Document JJGJopEB5vXd91BrJpryDdVJX

me 2930524 ReviDsiuopnoNnutm1b4e1r621 TRADE SECRET AR2RG. 3583 Study Title PFO (L1i4n-eDaary/BOrraanlchGeadv)a,gAePSFtOud(yLiinneMara)l,eaRnadtsAPanFdOM(iBcreanched): AUTHOR: Carol Finlay, B.A. `ORIGINAL COMPLETED ON: August 1, 2005 REVISION 1 COMPLETED ON: January 12, 2006 PERFORMING LABORATORY: E.L du Pont de Nemours and Company HaskellTM Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 USA. LABORATORY PROJECT ID: DuPont-14162 `WORKREQUESTNUMBER: 15073 SERVICE CODE NUMBER: 1025 (Rats) and 879 (Mice) ww A14P-FDOay(OLrialneGaavraBgreaSntucdhyAePidnF)MO,l(eLiRnaetasr)n, dindMiAcPeFO (Branched): RevDisuiPonoNnutm1b4e1r621 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT `This study was conducted in compliance with U.S. EPA TSCA (40 CFR 792) Good Laboratory Practice Standards, which are compatible with current OECD Good Laboratory Practices, except for the items documented below. The items listed do not impact the validity of the study. 1. Linear and Branched APFO were characterized prior to the initiation of this study. Although the characterization was not performed under Good Laboratory Practice Standards, the accuracy of the data is considered sufficient for the purposes of this study. 2. Linearfbranched APFO is commercially available and was characterized prior to the initiation of this study. A certificate of analysis was provided. Although the characterization was not performed under Good Laboratory Practice Standards, based on our monitoring, we have no reason to doubt the validity of the analysis. StudyDirector: `Carl Fiinqley, B.A. Hask`eSlelniLoarbSotraaftfoTroyxfiocrolHoegailstth and Environmental Sciences = dy g- 2607 -_-- AP14F-DOsy(LOirnacaGr/aBvraagnechSed)d, AiPnFMOal(e RaLts ainadndMniAcPeeFO(aBra)nche,d): ReviDsuiopnoNnutm1b4e1r62| QUALITY ASSURANCE DOCUMENTATION Report Number: `Work Request Number: Study Code Number: DuPont-14162 15073 1025 (Rats) and 879 (Mice) "The conduct of these studies has been subjected to periodic Quality Assurance inspections. The dates of inspection are indicated below. Phase Audited Conduct: Report/Records: Audit Dates Date Reportetdo Date Reported to Study Director Management 4 Mar 2004 25 Mar 2004 28-31 Mar 2005 4-5 Apr 2005 6-7 Apr 2005 6-8, 11-12 Apr 2005 6 May 2005 15,17, 18,19 Jul 2005 4 Mar 2004 25 Mar 2004 1 Apr 2005 5 Apr 2005 7 Apr 2005 13 Apr 2005 6 May 2005 19Jul 2005 4 Mar 2004 25 Mar 2004 12 Apr 2005 11 Apr 2005 7 Apr 2005 6May 2005 9 May 2005 29Jul 2005 Reported by: Amer. ReA igel Quality Assurance Auditor [-AvDeat-e 2005 _-- AFFLoc), AFe OLinar ,nd ATEBi -- on CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study. Aa ------,Cl3 aZg,ht," naiirraee 7oGrylATYEEN DiplomateA.C.V-P. . 29-Tbarl 200 auHi ld Bichon MesrepentsbyM : reeaer =Asg-3005 srt Jos eR TmosT h eapSunzeos IssuedbyStudy Director: lamaniLnateel Lofg10 of eT A1P4F-ODa(yLOinrcaarG/aBvraagncehSedt)u,dyAiPnFMOal(eLiRnaetasr)n, dandMiAcPeFO (Branched) RevDisuiponoNnutm1b4e1r62| TABLE OF CONTENTS Page GOODLABORATORY PRACTICE COMPLIANCE STATEMENT... 2 QUALITY ASSURANCE DOCUMENTATION... CERTIFICATION cco LIST OF TAB-LRATES S vrais LISTOF TABLES -MICE. ism---------------] LISTOF FIGURES - RATS. iss----------" LISTOF FIGU-MRICEE.S sp LISTOFAPPENDICES - RATS vcr mm LISTOFAPPENDI-CMEICSE wns erin DATES... m---------- 9 RECORDSAND SAMPLE STORAGE... ra------ MANUFOSRPUCBLIRCATIIONPTccc mmm) ABSTRACT tbmmmmmsmesmmmmmssmmtssssinmmmmgmmmdl INTRODUCTION sss mmm MATERIALSANDMETHODS cvs 13 DISCUSSION cosmid ACKNOWLEDGMENTS ...c.ccosvssnssnsnerssrensmsmsnsnmmsassssnsssnsssn 2S REFERENCES ..cocvrssssssesmsssssssssssessssssssmssssnenensssenssnsonosn 26 FESA TRBUES cms RATTABLES ......... arnsm---------- ELE J RATAPPENDICES ovens 86 MOUSE TABLES vrsnesessssessssssssssssnssensnnsonsosonsnss 229 MOUSEFIGURES css212 MOUSEAPPENDICES. 216 Ex A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetars)i,nadndMiAcPeFO (Branched): RevDiusipoonnNtum1b4e1r62| LIST OF TABLES - RATS Page TablIe HomogeneiVetrifiycat/ionCanodStnabicliteyAnnalytsisafortRaitSoYn vd Table2 RecofoH-2v4921e,H2r631y3, 26225 Added 0 Dosing Vehicle for Rat SY... Table CRoncAentrSation Verification and Siltyof 24921, H-26315, H26225inDing Solutions fosr ll Tabled SummaryofDosingSuspensionAnalysesforRaStudy. a Tables Mean Body Weights(8) ofMaleRatsDosed ithAPFO (LINGUBEARChed)...vvvvv dS Table Mean BodyWeights (g) ofMaleRtsDosed with APFO (LINO). Table? Mean Body Weights (8) of MaleRatsDosed ithAPFO(BFaICHed) v2 Tables Mesn Body Weight Gains () of MaleRatsDosed with APFO (Linear/Branhed) st Tabled Mean Body WeightGains () of MaleRatsDosedwith APFO) (LIA) v6 Table 10. Mean Body Weight Gains (5) of Male Rats Dosed with APFO (Branched) 58 Table 11 MeanDaily Food Consumption (gday) by Male Rats Dosed with APFO (LinesiBranched), Table 12. MeanDaily Food Consumption (gay) by Male Ras Dosed withAPFO (Lines). 61 Table 13. MeanDailyFoodConsumpion(g/day)by MaleRatsDose with APFO (Branched).. 62 Table 14. MeanDailyFood Efficiencyof MaleRatsDosed withAPFO (LIneat/BFanched).......vvv 63 Tabl1e5 MeanDailyFood Efcencyof MaleRatsDosed withAPFO(LID)... 6d Table16. MeanDailyFoodEfficiencyofMaleRats Dosed with APFO (Branched) os Table 17 SummaryofClinical Observationsfor Mal Rats Das with APFO(Linea Branched).. 66 "Table 18 Summary ofClinical Observationsfor Male RtsDose with APFO(LIBR)... 67 Table 19. SummaryofClinical Observationsfor Male RatsDose with ABFO (Branched). 6 TabIE20. PercentSurvOFiMavlaRalt ccs 10 Table21 SummaryofClinical Chemistry Vales for Male Rats Dosed with APFO (Lineas/Branched) 1 Table 22 SummaryofClinicalChemistyValuesfor MaleRtsDosed withAPFO (Linea) cc 72 Table 23 SummaryofClinical Chemisty Values for Male Rts Dosed withAPFO (Branched) cvT3 Tabl2e4 MeanFinal BodyandOrganWeights for Mal RatsDose with APFO (LineaBranched) ........74 Tabl2e5 MeanFinal BodyandOrganWeightsfor MaleRats Dosedwith APFO (Linear). send Table 26 MeanFinal BoanddOrygan Weights forMal Rats Dosed with APFO (Branched). 16 Tabl2e7 IncidencesofGross Observations in MaleRtsDosed withAPO (Linear/Branched). mn Tabl2e8 IncidncesofGross Observations inMaleRatsDosed withAPFO (Linea). 78 Table29. IncidencesofGrossObservations inMale Rts Dosedwith APFO (Branched) 7 Table30.SummryofPeroxisomal Beta-Oxidaion ACKvity inMale Rat... 50 Table 31 Summaryof % Relative Liver Weights in MAIeRA... To A14P-FDOay(LOirnaelaGra/BvraagnechSetdu),dyAiPnMFaOl(eLRianctasra),nadndMiAcPeFO (Branched): RevisDiuoPnoNnutm1b4e1r62| Table1 Table2 Tabl3e Tabled TableS Table Tabl7e Table Table Table 10 Table 11 "Table 12 Table 13 "Table 14 Table 15 Table 16 "Table 17 "Table 18 Table 19. Table 20. Table 21 Table 22. Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table31 LIST OF TABLES - MICE Page Homogencity/Concentation Verification and Stability AnalysisforMouse SY rv 231 RecoveryofH24921, H-26313, H.26225 Added to Dosing Vehicle for Mouse Study 232 HConcOentSraUtiBon VerificationmandoStanbilitiyofeH-2s4921, H-26313, H-26225 in DosinngeSolutions for 233 SummaryofDosing Suspension Analysis for MOUSE SWAY vernon 235 Mean Body Weights (g) of Male Mice Dosed with APFO (Linear/Banched)........ 236 Mean Body Weights (g) of Male Mice Dosed with APFO (Linear)... orn 238 Mean Body Weigh(gt)osf Male Mice Dosed with APFO (Branched)....... smd Mean Body Weight Gains (g)of Male Mice Dosed with APFO (Linesr/Branched)...... on Mean Body Weight Gains (g) ofMale Mice Dosedwith APFO(Linear)... on20 Mean Body Weight Gains ()ofMale Mice Dosed with APFO (Branched) ........ wenn Mean Daily Food Consumption (g/day) by Male Mice Dosed with APFO (Lincar/Branched), 28 Mean Daily Food Consumption (giday) by Male Mice Dosed with APFO (Linear). 249 Mean Daily Food Consumption (giday) by Male Mice Dosed with APFO (Branched) ............250 Mean Daily Food EfficiencyofMale Mice Dosed with APFO (Lineat/Banched)..........e. 251 Mean Daily Food EfficiencyofMaleMice Dosed with APFO (Linear). sminnB3 Mean Daily Food EfficiencyofMale Mice Dosed with APFO (Branched)...... wont SummaryofClinical Observations for Male Mice Dosed with APFO (Lincar/Branched). 254 Summary ofClinical Observations for Male Mice Dosed With APFO (Linea)...ccsvrvvrrvn 256 SummaryofClinical Observations for Male Mice Dosed With APFO (Branched). 258 Percent Survival ofMale Mice cv comand SummaryofClinical Chemistry Values for Male Mice Dosed with APFO (LincarBranched)..........261 SummaryofClinical Chemistry Values for Male Mice Dosed with APFO (Linea)... 262 SummaryofClinical Chemistry Values for Male Mice Dosed with APFO (Branched)... 263 Mean Final Body and Organ Weights for Male Mice Dosed with APFO (Linear/Branched) ......... 264 Mean Final Body and Organ Weights for Male Mice Dosed With APFO (Linear) ever 265. Mean Final Body and Organ Weights forMale Mice Dosed with APFO (Branched)... 266. IncidencesofGross Observations in Male Mice Dosed with APFO (Linear/Branched).....267 IncidencesofGross Observations in Male Mice Dosed with APFO (LIN)... 268. IncidencesofGross Observations in Male Mice Dosed with APFO (Branched)... 269 SummaryofPeroxisomal Beta-Oxidation ACUVity in Male Mice... 210 Summaryof % RelLaivteriWeivghets in Male Mice .......corvnnsonnn lit =e A14P-FDOay(LOirnaclaGrafBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetars)a,nadndMiAcPeFO (Branched): RevisDiuoPnoNnutm1b4e1r62| LIST OF FIGURES - RATS Figure1 Mean BodyWeightsof MaleRatsDose withAPFO (LInat/Branched). Figure Mean BodyWeights of MaleRatsDose WithAPFO(LINEA)... Figure 3 Mean Body Weights of Male Rats Dosed with APFO (Branched) Page vor 83 88 8s LIST OF FIGURES - MICE Page Figure1 Mean Body Weighsof MaleMiceDose withAPFO (Linat/Branched) vorrei 213 Figure? Mean Body Weightsof Male MiceDosedwithAPF (LIBGA)....vvvvrvrvr 214 Figure Mean Body Weightsof MaleMiceDosed withAPFO (BIANCHCA) verre 215 AppendiAx ADPEndixB AppendinC Appendix D Appendix E AppendiFx AppendiGx AppendiHx LIST OF APPENDICES - RATS Page Individual PFOASerum COncentatfoirRoants... 1 IdiBovdy WiEIgdhts aorRlat. 98 IndFoiod vConsiumpdtionufoarRatls. ssmmm--0 Individual Clinical Observations and Mortality Records or Rats 120 Individual Animal Clinical Pathology Data for Ras. 137 Individual Animal Body and OFgan WEghts or Rats... 166 Individual AnimalGross OBSSIVfoAfROaNtS vrs ATT dividualRat Bea-OXADARRO.N.. 21S AppendiAx. APPEOAiXB AppendiCx AppendiDx AppendiEx AppendiFx AppendiGx AppendiHx APDPERIRT LIST OF APPENDICES - MICE Individual PFOASerum CORCENTfoAr Ons MIC... Pa2g1e1 IiBodd yWIEa0) Mice. 383 IndFoiodCvonsiumpdtioun oarMilce. I IndividualClinical Observations and Mortality Recordsfor Mice mmm Individual Animal Clinical Pathology Data for Mice wei IndividualAnimalFinal Body andOrgan WeightsforMice ccc 335 Individual AnimalGrossObservatfoirMoincse. nim Individual MouseBeta-OSidaton Dat... wosmmni8H8 REVO1 consis a re A14P-FDOay(LOirnaclaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasra)nadndMiAcPeFO (Branched): RevisDiuoPnoNnut-m1b4e1r62| Rat Study Initiation Date: Rat Study Completion Date: Mouse Study Initiation Date: Mouse Study Completion Date: DATES January 22, 2004 See report cover page February 25, 2004 See report cover page: RECORDS AND SAMPLE STORAGE Specimens(ifapplicable), raw data, the protocols, amendments, and the final report will be: retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware. meee APFO (Lincar/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number | DuPont 14162 MANUSCRIPT FOR PUBLICATION - A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): RevisDiuoPnoNnutm1b4e1r62| CLIONMEPAARR,AOTRIBVREARNECSHPEODNSAEMSMOOFNRIAUTMS PAENRDFMLIUCOEREOXOPCOTSAENDOTAOTELI(NAEPAFOR)/BRANCHED, Scott E. Loveless+," Carol Finlay, Nancy E. Everds,* Steven R. Frame, Pete J. Gilles John C. O'Connor,* and Gerald L. Kennedy" #* DDuuPPoonntt HNuatsrkietlilonLaabnodraHteoalrtyhf,oNreHweaarltkh,aDnEd,E1n9v7i1r4o.nment Sciences, Newark, DE, 19714 ABSTRACT oAfmlminoenariuanmdpberrafnlcuhoerodoicstaonmoeartsei(naAratPiooaFfaOfpoprr)moerx,liymatuesleyd i8n0t:h2e0 (plriondeuacrtfoiroannocfhecd)o.mmeTrhceieaxltepnrosdiuvcetst,oxwiacosloagmiicxture database for APFO has been developed essentially using this mixtureof isomers. The current production of APFO ubiolsoagsiycnetachtesitviitcyoprfolciensesatrh/abtrapnrcohdeudceAsPoFnlOywtihtehltihnaetarofilsionmeearr. ATPhFeO.preIsnenatddsittuidoyn,waasfournmdeorftaAkPeFntOo ccoonmspisatrientgohfe only b3r0amngch/ekdgomfoeletchuelresthwealsinaelasro/ebvraalnucahteedd,.liRnaetas,oandbmrainccehewderAePgFivOenfodros1e3sdabyys.oraCllignaivcaalgesirgannsg,ibnogdfyrowmei0g3hst,o food cooxnisduamtpitoino,n,nsdelsecetreudmhPemFaOtAolcoognyceanntdrsaetirounmslwiepried epvaarlaumaetteedrsf,oriveearchanodf tkhiedntehyeewetiegshttmsa,theerpiaatlicinpearcoxhiosfomtahel two. brordaenncthesdpecAiPesF.O.ClMineiacanl bsoigdnyswweeirgehtgsenweerraell1y9u,n1r9e,maanrdka5bl%elionwreartsthaanndtmhiatcoefdocosnetdrowlisthinliantcsardfobsreadncwhietdh,l3i0nemarg,/korg o1f8,lianncdar3/%bralnocwheerd,thlainneatrh,ataonfd cbornatnroclhse,drAesPpFecOti,verleys)p.ectEixvevliyv.o Shiemmiollayrscihsawnagesssweeenreinprraetssenbtuitnnmoitcmeice(.meaInnsrawse,retot2a1l, dcheoclreesatseerdolt,oaHDsLi,mialanrdnexotennHtDwiLthchtohlelsitneeraorlfdoercmreparsoedsuwceinrge parroedsupcoendsebaytaalll3owmeartedroisael.s.InTrmiigcley,cearlild3esfowremrsereduced tbootchonttortoalloarnddeHcrDeLascehdolaetsttheerohligshiemsiltadrolsyeb.utL,iuvnelrikweeiignhttheinrcatr,eatsreisglwyceerreidseesenweirnebointchrsepaesceideastwliotwh dalolsetsh,ebeutfosrimmsi.lar mIantcerreiaals.ed hInepmaitciec,Ba-lolxdiodsaetisopnraocdtuicvietdy iwnacsresaeseend ihnepbaottihcsbpeetcai-eosxibduattiwoansalcetaisvtitpyrwointohunlictetldeidifrfaesregnicveennottheedberiathnecrhbedy mTaitneerairaflbrfaonrcmhetdeastneddborradnocshe.edImnatrearsi,als,earnudm2P0FpOpAmlaetvetlhsewLeOrEeLapoprfoxi0.3mmayte/lkyg5f0orptphemlaitnetahremLaOteEriLalof(L| OmELgS bafsored (p0r.3imamrgi/lkygu,pboansleidpiudppoanralmiveetserw)e.ighI)n,msiceer,umsePrFumOAPFleOvAelslewveelrsev1e0r-e14sipmpiml.ar fIonrbaollth3rmaattsearinadlsm.iceA,ttthhee LovOerEalLl rleessspopontseenst.otBhaseldinocnartihbersaencrheesdusa,ndthtehetolxiinceoarlofgoircamls doaftPabFaOseAdweevreelospiemidlaprr,imbauriltyhefbrroamntcehsetdinfgolrimneaaprpbearrasnc0hedbe APFO is applicable to linear APFO. Key Words: APFO, PFOA D"TEo 1w9h7o14m-0c0o5r0r.espEmoanidle:ncsecsohto.ulldovbeeleasdsd@ruessas.edduaptoDnutPcoonmt Haskell Laboratory, 0. Box 50, Elkton Rd, Newark, - APO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-DayOralGavage Study in Male Rats and Mice Revision Number 1 DuPont14162 INTRODUCTION Ammonium perflucrooctanoate (APFO; FC-143, Cs, C1Fi{COONH,', CAS Registry No. 3825-26-1) is a surfactant usedasaprocessianigd in the production of fluoropolymers. Perfluorooctanate (PFOA; C1F(sCOO), the dissociation product of APFO, is notmetabolized (Vanden Heuvel etal. 1991) and has been identified in blood `samples from exposed workers and the general population (Taves et al., 1976; Hansen etal. 2001: Olsenetal, 2003). Alarge databaseofexperimental studies on the potential health hazards ofPOA is available,a are recent toxicology reviews (USEPA, 2002; Kennedy et al. 2004). In addition 0 toxicology studies in laboratory animals, the potential associationofAPFOexposure with health effects in fluorochemical production workers has been Studied since 1976 through medical monitoring and epidemiological investigations (Ubel et al. 1980; Olsen tal, 1998, 2000). Clinical laboratory evaluations including liver tests and hormone concentrations (2. estradiol,testosterone, and cholecystokinin) havebeen normal (Olsenetal, 1998, 2000). A form of APFO containing both linear and branched components (generally ina ratioof 70-80% linear, 20-30% branched; denoted a linearbranched) has been used in studies to evaluate many biological endpoints. Numerous repeated-dose studies have been conducted with linear/branched APFO in a varietyof species (mic, rats, and monkeys), and these have been reviewed recently (Butenhofeft al. 2002; Kennedy et al. 2004; USEPA, 2002). Together, thse studies demonstrat tht liver isthe primary target organ for APFO toxicity. The hepatic changes include increased liver weights due to hepatocellular hypertrophy and proliferation of smooth endoplasmic reticulum and peroxisomes in rodents. Other effcts observed in rodents include body weight decreases, increased kidney. weights (without histological correlates), and hypolipidemia (decreased triglycerides and cholesterol) in mice. (Xieetal. 2003). Studies evaluating genotoxicity, reproductive toxicity, effects on the developing organism, and carcinogenicity have also usd this material (reviewed in Kennedy et al. 2004). "The purposeofthe curent study was to determine ifthere are substantial differences in the toxicity profile in rats and mice, based on selected endpoints, among the 3 formsofAPFO (linearbranched, linear, and branched). The test materials studied were linearfranched APFO (78:22), lineas APFO, and branched APFO (58:42 blendofthe: 2 most prevalent branched forms in linear/branched APFO). Doses for rats and mice were chosen ranging from those expected to be at or near no-observed effect levels to those expected to producecleareffects. This study focused specifically on evaluationofbody weights, serum lipid profiles, liver and kidney weights, and hepatic beia-oxidation. Tis APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number | DuPont14162 Test Materials MATERIALS AND METHODS Linear/branched APFO was provided by 3M Company, Specialty Materials Manufacturing Division (St. Paul, MN). "This test material was 77.65% linear. Mole percentsofbranched content were as follows: 12.6% internal monomethyl (non-alpha); 9% isopropyl; 02% rert-butyl;0.1% gem-dimethyl; and0.1% alpha monomethyl. The certificateof analysis indicated 2.01% lesser-homlog (C.-C) impurities. Homolog distribution was as follows: Cu 001%: C4, 003%; Cy, 043%; Cs, 0.57%; Cy, 97.99%; Cs, 0.16%. The sample aso included 0.09% monohydro APFO, 0.725% monounsaturated APFO, and 0.3% undefined material that was possibly substituted perfluorocyclo species (0.2% cyclopentyl and 0.1% cyclohexyD. This test material, a white solid, was 97.99% pure. Linear and branched APFO were provided by DuPont (Wilmington, DE). Linear APFO was a white to slightly `opaque liquidin 20% aqueous solution. Branched APFO was a white solid. 1t waspreparedby combining 58.3% Ammonium 2.2.34.4.55.6.6.17,1-pentadecafluoro-3-(ifluoromethyhep(ainntoearntael mono methyl-non alpha) (referred as Branch A) with 41.7% Ammonium 22,3,3.44,5,5,6.1,1,7-pentadecafluoro-6(siflaoromethyDheptanoate (isopropyl (referred t 1s Branch B) The Branch A material was a mixtureof3- and methyl ina ratofi9o235. Animals and Husbandry "The research described in hi study was conducted in a aboratory accredited by the Association fo the Assessment and AccreditationofLaboratory Animal Care (AAALAC) International and the investigators complied with the regulations and standardsofthe Animal Welfare Act ind adhered to th principlesofthe Guide for the Care and Use: ofLaboratory Animals. MaleCr:CD*(SD)IGS BR rats and Crl:CD-1(ICR)BR mice were obtained from Charles River Laboratories, Inc. (Raleigh, North Carolina). All ras and micewere housed individually in stainless steel, wire-mesh cages suspended above cage boards. Animal rooms were targeted at a temperatureof 22-24C and relative humidityof40-60%, and were artificially illuminated (fluorescent ight) on a 12-hour light/dark cycle. Thioughout the est period, LLC Certified Rodent LabDiet 5002 (PMI Nutrition International, Inc., St. Louis, MO) and tap water were available aa libitum. Prior o testing, rats and mice were evaluated by clinical observations and body weight determinations durai4-ndagy quarantineperiodtoassure freedom from potential confounding variables. Experimental Design At approximately 8 weeksofage, ras and mice were selected for the study on the basisofadequate body weight gain and freedom from clinical signsofdisease or injury. The animals were randomize ito 6 groups of 10 male: animals 50 that there were no statistically significant differences among group body weight means. Each animal was assigned an identification number which ws recorded on a card (ats) or label (mice) and affixed to the cage. The -_-- A14P-DOay(LOirnaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Revi`sDiuonPoNnutmb14e1r62| animals were tattooed withth identification number. Each tet group was administered one ofth test materials at daily doses of either 0,03, 1,3, 10, or 30 mg/kg. Studies with each test material were run a5 separate experiments, ach with ts own control group. The dose ofthe test material administered to the animals was adjusted for the percentageofactive material (APFO) such tha thedose of APFO was the same. The study was conducted in `compliance with U.S. EPATSCA (40 CFR part 792) Good Laboratory Practices Standards. `Control ofbiss was minimized by using a concurrent control group for each test material, starting each sub-study within one or twodaysofeach other, having identical study designs, and having day-to-day activities performed by a small pool of personnel. Interanimal variation was minimized by using animals in good healthth same age, of appropriate body weight range, and by randomly assigning animals 0 groups. Test Material Administration All test materials were prepared in NANOpure water for dosing. The rats and mice were dosed by intragastric intubation for 14 consecutive days ata volume of 10 mL/kgofbody weight. Control rats and mice received NANOpure water oly. The animals were dosed at approximately the same time each day. Individual dose: volumes were calculated using the body weight obtained prior 0 dosing AnalysisofDosing Preparations `Samplesofdosing preparations for linear/branched, linear, and branched APFO at concentrationof0, 0.03, 0.10, and 3.0 my/mL were analyzed for uniformityofmixing/concentration verification and stability. Concentrations of compound were measured by high performance liquid chromatography tandem mass spectrometry LC-MS/MS. In Vivo Parameters Body weights fo all ras and mice were recorded daily. Observations for clinicalsignsof oxicity and mortality were conducted at least twice daily throughout the study. Food consumption was measured twice weekly during the study. Body weight gains were calculated from day 0 0 day 13. In addition for mice, body weight gain was normalized for differences in liver weights using the following formula: final body weight - liver weight) - (bodyweightday 0 - mean weightofgroup A control livers) Collection, processing, and analoyfbslioosd and tissues Blood samples for clinical pathology and serum PFOA measurements were collected approximately 24 hours afer the lastdoseofAPFO, The orodfbelorod collection and euthanasia was stratified across dose groupsforeach test material; animals dosed with a given test article were sacrificed on the same day. Afer final body weights were determined, animals were anesthetized by CO;anesthesia, and blood was collected from the orbital sionfeuacsh rat and mouse, and from the abdominal ven cavaofeach rat. Animals were euthanized by exsanguination while under anesthesia. Livers and kidneys were removed and weighed and relative (1 body weigh) organ weights were calculated. ET A1PFO-(OrLsDiGnaveaagaeSByryaAPinnFMcOi(heLiRevadetss,)n,dandMAiPeFO (Branched RevisDiuopnoNnutm1b4e1r621 Clinical Pathology Evshation On the rst day of eopsy forts dosedwith ineabranched APFO, a dose-related increase in the incidence of bemolysis was noted the nial snus blood samples. In order ofr evalu Gis finding of hemolysis, blood meses were prepared fiom additonal blood colctd rom the abdominal vena cava fom al remaining ras half of the ails vested with lsysnshed APFO, ad al he ails rested with ther ines: APFOo branched APFO). WeightGiemsastained blo smears wer examined microscopically for calation of ed blood cel morphology Ser from orbital snus samples wer used or th determinationofpid parameters nthe mouse, and for concentrations of test material nthe mouse an 8 sored frozen 80C unl alyzed) Ser rom bdomial vn cava samples wer sed forthe determinationofid parmeers i the rt vem cava samples were es hemoyzed than orbital snus samples. thy were used minimize potential inrfbryheemnoglcobein with ---- Serumlipid parameters cholesterol, HDL cholesterol, non HDL chlestero cleulated), and wigycerides] were determined on an Olympus AUS40 clinical chemistry analyzer (Melville, NY). Hepatic Peroxisomal oxidation Evaluation Atnecropsy, a ection f ve ws removed fom 10 nial group and heptsperoxisomes were prepared or oxidation alysis, mesureofperoxisome prlferaton. A postionofthe vr was homogenized (1 sie mL bff for ts or ml buf for ice) in buffer coining 50 mM TiHCI, 50 mM Trigma-base, 025 M ella sucrose,daenbdi5..4mThMe EreDsuTlAti,ngpsuHpsm7.4.stTahnes hvoemroegreenmatoevsedwearned ccennrtriiffuggeedd astt 1155,.000000 xx gffoorr 1153 mmiinn aatt 44C;ttohreesemove elles conined he prcxisoml factions. The peroxisomal pellets were resuspended in homogenization buffer and sorset 50C ui alyzed. Pros suspensionsvere di 0prd otein concenzation of proximately 0.25 mg/mL (at) or 0 mpm. nice) or anys. Peroxisomal oxidation att vas determined using [CIpalitoy CoA a th substrate (Lazarow, 1981). Protein content of the peroxisomes was termined befor nd aftr analysis by the Biorad method (Brdird, 197), Fina rte calclaions were made using the postassay protein concentrations. Analytical Procedures Concentrationsof ranch and ina PROA were measured nt an mouse blood serum samples wing a modified version of th method decribed in Flaherty (2009 Brel, aceon was add oan aliquot f boo Serum added to 0 precipitate protein and e cach samp to ciliate xtract PFOA iso quantification. mers. A stable i The spe was sotope internal thn analyzed standard (dual "C-PFOA) by reversed-phase iid was. chromatoaphy with mass spectrometric detcion. HPLC conditions were adjusted ota somers i the branched APFO (Branch A and ranch B) ver parisly resolved from each the nd rom lar PEOA. This adjustment ET APFO (Lincar/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number | DuPont14162 also permitted partial resolutionofthe componentsof the mixed incarfbranched test materia. In all cases, the: resolution was adequate to permit individual quantification of linear PFOA, Branch A, and BranchB isomers. The mas spectrometer used was equipped with an electrospray interface operating inthe negative ion mode anda triple quadrupole (LC/MS/MS). The perent-to-daughter ion transition represMe--nCtOi;wnags monitored for all analytesandthe internal standard. Thelimitofquantification of the analytical method was5 ppb. For lineafbranched APFO, the serum concentrations of linear and branched APFO were added to determine the toal PFOA concentration and the ratio of branched to linear was calculated. For branched APFO, serum was analyzed separately for the2 branched isomers and added to determine tota serum PFOA concentration. The ratio of branched mateials (A to B) was calculated. Statistical Analysis For each form of APFO preliminary tests were conducted for homogeneityof variance (Levene, 1960) and normality (Shapiro-Wilk, 1965). If data were normally distributed and had homogeneity ofvarianaocnee-swa,y analysis of variance (Snedecor, 1967) was conducted, followed by Dunnett's test (1964). For data that did not show homogeneity of varianacroebsus,t version ofDunnet's est (1980) was used. Non-normaly disributed data was. analyzed by non-parametric procedures (Kruskal-Wallis test (1952) followed by Dunn's test (1964). Significance. wasjudged at p<0.05. To compare the three formsofAPFO at each dose a two-factor fll factorial ANOVA with dose and formulation was used asa preliminary analoyfseaicsh response. The Shapiro-Wilk (Shapiro and Wilk, 1965) and Levene tests (Levene, 1960) were used to assess normality and variance homogeneity, respectively, for cach response separately. `Where appropanrorimaalitzieng,, variance stabilizing transformation of th response was used, usuallay logarithm or square-root transform. The error term usedwhen comparing dose groupsfromdifferent compounds included both the pooled within-group variance and the between-experiments variance. The thee controls were used to estimate the between-experiments variance.REMLestimates (Searle etal, 1992)ofthese