Document JvE81EJ73DJd9jnRRz4OooJ12

'C__ Z Z -Z Z J Pathology Associates International A Company of Science Applications International Corporation /E|Rll.t~OSia> z^^^ An Employee-Owned Company PATHOLOGY REPORT (ANCILLARY STUDY) ELELCUTNRGOANNMD ILCIRGOHSTCMOIPCICROESVCAOLPUIACTEIOVNALOUFALTIIVOENROAFND LIVER IN CRL:CDBR VAF/PLUS RATS) ORAL (GAVAGE) PHARMACOKINETIC STUDY OF PFOS IN RATS PACILSITEUNDTYSNTUUDMYBENRUM99B-1E1R(E41M8-9091.339) 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 April 5,1999 PREPA3RMECDEFNOTRER3M, STC.OPRAPUOLR, AMTNE5T51O4X4-I1C0O00LOGY, 00154^ 4915 D Prospectus Drive Durham, North Carolina 27713 (919) 544-5257 (919) 544-3218 FAX Pathology Narrative MLiigchrtoMgraicprhosIcnoteprypraentadtiTornanFsomrmisssion Electron Transmission Electron Micrographs Quality Assurance Statement Section I n m TV 001543 I. Pathology Narrative 00154* Ancillary Pathology Report Primedica Argus No. 418-013 P(AATNHCOILLLOAGRYY RSTEUPODRYT) ELECTRON MICROSCOPIC EVALUATION OF LIVER AND LUNG AND LIGHT MICROSCOPIC EVALUATION OF LIVER IN CRL:CDBR VAF/PLUS RATS) ORAL (GAVAGE) PHARMACOKINETIC STUDY OF PFOS IN RATS PACILSITEUNDTYSTNUUDMYBENRUM99B-1E1R(E41M8-9091.339) SUMMMARY U(clotrnatsrotrlu),ct0u.4ra,l1e.6v,aloura3ti.o2nmogf/lkigv/edraayn(dhliugnhg-dsoosfe)raPtFpOupSsifdreonmtifdieadmisntcrreeaatseeddwniuthm0bers of pinedroicxaitseodmaetslewaistthtiwn ihceeptahteocnyutmesboerf ohifgphe-rdooxsiesormatepsuipnlaivneimrsa. lsQtureaantteitdatwiointho0f.4pemrogx/kisgo/mdaeys amnedmtrbirpalneetsheornmumitobcehr oinndthrioasewgeriveennot1.d6isocre3rn.2ibmlegb/kegtw/deaeyn. cDoniftfreorleanncdestrienacteedllualnairmals in tthheesseaomrpglaenseellxeasm. iInneldu;nhgoswamevpelre,ss,uthbeopptriemsaelncfiexaotfiotynpperIeIcplundeeudmaodcyetteasileadndevlaamluealtliaorn of bodies was evaluated. No significant ultrastructural differences were identified between lbuondgiefsrowmerceoindteronltiafinedd tirneaatleldlurnatgss. eRxaamndionmedtuylpteraIsItrpuncetuurmalolyc.ytes containing lamellar PROCEDURES The objective of this study was to examine by electron microscopy the livers and lungs from selected day-21 gestation rat fetuses in an oral (gavage) pharmacokinetic study of tPrFeaOteSd. aInnimadadlsit,iothnetoulatragsetnruercatul rqaulaelintdatpiovientesvainlucalutidoendfqouradnitfiftearteionnceosfbpeetrwoexeisnocmoenstrowlitahnind hsuerpfaatcotcaynttelsa,mmeellmarbrbaondeieasnidnmthietolcuhnogn.dLriiaglhcthmanicgreosscinophyepoaftopcayratefsfi,na-nedmtbheedqduedanltiivtaetrion of sections was also performed. Fttehosrrtouathrgethicpdlheaayormr2t0ahcepoovkseitnhpeiactriltceumsotnucadecyc,doa9ri0dlyifnebgmetgaoilneTneCixnrtIg:TC4aD2bldeaBy1Rs. pVriAorFt/oPLcUohSabitraattisonwewreithgiavemnalthee 1-1 0 0 1 5 4 ^ PriAmnecdililcaaryArPgautshoNloog. y41R8e-p0o1r3t Text Tablet. Dosage Levels, Concentrations and Volumes Dosage Group I II III IV V Number of Mated Female Rats 16 16 16 16 16 PFOS Dosage (mg/kg/day) 0 (Vehicle) 0.1 0.4 1.6 3.2 PFOS Concentration (mg/mL) 0 0.02 0.08 0.32 0.64 Dosage Volume (mL/kg) 5 5 5 5 5 McAaontcdllCDelaciovetweesdraerlffelrr-aooTnmmr-ussmetehclprteeicoefitnxefideanttguifvesoeteuns(sMdepsaecyrfDol2irot1twGeorerfolflpruoErpemMssuIf,,mivH1ee9Id7,li6IgtV)tee,asrtnsaadntpideosrunVb,dmolwusienatrtggeeedatnhgtodirnolt-uhispvlisi.ecrleSasdabammoanrppadllteeopssrlyaowcffeeolrdurening ealneicmtraolsn wmeirceroismcompeyrspioronc-efisxseindginanndeuetvraallubautifofenr.edSefcotrimonaslinofalnivdesrufbrmomitttehdesaelosnagmwe ith electron microscopy samples. Per sponsor request, tissue samples from selected pups were processed and evaluated p(TuepxntuTmabbleer 2fr).omThtheaftivdeamdi'gsitlitntuerm. ber is the dam number; the suffixes 1-4 denotes the Text Table 2. Animals Selected for Electron Microscopy Group I Control (0 mg/kg/day) 1199550054--13 19506-4 19509-1 19516-2 Group III 0.4 mg/kg/day 19534-1 1199553463--34 19546-1 19546-2 1.6Gmrogu/pkgI/Vday 19560-1 19560-2 19560-3 19562-2 19562-3 Group V 3.2 mg/kg/day 19568-2 1199557629--11 19577-4 19579-3 The lungs and livers were then processed into Spurr's resin for ultrastructural esexlaemctinreaptiroens.enTtahtiicvke (alrjeia)ssfeocrtifounrsthweerreeleccuttr,osntaminiecdrowsciothpytopluroidciensesibnlgu.e,Tahnidn esxecatmioinnsed to p(mtinrahaepolntpihtsvormaeomnrxiosiiscsmleiirccooatntgiueorrleanaylpsne,h9ycsw0tlroaoencrnfmeelmt)ipavwrtieecererfaoreaenrsnedcdcnouRtpltiu,aeen.lymlgnyCooweuelexdnnra'tteesmridltlieaonoakbendeudnl2c.a0iartR0rnha-deetmpepsr,eiaegsatshonnecidncfyitoecatpexatispanv,emtewruiegnhlltreeeridracdestsort,cornuslnetcaaatiruZnlryeeaidlsidsfwee9ani0ttthu0ifri5ea%sble wmmeaicrneruosagulrlmaypmchoaiurnnitzteeerddprffeootrrateeiaaoccnhhfocperhmnott.eorgTprhahepohntouagmnrdabpeahrneiodmf ahpleeporoanxtoaiscdoyemteseigasnnidantrehedecpotraradtnoescdmy.tiesssiwonaselectron Fpaorralfifginh,t cmuitcarot sacpoppryo,xifmoramteallyinf-ifviexemdilcirvoenrss,asmtapinleesdwweirteh phreomceastosexdylainndanedmeboesdidne, danind evaluated. 1-2 Ancillary Pathology Report Primedica Argus No. 418-013 RESULTS AND DISCUSSION Individual interpretations of light microscopy slides and electron micrographs for each alanbimeleadl aarnedsahroewsnhoinwSneicntiSoencItiIo. nSHelIe.cted representative electron photomicrographs were Light Microscopy A summary of the incidence and severity of light microscopic findings in the liver is esglihorvaoseniwrnusno.lapiTrhnihtiylTeiceosxgeftvrtaTheneraiubtclylyaetrooi3ftp.ytlhaTwisshamesfriodnefidwfihfnuaegsspeaialntnyoccridneyiacstesrtreseiadbisnuientdterdaeinaditcnoeiddsmeer-onarsctestelaacatnoenimdmd pfasaaelssrvheegidroiivnwtey.intoHhf1ec.e6pooanosttirornoc3ole.p2lrhlauitlliacr mangim/kagl/sdagyivoefnP0F.4OmS,gb/kugt/wdaays.prCeydtoompliansamntilcycpleearirpinogrtaolfihnep1aatnoicmytaelsgwivaesnp1ro.6mainndenint i3n caoccnutrmolulliavtieorns. oTf hgilsycmoogrepnhionlohgeipcaatlodceystecsri.ptIinonthiiss ustsuudayll,ythaessioncciiadteendcwe iatnhdthseevneorritmyaolf cytoplasmic clearing was almost inversely proportional to the occurrence of eosinophilic granularity. Thehme alitvoeproiisetaichceemllastoaproeieptriecseonrgt awnitihninratthfeetsuisneussoaindds ntheroonuagtehso.utTthhues,lilvaerrg.e Enxutmrabmeresduolflary hgreamdaetdopasoimesoisde(rEaMteHto) mococduerrraetdeliyn-saellvearnei.maTlhs,eisnecvluerdiitnygocfoEnMtroHlsw, aansdinwcaresausnedifoinrmthlye tfreetautseeds ganrodunpes.onRataensd. oTmhemreitoaspepseoarfehdeptoatboecyateslsigahret innocrrmeaasleininrahtelpiavteorcs,elelsuplaercimaliltyotiinc figures in the animals given 3.2 mg/kg/day PFOS. Text Table 3. Incidence and Severity of Light Microscopic Liver Findings Microscopic Finding (number examined) Eosinophilic granularity, cytoplasmic, increased minimal slight moderate Cytoplasmic clearing minimal slight moderate Extramedullary hematopoiesis moderate moderately-severe Mitotic Figures, increased minimal slight PFOS Dose Levels (mg/kg/day) (50) 0(5.4) (15.6) (35.2) 22 1- -33 i - - 14 - 1 4 2 1 -- 5 5 4- 1 1 -- - 14 5 2- -1 2- 22 1-3 0 0 1 5 4 ^ PriAmnecdililcaarAy rPgautshoNloog. y41R8e-p0o1r3t Electron Microscopy Fevixidaetinotninofththeelitvisesruceosmwpaasreledsswtihthanthoepltuimnga.l fLournegleicstrionnhemreinctrloyscleospsyd. eTnsheisthwaansleivsperecainadlly cdahlelatoarwialcsotbefrecitzyteetodrpibnlayfsilcmtlruiacmtiooprnignoagnfoethlfleelasfr,igxdeailtoaivrtgaetaiinonentolloetfsh,eedntidissocspoulnea.tsimnSuiucoburoseptpitcilmauslamulmafixmaanetdimotnbhrewannauessc,leloarss of cernivstealeo.peT, hgerapnouolrarfidxeaptioosnitsofinmtehme bmraitnoecshomnaddreiaul lmtraastrtirxu,catunrdaldailsasteastisomneonft omfittohcehseondrial pstrreuscetnucreesoifmppeorossxiibsloem. eFsixinattihoen,hheopwateovceyrt,eswaansdstliallmceolnlasridbeordeidesadineqthueatleuntogaasnsdestsofmorakthee general comparisons between control and treated samples. LIVER pFCriogonumtrirenoseln1(t0aenmnddg2o/.kplgHa/sdempaayict)o.rceytSitceuusblccuehmlal.rualCcatrleufremisatptiuicnraeglslyoofcftochnoetnaltiarnroglneuhomerpgearatoonucesylltemessit(aomrceihtodocenhmdoroinandsartinraad,ted in rough endoplasmic reticulum and peroxisomes) is indicative of poor fixation. In these cneoltlsberocauugsheeonfdsoupblaospmtimicarleftiicxuatliuomn.wMasiteovcihdoenndt,ribaugt esnmeoraoltlhyeanpdpoepalraesdmdiacrrketaincdulcuomntwaiansed sficxaatttieorned. dDeinlasteatdieopnoosfitsenadnodpslaosmmeicdirleattiecdulcurmistaaen,dbtohtehnaurctilfeaacrtsendvueelotopesuwbeorpetiamdadlitional gahrleytpicfaaotcogtcesynotepfsap.rotiFocorlerfsit.xhaePticeoornon.xtriTosohl melivefiesnrews,getrrheaeniaduvelaenrrtaimfgieaedtenrauinmadlbiqenurtaohneftpicteayrttoeodxpilisanosmmfreoisms ccrooeunpnsrtieesstdeennpttearwtiviteh rhaetplaivtoecryitseaphheomtoagtroappohieedticwtaisss4u.e2, paenrdoxniusmomereosuspehrecmeallto(TpoeixettiTcacbelells4)w. eFreeteavliadnedntnweoitnhaitnal the liver sinusoids. Text Table 4. Quantitation of Hepatocellular Peroxisomes 0 mg/kg 0.4 mg/kg 1.6 mg/kg 3.2 mg/kg Animal Number1 of Number Peroxisomes Animal Number Number of Peroxisomes Animal Number Number of Peroxisomes NAunmimbaelr Number of Peroxisomes 19504-3 3.2 19534-1 12.0 19560-1 11.6 19568-2 6.0 19505-1 3.0 19536-3 12.2 19560-2 12.8 19569-1 10.6 19506-4 4.4 19543-4 8.0 19560-3 10.2 19572-1 13.2 19509-1 5.2 19546-1 13.0 19562-2 10.6 19577-4 11.2 19516-2 5.0 19546-2 5.4 19562-3 20.0 19579-3 21.8 Mean = 4.2 Mean = 10.1 Mean = 13.0 Mean = 12.6 1Average number of peroxisomes per hepatocyte for five hepatocytes counted per animal. r0the.4epramensgiem/nktaaglts/idvgaeiyvh.eenTpa0ht.eo4camyvteger/akisgge/sdhnaouywmPnbFeiOnr SoFficgpouemrreopx3a.irseoQdmuweaisltihtpaectirovnhetelrypo,alsttoh(ceTyreetexwt(e1Tr0ea.1bn)loewi4da)se.nhtAiigfihaebrlein 1-4 0 0 1 5 4 J PriAmnecdililcaaryArPgautshoNloog. y41R8e-p0o1r3t ultrastructural differences between the hepatocytes treated with 0 (control) and 0.4 mg/kg/day. p1e.6r mhegp/aktgo/cdyatey.waFso1r3a.n0i.mFailgsugriev4enill1u.6stmragte/skga/dreapyr,etsheentaavteivraegheenpuatmocbyetreoffropmerotxhiissomes ltirveeartms ceonmt gpraoruepd. wOitthhecrownitsreo,l glievneersra. l ultrastructural morphology was similar in high-dose waHnaidgsh6h-iiDgllhouessretria(n3te.t2hreemphrgieg/skheg-nd/dtoaastieyv)ea.nhiTmephaaeltsoaccvoyemtreaspgeafrrneoudmmwhbiiteghrhco-dofonpstereorolasxnii(smToeamxlset.sTDpaeibrflfheeer4ep)na.ctoeFcsiygitnuere(s125.6) lmivietorsc.hoSnudbroiaptainmdacl eflixlualtaior nm, ehmowbreavneers, wofetrheentoistsduiessceprrneicblluedbeedtwdeeteaniletrdeaetveadluaantdiocnonotfrothlese organelles. LUNG T0hmerge/fkogr/ed,amyo(sCt oanlvteroolli).anLduanlgvesoamlarplseespwtaewreeraetecleoclltaaptiscedanwditnhotpionofrladteeldinweiatthiofnixoaftive. alveolar and airway spaces. Figures 7-9 illustrate some normal cellularity and luilntirnagstraulvcteuorlai,l tpeurlmmionnalarbyroanncahtoiomleys., oTrywpeitIhIinpnceoullmaposceydtessep(PtaN. 2T) ywpeereIIrpanndeuommolycyidteesntwifeiered eidleecnttriofine-ddebnystehelapmriensaetnecdemoefmlabmraenllea-rlibkoedpierso,fiwlehsi.chLaarmeeclylator pbloadsmiesicrevparceusoelnetstchoenmtaainteirnigal sweecrreeteemd pintyto, athseifatlhveeolalamreslplaarcemsaatsersiuarlfhaacdtanwta. shOecdcaosuitonoarlblyeesnomseecrleatmede.llaSrubrofadcytavnatcouroles loarmtreelalaterdmlautnegrsia.l TwhiethtiynpaeirIwpanyeuspmaocceystwe a(PsNon1l)yisoccchaasriaocntearlilsytiicdaelnlytiffileadtteinnecdonatnrdollilnuensgsthe IaIlvpenoeluamr sopcaycteesa.s Ma tahniyn pmnaerugminoocfytceystoapplpaesamre. dTtyopbeeIcpunbeouidmaolcwyittehsoduitffdeirsetinntciatitveefrloammetlylpare bodies, and may represent a transition stage between PN2s and PNls, especially since ethpeistheelluianlgcsewllserreepferetaslenanteddhtaedrmniontablebernonecxhpiaonladredepwitihtehliauirm. . Additionally, some cuboidal Type II pneumocytes and lamellar bodies were randomly identified in these control lungs. cSoonmtreollasmecetliloanr-sliekxeabmoidnieeds nwoerleamaleslolaprrbeosdenietswwitehriencclaeparilllyariydelnutmifiinead, ianltthhoeuaglhveionlathre lumina. 