Document 0Gd3V0VVD4gvG4g5yeqvenrM

ARR2G -- 14-90 ee ose PROTOCOL Perfluorooctanoic Acid: Inhalation Repeated Dose Pharmacokinetic Study in the Rat Project Number: DuPont-12944 Work Request Number: 14552 Service Code Number: 1017 ig 2 on xz 33z8=5 3 shell Ail Wels Commitee No BTIS2P -- eee ------ FaTseTp-- r------ ---------- ret + PIenoharloatoiconiRaenpoeaitceAdciDdo:sePharmacoSktuidyninethteiRact TAOFBCOL NTENETS DuPon1204BR4 Page UG rrrsmsmssmmmm--------------} `SPONSE AA TES FAGHLY cvrrrnrarrsrnrrnnsnsmssssssssssssssnssson3 A TOS SUBSE:3 Be TES SYSIOM cnn 1. ARAL HOUSING rnd FE ---------- 3. Fe 810e WHEdT cms sms 3 4. Animal HealthandEnvironmental MODIOFng PROGIAM...evurvensnsninnsS D. TohalationEXPOSUIE SYSIEM..rvrrr nn 2. Chamber COSITU0CADHEOEDN .rvvrvrvsorsrsssrsrsnsssssnnss E. CharacterizationofChamber ATOSPRETE ....vvvvvsororssssssssmsssinsnn 1. Test Substance Samplingand ARBIYSIS....ovvrvvsorinnbsssnesonnns6 Pg ---------- 3. EOVrONMERS] MOHOD..rcrvrssssssssnsonssnsn 6. F. TORAIStOREXPOSUIE.ccrrrsssissosssn | Ts I -------------- A ---------- EE. FE En ---- + InPbearloanioonocRteapneiatceAdcDio:se PharmacokineticStay itheRat Dupone12044 PR INTRODUCTION PweirtfhlPuoFrOoAoc,tawnhooilceabcioddy(PeFliOmAi)naitsiaonsoufrtfahcetacnotmipnoiundnudstwriaasl pfrooucnedssteosb.eInmuracthmemtoarbeolraipsimdsitnudies dfeesmcarliebsicngomtphearbeedhatvoiomraloefsPfFoOlAlowfionlgloorwailngdoorsailnegx.po"suTrhee.reThiseapluarrpgoespeohafrtmhaicsokwionrektiics tdoata set generate plasma PFOA data to bridge the oral and inhalation exposure data ses. OBJECTIVE "The objectiveofthis study i to generate plasma PFOA concentrations following repeated inhalation exposure at three concentrations. `SPONSOR AND TEST FACILITY B"Trhuisssesltsu,dyBeislgsipuomn,soTrheed bspyotnhseoArsssaopcpiraotviaolnowfasPleafsfteicctsiMvaentuhfeadcattuerethres sinpoEnusroorpaeut(hAoPrMizEe)d,the work on the Agreement between Haskell and the APME. "ETJh.e dsutuPdoynwtildlebNeemcoonudrusctaenddaCtoHmapsakenlyl,LNaebworaartko,ryDefloarwHaeraeltihnacnodmpElnivainrcoenmweintthaUl.SS.ciEenPcAesT, SCA (40 CFR part 792) Good Laboratory Practice Standards." MATERIALS AND METHODS A. Test Substance PHaFsOkeAllwiLlalbboeraotbotrayinNeudmfbreormuAplodnrircehceCihpte.miAcvaalisla(bMlielwianufkoremea,tWiionscoonnstihne)puarnitdya,scsoimgpnoesdiatiuonni,que tchoentvaemnidnoarntasn,dsydnoocnuymmesn,theadzianrtdhse,satnuddyharzeacrodrodsusanmda/toerriraelpocrlta.ssification(s)willbeprovided by tShienaccettuhailsdsotsuedeyaics hurtialtirzeincgeitvheedi.nhAalllateifofnecrtosuwtieollftexphoseurreb,ee10rfeaptootretmrepdtaewsilalfbue nmacdteoitfotoehnsetablish exposure concentration(s) rather than a functionofdose. CAS Registry Number: 335-671 Molecular Weight: 4141 Molecular Formula: ~~ CaFisO:H Structure: J THFRYEE -- EE ------------o-- e ------------ PInehfailscoiroonocRtnoeic ApDciodseePhaarmtacokeinedtic Study intheRat DuPont12044 BR B. Test System IMnacl.,eRaanldeifgeh,maNloerCtrhlC:aCroDli(nSaD.)ITGhSe BSpRraragtusew-iDlalwbleeyobrtaatiwnaesd fcrhoomseCnhafrolretshiRsisvteurdLyabbeocraatuosreoiefs,the lexotwenisnicviedeenxcpeeroifsepnocnetwaintehotuhsisdsitsrcaaisneas.ndFuitrstshueirtamboirlei,tytwhietShprreasgpuecet-Dtaowlloengyervaittyh,assebnesietnivuistye,dand previously for toxicokinetic testingof PFOA and other fluorinated test materials. Upon arrival at Haskell Laboratory, all rats will be housed singly, sexes separate, in quarantine. "The rats will be: quarantined for at least 5 days. identified temporarilybycage identification. weighed at least3 times during quarantine and once prior to initiation ofexposures. observedwithresptoweeicghttgainandanygrosssigasofdisease or injury. t"Thheebraastissowiflblobdeyrewleeiagshetdsfarnodm cqluianriacanltisniegnbsy. the laboratory animal veterinarian or designee on dRiastcsatrhdaetdawrietahcocuitdennetcarlolpyskyi.llReadtosrtrheatmoarveedfofurnodmsdteuaddyodruarriensgactrhiefipcreedteisntepxetrrieomdiwsildlurbieng the purpeotnestthpeesreifoidnwdiilnlgsb,efguritvheenr adigsrgonsossetxcampirnoacteidournetso mcaheycbkefoermpthleoypreedsaetnctehoefddiissceraetsieo.noDfetpheendant sintculduyddeidreicntotrh,eafipnaatlhroelpoogritsut,nolestshecolnasbiodrearteordysaingniimfailcavnettetroitnahreiaenv.alu`aTthieornoesfutlthsewisltludnyo.t be: AShtotuhledtniomteoefxcdeoesdin+g2,0ra%sofsthohueldmebaenapwperiogxhitmbatyeelxyp6o-s8urweeegrkosupo.f aEgaecahnadntihmealwewiilglhbevaarsisatiigonned a uidneinqtuiefiicdaetnitoinfnicuamtbioenrmwmbibeermtlaorbkleeudsoendtthhertoauiglhoouftctahcehastnuidym.aliTnhienldaeslti3bliegiintkso.fthe an?imal C. Animal Husbandry 1. Animal Housing Eaxbcoevpetcdaugreibnogaerxdpso.suEraec,hractasgweilrlacbkewhiollusceodntsaiinngloynliynrsattasionfloesnsesteseelx,.wire-mesh cages suspended 2. Environmental Conditions aRtaatstweimlplebreathuoruesoefd1i8n-p2r6oCxi(tmairtgoeytetdhetoin2h2a-l2a4tiCon)cahnadmaberresl.atiAvenihmuamildriotoymo(fs3)0wi-l7l0b%e (mtaairngtetaeidnetod 4102-h6o0u%r).liAghntidmaarlk cryocolem.s wUinlllebses jarutdigfiecdiabllyytihlelusmtiundayteddir(efcltuoorroesctehnetllaibgohtr)atoonryavneatpeprirnoaxriimaantteo En PinehraflucoiroonosRaenpecaitceAdciDdo:se PharmacokineticStudyintheRat Dupont12944 PR hinavteheshigonuisfiincagnrtloyoamfsfewcitlledbtehreerceosruldtesdofbtuthweilsltundoyt,bteheinrecllautdieved hinumtihdeiftiynaalnrdeptoermt.perature ranges 3. Feed and Water Etaxpcewpattedrurwiilnlgbeexpaosvurae,iPalMdIalibNbuilttrueimt.ion International, LLC Certified Rodent LabDiet" 5002 and. 4. Animal Health and Environmental Monitoring Program AfosllsopweciinfgiperdoicnetdhuereHsasakreelpleLrafboorrmaetdorpyerainodiimcaalllhyeatlotheansnudreentvhiartocnomnetnatmailnamnotniltevoerlisngarperboeglroamw, the