Document 0LzZQoR867DbyoXNaDw1EnGDV

: 2774 P4aCtohmpoalnyoogfySciAenscesAopcplicaatotnes sintIenrmtaetnranCaortpioaotnoanl e =sr r e-- e ------ -------- -- T-- T ------------ AR226-0149 P(AATNHCIOLLLOAGRYY RSETUPDOYR)T ELECTRON MICROSCOPIC EVALUATION `OF LIVER IN CYNOMOLGUS MONKEYS 2S6U:LWFEONEIKCCAACPISDUPLOETTAOSXSIICUIMTYSASLTTUD(PYFOWSI:TT-H62P9E5)RIFNLCUYONROOOMCOTLAGNUES MONKEYS CLIENT STUDY NUMBER 6329-223 PAI STUDY NUMBER EM 99.76 Prepared by: James B. Nold, D.V.M., Ph.D., Diplomate, A.C.V.P. Pathology Associates International 4915-D Prospectus Drive Durham, NC 27713 July 13,1999 PREPARED FOR 3M CORPORATE TOXICOLOGY, 3M CENTER, ST. PAUL, MN 55144-1000 03615 -- reer915 D-- Prospectus-- Drive + Dur-- ham, North -- CarolinaE 277-- 13 +o (319) 54-- 4.52i57e=e(e3-- 19) 544-321t8-- FaAXre Pathology Narrative Light Microscopy and Transmission Electron Micrograph Interpretation Forms Transmission Electron Micrographs Quality Assurance Statement Section 1 I m v 03616 L Pathology Namative 03617 CoAvnacniclelaSrytuPdaythNool.og6y32R9e-p2o2r3t PATHOLOGY REPORT (ANCILLARY STUDY) ELECTRON MICROSCOPIC EVALUATION OF LIVER IN CYNOMOLGUS MONKEYS 26-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS CLIENT STUDY NUMBER 6329-223 PAISTUDY NUMBER EM 99.76 SUMMMARY Treatment of cynomolgus monkeys with 0.75 mg PFOS/kg/day for 26 weeks resulted in hepatocellular vacuolation and hypertrophy by light microscopy. Hepatocellular vacuolation and hypertrophy were primarily centrilobular in distribution and did vary in incidence and severity between individual animals. Ulrastructurally, there were increased lipid droplets within hepatocytes. Increased lipid droplets were present in both the high-dose males examined and in two of four high-dose females examined. Increased hepatocellular glycogen was present in theremainingtwo high-dose females. These ultrastructural changes correlated with hepatocellular hypertrophy and vacuolation noted by light microscopy and with increased liver weight parameters in the high-dose animals. `The no-ffect level for hepatocellular vacuolation (lipid droplet accumulation) was 0.15 `mg/kg/day of PFOS (mid-dose group). Quantitation of peroxisomes within hepatocytes by electron microscopy indicated no remarkable differences between control livers and livers treated with 0.03, 0.15, or 0.75 mg PFOS/kg/day. Ultrastructural differences in cellular membranes or mitochondria were not discemible between control and treated animals in the samples examined. PROCEDURES The objective of this study was to examine by electron microscopy the livers from Selected animals in a 26-week capsule toxicity study with PFOS in cynomolgus monkeys. In addition to a general qualitative evaluation for differences between control and treated : animals, the ultrastructural endpoints included quantitation of peroxisomes within hepatocytes and membrane and mitochondrial changes in hepatocytes. Light microscopy of paraffin-embedded liver sections was also performed. For the toxicity study, 22 male and 22 female cynomolgus monkeys were given the test article or the vehicle once daily for at least 26 weeks according to Text Table 1. 03618 Io CoAvnacniclleaSrytuPdaythNool.og6y32R9e-p2o2r3t Text Table I. Group Designations and Dosage Levels - Dosage Dose Level Grow ___(msfkgiday TLoeuvellM(amtperfikaglfdDaoyse Number of Males Numberof Females T 0o03 3i0s 4 4 vm 00.1155 0& 6& 66 + oTgehsleaetliTonewcv-aedpsoswsuelepergserrsoupoth(evGtrooiaulpdTm2ha)eteerredcicaoeln.irvaoedldmgitrnhiosuitpeesr(teGmdrattoeourGpiar1l)oduril4peu.tcedewiiavtnheelqdaucitvoasele(n1t:a49m9o,uwnwt)o.f lactose in T1h:e39m,iwd-wd)o.sein(GGrroouupp 3) and high-dose (Group 1,3, and 4,dete 4) groups received the testmaterial diluted with lactose: covey sls, wer sedfo aes26weeks ohcecnurtrreenactemeonfttwoaxiscdeifsfceocntstifnoureadtalneadstth1e3awneimeaklsspowsetrueeaotbmseenrtv.ed for reversibility. persistence, of delayed Aanneismtahlestitzoedbewistahcrkiefticaemdinatesacnhdedxuyllaezditnee,rmwieniaglhaendd, rcexcsoavnegruyinsaatceridf,icaendtinmeecsrowpesrieed. Mtoultthiepplreottoicsoslue.s Awdedrieticoonlallelcyt,edpiaencdesproefsleirvveerdfirnom10ca%chneauntirmaal-lbuwfefreeretdhifno-rsmlailciedn aancdcording pinla0c.e1dMinp%hosspthreantgethbuKfafemro)vfsokrys'usbsfeiqxuateinvte u(l2t.ra0s%trpuactruarfaolremxaalmdienhatyidoen/.2.5T%hegsleutlairvaelrdsewheyrdee pmrioccreosssceodpyinptrooEcpeossninbgloacnkdseavnadlusautbimoni.tteHdemtaottohxisylliabnoarantdoreyosfionr (suHb&sEe)q-usetnatineeldecstlriodne sections of formalin-fixed, paraffin-embedded livers were submitted for light microscopic examination. Paenrd sfpeomnasloers rweeqrueestin,ittiiaslsluyepsraomcpelsessedfarnodm etvearlmuiantaeldsauclrtirfaiscteruccotnutrraolllya(nTdexhtigTha-bdloese2)m.aTlewso choingdhi-tdioosne pmrailoerst,o AsncihmeadlusleNdotse.rm1i0n5a5l06sacarnidfi1c0e.55U0l9r,asdtireudcotrurwaelreexsaamcirniafitcieodnionfalmivoerrisbfurnodm ethleescetrtonwomiucnrsocghreadpuhlsedfrdoematthheanciomnatlrsolwaansdnhoitgphe-rdfoosremleidv.ersF,otlhleoswpionngseovrarleuqautieosnteodftthhaet electron microscobpey performed on the increased lipid droplet accumulation was low- and mid-dose liversto evaluate evident in these dose groups. whether Text Table 2. Animals Selected for Electron Microscopy (Group 1 Con) Group 2 low-dose) | (Group 3 mid-dose) | (Group 4 High-Dose) Males Females | Males Females | Males Females | Males Females lloossss1t7o 110o5s5s335 || floossssii6s 0l5os4sa7l || lIoossss2is 1I0ossssa3s | I0ssiz 1I005s5s4a60 i loss27 tosses | toss iossso | lossas tosses =o 105551 Tohni2n0s0e-cmteiosnhsc(oapppperroxgirmiadst,elsyta9i0neadmw)itfhro5m%tmheetEhpaonnol-iecmbureadndyeldacleitveartse waenrdeRceuytn,omlodu'sntleedad i" 03619 - CoAvnacniclleaSrytuPdaythNool.og6y32R9e-p2o2r3t ctirtarnatsem,isasnidonexealemcitnreodn moincaroZseciospse.EMCIeOnCtr/iCloRb,ulaaZreihespsatEoMc1yt0e,s,orwhaeJrEeOcLlea1r0l0y8identifiable pinholtivoemriscercotgironasp,hsweorfeipvreerfewreernteiatlalkyeenxaanmdinseigdn.ifRiceapnrtesueltnrtaasttirvuecteulreacltfreoantures were `Smuimcmraorgriazpehdifnotrereparcehtaptihoontofgorram.phTahned naunmimbaelroonf apedreosxiigasaotmeeds tirnahnespmaitsosciyotneeslewcatsron mmiacnruoaslcloypcyo,utnhteedH&foEr esalcidhescefnrteormpthhoetsoagmreapahneidmahlespasteolceyctteedanfodrreelceocrtdreodn.miFcorrolsicgohtpy were evaluated and significant features were summarized on a light microscopic evaluation form. RESULTS AND DISCUSSION Ianndiimvailduaarle isnhtoerwpnreitnatSieocntsioofnlIiL.ghtRempircersoesnctaotpiyvseliedleesctarnodn pelheocttormoincmriocgrroagprhaspwhesrfeosreelaecchted `2smircerpoogrrtapfihgsuraerse,mlaaibnetleadi,neadndianrtehesahrocwhniviendSsetcutdiyonfilIeL.. All remaining electron Light Microscopy A summary of the high-dose livers is incidence shown in and severity of light Text Table 3. There microscopic findings in the was an increased incidence control of and cvoancturoollatainoinmaolfs.theThcyetdoipsltarisbmuotifohnoefpatthoicsytveascuionlhaitgiho-ndwoases tprreeadtoedmiannainmtallys cceontmrpialrobeudlawri,th vbauctufoolratoinoen.hiAgfhf-edcotseedfaenmialmea,lsAngeinmearlalNloy.al1s0o55h3a4d,etnhlearregweamesndtif(fhuyspeerstlirgohpthyh)epoaftocellular cGeenmtarlitlooblualragrehveapcatuooclyetsesw.ithTthhiseecnyltaorpglaesmme.ntSaoppmeearsepdortaodibce vraelcautoeldattiootnhenoptreedseinncleoowf- tahned mid-dose animals did not appear to be treatment-related and was not clearly associated with hepatocellular hypertrophy. Ft Text Table 3. Incidence and Conon Severity of Light Microscopic Liver (LowDose idDose) = Findings Giigh Dove) meee 1] Vasaotator n. hepe atocellm ular, @@| |@ cencilobular minimal modesty sseivgerhe aifse sig mifocal minimal \\ Lo @ S : a: 3i "| -. i" 03620 - CoAvnacniclleaSrytuPdaythNool.og6y32R9e-p2o2r3t Text Table 3 Continued. Incidence and Severity of Light Microscopic Liver Findings el i (Control) owDose) GtigDoss | igh Dos [rs Frll" Fo Tperaophym . hepioca ellar. @ cenobular minimal modSeirgh Cceimeialnogbcaropmc. insiigt Cafctaeng cope. isniiit Tal, trmpmaRgmcinyiimeal si | we [ew s - a| a 1b 2: i: i . a. -- .: v : s: ralomatous minimal asi a I I ceniotular sight me aT] minimal = CT inimat RE-' N :- :. Sa :. : -5 -. .5 Electron Microscopy CiznobnuFntidrgauornlet(se01nmd-go3/p.klgaH/sedmpaiayct)o.rceyttiUeclutsrlcauhsmat.rrauPcctteeurrroiaxsltiifsceoaamlteluysrecasoorneftcacioonnmtnmruoomlnehroeorpugaastnomecliyltteoescshcaoornmedprdoiesameoadnnsdoefaated fmiincergornasnuinladriammaettreirx.sHuerpraotuoncdyetdesbyexahimbeimtbarmainceroavnidllnooursmbaolrldyervawrhyiicnhspizreotfrruodmes0.i1nto- LthSe pGelryicsoignuesnoiidsaclosmpamcoe.n Tiingthhtejcuyntcotpiloanssmboarnddermabiylebecainnaltihceulfiobremtowfeesmnahlelpgartaoncyutleess.of sCalooinrgtmhataillnyillniagvregerelrfeucrntocsretotintoedns,e.nasnRedesdieitgd'seunanelorrbamotadiliveeoscaysrteeoepsrleaacsnomndidocamrmylaitlpeiyrdisadolrs.oopmlLeeistpsi(dwpihmtaehgtioanlbhyoeslpoiasstomomceiysst)aes. TaThanebdrlaeell4w.weerOrenenecoomndasilsiecd,eerrAnenidiblmneaorldmiNaffloe..reIAn0c5es5su27bm,emtaawrpepyeeonafrcueoldnttrtraooslthramuvacetlueirsnaclarnefdaisnfededimnnaguslemisbsesinrhstohwoifns sitnudTye,xt pPeardoixnidsiovmiedusaclohmeppaatroecdytweisthwetrheeoetxhaemricnoendt,rotlhiasnivmaalluse.mHaoywneovtebre, sbiegcnaiufisceanstolyfeiwncarneaismeadl.s " CO.3621 F744 Patohoo logycaArsesssotcoistaatnessmaInttoenrnCaotrional a = a = eee eee Text Table 4. Summary of Ultrastructural Findings B Tmreosumnengs Gerorvp Asimai No. R Commens MMMaaeklee l1o3s5s1t67 109527 NNoormmaadl Normal, ncessd prossomes Oophale [0ssis SMiingcesmin bipddrospes (Q0.O0p3)MMaallee a 1__0l5os5s1261 NNNoreomamml CiIsMMdAe igus l[osss1s leossszrs NNoomma. ightincrese in peroxisomes NLioimdidroplet seeamaaion Peper moder sre. (079 Male 105512 LInicoprdeadnsredoepgllycaocgceunmvlation, madert, hepatocellular. Increased ENE e E ((0OF)FeFeemmmaallleee lT10oo5ss5ss33e1ss NNoNerommwaaalll (((000O.000053n%)FFFFeeeemmmmaaailllleeee 10[10505555634177 105550 `NNNooommrmmaaalll Nemal (O1e5 Feemale O15 Female [00558348s NInecemsed glycogen Nomal (0e15 Feemale 105548 O70 ffeemmailee l08o8s4s0 s NLioprimdadla ropletmaecumulaon, moderately severe Lipid droplet sccumulaion, mild to moderate (075 Female 105581 Increased ghcogen Pcoenrtorxoilsloimveerss,wtehreeaivdeernatigfeiendumanbderquoafntpietraotxeidsionmreesprceosuenntteadtipveerhheeppataotcoyctyetse.Fphoorttoghreaphed T"vaabsle115.).50Dfeorpecnondtirnogl umpaloensfiaxnadti1o0n.a94ndpestraoixniisngo,mepsepreorxcieslolmefsormcaoynbtreoldiffefmiaclulets.to(Text differentiate in routine electron photomicrographs from primary lysosomes or`marginal cuts are a through vailable the for espnedcsifoifc: a`lmliytoicdheonntdirfiyai.ng Cpyetroocxhiesmoimceasl bayndliighmtmaunndoceyltecotcrhoen mmiiccarlosmceotphyo,ds and utilization of these methods would provide a more `specific and accurate `method of peroxisome quantitation (Beier K, 1992; Reddy UN, 1988). 