0Fap.i4gpuemraerge/1dk0g.e/sdRsaeaynn.tdiaoQlmluyattlyhitpeaetsiaIvImepleyn,eatsuhmceoolnuctnyrgotelsssacamomnpptlaeleisns.firnoAgmlraeampnrieemlslaaelrnstbagotiidvvieeenss0awm.4erpemleigdi/sekngst/hidfoaiweydn, iannd only occasionally some lamellar material was seen within alveolar lumina. 1-5 0 0 1 5 4 ^ Ancillary Pathology Report Primedica Argus No. 418-013 tfs1yri.omp6meimlIarIgra/pttkonfgeet/tuhdamelaylcouo.cnnyFgttreisogsalumaranenpdsdl,e1oos1ctghcaieanvrsdeitnor1en21aa.tli6ellyldmu,ssgwtar/mikattghpe/ildnesaosay.ml.vLeeTaorhmeliep.esrleelsawernebtroaedticiveoesnuswildtereraersetidrdueecnststuierfnaieltidafelwlaytiuthriens e3s.2semntgia/kllgy/dsiamyil(aHr itgohc-oDnotrsoel),. loUwlt-raasntrdumctuidr-adlopsaethsoalmopglyeso.f tThheehcioglhl-adposseedlnuantgusrewoafs most Fowfiegtruhereeidsaelv1ne3tiofalinieddan1wd4istihellipuntsactramaptaieldlseaordymelefuinrmeitpiinrveaesaeqnnudtaanotitnvilteyatliauonsnmgimafilelplradamsctfoircuoanmlt. wtShaeosmhsieegehlna--mdwoeistlhelaianrnbaiomlvdaeielossl.i. CONCLUSION Ultrastructural evaluation of liver and lungs of rat pups from dams treated with 0 bpmQa(cneeugotirwma/onknxteagrtieoli/sstdnloa)atmt,cryie0ooe.a.nns4ttDe,orwdoif1filt.pwf6heae,iirnrtneohdonrhx0tc3eire.sep.4so2aamtmitmenoedgcgcs/y/aekkitnlgnegli/usdm/ddlioaacaayfralystrmeaa(idnthnedmipagtuhttbhrpelri-epadslanlioasevesmtesettrhp)wsoelPerifcnsFrmeouOemmitxtShoabedcmieadhnrmieouninnnsmetdditgbfrh;iiieeovahrdseowoenwifenge1rpciev.ver6eeernraoono,sxrtes1i3udds..6oib2snmoocumperemtrgs3inbm/.iik2enbagrlls/edoafy. fixation precluded a detailed evaluation of these organelles. INnolusniggnsifaimcapnltesu,lttrhaestprurecsteunracledoifffteyrpeencIeIspnweeurme oidceyntetisfiaenddbleatmweelelnarlubnogdifersomwacsoenvtarolulaatnedd. tarlel altuendgrsaetsx.amRianneddomulttryapsteruIIctpunraelulmy.ocAylttehsocuognhtasionmineglalammeelllalarrmbaotdeireisalw(seurerfiadcetanntitf)iewdaisn bmeotwrpeheonlocgoinctarlolyl ainddenttriefaiatebdleswamitphliens.alveolar lumina, no significant differences were noted SIGNATURE OF AUTHOR Diplomate, A.C.V.P. REFERENCES eMleccDtroownemlli,cEroMscaonpdy.TArurmchp., PBaFt:hoHl.isLtaoblo. gMicedf.i,xa1t0iv0e:4f0o5r-r4o1u4t,in1e9d76ia.gnostic light and 1-6 II. LighMt iMcriocgroraspchopIyntaenrpdreTtraatniosnmFisosrimons E1lectron Forms are typographically corrected versions of signed/dated raw data sheets maintained in archived study file. 00155$ LIGHT MICROSCOPIC EVALUATION Study No.: 418-013 (PAI 99-1 l Species/Strain: Crl:CDBR VAF/Plus Rats. Term Fetuses Animal No: see below______ Tissue: Liver___________ Sex: n/a Interpreting Pathologist (signature and date):____________________________ Dose 0 mg/kg NAunmimbaelr Microscopic Findings and Comments 19504-3 j 1. Extramedullary hematopoiesis (EMH), diffuse, moderate i 2. Cytoplasmic clearing, diffuse, moderate j 3. Mitotic figures, minimal, multifocal 19505-1 I 1. EMH, diffuse, moderate i 2. Cytoplasmic clearing, diffuse, moderate 19506-4 j 1. EMH, diffuse, moderate ; 2. Cytoplasmic clearing, diffuse, moderate j 3. Eosinophilic granularity, cytoplasmic, increased, periportal, minimal 19509-1 j 1. EMH, diffuse, moderate j 2. Cytoplasmic clearing, diffuse, moderate j 3. Eosinophilic granularity, cytoplasmic, increased, periportal, minimal 19516-2 i 1. EMH, diffuse, moderate j 2. Cytoplasmic clearing, diffuse, moderate i 3. Mitotic figures, minimal, multifocal 0.4 mg/kg 19534-1 j 19536-3 1 19543-4 19546-1 19546-2 | 1. EMH, diffuse, moderate j 2. Cytoplasmic clearing, diffuse, minimal i 3. Eosinophilic granularity, cytoplasmic, increased, diffuse, minimal i 1. EMH, diffuse, moderate ! 2. Cytoplasmic clearing, diffuse, slight : 3. Eosinophilic granularity, cytoplasmic, increased, periportal, slight j 1. EMH, diffuse, moderate j 2. Cytoplasmic clearing, diffuse, slight i 3. Eosinophilic granularity, cytoplasmic, increased, periportal, slight i 1. EMH, diffuse, moderate j! 23.. CEoystoinpolapshmiliicc cglreaanruinlagr,itdyi,ffcuysteo,psllaisgmhtic, increased, diffuse, minimal j 1. EMH, diffuse, moderately-severe | 2. Cytoplasmic clearing, diffuse, slight i143.. EMoistointiocpfhigiluicregsr,amnuinlaimritayl,, cmyutoltpiflaoscmalic, increased, periportal, slight Page 1 of 3 00155^ Dose 1.6 mg/kg | Animal Number 19560-1 19560-2 19560-3 19562-2 19562-3 j Microscopic Findings and Comments I 1. Eosinophilic granularity, cytoplasmic, increased, moderate, diffuse 1 2. EMH, diffuse, moderately-severe | 1. EMH, diffuse, moderately-severe | 2. Cytoplasmic clearing, diffuse, minimal i 3. Eosinophilic granularity, cytoplasmic, increased, diffuse, slight i 4. Mitotic figures, minimal, multifocal j 1. EMH, diffuse, moderate | 2. Cytoplasmic clearing, diffuse, moderate ! 3. Eosinophilic granularity, cytoplasmic, increased, periportal, minimal ! 4. Mitotic figures, minimal, multifocal ; 1. EMH, diffuse, moderately-severe i 2. Cytoplasmic clearing, diffuse, slight i 3. Eosinophilic granularity, cytoplasmic, increased, diffuse, slight ] 1. EMH, diffuse, moderately-severe j1 23.. CEoystoinpolapshmiliicc cglreaanruinlagr,itdyi,ffcuysteo,pmlaisnmimica,lincreased, diffuse, slight 3.2 mg/kg I 19568-2 19569-1 19572-1 19577-4 19579-3 j 1. Eosinophilic granularity, cytoplasmic, increased, moderate, diffuse i 2. EMH, diffuse, moderately-severe i 3. Mitotic figures, slight, multifocal j 1. Eosinophilic granularity, cytoplasmic, increased, slight diffuse ! 2. EMH, diffuse, moderately-severe | 3. Mitotic figures, slight, multifocal | 1. Eosinophilic granularity, cytoplasmic, increased, moderate, diffuse |i 23.. EMMitoHt,icdfifigfuusree,s,mmoidneirmaatel,lym-suelvteifroecal i 1. Eosinophilic granularity, cytoplasmic, increased, moderate, diffuse 1 2. EMH, diffuse, moderately-severe : 3. Mitotic figures, minimal, multifocal j 1. Eosinophilic granularity, cytoplasmic, increased, moderate, diffuse i 2. EMH, diffuse, moderately-severe Page 2 of 3 00155J Incidence and Severity of Light Microscopic Liver Findings Microscopic Finding (number examined) iEnocsrienaospedhilic granularity, cytoplasmic, mmoidnseliimrgahatelt Cytoplasmic clearing minsliimghalt moderate Extramedullary hematopoiesis moderate moderately-severe Mitotic figures, increased minsliimghalt PFOS Dose Levels (mg/kg/day) 0 (5) 0.4 (5) 1.6 (5) 3(5.2) 2-- 2 3- 1 31 41 -- 41 21 -5- 1- 54 1- 14 5 2- -1 2- 22 Page 3 of 3 001554 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animal No.: 19504-3_________ Treatment Group: 0 mg/kg. Control Sex: non applicable________ Species/Strain: CrhCDOBR VAF/Plus Rat Tissue:_____ Liver_____________ ^ Block No(s).: Photo/Negative No99(s.)3.9:Z-11Z5_1_75_77_88_2_- ___ Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________________3-10-99 Fcaenaatluicreuslu:s aZt1t5o7p7. 8C. yLtoivpelra.smHiecpoartgoacnyetelleasdjaarceecnltutmo pceednttroagl evtehienrawt iltehftinantedrvbeontitnogm.spBacilees of fine granular material. Mitochondria appear dense and have some dilated cristae. Five Zp(5e1)r5op7xe7irs9oo.xmiLseoisvmecerl.esacHrolyeupniadtteeodnc.tyiftieedex. hibiting similar cellular details as Z15778. Zero (0) ZA1h5e7m80a.toLpoivieetri.c Hceelplaistoicnyttheeatpoppearrigshstimsiinluarsotoidaabnodveaebxilaemcpalneasliwcuitlhuscliusmprpeesdenotrginantehleles. lower left. Mitochondria appear dense and have some dilated cristae. Three (3) Zpe1r5o7x8i1so. mLeisvecro.uHnteepda.tocyte and adjacent sinusoid containing two nucleated red blood cneulmls.beMrsiotofcpheornodxriisaomapepseiadrednetinfsieedw, iatlhthsooumgeh gproaonrufliaxradtieopnosmitaskaensdthdeiilratceldeacrriisdteanet.ifFiceawtion dZi1f5fi7c8u2lt.. LFiovuerr.(4)Cpeenrtoexr ihseopmaetosccyoteunitsesdu.rrounded by several other hepatocytes, with a dspiionlrauttiseoodnidcorcfisoptnahteoa.itnoFginorgauprah(.n4u)Mcpleietraootcexhdiosoenrmdyretihasrocaopcuypnteetaeridnd.ebnostetowmitrhigshotmanedgarabniulelacradneaploicsuitlsusanind top Conclusions: Normal hepatocyte. Suboptimal fixation. Average 3.2 peroxisomes per hepatocyte. o o issj1 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animal No.: 19504-3________ Treatment Group: 0 mg/kg, control Sex: non applicable________ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue: Lung________________ Block No(s).: 99.39-2_______ Photo/Negative No(s).:Z1Z517587387- Significant Lesions (check one): ________ Yes _____ X No Interpreting Pathologist (signature and date):___________________ ZeZFPsZccmZggmmcFlamaunyeynlrr1N1I1eaamiaaglaadt5dt55t5loactcconnlgoos7t77e8srprrtaepuuect8o8lo8o.u4hhlnlslllhca7p56ppaaa.aaerteoTesi-h.sh.rrhrvledvmnlLimhaaaeslbmmaedLLLgggPeu:,olwnraeaeucueunoNdiaccot,t.i.oannngfpieeetetelngghwgZ.rlrpanasAsflis.i..1natshal.aaPCiral.rd5slloncaiAAANe,tetnA7asltiensnnepoerne8p2ncodctentrb3.ilerttlmcajatolyelhuaah.llylowbdTlaevlocesigtnasrLtecheoifdolyeaebgtnooyeucphacurlnltnlevcnlrayontduloakglt.onegloullaossilfglogd.SncnamiylpilcnleiwlgsiupycalneeDnunsabsociprinuccgb.tsenajogsorsdhlsoamdrgoeegecpnTockiavfbsneediatatechtnecalehan.lcalnelivdiiivrbeeslsnslnrtaeaSellsleaeislaiyrtsmp.onutiaobaprisrvlagbwlelcaguioiNtabtjayuclnhcbehccaacuyoeludleePaecnuubuncllsblbale.dbNlolemodlieannolaolgiay2icmDaestitliisenadassdtlaotwtcnentapaoiaeowanelrp.dlililrlstlilttiatmAhyclaallphdhwhssiraaiprliee-neidcltrdpisblenwvyiiithjie-isfnrheoaakellaiIvuisglilcdirtemgIcsaakerh.aeibhftprcbreelamna.ayrataEensuyntdocl,dblaoenDrelenelrtruyillsufidenovsaceio.nnitmntraosmhsppihrhidAidinelnsilarroneaaaoeeeeatollgcggtnltnllslcgPcesleyilrtectaaaneyyd.rNa.tnear_gpponetnilc2etnir_pirdbtlusl(esa.sseu_eoloalPlnaamelac_lwntdcNar,uhsry_ociypr,ilaeew2ta_nttatolsplmoh)ayp_trvii.praiatniw_ebanohmllilldolnta_aebAhaeccansml_earriuuaaetmuc_ynibelesplbnamha_lldr,liulfyairlw_lolaapecangnlia_ntalarnorhreddthoo_rdtnoiabeietunab_aetshnolnaarsa_seiettcedeaib._hinoadFillrl_eeisuyincoin_spreifef_anlole_lgu_r Conclusions: Normal lung. Few type II pneumocytes and lamellar bodies identified. 