those that would be expected to impact the scientific integrityofthe study: + Water samples are analyzed for total bacterial counts, and the presenceofcoliforms, lead, and other contaminants. + Fead samples are anafolrtoytalzbacteeridal, spoanrdfueng,al counts. + Samplesfromfreshlywashed cagesandcageracksareanalyzedtoensureadequate sanitation by the cagewashers. Creerqtuiifrieemdeanntismaanldfneoetdtios uesxecde,edgusatraatnetdemeadxbiymtuhemmcaonnucfeancttruatrieorntsoomfkeeetyscpoenctifaimeidnanauttrsi,tiionncalluding sppreecsiefniceedohfetahveysemectoanlts,amaifnlaatnotxsinb,elcholwortihneamteadxhiymdruomcacrobnocnesn,traantdioonrsgtaantoepdhboyspthhatemsa.nufTahceturer would not be expested to impact the integrityofthe study. : `lTheaanbimaoalnhriemaalatlhvetatnedroiennarvriirayon.nmDeanttaalarmoenmiationrtianignepdrsoegpraarmatiselaydfmrionmistsetrueddyrbeycothredsatatnenddmiangybe included in the final report at the discretionofthe study director. D. Inhalation Exposure System 1. Atmosphere Generation sFuobrstthainscsetuidnyd,eaio2n0iz%ed(wweaitgehrt.iwCehiaghmtb)esroaluttmioosnpwhielrlebsewiplrlepbaergeednbeyradtieldutbiyngatehroespooliwzdaetrieondotfetsthe n2e0b%ultiezsetrswuibtshtaanscyersionlguetiionnfuisniaoinrpwuimtph.a nFeiblutleriezde,r.hiTghh-eprteesstsusruebsatia,ncmeetweirlledbeinmtoettehreendebiuntloiztehre bpyumapmaasnsd ffllooww ccoonnttrroollleerr,wwiillllbceacroynttrhoelrleesdualtnidngmoantimtoosrpehderbeyitnhteoCthaeiexlpoIsnuhraelacthioanmbTeorx.icTohleogy AbuytvoamraytinegdtDhaetsaySriynsgteeimnf(uCsIiToAnDrSa)t.e toCthhaemnbeebrulcioznecreanntdr/aotriobnysofinttersotduscuibnsgtkanncoewwivlollbuemecsonotfrolled dilutional sir into the exposure chambers. . = -_--  PinehfailuaotiroonocRtnoele ApcDiod:seePhsarmtacokeinedtic Study in theRat Dupont12964 PR "dTiesscthaatrmgoeisnpthoetrhesewfiullmebehoeoxdh.ausAtirefdrtohmrtouhgeh caonntMroSlAcchhaamrbceorawliHllEbPeAexhfialtuesrtceadrtdriirdegcetplyriinotrottohe fume hood. 2. Chamber Construction and Design nAlolmienxaplosiunrteercnahlamvboelrusmewiolfl b1e50coL.nsAtrudcitsepdeorfsisotnaipnllaetsesisntseiedleatnhdegclhaasmsb(eNrYwUillstpylreo)mwoittehuaniform chamber distributionofthe test atmosphere. 3. Exposure Mode Dwiutrhincgoneixcpaolsnuores,e paineicmeasl.sTwihlel rbeestiznadiinveirdsuwaillllybreesitnrsaeirnteeddiinnptoerafporoaltyemdestthayinmleetsshasctreeyllcaytleinders finatcoeptlhaeteexwphoiscuhrewiclhlabmebeart.tacBheefdotroe tthhee esxtaprotosufrtehceheaxmpboesrurseo pthhaastet,heanniomsaelosfweialcl hbeanpilmaaceldeixntends sestrainers on 2 separate days for approximately 1S minutes each day to acclimate the animals to the restrainers E. Characterization of Chamber Atmosphere | 1. Test Substance Sampling and Analysis