Document rB2ngrr8yY3y1aBwJwbr8joyv

A I RR ETT TE we ITTT 22779988..00000011 Exhibit 22779988 33MM_MMNND011669955661166 vo Two Haek Week OOorrtaallm2RRaasnn0ggsoecffoiirnnddiiinnnggnaTTtoosxxiicciittyy Study Study of T-2509COC in Rats EExxppeerriimmeenntt Ntoo..:: DDoosstinngg started: Started: Recovery Intervals Completed: Recovery Intervals Completed: Ssttuudtyy DDiirreeccttoorr:: TTeessttiinngg FFaacciilliittyy:: sponcors Sponsor: s17m9mR0R0z233 ostaber 3, 1975 October 3, 1979 Novesber 15, 1579 November 15, 1979 GR. stetten, 15 G. R. Steffen, BS RSSRSaiiaetkkfeeeetrrtpayynLLtEEaa,vvbbaaoolMlrruiuaantataoonttrreiiiisooeeonnsst;,aLLaabbIIoonnrrce.aas,ttoorryy .St. Paul, Minnesota WTu..oxcCi..coMnlecocCgooymrmmSiieccrkkvices Fecomypany-- Toxicology Services 3M Company St. Paul, Minnesota GESSS.ietnnXatRis.oonrSaDTtTito~ortfxxeefiicecctnnooo,,llr/io~sg.iiastt Study Director bz/fGaote Date iMM.an.aTg.erCc,aasseeP,,athDbVooMntA,,ogP7yh-DDRoxicoto2sybs/bDsaaottee Manager, fvPaaltehaoclioogny-LTaobxoircaotloorgyy Safety Evaluation Laboratory 2798.0002 2798.0002 W_MND16S5617 3M MN01695617 T TABLAEOOFBF CCoOLNNTTEEENNTTSS Ppaaggee 1 IInnttrroodduuccttiioonn .L.o.e....u .e ....e .....e ..... .... 22 MMOetBhHoRdEs . + . sc..bu.s.t.a..ru.t.. r. a. t. a. t. e. n. nc.r.n.c.n.n.s.s. 2B FE Results ........................... 3| DiDSiescuussssiioonn L.L.........i ...L ..... ..... ..... ... 2222 AAopppeennddiicceess L.i.....i..i .i.a.i.a.a.i.a.a.a.a.a.l.a...a..... BD 23 22779988..00000033 I3MM_MMNND011669955661188 1 sSuummmmaarr~y TTthhweeo ooparrraatlls.rraannggIeenffiPiannrddteerrItttoohxxeiicciiattcyyutessttuourddayylooAffLDTTS--O2255w00a93sCCcOCdCefiiinnnerrdaattssinwwmaassaleccooCmmDpplleerttaetesdd iinn mStSiwiinoxxispggtarrerootruusepp.dss hhsaiaInvvngiilnnPeggardtssoiisxxIesrtrhaaetrtsas//nagggcrriuoontuugepp,,forrao55lm11--A552L995D0Sdd-0aa1yy0sws,a0s0oo0ffdmeaafgg/eieknswew.hdheenninTdndomosasPeleadder,,tCvIwDIee,rrreeatTs-aa.2d45--09CoC wTwmauaissenlivasaedtdmemirrineanditisss/ttsseeierrnxgee/lddgerbboyyduopsdd,eaasiill51yyragdngaagaysissttnrrgiioccffriaoignmnettuu2bob5ana0tt-dii1ooo0snn,e00tt0oodaymmmgaa/ll1k,eeg.waaennrddeIfnfdeeommPsaaaellredet CCaIDDft, rr2aaT0tt0-ss2..5o0r9CoC Ta7755wneBmlggvf//eokkrggr//nadditaansyye/..sedxa/yDDgsoorssoiaiutnnpgg,thcceoo5n1nttliidonnawyuuseelddevoefffloorrag(eff7ii5vvomeene/dddkaaosyys/ssedadaaytta)y.tthhiee, AwhhLeiiLsrghehsudrllvoeeisvvveeelidlnga({t22h00i002g0hm0mga//dokkorgss//eddaayy)) aafannnodiilmelaaofllwossirngananniddGneoshhiaadnllagfyf.s ooffatSettlhhteeehectlleooldwwowddlooolssweeevdeloggsrreoo(uu7ppa5 nhmhiagam/ddaklgsaa/dw11ae44yr--)e11.55 edduaAatlyyhlanrreaesctcuoiorvzvveeeirrdvyyi,nogininndhttiaeegrryhvvaa1ll0d.oseALL issfnuuotrrlevvlriiovvvwaiiilnnn.ggg adaBnonrsiiaimminaangll,.ss isintnSoembblaooecttchhht,eggdrrlooiluuvoppewssr,dwwoeesarredeereannesaiuulmttahhalaasnnndaawttekiirizzedeenddeeyauatttthitatshnhseaeuteeiesnznddedvoeofrfoentthhdceeavyarlrueeiacc0.tooevvdeerrAyyll miminictcerrroovssaccloo.ppiiccaaBllrllayyi..n, stomach, liver, adrenal and kidney tissues were evaluated TTfhhieedenaaccceuutteelioonrriaatlls oAAfLLDD5S50O56o-off139TT9--2255n00g9/9CkCgOo.CC iinnGammsaatllreeoinrratatetssstiwwnaaassl 8877i88rrmmiggt//akktggiowwniittwhahs9955t%%heccomonno--st cocfocoimcmdmumeoronncrneedeefflffiienemccitttssomcceoaafuusdseeo5dds5e8bb-gy1yr3o9hhu9iipggshhmg/aa2kcc-g7uu.tteedaySddsooassseetfssro..olilnoHHtwaaeinnsntddgillndlioannslggi--nppigrrr.eercciiitppaTiithtteiaaottnleeoddwvaesccsotonntdvvhoueusllessmiiooogsnntrssoup o((c22c5500urmmrgge//dkkggil)n wvsaaossme ffdrreoeeeseooffgrotturrpeesaattmm2ee-n7ntt--drraeyesllaattfeeoddlleeoffwffieenccgttssd..osing. The lowest dose group aDDnaadiillyysegxgaa-ssrtterlriaictcediinnettfuufbbeaactttiisoo.nn oofTfherraatptssriwwmiiattrhhy eTTf--f22e55c00t99sCCOowCCerrreeessguuallsttteerddiciinnitrtrrreieatatatmtmeienontnt-,-,, hddaoonssdaalggieen--gparndecispeixt-raetleadtecdonveuflfsecitosn.s aTnhdempircirmosacroypiecffelcitvserwechraenggeass.tricTheisreriteaftfieocnt,s hcaonndlingptttrrureicicbkbiueutpdtei-edtudaptttoaoepddpdeoocassoraanaggvneeuc--lersr,ieeollnaaasntteedduanndkddeeeaammttpihhtcssr..oasppcSeoSaepercicaoocnnncddleaai,rrvyyerseoefffcftfheeaccnfttgossecse.saa,tt bbbTooohttdehhysewlleeeeivvfegefllhesscttswwleeorrsceesond-aauring ntttohhuteec. kdedtdooh-sesuiipnnlggowapppeepdrreoiiasooredda,,ngcreohh,ueepaa,ddanhttaurrdneemkmhoeoirmrsspsttoaalnnaoddpgpihehcyayrppaeeenrrvcaaieccd,tteiinvvcsiieottfyyto..f fgeTcaTehhsseet,rihhciibgoghdhiyrdrdwiooetssaeietgihgGotrrnoo.uulppo,,ssTbbhuuedtrtuering wwwnieeotrrtehe ttnhneohoe mmliCioNcwcSrroodssoescfcefooeppciigtrccso.uccphh,aannTgghheeaessd thiriinnesattttohhmleeeongbbtirr-caariiennleavtissdeeeecdcnttciileooinnvssoerf ffgerrafoofsmmetcreetiiisctthheecirrorrnislltieeasvvteteilleodntt.ooof ccToofhrroerrcraeeelllaattee wmnnioeetrccherroossctiiohssnevuaCalNnnsSddivfefeafafttettecyyptisscc.ohhdaaennsggTeehssea..ndtrmTTeohhaeretemmmeaaanllnteei-ssmraelglgseaentnweeeirdrtaahllllliyylviehhvraaeddrefcefehaeaarcrntllgsiieeesrrc.onooscccicusurtrreridinnggofddeefaaottchhassl,, more convulsive episodes and more animals with liver changes. RnReeSvveerressfaaflelctoosff dttihhdee tntoooxtxiicoccceeuffrffeeccdttussrinoogccccuurrrecrroeevdderaayff.tteerrThddeoosssiinangsgtrssittcooppppleeedds..ionsSSeevvaenerdreeodtdeehlleaaryyeedd sGCsaNeeiSccnoo.nneddfaafrTreyychteseeffrfdfeeiecccdottvssenroytssuuoabbcsnsciiiudmdreaedldsduddruduiirrndiignnggharverreceeoccmvooeivvreleyrrd.yy..faTtAhAtlelyllglarriseveteccrrooivvceecrrhyyalnegaasennisioimnmsaabllusstanhdhnaoadtdotwwhleeeiiirvggerhhtt nngeeacicnrr.oossiissT..he recovery animals did have mild fatty liver changes but not liver 22779988..00000044 33MM_MMNND011669955661199 2 IInnttrroodduuccttiioonn TTwhhoee two opoarrraatlls.rraanngPgeaeffriitnnddIeerrevattloouxxaiitcceiidttyythssettuudadycyutooeff parts. Part I evaluated the acute ToTorr--aa22ll5500A9A3LCLCDODo5CSC0Oiinniinnrrmaamttaasslleevwaarrssaattsscc..oommpplPPlaaeerrtttteeddIITIiinn e2envvdaalluufaaettmeeaddletthrheeatsttooxxuiisccingeeffcffoeesccettsslaaennvddelsrreescceoolvveeecrrtyyedffoofllrllooowwmiinntggheddaaziiallsyyultoosrraallinddooPssaiirnntgg1.iinn mmaallee and female rats using dose levels selected from the results in Part X. TTThooexxiiccsootulldooyggyywSaSeserrvvciioccneedssu,,cteI3dM bCCyoommpptaahnneyy,,SaSfStte..tyPPaEauuvlla,,luMaMtiiinnonnneessooLttaaaborwwaaatssorttyhh,ee Rsstitukudedyry sLspapobononssrooarrt..ories, TZIInhneccep..a,,asttSSuttdd..oysewPPaaauuspllo,,rctoMiMnioidnnnunncewetssaeoosdttaabc..yomptAlAhceecututetSedeafoddenootssyiiNnnEoggvveamlssbutteaaartrrittoee1ndd5, oLonna1b97oOO9rcc.atttooobbrTeeyrhr,e33,,Rpirok11te99or77c99oLlaaabnnwddoriatttthhhoeeries, aarfmmeoeepunnenddadtmneeinnndttoAssspepaaepnnnodddritaacieollsniisswtTtasaooffndcpporrmIiiTpnnlcceriiteppseaapdllecotppniaavrrNettoliivycce.iimppbaaennrttss15,aanndd197ss9uu.ppeezr-vTvihisesoorpryryotppoeecrrossloonnwnneiellthaarree found in Appendices I and II respectively. SLSiainbnccoeeratttohhreey ssPttruuaddcyytiwwcaaess aa(GrLrPaa)nnggerefefigiunnlddaeetrrioeenxxspp,eerriihmnoeevnnettv,,er,iitttwwhaaesssetexuxcdclyluuwddaeesdd cfforrnoodmmucGGtooeooddd in LraaaeccqbccuoooirrrrddaeaatmnnoeccrneeytswwP.iirttahhctTiohocueuerrsStS(totGraaLaPnn)gddeaarrrddelgoOuOcplpaaeettririaoaonttniisnnf,ggorhPPorsrwopoeeccvceeeiddrmuu,errneessst,hwewrhhiaisccwthhuddyiiatnnwaccaoosrrappnodocrroaanfttdieneuaclGGtLLePPdrepionrt