03622 4915D Prospectus Drive Durham, North Carita 27713 (919) 544-5257 + (919) 544-3218FAX CoAvnacnicllearSytuPdaythNool.og6y32R9e-p2o2r3t Text Table 5. Quantitation of Hepatocellular Peroxisomes a Ma5Nlemeg wPReOSr/kg/daAym(aCloFneimaaNluemberof| 0M0a3lmeg PFOS/Ag/day (Low-FDeomsael)e Amal Nomberol NAunmimbaelr _NPeurmobteisromoefs A Pasisomes eT Number oss0 _Per1o2si7s5ome|s| Nluomssbieer Peroxisome 600 [ISS REQ eSyy iGsas || mmssss uso | Mes 0720s || mmossss 1094 | Means 170820 || IHoossssseo 975 |2 Man= 11070600 8 1200 eB l E 0.15 mg PFOS/ke/day (Mid-Dose) 0.M7a5lmeg PFOS/kg/day (HighF-eDmoaslee) a MaNleoms of A Perpxsomes AmalFemaNleemberof | Amma Number _Per4o2xs0omes|| Nluomssboerr _NPuermobresroomefs uo NAunimmbaelr [ISS PNeuromrbiesromoefs 830 eoes -- ldoesa | lmossss: loss2 2320 | 105845 o90a0 | mssiz mas | l10o5s54e0 132750 Mioomn-stocebgero1_ru16pE ss7%o0fanpd|efvrMhoeepaxantE poi=ceyrstheosecpmoou9enet3yes5depF f|roafnoiuMrmaeelpnfao =tolcoywesacnod1u7mn4ie2dd-dpo|sseaGMMrnoeiumolps=or conto71l81and HPFiOgSh/-kDgo/sdea(y0.(7T5exmtg/Tkagb/lde1a04y5)).5.0T7hLiaisnpdiidn1cd0rr5eo5ap1sl2ee)twsaawnsderpirenesitenwncotrehiainsgebhdo-tdihnoshaeingifhme-amdlaoslseegsimv(aeAlnnei0sm.a75l mNogs. e1dix0sa5t5mr3iib6nueatdendd(Ai1nn0it5hm5e4a0lc)y.NtooTss,ohlesaendarveariilleudstirnasteidzeinfrFiogmulreesss 4 -7. than .1Limpiicdrodrnoptolegtrseawteerrethraanndomly STeevmeerlallasmimactreornisalinorddifeaafmiienntteesdrm.moaoTrthgheiynelgweeicntterhroasnludlreyrnowsuientryde.incgTlehcaery,ytobwpuletarsoemc.ncoatsTihmoeensamleblrlyaicpnioedn-tdbaroiounpnleeddt,wsibsutpy appeared comelate to form a with hepatocellular vacuolation described in these animals by light microscopy. I1n0c5r5e3a4seadncdy1t0o8p5l5a1ds)rm,oipcalnegtdlsy,ocfbotuegtnencfoownratmaseiednvidinidgsetgnitlnycitcno"tgpewonockpheaitrgtshi"-clodefossge(lFyficegomugarelene,8s)r.(eAsTnehimemballinNgos. v`eascccuurmoiulbleeasdtoibroycnlleoiagfrhgtlmyiccorgoesncaopppyarienntthleysecotrwreolaatneismawlist.h tLhiepihdepdartoopcleeltlsudlaird vnaoctuaoplpaetiaorn increased in these two animals. FToarlehsigahn-ddo7s.8e1anfiomrpafleesrm,ahtlehpeeasta(ovTceeyrxtateg,eTahnboulwmeebv5ee)rr. ,oOftnipesermiosaxlnioesko(mrAeenmsiampraekrlabhNleoyp.aht1io0gc5hy5et1re2t)whaaasnvet1rh7aa.gt1ef2dofuonrd 2p5e:rh2he3eppcaoetnrotocrxyoitlsem,oamsleiesmiAlnarimtaolthNeoa.v1e0r5a5g2e7c.onAtrnoilmavallNuoe.fo1r0nm5oa5tl0e7asp.apveTeahrruatsgo,ediand1dm1ui.cn0eisppteerrraotoxixioisnsooommfees 75 mykgday of PFOS to monkeys for 26 weeks did proliferation in the liver. 1 03623 CoAvnacniclelrSytuPdaythNool.og6y32R9e-p2o2r3t Differoeuncceosnitnromlitliovcerhso.ndMriitaoacnhdoncderlliualafrrmoemmcborntarnoelsawnedrheignho-tddoissecelrinviebrlsedbidetnwoeteenxhhiibgihtremarkable differences ultrastructurally (Figures 3.9, 10) `mLoonwk-eDyossegi(v0e.n030.m0g3/kmgg//dkagy/)d.ayEsloaefmcPptFlreoO.nSmLdiiicpdriodnsocdtrooippdilecenteisxfaywmeairnneyatiaditeoynnptiiocffailuetldhteirnlaissvtoerrmusecftruorma,l Sfheeeapmtatutroaecstytcieosom,npaan(rdAendtiwwmoiatllhoNwcoo-snd.tors1oe0l5m5a1l4esanadpp1e05a5r1e5d)t.o Hhaovweevselirg,htilnycirnecarseeadslemidapilldeipsdirdaondprldeoftpelmeatles, tSeithios obnsvearrviwaaatnscieonnoatindstesheaenmtpilwiotnhlge.owl-oAdwso-sdneoostmeeadfleeeamsralwlieeasss,obfleilipiniedtvhmeeedtmtaiobdro-eldpiorssemeseinst2nnoorrmmaall liver bE iilolulsoo tgriactaelsaandheiptastoncoyrtmealfrtoosmetehrealnowd-odmosleipgirdodurpo.plets within hepatocytes. Figure 11 F`moarlelsowa-nddos1e2.a1n0imfoarlsf,emtaheleasve(rTaegxet nTuambbleer5)o.f peroxisomes per hepatocyte was 9.75 for Meiad-sDeodseli(p0i.d15drmogp/lektg/adcacyum)mi.udl-Tadhtoeisroeen liwenavetslh,en0ol.ic1vo5enrssmigos/ftketnght/edumlairyda-sstdrotushceetumnrooa-nlekfefeveyicdstelgneicvveeelonff0o.r1t3he IPTnEogOnSkgeeylsyagtieovdfePnefEPfOeFScOt.So.TfhiOinsncrefeaesmeadlhee,pAantoicmelallulNaor.l1ip0i5d5a3c8c,uhmaudlaitnicorlneiav(severasdceugxollayamctoiignoeennd),.ibnut a marked increase in glycogen was not seen in any other mid-dose FFoer smida-nddo0s.e35anfiomralfse,matlheesa(vTeerxatgTeanbulmebe5r)o. fFpiegruorexi1s2omilelsusptreartehsepaahteopcayttoecwytaesf1r6o.m70thfeor `mid-dose group. CONCLUSION UPlEtrOaSst/rukcgtduraayl feovral2u6atwieoenkosfivdpeernretsisefnifterdioinmnbccorytenhaostmerodelaltgieupdisdmmdaorlonepskleeetyxssawmtiirtenhaeitdendhawenipdattihon0cty7ht5eosom.fgfour Iernencmraeeidansiefndegmlatiplwieodshderixogaphml-eidtnosesdew.efreIemnaclreesa.seTdhheespeatuolcteralslturluacrtugrlaylccohgaenngweasscoprrreesleaanntteddiwnwitiththehincreased hievpeartowceeilglhutla(praphriyadpmeedrtrteorrposlpeithnyatcahcneudhmiuvglahac-utdoioloasnte)iwaonnaisnmao0li.se1.d5bTmyhg/elikgngho/t-demafiyfceorcftosPlceFovOeplySf(ormihde-pdatoosceelglruoluapr). e`bQcuuaonlttiatteaitoinonifoffepreernocxeissboemtewseweinthcionnthreoplaivtnoeccerylstleoalsnabrdymleeivlmeebrcsrtratornneeamstieocdfrwomisitcthoo0pc.yh0o3in,ndd0rii1caa5tweoedrrne0o.n7o5t mg/kg/day. cenit bUeltrwaesetnrcctounrtraolldainffdetrreenacteesd animals in the samples examined. 1 03624 SIGNATURE OF AUTHOR = DrafCtoAvnacniclleaSryuPcaythNool,og6y32R9e.p2o2r3t pores BAS DiplosmBa.teN,olAdC,.VD..PV..M., PD. 3 13 44g te RBeEiFerEKR:ELNigChEtSmaigcersosocfoipmimcumnoorsptahionmientgicovaenraltyhseiaslokaflpieneroDxAisBom`emsetbhyoda.uJt.omHaitsitcocihmeamg.e aCnyatloycsihse:m.a,dv4a0n(t1) 115-121, 1992. Reddy, UN et. al: Tissue specificity `and species differences in the distribution of urate oxidase in peroxisomes. Lab. Invest., 58(1)100-111,1988. 1 003625 IL Light Microscopy and Transmission Electron Micrograph Interpretation Forms Forms are typographically corrected versions of signed/dated raw data sheets maintained in archived study file. 03626 LIGHT MICROSCOPIC EVALUATION Study No.: 6329(-EM2992.736) Species/Strain:_Cynomolgus Monkeys Animal No:_seebelow Sex: seebelow Interpreting Pathologist (signawreand date): Tissue: __ Liver Dose/Group|[mNuambler MicrFiondisngscanod Cpommiencts (OComngtrhogl) |[101505551078 | | 1. 1. _IInnffliartaee,, lTyymphmobpishtooeyhe,ismmuutlliiiffoocoaclea,lymmiitnniiimm,aall Males [77105519] 1." Inflate, lymphobistoeytc,mulufocal minimal f{o7T08527 21.." CIlenstiintg,.cyltoyplmaspmihc,ocheniilsomtbouliliafoo,ccmaiyln,imtmiianilcma_,l____ (OCmogkls) [i|710155030551|31I2.."1 IAnnnfgfiileulcatta,es,ilsy,yfmomcpapl.hmhiaonihbmaiilssmmutialiilfooococael.y,ymmiiitnnicicmma,a,ll ~~ Females 10553512.."ICnlefarliangt,eclytoyplamsmpic,hcenotrihlomiblulisafr,oimciacn.imymiatln c |{f 7TT053t 4 ||12.2._",CliIennaffrlilanatgem.,cmlyattoypilmoansp.mihcc,ooscienhonpthiirliigcls-rombauiulnltuaoilrfo,commcaayitlno,tumismii,anfcloa_c,la_l _li_gh_t (0H7i5gh-mdgokseg) || 105507 1|12.. VIancfuloaltaet,ioln,yhmeppatohceollhuliars,ctfeonoatrlci,lmyoibutnliacmr,a,mloderately-severe Males | | T05_ 12 _ || 21.._ HCyHlyep_ paeerrtrirvonpgoh.yp._ chyytho,pehlpeaap_ stamoticocce.elcllelun_ ultlarairrloccbeeun| lniailrlo,bosubiluga3 lhrat,,mmiondie. mraalte (0H7i5ghm-dposeg) || 105538 1|I2.. InVafcluaotlaet,ioln,yhmeppathocoehlliulsart,fdioifocfaucls,eym,tisnliiigcmhat,l Females {| 7TE83|13..6_VHaycpveorloapohny,.hheepaptoaeltloulca,lceantail,obcuelan,mmolidenoriabmiauellly averr, | }[e7e05530 12.. 12. HIynVpfaeicrultourtaoattp,iholyn,,yhheepmpaatptoochceelollluhullasirr,,scmcetuenntiitrfriioollococbabuulyll,aartmr,,iimnomicdimena,rilamtael | | f[oT0831 13. Clearing cytoplasmic, cenvilobular,slight [14. HTyapefrau,oplhyy,mhepphwoocehliulsrmcutelnuiiflooocbasull,ymarit,nmicimna,ilmal | | [2 Yacmiaion epoca, envi. minima ! 3. Clearing,cytoplasmic.centrilobular, slight . 03627 Dose/Grou|pT NAunmimbaelr | MicroscopicFindingsand Comments 003mgkg | 105514 || 2I.. IInnffliawmamta,tilonm, cposhinoopbhiilcs-gtmruailniuolfoocmcaaytlo,tumsi,inifcomca,al, minimal (Lowdose) |brTe08e37" | 3. 4 CPliegrmeinntg, chyetpoaptloacsemlliucl,ac.emmuulitoibfouclaalr.cselnitgihltobular, minimal 1. Inflate,lymphobimsultufooccalymtiricma,l Males L [103o516 |112,.IVancuiotla,ioln,yhmeppathoocehlia.scmotumlitlioofobccuayla,rmtiimniienmi,amlal i |[L 7TGSS31 1o 1122.. CPIlinogfwmleiantnteg,,chleyptyaotpomlceaplslmuhilcao,r,ckemumilmtimisoufblottcuiallfoa,orcce.aelnymiiltlnoiibegmlha,atrl_,_s_l_i_gh_t_ | } 34.._CVlaecauroilnagi.coynt,ophelpaastmoiccel,lcuelnatrr,ilmobiuflaorc,asl,imghitnimal CG3myhg I| 105537 | 21.. CIlneafrliantge,,clytyopmlpashm,ocebnliombsuolltGafsoo,caclliygmhittricma,l (owdose) I[TBST |1.2". Clneafrilng,,clytoyplmaspmihc,ocenbtiilmosbuulltairif,ooamilcnmiiymsatlma, Females |" 103547 Lo |2.1.EcItnafsraa,e,billiayrym. fpocahl.omibniimamslultifoocealy,m-- tincima,l [| 7T08550 112.. IClneairitng,,clytyopmlapsmhico,chenitislomtbuluitliaofro,ccmaliy,nmtiiminailcma,l OlSmgkg || 105510 13. | 1. IVnafcruaoel,altyiomhnep.pahtocoelhluilasr,mtmuulilftoiofcoeaclayl,.tmmiiinnicimm,aall (Mid-dose) [| T081| 8 12..CIlenafrrianegc,. lyytmopphlodaibffsuismmesu,lmitiunfcoiomcc,aal,ymitnicm,al Males [fie68r53.4 |12. CClleeaarriinngg,.ccyyttooppllaassmmiicc,,cceenmuiilloobbuallarr.,msilingihmtal }[TI05528 TL2. CIlenariitng,,clytoyplmaspmich,doiffbusime,osslliiigfhtoocclmyiina,l O(MIiSd-mdgosheg) | 110053553382 1| .1. IInnffilluaattee,,llyymmpphhoohbiismmstuulltiiiffooooccccaally,.ytmmtiiinnciicmm,a,l | Females {f |71i0055554458 |1o 2.1., ICnIlfneiafuriaiatnetg,e,lcyymyte pophmloaipssmtihocc,yocteinhcr,iil] mmouublsutiilifaiforoccosaall,,icsmgiihygnthittmacl , 12. Clearing. cytoplasmic,cemilbular, light Interpreting Pathologist (signawre and date: . 