m`Tihneiamtmuomsopfhaeprpircocxoinmcaentterlayti6o0n-mofitneusttesiunbtsetrvaanlcsedwuirlilnbgeedaectheerxmpionseudreb.y gKrnavoiwmnetvriocluamnaelsysoifs ata cahparmeb-eweraitgmhoedspghlearssewfiiblelrbfieltderr.avThferfoilmtterhsewsiallmpbleiwnegipgohretdthornoaunghanaalfiylttiecracl baalsancste.haetTchtoenttfailiteners cwoenicgehnttsrawtililonbsebaausteodmaotnictahleldyitfrfaenrsefnecrereidn tporeC-IaTnAdDpSo,stw-hsiacmhplwiinlglfcialltecrulwaetiegthhtes cdhivaimdbeedbr ythe vsaomlpulmeeowifllchbaemcboenrtraotllmeodspahnedrreescaomrpdleeddb.yGCrIaTvAimDeSt.ric sample stat- and stop-fimes for cach 2. Particle Size Determination 2 `paSratmipclleesslteossdtehtearnmi1,ne3,paarntdic1le0suizmeddiiasmtertibeurt)iwoinl(lmabsetsamkeednioan anepreorcdwyeneeamkifcrdoimaemaetcehrteasntdcpheracmebnetr `with a Sierra Series 210 cyclone preseparator/Cascade impactor and Sierra series 110 constant flow air sampler. 3. Environmental Monitoring pCehrahmobuerraanidrfwliolwlwbiellmobneisteotraedtchoenbteigniunounsilnygowfitehacahcaelxipborsatuerdeBoroaockhsieMvaesast lFelaostw1C0onatirroclhlearn.ges Cthhearmmbomeertetre.mpeCrhaatumrbeewrilrlelbaetitvaerhguemteiddiatty22wi+ll3beCtaarngdetmeedaastur5e0d&w2it0h%aannOdmmeegaasuTrheedrwmiotchouaple Jhuummiodiwteyt-wbiulllbb/edrmyo-nbiutlobrreedsicsotnatnicneutoeumspleyrwaittuhrethdeetCeactmoirl.eAIinrhfalloawt,iotneTmopxeriactoulroegyanAdutreolmaatitveed Data Systemand recorded at 15-minute intervals during exposure. Chamber oxygen En  PIenrhlaoiroonocRtenpoeiateeAdciDdo:se Pharmacokinetic Stody i theRat DuPont12944 PR caonndcernetcroartdieodnawtillelabstettwaircgeetdeudrtiongbeeaacthleeaxsptos1u9r%e,. mIedaesaullrye,dtwheitchhaamBbieorsycsotnedmistiooxnsygweilnlabnealsyeztesro thhuamtitdeimtpyevraartiuarteiownislloubtesi2d0e-o2f4thCeasnedrahnugmeisdiatrye wciolmlmboen3l0y-7e0n%c.ounHtoewreevdedru,etteomptheeragteunreeraatnidon procedures used and the characteristicsofthe test substance itself. These variations are not erexspuelcttiengd ftorosmigvnairfiiactainotnlsy aifnfteecmtptehrearteusruel,tsreolftathiivse htuympieodiftsyt,udoyr.oxPyogteennticaolnltyenatdvweirllsebecfafedcdtrsessed in the final report F. Inhalation Exposure rTaotsdeaechtweillrtbhmeepeirxopnposeeerde(xnpoosseuroenllye)veflosrfoarstihngelme,a6i-nbsotuurdpye,rfiooudrtgoraonupaseroos3folomfatleheantedst3 female: substance. One test group will be exposed to an atmospheric concentration of|mg/m', the second test group will be exposed to an atmospheric concentration of 10 mg/m', the third test gbreoeuxppwoisleldbteoeaxirpoosnleyd. toBlaonoadtmwiolslphbeerciocllceocntceedntvriaattihoenotafil2v5eimng/pmr'i.o 1A0ceoxnptorsoulreg,raotupseofverraatlstwiimlel `aploliontws fdourrtiinmgeedxbpolsouordec,oallnedctaitosnse,veerxaplotsiumree psotiarnttswaifebredosstianggg,eraecdcolersdsitnhgatnoHamsikneultlesSOfPors.cacTho