00155^ TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animal No.: 19505-1_________ Treatment Group: 0 mg/kg, control Sex: non applicable________ Species/Strain: Crl:CD@BR VAF/Plus Rat Tissue:______ Liver_____________ Block No(s).: Photo/Negative No(9s9..:3Z91Z-5317_58_7_89_2-___ Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ Fsoemateucrelusm: piZng15o7f8m8.itoLcivheorn.drHiaepaantdoceyntdeocpolanstmainics raebtiucnudluanmt.fiMneitgorcahnounladrrima aatreeridaelnasnedand cZo1n5t7a8in9.soLmiveedr.ilaHteedpactroisctyatee. aFpepwearpsersoimxiisloamr teosZar1e57n8o8te,dw, iftohufrin(4e)gcroaunnutleadr .cytoplasmic Zrmsoe1auv5tgee7rhr9aila0eln.edrayLnotidphvlrecaorlscu.mymHtiecpesirp.neagtAtiococuhfylelutamemr.gate(VoRrpeoEonrRitger)aatinlacleryelcleieeslsvl.aiidslFaeoorngnuteritnhs(4eitn)hlueopsweocreieodnrxtwrieisgriothhhmte.eapsaSKtcoouomcpuyefntfetede.ridl.c.aetMelldiatbomlceohbnosgnodfria cZsauop1bup5one7pta9ert1dimd..eaLnlsliyveewfri.ixtheHdes.op.maMtoecigtyortacenhauoplnapdrerdaiareppaopasrptieitasalrlaynddednedstiealcawhteeidtdhcfsrroiosmmtaeea.gdrjOaancnueenla(t1rc)depellepsrooasxnitidssoamnde dilated cZAr1bis5ut7an9ed2.a.nTtLwfiiovnee(r2.g)rHapneerupolaaxtriosmcoymatteeesraipacploeuinanrtcseydet.sospelnatsimal.ly. sMimitiolacrhtoondthroiaseapdpeescarribdeednsaebwoviteh. some granular deposits and dilated cristae. Some dilated blebs of RER noted. Four (4) peroxisomes counted. hCeopnactolucsyitoe.ns: Normal hepatocyte. Suboptimal fixation. Average 3.0 peroxisomes per TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animal No.: 19505-1_______ Treatment Group: 0 mg/kg. Control Sex: non applicable________ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue: Lung_______________ Block No(s).: 99.39Z-145_7_9__3_-___ Photo/Negative No(s.: Z15797 Significant Lesions (check one): ________ Yes _____ X No Interpreting Pathologist (signature and date): __________________ Features: Z15793. Lung. Alveolus with lining cells. Two cuboidal pneumocytes with flainmeegllraarn-ulilkaer sctyrtuocptularsem, a.nTdompacyelblehaasPaNn2etxhtaetnidsebdefcloamtteinnegdapPoNrt1io.nNthoartmcaoln, tmaionrse a Zfl1at5t7e9n4ed. PLNunlgs.arTewporeosefnfot uardjcaucbeonitdtaol tlhineisnegtwceollcsehnatvrael lcaemllse.llar bodies characteristic of PN2. Smaller and darker cells has a microvillous border than contains a lamellar Zsset1rvu5ec7rta9ul5re.la,mLpureonlblgaa.rbblAyoldvaielevosel.uoSslaowrmsietuhrffllaainctttieannnget.cdePllsN. lsDaarrek pcruebsoeindtaalscwelel lilsaas PaNno2thaenrdccuobnotiadianls pZn1e5u7m96o.cyLteu.ngA. cAalpvielloalruyscaonndtaairneiangofercyotlhlaropcseydtesseipstaw.itThiwnothPeNa2lvseaorlearprseespetnutm, .both containing two to six lamellar bodies. No alveolar luminal lamellar structures are eZsev1vi5de7er9anl7t..lamLuenllga.r bAoldvieeosl.usThaendlelfitniandgjacceelnlst.pnTehuemdoacrkytceoslaupmpneaarr cneoltl tios ahaPvNe2flaanttdenceodntoauint s casonmtaoirnes dsiefvfeerreanl tsimataeldl PlaNmlesl.laAr bsoedcioens.d PSNub2jaicsejuntsttotot htheearlvigehotluosfisthaeccaepnitlrlaalryPNco2n,taaninding a leucocyte and endothelial cell. Conclusions: Normal lung. A moderate number of type II pneumocytes were identifiable, and contained lamellar bodies. 001S5J TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animal No.: 19506-4___________ Treatment Group: 0 mg/kg, control Sex: non applicable________ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue: Liver______________ Block No(s).: 99.39Z-155_8_0__8_-____ Photo/Negative No(s).: Z15812 Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ Fmeaateturiraelsa:ndZ1s5o8m0e8.cluLmivpeirn.gHoefpparteodcoymteincaonnttlayinms iatobcuhnodnandtrifainaendgrraonuuglharecnydtooppllaassmmiicc Zre1ti5c8u0lu9m. .LiFvievre. (H5)eppaetroocxyisteomapepsecaorsunstiemdi.lar to Z 15808. Some dilated blebs of RER are Zno1t5e8d1. 0S. ixLi(v6e)r.perHoexpisaotomceystecohuanstaedw. ashed-out appearance to much of its cytoplasm, and cZdisoe1ufs5iunn8rtere1dod1.u.. nLAdivet dethrb.eytHohpeepmlaeatfottocopyftoetihewetiicpthhcoeptlrolosgmvraeipnnhetrnaitsllbyai.lbeiElcenadcnaoantlhiaceluilcilauulslucaset.lllsoTwawreoer i(n2c)opmerpolxetiesloymes left and sinusoid are on right margin of photograph. Mitochondria are dense and contain some dense deposit and dZRi1Ela5Rt8e1da2nc.driLmstiiavteoe.rc.hSoHinxedp(r6aia)to.pceAyrtotexthciseoontmtoapeinsascreoaubtwnutnoeddha.enmt wataosphoeide-toicutceclylstoapnladsambailnedccalnuamlipciunlgusoifs present in lower right of photograph. Three (3) peroxisomes counted. Conclusions: Normal liver. Suboptimal fixation. Average 4.4 peroxisomes per hepatocyte 00X550 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animal No.: 19506-4_________ Treatment Group: 0 mg/kg. control Sex: non applicable________ Species/Strain: Crl:CPBR VAF/Plus Rat Tissue:_____ Lung_______________ Block No(s).: 99.39-6________ Photo/Negative No(s).:Z15Z811588-22 Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ ZeoceZcmsmZlcetcZoFilehsoiveovyrfy1f1n1efaie1ylminittsit5t5elt5ydado5otmhhstcs8ha88eet8aewppieeerup2nrmwn21in2ltlenoinahrp2pagt0pt91tphe,te.csshese.h..h.r.rdmaysmaaaoeaLoLaNtsi:tlTLrlLsta.teteluusocloehovruwtbu.vyZnnleegngotennoeemgogdolp1rtTrougyagtra..iar5taplgrl.bPos.eoppaa8lahchescPmhNrmhA1dtAAedoelyh.N.ost8rj_nicletllweanpilsn.ovvt_ytslalTchiaslgorspeeL_ttbaeaaciwieeoola_ngrnlrutesladeellnoilo_-hatmn.subuanmn_mttgPlerssoeaaeahaSdg_v.inaddNnlm,easasee_ilrjidanned2wDegvea_aPevotvddensscieny_lhaNantse.neldrpuh_orsilcaoarnt2ocikeceeo_aurrAmlnth.otvlll_fohlicbeIlinPeeanaa_clsPeThaeoperwNmgmela_ltltNaadhnsleihpp_h1lsaieceeed1cetweiin_.allealunllesllilrt'_leirslcam.aantletAiilaru_dserhnrgsrimcyo.nrlyMa_lhbobltcratricgra_hhtoonomoAacpkyloi_rudiiipdcumonpetossnnp_nieeiinPndrteceiglael_,lpdndtleaeNoyPslrsaa_hsswgrrtpgtfNri2en.a_oaeninoytailtarnur.o_t2thyeiifeMoehcpnsc,_uesoltgIlegrfoew_ihwmnpaeoforlnlvpne_auarasitthetloittetttwtp_rsmhadhaatithcushtecir_ilaeeioieihyssegdnhnn.np_ncsnetleciieanpt_eulantnctei.aDdlchupee_ptgognvlarsaaeicoio_notetilnprmslacesrl_lutocetieyaisnayrth_nltealacaporgil.taec_gnyttonealotoeerlaub_.trrlspNybnrtdelpyysem_hial,oarpsaio,ta_ecplPlhtetlasilwtea_hsvdsraconamNinlee_oerenhellmuaddysv_c.rlf.icsasticyeP_eochlnaaolThoLte_Npawlceiefullvhtg_atpcscaui2aitseer_rwevuiotmhslgaloh_ep.wanlelinbeclaea_tnitiauohahPerlapIr_dnblypatgdilsiiNha_noucnunieiimro_thlieccs2sndhnlttcs_bylashodoteepalsoh_trtesageiuniaahyesed_rtcnarrsrpleisi_aeyttrgdeetciop_amhapsaecnh._l.trtllilulk_edystImhea_idindserr_lee iCdoenntcilfuiesdio. nNs:o Nlaomrmellaalrlumnagt.eriOacl cnaostieodnawlittyhpine aIIlvpenoeluarmsopcaycteess. containing lamellar bodies TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animal No.: 19509-1_________ Treatment Group: 0 mg/kg. control Sex: non applicable________ Species/Strain: Crl:CD0BR vaf/PIus Rat Tissue: Liver_______________ Block No(s).: 99.39-7 Photo/Negative No(s).:Z 1Z518528327- Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ Fereyathturorecsy:te oZn1l5e8ft23an. dLoivtheer.r hHeeppaatotoccyytetes obnorbdoetrteodmbyansdinruigshoti.d cAonnteanindiontghenliuacllecaetlel dis in wthiethupanpeirntleerfvt epnoirntigonopoefnthaerepahoortoagreraapshf.illTedhewreithisfcinluemgprainnguloafr tmheatmeriitaol.chTohnedrRiaEaRndisRER Zdi1la5t8e2d4. , MLiitvoecrh. oHnderpiaatoccoynttea.inAstomthee gtorpaniuslaarnduecpleoastietsd. eFryivthero(5c)ytpee.roSxiinsuosmoiedsacl ounted. emnidtoocthheolniudmriaishapvoeorsloymdeeldineenasteedd.epTohseitsREanRdsshoomwesdsiolamtaetibolnebobfincgrisatnaed.dFiliavtaeti(o5n) , and Zpe1r5o8x2i5so. mLeisvecro.unHteepd.atocyte surrounded by hematopoietic cells. The RER and nuclear egnravneulolapredsehpoowsistssoamndeddiillaatteadtiocrnisataned.bSleebvbeinng(.7)Mpeitroocxhisoonmdreisa caopupnetaerdd. ense and have some Zclu15m8p2i6n.gLoifvmera. joHreopragtaonceyltleesa.ppFeivaers(e5s)speenrtoiaxlilsyosmimesilcaorutontaebdo. ve described cells with Zpr1e5s8e2n7t .inLthiveerc.yHtoepplaastomcyatnedscuorrnotuainndseda fblyochceumleanttopliokieetmicatceerlilasl..AFosuinrg(l4e) lpaergroexrivsaocmueosle is counted. Conclusions: Normal hepatocyte. Suboptimal fixation. Average 5.2 peroxisomes per hepatocyte. 00156# TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animal No.: 19509-1________ __ Treatment Group: 0 mg/kg. control Sex: non applicable________ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue:_____ Lung_______________ Block No(s).: 99.39-8_________ Photo/Negative No(s).:Z1Z51852883-2 Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ decZtZDeSZZftbicablFhsoilnanaopo1ouk11aoee1prddanpd5dbett55ra5kithoolesti8ij8e8lt8tuaeemaeatltahuc3n323hahismsclrien2rer01a9.reesneleitaydse.t...llnlog-enistTinswtaosharla:LLdLLtouiellwtonahaabuuuuvmZrildcifoclihesnnlnseneteee1fitistggrgganlhplcowadc5atll...p.raherhrssol8iitoep.s.,etghlA2cAlcebhleTAaaheeaa8odpiaarlnmnwtnppr.nevatbrrdeudisiairteelostltagLaekmoyolohlboahidlateueolnlaPharcfturocnyfrfseyNoasocoolPgle.clbatlanofdni2.pvNhaoomtatlt.tntetralldlca2heAaolaoedieiaineBncpcllenalilpleuevnlyslsenPiaissldssen.etnndrleeNte.dsogriwevPdbsAnaa2laelANsouaingiaatnrtemndashsh1tarlcpcpivieieliatiantetetnopxeariaphnvswgloyonept.lidecausntlaaidlasahcl.tarlTrnlaeheepurtrsctidrohfioTonioacynstoltecilphoelaeaniefiayattlriepslgsshlrPletsbnatslieaeeasreNadetlcPgpmhe.trspiech1wNfyetsea.lanaate.Arlt.i2iplsrleytiSmlosmt.sshiuAtTceole.uhitmmlreaahpTnhmanrflydOoeterlcoeldhaesayaacudcehtlltrychaceybiailatklandaletrafemutoveeettemcnaprcmieea.ledrmeiecclwurekllyecadloellldlicenoalhalldlitPeral.rlirniPnodssalycrNctlgNslphTatuaadet1lhisirr1phubesnhPeeuea.enbmoiedaancNslrceidstdlTeedicoutiu2isnfomtnauhlmmrrwta.glaiwebeimnomgppeoocoAiagflhtrpceteiaehpshedttlytedpmlmehlpsalamtitsnsraeeeahlireae.esersastiellpvPdedulrlbaataenlsNdbmoyolpnrrPelaota2ddneoubooNmotli-etcmereanto2lubeyosnammowlem.ttpdmlaeocayinwsoyptrareedhic-trilaglelaeitylirinhah.nnketiretdens, mCoatnecrliaulsiaolsnos:preNsoenrmt walitlhuinng.caSpcilaltatreireesd. tNypoelaIImpenlleaurmboocdyietessnporteesdenint.alSvoemolearlasmpaeclelasr. 00156JL/ TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animal No.: 19516-2_________ Treatment Group: 0 mg/kg, control Sex: non applicable________ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue: Lung________________ Block No(s).: 99.39-10______ Photo/Negative No(s).:Z15Z8135884-2 Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ Features: Z15838. Lung. Two pneumocytes at the bottom are PN2 and contain some laanmdeelnladrobthoedliieasl.ceDllosr.sal to them are collapsed septa containing primarily pneumocytes Zla1m5e8l3la9r. bLoudniegs. aSnedviesraalPpNne2u. mFolactytetensedarPe Nprlesselinnte. tCheenptrroatlrpundeinugmsoecpyttuemcownhtaicinhscsoenvtearianls Za c1a5p8i4l0la,ryL,uenngd.otShienlgialle cseelpltaunmd llienuecdocbyytePNwiltshionntehiethcearpsilildaer.y.On the right top is a PN2 bwoidthy.seTvherealselpamtalelclaapriblloadryiesa.ndTehnedroigthhetlliouwmearrpenaelusomeovciydteenat.lso contains a single lamellar Zm1u5lt8ip4lLe laLmunegll.ar Aboredaieos.f cOoltlhaeprsceodmseppretas.seAdtsreipgthatl acreelltswaopppenaerutmoobceyptensewumhiocchycteosntaanidn eZn1d5o8t4h2e.liaLl ucenlgls.. Area of collapsed septa. Several cuboidal pneumocytes are present. Cstreunctrtaulrleys itshaatcaapppilelaarrytocobnetawinitihnign athneecraypthilrloacryytelu.mNeenx. t to it is a couple lamellar Conclusions: Normal lung. Random type II pneumocytes containing lamellar bodies were identified. No lamellar bodies were clearly identified within alveolar spaces. 