Document Lgx9BNJEpvYXeQoY4279NOyBz

. Suk o . /nins l-L~,Icton Inc. iinsn1 537027545 re jOIadison, WI. 53707-754~ "3301 Karn Bod, Medion, 1 5 *r ~f~de.io2vs4~21a.s1~:477311301 K 66008i8.l.22n6411.B.77l2v22d27.7,FM Fa~x~on, WI 537~ ~ SSppoonnssoorr:: En3M SStt.. PPaauull,, MMiinnnneessoottaa FINAL REPORT FINAL REPORT SSttuuddyy TTiidtlee:: AAccuuttee OOrraall TT(ooxOxiEicciCittDyy SSttuuddyyooffTT--66666699 Guidelines) iinn KRaattss (OECD Guidelines) Author: Author: SStteevveennMM.. GGllaazzaa SSttuuddyy CCoommplpelettiioonn DDaattee:: JTaannuuaarryy 1l00,,11999977 Performing Laboratory: Performing Laboratory: 3301 Kinsman Boulevard CCoommiinngg HHaazzlleettoonn IInncc.. 3301 Kinsman Boulevard `MMaaddiissoonn,, WWiissccoonnssiinn 5533770044 LLaabboorraattoorryy PPrro~jeeccttldIdeennttiiffiiccaattiioonn:: CCHHWW611000011776600 `CCOORRNNIINNOGHHaazzlleettoonn PPaaggee 11 ooff3355 DECEIVER! EO ET 11446699..00000011 EExxhhiibbiitt amar: | sw worse 11446699 State of Minnesota v. 3M Co., Court File No. 27-CV-10-28862 3M MN01688780 CCOOMMPPLLIIAANNCCEE SSTTAATTEEMMEENNTT A`Accuuttee OOrraall TTooxxiicciittyy SSttuuddyyooffTT--66666699 iina RRaattss ((OOEECCDD GGuuiiddeelliinneess)) cHw 61001760 CHV61001760 a"TTnhhdiissDssettuvudedylyowwpamassencctoonnaddnuudcctPteeriddnciininpaalccesccooofrrddGaannoccoeedwwLiiattbhhottrhhaeetoOOrrrgygaaPnrniaiscsatatitiicooen,n Cfoo(rr81EE)cc3oo0nn(ooFmmiiniacc)CCowooioptpheertrahatetiioonn eheaxoxncmcdeoepDgpteteiinovoeneniltottyhhp/aamsttoeaalnnnuatablliayylnsstidissyPoaorfnfindttschhtieeapbltteieeslsstitotmmyfawGatateoersroiiadanlloLmtmaiicbxxototnuurdrarueetcosstreffyodo.rPr rccaoocnntcicecenent,trrCaat(ti8ioolnn),3, 0(Final) with the homogeneity/solubility and stability was not conducted. Nee WN SSSttueedvvyeneDnMi.r.ecGGtlloaarzzaa AACScotcuumudtityeenDSSgttiuurHdedaicizeetlosserton Inc. Coming Hazleton Inc. A,t= DDaattee 110-97 2 11446699..00000022 IM_MNO168S781 3M MN01688781 QQUUAALLIITTYY AASSSSUURRAANNCCEE SSTTAATTEEMMEENNTT cH 61001760 61001760 `TThhiissrreeppoorrtthhaassbbeeeennrreevviieewweeddbbyytthheeQQuaulailtityyAAssssuurraannccee UUnniittooff CCoommiinnggHHazalzelettoonn IInncc..,, iinn a`accccoorrddaannccee wwiitthh tthhee OOrrggamniissaattiioonn ffoorr EEccoonnoommiicc CCooooppeerraattiioonn aanndd DDeevveellooppmmeenntt ((OOEECCDD)) Principlesof Good Laboratory Practice, C(81)30(Final). The following inspections were Principles of Good Laboratory Practice, C(81)30(Final). The following inspections were conducted and findings reported to the StudyDirectorand management conducted and findings reported to the Study Director and management. FIInnossppmeeccttiioonn DDaaTtteoess From To PhPhaassee TI0R4%6 10/24/96 1122//2299//9966 1028/56 Necropsy 10/24/96 Necropsy 1122//3300//9966DaDtaat/aR!RepepoorrttRReevviieeww DDaattteeoRRSeeuppdooryrtteedd tDDoiirrSeetccuttdooyrr 024% 10/24/96 1122//3300//9966 ManDaDaagtteeemttoeont Management 102e%6 10/24/96 1122/73300/1996 Lvsfo Hen RReepprreesseennttaattiivvee,, QQuuaalliittyy AAssssuurraannccee UUnniitt 1-10-97 DDaattee 3 11446699..00000033 33M_MNMoNt0e1868s8T7s822 SSTTUUDDYY I[DDEENNTTIIF~ICCAATTIIOONN AAccuutteeOOrraallTTo(oxOixcEiciCittDyy SSGtutuiudddeyyoliofnfeTTs-)-66666699 iinn RRaattss (OECD Guidelines) CcHwW6611000011776600 TTeesstt MMataeterriiaall SSppoonnssoorr SSppoonnssoorr''ss RReepprreesseentnatatitivvee. SSttuuddyy DDiirreeccttoorr SSttuuddyy LLooccaattiioonn SSttSuutdduyydTTyiiImmneietttaiaabbtllieeon Date EIESxnxtupipedferyeriimIEmneneindtnitataaDtlilaot((nlIennD--llaiiffteee)) SSttaartt DDaattee EIESnxtx-pupleidefryeriiCmmEoenenmdntptalDalelaTtTteieerormnmiDninaaattteiioonnDDaattee Study Completion Date TT-66666699 MT3oMxicology Service 3ToMMMxeieCdcedioniccltaoaelglr,yDDeBSeplpedaragrvr.titcmm2eee2nn0tt-2602 PPS3.tM.OO.P.CaBBueloon,xxteMr33,N33B22l22d500g5.1232303-222E0-02 St. Paul, MN 55133-3220 RoRgoegerrGG.. PPeerrkkiinnss,, PPhhDD,, DDAABBTT T3MoMxicology Service 3ToMMMxeieCdcedioniclctaoaelgrly,DDeBSeplpedaragrvr.titcmm2eee2nn0tt-26-02 P3PS.tM.OO.P.CaBBueloon,xtxeMr33,N33B222l2d500g5.13232-03-22E20-02 12733322 St. Paul, ~ 55133-3220 (612) 733-3222 SCStoteervvneeinnngMM.H.aGzGllleaatzzoaan Inc PCMP.a.oOOd.mi.siBBonnogo,xxHW77a55Iz44le555to3n70In7c-.7545 (M60a8d)iso2n4,1-W72I 9253707-7545 (608) 241-7292 C3C3oo0mm1iinnKgginHHsaamzzallneettBooonnuIIlnnecc.v.ard M3a3d0i1soKni,nsWmIan $B3o7u0l4evard Madison, WI 53704 OOOccctttooobbbeeerrr991,,0,11919999696 NOocvtoebmebre1r0,141,9916996 JJJNaaaonnnvuuueaaamrrryyyb1e11000r,,, 11411,9999991777996 January 10, 1997 4 11446699..00000044 I3MM_MMNNO011668888778833 AAccuuttee SSttuuddiieess SSSttteuevdeyvneDMMinr..ecGGtlloaarzzaa Manager Study Director Manager SSSttteeuvvdeeynnCRRo.o. rSSdooirnreeanntssooornn Study Coordinator JJIeeffnffrreeeyySBBu.p. eHHriviccikksssor In-life Supervisor RRAdoomssieeniMMs.t.rBBartriiiddvgegeeSupervisor Administrative Supervisor TTooxxiiccoollooggyy SSuuppppoorrtt MKKaaantthhayygeMMryyeerrss Manager SuCCpaaellvrvivniiLLsn.o. rHHoorrttoonn Supervisor KKEEYY PPEERRSSOONNNNEELL QQuuaalilittyy AAssssuurraannccee MSSahhneearrrgyreRry_ WRW.. PPeettsseell Manager cCHHW6160100011776600 LLaabboorraattoorryy AAnniimmaall MMeeddiicciinnee CCDiiipnnlddoyymJJa..teCC,aarrAyy,C, DDLVVAMMM DSSuuipppeleorrvmviiasstooerr, ACLAM AAnnaattoommiiccaall PPaatthhoollooggyy TTAnhhaootmommaaisEcsEa..l PPPaaalltmmheoerlr,o,gPPishhtDD Anatomical Pathologist JDDaeecbbkoorSraearhhfoLL.r.tPPiirrkkeell// SNJSaueucpcpkererorSvvpieissrsyfooorrrsst Necropsy AASunnpnneeervMMiosososrhheerr PPSaauttphheoorllvooigsgyoyrDDaattaa s 11446699..00000055 33M_MNMoN1061868s8T7S8S4 CONTENTS CONTENTS cH si001760 CHW61001760 COMPLIANCE STATEMENT... co 2 COMPLIANCE STATEMENT ....................................................................................... 2 QUALITY ASSURANCE STATEMENT... mmm QUALITY ASSURANCE STATEMENT ....................................................................... 3 STUDYIDENTIFICATION... ei STUDY IDENTIFICATION ........................................................................................... 4 KKEEYY PPEERRSSOONNNNEELL - - iS ......................................................................................................... 5 OOBBJEJCETCITVEIV..E. ................................................................................................................... 88 TEST MATERIAL .......................................................................................................... 