ainnihmaalla.tioAnpepxrpooxsiumraetefollylfoowuerdsbaympalpepsrowxiilmlabteeldyrasiwxnafdrdiotmioenaaclhbalnoiomdadlrdauwrsindgurtihnegstixheh2o4u-rhour rreeccoorvdesr.y pReartisowdi.llTbheesascarmipfliececdolfloelcltoiwoinnagntdheexfpionaslurbelotoidmecsolwliecltiboen.documented in the study PcloanscteunatrdaetriiovnedanfdrothmetrheesuwlhtoslceomblpoaordedsatmopplheasrmwialclokbienaentailcydzaetdabfyroLmCl-iMteSraftuorrePdFerOiAved oral pdolsaisnmgasctoundcieens.traTthieonesxpsoismuirleatlorevpellsassemlaecctoendcefnotrrtahteiomnasionbssteurdvyedwinllabperleevvieolussthsattudpyr.o)duTcehe exposure levels will be documented in the study records. Afextpeorstehde(enxopsoesounrley)lefvoerlsaa6r-ehoseulrepcteerdi,odf,ou5rdgaryosuppesrowf5eemka(lweeaenkden5dsfeexclmuadaetds)el,acoehrw3ilwlebeeks to an wahereonsolthoeftgehneetreasttiosnubssytsatnceem.isThteusretd oan. rTthitmeeoienfdneiancgghteixmpeoofsueraecwhilelxpboesudree wfililansbeethddeeftiinmeed as dtuhreitnigmbeotwhhtehnetthiemgeeintetraakteisofnosrytshteecmhiasmtbuemretdoorfef.acRhactosncweinltrbaeteixopno,asenddttohetthiemteesitt staukbesstafnocrethe cteasgtess.ubsTthaenceexptoosbuerpeupregreidodfwriolml tbheedcehfaimnbeedra.s tAhfeteprereiaocdhbeextpwoeseurnei,nirtaitastwiiolnlofbtehreefitrsutmeextpodosthuerier Eanxdpocsoumrpelesttairotntoifmtehsewilalstbeexsptoasgugreer.eTdhbeyc1o0n-tr3o0lmgirnouutpeosfbryatesxpwoisllurbeeceoxnpcoesnetdrattoioanigornoluyp. to ailnltohwe fsotrudbyloroecdocrdosl.lecAtsiionnttihmeep.ilTohtesstuadmyp,lbelcoooldlewcitlilobneancodlelexcptoesdurvieattihmeestawilivleibne. dBolcouomdenwitleldbe collected before and after the daily inhalation exposure period three days per week. Rats will be sacrificed following the final blood collection. =e IuPbesrlfauioornoRoecpaneotieAdcDiods:ePharmacokinetic StudyintheRt. G. Statistical Analysis Dupont 12944PR mExpoe se Comeniraion ompreolimyinarty eTesst EnvirDoinamental Dats None [asiipimtiscant or [saigniaficanat | Descriptivesaints e.g,meen, standarddeviation) Other methods will be usedifappropriate, at the timeofanalysis. The statistical methods used willbe described in the final report. SAFETY AND HOUSEKEEPING All chemicals used during this study wil be handled according to the procedures specified in the MSDS and disposedofaccording to the Stine-Haskell Waste Disposal Guidelines and the area Safety, Health and Environmental (SHE) manual. RECORDS AND SAMPLE STORAGE NSpeewcairmke,nDsel(iaawpeprlei,caobrlaet),IrronwMdoautnat,aainndRtehceofridnsalMraenpoargtewmielnltb,eWrieltamiinnegdtaotn,HaDseklealwlaLraeb.oratory, PROPOSED STUDY DATES Dateof Approval "Date Study Director signed Protocol Proposed Experimental Start April 28,2003 Proposed Experimental Termination: July 15,2003 Proposed Study Completion: December 31, 2003 REFERENCES 1. VDiasntdriebnutHieounv,eMle,taJbP.o,liKsums,liakinsd,EBl.iLm,inVaatnioRnaoffelPgehrefrlnu,orMo.oJc.taannodicPeAtcerisdoni,n MR.aEl.e (a1n9d9F1e)maTlies:sue Rats. J. Biochem. Toxicol. 