Document Gn01qXKmdmEbV5BodLGgGgRm

MIN 3131023622 PERFLUOROOCTANESULFONYL FLUORIDE (POSF; T-7661.4) TOXICITY STUDY BY INHALATION ADMINISTRATION TO CD RATS FOR 13 WEEKS FOLLOWED BY A 4 WEEK RECOVERY PERIOD Volume 1 Sponsor. 3M Center, 3M Corporate Toxicology, Building 220-2602, StPaul, MN 55133-3220, USA. Research Laboratory HWuonotlilnegydRoonaLdi,fe Sciences Ltd., Alconbury, Huntingdon, Cambridgeshire, PEEN2GL4AHNSD,. Report issued: 28 September 2005 Page 10f740 CONTENTS MIN313/023622 Page COMWIP THGL OOD I LABOA RATON RY CE PRACTICE.. 4 QUALITY ASSURANCE STATEMENT... ssnmm-- 3 INTRODUCTION... -------------- 9 EXPERIMENTAL PROCEDURE. ...cvvssnrmmmsssmsssonsssnnnns 11 `STTEUSDTYSSUCBHSAANE NTDDFSD OARTMUU NRLAUTCL IOCNE.E T..URE... 11 12 NSERIEAL COBSARENRDO VHAITP SITOONSLSO.G.YY. usmmmm.m.m.r..mcmomrosrissnmisimmoorsammtmrrmotmm eereea eeoenm snee e 15 19 DPAATTAHTOLROGEYATwM..E.cNcTrs.se.s.msnsa sssr ssse mmsmnsmoemossosssesonoeeon, | 22 22 QUALITYASSURANCEANDARCHIVINGPROCEDURES .........oooormrvrororr 26 kn -- QE escent 3 FIGURES tz: MIN313/023622 TABLES Page 1. 2. FBooOd CdOyWN- eSOUi-DUGMgTEOMAUhPNMPtEAHsDVAOIENVSAIUES......c...r.v.rroromorwvmrrnornmsrosrmmnresesrsorsosroneionrnnr,, 38 40 3. 4. HBiOoCCTh--BGGETTOOOmUUDDMMIMCCABIODVVSAAEIIUUrEEYSS.Y.........c.r.r..rrsoerswssosrmmrmmsrmmsomrrmooeteorroeeroereooeroneoon enn, 42 50 5. 6. OrUgarn wieig-hntgsrao-ugprmloeuapynmveaaslnuesi....s... values. cn ---- I gy 7. 8. MMaiccrrPpaattohohoollososggyy-ccGgrrOoooUuPpGppdIiSSHiitDIUDOcUcNO.R..w.covv.cr.ev.rvrrrrmrn-- emnmsmsnemrororeor. 8 87 APPENDICES 1. 2. DWaeielkylpyopshty-sdiocsaeolexbamisnateionr--ivinnddiaivviidtduuaaill ons SNFAndgISng.s...c.o..r.e..r.e..rororrororormorrnoro,rns WL 118 3. 4. FBoood cdyoWn-iesndiiuv-iigdnumdaihlvpitdutaslVialuoesValues.n ....o.r.........wmm wesorr mroree reeorm ororo-- noenn 18 135 5. 6. BHiaoemC-ah- intEddiivvomiidduluiaalloVVsAAIIgUrUESEySy...cccv.e.v.ocrorccmoorrrmrrsomrsmmsssmnsrnmsosmnrmmtroerroereenrroeooroeeonneons 138 150 7. 8. AUbsorluteior-gnIannGawIeViigldhatlVsyA- iIsnSdiivsidual c.VcAcIUcEcSc.e.e.n..o.o.r.m.o.e..n.m.s.noswnmowmneonrromroenrororrooro ores, 178 202 9. 10. IpndHiVvaildUuEaSlPfOraetrahlOWSIIINEONG.BSce.icceecvvsearrnnlrrmrrmmrmmrromrmmsmmeensmsswwmmsmmeromroenerereeereeoreooeooeoeeonnn.. 212 293 11. CellPrOfETRtOnSIGES...sersornrmrermrmmosmewmosereomroreroeoeoenors 296 ADMINISTRAOTFPIOOSNF BY INHALATTOIRATOS.N.. 298 SMICCARNONBIRNALGYESILEE.C.T.R.O|.N.M.IcoCmRmOmSmCaOmePmEsEmmXmAmMmImNmAsmTsIiOsNtsAmNtDmiXt-naRtAY stim 369 ANALPYHATSEIREPCORAT L cocoa S18 HEUYNETRIENSGEDAORNCRHECSEENATRRECGHCLEPNCTORMPELGILAPNCCEOMSPTLAITAENMCEENSTTSATEMENT.S....cccrcrcmrmroorro:rrs 735 738 VEE Beiicurmunmsmmetmrmmmmmmmems------------------sgssin 306 3: COMPLIANCEWITHGOOD LABORATORY PRACTICE Mss PERFLUOROOCTANESULFONYLFLUORIDE (POSF; 7.76616 TOXICITYSTUDY BY INHALATIONADMINISTRATION 70CDRATS FOR 13 WEEKS FOLLOWEDBYA4WEEKRECOVERY PERIOD TrhecstudSyadnetasseodin Cneronevass sponvtei ceompsle ith he loinGod Loony OBCD PrincesofGood Labor Pri us vied in 1997, ENVMC.CHEMORI7 `The UK Good Laboratory Practice `Statutory Instrument 2004 No. 994. Regulations 1999 (Statutory Instrument No 31as0am6 end) ed by EC Commission Directive 1999/11/EC of8 March 1999 (Official Jounal No. L 77/8), asamended by TEShCtesCeeoompfmriirsnsciieopne oDifn GreacntidveLo 2a0b0or4a/t1o0r/iyECProofcf1i1gcFsebsrruaarcayi20d0m4b(yOfhfeiciralgJuoturrnayl atNo. orsL50/44 ). ofthe Unie ASn aitydeefsoarthest btn va okgiven. Th marlvassnd fesors pSGeaLsmPtiminsgoErlcnronroMgeimmse,aNnodaXmrafsssplsinveaconGdLuPc brkaeiywhichofspunto TSRoieymeit]naiKrLeiys,Sia5cses(H1or8s), Due MIN 3130023622 QUALITY ASSURANCE STATEMENT PERFLUOROOCTANESULFONYL FLUORIDE (POSF; T-7661.4) TOXICITY STUDY BY INHALATION ADMINISTRATION TO CD RATS FOR 13 WEEKS FOLLOWED BY A 4 WEEK RECOVERY PERIOD The following inspections andauditshavebeen carriedoutinrelatioton this study: Study Phase DateofInspection Date ofReporting Protocol Audit 10December 2001 11December2001 SSttuuddyypBraespaerdatIinosnpections Tes Item control and disposition 2200DDeecceemmbbeerr22000011 2200 DDeecceemmbbeerr 22000011 mExopsopshureereand generationoftet 20December 2001 20December 2001 AClminoircaplhseigrnssa(mpposlti-ndgose) Clinical signs (eekly) 2200 DDeecceemmbbeerr22000011 8 January 2002 2200 DDeecceemmbbeerr 22000012 8 January 2002 NFreocsryhsoipsu.sriyne callction for SEM 14 January 2062 21 March 2002 14 January 2002 26 March 2002 Report Audit 9 1J9unJe 20ya0n4d2252 Jlyune20200504 22 September 2005 2245JJuunley 22000054 22 September 2005 DiPrreocttocoorlanAuddCito:mpAannyauMdainoafgtehmeepnraottoicnodlicfaotredthaibsovset.udy was conducted and hareported to the Study SStuuddyDbraesmeodriannspeCcotimopnas:ny maInsgpectieons noftophcasescofsthois sotudy were conducted and epened to the Prporruootmcipentselsyabnradseerdeppieattosiopvaeerpcptpirtoronopscer:eidadAuttreeCsoroemampbpaolunotyyetMhdaenoatnigmetemiestnhtiys.psteuodfystwuadsyinwapreogcraesmsieidnsopue.ctioTnshoofsotnheyr cRoenpdourctteAdudaintd:rTehpiorsterdepoortthheaSstbaeyenDiaruedcittoerdabnydCthoemQpuaalnityyMiAasgseurmaenncetDepiartmaent. sThhoirseaudit was Trheemettoshroedfslu,ecpsrtohceredauwredsataan.d observations were found to be accurately described and the reported DIenhtveaesitllisegvoealfttoorh'fe PrQueOaploSitry,t iPnAFcslOsuudread4nncadeaiFnnsRapdOecdAteiniodnsuIamnntgdoahu3dihistsmtapioenrmtraeipSonriptn.giteostheAnamlytiecal ePhasededetteerrmmiinniinng dobFi, Huntingdeonnt oLfifeQSucaliietnyces Lid. Asurance. is: CONTRIBUTING SCIENTISTS STUDY MANAGEMENT TSteurdeynDciJer.ecKtoern.ny, B.Sc. (Hons), RSehniiaonrnSotnuDdayviSeusp,erBv.iSse.or(Hons), DSeenrieokrWT.oxCicooolmobgiss,t.B.Sc, Ms, MIN 313/023622 AEROSOL TECHNOLOGY AND ANALYSIS ISenctSi.onGiHlekaisdo,nA,eMroAs,olPTehcDh,nology and Analysis. CLINICAL PATHOLOGY HP.eTardaovfisC,enBtSrcal,LMa.bSocra,tory Services and Clinical Analytical Service Manager, Centralabs Clinical Research. PATHOLOGY SDiarmeucetloroMfcCPaotrhmoilcokg,y.M.V.B, MRC.V.S., Ph.D, FRC Path, STATISTICS HGeraadh,aDmeFp.arHtemaleenyt,ofB.SStca.tis(tHiocns.s), MSe, ARCS, BIOANALYSIS ERixcyhgaernd RAe.seGraarzczhi,ni, 3St0a5t8e RCoelsleeagrec,hPDAriv1e6,800, USA. te: SUMMARY MIN 313023622 aoTdhumeipnssiysstotrfeatmteiinconmowaxalisec aapsonstdeensttseienadlfooevfmeatrlhaepertaretsistorsdeucboesfitva1en3dcewP,eOePSkOsFS,Fbf,yoltslonooCwuertd:obCnyDlya i(4nShwDael)eaItkGioSrneBacoRveerxrapytopseburyrieoidnl.heavlTealhtsrieooenf df2u6or,steh1de0fr4o$ran4mdwale2ee9s9ksaponpndmlb$y.yfveTomealnluemmsaelweefaorrned1a3tlelwnoefceaektmse.adlaAesrasstiastmeiillnlaiGrtlreyoaucnopinmssatli1ts-4utwteoedrGCerooneutxrppool1sgeardnofduoprr1oe3cnweyeievaekdnsda,iaw.fereAer c`awhcihchgrSomuaplewseraendal$lofcaetmeadleass preercogvreoruyp following the 13 weeks exposure. gwreoruep saacnriimfailcesd.anTdhweerreemaailnlionwged tmoarleecoavnedr Sfofremfaoluer Fwaetsekisn uDruirnialnygsitsh,eosrtguadny,Wciligni,calmaccornodistcioopni,cbaonddywmeiicgrhots,cofpoiocdpcaotnhsoluomgpytiionnv,eshtaigeamtaitoonlsowgeyr,ebulnodoedrtcahkeemni.stry, Principal findings ae summarised below: Results Mortality and clinical signs rTehceorveewreyarneinmaolsrdeuriangtthmee4wneetefkf.eecsetosvldeuraryiptnegretiohdde. 13weeksofthetreatmentperiodorinany ofthe Bodyweight Following 13 weeksoftrestment with POSF there was a dose-related reduction in bodyweight gain. Food consumption As4iwgenreiefkdiusccoatnficoreneactoianvienrfeoydofdefomrcaolmneaslfueomso,pdtcciooomnnpsauwrmaepsdtiwsoientewhnaCsionsnttGrlorloruefpdoulcl4eowd(iHningitgr1ha3tdweodesegekr)soouafpnistm.raelast,mewnitt.h Fsoulilsoiwcianlg Haematology "There were no findings considered to beoftoxicological importance Blood chemistry AmlallaelsicneompphaorsephdawtiatsheCloenvterlolwaenrderheimgahienrefdohriGgrheorupfo3llo(Iwnitnegr4mewdeiaetkesodfosree)coavnedryG.roup 4 (High dose) Arleamnaiinneedamhignho-etrfaonlslioewaisneg 4lewveeleskwsoerferehciogvheerry.i al treated male groups compared with Control, and fChoollleostweirno4gl wleevseklssowferreecolvoewreyr. inal treated male groups compared with Control and remained lower Cfroelaltoiwniinnge4awnedektsriogfrlyecceorivdeeryletvheelslevweelrsewerreedcuocemdparfoarblaellwittrheaCtoendtroglr.oups compared with Control, 17 Urinalysis MIN 313/023622 `There were no findings considered to be oftoxicological importance. Organ weights 3Agrbeosuoeplsku.tereTlshioveveerrdyiwfepfieegrrhietonsdcewtsehwereerregecroesvatetaretyristatinhciaamlnlaylc'ossnitgirnovilfesircaiwnnetibgwohththe,nsweaxhdeejsnuosfatdetjdhuesftoerIdnbtfoeodrrymwbeedoiidgahyttew.eaingdFhoHlirlegomhwaiidnnogesde8 sdsiougstneii)sf.iicIcaanlnlStylaytsegilrgienitafteirecarattnhtlaaynfhtcirogn4htrweorelfewokerisgGehrxtposo,uspur3e(aInttehredHoisgeh)domsaleeslevaenldthien lbiovtehrwsexeesoifweGgrreosuthapti4stti(cHasillgyh Llsauutnniggsaicanandldlbyrbosrniocgnhnciihfiwiecwainegtihlgtyhsthising(hmaeabrlsetolhHuatinegchoanndtdorsobelordaayftstweerrie1gm3hatiwneaeeddjkusssotattfeides)txipcioanlsluHyrisegi.hgniAdffoitsceearnrt4altywsoehiefgkbhsoeortfthrheascneoxcveoesnrtyrwoetlrhse,e alnuinmgaalnsdafbtreornc4hiwweeeikgshtosfien xfpesmoaluers significantly higher than controls. awtertehesiHmiiglhartdoosceo,ntlruonlgs aafnedrb4rownecehkisowefirgehctosvewreyr.e sItnatSiastteilclailtley sKaidtidifsnfteeriyeanwlceleiysgshiintgsfne,imfawilhceaesn.ntlAayfdhjtiuesgrthe4edwreftoerhkabsonodcfyorwneetcirogovhletsr,ayftinthemerabloe1d3ryawtwesefiergkohsmtoatfdhjeeuxIsptnoetsdeKuirredm.needyTiwheaeintrgdehetwHsieogrfheHdiongsohe wdSeousrceeh anmcoacdloieufsnfwetreeerdnfecoesrtstaihtnieskhtiiidcganhleleyyrwsbieogidngiyfhwitecaaifngtthleytrag4drwejaeutesetkrestdokhfainedxcnpoenoytsrwuoelriseg..htTshneoretewdeirnemnaolehsi.stTonpsathaoltogyeafitlnsdtilhnegrisewwtheireceh. Macroscopic pathology 1`Ew3intwhleneaokrnsegcioenmmotphefaetrnheCtedownliitvtreohrlnmwoaanlseeoirbnasttehsreavCneoddnitinrno4l3//r55ammtaa.llTeehrriaatstssfatirnneddait2ne/gdw5wafiestmnhaol3te0ar0papptasprtmerneftaotrfeod4lwlwioetwiehnkg3s04c0owpmeppeamkrsfeoodrf. recovery. Microscopie pathology `The following findings were related to the administrationof 300 ppmofthe compound: rleacroynvxer-ynin efemacloefsrvenotralscaritilasge,with no evidoferencocverey inmalesand with incomplete sleuxnegsswitfhoianmcyomapllveetoelraercmoavcerroypihnagmeasl/esseaptnadlcotmhpclkeentienrge/csocvaetreyriendfaelmvaeloelasr. macrophages in both nliovtearbl-yceanftfreicltoebdu,laprrhoempianteonctytecenhtyrpielrotbruolaprhyheexptaetnodciyntge recoveryofthese findings in both sexes. tpoigthmeenmtidzinonfaelmaalreesa, waitnhd mianlceosmpmloertee `erTexhcteoevnaeddrimynignaitstttohrteashteeiodmnoisodefzol3en0vaelplsp.amreoaro1r0c0enptprimlowbualsarashseopcaitaotceydtweithhypceernttrriolpohbyulianr mhaelpeast,ocwyittehhycpoemrptrloepthey Conclusion oe`xrTtheceenanddtimrniinlgiotsboiurltaahrtheieomnpi.adtzooofcnya3tl0eaphyrppemearootrrrco1epn0ht0yriiplnpombmuallwaersah,sewapisatstohocicinyacttoeemhdpywlpieettrhetrrcoeepncthoryvieelrxoytbaeutlntadhriehnsegeptadototoshcyeltemveieldhszy.poenratlraorpheya Tt was not possible to identifay no effect levelinthis study. 18: INTRODUCTION MIN 313023622 Objective TanTnhoiyereiofb3cfje0ec(ctstPdioOwvsSaee)sdo,sffswotrhshdiessnemsedsusddsdmu.yirniwinagsse8retSodvabesysksesnrootthveoemsryysteienrmhoiascl.attiooxSniec1t4plonrtaeenstrioiastl wo1r3fkepeSsrlfeoocraoeRodceatcnseoCsonuvfoeSnnoy}pl Regulatory compliance Thestudy was designedto meeth requirements of GEuuirdoepleiannesEfocrontohemiTceCsoinmomfCiehsemica41l3 TG(hoSEeestiunbdey wPraroscecdounrideusc)tseAdckiA n19a8c6cordaL nce withthSe preequireomentsfof ceuetn,einterrnatiaonallly recroogmniinseedd Test system T2h5nedd haB etwraeqsueicrheotmsheea nentaHsfitoorhsarerctoeldscetnsotpmseppcelcsiGebseasbayusegosvfetlrbtslyeacsheeepiHnaniresTahe.Jpreadicrtoroftoxic chainmeagdn Route ofadministration eThxepoisneha.lation route of administration was chosen to simulate the condidons of potential human Treatment groups and dosages TtahaShonernegiedntocgsoadi ngcoeennszu1aesteiodrniScnn7enh0iest0sosptRpueppdeoyrhlt(e0ea,rbe3wT0e,etk1n,0s0wMaeiInhNhdi33i1c301l001p(4p37pm8c))otwnewrdeerpseoerlseoncttnedeirnicnonj,huonsctioobnbwoiotrheiths:e Study locaton Thetestsystemwasmainsetdhe folowing borat: HHFuuonnottiilnnyggddRoonnocRLi:efseeSaceihenCcoesntLri, Noonsayy CPENSaGRLmGAENeSD.. Histwaospelrfoormgedy BHuenStiengi don Life Sciences Li, SfENeiGL,AND. ios seFtaO ---- University ofPlymouth, BE PLASAR, TS&ibrE,maorms S088 Research Dive -- EXPERIMENTAL PROCEDURE MIN 3131023622 STUDY SCHEDULE AND STRUCTURE Durationof treatment T1h3ecotnessetcsuutbisvteanwceee,kPsOSanFd,wfaorssaadtmelilniitestaetrsedafopreri6ohdouorfs4adweaeyk,s.$dTahyesneawcreoepskyovpreorceadpuerresiowdeorfe OGbosmeprlvaeteidonisn w| edraye, rdeucroirndgewdhiacthatpipmreoptrrieaattemeninttecrovnaltsi.nueTdheupdtuoratthieodnayofprtireoarotmneenctroipssyr,epaonrdtesderiaa5l 13 weeks.Animalsassignedotherecoveryphasecompleted futherfourweekswithouttreatment. Time schedule (SPtruodtyocionlitisaitgionne:d by Study Director) Experimentalstartdate: Treatment commenced: NecropSsaytelcloimtpelSettueddy: MReacionveSrtuydSytudy Experimental completion date: Study completion: 6December2001 6December2001 20 December 2001 2115 JMaanrucahry22000022 19 April 2002 29October 2002 28 September 2005 Identityoftreatment groups Thestudy consistedofone Controlandthreeratedgroupsofrat, identifiedas follows: Group Treatment expoTsaurrgeeltevel No.ofanimals MaiAnvismtauldyn(u1m3bweeresks) Cage numbers 1 Comal Gp0m) Masle Fem5ale0%Male Faemiasle Ma0le Fem5ale 23 ppoossee 3100 55 sseals wslns 23 57 i pos 300 5 sen ew 4 s in Growp Treatment eTxaprogsuerte l(epveml) 21 PCoOnSroFl 300 3 PPOOSSEE 130000 Growp Treatment exTpaorsguerte level 1 Conal (p0m) 4 POSE 300 MIN313/023622 (13 weekRsec+ov4ewreyepkhsasreecovery) MNaol.eofaniFmeamlasle AMnailmeal nuFmebmearlse MCaalgee numFbeemrasle s5 55 aaless eles 6 9 10 3 1 55 55 ossese m7a8s0 o1u2 11s6 Sat(e4llwieteeksst)udy No.ofanimals Male Female AMnailmeal nuFmebmearlse 5 5 sms S80 oles %ei00 MCaalgee numFbeemrasle 07 19 18 2 `TEST SUBSTANCE AND FORMULATION Test substance dIantfaorsmhaeteti,onwhsiucphpilierdetbayintehdeiSnptohnessotrudryegraercodridnsg.the test substance is contained in the test substance. `The following information is given in summary: Identification: POSE, T7661.4 Description: Liquid Storage conditions: Roomtemperature Supplier: `Sponsor Batch number: 040227 Dateofreceipt: 14 June 2001 Quantity received: 4x20kg Stabiliy: Assumedstableforduraoftthiesotundy Purity: >995% tAemspmeraaltlursea.mple (1 mi) was sealed in a suitable container and stored in Archives at an appropriate t`ThheemSeptohnosdosrowfsaysntrheesspiosn,sifblae fborrthioerccdhearraaicvttaetriiiosnaoatinnodnosfttabhielittey.st substance and the documentation of rn ANIMAL MANAGEMENT MIN 313/023622 Animal supply, acclimatisation and allocation ALotfdt,1o1tMaglafroogfart5ce5a,cmhKaelsneetx,a.nEdng5l5anfd.emaTlheeCrralt:sCwDere(SoDrd)eIrGeSd aBtR40r-a4s4wdearyesorfecaegiveedanfrdowmitChhianrlaesweRiigvhetrr(aUnKg)e sebOeqniuneagrnrcirveeaople,fattcheaedgaeunsnitiimlnalteshaewcbhearcteaergreeym,ohoevnlededatfnhreiommaapltpahreotptrraiatnaistiemtenbwuoaxmebsseprlaanodcfeadalinlionmccaatlaescd.htcoaEsagtceuhwdyistceahxgetwsh.aepsrUaoslcilenocdgauttrehede separately. TtbhrheeeeadldiadtniegtsitocHnoealolanlyct.ohnSsciTrgheneemsneenRtedpooofcrutamnpeiunmbtalslisswhieendrcelbuysdeetndhteaatnhoieamHlautlnhstuispcnprgledieeonrnwreLalisafteipnrgSoctvioiedntechdeestcouVreHrtLeeSnr.tinsatIranytuasdSodefirttviihocnee, immediately upon receipt for review and subsequent archiving. beTaqhtuetielricibaergsaetsesdo.c,oantsshftaiattruaptosisnsgwiabelasecphreangcvrtiiocruaopbnlmwee.enrtAeadldbiltioincofknlaeuldelnytc,oegsbeatathreeirrseibnsyog fsfecrxaogmaensdthwetiehreregsprraoottuiapatlsedwdeaisrrtoeruidnbidusttipohenersrewodeorimen at weekly intervals to further minimise possible spatial variations. cEaagceh laanbiemlalwawsascoalsosuirg-nceoddead naucmcboredrinagndtoungirqouueplyaniddenwtaisfieudniwqiutehliyn number, as well asthe identityofthe occupant, tnhuembseturdeyd bwyitah tcialgetataonod, sEtaucdhy rT55ehtseotma5en8nidtmaacylossmamwneednrtcehedail.rlboFowoderydwthetooisgeahctaenslwiimemaarltesiissenltethcoteertdhafenogrcetoonhfdsi2tsi3to9ungdsy,tdoehse2ci9r2iabggefedoarbtmetalholewesstfaaornrtdof141tr7de0aa.ty3ms1e0nbt2e0fw9oarse for females. `The spare animals were removed from the study roomafte treatment commenced. Animal housing, diet andwater supply mAwinanisimmdaielssseigwtneheredetarhnaondussfoeepdreerinanctseeioddfestaourecmshitnraiigmcetinestdesetbnhetertyweenretorndyeornotfoemfxsact.ielriBtnyeafl(oBbruieioltldhoiegnigscau1ld4ya,ntdhRecohroeommoim0c0aw7la).sagcTelnheteasnfaeadncidalinttdoy disinfected with a bactercide fEislctehreadnfirmeaslh arro,owmhiwcahswkaesptpaastsepdostiotiavtemoprsepshseurreeawnidthnortesrep-eccitrctuolattehde. ouTthseidteembpyeriatstuorwenansduprepllaytiovef hPheuurmmiiiodddiiittcyy ccwhoeenrctekrsomlwsoenwireterormeeadmdaeciononttnaiintnuheoedusnwluiymt.hbienRraotnhfgeaeirsranocgchecaanosigfoens1a9lilntyotdh2ee3viaanCtiemadanldfrr4oo0momtstoa.r7ge0Tt%e,mapnerdersatptheeuctriaevcetalunya.dl rashtonuugdreyssocrouentctcoiornmdueeo.duswAedrtarirefki1cp7iealr02l4i2g1hhtoiuCnrgsa.wnads 2c9otntor7o4le%d.tDoevgiivaetaiocnysewleorfem12inhoorurasndcohnatdinnuoouismpiaghcttoanndth1e2 Pc MIN 3131023622 Aexlcaeramdsedw.erAe sacttainvda-tbeyd eilfetchterirceitwyassuapnpylyfawialusreoavfatilhaeblveenttoilbateioanutsoymsatteimc,alolrytbermopuegrhatturinetoliomiptesrawteiroen should th public supply fil `iTsohleatainoin.maTlhsewecargeeshowuesreedmfaivdeeofoafansetaisnelxespsesrtceaegleb,oudnylewsistthhiassntuaimnbleesrs wstaeselrmeedsuchedlidbyanmdorftlaoolri,tyanodr cwaegre-erasyuss,pfeonoddehdopapbeovresaanbdswoartbeenrtbopatpserwewrheicchhanwgaesdacthaapnpgreodpriaatteaipnptreorpvrailast.e intervals. Cages, TDiheetafnriommalSspewceirale DaileltosweSderfvrieceesacLcieds,,s W10ithastma,ndEasrsdexr,odEenngtladnide)t,(eRxacteapntdduMroiungsethNeo.6 h|ouMrasinetxepnoasnucree onroawdhdeenduarinnetiwabsiobroeitnhigeccrolclheecmtoetdhaernadpeouvterinciogrhtprboepfhoyrleacrtoiuctiangeenbt.lood sampling. This dit contained