8 Identification. 8 Identification................................................................................................................ 8 PurityandStability 8 Purity and Stability....................................................................................................... 8 i Storage and Retention .................................................................................................. 8 Safty PIECRUIIONS ooo oer 8 Safety Precautions ....................................................................................................... 8 TEST SYSTEM cn TEST SYSTEM .............................................................................................................. 9 Test Animal 9 Test Animal ................................................................................................................. 9 A 9 Housing ....................................................................................................................... 9 AvimalDiet - ed Animal Diet ................................................................................................................. 9 `Animal Selection and Grouping 5 Animal Selection and Grouping .................................................................................... 9 JustifforiSpecciaestSeliecotionn. ---- Justification for Species Selection .............................................................................. 10 PROCEDURES. . SE 10 PROCEDURES ............................................................................................................. l 0 Preparation and AdminisotfTreasttMaiteorianl ....._...........................10 Preparation and Administration of Test Material ........................................................ 10 Reson forROULE OfAGMISUAION........r...roerrroveror errs 10 Reason for Route of Administration ........................................................................... 10 FS, Observations .............................................................................................................. I 0 -------- ---- Pathology .................................................................................................................. 10 Statistical ABSISES ..._......o...ooooeoroemernssms eo 11 Statistical Analyses .................................................................................................... ! 1 LocoaftRaiwDoatna, Records,and FinalReport... 11 Location of Raw Data, Records, and Final Report...................................................... 11 RERESSUULLTTSS ..................................................................................................................... 111 Mortality ................................................................................................................... 11 Body Weights . _. . on im Body Weights ............................................................................................................ 11 ClinicalSigns 1" Clinical Signs ............................................................................................................. 11 EitlofY wmmmmamamsmmanmmmm-------- Pathology .................................................................................................................. 12 DDIISSCCUUSSSSIIOONN. ....... mmmmm--------kE ............................................................................................................... 12 6 6 4146699..00000066 33M_MNMoN1061868s877S8S5 CHW CI--IV~ 6611000011776600 SSIIGGNNAATTUKUER.E.....................................................................s....m.....m.....m.....--.....--.....--....."....1.....312 REFERENCE...... " " rmsd KEFEKENCE ................................................................................................................ 13 PPAATTHHOOLLOOGGYYRREEPPOORRTT............................................................t.on...................o....r....n........ 114 TTAA1BBLMLoEErtlitySummary. -- - 1s 21 IMndoirvtiadluitaylaSnumd mMearayn..B..o..d..y...W..e..i..g.h..t..s.!...B..o..d..y...W..e..i..g.h..t...G.a..i..n..s...........(.g). ...............-- .............. 15 323 IndividualClinicalSigns. Individual and Mean Body Weights/Body Weight G',fins (g) ................................. Individual Clinical Signs ........................................................................................ 111863 44 IInnddiivviidduuaall PPaatthhoollooggyy Comments.......... i J Comments ............................................................................ 2211 APPENDIX. 23 APPENDIX ................................................................................................................... 23 PIOIOCOI TP20D. cosines 24 Protocol TP2069 ....................................................................................................... 24 Protocol Amendment No. | 3 Protocol Amendment No. 1 ....................................................................................... 33 Protocol Amendment No. 2 34 Protocol Amendment No. 2 ....................................................................................... 34 Protocol Amendment No. 3 i. ni 35 Protocol Amendment No. 3 ....................................................................................... 35 7 11446699..00000077 I3MM_MMNNO011668888778866 OOBBJJEECCTTIIVVEE cw si001760 CHW61001760 T"Thhee oobbjjeeccttiivveeofotfhthiiss ssttuuddyywwaassttoo aasssseesssstthhee aaccuutteeoroarallttooxxiicciittyypprroodduucceedd wwhheenntthhe tteesstt mmaatteerriiaall iis aaddmmininiisstteerreedd bbyy tthhee oorraall roouuttee ((ggaavvaaggee)) ttoo rraatss.' AAllll pprroocceedduurraall ttiimmeess pprreesseenntteedd iinn tthhiss rreeppoorrtt ffaallll wwiitthhiinn tthhee aacccceeppttaabbllee rraannggeess aass ssppeecciiffiieedd iinn tthhee W Wiissccoonnssiinn ffaacciilliittyyooffCCoormniinngg HHaazzlleettoonn ((CCHHW W)) IInncc.. SSttaannddaarrdd OOppeerraattiinngg PPrroocceedduurree ((SSOOPP)). TTEESSTT MMAATTEERRIIAALL IIddeennttiiffiiccaattiioonn "TThhee tteesstt mmaateterriiaall wwaass iiddeennttiiffiieedd aass TT--66666699 aanndd ddeessccrriibbeedd aass aa wwhhiittee ppoowwddeerr. PPaurriittyy aanndd SSttaabbiilliittyy T`Thhee SSppoonnssoorr aassssuummeess rreessppoonnssiibbiilliittyy ffoorr ppuurriittyy aanndd ssttaabbiilliittyy ddeetteerrmmiinnaattiioonnss ((iinncclluuddiinngg uunnddeerr tteesstt ccoonnddititiioonnss)).. AAnnaallyyssiissoofftthhee teesstt mmaatteerriiaall mmiixxttuurreeffoorrccoonncceentnrtraattiioonn,, hhoommagoegneenietiyt/ys/osolulubbililiittyy aanndd ssttaabbiilliittyywwaassnnoott ccoonndduucctteedd SSttoorraaggee aanndd RReetteennttiioonn TThhee tteesstt mmaatteerriiaallwwaassssotroreedd aattorooommtetemmpepreartauturree., AAnnyy uunnuusseedd tteesstt mmaatteerriiaall wwiillll bbee rreettuurmneedd 0to tthhee ssppoonnssoorr aaffteerr iissssuuaanncceeoofftthhee ffiinnaall rreeppoorrtt aaccccoorrddiinngg ttoo CCHHWW SSOOPP.. SSaaffeettyy PPrreeccaauuttiioonnss "TThhee tteesstt mmaatteerriiaall hhaannddlliinngg pprroocceedduurreess wweerree aaccccoorrddiinngg ttoo CCHHWW SSOOPPss aanndd ppeolliicciieess.. 