach Sent Gompany Sanfized. Does not contain TSCA CBI -- -- H-25231: Developmental Toxicity StiunRdays --~ TAOFBCOL NTEE NTS DuPont-10309 Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT c.vsvsmannsnnn QUALITY ASSURANCE STATEMENT cov CERTIFICATION crs LIST OF APPENDICES wocossmsmsmsmsmmsssssmmsmssssmsmsmsssmsssmosnd STUDY INFORMATION cmos] OBIECHIVE commend MATERIALS AND METHODS wc A0 -- Ar Tot CHS corms A swimsinmimm-- I-- I-- FE ------ E, SY DONG amram smt-------- J ET -- 1. Preparation, Administration, and Analysisof Test FORMUIAHONS........orcnrrvoroee 13 LT A ---------------- M.S ARIS cntmmmmmmmmmnismmmm--------T RESULTS AND DISCUSSION ccna8 ANALYTICAL EVALUATIONS wocvvnssssssmssmssmsssssssssssssnc8 A. B. CHIOMBOGIAPNY..rrvvvsssesessnsssssnssmsnsssssnnnonnc Concentration Verification and Stability SAMPIES.........rvevrvrmrorevrnemsone 8 18 C.ConcentrationVerification Sampls........ CA ---- D. ATBIYHiCal COCISIONS orrnesrrrsrsrsmenrnrnmnemssmssseonree 19 DEVELOPMENTAL TOXICOLOGY cme20 ~ A. Maternal Findings ........ooveurec wml * Comoany Sanitized. Doss not contain TSCACal H:25231: DeveloToxpicmityeStnudytinaRalts DuPont10309 --~ B. PUATIAOG ccoimmmguammismstpugmmmmmmoonsi] CONCLUSIONS sms 23 RECORDS AND SAMPLE STORAGE wns 23 REFERENCES covssssssmsmsamsmssssmmssmmmmmsissmmsmsndd TABLES corsets APPENDICEScorms4) LI OF TSABLTES `TABLE | SUMMARYOFDOSINGSOLUTIONANALYSES vc... `TABLE 2MEANMATEBORDYNAL WEIGHTS... `TABLE 3MEANMATERNAL BODYWEIGHT CHANGES... `TABLE MEANMATERNAL FOODCONSUMPTION... `TABLE 5 CLINICAL OBSERVATIONS... TABLE 6REPRODUCTIVE OUTCOME... TABLE 7INCIDENCE OFFETALMALFORMATIONS........... TABLE INCI OFFDETAELVANRIACTIOENS... I ssmnds? smmm-- msl nnn snmp sms dl smn 51 --~ APPAEANANLYTD ICAI L X DLATA.I....S....T OF APPc ENDICm ES ---- APPENDIX BINDIVBOIDYDWEUIGAHTLS... tmnt APPENDIX CINDIBOVDYWIEIDGHTUAL CHANGES. A APPENDIX DINDIFVOOIDCODNSUUMPATILON vn mma TH APPENDIX EINDIVIDUAL CLINICAL OBSERVATIONS.......... mms APPENFDGRIOSXS POSTMORTEM FINDINGS... commend APPENDIX GINDIVIDUALREPRODUCTIVE DATA... comms 0 APPENDIX HINDIVIDUALFETAL WEIGHTSANDALTERATIONS. orm 06 --~ --_--_-- `Company Sanitized. Dossnotcontain TSCA CBI STUDY INFORMATION H-25231 SubmitsNetbookNumber 1022621 50; ELN 00788-5 1 Haskell Number: 25231 Physical Charteris: Tanliquid Stability: The test substance appeared to be stable underthe conditionsofthe study; no evidence of instability was observed. Sponsor; E.L du Pontde Nemours and Company USA. `Wilmington, Delaware 19898 Study Initiated/Completed: April 12, 2002 / (see report cover page) In-Life Initiated/Completed: April 14, 2002 / May 2, 2002 -_-- 125231; Developmental Toxicity StuindRayts --~ STUDY PERSONNEL DuPon-10309 Study Director: Susan M. Munley, M.A. Management: Robert M. Parker, Ph.D., D.A.B.T. Primary Technician: Gregory L. Poindexter Management: Scott E. Loveless, Ph.D. Analytical Chemist: Janet C. Maslanka, B.S. Management: S. Mark Kennedy, Ph.D. Toxicology Report Preparation: Mary K. LaRoe Management: Nancy S. Selzer, M.S. Laboratory Veterinarian: William Singleton, D.V.M., A. CLAM. -- --_-- onTSCACE comes gentizedposs oto" H25231: Developments) Toxicity Sudy in Rats Dubont10309 SUMMARY H-25231 was administered by gavage to groupsof22 Crl:CD(SD)IGS BR rats once daily at dose levels of 0, 625, 1250, or 2500 mg/kg/day. Doses were administeredas a suspension in deionized water ata volume of 10 mUkg/day and dosing took place over days 6 through 20 of gestation (G). Body weight, food consumption, and clinical sign data were collected during the in-life phase. On day 21G, dams were euthanized and subjected to a gross extemal and intemal examination. Uterine contents were described; all fetuses were removed and individually weighed, sexed, and examined for extemal alterations. Approximately one-hoaftlhfe fetuses were subjected to fresh visceral and fixed head evaluations; all fetuses were examined for skeletal alterations. Under the conditionsofthis study, maternal toxicity evident as reductions in body weight `wpearreamaeltseorsrewpaosrtoebdsaetr2ve5d00atmg1/2k5g0/daanyd.25N0o0n-magd/vkegr/sdeaym.ateEfrfneacltsefofnecmtsatoecrcnuarlrefdooadt 6c2o5nsmugm/pktgi/odnay; Dtheuvse,ltohpemmeanttearlnatloxnioc-itoybswearsveedv-iedfefnetctatle2v5e0l0(mNgO/EkLg)/'dawyasevciodnesnitdaesrerded6u2c5edmgm/ekag/ndfaeyt.al weight. `The NOEL for developmental toxicity was considered 1250 mg/kg/day. -- containTSCA cet company Sontzod. 00087 -- `a `TwheereNnOotEdLetfecotretd.isTsthuudsyfiosrdethfiisnesdtuadsy,thtehehiNghOeEstLdsoseeqautivwahliecnht oadtvheersNeOefEfLect1s adterfibnuetdabbly tthoetUh.eS,esEtPsuAbs(t1a9n8c5e) 0d 10 the o-dbserved-adverse-efect level (NOAEL) 1s defined by the European Union (1994). 5 -- H25231: Developmental Toxicity Stdiyn Rats DuPont-10309 OBJECTIVE `The purpose of this study was to evaluate the potential maternal and developmental toxicity of H-25231 in ats. MATERIALS AND METHODS A. Test Guidelines "The study design complies with the following test guidelines: + United States Environmental Protection Agency (EPA), OfficeofPrevention, Pesticides, and Toxic Substances (OPPTS) Health Effects Test Guidelines, OPPTS 870.3700 Prenatal Developmental Toxicity Study (1998). B. Test Substance ~ `ETnhteertperstisseub(sDtCaSnEc)e,(HE.-2I5. 2D3u1)PwoantsdseupNpelmieodubrystahnedsCpoomnspoarn,yt,heWiDlumPionngttoCnh,emDielcaawlarSeo.lutIitownass assigned Haskell Laboratory Number 25231. The sponsor was responsible for the characterization and stabilityofthe test substance. Test substance analyses were conducted by `DuPont Regional Analytical Services (RAS), Jackson Laboratories, Deepwater, New Jersey. A reserve sampleofthe test substance was collected and retained by DuPont Haskell Laboratory. C. Test Species `dTehveelCorplm:eCnDta(lStDo)xIicGiStytBeRstriantgawassrseecleocmtmedenfdoredtbhiys tshtuedgyubiedeclaiunsees.it Tishae pCrrelfe:rCrDe*d(sSpDe)ciIeGsSfBorR strain was chosen because extensive background information is available from the literature, the supplier, and previous studies with other compounds at Haskell Laboratory. This strain is also considered suitable relative to hardiness and incidenceof spontaneous disease. --_ `Company Sanitized. Doss not conta-- in TSCA O81 H25231:Developmental ToxicitySudyinRats ~~ DuPomel0309 = Eighty-cight nulliparous time-matedfemaleswere received on April 11,2002 (66 females) and April 12, 2002 (22 females) from Charles River Laboratories, Inc., Raleigh, North Carolina. Body weights on the day the rats were mated, day 0ofgestation (day 0G), were supplied by the vendor, The rats for this study were at either 1, 2,or3 daysofgestation upon arrival. D. Animal Husbandry 1. Housing Animal rooms were maintained at an acceptable temperature of20-26C (targeted at 23C) and a targeted relative humidity of 50% 10%. Animal rooms were artificially illuminated (uorescent light) on a 12-hour lightdark cycle (approximately 0600-1800 hours). Animals were housed individually in suspended, wire-mesh, stainless steel cages. Nesting material was not provided because the dams were euthanized prior to parturition. 2. Feedand Water PMINutrition International, Inc. Certified Rodent LabDiet 5002 (formerly known as Purina CertifiedRodent" Chow) was available ad libitum. Water from the United Water Delaware was availableadlibitum. 3. Identification ~ Each animal was assigned a unique number and was identified with an AVID Microchip implant by the supplier prior to shipping. Upon receipt, each animal was assigned a unique Haskell animal number. Both the Haskell animal number and the AVID Microchip implant number were recorded oneachcage card. A master listofunique Haskell animal numbers and corresponding unique AVID Microchip implant numbers is maintained with the study records. 4. Health Monitoring Program `As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impact the scientific integrityofthe study: + Watersamplesare analyzed for total bacterial counts, and the presenceofcoliforms, lead, and other contaminants. + Feed samples are analyzed for total bacterial, spore and fungal counts. + Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional ~ srpeeqcuiifrieemdehnetasvayndmentoatlst,oaefxlcateoexdins,tactheldormianaxtiedmuhymdrcoonccaernbtornast,ioannsdoforkgeaynocpohnotsapmhiantaenst.s,Tihnecluding 7CommySTmr ow TomTISCA CB H-25231; Developmental Toriciy Stdy in Rats DuPont.10309 ~. `cconotnrsoulmpgtrioounp(mdeaaysns6-f2o1rGt)hev2al5u0e0sawnedre50c0on0simsgt/ekngt/wdiatyhgtrhoeuspesb,ordesypewcetiigvhelty.effMecetas nanodvewrearlle f9o5o%d `acnodmp8o9u%nod-frtehleatceodnetfrfoelctgsroounpemitehaernmaatt2e5rn0a0lawnedig5h0t00ormfgo/okdg/pdaarya,merteespresctaitv6e2ly5.oTrhere were no w1e2i5g0htm,g/skegx/rdaatyo., lTihteerresiwzea,srneosoervpitdioenncienocfidednecvee,laopnmdeenxttaelrntaolxiaclitteyraattioannyinlceivdeelntceestdeadt;amweearne fetal comparable across all groups. Based on these results, were selected for the current study. the dose levels listedin the table above H. Randomization rDeasmpesctwievreeloatsssoingntehde tboasloitssofacdcaoyrd0inGgbtoodtyhewieriggehsttsatainond daasys.igTnheednt,o tchoentyrwoelraenrdaenxkpeedriwmietnhtianltheir fgorroaulplsgbryourpasntdhoamt wsearmeplniontgstfartoismtitchaellryadnikfefderleinstt.(pTh>e0.d0i5s)t.ribution resulted in mean body weights 1. Preparation, Administration, and Analysisof Test Formulations 1. Test Substance Preparation sFtoorrmeudlaintiaocnlsoosfetdhceonttesatinseurbsattarnocoemintethmepevreahtiucrlee u(ndteiilounsiezde.d wTahteerm)ewtehroedoprfempiaxriedngdatihleytaensdt ~ substance with the vehicle was documented in the study records. 2. Test substance Administration rTehceotmesmtesnudbesdtabnycerewgauslaatdomriynaigsetnecrieedsbfyorgtahviasgteypbeeocfaussteudtyh.e oTrhalervooutleumisetahdemrionuitsetetrhaetdis (10 mLkg) was based on the most recent body weight. 3. Test Substance Sampling cSoalmlpeclteesdcoonntAapirniilng16H,-220502231foartutnhiefocromnicteyn/tcroantcieonntsoraft0io,n6v2e.r5i,fi1c2a5t,ioannadn2d550-mhogu/rmrLoowemre `tAepmrpielr3a0t,u2re00st2abfiolritcy.oncSeanmtpralteisonatvaelrlifciocnacteinotnraantailoynsiss.were collected on April 23, 2002 and All dosing solution samples were collected solution vehicle was deionized water. on the same day the solutions were prepared. The 4. Analytical Methods a Dosing Solution Treatment cEharcohma| tmogLrdaopshiyn(gHsPaLmCp)legrwaadsedwialtuetre.d iTnh1e0s0ammpLlevsolwuemreetrfiucrtwhietrhdihliugthedpewriftohr5m0a:n5c0e liquid ~ `methanol/water to final concentrationsof0.000625 mg/mL (0.625 ppm) H-25231. Prior to this [0 `Company=Sanitized. Does n-- otcontain TSCA Cai 25231: Developmental Toxicity Study in Rats DuPont-10309 ~~ final dilution, each aliquot was corrected with HPLC grade water so that all samples to be analyzed contained an equivalent amountofwater. Samples submitted for analysis were analyzed the day the solutions were received or were frozen unil analyzed. b. Chromatographic Conditions LC/MSMethod HPLC Instrument MS Instrument: `Waters Model 2790 HPLC Micromass Quattro Micro LC MS with "Z-spray" electrospray LCpoCalruammne:ters: XTerra MS C18, 2.x13m0mmm Mobile Phase (Time Table), flow rate: 0.00 minutes: 50% methanol/50% 10 mM Ammonium Acetate, 0.25 mL/min. 8.00 minutes: 100% methanol/0% 10 mM Ammonium Acetate, 0.25 mL/min. 9.00 minutes: 100% methanol/0% 10 mM Ammonium Acetate, 0.25 mL/min. 9.10 minutes: 100% methanol/0% 10 mM Ammonium Acetate, 0.40 mL/min. --_ 12.00 minutes: 100% methanol/0% 10 mM Ammonium Acetate, 0.50 mL/min. 12.10minutes: 50% methanol/50% 10 mM Ammonium Acetate, 0.40 mL/min. 18.00 minutes: 50% methanol/50% 10 mM Ammonium Acetate, 0.25 mL/min. Run Time: Flow rate: Injection Volume: Column Temperature: 18.0 minutes (noted above with mobile phase) 20 microliters 35C MpTSoanrizaamtieotneMrosd:e: Electrospray (EST), negative ions Capillary Voltage: 35kV Cone Voltage: 40v Source Temperature: 120 Desolvation Temperature: ~~ 300 Scan Function: SIR: 789, 889, 989 and 1089 m/z time: 0-10 minutes c. Calibration and Quantitation rAefsetroecnkces)olwuatsiomnoafdtehienHH-P2L52C31grtaedset wmaatteerr.ialAp(psreopparraitaetesaamlipqlueostosofftH-h2e52s3t1o,ckuwseerdeasdialnuatleydtiwciatlh --_ 50:50 methanol/water afer a correction with HPLC grade water so that an amount equivalent to `Company Senltized. Doss not contain TSCA CBI B25231: Developmental Toxicity Study in Rats DuPont. 10305 ~~ the dosing samples would be maintained in each diluted standard. These solutions were used as calibration standards that bracketed the target concentrationofthe diluted dosing samples. Mass to charge ratio (m/z) from LC/MS analysis using negative ion electrospray ionization and selective ion monitoringofthese standards over the mass rangeof 789 to 1089 (m/z = 789, 889, 989, 1089) were used to construct calibration curves by the appropriate regression (see Appendix A, Figure 1a 1d for representative calibration curves). Measured concentrations for dosing solutions were determined by applying the peak area from replicate injectionsofthe samples to each calibration curve. The mean result from the concentrations at all selected m/z (n = 4) is reported as the concentration for the sample. Test substance uniformity in the vehicle was evaluated by calculating the coefficientofvariation (C.V. = standard deviation/mean x 100)ofthe measured concentrations in duplicate samples for each dosing level. A coefficientofvariationof less than or equal to 10% is the standard criterion at Haskell Laboratory for acceptable distributionofthe test substance throughout the solution. However,ifthe test substance has been shown to be difficult to disperse in the vehicle or the `analysis has shown variability,a coefficient greater than 10 may be acceptable. `The mean resultofthe duplicate samples for each dosing level was used to determine the concentrationofthe test substance for the respective dosing levels. Stability was evaluated by using the mean resultofthe duplicate samples from the concentration --~ verification as the baseline for comparing the corresponding stability results. J. Animal Euthanasia Females were euthanized by carbon dioxide asphyxiation. Fetuses were decapitated before proceeding with visceral examinations; thoseto be viscerally examined without decapitation were injected with sodium pentobarbital. All other fetuses also were injected with sodium pentobarbital before fixation. K. Parameters to be Studied I. Inlife Observationsof Females Body weights were recorded at least twice prior to dosing to provide data for quarantine release, and ondays6-21G. Foodconsumption was measured on days 4, 6, 8, 10, 12, 14, 16, 18, 20, and 21G. Clinical signs were recorded at least twice prior to dosing to provide data for quarantine release; signs were recorded once daily on days 4, 5, and 21G and twice daily on days 6-20G. 2. Postmortem ObservationsofFemales Surviving to Scheduled Euthanasia. `The abdominal and thoracic viscera were examined grossly immediately after euthanasia on day 21G. The intact and the empty uterusofeach dam having a least one viable fetus was weighed CompanyanlSianztiezdac. Doss not contain Tc ogy 25231: Developmental Toxic Study in Rats Duont10309 po to permit calculationofmatemal body weight adjusted to exclude the productsofconception. `The corpora lutea count for each ovaryoffemales with viable fetuses was recorded. For each female with visible implantation sites, the typesofimplants (live and dead fetuses, and resorptions) and their relative positions were recorded. The uterusofeach apparenily "nonpregnant" female was stained with ammonium sulfide to detect very early resorptions. 