Document 6bj5D3gLaBkDbVeYJ84OOojR4

Sees Experiment No.: Conducted At: sven conta Dates Conducted: SP Conducted By: RReevviieewweedd BByy:: Acute Oral Toxicity Screen wan mens with T-3421 1 sibin acs in Albino Rats assanoer 0883AR0287 f Fan h Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota pone Te 988 0 She Te 902 August 2, 1983 to September 7, 1983 Die tmnbocs D. M. Markoe, Jr., BS LE Toxico logi s t Ruder) Study Director ~} eps REO K.' D. O'Malley,'BS am Senior Toxicologist STs Acute Toxicology afer, Viz jad Da te , pe 54 ECEieoot mnt 3a Supervisor, Toxicology Testing wdc: nce Mo T, Case SVod Same ~,~.~D~riffth~ ~ W. Co McCormick 22881111..00000011 Exhibit 2811 Sovthiofe fo 33MMAA1100001199999977 1 Sunnary Summary The acute oral toxicity screen with T-3421 vas conducted from The acute oral toxicity screen with T-3421 was conducted from August 2, 1983 to September 7, 1981 at Riker Laboratories, Inc., St. Paul, Auqust 2, 1983 to September 7, 1983 at Riker Laboratories, Inc., St. Paul, Minnesota using male and female albino rats ranging in body weight from Minnesota using male and female albino rats ranging in body weight from 191-258 grams. The test article vas administered by sastric intubation at 191-258 grams. The test article was administered by gastric intubation at Gosage levels of 5,000, 2,000, 500 and 200 ng/kg body weight with mortalities dosage levels of 5,000, 2,000, 500 and 200 mg/kg body weight with mortalities of 10/10, 10/10, 10/10 and 2/10 noted respectively fron one hour to six days of 10/10, 10/10, 10/10 and 2/10 noted respectively from one hour to six days ppoosstt ddoossee aaddmmiinniissttrraattiioonn.. The untovard behavioral reactions which occurred The untoward behavioral reactions which occurred auring during the the 12 14 day day observation observation ppeerriioodd ggeenneerraallllyy ccoonnssiisstteedd ooff hhyyppooaaccttiivviittyy,, Lethargy, prostration, diarrhea and unkempt appearance with the onset lethargy, prostration, diarrhea and unkempt appearance with the onset occurring fron 1-30 minutes to day four post dose administration. Clonic occurring from 1-30 minutes to day four post dose administration. Clonic convulsions were noted in two aninals prior to death, trancient alopecia vas convulsions were noted in two animals prior to death, trancient alopecia was noted in two anisals While dyspnea and salivation were noted in one anisal noted in two animals while dyspnea and salivation were noted in one animal uring the stuty. All reactions subsided by day eleven or death precluded during the study. All reactions subsided by day eleven or death precluded recovery. Body weight gains were noted in animals which survived the study recovery. Body weight gains were noted in animals which survived the study pericd. Necropsies performed at temination of the study revealed no visible period. Necropsies performed at termination of the study revealed no visible Lesions while hyperemic or hemorchagic lungs and/or hesorrhagic intestinal lesions while