8 8 11446699..00000088 33MM_MMNNo0116688s877S8T7 TTEESSTT SSYYSSTTEEMM cw 61001760 61001760 TTeesstt AAnniimmaall Y`Yoouunngg aadduulltt aallbbiinnoo rraattssoofftthhee CCrrll:CCDD ((SSDD))BBRR ssttrraaiinn wweerree pprrooccuurreedd ffrroomm CChhaarrlleess RRiivveerr LLaabboorraattoorriieess,, IInncc.. oonn SSeepptteemmbbeerr 2233,, OOccttoobbeerr 77,,OOctctoobbeerr2211,, 11999966 ((PPoorrttaaggee,, MMiicchhiiggaann ffaacciilliittyy)) aanndd oonn OOccttoobbeerr 11 aanndd OOccttoobbeerr 1155,, 11999966 ((KKiinnggssttoonn,, NNeeww YYoorrkk ffaacciilliittyy)).. HHoouussiinngg AAfftteerr rreecceeiipptt,, tthhee aanniimmaallss wweerree aacccclliimmaatteedd ffoorraa ppeerriiooddooffaatt lleeaasstt 77 ddaayyss.. DDuurriinngg aacccclliimmaattiioonn aanndd tthhrroouugghhoouutt tthhee ssttuuddyy,, tthhee aanniimmaallss wweerree sseeppaarraatteedd bbyy sseexx aanndd ggrroouupp hhoouusseedd iinn ssccrreeeenn--bboottttoomm ssttaaiinnlleessss sstteeeell ccaaggeess.. EEnnvviirroonnmmeennttaall ccoonnttrroollssffoorrtthhee aanniimmaall rroooomm wweerree sseett ttoo mmaaiinnttaaiinn aa tteemmppeerraattuurree ooff 1199 t1o0 2255CC,, aa rreellaattiivvee hhuummiiddiittyy ooff 5500%% +_2200%%,, aanndd aa 1122--hhoouurr iligghhtt//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 tthhee ssttuuddyy oouuttccoommee.. AAnniimmaall DDiieett "TThhee aanniimmaallss wweerree pprroovviiddeedd ccoonnttiinnuuoouuss aacccceessss ttoo LLaabboorraattoorryy RRooddeenntt DDiieett ##55000011,, PPMMII FFeeeeddss,, IInncc.,, aanndd wwaatteerr eexxcceeppt ffoorr aapppprrooxxiimmaatteellyy 1177 1to0 2200 hhoouurrss bbeeffoorree tteesstt mmaatteerriiaall aaddmmininisisttrraattiioonn wwhheenn ffoooodd,, bbuutt nnoott wwaatteerr,, wwaass wwiitthhhheelldd.. TThhee ffeeeedd iiss rroouuttiinneellyy aannaallyyzzeedd bbyy tthhee mmaannuuffaaccttuurreerr ffoorr nnuuttrriittiioonnaallccoommpopnoneennttssaanndd eennvviirroonnmmeennttaall ccoonnttaammininaanntsts.. SSaammpplleess ooff tthhee wwaatteerr aarree ppeerriiooddiiccaallllyy aannaallyyzzeeddbbyy CCHHWW.. TThheerree wweerree nnoo kknnoowwnn ccoonnttaammiinnaannttss iinn tthhee ffeeeedd oorr wwaatteerr aatt lleevveells tthhaatt ccoouulldd bbee eexxppeecctteedd ttoo iinntteerrffeerree wwiitthh oorr aaf.ffleecett tthhee rreessuullttssoofftthhee ssttuuddyy.. AAnniimmaall SSeelleeccttiioonn aanndd GGrroouuppiinngg "TTeenn mmaallee aanndd 1100 ffeemmaallee hheeaalltthhyy,, aacccclliimmaatteedd rraattss,, wweeiigghhiinngg ffrroomm 220088 ttoo 226699 gg aanndd aapppprrooxxiimmaatteellyy 88 t1o0 1122 wweeeekkss ooffaaggee,, wweerree aassssiiggnneedd ttoo ttwwoo ttrreeaattmmeenntt ggrroouuppss ooff225500 aanndd 550000 mmgg//kkggooffbbooddyy wweeiigghhtt. EEaacchh ddoossee lleevveell ccoonnssiisstteeddooff 5mmalaleeaanndd 5 ffeemmaallee rraattss.. TThhee aanniimmaallss wweerree iiddeennttiiffiieedd bbyy aanniimmaall nnuummbbeerr aanndd ccoorrrreessppoonnddiinngg eeaarr ttaagg tthhrroouugghhoouutt tthhee ssttuuddyy.. 9 11446699..00000099 33MM_MMNNO011668888778888 cCwHW s6i1o0001i776600 JJuussttiiffiiccaattiioonn ffoorr SSppeecciieess SSeelleeccttiioonn HHiissttoorriiccaallllyy~, rraattss hhaavvee bbeeeenn uusseedd aass aa rreepprreesseennttaattiivveeooffaa rrooddeenntt ssppeecciieess aanndd aarree pprreeffeerrrreedd bbyy vvaarriioouuss rreegguullaattoorryy aaggeenncciieess.. PPRROOCCEEDDUURREESS PPrreeppaarraattiioonn aanndd AAddmminiinsisttrraattiioonnooff TTeesstt MMataeterriiaall `TThhee tteesstt mmaateterriiaall wwaass mmiixxeedd wwiitthh ddiisstiillleedd wwaatteerr ttoaoa ccoonncceennttrraattiioonnoof0f.0.002255 gg//mmLL foorr tthhee 225500 mmge/kkg ddoossee lleevveell aanndd 00..005500 gg//mmLL ffoorr tthhee 550000 mmgeikkg ddoossee lleevveel.l. TThhee pprreeppaarreedd tteesstt mmaatteerriiaall mmiixxttuurreess aappppeeaarreedd ttoo bbee ssoolluuttiioonnss.. AAnn iinnddiivviidduuaall ddoosseeoofftthhee rreessppeeccttiivvee tteesstt mmiixxttuurree wwaass ccaallccuullaatteedd ffoorr eeaacchh aanniimmaall bbaasseedd oonn ittss ffaasstteeddbbooddyywweieigghhtt aanndd aaddmmiinniisstteerreedd bbyy ggaavraaggee aatt aa vvoolluummeeooff 1I00 mmLL//kkggooffbbooddyy wweeigighth.t.TThhee tteesstt mmaateterriiaall mmiixxttuurreess wweerree ssttoorreedd aatt rroooomm tteemmppeerraattuurree uunnttiill aaddmmininisistteerreedd.. RReeaassoonn ffoorr RRoouuttee ooff AAddmminiinsisttrraattiioonn HHiissttoorriiccaallllyy,, tthhee oorraall rroouuttee hhaass bbeeeenn tthhee rroouutteeooffcchhooiiccee ffoorr aaddmmininiisstteerriinngg aa kknnoowwnn aammoouunntt oofftteesstt mmaateterriiaall. OObbsseerrvvaattiioonnss CClliinniiccaall oobbsseerrvvaattiioonnss aanndd mmoorratlailittyy cchheecckkss wweerree ccoonndduucctetdeaadtt 11,, 22..55,, aanndd 44 hhoouurrssafat~eerrtteesstt mmaatteerriiaall aaddmmininisisttrraattiioonn aanndd ddaaiillyy tthheerreeaafftteerr ffoorr 1144 ddaayyss.. MMoorratlailittyy cchheecckkss wweerree ccoonndduucctteedd ttwwiiccee aa ddaayy ((mmoorrnniinngg aanndd aatf~teemmoooonn)) ffoorr 1133 ddaayyss aaffteerr tteesstt mmaateterriiaall aaddmmininisisttrraattiioonn aanndd aaggaaiinn tthhee mmoomrniinnggooff DDaayy 1144.. BBooddyy wweeiigghhttss wweerree ddeetteerrmmiinneedd bbeeffoorree tteesstt mmaatteerriiaall aaddmmininisisttrraattiioonn ((DDaayy 00)).. AAddddiittiioonnaall bbooddyy wweeiigghhtss wweerree ddeetteerrmmiinneedd aatt DDaayy 77,, aatt tteerrmmiinnaattiioonnooff tthhee iinn-lliiffee pphhaassee ((DDaayy 1144)),, oorr aatt ddeeaatthh wwhheenn ssuurrvviivvaall eexxcceeeeddeedd 11 ddaayy. PPaatthhoollooggyy AAtt tteerrmmiinnaattiioonnoofftthhee rreessppeeccttiivvee iinn--liiffee pphhaassee ffoorr eeaacchh ddoossee lleevveell,, aallll