Document bag55q85BqGje8V64dRM0wayZ

FFIINNAALL RREEPPOORRTT PROTOCOL 418.011 PROTOCOL 418-011 ORAL ORAL (GAVAGE) (GAVAGE) DDEEVVEELLOOPPMMEEINNNTTRAAALLTTTSOOXXIICCIITTYY STUDY STUDY OOFF NN--EEtIFFOOSSEE IN RATS \ SSPPOONNSSOORR''SS SSTTUUDDYY NNUUMMBBEERR:: TT--66331166..77 FINAL REPORT DATE: 17 DECEMBER 1998 FINAL REPORT DATE: 17 DECEMBER 1998 22778888..00000011 1100117711118811 Exhibit 2788 rostivrtieiorl RN 3MA10083119 PPRROOTTOOCCOOLL 441188--001111 prot OORRAALL ((GGAAVVAAGGEE)) DDEEVVEELLOOPPMMEENNTTAALL TTOOXXIICCIITTYY SSTTUUDDYY OOFF NN--EEttFFOOSSEE IN RATS `SSPPOONNSSOORR''SS SSTTUUDDYY NNUUMMBBEERR:: TT--66331166..77 T TABLA EOOFB F CCOONL NTTEENE NTTS SSUUBBJJEECCTT | SUMMARY AND CONCLUSION I. SUMMARY AND CONCLUSION A Moods A. Methods c Concusen B. Results C. Conclusion A conductSusy In1. DDEESSCCRRIIPPTTIIOONN OOFF TTEESSTT PPRROOCCEEDDUURREESS A. Conduct of Study Az. Tosing Fait AAl.1.. SSppoonnssoorr A.2. Testing Facility A.3. Study Number AA4.4.. SSppoonnssoorr''ss SSttuuddyy NNuummbbeerr AAS.5.. PPuurrppoosseeooff tthhee SSttuuddyy . AAB.6.. SSttuuddyy DDeessiiggnn PAGE I-1 4I-1 I-2 I-4 w1I1--11 I1-1 1 I1-1 I1-1 I1-1 I11--11 I11--11 I11-11 1100117711118822 22778888..00000022 3MA10083120 SSUUBBJJEECCTT A7. Regulatory Compliance. A.7. Regulatory Compliance AAB.8.. OOwwnneerrsshhiipp ooff tthhee SSttuuddyy AAS.9.. SSttuuddyy MMoonnititoorr A10. A.10. AAlltteerrnnaattee SSttuuddyy MMoonnititoorr A11. A.11. SSttuuddyy DDiirreeccttoorr AA1.122.. TTeecchhnniiccaall PPeerrffoorrmmaannccee AA1.133.. RReeppoorrtt PPrreeppaarraattiioonn AA1.144.. RReeppoorrtt RReevviieeww AA1.155.. DDaattee PPrroottooccooll SSiiggnneedd AA..1166.. DDaatteess ooff TTeecchhnniiccaall PPeerrffoorrmmaannccee AAA.177.. RReeccoorrddss MMaaiinnttaaiinneedd BB.. TTeesstt AAtrttiiccllee IInnffoorrmmaattiioonn BB.1..I. DDeesscrcirippttiioonn BB8.22.. LLoout/BBaattcchh NNuummbbeerr BBA.3.. DDaattee RReecceeiivveedd aanndd SSttoorraaggee CCoonnddititiioonnss BB..44.. SSppeecciiaall HHaannddlliinngg IInnssttrruuccttiioonnss BB5.5.. AAnnaallyyssiissooff AAccttiivviittyy CC.. VVeenhiicclee IInnffoorrmmaattiioonn CCa..1. DDeessccririppttiioonn CC2.2.. LLoott NNuummbbeerr CC3.3.. DDaattee RReecceeiivveedd aanndd SSttoorraaggee CCoonnddititiioonnss CCa.4.. SSppeecciiaall HHaannddilinngg IInnssttrruuccttiioonnss. " 2277888..00000033 PPAAGGEE II1-1 211-2 211-2 111--22 211-2 211-2 211-2 211-2 211-2 "113-3 311-3 311-3 "113-3 "113-3 311-3 311-3 411-4 411-4 [113-4 411-4 411-4 411-4 1100117711118833 33MMAA1100008833112211 SSUUBBJJEECCTT C5. AAnnaallyyssiiss of of Purity Purity 0,5. D. Test Article Preparation D. Test Article Preparation DD1..I. SSaammppllee IInnffoorrmmaattiioonn E TestSystem E. Test System EE1..I. SSppeecciieess 2. E.2. SSwtraaiinn 3. E.3. SSuupppplilieerr (Source) (Source) 4. Sex E.4. Sex 5. E.5. RRaattiioonnaallee ffoorr Test Test System System EE6.6.. TTeesstt SSyysstteemm DDaattaa E7.7.. BBrreeeeddeerr MMaallee RRaatt DDaattaa EES.8.. Method of Randomization Method of Randomization E9.9.. SSyysstteemm ooff IIddeennttiiffiiccaattiioonn F. F. Husbandry Husbandry FF.1..I. RReesseeaarrcchh FFaacciiilittyy Registration Registration F2. F.2. Study Room Study Room 3. F.3. HHoouussiinngg Fa. Lighting F.4. Lighting FF5.5.. Sanitization Sanitization F6. FFeeeedd F7. F.7. FFeeeedd AAnnaallyyssiiss FB. F.8. Water Water iiii 278.0004 278810004 PPAAGGEE 411-4 I11-4 Is11-5 ws11-5 Is11-5 Is11-5 ws11-5 ws11-5 Is11-6 611-6 Ie11-6 Ie11-6 ie11-6 wr11-7 wr11-7 wr11-7 =e11-7 1I1x-]7 Is11-7 Ww11-7 Ww11-7 811-8 1100117711118844 mAtoc83122 3MA10083122 SSUUBBJJEECCTT FO.Fog. WWaatteerr AAnnaallyyssiiss GG.. MMeetthhooddss GG1..I. DDoossaaggee AAddmminiinsisttrraattiioonn GG2.2.. RRaattiioonnaallee ffoorr DDoossaaggee SSeelleeccttiioonn GG3.3.. RRoouuttee ooff AAddmmininisisttrraattiioonn GGao.4. RRaattiioonnaallee ffoorr RRoouutteeooff AAddmminiinsisttrraattiioonn G5. G.5. FFrreeqquueennccyyooff AAddmminiinsisttrraattiioonn GG6.6.. LLeennggtthh ooff SSttuuddyy GG77.. MMeetthhoodd ooff SSttuuddyy PPeerrffoorrmmaannccee GG8.8.. GGrroossss NNeeccrrooppssyy GG.o9 SSttaattiissttiiccaall AAnnaallyysseess III. RREESSUULLTTSS AA. MMorotratlailtityy,, CClliinniiccaall aanndd NNeeccrrooppssyy OObbsseerrvvaattiioonnss AAl..1. MMorotratalilittyy AA2.2.. CClliinniiccaall OObbsseerrvvaattiioonnss AA3.3.. NNeeccrrooppssyy OObbsseerrvvaattiioonnss BB.. MMaatteermnaall BBooddyy W Weeiigghhttss aanndd BBooddyy WWeeiigghhtt CChhaannggeess GC. C. FMMaeateteedrrnnCaoalnl sAAbubsmsopoltluuittoeen((Vgga//ddlaauyye))saanndd RReellaattiivvee ((ggl/kkgg//ddaayy)) Feed Consumption Values D. CCaaeessaarreeaann--SSeeccttiioonniinngg aanndd LLiitttteerr OObbsseerrvvaattiioonnss EE. FFeettaall AAtlteerraattiioonnss E1..1. SSuummmmaarryy ooff FFeettaall AAlltteerraattiioonnss E2. Fetal Gross External Alterations. E.2. Fetal Gross External Alterations 1100117711118855 PPAAGGEE 811-8 811-8 811-8 I11s-9 I11e-9 I11e-9 I11e-9 I11g-9 I11g-9 111-010 111-212 nII1t-1 "II11-1 nII1e-1 nII1e-t1 1II1-1 nII1e-t1 2111-2 2111-2 3111-3 011-1-33 wa111-4 22778888..00000055 I3MMAAt100008833112233 SSUUBBJJEECCTT E3.3.. FFeettaall SSoofftt TTiissssuuee AAlltteerraattiioonnss EEd.4.. FFeettaall SSkkeelleettaall AAlltteerraattiioonnss RREEFFEERREENNCCEESS AAPPPPEENNDDIIXX AA -- RREEPPOORRTT FFIIGGUURREE FFiigguurree 11. . MMaatteerrnnaall BBooddyy W Weeiigghhttss AAPPPPEENNDDIIXX BB -- RREEPPOORRTT TTAABBLLEESS TTaabbllee 11.. CClliinniiccaall OObbsseerrvvaattiioonnss --- SSuummmmaarryy TTaabbllee 22.. NNeeccrrooppssyy OObbsseerrvvaattiioonnss -~ SSuum mmmaarryy TTaabbllee 33.. MMaatteerrnnaall BBooddyy WWeeiigghhttss --- SSuummmmaarryy TTaabbllee 44.. TTaabbllee 55.. MMaatteerrnnaall BBooddyy W Weeiigghhtt CChhaannggeess ~ - Summary Summary MMaatteerrnnaall AAbbssoolluuttee FFeeeedd Consumption Consumption Values Values (g/day) (g/day) -- - SSuummmmaarryy TTaabbllee 66.. MMSauatmteemrmanaralyl RReellaattiivvee FFeeeedd CCoonnssuummppttiioonn Values Values (g/kg/day) (g/kg/day) ~ - Summary Table 7. CCaaeessaarreeaann--SSeectcitioonniinngg OObbsseerrvvaattiioonnss ~ - Summary Summary Table 7. TTaabbllee 88.. SLLiiuttttmeemrr aOOrbbysseerrvvaattiioonnss (Caesarean-Delivered (Caesarean-Delivered Fetuses) Fetuses) - Summary TTaabbllee 99.. FFeettaall AAlltteerraatitoinosn~-s SSuum mmmaarryy TTaabbllee 1100.. FFeettaall GGrroossss EExxtteerrnnaall AAlltteerraattiioonnss -- - Summary Summary TTaabbllee 1111.. FFeettaall SSoofftt TTiissssuuee Alterations Alterations ~ - Summary Summary TTaabbllee 1122.. FFeettoall SSkkeelleettaall AAlltteerraattiioonnss -- - Summary Summary TTaabbllee 1133.. FFFeeetttaaullsOeOssssis(fiDfiiaccyaatt2iio0onnoSSfiiGtteeessst--atCCiaaoeens)saa--rreeSaaunnm--DDmeaeilrivvyeerreedd Live Live Fetuses (Day 20 of Gestation) - Summary TTaabbllee 1144.. CClliinniiccaall OObbsseerrvvaattiioonnss - - Individual Individual Data Data PPAAGGEE 4111-4 ns111-5 nr111-7 AA-t1 8B-11 B8-22 BB8-33 BB-s5 )B-6 87 88 8B-99 B8--1100 BB-1111 BB-1122 BB-1133 8B1-166 8B-1177 1100 117711118866 22778888..00000066 M3MATA010008833112244 SSUUBBJJEECCTT PPAAGGEE TTaabbllee 1155.. NNeeccrrooppssyy OObbsseerrvvaattiioonnss -- IInnddiivviidduuaall DDaattaa BB2-233 TTaabbllee 1166.. MMaatteerrnnaall BBooddyy WWeeiigghhttss -- IInnddiivviidduuaall DDaattaa BB-2299 TTaabbllee 1177.. MMaatteerrnnaall FFeeeedd CCoonnssuummppttiioonn VVaalluueess -- IInnddiivviidduuaall DDaattaa BB4-444 TTaabbllee 1188.. CCaaeessaarreeaann--SSeeccttiioonniinngg OObbsseerrvvaattioinosn-s- IInnddiivviidduuaall DDaattaa BB--5500 TTaabbllee 1199.. LLIinittdttieevrriOOdubbassleerDrvavatatatiioonnss ((CCaaeessaarreeaann--DDeelliivveerreedd FFeettuusseess)) - B56 Individual Data B-56 TTaabbllee 2200.. FFeettaall SSeexx,, VViittaall SSttaattuuss aanndd BBooddyy WWeeiigghhtt -- IInnddiivviidduuaall DDaattaa BB--6622 TTaabbllee 2211.. FFeettaall AAlltteerraattiioonnss -- IInnddiivviidduuaall DDaattaa BB7-744 AAPPPPEENNDDIIXX CC -- PPRROOTTOOCCOOLL AANNDD AAMMEENNDDMMEENNTTSS CC--11tto0CC--3333 AAPPPPEENNDDIIXXDD -- DSDETEVAVINIAADTTAIIORONDNSSOFFPREROROAMMTTTIHHNEEG PPPRRROOOTTCOOECCDOOULLREAASNNDDOFTTHHTEEHE TTSEETSSATTNIIDNNAGGRD OPERATING PROCEDURES OF THE DD--11 AAPPPPEENNDDIIXXE-E- RTTEEEPMMOPPREETRRAATTUURREE AANNDD RREELLAATTIIVVEE HHUUMMIIDDIITTYY E1 REPORT E-1 AAPPPPEENNDDIIXX FF -- PPIILLOOTT RREEPPOORRTT FF-111t0o FF--8877 AAPPPPEENNDDIIXX GG -- HHIISSTTOORRIICCAALL CCOONNTTRROOLL DDAATTAA GG1-11t0oGG--1166 AAPPPPEENNDDIIXXHH -- SSTTAATTEEMMEENNTT OOFF TTHHEE SSTTUUDDYY DDIIRREECCTTOORR HH-T1 AAPPPPEENNDDIIXX I|-- QQUUAALLIITTYY AASSSSUURRAANNCCEE UUNNIITT FFIINNAALL RREEPPOORRTT SSTTAATTEEMMEENNTT I-lttool-s5 22778888..00000077 10 171187 33MMAA1100008833112255 441188--001111::PPAAGGEE II--11 TITLE: TITLE: OORRAALL ((GGAAVVAAGGEE)) DDEEVVEELLOOPPMMEENNTTAALL TTOOXXIICCIITTYY SSTTUUDDYY OOFF NN--EEtfFFOOSSEE IINN RRAATTSS AARRGGUUSS RREESSEEAARRCCHH LLAABBOORRAATTOORRIIEESS,, IINNCC.. PPRROOTTOOCCOOLL NNUUMMBBEERR:: 441188--001111 SSPPOONNSSOORR''SS SSTTUUDDYY NNUUMMBBEERR:: TT--66331166..77 II.. SSUUMMMMAARRYY AANNDD CCOONNCCLLUUSSIIOONN AA.. MMeetthhooddss'a Twenty-five Cr:CDBR VAF/Plus (Sprague-Dawley) presumed pregnant fTewmeanltey-rfaivtes wCerrI:eCDassBigRneVdAtFoIPealucshof(Sfpivreagduoes-aDgaewgleroyu) ppsre(sGurmouepds|prtehgrnoaunght V). ftNNehiimenneeasttaleeteeeelrnnlaittaasedddwsditeittuiiroedonnyaaa(lsltshffeiregemmnea,aeldlfeeivterro,aattetssahrwwceeheer,roeeftaahfissrvseseeiiggdannoneesdddagfttioeoveoognnrroaeetusoopfafssffii(svGvieegroddnuooedpssasatggoIeetGhggrrrroooouuuugppphsss|Vffo)o.rr tttihhnherrRooeusuvaggethherlVVsl.i,te,errOeesssstpumpedoecystciit(visvtehelryMley)ee.).m, bfTTirvhheaee,nttteheerssPettreaao,rrctttieihccsrlleese,,eedNNa--nDEEdettiFfFoiOvOneiSSzEErea,,dtsooWrraavvsteesehhiirgcicnl(leeRe,.d,O.22to%%DGeTTirwowouneepieezsnneId 8800 WW i1na7atReoteerfr)vp),e,rrwwesaseaussOmaaesdddmmmiogniesnisiissstttaM eetrrieeeomddn bv(vriiDaaaGnggseaa6vvPaartgoghceereooosunnsgcecheed17ddD)aa.eliliyyoDnttooiozseffaedegmmeW aasllaeeotferrara0tt(ss(RVoo.eOhnni.cddlDaaey)ey,ssio6n61,iztth5eh,rdroo1uu0gghh a1n7do2f 0prmegs/ukmge/ddagyewsetarteionad(mDinGisst6ertherdouatgha d1o7s).agDeovsoalguemseooff05(VmeLhkigcl,e)a, d1j,us5t, e1d0 daanidly2o0nmthgelkbga/dsiasyowfeirnediaviddmuailnisbtoedryedweaitghatsd.osage volume of 5 mL/kg, adjusted daily on the basis of individual body weights. TThhee ffeemmaallee rraattss wweerree oobbsseerrvveedd ffoorr vviiaabbililiittyy aatt lleeaasstt ttwwiiccee eeaacchh ddaayy ooff tthhee ssttuuddyy. TTabhhoeertrriaaottnsss,wweeprrreeemaaalltssouoreeexxdaaemmliiinnveeerddieffsoorranccldliinndiicceaaalltoohbbsssbeeerrfvvoaartteiiooannnssdoofaf peepffffreeoccxttissmaooftfetthlhyee ottenessett haarorttuiicrcllee,, aaaffbtteoerrrtiddooonsssaa, ggpeere((mDDGaGtssur66e ttdhherroloiuvugeghrhie11s77)a.),naadnndddeooannthccsee bddaeaifilolyyredduuarrniindnggattphhpeeroppxooissmttdadotoesslayaggoeeneppeerhriiooodud.r. a.ao DpDeretotavaiiilldeeeddd ddienesstcchrreiippattpiioponrnosspoorfifaaaltllel ppsrreoocccteeioddnuusrreeossf utuhssieesddreiinpnottrhhteeaccnoodnndidnuucActPt oPoffEttNhhiDissIssXttuuCddyy aarree p(rPoRviOdTedOCinOtLheANapDprAoMpEriNatDeMsEeNcTti)o.ns of this report and in APPENDIX C (PROTOCOL AND AMENDMENT). 10 171188 2277888..00000088 33MMAA1100008833112266 441188--001111::PPAAGGEE 1I-22 BBpooosddtyydwwoeseiaiggghhettsspewwrieeorrdees.rreeccFooerredddeeddcooonnnsuDDmGGpstsi00onaannvddal44ueaasnnwddeddraaeiillyyreddcuuorrriidnneggdtthoheen ddDooGssaagg0ee, 4aa,nn6dd, 8, p10o,st1d2o.s1a4g. e1p6.er1io8das.ndF2e0e. d consumption values were recorded on DGs 0, 4, 6, 8, 10, 12, 14, 16, 18 and 20. AADllGl rra2att0ss aiinnndtthhaee gmmraaoisinns ssntteuucddryyowwpeseryreeofssaatchcreriifftiichcoeerddacbbiyyc,ccaaabrrbdbooomnniddniiaoolxxiidadneedaaspsepplhhvyyixcxiiavatitisioconenrooannwas DppUteeGerrrffo2uors0rmmoaeefndded..aacTThhghreeroastnnsuuwm manbsebeceerrroxoopaffsmCcyioonorrepfpdotohrrfeaaortllhupuottreereaaagcniiianncn,eecaaay.cbchhdnoooumvvmaainbrraeyylrwwaaaannssddrrpeedeciclsoovtrrirdcdieebvdud.ist.icoeTTnrhhaoeefwas wiuimmateppsrlluaaisnndtetoaantfttiiieofoainnecs,dh,, lfwriivaeveteiwgaahnnaeddsdeddaxeeanaadmdd ieffnexeettaudumssifeeonssrepaadnnrefddogreneasaarenrllxcyyyaaa,nnnndddugmllarattboeesesrrreeaessxnootrdrepprtdtiniiooasnlntsrsi.ab.lutetEEiroaaantccihhoonffsfe.ettuuss AawAlppatppserrroaoidxtxeiiiom mnnatsiatfiteaeelndlyy,dowotnnheeeei-g-hrhhaeealmdlffaiooanffnittdnhhgeeexfffeaeetttmuuusissneeeesssdiiinnnfoeeeraaascccehhhxlllaiiittnttteeedrrr wgwwereeorrrseeeseeeexxxxaaatmem miriinnnnaeeeldddafffltoooerrrrsasskotoeifoflttnetttsiias.slssuuee alterations. alterations and alterations. the remaining fetuses in each litter were examined for skeletal cRRoaalttlsseciitnnettdhheaenssdaattceeellnilitttreeifssuttguuedddyy. wweTerhreee sslaaicvcerrriiffwiicaceesdd eooxnnciDDseGGd,118w8.e. iBBglhlooeooddd assnaadmmpsplelceetssiowwneeerdr.ee caFFoseeslttlueiugscsneteeessddwwateeonrrdteehceeeexxmnaaatmmriiifniunngeestedduddgg.yrr.ooTsshsFsleelyytliuttvooseetrtshhweeaaneesxdxteteepxnnlctatiscppeeoodnsst,ssaiwiebbellweeigeaharsseedddpeeaossonccldrreiibdsbeeepcddetirffooonlrrietrredara..ttss After wacceoosmrsmpiegplnelseethtidiioopntnpoeoodtfhf esstoaammmthpapelinleeSspcctoooulnldllseeycoc.trtiiooFfnneo,,rtussaseenerarsuulmymas,,insdliivvpeelrracsseeecnctttiiaooenn,,wffeeetrtaaell paaonnoddleppdllaapcceeenrnttlaiatltlessr.aam mAppfltleeerss were shipped to the Sponsor for analysis. BB.. RReessuultl~s sNNuoorvddieevaaetdthhssu,n,tiaalbbosorcrtthiioeodnnusslooerrd ppsrraeecmrmiaaftitucuerreeonddeeglleiivsveterariiteeissonooccdccauuyrrrr2ee0dd during the (dOuGrin2g0).the study. study. All rats All rats survived until scheduled sacrifice on gestation day 20 (DG 20). AAllll cclliinniiccaall aanndd nneeccrrooppssyy oobbsseerrvvaattiioonnss were were considered considered unrelated unrelated to to the the test test aar~tiiccllee.. M5Mamatgteeirrknngaa/lldbbaooyddayynwwdeeihiggihghthteggraaidinnosssawwgeeerrseeossfiiggtnnhieiffiictcaeasnntttllayyrtrrieecdldeuu.cceeTddheiinneggffrroeocuutppwssaaasddmmmiininniiissmttaeelrreeaddnd tt51rr0am annmgssgii/e/kenkngtgt/dliiandnyatthyhaeedndo5smmhagiggg/eh/kkegggr/r/dodduaaopyys.addgsooiessgsanaiggofeefictgahgnrretoouutreppes,,dtuooaccctrcctiuiucorlrntersii.nniggTn hmoonaenltlyeyefroofnennacltDDwbGGoassdsy88mwttoioenii11mg00.ha.tl Ianntdhe Ignaithnes occurred on DGs 6 to 10 mgtkg/day dosage occurred on DGs 6 to gain on DGs 14 to 16. 88gTraaohnnueddp2,110s00imgttgono/if11kic22g,a,/nfdfotoallryloelwoddwoueescddtaiobbgynyesaagirnssoiiggumnnpiaiffthiiecacradannnatstliiigbnnnocicrdfreiyecaaawssneeteiwiignnehiwwtgeeghiiatggihnhtst gloasins foonllDowGesd 1b4y tsoig1n6if.icTahnter2e0dumctgilokngsldianymadtoesrangael gbrooduypwheaigdhstiggnaiifnicaonntDwGeig8htto l1o4ssanfodllo1w6 etdo 1b8y. sTighneifsiceaenftfreectdsucoftiotnhes tinestmaartteircnlealrbesoudiytewd eiingahttgeanidnenocnyDfGors 8 to rrr1eee4ddduauucncctedeiddo1nww6seetiioingghh1tth8t e.ggaa2Ti0inhn emiinsgne/tthkhegeef/fe11d0c0atysmmgdog/of/ksktghgaie/gddetaaeyygsrtddoaoourssptaaicfggloeeer rgersouultpedanidn asigteninfdiecanncty for tghreouepntiarnedtsriegantimfiecnatnpt eriod (tr(DehDedGGuesscntt66iiorttnoeosg11ei0n0s))t,,tahtttehhieeo2n0eennpmtetiirrgriee/okidignn/tt(deeDarrvvGyaasldl o0aafsftttaeeogrr2e0iin)n.giittriiaoaMtutiaoipotnneforoonrffattthlrreeebaaoettmdnmyteeirnnwettetir((geDDhaGtGtsmsswe66entrttooep22e00r)i)odaanndd the entire gestation period (DGs 0 to 20). Maternal body weights were 1100117711118899 22778888..00000099 I3MMAAt1o000s833112277 441188--001111:PPAAGGEE 1I--33 ssiiggnniiffiiccaannttllyy rreedduucceedd iinn tthhee 1100 aanndd 2200 mmggi/kkgg//ddaayy ddoossaaggee ggrroouuppss on on DGs DGs 11 11 tthhrroouugghh 1133 aanndd 88 tthhrroouugghh 2200,, rreessppeectcitviveelyly.. dBBooosddayygwweeeioifgghhtthtsse aatnnesddt bbarootiddcyyle.wweeiigghhtt ggaaiinnss wweerree unaffected unaffected by by the the 1 1 mg/kg/day mg/kg/day dosage of the test article. The absolute feed consumption value was significantly reduced in the Tc11oh00nemmsgaugmkb/pksggtoiitldudoataneyyvfddeaooleussdeaacsggoeewneggsrrureoomuuspppitgioonoinnnfiDDvcaGaGnlsutsley66wrttoeoads88uscaaienngdddniifaanicbbtasshonoeltlluuy2tt0eeremaadgnnu/ddckegrrdee/lldaainattiiyvtvheedeoffeseeeaddge gcgarborosonuouslppuumtffooeprrtftitoehheneedveecnantoltiunirreseeusddmwoopetssiaraeoggneesivgppaenelrirfiuiiooceddacnaoatnnnlytddirnaaetutdeauadllcl etiinodnttbeienerrvvtsaahillegssni2wwfi0iittchhmaiinnngt/lttkhyhgiirss/deppdaeeuyrriciodoedodd.s. aanTTgdhheeethe darreeobllssaaotatiilvguveeeteffgeerfeeeodedudpccoocdnnoussrnuiusnmmugpmptttpihiotoeinonpnovvasavltlauudleueoestteaecngnodedneetiiddnntuettoreovdabblee.torreTbedhedueusccsieegeddneiffiininfceattchhnteetsly22o00fretmmdhgueg/c/k2keg0gd//mddagaan/yydkgth/eday fdddeoooesssdaaagggceeeongoosfrfuottmhuhpepetittdeeoussnrttinvaagarriltitcuchleleeesprroeeonsssuutDldlttGoeesdsda6iignne1ss0iiigng2nnt0eiiffraiivccnaaadlnn.ttDllTyyGhrrseeesdd0euutcceoeefdf2de0caatbbsssooolfluutthteee aa2nn0ddmrreegll/aakttgiiv/vedeay feed consumption values on DGs 6 to 20 and DGs 0 to 20. AAthbbessootleluusttteearaatinncddlerreaelslaatthiivivegehffeaeesedd5ccmoognn/sskuugm/mpdpatytii.oonn vvaalluueess wweerree unaffected unaffected by by dosages dosages of of the test article as high as 5 mg/kg/day. F1Fe0ettaaalnl dbboo2dd0yy mwwgee/iikggghh/tssda((yttootdtaaoll,s, ammgaaelleegraaonnuddp/s/oo,rr affesemmcaaollmee)p)awwreeerrdee tssoiiggtnnhiieffiicccaoannntttlrlyyolrregedrduoucucepeddvaiinlnuttehshe.e CDD1a0ooessasaaanggrdeeea2ssn0oo-fmfseNNgc--/tkEEigttoF/FdnOiOaSnySgEEdooaarsssalihhgtiieeggrhhgpraaaorssuap22ms0e0,tmmeagrsg/s/k.ckgog/m T/ddhpaaeayyrleddiiditddertnonaoovtttheaaerffaffcegeoccenttstaarfonnolryygcooroottrhhupeeporrrvaalluuetesa., cCiimmoapnpelclasaenanptrttaeatutaiisonoenn-ssss,e,acnilitttditoeenrprienssrigiczzeeeonssr,t, limiltivtvaeeelreffpeefattuerutassuemesssee,,st,eeeraaasrrs.llywTerrhelelsesooarlrisppttttetiiorhonenassvn.,eupprmaeebgrreccereesnsntftoorrrfeecdssooaorrrmpbboseerddwaitluhteaan,y crareeonssndoocrrdeppiptdtiitouonnnsosstesosoirragwwnniidiftthihpcavevniirataclbbeyllneedtifffmeeetrtau.ulseseeNfsseotwwudeseraereems,sccaoohsmmapwdpaearllrialatbaeblrslesetwhiininettthnhhueaelmlffiicbvvoeeenrddscooeosspfaatdgguaseemeggssrroowuuiptphss any aarreepnsspdooerrdabbierdeded.nd,oanatonnsrddimgattnlhhi.efeicrreeaAlnwwlteleoyrfreedtihfnnfeeoosr.eddeevNaaaoddludffeeeasttmuuwssseeershseaoodwrilltliaathtttieeenrsrrteehwsseoiotrrhrppatatniilooglnnecsss.o.nocbAAesllleprpptulvlasaececdeesnnttaaee historically a the Testing Facilty appeared normal. All of these values historically at the Testing Facility. were within the ranges observed fRReetevavelerbrssoiidbblyleewddeeeilglaahyytsss iiinnn ffteehtteaall1oo0sssasiinffiidccaa2tt0iioonnmgaa/sskssgoo/ccdiiaaaytteedddowwsiaittghhetthhgeerossuiipggsnn,iiffiiwcceaarnntetllyyevrrieedddeuunccteeadds. sfs1eii0ggtannaliinffbiidcocaad2nny0tt wrmreeoeddikguugchctlttsiidooaninnyssthidinneottshh1aee0gellaiitnttgtederrro2aau0vvpeesmrraaagggn/keedgssa/dffoaosrirygoondssisofsiisiffcaiiaegenddteccigaanrucuodrduaeaplalss,vveeewriretnteetrebbhrreeaavefeeidtiianenlntththeeas incidence of wavy ios in the 20 mg/kgiday dosage group. 10 and 20 mg/kg/day dosage groups and a significant increase incidence of wavy ribs in the 20 mg/kg/day dosage group. in the fetal AAalnllldoottvhhaeerirraffteeittoaanlls)ggrrwooessrsseeexcxtoteenrrsnnaiald,le, rsseoodffttuttniisrssesluuaeeteaadnnddtosstkkheeelleettteaaslltaaallrttteeirrcaaiettiiobonencssa((ummsaeal:lffoorr1mm)aattthiioeonnss ariinnanccndiidgdveeeasnnrccioaeebtssisoewwnresevr)reeewdnnehooritesttddocooroissncaaasglgidleey-e-adrdeteedptpeheunenndTdreeeenslnatttt:i;endaagnntdFdoa//cootihrrlet22y).)tettshhteeaiirnnticcciildedeebnneccceeassuwwseeer:ree 1ww)iittthhhieinn ranges observed historically at the Testing Facility. 1100 117711119900 22778888..00001100 MA10083128 3MA10083128 441188--001111::PPAAGGEE |I-44 CC.. CCoonncclluussiioonn ONiONm-nn-pEEotttIrhFhtFeeOaOnbbSStaaEEssaiiniissssdoo5fsftmmttahghtg/eie/skssktgeeigc//addddlaaaaltytyyaa,s,((ittttghhhhneeeief11mim00caaatanatteennrmddrnaea22dllu00cnnmtmooi-g-goo/obnlkbkssggse/ireldndvravaabbyayolbdeddly-eooe-sswfeaaeffggfieegceecthsst-t-lcclegeaavvauueiesslnlees((ddNNoOrbbOiiEEwooLelLlooi))gggiohoiccftfaallllyy limospsoesrt,anatndantdhest2a0tismtgic/akllgy/dsaigyndifoicsaangtereadluscotipoenrssisintebnotldyyrweediugchetdgtahinesabosrowluetigehatnd losses, and the 20 mg/kg/day dosage also persistently reduced the absolute and weights and rreellaattiivvee ffeeeedd 55 mmggl/kkgg//ddaayy caused minimal, but statistically significant reversible delays in c(ctoohnnessuu1m0mpaptntiidoonn2v0vaalmluugee/ssk).)g./dTTahhyeedddoeesvvaeeglleoosppmmseiengnntitaaflilcNNanOOtlEEyLLreiissduaacllsseood fetal body (the 10 and 20 mg/kg/day dosages significantly reduced fetal body woIosnseecsiirgifiehiccataasstteiiadoonnntdhooecffattihuhneseceiccddaaeuunmdcdiaeanlliomfvveaewrlra,ttevebbbyurrtaarseeib;t;as,ttthihsaeetnic22aa00dlldymmiltsgiki/ogkgnngiai/lfddicaraaeyyvneddtroorsessivbaaelggereesdiaabellllsesaooydsseiiinlgganonyisisffsiiiccifnaainncttalltyyion `associated wih the reduced fetal body weights), increased the incidence of wavy ribs, an additional associated with the reduced fetal body weights). reversible delay in ossification MMExiielddcrrueetddivSSe.. DCCihhrreriicsstttoiiaranno,,fPPRhhe..sDD.e..a, rFFcelhloloww,, ATS ATS _ DDaattee Executive Director of Research / -- AADlilaraennctMMo..r HHofoobRbeeersrm meaaanrn,c, hPPhh.DD..,, DABT. DABT. Director of Research DV Date Date 2 17:9y AasnsdocSitauntddeyGDD.iirrYeeoccrttokor,roPfh,ResearcBhT DDaattee and Study Director 22778888..00001111 10 171191 MAT0083129 3MA10083129 441188--001111::PPAAGGEE II1I--11 nII. DDEESSCCRRIIPPTTIIOONN OOFF TTEESSTT PPRROOCCEEDDUURREESS AA. CCoonndduucctt ooff Study: Study: AAd.1.. sSppoonnssoorr:: 3M CorporateToxicology, 3M Center, Building 220-2-02, St. Paul, Minnesota 55144-1000 3M CorporateToxicology, Minnesota 55144-1000 3M Center, Building 220-2E-02, St. Paul, AA2.2.. TTeessttiinnag FFaaccililiittyy:: AArrgguuss RReesseeaarrcchh LLaabbooraratotoririeess,, IInncc..,, 980055 SShheeeehhyy Drive, Drive, Building Building A, A, Horsham, Horsham, PPeennnnssyyllvvaanniiaa 1199004444--11229977 AA3.3.. SSttuuddy.y_~N_uNummbbeerr:: 441188-001111 A4. Sponsor's StudyNumbor: A.4. Sponsor's Study Number: 6316.7 T-6316.7 AAS.5.. PPuruposreoopfftthoheeSSsttuudedyy:: TTChhreeiCppuuOrrBppBooRsseeVoAofFf ItthhPiisIs usssttuuddpyyrwweaasssumttoeodddeepttreeeccgttnaaadndvtveefrressmeeaelefefffeerccatttsss aoofnf dNN--dEEettvFFeOlOSoSpEEmeoonnnt of the eCCelmmroIb:bsCruryyrDooeoaaBfnnRtddhVeffeeAhttuFausr/sPdccluoopasnnlssaeetepqq.ruueeesTnnuhttmittsoeosdeetxxupppdrooeyssgeuunvrraaeenloutofafftetthemhdeeaIlddeCaaHrmmaHtsffarroraommnmodinimdmipesplvelaaednnltotTaaprttimiipooaennrntttitootoef the Gcluoisduereinoef sthteagheasrdC and D palate. ofThthise srteupdryodeuvcailuvaetepdrocICesHs.Harmonised Tripartite Guideline stages C and D of the reproductive process. AAs.6.. SSttuuddyDDeey_s_i~g.~nj~:: The requirements of the Intemational Conference on Harmonisation (ICH) THHaharermmroeonqniuissireeeddmTTerrniipptasarrtotiiftteethGGeuuiIidndeteelilnrienn~ae1t"i1onwwaeelrreeCouunssfeeeddreaansscetthheoenbbaaHssaiissrmoooff nssittsuuaddtyyionddeessiiggnn.. A7. Regulatory Compliance: A.7. Re,qulatory Compliance: TThhee ssttuuddyy wwaass ccoonndduucctteedd iinn ccoommpplliiaannccee wwiitthh GGoooodd LLaabboorraattoorryy Practice Practice (GLP) (GLP) rreegguullaattiioonnss ooff tthhee UU..SS.. FFoooodd aanndd DDrruugg AAddmmininisisttrraattiioonn ((FFDDAA)){2,~, the the Japanese Japanese Ministry of Health and Welfare (MHW) and the European Economic Community Ministry of Health and Welfare (MHVV) 31 and the European Economic Community (EEC). There were no significant deviations from the GLP regulations that (EEC){`~. There were no significant deviations from the GLP regulations that "ected the ually or integrity of the study. Quality Assurance Unit findings affected the quality or integrity of the study. Quality Assurance Unit findings Gerived from he inspections during the conduct of this study are documented derived from the inspections during the conduct of this study are documented 10 171192 22778888..00001122 MAI0083130 3MA10083130 441188-001111:PPAAGGEE 1112-2 aMannaddnahhgaaevvmeeenbbtee.eenn pprroovviiddeedd ttoo tthhee SSttuuddyy DDiirreeccttoorr aanndd tthhee TTeessttiinngg FFaacicliliittyy Management. AAS.8.. OOwwnenrsheiporoffstthheehSStituuddpyy:: The Sponsor owns the study. All raw data, analyses, reports and preserved TttiishssesuuSeesspoaanrreseotthrheeowpprnroosppetehrrettyystoouffdttyhh.ee Sponsor. All raw data, Sponsor. analyses, reports and preserved AAS.9.. SSttuuddyy MMoonnititoorr:: MarviTn. Case, D.VM., Ph.D. Marvin T. Case, D.V.M., Ph.D. A10. Alternate Study Monitor: A.10. Alternate Study Monitor: Andrew M. Seacat, Ph.D. Andrew M. Seacat, Ph.D. AA.111.. SStutuddyyDiDriereccttoorr:: RRaayymmoonndd GG. YYoorrkk,, PPhh.D.D.,., DDAABBTT ((AAssssoocciiaattee DDiirreeccttoorr ooff RReesseeaarrcchh)) AA1.122.. TTeecchhnnicicaall PPeerrffoorrmmaannccee:: JJKoroihhsnnteFFn.. lBBaaanrdrnnoeeltatt,,ShBB.e.SrS.e.r,((DDiBirr.eeSc.cttoo(rrRooefsf eLLaaarbbocorhraaAttsoosrroyyciOOappteeer/araFtetiitooannlss))Evaluation) Sharon Kristen Sharon Adamski (Laboratory Technician) landola Sherer, B.S. IResearch Associate/Fetal Adamski (Laboratory Technician) Evaluation) A13. Report Preparation: A.13. Report Preparation: JRRoaayAymmnnoonnFddraGGz.eeYY,oorrMkkS,,.PPhh.(.DSD.t.u,dDDyAACBBooTTrdinator) JSKSoauurssAeaannnnnGKK..F. rPaBBazrrreaakedde,ssrh,hMaaA.wwSA,,.. BB(S.