03628 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No: 6329-223 (EM 99.76) Animal No: _105508 `Treatment Group:_0 mg/kg(Control) Sexi Mae Species/Strain: CynomolgusMonkey Tissue: ___ Liver Block No(s).: __99.76- Photo/Negative No(s).4:3_44034105 Significant Lesions (check one): _____ Yes Interpreting Pathologist (signature and date): __X No Fcoenattauirness:man4y34m0i1t:ocLhiovnedrr.iaHeapnadtoacbyutnedaenxthiebnidtoinpglalsamrgieccreenttircaullnuumc,leBusi.le cTahnealciycutloiplaraese v20i-d2e5n)toaftstmhaelllotwoemrerdiiguhtm-asnidzleefctlmeaarrgliipnisdodfrtohpilsethseapraetopcryetsee.nt,Aprniunmcbipearll(yaipnprtohxeiumpapteerly `mpoosrtt.ionSeovfetrhaelclelyls.osMoimteoschaonnddrpiearoaxpipseoamrensoarrmealp;renseonrtm.alFimvaetr(i5x) gprearnouxliessoamreesecvoiudnetnetd.in 4th3e40n2uc;leLuisv.er.SoHmeepastmoaclyltetoims epdoissuimb-lsyibzie-dnculcelaeratel,ipbidutdrtohipslemtas yprbeesefnutn,cstiimoinlaorf tcout43t4h0r1o.ugh Mmyieclrionv-illilkoeusbobdoiredserpriensesnptacweiotfhDiinslsyesoesvoimdeesn.t Fativteop(5m)apregrionxoifsocemlle.s cSoeuvnetreadl.lamellar 4m3e4d0i3u,m-sLiivzeer.clHeaerpalitpoicdydtreopwlietths bairlee ecvaindaelnitc.ulNusumaterloowuesrmriigthot.choOnndlryiaaafnedwasbmuanldlatnot endoplasmic reticulum or reticulum are artifact. Nine e(v9i)dpeentr.oxCilseoamresstcrouuctnutreed.at the bottom may be dilated Golgi, 4ph3o4t0o4g:rapLhi.ver.HHeeppaattooccyytteecownittahinasdjsaecveenrtalensdmoatlhleltioalmecedliluamn-dsiszienduscoliedaratlitphiedbdorotptloetms,of the. One droplet contains some 43405; Liver. Hepatocyte lamellar material. Eleven with higher magnification (11) peroxisomes of mitochondria. counted. Seven `mmeimtborcahonned,ricaripsrteaes,enmtatwriitxh ainntdegrrvaennuinlgesroapupgehaernndoorpmlaals,mic reticulum and cytosol. Outer Conclusions: Normal hepatocyte. Average 7.5 peroxisomes counted per Bepatocey. 03629 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: _6329-223 (EM 99.76 Animal No. __105517 Treatment Group:_0me/kg(control) Sex: __ Male Species/Strain: CynomolgusMonkey. Tissue: ___ Liver Block No(s): ___99.76-2 43406Photo/Negative No(s)..__43410 Significant Lesions (checkone): Yes _X No Interpreting Pathologist (signature and date): `Fceaantaluirceusli: in43t4he06l:owLeirverri.ghHteapnadtoucpypteersluefrtromuanrdgeidnsbyofotthheercehlelp.atTohceyrteesarweinthumbeilreous `slmiigthotclhyodnidlraitaeda.ndOnalbyunadacnoutpelnedsompallalsmcilecarreltiipciudldurmo.plTehtse ER and evident. nuclear envelope Several small appear lysosomes counted. or vacuoles with microvesicles in them are present. Five (5) peroxisomes 4a3n4d0u7p:peLrivleerft.oHfepphaottoocgyrtaephw.itAhbpielreicsiannuasloiicduallusmiicsrporveislelnotuosnbotrhdeerrigehvtimdeindtdlien lmoawregrinriogfht the cell. contains Several small some lamellar tporomfeidleisu.m-Fsoiuzre(d4)clpeearrolxiipisdomderosplceotusnatreed.evident. One larger one 4c3o4n0t8a;iniLnigvepre.risHienpuastooidcayltecewllit(hItosicneulsloiisdpcroensteanitniatngtheeryttohprolecfyttaesndatatbhieletocpa.naAlicliupliuds- is cpyretsoepnltaastmtahnedbostotmoem.ofRtahendEoRmaspmpaelalrsclmeialrdlliypiddildartoepdl.etEslaerveenpr(e1s1e)ntpeinrotxhieshoempeastoccoeulnltuelda.r 4i3nt4e0r9m:ixLeidvewri.thHempiatotcohcoyntdercioantaanidnsabnuunmdearnotuEsRd.enSseevelryaslossmoamlelscalneda/rolrippiedrdorxoipsloemtessare evident. Twenty-nine (29) peroxisomes counted. 4to3g4e1t0h:erLiinvetrhi.s Ephnoltaorggreadpphh.otAolgtrhaopuhghoftmheitiomcahgonedirsiaa.litTtelenomuittoofchfoocnudsr,iathaerseecolrugsatneerleldes `appear essentially normal. There may be mild dilatationofthe ER in the cytoplasm. Conclusions: Normal hepatocyte. Average 12.25 peroxisomesperhepatocyte. G03630 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: _6329(E-M929.2763) AnimalNo: ___105519 `Treatment Group:_0mg/kg(control) Sexi Male Species/Strain: Cynomolgus Monkey `Tissue: Liver Block No(s).: __99.76-3 43421 - 43425, Photo/Negative No(s).:_4343 Significant Lesions (checkone): _____Yes _X No Interpreting Pathologist (signature and date): Fsteoartiunrgecse:ll4(3I4to21ce;ll)Licvoenrt.aiHneipnagtoncuymteer.ouAstllaorwgeerclleofatrilsipaipdrdormopilneetnst. pTehriesciennustoeirdeadl fat- heenpvaetloocpyeteancdonEtRaiinssmoinledllyardgielactleeda.r lMiopdiedrdartopelnetumabnedrsseovfergallyscmoaglelnergornaensu.leTshperesneunctl.ear Scattered residual bodies noted. Four (4) peroxisomes counted. 43422; Liver. Mitochondrainda surrounding cytosol and ER. MembranesofER are not `vmereymbdriastniencst.anGdlcyrcisotgaeeniapnpceyatrospoarla.lleMli.toScehvoenrdarlinaoarpmpaelargreasnsuelnetsiailnlythneormmaatlr.ixLoafmtihnea of `mitochondria 43423; Liver. Mitochondria. Same view as 43422 but slightly less magnification. Some dilatation of ER. Mitochondria of the photograph. appear normal. A peroxisome is present in the lower left 43224; Liver. Hepatocyte with several medium-sized and one large clear lipid droplets. rSimbaolslogmreasnualneds pwoiltyhriinbcoystoomseosl.anFdouarro(u4)ndpeErRoxaipspoemaerstocbouentgeldy.coSgleignhtplayrtoiuclteosforfocus. 43425; Several bLiilveerc.anaHleipcautloiceyvtiedesnutrbreotwuenednbeyhdepoatthoecrytheesp.atAocsyitnegslaenmdeadisuimn-ussoiizdeadtclloeawrerlirpiigdht. droplet is present in the hepatocyte. dense lysosomes also identified. Four (4) peroxisomes counted. A couple of larger 4d3oe4s3n1';t cLoinvteari.nTahneycdeinsttienrcetdlhipeipdatdroocpylteetsi.s oAblfoenwg ldiipaigdodnraolpllyetisn tahree pprheosteongtraipnha,djaancdent hepatocytes. There is mild lysosomal structures noted. dilationofthe ER and nuclear envelope. Two (2) peroxisomes counted. Only a few `Conclusions: Normal hepatocyte. Average 3.5 peroxisomes per hepatocyte. : 03631 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6320-223 (EM 99.76) Animal No.: __105527 Treatment Group:_0mg/kg(control) Sexi Mae Species/Strain: CynomolgusMonkey Tissue: Liver Block No(s): __99.764 Photo/Negative No(s).4:3_4432462-0 Significant Lesions (check one): __X Yes No Interpreting Pathologist (signature and date): F(aepaptruorxeism:at4e3l4y2620;).LiTvhere.adHjeapcaetnotclyotweewriltehftsheevpearatlocsymtaellshtoowmsedsiigunmi-fsiciaznetddliilpaitdatdiroonpolfettss `ESR.omeAtretsiodpulaelftbaodnidesringohttemda.rTgwine,ntthye-eoxntera(c2e1l)luplearroxinitseormsetisticuomunhtaesds.ome collagen fibers. 4n3o4r2m7a:l gLriavneurl.esMiptroecsheontndmraitar.ix.MeSmobmraenreo,ugchriEsRtaeparnedsemnattraidjxaacepnpteatro nmoirtmoaclh.ondSreivae.ral 4L3y4s2o8s:omLeivperr.eseHnetpaattolcefyttoef.ceTnhteerremiistmoiclhdonddirliaotino.nof theER and nuclear envelope. rSecsaitdtuearledbosdmiaelslntootmede.diTuwme-nstiy-zfeicvleea(r25li)pipderdoroxpilseotmse(sacpopurnotxeidm.ately 18). Scattered c4e3l4l.20T:heLiEveRr.isHmeipladtloycydtilea.tedB.ileSccaatntaelriecdulcileaarre leivpiiddednrtoaptletthsealroeweevrirdiegnhtt. aAnbdutnodpaonftthe Tnhuimrbteyr(s3o0f)dpeenrsoxeibsoodmieessc(opuenrteodx.isomes)lysosomes and residual bodies are present, 4sc3a4t3t0e;redLisvmearl.l Htoepmaetdoicuymt-esiazppeecalresarsilmiiplidardrtoopalbetosv.e Sdeosmcerirbeesdicdeulalls.boTdhieersearaereprseosmeen. Fifieen (15) peroxisomes counted. Ccoonmcplaurseidonwsi:thNootrhemraclonhterpoaltoscaymtpel.es.AppAevaerratgo ebe22i.n7c5repaesreodxniusmobmeesrspeorf hpeepraotxoicsyotem.es . 03632 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No: _6329-223 (EM 99.76) AnimalNo: 105530 `Treatment Gr_0omg/ukg(pcont: rol) Sex: Female Species/Strain: CynomolgusMonkey Tissue: ___Liver Block No__(99s 7164-75) 56 - : Photo/Negative No(s).;_LAT60 Significant Lesions (check one): ______ Yes _X No Interpreting Pathologist (signatureand date): cFaenaatluirceusli: atLAtThe56t;oprLiigvhetra.tHteoppatloefcty,taendcoanpteariinssintuhrseoeidsamlalmliclriopvidildlrooupslebtos.rdeTrheartethaere bile bottom. The nuclear envelope and ER shows Numerous mitochondria are present. Five (5) some mild artifactual (fixation) peroxisomes counted. dilation. LdAeTnSsTe:graLniuvelre.s aMpipteoacrhonnodrrmiaal..HEigRhbeertmawgeneinfmiicattoicohnoonfdfriivsae smliitgohcthloynddirliaat.ed.Matrix and aLn47en8d;othLeilviearl.ceHlelp.atFoocuyrte(.4) Amesdiiunmu-ssoiizsdedprleispiedntdraotptlheetstoaproepfrtehseenpthiontotghriaspche,lLl.inTehdeby nuclear envelope `mitochondria are and ER shows some mild artifactual (fixation) present. Four (4) peroxisomes counted. dilation. Numerous (LaApTp5r9o:xiLmiavteerl:y H1e4)p.at~oSccyattetecroendtapirniimnagrysclayttseorseodmsemsalalndtloomrepdeiruomx-issiozmeeds plirpeisdendtr.oTphleetrseis a perisinusoidal microvillous border at the `Twenty-five (25) peroxisomes counted. top beneath an endothelial cell and sinusoid. LAT60: Liver. lipid droplets. Hepatocyte containing approximately Seventeen (17) peroxisomes counted. nine (9) small to medium-sized Conclusions: Normal hepatocyte. Average 12.75 peroxisomes per hepatocyte. 03633 "TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No: _6329-223 (EM 99.76) Animal No: __10553 `Treatment Group:_0me/ke(control) Sex: Female Species/Strain: CynomolgusMonkey Tissue: ____Liver Block No(s): __ 99.766 L4761 Photo/Negative No(s).;__L4765 Significant Lesions (check one): Yes Interpreting Pathologist (signature and date): _X No Features: LAT6L: Liver. straight-edged by the grid Hepatocyte with bar. Afew small large central nucleus. Two margins arc to medium-sized cltoesliaghtrly shaded lipid dtrhorpoluegthsouartetphreecsyetnotso(la.ppAroxmiomdaetrealtye3n2)u.mEbeRrporfofpirliemsarayndlygsloyscoomgeesn agnrda/nourlepsearroexiscsaotmteesred noted. Nine (9) peroxisomes counted. L4762; Liver. Mitochondria. One oval and one club-shaped mitochondria present. Both asepvpeeraarlnnoorrmmaall wdietnhsecrgirstaaneu,lmesemabnrdasneosm,e aslnidghmtaltyridxi.latTehdecrcilstuabe-,sphraopbeadbolnyeficxoanttiaoinnsartifact. Some RER and smooth ER (SER)areevident in the cytosol. LA763; Liver. Hepatocyte surrounded by interstitium containing some collagen fibers. Cells has slightly dilated ER and nuclear envelope.A in this cell. Four (4) peroxisomes counted. single small lipid droplet is present LboAd7i6e4s:inLitvheerc.ytTohpilsahsemp.atFoocuyrte(4s)hsomwasllsolimpeidddirloaptlieontosfaEreRevaidnednts.eveNruamlelramoeulslasrcartetseirdeudal glycogen granulesarepresent. Eight (8) peroxisomes counted. L4765: Liver. Hepatocyte containing 5 small to medium-sized clear lipid droplets. Bile canaliculiare evident RER is present in the at the lower lower left and left side of the top right nucleus. of the cell margins. Some larger dark ~ A cluster of lpyesroosxoimseosm/epsecroouxnitseodm.es are present among someofthe mitochondria. Thirty-four (34) Conclusions: Normal hepatocyte. Average 13.75 peroxisomes per hepatocyte. .. 