00156 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animal No.: 19516-2__________ Treatment Group: 0 mg/kg. control Sex: non applicable________ Species/Strain: RCralt:CP<BBR va f/PIus Tissue:_____ Liver______________ Block No(s).: 99.39-9_______ Photo/Negative No(s).:Z15Z8135383-7 Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ Fcmaeintaoatlcuihcroeusnlu:dsrioZan1a5tnh8de3R3le.EftRL. .ivCTeerhl.lehrHeaesipsaadbtoiulcnaytdataetniowtnwitohafsahResEdinR-uosuaontidcdytahtoteplonlawuscemlreraairngdehntcvaleunlmdoppaeinb. gileof Mmeitmocbhraonnedsriaancdosnitnauinsosiodmaleegnrdaontuhlealriadlecpeollssitasreanpdosoorlmyeddeliilnateeadtecdr.isFtaiev.e P(5la)spmeraoxisomes counted. Zm1it5o8c3h4o.ndLriivae.r.NDiniela(t9io)npearnodxbisloembbeisngcooufnRteEdR. . Some granular deposits present in Zbl1e5b8b3in5g. oLfivtheer.RMERit.ocPhloansmdraiamcoemntbairnanseosmaeredpenosoerldyedpeofsinitesda.ndFidviela(t5e)dpcerrisotxaies.omTehsere is ZFcoo1uu5n8rt3(e46d).. pLeirvoexri.soHmeepsatcoocuenltleudla.r morphology essentially similar as those described above. Znmu1ec5ml8eb3ur7sa..neCLseivallerera.tpMloooiwtroleycrhdloeenfftdinareipadp.ceoaArnstatmoinublsetoivmaeneseidcneudnloastrehbedoleidapylocsisietlspl,raebnsudetndmtiltaaoytetbhdeecarriigshtheamteo.aftPothlpaeosimetaic cell in the sinusoids. Two (2) peroxisomes counted. hCeopnactolucsyitoe.ns: Normal liver. Suboptimal fixation. Average 5.0 peroxisomes per e o i5 Q TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19534-1 Treatment Group: 0.4 mg/kg Sex: non applicable_______ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue: Liver_______________ Block No(s).: 99.39-31_________ Photo/Negative NofsT:Z15Z9135593- 9 Significant Lesions (check one): X Yes ________ No Interpreting Pathologist (signature and date): __________________ Fsuerarotuurnedsi:ngZe1n5d9o3t5h.elLiailvecre.llsH. eSpoatmoceyhteemwaittohppooieotrilcy-cdeellfsinaerde palraosumnda mthiesmhberpaanteocayntde.no Manidtoschhoownsdrsioamceonbtlaeibnbsinogm.e gFroaunru(l4a)r dpeeprooxsiistsomaneds scoomuneteddil.ated cristae. RER is dilated Zpl1a5s9m3a6.mLemivberra.neH. eTphateoncyutcelesahroewnsvemloaprkeeids dalislaotidoinlaotefdR. EARlaanrgdepcoloearrdvealicnueoalteioins porfetsheent iZn1th5e93r7ig.hLt sivideer.oHf tehpeactoeclly.teEwigihthtecelnum(1p8i)npgeorofxoirsgoamneesllecsouanntdedin. tervening washed-out carriesatsaeo.f cRyEtoRplisasdmil.atMeditoanchdosnhdorwiascsoonmtaeinblseobmbiengg.raEnulelavrende(p1o1s)itPsearnodxissoommeesdciloautendted. Zab1o5v9e3,8w. iLthivseurb.oHpteimpaatlocfiyxtaetisohno.wAs smimulitliavreuslitcrualsatrrubcotudryalismporerpsehnotlotogythaes rtihgohsteodfetshceribed Znu1c5l9e3u9s.. ELlievveer.nH(1e1p)atpoecryotxeiswoimthecslucomupnitnegd.of organelles and intervening washed-out oarfetahseopfhcoytotogprlaapshm. . MPliatsomchaomndermiabcraonnetaiisnisnodmisetingcrta.nuAlahredmepaotospitosieatnidc csoelml eisdaitlathteedbottom cristae. RER is dilated and shows some blebbing. Sixteen (16) peroxisomes counted. Conclusions: There appears to be increased numbers of peroxisomes per hepatocyte csuobmoppatirmedalw. ith control liver. Average 12.0 peroxisomes per hepatocyte. Cellular fixation 00156^ TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19534-1 Treatment Group: 0.4 mg/kg Sex: non applicable_______ Species/Strain: CrhCDOBR va f/PIus Rat Tissue:_____ Lung_______________ Block No(s).: Photo/Negative N9o9(.3sL9-:Z3125_19_54_91_4_5-___ Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ TZttilZiZbpbPbvpoZFihhnednouhoanhf1Nfe1eee11ctdtotdee5isna55.5h2tuspyutiea9s9tt99eeooeo.ihculm4a444stsgpctltocynr4h5.3eo2iySotrehotd..as.ea.otceisTaan.lorpsgypc:LtLrLLphhwtlartoutiaiuuueleusaa,cZnnnaacnsnlnpntasilstcl1heggglnahgilwom(l5gert..ie.g.Pmahins9aha;asnNoslcpTA4AtArtewtldeui,eh1pswlhcsllrllgsib.eivavve-eltash)htsasuhrveeen.ya,LedtritooeoadapststaaurllwBlPmieuuarflandavnatklNelossraihalegaItnnvycytvto.sllaapaaegeisupapuntnnndbcao.hAocaedgdpiejehtlruclnahhinluoeeIellovcagNIemaiidutcleennahauremopgcunoedoiianemsennnhbtlncjaldlcugeagPaeoycmoldtouscmmhilrctNcocldiemoeoseyalneenepnauarplnltliofletssltprlelnhtlady,sserchastgaslio..paoayreeusholgutptitcdcTbiTafenaternotpeheloihihcahdlngeronen(dleowneoeePa.hsrtgindtdu.rNetaftdoPetwcansltcenpanb2lTNored.onrdoaoy)lhklln.lltrborteessseedomstetff.n..aTohattdsupiaprmehATnnaeaNklcolnilerusihellslspeokanellcyeosiuulueilgntselasiemlhxsccaneoivnmunepotemnoedirsatlgrsnoarhacllpeoiat.snmclpyelcnapbolaelsacteiiaeaAamerlnelnrelyralbyastlsgulersmllclbobyilwawtatcnabocwfereoperhiooadhclanolialihtbnailllalcghenislftieitpsahrstlnaicefaaair""ibimdlnyehctnppeneaot-lotamigpepimtlludinltvtsinseeaeerikpcg.peaeaeerndpeettr-drsy5eTnlyraiilmfteds"oa"n,pphollsnatanpieaalleltndtbamiafnheetntntdelmeemuadioatieirsinrsmntpistelaeittayeltgnlhaetlaiolldcplngen.artaccePehcreareylbpNIteldIlltot.loles2aitdonn,oni.isugpeetas bCoodniecsluisdieonntsif:iedE.ssNenotiraelmlyarnkoarbmlealafbentaolrmluanlgi.tieRsannodtoedm. type II pneumocytes with lamellar 00156< TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19536-3________ Treatment Group: 0.4 mg/kg Sex: non applicable________ Species/Strain: Crl:CDBR VAF/PIus Rat Tissue:______ Liver_____________ Block No(s).: 99.39-33_________ Photo/Negative No(s~).:Z1Z519549650- Significant Lesions (check one): X Yes ________ No Interpreting Pathologist (signature and date): __________________ Fenevaetulorpees.: SZo1m5e94g6r.anLuilvaerrd. eHpoespiatstoacryetee.viTdhenertewiisthdiinlastaotmioenmoiftoRcEhRonadnrdiao. fFthoeurn(u4c)lear pZneu1rc5ol9ex4ais7ro.emnLveiesvlecorop.uenHatereepda.dtiolactyetde.. STehveerentiesesno(m17e)cpluemropxiinsgomofesorcgoaunnetlelde.s. The RER and Z15948. Liver. Hepatocyte. There is poor definition of the plasma membrane. RER and Zth1e5n9u4c9l.eaLrievnevr.elHopeepaatroecdyitleataepdp.eaFrosusritmeeinlar(1t4o)thpoersoexdiseoscmriebsecdoaubnotevde.. Eighteen (18) Zpe1r5o9x5i0so. mLeisvecro.unHteepda. tocyte. At the top is an endothelial cell and several adjacent epinreydrtoihsxtriionscocytmtaeenssdacnoodrugnoatnneeedl.nleusclaeraetecdluemryptehdroicnytthee. cTyhtoepplalassmm.aRmEeRmbisradnileatoefdt.heEihgehpta(t8o)cyte is Csaomnpclleuss.ioAnvs:eraIgnecr1e2a.s2edpenruomxibsoemr oefsppeerrohxeispoamtoecsytpee.r Sheupbaotpotcimytaelcfoixmaptiaorne.d with control 00156 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal N o.:_____ 19536-3_______ Treatment Group: 0.4 mg/kg Sex: non applicable________ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue:______ Lung_____________ Block No(s).: 99.39-34_________ Photo/Negative No(s).:Z15Z9155195-5 Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): psaZZsbafZbZtsaidFfishloednrnurooe1a11ec1oopemeddgwdtbt555aa5mttnmtgirr9oape9e99tiiietiietsusnm5iii5s55gshPffnlmsre5,43aa2ihliitiNeelaend.l..nat.oalnstPsrd2ychftoyto:atPLL.NLLhhlsituubsN.iuuecauheau2nAZtdeannnnec.n.2nPTt1ipttdggegogfn.uhNp5hAilTi...lp.gllncehse9eNl2hloeaaomATLo5cAcse.elomrsta1ofeuiahlyltoalnapa.vmnmvsateeygtimhdiestbewnblraeLepenepjolonagenaearolroaulllpollpcoduraucnaplonahyrcaeamsmesrinmfgcganrPd.icebae.pitaeetneNamhnounlon.ilTcnllAellenmdt2ddialeathytnbNtai.itlpliraoeplfeleevtlreihiioimicsrennsOenedniceoiyseoidaiaaosiwanttn1ntanllrbhcolteo.ugcagitklegpunegsthatersrhnerbocrTelcpilsaidaateaaleorceesnhhsrppm.mnulllieeve.eelldrhdmlcdasseeaelaa..Po.NnrsllsaPollsaliNnul,eroaStAeicNPlsnecinfrb1pyoeiNeall2ltusttseasomtaraecthimtoaytlmrlenlsnotseeittfaennmaeoanhetapncpdltledrthtrlirlypeeoealheonweeatcddeecailboechnlreilaf.ecryate_tiailslrnotoibhnsaptlhss_netlago-taserlda_stlsltirdaeaaeitsvoes_aakdpilanacicepte_plnespbnhedreovshs_reegepeddlaebeleld_talaerapoesoeataar_krwaroetdlsdenea_pardnseplchyd.ir_ppnlaptteeniaoc_rarectsilnliTimeaoknlcinhpun_dbnlshneacgm_etoleeetc.etahcoahl_natoeolrePmehnte_baieCtnnhcnetNr_aoaceeitadayosln.an_etbliilotlltlaainvnde_tslooatntwallse.hht_dmrvswepaoceeo_i3ebrrsNeeltlh_e-oaaeowiaslol4iao_llardlldcffsvoalv(_mlyhl,lPsretaaeau_ch,lugoteNlosemahm_tverwlrlplelma_fl2uaelaeeanaasph_nssorlencircehil_sulnle,caaltdciobl_ualoh.rraoa.otoane_mtronnbcdnAt_Ogdt)eoydia_retnndtia_es.ntiph_esihes_n cCoonntacilnuisnigonlsa:meElslaser nbtoiadlileys.noSrommale fleatmalellulanrg.boSdoiemseptryepseenItI wpnitehuinmaolcvyetoelsi.identified TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19543-4 Treatment Group: 0.4 mg/kg Sex: non applicable_______ Species/Strain: Cri:CDBR VAF/PIus Rat Tissue:_______ Liver____________ Block No(s).: 99.39-35_________ Photo/Negative No(s).:Z_1_5Z915569-60___ Significant Lesions (check one): X Yes ______ No Interpreting Pathologist (signature and date): ________________ Features: Z15956. Liver. Hepatocyte with clumping of RER and mitochondria. iPslapsrmesaenmt eamt tbhreantoeps rairgehitn. dSisetvinecrta.l hCermosast-ospeociteiotincscoefllRs EarRe aapropuenadr dthaerkp. eAripbhieleryc.analiculus MZclu1it5mo9cp5he7od.niLdnrivithaeer.ccoynHtotaepipnlaatssomocm;yteiendtmeilraovtreepndhinocglroissgtpyaaeac.pesEpeicgaorhnsttas(8iimn) ipflieanrreotxogirsZaon1mu5le9as5r6cm.oauOtnertregiadal.nwelhleischaries FZpri1fo5tbe9ae5bn8ly.(1gL5l)iyvpceeorr.goexnHisaeonpmdatecosycctyootseuonwltiecitdhd.ebbFilrieixsac.taiFnoianvlieicsu(v5lie)rppyreeprsooexonirts.oamt teospcaonudntbeodt.tom of cell. Zce1l5ls95ar9e. pLreivseern.t aHtetphaetobcoytttoemwoitfhthmeaprkheodtocglruamphp.inTghorfeeor(g3a)npeellreosx.iTsowmoehsecmouatnotpedo.ietic Zen1d5o9t6h0e.liaLlicveelrl.s Hareepaabtosecnyttedusuertrooupnodoerdfipxraitmioanr.ilyHbeypahteomcyattiocpmoiiettoicchcoenlldsr.iaScionnutsaoiindaslome granular deposits and dilated cristae. Nine (9) peroxisomes counted. ppCeeorroonxxcliissuoosmmioeenssp:peerrShheeceptpaiaototnoccyoytfetelio.vnelryevxehriybistlsigshutblyophtiigmhaelrttohapnoocronfitxroatliovna.lueNs.umAbveerrsagoef 8.0 00156 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal N o.:_____ 19543-4_______ Treatment Group: 0.4 mg/kg Sex: non applicable________ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue:______ Lung______________ Block No(s).: 99.39Z-13569_6_1__-___ Photo/Negative No(s).: Z15965 Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ cZcacbZamZacZcPgamFaoeapaoop1rN11Pceyt1annpappndi5e55laN5tce2tnitieetir9e99rlatla9laesmuaa2allrui666ilis6aanirrllnna5ra43ia2rrwv-aneritvyll.ir..l.noeaaineasiainikccgbtstd:lnLLcLLehbiouyeuunvbaueiduuutiotZnnogtsrrshoinannnlhddedo1lteperggggpetrceeiank5shiul.pf...renrna.c9fesolcrletseethule6lASPtb.rT.mScufruisgg1yaehteoolmoehrArg.iTbvtvnoolelnacmheeellieetthfntanLyri.ofsnor,bceeaoplutataugelaehaiotacT.slullvderanltcaenaeyalstPhcdreagkremdetpulaerN.teagniomPhkhtbdnesnsrec2feANeooltoiaddvsehla.napuirtahltnarledengslPtvonrseoNcituarapenrN.bduwicm"lmlbaoaoilo.eeo1inlyepslSla.sltmllungltcnOteieassioaenwseusepvme.cnnrPmmabutveaiiptedytteaNhomrneelahhrT"lalloeireidoylisldoltahaintfissn.lhhrslaclereramteeieelyahlcmncTpnbircpiytevuctnricsotheeesrnetoeebeuaadleespoilgsnlclodplrtsilhpteafthlelehieiatcrioalnircdlshontnaaneelctotaaaebnelstolitnernllanilrhmodgeyansorytitegepdhri.rar.t,gdtipnayteiiswbacshswnhepLid.BeppeoteposthauhaiahloatAinlnltmctaeiniscetsdocoricdehlleetnwaopovimhdaaevugrwanccelroadaekomveiyootrnydriclseaefklettnal.epaarhieoactfotltnlerhmrhtsrlaoclrNkelaisr,eseicona,syedantoocspvmmsaralathloeoliihnvaapnsleamagspevvcltrocepdtbrlhaloereteeuomaileneoit.rnbcaonnopln.aasopeayoaroltlsrsslarrentdTebewlcmceralataysddoaweaulbipsm.yaiflmrdtbspnslocaehelioeeiTaecofweeoptpclpligcleirlshlrafdlaelrtme.aleseatsueaypwws.rtsmrmslaewTcide,ahimlelnTbotanlhar.ihinahaeotglecwyrteiinltirdkdehceeyniidnolinnhesilnaaleociaa.samnsnmsonttcltmehe-ldfoohnNalaepideitenntyenlto.keallteaddaiealblnar.ieinrss lCamoneclllaursiboondsi:esE. sAselnsoti,aslloymneorlammael lfleatralstlruuncgtu. reSsevneortaeldtywpiethIiInpanlveueomlaorcyspteasceids.entified with OOlSjflO TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19546-1______ Treatment Group: 0.4 mg/kg Sex: non applicable_______ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue:_____ Liver______________ Block No(s).: 99.39-37_______ Photo/Negative NofsT:Z15Z916569-70 Significant Lesions (check one): _____ X Yes ________ No Interpreting Pathologist (signature and date): __________________ Foregaatnuerleles:s aZre15c9lu6m6.peLdivteorg.etHheerp.atMociytotec.hoPnladsrmiaashmoewmsbormaneediesnisnedidsetipnocstiatsndancdytdoiplaltaesdmic Zcr1is5t9ae6.7.FLifitveeern. (H15e)ppaetorocyxtiesoamppeesacrosumntoerdp.hologically similar to Z15966, with clumping doiflaotregda.neSlelevse,nin(d7)isptienrcotxpislaosmmeas mcoeumnbterda.nes, and mitochondrial changes. RER appears MZco1ir5tno9ec6rh.8o.OnLdrgriivaaenrse.hlloeHwseapsraoetmoccelyudtmee.pnesAed dpweriopthmosliiantrsegnaetnibdnitldeeirlvcaaetenndainlcigcriusslptuaasec.eissTpowrfeefsnientnyet (gi2nr0at)nhupeleabrrootmxtioasmtoemrriiaegls.ht Zco1u5n9t6e9d.. Liver. Hepatocyte appears essentially similar to Z15968. Fixation is poor. TZiEswl1en5evo9letv7npe0r.