(.SSAt.ud. dm((iyDDnaaiCtstoaatroMMartdaaiinnvnaeaatggAoesers)mmiesentnattntSS)ppeecicaialilisstt)) Karen (3. Parker, A.A. (Administrative Assistant) A14. Report Review: A.14. Report Review: Alan M. AMilalndreMd. SHH.ooCbbheerrrimmstaainan,n,,PPPhhh...DDD,,.,DDAFAeBBlTlTow((,DDiiArreeTccSttoor(rEooxffeRRceuetssieevaaerrcDchihr))ector of Research) Mildred S. Christian, Ph.D., Fellow, ATS (Executive Director of Research) A115. Dat 1 Signed: A.15. Date Protocol Si~lned: 2299 JJuullyy 11999988 10 171193 22778888..00001133 MAT0083131 3MA10083131 441188--001111::PPAAGGEE 1111-33 AA1.166.. DDaatteess ooff TTeecchhnniiccaall PPeerrffoorrmmaannccee:: RCRoaahttaAAbrirrrtiiavvtaalil oDDnaaPtteeeriod CDDDaooaysyhaa00gbeooitfafPtPPieorrrneiesosPuduemm(reeiDoddGdsGGe6esstttahatrtiiooounngh((D01G7G) 00)) TDToaooxnxsidiaccogoCkekaiiennPeseetatirricicoeadSSnaa(-mDmSpeGplclseeti6CCootnohlillrlneoegccuttgiiPohoennr1i7od) Caa((Den0sGdGarC11e88aa))ens---aSSSraeaetctaetelnilil-oitStneeeiScnSttgtiuuoPddneyyirnigodP-eriod C`aMeaisnarSetaund-ySe(c0tGion20in)g Period - Main Study (DG 20) 18 AUG 98111P1MAAUU-GG2399A88UG 98 AM 18 A112U995GAAAUU9U8GGGP999M888---- 2233 2039 AAUUGG ASUEGP 99938888 AM 25 AUG 98 - 09 SEP 98 1100SSEEPP 9988 0088 SSEEPP 9988-- 1122 SSEEPP 9988 AAA.177..ReRceocorrddssMMaianintataiinneedd:: TTarhheeerooerrtiiaggiiinnnaaeldl rrieenppotorhtre,t,arrraacwwhiddvaaetstaaofaannAddrgrrueessseeRrrevvseeessaaarmmcphpllLeeassbooorffattthhoereiteteesss,tt aaIrnrctt.iicclleAenaaynnddprvveeeshheiircclvleeed tm{aiiasresissluurieeensstgaaoainfrreeetdhrreeeinttdaatriihnaneeteddairniicnnahlttihvhreeeespaaorrorccfthhAiiavvrfegetssueorsofwfRththeihceseheTTateerscmsthteiinnLtggahebFFaoaScrcpiailoltiotntyyrsieoffoosrrr,wooiInlnnlcee.dyyeAeecaniardyreaapftfrttheeeesrriertthrhfveieenadl ddmUiinssapupiolsiosneisgtidtiiooobnfnu.t.lhkePPtrdereesrtpapafaatrrrfteeiinddcalfefloowrrreimmpluuolrlraatet,tmiioaaonifntnsesrwwawteerhtreehicehddTiitsesimcsctaaeirrdndtgehededFaaSacttiplttohthnyeesuTToneretssiwttiiitlnnlsggddeFFicasaicpdcioielslititytyth.ieoinr final is dUencuisdeedd bbuylkthteesStpoanrtsicolre. will remain at the Testing Facility until its disposition is decided by the Spor~sor. B. Test Article Information: B. Test Article Information: B8..11. DDeessccrriippttiioonn:: NN--EEtIFFOOSSEE -- aa wwaaxxyy ssoolliidd BB2.2.. LLooyt/BBaattcchh Number: Number: FMM--33992299 [(3300003355,, 3300003377,, 30039 30039 (Expiration (Expiration date: date: May 2000)] May 2000)] BB3.3.. DaR Dtatee e Recec ivedae annddSSi ttoorraav qgeeCConoe dnidtiitd ioonnss:: TTPrhheeepttaeerssettdaarrfttoiicrcllmeeulwwaaatsisornreesccweeeiivvreeeddsootnnor22ed00 rMMeafaryyig1e1r99a99t8e8,d,.aanndd stored stored at at room room temperature temperature. Prepared formulations were stored refrigerated. BB8.44.. SSppeecciiaall HHaannddlliinncgj Instructions: Instructions: SrSettsaapnnidrdaaatrroddr,sssaaafffeeettytyyppgrreeoccgaaguultetiisoonnossr s((uaufsseeetyooffgplprarooststeeeccsttiiavvneedccllaoottfhhaiincngeg,-,shggilloeolvvdee)ss,,weddruusestt.t-mmaikissettn when handing the bulk respirator, safety handling the bulk gteosgtgalertscioer test article and prepared formulations. safety glasses and a face-shield) and prepared formulations. were taken when 10 171194 22778888..00001144 MAT0083132 3MA10083132 441188--001111::PPAAGGEE 1Il1--44 BBS.5.. AAnnaallyyssiiss ooff PPuurriittyy:: Information regarding the identity, composition, strength, and purity of the test Information regarding the identity, composition, strength, and purity of the test aarrttiiccllee iiss oonn ffiillee wwiitthh tthhee SSppoonnssoor.r. CC.. VVeehhiiccllee IInnffoorrmmaattiioonn:: CA. Description: C.1 Description: 2(2R%%O.TTwwDeeeeeinonni8z80e0d iinWnatRReeerv)ve.errssee Osmosis Osmosis Membrane Membrane Processed Processed Deionized Deionized Water Water (R.O. Deionized Water). C2. LotNumber: 0.2. Lot Number: MMO033HHO0S5 CC3.3.. DaDtateeRRececeeiivveeddaannddSSttoorraagqeeCCoonndidtitiioonnss:: TTNhheeewvvJeeehhtisiccellyee, wwaaanssdrrseetccoeeriievvdeeddatoornno88omJJuutlleyymp11e99r99a88tuffrrroeom.m JJR...TTO... BBaDakekeieror,n, iPPzhheidillliiWppasstbbueurrrgg,i, available fNreowm Jaecrosnetyi, naunodusstsooruerdceatatrotohme Tteem stpinegraFtuacreil.tyRa.Ond. DisemioaniinzteadinWedataetr room is available ftreommperaactournet.inuous source at the Testing Facility and is maintained at room temperature. CC4.4.. SpSepceicaiall HHaannddlliinnggInInssttrruuccttiioonnss:: `SrSetstapanindrdaaatrroddr.sssaaafffeetetyylyppgrreeocgcagaulutetiisoonnossr s((uaufsseeetyooffgplpraroosttseeeccsttiiavvenedccllaoottfhhaiicnnegg-,,shggilloeovlvedes)s,,weddurusestt-t-mmaikissetnt when rheasnpdiriantgort, hseavfeethyicgloeggles or safety glasses and a face-shield) were taken when handling the vehicle. C5. Analysis of Purity: C.5. Analysis of Purity: NcNeoeinittthhaeemrrintthaheentSSsppoloinknseslooyrrtonnoobrretthphereeSSstetuundtdyyinDDtiirhreeecctvtooerhriwwcalaesstaahwwataarwreeouoolffdaainnnyytepprofoteterenenttiwiaialtlh the contaminants likely to be present in the vehicle that would interfere with the rreessuullttss ooff tthhiiss ssttuuddyy.. DD.. TeTsetsAtrAtritciclleePPrreeppaarraattiioonn:: and 4 mg/mL. The test article was considered 100% pure for the purpose of SSuussppeennssiioonnss ooff NN--EEttFFOOSSEE wweerree pprreeppaarreedd ddaaiillyy aatt ccoonncceenntrtraattiioonnss of of 0,021.2 0, 0.2, 1, 2 and 4 mg/mL. The test article was considered 100% pure for the purpose of ddoossaaggee ccaallccuullaattiioonnss.. 22778888..00001155 MAI0083133 3MA10083133 441188--001111:P:PAAGGEE 1II1--55. DD..11.. SSaammplpeleInInffoorrmmaattiioonn:: 5 Sample Type iz Sart ah Concentration [morme | 0 TeaSeg o a es Fin[ot] Se (all levels) Bulk Test EA I IN lal=O id ad Article Reserve rere commates|ress Vehicle wo daIl5 al e =o r Gl TolTil Reserve Components N/A N/A Tween 80 R.O. Deionized Water Size 2 mL= 1 g 5 mL 5 mL Date Retained 25 AUG 98~ 09 SEP 98c 25 AUG 98 25 AUG 98 25 AUG 98 Storage Conditions Frozen Shipped To Sponsor Room Temperature Room Temperature Room Temperature Testing Facility Archives Testing Facility Archives Testing Facility Archives Date Shipped 26 AUG 98 10 SEP 98 01 OCT 98 01 OCT 98 01 OCT 98 Dupe seempser arettombeStrda teonaesserTvedra aimopussveOroe Duplicate samples were taken from the first and last preparation on the day prepared. One sample of each set was shipped to the Sponsor for analysis. The remaining samples were ee eam ereonons retained at the Testing Facility as backup samples. bea First day of preparation. vo mains Last day of preparation. Homogeneity and stabi of prepared formulations are on le with the Sponsor Homogeneity and stability of prepared formulations are on file with the Sponsor. DD..22.. AnAanlayltyiticcaall RReessuultltss:: Concentration samples (2m) were taken on the rst and ast days of Concentration samples (2 mL) were taken on the first and last days of reporaton fo anayess by 3M Envionmentl Technology and Safety Services. preparation for analyses by 3M Environmental Technology and Safety Services. Fe fests ofthese analyses were not avaiable at he te of i report The results of these analyses were not available at the time of this report. EE.. TTeessttSSyysstteemm:: EEA.I.. SSppeecciieess:: RatRat 2 stain: E.2. Strain: CiHCDBBR VAFIPUS (Sprague-Dawley CrI:CDBR VAF/Plus (Sprague-Dawley) 3. Supplier (Source) E.3. Supplier (Source): Ghrtes River Laboratories, Inc., Raleigh, North Carolina Charles River Laboratories, Inc., Raleigh, North Carolina Ee sex E.4. Sex: Formate (Note: Male ats were used only for the purposes of breeding and are not Female (Note: Male rats were used only for the purposes of breeding and are not Coniderots par of ne Too System) considered part of the Test System.) 22778888..00001166 awaroosa1s 3MA10083134 441188-.001111:PPAAGGEE 1111-66 EES.~.. RRaattiioonnaallee ffoorr TTeesstt SSyysstteemm:: TTShhyeestCCerrmIl:CbCeDDcauBBsRRe:VVAA1FF)I/tPPiIlsuusosne((SSmpparrmaamggauulee-i-DDaaanwwlslepeyeyc))irreaastt awwcaacssepssteeelleedccatteenddd as the awsidtehley Test Tuessetd tttShohyxrrsoioctuueiggmthhyhoobeuurettactiiaonnugddesuunessit:ctrriyyt1y)ff)ooi:rtr i2nns)oonotnchnclieislinnm siitccraaaam llinssmtthuauaddlisiaieenbssesooepffneddcdeeievevmeesloloaonppscmm tcereenapntttetaeadldl atttooonxxdibicceiwittyisyde(e(neeslymmibtubirsvryyeeoo-dtf-ofeettaall dtdFoeaexvcviiecellilttooyypp/tmme"ereannattontaagdllet4tno)oixcxtiiinthnyses);;t33e2)s))thhtiahissritsttoorisriitcccraaaillisnddbaaihtotaalasogaabinnceddaelneelyxxdppaeecemrtriiioevennenscciteenrateethxexiiisdsststtpoaaettbcttiehheeesseTTaneensssdtittiiinvsngtegratoin Facility~5-7~; and 4) the test article is biologically active in this species and strain. 6E..6. TeTsetstSSysystteemmDaDtaata:: ANNpuupmmrbobexerirmooafftRReaaDttasste of Birth AAAWepppipppgrrrhoootxxxiiim m(mgaaa)tttoeeenAADtggaheeeteDaaottafAAyBrrrariirifvtvthaaelrl Arrival Weight Weight Weight ()at (g) on (g) at Study Assignment the Day after Arrival Study Assignment 08A11U9900G 98 01866944A5Udd-aaG2yy3ss948 210-251 195 - 234 210 - 251 EE7.7.. BBreredeerMMaealleedRRaatetDDaarttaa:: ANNpuupmmrbobexerirmooafftRReaaDttasste of Birth `AAWAepppipppgrrrhoooxtxxiiim m(mga)aatttoeeenAADgtgaheeteeaaDottafAAyrBrrraiirifvtvthaaellr Arrival Weight Weight Weight (g)(g) (g) at Study Assignment on the Day after Arrival at Study Assignment SShhiippmmeenntt 11 SShhiippmmeennt 2t2 13 J11A1100N 98 26 J11A2200N 98 13388077J0Add-Naa3yy5ss968 23677055J0Add-aNa3yy5ss968 300-356 449988--778844 300-356 E8.8.. M Methe odoot ffRRaanh nddoomm ioziaztaitd ioonn:: UgUeppnooennraaatrrteriidvvaalr,l,anrraadttossmwweuenrrieets.aassssFiieggmnnaeelddettoor individual housing aitnsdwiveidrueaal shsoiugsniendg on the toonotnhee basis obfafsivise of computer dosage of computer- ggggrereoonnuueepprrsasatte((eGGddrror(oawuuneppidssgohm I| ttt-hhourrronoduiutegsgr.hhedVVF))e),,rma22an55dleorramartitassztsappteewirroenddreoopssaraasoggsceeiegdggnurreroodeuupptbo.,auousssneiiednnggoonfaafibccvoooedmmdpypouwutseetaeirggr-e-hts gfdreeoeccsnooaerrgrddaeeetdedgdrooonn(uwpDDesGGigfho00.rt.-othNNrdeiiennsreeaetttedeeel)einnrtaeaanddsddtdiouitm tdiioyoiznn(aaatltlhiorffeeneemm,paafrlloieevce,erraadtttuhssrreewwee.ebrraeetshaaersedsessoiiagngnnndebedodfdittvyooewooranneteesig. hooftfsffiivvee daraasosnsssdiiagoggnmneeiezddgartttoooiuoGGpnrsroobfuuaoppsrssethd|IetothhsnrraobotueuoglgdlhihtyeVVw,s,etiruregedshsyptpese(ctchtrtireievvceeeol,lryyfd))iveuuedss,iointnnhggreDaaeGc,coot0h.mmrpepueutetaernr--dggeefinnveeerraarattetesdd randomization based on body weights recorded on DG 0. . EES.9.. SSyysstteemm ooff IIddeennttiiffiiccaattiioonn:: EEBaaacnchhd rraaanttdwwaTasasgiinnCddoi.ivviiddIuunacal.l,llyyNiiodd.eennMttiiSffiiePeddTww2ii0tthh10aa1)M Moionnnseecilrisbeseldeflf.w-pipitieherrctcihinneggraeetaa'rrdttaeasggi(g(GnGaeetyyed uBupnneairinqqmduuaeeanneppdneetrrTmmraaaagtnnenCenunotmt.b,nneIurunm.mcb.,bereN.ro. . Cage tags were marked MSPT 20101) inscribed Cage tags were marked with with with thethe the study number and rat's designated study number and permanent rat number. 10 171197 22778888..00001177 MAT0083135 3MA10083135 441188--001111::PPAAGGEE I1I1--77 FF.. HHuussbbaannddrryy:: FAA. Research Facility Registration: F.I. Research Facility Registration: USDA Registration No. 23-R.008 under the Animal Welfare Act, 7 U.S C. 2131 et seq. USDA et seq. Registration No. 23-R-099 under the Animal Welfare Act, 7 U_S.C. 2131 FF2.2.. StSutuddyyRRoooommss:: TTahhheealsslttwuuaddyyyarrnoodoommissndwweepererneedmmeanaitinlntytaasiinunpeepddliuuenndddeweirrtchcooannddmiititiinooinnmssuoomff ppoofosstieittniivvceehaaaiinrrffgloleowsw rrpeeellraatthiivoveeurttooof a hallway and independently supplied with a minimum of ten changes per hour of r11o00o0m0%)%. ffrreResoshhoaamiirrtttehhmaapttehhraaaddtubbreeeeeannnpdpaahssussmeeidddittthhyrrowoueuggrhhe 99m99on..9i97t7%o%reHHdEEcPPoAAnsftfiialltnetterrlssy((tAAhiirrrooouCCgllheeoauantn trtrhoehleoeamtssitt)vuu.eddyRyh..uomoiRRmdooiootteymmmwttpaeeem smrpaptetaerurraragetetuutarerneeddawwthaau3ssm0ttai%adrrgigttyeoetlwe7e0ded%r.aeattSm66e44oneFFitoAttoroPeP77d9E9cNFoFDn(I(s11Xt8a8nCCtlyttooth22r66ouCCg))h:; out (reTlaEtiMvePEhRuAmTidUitRyEwAasNDtarRgEeLteAdTaItV3E0H%UMtoID70I%TY. RSEePeOARPTP)ENDIX E (TEMPERATURE AND RELATIVE HUMIDITY REPORT). F3. Housing: F.3. Housinq: RcRoaahttassbiwwteaertrieeoniin,nddeiivvaiicddhuuaalpllalyyirhhooofuumssaeelddeeeaxxnccedeppftteddmuuarrliinenggrattthhseewccaooshhaahbboitiutaastteiiodonninppeetrhriieooddm..alDDeuurrriaintn'ggs Gcaoghea.bitAalltioGna,geeascihzepsaairnodf hmoausleinagndcofnedmitailoensrawtserweasinhcooumspeldiainnctehewimthalteherat's cage. All cage sizes and housing conditions were in compliance with the GGuuiiddee ffoorr tthhee CCaarree aanndd UUsseeooff LLaabboorraattoorryy AAnniimmaallssC~ Fa. Lighting F.4. Lighting: AAlingnht:aauut1too2m-mahtaoitucicraalsllldyya--rcckoo,nntwtrriootllhlieeeddacffllhuuodorraeersskcceepnnetrtiiloiggdhhtbt eccgyyiccnlleneiwwnagassatmma1ai8in0nt0taaiihnnoeeuddrsaattES11T22.--hhoouurrss light: 12-hours dark, with each dark period beginning at 1900 hours EST. FF..55.. SSaannititiizzaattiioonn:: Cage wCeargee cpphaaannnglliinenederrssapwwpereroreexiccmhhaataennlggyeeddevaaepprpyprroooxtxihimemraatwteeelelyyk.tthhrreeee times times each each week. week. Cages. Cages were changed approximately every other week. FF6.6.. FFeeeedd:: Nutrition International, St. Louis, Missouri) in individual feeders. RRaattss wweerree ggiivveenn aadd lliibbitiutmum aacccceessss ttoo CCeertrtiiffiieedd RRooddeenntt DDiieett~ ##55000022 ((PPMMII Nutrition International, St. Louis, Missouri) in individual feeders. FF7.7.. FeFeeeddAAnnalaylyssiiss:: lAAennvaaelllyyssseeexsscwweeeedrrieengrroouutthtiienneemllayyxppieemrrffuoomrrmmceeoddncbbeyyntttrhhaeetiffeoeneeddfossruucppepprltiliieefrri._ed NNfoeoeccdooonnrttaadm meiviinnaaatnnittossnsaattfrom levels exceeding the maximum concentration for certified feed or deviations from 10 171198 22778888..00001188 MAI0083136 3MA10083136 441188--001111P:PAAGGEE I1I1--88 exppeecctted nnuuttrriittiioonnaall rreeqquuiirreemmeennttss wweerree ddeetteecctteedd bbyy tthheessee aannaallyysseess.. CCooppiieess ooff Tn rests of the feed analyses ar availabe nth faw dota the results of the feed analyses are available in the raw data. Neither the Study Director or the Sponsor was awareofany agent resent in Neither the Study Director nor the Sponsor was aware of any agent present in tthhee ffeeeedd tthhaatt wwaass kknnoowwnn ttoo iinntteerrffeerree wwiitthh tthhee rreessuullttssooffththiiss ssttuuddyy.. [-- F.8. Water: Locat water that ha been processed by passage tough a reverse osmass Local water that had been processed by passage through a reverse osmosis n(n ty wa ovat hs as 2 sur om ot water membrane (R.O. water) was available to the rats ad libitum from individual water oes monet ta th ages andlor Hom am aviomatis watag oysom bottles attached to the cages and/or from an automatic watering system. CChhlloorriinnee wwaass aaddddeedd ttoo tthhee pprroocceesssseedd wwaatteerr aass aa bbaaccteteririoosstatat.t. FF..99.. WaWtaeterrAAnnalaylyssiiss:: The processed water is analyzed twice annually or possible cherical The processed water is analyzed twice annually for possible chemical `ccoonnttaammiinnaattiioonn ((LLaannccaasstteerr LLaabbooraratotoririeess,, LLaannccaasstteerr,, PPeennnnssyyllvvaanniiaa)) aanndd mmoonntthhllyy ffoorr ppoossssiibbllee bbaacctteerriiaall ccoonnttaammiinnaattiioonn ((AAnnaalylyttiiccaall LLaabbooraratotoririeess,, IInncc.,., CChhaalflfoonntt,, Femasnaany. Copies of he resus o i water analyses at avataple the Pennsylvania). Copies of the results of the water analyses are available in the NTeitrheretheaSvtusy Dmicotooratrhe sSpaonfstortwhasroauwtasreofof1asnyhaogaent resent in rraaww ddaattaa.. Neither the Study Director nor the Sponsor was aware of any agent present in the water that was known to interfere with the results of this study. GA. Dosage Administration: GG.. MMeetthhooddss:: G.1. Dosage Administration: oem] cor Dosage | TH RC Group Numl:)er of Rats Dosage (mg/kg/day) Tes owen[o rec [I enn| i 25 + 3= 0 (Vehicle) Tseee we [men] II 25 + 5= 1 Concentration (rng/mL) 0 0.2 Dosage Volume (mL/kg) 5 Assigned Numbe~ Main Study Satellite Study= 12801-12825 12826-12850 12573-12575 12576-12580 CoforTo | Ton[ow III 25 + 3= 5 1 12851-12875 12581-12583 Tes we a[ws we mee| IV 25 + 3= 10 2 5 12876-12900 Ime mo | + | 5 wv [vr | V 25 + 5' 2O 4 5 12901-19295 E Tt E Tae The test article was considered 100% pure for the purDose of dosage calculations. 12584-12586 12587-12591 a. Rats assigned to the satellite group for blood collection. he est atc was considered 100% pure for he purpose of dosage The test a~iclewas considered 100% pure for the purpose of dosage Caton calculations. 10 1711gg 22778888..00001199 3MA10083137 441188--001111::PPAAGGEE I111-99 GG2.2.. RRaattiioonnaallee ffoorr Dosage Dosage Selection: Selection: DLDaoobsosaraaggteeosrsiewwsee,rreeInsscee.,lleePccrtteoetddocooonnltt4hh1ee8bb-aa0s1sii1ssPo)offtaahaddtootsseaasggteee-d-rr0aa,nng1g,ee5s,sttu1u0dd,yy2((5AArraggnuudss Research Research `33La55anbdmmoghrg/iak/gktgohg/er/dirdeaasdyy,o..sIangIIcnne.,stth,Phaartotatnssotdtcuuoddfylye,,4ed1bb8ooc-ddo0yyn1sw1wuePemi)ipggtthhhittaoggtnaateivinnsatlwweuadaesss0,wddeee1cr,crer5ee, raa1ess0dee,uddc2aae5tdt a11an00tdammlglg/d/kkoggs//addgaaeyys tested and higher tested. dosages, and feed consumption values were reduced at all dosages GG3.3.. RoARuodtumteeionoffiAsdtmrinaisttiraotinon:: OOrraall ((ggaavvaaggee)) GG4.4.. RRaattiioonnaallee ffoorr RRoouuttee ooff Administration: Administration: dTTihheeetaoorryraalrl o((uggtaae,vvaatggheee))errxooauuctttee dwwoaasssagsseeellceeacctnteedbdeffooarrccuuussreeatbbeeelccyaauausdseme:i:ni11s))teiinrneccdoo;mmappanardrii2ss)oonnitiwvsiittahh the the dppirreootppaoorysseerddourrtooeuu,ttteeheooffehhxuuammctaadnnoeesxxappgooessucuraeren.. be accurately administered; and 2) it is a GG5.5.. EFrerqueencyqooffuAAdmdeimniinnsitsrtcraattiiyoonn:: AAopnppcpreroopdprariiilaaytteetoddfooessmaaaggleeessrooaftfstthhoeen ttDeessGttsaarr6ttiictcllheerowwueegrrhee1aa7.ddmmiDninoiissstateegrreeesdd ooofrraa0lllly(yVe((vhviiiacalgge)aa.vvaa1gg.ee5)). 10 aoa5nnnmddcieJ22kd00ga,mmilgyagkd/tkojggulfs/eddtmaaeydyaldooeaffirttlahhyteesottnoeenssttthDeaaGrrbttsaiiccsll6ieestwwhoereforruteehgeaahddim1mnid7nii.nviiissDdttueoearrsleeaddbgoeaadsttyaaowfdde0ooigss(Vhaatgegseheircvvelooecll)ou,urmmd1eee,5doo,ff 10 5bemfoLr/ekgd,osaadgjue.steTdhdearilaytsonwethree bdaossiesdoaftthaeppirnodxiviimdautaellybotdhye wsaeimgehttsimreeceoardcehdday. before dosage. The rats were dosed at approximately the same time each day. GG6.6.. LLenegtnhoofgfSStttuuddhyy:: AApppprrooxxiimmaatteellyy 44 wweeeekkss GG7.7.. MMeetthhoodd ooff Study Study Performance: Performance: wAAfifttteehrr1aa9cc0ccllbiimrmaeatetidiooennr,, m11a99l00ehhreeaatalsltth(hyyonvveiirrgmgiainnleffeermmaatallpeeerrraafttessmwwaeelrereerapptllaaicnceetddheiinnmttaoolcceoohhraaabtb'istitaactatiigoeon)n. wFaFneeitdmhmlaoa1lrl9eea0rracabtotrssepuewwlidiattehthrossrmpypaeeplrrelmmuargaatttioosnzzs(ooioaatnueoowbbmessreaeerlrevvceeordadntsiipnindeaaerrssfeemmdmeetaaaorlrebooerffaattththieneDtvvGhaaegg0iimnnaaaanllldeccoorrneantttt'eeusnrnncttseasdget)o. iainnndddiiv/voiidrduuaaallchohopouuusslaiintnoggr.y plug in situ were considered to be at DG 0 and returned to TThhee and ffeemmaallee rraattss for general awwpeeprreeeaorobabsnsecerervveweeddeffkoolrryvvdiiaaubbriiillnittgyy at least twice each aactclleiamsatttiwoniceanedaochn day dDaGy of 0o. f the study tThhe estruadtsy wwaenerdreefoaarllssgooeneeexxraaammliiannpeepddeffaoorrraccnllciinneiiccwaalel eookbbslsyeerdrvvuaartitniiogonnasscoocfflimeeffaffeeticcottnss oafntdheonteDstGar0t.iclTe,he of the test article, rats 10 171200 2277888..00002200 33MMAA1100008833113388 441188--001111:PPAAGGEE I11--1100 aaafbbtooerrrttiidooonnsss,a, gpperree(mmDaaGttsuurr6eethddereloliiuvvegerrhiiee1ss7aa)nn, ddandddeeaaottnhhcssebbedeaffioolrryeedaaunrniddngaapptpphrreooxpxioimmsatatdteeollsyyaoogenneepehhrooiouudrr. after dosage (DGs 6 through 17a), and once daily during the postdosage period. dBBaooidldyyydwwuereiiiggnhghtttsshwweeedrroeesrraeegcceoorraddneedddpwwoeeseetkdklolyysaddugureriinnpggeraaiccoccdllsiimm(aaDttiGioosnn,,6ootnnhrGDouGsgsh 0020aa).nnddF44eeaannddd cdcooannilyssuudmmuprptintiigoonnthvveaallduuoeesssawwgeeerraeenrrdeeccpooorrsddteedddosooanngeDDGGpSesr0i0o,,d44s,, (6D, G8,s 160,th1r2o,ug14h, 6, 8, 10, 12, 14. 2106),. 16, 1F8eaendd 18 and 20. 20. GG8.8.. GGrroossssNNeeccrrooppssyy"b:: Rats Assigned to the Main Study Rats Assigned to the Main Study: AAslelllcrrtaaittossnewwdeerraeendssaaaccrrgiiffriioccseesdd nbbeyyc rccoaaprrbsboyonno fddiitoohxxeiiddteehoaarasscppihhcy,yxxiaiaabttdiiooomnnioonnnalDDaGGn 20, Caesareand20p,elCviacesviasrceearna- w`sweaaacmsstmioppoenenreriffdouorrmammneseddudl.f.aidgUUerttoetersorisicooonffnefaacipprrpopmapartsreheynentotlalfyybthsnneeoonnntcphperoreeroaggfcnniiacamn,npttalabrrnaadtttossamtwwiieoennrraeelsiassttnteaasdii"n.npeeeddTlviwwicisittshvhuies11sc00e%w%riath geagvrm raoolmssussaotnlleieioussnimio:onnassslulwwlofeietdrhreeeertppomrreacetsoseeenrrrfvmivreameldd thinenaeubtsreanlcbeufofferimedpla1n0t%atifoonrmsailteisn~9f~o.r tinisnsueeustrwael rbeufdfeirsecadrd1e0d%. formalin for Tpoissssuibelsewfuitthure: possible future evaluation; all other maternal tissues were discarded. TTwhhaees nenxuucm mibsbeeerdr ooaffncdcooerrppxooarrmaainlluuettdeeaafoiirnn each ovary peraecghnaonvcayr,y nwwuaamssbrereerccooarrndddeeddd.i.stTTrhhibeeutuuitoteenrruoufss of of each each rat rat wirimmeapspslolaraenpnxtttaciatoitsinioeownndsas.a,snlliddiveveefeixaanannemdddiddnaeeesaadoddnfoffeerettipunursseweeghssinacaahnnnddcoyree,gaaanrrlnulyyomgaabennenddresllaaainttsede wrrdeeaissssotorrrinpbptoutitiootingonsrns.o.sosAAflynn eeevaairrdlleyynt AAwreasllsaoattregeprtrroieoesssnsoolrwyrppatetviisoiondndeenwwftiaa.nssedAddeeafIfsiivnneoeendfdeetaauissnsoowwnnaheesiciihndnewwofhrihginiaccehndhotatghhseeeanooectcsceciusrurmrwrrefeaennstccueensotoothffagootrrrogrgseaassnnlypoooggeneevdnnideeeedssniitstso. wessttaiaimmsudlugil.ifr.eotsNuNssooelynsnr)re.eevssidppDoeoennnadtd.diinnAfggetlttiuveeserrmemfsefftaeuentstuduswsleeaasstseaadrrreeeefsicconoorepnndtssiiiadodsneesrraeeadtdreerttmoodibbffeeefetudrdeseenaatthdidaat((tetthdrheeebsrreyepowtwnheeedrreeednntooo ddeegardefeetoufsaeust)o.lyDsiesadprfeesteunste;smaanrdkeldatetoreexstorrpetmioenasutaorleysdiisffeirnednictiaatteeddtbhaytththee fetus was a late resorption degree of autolysis present; was a late resorption. marked to extreme autolysis indicated that the fetus EiEdaaecncthhifffieeettduusswiwwthaassa rrteaemgmoonvvoteeiddngffrrotohmme ttshhteeuduuytteenrruuumssb,,epprll,aaccleeidtderiinnnaaumnnbiiennrdd,iivviiuddtuueaarlil ncceoondnittsaatiirnnieebrurtaainnondd agaidrnneoddnstfsfiiifxixeeaaxdtttiivevweren.i.tahlEEaaaalccttahhegrffaetneittououtnssisn.wwgaatsLhsievsseuusbtbfusesdeteyququsuneeeusnnmtwltbleyyerwwre,eesiliiagtgcthehreriefddniucaaemnndbddbeyeer,xxaaaunmmteiiirnnninreeaeddpedffrooisirrttrssoieebnxxeuataailonnndd gross external alterations. Live fetuses were sacrificed by an intraperitoneal a SSSeeTeeAANAPPDPPAEERNNDDDIOIXXPEDDRA((DTDEEIVVNIIGAATTPIIOROONNCSSEFFDRRUOORMMESTTHHOEEFPPTRRHOOETTTOOECCSOOTLLINAAGNNDDFACILITY), b. iASitteTetmAambNl11De. AofRrDanOdPoEmRuAniTtIsNwGasPRusOeCdEtDo UseRleEcSt OF one THE contr TESTING ol group r FACILITY), at from Awwcohhtniaictcbhrhloeaaltlollifttsiirssasussneuusdeeosfsmoreexxauaannmmyitisipnnoweesddassiaabttulsenneeehdccirrstoootppospssaeyytlehwwoceeltroroeegnirrceeeattlcaaoeiinnnveeatrddlo,,ulaiigntnrioooorurnddspeoerrrfagtttoorfropporsrmoosvviiddee cleosniotrnos.l tissues for any possible histopathological evaluations of gross lesions. 10 171201 22778888..00002211 33MMAAT100008833113399 441188--001111::PPAAGGEE II1I--1111 iinnjjeeccttiioonn ooff BBeeuutthhaannaassiiaa--DD SSppeecciiaall ((SScchheerriinngg--PPlloouugghh AAnniimmaall Photographs of gross extemal fetal alterations are available in HHeeaaltlthh)).. the raw data. Photographs of gross external fetal alterations are available in the raw data. AApppprrooxxiim maatteellyy oonnee--hhaallff ooff tthhee ffeettuusseess iinn eeaacchh lliitttteerr wweerree examined examined alterations using an adaptationofWilson's sectioning technique". for soft tissue foTrhseofftettisussuese wwaeletrereeraitininoiittniiasallllyuy sffiiinxxegeddaniinn aBdoauipnta'stiosnoloutfiW on;ilssoenc'tsiosnesctwioenriengsttoercehdniqinuea{l~coh).ol.TheThfeetuses Bouin's solution; sections were stored in alcohol. The rrreeemdmaa5ii"nni.innggfiffxeeettduusisneesasliicnnoheeoaalcchhanlldiitttteeerrxwwaemerireeneeedvviifssoccreesrrkaaettleeeddt,,alccllaeelaatrerereaddt,,iossnttsaa.iinneeSddkewwlieittthhalaalliizzaarriinn rpperrdeeppSaa~r1ra~a)t,tiiofoixnnessdwweienrreealcrreoetthaaoiinlneaednddiinneggxllayymcceeirnriienndwwifiotthhr stkheylmeotlal aadldteerdatiaosnas. thymol added as a prSekseerlevatatil ve. preservative. RRaattss AAssssii,qgnneedd to to the the Satelite Satellite Study: Study: OOnn DDGG 1188,, rraattss aassssiiggnneedd ttoo tthhee ttooxxiiccookkiinneettiicc following samples collected. Blood samples evaluation were sacrificed and the. e(avappluraotxioinmawteerle4ysmaciripfiecredrata)nwdetrhee fcTcooohlllleolleewrcceittneseguddltsffiraronm ogmmpsttlehehreseuciimnnoff(leelaerripicooptrrerdovvxe.einnmBaaaltocceoaaldvvyaas2aiinmnmttLoop)lsseweesraru(usammpipssmermeopepxadairimraaattatooetrelrlyttyuuf4bbreeomsszeLaannnpoddenrccerdeanrntty)trriiwiffcueueggraeeednd.d. Tmmahaieinntrteaasiinuneeltddinfgfrrooszzeeernnum((--7(70a0pCCp))rouuxnntimtiillassthehiliyppmm2eemnntLt )ttoowttahhsee iSmpmonesdoiartefolyr Sponsor for farnoazlyesniso.n analysis. was excised, weighed, and a sample section (lateral lobe) was frozen Tdhrye Tahned icleivearnd liver wrreeattasaiinenexedcdisaaettd--7,70w0eCCiguuhnnettidill,ssahhniipdpmmaeensntat mttoopttlheheeseSScpptooionnnssoo(rlrafftoeorrraaalnnaloalbylysesi)sis.w. as frozen and eRRxaatttessntwweperoresesCCiabaleeessaaarsreeadanen-s-cssreeiccbtteiiodonnaeebddovaaennddfoffreetrtuaustsseessaswwseeirrgeeneeedxxaatom mitinhneeeddmaggirrnoossssstlluyydytto.o the thFeetuses ateaonnxtdtdehnppetllaSapcpcoeeosnnnsttsiaaboeelrewwfaeoesrrreeadneppaslooycoosrliliebesd.eddppAeeafrrbteolliirtvttteecerorfmoaaprnnlddreatrrtiseeottaanasiinosnefiegddsnaffermrodpozzlteeoenntch((o-el-7l7e0m0ctaCCiio)n)n.uusnnttsuitieldl ryssu.hhmii,pFpmemlteieuvnnestrtes stsoeecctthtiieoonnS(p(llaoatnteesrroaalrl lfoobrea),nafleytsailsa. nAdftpelracceonmtapllestaiomnploefssawmerpeleschoilplepcetdio(nf,roszeernumon, lobe), fetal and placental samples were shipped (frozen on ldivreyr dry iiccee)) ttoo tthhee SSppoonnssoorr ffoorr aannaalylyssisis.. 