Document 9JBw3VN8KdNYnJD6Yz59VzvN6

[---- Coming Hazleton Inc. Fan EO. Box 7545 DSens 350s1 yans Bo, dion, 1 5704 Madison, WI 53707-7545 D60el8iv2e4r1ie4s:4731301 K6in0s8m.2a4n1.B7lv2d2.7, MFaaxdison, WI 53704 608.241.4471 608.241.7227 Fax CCOORRNNIINNGG HHaazzlleettoonn Sponsor: Sponsor: nM SStt.. PPaauull,, MMiinnnneessoottaa FINAL REPORT FINAL REPORT (om nn oo, sb SEP 09 fg | I\, SEP09 1w9i98,) No, SSttuuddyy TTiittllee:: PPrrii`mmSataurrdyyyoEBfyyeeTI-Ir6ar5itt6ai4tioonnn/CRCaoobrrbrriootsssiioonn Study of T-6564 in Rabbits ((OOEECCDD GGuuiiddeelliinneess)) Author: Author: StevenM. Gla Steven M. Glaza Study Completion Date: Study Completion Date: SSeepptteemmbbeerr 55,, 11999966 Performing Laboratory: Performing Laboratory: 33CC0oo1rmnKiiinnnggsHHmaaaznzleBotoounnleIInvcac.rd Ma3d3i0s1oKn,inWsimsacnonBsoiunle5v3a7r0d4 Madison, Wisconsin 53704 Laboratory Project dentfcaton: Laboratory Project Identification: CCHHWW G6o0s5o0s4s577s4 PPaaggee 1looff3311 22880099..00000011 Exhibit 2809 EEE ons 3MA10006895 2 2 CCOOMMPPLLIIAANNCCEE SSTTAATTEEMMEENNTT PPrriiSmmtaaurrdyyyEEoyyfeeTI-Iri6rt5ita6at4tiiooinnn//RCCaoobrrbrriootsssiioonn Stud((yOOEoEfCCTDD-6GG5uu6iid4deelinliinnReesas)b) bits cu susoisns CHW60504574 "TaTnhhdiissDssettvuueddlyyowwpamasesncctoonnPddruiuncccttieepddleiisnnoaafccGccooorrodddaannLccaeebwowriitathhtottrhhyee POOrrargcgataninicises,aattCii(oo8nn1)ff3oo0rr(EFEiccnooannl)oo,mmiicc CCooooppeerraattiioonn and Development Principles of Good Laboratory Practice, C(81)30(Final). Yo StSSetteuvvdeeynnDMMir..ecGGtlloaarzzaa `ASACctcuouudmttiyeenDSSgttiuuHrdeadiczieetlosserton [nc Coming Hazleton Inc. Woe ss DDaattee 22880099..00000022 33MMAA1100000056889966 5 cow awsoisny 3 CHW60504574 QQUUAALLIITTYY AASSSSUURRAANNCCEE SSTTAATTEEMMEENNTT T"aTchhciisosrrrdeeappnoocrrtethhwaaisstbhbeeteehnenrOreervvgiaieenwwiseeaddtibboyynttfhhoeer QQEucuaoalnliitotyymiAAcssssCuuorroaapnneccreeatUUinnoiinttooafnfdCCooDrmerviiennlggoHHpamazezlnleetttoo(nnOIEInnCccD.,,)iinn PaPcrcoriicnnnodccruiidppcallteenesscdoeofafwnGGdiotohfooitdndhdeiLLnaOagbbsrogorrareaanpttiooosrrratyyteiodPPnrrtaaofccotttirihccEeee,c,SotCCnu((o8d81ym1))D3i3c0i0(rCF(eFiconitonaopalrel))a.r.antdTTiohhmneaenaffanoogdllleloDmoweweniivntneg.gloiinpnsmsppeeencctttiio(oOnnssEwwCeDerr)ee conducted and findings reported to the Study Director and management. IInnssppeeccttiioonn DDaatteess Ffroomm 000966///202828//199966 09/02/96 TToo PhPahassee 000696///220882///999666 DDDaootssaeeRPPerrpeeoppraartraaRttiieoovnniew 09/02/96 Data/Report Review DDaatt1ee0RRSetepupodoryrtteedd Date to tDDoiirrSeetccuttdooyrr __ MMaanDnaaagtgeeemmtoeenmt 000606//22808/39996 000966//220838/79969 09/03/96 09/03/96 A 4x Z RReepprreesseennf(aattii,v~ee,, QQuuaalliitt~y AAssssuurraannccee UUnniitt 7556 DDaattee 22880099..00000033 33MMAA1100000086885977 Bp gp 4 CHW60504574 STUDY IDENTIFICATION STUDY IDENTIFICATION Studyof T-6564 in Rabbits PPrriimmaarryy EEyyee IIrrrriitatatitoinon/C/Coorrrroossiioonn Study ofT-6564 in Rabbits ((OOEECCDD GGuuiiddeelliinneess)) TTeesstt MMataeterfiiaall SSppoonnssoorr Sponsor's Representative S ponsor' s Representative SSttuuddyy DDiirreeccttoorr SSttuuddyy LLooccaattiioonn SSttSuutdduyydTTyiiImmneietttaiaabbtllieeon Date EEISxntxupipedferyeriiImmEneneintdntiataaDtlilaotI(nIenn-D-ilaiffteee)) SSttaarrtt DDaattee IEESnxtx-pupleidefryeriimCEmoenenmdntptalDalelatTTtieeeorrnmmiDinnaaattteiioonn Date: Date Study Completion Date TT6-6556614 3aMM `TTooMxxeiicdcoiolclooagglyyDSSeeeprravvriitccmeeent Medical Department 3P3M.MC0e.nCBteoenxtre,r3,3BB2l2ldd0gg.. 222200--22EE--0022 PSSt.tO..PP.aaBuulol,,xMM3N3N2255055113333--33222200 RRMooggeerr GG.. PPeerrkkiinnss,, PPhHDD T3ToMoxxiiccoollooggyy SSeerrvviiccee 3M`MMCeeeddniitcceaarll,DDBeeipdpasa,rrttm2me2en0nt-t 2602 P3P.M.O0..CBBeomoxxer33,33B22l22d00g. 220-2E-02 612) 753322 SSt.t. PPaauull,, MMNN 5555113333--33222200 (612) 733-3222 SCStoteervvneeinnngMM.H.aGGzlaleaztzaaon Inc. PPMC.a.oOOd.mi. siBBnoogno,xxH7W7a55Iz44le55t5o3n70In7c-.7545 M(6a0d8)iso2n4,1-W72I 9253707-7545 (608) 241-7292 CCoommiinngg HHaazzlleettoonn IInncc.. 3M3a33d00i11sKKonii,nnssWmmIaann 5BB3oo7uu0ll4eevvaarrdd Madison, WI 53704 JJJuuunnneee 222500,,,111999999666 JJJJuuuulln~yye22225558,,,,1119199999996666 JSSueep~ptte2emm5b,b1ee9rr9556,,11999966 22880099..00000044 3SMMAA1100000056089988 AAccuuttee SSttuuddiieess SSSttteeuvvdeeynnDMMi.r.esGGtlloaarzzaa Manager Study Director Manager SSSttteeuvvdeeynnCRRo.o. rSSdooirrneeanntssooornn Study Coordinator JJIeenffdflriieeeyySBBu..peHHriivccikksssor In-life Supervisor RRAdoomssieeniMMs.t.rBBartriiiddvgegeeSupervisor Administrative Supervisor TTooxxiiccoollooggyy SSuuppppoorrtt KKMaaatnthhayygeMMryyeerrss Manager CSCaualplvevirinnviLLs..orHHoorrttoonn Supervisor 5 s KKEEYY PPEERRSSOONNNNEELL cw cosnasta CHW60504574 QQuuaalilittyy AAssssuurraannccee Sherry R. W. Petsel Manager Sherry R. Manager W. Petsel LLaabboorraattoorryy AAnniimmaall M Meeddiicciinnee CCDiiipnnlddoyymJaJ..teCC,aarrAyy,C, DDLVVAMMM. DSSuuipppeleorrvmviiasstooerr, ACLAM 22880099..00000055 33MMAA1100000056889999 56 CCOONNTTEENNTTSS ciweososny CHW60504574 CCOOMMPPLLIIAANNCCEE SSTTAATTEEMMEENNTT ........................................... 22 QQUUAALLIITTYY AASSSSUURRAANNCCEE SSTTAATTEEMMEENNTT oo ................................... 33 SSTTUUDDYY IIDDEENNTTIIFFIICCAATTIIOONN . ............................................. 44 KKEEYY PPEERRSSOONNNNEELL ................................................... 5s OOBJBEJECCTTIIVVEE . . ......................................................... 38 TEST MATERIAL. 3 TEST MATERIAL .................................................... 8 Identification . 3 Identification ....................................................... 8 Purity and Stability 8 Purity and Stability .................................................. 