3. Fetuses of Females Surviving to Scheduled Euthanasia For cach fetus, the following parameters were recorded: identification number, intrauterine location, sex, and body weight. The extemal alterations detected for cach live fetus were also recorded. For each lite, the first live fetus and every other live fetus thereafter were examined for visceral aIlntaedrdaittiioonns,.)alRleitvaerfdeetdusreesnawlitdhevmeallofpomremnattiwoanss vcilsaisbsliefiaetdeuxstienrgnatlheexsacmhienmaetioofnWwoeroeaenxdamHionaerd. for sof tissue alterations; decapitationofthese fetuses was at the discretionofthe study director ora designee. After fixation in Bouin's fixative, the headsofdecapitated fetuses were examined and alterations f`iwxearteiroen,cotrhdeeda.lizEaxrainm-isntaatinieodnsskweelreteobnsasweedreonetxhaemmineetdhoadnodfBskaerlertoalwalatnedraTtaiyonlsorw.e"reArfetceorradlecdohfoolr all lve fetuses, excludingthe fetal heads fixed in Bouin's fixative. L. Controlof Bias Inadditiotno random assignment to groups, all females were coded before scheduled euthanasia and remained coded during the collectionofpostmortem and fetal data. -- 03 -- Company Saniized. Doss not contain TSCA CBI 1.25251: Developmental Tosicity Study Rats Duont10309 ~~ M. Statistical Analyses bSeeqluoewn.tiIaflastiwgon-itfaiiclaednttrdeonsde-treesstpionnsgewwaassadpeptleicetdedt,o tdahteadaftraomftohreetaochp pdaorsaemegtreorupaswtaasbuelxactleudded and the test repeated until no significant trend was detected. For lter parameters, the proportion ofaffected fetuses per liter or the litter mean was used as the experimental unit for statistical evaluation. The levelofsignificance selected was p < 0.05. `Wherethe data were tiedandthe standard large sample versionof Jonckheere's test was not applicable, exact p values were calculated using permutation methodology. Parameter TrendTest Maternal weight MMaatteerrnnaall wfeoiogdhctocnhsaunmgpetsion Linear contrastofmeans" LDievaedffeettuusseess Resorptions ~ IInmcpildaenntcaetoiofnsfetal alterations Jonckheere's est" IClnicniidceanlceoobsfeprrvaetginoannscy FMeamtearlneaslwmiotrhtatlotiatlyresorptions Early deliveries Cochran Armitage test" Fetal weight (Covariates:litersize, Linear contrastof east square means : sex ratio) Sex ratio (Covarate: liter size) -- S200,Do ny, CONaln 7571p any TE H:25231: Developmental Toxicity Study in Rats DuPont10305 RESULTS AND DISCUSSION ANALYTICAL EVALUATIONS A. Chromatography Appendix A a H-25231 eluted fiom the HPLC columa as resolved peaks over mass to charge ratio (1/2) range ofapproximately 789 to 1089. For the purpose ofquantitation, the m/z ratigs of 789, 889, 989, be representative Of the H-25231 In the dosing matrix. RepresentativeLOMSchromatograms are showninAppendix A, Figures 2(a -). Test substance was not detected in the 0 mg/mL. control B. Concentration Verification and Stability Samples Table 1, Appendix A Analytical results from dosing solutions prepared April 16, 2002 and analyzed for ~ uniformity/concentration verification and stability are shown in Summary Table 1 and Appendix A, Table 1 The following table summarizes the results for uniformity/concentration verification and stability analyses for the H-25231 sample preparation on April 16, 2002. [Preparation Nominal" Measured Average CV Stability' Day mgml mgml %Nominal % 9N% ominal TestDay2 625 613,636 1000 3 912 125 13,160 920 2 90 250 28242 940 4 984 `@ HDo-s2i5n2g31sioaoppnrocxoimnacteenlryaionmgFi-v2e5i2n3gr1e/dmiLen,t.based on 10 Lg dose vorme. 5 DSuapbliilctaytesasammpplleeshealndalfo hours at room temperature. Percen Nominal based on messed. d Repored result based on reanalysisoftheoriginal sample. "The results for H-25231 samples prepared on April 16, 2002 show that the test substance was at the targeted concentration, adequately mixed (CV's less than 10) and stable in the vehicle when held 5 hours at room temperature. Test substance was not detected in the 0 mg/mL samples. Tw Company Santized. Doss notconten sca cay 25231; Developmental Tricity Study in Rats DuPont10309 Pe C. Concentration Verification Samples Table 1, Appendix A `Analytical resultsfromdosingsolutions prepared April 23, 2002 and April 30, 2002 and analyzed for concentration verification are shown in Summary Table 1 and Appendix A, Table IL `The following table summarizes the results for concentration verification analyses for the both sampling daysofthe H-25231 sample preparation. Preparation Da 23-April2002 Nominal" ng/m 625 125 250 Measured" mg/mL. 65.9,63.1 119,128 268,249 Average CV % Nominal __% 103.2 3 99.2 5 103.6 5 30-April2002 625 607,554 929 6 125 127, 18 98.4 5 250 213,228 884 5 `a Dapopsrionxgimoalteultyion cogeencttavtiionngrmedgicWs2.52 1mL, based on mLdose volume. B25231 1s b DRuepploirctaetdersaompultesbapseedlovnerleawnealryesiasnaolyfzheed.orCg.iVn.alcsaalcmupllaet.ed fo verify uniformityofmixture. ~ `The results forsamplesprepared on April 23, 2002 and April 30, 2002 indicate that the test substance was at the targeted levels (target = + 11.6%ofnominal) and adequately mixed (CV's Tess than 10) for all H-25231 samples. Test substance was not detected in the 0 mg/mL samples. D. Analytical Conclusions tReesstauslutbssftraoncmetwheasanmailyxseidsopfrtohpeerltye,stastutbhsettaanrcgeedteodsilnevgelsso,luatnidonsstadbulreiungndtehre tshteudcyonidnidtiicoatnes tohfatthtehe study. Test substance was not found in the 0 mg/mL samples. ~~ BompanySenitred. pgs otcontain Tsea ogy -- B-25231: Development) Toxicity Sudy in Rats --~ DEVELOPMENTAL TOXICOLOGY DuPont10309 A. Maternal Findings 1. Morality `There was no compound-related mortality at any level tested; al animals on study survived to scheduled sacrifice. 2. Body Weights and Body Weight Changes (Tables 2 and 3, Appendices Band C) There were sligh, statistically significant, compound-related effects on maternal body weight `parameters at 1250 and 2500 mg/kg/day. rAetsu2l5t0e0d imngs/ikggni/fdiacya,nttlhyerreedwuacseda mmeeaann bmoatdeyrwnealigwhetiglohstssa(t3t%h-e4o%n)seotovefrdodasyisng8-(1d4aGy.s 6T-h8eG)imtphaatct owfhtehnesteherefdinuacltiwoenisghwtaswamsinaidmjauslt(ed2%f)orotnheabwseoilguhtte offitnhalebpordoyduwcetisgohftcbountcewpatsimoonr(e4%p)r.onMoeunacned govreoruapl;l hwoewiegvhetrg,awinheatn2t5h0e0admjgu/sktge/ddfaiynalwawseirgehdtucweadsbuyse7dt%owcahlecnulcaotmeptahreegdawini,ththtehemecoanntrwoelight ~~ w`gearinewsaigsnirfeidcuacnetldy2i6nc%rewahseednocvoemrpdaaryesd1w4i-t1ht6hGeacnodntsrioglnigfircoaunpt.lyOdtehcerrewaisseed,omveearndawyesig1h8t-2g0aiGn;s these two occurrences were not considered to be ofmajor toxicological relevance. tAhte 1o2ns5e0tomgf/dkogs/idnagy,(dtaheyrse6w-e8rG)e.alTshoestmataigsntiictaulldyeosfigtnhifeicbaontdyrewdeuicgthitonesffiencmtaate1rn2a5l0wmegi/gkhgt/dgaaiyn at rweadsucstiimoinlaorntofibnualt bsmoadlylewreitghhatn wthaesemffiencitmoablse(r2v%e)dbautt2w5a0s0smtga/tiksgt/idcaalyl.y sTighneifiimcapnatct(3of%thriesduscltiigohnt) w12h5e0nmtgh/ekagd/jduastyewdafsinarledbuocdeydw5e%igwhthemneacnomwpaasrecodnwsiidtehrtehde.coMnetaronlogvreoruapl;l hweoiwgehvterg,aiwnhaetn the adjusted final weight `when compared with was used to calculate the control group. the gain, the mean weight gainwasreduced 22% `AWth6i2le5tmhigs/krge/dducatyi,otnhweareswcaosnsaidseirgneidfircealnatterdetdouctthieocnoimnpmoautnedrn,ailt wweaisghntotgacionnsoivdeerreddayasdv6e-r8sGe. t`hbiescaduosseietlhevaedln. o appreciable impact on either final body weight or overall body weight gain at 3. Food Consumption (Table 4, Appendix D) ~~ Tfohoedrecwoanssuamceodmwpoausnsdi-grneilfaictaendtlryerduecdtuicoendiantmtheiasnlefvoelodovceornsduamypst6i-o8n, a8t-1205,0a0nmdg/1k0g-/1d2aGy.. OMveeraanll `CompanySanitizod.DossnotcontainTSCA CBI Wo 125231: Developmen Toxicity Study in Ras DuPont10309 --_~ food consumption (days 6-21G) was not significantly reduced but was reduced by 8% when compared with the control group. `At 625 and 1250 mg/kg/day, there was a significant decrease in mean food consumption over days 10-12G. These transient reductions were considered spurious and unrelated to the compound. 4 Clinical Observations (Table 5, Appendix E) "There were no compound-related clinical observations at any level tested. Occasional occurrencesofalopecia were reported fora few animals from each group across all levels including the control group during the study. 5. Postmortem Findings (Appendix F) `There were no compound-related matemal gross postmortem findings observed at any level tested. One rat from the 1250 mg/kg/day group had afirmwhitemass in the location ofa `mammary gland; this was not considered to be a compound-related finding. B. Fetal Findings ~ 1. Morality (Table 6, Appendix G) `There was no compound-related fetal mortality at any level tested; data for fetal resorptions and dead fetuses were comparable across all groups on study. 2 Body Weight (Table 6, Appendices G and H) There was a compound-related reduction (4%) in mean fotal weight at 2500 mg/kg/day. Mean fetalweightwas unaffected by the compoundatdoses up to 1250 mg/kg/day. 3. Malformations (Table 7, Appendix H) `There were no compound-related fetal malformations observed at any level tested. One fetus from the 2500 mg/kg/day group was observed with caudal agenesis. Because only one fetus from the whole study was thusly affected, this finding was considered to have occurred by chance and `was not considered related to the compound. Company Sanitzeq, --~ * Doss not contain Ts gy EE -- H25231: Developmental Tosiiy Study in Rats Dupont 10309 ~ 4. V(aTraibalteio,nsAppendix H) `There was a significant increase in the incidenceof supernumerary ribs at 2500 mg/kg/day (15 affected fetuses from 11 litters). Although this finding was statistically significant, it was not considered to be toxicologically relevant because the incidence ofthis finding was within the rangeofrelevant historical control data (see below); the statistical significance appears to be. resulting from theunusually low control group value (3 affected fetuses from 3 litters). There `owfer1e25n0o mogt/hekrg/cdoamypoourndl-owreerlated fetal variations at 2500 mg/kg/day nor were there any at doses Control Group Incidence of Supernumerary Ribs Coy" Study Reference Year Conducted [ ] | 2001 No. Affected Fetuses lo. Affected Litters) 16(5) i J 2001 28) - Omg)|| I0 j | 2000 146) [Bompany Sanitized. Do note conts ain TSCACBI = --- 25231: Developmental Toxicity Sudy in Rats DuPort-10305 ~~ (CONCLUSIONS Under the conditionsofthis study, matemal toxicity evident as reductions in body weight parameters was observed at 1250 and 2500 mg/kg/day. Effects on maternal food consumption were also reported at 2500 mg/kg/day. Non-adverse matemal effects occurred at 625 mg/kg/day; thus, the maternal no-observed-effect level (NOEL)* was considered 625 mg/kg/day. Developmental toxicity was evident at 2500 mg/kg/day evident as reduced mean fetal weight. `The NOEL for developmental toxicity was considered 1250 mg/kg/day. 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, raw data, and the final report wil be retained at Haskell Laboratory, wNielwlabrekr,etDaeilnaewdaraet,HoarsaketllIrLoanbMoorautnotrayi,nNeRweacorrkd,sDMealnaawagreem.enCth,arWaicltmeirinzgattoino,n Ddeatlaaw(apreer.cenRtapwuridtayt,a composition, and known impurities) will be stored at Regional Analytical Services (RAS), -- Jackson Laboratories, Deepwater, New Jersey. Characterization data used to support test substance stability will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware. @ `"TwheereNnOotEdLetfeocrtetdh.isTsthusd,y fiordetfiisnesdtuadsy,thtehehiNghOeEstLdsoseqautivwahliecnht oadtvheersNeOefEfeLctassadrefbiuntedabblytthoetUh.eSe.stEPsuAbCst?anacned ~~ 10 he po-observed-adverse-efect level (NOAEL)a defined by the European Union. = Company Sanilized. DoesnotcontainTSCA CBI HT AR mein ReFERENCES C---- Nant | 2. Salewski, E. (1964). Farbemethode zum makroskopischen Nachweis von Implantationstellen `amUterus der Ratte. Archiv. Path. Exp. Pharmakol. 247:367. 3. Staples, RE. (1974). DetectionofVisceral Alterations in Mammalian Fetuses. Teratology, 9(3):A37-A38. 4. Woo, D.C.and Hoar, R.M. (1972). Apparent Hydronephrosis as a Normal Aspectof Renal Development in Late GestationofRats: The Effect of Methyl Salicylate. Teratology, 6:191-196. 5. Barrow, M.V. and Taylor, W.J. (1969). A Rapid Method for Detecting Malformations in Rat Fetuses. J. Morph., 127(3):291-306. 6. Selwyn, MR. (1995). The UseofTrend Tests to Determine a No-Observable-Effect Level in Animal Safety Studies. Journalofthe American Collegeof Toxicology 14(2):158-168. 7. Haseman, JK. and Hogan, M.D. (1975). Selection ofthe Experimental Unit in Teratology ~ Studies. Teratology, 12:165-171. 