22778888..00002222 10 171202 33MMAA1100008833114400 441188--001111:PPAAGGEE 1I11-1122 GGS.9.. StSattaitsisttiiccaall AAnnaallyysseess:: The following schematic represents the statistical analyses of data The following schematic represents the statistical analyses of data: TTypyeoofpfTTeesestt*' 1I.. PPaarraammetertriicc I. Nonparametric" II. Nonparametric~ AA.. BBaartrltleetttt''ss TTeesstt~*d (<755% ties) AA.. KKrruusskkaalI--WWalallliiss TTeesstt (-<75% ties) Nonpalametric at ps0.05 SiSgigninfifiiccaanntt at p<_0.05 Nonparametric NNoott |SSiiggnniiffiiccaanntt AnalysiIs of Variance Analysis of Variance SiSgigninfifiiccaanntt atp0.05 at p_<0.05 Dunn'|s Test Dunn's Test NNoott SSiiggnniiffiiccaanntt SignifI icant atp=0.05 Significant at p<O.05 NNoott SSiiggnniiffiiccaanntt BB.. FFiisshh(eer7r''ss5EE%xxatacicetts)TTeesstt (>75% ties) DDuunnnneettt'ts TTeesstt Il. Testfor Proportion Data III. Test for Proportion Data VVoafarrtiihaaennccBeeinTToemesistatlffooDrrisHHtoormimbouogtgeinoenenietityy of the Binomial Distribution 10 171203 aba... SPStrtaoatptiiossrttiticciaaollnllyydssaiitgganniiaffiricceaannntottppriroonbcbalabuibdlieilitdtiieeissn are tahries reported rceapteogroteryd. as as either either p<0.0 p_<0.05 or or p<0.01 p_<0.01. cdb.... UUTPessrsoeetpddofooortrnnilolhyynottmdoooagaatanenanaalelyryiezzteeynoddotaaftitnvaaacrwwluiiiadttnhhecdehh.ooinmmotohggiesennecaiettiteyygooofrfyvv.aarriiaannccee.. 10 171203 d. Test for homogeneity of variance. 22778888..00002233 MAI0083141 3MA10083141 418-011:PAGE 11-13 || 418-011:PAGE 11-13 TCCleliisnntiiccfaaollr ooHbbossmeeorrgvvaeatntiieooinntaaynnoddf ootththheeeBrrippnrrooomppiooarlrttiioDoinnstddraaittbaautwwieoenrr'ee. analyzed analyzed using using the the Variance Variance Test for Homogeneity of the Binomial Distribution(12). CCcooonnntstiuinnmuupootuuissonddaavtataalu((eee.s.gg.a.,,nmmdaaltitetetrernrnaaallvebbrooaddgyyewwseeifioggrhhtptsse,r, cbbeoonddtyymwwaeleieigghfhtettccuhhsaeasnn,ggepeses.r,cffeeeneetdd rocreseosssnioosfrriubbcmeeatddpitoccionoonnsniccvteeeappldlutauuetsssaee)sas,wn, edffreeltetiaattlleabnrbaooalddvyyyezrwewaedgeieiuggsshhtitfsnso,g,r fpeetarlceanntommaalley fdeattuaseasn,dpfeertcael nt fBeatratlleattn'osmTeaslyt doaftaHoamnodgefenteailty of VoVTaesasrsritiiafianwccnaaectssieo{s1nn3o)tsiaatsennigdddniatthfthiaeec)aAAwnnntaeal(rlpeyy>ss0aii.ssn09aoo)lf)yf .zVVeaadrrIifaiutnahscneeicn(Aeg1n"4aB),,laywwrsthhileeestonnt'fsaapVTppaeprrsroiotpapornrifciaaHetteoewma[[ii.so.eeg..s,,eiBBnganeariirtfttyilleceaotttn'f'tss T((ppe<<s00t..w0055a))s,, individual nDDguorunotnnusnepisteg.ttnt''isfsiIcfTTaetenshstte(~t(5ApTM1n>aww0la.ay0sss5i)uus]os.seefIddfVtatthooreiiidaAdenenncntaetiilffywyysaittshsheeonfossVtttaaatatiirpssipattirinccocaaplelrssiwiaiggatnnesiiff[isici.iacge.ann,ncicfBeiaecraotolfnfetttthth'ees TtTinheedassintvtiwwodrauaaseslqssugiiarggolnnuiitffpoiicsc7a.ann5tIt%f ((tphpt=<ie0e0.sA.00w5n5)ea])r,l]y,estthiphsreeeosKKfernVruutas.skrkiaaalInl-n-cWWcaealaswlllieiassssTTwnehesoetst(1rat6e)ptwwphraaeosspKruuriasusseteekdda,,[li.ww-eWhh.a,eelBnlniasllreetlTsseesstst'ts wwtwhaaaasssn ssuottsraaetteidissqttutiicoacaalilldltlyoeynsst7iii5ggf% nyniitfftihicieceaassnntttwat((epiprs_<et<0i0.cp0.a0rl5e5)ss),,iegDDnnutiu.nfnninI'cn'assnccM MaeeseeottfhshootwhddheooeiffrneMMduitulvhitletdiiuppKallelerugCCsrookommuapplp-saW a.rriasilofslinsotshn(T1eser~"se)t were greater than 75% ties, Fisher's Exact Test" was used to was used to identify the statistical significance of the individual were greater than 75% ties, Fisher's Exact Test(~8) was used to garnoaulpysz.e analyze the data If there the data. CtCohoueunpntrtdodactaeatdaurooebbtstaadiinenesecddraaitbt eCCdaaeaesbsaoarvreeeaanfn-os-rsetechctetiiooKnrnuiinsngkgaolof-fWttahhleeliddsaamTmessstww"ee.rree evaluated evaluated using using the procedures described above for the Kruskal-Wallis Test(~6). DDaamm 1122886688 ((55 m mgg//kkgg//ddaayy and two early resorptions addnoodssaadggaeemggrr1oo2uu8pp3))9hh(aa1dd0 a liter consisting of amgli/ttkegr/cdoanysidsotisnaggoef five live fetuses gfirvoeupli)vehfaedtuases allsiitnkttedeerrwtccwtooohnnesseiidassitrtsliiyntnrggireboousftfoittrohhpnrrteioeoefendlsliiavvaetenaffd"ee,ttduuasssteemasst..i1st2BBi8cee8accl9aaauu(n1ssa0eelymsssuugeccs/khhgwoo/edccrcaceuyurmrdrraeoednnsccaeeegwsseitccghaarnnoaunaapdbb)nnwohioratrmdmhaoalaultllyy sttvhhkaeeleuwvveaastllhuuaeeenssddiffsoCotrarriettbhshuaeetrsisoeeenanrroaa-tftsssdeaaacttnnai(dd1o9lln!iit,ttdtesearrtstsa.a.tisfMMtoiacratattelehrraennnsaaeallldybbsaooemddsyyswwwaeeneirdigeghhltmtissta,,edrffseeeewewdedirthcceooanennxssdcuulmmwuppdtitetihidooonnut vffraroolmumesssuuammnmmdaraCirziazaeatstiiaoornneaaannn-ddsesscttaatitotiissnttiicdcaaalltaaannfoaalrlyytshseeesss;;eaaldllvavamalsluueaesnsdaarrlieettepprrrseeswseeennrtteeeddexoocnnluttdhheee.d iinnddiivviidduuaall ttaabbllees.s 2277888..00002244 1100 117711220044 33MMAA1100008833114422 441188--001111:P:PAAGGEE III1l-1 mIIlI.. RREESSUULLTTSS AAo aMMonordratl2a:ilittyyIn,,dCCilvliiinndiuiccaaalllDaaanntdda -NNTeeaccbrrlooeppsssyy14OObabsnsederrv1va5attiioonnss (Summaries (Summaries - - Tables Tables 1 1 and 2; Individual Data - Tables 14 and 15) AAl..1. MMoortratalilittyy NNoo ddeeaatthhss,, aabboorrttiioonnss oorr pprreemmaattuurree ddeelliivveerriieess occurred during occurred during the the study. study. Al All rats rats ssuurrvviivveedd uunntitill sscchheedduulleedd ssaaccrriiffiiccee oonn ggeessttaattiioonn ddaayy 2200 ((DDGG 2200)).. AA2.2.. CClliinniical rat Observations AA)llll tcchlleiinniiiccnaacllioodbebsnsecerervsvaawtteiioornnessnwwoeterrdeeosccaoognnessi-idddeeerrpeeeddnduuennnrrtee;llaa2tte)eddthtteoo tothhbeesettreevssatttaairrottniiccslleeocbbceeuccraaruuessdee:i:n 1) the incidences were not dosage-dependent; 2) the observations occurred in oeoelnninnlvmlvyyibirrsoooonannnnememdeerlrnaaotnt;tr.;t.anaenCCnclddlikli/nn,ooiircrcuaa33nll))goottrhbbhoseesoeeormorbvebvsaadsetetriicorvoovnanaaststt,iioiionncnncocssllluduaaddrrteeeeoddctclloooooumccmcaammhllioizoazennnedddeeaavvflleeuoonsnppteteessdcciiisinanaettcoohhonneenttldlhahaeebaboonuurrdnnaadtdtteooherrirrsyrysididdee,, dliimgibtss aonndt/hoer rniegchtk,fournegpraowo.med coat, cold to touch and fused second and third digits on the right forepaw. AA3.3.. NeNcercrooppssyyOObsbesrevrvaattiioonnss TTofhheethooennIllvyyenrneeiccnrrooonppessyy2ff0iinnmddgiinrngkggwwiaadsasyaadttoaasnnaaagrreeeaagr((o00u..6p6 om x cdmamx 0.8 cm) (01.2891c3m).) on the onThtihse median lobe ombseedrivaantiloobne was considered unrelated to the of the liver in one 20 mg/kglday was considered unrelated to the test arlicle because it occurred in dosage group dam (12913). This test article because it occurred in only ane rat observation only one rat. 8. MaM`tSauetmermrnnaaarlil eBBsoodd- yyTWaWbelieegi.sqhht3tssaanandndd4B;BoIondddyiyvWiWeduieaigglhhDttaCCthahaa-nTngatiebeslse((FF1ii)gguurree11;; Summaries - Tables 3 and 4; Individual Data - Table 16) MMaatteermnaall bbooddyy wweeiigghhtt ggaaiinnss wweerree ssiiggnniiffiiccaannttllyy reduced reduced (p<0.05 (p<0.05 or or p<0.01) p_<0.01) in in ggeeofrnrfffoloeeyuuccptpotssnwwaaaaDdsdsGmmimsmniiniin8nissiimttmteoeaarrle1le0dda.ann55ddInmmttgrtrga/ha/nnekkssggi1i/e/e0ddnnaatmtyygiin/naaktnnthghdd/eedhh55aiiggymmhhgdeeg/ror/kksddggaoo/lgdsdseaaaayygggeerddossooussoopfaa,f ggttshheeieegggnttrireeofossiuuttcppaaa,,nrrtttooiiccrccllecece.duu.urrcriTTitnnhhiggoeens {fo(pon<l=lyl00o..o0w0ne55d))DbiinGnysmmaa8atsteiteogrrnnni1aaf0lil.cbbaInoontddtyyihnewwcere1iei0ggahshmtet ggg(/aa<kii0gnn./ssd0aoo5ycc)ccdiuunorrsrrweaeeddgigeoohnngtrgDDoauGGipsns, 6stigoni8ficaanndt o6ntoD8Gsan1d4 1re0dtuoct1i2o.ns 1t0o t1o6.12T, he ff22oo00lllolmmwogwglee/kdkdggibb/ddyyaasayyigsddniogoifsnsiaaicfiggacneeatnggrtrreooidnuuucppcrtehhiaaoasnddes ss((iipgpg_n<n<i0iOff.ii.c00ca55ann) ttoinrwwewpei<iegg0ihhg.t0th1tolo)gssasisnin((mppao_<tn<0e0.rD.00n1G1a))lsoob1nno4dDDtyoGGsws1e666i.gtthoToth88e tendency for reduced weight gain in the 10 mg/kg/day d followed by significant reductions (p_<0.05 or p_<0.01)in ggaaiinn oonn DDGGss 88 ttoo 1144 aanndd 1166 ttoo 1188.. TThheessee eeffffeeccttss ooff tthhee osage group and tmesattearrntiaclleboredsyulwteedighint test article resulted in aa tSseiiggnnndiieffiincccaaynnttforrereddrueucdcttuiiocoenndss w((ppe<<i00g..h00t11)g) aiininntthihneet2h20e0 m1g0/mkgg/lkdgay/ddaoysdaogseaggerogurpoufopr mglkg/day dosage group for athned the entire entire tttrrreeeaaatttmmmeeennnttt p(peeDrrGiiosodd6((ctcoaall2cc0uu)llaaatteneddd aatshseDDeGGnstsi6r6e ttgooes11t88a))t.,ittohhneepeeenrntitiiorrdee (DGs 0 iinntteerrvvaall taaofftt2ee0rr).iinniiMttiiaaatttieioornnnaoolff treatment (DGs 6 to 20) and the entire gestation period (DGs 0 to 20). Maternal 10 171205 22778888..00002255 MAI0083143 3MA10083143 441188--001111:PPAAGGEE 1I1l1l-22 bbooddyy wweeiigghhttss wweerree ssiiggnniiffiiccaannttllyy rreedduucceedd ((p<<0_.0.0055 oorr pp<_<00..0011)) in in the the 10 10 and and 20 mg/kg/day dosage groups on DGs 11 through 14 and 8 through 20, respectively. 20 mg/kg/day respectively. dosage groups on DGs 11 through 14 and 8 through 20, Body weights and body weight gains were unaffected by the 1 mg/kg/day dosage of the Body weights dosage of the attenessdtt article. body weight article. gains were unaffected by the 1 mg/kg/day C. VMMaaatlteuerernnsaall(SAAubbmssmoolalurutiteees((g-gliTddaaabyyl))eaasnnd5d aRReneldlaat6t;iivvIeend((qigvlkli_kdaquiiaddlaayyD))aFtFaeeee-ddTaCCboolnness1uu7m)mppttiioonn Values (Summaries - Tables 5 and 6; Individual Data - Table 17) TThhee aabbssoolluuttee ((gg//kkgg//ddaayy)) ffeeeedd (9<0.05) in the 10 mg/kg/day dccooonnsssauugmmepptgtiriooonnupvvaaolnluueeDwwGaass6 sstiioggnn8iiffaiicncaadnnttallbyysrroeeldduutucecee(ddg/day) aa((p9nn<:dd00..rr0e0el51laa))ttiiiivnvneetth((hgege//k12kgg00//ddm maaggyy/)/)kkffggeei/ededddaayyccooddnnoossssuuaammggpeepttiggioorrnonouuvvppaallofuuoneerssDthwwGeeesrern6eetitssoriiegg8nndiiaoffiinsccdaaangnatetllbyyspoerrereluiddtouuedcce(egdd/day) (f((pcce<aae_lldcc0uuc.0lloa1ant)teseidnudmtaaphssteiDD2oGG0nssmva66glt/tuokoeg11/cd88o)a)nytaainndnddouseaaadttgataelolll gbiinernotteseurirpvgvanafillosfsriwwctiahinttehthliienynnrttthhieriiedssudppceoeersrdiiaoo(dgd.pe.=0pTT.ehh0r1eeio)aadabbnssodolltuuhtteee dfrreeeoellsaadattiivgcveoeenffgesereueodmduppcctoodionnunssriuuvnmmagppltuttiheiooenncpoovvnasatltliunudeueoesttdeaengntdoedeebiddnettteosorivgbbaneelif(rriceDeaddGnuustcclyee1dd8retiidnnoutt2ch0he)ee.d22(00Tph_mm<eg0gs/./ek0kg1ge)//fddafaaencyydtsthoef dtt(hhpoee=s0a22.g000e1mm)ggga/ro/bkkusggop//lddudaatuyyeriddnaoognssdtaahgrgeeeelpaootofifsvtttehdheeofestteeaedssgttecaaoirrnnttsiticecullremevparrteleis(soDuunlGtteevsddal1iiun8nestssoiiggo2nnni0iff)iDi.ccGaaTnnsthtll6eyystrreoeedd2euu0ffcce(eectddthse of entire interval after the (p_<0.01) absolute and entire interval after the first dosage relative feed first dosage was administered) and consumption values on was administered) and DGsDGs DGs 06 0 toto to 2020 20 (the(the (the eennttiirree ggeessttaattiioonn period) period). AAtbhbessotoleluusttteearaatnnicddlerreaellsaatthiivivegehffeaeesedd5ccmoognn/sskuugm/mpdpatytii.oonn Tvvhaaleluueseissgnwwieefrirceeanuutnnarafefdffeuecccttteiedodnbb(yypdd<0oo.ss0aa5gg)eeissn of othf e trwrheeaellasatttieicvvsoeetnfsfaeeireetdiddcelrecceoodannssusnuuhrmmigeplhptatitiaooesnnd5tvvoaamlltuguhe/eekgiitnn/edsttathhyeea.r11iTcmmihgeeg/b/kkseggigc//ndadaiaufiyysceaddnootthsseraaeggvdeaeulcggutrreiooowunuapp(spoo<nnn0oDDt.0Gd5Go)ssi66nagtttoeho-e88 wdeapsecnodnesnitdered unrelated to the test article because the value was not dosage- dependent. D.Do aCCnaadeess8a;arreeIaandnni--vSSieedcucattliiooDnnaiintnagg -aaTnnaddblLeLitisttet1err8OObbtshsererorvuvagahttii2oo0nnss (Summaries (Summaries -Tables -Tables 7 7 and 8; Individual Data - Tables 18 throu_ah 20) oPPfrretehggennaarnantccsyyiooncctcchuuerrrr0eed(dVeiinhni22cl44e)((,99661%%.))5,,. 221330 ((a99n22d%%)2),,022m44g/((9k9g66/%%d)),a,y22d55o((s11a00g00e%%)g)raaonnuddps2244 (96%) (96%) orareefnsstdphpeetecwtcritoaivvteeeslalyryi.nl,ythOOreennsee0or5(5pVtmmeighog/in/ckk,lgge/a)/d,dnaad1yy, o5ddn,ooes1s0aa1gg0aeenmdgggr/r2ook0uugpp/mdllagiityt/tekergrd/occdsooananysgsieidssottgeserdadoguooefpf ffgliivirvoteeeurlpivcvesoe,nffseeittsuutsseeedssof tatdhihnrsrdetereetiwblluioivtveieeoaffneerttolyuufsstreeehsss.e.odrBpaBtteeioaccn"aas,uu,ssveeaanlssduuueccoshhnfeooorcc1cct0uuhremrrrsegeen/nkdccgeae/ssmdasccyaaanndnodaasbbalnnigotoreerrmmsgaalrwolleluyyrpesskklieetetxwewcrlttcuhhodeeendsisftreodm of doddabiaststtaaerirbssvuuuatmmtiomimnaonraosirfziwztaheatertiioeodnnabtaaaa(snn1edd9d),sStvtoaaanttiliuss2tet4ii,cscaa2fllo3,aar nnt2aha3lel,yyssse2ee4ssd..aanmAAdsss2aaa4nrrdpeersslueiutlgtltetn,,rasCCnatwaeeedssaraemarsreee.axancn-ls-usedecectdtiioofrnnoiinmngg observations were based on 24, 23, 23, 24 and 24 pregnant dams. 10 171206 22778888..00002266 I3MMAAT100008833114444 441188-:001111::PPAAGGEE 1I1I1l-33 FFeettaall bbooddyy wweeiigghhttss ((ttoottaal,l, mmaallee aanndd//oorr ffeemmaallee)) wweerree ssiiggnniiffiiccaannttllyy reduced reduced (<0.05 (p_<0.05 cooorrnppt_<ro<0l0..0g01r1))ouiinnp ttvhhaeelu1!e0s0.aannTddhe2200rmemd/guk/ckgegldtddfaaeyytalddoobssoaadggyeewgegrirooguuhptpsss,,inaassthcceoom1m0ppaaarnreeddd2tt0oomttghh/eekgiday dcdhoioognsshtaareggoreel dgggorrrosoouauupgppessvalwweluveeeerlrssee.. aaTDrrheoeeffslleaerccegttdeiiousonncoeoofdffNbbfe-ootEddatyyl FbwwOoeeSdiiEgyghhawttserriehegiddhguuthcscttaiiionsonnt2hoo0effmtt1hgh0e/ekaddgnaa/dmdm2assy0aamdttigttdh/hkneegoss/teeday hafaofifgrffeehccceottrraapdnnooyyrsaooatltghuheteeerarl,eCCvaeiaemlessps.alaarnDreteaoaantsn-iaos-gsneesec,scttiiolooifnntNieinrn-ggEsitoozFrerOsll,iSitttlEeeirrveappsafarerhtaaiumgmseheteseta,erssres.2a.r0lTTymhhrgeee/sklloigitrtt/epedtrraiaayovnvdsee,irrdaaggneeosst fpopofeerrdrcccaeoemnrnptstorrwreeaisstoholurrbtabeeneaydd, crcimeoosnnpoclcraeepnptpttiatuoutnissoseenssosr,aawnnliitddttehpprevesriricazcbeeelnsnet,t mlivaelefeftuetsuesses,,eaarslywerellsoarspttiohnesn,umbers fmetaulesefsetwuesrees,caosmpwaerlal balsethinetnhuemfibveers odcdofoonssdcaaaeggmpeestgugwsrroieothusupparssensaayonnrrddebesdddoiid,drpanntionootdtnssstiihggoennrriifwefiiciwctaahennrtvtleliyyanbddiolifefffdeefreer..atudNNsfeooestddwuaasmemerssseohhcfaaoddlmatllpeiitattreerearrsssbolrwwepiitttihinhonatahlslll.e five All chppilolsaantccoceereinnpcttataauleelsyeaaaspptpprteeehasaeroreTerbeddsetnndioo,nrragmmnaaFldal.c.tihiAAetlylrll"e.oofwf ttehhreeesseneovvaadleluuaeedss fwweeteurrseeewwsiittohhriinnlatttheheererrasaonnrggpeetissonoosbb.sseeArrvlvleedd historically at the Testing Facilitya. E.Eo FeTFtaebatallleAAl2tl1teerraattiioonnss((SSuummmmarairieess -- TTaabblleess 99 tthhrroouugghh 13;IndividualData: 13; Individual Data - Table 21) FoFecetctaaullr aaallttteelrroaawttiioionnnscsiwwdeeenrrceeedsdeeiffniinnteheidds aasssp::ec11i))esmmaaalnlffdoorrsmmtaraattiiinoo)nn;ssa n((iidrrrre2ev)veevrrassriiibballeteicconhhsaann(ggceeossm that mthoant fofdiinecnvdcdeuiinlrngogapsstmeiilnonnwttth)hi.iisns cssiLpdpieeetcnceirieceseas/sv/ssteitrnrraaatiihgnnei,,ssaaswnnpeddercrreieeevvcseearlrasscniiubdblllaeestteddradeeillnfaao)yyr; ssaspnooerdrciaa2fcc)icccveelafleeertriraaaaltttiioioosonnsnsissf(iiicncnoatmiomnosnites as part of the evaluation of the development). Litter averages as part of the evaluation of the degree of fetal ossification. were calculated for specific degree of fetal ossification. fetal ossification sites dFFeeelttaialvleeervveaadlluuliaavtteiiofonentssuwwseeesrreeinbb2aa4ss,ee2dd3,oonn2433,44222,5,33a44n99d,, 23344477.l,it33e55rs44 iaannntddhe3302266(VDDehGGic22l00e),CCaa1e,ess5a,arr1ee0aann-- dagarnenoddlisvs22e00reexm mdtgeglfri/vknkeaggl//fdedaaatlutyyesrdedaosotissionaanggs2.ee4,ggOrr2foo3uut,pphs2se,4,s,err2eer5sseppseaepcntecdictvitve2iel4vylye.l.iftteeEEtraauscsciehhnsffteh1e6tteu6u,ss0 w(Vaseheicxlea)m,i1n,e5d, w16a7s,e1x6a9m, i1n7e0d f1o0r afonrd g1r5o8swseerxeteerxnaaml ianlteedraftioornsso.ft w1e5r8eweexraemeixnaemd infoerdskfoelrestoalft Oattliifststsehsurueaeetsieaaollnttreseerrsaaapnttieidoocnnftsisevteaaalnnfedodstus11is77fe66i,sc, a11t1i686o226n,,, s111i77t68e87,,,av111e886r449a,gaae1nns7dd.0 168and 168 were examined for skeletal alterations and fetal ossification site averages. EEA.1.. SSTuaumbmlmema2ra1ryyooffFFeettaallAAltlteerraattiioonnss((SSuummmmaarryy--TTaabbllee99;;IInnddiivviidduuaallDDaattaa-Table 21) In the five Innutmhbeefriveed respective r6es(p25e.c0ti%v)e. dosage groups, liters d8os(3a4g.e8%g)r,ou4p(s1, 6l.it7te%r)s. ww7iit(hh28ffe.ett0uu%ss)eessanwwdiitth8h (aa3llt3te.err3aa%tt)iio.onnssThpprereesseenntt 6nnnuuu(mmm1b.bb7eee%rrr)ses,doo8ff6(ffe2(e2t.tu52us.%s0ee)%ssa)wwn,iidtt8hh1(3aa2n4n(y.y83.% aa7lltt%)e,e)rr,4aatta(iio1non6dn .7oot% bhbess)ee,prre7vvree(cdd2e8nww.t0eea% rrgeee) s11a55nofd((4f48e..4t4(%u%3s)3),e,.s311%w00i)t.((h22..Ta99hn%%ey)),, alteration 6 (1.7%), alteration were 4 4%, 2.8%, 1.6%, 8 (2.2%) and 12 (3.7%), were 4.4%, 2.8%, 1.6%, 2.1% and 4.0%, in these same and the percentages of fetuses 2.1% and 4.0%, in these same respective with any respective ddoossaaggee ggrroouuppss.. a See APPENDIX G (HISTORICAL CONTROL DATA) See APPENDIX G (HISTORICAL CONTROL DATA). 10471207 10 1"/1207 2277888..00002277 MAT0083145 3MA10083145 441188--001111::PPAAGGEE l1l1l1--44 RReevveerrssiibbllee ddeellaayyss iinn ffeettaall oossssiififciactiaotni(2on'2?1") aassssoocciiaatteedd wwiitthh tthhee ssiiggnniiffiiccaannttllyy rreedduucceedd ((pp<<00..0055 oorr pp<<00..0011)) ffeettaall bbooddyy wweeiigghhttss iinn tthhee 1100 aanndd 2200 mmgg//kkgg/lddaayy dosage groups, were evident as significant reductions (p<0.05) in he ler dosage groups, were evident as significant reductions (p<0.05) in the litter averages for ossified caudal vertebrae in the 10 and 20 mglkglday dosage averages for ossified caudal vertebrae in the 10 and 20 mg/kg/day dosage groups and a significant increase (p:0.05) in the fetal incidence of wavy ribs in groups and a significant increase (p<_0.05) in the fetal incidence of wavy ribs in he 20 mg/kgday dosage group. the 20 mg/kg/day dosage group. Al other fetal gross external, sof tissue and skeletal alterations (malformations All other fetal gross external, soft tissue and skeletal alterations (malformations `and variations) were considered unrelated to the test aticle because: 1) the and variations) were considered unrelated to the test article because: 1) the iinncciiddeenncceess wweerree nnoott ddoossaaggee--ddeeppeennddeenntt;; aanndd/loorr 22)) tthhee iinncciiddeenncceess wweerree wwiitthhiinn ranges observed historically at the Testing Faciity. ranges observed historically at the Testing Facility. E2.2.. FDFoaetttaalal -GGTarbrleoossss EE2x1xtteerrnnaall Alterations Alterations (Summary (Summary - - Table Table 10; 10; Individual Individual Data - Table 21) EE..22..aa.. MMaallffoorrmmaattiioonnss O{Oaninlee S11u00bm msgeglq/kkuggel/nddtaayyskddelooesstaaaggleeexggarrmooiuunppatffeeittouunsso((f11t22h86i8s855f--e11t55u)s) hrheaavddeaaalseshdhootrrhttatttrruounnnlkkyaafnnodduraabbsseenntt tccoaereirlr.cvviaiccSuaadullablvvseeverreqttreuelbbeorrbnaarteeascwwk,eeeorlrereetafppilbrrseee.xssaeeTnmnhttiinsaaannftddeiotttnuhhsaaotatfltttshhhoeiesrrheefaedwwtueeasrreevraernnviooeatattihhleooonrdraaictcnhiicacp,e,tlollvuuinmcmlybboasfarosr,iu,frssiacacactrriaaolln or caudal vertebrae, or ribs. This fetus also had a variation in pelvic ossification ((tthhee ppuubbeess wweerree nnoott oossssififiieedd).). EE..22.bb.. VVaarriiaattiioonnss NNoo ggrroossss eexxtteerrnnaal vvaarriiaattiioonnss occurred occurred in in the the fetuses fetuses in in tis this study. study. 3. Fetal Soft Tissue Alterations (Summary - Table 11; Individual Data E.3. TFaebtalleS2o1ft Tissue Alterations (Summary - Table 11; Individual Data - Table 21) .3.a. Malformations E.3.a. Malformations NNoo ffeettaall mmaallffoorrmmaattiioonnss wweerree iiddeennttiiffiieedd aatt vviisscceerraall eexxaammininataitioonn.. . EE:.33.bb.. VVaarriiaattiioonnss Eb. E.3.b.1. VVeesssseellss TdThohrsreeaeegeccoognnrttorrouolpl ggfrraootuuupsp (ffe1ett2uu8ss3ee4ss1((411)2288a00n11d--11t00w;o; 11522m881y10/0-k-11g0i0;d; a11y226d82o21s1-a-66g)),e, oognnreeou11pmmiatgfe/kkrggmla/ddtaaeyys dosage group fetus (12834-14) and two 5 mg/kg/day dosage group littermates 10 171208 22778888..00002288 MAT0083146 3MA10083146 441188--001111P.PAAGGEE l11I1-55 (12860-5, -9) had the umbilical artery descending to the left of the bladder. T(1h2e8s6e0-f5e,tu-s9e)shahdadthneo uemxtbeirlincaall fairntediryngdseasncdenndoinogthteortshoeftleifstsoufethaeltebrlaatdidonesr.. These fetuses had no external findings and no other soft tissue alterations. TiTnwwnooom11inmmaggt/elkkggar//tddeaaryyy. ddooNssoaaggaededggirirooounupaplffeaelttutusesreeassti((o11n22s88o22c66c--u11r22r;;ed1122i88n 33t77h-e-9s))ehhfaaeddtusaaenns.aabbsseenntt innominate artery. No additional alterations occurred in these fetuses. EE3.3b.b2.2.. LLuunnggss OO1 nnmeeafcckoognnlttrdrooallyggdrrooosuuappgffeeettguursso(u(11p228f8e22t22u--s44)()1hh2aa8dd50aa-nn16aa)bbshseaendnttaaanppiiaccbaasllellnuutnnggdilloaobpbehe,r, aaagnnmddatooinnceelung l1obme.g/kNgo/daadydidioosnaaglealgtreoruaptifoentsuosc(c1u2r8r5ed0-i1n6t)hheasde faentuasbess.ent diaphragmatic lung lobe. No additional alterations occurred in these fetuses. EE..33..bb..33.. KKiiddnneeyyss gTTrwwoooupccoofnnetttrruoosll (gg1rr2oo8uu7pp7-ffe1et4tuu)ssehesasd((11s22li88g00h22t--o11r11;m; o11d22e88r00a33t--e22))diaalnnadtdiooonnnoeeft11h00emmpgge/llkkvgigs/lddoaafyyoddnooessoaarggee gbboocrootcthuhurpkkriifededdnntueeiysynsst(,,1ha2eas8rre7ee7vvf-eee1rtrus4ssii)ebbslhle.eadddeesvvleiegllhootppom mreenmnttoaaldleddreealalteya12yd2.il}a. tioNNnoo additional alterations of the pelvis of one or additional alterations occurred in these fetuses. E4.4.. DFFateaettaall -SSkTekleateabllleetalA2lA1 teltreartaiotinosns (Summaries (Summaries - - Tables 12and13; 12 and 13; Individual Individual Data - Table 21) EE..44..aa.. MMaallffoorrmmaattiioonnss EcEexxrttveeirrcnnaaalllllvyyermmtaaelblffrooarremmaeenddd11n00ommtggh/o/kkrgagc/liddcaa.yyldduoombssaaargg,eesggarrcorouaulpp offreettcuuassud11a22l88v88e55r--t11e55brhhaaaedd ooofnnlilyybsff,oouuasrr. cwweeelrllvl iaacsaslaavevvaarrtreiiaabttriiaooenn ainndpelnvoicthoosrsaicfiicc,atliuomnb(anor,t soasscirafileodrpcuabeusd)a,l in pelvic ossification (not ossified pubes), as previously vertebrae or ribs, as previously as ddeessccrriibbeedd.. EE.b4..b. VVaarriiaattiioonnss Eab1. Skul E.4.b.l. Skull AA llaarrggee nnaassaal-l-ffrroonnttaall ssuuttuurree ooccccuurrrreedd iinn oonnee 10 10 mglkg/day mg/kg/day dosage dosage group group fetus fetus ((1122889933--1133).). NNoo aaddddiittiioonnaall aalltteerraattiioonnss ooccccuurrrreedd iinn tthhiiss ffeettuuss.. EE.44b.b2.2.. RRiibbss A cervical fb at the 7th cervical vertebra, a common variation in this stain of A00rrfaaet((tctVVu~e2ees,3rh>veh,isiiococcachlclecleac)u)udr,rirb1rr1ne.,eaodd55t.o,tiihnne11e0000r,,7aat33ennh,,xddtc11e,22e,r00r33nvaimmaalcgnnagolddlr/kkvg44sgelklrffeddteeleaattebuyytursasaddlee,oossassalffaatrcreoggroomeeammtgigm00orr,,nooosu22u.n,p,pssv,11,,,ar3r3rieeaasastpinnpoeddecntc44itinivvleliietlthttylteyi.esr.rsssTTiitnrnhhaeettihnhsseeeeof fetuses had no other external or skeletal alterations. 10 171209 22778888..00002299 MAI008314T 3MA10083147 441188--001111:PPAAGGEE 6II I-6 WWaavvyy rriibbss,, aa rreevveerrssiibbllee ddeellaayy iinn oossssiifficiactaiotni~on21"~,, oocccuurrrreedd iinn oonnee 11 mmgg//kkgg//ddaayy d(d1oo2ss6aa0gg4ee-1gg,rroo1uu2pp90ff9ee-tt5uu,ss 7((1,122-8814408,8--1-1)1)2,aann1dd21sse9evv-ee3nn, ((-pp9_)<.<00.O.005n5))e222000mmmgggk/lkgkglg//dddaaayyyggdrrooosuuappgffeeettguurssoeeussp fft(e1ehtt2euu9sfs0et4((a11-l122;8i9n001c992i--9d77e0))n9aac-le5lsos,oof-7hhw,aaad-dv10yiin,ncrc-ioo1bmm2sp;piln1leet2ttee9hlel1yy92-oo03sss,smi-igff9i/ie)ek.ddgiOrriidbnbasse.y. 2dTT0ohhsmeeagssgi/iekgggnngi/irfdfiiocacuayapnndttwoiiansnsaccrgreeeaasgseeroiiunnp tchoensfiedtaelreindciadetnrecaetmoefnwtarevlyatriebds dinevtheelo2p0memntga/klgd/dealayy,doassasgoceiagtroedupwiwthasthe sciognnisfidicearnetdlyaretrdeuactmede(npt-<r0e.la0t5edordpe<v0e.0lo1p)mfeetnaltabl oddeylawye,iagshstosciian ttehdswdiothsathgee group. significantly reduced (p_<0.05 or p_<0.01) fetal body weights in this dosage group. EE4.4b..b3.3.. SStteerrnnuumm Delayed sternal ossification (incompletely ossified or not ossified 1st stemebra) o0oDcce(ccVluaueryrhrrieeecddldes)iintn.e7r71n.,.a225l,",*o,1s0s11i"fa*i,c,nad11t"i2o*0anannm(didon/c11ko"g*m/ffdpeealtetyuutsesdeeloysssofafrsrgosoemimf3ige3,rd,ou22o,p,rs11n,,,or11teosaapsnnesddcitfii11evdellilttty1e.rsrstssOiitnfnertttnhhheeeebsrea) aff0eedttd(uuVissteeeishos.inc, lotoeonn),eae1ncc,oou5nnn,totrr1soos0llifagginrreododuu2pp10sffteemttsuugtsse/kr((ng11a/2l2d88ac00ye22n-d-t11or))suamhh.gaaedd incompletely ossified groups, respectively. incompletely ossified pubes in Of these pubes in addition to an unossified 1st sternal centrum. EE..4a.bb..a4.. PPeellvviiss TT0hhfeeetiiusssccehhsiiaafaarnondmd//o1o,rr 0pp,uu1bb,ee2ss awwneedrree0 iitnneccorommspplilenettteehlleyy of not ossified in 0or(Vneohit colses),ifie1,d 5i,n 3, 130, 0,2, a0,nd2, 2 2 and and 022(100f2emm 8tua0g2hs/-kek1gsg)//fddraaoanyymdddo1oon,sse0aa,gg11ee0, ggm2rroooakuungppdsls,0d, arrlieeyttssepdperoescstciiatnvivgetelehyley.g.r0oOO(uVnnpeeefheffietceutlteusu)ss,(1ii1nn2,8tt5h8h,e5e-1cc10oo5nan)tntrrhdooalldggrraooduduipptional s(1ke2l8e0t2al-1a)ltaenrdatioonnes, 1a0s mprge/vkigo/udsalyy ddeosscargiebedg.roup fetus (12885-15) had additional skeletal alterations, as previously described. EE..44.bb..55.. Fetal Ossification Site Ave Fetal Ossification Site Averages TTrehhdeeuclliitettdeerr(aa2vv0ee.rr0aa5gg)eessinffootrrheooss1ss0iiffiaieendddcc2aa0uuddmaagll/vvkeegrrittdeeabbyrraadeeosppeaergr effeogtturuossuwwpsee.rreeTsshiigegnnsiieffiicdcaaennlttallyyys in wccreiaatduuhuddactalehl devvese(riprgtt_ene<ibb0frri.aa0cl5lan)ootssilnssyiitffrhiiceecadattu1iioc0oennadnww(dee<rr2e0e0.cc0moo5nngsso/ikirddgpee/=drre0ea.ddy0ee1df)foffesefccaetttgsasel oobgfforttodhhuyeepwttseee.ssittgThaahrtreitsisccilelneedtaahesselsssaeooy.ccsiiaaintteedd dosage with the dosage groups. significantly groups. reduced (p_<0.05 or p_<0.01) fetal body weights in these AArnenvaaellayylsseeassnyoofof ttthhheeeraasvvteaetrriaasgtgieecannlluuymmsbbiegernrissfioocffanffetettdaaillfoofsessrsieiffniicccaeasttiioaonnmossiinttegesstppheeerrfffieevtteuudssoddsiaiddgenn:oott Sggrearrcoovrueuapapls)ls.,.anrOOiybsssso.istfihsfiitecceraarttsiinotoaunnmtisoo(ftfimcttahahneleluybhhysryoiiogiuidndm,i,f,ivcvseeatrrntteteeadbblrirfafaeeceree((nccnteecerrrevvsisiccaaaalnlm,,dotthhxnooigrpraahtcohciiieccd,),f,illvufuemomrdbbeoaalsriramaabgnnsedd (ps(ccahaaacrrlrpapaaaln)ll,gs,e,risbmm)ese,totascactcceauarrrrnprpuaeamldlssa(taamnnsaddinmppuihhbaaarrilluaiamnnncgg,ieesdsste)e)nrcaanennasddl ichhneiinlnnidtdtelleirmrissmbbaissnnd(a(lttalaxrrdispsoaahlslossa,i,dgmm)e,eetgfoatratoretuaaplrirsmss.aabllsssAlaanndd vVpaahllauuleaessngwweeesrr)eeowwcicittuhhirinrnettdhheeatrrasaninmggieelassr ooinbbcssieedrrevvneecddeshhiissinttoorlriititcceaarllsllyyinaattattlhlhedeoTTseeassgttieinngggrFoFauacpicisilti.tyy..All = Signficanty arent fom the venice contol group es oon. 10 1171210 Significantly different from the vehicle control group (p< 0.01). 