Document NeQZBy1Qb5B1wKG3YBZ9M5Y6V

RGoo0.riBnokH7as54t5oo r7s4s ro ric 3301 Kim ld, Mion, bry2414471 608.241.7227 Fax AR226032\ CORNING Hazleton Sponsor: 3M St. Paul, Minnesota FINAL REPORT Study Title: Primary Dermal Irritation/Corrosion `Study of T-6684 in Rabbits (OECD Guidelines) Author: Steven M. Glaza Study Completion Date: January 10, 1997 Performing Laboratory: Corning Hazleton Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704 Laboratory Project Identification: CHW 61101150 Page 1 027 NNHEECEEIIMVEE, Shp AN 13a Re 005684 (COMPLIANCE STATEMENT Primary Dermal Iritation/Corrosion StudyofT-6684 in Rabbits (OECD Guidelines) CHW 61101150 `This study was conducted in accordance with the Organisation for Economic Cooperation and Development Principlesof Good Laboratory Practice, C(81)30(Final). Ne ee WN Steven M. Glaza, Study Director Acute Studies Coming Hazleton Inc. Noo Date | 2 005685 QUALITY ASSURANCE STATEMENT cv stionso `This rephaosbreetn reviewed by the Quality Assurance UnitofCorning Hazleton Inc., in accordance with the Organisation for Ecomonic Cooperation and Development (OECD) Principles conducted of Good Laboratory Practice, C(81)30(Final). The following. and findings reported to the Study Director and management. inspections were Inspection Dates From --To Phase Date Reported to StudyDirector Date Reported to Management 11/25/96 01/08/97 11/25/96 01/08/97 Dose Preparation Data/Report Review 11/25/96 01/08/97 11/25/96 01/08/97 LooboGoatid- Representative, Quality Assurance Unit 1-10-97 Date 3 C05686 STUDY IDENTIFICATION CHW 61101150 Primary Dermal Iritation/Corrosion StudyofT-6684 in Rabbits (OECD Guidelines) Test Material T6684 Sponsor 3M Toxicology Service Medical Department 3M Center, Bldg. 220-2E-02 P.0. Box 33220 St. Paul, MN 55133-3220 `Sponsor's Representative Roger G. Perkins 3M Toxicology Service Medical Department 3M Center, Bldg. 220-2E-02 P.0. Box 33220 St. Paul, MN 55133-3220 (612) 736-7428 Study Director Study Location Study Timetable Study Initiation Date Experimental (In-lfe) Start Date: In-life End Date Experimental Termination Date: Study Completion Date Steven M. Glaza Corning Hazleton Inc. P.0. Box 7545 Madison, WI 53707-7545 (608) 241-7292 Coming Hazleton Inc. 3301 Kinsman Boulevard Madison, WI 53704 November 22, 1996 November 25, 1996 December 9, 1996 December 9, 1996 January 10, 1997 4 005687 Acute Studies Steven M. Glaza SMtaundaygeDirrector Steven R. Sorenson Study Coordinator Jeffrey B. Hicks In-life Supervisor Rose M. Bridge Administrative Supervisor Toxicology Support Kathy Myers Manager Calvin L. Horton Supervisor KEY PERSONNEL Quality Assurance Sherry R. W. Petsel Manager cCHiW 6e11011s50 Laboratory Animal Medicine Cindy J. Cary, DVM Diplomate, ACLAM Supervisor 5 G0s5688 CONTENTS CHW 61101150 COMPLIANCE STATEMENT... d QUALITY ASSURANCE STATEMENT ccs3 STUDY IDENTIFICATION ccs KEY PERSONNEL vc. sss sins OBIECTIVE cucsmmmmmmmmmsssssmomsmmses sss TEST MATERIAL covssssssusssssmmmmmmnosssmsssossmmnl SHOT AA REACTION vrs Sty PIECAUIONS..o.cvrssssssssmssssssssssssnd TEST SYSTEM summonses TUSSHRcsmmsm------ I---- A A ------ Animal Selection and PreparationOfEXPOSUIEATCA resid JuStFiCation fOr Species Selection ....vmnesmmmmemsmnsmsmm1n0 BROCEDUBES cssmmmmimnmmisssmsmsmmmimmmmsssomssmemmmmmmdlly 'PrEPATation OfTestMAEIial vss 10 THR inpimiss------------------------g Reason for Route OfAMIBISHTBHON vss10 OUI commas ------ 0 I ---- Locationof Raw Data, Records, and Final REPOrt......oesrvisrreel RESULTS/DISCUSSION cocvmmssummmsssssmmmmsmmmsmmmsmansonsdL 6 LU5689 -_-- cCHHWWe6n11o01u1s50 TABLE 1 2 AInvdeirvaigdueaPlrDiemramraylDeIrTmHaBlOINTHSaCtOiTONSSr COTES .e vrvs ret nems nre|143. 