((e11sL12e)i)nvptpeearer.trooRsxxiEinissuRoosmmiasetesdstoiclcpaoo.tuuendnMtteaeidtndo.d.chpolansdmriaamsheomwbrsaonmese adreensineddisetpinocsti.ts Aanndednidloattehdelciarilsctaeell. pCeornoxcliusosmioenss:peLrihveepraetxohciybteit.s pAovoerrafigxeat1io3n.0. pTehroexreisaopmpeesarpsetrohbeepaintoccryetaes.ed numbers of TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19546-1______ Treatment Group: 0.4 mg/kg Sex: non applicable_______ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue:______ Lung______________ Block No(s).: Photo/Negative N9o(9s.)3.9:Z-1358Z9_17_51_9_7-_5__ Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): _________________ TFlahemiasetulilsraearsbd: oisdZtii1en5sc,9ti7mv1eo. sPtLNpu2rne.gd.TomhAeilnvtahenroetlleuyscteahlneldscaleitnnttihenergctcoeepllllosw.fittShheeavptehlreaoaltsoltignnriainnpgehclaaepmllpseelcaloar rntotbaobindeies. pZn1e5u9m72o.cyLteusngw.hPosheotaolgvreaoplihasrleigohuttlyofouptlaonfefoocfusse.ctAionn uonraatrteacchoeldlaPpsNe2d.is present in the eanlvdeootlhaerlisaplacceel.l aBroethevsiiddeenstowfitthheinsethpetusmepatureml.inNedoblaymflealtltaernmedatPeNrialsl.isAprceaspeinltlairnythaned Zal1v5e9o7li3. . Lung. Alveoli and septum. The dark cell on the top left is a PN2 with several TZte"ahrleh1veyme5etah9opvlr7lvtaoiy4.ecc".ouyloltLuaelsmeu.isnsegaNlpl.rareeerxAs"bteleovtnmodetoipiietlntsuyi.sst"haTaleanhccmdeuebenloilotntleihaidrrnearogblflocpitdnenhiileeenlsusgs..mecpAToetclhulfyesmltaeac.ttreNewennotiPerthaNdllaslPmcseNe.vel1elllArawalrilcinmtacehplsaeiatlatelhmrareirvaiycbalrcowioustvtiootpihllmreleosas,umelasunamtbPrgoiNininrn2dat.ehloref, edxilhaitbeidtinnugcsleoamreenevleemloepnetsanodf sduibstoepntdimedalenfidxoaptiloansm. iNcoreltaimcuellulamr bisoadiceusbnooidteadl pinnethuemaolcvyetoeli. Zor15tw97o5v.acLuuonlge.s wChuibcohidaaplpleianrintgo bceelllaimn ceellnatrebrordigiehst.anTdhecseellcaetllcseanrteerplreofbt abboltyh PcNon2tsain one cmoantveeriratlinngotteodPiNn ltsheafatlevreeoxlip.ressing their lamellar (surfactant) material. No lamellar bCoodniecsluisdieonntsif:ieEd.sseNntoiallalymnelolramr amlafteetrailalluinsgp.reSsceanttteinretdhetyapleveIoIlpi.neumocytes with lamellar 00157J, TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal N o.:_____ 19546-2 Treatment Group: 0.4 mg/kg Sex: non applicable_______ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue: Liver______________ Block No(s).: Photo/Negative N9o9(.3sV9-.Z3195_Z_91_75_69_-8_0__ Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ Foregaatnuerleles:s aZre15c9lu7m6.peLdivaenrd. tHheepmatiotoccyhteonedxrhiiabisthsoawpdoiolarltye-ddcerfiisnteade.plAastmtoapmriegmhtbirsanaen. The ihnetmerasttoitpiaoliecteilcl cseulrlrsowunitdheidn baysicnoulslaogide.n, Fprooubra(b4l)ypaerfoibxriosbolmasets. cAotunthteedl.ower left are some cZe1l5ls97ar7e. pLreivseern.t inTwthoe huepppaetrorciygthets awnidthloawneirntleerfvt esniniunsgobidilse. cTanhaelilcaurgluesr.cyHtoepmlaastompiocietic organelles are clumped together and the cytosol appears washed-out or contains a fine cgeralln)uclaornmtaaintesrisaelv. eTnh(e7)mpietorocxhiosnodmreias.show some dilated cristae. The hepatocyte (bottom ZaZb11o55v99e77,89f..ixLLatiiivvoeenrr..isHCpeeonpotarrt.aolcThywetepo,awt(o2hc)oypsteeeroimnxoipsrhopomhtooelgsorgcayopuhinsatsepidpm.eialarsr similar to those described to those described above. Five Z(51)5p9e8r0o.xiLsoivmeer.sHcoeupnattoedcy. te exhibits a poorly-defined plasma membrane. The organelles pareerocxluismompeeds acnodunthteedm. itochondria show dilated cristae. RER is dilated. Nine (9) pCeornocxliusosmioenss:perEhsespeanttoiaclyltye.normal liver. Poor cellular fixation. Average 5.4 00157J TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19546-2______ Treatment Group: 0.4 mg/kg Sex: non applicable_______ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue:_____ Lung_______________ Block No(s).: 99.39-40________ Photo/Negative No(s).:Z15Z9185198-5 Significant Lesions (check one): ________ Yes ______X No Interpreting Pathologist (signature and date): __________________ Features: Z15981. Lung. Alveolus and lining cells. A partially detached pneumocyte itsopprmesaerngitni.n tThheeaoirthsepracdea.rkLoarrggaenreilglehst caepnpteraarl ctoelblecopnretadionms iansainntglylemlaimtoeclhloanr dbroiday. nTehaer its cgylytocopglaesnm. of these cuboidal pneumocytes contains a fine granular material suggestive of ZPN1529.8T2.hiLs uisngin. aCneanrteraalocfeclloclloanptsaeidnsalmveuoltliipalendlasmepetlala.r Abocdaiepsillaanrdy iasntdheencdyotothpelalisaml coeflla calreeaarltythiedelneftitfoiafbtlhee. pThhoetobgortatpohm. rTighhet tcweoll disarakPcNel1l.s oNnoeaitbhneorrsmidaelitoiefsthdeesPcNri2beadre. not bZtho1et5tmo9m8a3jo.orfiLttyhuenogfp.hthoTetwoirgocryacptoohlpulamansndmaarcccoaenpllsisillsoatnroytfhafenindreigegnhrdtaobntouhtlehalricamolnactteaelirlniaallra.emaPetNltlhalser balepofpdt.eieasr, taoltbheouatghthe Zro1u5n9d84to. pLoulynggo. nAalncaerllesatohfatcocollnatpasiendsoalmveeollaimanedllasrepbtoad.ieAstctohnesitostpenatnwd ibthotttyopme aIIre two bpontetuommoPcNyt2e.s (TPhNe2cse)n. traSlocmeellslaamlleallpapremarattoeribael PapNplesa.rsAttotbhee ebxottrtaocmelrliuglhart aisdajaccaepnitlltaoryth,e eZn1d5o9t8h5e.liaLlucnegll. anAdt ethryethtoropcryitgeh.t Nisoa lcaumbeolildaarlbPoNdi2eslinnointegdthine aallvveeoolliu.s. This cell contains sceovnetarainl ilnagmtewlloarlabrogdeieesn,daonthdesliitasl nceexllt ntoucalemi oarnedfalantteernyethdroPcNy1te.. Centrally is a capillary Conclusions: Essentially normal fetal lung. Random type II pneumocytes (PN2s) cidoenntatiifnieindgoluatmsidelelaor nbeodtyiepsewIIepreneiduemnoticfyietde..__S_o_m__e_e_x_t_r_a_c_el_l_u_la_r__la_m__e_ll_a_r_m__a_t_e_ri_a_l__ 00157- TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19560-1______ Treatment Group: 1.6 mg/kg Sex: non applicable_______ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue:_____ Liver______________ Block No(s).: 99.39-21_________ Photo/Negative Nofs).:Z1Z51858848-8 Significant Lesions (check one): X Yes ________ No Interpreting Pathologist (signature and date): __________________ Features: Z 15884. Liver. Hepatocyte. Plasma membranes and adjacent endothelial bcceyleltlbossp.alareSsmoinmdoeinsdttihinleacttre,idgchoctnrisssiitdsateeenointf wtmhieitthoccesulhlbo. onFpditrfiitmae.eanlAf(i1sxi5an)tgipoleenr.colxDeiasirloavmtiaoecnsuocolofeuRnisEtepRdr.ewseitnht sinomthee Z15885. Liver. Some granular deposits present in mitochondria and dilatation of RER. ZT1w5e8n8t6y.-oLneiv(e2r1. )Hpeeproaxtoiscoymteeisnccoeunntteerdo. f photograph with hematopoietic cells at top. ZSo1m58e8c7l.umLipvienrg. oHfempaittoocchyotendcroinataainndinRgEaRs.inDglielaltaerdgeREliRpi.d Sdirxop(l6e)tpinerdooxrissaolmceystocpoluansmte.d. ZpcAle1tur5mtoo8xpp8ii8snro.iggmLhoetifsvicsecyroa.tuohnHpetlemeapdsama.ttooicpcoyoitreegtiascnimecleilllealsra. tnoRdtEahtRolsoaewnddeersncluercfiblteeiasdraaebbnoivlveeeloc.apnSeaoalmipcpeuelsuatrsa.idniTlpahtreeedrce.ipiiFstaivtee (5) is present on photograph. Eleven (11) peroxisomes counted. ctCiososmnupcealufriesxidaotwniosin:th. Tchoenrteroalpspaemaprsletso. bAe vinecraregaese1d1.n6upmerboexrsisoomf peesropxerishoempeastopceyrteh.epSautobcoyptteimal 00157^ TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19560-1______ Treatment Group: 1.6 mg/kg Sex: non applicable_______ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue:_______ Lung_____________ Block No(s).: 99.39-22_______ Photo/Negative No(s).:Z1Z518588993- Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ cZwZbPeibZslpaTZoarasFsaoainreeeNrnr1b111ihgemeneelcpnttdd5l555elhwah2osdteroaa8e8p8i8titseecnwacogettnlu99r99nsohlotgeeneoi3ta2rhei10tnefnhnninc.ber.n.t..nletithts;tasittnabrhtuhAuhe:bLLwaLtLitleoiecihmdnotullnuusuhudloycZispmPPecnnsnneiiatp1uneaeNPNgtehgggerpahwrs5lasixe..n.N.i2lebp2gol8lpo.iwveplhiatsAF8lpTarashoeteltsile9rNwArre.vaahgoltaaaeseyvh.aslemrrlroeslPsitAaiePaePsvoneeeiunaLNroepesNleldniNnnrtaalunldhosoie2ptlul1mrtnplgat.aliils,srasaw.rnusbrargseeramttkacTispecs.eowhblwnBnr,yteaelhgeeeehoagdait.ceAflinelutroeditrlelnhasytfnhcailalpi.icilmtaeuveteitabrmvslhnatmraclpseatereeablprgto.oisonpsntvtohooolimhnelbueaelcelrcTaudrlettulerrcderya.naihsaihasallelrtbtidselele.PloelyenaCsustouf.ncP,sNaciltTttaesiasuodhtNesa,pv3ctoahlbwonpnspaie1snmlteodlstdrihopnredlneeliieacPemiiridscsilsltnsryldneNclhecaaobieeiatafegeenelponowno2trnrsslptiugyppttcnlcolectregclinleiorioafrnataoabxnohilehmlmrsbrltnrlstnutesihemiteeethote.tghmiheancadaense.ehleicois.loTavpentnvafoincmTcnilhsoooileCondaatynvtohpnraoemetfspetgeRtaeilelZeniontoncuolielvhsEtadncgetlsfs1l.l.eearraallaRsr.5aarlaararprbTpTa8ylntrkpwTliwaosllh9.hhylamhpunhldie1oeleoma.tadaneiri.tahrrescyocmieptyeNsdiPeeeAtgdarsl.hea.enrlNoaroa_ailrPrsnatnmrsalA_oe2rruplaktNidlaai_cnrrithmenfclrmniy2_gil.rstooboeidety_hlneestouncednnaeNe_olsiydtncortlln_Pacmiotkatlidangvio_oeeeNlrneneo-casap_lpldesalmld2.wrecn_linlmlanoluTgs_ybeahllidseeuosie_yftheamonwevdtltrl_etpseetrlesiaoieh_tairssdotricrnaev,fehts_raumeildsbil_lpnwcmladieayilea_lcttsennhaPuoal_tntinitrN_ccvetete.ehh_re2lieo_alfl wCeornecilduesniotinfsie:d.EsFsiexnattiiaolnlywnaosrmcoanl sluidnegr.edSaecvceerapltatbylpee. II pneumocytes with lamellar bodies 00157$ TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19560-2______ Treatment Group: 1.6 mg/kg Sex: non applicable________ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue:_____ Liver______________ Block No(s).: 00.39-23_________ Photo/Negative Nofs).:Z 158Z91458- 98 Significant Lesions (check one): X Yes ________ No Interpreting Pathologist (signature and date): __________________ ZTFpcarpr1heiepa5sestert8eauea9nerr5itsesi.sispnc:naLlturohiZtvmtieeae1dplrl5lo..iy8nw9THgd4eheeor.tipfarrLaticmegthioevhienctetdoyro(c.tf1efhr3Hoopa)mnhpepdopperateaoirdtaaogojr,xarscRaciysspetEoienhmmRt,wihaelaailesntlrphdctathoostsruuooecnrcemerytolesteludehdns.pae,dersiarincnolrgtgxhibioahseuoecdgmmohimeansttmwo.Zpo1oSon5ohi8ebme9tipi4lecaetwdcoceiicalltaynlhsttaa.ecltsilicTuoaumhnrlieupsosifc.negllof ocorguannteedll.es. Some granular deposits noted in mitochondria. Fourteen (14) peroxisomes Zw1it5h8f9i6n.e gLriavneur.laHr mepaatteorciaylt,ephroabsacblulymppriendgoomfinoragnatlnyelglelyscwogitehn.intMerivtoecnhinogndcryitaopaplapsemarfilled Zcdoe1un5ns8et9e7adn.. dLciovnerta. inHseopmateocgyrtaenuaplapredaersposismitsilaarndtodtihlaotseeddcersisctraibe.edTaebno(v1e0.) peroxisomes Plasma Fmoeumrtbereanne(1s4a)repeinrodxisistionmcte.sAarehecmouantotepdo.ietic cell is at the bottom of the photograph. sZe1r5v8es98f.ouLriavtetra.chHedephaetopcaytotecymteosrpinhothloegtyopescseenntteiralolyf tshaempehaostoagbroavpeh.. AThbiirlteeecnan(1al3i)culus peroxisomes counted. Conclusions: There appear to be increased numbers of peroxisomes per hepatocyte. Average 12.8 per hepatocyte. Suboptimal fixation of tissue. 