8 Storage and Retention 8 Storage and Retention ................................................ 8 Safety Precautions 8 Safety Precautions ................................................... 8 TEST SYSTEM 9 TEST SYSTEM ...................................................... 9 Test Animal... a. 9 Test Animal ........................................................ 9 Housing Housing .......................................................... 9 Animal Diet... 0 Animal Diet ........................................................ 9 Animal Selection ? Animal Selection .................................................... 9 Justification for Species Selection 9 Justification for Species Selection ....................................... 9 PPRRPOOrCeCpEEaDrDaUUtiRRoEnEoSSfT.e.s.t..M.a.te.r.i.al........Lo ....................Lo ................ 111000 Treatment Preparation of Test Material .......................................... Treatment ........................................................ 111000 ORRbeesaaessroovnnatffiooorrnRRsoouutteeooffAAdmdimniinsitsrtraattiioonn .................................... 111000 Termination Observationg ...................................................... Termination ....................................................... 111000 SLStotaacttaiiststtiiioccnaaoll fAAnRnaaallyywsseeDssata.,..Re.c.o.r.d.s.,.a.n.d.F.i.n.al.. .R.ep.o.r.t........................... 1n100 Location of Raw Data, Records, and Final Report .......................... 11 RREESSUULLTTSS//DDIISSCCUUSSSSIIOONN .............................................. 1i1 SIGNATURE... SIGNATURE ....................................................... 1n1 RREEFFEERREENNCCEESS Ln ...................................................... 1n1 22880099..00000066 33MMAA110000006690000 1 cw s0ss74 7 CHW60504574 TTAABBLLEE 211 IAAnvvdeiervraaidggueealPPrrEiiymmeaarrIyyriEEtyyateeioIIrnrrriiSttcaaottirioeonns SSccoorreess ................................ 11322 3423 ISISnnooddddiiiivvuiiumddmuuaaFFlllluuEBoooyrrdeeeyssIccrWeeriieitnniagtEEihoxxtanasmmSi(nci5nao)atrteiisoonnss........................................................................ 1171378 4 Individual Body Weights (g) ........................................ 18 APPENDIX 1 APPENDIX ......................................................... 19 Protocol 20 Protocol ......................................................... 20 Protocol Amendment No. 1 31 Protocol Amendment No. 1 ........................................... 31 22880099..00000077 33MMAA1100000066590011 5 8 OBJECTIVE OBJECTIVE ciwensoisn CHW60504574 T"Thhee oobbjjeeccttiivvee oofftthhiss ssttuuddyy wwaass ttoo aasssseessss tthhe rreellaattiivvee lleevveellooffiirrrtiatattoion/nc]coorrrroossiioonn pprroodduucceedd ffoolllloowwiinngg aa ssiinnggllee eexxppoossuurree ooffaa tteesstt mmaatteerriiaall t0o oonnee eeyee ooff lalibninoo rraabbbbiitst.s1 AAllll pprroocceedduurreess uusseedd iinn tthhiss ssttuuddyy wweerree iinn ccoommpplliiaannccee wwiitthh tthhee AAnniimmaall WWeellffaarree AAcctt RReegguulalatitioonnss.. IInn tthhee ooppiinniioonn oofftthhee SSppoonnssoorr aanndd ssttuuddyy ddiirreeccttoorr,, tthhee ssttuuddyy ddiidd nnoott uunnnneecceessssaariillyy dduupplliiccaattee aannyy pprreevviioouuss wwoorrkk.. AAllll pprroocceedduurraall ttiimmeess pprreessecnatteedd iinn tthiiss rreeppoorrtt faallll wwiithkiin tthhee aacccceeppttaabbllee rraannggeess aass ssppeecciiffiieedd iinn tthhee WWisisccoonnssiinn ffaacciliitlyooffCCoormniinngg HHaazzlleettoonn IInncc.. ((CCHHWW)) SSttaannddaarrdd OOppeerraattiinngg PPrroocceedduurree ((SSOOPP).). TTEESSTT MMAATTEERRIIAALL IIddeennttiiffiiccaattiioonn "TThhee tteesstt mmaatteerriiaall wwaass iiddeennttiiffiieedd aass TT--66556644 aanndd ddeessccrriibbeedd aass aa cclleeaarr,, ccoolloorrlleessss lliiqquuiidd.. PPuurriittyy aanndd SSttaabbiilliittyy Thhee SSppoonnssoorr aassssuummeess rreessppoonnssiibbiillittyy ffoorr ppuurrittyy aanndd sstaabbiillittyy ddeecteerrmmiinnaattioionns ((iinncclluuddiinngg uunnddeerr test conditions). test conditions). SSttoorraaggee aanndd RReetteennttiioonn TThhee tteesstt mmaatteerriiaallwwaassssotorreedd aatt rroooomm tteemmppeerraattuurree.. AAnnyy uunnuusseedd tteesstt mmaateterriiaall wwiillll bbee rreettuurnmeedd ttootthhee SSppoonnssoorr aafftterr iissssuuaanncceeoofftthhee fiinnaall rreeppoorrtt aaccccoorrddiinngg ttoo CCHHWW SSOOPP.. SSaaffeettyy PPrreeccaauuttiioonnss "The test material handling procedures were according to CHW SOPs and policies The test material handling procedures were according to CHW SOPs and policies. 22880099..00000088 33MMAA1100000086990022 5 9 TTEESSTT SSYYSSTTEEMM cw gosousns CHW60504574 Test Animal ATdeuslttAanlbiminaolrabbofithse Hra:(NZW)SPF strain were procured from HRP, Inc, KAadlualmt aazlboion,o MriabchbiitgsaonfothneMHarya:2(9N,Z1W99)6SPF strain were procured from HRP, Inc., Kalamazoo, Michigan on May 29, 1996. HHoouussiinngg AAfftteerr rreecceeiipptt,, tthhee aanniimmaallss wweerree aacccclliimmaatteedd ffoorr a ppeerriioodd ooffaatt lleeaasstt 77 ddaayyss.. DDuurriinngg aacccclliimmaattiioonn aanndd tthhrroouugghhoouutt tthhee ssttuuddyy,, tthhee aanniimmaallss wweerree iinnddiivviidduuaallllyy hhoouusseedd iinn ssccrreeeennbboottttoomm ssttaaiinnlleessss sstteeeell ccaaggeess.. EEnnvviirroonnmmeennttaall ccoonnttrroollsffoor tthhee aanniimmaall rroooomm wweerree ssett ttoo mmaaintaiinanattetemmpaepreariattuunrreeooff 1199" ttoo 2233*CC,, aa rreellaattiivvee hhuummiiddiittyyooff 5500%% +2200%/'o,, aanndd aa 1122--hhoouurr lliigghhtt//1122--hhoouurr ddaarrkk lliigghhttiinngg ccyyccllee.. IInn ccaasseess wwhheerree vvaarriiaattiioonnss ffrroomm tthheessee ccoonnddiittiioonnss eexxiisstteedd,, tthheeyy wweerree ddooccuummeenntteedd