2277888..00003300 MAT0083143 3MA10083148 441188--001111P:PAAGGEE I11I1l-77 RREEFFEERREENNCCEESS 1. UUS..S FFoooodd aanndd Harmonisation; DDGruruuiggdeAAldidmnmieniinosinsttrdraaetttiieoocnnti((o11n8999o4f4).)t.oxiIIncnittteeyrrnntaaottiriooennpaarlol dCCuocontnfifeoenrreefnnoccree on on NmHmoea.edrdimc1ici8oinn3naailslapptrirooodndu;uccGtstsu..ideFFleeinddeeerroaanll Rdeegtiesctteior,n Register, Soef ptotxeimcbityerto22r,ep1r9o0d4u,cVtiooln. September 22, 1994, Vol. f5o9r, 59, No. 183. 2. UURSe.SSg.u. lFFaotoioooddnsaa;nnddFinDDarrluuggRuAlAedd.mmin2iin1sitsrCtarFatitRioonnP.a. rtGGo5o8oo.dd Laboratory Laboratory Practice Practice Regulations; Final Rule. 21 CFR Part 58. 3. JJPraaappcaatnnieecesseeStMMainninidissattrrrdyy foooffrHHSeeaafalelttthhyaaSnntddudWWieeelsflfoaanrreeDr((11u99g8s86.8).)P. haGGroomooaddceLLuaatbbiocoraraalttooArfrfyyairs Bureau, Practice Bureau, April 1, 1983, amended October 5, 1988. Standard for Safety Studies on Drugs, Pharmaceutical April 1, 1983, amended October 5, 1988. Affairs 4. EE1u9ur8roo9ppoeenaannthEEeccaoocnncooemmpiticcanCCcooemmbmmyunutinhteityyEu((11r99o88p99e))a..nCCEoocuuonnnccioliml iddececciCissoiioonmn moonnu22n88oiJJfutuallyyyn lOO1a9EEb8oCC9rDDaotnoddreetychcipeisrsiaaiococntnci/crveeerp.cetoacmnoOfmcm fmeiecebinnaydldataJthotieiuoornEnnuaoolrnnoopccfeootammhpnepllEiEiaacunnorccnoeeopm ewwaiiitctnhhCCpporormiimnmnccumiinppuillteneisistoeyosfo:fgfgoaoonodd Legislation. 32(No. laboratory practice. Legislation. 32(No. L 315; 28 October): 1-17. Official Journal of the European L 315; 28 October): 1-17. Communities: 5. CCMhuhitrsaistgtieiaannni,c, iMMt.y.SS.T.esaatnnsd.d VVoEoynytvteiekrk,o, nPPm..eEE.n.ta((11l998P82r2)o.)t.ecIItnnioVVniivvAoogeRRneecppryro,oddWuuaccstthiivivenegaatnnoddn, D.C. MNSNpaarutititinaooggnnfiaeaelnlldiTTc.eeitccyVhhnATnieiccs2aatl2sl1.II6nnE1ffonorrvmmiraaottniioomnneSSneterarvlviiPcceero,,teUU.c.SSt.io. nDDeAeppgaaerrnttcmmyee,nnWtt ooafsf hCCionomgmmtomenre,crcDee,.,C. Springfield, VA 22161. 6. nCChahrlirtissrtteiiaxaonn,n,eMM(..PSSr..o((c11e99e88d44)i.)n.gsRReoefpprNrooadldutucrctetiixvvoeenettooSxxiyiccmiittpyyoaasnniddumtt,eerraNatteoowlloogYgyoyreekvvaAallcuuaaatdtiieoonmnssy ooff onfalStcreiexnocnees,(PNroocveeemdbiengrs7.of19N8a3)lt,reJx. onClein.SyPmsypcohisaiutm. 4, 5N(9e)w.7Y-o1r0k Academy of Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10. 7. LLCaoannngtg,r,olPP..DLL.a.t((a1199i88n88)t.)h.e Embryo EChmabriryeos aRainnvddeFrFeeCttraaill :DDCeeDvv7eeBllooRppRmmaete.nnttaCalhl aTTroolxxeiiscciittRyyiv((eTTreerraattoollooggyy)) ALCLaraobgbnouortsraroatRlotoreDirsiaeeestsaa,,ricnIInnhcct.h.L.,eaW WbCioirmhlmaiatnrionlgergtisteoosRnn,,i,vIMMencrAA.C) d00:11C88D887T7-B-00R66330R0.a.t. ((DDCaahttaaarlbbeaassseRe ippvreroorvviiddeedd by by Argus Research Laboratories, Inc.) 8 IIUnnssstetiittouuftteeLaoobffoLLraaabbtooorrraayttooArnryyimAAannlisimm.aalNl aRRteiesosonoauulrrccAeecssad((11e99m996y6).)P.reGGsusui,iddWeeaffsoohrrittnhhgeetoCCnaa,rreeD.aaCnn.dd Use of Laboratory Animals. National Academy Press, Washington, D.C. 9 SS\amalplelewawsnktsiak,ti,ioEE.n.ss((11t9e96l64l4)e.)n. aFFma~UrrtbbeeermmueesttdhheoorddeeRazztuutmme.mmaAarkckrhro.osskPkaootpphioisls.cchheEexnnp.NNaaPcchhhawwremeiaisskovyloonn 247:367 Implantationsstellen am Uterus der Ratte. Arch. Pathol. Exp. Pharmakol. 247:367. 10 171211 22778888..00003311 I3MMAAT100008833114499 441188--001111::PPAAGGEE I1l1l1--88 1100.. WWiillssoonn,, JJ..GG.. ((11996655).). MMeetthhooddss ffoorr aaddmmininiisstteerriinngg aaggeennttss aanndd ddeetteeccttiinngg mmTaealclfhfoonrrimmqauatetiisoo,nnssWiilinnsoeenxx,ppeeJr.riGim.meenantntadallWaaannriikmmaaalnslys... JTT.e(ereradastt.oo)l,looggUyyn::ivPPerrrisinnictciyippollefessChaainncddago PPTrreeecssshs.n,iqppupp.e. s22,66W22--2i2ls777o7.n., J.G. and Warkany, J.(eds.), University of Chicago 1111.. tSStetaacphplnleeissq,,ueRRE.iE.n.thaaennddKOSSHcc-hhanlneilezllla,,rVVi.n.LL.re((d1199$6644m).)e.thRRoeedffiinfnoeermmfeeetnnatlt iibnnonrraaepp.iiddScctilaeeiaanrriiTnneggchnol 3t3e99c6:h61n1-i-q66u33e. in the KOH-alizarin red S method for fetal bone. Stain Technol. 1122.. Snedecor, GW. and Cochran, W.G. (1967). Variance test for Shonmeodgeecnoer,itGy.Wof. tahnedbiCnoocmhiaralnd,isWtr.iGbu.ti(o1n9.67S)t.atVisatriicaanlcMeettehsotdsfo,r 6th Edition, hlIooowwmaaoSSgtetaantteeeitUUynniovivfeetrhrsseiittbyyinPPorreemssissa,,l Ames, pp. 240-241 distribution. Statistical Ames, pp. 240-241. Methods, 6th Edition, 1133.. Sokal, RR. and Rohlf, F.J. (1969). Bartlett'stest of homogeneity of vSaorkiaanl,ceRs..R. BainodmetRroyh,lf,W.FH.J.. F(1r9e6e9m).anBaanrtdleCtto's.,teSsatnofFrhaonmciosgceo,neity of pp. 370-371 variances. Biometry, pp. 370-371. W.H. Freeman and Co., San Francisco, 1144.. SSnneeddeeccoorr,, GGW.W.. aanndd CCoocchhrraann,, WW..GG.. ((11996677).). AAnnaallyyssiissooffVVaarriiaannccee.. Statistical Methods, 6th Edition, lowa State University Press, Ames, pp. 258-275. Statistical Methods, pp. 258-275. 6th Edition, Iowa State University Press, Ames, 1155.. DsDeuuvnnennreatelttt,,irCCeW.aW.tm. e((n11t99s55w55)i.)t.h aAAmcmuolnuttlritiopplll.ee ccJ.oommApmpaearrri.issooSnntatpp.rrooAccseesdodcuu.rree for comparing 5f0o:r1c0o9m6-p1a12ri8n.g several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1129. 1166.. SoWS.koHak.la,l,FRrRRe.R.e.maaannnddanRRodohihCflo,f,.F,F..SJJ.a. n((11F996r69a9)n.)c.isKKcroruu,sskpkpaa.lI--3WW8a8al-lil3iss80TT.eesst.t. BBiioommeetrtryy,, W.H. Freeman and Co., San Francisco, pp. 388-389. 1177.. `DDTuuenncnnh,,noO0m..eJJ.t.r(i(11c99s66464)().3.):MM2u4ul1li-ti2pp5ll2ee.ccoommppaarriissoonnss uussiinngg rraannkk ssuummss.. Technometrics 6(3):241-252. 1188.. SSMicieeGggreaelwl,,-HSS.i.l((l11,9955N66)e.)w. YNNooornknp,paarppra.amme9t6er-tri1i0cc4SS.ttaattiissttiiccssfofor rtthhee Behavioral Behavioral Sciences, Sciences, McGraw-Hill, New York, pp. 96-104. 1199.. Z`Zaaanmm dbbprlraaacmmeana,t,aMMlAw.A.e.igaahnntddofGGvrraeereeinnowwuaasllddn,, GGuS.S.m. o((11fb99f77e11te).u).sreEEsffffeiencctttsshoeoffrfafete.ttaallBiooolvv.aaroriifaann Reprod. 4:216-223. and placental weight Reprod. 4:216-223. of various number of fetuses in the rat. Biol. of 2200.. CCMo.olWlll.iin,nss,,Jr.TT..(FF1..9XX.8.,7,)WW.eelPlsoshth,e,ntJJ.i.JJa..l,, rBBellvaaeccrkski,,biTTl..iNNt.y..,oWWfhshiktietbblyye.t,aKKl..EeE.f.feaacnntdds OOin''DDroaontnsnneeelxl.lp,osed iMn.uWte.,roJrt. o(1ca9f8f7ei)n.e.PoFtde.ntCiahlerme.veTrsoxibicil.ity25o(f9s)ke64le7t-a6l 6e2ffects in rats exposed in utero to caffeine. Fd. Chem. Toxic. 25(9):647-662. 2211.. NNDrisiuhgsi-mihundriau,cmMeM,du.,,l"rilWizzaauuvkky,aa,,RMMi.b.,s, "IIwwianakkRii,a,tS..OfaafnnspddriKKngaa.sstt,AAA,r..zn((1e19i98m82.2)-.)F. orRRseecpphaa.i/irrDarabubilgiitylRoteosyff. 321), Nr. 12., Drug-induced 32(11), Nr. 12., pp. 1518-1522. "Wavy Ribs" in Rat pp. 1518-1522. Offspring. Arzneim.-Forsch./Drug Res. 10 171212 2277888..00003322 33MMAA1100008833115500 441188--001111::PPAAGGEE 1ll1l1--9 2222.. WWoooo,, DD.. aanndd HHooaar,r, RR.. ((11997722).). Aspect of Renal Development "i"nAApLppapataerreeGnnettstHHayytddirrooonnneoepfphRhrarotosss:iiss""Tahasse aaEfNNfoeocrrtmmaoafll AMMesetpthheyycllt SSoafalilRiccyeylnlaaattele.D. eTTveeerrlaaottpoomllooeggnyyt 66in::11L991a1-t-e1199G66.e.station of Rats: The Effect of 2233.. KKhheerraa,, KK..SS.. significance: ((11a9988r1e1)v).i. ewCC.oommFmumnodo.nn ffaeenttdaall aberrations and their teratologic: Aapbple.rraTotixoicnosl.an1d:1t3h-e18ir.teratologic significance: a review. Fund. and Appl. Toxicol. 113-18. 2277888..00003333 10 171213 33MMAA1100008833115511 AAPPPPEENNDDIIXX AA RREEPPOORRTT FFIIGGUURREE 2277888..00003344 1100 117711221144 amAtoc83ts2 3MA10083152 441188--001111::PPAAGGEE AA--11 Jalddd od 2 s 41 11To8 &un rr ee--_--t ee vee ee =2 FR a ae " . LN : eEo ACNeA = "r" ne x : g >a ee * Le x: :5 3 woe = OF =< \ Rex 32 gz ep 3 2 we x . = Mw - nes . Eo. . +08 Fx & 8 8 & 1% 8 22778888..00003355 amAtooss1ss 3MA10083153 AAPPPPEENNDDIIXX BB RREEPPOORRTT TTAABBLLEESS 2277888..00003366 1100 117711221166 33MMAA1100008833115544 :i rarBoa arena d: Eo ia: : PT fol Sst : if &: g emme oo ob53 3 sig gave 5 5 sid i fad E3 BiEg EHE id fi i;3 3 TETgBmh 5 EE S aiigg gigdg- ii : Figg i:f gE ;faiield 1Tyi.poooilBEEgiiZ,zrgpi8of fi 08iE jie BpiRiEahE e Zi3%ER ig. 441188--001111::PPAAGGEE BB--11 =~ =o~NN = 22778888..00003377 swatoossiss 3MA10083155 : EERE : f oissis--ne : i i 8 g IfFE,E : 5: i8 : :} iF iis iT,i0a3re ;foGgif ME HH RHETo bgrroa miiiElei!. 22778888..00003388 441188--001111::PPAAGGEE BB--22 =4S&==] 2 swatoossiss 3MA10083156 Riazor 441188--001111P:PAAGGEE BB--33 =Nn didif3disiiii:zsi =~ poarorrirll = u | EAE EES LEEELE! : Piiiiiiiiii om fyi. PpoE 0, EL, iE ee eee. SE GEissezrical HIE amor nasa silgdd i sf LL. 3IiEiRiRiRiRiEzEoaRiEaINHgiltls i ii gy ig EHE aEnNk 1,08 i EaiiiEE PIz yhpgidrilafefsesseaoasos+oezssozse2eii8a8r0n33s3ndd [ERIoo RE RE] iETadiuet 22778888..00003399 swaro0m157 3MA10083157 441188--001111P:APAGGEE BB4-4. o : 111113i18 oNo~N i Fiscs = iii = 5 i4 LI i PE cronoe zl iii +1 +1 1 iin 1 l 1 i Ioqmmmaas Sano. ME 22g Doo opp ELL i g 4 cEeoma 1% LL... EEEERIE: pon Ral ais ii FREER an 3Plo. es2 Hsaiad ip i gE di pTfCDsoosossEhReeE f3L2RGBCEezczoszonila[i:iFigEE fF BEiEERE Eiger ~ 227788881.00004400 amAtooss1se 3MA10083158 Pris zx 441188-0-1011"P1A:GPEABBG--E55 . T II PEE E siR ze ~ = poroororroil 2 Se rortrisoE: ~ bot iii ig + 2 ! 2d tB1Eddsaazma2n3a2n:d8 H [EREREEEREE | iPosmiras HA i P 2 5. LSe.r g rrerrnIe Irria iAirian EEREERE E LoLrIrLoIrLoLiAiLrLdL 3333355 sz3g goy mEE a IiH BEgEl sig HoHf 133333 iia p$Hi ii EfiEd REREi ERiE d iRdINdi TnIgLT if LE 2 Bgsaaiis giraaail PgBg grTrrrranAnG a E bPEyRoHw gEEpErEi iEiRhL peasi dii iai siiesaf2Eiaineiie inng: O0 22778888..00004411 swatoossiss 3MA10083159 HE Paii n ax 441188-0-1011:P1A:GPEABBG--6E6 Spiiiiiiii s IpErEoEoRoEaErEwErwRnEwg]w - p= -~ aga TTT em BaLuanal ra iasii iia g} g! 13333333233 1 PRERREEEREE 4h $F osiras Dorrraliiii oes EF, Bid E$gffg:ovina i: :3 ii:z TCT einaseaen EREER EERE HEE 1 CFEiAiRiAiEiEciEiEaRgE Eroooorooony +1~ +l +1 +1 1 +1 1 +~ +1 1 +t i si uag Doping HERE-E EE-E HTEF- T F PEii IiEiERii EiRiGiE Gounlaens ERE PE ciazaazaae fein DPEispde s2d80.-comaaos sLoiSaekipnsfl fEyRpiEliEf]eesaiiniais Epiiriaans 22778888..00004422 swAtoossiso 3MA10083160 : _ 441188-0-1011:P1A:GPEABBG--E77 pLiihiriiiiiiiiiaaiidi oI=N EE+1 ~ +1 1 +1 1 +1 1 1 ~ t e f ingingd Gum Baamuman ii Pig di iE ong i $3lemimaa PrIIIIEIIE Dror qm oan st Piidaifiiii dn FEREeE iEIlEL E ,IHELELRLELELEIELLL EnHHtT gi LL. 3333iiiiia gfiiim ii 883883333% frais i% Pa . FfoiRaiEil Proali, SL ENE L REElLoLii liiiiiii oiicoa idni gp i.d PFrogEHrEiilegHrEiEIERERRrAIeNeLE 22778888..00004433 swatoossist 3MA10083161 : : i 441188-0-1011:P1A:GPEABBG--E88 Cee ee 23 sass = 333% 33 : 23% = 2 i 3 EE Prii yg Pyeind osazroaeparci ZiDR PEE. pioERr 8% i 2 TIT ZOE sai seoRi tld Dt i 553 Sis3 Ss. sai Bo. a Eypg bg F HEElE RlRe BEsHii8zilEg elggfeyFEEiD3Ligiiidnils: f, rpeEidegsfiifaigfiEof 3rTpd BGaRdiRilNE oo 22778888..00004444 aniossiez 3MA10083162 441188-.0-1011:P1A:GPEABBG--E98 Lae BEE. wN=n i TTR pire = : H i E i FE, 22 : orp tba 19523 D373 8%: ifr oior ii co Tot i i TEos Elsm Ioi piga oo oa res FRET, cin LEE jes EEToor Si ir LL. PCF igi 188 sn fia j5E0 a fg giitH fgRE EEe Pre$Fiogfo2 sBiRnEInL E B oflsaaigiBfE fFaEnEdEg defindiss oo 227788881.00004455 stone 3MA10083163 sos t. ~ FoERL 2DOsCtS f: oseieHI mn oC & i elP Eg oofg o.% o z ooo . E s Prod pti FETs Is 3 38 : gi5 i,ERIBSE f Et E SE osigl Ei 1; pal 33 BBooRREEEE EEj EERf 22778888..00004466 441188.--001111::PPAAGGEEBB--1100 oo=LTMNd o=] swatoossiss 3MA10083164 : o o 4411884-301111::PPAAGGEE BB--1111 = o~ =~} | IEREIL: tT { won H o o o o Es, JEL 0 Gis El 2 0 i =3 if fez ozzid De Bigg BEE: DpH gti MERE Hi i iE FO 227788881.00004477 stares 3MA10083165 441188--001111::PPAAGGEE BB--1122 i: .i o8R[~ oEmoampiocc cece 0 0f i I| fF ieigg 2B OH OBE : ! I LpEa nnn i i PEE mom omomom ond hhpgrrrersy i : ie = 2:: =x ii23222 z22z B32E2E o23E 3a33 DieipEifl iips FAT iE t dTyTTfd HT iPI oolgiiag d 3I8EsR l 8I 2REsD n5G8EsD m i4g8nEg H@iE] oiPEiEM Goodin oR RCE GE GEEo 227788881.00004488 f-- 3MA10083166 Nn & 441188-001111::PPAAGGEEBB--1133 &F ==eSS i I pmuuzmmnmaas 0 oo ~o oo oo oo oo oo oo PLL marnmomononononn oo 308 Le ood oT ON ON ONE Ppia elC ma omoT minmanm T oun gm f8 ua: E fof of oE go: fC i Los, mamma Gib Jb Dpi goaBrEdaECgp HtEEEeRRE r oEREhr ERhE hErR BoENhE r BrTM Re BrOE RBCH 22778888..00004499 -- 3MA10083167 441188--001111::PPAAGGEE BB--1144 : 8K= | ss oss ss ss 3: as oss aoe= SS SS SS oo ~ ....... naar 33 BOB OHO OB ONT POTTED DS i somo ow ss ss ss 33 33 33 33 33) oo oo oo oo oo oo oo oo oo oo oo oo oo oo H HE HE FUE as ss ss ss oss oss F~ EoHIE Hit EA ifs I EJgH: ee smz m32 m822 zmz onzz zozu ii Prog 5i EBofl pig ifHsToE g SEE kf GEE GHD ETR TRE SggolanERBE BEEaElDIlE iBnEBthEs 3x (BRiiieiiid [IERIE 11 a CEE A CEE A ORR CER A CEE oss as 3 zHz Egzz f f RBEEED BGEED oOCeLmE fCiEaD 22778888..00005500 swatonss1ss 3MA10083168 : em DT 441188--001111::PPAAGGEEBB--1155 5-oSNN DDI L aS : i : Bo BBR OBRNE il i sims af sg cBazp An tooo 1iz L5h5 ss oss sss vl as wl oss ssiigg toonote ot BE zz 5fz oz HdR az 143i oJaE~ oRiBgEEy1Ei1gRgtigCHrELieEE hESF EI SE aapEhnhrER SF ROIF BOF gmponE 22778888..00005511 sssonss 3MA10083169 FTE ti Poommaml DT ogem2e.eszd ozmg mri gn 441188--001111:P:PAAGGEE BB--1166 ~ 3333 sty: WoNo tt EB oun oun oe Poem oamommomn gogminooononnos bro, oo om amen is {4 smssoss gaz sass ssssl DEOSTISEE OGD HEooo ai ang PFog Lxo o MszT133z wsawz teaeseen saz fg mild FiEET i g1 oTsFs amon onnn3g3g i si HEE OB OBE dy i; bgt EI + i3 :fa[HiEEr gf... HERI Er L3%ed WH3TEeHf uid ff HE er sr pb 22778888..00005522 sso 3MA10083170 _! 441188--001111:P:PAAGGEE BB--1177 o o oN | == e i ii | Eo ; i R :isoe ` 3 fa!gEL ` Eg 2% i3isiEciegeasasisfansasisziaagaainasnaaznansnsginegns; $f Fi33isisiasssseaisadaiaizian: E: %.isssceseeesessessesesedizse i ; 8i1: =f5 if if 370i gl HH 2 5d E3RRRIIRAERNASNNNANE BES; 22778888..00005533 swatonss171 3MA10083171 414188--001111::PPAAGGEE BB--1188 =< oa=NS = i : i : g i ; Pi3o 00 Ho i i PPEEEEL i;ii i : to H sip ig i8.,.,,, H sssnE nnnnR annsI he, io oa y4 Piido[,'1:3 mom Piki.,.~ Eisi ii. 227788881.00005544 steer 3MA10083172 . Po : 441188--001111::PPAAGGEE BB--1199 nn &= > = e ; PE31Zio `i B HgpEpEreHrRrEsasEHssErHazHsEtcEainnLbiuaR arNnangH saGgd2 SE5F0 fY ieResrscheariisisienssiisisibiotieinariaaraess } : EL 2 85 51 D5iFE .EI iniEHnidEsEmEaEnREaNnRaRnReRGnEaRnEnBiERnEaEaGiEEgN{iEogRds3 0 r~ 0 [-, o i in: 22778888..00005555 SwAtoossI7S 3MA10083173 i = i : i i Pi 2 418--001111::PPAAGGEE BB--2200 "o @" ~ == e= : P3E, SH issiigsaL apeiaziizL zRRiifei ERE ERR(f2Rp1iB%cIisEH saBewnEsmEesEaEpnIczEeusMseIsnIent eauafdsiBisaauanfgi.ofndnYEeRB:nRE'E | HH H 3SiizePRE is: 2 hi siElFos2 iEgiz i8 32 PLE is iTE:s (g51l7eBpRrEeGsEzRiRrEzAaRsAaRaRnReEsE SMERIERAEEERIRIRRIC4Ep i: { 8: 22778888..00005566 SwAtoossi7e 3MA10083174 441188--001111::PPAAGGEE B21 B-21 Ba== ae :HE : i 3 :} : De ii iPT1ip pm geaeaassenaRnelnR Pam lEiFnisB dsisgeEES m ctiftiieaah Pion i fg DEinH EaUgd EnEuRE iRi eIiEIiIia SaRtIin EiSnIeNa nEIeGiSiNeNtReRy [RR 5g i Rn i1 soaLosomo EamiRly SAE | ER s i i pszaaiazinipaeinezsiziziz@aisl (Ho5u%i bi 1 $i3P8ctoipni .inaElEamRsEanRInEAhRnGRnARnRRNAREIAREE 22778888..00005577 sssos 3MA10083175 . Pod 5 4188--001111 :PpAAGGEE B22 B-22 =~=eoe~ : : : : : : : 2 izi i id z Pioyr xiizkd g 3t FI i 5 Eo. oe oz 2 8 . i ananl' t3 Loigiet w3g32388% iiB iE gEugEE lf(Bi iin E iB :3 E0 E FEEEET ig HRHiEE EgLgE: EY 8H a81) [EghaaEgnel si jese Piel 12 aa igep; 2238 phe 1sEd Bort ut EY gin 131 t 33 $5g0i7:s 8i0y% % i 3d i: gi iEa 3 i ; ies gE 22787188.8.00005588 ABE 3MA10083176 441188.-001111::PPAAGGEE BB--2233 2an o===~ =2 : BE | 5 :3 pP o b@ 3Eos S PoBdE E F33iiddsR isgasazaiiE aie S sgspsssgsE azzasisraE sagsnsed jociiaafesdseidiziauziizsd aHmnEnnRnnEanImnNi smsamaszeaseazeazanaaass: fF EE Fg 5 iy iif0 ~ o ii i SiiaieasinEasEEIRaEeaREEEE: ii f Hi Es 1; iE, io Dookie ii HE iEB BEd is 22778888..00005599 swato0ss177 3MA10083177 : s 441188--001111::PPAAGGEE BB--2244 =S3 =~ = - !: sHpEpiziadddidiiiinianag :i gS eggsa ansaan naaain eanraa nase H BR rina EE x i ai3gassasmEdEERaigEg I ois 5 HE gg, crnmmmmmmmmmmmmmmmmmmmT i Poa EER 3: = . if Es ig tf 2P"ELfoRigoegIdfMne iiifs8: iif i 22778888..00006600 swaro0m178 3MA10083178 441188--001111::PPAAGGEE BB--2255 SRY = = 5 Hina .i E H EH E EH TH 22 BBE 3s 33da dddsa dsdi dsaai daay aan I ois ig3 32 . iPyE s30ih~ seesssSsRsSeSrEeisRaEzSsEeEaRsRsEsSsEaRsEesEsEsEl 0 5% EH i En PE ofniee Pfonig b H Hg HE 22778888..00006611 sssos 3MA10083179 414188-.0-01111::PPAAGGEE BB--2266 xSE==- e 3 & HgggE eaioR gnainE angsI eangN iace i CHEE i gt I EERE avs fF Bamana EE iy LE if snsstasnagRatizinRciIAARA ShapicessseasiERERREREEEE i [A ttf h g: iFRH ET] i(E82 22778888..00006622 aniossizo 3MA10083180 441188--001111::PPAAGGEE 827 B-27 o" <==oQo~ ` 2 e i El ! :: T fH ER Sessssaprant gx ii ie 1333E9EEE0 gt z I ogaazaagaaadd FERFEEEEFEEEEEE] [I : 88) L.ianssgEoRaEnzEno SETETEEEERNEEEd 3 8 paspa Bg 0. Peon parsnttin|l Dhaaseseani: 3E = if HH Es it is F ti Eogiie iiH t8o gigEE ile 2788.06 2788.0063 st3MA10083181 441188--001111::PPAAGGEE BB--2288 e=3~No 2 T : a EE o i i faa oo Dogg 3 JERE HE REERE EE =a: BEz~Z ERD ORHED ERE p fF F RaEpE OoEEaEEnD EaHHD OaBHmD RmmE 2g ogg om EE [I SF fg 4g gf ees see szze wees osm EES ozzzozazas 388 B88EE: E = E200. reer 53s 3p BESES E HRTE H 8 iE em eBiH I J 2788.0064 swaro0m192 3MA10083182 441188--001111::PPAAGGEE BB--2299 = == BRSREEEEEEIIIRIRIifEd = ; 2 20 P:sooim (3REREiEIEiiRsEREiEsisAs: FidEsEddsgdndraafazeafiiasd HA rem i D1 c gmemsimmenaa fe FREii i seas as RARAREALSo(sLEi zEgi % i53g53 2 BRL inee tta n e venrsse anae nn SEBS z iaEds 22778888..00006655 A008 3MA10083183 . Pi i EB g 441188.--001111::PPAAGGEEBB--3300 &== o~ ==e igii MERE EEE LEE HHi gil ii 1 cpmmmmmuamaa i E$0Us8 smmmmmrngansassndnniE1eHHs it,ig . =sis $x I1 BF. [%ix iRiEsRiRiRaSnSiSiRaaiRieaaiiaiRisidssssiRaEeRseFR-bsa0l 0 o 22778888..00006666 swatoossiss 3MA10083184 441188--001111::PPAAGGEE BB--3311 ~ = ~ BEELEREERREIIZRIZIZNNGNER =~ =i szzisxddsiisaaaaspEssiisd == jo ig AnERAARRERERRERERRRER BPo g Blimsmssnnantininasninieg i SE. apssrsigndifessisisiaisisic S BE: l anminanmsinaddsiadcenaaidlnf SE 0 psssssifsdsdadsisidsseiiile Pgfic g ammsa apeneeeeneng#z5s B0{i8s FiJLE 5* ol pmmanaannaaasiadidiaHRaSiEEgE i, 22= MBeEElIGiiiRiiEisiiiaieiaasaasaanssinascciaaaanitztioFEcf3inaggssf gPo:o[.-, BHEBRRRIEEEEEID3G3S: 22778888..00006677 amatoosa1ss 3MA10083185 441188--001111::PPAAGGEEBB--3322 S==== eoo i :t i 3 is i hms : 5 i: i: : . it | i i 5: gi PE ippmmmpnmnaienig iE1s0 a lpm csdiidiil 1 iif sCpElmiEaseeEpsszazisaingizagaiidoecn ig0tzt= iEfC ciEBliipinsginiasnaazaiiindaanniiaanaiiaigiAsaznioHEty fTErog0s eiecamsacencssecansisealn.oaseiifByB {i Ep mRRERNIEES 22778888..00006688 stn 3MA10083186 441188--001111:P:PAAGGEE BB--3333 = gi3REBE9dRIfESErIiIsRsEzRaEgAsNzEsEsiEzE [= x=] of igsziedsrsssiiiisissasisag ==jo : ~Dgmmiaasasnniasininaaiaed gf fs EE di gpsiisssdsierisiiiiicassic iC.E oo oiarpmepsizasssessaasisifanilEL 80] Hi z dmsaniasnienimiiatimaeiyLioe d E10 iSiigsssaziggsineccecisiisd fil EFFo cLiYdiaasassssssiinidininiaanintiasniasniiaainnsiaOdBaMEnEEg f: y2 . 2 Lo EEE52 e1dibF nEaaEniEiaEsiiMiiEenMiiaEiiRiiEe LRiiH Gs fz RE 22778888..00006699 amAtooss1e7 3MA10083187 418-011:PAGE B34 418-011 :PAGE B-34 2 S== i = e i : Boi - 1 [I i i FE 1 i 1 ig ip i FLL pmanpnnnindig g 21 Ry [RRR EPREERE Lain tt 3 i [EI 20 aly sigiiarazainraeniiiaeisaaniiaiiaiaid he) itive, E51070 copgi1sd EE psn LG gota ijx gBp mcmemsnsaenfnseewseensBaBY3,2 Be 22778888..00007700 stn 3MA10083188 441188.-001111::PPAAGGEEBB--3355 in 2 pag3IgiziEiEsAiRgRnIiEfIfRgRzAaRiEiInEgR =s~z=N e :i3 oo ; diipiciiiiEiasiiRnEsaiisisiifiEiRsRaEdAiRtl] 33 Dole apesmmninmiaiiainEaEnl m P= pmummanERRREARRAERME ;: Por mms o io : CE smmnaniistiaiae gf EEEE ol gppgssmimnaatmRiERRlEy d :B!EL csiigigaiiagaeiriasneiiasaainitanisiaicLI i 88 0 El iiiaieseeeesenensenegizifin Hh nha Bl if ifYi2iaszRsRiIiIiRRiAiRiRsRaEAsRaEnAiERaAtRiAnRft Ig1LhiEHLdSHE iiyi f evernneness 02H 3 RE BERRREERERIEEERREREAOEWRSR 22778888..00007711 swatoossies 3MA10083189 441188--001111::PPAAGGEE BB--3366 o~ ww ~N e==&oS i Po :i i siis iFiI st Ei Ti EEL gmetad] i J Lf 23333802 33RRRERRARR3RE0 i % 2 3 iz $ESSERSZZAEREAZNERAEAMRA i: 1PE clsseirindan iein nagn 0 g TRE fyb HE I0 0 F in 22778888..00007722 stan 3MA10083190 441188--001111::PPAAGGEE BB--3377 seisdiinaiiiiel kind 2. $3RRERESRREREAFARARARNAAN ~ = = ppassiiRfiARfiEREREERILA = i = irspisREaiaRiREIRiEREE :5 mi opigepssssgsiiaiiiaiiiidsiiiiRiEsAifisasiERi : a. pirirgsaignsfsEiiafasniil : Fe oo 8 iusecsesszateiiziafidding 0 : gi : IE 5 0. : gssspesifaiiensziissafai ge iP f i 3: p i3i3Ra iSEREECCCCCCCCCCEARIB5I Ed: Ted HPEyE tf aiasiaiaiaRdniiRanAER fll it seeeansreannses 531 DfpE=o E(grBpErisHzEaesEzRerMiRriRisRRRiiEiIiIRARRRiEaiREiRRiNRnEiARiERnATEBRA3OeREsZ 22778888..00007733 swatoosstot 3MA10083191 BS== 441188--001111::PPAAGGEE B-38 B-38 eoo &i | 2 i :: i 3: : 8 B50, gasuiainnnaniinnaaaiatig iii LiisnssasaiasnaneasaRiaiiilg5c5g E 81h20.E annnsasdanzigaansastiarasadnigiangeifiiie $3PE0f80R: E pasgnpeaatataenrsianeasndanandcinsRRssRaRasRRaRasLE&ea5EhEs nanaie Eg PHEELRE a nm 227788881.00007744 swar0083192 3MA10083192 i cas g 418.011:PAGE B 418-011 :pAGE B-39 =fae 2 = ti = ii3h83 E 1 on :] Po 2 i Soha 3 iia 3 BE gd i 3: ibs d Pole3 TE Lge ie FFeRoE8 LifigpgieineniiigH iE 5 PPEER cDba RCeR AiRE3 I EEIE T LT sanars 2788.0075 swatooss1ss 3MA10083193 E1 RE2p3EEHE 418-011:PAGE B40 41B-011 :PAGE B..40 I|==='d e2 1 sigidd ! :: PPEeT 2 Eigzgds 3 EE. igen 3 [ ti Sre3Re adE `:2 fir. 31iagieasatd ie5 gy Hi 558 [$8I0 ESEnTEFPEPRIEREE EEE [HH 3B70 % eiiRiasdsninniizRizazEdlRRLbdE SE : f tgixi3 BEiEpiEaeEEReRE sRi ERaMEnI3E BE i 22778888..00007766 SwAtoossiss 3MA10083194 B. iE3k8E2 | ; 2. 32 ; FEET :: 2 :> Ey 5 8 PE ingen fe HiE E395a % iEt edifEe iJE SiE Eigdaio tig KHHed Soil TiBIERE C ERICE: ig FB 5 2D%Lofsgbln ani$5t2 Py if phan EERIE 441188--001111::PPAAGGEE BB--4411 ~~ mn =~N =I~ = 22778888..00007777 SwAtooss19S 3MA10083195 Sesas oon vi gg al am i : =i 33d i i ; so io 3: = E ERE TEiE. =ig iz! fp: x gif PA] Sg cifigdeizisaaifEs S37E0 LE Heche Edel Bi a le ifs FH ,441188.--001111::PPAAGGEE BB-.-4422 8 N~ ~ = = 22778888..00007788 amAtooss1se 3MA10083196 . RiRmEsEsRr BEF 7 memes i =. igEEER } } pov oad : i ; 1 =izigRagE : : g = SEs ~ 441188--001111::PPAAGGEEBB--4433 adaD ~ in ~oS~ --- fe . HR IHF is sb 3g vifidgde @izzans g5Ed. SE gif EL of ages pian l HFRS i =: gEx EBEinieaeEeE |g (Fie RE0EE; ilneaaaseess BBEBDE (RERRRIEY 22778888..00007799 SwAtoosst7 3MA10083197 .: 414188--0.01111:"PPAAGGEE BB-4444 ==~S2N = = i i Poe g mig! := i 2% id dideddasiddl 3 Pog :3 Pg Tiliesssdaivavecsieddiianededl By i : Eri argasisississasazessaniei if : EE i iF oq PED essessaaiiesdninniinisf gg3 LRRTiI Di ef: E sfgiggi: o o ii sm + NT E2dht} (5 BeeH iE. 22778888..00008800 swarsssies 3MA10083198 441188--001111::PPAAGGEE BB4-455 ==o~ = i Poel 3 sssssensssnssssisins D5 iiiisiadesaiiddsadesesdds EET Eg 2 BgEr.f LiiET iiggassssdesisvasidiadnigkb HE igsesississsisssascsesiiedl}HI i liisissdssvisdssisisresisiiHal oF 81 TT ssunssassssnasiai sii I i 11] PtyEDg esseeeseeessseennatiins HE5E8D1 P(iE:OEiEciiinniaaiaaianasanimniifaiaEend 22778888..00008811 SwAtoossios 3MA10083199 414188--001111::PPAAGGEE BB.4..466 &B~y = = = $ Poi Co Et lisssssssdssisadisiaiiciss Eg o=ig E IoLsE H EPrHE SE 3 i gr: P10 :: emmessnssssersessvenien Bi go io ih iio 4 . i sesssegrspeasnvadasicaass HEE itli:d RN . ishie ico i PORE ssensamfop nssEiRonTsEnsLsaEiEsnEnr18Sa0n0hs8 2 i223. 22778888..00008822 SwAtooss200 3MA10083200 441188--001111::PPAAGGEE BB-4477 o w8$w2 ~~ i == : [IE i cisiscqianeiiedi 1 :[PRERlisssresdgissuiaienainiiiy, : ME BBEooleOf EEF Bi :EL iiiiidesdgassasievasissdil1 3i mssssssisinismesiiis t i sssissiesiiisiiveaniisediiyg JoNof 80 11-4 iasssassassssanasiis gli RET . i ogsasareszsgrneaninac0an0a0neE Tr c 3 Hi silt ippSTBEEE npinRiRnaaaiiiaRnRiRiRiIAaRzRiRiRiRSeEiAiRaEsRINHt.HeR .] 