00157# TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19560-2 Treatment Group: 1.6 mg/kg Sex: non applicable_______ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue: Lung________________ Block No(s).: 99.39-24_______ Photo/Negative No(s).:Z 1Z58195990- 3 Significant Lesions (check one): X Yes _______ No Interpreting Pathologist (signature and date): _________________ bpFraeesasitleuanrrteliasnm: tehZle1la5arl8vb9eo9od.liaeLrsu.snpAgac.dejA.aclAevnettothlliuensilneagfntdcoelfilnltshineagpppcheeoaltlrosg.torCabpeehnPtirsNalalscs.emllAailslfrcaeaePpNeilrl2yartwhyrictohocnystetaevienisrianlg Za l1u5m90in0a. l Leuryntgh.roAcylvtee.olNusoaanbdnolirnminaglitcieelslsn.otAedt .top center is a single PN2 which contains fwivitehilnamcaeplliallrabryodliuems.inTa.woNloamlaemllealrlamr ymealitner-ilaikleissitdruecnttuifrieesdinwimthiidndlaelvleefotlaorf spphaocteosg. raph are Zly1m5p9h0o1c. yLteu.ngT.wAo lcveenotleursliannidnglicneinllgs cbeoltlhs.coNnutacilnealtaemd eclellalrfbreoediiensaalnvdeoalrues PaNpp2esaersveton be a Zccthho1oan5urt9aag0ichn2tes.ornsiLsoetumiicnsego".llfaigPmAhNetcl2"llsuaa.srntNbdeoroodonliafeemspinseaeln"luddamracrmookcn"aynt.teeerLcsitaa,slrfgotioseuritcdhuoeebfnonwtiiefdhxiaeitcldfhplwanctoeitteunhnmtiaenidonacPlylvaNteemo1aelsatlelrlagosrmwpbaeeocnrdetls.iee.fst Zwi1t5h9in03a. sLeputnagl.wAallg. roTuwpoocfeclulsbcooidnatal ianncdleflfatstt,ebnuetdnponneeucmoonctayitnesdaenfidnivtievnetrlaalmcaepllialrlabryodies. No abnormalities noted. oCnoencclluusstieornosf: PNTy2p, epoIIsspinbelyumsuogcgyetsetsivfeaiorlfyineacsrielayseiddennutimfiebderisnothf iPsNa2n.imOatlh,earnwdisaet uleltarsatstructural morphology appeared essentially similar to control sections. TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19560-3 Treatment Group: 1.6 mg/kg Sex: non applicable_______ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue:_____ Liver______________ Block No(s).: Photo/Negative No9(9s.)3.9:Z-1255Z_91_05_49_-0_8__ Significant Lesions (check one): X Yes ________ No Interpreting Pathologist (signature and date): __________________ Features: Z 15904. Liver. Hepatocyte bordered by hepatocytes on three sides and ZcScsilre1nuivs5umte9sanp0oei5.i(nd.7gT)Lweopiinvfteherl(roa1h.rx0egi)Hmseopreamepotroareogptsxoaoiccnisyeoeottulmielcneetwsceseidwtcl.hliotouhcnlniuntrmeitdghp.heitnc.gyBtooifpleolarcsgamann.aelliMlceuistl.oi caThthoteonpdRraEinaRdcaoopnnptaleeianfrts.sodTmihlaeetrededil.iasted Zdisil1ca5ltu9em0d6pc.irniLsgtiavoeef.r.thFHeifteleaperagnteo(rc1yo5tr)egpawenrietolhlxeihsse.ommMaetisotopccoohiueontnitcdedrci.aelSlcsoonamltoaeinnpgesrtooompx,iesloedmfetn,esaseneddxebhpoibottsiotitmms .aarnTkdehdere Zde1g5e9n0e7r.atiLoinv.er. Hepatocyte morphology essentially same as described above. Seven (7) Zpe1r5o9x0is8o. mLeisvecro.uHnteepda.tocyte adjacent to central vein. Appears similar to previously dcoeuscnrtiebde.d cells with clumping of mitochondria and RER. Twelve (12) peroxisomes piCneocrrnoexcalisuseosdmionenussm:pbeCreerhsleluoplafatproecfryioxtxea.tiisoonmseusbcoopmtimpaarledtowpiothorc. oTnthreorleliavpepre. aArsvteorabgeesl1i0g.h2tly 00157^ TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19560-3_________ Treatment Group: 1.6 mg/kg Sex: non applicable________ Species/Strain: Crl:CDBR v a f/PIus Rat Tissue:______ Lung______________ Block No(s).: 99.39-26_______ Photo/Negative No(s).Z:_1Z51951901- 4_ Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ Features: Z15910. Lung. Alveolus and lining cells. All pneumocytes are cuboidal in PthNis2p. hTohtoegtrhaiprhd.ceTlhl ealsseoccoonndtacienlsl ftrwoomstmhealrlilgahmt eclolnartabinosdiseesv. eNraol loatmheerllraermbaordkiaesblaend is a Zfaep1ap5teu9ar1res1s.tnoLobtueendga..PTNh2eadltahrokucguhbodiedfainliltiinvienglamceellllcaornsttaruincstumreusltaiprelencoyt twopitlhaisnmtihcevvaaccuuoolleess.and The pneumocyte at top right also contains 1-2 vacuoles which probably are/were lamellar Zbflo1adt5ti9een1se2. d. aLnudngto. bAelPveNollsu.s Aantdblointtionmg coefllpsh. oAtolgornagphthienaclovleloaplussedpnseeupmtalocayreteasisalal caeplplear cporensteanintiinngthmeualtlivpeloellaarmspeallcaer.structures, cytoplasm of a PN2. No lamellar structures are ZPN1519l1i3n.esLthuengr.emAaitntdoeprcoefnttheer aailrawrgaey PspNa2cec.onAtat ibnosttmomultriipglhetlaamcaeplliallrabryodcioens.taiAnsdaarlkartghein wanhditneubclloeoadr ecnevlle.loDpoe.rsal to this is an unidentified cell with dilated endoplasmic reticulum eZSxe1tv5rea9rc1ae4ll.lcuaLlpauirlnllagar.mieesAllalavrreebopolraderisesespn.atcLieninatihnnedgplpihnnoietnouggmrcoaepcllyhst..esWiniththinistrheegiaolvneaollluaspapreeamr tuoltbipelePNls. bCoodniecsluisdieonntsif:iedE.ssSeonmtiaelllyamnoerllmaralbfoedtiaelsluwnegr.e SococmaesitoynpaellIyI pprneesuemntoicnyatelvseaonldi. lamellar 0015JO TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19562-2______ Treatment Group: 1.6 mg/kg Sex: non applicable_______ Species/Strain: RCarlt:CDBR VAF/Plus Tissue:_____ Liver______________ Block No(s).: 99.39-27_______ Photo/Negative Nois).:Z15Z9115591- 9 Significant Lesions (check one): X Yes ________ No Interpreting Pathologist (signature and date): __________________ Features: Z15915. Liver. Hepatocyte and surrounding hematopoietic cells. Sinusoidal eenvednoltyhedliisupmerasendd.plDasilmataedmcermisbtareanaerse aprreesinendtisitnintchte, bmuittoccyhtoopnldarsima.icNoinrgea(n9e)llpeesraorxeisfoamirleys cZpor1eu5sn9et1ne6dt ..inLthiveerm. iHtoecphaotoncdyritae. aSnidnussuorirdoaulnednindgothheemliuamtopaonidetpiclacsemllas.mDeimlabterdancersisataree are Zimn1ud5cis9ht1ion7cf. tt.hLeiDvceiylra.ttoapHtiloeapsnmaot.ofcRPylEtaeRsmw. iaEthmlecevlmuemnbrp(a1inn1eg) piosefironordxgiisastoninmelclete.sscTaonwudenltwveedas.(h1e2d)-opuertoaxpipsoeamraensce of cZo1u5n9t1e8d.. Liver. Hepatocyte morphology similar to those described above. Mitochondria cZRo1En5Rt9a.1in9M.sioLtmoicvehedor.enndHsreieapdcaetoponoctsyaititens csaoonmndteadiidnlaestnemsdeucldtrieipsptloaeesci.tlseEaairngvdhatdc(iu8lao)tlepedseraconrxidsistmaoema.rekTsehcdiorduteinleatnetido(.1n3o)f peroxisomes counted. Cinotnhcelnuusimonbse:r oPf opoerrocxeilsloumlaersfipxeartihoenpoaftolcivyeter.tisAsuvee.ragTehe1r0e.6apppeeroarxsistoombeesapselrighhetpiantcorceyatsee. C015S TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19562-2______ Treatment Group: 1.6 mg/kg Sex: non applicable_______ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue: Lung________________ Block No(s).: Photo/Negative N9o9(s.)3.9:Z-1258Z_91_25_09_-2_4__ Significant Lesions (check one): ________ Yes ______X No Interpreting Pathologist (signature and date): __________________ jZecZacbTeZmcZmpFw"Pvfulnpoerooen1a11h1Naesyuhindnpdmnce555tet5talitottotelutiut9ch999teeatesapidcatoumoh2r2p2n2r.isihtharonlnry432le1seeooctroeeecisSh,"d..k.lsoncfnvtsyieioloayng:ldimttAowLoLaLadhelnttrlumbbaemuueue.hleeiieZctvellairnfnnni.eaoenweytcce,Lr1gggtlerlnsolohotlo5lbl.i.li.xhwasguytalnl9futhtluarrwn,riAIr2aiatotnponsAntadbhanb0pohcaupulgcot.idaoslvytilcvestevhnsddenldLettlalaoecrehdeeiicedolyruecesafoouseeulectmctusnlallunllvsidvo.aiuealsorcgnstna.aeenennrsatel.ctcrioIaleopadoitntntyktuan.aenlAtAtgiaanavuoiirabirdtwsnnnbatsrdlamlecovlesdlglcbiltysetefscetiehuopioalnhom.emosomtelopaduhinisrllfnnpclaTiyu.nlupteeelsaoeghttldeswthcstoapsthpApyoif,eiuec.pnasrthpcc_dbveaoleingoaylslis_aolnaodecsidiuoplttmn_fncdsayioeniiaodsi_.ulngstltgenniehalpea(h_olTenralgvpepeislelia_lieirshaetnnetpnnpcync_aadhernsdgeigeh.edr_ascetbosaleclwror_Alfrlcplrioatakeeestse_hsphpsaltdhnfafllie_rcttoiratitletyldbysceoloeeusr_anli)eohspsa..stitra_t.ecbrattleeh.elbe_tumnrlAe,iaoTdnDoycI_dtTttcmaahIataeloe_ieohalnyfraneldcpe_lkPltlredpirrglaednstb_NtPipnstncalsoogeie_tiiNeulislto2enpunhfrda_leaclni.lty1pmitmeaarg_roulnre.remiih_Trmgoatcdosoegutiot_nhacblhgefhsnaAclP_pdyielaeh.abttnesalh_iNtbsnretalarlvleaeiol_lluoroniselyca"sv_cimstlradbneershirao_.yapaonlmtomeelpllrn_piduonrPraCcrcntp_ayoeinwlaeNocegetat_lweausidyylanspen1t_lrelnPph.hi"trisc_nncaadwlNiiewel_lltcl-rAoiemeaa,lnehll1h_ldnhailfrmowio.ka_triilscna.cwecalsynei_eahigroseshrynl_peeiNgtfnilceiali_sricahepntifglhony_arnllrladirguaatenit_oecsbalPnorrtfadcwn_omrteoittspNemekeh_'ndiilbnitstltets_tani1hlewhyaees_elaaidsimlo_nsnt.a_str cCoonntacilnuisnigonlsa:meElslasernbtoiadlileysnwoermreaildfeentatilfileudn.g.NSoolmame erlalnadr obmodtiyepsewIeIrpenseeuemn oincyatlevseolar spaces. 0015SJU TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 15962-3______ Treatment Group: 1.6 mg/kg Sex: non applicable_______ Species/Strain: RCarlt:CDBR VAF/Plus Tissue:_______ Liver____________ Block No(s).: Photo/Negative No9e9s.'3).9:Z-2159Z9_12_55_9_-2_9__ Significant Lesions (check one): _____ X Yes ________ No Interpreting Pathologist (signature and date): __________________ Fheematautroepso:ietZic15ce9l2l5o.nLthiveerri.ghHt.epTahtoecreyties sculurrmoupnindgedofbytheotchyetrohpelpasamtoiccyotersgaannedllaes and ldaerngseitaieresaasnodfswomaseheddilaotuetdccyrtiosptalaes.mT. hMerietoicshdoinladtraitaioanppaneadrbtloebhbavinegsoofmReEgRra.nTulwarenty-six Z(2165)9p2e6r.oxLiisvoemr.esHceopuantotecdy.te appears similar to hepatocyte in Z 15925. There are hZe1m59a2to7p. oLieitvicerc. elHlsepoantothceytleefwt iatnhdinbdoitstotimnc.t cTywtoepnltays-mthirceebo(2rd3e)rps.erToxhiesroemisesdicloatuanttieodn. and blebbing of RER. Mitochondria appear to have some granular densities and some dilated cZr1is5t9a2e8. .TLwievnetry. -oHneepa(2to1c)ypteeraopxpiseoamrseesscseonutnitaeldly. similar to above cells. Fixation is sZRuE1b5Ro9p.2t9imM. aiLtlo.ivcTehwro.enHldvereipaa(1tao2pc)pyeptaeerrwotoxitihhsoaivmnedeisssotcimnocuetngctreyadtno.upllaarsmdeincsbitoierdsearns.d Tsohmereediisladtieladtactriiostnaeo.f Eighteen (18) peroxisomes counted. Conclusions: Increased numbers of peroxisomes per hepatocyte. Average 20.0 peroxisomes per hepatocyte. Poor, suboptimal fixation. coissj TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19562-3______ Treatment Group: 1.6 mg/kg Sex: non applicable_______ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue:______ Lung______________ Block No(s).: Photo/Negative No9f9s.)3.9:Z-1350Z_91_35_09_-3_4__ Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date):__________________ eaZnaarZaaZaZbowlpblFpPaeannnlpnpuuprer1N11ev1hmlmeedddpgpnctee555a5ei2ssoleueenactee99t99oeeeemhaatashull-lc33r3nunl3halleefrtraayroaa324htsatre1diey.rfttrrsno...cl.oihlnsstintlenalbbnhcaOhr:uuaaLLLLdtbeooooloeoittcmmnuueuunhedcdntlwconZelnnnenneyseyyetecPinuaungigeggn1tl,llPsnacelNildd.es....i5taenilNglnhoa..nve9rvalaegAerAArs2auuec3de.blssNA,.yosocr0ljllculaocevaavvoallnoe.llrvobxeaclieveewfltdPeutuuhrelaaoooleLloseaepstNnaciilolll.iubn.nmruuurutlttail2aegntistsussmalisttienSsegsossfnewsaalaoteion,.dlme.acnennpnaihmuvlcytddddsAr.Pip.miceotnecetNlobarllllnuihyCeNiviiiapsnods1ntnudnleamaoglddhlitisioaopainonnvnila.npascuemeliggsgaumullcseosnTcllcreseldcacdcuuisilalhtllreiceesgeiseulalorfeialalluuehvnefbllalltvreesassstyecsodunpa....rslrvepfadlcewr,allaaefpeTiucTnCWllwircnc.ispynotthhieuolieishehmtidalnaeeAnolnttoeaimilrtghetcltmsprnaeulmlre.inslh.apeadglcncseadriltlsestt.AdahgdlSlsouoietlaynmphdeeilnotrdtTrascthpeleomtio.tdelhobsseaheeetiaoeeennollaelxaTlailivdryiitdrnvatosnnsawtPe.edileao_tmbioigeotnNoanonolph_cnlsldragsolp1ee,ac_bkPuliitnlnr.ll_ensasoclsNlePgeseu_sgtepaaPN"uuiveN2ml_sarnelNibpmeoslo_nn2muapeartuwf2_tdawroacnnlolpwgft._.aillcaehriteeetom_ytrhtehuvyiTruThhfs_etyiesma"eseheoch_utntcldlsahhehneaollb_rudaanaaeflmrcae_looocrylrmadovynpki_loattcecnbeehhtepaelu_ntlyeciosvoeaaellenn_teatslledtlanraehaagau_hmilroiitralnsralts_nebliptlasbdt.ctubnsa_sahoolnoocscoil_rneodTnoeneednhbd_opnmiuonlghPiteeeit_lpoeeamteeedNsae_cfsrirnfsyndldetdeol_o.a2ucaiaassilicor_tectbslrsteiehTtiysnnlte_tlateesnleeieithn_nnntneuorae_ecscensf_dttda_,ll Conclusions: Several type II pneumocytes with lamellar bodies seen. Also, some lamellar substance within alveoli noted. 0015S4 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animai No.: 19568-2_________ Treatment Group: 3.2 mg/kg. high-dose Sex: non applicable________ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue:______ Liver_____________ Block No(s).: Z159799.399--1Z11_5_8__0_2_, __ Photo/Negative No(s).:_Z15909__ Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ Features: Z15799. Liver. Hepatocyte with sinusoid containing hematopoietic cell at ctdoriipssttiaannecd,t amlonundlgttiihtvueerdseiinciasullsasoremgbemoddeyni.ltatoNefdubmbilleeerbocbauinsnagmlicoitufolRcuhsEoRant.dbrSoiaitntsouhmsoowriidgsaholtme. neHdsoeltpihgaehtloticadyliltcaeetilcolonanttoatfoinpsisone Zpo1o5r8ly00d.efLiniveedr,. suHgegpeasttoicvyeteofssuurrbooupntidmedalbfyixhaetimona.toFpoivieeti(c5)ceplelsro. xSisioxm(6e)spceoruonxtiesdo.mes cZhoe1up5na8tt0oe1dc..yteLiivseirn.dHisteipnacttoacnydtefisxuartrioounnidsepdoboyr.h.emMaittoopchooientdicricaeallpsp. eParladsemnasemwemithbrsaonmeeof the gpZer1ar5on8xu0ilsa2or. mdLeeipsvoecsroi.tusnSatienmddi.ldairlaotveedraclrlisctealel.ulDarilmatoerdpbhloelbosgyoftoRZER15a8r0e1.noPtelads.mTahmreeem(3b)rane is indistinct. . Mitochondria appear dense with some granular deposits and dilated cristae. ZSReE1v5Re9n,0a9(n7.d)Lpriaevnreodrxo. imsHopempeeraostoxcciosyuotenmtweedsi..th. gMraintouclharoncydtroiaplaapspmeairntdeernmsiexewditwh istohmmeitgorcahnounladrria, Zde1p5o7s9i8ts: aLndivedri.latNedo cnreigstaateiv. eN; ninoep(r9in) tpdeerovxeliosopmede._s_c_o_u_n_t_e_d_. __________________________ Conclusions: Normal hepatocyte. Suboptimal fixation. Average 6 peroxisomes per hepatocyte. 