aanndd ccoonnssiiddeerreedd ttoo hhaavvee hhaadd nnoo aaddvveerrssee eeffffeecctt oonn tthhe ssttuuddyy outcome. AAnniimmaall DDiieett "TThhee aanniimmaallss wweerree pprroovviiddeedd aacccceessss ttoo wwaatteerraaddlliibbiittuumm aanndd aa mmeeaassuurreedd aammoouunntt ooff LLaabboorraattoorryy RRaabbbbiitt DDiieett HHFF ##55332266,, PPMMII FFeeeeddss,, IInncc.. TThhee ffeeeedd iiss rroouuttiinneellyy aannaallyyzzeedd bbyy tthhee m`maannuuffaaccttuurreerr ffoorr nnuuttrriittiioonnaall ccoommppoonneennttss aanndd eennvviirroonnmmeennttaall ccoonnttaammininaantnsts.. SSaammpplleessoofftthhee wwaatteerr aarree ppeerriiooddiiccaallllyy aannaallyyzzeedd.. TThheerree wweerree nnoo kknnoowwnn ccoonnttaammiinnaannttss iin tthhee ffeeeedd oorr wwaatteerr aatt lleevveells tthhaatt ccoouulldd bbee eexxppeecctteedd ttoo iinntteerrffeerree wwiitthh oorr aaffffeecctt tthhee rreessuullttsooff tthhee ssttuuddyy.. AAnniimmaall SSeelleeccttiioonn "TThhrreeee hheeaalltthhyy,, aacccclliimmaatteedd ffeemmaallee rraabbbbiittss,, wweeiigghhiinngg ffrroomm 22,,119922 tto0 22,,552299 gg aanndd aapppprrooxxiimmaatteellyy 1144 ttoo 1188 wweeeekkss oofafgagee,, wweerree sseelleecctteedd aatt rraannddoomm aanndd iiddeennttiiffiieedd bbyy aanniimmaall nnuummbbeerr aanndd ccoorrrreessppoonnddiinngg eeaarr ttaagg.. TThhee aanniimmaalls'' eeyyeess wweerree eexxaammiinneedd oonn tthhee ddaayy bbeeffoorree test material administration using sodium fluorescein dye procedures. Only those annals twweiisttthhmn1ao0tessriiiggannloaofdfomocciunulilasatrrraiintnijjouunrryyuosoirrniigrirsiatotadtiiiuoomnn wwfeleurroeereuussseceded.i.n dye procedures. Only those animals Justification for Species Selection JHiussttoirfiiccaaltliyo,nthfoerNSepwecZieeaslSanedleWcthiiotne albino rabbit has beea the animalof choice based on Hitsisltaorrgiceaollryb,itthaendNneownpZiegamlaenndteWd hiiste. albino rabbit has been the animal of choice based on its large orbit and nonpigmented iris. 22880099..00000099 33MMAAT100000066990033 010 PROCEDURES PROCEDURES caw cososss CHW60504574 PPrreeppaarraattiioonnooffTTeesstt MMaateterriiaall T"Thhee tteesstt mmaatteerriiaall wwaass aaddmmiinniisstteerreeddaassrerecceeiivveedd.. TThhee ppHHooff tthhee tteesstt mmaatteerriiaall wwaass. ddeetteerrmmiinneedd ttoo,bbee 38..44.. TTrreeaattmmeenntt EEaacchh rraabbbbiitt rreecceeiivveedd 00..11 mmLLoofftthhee uunnddiilluutteedd tteesstt mmaateterriiaall ppllaacceedd iinnttoo tthhee eevveerrtteedd lloowweerr lliidd oofftthhee irigghhtt eeyye,, wwiitthh tthhee lleefft eeyyee sseerrvviinnggaass tthhee uunnttrreeaatteedd ccoonntrtrool.l. TThhee uuppppeerr aanndd lloowweerr lliiddss wweerree ggeennttllyy hheelldd ttooggeetthheerr ffoorr 1| sseeccoonndd ttoo pprreevveenntt lloossssooffmmataeterriiaall aanndd tthheenn rreelleeaasseedd.. "TThhee eeyyeessooff tthhee rraabbbbiittss rreemmaaiinneedd uunnfflluusshheedd iimmmmedeidaiatteellyy aaftteerr ttrreeaattmmeennt.t. RReeaassoonn ffoorr RRoouutteeooffAAdmdimniinsitstrraattiioonn HHiissttoorriiccaallllyy,, tthhee ooccuullaarr rroouuttee hhaass bbeeeenn tthhee rroouutteeooffcchhooiiccee bbaasseedd oonn tthhee mmeetthhooddooffDDrraaizize.e".2 OObbsseerrvvaattiioonnss T"Thhee ttrreeaatteedd eeyyeess wweerree oobbsseerrvveedd ffoorr ooccuullaarr iirirtitaattiioonn aatt 11,, 2244,, 4488,, 7722,, aanndd 9966 hhoouurrss aanndd DDaayyss 77,, 1144,, aanndd 2211 aaftteerr ttrreeaattmmeennt.t. IIrrrriittaattiioonn wwaass ggrraaddeedd aanndd ssccoorreedd aaccccoorrddiinngg ttoo tthhee DDrraaiizzee tteecchhnniiqquuee uussiinngg aa ppeeanlliigghhttaass tthhee ssouroceouoffiillrlluummicninataiteioonn.. SSooddiiuumm fflluuoorreesscceeiinn eexxaammiinnaattiioonnss wweerree uusseedd t1o0 iaidd iinn rreevveeaalliinngg ppoossssiibbllee ccoorrnneeaall iinnjjuurryy aatt tthhee oobbsseerrvvaattiioonnss. ccoonndduucctteedd aatt 2244,, 4488,, 7722,, aanndd996 hhoouurrss aanndd DDaayyss 77,, 1144,, aanndd 2211. AAnniimmaallss wweerree wweeiigghheedd bbeeffoorree tteesstt mmaateterriiaall aaddmmininisisttrraattiioonn aanndd aatt wweeeekkllyy iinntteerrvvaallss tthhrroouugghhoouutt tthhee ssttuuddyy.. TTeerrmmiinnaattiioonn AAtt tteerrmmiinnaattiioonnoofftthhee iinn--lliiffee pphhaassee,, aallll aanniimmaallss wweerree eeuutthhaanniizzeedd aanndd ddiissccaarrddeedd.. SSttaattiissttiiccaall AAnnaallyysseess NNoo ssttaattiissttiiccaall aannaallyysseess wweerree rreeqquuiirreedd bbyy tthhee pprroottooccooll. 22880099..00001100 33MMAA1100000066990044 u cweosoisna 11 CHW60504574 LLooccaattiioonn ooff RRaaww DDaattsa,, RReeccoorrddss,, aanndd FFiinnaall RReeppoorrtt "TThhee rraaww ddaattaa,, rreeccoorrddss,, aanndd aann oorriiggiinnaal ssiiggnneedd ccooppyyoofftthhee fiinnaall rreeppoorrtt wwiillll bbee rreettaaiinneedd iinn tthhee aarrcchhiivveess ooff CCHHWW iinn aaccccoorrddaannccee wwiitthh CCHHWW SSOOPP.. RREESSUULLTTSS//DDIISSCCUUSSSSIIOONN AAvveerraaggee pprriimmaarryy eeyye iimmittaattiioonn ssccoorreess aarree iinn TTaabblee 11,, wwiitthh iinnddiivviidduuaall eeyyee iircriatattiioonn sccoorreess iinn "TTaabbllee22.. SSooddiiuumm fflluuoorreesscceeiinn eexxaammiinnaattiioonnss aanndd tthhee iinnddiivviidduuaall bbooddyy wweeiigghhttss aarree iinn TTaabblleess 33 aanndd 44,, rreessppeecctiivveeyly.. "TThhee tteesstt mmaatteerriiaal,, TT--66556644,, wwhheenn eevvaalluuaatteedd ffoor iittss pprriimmaarryy yeyee riririatattiioonn ppootteennttiiaall iinn rraabbbbiitss,, pprroodduucceedd ccoormneeaall aanndd iirriiddaall iinnvvoollvvememeennt aanndd sseevveerree ccoonnjjuunnccttiivvaall iirirtittaitoionn.. OOccuullaarr iirnriittaattiioonn wwaass ssttiilll pprreesseenntt iin ttwwoo aanniimmaallss aatt DDaayy 2211aafftterr ttrreeaattmmeenntt. SSIIGGNNAATTUURREE oe SStteevveenn MM.. GGllaazzaa SSttuuddyy DDiirreeccttoorr AAccuuttee SStduideiess NN, ase DDaattee REFERENCES REFERENCES 1. "Acute Eye Iiation/Corrosion," Organisationfor Economic Cooperation and D"AevceulteopEmyeentIrGruitiadteiolni/nCeosfrroorsioTnes,"tiOngorgfanCihseamtiiocnalfos,r ESeccotnioonm4ic05C(oaodpoeprtaetidoMnaaynd12, 1981) Development Cruidelinesfor Testing of Chemicals, Section 405 (adopted May 12, 1981). 