6(2): 83-92. 2. DUnupPuobnltisHhaeskderlelpoLratb,oDruaPtoonrty-(72407033,). Perfluorooctanoic Acid: Toxicokinetics inthe Rat. 3. USS. EPA Good Laboratory Practice Standard, TSCA (40 CFR 792). (1989) 4. BHiacsgkeell,lLLBa.bor(a1to9r9y7.) Hazard Characterization for Human Health C8Exposure. DuPont = -_-- PEI-- ban RepeatedDosePharsscokineic Stdyi th Rat Dupont 12944 PR Toxicology, 7(1): 31-36. 5. Vanden Heuvel, J.P., Davis, J.W., Sommers, R., and Peterson, R.E. (1992). Renal Excretion ofPerfluorooctanoic Acid in Male Rats: Inhibitory Effect ofTestosterone. J Biochem 6. Calculation described in Sierra Instruments, Inc., Bulletin 7-79-219IM, Instruction Manual: Series 210 Ambient Cascade Impactors and Cyclone Preseparators. SIGNATURES `fWorrtIisesnueabnyd SAtpupdryoved Director: Paul M. Hinderliter, Ph.D. Research Toxicologist 22. fproe3 Date Approvedby: =. G-- -- GoWimsaD 22-APR-2003 Dw PrincipalResearchToxicologis andManager CC: MSHSSvBaoygiaaen,tHyA,SHKA.SKH,I HI MGLPKDeemonreed,y HBAASSKK.. HHII RAJJ BOa'rNieci,lH,AASSK.K.HIFl i SAAL GDainMantotne,oH, AASSKK..HI.HI. LIFS SFloorsdk,eyH,AHSAKS.KH,iHi 1GNMBuWriclhffoiredl,d,HAASSKK.,HIH.I =n | PROTOCOL AMENDMENT AmendmentNo: 1 Work Request No.: Service Code: Project Number: Proto] Tide: 14552 1017 DuPont-12944 Perfluorooctanoic Acid: Inhalation Repeated Dose Pharmacokinetic Study in the Rat DOCUMENTATION Changes to be made to existing protocol: . 1. Page 3, Test Substance, replacefirst sentence with: PFOA was obtained from Aldrich Chemicals (Milwaukee, Wisconsin) and assigned Haskell Laboratory Number 25811 upon receipt. 2. Page, D. Inhalation Exposure System, 1, Atmosphere Generation, replace first two `sentences with: , For this study, a 5% (weight/sweight) solution will be prepared by diluting the powdered test substance in deionized water. The solution will be titrated with a concentrated ammonium `hydroxide solution to achievea test substance solution pHofapproximately 6.0 to 8.0%. Cinhaaimrbweirthatamnoesbpulhiezreers. will be generated by aerosolizationofthe 5% test substance solution Rationale: The test substance (H-25811) is a free acid and is not as soluble in deionized water as initially anticipated. In ordertoget H-25811 to dissolve inwater,the pH mustbe adjusted to approximately 6.0 to 8.0. SIGNATURES o`Wiitemn and Approved Director: CC SMHSSBwoaglyunneiBlyASHKASHKI,HI OGLWKeJrompoend,y,EAASSKK,.IHI MP Delors, BASK. HI ttt ResMearHcnhdTeocriitceorl,ogPihs.tD. 28-Akpe--2003 Dew RAJJOBaericl,,AHSAKS.KH.lH.I SAAL DGiaMnaotn,o,AHSAKS.K.HIHI JP Slskey, HASK, Hi NLSMFoWridk,oHrAdS,KA.SHKI. H1 10 BurhfiAeSlK.dH,I -- ww 10 J PROTOCOL AMENDMENT -- AmendmentNo: 2 Work Request No.: 14552 Service Code: 1017 Project Number: ~~ DPeurPfolnuto-ro1o2c9t4a4noic Acid: Protocol Title: Inhalation Repeated Dose Pharmacokinetic StiunthdeRyat DOCUMENTATION Changes to be made to existing protocol: 1. Page, B. Test System, replace third bullet with: + weighed twice during the quarantine procedure, Rationale: Protocol 14552/1017 is a metabolic study, nita testofsub-acute toxicity ofthe. test substance. 