3 Individual Body WEIhtS(2) unrrssesneen 14 APPENDIX a conse15 1 Protocol AMERAMENt NO. Lessin21 7 0605690 -_-- cCHHwWen61o10n11s5o0 OBJECTIVE `The objectiveofthis study was to assess the relative level ofprimary skin initation/corrosion ofa test material on rabbits under semioceluded conditions." All procedures used in this study were in compliance with the Animal Welfare Act Regulations. In the opinionofthe Sponsorand study director, the study did not unnecessarily duplicate any previous work. All procedural times presented in this report fall within the acceptable ranges as specified in the Wisconsin facility of Corning Hazleton Inc. (CHW) Standard Operating Procedure (SOF). TEST MATERIAL Identification `The test material was identified as T-6684 and described as an off-white liquid. Purity and Stability `The Sponsorassumes responsibility for purity and stability determinations (including `under test conditions). Storage and Retention `Thetestmaterial wasstoredatroomtemperature.Anyunutesstmaeterdialwillbe retumed to the Spoafntersissouanrceofthefinalreport according to CHW SOP. Safety Precautions The test material handling procedures were according to CHW SOPsand policies. 8 005691 - 0000000 chcwa0 ewn61o1u01s15m0 TEST SYSTEM Test Animal Adult albino rabbits ofthe Hra:(NZW)SPF strain were procured from HRP, Inc., Kalamazoo,Michiganon October 30, 1996. Housing After receipt, the animals were acclimatedfor a period ofat least 7 days. During acclimation and throughout the study, the animals were: individually housed in stainless steel cages. Environmental controlsfor theanimalroom were settomaintaian temperatureof 19to 23C, a relative humidityof 50% 20%, and a 12-hour light/ 12-hour dark lighting cycle. In cases where variations from these conditions existed, they `were documented and considered to have hadno adverse effectonthe study outcome. `Animal Diet The animals were provided access to waterad libitum and a measured amount of Laboratory Rabbit Diet HF #5326, PMI Feeds, Inc. The feed is routinely analyzed by the `manufacturer for nutritional components and environmental contaminants. Samples of the water are periodically analyzed. There were no known contaminanitns the feed or `water at levels that could be expected to interfere with or affect the resultsofthe study. Animal Selection and Preparation of Exposure Area "Two male and one female healthy, acclimated rabbits, weighing from 2,662 10 2,937 g. `and approximately 14 to 18 weeks ofage,were selected at randomandidentified by `animal number and correspondingeartag. Onthe day before treatment, the back and/or flanks ofeach animal were clipped fr ofhe aireto obtain one unblemished skin site. The `animals were clipped as needed throughout the study. 