2 Draize, J. H, "Eye Mucosa" In: Appraiosfathle SafetyofChemicals in Foods, DDrruaigzsea, nJ.dHC.o, s"mEeyteicMsu-cDoesar,m"aIln:ToAxipcpitrya,isAaslsoofctihaetSoanfoeftFyooofdChaenmd iDcarlusginOfFfiocoidalss, of tDhreuUgsSa,ndpp.Co4s9m-5e0tic(s19-5D9)e.rmal Toxicity, Association of Food and Drag Officials of the U.S., pp. 49-50 (1959). 22880099..00001111 3SMWMAA1100000066990055 Bn 12 Table 1 Table 1 Average Primary Eye Irritation Scores Average Primary Eye Irritation Scores cws0s0ss74 CHW60504574 ObOsPbeesrrevriavotaditioonn Period |1 HHoouurr 2244 HHoouurr 4488 HHoouurr 7722 HHoouurr 9966 HHoouurr DDaayy?7 DDaayy 1144 DDaayy 2211 AASvvceeorraraggeee Score* 4a1r.7 4220.0 3366.77 3223.3 2240.0 1166.33 88.77 66.77 * TtTohhteaelaaevvyeeerraaiggreeiapptrriiimomnaarrsyycoeeryyefeeoiirrrraiittlaattitiooenn ssaccnooirrmeealiisss tdthihveeided. tboytatlheeyne iurritmaotiofbnanseicmoarrlesfo(r3)alalttheaecahniombsaelrsvadtivioidn.ed bppeyerrtiihooedd.number of animals (3) at each observation 22880099..00001122 33MMAA1100000066990066 u1b3 TTaabbllee 22 IInnddiivviidduuaall EEyyee IIrrrriittaattiioonn SSccoorreess cw ansosss CHW60504574 ANnAuimnmibmaeallr Number FF555909555444121"*u FFF555099555444323uu A CCoomrB eneaa A B 111a44 1 1 1 444 IiCriss 5 C D 11 HHoouurr i"1i 2 1i 2 "1i 2? CCoonnjjuunE nccttiivvF aaee E F 43 3 x x 433 3x MMeeaann STTeoototaralel Score* a0 a410.0 a430.0 41.0 4411.77 FFFs5999555444211 FFF555999555444332 1v vj a 34 va 1j 3 1j 4 24 Hours 24 Hours "1i rv *F 3b 033333 wo 4m30.0 *1i 1i Fa 3b 3 3b 3 a38s.o0 4 45.0 MMeeaann 4422.00 CCoronrneeaa Irriiss CCoonnjjuunnccttiivvaaee ABA--- DADreeeggarroeeeefoiofnfvooopplaavcceiimttyeynt B - Area of involvement CCimi--tDDateeigogrnreeeeooff rirdidaall irritation DDE --- CRRheeeddmnnoeesssisss EFF --- DDCiihsseccmhhaaorrsggiese b**ToTBtloaatnalclhssiccnoogrr.ee == ((AAxx BBxx 55))++((CCxx55)) ++ [[((DD ++ EE ++ FF))xx22]].. be CBCllelaeanarcrdhdiiisnscgch.haarrggee.. 4d PIPnuujrreuucltleeednn.tt ddiisscchhaarrggee.. Jji ICCnoojmernceteaealdl.eeppiitthheelliiaall ppeecelliinngg.. uu EExxcceessssiivvee ppaawwiinngg aatt tthhee ttrreeaatteedd eeyyee aafftteerr tteesstt mmaateterriiaall iinnssttiillllaattioionn. 22880099..00001133 33MMAA1100000066990077 i14 Table2 (Continued) Table 2 (Continued) IInnddiivviidduuaall EEyyee IIrrrriittaattiioonn SSccoorreess coveosousns CHW60504574 ANAninimmeaall Number FsFF959os544s11 Foss F59542 F59543 C"oCoAmreneBaa A B 1v0j os24 v3 1j 2 1~ 3 IrC riiss DCoCnojnuinuE cntcitivvaF aee C D E F 4488 HHoouurrss Eo 3 x 1i 3~'b 3 3d E52 1i 3a'b 3 2d Boo 2 x 1i 3a'b 2 3~ Mean Mean STTooortalel' Score* ap43.0 ai31.0 36036.0 3366.77 FsFB959os544s11 Fs9543 F59542 F59543 [v 1Ij 24 voz 1j 2 1~ 2 72Hours 72 Hours os 1i 3"b 3 [EE 1i 3~'b 2 [EEE 1i 3~'b 2 2 aw 2a 41.0 13 1~ 27.0 2a 29.0 MMeeaann 3322.33 CCoorrnneeaa AAB---ArDDeeeggarroeeefeoiofnfvooopplaavcceiimttyeynt B - Area of involvement IIrriiss CCii-t-aDDteiegogrnreeee ooffiirriiddaall irritation *Total score= (Ax Bx 5) + (Cx 5) + [(D + E+F) x2]. a+*BlPTPeaeotnttiiacttleehishhcneeogmmroeorrr=rhh(aaAggiixnnggB.. x 5) + (C x 5) + [(D + E + F) x 21. b4c CPluBCrellaueanlarrcedhndiitinsdscgcihhsaacrrhggaeer..ge. +dL J PIICnnoujjrreeuncceltteeaendldt.edpiistchehlairaglep. eeing j Corneal epithelial peeling. CCoonnjjuunnccttiivvaaee DDE--C- hRReeedmdnoneesssisss FEF ---DDCisihscechmhaaorrsggiees 22880099..00001144 33MMAA1100000056990088 1i5s `Table Table 22 ((CCoonnttiinnuueedd)) IInnddiivviidduuaall EEyyee IIrrrriittaattiioonn SSccoorreess cw gosoasns CHW60504574 AAnNuinmmimbaaellr Number Fs9541 FsFFF9s55999555544443122 F59543 "CCoAommeeBaa A B vos 11[vIojj 3 2 1j 1 IiCriss D CCoonnjjuunE nccrtiivvF aaee C D E F 9966 HHoouurrss v 2 or Ii 3~b 2 1d 0 2 2 0 2b 2 1d v 2 1i 2b 2 1d Mean Mean STTcoooutalrle Score* 3a0200.0 2200.00 20.0 2244.00 Fs9541 FFFF55s5999o555s444a1322 F59543 ros o 1[1Apj o31 0 0 DDaayy?7 i 22 300 1i 2~ 2 1d 30.0 0 > Bo 0 2b 1 1a 13.0 0 2 1 0 60 o 2 1 0 6.0 M Meeaann 1166.33 CCoorreneaa AAB--D-eADgreergaereoeefoiofnfvooopplaavccieitmtyyent B - Area of involvement IIrriiss CCir-r-iDtDaetegigronreeeeooffirriiddaall irritation *Totalscore = (Ax Bx5) + (Cx) + (0 +E+F)x2]. a* ba TPBPeleoiattiinattcelehshhiceenommgroeorrr=rhha(agAgiinxngg.B. x 5) + (C x 5) + [(D + E + F) x 21. 4bdinjBPPueulracranutlcleeehnnditnt gddiisscchhaarrggee. j5i Comeal Injected. Corneal eeppiitthheelliiaall ppeeeeliinngg. p PPaannnnuuss.. CCoonnjjuunnccttiivvaaee DDE---CRRheededmanoeesssisss EFF---DDiCsihcsehcmahraogrsgeise. 22880099..00001155 33MMAA1100000056990099 316 TTaabbllee 22 ((CCoonnttiinnuueedd)) IInnddiivviidduuaall EEyyee IIrrrriittaattiioonn SSccoorreess cuvasusrs CHW60504574 AnANiunmmimbaeallr Number FsFFo5599s55a44l12 FF5o9s54s2 F59543 C"oCoAmreneBaa A B L1BE o1 01j,n 0 01 0 ItC riiss B C D DDaayy 1144 oo0 222 00 0 2 0 0 CCoonnjiuunE nccttiivvF aaee E F 111 1rodrr 00 1 01d 0 Man Mean STTooorutalelt Score* 1nn3oo.0 0013.0 0.0 87 8.7 DDaayy2211 . Fsosal Bo Too 90 Eos F59541 pr1j'n 11 0 o 21 1 1 00 u9o.0 Boss F59542 F59543 01j'n 0 01 0 00 0 02 0 01 0 00 0 0011.0 0.0 Men 67 Mean 67 CCoormneeaa BAA--DADecegegrareoeefeoionffvooplpacvaicetimtyyent B - Area of involvement TIrriiss iCC-rr-DitDateeigonrgeeoroffeririiddeaall irritation 4** ToTPutoratualllessncctoordreies==ch(a(rAAgexx. BBxx 55)) ++ (C x 5(C)x++) [[((DO ++ EE++ FF))xx22]].. Jjad PCCCoouormmruneeleaaeanlllteendpepiioisttvchhaheesallciriuagalleapp.reeieezilaintngig.o.n. n Corneal