t`uWbaetse,retxackeepntfdruormintghtehepublhiocursueppxlypwoaossrfuwrehreelyenuavraiinlaebwlaesvbieaipnoglyccoalrlebcotneadt.e bottle fied with sipper cEhaecmhicbaaltcahndofmidicertobwiaoslogaincaallysceodntraomutiinnaenlsy.bySutphpeliseurp'psliaenralfyotricvaalricoeurtsifniuctartietsiownealrecoscmrpuotnineinstesd aanndd abpyprroegvueldatbieofnosrepuabnlyisbhaetdchboyftdhieetDweapsarrtelmeeanstedffoorruEsnv.iroTnhmeenqtu,aliFtoyoodftahnedwaRtuerarlsupAfpflayirsis (gfoovremrenreldy tkhneoswunppalsietrh.e DSeipnacerttmheentroesfultthseofEtnhveisroenmveanrti)o.us Caenratliyfsiecsatdeisodfnaontalpyrsoivsidweeerveirdeecnecieveodfrcoounttianmeilnyaftrioomn thatmighthave prejudiced thestudy,they arenotpresented. aNnaoloytsheed,raspneosniiecthcaotnmtaamyihnaanvtesitntheartfewreerdweiltihkeolryptroejhuadviceebdteheenopurtecsoemnetionftthheestduideytwoarswkantoewrnw.ere Administration `1T3hweveaepkosu,rC-ognetnreorlatraetdsfrreocmeitvheedtaeistosnulbysctoannsceecwutaisvaeddmaiynsi.steredfor 6hours aday,for 5 daaweyekfsor sTihzectaemstomfaatierfioarlawdamisndiesltriavteiroendtotahnalratgslbayssinvhaaploautriiosne fraonmdsgennoeurtaotneldyaexapovsauproeucrhaatmmboseprhse.reT,hientfeosat sdiurbescttalnyceinwtoasthmeeteexrpeodsutroe tchheamvabpeorr.iseTrhferotmaragent icnhfausmiboenrpcuomnpc.entrTahteionvapwoausr/aaicrhimeivxetdurbeypausssiendg Giffrent liquid eedratescontrolledbyth infusionpumpand using syringesofanappropriate value `Thetarget concenforttrreataedrtatiswoerne3s0,100and 300pps. Corants rteceirvedaoionlly. TDehveerlaospwmeenrteseLxipdo,sHeidttcohitnh,eHceornttforrodlstheisrtea,tEmnogslpahnde)r.eusing ADGsnout<nlyexposure chambers(ADG doAslilnagn)i,mfaolsr($icnoclnusdeincguirevseedraveyss)pwreiroer stoubtjheectsetdarttoorfeestxrpaoisnurperso,ceidnuorersdearntdoesxcpcoussetdotmoaaniimoanllsyf(oSthhame prreosgtrreaisnsiinvgeplryo(c0e5d,ur1e,.2,T4haenrda6tshweorfeourrDearyssst5rotona-c1eipreesnpredectaiydve,ly)i. nctrheSehaam dsosiing'nperigod DperteasielnstoedfiandmAiDniMsItrNaItiSoTnaRnAdTaInOalNysOiFsoPfOtShFtBeYstIatNmHosApLhAerTeIs tOoNgeTtOheRrAwiTtShtaphperensdueldttsootbhaiisnreepdoartr.e tu MIN 313023622 SERIAL OBSERVATIONS sDtautdeydwaintdhisnigtnheedarneicmoarldsunoift aals awcetliviatsestoretlhaetignrgotuoptohbesderavyatbiyondsayanrdunenxianmginaantdiomnasinotuelniannecdeoifn tthhies apnriomcaedlusrmeawdeertehrreocourgdhedotuihtne tdhaeywSetruedryecDoarydeBdo.ok. In addition, observations relating to individual oSbesriearlvatoibosnesr,vabtoidoynswepiegrhftosramnedd foonodthceonsaunmipmtailosn.from the Satelite groups were confined to clinical Ainldlicaabtseed.rvations described below were performed in cage number sequence except where otherwise Clinical observations CAangiemsaalnsdwecraegei-nrsapeycstwederveisuianlslpyecatteldeadsatiltywfoir deaviildyenfcoreeovfiidleln-cheeaoltfhh eamaolngtshtothereoascctuiponanf(ost,resautcmehnta,s dlaotoeseanfadccteism.eoAfnoynsdete,vidautriaotniofnroamndnoprromgarleswsaosftrheceoorbdseedartvehdeconfdiimteioinn,raesspaepcptroopfrinaatteu.re and severity, In addition, detailed observations were recorded daily, onthe daysofexposure a follows: PDruer-ienxgpoesxuproesuorbese(rhvoawteivoenr, observation was severely restricted due tothe tube restraint] ``AAss claatceahsapnimaolwsasirstehtieuwmoerbdktionligtdseahyomecage. In addition, a more general health. detailed weekly physical examination was performed on each animal to monitor Dreucroirndgedtahe eaacsctliomnacteispaetrondaya.nd recovery periods, observations of the animals and their cages were Bodyweight "tThhatewteriegahttmeonftccaocmhmreantcweadsr(eWceoerkde0d)o,nweeweekelky btehfroorueghtoruetattmheenttcreoamtmmeenntcaendd(rWeecoevker-y1)p,eornitodhse,daanyd before necropsy. Food consumption Tfohretwheeigwheteokffboeofdorseuptprleiaetdmteonctacsthacrtaegde,(tWheatekre-m1a)i,nianngd aenadcahnewesektithmoroafuagtnheoyustpitlhleedtwraesatmreenctoradnedd rcaelccouvleartyedpoerrioedsa.ch cFargeo.m these records the mean weekly consumption per animal (grauweek) was 15: MIN 313023622 `Haematology, peripheral blood oDbutraiinngedWeferokm 1a3llofantirmeaaltsmeantte(rbeofvoeremidgohstinsgt)aravantdioni.n WeAenkima5lsofwreerceovehreyl,d bulnodoedr slaimgphtlegsenweerrael anaesthesia indbyuiscofleuradne andbloodsampleswerewithdrawnfrom theretro-orbitalsinus. Blood samples (nominally 0.5 ml) were collected into EDTA as anticoagulant and examinedforthe following characteristics: Thefollowingweremeasuredusing a Bayer-TechniHcIoEn haematologyanalyser: `HHaaeemmoagtolcorbiitn(H(eHt5)) RReedticbullooocdycteelsl(cRoetuinct)(REC) MMeeaann ccellll hhaaeemmoogglloobbiinn (coMnCceHn)tration (MCHC) Mean cell volume (MCV) Total white cell count (WBC) DiffereNnetiuatl rWoBpChi(clNosu)nt LEoysmipnhoopchiyltses(E()L) BMaosnoopchyitless(B()M) Large unstained cells (LUC) Platelet count (Plt) Raentdiacbunloorcmyatleictoiuenstus(iRnegtiacS) y-sbrmiellxiaRnt30cr0e0sRyeltbiluuelosctayitn,eCeoxuanmtienre.d by light microscopy for reticulocytes Bunluosoudalficleml -tyRpeosm,ainnocwlusdkiyngsntoarinm,obelxaasmt.ineTdhebmyoslitghctommimcornoscmoorppyhoflorogiacbanlorcmhaalngemso,rpahnoislooegyytosainsd, `micro/macrocytosis, hypo/hyperchromasiawererecoarsfdolleowds: = + "= = lnoiagbenomalitis detested moderate `rAedsdpietcitonofa:l blood samples (nominally 0.5 mi) were taken into citrate anticoagulant and examined in Prothrombin time(PT)using an ACL 3000 PlusanalyserandILPT-Fibrinogen reagent IAcLtAivPaTteTdrepaagreanlt thromboplastin time (APTT) using an ACL 3000 Plus Analyser and D16 Blood chemistry MIN 313023622 (Antomtihenaslalyme0.t7immie)anwderuesicnolgltechteedsaimneto alniitmhiaulms haespafrorinpearsipahnetriacloahgualeamnatt.olAlolgyt,ubfeusrwtheerrebmleocohdansiacmapllleys agitated plasma. for at After least five separation, mtihneuptleassmaandwatsheexsaammipnleedsiunbsreeqspueecnttlofy: centrifuged in order to separate the Using a Hitachi 917 Clinical Chemistry Analyser: AAllkaanliinneeapmhionsoptrhaantsafseer(asAeLP()ALT) LAascptaartteatdeeahmyidnrootgreannassfeer(asLeDH(ATSoTt)al) and iso enzymes CSorrebaittionledPehhoysdprhoogkeinnaassee((SCDPHK)Total) TUorteaal Bilirubin Bill) CGrleuactoisnein(eGl(Curee)at) TTroitgallyccheorliedsetser(oTlri(gC)hl) PSootdaisusmiu(mNa()K) CChallocriiudme ((CCaI)) ITontoarlgapnrioctepihno(sTpohtoarluPsro(tP)hos) 7PEloengclctoerbaouuplh-ioSnrae(tniGdcsacmparmonatne)iinnwgfweriraectthiaoannsas;luyiastleabbdulmewidinetn(hsAiltabog)ma,ertaoe1sre.glgoebl,uliunsi(nag1),a2Begclokbmualnin t(e2s2t),kBit,glsotbauilniinn(gBewtiat)h, aAllbbuummiinn/cgolnocbeunltirnatiraotni.o (A/G Ratio) was calculated from total protein concentration and analysed ts Urinalysis MIN3I30z362 iaDlnuldriiivnilgdusWale.ekmAesntai1bm3ooalflisrsemwsetrcmeaegdneetprwaiinvtdehdoWouetfewkfaotoeodrffooersmovwaaetprepyrr,yoaxviwemriamntieeglhywta1rs6i3nc0eo/ls1le6c0at0edhmouwwenpsrlealcnaodlpeplelpcaostcesediifntoaemn 07:3007:45 hours respectivehley Following dn: The individual sampleswereexamined forthefollowing characteristics: VAoopHpleuamrean(cVeol()App.) PSSrpooedtcieiuifnimc((grUr-oaNv)oit)y, (SG) potas s i um (U-K) and chloride (U-C apGM5olasulqtciuiosavstelexao(tfaGirlnevuecdg)iia,natdgiiknvceoaetstotonnirlecssyrof(eawKanhegiatellons)ytt,sterboeibscltuoealnitcpsneienfgdtmorefantogtilmosunc.(BoBsaieyRl,iee)sr,kueplhttlaos,neeomNsrepwahibngudamreebyni,ltpesiEgnp(mgiBegllnmaotenosnddt)rasenbsdyrreweMpuerolertepitsoeutrdsitxeae.dcd Scconding othe lowing somventon TM0 == += mepeuive mall amoweofanalyte wsAaasmmpielcxeraowmsiacnsoepcdiecfnoterrxitafhmuigpneradetasineodnnoctfehoetfhrteeeuurlainlngelsowdeeidpniogms:eitntswparesadpoenrformmiecdr.oscAonpaelsiqhueo.t oTfhtehedeuprienne LeCEuprciytoshtceayllitsaelscll Ee(Cpruy)s)t) Erythrocytes (RBC) Casts (Casts) Spermatozoa and precursors (Sperm) `Other abnormal components ~~ (Abn.) Thegrading ofel frequency inthe entifuged depaooillosws: 201 == = FNonee fwounidifnniaenlsydsfoiaemdmienxeeadmined Fewinallfeldscramined he sample resweireddespuatcehedstoExygenResearch fortestsubtance/metboltc analyses. cis MIN313/023622 Urine SEM xray analysis g"IrTnohdeuivpsiaadnumiapmllaeulsrsiwneedursreaimnipgnlteahsdedlwiaetsirotenwcetooellktehocotfsered fecroolcmlmcoiaeivdanneosdvtferurrdonyyimgashanttiemflaollristuerdiaunrnaiilnmygasilWssedaeunkrdi1nm3getoaWfbeoxlpioe t4seuoarfsese,eaxyrpse.ocsk ouvrTeehr.ey `swahmeprleespowsseieblceo.llFeocrteadnfirmoamltshfaialniimntaoglsprwoidtuhcein2a hsopuercsimfeonllodwuirnignlgigthhitssionnteirnvalt,heurainniemawlashoclodlilnegcrteodoamt nSeEcrMopssyt.ubsTdheespuarticnhesedamtpolPelsywmoeurtehiUmnmievdeirasitteylyfoasscaalyceudlifoandpHcryusstianlgan8amliycsriosebleyctSrEodMe,X-arnadypcrleepmaernetd identification. NECROPSY AND HISTOLOGY Methodof kil erAxensciaomvnaeglrusyinkapietlrolienod.dduwTrehirenegsketihqleuleesndtcuebdyyinainnwtdhriatpcehhroisttehoenseuaarlnviimivnaijlnesgctwiueonntrielofktihlseloeeddniadufomefrptechnotemopbslacerhtbeiidtouonnleeo,df tftrroeelaalttommweeenndtt booyrf recovery pewrasiseloectded to allow satisfactory intergroup comparison. Testsubstancemetabolite analyses Shealmdplunedsoerftbelrmoiondal(fsoordsieurmump)enwteorbearobbittaoinneeadnaatenstehcersioap.sy by cardis/aora puncture while theratswere "seTphaerbaltoeoddasnadmfprloezse (iunpltioqu4idmln)itwreorgeernuprnionr ttodtuebseps,aaclhltoowEexdytgoecnloRtesaearrocohm.temperatureand theserum RSaetseildiutaelrastasdmpulreisngofWeueriknse 4fwoelrloewfirnogzewniananldydsiessppaartamcehteterdosEaxsysgaeynaRnedseuarricnhe.samples collected from DniutrrionggennaencdrodpessypastacmhpeldestooEfxlyigveernwReerseeacroclhl.ected from all animals. The samples were frozen liquid Macroscopic pathology All animals were subtojadeetcailted necropsy. 1pA0efreaflrolroamwerdoe.bvsieAerlvwloaetfxitotenhroenfalthhfieseattoburryraeisnoa,fnpcidatcuoihrtiafarinyciegmsallaw,nedraeanfeudxlalcmrmiaanniceardlosnvicesrouvpaeilscl.y.eAxTfamheiernacvtreainntoirnaaollrfmotiohdf-welaitnsiessriuneecmsioswivoeands, hexeponseecdkaannddeaxssoacimatieidnntsiesidu.eAs nanydathebthorancpiocs,oitaibodrno,mmionmraplhaoanldogplyeolvricicanvittieesrawnadscthreteirciovriodsecnde.ra were reTechoexrdreeaqduaimasnisdtteihapoepnrrgroaepenqrsuiaidtwreee.dreiAsnwuyeeiasgbahnmeopdrlmeaasnldipteyrxitneetmahsleiaeanpnspdrpeapcvrruatonpesciuesdrefoarcfseiisxaztoeifovtefh. eanoyrograngsanaandndtitsissuseusewwearse `Any photographsofunusual finwedritankengat sthe discretionofthe necropsy supervisor. ta The retained issueswere checked before disposalofthecarcass. Organ weights MIN313023622 rTehceovferoyl,lowweirnge dorgains,stfaeekeenocffardoijmaccdeancthfaatnainmdalothkielrlceodnatfitgeurou13s sweueeksanodftthreewaetimegnhttsorre4corwdeeedk:s of ABrdariennals KHiedanreys LLiuvnegrs with mainstem bronchi (Lungs&br) Bilateral orwgereawenighsed together. Fisation BTionedusutisents'risaalnsdomlecutpihioydnliadtySemadimdspelpsersw.e(roerEytfehisexewdwehironleeB)foiouxifentd'hsiensoDolatuvhtiirdonst,oinsps'rusieosrliltidos.tterdaUnbrsefilenorawroyffrbtolhmaesdedalelrtiaswnsaiusemsafltisxew7de0ri%en preserved in 10% neutral buffered formalin. AAdorretnaaltshoracic Brain Caecum Colon Duodenum Epididymides EHFyaeermdsuerriaanndgjloainndts+ Head IeHTeueaumrntu*m KLaicdhnreyymsa+l glands LLaiyveertr Lungs* Lymph nodes -"tmmreaasncedhnietboeurbliracornchial NMaasmalmaurriynaatreesa - caudal OOpetsiopnhearvgess POavnacrrieeass Pinitry Prostate. Rectum Salivary glands+ Sciatic nerves+ SSSkkeeimlnientaall vmeussiccllees- thighs+ Spinal cord SSStptloeemreauncmh TTehsytmesus T"onTguehwiythrparothyiroidds Trachea VUUraigtnianreaynbrdlacduedrevsri*x +Only oneprocfoeresxamsinaetiodn * Sections included the pelvic epithelium p20 MIN 313/023622 w`Shaemrpelaelseosfiaonnywaasbnnoortmcalleatrilsysdueesliwncearteeda,lscoonrteitgauionuesdiasnsduepwroacsefsisxeeddfowritehxatmhiengartoisosnl.y aIfnfetchtoesderceagsieosn and sectioned as appropriate. `This extensive list further examination of tissues oftissues. preserved is intended to satisfy any possible future requirement for fSeammuprl,essoalfitvahrey ghleaandd,(iscnicaltuidcinngernvaesaalndcasvkietlye,taplarmaunsacslale (shiniugshe)swaenrdennaostoephxaarmyinnxe)dahnisdtotlhoegirceamllayi,nibnugt are retained against any future requirementformicroscopic examination. Histology For those subject to hainsitmoallogsicsaplecpirfoiceedssiinngt.he Pathology section, the relevant tissues with an asterisk () were ``Tmiiscsruoenstahmipcklneessswearned dsethaiynderdatweidt,hehmabemeadtdoexdyliinnpaanradffeionsiwna,xe,xcseepcttitohneetdesattesapwphriocxhimwaetreelystfaoiunredtousfiinvge. 2 standard periodicacid/Schiff(PAS) method. `Thosetissues subjected to histological processing included the following regions: LHeiavret-r siencctliuodnedfraoumriaclullmaraianndlvoebnetsricularregions `LTurnagcshe-a-seicntcilonudferdobmiftuwrocamtaijonor lobes, to include bronchi Ulirgihntamriycbrloasdcdoepry-asnedctcieolnlsprtoalkiefnersaatgiiotnalilnyd(euxs)ing onehalffor SEM analysis and the other half for Foofrtbhielarteemraalionirnggantsis,ssueecstrieoqnusiorfedbofotrhmoircgraonsscwoepriceppraethpoalroegyd.. Asinglesectionwaspreparedfromeach san: PATHOLOGY MIN 313/023622 Light microscopy Microscopic examination was performed as follows: All and tissues 4 (300 pprepsme)rvesadcrfiofriceexdamoinnactoimopnlewteiroen eoxfamtihenesdchfeordualleldantirmeaaltmseonft Groups period, | (Control) and for all `animals killed or dying during the study. TalilsMsuaeisnrsetpuodryteadndatRmeaccorvoesrcyoapniicmaelxsamination as being grossly abnormal were examined for `dTohseagfeo,llwoewriengextaimssiunese,d wfhoricalhl wMearien csotnusdiydaenrdedRetcooevxehriybiatn2imraelasc;tiloanrytnox,tlrievaetrmeanntd at the lungs. high Ffoilnldoiwnignsgwefriveeeigtrhaedrersepwoartseduassed"p-remsiennti"maolr,asssliigghnte,d masoedveerartiet,y gmraadrek.edInortheselvaetrtee.r casAe orneevoiefwtihneg pathologist undertook a peer reviewofthe microscopic findings. PCNA Staining for cel proliferation Sedcteiognosroffeeuerlilnaprryoblilfaedrdateirowneprreesteankte.nfrAomtoatlalloanfi3m,al0s0f0ocrelPlCsNwAeirmemcuonuonstteadinfirnogmin3osredpearrtaotaessseecststiohnes w(e1r,e00c0oucenltlesd's,eacntidoen)xaimnionreddebrytothdeeptaetrhmoilnoegitshte tcoaelslseprsosltihfeerasteicotnioinnsdaenx.dcoPousnittSiv-ephPaCseNpAossittaiivneicnegllce,lilfs practicable. Icnonatdrdoiltsifoonr,tsheectiimomnusnoofsttahienidnugomdeetnhuodmoflroogym.eachanimalwere takenandstainedto actaspositive DATA TREATMENT `tTohgiestrheeprowrittchosnitganisnsdasteraicalololbescetrevdadtuiroinnsgptehretaniencirnogptsoyaplelrwieode.ksTohfetornelaytmseernitalanodbsreercvoavtieornyscroemlpalteintgedt,o the acclimatisation consumption, period included in this report relate to the Week-1 bodyweights and food c`oSmupmumtaerr-yssttoartiesdtiincsdi(ve.igd.umaelraanwsadnatda.stTahndearsdudmemviaartyiosntsa)tipstriecsseantneddtihnetihnisdrievpiodrutawledarteacwaelrcuelsattoerdefdrionm pthuerpcoosmesp,utheorwetvoear,cetrhteayinwenruembuesuroalfydercouinmdaeldptloacfeesw,erdipflfaecreesn.t fIotric,atchherpeafroraem,etneort.geFnoerraplrleyspeonstsaitbiloen to reproduce the presented means and standard deviations exactly using the presented individual data. `Throughout thereportthe following abbreviations are used: R Norn SDorsd Recovery `SNtuanmdbaerrdodfaevniiamtiaoln.s examined. i: Definitionof "Week" MIN 313/023622 "oSTnahmetehferdssutervwaeennet.kh dofayrfeoallmoewinngs.tarStuebdsaetqmuiednntiegxhpteprirmieontoaltrweesetkmsenotfrceoammmeennctinagndanrdeceonvdeerdyawemridonfigiht Signs A detailed history of individual animals that showed signs i presented n Appendix 1, asthe weeks in `which the sign was observed. Only animals with findings are presented. Owbeseekrsvoaftrieocnosvdeurryinagstfhoelrleocwso:very phase re recorded on astudy week basis, Weeksofstudy rete to Week ofiryecovery =xx = Dest code key 7= terminal il. H=erheucmovaenrey ikill Fe found dead Weeko1f4 Sudy 11ss 87 `Appendix 2 presents the individual observationsofsigns related to dose administration Bodyweight Group mean wight changes were calulated from the weight changesofindividual animals. Food consumption Vaanlyuaensipraeshentteddifod tohewaamsoKundtofufroiondgchoenseucmkedin schcag i eachexperimentalweekallow for Weekly group mean fod consumptions and standard deviations were derived from wounded cage `values, which were weighted to allow for any deaths as follows: Todt we 309 fa(fd e-x.w)*] VET `Where: Xw =weighted mean,ad = animaldays,fo =cagevalue andsd =standarddeviation. Blood chemistry Albumin to globulin (AIG) ratios were calelated as: Alin consnsion Totalprotein bmionccarsion 1B: Urinalysis MIN 3131023622 `Theabbreviationsused in Appendix 7havethe following meanings: PMYY MPaeldeiyuemllyoewlalpopweaaprpaenacreance CCPMYY CClloouuddyy,, mpaeldeiyuemlyleolwlaopwpaepapreanacreance TR Tracedetected Gelreocutrpolmyteeasnosnya.nd standard deviations are presented for volume, pH, spesific gravity, protein, and Organ weights thcToehvoearrgaidiajnnucaselt.,eduTnohtrirsgaanansnfawoleryismgiehsdt,tstoeoprkrmetishneeanlttberodadniysnwfeoTiragmbehldtesa6basstahoe nlcduotvAeaporprieganatdnei.wxeLigihwnteesraersrtethgohrseeesrsefisroponomnistneheesvwaareniraalebylsefiisattnoeddf wtteeoiregmahicntahslg(braoondudypw,tehaiesgrshetuf,moritenhtguhstehreegmrloiovnueispnmgfoetrhaaenllefogfrergcotauopnfswbweoeidrgyehwtepsia)grhawltel.erleToahdeojunstseatnaenddoattrhdoewrd.aevridTasthtiehoneisnodwvieevriredaulbalalsmoeredgaoannn thevariabilityafterallowingthecovariate,ratherthan the usualunadjustedstandarddeviations, Pathology Tntioisrssmsuauele.sscwhTheiidscushlueecdsoufrloedrconeroxdtabemdeineaasxtaaimboinnontrehmdearlaerfmeoarsecpreiocnsidcfioicpeaditceiasnlttlhhyaetbautpthpeefnotduiisnxsd.uetoTwhbaees aneoxrabmmailsnoemdfiecaraoncnsdocomfcpmoiuecenandltltyfo oabraree pdreesscernitbaetdionassof`dNaotasitghneiftiicsasnuteslesspieocni'fieidn other tissues. inthtehempircortoosccoolpifcor phaitshtooplaotghyoloagpipceanldiexx.aminIantiaolnl ptraebcueldaer BE MIN 313/023622 Statistical analysis All statistical analyses were carried out separately for males and females. Data relating `analyses were tcoarrfioeoddouctonussiunmgpttiheoninwdiavsidaunalalaynsiemdalonasathceabgaesibcaseixsp.eriFmoerntaalll other unit. parameters, the `The following data types were analysed at ach timepoint separately:- FBoodoydwceoingshutm,ptusiionng,goavienrsaopvperroparpipartoeprsitautdeyspteurdiyodpse,ruiosdisng cumulative cage totals Blood chemistry, haematology and urinalysis: `POartghaonlowgeiicgahltsfi,nbdointghs,abfsoorltuhteenanduadmjousfbtaendfeiomrartlesrmwiitnhalanbdowdiytwheoiugthetach finding. FFiosrhecra'tsegEoxraiccatltedsatta(,Fisihnecrlu1d9i7n3g)pfaotrhoelaocghictarleaftienddginrgosu,ptvheerspursoptohretcioonntroofl.animals was analysed using Fvaorriacnocnetibneutowuesendatthee, gBraorutplse.tt'Usstiensgt t(eBsatrstldeetpten1d9e3n7t)ownatshefiorusttcaopmpeloiefdBatrotlteetstt'sthteesth,ormeoagteendeigrtoyuposf nweecreesstahreyn. compared with the Control group, incorporatingadjustment for multiple comparisons where `aTnhdecfloilnlicoawlinpgatsheoqluoegnycdeatofastatistical tests was usedforbodyweight, food consumption, organ weight `Ia7na5ly%siosfwtahseadpapltiaed(.acroTsrseaaltlmegnrtougprso)uwpesrweetrhee csoammpearvaeldueu,sifnorg eaxaMmanptleelc,tetshtefno&r afrterqeunednciyn `pgrroopuoprtaigoanisns(tMtahnetceolnt1r9o6l3b)oatnhdfoals)ovpaaliurewsis<ecFviesrhseurs'svEalxuaecstt>e=sct,s a(nFdisfhoerri1)9v7a3l)uefosr<e=achvedrossues. values >c, as applicable. IfthBeanrtlpeetrta'msertreiscfoarnvaalryisiasncweahsomaoppgleineedi.ty(IBfatrhteletFtI 1t9e3s7t) fwoarsmnoontotsoingniicfiitcyantofatdtohsee-1re%sploenvseel,. ((WHielallieayms1919997)1,wa1s972n)otwasisgnaipfpilciaendt. at the Ifthe 1% FI. telsetvewl,asWislilgniiafmisc'antt,esstugfgoers&tinmgotnhoattontihce trend dose- response was not monotone, Dunnetf's test (Dunnett 1955, 1964) was performed instead. tIrfanBsfaorrmeatsiontseswterweastriesdi.gniIfficBaanrttlaetttthteest1w%as lsetviell,sigtnhiefnicalnot,gatrhietnhmnicon-apnadramseqturairce-treosotst swiegrneifiacpapnltieadt.theIf1%thelevHeIl, Stheisrtlefyo'rs tmeosntoftoorniacmiotnyootfondiocset-rernedsp(oSnhsierle(yHe1a9l7e7y) w1a9s99a)ppwliaesd.otIf the HI (Steel t19e5s9t)wwaassspigenriffoircamnetd, isnusgtgeeasd.ting that the dose-response was not monotone, Steels test `seWqhueernecea.pprFooprriaotreg,ananwaeliygshist doaftac,ovaanrailaysnicse owfavsaruisaendceinwapslapceerfooframneadlyussiisngoftevramriinaanlceboidnytwheeigahbtovaes tcohvear1i0a%telwehveeln(tAhnegewrivtahlilnagnrdouCparrellsartoimon,sh1i9p63b)e,twieneannoartgatnewmepitotghatlalonwd fboorddyiwfefiegrhetncwesasinsibgondiyfiwceaingthatt which might influence the organ weights. 