variance components. were obiained using SAS 9:2 Proc Mixed. Differences between formulations at each dose level and dose effects within each formation were then obtained from contrasts within the 2factor ANOVA. In addition to the comparisons discussed above, regression analyses wer also performed to distinguish whether there were statistical differences among the 3 APFO test material for each endpoint. These analyses were done using both administered dose vs each endpoint as well as individual serum concentrations vs. each endpoint n order to smooth the dose response. Each endpoint was modeled, using a polynomial ofdegree 1,2, or 3 with separate intercepts, slopes, and curvatures. Backward elimination methods were used to determine which terms were retained in the final model. If adjustments to thej-th order term,j=1, 2, 3, for diffrent test substances were retained on this basis, then the overaljth order term was likewise retained whether or not it was significant - see Pack (1993); USEPA (1995); See and Baylor (1998); Kalliomaa et a. (1998); and Slob (2002). ST AP14F-ODay(LOirnaclaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadrMdiAcPeFO (Branched): Revision Number | DuPont14162 RESULTS Rats Clinical Signs/Mortality All rats dosed with the 3 APFO test materials were feeofclinical sigas oftoxicity and survived unil th endofthe: study. Body Weights and Body Weight Gains `Statistically significant reductions in mean body weights were observed in rats dosed with 30 mg/kg linear/branched orlinear APFO. The changes were associated with statistically significant lower body weight gains in rats dosed with 210mg/kgof inear/branched APFO (Table 1). Mean body weightsofrats dosed with 30 mg/kg Jinearfbranched or linear APFO were 73 and 69%ofcontrol at mid-study (test day 7). respectively, and 81% of control for both at the endofstudy (est day 13). Mean body weightsofrats dosed with 10 mg/kgoflinear/branched APFO were 89%ofcontrol only on test day 13. Overall body weight gains (test days 0-13) were 55 and 225 of contol, respectively, in ats dosed with 10or 30 mg/kg linearbranched APFO, and 74 and 15%ofcontrol, respectively, in rats dosed with 10 or 30 mg/kg linear APO. In ras dosed with 3 mg/kg linearAPFOor 30 mg/kg. branched APFO, there were slight, albeit statistically significant, decreases in mean body weight gain (74-76% of controls) that did not result in statistically significant decreases in mean body weights. Overall, the magnitudes of the decreases in mean body weight gain in rats dosed with lineat/branched APFO and linear APFO were similar, while the magnitude ofeffect in ras dosed with branched APFO was less pronounced. Food Consumption/Food Efficiency Mean food consumption and food efficiency (test day 0-13; data not shown) in rats given 30 mg/kgofcither linearfbranched of linear were similarly reduced (food consumption was 73% and 78% ofcontrol, and food efficiency was 24% and 185% ofcontrol, respectively, for linear/branched and linear APFO). With the branched `material, both food consumption and food efficiency were approximately 90% of control (nt statistically significa). AnalysisofDosing Preparations "The resultsof analysis indicate that branchedlinear, linear, and branched APFO were at the targeted concentrations, adequately mixed, and stable in the vehicle. No test material was detected in the control (0 mg/mL) samples Hematology Numerous serum samples from al treatment groups were hemolyzed, and hemolysis increased with increasingdose (data not shown). Hemolysis in control samples was never greater than trace. Ina given rat, hemolysis was more severe in serum samples from the orbital sinus compared ( those from the vena cava. Hemolysis greater than a A1P4-FDOay(OLrianleaGraBvraagncehSetdu)d,yAiPnFMOal(eLiRnaetars)a,nadnMdiAcPeFO (Branched): RevisDiuoPnoNnucm1b4e1r62| respective control values was observed in vena cava samples from ras dosed with the linearfbranched and linear APFO at doses 23 mek, and with the branched APFO at doses of 10 and 30 mg/kg. Hemolyss greater than respective control values was observed n obial sinus samples from rats dosed with linearbranched APFO at 0.3 mk, with near APFO at dose 21 make, and with branched APFO at doses 23 make. To investigate the cause ofhemolysis, red blood cll morphology was evaluated on all available peripheral blood smears to determine whether or not the hemolysis occured in vivo (prio 0 blood collection) oronly in vir (during blood collection or processing). There were noucatmentrelated changes in polychromasia, suggesting tht hemolysis occured only during blood collection, not in vivo Treatment elated increases in acanthocyts were observed on the peripheral blood smears of rats dosed with linearbranched and linear APFO at doses 23 my, and with the branched APFO at 10nd 30 mks. Treatment: related increases in poiloeytes or schistoctes wer observed i at dosed ith lneafbranched and branched APO only at he 30 mg/kg dos, and n rts dosed with linear APFO at doses 23 mg/ke. Although for ach chemical form there appeared 10be dos.response, acanihocyes,pikilocytes, and seistoeyes were never present in high numbers, even atthe highest doses. et "Totalserum cholesterol concentrations were decreased in rasdosed with 20.3 mg/g linear APFO, and i rat dosed with 21 mg/kg linearbranched APFO or branched ABFO (Table 2) Serum cholesterol concentrations were less affected at doses of 30 my than a 3 or 10 mglkg for cachofthe 3 test materials. For lincasfranched APO, otal cholesterol concentrations wer lowest natsdosedwith 3 mg/kg (45%ofcontrol). However, or linear and branched APFO, total cholesterol concentrations were similar at doss of3 and 10 mg/kg (56-60%ofcontrol and 56.59%ofcontol, respectively). HDL cholesterol concentrations were significantly decreas at doses 23 mg/kgbyeach ofthe3 test materials. Like. {otal cholesterol, the lowest HDL cholesterol concentrations occurredadosofe3so 10mg/kg foreachofthe test. `material. HDL cholestrol concentrations as a peccenofcontrol fo these twodoses were 257% inearbranched), 58% (incar), and 65-70% (branched). Changes at dose of30 mg/kg were les prominent than at Tower doses for cach ofthe tet materiel. Non-HDL cholesterol concentrations were decreased at doses 21 mg/kg by each ofthe3 est materials. Tn addition, non-HDL cholesterol concentrations were satisclly significantly decreased at doseosf | mg/kg for Jinearfranched APFO, and at 0.3 and 1 mg/kg or linear APO. Like tial andHDLcholestrol, the lowest nonHDLcholesterol concentrations occurredatdoses of3 or 10 mg/kg for each ofthe est materials. Non-HDL cholestrol concentrations 1s a percentofcontrolforthese twodoses wre 40-60% (inearbranched, excluding an outien), 52.64% linea), nd 0% (branched). Non-HDL cholesterol changes a doses of 30 mglkg were less prominent or were not presen. Tse A14P-FDOay(OLrail nGaevaagre/StBurdyAaPinnFMcOah(lLeeinRdeaat)rs),a,nadnMdiAcPeFO (Branched) RevisDiuoPnoNntu-m1b41e6r2 `Serum rglyceride concentrations were decreased in ais dosed with 20.3 mg/kg linear APFO, and in rats dosed with 1 mykg linear/branched APFO or branched APFO (Table2 and Figure 1). Unlike cholesterol, the dose-response. for wiglyceride concentration foreach of the test materials was flat at doses 23 mg/kg. At doses 23 mgs. wiglyeeride concentrations ranged from 1.675%ofcontrol for inearbranched APFO, 72-79%ofcontrol or linear APFO,and 53.6266ofcontrolforbranched APFO. Organ Weights Absolute liver weights were significantly increased in ats dosed with 21 mg/kg branched APFO or 23 mg/kg linearforanched APFO or linear APFO (Table 3). Liver weights relative to body weights were increased in dosedependent manner in all groups dosed with the test materials (Table 3 and Figure 2), with the highest relative liver weights at 30 mg/kg (means were 199, 183, and 188%of control for linearbranched, linear, and branched APFO, respectively). A few instances ofstatistically significant aleraions in absolute or relative kidney weights were observed with all 3 test materials. Overall,the magnitudes of the alterations were small and were not consideredtreatment elated. Hepatic Peroxisomal f-Oxidation nats, cachofthethreeAPFOtest materials caused siaistically significant increases in hepatic oxidation ctvity (Tab4alned Figure 3). Rats dosedwith lincar/branched or lincar APFOhad adose-dependent increase in hepatic oxidation activity that was statistically significant at dosages of1 mg/kg, with the greatest increases at30 mp/kg. 465 and 5675%of control, respeciively). Hepatic f-oxidation was significantly increased in rats dosed with 3 mg/kg branched APFO, with the greatest increase at 30 mg/kg (289%ofcontro. Overal, the inearbranched. and linear APFO increased hepatic oxidation activity to similar magnitudes, while the branched APFO was less potent. `Serum PFOA Concentrations `Small amounts (<1 g/m)ofPFOA were detected in sera control rats (Table 5. Overall,serumPFOA concentrations increased proportionally with dose. For example, at dosesof0.3, 1, and 3 mg/kg APFO, serum levelsofPFOA were approximately 20, 60, and 100 ug/ml, respectively, for all 3 test materials. However, for branched APFO, the slope ofthedose response diminished at th three higher doses compared to linear/branched APFO and linear APFO (Figure 4). For linearbranched APFO, the atoof linear to branched APFO administered was 3.5. Theraotfliincoar 0branchedPFOAinserum increasedasthedoseincre(afrsome5.d1at 03mg/kgto 11 4130 mg/kg). With branched APFO,th ratioof Branch A to Branch B administered was 14:1. With increasing dose,the atoofBrancAh 0 BrancBh inserum increased (13:1 at0.3my/1k02g8:1at 30 mk). Regression Analysis `When analyzed by administered dose, there were no statistically significant differences detected between endpoints measuredforratsdosed withlinearAPFOand lincarfbranched APFO, For mst endpoint, especialya higher -_-- APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number 1 DuPont 14162 doses, the branched formofAPFO was statistically differen from the linear or linearfbranched forms. In general, his regression analysis confirmed the findings of the ANOVA tests concerning the effects of branched APFO on the nutsitional endpoints of body weigh, body weight gan, and food efficiency. `When analyzed by PFOA serum concentration, however, there were no differences observed for nuridonsl endpoints among the three forms of APFO. In contrast or a given serum concentration ofPOA, relative liver weights were higher and relative kidney weights were lowesi rats dosed with branched APFO compared to the other two test materials. Mice ClinicalSignsMortality No adverse clinical signsoftoxicity were observed in mice dosed with either lincarfbranched APFO or branched APFO.The incidenceofenophthalmos (3/10) and lethargy (2/10) was significantly increased in mice dosed with 30 mg/kg linear APFO. No clinical signs were seen in mice given 10 mg/kg linear APFO or les. One mouse dosed with 30 mg/kg linear APFO died during the study; the causeofdeath was not determined. Body Weights and Body Weight Gains. Mean body weights were significantly lower compared to controls following 7 and 13 daysofdosing with 30 mg/kg oflineat/branched APFO (84 and 79%of control) or linear APFO (84 and 82%of control) at both days (Table 1). Overall men body weight gains were also lower for these two groups. Mean body weighsof control mice: increased 102 grams over the course otfh study (test days 0-13); however, mean body weights ofgroups dosed with 210 mg/kg linearfbranched APFO or linear APFO decreased between 1 and 6 grams.Treatmentrelated increases in iver weights (Table 3) decreased the apparent magnitude ofbodyweighteffects. At necropsy body `weight excluding liver weights of mice dosed with 30 mg/kg were 67%of control for linear/branched APFO, 75% ofcontrol for linear APFO, and 835%of contol for branched APFO (data not shown). Therefore, all 3 groups dosed. with 30 mg/kg APFO had significant body weight loss. Mean body weight gainsofmice, when adjusted for increased liver weights, werebetween -1.3and 0.3 gfor controlmiceandmicedosed with <3 mg/kg respectively. However, body weight gains adjusted for increased liver weights were substantially lower for mice dosed with 210 my/ke of inear/branched and linear (-57 10-95 5), or dosed with 30 mg/kg of branched (5.1 8). Other Changes in mean body weights or body weight gain were observed but were considered to be unrelated to weatment. Overall, the effects on mean body weight and body weight gain wereofsimilar magnitude in mice dosed with linearfbranchedAPFO andlinearAPFO. Mean body weights and mean body weight gains were generally less affected in mic dosed with branched APFO, even when adjusted for liver weight increases. Food Consumption/Food Efficiency Mean food consumption (est day 0-13; data not shown) was decreased, compared to controls, in mice dosed with linearfbrsnchied or linear APFO only at 30 mg/kg (85% and 91% ofcontrol, respectively). Over the same time oo A14P-FDOay(LOirnacaGra/BvraagnechSedt),yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): RevisDiuoPnoNnu-m1b4e1r621 period in the 30 mg/kg groups, mean food eficieicy ( body weight gain/g food consumed) was negative only in the linearbranched formofAPFO (data no shown). Food consumption and food efficiency were less afected in mice dosed with branched APFO (food consumpion was 95%ofcontol. Analysis of Dosing Preparations "The resultsofanalysis indicate that branchedinear, linear, and branched APFO were a the targeted concentrations, adequately mixed, and siable inthe vehicle. No test material was detected inth control (0 mg/mL) samples. Clinical Chemistry Serum total and HDL cholesterol concentrations were decreased (varisbl saistical significance) in mice dosed with 23 mg/kg for ach of the est materials (Table 2). The dose-response for both parameters was lat at doses 23 my for eachofthe thre test materials. Concentrations in these groups were 61-825 of control fr total cholesterol and 51.71%ofcontrol for HDL cholesterol. In addition, HDL cholesterol concentrations in mice dosed with | mg/kgofeschofthe test materials were minimally lower than controls (82:847%ofconirol group means for the three APFO test materi). "There were notreatmentelated changes in mean nonHDL. cholesterol concentrations in mice. However, mice neat with each ofthe test materials tended to have wider ranges both increased and deceased)ofon-HDL. cholesterol concentrations compared o control mice. `Serum triglyceride concentrations were statistically significantly increase in mice dosed with 03, 1,3, or 10 mg/kg oflincarfranched APFO (Table 2 and Figure 1); mean triglyceride concentration was highest a 10 mg/kg (161% of control). In addition, a few mice dosed with linear APFO or branched APFO at doses >1 mk had increased triglyceride concentrations, resulting in increases in mean rglyceide concentrations ranging rom 111-1495% of contol. Triglyceride concentrations of mice dosed with 30 mg/kg were either similar o controls (branched -95% of control group mean) or somewhat ess than controls (linearbranched and linea - 365% and 836 of control group mean, respectively). Organ Weights As ints, absolute and relative liver weights wer increased in mice dosed with each ofth test materials (Table 3 and Figure 2). Absolute liver weights were significantly incressed in ice dosed with 23 mg/kgofeach of the three test materials; maximum mean absolute liver weights occurred at doses of 10or 30 mykg. Relative liver weights were increased (variable statistical significance) i a dose-related manner in mice dosed with 30.3 mg/ofkcagch of the three test materials. Maximum relative liver weights occurred at dosesof 30 mg/kg for each test material; means were 356,325, and409%ofcontrol means for linesrbranched,linear, and branched, respectively. --- APFO (LinearfBranched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number 1 DuPont14162 A few instancesofstatistically significant decreases in absolute or relative kidney weights were observed with linear and linearfranched APFO Overall the magnitudesofthe alterations were small when normalized for body weight, id not show a dose-dependent effect, and thus were considered to be unrelated to treatment withthe test material. Hepatic Peroxisomal f-Oxidation Similar to th effects observed in ras, each of the thee formsof APFO caused statistically significant increases in hepatic B-oxidation activity in mice (Table 4). Statistically significant increases in hepatic oxidationwere observed at dosesof20.3 mg/kg for linearbranched and linear APFO and 21 mg/kg for branched APFO. The `magnitudeofthe increases was not proportional to the dose administered as the greatest increase was seen ata dose of1 or 3 mg/kg rather than at 30 mg/kg. Linearfbranched and linear APFO caused similar increases in hepatic: oxidation at 1 and 3 mgkg (263-2735% and 260-2875%ofcontrol, respectively, orthe two test materials), while branched APFO caused the greatest increase at 3 mg/kg (245% ofcontro. Overall increases in hepatic f-oxidation wereofsimilar magnitude for each ofthe three APFO test materials. `Serum PFOA Concentration Inthe mouse, PFOA serum concentrations increased with increasing dose (Table 5 and Figure 4). The serum concentrations at agivendoseofeach test material ppesred similar, and, lke the ra, concentrationsofPFOA in mice dosed with linear APFO were higher than thoseofmice dosed with the other two test materials following. exposure 0 10 or 30 mg/kg. Inmice dosed with lineafbranched APFO, the ratio oflinear to branched PFOA in the serum increased from 4.1 at adoseof 03 mg/kg 10.9.9 at a doseof30 me/ke. With branched APFO, the ratio of Branch Ato Branch B increased from 1.4 ata dose of 0.3 mg/kg 105 at a dose of 30 mg/kg Regression Analysis `Regression analysis resuls for mice did not differ when analyzed by administered dose or serum PFOA concentration. The regression analysis confirmed the ress of pair-wise statistical tess. DISCUSSION "The purposeof the current study was to determine if there are substantial differences inthe toxicity profile, based on selected endpoints, amongthethre isomeric formsofAPFO (inear/branched, linear, and branched). For completeness,bothats and mice were utilized,and awide rangeofdoses was employed. Because linear/branched APFO is 785% linear APFO, we hypothesized tha th toxicity profile of inear/branched and linear APFO would be: similar. Todeterminethecontributionofbranched APFO to the toxicityoflinearfbranched APFO, we synthesized a formofAPFO that was 100% branched. Body weight and nutritional parameters, organ weight, and hepatic oxidation results in ths study were consistent with thoseof previous studies conducted with linear/branched APFO (reviewed in Kennedy etal. 2004). Branched APFO had the least effect on body weight, body weight gain, and food consumption for both rats and mice -- = A14P-DOay(OLrianleaGr/aBvraagnechSetdu)d,yAPinFMOal(LeiRnaetasra),ndandMiAceP.FO (Branched): Revision Number 1 DuPont.14162 `compared to both the linearfbranched and linear forms. Tn the ra, however, these differences were not significant when effects were compared using serum concentrations, rather than administered dose. Internal dose, defined as serum PFOA concentrations, increased with administered APFO dose for cach test mateial. In rats given equivalent doses, branched APFO resulied in lower serum PFOA concentrations compared to the other two test materials. Possible explanations for this finding might include timeofblood cllection, absorption differoredinffcereensce,s in urinary excretion between the branched forms and the other two formsofAPO. Differences in renal excretion oforganic anions may be driven by differential affinity for organic anion transporters among the different forms ofAPFO, which may contribute o the lower relative serum concentrations at higher doses (Kudo and Kawashima, 2003). `The ratio of linearfranched APFO administered daily to rats and mice was approximately 4:1 (80/209). Following 14 daily doses of 03 my/kg in ras, the serum ratio of near 0 branched was 5:1 and ths ratio became greater with dose (62,69, 8.5, and L151 with doses of 1,3, 10, and 30 mg/kg, respectively). In mice, the same trend was observed with th starting ratioof 3.84.4 seen in mice treated with either 0.3, 1, or 3 mg/kg and higher ratios observed with the 2 highest doses (6.6 at 10 mg/kg, 9.9 t 30 mg/kg). The reason forthe changing isomer patien is unknown. Tissue storageofAPFO (ether linear/branched or linea) is minimal and no particular tissue storage site appears 0 exist (Johnson, 1984; Kemper, 2003). However, in ats exposed orally to linearbranched APFO, the amount of branched isomer inserumdecreases afte cessationofdosing (DuPont, unpublished observations). Therefore, this changing isomer patternmostlikely reflects altered absorption or preferential clearance of branched APFO. "The branched material tested contained internal mono-methyl non-alpha branching (BranchA)and isopropyl branching (Branch B)inaratio of 14:1 (58.3% Branch A 141.7% Branch B). In serum samples collected afer 14 doses, the percentageofmono-methyl branching rose with escalating dose, 0.2.8: in ras and 5.0:1 in mice: receiving 30 mg/kg. Again, th reason for this shift is unknown but is most likely a reflectionof changes in absorption andlor clearance of the specific isomers. `The activityofhepatic oxidation paralleled serum PFOA concentrations in ras. The increase inactivity seen with the branched material was lower than that for the other 2 materials. A 2 (03 fold increase was seen at 30 mg/kg, the same relative increase as produced by 1103 mg/kgofeither th lincarbranched or the linear forms. Tn mice, oxidation increases similarly forall 3 materials with a relatively fla dose responsea the dose increased from 0.3 10.30 mg/kg. The sctual numerical levels off oxidation were great in the groupsreceivingeither 1 or 3, not 30 mg/kg. Liver weights in both species increased proportionately to dose suggesting that the liver weight increases are not due solely to peroxisomal proliferation. Given that APFO exhibits PPAR activity (Intrasuksri et al, 1998; Maloney and Waxman, 1999), it was expected that it would lowerserumcholesterol and triglycerides levels in rats. Haughom and Spydevold (1992)reported decreases in total cholesterol (50-70%ofcontrols) and triglycerides (60%ofcontrols) after dietary administration of --_--_-- mm APFO (LinearfBranched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number | DuPont14162 0.025% APFO (estimated dose of 10 mg/kg). These resultsare consistent with the current study. Although the dose response in our study varied amongthe 3 test material, serum cholesterol concentrations in rats were decreased in the dose range (10 10 mg/kg) consistent with that used by Haughom and Spydevold, but were generally less. affected at the highest dose (30 mk). In mice, Xieetal. (2003)repoardetcreeadse in serum cholesterol (80%ofcontrols) in CSTBLI6 miceafer 7 days ofdietary administrationof0.025% APFO (estimated dose of 30 mg/kg). In our study, cholesterol was decreased in mice at doses greater than 3 mg/kg, and thus th effects on cholesterol were consistent with thoseof Xie etal. In the `same experiment, Xie also reported a decrease in serum triglycerides estimated at 60% ofcontrols). In our study, triglyceride concentration in mice increased withincreasingdose (up 0 61% at 10 mg/kg of inearbranched), but were sila to controls or slightly decreased at 30 mg/kg. Therefore, ot a similar high doseof30 mg/kg. wiglyceride concentrations were similar between the two studies. The more definitive decrease n triglyceride: concentrations reported by Xie etal. may be due to effectsof the routeofadministration (dietary), differing mouse strain,o differingdurationsofexposure `Serum lipid perturbations observed in rodents at high doses (30 mg/kg) of linear/branched APFO have not been observed in morkeys. Cynomolgus monkeys dosed with up (0 30720 mg/kg by gavage for up to 6 months showed notreatment elated alterations in serum lipids (Butenhofeft al., 2002). Cynomolgus monkeys ar similar 0 humans with respect to cholesterol and riglyceride metabolism, and have been used as animal models in the developmentofhypolipidemic pharmacologic agents "The increase in serum triglycerides in mice a lower concentrationsofAPFOoccurred despite increased hepatic: Poxidation. This finding suggests that in mice, butnotin rats or primates, perturbations i lipid metabolism beyond those associated with PPAR meditated events underlie this observation. Other investigators have aso noted that effects ofAPFO on hepatic lipid content are different from thofoclofsibraete, awell-characterized peroxisome proliferating agent (Kawashima et al, 1995). Although dosing with fibrats generally decreases serum cholesterol and triglyceride concentrations in ras and mice, other peroxisomal prolifecators have no lipid-lowering effects (Kawashima etal, 1995). Dose-related ex vivo hemolysis in rats (but not mice) was detected in serum samples collected from the orbital sinus. and vena cava. This effect was considered 0 be an ex iv effect because the extensive database on APFO-exposed ras contains no indicationofred cll effets despite rigorous investigationofclinical and anstomic pathology endpoints. Sensitive indicatoofrisn vivo hemolysis (including, but not limited to, increased splenic weights, increased extramedullary hematopoiesis, increased splenic pigment, decreased red cell mass, inreased reticulocytes, increased mean cell volume, and decreased mean cell hemoglobin concentration) have never been affected in any previous toxicity study conducted with APO. Therefore, hemolysis observed in serum from ras most likely resulted from a test-materil related increase in fragility ofred cell exvivoduring blood collection and/or processing. _-- AP14F-ODay(LOirnaclaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnactasr)a,nadnMdiAcPeFO (Branched): RevDiusiPoonnNtu.m1b4e1r621 Acanthoeytes were observed on some bloodsmearsof ras on this study. Acanthaeytes are red blood cells with ireegular projections, thought to arse as a result ofasymmetry between th lipid bilayer hemileaflets ofred blood cells (Bull, 2000). They have been associated with altered lipid content of the red cel lipid bilayer, because lipid `content of mammalian erythrocytes is refleocftpliavsmea lipid concentrations. Other shape changes (poikilocytes or schistoeytes) were observed occasionally on some blood smearsofrats on this study. Bothofthese shape. changes were only present in race amounts and did not appear (0 have any effect on ed cell survival. The morphologic changes were similar with each test material. These morphologic changes, as well sexvivo. hemolysis, were likely due to alterations in plasma ipids. A wide varity ofendpoints were examined in rats and mice using a rangeofdoses from 0.3 to 30 mg/kg. For each endpoint the lowest dose tested producing an effect (LOEL) was determined for each of the 3 materials (Table 6). In rats, the LOEL was 1 mg/kg for linear/branched and branched, and 0.3 mg/kg for linea, based on reductions in total cholesterol and riglycerides. In mice, the LOEL was 0.3 mg/kg for all materials, based on liver weight changes and hepatic oxidation (and on increases in triglycerides with the inear/branched material). These LOEL doses correspond ( serum PFOA levelsof approximately 20-50 pg/mL (ppm) in ats and approximately 10-15 pg/mL in In conclusion, the toxicity profi of linear/branched APFO and linear APFO was similar for the endpoints measured in rats and mice. The observations in this experiment were similar 0 those seen in other rodent studies. Internal dose, as determined by serum PFOA concentrations, increased with dose for each APFO test material. In ais, branched APFO resulted in considerably lower serum PFOA concentrations compared to the other two test materials. These lower serum PFOA concentrations also correlated with lower hepatic oxidation levels. At the highest dose, the ati oflinear (0 branched forms in serum was twice thatofthe administered test material, and the ratio ofthe internal monomethyl isomer to the isopropyl more than doubled. In rats and mice, serum cholesterol `generally decreased with increasingdosesoftest material. In ras, serum triglyceride concentrations decreased with increasing doses oftest material. However, in mice, rglyeeride concentrations increased up to doses of 10 mgs, then decreased at 30 mg/kg. In both ras and mice, the overal responses 0 the linearfbranched and th linear forms. of PFOA were similar, but the branched form appears to be less potent. Based on these result, the toxicological database developed primarily from testing lineafbranched APFO is applicable o linear APFO. ACKNOWLEDGMENTS "The authors would like o thank Dr. John W. Green for his statistical analysis ofthe data and Charlene Smith and `Diana Ritchie for thir expert technical asistance. - A1P4-FDOay(OrLaliGnaveaagerSt/uBdyArPinaFMOna(lcLeihnReaeatrsd),a)nadn.dMiAcPeFO (Branched): RevDiusiPoon nNtum1b4e1r62| REFERENCES `Bradford, MM. (1976). A Rapid and Sensitive Method for the Quantitationof Microgram QuantitiesofProtein Utilizing the PrincipleofPotein-Dye Binding. Anal. Biochem. 