neovascularization. CCoonnjjuunnccttiivvaaee DDE--~RCRehdeednmneoessssiss EFF--- DDCiihsseccmhhaaorrsggisee 22880099..00001166 M3MA1A010000086991100 un 17 TTaabbllee33 SSooddiiuumm FFlluuoorreesscceeiinn EExxaammininaattiioonnss ciweosossrs CHW60504574 Anim) | ------OObbs-- seerrvvaattii-- oonn PPeerriio-- odd ---- NANunumimmbbeaelrr PPrreeiinniitiiaattiioonn 2424HHoouurr 4488 HHoouurr 7722HHoouurr F5509554411 FFs5o9s5a422 FFs599554433 NNEEGG POS(95%) POS(90%) POS(85%) POS (95%) POS (90%) POS (85%) NNEEGG PPOOSS ((5555%%)) PPOOSS((4455%%)) PPOOSS((2200%%)) NNEEGG PPOOSS((5800%%)) PPOOSS((6600%%)) PPOOSS ((4400%%)) NAAunimimblealr Number FF5s9S5a4l1 FFS599554422 FFS599554433 me --ObOsbe-- srevravta-- itioonnPP-- eerriioodd-------- 9966HHoouuwr DDaayy?7 DDaayyl1d4 DDaayy22l1 POS(10%) POS (70%) POS(55%) POS (55%) PPOOSS((1155%%)) PPOOSS((55%%)) POS(IS%) POS (10%) POS (10%) POS (10%) POS (15%) POS (10%) POS (10%) POS (10%) POS(20%) POS (20%) NNEEGG - - - NNPOEESG.GNeNPogesagittaiitivvveeesststataaiiinnnrrereettteeennnttitiiooonnn,(.areaofcornea involved). POS PSoosdiitiuvme fsltauoinrersecteeinntieoxnam(airneaatioofncnoortnecaonidnuvcotlevde.d). Sodium fluorescein examination not conducted. 22880099..00001177 I3MMAA1100000066991111 ANnAuinmmimbaealrl Number Fso541 F59541 Fs9542 F59542 F509554433 is 18 TTaabbllee 44 IInnddiivviidduuaall BBooddyy W Weeiigghhttss ((gg)) _-- DDaayy Sex Initial 7 Initial 1144 F 2470 2575 2608 F 2,470 2,575 2,608 FF 259 2,529 26m 2,671 22,770066 FF 22,119922 22,227744 2335 2,335 cw osassTs CHW60504574 2211 22,77333 22,887722 248 2,483 22880099..00001188 I3MMAA1100000066991122 119 AAPPPPEENNDDIIXX Protocol APPrmrooettnoodccmoolel nt No. | Protocol Amendment No. 1 civ 6osoasTy CI-IW60504574 22880099..00001199 33MMAA1100000066991133  caweosoisns 20 CHW60504574 Sample Submittal Form Sample Submittal Form ito vansrg arp ns This lon'n is to be used when submitling samples for routine DEC NTa ISS?SSsMAtTIyIS1S55,., acute tesf~g. Sp~cml test~'~J needs ~ be easily arranged by contacting the Acute Studies Department at (608) 241-7292. owsuto _camucrs CHW Study No. bps Enclose w~ s~p/es ~d send to: Sone C~ming H~leton I~. oe, 3301 Kin~ ~uleva~ Madison, W~ns~ ~7~ C"oSarmtad. RFOAGEG R PECEINS _ ouosuarmcieeespwe et Far rp. KEolr rRoEmeRey oZg S re = searniroinne:e_T- Loge SToecmenipngepsrdca.yoSmcan(DrIcOsL DerLoEcriTs)E]fwSri 2 Yer Teresweoceaohn ons Yu Smet yo Samet Dispos:2X_ unm Spas towing lon: Xe na `SampleSirage Focuramans: n_ XC Room wrpucane [=wSE U] tPumi mIaE NSoSnTFGmAa0y0s erm paT toan red S s -- Tests AcuteOraToiey inRats B Livan STT a, Acute Oral Toxicity In Rail ~TP8084 Up and down LDS0 procedure ireBnsenm k mio TeriPn et ni ~TP3206 R-ISA =e~'een; 5M-SF at 5.0 g~9 oc aa sen 80080 i de -- ~ de~'md study if death occurs at 8.0 g~g oi rs Ho [= ~TP3013 EPA screen; 5M-SF at 5.0 g~kg 2Cromsna oy se 480543 ------ -- Conduct defined study I~ death o<:curl at 5.0 g~g Ari eh Ao _"~TP2069 OECD =~reen; SM-SF M 5.0 9/kg RII em atoms __ Cortdgct defined stud,/II d~ath occt~m at 5.0 g~g SApcI etruT mma Toy thtT -- p 1 Sntwy Heam tin s Acute Dennal Toxicity In Rabbits rr itasovesut wzo wn Shes Shue ~TP3207 FHSA screen; 5M-5F at 2.0 RRP ee inn __TP3016 EPA screen; 5M-5F at 2.0 -- Co,duct d~fmKI study il death occur= at 2.0 TPES ECD rk 20% Swans __TP2070 OECD screen; 5M-SF at 2.0 g/kg ti mez ~ Conduct de41ned atudy II de=th occure at 2.0 9/~g ------ r-- yeat fuoemT tsseonhta ir pe comomainnte i F~ CHW Use Only Poke x0 Tre ST emt pre) ' . ?mtocol Issue Dale~. % ~ "~ Primary Skin Irritation __TP3208 FHSA: 6 rabbit$-I abraded. 1 Irdact slt~Yabb8 TP3014 EPA: 6 rabbits-1 Intact sll~/rabt)it ~TP2071 OECD; 3 rabbits.1 intact sitetrebbll --TP4206 DOT conoslvlty; 8 rabbtt~t Intact ,~te~rabblt --TP7145 Phototoxlcity: 6 rabblls-2 intact slteshalobl~ (o~e ~o with UVA exposure) Special ]nst~udlons: Prlmmy Eye Irritation __TP6360 Low-volume procedure: 6 rat~ita unwaabed __TP320~ FHS/~ 6 rabbits unwashed --TP2012 1978 EPA; 6rabbitsunwashad,3washad ..-~.TP30t5 1982 EPA; 6 rabbit= unwashed TP2072 OECD; 3 rabbits unwashed ~ 3 rabbits washed at 4 seconds -- 3 rabbitswashad at 30 seconds Guinea Pig Sensitization __~P2017 EPA Magnusson-K]lgman maximization ~TP6164.EC OECD/~C Magnu.un-KIkjmsn maximization __'rP~,2~ Photoal~rgenlc omact dermatitis (Armstrong) pv i c Voor ers od I. Kraan d SX Dal TRinEgTle - W~te oW--CHW Yellow copy--Submitter 22880099..00002200 M3MAAT10000006691144 a21 HAZLETON neg NEN ~Wo Ir S C 0 N S I N $ OFFICE st. usteaPYhrmsesoa St. Paul, ~tnnesota orca trae PROTOCOL TP2072 SutTes Study Tltl#: riGe ition stay tn hits Primary Eye rine 1 Irritatlon/Corroslon Study in (OECO Guidelines) Pe Rabbits sa 1, 18 DDaattee:: June l, 1993 [m-- Performlnq LaboratorY: sito wom, oe. Hazleton Wisconsin, Inc. winaVenteods 3301 Kinsman Boulevard Madison, Wisconsin 53704 LabroarattoorwryyiPrtrooa~seecsstslIeidenonstsicfiiccaattiaosn: HWI ~r~l~ awsome CHW60504574 22880099..00002211 SMATo006815 3MA10006915 2 cuwesossrs 22 CHW60504574 Lveasrs TP2072 Page 2 stor osicTIon STUDY IDENTIFICATION Frimry Ee Irritatton/Corrasion study in Rabits Primary Eye Irrltation/Corrosion Study in Rabbits fritid {OECD Guidelines) ve. HWI No. Tost Watertat Test Material Sponsor Sponsor Sponsor's Rgresenative Sponsor's Representative stu Study dDiirreeccttoorr study Location Study Location Proposed suey Timetable Proposed Study Timetable etal ae sate Experimental Start Date Bein) Tontion ote Experimental Termination Date Fini Ret poe Final Report Date (tseoe ssuatsem startin ors) (See sample submittal fo~) TMoccatony services HOE Canter 3M Toxicology Services ZZO-ZE-02 3N Center ena St. Paul, HN 55144 230 1. uenert, po John L. Butenhoff, PhO 3M Toxcalog Services Toxicology Services See ZZO-ZE-02 3M Center Ta St. Paul, HN 