128: MIN 313/023622 (Sig=n0i0fi1c)anotrd0i.ff1e%re(npc<e0s.0b0e1t)weleevnelC.ontWriollliaanmds ttersetatiesddgernooutpesd bweyr*e*'e;xpDruensnseetdta'ttteshte i5s% do(npa<t0e.d05b)y, =1"%, Shirley's tet is donated by '+" and t tests are denoted by *+' QUALITY ASSURANCE AND ARCHIVING PROCEDURES Quality Assurance Details of Statement. the Quality Assurance inspections and audits are presented on the Quality Assurance Archives uFosleldodwuirnigngcoamnpyletSipoonnsoofrt'hsisorsstuupdpyliaellr'rsaawnadlaytsai,s,spweecriemesntsoraenddinsatmhpeleasr,cheixvceesptofthHousnetgienngedroantedLifoer Sciences. retention aTnydpeasrochfisvainmgplmeaayndbespdeicsipmoesnedwhoifcahfatrre unsuitable, the periods bsytarteeadsoinnoHfuinnsttianbgildiotny,Lfiofre long term Sciences Standard Operating Procedures. ASclilednacteas.generated by Exygen Research and Plymouth University will be archived by Huntingdon Life AAllcootphyoerftaphperopfriniaalteresppoerctiamnednsalalnQduraelciotrydsAswsilulrbanecreetianisnpeecdftioorn aremcionrdismwuimlplebreioredtoafifneidveiynedaefrisnitferloy.m thcoendtaactteeodfainsdsuaedovfictehesfoiungahlt report. on the aAbtotvheeerenqduoirfetmehnetsf.ive yUenaderrretneontciiorncpuemsrtiaondctehsewiSlplonasnoyrwitielm be be discarded without the Sponsor's knowledge. 2: RESULTS MIN 3131023622 CHAMBER ATMOSPHERE CONDITIONS Chamber analysed concentrationofPOSF Ttohtehidsatraepoaret.presented in ADMINISTRATION OF POSE TO RATS BY INHALATION appended `The mean chamber concentrations (pm) are summarized below: 2 Meanchamberconcentration (ppm) 2% `The achieved concentrations were close o target. Gro3up 4 104 299 Sigas and mortality (Appendix 1 and 2) AtbhnoediymsattuledmyNp.oe.ra`6Tt3hui,rseG,arnpoioumoparlr1 ih(gaRhdetcisonigvgernresfyloeCfxoehnsetaarndad)lfaeebamnnaionlrgmeawtloagstahiektirlilgehdt,fodrihspulmaacneemernetasoofnshidnudrliinmgbsW,ereekdu3ceodf AWneiemkal13N.o. 23, Group 2 (Low dose) died during the bleed forhaematologyand biochemistry during Neitherofthe 2deathswereconsideredtoberelatedto exposureto POSE. `rTehceorveewryearneinmoalsrdeusrienngtthreel4awteedeekffreecctsovdeurryipnegrtihode. 13weeks ofth testmentperiodor inanyofthe Bodyweight(Figure1; Table1; Appendi3x) bocFdoolymlwpoaewriiegndhgtw4ifotwrheeCeoskntstreoodlfr.artse,Fawoitltmlheownitnattghesrt1ei3awlwaessiegknasifroiecfdauntccrteeibaoetnimneignntatbttohaediryneweedwifagoshrtaalfldororsaattgreee-adtremedlaatlseastdealrnietddeuGcartnoiioumnpali3sn (Girnoteurpdo4s(eH)iagnhddGorsoeu)pan4i(mHailgshbdoodsyw)efiegmhatlsesr,eccoovmepraedr,edwwiitthhbCoodnytwreoilg.htFs coomplaral4blwoeeoewrksrireescntovreg(roy Control. Food consumption(Table2; Appendix 4) TTohwreorutghhaonutthtahteof1t3h-weeceokntreoxlpso.suTreopealreisosderfdoeodgrceoenasnumdpwtiitonh bafyeHwiegxhc-edpotsieornastcsoonfsubmoptthiosnexbesytwhaes Io1nn3ltywe,remehekodswieaotvfeeerxa,pnodtshLusorewwathdsosieneffcgeorcnotturwpaassswt atsmsoaapllrlsaeondodlsaoecwhecritoehnvsaeundmpscttoanittoirsnotilwcahcloensrisegunmtiphfteiic3oannt.creeaOitnveemdragltrehoeuHpicsoguhcrdosenoossfutmraheteds misinomcrirleeatra.hseadnItwnhhfieelmecaomlnaterlsoelcsco.onDnstuuomrlpitcniogontnshuebmyp4twHiieognehkrderomesacei,onvLeedorywcpoendrsotisaoendtacnsoduncschuotnmthpratoilcsoonnibsnucyrmaepatlsieodr.nebtCyeodnalmsluagmlrpeotuigporsnowuibpsys tgHhrieoguhfpesdmoacsloeencsIounnmtspeurtmmiepodtniiswotaneswdlaoossweeorwwtaehsratnshiatmhinaltacorofn0tcrootnlhtasrtionslesbeoontvhedrusterhxieensrtaehvceeordvoehsreiynpgerwpieeoredi.kosd.oIfneIsxnaptaoelsluiatreet.aemdimaflesmatlhee J `Haematology (Table 3; Appendix 5) MIN 313/023622 FinolGlroowuipng41(3Hiwgehekdsoosfet)rmeaaltemsenctomgpraoruepdmweiatnh rCeotnitcruollo,chytoewecovuenrtsnowesruechstaetfifsetcitcawllayssipgrneisfeinctanitnlyfehmiaglheesr andthedifferenceisconsidtoeberofendo toxicological importance Gdorsoeu)panmdeaGnronueuptr4op(hHiilgshadnodsem)omnaolceystewictohunsttastiwsetirceallryedsiugcneidfiicnanWceeebkein1g3 aftoarinGerdoufopr3Gr(oInutper4me(dHiiagthe Wdeoesek),1h3owleavregrethuenrsteawienredeccoenlslsid(eLrUedC)0bcouennotsefwfeercetosnttahtiesstieccaolluyntssifgnoilfilcoanwtilyn4glowwereionfertreeckaotveedsrym.aleIsn ``wceormepnaorteddowsietrhelCaotnetdroalndawnedrtehiensdeepreenmdaeinnteod flsoewxe,rthfeoylalorweicnogns4idweereekdsunorfelreactoevdetroy. reTahmeenste. differences Freodlulcoewdinlgeu4cowceyeteks(oL)frbaescoopvheilry()thearned wmasoanreodu(VccDe)dycwohtuintete,bwliotohd sctealtlistciocualntsi(gnWiBfiCc)ancinebefeimnaglaetst,aiwnietdh. foalrsGorevoiude3pn(tInintearlmledtrieaatteeddogsreo)uapnsdfGolrloowui4png(H4igwhedeoksse)offermeacloevse.ry,A wliotnhgesraptirsicoaltshignriifmoiceam(ncPebT)biweainnsg. adtifafienreendcfeosrwaelrlemnaoltesseaenndfoGlrloowuipng31(3Iwneteerkmseodifatteredaotsmee)ntawnitdhGPrOouSpFa4n(dHairgehtdheorseef)orfeecmoanlseisd.ereTdhneoste to beofanytoxicological significance. Otah4erwienetekr-rgercoouvperdyiffpeerreinocdestihnatthaetthaaienemdatostlaotgiistciaclalpasriganmieftiecrasncienvwesetriegatsemdali,n Wneoetkdo1s3e-orrelfaotleldowainndg inconsistent between the sexes and considered incidental andofno toxicological significance. Blood chemistry (Table 4; Appendix 6) sFioglnliofiwcianngtly13hiwgeheerksfoorfGtrroeuaptm3en(tIngtreorumpedmiaetaendoaslek)alainned pGhrosopuh4apta(sHeig(hALdoPs)e)lemvaelless.weTrehestvaatlisuteiscaflolry tshtiasinpeadrafmoertGerroruemp4ai(nHeidghhdiogshee)r cfoomlploawriendgw4itwheCeonktsrolo,f recovery with statistical significance being cFoolmlpoawriendg 1w3itwheeCkosnotrfole,atamnedntreamlaaniinneedamhiinghoe-rranfoslflroawsieng(A4LTw)eleekvselsowferreechoivgehreyr iwnirtehstseudtimsatlieasl significance in Group 4 (High dose) only. Gforloluopwimngea1n3 wlaecetkatseofdterheyadtrmoegnentacsoem(paLrDeHd)wlietvhelCsonwterorle. loHwoewrevienra,llfotlrlaotweidnggr4owupesekosfobfotrhecosveexreys d`ciofnfterroelncvealwueersewneortedolsoew-errelaatnedd caonndsisdtaetriestdictaol sbiegnrifeiacsaonncaeblwyassiamtialiarnetdoftohrofseemoafletsesvtalgureosuopns.ly tThheey areconsitdobeeroefndo toxicological importance. ``CCohnotlreoslt,erwoilthlevsetaltsiswtiecrale sliogwneifricianncterebaeteidngmaalteaisnefdollfoorwiGnrgou13p w3ee(Iknsteorfmetdiraetaetmdeonste)coamnpdarGerdouwpit4h (`mHailgehs wdiotshe)stmaatilsetsic.alFosilglnoiwfiincgan4cewbeeeiknsgoafttraeicnoedvieryallthreeslteevedlgwroauspss.till lower than controls in treated Csirgenaitfiinciannece(Cbreeiant)g laetvtealisnewdefroer rGerdouucped2f(orLoalwl dtorseaet)edfegmraoluepssacnodmpGarroeudp t3o (CIonntterromle,diwaittehdsotsatei)staicnadl Grercoouvper4y t(hHeiglehvedlossein)tarneaitmeadlgsroofubpostwherseexceosmpfaorlalbolweinwgit1h3Cwoenterkosl.of treatment. Following 4 weeks 128 MIN 313/023622 Ti riglycn erideg levels wweearke rreduoced ion trgeateod grrooupss wviito h statc isticalpsiiglnieficsancsetaattianineeddfoorrffeemmales wCOotenhseiekdeirnteredercgiornvoceuipdreyntdpaielfrfaienorddenocwfeesnroeintomtxhaeelab,lioogocihteesmdiSociasglipfeaeraeanmcseetearnsd.invIesnticgoatmedein bWeeeeken13 tohrefsoelnltoswinogda Urinalysis(Table 5; Appendi7x) teIonrxtieecroglsromgoailuclpa,ldinsfoiftgenridefoniscceae-nsrceeil.nattheed paanrdameintceornssiisntveensttibgeattewdeeinn Wteheeksex1e3s.andNfoonleloawrei.n4cgonwseiedkesroedfrfeocobveeroyf Urinary pH (Appendix 10) PH valuesofrestedand Controlanimalsweresimilar. Organ weights (Table 6; Appendi8x) wAgrbeosueoplsku.tereTlchioveveerrdywiefpfieegrrhietonscdewstehewreerregecroesvatetaretyrisatinchiaalmnlaylco'snsitgrTnovilfesircaiwnnetibgwohththse,nsweaxhdeejsnusoatfeddjthufesoerIdnbtfoeodrymwebedoiidagythwete.iagnhdtF,oHlirlegomhwaidinongseed8 sasstaetliisittigecarlialtysfgsarigfeintaitefcerircta4ahnwtaelnnyechoktinsgthreyeoxrlpofwoseruigrGhersao.utpth3 e(iHnitegrhmeddoiasteeJdoovse)tmhaeisivnerdweGirgohutps 4we(rHeigShandossiek).allIyn Lung and bronchi weights (absolute and bodyweight adjusted) in High dose ratsof both sexes were anlustuinanmtggiaaasltnnisdcdaablbflrrytoosrnniccgh4nhiiiwfwwieeceeaiikngtghslthoysshfiienngxhmfepaerolmtseahuHalrineegsachwotdenotrtrsehoeelsrsiHamatiifstglerahrerdm1toa3osiswneee,oedklrssutoansftgiaeastxnfipecdoarslbluryr4oeswn.iegcnehAikiffswitceearoinftg4lrhyw"etheciseogwvkheeseorrryfte.rhIsaenincctoSovsnteitrcerylollltshey,e significantlyhigherthan controls. Kisdudiinfseteirycewanlelicyigehnstsisfg,enmwiafhlieecsan.ntaldAyjfuhstitege4rhdefwrortbheoadnoyefwcroeenikctgorhvotsel,riyanftmtheaerlbeo13rdaytwwseefiergkohsmttoahfdejIeunxstpeeodrsmuKeridedi.nae|tyeTwahneerdeiHiwgogehfhrdeotisgnseohwdSeoursceth mcaclmesuwmeerdefstoarttishticialhlyesibgnifoicangtly gareiatuerttdhan cnoenytrwoelis.ghTthseroedwerien nloehsi.sto1psatshtoellolgyefirnadsingrsewwheirceh nodifferencesinkidneyweight 4weoe f exk posus re. Othe intergroup differences were small, not dose-related and inconsistentbetweenth sexes. Macropathology (Table 7; Appendix 5) `The macroscopic examination perfaottrermminaetiodnrevealedthe following change: Liver EnonnleairntgheemCeownnattsrolobmsaelrevemdacinro4p/a5thsoatleolgiiteeamlaalter.atstreated with 300 ppm for 4 weeks compared with A13nweenelkasrcgeommepnatroefdtwhietihvneornweaisntohbesCeornvterdiolnr3i/s5.maleratsand2/5 femaleairatedwith 300 ppmfor Ftohelrlotrweiant4gmenwtereeklsaotferdemcaocrvoepraytnhooleongilcaalrngdienmogefsnthteliverwassenamongst recovery animoaralnsy `mTahceirnocsicdoepinccecahnandgdeiss.tributionofal th findingswereconsideredtofllwithinthebackgroundrangeof Micropathology (Table ; Appendix 9) Treatment-related findings MIN 3137023622 Larynx N`Tehcerroesiwseroef 100 ppm. ntohefivnednitnrgasl wcharitcihlagweerweascoansssiodceiraetdedtowbiethrthee altdmoaintirtsetaretamteidnotn ionf r3a0s0repcpeimvifnogr 3103 pwepemkso.F DNeocsraogsei(sopfpmv)entalcatlage 0 3Males100 30 0 Females 30 10 30 Tol 0 0 0 4 0 0 0 5 Numberoflanyuzexamined 5 5S 5 5s 5 5 a* I=nclpu<dDe0soSn,ebs-ppo<ra0d0ic1awniitmhalFisher'sExact Tet Fcoalrlioawgiengintmhael4ewseperkevrieocuosvleyryrecpeeirvioidn,g t3h0e0repwpam.snT0heeviidnecnicdeeonfceroefcotvhesryfifnrdoinmngeicnrfoesmiasloefsthperevvieonutsrlaly receiving 300 ppmwasonlymarginallyreducedcomparedfothat notedinthemainpar ofthestudy. DNoescraogseis(opfpmve)ntral carlage 0 3Males100 30 0 30Female1s0 300 Tal 0 0 0 4 0 0 0 3 Numberoflarmxeamind 5 5 5 5s 5 5 5 a* -Ipn<c0lu.d0eSs wointehsFpiosrhaedri'cs aEnxiamcatlTest Lungs mBaoctrhopthheagiensc,idweenrcee ianncdredaesgerdeien orfasforaecmeyivailnvgeo3l0a0r pmapcmrofpohrag1e3swiseeepktsalwhtehinckceonmipnga/rsecdatwtirtehdcaolnvteroollasr Trehciesivfiinngdi3n0g0cpompemlawtehdenwictohmptahreedhiwgihtehr bcoondtyrowlesi.gh_tAlatdjhuosutgehd flouangmyanaldveborlaorncmhaicrwoepihgahgtess/inserpaatls tohciccukreennicnge/sicsantoetreudnumsaucarlopihnacgoenstrwoalss annodtetdhearsefmoirneimmaalyinbeafiegmnaorleedr.ecTehievriengwe1r0e0npopmf,intdhiinsgslenveltohef lungs which wererelatedtothe administrationofthe compound inratsreceiving 30ppmor 100 ppm. 30: MIN 313/023622 Dosage (ppm) 0 3M0ales10 30 0 Females 30 100 300 Fseopatamlytahlcvkeeonlianrg/msaccartotpehraegdes! alveolar macrophages Minimal Sigt 0 0 0 0 0 3 1 0 0 0 0 1 0 2 2 Moderwe 0 Tal 0 0 0 0 0 1 5 0 0 0 0 0 1 0 4 Numberoflungs examined 5 5 5 5 5s 5 8 -*pI<nc0l.u0d5es,obn-eps<p0o.ra0d]icwiatnhimFailsher's Exact Test Fproelvlioowuisnlgytrheece4ivwienegk30r0ecpovpemrybupterlieosds ctohenrveinwcaisnggoroecdoevevriydeinncmeoaflersevperresviiboiluistlyyorfetcheeivfiinngd3i0n0g ipnpfme.mTahliess cnoortrfeelamtaeldesw,ictohmtphaerbeoddwyiwtehigthhetiradcjounstteemdplournagneaonuds bronchi weights, recovery Control which remained groups high for males but Dosage (ppm) 0 Males 30 10 300 0 3F0emale1s00 300 Foamy alveolar macrophages/ septal thickening/scattered alveolar macrophages Mim 11 Sigt 0 0 1 0 2 3 0 0 1 0 0 0 2 0 Tw 1 1 1 sa 0 1 0 2 Numberoflungs examined 5 5 5 5 5 5 5 8 a* -Ipn<c0lu.d0e5s wointehsFpiosrhaedri'csaEnxiamcatlTest Liver `Cweenrteraislsoobcuilaatredhewpiatthotchyteeahdympeirtnriopshytoerxfat3etn0dipipnomgn,to10t0hp e mip dozorn3m a0l0ap, rpeamanfdor1ce3ntwriloe builanre mahylpekesrwtirs tophhay do`asdamigneisrterlaattiioonnsohifp.30I0nfpepmma.lestPhreomsienfeinntdicnegnstrwialosbluelasrsphreopnaotoucnycteedpaingdmwenetrewaasssoncoitaetdedoocncalsyiwoinatlhltyhien females receiving 300 ppm and this was likely to reflec increased hepatocytemetabolicactiviy. `Hmeaplaetsoacnytde2h/y5pefretmraolpehsyrceocrreeilvaitnegdp3o0s0iptipvmel,ywciotmhptahreeednwlairtghenmoennteoifntchoentlriovlesrn.otTedahtwneacesrcooprsrryeilane ti3o/n5 sbtaettiwsteiecnahlleyphaitgohceyrtienhyrpatesrrterceoipvhiynagnd1t00hpehpimgohrer3l0e0vpelpomfcAoLmTpa.rBeoddwyiwtehicgohnttardoljsu.stedliverweightswere 131: MIN3131023622 CDeonstaigloeb(ulpaprm)hepatocyte 0 hexytpeenrdtirnogphtyo midzonal area ModSeiwget 00 Centilobularhepatocyte Toal 0 hypertrophy STigae 00 Prominent centrilobular hepatocyte pigment Mama 0 Ta 0 3Males100 300 0 40 05 05s 00 4 Sb Sb 0 11 00 00 00 00 00 00 00 3F0emale1s00 300 00 00 23 0 05 00 00 00 00 00 11 Numberofliversexamined ss 5s 0s 5s os 5 5 *2-Ipn<c0l.ud0e5s,obn-eps<p0o.ra0d1iwciatnhiFmiaslher'sExactTest Fohlylpeorwtirnogpthyhien a4llwaefefekctreedcgorvoeurpys,pepraritoidcutlhaerlryeiwnafsemgaoleosdperveividoeunscleyorfecreeivveirnsgib3i0l0itpypomf,hwehpearteocoyntley tbhoedycweentirgihltobualdajrusatreeda was liver affected. weights rTehmeaihniisntgoloignicmaallefsindpirnegvsiocuosrlryelraetceedivwiintgh 1th0e0 sptaptimstiocral3ly00hipghpemr mcaolmepgarroeudpswiththeircontemporancous controlgroup,andalsowithth increasedALTinal rated Dosage (ppm) 0 3Males100 30 0 Cheynpteirltorbouplhayrexhteepnadtioncgyitneto midzonalarea STioglh 00 00 22 %5 00 Cheynpterritlroobpuhlyarhepatocyte MiSniimgatl 00 21 03 00 00 Prominentcentrilobular Tal 0 3 3 0 0 hepatocyte pigment MiTmal 00 00 00 00 00 Numberof liversexamined 5s 5s 5s 5 s a* I-pn<coDnel0spo5ura,ddibcweain-tihsm<Failsphe<r's0Ex.act0Telst 3F0emale1s00 300 00 00 00 00 00 40 0 04 00 00 22 555 132: MIN 3137023622 Other findings `Mwoadsenroatteedciennttrhielolbivuelrarofheapnaitmoaslyt5e6n(emcarloesipsrienvfioluasmlmyatroercyeicveilnlg i3n0f0iltprpamti)o.n aSnidncseintuhissoiwdaals caornegceosvteiroyn rIant atnhde thlearreywnxasaornyltyeanoisidngleepiitnhecliidaelncehoyfpetrhpilsasfiian,dinhgyipteirkeurnalitkoesliysptaorbakeearsastoocsiiastedanwdi.thsturbeeaptimtehenlti.al iinnffilltarmamtiaotno;rayndcevlelntrinoflialtterraatlioenp;itahenldialvehnytprearlplpaosuicahanedpistqhuelaimaolushmyeptearppllaassiiaawaenrde niontfeldaimnmaoctcoarsyiocnealll afnoirmeailgsn.boTdhyesfeoofdinmdaitnegrsiawle),rreatchoenrstihdaenretdoltihkeelaydmtionibsetrraetlaitoendofothtehecopmrpeoseunncde.ofan irritant (probably Incidental findings aAlgleoatnhdersftiranidnionfgsawteraendcoanssisduecrhed1t0obbeeofpanrot oftotxhiecoulsougailcablacikmgprorotuanndcep.athIonlopgarytitcoublaer,extpheecrteewdierethnios f3i0n0dipnpgsmwchoimcpharaecdcowuintthedCofnotrrtohleshwihgihcehr rbeomdayiwneeidghftolaldojwuisntgedthkeidrenceoyvweeriygphetrinodo.ted in males receiving Conclusion `The following findings were related t the administrationof300 ppmofthe compound: rleacroynvxer-yneicnrfoesmiasleofsventral catlage,with no evidenceofrecovery in malesand with incomplete sleuxnegssw-itfhoianmcyomapllveetoelrarecmoavcerroypihnagmeasl'esseaptnadlcothmipclkeetninrge/csocvtetreyriendfaelmvaeloleasr macrophages in both nloivtearb-lyceanftfreicltoebdu,laprrhoempianteonctytecenhtyrpielrotbruolaprhyheexptaetnodciyntge tpoigthmeenmtidiznonfaelmaalrese,wiatnhd mianlceosmpmloertee recoveryofthese findings in both sexes eTxhteenaddiminngisttortahteiomniodfzo3n0alppamreoaror10c0enptprimlowbaulsarashseopcaitaotecdytweithhypceernttrroilpohbyulianr mhaelpeast,ocwyittehhyipnecromtprloepthey recovery a thse dose levels. twas not possible to identify a no effect level in this study. Cell proliferation (Appendix 11) `There were notreatment related