00155$ TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animai No.: 19568-2__________ Treatment Group: 3.2 mg/kg. high-dose Sex: non applicable________ Species/Strain: Crl:crxBR VAF/Plus Rat T is s u e :________ Lune____________ Block No(s).: 99.39-12________ Photo/Negative No(s).:Z ZI518508307- Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): ___________________ Features: Z15803. Lung. Air space lined by several cuboidal epithelial cells. These Tcehlelsyahpapveeafritnoebgerapnnueluamr coyctyotpelsaswmhiwchithhoavuet mnoatnyfladtitsetninedctoourtgainnteolldeisf.feDreonrtsiaaltleydaPreNtlws.o Zbl1o5o8d0v4e. sLseulnsgli.neAdlvbeyoelunsdoanthdelliianlincgelclse.llsN. oTlwamo eclulabrobidoadliepsnenuomteodc. ytes are PN2s and TcZtioso1ns5utt8hae0ein5isl.elcafLtomliulsenalapglas.creadbApoislcdelliapuertssya.telariTnnodwefdoccebualylbdojtaayincdpeaeenlsntpdaPnoreetNhulelemslsisoaalcrceycleteaealsslrs.loysiWcmdiaeiittflheaindirnatwbotlhiettehh. octsahepeisdleleascrceyrlilabsr.eedAtwidnojaZc1e5n8t03. lamellar-like structures that appear to be extracellular. No PN2s or alveolar lamellar bZo1d5i8e0s6n.otLeudn. g. Alveolus with lining cells. Pneumocytes are low cuboidal and appear to bweitPhNanIso, ballothnogunguhcnleoutscaopmppelaertseltyo bfleatatefniebdroobulat.st.NoIt PcNon2tsainnostendu.mTerhoeucseRllEtRo tahnedrisgohmt e cZo1l5la8g0e7n. fLiburnilgs. arAelvpereosleunstweixtthratcweolluPlNarlys., although cells are not flattened. Adjacent tissue is collapsed septa and interstitium. No PN2s or alveolar lamellar bodies noted. mCoatnecrliualsiaolsnos:prOescecnats.ioMnaalntyyptyepIeI Ipnpenuemumocoyctyetsesnohtaevde. aSpopmareenintltyranvoatscflualtaternlaemd oelulta,r-like probably normal fetal lung. 0015S< TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animal No.: 19569-1__________ Treatment Group: 3.2 mg/kg, high-dose Sex: non applicable________ Species/Strain: RCartl:CDBR VAF/Pius Tissue:_____ Liver______________ Block No(s).: 99.39-13______ Photo/Negative No(s).:Z1Z518548347- Significant Lesions (check one): X Yes ________ No Interpreting Pathologist (signature and date): __________________ Features: Z 15843. Liver. Hepatocyte adjacent to central vein. Abundant numbers of mareitopcohoorlnydrdiealiannedatRedE.RCarriestpareesaernetd, iblauttepdlaasnmd abrmokemenburapniens saonmdesimnuitsoocihdoalndernidao. thelium MZ1u5l8ti4v4e.sicLuivlaerr.boHdeyppartoesceyntet. wiEthlesvoemne(1ra1r)epfaecrtoixoinsoomf ceystcoopulanstmed.. Dilated RER are epveirdoexnistoamndessoarmeecogurannteudla. r deposits are present in mitochondria. Eleven (11) Zph1o5t8o4g5r.apLhi.veMr.itoHcehpoantodcriyateinwhiethpahteomcyatteopcooinettaiicncdeilllaitnedsicnruisstoaied. aTt wloowmerulletfivt eosficular bCoydtoiessolaraepppereasrsenrtarineftihede cayntdoppllaassmm.a mTheemRbrEaRneaipsppeoaorsrldyildaetefidnewdi.thEsloemveenb(l1e1b)bing. peroxisomes counted. Zth1o5se84d6e.scLriivbeerd. aHboevpea.toAcygteolsguirraosusnodcieadtebdywhietmh amtouplotiiveetisciccuellalsr.boMdoyrpishporleosgeynts.imTihlaer to mpeirtooxcihsoonmderisaccoounnttaeidn. multiple granular deposits and dilated cristae. Eleven (11) Zdane1df5in8de4idl7a.taenLddicvfreiixrs.atatiHeo.enpNiasitnosecuyb(t9oe)p,tpsimeimraoilxl.aisTrohtmoe eamsbioctvooecuhndoteensddc.rr_ii_pa_tci_oo_nn_st_.a_i_nP_lma_s_um_l_tai_p_ml_ee_gm_r_ba_nr_au_nl_ea_ri_sd_ep_po_o_os_ril_tys_ Conclusions: Hepatocytes appear to contain slightly more peroxisomes. Average 10.6 pweirthoxciosnotmroels. per hepatocyte. Suboptimal fixation. No other difference noted compared ^0 0 1 5 8 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animai No.: 19569-1_________ Treatment Group: 3.2 mg/kg. high-dose Sex: non applicable________ Species/Strain: RCarlt:CDBR VAF/Pius Tissue:_____ Lune_______________ Block No(s).: 99.39-14_______ Photo/Negative No(s).:Z15Z8145885-2 Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ Features: Z 15848. Lung. Alveolus with lining cells. Several cuboidal pneumocytes are pboredsieens,t.alTthhoeucgehnttrhael lcaemllehllaasrtmwaotebraisaillaisr avbasceunotleins wthheimch. pArosbmaablllyproerptrioesneontf laasmeepltlaalr cZa1p5il8l4a9ry. iLsupnrge.seSntecattiolenfts.hows several cuboidal to columnar epithelial cells. The central claemllealplaprebarosdyto. cToonttahien ltowwoesrmriaglhltvoafcuthoilsesc,eollnies wa ictehllsowmiteh lainpiidr-rleigkuelmaranteurcilaelu, spoasnsdibly a tsheevecreanltleirpiodf othrelapmhoeltloagrrvapachuwolieths;atnhiesncdeollthaeplpiaelalrisnitnogbeceallms. acrophage. A capillary is in Zfin1e58g5r0a.nuLlaurnmg.atAericallu. stNeroocfhcaurabcotiedraisl tpicnelaummeolclayrtebso, dwieitshamreopsrtleysecnyttoinpltahsemsecponnetauimnioncgytaes obrutinthtihsecaellvl eisolnaortscplaecaer.lyAindeinntteifrisetditiaasl tcoelclecllontytapien.s a single myelin-like or lamellar body, pZZaPfiphN11bpo55rleot88soab.55grl12rat..asoptLLbhaueuspn.nppggen.T.aehruTAsemwttocooolpcucyPoscttnNeeetlsr2al sio(cnPfoaNtnprhetnelaepsi)uenrelmswosnaeohngcicctayohttaueenpdhsdlaeonvtruhleaceenmlyp'etiuetcfhlsolleaantltortitaaebtilnhnoeceddemirleiluossgluhtaatit,nspodoldefreiltsPshacNamersi2PebesNlelPdia2nNr.inbt2rTosaa.hdnbeisoeivcsti.eeolnlAsto Conclusions: Essentially normal lung. Some random PN2s were identified. There are numerous cuboidal pneumocytes which appear to not have flattened out. 0015SJ TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animai No.: 19572-1_______ Treatment Group: 3.2 mg/kg. high-dose Sex: non applicatile________ Species/Strain: Crl:CDBR VAF/Pius Rat Tissue: Liver_______________ Block No(s).: Photo/Negative No(9s9)..3:Z91-51Z8515_53_8_5-_7__ Significant Lesions (check one): _____ X Yes ________ No Interpreting Pathologist (signature and date): __________________ NFdeeitnaaetiulsr(e9a)sre:paeZpro1p5xa8irse5on3mt.lyeLsliocvsoetur..nMtPedlea.msmbraanmeesmabnrdacnreisstaareewpoitohrilnymdeitfoinchedonadnrdiamaarenyincdyitsotipnlcats.mic ZZdu11e5588to5554p..ooLLriivvfieexrra.. tiHSoinem.pialRtaoErcRtyoteaZpw1p5iet8ah5rsh3,emmpalaarktsomepdaolyiaendtidiclaccteeelldllu.sltaTorhtmihreteemreinbgrh(at1n3me)sapraegrreionpxaoinsoodrmlaynedsoetchfoienurendted. mheepmatborcaynteesaanrde binildeisctainncatl.icTulwuselavteth(1e2t)opp.eroRxEisRompreosficleosunatreedd.ilated and plasma Z(1145)8p5e6r.oxLisivoemr.esHceopuanttoecde.llular morphology is similar to cells described above. Fourteen Zm1e5m8b5r7a.neLsivaerer.poHoerlpyatdoecfyinteeda.ndEsiugrhrtoeuennd(i1n8g)hpeemroaxtoispoomieetiscccoeulnlst.edP. lasma and cellular hwCeoiptnhaictnoluchyseitope.natso:cyHteespaastoccoymtepsapreodorwlyithfixceodn.trTolhse. reAavreerahgigehe1r3.n2upmebreorxsisoofmpeesropxeirsomes 00158^ TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animal No.: 19572-1__________ Treatment Group: 3.2 mg/kg. high-dose Sex: non applicable________ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue:_____ Lung_______________ Block No(sL: 99.39-16_______ Photo/Negative NoisT:Z15Z815588-63 Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ pZwmdZbbrplgZnpbZaesbFZliiahouielorreugn1o1g11i1eartmaydltobsmhh5et5ehy555aohanttsytotuco88eoth8n8t8nio.uie,bptunmu6bl6m_r65i6ggrllles"togyr32oloT_a091rioayeecthm..aucra_..rph.ocbmsycpiysL_blreyga:sneLLtLaaLheta_poeumtlchleopmcs.ueuuuo_tdnyftfteoiyZsaannninwi_iylegtnsblbfnxl"logggg1_lla.laltordlaa.tppa...5pt_lroaopthtpiatlryC8phi_nrlbtaoCCeesmoiet5Le_Aolsdnrehslctnnaooa8gmut_eehlaedieoli.slellrn.rmln_rveoballtnildagraaga.tte_cnrapSitLoenaepripogra_isoseoenluNniuosslievhb_.ubtnnam.nuleenofdeoteo_totcddsd.gcThpoaeTsc_oldoPsaou.eoalhyss_yfhtcNeccubnsNnehmeit._peceeAeisinsetpodpetolnat_al.Ole.soltaltltlcspnit_aoipvuulrlneten.walais._mphmrelAalrlsalumaelli_oemNiratcLcatradcssr_lehmearellieueooetidaeyi_alnrlhlnlvtlslamsi.leul_dilsaesinogey.aebasnpaip_riirTmrtss,rrblnnngeaab_Pabiithoaabncdgaslcneneh_lotetnioeaiohue_Plptfdincllatisdsotiiilyl_nNligeigecsmnoraymeysPspl_ehidimc2slogacaNuanr_lst.vcy.riehse-blmgie_nuae2tasoeladstnNell_cebt.nfepmlcoesTaosotuda_odon.epwnceirTorreoi_niltevtymbsdclislMilha_miastetiaifyeenaanhetae.ir_trmssmlleygoh.liaal_dttniodueCslalaloehta_paievAft.iltnllncefeaeilr_afnlabaldnaaritkatnsraF_leeancoptp-retiittau_liamlgnpnrtpstpertvxibspeamp_yohkueneaeaecoclnpi_ptdaaeceaotomleeedeelcierg_llodrllicdloedaimaallne_abrteyt.sIurnroPspo.rir_swy.patsnapaitNe_ts,inblolccghTnnessLlnp_ee1loiarimeehtbeeapci_cuai.rnssunteacxaeeoyhn_maytmleiretlaaSodr_npcPll.cncgoriityroe_oegnnNoeooa.ediclm_cnpnennlyoIc2pttsy_pvhtdhtetteaosioptaa_ehseieloite.monidissll_easntnatv,retehlr_oT.oeovlsimiausnbyenn_appheccmaAtlolge_tseuirdrrotclias_yntoliiohnleaeeoalgga_succlbnflnmthhertdtc_yiocohahtnateta_ltnmeettleieeeplrthsas_wrtllruoksdaaplsna_a,iomistti.etdstw_aerndrhanm_ruAoriod_esaan_lytte_oo pCnoenucmluosciyotness:. FEisxsaetnitoinallwyansosrumbaolpftiemtaall.l_u_n_g_. _S_o_m__e_l_a_m_e_l_l_a_r _b_o_d_i_e_s_n_o_t_e_d_i_n__ty_p_e__I_I 00159 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animai No.: 19577-4_________ Treatment Group: 3.2 mg/kg, high-dose Sex: non applicable________ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue:______ Liver____________ Block No(s).: 99.39-17_______ Photo/Negative NZo1(s5)8.:64 Z- 1Z519548068 Significant Lesions (check one): X Yes ________ No Interpreting Pathologist (signature and date): __________________ FPleaastmuraeasn: d Zce1l5lu8l6a4r.mLeimvebrr.anHeespaarteocinydteiswtinitcht sduurerotounpdoionrgfeixryatthioron.cyMtesitoinchsoinnudsroiaidssh. ow Zso1m58e6g5r.anLuilvaerr.deHpoespiatstoacnydtedsiulartreoduncrdiesdtabe.y Tadhjraeceen(3t)hpeepraotoxcisyotmeseasncdouhnemteda.topoietic cells. cAoubnilteedc.analiculus is present at the bottom of the photograph. Eleven (11) peroxisomes Z15866. No negative. ZZRpZe11E1r555Ro589x.664i8s70Po...lmaLLLsiemivisvveaeesrrrh.m..oHewHTmehepabepdaraptvatolanoacnecsycsymteteaedarweamdineitendhgmdeapinbsdoetrjoiraanarncclteeyiton.