ssuurrvviivviinngg aanniimmaallss wweerree eeuutthhaanniizzeedd.. AAlll aanniimmaallss,, wwhheetthheerr ffoouunndd ddeeaadd dduurriinngg tthhee ssttuuddyy oorr eeuutthhaanniizzeedd,, wweerree 10 10 11446699..00001100 33MM_MMNNO011668888778899 CHHwW 6611000011776600 Ssuubbjjeecctteedd ttooaannaabbbbrreevviiaatteedd ggrroossss nneeccrrooppssyy eexxaammiinnaattiioonn aanndd aannyy aabbnnoorrmmalailittiieess wweerree rreeccoorrddeedd.. AAfftteerr nneeccrrooppssyy,, tthheeaanniimmaallss wweerree ddiissccaarrddeexdt aanndd nnoo ttiissssuueess wweerree ssaavveedd.. SSttaattiissttiiccaall AAnnaallyysseess NNoo ssttaattiissttiiccaall aannaallyysseess wweerree rreeqquuiirreedd bbyy tthhee pprroottooccooll. LLooccaattiioonnooffRRaaww DDaattaa,, RReeccoorrddss,, aanndd FFiinnaall RReeppoorrtt `TThhee rraaww ddaattaa,, rreeccoorrddss,, aanndd aann oorriiggiinnaall ssiiggnneedd ccooppyy oofftthhee ffiinnaall rreeppoorrtt wwiillllbbee rreettaaiinneedd iinn tthhee aarrcchhiivveessooffCCHHWW iinn aaccccoorrddaannccee wwiitthh CCHHWW SSOOPP.. RREESSUULLTTSS MMoortratalliittyy AA ssuummmmaarryyoofftthhee oobbsseerrvveedd mmoortrtaalliittyy iiss iinn TTaabbllee 11. . NNoo mmoorratlailittyy wwaass oobbsseerrvveedd aatt tthhee 225500 mmgg//kkgg ddoossee lleevveel.l. TTwwoo mmaalleessaannddalalll ffiivvee ffeemmaalleess ttrreeaatteedd aatt 550000mmgg//kkggwweerree ffoouunndd ddeeaadd wwiitthhiinn 44 ddaayyssooff tteesstt mmaatteerriiaall aaddmmiriinsitsrtraattiioonn.. NNoo ootthheerr mmoortrtaalliittyy wwaass oobbsseerrvveedd.. BBaasseedd oonn tthhee oobbsseerrvveedd mmoortratalliittyy,, tthhee eessttiimmaatteedd oorraall LLDDssa0 vvaalluueess wweerree ddeetteerrmmiinneeds ttoo bbee ggrreeaatteerr tthhaann 550000 mmgg//kkgg ffoorr mmaalleess aanndd bbeettwweeeenn 225500 aanndd 50000 mmgg//kkgg ffoorr ffeemmaaleless.. BBooddyy WWeieigghhttss IInnddiivviidduuaall aanndd mmeeaann bbooddyy wweeiigghhttss aanndd bbooddyy wweeiigghhtt ggaaiinnss aarree iinn TTaabbllee 22.. AAllll ssuurrvviivviinngg aanniimmaallss eexxhhiibbiitteedd bbooddyy wweeiigghhtt ggaaiinn tthhrroouugghhoouutt tthhee ssttuuddyy.. CClliinniiccaall SSiiggnnss IInnddiivviidduuaall cclliinniiccaall ssiiggnnss aarree iinn TTaabbllee33.. AAllll aanniimmaallss ttrreeaatteedd aatt 225500 mmggk/kgg aappppeeaarreedd nnoorrmmaall dduurriinngg tthhee ssttuuddyy wwiitthh tthhee eexxcceeppttiioonn ooffttwwoo ffeemmaalleess wwhhiicchh eexxthiibbiitteedd rreedd--ssttaaiinneedd ffaaccee aanndd//oorr wweett uurrooggeenniittaall aarreeaa wwiitthhiinn 2244 hhoouurrssoofftteesstt mmaatteerriiaall aaddmminiinsitsrtraattiioonn.. CClliinniiccaall ssiiggnnss ooff ttooxxiicciittyy oobbsseerrvveedd iinn tthhee aanniimmaallss ttrreeaatteedd aatt 550000 mmgg//kkgg iinncclluuddeedd rreedd--ssttaaiinneedd ffaacee,, yyeellllooww-- ssttaaiinneedd oorr wweett uurrooggeenniittaall aarreeaa,, hhyyppooaacctitivviittyy,, hhuunncchheedd ppoossttuurree,, ssttaaggggeerreedd ggaaiitt,, eexxcceessssiivvee uII 1144699..00001111 33MM_MMNNo011668888779900 CHW 61001760 CHW 61001760 ssaallivvaattiioonn,, aanndd ddeeaatthh.. TThhee ssuurrvviivviinngg aanniimmaallss ttrreeaatteedd aatt S50000 mmgg//kkgg rreettuurnmeedd ttoo aa nnoorrmmaall aappppeeaarraannccee bbyy DDaayy 77.. PPaatthhoollooggyy IInnddiivviidduuaall ggrroossss nneeccrrooppssyy ppaatthhoollooggyy ffiinnddiinnggss aarree iinn TTaabbllee 44.. AA ssuummmmaarryy rreeppoorrtt bbyy tthhee ssttuuddyy ppaatthhoollooggiisstt iiss oonn PPaaggee 1144.. TThheerree wweerree nnoo tteesstt mmaatteerriiaall erellaatteedd lleessiioonnss oobbsseerrvveedd aatt nneeccrrooppssyy.. DISCUSSION DISCUSSION TThhee aaccuuttee oorraall ttooxxiicciittyyooffTT--66666699 wwaass eevvaalluuaatteedd iinn mmaallee aanndd ffeemmaallee rraattss wwhheenn aaddmmininiisstteerreedd aass aa ssiinnggllee ggaavvaaggee ddoossee aat lleevveellssooff225500 aanndd 550000 mmgg//kkggooffbbooddyy wweeiigghhtt. BBaasseedd oonn tthhee oobbsseerrvveedd mmoortratalliittyy,, tthhee eessttiimmaatteedd oorraall LLDDs,0 vvaalluueess ffoorr mmaallee rraattss wwaass ddeetteerrmmiinneedd ttoo bbee ggrreeaatteerr tthhaann 550000 mmgg//kkgg aanndd bbeettwweeeenn 225500 aanndd 550000 mmgg//kkgg ffoorr ffeemmaaleless.. AAllll mmoorratlailittyy ooccccuurrrreedd aatt tthhee 550000 mmgg//kkgg ddoossee lleevveell wwiitthhiinn 44 ddaayyssoofftteesstt mmaateterriiaall aaddmminiinsitsrtraattiioonn.. AAllll aanniimmaallss ttrreeaatteedd aatt 225500 mmgg//kkgg aappppeeaarreedd nnoorrmmaall dduurriinngg tthhee ssttuuddyy wwiitthh tthhee eexxcceeppttiioonnooffttwwoo ffeemmaalleess wwhhiicchh eexxhhiibbiitteedd rreedd--ssttaaiinneedd ffaaccee aanndd/oorr wweett uurrooggeenniittaall aarreeaa wwiitthhiinn 2244 hhoouurrss ooff ttrreeaattmmeennt.t. CClliinniiccaall ssiiggnnssooffttooxxiicciittyy oobbsseerrvveedd iinn tthhee aanniimmaallss ttrreeaatteedd aatt 550000 mmeg//kkgg iinncclluuddeedd rreedd--ssttaaiinneedd ffaaccee,, yyeellllooww--ssttaainneedd oorr wweett uurrooggeenniittaall aarreeaa,, hhyyppooaactcitivviittyy,, hhuunncchheedd ppoossttuurree,, ssttaaggggeerreedd ggiatit,, aanndd eexxcceessssiivvee ssaalliivvaattiioonn.. AAnniimmaallss ssuurrvviivviinngg ttoo tthhee eenndd ooff tthhee oobbsseerrvvaattiioonn ppeerriioodd eexxhhiibbiitteedd bbooddyy wweeiigghhtt ggaainn dduurriinngg tthhee ssttuuddyy.. TThhee ggrroossss nneeccrrooppssyy eexxaammiinnaattiioonnss ddiidd nnoott rreevveeaall aannyy tteesstt mmaatteerriiaall rreellaatteedd lleessiioonnss. SSIIGGNNAATTUURREE SStteevveenn MM.. GGllaazzaa SSttuuddyy DDiirreeccttoorr AAccuuttee SSttuuddiieess . DDaatee 1-16-37 212 11446699..00001122 33M_MNMoN1061868s8779911 CCHHWW 6611000011776600 REFERENCE 1. ""AAccuuttee OOrraall TTooxxiicciittyy,,"" OOrrggaanniissaattiioonnffoorr EEccoonnoommiicc CCooooppeerraattiioonnaannddDDeevveellooppmmeenntt GGuuiiddeelliinneessffoorr TTeessttiinnggooffCChheemmicicaallss,, SSeeccttiioonn 44,, HHeeaalltthh EEffffeeccttss,, NNuummbbeerr 440011,, PPaarriiss CCeeddeexx ((FFeebbrruuaarryy 2244,, 11998877).). 