findings. SEM and X-ray analysisof urineand bladder tissue TElheectrreosnuMliscroofsceoxapmeiEnxaatmiionnattoigoenthaenrd wXi-tRhaySMEiMcropahnoatloymsiicsrroegproarpthasppaernedperdetsoentthiesdMianinthreepSocratnning 3: MIN 313023622 Test substance and metabolite analysis sPaFmOpSleisnrtahnegreadtfliovemr snoanm-pdleetsecrtaendgeedvfreomsn0o.n8-27d0etneg/cgt.edTlheevreelws atosn53o5,0P0O0nSgF/gd.etePctFeOdAinianntyhoefrtathelirvaetr. PliFveOrAsaimnpltehse. atPFsOerSuminstahmplraetssrearnugmedsafmrpolmesnorna-ndgeetdecftredomlenvoenl-sdettoec1t2e,d10l0evnegls/mtLo.15T8h,e0r0e0 nwga/smLn,o PdeOtSecFteddetleesvtelesd tion 4a7n1y0onfgt/mhL.rat PsFerOuAm sinamtphleesr.at uPrFinOeSsainmptlheesartanugreidnefrsaommplneons-dreatnegcetdedfrloemvelnsont-o 18,600 ng/mL. There was no POSF detectedinanyofth raturinesamples. w`eThreea9v6er%age= p1e1rc%e,nt1r0e2c%ove+ri1e4s%,staannddar7dd%evia1t1i%o,n rfeosrpePctFiOveSlyi.nTrahtelivaevre,rsaegreump,eracnednturrienceovsearmipelses satnadnd1ar1d0de%vi1a7ti%o,nsrefsoprecPtiFveOlAy. inThraetalvieverra,gseepreurmc,enatnrdecuorvienreiessamplsetsanwdearrdede9v9i%ati=o9ns%f,or10P5O%S= i1n4a%t, Vier, serum,andurinesamwperle9e9%s 18%,92% + 18%,and99% 18% respectively. tM DISCUSSION MIN313/023622 AmodrmailniitsitersatiaosnsoocfiaPtOedSFwittohattrseaattmdeonstagaensdofno30,cli1n0i0caalnsdi3gn0s0 tphpatm waedraey coovnesrid1e3rewdeetkosbperotdruecaetdmennot rCeolnatterdo.l fTohlelroewiwnags1a3 rweedeucktsioonfitnrfeaotomdenctonwshuimcphtiwoansinstGilrloaupppa4re(nHtigfholdlooswei)ngan4imwaeleskcsomrepcaorveedrywiftohr females only 4Liwveerekwseiogfhrtescowveerrey.stLtuinsigcsalalnydsbirgoninfcihcianwteliyghhtisghweerrien htirgehaeterdinantirmeaatlesdamnadlerseamanidnfeedmahliegsherresfpoelcltoiwvienlgy cproemvpiaoruseldyweixtphosCoendtrtoolthaenhdifgohlcloonwcienngtr4atwieone.ksofrecovery still remained high for males but not females wEintlhanrogenmeeinntotfhte hConltirvoerl wmaasleorbastesravneddiinn34//55 mmaalleerratassatnrdea2t/e5dfweimthal3e0r0aipsptmraftoerd4wiwtehek3s00cpopmpmafroerd 1r3ecwoeveerky.scompared with none in the Control rats. This fining was not apparent followin4g weeks of Hliasrtyonpxatnheoclroogsiiscoaflvfeinntdrianlgscraerltaitlaegdet,woithtehnadomeivniidsernacteioofnorefco3v0e0rpypimnmoafltehseacnodmwpiotuhnindcwoemrpelseeteerne.cIonvtehrey iinnbfoetmahlseesx.esIwnitthheilnucnogmspfloetaemryecaolvveerolyairnmmaaclreospahangdecso/msepplteatlerteicckoevneirngy/sncfatetmearleeds.alveolar macrophages w`Ceernetrialsosboucliaartehdepwaittohcytthee haydpmienritsrtorpahtyioenxtoefn3d0i,ng10t0o,thoer 3mi0d0zopnpaml faorrea13anwdeeckenstriinlombaulleasr. hyTpheerrterowpahsy swiotmhetheevihdiegnhceerolfevaeldsoosfagAeL-rTlasteieonnsihnitpreiantetdermmalseso.f iInncifdeemnacleeasncdendtergirleobeulaanrdhtehpeatfoicnydtienghsypcoerrrterloaptheyd ecexntternidlionbgulatrohtehpeatmociydtzeonpailgmaernetawoanslynotweadsocsceaesnioninallayniimnaflesmawleeasterdecewiivtihng330000 ppppmm. andPrtohmiisnweanst cloirkerleylattoedrepfolseicttivienlcyrewaistehdthheepaetnolcayrtgeemmeenttaobfoltihce acltiivveirtya.ndIhnigbhoertbsoedxyewsetihgehtheapdajtuosctyetdelihvyeprewretirgohpthsy noted at necropsy. hFyoplelrotwrionpghythien a4ll wafefeekcterdecgorvoeurpys, ppearritoidcultahrelrye inwafsemagloeosdpreevviidoeunscley of reversibility of receiving 300 ppm, hepatocyte where only tbhoedycwenetirgihltobaudljaursatreedalwivaesr waeffiegchtteds.reTmahienihnisgtoilnomgiaclaelsfpirnedviinogusscloyrrreelcaetievdinwgit1h00thpepsmtoatri3st0ic0allpyphmiagnhedr alsowiththeincreasedALT inall treatedmalegroups. I(tLwOaAsEnLo)twpaosscsoinsbitldeoerieddetnotibfey30anppome.ffect levelinthisstudy. TheLowestAdverse EffectLevel : 3s REFERENCES MIN313/023622 Haematology APRmO.CTClOiRn.,PaRtRh., 3a6n,d21R2A-P21A9P.ORT, S.1. (1961). The Patial Thromboplastin Time with Kaolin. Qp2U4I-CK4,0.AJ. (1942). In: The Haemorrhage Diseases and the PhysiologyofHaemostasis. ch I, Statistics AanNdGsEimRiVlaArLrLat,iosLiannbdioClAogRy,LJS.TRTOheMo,reEt.(B1i9o6l3.)4T2h5eo4r-e2t5i9ca.l criteria forthe useofreltiveorgan weights BARTLETT, M.S.(1937), Propertiesofsufficiencyandstatisticaltest,Proc. Roy:Soc A 160: 268 282. DcoUntNrNolE.TJT. ,AmC.WSt.a.(A19s5s5o)c,A$0m,ul10t9i6l.e comparison procedure for comparing several treatments with a DUNNETT, C.W. (1964)New ablesformaltiple comparisons with a control. Biometrics, 20,452. FISHER, R.A. (1973) in: (B4s) Statistical MethodsforResearch Workers. Oliver and Boyd, Edinburgh. HT9E7A2L5E,Y,DepGaFr.tm(e1n9t9o9f)STtahteisFtiIcsa,pHpurnotxiinmgadtoenpaLriafmeeStceiretnceets.for monotonicity. Statistical Specification HSpEeAciLfEicYa,tionGFS.T97(2169,9D9e)paTrhtemenHtIofSatpaptirsotxiicmsa,tHeunntoinn-gpdaornamLeitfeerSctieesntcefsor monotonicity. ~ Statistical pMrAocNedTurEe,LN,J.A(m1e9r.63S)tCathi-sts.qAusasr,et5e8s,t6s9w0i-t1h0o0.nedegree offreedom :ExtenoftthieMoanntesl Hacnszel SleHvIelRsLoEYfa,trEe.at(m1e9n7t7,)B,ioAmetnroinc-sp,ar3a3m:e3t8r6i.c e3q8u9i.valent of Williams' test for contrasting increasing dose ST14E:E56L0,5R7.2.G. D,(195Am9ul)tip,lecomparison ranksumtest: treatmentsversuscontrol, Biometrics, cWoImLpLarIeAdMwSi,thD.Az.er(o1d97o1s)e,cAonttersolf,oBridoimfefterriecnsc,es2b7e:t1w0e3e-nt1r7e.atmentmeanswhen several doselevelsare WILLIAMS, 28:519-531, D.A. (1972),Thecomparisonofseveral doselevelswith azero dose control, Biomerris, i 36 Hy tiiisf eo Fd | | [2 i: \\ NY - 2 = a. 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B &2 g! e FE 5 ot ws ox :| 8 [Bs| 2% 3%..28..3%. EE EH 7 : I TM ~ mo - = JI fa- Ia- fa- fa- |3f 5 5Fgiifrs : = oF oF o8y ss: MIN 313/023622 3B%ol |e ome ofr ioe egowtsuo #3i| 35g. P8Y5. 323. BR2. Lael$| gEg,EEg5..5%..8 i J3 : i ~22 Pf| 5 870 57 g7e Er i FEf om <3ki| si. ad3. sia ch g Ea 2 [| ue gfe ge ot ae | Ef = = EL LSE CIN CE CR 2z iil g5 fx 8 2 2: MIN 313/023622 eg| 228%. 22%5. 2338. o2f. iBs| oe o2n wn oma JYPO CRE REFER i fo. ga 1] . 33 3|g [33 | =3Lvon.Te a3. a3. 8 EI 2 = 3 o 8 [ag] 2% 20 g%e 7. [F : = -zE-loy| g3we gaw Taeeepe [|F I F5 iGif e: 2 2 oz kJiHR i MIN313023622 Bz | gee dee gipniee ES| aBe 2fn ofn 3. Bi | uf +20 ole ~De Be| 58+ 23 27a 42. 1 2 | afc 2% 2% ade 1 if 0 iE Lg 3 FF BRETEEv gEE RgEe 3fe ~8| 8 ig- egake sguhe gsa f=3 7 3 8 [38| 8% sf eRe sd i Ek 2 TE | 35| gi~ gd~ zi- pi-~ |_ zI3 [5-2 1 gee o2 e 32: FEEEE I: ross RE sa: MIN 313/023622 S| | a gS s.38 k5e 8 d 2 e2| 28 58 23 3 8% NSwe dSw Mew =cw cE 23H | ser a~ faR~egrt=o i a i. CF g i2 b4g 5BR3| 3o2+e waBeu o3aZwe a3a3. | i g8 Ft T g i g os [Bg | 2%. 3%. 2%. TTT pTiT. RfF 1 ig "-3 BE gEe- ge ge gfe i[31 3 Ia- fa- fo- fa- i T= sRi5ltg |e x = 0s i[BkL gk HAE B zg sss: MIN 313/023622 i33| #7a.0 2%2n TLoSeue..t%e 52 ef, 23., ssff ssfi, 3 | s8, 35 ef =f _ _ 53 New ANSw dSw New fp1 | zii ~f2s% 3 g8e5 55gle7 g7gfe0 ggtv? i i C2 ILj | a3. 23. 23. 53. Fo li] en %E|le3g7ieg= gg=ineg7- Elbe bee Bee =0 FELE |: 5 = S56: MIN 313/023622 gg | 25. 2%. 28. 5B Bi | o2e oBn oZa ola Ls 83 | 23+ 23e 23w 22. i | Lii B|E I z| fi z 1 8 leg| a%e 25a sBeraza |E se 2%| 52 gw 5Rwiglne is 2 5 2 fo- for foe Joe 22 _IFsEEIEE|:sx= =0s 0s [i[EiEf a ate Es az- 83. E2- 33- Bs pan sme zie ede Es 280 w%n w3e =n BS [ue ode =3e 23 = =20 ZZ 93% 0w 1 fe B- gee go HE zd ER EES g8- gi gd~ gd- cf z -8 J, 2 | ereegioestonsge " |B 2 % os [2 oF aE oewadn [B . ii -Fo [23 | gfe gE geez 5 . Tig i 258 s Hi fil: = x oz [33% = og 2 i git 5? & a I S2 45 58: MIN 313023622 #3$s || 3=8 2383, s3%3, g3f5. er I LIER 4573 || 8385. 33%. 328 8 2w""# i g=" gue gen gee Li: 83 || 8389,. 8s%. 5sE_h sEgE = Jog | w3e a3w -3e 3. [F ig: 2 = og! =[B8 | a839e E8e a3f3. 2283. :3 P| [ge ge fee pee fH -3I.- [3d345ozi. g3Lo.- aLud. 5us3. |B . Hi <1 55% aTiRRil lBE |EgE |=z 2 2 Fz [5558% 3 159: MIN 313/023622 B 5: 3|a$7 gnelean gluma 2g | 82. sf. sf. sR, I <8 - i [PSEl | 85.5 g3ww~ gweordw. be P f Li | 4a8f. 2of5. wsff ae8f i g . [1] -- 23 gn giv g3a- 35. i . 73% I fer Bee fs- Bec Eg zF= HJ2 iFe: B2 OFozo E [EEE 160: MIN 313/023622 5g | 28. 22. 3B, sf. i "fe wZe we wie Lp EPIR =ETe ae 2m sno g A Li og | #30 w2e <3e a3. B ii 2 El 4 =3 o 8 [33 | a3n 22 g%n alw I 4 3! E log| a2weigZatigSe 52a [TT on FE Pg go gee gee fi : Ii LH pth: = 2 2 iE 161: MIN 313/023622 Es piv 2E- 3E- Rie BS [env af =e eg. =H rv 25w ofe egw Bs [roe 23v egw z3e 5 is los 2%w 2Ze Zw :3 #EF1l E. Bzs85 8E=- gd-- gi"- g-e g Es| g2g5|| ggs3+ gFz~3 =~z3~ scsB- :[E i : 5 [33] 837 28e 23~ se i -EEely2] wm i PEP 5 2iz e =F gE 2i sie soe g3e adoe i|B% =: f2- Is: Is- a- 32 it . ZE2I:aN% |e & & & sz s ca MIN 31323622 #73 | E28E. 5388 8L 8 E = 53gi|| 2385. aa85. g328. =3f5. 4}2|| 8885. 2h3 o2n3 sE3AL L53ERIFoCEI-CIECEyIE Li2Z 7g| 828. s3f5. =8 sER i;EiI EIE BE fer aBBuos e2a :E g I os B2|3Ee % 2%. st 2%. wh gE. fBFE 3 ks i 8 [E28 A ede gd- 280 ! fo- fo- fz- fo iH 2FgHEI FE 0s x 8 [H3e3 co: MIN313/023622 gts we gle gle Be 2s3s) | 8855.. 8E%EL E ef LoEf oFf| 5. 2%. 3288.. 3s%E. z ii= -i1,& bPo32|8?noe ega?fguenlBuaraz?n [F2 i n "2 ASe 33. 23. 25. i Ff Hd g 3 i 323 | ggT%TrrgBSeestgpTeeriggn [EiB f . iH i f2- Bs I3- f3- iz 3 5: 3 fil: & = 0s [ZF Co: MIN 313/023622 23: 85E . 3882, e5%8. 3% m8. &Bi v2. we Be w2a L2 Y 28+ 23w 2%n 22a Po wm I a%g [93 | +3% Zw Zu <3. | iEi 3| UEg 3 0 2% [23| a%e an 27w au [3 8% jg| 5Fe gfe gfe aa fF 2 22 fa- fo- fo- fs- : 8 Li} F Y kEE5 := &5 =ss= 2 =[F a: MIN 313/023622 o2s% | 382- F-8a- Re8- FF3- eS | 22. 2% | g5 88. 53 2g3s. g.as8r 25 55 B 2osW gg8vgw g zg=w za Zdaw EH1 l.es| 33. Ea82. g3fE. z33. i i z2o 5fI ~ZSeIg [[8283|| g%g%ee 332aZo ggBeeiiagd3ea i||HB 26 ge ERE SEHR Ea ii lz | rE. 28. 28.:ed. |E z - 52 | 8. 25. 2%. 29. |B} . 35 3$ f. o: f3- fp. s- gitz F2sIN si| ll3 s = 2 2 fz23gi 66: MIN 313/023622 Sf=| 3<88 R3aw d8ae FLlie 11= ggSe g2%iegl8 es=de ZZsz ts Eg8x20 "Zzg=g" w mn3=ew dgaew | oe - z4s | 238%. 538%. g3f%..3=EF. i: Se ioe oguren. |B i -58 "I gi g%0 giggle : g 2g | 3%. 58. 3%. 8d. 2 ig -ii. ze| 9%o. v8. ad=. ad=z. [|E5 3IT PA A FiEs PFa UbEg|s= =& 5& & RT co: MIN 313/023622 l2o3 d2e F"8e 2aae = IZ ga- " 5 2% 330: gfe z3or ge 1 .: Es 255. 2381. w8g. a4g. :ii ~2: 53| g%Sun gfefe egiaieonghaiee |;B S i ali e |=3. 2R..siacd. 2 |E "8 lz | R%. of. 23. af. BE El pbs Be Be |S 5 It ig pla: 2 =o fix Ja: N30 2E7g) 5(235,. 88%5. 5=f. E=fe Hd 1_ .s E5s s| BE. 3E, 3283,. s2t3. w 0 i gs sg gt gle gt z3 == 22222 ec .~si fg [3% 98. 35. 85. |31 "8 ge | 38. 38. SB. 3B. : zEl [fer oe 3o- 15- 2: <1 i 3HEiLil LHEADIL & EL= a c o: MINE 8 | 5[BsE -g8 -|3%- 8i- 3-%d- aa8 %: LoDoBdE| pERgT. cEeBe. gEe8e. sE0f. 3EiPi JE=-. dF3tE | -89+ a2d3- 238i- -8ae 1 fo- I5- B3- 5- 8 of EE rE &5& 0: PE f 5 aiyboy MIN 313/023622 i i i i i i Bh 8 i'd aaa i i i i i Ch adel PETE 2Po H|BR r Poeleos host rod JLoRzE] Po ||||| | |||i|| i EL A EE Brfndlat Glh i TEBi iHtL HeBad "3Lael K LEE H ml msailh all | i 3 4 4 3 Gig on 33 MIN 313/023622 LEII PaEollboe ef BprELEE Ime _ iDa2il, l0 al[| g2TE o CLEA Aa FoP|oEEPiTdgtEFEaEhTEHE f ipo e S--_ i, I i aTkE gal28 aBe ll HMEoLa a i $3 MIN 313/023622 giz: 5 I i i Ri R| : i iid ohh 1 ITI obo EE E ior bE hhoaae PPEEeEDbLerrTEb Eb 2 PRL bah bd | Poh ER i Pb El i orb eEo CF PPyrbo de sel sl ms ad Flore oR Rag lglg eo nl fod a gl LPOE RTHT ER ees edd ean iE Eg IF]l iE idTe]l gigi eCnene]loWsesep] oh ed (BveEeDp eed BvEedD] en avmaigdy ood] all i iH oxi 4 0 4 i Cn ty Hy ETE PROT i gilai 1 5 Ho gr ok "FLbodko lpeh yTE E15 DEOE I aml all ENTIRE Moai ag{18 HSLoa Eo She T so hPm e Et iLyE EO rT a dl em a Fofybkeoamn lE a aE ll Foo llamo ml aoa z i gE! i ai ai ai a ig? : 5 2, } ) MSE l iby L 0 EDoobeLe a Laat hs Hi i (HL i t] dg ohH aa El Lh 4L1 oip]lge mBl E mi mp | i l ab . 1H FRET F p10p ilne.mlomiHbE MEOW a a Co. . MIN 313023622 bon lalalaa belo or or aL Bao Uh Doaidel LarWE Ee ToPC al H Paayia rL l EE a sooi For |0 | | | | Alem BE a diailPgEjhiiTebgEfld aiT8Ti i ig TT 4 i EE al ol ull Lal Pjroid n 0 lEo aoma Ee sl SOE Rlda Hig i eb dd oeboan y GoBn) ed oa i Rogat ry on MIN 313/023622 or Boedl aed0 WEgd Bao eT EINER POR i { , I PTET igir Po 00 EU Bm LoD ARIS EE 4 i or PEERED it all fH BEY a ap shy Lh Pvp 0 bd TO oo Eo 8ii Aj Ei Ei i i i sD aa E ER 0| 0; FETaEl aLaTdT, vil Bo SET i Hl 3 Ea JE ag 5: 5. By i bo MIN313/023622 SE ri) mia 33 BET |S RIPogLieEel oF 0E WE A E 0 EL I | is "iE |]i ! 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M Hhummmn momen-- Po Hb be fBald hdmi dE H2 1 I MIN313/023622 ooRnmmImo I fhe ii HE Po HHiE ad Ti lyEEE PFELolRiEE tdnideosk al iyi mE MIN 313/023622 boogpnooomoooon sb hae Ey | HEE Pfo ai | 3i EfLoooliePo i bed i toon brag gd |i bog Pi i gC [BoHmR THREE IE 08 iodq all inl Bhasin ne FIFigprperoe concen soon joEpnnnniiiion Lad lil Saaol er a tooCg pH bai dd i fWa l nI l T , Ff E HB E fim iponi nmin pogo B] HUE epg Wat Sa bd fro ae 4 i Hi Hi Yh i LoiREL PHD iidi hl BTR gp iT l ET E By i Rpann mine. } EpooIIIIIIII i CHR dlCa drblre a I + InREhNE ifie LTE iE laR ! alll qT TTT fd 2 giz iid: ED yop oe enor oes oe non an ano nn 1 pnnmmnoonnon PL I flpmpmppep WigNy i iin | ii c+ Boo odoyl ii: d aHIEllEl Fi|hREER i : 90: fd fpoinnnnnoon J | Eri HEE 1a 1 | EHH t+ Sooon oo i h g e all YE, FpooIooIiIn i| fihpannonnoooonoaonoe b2o UTTAEphEEREENE m oa ot ndop big Pifpnninominn Hip "n 5 Be 906 ee so wn 98 1 rnin al] HE Liz ICo NEbi RarRiE5 nEgi ," PIa oop IiEEEEHTETIEREED a galbi nrlEFF HEED LE Py MIN 313/023622 fpnnnnnnomnIo { dpnoooooooon it HLRE EER ii hs k HE HR t CH albiena fo gr dd BRL Pa f iE t EEi E file han ed a 0 plnoomne tk i Sh 1 # wo 1h,e0h Iomh to C Hp El D LorEi Lifobir elHi iEi lL og fil BE Tainan 1 pT fo dh cali tigd Ze 1H i : i Li ab geri pT ig; gE 2B iE [I dponmonmnn { Egonmnimun 1 yEermpng L gs t PE ER FS o lPo do HE + na LH He HE : ii CELeonoininnonon g GpuToininnnnu Po Tee EL TREE t mn aH is ks ks is Is ks To lpi ul min E] iHlE i Pll woe 199: Hy 23% 3, MIN313/023622 { E Lplpop ono non oo FiHe + of oo oo oo oo oo oo ooo LHhL p gn n Po RBBBEDE 0 iii IloRnIE Woden Hi Egoo 3 Lo IPoFC) oLgd l f i i i J gle JE i Eis =2== fi ee yy -- Eo FC Poel Eon b:i"d hLadtdJo J RLEdJp piso fh ib Po HPiyi i i oe fLnay 3 1 1i | oar f 1i Elbi fefdl ig Hh ie ee wig. - $103: THiE iF 3i opP]o MiFd bIusg 15. - Mig:- ily Bl Eglboo Eo To g:i |PE] OB iPo ot J oa. Fost lTlg ptdjp diljug ape Ei Hi fig: fi| a, ~ zx xa =. ~ - ~- Hi 1 'nsi | gr Lin +lI pid pg Mig: - Hi TEN TiE o! gi iEii j[ii - T[EiIti: [EdR BoE dt bE ollsydaPhtJe pe lJPdod Mig: +. ST i dol Eo l n h5 g Foldligie pe J Eye : dine : beiby | fi iBi i Ho ITT EEldf]F P3RgonLisnigmi Pol 3 +d100 go pe HHog e hHag e Be10 RIFE HH FH = 2 Mig + - iba nflDyo Eo if Fs Z3 io T Fo0s0i 0 FEL deb + CELeR IPRiEdTt Hr if iy FO i i i i 7 2i asl Eo Jeb oCgH J pHeP pe pe E Pl Bngs.2 z - fig. sz os -ax -. i 8H Tol io 2 oF Lb Ld i PfEie Ege Hi:- ii i Pogo MIN313/023622 Ll TtLy J H FE eR dI " ` PR il ; i # -. Blht Jotih ge . x. := := 5 s 2 EN Eglbo o Nn fi jE) WW 82 II I3 ab Hd + LJpH plBi oplingdel yg hime finl- - -0.. 53 3 ) iHtii] fn Eo MIN 313/023622 3 Pol PE fx B iF ti hios Pog | FHdp Plu. iiPag i ss 5. ) MIN 313/023622 fo i i 5| To z Lo Fi 1 1 ELL. Ei PoePlod Lf I p LE F Tn l piPind Hy. oe Mig: o-oo 118 ifbyy fi bo H "I | MIN 313/023622 Poliyzi 11 Hi ELL. fol defi Ral dHigi. - J 25 - - - APPENDI2X Dailypost-dose observation MIN 313/023622 GCroomuppound oCaonzal 2 eePO5SF 4 Exposurelevel(pm) 0 00 30 Mainstudyanimals "Group RaNiom.a] mb ofdaysiWnweeekeksigns observed (ConTtMrol) ReJbrownsaining wound eyes| 21 1 T T2 T i 43023 22 2411121 11321 5 1 (Wetfur 21325s345s5s335a333a431 111 i3f0245s335555845533333a112231 5125855344332 [Brownsangonhead 21 3a s 1 1Torra oa 22 113111 2 1 1 [Brownsainingmuzzle 4 1 [Brownssiningbody 1 4 (Low2dMose)|Redbrownsuiningarou6n7 d[e3ye1s1| 241 21 1 ro $s [41112 111 120[IE1 031 1 Wetfur 670434433445433554435331 2 89 |434433444435345345453311 0034345354453 [Brownsainingbody. 6 3 [Brown stainingonhead 76 2 11 11 5s |[11 41 I 1 AnimalsexposedTo 5 Gays 3week or 3weeks 10 1 1 *Animal sentfornecropsyoverfirst3daysofWeek 14 cus: APPENDI2X (Dailypost- doseobserv-acotntiinouend) MIN 313/023622 GCromopwound Cont1rol 2 eeeP3 OSF 4 Exposurelevel(pm) 0 00 30 Mainstudy animals Grow ANaoim.al Numberofdays inWweeeekksigns observed SM [Redbrownsagwomdeyes| 11 [1T12354356T 7805 01206 ote.dose) 2 31 31 r1or 1 1 sn oa 2 wet for [2 (344433445543554444337211 B$ [(3344334444335585448313511 15 (4434435853121 [Brownstainingonhead 1 2 [1 ro 1 1 514 11 1s 1 4M |Redbrownsuingaroundeyes| (Highdose) 16 [1 i 3 23 1 5 4222231 21 iBl41223 221534t2o22 2 [11 Wetfr 716 (34553344553344855543544171 1 891353 154553344544345585352 5321 20 (3534534453111 [Brownsainingonhead "6012121 3 2[a1252 1 i1s9 Tr[I 12 1a 2 1 2 [Brownstainingonmuzzle 16 [Brown staining ailsexposedfor 3days onbod: aweekfof 13 1 Weeks *Animalsset ornecropsy ove first3days ofWeek14. 1 1 sug: APPENDI2X (Dailypost -doseobserv-acotntiinouend) MIN 313/023622 GCroomuppound tCyoral Exposurelevel(ppm) 2 a 3 4 00 100 300 Mainstudy animals AniNmoa.l mberofdaysinWweeekeksigns observed (ConTtFrol) Redorownsambgaodeyes| 221 [1 2 2 3 1 2 1 1 u3 To 2 ERE Wetfur 220 ( (44553555 5555555 554 a5s55s5522 22 (435533555522448385441455515 (3545524444355: [Brown stainingon head 22 31231 111132123224341 5u 13 2 111122433428333411 2s v2 1 T210 (Low2dFose|)Red/brown staining aroundeyes| 26 7 122T 323512 2B[111 231 122211 30 1 i [Wetfr 2%76 [ (8344334455 5333554 555555 455a:3 522 22 [(5344334455a34555455a554545:327:2 0 (3534545553545: [Brownstainingonhead 27% 1 1 1 IE2 31 22 [1 22113111 11 2 2[3a2 "Animalsexposedfor 3 Gays aweek To 13wee3k0s Los 21 *+AAnimnalNssoie.n2t3mfdoiendeaacrobpl lseyeodverfirst 3daysofWeek14. t120: APPENDI2X (Dailypost-dose observ-caonttiinuoedn) MIN 313/023622 GCroomwpound soControl Exposure level (ppm) o 2 PO3 S 4 0 00 sw MaiGnroswtudy animals ial Week No. umberofdaysinwesigne sobsek rved SF (ner. dose) Redsainbingr womodeywes|s31 2 [4 T27355 TT6 1 97 101112 8 B 1 BM[4211 4243324352211241121 3 [1 tr dz22010 ' [Wetfur 315 5345354555542 B2 [|3554334453a5534554555335555;]:12 334 ((55554444554455445555535555:;:22 [Brownsainingonhead 321 oso1 21 1221 3#[1121223 12o1r3s2213221 3s 1 i 2221 (High4dFose) (Rseuindingbarorundeoyesw| n376 211 1 1 11a 1 3#0 1 2 t2212 211 ws 21 2 3 (wetfur 3 [[4s553354545355545544a546553::22 3(555543545554455555s544445:322 w[5534835555452: [Brownsaiingonhead 33 [1 339 [1 w [1 1 1 12 331 1y 1 21 1 1 IRENE Brown saningbody 37 AaimalsexposedTo 3 ays aweekfor 3wee3ks8 *Animalssentfornecropsy overfirst3days ofWeek 14. 