03634 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6329(-EM2992 .763) AnimalNo._ [05535 `Treatment Group: _0mg/kg(control) Sex: Female Species/Strain: CynomolgusMonkey Tissue: iver Block No(s). __99.76-7 L4766 Photo/Negative No(s).:_L4770. Significant Lesions (check one): Yes X No Interpreting Pathologist (signature and date): Features: LAT66; Liver. Hepatocyte contains some mild dilatationofthe nuclear envelope andER(fixation artifact). On the left and right sides are bile canaliculi, and ventrally is the sinusoidal margin showing the perisinusoidal microvillous border. Several dense residual bodies are present in the cytoplasm. Three smal lipid droplets, one containing a lamellar body, are evident. One (1) peroxisome counted. LAT67: Liver. Mitochondria. Higher magnification of four mitochondria show normal morphology. Membranes, cristae and matrix appear normal. Scattered dense granules are present. TheERin the cytosol is mildly dilated. L4768: Liver. Hepatocyte. There is moderate dilatation of the ER and nuclear envelope. Several scattered small to medium-sized clear lipid droplets are evident, as are some. scattered residual bodies. Sinusoids are present at the bottom right and upper left of the photograph, and a bile canaliculus is present on the right margin of this centered hepatocyte with its neighbor hepatocyte. Two (2) peroxisomes counted. A769: Liver. Hepatocyte with sinusoid in upper right coanmdcanealicruli prominent along the bottom border. The cell exhibits dilated ER and nuclear envelope like the previously described cells for this animal - indicating suboptimal fixation. Multiple residual bodies are present. Nineteen (19) peroxisomes counted. LATI0: Liver. Hepatocyte with similar overall morphology as L4769. Six (6) peroxisomes counted. Conclusions: Normal hepatocyte. Suboptimal fixation. Average 7.0 peroxisomes per hepatocyte. 03635 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6329-223 (EM 99.76) Animal No: __J05544 Treatment Group:_0mg/kg(control) Sex: Female Species/Strain: CynomolgusMonkey Tissue: ___ Liver Block No(s). 9976-8 LAL Photo/Negative No(s).._LATIS Significant Lesions (check one): _____ Yes _X No Interpreting Pathologist (signature and date): Fcoelaltaugreens:fibLeArsT.TLH:epLaitvoecry.teAlcoonntgailenfst ampaprrgoixnimoafhteelpyat1o7cystmealalretosmoemdeiuinmt-esristzietdiucmleaanrdlipid droplets. A ER. Eight few residual bodies are evident. (8) peroxisomes counted. There is some minimal to mild dilatation of LA772: Liver. Enlarged photographofthree mitochondria. No abnormalities noted. LAT73: Liver. Hepatocyte with one large and several small to medium-sized lipid droplets in the cytoplasm. Eight (8) peroxisomes counted. LAT74: Liver. An endothelial Hepatocyte cell nucleus with prominent microvillous is evident alongthisborder. border along bottom In the hepatocyte are sinusoid. several `ambeudniduamn-tsigzleydcocgleenarglriapniudldersoipnletthse. cTyhteopElaRsmd.oeSsesvehroawl sdaormkermeisildduadlilbaotdatiieosnaarnedptrheseerneta.re Eight (8) peroxisomes counted. LAT75: Liver. Hepatocyte with sinusoid on the right and prominent canaliculus on top. and left margins. No lipid droplets present in centered hepatocyte, although one medium- bsuitzendoltipmiudcdhroSplEeRt,ispopsrseisbelnyt ainpetroippoardtjaalcehnetpahteopcayttoec.yteR.anCdyotompplearsomxicsonotmaeisnsansdo/more RER primary lysosomes noted. Seventeen (17) peroxisomes counted. Conclusions: Normal hepatocyte. Average 10.25 peroxisomesperhepatocyte. . 03636 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: _6329-223 (EM99.76) Animal No: __[05514 `Treatment Group:_03mg/kg(low-dose) Sex: Male Species/Strain: CynomolgusMonkey Tissue: iver Block No(s).: __99.76-15 216232 Photo/Negative No(s).:_Z16236 Significant Lesions (check one): __X___ Yes No Interpreting Pathologist (signature and date): Features: sized lipid 216232, droplets Liver. Hepatocyte. scattered throughout Hepatocyte contains its cytoplasm. At the multiple small to top margin is a medium `rmeitcircouvliulmlo(uSsEbRo)rdaenrdarnodusghomeendcooplllaasgemnicfirbeetrisciunltuhme(sRpEaRc)e aorfeDpirsessee.ntSmthorootuhgheonudtopthleasmic cayntdocprlisatsame,wgirtahnmulaensyamnidtmoacthroinxdrairae acllesaortlyhreovuigdheonutt.. SMeivteroaclhoinrdrregiualaarredawreklls-tpariensinegrved residual 216233. bodies Liver. are present. Hepatocyte. One (1) peroxisome counted. A moderate number of small to medium-sized lipid droplets aarnedplroewseenrtleifnttbhoerdceyrtsopslhaosmw,maiscrwoevlilllaisasnedvecroalllpargoemnifniebenrtsraedsjiadcueanltbtoodiaess.inuTshoeiduporper left central vein. peroxisomes The RER counted. forms a distinct palisade a the bottom ofthe cell. Nine (9) Zs1o6m2e34sl.ighLtivdeirl.ataHteipoantoocfySteE.R aCnendttehreednuhcelpeaatroecnyvteelsopheo.wsThmeirneimaarle afifxeatwiosnmaalrtliftaoct with Z`1me6d2i3u5m,-sLiizveedr.lipHiedpdartoopclyettes.preCseelnlt.apFpoeuarrs(4s)impielraorxtiostohmoessecdoeusnctreidb.ed above. There are. 2r1a6n2d3o6m.liLpiivderd.ropHleeptastaocnydtemu.ltMiupllteirpelseidsumaalllbotdoiemse.diFuimv-esi(5z)edpelriopixdisdorompelsetcsoupnrteesde.nt in the cytoplasm. Only a small peroxisomes counted. nuclear profile is evident in this cell. Eleven (11) probable 1C0onbcelausmiiolnds:incTriesassueeianpnpuemabrserwselolf-fliixpiedddfroorpluelttsr.astArvucetruaraglee6x.a0mpienartoixoins.omeTshepreer appears hepatocyte. 03637 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6329-223 (EM 99.76 Animal No.: _[05515 `Treatment Group: 03mg/kg(low-dose) Sexi Male `Species/Strain: CynomolgusMonkey Tissue: iver Block No(s).: __99.76-16 Photo/Negative 216237No(s).:_Z1624] Significant Lesions (check one): __X__ Yes No Interpreting Pathologist (signature and date): cFoenattauirness:a l2a1r6g2e3a7m,ouLnitveorf.coHlelpaagteoncyetxetr.acAellcuelnatrrlayl.veAinbiilsepcraensaelnitcualutsheistporpemseanrtgionnatnhed sllefitghbteltywdeielnatthe~rdeethhiespaistoacfyitxeast.ionthaerteinfdacotp.laSsemviecrarleltiipciudldurmopalnedtsnuacrleeparreesnenvte.loPpreoamrienent Zg1l6yc2o3g8e.n Lgirvaenru.leHseapraetopcryetseen.t Athbriloeucganhaoltiuhcetulcuystiosplparsesme.ntTwatenthtey-totpwobo(r2d2e)rpweirtohxiasnoomtehse.r ahepppaetaorcyntoer.maOlnaendlahrageveanfdinseecvreirsatlaes,mmaaltlreirx,liapindddrgorpalneutlsesa.reTwpreensteynt-.onMei(t2o1c)hopnedrroxiiasomes. Zf1e6w2s3m9a.lleLrivleirp.idHderpoaptloectsytaer.e pLraersgeentc.enTthrealrenuicslaerutisfaisctaudajladcielnattattoioanloafrgteheliRpiEdRdroapnledt.theA nuclear envelope. counted. Several residual bodies are present. Fourteen (14) peroxisomes lZi1p6i2d4d0r,oplLeitvse.r.ThHeerpeatioscmyatrek.edThdeilcaetnattieornedofhetpheatRoEcyRteacnodntthaeinnsuscelveearraelnmveeldoipuem.-sAizbeidle canaliculus i in the upper present on the right. Ten (10) left margin of this cell peroxisomes counted. and extracellular collagen is evident sZm16a2l4l1e,r oneLsi.verT.heHeRpaEtRocyatned.nuHcelpeaatroecnyvteelcoopnetaairnesditlwatoedl.argTehrelivpeindtdrarlopmlaetrsgianndshsoevwesraal c`maincarloivciullluosusisbporredseerntneoxnt tthoealnefet,ndsoutrhreoluianldecdelblyatdathrekbdoetstmooms.omAesp.romEiignhetnt(8b)ile: peroxisomes counted. Conclusions:~ Slight per hepatocyte. (equivocal) increase in lipid droplets. Average 15.0 peroxisomes 03638 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No: _632(9E-M929.2763) Animal No. _1_ 05516 `Treatment Group: _03mg/kg(low-dose) Sex: Male Species/Strain: CynomolgusMonkey Tissue: ___ Liver Block No(s).: 97.76-17 Photo/Negative No(s).Z:1_6_Z214622-46 Significant Lesions (check one): _____ Yes Interpreting Pathologist (signature and date): __X No clFoaenratgteauirlniespsi:ndud2mr1eo6pr2loe4ut2,s,pnroLoribmvaaeblrl.-yapHapeppeeaartrioiscniygntumesi.otiodcaHhleofpnaadttr-osictaoyratinendgisscecaladltjtaIectreoendtcedltalo)r.ak cTeihlrlreecghouenlptaaartironciyntgea pboedrioexsi.soSmmeoocotuhntaendd.RER are present throuthgechytoopluastm. One (1) esidual probable m21a6r2g4i3n.wiLtihvearn.adHjeapcaetnotcyhteep.atoHceyptaet.ocTyhteechyatsosaoblicleonctaanianlsicaubluunsdparnetsesnmtoaoltohnganidts RriEghRt and 2n1u6m2e4r4o.usLimvietro.choHnedpraitao.cytAe.fewHerepsaitdoucayltbeodexiheisbiatrse pvreersyenstl.ighTtwdiola(t2a)tipoenroofxitshoemes seen, tehnedocpytloapslmaiscm,reatnidcuslcuamttaenrdednurecsliedauraelnbvoedlioepse.arGelpyrecsoegnte.n gTrwanoul(e2s) aprreobparbelseeaptetrhorxoiusgohmoeust identified. t2h1e62le4f5t,oftLhiveern.ucHleepuastoofctyhtee.heApcalteocayrtev.acTuhoilse awpiptehaarcsentotrbaelarocuytnodpdleanssmiitcyiinsvpargeisneanttiotno cfyrtoompltahesmp.laAsmfaemwermebsirdaunael.boNdoiremsaalr-eapprpeesaernti.ngFmiifttoecehno(n1d5r)iapearroexpirseosmeenst ctohurnotuegdh.out the a2b1o6v2e4-6d.escLriviebre.d cHeelplas.toTchyteer.e aTrheegcleynctoegreendghreapnautloecsyttehraopupgehaorustetshseenctyitaollpylassimm,ilaSrixttoeen 16) peroxisomes counted. Conclusions: Essentially normal hepatocytes. Average 7.2 peroxisomes per hepatocyte, k 03639 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No: _6329.223 (EM 99.76 Animal No: _[05521 `Treatment Group: _0.03mg/kg(low-dose) Sex: Male Species/Strain: CynomolgusMonkey Tissue: ___ Liver Block Nofs).: __99.76-18 Photo/Negative No(s).2:1_6_2Z146725- | Significant Lesions (check one): Yes Interpreting Pathologist (signature and date): X No Features: bodies are Z16247. present in Liver. Hepatocyte. Several the centered hepatocyte and ltahregseubirjraecgeunltarheeplaetcotcryotne-.denTsheereSsEidRuaalnd anlutchleoaurghentvhiesloapppeeaarresstloigbhetlayrtdiiflaactteuda.l Aallsoon,g twhiethmitthoecdhiolnadtreidaSaEpRp.eAarsfseliwghstmlaylslwloilpliedn, droplets 216248, aLrieveprr.eseHnetp.atFoocuyrttee.enC(l1u4st)epresroofxifisnoemegrsacnouulenst,edp.robably glycogen, are present in thheepactyotcoyptleatsom.thTehteopmiletfot.chTohndersimaoaoptpheaErRs silsipghotolrylydildaetfeidn,eda.s dSoeevsertahlesSmEalRlilnipaind addrjoapcleetnst are present. Two (11) peroxisomes erythrocytes counted. are present at the lower rightofthe photograph. Eleven s2l1i6g2ht4l9y,diLliavteedr,. cHoenpsaitsotceynttew.ithThseomReERfi,xantuicolneaarrtiefnavcet.lopSee,vearnadl SsmEaRllilnitphide dhreoppalteotcsytaendare ratestihdeuallowbeordireisghatr,eadprjeasceenntt.toAasnmeanldlotsheeglmieanltcoelfl.aSpiexrtiseiennus(o1i6d)aplefraotx-istsoormiensg ciedlelntiisfpierde,sent ZMu1l6t2i5p0l.e dLairvekr.andHeiprarteoguclyatre.resSiedvuearlablosdmiaelslalriepiadlsdoropprleestesnta.reTphreesEeRntiisnstlhigehhtelypadtiolcaytteed. ZtIh6r2o5uLg.houtL.iveTrh.reHeep(a3t)opcryotbea.blTehpeerreoixsimsiolmdesdicloautnattieodn.of the nuclear envelope and the eennldaorpgleads.miOcnrtehteicluefltuimstthhreouhgehpoautto.cytMei'tsocmihcornodvriilalohuasveboardpearl,erwimtahtrainxaadnjdacmeanyt ebnedostlhieglhitalyl cell and erythrocyte in the sinusoid. (10) peroxisomes counted. A bile canaliculus i present in the lower right, Ten