8. Patefield, W. (1982). Exact Testsfor Trends in Ordered Contingency Tables. Applied `Statistics 31:32-43. 9. Snedecor, G.W. and Cochran, W.G. (1967). Statistical Methods, 6th ed. The Iowa State University Press, lowa, pp. 246-248, 349-352. 10. Jonckheere, A.R. (1954). A Distribution-Free K-Sample Test Against Ordered Alternatives. Biometrika 41:133-145. 11. Dempster, A.P., Selwyn, M.R., Patel, C.M., and Roth, A.J. (1984). Statistical and `Computational Aspects of Mixed Model Analysis. The Journalofthe Royal Statistical Society, Series C (Applied Statistics), 33(2):203-214. 12. Hazard Evaluation Division, Standard Evaluation Procedure, Toxicity Potential: Guidance for Analysis and Evaluationof Subchronic and Chronic Exposure Studies. Paynter, O.E. etal. United States Environmental Protection Agency, OfficeofPesticide Programs, `Washington, D.C., 20460. EPA-540/9-85-020, June 1985. ~ 13. Risk Assessment of Notified New Substances Technical Guidance Document (XU/283/94-EN), Chapter I, Sections 2.24 and 2.25. pompenySanitized.Does notcontainTSCACBI _----m--n H:25231: Developmental Toxicity Study in Rats DuPont-10309 TABLES Jo ~ [EompanySentizod.Doesnot contain TscA Cat 3 1.25231: Developmental Toxity Sudy in Rats Dupont 10309 TABLE | SUMMARY OF DOSING SOLUTION ANALYSES SampleType 16-Apr-2002 Concentration Verification Average Measured Coc. SAtvaenrdaagredDPeorvceinot nNominate CoefficientofVarstion Dosing ConcentranadtSiaoinlsyof25231 (mg/mL)? Nonint os 15 250 O68113 01143) 02128) ao6s 1216 8 2608) 62s 115 235 +01060 2210) 24909) B) 2% " 0St-aDbailyitRyoom Temperature Sour Room Temperature _ aia 23Aprit 2002 30-Apr-2002 as 115 55 (10507.00) ) 921.200) 060) (9244.60) G8) a6nss) 0224) a2n59e 25590 8142) 21 G89) = & DNHoiEun omi-- opnibrecneoesnernreinBe gFe2g52s3pp1inebtaocfdsoton 3iimvadvloss.volume, -- 4 DMMueeaalnn,ce5eu.sa2fmxop1rlceCosVn.bcfeinoaetdoo,pnvlMeiitecfoasrmtpeolnelsscpaamopllise sedtovebyassoefrolarsiubnolfiemyiStrpei,. Company Senticad. Dogs po,containTscacay r re e-------- %i -- eeeseeee eiomstoc er-- e-- ~ 3% 2 --_ 3 3 z 2 X ~ 5 Hpg z5 |.| 548%g 3R48%g 28484 g38a4 gg 2548 RTE E . 5 EOE.| 2% 2% uy IN Z gaTM d4% ga" 2Y =z g 23, 23, 3%, 36 = |v | ga gLER4EE% 8TL4% Fa Jaq 284 224 23g 2g3 g s f 37 lv 8 8 = CompanySankiized.DoesnotcontainTSCA CBI ~ 3 3 --~ 2 2 : 2 g 3 & ~ 2BH 3 zg |" EEREE-EANERE EPA 2 EH, | 23, 28, 2%, "8, LEE EEA EA PA 8 24 2 zEF 84o| cgaagf%s S2e4si%a o2asad i3hseda 3< z |. |c3, 8. 8, 40 = 7] ggea"8 gRau"d FEzAN ggsod 2 | 3% 280 2h TEEN &3% &dY gst gg 8 0% 2 8g|l~ & = | SaniDtosisnzotecondta.inTEA CBI 2 ~-- 3 g --~ :3 Z3 gg g:l <& --~ &g8 % 3 | 84 da gd" ga" 2 3 A |a| g(3is gWdFRgin gis :3 EB |e, oy, nm, os, 2 Tg]5% 83% E2Y EsY Rk i is. g =24Z wg ag ey =z 2$324 & SZ2 [%]e8aaY gEATi EYg8 Ed8 3si4a ZgzE 13E%- 3 o | B, 28, 28, 28, EE z TREY RET BRT 240 FR g 43} igo 8 F5 Oog HE28ipeiSn2h o g3%aydasidc gEle =o =8 = if1ie8s3 5T B5i8p1 |g 5a lszi E3E3Ed gE ean CompenySanttzed. Dossnot contin780AGBH ~ 3 z g I 2% 2%: ie 389 23 040 -- 8, 2ERE8 BER3E8 3As% 834%N 3aa3 = g Z8 S858 23 3% I E Zsz l1,6 | h84y8 &3x IN 23g SN Ag aad . 3 Z2| i4 & --_ le | nay aq v3q SEg | S28 DZS ag age 38<3] s 8& 33 - n Ez | `pompeny S21 ossnotcontain TSCACE! ~ 3Z . 3 | Eat sf eaf EE i 5 22 H8F.| [e4n5s 3=ea 2% 3% s2 iz ge |%e 84 34 Is I Pi g E EF 2eSlgo.dE | n5a.% =3a% iin ihe i i5: _ H$SIsiER,EREERE ERE 3i et [ 22 || ne zee gi is jE Z a | 438 g38 g3 g78 iH3 E 5 Hl 83 - sf 2 Bug : 3 i 88 gf 22 4 gm = FE seil !: HciHdes I s Buy i ogpd iF oa companySantzsd. Does notcontan TSCACE! ~1 3 3 [3] 4a ad8 438 108 iEsZ || &a &3F 408 438 2 81s ge ae ie FE -- 5.8 4 af get og a i gEJ I TE To Zz || a3% a3 428 3 3 e | 23 S34 28g I%g 3g 5 : ~ uf ez gg 3% & l- 2 8 ox gasznd 0002"contain TSCACEL ~3 Z2 ~ 30A : :: ~Z 3 53 |F 8% de ge ihe z5 FoEE S E 88ER4| EdEAy 28; 3Ea8x 23x : g$28 8a luge an ae ua i3s # 3 Plaid gin dfs] Ey agz2 | 7g iiEr ZEz uBjye -8 *FFoz OE F iop 0F 551 fiF ssm FwFw Row o[HEeil BSaivlEdd fiigs Ei E: CompanySanftized. Does notcontain TSCACBI --~ E3 .i g i 2 i 2: if 2 wfaf ow g i . E i 8 = ai a 2 i = sewasgneld 5 gad "i3 #8 Bi z 4 gii g i Bb5 2 ~F FEE 8340 i: 37 5: i Big : = fotcontainTSCACo CompanySenitired.Does 525231; DeveloTopicmyeStundytinaRalts --~ TABLE 6 Dupont10305 "REPRODUCTIVE OUTCOME p-- : x po w ose angi: o P uso ase Yo. vated = = = = Yo. sregmant = = = = Ho Delivered Barly . o . o so. Deaths . . . o Yo. With Total Resorptions . . o o Yo. Litcers = n = = MMeeasnsCovreporLaistaetrest 03600 0100 6s@e 1707 Iaplantations Baee mace aes see Resomptine: Tol 0.20.8 may ozs 003200.m) 0o30s.6e0 s0.3o0.m8) Late 0 0 00 00 --~ Sead setuses 00 os 0 00 Live peerts mow BAGS) 280.0 5.860 1600.0 Wl saa 6e@n 1.4@e 626.0 remo 7300 ame eis 730.0 Mean Fetal eight: Total S400.) 5.330.) 5.4203 5.00.4) wie 5a.) mies sa. 5500.50 SBOE 555300..0020 550967006.300 sox massed 0450.30) 0.520038) 0.53010) 0.480019) "4 SSDtrraeacsnsesenarcriesosadlefvoirsamtaiilroyinsoemsm35aatxrieeopnomrooctrelydc.onindupcutreedncohnesmeesw.n corpore Tutes dave; These data ore 2 SPieayrtiAeEtEihcear.t s"miTihyesmeesnsrneeonrlyofconmadlueestenanodnfethmealmeeswnaretoptralesemmanmebderfoofr SIinvfeorfmeattuisoens a Wmber sate fevuses/tosal mmber fetuses per Lister NoteaG:arteaThsTeeexbpcreiepTsgImfseocrnyyfseatStaoelnidvyaencieaod,htuahdianinge csmhooexrCtToaeclchiirto)ayndwhaeetreaei,tSaangnaedivteSheeendt.tiostiaBnlLgLrJeLosimovmripeererirosenarmsdeata ESahsatr.e "meFaencsh.i"WeiNgeneSiaonnai-csieosntxattiroenvdesrveersemaSiyiseedstsaain3 5 fbiin0e5st Soncrent of sense --~ GompanySeniized.DoosnotcanrtainTSCACBI EE -- 25231: DeveloTopsicmityeStnudytinaRalts DuPoni-10309 --~ TABLE 7 INCIDENCE OF FETAL MALFORMATIONS Growp: 1 ES mr w Dose (mg/kg/day): as 1250 2500 xrzmnn Yo. Bxamineds Caudal agenesis Yo. Atfocted 202) my sepa 309022) bee 1a) or ote oro) 1m viscemt Yo. Examined Stomach - Absent. Yo. Attected 1022) 162021 157022) ssa) --- -- ser 1 om oor oto 1m sm Yo. Examined ~ Yo. Attected 1022) 142021 3570220 sea) om oo oto oto) storTmL Yo. Examined Appendicular Skeleton - Absent Femur - Absent Rib - Fused Sternebra - Fused No. Atfected esi22) aman sos) 309032) -- --- -- 1 -- ase ae 1 . ey re 1m -- --- - 1) ot} owl oto) 1 TOTAL WOMBER APFECTED sw om om 1m a Nmaulmfboerrmaecxiaomnisnedaraendexapfrfeescsteedd,asinFceltuusdeisng(Ltihtteernsu)mbeorr aFettfuescetsed(wLiitthtertsh)e. listed b Faolrfoeramsaetioofns.reading, zeros have been replaced with dashes for the listed No significant trends were detected. Note: S`toavteriasltlictaoltaalnaalnydsetsotaarles obnylyexcaomndtuycpteedaroen ptrheeseinntdeidvifdouralinefnodrpmoaitnitosn. alTyh.e ~ `Company Sanitized. Doesnotcontain TSCA CBI 3% 125231: DevelopmentalToxicityStudyinRats Dupont 10309 ~ TABL8E INCIDENCE OF FETAL VARIATIONS Grow: 1 un mr w Dose (safka/an): es mse aso DEVELOPMENTAL VARIATIONS Exmmar Yo. Bxanineas Yo. Atfacted mez) za) soiz2) 309022) ol ol oto) oto) vise Yo. Examined Yo. Attected 1002) e201 15702) isla) ol ol om om mYo.oSxanined Yo. ftected stmemn Yo. sxaminea ~ Rib - Supermmerary Yo. attested soz 1201 isa) siz) or etl ol otal woz men mia 300) 3m se em sane sm ste ats) ast TOTAL WITH DEVELOPMENTAL VARIATIONS ese sm san -- `CompanySanitized.Dossnotcontain TSCACE! -- H-25231; Developmental Toricity Study in Rats DuPont 10309 rm TABLE 8 (Continued) INCIDENCE OF FETAL VARIATIONS Grow: 1 on m TM Dose (ea/kg/dar): as 1250 2500 VARINTIONS DUE TO RETARDED DEVELORMENT -- Yo. Examined Yo. Affected eta) zatal ssa) 309022) ota) ow) owl oto) vise Yo. Examined Kidney? Seal) papilla - size 2 Papiila - size 3 No. Atfocted soz a ase ssa se aw 1a) ae wan sw 710) ss wna ve ata =Yo.pExamined --~ No. Atfacted wsota2l 1ez0;) asa) asetza) oto) stor oto) oto) sxeuETaL Yo. Examined Pelvis - Retarded Oasitication Skul - Retarded ossification Stemebra - Retarded Ossification Vestebra - Retarded ossification No. Afoctea 2t221 2ilzn) 032) 309022) 1 oe --- IY sue man seas san --- 1a) -- 2 an eon eas sae we sun sen niu -- pompanySantzed. Doss notcontain TSCACSL EJ HL2521: Developmental Toxicity Study in Rats DuPont10309 TA8B(ConLtinuEed) INCIDENCE OF FETAL VARIATIONS Group: 1 Dose (mafkg/dan): n m w as 1250 2500 TOTAL WITH VARIATIONS DUE 0 RETARDED DEVELOPHENT mon ese en ven TOTAL NMDER FETUSES WITH VARIATIONS men sen wien woes 4 b uVSatmrabiteairtsitoiencxsaa,lninaacenedalaeynsxdepsreastafcseeecdtceaodsn,duFceittneucsdleusodni(nLgtihtetcehrecso)nuubroibrneerdFetaiufnsfceeiscdteen(dcLeiwstittoefrhs)tshpealllisrteneadl BBaoprileiassee;oftheseaddeitnagi,lszefroorsehaacvhesbiezeenarreeppiraecesdentweidthfdorashiensforfmoratitohne olnilsyt.ed Variations + Significant trend (Jonckheere's test); p < 0.05. Notev:eraSltlatitsotriac:alanadnatloytsaelss abryeeoxnalmyacroendpurcetseedntoend tfhoer iinndfiovrimdautailonenodnpyo.ints. The --~ --_ EompanySanitized.Dossnotcontain TSCA CBI EJ 125231: Developmental Tosiiy Study in Rass ~~ DuPont 10309 ~~ APPENDICES _ `BompanySanitized. Donotecontsain TSCA CBI e e e--------w---------- H25231: Developmen Toxicity Study in Rats --~ DuPont 10309 -- APPENDIX A Analytical Data -- -_-- "MP20Y Sanitized, Dog, noteontain Ts gy H:25251: Developmental Toric Study in Rts DuPont10309 `Table L ConcentrationVerificationand Stability of H-25231 in Dosing Preparation Day Sample Type mg/mL H-25231(4) Nominal Measured 16-April2002 Concentration Verification(8) Control 00 NDC) 62510) 6252 Mean() 613 66 6251.6 cv.3% Solutions Percent Nominal -- 98.1 1018 (200.0) 125-10) 13 1252 6 90.4 9238 Mean() 1152.1 020 cv.2% 250-1 28 912 2502 242 9%8 ~ Mean() 2C3V5.94.%9 94.0) Stability 6s 570 92 125 120 96.0 250 246 98.4 HDoasisngtsop laion con-- ceriongpg H-25i2n3g1rmdLin,.bison 5 mi. dose volume. ((8)) D) DRDueeppnloiircetasetdeortesdpueslasfdopr.ethlee6v2e.l5wrgt/malmlaynzded1.25Mmye.sapsnldcC.Vs.acmaplleesufsoedmtorveeriafylusnofiorfigoinoraflmmsieitrrptesy.. . {) Meares for anysonduplicate samples. mr "ny Sanitzed. Do note conts ain Tsca car = H25231; Developmental Toxicity Study in Rats Dupont10309 ~ Table IL. Concentration Verificationof H-25231 in Dosing Solutions Preparation Day mg/ml H-25231(A) Percent Sample Type Nominal Measured Nominal 23-April-2002 Concentration Verification(B) Control 00 he) -- 6251 659 1054 6252 al 1010 Mean) 64.5+2.0 cv.3% 103.2) 1251 19 952 1252 128 1024 Mean) 124%64 9.2) cv.s% 250-1 268(E) 1072 2502 249 9.6 Mean) 2c5v.9153% (103.6) --~ 30-April-2002 Concentrati`oCnonVterroilfication() 00 ND) -- 6251 60.7 97.1 6252 554 886 Mean): 58023.7 029 cv.6% 1251 127 1016 1252 us 944 Mean(D): C1v2.35%64 98.4) 250.1 213 852 2502 28 912 ~ Ln co a8 Mean): 22111 (88.4) CV.5% DRosS ainsgstan -- 25i2n3gr1edmieLntb.asedon mldos volume (2) (5)) DDeinecsenostpdieetsepr.rev Men ret for smalyes on OR analyzed. Moan, duplicate samples. 5D, and CV, aesstod to very unifoorfmictry. )Meriotr upleste ofr Origin sys notreporteddotoesiqorerr. --& -- H25231: Developmental Toxicity Study in Rats Dupont10309 ~~ Figure 1 Representative Analytical Calibration Curves 2200] Bia30u2fao+rt2th2e76it6e2od+lXinne: 2000] ReSauared =0.991607 | | oo Fg remo z Eo Concentration, ppm. Figure 1a: Calibration curve ons Tg ovis linear fit (ine) to replicate peak area me ents (squares) for calibration Solutions of H-25231 diluted over a concentration range of0.24 100.75 ppm (0.00024 to 0.00075 mg/mL). ~~ #as7o] EYqnua2ti3o4n5f2o3rt3h1e3f0i.e5d2li+neX: 1 2100] R-Sauared= 0.970806. 200 3 wo Concenteation, ppm. Figure 1b: Calibration curve (LC/f MS --..o.c linear fit (line) toreplicatepeak area measuriments (squares) for calibration solutions of H-25231 diluted over a concentration range of 0.24 100.75 ppm (0.00024 t0.0.00075 mg/mL). ~~ Company Sanitized. Doss not contain TSCA CBI " ---- H25231 Developmen Toxic Study in Ras ~~ Figure 1 (continued) ano] BFReeSaaetqiuaoirnedfon=r t+0h.e1969S00u90e55d41lixe: 5 Dupont 10509 Concentration, pom Figure 1c: Calibration curve (LC/MS -JMJshovwing non-linear fit (line) to replicate peak area measurements (squares) for calibration solutions of H-25231 diluted over a concentration -- rangeof 0.24100.75 ppm (0.00024 to 0.00075 mg/mL). roo] BFaur atfoira othnevss teedmine: ) 5 ReScuired = 0.987561 ar 03 Coonscenteaotosn, ppmoe or os Figure 1d: Calibration curve (LCIMS --.ix non-linear fit (line) to replicate peak area mea: Is (squares) for calibration solutionsofH-25231 diluted over a concentration rangeof 0.24 to 0.75 ppm (0.00024 to 0.00075 mg/mL). Company Sanitized. Does not contain TSCA CBI = H252315 Developmental Toxicity Study in Rats Dupont10309 -- Representative HPLC/MSFCihgruormea2tography Chromatograms 050102168 Smooth(in 2:3) 100: 002 011 156 % Rr 684 SIR of4channel7s89.50-8 os 204904002 o 050102168 Smooth(n 2:3) +0000 " 140205290 344*1%A2 x SIRofchannels m5i-n a89.06 520 gas70s), 883261 o 050102368 Smooth(n2) SIRof 4channls m5i-n --~ 100 oot 089 181 555 20 38s 489 5g epof90 THO 89g 24550P5A6S9.E0O6 " o 050102168 Smooth(th23) 0s, 0 080150 303 359429 52 % `SIRo4fchannels m5i-n 1082.04 637 783827 869 27214002 200 - io 500 500 min Figure 2a: Representative HPLC/MS chromatogramsof0.00 mg/mL dosing solution of H25231 DompanySanitized. Doss not contain TSCA CBI % H:25231: Developmental Toicity Study in Rats DuPont-10309 ~~ Figure 2 (continued) Representative HPLC/MS Chromatography Chromatograms 0501020011 Smooth(he223) 780 SIR of4channel7s83508- 163848 735704003 * 050o102611Smooth(n258) oe 513 min o9 SIR of4 channe9l0ES6- 7184671.18 916160003 * o 050102111Smooth 23) 100; 021 min TM SRofdchannel9s80058- 738 308 434600003 ~~ * o 050102111 Smoath(W.29) 100 44 min 155008]8SIRof 4ch2a98n15n066e490l.500s439734 % 35980 o 2% 5 5% abo min Figure 2b: Representative HPLC/MS chromatogramsof 0.51 ppm (0.00051 mg/mL) analytical reference solution of H-25231. --_ Gompny Saritized. Loss fot containTSCACBI - H25231: Developmen Torii Study in Ras Duran 10305 - Re (ive HPLCIMS FCighurroem2at(coognrtaipnuheyd) Chromatogra os0t0cte Smoonn20) oo o7ns Sots shiamT]os5s- * ot sss oz cs01caers Soon aa) oo bwro rots ca125m3S00oo0o05o4. 