72, 248-254 Bull, B.S. (2000). Morphology of the erythron. In Williams" Hematolo(gEy.Beutler, M.A. Lichtman, B.S. Collier, T.J. Kipps, and U. Seligsohn, Eds) 6"ed, Chapter 22, McCHillrPublaishewrs, NY, NY. ButenhoftJ,,Costa, G., Elcombe, C., Farrar, D., Hansen, K., Iwai, H., Jung, R., Kennedy, G. Lieder, P., Olsen, G.. `Thomford., (2002): Toxicity of ammonium perfluorooctanoate (APFO) in male Cynomolgus monkeys afer oral dosingforsix months. Toxicol. Sci. 69, 244.257. `Dunn, 0.J. (1964). Multiple contrasts using rank sums. Technometrics 6, 241-252. `Dunnett, C:W. (1964). New tables for multiple comparisons with a control. Biometrics 20, 452491. Dunnett, C.W. (1980). Pairwise multiple comparisons in the unequal variance case. J. Amer. Satit. Assoc. 75, 796.800. Flaherty, J. M., etal. 2005). Quantitative determinationofperfluorooctanoic acid (PFOA) in serum and plasma by liquid chromatography tandem mass spectrometry. J. Chromalogr. B., manuscript submited. Hansen, K 1, Clemen,L.A.,Ellefion, M.E., Johnson, H.O. (2001). Compound:specific, quantiative. characterization oforganic fluorochemicals in biological matices. Environ. Sci. Technol. 35, 66770. Haughom B. and Spydevold O. The mechanism underlying the hypolipemic effect ofperluorooctanoic acid (PFOA), perluorooctane sulphonic acid (PFOSA) and clofibrc acid. BiochimBiophysActa. 1992Sep22; 112801):65.72. Intrasuksr, U, Rangwala, S.M., O'Brien, M., Noonan, D.J, and Feller, D. (1998). Mechanismsofperoxisome. proliferatiboyn perfluorooctanioic acid and endogenous fatty acids. Gen. Pharmacol. 31:187-197. Johnson, 1.D., Gibson, $1, and Ober, R.E. (1984). Cholestyramine-enhanced fecal liminationofcarbon-14 in ats after administration of ammonium [14-Clperfluororopooctatssainumo[a1t4e] perfluorooctanesulfonate. Fund. Applied Tox. 4)972:976. Kalliomaa, K.,HaagGroenlund, M., Victorin, K. (199). A new model function forcontinuous data sets in health risk assessmentofchemicals using the benchmarkdoseconcept. Regul. Toxicol. Pharmacol. 27, 98-107. = APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number | DuPont14162 Kawashima, Yoichi; Kobayashi, Hiromi; Mira, Hiroaki; Kozuka, Hiroshi. (1995). Characterizationofhepatic responses ofrat to administrationofperfluorooctanoic and perfluorodecanoic acids a low levels. Toxicology 99(3), 169.78 Kemper, R.A. (2003). Perfluorooctonanoic acid: Toxicokinetics i the at. USEPA Administrative Record 226-149. Kennedy, G.L., Butenhof, J. Olsen, G:W., O'Connor, J.C, Sescat, AM. Perkins, RG. Biegel, LB., `Murphy, SR. (2004). The toxicologyofperfluorooctanoate. Cri. Rev Toxicol 34:351-384. Kruskal, WH. and Wallis, W.A. (1952). Use of ranks in one-critrion analysisofvariance. J. Amer. Statist. Assoc. a. 583.621. Kudo, N. and Kawashima, Y. (2003). Toxicity and toxicokinetis of perfluoorooctanoic acid in humans and animals. J. Tox. Sci 28, 49-57. Lazarow, PB. (1981). Assay of Peroxisomal Beta Oxidation of Fatty Acids. Methods in Enzymology 72, 315-319. Levene, H. (1960). Robust estforequaoflvariiatnceys. In ContributionstoProbability and Statistics (1. Olkin, Ed). pp 278.292. Stanford University Press, Palo Alto, Maloney, EK. and Waxman, E.J. (199) rans-Activationof PPAR.-ct andPPAR-yby structurally diverse environments chemicals. Toxicol. Applied Pharmacol. 161:209-215. Olsen, G.W., Gilliland, F.D., Burlew, MM., Burrs, JM. Mandel, .S., Mandel, H. (1998). An epidemiologic investigation of reproductive hormones in men with occupational exposure to perfluorooctanie acid. J. Occup. Environ. Med. 40, 614-620. Olsen, G:W., Burrs, JM. Burlew, M.M., Mandel, 1H. (2000). Plasma cholecystokinin and hepatic enzymes, cholestrol and lipoproteins in ammonium perfluorooctancate production workers. Drug Chem. Toxicol. 23, 603.620. Pack, S. (1993). A reviewofstatistical data analysis and experimental design in OECD aquatic toxicology test guidelines. Shell Research Lid. Sittingbourne Research Centre, Sitingbourne, Kent, MES SAG, UK. Searle, S. R., Casela, G., McCulloch, C:E. (1992). Variance Components, Wiley, New York. See, K.and Baylor, A.J. (1998). Added risk and inverse estimation for count responses in reproductive aquatic toxicology studies, Biometrics $4, 67-73. EE APFO(LinearfBranched),APFO (Linear), andAPFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number 1 DuPont-14162 Shapiro, .5. and Wilk, M.B. (1965). An analysisofvariance tet or normality (complete samples). Biomerika 52, 91611 Slob, Wout (2002). Dose-Response Modelingof Continuous Endpoints, Toxicol. Sci. 66, 298-312. Snedecor, G.W. and Cochran, W.G. (1967). In Statistical Methods, 6 edition, pp 246-248 and 349-352. The Iowa. State University Press, Iowa. Taves,D.,Guy, W., Brey, W. (1976). Organic florocarbons in human plasma: prevanadchlaraectenrizcatieon. In: Biochemistry Involving Carbon-Fluorine Bonds (R. Filer, 4.) pp. 117-134. American Chemical Society, `Washinglon, DC. Ube, FA. Sorenson, $.D., Roach, D.E. (1980). Health satus ofplant workers exposed o fluorochemicals--a. preliminary report. Am. Ind. Hy. Assoc. J. 41, 584-589. USEPA. (2002). Revised draft. Hazard assessmentofperfluorooctanoic acid and is sals. USEPA Public Docket AR226. `Vanden Heuvel, J, Kusliki, B., Van Rafelghem, M. (1991). Tissue distribution, metabolism, and elimination of perfluorooctanoic acid in male and female ras. Biochem. Toxicol 6, 83.92. Xie, Y., Yang, Q. Nelson, B.D, and DePierre, J.W. (2003). The relationship between liver peroxisome. proliferation snd adipose tissueatrophy induced by peroxisome proliferator exposure and withdrawal in mice. Biochem. Pharmacol. 66: 749-756. = A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a.nadndMiAcPeFO (Branched): RevisDiuoPnoNntu-m1b4e1r62| FIGURES EE -- # [T1171] mh A L0I0FL]| emo 7A AA Cr i LLL f TTT 2 Fy . Te i i CRE FL | IRSA IE - ji CL CL ii li LC eE3 s: l8 i 1 TEIL p = i 1.1 il Hie EEEE : 14 ir+er+e ||A)N i! 5gs P1U1LL11 LY ": - 24 88 fg88g88s8R8" g (Ip/Buw) uopeUSUCD BPLIAIBLL A J N . i | i | 22: | 3| o:z || 3 - s ot A sz ts A i iii] | i tithe: | 82 8 13] 8 5 asa | : 24 23 3i8 -- I T : Zz | i | [1] | | | |1 LY| } i ii [a iN B | 23 5g || EAN : >i 3. i | N : 1 zgEF || 0: Fo| v || s WO . DU FR = a i ; oF SE 3 11; i: 14 4if []: || H NG Ll] | Cr | | |i Pop | P| ool Ji iz 2g 88: 8 38 % 8 8 2 g4 (us101d BuYUILOWL) UORERUSOUED UOREPIXC-d AL | "WN | : i SN #| 3 i H| | i| } ; 2 FORN 5 | . \ A ni , or | :RB C 7 EduE EEh \\ Sf x oz sos = 8 53 (uyBr) uopenueouod VOId APFO (Linear/Branched). APFO (Linear), andAPFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number | DuPont-14162 TABLES 3i8z 3BEAaNfImE [EmmEm JBoEmRo [RoEoEk [IfeEt [42983a 2% : 2Naag [wan [22a 283 [483 [R88 i: EH] TTT 32f Elon one ogg [siz (kes (Bie 35352 | B5 SIRIRER (EEE (RRR |2gs |S%R Bad IAT Hag (FRG leas [227 . 1:3 iE ae os aa aio pe os put : Is.| k2 ] BE SRA |A3% BAY [28% RRB ii e 2 & =28 |o2n |=ax [ax [see [SEs 8 FORE HER iis BR il rel Find i SH5E88 [[233388 [H9a588 [|8S%EH [2R2258 [[2B3823 [22 i ON SR I A --_-- 23 Ss 3 3 Hi ood Ll[LLF 233 fe2Ah3n2EeBE2E2EleBn.5n2EleBa4E4EEMp.i2ndE EfR.Aa3S pI2d LH FECEERCEEREE NEN EE zc2 = rrr 2 Eee3s [555 GSS BRE G3 Bn FES2c [sng [Res 3%3 [83 [29% B 33% 530 [E37 BAD ARG git 3; [523 [82k [z2 [25g [23% |28E 2 | E[TEa3l5a5c5n [|zaz2538 [n3g3a0 [m2a3s% |B3Eo%e R[nEeSs z li:e E25 [S88 228 (3342 i or rrr 71 357 | SEE | BEaEh0iIs0fo[oR3n0fo[e35s5 l[AaRFg h[3o5s% [f3a3s% 2i35::%|||E[BHene [79% [38% [338 298 |RS3 . #: E5E | Bian hn Bhi [3 Ps pn s| Biy | [Eros [ssn S312 adc 38s (Ras HE cas oan Joes fon 8 ELHE EEi 5: Baie ote [ota [raz (Red [enn |E 5 g S Eicf 949 34 ARS 888 [FEF |Bi 2] zz E52 efiZ2| 3 fd [LLEP ad EE23532 [aEdRBLa5Ed% adELT B[hLa2Eg fad ei ELT|B 135% |25 gid ~gl flocs [zen noo |nwe |sfo lwec 233 :gsG9i5 [[3E955f [[3$5R5e [$3E545 [[3S9959 [e3t3n9 :34 F5 adl [seg fos eis poPt yce 3 her E5H5 |[5 3[E3e3d e[3d33 (H3E5S3 [l33d5 it 3358|| goFaze feos rg oEng 2%:| (8355 [35 Ril GEE F3E1E [54l2an8g0 psaazg Ezsisg a[Basg S| Br) 2ERd [ERK Rag Fa8 i Sg|,| 71 g ong gBd+ || F5a:2d0 4 [axg S33 Bah [339383 B8E (B3E39% FEE e ls 2 3 o oh [BEY Sy 288 [G28 83% 348 3 == [SoZ [dog Eel ) 3 i:S35 3R;3L3BfSadE adE af2 her hs [259343 [Raisg 11 mad2 lfeset RIE fs sgaass Boeost gdE Rd 84f dS |[h3k [kit |g (330 [es |A5L 123% ls [934 [$54 | [e==2 ecg 5 z 33 id id BEE 5% [23 HH FH i 2 $T0H3i0s [lWaIkE 3[a3i3d P|nRkEnD [[2R3D3 [[Eainsi g 1[3REECE [355 |e53 [74% [284 [aaa 2% 2 i5f|r leg rr rT ge 282 |[E5usn Bef (ge fnan [mas Zz oka BRT Ben NNT 25% [GEE [83h 95 ff [5 4. Eii:EEFE=ac [228 |S8= 222 [434 (332 [5 < | BH i sgl2 fd 2.S332 1d [5E.F2 [d55.222 [5a[R,dA2E [Rl5E,dZ2 [5.2% |i: Rif Lf bh i: 3 2o3: 2323 = lh 5i2 i & E2E oe 2 HE5% 34% : 2 lls i 2 3= 23 aFF4 12 : 2gg=3 i F00 8 3 0 2 i f =" 258 223 83 $88 88% 533 5 21 nr 13 22| aid : 5 03 85 og i i Bir| E58 pEIdf EET E HS " =HELi LH.E I -s22 i EERIE ERNE TREE TRIES BgEzBE|[8s |zax gan exe gon 33s AL. ij : = [835 Re Fes Eh EER ERG S3 31 BE: 3 [2nd id 0 Bf lad 23 205,73 5,7 ,7 9.7 5,7 , 75811 58 223 H 2 E o .I 223:522 i COE [Hr] g J35E5[] Jopoeeeer-e+n|e ti313 HE ERIN & } % 3$2333 LE HEA CRC i 2a: ls jEsiit i 553B5333E28% 2 3 janis iz is A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): RevDiusiPoonnNtu.m1b4e1r62| RAT TABLES -_-- A1P4-FDOay(OLrianleaGraBvraagncehSetd)u,dyAiPnFMOal(eLiRnaetas),anadnMdiAcPeFO (Branched): RevisDiuoPnoNnutmb1e41r621 RAT TABLES EXPLANATORY NOTES -_ ~~ _ STUDYDESIGN Groups H-24921 H-26313 H26225 APFO (Linear/Branched) APFO (Linear) APFO (Branched) 1A B ic ma mB me VA VB ve via VIB vic XA XB IXC XIA XIB Xic Dosage (mg/kg) 0 (Control) 03 1 3 10 30 Abbreviations mg/kg = mg/kg/day `Summary of Clinical Chemistry Values CHOL - cholesterol TRIG - triglycerides HDL - high-densitylipoproteincholesterol nonHDL - non-high-density lipoprotein cholesterol NOTES: `SummaryofClinical Chemistry Values Groups with identical values may vary in statistical significance, because tabulated statistics arc: rounded to fewer decimal places than the values used for statistical determination. -- - A14P-FDOay(LOirnaelaGra/BvraagnechSed)t, iAuPnMFdaOly(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Revision Number 1 Dupon-14162 Table 1 Homogeneity/Concentration Verification and Stability Analysis for Rat Study. Sample `Sample Day H24921 15-Mar-2004 Nominal mg/mL 0 003 010 30 Measured * mg/mL ND 0029,0029 0.09,0.095 284,269 Mean % Nominal -- 96.7 97.0 922 CV. Swbiliy' _(%) % Nominall --- 0 96.7 2 910 4 87.3 H26313 16-Mar-2004 H26225 17-Mar-2004 0 ND - 003 00300029 96.7 0.10 009,0.102 96.0 30 275,294 95.0 0 ND --- 003 0029,0031 1000 010 0.112,0.105 109.0 30 272,291 94.0 -2 1000 8 97.0 5 970 --- 4 1033 5 1040 51030 ba SMaemapnlerseshuelltdo5rhothuersanaatloysoismotfetmhpeerdautpulriec.ate samples. 4 DReepnoortteesdnroenseuldtsetbeacsteedd on re-analysisofth original sample. Original analysis was ower than expected du 10aliquotcorandnotreported. - A14P-FDOay(OLrianleaGraBvraangcehSetd)u,dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): RevisDiuonPoNnutm1b4e1r62{ Table 2 Recovery of H-24921, H-26313, H-26225 Added to Dosing Vehicle for Rat Study Sample LS RECOVERY" RECOVERYTM RECOVERY `mg/mL Nominal __ Measured 0.030 0.033 0.030 0.032 0030 030 Mean Percent Nominal 1100 106.7 11050.060251, Cv. RECOVERY RECOVERYTM RECOVERY 0.10 0.103 1030 0.10 0.097 97.0 0.10 0.100 Mean 110000.0030, Cv.003% RREECCOOVVEERRYY") 33.0000 2276:92 8990.77 RECOVERY 300 204 980 Mean 9C2.V8.54%5, Processed with H-24921 samples from dosing prepared on March 15, 2004. processed with H-26313 samples from dosing prepared on March 16, 2004. Processed with H-26225 samples from dosing prepared on March 17, 2004. == --_-- A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): RevDiusiPoonnNtum1b4e1r62| Table 3 Concentration Verification and Stability of H-24921, H-26313, H-26225 in Dosing Solutions for Rat Study T`eSsatmSpulbestDaantcee: Nominal mg/mL Messured Percent Nominal H2C4o9v21Tr(o15L/08) 000 NDA -- "" "" " 5 How) 000033 00002290 996677 Mean(; 0.0290.00 067% 010 0c0v98.0% 9580 010 Mean(: 00.0090750.002 95.0 7.0%) 300 2c8v4.2% 947 300 269 50.7 Mean); 2.770.10 022% 003 0c0v2.9a% 967 031000 20609210) 79130 H26C3o1n3T(Ro1L604) 000 NDA) - "" na "" 5HOR) 000033 00002300 1960.070 Mean); 0.c02v9.02.%001 067%) 001100 00.019002 10020 Mean); 0.0960.008 (960%) 300 2c7v5.s% 917 300 Mean(); 228954013 959.800%) cv.s% 003 0030 1000 031000 0209917 97.0 970 - = A1P-DFaOy(OLrianlcaGraBvraagncehSetdu)d,yAPinFMOal(eLiRnaetasra,nadndMiAcPeFO (Branched): RevisDiuoPnoNnutm1b4e1r62| Concentration Verification and Table 3 Stability of H-24921, H-26313, H-26225 in Dosing Solutions for Rat Study (Continued) TSesatmpSlubesDtaatnece Nommt mg/mL Messed NoPmericneanlt H26C22o5w1o7w108) 000 NDA) - nn n n" 5 How( 000033 00003219 1906373 Mean); 0.030 20001 (100.0%) 010 oClciv.a% 120 010 Mean(): 00..11009520.005 091.0050%) 300 2c7ise 907 300 Mean); 2298210.3 094700%) 003 0c0vs.ts% 1033 o3l00 03.10004 11004030 @(8)) ToDfehnevoaatrvetesarinaoognenoefmdeduapeslueircedadtecosnacmepnitcrsa.tion, verge percentofpoi in parece) standard deviation, and coeficent (D9 eSReripolotracnyddsoetselespbrahteddl.donhroaeuarlsysoiosmofethporeigienal sample. Original analysis was lower han expected de 0 ait _-- A14P-FDOay(LOirnaelaGra/BvraagnechSedt)u,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched) Revision Number | DuPont 14162 Table 4 Summaryof Dosing Suspension Analyses for Rat Study Sample Type ConHn24o52n1 GN152008) " " AAvveerraaggee PMeeracseunrteNdoCmoinneal? Standard Deviation SCouebfliiciyent of Variation? SourRoom Temperaure ConceHn2t6ai3o1n3 (31162009) a n Average Measured Cone? Average Percent Nominal Standard Deviation? SCuobeifictyentofVariation? Shour Room Temperaure Conce1n2r6t2o2n5 GN172008) " " AAvveerraaggeePMeeracseunrteNdoCmoinnaclh? Standard Deviation CoefficientofVariation Concentrations and ibility of24921, H26313, 26225 (mgm) Nominal 00s 010 50 0029 670 00 080) 024578) 0029 0095 26 67) 50 [2 006072)9 01009)7 222m) 2000 20002 2010 os 2% as 009 0001 206 067) 010 13 c0o0o%) 0000%) o21i5 06072)9 10012002) 82064) o0a67) 00600%) 025505) 20001 0008 po Ed 8% s% 0030 0097 291 000) 10) 0 o06079) 0031 0a0.11n10o25 o22o07n12) 1033) 1050) 10 a0m0o30) 0109 a0) 2 10) 20001 20005 2013 a s% 5% SS-huobuirlRyoomTemperature 00st 0104 309 1053 a0s0) 1030 Numbers in parentheses areth respective percent ofnominal values. Tcoheeffaivcieernatgoefmverasiuarteodnocofncdeunptlriactaitoens,aamvpelreasge percentofnominal (in parentheses), standard deviation, and aRleipqourotteedrrroersualntdbansoetdreopnorrtee-da.nalysis ofthe original sample. Original analysis was lower than expected due 0 - iFE 23 Z | 2 5:33: ::z3iiso; fer nmaNmsnSagns & 8&7 &= 8 8 KF Y }% 3 RR" 3" * 4 2 2 Co frdddndiadiaddd rnd EEE EEEEE ` .i s3: 3:3: :3izzzs 3 PE HBu NaS N <S N25 R45 E oF E45 E43 R<3 N 5 aE f nE E oFSF gg 2 3 2 FE . x 2 g% 9 2% #7 g9 25 35 4 g9 39 8] 44 gd 2 33 EE HE 3 <4 1 2gs8 Hi e 8 z zs 8 s mz z e i3 i8d% 33g:3 35 & a FER S 82 35 30 g5 Fad ad i% wE fa f23 lesaz] fIEh : 3. Zg _ | 23 a82F 3 gl Boz of 1h 5 a= EF : it LL] ii ii: . iii5:1 is & EI g24z4 fiIiPREi i le F25E3 25 2 Ea g 3B CEFv F23 OGE3T R30S 3R4Y 8T9E2R4 3B9Y 5p4T gARe AETe gReY AAfR ge g pt2 GP $J 2 5 0% 08J 8 5J J 8 O 8 2 3J 8 n2 EZ5 "gFsT gRsT gR7T gR4T Ag5T gAdT gSnT gRdT 5BT gEdT Ag4T AgdTAgs i 2: %: 3 3: :z:3:z g5 T ERYH BUE R EE RS EE RE R E E R EH g Boof L.. iii: iz JJ 0.J J.J J 0%.J J S5 Fo gs gd 54 #3 dd 44 59 4% 9 gd gd gd ga 1] 8 i z 3 : 4 riseris ii 333 ZH5H 2 5 3J Eo aBn TT g2d72 gene2 i <35 21 5 Eger IE i .z iz 2i 52. 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' :, IEEE EEE &| Zz 3B2 f sFsREsE 227) 4 39 g . SF $Fo8o8s 88 38 3 4 8g2e% f fE f2 INE ZE aOH 1ii za 33 HE H 2%|3zEZ 5i |8 0 3i: i 2 I g S se 3 9g g g ooo I g: < foo i 3: : | i: az Esg ee . g z | iizz =225 :iEog | jees I3 2 ig S25 Egnlz 32g5g 532 Ss 3 EsPb . g3g 3 H3 5 i Bf 253 Bidig iEIR 5 | sy 8 z 5: 8 g"o iF5tE5]gH ooo- ]: i 3 E Poor E | #1 0fof jg3i| aEcFF: Hg HOHE fg (EZ #1 : 3 z Lge oo oo 3 g2 z 53 Baz . - - = 4 a g z :| 5. z : Z| Es UE Ere ~% - as - ht] iz . 2% : zz | BE 2 : fF EE : To gl 13 g Bog 52% fz 3 58 a3, Gi gs degt - oo oo : LI 0 m0 mm PoE ob 1 3 of gf Gf pf Ad og BE gf #8 8 B8g gg =: |3zE i i5 me 22 HE HELE E2 i: |i 3i8s 5 2 & &E ofgaese = fg: ."- : 2 oie .= : gg Tn Ta :. : : P2E3 E_ 2 FEL. oo oa = % oz, _: 2 g Hi= gl iB: z : : I 5 i 2Iz gs :P1 E 1 E % 1 ef sf gf gi gi sOpfE. BE ETDEE TdT le , iE : ` i i538 253 :3 3 2 ga: : 2 & Haz - 5 z i 28 572 _ EH g z RE 3 "332 :f|liied EERE] "au gf = i"l 2 sd 5 3 S| BE 8 cIf E I 5 ses C SE2G 4 : ih] as: S Boy 35 33 33 APFO (Lincar/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice RevDiusiPoon nNutm1b4e1r621 `Table 20 Percent Survival of Male Rats DAYSONTEST __ GoOrmogukpe] GrOo3umppkIlsl GIrmouppsV Gro3umppkVyl Te7 1 Number at study start Sacrificed by design Alointevstdeay 14. APFO (Linear/Branched) - A 1w0w0 1i0w0 1w0o0 1i0w0 100 100 100 100 10 10 10 10 10 10 10 10 10 10 10 10 Gr1o0umpgkIsX 10 00 100 10 10 10 G3r0omuepkXsT 11000 100 10 10 10 APFO (Linear) - B -- 7%7 14 1Ww00 1100 11000 110000 110000 01000 100 100 100 100 100 100 Number at study start 10 10 10 10 10 10 Sacrificed by design 10 10 10 10 10 10 Alive on test day 14 10 10 10 10 10 10 APFO (Branched) - C T7o 100 1 100 Number at study start 10 SAalcirviefiocnedtebstyddaeysi1g4n. 1100 100 11000 101000 11000 110000 100 100 100 100 100 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 Percent Survival = (Number of Rats AliveNuomfbReatss aRisk)?100 There were no sisicaly significantdecease in survival at p <0.05byCochranArmitage rnd est EE sg z23 & < 3 2[3B8 =%S 8gf E2F &FE 5g 9 5g25 3E328g =8F58se aS7&05F28 =&F %o8 a38%8& gIE 58 3 ~ 8 8 8 428 z 8% Ff 3% 8% | % a 2= = 3 & 3 22 |slZa sg of8 82 eE8| 31:2Z _2 |EE =8 % ef =cF ES . 52 |. "iE gs gg g8| 4%9 s S55 98 28 & 85 | fE I g [5 3 &2 55 [|=3 ga g&g 85 &&g| 33si E2L8 3 [25F =F = =Y 2%| 3533 22 oS 3 oz 3 85 3 3 5 a 33S.= 3$= 53:.Es 08 gr io:z |g 33 gd gd 73 4 i 2 H5H 5 #2 EB & 3 33 2 A 2 2.8 & 8 is SZ 3% 27 8% 3ile SEY 8 g.8 .8 5|8 &F 98 8 & i tc Eh5E y8 &8s ,&%Es&s.E:2=.E&2F|g|| f3FEi:: 5B Z: &$88 8.8 8 .8| sg Z|58 ag lg 33 EF T oF iF - ga FI . # 32l0a = = = =| E3R% = E1Y55 5.%2.2% oF2.E8R | 2fi%: 3 5 (53 5: : ge|= g gs E8g .8 8E OE 5gl 5 EE[ 9% oI oF = 2T7H3 33 g g:+ 2 22 i34s 33 o $E2C9E:C3R: 88 gd 3 5E8 3 |: 3 ET: HEi E3 =4 i 2 & . 43 ii 2 >< EL8E Lg Lg g ge" SzEe4Y 2s .c2e .28 .28 2LE RE 5% HF 2% = |g 5 I 58 i I g &% g% ,8 18 28% | 3E3l% Bor, Lg |: H3 a s gg g| 32 kE3 2g%eSs Pp||g&- B 5 3%==F =% = 2 ad 3 E2z2 . : EZ lo 5 99 zs Eg gE Eg EE & ET . Er [SE a% o& gn 5 sT I EREI A 2 2 iHHf 2 lo g [a s 2 & EE s EE os | 2 :i:i 2B3fHg 5oEs 8|sZE % 9% gv gn| = sif 5&% 2 ~ 22 12335 a 24 5 3S2S3:%gS;si P3jE:oa8E:3x 2 | |fiF zz 4OI 3E8 & Le 4 3i8 32 3 i L. alias FR ie ga es eel 2 = 53.3.3 Eo ki luE 5 c1 ET 11 3H 24 3Ii] ZzTzE, G a8 g , a3% ft5 Sif HIESHE 53 $3 3 3% EP 5S El SkB HOEF:d B5L3E o,s E3E:| iE: iig: FTera FmLEa E .aEE] EEE| 33gd f2%l 2 43 Cs | 4533% iiz 2: EEEEo, i is ER flag i 2 Bz gd dCgg ed Ss & EB iNgun 1 < 5I g gl I:T 3%EE kyREE 88 SE Li 2 Zy%y 1] 3% gi. gi. amu| fois 4 gg me os 3 =3] g= EE ed fs IL [I gl ipa t on FiE I s 3 _ 33 Ez ge 4H5IpEf RDEE TaEe 52 wa zToe Z BEFB2E8 . ez si.2 2% 3% : 27 C 1 5 =5 23 53.33| z3a2 g 82 %8B .HI s3%hiazdz.3ls4dig32i| ITEY g tT i: gl igeliir|'? i# { 3 23 B3 5. d5l2% ii 2] 8 : 32 EI s gl Fol, i $2.88) FZgi sdsi.iziaE| ods Gi 4S 3;3 eesE s E gi gs = E 383 2 2d [IE EERE i 33 H iz TIE ET CR as. 1P3p Lo h ss egc CPsT E PoigiE gioEE |Te27 s2e7 iisg Sg iiBgligsiimy--if--o-o--------5-,--il%a3d E iE] i.@s | 2% 33 1 TEIEE SIEEEBSR. 2B.ig neaz |ILibjeT mEy sr|TeETTR BFL T5T.T i[EE.E 3 gm (1 S| Ei iE Il 1 iF 42 i11 od il 2 3| | if H8 o i i| Hs18a 5: 8d I] 8 isd nog Eb g34l =| i POE I Es EGE E52 a, | BE iE noo oF hy <E<2H :i iLiF gEefFEifie giidg FiiH:: i EE : iTiLsE$f |E2E% 8ga! 72Piiisi ii238si! ifr I Tis * 81 E 111] EJ :i : FoOIAEEar ii sirF 5rg h e iaA% IsiRgE! i {77n 77 5 :Fi} oPiEoEn E igT s E3sin i 25 + [i 1 i Te TEO ER L POE ly = i 1 iBoogi | Ho haf is 5i P|ooee i {BE 1Eis] ji 3 gg il8asg H | i E IM sft |; f8g ||g ied gg2eiiiEesdi i& | B) E i 8 Eig iz| J PP o lljm, EE SlCsT angEeR | PETE gE Ip iB Ee dd 3EABD B TeERE ey aF ii BE c2m 2i : fi i s| Bi EE is gil &gi fon} iIRE 1 Popo isd 3% 2 !g g iar 24 ii Pi osEs FE iiidf i24 |iPOEes | BIaRE, 1iE3: 548 iAEI PL EE Eig FiiH3 FE5 & z 2 FEEEEREEE Zg z2] 2 oT it ; $z1z88 f feoezeobit ZA IEE g EEeEgEzEnE E2 i leg ge=fE8FE 2S |2 : 2813 =| g : i) : so] |fEidzgyild f 2: s 5 8 fd | i Boz i plznesng sl 22833 : E : ie 23 EE 2 i}f ges -r=2r| dd i; E ERE i iSEoR. a3 Z43 FE 3 2 2 gu55SSS 2 giiasacs Z J F 2 |Z |g H2E]E gEeEasEsEeEs 1 3 |Z Z = [BL] 1 =: [3 2 = s| EE 5&) |B9iiziiy [2 oSf le Sox2ox32s%l if 5 2dL : : FERRER 8 =| 2 og 5g " i25z 2 2Ss3 2 i: i 3 :f $3 cg ~eo2g|ldHI a3 El HiI R]2 fa 2 o HE g-=>5mx% 22 wo i & APFO (LinearfBranched), APFO (Linear), nd APFO (Branched): 14-Day Oral Gavage Study inMale Rats and Mice RevisDiuoPnoNnutm1b4e1r621 RAT FIGURES = _-- : FEES | 1 | oil : I) | | | | | : ORL E | | | 1|ANo : i|| \ || ? & 3 | | | A) | ; i $8 8 38F & 8 gs" 5 : Tebith | [. AWRi .i Z1 . z \| . cI NL Bo h CY | BHlo= Iisd 3 i . || \" | | = (3) 1 Apoguw : HHH 74 [. tM E Ll | 2 :| I | 1. % = 1 nN ik HE E fl 1 nl Wn EEE . i | | 1 LL APO (Linear/Branched),APFO (Lina), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice ReviDsuiPonoNnutm1b4e1r62| RAT APPENDICES - s._______________ A14P-FDOay(LOirnaelaGr/aBvraagnechSedt),yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): ReviDsuioPnoNnutm1b4e1r62| Appendix A Individual PFOA Serum Concentrations for Rats -_-- A1P4-FDOay(LOirnaelaGr/aBvraagnechSedt)u,yAPinFMOl(eLiRnaetasr,anadnMdiAcPeFO (Branched): ReviDsiuopnoNnutm1b4e1r621 INDIVIDUAL PFOA SERUM CONCENTRATIONS FOR RATS EXPLANATORY NOTES STUDY DESIGN H24921 APFO (Lincar/Branched) m1aA VA VIA IXA XIA Groups. 126313 APFO (Linear) mBB vB VIB XB XIB H26225 APFO (Branched) imce ve vic XC XIC Dosage (mg/ke) 0 (Control) 03 1 3 10 30 Gdersocurpisbemdaiyn tahlesottbleei(dAenPtFifOie(dLbiynctahre/Bgrraonucphendu)m,bAePrFonOly(L(i1n,eIar,),etocr.)AwPiFthOt(hBertaenscthseudb)s.tance Abbreviations mg/kg = mg/kg/day L= Linear B = Branched 5Avdegv==Asvtearnadgared deviation NIA = Not applicable Note F-26225 is comprised of two components, H-26203 and F-26204. _-- A14P-FDOay(LOirnaclaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasra,nadndMiAcPeFO (Branched): Individual PFOA Serum Concentrations for Rats Dose Group Level ID IA Omgkg 101 102 103 104 105 106 107 108 109 110 Avg ng/ml pg/mL Linear Branched [+B 0249 0405 065 0153 0229 0382 0187 0260 0447 0262 0257 050 0218 0265 0483 0102 0121 0223 0101 0155 025 0086 0087 0173 0234 0196 0430 0083 0084 0167 0168 0206 0373 sdev 0138 mA 03mgkg 301 191 44 237 302 138 28 167 303 170 42 202 304 149 35 185 305 170 42 204 306 153 28 182 307 159 33 192 308 169 32 201 309 155 27 182 310 1517 152 Avg 160 33 192 sdev 25 RevisDiuoPnoNnucm1b4e1r62| L/B 0.62 0.67 072 102 082 084 0.65 0.99 119 0.98 085 0.8 438 484 409 435 413 543 488 521 576 789 510 113 - A14P-FDOay(OLrianleaGraBvraangcehSetd)u,dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Individual PFOA Serum Concentrations for Rats Dose pg/ml pg/ml Group Level ID Linear Branched L+B VA 10mgkg S01 456 98 554 502 433 73 506 503 446 80 526 S04 385 63 448 505 613 128 TA 506 465 83 549 507 434 65 499 508 338 57 395 509 452 62 Sl4 510 328 34 362 Ave 435 74 509 sdev 103 VIA 30mgkg 701 923 140 1062 02 923 144 1067 03 834 134 968 04 803 133 936 05 863 125 988 06 1049 169 1218 07 1001 127 1128 08 1062 166 1228 709 893 122 1015 710 903 104 1007 Avg 925 136 1062 sdev 10.1 ReviDsuioPnoNnutm1b4e1r62| L/B 464 591 556 607 471 559 670 593 723 961 620 143 661 643 623 603 690 619 789 638 7.32 868 686 085 _-- A14P-FDOay(LOirnaelaGra/BvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Individual PFOA Serum Concentrations for Rats Dose wgmlL pg/ml Group _ Level ID Linear Branched L+B XA lomgkg 901 121 151 1357 902 161 182 1789 93 206 255 2318 94 94 110 1051 905 147 170 1640 906 163 163 1788 97 188 226 2108 908 223 299 2526 909 M42 166 1581 910 194 245 2190 Avg 164 20 183 sdev 455 XIA 30mgkg 1101 133 13 1463 oz 229 27 2567 1103 193 19 2119 104 135 14 1488 10s 182 181993 106 198 19 2172 17 124 6 1296 10s 227 2 2499 109 232 18 2500 no 247 23 2603 Avg 190 18 208 sdev 509 RevDiusiPonoNnutm1b4e1r621 L/B 801 885 810 859 8.66 1000 835 746 852 795 84s 0.68 985 843 1009 970 1024 1030 2089 1045 1294 1088 1135 354 Test substance H24921 L/B raio= 0.781022 = 355 nmgul/impLlvyailnugelsicnoeraercvtaeluesfobryst0a.n0d0a0r7d8caonmdpobsriatnicohnedanvdalcuoensvebryte0d.0o002g2/. mL by - A1P4F-DOay(OLrianleaGraBvraangcehSetd)u,dyAiPnFMOal(eLiRneaatrs),anadndMiAcPeFO (Branched): Individual PFOA Serum Concentrations for Rats Dose ng/mL Group Level ID Linear IB Omgkg 101 0236 102 0.199 103 0.192 104 0275 105 0230 106 0303 107 0191 108 0.181 109 0260 10 1.846 Avg 0391 sdev 0513 MB 03mgkg 301 240 302 219 303 232 304 209 305 209 306 199 307 148 08 155 309 226 310 176 Avg 200 sdev 32 RevisDiuoPnoNnutmb1e41r62| _-- A1P4-FDOay(LOirnaclaGr/aBvraagnechSetdu)d,yAiPnFMOal(e RaLtsiaandnndMiAecPeFaO(Brran)che,d) Individual PFOA Serum Concentrations for Rats Dose ng/mL Group Level ID Linear VB 1Omgkg S01 730 502 869 503 65.7 504 520 505 716 506 499 507 574 508 712 509 645 510 564 Avg 649 sdev 113 VIB 30mgkg 701 124 702 108 703 131 704 164 705 132 706 125 707 153 08 162 709 133 70 136 Avg 137 sdev 18 ReviDsuioPnoNnutm1b4e1r621 EE A14P-FDOay(OLrianleaGraBvraangcehSetd)u,dyAiPnFMOal(eLiRnaetasr)a,nnddMiAcPeFO (Branched): Individual PFOA Serum Concentrations for Rats Dose pg/ml Group Level ID Linear IXB 10mgkg 901 115 902 254 903 230 904 337 905 225 906 192 907 17 908 238 909 129 910 170 Ave 206 sev 65 XIB 30mgkg 1101 291 102 206 103 185 104 244 10s 363 106 88 107 165 1108 290 109 205 mo 19 Ave 23 sdv 71 ReviDsuioPnoNnutm1b4e1r62| _-- APFO (Linear/BrAaPnFOc(hLeindea)r),, and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number | DuPont 14162 Individual PFOA Serum Concentrations for Rats Dose Group Level ID IC Omgkg 101 102 103 104 105 106 107 108 109 110 Avg pg/mL H26203 * * * * * 000 011 000 002 000 pgml H26204 = * * * * 000 043 000 0 000 sdev H26203 + H26204 * * * * * 000 054 000 002 000 on 024 H26204/ H26203 NA NA NA NA NA NA NA NA NA NA mC 03mgkg 301 56 65 121 117 302 61 81 M43 132 303 83 104 187 127 304 66 98 164 149 305 94 132 26 140 306 68 82 150 120 307 65 58 123 091 308 77 103 180 134 300 62 80 141 129 310 76 87 163 115 Avg. 71 89 160 125 sdev 319 016 * lFiinvkeeodf0thtehe10apsperrouprmisataempalneismallasbealnedd waserceontthreorlesfocroeuledxcnloutdceodncflruosmivtehley be. calculationofthe mean. _--_-- A14P-FDOay(LOirnaelaGra/BvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): RevDisuiPonoNnutm1b4e1r621 Individual PFOA Serum Concentrations for Rats Dose Group Level ID VC 10mghg S01 502 503 504 505 506 507 508 500 50 Ave ngml F26203 163 217 185 170 194 209 186 1s 167 136 174 pgml FH26204 34 462 416 312 385 260 294 152 252 199 305 sdev H26203 + FH26204 476 679 601 482 580 469 450 267 419 335 419 1222 H26204/ H26203 193 214 225 184 198 125 158 133 151 146 173 035 VIC 30mgkg 701 398 796 1194 200 702 258 S01 849 229 703 22 43 665 200 704 298 642 940 216 705 240 559 799 233 706 180 299 479 166 707 122 262 384 24 708 317 538 854 170 709 207 408 615 198 70 185 298 483 161 Avg. 243 484 126 19 sdev 2484 026 BR A14P-FDOay(LOirnaelaGra/BvraagnechSetdu),dyAiPnFMOal(eLiRnaetars)a,nadndMiAcPeFO (Branched) RevisDiuoPnoNnutm1b4e1r621 Individual PFOA Serum Concentrations for Rats Dose Group Level ID IXC lomgkg 91 02 903 904 05 96 07 908 909 910 Avg wml H26203 34 37 21 30 29 25 30 31 36 32 30 pgmL H26204 72 6 26 48 60 59 58 75 76 76 61 sdev H26203 + H26204 105 102 46 kd 89 83 87 106 12 108 92 20 H26204/ H26203 214 17 123 161 207 237 193 239 212 235 200 037 XIC 30mgkg 1101 39 3 11 241 12 40 m6 155 292 13 29 104 133 362 104 47 139 186 2.99 10s 18 53 7 2.96 106 3% 105 143 275 171 29 8 12 286 1s 27 78 105 287 19 27 6 9% 231 mo 4 8 16 244 Avg 3 2 124 281 sdev 33 038 Test substance H26225 ratio = 58% H26204/42% H26203 = 138 EO EE EAA U. iarI A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): RevisDiuoPnoNnutm-1b4e1r621 Appendix B Individual Body Weights for Rats = -_-- A1P4-FDOay(LOirnaelaGs/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): RevisDiuoPnoNnutm1b4e1r621 INDIVIDUAL BODY WEIGHTS FOR RATS EXPLANATORY NOTES STUDY DESIGN Groups H24921 H26313 APFO (Linear/Branched) APFO (Linear) H-26225 APFO (Branched) Dosage (mg/kg) 1A B ic mA mB mc VA VB ve VIIA VIB vic XA XB XC XIA XIB Xic 0 (Control) 03 1 3 10 30 `Groups may also be identified by the group number only (I, I, etc.) with the test substance described in the title (APFO (Linear/Branched), APFO (Linear), or APFO (Branched) Abbreviations mg/kg = mg/kg/day -_-- es Bl, iZF T= . .3a pmo oosmsEnnann params ooammsnane pneenaons TH Teh Shmi iy 4. geessavnan saaneacsss sessseaees g $1 13. commer seen sme 2 for BHRARRRRAE REREBNRRRR EERAREEIEE 13 i gisdindEse RASRsSREER NfsdsREEms BE amimER iE Hae eo : : i i 2 EH E &. 