005687 05692 -_-- cHCHwWen61o10u11s50 Justification for Species Selection Historically, the New Zealand White albino rabbit has been the animalofchoice for evaluating the effect ofchemicals on the skin. PROCEDURES Preparationof Test Material The test material was administered as received. The pHofthe test material was not able 10 be determined. Treatment `Theunditlesutmtateeriadlwasappliedtothe intact skin site on cach animal's back (approximate exposure areaof 6.25 cm') intheamountof0.5 mL.Thearea of `application was covered with an 8-ply 2.5-cm x 2.5-cm gauze patch secured with paper tape, loosely overwrapped with Saran Wrap, and secured with Elastoplast to provide a semiocclusive dressing. . At the endofthe 4-hour exposure period, the patches were removed and the test sites `were washed using tap water and disposable paper towels. The test material was removed from the test ites as thoroughly as possible without imitating the skin. Reason for RouteofAdministration Historically, the dermalroutehas been the routeofchoicebasedon the method of Draize.* Observations `Thirty minutesafter removalofthe test material, the degree of erythema and edema at each test ste was read according to the Draize technique (recorded as the 4-hour score). Subsequent examinations were made at 24, 48, 72, 96 hours and Days 7 and 14. The untreated skinofeach animal was used for comparison. 10 U5693 -_-- cucwHw n61o10n11s50 Animals were weighed before test material administration and at weekly intervals throughout the study. Termination At terminationofthe in-ife phase, al animalswerecuthanized and discarded. Statistical Analyses No statistical analyses were required by the protocol. Location ofRaw Dats, Records, and Final Report `Therawdata,records,andanoriginalsignedcopy ofthefinalreportwillberetainedin the archives ofCHW in accordance with CHW SOP. RESULTS/DISCUSSION Individual dermal irritation scoresarepreseinntTaeblde 1. Average primary dermal imitation scores and individual body weights arein Tables 2 and 3, respectively. `Applicationof T-6684 to the skin ofrabbits under 4-hour semioceluded conditions resulted in well-defined erythema and slight to moderate edema reactions. Desquamation and fissuring were also observed. All iitation cleared by the Day 14 observation. SIGNATURE Steven M. Glaza . Study Director Acute Studies Date 10-4) (Lig9q 1 -_ ccaawweeiionn15s0 REFERENCES 1. "Acute Dermal Irritation/Corrosion," Organisatiforn Economic Cooperation and `Development Guidelinesfor TestingofChemicals, Section 4, Health Effects, November 404, Paris Cedex (July 17, 1992). 2. Draize, J. H., "Primary Irritationofthe Skin," In: Appraisalof the Safety of Chemicals in Foods, Drugs, and Cosmetics - Dermal Toxicity, Associationof Food `and Drug Officialsofthe U.S., pp. 46-47 (1959). 005695 12 Table 1 Individual Dermal Irritation Scores CHW 61101150 Animal Hour Number ~ 424 48 739 Erythema F697 2 1 1 1 2 F61198 2 2 2 2 2 F619 2 2 2 2 2 Edema F617 3 11 12 F698 2 1 1 1 F199 3 2 2 2 2 @ Desquamaton f Fissuring. Day 714 oo 20 "0 oo 10 20 -_ 13 LU5G696 Table 2 Average Primary Dermal Irritation Scores servation Period Average Score 4 Hour 47 24 Hour 30 48 Hour 30 72 Hour 30 96 Hour 37 Day7 27 Day 14 00 +The average primary dermal imitation score is the total dermal iritation score for all the `animals (erythema and edema) divided by the numberoftest sites (3) at cach observation period. CHW 61101150 "Animal Number F697 F6l198 F619 Table3 Individual Body Weights (g) Sex Predose Day 7 TT M 2,937 3,036 3,137 F 2,662 2,836 2,919 M 2,755 2,906 2,943 605697 14 - APPENDIX Protocol TP2071 Protocol Amendment No. 1 cCaHwW 61101150 1s 005698 caw ionso TSeample Subtmietntal Form nats pr RGR,SPeO esfaeseow fSernges) ECoHWSwdNoy. U LeedSUI 5301 KinwrmaineBouvard Snmavy,ROGER C Phoeint Company: eset /0fe NumborolReporisReq3 uied: FulGLPCompliance: TXK.t Yes _ _e_pa_((F s21cCOaFRo8A8c)ran) KX EOPEAD(FFRA--OC1F80R) MvAoFw F `PSaomprleiNOanmes:to: [= Lagos - GC ~66 6 SToecamtailmaanrg ansa Horan(chin arc st or) w0lS7n7r5,75,AY0or TSounmgaDripstrX._orotecrrtpemrmoerhtoommabgeaoaebcabnlny --ZwYok St -- rr ern ia-- 3-350 el m------------ mp.": T Retigeratad. + e ratedot Sn rwr reri tn i enthri AcuteoatTotty n Rats pial Train COuotr:en a se vatdse aatssn h int ptatdnree StSaryoy 4osS ce 5Y0510 -- IPAS Pramto-- eaaa-- 2 at-- esa s XXTP20e 68Oo ECD screent :SMSFe 5t .0T9%)Tuo sToYgg ye aon ATteTDermal Tricine h fIcRimSmtEn m pek oe im e me estwans rinmminso aveysuseeydzoae ra20 Ri lEae me, SpToos nT OECDwat na BeT e 4Soar c .PS p m_ eme nt : ev -- eree SC es oyu ma in nersas anan 5 taNo pA aoA e eo Voom 605699 16 - @HAZLETON HS SO NSN ccowwseionnws st. r`aSpiownshoor:nors marca ros Primary Derma raSttuodyTGiotrlaes:ton Study i ktbits ' (OECD Guide] ines) ur in aneDa1t,e:19m dPsietroeftnoo,rtnmieWnvsgitsLosarcbsSonirtsna,toorornyyc:t. LabPorofreca tIdetntio ficr atiy on: Wl Luouss 605700 17 cwenoniso wPaat sor wenTIFICATIOn Prisary Dermal Trritation/Goreaston Study Tn Rabbits ~ (OECD Guide] ines) wi bo. Test Material sponsor Sponsor's Representative study Director sty Location PrFoBBpppIoeesTrretidezRaesetnpuntgotyraatl oSTTeiaeemnsittnaavbtiliteoen ste cisnss (see same sutnitea ore) JTSroshtcoatons services Jon L. steer, mo T2SGo2ix0t5aco)EtRonT.y 0aiEseerCviaincteeesr o Rsteevtenrs W.wiGzltaosnsstn, Toc. d60i8a)nZ,in7UF 8"s3707.7545 SaB5al0le2attPoohnnaWhrio:srcsoAnvseinnu,e Tn. Hadise, Wi- S354 SVseeetoekkk ooofff 112313--11029-59590 18 605701 CHW 61101150 PPa2g0e713 1. Psrtiumdayry Dermal Irritation/Corroston Study fn Rabbits (OECD Guidelines) 2. PTuorpaossseess the relative level of primary skin frritation/corrosion of a test material on rabbits under semfoccluded conditions 3. RISES, ted tn accordance with the folloving Good Laboratory Practice Regulations/Standards/Guiindees:l FaCionndutct as da oHomnreegulated Study [1 4400 CCIFRR 716902 ((EEPPAA--TFSICFAR)A) {7 lcoltiotincat(tfoinnahlo). (sGEaCsD,) august 10, 1984 (dpunese WHEE) 1 NNoottiiffiiccaattiioonn NNoo.. 381730,, MOacrtcohber31,, 1916328,5 a(nJdapaasnesaemeOndHed) by AdWierlefcaptrroeorc,AecdtuthreeRsegsutilunadtytihoidnsose.sprontoItoncotulnhneeacroeepsisniainornicloyoafpdlutfphalenicceSaptwoeintshaonrythaenpdrAesnvitimuoadl:y 4. QFuoarlirteyguAlsastuerdanstcuedfes, the protocol, study conduct, and the final wrietphortHazwlielltonbeWaiusdciotnesdinby(HNtIh)e and pol fetes. SQtuaanldiairydAsOspuerraanticnegUPnriotceidnuraecscor(dSaOPnsc)e 5. lestMaterial A. Jdentification (See sample submittal form) 8. Ph(ySseeicsaalmpelescsruibatiittoanl form) C. PThe uSpaarnnsdoriStaastbsiulsyietsyresponsibility for purity and stability dLeestternmitneartiiaoln/sva(hiincclleudminigxtuunrdeesr)te(sitf caopnpdliitciaobnlse)). forSasples of