hyperemic or hemorrhagic lungs and/or hemorrhagic intestinal cract generally were noted in the animals which died during the conduct of the tract generally were noted in the animals which died during the conduct of the study. The acute oral LOSO of T-3421 is greater than 200 mg/kg and less than study. The acute oral LDS0 of T-3421 is greater than 200 mg/kg and less than 500 ng/kg in sale and ferale albino rats. 500 mg/kg in male and female albino rats. IInnttrroodduuccttiioonn The objective of this study was to determine the acute oral LoSO of The objective of this study was to determine the acute oral LD50 of 7T--33442211 iinn aallbbiinnoo rraattss.. TThhiiss ssttuuddyy wwaass ccoonndduucctteedd iinn aaccccoorrddaannccee wwiitthh tthhee FFoooodd aanndd DDrruugg AAddmmiinniissttrraattiioonn''ss GGoooodd LLaabboorraattoorryy PPrraaccttiiccee RReegguullaattiioonn ooff 11997788.. TThhee rraaww ddaattaa ggeenneerraatteedd bbyy tthhee SSttuuddyy DDiirreeccttoorr aanndd tthhee ffiinnaall rreeppoorrtt aarree ssttoorreedd iinn tthhee ccoonndduuccttiinngg llaabboorraattoorryy''ss aarrcchhiivveess.. 22881111..00000022 33MMAA1100001199999988 2 MMeetthhoodd aanndd RReessuullttss YYoouunngg aallbbiinnoo rrattss~?a wweerree uusseedd iinn tthhiiss tteesstt.. AAllll aanniinmaallss wweerree hheelldd uunnddeerr qquuaarraannttiinnee ffoorr sseevveerraall ddaayyss pprriioorr ttoo tteessttiinngg wwiitthh oonnllyy aanniimmaallss wwhhiicchh aappppeeaarreedd t0o bbee iinn ggoooodd hheeaalltthh aanndd ssuuiittaabbllee aass tteesstt aanniimmaallss aatt tthhee iinniittiiaattiioonn ooff tthhee ssttuuddyy uusseedd.. TThhee rraattss vweerree hhoouusseedd iinn ssttoocckk ccaaggeess iinn tteemmppeerraattuurree aanndd hhuummiiddiittyy ccoonnttrroolllleedd rroooommss aanndd ppeerrmmiitttteedd aa ssttaannddaarrdd llaabboorraattoorryy ddiiete~tb pplluuss wwaatteerr aadd Lliibbiittuunm eexxcceepptt dduurriinngg tthhee 1166 hhoouurr ppeerriioodd iimmmmeeddiiaatteellyy pprriioorr ttoo ggaassttrriicc iinnttuubbaattiioonn wwhheenn ffoooodd wwaass wwiitthhhheelldd.. FFiivvee pmaallee aanndd ffiivvee ffeemmaallee rraattss wwoerree aaddmmiinniisstteerreedd tthhee tteesstt mmaatteerriiaall aatt pprreesseelleecctteedd ddoossaaggee lleevveellss.. TThhee ddoosseess vweerree aaddmmiinniisstteerreedd aatt aa ccoonnssttaanntt vvoolluummee ooff 1100 mmll//kkgg ddiirreeccttllyy iinnttoo tthhee ssttoommaacchhss ooff tthhee rraattss uussiinngg aa hhyyppooddeerrmmiicc ssyyrriinnggee eeqquuiippppeedd wwiitthh aann iinnttuubbaattiioonn nneeeeddllee.. AAfftteerr ggaassttrriicc aaddmmiinniissttrraattiioonn ooff tthhee tteesstt mmaatteerriiaall,, tthhee rraattss wweerree rreettuurrnneedd ttoo tthheeiirr ccaaggeess aanndd oobbsseerrvveedd ffoorr tthhee ffoolllloowwiinngg 1144 ddaayyss.. IInniittiiaall,, sseevveenn ddaayy aanndd ffiinnaall bbooddyy wweeiigghhttss,, mmoorrttaalliittiieess ((TTaabbllee I1)) aanndd aaddvveerrssee rreeaaccttiioonnss ((TTaabbllee 22)) wweerree rreeccoorrddeedd.. AA nneeccrrooppssyy wwaass ccoonndduucctteedd oonn