2 covnmrauce Foonmrcounay 2 oasansesnan LH ssazssazss ssmmmnases 4 saasnenans i ii gic ji' i| i i }: 371 BmERoImAEnIRnES mIEuNAnRAnEInNE D AERRRm RESER i3 Y=: Hoff S3 2 52 12.f7 oBEnABmIoRRnAEnS mIANu RNERm NSY mSEEm SaEsmEER : ennnnnone gafssgazss wunesnandn | smmmengmes AssZissds sIssssssas # 8| =1Z; o; FoAsdzzdgssd i msddsdidds b: andadsddss HE BOE Do IIMINE Maen nmmnE 5 bo. m ZRE%o283m E38 mRONm GREEm RER mRNRiERnEEiREmE Th2 3 i | FTE. seamen pmmameenr rgmanases i He RSRNRRAARE SARANIIIRE ARIIIIRERR 4 fo apmmeemens gpmmenaans sneneenna 2 *z RARARRRARE SRRRRARRRE SANERAIRAS 5 3 7 gegfefiEse fainisNsd dsddesddaR Bl 1 sof # gdHE;) i g Ss saszesasas s gszasssses HzEuRzIzEsEeEsEeEaEs 53 & HIE i IPiEe mISRRmNNRmEAR mAmamdRendss RE nelRRElEmd BEiRaniEss E i: REEfLio HSIEMAE mDEiEmS GRERREEERAERR : i i Ce i bgaeoaT mams mn mHaEnMsE oo BRREEEERERRRR i PE g 25 5.7 iEEidE AdiE dil d8i5dcdddsaadddind sirsscasis 33 oo; a faSamaeEaanaamd fIamnEEiEE Rz aman REREsE IE gd 3 57s ? seezpsszee BREE ssuuzmaessesss = : sgdE EREEEEEEED =a 2s Tg 23) = 5 fs i i 3 E SEBRAIRRRZ ERARARRAAL SRAAERNANR | :2 i. ivfy mmm FRARARAREE mmm RRSRNERAAE monn RUBRAEREER i! gs %. iz 37 2 Fo gg for sescoosesn REZE3ERA3% INEINNIIIY EREARNREAR numscessan REEERNRAER OSNIRIEENY RERGRREREE aaacaceens EEREARRssR fIniIn;: RERRIANERE 12 I ERE iz EE 3I aeenananns RRERRARRGR TJ aNsRnAaCnRaRaRaRnRnR 2I onanRnEnRRaEemsd Fy : i : gd 3 a3aassnsas aaszssases sasagssiss 353g. 25 I ie 38.7 dafssadsd sEsddisiiz desdasad ' B Pie smmumn pmunu annum gy . if ZB i 23 qsegmaanc eayenentas SSENIfnIe wveysdyees Ssseancins novsmeaann 2 i 2 EHS 2 smveenson Foonsncanans nnvanaanae 33] i 3 2 i 2 gd: zsazssssas gzasesases spasssnga: HE 3 .8 ig Ep nomnsmaney | `wessanvvey gadngisE asfdsddsdn whdnensnds adesadadss : % gumnuinans Triaegy 9994999977 g ji' : ii digzsasdsr fifdsdssy ERseeReRds 3 gi }. mommy poms mena 3 fo BLRRANEREE RRENARARER ENRRRREEER 53 fF ig& & fogoT; - gdedsuceRe o: RRERENENE .: fEENAEEEsE Fl pif ii? | ii. oman ummm nnhamon : 3 A7ABRR3827 S538ARNERR CRRRARKERR i! 23 Flo ioITitl udniIninny sdIiszasm zg] [4 BERZREDNES #2X3R88033 RRZAREAEER 1 gz 2 2 2 ig: 3 8 8 g8d: s seezpeseee $ sspssvsses zBsEzRzGsEsEsNsEsEs Bl i 3258] = 25 5 85 Amadis dEiREEA IAAEdREEE 3foEF AMRAEHGIRuERZRR GBEEGmRMNEARSREAmRT. m namAmRsia nss ii t| Ti. sown noo mun : 37% B358R5888% 2R3R3MSREL 3RARRHREAR Ho! 2. gl 2 3.7 ia%adsiids sistedsies sfsisinsss #9 1 EH ff eeniaiaens Fooencacies 2oonaecacan 1: fT: 8B 2 38 # HE ge 1 IEEE BHENE BEEN 7 i Yoo onmmmm amen mim : if iq,2E3s Te IS3IBSERI05I38n% : Inia SS8R8838A% nanan: ZEERSEs3E' 35: 37: i 2 38 in i Bop fiiiRiaes inasdsagar i ji Hizifdzaes iifisisdaagaastsie } i: :i o iiiie iaae Agtdenasis NILE iEiiliieaainse :: N | Epn HsAReaies | i - : ; o3sr gRsasssd HifRtEagReess H# erida `i i ; iiiifEEERR fiteRs iE iRERREEE.E ily;: jg: Fie E} omngEaEEE|lam i % BR | HH i ,spezsgraes as3mszssases : 3R-- REREaEy F3E a i i ji Hdd diiadEEN iiile mmm am $838 sagsEsads : H!i!| o 1h.% 57 miimdsamsisii fsiAiseas issgfe3dinRn3e4n8aFl . AfaAndesdafa5n8REesE | i H oe i ioiRmAEaEEnaE owdBa3n3enngaaEsendds AiS5Ri8AiAMagiaEaAnEsn i&Edl oDoog nmmnn doHwniaiansiane 3IavisEAAnd r3 4E: $2. i:BF i EE 7H35a33l07s30ei 3:-{ sdReeiRidie 2?: SEE33RECaoAE54S semsersnanges a2 ssassEiEnRsIE; BEREREEEEERE : ADPaFOy(OLrianlcaGra/vBraagnechSetdu)d.yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched) RevisDiuoPnoNnutm1b4e1r621 Appendix C Individual Food Consumption for Rats Tes A14P-FDOay(LOirnaelaGrfaBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): RevDisuiPononNtum1b4e1r62| INDIVIDUAL FOOD CONSUMPTION FOR RATS EXPLANATORY NOTES STUDY DESIGN H-24921 APFO (Linear/Branched) 1A ma VA VIA XA XIA Groups H26313 APFO (Linear) B mB VB VIB XB XIB H26225 ~ APFO (Branched) ic me ve vic IXC Xic Dosage (mg/kg) 0 (Control) 03 1 3 10 30 Abbreviations mg/kg = mg/kg/day ganmiday = grams/animal/day we Hi i i| : i ij gHa gf4maidamnsR sR aimmmm H S : ofh men man sacanassaas ob 23: B5$7 dReRARRdAAiRiEdNdEd . RReEdAaRsSsEsRiEaAsR NAAAARRAAR HiHE: HERi R : :mmm : wane FE4 Po 38g3zssssasseds aARsRmEaAsErRazas assasssass 3g. 3] 2. z Le : g = i oS P| aE 5kk mmaman oammmn ann iz i 5% 3 iE 3 EF | So He INIEN ERINDD Boum Sg RARBERA8NS RAZZNTANER IENAIALIRY ij. usensmoses LH dddddngdd ops BB Bec ToARASAdERR sssasmessas dandgdddds ;2 PoAmAsEsas os-oSa-cdagsiadaecqeg i2 Tinniniiis i #2 it i ! 5 : 3 3 i0 ifiiE mamun Suman seam gi i MER AnEEn aunnn i,od 5 588 8: 58: gdal : $j. egeasaatse neesassass vesnassces 33 LERRINNAER HINKRERIIR QANINARGIRS i i Ff AcoHnEeRnEnRaAnNnEaA 2 wAazqaesnnededannded i csmrrdnsesos<ieaannd Bq E g 8 ssgzssssss $ sas3ssesss $ sugsssssns 38 2H3]ER3E gal 2 2 Hi a7 : = i 5Sb F! 3i%3n 2 ii ie gi Bi. oon GRINGNEERE SREREARARN aamamnangs GRAMERER GRARdAARAR gaaamassas sams ARdessdisd suseeasane iERio LEi aniziianes i: sitinanass f: orme 3g. i$3 8 la ; : = i TCE i Ey E i Bi mm RREAAEEEN aREEEIEED GREERE Emm HEEEE g BE GREERERE GEINIEERER BMREMEE ea y : : 1 1 2 : HiEgE: FwnAsTovaEen C I anI qmenI neey TaOnavRnanEte 3 &5 ; asaassasas sasassases sagasgeses 5%= 4] 13 Si 2 i:i s2: I iPo ssw o BgN i ommmnn 4 Bi mame 23 5s mmm osomnn aman somn osname mmung gSoEl; gB3-gI RRRRdAReRS I` GRREEEAAER :PaEEiiiEin A1P4F-DOay(LOirnaclaGrfaBvraangchSetdu)d,yAPinFMOal(eLiRnaetars)a,nadndMiAcPeFO (Branched): RevDisuiPonoNnutm1b4e1r62| Appendix D Individual Clinical Observations and Mortality Records for Rats = A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAceP.FO (Branched): ReviDsuiPonoNnutm1b4e1r62| INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS FOR RATS EXPLANATORY NOTES STUDY DESIGN Groups H.24921 H-26313 APFO (Linear/Branched) APFO (Linear) TA B mA mB VA VB VIA VIB IXA XB XIA XIB H26225 ~APFO (Branched) ic me ve vic XC XC Dosage (mg/kg) 0 (Control) 03 1 3 10 30 Tis -- 3, 2i 3 i1:: Hi i Sia hsnhahlhnhEhihalh ilEh iah lhEk 2 3 2 {3 Trriliiiiiii ; i 2 & 3 &2 # # # 2 8 2 2 Ili S|0S Bgl 3 iii iiiiid iid id iidi ddd a oa 8 8 2g fog 2 22222 Hoon BHEERREERERER 5| - 33fr i5%r 5b8r 6$33 5f3n 5E3n 5G8r G3r 5G32 5G3n 5b8n 5b8x i53x 3 gaan ngag 2 - $f8 iloses 3338333833: BE 1. LL. ess ffe s BAS 5. 2 cx x ss sexx os oxo a, abs &3 for rom 3% ronoror oarromi: ae SF oN SF SF SF 4% oN of odN 43 SF 4% oF i 3 a Dr I1IIIIOIOLOLOLI: - s| d3 # frr3 rri2 io2 :i2i2r3 2o2g23 o3i2o32 d73d Piiiiiiiiiioiind IEEEEEEEEE EEE Bgl 8 of 2 2 2 2 02 8 oz 2% 2 2 2 2 HHcgH = sE%hLaE hn5LLh3 Bh53Lh3LhLh52na83LdLaIg5%RiLi5 i3hi5hg5i inngnnnnniMEEENG Ye i SHE Br 8888S sososs os osos os i. 23g 3iz iE il $53, 3. 3,3, 3. F. J. F. J. Fo 5. 3. 3. 3. F BE 03% 43 43 5% SF oF oF SN 4% 8X oN 8% SX SX oS & 3 : i 3 2 31 vyTOROTOYTTITIiiiii : FE :Ff2 3 f3F: % EB& 2 38 g&z 23: g2z & k: &: of& IEREERERERE RR ER D gl 2 231%: i454 440d By| 3 or ozo:oa gooss aoo a oz 3o3ois os { G48 8 g8 8 B 48 8 48 48 4B 0B 4B 8 48 of Ea 38 28 95 33 38 48 2d 22 88 83 43 18 3 38 3 Gilz fEhp xhfhx Ebx Ehx hEx hEx hEx hEm aBx h5 hBphBxhE5hfx 23 idafunuiguigunnu fg fREEEEEEEREEEEEES ES] 5: = = = ox = ox ox ox ox ox ox ox ox = i i i: 3] a i i Pgimh , mom.om o%_h om.o%.oS. 3%h . d o%.odiil {11313 1TTGToToIiiii : fF &E &2 ZF % & & 2 2 Z 3 1 3} HHIiEtRErEiEiEtRiEiEEiEtEiEiEgE 4 22 222 2 22222288 SE 7 38 58 8 98 88 28 93 18 28 93 Ed 3 id id FGEE tEhx fhx aEx hfx afpnG2nirn3aGh5 Ehn hEx h3 hirhix 31 4 53% 5% 8% 83 83 3% 33 23 3% 34 53 8: 338 13 efsdls; EE gs: FETf. ,8 .8 2 0s8 0s8% ss% f233 3353 38:3 . 4i 5 it i113 ; i & zz 5Hel EE gy i ELE 5S723 # = jenn EE2E4 8d 2 = LE 3 34 8 i8x8 x i8x3 Eos BR ET iz - e5Eg s := i#:3 po: 3= EE EE E74. 2H5 E13 ae ji Lh hihi iii is i i i 1113 111 O1IRl * 3 2& 2 2 2&3 3 && & 2 af$sl]0:3 8r Tir 2tr 222 og r Zrrz :z1o21 rr zd r o2 Hiliiigiiiiin] Bol 2 2 2 2 E12 2 2 25 2 2 2 1E23l = hh hhanhhighhhg i8s 5p3i5r3 i$z3 i$8n3 bh59 5i8r E8x EHPHS i8x 5i8ri2r3 iE3e bE fgunuEmadnEangg M88. LEE 1: ssa I zso1 z:o3 s oa 38 8) i: iE i: i EEE EEE EEE RE EE 2 i i = If trig tilted DIoE3EorEiEiEiiEoEroEiEl 1I1I1E% - 5 & : 3 5: & & % 2 & EF:i sl = zz zz zz z zz 3 zzz | F FF Ff 3 i 3E Gif oEioEd Bgl] 2 2 8 8 2 2 2 2 2 7 2 2 2 2 iE iF gaggaagndmanag iHSlzE = fs hhhhnhhhbhhanhah 8E8r 5i3x Ex i3x 5j3 p$8op58 58 E3r 3Bin 5f3x 3 2 5E33 5x E% n & pHBHangHaagiHany Heol.. 0. s 2E3]L = 8 BE BE E BE E 3: 8 = = = ox ox ox ox ox = ox x ox ox = 38 3 &, 253 513 a frazo3izaiiiliiil ol gee SF SF SF S63 43 oF 4X 43 43 4% 4% san fPoyfif o8rrorri8i8i i&i oa oe o ; & 8 8&8 & & & 8&8 & 2 2 32 2 2 IEEEEEREEEE ig i IEEEERER g,] = 28 2 8 2 28 2 2 2 2 2 2 aif i BnnBnnRRng i i Hi 59 3 dy dp dy dy dy 43 47 4 dy 07 bg fi gl 3 gf IERIE gf gr gf RRR gd gd Y ES RINNE gE g% gu gids RRR H iPdei s rrr 3g. 5: i fiizinizizizizindndndadnis nin : s Sf viririviiiiiiii | 2 & 2&8 8&8 8&8 & & & 8&8 &2 & & zx z 2 HIEEEEEEEEEE ERE EE E I EE E E EE EE EE E E NEEEE EE E EE EEE By 1 8 2 2 2 8 2 2 2 2 2 2 2 2 22 i shE EEE ERE EEL, x i $8 58 58 8 58 8 53 3 55 53 53 58 33 58 3 3 5 E3 fr Gr fn En in fr G3 fx i Gn fx Gx 2 33 jana nnEnuanEng Bt lesssrrssssatzns Sf Prezzoaozoaorozoegogoeoos 38 5 sg ZgaFl i1:2 il;i i fri. 33s 3s 3s 11111 : i &2& 2z HEE EEEEE HBl EEo RfoE8oE8 EfEf gy 2 2 2 2 3 3% a 8 5% 33 33 33 Si3z5 _ bx Er Er ix ix F383 8g 8g 4; H2o2o 598:8 -fag i3s #5& 55 327 34 H3E8 F # $sR 828E 8 3 BY 22 22 5 = 34 HSy{lg8E: 224|] 22 il Sesb3bs,bv5b.3hobn.bslhlEhnhL bThLRh. hl i 5 rT 1iiiiloOTiiiii - fof EF for op ror ofop bb oE fod H ofa dE aEtErEaErEE r EEiEtRe E 1 fi ii1iii ii1@iifi H EE E EERE EE E EEEEE gl 2 2G 245 258 24B 2g8 2g8 258 2GB 3g%g 28 2gE 28G8 28 28 = i2] thh5 gaEF h3R aBh3Xi2XahF h nhhFgER bE nna nmunnnun Aote 1dessa: nas i33]9.. =z 5 13 iE i i TFBreadxn ls eixz ian leiz adae n ls elw ayiaiE aidalss PPoTiTiiIiTiIoTiIiEioIiIiIiIiIii - s| 2 Eo] 4 880d idiid iia 2 2 2 28 2 2 2 5 2 2 2 2 3 3} 5Bo:s2h Eris Rfa EfEaiRbsaEbe RbatsEfEn brLbr ba 10a 3 innBnEnEBEnEEnE Hs sol? 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HE EEETE 2s38a38 os s2ozozos 3g3 2332 ii az i $E 53,l 9x.i3,xz i5n,l3n Hiei P EOE 1OE11 LO1 EB F FEE Eid El 0 42d id gy i 2 2 = = 2 2% R58 9% 8 Es 3 iHzq iihr ihr hEx hx hEx 3 IRIRIRIRIRI] 1gg%:; T=g: 0d5 83 8Fd2 gs 1 f= = = = = A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnteasr)a,nnddMiAcPeFO (Branched): RevDisuiponoNnutm1b4e1r621 Appendix E Individual Animal Clinical Pathology Data for Rats -- = APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in MaleRatsand Mice Revision Number 1 DuPont 14162 INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA FOR RATS EXPLANATORY NOTES APFO_(uiEnearT/Branched) 1EmY vinta an STUDY DESIGN ee[== AFRO 1(E1lJsinear) viis F"xH AeTOI(Brsanched) m3e vreie ixee _D(omsaa/kgae) T(Co0niteoTT i33 ssssprmnions Gonozale akVegd - mmaadsevtaascaesy InatvidualWTReSd BlooadniCsoolclytMoosrtpshology Values: WWieC - mmiccrrooccyytteass PWOoLY |- phoylpyeecnhoammssiiaa EACCER | eaccahnatnhooocyytteess THGRB C| Hsaoorwugeaols:lu-ncJeollllsy body OTR- ofottheorbszeerdvebdlooodf cneoltlemxoanripnheodl;ogysoe whole blood sarple condition PsOcIi psocihkiisltooccyrtteosis IndividualSSiuCmilirinica)lhieCpmheoenlmiytassitsrfryotmVraomlvueevnsea:nacacvaavasasmapmlpele GSiIgCiT cihcotleersutserforlom vena cava sample noMOInLGi, nhtoirnoi-hgh-iidygeehnosrdiiedtneyssiltiypo1pirpootperiontecthnolecshtoelrsoslterol MLiBe | hliepmeomliyasisfrofmronorboirtbailtalsinsuisnussasmapmlpele Tor iclerue from orbital sinus sample 18- A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): RevisDiuoPnoNnutm1b4e1r62| INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA FOR RATS. EXPLANATORY NOTES (Continued) D"urreianrgs vtahse mcaodlel.ectAiLoLn rofesabilnoiondganadnimtailsssueasrefoirncKl-u2d4e5d2)inSectheAaapnpiernadlisx, a decision to prepare blood OWhtehnerirnedaisvoindsu,alalalnioofalhdiaccha aarree enoxtplarienpoerdteidn, thiet msatyudyberdeucoerdtso ono of the following reasons or Cthheoresawmapsleiwnapsutcliocitotnetd s(aCmLpTl)e for testing (QNS) tthha4e 1as5nadimzpalFleosudwlaitsedncoopturlidosruinotttoablbseaamofiboertacitoneleslcdeicn(gtRiVo)n f7o0xspaorcptleormwaasd a(vXPa)ilable for testing (VSR) --_-- ziz 2 i PR pf g I i i i 32 :3 Eg viv g g S| i . gs Toad gE gE iz i : 2 i2] g. f co i2 f IEEE if TRY iz : ? 3 T fu E Ty iz ] f ! 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I 1111T HH 2RER REE 2 & 22 3 Crore |IEEE I. i F]:ffie3re.5s.88 prpFoTf]. un :: ie goon Foon 82 32 2 8 8 iii E TTY E E g : 3: : I: 2g oe Bon pg2H3 E:T,e ziF,e is4 sos 2 I | 8 4Z| i: i| s3s8p3s8e8s8c8e8e%s 5 3 d3=33zaaasEsasEsEsEs 333g3 H E ig E i Eoin CIRREERRREEN 3 i 3 8.8,.8 ii 8 5i s2l #3 0, s Ty 24 SEE pd i i 4 5 gt 23 i, i PF 3 1 { 2 g2 E 5 33 cf sszGRsRsRsRsRAsRaSzS gogF oRgRsAsRsRsSzAsRssaRs 32 2i: 52 2 rod t 1z z iz :2i 2 sdi Foor g 8 Por3FgEy oo 2 Df rerrreinr Hd 3 i tg Te F g en :p = 3 F po B verererees 3 : J 4] | sansanmaERg gg eReeneEmR 3i3 CH 2 .Eof 2 IE . 1f 0H 2 28 o i d8 oi g i i i fl fF = yoof COPEL T i E 33 i i 3 z, :, =3] BoE rrrrrrrrrrogog rrr Hoo : fs FF 3 Crna 33 f. i gd4 s gTRsEzRzRsERsEsSsSs.zg so 30 sAsAzmzAsssmaAsEasss is 3 = i i3 : ii 8i38%r gzoammcsaznannyeaans iHsy susamssans 2: :: i3% sasmamaazzrzassss 839} ssaesanneazmaaaaanss 3i i2 2E8f ssarsiazes Bf3 smsswseses & x El i F. : #33 smsgoreemssesennesas G3 88] szasnassse i i : i2 &CELETHTE ION3| EH 18858H 3| i 5 Epmssszsy 2Bon sBBEBBaas: 52 HE giapeaaes 2d HHH 2 F BEREBEBEE O% E npnpnpnu 3 FIR EEELEEE ELI I EEEEEE E $ I. i 32 : asmzmzmzmssasmzaeas g. fI asnzazmsasmsasnsesds 2 i i i :i 333 "wananaang 83 oomaderens 3 : i 23 Fg asnsmsAannnnnaannsses 3B3g zmarznnmzmeeesmcesss = i 3 3 # ARARARATLR | iy somsazsass 4 BY ssesageesz I 3% samzmusmass i OHBBHE O npn 2 ao i HIER UHH HTH 5 ER HH : rpm forphlmn 3 i { sasazansn $ 1 seazmpen: 2 i i 3 3 fg rAnmRReAs gp nnenRRsEsn 2 i3 3293 SsAzRsAeAsRnRseesnsz B3%F RaAnWeRnAnRsRaAsReSn } 5i . i i i ARBRARANAR i EEEEREEEE) Fz 3% gasasseass 3 33 ssusssanes i OF BBBBEEMEEE B MHIMH 33 BoBREEIEEEED OB BEEEEBEEM Hb 8 bE 3 &=HS ori TzgEazRssRssEss G g gmssessmssees i i : FH 2285RRERS i saszagazss : : a seaRsanang 8% suensagnss 5] i i Bf sessozsans Y amaemsnnan gs - 8 $353528898 x } xNsAAvaIIR i i ; i o OHEIEINE Gf mnHLIM 23 i 2 33 TF BEEIEEE Df mppnnm iis: =Tg BOrMEsBEMEES :Bog OF poamspespninin 38 i i gs i 1 sazzasanas i { smazesnemm 52 ii2: i i : iPEFEPEEEEN i CEMTTETELY 4 : i EPRCTPPEEEE] EH S2eg228en i 2 : 82 sacassnaze 88 cunsagseng 2 i Eg mnnavEoans Eg monvnInIas gy : 2 8 2233888888 3 #EEEEEEREEH] 3I : i o OBRERREREEE BEBEBRMEME & 8 OF HEMEL 8 HEHEHE i4i) aCg prsrrsias 5 -- BHC Efe is 24 i Daman essen 3 it i : 38 ii z i i : & annzesnags i aReInasens i i ] -ozzoszann 3% sasmazzaen = 2 i i 8 3sagssesas } sassasasss : 8% snsansnass : 8} secmmanan Z3 y . i OF HHUIM Ob HuBHY =3 vTo5u BsEsReEsBsEsErEsEsRs vEoBs HssErBrRsRrMsEaEsM: 34 .TOF pEsHsIsfmeBsMfeMsEs fo Sss8m asfes i3 i i. 4] + 1 suzassssss go 1 saasmaas =| if @ mnnnmmnees FH LH 2 i i i : HH 2233R3RAR is 2237RR8R58 5 i kil i: 2i 35 seeamanaia 23} sssanssasa 38 cunressnss EMECEEEEEEEE] 235 sssasazsss 8% sssmuapens i: < OBREBREEEEE BEBEBRMEME 23 g . 3 S 2 53 BFR oy oN 222333 Y7 o pu2n 2 % : 8H COG 5B srraE szree :2 i. P. ; zzszssszsz of zgszsssszes 2iz i ; Pf enon ff meses s 2 8} sazanzsass $] ammmnunann & i N i BY masmssessn f sessasssnz sily f 2 8} sanmsnseas :Ls ssxasasazs i3: g% . HvEeeEiItEEBsEiMEDE.5 BF HLEALMUBBEEEEMREEME 2333 7 BEA EEMBEMEE 0 MBEMEMOM 1 ovummug fF pun Iz i 43 5i 13 sRRsIaBsRaRsRaRzIeAs $of3 gRRgEzRsRsEsRsEsEeRsR Zz 5 2 i i i E88 iaicivnmes 32 caamasnees 3 [EE : : 8 sg2nenzzag 8 asssozaass sl fe i" 1 3 3 smRR=aIRss Ey seszssases Hy Pe $e Sl 5 gl = gl manmzesnen 3 EY assmasszes 4 OG BERRIEN HBlaBsM 43 E[ER o,HH TEoEe ssassssess i (ERR RH 22 i f. EH2 oF zoF gFazRssEsEsaRz pod gs@msAzRsRsAAsReRsEsS iH 2 : ; 3 g . HI Ed 7. 2 i3i Ez THIE: RTI $33 HHI ERHHHU IER HiH,H LLa RRR THER" HTH FE i z g2d &s 4azazesazes 1 asezssasss 4 iE" iz 3g 5i32 3 ii 2 i y : 2 13 3 3 I i oF ORERRERENEE oe BEBREBREM 24 EER HHH IER HHH 25 i! : i i il 8 : : 5 i d i Ep RRBEREENS fv HBRBEIMEME gs 3 EL 8 searrsrrss HEHEMH fvss HsrrEerHssrEas i : jrigegagas i Bgigiagenn S| 5 0 sapzassass 0 ssagssssns 38 25 552EL i i g : 5 3 i : ii 8 3 Yi o:i i ERR 23 i 33 es 3 : 38 4 i HHH HEIN ss ammmmmnnn . :: EERE HHH HHH 2 Ds pany Bor sates 1 ameeemaams 33 ZF i: 3 i z " 3 : 5 i: z3 : i: 2i . 24 x 4 i i d i 5. B BgEgReEgReEgReEgEeE: 28p gBgReEzReENEN2S <33 2 a grzazzasez =foo gzsrssesss 5 BREREEREEE ou BRRRBINEE Fr8 GBaRiEasELREi EGUy fHpirIiasBen: 23584] 5&i8 zTassasnnnas 8ig z1 eeeeeenens 3 i i : 2 5i 3gy LE: 3i I 0 HIME fu HEEHEMIM 333 zB,s g5538823888s8s888e zFEs ogagaEagazagnsaeasns I: [2 LEE EH 3 ERRRgERRSS 3 5 i 4Z| ; sszasnsRsEsmsRsRsREz 45 I og3ggazasEssniEeEs HEHi iEH 2 : 3 i 2: :i 2 x z i i 7 o BRBEBEREEE : Ge BBRBRBEMS 3 Bs HALE 1s HHH HE 2 i & z"uozozosmsmsosmensn : og 7 zn3nzesnsesesnsesnss 25 253 3 2 2 : i 5 ii I 2: 33 gC. i3 x 3I3 i EHH 23 z gggsrsrnEl = 22 [xER HHH H E H: L H 989H 288H 8H2H2 g34s] i s faznznznzasnsnsnsnsrz :3 EiER HHH Sos ppBpnpans: RE HH HHH : EExE T$2H888sTu2H88s goof1 sepnemzesnsaensesss 58 24] i i i i $ = i id : . : : i 8 JEIBRRIENE ov HEMBLIMEM 53 T 5 HHMI 0 HEHEHE f or:. Lszsizznzedhes c s SgogHgsElenEs i3 f od : EHg 5is1 gazzssssaz oo @ sAsRsAzmsAsRsAsEaEsE AP14F-ODay(LOirnaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetass)a,nadndMiAcPeFO (Branched): ReviDsuiPononNtum1b4e1r621 Appendix F Individual Animal Body and Organ Weights for Rats Te A1P4F-ODay(LOirnaelaGr/aBvraagnechSetd)u,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): RevisDiuoPnoNnutm1b4e1r62| INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS FOR RATS EXPLANATORY NOTES STUDY DESIGN H-24921 APFO (Lincar/Branched) 1A mA VA VIA IXA XIA Groups H26313 APFO (Linear) B mB VB VIB IXB XIB H-26225 ~ APFO (Branched) ic nc ve vic XC Xic Dosage (mg/kg) 0 (Control) 03 1 3 10 30 Abbreviations mg/kg = mg/kg/day FBW = Final Body Weight Note 1025 = Rats ies ES iE Fh 5 Pf gi djcisdtemane a Ln Bisdddasadoaosf 4S50 Ri D TTT[EI |i Sa |B FjSANNRSEAAE S50 gf gleddatadide G3 4 W rugS mnnnE M jummn End ? Bl 29 i i ETTRE -i issssssssez i TTT -i is3s3ssEsEl Li Ry he 23 isi 35 iH iq!o i 13 i ; TT i i EEE jE glooi BjmmS Esasi mice amas E iao P sM j mE e B R m # 2a # #0 0 pb gE EE = uh Bgi l o B |gERR esnsEe 2 Bohan || 8 Lo FH Frese to mn 83 | xERzazhan 5 janET=; Hoi a 4 : a E asnse naags go flppma mesan nnz i: re} fig 15 |emim nem 5! : 3 aT PTT Hoos HE gSllo a pj djg mntai ina2nn s 0 |jpHasEasEiiRa5nG)s iEE21of cfiIgEBIizAaEsEsIzEsAsNsZsTs 3B3R): iBgi,gR: BBasEuEIfmsEsEE a AE tI gemma ay i EY | Mipgissssssasas spl Bg isassasasas if 53 Be) fpr BPREITTTUEUEU FL I. LER gE it HI 1 ldHyEIN $| 1 os nim mma nn a8 yDg nautnin B g S8 lal gImEe LLe ELEEr Rs EDa3 B 2sg E ei na n i 2of! a aE gBBl0oN Do 0njTiEgci, pnS nEeEsBnrEE aMenMnEs 1% 1 w#OnBR pfGLeifgmifEatRnnmnn an iH fps JARRREIEREE CEL g H i uo ol3 Flagja sEEesn RaRNminERnAa|) p NT HT mrss i 1 0 TTTPEA ep TT Fiile FE 5] BE FH BE iq ER I Pod i I BEamamiion a fe ttm 1} isl | 3] Ipiissdeasdgsssecmaasmde gi a=] 0 Fi 1ilsscnascdaeesdndes ga a4] oir fn Spam a pawn a, 8 | 2iTissiaseansse! Filsizssesssaisnni i 28 1 gl |jpntE yisussamemE nn|, iyissmE ssmem,m|e i 2i3l i i1PE31 iHqh iy ; a Ty gg Pal i Jg) rhmnEmREmEEaE fg | |p limonene n . go HEEmEER p Bmemmn Boon Pad 3B3l pilhne gBRr33aREmREsER sBEe DiGy g EREEnIEEEEEHIIEEES BgEl gSgl] Ld| pifl eiAeTmIEiRaEATA A2T1L! 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B i e seen gl Bp SeERIEER oEhE BE hp BREEN 2 0 pm Bogan a a I| 3| 0| |cpgfudfcnE efmsomnzEnsE manneeannE g 5E|E bymma ak H EER sal] SpE TTTER A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): RevisDiuoPnonNtu-m1b4e16r2,| Appendix G Individual Animal Gross Observations for Rats -- me re APFO (Lincar/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice ReviDsuiPononNtum1b4e1r62| INDIVIDUAL ANIMAL GROSS OBSERVATIONS FOR RATS EXPLANATORY NOTES STUDY DESIGN H-24921 APFO (Linear/Branched) 1A mA VA VIIA IXA XIA Groups H26313 APFO (Linear) B mB VB VIB IXB XIB H.26225 ~ APFO (Branched) miiCc ve vie XC XIC Dosage (mg/kg) 003(Control) 1 3 10 30 Abbreviation mg/kg = mg/kg/day Note 1025 = Rats m APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats nd Mice Showing anIinrdailvidduaatla AfnoirmailndLiivisdtuianlg SDoTsUeDYGr: ou1p5073T1h0205mAg/k(g* ATPrPeRaOtVmEeDnt:PROTO0CmOgL/k*)g TA Sex: Animal Ref Macroscopic Findings Only 101 TKoirlnliendalonSDaacyrif: ic14e Aninal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed 102 TKeirlmliendalonSDaacyrif: ic14e Aninal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed 03 TKeirlmliendalonSDaacyrif: ic14e Animal is signed oft from necropsy No MaLcivreors,copKiIcDNEAYbSnormality Observed : 108 TKoirlnliendalon sDaacyrif: ic1e4 Animal is signed off from necropsy No MLaIcVrEoRs,copKiIcDNEAYbSnormality Observed : 105 TKeirlmliendalon SDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : animals Males Revision Number | DuPont 14162 Date: 21-70-04 7: APFO (LinearfBranched), APFO (Lineas), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Showing anIinmdailviddautaal AfnoirmailndLiivisdtuianlg animals DSoTsUeDYGr:ou1p50:73Ih10205naA/k(y* ATPrPeRaOtVmEeDnt:PROTO0COmLg/k*)g IA Sex: Males Animal Ret Macroscopic Findings Only 106 KTeirlmliendalonSDaacyri:fic14e Animal is signed off from necropsy No Macroscopic Abnormality Observed : 107 KTeirlmliendalonSDaacyrif: ic14e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : 108 KTeirlmliendalon sDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : 109 KTeirlmliendalonsDaacyrif: ic1e4 Animal is signed oft from necropsy No Macroscopic Amormality Observed 10 TKeirlmliendalonSDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,coKpIiDcNAEbYnSormality Observed : Revision Number 1 DuPont14162 Date:21-qui-08 - ww A1P-FDaOy(LOirnaclaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnactasr)a,nadndMiAcPeFO (Branched): Showing anIinndailviddautaal AfnorimailndiLviisdtuianlg animals DSoTsUeDYG:rou1p507:3I1I0x250A.3 (m+g/AkBgPROVTrEeDatPmReOTnOtC:OL.0.+3) ma/ky IIIA Sex: Aninal Ret Macroscopic Findings Only S01 FTeirlmliendalonSDaacryif: ic1e4 Animal is signed off from necropsy No MaLcivreons,copKiIcNEAYbSnormality Observed s02 KTeirlmliendalonsDaacryif: ic14e Animal is signed off from necropsy No MaLcivreons,copRiIc EAmSormality Observed : 303 KTeirlmliendalonSDaacyrif: ic14e Animal is signed off from necxopsy Ho MLaicvreons,coRpiIcWEATbSormality Observed : 0 KTeirlmliendalonSDaacyri:fic1e4 Aninal is signed oft rom necropsy Yo MaLcIVrEoRs,copKiIDcNAEbYSmormality Observed : 305 FTeirlmliendalonsDaacryif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality observed : RevDiusiPoonnNtum1b4e1r621 Date:21-au-08 Males -- - THE AP14F-ODa(yLiOnrealarG/aBvraangcehSedt)u,dyAPinFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Showing anIinmdailvidduaatla AfnoirmailndLiivsitdiunagl animals SDoTsUeDYGr: ou1p507 3I1I0I2A50A.3 (m+a/AkPPyROTVrEeDatBmReOnTtO:COL0.*3) mg/kg IIA Sex: Animal Ref Macroscopic Findings Only 306 TKeirlmliendalonsDaacry:ific1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : 307 TKeirlmliendalon sDaacyrif: ic1e4 Aninal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : 308 TKeirlmliendalon sDaacyrif: ic1e4 Aniral is signed oft from necropsy No MaLcivxEoRs,copKiIcDNEAYbSnormality Observed : 309 TKeirlmliendalonsDaacyri:fic1e0 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : 30 TKeirlmliendalon sDacaryif: ic1e Animal is signed off from necropsy No MLaIcVrEoRs,copKiIcDNAEbYnSommality Observed : ReviDsuiPonoNnutm1b4e1r62| Date:21-Jun-04 Males Tim A14P-FDOay(LOirnaclaGr/aBvraagnechSetdu)d,yAiPnMFaOl(eLRinactasr)a,nadndMiAcPeFO (Branched): Shosing anIinmdailviddautaal AfnorimailndLiivisdtuianlg animals DSoTsUeDYGr: ou1p507:3VA10215mgA/k(y+ ATPrPeRaOtVmEeDntP:ROTO1CmOgL/k*)g VA Sex: Males Animal Ref Macroscopic Findings only s01 KTeirlnliendalon SDaacyrif: ic14e Animal is signed off from necropsy No MaLcivreoRs,copKiIDcNAEbYSnormality Observed soz KTeirlmliendalonSDaacryif: ic1e4 Aniral is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : s03 KfeirlnliendalonsDaacryi:fic1e4 Animal is signed off from necropsy No MaLcivreors,copKiicowEAvbsnormality Observed so KToirlnliendalonSDaacyrif: ic14e Animal is signed off from necropsy No MLaIcVrEoRs,coKpIiDcNAEbYSnormality Observed 505 KTeirlmliendalonSDaacryi:fic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYSnormality Observed : RevisDiuoPnoNnutm1b4e1r62| Date:21-70N-04 -------------- ------ APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Showing anIinndailvidduaatla AfnorinailndLiivisdtuianlg DSoTsUeDYGr:ou1p5073VA10215mA/k(g+ APTPreRaOtVmEeDntP:ROTO1CmOgL/k*)g VA Sex: Animal Ref Macroscopic Findings Only 506 TKeirlmliendalon sDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : 07 TKeirlmliendalonsDaacryif: ic1e4 Animal ie signed off from necropsy No MLaIcVrEoRs,copKiIcDNAEbYnSormality Observed : 508 TKeirlmliendalonSDaacryif: ic1e Animal ie signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEtYnSormality Observed : 509 TKeirlmliendalonsDaacyrif: ic1e4 Aninal is signed off fron necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed 510 TKeirlmliendalon sDaacyrif: ic1e4 Animal io signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : animals Males RevisDiuoPnoNnutm-1b4e1r62| Date:21-ou-04 Tes A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Showing anIinndailviddautaal AfnoirmailndiLviisdtuianlg DSToUsDeYG:rou1p507:3VI1I0A253Amg(/+kyAPPTRrOeVaEtDmePnRtO:TOCO3Lmg*)/kg VIIA Animal Ref Facroscopic Findings only 00 KTielrlmeindalonsDaacyri:fic14e Animal is signed oft from necropsy No NaLcivreors,coKpIicDNEAYbnSormality Observed : 202 KTeirlmliendalonSDaacyrif: ic14e Animal is signed oft from necropsy No HLaIcVrEoRs,coKpiiocvAEbvsnormality Observed : 03 KTeirlmliendalonSDaacryif:ic1e4 Animal is signed off from necropsy Yo MaLcIVrEoRs,copKiIcDNAEbYSnormality Observed 08 KTeirlmliendalonsDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality observed : 705 TKeirlmliendalonsDaacyrif: ic14e Animal is signed oft from necropsy No MLaIcVrEoRs,coKpIiDcNAEbYSnormality Observed : animals Sex: Males RevDiusiPonoNnutm1b4e1r62| Date:21-3um-04 TTT Ti6- APFO (Lineas/BrAaPnFOc(hLeindea)r),, and APFO (Branched): 14-Day Oral Gavage Swdy in Male Rats and Mice Showing anIinmdailvidduaatla AfnoirmailndLiivsitdiunagl DSoTsUeDYG:rou1p5073VI1I02A53Amg(/+kgAPPRTOreVaEtDmePnRtO:TOCO3Lmg*/)kg VIIA Animal Ref Macroscopic Findings only 206 TKeirlmliendalonSDaacryif: ic1e4 Animal is signed off from necropsy No MLaIcVrEoRs,copKiIcDNAEbYnSormality Observed 707 TKeirlmliendalonSDaacryif:ic1e4 Animal is signed off from necropsy Yo MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed 208 TKeirlmliendalon sDaacyrif: ic1e4 Aninal is signed otf from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : 709 TKeirlmliendalonsDaacyri:fic14e Animal is signed off from necropsy No MaLcivreoRs,copKiIcDNAEbYnSormality Observed 710 TKeirlmliendalonSDaacryif: ic14e Animal is signed off from necropsy No MLaicvreoRs,coKpIiDcNAEbYnSormality Observed : animals Sex: Males RevDiusiPoonnNtu.m1b4e1r621 Date:21-0UN-04 TTeo- A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Showing anIinmdailviddautaal AfnoirmailndLiivisdtuianlg SDToUsDeYGr:ou1p507:3I1X0A2510Ama(/+kyAPPTRrOeVaEtDmePntR:OTOCO1L0 m*g)/kg TG Animal