113 11446699..00001133 33MM_MMNNO011668888779922 PATHOLOGY REPORT PATHOLOGY REPORT aman CHW61001760 TThheerree wweerree 1100 rraattss ((ffiivvee mmaallee,, ffiivvee ffeemmaallee)) eeaacchh ffrroomm ddoossee lleevveellssooff 225500 aanndd 550000 mmgg//kkgg. acon. Alanis gen 500 mgs, eto ree, id one. Th necropsied. All animals given 500 mg/kg, except for three males, died on test. The ing ils wie chain ot raped nto 0 sy. The surviving animals were euthanized and necropsied at the termination ofthe study. The i ------ ddoossee lleevveell,, ddaayyooff ddeeaatthh,, aanndd ggrroossss oobbsseerrvvaattiioonnss rreeccoorrddeedd ffoorr eeaacchh aanniimmaall aarree iinn tthhee Individual Pathology Comments that follow this report. tt ey, th wre fgets ofewes ssid eal snd At necropsy, there were few findings and all ofthese were considered incidental and uunnrreellaatteedd ttoo tthhee tteesstt mmataeterriiaall.. IInn tthhee aanniimmaallss tthhaatt ddiieedd oonn tteesstt,, oone mmaalle wwaas ppaarrttialllyy ccaannnniibbaalliizzeedd,, oonnee ffeemmaallee hhaadd mmuultltiippllee,, ddaarrkk bbrroowwnn aarreeaassooffvvaarriiaabbllee ssiizzee iinn tthhee ggllaanndduullaarr re Toe we violas hemo srl clear fluid. The pelvisofboth kidneys in one female given 250 mg/kg was observed to be m`muuccoossaa ooff tthhee ssttoommaacchh,, aanndd bbootthh hhoorrnnssooftfthhee uutteerruuss iinn aannootthheerr ffeemmaallee wweerree ffiilllleedd wwiitthh clear fluid. The pelvis of'both kidneys in one female given 250 mg/kg was observed to be large. There were no visible lesions in the remaining animals. Tbr, "ThomasE. Palmer," fii Pathologist fo ((6611000011776600.ffiinn)) 121696 e022 DDaattee "14 11446699..00001144 au noresres 3M MN01688793 --- I ' O0 OO 0 QCcHwW6e100w17m60 "TTaabblel1e1 Morality Summary MortaiRy Summary D D(omseakLo ee)vel w Sex i No.VMDoorre tiamliNytyeoRR.eeDdsd omusltn!esd (m~k~) Sex No. Died/No. Dosed* 22255%00 MMEooss015 250 F 0/5 550000 MM25 D2/5a, Dyayss 3,a 550000 FF 5/55/5D, Daaysys1,03,'4 SiSouappeelrscrrfioputmnndaumembabederr oinndtoichwaeetiesnsdmniucbamtaebdrercoaoyf.f animals found dead on the indicated day. 1i5s 11446699..00001155 S3Mu wMNNo0t1e6s8s8T7o9s4 Table 2 Table 2 IInnddiivviiddBuuoaaldl yaannWddeiMMgeheaatnnGaBBioonddsyy(W We) iegighhttss!/ Body Weight Gains (g) cw 1001760 CHW61001760 "AAnniimmaall DaDyay00_ Number Weight Number Weight ccCii1a22ss5s55t10 222666099 CCcC11is2265ie1510 222245468998 cies C12612 C12613 222555339 MMeeaann 226600 Day 7 WeighDt ay 7_Gain Weight Gain* Males (250 mg/kg) Males (250 mg/kg) 3233050 e66l1 233390205617 38557996 EE296 296 37 43 3s11 ms51 Day 1% WeighDta_y 1G4ain" Weight Cram* #14 373383s939 0114 o7w0 337a5 1o2s7 7s354 375 a295 122 3366s5 110066 FFeemmaalleess ((225500 mmgg//kkgg)) cCci1n2336n771 22246618 ccCC11ii22sn3366ee87 222235345958 ann C12369 C12370 2259 252 2429845 33337 2223808350 a44357 2%303 287 3435s4 MMeeaann 225511 2E90 E]39 * GGaaiinm ffrroomm DDaayy 00 bbooddyy wweeiigghht.t. 23301s54 65se4 8322809549 45556000 8309 288 353606 EX298 47 1166 11446699..00001166 33MM_MMNNO011668888779955 Table 2 (Continued) Table 2 (Continued) IInnddiivviiddBuuoaaldl yaannWddeiM MgeheaatnnGaBBioonddsyy(W W5)eieigghhttss// Body Weight Gains (g) cH si001760 CHW61001760 NAAunnmiambelarl _ WDDeaiaygy0h0t Number Weight ccC1uo2s2n3t1 2221133 CccC11ou22n22s22s87 822220718 cso C12229 C12230 2s217 215 MMeeann 221155 WeigDhatDayy 77_GanTM Weisht Gain* M Maalleess ((550000 mmgg//kkgg)) a22e49n9t 3366 a(1s6s7)y4 -- (168)3 - m ms s 271 54 274 59 5265 5500 Day 1% WeighDtay 1G4ain" Weisht Gain* -302 88p9y :N 233200419110033 334 119 35199 10044 FFeemmalaeless ((550000mmg/g/kkgg)) Cc1u22s76 224488 Ccc1iu22rs77 22222433 cis cz C 12278 C 12279 22222446466 C12280 236 @y Ta((2137r15t))34 -(a@2s3s~a4))0 - (193)4 - - -: *- :- :- MMeeaann 235 235 -- - , T GGuainnffroommDDmayyO0bbooddyywweeisghnt. + Animal wasfounddead on thedayof dosing. Nobodyweight required Animal was required. found dead on the day of dosing. No body weight (()) cVVoaanllsuuieedeiinnreppdaarrieennncttahhleecssueelssatiisna gatdhdeeeaamddebbaoondd.yy wwSueepiieggrhhsttcraainnpddtwwnaaussmbnneootrt indicates ttchhoeensddiaadyyerttehhdee animal was found dead in calculating the mean. animal was found dead. Superscript number indicates - Notapplicable. Not applicable. 117 11446699..00001177 33MM_MMNNo0116688s87799S6 IntlClic sign Table 3 Individual L-~JKic~I ~i~ CCHHWW6611000011776600 Ammal Numb~ Observation BR EEE MalaEEsomeR) EEEAA C12551 A~pea~d normal A AEA A I A A C12550 Appeared normal BR EEEEEEEEE I AAA C126|1 A~pca~eal normal A A A A A A C12612 Appea*d normal BE AEEE EE AA C 12613 A~pea~d no~a~l Ep C12371 Ap~:d normal C12367 App~d normal Fem23a0mliee) EE EE III AA a I EE EEERI Rcd-stamd fa~ Ci Appenorml C12368 Appcared normal C12369 A~peared normal Red-mained face Vapi Wet urogenital area Ep {712370 Appeared normal EAE A A A 4 RE I A E <4 : : Sonn EE EE RII AA 4- Condition gisled. Condition not evident 1I8) 11446699..00001188 33MM_MMNN0011668888779977 TobeComte) IndieConnSim CHW61001760 CHW61001760 Tr Em ------ Anin~ fe EE J CS Number Ol~e~v~.ion Hour 1.0 2.5 4.0 Day | 2 3 ,4 5 6 7 8 9 10 I I 12 13 14 P Remm=i p Lo[ co-- sE 0000EPEE00R 0 E C12231 Appea~d non~l Red.s~ined face Yellow-s~med urog~i~l are~ cnfs H Moeiy gfp onsy a 4c04oD2 t 4 lnt0 os i0 o tgo C12227 Appeared normal Red-s~smed face H.vpoactivity HunChed posture Staggered gait Found de~d cuma[pep--iwses C12228 A~pea~l normal Red-stained face Hypos_~tivity Yellow-stained urogenital area 444- Te Found d~ad A AEII II C12229 Appeared normal [omni Jolt Red-s~ined fa~e CloApes 4 4 4S 4S LLL LL sss C12230 Appeared normal Condition existed. Condition not evident 1199 11446699..00001199 33MM_MMNNO011668888779988 : CCHHWW6611000011776600 Tbh Continent) Table 3 (Continued) nInddil~daonanl usc Sg Clinical StUns ---- i ---------- Ammal Nimo Oermin TTB 0TTTTTCTTSRWEOE Number Observation cmeppWreaepdpoten 4PE 44 a7 ] C12276 Appeared normal Red.stained face Wet urogenital area Hypoactivity Hour 1.0 2.5 4.0 D~' I 2 3 4 -~ 6 ")' 8 9 10 11 12 13 14 Femalea (-~00 m~,/k~) ,/ / Hunched posture / Found dead P WRaTieoucmprhampnarpeayE eawees !Lol7 7L AlE7ly7 Ci2277 Appeared normal Red-stained face Wet urogenital area H .x~oactivity Hunched postur~ cm pdm Found dead C12278 Appeared normal 4 Excessive salivation Found dead cum pis C12279 cinTHmsHmeoopaaenpepremderdersardogaenrieiines) C12280 A~peared normal Red-stained face Wet urogenital a~ea Hypoactivity Staggered gait Found dead clinical obserCafi~n) Appeared normal Red-stained face Wet urogmfital Hypoactivity Hunched postur~ Staggered gait 44 LL ' LL , 4 4L4 s "ry DDLoDnd7 7 Emm Found dead Condition existed. Condition not evident, 2200 11446699..00002200 33MM_MMNNO011668858779999 TTaabbllee 44 IInnddiivviidduuaall PPaatthhoollooggyy CCoommmmeennttss DDoossee LLeevveell:: 225500 mmgg//kkggooff BBooddyy W Weeiigghhtt cw 61001760 CHW61001?60 "ANAmunmmibmea~r Sex Number Sex cCi1z2s5s5i1 MM cC1s25o50 MM Cc1e2l61l1 MM ce C12612 MM cC1i2e61s3 MM cC1n23n71 OFF cer C12367 OF F cizses C12368 F F cise C12369 F F cir OF C12370 F TNotNaopt paplpcliacbabilee. DiTedeTetsDt SDwaacyryificed Died Sacrificed - - 1144 - - 114 -- "14 - 1144 - 124) - 11"4 - 11"4 . 