irisseqmmuaiariiennmtteaaniitnnsee.dd iiTnnhetthheestorrreeaccgooerrddlaaorrcccahhtiiivvoeenss foffroorrspttheheceimSSeaanffsee,ttyyrEEavwvaallduuasatttaiiooannndLLaafbbioonrraaalttoorrreyyp..ort MMeetthhooddss PPaarrrottn ICI::harlTTehhsee aRapippvpreroroxxiiLmmaaabttoeeratooorrraaillesAA,LLDD5SI0nOc.wwaassTdhdeeetteerrramtmisinnewededreiinncmmoaanlldeeitiCCoDDnerrdaattssinoo-hbbottuaasiienneeddfor aWafipprtppohrmroox~fxiohionamdaraltteeeasllnydyRwoionanveeteerrwweeLeeaakkbvoarpiparlrtiiaooobrrlrieettsaoo,dddoolIssinicib.ningtg.u.mT.hTeThheeArynyaitmwswaeelrrweeeriehhdooeuuncsstoeeinddfdiitcssiaiiotxxni//eowwdniirrveeia--nstt-oohppboyuscceaiaggneefdoirvi waudinuatadlhlhunnfsuuoimrodbdbeiercrasysndcaawnonaddntteraarolcclaooevlldooarrilaanccbdoolddeiihnnaggdadassyylssi1ttb2eeimthm.u.omu.rTThhleeAingiaahmnntaii/lnmdaaallrikdhheooncyuutcssiliifenni.ggcatrriooooonmm wwwaaasss bttyeemmppieenrrdaaittvuuirr-ee and humidity controlled and had a 12 hour light/dark cycle. wSSeiizxxerra5at1t-se5//9ddoossdeaeysggrroooluupdp wwaeenrrdeewessieegllheeecctdteedd17f9fr-ro2o6mm2ttghheeramccsoonnwddhiiettniioonndeoesddedaa.nniimmaaAllssc..onsTTthhaeentaadnnoiimrsaaellss whvveooerlleuummteee5s1to-of5f9ari1t0d0iammycslll/e/kkoggltdowwaaatssnhdeuuwassepeeipddgrhoaaepttdrieeaaa1tcc7ehh9-2cll6oee2vnveeclleg..nrtamrsaDDtiiiswsothtneiisnll.lleeddodsewwdaa.tteerrAwwaacssonuusssteaenddtttdooosddeiilluuttee the test article to the appropriate concentrations. TT1hh4eetoaannii2mn0aalldssaysww.eerreeBooodbbysseevrrevvieegddht33s--66wehhrooeuurrssobtffaooillnlleoodwwiinnjggustddoopssriiinngograanntddo dddoaasiiillnyygttahhneedrreeoaanfftteterhreffdoorary ood1ff4iedntneoecocrrr2oo0pwpssedyyar..yes.kGGirrlooBlssoessddynnaweeteccirrtgoohhppetsssyyenwdaaebbronneoofrrmmotaahbleltiiatticiinbeeesssdervwvjeeaurrtseeitonprrreeiccpoooerrrrdideoetdddo bdffuoootrrsinaatgllillssaunaadennsiiommawnalelsrstehetthnhdaoatatty dssaiavveeeddd..or were killed at the end of the observation period but tissues were not PPTaanerr.tt aIIIIn::d cMMoaanlldeietiaaonnnddedffeemimaanll-eehoCuCDDserraafttossr wwteewrroeewoeoebbkttsaaiipnnreeiddorffrrootomm CCdohhsaairrnllgee.ss RRiTihvveeerraLLnaaibbmooarrlaasttoowrreiireeess,, aiIinnnncddd.iivvvaiaitnddeduuraallcvloleynyrdehhiootuiuasosveneadedidlaiibnnilnehh-aahnnoagdugisiennlggifbiocctraauggneet.sswohhwaAaenvvieiimknnasgglvwpiirirrideeoernmmteeitssfohhicdaofftsrriioononngtnt.sswaaasnnTddhebbybooattnittinoomdmmaisslv..siduwaFFeloorooedd eheaaaanrdrd wtataaatgg1ess2rhaawonneuddrreccaa1ggaieevgahitccl/aaardrbddasslr..ek caTydThchelelei.brriootooummm.wwaassAnttieemmmappleerraaittduuerrneetiafaninddcahhtuuiommniiddwiiattsyy bccyoonnttirrnoodllillveeiddduaaalnndd had a 12 hour light/dark cycle. 22779988..00000055 33MM_MMNND011669955662200 3 TTawsweselilvgveneedrraatttsos//ssteehexx//ll2ee0vv0eellorvwee7rr5eemgss/eekllgee/ccdttaeeydd gffrrroooummp.tthheeOnccoodnnaddyiittii1oonnteheedd aaannniiimmmaaalllsss vaaennrdde a55111s4s6ddi-aag1yyn8sse5dgoorlltaddomsaat.nnhdde Ttt2hhh0eee0 mtmoaarellseet7ss5awmwregteii/igckglhghee/edddasyo11l55ug44rt--oi22uo11pn11.sggwrraaeOmmrnssedpaaanryndedpIatthhrteeehedffdeaeamnmisailllmeyeasslsuwwseewiiienggrghheeedd ddu1iis4sse4ttd-ii1ll8fll5oeerddgeravawcmaashtt.eerrdosTaasehsettlhehteveeeslddt.iillauureeDtnnoittsc..ilnegAAscoolccnuoottnniissonttnuaasenntdtweddfroooresseepfvvriooevlelpuuammrdeeaeydsooffdaati11l00ytmmhellu//shkkiiggnsgwhwaass ddu(oos7sse5eedm/lflkeeovvr3ee/lledaac(y(h22)00.00dommsTgge//hkkelgge//vlddeoaalwyy.))dosaDaennoddsignrffgooorrupcnonhiinanntdeeinsdudiaaexyydssafanaotitrmattflhhieesve/slledooxawwysddrooesstaeetaintlleheedevveellhfiorgh Tdr(aee7ycc5oomvv10gee./rr' kyyg/Aaadlffalttyee)rrs.uddroovssiTeevhienddgaalyyoaw9n9idmoaaasnnledds gtthhireenouprrtehehemmaaahidiinnciisnhniggxdoaaasnnneiiimmmgaaallrlssosu/pwwseeerrxweeerreeoetuuattrihhenaatennadaaittniiefzzdoeerddfooronn rdLreaoeycwcoodvvio0ee.srreyy Agaalrfflottueeprrsudadronovdssiiivnni1ggn5gdsstataooynppsippmeeafddlo..sr tiThTnheheethherrigeehhccioogvdvhoeesrredyyosgiirennottueegprrr.vvoaaullp wwwaaessre1144reddtaaayyissnedffoorrfortthhee low dose group and 15 days for the high dose group. ToTbhhteeaaiannniiemmdaallpssrewdwoeesrreee, oobbbissewerervveeekddlydddaauiirlliyyngffoodrrosssiiingggnnssaonofdf ottnoocxxeiiccioittryy..twicBBeooddyya wwweeeeiikgghhttdssuriwvneegrree rorFbeeoctcsooaevvieenrrenyyde..cprroeAApdlleollyseaaa,nnniidmmbaaitllwieseseskuttelhhsyaattwddeudirrieeieddngsooarrdvoewwsdeeirrnfeegoreaeunhudtithshaotannoncapaetatitizohzeroedldotwswweieicrrceaoelssaeuuwvbbeajjeloeukccattteedidduornitt.onoga& gross necropsy and tissues were saved for histopathological evaluation. TTThhheee dd7oo5sseema/llkeegvvee/lldssayffoolrrevePPlaarrfttorIIIItwwheeerreerepsseeeallteeccdttoeesddeaapttorttthhieeonccooommfpplleetttheiioonsntuoodffyPPwaaarrstt IsI..elected TTthho0eeddee27l05l0iimvvmegegr/r/kkgaa/gd/ccaduuyammymuulllelaavettevilievlveefwoar11s44 tdsdheeaaylyerdcdeotopsseeeedatataopdppoprsbroeeoxxipiconmlraaotstteieeollnyytoeoeqfqtuuhaaetllheacttuoostteuttdhhneeyoAw-ALaLesDDfSSfO0escetvvlaaellcuuteee..d TltLheehevvaeenll20t0haaenndmdAgL/ttDkooSgOd/ddeeallvyaiilvvueelerre.vaealccwuuammsmuullsaaettliievvceeted1144tdodaabyyeddoocssleeoseaatttolleeaatshsett tatwwcooutettiimmneeoss-egfgrrfeeeaacttteerr than the ALDS0 value. RReessuullttss PP55aa%rrttcoII::nfidhTheeenceaaccuulttieenitoosrraalolfAALL5DD5S8S0Otoooff1T379--9225500m9g9/CCkOegCC.iinn mmaallee rraattss wwaass 887788 mmgy//kkgg hhaavviinngg 95% confidence limits of 558 to 1399 mg/kg. DDClooissnaaiggceea--lrreellsaaittgeendsd ggiaansscttlrruodoieindntteeasstttiiunncaaklled-ttuoopxxiiccaiipttpyyeavrwaaasnscett,hheespporrfiitmmaafrreyyceTsT-/-2d25i50a099rCCrOohCeCaeeffaffneedcctth..ypoCrorleveiaeancrcitntciiiavgvlihitttyyso/ihnhgynypsptoohaeaiccnttdciailvyvuiidtteoydyf ad((oTTstaaiubbnlclegeked1i()-)f..uopunMMadoopssdptteeaardddaeenaoactntehh,ssstuasadttoyftttdhheaefyehhciie2)ggshh/eedwrrihairlllreeehvveeetallhssoasnoeodccccahuutyrrprrtoeeh-dde dolLevooawewdererrnhiaglldhaetvvegelrlossonswswteehrreeeeviddaddeyeelnlacaoyefyeedddofosttihhrnrregooduudgge(hhnfeodssuttnuoudrddyydhedeadamdaoyyrorn88has((gtTTiuaacdbbyllegeadsa22yt))..ro2)iMMnootwssehttsit'liaeannnaiitlmmhaaollmsseiecoaffstooauunntddhe d((erTaaadbbllheead33))..gross evidence of reddened or hemorrhagic gastrointestinal mucosa DDteehlleaayy5ee00dd0,CCNNSS200tt0ooxxiaicncidittyy10w0w0aassmaee/vvkiigddeennlttevaeatltssscho~amede dcdoolssoaanggieec/tlloeenvveiellcss..conOOvnnaeelsiaaonnniismmaallonaadttayeesaacchh6, ooff Wt22ehreoosrr50f770o0urr,needsspp2eed0cc0ett0aiidvvaeewnlldiyyz..hIi00n0zEaa2mc4cghh/hkoeeugppriisssl.ooeddveeelHswvyaapssehrappderraeecccctliiioppvniiiltttcaay/ttteeooddcniccbubyryrchheoadannnvddutlllhiisreinneoggnsatanonddonnittnhdheeeaysaadannyii6,smmaallss wcffeooovrlleellrooewwfdiio.nnuggnddTdhoodesseiianndoggbwsiaeatttrhvaitttnhhieeo2n4220000hp00oe,,~rriso11.d0000w00aHsyaapnndederxet55ea0000ncdtemimdgvg/i/ktktgygo oll20ceecvvedeulalrsysrsebdbauutttthttrthehheeeesseet1o0aa0n0nniiimmnaaanelldssdaSyrr0sea0-Bc9o/vekrgedl.evelTshebeocbasuesrevatofiontheperdieoldayweadsdeeaxtthesndebduttono20adddaiytsionaatlteheffeIc0t0s0 aoncdcur5r0e0d. mg/kg levels because of the delayed deaths but no additional effects occurred. TTthhheeeselloowaweenssnttalddsoosseeshggorrwooeuudppno((r22m55a00lnmwgg//ekkigss))htwwaagssainff.rreeeeAolof)f attnrrieemaaattlmmseennattt--rreeeallcaathteedddoseeeffffeelccettvsselaanntddhat otssfhuuerrsvvoeiibvvveeiaddonuismffaoolrgrsrotthshseeshodwdlueuerdrsaaiottnniiosoornmnaalotoffwneettichhgerehoptsssttyuug.addiyyn.hhaaddAlaalcccceeappnttiamaabblllsee wwaeetiiggehahctthggaadiionnseaannlddevwveeelrreethaffrtreeee of obvious gross lesions at necropsy. 