aallll aanniimmaallss tthhaatt ddiieedd dauurriinngg tthhee ssttuuddyy aass wweellll aass tthhoossee eeuutthhaannaattiizzeedd aatt tthhee eenndd ooff tthhee 1144 ddaayy oobbsseerrvvaattiioonn ppeerriioodd ((TTaabbllee I1)).. TThhee pprroottooccooll,, pprriinncciippaall ppeerrssoonnnneell iinnvvoollvveedd iinn tthhee ssttuuddyy,, ccoommppoossiittiioonn cchhaarraacctteerriissttiiccss aanndd QQuuaalliittyy AAssssuurraannccee ssttaatteemmeenntt aarree ccoonnttaaiinneedd iinn AAppppeennddiicceess 1I =- IIvV.. 2xiKRiannlggstoLLnaabbssP,,urOOirrneeaggooLnna,,borWWIlatory Chow, Ralston Purina, St. Louis, WO Ralston Purina Laboratory Chow, Ralston Purina, St. Louis, MO 22881111..00000033 33MMAA1100001199999999 ACUTE ORAL TOYICTTTTAAYBBLLSE~TU1iDY - ALBINO RAIS ACUTE ORAL TOXICITY STUDY - ALBINO RAS wwiltthh TT-330~2201 MMoorrttaallilttyy,, NNeeccrrooppssyy aanndd BBoodyy WWeeiigghhtt DDaattaa TdL ose & ((Dnmoggs//ekkgg-))s50O0O0O soo 50OO 2000 2000 22000000 s5O0O0 s5OoO Sex AASnnuiimmmbaaellr Sex Number w M 33IRRm3Is5sS55I3E 33mm33RR3333885555555645 fr33eRR33e555567 FIm3Ra3T5s7a3 S33rRRR33335577776545 33mRRs3355777776 nu M 33m3Rms3s55s59e8 33mm3333RR33555566560190 3m33aRR33s55666221 F F 33m3R5m357s7978 3333RR3r33555588871009 fr33RRe3355e8812 CM 33RR8e4400c77h10 3333RrR4a44000077773221 333RRR4e4000777344 F 333Rrm4aa11000067 3r333RRra444111100008788 33Rr4a111009 3R4110 ImndimTveisdmtualDeyaBodNyuymbWeeeri:gshts @(g) oTest 0 , 1a Day Number: 7 14 22200088 Gw(Daaayyy6))) -212119900775 a([(DDHaaEoyyu)26r))) -22N11e94 G((iDaayyHoeu6)r)) - 0119011 (QI eMHoou)ur)) -- 122290002077 ((((iIHHHHoooowwuurr)))) -- 12290529 ayn (I Hour) (Day l) = 1019755 aG(Dayayyee6))) -- 22220007798 (G((DDaaaayyyye666)))) -- 22010077 G((DDaaayyy 6) 2) 21199899 (a(DHaoyeu6r)) -20220105810 (((aiiHyHHooonwuurr))) -222000355 (QDoaywr) - 22W1w00 c(aDaayyy y38)) -222211323 o((wDDwaaayyey)6s4)) 22211676 (w(DDaaayyy 54a))) - 222000400 ww(Daaayyy)6&)) -2222000055 GL((DDaaaayyyys45))) -211299188 d((DDaaayyy &34))) SNNuuub.se-bbreerrTeDDseecaaeddd Number Te s~ed s5/15s s/51s5 5s/r5s s5//ss s/5/s5 s5//5s 3 pPeerrbcceeeanndtt Dead 1I0000 1Io0o0 100 I00 i1o000 1i0o00 1i0000 22881111..00000044 33MMAA1100002200000000 TT. (oDnogss/eekg&-)- (mg/kg) 220000 220000 AAnniiomaall SSeexx NNuummbbeerr uMo 3337mR4a4000777655 3333R8R4444000077778677 333rRR444000777989 FF a33mR441!1aI2I 333RRRa44111111233 333RR444111111S44 3R4115 TTAABBLLEE [1 ((ccoonncclluuddeedd)) AACCUUTTEE OORRAALL TTOOXXIICCIITTYY SSTTUUDDYY -- AALLBBIINNOO RRAATTSS wwiitthh TT--33442211 MMoorrttaalliittyy,, NNeeccrrooppssyy aanndd BBooddyy WWeeiigghhtt DDaetta Iandii Tueisdn tualDayBsoedNyyumbwweeeri:gehtss G{gV) 0Test Day77Nut,her:1164 22535161 2(O7De4ayy 66)) --297 222253553368 233370003432 233393347665 24254888 322046299 22394757 2a22200 222343200 222464323 22221128277 222243532663 222243352667 22232585 2(O5De3ayy 5)) 2--57 NNu~zbbeerr DDe~aadd NSuu_-bueberr TTe~sstteedd v1/s5 v1/s5 PPeerrDcceeeanndtt Dead 22o0 220O NNoottee:: FFiigguurreess iinn ppaarreenntthheessiiss