114 - 114 -" 14 NNeeccrrooppssyy OObbsseerrvvaattiioonn NNoo vviissiibbllee lleessiioonnss.. NNoo vviissiibbllee lleessiioonnss.. NNoovivsiisibbllee lleessiioonnss. NNoo vviissiibbllee lleessiioonnss.. NNoo vviissiibbllee lleessiioonnss.. BBpeolovttihhso.off tthhee kkiiddnneeyyss hhavaeaavllaarreggee pelvis. NNoo vviissiibbllee lleessiioonnss. NNoo vviissiibbllee lleessiioonnss. NNoo vviissiibbllee lleessiioonnss.. NNoo vviissiibbllee lleessiioonnss. 221 11446699..00002211 33MM_MMNN0011668838880000 `Table 4 (Continued) Table 4 (Continued) IInnddiivviidduusall PPaatthhoollooggyy CCoommmmenenttss DDoossee LLeevveell:: 550000 mmgg//kkgg ooff BBooddyy WWeeiigghhtt Hw 61001760 CHW61001760 "ANmAunmmimbaeMr Sex Number Sex Cc1s22i31 MM cM C12227 M cC1o2n22s8 MMm Cc1z22y29 M0M aC1m22o30 MM cC1i22r76 F F _ DiedTe~ SDaacTerydyificed Died Sacrificed -- 1144 44 -- 33 -- - - 114 - - 114 3 3 - - cm C12277 OFF 4 4 - cms OF 0 - C12278 F 0 cm C12279 OFF 11 - ci C12280 OFF 44 - TNoNtoat papppiliceabmlee. Necropsy Observation Necropsy Observation NNoo vviissiibbllee lleessiioonnss.. `TThhee rriigghhtt ffllaannkk wwaass ccaannnniibbaalliizzeedd.. NNoo vviissiibbllee lleessiioonnss. NNoo vviissiibbllee lleessiioonnss. NNoo vviissiibbllee lleessiioonnss. "sTTthhoeemggallcaahnnddhuualslaarrmummluiucpcolosesaaodaofrfktthhbeerown asartroeeamass,a, cuuhpphttaoos22mxxul1Itipmmlmem..dark brown NNoo vviissiibbllee lleessiioonnss.. NNoo vviissiibbllee lleessiioonnss. T"tThhheeeulltuuemrmueesnniiisnnfittlhhleeedbbiwilliaatttheerrcaalllehhaororrlnnissdooff the uterus is filled with clear fluid. NNoo vviissiibbllee lleessiioonnss. 222 11446699..00002222 33MM_MMNNO011668838880011 --eCCHW61001760 AAPPPPEENNDDIIXX PProrottooccooll TTPP22006699 Protocol Amendment No. | Protocol Amendment No. 1 PPrroottooccooll AAmmeennddmmeenntt NNoo.. 22 ProtocalAmendment No. 3 Protocol Amendment No. 3 n23 11446699..00002233 33M uMNNo0T1668E8880022 -- : ern emmmaseeammsnCSCeHHWWUn6611O00Oe11776600 | SLEELLEINAETaIIRmTe, `SSaammpplleeiSSuubbmmititttaall FFoorrmm cS EowRpaId h EHo.h(.LeD h , RUQ_ Teor Bones GC VERGNS ouetepete Gisele. comomy INN Member Regors Raed 5 Fr suneLtPCaoi mepince_:TmY:Lew0o0UN--T E POEo A@o1 Pm RON) e KoEoA IRA CIR100 --WoEw Sea orac rrnaonm gpiaecoon c:Sr5r8ane SDrErOs FoOrmOoi TyLT rma Ewoew rein 2 rampage = SEEPREIT S53c-o35h 51 TnsCae -- omni surg sce ecm: E m f = Jme m mm i I Tests I tJ ThIrmE itmoen nT , aAsEo [ S e TET tavl coutmn mt e a s SE RERe r STe) ] u -- sin Primary Eye Irrltsllon __TP32DI~ FHSA; e r~J~l~ w',W~llhed `AcuteDermalTacIn Rabbits BI E E pi]i me e A eieeerrSaeTI en Jilin rae tiirtsiad Zr earnavsadsveese __TP2012 1078 EPA; 6 rab~ u~ssh~. 3 wll~ ProtOCOl Ictus Dale: , Ir----on While op,/-,-CHW tO-%~, ------ Yellow o~)y--$ubmlller | I oar 24 11446699..00002244 aw otessans 3M MN01688803 @HAZLETON HAS La MSLN sur: SDOnSO~: ranPas 3H Paul, Htnnesota rca ss PROTOCOL TPg069 su Te Study Title: [A S--S ---- Acute Oral Tox~c|ty Study in Rats (OECD Guidel|nes) ous:Date: ome 1, 100 3une 1, 1993 [---- PerfOrmina Laboratory: gAen wisconsin, tc. Haz]eton ~isconsin, Inc. 3301 Kinsman Boulevard Hadison, Wisconsin 5370~ Laboratory Proiect Identification: amon CFIW61001760 225 11446699..00002255 aw notesaans 3M MN01688804 wenn CHW 61001760 aanees TP2069 Page stor omricaTion STUDY IDENTIFICATION Rest Or Testy study tn Rats Acute Oral Toxicity Study tn Rats Todinie (OECD Guidelines) Wi Ke. HWI No. Test water Test Nater|al spose Sponsor Sponsor's Representative Sponsor's Representative sty director Study Director stu Location Study Location Propose stugy Tioetaple Proposed Study Timetable Toperiariat Sort oie Experimental Start Date F ERnI Tomiostion sue Experimental Termination Date F~nal Report Date cmon (see samle smiten) fore) (See sample submittal form) Toacoton servi H0SE0I0 Canter 3H ~oxico]ogy Services 220-2E-02 3H Center Em St. Paul, NN 55144 J L bteort, m0 Oohn L. Butenhoff, PhD Tiecate services HOSEI0 Canter 3H Toxicology Services 220-2E-02 3H Center SUTSt. Paul, I~l 55144 ia] 3 (512) 733-196Z steven. cra SLeven N. Glaza BET whee, nc Hazleton Wisconsin, Inc. HoP.O. Box 7545 Radian: i sa70-750s HadJson, W! 53707-7545 [rahe (608) 241-7292 ateten Wscsnstn, In. Hazleton Wisconsin, fritid Building No. 3 S30 Avene 3802 Packers Avenue Rattan, ur hon Hadtson, W! 53704 Inc. Whdweoeanektk ooofff E1932T7C:9 Meek of Meek of 226 4146699..00002286 33M_MNMON106186838880055 : CHW61001760 CHW 61001760 7 Page 3 "pEeE rt ton ]o Study sy 0 00 ato Acute Ore] Toxicity Study in Rats (OECD Guidelines) pePurno$~ To assess the acute oral toxicity produced when the test materla] fs Fh a vit an administered by the oral route (gavage) to rats piAeEciscs 1 tes te i Requlatory ComplianGe This study will be conducted in accordance with the following Good SEEN ean Laboratory Practice Regulations/Standards/Guidelines: rt rete Conduct as a Nonregulated Study H{] GrEetaRarEs " 21CFR 58 (FDA) 40 CFR 150 (EPA-FIFRA) HEGRE 40 CFR 79Z (EPA-TSCA) TS se me C(81)30 (Final) (OCD) [1 Bie hm op pom, Notification No. 3850, August lO, 1984 (Japanese MAFF) Notification No. 313, March 31, 1982, and as aBended by EEE EE Notification No. 870, October 5, 1988 (Japanese HOHW) n ree ai cms ae)s A1] procedures in this protocol are in compliance with the Animal Welfare Act Regulations. In the opinion of the Sponsor and study director, the study does not unnecessarily duplicate any previous work. PMR ern ty cots, 0 Ouality Assurance For regulated studies, the protocol, study conduct, and the final da EAE el report will be audited by the Quality Assurance Unit in accordance with Hazleton Wisconsin (HWI) Standard Operating Procedures (SOPs) and policies. So T~It Material + nLasp e . Identification (See sample submittal form) Physical Description RES, ny (See sample submittal form) o SFEEISR iy ry ay Purity and Stability Sm ym The Sponsor assumes responsibility for purity and stability Sri iEh determinations (including under test conditions). Samples of test material/vehicle mixture(s) (if applicable) for concentration, solubility, homogeneity, and stability analyses will be taken before administration if requested by the Sponsor. These samples (if taken) will be sent to the Sponsor after experimental termination for possible analysis. 