20st % oso010ers Soon) oo Shots mao0 m i5n. iww serSeensas sen --~ % ou G5010ets Smoomn a) oo onrmo)Rots aanozasesrss5s. sto hor o Bo po 5 ho em in e eee s -------- selr ee -- e -- Figure 2c: nReopmriensaelntcaotnicveentHrPatLiCon/oMfS0c.h0r0o0m6a2t5omgrgamms.of(602.6.255 mpgpm/)moLfdHo-s2i5ng23s1o.lutTihoen dmielausteudretdo concentration ofthe representative solution i 60.7 mg/mL. ~ Bompany soni Boos notaain Tsca ogy 25231: Developmental Toxicity StudyinRats --~ DuPont10309 APPENDIX B --~ Individual Body Weights Company Sanitizeq' Does not,contain Tsca ogy W H25231: Developmental Toxicity Sudy in Rats --~ Individual Body Weights Explanatory Notes DuPon-10309 Note Reportingofbody weight data that were collected prior to study start (day 6G) are limited to day 0 and day 4G because weight data are available for all animals on these days. Any additional body weight data collected for the separate breeding lotsofanimals on days prior to day 6G are available in the raw data. Footnote a Matemal body weight minus the weight ofthe productsofconception. Abbreviations NP = Not Pregnant ----=No Data -- --_ Company" saSantzed. Dossnotcontain Tsp cpp E] -- -- H-25231: Developmental Toxicity Study in Rats DuPont-10309 ~ INDIVIDUAL BODY WEIGHTS (gras) GROUP 1: 0 MG/KG/DAY WaounsEsR DATO DAY4 DAYDSAYS OFDGAEYS?TATIONDATS DAYS sassaer70i83 ssseemes sssseenr22s7 ssaesa772390 pessi7a1 ssssaarraaaz GGssae77s835 GsSaess8e77r556851 aassea7m7e3 GsGses8ra7s78117 2D3e5l.o0 30 2s5ms3 ees 2e8s5.s9 aes 222e.23 ser 23090.34 2947 3204m5 3002 3Zu0o lo aamsas alr gaeas amis 22s0 aes aammi2 asa aamzs amis 3B50000 Zelo 3360er7s ames z2eea 200 z2ens asa2 a2es12 28a 22m07 2800 3B320l00 Zio 20a0m21 seas a2ess aes 2a6ma 26ers a22s07d39 a2m6i8s2 ams 336300 3700 sseeor 267s a26127 aes zaamlls amis a2mleals wes aasne s ass 2s:l0o0 Zio. aeslao es 2e20s7sss a2aa3sn4s a2s9s6i9s amas 3as0s0i5s 2970 B3e0l00o Ilo s2e0z2 sls saeino a7 aoaesess 2633 s26l1s4 aes2 2219s08 aw 30 36 ea ze amis als -- -- CompanySanitzed. DossnotconTtSaCAiGBnI 5 H-25251: Developmental Toxicity StudyinRats DuPoni-10309 ~ INDIVIDUAL BODY WEIGHTS (grass) GROUP 1: 0 MG/KG/DAY aonosEaR Arlo Davi DAY D12as oDFAYges13TaTIODNAY 1a DAY 1s DAY 36 6ss5e8n710s8 psesene1s pssee727 sssse8772300 sssse87734s1 ss5ss8e87775a43z0 5p07d55 Gsssss8ea77757e531 Gsaes8778716 GSss8e778s71 3306.24 307 a29s8 es d3a0z1es mle eosss aes 3m1s.e2 m2 332612i 0d 3img 3s eIsoo sao 3aoess7 dons 02s521s oss jawoailn0 309s 0329220 m7 w3i2z7 3003 334s47 3294 2G2a4s3 Ils 2amse dele 2a9e5s2 sora 3a0m0e7 oes d2oseess alas m301a 3s 3312270 3309 DIann Zs Gdaassa 2320s aao:r sos aso:ls sols sesz ana 336s0 3am m3alslso ase 3J0a2i2 2a aGaeds sen d23o0e0s1 aoe 0sl93 sos a3vi0s 4 zis 33:m2 msl aa31sl0i0sz9 3601624 eso aaoess aes azlolos asd saavciss 01a s2smo a1siz 3e0s0 ms sslloa 29s fZ0i.c4s i133 Saolo s 273 aamoieee ams mzaelee a:ls sasaslies ass 2389:s 2s a00l88rs2 27.4 293 ase sora ama als slo -- ~ (Company Sanitized.DoesnotcontainTSCACBI 2 125231: Developmental Toxicity StudyinRats Dupont 10309 ~ IIVIDUAL BODY WEIGHTS (rans) GROUP I: MG/KG/DAY wnoimneon, D1 avis oatsoaoprsGESTADTIaOvNo Darzi ony 210 pSeeense ppSraeiirn pGeanreoa GGSeoarrriaaznn GGE0ae7rr3aa0 pSEeaaran ESEooanraeers pH 3SS0iyae sBawel aWSwSea aSEemeSos saWetsehsr Lasemzles SSS3ha3si 0 daBseelseo dmWeeans adammSle IGeahen e0dm0n3 sSdaehs BBEeanne dddeemnn demesee da ealen Bnmhsis SSwe0hn3 BE dee damamnla aisomlwsn Baeaielts emdlenas SSBeeol dMBaoSns dddaaedss d3ame0id3s Bsasialslo mhasalo SSSoss7 Sddeaanss daaeamans addneoa>e aeaaamdas oeoelors SBSese ddames doeolSse asaemdees daaewmeess jadaemso FIER EOC HERE HS CRJ ~~ --~ `CompanySanitized.Doesnotcontain TSCACBI = H-25231: Developmental Toxicity StudyinRats DuPont-10309 ~ INDIVIDUAL BODY WEIGHTS (grams) GROUP 11: 625 MG/KG/DAY pr BER DAO DAY 4 DADGav OFDgASTT?ATIONDAYS DAYS sssse8700s6 seria 23390000 230 3200as zee 229.27 ams 2m6.r8 2er1 22:7207 2m aa2mm:ea3s sssseo720 S583 3360 210 2ae0s sei asi0s sea 22:e2l20 a6 229e4a29 ses 32068s0l0n assis spGseeT7ea306 332530000000 aamsmlioos saaeessas aaasemssr 222ss3sa9l279 e20090n880s7 s5uer7e4s3 BBioo Saris aw) ial asselso ae2ls oeasses esa azsesies 26ers azsos 290 a28d2s3 amd sGssear78s4a Gsarez B[6i0o Dslo aaa7a aa aemees asa aasmuis aslo aamsae za aamsiss aes ssasssaee777677320 ZBeiloo Delo a3s:s0l52 mle 2sesa eso 2262a3 2692 z2ea0 2s 32670003s 2763 aas58e777757 ase7sa 3D0o00 slo aaarae ssn aoaesis sens o2a6siss aes 226260 257 2am7i8s0s 20s sserse oo sma se ean 2667 256s --~ (Company Sanitized. Dossnot taincortef SCACBI 5 125231: DeveloTopsicmiyeStnudytinaRalts DuPont-10309 ~ INDIVIDUAL BODY WEIGHTS (grams) Grove 11: 625 Ho/XG/DRY aomwaesr mio mri Dwioats oDF WGEISTATIODNA DAYS DAY 36 asGeasenr700as8 aI5mnaa ademaledo aSdmEmasa aSanmsosl snammsalis mssoabss 3wdaissz GSeee7rr2ma0 DS630s0 dmmelmeas mmBeeslse mmJslolss esaosnee mdoiaas0less e330r9ss8 SGSeaerrniaee SfS0eo3do da3em0saa ddnoabllses madelbss admewllass asmmalsss dmdeense sGGaoarrriiass ae ZaJomeean maaeeasa ddeeeeeess aoaisess saseeeesen aasimmsaai 6 samiiss GGseeervreeanr ITDonmeei amamansos asdesenaes seamssaaas aaasssls Jasenosenss ddiaelmde ceGoaarre7s2 ZDBeeieee adaomenas mmalewsan aaemwaaa adomewses aamemslaa asmmelises GpEssra7r7e5a DZDoeSnlae eaasemes mdsmeso asovns2s sosmsosee ga3aw0sas 3ed0a0eo7 ers Dolo aman aan mals mis 0s slo ~~ -- `Company Sanitized.Doosnotcontain TSCA CBI = 25231: DeveloTorpicmityeStnudytinaRalts DuPont-10369 --~ INDIVIDUAL BODY WEIGHTS (grams) GROUP 11: 625 MG/KG/DAY peveER DAY 17 DAY DAYSDoAFY G1ESSTATIDOANY 20 DAY 21 DAY 218 sassee770056 Gsemz 3336234 Sean 3ase0s0 seals 3a0m3e ams 3a0w4 sez 4daae2d3s 2336sda &sss8a720 sse73a SJeai Jes mdaalla an aassas dais assim2 sz aalmsl 33a2kls mls aan ssss8e773386 Seno 33660.77 37 a3ma1s aml a3e91s 3m. 4sm0iz sez aadmslio ddoainss az 3m ssaarmias Gara we) 33o3a70 2778 331aa 2023 admeioe ses daamnos amis ssellas 2m 2a3si0o.6n sSsse8r75s4a ase76z HJoes ea 3dsms a mdelmss 3ssiz Gseoss ess asge0dslns7 o33a00s05es3s Gass88777603 Gsern2 3352358 Jes a30a6.p4 307 3al6s7 dese 33:2m0 ams mmsss 0m9s aslo 3m GSs5877775 ssa7ea 3i3o8s 33405 3s6sso 38a3 ddeenss7 des 3eoss ams ddosaollss 3a1021 aon 3120 Sserse dels 387 mls ses sls asa --~ . CompanySanitilized.zeq,Does not containTscacp E3 H-25231: Developmental ToxicityStudyinRats DuPoni-10309 ~~ INDIVIDUAL BODY WEIGHTS (grams) GROUP III: 1250 MO/KG/DRY NawonuER oAto oa4 DADSave OFDGAESTTATIONDara DAYO -- 8ss88770097 Ssa71s s2:e0o0 30 2a0s.s6 ass s2ema ses 2ae8s9 20a aa28ss9n.ss9 22299622.218 epiznd sna Foooo eo aases asa 2a6m2o5 2eon osaeses 2m2ls 227eas7 2767 3aa0meSad ss5s8e7r2a8 ssers2 JJaaoo a0 aaress ass 2am0o 2a 2aa0peaas 2zaeins 2malmssr GsEa3783757 asersi a35050 Jil aasmea7 as aaseaisn amie 2oa6s2e1s ams a2esss2 amo 2307263 aes SGssseeer7resese 3J325a00o0 asseewsoe aaammmao w2ae:ms22 aaassmieln 22a91e02s0 S5s8e767 sse178 3Be0lo 330 zae7e asa 2a6s9as ase aaewal2 oasis a27e6s3 ase 2272m08 2642 Gspee7iez Gs8786 3$07000 30 aaemaao ams s20e1z aes aameas aea7 masss 2653 2a7ms2 2m Gse7es Polo seas ass 20 233 2608 ~~ -- - CompanySantized. Doesnotcontain TSCA CBI 57 H25231: Developmental TosicityStudy n Rats DuPont-10309 --_~ INDIVIDUAL BODY WEIGHTS (grams) GROUP III: 1250 MG/KG/DAY WonMoBEsR DAY 10 DAY IL DAY IDZAYS ODFAYGES13TATIODNAY 14 DAY 1S DAY 16 as&828770078 Ssteann?s Sssseerr22e2 psenm GSasss8ee77733327s aGssear7ssie &sssssaee7r7es6se7 Gsse7r7m8 5SSs95e77r7s692 Seve 03003s0 3a0m8.24 e000 0dass aa 3s2l1o3 amo 3s3m0s.i4z asi a3ss asus 3dsesd2 2s. 2ZZ7ea92c.li2s amso 022 2d9o2e11 2555 2v9a5l3s 3003 3m0a3o3 30s aawo oasis 33sa duis 3J8e. 33200 2s3esn eels aassaa0 oases 23025s 29a 3a0m3o3 oases dsnslssao 3di2s4 337 I57l3e Z28 a3e2s7s Zele a2lese3 2913 a20s00o7 sols a29284 02d m0l0sa sls lduee desl7 3e729533 3.4 Z2seeo is0s4 asel7 oslo e05s.a2 ea 2391704 22 3o2r8e4 3s a332a66a75 m270s als admsss aee.s 2ass0is 3 slr 22e9;5l2s ees 030007 291 doeslss 3003 33i2sims 3207 229.02% S26 aasma y ase 2e92as amo oaassees 2382 dsooelss 297 32as 3osi6 3a2n.i0 37 Pils aes a0 asa sous dsl a2 --_~ --~ Otc cacy) 5 H-25231: Developmental Toxicity StudyinRats DuPoni-10309 --~ INDIVIDUAL BODY WEIGHTS (grams) GROUP 111: 1250 MG/KG/DAY ana eer DAY 17 DAY18DAYS DoAFY1GSESTATIDOANY 20 DAY 21 DAY 218 as85a8770057 GsGese7711s7 Gsssae772202 aGssaan7z3e1 aSsss8ae777333725 GsGaser7s516 asSas8r7e6e5 SSssae776n71 s&ssss8a87r77e7829 sassaarr8s6s 3a537s 3s seelse oases s39e7e4 27a a407a 0m0 aasiead 332322 uz 29s 3l30i45s53e Gdaaesellsss doaaemsleoss mmiioo mls laleo 3a00s2 esis aes 3B2e8ss 366 3d9s3 302 selza aes emsiios mia s0z3 a30o0s0 aez ass 330076 Jos aaslos 3ses waolns asa ssellss sels sdeelse awa 33mo3ia4ll0ss 33B7e20l20e 33a3m70o aaammi2os emslls apis aesains d3w0s7 eal 3290 3Ja413z 363 4se3l2s 373 msleso ss dmezs ses s0uss 33007ss sels 290% 3367s saesss mamaz seslla sao0d 00s7l7 330s3 eeellos dseelnes 33ms e3sls 3300360009 --~ CompanySanitized. Does not contain TSCA Cy -- 5 125231: DeveloTospicimtyeStnudytinaRalts Dupont10309 --_ INDIVIDUAL BODY WEIGHTS (grams) Grove 1: 2500 wa/Ka/OAY Tsoomnos sro ows owoeats orPGAesTtationbare oars SSsseaarnrei0 SGSaaaernse pSGieairsze prpeieaodr] pGGreaerrayen pSrGaeirreoae pGra0er7e0s0 Sane MBse0oo BB26ee6in7s ddamemana aIsmmmaia mmameelss adaeeeess BSeoooo mdanm3dl Mmmenn GGfeeaels ademenal adameso HBfeooooo dademenin dmmmliaen dgeemess aIEmDna aaImisds S0 Baoho geBeannlsse mGdemess aGdaeoana assmmeaa aaaeeess 0 ZZooo dadalnla mdFnlol en asIemalls m0dlass aadlesarsse BFBoOEo dn hse dHmaaonn da+sessGR kvsel4na d1aea4ss BBfeooo BBdEaeEn dddaallne BdAaa:en kddeeeeda 2da0aedns neo aE am amd ad ER -- ~~ "=notcontalnTscaogy w H-25231: Developmental Toxicity StiundRatys DuPont-10309 --~ INDIVIDUAL BODY WEIGHTS (grams) GROUP 1V: 2500 MG/KG/DAY mBLER DAY 10 DAY I DAYID2AYS ODFAYGES13TATIODNAY 4 DAY 1S DAY 16 685588770180 GGssssaaa777i1ec sGss88772236 aassa8r7a3s3 ssssae774a6r GsGs88775570 sGsa87r6d0 GsGaa7r6e9 GsG9s8777840 ssss8a778e3s as8730 2e0a.s7 esis 230736.s8 zm 320982.18 ae2 3219.598 280s 2d0sEs 3n8e.n6 2947 3m331002.000 I2n3a0lsa Zeal e2aa0se0a a2sms ama s29e51s5 amie 2a0377 amas 0ne2l8s 293 330312209 30 228820 330. seessa sels sdoaenn 278 doomsa 298s uwailes 021 saalas sls 3as2 32800 3357004s 33007 2e0s7ss 29903 aeema 309i aammiar sols eoless ssa 20:l8s aa 33s6wi0iz02 2D7a30l6 2073 easoersols 2es2 2978 amssos 20ss 2sl2s duals 3sa0s 3005 3 mlz 330.7 Z3e0sa7 Jeo 0se2z aes aelsss aoe aacae a 2523 aamsaa ass 229s013s als 323003090 aaa 23365775.0s23 zeeo2sl0ss6 a2a6ss00se7 o3ma0es0is7s 232e0sn0ss02 2d39o57is 3330830130877 ME 2 del 7 mel wl ol --~ --~ CompanySt anitized. DDooesssnotcontain TSCACB! o H25231; Developmental Toxicity StuindRayts DuPont10309 -- INDIVIDUAL BODY WEIGHTS (grams) Rove 1v: 2500 Na/Ka/ORY romwoasn oir oarisoatsDoaFrGiESTATDIONo oar: oY 218 eGEse0om7on0s SMsameaioodsomsalan dsReaGsn adWmaSol daasmns aswLnd7 6eG3o00r77i12a3 SBMossn edelnns dmaeimldse mdmeehss saaeslmas mnamnsar pG63oe0rt7ai2n6 SSS3e6al bdaaansn mddahaies JWeennd asdaselne Baeeedsn 6EG33o0er77a3ar0s JeJadee dddemns amawmsaa amasmdld admmlio mdfelasisns EE63a00n77e65s07 M1 Mees 3BmEl sWsemnlo ammnelscs asemailss smasmleas GGGoeerrreees SSS0oo3s Bhdaaelsie dmoeemlaee daaamemees edaeeees 6evaesnn 66E33300777888035 eMMeesde BBdaaElz EddeelEes Ea3mDhe aasmlmosn aeamemelss Ears SeES HWE EI mn ml --~ ~ "oY Santizeg,D0no0ts8otyonTseAce @ H25231: Developmental Toxicity Study in Rats -- DuPont-10309 APPENDIX C --~ Individual Body Weight Changes -- Company Sanitized. Dossnotcontain TSCA CBI @ -- H:25231; Developmental Tosisiy Study in Rs ~ Individual Body Weight Changes Explanatory Notes Footnote a Maternal body weight minus the weightofthe productsofconception. Abbreviations NP = Not Pregnant ----=No Data DuPoni-10305 -- --~ PY Sanlized. Donotsconsta Tscacay @ er - H-25231: DeveloTorpicmityeSundytinaRalts DuPont10309 --~ INDIVIDUAL BODY WEIGHT CHANGES (grams) GROUP 1: 0 MO/KG/ORY fporre os as 8Das oF G8E0STATION102 121 ele ssseem1i0s8 3I0s0 21078 wwsr 1n.a8 m26a4 15s3 2s.e6 pseeis 58725. 2I1s Bis 126s1 122 1wae a2 pwos i7 swas ws a3lss we mablo oe ssssww2279 sse130 21077s 333s ul? a0 7a02 ed ssia a1s7 asl2 1oa7si7s 5's ss as2 oasis Ssss8e7r3a51 L20s1 waes 00i3 o u3l2e 65s:2 a7e8 1a6s0 GGsaarriasz sse7s3 a2l8s 2500 2aso 5 aas1s 57 m7i8s na aeees ma aasse unl a1sl aa sGsse8r7s5s8. ss8755 30w08r 1902 a2l2 ie 7g7s aa ue l 0s2 o 1 ul ss ui mls 1253 wh sGsarrenr sse776 225003 267 FsEs ss alss swlaa a0 oaule a m27s es 110sa 1008 Gassae778817 a10l02s S 1 84 als saoo owwhlas uusl nulb seers 25% ale i ols S30 wir mE ~~ ~ Company Sanitized.Doss not contain TSCACBI w= H:25231; DeveloToxpicmityeStnudytinaRalts --~ INDIVIDUAL B00 WEIGHT CHANGES (gears) GROUR 1: 0 /XG/DAY awnonuuBEaR we 820 2aoavs oF GeansTatioweas ssGaaarnm0as8 sGsaaew7nrzzssy Gssseeerrmaaas GsEss0eo7r4e2 Gs6G3ee077r55s03 EGewen7ee7sr3 Gea7earr7se6tr aren Ws3uli z3eaa 26B3a EBseSee HBBeos m330ssa HW Ha I iI sBa ZIBiei m3masa ZZRo3o38mm5ia B2S32303 wm3l3 ROBE aE3sIs ellseaha 7smeaha wRnil3s lauensins sw3zla mmfeas aawesss a2 0ds ABmsE3 aaemlss wwelsils mamssa aaemsne eaelsll DmkL3sE aaame3iss waalss LBmIaI mmimsEa nasloss Es RS si DuPont10309 --~ CompanySanitizeq. pgs,notcontainTscacay w H-25231: DeveloToxpicimtyeStundytinaRalts DuPont10309 ~ INDIVIDUAL BODY WEIGHT CHANGES (grass) GROUP 11: 625 MG/KO/OAY WmBeEn" o-s as eDAY8S O8F G0ESTATION102 121 16036 asGasar7o0s8 sanz awlas 25 a2s.s7 so 1S3s0 ols wsls Ss aaaeds as sszs owls 1a077 als ssss8e772201 Sse730 770 alulzo 0s ils 2724 i aalls ua a5s0 22 sowzls als a2s0s2 160 ssssee773368 sama 1al0e m5as 25 1 3is 3s wSlh ss aalse 12s waaes ols 1m00i2 208 pssenyis 1s6l%s esis me) os msie 253 2235 a0 0 ule 07 a321 sls aolss 1n2las sa iz spseirs2 sere2 673.2 nsia sl als ssas o1lss 1826d mass 1as9i 35 ule alo als als G&ssea777603 sser72 6ssa o3lss a5s3 we sis als 2s0lss 51 &231 1a2rss mwaozs Ss ma 183 GGearrsr as8784 2u60i8 267 aisss 20 sls112a32 1s on noiwas asl aoml 7a amel0ss Ssa7se az de nh 3 ub s2 161 -- [CompanySanitized.Dossnotcontaln TSCACBI & 25231: DevelopmentalToxicitySudyinRats -- INDIVIDUAL BODY WEIGHT CHANGES (grams) GROUP II: 625 MO/KO/DAY maommosn 18 1820 2mDays op eGEmSTATIONene sssssse8er7ri0o26s fR33.z70 maas10e 7 E2es ea 12s8 ea6see s5e8r7a20 aSlse mas3a mjona lasessiss eslss sGseer7aas 22s6 m0a1 w1s7 uusras asseae s55e8677m4430 2W25a33 a mwes E2BL3D d1me6en0n aa56nod GsGssoeer77es0s2 om H1Es 33 acass aa os aoehmzs