55144 iia) iTo (612) 733-]962 steven. Glaza Steven M. Glaza ntleton wiinsin, nc. Hazleton Wisconsin, Inc. Bn ie P.O. Box 7545 Rigi U1 saror.1s Hadison, WI 53707-7545 Gaeta (608) 241-7292 asieton Wscensta, Inc. Hazleton Wisconsin, Inc. Sahaing bo. 5 Building No. 3 SITES dene 3802 Packers Avenue Raton 350 Madison, WI 53704 - eVekk oI off 4-R 24AC9 22880099..00002222 M3MATA010000066991166  cwsosossna 23 CHW60504574 fvaerds TP2072 Page 3 Ls1. ~tudy Fribiy Ee Irritation Corrosion Stuy tn RatbiEs (OED Gulden) Primary Eye Irritation/Corrosion Study in Rabbits (OECD Guidelines} 2 ham 2. Puroose FEBEss the relative eve of trtationcorraston prodcsd To assess the relative level of irritation/corrosion produced a F1ioein 4 sirgle Srsiir oF 3 mek meteor 0 one seek bir following a single exposure of a test material to one eye of albino rabbits p Requlatory Compliance CA RRraiey S Br cd tn accords wit te folowing Coot This study will be conducted in accordance with the following Good aces Regtstton/SeanCnodes os. Laboratory Practice Regulations/Standards/Guidelines: } Contact 15 2 onresuated tots [ ] Conduct as a Nonregulated Study | [REE [ ] 21CFR 58 (FDA) lo it 1805 rewny { ] 40 CFR 160 (EPA-FIFIL~) {140 ca 158 (ERT 40 CFR 792 (EPA-TSCA) ~]~ Clio haat) (eth C(81)30 (Final) (OECD) eRoltioeainatn na S850 onus 10, 1984 (upanese AT) [ ] Notification No. 38S0, August I0, ]984 (Japanese HAFF) or sh op Gre ir) [ ] Notification No. 313, March 31, 1982, and as amended by NotICoRn ho. 10, Oatr 5. 1588 {ipunse Fo) Notification No. 870, October 5, 1988 (Japanese HOHW) AI pracadres fn hi protacl are tn comltasce wh the Animal All procedures in this protocol are in compliance with the Animal Sele Re Repsaticrs" In th spinon oF 1h Spenr nd uty Welfare Act Regulations. In the opinion of the Sponsor and study Seca Tl es wl merry apes ny meio director, the study does not unnecessarily duplicate any previous work. 4 palinbusses Quality Assurance rFoer prosrett TEhtes, we protocol stats contac, and te rina) For regulated studies, the protocol, study conduct, and the final CIE a Se sited by RL Bath nari tale organ report will be audited by the Quality Assurance Unit in accordance natcteir" ucansin WT) Standard Operation prcedrs 07) with Hazleton Wisconsin (HWI) Standard Operating Procedures (SOPs) and policies. 5 Jost ate Test Materia~l ---- Ao ,Identification ESE Rea om) (See sample submittal form) * pia pute Physical De@cription Baakhaee, (.. (See sample submittal form) Bchroengca erShniesir nhr huSmoul lrie:spe ootnasgtty.ain tsfor a pe uritSyhaidttosbrtwya omatles STS hen seo calatsiration 1 reaveste by ph purity and Stabilltv TddheeetteerrSmapiionnnaasttoiiroonnassssu((mi1ennsccllurudeaisinpggonssuinnbdierlritttyeasttfosrcoonpdubirtoiitnoynesa)]n.d sSStaeambmpipllheiestsyooff test material/vehicle mixture(s) (if applicable) for concentration, solubility, homogeneity, and stability analyses will be taken before administration if requested by the Sponser Rese Tpit (11 tary wl Be sat to the Sonsor Sponsor. These samples (if taken) will be sent to the Sponsor Rr Cperinenal Seraihation or poskibte sales after experimental termination for possible analysis. 22880099..00002233 M3MATA010000006991177 a civ sosoisn 24 CHW60504574 wfeaty T~207Z Page 4 0. ~8tostraoqrmee1e sumittat form) fSRSR{oateSHvuserdeeeAirevesRrsaeemssSoaSipfralmeemReollleseEesussssibmmpttlhhiteaatsnnal ~Om) 4rewwfeseeienkkessd.i1n0 eexxppeerriimmeennttaall dduurraattiioonn wlwill snoott have reserve samples retained. Baetseerrve samla(s) of exch batc/lot of test matertal wil) Reserve sample(s} of each batch/lot oF test material will aratioT n. y or tn eee Sperfat taken if this study is more than 4 weeks in experimental bbee dsrTTfehuhrereereeaestztteieeeotsrsntt.3ss0mmee9taub.tteet1rro0it1aaSm1llaainnSrratepeaissaieennnrrs'vvoseera YsttsaeeaEmmmpppplleoeebrrnaawwttiuaiclrrolleentoabobefcfeteSbssdettelootrorsseewiddteO0r'aaCtt1fiH0foWoIpre1fiInn06nsypaaeeTaaorrrss dGEpieiSrstrppooHtWsneIiittriiSyoOoPnn.piirnnaTchcatecoicrcSodeproadnannsccoeer withwill with te appropriate reauiatory Good be contacted after I0 years for the appropriate regulatory Good F. fHA~htneoaeytbteouanruFstaniIiuttoosoT~nerdyrttPeeerpssaottcrttimmcaaettaseet.rreitsaalls wSwiiilrlacbbteedddiissstcchaararddreevddeaaBffytteerrSheIIssSssupuaaennmccaeen,ooff 6.G= faRptreIecRaTutRiIonEs sore and porictes the final report, unless directed otherwise Safety Precaut|ons by the Sponsor. 6. DowrAssnrieaqu)irepdesbtyoHWI SOPs and policles 6. A fasts Exoerimental Oeslon A. stpeecter ~nimall (1) SPecies @ ERSGtaEsrbabiouint/srSooiurcee ton esearch products, tne (3)) taaanct itso Hra:(NZW)SPF/Hazleton Aqe at Initiatioo Research Proddcts, Inc. (4) gAWE edeiualohtt E atinIinlttiiaattilogrnI 2.0 to 3.5 kg (5)) mNSbumoaberraanngdsexer aro (6) 3IEddoeefnntsRaiinfcyicaastteiixoonnpeerr group or tag Individual numbered ear tag 22880099..00002244 M3MA1A010000066991188 5 cuwersnasns 25 CHW60504574 nTaae TP2072 Page 5 (07)) tsbunery Husbandry (a) Housinq ) SB i rentetem states stent cues Individually, in screen-bottom stainless steel cages Gears sagt. (heavy gauge). (b) Foo~ Kure mun of i Fier att. ch? 535 A measured amount of High Fiber Rabbit Chow" #5326 Se tae ea (Purina Mills, Inc.). The food is routinely analyzed hi mimiitiss formth ora) Sassen by the manufacturer for nutritional components and ram tomas" environmental contaminants. we (c) Water Cateircaadnutirromatisn utomtic sytem. umples of the Ad libltum from an automatic system. Samples of the pa Bar Te anne Se, water are analyzed by HWI for total dissolved solids, EE hardness, and specified microbiological content and Bead elon hey tare orossshorpses for selected elements, heavy metals, organophosphates 5 Slerinaed Tracarsnt and chlorinated