22779988..00000066 33MM_MMNNO011669955662211 ' Ebd vv 2Ie 8Elo on :igceiE ||ff 2z fats olor sd ol ve ee Becton o JU Econ Bo Bo nnamEE o Gf nmgEEEREE o ci sli,e0 Pleiii ai8id.0g|%8 FARIEREZFRERReEEERRE]RZEE8E3EEEE2B . z 22779988..00000077 . a nossezz 3M MN01695622 | 5 BEF LEIS Eee ; iis fib I | I I I I I I Hl eseeesnns ffl ~eeEErged fl nereeeees. S| oggrErEEE of cEEEEEEEE o WezEEEBEEEE o gl ~~ ne Baam8 oo J -ggaraane A crag. gf emno tego $ i g 3 2 gliifgo!heis gf1Polii|sii LEAlRiS ZgiE aEcRiEzE eEd| RAdRt 22779988..00000088 awotessezs 3M MN01695623 Ih ll 1 3 Boj bzeererezEe En eree.zere.8 C83 | leree sees. Ppffl ererrraza.. FARE fll cesrrrnense : ii | cEEEEREE BE o Fad | Ee Enod gEEE 0 i | ff e--tereraze ol svensnrree . Gl ogererezaes 7 i: ii 5 is fled, 533 2588 2 8&8 3: 5: PEl liseEsElaEsYeEiLsaEEbEiEled 22779988..00000099 a MNOTe9sozs 3M MN01695624 E8E : 32 32f2ig%s ESRD : iE 4i gH3He 3 fl ~sezeoc =| | nrEEE of nEEEEo | ~tege of n2EEE | g2E no Heol 228 Al one. fg] ree o ff|g meee Pf errr of crEEE | c2B2Eo forreeo Jf eer Hl ceser ff ezeee i i 38 yi: El [2F%I 3 gi1 FP llieyg:egsralilPlvBe0IIEsd"~~ 22779988..00001100 . 33M UMNoNT06169955662255 nl 8 4 v8 nf oe o| Bw o Hef 20 0 Boe Eller] 3TPEhEie,Eo:u [fgBHLoLt.e C Sgek ~ 0 got. JY ce 8 Boe o 3 ot ol ffl Beoo BRM Hes f|EgiLllLoee 2% o 4 ee LEI i ee TERE B$l8eed)." of P E:5 22779988..00001111 3M MN01695626 s TTaabbllee 22 AoAfccuuttTee-25Oor0raa9ll00TCTooxxiiincciiMttayyleSStRtuautddsyy of T-2D5De0ea9attChhOCPPaaictnctMeearrlnne Rats BLDeoovseeel ~ Level 1TF2 33 1100000000 mmgg~/gk~g-? 1155 em 55000000 mmag//kkgga- 0 33 11 22000000 mm3g//kkgg 06 33 00 10i00000 mmgg//kkgg 00 00 00 500m3/kg 500 mg/kg oo 0 0 00 250ng/kg 250 mg/kg 0 00 0 0 AAL9L5DD1S5O0Con==fi88d77e88mncmaeg//kkLsgimits = 558 to 95% Confidence Limits = 558 to 4bDeeaat5thsh/eDaayy(sm) 7 4 5 6 7 mmm em een een 00 00 11 11 11 0oo 11 00 00 11 11 00 00 00 11 00 00 00 00 00 1399 ma/ks 1399 mg/kg~ 85 f9-eTemrm ee e-e-e.==..... 11 =--=11 00 0o 0 0o 0 TTooWtot.aallbbDoeesaeatsthss No. Dosed 66//66 6 6/6 o6//66 6 v13//e66 o0//s6 2 2 pDaattaa ffrroomm tthhiiss lleevveell nnoott uusseedd Computations by Duluth Probit ffoorr AALLDD5S0O Analysis, cEcnaavlliccruulolanatmtieionontnsasl Research Laboratery FCPrormoopggurrtaaamntions by Duluth Probit Analysis, Environmental Research Laboratory 22779988..00001122 33MM_MMNND011669955662277 TT oo R-- E C lO u'~ 0 0 ,.4 0 ~q ,..4 0 ,~ 0 NEE EERE Fog [fs idr~ ~j ~4 cenaoo .i $3 1ol 38 5LE1% i: llgofegs i2i2 l 5 o5g ) 2 fla iid 22779988..00001133 3M MN01695628 nIi PPaarrtt IIII:: proninant TeTfrrfeeesactttmmeennctta--useaadnnddbyddoodssaaaiggleey--rroeerllaaaltteeddadgmgaaissnttirrsiitccratiiirrorrniittoaafttiioo1nn-2ww5aa09ssCottChh.ee mmooTsshtte phhgiriaggoshhtmriinddcoaossneetirgrgerrifootfuuaepptc,,itonbbc.uuattusneTnohodittsbytthhiederariillltooywawtdiodorooassnleevagagrsrdoomuupipprn,,eissehthnaartddathhiiiionssntt1ooo1llfooosgfTii-cc21520ee9mvvCaiiOlddCeee.snncceeaTnohdofef 8ug8lacsoOetffrrsi11c22veffireeremrnaiatllfaeeotsusindo((.nTT.aabbCllleeTihin44si))..cailrrIIninstiasgsntoosimmoeenaisiwnsnsasotstcaainnpaccrteeeesssdewneeitaatrrhlliyynghahieesismtoororfrirrchh1aa2iggrimircaciltegagsaatssittoarrnniidcc wwuaeelprrpceeeearrpsparrneewcsseeeer,nenttdfooiisunnnadgbb.eoo-ttrhheCldldaoiotssneeeidcagglsrrooofuustppissgnfseaacnndedasssiiofnncoccirllauuttddheeeeddd wmaaiatlddehoossoaganagglseeyt--rrraieenclldaattieeradndrituttnuuakctceikkmoeepnddt--uupp aaa(pppTpppaeeebaaalrrreaaasnnnccc5eee,ammnooddrroees6)a.gcceoo-mmrmBmeoeonltnatteiiernndsttshhuoeerfvtillvooavwfledcdoeoasssteeftogghrreroouutlpphoevttmhdhaaoalnsneetthholeenelvheyhliicgahhnndoddodoassoneeubutgngkrreoaoumlwppltowed Agg(brrTdeeaoaabmttlieeensrralee5xxppapanrrideensss6s)ii(.oocnnucBookffeetdt-aaeurpsseeaccspooupnnreddvaaairrrvayaynlceeeaff)tffeecctcttho,,entssiluunoccuwhheddaoasssfeoraannltehuuvenenlkkeefrmnipoprtsttdoaaupfpbpeptweeaarrdaaaalnnylccsoeew..ed Aooabffpdpoerrmaeeirccnooeavvdleerruyypn..akiennTpTthh(eettushscruukorreuvvdgii-hvuvopiiunntggaphphteiihaeggrhharndedcoocesso)eeveaarcnnyoiinzmitaanilltnsseurevdaaannlddforssoovmteehe llofowiwrddsotosseefeawanniidmmaaaysllss appeared unkempt throughout the recovery interval. DeDofosfsaeacggtees--rrweeollaartteeeddexCCpNNrSSeseesffeffdeeccattssscoooccnccvuuulrrsrrieeoddnsaattabbnoodtthhistotlrraeetaaettdmmeennittnstllaeenvvceeellsss.. ofTThhheeessaeed tfetorrfueefnmmedoocrtrsssinwaaennarddneihhmyyaepplxeesprrraaeacctsttsiieevvidiittthayyse..rcolnHeHvviieusslltt.sooippoaaTnttshhheoollabonordggaiiiccianaslloslbbearctretaadiiionnnisnllseewtsseiaironoencnsessovwbeteorarfeienheenndaoodttat tofthchoeecuundrffroorerieedn--,,ainnimmmiitdadwlisacaennddatthhhieienniddtnhubbemrrrbaeairilnenovfelllee.vmveealllssTe..hsecbTToroomannpiiiaccnredosorrecttccoillooofnnnesiimaccwl//eettsroo:enniiccobstcciaoxoinnhnvvieuugldlhssiiaoodtnnossse ommTacahllceeeussrl,,reesdstthhrirseneeesvethhwriiieggchheCStddhooesseeeffneuffcemetmbmsaae,llreessho,,feadmttawwlootersellmooowcvrosmddpooossaeerremdmhaayllpteeeossrafcaeatnmniaddvlieootsnn:yee, llosoowiwcxcdduhoorissreegehdffdeeiomnmasalleee.. osToihnngellnyysl.ooennsseeOnasaenenivimemlaraolelv CidiNnnoSseeeaaeccffhhfeemcaddtloosess,eechgGoerrnaotoduiupnputeeredexxmccoeetrpposttbeottrhhaahtthyyppenneororaahhcciittcgiihhvveiddtoodyssu,eerimmnoaagcllceeutssrherhehaadrddeicnttohhveeessreey isiningttneesrr.vvaall..One low dose female continued to be hyperactive during the recovery Tihhneecreccaoosnnevvuullissniivvfeereeqepupieisnsocodydeessafwwteeerrreedggoeesnnieenrrgaallvllayys ppsrrteeoccppiieppdii.ttaatteeHddanbdbylyihnhag~n-npddrlleiicnniggpiaatnnaddtedddiiddconnnoo-tt vvciuuonllncssvriieiooalnnsssseedisswnttaaasrfrtrtdeeeedqdaudeoonnnwcyiddtooshsaeeifnteddraa2yy4dho55osuiaarnttsg.ttwhhaeesThhhiiesggthholpopddweoodssd.eeosellHeeavvfeneelldmlailaanenngdd-cpeeoraaneccvchhuilpsaaienntidiammtaaoellndtsththcaauottnd-y GdctaaooyynPvlu9alnasanneneddddwssaunusrrevvciidzvveoeeapddds..iweistTThhhoeienndllaoo2yww4sdhdooo6ussreeasn.mdmaall1eeT0s.sheccOoolnnnoevvwaullhdzsioesegedhd dddfouuesrrmeiianlneggmalhhceaaonnnddvclluoiilnnnsvggeudlsjjeuoundssttsttphpurerdiiyoorr tteohhpiiirrspddoldaenddasnayyewde((rnddeeaayycrnoo88))ptsiaaieffnsttceerrreonaddsoodisasnyiigsnnggco8vwmaapassnadressdttIo0o.pptppoeeddOtnhebbeuutthriatgttshhheeddfofosrrseeeeqdqmuuaeealnnceccuyytecolooyffnvucicloonsnnPevvdauulrlssttiihvveIee. wAAeLhlpLililseoaadnnebiismmeaaillwnssegrewwdeoesrrneeeodt.hhaainnnddcllreeeddasi((nppgiiccckkoeedmdpauuppr))edaasstommuutcchheh druatrsingdosreedcoavceurtyelays during recovery as tihneyPavretreI. they were while being dosed. TTtrroeexaaittcnmieetnintet-s-.aannddDeddaotoshsasaggeeo--crrceeullraartteeedddeddaeeraalttihhessr rrieenssuutllhtteeeddstuffdrryoommfttohhreethtterreehaaittgmmheenndtto--srreeellmaaattleeedds tWtthehoarxainencidffteooiraredstt.bhhyee hDhdiieaggayhhth6sddooassoneedccbuffyreemmraadelldaeeysse..6arlaliSSleeervveetnnhienoofmftahle11e22ssmmtaaualldneeydssfsaoaernnvdednthttewowoofhoio1f2gfh11f22deomsaffeleeemrmsaaallwleeesesrse wWGdeeeiaartddeh.. dtewaoTTdhheesbuyhhriivggdihhavyinddgo6osseeatnhdrffoeebummyaagllheeodssauytcco8otnnhtetaililnnruueeetcddhoevettmoroaylddeiiiseenteattrnhhvdrraoolsuu.egghvhendTdhaayoeyf