Ref Macroscopic Findings only 01 KTeirlmliendalonsDaacyrif: ic14e Animal is signed oft from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed s02 KTeirlmliendalonSDaacyrific14e Animal is signed off from necropsy No MaLcivreors,copKiIcDNEAYbSnormality Observed : 03 KTielrlmeindalonSaDcaryif: ic14e Animal is signed oft from necropsy No MaLcivreors,copKiIcDNEAYbSnormality Observed 506 KTielrlmeindalonSDaacyr:ific14e Animal is signed off from necropsy No MLaIcVrEoRs,coKpIiDcNEAYnSormality Observed : 905 TKeirlmliendalonSDaacyrif:ic1e4 Animal is signed off from necropsy No MLaIcVrEoRs,coKpIiDcNAEbYSmormality Observed animals Sex: Males RevisDiuoPnoNnutm1b4e1r62| Date:21-Jum-04 - APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Ras and Mice Showing anIinmdailvidduaatla AfnoirmailndiLviisdtuianlg SDToUsDeYGr:ou1p50:73T1i0a2510Amg(/*kgAPPRTrOeVaEtDmePnRt:OTOCO10L m*)g/kg DXA Animal Ret Macroscopic Findings Only 506 TKoirlnliendalon SDaacyrif: ic1e4 Animal is signed off fron necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed 507 TKeirlmliendalonSDaacyr:ific1e4 Mnimal is signed off fron necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed 908 TKoirlnliendalonSDaacyri:fic1e4 Animal is signed off from necropsy No MLaIcVrEoRs,copKiIcDNAEtYnSormality Observed : 50s TKoirlnliendalonSDaacryif: ic1e4 Animal is signed off from necropsy Laver`DISCOLORATION, TAN, MIDDLE. No M`aRcorwoesrcsopic Abnormality Observed s10 TKeirlmliendalonSDaacryif: ic1e4 Animal is signed off from necropsy No MLaIcVrEoRs,coKpIiDcNAEbYnSormality Observed : animals Sex: Males Revision Number 1 DuPont14162 Date:21-am-04 -_-- APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Showing anIinmdailviddautaal AfnoirmailndLiivisdtuianlg SDToUsDeYGr:ou1p50:73XI1A02530Amg(/+kyAPETRrOeVaEtDmePnRtO:TOCO3L0 m*)g/kg XIA Animal Ref Macroscopic Findings only 101 KTeirlmliendalonSDaacryif: ic14e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed 1202 TKeirlmliendalonsDaacryif: ic14e Animal is signed oft from necropsy animals Sex: Males DISCOLORATION, TAN, MIDDLE. No MaKIcDrNoEsYcSo.pic Abnormality Observed : 103 TKoirlnliendalonsDaacyrif: ic14e Animal is signed oft from necropsy No MaLcivreors,copKiIcDNEAYbSnormality Observed 1100 TKeirlmliendalonSDaacyrif: ic14e Aninal is signed off from necropsy No MLaIcVrEoRs,coKpIiDcNEAYbSnormality Observed : 1105 TKeirlmliendalonSDaacryif:ic1e4 Animal is signed off from necropsy Yo MaLcIVrEoRs,copKiIDcNAEbYSnormality Observed : Revision Number 1 DuPont-14162 Date:21-us-04 -0. A14P-FDOay(LOirnaelaGra/BvraagnechSetdu)d,yAiPnFMOal(eLiRnaetars)a,nadndMiAcPeFO (Branched): Showing anIinndailvidduaatla AfnoirmailndLiviisdtuianlg SDToUsDeYG:rou1p507:3X1I0A2530Ang(/+kgAPPTRrOeVaEtDmePnRtO:TOCO30L n*)g/kg KIA Animal Ref Hacroscopic Findings Only 1106 TKeirlmliendalonSDaacyri:fic14e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 107 TKeirlmliendalonSDaacyri:fic1e Animal is signed off from necropsy No MLaIcVrEoRs,copKiIcDNAEbYnSormality Observed : 1108 TKeirlmliendalonSDaacyri:fic1e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed 1100 TKeirlmliendalonsDaacyrit: ic14e Animal io signed off from necropsy No MaLcivreors,copKiIcDNAEbYnSormality Observed : mo TKeirlmliendalonSDaacryif: ic1e4 Animal is signed of from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : "++ Listing Complete t+ animals Sex: Males RevisDiuoPnoNnutm-1b4e1r621 Date:21-ouN-04 "190- AP14F-ODay(LOirnaelaGr/aBvraagnechSetdu),dyAPinFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): Showing anIinmdailvidduaatla AfnoirmailndLiivsitdiunagl animals DSoTsUeDYGr:ou1p507:3 1810205moB/k(y+ ATVrEeRaOtVmEeDntP:ROTO0CmOoL/k*)y 18 Sex: Males Animal Rot Macroscopic Findings only 101 KATnieilrnlmaeilndaloinsSDasaciyrginfe:dic14eoff fron neczopsy Ho MLaicvreons,copKiIcDNAEbYSnormality Observed : 102 TKeirlmliendalonSDaacyrif: ic1e4 Aninal is signed off from necxopsy Yo MLaicvzeons,copRiicmAebsnormality Observed : 103 TKeirlmliendalonsDaacyrif: ic1e4 Animal is signed off from necropsy No Macroscopic Abnormality Observed : 108 KATneiirlmmlaielndalo1n5sDsaaicygrnief:dic1e4oft rom necropsy No MaLcIVrEoRs,copKiIcDNAEYmSormality Observed 105 TKeirlmliendalonsDaacyrit: ic14e Animal is signed off from necropsy Yo MaLcIVrEoRs,copKiIcDNAEbYSnormality Observed RevisDiuoPnoNnu-m1b4e1r621 Date: 21-qum-08 or oI A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Showing anIinmdailvidduaatla AfnoirmailndiLviisdtuianlg animals SDToUsDeYGr:ou1p50:73I10205Bmg/k(g+ APTPreRaOtVmEeDntP:ROTO0COmLg/k*)g 13 Sex: Males Animal Ret Macroscopic Findings Only 106 TKeirlmliendalonSDaacyrif: ic1e4 Aniral is sioned off from necropsy No MLaicvrsoRs,copKiicowAEbvnsormality Observed : 107 TKeirlnliendalonSDaacyrif: ic1e4 Animal is signed off from necropsy No MLaicvreors,copKiIcowAEbYnsormality Observed : 108 TKoirlnliendalonSDaacyrif: ic1e Animal 1s signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 109 TKeirlmliendalonSDaacyrif: ic1e4 Animal is signed off from necropsy No MLaicvreoRs,copKiIcDNAEbYnSormality Observed : 10 TKeirlnliendalonSDaacryif: ic1e4 Animal is signed off from necropsy No MLaicvreors,copKiIcDNAEbYnSormality Observed : RevisDiuoPnoNnutm-1b4e1r62| Date:21-ouN-04 T102- A1P4-FDOay(LOirnaclaGr/aBvraagnechSetd)u,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Showing anIinmdailvidduaatla AfnoirmailndLiivsitdiunagl animals DSoTsUeDYG:rou1p50:73TI1108250B._3 (m+g/AkPgPROTVrEeDatPmReOnTt:OCOL0.*3) ma/ks IIIB Sex: Animal Rot Macroscopic Findings only S01 KToirlmliendalonSDaacyri:fic1e4 Animal is signed off from necopsy Yo Macroscopic Abnormality Observed : RevisDiuoPnoNnutm1b4e1r621 Date:21-am-04 Males or s02 KTeirlmliendalonsDaacryi:tic1e4 Animal is signed off from necxopsy Yo MaLcIVrEoRs,copKiIcNEAYbSnormality Observed : 503 TKeirlmliendalonsDaacyri:fic14e Animal is signed off from necropsy No MaLcivreons,copKiIcNEAYtSmormality Observed 308 TKeirlmliendalonsDaacyri:fic14e Animal is signed off from necropsy No MaLcIVrEoRs,coKpIiOcNAEbYSnormality Observed : 205 AKtneiirlnmlaielndaloinsSDsaaicyrginfe: idc1eo4ft trom necropsy Yo MLaIcVrEoRs,copKiIcDNAEbYSnormality Observed Te APFO (Lincar/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Showing anIinndailvidduaatla AfnoirmailndLiivisdtuianlg animals SDToUsDeYG:rou1p507:3I1I0I2B50.B_3 (m+g/AkPgPROVTrEeDatPmReOnTt:OCOL0.*)3 mg/kg IIIB Sex: Animal Ref Macroscopic Findings Only 306 TKeirlmliendalonsDaacryif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 307 TKeirlmliendalonSDaacyri:fic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed 308 TKeirlmliendalonsDaacryi:fic1e4 Animal is signed off from necropsy No MLaIcVrEoRs,copKiIcDNAEbYnSormality Observed 309 TKoirlnliendalonSDaacyrif: ic1e4 Aniral is signed off from necropsy No MLaicvrEoRs,copKiIcDNAEbYnSormality Observed : 310 TKoirlnliendalonSDaacryif: ic2e4 Animal is signed off from necropsy No MLaIcVrEoRs,coKpIiDcNAEYtSormality Observed Revision Number 1 DuPont 14162 Date:21-7UN-04 Males Tis A1P4-FDOay(LOirnaelaGra/BvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAceP.FO (Branched): Showing anIinmdailvidduaatla AfnoirmailndLiivsitdiunagl animals SDToUsDeYG:rou1p507:3VB10215mgB/k(g+ APTrPeRaOtVmEeDnt:PROT1OCmOgL/k*g) VB Sex: ales Animal Ref Macroscopic Findings Only so1 TKeirlmliendalonSDaacryif: ic1e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYSnormality Observed : s02 TKeirlmliendalonSDaacryif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed s03 TKeirlmliendalonSDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcirvoes,copKiIcDNEAYbSnormality Observed : sos TKeirlmliendalonsDaacyri:fic14e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed 505 TKoirlnliendalonSDaacryi:fic1e4 Animal is signed off from necropsy No MLaIcVrEoRs,coKpIiDcNAEbYSnormality Observed : Revision Number | DuPont14162 Date:21-0uN-04 TTT T105- A14P-DOay(OLrianelaGra/vBraagnechSetdu)d,yAiPnFMOal(eLiRnaetars)a,nadndMiAcPeFO (Branched): Showing anIinndailvidduaatla AfnoirmailndLiviisdtuianlg animals DSoTsUeDYGr:ou1p50:73VB10215maB/k(g+ APTPreRaOtVmEeDntP:ROTO1CnOgL/k*g) VB Sex: Males Animal Ret Macroscopic Findings only 506 TKoirlnliendalonsDaacryif: ic1e4 Aniral is signed off from necropsy No MLaicvreoRs,copKiIcDNAEbYnSormality Observed : s07 TKeirlnliendalonSDaacyrif: ic1e Animal is signed off from necropsy No MLaIcVrEoRs,copKiIcDNAEbYnSormality Observed 508 TKoirlnliendalonSDaacyri:fic1e4 Aniral is signed off from necropsy No MLaIcVrEoRs,copKiIcDNAEbYnSormality Observed : 509 TKoirlnliendalonSDaacyrif: ic1e4 Anial is signed off from necropsy No MLacvreoRs,copKiicowAEbYnsormality Observed : s10 TKeirlnliendalonSDaacryif: ic1e4 Animal is signed off from necropsy No MLaIcVrEoRs,coKpIiDcNAEbYnSormality Observed : RevDisuiPonoNnutm1b4e1r62| Date:21-o0N-04 Tes A14P-FDOay(LOirnaelaGra/BvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Showing anIinmdailvidduaatla AfnoirmailndiLviisdtuianlg SDToUsDeYG:rou1p50:73VI1I0B253Bma(/+kgAPPTRrOeVaEtDmePntR:OTOCO3Lma*)/ky VIB Animal Ret Macroscopic Findings Only 01 TKeirlmliendalonSDaacryi:fic1e4 nial is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed 702 TKeirlmliendalonSDaacryi:fic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 703 TKeirlmliendalon sDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed 708 TKoirlnliendalonSDaacyr:ific1e4 Animal is signed off from necropsy No MaLcivreors,copKiIcDNAEbYnSormality Observed 705 TKoirlnliendalonSDaacryi:fic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed Revision Number | DuPont 14162 Date:21-7u-04 animals Sex: Males TTT T1o7- APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Showing anIinndailvidduastla AfnoirmailndLiivsitdiunagl SDoTsUeDYGr: ou1p5073VI1I02B53Bmg(/+kgAPPTRrOeVaEtDmePnRtO:TOCO3Lmg*)/kg VII Animal Ref Macroscopic Findings Only 206 TKeirlmliendalonsDaacryif+ ic1ed Aninal is signed off from necropsy No MaLcIVrEoRs,coKpIiDcNAEbYnSormality Observed : 707 TKeirlmliendalonsDaacryif+ ic1e4 ninal is signed off from necropsy No MaLcIVrEoRs,coKpIiDcNAEbYnSormality Observed 708 TKeirlmliendalonsDaacryif:ic1e4 Aninal is signed off from necropsy No MaLcIVrEoRs,coKpIiDcNAEbYSnormality Observed 709 TKeirlmliendalonsDaacryif:ic1e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 710 TKeirlmliendalon SDaacyrit: ic14e Animal is signed of from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed animals Sex: Males RevDisuiPoonnNtu.m1b4e1r621 Date:21-J0N-08 18- A14P-FDOay(LOirnaelaGrfaBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasra)nadnMdiAcPeFO (Branched): Showing anIinmdailvidduaatla AfnoirmailndLiivisdtuianlg SDoTsUeDYGr:ou1p507:3T1X0B25103mg(/*kyAPPRTrOeVaEtDmePnRt:OTOCO10L m*g)/kg IB Aninal Ref Macroscopic Findings Only 501 KTeirlnliendalonSDaacyrif:ic1e4 Animal is signed off from necropsy No MLaIcVrEoRs,copKiIcDNAEbYnSormality Observed 02 TKeirlmliendalonSDaacryif: ic1e4 Animal is signed off from necropsy No MLaIcVrEoRs,copKiIcDNAEbYSnormality Observed 503 TKeirlmliendalonSDaacyrif: ic1e4 Animal is signed off fron necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 908 eKirlnliendalon sDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcirvoes,copKiIcDNEAYbSnormality Observed : 50s KTielrlmeindalonsDaacyri:fic1e4 Animal is signed off from necropsy No MLaIcVrEoRs,copKiIcDNAEbYnSormality Observed animals Sex: Males ReviDsuiPonoNnutm1b4e1r62| Date:21-0uN-04 TT 159 APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice SDToUsDeYGr: ou1p507:3 Animal Ref 506 907 s08 909 910 Showing anIinmdailvidduaatla AfnoirmailndLiviisdtuianlg T1X0B2510Bng(/*kgAPPRTrOeVaEtDmePnRt:OTOCO10L n*)g/kg IXB Macroscopic Findings Only TKeirlmliendalonsDaacyri:fic14e Aniral io signed off from necxopsy No MLaIcVrEoRs,copKiIcDNEAYbSnormality Observed : TKeirlnliendalonsDaacyrif: ic14e Animal is signed off from necropsy No MLaIcVrEoRs,copKiIcDNEAYbSnormality Observed TKeirlmliendalonsDaacyrif: ic14e Animal is signed off from necropsy Liver`DISCOLORATION, TAN, MOTFLED. No MKaIcDrNoEsYcSopic Abnormality Observed TKoirlnliendalonSDaacyrit: ic14e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDwEAYbSnormality Observed : TKoirlnliendalonsDaacyri:tic1e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed animals Sex: Wales Revision Number | DuPont14162 bate:21-au-04 T300- A14P-FDOay(LOirnaclaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Showing anIinmdailvidduaatla AfnoripailndLiivsitdiunagl SDToUsDeYG:rou1p507:3XI1B025305mg(/+kgAPPTRrOeVaEtDmePntR:OTOCO3L0 m*)g/kg KIB Animal Ref Maczoscopic Findings Only 1100 KTeirlmliendalonSDaacryi:fic1e Animal is signed off from necropsy No MaLcivreoRs,copKiIcDNAEbYnSormality Observed 1102 TKeirlnliendalonSDaacryi:fic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 1103 KTeirlmliendalonSDaacryi:fic1e8 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIDcNAEbYnSormality Observed 1108 TKeirlmliendalonSDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIDcNEAYbSnormality Observed : 1105 TKeirlnliendalonSDaacryif: ic1e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIDcNAEbYnSormality Observed : animals Sex: Males ReviDsuioPnoNnutm1b4e1r62| Date:21-7uN-04 201- A14P-FDOay(LOirnaclaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Showing anIinmdailviddautaal AfnoirmailndiLviisdtuianlg SDoTsUeDYGr:ou1p5073XI1B02530Bma(/*ksAPPRTrOeVaEtDmePnRtO:TOCO3L0 n*)g/kg KIB antral Ret Macroscopic Findings Only 1106 TKeirlmliendalonSDaacry:ific1e4 Animal is signed off fxom necropsy No MaLcIVrEoRs,coKpIiDcNAEbYnSormality Observed 1107 TKeirlmliendalonsDaacyrif: ic14e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 1108 TKoirlnliendalonsDaacyrit: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : 1100 TKoirlnliendalonSDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed m0 TKeirlmliendalonSDaacyr:ific14e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed +++ Listing Complete +++ anirals Sex: Males ReviDsuiPonoNnutm1b4e1r621 Date:21-0uN-04 -= A14P-FDOay(LOirnaelaGra/BvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): Showing anIinmdailvidduaatla AfnoirmailndLiivisdtuianlg animals DSoTsUeDYGr:ou1p507:3IC10205mgC/k(y+ ATPrPeRaOtVmEeDntP:ROT0OCmOgL/k*)g IC Sex: Males Animal Ref Macroscopic Findings Only 101 KTeirlmliendalonSDaacryi:fic1e4 Animal is signed off from necropsy No MLaicvreoRs,coKpIiDcNAEbYSnormality Observed 102 TKeirlnliendalonSDaacryif: ic1e0 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIDcNAEbYnSormality Observed 103 TKeirlmliendalonSDaacyri:fic1e4 Aninal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 108 KTeirlmliendalonSDaacyrif: ic1e4 Anipal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEYmSornality Observed : 105 TKeirlmliendalonSDaacyrif: ic14e Animal is signed oft from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed ReviDsuiPoonnNtu.m1b4e1r62| Date:21-7u-08 203 APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Showing anIinmdailvidduaatla AfnoirmailndLiivsitduianlg animals SDoTsUeDYGr: ou1p5073IC10205Cmg/k(g* ATPrPeRaOtVmEeDntP:ROTOOCmOaL/k*)g IC Sex: Males Animal Ref Macroscopic Findings Only 106 TKeirlmliendalonsDaacryif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed 107 TKeirlmliendalonsDaacryif: ic1e4 Animal is signed off from necropsy No HaLcIVzEoRs,coKpIiDcNAEbYSnormality Observed : 108 TKeirlmliendalonsDaacry:ific1e4 Aninal is signed off from necropsy No Nacroscopic Abnormality Observed 109 TKeirlmliendalonsDaacyr:ific1e4 Aniral is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed 10 TKeirlmliendalonsDaacryif: ic1e4 Animal is signed off fxom necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : RevDiusPioonnNtu.m1b4e1r621 Date:21-0uN-04 01. APO (Linear/Branched), APFO (Linear), and APFO (Branched): 14Or-al GDavagaeStyudyinMaleRatsandMice Showing anIinmdailvidduaatla AfnoirmailndiLviisdtuianlg animals SDToUsDeYGr:ou1p507:3I1T0I2C50C._3(+mg/AkPgPROVTrEeDatBmReOnTtO:COL0.*)3 ng/kg ITIC Sex: Animal Ref acroscopic Findings Only 301 TKeirlmliendalonSDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIDcNAEbYSnormality Observed : 02 eKirlnliendalonSDaacyrif: ic1e4 Animal is signed off fron necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 303 TKeirlmliendalonSDaacyrif: ic1e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 308 TKeirlmliendalonSDaacyrif: ic14e Animal is signed oft from necropsy No MLaIcVrEoRs,copKiIcDNEAYbSnormality Observed 305 KTeirlmliendalonSDaacyri:fic14e Animal is signed off from necropsy No MLaIcVrEoRs,coKpIiDcNAEbYSnormality Observed : Revision Number | DuPont.14162 Date:21-0u-04 Males 05 APFO (Linear/Branched), APFO (Linear), 1nd APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Showing anIinmdailvidduaatla AfnorimailndLiivisdtuianlg animals SDToUsDeYGr: ou1p50:73T1I0I2C50.C3_(*mg/AkPgPROTVrEeDatBmReOnTtO:COL0.*3) mg/kg INC Sex: Animal Ref Macroscopic Findings Only 306 TKoirlnliendalonSDaacryif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,coKpIiDcNAEbYnSowmality Observed 307 TKeirlmliendalonsDaacryif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 308 TKeirlmliendalonSDaacryif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,coKpIiDcNAEbYnSormality Observed 309 TKeirlmliendalonsDaacyrific14e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEYbSormality Observed : 310 TKeirlmliendalonSDaacryif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,coKpIiDcNAEbYnSormality Observed : Revision Number 1 DuPont14162 Date: 21-0u-04 ales "206 APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Showing anIinmdailvidduaatla AfnorimailndLiivsitdiunagl animals SDToUsDeYGr:ou1p507:3UC10215mgC/k(g+ APTPrReaOtVmEeDntB:ROTO1CmOgL/k*)g VC Sex: Males Animal Ref Macroscopic Findings only sor eKirlmliendalonSDaacryi:fic1e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIDcNAEbYnSormality Observed : so2 KTeirlmliendalonSDaacryif: ic1e4 Animal is signed oft from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed s03 TKoirlnliendalonSDaacryif: ic1e4 Animal is signed oft from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed s00 TKeirlmliendalonSDaacyrif: ic14e Animal is signed off from necropsy No MLaIcVrEoRs,coKpIiDcNEAYbSnormality Observed : sos KTeirlmliendalonSDaacyri:fic1e4 Anial is signed off from necropsy No MaLcIVrEoRs,copKiIDcNAEbYnSormality Observed : Revision Number | DuPont 14162 Date: 217-04 207- A14P-FDOay(LOirnaelaGsfaBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Showing anIinndailviddautaal AfnoirmailndLiivsitdiunagl animals SDoTsUeDYG:rou1p50:73VC10215mCg/k(g+ ATPrPeRaOtVmEeDnt:BROTO1COmLg/k+)g VC Sex: Males Aniral Ret Macroscopic Findings Only 506 TKeirlmliendalonsDaacyrif: ic1e4 Animal {s signed off from necropsy No MaLcIrVEoRs,copKiIcDNAEbYnSormality Observed s07 TKeirlmliendalonsDaacyrif+ ic1e4 Animal s signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : sos TKeirlmliendalonsDaacyrif: ic1e4 Aniral s signed off from necropsy No MaLcivreors,copKiIcDNAEbYnSormality Observed : 509 TKeirlmliendalonsDaacryif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEYmSormality Observed : s10 TKeirlmliendalonsDaacyrif: ic1e4 Aniral is signed oft from necropsy No MaLcIvreoRs,copKiIcDNAEbYnSormality Observed : Revis`iDounPNonutm1b4e1r62| Date:21-u-04 _-- A14P-DOay(LOirnaelaGra/BvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Showing anIinmdailvidduaatla AfnoirmailndLiivsitdiunagl SDoTsUeDYGr:ou1p507:3VI1I0C253Cmg(/+kgAPPTRrOeVaEtDmePnRtO:TOCO3Lmg*)/kg VIC Animal Ref Macroscopic Findings Only 01 KTeirlmliendalonSDaacryi:fic1e4 Animal is signed off from necropsy No MaLcivreoRs,copKiIDcNAEbYSnormality Observed 202 TKeirlmliendalonSDaacryif:ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYSnormality Observed 203 TKeirlmliendalonSDaacryif: ic1e Animal iz signed off fron necropsy No MaLcivrEoRs,copKiIcDNAEbYnSormality Observed 08 TKeirlmliendalonSDaacyri:fic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed 705 TKeirlmliendalonSDaacryif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : animals Sex: Males RevDiusiPoonnNtu.m1b4e1r621 Date:21-u-04 "209- APFO (Linea/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Showing anIinmdailvidduaatla AfnoirmailndLiviisdtuianlg DSoTsUeDYGr:ou1p5073VI1I0C253Cmg(/+kgAPPTRrOeVaEtDmePnRtO:TOCO3Lmg*)/kg VIIC Animal Ret Macroscopic Findings Only 208 TKeirlnliendalon sDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcivreors,copKiIcDNEAYbSnormality Observed 207 TKeirlmliendalon sDaacyrif: ic1e4 Animal is signed oft from necropsy No NaLcivreors,copKiicoNEAYbsnormality Observed : 08 TKeirlmliendalonsDaacyri:fic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : 709 TKeirlmliendalonsDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : 710 TKeirlmliendalonsDaacyr:ific1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEYoSrmality Observed : animals Sex: Males Revision Number | DuPont.14162 Date:21-J0N-08 i AP14F-ODa(yLOirnaelarG/aBvraangcehSetdu)d,yAiPnFMOal(eLRianetasr)a,nadndMiAcPeFO (Branched): Showing anIinmdailviddautaal AfnoirmailndLiivisdtuianlg SDToUsDeYG:rou1p50:73 I1C02510Cmg(/*kgAPPRTrOeVaEtDmePnRt:OTOCO1L0 m*a)/kg IXC Animal Ref Macroscopic Findings only 501 TKeirlmliendalon SDaacyrif: ic14e Animal is signed off from necropsy No MLaIcVrEoRs,copKiIcDNAEbYSnormality Observed s02 TKeirlnliendalonSDaacyrif: ic14e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 903 TKeirlmliendalonSDaacryif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 50s KTielrlmeindalonSDaacyri:fic14e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : 505 TKeirlmliendalonSDaacyri:fic14e nial is signed off from necropsy No MaLcIVrEoRs,copKiIDcNAEbYSnormality Observed : animals Sex: Males Revision Number | DuPont14162 Date:21-00N-04 TTT ans APFO (Linear/Branched), APFO (Lines), and APFO (Branched): 14-Day Oral Gavag Study in Male Rats and Mice SDToUsDeYGr: ou1p5073 Antal Ref 506 s07 s08 s03 910 Showing anIinmdailvidduaatla AfnorimailndLiivsitdiunagl TH1C02510Cmg(/+kgAPPRTrOeVaEtDmePnRtO:TOCO1L0 m*a)/ky DIC Macroscopic Findings Only TKeirlmliendalonSDaacyri:fic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed TKeirlmliendalonsDaacyri:fic1e4 Aninal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : TKeirlmliendalonSDaacyri:fic10e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnomality Observed : TKeirlmliendalonSDaacyri:fic14e Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed : TKeirlnliendalonSDaacryif: ic1e4 nial is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : animals Sex: Males Revision Number | DuPont14162 Date:21-JuN-04 Tn AP14F-ODay(LOirnaelaGr/aBvraagnechSetdu),dyAPinFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched) Showing anIinmaailviddautaal AfnoirmailndLiivisdtuianlg SDoTsUeDYGr: ou1p507:3XI1C02530Cg/(+kgAPPTRrOeVaEtDmePnRt:OTOCO30L m*)a/kg KIC Animal Ref Macroscopic Findings Only 1101 KTeirlmliendalonSDaacyrit: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 102 TKeirlmliendalonSDaacyri:fic1e Animal is signed off from necropsy No MLaIcVrEoRs,copKiIcDNAEbYnSormality Observed : 1103 TKeirlmliendalonsDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYSnormality Observed : no TKeirlmliendalonSDaacyrif: ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEbYnSormality Observed : 1105 KTeirlmliendalonsDaacyri:fic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,copKiIcDNAEYbSnomality Observed : animals Sex: Males RevDiusiPoonnNtu.m1b4e1r621 Date:21-0u-04 - = A14P-FDOay(OLrinaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Showing anIiamdailvidduaatla AfnoirmailndLiivisdtuianlg SDToUsDeYGr: ou1p507:3XI1C02530Cmg(/+kgAPPTRrOeVaEtDmePnRtO:TOCO3L0 n*)g/kg KIC Animal Ref Macroscopic Findings Only 1106 TKeirlmliendalonSDaacryif:ic1e4 Animal is signed off from necropsy verDISCOLORKTION, TAN, MOTTLED. No MaKcIrDoNsEcYSopic Abnormality Observed : 1107 TKeirlmliendalonSDaacyrif:ic1e4 Animal is signed off from necropsy No MaLcIVrEoRs,coKpIiDcNAEYmSormality Observed : 1108 TKeirlmliendalonSDaacyrif: ic1e4 Animal is signed off from necropsy No MLaIcVrEoRs,coKpIiDcNAEbYnSormality Observed : 1109 TKeirlnliendalonSDaacryif: ic1e8 Animal is signed off from necropsy No MLaIcVrEoRs,coKpIiDcNAEbYnSormality Observed : 1110 TKeirlnliendalonSDaacryif: ic1e Animal is signed off from necropsy No MLaicvreors,copKiIcDNAEbYnSormality Observed : *++ Listing Complete *++ animals Sex: Males RevDisuiPonoNnutm1b4e1r62| Date:21-90N-04 Ere AP14F-ODay(LOirnaelarG/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a.nadnMdiAcPeFO (Branched): ReviDsuioPnoNnutm1b4e1r621 Appendix H Individual Rat Beta-Oxidation Data - = A14P-FDOay(LOirnaelaGra/BvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): RevisDiuoPnoNnutm-1b4e1r62| INDIVIDUAL RAT BETA-OXIDATION DATA EXPLANATORY NOTES STUDY DESIGN H-24921 APFO (Linear/Branched) IA mA VA VIIA IXA XIA Groups H26313 H26225 APFO (Linear) ~ APFO (Branched) B iC 1B me VB ve VIB vic XB XC XIB Xic Dosage (mg/kg) 0 (Control) 03 1 3 10 30 Abbreviation mg/kg = mg/kg/day oe A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadrMdiAcPeFO (Branched): ReviDsuiPonoNnutm1b4e1r62| Individual Rat Beta-Oxidation Data Group Animal Beta-Oxidation Rate Number __(nmoVmin/mg protein) I' 101 17.09 102 1693 103 1495 104 14.94 105 14.80 106 1765 107 2605 108 2338 109 19.60 110 16.86 mA 301 13.86 302 16.63 303 1625 304 1726 305 1630 306 16.40 307 23.65 308 2047 309 24.58 310 1457 VA 501 2938 502 2873 503 25.82 504 1898 505 3082 506 30.12 507 21.36 508 3174 509 20.56 510 2609 -a A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nsdndMiAcPeFO (Branched): RevisDiuoPnoNnutm1b4e1r621 Individual Rat Beta-Oxidation Data Group Animal Beta-Oxidation Rate Number __(nmol/min/mg protein) VIA 701 59.93 702 5479 703 74.45 704 40.52 705 54.04 706 58.77 707 70.55 708 62.69 709 50.56 710 49.92 IXA 901 8272 902 101.91 903 11555 904 52.42 905 79.18 906 91.52 907 72.55 908. 75.17 909 72.86 910 7237 XIA 1101 93.91 1102 102.06 1103 97.54 1104 64.77 1105 10030 1106 71.03 1107 68.73 1108 65.20 1109 8042 1110 103.40 -= A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): Individual Rat Beta-Oxidation Data Group "Animal Beta-Oxidation Rate Number __(nmol/min/mg protein) B 101 1929 102 1822 103 1237 104 9.81 105 17.61 106 21.27 107 14.46 108 1540 109 1678 110 12.00 mB 301 1571 302 2172 303 1439 304 12.43 305 20.50 306 15.49 307 16.59 308 1498 309 1222 310 1571 VB 501 29.03 502 2805 503 24.26 504 3397 505 3822 506 28.10 507 26.60 508 39.73 500 25.55 510 2429 Revision Number 1 DuPont.14162 aC -- AP14F-ODa(yLiOnrealarG/aBvraagncehSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): ReviDsuiPoonnNtu.mb14e1r62| Individual Rat Beta-Oxidation Data Group "Animal Beta-Oxidation Rate Number (nmol/min/meg protein) VIB 701 56.15 702 48.99 703 58.17 704 4197 705 8836 706 81.91 707 7375 708 7033 709 66.61 710 82.36 XB 901 59.47 902 79.42 903 85.31 904 66.29 905 91.07 906 82.03 907 6262 908 7445 909 71.19 910 75.80 XIB 1101 101.30 1102 106.79 1103 85.94 1104 82.90 1105 96.87 1106 73.28 1107 96.05 1108 97.16 1109 81.73 1110 61.90 - = A14P-FDOay(LOirnaclaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): Individual Rat Beta-Oxidation Data Group Animal Beta-Oxidation Rate Number __(amol/min/mg protein) ic 101 1335 102 1036 103 8.61 104 14.46 105 1485 106 12.64 107 1382 108 2048 109 1152 110 1028 me 301 14.43 302 18.14 303 1007 304 8.14 305 1092 306 11.54 307 17.73 308 17.80 309 10.64 310 9.54 ve 501 1374 502 16.13 503 13.83 504 12.00 505 14.66 506 1125 507 1763 508 1942 509 14.43 510 2070 RevisDiuoPnoNnutm-1b4e1r621 -_-- APFO (Lincar/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Individual Rat Beta-Oxidation Data Group Animal Beta-Oxidation Rate Number __(nmol/min/mg protein) vic 701 21.69 702 21.80 703 1834 704 14.05 705 15.09 706 17.25 707 13.08 708 2229 709 17.23 710 13.59 XC 901 26.89 902 34.80 903 30.64 904 43.61 905 18.41 906 18.69 907 2767 908 2055 909 3437 910 3161 Xic 1101 3228 1102 59.10 1103 27.60 1104 44.94 1105 2114 1106 50.85 1107 37.19 1108 46.31 1109 2651 1110 2994 Revi`sDiuoPnonNtu.m1b4e1r62| - = A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Individual Rat Beta-Oxidation Liver Data Group Animal Number Relative Liver to Full Body Weight (%) jy 101 27 102 34 103 35 104 35 105 34 106 32 107 34 108 40 109 41 110 32 mA 301 32 302 38 303 37 304 36 305 34 306 3s 307 36 308 37 309 37 310 40 VA 501 38 502 41 503 40 504 35 505 37 506 40 507 42 508 40 509 39 510 41 RevisDiuoPnoNnutm-1b4e1r62| m3 -- A14P-FDOay(LOirnaelaGra/BvraagnechSetdu)d,yAiPnFMOal(eLiRnaetars)a,nadndMiAcPeFO (Branched): Individual Rat Beta-Oxidation Liver Data Group Animal Number Relative Livetro Full Body Weight (%) VIA 701 51 702 51 703 54 704 60 705 55 706 55 707 57 708 54 709 59 710 47 IXA 901 54 902 53 903 62 904 46 905 56 906 59 907 53 908 59 909 63 910 61 XIA 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 No data 74 64 61 6.1 72 71 67 76 67 RevisDiuoPnoNnutm-1b4e1r62| Ee APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Individual Rat Beta-Oxidation Liver Data Group Animal Number Relative Liver to Full Body Weight (%) B 101 34 102 41 103 35 104 35 105 32 106 44 107 35 108 36 109 35 110 36 mB 301 3s 302 39 303 39 304 38 305 38 306 39 307 39 308 38 309 40 310 40 vB 501 37 502 41 503 39 504 42 505 438 506 46 507 4.1 508 39 509 40 510 41 Revision Number | DuPont. 