5s sss sss2 sn APPENDI2X (Dailypost- doseobserv-caonttiinuoedn) MIN313023622 GCrEoomxuppopunoledvsel Guprm)eivC1onm0ol E2I PO3SE 4 Recophavseeanirmayls No. amber of days iweeksigns observed (ConTtNe) Redorownsaimagwom 7% 2s s3 iz aTii TT 5"Bls223 423112321037 Wettur 24103355s5s5s53344334353 "03535534343 331)2 #"l0s35s3a5ss5a3a4s4z5a3s31 a1 [Brownsaiingon head aa lts pr I11o 111 pH" 221 21 1d Low2dMose) [Resstaadiinniinnbgg rrounodeyews|n4a6 lsa l1d2 2 1P21 1 2 ' "0 lt2r121131as233311 0 23121 Wet ur 6A1I3R4E3R4R4E3R5R4E4R5E3R 1 #90100335384833544455533455538585348435315131231 [Brownstainingan bead ai 1 1! Pon 1 11 s 50 s 2 2 L1o1l22 21 33 *Animalssentfor necropsyoverfirst 3daysof Week 14. D2 APPENDI2X (Dailypost -doseobserv-acotntiinuoedn) MIN 313/023622 CGormopwound : Contr1 ol Expolevselugpmr)e 0 2 J3 -- 4 0 100 30 Group amberof daysinWweeeekk signs observed) SM [Redbrownsangwoudeyes| ST T2Tz345 6T 78l 9100 BB T ter.dos) 2s [[11 131 2 1 s5t5 1 1 2i otfr 2sil4a4433448533554448533 111 Bslses4s354sa5a3333554a555332242 55 [443453545321 [Brownsaiingonhead s2t tro 1 s5t 1 11 ss 1 13 2 2 4M [Resadininbgarroundoeyews| n56 (High dose) 758 02 22 11 1 1 1 6 [11 32233222 541 [Wetfr (74455334485334484553331 21 $589 4(455a44445a354a4553334252: [4534334453 1 [Brownsainingonhead 56 [1 11 g 8s [121 1211 2i 1 Aa*AimnailmsaesxspaotsfeodrfnoercSrGoapyssyo&vweerefkirsTto 3d13aywseoekfsWeek 14. 1123 APPENDI2X (Daily post - dose observation - continued) MIN313/023622 GCroomwpound :a Cont3rol Expolevseluprm)e 0 2 eePO3 SE 4 0 00 30 oup iNoa.l amberofdaysinWweeekeksigns observed TF (Redbrownsamigwoudeyes| 61 [4T21 341 5 678319000T (Control) 8@ [11 1 11 1142 2 a6 [[121 11 1a wetfur 6 [ [4 355345555345554a54 554S5 55ss &6 [[52s 5531 553555445; 6 |5353552545455s [Brownstainingonhead [Loss ofuseofhindlimbs Q6 12T12323241 3234125133 6o 4 4 2234353 6 2 2 25432 on 1 [Unsteadygait oa 1 [Brownsuaining muzzle el (Lo2wdFose)[Red/brownsaningaroundeyes| 6a6 g|l1 2312I2ot2a1 & to 2 Ts no 2110 1 a12213 Wet for 6 45543344535435545as554a555s;5Ss @ 44553345355535554555454554: 4535555555555 [Brownsainngonhead a& gli 22 21 oo 222 21 & 2T1o3r 11i123is1 a nl 215422 1 2 "Animalsex[pBorsoewndfsoarnSidnagybsoad:week To 13 n weeks ' 2*AAnniimmalas63seknitlloerdnfeocrrhoupmsaynoevreerafsiornstsi3dnaWyeseoflW.eek 14. 24: APPENDI2X (Dailypost-dose observ-caonttiinuoedn) MIN 313023622 GCroomuppound Cont1rol 2 PO5 F 4 ExposwelevelGpm) 0 30 100 300 RecGorvoewrpyphaseanimalsES Animal Week No. T2735 u4mb5oefd6rays7inwee8k si5gns NobserDved BW (One.SdFos)[Redonsammgwowdyes| 7n | 2 12 1 1 7"5 1 1 121 Wetfr Mm s4s53344s54a5ss55s5s5s 5s4s B745 435435445545554555355454 [4434545455554 [Brown sainnganbead n7 "7 7s 21 111 o 1 z11 122114 1112122 ighSdFose) [Resudininbgarroundoyesw|n776 (4 22227 1 3 1 B 9 (1 432 P1112aaa 8 1 Wetfr 7sss5 3344s5saa5a45s4as45s3s M9s0s4533s 4s 53a 4s5s s5s5s o5s54s 0 (4535545554554 [Brownsainingonhead 7 13 M7la 1 8 1i 22 3 1sI12 421 211145532 [Brownsainingbody 77% "Aimalsexposedfor Gays 3weekFor 13weeks 35 *Animalssentfo necropsyoverfrst3daysofWeek 14. 112s: APPENDI2X (aitpost -dose observ-caonttiinuoedn) MIN 313/023622 CGormopwound ContrE ol E POSE EposuclewlGem) 0 30100 300 Satelitestudy animals Group Sign AnNiom.al| eOctukmbeWsirgnseaefokdiasyesveidn (ConTvVo) Redonsangwonders| Wetfir Brownsainingon esd (CoIFn)| Redbrownsaimingarondeyes| wer Brownsainingon esd Als xpos oS aeswerkor Awe 02 [[4113212 88 [[[41 503 2z41 2sol[5es534s5 8s3s0s50505 o5s ss 05 050s a | 2i 555 | [1 3 ii z 291 2|1 22 3 1 5ssse ||1(3 1 2 2os[3s05 43 s5 5wo 202 505 44 s3 [2053 5 a2 [1 s1o 55 i2 s 5 FI 126 APPENDI2X (Dailypost-dose observ-caonttiinuoedn) MIN 3131023622 CGormopuopund Cont!al 2 a 5 4 EgoswelelGem) 0 30 100 300 Satelite study animals Group smNoa.l| (NumbeWreoafkdaysin wessigns observed | Redonsangwoundeyes| 8 |[ 41T35z 3] Gdioiseg)h w@ ||1 ! 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DEE ERD gn i | feos lesser | fin i. 5 " 2. ste lo iBeedlo } MII Pal Lo IT Bam mum : i2 ;| nPlem ngew 2 longue :| ETT ZB|,| glessar lmspsmss | + 4Bf iP Hossss fsaes | win os 2s a, } } se f1H gRE Th HgE 0d || |i J HREREH us i To bmw omm 3 fom jm : Pod i i Ih S ge Blames sme wg BT i | acon fzsase | Mie a0 iE IE Br mE Folge fmm oem 15 anes jeeese | fiRbR Pi Hleen jseneg | APPENDIX9 Individual pathological findings MIN 313023622 b`pyTathtehhomeliosgctirsuotds.cyoTpphiectpdiahatghnooolsoteghlsyewrreaoepssocurgaltrtersdiiohefedrw.eohurite,bcpryhewsteewnrtotpthaehtehconolnossguiebsnjtsesu.csteoTdphtioeniiaonnirstoauoltfbientxeaphmeiepnaratrthioolenogwiasvbts.yuin2deesretcawoknedn Study pathologist: Peer review: MPaothrovloegLinstP,etersen-Jones, BV.MS, MRCS, DepartmentofPathology SDamiuerl.oeGf.PcMacttChooloromgiryc,k, M.V.B., MRC.V.S, PhD, FR CPah., Department ofPathology. om Hig iy ; iLHHildo | iH4o] hmiinadE ACREHIEEE FREED WiE 1b bei iATElo iH f f it oF i dtgH Wo wt CHhiPig LbPH pi Hi i "crhg | 1 tig NE. Bly mi amlilsr boapigd i Be i it UT Lgl +b dlwohi f T ig g1| gy Hin itl TLIERRE | nr | 3 Lith | . 4 Bile gE IE ]| TLE Nn WT STae idE 0 M1 is ty MIN 313/023622 THRIHoNll a i iL l Toiigil bgio mLiilg FE Ip $ qn i bg il diH gE| gi HRa nLo LaNli oat of ii: i | ] 7 ie phi J i jE Hd : Ho f1he IE Hg a1 i r lo Uh Po , iHE EHEL E RTI | IE BI f1 ail 1,00 deigj Pii fig | iE og i wk gf BE Hal i EE He Hl dr HR HE dll En dil dig ,or ine sb iE IEE] imTE ToPLE TdT al oan LE EE HHI Poot digo Hing iH Toki gB3i EiHdii Pople o Pp Ei deg HE Hh HEHE HE Figg MBEolde ol ELNHD (E1ECo: aEBEivB ] na ig I | | a fig|| ! 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oWH add 11 rE BEE | "1i8 mtei | +o0p0 : | fp il HI | i ii! B Blg Lili,ho HIEEDE aE ERT poW H ddH y a hdiEll fe l gf Hl Pop 1 121s i liltlh ii i i: ii ]| i | 0b wid HdEi |: iE qr Bdiriihlile 1 i Hm Liiiilei |b| gd3Lo ida mBaiEr :iy RBgl UG 51 EF 0 al Po | S Ey yLo Hp EH TI i moh fpgl dF The ib Cwio digo : 1 ih dom | a tnhhfy Bil B Bogle ie . y of | il WbMo iid Pohieithil || Si ForI LEE ed' | Jeg I HAH hi8 g 4 ATE gWoyo gE ybohH Biio odod EgHE I lilg' e [i od tn TeRgE ol +WHR E, L plEE dig ge He id A Eg i cbPoRiEdAsM 1 0 fip aiil ihjl i| Phd 1 Fl hebbo a T Ppg la Eihh gfp ni ( ] did 1 I Lobo || g IE iy | PJE a sE l il iH of Mi | 4d 1 3 3 , ' df] i Ewlur | LE gf HE 2 PEEIS | H iF ir El Ein i f LED Lapis gd ALFlOil b I VEfRoE ab BTlEy oy fy on hBiEg IPopeimd | FgdF o Hight flo LdoIg EDEe oin Mig Plhia yo milo | $F [ 3 0 EE i MIP } Wilf +0 [ i MF Rig (10 aWLglHl1E% i0 coir bos id: 12 Hg {EEIS (3843 0 F BC 0 LIeigie op pdlr beh 1 0 UfIiE mn dil 8a, ; Thy | FoR HE rni rH eEeE igi $1 gfi| Told PSoEnEd it | f mia il BF dS HE EEL | Pari $e i iH Lodged wis iEzi i|| 4H i | Ef i b| whi | I I i PE Har Hi i i | fEod ENos H | FRET fE ig 1| 0Fl BPidg |0 BE wly y ILE gfPo oi) Ib For 3RH ahs | BL pl bp ry dhiags gg | ily 0 FaAm NE Po ihylo | Pboreiangtooo dopo FLEEed dPeI d pd a semen fig HIdi 8 8 , 77 ilfeo gTPooEPiSER gd EE 83F Pgs T oom a onoo, Teg SFoElL LERRIE noo dhs 8, : Bb0ind)4| hBoob PoI E gf Hi Gh ol Toa fe F Gj mhii } #0gf | HHT. dg i Ey dhir te Bd dfToHHkiEiga EF | ToICFEE || f E AFRaginki2 n| PoE i | pdr deii las) | i i al vf1a1 fg fed # I 8 ; Bllis Ios i a EFHl MIN313/023622 Pohl dog] +iil Tbrdiliiniie WE il EE if wo lpon in o bob |i | pi fey MFiig iE id El | gl | Iomi | Sly Wwrg it aHE | MIN 313/023622 8 3% 3, .. dha be Tge lo He 0d J RTLEEE0 i LE 4 P po oe E z: Hi dod 31 L4E0 o4d Tosi Fo inh Pooiedl ig JR Aum d E ig g "El PR BiB pd pp dPhlao Hi Fhe ie dy wBhHoE PI s oooHnkE E1F di Peg ol Hi Lh b ERiLg e dlls Wi -- Hd Co Hmeaoylo 1ER 1 i 4PrlI0E]E 0, +E EEE ed eee 18 PEE dPlsom Bly PRm EL BHlien 1 ola HDom[FiREE : i hil | 3 Pgs jE H Aol on FT0REE00 RAEI bE digo Bly gf Hig Ingih Ei || le MiiHgnH oPog a3t 8 woo [aElE MIN 313/023622 + Fra EI [i od f1i LLEEE OEST HEIE le HEHE wd by dblpl 55 5, , MIN 313/023622 ' Bory Wal i Hid mii HeEH Po I ods = {8Bi, iE i Popa 2 i i i 5Poof fngla 1 | Po EE | ME | PEL al aP i B Bl PlI an EH wRhEni || gfboHmilbliy l iri A PombEo E dedg b Ed Wg ig 1: bH g EUih Eb B 2 igbh g 2 oir Epo PEE +wlhl Poo do Blieg hy 4 Faheryo4d HE oteirla o0hp d+ oamlyE hgwoke hy gaol wt goi[HdR 8 ci Ei Er REE dpogl dPEqI bg | dE HgIiEdg | Beoo obi er i PEosaiL fispy o i FEIETT ai RTE [ PElTtE dis Hr d LEERbI | b,Pooh Hgim rideeler: 4 pd Beige go paeHen LH wi WaEt Elly di BPiWdaiblbi CToohseieddl I Bile I i i Jgdb d HiE oag "io Po mE PEIN AnEhHR +R EI "giIrigHd | dis | || || | i| phy FH nBooigigl ili) ily gH l 1N WaaT g Bltid ge | lHy EHE |ff R1E | fp gtd E10 nnd | I Ep LlL i a[d NEi be 1dE bwoty p || AHlik | l pl d ELo N Sabot fled | NE dwdoodd pd EHoEiEn wSiTi ba an PP IEoRm REp) E ep EE Bril if it it tPeoll | +g Pog Wg 4 i i TEald4 Ch Ho :4iPoLoEH1i3% Eia{ 8di i 3 Ef pnng Et i| bEeRLgEs "rid | | MPgED| o8b HrE ireLoi Sand MW po 1 HEH of li ll I) sy i Ll | +lb | "P1iA Bo o ihb poWidi dipoHmigh iF a oak | te 11 I te 1 Mis i 1 Lo Ha gE if gi) iH i : I | i i no rh | Lil | HEL jal | Ey3 IME LEE | i PE 3 | i Hy H1 did rTEh iH Wi n tieL | HIed Mw ia | a Wall Bla go DE gd i ig81 i ab iy Bo ; Li | Poin | . ELE ji hie ER afGal: 4 eet Jeg 1 1 Hal E AEH Wl dig APPENDIX 10 `pH values for terminal urine - individual values MIN 313/023622 `GCroomwpound Conz1 al Exposure level pm) 0 2 eeeP3OSFr 4 00 00 30 Main study animals [Males 1 Females | |" umber umber ETE 2T 5-0 2a 73 82 31 7-5 32 7 5 78 2 e q2 3504 226 3 79 8s 8746 22% 80 1TT0 7747 3310 252 25 8-0 32 61 11s 8:4 33s 7732 "is 8:1 336 19 11s i:- 338 8840 + Sample mien from2bladderat nec8r1opsy a 82 ~ Samplevolume <8 lrequiredtoobtainaccuratepH reading/Nosample 1203: APPENDIX 10 (pH values for terminal urine - continued) MIN 313/023622 CGormopwound Cont1rol Exposure level Gpm) 0 2 BO3SE 4 0 00 0 covery study animals Grow | RomaMales pA || AmmaFlemales pH | umber umber T 2El 636 @) 75 - a8" 7-8 o& De:ad aas 6782 56 -- aa :- 6a8 7is6 50 8- 7 - S2t 7739 71 n - s5t 5= 7 I] i 6 7 3565 1-2 776s 7<8 EF5] .- n7% :i 5 66 "5 :I ~ Ssaammpplleevolume <8 lrequired oobtainaccuratepH readingNo Animal 63 - unscheduled sacrifice 1294: APPENDIX 10 (pH values for terminal urin-e continued) MIN 313/023622 GCromopwopund iso Contol Exposure level (ppm) 0 2 a 3 4 0 100 0 Satellite animals Group | Males umber | Females | umber aT2 A- o2T 3 76 58 7.5 99% 60 88 64- 99% 65 61 53 6707 99% 6539 %I0 7z1 1900 6pi0 *+ SSaammpplleevpoHl'udmeapp<r8opxilmraetqeuliyre1d.50hoobutrsaifnoalclcouwriantgespaHmprleeading collection due to failure ofpH hardware 1295: seme Eeasagzeanannsssany EEzzzzessssssssssssss Feesessessarasaznasas S2| pazadzennssaassTenny Ef 5 [7ERsISEeIIARsRauRay ; Tezzzssassssssssssses CR z HIsszsassissrszeazsasy 2 CFR 2 4 FresasReRanmesnanasey I "8P| HBoErammepsrksenaasdmbeonoaaeikaaeasnsd le ~ 8 BEzzzzazeazaszazsesss; 3 3 Fl IE ToE: s feanzsrenanesanapasest i 4 fhe sii 3 mye FFF OTE lis F1 m6. MIN3I3023622 Sezsszmzsszsszezersss | Eeszzspssssssszsyesy EHIeszmrmsmsasasasses EFlry ezsszr zsssszs ssssszrnsssy 3 ErzzsEsssssssrgyyyy ErzzsEsssrsssrrerysy HE Ulsszesersaskennesnass Ei gE o:)41 Erzsspa sssszzzssTy1y3sy t 2 EeEzzzEzzszssssssesy |g vs |=7nEemmmssmssersasssanen)i: E|EBY 3 FpEzzzszzzaszasssssesl EF co = esyssesasanssanssll E E :5 FEEEEZEzEEzEsasssssss; = 1 3 2s ezegzanankRERas(E 7i: &29 53 23 1s MIN 313/023622 ADMINISTRATION OF POSF BY INHALATION TO RATS Author Simon Moore 298: CONTENTS MIN 313023622 Page `TEST SUBASNDTADMAININSTRCATIEON TRAD msmmmsrmesmmmmm------ S--) FR -- eran, Procedure. EE ---- ss Sn -- A Chamber MODOTINgSYSKET..vrrrrrrrerre S-- LE -- RESULTS NE OMTAl GODGES RTRION. 1.1-- m Discussion. ---------------- A S--1 30 FIGURES AB.. SScchheemmaattiicc ooffa rFooudreinetrisTrhaanastfoonrdmOSIInfNrGared SpeSYcSEtMr..o.a.pn.d.thhveoosvatmvprolvinemgrseyrsrtteme330r098 TABLES BA.. COphearmabtienrgccoonncdeinttiroantsioonfsothfeiPnOhSalFa(tpiopnm)XPOdSaUiTlEy SMeYanSVIAEs........rvr 33110 DC.. CNhoammibnaelrceomnpceernattrautrieon-sofPOPSOUSTeF(IpApmD)-YaiInUdESividualandmeraner xposurreva. lues. 331230 APPENDICES AB.. IMndievitduhaolfPosOadSmpFslOencGENoTatlionalnMdeEanaQclySstiUsifIOrCoEnN..PS.F.....oororososs333s222 1299: TEST SUBSTANCE AND ADMINISTRATION MIN 313023622 TEST SUBSTANCE The test substance, POSF, i a liquid with boiling point of 154C. A14coJnusniegn20m0e1n.tTofhtehteeTstessutbAsrttaicnlceew(a4 sxs2t0okrge,dLseocturneulmybienrth0e40o2r2i7g)in,walacsornetcaeiinveerdsfarormotohmetSepmopnersaotruorne untilitwastransferedto theatmospheregenerationsystem. dInfourmartoifoanuspertoovniidtehdeosbtyundtyhe. STphoensstoarteidndipucraitteydwtahast>t95h.5t%e.t sIunbfsotramnacteiownarsegsatarbdliengfotrhtehpeuriinttyeandnedd stability ofthe est substance ith responsibilityofth Sponsor. ADMINISTRATION Tbehleowt:est material was administered to the rats using snoutonly exposure chambers, as described g`eTnheecrahtaomrbtherroautgmhoswphhiecrhderiweadsapirrowdauscpeadsbsyedmaettearfing lthraetoeloiqfuw2id9tesUtsubi stfanon creiadnmtu ionisatgtrlaatsiosenvtaopotuhre aacths,iebvyedibnhyalmaettieonrifngrotmhesntoesutt sounblsytaenxcpeossuurpeplcyhaumsbienrgsp.olyTphreoptyalregneet cshyraimnbgeers mcoonucnetnetdratoinonssyrwienrgee drivers into thechamberar inDiitfafelrseentttcinogsnrceequnitrerdaottfoiPoboOtnSaFsintwheeretaprrogdeutccehdabmybetrhecosnelceecnttiroanotfiodnisffweerrenetdestyreirnmgienfeededdurratiensg. tThhee praenalliymsiinsaorfycgheanmerbaetrioanttmiaolsspwhietrheosuatmapnleism)a.lsMpriensoerntadjbuasstemdeonntstwheerFeoumraiedreTtroatnhsefotremstImnaftrearrieald(dFeTl-ivIeRr)y ates i ordertomaintainthechamberconcentration lose to target. A`nciommparlesssaesdsaiignseodurtcoeGasruosuepdfo1rt(hAeigrecnoenrtartoil)onroefcethivetdesatantmeoxsppohseurreest. oaironly,fromthe same th`TeheweuisgahgetoofftPhOeSteFstwmaastedrieatlerumsiendedd,faroirnegaeacchhdeaxypoofsutrree.atment,foreachofthethreedosegroup from "aTnhdedtuwroatfiuornthoefraexpdosurmes fior twnearmsiinaastiisnognlepturhpoorsuerse.axposturei,daioly,nfor 13 weeks for 5dayseach week 300: `TEST ATMOSPHERE GENERATION MIN 313/023622 o`Tnhe svyarpionugrededlriivveerryssy(sPtreecmfidoorrt,heMdoodseelgro50u0p3s)c,omwphriicsheddienldiivveirdeudal tphoelyplrioqpuiydlenteesstyrmiantgeersiallocatveida PaonldysTyertirnagFeludorrioveErtshysleetnieng(sPrTeFqEu)irteudbtiongacthoiaevgelatshse ftiatrgceotnctoanicneendtriantaiognlsaswserveesseeslt.abTlhieshesdyrdiunrgiengsitzhees pVeproureiailrmipixhtamusreeiopfantshsaeesdrtouudyty.oAftihrewvaasppouarsisseedrthirnotoutghhethcehvaampboeurriinsleerattdu4crtaitnegotfhr2o9ugUhmian2ut2em. Tmhe diameter flexible pipe. Allequipmentwas housed inindividualenclosedextractedcabinets. Eflaocwhoftetsht egraopuprpopirnihaaltaetidoilnuctihoanmibnearirwoafsPcOoSnnFecvtaepdoutro mainxtautrmeo.sAphecraeligbernaetredatfiloonwosyfst3e0mUsmuipnpultyeinwgasa ucsheadmbaesrexatnrdact| fVormienauctheGdroruapw.n Ffoorr tahnealdyotsicealgrsoaumppslitnhgi.s coAmpr1iUsmeidn2u9teUmdiifnfuetreentfiraolmwtahse bmaasienotafitnheed `bTehteweine-nlitnheefilnolewtmeatnedrosutwleerteaicraflilborwastetdo pdraoilvyidaegaainssmtalhlignhegqautailvietyprteaspseurreedwtiutbheinrtohteameextpeorssurmeeassyustreimn.g thefree flow ofairatpointsofatachmentofthesupplyandextractlinestoeachchamber. 3T0heUmaiinructoentfrroolmgtrhoeubpasreoecfetivheedcchlaemabnera.ir only at a rate of 29 Uminute and a calibrated flow of Ftohuercoenxtproolsugrreouspy.stems were used, oneforeachofthe three dosegroups and theotherused solely for For all period. dose groups, the syringes were filled with sufficient POSF to complete the six-hour exposure SrcehsepmeacttiivcesloyfatnhdetihneheaxlpaotisounreexspyosstuermeocphearmatbienrgacnonddeixtpioosnsuraerseypsrteesemnatredepirneTsaebnlteedA.inFigures AandB. EXPOSURE CHAMBERS rTehsetraiinnhianlgattuiboens.exApcocseusrseorsiyesstienmclcuodemdpraiisresdupspnloyuta-nodnleyxtrinahcallaitneiso,n wehxipcohsuartetacchheadmtboertshe atnopd arnadt bottomofthechamberrespectively. A filtrationsystemwasincorporatedinotheextractline. SA sycheasmraetdtiecscderiiabgmerdamionffuarntheerxdeptoasiulrbeeclhoawm:ber is shown in Figure A. The component partsofthe Inhalation chamber `AThDisG issnaoumto-dounllayr ianphpaalrataitounsocfhaalmubmeirn(iuAmDGallDoeyvceolnosptmreuncttisonLtcdo,mpHriitscihning, ofHeartbfoarsdeshuinrie,, England). a variable `ucemnbtrealrovafpaonuirmianlleetxspuorsruoruensdeecdtiboynsa,tcaancgehnhtaivalianig2i0nleetx.posureports,and atopsectionincorporating `1Th1ec0hpa0m)b3er(sbuotsteodmo).ntAhlilssetxpuodsyuwreesreecatsisoensmhbaldedu20spionrgts3aronddefnotremxepdosau2r8escecmtdiioanmse,itdeernctyifliienddaesrwlievtehlas vveonltuimlaeteodfcabaipnperto.ximately 47 litres. During dosing, each chamber was housed in an enclosed 300: Ratsrestraintiunbegs MIN 313023622 eMnodu.iTdhedeoptohlyecraernbdonaistneotmunbaelsl,yaclposeedrbatyeoinndseeretiontnoaoflladonwetxhepsanonutpodlnaesltyditcopbungr. Aopfrojmuterhoesdtcpaapshetsreesd tThtuhrbeoeausngwihmetarhleeaecxteptnoatscruehreedoftsteohcatecibohnuasn.mgbaenrdbyimsaedajnusstoafblpeutsho-mfiati"n0t"arnitnhgespeoaslistlioocnatoeftdhinetrhaeiesdxuprosiunrgerpeorstisonf sCehaalmebdewritlheavenlesxtpwaonadenddptlharseteicwbeurnegu.sed toexpose theanimals. All expporotsnsotiunusreweere Air supanpdexltrayct aAnidr swuapspldireisedwe(rdeewppoirnto~2bvCy)a.icomdpreessodr.The iewas filteredtoremoveany residual particulate "seTyxhshectaaeulmsitbcroamTtpehrdeiesxaiihnrgafulasowtFaleiuxrotsfrolarocbtwerreocqamuirrbteohdnefbvoaaspoetuohreffvtialhtpeoeruxarpnodcsoaunrcseeisnltiycrsaattgieeomlnwcaaonlsaulpmyasnsissbeewfdaotrshersfootluwegalhysaptpaaasspsspeedidntfgoo exhaustaferbeing diluted witroohmatirehxtraect. Theinlet andexhaustflowsusedforeachgrouparedetailedinTableA. `aThetchmamboevrasaiarpneexxhthraaucetswtartsapecrko.videdbyvacuumpumpslocatedoutsideth buildingthatventedto PROCEDURE Fsdieomsuicrlreaixrpptioeoxsncuerpettsheytshatc,eommosmrweentrtheseucsorneetdlra,otloinnggerfoo1u0p.,etathhceehgarsioasumppr.leicTnehgiveeadpnradoicretodhnuelrye.FfoouTlrhlieoerwreefdofTrorearcnisnafctohhremgrfooIlunlfporwwaairensdg spectroappplhy toothtdoosemgreoutpsoenlry. TVhaleueFwTaIsRzedraot,ascuabpsteuqrueepntrloyg,rabmamcekgwraosuinndistciaalniwseadsarnedctorhdeepdaatnhddtihfefereelncpeawtahslecnhgetchwkeadstcoaliebnrsautreedt.he