zn:es ml 165 45 ssGssseee77766532e 275057 amdmoss mailss i2mlls2s sd3si2ra Ssseer77r0 3233 emes mmla amszo sazs EEssseaer7rres?s 3230353 omaso6s fameasa m1aemlsoa sseoos Esares 33 a Bl mi: a ~~ DuPont-10309 Company Sanitized. Doss not contain TSCA CBI --~ H25231: Developmental Toricity Study in Rats DuPont-10309 --~ INDIVIDUAL BODY WEIGHT CHANGES (grams) GROUP 111: 1250 MO/KG/DAY rBeER os as 6D8AYS OF G8E2S0TATION10-2 12-6 Ll asEe8770079 GGassse8e77721s27 ppnn asssae7n3312 sssse7n3351 ssss88775561 assse7e6s ssseer67 s5s8e777789 sssssseeerrreeezss 310.26 ws 47as als 1a5.2s iz 150.2s 5s M501 $2 mas 5.0 21380 ils AS2e3 l8e%a ise dwe=s 7's wwies Ss nowils nla m7ls a2 amla 200s fals as o5u3s ule sihs ol m7l0e 3 wsls a0 aas 30 awrle ale F 2a re nr Gls ws a22p 0s anlh ss uel7 ass aaeslaiz 2anlal 129060 3001 S1o 53 amsloo az oslwa doe a18lao 1s aaslas 12 2nl7s 2s annin: n3z2 10s 3s i7s0 255 1522 wl ual2e als 1amsl7ls luussb 2150s0 3 0islis a2s3i as eosls 2007 7is 30 wmnls wl 11822 aso 202 a te mls 83 als ass --_ ~ CompanySanitized.Doesnot conTtSaCAiGnBI 3 HASI31: Developmen Toi Study Rats ~ NOIVIOUAL BODY WEIGHT CNGES (grass) Gros 111: 1250 Wa/KO/ERY wsomoen wa tem amons or ceenstaTionend eGSsaaerrn0osn sans nwwsas RnLsae moi oEumnenoiHseSs gn ave soLsnn wi GGGaaannnas Ga BBBahokokeksa we m3 nBBmLSe mmmeeEls B3omd 8na0n3 ue Gssaaaamnns: Gest sBR3oi0 BBhse3oRonhaan aoaakesei:s bu3nnd Sony Bnowd Wn SGGaasaaarrrsise Ssarsn wwmr3oo3mln Snoouid RkhnsE mmoeemele B3aS0i Beomi oun SSpoomHne a Waeiendms3 mBoymaimoomeness Bnomnd Ssoeaarneeeez wwwepeooEmkDis momadaismWaeyowBnsln Pa . Duponc10309 --~ Compan anitDoczsFoek d.TSCACBL 7 125231; DeveloTovpicimtyeStnudytinaRlas Dupon-10309 --~ INDIVIDUAL S0DY WEIGHT CHANGES (grams) Rou Tv: 2500 O/XG/ORY smanns es as eoBars op egedsoTATIONaemr mae ies eGse9o77m00a 1Bw2Is7 mLWeos w9Is5 WaSssfe 1B403320 am2hh7 aenelld GE63oo0n72s3 a 25350 aa0see aHdne aLWeaEs wsBsnE mn7hnh anulais GGsseaa7ri2ss6 7 2as iawaees oeRnnaINmBDle omaSrEEs s34lss aaElleee GsGGaaoe77r5aa07s 3 5w3o 1B Bsa SECoena aBwgEee wWwm sy 1o7wsn 0 waaa G&sGseeer77s66a0 a4B3i0 LwwEid EH3ED aBNseEh oBmmESa owgunhs aailns G6s3ee0rr7r6sa0 BwGosiowl5a aw3n5a 8wBshE waon lh nwshh oawuli Gs&Ee3s70a7708030 Bwdoee aZ3si SDTkEe wBeYLn awWsdhs iBnsEss 2Eh0hi0 GSar00 Bean an aR Bh ms oan -- Company Saritizod.Doss notcontaiinnTSCATSCACB -- 7 H-25231: DeveloTospicmityeSundytinaRalts ~ INDIVIDUAL BODY WEIGHT CHANGES (grams) GROUP 1: 2500 MG/KG/DAY aaEmr 18 120 200Dmave OF eGEmSTATIONema sssseom0 ssseennta spseins aSssssees7773a23a6 sS3sae77as7 Gass8e775807 aSss8e776600 GGssaa7r6e5e Gs&Gs378877788403 GSa8an7e0s 230045 230s2 m12s3 m1es m2as a2l7s aellas oollss 1amls sassllo 3307 2eslsa 2s0e0 aemlal 2nsl 223s2s sa2ll6sa7 3230:8s77 11aaa s31s9ss% 2G030 l1es aeens adlms 2sse 23303s 3 206 220a05 d1e3ear sms5 a20s5 3322s2 sas1 maszs aalss aI6h aassa mamle d1a3ss 3a3nse 23206s30 32a1la2s 2220:681a s118e40d73 4os6ilsss l8e0 m32ls a1as aaslle aaaaaa --_ DuPont-10309 --_ CompanySanitized.Dossnotcontain TSCACBI 7 H25231: DevelopmentalToxicity Sudy inRats --~ Dupont10309 -- APPENDIX D Individual Food Consumption Company Santized. Dos not contain TSCA CB! --~ = 125231: Developmental Toxicity Study in Rats ~~ Individual Food Consumption Abbreviations NP =Not Pregnant ExplanatoryNotes Dupont 10309 ~ _-- `CompanySanitized. Doss not contin Tscacer H:25231: DeveloTorpicmityeStndytinaRalts DuPont-10309 ~~ TDIVIDUAL 00D CONSTMPTION (grams) GROUP + 0 WO/KG/OAY peER ws G0 slD0AYS OF2G0ES2TATION.12-4 nes 61s ssssesr710s8 semis 3522.0 33 238014 an es 2sa as a3a0 aa3ne7ss seaasslsa a3a5dsa Ssseernzss esenz7 aalls ma amllsn om 2a0sh m5 assz is melos aes male mle aan0 ans eGeerra eens Bmllas sls aaosmai a2w0shss mzaees aa3sasa 2sae0as ssaaallsee spsaeorrenee a8alss lamlsae mmalzsd amzlehas ah2ea7s ssseeeaea s2a0ee0ss e5s8e7r5s3s eserss 2ise aa 2am0ll0es7 smals2ss omaalssiss a3sle0on osaleesds a0j5so ssesoeerrrsess s a1lss z amlhs a1sh oan male mls mslask sed asmeee es sais a sssseer7e7r6 ssa787 0Bw05o18 mmmliisss 22m031s m2mlas maelezs am3so srnllass Sars 4 3 2b; me ed see -- Bompey Santzoq098notcontsacaiogny _-- 7 ee H25231: DelopToxmiciety nSudtyianRlats --~ INDIVIDUAL $00 CONSUMPTION (grams) Grove 1: wo/xo/ome shinEs wa DaztsaoF GasaeTImON sGssoaarnri0es ;Mws5a sa2eosss 2amas7 EGEss0aa777122575 IwRsee ekmlss 3EBnsn sa0am7m3oss W#Si3s amAss: abkas GGssaaarr7iiinsz BIieoo mRmeiE xnEsos p6r3300775553 BBF1os0 kdkesGa aakmsaa EE5ss6aa7r77es3r5 B2Zs1s Bhamesr kkaias GSssoaor7e7y16 #S0323RBzSae Banvnes ost Be mi ES -- Dupont 10309 ~~ `SCoommppanyy SSaaniizad,Doesnot containTscA 05 7 H2231 DeveTloxiocitypSamdyein Rnats DuPont10309 -- IDIVIDAL Fo0D CONSTHPTION (game) GROUP 11: 625 WS/Ka/ORY soomvoesn ween eleasns oFTcOeEsitzonMane seas sen asGGeameense ERm01o0o0mBwssa HmBaTn mMmsI3 mNRDas mREoin hB0nIa eSGreriei)n NBweoimnBs:IERBR3s0 EBBSsl nBRnsR BBAinn RBfIad ppperreei]] Rn2E350BRm:330 maoannn Rmmeii BRR3Dl0 oRkDRs aBnS GEaaoinesss am 3Ro0oenmBd3E pabdde mmmaee dmnsnp sBomsia daaenss pEiaviees amBnioooBhR:Ed mnn3se BBEanY REBIsS OmRRnSS aRanS Epaaenrees aa Benom omorBIoou3nsse mELnDy BkB3Ll0 EnknDn B5BIS SSciaerneen @#Re:ooRoBB7oD RHBSDE BBBSsL BBB3DI0 BNmiD3 6nE3di pi Benn nS Rs Hr mB -- ~ Company SantizeDdo.28notcontainTSCA cay 7 125231: Developmental Toxicity Study in Rats ' INDIVIDUAL FOOD CONSUMPTION (grams) Rove 11: 625 wo/Ko/AY jmoae 20 omarosaroF cesmaetazon sSssseeonrr0os8s 3n7a0s aawhea amassa GSee76r24n0 n2Frss BmsuG+Rass EGs3so0er7723a6 2HB3as kBmihs 5Ba3sn GGSr3ei6r3ss om fBdyos ldW3os00 amkaes GGGseeerr7ee5n2 33 #55 mkmeess mLmasi pse0a7r6as F25C2 HmaE5s 0mse SSGoeerrmas Z3ERs7A mmLs ahoo sors 231 hs nH: --_ Dupont10305 -- `Company Sanitized. DoesnotcontainTSCA cay 7 H25231: DeveloToxpicimtyeStundytinaRalts DuPont 10309 -- INDIVIDUAL 700D CONSUMPTION (grams) GROUP I11: 1250 MG/KG/DAY NnoeuneER as 65 82D0AYS OP1G0E0S2TATION12m 1446 1638 ass8s8770097 asGeerri?s GsGaser7a2z4 ssseerr2e 8s5s8e773352 ssssee7n571 ssssseee77r6ses6 sssese776n71 sasss8a8777787528 S38378886 a3slao als 2a0ss 204 mm2s 25 masza 13 2299s0 ms maaa 2s n3a0 2 nllrs sls zailee m1 2alss wr mmmilhas asawelss aa29se0e7 s82e03a3 2al1s als 1208021 am m20l0z1 263 ;asllso mls m1e3sa ass ssaes me 23650 ae 3al2s alo a22ia 1 wmias ms mal3s ma m2lss oma a4sa see aamse a6 32a047 a22l6asa mamsl3ae mmmlloss 2os6ss7 aa0mm0ss a3300a020 aal6s mls o2a6si4s sls m13l5s3 20s 2asss 22 m29s0 ais z0s4 zs a33a0 24a 230a3 an awwliiiee mwiis ah m2l:s mls asass mo daaeae awa 233460s0 2h ars mls ml ms mle aa -- -- BompanySaniizeq,pegs, notcontainTaogy EJ 25231: Developmental Torisity StudyinRts ~ TDIVIOUAL 7000 CONSUMPTION (grams) Rou 111: 1250 Wo/EO/OAY a sn wa oartosanoF GesTaeTaION ssGaoar0no7s 6Gs5oo07nr3y0 SGssseaerr7aatzs SSseaermrearr GsSseoorr7ees GSeeseeerrrrr6a7 SGeearrrm0eszs ares 2Ss02s7 a Zaea 3aa0eaas FF2URs als es Ei Za2n3s Aoml3a BnBhsn E wWeo R 3 as R Ians FwBOrlC 3as kede Fm#Rs1G m233 n2aa Sr 26 eas 2ms0lss amBeaa Is ma a DuPont 10309 --~ _-- "PYSte, pg, "otContaty scacy Ww H25231: DeveloTopsicmiyeStundytinaRalts DuPont-10309 INDIVIDUAL 700D CONSUMPTION (grams) GRODP 1: 2500 MG/KG/DAY WOnMBaER as 68 s0DAYS OF1G0ES2TATION12 4-16 168 ss85e8r7010 ssearniia sssseern2s3 ass5es8er77a32a36 GGssa877a4s7 6Gs388775507 s&sse8r766s0 sSseereess sssSessee7re030 Ssser73s0 --~ a2l.s6 12 22324h 16 2e2a wa 2200s1 al 22654 as 2050 ms 221a6 es 22031 1m0hl a19m0e8 =2a1 2nl6a3 220s3 2a9as aDliee aalss 2m:2a 2a33 2a6r4 a2mns 32297s a2sl2o 2a2ss mw1s 226642 n23z a2mme a21005 2al0as a1asia m1820 w2m3a 2277 2aaa aasse 2 asls waissl 2a00s 226s3 m2023 22677 m28a4 2al8s 2s aallss als 2s0is al 2263s 233 amlo 24 m27a2 mo 227664s 22062 ullae 218h3 amso wmss oa3s :25as 2a0l3s 2s 1ml0z7 asia awa s. me 20 m7 2se0s 26s 2do1o 2d s26h2o 2600 slo ul mls 3 ms 2a 5 --~ Company Sanitized. Does not contain TSCA CBI El 1125231: Developmental Toviciy StuindRayts ~ INDIVIDUAL 00D CONSUMPTION (grams) RouP 1V: 2500 W/K/oRY jeere EET DAYS oF GESTATION eGesa7ar2n00as 5 2 a mmB0yo maBsans eGaaanrmissa ZW26es0 mhwieo BB2sns GEGsaaari7z3aa3 an B3e hs3B3s hkRssS Esseaorrniiss 23535 m3mi3i u2ws0s GsSGa5a77re4e0 2s25o3 m#ns1n mRBasS Spsaoivreenss 2WBaes 3mm35s 2BEaus SpSaarriaa B8 Zis Bawleie Hmasaa Sars 5 Es Bn ~~ Dupont10309 `Company Sanitized. Doosnotcontain TSCA CBI --~ 2 H25231; DevelopmentalTorii Stdy in Rats --_ DuPonc1030p ~ APPENDIX E Individual Clinical Observations _ CompanySez, D0 notcont75aicny = --_-- H25231: Developmental Tricity Study in Rats DuPont10305 ~ Individual Clinical Observations Explanatory Notes Foomote a The first observation recorded each day is indicated by "a"; the second by "b". Observations were made twice daily on days 6-20G. Ino signs were observed during the study examinations, the "bY entries are omitted from the printout. BompanySanit.Dossnot conta Tc car w= -- --~ og i 8 j gif tt tor oT roto RR RR Et 1J EOE. oo ooo EFosEgh c c c eee &8 4 gsi lC1 oloIl o o o ln o: l BEgoEgs l Silo o l l ol o o l l fs 5 3 5 5 & 35 & 5 & 3 3 3 iz 3 23:22:33i3: = if 8 8 8g gE BE BOE EOE OB OB J I pif #8 8 8B BE EOE OBOE OEoEOE FEis os oz 5 5 ox oz: 3% 3 oa aFooes" gi iEiE giisd EEEE af =f afE EOoEf O58EE EoE f E 28 EafEOE 4E28 E oF8 EoF8 ~ 88] E& EgRgIiEg" EE7 87 8% 2 7 8 % f9 32% 3 0 EE 283% Re "Contain 15acay ~8 i 2 i galas 00 Domal Eel LEER EED DD Doesnt EEELE EE --~ SoBEbag 3 Esiggs odd Ed vc ddr dec css - EoB dspZaAt.oo.oono0 naARmtEossg0miononon posses non 3 sme se 2 fase 5 4 & ass sasas & & & a 3 Pgs oe gg 08g I 3 II10I8RBEBE E 3 opEI oggN f E BoB oR oE I ogi Boi Eogf xopE EpEoo s soE sos J 8i Ic#o di PiEEi PE BE FE BE EPoOE EBCEB BcEEEcEEf PEPoERP OEPEOE: --- PEHERETE RUE EB RI IE gsi of 8 8 8 3 8 3 CompanySanitiDozesendo.tcontain ISCA CBI ~8 i 2 i Epo FE 1 DDD DDD Pombo nll HN oF Donon nnn g Pi os os os os 8 3: o& os 8 33 3 IEEEEEEEEREEEEREI g SEid g& 8 # # #&# 8 8 8 #&# #4 4 3 8: % % % E & EE OE OB EB } :i %ijjf% E gE 8 EEE8 E E EF E8 EEE EE EEOE E OEBE ~ B gs B 2ERiIzE%" 22% 21%7 233U 2gd7 239 B24T E28Y 340 23d 2ofY 238 gl gE 8 BB & 3 # # 8 GompanySanitzed. Donotscontsain Toa opt ~3 i 2 i Bai oat. LL od LTT LED owD 0 Ee n gsi ode coo o- - EOoo Pog EE Bic osc cc cc odd cs ~ ERE Fai3coder oNo Nd SN oo : 8 gel DID TT 1 eel lol g ged oll ono g Pi GAS 8&8 & s&s soa 3 is 8 8&8 $888 JE | EgEE.ii44 sEd f8 of o5B ggf8 omc28ioBdE of% od88 I viiz EE ooxo: 5 op:o:oo: Josip ddd 30d 2] ~ dl EME PE fOBgE BE2 BE 8BE BE Q8E 8OE EOE EOE fi fF FE OE OF: 3: od Company Sanitized, Dogs.notcontain TSCA cay ~3 i 3 i Bai0 0 sgl. 00 0 00 gc CCC EST Zn: - . Ie... . - - . - - . 8 zai - BE SU ~ Esco ono EEgBalon: : .-N:::N- * a ESET IH g Piss sazas sos: 8 ios 3 f SE :1i3s 52 o5z kt 8 8 8#4 o% g3%oEo@ o#@og3 1 fEE5iiEz x4&8oz Egf% 85 8 8 8 5 8 08 8 8 4 8 #4 3% 2 PE IEBaE HiPIgoEE E8OE LE8OB C8OB8RE:REE8ON L8oHEL8OE EL8OE ELO8E EO8NLEO8K Z| 2818 copa std Do ATCA ~3 : Lo ELD Eogd.oo DEE nnn 0 Donn AEE F Ear llo E ilo BOE4E DOT Donn 4 1| Ps.sEilids88s 8o:2pE:Er8Fsz88o88s3%c3:o86so86eq ;::& 5i Ssgeiif; EFE Eo.E.8o2:8o8z8o8E8o%E3oo8Ex PO IEEE ETE RTI ompanySanitized. DoesnotcontainTscAcay ~3 1 1 gsiggs Bab aa" Saf gg" gaia J ERpaRl I CC Ct Todds 7 TT TT Tgads" CC TTT 00 00 DD asds" men] 00000 LL EEER ~ Eagan Eo8aboaat ood oT ooo&ariiit = dE ooo Thin Geb osoT ono g i osas 5 " - i Ek] a 5 sacaeae Z| igs 2 2 2 2 3% 2 32 z gd 3 ssgciiegdz #8 zo: 4 28 8 284 58:3: 88 ipgs J o: dii<gfs BBE Bo& E EE EE E EBOEE BcR.EfE 52 gi.id88di8gs% z8ioz&ias& g&an zi ddsg CompanySanitze. Dos nocontain 5G Oot --~ gl i i Badd. CL LL LL... Sia oll D [ o EE N ~ lg& zE at ccc T o TD T PE fos F8oes n %&i coo ool o3 n EBS ce cc, 9 ; ifisegrgozpozgce Hf So1s8g5iofge@d#18 d #ia 1 a #&4 838 28 %4d# 3 fiEz 5B 5 BEE EBB EZ 4| ossiP iRgi:iifafggaFE gEefga oFE@oaEgE8og8EEE8oEEOlEa o& gsoasiPsRE 5O8E 34EE 33 OgEd O3E8 22 28gE OF3 gdEE 33& g3E ~ | EEBiisk gEz T:z 53 :8% 38 3 FB B oE% o%:& o3 CompanySanitized.DoesnotcontainTSCA CBI f ! % i g i 82 Bai , EC gianEii - 8 gif ~ 28 dEEdd=ili . HEN 8 gai 3 is 3 ii: i gadis ~ dl 8 EE = Company Said.Dos rtcontain TSGACS! H25231: Developmental Toricity Study in Rats ~ DuPoni-10309 APPENDIX F --~ Gross Postmortem Findings -- Si GompanySaniized. Docs not contain TSCA CBI H25231:Development ToxictySwdyinRas _ ~ Gross Postmortem Findings Explanatory Notes. Abbreviations --NAD NP =NoData = No Abnormalities Detected = Not Pregnant Dubontlosny -- -_-- `Company Saniizsd. Docs not cortan TSCA CBI 325231: Developmental Toxicity Study in Rats ~ GROSS POSTMORTEM FINDINGS Dupont10309 Group I: 0 ng/ks/day Naunmibnearl structures) sssaar7i0s8 =--- ssssannie == ssssaer7a2s7 pi= ssssa772300 ppoa eSGsssaa87r7aa31z9 === aessaa7r5a3s == ssssea77s5e5 pops sSsaar7se1 == ssss88777753 pa= --~ eessaar7es17 == Gsars1 = Finding(e) aap mwop Fxya wwwx wxwowx xwon wwon woo wwp wo wawo>p ~~ % Eompeny Sanltzed.Dose notcontinTSCA 01 F-25231: DeveloTorpicmityeStundytinaRalts --~ GROSS POSTMORTEM FINDINGS DuPont10309 Group 11: 625 mg/kg/day `NAunimmbaelr Structure(s) 565568770065 oeCe 665568771220 oooC s55s8e773241 o---o ss65a8773386 == ssssaa774430 =- 6s5s8a7n4e5s (ve) ---- 656568775542 ooCo 665588776632 o-C 656588777702 =-- 655588777757 == --~ 665588778884 -- Finding(s) nNaapp NNDa xxDD xxDD NNDD NDD aND AD AaDD NAADD NAADD ANADD --_ pompanySanitzed.Doesnot continTSCACBI 57 HE25231: DeveloToxpicimtyeStnudytinaRals -- GROSS POSTMORTEM FINDINGS DuPont 10309 Group III: 1250 mg/kg/day animal ssse58770079 =- Gssaea7r1as == Gpoea73a =i ppeettii Spkoin ssss87n35 po pssessee773376 p==h ssssaerneess == Seaaaerremr j=e SSs5e77778 =pt 2 ss6s5se8777s88s62 -==-- Nwapp ssaapp aNapp MasFsirm(,1.0naxmNa1a.rp5y cgml)anwdhi-te, Toftaside weoy wwoo wioo ai>o aa>> XaNAo>D --_ CompanySanitized. Doesnotcontain TSCACBI 5 125231: Developmental Toxcy Sudy in Rats --~ GROSS POSTMORTEM FINDINGS Dupont10309 Group TV: 2500 mg/kg/day ANunmibvearl Structure (s) assese771000 -= Ss5s7s1 == sssssss8e777221s3s === ssss877a3a3 j=o ssSasr7a4s7 =js ssss88775570 == ssssae77e6a0 == assasarresns == ss6sa5a87r768a03 === ~ 6s5s8e7e9s0 == Finging(e) Pfyy awap wxwowa wwpp mmnn man wwpo wwow mxwoxo wwop r~ `Company SantDoiesnzotcoentaidnTS.CA cal 5 H25231 DevelopmenToxisy Sty inRats --_ Dupont 10309 APPENDIX G Individual Reproductive Data `CompanySantzod. Dos