cwio1n1cenbterattaikoenn,'besfoolruebilaidtuyi,nishtorsaotgieonneit{yf,reaqnduesstteadbilbiytytheanalyses Sapfotnesrore.xperTihmeesnetaslamptleersmin(aitfiotnakefno)r wpiolslsibbelesaenntalytsoist.he Sponsor C05 702 19 -_-- cCHHWW6l11o01u1s50 PPa2g0e714 0. S(tSoeeragseample subaitta) form) E ShavHe rEesEervTe Ssamptlheasn 4resteaoinkesd.10 experimental duration wit not RLeasekrevens"atmhipslesst)udyof1e5acmohrebattchha/nTo4tweoefkstesitn emxapteerrifsaelntwailll be Tfhreeezteerstsmetatetroiamlainrteasienrvea gir Ji Sop. The Sponsor usteasmbppelereatwiuclrolentabofectebsdteolarofewtde0raCt10fINoyIrouf1rn0syaefaorrs dLiasbpoorsaitotriyonPrianctaiccceosr.dance with the appropriate. regulatory Good F. RAentyenutnuisoend test mater(al the final report, unless {di1r1ectbeeddiostchaerrdweisdeabfyterthefsSspuoannscoer.of 6. SaRsferteyquPirreecdaubtyioWnHsI SOPs and policies 6. Excerisental Desian A dnimals (0) SRoaebcbittes 2) S Straio/E Source S eton research products, Tc. (3) fIaauenatittiation (4) M200e3a.lt5Isnkigthtattion (5) offuasnaynedseSxrex (6) IIdnednitviifduiaclatinounmbered ear tag. 005703 - 20 -_-- cHCWHWe6n1O10H11S50 PPa2g0e715 (1) Husbandry (a) HIonudsiivindgually, in screen-bottom stainless steel cages (heavy gauge]. O (b) E Food red amount or High Fiber Rabbit Cho" #5326 be{nyPvuitrrhioennasmeaHnnitlualflsa,cctouInrntcea.rm)i.fnoarntnsTuhe.trfiotoidoniasl rocuotmiponneelnytsanaanldy.zed (c) aatteetrr uarne arnaeymzeady bwyte4mtifcorsfyosrtae)n.disSsaomlpvleeds sooflitdhse, hfaorrdnseeslse,cteadndelspeeecnitfsi,edhmeiacvryobmieotlaolgs,ical content and organophosphates, and' chlorinated hydracarbons. ((@) SCoEntamEinaSnts ory contantants fn the fad or vater that would interfere with this study. (e) EEsnenvtviirrtooonnsmseaenintntatlainconatrtoelssperfaotrurteheofani1s9altoro23omC,wilal be Treilgahtti/v1e2-hhouuariddiatrykocfyc5l0e%.420%, and a 12-hour 0 f) fAccleisamtiondays. (8) SBadaeseqeudaltoen ehnoeufascTlbetetrhstoaifnAdneoixbmtoardnalyswaeniigehatlsawciclolrdbiengputrochHaMIsedSOPsso. thaAtn no antaal in obviously poor health fs placed on test. (9) tHhiestoanriiscaalllyo,f tchheofcNeewfZoeraelvaanlduaWthiintge athlebienfofercatbbiotf has been chenicals on the skin. 2 C85704 -_ chCwHWe61n10o11u50m TFieoeenyd 5. bMadsneintstration ) TGaphnnedtjrtharereeGaFta1my2renonkBtsefafosoEirfxtteoeeosaesicushictleoaimnpairmtbneaeealrifaMnls1p1eacdtbseoidnlsfitorpfapteiidnotneF,rrfeettrhoeinfgbhaecikr. SuleseeebdeeOdFn,dShrryTorovfgihaohudetsst,hnetomrsatlduedeyh.Tehte atnaitmatweeWtITrebceicuheippeed as 0) pAotsseinistration @ mCtGBahegtTefpeorrRrmieaoattleaerdivimaiitllnelinusitbtrSe]aetspiboaooelfntdlee)oTdtfaelrto1ohsiaiqtntsueihitdedah{t(niTe1asctlkeptmoe,asstieabrBlineae)lSa:sreeacatm`hoToehroupnotHtfesotoff sdsiionodsilicisldhtusaai,rneged"ed.1"d1w'ii3tnThtT'ois0a3.us5tab%dlei,ssdak,ietrhnehe3e1tdest`tAeAsdemtaraiotmnseoairltsietarmeliriaetldWerIi3W3aItg}s3obw}ainpiqpultidb:eed Se2Th1ire5ht-oCaSarceiGseuauotdzfteeaepprepeilciithctnaidtsniegloc.knusrsemodp1tWaistibthe!pcnaoLvEvaTeeprreedttaowpeipthrhaoonv&dibdes2ev.eC5sruaecreraepxpsed airing the hour aplication period. ) R CehaoticeenfboA arseRdouotneR tohfe MedtshionstTsUotfrEaDtrNiaEoinzeb:een the route of (4) R Asaafttteeee rrriatSlm ohaedf1aTo 1rehsoatv unbMresasrpta epoersfraoil pvearexlipdaotsae5uresS,ohlovrtehoneutghptlaythchaeessepaasSnsdriHbtCieRstLuisningthe