27 11446699..00002277 aw noresons 3M MN01688806 ci stoo7s0 CHW 61001'760 wFaaest Page 4 0. tora Storaoe THe cmtetnt tom) (See s~mple submittal fonu) Reserve Samoles SHARE INE tn 4 weeks 10 exertaste) uration sa ot Studies of less than 4 weeks in exper|mental duration will not Rive resaes Samper rebuined have reserve samples retained, Reserve sumple(s) of exchbatch lat of test matrfal will be Reserve sample(s) of each batch/lot of test mater|al wtll be ker TTT Ey 13 Sor than 4 vee in sxprioental taken if this study ts more than 4 weeks in experimental tn. duration. The test materia) reserve sale wil be stores at WI ino The test material reserve Tete artis fetes 8 Boat 18 Jur freezer set to maintain a por $5. "The Synsor wT bocontacted site 1 years for per H~I S0P. The Sponsor Eitport on in accordance with te spproriate ressatory Good disposition in accordance Catoratory practice Laboratory Practices. sample will be stored at HWI tn a temperature of below 0"C for l0 years wil] be contacted after 10 years for with the appropriate regulatory Good [arro Retention SESE, test material wi be discarded aftr tsqnce of Any unused test material will be discarded after issuance of ARE Fim report atess Giected stharvise by the Sponsor the final report, unless directed otherl(tse by the Sponsor. 6. safety precastions Go Safe)v Precaution; REGIE sor na porter As required by HWI SOPs and policies 6. Dsrisenta) Desir 6. [xoerimental Desiqn [aA. ~nimalT gassie (l) Species iRat @ g ~train/Sourc( OF LIEaries ie uberatories, In (~" Crl:CO'BR/Charles River Laboratories, Inc. BY Raion SR Er: ia, oc [ ] Hsd:Sprague Dawle SOe/Harlan Sprague Oawley, Inc. ) facat inti (3) Aoe at Initlatlo~ Toi ait Young adult ) geptioistiattion (4) Weiqht @t |nitiatipq for Z00 to 300 g 5) Naber and sex (S) Number and Sex (6) MEAS res for te dni use teva) 5 males and 5 females for the initial dose level $3010 nazar 5 femles fo any scaition) dose levels 5 males and/or 5 females for any additional dose levels [phe [if required) (6) Identification fi Individual numbered ear tag 225 11446699..00002288 33MM_MMNNO011668838880077 cw stoo1760 ChrW 61001760 0Fi6ge9s TP2069 Page 5 0) tushantry (7) Husbandry fusing (a) Houst,q $8338 by sex ad gray housed tn scren-totten Separated by sex and group housed fn screen-bottom frit Ao gbiekit edb) stainless steel cages (heavy gauge) pa (b) Food Efe chou 15001 (puri NTL, Tn.) ad Tibitom Rodent Chow 15001 (Purina Hills, Inc.) ad 7fbftum itt So rad fry a sie except for overnight before test material Seethistratton. The fond 1s routinely analyzed by administration. The food is routinely analyzed by ihe maruactaner for mtritiona comarents snd the manufacturer for nutritional components and rates environmental contaminants. we (c) Water 32 bitun fron an automtic syste. Sumples of the Ad (ibitum from an automatic system. Samples of the Sater are smizekd by Wl for Sots dssiatved slice, water are analyzed by HWI for total dissolved solids, Tirinetrs 1 pacified ascrablologicl content and hardness, and specified microbiological content and For Teecens closets, Deby sears, for selected elements, heavy metals, Crgsmopmorpates and chlorine Rdrecarbons. organophosphates, and chlorinated hydrocarbons. gontaminants (d) Contaminants RUE en contastuants 1 the foodor vater There are no known contaminants in the food or water ET terror in th soy that would interfere with this study. ((e)l [RUISL [nvironment Environmental ccoonnttrroollss ffoorr tthhee aanniimmaal rraogome wwiilll bbee 30 to maintain a teers of 19-10 25C set to maintain a temperature of 19 to Z5"C, a SEhathe htitey SFT ae Lod hee relative humidity of 50%20%, and a 12-hour TEER her eo sree. light/12-hour dark cycle. 0 climtion (f) Fcclimatlon HA as At least 7 days seleotc10tstipooinnts Selection of Test Animals BRET eto accorain to 1 Sov. Based on health and body wetght according to HWI SOPs. An Sitoate meaner SF erirs seioal Sh be Porhases 30 th adequate number of extra animals will be purchased so that 2a Sint" Shefoufly poor Resi 13 FIoces on Sect. no animal in obviously poor health is placed on test. Opitrasit e sien Justification for Tpqtes Selection FEHR SEER, resentative of + Historically, rats have been used as representative of a Tose Spectis and are preferred} varios repuTstory rodent species and are preferred by various regulatory enter, agencies. 6. dMaasientstration Dose Administration 8 Dose Leve! 0 REESse of 5.000 ig of uty eight wil be A single dose of 5,000 mg/kg of body weight will be Saninttered to Five mIgh and five Gmates. 11 mo test administered to five males and five females. If no test eT er he hs een he material-related mortality is produced at this level, no 229 4146699..00002299 33MM_MMNNO011668838880088 e-- r ------------------------ CHW-- 601080-- 1786O rFuseen6 TP2069 Page 6 LBffateuuhrrtLttechhhedeeerrd5S1t,t0e0a33s00s0t0tiit0nmhneggg/0ikwriglel)clodtossbibeeeeonrrlTeeeecovqvseueftltlr,.rieehddea,a.dddsdititutIIidifFooynnaanaadnyllyirddmmeoooocsvrrteettoaarlllleiieivttvneyeyllossroodccmcecmauruarryyss tboe5 nmaedeedetedtthhaeet ootbbhjejeeccdttiiirvveeecsstiooonff ottfhheethssettuudsdyty.udy director in order @(2) Bg A ADliolssteiarPnerimo epDaealsrradwtilol0ss lnewraTonedvdceel:iAt vdsemuinttIihfsestto rEsnaa1tmtI0iie1oe3ncc,oenncitehnertarttaetistioonnmaotoeffrittaee]sstt wSTdmtihhIeileexFnltIsuIitterTtebsseeEyttS1psS3mieuaartsttdppeeeeedrrrnnoiiesdiaareeeslmddilwnwetii.vrnhle}ll1ta.3nheboeeasdppIdodpgfosorrsevoaoepepdvrsrsiiooalaiuttitnndeeedg,ihslwvuuethtthhiaeie1cddc1t.,lteete,.hsudetsuitnmhEI1gagf1tteehta&rrheiie1laaiillgqbBuuuuitll1ddkk1,, SpdaanidennmniSisaneniatriitohssyrsettdoeetlrroia,iedddteiSLttaasemswrUaimalHilnblleoiidCqqbyeueutiihdddIde..tigisdccAohhsTILaaennrrdaggSivteeavovddiiliedudunmiauaeni]l.tJouodsdtooAaIssfeeabbssetesfhakwewokeiirerllermllatstaenebnbrdesdeitabblausseeidds smuaSLapnntioiieenmertausil1taes3htlewweie aalTdnrlmiimhnahd ailsasv'vatseeiraabfTtt tooosidontodygrna,wwitieitlaaohgnnhdhe:ettlaaadtdamTthiffeehoonnrripsrtj11ed7ue7psratettrodoebd2b2e0yftohegrhsaeoFtovuauartrgseassesf.tsbbteetufforoTerehreese