s"ytTruhbieinsnggy.ersiTwnhgeeerspewumemorpuensstwleeedrcetonettda,hmefeislydlroeidnnwigbterdhiretifhvleyirtsne.soTtrhdseuebsrstytroaienncngeg,eastgwheeetwrheeeicggoehnantresiocntfgleaidnqtduoittdohsewmveoarpveoeruterhcisoeerlrdiseqbudiaydnaPldTotFnhEge thePTFEtubingalmost thesurfaceoftheglassfit.Theinjectionrat tobeused wasthenset. fofTohtrehtheaettcsrheawametbrmeeern.rtUegnmrouovsuepeddafnerxdopmnoustumhrbeeieprroceradtgfseowseearanecdsheaplnsaiecmdeadwlin.tthTobhleraentstukrbiaenisgnwiepnlgruetgutsb.hees,nawthaicchhewderoelceovlelosur2acnodde3d `gTlhasesitnulbeteafnlodwoumtelteetra.iflowsoftheexposuresystem werecalibratedusingpression madetapered ``wTehreeccononecrtiaornndsowefortckhientgge.nerationandextractsystems tothe chamberwerecheckedtoensurethey "Thebarometric pressurewasrecordedmanly 302: `Generationcommencedasthesyringedriverswere tumedon,theexposurestarttMiImNe3s1w3e/r0e2t3h6e2n2 cronteinucallTyodheelritivmeder-ecdeotnthdreocllh.eadmcbhearmabtemrosswpithcehrienfgrsoymseteamchwatsestfucmhedaonmstbiomeutlhrteanteiomues-lcyo.ntAoslalmedplcehpaumbmepr switchingsystemat aflow rateof 1 Uminute. Atthe smtiantutoefseixnptoosturhee,extpheostuirmee,-tcohnetdraotllacedapcthuarmebseyrstsewmiwtcahsinagctsiyvsatteemd.rAetdiirecntedtthoeeft1ers0tmmviinxutatuerselffrrsoomm edaecthermeixnpaotsiuornecohfaPmbOeSrFincotnhceenotrradteiroGnroocucpur4r,ed 3aatnedxac2ttloyt3h0eFmTin-uItReanianltyersvearl.s Atnharloyusgihsofutoretahceh ceoxnptorsoulrlee.dAclhlacmbhearmsbweirtachtimnogsspyhsetreems.werepumped towastefromboththeFT-IRanalyserandtimecAhtainmtbeerrvoalpseorafti3o0nmailnpuatreasm,eatneyrrse(aicntciloundsibngyttehmpeeartastutroeeaxpnodsiunrlee,ttaongdeotuhtelrewtiatihrcfhleocwkrsaotef)wgeenreermaatniuoanalnlyd trecoreded.mwTphaesreaeicrolrrodwesdatwherrtoeumgehuaasmurordeidfeitehdrobulgahnokuitngtphleugexsposiuretsa uutshienagsatimn-elelienevdeflloiwnmtehteercsh.ambTehres astheanimals. sAytritnhegecendoofnsxtwheoreuerrsnegceontrerdaestdi.oTn,hteetismyer-icnognetdrroilvieedrcswhearmebetursmweidtocfhfianngsdytshteewmewigahstsowfitthcehreedmoafifnainndg r`emsientu.tGees(nceqruaitiibornataiirofnlotwiwmaetsytiusme7dmoifnfuatnesd)t.hTehchedaamtbaerceaxpttruarcetparlolgorwaemdmtoechlaelatretdheauvtaopmoautrifcoaly5a-f1te0r collecting 12samplesfromeachdosegroup. Ahotltdhiengecnagdeosf. thistime,therats wereunloadedfromthe chambersandretumedtothei respective `The chamberswerewashedwithhotwater. "tThheIrR coelultphgetehhxpoloesnuugrtteh,wasretestedtoensurethatthinitalvaluepriototheexposurewasconsistent TEST ATMOSPHERE ANALYSIS (FIGURE B) Aicrosanmpcleeswoenfrtetherreemsatovattemdoifsprohoemrnteh.e inhalationexposuresystem inordertoestimatethevapour `uThescoanicFenTnt-rgIaRtiSopnesctorfoPpOhoStFoimentaeirr.wiDetfhiinnittihveeindhealtataiooifntlchsheaFmTb-eIrRs,ofitshsteadnodsaredgirsoautpiosnweanrdemveaalisduartieodn aregiinvAppeendinxA. TvehnetiSlpateecdtcraobpihnoetto.meterwaslocatedadjacent tothe exposure chambersin a separately housed `cTheoinnasssptawtratosrrfctohuunenetmccitmeee-dtctononeteraotlcdlhedseclheacmtbedersswitachimnpgosrpytsbtelymp.rAiolglrngaamsmgsedaswmitcphliinlnegsowifevrnael0vg.e6s omdiameterTeflon tubing. chEaacmhbesralmepvleelw2a,tshreesmaomveeadstfrhomtraeastpeadraeniamnailmasl exposure port through a modified blanking plug at $303: MIN313023622 CHAMBER MONITORING SYSTEM Ad`cuorPmiCpnugrtueernanc(ihPnCge)xApauontsduorQaelu.lainnTtfho3re.m0ad1taistooanftccowolalllreeecctwtieoadnswusasesequddeitnscopemlaoaynneiddtoodnrisaapnlmadoynriewtceoorr,redtcSohinemisuryolltslatenedemobupsyelyra,foptrehrmesadonanctaeal a`nsweadtspisrnoegsreuenpdta(etplireoecnt-repoxnhpiaocsasluelr.ye.)TpThhheaipsser,poagnrraeoxmpmogesuawrrneadsamFcoTnomiImtRpomorhsianeergddowpfhaatrsheerweaeenbrdaestihleoaspnoesdttbeyoxatpfohosgpeuerrSeaeptoidsonansi:oarcnfoloilrnaitttihaoeln duroaftthiestoudny. Rawdataprinted 2 hardcopy. Setting-up phase Ipfnaotlhhlleoewniegnditthibwaylapsahtabhsaeec,nkpgcrraolomiubpnrtdaetdesdcbauyn.thsAenapicuelrrtntriaofgipeugdrescrcnryieaterlnodmgiioesnfmnplccyadtelyhiy,enldetrenhree iwinnassntirtuurmsoeegnednt.froerAsptohrniessgeuplwuaratpesodscefh.leocwkrTeahdte,e oVmcfionnj2uunUtcmetioinoufnttewhietwhagstahseucssyelcdinadfomerrastwnheedrtneihtmerorgeoemnanainnddiueserittwnhyagolsencvreaeilninbterneaidtdtetrdooginew-nalisncteyelt.ianpTdeehrreesf,dlttouhbwemeagneaaslyftsleorweudmsertreeedrws.in1 sahmeplistnugd)ywedreteaielnste(rinecdlaundidnsgtotrheeddianitlotyhpeatdhalteancgatpht,urneupmrboegrroafmmsecapnrsioarntdotshaemepxlpesosaunrde.frequency of Exposure monitoring phase "caTnhhidasmpsbhuebarssseeqewueannstslvyariatferedrwo7emaxinasncmutmotlneyeist1on0lratmeteirdntuhdtaensutGharrso3u0tip-rm3niofnwugaatstemoacsnyapclhlyeesrweehdgeefnnoeltrlhaoetawineoadnl.byysGeGdcroornucp4enwo2ta.rsaatEuinaoacnlhywpstaeessdt corefcwohroidecdh.mraTenphdrpaeesndeeanuxttteaedrwt3ne2arlcee2odiaipddsdrpieldsa.syAceatdnsoo,tnalscorfetewne,lpvreisnatmepdlaenpodisnttosrpeedrodnostehgerlooucpawlehraerrdedcroirdveedo,fetahche "Thechamber slewacsctontroollnedbyantime-controlled chamber switching system. Post exposure phase Avtaltuheese, ongdetohfetrhwietehxsptoasnudraer,td hdeevdiaattiaocnowlelreecctaeldcduulraitnegdefxo poesacuhrpeawraamsectoelrlraetceodradnedd.printed.The mean MidacGr3a2vemrsiosn 4.11softwarewassollyused togenerate ahardcopyoftheinfrareddata. tcTahlheieberIxaRpt.ociseoulnlripefaawntyahplsreconogbntlhseicmsastlweiibnrttaththitorhneooaufngtahlhoyeusFtitsThh-eaIdeRoxwpsaoessuruereaeds.dsTuehrsiissnewgdttaohesentesxouprpoerstoheva.itdteheaisneticaolvnadluoerpbraicorkutpo Detailsofthe analytical methodologies usaregidven in AppendiAx. $304: TARGET CONCENTRATIONS MIN 313/023622 `The target concentrationsofPOSF were: Group Designation Conc(eonptrma)tion 32 InLteormewdidaotseedose i30o 3 Highdose 300 `aTvhaeilatabrlgedetatcaoancnedntHruatnitoinnsgdwoenreLisfeelSecctieedncienscroenpsourlttMaItiNo3n12w/it0h14t2h7e2.Sponsor, following the review of EXPOSURE CHAMBER CONDITIONS Chamber analysed concentrationofPOSF ``Twhaes tceosnttiantumaolslpyhderreawwnasthsraomupghlead tfrraonmsfelrevleilne2 aitn &eafclhowtreastteatom1fospVhierneutceh,amwbheirc.h Ewaacshtahtemroesfpohreerei.n etrqaunislfiebrlriiunmewwiatshstahmepmleeadnbycotnhceenstorfattiwoanreffroormatuhteotmeasttecdhaanmableyrs.isiEvnetrhyetoerndemirnouftedse,saceindfirnogmdeoasceh ``vgeroruypf3o0rmdianuttaelso.gWgihnegnactniovtabteeidnbgysatmhpelFeTd-,tIhReAsuettoraQnusafnertlsionfetswwareer.eEpaucmhpdeodsteocwashtea(FwimgausrbaenBa)el.ysred `wTehreeadcehriievveeddcfhraommbBeerecronLcaemnbterratt'isonLsawo.fPTOhSeFvaarleuepsreosbetnatiendedinftreormmstohefpSaprotnssopre'rs mPiOllSiFonocfalaiibrratainodn `wceornceensttraantdioanrsd.isTehdeamgeatihnsotdovlaolgiydaatneddfguatshbeargdsetabiyl aarpeplpyriensgentaedcoinnvAeprpseinodnifxaAc.tor to give the vapour Chamberspatial distribution A`lanlaltyhtiecaalnsiammapllsinwgeproeisnittwuaatsesditounatleedvoenllsetvweoltawnodotfhtrheeeeoxfpotshueretchhraeemlbeevre,lexposure chamber. The p`rvTeahlreiysimpniagntciaahrlyadmtiibsatelrrislbfeuotvieotlnhwioasfssvtouabdpsyoe.urvrAieddin,ftfwhehericechnhacwemiabnsecrwowenlaclesnwticrthahetiicnoktnehdobefel1te0ws%estetnhcaohn2am%lbefliroemrlaieltvrlsednloosras2meagalnnrldoyua3pcldsluworeiiwtnehgd fortheanalysisofsuchexposuresystems. `Nominal concentrationofchamber atmospheres `Eeaxpcohsucrheapmebreirodnaonmditnahleecxopnocesnutrreatmieonanwaaisrfclaolwc.ulTahteedifdreoamlgtahseemqausastioonf wliaqusiudsuesdedwiotvhetrhtehemosliexc-uhloaurr f`rwoeimgthhtoefmtahsesolfiqluiiqduainddustehed.meTahseurceadlcculhaatmiboneriscdoentdaiitlieodnisntToacbolmepCu.te the volumeofvapour produced `The nominal concentration i presented in parts per millionofir. Airflow and temperature ``gTehneesreatpiaonraamnedtePrrsocweedruererseecctoirodnesd. manually, as described previously under the Test Atmosphere 305: RESULTS MIN 313023622 VAPOUR CONCENTRATION "The data are presented as follows: DInadiilvyimdueaalnvavlavleuses TAapbpleendBix B Tprheesesnttueddybmeelaown:concentrati(otnhse mean ofdaily mean values)foreach groupexposed to POSF are Group `CThaarmgbeetrconcentratiAonnal(ypspemd) 32 1050 12064 3 30 299 `The analysedconcentrationswere in reasonably good agreement with target concentrations. Group 2 l1(o5Lw5o,awn6adl4oyasseni)sdrw5ea.ssu3l%tosnlfdoyurrGmiranrogguiepnxsap2lol,syu3rabeensldoaw4n(1Ld0o%w10,.fIrTnohtmeerctmheoedietaarftgeeaftnicdooHcncfiievgnaethrridnaaottsitieoonssn,)oprfaetrstphleeycdtdaiuvieellytyamo enuadnunrsweufeallrelceyt tcohnecenitnrcarteiaosni.ng difficulty of controlling the test material feed rate with decreasing vapour NOMINAL CONCENTRATION Thedaa andequation arepresentedinTable Candsummarisedbelow: Group. concenNtormatiinoanl(ppm) AN(%r)ato 23 10331 10516 3 305 % AN dNonei!cconocemncmaetonn ) 100 `oTfhePnOoSmFindaellicvoenrceednitnrtaottihoenfgoenreeraatcohr.exposureperiodwascalculatedfo th tes groupfromthemass `tThheeesxupdey,ctsehdomueldabneraatpiporsooxfimaantaellyyse1dt00o%nfomoirnaalllcdoonsceegntrratiaoonn(duAGIrNo)p,uepxssp3resasnedd4as(intpeerrmceednitaatgeeafnodr High doses) showed excelent agreement with this value. The coefficientsof variations orthe mean nominal concentrationsforGroups 3and 4(IntermediateandHighdoses)werelessthan 7.5% for `tbTeohsttehAsguNrbosutrpaasnt.cieoTfrhoeirssiGdirunoedsuicbpaeti2en(sgLcrooenwtsadiiosntseeden)cwyiwtavhasipnlootuhrweiesgraetntiehorananoetfixtophneescyttseetsdetbmmu.attcerainabl eanacdcvoeurnytleidttfleorlbikyetlihheooldoossf oftestmaterialduringth initialprimingofthe inletlinestothe vapporiourtorthiesasreoftrhe +306 : exposure. Thiseffec is moremarkedforGroup2,where lesstestmateria iusedoMveIrNal3l1d3u0r2in3g6a2n2 exposure. CHAMBER TEMPERATURE `Thedaily meanchambertemperaaretpruesrenetesdin Table D. The chamber temperatures were similar for all groups on each dayofthe study. DISCUSSION `4Co(nItnrtoelromfetdihaetPeOaSnFd vHiagphoudrosdeesl)i.vTehreyltootwhveapexopuorscuorneccehntarmabtieornswaansdgtoheod1e5s.p5e%cicaolelfyfficoireGntroofuvaprsia3tainodn froareG.rou2p(Lowdose)reflectthedifficultyincontrollingthetestmaterial inaptauvertylowfeed Oauntomoacctaesdidoantapcraopbtluerem.s Wwhietrhetnhoe aannaallyytsiicsalodcactuarwreads. avaMiolasbtle,ofitiherse eproablsemtsooarsesnlautmeae(diubrseiclntlgytehteo bceotnwseisetnenttheAa/Nnarlatyisoe)dtahnadttnohmeianniamlcaolnscweenrtreaetxipoonssewdatsoobtsheecrovrerde.ctconcentration, as 2good agreement CALCULATIONS tihnoerddaetrationtmhiinsimreipsoertthheascubmeuelantciavleceurlraotresd, cwohnitcihnuroeussullty fursoimngruepneraotuenddreodunnduimnbgerosfnaunmdbeornsl,y mrouucnhdeodf fifgourrper,ipnotisnsgi,blCyonlseeaqduienngttloys,mathlelsaeppraorunednetddinsucmrebpearnscimeaswyiitnhcoltuhdeerrdoautnadiinntgheerrreoprosrnt.the las significant +307 FIGURE A Schematic ofa rodent inhalation dosing system MIN 313023622 a o so: uf z c nil iin iM Lew] ME J Lewl2 i ' iW Lewd pm L rr KabeyPSyorliynpgreopdyrlievnere syringe 4TGleasstscVoapmourpisofeeruednlidne o SAiinresrupdpilaymeter & Exposure chamber 1i OBblsaenrkviantgipolnupgosrt J Roidtehn2t0eretaxinipngptoruotbseossn(lsetuvaendlasrr1d1s0ee3c3t)ions K1k FEixlhvaauisotnplenum m Aree +308: FIGURBE MIN 313023622 Schematicofa Fourier Transform Infrared spectrophotometer and the sampling system 1 -- ==] me FL dE] 5 wt 1 omer I Lt = | --F |. F 4| 2 3 = Co IR Bt] SE | 3 KaeNyitrogencylinder f FIRspecrophotometer b EFlotwmehtienryrneigtulrloagteeendcyonl1iUnedmeirnte ~~ h& DFlioawpmhertaegrmpreogmulpatedto Uminte d Tchaembsertcosmampploeliunefnodm J{ToSgglaelVamnlvreespamltowaeste & 10cm Reell k Time-ccohanmbetrsrwitochlinlgyestdm . TABLAE MIN 313023622 Operatingconditionsfo th inbalationexposuresystem Parameter T (Aircontrol) Ter soneenSTPaOSiFGomn)| 0 CChahEmablemirbsseirtisoonpsti(Umaimtb)er le)| 229 VapSouirnegednarmoersst(imnygs Tetmate sd NNAa NASingotisep(lmepase NA 3 w (Lowdose) T ul (Highdose) 10 TM 5 4s Prc00i312syrdingoeprp104 +310 TABLEB MIN 313/023622 Chamber concentration ofPOSE (ppm) - daily mean values 21 3% 5= lTuws 6 | wm [Tsmm | 3TB | wTse | mw [we | Bm [0 | io 7i5 22 |[ww ||me | 3|B" [wm[9 | o|ums 1i0t i Far a lfImwr [so [mo | | Aon I [we |oa4 moe | me is1i s 2 |m so lw | |e [mo || |3 = |[les || [es |e i16 it 2ws | [m ms |mw | [ws | m | 5|% [[aumw m | ow | ||mw 21 s w m[ms || mme | |3 ||osos | |e 5zat a 240 s [nlwrow [ww | | 3m54 [wm || | a22o%6m || 9e8o9 [mm ||| 2u3w8smn3 ES% 7 amol a omse [|see |e ||| 2oz mo ||eu| [es || oomm om 3F5 22 w [| m|mm lw | m || 3zm | [[iise || wm es | wm a2 5 a50 wo l[mws [ms | ||ee m | || %m3 o| ed[wdm || | wwmee EH354! n a |fois oe J[swe wm || | 23% 3% | [[iwme ||| 6 35 ao 2a | m ue |wwm 2 | | ms || | 33 3 [[aWss | | |e | sw VoGa oloieddoTo computesprob idts AESprog : `Problemwithethyleneinnitrogencalibrationcylinder,nodataanalyticaldatacollected +3 N`EethwyEltehneyilnennietirnongietnrcogaenclailbicybrlrianacdytetlririinaodnoeonrunt $310: TABLE B MIN 313023622 (Chamber concentrationofPOSF (ppm) - daily mean values - continued) aa bs moT ole a lo [[osme | 3a |e | nm |e e |mom [wm | om "ii wE|Iome [os |I |e || A3% |Ae 3% | || oamm a fw se | 3% [we |om i545o08? 3ww9 ooems129 o [wm | m3[[6s|4w | 2Ba5wm | 2% || 9w|9ee ||| 2o9m1 Im 52 S 2wo [uwsw fe [|ams || 37% Is | oa |[aen | | [mo | 55 5 2 llww [ws | [[w|m om || 3x 3 || w[iew | | |m 55 " a | | m 0 fe llmws [mo || | 3n3m o| w|aem | | o|se ai 5 w# # |lmwo fw || @mm mo || |3o [||ee | mm|e && a 2saw || om[pse llaans as ||| o3m 3 ||ee |g ||| aBss am o a w lu lwsw || 32 || ow |B ovw 1419 View (650 2Si || 1420 || eese Ta Tor ISwd Byl1e530s Ts gen calibrati1on95o42 der oo 6s6e wVCH StCanodaerdfdeovifivicaorniiieonn(sdtx 100mess) an TABLCE MIN 313/023622 `Nominalconcentrationsof POSF(ppm) -individualandmeanexposurevalues `The following footnotes relate to Table C and are as follows: :! PNroodbalteamcwoiltlehcettehdydleuneitoncnoimtprougteencparlofbrlaeimonwciytlhdinadtearc,apntoudraetparanoaglrytaimcmaledatacollected : Nominalconcentrationswerecalculatedfrom thefollowingequations: Concenptmr)=a3txYio1o0un ve WxRxT 760mmHg M Am where WV == gmaseesooufsvPoOlSuFmeof POSF. R M == mgoalseccounlsaarnw:ei(g0.h0t8P20O5SFa(tSm0m2.o14 Kg'in)o) TAm == tsemmopseprhaetruircep(rKe)s,sutreemp(emrmaHtgur)e(C,see Table D) +273 thV.eexposu=re volumeofair res)passingthroughth chamberduring. oAN Amlysednoninalconcentration aioexpressedas a percentage CV(04) Coeoffvariaitionc(sdex10n0/metan) 133: TABLEC MIN 3131023622 (Nominal concentrationsofPOS (ppm) - individualexposurevalues - continued) i Grou2p (Low dose-T)arget concentra3t0ipopmn NoT. (m5i6n0g) |Pressur7e(mmbg) | ws3aage | G2ow) | G2o%pm) 2% 23 336600 775599 538 559 2 23 2 2s 5 os 45 363600 765 71 619 613 i7 #7 67 336600 71 7% 605 604 )2 2 2 103 85 336600 775%6 6so51 2 22 " 110 336600 mm 00 606 i 7 2% 7 at 101 2 360 5 360 Ei) TM 91 666 72 2 104 9% u 360 is 360 m 7s 561 525 2 2 2 2 mn 57 176 336600 i] 0 634 pr 31 30 30 2 108 103 18 360 1 360 m 76 653 61 22 2 30 Fa 9% 2210 336600 75 1 643 on 2 2 2% 3 104 8s 23 3s6600 77505 770010 22 331 55 22% 363600 775545 633 657 a 25 2 2 193 8 72% 336600 7464 667247 27 25%1 &96 2 360 2 360 765 761 6% 700 2 30 2 31 91 8 30 360 3 360 71 75 68 707 2 31 7 po %6 8 20 3 360 760 760 705 72 25 2 31 2 8 5 3 36 3s 360 760 765 636 675 2i 300 0 134 TABLEC MIN 313023622 (Nominal concentrations ofPOSF (ppm) - individual exposure values - continued) oup 2(Lowdose)-Target concentra3t0ipopmn No. 3% (mins) 3% | Pres7sur6e (mmHg)| usage ) | p2%m) | (o3p1m) w% 5 360 3 360 761 71 7 69% 22 32 P 39 "0 360 360 7 748 179 7 72 36 "91 a 2 360 360 m ms 721 02 2 31 2s 31 3 8 "5 336600 77968 67095 73 3310 %E) 16s 336600 776658 66395 22 330 8& a" 360 360 68 768 68s 698 2 30 23 8 8 P0y 336600 776618 68 661 2 23 30 2 0 521 336600 7745 773106 22 323 8 15 363600 7664 731 729 2 2% 2 2 50 2 s3s6 363600 765 760 725 719 25 2 2 2 2 57 5 360 360 768 7 728 EF) 3 7 2 3 5 8 5 360 360 758 736 763 667 23 330 a& 6& 33660 778651 s7o914 22 336s 01 P 363600 7516 779998 321 3366 8Pl & 336600 74580 798 786 F 2 3 3 7 @ 360 Overall View| 360 58 762 73 os 2 2% 2 3 5 % sa 00 oven 00 50 11 1059 1533 10 4s 12 | 157 151 17s 31s: TABLE C MIN313/023622 (Nominal concentraotfiPoOnSFs (p-ipndimvid)ual exposure val- countienuesd) 5 [TE mee | | Group3(Intermediatedose) - Target concentration 100 ppm T 3% 23 363600 45 336600 6 360 87 336600 190 336600 i2 336600 15 363600 1165 336600 " 360 118 336600 22 336600 2 360 5Fl 336600 22% 336600 =7 336600 320 336600 32 336600 3 360 F35 336600 bi] 759 To77 1988 557 %5 01001 759 765 221 1959 101i E 8 103 i81d 25255575 t3 41s 775566 323257 1714 110045 1o0u8 i5]6 223100 100: 103 101 9 im 28 2167 11s 10 101 95 11a 107 TMm 2105:568 1525 %80 110 m5s 2215911 1028 osss n3s m m 1918 1934 % 9% a 8 12 3 6 6 2010 Fy 1989 9% 5 8 107 m 071 2096 2081 8 91 5 2 9% 99 755 54 2134 2080 El m os 5 103 ns 4785 248 2319 04 104 100 10s 5 9 6657 223665 1100s2 110004 110002 6617 230106 110035 11022 110013 77560 253723 110084 11008s 1900 760 760 52976 107i 11m0s % 765 228 104 107 9 $316: TABLEC MIN 313023622 (Nominal concentrations ofPOSF (ppm)- individual exposure value-s continued) we rom eto | ms| em || Group 3 Intermediatedose) - Target concentr1a0t0ipopn N3o%. (mEinDg) |Pressurae (mmHg) | w7s9a1ge | o10m5 ) | 1p0m6)' 5 338 336600 77611 2335028 110035 110044 19019 3"9 336600 77418 242140 111036 110017 1100s4 a2 336600 m7s 521336 1E0d3 110016 9967 360 " 360 Ed 768 250 238 110017 1100s6 1901% a 360 i 360 765 768 32 268 110067 110078 55 a 360 a 360 768 768 2538 268 109 114 5 100 %6 EY 5a0 336600 6681 224833 110024 110039 9% 521 336600 m75s7 22550310 110099 11ms o5s 55 336600 0764 2621559 1113 1110s9 15082 s5s6 36600 776650 2523617 11008 11029 5s8 5 360 5 360 768 57 2566 237 110m7 11039 %0 EY 336600 775%8 22554981 11028 1u1s4 49% al 336600 515 26253180 111046 m2w 795 360 6 360 51 56 2569 2021 109 11s 106 108 95 0| 2 360 & 360 8 50 um 2528 106 12 107 113 95 ot @ 60 Overall Vea| 360 758 762 2672 537 1 Tor 119 I 9s Tor PF) 00 oven 00 80 11 1958 84 6646 9807 6612 37 Mss (RotcnnainPOSEpn) du TABLEC lxaos conic Gp 4h or) Tos psn 0 I PPEEe,on `Exposure | Time Period| Barometric eAaso | (gEn BEEage' | |Test Compound| Analysed 2 4 360 765 68.06 ' 301 PVlEa s 360 6 360 E wE anwe R .