o1122n12ly((frreteemrccaeoolavveteesrmryyewnetddr-aaeyy 7) 7) wrrieetllhaatteetddwoddeesaauttrhhvivaaittngtthheethrllooowuwgdhdooossueet tllheeevveellrevwcaaossveraayffeeimmnatalelerevaoolnn. ddaayyThe99.. only treatment- TTFrroeelaalttonmweeinnnttg--rrteehlelaattreeeddcommviieccrrryoossiccnootppeiircvcalll.iivveeTrrhettooxxliiiccviiettryyesfshfhoeovcwetedsd eecvvoiinddseeinnsccteeedooffofrreefvvaeetrrtssyaall Cfhoalnlgoewsingandthefocraelcovaerreyasinotfernveacrlo.sisT.he Mliinviemraleffteoctmsodecroantseilsytedseovferefatftaytty changes and focal areas of necrosis. Minimal to moderately severe fatty 22779988..00001144 33MM_MMNND011669955662299 2 12 hccihhgaahnnggeedssosewweerrleeevpeplrreesasneednnttthiirnneeffiivovefe oofffive1122mammlaaellseessataannddthetthhrrleeoeew oodffose1122leffveeemmlaa.lleessFoaacttaltthhee haatirrhgeeehaasshidgooofhfsendnoeelscceerrvoeolssliiessvanedlooccacctnuuhdrrrerreeetddhrofeiiennfoittfvwweoofmooifafvlee11sm22ammlaaaetllseetsshaendaannlddotwwooodnneoeOsfeoofffilve11ev22elfff.eeemnmaaaFllloeeescssalaaattt ttfthhoheere htlliohogwewhddioondssoteeseerillenelvveeevnllee..lcroapTnTshdhyee.ssteehreTllehooewwofddlooasssfeeitveeetfhfrfmfeeaeeclctetssshigrraheenffddlloeetcscwtoet ooofnnfellmyyaflievttsehhoosstfeeheamXtraaaltetdsssiedkkatiidllullreeiddng tCtfhhhoeaerngrtreheesecc.oovvieenrrTtyyheeriiinmtntwtoeenrrevvcfaarellompasl((yedd.siieeiddnTohoenntheddlaaayhysssitgh99t,,hdroe1ie1siehoorirggrh1o122u))dpohhstaeahddatfnneoomsaulhhreiivssistvtoeotdpphaaattthhhaooddlliooeoggdniieccdaaullring 4aacn1nhiadimnmgaanellost.wvhiiattvhhTeheoonnfllotyycwaolffaafttelttmiyayvleecrcshhaannneiggnceerssotsheiaastthbnineguechctrroodtppohssseyyey.. gsrtiToThlhuelep hltlahoodavwtmddioosnssuieermvairrlveeeccdootvvoheearrmydyildoaannnefiiammataltlsys dCYciohhdwaannggdneeoosstsehiiannrvaetffsiivvfeeoccoanoolffpasrslieiixdvxermmtaaollneeehssicgrhoaasnnidddsosoobennueetrooaftftshesswyiiixxtshtffieelmmllaaillveehessar..dcmhiTaTnhnhieegmesagglrreeraatettofeelrmreicltnndeuudmmbbfeeatrrthteyooff bleotwtedrosesurravtisvalcomrpataeredat tothehiglhovddosoeseraltesvelwitahnd lithveersucbhcahngreosnicrenfalteucrteedofthethe blleiitvvteererrrreesssupproovnnissveea..l rate at the low dose level and the subchronic nature of the TTgrraeeianattamoeecnncttu--rrrreeelldaattdeeuddrinbbgooddyythweweeiirggehhcttovellrooyssssionotcceccruuvrrarrlee.dd ddTuuhrreiinnwggeiddcoohssiitnngglosaaennddwabbsooddyysiwwmeeiiilggahhrttat Abgbnoaoittimhhnaldodsoocssceeuirnrllbeeeodvvteelhldssurdbbiouunsttge gtttrhhheoeeuprffseeecmmoaaalvlleesesresylalopoispsnttteeamrmrvooearrdlee.tvwheieniiT.sghehhttwTehtteihhgaahnnstuttrhhvleeoisvmsmiaanllwgeeassshigs((hiTTmaadibbolllesaeer77))a..t AfGfneueimrmmaiaallnleegsss taahinennddbrmmoeaatcnnhoyyvedrooosfyfe tithhngeertoeurllpvoosawwlddaoolesssveeoen rarepetcpchoeoovavueresrerhydy tahtahneniiyinmm.awallessreThccegooannittsniiuninruunveegiddvwienttigooghhaatipp.gppheeaarrFdooosttedhhiinn cdcouornnissnuugrmpptttiihoeonnreffcoorroveaarllyll aiannniitmmeaarllvssalaaeppvppeeenaarreetddhounngoohrrmmaatllhetythhwrreooruuegghhooguuattinittnhheeg wsetiudgyh.t. study. Food hTTheheemoroornnhllayygiooctthhaeerdrrettnrraeelaasttnmeeinnntt--ornreeellaaottfeedd12hhmiiassltteoosppaattahhnoodllootggwiioccaaollf cc1hh2aannfggeeemavlwaeasss ccatoonntggheeesstteehddighaanndd hdmdeooormsseoeerrlolhfeeavvegetllih..ce oaTtTdhhhreeeenraaalddtszrreeennaiaantl~moeneneeftff-feroecfecttla1wtw2aaesmsdalppterrosooxbibcaaaibbntldliyyetswdd.ouueeoAfttnoo12ssittnrrffeeerssmessaqlueeccsnaatuussaetetddrtebbhaeyytmehooninntege-hoorr mrTroeherleleaattieeondfdcontcchtlleiiinnnioiectcnahaclelereeofftcffcreeueccrattrtemwwdeaansstf-oururrreiilsnnaeaatvrreeyydralitinondxccaiooycnnsitttiiinnpeeersnni.ccoeer Aiitnnno dffieoonauuftrrrhehhqiiubggeuhhnttdvdoaotsssreeeanatmoamtlleeensst.oTaahnssessoodccaiiyinaactto8eendtdhiawwnvieiitntnhchgemm&iiocccsrrcoooufssrtccroeospdupibicccfuotrkkaiinddscnneoeevuyyesracclhhlaaunndmggapeeysssc..apursiOeOdnonerebtylloooawwndeddaooitssnheetubmmbuaaatllteeiwowawnaas-ssinnocdetuuutcthehadannpsatetiriz-zeedd offnoorraadtatyeedd8eehssaoopvphihaanggguussa.. soft subcutaneous lump caused by an intubation-induced per- 22779988..00001155 I3MM_MMNND011669955663300 1 13 TE! tForlleow.ing NOTEs Foil~ng kidneys. ee and ~tat No. 20 mpg mies 200 nq/kg liales re gR17285 a 0 (died day 6) c~ ToEmlp6eletttieaenggerroos1ssss owe Xf tissue is O~an stoma Stomach mcGervopeeny.anhtiMstioclroogaiccotecxamHiansasteiohnmversvadceinosnson rain, Lives, stomach, wirensis 4nd hot Tones, 7 significant Surges vere founds 14 aly ssrormaision sre 1isces necropsy, bist~logic exastnation ~u done o~ brain, liver, stoeach, adrenals and Crone corereations not listed, no significant Sicrosopis aevations changes were found, le only abnormalities are listed. Gross Observations Ittcros:opic ~servs~-tons mSa aMiIdI hDee~morrrrhhaeggilcc ares areas (ulcers?) wAae AetCcreetthhseese ccoaooututttteeeerrrresadrreggfortiooeocnnassslhoaoaaffrreeah~tssheeooeffqs~ucsa~ttToorrnmoilgpdcceestematiuuioctconoonmssaaoanntddt~hheerrse hemorrhage. These hemorrhagic focl were not assoc!ated with any i.f1~tfon nor with any particular n~roais of t)~ qas~rlc ~aucose. re Wo significant charges Moderately severe futey chanaes ve present, ~kxieretely severe fatty chanqes were present, as Lopreniastely soa-shirh of the Meomocyin had approximately one-third of ~e heDa~tes had tepiammic ax veces. Th inetess cite soma ~topl~c fat vat.lea. ~e tn~lved cells SI TA but ~t always, had a cen~al lobular m[rrzeise 9R17286 (died day 8) prStomach re. ~Irenals mans vie areas Saall black areas [= 0wmorrhages?) oust amorshagten D~rk (hmmorrhsgic?) ~but~on. scaccared fuck of consencion 406 hemorrtace were SClt~ered feel of conaestion and he~rrhace were Peasene in he outer reaions 5 he StFIe macons present in the outer regions of the ~as~ric mucosa. Sather marked comguetion va present, curtiestaciy ltather ~arked o~es~ion w~ present, particularly sma 9R17287 Gd 0 (died day 6) mies 9R17288 an (died day 7) [--. 8~omach Stomsen 5~x~ach Large bemorchagic aress Large h~morrhagic a~eas wm (ul~rs?) Sarge black spots Large black spots SE (hemorrhages?) in the ~edulla but in the cortex as well. Scattered fock of conserticn and hesorzbace vere Scattered focl of congestion and he~0rrhsue were Fresane in he gascrie moon l~eesnt in the gastric ~ucosa. Scuttared feck of competion and bemorehase vers S~ttered fo~i of ~ngeetion and hemorrhage were Fran ST present in the gastric mucosa. At one of these foci there wa~ s~ee r~crosis of the ~as~ric i RT EA ee spltheliu~ (developamnt of a shallow he~orrhaalc s9mTRa1or7zr2e8as9 y (died day 8) swmoe 0 9R17290 (died day 6) mm gR17291 wa 0 (died d~y 6) mrs 9]Ll7292 Wen (~ ~y ?) Aaranaie aA~trslnaIleacertine war ~sall Intestine stomen Stosmch Dark Qumorenagten Dark (ha~orrhegic?) hadduned axons Reddened a~eas Mo simiticans chasers NO significant cha~es Duck Hoes Memscchoge) Dark lines (hemorrhages?) waver stomS~mar~ fo. 9~ch re~ver No significant chasons No sl~nific~nt changes mat pha specs Saall black specks = (hemorrhages?) at tran ~d lines No signiticant changes ~ si~f~c~t ~ges ulcer). 