ACvoencrlaugseio1n0.s8:pEesrsoexnitsiaolmleysnpoerrmhaelpahteopcayttoec.ytes. Some minimal to slight fixation artifacts. k c0364q TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: _6329.223 (EM 99.76) Animal No.: __105537 Treatment Group: _.03 mg/kg (low-dose) Sex: Female Species/Strain: CynomolgusMonkey Tissue: Liver Block No(s).: __99.76-19 Photo/Negative No(s).2:1_6Z21652256 Significant Lesions (check one): _____Yes _X No Interpreting Pathologist (signature and date): ___ phFreeepasatetunortceysitn:eth2ie1a6c2yct5eon2tp.rlaaLlsimvv.eeri.nFionHreepsgailtnyoucscooygitdeen.argeraFa.inxuSaleteviseoranaralepmspceeadatritsuemrge-odsoitdzh.erodDuolgrihpsoiaudltd(rtoohpetlhceeyttsoaprleasm. pAerdoexsimsoosmoesmecoiuspnrteeds.entat the lower left margin with an adjacent hepatocyte, Ten (10) r2e1t6i2c5u3l,um.LiTvehre.reHiespoatnoecylatreg.e lHieppiadtdorcoyplteetsahnodwssevveerraylsslimgahltlddilraotpalteitosnowiftheinndotphleasmic cytoplasm. A bile canaliculus peroxisomes counted. is preseat at the top right margin of the cell, Five (5) 216254, there are Liver. lesser nuHmepbaetroscoyftlei.piTdhidsrocpelleltsa.ppTeawros eisrsreengtuilaalrldyasrikm-isltaarintoinZg1r6e2s5id3u,alalbtohdoiuegshare vparceusoelnattoend.thEelleevftenan(d11r)igphetrsoixdieosofmtehseconuucnlteeuds.. The one on the right is somewhat Z16255. material Liver. Hepatocyte. is present to the right A medium-sized lipid of the nucleus. Justa dfreowplsemtalcloenrtaliinpiidngdrsoopmleetslaamreellparresent ieslstehewhmeirceroivnitlhleoucsytbooprldaesrme.xtTehnedienngdionptloatshmeicspraecteicouflDuimsisse.sliAghtfleywdsimlaatleld.reAsitdutahle bboodtiteosm are present. Six 216256. Liver. (6) probable Hepatocyte. peroxisomes counted. In his hepatocyte two mitochondria appear paler and somewhat swollen. The rest appear normal. Twelve (12) probable peroxisomes counted. eCxopneccltautsiioonnss.: AvEsesreangteia8l.l8y pneorromxailshoempeastopceyrtehse.patQoucaynttei.ty oflipid appears within normal 03641 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No: _6329.223 (EM 99.76) Animal No.: __[0554 Treatment Group: _.03 mg/kg (low-dose) Sex: Female Species/Strain: CynomolgusMonkey Tissue: ___ Liver Block No(s).: __99.76:20 Photo/Negative No(s).Z:1_6Z215672-6 Significant Lesions (check onc): Yes X No Interpreting Pathologist (signature and date): Fleefattaunrdesu:pp2e1r6r2i5g7h,t maLirvgeirn.s Hoefptahtioschyetpea.toMciyctre.oviAllbairlebocradnearlsicaurleuspriesspernetsaenltonagt tthhee Tloowweerr rniugchlte.usL.amTehlelraerimsaatebruinadlanwtitShiEnRatlhirpoidugdhrooupltettheiscperlle,seanntdtthoethRe EloRwearppreiagrhts oslfitghhetlcyentral dilated. Z16258. SLeivveern.(7H)eppraotboacbyltee.peSreovxeirsaolmmeesdciouumn-tseidz.e lipid droplets are present, as well as amipcprroovxiilmlaotueslyboeridgehrt,raensdidauablilbeodciaensa,liicnultuhseicytporpelseanstm.inTthheemliodwearnldefutpmpaerrgriinghits amargins 2o1f6t2hi5s9.hepLaitvoecry.teH.epEaitgohctyt(e8). pTehriosxiceslolmiessscuorurnotuendd.ed by several other hepatocytes, and cdoanrtkarinosunadpptroooxviamlatreesliydutaeln bmoeddiieusma-rseipzreedselinptidatdtrhoeplteotpsofintihtescceyltlo.plSaesvme.raSledvaerrakl very pmeirtooxcihsoonmdersi.a nFootuerdt;etehnes(e14a)repeorfotexnisdoifmfeiscuclotutontedidf.ferentiatefrom lysosomes or 2ab1o6v2e6.0,TwLiovelri.pidHedpraoptloectysten.oteHde.paTthoecryeteisaspipgeahrtsdeislsateanttiioanlloyfstihmeileanrdtooplthaossmeicdersectriicbueldum 2a1n6d26n1u,cleaLriveenrv.elHoeppea.toTcwyetnet.y-Ctehlrleceon(t2a3i)npsearpopxriosxoimmeasteclouyntesdm.all to medium-sized lipid dtrhoepcliertcsu.laAtitont.heAbaoottthoemrissianussioniudsaolidmacrognitanianinndgmaicprloavtielleltouosr sbeorgdmeerntisopfaresgerntanautltohceytteopi.n There is slight dilatation of the endoplasmic reticulum. Eight (8) peroxisomes counted. Cnoonremlaulseixopnesc:tatiEosnssenftoirahlleypantoorcymtaels.hepAavteorcaytgees.12S.0opmeerolxipiisdodmreosplpeetrs hneoptaetdo,cbyatet.within 03642 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6329-223 (EM 99.76 Animal No: __ 105547 Treatment Group: 0.03 me/kg (low-dose) Sex: Female Species/Strain: CynomolgusMonkey Tissue: Liver Block No(s).: __99.76:2. Photo/Negative No(s).Z;1_6Z216622-66 Significant Lesions (checkone): _____ Yes _X No Interpreting Pathologist (signature and date): sFmeaaltlurneusc:le2ar16pr2o6f2i.le.LiAverm.icrHoevpialtloocuysteb.ordePrhoitsopgrreasepnhtsahtotwhse atohperpiagthto.cytSeomwietharjtuisftacatual `ksnmiaflel mliaprikdsdraorpelpertessaenrte.evSiedveenrtalintdharekcryetsoipdluaalsmb.odAibeusnadraenptreSseEnRt,aannddRonElRy aarbeoutthrsoiuxghout 2th1e62c6y3t.oplLaisvemr.intHeerpmaitxoecdytwei.thNnuummeerroouusscmoiltloacgheonndfirbiear.s aFroeuprr(e4s)enptearlooxnigsotmheesdoirdsenatlified. tehxetrsapcealcleuloafrDmiasrsgei.n.ThAetrethies slloiwghetrdlielftattahtiisonheopfattohceyntuec'lsemaircernovveillolopuesabnodrdeenrdoepxltaesnmdsicin rareetircaulnudmo.mlSyevsecartatlerreesditdhuarloubgohdoiuets tahnedcylitpoipdldarsomp.leStisx a(r6e) ppreersoenxti.soFmiensecglleyarcloygeindegntriafniuelde.s n2u1c6l2e6a4r,enLvievleor.pe.HeApatbiolceytcea.nalTihceurleusisisslpirgehstenditlaattatthieondoorfsatlheriegnhdtompalragsimnicofretthieccuellulm, aanndd sainmoitlhaerrthoetphaetoacbyotveeisdepsrcersiebnetdacleolnlsg.thOenlveyntornael lmiaprigdidnr.opTlehteigseenveirdaelntmoirnpthhioslcoeglly.isSeveral Zre1s6i2d6u5al.bLoidvieers.arHeepeavtiodceyntte.. FouArtceeenntr(a1l4)vepirnoabanbdlseipnuesrooixdissoumrreosuinddentthiifsiehde.patocyte on Wthiethlionwetrheanhdepuaptpoecrytleeftthemraergiisnssl.ighEtrydtihlartoactyitoenosfatrhe epreesnednotplinastmhiecvarsectuilcaurlulmumaennds.nuclear Ze1n6ve2l6o6p.e.LiTvwero. sHmeaplaltolicpyitded.roHpelpeatstoacryetpereaspepnet.arsNiesnseen(t9i)alpleyrsoixmiisloamretsoccoeullnstedde.scribed laabrogvee.irrTehgeurlearilsys-lsihgahpteddirleastiadtuiaolnobfotdhyeies npdroepselnatsmtiocthreetliocwuelrumleaftnodfntuhcelenaurcleenuvse.lope. A Seventeen (17) probable peroxisomes counted. Conclusions: hepatocyte. Essentially normal hepatocytes. Average 10.0 peroxisomes per 03643 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6329-223 (EM 99.76 Animal No; __[05550 Treatment Group:_.03 me/kg(low-dose) Sex: Female Species/Strain: CynomolgusMonkey Tissue: ___ Liver Block No(s).: __99.76.:22 Photo/Negative No(s).2.1_6_2Z1667272 Significant Lesions (check one): Yes Interpreting Pathologist (signature and date): X_ No tlFhoerwaoeturugrlheeosfu:tmaZtr1hg6ei2nc6sy7.t,opAlLailvsaemrrg.oefdHtaeirpskathroeecpsyaitdteuo.aclytAbebo.udnyBdiialsenptcraennsuaelmnibtceuirlnsi aaonrfeagedlvjyiacdcoeegnnettnohgenrpatahnteuolcreyisgtheatr,aetltephfreteavonendpt Mpleriftot.boacSbhelovenedprreailraosxamipasploelmeaerrsrneocsroiumdnautlae,ldh.baovdiiensg acrriesptaree,sesnptoriandtihc gcryatnuolpelsasamndofathfeinceengrtaeirneydmhaetpraitxo.cyFtiev,e (5) o2ffi1tx6ah2tei6o8en,n-rdeLolipavlteaerds.mciHhceapnragetetosic.cyutlPeur.mo.mCiTynhteeonnptulcbailsleemachraanesanlaviecsluoolmipeeawrihesapatrleslsoiegsnhlttigaohpntplteyhaderilalanetcfeeda.dndTthlueooswseelrieagrrhietgahdrtitlciaeftlaalctutiluoaanrl 2bmea1r6ag2bi6nu9sn.,daLnNitovegrll.iypciHdoegdperanotpoglcreyattnseue.lveisCdeeilnnltt.ahpeFpiceyfattroesseonsl.i(m1i5l)AarpmetirocorZxo1iv6si2lol6moe7ussdcebosoucrnrtdieebdre.diparbeovsee.ntaTthetrheeauppppeearrs to ufipgphetrexletfetnmdairngginisn.toTthheersepaarceemoafnDyisdsae,rkwhmiilteocbhiolendcrainaalwichuilciharaereedviifdfeincutltaltoondgiftfheerelnotwieartelfortoamnd 2p1er6o2x1i0s,omeLsiv.er.TwHeenptayt-osceyvteen. (T2h7i)sprhoebpaabtloceypteeraopxpiesaormsestocbouenbtiendu.cleate. An endothelial cell is pernedsoepnltaslimniicngrethteicsuilnuumsoainddvneunctlrealalryeannvdeltowpoe eirsystlhirgohtclyytedsilaatreed.prTewseennttdyor(s2a0l)tpoetrhoixsicseollm.esThseeen. a2hne1p6ea2ntd7oo2cty,hteelL.iiavleDro.creslalH.lelpyaV,teoatcthyretaeml.ilcyrTaovwiaolrlslomauaersglebloasrndedegrmmeuelnxtttieopnfldesasilmnpatilodl-tehcreolnistppaiaidcndeirnoogpflcDeeiltlss,saeprraeonpbdraiebsleyandtajiancetnhtisto ppeerriosxiinussoomiedsalcofuantt-setdo.ring cell andanadjacent hepatocyte. Twenty-one (21) probable. dCroonpclletuss,iotnhse:oveErsaslelntiimapllryesnsoiromnail htehaptatloicpyidtecso.ntAelntthionutghhis loinveercwelals(wZiIt6h2i7n2e)xpheacdtaedlontoorfmpalid limits. Average 17.6 peroxpiesrheopamtoceytse. 03644 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6329-223 (EM 99.76) Animal No: 105510 `Treatment Group:_.15mg/kg(mid-dose) Sex: Male Species/Strain: CynomolgusMonkey Tissue: iver Block No(s).: __99.76-23 Photo/Negative No(s).2:1_6_2Z17632-77 Significant Lesions (check one): _____ Yes X_ No Interpreting Pathologist (signature and date): rFeaantduormelsy:thZr1o6u2g7h3o.utLtihveerS.EHRepaantdoccyyttoes.olN. uFmiexraotiuosn galpypceoagresnggoroadn.ulOens earsewporlelseennt"barbell- sdahrakperde"simdiuatlocbhoodnidersiaarse pprreesseenntt., bThuitratleeonth(e13r)mpiteorcohxoinsdormieasacpopuenaterdn.ormal. Scattered 2th1e62c7yt4o,plLaisvemro.fHtehpeahteopcayttoec.yteS.eveArlaolnsgmaitlslritgohmtemdairugmi-nsitzsemdiclripoivdildlrooupslebtosradreerpfraecseesnt in canyottohpelrashmepiastfoiclylteed.wiAthpoSoErRl,y-RdEefRi,nemditbiolcehcoanndarliiacaulnudsgilsypcroegseenntgratantuhleelsotwherroulegfht,outT.he Some peroxisomes are peroxisomes counted. noted. Scattered dark residual bodies are present, Ten (10) tZh1e62b7o5t.tomLiivsera.ceHnetpraatlovceyitne.surCreonutnedreedd bheypaantoecnydtoethhealsiaolnlceylla asmnadlal mnoucdleeraarteprnofuimleb.erAtof Texhtrreaecellilpuildardrcoopllleatgsepnrfeisbeenrts.inAtnheecndyottohpellaisaml.clTlhiirstetehen l(i1g3h)tepresrhoaxdiesdomceelslcaotunttheedt.op right. 216276. small to mLeidvieurm.-sHiepzaetdoclyiptied.drTohpilsetcselalreapppreeasresntsiimnitlhaer ctyotZo1p6l2a7s3m.. Approximately 10 Numerous glycogen tghreancuellle.sFaorueretveiednen(t14i)nptehreocxyitsosoomle.s cAoulnatmeedl.lar body is presenta the bottom margin of d2r1o6p2l7et]s,arLeivperre.seHnetpaitnotchyetcey.toAplpapsrmo.xiTmhaetecllyusatedroozef5n dsrmoaplllettso amtedthieumf-arsirizgehdt lairpeidin banoodtiheesracreelln.otTedh.e cTyhtroepela(3s) mpcroonbtaabilnes paebruonxdiasnotmfeisnecogulnytceodg.en granules. Several residual Conclusions: cells. Number Eosfselinptiidaldlryopnloertmsaalppheeapartsocnyotremsa.l. Moderate Average amount of glycogen in 10.6 peroxisomes per several hepatocyte. 