potcontaln TSCACEL _-- H25231: Developmental Toricity Study in Rats -- Individual Reproductive Data Explanatory Notes Abbreviations N-P--==NNootDParteagnant DuPont 10309 --~ [EompanySanitized.DossnotcontainTSCA CBI -- ~ 3 3| i2| sGa2a3a5d3a2d9d3i8isa3dnizanlsiannaninasis | annrernensennnvesanane 2| eqgevenvargggonneggene iE 22ERRCEoaEmEeEEEmRMEeETEANEOETENEHAAMENHEEREEHEOEY | ; ccccoo0ccc000000000000 58 7 g 4 ~ poi 2EZ3 | coocscccncmccccancaans Zk| coveccccncncccccnssans 48 | s2azza-zsasaasonnesans i8E | razasazansazasaasazazs ag JBE || EBREEEECRERRRnRnRoTIEIRIRZIEREREEiREEiRiEsEE i | EEbaLEEERER EERE EEEES {BsmpanySanitized.DossnotcontainTSCA CB) ~ 2 5%| seonnunsans iassnssenas Be| GRIGG3GAIETAAIGEAGGE i | eoomennonsnianenngacan BEsf| snegoncacgioconeaccag 5 g CBg | sssssassnanisesenannss ~ 1d : i g | ceccccccconinoooccccoe g Z| |3 3 1g ~~ 3 2 ccccccconioioncsssscos g g esas0ssennsansssscsne {% 8ii8|| ysuazznsgngaansgasnsissasssgsenngannnaaass H J ge | suzsenssnas iaanssssan 8 : $F| 3333833308882228833848 GompanySanizec Docs ntcostaTSCACBI ~3 3 3 B| szassnnnerasesannanne | remeamreepenezesengene 2ue g ER IEEREEEREEREEEEEEREEERE] ~ |E gE | SP, :z { | ceccococconcococcoccos io,HE| oemneosoncooosncosonn g ! f2 B 7: F. ]88 4 i 2 4 FESE 8 8 eddaMoc00OMOOCOCO0C0OH seramnanmsssasngnasRnErzaInsaEnnsys EEREEERER EPR EEE EPR RERER && ro | J ---- N HET L] | SCEAENrIaIpRLANnAgCoH ARO smN REAENE ESnS 8 38 | SUCE8L000800808008888% ~ :2 88| saungmenzezasszazceass Be| GIIGIITEAANECNAAN 5 4i NAP REIR TR geHA gNeeOC nMeDgOE ENY IM2 | seeneangraongageasean g5 iB 2298TNATIIARARIINRIANG ~ | &2 ] g| ceccoccccccnoccacaccas iEEf| somenesnennnocenennace i | ssssnsonssessasasseans :5 gEEg | saszsnsszzasansasnase 1 en i z g i savssanEAzNASEnAnIAngd i 5f | 3333E33373853500330s CompanySanitized. Doesnotcontain TSCACBI H25231 Developmen Toxicity Study in Rats --~ Dupont10309 APPENDIX H Individual Fetal Weights and Alterations --~ `CompanySenitized.Dossnt usinTSCACE - Ts H25231: Developmental Toxicity Sudy in Rats ~~ Individual Fetal Weights and Alterations DuPont-10309 Explanatory Notes For easeofrecording, manyofthe findings have been abbreviated or coded, as listed below: a = arch(es) bil = bilateral cen = centrum or centra it = left = lumbar NAD = No Abnommalities Detected rt = right th = thoracic -- = NoDaa * Subcutaneous hemorrhage that was not present in utero. Renal papillary sizes refer to papillary development using the scheme ofWoo and Hoard Alterations are classed as: N= Notes --~ DV = Developmental Variations VR = Variation due to Retarded Development M = Malformations Numbers are used to: Indicate renal papillary size + ldentify specific stemebra Refer to skeletal position for ribsorvertebra Specify skull bones according to the following key: I. Interparietal 2. Parietal 3. Frontal 4. Nasal 5. Premaxilla 6. Maxilla 7. Zysoma 8. Squamosal 9. Tympanic annulus 10. Basioccipital 11. Exoceipital 12. Supreoccipital 13. Hyoid -- a LWaotoe,GeDs.Ct.atiaonndoHfoRaari,s:RMT.he(1E9f7f2e)c.t oAfpMpeatrheynltSHaliycyladte.rTeoratnaoslaoegNy,opr6:m1ha9l1A-r1s9p6oe.ctsofiRensalDneovetlcoopnmteanitninTSCA on -- oon 525231 DeveloToxpicimtyeStnudytinaRalts Dupont 10309 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GRoup 1: 0 WO/KS/oRY oFEtTsvo00../ pervswr. _sTeveroRe moms) cusstrrextion csar7:on sian whoo 3i: HH$i3E0 xidner hwSooa mpiila - sine 2 GAD Ww :5: Hiiea sen 5 ir awRewtarded ossitication (2 bil WR SSR = E3S02 sHiEanC 3i iWRebotarded ossstication (2 541) a iiH i85% sen sn RTTeeottaarrddoedd ossitication ossitication (2 (2 541) bil) Ww WR can:7is sins awoo 3 $8 verter . sa wn RSeutpoaerrndmeudmtenorasa)etiyti(csaittieon12 bi =BY :i 8 ~~ 65 33.858 SVkeunltlana . sae RRweeotteaaorrnadseadanOotsm]seiifiiccaactiioonn (2 bil) WR = 5i05 iseide wwwooo p3r 5365 verona nReoteaerndedBosssi)tication ww asa7:me sHEe wwoo -- aTSCACP -- pe r t---- 26251: DelTom ilSo udyinnRat Dupont10309 ~ INDIVIDUAL FETAL WEIGHTS (rane) AND ALTERATIONS Grom 51 0 wosse/one oBwCv0,./ eros wr. savers enone) cussstricarion [7 --Lao vertenna . sev sun RreettatieedeoDsasnitiiccaattiioonn @ 541) - fer s: om8 san mnrsaineadhaccalmsificaacniosn 2 341) w $:3 3HFiE5r J. HEEeySRaraed ossiicacion 2 511) 8 F#H uLit a EA Sft-- w u3 sEAe a= osar7:is w58e verona wroit ed n ousiication 5i: ox5n : IE venom ww[se csed oasicicarion ~ ;:: vi[.0a50 J. wwMosetfurdees tompiticasion w " 5.25 vertebea Retfiresheitanpiticacion w =3 sImZ vere u 5.08 wJFoosgbusdesheosnsistication - 2 fic J arsedhoassinsicacion w ~ in TSCACE! Tw `GompenySenet 0 sso H25231: DevelopmentalToxicity StudyinRats DuPont 10309 ~ TNDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 W/KG/DAY FoEaTUSwoN.O/. _pETUS wr. STRUCTURE FoI (5) cuassercation 658is719 (cont)5.33 16 5.04 sse712s ase 32 si ie :5i 5.sl0e5s als7 87 s5l5s2 105 slaloess 112 sins 11 isoesr vertebra vertebra ska swan ska shan sean Ret(acrednedthio2s)sification w Ret(aerodnedthaOts)eitication w nwRe>atarded Ossitication (2 bil) WR ARe>tarded Ossification (2 bil) WR AReDtarded Ossification (2 bil) WR wwww xReDtarded ossification (2 bl) VR wwoD Retarded Ossitication (2 bil) WR ss1a 5.26 vertebra ~ 2 5.92 vertebra 3 5.65 vertebra ` 5.3 vertebra s 5.33 vertebra ` 4.62 vertebra 7 4.90 vertebra s5 i5.2s3 skal Ret(acrednedchiols)sification w Ret(acrednedthoOs1s3i)fication w RReett(aacrroddneeddthOaOstss)siiffiiccaattiioonn w RetTaerendedthOos)si ication w Ret(acrendedth1O0s,1i2t)ication w Ret(acrodnedchiOls)sitication w . XReot(acrednedthaOts)sitication (12) VwR sanitasd.Doss2A SCACE ~ ompa2nt To 125231: Developmen Toicy StudyinRats Dupont10309 ~ INDIVIDUAL FETAL VBIGHTS (grams) AND ALTERATIONS Group 11 0 w/K/ORY oPrtosv0.i. ramos wn. _sverns somos) cusstercaon p tiHH r--DLa2s verte wFeoRacced ossiticasion 23 SoRn verte wHRsaorodnedoiods)sisication - hans w esaIms os xVieafnteeyte sRapoiiinta sh- oasnrisiziaet)it3 at(iboiln) w w 2 err vertebra 5 Gas vertebra RReetteaassndieeddnbSisonsbii13ff)iicoaatciioonn w a a5 vertebra RetofarnadetsdebhaahsiisF)heation = w asan13so Lo3s ssuaenrte H[ersaortztheagei(lreft iene) Ix 3i iSeR satnhen SFReeottaarrddeedd oSsosmiittiicaattiioonn (2 bil) VR ~ s so vertebra ReteCaeornndednthoisnob)i)tention w w . ws sfanr RTeetteeeerrnddeeddthSoisusspiifiiccaattiioonn (2 bil) VR w . cas vertebra . sao sant RReetteaerrddreedd )oSsopbiittiiccaatviioonn (2 bil) =VR ii3 ii8an sen jHioeoytarded ossification (2 bil) VR i $5 sen Totarded ossitication (2 bl) VR -- `Gompany Seritized. DOSn!ot contain TSCAC!8 iE H25231: DevelopmentalToxicitySudy inRats DuPont 10309 --- INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS rove 1: 0 wo/KO/IAY oPEiTu1s0i.o. remus wr. _staeruns snomots) cunssrrreaion esamo (cont.) Vertenra Ret(acrednedchoas)siication = n 51 vertebra 1 ao sen RReett(aaerraddneeddtraOO2ss)psiittiiccaattiioonn (2 51) VwR ase:7ms s3s8 Ssueoruetntas HRoenteoaaxrneaheaegreaots)s(nieicckast)ion x = 5 5.24 vertebra . saz vertebra RReetteaaerrnddeeddchaOOnss)siiteiiccaattiioonn een ntoo12) w s ss vertebra . sas sTeartnenra RReetteaaorrnddeeddchasOzss)iitiiccaattitoonn (2 51) VwR Retarded casicication - 52 versensa RetGcaeerendnedtthhiiOn2s))siticacion w w 15. 1i 5.5600 vertebra 0RWe0otarded casitication cen Tuta) w ~ re Reteaerndedshoasrseisf)ication w 32un sswioiss 1aw2os0 san:7 a HsuEa cadney 3 peed aRpeaofpairldlead-ossisziefic3at(iino)n (2 5) VR i:: ooShni 0wwseo - CompanySanized.Dossnotcontain TSCACB TZ H25231: DevelopmentalToxicity SuidnRayts DuPont10309 r INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP I: 0 MG/KO/DRY oFwEtTU0S.H7o. _rerus wr. _steucroRe enone(s) cuasstercaTIoN ser2 a (cont.5.23 5o a5l.e2s9 01 ssiasr 21u S5S1552179 Fy 5a Kssihudaenluettyis sn sum RPHeaetpmaiorirdlreahdageOssis(zilefeiftc3atr(ieboaindr) p(2awb)il) VwR wwoo wReotarded Ossification (2 bil) VR wRwewotarded Ossification (2 bil) VR ase37nz s51a9 5 53 vertebra " 5.76 vertebra 5s s5.o06 87 sSi37 san vertebra ~ 05 55.4529 vertebra un 5.53 vertebra 12 s5i2s0 san 1 Sad vesrecenbra 1s 5.43 vertebra kFsy Ret(acredneed13o2s)sification = wReot(acrendetdhaots)sification = wm=o RReettaarrddeedd oOssssiiffiiccaattiioonn (2 bil) VR wRewt(acrednedchiots)sification w RetcaerndedtheO)ssitication = wRewt(acrednedtaOts)sitication (2 bil) VwR RReettaarrddeedd oossssiiffiiccaattiioonn (2 bil) WR RettaerednedthOrs)sitication w Teen ena) = -- `H CompanE ySaniY ized. Does notcontainTSCACBE Ig H28231: Developmental Toicty Study in Rats DuPont1039 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS owe 1: wo/xo/one oPEwTS0.0. pervs wr. _swaveroRe Fuwmo(s) cussterexion ss3a (conc)S66 vertenra ReteaorndedBiosdsiication = ss37n ie3n0 wwoo 3 $8 verte . 520 sen RReettEaarrddEeedd )oomsssiittiiccaatiioonn (1) w SSeaaienn , RRReeetttaaarrrddaeecdda OOomsmassiiitfiiicccaaacttiiiooonnn ((21)541) WVWA s 5.60 vertenra Retceaeernndedttohinaoe)nisz)ication = = . 599 vertenea - 570 vertenea RReett(aaerreadneendtnooasrea1ii2t)tiiccaattiioonn = . 5.59 vertebra Ret{(aeeroednnedtchroiion1-e11t23t))hcation = = 5 5.67 vertenea 0 5.55 vertenra RReettTaaerredndeeddthossra)miiciiccaattiioonn = ~ n S78 vertene RecToerednedenoiptaitication = x sar vertebra RetTEoerednetaerbirieeiatst)hcation 5.99 vertebra 0 sist vertenna RReetteaaerrnddeedderdOarsetpiitihceaattioonn w en mies) = sso7:7s3 iwnm wmow . 3 pd wo --~ `GompanySanitzed. 00581!contin TSCACE! TM H25231; Developmental Tovcity Study in Rats DuPont 10309 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS Grove 1: M/K/oAY oFnutsvoo. . remus wr. _stavcrons enone) csstrioaton ese7i:s3 (cont)aS00 : 38 avis 5): pie52 ibit iiHhe i3nun peiiriet esan1:ss sSon :i3 2isah 5:: pi$ea3 san ~ i15 biais ese77:se sHse3 g----" :i> os5ne : SE verte :. o5.e00 wnReootarded ossification n0o[rest = nnnooo wwbWoodo wwwooo aWReootasded Ossitication (2 p41) WR wwwooo wWoo wReoteaosndedonaons)sification = pw0eo wReoteaorndedthions)sitication w wo contain15o t --_-- a H:25231: Developmental Toxicity StudyinRats DuPont-10309 ~~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP 1: 0 MG/KG/DAY oFaEkTUS0.NO. FETUS WI. STRUCTURE PIONS) CLASSIPICATION 6567o58 (Cont)5.05 wo sse7159 6.11 2 6.28 vertebra 3 s.e4 VReirbtebra 6.00 vertebra s 6.23 vertebra i 6.17 vertebra 7 6.58 vertebra 8 6.30 vsekrutlelbra B 6.36 vertebra 1u0 65..4529 vertebra ~ 12 677 sk 3 6.35 skveurltlebra wReDtarded Ossitication Sup(ecrennumtehiria-r1y2)(site 14 re) worv Ret(acrednedthiOes)sification w Ret(acrednedth1O0s-s1i1f,i1c3a)tion A Ret(acrednedth1O3s)sification ha Ret(acrednedthiOzs)sification w Ret(acrednedth1O1s-s1i2t)ication = RReettaarrddeedd OOssssiiffiiccaattiioonn (2 bil) VR Ret(acrednedth1O2s)sitication w= Es)(cen th12) i Ret(acrednetdhiO1s,s1i3f)ication w RReettaarrddeedd OOpsssiiffiiccaattiioonn ((28 7bti)l) VVRR Ret(acrednedth1O1s-s1i2f)ication ww 6587161 5.36 an 33 s5i.a27 naa0p 55 5s1s7o0 wNADD 7 clos wo pm 6 sschCB H25231: Developmental Tovcity Studyi Rats Dupont10309 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS cove 1: wo/xo/oae oFEwTU0S 0.. _rerus wr. _stavcroRe snwmG(s) cnssrrroarion ssa75a61 cont.)5.500 12 Hsta ss21a 5$.058 san SVearcnenea 3 5.30 vertebra . s sie 5.0 sSaan : 33 Vseretnabra 5:. 55.550 vertenea -- 0 56 sSwaannt 2n 5s5a7 Vserntabra n S34 vertebra 1i 55.5055 vertebra 1 sss san es1r wm nfwieood Wo wRReeottaarrddeedd OOssssiittiiccaattiioonn ((11)2) wWX RReettoaaorrnddeedde22oO2ss)ssiiftiiccaatciioonn = RReettTaaerrenddeeddhdGasezssti)ttliccaattiioonn ((122)51) wVVXR IRReettaarrddeedd Ossssiictiiccaattiioonn (12) VR 0120(een ehioiz) w RReett(aaczrenddeeddthoOiss)ssiitgiiccaattiioonn (1) wWR IRReettaarrddeedd ossification ossification (1) 12) A WR RReectcaaerrnddeeddhaOOzss)esiifiiccaattiioonn w 0Ret(aCrednedStoos)stication = RetTaerednedthOas)sification (1) WR wo TI compan ST E Dose ekena 0A cB ~ RDIVIDUAL FETAL VSIGHTS (grass) AND ALTERATIONS Group 1. 0 vo/xo/onr oott0. fr [er -- J73 --LHaeo san REeSrarded Oasitication (3 bi) i:: ffHeiir wnee $:3 $i$an2 san =HFoSPardad ossitication (@ bil) VR 3i3 HfiiEi HE=oSRarded ossticacion 511) 8Ni SiLaeo =FwY i# LEaR ane kotita - size s min w ee73. sHearp wHooRarced ossitication @ bil) VR 3i: iEn3A san =ERoSParded ossitication @ bil) VE - :: $i83 san sn hEFoeotbaurrddeedd ousiicacion ossification 3 2 p11) bi) VR 583 iEn3E san =EReSbarced ossttication @ bi1) VE sse:7re ss3s oan wHtouraes osstrication (2 1) 3 ia ao :5: 5ii.2h7 NF8ASD stain TSCACE -- gomp5es5nanizDoeod. TW H25231:DevelopmentalTovietySudyinRats DuPowlows ~ INDIVIDUAL PETAL WEIGHTS (grams) AND ALTERATIONS rou 1: 0 wo/xo/AY oFEnTtUSwo.ib. remus wr. _stavcrons fr cnssrionmion esen5ae7 (cont)asa80 0 on eser:7nn 5S.9E0 KViedrneebyna 2 s.00 jrKidney : Ht J---- . 56 vertebra . ser mVenrsenra 1.5 si5i7n 3 HE g-- ~ 22 se vertebra 1i so.0o4 Kidney nnweoo Rseabepaernid:lea-eahoo-ssiisazi)eio3atbiioln) w w Rseabp(aiGtzeidnaede-aotin)asiefic3at1i2on) = RReetteaaorxndd:eeddchaoOsss)saittiiccaattiioonn w sRuepfeeaerrnnauemathearosar)rsyiei(csaictieon14x) wBY mnooeen' thaz) nReot(aeeznd:edthoasssatzs)cation w Rseuteaaelrnd:epadthpaiosts)lsaifi-castizieon2 Qu wA Ee) soACE ~ t= TM H-25231: Developmental TosicityStudyinRats DuPont-10309 -- INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP 11: 625 MO/KG/DAY oSnotuswo.H/o. _pETUS Wr. sTeucTURe FIoNG(s) crassrercaTIon sse105 2 sssoa mm 3a Ssiasn mn 5s 7 s5.a35 sis a5 sS5e2 kidney 1n s550s 2 sie >Stpernumerary (short 13 rt) OV wSDu.pernumerary (site 13 1t) DV wrwy hnyo Papilla - size 3 (bil) = wNoD No ss87106 5.61 23 l5.o2z3 i5 S8l0e1e vertebra s7 5sia.60 o5 sprs ~~ 012 slsie es Siss wxoD x00 Retarded ossitication wo{cen hiz) ww wwoo w0w xEs) sse1mz 5.05 2 528 wnop 3i 5s3a9a 5 saz aao a0 $5 si5s3 8 pS nxwo n> : -- CompanySanltized. Dogsnnotlcontain TSCACBI 120 25231: Developmental TosicityStudyinRats DuPont. 