22778888..00008833 aMAto0s3201 3MA10083201 4411884-301111::PPAAGGEEBB4-488 == ~===N e bd ssn : zd Ef Lasmssssasesssdzeieniies E50 x TD gssaeciidsisdsieiiediiiad li 8% ig Ciiiggasedssedacasiensand | $iii.n : ' PT lesssmssisiisnenennii PE issssssiiensiniinii 3 $8 esnsresiissisnJsE gF 0-4 52 : Jao cid : i Zu 2 3 =2 Hi i5 BBg EogpoEEmanRanRAbRecAnREnRRnRRnAnRRnERsERiISaS 227788881.00008844 amAtoos202 3MA10083202 441188"-001111::PPAAGGEE B49 B-49 Bn e==&&<So PiEoggs phmaosat ess] mgeEs (3IRI0 : : BH : sesi assaB y aEeTd 13a Fieasad 8. Te if ELE ae ten mE EE, BTs L a sess js S pcessoe e ges a peml edh ie d 1 fir!o Tes Jlosses 5flees 3: BsBi fi Ramaiy rg mmm onl To oLigiEERiET g 2 | it owen dst fy gs Ripa in ERERE RR BRE ARERR 22778888..00008855 races 3MA10083203 441188--001111::PPAAGGEEBB--5500 &==e~~ i Lop ob Php E37 iPORHEr EEL :' !Eig : EE eeegers esenans eeeregmeges peeeneegenn iicececcese oooooooOOO m: aeemzenEnt mrss genevrneeRl cemeaseeemnrtrEgee sessecoeeole oooooooooo J oooooooooO escccecece oooooooooO oooooOoOoO ii : "ecmoe Eg 2 ieeenanennnes oon . ecososoee ooOOOOOooO ooOOoooooo 300 coe cecscceesses i 0 ooOOOOooo : i HA g ooooOOOooo 1 wocessceceas seeceses i 8 ooooOOOOo $8 gl TET epee eaearfeengzeneenaic.d P P3L0palp pg BUaE nn e aedA LE i 22778888..00008866 -- 3MA10083204 418-.001111::pPAAGGB EE BS -51 ~5o~ azs= } 2 i} Femme Lat 2 Loseazgrezgzezaeszizfeieinits EE UTE 2 . y bi seereenemezeeted oa : :- : ii ese eceeooe * eosoeoo o 11 EE eee gE:% : : 2 i BE Bg pi it bs gf oiy = pocoseseeeooT eoses ` Td it p emaena TT i gema eemznzet EE 2 3 278888..00008877 3MMATA010008833220055 $5 f:Fi ogi30 tT BEE : EE EBL 441188--001111::PPAAGGEE BB--5522 >2 i o~N ilmamgzesr eraaszsesamemeszseseagzzzezeazazzeaonnoza.eii =~ =e imate cata i. apepepecnegennvegene seer sessssssmsmeersrese igen agerewsgessgeszzezze Ti r PogE, Beg. HEH gi og ~ooo oooo ee oooooooooooooooooooo ; E, EE fog f oooo oooooooooooooooooooo i 80 sii: oooo oooooooooooooooooooo i oooo oooooooooooooooooooo i i Elf sees sperevesveesnezenzenl 3i &8 3z g _iwegr.funagvesrgrzrans men i$ Fl: iiTieengEiacnreveneggorezennani joih PEER Heeseereunnnanvenane TE gr3zs ii IfTHEEiEgEzRaAzEzRaAssRieEsrREiRnEasRIiABySIsEIRaRAEtNNuEErRIaAEi1rRYs9yAYl o ~ 22778888..00008888 aMAtoos208 3MA10083206 i Ci, Pod Ep Poa 441188--001111::PPAAGGEE BB--5533 Nn : o==="~ lamsagssnaszsEsenszoaszesn o eeaeeemmeetzzeaoenzees eeeessesesmzenenzes szmsazioaamazeasareaass: eens LI Mgi FH : gel EFEE i 2 oo~oooOoooooOoooooOO iccsceescccucosccccccoasas ecececsocss0c0000 o~oo~ooooooooOooooooo leceomammononamsscnnceene Loh f0~ g: FR pa ooooooooOOOOoooo~oooOo ; smmneermanaaneninanan it ooooooooOOOOoooooooooo o P3y: lalipg { jd 1 apnI iEE | 22778888..00008899 SwAtooss207 3MA10083207 441188.-001111::PPAAGGEE BB--5544 i 2o=oS~ , = [.-, 0 i El ~ ,.-1 ~ PoE o 0 F~ 0 1g 3 B 2: EiE gi nerveens voegmeznennanee i : secnsanne sesemmonsosnece] Pie Eg ooooooooo ooooooooo ooooooooo ooooooooooooooo 3 reeeeenai ooooooooooooooo B ooooooooooooooo CE TR Eos OS : | 3 unenrfanegeanzeorrese 2h 35 3g sres SE in i] > [.., 0 t~ srenc0s0 2788.0090 o-- 3MA10083208 44118B-0O111T:PPAAGGEEBBS-5S5 = =o==eo~N EE =n i Bg oes emer isan) pmax] (EEE Eoiet fe) 3 gE: FI FEV Bg ip : giBiaeel 5 8 Bi Gaeenal fem) : : leemeniivet fem ! noni i leeem=: pg EE Bron E tr dgh i Big mt lee focoeni fone} oon A feeoeeif Sd TEit3 e iiHE(t~DZ 0a00e: itn: ween 8 geil ER t 0 igi iE ti iz 788.0001 2788.0091 staan 3MA10083209 418-011|:PAGEB-56 ~ IS 418-011 :PAGE B-56 2===oo~ ti : - go i3 gEi T 2 FER 133% esnmoeo" nanonamooneS } sesprsanzi ggi ifSERloenasmcrIeIRaIInN 3Saanssssieinziil TH i IH i ir ] 11h sme RENEE, BE] pene mT iPrioadg pagi eant i } (1g ee : iiPtERRI:Sespeprnrnnzaainiiiiatiigi 2708.0092 2788.0092 staan 3MA10083210 418.011:PAGEB57 - eo 418--011 :PAGE B-57 o=e=~s e[=] n Eiki PE hy paepezzaasessssadssseadafziaNzIitA ASeEan fr Br 3 (naanizprRiffIIIL SAR 3 2 ii id sapzaszasteianaias ameril at f5issui.d eeengemeengrzeensni HE i: i ig i FREI ty: HH + pi RiRnanaE i Bi i 278.0003 2788.0093 a3MmaAt1o0o0s8a3221111 441188--001111::PPAAGGEE BB--5588 = ==op~ Ses fF. DoE go. =i 5 BGR lgsse zaznzzsszoazcassrass ma ImmMERLIIMILROANIM ii go i S03 E PEFC i: $50 BE 0d [TREE RERESRARERSIEETEEST ecesfi eercesenezzevegeneenisi : t 3# zE : PE i i 22778888..00009944 awaaszrz 3MA10083212 441188.-.001111::PPAAGGEE BB5-599 2 oS==~ i = e .... SS~; i 28 5 FT ; f:gfoit ei : lmzssszmsanaszeessassznaessae i By ammmenanaERAnAL P3ERchCil :"%i4l [I i2, iF2 EBfyi Sit fait snmeannaasaasnananan gnossnpsmasmasissasaszaas `2 ! ileezeammenaesenvIenenear2nsmcnagneinEeIoIeEgAnani2gig 2 HH He iz HN i ) o2HE 03 i= f8leEcRrRrReEzGiEoRaEsEiRrEIGIRREEgSiEERiRiEiEnSiMELfi2t Io i~ i i I" 3 22778888..00009955 swatooss21s 3MA10083213 S=e==es 441188--001111:P:APGAEGEBB-S600 FR sppsna : : PoE : + nzazszesz ; zamssssrzazzaas if i FpoRpiEEERED IEREITDILLGAGER i i i fo LfygiEni20g2R mE RIREDTIMERERRLG ; is mmmmmaas sammanznIEIER ie iercneefevnrearg=uenareniy: 0 Ee= psif8isEgEaRzEpRzRaGaRaAzEaRnAaRnAaRaRnEnIaEnNnEiEaNaEg 3 0 EgPy:E Phd ; iiEo 22778888..00009966 swatooss21 3MA10083214 441188--001111::PPAAGGEEBB-.6.611 = o~ e==8oo Dogma oER EE od g i: 1I,0 ai : Pi PdPod wae ! imemari Doigraazg)l imzmaa; izezes ff 5 LoL TEgylpien fom i: nit: mn : tig ffl : Li BEng meat ET HhEoE IiF EiI rSob 8miifdiiEgaeariik3diokzRaRzEaRiSitdeoagsngdrBHii3REA RdER CRiEERRnD 22778888..00009977 anions 3MA10083215 441188--001111::PPAAGGEEBB6-622 =oS2= . e % =] FE o5e i Boil 3 aH | gP o L aEmRen agfeefieesllfenfl E2S60E fLaE TgR sa iesihged t3sgtigeide ssitsalein leiieall l sf2h3e8el 3EEs FH EpEERetLelg Th L eGi negteet ddaleeda laaleddaansai:sf HE Pfyl AE Hgsimenmrnsceentmsasaedaatdisaainaaoadaenss oBf 4 n E ftfiEEoRE a S osts aIelea E lelAiad liReeifnNa fnBg0s 3B 5 i: foBL eineaetdae eelinaiseo deelesenrsheg daleeeileelelnsediisylilg2 [PSEibERE R pse iegedteieseinaieendeisa lelaleces it IE ty oabEgnGgiiipiaaiairiRziRaiEagRnIdiYdg igPtyE B EREERERR it 2788.00 2788.0098 -- 3MA10083216 418011:y PAGBE 63 I@d 418-011 :PAGE B-63 ==ooN . o Pe 2 Bohl LJ N oe eed este sfedif ut :5 . s8SgE3gheieeriagleflginninel Se1i1s vEmiTinl MRgRagretetendaLfealmealneesenefdaidns EPrEog r A a eaedeu tetedel T3ELmig eimelealaelaalteenitileiotetil e Dp ec senenseelniesiiil DEloEL eeeEnidelanaianiait eientelebE [E3r IEoEan LgiTefgRdesefssiheedleGlseEeoitea ii sigteiats sfelsleleni foie PtEil aahcaeeaddoaodnaadnintnoigdd Bg in gereagataielaanein LEE LL srerenetaieielelenge g P 5 E. neo gdeerlgeiteenlseiletlascieealisotaidiid Tid RL iy ier yriaazi aO c lg P (3llEEiERiRrErRiEiEiEiSiian12 if I 2788.0099 satonss217 3MA10083217 441188--001111::PPAAGGEE BB-66.44 z SNS 5a - =No -- fio agnmemmidaadga FE 2 Eo &a Ei 1 ft 3 3 Po ie! D s353s8eiet 23 ereereglidgatleiaglieglfeelnsel? gflfeaeifsletdy foal ede stelalefeiedel elelelly PL: efelelelfiielslal clalelige 8 aig efefeieleieiaielsl sfelsl BF DB: EioanEEeclreeT dfeilneglteeltsefisefleeilfesltaelalselrleealalsnlteiift}:E PE PL eneaanacaia B ded nnidadall PE oe PE aenfeedfesliaelteallealldadieeleallaedicaldeelesllingg E HH do 3 Bom eciFieeClfegdI feefeedleedeeldselfealleledfsedleaeleldiEElN E Lori E isleRlReslteellealteslielastleatlgsidaiBataeatith ttiapansisszisisisa itt ER EEREL REERRE RE Bt, 3 oT 3 22778888..00110000 swatooss2ts 3MA10083218 a 2N 2 441188--001111::PPAAGGEE BB-6.655 == &~ ~ = 2 is D1 opawer 3 = gigs 2e8 sgvtes efgn 5323 2} Po aRkel od aie FE jor mee so DERN Ppo l, oial suRseldeeileaieeloef ssieilaalel,'s gizi 1 iY s3Fs3sfE sds Eted mip elelelzielsl sTeios3enEig sfeleds Ef TELE hgerteiss B$0g moigr eElsElelEeledsl gredgreife eTleUlIalTeEl ts4 ElEe aRebmeimidteer aeltefeetdin B8l fFrgoovni, emlmseieemlesilnagdnd Thi | dheleladd sBaAdSeE gy allel PEL hides adds g (P1i0o, Seemsmiiaaddayly daaaaad oo-igl elefeleleleli OB laleleglg PIsEFlReEEEoE E gl gae tiEc iEaEscRgiEiEsEiizEriR g i iEy 22778888..00110011 swatooss21s 3MA10083219 441188--001111::PPAAGGEEBB6-666 z: 8~ e= : = : e HE I I [oe elsiela E xl g%g%efe? Boos lle EE Phos elfelad PE aE sRelgfed B3g] Lif 4E.E2.8.8 BPgg oov- eeiieslieloesid B[EgERoEi | gfsBgRgdI gFEE oer emfeeifeellearl To - slate (Borg sasial Dong sell elidel ened glelelefelelelsdil addenda a sledelsielelalal BF egfaiafistefelst fx 3E zfetgfgfil teist of aareeilneliedfssliediaedn B e giglifgngnt glelsdizh sadleelleedeelleellaelieellsat fp anenalenane eter dade ae eel tigigss iss E8388 ig ge itiSireggiaieiiagggyt 22778888..00110022 swsioomazn 3MA10083220 441188--.001111::PPAAGGEEBB6-677 5 2 as &o~ -% ~ = ios ; F Joel 8= 2Pos i Pls Plog FE aE ene enele sided sigisied stele g3elsfel eeA isatelesl eaheedieleileoalveealnedelhedeldiiysi stemmed sneleclalend H ffeleled eielgfazatiate Sx Bini Bgom stemmed flhelea lsiegldads elale al2alin, BEool 21 i aBsfstefe ign. gislsdelelelisiial chnerietensgiEs igiE8: iv : 5 - g%ffl5ee8blseps7lsla%elsI laneel3E0elaeenele sailate elilaetoialaI enlTtueE aalliio0df8 id - DE siedsieteisfataiafalele seisandeidaas of Do-lE eseeietetelelsiaielels PPrgim iiziigEiairiozairiraaaiyriaicoyl fEiayi iPgfRifElErEeErEsErRrErReiEiEiiiIfE3. 22778888..00110033 swatoossz21 3MA10083221 441188--001111::PPAAGGEE BB--6688 .= &S== x 5 e~ = Po gz EL, a ef oe ; si EL :Ea Daf afele? s3ed sf 3 in Beietgrecgiete gigReign 0 sfE aleleled lc islcen lsalerleeala eenlgasliosd PyF =i i5t% isiplEten goon Eg oc P: oo Brot EE vl Ei:E8 0 g Boo, LF ip sf%eislefeialefefelelelala] i eisfelefRnefaegifegfRegliagdlaalbeedleelles 8x2 ssmmsRsiinatetedavaziteist f sa isielslela alsfelelela eledsd HiE sisisriariiranaimeasniaa bh sfeisieislslade sfelelslel 2 efeisiedelelaleledalalelel if f elReglle gsRfaete lgegdregdaheilgen llieglhnoglRagiliegllassl 82 Lo slalelelels alelaiedelelel 2 erselelelclelelalsialalgegl S ptE lno iein i neip iErite iaiaiis iy fs BEEEREEEEEEEEE 5. 22778888..00110044 amAtoos222 3MA10083222 41188--001111::PPAAGGEEBB6-699 S82 a:= l =-- ~ -- = spp iiiiii Io i i EHR PLE 5 eens 2 sae 3 ls gon gieieledeiaieratel tl,00 sdhedfgidsisdediaiesialaaialdo Sadoasadnaid PPPEEETE Gaaindgnaeideaisdisetqninotn Pg oeit asideigeladasa g iBFfiio. sBRCrgrfeisrefisziieescisnatee2ileefaddesh.g.2lRiaE8iEdf8 iy2 oe Tih E iViderde eideideideiaiitiiai.snaedrsenirieidnlfd Bio iq i- cgeretasieiaieieiel geleleietdannanaiet i PSil RdeasiaeidedfealadiealnedaelaatdeilijE iy LEST iEso rEERERERR EEE BI1H3 22778888..00110055 stn: 3MA10083223 441188--001111::PPAAGGEE BB--7700 5 eww Ql ai : ~ o=N CHE galls? os} 2 ix Posen og oF Boni eeseiel ef +l slelells sfoism sRelalefelel asia ofl da slelelifs sled | 3% ai=iing 3erfieilpeidee egfiegiRegfieglreel sgfisshteelr Ue i Boom ee ane ede sfelelefelelel REE eleleligl F2B!Do. dsi3eeiadeindiisitaideefisesisrlreelnsasiiteeeeslsasidseiiElEf FSEE mrE elefele e felelelel oRpslielde PEL anetaldadel fo - abdsiecaidingg shel elf gCeBoonmpnl eshimeisaisisiilsedtmesandlssaaligeatdesddtadescoeesdtlaafa0dlBs Sp oriralioiriEEIoTiiii B gi:rio iFR ti rE iaiir E E iE tsE iie sR EiEsA .ER ITP2f:uf 22778888..00110066 swatoossz24 3MA10083224 441188--001111:P:PAAGGEE BB--7711 ~ 2; =&ENo] A.' ==-- i2 i5 is slSeed8 Pos ae ele PoIEshSoktudEtdbr adSEaSdEadsdolf] I EBEi, Fhe eh gPafitaBstgReleRglat ie PE = i efelelsielalalelalalelel Foz Fg oof PPD io 2 gfg%e s3s%alalale 70347 52 endfeielelslis lela f eedBaddasaacadnsdideagd BI irene oh 5 ini elelefelelelalalelalelienlg gr me ma $B inl elelefelelsfelalelelailad BE 1 5 vig slelelslelelelelalelelal 8 PF lgao miaig aaae ie aaeael saE of 2a: E~llo er ae caazazzz gf 22778888..00110077 awaraaszzs 3MA10083225 441188--001111::PPAAGGEE BB--7722 2 -2 x E=o=N 2 . =e Lo Goi de [pr [I za? pro Poa Boia aad | lapel jada) 8, de aTeRaReR! ieiefad BfEgEaOimilg eeerrl cdideemRaedneemzesr| fae 3aEd=3eEn g g3 ie go Co eid BPo3m0g cEieGl EpciRelneRiEnniEgfences zaElE Py o- Dan Biddadlaaaily EEL fi Ref Tie cGeReieRel! iviiesa ieRanad tf la..ciil PEE ER BR NH Sed FEL ia aad ddan fi Siig gaat FRAT THE ERD iT PfIbE p nnonsites aad) EEL Cicbciiaa] deans g sf fose daiiSs odioiEo giihgeiegE ott sbie ERGSEEIRLECRRECEEID ECCBGR:E sih 22778888..00110088 swatoossz2s 3MA10083226 .7 : #% + - 441188--001111::PPAAGGEE BB--7733 D =oTMN =--- --- Pole Joel ene BL] lReet Pon <hendl ae aed leneezedes dE B 81 E=lE a <IeeRa paRaa dddd} l ELE SE Dida i Gi PFEELoini LEellEeRdEEifileldReadRdaedd<Biis2gE FilEL i Glaa cdaaelzeaedd gdEE PFEronel BTedenll r LaBaEadaal dily PFiE0 L adadd dGe era da BF Pel LUI PBlil cai didaaag i pins 11353304 ZaDEofiE: gEgE iPp Es iia oIiREE 22778888..00110099 swatoossz27 3MA10083227 441188--001111::PPAAGGEE BB--7744 2 I] J ` ~ E . s; f4dfF og ifos =e % 2 Hg Y LSfEiTnEn 5 CE Bog dt LGE LSEn elf P2 oo: ti h FEITiJEmI La IE i i. 2 : : fd 5 Poor ged i Pople BZ 0 inds oad c5d 5 gif ipBE; pEx i OFETY IoEEEs: Pg| Ei i PE o : 1f:i0i3 , 3 iTy 2 E gsE:igFf 2i i P8800 #3L 3 ELHi i ESo z ogyshe = s. iii PopDi=yoirig2EEzEi:z c3 .: id-$ i F5i ig dfEig 2i gPoxi: 22778888..00111100 swatonss22s 3MA10083228 iEz 5: iPEs0 ii Pi d $133333% 3% E FH i ; : : od il 0 =PoE Erk f3igt?s PPOoETE 5 LL.1 .. sery Bole! ERT 3 i:SEE| io EE sd 3 414188--001111::PPAAGGEEBB--7755 -- =aN ~ = = = iiss ; s s eees nsri id i : : i f: o o ooo tiopbizzizzer Sy sEfissizaz gad 8 Szriiii: iii HEEERERE] ozi~ i zssigad ssisssssig4 FEI5G3I3E8G3 G8R:G8d3i}s 22778888.0.10111 swatoossz2s 3MA10083229 441188--001111::PPAAGGEE BB--7766 o a : FEE . o=N Pigi i 3 d4 ggi = : dd0 H LE RR P: ooi h nodal i $53 HEN z : 3= E EeEfBF cBEdES POET ss iB $i BE oR, iE SE ; se si dE Pope za 8 5. Pid adie Eaikd o : sis i : g { 2 3 LL | ;ozrd o o o = zag o o o Lf EoRiis 22778888..00111122 stan 3MA10083230 441188--001111::PPAAGGEE BB--7777 2 c= ~ = io - ! io = . ide [HT :ii iiiP :i 325388, ccfdRs, BREE EEEFZ i: . -- 2 $5 3isiia $30 i: ! o.t Pir dt : i i gif nl z:: sf Pp iihs 5DEigiEL3S gz CgLit gi gBIE i Fl 3 i3 e3 ee s i iE 2H38H: eErE id i :3 3:: 53 HEE iF 3k : : *: g38 iz ssssaa zz 5 EfpEMELBEEPEEERI: sess ME M E PEE i E Fi f afEp sP@EiEzEiEsE iHFE i 22778888..00111133 swatoosszst 3MA10083231 441188--001111::PPAAGGEE BB--7788 i5 if - i: P : oSgt =< ND 2 5 oN = Eg48o8 joes 2 gf TBaLf EZEeEeE? i [EN io : 22 EE E :5 : t% sg f o2d3,8 Eg Ei =EiFgR Cd oc es ee F5 isz $;353 333 3% Elon ifEtz:iii2:F :g [ 3s ] ig i: ; 55 i gc 0% i Si:E 338% $5% 83 $5 50% . 3f25giifsgesafzf;is2ia:az. sss zSosn: 33 s2%x IsssRsIBiiN iE idE: E ses i' Pi3Tids gSEii2ni3s3E:% 32B383E233E%3 32 O:B3E 22f13i38%i:: 22778888..00111144 swatooss2s2 3MA10083232 : 3 % - ::is : i 2g :i i: d BE ERp i! HER03E7 IN13 i : i : i Pe : : Ei ii oigEi ery 3 i 222 Hi prod: Po i FEEEN :i iz dg Pol.i 004 E8 : EgfigEEE :i i35030 $i e0y3% 231% if if Th i :ioppbides ze P i E2if.P 85igE20 oaxf iis 441188--001111::PPAAGGEE BB--7798 n<oanSN = 2e 22778888..00111155 SwAtooss23 3MA10083233 441188--001111":PPAAGGEE BB--8800 oo I : Ef Es : i gf = : [I] Bis gis i Caio: siz : io ide zi 5ti5 P5o3gb 33L3sL: 32 PP 3LL3..s. fis iff Hi Bsiigss H3izEs :. i: i i [EI dd 1a i; $833d $884 gf PD omneiredenss fy oli isaaEas 4 i 3 : i : iix: z : 22778888..00111166 stn 3MA10083234 z: .oo FH FE . 4BE E$3fF a3 og Ez 441188--001111::PPAAGGEE BB--8811 ~ on o~N == Eai i Bid 31 B3iiiiiiii iO : = s Ei 2 i Pod g Ee : FI BEE : 3 0 iz i 2 $3 $5535 53 3 278 iz 5 = $2 sPa EE geE fTiE l2l0 l i2i0 Pig Pi50l3 oJdeegry roprr HERE 2255553 E S3 is t$iriTiesriziaoiiiiii: { 1pEiIiERIEEiLiEiGLv:d 22778888..00111177 FAR 3MA10083235 441188--001111:"PPAAGGEE BB--8822 i: 2 := iEEz 5528g 4 ~ E 8 ii = = S5i5:3 > i FINES i 3 2= iEi oifE gP 2 Oi E g fsED asgielz 4 EET = BERL. 55ie3g $ixx EEE LLL. 333s i i : i `s -3 3 ai g is if:r 2i , ii .0 3 2 top i T=f 0 : i: sssz: zal: 8i,f 3ii fiis ix cE ophir zzz rad Typ lif: sss: s 5d 108 Jr: iid HEE ozzgsg 3383 ii 8 8: 22778888..00111188 swAtooss2ss 3MA10083236 441188--001111::PPAAGGEE BB--8833 } 4o&N Lo 3odpicB pelE f gafdasmg8l.glg i Gm8i. aipLo e3 =Yo FT i DOE namin AER 0 : opm i5Po i 13 Io i og i 3 $s IH ga EpiEE BH gt pf e Eehn 28 38g 7 1d sid 22778888..00111199 I iEsH 5iok 3 i races 3MA10083237 441188--001111":PPAAGGEE BB--8844 2 2 i \: 8 IP=) 2 gE CF gE = pb :EGEHI a a = ! 555 ! i1 i E:B iHzE : ig irosE . ie fiir ER] i i: gi 5 0 ig f 3 $i saz% 3 Jz BEET S PEogpTt R ss 33 11 53BiFsEsA g is g: 2 3_--3 $2 52i3f if 3d gis sz ssid i $2 3 ggic iiiz 22778888..00112200 stn 3MA10083238 i s i d = Po: i8e : : fiat : FLEE I 5, sgiit i253 33. Biel -s 441188--001111::PPAAGGEE BB--8855 -_ oo = e g i2 iz = sf 3Pog [I !5 t ie fof 8d $333 33 EEE 5 B ifF::EEf2 s :i: ,8 iE4 33 :i fai $f $3333 $3 HN 5 : L8 (8EEST T3Ead 33s Sg tlt: iiss: ETH Lae i iSi0i3 HfsERrErErE:E i$i8: 22778888..00112211 amAtoos2s8 3MA10083239 441188--001111::PPAAGGEE BB--8866 i: FCT 5k 8oN oo = iiti i: FA OHAg i == i= ifiE Sr8 oEfLI aCgEgA oF = PoE Bi: BE Eaees fi: if PHo : g| is 33% 3 I Ii i2i iz iPEz E FE L1 I OT ! :7 i Er iy : E1f:fiiii 4 3i5 sf og C i;23:E 8 5s8a3z 8 sophie S Plap teE: pPiDd gErEeReE: f s8a3n3. 8 2 %2 i 3 orzroz oz ssi: + iH12 oBiEiE: oO:G i1 iz 22778888..00112222 satonss240 3MA10083240 441188--001111::PPAAGGEEBB--8877 S 3 31 x5 e Sifgf Ef sii = 1 F3 oapliBEoaEadRis GEEer MoEo wi2i2 Po i ; 3: iiss o 2PE1E: 2Poi ig OE 2 Es E3B 3iz Egfifig Bd FE ifgs 1 i HI so EEE T3 yo> Gmdz sa 3 3 $3 sisi if iE is : i i nti i gi? Ties fsx xzeafrr l 3 22778888..00112233 swatooss2s1 3MA10083241 414188--001111:"PPAAGGEE BB--8888 =- 3 L FH I LEFTHz]s F5i5% [@=] CE= =: ioz isso:os cEinf SE EEE ag ie:28 BEE 2- :: gP0t0 bBi.eBBie. iBniimsg H2e03 i $333 HESS Po = FE 2 gg Pog [5IPE 8 3s s 3iz [iIgEE i: 0 0F gz $555 HE c= 13351337 Tyga bi3d8 HBErEi]s g -- CL 3 353 33i is: i: i 5 $8 Py i 3 33d zie # sz 5o si) 2i P1E3E iEiiig. 22778888..00112244 swatooss212 3MA10083242 AAPPPPEENNDDIIXX CC PPRROOTTOOCCOOLL AANNDD AAMMEENNDDMMEENNTTSS 22778888..00112255 1100117"/11330055 33MMAA1100008833224433 441188--~01111::PPAAGGEE CC--11 PJlRIMED]ICA Argus Research I =bor~tories, Inc. lrS EpS E nE n 905 Sheehy Drive, Building A rE Hor=ham, PA 19044 Telephone: (215) 443-8710 ecR w a "l'elefax: (215) 443-8587 PROTOCOL #18011 PROTOCOL 418-011 SPONSOR'S STUDY NUMBER: 6316.7 sPONSOR'S STUDY NUMBER: T~316.7 SSTTUUDDYYTTIITTLLEE:: PURPOSE PURPOSE: IESINGEAGLITY: TESTING FACILITY: SSTTUUDDYYDDIIRREECCTTOORR:: sponsor: SPONSOR: STUDY MONITOR: STUDY MONITOR: ALTWORTOR: AALLTTEERRNNAATTEE STUDY MONITOR: OOrraall ((GGaavvaaggee)) DDeevveellooppmmeennttaall TTooxxiicciittyy SSttuuddyy ooff NN--EEttFFOOSSEE he in Rats The purposeofthis studyis todetect adverse ofectsof The purpose of this study is to detect adverse effects of NEE on CA DBAOF iRss presumed pregnant N-EtFOSE on CrI:CD~BR VAF/Plus presumed pregnant erent ats ans dosage fo otro ant eh female rats and development of the embryo and fetus aro Eat a consequent to exposure of the dam from implantation to omhoee s atte:Thi shay evaluatIeCsH closure of the hard palate. This study evaluates ICH ommeaoa Trparhe Gudeine ages Cand 5 af tho Harmonised Tripartite Guideline stages C and D of the repro pasos. reproductive process. ArgusResearch Laboratories, Argus Research Laboratories, Inc. O03 Shoery Ove. BingA. 905 Sheehy Ddve, Building A Seaman Bonnegiania 0044-1257 Horsham, Pennsylvania 190~.~, 1297 Telemone. (315) 445.8710 Telephone: (215) 443-8710 focal SH prer is Telefax: (215) 443-8587 Raymmoond GG.. YYoorrkk,, PPhh..DD..,,DDAABBTT Aetosats DeofcReseatrch Associate Director of Research 3MToxicology Services 3M Toxicology Services SM Canter ildng 2202.62. 3M Center, Building 220-2E-02 8 pl vinnescs 65144-1000 St. Paul, Minnesota 55144-1000 ManinT. Case, DVM.PhD. Marvin T. Case, D.V.M., Ph.D. Telephone." (50 798:180 Telephone: (651) 733-5180 Tome (Gh rast7s Telefax: (651) 733-1773 AndroMw. Seacat, PhD. Andrew M. Seacat, Ph.D. Tetopmonc: (8515763181 Telefax (651)733-1773 Telephone: (651) 575-3161 Telefax: (651 ) 733-1773 1100117711330066 22778888..00112266 Fr, 3MA10083244 441188--001111::PPAAGGEE CC-22 Procol 418-11 Protocol Page? 418-011 Page 2 RREEGGUULLAATTOORRYYCICTITAATTIIOONNSS:: HUUSa.SrS.m.oFFnooiosoaddtiaaonnndd;DDGruruuiggdeAAlddimnmieniinosinsttrdraaetttiieoocnnti((o11n9999o4f4).)t.oxiIIncnittteeyrmntaoattiriooennparaloldCCuoocntnfifeeonrreefnnocrceemeoodnnicinal products. Federal Register, September 22, 1994, Vol. 59, No. 183. Harrnonisation; Guideline on detection of toxicity to reproduction Federal Register, September 22, 1994, Vol. 59, No. 183. for medicinal products. U2U.1.SS.C. FFFRooooPddaraatnn5dd8.DDrruugg AAddmminiinsitsrtraatitioonn.. GoodLaboratoryPractice Regulations; Good Laboratory Practice Regulations; Final Rule. Final Rule. 21 CFR Part 58. JJJoaarppSaaannfeeessteey MSMitniunidissitterrsyy ooonff HHDereaualglttshh, aaMnnHdd WWWeelOflrfaadrireena((n11c896e977)N.)u. GmGbooeoordd21LL,aabbMooarrraatctohorr2yy6PP,rra1ac9ct9ti7icc.ee Standard Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. `EEauucrrcooepppeetaaannncEEeccbooynntoohmmeiiEccuCCrooompmmemuannuinEtictyyo((n11o99m88i99)c)..CCoComoumuncnuicnililddteecoicfsisaiioonnnOooEnnC22D88 JdJueulclyyis11i99o88n99/rooenncottmhh-ee IamcecnedpattainocneobnyctohmepEiuarnocpeeawinthEcproinnocmipilcesCoofmgomoudniatyboorfaatnorOypErCacDtidceec.isOioffni/crieacl oJmou-rnal of tmheenEduartioopneaonn Ccoommmupnliiatnicees:withLepgirsinlactipiolen.s o3f2g(oNoo.d lLab31o5r;ato28ryOpcrtaocbetirc)e:. O1-f1fi7c.ial Journal of the European Communities: Legislation. 32(No. L 315; 28 October): 1-17. RERGEGUULLAATTOORRYYCCOOMMPLPILIAANNCCEE:: TTtehhgiiussissatttuuidodnyyswwicliillltebbdeeaccbooonvnedd.uucctteedd in in compliance compliance with with the the Good Good Laboratory Laboratory Practice Practice (GLP) (GLP) regulations cited above. AADlilllreccchhtaaonnrggaeenssd ootrrherreeSvvpiisosiinoosnnossr,ooffdtthahtiissedpprraoonttoodccmoolalissnhhtaalallil bnbeeedddwooicctuhummtehenetnepterdod,t,ocssoiilgg.nneedd by by the the Study Study Director and the Sponsor, dated and maintained with the protocol. aTTnhhdee wQQiuulaalIilnittsyypAAecsstssuucrrraiacnnaccleepUUhnnaiitste((QsQAAofUU)t)hwweiillsltaauuudddyiittintthhaeeccpporroortdtooaccnoolcl,e, ttwhhieethrraatwhweddSaatttaaanaadnnaddrdtthhOeeperrreeapptooirrtnt,g Procedures of Argus Research Laboratories, and will inspect critical phases of the study in Procedures of Argus Research Laboratories, nc.accordance Inc. with the Standard Operating `2TaTachhcceecauupffrrpiiaanlnttaiaeelclllayyrrbeerlrppeeeooffrllGretteLccwwttPissilllttrhiiehnnegecculrlrluauaadwdtweeioddaanaastsstaattwaaeootterbbetmetmaaeefiinnonneltetlddssoiiwddggeuunndrdeeindidnbgngbtytthyhtheetehhcepepoeenSSrrdtfftuouuocrddrmtyymaoaDDfnniticcrrheeeeoecctoftsooftrrttuhdhttheyhe.aaststttttuSuhhhddeeoyyurraaelennpdpoddorrtttthhaatt TasSoiillgggnnaeiitpffhipiceclairacnnawttibddtleehevviGhiaaoLttwPiiootnnrhessegffrduroeloavmmitiaoGGtniLLsoPPnwrrmeeeirgggeuuhiftloaatlatliiofoowenncesstdootccihcnceuutrqhr,,ueaeelcaaiotccynhhdowwfuilcililltnbbtoeeefgrtddhieteeysscsocrtfruiibtdbheyeed.d siiStnnuhdddoyee.uttaladiill, together with how the deviation might affect the quality or integrity of the study. SSCCHHEEMMAATTIICCOOFFSSTTUUDDYYDDEESSIIGGNN AANNDDSSTTUUDDYYSSCCHHEEDDUULLEE:: SSeeee AA-TI-TI-AACCHHMMEENNTT 1 1 to to the the protocol. protocol. 10 171307 22778888..00112277 MAI0083245 3MA10083245 441188--001111::PPAAGGEE CC--33 Protocol Protocol 44P118a8-g001e1113 Page 3 TA TEESSTTRART TICLI EAANNCDDVVELHEIHCIE CLLEE:: IIddeennttiiffiiccaattiioonn:: TToesstt AArrttiiccllee:: NPNahamymseie:c:al Description:~~ WNN-a-EExWtyFFOOsSoSlEiE.d.. `LPLSoohpttey/cBBsiaiafctitaccclhhGDrNNaevuusimmctbrybie:pertri::o. n: WF"F1MMa7--x.33y99s22o99lid((3.300003355,, 3300003377,, 3300003399)).. PuSPErxupptreiiytcry:ai:fticioGnrDaavtitey:: -99M19a9.y.171,%.%2..000. Expiration Date: May, 2000. IInnffoorrmmaattiioonn oonn tthhee iiddeennttiittyy,, ccoommpopsoistitiioonn,, strength strength and and purty purity of of the the test test artcie article is is on on fie file with the Sponsor. with the Sponsor. VVeehhicicllee:: 22De9%i%oTTnwwizeeeeednnWat88e00r)iin.n RRSeeuvvpeperlrssieeerOOassnmmdooslsoitissidMMeenetmmibfibrcraaatnnieeonoPPfrrooTccweesessseeenddDD8ee0iioownniliilzzeebdde WWdaoatcteuermre((RnR.t.OOe..d in ttDhheeei0rrnaawiwzedddaattWaa..ater). Supplier and lot identification of Tween 80 will be documented in 1tNnNo0eoeibbitateehhneeapprrlrryetethsssheeeeesnnSSttopptiiononhnnettsrhshoeoetrrhvvanneenohohrirticchttllhhoeeeesttehSShaatmttuuteddwwnyyotouiuDDloiliddnrreeeiicdcnnttttooeiernrrrfftiiesohsrrieaaoswwwpwaariirottrheethtootochhfofeealranerwneisyyluslluppbtolottsesteoencofntoftitniathadhliluissccctoossennttdutut.adadymmy.i.innTTaahnhnetetrssreefllfiiokokrereeelly.y. no analyses other than those mentioned in this protocol will be conducted. SSafaefettyyPPrereccaauuttiioonnss;: GfGollroomvvueelssa,,timmoanasskpkr,,eaappapprprarotopiproriniaaattenedeeyyadeemippnrrioosttteerccatttiioiononn.aannTddhaaeuuMnnaiitffeoorrrimmavl/ilaaSbbafcceootaayttaDarareettatooShbbeeeewwtoo(rmMnSddDuuSrri)innggis faaottrttamaccuhhleaedtdiottnoo tpthhreee ppparrrooattotoicocoonll a(nsdeeaAdTmTinAisCtrHaMtioEnN. TT2h).e (see ATTACHMENT 2). Material Safety Data Sheet (MSDS) is SSttoorraaggee:: VBBeuuhllikkcTTleeessCttoAAmrrpttioiccnlleee::nts: RRRoooooommm TTTeeemmmppeeprreaarttauuturrreee... VPPPrrereeehpppicaaalrrreeeeddCd oVVFemoehrhipmcioucllnelea:et:nitosn:s: RRRReooofooormimmgeTTTreeeammtmpeeppdreea(rrtaasuattuurmrerpee.l..esto be frozen). Prepared Formulations: Refrigerated (samples to be frozen). AAJlullllittaeenssttGauarlrtbtiiiccnllesekssihh,iipMpmamneeanntgtsserttooottfhhFeeorTTmeeusslttaiintnggioFFnasac,ciiialitttyytsshhehoopuurlleddvibboeeusaalddyddcrrieetssesdseeaddddttoroettshhsee aaatntttdeennttiioonn of of tJteuellleiaeppnhhoGonnueelbnninuusmmkbbie,erMr.. anager of Formulations, at the previously cited address and 1100 117711330088 `cSaShrhiiipopmnmseennstthssosushlhodouubllded liinancbcleluludedede iainpnfpfororormpmraaittaiiotoennlycc.oonnTcceherernnriinencggipssitteoonrrtaagsgeheoccuoolnndddibitteiioonnnosstiaafinneddd ssinhhiiappdppviinanggnce of cssahhriiptpommneesnntst.hould be labeled appropriately. The recipient should be notified in advance of 22778888..00112288 33MMAA1100008833224466 441188--001111::PPAAGGEE CC-44 Protocol Protocol 44P1188a.