03645 `TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: _6329-223 (EM 99.76 Animal No: __[0S518 `Treatment Group: _.15 mg/kg (mid-dose Sex: Male Species/Strain: Cynomolgus Monkey Tissue: iver Block No(s).: ___99.76:24 Photo/Negative No(s).Z.1_6_2Z1768282 Significant Lesions (check one): Yes X No Interpreting Pathologist (signatureand date): pFeeraitsuirneuss:oidZaIl6f2a7t8-,stoLriivnegrc.elHlecpoanttoaciyntien.g sAevlertahle tporpomriinghetntthlisiphiedpdartoopcleyttse.isFboourrdsemraeldlby a lriepsiiddudarlopbloedtys,airsepprreesseennttoinn tthhee lheefptamtaocrygtien.oAf tbhielececlal.nalTihceurleusi,sasdljiaghctendtiltaotaatilaorngoe.fthe envuicdleenatr.eTnhvierltoepeena(n1d3)enpdeorpolxaissmoimcesrectliecaurllyumi.denMtuilftiiepd.le irregular residual bodies are o2n16t2h7e9r.ighLti.veOr.n Hitesplateofcitsytae.baTnhdeocfenintteerrsetdithiaelpactoollcaygteen.is Tbohredenruecdlebayr eandvaerlkoeprehaenpadtocyte ethnedorpiglhatscmeilclurleatrimceumlubmraarnee.sliSgihtxltyeednil(a1t6ed).prSoebvaebrlael peenrdooxciystoimecsvceosuinctleeds.are present along. a2n1d62l8ef0t.maLrivgeirn.s Hweiptahttohceytaed.jacHeenptatheopcayttoecyhtaess.proOmnienesnmtalblilleipciadnadlriocpulleitanlootnedg.its right MMuilttoicphloendclruisatesrtsaionfsRoEmeRwehvaitdemnot.reTpwaellevien(t1h2is) cpeelrloaxnidsocmonetsracsotunwtietdh.darker peroxisomes. ZaIn6e2r8yLt.hroLciyvteer.wiHtehpianttohceytcee.ntrTahlivsehienpoartosciynutseoiadp.peaServsetroalbesmbianluclliepaitded.roAptletthseatroepplreeftseinst iin the cytoplasm. nuclear envelope. There Some is slight to moderate dilatationoftheendoplasmic reticulum shrunken mitochondria are difficult to differentiate from and ZI1y6s2o8s2o.mesLiovrerp.erHoexpiastoomceyst.e.ThGiernteyr-atlwoce(l3l2u)laprromboarbplheopleorgoyxiissosmiesmciotulonctaeeldrl. described Nabionveet.eenTh(e1r9e) ipsesrloixgihtsodmileastactoiuoanteodf.the endoplasmic reticulum and nuclear envelope. Conclusions: scen. Average Essentially normal hepatocytes. Only 18.4 peroxisomes per hepatocyte. small numbers of lipid droplets : 03646 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6329-223 (EM 99.76 Animal No.: _ 105524 Treatment Group: _.15me/kg(mid-dose) Sex: Male Species/Strain: CynomolgusMonkey Tissue: ___ Liver Block No(s).: __99.76-25 Photo/Negative 216283 No(s).:__Z16287 Significant Lesions (check one): __X Yes __ No Interpreting Pathologist (signature and date): dFreoaptluertse.s:ThZe16n2u8c3l.earLievnevre.loHpeepaatnodcyetned.opHleapsamtioccyrteeticcounltuaminasretswloigmhetldyiudiml-asteidz.edAtlitpihde taroep prrigehsteast aarboiulendctahnealciacnualluiscubleutsw.eeTnhitrhtisy-coenlle a(n31d)apneradojxaicseonmtehsepcaotuonctyetde.. Desmosomes 2he1p6a2t8o4c.yteLsivoern.alHlempaartgoicnystei.n tThhiissphceonttoegrreadphh.epBaitloecyctaenailsicsuulriroaurendeevdidbeyntotahtetrhe top left and and bottom left margins. SER appear normal. TNwoenltiypi-dndirnoepl(e2t9s)arpreoebvaibdleenpteirnotxhiissocmelels. Mitochondria, counted. RER LZe1f6t2o8f5.thisLihveepra.toHceyptaet.ocCyotlel.agTenwofibeerrystharreocpyrteessenatreinprtehseenstpaicnethoef sDiisnsues.oidAladojnagcetnhte troigthhte margin of is present this cell is in this cell. aTpwreonmtiyn-esnetvbeinle(c27a)napleircouxlius.somAesscionugnlteemd.edium-sized lipid droplet ZA1t6t2o8p6l.eftLiavnedr.boHtetpoamtorciygthte.areCeelrlytahprpoecayrtesseswsietnhtiinalsliynussiomiidlsa.r tNoocedlilsstdiencstcrliipbiedddarboopvlee.ts anrueclperaerseenntveilnotphei.s cSeellv.erTahledraerki rselsiigdhutadliblaotdaiteisonaroefptrheeseenntd.opTlwaesnmtiyc-roenteic(u2l1u)m and peroxisomes counted. 2in1i6t2s8c7y.toLpilvaesrm.. HTehpearteocisytseli.ghCtedlillahtaastitownooflatrhgeeeannddopslevaesrmailcsmraeltliecrulluimpiadnddronpulceltesarpresent etnhvreoluogpheo.utStehveercayltodpalraksmr.esidEuiaglhtbo(d8i)epsearroexiprseosmeenst.coGulntyecdo.gen granules are present Cpeornocxliussoimoenss.: NEosseinntciraelalsye nionrlmiapildhneoptaetd.ocyAtvees.raSgleig2h3t.i2npcereraosxeisionmaevserpaegrehnepuamtboecyrteo.f : 0364'7 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6329-203 (EM 99.76 Animal No.: __[05528 `Treatment Group: __ 15mg/kg(mid-dose) Sexi Male Species/Strain: CynomolgusMonkey Tissue: __ Liver Block Nofs).: __99.76-26 Z16288 - Photo/Negative No(s).: __Z16292 Significant Lesions (check one): _____ Yes Interpreting Pathologist (signature and date): _ x No bFsoiezraedtdeurraenbsde:naepZapt1rh6o2ex8nid8mo,atthLeeillvyiearfl.ifcteHeleelpnsasatmroaeclyeltveil.idpeindTthdairtsopthhleeeptuasptiponceyrttsreicgcyhottnotapanlidanssm.aboMuitcrFoivveilmleoudsium Sbcilaettcearneldidcaurlkusstsauirnrinogunrdeesdidbuyaldbeosdmioessoamreespriesspernetsienntthaet ctyhetolpolwaesrml.roiwgTehhrtemIreaefzyigs`imsnal.riggihnts. A dcilleaatraltyiiodnenotfitfiheed.endoplasmic reticulum and the nuclear envelope. Five (5) peroxisomes 2sp1a6c2e89o,f DLiisvseer.atHtehpeautpopcyetrel.eftTmhairsghienpoafttohcyetep'hsotmoigcrraopvhi.lloAutstbhoerdleorweerxtleefntdsis i4nto the rppeeetrriioscxiuinlsuuosmomiaedsnadlcotfuhanettn-eusdtc.olreiangrcelavle(lLoopec.el)T.wTohsemraelils lliipgihdtdrdoipllaettastiaornoefetvihdeenetn.doSpilxatsemenic(16) p2le1or6wi2es9ri0nl.uesftoLiaidvagelrraf.nautHl-esoptcoayrttioencgiyscteeplr.le(sTIehtniotsciecnellt)lheiissspiarlneiustsetonlited.daoSrrekcveeernrtasrltaalsinmvieainnlg.thAatn pthreevtioopursicgehltlsa., At einndtoheplhaespmaitcocryetteicaunlduam afnedwtrheesinduucalleabrodeinevsaelroepeev.idNeinnte.teTehner(e19i)s spllieiprgiohdtxdidrsioolpamlteeatstsicoaonruoenftpertdeh,seent ZcIo6m2pLo,sedLoifveSr.ERH,epgaltyoccoygteen.grMaunuclheos,ftahned cpryotboapbllaesmcyhtaosskeldeetnaslecgormapnounlearntasppearance. pArpopbraobxliempaetreolxyiesiogmhetseecnousnmtaeldl. to medium-sized lipid droplets are present. Nineteen (19) l2i1p6i2d9d2r,oplLeitvserp.reHseenptationctyhtee.cytHoepplaatsomc.ytFeoauprpteeaernspsriombialbalreto(Z14I) 62p9e1r.oxiTshoemreesacroensneevder.al Conclusions: expectations. AEsvseernatgiaell1y4.n6orpmearloxhiespoamteoscytpeers.heLpiatpoicdydtreo.plet numbers within normal 03648 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6329-223 (EM 99.76) AnimalNo:___ 105532 `Treatment Group: _.15mg/kg(mid-dose) Sex: Female Species/Strain: CynomolgusMonkey `Tissue: Liver Block Nofs).: __99.76-27 Photo/Negative No(s).Z:1_6Z219632-97 Significant Lesions (check one): _____Yes X_ No Interpreting Pathologist (signature and date): Features: the top are Z16293, multiple Liver. Hepatocyte. lipid droplets which This are in photograph an adjacent has a centered hepatocyte. perisinusoidalfat. storing AT cell i(nLtoecremlilx),ednowtitihntthhiesehnedpaotpolcaystmei.cTrheetirceulaurme.nuTmweorovuesryglsymcaollgelnipgirdadnruolpelsetisn tahree cpyrtesoesnotl. `Mmiattroicxh.onFdoruira(a4p)ppeearronxoirsmoamle.s Tclheeayrlsyhiodewntfiifineedc.ristae, some granules and finely grainy 2b1en6e2a9t4h,thLeivneurc.leHuesp.atSoicmyitlea.r tAo sZi1n6g2l9e3l,artgheerleipairdedrmoapnleytfiisnpergersaennutlienstihnetchyetcoyptloapslmasm `which appearto hepatocyte. be glycogen granules. Three (3) peroxisomes identified in this hZe1p6a2t0o5c,yteL.iveArt.thHeepuaptpoecrytreig.htSiesvaer"aPl"m-esdhiapuemd-seixztreadcellilpuildadrraorpclaetcsoanrteaipnriensgenctolilnatgheisn. Sfiebveersr.al Mroedsiedruaatlebaodmioeusntarseofalsgolypcreosgeennt.arFeipvrees(e5n)tprinobtahbelceypteorpolxaissmoomfesthceohuenptaetdo.cyte. a2b1o6v2e9.6.ThLrieveerl.ipHidepdartoopclyettes.areCeenvtiedreendt ihnepiatstoccyyttoeplaapspme.arAststihmeilbaortttootmhiossea dleosngcirtiubdeidnal pgrloyfciolgeeonfagrbainluelecsanaarleicpurleussenatndtharcoruogshso-uste.ctSiioxno(f6)apecraonaxliiscoumleuss at the top counted. margin. Fine a2b1o6v2e9.7.TwLiovemre.diHuemp-atsoiczyetde.a.ndCseenvteerraledsmhaelplatloicpyidtedraopppleeatrsspsriesmeinlta.r tToothtohseerdieghstcriisbaend eanrdeoatohefliinatlercsetlli.tiTumhrceoenta(i3) nipnegrsoxoimseomceosllcaoguenntefdib.ers. The nucleus probably belongs to an mCoonsctleulsliso.nsL:ipEisdsdernotpialleltynnuomrbmearlshaepppaetaorcyntoersm.alM.odAevreartaegaem4o.u2nptesroofxigsloymceosgepnerpresent in hepatocyte. 03649 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6329-223 (EM 99.76 Animal No: __105538 `Treatment Group:_.15 me/kg (mid-dose) Sex: Female Species/Strain: Cynomolgus Monkey Tissue: iver Block No(s).: __99.76-28 Photo/Negative Z16298 No(s).:__Z16302 Significant Lesions (check one): __X Yes No Interpreting Pathologist (signatureanddate): Features: transecting cytoplasm. Zth1e62c0el8l.beLnievaert.h tHheepanutcolceyutse.. NSuemcteiroonuhsasglaypcroogmeinngernatnusliensglaerkenpirfeesemnatrkin A single smal lipid droplet is present. Mitochondria and other org the appear normal. 216299. Liver. HFeipvaet(o5c)ytpee.roxHiespoatmoecsyctoeunhtaesdas.ingle large and several small anelles lipid `edxrSotopemlneedtmssi.itnotcAohtoshniednrusispoaaicaderieosflpirDgiehsstseern.tstaTathitnehireneguaptrpheaenrabtluehnfetdmamanajtrogrgiiltnyycwoohgfeerdnaergktrheaernumolineces.roivTnihtlehlseoeucsyltibgoohprtldaesrm. Emiigthotceheonnd(r1i8a) aprreobsaobmleewpheartoxdiifsfoimcuelstctooudnitfefde.rentiate from lysosomes or peroxisomes. is2dp1ea6nct3ie0fs0ieo.dr.Lpiovcekre.tsHienpatthoeccyytteo.soCl.elAl csoinntgaliensliapbidunddraonpltegtliyscporgeseennto.fteTnhrineeir(r3e)guplearrocxliesaormes aZIn6d30vLe.ntraLlilvyera.ndHaepmaitcorcoyvtiel.louTsh-issincuesnotiedraeldbhoerpdaetrocaytttehehatsopadrjigahcte.ntIthsecpayttoocpyltaesmdocrosnatlaliyns cmullutmippelde ibrertewgueleanr pthoeckgeltyscoogfegnlypcoockgeetns.graNniunlees.(9)Optehreorxoirsgoamneesllceosuantpepde.ar somewhat p2o1c6k3e0t2s. ofLigvleyrc.ogHeenpagtroacnyutlee.s aTnhdishacesllanapopveeararlslsliimgihltaraptpoeZar1a6n3c0e1., Oatlhtehoruogrhgaitnehlalsesmore. appear clumped between the glycogen granules. One (1) peroxisome clearly identified. tChoenscelhuespiaotnoscy:teEss.senAtviearllaygeno7r.m2aplehreopxaitsocoymteess.perThheerpaetioscyitnec.reased glycogen in some of 03650 `TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6329-223 (EM 99.76 AnimalNo: ___Jossas `Treatment Group:_.1Smg/kg(mid-dose) Sex Female Species/Strain: Cynomolgus Monkey Tissue: ___Liver Block No(s).: __99.76-29 Photo/Negative No(s)2.1:6_3Z01363-07 Significant Lesions (check one): Yes __X No Interpreting Pathologist (signature and date): Fiegahttuarneds:bo2t1t6o3m0r3i.ghtLiavnerd.byHeapnationcteyrtseti.tiaTlhimsarcgelilniosnbotrhdeelreeftd. byPrhoempiantoecnyttbeisleoncatnhaelitcoupli arreetiecvuilduemntanbdetnwuecelenaardejnavceelnotphee.paNtoocyltiepisd. dTrohpelreetsiasrseleivgihtdednilta.taStieovneroafltdhaereknidmoepglualsamric 2re1s6i3d0u4al,bLoidveesr.arHeeppraetsoecnyt.te.SiCxe(n6t)eprreodbhaebplaetpoecryotxeiissosmuersrocuounndteedd.by hepatocytes on all mreatrigciunlsu.m Bainldencuacnlaleiacruelniavreeloepveiadreenstliagthtthleyrdiiglhattaedn.d Sbeovtetroamlmraersgiidnusal. bIosdieensdaorpelparsemsiecnt. No lipid 216305. droplets are present. Liver. Hepatocyte. HFeopuarttoeceynt(e14a)ppperaorbsabsliemiplearrotxoiZs1o6m3e0c3ouanbtoevde.. At top leftis Nacoenltirpaidl dvreoipnl,etlsinaerdebeyvaindeenntdionthtehliisahlecpealtlocayntde.conSteaviennin(g7)apseergomxeinstomoefsacnleerayrtlhyroicdeynttei.fied. Zhe1p6a3t0o6c.yteLsi,vearl.thHoeupgahtotchyetmei.toTchhiosndcrelilaisstislloamreewshtaatinliingghtfearirsltyadianrinkglyt.h`aCnelplreovniotuhse far right may be an 216307. Liver. eHnedpoatthoelciyatle.cellA.llTmwietlovceho(n1d2r)iparoinbatbhlisecpeellroaxriesdoamrekslycosutnatiendin.g. There is slight dilatation of the endoplasmic reticulum. Six (6) peroxisomes identified. ACvoencrlaugsei9o.n0s:perEsosxeinstoimalelsypneorhmeaplathoecpyatteo.cytes. No evidence of increased lipid droplets. 