20 stanteicans cnanaes ~ e~nificant chanqes Hasse not promeses for smamiation Tissue not processed for s~uairation X18 facty chan vere indicated ar asoroxinately Mild fe~t'y chan~es were indicated as eu~roxi~atelv ratify lO-15t of the hepatocytes had ~toplas~ic fat FpvFPCoraorhcceceiauassnolleelvnneaattassrr.eeaiaansrssesthoooheffceipgscotoumrep~~dtesrisslwttsciiltooh~mnnue~saooaessmnn.aded. hhneeemcIIsronncorarnrornth~hsaeggeeoiLfnnvwsveettarzahneenecee sTuerrersaspteinsaeleinn. (seelopment of an surly this was ~l~lat~w/~ I~ necr~/s of ~e ~strlc epl~li~ (~l~nt of ~ early M h SiV!n~ niCisag adtl itffc aaettttpyyuatl~cb~hhiraayn)nig.geessss wvhaeesrreerppirrseepssieeennettmiaasss aaFoppkpprrvoosxiiisncm aetteesllyy wo5q siomieicant changes of the hepatoc3rtes had ~toples~tc fat vacuoles. Focal scuss of competion 4nd hemorrhage vere Focal areu of oonqe81=to~ and he~orrhaqe were Present In a goscric mows. present in the gastric R~osa. NL Catcy changes vere peasant as approxisately ~tld fa~y ch&~e8 were present as approximately Toe LR Shlnis 10-15% of the hapa~s ha8 fine cVtoplasmic mi re 0 gR17293 (died day 6) seamen Stomach EeLseoannrggmbbmlimanicckkennlitnaess ~emorrh~lc?) Frorcaan)entarTeansaof Gcaosmtpreitciomno1o08.husozrage vere fat vacuoles. Focal areas of co~ast~to~ ~d hemorrhage were present in thm gastric muc~sa. 22779988..00001166 33MM_MMNNO011669955663311 Fr 190 mre mates (or masden scomten re aa mirzss stoma mWir a a gR172~6 (d!ed day 6) soteen stom 299 mag remares 200 ~,/k~ rein.lea mWie asocamneantn (died day 8) Aarensls medee 9R17344 (diex5 day ?) enone re. Liver mrssnn 9R17345 (die~ day 7) Somer saver mrs 9R17346 aa w (died day 11) mrs 9R17347 ma ars ~17~8 no (~ ~y 6) mrs 9~7349 [rye (~ ~y 7) mse 9R17350 de 0 (died ~ay 6) coma stoma comer scone Fate 4 Contin) 14 orcas ad MTiacbrleeac4nt(coT~itianunea4)Chmsrvations Crone corsrvacions LtBaLec~coesenbbsilaancrukerssypoortss Mo simicicunt ~eao:rhagas? ) changes mo significant copes tS~atttaerablantdoboen le~t r---- SADal~rageeamrsbalagpcakelesapocs (hemorrhages icroncopic weervation are vere focal acess of competion and hemorehase There were ~ocsl areas o~ ~onges1::[on and hemo:~haqe Tre ey in the gastric mucosa. 1 one aren Shere vere sevecal sma fost of one area there were several 8--11 loci of Ttuecenveerre ffocatl acaensstoef cmovpontion and Tha~e were focal ~ress of congestdon end hemorrhage ::in the gastric meccas. Tomsitosingl area of soemsiation necrorts: Tn The area o~8ez~ed -rossly appeared to be a longitudinal axes of coagulation necrosis. :In Teo hare re Sint fas chants ar ad~it:~on, ~here were m4nimal fatty changes ss Ioproxiacaly Su oF he hopacotyvin ma ire app~oxima~ly St of the hepstocytes ha~ fine Seomamic Tat vision: cytoplssn!c fst vacuoles. Harun noe processed for exsiastion Tissue not pro~eesed for examination. roces acess of consertion 4nd hemorrhage vere Focal areas of congestion an8 hemorrhage ware Fresent In the Sustri socon ra at severes axeas pawsent in the gastric ~c~a ~d at several ~eas Fre ansostatad with socroels oF the Suskrie ~re ass~la~ wi~ nectars of ~he gas%ri~ Laroe gu aren Gemor- L~rge dark area fsa rhagss?) Dark (rmcrzhaaicn) Dark (h~rrhagic?) nats black spots S~ll black spots Bandcenaanery (~emorrhs~es?) so inition chums No significant changes Duck red Linen NDoarksioremdicilicnaerss chases oon) (none) Buon rod serene Dark red m~eake ho significant chges No significant changes ~ tBagreoenebbnilian~ee}sors ~ hTiiannmt~oarrkkaLl?iins)easn ~rhaqes?) A bemocehasic vices vas presen itn localised & h~aorrhaglc ulcer was present with localized Aeron of he guar Spite necrosis of the gastric epithelia. pe pp---- Rather ex~onsive con~estlon and s~ areas of Terie vers pret: ~rzhaqe were p~sen~. Foc of conpuation 4nd bemorshune vere present FOC~ of ~ngest~on ~d h~r~aqe ~re present ine rar portion of he SRRRIE machen In ~e ~r ~on of ~e gastric ~sa. Setar fot of camation secrets wee ~attered f~l of ~a~lat~on necr~is were p~sen~. Inf~l~a~1on of ~nonuclear cells ~ woresipgnreisfiecnatntvc~niannaess~ of ~ese nec~ic fool. W~TMasf~acfEcioy ~ecthmaen~tgg ereea8 cneapsreseevnp:ta4srmpimecoFnaitmavtaecloysien I~1 Of ~e h~te8 h~ ~toplas~c fat vat.lea oct of consuation and hemorehage ere present Fo of son,.eats.ton and hemorrhage were present i ar resins of he suserie mons in the upper r~l~s of the gastric mucosa. A small, shallow bemorrhar vice vas present. A e~all, shallo~ hemorrhagic ulcer was present. Sma focad ares of conection ans emcees S~all focal area~ of mnqest.ton s~d hee~rrha~e er presen Tn th suscrle maeons. were present in ~he gastric ~ucosa. wo simsticans cum NO significant chancres 22779988..00001177 33MM_MMNNo011669955663322 1s Taste Cconctnmt 15 ceoe and croncpte Town corruaions EE em Dose Group an~ ~at li~. O~gan p2e020p remtes P(ec.one 9R1?351 on ciooemmouinnten t day 20) anna [, 9R17352 Wn [re idled day 9) en sss 9R17353 on somponna 5 (~n 0apo~nd 5 RE 0 tendnated day 20) mine 9R17354 ey (~L~d day 12) mg tee ?S ~g/kg ~las wr 9R17297 on cmpna (on ~pound 9 nT. days, terminated a day ~) ~Lver wre ae 9;t17298 - omans (on ccmpo~t~d 9 do erates days, tez~Lnated a day 23) LLver amare sr + 9]t17299 fon cemponma 5 (on c~po~nd drains days, ie day 10) ero amare Gro~s ~l~e:vattons Jo siitiourt chug Je-- Blar.k lines [==Y (hItr~gsa ? ) Ensaryed a duck ~l~-~ed 8~1 (t~rk Tin (hIr~hagl) Jo siniticas cham No 81gnifcant ch~ngei na (no~e) [No signin changes Jo sianitions chugs Jo siniticnt chingm No aignifica~t changes [r---- Microscopic Obss~vetions Patcy cehangies vdere paresenpt anospposoimgacrealyid0-i400 Fatty changes were present as approxlma~ely 30-40t of ~ hepmtocytaa had cytoplaealc fat vacuoles. [PP Srv of compen nt mbar wees presen R~1ld8pfsaaatty~t~ cehq raehnsav~reariepppirraeessesensst 2afssat~ hveues~rml1ios8t.ooff NM Casey charges va present a approximately ~ld fatty changes were l~eeent as aF~roxlmately Ton oF i epasmeyin sad ertotamnie Ta lO-20t of the hepatocytee had ~ytoplasmic fat =o vacuoles. Xp3r4 iEgastypsnhadnogevrabporiegssloaiepstppreosiartelyi )L~ld ~a~t~ r.hangee were present as approximately lOt of ~he hepal~.-~tss had =y~oplas~c fat vacuoles. Noratay suve fate humps we presen on l~oderately severe ~et~y changes were present as rossi msi shpat api~roxf~ately 50t of the hepatocytes had c~toPern at macs. Tn satin in gos section pla~c Eat vat.else, ~. eddftion, in one section Ther curs severe atl, Tas aiuto s1oe there were several e~11, ~ocal areas o~ older coagulates, necro~s wth nf1tratton of numerous 9((Roonn17cc3co0m 0mppoou~ndd 9 " da~, te~Lnated We [r-- day * Pale streaks and foe1 oust, antares Dark, enlarged? mines 9R17301 STE faced a 10) tara- day 10) rates ~drenals * L~er totargetr ~nlar~e~? fp Pale streaks manos Meer 9{Ron17c3o0m2pound 3. (on coa~n~ 9 Y~4VSr days ~ tsn[Lnated ria day +o simitit copes ed `TcSohoeawgml~uellseaLttoiononns osebcsreorsvlesd. necromLs. A Matted swe qromely were f~cal A lmted ;ont oafreassesoeef of acute to 8~te lnflmto~ r~nse was present p vsie crsiaaSmei tasgsene sre ~reas of congest.tOn ~nd he~orKhege were oresent the ~ortex. [ha rRuse--hav-rre--groay ware areas of cegsie- The areas obeex~ed ~o~sly ~re areas of coag~la- tlon necro~s, fr~ently accompanied by a Had LS te eatery l~ted ~t of ~uute ~ m~acute infl~to~ Apprataaaly 10-2u of te bapsacries ud fAatpepyrozc~hmats.~el~s a1n0-i2n0ttiocaftle~debybepcyattoopclyatesssishadfat fatty ch~ges as nd~ceted kq~ cytoplas~t~ fat 22779988..00001188 W3M_MNM0N106196955663333 o o 1 te (cman 16 Gros at oases ines hmarvsions Em Do~e Group ~ ]tat ~o. ma mine re 7S nq/kq Nales O~Jan JEon-- heirt--n+ --T-- 9R17304 mors > (on co~po~d 9 Se. days, ~erain~t~d 2S day 23) Liver mos sive 9~17305 , or Skgoms 8 (on o~x.