-g00e11t1 Page FFOORRMMUULLAATTIIOONN:: EFrerquoencqyoouffPPerreepnpaarrcaattiiyoonn: FFoorrmmuullaattiioonnss ssuussppeennssiioonnss will will be be prepared prepared weekly weekly at at the the Testing Testing Fact. Facility. DDeettaaiilleedd pprreeppaarraattiioonn pprroocceedduurreess are are attached attached to to this this protocol protocol (ATTACHMENT (ATTACHMENT 3) 3). AAddjujstumesnttffoomrrPePuurnriittWy: TThhee tteesstt aarrttiiccllee wwililll bbee ccoonnssiiddeerreedd 100% 100% pure pure for for the the purposeof purpose of dosage dosage calculations. calculations. TTeessttiinnqgFaFcaicliiltityyRReesseerrvveeSSaammpplleess: TdTuhhreeinTTgeeststhtiienngcgoFFuaarcscieilloittyyfwwtihiilllsrresetssueedrryvv.ee doutorifngvothhieciceoucrosmepoonf ethnistsstuusdeyd. dTTaauhhrsseeiaanmmTTgpeeptslslhteetieinn((cg1g1oguFF)a)racsoociefiflloiteetfyyaaccwtwhhhiillellloorsrtetteusosodefefyrr.bbvvuueellSkkaaattmsseeapasstmlmt peaaprlsrtlteeiiwccill((e5le5 uumss)eeoddfeach bmel) sotforeeadch uluonntddoeefrrvttehhheeicpplerreecvvioioomuuspslolyynGceinetetdsd ucosnedditdiounrsin.g conditions. the course of the study. Samples will be stored AANNAALLYYSSEESS:: S`nSaeammcppollueersssaaeddoddfiitttiiohoennaasltl uttodoy.tthhoossee ddeessccrriibbeedd below below may may be be taken taken if if dsemed deemed necessary necessary during during the course of the study. BuBlulkkTTeessttAArtrtiicclleeSSaammplpilinngg:: NINnoofoaarnnmaaaltlyyissoeenssooonff ttthhheee sbbtuuallbkkittteeysstotfaartrtthiicecllebeuwwlikillltbbeees ccaoornniddluueccttieseddondduuirreiinnwggittthhheethcceoouuSrrpssoeensoooftfrht.hiiss study. study. Information on the stability of the bulk test article is on file with the Sponsor. Analyses of Prepare tations: AAAGfcitootnennttahdwdhlieuyeutcschrrtteeeeetsqqdhduueoeeddsfSusutprPtroiionornnefgfgspttohttharhhee.reeeSSdccpHpooooFouunwnorrsesssrovem oereor,uo,rf,flnntatoohhrtieeeoaacnnnssoaasttrluul:dyyddsssyye.ew.isslHHooofbofmempporrmogeeaegppineaanenrrteieeadtdiityyntteeeaadssnntttddaaorrsstdtttiiaocacbllbceieiulliffmttooyyerrmniimnntuufflolhoaarrtomtmiiwoaaontnttiissohoennwwitliiilselslsbbooteonn afilretiwcithfotrhmeulSaptoionnssorw.erHeopwreevpearr,edr.ecords will be maintained to document how the test article formulations were prepared. 10 171309 CConocenntractioneooffnTTeeststtAArrtrtiiccalleeFFtoorrmmiulualoatitioonnnss:: oSCCstotnouunnddciycyeh.e.netndDDrtaruauayptptliipolioirccnneaaptootaeeffrttesshdhaae.emmpppplOrrleeeenppsseaa((rr2s2eeaddmmmLffpLoolrereemmaauocuclfhhlaa)e)ttaiiwwoocininllhlssbbswweeeitlillttlawabbikkleeelennvbveeeffrrrrioisffomihiemeiddptthphddeeeuudrrffiiiifnrnrsosggrtt ttaaahhnnneaeddlccyalosoasiuustsrtr:ssppeetrrheeooeppffaarttrhhaaiitstsiioonn on the day prepared. One rreemmaaiinniinngg ssaammpplleess wwiillll bbee sample rreettaaiinneedd oaaftt etthaheechTTeesssetttiinwnggillFFbaaceiclisliihttyyipaapssedbbaafcockkruuappnasslaaymmspispl;leetssh..e BBaacckkuupp sTTseaaesmmstptipilnnleggsFFawwaicliicllllilibibttyeey uusstpptoooorrnneeddrreeuuqqnnuuddeeeessrtrttothohfefetthhppeerreeSSvvpipioooouunnsssslolyyorr.cc.iitteedd ccoonnddiittiioonnss aanndd ddiissccaarrddeedd aatt tthhe1e 017130 22778888..00112299 MAI0083247 3MA10083247 441188-.001111::PPAAGGEE CC--55 PrPortootoccooll 441P18a8-g00e1111s Page 5 `SShhiippppiinngqIInnssttrruuccttiioonnss:: `Samples to be analyzed willbe shipped (frozen on dry ice) to: Samples to be analyzed will be shipped (frozen on dry ice) to: 3KKiMrissEJJn..vHHiaranonnssmeeennn,,tPaPhlh..TDDe..chnology and Safety Services 9B39uM33i55lEdBBinuunvsgsirhh2o-nAA3mvv6ee-enn0nuu9taeel Technology and Safety Services TBSSettu.lilePPdpaainuhulgol,,n2eMM-:i3innEnn-(ee06ss91oo2tt)aa7755855-116330331--833333311 TTeelleefpaxh:one: ((661122)) 777788--66011786 Telefax: (612) 778-6176 The recipient will be notified in advanceofsample shipment. The recipient will be notified in advance of sample shipment. DISPOSITION DISPOSITIO______~N: PEPrrrteeippiaaerwreeiddlffbooerrmmruuellatatutiimooenndss twwoililltlhbbeeeSddtiiussdccyaarrMddoeendditaaotrt atththeethTTeeesstptiirnneggviFFoaaucscilillyittyyc'..itAAeldlll arrdeedmmraeaisinnsii.nngg bulk bulk test test article will be returned to the Study Monitor at the previously cited address. TTEESSTT SSYYSSTTEEMM:: `SpSecipesieStrcainiaanneddRsReea/assoosnnftfoorrrSSeleaeleccittiioonnn:: TTbbinehehdcceeuaasuCCutsesrreIye::CC:fDoDr11~))nBBoiitntRRicisslVVioonAAnniFceeF/a/lmPmPIaslautummussmd~maile(a(SsiSliaappofrnnraadssggeppuuveeeeec-c-liDDioeeaapsswmwiaaeleecncyctcy)eea)plprrtatateettoddwwxaaaainsncsdydsswew(eileldieemdeccbeltrtleyyeydoduu-aafssseseetddttahltthehhrrTTooeeuussggtthhSSooyuyutssttteemm ttidGFnoooeaxdxvivciucceeiisillttottyoyrp/yypRtemmefr3eor;aeanrtnattonotnagaogeldlnenttic4nooc)lixxicinititininthycysse)a;);:;lt33es22))s)t)uthhttdihahissriiietsttsooisrcssriltiotccerrfaaaaildiilsnneddpavahhhteataaaalrssomaapbbannmeecddoeeelnneenoxxtgddappieeleecmmrtarooiiloenxelnsnincytsccitrtaeeyrcaateet(tixeexeivmiddsesttbttnoaoartyttbbothteeh-ihfsseeesestenTTapsneeleissscttititiiiivnevnesgegtatoond strain. Facility(l-z); and 4) the test article is pharmacologically active in this species and strain. Number Number: Initial population accimated: 119800 vviirrggiinn ffeemmaallee rraattss.. Initial population acclimated: Population selected for study: 112255 mmaatteedd ffeemmaallee rats rats (25 (25 per per dosage group). dosage group). Population selected for study: PPooppuullaattiioonn aassssiiggnneedd to to satelite satellite study: study: a11n99dmmtaahttreeedde ffpeeemmraaGllreeorruaaptsss ((|ff,iivIvleel appneerdr GGIrVr)oouuappssssiIIglInaaenndddtVVo tatoonxxdiicctoohkkrieinneeettpiiccereevGvaarllouuuaatptiisoonnI,. III and IV) assigned to BWBooddeyy WieiqghtaanhnddAAtg~ee:: wwFFbheeehimmicrcaheahlcleettoiimrrrmdaaeeettsadtthhwwteiehilyylell wwbbdieeailllyboobrreaeddfeeeeerrxrxeeppdrdeeecttccooteteiehhpddaatvttvaooeenbbdbbeeoowddaialtyytlllwwbeeeaeaeissigdtgthoh66tct00ssuomddofeaafnyy22tss00oe00ofdfggaaittgngooeet.22h. e22AA55rccatggtwuueeaadlaalacctbbahhoo.ddaaTytythrrwweeeeeccieweiggieiphphitttt,g,sshaawwtttiilll brraaenngrgeeecowwirlidlllebbdeethiinneccllduuaddyeeddafiitnen rtthhreeecffeiinnipaaltl rareenppdoorwrtt..ill be documented in the raw data. Th11e 0w0e11ig77ht1310 22778888..00113300 MA10083248 3MA10083248 441188.-001111::PPAAGGEE CC-66 Protocol Protocol 441P188a-0g01e111s Page 6 sSeexx:: FFFeeemm'alaaloleedrtraoatntsslwywiaill8l bbbeereggeiidvveeernnstthahenedtteeassrtteaanrrotiitccelec.o. nsMMiaadlleeereraadttsspoaofrfttthohfeetsshaaemmTeeessstooSuuyrrcsceeteaamnndd strain strain will will be used only as breeders and are not considered part of the -rest System. Source: Source: Chares River Laboratories, Inc. Chades River Laboratories, Inc. TTLahhbeeorrraaatttossrwwiielilsll,bbeeInc.ss,hhiiptpoppetehddieinnTeffisilttteeirrneegddFacccaairrltttoyon.nss by by ar air freight freight andlor and/or truckfrom truck from Charies Chades River River Laboratories, Inc., to the Testing Facility. IIddeennttiifficiactaioti.oonn:: RERaatotssanareree. CSeor.i, bInercs., ppuNNeeopor,ro.mmnaMMananSePsenPsnTtiTltglyy22n00miid1e1d0een0n1nt1t)ti)i.tff.ioieeMMtddhaaueullsseeTiiennrrsgagatttsiM sMnoaagonrrneFeeealggcl~iiivlvessteyeenn'llsffuu--pnnbpiirieiqqeeruuecceediinneppggreeeemrramaamrlraaenttnaraeegagnnssttt ((iGGdeeenyytiBBfiaacnnatddioaannndd pidopeunltaifticiaonti.on Tag Tag FnFauemmmibafrelceerastrraiautotpsnaoanrnreueaamsasbsselisgrgingsnmnweeehddnetttneteommaptsphosoeriraagTrnreyyesdnntiuutnommgtbhbFeeearsrcsstiluiaatdlyt y'rrseeobccenerieipptethtdeaaennbrddmaggaiilvsoveeefnrniadutuasnpnyioiqq0puuueoelfapptpieeorrrnemm.saaunnmeeenndtt gideestnatitfiicoantiboondnyuwmeibgehrtsswhen assigned to the study on the basis of day 0 of presumed gestation body weights. AANNIIMMAALLHHUUSSBBAANNDDRRYY:: AAalnllldccaaUggseeeossfiizzeLesasbaaonnrddathhoooruuyssAiinnngigmccaoolnnsdd'iittiioonnss are are in in compliance compliance with with the the Guideforthe Guide for the Care Care and Use of Laboratory Anima/~4). HTuHTdouhhonudeeusnNgsrrigaiannottttgsqshh::ewwerilaiccllltaosbnbhaeecababiiignntietdda.aiittvviiioiodNdnnuuoaapplenlellreyyrisioohhtddio.on.uugssDDeemuauddrtdieiinnnnrggissattcclaaoosiihhnnawallbielebislstistsabatesstiittooeesnneuel,,pl,,peewiwaaiiccierrhhede--pbpbbaaeoaiictrtrtaotoouomffmseraeeadtdttsscchwweaaiggifllleeebssbmeeeeaxxhhlccooeeruupapssttteesddwiiinln tbheesmacarliefircaetd'sbceafgoree. pNarotunreitsitoinngismeaxpteercitaelsd.will be supplied because the female rats will be sacrificed before parturition is expected. Room Air, Temperature and Humidity: TeThheeaaalnniimmtaahllatrroohooamms biisseiiennnddeepppaeesnnsddeeednntttlhlyyrossuuugpphppl9liie9edd.9ww7iitt%hh HaatEt llPeeAaasstftittteeenrnscc(hhAlaatnnoggCeelsseppaeenrrhh(ooouuorrm)oo.ff 100% 100% Romy" Room humid wil also be monitored constantly and maintained at 30% fresh air that has been RRooomm tteemmppeerraattuurree wwililll bpbaeesmmsaeaidinnttthaariinoneuedgdhaatt96904.947FF%((11H88ECCP))Attofoilt77e99rsFF(A((2i2r6o6CCC)l)eaaannndd mmrooononimitt)oo.rreedd to 70% constantly. Room humidity will also be monitored constantly and maintained at 30% to 70%. 10 171311 LLiigghhtt AAmanninaatuuatitoonmmeadta.iticcaEalalllycyhccoodnnattrrrokolllpleeedrdi11o2d2--whhiololuurbrelligiggihhtnt:: a11t22-1-hh9oo0uu0rr hddoaaurrrkksfflEluuoSorTreesscceenntt light light cycle cycle wwi1illll0bbe1e 71311 maintained. Each dark pedod will begin at 1900 hours EST. 22778888..00113311 MAI0083249 3MA10083249 441188--001111::PPAAGGEE CC--77 PPrroottooccooll 441P188a.0g01e11? Page DDiiset~: Rats wil be given Certified Rodent Diet #5002 (PM Nuton Intemational) avaiable Rats will be given Certified Rodent Diet~ #5002 (PMI Nutrition International) available 2d itm from mica feeders ad libitum from individual feeders. water Water: Water il be avaiable ad itu fom individual bots ataches to the cages or fom Water will be available ad libitum from individual bottles attached to the cages or from mate watesng access systom. All wate wil be rom local source and passed an automatic watering access system. All water will be from a local source and passed ia reverse csrmotia membrane before use. Cniorinewil be added[0 he through a reverse osmosis membrane before pprroocceesssseedd wwaatteerr aass aa bbaacctteerriioossttaatt;; pprroocceesssseedd use. Chlorine will be wwaatteerriiss eexxppeecctetdtetodo caodndteadintonothmeore contain no more rome pm citing at he me of analysis. Water is analyzed morihlyfo possible than 1.2 ppm chlodne at the time of analysis. Water is analyzed monthly for possible Seria ontamination and wice annual fo possible chemical contamination bacterial contamination and twice annually for possible chemical contamination. CCoonnttaammininaanntsts:: Netherthe Sponsor nor the Study Ditctor is awareof any potential contaminants ely Neither the Sponsor nor the Study Director is aware of any potential contaminants likely emai. cored diet of i tne inking water at lve that woud interfere to be present in the certified diet or in the drinking water at levels that would interfere wwiitthh tthhee rreessuullttssoofftthhiiss ssttuuddyy.. TThheerreeffoorree,, nnoo aannaallyysseess ootthheerr tthhaann tthhoossee rroouuttiinneellyy meas by th feed suppolrioesre Menton n tis protocol wi be canductes performed by the feed supplier or those mentioned in this protocol will be conducted. TION AND COHABITATION: UeRcUoppAmooNnnpdDtuaaOatrretriMairva-tIagilZi,le,AnhnmemTearIbraOalarlteetNeeeeaadddAnnerNrddraaDnffnmededmCaomoamOlamllHeefuuaAnntrriasBait,sttsIs.sT.owwAnAAieiTllfeltImeObbrreoaNaalaa:ccssccrssliaiiitmgmgnpanateetrioddonfntt,o,eo mveiiniagnrddgiliiinvnvaiifdtdfoeu.umamalalTalhhhleoeoeuurrcssaaoiittnhnssaggbwwiiooitllnnlabbttthieehoeenbbpaaessriiisscdooff mwcsoomilehleaicaeborinttoeesfdisthhtweeoo1ift0fhvvaaababgegmmirieannaaateaxxldlciimecCmaroouunnymm0mtteeaonoonleftftfssfpriavrafaetennsds,dddlua/oaooymnyrsrese.daa. mocgFFeoapesepluemtuaamarlttaaalioettoorrpnrryyaeaatrssppnfldieuwwmggiiathhsaOoslbbessissppgreeenearretrrv.vmdmeeaTaddotithoionneizsznooscdaiiaiotvuhooiadwwbbubissiallieelltarrbbHvtveeioeoeudndsiipinnneg.aariod considered to be at day 0 of presumed gestation and assigned to individual housing. nHeaetirhydmatewedifgehmoarlderraetde)wirlalnbdeomaiszsaitginoendp0rocdeodsuargese.groups based on computer: Healthy mated female rats will be assigned to dosage groups based on computer- generated (weight-ordered) randomization procedures. AADDMMIINNIISSTTRRAATTIIOONN: RR outaae nd so forChn oice: Route and Reason for Choice: The ora (gavage) route was selected fo use because: 1) in comparison wih the dTdiiheetaoryrarlo(uugttaee,v, atthgheee)eerxxoaauccttet ddwooasssaaggseeeleccacantnedbbeefoaarcccucusureraatbteeellcyya`auadsdmemi:innii1ss)tteienrreecddo;;maapnnaddri22s))oniitt iws iothnethoefthe is one of the oroposed totes for cinical use Droposed routes for clinical use. 171312 MsMtehthooddaannddFFrreeqquueennccyy: 10 171312 10 FBFgeeesmmotaaaltlieetonrra,aottthssheeewislippllwoebbindoegoohddggtiivaovfeafennonodrrttgghhgaaeenneottoeegngsseettnaneaatesrtatsiipicisspl,ce.roooDDxnnooiccssmeeaaagddgtaeaealsyislyywtwihaoilelnnl bsbddeeaaamyaayseds&j6uutisttmhtdheerrdooeuuffagogcrhrhhtt11hhd77eey.oommffooppssrrtteesrrseueucmcmeeeennddtlty recorded body weight and given at approximately the same time each day. 22778888..00113322 swAtooss250 3MA10083250 441188--001111":PPAAGGEE CC--88 Proocs Protocol 4411P88a-00g11e11 Page 8 RRatiaonatleffoiorr DDooossanaggeeaSSeleellecctUieoonn: DDoossaaggeesswweerreesseelleecctteedd oonn tthhee bbaassiissooff a a dosage-range dosage-range study study (Argus (Argus Research Research tL{fLhhaoaaabobtodtorssacrttatuouotdndorysyri.i,ueemsbbs,poo,tddIIinnyyocc.wnw..,eevPiPiagrgrlohohutttteooggsccaoaowililnen44wrw11ea88as-r-s00ed1d1de1e1ucPccPr)re)eetdatahhasasatteetatddlteelaassdltttoee11sdd00a00mgm,,gegi1s1./k,ktgg55e,i,/sddt11aae00dyy,,.aa22nn55ddaanhnhiddigghh33ee55rrmmddgoog/ss/kkaaggg/g/ededsasay,,y.a.annIIddnn feed consumption values were reduced at all dosages tested. DCDoossaoaggeenLLeevcveellses,, CnontcenrtraationtsaaninddVoVoollnuummesess:: Group [0 oor Lome | 0 | & |cosorapmuomie|n I Toes| +| or | 5|ousosvmunn| II Culos[oT0 Ts |eusonsommmnr | III TvToo| ww [2To|eneonconmen|m IV CyToeLo12To|sueonoonmenen V o~ Rat= 25 + 3" 25 + 5" 25 + 3" 25 + 3" 2.5 ~ 5" In'K~/kg/daY) 0 ~'Vehiclel 1 5 10 :20 (mg/mL) 0 0.2 1 2 4 (mL/kg) 5 5 5 5 5 ,a~:jus Batch Number B-418-O11-,A(D~.Montb.Yearl B-41~1 l~Day.~n~.Year) ~1~1 l~.Mo~.Tem) ~1~11~{Oa~.M~.Year~ ~1~ 11 ~(Day.M~.Year~ reticle cre 100% 0ume denncl The test article will be considered 100% puro ~or the purpose of dosage calculations. ST Wnan . Rats assigned to ~e satellite group for blood collection. TTA EESSTTSSN ,, ANA ALYSL ESAANNY DDMMES EAASSUURE REEMMENES TNST:S: VViiaabibliilittyy:: AAllll Periods: Periods: AAtt lleeaasstt ttwwiiccee daily. daily. CO Clilinniib ccaall Osbseervatrionsv anand/daolorrGt Geennei erraallAo Appppen eaarraans nccee:: AAcccclliimmaattiioonn PPeerriioodd:: PPrreeddoossaaggee Period: Period: W Weeekelkyly.. DDaayy 00ooffpprreessuummeedd gestation. gestation. DDoossaaggee PPeerriioodd:: approximately one hour postosage. TTwwiiccee ddaaiillyy.. P Priorrttooiddoo ossaar ggee aaddmmininisisttrraattiioonn aanndd oonnccee approximately one hour postdosage. PPoossttddoossaaggee PPeerriioodd:: OOnnccee ddaaiillyy.. C`ClalipinnpiriccoaapllriooabbtsseeebrrvyvaattthiioeonnSsstummdaayyyDbbireeecrreteoccroorraddneedddiommrooSrrteeudffryreeqMqouuneeinnttotllryy. than than cited cited above, above, if if Geemed deemed appropriate by the Study Director and/or Study Monitor. BBooddyWWy_e_i.~g_h~tghsts:: AAcccclliimmaattiioonn PPeerdioodd:: PPrreeddoossaaggee PPeerriioodd:: WW eeekekyl.y. DDaayy 00 aanndd 44 ooff pprreessuummeedd ggoessttaatitioonn.. 100117711313 22778888..00113333 MAt0083251 3MA10083251 441188--001111::PPAAGGEE CC--99 PPrroottooccooll 441P188a.-g00e11s11 Page 9 DDoossaaggee PPeerdioodd:: DDaaiil.y. PPoossttdoossaaggee PPeerriioodd:: DDaaiilly.. FFeeeeddCCoonnssuummptpitioonnVValaluuees,= ((rreeccoorrddeedd aanndd ttaabbuullaatteedd)):: PPrreeddoossaaggee PPeerriioodd:: DDaayy 00 aanndd 44ooffpprreessuummeedd ggeessttaattiioonn.. DDoossaaggee PPeerdioodd:: DaDyayss66,,88,, 1100,, 1122,, 1144 aanndd 1166ooffpprreessuummeedd gestation. gestation. PPoossttddoossaaggee PPeerriioodd:: DDaayyss 1188 aanndd 2200 ooff pprreessuummeedd ggeessttaattiioonn.. FrFeeepeelddencciooshnnsstuuhmmepfptetieioodnn. vvTaahllueueessse mminaatyyerbbvaeelsrreewccioolrrdndoeetdd bmmeootrraeebuffrlreaeqtqeuudee.nnttllyy if itis if it is necessatroy necessary to replenish the feed. These intervals will not be tabulated. MMataitinn.gqPPeerrffoorrm maannccee:: oMMbaastteiinrnvggawwtiililollbnboeefeevsvapaleluuraamtteeaddtoddaaziioillyynaddauurrsiinmnggeatthrhoeefcctoohhhaeabbivtiataagtitiinooannl ppceeornriitooeddntaasnnddanccdoo/nonfrfiirarmmceeoddpubblyyatory plug observed in observation observed in situof spermatozoa situ. in a smear of the vaginal contents and/or a copulatory plug CaCeaseasraeraena-nS-SecetciUoonniinngq OObsbesrevrvaatitioonnss:: bRRaeattrssewwmiliolllvbbeeedfCCraaoeemsstaahrereeaanun-t-sesereuccsttiiaoonnndeeddpolonancdedadayyin22i00ndooiffvippdrrueeaslsuucmomneetddaiggneeesrststa.attiiooTnnh..e The Trahtes fetuses fweiltulbsee.s wil will `beeexxaarmemmiinnoeevddeffdoorrfrnnouummmbtbheeerr uaatnneddruddsiissattnrridibbuupttliiaoocnneoodff::in individual containers. The rats will be CCoorrppoorraa LLuutteeaa.. II[mmPplplalacanentntaattatiieoonnapSSpiiteteeass.r.ance (size, color or shapeif abnormal) wil be noted in the raw d[Patlaa]c.entae appearance (size, color or shape if abnormal) will be noted in the raw data]. LL(iAivvelevaaennfddetDDueseaaidsddFFeeeftituunsseeedss.a.s one that responds to stimuli; a dead fetus is defined as a tdt(eAeerramlmidveffefeeftteututussutstsehhsaiastdtddedomeooefeinsnsseidnnrooatattsrrieenossgnppemooannthrddakttteoordetssstotiipmmeouxunltlidirsaaenntmoddestthahtiuaamtttouiilslsiy;snnaioosttdammeraaaerdrkckefoeedndtlsulyyisdaaiesuurttedoodlelyyftizznoeeedbd:de; alsatae drreeessaoodrrppftetiiotounnssse..))s demonstrating marked to extreme autolysis are considered to be late (EEaAarrcllyoynaacnneddptLLuaastteeisRRdeeesfsoiornprpetditiooannsss..a late resorptionifitis grossly evident that (ooeAarrgrgclaayonnnoroceggseeeopnrntepeutsssiioissins.hh)daaessfinooceccdcuurarrrseedda;; liaifftetthhiirssesiisos rnnpoottitottnhheeif ccitaaisssee,g, rttohhseeslccyooennvccieedppeltnuutssthiissadtdeeffiinneedd as as an an early resorption.) 10 171314 22778888..00113344 33MMAA1100008833225522 441188--001111::PPAAGGEE CC--1100 PPrroottoocconl 44P11a88g.-e00111110 Page 10 EFoettaall OObbsseerrvvaatUioonnss:: `GGrroossssEExtxeterrnnaallAAltlteerraattiioonnssaannddSSeexx: FaFenetdtuudsseeessawdiwlfillel tbbueeseeesxxaaalmmsiionneewiddlffbooerressxeeaxxmaainnnddeffdoofrroggrrrsooessxss eeaxxnttdeermfnoaarllgaarllotteserrsaatetiioxontnses.m. alLLaaattleeterrreeasstooirorpnpsltiiotoonnssthe eoearxxnttdseetnnadttteipspatodoiscssfaseilibtbuallnseeaeblbsuyutsatelssssuuo.ccwhhiloolbbbsseeerervvxaaattmiiooinnnssedwwilifllol rnnoostet xbbeeaniindncclfluoudrdegeddroiisnnseeeiittxhhteeerrrnddaaalttaaaltsseuurmmamtmiaoranirszizataottiitohonne or statistical analyses. `W BBooddyyeWeii ahtsg aannddIh dIdenetnit tfifiiccaats tiioonn:: TTbheheeusbbeoodddyytowwedeieiggthehtrtmooiffneeeaalccihhteffreeftteuutssalbwwioillldbbyeewerreeiccgoohrrtddeeaddv..eraOOgnnelslyy. bbooFddeyytuwwseeeiisgghhwtitlssloobffeliitvvaeegffgeeettudussweeissthwwiilll identification noting study number, liter number, uterine be used to determine litter fetal body weight averages. identification noting study number, litter number, uterine distribution Fetuses will distribution and fixative. be tagged with and fixative. `SSooffttTTiissssuueeEExaxmaimniantaitioonn: AaAlpptpperrroaoxtxiiiommnaasttebelylyyuoosnniene-g-hhaaalnlffaoodffattphhteeatffieeottunuossefessWiiinlnseeoaancc'hhs slliitettceetrriwwoinlilillnbbgeeteeecxxhaanmmiiqinnueeedd.ffoorrTshsooeffttfettiitssusssuueee.s will be intially fixed in Bouin's solution; sections will be retained in alcohol. alterations by using an adaptation of VVilson's sectioning technique(s). The be initially fixed in Bouin's solution; sections will be retained in alcohol. fetuses will `SSkkeeleletatall EExxaammininataitioonn:: TeTxhhaeemrrieenmmeadaifinnoiirnnggskffeeeltteuutssaeelssa(l(ataepprpparrtooixxoinimmsaaattfeetllryy sootnnaeei-n-hihanalglffwooifftththheaelfifezeattruuissneerssediinnSee.aacchhThlliitettteefrre))twwuilislllebsbeewill be iaeinndxiittadiiamealldlliyynaeffisidxxeaefdodpririnnseskaaeellrcclevooathhatoolilvl;a;el.sstekkerealleteitotaanllspprareeftppeaarrrsaatttaiioionnnissngwwilwilllitbbheearrleiezttaaariininneeddreiidnn SgIlsy).ceTrihnewfietthustehysmwolill glycerin with thymol be added as a preservative. RtReaepkprerenesseenntatattiivvee photographs photographs of of fetal fetal gross, gross, soft soft tissue tissue and and skeletal skeletal alterations alterations will will be: be taken. M METE HODTOOFFH SSAACCROIRFIFID ICCEE.: RaRanattissntwwirlialllpebbreeitssoaancecrariilfiicicneejddecbbtyiyoccnaaorrfbbeoounnthddiaioonxxaiisddieeaaasssopplhuhytyxixioainatt(iiooBnne..utLLhiiavvneeaffseeittauuss-eeDss wSwpiielllcbbiaeel,ssaaccrriiffiicceedd by by mamananniunuftfraaaccptteuurrrieteoddnebbyaylSSicnchjheeecrrtiiinongng--PoPllfooeuuuggthhhaAAnnnaiismmiaaallsHoHeleaulattilohth)n.).(Beuthanasia~)-D Special, NNEECCRROOPPSSYY.: 10 1"/1315 `GGervrooaslsussatlleieossniioo(nnasstwwaiblillllebboeefrrreeattanaiidnnoeemdd uiinnninnteseuuwtitrlraalllbbbeuufsfffeeerrdeeddto110s0e%%leffcootrrmomanaleliinncoffnootrrrppoolossgssriiobbullepe ffruuatttuufrrereom twweihvhsiaisccluuhheasaatlilofllonttriisa(ssansuyuteaespsboleeesxxsoaaibfmmliriaennneehdiddostamaottpnnuateenhcictorsrlooowppgssiillyycabwwleiiellluvbbsaeeeludrraeettottiaaosiinnneseeleddo,c,ftiignnornoooersrddsceeolrrentsttooirooppnlrsrg)oo.rvvoiiduUdenpelcceroasonstnt.ftrrrooolml specifciitcedabelllowy, tissues for any possible specifically cited below, all other tissues will bediscarded. histopathological evaluations of gross all other tissues will be discarded. lesions). Unless10171315 22778888..00113355 I3MMAAT100008833225533 441188--001111::PPAAGGEE CC--1l1l Protocol Protocol 4P41a18g8-e00111111 Page 11 SSaatetellilitteeRRaattssAAssssiiggnneeddttooTTooxxiiccookkiinneettiicc SSaammpplleeCColollleeccttiioonn:: OtOhnneddtaoayxyic11o88koionfef tppirrceeessvuuammleeuaddtggoeensstwtaialttliioobnne ((stthahceeriddfaaiyyceffdoolallolnowdwiintnhgge tthfhoeellllaoawssittnddgoosssaaagmgepe)l),,esrraacttsoslaalesscsstiieggdnn.eedd to to tBiBhnllteoooootsdodexssricaauommmkpspilneleeepsstaicr((aaaetppvopparrrltoouxuxaibitmmieoasantteeawllnyyildl44bcemmeLnsL.tarppcfeeurrigrfiecardaei.t)d) wwaTinilhllldebbeterhceeocsluoflolllteellicocntwtgeeisddnegffrrrosuoammmm(ttphahlpeeeipsnirnfocefxeroiirlmlioeoarcrtvteveelednyn.aa2 ccmaaLvv)aa wIwinihitlelollbSbsepeeoriiunmmsmmmoersedfeidoapiartateeralanlyyatolffyrrrsotoiuzzsbe.eennsToohannendddilriyycveeiicrnceewtriiaaflunnbgddeemmdea.axicinnTitthsaaeeiidnn,reeedwdseuffirlrotgionzhzegeednns,e((-ar-7u7n0m0dCCa()a)spuuanpntmritpoilllxssiemhhsiaipetmpcetmleiyeno2ntnttmoto L) t(hlaeteSraplolnosboe)r fwoilrlabnealfyrsoisz.enTahnedlirveetrawinileldbaet e-x7c0iseCdu,nwteisghhiepdm,eanntdtoathseaSmppolenssaerctifoonr (lateral lobe) will be frozen and retained at -70C until shipment to the Sponsor for aannaallyyssiiss.. RRpoaasttsssiwwbillielll abbsee dCCeaaseecsrsaiarbreeeaadnn-a-sbseeocvctteiioofnnoreeddraatasnnddasffseeittugusnseeedss{ww0itilllhlbebeemeeaxxiaanmmsiitnnueedydd. ggrrFooessstslulyyset1os0 ttahhneed extent extent ppSplploaaosccsneeisbnnolttearaeeafoswwridlialllenbabsleecyrspipbiooesoodlleeaddbppoeevrer ier and retained for rats assigned litter and retained frozen (70C) unt shipment to to the main study. Fetuses and frozen (-70 C) until shipment to the the Sponsor for analysis AAPflftateecrerncctooammlppslelaetmtiipoolnneosoffvssiaalmmbppelleeshcciooplllpleeeccdttiioo(nfn,c, zsseeenrruuommn,,dilrivvyeerircsse)eecctttoiiooKnnis((laaJt.teeHrraaalnllsooebbnee).),, Pefhet.taaDl.l aannaddt the ppPprolraeetcvivifeiooenudutsasilllnyysacacdiimttveepaddlnaeadcsdderwdoerifelslsssbsafemfoopsrhrlieaapnnpsaalehylidyspsim(sifse.r.ontzBB.eoontthhontthhdeeryrreeicccieipp)iieetonnttKaarnnisddJtt.hhHeeaSSnttsuueddnyy, Monitor wil be Ph.D., at the Monitor will be notified in advance of sample shipment. ScShcehdeduulleeddSSacarcirfifiiccee:: gOOrnnosddsaayyne22c00rooopffsppyrroeofsstuuhmmeeetddhoggreeassctitaact,tiiooannb,,dffoeemmimnaaallel rraaanttssd wwpieillllvbbieec vCCiaassecsesararareewaainln--sbseeecctptieioornnfoeerddm.,edaa.nndd Uaalteri of Spparenty nonpregnant rats will be stained with 10% gross necropsy of the thoracic, abdominal and pelvic apparently nonpregnant rats will be stained with 10% ammonium viscera will ammonium sulfide to confirm the. be performed. Uteri of sulfide to confirm the aabbsseennccee ooff iimmppllaannttaattiioonn ssiitteessr"n.. RRaattss FFoouunnddDDeeaaddoorrMMororiibbuunndd: GRReaalttvssettrhhyaatwtiddlilieebooarreaaxrraeemssiaanccerridiffiifccoeerddthbbeeecccaauuasseeouoofffdsmmeoaoretriihbbuuonnrddmccooornniddoiitutiinoodnn,,coaanbbdooirrtttiiiooonnn ooonrr pptrhreeemmdaaattyuurrteehe o2pdoabnnuebsddplsievesruaervwvttrieayarltdlitwiinnoboieenlonl ccbeiissooexnnmmatetameeaxdinndaetntem.sse.oidonfTTeftfhhfdoeeeetmmrfoheraaaerlttleteesshrxewwatriaetlicltnllssatwbbuwipeesloileeslelsxxbboiaaeefbmmldrrieeeei,nnccaeeooutrhddsrddiefofneodorgdr.rm.tgghrorAAeoodbbssbsoossurartntllmeeeedessddiicomoffoneneensstttu.d.uhsistoePPieodssrrnseeaaggondnnnndedaals/tnnocohcrrcreiyyddbdeesselatltdiiayavvttfeeutuohrrsrseeedd ffpeouttupussseesws.i.ll UbUteteerertixooaffmaaipnppepadarretenontttllhyyenneooxnntpperrneetggpnnoaasnnsttibrrlaaet,ss uwsililngbethsetasianmedewmitehth1o0d%s will be stained with 10% ammonium described for ammonium ssuullffiiddee ttoo ccoonnffiirrmm tthhee aabbsseennccee ooff iimmppllaannttaattiioonn ssiitetessrn.. 10 171316 22778888..00113366 MAI0083254 3MA10083254 441188--001111::PPAAGGEE CC--1122 Protocol Protocol 44P11a88g.