iinnddiiccaattee ttiimmee ooff death death ~TheTTeeasspttproaaxrrittniiacctlleee aaoddrmamliinniiLssDttSeOerreeidds ss a suspension in water. garseaatesrustpehnesnio2n00inng/wkagtera.nd less than S00 mg/kg in fasted mTmhaaelleeaapannpddroxffieemmmaaatlleee aoarllabbliinnooLDrSra0attssi..s greater than 200 mg/kg and less than 500 mg/kg in fasted NNNeeecccrrrooopppsssyyy of the animals which survived the observation period revealed no visible lesions hwwNhyheiipcllereeroepmsnniyeecccrrooofoprpsstyyhheemoooffarnritthmhhaaoogslsesiecwaahnnliiiucmnmhgaasll.sssuwwrhhvHiiiecvcmehhodrdrdihiteaehddgeicddouubrrssiiemnnraggvllatttihhieoenntcceoosptnneidrdniuueoccdttwaorosffevetntahohelteeeddssttuunatdodyytvhggieeesnniebelrr5eaa0ll0lllyymegs/ikhohganadsd owhdaoyssspeeerneollmteeeivvdceellaotarannddthheemooonnere5r,ha0aa0nn0giimimaacnllg/lkfufgnrrgoosmml.etvthehleeH.em220o000rrmmhgga//gkkigcg ddsoomssaeellggrrioonuutppe..stinOOenneewaiisnncciinddoeetnneccdee aotofftmmheoottttll5ee0dd0 mllgii/vvkeegrr was noted at the 5,000 mg/kg level. 2288111..00000055 33MMAA1100002200000011 HES . ql] ni... 2 I I CE PRR Lok Jide ale] ss oss EE 5 i Al 3% g a Cee CoeI I I I I I I I MED $OO SOF SS Lo 888% sg 53 55 3% 33% : 2240 SLOSS $s 38 g85i82l 8 HF8RE FH EZH ET FiR8EiE55 0 0 0 0 0 0 0 0 0 0 0 0 22881111..00000066 awatooz0002 3MA10020002 = . : 3% Bl. sss os i: 18 88 ie : .Hoe oz i : Hag 8 fy0 o0g o08 o0s 22881111..00000077 6. 1 1 tiez 24 ii 1 HN SwA10020008 3MA10020003 ct Riker Experiment No: " Riker Experiment No.: PROTOCOL aApPrPpENpDIInX yIl 7 PROTOCOL TTEESSTm " n O %': ] '}oxG ] t!t, .<.'cm: ------------------------ SPONSOR: aM__SeneilChiied "o" " '.:':i~ ! C,".'~, : -~," :1 owen SPONSOR: 3M Division CONDUCTEBYD: Safety Evaluation Laboratory, Riker Laboratories, Inc, St.Paul, Minnesota CONDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota estamos TEST ARTICLE" noT-- ' 4 ~ ~ covmouaRTOlE Ei CONTROL ARTICLE: '" PROPOSED STARTING/COMPLETION DATE OF TEST. PROPOSED STARI-ING/COMPLETION DATE OF TEST" TesTSYSTEM: fii z.0 A LD) juoa'" k/.y'5 / SOURCE: Fl 11s LV wr, (IST Cam, ti! SSeexx:: I1. . 7. Nomber:niPc| t WW NeueimigghbhtetrR:Raan.ngg,ee::~ _+7 ..~.:.__ = 7% OOBBJJEECCTITVIVEE:: METHOD: METHOD: TThhee oobbjjeeccttivvee ooff tthhiiss tteesstt wwiilll bbee ttoo cchhaarraacctteerriizzee tthhee aaccuuttee __,.2~ra]7al ttooxxiicciittyy ooff tthhee tteesstt aricle in abo IST Ei were selected a5 a fest sysiem 0! 19poGuCbINY of article in albino :';:;-~ F:- were selected as a test system for reproducibility of {esponse, historical use, ease in handing and genera avalabisy response, historical use, ease in handling and general availability. ThcTohenetaaonntiimemadaitlssowowimillsl bbdeeuhhnooguussbeeoddliinnthssettaaQiinnullaeerssassnssitnteeeelassnuudsspepeesnnddpeeeddriwwoiidrre,a mwmieehsshhoGcoaadggeeassniidnntweteammtpeeprrearfatetuurrreeeadanonddd ihhbuufmmuidmiitcy controlled rooms during both the quarantine and test periods, with fooda- and water offered ad libitumb-. cEaadcrhe,anwihmiaelhwwiil