03651 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6320-223 (EM 99.76 Animal No.: _105548 Treatment Group:_,15me/ke(mid-dose) Sexi Female Species/Strain: Cynomolgus Monkey Tissue: ___ Liver Block No(s). __99.7630 Photo/NegativeZN1o6(3s0)8.-:_2Z1166331019- Z16313 Significant Lesions (check one) _____ Yes _x no Interpreting Pathologist (signature and date): _-- iarialnlafrpytearsgn:ihg.ZhtFOixmEaaicgoinTnissvpe.re,OanrHtsehpoeaortdiogcahytntdeTaophrpeocmtoiinnercnatdobirplegacaatnnsoiisuslpu+se.brorsdpoirureyrd,oBysNiceiaspnpbshoepiartsoecdvyitdeeesnotrant Pleoircneaaanr daembrieizss.e:dTsmwnipeetnactacymhg-on,endlryAissbouwsnohdmiaecnhtaSperEedRisfefnicpaurltetbseonutctlne"a4:tr40hloey'ticfolepoeecnksi".ierTofhmreohmrepamrolsemi.byenascsodemfrrocmfplrneattsysareseomdeck, Zinitean, Seven Lyniovpeoe.HeoTpharteolecifynstemoefa.(tl2lh9Te)0hippsemhroheotdoxigiersuaompmp:esszaieedxehpnitibiifdtioddsr.oicpglehtysdirltaetaptreieosneontf.thAeneedorplrsioc reesctpuamaon7d0 ZmSiAetSvoeHcnIhtDoen,dernfi(ao1.v7r)PpeHereropoxaxiiosscooymmeees.sncColtreaycrsolauynlitldeoednditiinfnhtic.helidu.ssRihoaenpnsadtionomcsyodem.ekmaintdociheognudlira sansoclcasiboonaslsfimneinpgeinr vlZZerUAastI,,LLslLinigvhterydclfHeaipnaodtnoicgyhotfte,tmhaerOegnniednoslpawlriagteshmaiancddjravcteecnrutlshuesmpmaatalonlcdeyrtneius.iidStidsrcoenpeclnleot(sp1ea6.)epFrporrveasobelmneimpnetwrhoeexcieystoocpla:sm. ue renadopplhasemLiicoveprre.lteiHcteuplauarmte.ocpyrNteisene.ent(T9ih)niphsreohbcaebelpelopaeyr.oitxibTsoohrmedeeesrciesoduhbngysehsdjdslceinstiohneopfathteomoenen smammismeoccpoorurn, foZmUGeRa3E1rn2e..eaanLnigdvaeti,hheeHuiebpoatttomocmyatgeef.itoToffwtohhemepcdelhi.uom-TtshioezregdairrsanasdgophsmehevlernaalteisroalnslhecolelildaegdennrdoRpoolcpeesa.asrAerepveiilcdeeocnrrtm,iinoi tshuesyis canaliculus i contcilnesaoemneveelloepcet.ronA-daernsee mlaytseroisaol.me iFsouprrteeseennt n(14)copesroprnotxoimmeistys1ouhrsese i y17o.0 pesrtooxins:omEesssepnetrihaellpyatnoocrymtae.l hepatoeic. No ssbsanial Teese Tn id pies socAverage 03652 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6320(-EM299.2763) Animal No: __J0sso7 `Treatment Group: 0.75mg/kg(hi-dose) Sex: Male Species/Strain: CynomolgusMonkey. Tissue: iver. Block No(s).: 99.769 Photo/Negative No(s).4:3_44131415 Significant Lesions (check one): __X Yes No Interpreting Pathologist (signature and date): aFenadtmuraensy:s4m3a4l1l1,to mLeidveiru.m-Hseipzaetoclceyatrelcipoidndrtopaleiatsns.iinTnghlegerevearpypelaarrsgetcolbeearalnipiindcrderaopsleeitn Athefeawmosucnattteorfegdllyycsoogseonmea-sroasnedttpeergroaxniusloemse.sSneovteerda.l fNoicineof(9E)Rpearpopxeiasroimneesgucloaurnltyedd.ilated. d4r3o4p1l2e;tsLiinvetrh.e cHyetposaotloc(yatpeprcooxnitmaaitneslayl1a2r5g)e,nmuomsbtebroeifngsmvaelrly tsomamleld.iuAmb-usnidzaendtcglleyarcolgipeind 4234G1-3r:oseLtitveesr.is Hperepsaetnotcyitnethceonctyationpilnagsms.eveTrwaelnvteyr-ysilxar(g2e6c)lpeaerrolixpiisdodmreosplceotusntaendd.many lsmoawlelrerlefdtroopfletthse.phSootomgeraipnhte.rstiStioamletirsessuiedcuoanltbaoidniiensg psroemseentc.olMlaagneyn fgilbyercsogisenprreosseenttteast the present 43414; iLnivceyrt.opSlaesvme.ralThmrieteoc(h3o)npderrioaxairseomsehsowconunwtheidc.h appear essentially normal. Some. anpopremaarlndoernmsael.grIannutlheescayrteopprleassemntthienrtehaermeamturlitxipalnedtshmeaclrilsitpaide darnodpleentsv,eluospuianlglymembrane surrounded by 43415; Liver. fine dense granules Hepatocyte with a (glycogenorribosomes). bile canaliculus at the bottom margin and an interstitial fsiibzreodblcalsetairclcieplild adtrotphleeutspp(e>r17r0i)g.ht.RaThnedohemparetsoicdyutael cboondtiaeisnsaraebpurnedsaentt.smSailxl(t6o)medium- `peroxisomes counted gCloynccolguesni.onAsv:erLaigpeid1a1c.c0upmeurloatxiiosno,memsodpeerrahteeplayt-osceyvteer.e, hepatocellular. Increased : 03653 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6329(-EM2992.763) Animal No: 105534 `Treatment Group:,75mg/kg(hi-dose) Sex: __Female Species/Strain: CynomolgusMonkey Tissue: ___Liver Block Nos). 99.76. Photo/Negative No(s).L:4_L7498802- Significant Lesions (check one): __X Yes ____ No Interpreting Pathologist (signature and date): eaFnebvauetnludorapenset:annuLdmab7oef0r8ss;omoLfeivmEeiRrt..ocHhSeocpnaatdttreoircaeyadtnerdessEuiRrdur.aoluTnbhdoeedrdieebsiysamarideljpdarcedesineltnatth.aetpiJaoutnsotcoyfotntehse. nTutclceoantrains droplets evident. Four A799; Liver. Enlarged (4) peroxisomes counted. view of five mitochondria. e distinct lipid Mitochondria appear essentially tmnhoeermmnbaulrc.alenueSsse.vaerpapleadrennosremgarla.nuAltestahreeripgrhetsesnitdeinistthheemmaitlrdixl.y dTihlaetecdrinsutcaeleaanrdelnivmeiltoipnge and i`LnTAh8teh0ree0:cayretLioavplelsrao.samHbeauppnapdteaoancrtyttgoel.ycconoAtgaefinenwggrslamynaculollgesecnlienagrrtahlneiupcliydetsdorpwolipatlshemot.ustaAaredinpsrutemisnbecenttrliiopnfidt"hcelecayrtoarpelaass"m margin. Two (2) peroxisomes counted. droplet "L4pBo0cLk,etsL"ivienr.theHcepyattoopclyatsem.(aTphperroexiamreatneulmye5r7o)u.sSsommalelctoontmaeidniusmo-mseizweidspryarleafmieeldlar dmraotperlieatls,aarnednostoamsesghlayrcploygednefgirnaendulaesscalepaprearroutnodbeliipnidtdhreospelseptascuessu,aTllhyeamrea.rgFionusro(f4t)hese: peroxisomes counted. lLi4p8i0d2d:ropLlievtesr.anHdepotahteorcyratreefaipepdeaarresassiwmiiltahrgtloyLc4og8e0n! iwnitthhescoymteopslmaaslml(taopmperdoixiumma-tseilzyed29). tShormoeugchoonuttaitnhescoymteopwliasspm.y lTawmeelllvaer (m1at2e)rpiearl,oxTihseormeesarceouanltsoeda.bundant glycogen granules A`Cvoenrcalguesi5o.n5s:peIrnocxriesaosemdesglpyecrohgeepnationctyhties.animal. Increased numofbglyecogren granules. C6365 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 6329(-EM2992.763) AnimalNo:___J0ss40 Treatment Group:_75me/k (hi-dose) Sex: Female Species/Strain: CynomolgusMonkey Tissue: Liver Block No(s). __99.76-13 Photo/Negative No(s).L.4_8_L0498-13 Significant Lesions (check one): __X Yes No Interpreting Pathologist (signature and date): -_-- LFpoheoalttaourggrereaslp:ihp.i4d8Adr0bou9pnl:edtaLsni,vtberuE.tRnHaoenpdatotgoolmcyyactonegy.einOngnrtlahyinsualhseemspaaaltrloecspyertgeesme(ensntpt.poTrfhoexmirumelaerse seaptreerseedtsmalils LACdByartIkoOpr:lesaLisidmvueacrlo.nbtoaEdininlesasrsagoreemdeepvEihdoRetaoatgn.raFpihfotefense(v1e5r)alpemriotxoichsoonmdersiac.ounNtoeda.bantoerlmyal1i5t)i.esAnoftoend. (a2p8p1r1o;xiLmiavteerl.y 4H1e)p.atTohceyrtee icsoanbtaudinndssacanmttutlegtrlieypdclgeolgmyeecndoigineuntmhgetrocaynlutalorepgsle.acslme.arFliipvied(d5r)oppelertosxisomes counted. cLlyaArtBgoepLl:calsemaL.rivleiTrpw.iednHdterypo-apctlieotgcshy,ttet(.o2o8S)niupmmeierlroarxoiutssooLtm4oe8sc1ocuo1n.utn.HteeTpdha.etroecyitseabcuonntdaainntsgmluylctoipgleen simnatlhleto TlihLpAeiBrdLe3d:riospLmliievntesirm.aarlHeeptproaetmsoiencltyd.tdeiAlcnaotnaettnaidoionntshoefatlbhiuaenldEcaeRnltiamnidptronecushceolnnetadrratieanthvaeenltdoEpoRf.thOenplhyoatofgerwapchle.ar bodies are present. Two (2) peroxisomes clearly identified. ope. Scattered scaudual gCloynccolguesnioinnsm:osMtilhdeptaotomcoydteersa.teAvienrcaregaese12in.5cpyteorpolxaissmoimcesippeirdhderpopalteotcsy.teT.ncreased 03655 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: _6329.223 (EM 99.76) Animal No: __]0555 `Treatment Group:_75mg/kg(hi-dose) Sexi Female Species/Strain:CynomolgusMonkey. Tissue: ___ Liver Block No(s).: 99.76-14 Photo/Negative No(s).L.4_gLl4a8-18 Significant Lesions (check one): ___X Yes _____ No Interpreting Pathologist (signature and date): --_-- ctFoheenatthaueirpneatsgo:lcyyLcteo4.g8e4nI,ngrtaLhnieuvlecerys.t.oHpHelpoaawstemovcteyhretr,ee.aafrTeehewmruhelativispealsedorimaleraetefldiaemcdealanlraalcriacsmaatlthueasrtimaaotlshitnelytthaoeppnp,reiagTrhhtteoorf disisstliingchttldiipliadtadtrioopnloeftts haerenpurcelseeanrt einnvtehlisopheepaantdocEyRt.e, Shoowmeeverres,itdhuearlebaordeiessevaerrealprleispeiadt. e No pdreorpolxeitssoimnetshceopuenrtiesdi.nusoidal fat-storing cell (Ito cell at the top left. Nine (9) eLsas8eInSti:alLliyvnero.rmaEln.largementof aclusterofmitochondria. These organelles appear (cL4ya)t8op1pe6lr:aosxLmiisvceoormn.etsaHicenlpseaaatrboluycnyidtdaeenntctiogfnilteyadic.nosgaSeesnviengrrgaallneuslmmeaesl.dliudSeamvr-eksribazoledrdieescsildeauaparplleibaporiddtiodebrseopplrfeeitsp.esnotT,fheFour `mitochondria. cLyAtBoIpTl:asLmi,veorf.tenHempaaktioncgytceleaaprpaeracrasssciomnitlaairntiongL4j8us1t4.glyTchoegreenigsraabnuunledsa.ntSgelveyrcaolgecnluisntetrhse Of RER L818: pLrievseern.t.HeOpnaetoscmyatlelcloinptiadidnrsopmluelttipprleesernatr.efFioeudr"tepeonck(e14t)spoefrgolxyicsoogmeensgcroaunnutleeds,. No lipid droplets present. Eleven (11) peroxisomes counted. Conclusions: Increased glycogen. Average 9.5 peroxisomesperhepatocyte. C03656 IIL. Transmission Electron Micrographs 03657 = "DraCkoAvnacniclleaSrtyuPdaythNoo.lo6g3y2R9e.p3o2r3t Figure Legends mMaegansiufriecmaetnitonb.ar Porninctacmhagpnhifoitcoamtiicornogisrainpdhiceaqtueadlsonontehemibcarcoknof(0e.a0c0hmuphmo)t.ograph. The aFrieguirdeen1t.ifLieidvearn.dHoetphaetroncoyrtmeaslhoorwgiannegllneosr.mVaelnciyrtaolpylatshmeimcicorrgoavnielllloeuss. bSoordmeer peexrtoexnidssoimnetso mthaegnpiefriicsaitniuosno.idal space. Animal No. 105517, 0 mg/kg/day (control male), 10,920X Eiargtuirfaec2tu,al Ldiivleart.atiHoenpaotfoscoytmee.roSuegvehreanldloippildasdmroipclreettsiacruelupmr.eseSnot.meTheextrreaciselslluilgahrt collagen pisrepsreenstenltiniinngthteheinstienrusstoitiiduimntinhethleouwpeprerrirgihgthtcocmoemerorf.tAhen pehnodtotohgerlaipahl.ceAlnl inmuaclleNuos.is 105544, 0 mg/kg/day (control female), 11,200X magnification Eigure 3, granules. Liver. These gHreapnautloecsywtiet.hiMnitthoechmointdorchioansdhrioawlinmgatoruitxerarmeenmobrrmaanle,ancdriastraee,sitmeastroifx and mcaaglnciifuimcaatciconu.mulation. Animal No. 105519, 0 mg/kg/day (control male), 112,000X dEriogpluert4se.vaLriyvefrr.omHespmaatlolctyotevesrhyolwairngeg.inScerveearsaeldrleispiidduadlrobpoldeiteascacruemuplreasteinotn.. PLeirpoixdisomes are scare. Animal magnification. No. 105507, 0.75 mg/kg/day (high-dose male), 10920X pFiegruorxeis5o.mLeisvearr.e lHaebeplaetdo.cyAtneimsaholwNion.g1n05u5m1e2r,o0u.s7l5ipmigd/dkrgo/pdlaetys(ahnidghp-edroosxeimsaolmee)s,. 