10309 ? INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP II: 625 MG/KG/DAY DFoaTUS0.0. _ETUS Wr. STRUCTURE FmmG(s) cuasstercaTIon ss1e05m2 (cont.)S5.i5e5 xidney F1o2y 8sl3020 113 sseer >papilla - size 3 (xt) w= mw0o wEoS sse7120 5.3 2 iE vseretnebra 3: s.51e028 vertebra ss 5S.2363 vertebra 75 aS1m1 vertebra 05 S5.8300 vertebra ~ u 5.30 vertebra fg12 aSa8d svekratlebra 1 4.52 vertebra 5 2.00 wReotarded ossification (2 bil) WR Ret(acrodnedthO10s-s1i2i)cation w wReotarded ossification ww(eon th10-12) w Ret(acrodnedthiozs)sification w 0Retarded ossification ww(con tr10-12) w Ret(acrednedthoi0s-s1i2f)ication w Ret(acrednedchaozs)sification w RReettaarrddeedd Oossssiiffiiccaattiioonn (2 bil) VR Ret(acrodnedh1O-g1si2f)ication w wo(cen that) ww es1a 5.43 23 p5e4d5 wianey : 31 uwSmooall papilla - size 2 11) WR wd --_ CompanySanitized.DossnotcontainTSCA CBE [0 FL25231: DevelTooitpySmteynnhts Duron 10509 ~ INDIVIDUAL PETAL WEIGHTS (geass) AND ALTERATIONS anon 1: 625 va/scroRY oPwonwios. _vems wr. _omavenvns somos) cassrrscamon sserP FanC(o Icmoncu ]) wwwoso s F 5Oh m ] ww=ss i B3 ou5m5 er ws Bota sire 3 G41 w FiB iu nik iwwEo es:13o 5sim wane wiseeam sapinie - sine 1 Ww i:ER i sen on F5iebucsea onssrication (2 51 T :: EEi5n aan 3 pe] [uR=e5wtasdes omtication 2 51) ~ ii BBHH EwS ose3:1me sBperHsi rane IsReEpirtina ozaneiisc5atGiionn (2 bmw i:`; Btieioi8n oun [w=Re5otucaea omsstication (2 51) . i:; Baae wwweoo ~ ---- scacal 7 125231: Developmental Toicy StianRdatys Dupont10309 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS Rove 11: 625 wo/RO/DAY aF708w0.W/o. remus wr. _smavcrone rvs) cussteroaTon esa7:me 5h.e6 Kismey i53 H533E55 :7 5s5is 55 015 5 3$355 sen 32 SSl1i0 san x0BaDpiiia - size 3 (ih) w JxSetDspermumerary (site 1315) DV xwweoo RIReettaarrddeedd ossification ossification (2 (2 1) bil) VR WR wD 5 sien esarz140 psme :5 5p-8e vere ~ 5:s Ssis i5 xianey Py5: ie5an0 1H2 1psei5) xidney sar23 e s5s8 son Vestebra nap wwwooo 1Re0t(aerednedeaaons)sitication = 0Sul maptila - size 2 BA VE w0woD wwFabopilla - size 3 (bin) w wReotarded ossitication (2 bil) WR A RetTaerednedeaozs0s2i1f)ication w -- sod.Doss oto"vsoACH!i" 3 H25231: Developmental Toricity StudyinRats DuPont 10309 --_~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP 11: 625 MG/KG/DAY oFaEnTUSo.N/O. _PETUSWI. STRUCTURE smomG(s) cuasstricaTIOn 6587343 (cont)5.59 vertebra 43 ssme 2s ssme s8 5si8s veKritaneebyra 0n 55.8227 vertebra Ret{acrednedthiOos)sitication ww 0a) xx0 RxPeatpailrldaed - osSisziefic3at(iboinl) w I)(cen th1z) w Ret(aGrednedth1o0s-s1i1f)ication w esse3re 4.58 vertebra 23 5i.0e9 smkdull vertebra 4 PRE San ~~ s as? Sn s sa vseeratnebra 7 4.6 VKeirdtneebyra 5 4.72 vertebra 25 53.82a0 vertebra 1n2 i4.m58 Ret(acrodnedth1o0s-s1i3f)ication w RSeutpaerrdmemderOasrsyifi(csaiteion14 (2rt)611) VORV RReett(aacrredndeeddthoO10ss,ss1ii2ft)iiccaattiioonn (1) ww RReettaarrddeedd oOssssiiffiiccaattiioonn ((212)bil) WWRR RRRAeeDtt.aarrddeedd OOssssiiffiiccaattiioonn (2 bil) WR pap(iclelnath-i2S)ize 3 (xt) ww Ret(acrednedhiols)sification w wReat(acrodnedthots)sification w Ret(acrodnedth1o1s-s1i2f)ication w 00 ~ [BompanySanitaized. Does not contain TSCA CBI 0 25231: Developmental ToxiSctuidyitnRayts DuPont10309 ~~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP 11: 625 MO/KG/DAY AFEiTUSvo.N/o. _7eT0S wr. _sTRcTuRe sn (s) cuasstrreation afst874s (cont)5.05 Kidney u 383 vertebra 5 am PRaeptialrldaed - Ossisziefic3at(iboinl) = wo(cen th10,13) = sser1s2 5.25 vertebra 2 5.45 vertebra i3 ssaa 5 512 vertebra 7s s5.a2z5 5s ssaes 0 262 vertebra un 5.06 vertebra n 4.95 vertebra ~ n ae vertebra 1i 54.8010 Kidney 1 ie Vserecnebra ft) 5.09 Vmeirptebra RReett(aaerreddneeddthaOOtssss1ii3ft)iiccaattiioonn wr wn(cen th1) = Rxetarded Ossiication wa(cen that, 13) wr a> wReotasded Ossitication Ret({accreednnedhthaiOzzs))sitication w w Ret(acrednedthaOts-s1i2f)ication = wRewt{acrednedthOisza)s ication wr PRaeptialrldaed-Ossisziefic3at(iboiln) (12 bil) wWR Ret(acrednedth1o0s)sification w sReutpaerrdneudmerOasrsyifi(csaittieon141) DV (een ehaaz) w sser1sa 5.57 mo 2 oe wo ~ Company SanitizeDodos.cssnnoott contain TSCACB! 125 H-25231: Developments]Tosicity StuinRdatys DuPont 10309 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP 11: 625 MG/KG/DAY oFwEtTUwSo.0/. FETUS WT. STRUCTURE FuomG() cuasstercatIon 6587354. (Cont.)ae 5i SS8l1e vertebra ss7 ss5.ez7s2 skal 15 5s5a vertenra un 5.7 vKeirdtneebyra H12d Ssis n x00 Ret(acrednedchiols)sification w wwReootarded Ossitication (1) ww sRentarded ossification Pap(iclolnach-ilS)ize 3 (1%) b= 0Ret(aerodnedthaOts)sitication = ws sser:162 55.0587 vertebra i3 S5.212 5 535 vertebra --~ 7` 55.2360 vertebra 105 ss5am0n 11 ssan Rweotarded Oseification 00(een tha1 13) w Rhegtarded ossification wo(cen th13) w Ret(acrendedthOasl)sitication w xwo0op wwos ese7163 5.51 x0 32 psie et 0x i sz wo --_~ `CompanySanit10d. Doss not contain Tsea cay 2% H:25231: DeveloTonpicmityeStnudytinaRalts DuPont 10309 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP 11: 625 MG/KG/DAY DFEaTUSNo.0. _PETUS WT. STRUCTURE Foes) cuasstercaTion esem1m0 sa 23 S5356 sen i5 S5218 $2 s5i1a385 sKikdnaey 55 iSsss sadn 110 ssliss be2 5S3300 sem wReotarded Ossification (2 bil) WR RwADD wRPaeoptialrldaed-osSsiizfeic3at(iboiln) (2 bil) VwR SRebtarded ossification (2 bl) WR xxo wReotarded Ossitication (2 bil) VR as1e 5.8 i32 ssSia0za1 smn 7:5 ss5ms7 Kidney --~ 10s5 BS3452ETswikva n 5.57 Say 1u132 s3e0l sRikba saz ska 5 S31 kidney Rweotarded Ossification (2 bil) VR w0o rwyo pRaeptialrldaed-OsSsiizefic3at(iboiln) (2 bil) wVR ssuuppeerrnnuummeerraarryy ((ssiittee 1133 x1t6)) = oDvV =Retarded Ossification (2 bil) VR SRueptearrnduemderoasrsyifi(csaittieon13 (r2e)bi|l) VDRV RPeatpailrldaed-OsSiszietic3at(iboiln) (2 bil) =VR ase717s 5.66 :32 isliss 525 sam 3 slse 0oo Rwweootarded Ossification (2 bil) WR ~ `Company Sanitized. Does not contain TSCA C1 7 25231: DevelopmentalToxicityStudyinRats DuPont-10309 ~~ TNDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS ROU 1x: 625 MG/KG/DAY oFwEtTUS0.O. FETUS WI. STRUCTURE FDI (5) cusstricaton S58A 5 (cone)5.52 s7 s5a3r9 5 S15 1nun0 5s5.i35s00i b slo vertebra wwoo Rweotarded ossitication wp'(cen th12) w xwD Eg sse7177 5.36 vertebra 2 5.71 vertebra 3 5.47 vertebra ` 5.36 vertebra s 5.16 vertebra 57 S51.3065 vertebra --_ s 5.56 vertebra 15 555.5210 vertebra 12 55.5357 subeutis vertebra n 5.29 vertebra RReett(aacrroddneedtdho1os0s-ss1ii1ff)iiccaattiioonn w Ret(acrednedthaols)sification w Ret(acrednedtho10s-s1i2f)ication w Ret(acrodnedthOis-s1i2f)ication w ww(cen th1z) w Ret(acrednedtho10s,s1i2f)ication w wRwe.t(acrednedho10s-s1i3f)ication w Ret(aerodnetdhso,ss13i)fication w wBeonorrhage (chine) RReett(aacrreddneeddthoio1ss-ss1ii2ff)iiccaattiioonn = (cen th12-13) w sser3sa sa a `CompanySanitized. DoesnotconTtSaCAiCBnI 8 H25231 Developmental Tovisty StuindRays Den1039 ~ SDIVIDUNL FETAL WEIGHTS (grass) AND ALTERATIONS Group 13: 625 vo/RG/oRE oEaEso.. res wr. _omauerons nono) cussrpraaos esen::3en (cont)IuLoEns sem een ErSeestraaiieedd ositicacion omsstication 2 5a) 251) : IE Ven .I SseetEniiexerd ]oomimticiacicon (2 bi) VR 0:55 FHiiE5e san SR5ole'ptearrmduenderoasssysci(csaicteion20(12051) ov iu so8n = ean iSRootaErod eel oastscacion a (2541) vn 3 on as es:ai s 5so8r sen Eweofaraea ossitscacion (2 55) vm fTrertoens. > sas wRReesrt(aiernniaecdaBisSaesmisit)riiccaaiioann (130) w :: iinn wFSo ~~ ::5 5BtB.3oHo3 wIwNASowD ii ooinn uuWeeo 3 BH o campenyanitzed. ossnotcontain TSCACE! 3 H25201 Developmental Tovisy Stdy in Rats Duron 10305 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS aren 221. 1250 WorKONY sEaroe.s. roms wr. _smmuers momo) cunssreronrion --:7 iszs wwoo :::3 iBiBeEt wwnnoooe 5:5 BIBeAE sen ERoSt'arod ossiticacion (2 531) i8 BatoHt wwweoo i8 iBR wwee ese1nen ss vereenss : sar vertesma RReettfaarroadeeddthoopsissniEt)hiccaatsiioonn :: r5e w5e(tin : -- --~ ` ses vestenma RReebtfaaerrndteedd onssescation Opsstication , con verte . ss wReste(aorndnetdeoro)pibsit)ication w : Br j-- 550 vertebra RReeRteaisnrceeddeatooeasrssiiiiccaattiioonn = u sso vessabr u sar wReotmeottsdnnotsioeormsiist)icasion 8i Ed ~ Company Sanitzsd. Doss onlinnotcontanTSCACBI TM H:25231: DeveloToxpicimtyeStundytinaRalts DuPont-10309 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 1250 MG/KG/DAY aFETUwS0.0/. FETUS WT. STRUCTURE FDIS) cuassteicaTion 61586709 (Cont.)5.25 vertebra Ret(aerodnedh1O1s-s1i2i)cation w sen3 s 5.56 2 S46 vertebra Rweotarded ossification (con th12) w esa1 ? 5.50 :32 s&5leo%re :5 5s5s57 ridney 67 s3i3s8 15 5S331 un Ss vertebra 1n 5.66 vertebra --_~ B 5.60 asan1az 5.97 Rib :52 sSeieaii mb 5` ssiis mRiip 83 ssiies 15 S5.3o3 mam awo 0x0 >Papiila - size 3 (0) w ary awp RReett(aacrroddneeddth1oO2ss)ssiiffiiccaattiioonn wv ES(een th1z) ww Ssuuppeerrnmuummeerraarryy ((ssiittee 1143 1bti)l) DDVV wSumpermumerary (site 14 bil) DV wSSuubppeerrnnuummeerraarryy ((ssiittee 1164 bxitl)) DDvV xwo supernumerary (site 14 bil) DV `Company Saniized. Dossnot contain TSCA CBI Br H25231: Developmental ToxicityStudy inRats DuPont-10309 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP T11: 1250 MG/KG/DAY aFETUxS0.0. FETUS WE. STRUCTURE roms) cuasstrrcation sse22 (cont) 112n ssesr u5 3s8s vertebra mRiipb am Ret(acrednedthaols)sification = mSsmuu.ppeerrnnuummeerraarryy ((ssiittee 11441r8t)) DDVV Supernumerary (site 1416) ov sse7124 saz 2 535 vertebra a3 55..2447 3s5 sSsia 2l0s sRiebn 5 S35 vereebra 5 4.97 RiKibdney 10 5.35 vertebra 1n2 a5l.s6e0 skin --~ u5 55i2s56 skal 156 5s.i8s9 uw sia Rweotarded ossification 0(cen th10) = Sbuypernumerary (site 13 1t) Dv RReDtarded Ossification (2 bl) VR Ret(acrendetdh1o2s)siication w Ssouaplelrmupampeirlalray -(sSiitzee132 7(tr)t) DVVR wReat(acrondetdhiGza)sification w wRewtarded Ossitication (2 bil) WR xRetGar6debdio)ssification = w=o ssor128 5.97 wap 32 ssilasn waoD s: 557304 wwoo s san wo --_ Company Sanitized. Doss not contain TSCACBI 2 H-25231: DeveloTorpicmityeStnudytinaRalts DuPont-10309 N INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 1250 MG/KG/DAY oFwEtTUSwfNo. _serus wr. STRUCTURE smo (5) cuassezcaTion 6567728 (Cont.)5.60 a 5 sssaoo wwpo 110 Sshaes wwoo 12 pes 3 se1m 471 vertebra 32 L5e2r7 vsekrtaebra + 5.49 vertebra s 5.4 vertebra s 5.36 vertebra 28 i5.o26 sen vertebra ~ 105 s5.a5n1 skal 2n S53321 sean Ret(acrednedthsos1s1i-f1i2c)ation w RReettaarrddeedd Oossssiiffiiccaattiioonn (2 bil) VR Ret((accroednnedtthhioizis)-p1i2t)ication w w Rettaerednedthaols)sification w Ret(acrodnedthaOls)sitication ww Rweotarded Ossitication (2 p11) VR Ret(acrednedthO12s-s1i3f)ication = 0Retarded Ossitication (2 bil) WR RRAeDtarded Ossification (2 bil) WR esam1az 5.58 25 p56eat : ls vertebra 5s 55.2035 57 isasz w0o 0Ret(aerednedthiozs)sification = Iw)o rwyo --~ Company Sanitized. DocsnotcontainTSCACBI 5) H25231: Developmental Toxicity Study in Rats DuPont-10309 ~~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP IZ: 1250 MG/KG/DAY oFnEtTUxS0.W)o. ETS WE. STRUCTURE FmDIG(S) cuassteicaTion ss87532 (cone.)5.21 0 5.02 u1n sS1n0 n1 isiee 5 sls vertebra vertebra ska RetTaerendedth1o3s)steication ww Ret(aerednedthaols)sification w wReotarded ossification (6 rt) WR NaRaDo esa1 s 5.38 23 ssiie sem a3s 5SS0sE6e sam skal 78 sisme 105 ssssso a12 sSeaes skal ~ Fe1 ssinr sem 1i ssimn kd si wReotarded ossification (2 61) WR RReDtarded ossification (2 bil) WR wReotarded ossification (2 bil) WR IwYo wwoo R0etarded ossification (2 bil) WR aRetarded ossification (2 bil) WR RwADD wo ssam7a7 s.08 32 SS5465 ssuubpecuurriies 55i 3ss5i5ae5 vertebra Hweomorrhage (left hindquarters) N =Henorzhage (chin) Rweotarded ossification (cen tha1-12) ww ~~ CompanySaritzed. Doss notcontain TSCACB! 3 H25231: Developmental ToxicityStudyinRats DuPont10309 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 1250 MG/KG/DAY oFEaTUoS.0/. FETUS Wr. STRUCTURE FnomG(s) cuassteicatIon es87737 cone.)S40 mip 5: 5sl7o n0 si0ss ska kSuspermumerazy (site 13 18) DV Rxe0tarded Ossification (2 bl) VR XD ese1rss 5.38 32 ssiisse :5a 5 i5i7ss sam 83 slSios Kidney 10H ssinm Fai 5sa6e sam u5 ssaitr 1 iss xwo ooyy Rneotarded Ossitication (2 bil) VR wpabpilla - Size 3 (bil) w wmon Raeotarded Ossification (2 51) VR aA> wo ~ esar1se 5.04 vertebra 2 5.34 vertebra 3 5.22 vertebra . 5.15 vertebra s 5.15 vertebra s 5.68 vertebra Ret(acrednedth1O0s)sieication = RReett(aacrronddeeddchO1Os1ss)siifiiccaattiioonn ww Ret(aerodnedthaOts)sitication w Ret(acrednedth1o2s)sification w Ret(acrednedtOhasts)i ication w (cen thaz) = --~ CompanySanhized. DoosnotcontTSaCAiCBnI Ts F-25231: DeveloTorpicmityeStnudytinaRalts DuPont 10309 ~~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP 111: 1250 MG/KG/DAY oFnEsTUSx0.50/. FETUS WT. STRUCTURE FnDG(s) cuasstricaTIon ase7256 (cone)4.87 5 s5i.1s6 0 S36 F1H] sSu1a8s5 3 S44 1 5.79 1s 5.32 vertebra vertebra vertebra vertebra vertebra vertebra Ret(acrednedth1o0s,s1i2f)ication w wwop Ret(acrednedth1O1s-s1i2f)ication w ERSe)tarded ossification RetTaerednedth1O3s)itication w Retcaerndedth1o1s)sification w= Ret(acrodnedthiOzs)sitication w Teen th1112) w sse716s 5.40 535 aSSl7na1e vertenra s 5.46 vertebra ~ 35 s.Si2ss o S50 vertebra 105 s5l.e7s0 Kidney Far iseeo u5 ssemr 1 3si5s wwoo Rweotarded Ossitication Ret(acrednedthiozs)sification w I)(cen tha1) w xReotarded ossification sea[clenpathpiiol)la - Size 2 (611) WwR Dx> xxxo 0I . ~~ `CompanySanitized. Does notcontainTSCA CBI 3 H25231: DeveloTopximcySetundytinaRalts DuPont-10305 \ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP TIT: 1250 MG/KG/DAY oFEeTUwSo.HO. _pETUS Wr. _sTRvCTORE noes) cuassrricaTION see21 s sl5.e7s5 i3 ssioar :5 sSl1e5s0 vertenma .7 S5.i0 vseratnebra 105 $5.50 sw 12 sslia 51by S55i17s566 vertensa wwop wwoo R3et(aerednedchiots)sification w RmReeottaarrddeedd oossssiiffiiccaattiioonn (12) WR x(Gen th10-13) w Rweotarded ossification (12) WR xfwecot RetTaerednedtaots)sification w esa1 s 5.20 ~ 32 5S1i3s6 mip / :5i ss5l1i2as 5.7 sSl23a0 u1n0 S55242 Kidney 2 sas frRiyp 51 sSl4a9 san 15 5s1i3 wSwuoopermmerary (site 1376) BV wwpd owrmd wwmooo SPuappeirlnluame-rsairzye (3sit(ebi11)3 bil) wDV RSmeubtpaerrdmeudmeOrasrsyiti(csaitteion13 (b6i1l6) DV WR wwoo `Company Sanitzed. Does not contain TSCA CB 57 25231: DevelTooxipcitmySteudnyintRa]ts DuPont 10309 --~ INDIVIDUAL PETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 1250 MG/KG/DAY oFwEtTUxS0%.0/. FETUS Wr. STRUCTURE omnis) cuasstereaton as1e 5.32 23 5is2a0 smal : LG a=m 55 5i.3s40 a' iisme 105 5H3ed9 1n2 Sslleri 5 site wReotarded ossification (2 bl) VR wSuopernumerary (site 13 1) Retarded ossification (2 bil) DVVR >wo maoo wNAoD akDg wo se1re 5.35 vertebra 2 5.26 vertebra 3 5.30 vertebra s 5.95 vertebra ~ s 5.08 vertebra s 45842 vseertaebra . as vseurbtceubtrias 1n5 55S.326400 saan 2Fl i5s2o8 i 33s Ret(aerodnedtaots)sification w Ret(acrednedtno10s,s1i2f)ication ww Ret(acrednedthOi0s-s1i1t)ication ww Ret(acrednedthaOls)sitication w RReett(aacrroddneeddtho1O0ss-ss1ii3ft)iiccaattiioonn (12) wWR Ret(acrednedth1O1s,s1i3t)ication w= HReemtoarrrdheadgeOss(icfhiinca)tion Ea){een eha1) w ARe>tarded Ossitication (12) WR >a> wo ~~ companySanitized. Doss"etcontaiTnscACEl 3 B25231:Developmental Trichy SuindRayts DuPont 10309 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS Group 331: 1250 O/KG/DAY oFowrsvo.0. seus wr. ravers noms) cunssrprearion ase31ms i5.2e6 :i3 io5ah3 ::5 $$i68e sen sen 15 Si6e5 sVeertnenra F31S Sso5s sen 2un) 2s8d san i 5 sen as7a 454 vertebra ~ i23 5ss.i5re san ::5 i pe5) 1`5 5i8e 23i 3$555 3ii SpEe2) sen nwnooo hwReootarded ossification (2 bil) WR 50Re5tarded ossification (2 Bil) WR RReetteaaerrnddeeddthioooss)ssiittiiccaattiioonn (2 bi) VR w Rrwoyocarded ossitication (2 bill VR RRreeyttaarrddeedd ossisication ossification (2 (2 bi Bil) VR WR Rwooteaexndedthioos)sitication w Rwweootarded ossitication (2 bil) wR wewodo nwwooo wWwooo nReotasded Ossitication (2 Bi wR -- Gompany Sanilized. Dossnotcontinin TMTSCACBI. H:25231: DeveloToxpicimtyeStnudytinaRalts DuPont-10309 --~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS Goup 111: 1250 Wa/xo/one oFuEtTvwso.6. _veos wr. _smavcrone somos) cusstezcaria car1es a1 vertebra Reteaerndedhioas)siication 2 sat vertebra 5 529 vertebra RReetteaaorrnddeeddhiooaan)ppiitiiccaattiioonn " ` 545 vertebra Reteeaoernnanntirsaiv)osst)icaion :s sOaRs vereanna wReot'eaorndedhioas)sitication w . 