Cbeoreesnptoenddotbhyecoalonraclond,umacbcoonredairncgasr15dahe fab1orxlhoeneyu'ssdsatanodfahrd caapegrea.tiAngsnpoa: Each animal will be identified by color coding, according to the laboratory's standard operating pro- `dcdedoodossuacargugeeae,twoolffhyi5cchh,1a'w"a'i!l.clLicoerrmmraeggesi/pkhggoenwwdtiiltlooxbbtcheeteyaaaddonmfmiimtinnhasieslitneteuerraemetddbaeeerraasicco,hhn aaaanndciidmatmriaado.l,naahfhlfoioxwwaeendevivemteorar,lt,hseifiohtlhuiitsssbiedddeooassocaafmggtiheeseielecevvaregeeled.CdAoohseesssintngneosoleltt haaarirditseiccqllpeueraoaatttteoclssyouu,pcpphpTlaloeeremamecetnteentsrtataizllaeddrtoohtsseeaaggtwoeeixlillceebivvtseyelslaso..df iAAthnrnesyyitaeaeddrsdtdeiitdatiirootfninocaaltlelh,ddaooadssndaaiiggtmieeoalnllsaeevlvieenallsnshiemwwiaifllllsobbreewifddlleoobccceeuuvmmaeeeddnnmtoteienddmistaaetnnrdededffsilteephoddenswwteoiitrshnt this protocol. The test article will be administered to the animals in the form received from the sponsor. eunrlowasrddmbeahatvioornaolfretahceiotnss! faorrtihl,fhloewiannigma1l8sdawyisl.beiarleuamneddv1a5lebiodycawgeeisghasndwiCbosreercoorrd.anAy After administration of the test article, the animals will be returned to their cages and observed for any ugginnrrtoteoossswstiannnareedlccrrbroaaepphcssayywviiwwolirhabicclehhrecwwaoicinlltldioiuinnncccstllueufodddereo,,tnhbbeuuatftlohnlalooonttwibmbinaeeglslmi1mw4iihtdeidadcyhtstoo.iheIhneeiatGariatrutl,,Falgngudnstgfh,isne,avclliveobernor,d,duyKkciiwddonenfeeigtyyhsshtsaanntwddeilsl ggb2eee5nnerewerrcaeaollrggd2aae5ssdith.rroeA-- ianannenticeimmrsaotailnplsssaylssuutwrrraivvlciivtvbiinwneggillrthebeceotercesdostentddppuewecriritoehsdd..spoAAenncniyyafliGglcrraomonseissmntiaaiblsoonnomwr1ham0iclathlhieteidesisoerwWdghuahinriccinhhagnaatrhdeeCroocbssoseinerldrvuoecbdtseoddrfuuvrterhiidnne.ggthetThsheeteccaaosoncnwddeuuulcl tcmaooetsffditthhhaeeel Tanleenetthdchreaololpddfsooytsseewoi((lbLlLsDbeDe~r))vraeooifcfoottnhrhdeepeettdreeisowttdi.rath~iAlcsclpleeerwcawiiwfililcldbbameleaeccnagatiiloocurunllelateatoedtd.the,eifbyopprootgssahsnsibsilaie,nu,dcuuy/ssoiiGrnnrgsgeitacaetpprorrbooabsbineittdrvaahennadeal.lyynTssihilsse mmraeeectptuhhotooerddwmaaiet dtthbihaeeel Setnodreodf ne Riker Laboratores Archive, St Pad, Minnesota the observation period. All raw data generated by the study director and the final report will be stored in the Riker Laboratories' Archive, St. Paul, Minnesota. _ Wl Led vr en ee SET 2Ra_ PPouuirinnnaa LLaawbbaooreraattoorryy CBChwhooww,T, RRaaHllssttooAnn PPDuurninaa,F, aSSte.t. LLooAuusis,,fMMlioissrssoo2uurrii aVo.u.to F,-,i_.b,<r...o Ds OF. To DING.,<,, > `fo Local ' "'( 1' RF_TM'rT._S'7:IKVVEED JJUuNn 11331199533 L m: moa .... -...., t' ' ~+,,-',L~..'~-',~ Sewer,,. C. Sponsor ._ or~..a~.. Da ~'--"" Date Sigmar Dam t*. t-~-- C..~--.~-, ..... ~ _.. .