1S0e,v9e2r0alX magnification. pFiegruorxeis6o.mLeisvearr.e lHaebeplaetdo.cyDteeswmiotshommaensyasnmdalablitloelcaragnelilcipuildudsroispleevtisd.enRtepartetsheentraigthitv.e Animal No.I05536, 0.75 mg/kg/day (high-dose female), 11,200X magnification. Einigtuhreec7y.toLpilvaesrm.. HAenpiatmoaclyNteo.wi1t0h55m4u0l,ti0p.l7e5lmigpi/dkdgr/odpalyet(shainghd-adbosuendfaenmtalgel)y,c1o1g.en20g0rXanules magnification. | 1F0i5g5u51r,8e,0.7Li5vemrg./kHge/pdaatyoc(yhtieghc-odnotsaeinfienmgalne)u,me1r1o,u2s00"pXomcakgentisf"icoaftgiloync.ogen. Animal No. 03658 - DrafCtoAvnacniclelaSrtyuPdaythNool.og6y32R9e-p3o2r3t ESimgaulrlel9i.pidLidvreorp.leHtespaarteopcryetsee.ntMiintotchehosnudrrrioaunsdhionwgicnygtoosuotle.r mAenmibmraalnNeo,.c1r0is5t5a1e2a,n0d.7m5atrix. mg/kg/day (high-dose male), 112,000X magnification. Eaingdurgreanu10l.esL.iveTrh.e Hneupcalteoucsyties.preMsietnotcohnontdhreiraigshht.owAinnigmoaulteNrom.e1m0b5r5a3n4e,,0.c7ri5stmage/,kmga/tdriaxy, (high-dose female), 95,200X magnification. Eigure 11. Liver. Hepatocyte. Thereis moderate accumulationofsmall to medium- sized lipid droplets in this hepatocyte. `dTohseeemnadloep)l,a1sm1i,c20r0eXtimcauglnuimfiicsastliiognh.tly Only a dilated. small nuclear profile Animal No. 105514, is evident in this cell. 0.03 mg/kg/day (low- Figure bodies 12. Liver. Hepatocyte. make up the majority of Mitochondria, endoplasmic this hepatocytes cytoplasm. reticulum and A few small some dark residual d`rmoiptloecthsonadrreiapraerseenptreisnentth,isbcuetlln,oalctlehaorulgyhiadesnitnigflieablliepipderdorxoipsloeimstesprareesepnrtesienntt.he Nsuobjlaipciednt cell at the bottom of the photograph. Animal No. 105545, 0.15 mg/kg/day (mid-dose female), 11,200X magnification 03659 = DrafCtoAvnacniclelaSrtyuPdaythNoo.lo6gy32R9e-p3o3r3t IndexofLabels for Ultrastructural Structures Abbreviation Structure BC co Cr D EC G GR LD : MMv MX N om P RB RER SER CBoillelacgaennaliculus Cristae Desmosome GEnldyoctohgeelnial cell Granules Lipid droplet MMiictroocvhiolnlidria Matrix ONuutcelreumsembrane Peroxisome Residual body `RSomuogohtheennddooppllaassmmiiccrerteitciucluulmum 003660 Big nes She a May VESTCOPs YAVAMABIE "g cj "ian Gi ool ge lie CsSieh SS feoS c l pI oSEpR re rE We Ca g eeESERNEe G RSEc AaRe eEeYeS Av sE e a S4LS 5R8R S pr,oIe ET Ure a NaSeBnC lUEee jiALPBEta a SSe C NEe Bane BFiE) E weSepapnigrs N lebe inJn , Tut fi = Ske TE RENC Se Etaal adi: haan Rr eR ore eg ae y a es Rg | APPieE WT L eaaE ny pe Ren SAN) B | SESS an7h t el fe aa p le noQMe,Si n5he 0Sol io he Beadra : Eead LW ee ERED = Wn SANIT Re MS Sel oe AYas io HEo RL EREETYYL DTT RS eAAe gles BRIERE COWIE 03661 . @ BESTCOPYAVAILABLE : Le EE a yssee raOl n ees2BBeenogfhy TE TTry ad Bffirn ane oysabSal ge nF SRG LeTe 8 | wy Ertan Sw Ray wot Ba rie da 2 fi lB o ULi RI iS , SS RE E ND i ETCR AN E| Bi Y a WB ae. E S SRr EaRieth 5sh Seg s MRGAa lrorne CCR C LE E SE Bi RT tb(riaN aNRffcs PE ORpNR S2s TTRYAVERC L SOY h ae E oR a Ea n | ERB ASWRR RS N ER E h RoEsD0n aSe re L UT N EFe,l,Lo aEE oI T roee h Wel eeis te Fe Gl ey of iyNa AS e NEP Pak 2 or Eg ns LET 7 | E S 31 TfrI SM a R MM INNA RsS=E S S BE e ASR U E CRfAroe st vy S SL L 1 EE - Sea SR AEE Cnt Nem Snail ad onI a) (C2 REA TORRENS) AR ER EIN TE Ea TTC a ' "an AL el. Tams tae wr tei AR HK : 03662 BESTCOPY Ava apy an" - pe FIAT, Taio Ha LIER 2 APE is HR uGogh RR ISS ILE AE R SRS EES TRiE ak # On. - NNTe + LFRoteh er anid &Ger E EEF UAS od 5 Ea Be, Ne I, Sas Fas id AReTs 3 ERE < CRALS a og F CABREG, ee ST S EIEe N CS 5 Sng 5: LJ SES nf age) es CA SH ER OR FREER GT 5b, BG RRlSa ER SRR SEE GE VRE RES. L ASieR for EBYr TSE RIhLAaE ardNEi La Mre S.L iaTbhryagiLEtSei,n 0 CORRE (ORA IRE. JR EESR STEN RBERoR CaHEEN ACRESPr.odico - 5) PRE Lod Aa rRNAERR es ts OS Si RRR 1 Tong ot CARRERE,| D gRE EAS lPO hEr, sS EOaEERyE N T uhYTeN O A RC N AM M E id , I E EgReER RryRARREE) MR 7deeCCLSx) WTeOSW EHRN ATEhE I BYERS A AN RR BR, rE = L-- 03663 Fk] ST COPY AvatLapyg. . CF SLA EL ERE Bry LE A GENEPS SJE 1 fade id oye. Fy) he [Sas ERAo aesesSi GaU3WAR REATNTREiEEeT.E SSBRLR RooA:od 2 BE Lo wi $0 ; o NER Le - BN 3 TN JE & ko Be dn oF Lo 2 ~ EAERRIEN,, fef NER aS Cr BN IIEE tI NIG Ii C Ea N > SPERE E BE TSA A 4 TE aS o TeA dd i S1N wy} CR 0 ese ATE } 3 Sn) Coad I he 2 EN rae gl "20d RTaR BeReChRl T NT y y LI ai SRA Ca CY 8 wp& ipdB RRSEE rSf2SR Rx A or ok2 B rt Date A OEYDEIIR SIER ERS hoa HE CNEL LAs ogFo EN 4 2) ReRA Mes E ColaieSK eS W OPFRYA VOR oNAgEEE N ueoa ES APe SN a BE IRKhSLEeDeArJAocre a UE AE NE i 03664 L FNEEaEiAESnTCOPgYAVAR ILABLLE. FRE Ela gid er NC edn S12 ll I= Sates Leite ekAeCAPARNeELSPE FaRiEn SaCka,d,aw:saos) iedaShaRlEBfi aRgae,bN#Ed0uBEl4al D E ty ee st a bBK mHg e E Te ASoPsoiRaEW h FAA y e NIE RpdR a R ie 5= AN ! ey PARE a OTe ge oso FealitAXCP EL A ans Sg ee a Soe [ EpeeosE o T h2 ea os ByRsEa SAyR an : se PE g set FEE hei Ko LSeLDpoRoEeAis 7 A Le = n ie oo TLRS Sn8. =. rrao> n;3] 03665 STOOP LE _ eo BX A $m AodETR R AAoi Ca FP) Cia aN rR Fa s. gCEtRRiNA Ea SESR P Tw3 SonaPa lA 5 LWFo EA3E e LTe t g Wt a Jdiy e 55 2 PRE Re Ra p RAAFaXye FSuoASrPeo am a p bSdrefah BCmpee lE GdE sR FiEcW5,is ny ia2gXSR eon Gel PE Ea Fr Seton Rrra RE A jr) |a oF fgoe a gA hh ER ef irerann 1<2 TgreS atnd ST REEaNUR cFahnut Zin WF Login 2&7 RERe aR RAE or] n Gi R, ks bE 3 2 Weegy BBEa Ys Fe : RR CA a Koh i: a ah WERNERX Pact GE Ly 49 : - Ey 594 Ea : 2 03666 BET GUT AVAILABLE . Saves SY UY a En fhaR CTs % Bort | S aHA aLpE -..8 ER Eig iW pr EN SOY6% Cadb p= ' 87 od ZS A 3 plc Pe i 4 va PEN Sh Piilodlaw dws iLeI eiA aCgT rlGiS SR ER Es EE A gepedATAIh SEE ate yy oa iS ea S CIaE Lea yELe e o ReS lo sNa D , op-- s Lo pw. CE Et nh WP eles hy od CN 8 E Ti E Ta ; Ele RtEil... lS C ae SE Ws EN on ol .theatd ARE TOR TI coven ooN pighsNo|w . @G DEwgE aliWn RI BL=Em. SEER gs ag REUSE5 CIRO gE 2 , . de BRE, rin Ye Lis, CECE pal bo WT E oe oR & 1 RPE piGE iON ah A BLS hae EES 200 ape Nall s ood FY ag = ee Foye ne IE PENS eon Bagel SEY XA fo 3 Jo ge LY. oa kT elagin. Berd e4r) TallFiorn S adoR AEER 5a5RWe3 le ov Boh EWC Ee x p5 oo Wgss RSCRREeUalrUFe A5 E 418iSi g5 y 5 Ha tEs 2 A Ay OX Sh ail J Wr PP a GE GON Sodas Ae RE AE P; RTT ies.SJBR RE SWale y a A TE>* a aie Ra i B S, g YSt"eHAkdr,aA rSaotils GB aN on PR pGaO8]ER 8i, a Sink A 3 ES BriE bsitEl2R , WW B a y S RSE R EBraz Ret"R i E e l1W 3 SUE BR Cede AS SNe 4 LEBEN REE x 03668 BEST COPY AVAILABLE ] ow Sh ci . ERD) CY Wa E ; a ee SR Te i i iy oy 2 REr EESEK pn Rn "33 oi ay Ka oi 2 gr FE - ', TR Fo, A Sem - AE } Rs * KS RF": ARI, LER 3 PR ] ! SAR AS)Tpgwsy RE I fs Dor I~ ia A a. e SE ) Cg#4 Py <- ES i kd : : i2 5 TR- 47] Tone E3a oe A AARE BE" 5 A Kr WL aE Pian RES ] APr RR Ev S i LIERGRENRR: , 71 |" Ce i ; - L= ye PRN SRE . NE Tg ESRC. REE. Ren. CARRaERy AS oF ' Ce Wi. yo q Ag 3 J of3 7 Arr 3% Yo 5 Cd y- k ti BR On inte E C CSdR <q 03669 fa HaLI A RR IE BEST COPY AVAILABLE he on Cl Te =] . Fi RT Cel Ry Taga LE 1% FT TIE nF yRate Hr 3 See Sih : iyRa 3IE T CORH R eE f E wE t: CE ESECd C To Ee S RA Soi niyrHR i | oET S Sa eRSif shan Chobe a BY ELLLs LC OEAR N SAS E E Sein oneiod R oy r FNC Ei Tk ! ; oo ERE gn BJaaarrdeBRE9EES RAa SEtW,Y3CR OpRoeA EKENsl G eaE lr s Xo 34 r. D a Take i 24 BSDouiLdaiin,., a giriFeZeh eLSM E E r oSh. i E Beaaa pnatdT TE Fra AaL,2 E3I8E i)SiOa. SR Siw E i m oa a r a s AEMSE FhAoTEET E R R EE R a EN ECR oe BNA le Lela BT EC 2 PIER poe PAE TEER F i rWe S ge Sane bE SCs i Fr Sey: 9 { CxvCEeE e aPAEt NO PIE BLP FTR H a FJea ER ToeEe E oy n rs fi feos Sele En a EET Rn TIT loa | 3 Aree Sw 5 SE. RO 8. wes SE 0 . & } 3670 i Er ar WFCSPRL a Su Ti NL as cea B8 RiEe =Ei,aigStMy eRl YE STNRC5 SLE iTWR lRpaa poLie ege FreAe pNuaigl CNREE LD a Seas REA EgSeL Stull E WHS ATSRl<A IA EoCal SHER SB i RCE ST ol aA Se ER FE ASREAN so 2 TOE 2X S= EYASL BENTr3agRaYEh bTeasla So ) SER Za Ra IAT A REAiTReT Tsien G gPTR aE SR fT AmE Se SLWRE R C GE RR Bo EEN En At SY IR EEER EcRSLEt EENS TT NNREE TT Ce EN ga Te RE di Sl te og pRo g o DE AE y 3 Cg f i 5kTE A Reg Sy ED a a re i Jee L Eda a EUe R AO Te IIR eT SES GE r e Ua n EaRSsePYESLosTE Eg e y Bo NW, REC Sag WO als Ta BE Ant RT eesr EELos prINGei PTNnIRT EbLyRA TErR EEeRRESEYae r aTg an o ES AaDWoyA e E BS L AA ATTee SSaolFeLnTTS T a og a Te 003671 SEST COPY AVAILABLE A SB e C 8 <R EN a T ENEr b Ce ey etri N hAaiNE e eEaa 2) R RRL FRRCNLS olla Ee Sais han RR 4| cy Pe Pea at Sge SE eee eR 4 Erbe Te = eTSSaRY r X e Eh aE xC Ly cam en se F LRRRAe Sya hilr a 5 t yBEPeRlRaT w A yFit h- Si=ea = ST LronNg E fed So eoy= 0 5 b5L0E r30 AiATE SeEtSS R a Ne 2 aeGTRRE $i acy.aE)ES EL ie A RE NR Fs uo E R aN RR oN ess LS IRA R LTNA TI SE slyS pansdXE B a Wanwgf E T=CE gEN es GE NaW No L..TJ i 2 Wr CEE woM Ll E ANH rE Paile as =:Yl gYe 1858 os pS pE 8 e e paasees z, i, PER aa pa %t "ag bw 5 Ag iybw." Ed od | Tn& Evia a Pili a ou hire Ne a Sl 03672 IV.QualityAssurance Statement 03673 ' PZ 77 Pa4tChooloomgfyScpiAenscase oppcnticaatytonessiamIanitnearlnCoartpoiraotinoan l _--_-- == --, QUALITY ASSURANCE STATEMENT AssuranTcheisUenlietcatsrornemquiicrreodscboyptyhestGuodyodhaLsabboereantoirnyspPercactteidcaesndReaguudliatteidobnspyrtohme uQluaglaittyed by the U.S. Food and Drug Administration. PAI has a functioning andresponsive oQfuailnistpyecAtsisounrs/aanucdeitUsniatndwhtihcehirrreepsourlttsindgirreepocrttltsy:o management. The following is a record Date of Inspection PhaseInspected DfaotMeaFniangdeinmgesnRteported andStudyDirector an, 2/99 4/2/99 713/99 713/99 Data Audit Draft Report Audit Audit of Data from Additional Groups Final Report Audit 4/2/99 4/2/99 7113/99 7113/99 "= deWard, B.S., RQAP-GLP uality Assurance Specialist x Sponsor: 3M CorporateToxicology Test Article: PFOS Study Number: 6329-223, PAI Study EM-99.76 03674 s 4915 Dt Prospectuse Drive Dura ham. North Ct arolina 277o 13 e+e(9r1e9)e54s e4-52--57--+ (e9i 19e) 5e44.e377e8s eFAeX