14162 = -_-- APFO (Lincar/Branched),APFO (Lineas), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Individual Rat Beta-Oxidation Liver Data Group Animal Number Relative Liver to Full Body Weight (%) VIB 701 49 702 45 703 46 704 51 705 48 706 52 707 51 708 51 709 51 710 51 XB 901 59 902 60 903 62 904 58 905 55 906 61 907 58 908 66 909 55 910 67 XIB 1101 67 1102 72 1103 68 1104 69 1105 69 1106 54 1107 67 1108 68 1109 67 1110 62 RevisDiuoPnoNnutm1b4e1r621 Es A14P-FDOay(LOirnaclaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): Individual Rat Beta-Oxidation Liver Data Group Animal Number Relative Liver to Full Body Weight (%) ic 101 32 102 33 103 38 104 39 105 33 106 31 107 EN 108 33 109 34 110 32 me 301 34 302 38 303 39 304 39 305 34 306 31 307 37 308 35 309 35 310 34 ve 501 35 502 44 503 39 504 39 505 39 506 34 507 a1 508 36 509 a1 510 43 Revision Number 1 DuPont14162 = -_-- A14P-FDOay(LOirnaelaGrfaBvraagnechSetdu),dyAiPnFMOal(eLiRnaetars)a,nadndMiAcPeFO (Branched): Individual Rat Beta-Oxidation Liver Data Group Animal Number Relative Liver to Full Body Weight (%) vic 701 50 702 46 703 43 704 49 705 42 706 37 707 42 708 43 709 46 710 44 xc 901 60 902 60 903 53 904 65 905 49 906 55 907 48 908 51 909 68 910 67 Xic 1101 59 1102 13 1103 67 1104 62 1105 51 1106 14 1107 58 1108 64 1109 68 1110 6.1 ReviDsuioPnoNnutm1b4e1r62| -= -- APFO (Linear/Branched), APFO (Linear), andAPFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number 1 DuPont-14162 MOUSE TABLES - > A14P.FDOay(OLrianleaGraBvraagncehSetdu)d,yAiPnFMOal(eLiRnaetasr)n,dandMiAcPeFO (Branched) MOUSE TABLES EXPLANATORY NOTES H24921 APFO (Linear/Branched) 1A mA VA VIIA XA XIA STUDY DESIGN Groups H26313 H26225 ~APFO (Linear) ~APFO (Branched) B ic mB me VB ve VIB vic XB IXC XIB xic ReviDsuioPnoNnutm1b4e1r62| Dosage (mg/kg) 0 (Control) 03 1 3 10 30 Abbreviations mg/kg = mg/kg/day Summary of Clinical Chemistry Values CHOL - cholesterol TRIG - triglycerides HDL - high-density lipoprotein cholesterol nonHDL. - non-high-density lipoprotein cholesterol Clinical Chemistry Note Groups with identical values may vary in statistical significance, because tabulated statistics are rounded to fewer decimal places than the values used for statistical determination. = AP14F-ODay(OrLaliGanvacgeaSrtud/yABPinFrMOa(alLeinRnaectas)ha.naedndMdiAcP)eF,O (Branched): ReviDsuiPonoNnutm1b41e6|r2 Table 1 Homogeneity/Concentration Verification and Stability Analysis for Mouse Study Sample Nominal Mewswed Man CV. Sabi 1:HM2ar9-221004 0 N* o -- 003 002.0028 010 009,009 933 930 2 900 5 20 30 281,269 017 3 903 2HM2a6r3210304 3HM2a6r2220504 0 ND 005 00310033 010 0104,0108 30 nan 0 ND 003 00310032 010 01010111 30 334,300 - -~ 11006670 35 L10o33 1073 0 1003 -- --- 1067 0s 1000 1060 7 1020 107.0 6 1047 b= SMeemapnlersesuhletlsdf5hooTuirrsaantaloysoimsotfemhpeeradtupulriec,ate amples. 4 RDeepnoortteesdnroenseuldtestbecatseedd. on re-analysisofthe orginal sample. Original analysis was ower than expected Rdeupeofrotaeldiqreusoutltesrobarsaenddonnotrer-eapnoarltyesdi.s ofthe original sample. Original analysis was higher than expected due 1 aliquo eror and not reported. -=; A1P4.FDOay(LOirnaelaGra/BvraagnechSetdu),dyAiPnFMOal(eLiRnaetars)a,nadndMiAcPeFO (Branched): ReviDsuioPnoNnutm1b4e1r62| Table 2 Recovery of H-24921, H-26313, H-26225 Added to Dosing Vehicle for Mouse Study TT Samp Type RECOVERY RECOVERY" RECOVERY" mgm Nominal Measured 0.030 0031 0.030 0.032 0.030 0033 Mean Percent Nominal 1033 1067 1100 1067 3.4, CV.3% RECOVERY RREECCOOVVEERRYY" 0.10 0.108 1080 00.1100 00..110190 11100900 Mean 109.0 10, cv.1% RECOVERY RECOVERY" RECOVERY 300 275 91.7 300 317 1056 300 308 1027 Mean 100.0 73, CV.7% ab PPrroocceesssseedd wwiitthh HH2-246932113 ssaammpplleess ffrroomm ddoossiinnggpprreeppaarreedd oonn MMaarrcchh 21,,22000044 c4 PRreopcoerstseedrwesiutlhtHf.r2o6m2r2e5ansalaymspilsesofofrriogmindaolsisnagmpprleep.arTehd oonriMgairncahan3,a2ly0s0is4was higher than `Reexppoerctteedddreuseul0t farlioqmuorteaenrarloyrsiasnodfnootrgrienpaorltesda.mple. The original analysis was lower than `expected duc 0 aliquot error and not reported. --- ECE A14P-FDOay(OLirnacaGra/BvraagnechSetdu),dyAiPnFMOal(eLiRnaetas)n,dandMiAcPeFO (Branched): ReviDsuiopnoNnutmb14e1r62| Concentration Verification andTaSbtlabeil3ity of H-24921, H-26313, H-26225 in Dosing Solutions for Mouse Study TeSasmtpleSubDsaatnece Nominal mem Messed NPoemricennatl 24C9o2xt1roGnO. H 00 Not -- nn nn n0 SHou 26C3o1n3e(o3L104) 000033 00002278 92303 Mean c00v2.822%0001 033% 001100 00009%6 996000 Mean': c0.v0.93s2e0.004 (93.0%) 33000 226801 937 7 Mean': 2c7v5.230%09 oL.7%) 001003 00002072! 20 20 300 271 3 000 Not - nn 000033 00003313 11100330 Mean' c00v3.2s2%0001 067%) n n ol0 010 0108 0.108 1040 1080 Mean': c0.v1.0632%0.003 (106.0%) nn 330000 232 11007733 Mean": 3c.v2.2o2%000 (207.3%) Stout 001003 o00u3n1 1033 110 300 301 1003 me A14P-FDOay(OLrianleaGraBvraangcehSetd)u,dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): ReviDsuiopnoNnutm1b4e1r62| Table 3 Concentration Verification and Stability of H-24921, H-26313, H-26225 in Dosing Solutions for Mouse Study (Continued) TeSsatmSpulbestDaantcee: Nowiml mL. Measured NPoemricnenatl 26C2o2n5oGr.08) 000 Not me # 000033 00003312 11003637 Mean': 0c0v3.2o2s0%0002 (106.7%) nn 0.01100 0o.l10l1 11011100 Mean': 0c.v1.067%0007 (106.0%) "n 330000 330394 m10s30 Mean': 3c2v1.2o0%.182 (107.0%) s Hout 00.0130 00.013002 11000200 300 314 1047 2b DTehneoatveesrnaogenemedeatseuctreedd. concentration, average percentofnominal (in parentheses), standard deviation, aStnadbicloietfyfiscaimepnlteosfhvearlida5tihoonourfs daurploiocmatteesmapmeprlaetsu.re. 4 Rdeupeo1r0tealdiqrueosutletmboarseadnodnnorte-raenpaolrytseids. of the original sample. Original analysis was lower thin expected Rdeupeooratlediqrueosutltrboarseadnodnnoet-arenpaolrytseds.of the original sample. Original analysis was higher than expected = -_-- A14P-FDOay(OLrianlcaGraBvraagncehSetdu)d,yAiPnFMOal(eLiRnaetasra)nadndMiAcPeFO (Branched): ReviDsuioPnoNnutm1b4e1r621 Table 4 Summary of Dosing Suspension Analysis for Mouse Study Sample Type ConceHnt2r4a9t2io1n (112004) a " AAvveerraaggee PMeeracseunrteNdomCionnalc" CoSetfalnidcairedntDoevfiVaatriioant"ion hStoabuilritRyoom Temperature ConceHnt2r6a3ti1o3n (3212004) " n `AAvveerraaggee MPeeracseunrteNdoCmoinnea.l SCtoeafnfdiacriedntDoefviVaatriioant"ion" SuhboiulrtyRoom Temperature Conce2nt6r2at2i5on (31372008) " n Average Measured Conc." SAtvaenrdaagredPDeervcieanttiNono"minal SCaobeiflftiycieonft Variation" hour RoomTemperature NoCmoinnceanlt:rations an00St3abilityof H-249210,1H0-26313, H-262253(0mg/mL) 000027 00% 00) 251 0028 0096 269 030238) 006903) 2757) 03030)1 030004 2o00n9 2% 5% 3% 0027 0092 271 00) 20) 03) 0031 0.104 32 10003333) (01.014008) 03723) 01.00302) 01.018006) A302732) ave) 0001 210060.003) 0.0300) 5% 3% 0% 0031 oi 301 033) aio 103) 10003331) (01.0110.10) a3i3s4) 10006372) a01101 (1300390) 0032 67) 0.106 321 106.0) aor 0050%002 2070%07 0.6%82 (10000300) 01.012002) 103417) b T"Nhuemabveerrsaignepmaeraesnuthreesdescoanrceenhterarteisopne,catviveerapgeercpeenrtcoefntnoofminnoamlinvaallu(eisn.parentheses), standard deviation, Raenpdocroteefdfirceiseunlttobfvaasreidaotniorneo-fandaulpylsiiscaotftehseamoprliegsi.nal sample. Original analysis was lower than expected 4d Rdeupeotrotaeldiqruesoutletrbraosreadnonnorte-raenpaolrytseids.ofthe original sample. Original analysis was higher than expected du (0 aliquot error and not reported. -- me :i3 8 23 2 & e028 & 8.%8.8.8.8.;:2.;58.2.32 gs CEES aR 2 AT g, En G GREETi EERf EERfER EEgn Eaaed D8 o. giaiaiaialaiaiaiaiaefaE 3 E35 a a" a" 8 8% 8% 84 87 87 av 2% 8 i z3 ss 3:33 333s: 3: | tomer fissorieise 9 Hoo Ss ss oss oss osssooss {3888833888887 23 23 $HH2h F3H 2 4 iBil8e F2 FsosfTo%zF opfoFz os%OffogEi : : 53 2d 3 g 8% 5s :2 i 3zg:z E: I . kg 8 fs 3 1 gGl 3 ig3 : Teoas Ese iz 2 ss 10 Boz. Far of gf 3 Hi l 3s i go. | i &4 HE fi F:iE3 Ip SASS 3 SS 880A fe Bode desdrdsgdss 3 nnn ; Ha firdffgddfdds | 5 3 si 33:33:83 zs: 33 | fm ffddAdg EEE g35y =5 2= 5 3 3335 3 53 3533 33 2HE3 t8e 2433 g23d ga43 donF 8o4f &of A4S2 Ao+f o8f Ao=F @of A45 3434 3 3 i 3 58 1 24 88 ye cor oz oz oro: oz ozs O53 23 48 82 & 2 2 4 & 4 4 i iF & 7 FE IH ZZZ & ss 2. LEER 3 oEThgn. 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Iz S8 Efi2 EE, B8 EY E5H HfgEfp 0 #% 1 i 38 i:3 3 Z g2 ge - - A g gis a os :i.e gs of fie. . | 2 } 2s 2 2 3 i ? $ = e. i: i EC 15 z [A 1 CI A | FEE fi ii Seke o oo | FES oi| d pop|i [oEiE 29 [IE 3 Fi] Eda fINiE]g of igi A1P4-FDOay(OLrianlcaGraBvraagncehSedt),yAPinFMOl(eLiRnaetasr,anadndMiAcPeFO (Branched): RovisDiuonPoNnum1b4e1r621 DAYSONTEST 107 NFouumnbderdaetadstudy srt SAacrlifoiicnedtevbstydedaeysi1g4n Table 20 Percent Survival of Male Mice Growpl Omgkg GrowpIl O3mghg GroupV Imgkg G3romugphVgII G1r0omwgpkIsX APFO (Linear/Branched) - A 1%00 110000 110000 110000 110000 % 100 100 100 10 101 10[ 100 100 100 59 1100 1100 1100 1100 G3r0omugpkXeI 110000 100 100 1100 APFO (Linear) - B 7 7 mw 100 io 100 w10o0 11000 110000 11000 14 10 100 10 10 100 % Number atsudy sant 10 10 10 10 10 10 Found dead 0 0 0 0 0 1 SAalcirviefiocnedtebstyddaeysi1g4n 1100 1100 1100 1100 1100 99 /APFO (Branched) - C 7%7 1000 1100 1i0o0 1010 101000 11000 1 100 100 100 100 100 100 Number atswdy start 10 10 10 10 10 10 FSoaucnrdifdiecabdeyd design 100 100 100 Alointevstdeay 14 10 10 10 100 10 100 10 100 10 Percent Survival = (Number of Mice Alive/NumberofMice at Risk)*100 NumberofMice at Risk = Number at Study Start - Number Sacrificed by Design There were no statistically significant decreases in survival at p < 0.05 by Cochran-Armitage trend est = -_-- E52H3 < SJ F|Eg gf=F =.FE eesf eLdE & ls 5Zzi|Es5 os oo = =F2 3e2 %Z ef2 =f2 P 5 E[5283 S52%EE9oR2% AE2= e9r%2 EgH 2 i g3 E|< 5.8 8 s| 3 := P_E3N C[EeH 3% 58 =% w3 | if4g EE <a is ' y 25 aF EF aT s| Lf 38 325 1[ga e25l 22%%8 o58f8&8 5%8of| EN i iis 33 2 H2oa]E 22 24 | Eka5 32 % $= 82 3: B= 35 od 3A E53 =3 &E 8 &5 |g. i i E 3 ia 3 Is & ii3:: E2S 2 =o S2E5 = [ e382 .8%% 3RZ% 9n3 SgleB ss 5.8 sg 2 |8E =F 3% &% af Z [57 i 32: 1522 5 e53Zg% mE28 &.F28 $782 37%2: FR [RP =1g 5 g gs g| Iti i8 g23eZz 5|-2|F 2=8 = 285 z& E1H2E&3 . : #28 gs ss s| is 3. Ef(g |5g 7 c% a1% eT25 unAS Zi3t3 8 gi H 8 sg gg 8 g| 3 i g,iE s5 e[e25 F2%TF85 8% 83 | 2g2i 3&:& si3l og 5 i 22% 5% E 33a3 3 EF 23 a $= 3: 3: 2: fo 227: 8Ex8 gBdx B3x a8z3 | &Po3i gs 5E8 & Le 8 i iz 24 3 FH z 2 i <4 & 2.8 3 J Eg == 5% % F 2gEOQ g 858.8 o SE[25] o 8%F 8%EE&S F =$87 ] Ep i 3E28 EH 8%8 275.82% 4332 | 31 2= Sr - i 4, 3o 3 ze s 8g 858 g| i 85 2q%f2 (5 8% =F RE e | [2% 3: gggg 4 E E=EElLo gz og os %i,ivfv 3 He 8% 28% R= 2] 2 5 EE 1 19 g 8 :EE5c: geg 1 03 25 .85 .55 .55 3311l =f EEE 28 3% as ii 1 8 F3E os 4 cETiidE EE 3 52 - 32 ii g3g 4 $S= p3: a8: rE: |] 1303 $2 3% od 54 88 | 2 a ii 5 #8 8 & "ae Iz 25 3% FH LC oo. i f2 5 8 ga 44 Ad g oo oo z gg 5 LE oz 28 3i Ez : i: if| oRfi1 m pEoEs ogoEFH iGdEk z S2 # ik gg] EZ ; if B= 1=3: i : 333 F Zseb gs PH i: ify 5 oz | i EoGoEn Eg Bou |lH i 22 B= Js 33 G4 4 A : 18 . 3 3 5 = 2333 37 33 a2 : 8g Bagr .F E% oz i ? = 2TE _ z 23 -- Bia: El s23 ii Tl 5 i. sa .%osR os Bg 52s 9 3 i i bP o: oE 8 ri E sfi 234 E 1g) B HHH : " . 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EoEm ree ggg 20 iH q8f%3 LE0e amsf E0 F8 ETHi ' 5 PF oEO geF es BF f jl 4 h i i FEIT iH i fy og i 3 u5o i I C BE R TRF3 i Por i I PE dai LI nED IH : 2 EEE i bin iH g E : eTT 0 ody 1| Tzt2E oToeiE5saE | 3 Th 5 gat inf d | THEm Eis Ee EgEPiGdIs P E RREENE E 5 Il f i i i 3 1 = ; Cr: op! : ii C Coo mod i A i [I IHEgdd LS : CiE re28 i 2 ref 13 2EZ5] 35 3 3Hgoe 55 2oga 35 F 3 o gn 5% 3% 33 gl = Fg 3 9 7 312 = zs S:I35E8 o8f : 22 0s os 5os 4| | 33 2 1383 55PF= =OZ ss OR & on Z| 8 ios <E|lEgggl gg- s g 03% 8 2%23 FREE 228:1|5= | = 3i 0: < FO = F22R5E] 3LE 2 os 2 ox oa) 2gs Z8 RB 5 RES 5 2 5 0% 3% 3 32 2 fBYc2 3= 32 =5 27 38| |&3: 3%% z 3 TE 2 7 Bo 33 a i5 323 os 2 - oo 2 8 8%Li Pl Pd : ggg 3 2 33 g- => 5 = = 51 2 FF: 33 29 2234 3i83 523 2 134E 8 5 5 0&5 22 g 3S : := =3 2: 2 ET HEE 255 ox 41% ;i ; C SEEgE" Pid: Po ER EE | 2_a5 5 So 0%113 i Zz 5 ; {3 51 33IE % : JE z os l[t3 g og z$og i% 1Y2):ii |i]]8 Fl | gl 8 A 5 RE Fl | ii 833 Cae a] E: d 45 : | / 1 rd i . LF 1I] | | 2:52: !5 ' =t FF 2 Hi APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number 1 DuPont-14162 MOUSE FIGURES Tm thtkte 1 Ed cL Ld g : hNd J i0 3 I. = Hil o: d2 ozE { 0 1LJ | 4p 1. . - 1l:e |. "i l. [Fe i rT i : @ wip Apog ura 4 Fobitd i 4 :i IIl :g 1 |9 3 [I :I il 8 | Wy H oo: W = 32%3 | q |I | 1 Ls t= le l. l.r . :. . || bo 4 ig thptte |Z : $|4 * g0 la & i . i|l o=z Jii l. Wo] I EH | 1 3 2 a ] 8 a e s &3 (3) 1am Apog wap APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice ReviDsuiPononNtum1b4e1r621 MOUSE APPENDICES = AP14F-ODay(OLrailnGaevaagre/StBurdyAaPinnFMcOah(lLeeinRdeaat)rs),a,nadnMdiAcPeFO (Branched): RevDiusiPononNutm1b4e1r62| Appendix A Individual PFOA Serum Concentrations for Mice -_-- A1P-FDOay(LOirnaelaGra/BvraagnechSetdu),dyAPinFMOa(lLeinReaatrs),anidnMdiAcPeFO (Branched): ReviDsuiPonoNnutm1b4e1r62 INDIVIDUAL PFOA SERUM CONCENTRATIONS FOR MICE EXPLANATORY NOTES STUDY DESIGN H-24921 APFO (Linear/Branched) 1A ma VA VIA XA XIA Groups H26313 H26225 APFO (Linear) ~APFO (Branched) B ic mB mc vB ve VIB vic IXB XC XIB XiC Dosage (mg/kg) 0 (Control) 03 1 3 10 30 Abbreviations mgC/uklg== L= B= Avg.= Sdev= QNS= NSR= N/A= mCogn/tkrgo/lday Linear Branched Average Standard deviation Quantity not sufficient for analysis No sample received Not Applicable Note: H-26225 is comprised of two components, H-26203 and H-26204. -- --= A1P4-FDOay(LOirnaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): Revision Number | DuPont 14162 Individual PFOA Serum Concentrations for Mice: Group _DoseLevel ID pLign/emaLr Brpagn/cmhLed L+B__ L/B A Cul 100 NSR NSR NA NA 102 0041 0016 0057 2.50 103 0029 0010 0039 302 104 0067 0018 0085 379 105 0040 0012 0052 328 106 0019 0007 0026 2.67 107 0013 0000 0013 * 108 0017 0000 0017 * 109 0013 0009 002 136 10 0011 0008 0019 136 Avg. 0028 0009 0037 257 sev 0024 092 WA 03mgkg 301 81 24 105 337 302 78 18 96 435 303 65 16 81 420 304 81 23 104 355 305 97 28 126 342 306 94 20 114 462 307 88 21 109 421 308 72 17 88 433 309 95 20 115 483 30 73 17 90 431 Avg 82 20 103 412 sdev 14 050 VA lomgkg S01 ILI 32 502 232 54 503 238 62 504 233 69 505 222 56 506 206 70 507 216 55 508 177 44 509 260 56 510 209 53 Avg 210 55 Ratio not determined (divide by ero eon, sdev 143 348 286 431 300 38 302 337 219 395 276 292 270 394 220 401 316 467 262 395 266 384 50 049 -= A1P-FDaOy(LOirnaclaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched) RevisDiuoPnoNnutm1b4e1r62| Individual PFOA Serum Concentrations for Mice: Group DoseLevel ID pLign/emalr BrpagncmhLed [+B L/B VIA 30mgkg 701 450 90 539 502 702 S561 128 690 438 703 S81 145 726 401 04 477 132 609 360 705 S81 146 727 398 06 413 103 515 402 707 S61 121 682 464 08 554 10 664 504 09 537 120 657 448 70 657 140 797 468 Ave $37 123 661 439 sdev 86 048 IXA 10mgkg 901 155 296 1844 523 902 193 335 2268 577 903 166 258 1920 644 904 160 235 1830 680 90s 213 396 2522 538 906 146 197 1654 7.38 907 171 237 1944 721 908 147 206 1678 7.15 909 146 244 1709 600 910 ISI 169 1676 8.94 Avg 165 26 190 663 sdev 285 112 XIA 30mgkg 1101 198 223 2203 888 102 246 262 2718 936 103 191 203 2112 943 104 233 269 2599 8.67 105 208 212 288 981 106 222 217 240 1025 107 204 200 2245 1049 108 193 176 2104 1098 109 218 224 2400 971 110 272 242 2966 1126 Avg 28 2 241 99 sdev 280 084 TNngo/wmeLvaluuesscorrbect1ead49fo2rn1staLncBdarrdeacoom=po0si7t8io0n2a2n2d3c5on5verted o ig/ml. by multiplying linear values by 0/0007 andbranched valuesby 0.00022 ET A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasra)nadndMiAcPeFO (Branched): Individual PFOA Serum Concentrations for Mice Dose ng/mL Group Level ID Linear B cul 10l 0077 102 0037 103 0218 104 0062 105 0.131 106 0035 107 0018 108 0038 109 0022 110 0030 Ave 0067 sdev 0.060 WB 03mgkg 301 124 02 1s 303181 304 133 305 143 306 109 07 17 308 104 309 ONS 310 12 Avg 126 sdev 24 VB 10mgkg 501 343 502 421 503 310 504 384 505 318 506 309 507 251 508 329 509 280 510 266 Avg 321 sev 52 ReDuvPiosnNutimo1b4en1r62| --- ms A1P4-FDOay(OLrianleaGraBvraagncehSetdu)d,yAiPn MOal(eLiRnaetasr)a,nidndMiAcPeFO (Branched) Individual PFOA Serum Concentrations for Mice Group Dose Level ID gLi/nmeaLr VIB 30mgkg 701 77 02 6 70378 704 66 705 71 706 61 07 8 708 50 09 68 mn Ave 69 sdev 10 XB 10mgke 901 197 902 132 903 134 904 235 90s 372 906 233 907 216 908 233 909 266 910 231 Avg 225 sdev 68 XB 30mgkg 1101 253 102 276 1103 297 1104 218 1105 NSR 1106 298 1107 253 1108 286 1109 246 110 203 Avg. 259 sdev 34 RevDiusiPonoNnutm1b4e1r62| -= -- A14P-FDOay(LOirnaclaGra/BvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): RevDiusiPonoNnutm1b4e1r621 Individual PFOA Serum Concentrations for Mice: Dose Group Level iC cul 26203 wgml ugml + ID _H26203 H26204 H26204 H26204/H26203 dol + +0079 N/A 02 + 0043 NA 103 +00 NA 04 = 0029 NA 10s +0017 N/A 106 + * 0000 N/A 07 + +0000 NA 108 + * 0000 NA 100 + * 0000 NA no + +0000 NA Avg * 002 N/A sdev 003 mC 03mgkg 301 62 94 156 153 302 62 108 170 174 303 73 143 216 197 304 58 82 140 142 05 50 77 127 154 306 61 77 138 126 307 51 64 ILS 125 308 43 57 101 131 309 62 69 131 11 310 50 49 99 0.99 Avg 57 82 139 141 sdev 352 029 VC 10mgkg S01 144 349 494 242 502 121 281 402 233 503 124 298 422 240 504 ILS 242 357 211 505 114 270 384 2.38 506 113 267 380 235 507 83 153 235 184 508 95 143 238 151 509 88 172 260 194 510 78 108 186 138 Avg 108 228 336 207 sdev__100 038 A total branched content was determined instead of individual values. -= A1P4F-DOa(yLOirnaelarGBarvaangceheSdt)u,dyAiPnFMOal(eLiRnaetars)a,nadndMiAcPeFO (Branched): RevisDiuoPnoNnutm1b4e1r621 Individual PFOA Serum Concentrations for Mice: H26203 Dose pgml pg/ml + Group Level ID _H26203 H26204 H26204 H26204/H26203 VIC 30mgkg 701 250 739 988 2.96 702 154 500 654 324 03 24 762 985 340 04 180 632 812 351 705 201 656 857 32 06 200 596 797 297 07 241 590 832 244 08 214 570 783 2.67 09 195 537 735 271 70 215 516 79.1 2.67 Avg 208 616 823 2.99 sdev 103 036 IXC 10mgkg 901 38 145 183 387 902 41 171 202 414 903 35 136 171 387 904 36 115 151 3.19 905 47 184 232 390 906 38 112 150 296 907 33 107 139 327 908 40 119 160 294 909 39 14 154 291 910 46 125 170 273 Avg 39 133 72 338 sdev 29 052 XIC 30mgkg 101 48 276 324 579 12 39 213 252 543 1103 40 260 301 643 104 33 204 236 621 105 43 257 300 595 106 44 170 214 387 107 34 154 189 450 n08 42 155 197 366 109 36 145 182 4.02 10 50 194 244 389 Ave 41 203 244 497 sdev 50 1.09 Rote: Test substance F26225 ratio = 58% H26204/42% H26203 = 1.38 -= A14P-FDOay(OLrail nGaevaagre/StBurdyAaPinnFMcOah(lLeeiRndeaat)rs),a,nadndMiAcPeFO (Branched): ReviDsuioPnoNnutm1b4e1r621 Appendix B Individual Body Weights for Mice 285+ -- AP14F-ODay(LOirnaelaGsa/BvraagnechSetdu),dyAiPnFMOal(eLiRneaatrs),anadndMiAcPeFO (Branched): Revision Number 1 DuPont 14162 INDIVIDUAL BODY WEIGHTS FOR MICE EXPLANATORY NOTES STUDY DESIGN H-24921 APFO (Linear/Branched) A mA VA VIIA IXA XIA Groups H-26313 H-26225 APFO (Linear) ~ APFO (Branched) B ic mB me VB ve VIB VIC IXB XC XIB Xic Dosage (mg/kg) 0 (Control) 03 1 3 10 30 Abbreviations mg/kg = mg/kg/day me -- 3g. LER 3 x ii SRRRAARAA AARAARASAR RAAAdsaAnsd i agaszdsds dsnsddsdss gdddzsddds = RifAZAdEA ASARadiAds RAIMI :3 a2R'8RRa8R [A]IANIARRR ZARARIAANR i'E.; ZRsAsAdddd addddsddsn ddddandsAss il i 18. some nnmnn monn gy EL ancmsaen sssseiemen sesssseses i fez KARXARNRAR RARANDRARN S223838283 H HoL f samun ssumn mmm | HP $08 1% g 3; 1 : : i LE 2 2 3 REZ 1 BL maine Foceeniaens aiionenons fog i SRR2NZRAAN < 23833RaA23 I ARAR8RaAa% 2 i ssaasssaes asmsssasas sessamesss a 3g. Z|3 3ss & iI i: 3.7 BRGANAAEE ARGRRAEREE SEAEE 13f 8.2 GERfessRs sAssaRasAs RAsAsARsAn : jit i: lie? mamma snunn wma gy . wnssoanar emInoIais 5390993300 i i ASRRARAARR EERE SABARAARRR g: HE 5 ig: 24 23] z fo EEE EBNNE Sng ff sesnanann Foascenssans 2 gananeees fon ? RddnZsdns I fdddddddda FB dsAAdssdnd fT: i i supzeessey sepzosszzs smossszzes 5223282530 833283388 2 IRRARRIERD iE i 23 $8 Zo EEianSIasl | gIeasaaady Yaesnentse I. i Eo : i $Pylo PiE i | ununm d4A835844% WENEN Em adddddAAsd LENER Sam 3 ssIsEsasdl RHI ha ii2.t7 ddisdnndds Sddddsdddd dsedssssss : 1 tEer g282434883 4SsAAsAdAd : i i Lo mMnBNEE umnEm i:22 L2E3] S33o Pfi Dammam lama! zy =o i % $$e0s 2"R5E3E3a0s3s0i3z3a4y R LLLLa LLLn LLL 3 f nimecons oom 2 El: 4] 1 fs 5 smsgesszas soosssszas RRRRLRIRRRF 82828888 a F 2sasssddsd mI iRIAJA2iAiENdEaNaA annam 5333885883 anddmmmamd 32H583] Hx= & i8 ty 31.177 IEALGEAARE ARAGEEEEEN AMINEEEEH :i RABARRRARS 283A8ALRAR ININKREARE $1 fhe mmmmn muERE SEER He gl Le mmm ososmm ommEm i22 32 2 07 {ARARRINIS ARANRIRAASR AINRBRNERS 5H3 FE He : : 53 52 ZFeop ooaFiRzEzARaRsEaAaAsX go AToRaSnHdRiRdiAnHaAnRi o RFRoRadnsRiRndiuaszd EE IE i 3i a f EsRuRpEsRpEsRsEeRsRs 3 IsNgRmRsRnIsRnRsIeTs 4 AgdgdsAEasdsdnEEdeds I2ga fo i qo 3 : i Pl! y i shBo.y Ham33R33R38 idzngsnssn 3 RARAARAAAAS mEmEnm3 amsdnmmWnW E AAsmssAanss 8SRadEEEin BEER 2 oF@BEassAsds nBIoEnLn resassasas sAEEEwmaErme BN uum Co Aanddi- avam minum i i ii iR3iddnasR3 ahsarsaris. As aaveesduey BN : : sidsasdiad ddiiAani gI|s fLioo} onAamsmdaaiamn smu oggsanmeucaaames 1i io:: . RR3sAspRraseE ]oi ARHsSs5i3aARA%E EF nAniadRAnnsana 8i i4:: fti i ;EREsEaEzHsssazas : asmzazasas : 2s3n8e3s5:85223 Hi EE ae 13? & .7 &R2AARNRNR AARBMARRAR ARASRIARAR 7. EIEN MELEE nna i ii' Por i The oie 2EH 2..7 o%3 3I: 79. 1 BIE 3. 3 EEE asRofadmdefsacAaNnRs S BEPEIENE f1 aodddnasdesdd GRERR gseaadsAezdansnasaed : BSEeSeEnR DO xadsmdadodannd nnmam dwAediamdnaiaacdsayd aEsEadSa Fpodosdaidasends I i: i e 3g. 233 7: Ha Hof GHERD SEER am i. GRAEEIAASR 3 RAIRRRERAR RARRARAARR . 2oy Bi monn EEREEEEEER moun EEEEEREERE onan AR8]AIIRIRR ti i.) Aedsdsdndn ii SadAisisss Rensssiess: 1h 2g smamn sammm oaamamn |oo if ti Pig.a ITornimEndEnl EmmEm aENrED GsEmnmaisnsasnass g : ig &1. eAosRasnMasAse mMamEasRagnEen aRmmEneEneEenEy i3 5 i ; mRoEnAoRaAmReAnImReE moAmEaMvAeNnEcEnEm IcmnEonEnenEne Ho BH: 5. oeevenanes oansyanaenn ommesrense 28 s Boi - 8SSREEAASR go RASARASAd 3 Asdddddssd ig: fe 2 8 43 emmrensnee smasanann EREEEIEEE HE iGi iy :i EEREEEE] RARKARLRRE EEREEEEEE 5.3 ii? Addfdaddds dddfdddddd ddan sdRas ' i Flo omEEE BEER Emam if 4 be onnmmnn nusan num or gl 53 fo if MEHED BBREH B3aNH . i IH HEE 2 2 i HE RH EE Ee &4 3 ssezeseses ssasgases EREEEEREER 4 3g. 23 5. lu i. i fox [I i 3 iff. "F PE :5 nmnmn 28AAAA38R IREAEANEEE nonnn EREEREEER oman ARARNRARRR nonon EEEEEEEE RIEREAMEE mnnon SANARARRND hnmma RARBRIRRAR mioion EERE EES Emam nm ag3anaan8s nium EEEREEREEE i: henry AAI mma 5 id for EEdiddadan dfdiddgding ddsddsdasy 1 Php RREEN NEESn mung a 2 io! i $m = REARAIAIAR mmm aANAIRR3AR nnomn EEEEEE 2d f- non munnn nnn sg ie ` : i: i : FH 2 5 Eaesreianen Foosescncuns oessonssens i 5 fo3 F ARmARRAZSR : sRaddssdsa asdaddadds 3g 3 i= i i IRRAZAiAR GRGAGGNEE AANEEEEE $jf3yi.'0 A ERART ASAI REE TGOEGAUNTGnEeEnEeR | aGrNeEnNeEsR 2' 2 Vi: mmmpn samnmn mns 3 gs .2 Aegxdedmdzdadedndinn dwa3dedadsdnsinedIs 2A1and0nIdIsTdiaes:s i: i gio g ; gz .5 ddiddasins sansasssAs AdAassddsA 59, iF : i5E| = 8 . 2@ SaRunEcAaAaRvGeEaAsE Fo eSsEeRnEsAeEcEaEnNtE b2 AsaAvLiAeqSaNuEnRr 34. fx Z| if i = EHD ODODE INuDD 3Zon dAdddddddsd ddddssidgds Jdodesdand iFE Addddddsds d8gdddddsd Aggsgassas HE ZAAsadnias SEaddAiii SERIE if : fi. SA3ASRARE Aasdnssds sssasssias if i i . SISag7IaE. 3203970300 - ARs gy . 33 for iBb;: FH i Be 5u . ceneneeens AARRSR3RAR mom 2Eon nodvesanna 22333328 mwewm 2Does eenscacang AA8RRaAzAR mom Donan 5g. 53 fe 21s ad : 3 AsZizssdds ddsddnsddd Adddsdidas Fi. GEERdREAR GEEANANEER SaNEEEE ! iif P| fie mmoemn mommn mua : i? I 4 Loommnmn oonnmn B3oo lL mumn momm mam 53 i $e8l: Ls o Fff ans 2ann gs z s A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): RevisDiuoPnoNnut-m1b4e1r621 Appendix C Individual Food Consumption for Mice --- A14P-FDOay(OLrianleaGraBvraangcehSetd)u,dyAiPnFMOal(eLiRnaetars)n, dandMiAcPeFO (Branched): RevDisuiPonoNnutm1b4e1r62| INDIVIDUAL FOOD CONSUMPTION FOR MICE EXPLANATORY NOTES STUDY DESIGN H-24921 APFO (Linear/Branched) A mA VA VIA XA XIA Groups H26313 APFO (Linear) B mB VB VIB IXB XB H26225 APFO (Branched) ic me ve vic XC Xic Dosage (mg/kg) 0 (Control) 03 1 3 10 30 Abbreviations mg/kg = mg/kg/day ganm/day = grams/animaliday _-- 3g EERE Higg i . = i Sd i: Piin ommmnmommmona nmomam i3y 3a DmEII SIEMDANIIS Sasmanaam: iiz Hi g: 5iz3 . silLIE ig: $3. CITE SENSIeIan anmasoaans 3385 d dtg s. T gcuowmamemnmnananme gIp ynnaomnasnennasanass. oaaomsastmmaeemsny 3g 7 : 33 5 4g ae : ; ` 3 sdi P| fg amon s 3 i fp INET 3 i i gd s E5, IIT StdHE: gCaoebosom BE lg mmuoiam NmMNTS INI 2Poemwe 5 amma nhnam Jamnn PAamNnrnIrnErnSs 5 i 2G ag &: 2 i 3 1 3 FOR JRRIAINIIY ZAaManIE ImIIING I. iiz 332 I333333TT S03IEINIT EAC 13 iH . 3 3. J2AN332333 pmEGEAALY Co mnIMAMAM 4 : i aumanisiIs g suusaanas suzmzaaasy 298 2 8: 3g 35:72 28 88 ag # agsssscess S=22222884 4 zpozssszes BR8353R88F sazzssszas FRGGAsssdg 38 z Ld it : i 3 2 i f5n DITTO TEIINOINIT umeoamm 5g, HEkY iz {3s WELW NINN IRIE i: 1i id. ak ) Tg = 2 2 if 45. Foaauoazouss BosnIssaonzi oR onumamnaas fg: gig : : 22d3l 42 $ EsRnEsEgEoRsRpReRnFs 7 3g8u8o3z8e8s8u8s8e4s #J Bd3aSd3mEmEa3dLnLd8s ER a : i i : Dap mma oman mmamuEm 22 Bifz iz 3: ONIN INSIST 2MIININED ab og3: 3. saaGmidn IISaIGadSE onaaaesmsaanssaase 53 | 3 2 ge ag = gb Edn Guccncinns :I chcannaeen :P awveasanan IHH5aE : 3z s Zigz E3E5 3 = 5I. i i ii .f3 SHIINNSE IMSENUOIR SImIINIRRS 3h af32 GUINEAS SIMNINIT SIININRINS Hiiet i SMITA RITIII;I EINE yi f=a..FoanaonSens P2 osIGIINOT 72 OIBIRINNNS A1P4F-ODa(yLiOnrealarG/aBvraangcehSedt)u,dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): RevDiusiPonoNnutm1b4e1r621 Appendix D Individual Clinical Observations and Mortality Records for Mice - er A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): ReviDsuiPonoNnutm1b4e1r62| INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS FOR MICE EXPLANATORY NOTES STUDY DESIGN H24921 APFO (Linear/Branched) 1A MA VA VIIA IXA XIA Groups. H26313 APFO (Linear) 1B mB VB VIB IXB XIB H26225 ~ APFO (Branched) iC mc ve vic IXC Xic Dosage (mg/kg) 0 (Control) 03 1 3 10 30 = -_-- FE 2523 s5e2 i $82 fnf. ndnd3 ndad: a ia 5 i i i i i111 1IlTOLOll c & & & & & & & 3% & 2 I] iii $ SE Edi didi g 2282282822 iBl oohphahnhnhRnnnnnnangg 9 i [RHEgR ua E REn ERa E Es E 3= 4 3% 2 38 & 3 3% 3 23 3 = Bs ss 2 7a 858 38 8 = IER 2H5 E1% iE i 3 WM Epunpanias IEE EEER EEE E EiF 133bb3o1bo1E1or8oyoi%d 5 FFROEEI A i Tii iii gy 2 2 2 2 2 2 28 2 2 2 132g hha fy fr fr hhahLag bn in in fn fx ir ix 5 PHBH g tHei: 1$3 8 8 3 8% 3% 83 3iH:: gd] 1 les graiseng f= ox = = = =x = x = = i3 di, 2 24 2 ii shofene Boda fafa fe fa fa Bn Bs :i i : i3 1131%131131%% : S E, , k8 oi 4: 3% i8 B i8 i3 i t PP o A haEt irri gy rT HH2oH BERGER SEE3N8EiSx f58n 5f3n 5f3n f58n i53x i53n 5i3x i53 53 fmianganEng &l = iR iil HP 4 : 5 = 8 8 88 8 8 8 34 5s 5 5 8 == ox ox ox ox ox ox = 3g 5%] 85 Zgz aFE]] 21% 2| 5 az fitted tin Ba Be Be Ba i 2 i o. i 33 % To. TORO : RB & kB & BE % EE oz BE BE % 1 jr rtiiHdgqit Foi d 8 dd iE D0 dd 2 2 2 8 2 281 2 2 2 3 i3i 2%8 935 2%8 438 gf8 {g2fBs.8f 0g3b Fg8oF8 igff i Ep fn fn ix ir if-op fr fn bn ix 33 faaaaasibaayh 22 Eagg 538] 2= 2Bi4l 5 i gs 8 38 38 5. = = 2 Z $sRF5 3F8F gE FEE 88 ss 8KR EE 5888 DdgE 3 8 8 EaI ss os zH5 E(2 3%ii ti hhh hiadd i i i PPor oofrofroEroErEoYfoiEildl & & 8&8 & & 8&8 8&8 32 2 3 12 i FHI Pi dd EdgdIgdf g 282282222 5i3: 8 53 53 53 3 8 8 8 3 43 spp ii cd2 f E338i 3% EEn BY ESa B89 EEn iY iE 3 Huu Eg $39]:= EFSEESI:E T2e8 8ss8&8 5& 88 828:88 8238 33 fg of of 8 8 8 8 8 8 8 Hu 53 5 ag i 4 FT 1 tT % ?