~d 9 SRL. days, tez~tnated a day 23) Liver me ten. 9PA7306 &% cima (euthan~ti sed day S) Mowe -- 91~7307 ~ pry(on compound 9 St days, to ~ir~ted af day 23) pepe---- G=o~s Cl~0erva~.~on: prr---- lalcro~ oplc Obse~etlons "osimiticun hrgee MEtEn fS nty canes sS ur prs 2T peoistaly ~tniaml fatty changes were present as approx~nately 1-2t of the hepatoc~tes had ytopla~Lc fat vacuoles Ko eimitimt chaps No li~tfietnt changes oKien rfeyb hues p wer prp s 1 1-8 Se fatty ~hanqes were present as 1-2t of the hePatocytea had oytopIam~Lc fat vacuoles. No sittin chee No s~gnifcant changes dL gpoastalI y 134 of hT e psaceas Sad osiens J~l~=Ox~ately l-2t of the hepato~vtes had cVtoplasmi fat vacuoles indicating mild fatt~ changes. races te us Puncture hole )ust So Ede anterior to thoracic ina un let; leads to l~ge necrotic s~us ~ea Ln lef~ a~lla - ~nt~a~Lon ungkrmotets, Dark Che~orrhagic?), enl~ged ne) ohn re No tssue saved Conant4 eater wae een Congee~fon e~d hemorrhage were present. 9T(Roon1n?ec3oo0~m8ppoouanndd 99 ddaayyLssi,,ver Cn ter~n~ted day 10) 2 me rien 75 ~j'/k~ Females ermeamrys 9R17355 (on cc~pound 9 terminated day days, 10) me (none) ase 9R17356 MAe4erennaallea EEnnllaarrggeedd?? (died day 10) wm umes edie ie are 9R17357 ees (on ~epo=nd 9 Liver Tv ar 0 ~'ys, ~rla:Ln~ed day 10) ws ume cae ee 92173S8 L~ver pnt 3 (~ compound 9 Foe =r days, ter~nated day wi -- 9R17359 Poesible pale area Pals s~.r saks ( norm ) Wr(on a~uoua~ 9 ~ days~ t.ezlinated day 23) 11M00i%0lodoffftathhteteyhhecehppaaanttgooe~csyytteewsserehhaaddindcciyycttaootppelldaassmmaisiccapffauattroxvviaacmcuauotolleeelssv.. CCoonmgpeesuttiioonn nanddffooccua)lbhaesmoorrcrhhaaggeess wveerree pprreesseenntt o simticint cen in the curtez e~d ~ulla. significant changes oa Sic cored gosty are oc ares of The lesion~ ~etved grossly were focal areas of SSTIUNAT E RHT SLEITS oa~latio~ necrosis a~pan~ed b~ infiltra~lon of ~n acute to 8~acute Infl~atory exudate. 22779988..00001199 aW_MND16S5634 3M MN01695634 ew ow 15 mg remnien feon'e amoynre,ceomepronuinmdat3es wives any 100 aranate md~o(aRonrn1n7e,c3o6o1ss~emorpumniodna59tes uve ard~y 23) sC9(omooRnnrn1as7ci3eonx6z~ma2icp:,aooduunnddda5y9 dd2aa3ryas.., t.~rmir~t~d day 23) mt9(oR aonnnm1m7eci3ono6yma~3ptpoaoutunnSdday59 dd1a6ar1yes,, . terminated ~a m(onrceompa 5 9R17364 10) C(aornni~noa:~coaudndday9 23' ~.e~,tnat:ed d~y 23) 9SomRenir1m7rci3e6no5samtpesenda9y 3+3 ~:arukna*..ed day 231 9R17366 ~, on compona 3" (on ~mpound 9 cerminated day 23) terminated d~y 23) ft 17 able 4 (conciuon) Groas and Microscopic Tiassa erations Grows Ghasrvations Pale sere Pale t~reak Appase amtarged Mo significant charges (one) (none) (one) (none) (one) (none) (one) Microscopic oeervations hi~Thaacirfcheihavwvmeeatrroreeryufwsoeacuaamalldlleyatresaecacsccm~opofaannailoeewddgubblyyati8aonssuubnbaeacccurutoteseis Wo signiticant changes TaTlThc-Ehe2IsertNcreeivooewffeser.trtheheeem~ihhnneeipipsanamtstloolccyyftttaaeetrssrcyyhhacacdhdhasnncCg~ryeee~sosppllaaassasmnamsdippccpprrofofaxaxttiimmaatteellyy vncuole8, " 22779988..00002200 33MM_MMNNO011669955663355 & A ol 2 o B a 2 g =) 3 32 [I ii |p oo BeEE ff 3 EEE | Eif3 || F832 || 3 || [| "| || gmmmeee geeeggen gvemme~e eeiescereeeemze crvessee sesesee meeesesc CT "eg eg pecgg~sg oe ~pp i18 geepe-gr ge paces-er opp pEoegnee 0 eg peoegegg ec cep renege ec egy ngnggegr ce -ge "E-pE-gE gergggge gemegpe-,-I gvggmgme0c "gg png ge E oom grggegy,-I peospgese,-4o geempgepc games-gges euseepsee0 eessesspe a-zepesee nssseesec eseessrc conf cge 8 wmv f cme og cen cap cp spr 3 ser o o o Jd 18 gi Bia RTH] HERRdEedsiReHrTdR gg BERECEIE 4 5.8 EEE Ze Seis Das EIeR RtilTR of REfzadfi i FE | iii g Egg id R Riel E6 A BEE LJ SW MN0Te9so3s 3M MN01695636 22779988..00002211 {| A s| al s Bl of al [| ff af i,n f2 rof 3 FESEaS% [fo] 2 Ef ||| o 28EE || i SIE || $885 || 3 | | I~ Hl ceeegeweT cpepgeeo-c ~egempg ee cpegeepsoc vegesgpe cpepeegeoe Ni9d crmEepppe mpeppeese0 vrgegzpe trecesge creeespe npeggeoee ~popeeese0 ~eegeTone creeggpe ~gegeToss "meoggze mgeespe ~goggeese ~peggeese gegemme eo mgerzevmsemmeg2eo cmvggeg~e 3 menvnpgpgeespegoc | ::4~ egrgpo voammnnps oe 53 oe-ewee? eegpppee esmeeec eresraee regeee ec reppree ec cecppewpe| fF respppeec | 0 copesesr 2 sempessseo z assesses + sspesess i gEgEsge eesezere sEpgepEEeg 0 3 sppaprsse| 2 HEREIN 33: Pasi Bdo, p iisohe AE EMI IHR 8Ble BtsEiE33C3EgRG3 qs BF: : 0 if gg, gi LI0ggrifk. el | itgiid BIR I EAR IF of BR3E3E3R3IEE5Rg| L SEai SW MN01695657 3M MN01695637 22779988..00002222 TTaabbllee 66 TTwwoo WWeeeeokkf O7O-rr2aal5l0R3RaanongCgeeffiiinnnddRiiantnsgg SSttuuddyy SSuummmmaarryyNofuomofTfb-e2rCC5ll0Aii9fnnCifiOcceCaacllteiOnOdbb/ssGReearrrtosvvuaapttiioonnss Number Affected/Group siSClaEinRnical Sign o200ad NNoo ssiiggnnss tthhrroouugghh ssttuuddyy o0/m1a2 TTrreeaattnmeenntt--rreellaatteedd ddeeaatthhss 1122//1122 soft. feces Soft feces as/212 TTuucckkeedd--uupp aappppeeaarraannccee u11a/1z2 min sn2 Thin Unkempt. appearance Unkempt appearance 6a4//12122 TToonn`icioccnvoourrlsccillooonnsniicc//ttoonniicc 66/212 convulsions HHyyppeerraaccttiivvee o0/n122 HHeeaadd ttrreemmoorrss 001212 UUrriinnaarryy iinnccoonnttiinneennccee 11/1122 RReessppiirraattoorryy ccoonnggeessttiioonn o0/n122 BBllooooddyy nnoossee aanndd mmoouutthh o0/n122 LLuummpp oonn lleofftt ssiiddee o0/n122 HHaaiirr lloossss oonn aabbddoommeenn oo/n122 bD2eo0ss0seGGrreowup 200 ~ 0o/n1z2 1100//1122 onz 201/122 1n2n/1z2 lln/1z2 n3/1z2 3/12 1w/1z2 o0/n1z2 3n/1z2 0o/n1z2 n1/z12 on2 o0/n122 0/12 (G~a/fk7gk//daiya) 75 ~ 1m/212 0o/n122 212 o2/m122 68//1122 o8/212 87/1122 2/12 o0/n122 1w/1z2 o0/n1e2 7m/122 m1/122 1/1122 on2 0/12 F2Y0) =T 12/12 11/1122 0o/n1z2 66/1122 88/122 66/1122 1v/1z2 1w/1z2 o0/n122 0o/n1z2 11/122 o0/n122 0o/n122 2 1/12 22779988..00002233 33MM_MMNND011669955663388 Hell 2 2 oe a21 EoreIAIII fgg fF TF I I I I I I 3 II I I ogs 5 E20 rf ~ E5t 2 PhP] ae 38% sei i [EE EE $8 | oe 28 af E| IRI I I EEE |g I I I 3% 8% 8% 43 ARml ~n oR off Fl EF 0 5 835 iH ~M +I 32 wd of nf u3 23 | ES ED E0 8D 11 if PR i: $838 0H $28 so: Ir lI IF oy ii galo | 80 r~ lmal,~ll 22779988..00002244 SWMNot605639 3M MN01695639 2 22 DDiissccuussssiioonn DDdaoasiiallgyye-ggaaassnttdrriiccsexii-nnrtteuulbbaaattteiiodonneooffffecrrtaastt.ss wwiTiththeh Tp7--r22i55m00a9r9CyCoOCCeffrreeecsstuuslltteewddereiinngattsrretearattimmceennittr--r,,itation, hrhdaeaonsnspddaolglneiis-nneggs--aiinnndtddouusccteeehxdde-rgcecaolosnnatvvtruueilldcssiieoofennffsesfcetcaastnn.sdd wmmieiTcrchreeroosspaccrooitppmuiiacccrkyedll-iieuvvfpeefrrecatpccsphheaaannwgrgeeearssne..ceg,aDsDotaosrnsaiacggueen-k-irerremerlpliattatatteeiddon, raarpepepspsepepaooarnnrsasaenenscscee ttoaoannddtthheessooffggttaassttfferracciieeccss;;eeffffooeennccllttyyss ttwwhheeeerreemmaalltaeehssitnunhhceaaksdedsd-ssuoaopfrftdtabpffopeacdeceeayssr..avneciegTT,hrrteeaaattnlmmoeesusnnnttk-d-erurmerepiltlnaagtteedd d@srootessosiimpnnaoggcn..hsesiTTrhhrteeoitatfftheeeimmoaanllgeeawssshtirllcioohcsstteimmfnoofcrreleecutdwsweeediiwggeahhrttefewttthhhaaeinannrnlettyshhseehmmeaaamnllodeerssbr..ohdaygiGGcrrwooessigssgahsttaarnniddlcommsusiilcccrrdeoourssrscci,oonppgwiiaccs pposrrcteeocssmueearncnrthetdiiinnrinrttinhhtoeeartehihiiogagnhnhiwmhddaioolscssehe ggiirrnnooculutupphedeoodnnhlliyyga..hfdeCowCsooennevavurgullrlyssoiiuvvpheeemtoeherpaprniihssaootgddhieeecss lgo((asCOsNNdtSSorsissecttiimgumurlulcloaaeuttrpiisoo,annn))dwas