hydrocarbons. @ Contamina (d) Contamlnan~i FEEL ry ceppsrans 10 he ondor ater There are no known contaminants in the food or water Rae aban wh sta that would Interfere with thls study. (el [nvtronm~n[ 1 BIL) contro for the tea room wit 50 Environmental controls for the animal room will be rSealtaetemas emoitu o o to Fe set to maintain a temperature of 19 to 23"C, a TRI Nomaan oferBso. A, d's 12 relative humidity of 50%~20%, and a 12-hour light/I2-hour dark cyc]e. if) Acclimatioq AE as At least 7 days joattltst (8) Selection of Test Animals SSheeadtesr neat Shed eto sccoreton to it sos. an Based on health and body weight according to HWI SOPs. An ToatCeer oF ext nies BHT operant adequate number of extra animals will be purchased so that TE a ontesty soo bh 14 paces on ses os no animal in obviously poor health is placed on test. The Gracer I ltt ton a seat rabbits' eyes will be examined using sodium fluorescein s on ts Gay tar. tt setts) dye procedures on the day before test material SERSEEAon. ony SaTeats wth ne Sh of cornet administration. Only animals with no sign of cornea] ier ose soared res 11 he tt" tnjury or eye abnormalities will be used. ) sHtitftor cuscatsetoectnion (9) Justification for Soecies Sel)!oq The ShE ieh RE R tne risnit ms seen Historically, the New Zealand White albino rabbit has been opted371C6h1ee based spon 153 Tage ort so the animal of choice based upon its large orbit and nonptgmented Iris. 22880099..00002255 M3MAAI10000006691199 x amen: 26 CHW60504574 TP2072 Page 6 [y-- Oose Administration gsempnin (~) pose Administration Before administration of liquid test materials, the pH of the material will be determined (if possible). Each rabbit will receive 0.1 mL of undiluted liquid test mater|ai or the weight equivalent of 0.1 mL of solid test material (not to exceed 0.! g). If necessary, solid test materials will be finely ground into a dust or powder. The test material will be placed into the everted lower LSoipemaks aEmateriaa l, 11 th ht merit 1s lid of the rabbit's eye. The upper and lower lids will then be gently held together for ! second before releasing to prevent loss of material. If the test material is an aerosol, the test eye will be held open and the test material administered in a single burst of about ! second from a distance of approximately I0 cm directly in front of the eye. The eyes of the Croup 1 rabbits will remain unflushed for approximately 24 hours following Bl instillation of the test material. After 24 hours, a Sn washout may be used if considered appropriate. If Fr ecoifsied pTromar LE SehDa cer specified by the Sponsor, the treated eyes of two other aMT fn groups of animals (three animals/group) will be washed with lukewarm tap water for approximately 30 seconds a rea REE beginning approximately 4 and 30 seconds, respectively, ter nT n'of he Ls auterals Te viene gd after instillation of the test material. The volume and velocity of the flow should not cause injury. The right eye of each animal will be treated with the test material and the left eye will serve as the untreated control. (2) SeRaeassoonn ffoorrRRoouutteeooff AAfdsmiinniiasttrraattiioonn Historically, the ocular route has been the route of choice based on the method of Draize. aieen C. ~bservation of Animals te Readinq qf Ocular Irritation The treated eyes of all animals will be examined for ocular irritation at approximately ], 24, 48, and IZ hours after treatment. If no irritation or injury is present at I a A lZ hours, the group will be terminated. If irritation is F TfI oE i i E E TRe ne present at 12 hours, additional observations may be made S te at 96 hours and at 7, 14, and 2! days. If at any of these time points there is no irritation, the group will be ss l wry en aW e,e terminated. If injury is still present at 21 days, additional observations may be requested by the Sponsor, After recording the 24-hour observations, sodium fluorescein may be used to aid in revealing possible corneal injury. 22880099..00002266 Sunimono 3MA10006920 - 00 27 awmeasss CHW60504574 annast TP207Z Page 7 Itrercihtnaitcison(wtialchbmee graded 1: scored using the Dratze Irritation wtll be graded and scored ustn9 the Oratze record 1 amnat 117 "A165 hoard en eh be technique (Attachment 1). All eye abnormalities wtll be indo iat ees Smarties il be recorded. All animals that have a damaged eye producing SER Sirst ar isconart 1] be page hth undue stress or discomfort will be brought to the aIeiheoF {sts dhrctor oF esipmn secon to attention of the study director or designee according to HWI policy. @ par youn (2) pody Wetoht# CO) hBe L it itnstration nd okt hrsatier Before test material administration and week]y thereafter atic] (when applicable). o. pathol Pathology ASaayvtniiniie aayfianrg? during thestudywil be sseced to 1m Any animals dying during the study will be subjected to an TL recoTid. cro sain on an S11 semen ties abbreviated gross necropsy examination and all abnormalities Sinea "NEF crop: the ins MHL will be recorded. After necropsy, the animals will be Soped rSeheacheues WILD faved. A raat of the discarded and no tissues will be saved. At termination of the frat piStirhing anes 1 entestne e 0e experimental phase, surviving antmals will be designated to be sacrificed and discarded. fatten suis E. 5tatlstlca! AnalYSeS RHEE wr rire No statistical analyses are required. I. ben ReDoF~ KHIR report tncludtng these tems sted below 11 be suttted A final report including those items listed below will be submitted: rit of te test suet Description of the test material SciBtion of the Let Sten Description of the test system Price " Procedures SseAmEisSF perimental fitiation and tersimtion Dates of experimental initiation and te~ination oy Sok3e08ahRseornateion0hHgein SES 2 Hoh hseration period Summary