* 3 % 3 : & Bi, & & & &B kX % 2 1 jsPhhyri tit tf HooghimaRhhiiRah i2 8G8e o9ll 85 si2e3g2i8e i3n 3i8n g3i8n 9i3n g4e3 gisF i: HEHERI RI RIRIRIIRINI] ts2 IERRIRIIETHRHIREIRHIRE IRH IRE IRIR Hgfie fEis82z Fo:i oiRoofzs oo%goosd 4 1 $= = = = = = x= = x = Hh 323g.a ga 22 ag T1331 1TOYOTOToyLoloy - 2 & 8&8 2 2 & & & 2&2 2 : gobo it if t didrde id gE, 2 2 2 2 2% 2 2 8 2 2 iczE 2i H | Pa HIE 5E3r 3i3 5E8r 5i5x E.f3x 5PS e53 Ek8 E33 3 x sfoghghf hgf h gd ofi gE gh r g3i ddhudy FEE E EE ERE gli i... --.. oh ii il IEEE ; ST & & & & 2 & & 2 8 3 Pl g of FE tPi FE t iidi dd , 2 2 2 2 2 2 2 28 2 2 H HE 5 3 iIhEbEhEhhEhRhRhRhanE g 2i3 . 8 83 33 83 33 8% 83 3: 33 Bi i 4" 5i 3 8 8 3 8% 83% 8% 8 2: & EI i2G)2 i EE E EEEE EEE i i 5 Troy oEoToToTOoTIOTii ' = & & & & & 8 2 3 38 2 Ho oghhhhhhhahh 3a: Po53f ii1iilq r%r 32% 2ZF 2P2 R 3 E Z3ECZZZ 3 OZ3 S| Foi i iiiiiiid , i 22 $545 2 68 628 2828G28428 428 28 5: 3 E8r f53x 5f8n 8E3x 5E3x E53p8 533 E3x 5B3x 53 ED EE BH E E ES EE gf: 3 33 : igpHapiangs 9: ig: 3&5 gs 1 3 8% 8 8 & 8 8 % % 8 37 8 8 8&8 8 8&8 8 8 2 8 8 Fx ox = = ox x x = = = 3HEzE]4R8D2 ga2l2 2 28 & 8 ii de dn de Br de Glin Be Be Ba : i B oioF: zFozFoi3oz8o8idi f(I ii - TF 8 z & i 2 ., & BE 13a i3i0T5> 3T2 z2Fr oZ3z oiz loF:r oo2zi3E3f%ogz2o1ifBFodg2 EF FE dg 4 E d gy 2 2 2 2 28 2 2:%% 2 2 3 $8 8 28 8 fF 2 4RRER gf 8 oF El $3 33 8 8 Be Re foREs 8 5 gS EiHz ItRr Ekx EEEx REx EEx EEx E5iEx EEp EBx EEr 252 fe 58 23 = gS2EiH0le2s5 IRR IRR IR HIRE IL.. sos.os iE FE EE BRB a g 8 ZF $e 2 8 38 88 8 3085 82 F2 5= =5 5c0=B 8 88 5 x 8x := He i i i s 3 3 FP}OTOROROROY ' s| 4 3: :& i8 z% :38 z8zz& z& i& z% I 3% 1iii1iii g FF FFF ff: 1d g 35 22 S$5id45 m 25 225 i 28 8 835 n 248 248i 245 28 H5 ooslfair ihirnihriErcEtrEirEirRtrEt i jaan nung HE SS Fr srzaongogofos gg Fx = = = = = = = 2 = 38 24 i & thinkin hh ie kh i i 3 T1111 1 111 11 tigiiy 58 83 0% 0% 8% fig 1 fof 53: @ 3 S| I SF ir di i o1rg r1E o6gi io iE 2 i E i i2, g2h g25 gl2ng8n ng8f8 3fogg 2 d2l% 8 2erg2s i Binnie BHI 5 shi hai Ghd liabhy 3 HEHE INR Mgeli: oisgE 8go& s8 s8 gtEs 25:8 L1%a I is gs 5 8 BB LL LL. a 2 8 [I] Cea as 38 i ZF Te &7 85 13s Gg Fp 3a Bs du 3a Ba Oy 3a 3 4 i oF P3 PP7o3 TOEYOoRrOo1 TlOoYiOoYg - 0% 0% ZX & 38 2 & 2 2 & for ETI 1 Pod E i Ti Pld gy HEE ERE RE 2d iExH fii E522%y 5E3p 5i3x h5E3x B5B3xi$Ehx3 i5E3xh5Eh8a i3E3xhh5E3x = [REDE IEIREIEIE IEEE HP i de 1: soazozozazooz gs i Fx = ox = ox = = = = = 33393 25.: 33 & "| 3a dn faa dada de Bada da : iPF 17F1FE 111F1EF13E3g ; T 832&&%&3i2 3 i rzzporzoropopog 2 iAIEiEiE5Ef EE i gs 2222222822 3 5i: BREE 3E8r 5i8x 5E3x i5r3 5i3x REEEE 32 5i9r 5E3x 582 3 i br3 f Eg Eg E ERR naEgE HF e: Eterazs I5gd 3 gf 3 38% gEzF ogHE ogEH8 8FE o8 oHE ogHE8 2 ox = ox = = = = = = Fi3Ey Gis, 52 5 1h hhh hited : : g FT0o0s8 ofyF oFrFy of o3p ffoononf oogngy ' S&F & BE BE BE BE gggy 2 OZ 4 i PILE lah FFE 8 dd fs iid gy ERR RES uddd fg 2d S| 6 5 5 8 5 gguzanh 6 8 g i EEE GL iz a3 ir $97 ix 7 ix 93 ix Sy i Sy sigggin ditty Ep fy & fy Ex dn Ex ay EHHE inn minnHE H4E : 4: Pe 2 22 2 2 Fz = = z= = = 822 = oz ox ox 38 2= iE i i i i03 r 11111R = & & & 3 8&8 23 &8 & &8 3 Bosh hhhhhhahg SpE il E ddd 2, 3: 2 E 2 5E 2 GF 2 GF 2 4F 2 68 8gE 26F 24F o2 f 23 28 i 3883 83 83 gd Fd is El | RR F ER 3 $F 3 jaaanudnnay i: Teseeresss: SF: reser IE Sel 32 3= "|i tithe hhh hth : IIREEEE "EERE ii T3131: TT FoEoYoOg i' ' Poppi PrE rr 8 fF fF 8 i, E 2 BE 2 8 3 3=: IfiF r 3Pz zf3r 263%% zr fzr f z2irr1zzdr Fr1i H nnn Rann 2i 268 25 248 2G%%H525E28Egz8 848 gG%48 3gf of 3 iod 3 98 E $f if 54 8 LRIRIITRR ERR 4 PHBH 3: 0% 8 8 EE EE 4 2 Fr ox = = 8 8 5 3% 3 x oxox ox ox = 3tH,E Z| 12 2 i 2 28 & thin faded dnl in ks i i: i i3 7 3 ?POTOT3 OTOTOR : & & 2 EB 8 2 EB 2 X $0 fhanhhhihhas <: gy i xir: 233 i. 398 =2 gFoEbF Ed Fd dd 8d 2 2 2 2 2 28 2 8 2 #8 5 5% 25 45 oF 45 48 gf oF gf 2b8 h33 a93b5a8 5b8 b3bEsiEbS iss hE38 j EiniigbgniarfnninEgfgi E #i2z %5 3& 33 83 88 25 &8 &8 %3 3g8y# f fe e 28 880 88g 8 8y83 HE 32 22 2% # = = A14P-FDOay(LOirnaelaGra/BvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Revision Number | DuPont-14162 Appendix E Individual Animal Clinical Pathology Data for Mice 27- A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetars)a,nadndMiAcPeFO (Branched): RevisDiuoPnoNnutm-1b4e1r621 INDIVIDUAL ANIMAL CLINICAL PATHOLOGY DATA FOR MICE EXPLANATORY NOTES STUDY DESIGN H-24921 APFO (Linear/Branched) 1A mA VA VIIA IXA XIA Groups. H26313 APFO (Linear) B mB VB VIB XB XIB H-26225 ~ APFO (Branched) 1c me ve vic IXC XiC Dosage (mg/kg) 0 (Control) 03 1 3 10 30 ABBREVIATIONS: General: mg/NkSgR -- mngo/ksga/mdpalye received for testing N2 - not taken or not performed Individual Clinical Chemistry Values: HLEiMp -- hleimpoelmyiasis CHIOrL -- cihcotleersusterol TRHIDGL -- htirgihg-ldyecenrsiidteyslipoprotein cholesterol RoRHDL, - non-high-density lipoprotein cholesterol ores. Wfhoelnlowiinndgivirdeuaaslonasniomralotdhaetraraeraesonnso,t ralelporotfedw,hiciht maarye beexpdluaeinteod oinnetohfe tshteudy records the sample was clotted (CLOT) tahvearleiwdasresiunlstufcfoiuclidentnotsabmeploebtfaoirnetdest(iRnNVg) (ONS) tthhee asnaimmpalle wdaisednoptriosruittaoblseampfloer ctoelslteicngtion no sample was available for testing (NSR) = A14P-DOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLRianetasra),nadndMiAcPeFO (Branched): individual Animal Clinical Pathology Dota. for Mice wale, Grow 1 Maimal WM LP 1o0m2 Nweee Neonwe 11003 TNreancee NNoennee 110065 TNreancee NNoemnse 111000578 NdNeeennneee MNNeeemnneee Ho None Nene Wale, Grow IA Animal WEN LP 330021 mNaecnee MMoonme 330063 SMmeanlsl MNoomme 330065 SSmoanlel Nteonnee 330087 NNoeme oNmemee 33005 NNoenwe Ndeenmes mie, Gow ow Mnisal EEX Up 55S00512 TNNreeannceee NNMooennmeee 5S0045 mNaecnee NNoennee $5S000786 TNNroeanwcese WNNooommmeee 55009 Ndeonneo MNeemnee 0 ma/ky 24921 oyu OT scaoud smaicd mwg/uL maowan Nnoew w1eD NNeoww 1I3u NMoewwe 113878 NNNeoewww 11d82m31 Mew 17 w5 w7 w5 aam 1504 53 103 15079 i59 i756 12a05s% i531 an nso -0.3 ma/kg H-2921ICT mc/o.l mtgu/del MNeomwee I18n6 auss MNeemee 1a330 11338 NNoemnee 110 L9%o NNeemm 1D02 i1s3 NNoee 112a0 113s2 ym mwird mmoorwanl 79%7 3a @95 5a 17m% 32% 83 23 977 a2 1 moskg we2e021 by a IT mceotnh sTeMGa mWoLa naormeonr NNMeemwwe 11839m 1a:9 a& &h3d6 NNooww I93B m ime o 28 MMNeoomweee 2D101605 111133 1a015 is a6 MNoenee 11670 a1sm 7or E@S Revision Number | DuPont 14162 TC AP14F-ODay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(e RLatsiaandnndMAicePeFOa(Brran)che,d): wale, Grow neal WE 20700%15 SeTeinmsle 4705 TMroancse W070706 NNNoonmnsse 7N5o tNreacwe wale, Grow Meal WM 333000123 sNNomenewe 3350056 NNNooonnnee 330078 tNroawcee 23005 tNroawcee wale, Grow eimal WM 01012 NNeonees 1H10o03:5 fNNrooawnceae 110087 NNoennee 11100085 NnNeoessneee Individual Animal Clinical Pathology Daca for Mice VIM = 3 marke H2esl - by LP XT mcgi/od.L dIGL mgW/Ldl nmeewmnn wdMeoonneee MMMeeemmmeee 1S 7211 2191%30 w60o6 255 dMoonnee eKmemse 139 11&005 Nena Nome 0 12 7600 40 533 MNoonnea eRmesm Mone Nems 1730 $7 2o 1035m w3470 2aEH Nee New 0 13 & Do - 10 markg n2e21 - sym uP IT ecaarl mmiLo swoud mmo/woen nMMoeonnneoe NeRemesse u3l0 7 1z8d ds 562 de 3@ 2 NMNoaomamo NNNeeownmse 1a50m40 4i13se0 a750s7 3&5 NNoommee Neenne a6m m11m Mom Nene 36 ne 34& i2@ Nom Trace 208 1m msm A - 30 mg/kg w26921 = oy a Lp TT md eed mL mL NNoowmee dTeemacee 738 Now Nem 66 o5 m0 a& 37 23Fo NNoommee dNeennse 03s5 None Nene 60 53 5 2a a 323 NNNoeonnneee NdNeeemwses 1140522 11548 52&6 a30s Noe Wederate 85 5 b ReviDsuiPonoNntum1b41e6r12 T50- A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnactasr)a,nadnMdiAcPeFO (Branched): Individual Animal Clinical Pathology ata for Mice mle, Grow 1 Mumal NEN uP 111000123 TmNraeacnceee NNNeoonnneee 11005 FNeemm NNoomnea 110067 mVaacnse NNoonnea 11100055 TNNreeannceee NNNooennneee male, Grow 1B Misal W up 30021 TNreacwe dNeonme 330038 Ternacse NNoommee 330056 Termacse NKeonme 330078 mNeennee NMoomme 35005 eNemnse NMoemmee wie, Gow Ww J TE 555000125 eNennee New NNeonmee Nome 530045 TNraece MMeemne 05S00678 TeNreawncee NMoomme None 55005 eNennee NMoenmeo - 0 maskg ne26313 ICT scaand sTaMGd voNneoews 1125379 1%5s NNeosws D13 i91m NNeonnee 119m 6721 eNMneeeem i11l33 8i7 ya mwane maom a12ws &728 #71 a5 moa6 073) I&H 0.3 m/kg B26313- by ou IT mcioduh mmocd msoojue meomron mMeeww Mew 1I101 m 17: s8a a28 NNNeeowww 21i0me3 1l13a35bs aa51 a75 NNoeww New 1I2m29 111sm Da318 dE"odc Nene ils st 7 3 1 marks aes by ue EC col mi7Ac wu mown NNeww 1 12s 1m1 o&o 552 NNooww 113y i180 &6 5& NMNoeewewe 11d37 la1en9s 82a122 &5& NMoeew G182 11433 6538 2a Mee 12 1% 48 5 RevisDiuoPnoNnutm-1b4e1r62| THis AP14F-ODa(yOLrialnGeaavra/StBgurdeyaAPinnFcMOah(lLeeiRndaeta)rs),a,nadndMiAcPeFO (Branched): Individual Animal Clinical Pathology Data for Mice ale, Grow vie <3 mk H26313 - oy a mimal ww ue Ir mcodu mmeicd mWoeL mmeensat 20031 NNeonnea NNoomse MKeemnee 13 1I0n3 705 None Now Nene 71 HE 55 252 00645 NNdooonnnese NNNooowww MMeeenmmeee i9m6 6 a112m2 5ss 37 3% 2 0657 NNNooonnneee NNNooowww eTBmaemcsee 1811s2 71s3 133 @aa1 37% 5 Wo Nene Nowe Nene 58 22 de 2 wale, Grow me - 10 mark H-26313 - yu ised we up i scooldui rmoice mmwLa nmeowst 52001: 303 Ndoermee wNoonee NNeeense Nem Nene ems 111058 12753 ss 68 I5 333000456 NNMooonnneee NNNooonnneee TNNeeeannceee 115273> 11a3 56 2ia 532000785 tMNreoaswcsee NNNeeonnnea NNNoeomnmeee 1338589 maiy 113 553 ao @ So New None Nem 32 am 7 a ale, crow xi 30 sara H263 - by a emal We Lp IT gal mg/dl mpd mod 1H0o1a ENonnee NNoenwe TNreancee 1800 1P0y0 10 Nene New Nee 2 0m 6o 5 332% Hnooets 108 Nwoene me Noomwe Mone TeWrnawcee w57=95 77we w33o 425 511000980 NNNoeonnneee NNMoeemwwe TTsrreaaacclee 1798%7 2506 57 73 Fd 2a i Dio None New vee 0 11 6 5 RevDiusiPoonnNtu.m1b41e6|r2 Tn: AP14F-DOay(LOirnaelaGra/vBraagnecShtedu)d,yAPinFMOa(lLeinReaatrs)a,nadndMiAcPeFO (Branched): Individual Animal Clinical Pathology Data for Mico wale, Grow xc - 0 mark n-26225 - wy ou IEE cL I me wn momou 111000502 TTdroeanmceee MtMooomnnsee NNMeoonewe 1000685 TrTrreaacccoee MeNoomnmsee NNNoeemwwe 111000857 tTVroeamcnse NMNooommme NNNooewwwee Wo Nene Nome Nee 1123a0 s1asm 111203 11a0@m6 d1131m06 131ms le 150 19a7m aa #2911 2piH m8796 onai 22 H Wale, Grow mC imal WMP 330021 tdreancee mNaecmae 330049 TTrraaccee NNeommae 03065 TTrraaccee NNoemnae 330087 NNeonnee NMeonnee 33005 tNreacwe NNeonnee 0.30 sake W262 = Day 14 ICT ecao.d mtaod mwann mmoofwdln NMeenmee 11882 7 in 0m7 as NNoemwe 1a034 19%m @75 33 NMoomme L3s 11 7&3 i3 NNoemnee 11282 19172 8a 53 NNeenme 11081 179 5@2 a3 wale, Grow ve aimed WL S30012 TNreancee NMeemmees 3300345 NNeosn NNoonmee 330056 TNreancee NNoemnee 33078 NNeenwes NNoemnee 0S150 NNeennee NNeennee - 3 maskg He2eazs byw IT dciLo. smioc mmeu naormoan NNoewwe 1182 1is57s7 s2s NNeoww 1188 21109 l1o00d 8@5 NNoeww 1809 1i3ea 5512 Fse NNeoww 175 m16e 755 Wpto NMoewwe 113% 1a:22 s7s 52 RevisDiuoPnoNnutm-1b4e1r62| n- A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): Individual Animal Clinical Pathology Daca for Mice wale, Grow VI nikal WLP 07030 NMoenmee NNoennee 0705 NNeonnee NMoennes 70300657 NNNoeonnneee toNrowanceee M730058 MNNeoemnneee eNMoonnneeo male, Grow me Mmieal Wm LP 333000512 MMNoeenmneee mNNeoonmceee 33005 MNeomnee NNoonnee 330067 eBonnee rNeencae 330056 KNoennee NNoennee Mo None Mens male, Grow xc 1i11000312 NNdoeennmeee NNwoonnnsee 110015 NNoosw NNeonmee 1110076 TNroacwe NNoonnee 1100089 NNNoeomwse NNdooonnwee - 3 ma/kg H-26225 - by ou I mcyhoa mTRdIG eWaLe mmeelwdn Neemnse 1579 w 153 s7 ais aNomnee 1886 213 7537 35 NNNaeamnmeee 0577 m2 Be &ooa0s 323 MNNeeenmneee i162m88 d1989s6 7aaa1 iF3d - 10 mori H-26225 - bey 1 IT pad ma sgl me NeMeennmeee 17792s 2ww3m8 owo7w 23st eNemnse 17154 2e 5 o6 i5o0 eRmms 1105s 2d0s 30 55 eNennee 15:3 2d3u &se 7a me 21 de 06 10s - 30 mora H-2625 - by ou ECE CA NeNomewsme 11S20 6715 08 m8a4 i@5 NNoowwe 18058 1137 5@ i50 Nenosw 15233 o75e 7ok bad NNeoemewe 0120m8 111270 7@6 5552 RevDisuiPonoNnutm1b4e1r621 Te- AP14F-ODay(LOirnaelaGi/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)anadndMiAcPeFO (Branched): RevDiusiPononNutm1b4e1r621 Appendix F Individual Animal Final Body and Organ Weights for Mice ECE -- APLFeOy(OiresGBraavncehSedk,yAPinFOal(LRianse)a,nadndMiAcePFO (Branched: RevisDiuonpNounm1baeer2 INDIVIDUAL ANIMAL FINAL BODY AND ORGAN WEIGHTS FOR MICE EXPLANATORY NOTES STUDY DESIGN H-24921 APFO (Linear/Branched) Groups H-26313 APFO (Linear) H-26225 ~APFO (Branched) IA IA VA VIA IXA XIA 1B mB VB VIB IXB XIB IC mc ve VIC IXC XIC Dosage (mg/kg) 0 (Control) 0.3 1 3 10 30 Abbreviations mg/kg = mg/kg/day FBW = Final Body Weight Note 879 = Mice = --_-- F5 E ge 5 1 IF 2 5 HE : Ho (Ed gS|y ab gimr me apl ffd lamei s a Boia Pa | B sd ICTp Gmmammnomaa p Faumm a y 53 i | EH jidd3ddadas 35 g Jis4s3d3adss 3 3 5 i} 23) sess8E805 221 --iooistersetease} : S80 fhsasamaras oly sazsssza| s gl pe Eps TE LER il | jiEs ii} 33) iBiogepnssisiasneecaasEs nrll piioaesssiesaennsness Gasel S| ag EmEEREE ag enmnnne un gl DREHER EEL Eg E 53 I | |Tify i EECERNENNE 6: an LofE,GReIEeREsDEeME G1. a i2 Loran nme i | 8i-TiTeegsss2sgs, ogucgidSmEs8n88eSn5a8e8s8 aSO)ng LY IE rat preierirreati HealbreerirerealBE Bl pl TTT TTTRE : it i ig ZEl (851 EH EA gi iE By Dal |ii}" BiTg,iEgii0zUeSsRnReAsXsEaReEs 8Ra8l F3ig, Eg iINgNnNEAaRsAnNsIeIeTs aRsEi: gg og BT Emmeve o [1 i 81 i3333353383 I3% 4 giICIacIaNG Im il oE Pn 23 | | gidpiE8 Glsan BE gipp RasEEREeE 8B) EE iT ienaummnen un Fi pmmmammemap gail ga) |g BisoToueseSeosh gl Fieceecescsdesp mm Lymmm Bl pi TE gE TTR ER 35 ue i Ei R Ho ' gBy o| ioA dimmmm ge 3 Dol p poREEEIIEED IE gREEEEENENR ITY 4 8 i || P| faipifiainainiasneenamaarsyi ogigsAzIsIeIaIzAaAsEeEi1sl + 33) | fy iisssasasaz | C17 ssasssaza| z 4 23 El 2 HH 3I) ihm 2 | esgarszas ss! BTL i {snsnnaease ss! LF B|: E|gijisaa camEsrt an aniI iIa insalasaeinannay EE fh i 32 PE geese 5) gj diosssieess hf 3/1 11 S9 io -ig isgmgsssasz gqi 7i8 [FEEZEERERR i BH if 188 2B 1&5! 2 B28 i gJ | 7|i %[fig,siarpnnantnenn sagl 3ag,bisimaneaanseg ny gl ETE Las Big l0 E EDOd PHEE i Bl py semen cp unm a fl [Eon pRanEe a gf paEEEEEER glsiessy of Bel URE lp CHEBTRETTI ETR aE i 81 iB !i ERD io PE : | | |; isss3asEess gal ti isaERgses 33 gg | |, BTR AE pas Bon {3} Cl i: pms Piety laszacaszen sgl HBipppmlgeanmasseanzensds asgnl gf pETTRE gE TTT $8 | | Ei fissssssddad dab gi fisaddiiiide 33 BE | | fi iiiassasa5as. NiiZessssieassl 4S| |[]i RgaiplRstiaZcassdamisEsliasiasla cpyiplpiaaaniadmndasaadlaasatsnl gf SS) | | fig ssasssesE; | 3 aaEasEaas + 3L8ETH 23 iE ql Pl dBi saan Bf 1. $ |i" gies 3395925850 88) Fig, 5983333580 33 SBipEgBRrRReERmENEeE nEEL fgREo ACIIGEe RE BR 2i 2 0oEln PEIed ii YW tame inmaan | | | i Bi iazssEzazap sei gi iagassazaes ani <8 | i Bi is3disziis 33 fy id333dddadd 5 LI Rigg iaaaaanannl a opp aM EL 8 29] lpi TE i -i 8333838888 | ig isessesEEER BE1 3 5 1481 HB 2 Sai (E2g8!! 2 Ea gHf ig nnn nPefl nanny Sf| a Rgimm s nEnr gEsnmenn aa giylo op AmmenPrgp bmeei B2380| ||p Cifep iSoEmEvEeREaEsRsEsEs BnmEi : iRz.y iBzSsErIrRsEsAzReLsE SssOl Y | ESEg pian Dy og 38 Cy smmammasez| ni ammald 8A pL E RETR EE APFO (Lincar/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice RevisDiuoPnoNnutm1b4e1r621 Appendix G Individual Animal Gross Observations for Mice EE -- A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): RevisDiuoPnoNnutm1b4e1r621 INDIVIDUAL ANIMAL GROSS OBSERVATIONS FOR MICE EXPLANATORY NOTES STUDY DESIGN H-24921 APFO (Linear/Branched) 1A ma VA VIA XA XIA Groups H26313 H-26225 APFO (Linear) ~ APFO (Branched) 1B ic mB mc VB ve VIB vic XB XC XIB XC Dosage (mg/kg) 0 (Control) 01 3 3 10 30 Abbreviations mg/kg = mg/kg/day Note 879.= Mice - = A14P-FDOay(LOirnaclaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetars)a,nadnMdiAcPeFO (Branched): Showing aInnidai)vidduaatla AfnoirrailndLiivsitdiunagl antrals DSToUsDaY:Gro1w507+3/I2n45021m/a8r7k9sA. T(r+eaAtPmPeRnOtV:ED P0ROwTaOkCOaL.TA+) Sex: Males nized Rot Findings 101 FDouurnadtioDneaodf dosing-days: 4 nial is signed off from necropsy swan S+ TAIN, YRLLON, VENTRAL BODY, WET. No MaLcivreoss,copRiIcEATbSmorealiy Observed + 02 TAKenirilmnliaenldaloCnnsDasaciryiimfe+idc1e0oft from necropsy No Maicvreors,copRtIeNEAYbSnormality Observed + 103 TKAenirilmrliaenldaloinssaDscairyginfe:idc1e0of from necropsy Yo MaLcivreons,copKlieoNeArbsnorsality Observed + 100 TKRenirilmmliaenldaloinasaDscairyginfe+idc1e4oct from necropsy No MaLcivreons,copKiIcDNAEHmSorsality Observed 108 TKAneiirlsmlaielndaloinsDsaaicygenie+idc1e4oft from necropsy No Macroscopic Abaoreality Observed Revision Number 1 Dupont 14162 Date:19-r-08 Ere AP14F-ODa(y OLrialnGeavaagre/SBturdyaAiPnnFcMOah(lLeeinRdeaai)rs,)a,nadndMiAcPeFO(Branched): STUDY + 15073/24921S/hBo7w5iAng{+aAnIPinmPdaRilOvViEddDuaaclaPAOAfRnoGirCmOaiLl.ndLi+)ivisdtuianlg anieals Dose Group TA 0 mg/kg Troatment: mg/kg TA Sex: Males Animal Rot Findings Cr 08 TKeirlmliendalonSaDcaryif: ic14e Cr Animal is signed off from necropsy Yo Macroscopic Abmormality Observed : 107 TKoirlmliendalonsaDcaryif:ic1e4 Animal is signed off fron necropsy No Macroscopic Amormality Observed 108 TKeirlmliendalonSDaacyri:fic1e4 nical 5 signed oft rom necropsy No MaTcrrioas,copRiIcVEATbSnormality Observed 109 TKAneiirlmmlaielndaloinssaDsciargynief:dic1o4ef Erom necropsy No Nocxoscopic Abnormality Observed no TKeirlmliendalonSaDcaryif:ic1e4 Animal 1s signed off from necropsy No Macroscopic Amormality Observed RevDisuiPonoNnutm14b1e61r2 Date:15-mr-04 Ee AP14F-ODay(OLrialnGcavaarge/SBturdyAaPinnFcMOah(lLeeiRndaeta)sr)a,,nadndMAicPeFO (Branched): Showing anIinmdai)vidduaatla AfnoirnailndiLviisdtuianlg antsals SDoTsUaDYG:rou1p507: 3/T214I5A210./3879FAar(k+ APTrPeRaOtVpEoDnt:PROTO0C.O3L.g/+)kg IIIA Sex: Aizal Ret rt Findings TKAenirilmmliaenldaloinsSDasacieyginte:idc14eoff from necropsy No HapcrrosicopaictAebnormality Observed 302 TKeirlmliendalon saDcaryif: ic1e4 Anieal (a signed oft from necropsy No MaLcirvoes,copFiIc TAbSnormality Observed BY TKeirlmliendalonsaDcaryi:fic1e0 Aninal 13 signed oft from necropsy. No Macroscopic Abnormality Gbserved Dates1-wav-04 ales Revision Number | DuPont.14162 300 TKeirlmliendalonsaDcaryi:fic1e4 Aninal is signed off from necropsy No MaIcVrEoRs,copRiIcNEAYSm.ormality Observed 30s TKoirlnliendalonseDcaryit:ic1e4 Animal is signed otf from necropsy No Mapcrrooscgopaitc eAmyormality Observed + 206 TFAenirilmzliaenldaloinssDsaiacgryni+efdic11eott from necropsy No vapcrorscoopic tAbnormality Observed 350- A14P-FDOay(LOirnaelaGsa/BvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): Individual Animal Listing Dates1s-wav-08 STUDY + 15073/20521S/h8o7w5iAng(+anAiPmPaR)OVdEaDtaPROfToOrCOiLndi*)vidual aninals Dose Group + I5Ir 0.3 m/kg Treatment: 0.3 malky IITA Sex: Malas Aniral Rot Findings -------- 307 KTeirlmliendalonSDaacyrif: ic1e4 Tr Aninal 1s signed oft rom necropsy No Macroscopic Abnormality Observed Revision Number | DuPont.14162 28 KTielrlmeidnalonsaDcaryif: ic1e4 Animal is signed oft rom necropsy Ho Maicvreos,copKiIc TAbVnormality Observed 309 TKeirlmliendalonSaDcaryif: ic14e Animal is signed off from necropsy No Macroscopic Amormality Observed : s10 ZKairlmliendalonSaDcaryif:ic1e4 Aniral 5 signed oft from necropsy No Nacoscopic Amormality Observed IC A14P-FDOay(LOirnaclaGra/BvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): STUDY + 15073/24521SBhOowAing(*anAIiPnePdaRilOviVddEauDtaalPRAOfnToirOmCaOilLndLi+)ivisdtuianlg sninels Dose Group + VA 1 mo/ky Troateent: 1 ralka VA Sex: Males Animal Ref Findings son TKeirlmliendalonSaDcaryi:fic1e4 Anizal 3 signed off from necropsy. Yo Macroscopic Abmormality Observed 02 TKeirlmliendalensaDcaryi:fic1e4 nical 15 signed of fron necropsy. No MaLcivreoRs,copKiIcDNEArbSmormalizy Observed s02 TnKeiirlmalielndalo3nsaDscairyginfeidc1e4oft from necropsy No Macroscopic Amorsalicy Observed sou TKHenirilmnliaenldaloinsSaDscairygin+feidc1e4oct trom necropsy No MaTcxvreons,copKiIcDNAEbYmSorsality Observed + 50s TKoirlmliendalonsaDcaeyi:fic1e4 Aninal is signed off from necropsy No Macroscopic Amorsality Observed 506 TKAenirilmmlaielndaloinssaDscairyginfe:idc1e4otf from necropsy No MaLcivreoRs,copKiic eAbsmorsality Observed + RevDisuiPonoNnutm1b4e1r62| Dates19-00-04 2- A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): Showing aInncdei]vidduaacla afnoirmailndiLviisdtuianlg animals DSoTsUeDYGr+ ou1p50+73V/A24192r1a/r8k7g95 T{r+eaAtPmPeRnOtVsED 1PROmTaO/CkOgL,VA*) Sex: ales ntnal met minains s07 CrenKimilmalielndalon5saDseairygin:eedi1c4oeff from necropsy No MaTcrrvEoRs,copKiIcNEAYmSmorsality Observed sos AKTneiirlmrliaenldaloinssDsaaicgyrnief: idc1oe3ft rom necropsy No Mapcrroscoopipc Aabmormality Observed 09 AKTneiirlemlaielndaloinsssDaiacgyeniet:dic1eo4ft from necropsy Ho MaLcVrEoRs,copKiIcDNAEbYnSormality Observed : BY AKTnoiirlmmlaielndaliosnsasDcaiyeginte:idc1eo4tt tron necropsy No MaLcIVrEoRs,copRiIcNEAYtSmormality Observed : Revision Number | DuPont.14162 Dater1-waY-08 TTT 5. A14P-FDOay(LOirnaclaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetas)a,nadndMiAcPeFO (Branched): STUDY + 15073/24921S6h7o9wAing(+aAnIPinmPdaRilOviVdEduDaaclaPRAOfnToirOmCaOilLndLi+)ivsitdiunagl antsale Bose Group+ VIIA 3 ma/ky Treatment: 3 Palka VISTA Sex: Males Animal Rot Findings 701 TKeirlmliendalonsDaacryi:fic14e Animal 1s signed oft from necropsy. No Macroscopic Abmorrality Observed + Date:19-8Y-04 RevisDiuoPnoNnutm-1b4e1r62| 02 TAKenirilmzliaenldaloinssDsaiacgyrnief: idc10oete from necropsy. No MaLcivreors,copRiIcNEAYbSmorpalicy Observed 703 eKAnirilmzliaenldalon5SDsaiacgyrnief+ idc14oeft from necropsy. No MaLcirvoes,copRiIcMEAYbSmorpalicy Observed 00 oAKnriilmeliaenldaloinssDesaciryginte:idc1eo4ft from necropsy. No MaTcrvrEoRs,copRiIcNEAYbSnormality Observed 05 zKHaainrlimlnieanldaloinasDaaaciyrgin+feidc1e4oft from necropsy No MaLcivraons,copKiIcNEATmSmoreality Observed 06 TKHenirilmrliaenldaloisnSeDscairygin:teidc1e4ott trom necropsy No Maicvreos,copRtIeNEAYmSorsality Observed + Ts AP1FO4(-OLrianDelaGraa/vBrayagnechSetdu),dyAiPnFMOal(e RaLts ianadnndMiAcePeFOa(Brran)che,d): STUDY + 15073/24921S/h8o7w9i%ng(+aAnIPinmPdaRilOviVdEduDaatlaPROAfTnoOirCmOaiLln.diL+)viisdtuianlg animals Dose Group + VIIA 3 malka Treatment: 3 mg/kg VIIA Sex: Males nial Rot Findings mT 707 KTeirlmliendalonSDaacyri+fic1e4 Animal is signed off from necropsy No Macroscopic Amomality Observed : Date:19-uar-04 --------" A Revision Number 1 DuPont14162 08 TKeirlmliendalonsaDcaryif:ic1e4 Animal i signed ott fron necropsy No Maicvreos,copRiIcNRAYmSormality Observed : 709 ZKoirlmliendalonSaDcaryi:fic1e4 Aninal 1s signed off rom necropsy No MaLcirveors,copRiIcNEAYbSnormality Observed : 0 AKenirilmeliaenldaloinssDasaciyrginfe+ idc12oeff from necropsy DISCOLORATION, TAN, FEM. No Macroscopic Ammormality Observed TC APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number | DuPont-14162 Individual Animal Listing Dates 9-wAY-04 STUDY 15073/24921S/h8o7w9iAng(+aAnPinPaRlOVEdDataPROfTorOCOiLndi+)vidual anizals Dose Group: IXA 10 mg/ky Treatment: 10 mg/ko IXA Sex: Wales Animal Ref Findings 01 `KTielrlmeidnalonSDaacyrif: ic16e 2 Animal is signed off from necropsy No MaLcivreoss,copKiIcDEAYosrmality Observed s02 TKeirlsliendalon SDaacryif: ic1e4 Animal is signed off fom necropsy No Macroscopic Abnomality Observed 903 TKeirlmliendalonSDaacyr:ific1e Animal 1s signed oft from necropsy wivesDI+SCOLORATION, TAN, WOFTLED. No Macroscopic Abnomality Observed 04 TKeirlmliendalonSDaacyri:fic1e4 Animal is signed off from necxopsy No Macroscopic Abnormality Observed 505 TKeirlmliendalonSaDcary:ific1e4 Animal is signed off from necxopsy DISCOLORATION, TAN, MOTTLED, mild. No Macroscopic Amormality Obsexved : ~336- A14P-FDOay(OLirnaelaGra/BvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): STUDY + 15073/20521/S8h7o9wAing(+anAIiPnsPdaRilOviVddEauDtaalPROAfTnoOirCmOaiLl,ndLi+)ivisdtuianlg animals Dose Group + IGA 10 mg/kg Treatmenc: 10 ma/kg TXA Sex: Males Animal Ref Findings S06 AKZnaiirlmmliaenldalo15nSbasaciyrgin:feidc1o4eft from necropsy No Macroscepte Abnormality Observed Date:19-wav-04 CT a Revision Number | DuPont14162 so KairlmliendalonSDaacyrif: ic12e Animal 15 signed off from necropsy No MaLcirveors,copKiIcNEAYbSnormality Observed sos AKTneiirlrmlaielndaloGnsSsaaicygrni:efdic1eo4ft from necropsy No MaTcHrEoRs,copRiIcEAYbSmormality Observed : 909 AKTneiirlrmlaielndaloLnsssDaiaciyeniet:dic14eote from necropsy "DISCOLORATION, TAN, MOTTLED, severe. Yo Macroscopic Amormality Observed s10 TKeirlmliendalonsaDcaryif+ic1e4 Animal 54 signed oe from necropsy LoveDISCOLORATION, YELLOW, MIDDLE, 314 DIA. No Macroscopic Amormality Observed : ES APFO (Lineas/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in MaleRatsand Mice STUDY + 15073/24921/S5h7o9wAi.ng(+anAIiPnzPdaRilOviVdEduDaatlaPRAOfnToirOmCaOilLndLi+)ivsitdiunagl animals Dosa Group + KIA 30 o/ks Treatments 30 w/ks KIA Sex: Males Animal Raf Tor Findings TKAneiirlmmlaielndaloinSaDscaiyrgin+feidc1e4ott from neczopsy No NTacorvoes,copRtIcNEAYbSnoreality Observed 02 TKRneiirlnmlaielndaloinsaDaaicygeni+eidc1e4ote from neczopsy Revision Number 1 DuPont-14162 Date:19-AY-08 'DISCOLORKTION, YELLOW, PEW, < 334 DIA. No NKarcorNoEsvcSope Abnorrality Observed no TKeirlmliendalonsaDcaryi:fic1e4 Anisal is signed off fron necropsy No NaLcIVzEoRs,copRiIeNEAYbSnormality Observed 10s TKAneiirlrmlaielndaloinssDsaaicygen:ieidc1e4otf from necropsy 'DISCOLORKTION, TAN, MOTTLED, mild. No MKaicorwosvcso.pic Abmoreality Observed 105 TKRaeiirlnmlaielndaloinasDasaciyrgin:feidc1e4otf from neczopsy No Mapcrrosceopitc Aybmorsalcy Observed TEC A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): STUDY 15073/26521/S8h7o9wAing(+anAIinPmdPaiRlvOiVddEuaDatlaPROAfTnoOriCmOaiLlndi*L)viisdtuianlg animals Dose Group+ XIn 30 mg/kg Treatment: 30 mafxs UIA Sex: Males Animal Rat Findings ee 1105 ATKneiirlemlaielndaloinsSsDeiaegyrni+eedi1c4oef xem necropsy No MaLcIrEoRs,copKiIcDNEAYbSnormality Observed 107 AKTneiirlrmlaielndaloinsssDaiacgyrnief: dic1oe4ft rom necropsy `DISCOLORATION, TAN, MOTTLED. Ho Mapcroyscopie Abormality Observed : 1108 AKTeiirlnmleie!ndaliosnSasDcaiyrginfe+idc1eo4ft fron necropsy LaveDISCOLORATION, TAY, MOTTLED, mild. No MaRcorwoesrcsopic Atmormality Observed 1109 ZKeirlmliendalonSDaacyrif+ ic1e4 Aniral is signed oft rom necropsy No Macroscopic Abnormality Observed mo AKTinelirlmmeiadnlaloinssasDciagrynief+dic1o4eff from necropsy No MaTcivreoRs,copRiIc NAbTormality Observed : ++ Listing Complete +++ RevisDiuoPnoNntu-m1b4e1r62| 359 AP14F-ODay(LOirnaclaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetas)a,nsdndMiAcPeFO(Branched): Snowing anIinrdailvidduaatla AfnoirmailndiLviisdtuianlg animals SDToUsDeYGr+ou1p507+ 3/1286031m3a/s8k7s58 T(r=eaAtPmPeRnOtVsED P0RmOgT/OkCgOL18*) Sex: Males Animal Rot 101 Findings TKAneiirlnmlaielndaloinssaDscairygin+feidc1e4off from necropsy No Nacroscopie Abnormality Observed : 102 TKeirlmliendalonsaDcaryi:fic1e4 Aninal is signed off from necropsy. No Macroscopic Abnormality Observed + 0 TKeirlmliendalensaDcaryi+fic1e4 Aninal is signed off from necropsy. No Macroscopic Abnormality Observed 100 TAKneiirlmmlaielndaloinssaDscairyginfe:idc1eoff fron necropsy. No Macroscopic Abmorrality Observed + 108 TKeirlmliendalonsaDcaryif:ic1e4 Anizal is signed off from necropsy. No Macroscopic Abnormality Observed 106 TKeirlmliendalonsaDcaryif+ic1e0 Anizal is signed off from necropsy. No NaLicvoesRc,opKiIcDwAEbrnsormality Observed Revision Number | DuPont-14162 Dates1-uaY-04 360- A14P-DOay(OLrianelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLRianetasr)a,nadnMdiAcPeFO (Branched): STUDY + 15073/26313/S8h7o3w5i.ng{+aAInPniPadRO)sViEddDa,ucaaPROAfTnoOriCmOaiLln,di+L)viisdtuianlg anieals Dose Group + 10 0 Rak Treatments ng/g 1B Sex: ales Animal Rot 7 Findings TKeirlmliendalonSaDcaryif:ic1e4 Animal is signed oft from necropsy No MaLcIVrEoRs,copRiIcONAEbYmSorsality Observed : 108 KTeirlmliendalonsaDcayr:ific1e4 Aniral 15 signed oft rom necropsy No Macroscopic Abnormality Observed 109 KTeirlmliendalonsDaacyrific14e Anizal 5 signed oft rom necropsy No Macroscopic Abmormality Observed : no KTielrlmeidnalonSaDcaryif:ic1e4 Animal i signed off from necropsy No Macroscopic Aborality Observed : ReviDsuiPonoNnutm1b4e1r62| Dacesis-av-08 T TTT 361- A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetarsa),nadnMdiAcPeFO (Branched): STUDY 15073/26313S/h8o7w9i8ng(*anAIiPneRdaRilOviVddEauDtaalPRAfOnoTirOmCaiOlnLdiL*)viisdtuianlg animals Dose Group + 1118 0.3 my/ky Treatment: 0.3 Palkg IIIB Sex: niral Ret Findings 300 tKAneiirlmmlaielndaleinssaDscairygin:feidc1e4ote from necropsy No Macroscopic Amoreality Observed + 2 TKAnoiirlzmlaielndalo5nsaDscairygin+feidc1e4oft from necropsy No NLaicvoesnc,opKiEc YAbSnormality Observed 303 eKirlmliendalon sDaacryif: ic14e Aniral ia signed ott from necropsy. No NaTchirEoRs,copRiIcVEATbSaomalicy Observed 304 RKeirlmliendalon sDaaceyit+ ic1e0 