C. ObservoafAtniimoalns 1) R4edLRceoaohppdortriuehonrsesgtoDosacrfsfoairiecDezlre.eyyrtm3htaTee0lhscesahInirina{rqniniutdttaeeacsdtt(eiaAmosftsknttiaencr1hTsar)feenstbeoxevc1i)hanvgaaatnnptudaentsicr]eheedcswo,isridc]ectdahresdaesirnegThe 5SIE5pP1ro%vTISoGamteiClonyon21t45r,ap.r49e,seSnuatbndseats1u2ethnhetourr7se3s-dhaio1nuLgresFswpriaaTtmlcihmbtreieomtnaa,vkeern- st HaodudristioannadlatahDsaeyrssat7,ion1s,ialn)d 2b1e,moadreun3ti1speprToxidsreuiiiealtyio9n6 C05705 22 -_ chcawwesnioounss Tpoeodn] hna1ys8 dcGiflreeatcrhetedis.oentoiBefasstehdpeoionnSttsut,dhyetdhlieervaesclthuadonyf. miuryritbaetitoonrtombssteernvedatat : @) ote detonts ) Jhuesrteabfetfeorre (tsheesnt mFaPtIeIrGiAaSlIEa)d:afnistration and weekly 0. PAaarbtybhreoSvlaiotastyieed doryaicndg SIT brat" ndAeucrriTongpsyTthaeamrsitpnua.dytiw1oTn) danbgeesSsuhdeswcstvToevdmYeto aines Sedxaipesarcriaifrnrdecenedtdan]adndphoSa'srtes{,esaa`rvsieuerslviwviTngbaenimSaalvsed.KIALbeLedreesitnoertaitoendoffotbhee E. oH es Statistica)Analyses are requires. n SEBEL report tctudig those tems std brow iT be submited: scsrcirpipttiioonn ooff tthhee tLeesit mSatteerni) PGTDraieottsceucesTrdaiutporltfeoisnopneorfimIedrrniytaattloixoifncttdeefeatfttiaicotns and termination other than derma frritation 5 aSfcaaccethpfetLaantceeaaoeufdtihtbeingeFinhac e] sretpuot dryt.durWihnEegn1Lt5hepFroagr)essrepaonrdtbe1t.fororeepleted, TS1o1taianriegdinTanlthpeapearrcdhiavae,s oIfncWlHuIdisngictohrogsienfienis )11S50c5e:d baton oil) be DBTorsohetoecporlecpaaarnradteipsornotorceoclordasmendments Goodsytvaemrionnitsstration pSFtniuantdoaoyuiFcncoaorlgtreobpepaotonhrdeielethonygnocsisynaresciogrecandrsesd((icIfFopa)pplaipchafbclaeb)e) 05706 23 CHW 61101150 PP2ag0e718 Tnohte. fbeolalrocwhiinvgedsuwpiptohrttihneg rsetcuodrydsdatwai.ll be retatned at INI but will AManttear.lraneacleyfsipst'/arcecclor{dnsation records ARenfirsiager`raotooartaenmdperfarteeuzreerantdespheurmaitduirtey rreeccoorrddss G05707 2% - OO@O0O0O0O0O0@0@0@0@0@0@0c@hcaw0wes@iu0onn@ss TTaraeo'ns oTocoL epRONAL r SFTonfs eRel rrerttLa.7Ct0ivetl l SteveNn eeGamW, Hcaiztlse2toTnToWrriistcceonsin, Inc. TGReUlcrtTetelHannReWuitrsacnoncSseinU.ninSte.elon (TP2071.34) g = 2g x rx we rots, o oe pfes 005703 25 - 00000c0 Hawwe1n10o1n15s0 Attachaent 1 PrimaryODrermtal aIrriTteatcihoineS)coring Scale (1) Erythems and Eschar Formation HBVoeeedraTytHthEeRmiEnaedecryvitnrmesm(arty perceptive gfHoaordemerarstaitoeSnrto(aIsnmejuvreir(eeEseslitnytThdaeeipstnahe)) to high eschar Highest possible erythens score @ tem Formation trSoHysEteSmelsdtemao(easedaarrervehp)edreFtiinevdn: by SedHxeaetvdfeeeinrrndeaiittneecgderdebaeaeinyssoi(nnrd{gai)rsaaertdeeadapopfwrpoerxxoimxpatotmesalety]ely m1nmo)nd Highest possible edema score PTagree1n0 i0:: ` 0i i2 ` ` 2% GO.5709 CHW 61101150 oH lo. _Guiqugs PROTOCOL AMENDMENTS Aoendent No. _I__ Effective _Nsve2n 2,s/9c 9ee Portion of Protocol Being Modified: __Apolicable sections of the orotoco |[ReCasoaornnndfiotnorgHMroaedfzillFeeictctoatnaiiocnnoc:r.pT(aorOyiWd)nea.nmteriefcpyhlatanhcgeeewlhforecoranetviHeoarnrlawephtpeolrniecWtaihbseclosenttshuiedn'y,fwoIilnllclobi(enHgAccIo)hndaiuoocstesd|| |ModificatM ion: __e ____b coS3r0n1toRiae ntsansalnetBoonuw Tteovca,rd.or m) eam|| FRPP IWW3 { woos) -- -- 05710 - 27