|e 757 69.55 % 31 751 70.10 % 316 bBl n9 olllm am3Em60 7mRR o56 omEleaSa6201 e E m a5 ER e e278 e e . s BBllEaoRmlEm|moomeonmasaar |R ([e nBe mRE. e|e BBBol oolloaE R m o wooRnm|eea @ m2 nn aye . P FRE R ln Enmm BA oEnEnns. PRE |e ne P P R TE E REm n Elm a ae nsn Rs nEy. . P PlRa B ml san nees Plm 34 360 oe760 lw7158 le1 ls317 |. TABLEC MIN 3131023622 (Nominal concentraotfiPoOnSsF (ppm)- individualexposurevalues- continued) me `Group 4 (High 3% 33 3"9 a 2 "5 a6s a ] P0y st 52 0 3565 E5l 5 a2 &o &os OveralolrView| PF) coves dose) -Target concentrat3i0o0n pp (m0ins) |Pressur7e6(2mmHg)| usa3ge0(g) 336600 611 721196 336600 787 680365 360 360 m 5 e15522 336600 i76d8 o05n1 336600 776658 a1n 360 360 68 768 am 6676 336600 67681 66011867 360 360 4s 757 75 7084 336600 7664 53% 7294 363600 776605 7083 286 363600 77618 6s 44 336600 75568 759835 336600 778515 266s5 336600 75376 n73a64 363600 47580 028 360 360 758 0 761 7 00 00 80 sia 1 7s G29e5m) || (0o7pm[ )* ee% ] s3u6 | 303176 1900 s00r || s0s8 110030 aawm || o2e 00 2 | | 0mws 0o 2 || 0so 0055 2921 |293 90 225s || 20s8 0os7 229 || 3360 051 24 304 | ms 2 136 0 2 | 51 |a %6 % 9 sw | | ais sm 0 0 3s0s6 || o35ws 89% 3 || 4se6 08 33219 354258 19060 236 || 48 9ss 2 | sm EE PF % 65 | 2s ss 78 72 3 1319 ---- TABLED -- Ee TeTl ala | PH |B |B |B $320: --_-- MIN 313/023622 (Chamber temper-aetxpuosruree mean values - continued) 3 Lr a i hr ed a Eee 320 APPENDIX A Methodsof sample collection and analysis for POSE MIN 313/023622 SAMPLE COLLECTION Chamber concentration Ecahcahmbecrhasmwbietrcahitnmgosspyhsetreemwaat sacroengtuilnautaeldlyfdlroawwrnatferoofme| aUcihmtineusttecuhsaimnbgeartlaobotrhaetotriymep-ucmopnt.rolTlehde tchheamIbRecrellatamnodspshuebrseeqwuaenstdlyrapwunmptherdoutgohwatshtee.IR cela a regulated flow ate positioned downstream of `TThheescaomnpcelnetdraatiotnomfPoOSwFsaswppausmdhpeetdeetrmoirnweadsetaet.Texhaectaliyrf3l0owmitnouttheeinsteprvealcs tthrroougphohutoweatascohmmoenxeipottsouerrere.d tlhinreosuwgehoruetePaTcFhEotfutbhienge(x0p.o6scurmesdiuamseitenarg).calibrated in-line tapered tube gas flowmeter. Gas sampling `The sample line from each test chamber was located on level 2ofthechamber. METHOD OF ANALYSIS Cdehtaaimlbeed,rtaotgmetohseprhewrieths2amspulmemsawreyroefatnhaelymseetdhboyd evxatlriadcattiivoen,FTin-ItRh.e ITnhhealmateitohnoAdnaolfytsiacmapllPeraoncaeldyusries aits the endofths Appendix. ET APPENDIX A MIN 3130023622 (Methodsofsample collction and analysis for POSF- continued) CALCULATIONS FT-IR analysis `STphoenssoarmspleelsecotfrconhiacmbstearnadatrmdosfprhoemreBweeerre-pLaamsbseerdtt'hsroLuagwh.theAIRccoenlvle,rswihoinchfawctaosr cwaalsculaaptpeldieudsitnog tthhee t`hAeuatcotQuuaalnvtacopnocuernctornacteinotnrsaotbitoansi.neTdhwiistahrtohseeSfrpoomnsoadrisseclrecetpraonnciyc sotfbaendtawredetno2c3o%nvteortt4h7e%s,evinaclrueeassitnog with vapour concentration between validated gasbags, nominal chamber concentrations and the AsiuvteonQubantecaoslnceeqnuotartaitwoinon.1, Thhaedaecqourarteiloantuisoendfcooerftfhiceiecnotnovfer0s.i9o9n9c5oavlceurltatheed PfrOoSmFcvoalnicdeantterdagtaisobnargasngaen.d `Vapour Concentration (pp) = AOQuAT:CAEoncentratison-e82a41s4. [0] TMhIiNs31d2i/f0f1r4e2n7c2e biunt tvoalauelseswerasdegalrseo, tshpepraerfeornet, tduhriinngtroHduuncttiionngdooftnheLifteimeS-ccioenntcoelsledrecphoratmbneor sampling systemmay havepartlyresultedinthe increaseddiscrepancy. Otherdifferenceinthesevalues isattributedt acombinationofuncertaintiesa follows: ~ POOS$Ff% raesfseorcenicaetsepdewcitrtahatnhedmsu(rbessepqounesinbtiAluittyooQfutahnetSmpeotnhsoord)c;alculaTthiesoehnasv.e errors ~~The PrescsyulrienddreoropifnetthhyeleInRecienl;nitrogen standardhascerteirrofrsiofe2%d; ~The chaefmfbeecrtaotfmuossipnhgerulet)raispuunrkennoiwtnr.ogen forthebackgroundscans(ratherthanthecontrol Tcahpetuunrceeprrtaoignrtiaemsmreeblaastiendgon0 tthheelaansatlsyqsueadraensdstartoisotmicsa.irconcentrations wereestimatedbythedata s`tTahnedmaertdhuosidnfgotrhceanlocumliantailngfetheedcroantceeintgriavteinobneolofwPiOnSeFqufartoimontshe2amnads3s.usedtoprepareeach vapour where. Concentration = +--<1,00000ppm @ _WxRAT 760mm Hg yM Am i vW M === gmmaosaleesocouulsfavProOwleSuimFge(ho)tfofPOPSOFSF(m(l5)02.14 gimole) R = Gas constant (0.08205 ml atm mmol" K) TAm == atmeomsppehraetruirep(rKe)ssure (mmHg) Vi = `volume ofair (ml) 323 APPENDIX A MIN 313/023622 (Methodsofsample collection and analysis for POSF - continued) COMPOUND SPECIFIC INHALATION ANALYTICAL PROCEDURE FOR POSF `The analysisofPOSF (Perfluorooctane sulfonyl fluoride) in air sample substrate ``Tmhoenimtoertihnogdcoonudtiltiinoends in in athnisIndhaolcautmieonntTohxaiscobleoegny validated study. and is considered fit for the purpose of This from dtoesctuamtemnotspdheetraielss. thTehbeasriecsuplrtioncgedsuarmepslefso,r the of aapnparloyxsiismaotfe PcOonScFentsraamtpiloend2b4y0 etxotr3a6c0tivpepmF,T-aIrRe `anaamleynsdemdenutssianngdtahdeditMiIonDsAwiCllIb-eSedreiteasilesdpewcitthrionpahostuopmpelteermenatnadryAduotcouQmuenatn.t software. Study specific aNtOpTreEseTnhtr,obuutghwiolultbtehiisndcolcuudemdeninta,tShteusdyymsbpeoclifiicnsduipcpatleesmetnhta.th relevantinformationisnotavailable EFFECTIVE FROM:| 29 August 2001 Test substance POSE, perfluorooctane sulfony fluoride has the following formula: CF SOF. Appearance Clear liquid Storage Ambient temperature Reagents Air InHouse Compressed Ethylene in nitrogen Nitrogen Liquid nitrogen Sponsor Calibration gas (certified 2%) Sponsor Calibration gas (certified >99.9995%) BoC Cooling Medium 134: APPENDIX A MIN 3131023622 (Methods ofsample collection and analysis forPOSF - continued) Equipment Balance and Data printer Sartorius RIGOP with YDP-01 Flow meter GIinlsmtrounmtents 04Lpm FIR MCiordpaoeration 12001series (seria no. 151) Computer Compag LTES#00 Sotware CMoirdpaocration AutoQuant Version 3.01 MidacGr3a2Vemrsiosn 4.11 Chamber Syringe Driver ADG Precidor 3 level snout only Type 5003 UV Quartz Cells MCoirdpaocration ZnSe Gas Cell General laboratory glassware Aexchcaeussotrpiuemspsa.lso employed are: @ vacuum pump; cylinder regulators, power connectors; regulated Consumabies Syringes Aldrich 50 ml polypropylene MethodofSample Measurement AivvoealucmoenocefntPrOatSiFoniosfd3i0s,pe1n0s0eodrf3i0o0mptphm tineatndariumrsnttoro2ef5a30m0m!Unsiyrniuntgeea.irTfhleows,ymriinxgeeddtrhivoerrouigshsleyt tion tchheavmabpeorurailsoengathnedsfaemdpdlierleicntelyaitnatoltowheractheoamfbe1rU.iTnhuetteedsitraecttmloystphhreoruegihsthderIaRwnceflrl,om the exposure Production of Background Scan AdraflwonwtrhatoeugohfthIeUImiRncuetlel.ulAtraf-pautrpeeerniitorrdoogefn 3(-c5ylmiinnduetreNso,.anCOFCT-TI7R00s2in1g9le(nbietaromgesnpe9c9t.r9um9i9s5gene2r%a)teids approximately spectrum. every 2 seconds and continuously collected for 32 scans to produce a co-added i325 APPENDIX A MIN 3131023622 (Methodsofsample collection and analysisforPOSE continued) Storageofstandards and samples Stability experiments were not required for on-line analysis. Calibration and Quantification cTahcehsAaumtpoQlueamnetassuyrsetmeemntca,ltcuhleaatemdoaunctonpcreensternattiosndefoteremaicnheadbfsroormbatnhceeambesaosrubraenmceenstamapslfeolulsoiwnsg. tFhore equation below (Beer's Law): Amout(ppm)= 2A Where A= absorbanceatagivenfrequency ofPOSFin thesamplespectrum a = dearbsiovrepdtifornomcotehfefriceifeenrte(ncaebcasloibrrapttioionvftriPatOnsSyfFe)rstinantdhearsdamsppleecstpreumctrum,which is: b= pathlengthofthecel derivedfromcalibration data 3260 APPENDIX A MIN 313/023622 (Methodsofsample collection and analysisforPOSF - continued) Calibration ofCell Path Length Calibration ofthe cll path length s performed daily before each exposure. A29%c)eritsifpiaesdsceodnctehnrtoruagthiotnhoefseatmhpyllienngesiynstnietmropgreinor(ctoylsinadmeprleNoc.olClOecCt9io7n00to87c4he(cekthiynlsetnreum=en2t02r0epsppmomns=e mteahntedhcoadldeitubersraemtdiionne10cptyehlreinfdcoearrl.mibcraactehdspceecltrpaaltahnlaelnygstihs..ThCeelelthpyaltehnleevnagltuheiis arecraidtfircaolmtinhpeuttetso ctehretiafniaclaytteiocanl seAAfcttoeenrsdtasapanmedroconiostfionp3ou-dofhu5estlemyhyrcloielenleeincntaneFduTf-oiIrtRs3t2ieasnrtcgaalsnefobslteo,owagrpmartoesedopuenfccet1rauUlmmeisinssugnteoneieisrsyadstpreedacawtpnrpturhmor.xoTiumhgaihtsteplhryeoIdeuRvcecreeylsl.2a calibrated path length. This value s then entered into the POSF method file and manually recorded. QC caP1la4it0bh0r-alt6ei5no0gnstcihnlrLlidmroiegetisso:nno-toTrhceoifntcfaholeribmpr,aaattlhioonlfewtnhgietlhcbavleailrbuerepaetiaistooenudstesbtiyudepthptehaeruasrmearenitgfeenr0sow.1ip0le0labkteocis0h.ep1rc1ek5seedmn,.tIifntthhee QA peeIrnnidsotodrfsutsmhheeonetwxepCodasltuihrbaert.atthIienofsntirCnuhameleccnaktl:icbaTrlhaietbriacotanilgoianbrvcaehttieochnkespiaarrteehvewrliietfnhigietndhvaa5nl%du.seuRsbdesiefpqfeueertnetidlbotyfyitrloweesnocsftoouhrraanhdt2oteuh%dre (cfehrteohcmyklteshnteaeni=dnai2rtda0sl2,c0aplipbmra+ti2o%n)v.aluTehoeft2h%eveatlhuyeleisneinisnindiettrhoege5n% cytloilnedrearnc(ecylliimnidtesraNlol.owCeOdCa9s70q0ua8l7i4t.y Thetempeoftrhetaesttgausstrreeamandthe barporessmureewiltbermoniitocred manually. FT-IR analyser specification dTehteecMtoirdamcon1i2t0o0r0s stehreieasbsFoTr-bIaRncsepeocftrvoaprhiootuosmectheermihcaaslabownadvse.leAnugtthoQaucacnutravceyrsoifon0.35.e0m1".(MAIDMACCT, Irvine, CA) software is used foalr infrareddataacquisition and quantification, The will glievnegtaholifnteahrereIlRatcieolnlshoirp pbaetthwleeenngtahbs(oarpbparnocxeimaantdelcyonc1e0ntcrma)tidoinc.tates the concentration range that Tth`hceeoonopdpuecrttaietmdiauntgmtpfhrlaootcwefrdlauotrweefsroatrtoetrtheoedapIvrRooicxedilmdlaiilfsfte|orUtemhniceneFusoTt-ef,IcRwehsliycsphtrieessmss.uerTeth.beyFau2rnftalhleoyrswemderetdtarielarswacsnadn|aUblmelitonhbuettaaneifanlreyodsmifstrihosme gmaosnsittroreeadmbaynpdrtechiesrioenmsatianidnleerssissereeltaunmdedgltasostihne-leinxeproostuarmeetseyrss.temexhaust. Allexhaustlinesare 27: APPENDIX A MIN 313/023622 (Methodsof sample collection and analysis forPOSF - continued) Raw Data RtahnaedvFdTadta-etIdaRiissmydmseteefdmii.naedtTlhayes atrfhtaeewrfipdrrasitanthiainsrgd.pcrAoinpntyeeodluuesctitprnuognttiochbebtaaMciknIeuDdpAicCmompeGydorifaatmthseils3y2ifsossloalfvotewwdianrtgeo datahntedalwaoicclqalulibzseiiptsidiornginvebe.yd dIisfrteaocrretudonritynimtmhaeehyfablreedfcuoorsmpeaydtwtYaosgYneonMetroMabttDeatiaDnxhetadtrhdrcooupgyh,waphriinctherwfialullbt,etshieeglneecdtaronndicdcaotpeydf.Erxopmotshuerzeidpadtraiivse Computer hardware: FT-IR System hardware: Software: Safety Computersand VDUsaremaintainedbytheSponsor. Printer is maintainedbyth IT department. aTnhdemaSiponntseonranhcaeswsouuplpdlibeed mtahedehiarndcwoanrseu.ltAartainongweimtehntthseSfporonsserovri.cing `Documentation isthe responsibilityofthe Sponsor. ``TceohxnepsoisCdueOrreSedtHtohHtahteattshesseetssmtsaamtenendrtiaarpldrhoavniddleisngdeptraoiclsedruergeasrduisnegdwtihethtionxitchietydeopfartthemetnetsat rmeatseuriitaalblePOtoSpFr.evIet nits Iinmmceadsieateolfy.a total power failure, switch off the FT-IR and test compound generation equipment 138: APPENDIX A MIN 313/023622 (Methodsof sample collection and analysis for POSF - continued) Summaryofmethod validation `Therawdataforthemethodvalidationi located in study MIN312. Uncertainty ofPOSF analysis ``UgTnuhcieedrePtlOainiSensFt.ireOestfwheereerrnecpesraisinpdce(icpbtaylrtuhumneciseSrfptroaoninsmtoitreh)set3oweMbreeq:ulaeensttshitythalateinnvee 5lpia%btrfhaorlryetanhgnetdhAwuCaatsloiQgbeurnaaetnritaotnmeed(t2ah%to)3d;McianlutcseuirlnfagteirEoenPnscA.e from alkyl sufony! fluorides (<4.5% viv, but interference unknown). i390: APPENDIX A MN 313023622 (Methods ofsample collection and analysis for POSF - continued) PMRINO3CIE3DU- RSETFUODRY PSOPSEFC(IPFIECRFSLUUPOPRLOE-MOECNTTANTEOSUTLHFEONIYNLHFALLUAOTRIIODNE)ANALYTICAL P`TOhiSsEsuopbptalienmeedntrodemtaialisr asdadmiptlieosnseoalnldecaiemdeonndhmeensthtosotvehesuprdo.cedure to be usedforthe FT-IR.assayof TcTohhneeceaInsAtsPraaywt,iaoisnnscporwreppioarnarteihnaegshpraeartgaedofdoiMftIi2oN0n1s102an0.dpame.ndments, is sabe for the analysis ofPOSE, nai at Detsils given in is supplement supersede hos inthe compound specific AP. (EFFECTIVE DATE: [18Desember2oti Ansiytical standard [[uacmhmember [Puy TToFTuXoSBoy POGSeTr7i661i. Pnee luoMre oeoamnseeSsilEfonyFonrdke | Fourier Transform -Infrared Spectrophotometer The analysis is performed using FT-IR analyser supplied by the sponser, Preparationofstandard solutions Preparegasbas intherange 201400ppm. Calibration and Quantification u=Cadl2ei0lt2ri0anpteopnmfoor+ftgh2ee%n)cp.raatihQulnaegnntrgietffhiebcraeytnaiceonsetuphsysilnsegne(tohyi,en n3iMvoqgueanstainadivaed ocyrliyndegreNno.enCeOdCS#7010874s(sethyolenne Calibration Conversion Factor conversion factorstobeusedbeeennominaland analyserconcentrations. Gasbag cone (pm) = (AutoQut Cone ppm) 82614 12219 R*=0.9995 30 arma ste totsofsample collin snd ells for POSE - comin Cabriosd Quanitenion 0T m = 250n Cumin wwinyg Calibrationofthe pathlength by an ethylene in an nitrogen standard oder (cylinder NoNo. 570198 9701599 vin+e (ethylene = sam APPENDIBX dividualPOSEconcentration measurements MIN313/023622 ETeon | SEOw a 27 3 BW3i0s mmsae siie me :s ` MDiso sies mmeern nm me mw ;:5 Mnees Ne amsm ibs aawn nen 0i | MMike p | ue unises sw noiwe wn Vepm S le lioss ooo | io or eisae 2 ThfSeaaitalnointcn, ee oF pen Sed CVO) Coofnvatiotnodix 00nm) am APPENDIXE MIN 313/023622 (Individual POSFconcentration measurements -contioned) EYoe|| SNeu 7 C[oGnmrtTa TR | c Geer]n |coont wtta | L[hees[ w m3E ee re ] Ts SITE [Me17w67 sE 357a 4 e m 119.89 ms3u2e 1.n14 | I 2> Eaos es am 5a2 Bnee 26 enews uses aaoma ed 5u x nnams Bo esse. es wann ws FH Snnm uss ae E Sa E Sep we=y| 4meea ime seed vy 10 spr)m $ CVO STC ahenuigntio tdiaoliomf2nicvaoantctiecnottinrma(itooidoi nxns0meacsnur)ementofeachexposure were iam APPENDIX B aN 313023622 (Ondividual POSE concentration measurements - continued) Eons | See No. No. Group 2 Group 3. B2i | 3TmnH (Lowdose) | eaisnns (Inter.dose) | (High dose) aamn 5uo || uems 3 | me mmes bus vaews mies 6 || kmsm 3 | x% mmna mm emmm see oo a || mmee was oeswm bss mann sae wo"o | a0 5 irie naeisss 7 w=bo || dEma we esns wumwe P5I | aD n A um wa BPoO Bo | BR uns v vuasms esewm 050 | 2| wbies By uges ues wase we Ne5w | wT s usT s ww To ocooon|cen p5Geean oFihi2s7n fom cus w5as seT 4C VO C CShiammbeior ssoamifpnwlanetalitnit eosnnootdcixonn0ec0tntmo c)hamber sxe MIN 3131023622 APPENDIX B (Individual POSF concentration measure-mcoentnintuesd) -- cp Eo | Sae INT = 5 55 14034 56 154.99 57 17037% 58 18367 59 195.64 a60 Bu25ao27 nm mm105ne.90 me ewam 207.48" me "" FnaE ness as oM4 m62 Zo baeds mn a ew om a BDao no moses paw aemn an PE ) E[EVAA Ti HE nCVSo(n%ie)s 54 Re OT 3 pan S14ed 4 Sitmeoxg cme l30audoev, Sampling timeselectedat 1ratherthan every10minutesintervals, CFT V (%) GCreoensffiisciemm ntonfviaeriihmeeaowtd(eisihodgxnhec1d00r/fmooresanpn)ies 70 5d 7. Themoefthesntwo 1335: APPENDIX MIN 313/023622 (IndPiOSvFciondcenutraatilon measu-cronteinuesd) Epo | SNeom [TommT | Gems | Gow = TERE (Inter. dose) | eh (High dose) n 77 nn3nsg 0mnyse pes d3w3a0e2e7 sas n4 6Nie ne amre mea deewes en 54 nn2ee6 mooeee uasn mn V5em p Daiss E oetoms e aoesw E omal CcV (t%)s 42 e 08 29 U S5CoamnpS tuwtieanromeiablarfueencdtnioanDewaithoedatka coappture ve RoE CV) Conotfvaetionnotdx mes) i36: APPENDIBX MIN 313/023622 (Individual POSF concentration measurements -continued) ENxpoos.ure | SaNmop.le Gow? | Grows Groudp T w (Lo9wd6o0se) | (ntTer5.78do5se) | (H2i5g6h3d2o5se) 85 86 091 "087 15456 15978 33679 377.66 5 88 a6 "07 16338 163.10 38594 87.87 8 % an ws 16572 16494 38853 39200 ot 2 22 "079 152.18 12465 38973 39641 ES 4 023 aL 12531 12403 40570 36392 95 ear an EE 123.08 4734 35698 38017 sd oven [r= 16 18751 127 20016 53 7 % 97 05 55 as 12893 32545 9% 9 074 13338 Las 13381 36216 37847 100 101 044 4109 13396 13209 002 37641 102 103 4105 069 13216 13155 37609 ssn 100 10s 4100 129.85 a6 13053 37089 323s 106 107 4156 "08 13359 13164 373s nm ean sd an 0483 T5195 1676 36095 15366 "The niaol vcoencnentration me1asurementofcac1h3exposurewas 42 excluded = fSromelaelmicaslsceuldaati sions staredlat inerror CV (%) Coefficient ofvariati(osdn x 100mean) 137: APPENDIX B MIN 313/023622 (Individual POSF concentration measurements continued) ExpNoos.ure | SaNmop.le Grow? | Grows Groudp 108 (Lowdose) 3954 | (ner dose) S715 | (Hi3g6h8d5ose) 109 10 a6 an 11679 12036 32828 35456 m 2 als 4295 12012 12635 35649 39276 3 na 39 as 14133 38005 14121 37963 ns 11s a6 43.10 13795 13671 37908 38030 17 ng 62 se 13676 137.16 38004 38301 119 Mean 4416 Bis 14035 T5233 381.80 Ez ] oven 0393 14 9391 71 17985 49 70 121 El 2036 254 753 1996 32708 2 123 sss as 13104 37376 13456 36524 24 12s ats "sn 13130 13409 36661 36423 126 27 440438 1335 13622 36413 36866 128 129 89 540 13593 13468 36921 37031 130 131 um an 13465 13603 371.43 37360 Mean sd a3 7257 398 34506 36153 13011 "fTrheomanliaSlcaclTocnuc)leanttiroanstion mema1surement of ca2ch9exposureswas e3x6cluded sd CV(0%) SCunodaerfd dfeovifitvcairoiina.teionn(std x 100/meas) 1338 APPENDIX MN 313023622 (Individual POSE concentration measurements - continued) ETpeon | SNeoe [Gro] Gems] Ge 7 | nG ur T mea e1s 1Bu3es4 | a[6o8ms6e" wo | em wm14e3i.s16 wm ee38e2e5r2 mse mweo || wo | eaux an wween ma nmenw vem wwow || oaakn% ww | an mwunks oveesn ew Vpe | ovo | smesa Ttem is sism W wwse || E sdeem T asne eoew Wwoo || wwnm wo | wn emem wm weee wen || 1| wswmse easx ues weem owen 1156s | | | owwmsn uueess em weeee ees Serw ooo | R o1sss SotrT oss n2om TohmTlciosnicon s oF eh e pen ed C4= VO C`SSoyrhnintogeardmrvivoiefrvtianocrotriroecntl(yasdextamtsteareto)fexposure. (x9: MIN 313/023622 APPENDIX B (Individual POSF concentration measurements - continued) a ENpoo.sre| SaNmop.le Grow? Grows Crowd TS 157 29% ag TIS0F 15352 1276 340923 iss 159 "3 ats 12347 119.40 36805 36570 160 161 "e wa 12033 12194 36513 3718 1602 163 01 sss 1291 121.80 38305 38445 164 as 16s as2s 11955 12405 38435 38608 166 167 4526 4634 12818 2527 38302 38964 Mean sa wm 0813 297 3010 37556 12822 ove 168 19 Wor 24 T0436 34 2835 169 10 050 a0 12073 1200 3740 36615 m m 178 1267 208 12461 36599 36935 im 1m as an 12599 12621 36523 pate 7s 176 24 12693 2m 12519 36194 36871 id 78 an 2% 12638 127.85 38543 39329 179 ean 28 ars 12960 53 39875 TE sd oven 0838 20 2653 21 15016 40 "fTrhoeminailfaclaclocnulcaetnitornastionmeasurementof achexposarswasexcluded sd CV (4) Sundard deviation. Coeffiofcvairieatniotn sd x 100mear) 340: APPENDIXB MIN 313/023622 (Individual