Anieal io signed oft from necropsy No MaLcivreoss,copKiIcNEAYbSnormality Observed 305 TKeirlmliendalon sDaacryif+ ic1e0 Anieal a signed oft from necropsy. Yo Maicvreos,copFiIcNEAYbSnormality Observed + s06 TKReairilmnliaenldalo1nssDesaciryginte+idc1e4off from necropsy No MaLcEVrEoRs,copRiIcNEAYbSnormality Observed RevDiusiPoon nNutm1b4e1r62| Detest-war-0 Wales Ta: A14P-FDOay(LOirnaelaGra/BvraagnechSetdu)d,yAiPnFMaOl(eLRianetasra),nadnMdiAcPeFO (Branched): Snowing aInncdei]vidduaatla AfnoirmailndiLviisdtoinnlg anieals Dace:1s-uv-04 SDoTsUeDYGr ou1p5+073/I216128103./387m5a8/k{y+ APTPrReOaVtEmDe.ntPsROTO0.C3OLm+a)ks IIIB Sex: Wales Animal Raf Findings er 7 TKAenimilmrluieladndoisnSasDcairyginfe+idc1e4ott fron necropsy TT No MaIcVrEoRs,copRiIcNEAYmSmorsality Chsorved : 08 TAKenirilmrliaenldalon5sDasaciyegin:eeidc1e4oft rom necropsy No Macroscopic Amormality Observed RevDisuiPonoNnutm1b4e1r62| 209 TKeirlmliendalonsDaacyrif+ ic14e Anizal is signed off from necropsy No Macroscopic Abnormality Observed 0 Terminal sacrifice Animal is signed off from necropsy Yo Macroscopic Atmormality Observed : T36- A14P-FDOay(LOirnaelaGra/BvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Showing anIinmdatlvidduaacla AfnoirmailndLiivsitdiunagl animals SDoTsUeDYGr+ou1p50+73V/a26131m3o//8k7s9B T(r+eaAtPmPeRnOt:VED P1RoOaT/OxCgOLVB+) Sex: Males nial Rot Finaings son TKneiirlcmlaielndaloinoSDsaaicrygi:afeidc1e4ote from necropsy No MaTcrirEoRs,copRiIcNEAYbSnormality Observed + soz ZKairlmliendalon SDeacyrit: ic1e4 nical is signed oft trom necropsy. Yo Macroscopic Abnormality Observed 03 TKeirlmliendalonsDaacyrif+ ic14e Aniral is signed oft from necropsy. No Macroscopic Abnormality Observed sou TKAenirilmmliaenldaloinssDasaciyrgin+feidc1e4oct from necropsy No Macroscopic Abmorsality Observed + 505 TKAneiirlrmlaielndaloinsSaDscairygin+feidc14eo.ff from necropsy No Macroscopic Abnormality Observed : 506 TKAneiirlmmlaielndaloinssaDscairygin:feidc1e4otf from necropsy No MaLcivreons,copRiIcAEAYbSnormality Observed + RevDiusPioonnNtu.m1b4e1r62| Dates19-AY-08 361 A14P-FDOay(LOirnaclaGra/BvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Showing anIinmdailvidduaatle AfnoirmailndLiivisdtuianlg animals Datasis-r-os DSToUsDeYG+rou1p507+ 3V/B26311m3i/l8k7y58 T(r+eaAtPmPeRnOtV:ED 1PRmOaT/OCkOgL.VB+1 Sex: Males Animal Rot Findings ee 07 KTeirlmliendalonSDaacyri:fic1e3 ------ Animal 1s signed oft from necropsy No Macroscopic Abnormality Observed : Revision Number | DuPont-14162 sos KTielrlmeidnalonsDaacyrif: ic14e Animal is signed off trom necropsy Yo MaTcrvreoRs,copRiIcATAYbSnormality Observed sos ATKneiirlsmlaielndaliosnsasDciargyinfe:idc1eo4ft trom necropsy No MaTcOrRoRs,copKiIcNADbYmormality Observed s10 AKTneiirlnmlaielndaliosnsDasaciyrgin:feidc1e4off Eom necropsy No NaLcivxeans,copKiIcDNEAYbSnormality Observed T365- A14P-FDaOy(OLrianclaGrafvBraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Showing anIinmdailvidduaacla AfnoirmailndLiivisdtuianlg SBoTsUeDYG:rou1p5+072V/I2I6B3133 /m8a7/0kDg (+TrAePaPtRmOeVnEtD: PRO3 TOmCgO/Lkg+)VII Animal Ro Findings wo TKAeinrlimlnielndaloinsSDasacirygin:feidc16eoft from necropsy No Maicvreors,copRiIcNEAYbSmorealicy Observed + 0 TKeirlmliendalonsaDcaryif+ ic1e0 Animal is signed off from necropsy No Maicvreos,copRiIcNATbSnormality Observed + 0 TKeirlmliendalonsaDcaryif+ ic1e4 Aniral is signed oft from necropsy. No Macroscopic Abnormality Observed animale Sex: Males Daces1s-aY-08 ReviDsuiPononNtum1b4e1r621 708 TFAeinrlimlmieandlaloinssaDscairyginfe+idc1e4oct trom necropsy No Macroscopic Abnozmalicy Observed 708 TKeirlmliendalon sDaacryif+ ic14e Anizal is signed oft from necropsy No Macroscopic Abnormality Observed 706 TKReiirlnmlaielndaloinssDasacirygin+feidc1e0oft xom necropsy No MaLcirvoes,copKiIcowEArbsnormally Observed + T366- A14P-FDOay(LOirnaclaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetars)a,nadndMiAcPeFO (Branched): Showing anIinedailvidduaatla AfnoirmailndLiivsitdiunagl anirals SBoTsUeDYG:rou15p0+73/V2I6T3B123/8a79r5.k(+TrAePPaRtOmVeEnDt.:PR3OTmOgC/OkLg+)VII Sex: Males Sniral Rot Findings 707 TKAneiirlnmlaielndaloinsSasDcaiyrginfe:idc1eo4ft fron necropsy No MaLcivreors,copRiIcDNAEYmSormality Observed : 708 TKeirlmliendalonsaDcayrif:ic1e4 Anirul is aidned ote from necropsy No Macroscopic Amormality Observed : 70 TKeirlmliendalonsDaacyei:ic1e4 Animal is signed off from necropsy Yo Macroscopic Abnormality Observed : 0 TKairlmliendalonSDaacyri:fic1e4 Animal is signed off from necropsy. LoveeDISCOLORATION, TAN, WOTTLED. Yo Macroscopic Abmoreality Observed RevisDiuoPnoNnut-m1b4e1r621 Datasts-ny-08 Tee A14P-FDaOy(OLrianelaGra/vBraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): STUDY + 15073/26313/S8h7o9wDing(+aAnIPinrPdaRilOvViEddDautaalPRAOfnToiOrmCaOilLndLi*)ivsitdiunagl animals Dose Group + 1x3 10 mg/kg Treatment: 10 g/kg TXB Sex: Males frome Findings 01 TKeirlmliendalonSDaacyrif+ ic14e Animal io signed off from necropsy. ve No MaKcIrNoEsvcSopic Abmormalicy Observed 02 TKAinelirlrmeaidlnaloinssasDciargyinfe:idc1o4ett fron necropsy No MaTcErRos,copKiIcDNAEbYnSormality Observed 503 TKAneiirlzmlaielndaliosnsasDciargyinteidc1eo4tt from necropsy No MaLcirvoes,copRiIcNTAYbSnormality Observed 500 TKeirlmliendalonsaDcaryif:ic1e4 Animal is signed off from necropsy No Macroscopic Abnormality Observed : 50s TKoirlmliendalonsaDcayrif:ic1e4 Aalnal is signed off from necropsy Date:29-AY-08 RevisDiuoPnoNnutm1b4e1r62| 'DISCOLORNTION, TAN, MOTTLED. No MaKceroovEsvcsopte Abmorealicy Observed Tee APO (Linear/Branched), APFO (Linear), and APFO (Branched): HPp0u crap Bint MleRussdMite STUDY 15073/26313/S8h7o9w8i.ng(+nAIiPnPadRilOvViEddDua.atlaPRAOfnToirOmCaOilLndiL*)viisdtuianlg anisals Dose Group + 1x8 10 mg/kg Treatmenc: 10 g/kg 1X8 Sex: ales Sima Rot Findings 506 TKeirlmliendalonSDaacyrif: ic11e Binal is signed off from necropsy vem'D+ISCOLORNTION, TAN, HOTTLED. No Macroscopic Abmormality Observed : Dater19-av-08 Revision Number | 07 TKAeinrlimlnieandlaloinsssDaiacgyrnief+dic1o1eft from necropsy `DISCOLORATION, TAN, MOTTLED. No Mapcrrosecopic Abmormality Observed : 508 TKeirlmliendalonsDaacyrif ic14e Sninal is sined oft rom necropsy Lave No Mapcroescopic Abormality Observed : 50s TKRaeiirlrmlaielndaloinsssDaaciyrdief+dic1o4eff from necropsy DISCOLORATION, TAN, HOTTLED. Yo Macroscopic Abormality Observed : T36- A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetass)a,n1dndMiAcPeFO (Branched): RevisDiuoPnoNnutm1b4e1r621 Individual Animal Listing Dace: av-08 STUDY+ 15073/26313/S8h7o9wDing(+aAnPimEaRlOVEdDataPROfToOrCOiL.ndi*)vidual animals Bose Group + 4B 10 ma/kg Treatment: 10 a/ky xB Sex: Malas Animal Ro Findings 510 TKAneiirlmmlaielndaloinsSDsaiacgyrnief:dic1e4oft fron necropsy. - Love No Macroscopic Amormality Observed -= A14P-FDOay(OLrianleaGra/vBraagnechSetdu)d,yAiPnMFaOl(eLRianetasra),nadndMiAcPeFO (Branched): Showing anIinedailviddauatla AfnoirmailndiLviisdtuianlg anisals SDToUsDeYGr+ ou15p07+3/X216831330/8m7a3/5k.g(+TrAePaPtRmOeVnEtD PR3O0ROmCgOL/kg"1 KIS Sex: Males Animal Raf Findings on TKeirlmliendalonSaDcaryif:ic1e4 Animal is signed off from necropsy Date:15-wnt-04 RevisDiuoPnoNnutm-1b4e1r621 DISCOLORATION, TAN, MOTTLED. No Maecirnosecropic Abnormality Observed 102 TKBoniilmnliaenldaloinsSaDscairygin+feidc1e4ote trom necropsy No Maicvreors,copRiIcNEAYbSnormality Observed 10 ATKneiirlnmlaielndaloCsnsDasaciyrgin:feidc14eoft rom necropsy DISCOLORATION, TAN, MOTFLED. No Macroscopic Abnormality Observed : 1106 TAKenirilmnliaenldalo5nsDasaciyrginfe: idc1o0eft rom necropsy DISCOLORATION, TAY, MOTTLED. No Mpacroyscopic Ammommality Observed - AP14F-ODay(OLrail nGacvaagre/StBurdyAaPinnFMcOah(lLeeinRdeata)sr,)a,nadnMdiAcPeFO (Branched): STUDY + 15073/26313/S8h7o5w5ing(+aAnIPinPsdRailOviVdEduDaatlaPRAOfnToiOrmCaOi)LndiL*)viisdtuianlg anisals Bose Group + XIB 30 mg/kg Traatment: 30 mg/kg KIB Sex: Males Sima Rot Findings 05 DFuoruantdioenadof dosing-days: 10 Anizal is signed oft from necropsy. saw: No NaTcrvrEoRs,copKiIcDNAEYbSnormally Observed 1106 TKAenirilmrliaenldaloinssasDciaegyin:teidc1e4ott from necropsy "DISCOLORATION, TAN, MOTILED. No Naacixnozsrcsepic Abnormalicy Observed 07 TKAneiirlrmlaielndaloinssasDcaiyrginfe:idc1e4off from necropsy Love`DISCOLORATION, TAN, MOTTLED. No NaKcEzoYscSopic Abnormality Observed 1108 TKAneiirlrmloielndaloinssaDscaiyrgin:feidc1e4otf from neczopsy Dace: 19-uAY-08 Revis`iDounPNonutm1b41e6r|2 'DISCOLORKTION, TAN, MOTTLED. No MaKcorrossc.opic Abmormality Observed 7 A14P-FDOay(LOirnaelaGra/BvraagnechSetdu)d,yAiPnFMOal(e LRaitsnanaednadMiArcPe)FO, (Branched): ReviDsuiPoonnNtu.m1b41e6r|2 Showing anIinsdailvidduaatla AfnoirrailndLiivisdtuianlg anisals Datest-av-08 SDoTsUeDYGr ou1p50+73X/123631303/m8y7/9k5g(+TrAePaPtRmOaVnEcD:PRO3T0OCmOgL/,kg*)KIB Sex: Males 0s TT rKaimllmeed don eDeamyit:ic1s4 TTT Aninal is signed off from necropsy `DISCOLORATION, TAN, MOTTLED. No Marcorwoesrcsopic Abormality Observed : no TKReairilmrliienldaloinssDseaicygrniet:dic14eoft from necropsy No MaLcirvoes,copRIiDcNEAYbSm.ormality Observed : +e Listing comiote ser ne APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-DayOralGavage Study in Male Rats and Mice Showing aInntdei]vidduaatla Afnoirmailndiivsitdiunalg aninals SDoTsUeDYGr o1w50+73/1206202m5a//8k7y5 T(reaAtPmPeRnOtV:ED F0RmORaOCkOLIC*) sex: Malas Animal Rot Findings 10 ATKneiirlsmlaielndalo15nsaDscaiyrgin:feidc1oe4ff from necropsy. No Macroscopic Abnormality Observed + 102 TKAenirilmeliaenldaloLnosDasaciyrginfe: idc1oeft trom necropsy. No Naczoscople Abnormality Observed 10 eKirlmliende)onsDaacyrif: ic14e Aniral is signed oft fron necropsy. No Nacroscopic Abnormality Observed + 100 TKAeinrlimlzieandlalo1nssDsaaicygrnief: idc14oeft fron necropsy. No MaLcIVrEoRs,copKiIcDNEAYbSnormality Observed 108 TKAenirilmeliaenldaloinsssDaiacgyrnief dic1oe1ft fron neczopsy No MaTcireons,copKiIcNEAYbSnormality Observed 108 TKneiirlmlsielndaloinsssDaiacgyrnief dic1o1eft from necropsy No MaLcivreons,copKiIcDNEAYbSnormality Observed Revision Number 1 DuPont14162 Tas APFO (Linear/Branched), APFO (Linear), andAPFO(Branched): 14-Day Oral Gavage Study in Male Rats and Mice STUDY + 15073/26225/S8n7o5wing(+aAnIPinmPdaRilOviVddEauDatlaPRAfOnoTirOmCaOilLndLi+)ivisdtuianlg snirals Dose Grow + iC 0 ma/ky Treatment: 0 mg/kg IC Sex: Males Animal Rot Findings 107 TKRenirilmmliaenldaloinaSDseaicygrnief:dic14eoft from necropsy No Macroscopic Amormality Observed : 108 TKairlmliendalonSaDcaryi:fic1e4 Animal i signed off from necropey Ho Maicvreos,copRiIcNEAYbSmorsality hserved : 109 TKoilmliendalonSeDcaryitic1e4 Animal is signed off from necropsy No Macroscopic Abmormality Observed 10 ATKenirilmeliaenldaloCnosDasaciyrgin:feidc1e4oft rom necropsy Mo Naczoscopic Abmorpality Observed Revision Numbe|r DuPont-14162 Date:19-3v-04 375- AP14F-ODa(yOLrianleGaarv/aBgreaSntucdhyAePidnF)MO,al(eRaLts ianadnndMAiecPeFaO(Brran)che,d): STUDY + 15073/26228/S8h7o5wCing{anIAinPmdBaiRlvOiVddEeuDtaalPRAOfnToiOrmCaOilLndiL*)viisctuisnlg animale Dose Group + TIIC 0.3 mg/kg Troatment: 0.3 mg/kg IXIC Sex: Anisal fof Findings 301 TKeirlmliendalonSDaacyrif+ ic14e Rninol is signed of from necropsy No MahcvrEoRs,copRiIcNEAYbSnormality Observed 202 TKeirlmliendalonsDaacyrif+ ic14e Aniral is signed oft from necropsy No MaThcvreoRs,coKpTiOcNEAYbSnormality Observed 0 TAKenirilmeliaenldaloinaSDsaaciyrdief+dic1e0oft from necropsy No MaTcRvrEoRs,copRiIcVEARbSnormality Observed 300 KTAeinrlimleieandlaloinsssDaiacgyeniet:dic1eo4ft from necropsy No Macroscopic Abnormality Observed + 0s eKirlmliendalon SDaacryif: ic14e Animal is signed off from necropsy No Macroscopic Abnormality Observed 206 eKirlmliendalonsaDcaryif:ic1e4 Animal is signed off from necropsy No NaTcireons,copKiIcDNAEbYaSormality Observed RevisDiuoPnoNntu-m1b41e6r12 Dates19-v-04 Males T%6- APFO (Linear/BraAPnFcOh(Leindea)r),, and APFO (Branched): 14-Day Oral Gavage Study inMaleRats and Mice Revision Numbe|r DuPont14162 Showing aniinrdailvidduaatla AfnoirmailndLiivsitdiunagl animals SDoTsUeDYGr+ ou1p507+ 3/I2I6IC2250/.3873mask{s+ APTPrReOaVtEmDe.ntPsROTO0.C3OLmg*)/kg TLIC Sex: Males nieal Ref Findings oe 07 TKAenirilmnlaielndalo1nsSsDaiacgyrnief:dic14eoft from necropsy No MaLcirvoes,copKiIcDNAEbYmSormality Observed : s08 TKHenirilmnlaielndaloinsssDeiacgyxniet:dic14eoft from necropsy No Macroscopic Abnormality Observed : TTT 209 TKAenirilmnliaenldaloinsssDaaicygrnief:dic14eoft from necropsy No Macroscopic Aboreality Observed : a0 TAKenirilmzliaenldal1o5nSasDcaiyrginfe:idc1e4off from necropsy No MaLcIVrEoRs,copKiIcDNAEYmSormalicy Observed Te APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in MaleRatsand Mice STUDY + 15073/26225S/h8o7w5ing(+aAnIPinPmdRaiOlvViEddDua.atlaPRAOfnToirOmCaOilLndLi*)ivsitdiunagl animals Dose Group : VC 1 mo/ks Treatment: 1 ma/kg VC Sex: Males Sniral Rat Findings sot TKAneiirlrmlaielndaloinsSaDscairygin:feidc1e4oft from necropsy No Noczoscapic Amormality Observed 02 TKeirlmliendalonsDaacyri+ic1e4 Animal is signed off from necropsy No MaLcirvoes,copKiIc TAbSnormality Observed 03 TKAneiirlmmlaielndaloinssaDscaiyrgin+feidc1e4oct from neczopsy No MaLcivreons,copRiIcREAYbSnormality Observed EY TKAneiirlmmlaielndaloisnsasDcaiyrgin+feidc1e4oct from necropsy No MaEcvreons,copRlIeNEAYbSnormality Observed + 50s TKeirlmliendalonsDaacyri:fic14e Animal 1s signed off from necropsy No acroscapte Abmormalicy Observed 506 TKAneiirlmmlaielndaloinasDaaaciyrgimte: idc1e4oct from necropsy No MaLcivreons,copKiicoNEArbSmorsality Observed Revision Number 1 DuPont-14162 Date:19-1v-04 7. A14P-FDOay(LOirnaelaGra/vBraagnecShtedu)d,yAiPnFMOa(lLeinReaatrs)a,nadndMiAcPeFO (Branched): STUDY + 15073/26225S/h8o7w5ing(+anAItPnPrdRaiOlvViEddDau.atlaPROnfRoiGrCaOiLl,ndLi+)ivisdtuianlg animale Dose Group + VC 1 ma/ky Treatment: 1 ma/kg VC Sex: Males Aninal Raf Findings 7 TKoirlmliendalonSaDcaryif:ic1e4 Aniral is signed off rm necropsy No Macroscopic Abormality Observed s08 TKeirlmliendalonSaDcaryif:ic1e4 Aniral 15 signed oft Eom necropsy No Macroscopic Amormality Observed 505 eKirlmliendalonSaDcaryif:ic1e4 Aniral 5 signed off Erom necropsy No Macroscopic Amormality Observed s10 TKeirlmliendalonSaDcaryi:fic1e4 Anizal 5 signed off Erom necropsy Ho Macroscopic Abmormality Observed : RevisDiuoPnoNnutm-1b4e1r62| Dater1o-y-08 Tr 37 APFO (Linea/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage StinuMaldeRayts and Mice Showing anItnrdailvidduaacla AfnoirmailndLiivsitdiunagl SBToUsDYGr+ ow1p507+ 3V/I2T6C2253/m8a7/5kCy(TrAePaPtRmOeVnEtDs PRO3TmOCaOrLk+)VIIC Aninal Rot EY Findings TKnioilrslmeildnaloinsSasDcairygin+feidc1e4oct trom noczopsy Xo NaLicvoessc,opRiIcDAEbSmormalicy Observed 02 TKAenirilmrliaenldaloinssaDscaiyrgin+feidc1e4ott rom neczopsy No MaTcrrieoRs,copKiIcDNEAYbSmorealicy Observed 0 TKAnoiirlsmlaielndaliosnsasDcaiyrginfe+ idc1e4oct from necropsy No MaLcirvoes,copRiIcNEAYbSnormality Observed 8 TKAnoiirlrmlaielndaliosnsasDcaiyrginfe+ idc14eott from necropsy No MaLcirvoes,copFiIcNEAYbSnormality Observed + 708 TKAneiirlmmlaielndaloinssaDscaiyrginfe+ idc1e4ot trom necropsy No NeLcivreons,capRiIcEAYbSnormality Observed 706 TKAneiirlmmlaielndalioansDasaciyeginte+ idc14eoct from necropsy No NLoicvoesnc,opRiIcREAYbSnormality Observed animals Sex: Males Revision Number 1 DuPont-14162 3%0- A14P-FDOay(LOirnaelaGra/vBraagnecShtedu)d,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): Showing aInnidai)vidduaatla AfnoirmailndiLviisdtuianlg anials DSoTUsDeY:Grou1p50+73V/I2I6C2283/m8i7l5kCy (*TrAePaPtRnOaVnEc:D PRO3TOmCoO/Lk.g+)VIIC Sex: ales Snimal Raf Finings 7 TKeirlmliendalonSDaacyrif: ic14e Anizal 1 signed oft from necropsy No MaTcHrEoRs,copRiIcMAEbSnormality Observed : 08 TKeirlmliendalonsDaacyrif: ic14e Anizal Ls signed ott from necropsy No Macroscopic Abnormality Observed : 7 TKeirlmliendalonsaDcaryif:ic1e4 Anisal is signed off from necropsy Ho Macroscopic Abnormality Observed : m0 TKAeinrlimlsieandlalo1nsSasDciargyinfe:idc1eo4ft from necropsy No MapcirorsocogpaicteAbymormality Observed : ReviDsuiPonoNnutm1b4e1r62| Dases1s-uav-00 381 A14P-FDOay(LOirnaelaGra/BvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): STUDY + 15073/26225/S8h7o5wCing(*aAnIPinrPdaRilOviVddEauDatlaPROAfnToiOrmCaOilLndLi+)ivisdtuianlg animals Dose row + TAC 10 alka Treatment: 10 ma/ks THC Sex: wales Anisal Rot Findings 501 TKSneiirlrmlaielndaloinSaDscaiyrgin+feidc1e4off from necropsy Yo Macroscopic Abnormality Observed 02 eKirlmliendalonsaDcaryi:fic1e4 Sniral 5a signed of from necropsy Yo MaTcireons,copKiIcDNAEbYnSormality Observed + 03 TKSienlrilmreildnaloinssaDscaiyrginfe+ idc10oeff fron necropsy No MaLcivreons,copRiIcNEAYbSmorsality Observed 0a TKAnieilrrlmaeildneiosnsDasaciyrginfe: idc1o4ett from necopsy `biscoLoratzos, TAY, FEN. No Macroscopic Abnormality Observed : 505 TKeirlmliendalonsaDcyrif+ ic1e4 Animal is signed of from necropsy Dates1s-AY-08 RevDisuiPononNtum1b4e1r621 No Macroscopic Abmorsality Observed 8 A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): STUD: 15073/26225/S$h7o5wing{AaPnIPinsdRaiOlvViEddDuaatlaPROafRnoOirCmOasRl,ndLi*1ivisdtuienlg anirals Sore Group + 0 10 naa Freatmantc 30 ork TC Sex: wales Animal Rot Findings 06 RTToeTirmnoiadnialon2'SDasaciyrginfeidc1e4ote exon necropey Mo MapckaogscopaictAebmorsality Observed 507 SPToertrnmiailnval5e5sascirginteidceott trom necropsy No Macroscopic Abnormality Observed s08 SKTeTeiTrmaemidin"o5nsspaaciyra+inic1e8ote trom necropsy oaces1-m-08 i. RevisDiuoPnoNnu-m1b4e1r621 `DISCOLORATION, TA, MOTTLED. Yo Macxoscapic Abaorsality Observed : 509 TSKenirilmmlaielndal`3osnssbaaicygrinfe+idc3eo4 t tron necropsy Yo vactoscopic Amormality observed Te APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number 1 DuPont14162 Individual Animal Listing Date:19-10-04 SDoTsUeDY+Grou1p507+ 3/1256C22108/Sm8n7ao5swCiknsg(+aTnrAtePPraRacOleVeEndDta.:taPROf10TorOmCaOi/Lnkdgi*)viTdXuCal animale Sex: Males Animal Raf Findings 10 TKeirlmliendalonsDaucyrif+ ic1e0 nial 15 signed off fron necropsy. No MaRcorwoesrcsopic Abeormalicy Observed + EE APFO (Linear/Branched), APFO (Linear), and APFO (Branched): HP ONC ByAMIRI AMS, isis STUDY 15073/26225/S8h7o5wCing(+aAnIPinmPdaRilOviVdEduDaatlaPRAOfnToiOrmCaOilLndLi*)ivisdtuianlg animals Dose Group + XIC 30 mg/kg Treatment: 30 a/ky KIC Sex: ales Snical Rat Findings Hot TKeirlmliendalonSDaacyr:ific14e Animal is signed off from necropsy No Macroscopic Abormality Observed : 102 TKeirlmliendalon sDaacryif: ic1e1 Animal is signed off from necropey LoveeDiscotomanzox, TAY, Fe. No Macroscopic Abormality Observed : 0 TKaislmliendalon sDaacyrif: ic14e Animal is signed off from necropsy No Macroscopic Abmormality Observed 104 TKeirlmliendalonSaDcaryif:ic1e4 Animal 5 signed oft from necropsy No Macroscopic Amormality Observed 110s TKeirlmliendalonSaDcayrif:ic1e4 Anial 5 signed off from necropsy `DISCOLORATION, TAN, MOTTLED. No Macroscopic Abnormality Observed : Dacer19-1AY-08 Revision Number | EECA, 38 A14P-DOay(LOirnaelaGsa/vBarsagncehSetdu),dyAiPnFMOal(eLRianetasr)a,nadndMiAcPeFO (Branched): STUDY: 15073/26228/S8h7o5wCi.ng(+aAnSPinPrdRaiOlvVEidDda.ucnaPROAfZno0irCmOaiLl.ndLi+)ivsitdiunalg anicals Bose Group + KIC 30 mask Treatment: 30 ma/ky XC Sex: Wales Sisal Rat Findings 1106 TKAneiirlnmlaielndaloinsSDsaaicygrni+efdic14eoff from necropsy. ReviDsuiPonoNnutm1b4e1r621 Dates1s-nY-08 No Macroscopic Asmommalicy Observed sor eKirlmliendalon SDaacryif: ic14e Animal is signed oft trom necropsy No Macroscopic Abnormality Observed 1108 eKirlmliendalon sDaacyrif+ ic14e Anisal 1s signed off from necropsy No MaKcarooxsecrospic Abnormality Observed 1109 eKAinrlimlrieandlaloinasDaaiaciyrniet+dic14eoff tron necropsy `oiscoLoRATION, TAN, MOTTLED. No Macroscopic Aborealicy Observed 386 A14P-FDOay(LOirnaelaGra/BvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasra),nadndMiAcPeFO (Branched): Individual Anima) Listing Dates1-ar-08 STUDY + 15073/26225/S8h7o5wCing(+anAiPrPaRlOVdEaDtaPROfRoOrCOiL,ndi+)vidual animals Dose Group+ Xic 30 g/ka Treatsenc: 30 mafky KIC Sex: Males Animal Rot 110 Findings TAKenirilmzliaenldaliosnSDasaciyrginfeidc1e4of rom necropsy Tr TTT RevisDiuoPnoNnut-m1b4e1r62| No Macroscopic Abnormality Observed "4 Listing complete +r - A14P-FDOay(LOirnaclaGr/aBvraagnechSetdu)d,yAPinFMOal(eLiRnaeatrs)a,nadndMiAcPeFO (Branched): RevisDiuoPnoNnucm1b4e1r621 Appendix H Individual Mouse Beta-Oxidation Data -- me A14P-FDOay(OLrail nGaevaagre/StBurdyAaiPnnFMcOah(lLeeinRdeaat)rs),a,nadnMdiAcPeFO (Branched): ReviDsuiPononNtum1b4e1r62| INDIVIDUAL MOUSE BETA-OXIDATION DATA EXPLANATORY NOTES STUDY DESIGN H24921 APFO (Linear/Branched) A mA VA VIA IXA XIA Groups H26313 APFO (Linear) B mB VB VIB IXB XIB H26225 ~APFO (Branched) iC me ve vic IXC XIC Dosage (mg/kg) 0 (Control) 03 1 3 10 30 Abbreviations mgkg = mg/kg/day TC -- APFO (Linear/Branched), APFO (Lincs), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number 1 DuPont14162 INDIVIDUAL BETA-OXIDATION DATA IN MALE MICE DOSED WITH APFO (LINEAR/BRANCHED) Group Animal Beta-Oxidation Rate Number __(nmol/min/me protein) A 102 10.85 103 19.04 104 13.05 105 27.37 106 16.40 107 25.21 108 12.99 109 21.25 110 15.00 mA 301 29.17 302 26.26 303 21.84 304 36.38 305 39.63 306 41.56 307 44.52 308 40.53 309 3451 310 2077 VA 501 36.01 502 253 503 54.62 504 50.01 505 58.28 506 60.65 507 5046 508 4196 509 3428 510 53.56 EE A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnactasr)a,nadnMdiAcPeFO (Branched): RevDisuiPonoNnutm1b4e1r62| INDIVIDUAL BETA-OXIDATION DATA IN MALE MICE DOSED WITH APFO (LINEAR/BRANCHED) Group "Animal Beta-Oxidation Rate Number __(nmol/min/mg protein) via 701 46.41 702 4299 703 35.97 704 39.28 705 4821 706 58.01 707 4332 708 48.10 709 55.76 710 53.41 IXA 901 2879 902 21.58 903 33.48 904 20.15 905 28.00 906 36.66 907 19.74 908 29.69 909 4764 910 35.77 XIA 1101 21.65 1102 2027 1103 3541 1104 3131 1105 24.91 1106 28.68 1107 25.89 1108 38.33 1109 46.83 1110 33.38 = -_-- APFO (Lincar/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number 1 DuPont 14162 INDIVIDUAL BETA-OXIDATION DATA IN MALE MICE DOSED WITH APFO (LINEAR) Group Animal Beta-Oxidation Rate Number __(nmol/min/mg protein) B 101 13.89 102 1096 103 2343 104 1344 105 1638 106 2191 107 16.69 108 20.50 109 1543 110 2084 mB 301 27.42 302 2939 303 49.64 304 33.36 305 4132 306 4764 307 36.67 308 253 309 49.88 310 62.52 VB 501 36.57 502 36.78 503 52.01 504 4425 505 56.64 506 53.11 507 36.80 508 47.49 509 69.02 510 63.29 -- Tm APFO (Lineas/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number | DuPont14162 INDIVIDUAL BETA-OXIDATION DATA IN MALE MICE DOSED WITH APFO (LINEAR) Group Animal Beta-Oxidation Rate Number __(nmoVmin/mg protein) VIB 701 36.18 702 4522 703 44.09 704 4597 705 64.10 706 53.13 707 3844 708 38.50 709 58.57 710 60.45 XB 901 2.13 902 3793 903 3161 904 4259 905 54.84 906 39.08 907 3096 908 3225 909 4577 910 33.79 XIB 1101 32.59 1102 34.53 1103 33.85 1104 3273 1106 24.13 1107 39.67 1108 29.76 1109 32.96 1110 27.22 - AP14F-ODay(LOirnaelaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nsdndMiAcPeFO (Branched): RevisDiuoPnoNnutm1b4e1r62| INDIVIDUAL BETA-OXIDATION DATA IN MALE MICE DOSED WITH APFO (BRANCHED) Group Animal Beta-Oxidation Rate Number __(nmol/min/mg protein) ic 101 1154 102 1931 103 21.67 104 1820 105 1559 106 14.19 107 16.63 108 16.02 109 25.79 110 23.01 me 301 23.43 302 21.83 303 24.14 304 21.80 305 2622 306 32.93 307 24.79 308 25.84 309 1995 310 2135 ve EN 33.55 502 2595 503 36.55 504 38.84 505 56.70 506 50.80 507 33.79 508 34.79 509 35.10 510 2.70 -=. APFO (Linear/Branched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice Revision Number | DuPont 14162 INDIVIDUAL BETA-OXIDATION DATA IN MALE MICE DOSED WITH APFO (BRANCHED) Group Animal Beta-Oxidation Rate Number __(nmol/min/mg protein) vie 701 3172 702 4265 703 35.95 704 40.98 705 55.19 706 54.86 707 48.97 708 35.87 709 45.86 710 53.07 XC 901 41.68 902 4720 903 44.50 904 39.06 905 46.50 906 43.82 907 39.29 908 35.54 909 38.12 910 48.83 xic 1101 28.59 1102 3044 1103 2343 1104 2633 1105 36.80 1106 31.56 1107 35.04 1108 3341 1109 54.60 1110 4830 T395- A1P4-FDOay(OLrialneGaavra/gBerSatnucdhyAePidnF)MO,al(eLiRnaetasr)a,nadndMiAcPeFO (Branched): RevisDiuoPnoNnutm-1b4e1r621 INDIVIDUAL RELATIVE LIVER TO FULL BODY WEIGHT (FOR BETA-OXIDATION) IN MALE MICE DOSED WITH APFO (LINEAR/BRANCHED) Group Animal Number Relative Liver to Full Body Weight (%) A 102 56 103 53 104 50 105 53 106 50 107 51 108 53 109 46 110 51 mA 301 6.1 302 64 303 65 304 6.1 305 63 306 60 307 6.1 308 57 309 58 310 6.1 VA 501 88 502 74 503 82 504 82 505 70 506 82 507 17 ES 19 509 80 510 19 - == A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): Revision Number | DuPont14162 INDIVIDUAL RELATIVE LIVER TO FULL BODY WEIGHT (FOR BETA-OXIDATION) IN MALE MICE DOSED WITH APFO (LINEAR/BRANCHED) Group Animal Number Relative Liver to Full Body Weight (%) via 701 102 702 110 703 97 704 109 705 105 706 116 707 100 708 is 709 109 710 109 IXA 901 146 902 17.1 903 154 904 167 905 17.8 906 16.1 907 159 908 156 909 177 910 156 XIA 1101 179 1102 19.1 1103 173 1104 179 1105 186 1106 170 1107 20 1108 18.1 1109 187 1110 16.1 Se APFO (LinearfBranched), APFO (Linear), and APFO (Branched): 14-Day Oral Gavage Study in Male Rats and Mice RevDiusiPoon nNutm1b4e1r62| INDIVIDUAL RELATIVE LIVER TO FULL BODY WEIGHT (FOR BETA-OXIDATION) IN MALE MICE DOSED WITH APFO (LINEAR) Group Animal Number Relative Liver to Full Body Weight (%) B 101 st 102 56 103 55 104 57 105 59 106 52 107 54 108 54 109 58 110 56 iB 301 63 302 6.1 303 63 304 65 305 68 306 65 307 65 308 69 309 63 310 64 VB 501 80 502 85 503 88 504 82 505 86 506 82 507 80 508. 82 509 88 510 82 395- A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadndMiAcPeFO (Branched): RevDisuiPonoNnutm1b4e1r621 INDIVIDUAL RELATIVE LIVER TO FULL BODY WEIGHT (FOR BETA-OXIDATION) IN MALE MICE DOSED WITH APFO (LINEAR) Group Animal Number Relative Liver to Full Body Weight (%) VIB 701 9.8 702 111 703 107 704 113 705 119 706 123 707 136 708 106 709 106 710 17 XB 901 157 902 178 903 153 904 18.1 905 188 906 172 907 180 908 169 909 17 910 163 XB 1101 189 1102 176 1103 189 1104 17.8 1106 18.1 1107 182 1108 170 1109 192 1110 158 -_-- A14P-FDOay(LOirnaclaGr/aBvraagnechSetdu),dyAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched): RevisDiuoPnoNnutm1b4e1r621 INDIVIDUAL RELATIVE LIVER TO FULL BODY WEIGHT (FOR BETA-OXIDATION) IN MALE MICE DOSED WITH APFO (BRANCHED) Group Animal Number Relative Liver to Full Body Weight (%) ic 101 53 102 52 103 55 104 52 105 52 106 46 107 56 108 51 109 49 110 48 me 301 65 302 58 303 65 304 57 305 62 306 59 307 63 308 61 309 57 310 66 ve 501 81 502 80 503 82 504 83 505 94 506 8.5 507 72 508 70 509 71 510 66 --_-- A14P-FDOay(OLirnaclaGra/BvraagnechSetdu)d,yAiPnFMOal(eLiRnactars)a,nadndMiAcPeFO (Branched): Revision Number | DuPont.14162 INDIVIDUAL RELATIVE LIVER TO FULL BODY WEIGHT (FOR BETA-OXIDATION) IN MALE MICE DOSED WITH APFO (BRANCHED) Group Animal Number Relative Liver to Full Body Weight (%) vic 701 125 702 110 703 128 704 106 705 114 706 116 707 134 708 122 709 121 710 117 xc 901 17.5 902 162 903 186 904 176 905 175 906 154 907 18.1 908 157 909 190 910 216 Xic 1101 216 1102 207 1103 195 1104 199 1105 214 1106 194 1107 26 1108 19.5 1109 28 1110 27 --- e A14P-FDOay(LOirnaelaGr/aBvraagnechSetdu)d,yAiPnFMOal(eLiRnaetass)a,nadndMiAcPeFO (Branched): RevisDiounPNounmbter141612 Appendix I Revision 1 -_-- A1P-DFaOy(LOirnscaGr/aBvraagnechSedt)u,yAiPnMFaOl(eLiRnatesr)a,ndnMdiAcPeFO (Branched): RevDisuiponoNnutm4be1r62| REVISION 1 QUALITY ASSURANCE DOCUMENTATION Report Number: DuPont-14162 Work Request Number: ~~ 15073 Study Code Number: 1025 (Rats) and 879 (Mice) "The conduct of this study has been subjected to periodic Quality Assurance inspections. The dates of inspection are indicated below. Phase Audited Report Revision 1: Audit Dates 5 Jan 2006 Date Reported to Study Director 5 Jan 2006. Date Reported to `Management 11 Jan 2006 Reportedby: a Annet L. Reigel Quality Assurance Auditor [2 Jaw 2006 Date: = -_-- A14P-DOay(LOirnaeaGra/BvraagnechSetdu)d,yAiPnFMOal(eLiRnaetasr)a,nadnMdiAcPeFO (Branched) REVISION 1 EXPLANATION The report was revised as follows: Page 31 Manuscript Figure 2: Error bars corrected 402 AppendiIx: Revision 1 added. The following pages were revised to reflect these changes. Page 1 Title Page 8 "Table of Contents RevDiusiponoNnutm1b4e1r621 -_-- AP14F-ODay(OLrailnGaevaagre/StBurdyAaPinnFMcOah(lLeeinRdeaat)rs),a,nadndMiAcPeFO (Branched): REVISION 1 CERTIFICATION RevisDiuoPnoNnutm1b4e1r621 StudyDirector: [28 1H `SenCiaorroSlaff ToxHalaiy,cBoAlo.gist LL. ha - 20 0b TM --_--