530 vertebra . sus wResteeernaeaentosnai2t)ication = : 53 Vrearatnaebyea REeifpeaiorinitsadn=ioasssiaizz)feic3at(iioln) = = 0 5.63 vertebra ww sv vertebra RRoota(eesretanesdaontooonasr1isif)iiccaattiioonn w 2 532 vertebra RetTTaeereednnedtennoisso)pniitaication = ~ 5 sar oanae RpeafpEairtairsaa )ossisziefic3at(iboiln) = asar7:es s.80 sen wReovssdea ossitication (2 bi1) WR i3: HHoeEar fwReeotarded ossiication (2 551) WR ::5 ii8ha sen Rnweootarded onsstication (2 b1) WR 1: HiA EwSo --_ CompanySaniized.Dossnotcontain TSCACBI 0 H25231: Developmental Toricity StudyinRats DuPon-10309 --~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP III: 1250 MG/KG/DAY oFEwTUwSoH.O. FETUS Wr. STRUCTURE som) cunsstercaTION eseir8s (cont)6.1 2Bn S&7320 san wReotarded Ossification (2 bil) VR wo --~ Company' `sanitized. Does no!containTSCA cal Ta H5231: Developmental Toxicity Sudy in Rats Duron 10209 ~ DTVIOUAL FETAL WEIGHTS (ams) AD ALTERATIONS anoun 2v: 2500w/eon fowrsy ge---- frre) cusszrension esari10a H53e0 elanse sai SsSeaieapriassdd- oomsmsiiizfteiiscaattiaiocvns (Fi) WW=e s sa Gemma . wn wFooioarneesShoisostiat)ication w ;:: aHii n wiwsbo :: o HeR [e== RRSaeeffauprsaieadag ooaopssstiiatteiicScaatciiBoonn 1) kd 1i0 ia owes hing w i E5 vere FeREaaxrdes ossttication w asen37io HwoA nwoo 3 si FS ~~ ::: EHiReE verte RiuepeRazced ossitication . 30 vertebra s sat vertebra setoeaornndosnShiiosoo)nsiist)heation w setatiad ohsttication 1i0 irns FwSsen sy i8i Haoi h uaseb i iE FS ~ Companyantpiozsnoet cdon.i!nTSCACB! Te H25231: Development) Toxicity Study in Rats Dupont 10309 ~ INDIVIDUAL FETAL WEIGHTS (grams) AMD ALTERATIONS GROUP 1v: 2500 WO/KO/DAY oFhsTov30.0/. vers wr. sree noms) cunssirioaTion ss1:o wpesd wmoo 5 U6 verter ` we Rweotcaezndedenioos.s1t5t)ication w ::5 iS5sT3 mney nwBaoopitla - size 3 ba) w Vertebra . sas san RReeft(aaezredndeedtdhaoOoss)ssiiftiiccaattiioonn = vertebra RetseaeirntdeedtsuO)sbsiit)ication w" w vertebra s wot vertenra RReetteaaerrnddeedtd hOOsassioit)liccaattiioonn w 1i0 5D.350 vertensa wRse'tcaerndeedhoisosri3t)ication w 2 soz woeon shiz) w ~ sser:1aa 5.5650 sen wReotarded ossitication (2 541) VE i55 i 2288 sdosen SFVaiylptaorrmemaetriaorny (csaiutdeal13age1n6es|is) BV N Sommcn Appensicular RAbossekeinnatney(,tuhra-ectaesre,aets)ophagus) 4 FeSpHmyeutreton AFbisneendt ((crheilea)fibula only) Mu . . 5.28 Semana pfuysed (76) --_ Company' SaniDoissznoetcdon,an TCos = 25231:Developmental Toxicity Sudy inRats DuPont10309 ~~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP TV: 2500 MG/KG/DAY aFETU0S H.o. _rerus wr. _steucroRs Fnmmvo(s) cuassteicaTion ess7 a (cont)5.59 vertenra 005 HSsoHdn sen verter 1 5.036 sn u1 iHE n Vseratnabra is saz RReettcaaerrnddeeddchiOOlss)ssiitiiccaattiioonn (2 bil) VR Rweot(acrednedthiOos)sitication w SaRueptearrnduemderOasrsyiti(csaittieon13 (b2ilb)il|) VDRV RReett(aacrroddneeddthiOOoss)ssiieiiccaattiioonn (2 bil) VR w a ess27ms a6.s48 ::5 2Gai5ss vertebra a` 6.E5s6s --_ : E31 verter 5 6.73 vertebra 10 6.13 verter 12 6E.0556 vertewra 1u 6a.e0s0 es1e s.62 wwwooo Rweot(acrednedthioos)sification = wwReoptarded Ossiication RetcCaeornndedeeniOads))siication w = Rwept(acrednedthO11s-s1i2i)cation = Rwept(acrednedthOas)sitication = wn wo ~ companySen `possnotoontasCACEY Ta 125231: DeveloTopvimiyeStnudytinaRalts DuPont 10309 ~~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP Tv: 2500 Ha/KG/OAY oFEiTUSv0.Wo. _peTvs wr. sTRUCTURE rooms) cusstermon sse32723 (cont)s5l7s8 skal 3:: 5 2$58 sen sen 5a7 1siies%s sen 0 1 55 5.07 Saaen 3H 1s5a7 sen ssar126 sa Vsewretuatbirsa 2 as sTeertnenra --~ :2 1w%a Vseretnebra :s 11.56 vertebra 7: sS12a5 wTmeresa 5 2.45 FTaoinvgiuee vertebra 0 5.22 RoReeyttaazxddeedd Ossitication Ossitication (2 (2 5) 51) VR VR R4ae5tarded Ossitication (2 bil) VR kSRiesptaerrdmeudmeOrasrsyii(csaittieon13 (z2t)bl) VR Dv RaRee5ttaarrddeedd Ossitication Ossitication (3 (2 1) bl) VA VR BY RHeemt(oacrresdnheadtgheOis)s(isfiigchattisoenar paw 9) X RReetteaaerrnddeedtdhiOoess)ssiitfiiccaattiioonn (2 B41) Va w R0Reettaarrddaedd OOnaasiiftiiccaattiioonn (2 bl) WR wReotcaexndednaoias1i2t)ication = sRuepteearrnnduemdthearOnas)rsyii(csaittieon13 10) OY sRreottearerundaeidtnhgGas)siication w Ret(caoercndheidtuhaO1s1sb1ii2dt))ication w w wo otcontein Tcel ~ compen pa-- Tas H25231; Developmental Toxicity Study in Rats Dupont-10309 -- INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS rove Tv: 2500 Ma/xa/oRY oFEnTUSvo.Wo. _verus wr. smucone rooms) cussteicaTion eseHneze (cone.)5.0 vertensa 2 ass TesSrawtieetentssa na sUo5n sVeuretueenteas 1s 5.06 sTeuretuetntesa 1 ss as1e 4 vertesa 2 so sVeerenenea 5 5.0 vertebsa ::. 2o5%k5 san sen Tersenra 5:. 5$561157 msban 3 20 Verena iun Uso6n vertenra s0 Rseent(oacezeednneadegeao.ts)s(tchiicnaet)ion xw RReett(aaerroddneeddonGCaso)ssiifiiccaattiioonn (2 bil) WR wHReeomtoarrrdheadgeoss(icfhiincea)tion x HReemteoarersndheadegeno.as)s(icfhiicna)tion w ws(eon that) w RReett(aaerxeddneeddchOoass)astifiiccaattiioonn (8 B11) wVE RReett{aaerreddneeddthoOasrtsaisif)iiccaattiioonn w R0et(arGdedonO)paseication (2 bi) wVR RReetteaaerrnddeeddthoOass)satitfiiccaattiioonn (2 B11) VR w ESReiStpaerrdmeidmerOasrsyiti(csahtoiroen11(86)51) VDRY 0Reb(aereanedonCia)steication = wRestcaexndedeniots)stescation = ~ pmteDosd sTH, E" SCAB! we H25231: Developmental ToxicityStudyinRats DuPont-10309 --~ INDIVIDUAL FETAL WSIGHTS (grams) AND ALTERATIONS GROUP 1: 2500 MG/KG/DAY oFwEtTU0S.0. FETUS wr. STRUCTURE snone(s) cusstpicaTIon 6sa1733 (cont)5.01 vertebra Ret(acrodnedthO1s1,s1i3t)ication ww aser1sa a9 25 5siai2 i5: SSs21a08r sen sem 78 5s.i0t5e 105 si2e7 sueutis 1 4.62 sSeuabncutis 1Fue] s3ils3o ska wNwD xReDtarded ossification (77) WR NRAeDtarded ossification (2 bil) WR wa>o aHe>morrhage (chin) Retarded ossification (2 bil) xVR Haemorshage (chint) aReptarded Ossitication (2 bil) WR aser1as 5.39 ~ 2 335 sSaaaln 3 5.97 Sel i5 s3ie 47 vertebra s 5.37 sskaaill 78 5sie.10 05 eSr3t6 xioney a12 a5l2o8s Kskiuolnley 5 alse wReotarded ossification (1) w RReettaarrddeedd Oossssiiffiiccaattiioonn ((212)bil) WVRR wxDD Ret(acrendetdh1o2s)sification w RReettaarrddeedd oOssssiiffiiccaattiioonn ((12) 11) wVR WwDo papilla - size 3 (bil) w wpadpilla - size 3 (1) w . RNeDtarded ossification (2 bil) VR --~ possrotconTM SCCAB 7 H25231: DevelopmentTaolxicity StiunRdatys DuPont-10309 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS GROUP 1V: 2500 MG/KG/DAY oFEwTswos.o. _peTus wr. _sTRvcTuRE rvs) cuasstrcaTIon esnau7es (cont)ia sSeanl Vortebra esse1re ss 23i sla seas i: SS3h2 vaertebra 7.5 5i 5.19 sen 1n1 sssiiaasz swan B1 s56s0 Vseretnebra ~ eser7so 5.03 vertebra 2 4.55 vertebra 3 5.63 vertebra 4:: sS531a87 sr a 130 Verabra RRReeetttaaarxrdddeeeddd Ooossasssiiiffiiicccaaatttiiiooonnn ((12) bil) wVR can whiz) w wwoo rwSeowdpermmerary (site 1316) OV Retcaernded2os)sification w oReptarded ossification (2 bil) WR IREoeS)tarded ossification (2 Bil) WR w0w Retarded ossification (2 bil) VR Ret(acrednede21o3s)sification w RetcaerndedthOas)siticacion = RReett(aaGrreddneeddt1oo2ss)ssiiffiiccaattiioonn w 0(Can thi2) w wRReewttaarrddeedd oossssiiffiiccaattiioonn (2 bil) WR (Gen thrim12) w --_ ast Doom 7sCACE! Gorpan5y% Tas H25231; Developmental Toxicity Study in Rats Dupont 10309 --~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS Rove 1v: 2500 He/KS/ONY oFaOtTOSwoW.o. _perus wr. _smavcroms opm 6) cssreronion sse7550 (Cont. S02 vertebra Reteaerndedeaotssaiz)tication w 5 5.25 vertebra 0 sas vertebra RReett(aaerzeddneedathOGssossiiift)liccaattiioonn w u 495 vertebra Ret(eaeezendnedcthhOaaso)aatz)Lcation w = 2 oz vertebra a sz vertebra RReetteaaarrndaeedcdhaOOzss)ssiittiiccaattiioonn - 1 saz vertebra Retceaeernnd:edcthhaOots)s1ist)ication w w is 56 vertebra 1 498 vertebra RReetteaaarrnddeeddchaOOtss)ssiittiiccaattiioonn w FS sc vertebra RetcTaeerendnedeeahOtos)n1i2)tlcation w = --~ ese77s7 3: s3$a83s5 mSSotaenmenea i:: sSih sal san 7:S Tspeoet mb 3i3 ie soas e i2n wTmi SHermeba ee 3 ia sRRueoptbeaarrrndduesmdeOOrassresyilii(ccsaaitttiieoonn16 ((z38t)1) DVVVRE aRReettaarzddeedd Cesitication osstication (2 Bi) (2501) WE VR Snnieopernumerary (site 13 20) DV wwReootarded ossitication (2 51) VR RnSelotpaerrdneudmeGrasrsyii(csaittieon13 (166) WE Ov ow -- J Doesnet tainconte!TSCACt5 B25231: Devclopmenl TosiiySy ns Duron 1030 ~ INDIVIDUAL FETAL WEIGHTS (grass) AND ALTERATIONS Gao 2: 3500 wera oPentov0.i7o. remus wr._smaucmone eons 6) conssezaason es5as (cont)La sen Ratasced oasiticasion (2341) VR esa73eo sLaE ean wHeoRuxdas ossstication (2 bil ::: iisnin hEuoSe :5 aRE. WReetearndedthoanssseication w i.: siiains seuss saWseenor (chine) 3ii iBofar 3iipop FHii iinh ---- wFFeeShurdes ossteicacion et = -- ssa37se siais wwoe 3i: ifi8o FiESS :5: iiLhE ean wWHoeetarded ossticacion @ bil) =: oIfE setinnes iHTeootruaxrceeesd onsisiticiatoionn 2 51 n wos vertebra RetEardtedtssitbtication w \ --~ ses nan ames! 0 HL25231: Development Tovisty Sy in Rats Duper 10509 -- INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS amos 1: 2500 w/KG/0AY oFEmrvwao.b. _sarvs wr. _smucrone rw cussircaion sfse3Hree cone.)1L8o Vseenin RReettaaxrddeedd ooaussittiiccaattiioonn (2 bi) VR 46 s[em= nRoetteaaorrniaeasdextCCnaa)sstiiiccaatciioonn 2 bil 1 om verterna Reeecooonnrdninttooou))sitication 1 Py wo esaI: c 3 5ia.36 wwwooo : SI verte s oa wResteazdned hcss)iication w :: LSHu Wsnen RReettoaarrnddeeddtatoCasa)sstieiiccaatiioonn (252) WR w .: s3s8o sWeen n RReitkYairzdateeds ]Coasssiisfticcaattiioonn (251) WR w -- 0 we wo esa:f s ssro wwoo 3:: Sso8ae wwwooo 5: o3aa 55 wwwionooo . 1i pie n wwoe aeitzed 008"contain ace! --~ ol 125231: DeveloTopsimeSnytinaRtls DuPon10309 --_ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS Gaon 2: 2800 o/K/3RY oFontoswo.6/. _saos wr. socom rms) asstrroon css4res (cont)Li ws supernumerary (site 331 DY as73e ios wwoo : pC -- .: ePnE san RReort(aaorrnageoddenootssipsaiisfi)iccaattiioonn (2 bi) wVR Srpermamorary (shore bin) | EV Tercera . wn vertenea RReefteaaerrnaaeeantrooinm)sslieiiccaatciioonn = ene = -: wLEs sSeertnavea wRReeottaasrdaacda oosnsaiiftiiccaattiioonn (2 bi) WR 5 PES Reteeaeesnndemstrhioiree1i3)ication w w 0 fe verter P wo mResteaorndedtrois)piication w ~ iP TPREI vTeerreetberra RseutpTaeerredmneudneenortsasetiyci(csahtoirotn13201 wBY Refaraea ossltiencion 1 est vertenea Rot(eaornodtsrotiraeeni)i)cation w = is ar versenea 055 verona RReetteaaerrnddeeddniodasa)eniitthiccaattiioonn eon ntoras) w w Es ase ws co [EB] Cy pl 0 oe 125231: DeveloTripcimtyeStnudytinaRalts Dupont 10309 -- INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS cove 19: 2500 wo/xO/OAY oFEwtovs0.b. serv wr. _smovcrone roma) cssrrioaioy asar1a0 sas vertebra RetTaexednedchoaos-sai2t)ication w 2 saz Tesretennsa RReetteaaerrndaesddthaOosss-ssaiizff)liccaattiioonn (12) Vk w a s.01 vertenra . saz sen RReetteaaesrnad:seddchooO-ssiss2ii)ftiiccaattiioonn (12) wVR Verrenra s 5.03 vertebra RReett(aaerrenddeeddthaOorsossaizi)tiiccaattiioonn = . 56 versenra ReteeaeeznnasaetnhaiOzos).aaazi)cation w w :, Hstm -- Rwest(aerodnedthoasraosst)ication w 5 5.2 vertebra 0 sa Rwest{aerednedthOiosrpaini)casion w i IE Versenra SReifpeaeorrnansuameehsraasor1lyzt)i(c4atirot)n ov w ~ 2 sa vertana 3 se vertebra RReettTaaerreddneeddeaOorssssaiisfi)iccaattiioonn w wu sa vertebma RetE Taeernd"eytdhtOos)saist)ication esa:1na 5. 3 sen wReotarded Ossitication (2 54) WR ::3 Soeokr niwoo :5 iDE6 sen iRetarded Ossitication (6 bi) WR aaron"<schCE qantas 5 125231: DeveloTopsimiyeStnudytinaRalts DuPont10309 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS Group Tv. 2500 wo/K/oRY oFEuTUSvo.6. seus we. _smaveroRe samme) cussirronnroy cser5aea (cont)1L8o esena RReettaarsaeeda oomsasiitfiicceattiioonn (2 bi) 0i sFaeo san R5eteaorndedtroaisitication (2 bi) wVR i Bd ES esan1:es fbe ar Kianey swmoall maple - size 2 BW 3 8 rHaenreta BSeafpyairtaietaa-)omsinzieic3atiiodn) w w ::. iopeEs wnwoos 5 ECaTo.reabra NRBeipbpeairxnmaimnase-roaasrsiylzetiGc3iatt1ei0o)n1a 1) wbv . sm vertebra nekeoernaerdthaoitre1s3f1ication = = ~ 05 H5.E0 J-- wResc'eaerndedtoissitication = aer:1 o 5.320 wwoo i $3 vertebra :s psta Rwesr[ardrea eossitscasson wo . :5 TiH ae wSpoernumerary (atte 10 bi) ov aan TCH cB ~ ca sented Doeots IE) H25231: Developmen) Toxics Study Rts DuPont 10209 ~ INDIVIDUAL FETAL WEIGHTS (grams) AND ALTERATIONS Grou 2: 2500 /K RY oPuvs'oi.o. revs wr. _smvemne enna cunsszrrcanson ese3nso cont.)Lao verona Rec[axaEas Tosssticasion 1ii0 iisan oiwdos 3pid iiiaa wwwoeo -- . conai sche? ~ cones San2n0%a = rr