-idntsSe.hifienximndteeiasedttnoipnp(lco1at.s6iem)tEipacleemcrvoeeelxnmliss.b(o1rmDa1n)eielspaset.ciroooMunxniiasttneooddcm.hbeolSsenobcdmobriuieanngostehfodotf.hwe dilatation of cristae. Fifteen (15) peroxisomes counted. ihCneocprnaectaolsuceysitioen.ntsh:e nHuempbaetorcoyftepsereoxxhiisboimt feesaptuerresheopfaptoocoyrtefi.xaAtivoenr.agTehe1r1e.2appepreoaxrsistoombeesapselright 00159$ TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013: EM-99.39 Animai No.: 19577-4_________ Treatment Group: 3.2 mg/kg. high-dose Sex: non applicable________ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue: Lune_________________ Block No(s).: 99.39-18________ Photo/Negative No(s).Z:_1Z51856897-3___ Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ Features: Z15869. Lung. Alveolar space and lining cells. Central pneumocyte on raingdhtmcaoyntbaeinaspsneevuemraol claymteeollrapr obsosdibielsy aanldymispahoPcNy2te. . AAdtethtaechtoepd lceefltlisisajucsatpailblaorvye wthiitsh oanne oblong endothelial cell nucleus. Zse1v5e8ra7l0.cyLtoupnlga.smAicrevaaocfucoolellsa,ptsweod oaflvweohliacrhsceopntata.inCleanmtreallllayribsoaddyamrkatceerlilalt.haTt wcoontcaeilnls nbwoeinttheflaaatbthtuetnnhdeisadn.ctemll oalrseoccleoanrtaciyntospimlaislmar acpyptoepalratsombice tvyapceuoIlpenseaunmdomcyatyesb,eaPltNho2us.ghOtthheeyr acreells Zan1d58c7o1v.erLedunbgy. itVceonnttraailnlys amPuNlti1plleinsems athllecaleirawravyacsupoalcees., Tbuhtelsammaellllearr dmaartkerciealll iasdnjaoctent to ccleellasr,lycaepviildlaernyt.luDmoerns,alplnyetuhme oticsysutees,coanndtaiinnstecrsotliltaiupmse.d Nseoptaabwnoitrhmaalmitiiexstunroeteodf.endothelial Zva1c5u8o7l2e.s aLnudngla.mAelrleaar obof dcioelsl.apVseedntarlavlelyoliisaancdaspeiplltaar.y Ccoennttarainlliyngarae ltawmoePllNar2-tsycpoenbtaoidnying TZrwihg1iteh5h8ticn7ae3nni.dttsratLloluupcmnergeli.lgn.hcVot neantraetirncasallpyailcalaoreruipseelsevcesormanltaalcilunlbianomgidesalollampr-entyelupamemsoetlcrlyuatcretmsurlaeitnseirniinaglitaisnncatyhltveoeiprolllauasmrmsi.pnaaTc.eo.Atht e the top is a flattened pneumocyte._________________________________________________ sCtrouncctuluresisopnrse:senNtowrmithalinlucnagp.illSaorymleumtyipnea.II pneumocytes identified. Some lamellar 00159^ TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19579-3____________ Treatment Group: 3.2 mg/kg, high-dose Sex: non applicable________ Species/Strain: Crl:CDBR VAF/Plus Rat Tissue: Liver_______________ Block No(s).: 99.39-19______ Photo/Negative No(s).:Z15Z817548-78 Significant Lesions (check one): X Yes ________ No Interpreting Pathologist (signature and date): __________________ Features: Z15874. Liver. Hepatocyte surrounded by hematopoietic cell at lower left caaonnuddnhstieendpu.astooicdelclounlataripnliansgmearymthermocbyratensesataureppinedr irsitgihntc.t.ESnedvoethnetelieanl c(1e7ll)ipseproooxrilsyomdeelsineated Z15875. Liver. Hepatocyte mixed with some hematopoietic cells. Hepatocellular ebGnorduaonnpdulalaarsrimedsiecaproreestiiitncscuoalrumempp.lreeteseonnt itnhissocmeell,maintdocpheornodxriisao.mTehsearreeanpoptecaorsuntotebdefoarbuthnidsacnetllr.ough Zm1it5o8c7h6o.ndLriivae,re.ndHoepplaatsomcyicterewtiicthuliunmdi,satinndctppelraosxmisaommeesm. brTahniersty, b(u3t0c)opnetraoixnissoambuensdant cZZSaono11udm55n88net77eu8g7dc.r..laenLaLruiivvleaeenrrrv..deeHloHpepoepespaiatatsotpocapcyreyetaeterp,,rdsesiislimametnieiltladarw.riiniTtnhwoionvevenesrtorayaml-llfleommumororir(ptpo2hh4coh)ololopongegdyryoritxoatoi.stothEhmoonssedeesodpdceolesasucscnrmritibeibedced.dreaatbibcoouvvleue..m Sanodmneugcrlaenaruleanrvdeeloppoesitaspapreearprdeislaetnetdw. iSthixinteseonm(e16m) iptoecrohxoinsdormiae.s Econudnotpelda.smic reticulum ahCpeoppneacatolruscsytiotoenb(sef:oiunTrcircseesaulslesedcfioxnuauntmitoebnde)rs.suNboofoppoteitmrhoeaxrli,scbohumatnebgseeptsteenrrohttheeapdnactsooocmmypteea.rperAdevvwieoirtuahgsceaon2ni1tmr.7oa5llslp.iveTerhrse.re 001593 TRANSMISSION ELECTRON MICROGRAPH INTERPRETATION Study No.: 418-013 EM-99.39 Animal No.: 19579-3__________ Treatment Group: 3.2 mg/kg, high-dose Sex: non applicable________ Species/Strain: Crl:CDBR v a f /PIus Rat Tissue:_____ Lung_______________ Block No(s).: 99.39-20_______ Photo/Negative Nofs).:Z15Z817598-83 Significant Lesions (check one): ________ Yes X No Interpreting Pathologist (signature and date): __________________ cZcrZcZdmalmcZrFctmauouaeepyoe1111eraappllaplprtg55b5ll5atlcoctsiteee8eu8l88utarairpclarnuoo8r8t88lraoilvrieepra3ap1n0r2tstnnadedhilhsh.h...cteutsmteeaaaaLhPouLsc(:LLgigpaeoillNun"uaecbeuouerplZsnsntpasi2ee.nwneeigvg.1lpsf.saghgpvee.aa.O5eAer.a.txcerccsAv8auvtTootCtutrerh7AmreuitAnliohtnare9eaeghatatrl"idcnrrros.alheeectleelisthipcsaaktlylrnalleLtuaeepalaeco?anioiutmluolpmnnno)penalltflnsfeyiegndaldePeatcagvadrtchnallNonsiar,n.ea,ollesp,osilyanoua2lcnlepbmrallallctAo.lasuenuiaotplblrheflpamiroetllrsOisopbvosranaeronesldeteemueputrgetciodmhndoiocgsmaueeaageaelehalnnlsibaluaerrdlPasl.tvlea_vslmnaircvvNatemm,nsen_ecenmaeoleauold_loo1ouaucilpnlpll.e_lntspmullcaitiapeitlia_stelorilrnralehpelpaTa_silianmaguenmrean,rlw_hedresliPdsacbs_el.anas.aeuNteslsop_tgslmeafreeTglelTdpe_t2irlm,rpdgtgphsiiie_ih.hmxatleaehteaeai_iepalsaelsnstrsliS.._nn.tlxdsceeaaiamodm_eeodnCiTnrtmwmru_donSagacdweobbm_rityeoiancwtyagosm_aiythlotosuiidmhbyl_irnnpcaintbaeiebop_lhieypinataolentrsi_aslratsephsropcsgyei.i_ePupegobntePtsld_iomNiraemlmh.aTNmnl_srabtcaa2hZoeeuoe_2ralenlidseclymv,s_l1lstcet,yloie_e5bcbeofauepabtovi_8ouyelulblxucllPeal8e_sltsueataaelarr.0N_aaltrmallacP,iald_plPal2SolessreNtems_sce.Nonlcholoebldo_p.leliumedrae1mn_sstlmlil.alrb.tl_saessmaaarar_meaTyairifwypnisr_drnhgabe.ebti_ehdbetaahnoeebe_ie.Ttgdcdriar_lasTihihriaan_aesseermphdels_cpk.aer.vo_creopeeesn_TllTbplresint_ahaaneaehpt_rlbriarintinen_aasrltyegsll_a_a SCoomncelulasmioenlsla:r Emsasteenritaiallliydennotirfmieadl wluintgh.inSaolvmeeolni.ormal type II pneumocytes identified. 00159^ IH. Transmission Electron Micrographs 001594 NOTE: TDher.oMrigarinvainl gTl.oCssaysefiwguirthe pthheotdorgarfat pphasth(oFloigguyrersep1o-r1t 4on) wMearrechde1li9v,e1re9d99t.o 00159$ Figure Legends Ancillary Pathology Report Primedica Argus No. 418-013 rpMehpaoogtrontmiffiiigccuraortegiosranap.rhe Paetrqiuanatmlmsaoaggnnenifiimfcicaicatirtooionnno(i0fs.10in10d,12im0c0amtXe).d. oTnhethme ebaascukreomf eenacthbaprhoontoegarcahph. All Fmiigtuorceho1n. dLriiavearn.dHroeupgathoceyndteopshlaoswmiincgrneotircmulaulmcyrteofplelacstsmsicuboorpgtainmealllefsi.xaCtilounm. pSinogmoef mpisegpr/orkexgsi/sedonamtyaet(sctohanreetjruiodnle)c,ntit1oif1ni,e2od0.f0tXHhreemmeaahgtenopipfaiotcioaecttiyioctnecs.eilnlstahreetporpesleefnt.t vAenntirmalally.NoA. b1i9le50c6a-n4a,l0iculus Figure 2. Liver. Hepatocyte. Dilatation of the rough endoplasmic reticulum, an Minditiosctihnocnt dprliaasmarae mdeenmsebraannde,shanodwosrogmaneegllreancululamrpdienpgoisnidtsicaantde sduilbaotepdtimcraisltafiex.atSioonm. e rs(ecinopunrestrosoeidln)t,iant1i1tvh,e2e0pu0epXrpoexmrisaloegmfntiefcsiocmaartieeorlnao.bfetlheed.phAontoegnradpohth. eAlianlimcealll Nnuoc.le1u9s5i0s9p-1re,0semntgl/ikngin/dgatyhe lFaibgeulreed3a.ndLiavpepr.eaCr emllourlearnmumoreprhooulsotghyanisinsimcoinlatrrotlos.FiTghuerero2u. gShoemnedoppelraosxmisiocmreetsicaurleum panhdotnougcralepahr eAnnviemloapleNaor.e 1d9il5a3te4d-.1,A0.4bimlegc/aknga/dliacyu,lu1s1i,s20p0rXesemnatginniufipcpaetirolne.ft of the Figure 4, Liver. Mitochondria show dilatation of cristae. Some peroxisomes, increased iAnnnimumalbNero,.ar1e95la6b0e-l2e,d.1.6Sommge/khge/dmaayt,op1o1i,2et0i0cXcemllsaganriefipcraetisoenn.t in the adjacent sinusoid. Fwmiiggth/ukirnge/md5.aiytLo(cihvhieogrnh. d-dHrioaes.pea)S,toe1cv1ye,tr2ea0lw0pXietrhmoaxanigsnionimfdiiecssattiainorcent.lpalbaeslmeda. mAemnibmraalneN.o.C1ri9s5ta7e7a-4re,3d.2ilated Figure 6. Liver. Hepatocyte whose plasma membrane is indistinct. Representative pmeargonxiifsiocmateiosna.re labeled. Animal No. 19579-3, 3.2 mg/kg/day (high-dose), 11,200X Figure 7. Lung. Alveolus and lining cells. Two type II pneumocytes containing lamellar betoxoppdriaeenssdsaebrdeotipttsoremlsaemmntea.lrlgaTrihnbeoocdfeitnehster.aalTirdyasprpekacIceep.lnleSmuumabyjoacbcyeetneatstayclpaveneoIbIleipasnreeeeuncmolliolncaiypntsgeedtwheahniacdlhvtehhoealsus at the Nreop.re1s9e5n0te5d-1c,e0llsmagr/ekgp/ndeauym(ococyntterosl)a,nd11s.e2p0t0aXl cmelalsgnaitfdiciaffteiorenn. t functions of cut. Animal f0 0 1 5 9 Ancillary Pathology Report Primedica Argus No. 418-013 TFalihvgeeuooreltuh8se..r TLlinhuininsggc. ecAlelllclvsoenaortleaiitnaynspdseesIvepeprtnuaelmulm.amoAceyltlytaeprse.bIoIAdpnienseenucdmoonotthcaeyinltieianligscefpalrlienastenlndatmclaiinpniianltlgeadrtyhmeaarretiegrhiat l. p(croesnetrnotli)n, 1th1e,2s0e0pXtummaagtntihfiecatotipono.f the photograph. Animal No. 18915-1, 0 mg/kg/day Fpaselrivegpesutaoernlecutos9i.n.ntaNLthiunoenintlgyug.pmceAeaInplIvioplelonfalertuhiuesemsauownpcdipythesterelspcutamoapr.iinllTalaamhlryeee.rlcylaeFtrnhltarbrotoatceldyninteeeasdsr.ratoryAewpeelavaIlimvdpeeenonlelltuuairsmnmiosthcybyiesotleiupnsnh-dlloiietnkodeegbtrshaytreputhwc.toure is Animal No. 19504-3, 0 mg/kg/day (control), 11,200X magnification. Flaimguerlelar10b.odLiuensgi.s pArelvseeonltucsenantrdallliyn.inMg cueclhlso. fAthetylpaemIeIlplanremumatoecriyatlehcaosnwtaainshinegd-mouutltoipflethe lsainmgelellalarmboedlliaers.boAdys.ecTohnedrteympeaiInIinpgnecuemllsocayptpeeiasrptorebseenttynpeeaIrpthneeubmototocymte, sa.ndAcnoimntaalinNsoa. 19546-1, 0.4 mg/kg/day, 11,200X magnification. ccFwaoihgpniuitclarlhieanrhiy1na1vgs.epsLanecuvoenetsgr.fa.lalAtAltaenlmnvimeeedolallalourNustbo.ao.ndTd1ihe9lesi5n.6lian0Tmg-h2eec,lel1ala.dlr6sj.ammcAyegent/klttighnli/e-ndlitiakonyepg, sci1ster1lau,l2scc0tuau0bprXeopsiemdaaararlegtotneyixbpfetiercapaIcItniepeolunnlume.luaomrcwoyctieythstein lFikigeumreat1e2r.iaLl,uwngh.ichAlivsecoolnussisatnedntliwniitnhgscuerlflasc. taAnltvseeoclraertesdpafcreomcotnytpaeinIsI apbnuenudmanotcylatems.ellTahr-e CdreaamrpkailiclnaeirlnileugslaliwrnsiitnehggmlcineeilnnlstgnaeepnapdreotahtrheteoblioabtletoctmyelplsemaIarypenbpeerueamsneonectxydtteeonsrssoiaorllncyuoabfnoadidtayatpl tephneIIelupomnweoeucrmyrtioegcshy.tt.e. The Animal No. 19560-3, 1.6 mg/kg/day (high-dose), 11,200X magnification. Flaimguerlelar13b.odLiuensga.reAplrveesoelnuts. aAndtylpineinIgpnceelulsm. oTcywteo itsyppereIsIepnnt eliunminogcythteesaclvoenotaluinsinvgentral to ethveidteynpte. ITI hpenemumateorciyalteisn. thWeiathlvineothluessiespntaolnwdeasllcrciopltlacgeellnulfairbedresbarinsd. aAfnibimroabllaNsot .ar1e9569-4, 3.2 mg/kg/day (high-dose), 11.200X magnification. TFpnwigeouurmceeol1cl4sy.tveLesnu. tnrTgahl.leyAlcalovrgneetoalciineanlntadrmasleeclpleatlurlmbino. dthBieeostshaenpsdtiudamerseaotpyfppteheaerIIsseptponteubuemmaaotrcyeyptleeinsIe.pdAnbenyuimmfloaatlctyeNtneoe..d 19579-3, 3.2 mg/kg/day (high-dose), 11,200X magnification. Abbreviation A BBEC CCCNLap DCCPO DDCD DDNR EECR FGB LHC LMNPB PPNN12 PRMER Ancillary Pathology Report Primedica Argus No. 418-013 Index of Labels for Ultrastructural Structures Structure Alveolar space BCBarilopenilcclaahnriyoalllaiucrmuelepunisthelium CCeapnitlrliaorlyes CCoulbloagideanl pneumocyte Desmosome DDDiiellnaastteeedddcnerupicostlsaeietasr envelope EDnildaotethdeRliaElRcell EFHGirelbyymrtcohoabrtgoloeacpnsyottieetic cells Lipid droplet MLaimtoeclhlaornbdoriday NPeurcolxeiussome TTyyppee IIIppnneeuummooccyytete PRloausmghaemndemopblraasnmeic reticulum 00159^ mumBEST COPY o o ilfo BEST COPY AVAILABLE 00160$ Y ostoo m nnm m m 41BEST COPY W M *' 001602 ^OSTOO J mimkamm ft ,. 3 * '- . '` i iC :- ; --If-v-sV VV * j^rr:.*- - 1. *I , ..-T* ? f: I7 rV'-.yVvi.ApJ ~ ....."r . ^ - & M s^Tra- m? pT?v</'*"rv`O'v/">.'.*s-.vPpi*,m*..v^-`..'^.vi*- . r-fc- \ <*, \VLv-SSS*' 4.*' BEST COPY AVAILABLE ooieof BEST COPY AVAILABLE OOlGOtf BEST COPY AVAILABLE f0 0 1 6 0 BEST COPY AVAILABLE 001G09 BEST COPY AVAILABLE 00161^ 00161JJ BEST COPYAVAILABLE 001613 IV. Quality Assurance Statement 00161* Pathology Associates International A Company of Science Applications International Corporation An Employee-Owned Company QUALITY ASSURANCE STATEMENT This electron microscopy study has been inspected and audited by the Quality A ssurance Unit a s required by the Good Laboratory Practices Regulations promulgated by the U.S. Food and Drug Administration. PAI has a functioning and responsive Quality A ssurance Unit which reports directly to m anagem ent. The following is a record of inspections/audits and their resulting reports: Date of Inspection Phase Inspected Date Findings Reported to M anagement and Study Director 2/22/99 Processing and Embedding 3/22, 2 3 , 2 4 , 2 5 /99 Data Audit 3/25/99 Draft Report Audit 4/5/99 Final Report Audit 2/22/99 3/25/99 3/25/99 4/5/99 --------- ---------------- .Jeanne deWard, B.S., RQAP-GLP Quality Assurance Specialist H/ f Liate Sponsor: 3M Corporate Toxicology T est Article: PFOS Study Number: 4 1 8 -0 1 3 , PAI Study EM -99.39 C0161JI 4915 D Prospectus Drive Durham, North Carolina 27713 (919) 544-5257 (919) 544-3218 FAX