table showing the irritation data at each were rca Any special observations that were recorded observation period 5 goonLocation of Raw Oata. Records, and Final Reoort SEcaaerSbdousger daBhts, shaey rsptuettF ann1t1br,aprnopreesndwopir SECURES $1 theTra) Fest Uh (han rene replete, Original data, or copies thereof, will be available at Hg[ to facilitate auditing the study during its progress and before acceptance of the final report. When the final report is completed, Tetained Tn ha Srchive thse rem ren etc an 5 all original paper data, including those items listed below will be oF A cores tom retained in the archives oF I-PA! according to HW! SOP. Protace] 1d protocol aenieents Protocol and protocol amendments So Brean rear Dose preparatlon records eR ~n-ilfe records oy wins Body weights BitSa ration Dose administration Observations atatcal sahalog records (1 ap cab AStudry c an sehaogy recor (1spl cale) Anatomical pathology records (if applicable) orrespondents >! Study correspondence Find rep Torin signed conn) Final report (original signed copy) 22880099..00002277 3aMWMAA1T00000066992211 a28 ciweosossns CHW60504574 Foanrs TPZ072 Page 8 Th forloetag superking records wi be retained at 1 but 11 nokThe not be Arenived w1eh the fol]owtng supporting be archtved with the ody dua. records w~11 study data. be retained at HWI but wtll Jotareceipt/acl aation records A~tmal receipt/acclimation records Water analysts records An Tet ems and mdi records An|Bal room temperature and humidity records Refrloersior 1nd fresser seaperstrs records, Refrigerator and freezer temperature records Tsirinest alfbrition aad santemance seconds ]nstrumenL ca]|bratton and maintenance records 22880099..00002288 I3MMAA1100000086992222 _ ow29 cocCiHwwWee6ss0o5w0s4ss5n7s4 morocaL arson PROTOCOL APPROVAL wPaoens TP~072 Page g r SE)ooner pressatE ive Gln 2. Lith John L. Butenhoff, PhO Sponsor's Representative 3N SoWmo tN Steve~ H. Glaza ~ enhits Toirmncatar Hatie Wisconttn, nc. Study Oi rector Acute Toxicology Hazleton )#lscon$in, (nc. EEDReeate _unSt Hilson Hizletan Viscensin, Inc. Representative Oual lty Assurance Unit Hazleton Wisconsin, Inc. arn. (TP207Z.3H) Duly 22, 1991 Eo i Oate elf: Oate 22880099..00002299 M3MA1A010000066992233 30 CHW60504574 cam re Attachment 1 oEEn TP2072 Page lO O~tty - Oegree of demlty (ires amt ds~e tikes1 for reading) Me o~a t ty ....................................... ...................................... Scattered or diffuse area, details of Iris lesrLyvlslbto .............................. Easily discernible tronoluce~t areas+ cktoiis of Iris sttghtty ~scure~ ................. Opalescent areas, no dsta|ts of Iris visible, size of p4)lt barely discernible .......... 0p~lue. iris invisible .................................................................. wi Area of Cornea one- ~rter (or tess), ~ not zero ..................................................... Greeter than or,e-~uarter, but Leas than half ............................................2 Greeter then half, but tess tha~ three-quarters ......................................... 3 Greeter th~ three-cpJnrters ~ to ~hol`e ares ............................................ A x | x S Torsi Pastu~ ~0 (A) yelues EET RIN Hemal .......................................................... ~ .......................0 Folds m nomt, cm~eette~, s~ttl~, clrcuu~mel` InJectlm (~y~r sit of thee or ce~blnattm of any thereof) iris Is still ro~tlng to Light (Itugiish re.tim Is positive) .............................................................................. le Me resetio~ to Llghto he~orrh~geo greys destru~tl~n (enyer all` of these] ...............2e A x 5 Total ~exiu- 10 ts 1 tt mb cto tt ee) (A) Et'~ess (refers to p~lpekrll a~d ixJtl,-r eonlunctlvll excluding corr4s ~ Iris) Vessels no~l~L ............................................ ............................. Vessels ckfiniteiy injected elx~ce naomi ................................................ Nora diffuse, deeper crimson red. Ir~|vldue[ vessels not easily discernible ............. ~iffu~e beefy red ....................................................................... (I) Me s~el tlng ............................................................................. ~.y swelling above namer {Imtudes nlctltltlng losd)rsl~e) ............................... Ol~i~ s~eliing with p~rtill ~,ersl~n of the lids ...................................... S.~tl+r~ +ith lids shout half closed .................................................... Sk~llirql with lids ll:x~t hllf erased to cxlq)lsteiy closed ............................... I)i$chsrQe Any mou~t different fr~ natal (does not include sml`t ~e~mts o~erved In I~r ~th~ of nor-mot enixcl$) .............................................................. PiKltlrge with moistening of the llck ~nd heirs Just edj~ent to the lids ............... 2 Discharge wlth amiste~Ing of the tick and hllrl+ lad cmlder-kte irel ~rcxl'v:l the TT ores vembte s r00 Score (A * ~ C) x 2 Total, Xulu u ~ TIll tote| ~ore for the t-pc ts tee sial of sit scores ~toined f~- the COrnel, Iris+ * Indicates positive effect. (FH~A Interpretation) 22880099..00003300 awA0000926 3MA10006924 , coos 31 CI-~7 6050457~ CHW No. SR. PROTOCOL AMENDMENTS = Amendment. No. I EEffffeeccttiivvee 2"TTo0 us,~e".,,qc0 ~, t9 t%t_. 9 Portion of Protocol Being Rodlfied: Applicable sections of the protocol. Reason for Modtf|cation: To tdenttfv the location where the study will be conducted and to reflect a company name change from Hazleton Wisconsin, Inc. (Hgl) to Corn|nq Hazleton Inc. (CHW), replace wherever appllcabl~ the followinq chanqes Modification: Corntnq Ha~leton Inc. (CH~) 3301 Kinsman Boulevard. Madtson, WI 5370~ (G21/01-07-91) Study Dlrector Approv~l: EN can 22880099..00003311 3MA10006925