2. Paged, B. Test System, last paragraph, first sentence, change "At the timeofdosing" to "At the timeof exposure". Rationale: To indicateproperterminology for an inhalation system. 3. Page, C. Animal Husbandry, 2. Environmental Conditions, change third sentence to: Alingihmta/dlarrkocoymcslew,ielxlcbeeptarotinfibclioaloldy ciolllluemcitniaotnedda(yfsluwohreesrceenltiglhitgshmtayyonbaentauprpnreodxoinmaatsen1e2e-dheodur up to one hour extra per day. : Rcaytciloentaoleb:egSitnucdoyllpeecrtsionngntehlemparey-enxepeodsutroeenbtleorotdhderaanwi.mal room before the endofthe dark. 4. Page 6, D. Inhalation Exposure System, 3. Exposure Mode, replace entire paragraph with: Dorurpilansgtiecxpcoysliunrdee,rsanwiimtahlscowniilclablenoisndeipviiedcueasl.lyTrheestrreaisnreadinienresiwtihlelr pbeerfinosreartteeddsitnationlaess steel `tphoelnyomseetohyflmeeatchhacarnyilmaatleefxatceenpdlastienwtohitchehewxilplosbueraetcthaacmhbeedrt.o tBheefeoxrpeotshuerestcarhtaomfbtehreseoxptohsautre. pchaacshe,daaynitmoaalcsclwiimlatbeetphleaacneidimanlrsestotatihneerresstornai2nesrse.paDrautreidnagyesxfpoorsuarpep,rotxheimaantiemlayls15wimlilnbuetes kept warm with heat lamp placed behind the inhalation system. Ralastoionneaelde:toTbheekerepsttwraairnemrdmuartiernigaltwhielelxbpeosduorceutmoenmitneidmiinztehpehsatrumdaycorkecionredtsi.cTdhieffaenriemnacless and to allow for efficient drawingofblood. - Tage 1012 i" . SIGNATURES `Written and Approved for Issue by Study Director: Protocol AmDeunPdmoenntt1N2o0.424 "PaliResMe.arHcihndTeorxlitceorl,ogPihs.tD. 23-, & BY CC: MSSHSwBaogydzaend,lyH,ASHKA,SHKI, HI GGLWKeJnepnseodny,,HAASSKK.,HHII MPDelorme,HASK, HI RAUJBOa'rNie,il,RAHSAKS,KH.HI I SAALGDaiMnaotne,d,BAHSAKS,K,HIHI JP Sloskey, HASK, Hl LMSMFoWridl,fBorAdS,KH.ASHKI, HI LDGHoBbuanr,cHhASfKi,RHeASIlK,dH,I J12 ---------------- | PROTOCOLAMENDMENT WAnoernkdRmeeqnuteNsot:Noi ServiceCode PrPortoojceolNuTmibee:r: 314552 D1u0P1o7nt1298 ePaearicornoRaopcestenAdcDoioid:ePharmacoSkiynnethteiRact DOCUMENTATION Changes tobemadetoexistingprotocol: 1. Amendment No. 1 tem#2,eave "A" romthesecondsee Ratonae; Typogspica er 2. age, . nbaaionBupa,addtheflowing th ndfhetidprs Rarteseatthsestncoafrafodtfihocsnsssedt.dyDaedpreenacdiaern,stcpaiotfnbihleosgsetxntodrtienhmg,HiwbitollerborirgGyivsaegnnolgrvopsersteoecxroandcmrieinsn.mTahye becchpeclkowyfu ioerldhtsetbe ouded te ol eportnlscond giant te valunion of dy. 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