moeFocforfrceeeucrtmmrsaaelldeewsseirnettmhhohaanreneadffaeemntmaiarlmleeaemsslosrhshaaiaddnndcctoohhnneyvvpuuhlleissrgiiahoocnntdssio..vsietyLgL.eerssossupDoffstrraheegaqqenuu-eennttthanedttrrlseeoweaaxtt-dmnoreesenneltta--trgreeredlolauatptleeiddavenCrdCNNSS ecttfhoofaxxeniicgccteiissttyywooecorcccecucururrrhrereeedadddintiinrnmeomttrohheeersmffaaoolnrredmmsohofyftpheaffrnooacccaaftlleimvannileeteccysrr..oossiissDoasananddge-ffaattattnyyd ccshheaaxnn-ggreeessl..atedTThheelivlleiirvveerr changes occurred in more males than famales. DDmoaolsseaasggee--drrieeelldaattteehddanddeehaaittghhhssdwoweserreeefcecamauauslseeedds bbayyndTT--t22h55e009m3CaCOlcCeCsttrrseetaaattrmmteeenndtt..dyiMMnoogrreeeahhriilggihherddooissneethe mssattuulddeyys.. died than high dose females and the males started dying earlier in the TGTahhseetrrrieecccoovvleeerrsyyioniisnnttewerrevvraaellnorrteesspuurllettseeeddntiinninrreetvvheeerrssaatllwooorrsucrceveissvssiaanttgiioonnhiogofhf tdthhoeesettoofxxeiimccaleeesff.ffeeccttss.. GGGaaaacsssotttvrrreiiircccypplaaaeniisdninona((sttfuuweccewkkreeeaddn--niuuompptalaaepppprpeeecaasorrenaantnnticcneeui))endctcohotennottiitannwpuoupeeedadsrurffuvoornrivkiettnmhhgeepthffiaiingrrdhssttdtohffsieeneww. ddfaaeyAymsLsaLleoosffr.ecovery rlaanenaiictmmoeaavrlle-ssro,,ycohuhaoornwwrdeeivvnaeegrrf,,deewahhtaaahddnsibbmooailddnsyytwwhceeeoiinhggtihhigttnhueggdaadoiisnnteottafhhperrmpooaeuulaggerhhoouuugttnrkoeuttmphhpeewterrreeaeccnodopvvreetorrhbiyyna.biilnnyttAeelrrdvlvuaaellr..etcooTvTahehreey ggClheeaanntneeegrrreaa-sll.oiiczzceeuddrSreidvdneeegbrbieillddiieeatttlaahattseyededdicncoocnntodhdneiivttuhiilisooignnohnbbseedccoaadsuueissdeefnenonmotoannleeeococogffurrotuthdpheuewsrseeeirnegaannipirnrmeaaocllobssvaebrlhhyyaa.dddmumeiFiocccrrteooolssccaooppiicc gclLrhiiaovvneeugrrpesnhn.aeedccrroonSssoeiirvseserwewmaaassldeesnnlooattytehpdparnreecssfoeeennnmvttaullseiiisnnonwttsihhteehdirrdmeeiccloondovvteerrfyyoactctaayunnriimmcaahdllaussnr..giensgTThhireenecotllvhooeewwryddl.ooissveeerF.orrceeaccloovveerryy group had more males than females with mild fatty changes in the liver. 22779988..00002255 I3MM_MMNND011669955664400 2 23 AAppppeennddiixx I TTwwoo WWeeeekk OOorrfaall7-RR2aa5nn0gg8eeCffciiCnnddiiinnnggRTaTtoosxxiicciittyy SSttuuddyy of T-25PP0rr9ooCttoOocCcoollin Rats TITLE: PP(rrsootttuoodccyoollNumffbooerrraa17TT9wwRooR0WW2ee3ee)kk OOrraall RRaannggeeffiinnddiinngg TTooxxiicciittyy SSttuuddyy iinn RRaattss (Study Number 179RR023) TTEESSTT AARRTTIICCLLEE:: AAchceclmleeiaacrra,,l wppiaalllele ybyeeellllsoouwwpplssiooellduuttiibooynnToiixddieecnnottliioffgiiyeeddSeaarssviTTc--e22s55,0099CC3oOCC..CompTTahhniiyss, SSctth..emPPiaacuualll,,wMiMilinnlnneebsseoottsaau..pplied by Toxicology Services, 3M Company, OOBBJJEECCTTIIVVEE:: TiThnheerppartrsiimmaadrruyyrinoogbbjjeetccwtotiiwvveeeekwwsiillllofbbdeeaittlooyiigddaeesnntttriiiffcyy iaannnyytummbaaajjtooirornttooofxxii7cc-2ee5ff0ff3eeCccottCss. hBiBoenewffeoorvrareteers,ttdhheuethrdeidonossgaeecssuttwwewoiillwollereakblbseeALossDfeeSllOeedccattiofeelddyT-gtt2aoo5s0tccr9ooimCmcpoplCleeittineentubtrtahhaeettsiaoawnbbioolvvolefe onTobe-bje2j5ede0cc9tttCiioOvvCeeb.e dhdseoeutwtpeeeprvrlmemiirie,nnre,eddt..shetraTTaihhcniiussteaanadccourutataelegeppAoLorrDrat5tn0igieoononfowfwiiTll-rlla2t5su0uss9aeeCsOmCmadaleliesenscsrroiaontbnslelydywibfflerrllooommwnettehfhdeoerstsoatahmmebeee Esrrvueepapppleeluaaiattetrdid,ooossneesMtpeprootarrhittoniidooannn6..d05AagTTwehhieelrlaggneegbnneeeerraaoullfsedpprrartoofsccoereddauustrrheeedssesaccffurootirrebeaaddRRobiisekkileenorrgweSSxaafcffoeereptttyythethat Essuvsiieaxxlnmutaaahellteeissao//cnllueetMvveeeetllhdoavtwdaiill6llt0o5bbAeesweidldoloesscleetddb..etheusTThdehedeosassfgppoeoornnsstlooherervelaaasnncdudtfeossrttududdtoyyhseinddgitiurroeeeccxwttceooeerrpktwwiitllhllat zuroseeppeeaatthteddooacsceeutessttuudddayyt..a to select the dosage levels for the two week AAttthetthhseetudccyoonnccdlliurusesiciotoonnroofhfavttehheethttewwooowwpeeteiekoknddooofssiinncggontiiinntnteeurrivvnaagll~,thetthheoebsssepproovnnasstooirronaanndd peptxeehtrreeiinoosddtdeuddffyooorrbdsaaiebbrrooevuucattttooriononehnea--vphheeaarllifftohdetthhweeoiplmmtlaailloeenbsseofatanwndodcownffeeetemmikaansllueeissningaattltheeenegaatccohhhbsaellnreedvvveealltd..ioosniTTnhhgee wWeiixlltllendnneoodtt oooccbccsuuerrrvadQtuuririoinnnggpettrhhiaaottdiiwnnittleelrrvvaablle.. two weeks in length and dosing CCOONNTTRROOLL AARRTTIICCLLEE:: NNoonnee SSPPOONNSSOORR:: TTooxxiiccoollooggyy SSeerrvviicceess,, 33M CCoommppaannyy,, SStt.. PPaauull,, MMiinnnneessoottaa TTEESSTTIINNGG FFAACCIILLIITTYY:: SSStaa.ffeettPyayulEB,vvaaMlliuunaantteiisooonntaLL.aabboorraattoorryy,, RRiikkeerr LLaabboorraattoorriieess,, IInncc..,, St. Paul, Minnesota. DDOOSSIINNGG IINNTTEERRVVAALL:: SSeepptteemmbbeerr--OOccttoobbeerr,, 11997799 DDOOSSAAGGEE LLEEVVEELLSSb,,ecaRROOuUUsTTeEE,,itGGRRaOOpUUpPPe,,arsSSIIZZtEEo,, bEeETICCa..n:: apOp0rrraaollpriggaaatssettrriirccoutiiennttu~fbboaarttiieoovnnalwwuiialltllinbgbeetuuhsseeedd sbsyeyscstatmmuiiscce itttooxxiiacpcpiiettayyrsiinntoraattbsse.. anTThhaeepprrroaattpseriwwaiitllellrbboeeuteddoossfeeoddr deaviallyuatfiorng twtohe weeks daily for two weeks (1). (I). AAlevcceoolnn.ssttaannDttisdtdoiossleleedvvoowllauutmmeeeroowffil1il00 bmmell//kkugsgedwwiillfllorbbeealluusseenddeceffosorrsaereayaccdhhildduootssiaaoggnees oolffevettlhh.ee ttDeesiststtiaalrrtltiieccdlleew..ater will be used for all necessary dilutions 22779988..00002266 33MM_MMNNO011669955664411 Appendix I (continued) 224 Appendix I (continued) DDoossee GGrroouupp. niHigghh 10Lo0w DDoossaaggee LLeevveellss ((22)) a[(rttcooerbbeethsseeelleeaccctuteteded pacPooformtrptetlirieootnntehdehh)aassacbubeteeeenn completed) GGrroouupp Ssiizzee 1122~g, 1122%~ 1122~4,,01229~ AANWAALLYYTTIICCAALL CCHHfAAoRRlAAlCCoTTwEEiRRnIIgZZAAoTTrIIOOoNNtSSh::er pTTehhreetissnppeoonnntssoorrchhahaarssacotonenriffziialleteiooonnnsee oooffr mmtoohrreeetoeofsfttthhee faarrottliilccollweei::ng oiirddeennotttiihtteyyr,,pessryytnntithhneeessniitss,,chassttrrraeecnntggettrhhi,,zatppiuuorrniitstyy,,ofsstttahaebbiilltiiettsyyt.. PPtrrheeeppaatrreaastttiiooannrtaainncddlemmweeiaalssluurrbeemmeeenncttonsrrieedcceoorrrdedsds affdooerrquttahhteeevvaavrreiirooiuufssicaddtiiillouunttiiooonnfss ooff rtccahooennngtteetetnentistntadainannddrgticccosoltnneuccdeeywnn.ittlrrlaattbiieoonncoooffnsittdhheeeredddoossiianndggequssaootlleuuttiivooennrssififfcooarrtittohhniissof rangefinding study. TTEESSTT SSYYSSTTEEMM::01dTTwwoeennnttdyyo--sffeoouudrrammyaall1ee, waainnlddl 22b44effueesmmeaadlleefCoCrhhaarrtllheeessrReRiipvveeearrt CdCDDosreraattssst,,udy44.55--5555Theddaayyss ((33)) oacalnnadiigmmeaasollnwssidtwwohiisllellwidrbabeeye mhhi,oeousuwshsieelddflloiiobnnreddsiivuviasidednududaallffllroyoyrntiitsnnh.ehhaarnnTegghpeiiennaggtroodssmottsaaewiiinnlllsleetsusdssbye.ssttteeeeeTmllhpeeraccttayuugcrrleeees.aawnniddthhhuuwmmiiirddeiittyymescchoonnttfrrloooollrllseeddawwniidtthhfrottnhhtees.lliigshhTtthsse oronnooam& w11i22llhhoobuuerr tlleiimggphhettr//add-aarrkk cycle. JJUUSSTTIIFFIICCAATTIIOObNNecFFaOOuRRseSSEEoLLfEECChTTiIIsOOtNNorOOiFFcaTTlEESSTTin-SShYYoSSTTuEEsMMe:: daCCthhaaarrollneesstheRRiivvseetrrraiCCnDD rraattss wwiillll bbeo uusseedd because of historical in-house data on the strain. TTEESSTT SSYYSSTTEEMM IiIDnDEdENNiTTcIIaFFtIIeCCdAATToIInOONNt::he EEoaauccthhsidaaenniimmoaaflltwwhiiellllcabbgeee aaanssdssiioggnnneeddanaairnnuduirmvbbieedrruwawhlhiiccshharwwiitllallg. bbee