-. Study Director , ,' Date 22881111..00000088 3aMMAA1100002200000044 Riker Experiment vo. ; 0203AR0267 6 SeviationsAA~aPPnEdND/PIoXrTEaI(zecN(cnoodnDmnce:llnuuIcddseeXddt))o protocol Dev%ations and/or Azendments to Protocol 1. _seskend observation for August 6 ard 7 were inadvertently missed and on Weekend observation for August 6 and 7 were inadvertently missed and on _seSeppetemmvbeerr3dred.. DDS..uHdM..y MMOaairrkckeeoece,t,or3Jxr.. Study Director 010//55//8833=m Date 3. _bue to a delay in study conduct the proposed completion date should be amended Due to a delay in study conduct the proposed completion date should be amended so 1/64. to 1/84. 5Du.. dMu..y Maaorrikkroeeec,,toJ3rrx.. Study Director 1122//2299//E8833X .Date wo TT mStumdy Dmireecntoer aDaete . wag omer an 5. -- wwe an 2288111..00000099 3SMMAA1100002200000055 5 ApoiDr1x1 principal participating personnel Involved in che Study sase 0. K. Macxos, Jr, BS L. mens, 8 <0. o'miley, 8 oc. pacers G. C. pecoce funceson TSoexasycotooagrieacttor Sr.ud Ssupeervoiswor macng ~x~ o 1o9-~ SSeeuncieocroTxoixciscloolgoygist ssMueu~tpeae~arvlviissLooa~rnoratory 22881111..00001100 3aMMAA1100002200000068 Lo. i0. - AAPPPPEENNDDIIXX 1I1~I1 rTeesstt aanndd//oorr CCoonnttrrooll AArrttiiccllee Craracterization Characterization KT 2-15 (ecsver) T3431 1. I. TSTtThhieeenetennsitGddeeenCncrcthaoiiaimttreiyyatncsetssrsetcirrriseaeznmingasegttihhido,,oonncssuuwmnnoeioifffnfoocrrettmmdhhiieetcsyyaLt,,eososftccoomamappnooodJss/siioEttriiCooconnMor,,noetyrrppsouuhlrriiGttpsyy1upbsoostirrtaaSgoonetctshehseserr~papveeJierrve~--_~=2% 22. . TThhee mmeetthhoodd ooff ssyynntthheessiiss oorr dTocumeentedoe irhint ana including their amount and the method of oorriiggiinn ooff tthhee the method of bioassay tteesstt and and bioassay (if applicabie) is control substances, control substances, (if applicable) is documented ~ yu Em 5. 3. TmIheeeeesstoairbisLliittLy booffe yes no cttehheecerttmeesirtenedganeda/srorofccono2tr6rol Tasuwbisetanfsc3es mhtmaovcve.bbeeenAddeetTtere-= TIChhoeerdsaa.bboovvee iinnffoorrmmaattiioonn aanndd documentation documentation are are located locatel in in the the sponsor's sponsor's re- re- cords. - er Hi4 shslsz Sonar See Date Sponsor cc pb widen 2362 Wc. he ComicK 220C WH. Reakon 223-656 d Panty 26-7 --- 2 . wa31198 reas F ne 1 uses 1 SAsaRdTY BYAALLL ATA| 22881111..00001111 3aMMAA1100002200000077 a APgENDIX IV suse ss en QUALITY ASSURAI~CE STATEMENT este Toxicolosy Laboratory Seuss Acute Toxicology Laboratory Studies Study Nou: LZT3ALC223 This short term study was audited by Compliance Audit, and tthhee ffiinnaall rreeppoorrtt eexxaammiinneedd against the against the raw data on raw data on IRE ~_, ~ TN.1. 1) ~ )'~ /~. The results of the audit were reported to the study director and ttOo mmaannaaggeemmeenntt oonn _f _ ~,.e w-v-~s O ~F~ s S,IP~/A~/e Leutien andmay a the Acute Toxicolosy Laboratory ate Snspaciad veskly In additionto the data audit, different significanZ phases for studies underway in the Acute Toxicoloqy Laboratory. are inspected weekly on a recurring cycle, and the facilities are examined by Compliance Audit on a three month schedule. arfbg (ATR Compliance Audmt fr Date 2 LFF 22881111..00001122 sunroozome 3MA10020008