POSF concentration measurements - continued) ExpNoos.ure| SaNmop.le Gow? | Grows Grow 10 181% i) 183 31 12529 240 12564 39931 arse 184 13s 309 12145 a1 12064 38088 3m 186 157 493 12318 231 12402 36636 36396 188 189 4139 58 12333 12547 36405 31s 190 191 "a 455 12677 12659 38673 3845 ES sd BIE Tas 09569 184 Ha 1578 oven 52 22 22% 1s T0008 41 3 193 194 7348 3057 12330 12659 3236 387.60 195 196 3990 3844 12530 ns 39128 38929 197 198 a2 061 12410 12395 08 1% 199 20 aLsi 12355 ans 12375 3023 36934 201 2 4138 250 12530 15193 376s 750 203 ean a7 wT 130.40 578 37 37621 sd S70) 9918 27 2861 23 11s 30 "fTrhoemnailaclalccounlcaetnitornastion measurement ofcach exposure was excladed * ``Tmiemaemn-caonendrsoatlalnsedsdaarmcdpuhldaeemvcriboaeltrileocnstwemidtocvehienrgn2dgetrvoiuc,eps,ovutaloufesesyxncclhurdoendyfrwiotmh sd CV (4) Sundard devition Coefficientofvariation sd x 100/mean) 1341: APPENDIX B MIN 313/023622 (Individual POSF concentration measurement-s continued) ENxpoo.sure | NSaom.ple Grow? | Grows Group 7 %6 25 3854 5476 1361 555 31236 26 207 398 39.70 nn 11533 35213 35536 208 29 3895 3928 1383 11343 36607 33520 210 an 3837 050 11561 19.13 31835 36239 a a 036 059 1931 19.82 ms me 214 215 4020 4006 12053 12105 37354 31245 Mean sd B70 ost 7.16 292 35396 238 = oven 6 20 3930 25 T0038 63 TIZ06 a 218 39.86 3974 117.88 12056 35492 37631 219 20 "010 39.06 17.48 7.8 385.68 3862 21 2 3869 12075 3969 1218 3w281 391.60 23 24 3089 3867 11989 19.04 39029 3270 25 26 016 3998 119.18 12002 391.00 30068 27 Mean 160 12438 77 T1990 391.23 38436 sd STD) 0x20 21 202 17 11.067 29 f"Trhoemnaliaclalccounlcaetnitornastion measurement ofach exposare was excluded 88 CV(0%) SCunodaerdfdfeovifisvctaroinia.teionnstd x 100/mean) 1342: MIN 313023622 APPENDIX B (Individual POSF concentration measurements- continued) a ExNpoos.ure| SaNmop.le Grows | Grow? Ed 20 wn 2 12 601 326577.4453 20 231 4026 "089 12921 12967 00904317 2 23 azn ars 2841 234 39645 3104 234 235 4095 a 12651 12668 38236 38013 236 27 91 268 12906 13120 388436994 238 239 1s 281 13105 13097 838228977 Mesadn 105800 87 L385 346 11.444 coveo y 29385 21s 30 TH 70 22001 e02a3 0149254 70576314 2434 5613710 LL 103 0047 39396 25 26 S657 s628 1523 1413 96 9174 207 218 $135 499 18486 13936 39228 39170 25 20 S608 5606 1081 121 3399426368 251 Mean S662 578 14156 1538 39335 951 sd oven 2564 a 207 21 715971 f"rTohemafllfclaclocnulcaetnitornastionmeasurementofcach Exposirswas exeladed sd CV (0%) Sandard deviation Coefficient ofvariation (sd x 100mean) 343: APPENDIXB MIN 313/023622 (Individual POSF concentration measurements - continued) ori ExpNoos.ure | NSaom.ple Gow? | Grows Group 7 23 3088 52 TIT70 ns 2 3479 256 3865 255 3764 119.84 12048 36366 36652 25 27 3695 3855 12098 nse 36655 36526 258 259 "024 30.18 17.84 12660 36608 36696 260 21 39.10 152 12790 12576 367.12 36640 22 263 3985 07 12645 12659 36691 36585 Nea a 3846 2002 m7 3889 3665 9682 oven 53 %1 Ea 32 27 T0565 448 25 26 3950 "0 13268 13633 52 36837 267 268 064 "073 BLT 13168 367.59 367.15 269 mn 4055 38 136.58 366.16 13720 36656 m m "05 13476 036 13574 36563 36614 am 2 26 a3 13596 365.94 13594 36944 2s Men 4116 317 1 36957 36525 sd oil oven 20 2141 1s 6783 19 "fTrheomnailalcalocnuclaetniiornaston measuorfeeacmhexeponsutrewasexcluded CsdV (04) StCoaenfdfaicridednetvoifavtairoina.tion (sd x 100/mean) 134: APPENDIX B MIN 313/023622 (Individual POSF concentration measurements- continued) Exposure No. | SaNmop.le Group 2 Grow Groudp 5 6 m 018 031 10826 15281 97.60 33361 Ed Ed 4130 3956 13852 13687 36551 m6 20 21 a2 3965 136.02 13474 36845 36471 2 2x 044 080 13430 135.44 361.65 36084 21 25 a2 "06 13577 136.2 36229 36536 26 287 295 085 13709 137.40 36596 37096 Mean sd 081 os21 T3599 1549 363.00 10395 oven 288 23 Ea 11 TIS18 29 T0136 29 290 a7 au 12992 15101 36693 375.46 21 2 ae 401s 13433 13365 37524 ms 293 204 28 az 13206 5152 373.03 371.78 205 26 26 24 13297 371 368.54 37567 27 208 28 ey 13386 133.402 359 3612 29 View an 9% 13204 T% 375.06 BI sd 0838 oven 20 138 10 3019 08 Tfrhoemnailaclalccounlcaetnitornastion measurement ofeach exposire was excladed sd CV(0%) Sundard deviston. Coeffoifvacriiatieonnstd x 100/mean) 345: APPENDIX MIN 3131023622 (Individual POSE concentration measurements - continued) ELpOo | Sawe a o0T || wmne (Lowdose) | me ewe en a mwee (Inter. dose) | (High dose) Owoo || 0s | daiwl wm psoiwe mo amees es owso || maml | de mimes oie wmep ame sWow || maax | se mbine new ymee wes Ne"at om eaome ooo| an 5 aism T mo B | Rus we | Mw Tameee aTaT men waBose | || mBmw un muaees wa mmsee ae wao || wwee 2 | sa obnsees pes meeew ee 2wm || awims wm | bw bbee oes wyeess I pi osm ooo| is 5s)w o2s 4 SoTovGlsT ccooncneosalon ese each pon a ed CV(%) Coeffoifvcariiateionn(std x 100/mean) TT APPENDIXB MIN 313/023622 (Individual POSF concentration measurements- continued) ne | cig ENxpoo.sure | SaNmop.le Grow? Grows Group 3 Es 25 am 4138 225 5277 138.49 34871 326 27 193 136.16 4136 17 38929 391.07 28 329 4199 08s 140.66 37682 14085 ma 30 Eo 098 a12s 140.13 1452 37977 38400 32 33 3997 ase 14082 385.50 19292 38636 34 335 410 ass 14163 14135 38660 39094 Mean sa as 0705 15953 2545 BIE 1194s ST) 17 36 E33 18 T0807 31 557 7 3814 338 3861 12815 13552 32886 36671 339 30 ne 3801 13433 13473 36947 37031 341 32 3861 3018 13352 13524 368.87 n246 30 344 W090 3906 137.13 137.00 37519 me 345 346 "0s 060 13698 13677 37386 mes 347 Mean Let 13990 36 13539 37560 364 sd ov ee 1346 34 2964 22 13520 37 "fTrhoemianlitaclaclocnuclaetnitornastionmeasurement ofeachexposarewasexcluded sCdV (%) SCunodearfdfdeivoifcavtaiiroineatniotn sd x 100/mear) 1347: APPENDIX MNs13023622 (Individual POSEconcentrationmeasure-mcoentnintueds) ELOp | Sae a a = Sw|T dTne m | km ToEe en smeen so | | wwsn | wy bbmeesm ss mmee 3s | | dwnk 36 | we voreees es vmenm me w | | wassm 39 | as waewn es mmsee ves Ve"m [pRAr IRSSTH Fo ER | CV(%) wa1m7 i | dm 15 imses 23 emnn | | adws For I A bseern or aawne M6 || wens | ow mmams nes wwee me wTo | | aan nm | dem sosae me rwemsa me PV)er |oWme oven| is iiamne1s os Sis 4 THSoEraGalmliitotanicePes OhCp 8coed CVOH Coofnvatiotnodix 00nm) ey APPENDIX B MIN 313/023622 (Individual POSF concentration measurements- continued) ExpNoos.ure | SaNmop.le Group 2 Grow 3 Gro4w 37 (Lowdose) Be | (lntr.dose) | TL (ighdose) 20270 373 34 3923 39.40 13197 13449 367.10 389.06 375 376 3878 133.54 3841 13127 37505 366.55 3m 3938 378 3931 13275 135.10 36.17 36481 Ed 39.99 380 3881 13492 134.00 36186 36423 381 382 3983 "083 13503 13450 36888 36928 383 013 13651 37027 ean 3946 T3401 En sd 0693 1524 7585 37 ven) 18 38 3707 1 T5355 21 T1543 385 38 39.19 3878 14086 19203 35404 379.80 387 4023 388 3956 13928 1342 38251 38625 389 39% 4025 3941 13233 13181 388.03 386.03 31 39.50 13166 38407 392 393 4019 4006 13259 13290 38471 38054 304 3951 395 4024 131.69 12853 38982 390.12 Mean 7 Ta28 380236 4 0503 4365 9985 "Theinitaclvconecne)ntration 13 measurement of 33 26 each exposurewasexcluded sd frStoamndaalrldcdaelvciualtaitoino.ns CV (%) Coefficient ofvarition (sd x 100mean) 1349 APPENDIX B MIN 313/023622 (Individual POSF concentration measurements - continued) ENxpoos.ure | NSaom.ple Grow 2 Group 3 Group? 3% (owdose) 2% | (inter.dose) T0594 | (High dose) 13480 397 398 4171 052 133.83 37004 13446 39260 399 40 41 13621 41s 13835 39235 39119 40 a an 41.68 137.96 13682 3995 38697 403 04 230 414s 13446 38602 13547 387.15 40s 406 43.00 236 B72 388.95 14081 39432 07 Mean 360 200 13835 39435 T3639 386 sd 0880 oven 21 2117 1s 6812 18 ws A710 409 206s 12938 146.13 0 388.04 410 ai 4679 80 14534 en 39602 39447 a2 413 a a1 14681 144.46 396.60 397.08 414 41s 4239 269 143.14 14555 396.75 39835 416 a7 am 48 14591 146.06 40086 39623 a1 36 419 441 147.08 39593 14597 394.04 Mean sd Tas 7.009 TST8 Ln 587 3188 "The ST) 169 initialconcentrationmeasurement of 08 each exposure Was 08 Excluded sd fSrtoanmdaalrldcdaelvciualtaitoino.ns CV(0%) Coefofvfariaitiocn(sdixe100nmeatn) 350 : APPENDIXB MIN 313/023622 (Individual POSF concentration measurements-continued) ExpNoos.ure| NSaom.ple Grow? | Grows Groudp CsVd (%) 0 a1 TH 16 TILST 13538 BEd 36321 = re 28 240 137.89 13852 383.43 38636 a1 as avs aa 13876 38198 13760 38203 a6 a as ast 13632 13734 38598 391.57 a a9 as 4176 13838 13637 39155 9140 430 a1 276 13597 39097 a6 136.10 393.04 ean sd a3 [= 721 3835 L107 454 wen 1s [2 %2 [ 790 22 T3618 a3 ae 3620 3678 13474 13104 34449 35289 as 6 37.0 3696 12550 12469 sas 34902 a7 a8 41 37.55 12596 34881 12635 35020 9 40 23 6 12559 2102 302 35255 pt a2 na 3867 12369 12388 33582 357.96 "3 Mea 3826 12490 3739 12667 35365 157 sd 06m 3335 oven) 18 26 3677 10 "fTohemianlflaclalccounlcaetnitornastion measurementofcach Exposurewas excluded CSaondaerdfdefovfiiavtaircoin.aitieon(nsdtx 100imear) 351: APPENDIX B MIN 313/023622 (Individual POSF concentration measurements-continued) Sr EpNoo. s | SaNmop.le Grow? | Grows Group Eo 4s 3702 3849 T0770 13589 57 2230 46 3764 wr 862 136.10 13568 267 34365 a8 a9 21 28 133.49 13324 34874 35007 450 3895 as1 3789 1332 13396 351.09 12 a2 53 3901 3878 133.02 13247 35205 35213 as ass ne 083 13538 13589 323 35037 Mean sd 384 0547 T3440 1382 S4LsT 21440 S70) 6" 25 10 63 457 458 as a3 13878 14136 33691 36084 aso 60 076 a1s6 13900 13838 36644 367.70 61 0 am 4036 13697 137.62 36683 368.55 6 64 4150 41.00 139.47 13879 36900 36529 465 466 238 as 13728 137.5 36864 36923 467 Mean 4140 Ta 14133 138.766 37468 36192 sd over 0361 14 14997 1 9862 27 "fTohemnlilaclalccounlacteinornaston measureomfeGancth exposars was excluded sd CSoumnpduatredrdmeavlifautnicotnion withdatacaptureprogrammeduringexposure CV (0%) Coeffiofcviarieatniotn (sdx 100/mear) 13m: APPENDIXB MIN 313/023622 (Individual POSF concentration measurements- continued) ExNpoos.ure| SaNmo.ple Grow? | Grows Crowd Ws 469 3625 3670 T0761 14464 1581 35578 an an 3519 un 13531 13279 36672 35887 mn am 3557 3614 1316 10964 35786 35545 an 415 3539 3532 13455 13004 35391 35531 a6 mn 3555 3715 130.18 13207 35581 35999 ams an 3529 3642 12976 BLL 36208 363.46 Mean sd 77 0736 BLE 8257 35866 4031 oven 21 0 3688 63 B70 11 a 003 3954 13729 1974 2431 348.06 a3 a 3937 3965 14054 137.62 36002 363.46 ass 6 3864 013 13634 13574 36359 36467 ar a8 3969 01s 13498 13673 317 36070 a 490 3926 005 153775 13859 36069 36270 91 Mea 6 13863 576 36480 TT sd 04m cv eR 12 167 12013 12 34 "fTohemianltliaclalCcounlcaetnitornastion measurementofeach exposure was excladed "Computer exposure dana capureprogrammefrozeandhadtoberesetduring. sV7d ESduhnydleanredidnevniisttrioognencalibrationcylinder leftoninerror CV/(%) Coeffofivacriitioen(nsdtx 100imeas) 1353 APPENDIXB MIN 313/023622 (Individual POSF concentration measurements- continued) ot| cian ENxpoo.sure| SaNmop.le Gow? | Grows Grou4p 2 93 3m 3969 377 137.02 10827 3570 94 495 060 3979 13854 139.06 33872 36689 96 07 3888 3964 13806 137.87 363.84 35895 98 09 02 044 137.10 13643 36408 35723 500 sou aL az 1163 14092 361.55 364.44 02 03 023 203 137.49 13907 36550 36507 Mean sd 038 009 T3847 1623 Ean 8702 7 ove 23 oq 12 24 SSo0e5 07 009 S08 3895 3 14833 * 36291 509 sto 3896 3978 14582 14552 36001 36067 si siz 39.88 ads 146.64 143.04 36014 361.02 st51a3 3969 019 13286 13201 36221 36513 sis Mean 183 Eg 13285 T9053 367.15 e241 4 oven 0987 25 080 50 257 01 "fTrhoemiailtclalccounlcaetnitornastion measurement ofeach xposarewasexcluded I* Semplemmisesdedsas mac started ate in eror CV (%) Coefficientofvariation (sd x 100/mean) 354: APPENDIX MIN 313/023622 (IndividualPOSEconcentrationmeasurements -continued) ELoOn | Saee comin| cir TwTo | as | wm s e me ww ome aan sen 2$9 || wBem 2 | we moees me seeann es @2 || 2| wwnm Bn mbss mm eoann sem i225 || mens beemm soewn A EpEa oss 5dom Imi)me Tm2 | pEaE 0 | me momE ms eank omo2 | kmse | me muses mee eens wn SSs| | 26 | xons se mmeem mm weewn em 9wsso ||| mxwn2a mmees mse emne en W"e SwTe TRsSw ove| is " eisms 4 TfhSoemalclnoownanceere ofoh5 eS C700 Coonfvotnexnmten) sass MN 313023622 APPENDIBX (Individual POSFconcemenasturermenatst-ciontoinuend) TTeoo | SNuomm R[GAIT Gms GT ssE oe || muemr omwen awme ssoa || smse Ss | pa mmme msn wweeen sen ssos || wwins se | ns miw un wawee we swo || ummp si | wm wmemn bran wmee wee Ve"m TLREe woo | 5s s3sis emeas i sWmTo | se | RmnA ms emeses re smaem ssss || wwxm | ww auis; um maee nee ssoo || amee sw | am momee ee mmmm ven Sste || so | wan wn ruimeaess emee me E " Eom ooo| 2 t2s n5am 4 Ta So aAmSonae mes OT th pes aed CV(%) Coef ofvf ariai tioc n(si dx1e00/nmeatn) (3s: APPENDIX B MIN 313/023622 (Individual POSF concentration measurements- continued) EpNoo. s | SaNmop.le Grow? [Grows Groudp Ea) (owdose) 38 | (ter dose) 1054 | (hig5h3d4o8se) S65 366 "088 036 1200 1612 34687 373.08 67 s68 4098 an 14498 14101 37568 am 369 50 ar09 230 1011 14128 3126 3788 sn sm 240 086 143.43 14393 37845 37585 Ea 574 an 4138 13833 13635 321 37673 515 Mean B14 13830 WH T153 37645 I 4 oven 0882 21 2907 21 8969 24 7% sm 336 3708 340 10241 57 376 578 579 3899 3823 14411 14350 0897 41005 S80 81 3995 081 14336 1778 0735 aes 52 83 3991 3898 15581 15108 s002 40838 S84 3976 ss 3906 14726 14763 30882 39667 S86 587 "011 4538 1201 14588 39594 39994 Mea 4 E23 2098 T4644 4160 067 13a "The initoalvcoenc)entration me5a3surement of ac2h8exposars was e3x3cluded $4 fSruonmdaalrdcdaelvciualtaitoino.ns CV (0%). Coefficientofvariation (sd x 100/mean) 1357: APPENDIX B (Individual POSF concentration measurements - continued) Soe | Same No. No. EI Group 2 Group 3 aT oii SS|o | dwenm S| we msms use aasmm wma m || wwem S| de uusses use veens mse SS5e0 ||| wwweaw wase as mmee ae S9| | owom Ver TRE uwse dweas Tess oT opo| E 3w0ae E5te abSsw w@ | | 5we%s veeos o | neuen wwema am ww | | amms 0 | x anese un moees ve @of | | wwen w | we awns ue wmee we ado | | wwei Vem [RS awne wmme ean ThE oloSoPoo|nne2lsase oF e5ih sor vi iosso ned 4 E Sate in CV(%) Coeffiofcvairieatniotn (sxd 100/mean) 313023622 Jas MIN313023622 APPENDIX B (Individual POSF concentration measurements - continued) EoYons| Ne [amr ter at WaTw | Rnnh ac | wx wass ew aanms en aass | | dwxx | eis viesm we veeemr mm aass || wwex a | bw weaees mwess ww a@ | | wwmo @ | bw ieswe on wwee we V"e | B Le GTaes mam CV) 28 17 35 57 6@a2s4 | | aa39sn04 @ | a uoseo use mai.me am aa | | aane G0 | ae uusses wes eowees me a@ | | Baen @ | es sues use awweesd me aosn || Vem bBnn ussee wmme [EEE The llcvopoon|cePeaoas aisw m10e7n oT th pene Sled oral tains W C= VO S C`Samoplenmitsosefedvaasnrtaintaolnys(issdsxta rted late in 100m) error i359 APPENDIXB MIN 313/023622 (Individual POSF concentration measurements - continued) SYop | SNuoe [oT] mms | Gm =@ | (LoaBwdsHose) | (intsmer.oAdwose) | (Hmiigehadnnose) PEa | wEiSs we sum ssiot | aases momee mmse ssoe || a em oe use mmeass ass | | aamm mbases wwoem ss61 || eaons mbiaos wwees Vae | A os ASwn HaE0 5 oaven | T 7 ew61 m7es 6sa4o9 | so0mee3r" om13e8n.s5s5 e3s0u4r2n7 ss | | wwmm emnw owmees esso | mmsas eome wwma sa1e | | wwam wweeas wwes asss | | aaoss wwess ser Ve"r | 1R21E5 Wasmsaan TSoomawlacolooin|sesmmseeno ieho POS 5 71 eT 4CV0H) LCoSouwnnctionemcnientdteorvaftiviaoornnndiuoent4oairxb1ub0b0lmeeisnnt)estmaterialfeedline 300: APPENDIXB MIN 313/023622 (Individual POSF concentration measurements - continued) EpNoo. s | SaNmop.le Grow? | Grows Grou&p 0 (Lowdose) 3 | (ter dose) 1062 | (high dose) T6067 61 62 375 3813 139.46 143.48 363.69 381.80 663 6st 3731 3706 14436 14510 38925 39701 665 66 3885 3929 14511 145.18 393.56 394.04 7 668 3966 3928 14525 14554 3412 39833 669 0 3004 a2 14720 146.10 0295 0239 671 Mean 3987 358 18433 1865 40271 39271 sd 1262 wen 32 1973 1516 14 29 "fTrhoemnailaclalccounlcaetnitornastion measurementofcach exposure was excladed sd Sundard deviation. CV (0%) Coefficientofvariation (sd x 100/mean) 1361: APPENDIX B MIN313/023622 (Individual POS concentration measurements - continued) ExNpoos.ure | SXaom.ple Gop? | Grows | Ged wT Qowdos) | (er. dose) | ig9h66do5se) eoonuvn " u12s016 eenm 88050009 ane en 896 54.05 0 ae 170.18503 nasr 1100950345 a a6ss f1i2ir3e1d we ass aas 555527 0 61% p61r4 0 PS 4s60311s 1787 au oos ssouent 1154355716 221392 os ba a4n522s3 1u5s52s a21s47s5 Pl I ass 570 14523 asa pried 198 001 44553786 u14s60275 aa1anss 23 44699631 1144885200 2021 Vsedm E2E5)2 72489 msin Sei oivecn d 1 abeprr)anve TO 17i a Vis16od # SlTieRoidErs,Evie, s xeid oms eh ndt srwi o meioennt ,si CVO) Cotiosmtofatinux 00mm) 362 APPENDIXB MIN 313/023622 (Individual POSF concentration measurement-s continued) ENxpoos.ures | SNaomp.le Grow 2 Grow Grou4p 04 705 5 20 a6 13440 016 12687 06 07 49 13952 4336 139.84 394.16 403.15 708 709 als wa21 B 137.89 40062 "0342 70 it 390 a 137.15 13705 0390 0334 mn m 46 13831 sss 13815 026 40390 74 7s 669 "08 13865 0652 13814 40598 Mean sd 69 1476 5753 Laz 377.6 825 ST) ie 34 Ex] Ll 0548 20 109.10 Ld 78 ass aso 13725 139.46 38019 41027 79 2 628 wun 139.66 41329 1253 ase 71 = sn 4553 14264 14135 41757 41617 TM 7 4609 700 14183 12230 41558 4183 ns 76 4766 4891 1187 14199 ans ang m Mean' 11s Bs 19220 TLS 42087 nw sd oven 884 203 1679 212 12 27 "fTrheomnailaclaclocnuclaetnitornastion messurementof cach exposurewasexcluded sd CV (%) Sundurd deviation. Coeffiofcvairieatniotn (sd x 100fmear) 1363: MN 313023622 APPENDIX B (tndividual POS concentration measurements - continued) Epes | Sem No. No. Group 2 `Group 4 wTMT mo | (LoEwwdinosse) | | an mmwnwr (inter.dose) | saemn (High dose) mmo || awnn | km ewees baw asmean see mnse | | woow me | se mbeayw um wsseiinee mmoo | uawn m | an ndeesn ise saunnn em V"e ooo | T 0 RIame is is a5a2n mToo | wo | wTe TT sas es wm awmea wwoo || us| aasm as ooem vk ssins ass wHos || Mo | dmne an ernk ness mwess me mwoo || wdsnl wm | wa sissm im haeens asm E " E2m am ooo| 5 os aSh PI r Tool cy ciooelomic CV (%) Coefficientofvariation (sd x 100/mean) -- Arron (lniPOvS iconcdentsratiton measurements contsnd) Ea mE7 ort [em ci:an T7BWooo3|l| hAowemn bwm enm eewww wTWoool | | Baaoww Bmmsws ahaewm TWoo| | | aBBnnE didaawmm eaoeew NaSle| TGSeSE T eCneeaseTee CTT WVoa|)| mu5mm0 E eow1x2n aa1w7 wTTooo | | wkbnem iwwseeese weawme WmToo|olkelGnne wwemss wewenme Tnee||| aBbhnn eiuseem aeanwwe Nae | T Te Ns a Tm CR CV (%) A45 T 10 38 P 0) fCpr rohuax 0an 0gm)fie 1Sey io "w `Time-controlledchamberswitching deviceoutofsynchronywith sis 365: psn AEmmreesesme f-tsce an 5 sen wo " rm escent cory aER eure r Eremey C py LR neon rE Wnsoemcots | Riad schon ae.