indicated on the outside of the cage and on an individual ear tag. RRAANNDDOOMMIIZZAATTIIOONNthOeOFFsThTEiEpSSpTTinSSgYYSSTTbEEoMMx::es bTTyhheeAnaainnmiiammlaallssCawwriiellllpebbreesoniinnneddliissccarrniidmmipinlnaaatcteeelldyyinrreemmtoohevveeddracffkrroomm ohtofhfeeccaassggtheeuissdpypiffnrrdgooimmrbeocllxteeeoffsrtt wbttiyoollArrniiigagmhhsattsligssCnttaaarcrreottsiipnneeggrgrsaaoottunpnttsehhleebyattnoodpvpeparalntnaiddccwaweloodrrkkiriinonnwggst.heddoovwrnna..ck The study director will assign dose groups by vertical rows. DDIIEETT SSPPEECCIIFFIICCLAAiTTbIIiOOtNNuSSn:: thPPruuorruiignnhaaouLLtaabbtohoreraattsootrurdyyy.CChhooww aanndd wwaatteerr wwiillll be be available available ad ad libitum throughout the study. BBIIOOAAVVAAIILLAABBIILLIIaTTtYYs,OOFFsTyTEsEtSSeTTmiAAcRRTTIIaCCbLLsEEo::rptiDDouunrriinnoggf pptrrheeevviitooeuussst aaaccruutttieeclettooxxaiipcpceiiattryyssstttuuoddiiheeassveiinn ooracctccsuu,rrrreesddystiiennmittchheeabffsooorrmrmptoofifonddeelloaafyyeetddheCCNNtSSesteeffffaeercctttissc..le appears to have CCLLIINNIICCAALL OOBBSSEEiRRnVVtAAeTTrIIvOOaNNlSS::forTThheeevidaaneniinmmcaaellssofwwiitllrlleabbteemeoonbbtss-eerrrevvleeadtdedddaaiitlloyyxicttihhtrryoo.uugghhBoououtdtyttwhheeeigddhoostsisinngg wdwiiionllstlleervdbbaaeelyrreef1occrooarnredddveebiddidweaaenppecppkerrlooyxxoiifmmtaahttterereelelayaytfmtooeennnreet.-wwreeeeleFakkotoedppdrricioootrrnosxiuttcomoiptdtdyoio.soseen wBddioaaldyyly 1iw,,beeioognnhts Gdercoseasttteiaimimdanaaettydeedd1fwwoeeareenkkdtllwybyoiwattedhhedrrkiootluuiyggohhnootauuhltterwetteahhofeetkesddroo.ssfiionnlgFglooowiidinnttneegcrrovvdnaaosllsu..imnpgt,iIIoffntaahwnneiiiylmmwlaailllssbleaabrreee oorbbessteearirnvveeeddd afanondrd wwteewiiogghhaeeddddiatasisoniiannlddiiwcceaaettkeesdd faabobolovvleeowi((n44))g.. dosing, they will be 22779988..00002277 33MM_MMNND011669955664422 AAppppeennddiixx II ((ccoonnttiinnuueedd)) 225 TTIISSSSUUEE PPAATTHHOOLLdOOuGGrYYi::ng GGtrrhooessssstunndeeycc.rrooppssIiineessanwwiiimllalllsbbweeitcchoonndaduuutccottleeyddsioosnn, aallalls arraatmtsisnivwmhhuiincc,hh ddiiee dsbseuaamrmppifllnieegxssedthooeffinslltuufnunogdgr,,ym.allliiinvvI.eenrr,,aMnkiikiicmddarnnloeessyyc,,woipbtbirhrcaaiieannxutaaoamlnniyddnsaiatasnni,yyonggawrsrioolssalssmidllneeeitssmeiiuroommnn,iwnwieillllif bittenhheefaittxriieossdrssiuubeeisusnndaafrroecermoanssldaaiittntii.issoffnaaMccistthcooorrruoyylsdcffoooprrbiechhiitsseettxrooamllimoonigganitiacectdioddnitioaawggniniolonslssiiussrd..eetseAarAmtnniiyynsefrraaacttitfory ittthniiessssauuseemeolsresaicambtmppeulldneedsss..ucrovnAAidppvippotrrriosooxxnwiiimmslaahlttoeeulllbyyed kb22ie44llhhteooeduurrrmssifnorafftoogellrdlloowswtisionnggniensctturhhreeoepsllysaaassttetixsdadomofssiaeenc,,attoiroyn. TTthhheee any aaasrnneeiilmmeaasclletssleedcsstseeeulldree,vccittwveeioddlrlsffoobwrrielaalddkddiiilbttleieidooknniaalfllloerodobbgssrfeoeosrrrsvvaagttrnioiesoocsnnrowwpnsiieyttchhroooeuupxtstaymiddoonessaxiitannmiggio,,nnatiaiiftfon. atSSnhhoyeermeaeanrnleddinoosffealreettchhtaalettids,tiinentwtdeierlrbvvleaalllob..we.kiSSlaalmmppelldeessforttoogbbreeossffiixxneeeddcroiipnnsy1100%%exbbauumffiffneearrteeiddon at formalin are listed below. 12!. MMBayaemmsmmaarr(yy2) GGllaanndd ((ffeemmaallee)) 33. ETTTyhhheyyysmmruuossl(d2)/Paxathyrold/Trachea/Esophagus 6455.... Thyroid/Parathyroid/Trachea/Es ophagus zHeuagrt Lung 6767.... LAHLideivraveererntrals (2) 15098.... AUKKdriirdidennnneeaayyrslsysB((l22())a2)dder iI110i12..10 TvUTteeressirttnueeasssr//yEEoppBriilddaPiidrddoyyesmmrtiiastseoorr OOvvaarriieess 113400 spUSpatplenlerceueresnenasor Prostate 111564].. sPSStatmonoacmlmrlaaeccahhIsntestine (a: least two areas) 11117867... MSLLeamasrargegleelnteIIIrnnnitttceeessstLttiiiynnnmeeeph (at least Node two areas) 12110998.] MSssepccsiiienaaanttltiieccrCiNNoceerrrdvvL/eeyBmopneh Node Marrow (cervical and thoracic) 2222O121) SBpBpieritaanuiiainnltarCyord/Bone Marrow (cervical and thoracic) 222323.. AAPnniytyuiGGtrraoorsssys LLeessiioonn TTshheeelectttiisassdsuuebessy tttohoebbepeapptrrhoooccleeossgssieesddt aaantnddteheexxaanmciionnneecddluhhsiiissottnoololfooggiitccheaallgllryyoswwsiillllnecbbreeopsy. TpTshrheeeolceecttstiisessidssnuugeebyss(e5te)lhl.eeeccttpiiaootnnhssolwwoiigllillstbbeeatrreetvvhieieewwceeoddncwwliiuttshhiontthheeofssptphooennssogorrrosppsrriioonrercrttooopsy. processing (5). DDAATTAA AANNAALLYYSSTISSWilAAlNNDDbFeFIINNsAAeLLleFRcEEtPPeOOdRRTTa::t tTThhheeecaaoppnppcrrloouppsrriiioaantteeofsstttaahtetiissstttiiuccdayal.l aaTnnhaaellyysspeersso,,posiieffdaarndyya,,te wZf(iooalrrplpttrbhhoeeexisffrieiannltaaeellcltyerrde2ep-p5ooartrmttotnihitseshsc11-o-22ancfmmltoouennsrttihhonssnecaroafoffpttseetyrhr)e.ssllstiiudddeey.rreeaaddTiihennggpriiosspoccsooemmdpplldeeattteeedd (approximately 2-5 months after necropsy). 22779988..00002288 I3MM_MMNND011669955664433 226 AAppppeennddiixx I1 ((ccoonncclluuddeedd)) AAMEEDNDHMEENNTTSS: 1. 2. 2. 33.. 44.. 5. 5. TwThahese dllaaaysstt5ddaaaynydooftfheddoossliiannsggt dffooorrsettdhheaeyhhiifggohhr dtdohosesee lggorrwoouudppose((22g00r00onmuggp//kkag//ddaayy)) ww({ea77rs55enmdagca//yhkksage5//rddvaaaneyydd)) ftwowhraaess laddapaaspytyro5x9d..iomsaetAAelldlllayysstuufwrroorvviiwvvteiihennekggslhhoiiwfggohhldoldsodeowossieneggraoanuntipihmmeaalllssast wdtdeoohssreeee..aopbpFFsrooeollrpllvrooeiwwdaiitnnefggonruccmooabmmpeppprllreeoottxfiiiomonanmtaelooeflfsyddoaotsnswodiinnggwfeeeamakttaslettshhfeeowlelllroooevwwinkddgooissleeltheedlleetvvloeeallst ethaechapaprotoptrailateofnu6m/aboexr doefadm.alesTheanrdemfaeimnailensg w6e/raeexkwielrleedobt~o rsseeearrcvvheeddaffotorortaaalpppprrofooxxii6mm/aastteeexllyydeattdww.oo mmooTrrheee wwreeeeemkkassi..ning 6/sex were ob- TTshheeelecssteeelldeeccttleeoddv dhhoiisggehh dldooesvseeel llweeavvseell7ww5aassmg/22k00g00/dmmaggyi/.kkgg//ddaayy and and the the selected low dose level was 75 mg/kg/day. Aaaggaeey rorfaanngdgeoesiffnoogrr. tthhee aaccuuttee rraattss eexxtteennddeedd ttoo 5599 ddaayyss oolldd oonn tthhee day of dosing. BrBooaddtyyhewwreeiitgghhhattnssboiovbbetteaaxiilnnyee.dd oonnccee oorr ttwwiiccee aa wweeeekk dduurriinngg rreeccoovveerryy rather than biweekly. TTlhhieevertt,iissassduureeessnapplrrsoo,cceesssssteeodmdacffhoo,rr hhkiiissdtntoeoyppsaatthehnoodllooggbriiacciaanll. eevvaalluuaattiioonn weerree liver, adrenals, stomach, kidneys and brain. 22779988..00002299 I3MM_MMNND011669955664444 n 27 AAppppeennddiixx 11 TTwwoo WWeeeekk OOr`roaafllT-RR2aa5nng0ge8efCfii0nnCddiiinnnggRTTaotoxsxiicciittyy Study Study LLiisstt ooff PPrriionnfcciTip-paa2ll509PPCaaOrrCttiicciiinppaaRttaitisnngg Personnel Personnel Name Name MMaarrvviinn 7T.. CCaassee JJaammeess DD.. Henderson, Henderson, Ix. Jr. CCaatthhyy EE.. LLuuddeemnaannnn GGaarryy C.. PPeeccoorree IInnaarraa PPoorriteettiiss aJann H. H. Skroms Skroms GG.. RRaayy SStteeffffeenn FFuunnccttiioonn Vveetteerriinnaarryy PPaatthhoollooggiisstt SSttaaffff VVeetteerriinnaarriiaann CCoooorrddiinnaattoorr -- Cclliinniiccaall PPaatthhoollooggyy CCoooorrddiinnaattoorr =- AAnniimmaall Care Care HHiissttooppaatthhoollooggyy TTeecchhnniicciiaann TTooxxiiccoollooggyy TTeecchhnniicciiaann SSttuuddyy DDiirreeccttoorr 22779988..00003300 33MM_MMNND011669955664455 DDIISSTTRRIIBBUUTTIIOONN LLIISSTT MM.TT.. cCaassee KK..~ LL.. EEbobbeennss 7F.. D0.. GGrriiefeftitehn WW.. CC.. MMccCCoorrmmiicckk RR.. AA.. NNeellssoonn GG.. RR.. SStteetfffeenn ((22)) 22779988..00003311 33MM_MMNND011669955664466