wASidti1feitl1tssel1tecrraBmbreeaaSdtdeeemnsSrTiitoinaorairtelsesdtdt"rraaaadSttttmiiioonornnioo,,sontmraaantnttyyeeimmorpprneeee.rrmmaaasttiiuunTnrrihieeneggnpunerttteeitps]latresmaddidntxmiattinruenirsiesetstsstrrmaawwittiixi1litol1ounnr:.ebbsee (93) ISr nC t intsEete discarded. Reason for Rout~ of Administration rote of corer Tor Soninistiring Historically, the for administering known snout oral route has a known amount of Rest Evteriel been the route of of test material. choice . C. obssraoftkniimoalns Observation of Animals (1) QASS~utTldiiaSntanoinptctEpoasrrl)toEroxaOibatbmstisaeoeetrnrelvlayayattniid11oo,n2dnsa2ssl.l5.,y aatnnhddere4afhhtooeuurrrssfoaarfftteearLr tlteeosswttsmmaa1tteerraiiaasll BmTTafoohdoorrremtirancSclilaltiisitntlyynir.caiaatcliiroGOenhbsscisiitggeeaennrrnsrsvidaattdaaiinanoddoinnlssytbwusimtcacaheyeyerdebbdeaeaaifllteeyyexxrttee((nnafadd.ommeer,.ddawtwawhhndedelnneppao.dsdsmiti..rr))ee1cc4ttffeedooddrarysbbyy the study director. (goBBBRdeoErfdsSoyerdemWaeetieeseqxirhpsitetasraliimmeeanndttmaail)nsiiinnriiatttiiiaaottnii,oonn,,4ndaattat77 adanendadth]144(ddsahuyessn aasffuttreveirrval riven 3 oan test material exceeds day} administration, and at death (when survival 0 1 FWAPtIaItHhteoErloRmSqiynRauotiihnoannisooeffd,tthheeATeaTxxpseesrpriitmnaeernlatsta,altsopgehhaLashsee,,r 6ssuu1rrvvgiivvGiiunnrgglsanoimmtaahtless ASIwnsieettlccuuelrdrdyioyppbsseooeyyrraeeseeusuruxttithayhmhaman.aiininnniziiazeztthdeeiie.ddoo,,nnawwAna1iilninlllddnllataaalsbnbTleiewmiasassTlobuuhsvnbb,oojjbrreeeemcwcaatthtleeediiddthtthsiiectteaoroassrdudawwennyidiilnasllg4binbbbddbrr~eueernvvoiiirrnaaeegttcLceeoiddrostdhsreegugddrer.oosssss eed, After necropsy, the animals will be discarded and no tissues will be saved. 33O0 11446699..00003300 33MM_MMNN0011668838880099 cmon CI-I'W61001760 ofenyTP2069 Ptge 7 E. OStthateirsttlhcaanl LDAsnoalmyaslecsullaatitonlsons ((wwhheen appplliiccaabbllee)) nnoo ststaattiissttiiccaall aan ieFeghre: analyses are required. pSEmED eon cht hee i std ee 1 bi sent, A final report including those ite~ listed below will be submitted. gir ft tt rt Oescrlptlon of the test material paOescriptlon of the test system HEE pt t> n tn Procedures Dates of experimental Inlt(atlon and termination Hni A anL Tabulation of mortality data by sex and dose level Description of any toxic effects EE SH oe oe Tabulation of mean body weights by sex and dose level GGe E LD calculations for sex Er(~hen applicable) each with g5% confidence intervals Gross pathology findings/gross pathology report (when applicable) in Sr ht CAA Location of Raw Data, R@(Or~s. and Final Re~ort i ne She Original data, or copies thereof, will be available at h~(l to facilitate auditing the study during its progress and before LE i i acceptance of the final report. Nhen the final report is completed, natal fn TE all original paper data, including those |te~s listed below will be Rr a Fan SE retained in the archives of HWI according to iIWI SOP. Ie nt pa cs Protocol and protocol amendments ErmOose preparation records In-life records pEtir, Body weights Sa Dose administration A rt recor Observations fe en Anatomical pathology records Study correspondence FR TER ts con Final report (original signed copy) J The following supporting records will be retained at HWI but will Drnot be archived with the study data. ints scatters Animal receipt/acclimation records Water analysis records FETC A Animal room temperature and humidity records Refrigerator and freezer temperature records HR RE, Instrument calibration and maintenance records 31 11446699..00003311 sw mranio 3M MN01688810 : cw s1001760 CI-'IW 61001760 akess orca row PROTOCOL APPROVAL SFt SEp)poonnssoorr'ss RRperpl ersee;estnatatti|vvee a -- SoNmeee Mage Steven H. Glaza Study D|rector Reet orice Acute Tox]colo9! HiElewan visconti, oc. Haz]eton i/]sconstn, Inc. affels-re-- Datk i we dy Date RepresenLat|ve SATE Aeturnce unit He ~ual~t~ Assurance Untt Radlett Wisconsin, Tne. Hazleton ~isconstn, Inc. (2069.30) (TPZ0~9.3H) Date 32 11446699..00003322 3M. MNotess81 3M MN01688811 . --oom cCwI-IW6110000117~6600 on te. _cresizes PROTOCOL AMENDMENTCSHW No. PROTOCOL AMENDMENTS Jeena Ho. _L_ 1] Amendment No. ~ Effective _ cross 9./99 { Effective ert ion of protocat sto Hot iad; eat icale secant of the rosa Portion of Protocol Being Modified: Aoolicable sections of the nrotocol. ssnattormToeteacicatiSone: aTloysHenRate the EacStTiEwhe tVheestoat w11becontre | Reason for Modification: To identify the location where the study will be conducted and to reflect a company name change from Hazleton Wisconsin, Inc. (HWI) to ,Corninq Haileton Inc. (CHWI~ replace wherever apQli~ble the fo]lowinq chanqes | mericacsn: ma"ene ga Modification: Corninq Ha(leton Inc. (HWj 3301 Kinsman Boulevard. . Madison~ WI 53704 I I @ro (G21/Ol-O7-gl) ---- Study Director Approval: 3R WEW C Y 353 11446699..00003333 33M_MNMONT061868S8881122 : cCoI-{wW s6i1000011776600 [ON PPRROOTTOOCCOOLL AAMEENNDDNHEENNTTSS -- Sotninet No. _2 1 effective _ Omanr,o A~endment No. Q | Effective EA er Te | portion of rotocon tng sified: pac perosata) Deion:A oimls| |wsowsre Portion of Protocol Being Hodified: , P~qe 4. 6. Exoerimental Desian: A. | Animals essen((} Reason for edification: Strain/Source for Hodification: _TToo ccoorrrreeccttllyysitdeennttifys)hhee cnoommeesncll,aattuurreewuisedd ffoorr aanniinBaallss | rectreenCiharvleseRivder Laboratories loc. | hceirteicceaitvieodn:from CShaaarllees Rtihviesr sLeacbtoiroantwoirtiehst.heIncf.olloving canes: | Modification: Replace thi~ section,with the followinq chanqe: (~) . Strain/.Source r~ CHsrdl::SCoDra(qSuD.)eBRp/aCwhlaeryleSsDR/iHvaerlranLaSbporraatqoureiepsa,wleIyn,c. Inc. | oon (6ZI/01-07-91) stag rectorsgprovnt:___I8menXd Woe Study Director Approval: aw 3544 11446699..00003344 33MM_MMNNo01166888881133 i tv _-- owe CHW 61001760 CoHnWtNoo.. PPRROOTTOOCCOOLL AAMMEENNDDMMEENNTTSS sian J Aeendment No. 3 retive __octoer 3.1m Effective October 9, 1996 rion of protect eteWot: pi 5 6, spripatal peste: Portion of Protocol Being Modified: Paae 5. 6. Exoerimental Oesian: fn fr estcsn: etecom a et ot me | | 8B.-DoDosseeAAdmdimniinsitsrtraattiioonn::((Dl)oDsosee lLeevveell.. | Reason for Modification: The Soonsor reauested that a l~vel 9f so0 mq/kq be treated initially. Modification: Replace 5.000 mq/kq with 500 mqfkq wherever listed in this section. are G21/01-07-91) Study Director Approval: ~ ~ ~ ,~-~-~i 33s5 11446699..00003355 aW_MD1sBs81S 3M MN01688814