-e00111112 Page 12 PPRROOPPOOSSEEDDSSTTAATTIISSTTIICCAALLMMEETTHHOODDSS(aTM'14TM) : SAApvvpeerrroaapggreeastseaa.nnddAdppdeeirrtccieeonnnattalaggpeerssocwweiidlllulbbreeesccaaallnccduullloaartteeaddn..aLlLiyittsteeersr vvmaaalluyueebssewwipillelrbbfeeoruumsseeeddd, wwfhhaeeprpreeropriate appropriate. Additional procedures and/or analyses may be performed, if appropriate. TyTyppeeooffTTeesstt" II.. PPaarraammetertriicc AA.. BBaratretltettts's Test Test=d IIlI.. NNoonnppaarraammetertriicc~" AA..KrKunsJ(ks7akal5lW-%Watalilelisis)TTeesstt (~75% ties) I SSiiggnniiffiiccaanntt aatt pp<~00..0055 NNoott SSiiggnniiffiiccaanntt Significantat p<0.05 Not Significant Significant at p~0.05 Not Significant NoNnopnapraarmaemtertiricc i Analysis of VVaardiaannccee DDuunnnn''ss TTeesstt i SSiiggnniiffiiccaanntt aatt| pp<~00..0055 Dunnett Test Dunnett's Test NNoott SSiiggnniiffiiccaanntt BB.. FFiisshheer7r''ss5EE%xxaactcittesTT)eesstt (>75% ties) IIIhI.. TTPeesrsttfofoorrpPoroprorttioin DoDaatntaa VVaardiaannccee TTeesstt ffoorr HHoommooggeenneeiittyy ooff tthhee BBiinnoommiiaall DDiissttrriibbuuttiioonn 5aa... PSSrtotaapttoiisrstttiiiccoaanllllydyasstiigagnnaiifrfiieccnaaonnttt ppirrnoocbblaaubbdieilldititieenssthaairrseecrraeetppeoogrorttreeydd. as as either either ps0.05or p~0.05 or p<0.01 p~0.01. c3cb.... Test for homogeneityofvariance. PUUrssoeepddoorontinollnyytdtooataaannaaalrlyyezzneedodatatintaacwlwuidittehhdhhionomthomigsoecnageteitegyooonfryfve.vaaririiaatnnccyee.. 1100117711331177 d. Test for homogeneity of variance. 22778888..00113377 MAT0083255 3MA10083255 441188--001111::PPAAGGEE CC--1133 Protocol Protocol 4P41a18g6-e00111113 Page 13 DDAATTAAAACCQUQIUSIISTITIIOONN,,VVEERRIIFFIICCAATTIIOONNAANNDDSSTTOORRAAGGEE:: DoDDDiraraiirtegteaiaccntatwwooilrlirllfalaenbbncdeedolr/hhoodaarrsnnaadwdpip--lpplraaronbnopdedprl/risooiaatrrtoteccerooemmmdmapaipunnntuaatetgehgreer-e-mrmraeeereccncoonhtrrtiddvppeeeeedsdrro..ssfooRRnntenhneceeecololTrrwweddisiststthhiwwiinniniglll221Fb1baeecddirraaleeyytvvyssi.ieaaewfwtAtteleeelddrroggbrbeieyyngneitternhhaareealtitSSdiootatnunut.dda. yywAAillllll brboereeqigubbienoosauutlnn.rddePcaaronnerddsdesiinrnwdvdeeeilxdlxeebdtde.i.ssstAuAoecrsceoodwpiplyiylnobotfhefaealslltlaorarrcaewhwdivddaeaatstttaaohefwwiTtlihelllesbbteTeisensusguptippnFplagcliiieFelddatcyttoiolaittttyhh.neeo ASSclplphoooanrnrisgsgoioenrrafouul rppdoooannntae will y{yrfeeeoqaadrureetaasefftttr.eemrriPmmnraeeaistlilhieinnerggvdeioodsffptttoihshseseiutddierroasanofRwtfffitilinlnhabaelelsrrseeeptpoomorrarettt,de, raaiaffatteletsrhr.ewwhhTiieccshhtitntiimgmeeFtathhceeilitSSyppaootnnsnsooorrcwwhialillrlgbbeeefccooornnottnaaecctteedd to determine the disposition of these materials. R RECOERDSC TTOOBOBEEMR MAAININD TTAAIINNS EEDD:: PTPrerosotttooAccrootlilcaalenn,ddVAAemhmieecnlndedmmaennedtn/stos.r. Reagent Receipt, Preparation and Use. AATRnaeninsimmdtaoAalmlritAAizcccalqequt,iuisVioisnteitihiSooinccn.hl.eedaulnedslo.r Reagent Receipt, Preparation and Use. MMTRaraatentiaidnntoggmmeHHniiztisstato(otrfiroyy.pn.reSscchreidbeudlebsy. Staff Veterinarian). TGGClereiennnaeiectrmaralalelOnCCbtoso(emmifrmmpveareentnsittcsos_rnisbeadndblyorSGtaefnfeVreatlerAinppaeriaarna)n.ce. CBBBlolloiodnooiycddaWaalhnnOiddgbhTTstieisssrssvuuaeetioSSnaasmmappnlldee/oCCorolGllleeeccnttieioornna,,l Processing and Appearance. Processing and Shipment. Shipment. FCBFaeeoceedsddyarW CCeo~eanninsgs-uhuSmtmespc.ptttiiiooonnniVVnaaglluuaeenssd.. Fetal Observations. CGGOrraroogessasssnarNNWeeeeacicnrgr-oohStppessscyytiOOobnbsisenregvrvaatanitdioonFnsse..tal Observations. OPSPhthrougotdatoyonggMrWraaaieppnihhgtsshet((nsiff.arrneecqqeuui(irrreedod)o).m. and environmental records) SFPFaeetuceedkddiynaaMgnnddaainWW ndatleatonterearrSnAAhcnienapal(mlryyoessoneesmts..Laisntds. environmental records). Packing and/or Shipment Lists. KEY PERSONNEL: KEY PERSONNEL: EEDixxreeecccututotiirvvoeefDDRiierresecectatoorrrcohof:f RRAeelssaeenaarMrc.chh::HoMMbieildrdrmreeadnd,SS..PhCC.hhrDir.is.sttiiDaaAnn,,BPPThh..DD.., Fellow, Fellow, ATS ATS AADDsisisrsreooecccctioitaartoteoerffDDLRiiarrebeescocetrtaooarrrtcooohrff:yRROAeepslsaeeernaaartMrcci.hohnHaaso:nnbddeJSSromtthuuanddnyyF,. DDPiBhirra.eemDccet.tt,oortrD:.,ABRRB.aa5Ty.ymmoonndd G. G. York, York, Ph... Ph.D., DABT DABT MMMDaaiarnnenaacaggtgoeeerrrrooooffffLASSanttbuiuomddrayyaltCCooOrooyporedrOrdiapinnteaiatroatiintooisnon.n:asnVV:daaJMlleoeerhmirenbiAeAeFr.. ,SBShahIanrarsnrtpepietetrtu,r,t,iBMMo.n.S.aSS.l..Animal Care and MMaaUUnnssaaeeggeCCerorommoomffmiARtientetgieemue:la:altDDOoerepynneaaCraoCCtm.i.oplnLLieseabbnaoocn,,edV:V.M.MMeK..DmaD.tb. ehrl, eIneAsn.titMuotiroanna,l Animal M.S. Care and CCMaoannnssauugklaetanrntot,,f VVReeettgeeruriilnanataorrryyyPPCaatothhmoolploolgiagyny::ceWW:..KRRaaathyyleBBerrnoowwAnn.,,MDDo..rVVa..nMM,..,MPP.Shh.D.D.., ACVP ACVP 10 171318 22778888..00113388 MA10083256 3MA10083256 441188--001111::PPAAGGEE CC--1144 PPrroottooccooll 4P411a88g--e00111114 Page 14 FFIINNAALLRREEPPOORRTT: AbAeccfooimmnpaplrireezhehdeenfnsosililvvoeewiddnrrgaaffcttoffniinsnuaalll trraeetppiooorrntt wil wwiitllh bbteehepprrSeeppponaasrroeerdd. oonnTchcooemmprpelpeleotrtiitoonwnoiloflftithnhceelussdtteuuddtyyheaanndd will will following: be finalized following: following consultation with the Sponsor. The report will include the `ESxSupumemrmmiaamreryyntaaannlddDCCeosonincgclnulusasinioondn..Method. AEADEEvappvxatpapplaeleeu,nurnadaiPtimdtriciiooceoetnennsos.tocoa:fofllTTFFDeiaeieggsnssuutdtirrgeeRRAnsesse,s,sasuSSounlctuldutsismm.aM.mtmeaetadrhryoAydmaa.ennndddIImnneddinivvtiidsduuaaallnTTdaaDbbellveeissatSSiuuomnmms,maraSitrziuzidinnyggDttihhreeecAAtobbroo'svvee GDGLaLtPPa,CCPoomrmoptlpoilciaaonnl ccaeendSSttAaasttesemomecenianttt,e, dRReeAppmoorerttnssdoomffSeSunuptspppoarontrdtiinnDggeDDvaiaatttaaio((niisf ,aappSpptruroodppyrriiDaattireee))caatonnrdd's QQAAUU SSttaatteemmeentn.t. ININSSTTIITTUUTTIIOONNAALLAANNIIMMAALLCCAARREEAANNDDUUSSEE COMMITTEE COMMI3-1"EE STAEMN: STATEMENT: TITnhhseetitppurrtooioccneeaddluuArrneeissmddaelessCccrariirbbeeeddaininndtthUhisisseppCrrooomttomocicotoltl ehheaa.vveeAbblleeeeprnnorrceeevvdiiueerwweeesdddbebysytctrhhieebeTTdeessitntiintnhggisFFapacrcioiltlitotyyc''ossl that involve Institutional that involve discomfort, dAssittnsuutidmdryyeasaalsnnCoiirmamrapaelalssiannwwidtlilollUtbbsheeeeccaCoonnnoidmdmauulmccstt.iteeteddeii.nn a manner to avoid of minimize. All procedures described in this a manner to avoid or minimize protocol discomfort, distress or pain to the animals. TTnehhceeesSSsppiotonynssofoorrr''sscossniidggunncaatttiuunrrege tbbheeilslooswwtudddooyccauunmmdeetnnhttessfttahhceet fftaahccatttttthhhaaitts iiinnsffonorormtmaaattniioounnncncoeocnneccseesrrannriiinnlggy the: the ddpnuruepopclceliieccsdaasuttitiirvyveeefsossrwttuecudrodeyyndmmauvaacayytiilnbbagebeltoehobbifstotaarsiitnmuneeededdytffiarrnonogmdmtttthhhheeeesfSSatpacpottoentndshsoaportu.rt.rhpiNNossooiesaasnlolttfoeettrmnahaantetiivuvsenteund((eiiynn.cevvisittsrroao))rily procedures were available for meeting the stated purposes of the study. RREEFFEERREENNCCEESS:: 1. CCThehrsritissst.tiiaaEnn,n, vMMi.r.SSo..nmaaennnddtaVVlooyyPtrteeokkt,e,cPPt..iEEo..n ((A11g99e882n2)c.)y.,IIWnnaVVsihivvioonRRgteeoppnrr,oodDud.Ccu.tcivNteaiataivnnodednaMMluuTteatacggheenniincciciaitltyy IITnneffosotrrsmm.aatEtiiononnvirSSoeenrrvmviiecceen,,taUUl..PSS.r.oDDteeceptiaoprntmAaegnertnoocftyf ,CCmW oommeamsmehnreicnrtcege,to, nSS,pprDriin.nCggf.fiieNelladd,t,ioVVnAAal 22161. Technical 22161. 2. CnChahrlritissrtteiiaxaonnn,,eMM.(.SPS.r.o((c11e99e88d44)i.)n.gsRReoepfprNrooadldutucrctetixivvoeenettooSxxiyiccmiittpyyoaasnniddumtte,errNaatteoowlloogYgyyoreekvvaaAllcuuaaatdtiioeonmnssy ooofff SnScaciliteernneccxeeossn,,eNN(oPovvroeecmmebbeeedrrin77g,,s11o998f833N)),a, ltJJr.eCCxloilinnn..ePPSssyyycmchihpaioat.st.iu44m55((,99)N)::e77-w-1100Y..ork Academy of 3. LLCaoannntggr.,olPP..DLL.a.t((a1199i88n88)t.)h.e EEChmmabbrrlryyeoos aaRinnvddeFFreetCtaral.lDDCeeDvveelBlooRppRmmaeten.nttaaClhl aTTrooxlxieiccsiittRyyi(v(TTeererrLaaattbooolloroaggtyyo))ries, CIInnocc..n,,trWWoilillDmmiainntgagttioonnn,t,hMMeAACh00a11d88e88s77-R-00i66v3e30r0..Cr((ID:DCaatDtaa~bbBaaRsseeRapptrr.oovvCiiddheeadddebbsyy RArivgeursLRaebsoeraartocrhies, Argus Research LLaabboorraattoorriieess,, IInncc..)) 4. ILInnassbttoiittruuattteeooorfyf LLAaanbibomoraralastt.oorryyNaAAtnniiiommnaaalll RRAecesasooduuerrmccyeessPr((1e1s999s96,6))W..asGGhuuiiniddgeetfoofonrr,tthhDe.eC.CCaarreo and and Use Use of of Laboratory Animals. National Academy Press, Washington, D.C. 10 171319 2277888..00113399 33MMAA1100008833225577 441188--001111::PPAAGGEE CC--1155 PrPortootoccooll4P411a88g.-e0011115 Page 5. W W(mmaWiailislslfsofoooonnrrn,m,m,aJJatJ..t.GGiiGo.o..nn((ss1a199niin6n6d55ee)Wx.)xa.ppreeMMkrreiaiemmtnteyhhen,oontddtaJa.ss,lloffaadoonnsrrii.mmaa)adda,lmmslis.Uni.nniiissvTTtteeeeerrrrrsaiaiintnttogogyllooaaoggfggyyeeC::nnPhtrtiPssicrniaaancgnncioddipplPddleereesesttseeaasccn,tntiiddnpnpgg.TTee2cc6hh2nn-ii2qq7uu7ee.ss (Wilson, J.G. and Warkany, J., eds.), University of Chicago Press, pp. 262-277. 6. StSthtaeappKllOeesHs,-,aRRliE.Ez.a. raainnnddrSSecdchhSnnemleelll,t, hVV.o.LLd.. f((o11r996f64e4)t.)a.l bRRoenefefii.nneeSmmteeanintnt iiTnnecrrahanppioiddl.ccll3ee9aa:rr6iin1n-gg63tte.ecchhnniiqquuee in in the KOH-alizarin red S method for fetal bone. Stain Technol. 39:61-63. 7. SISmaapllleeawwnsstkakiti,,ioEE.n.s((s11t99e6l64i4)e.)n. aFFma~UrrtbbeeermmueesttdhheoorddeeRazztuutmem. mmAaarkckrhro.ossPkkaootpphioisls.cchhEeexnnp.NNaaPcchhhawrwemeaiikssovvlo.onn 247:367. Implantationsstellen 247:367. am Uterus der Ratte. Arch. Pathol. Exp. Pharmakol. 8. StShnneeedbdeiecncooormr,i,aGGl W.dWi.st.raaibnnuddtiCoCnoo.cchhrSrtaaannt,i,sW tWi.c.GGa.l.M((e11t89h667o7)d.)s. ,VV6aatrrhiiaaEnndcicteetiotenes,sttlffooowrrahhSootmmaotogegeeUnnneiievtietyyrsooiftfy Press, Ames, pp. 240-241 the binomial distribution. Statistical Press, Ames, pp. 240-241. Methods, 6th Edition, Iowa State University 8. BSSoiokokamalel.t,rRRyR,.R.W..aaHnn.ddFRRrooehhellmf,,aFFn..JJa..n((d1199C66o99.),.). SBBaanarrttFllereatttn'stctitesescsott,oofpfp.hho3om70om-g3eo7n1.geiteyoofnfvveaarriiiaanntcceeyss.. Biornetry, W.H. Freeman and Co., San Francisco, pp. 370-371. 1100.. SSMnenetedhdoeedccsoo,rr,,61GGh..W WE.d.itaainnoddn,CCloooccwhharraaSntn,a,tWWe..GUG.ni. v((e11r96s66i7t7)y)..PrAAennsaasl,lyyssAiimsseoosff,VVaparpr.iiaa2nn5cc8ee-..27SS5t.taattiissttiiccaall Methods, 6th Edition, Iowa State University Press, Ames, pp. 258-275. 1111. . tDDruunennaenttemtet,tn, tCCsW.wW.it. h((11a995c55o5)n.t).rolAA. mmuJ.ultlAtiimppellere.ccooSmmtpapta.arriAisssosoonncpp.rro5oc0c:ee1dd0uu9rr6ee-1ffoo1rr29cc.oommppaarriinngg several several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1129. 1122.. SSWoHokk.aall,,FrRRRe.R.e.maaannnddanRRdoohhClo,f,.,FFJ.S.Ja. n((119F96r69a9)n.)c.isKKcroruu,sskpkapa.ll--W3Wa8l6al-lli3iss89TT.eesst.t. Biometry, Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389. 1133.. D6D(uu3nn)n:n,2, 4OO1.-.J2J.5. 2((.11996644)).. Multiple comparisons using rank sums. Multiple comparisons using rank sums. Technometrics. Technometrics 6(3):241-252. 1144.. SMSicieeGggreeall.w, .S.H.i((l11,995N566)e.)w. YNNooronknp,paaprpra.amme9t6er-tr1ii0cc4.SSttaattiissttiiccssffoorrtthhee Behavioral Behavioral Sciences. Sciences, McGraw-Hill, New York, pp. 96-104. 2277888..00114400 10 171320 33MMAA1100008833225588 PPRROOTTOOCCOOLLAAPPPPRROOVVAALL:: FOR THE TESTING FACILITY FOR THE TESTING FACILITY Q Fin . Fau pnran, 1t 0.DRST b Alan M. Hoberman, Ph.D.,DABT Ree Director of Research EM Bie saBrsacoorv)dhreaarcrn Study Director DBaimeotshe, YlMo.te Dena C. Lebo, V.M.D. DC vans Anal Care and Member, Institutional Animal Care and ae Use Committee FORTHE SPONSOR FOR THE SPONSOR WSionrntGaete, DVM. PRD. N/A Marvin T. Case, D.V.M., Ph.D. Study Monitor 441188--001111::PPAAGGEE CC--1166 Popoay Protocol 418-011 Page 16 = ims Date aun PoDate a = nda Date mePhy trop Date 10 171321 22778888..00114411 sssonis 3MA10083259 441188-.001111::PPAAGGEE CC-1177 AATTIT'AACCHHMMEENNTT 1 1 SSCCHHEEMMAATTIICC OOFF SSTTUUDDYY DESIGN DESIGN AND AND STUDY STUDY SCHEDULE SCHEDULE 22778888..00114422 1100117711332222 aMAtoosa260 3MA10083260 ATTACHmeMEN1T ATTACHMENT 1 441188--001111:PPAAGGEE CC--1188 PPrrooctoocFlol #4a1188-001111 Page 1 of 2 SSTTUUDDYY sScCHHEEMMAATTIICC DDEEVVEELLOOPPMMEENNTTAALL TOXICITY TOXICITY STUDY STUDY DSSottsaara~tgooeff CoChoahbaibt~aatSioonn Dosage FReamtaele P`PrGDDraeeyeassstyuua77mtmoieeoofdfdn Gestation nEonasdaoo0fe Dosage cCSaaeeeRssaoarnreeaiannng;, Sectioningn PGPDDerraaseyytsaluu1t7mm7ioeoeofnddf Gestation PPDGerDraeseaytsysauZ2utm00mieoeeofnddf Gestation sm a= FMF==oeoDDraroosaassduddaardiggeitteemiiooePPnnneaaetrlrlsiioddo"eddetstaaeicilltssiossneceeof""TtTheeessttpssr,.oAtAnoncaoalllyysseess and and b= Measurements" section of the protocol FoR olcUssvuemorastkeolcantlas ral 12 per Fetal e~aluations (all - extrnal, lr2 per hr- litter - soft tissue or skeletal) 2277888..00114433 10171323 10 171323 amatocss2st 3MA10083261 441188--001111::PPAAGGEE CC--2200 ATTACHMENT 2 ATTACHMENT 2 MMAATTEERRIIAALL SAFETY SAFETY DATA DATA SHEET SHEET 22778888..00114444 1100117711332244 amAtoosa2s2 3MA10083262 441188-.001111::PPAAGGEE CC--2211 MMAAT'I"EERRI~IAALL SSAAFFEETTYY DATA SHEET aS53t55.10c40a4Pna-3u1t6l0e4,0r-03M5i7m7esoorts(612) 77-6501 (24 hours) DA~'A SHEET a3wM 3M Center St. Paul, M nnesota 55144-1000 1.800-364-3577 or (612) 737-6501 N-E4FOSE (24 hours) CO opyriO ght, 1T9a0s8e,rveMdi.nnesCootpayiWnignianngd/oarnddMoawnnultoaacdtiunrginogf tCohmipsany. Copyright, 1998, ~innesot& M~ning and Manufacturing Company. A rt ine purpose of properly Utilizing SH products All r~ghts reserved. Copyng andlor Oo~nZoadLng of this information for the purpose of properly utilizing 3M pro~uc~s 1L"E Lionoe us providedamtishacto:pied in full with no changes unless ~s allowed provided the~: 1) the information is coped n full with no changes unless a oE e orey esent 16noorbttahieneodrifgrionnalOKi,b ranedsold or ctheruise prior agreement ~s obtained from 3M, and Te EY ne intention of earning a profit thereon. 2) neLthe~ the copy nor the or~g~n&1 s resold or otherwise distributed w~h the intention of earning a proft thereon. DIVISION: 30 CHEMICALS DIVISION: 3M CHEMICALS ThAosEwakieo:mAD Brand Fluorochesical Alsonol TRADE NAME: FC-IO FLUORAD Brand FZuorochsmical Alcohol 10 KangEeRn PPCC. p.51135.00435-2 98-0211-1163-0 00-51135-09542-3 ID NUMBER/U.P.C.: TS oeoiis6.0cie-5 96.0211.6620.6 00.51135-10435:2 98-0211-1113-7 98-0211-1575-7 SP iaoiieraz oo - ZF-0002-0572-2 00-51135-09495-2 00-51135-02145-3 " " 98-0211-1183-0 98-0211-6620-6 1S8UED: sanuary 29, 1998 ISSUED: January 29, 1998 Sopenseoes: November 05, 1957 SUPERSEDES: November 05, 1997 DOCUMENT: 10-3776-7 DOCUHENT: 10-3778-7 00-51135-09542-3 00-51135-10439-2 1 inenepinT .................................. 1. INGREDIENT CPLUOROOCTANESULFONANIDD ALCOHOL... PERFLUOROOCTANESULFONARIDO ALCOHOL ...... Pat ronanlo0 ALCOHOL... PERFLUOROHEXANESULFONAHIDO ALCOHOL ...... PSROWAZ00 ALCOWOL. |... P~RFLUOROHEPTANESULFONAMIDO ALCOHOL ..... BO ownibo ALCOHOL... PERFLUOROBUTANESULFONAHIDO ALCOHOL ...... DO ecavL FOMIIDO ALCOWL.... P~RFLUOROPENTANESULFONAH~DO ALCOHOL ..... Sas vo. C.A.S. NO. 113646949181:5-89-909:3-22-3 363S448a445s455s055s.---078T033o:--3773 3e4s4s4s9s-.8792-36 68555-72-6 secant PERCENT 8380.0.0.00 32..00 == 9910.0.0.00 - 607.0 2221....0000 - 6.0 3.006.0 1.0 3.0 3 avsicaL DATA 2. PHYSICAL DATA BOLLING POINT: ce. cerssnes BOILING POINT: ................. VAPOR PRESSURE: . . . . canis VAPOR PRESSURE: ................ VAPOR DENSITY: ..e.vocscunsns VAPOR DENSITY: ................. CUAPORATION RATE: o.oo... EVAPORATION RATE: .............. SOLATLITY IN WATERS |L101. 1.0. SOLUBILITY IN HATER: ........... PETE GRAVEL SPECIFIC GRAVITY: .............. PERGENT VOLATILE: ......o. oo core PERCENT VOLATZLE: .............. ph ATE pH: ............................ Ssosirvi,11 IIIIN VISCOSITY: ..................... NecTINe poi: HELTING POINT:... .............. GcB1a.. a11m118 8vCo << > @CCa111al001:lcc0mB~m@0AH HLDgHT22E00g) C ><CC11aa:.lc0c0 A@Bu~O22rA00=Cl=Ci. < 1.0 BuOAc=l neglio neglig. catror1.e7rtW)aters ca. 1.7 Nater=l O %(of melt) 0 . Nwwi/eDe N/D 10174325 10 171325 2728788.8.00114455 a3MMmAA1t0o0o8s3a2263 4411884:301111::PPAAGGEE C-22 C-22 po om _(comminee) ps: FG-10 FLUORADgrand FiuorochesicalAlconol ,SOS: FC-10 aannuuaarrYy 28, 29, F1L9U9O8RAD 1998 Brand Fluoroohemic&l AlcohOl .............. 2. pHYSICAL DATA (continued) ......................... oe 2 pAGE 2 AApPpPeEEAmAReRAArNNCGwEEaxAAyNNDDsoOO1DDiOOdRR:: Naber ~axY solid "Ta. 4p setatiash 3. FIRE ANDEXPLOSION H~AZZ~AROD ODAAT~A FIRE AND EXPLOSION ................. > 148 C Setaflash uFFumOnBPLtOIENThLE rIsSerLbE ese WR FLASH PoINt: ........... .. FLA~F~BLE LIRIT5 " LEL: ...... .. empmaTine ++ FL~HA~L~ LIHITS " UEL; ...... NIA ~EEUXXTTTT~OIIaNNI~GGGoeNUUrIII,TSSIFHHOcCIIIaaNNRNrrEGbGbTooEFMHnnIREEGPDddDHIiiTRIAoAoIASxx:NTiiGUddReePE,,RR: OO.ODCG.~EY.EC.DU.UctT.hRnEgeEeR:mSn!:i{cCnaacl1l.,,u.goF.iosn.agmm..heell~meet~,, n psspeeaLlrfE.sc-uoCsn,OTNaDEiInTNeKGd:", co at _ Se.HcE~pecIo.ni~ AsaLiI tvFieIRvEepprFrePIosrGtasHmeueTacrsZrteNaianGvorgeroPufcBn-ol-dr-oLtrehhaiixOnt~,p,enSiEnAhceTLe,uaa~anogtfei~tp.hns.e,.g.hresaaac~denamra~suk.s, andbunke~ coa~ vawapnsnFdudoA~DpLeoaecnF~~IuevSRe,E sbccAaooInvvDdeDsFEEe~XXca,PoPgFLsLoOOpufSoSonIsIdOrOsNNteixHMopn/~Ao.sAZ3eR6dEO,S5a:5re"asorof ~be head. products of coRDUSTION UNUSUAL FIR~ A~D~.o ~os~lon seo~on for producTS of combustion- see HazarDOUS u=~ ~ o REACTIVITY DATA 4. REACTIVITY DATA ........... sagiLITY: Stave TCOUPAaTpIpBlIiLcIaTbYle: ATERTALSICOUDITIONS TO AVOID: wild not S5SUT: fot LsaaRDoLS POLYMUEPROISZIATTIIOONN:PRHOaDzUeCrEd,ol porymerszation oxtes of Nitrogen, Ouxliadteess:of nzaACsaiOroboSounsMaaDrEeCeO .enanFauaCrasrdtea,n DToOxiAc ,1287S Soto or partic L ErviROWENTAL INFORMATION SPITLeLLreRREcESSkPPyOONIaSnSEo:ELheaslatchiohnEsZiFoPfORSL,tiLh:isswOpeireSat1oCr7y TriinotveoercastTsi:tmoianoc,nerriveaglea.rrditCngeia:a7no BBYeetea. prPoltaeccetiivne 8eaUUSL Orapproved coNRNE 10 1;1326 22778888..00114466 33MMAA1100008833226644 441188--001111::PPAAGGEE CC--2233 MSDS: FG-10 FLUORAD Brand Fluorochemical Alcohol January 29, HSDS: FC-IO january 29, 1998 FLUORAD 1998 Brand FIuorochemic&l A!cobol La PAGE 3 5. ENVIRONMENTAL INFORMATION 5. ENVIRONRENTAL INFORHATION (continued) (continued) RREECC2oIoO0nfc~MciRMaianEnEeNNeccrDDrooaEaEm mtDDtueebsDDutiIiIsnSinStPbiPbOOlaalSeeSAppALm meLe:ar:ratmmeiterittittreiaealddl..ihhnaazCCzaaoaormrfmddbaoobucuuusisstsltiiiowwotnanyasstpppteereroordidimnuinucctcctititnssenedewr~raiattolLtool1rraiicninccnncellpututtdhdheeeechHppHeFrmrF.eei. ssceeannlccee waDDsitssepp.oossee ooff wwaassttee pprroodduucctt in a facility permitted to accept chemcal . Haste. EENNVVLIIaRRbOOoNNrHMaEEtNNoTrTAAyLL DATA: tDesAtTsA: showed (Pinephales promelas) - LaDoratory tests sho~ed (Pimephales promelas) Nnnooo mbboiiorodtdaeelggirratadydaatatitioonnw.a. ter9966-s-HHartr.u.raLLtDDiS5oO0n.FFaatthhMeeoaadd Minnow HnnoH Noefmfoecrttaloitny%ahtat~caht,er%ssauturvraivtaol,n. weiNgoht, and slJaHeetotnnaiaggstttithshbiiticoi~cnncaaol33nll00lcyyeddnaasstyiyrigganFFtniaisifotfthiinhceceaaaaonnddfttMHFiGen-nfn1fne0oow~citeneggtoggno fmfrurysyhcalSsttcetuuhddf,yiy.~l. lestuLLsaarvbb~ovtfteaeZsscth,tssaw nnsseehhiloog~uheectdd,at22af00ni0d0sh fold boconcentration of FC-10 into muscle fillets of channel catfish. RREEGGVUUoLLlAAaTTtOOiRRlYYe VVOoClaLteilses OIZNrNFgFOaORnRMiHAcATTICIOOoNmN:p: ounds: N/A. O H2r0ga&nicExCemopmtpoSuonldvse: ntNs/:A. N/A. vOC Less H20 This product & Exempt complies Solvents: N/A. with the chemical registration requirements of TTShCiAs, prEoIdNEuCcSt, cCoOmSLp,liesAI~CSithandtheKorcehae.mical registration requirements of TSCA, EINECS, CDSL, AICS and Korea. EEPPFCCIRRREAA HHWAAAZZZAAARRRDDD: CCLNLAoASSSS:P: RESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: Yes FIRE HAZARD: No PRESSURE: No REACTIVZTY: No ACUTE: Yes CHRONIC: Yes 6. SUGGESTED FIRST AID 6. SUGGESTED FIRST AID EEYYEEIImmCCmmOOeNedNTidTAaAiaCtCTteTel:lyy fflluusshh eeyyeess wNi~tt~h large large amounts amounts of of water. Hater. Get Ge~ immediate immediate mmeeddiccaall attention. a~ent~on. SSKKIIIcJcNmNomomnnmCCetteaOOdadNm imNTaiTiAatnnACteaaCeTlttTl:eyye: ddwwaccassllohhotthhssiikcknnilinggno.t. hWNiiIIntffthgh ssLisbsoggoeaannfppossr/lseasaynynmddmrppettlluoaoasmrsregsgseeanoodcaaccmmcuoduoruiru,ns,ntptssoccsaaleoolflfloww faaaatppctehoehrynry.s.tsiacRRmcieieiaammnnonaovt.veeed HHaasshh ccoonn~taamminnaatteedd clothing before reuse and dspose of con~amnated shoes. IINNHHIAAfLLAAsTTiIIgOOnNNs::/syaptons occur, remove person to fresh air. If signs/synptoms continue, If sgns/symptoms occur, szgns/symp%oms continue, call a physician. remove person to fresh call a physician. air. If IIFF C aCSSamaWlNeAllAdlLLiLLaaOa0Wt~ppEeEhDhl:Dyyys:siiccaisiaanndirIIHeMHcMEtEDeDdIZAATbTEyELLYmY.e. diI;ffcalssw~apalelllroos~woeendnd,e,l.iinnddNuueccveeervvogomimvietitiinnaggnything by mmlmoouumttehhdttaooteaalynn uasncodnirseccitoeuds unconscious pbey rsmoen.dical person. personnel. Never give anything by 10 171327 22778888..00114477 33MMAA1100008833226655 441188-)01111::PPAAGGEE CC--2244 SDS: FC-10 FLUORAD Brand Fluorochesical Alcanol HjJaaSnnDuuSaa: rryyFC22-199,0, 1998 FLUORAD 1998 Brand Fluorochem~cal A~coNol PPAAGGEE 4 7. PRECAUTIONARY INFORKATION 7. PRECAUTIONARY INFORMATION EEYYEE PPRROOTTEoECCeTTIIOOcNoN:n:tact. Wear safety glasses with si| de shields. Avoid eye contact. Wear safety glasses wth side shields. SSKKIAOA m IdNNNvaRouPPtifedRROrOidTssaTaEkkElC.iinCn:TnTIIOOAccNNoo:npR:ntbaitauainctrctyt.l.ooff rWHgpuelbleoaboavrevrere.ssaapppmmpraUarodsdoepeeprriffoiraanroteotmeeaogtrgthhlloeeomvvoeeffrOssoe~llwOwohofh~eweLninttnnhgghehaanmfm ndaodaltllielitnenroggiwriaialtntlh(hg(ssiis)s) are are TreecCoommmaelndperdo: tecbtuitoynl trurDamDsera. s Unesecesonsearyortmo oprereovefntthesk?ino~cloowntinagct: Coveralls. personal proteotion coveraZZs. items as necessary to prevent skin contact: RREECCO UvUOOseeMMenMMetEE Ew lilNNaaiDDtt~hEEiDiDooaannVVppEEppNttrN~oToooTIppILLrm mrAAiaaTaiTaIitnItnOOeettNNaa:i~l:innoocicaseealnm l iniseoesstxxsihhiooaaannudusssestqtubbavveetelleoenonw,twitillruraeasecttecoiioomoaannmsp..epenrndodePepPddrrroiovaeevitxxiddeppeeoosrsusseurusrueefp~fii~rilccaiiim itmeeoiinnrtttsyst . eITf haus exhaust vveennttiillaattiioonn is not adequate, use appropriate respiratory pprrootteeccttioonn.. RREESSAA oNPPIvOaIIoRRSniAAdHTTOOabaaRRrpprYYeeppsrarotPPothvhvRReieOiOndndTaTggEnECgrrCTeooeTIfissfIOOnppNaNiai:irra:aracrbbtctooooorrrrrnsnsdeeanDbmcm aaaesstaeeedwdtreiitrooaihnnla.l.aOaSi~HrrbSAbSooeerlrrlneneeecceg~tulccaooootnnnnieeccoeennoosnftf:trrttaahhtteeihiooanfnlfofol-ololofmlfaowswikinnggdust AcCeoonaa~pnaiirmnatanonartn,tss faunldl-finaceaccsourpdpalniceed air respirator w~th OSHA regulations: hal~-mask dust respirator, full-face suppled ar respirator. PPRREEDOVVoEEoNNnTToIItOOmNNesaaragOObt,F,FugAAddhCCrrlCaiCnynIIDkkDEEWNiNootTrTrhAALLssmsoIIookNNakeGeGpEESWwSaThnhTIedeIOOnnNNw:au:utsseiinrn.gg tthhWiaissshpphrrooadnduducsctt..afWHtiearsshhheaexnxppdoolssieenddg and before eating. areas thoroughZy Defore eating. with soap and water. Hash hands after handling and "RREECSCOoOMMrMMeEENNDaDEEuDDdySSTTfOOrRoRAmAGGEhE:e:at. Keep container closed when not in use Store away from heat. Keep container c%osed when not ~n use. 10 171328 FFIIRRNEEonfAAlNNaDDsmEEaXXbPPlLLeOO.SSIIOONN AVOIDANCE: AVOIDANCE: Nonflammable. OOTTHHoNNEEoonRRtssamm PPnoRRiokEEnkiCCainnAAtgUgUi.T:ToIIOnOSSNNmmAAoooRRkfkYYiinntggIIhNNeFFwwOOhhtRRiioMllMbAeeaATcTIcuuIOOsosNNii:nna: ggndpt/trhhooiridssucstppasrorookddemueucnacttnt dioccaanlnneedardreeisstnuuolZsttet hceitinnifoonrm4atoifon cot4ohf nistttahhmeeMSEDnhnSaaa.zztaaorrdndoouuossf decomposition the tobacco andlor smoke and Zead decompostion products mentoned to n the formation sectEon 4 of this MSDS. HMHIISS HHAAZZAARRDD RATINGS: RATINGS: HWPEEEARALSLTOTHNH:A: L 1 1 PROFFTLLEAACMMTAMIAOSANIB:LILIITTXYY::(S11ee RpRErEAeACcCTaTIuVItVIiIToTYnY:s: , 0 0 sec ti o n 7.) PERSONAL PROTECTION: X (See EXPOSURE LIMITS precautions, section170.)171328 INGREDIENT VVAALLUUEE UUNNIITT TYPE AAUUTTHH SSKKIINN* TYPE INGREDIENT PPPEEERRRFFFLLLUUUOOORRROOOOOHCCETTXAAANNEEESSSUUULLLFFFOOONNAAANMMIIIDDOO0O AAALLLCCCOOOHHOHOLLO...L...... 000...111 MMMOG/M/SMs.3. TTTWWWAAA 33SMM0. TWA 3M Y Y PERFLUOROHEPTANESULFONAMIDO erie PERFLUOROHEXANESULFONAMID0 ALCOHOL... PERFLUOROHEPTANESULFONAMIDO 0.1 00.11 MG/M3 MMoG/mMa3 TTNwAa 3M M YY ALCOHOL ............................ 22778888..00114488 33MMAA1100008833226666 441188--001111::PPAAGGEE CC--2255 mat 5 MHSSDDS$:: FFCC--1IO0 FFLLUUOORRAAD9 Brand Brand Fluorochemical Alcohol F1uorocheliCa~ Alcohol Seruary 2, 1998 Jar.uary 29, 1998 PAGE 5 exrosune Luts (continuse) EXPOSURE LIMITS (cont&nued) ananepien wie oar we wm saw INGREDIENT VALUE UNIT TYPE AUTH SKIN" serra rowioe Meal 01 vem Ta wy pERFLUOROBUTANESULFONAHIDO ALCOHOL... 0.1 HGIR3 THA 3M Y PEIPLnORiITpMEsSLFoTuOaHWIAooLY ot OME Te WY P~RFLUOROPEN'rANESULFDNAPIIDO 0.1 HGIR3 TNA 3H Y ALCOHOL ............................ Ska NOTATIONt: iLisoeasnsuvbestatnhceessveirndailcsatsedpwoisth b"yY" thuendecrutSanKeNousTerorvesto * SKIN NOTATION: under SKIN refer ;o Llsted substances ndcated ~th 'Y' a2" 3 ve, shiner by saruarna or; Bore partscalary, t~e potentia/ contribution to the overall exposure by the cutaneous route a eibeince. vhisles can a1ter Bn aDsorpHion. includzng mucous membrane and eye, either by alrborne or, more particularly, sounceOoFr exoratsousnseanLaiensaExopaon:ure Guidelines by direct contact ~lth the substance. Vehicles can alter skin absorption. SOURCE OF EXPOSURE LZHIT DATA: - 3H: 3H Recommended Exposure Guidelines SRA Waza OATA 8. HEALTH HAZARD DATA eveScOomMerE: hear tects are expected from oye contact. EYE CONTACT: No adverse health effects are expected from eye contact. saw comer: SKIN CONTACT: Produc~ Zs not expected to be irrltatng to the skin. tay oe assorved Through the skin and persis in the Body for Hay be absorbed through the skn and persist ~n the body for rene extended time. TaAArTiIOoNnos by sonsdation and persist sn the body for an INHALATION: May be absorbed by inhalation and pepsst in the body ~Or an anan extended extended time. irSsSIiALnEDeL,: to 4 dikely route of exposure to this proce. IF SNALLONED: Ingestion is not a ~lkely route of exposure to thls product. Liiness say scour afcar s single satloning of relatively Jaros Illness may occur after a single s~alZo~ing of relatively large Sha I quantl~ies of thZs material. mmcenerry: HUTAGENICITY: oC Bisons sn in-visro assays Not mutagenic in in-vltro assays. REPRODUCTIVELoEeVEnLoOxPHoErNaTtAeLpoTnOiRcTSi:n the rat at doses 55 nigh 35 90 REPRODUCTIVEIDEVELOPHENTAL TOXINS: Substance ~as not teratogen~c in the rat at doses as high as 30 IIL Se Chacaran or aa via ora route: milligrams per kilogram per day va oral route. OTHER HEeALTtH AoReOookTHEhORoAATITOoN:contain any substances ragulates onder OTHER HEALTH HAZARD INFORHATION: This product s not knoNn to contan any substances regulated under Cadi proposition 5. A product Toxicity Susmary Sheet is available. Cal~orn~a Proposition 65. A Product Toxicity Summary Sheet is available. 1100117711332299 22778888..00114499 swntoone? 3MA10083267 441188--001111::PPAAGGEE CC-2266 HJGaGDnDSuS:a:ryFFCC-2-113,00 FF1L9LU3UO8GRRAADD Brand Brand Fluorochemical FZuoroche~i=a~ Alcohol Alcohol j~uary 29, 1998 PPAAGGEE 66 SECTION CHANGE DATES. sECTION CHANGE DATES .................. esos SECTION CHANGED SINCE Novesber 05, 1957 ISSUE HP_ADING SECTION CHANGED SZNCE November 05, 1997 ZSSUE A ovbrbarveivsiatitioonnss:: NNi/Db - hNeott Detersined Determined WIA - Not Applicable N/A - Not ApplicabZe CA - Approxisstely CA - Approximately er htatnes tron a. datibae Say rot be 22 curren,ot0a5 oo76. 1100 mTTOheee e iinnffoorrmsesarttUiioBonnINiiGnnT,ntethhBiaUissTteMM NaOatTseatFevrOLuirRIeisaMdlAI.lTSSEPaDAafORfeTheT0tIt,yyWCAUKDADLEiNAatSYRtaaNPIOSSUMhRPhWePLeAeOIeTtSEtREDA((RNWOWTSARSIDRSESCR)S)OA,UTiiRsYsESXEbbPOeFROelEFliiSeeSvvEeeDddOtFtoo be correct as of the date issued. 3H HAKES NO ~ARRANTIES, EXPRESSED OR LE iCiov on' FITNESS IMPLIED, INCLUDING, BUT NOT LIRITED TO, ANY IMPLIED ~ARRANTY OF HPErEox on eUSnAaGuEctOF iTeRAfDiEt. foUrsearpaisrtirecsuploanrsipbulreposfeoranddetesrumiitnaibnlge for HPEERRFCOHRAHNATNACBEILOITRYUSOARGEFITONFESTSRAFDOER. AUPsAeRr TiICsULrAeRspPoUnRsPiObSleE OfoR rCOdUeRteSErmOiFning Hr of use. or application. Given tne variestoymeofoffawchtiocrhs atrheat whether the 3H product is fit for a particular purpose and suitable for a e ucuasnneiqreua's#eyfle ym ecean~tthiotithhdtenino~uhussttheeuneeeseaaannnvudddo.se3renasasrapup'rsppsppirtpliokakilccdnnbicaauooltacswetiitltolieoefondndtonggoree.oofdfuaeasGananteddariv3Or'eHMcacsnoionpnpsnttreerhtroocreoddwholuhoulc,ve,dcttat,h,iior~tefiersotiiuymsssSeetoeesofoisssrfsfeaeNnTacntipbttitpioicaalhrlfclsoEtartChthrhieaa&oattnt: Z~e user evaluate the 3H product to determine ~hether it is fit for a ee punpore particular purpose and suitable for user's method of use or application. an prLoviedes eineforsaptoisoenibiinliteylectthraotnieclefcottrrhoainsiscsint8froasrnsesarftvioiocrne,asfyo34hitaasavekecsuressntouolnteerds 3H provides information in electronic form as a service to its customers. Se Catetione or alterations in Due to the remote possibilitY that electronic transfer, maY have resulted BEomtutioss 2s to ite completensss or accuracy. In additi n, in errors, o~ssions or =Iterations in this information, 3H Bakes no representations as ~o its completeness or accuracy- In information obtained from a database may not be as current as the 117711333300 272788.80.0115500 a3MMAAt10000s83322668 441188-001111::PPAAGGEE CC--2277 ATTACHMENT 3 ATTACHMENT 3 TTEESSTT AARRTTIICCLLEE PREPARATION PREPARATION PROCEDURE PROCEDURE 22778888..00115511 1100 117711333311 amAtoosa2ss 3MA10083269 441188--001111::PPAAGGEE CC--2288 AATTTTAACCHHMMEENNTT 33 VVeerrssi~onn:: 4411P88r.P-o00rt11oo11toc(c(oP22ola88lg44JJe11UU88L1-L-0009911188113)) TJEESSTT AARRTTIICCLLEE AANNDD CCOONNTTRROOLL AARRTTIICCLLEE PREPARATION PREPARATION PROCEDURPaEge PROCEDURE 1 of 3 Tost Article: NN--EEtFFOOSSEE Test Article: Vehicle: 29% Tween 80, in R.O. Water 2% Tweer~ 80, in R.O. Water A. PPuurrVppoeoshseei:c:leTT:hheeppaurru peossuerosopffetpthnhisissiopoprnrososcocefeddNeuu-rrEeeWiFsisOtStooEppraroonvvididdteeheaa cmmoenettthrhooolddfaofrorirtcthheefepoprrreoeprpaaar!raattiioonn Ao o`aafdddmmoiinsnaisigtsretartsiaoutnsitpotooennrrsaaittossnoosnnoAAf rrNgg-uuEsstFSSOttuuSddEyy a4n1d8-t0h1e1control 418-011. article for oral 8. GGeenneerraall 4 Information: Information: All suspensionotcoocnotlaninuemrbserw,iltebset lraibecleedidaenndtifcioclaotriocno,dAerdg.usEabacthchtabel will 1. All suspension containers will be labeled and color coded. Each label will BSreAeeenpcreriration, dosage level, preparation date, expiration date specify the protocol number, test article identification, Argus batch number, concentration, dosage level, preparation date, expiration date `aanndd ssttoorraaggee conditions. conditions. 22aa.. --SSuussppeennossaiioioynnss wwililll bbeepPprXree'ppaarreeWdde::ekly Weekly ~~ _For__daysofuse __ For days of use Daily ~ 22bb.. VV--eehhiicclleeDpwwaiiliylll be be prepared: prepa*r%e_d: W Weeeekktlyy ~~ ___FoForr__d..adyasysooffuussee 3. Daily SSuussppeennssiioonnss wwiilll bbee ~ pprreeppaarreedd at at a final a final dosage dosage volume volume of$ of 5 MLA. mI.Jkg. 4o SSSXXaaE_ffeettyy::GSDtuloosvvteeMssi,,sltlaabbReccsoopaaitrt,,agtgooorgggglleess or or safey safety glasses glasses and and facashicld faceshield X~~~ DHHFauaulsllfft----FFMFaaaicccseeet RRRReeeessspsppipiririrraaaattttoooorrrr/Posiive Pressure Hood -- FTyuvll-eFkaScueiRvAepsrpoirnatorlPositive Pressure Hood 5. w Tyvek Suit/Apron DDoossaaggee ssuussppeennssiioonnss Yes adjusted aX_d_ justNeod f(fooCrralFFcrrueeleeatbbiaaonssseebaaannsdded%%oPPnuu1rri0tyy0.%) T YFFerreseeeBBaassee __ Purity ~ No (Calculations based on 100%) ~ Pudty 6. SSaammpplliinngg rreeqquuiirreemmeennttss:: Cited in Cited in protocol. protocol. 7. Storage: Cited in protocol Storage: Cited in protocol. 10 171332 288.0152 2788.0152 33MMAA1100008833227700 441188--001111::PPAAGGEE CC--2299 AATTTTAACCHHMMEENNTTS.3 Version: 418.PP0rro1ot1too(cc2ool8l 44J11U88L.-00911811) Version: 418-011 Page 2013 (28 JUL 98) Page 2 of 3 TTEESSTT AARRTTIICCLLEE AANNDD CCOONNTTRROOLL AARRTTIICCLLEE PREPARATION PREPARATION PROCEDURE PROCEDURE NNOOTTEE:: tTTheeessttlaoarwrttiidccolleseawwgieill.l bbeeOnppcrreeeptpaahrreeefddinaaasslaavossleeruriimaalel sddiiallurutteiiooannchffriroeomvmedtth,heeshhtiiiggbhhaddrsoossaaargegeetottoobe. atahddeddeeloddwttodootthsheaegcceoo.nnttOaaiinnnceerersst;;hmmeiifxxiniinnaggl vssohhloouuumllddesooccaccrueurraddcuuhrdiiennvggedss,aammsptiplrliibnnaggrsaannaddr/e/oortro be aaddmminiinsitsrtraatitioonn.. C. PPrreeppaarraattiioonn ooff VVeehhiiccllee 1. AAladdbddelttehhdee crroeenqqtuuaiiirrneeeddr.aaHmmeooauuntntttohoeffRRw.a.OOt.e.rddeteoiioo5nn0iizz:ee5ddwwCa,attaeerdrdttoothaaennraaeppqppuriroorpeprdiriaaattemelloyy unotf Tlabweeleed nc8o0ntaainnderm.ixHeunatitlthueniwfoartemr(tSoe5e0TE5STC,AaRdTdICthLeEreCqAuLiCreUdLAaTmIoOuNnSt)o.f Tween~ 80 and mix until uniform (See TEST ARTICLE CALCULATIONS). D. TTeesstt AAtriticcilee SSuussppeennssiioonn Preparation: Preparation: Do 1. TTofootppersreteppaaratrrieectltehhe(eS44e..e00--TmmEggSiimTmLLA,,RGGTrIrooCuuLppEVVCssAuuLssCppeUenLnsAsiiToonIn.O, aNaddSdd) ttihhneetorreaeqqnuuiirreedd amount amount Voaaeppfhptpierrcosolptperariairaatntitcdeellleyyhe(ssSaiiztzeeeetddh,,TeEllamaSbibxTeetlleAuedrdReccTtooIonCnt8tLaa0iEinn+eeCr5r.A. CLAACfddUoddrLtatAhhpTeepIrOrroeexNqqiuuSmiia)rreteineddltoayamma3on0ouumnnittnuootffes. vehicle and heat the mixture to 80 ~5C for approximately 30 minutes. 2. OcOonnolocsee. tthh(eeBetteesssuttraaerrtttiichclleeerhehiaasssdadisivssissooilblvvleeeddv;o;rssteppxii,nn toohvvieesrrwninliilgghahtct hwwihheiivlleee the tthhee solution sdeosluitrioedn ecmouollssi.on.(B) e sure there is a visible vortex, this will achieve the desired emulsion.) 3. `TTaoompoprureenpptaarorfeesttthhoeeck22s..0u0--smmpgeg/n/mmsLiL,o,nGGr(rGooruuoppupIIVVVss)uu(ssSppeeenenssTiiooEnnS,,TrreAemRmoTovIveeCLtthhEee required required aCCmAALoLCuCUnULtLAoATfTIsItOOoNcNSkS)s),u, saapddeddnttshhioeenrree(Gqquurioirrueepdd Vam) o(Sunete amount TofEvSeThiAclReTaInCdLEmix. of vehicle and mix. 4. TT`oaompporureenptpaaorrfeesttthhoeeck11s..0u0-s-mpmeggn//mmsLiL,o,nGG(rrGooruuoppupiIIlI IssVuu)ss(ppSeeennessiTiooEnn,S, TrreeAmmRooTvvIeeCtthLheEe rreeqquuiirreedd aCCmAALLoCCuUnULtLAoATfTIsItOOoNcNSkS)s),u, saapddeddnttshhioeenrree(Gqquurioirrueepdd IaV) m(SeoeofTuvEeSnhiTctAleRTanICdLmEix. amount of vehicle and mix. 2277888..00115533 10 171333 33MMAA1100008833227711 441188-.001111:,PPAAGGEE C30 C-30 Versa: 418.71 2Ga3w93a)s PPrroottoaccool1441186--001111 AATTTTAACCHHMMEENNTT 33 Version: 418-011 (28 JUL 98} Page 3 of 3 TTEESST ARRTTIICCLLEE AANNDD CcOONNTTRROOLL ARTICLE ARTICLE PREPARATION PREPARATION PROCEDURE PROCEDURE 5 TTopre oparotohek0s2usmpegns.ionGr(GoruopuIpl sIu)s(pSeenesiToEnS= T ARTICLErequired To prepare the 0.2-mglmL, Group II aCmALoCuUnLt AoTf IstOoNcSk)s,usapdedntshioenre(Gqurioruepd s|a1u1m)sop(uSenentesioTofnEv,SerhTeimcAloRevTaeInCtdhLemEirxe.quired CALCULATIONS), add the required amount of vehicle and mix. wirten by: rl Qype Written by: Approved dy Date: SEL Approved by' Custoatons _XNo __\d (eoattachedclrfcsionorn) Clarification: ~ No ~~ (See attached cla"nfication form.) niiatDate: pC 9-2E Initials/Date " 27880154 2788.0154 10 171334 s3MwaAt1o00o8s3s2z722 41188--001111::PPAAGGEE CC--3311 4PRIMEDICA as san abn. nc Argus Research Laboratories, Inc. Re Se BangA 905 Sheehy Dr~ve, Building A reoh OvEe uA ng Horsham, PA 19044 tee Ase Telephone: (215) 443-6710 Te|efax: (215) 443.8587 ---- PROTOCOL 418-011 (OORRAALL ((GGAAVVAAGGEE)) DDEEVVEELLOOPPMMEENNTTAALL TTOOXXIICCIITTYY SSTTUUDDYY OOFF N-ETFOSE N-ETFOSE IN IN RATS RATS SPONSOR'S STUDY NUMBER: T3167 SPONSOR'S STUDY NUMBER: T-6316.7 Aenenimont 1-2 August 1998 Amendment 1 - 12 August 1998 tons (ausposons il prepare day ah Tesi Fac. aber 1. FFrereqquueennccyyooffPPrereppaarraattiioo_nn (page (page 4 4 and and page page 1of 1 of Attachment Attachment 3 3 to to the the protocol): protocol): Formulations (suspensions) will be prepared daily at the Testing Facility, rather tthhaann wweeeekkllyy.. ` ReR asoenffa oorrs CChhaoanrgn ieo:t: gopp--eey oberman, Ph.D., DABT Da' Be hasearch ~~~ Hr o,RTehsiesa~rchcrrects the prtcl" RTootr)raM oYcrosnatilioearrcth ~o~-n~- G. york~h.~., DABT vec ~~ ~_us~~'a~ D~t_ir_ eeD~ c~r/.~~r~~H, ~esearch maonwes Date --S~omes Leno. UMD ova we Dhaeme Clb salu? 2 Date - DomaLebo MD, eiCoreand SyMondor Dena C. Lebo, V.M.D. 17ate Marvin T. Case, D.V.M., Ph.D. Member, Institutional Animal Care and Study Monitor ameter Use Committee J 2788.0155 10 171335 stents 3MA10083273 441188--001111::PPAAGGEE CC--3322 Argus Research Laboratories, Inc. OPRIMEDICA Ry Ee 905 Sheehy Drive, Building A Hor~ham, PA 19044 Telephone: (215) 443-8710 -0000@@@@==TWo--i)-s--e Telefax: (215) 443-8587 sroTocoL 8011 PROTOCOL 418-011 ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS SPONSOR'S STUDY NUMBER: T3107 SPONSOR'S STUDY NUMBER: T-6316.7 Ameninert2. 11 Dacanbor 198 Amendment 2 - 11 December 1998 1. Soon age 1th protocol Sponsor (page 1 of the protocol): Th Sponsor 3 Carport Toscoy, rather han M Toxdgy Sri The Sponsor is 3M Corporate Toxicology, rather than 3M Toxicology Services. RReaesonaffoorsr CChohaanngngee:: TThhiiss cchhaannggee wwaass mmaaddee aatt tthhee rreeqquueesstt ooff tthhee SSppoonnssoor.r. A ------------ 2 SSpp ecie eslc Stri aine aannsddRR/ eeaasSsoont nfoforrr SSaeeleleiccttiinoonn ((ppaaggee 55 ooff tthhee pprroottooccolo)l:): The test article is biologically active, rather than pharmacologically active in this strain. ess or Change Reason for Chanqe: Tis chang was mad th recast fh Spoor ta cot proce This change was made at the request of the Sponsor to correct the protocol. 3 RRououtteeaannddRReeaassoonnffoorr CChhooiiccee ((ppaaggee 77oofftthhee pprroottooccooll)): TThhee oorraall ((ggaavvaaggee)) rroouuttee iiss aa ppoossssiibbllee rroouutteeooff hhuummaann eexxppoossuurree,, rraatthheerr tthhaann tthhee oonnee pprrooppoosseedd ffoorr cclliinniiccaall uussee.. 110011771133336 22778888..00115566 3MA10083274 441188--001111::PPAAGGEE CC--3333 PoAimeedxiihmevnstt2 Amendment 2 P rotocol 418-011 PPaaggee 22 RReaesonaffoosrrCChohaanngn,eq:e: TThhiiss cchhaannggee wwaass mmaaddee aatt tthhee rreeqquueesstt ooff tthhee SSppoonnssoorr ttoo ccoorrrreecctt tthhee pprroottooccool.l. i Director of Research Aln#1. HHoobbeerrmmaann,, PPhh..DD..,, DDAABBTT DDaattee of Research etacate Director { R: GG.. YYoorrkk,, ~ Director SSttuuddyy DDiirreeccttoorr 11-DeC 98 psearch ., DDAABBTT irch DDaattee WaRDDseeennsaamoCC...nLLooesbboso,i,oVVo.onMMna.DtDl.Aivni]maJloCuarseiDDa-naa0dtt.5eee. SMMtaaoPrdivyinlnMTToa.rCCtnoaansseeT, DDl.VVe.MM.., PRD.Ph.D. stp Dagtee Date ri Member, Institutional Animal Care and Study Monitor Use Committee 22778888..00115577 10 171337 swaroos2rs 3MA10083275 AAPPPPEENNDDIIXX DD DDEEVVIIAATTIIOONNSS FFPRRROOOMMCTTEHHDEEURPPREROSOTTOOOFCCTOOHLLEAATNNEDDSTTTIHHNEEGSSFTTAAACNNILDDIAATRRYDD OPERATING OPERATING PROCEDURES OF THE TESTING FACILITY 2277888..00115588 10 171338 33MMAA1100008833227766 441188--001111::PPAAGGEE DD--11 DEEVVIIAATIIOONNSS FFRROOMM TTHHEE PPRROOTTOOCCOOLL AANNDD STTAANNDARD OPEIR::Ab~TTIING PROCEDURES OOFF TTHHEE TTEESSTTIINNGG FFAACCIILLIITTYY 1. 2266 AAUUGG 9988 ((DDaay4y4 ooff pprreessuummeedd ggeesstatatitioonn):): CClliinniiccaall oobbsseerrvvaattiioonnss aanndd bbooddyy `wweeiigghhts wweerree nnoott rreeccoorrddeedd ffoorr tthhee ffoolllolowwiinngg rraattss:: copes Dosage gum Mme GGrroup I po me nII Boog mma III Dosage ((mmg~//k.ga//daayv)) 0 (Vehicle) 1 1 5 Assigned NNuummbbeerrs 12814 - 12818 1122883399-- 1122884477 12864 - 12872 IV 10 12883- 12897 VVv 2200 1122991122-- 1122992222 icon dssr tects cme of sty bt T"Thhiiss ddeevviiaattiioonn ddiidd nnoott aaddvveerrsseellyy aaffffeecctt tthhee oouuttccoommeeoofftthhee ssttuuddyy bbeeccaauussee iitt occurred before initiation of the dosage period and represents a small loss of res rine data across all dosage groups. oars one All deviations are documented in the raw data. SAfgVvoriarEveLo, PmhSeAgtBeT roeDate Date 22778888..00115599 10 171339 3MA10083277 AAPPPPEENNDDIIXX EE TTEEMMPPEERRAATTUURREE AANNDD RREELLAATTIIVVEE HUMIDITY HUMIDITY REPORTS REPORTS 788.0160 2788.0160 1100 117711334400 a3MmaAt1o00o8s3227788 41188-.001111::PPAAGGEE EA E-1 -- in ARGUS TTeemmppeerraattuurreeLoaacnnaddtiRRoeenl:laattRiivoveeoHHmuum0mi4didiittyyReRpeoporrtt | Location: Room 04 Protocol Number: 418-011 | | ! 7 Protocol Number: 418-011 RaonfDgateesss:: 11-1Aug-AugE -A 1998 13:45 to 12-ST ep-1898 10:26 Lo Range of Dates: 11 T -Aug-1998p1TT3roe:mm 4ep5pepertrosattu1urr2ee-Se|pR-1Rel9ea9lat80itivv%1ee100HH:2u7um60mid%iidtityy | TT`SaaprreggceeitetRsRa:anRngagele:: | STopteaclieNs: uRamt obfDeayrs: 64"F to 7gF 765343349 30% to 70% T6T43534e9 || TTTTooootttraaanlll NNNNuummuubbeemrromooobffffDHDHbeoaaouyuarrsrseF:s::irrs: | 764.49 766 764.49 766 Total Number of Data Points: | 603 (x04) | 4a77.7 @29 | (+ 2.4) | MMeeaann((+-SSDD)):: | maximum: 69.3 032 4a17 70.2 (~: 0.4) 54.1 47.7 I Medtan: Maximum: Median: Meinimmumbo:fPPeoeoinrrnts HinigRhan(g4)e:04: 69.3 67.7 ||e779686 0(1f00e00).00)| 88 4T71G600e.?63 e(01se0000o.0))] || Number of Points NNoommoobbffPaeinrts Number of points Low (4): in Range High (%): (%): |o o (o.o) (o.o) o (o.o) Number of Points Low (%): Report Generated 25-0198 8 0915 Report Generated: 23-Oct-1998 at 09:15 COMMENTS: _ COMMENTS: I --- - --V _ REVIEWED BY: ~ / ------ ome TT = li DATE: CCuummulualattiivvee by by Location Location (049197) (v04.01.97) 2788.0161 2788.0161 10 171341 m3MAtA010008833227799 AAPPPPEENNDDIIXX FF PPIILLOOTT RREEPPOORRTT 2277888..00116622 1100117711334422 33MMAA1100008833228800 441188-.001111::PPAAGGEE FF--11 FFIINNAALL PPIILLOOTT RREEPPOORRTT SSttuuddyy TTititllee OOrraall ((GGaavvaaggee)) DDoossaaggee--RRaannggee DDeevvienellRooapptmmseennttaall TTooxxiicciittyy SSttuuddyy ooff N-EWFOSE N-EtFOSE in Rats SSppoonnssoorr'ss SSttuuddyy NNuummbbeerr:: TT--66331166..77 AAuutthhoorr RRaayymmoonndd(StGG.u.dYYyoorDrikkr,,ecPPthho..r0D)..,, DDAABBTT (Study Director) SSttuuddyy CCoommplpeletteedd OOnn 10 December 1998 (Final Pilot Report) 10 December 1998 (Final Pilot Report) PePrefroforrmmiinngqLLaabobroarattoorryy AArrgg9uu0ss5 RRSeehsseeeeaahrrycchhDrLLiavabebo,orBraatutoiordriiieenssg,, AIInncc.. Horsham, Pennsyivania 19044-1297 905 Sheehy Drive, Building A Horsham, Pennsylvania 19044-1297 LaLbaobroartaotorryyPProrojjeeccttIIDD AArrgguuss RReesseeaarrcchh LLaabboorraattoorriieess,, IInncc..,, PPrroottooccooll NNuummbebre:r: 441188--001111PP 22778888..00116633 10 171343 MAT0083281 3MA10083281 441188-001111::PPAAGGEE FF--22 418.011PPAG2E 418-011P:PAGE 2 PROTOCOL 418-011P: PROTOCOL 418-011 P: OODRERAVALELL((GOGPAAMVVEAAGNGETE)A) LDDOOTSOSAXAIGGCEEI.-TRRYAASNNTGGUEEDY OF N-EWFOSE IN RATS DEVELOPMENTAL N-EtFOSE IN RATS TOXICITY STUDY OF TABLE OF CONTENTS TABLE OF CONTENTS SUBJECT SUBJECT AABBSSTTRRAACCTT I Pumose Purpose I. I Methods II. Methods WL Results III. Results W. Conclusion Conclusion IV. Figure 1. MMaatteerrnnaall BBooddyy Weights Weights Figure 1. Table 1. Giical and Necropsy Observations- Summary Table 1. Clinical and Necropsy Observations - Summary Table 2. MMaatteermnaall BodyWeig- Shumtmasry Body Weights - Summary Table 2. Table 3. MMaatteermnaall BBooddyy WWeiegighhtt Cha-nSgumemasry Changes - Summary Table 3. Table 4 Table 4. MSMauatmteemrmanarallyAAbbssoolluuttee Feed Feed Consumption Consumption Values Values (g/day) (g/day) - - Summary TTaabbllee 55.. TTaabbllee 6. 6. VMMaaatlteuerernnsaal(lgRRhekelglalatdtiaivvyee) F-FeeSeeuddmmCCaoonrnsysuummppttiioonn Values (g/kg/day) - Summary GCaasessaarreeaann--SSeeccttiioonniinngg Observations Observations - - Summary Summary PPAAGGEE . 4 66 66 77 9 1100 1"1n 313 11s5 17 1109 221 1100 117711334444 J 2788.0164 a3mMAAt1o0o0s8s322s822 441188--001111::PPAAGGEE FF--33 "1801p PAGES 418-011P:PAGE 3 SUSUBBJJEECCTT PPAAGGEE TTaabbllee 77.. Liter Observations (Cassarean-Delvered Fetuses) Summary Litter Observations (Caesarean-Delivered Fetuses) - 2| Summary 23 Table 8 FFeettaall GGrroossss EExxtteerrnnaall AAllteerraattiioonnss --- SSuummmmaarryy 225 Table 8 Table 8. CClliinniiccaall OObbsseerrvvaattiioonnss --InInddiivviidduuaall Data Data 27 27 Table 9. Table 10. NNeeccrrooppssyy OObbsseerrvvaattiioonnss -- IInnddiivviidduuaall DDaattaa 331 Table 10. Table 11. MMaatteerrnnaall BBooddyy WWeeiigghhitss -- IInnddiivviidduuaall DDaattaa 335s Table 11. Table 12. MMaatteerrnnaall FFeeeedd CCoonnssuummpptitioonn Values- Values - Individual Individual Data Data 4a22 Table 12. Table 13. GCaasessaarreeaann--SSeectcitioonniinngg OObbsseervrvaatitioonnss-- Individual Individual Data Data 446 Table 13. Table 14. Table 14. LLIniitdttieevrriOdOubbaslseerDrvavatatatiioonnss (Cassarean-Delivered (Caesarean-Delivered Fetuses) Fetuses) - - 50 Individual Data 5O TTaabbllee 15. 15. FFIneedttiaavlliSdSueeaxxl,, DVVaiitttaaall Status Status and and Body Body Weight Weight - - 54 Individual Data 54 ATTACHMENT 1- PROTOCOL AND AMENDMENT 5s8e ATTACHMENT 1 - PROTOCOL AND AMENDMENT 22778888..00116655 1100 117711334455 aMAtoosa28s 3MA10083283 441188--001111::PPAAGGEE FF-44 441188.-001111PP:PPAAGGEE 4 TTIITTLLEE:: OOSRTRAUADLLY((GGOAAFVVNAA-GGEEEt))FDDOSOOESSAAINGGERE-A-RRTAASNNGGEE DEVELOPMENTAL DEVELOPMENTAL TOXICITY IOXlCIFY STUDY OF N-EtFOSE IN RATS AAPRRRGGOUTUSOSCRROEELSSEENAUAMRRBCCEHHR:LLAABB41OO8RR-AA0T1TO1ORRIIEESS,, IINNCC.. SSPPPROOONNTSOSOOCRRO''LSS NSSUTTMUUDBDEYYRNN:UU4MM1BB8EE-0RR1::1PTT--66331166..77 AABBSSTTRRAACCTT Fifty-six presumed pregnant Cr: CDBBR VAF/Plus (Sprague-Dawley) rats were VrFrIaaiIfn)nt.ydd-oosm mSixlulyysppraaeesssnssusiigmignoneeendddspttoorofesstgheenevvaeeNnnnt-CEddotorIssF:CaaOggSDeeE~ggBwrrReooruueVppAssaFd[[me/ePiiigngluhhitsst tppeeer(rrSegdgprrroooaruuagplpuley((-GGvDirraaoowuugpplaessvya)|I gttrheharrtosoounuwggchehere VgddaeaIiIsi)llt]yy.atttoiSoouttnhshe(pessDeeeGnssnniaao6ttnuutsrroaaoll1llfy7yt)-h-bbearrteeNddd-offEseetamFmgaOaellSseeEorrafawttOsser(ooeVnneahddidcaamlyyessi)n.6i6s1ttte.hhrrr5eo.oduu1ggo0hh,ra211ll077y.oov2fifa5ppgrraeaensvsduaumgmeeeddonce 3tg3h55eesmmtigang/tdik/oikgvngiidd/(duaDayaGl.ybsoTT6dhhyteeowdd1eoo7issg) haaatggtseedorvvesoocalluogum remdseeedowwfaia0mssm(e55VdemmihUaLiktc/egklelg,)y,, a1d,j5u,st1e0d, d2a0i,ly25onantdhe baedfjuorseteaddmdianiilystornattihoen basis bofastihse of of ttheset inardtiicvlied.ual body weights recorded immediately before administration of the test article. Checks for viability were made twice daily. Clinical observations were recorded Cddsaiahixilelyhycokbbuseerffsfooorrlreaetveddira.oobssiaaTligtghyeee.w,seeaaprpoeppbrrmsooexxariidvmmeaaatttiteweollinycyseoownndeeearilehhyo.oauulCrrsolaainffrttieececrarolaarodddmbmeisdnieniorsivsntatrcrtaaeitotiidnooasnnilwaaynnedddruerttihrhneeegcnnoftforhodueurerdttoo spioxshtoduosrsaglaetepre.rioTdh.esBeoodbysweerivgahtitosnswewreerereaclosrodreedcdoaridleydduornicneg dthaeilydodsuarigneg athned pppooossstttdddooosssaaagggeee pppeeerrriiioooddd.ss aaBnnodddyffeeweededigcchoontnsssuwummeprptetiioroenncvovaardllueueedssdwwaeeilryreedrrueercicnoogrrddteheded on DGs dosage on DGs a00,n, d44,, 66,, 88,,1100,, 1122,, 1144,, 1166,, 1188 aanndd 2200.. AAolflllcrroaarttpsswowreaerreleutsseaaac,crriiiffmiicpceleaddntooanntiDDoGGn s22i00tesaannaddndeexxuaatm meriiinnneeeddcoffnootrrettnhhtees.nnuuAm mbgbereorrsaasnnnddecddirissottprrisibbyuuttoiiofonn wttohhefeeicgotthhhrooperrodaarcacaiicncl,ud, taaeebbaxdd,aooimmmmiipninnleaaadlnltfaaaonntriddognrppoeesslilvtvseiiccsexvvatiienssrdccneeaurrlataeawrwlinataeessracpptoeeirnorfnftoeosrrnammtnsee.ddd..AseFxFge.retotuusssseenssewwcererorpeesy of weighed and examined for gross external alterations and sex. AcAlolllnrrsaaittdssessruuerdrvviitvvreeedadtumunentntiitll-ssrccehlhaeetddeuudlleewddersseaaccilirifimfiiiccteee..d tCColliisnniiinccgaallleoorbbassteserrwvviaattthiioocnnhssroddmuuorrriinhngignggoeersrsthtaaettaiio,onn ccchohrnroosmmidooeddraeacdcrrytyroeorarrrthhmeeeaanoot-rrreeelmmaataecicdaiatwtiieoornneaaltitmtthihteeed2200toaasnniddng33le55 rmmagtg/s/kkwgg/i/tdhdaacyyhddrooosmsaaoggrehesis.n.orCCrlhliienniaicc,aall oobbsseerrvvaattiioonnss ooff llooccaalliizzeedd aallooppeecciiaa aanndd eemmaacicaiattiioonn wweerree ccoonnffiirrmmeedd aatt nneeccrrooppssyy.. NNoo aaddddiittiioonnaall nneeccrrooppssyy oobbsseerrvvaattiioonnss ooccccuurrrreedd.. 10 171346 2277888..00116666 33MMAA1100008833228844 441188--001111::PPAAGGEE FF--55 441188.-001111PP:PPAAGGEE 55 eBBnaotddiryye wwdeeoiisggahhtgteggaapieinnrssioaadnn(ddcaaalbbcssuoollaluuttteeed and relative aansdDreGlat6ivteo feed f1e8e)d, consumption values for tchoensenutmirpetiionntevravalul easftfeor r the the eiwinneniitrttiiiareaettiroidoennodsooufacf gettredreeaipanttemtmriheeoenndtt1(((0cDDamGGlcgssu/kl66agttt/eoodda22ya00)s)aaaDnnndGddshttih6gheheteoeernn1tdt8iiorr)es,eatgghgeeeesstetgaanrttotiiiouroepnns,pipneetrceriioroovmddapl((aDarDfGeteGdsr 0 to 20) 0totothe2.0) wccooennrtetrroolrleggdrruoocuueppd.. in the 10 mg/kg/day and higher dosage groups, compared to the RrReeeldadtuuiccveeeddtoffeetthtaaell cbbooondtdryyolwwegeiriggohhuttpss occurred (o8c.cu5r%readn at the 25 and 35 mglkgiday dat-t1h3e.82%5,arnedspe3c5timvegly/k)g. /dNayo dosages, doothsearges, CaCrreaatleaiesctsliavearereaeastaonnh-tis-hsgeeehcctcatioisoonnn3trii5onnlggmggoor/rokruglliiiptttdtea(er-ry8.pp.a5ar% rOaanmmaeeentdtleeirr-tss1er3ww.ie8ner%rteeh,eaarfef3ffse5epccmettegecd/dtikvbbgeyy/lyddd)a.ooyssNaadoggoeesossathgooeeffrttghhreeoutteepsstt cwacoohrtnonicslsileiessttbaeeosdddohyofigfehttdwweaoomsaee)3aa.5rrllyymTrrghee/esksosgore/rdpptfatiieyoto.annlssOfaainnnnedddilni11tgt33serffweeientturutsehseeecsso3wnw5isittimhhdegccrl/lekeefgdftt/dpgpaeaalnylaaettdteeiocs((tatiwnwgooeoraaigllgsrsiooonuhhapaanddd wRohtotleestboardtyiceled-eremlaat)e.d.These fetal findings were considered genetic in origin and not test article-related. aBBnaadssee2dd0 oomnng/tthkheeglrrdeeassuyullwttsseorofeftthrhieisscddooomssmaaeggneed--erraadnnfggoeer finding ftihnedifnulgl study, dosagesof0, 1, dsteuvdeyl,odpmoesnatgaels tooxfi0c,it1y, 5, 10 s5t,ud1y0 of aNNn--dEEtt2FF0OOSmSEEg/kiinng/rrdaatatss.y. were recommended for the full developmental toxicity study of 2277888..00116677 10 171347 33MMAA1100008833228855 441188-001111::PPAAGGEE FF-66 441188-.0011l1PP:PPAAGGEES6 IT.he puPrupropsoesotefh:ethdisevsetluodpymweanstatloopxriocvtidye(ienmfborrymoa-tfieotnal{otroxtihceitsyealrodCi1Eelro3f0dgoEsNaEges The purpose of this study was to provide information for the selection of dosages TIemtB eniie a study of N-EIFOSE administered orally via g2vage (0 CriCDBBR to be used in the developmental toxicity (embryo-fetal toxicity and teratogenic {AF Plus presumed pregnant female rats. potential) study of N-EtFOSE administered orally via gavage to CrI:CD~BR VAF/Plus presumed pregnant female rats. IN1l.. n e te M Meetthhoddss"t: st artic. N-0EIMFaOySE16[98l,oaantdhstnourmebdeart rFoIo-m38t2em9pe(r3a0t0u3r5e,, 30T0he97v3e0f0e39e). TT wwEthaanSessoe tr2ee%dsceteiTeae iovrwnetciiecdzleoeeoan,dnnnNw72a-880tE00ertr1MFs)inne.Oayyrf,SeeTE1vvoh9eene[9rrlsos82Tete,2/bwaooaMnesstadmmceyohosnstsn1ioi88ussr9e0mm 8mdw,beeeaamamtrsbnrbFrdorrMaoeawcnmn-ae3eesi9tvepp2esmrr9tdooopc(cfre3eree0rsdosa0smsta3euetJ5drd.e,0dd.B3%eea0iT,iok0ohtnen3eeiir7zmz.,vepee3dedh0rWwia0cat3alleu9tere)!e]r,. (hPRih.piOlisp.bsduberuiorggin.,oizNNneieedwzwweJJadeeterwsra)e.tye,Troh1nes TTEhefRy.Oa.ndde=ionmiaziendtawiantueerdreai.st 2aarTTv2voweaaosMeiiml!leaaantbayberleemi1pc98ffeir90roero8amwfmt,ouaaraarsnmeccud.roloewanncttTteaiiihnisovneuneusosodtpuouwrssfreereoprssdmaeooruaueprJtrdrc.crTeeoev.poeaaaBmntrtaietfkthcdeeeeemrd,HTTapeleeEsysrtatiintnuggre. FBsFtiaofctroieyl-idtsyiaxatpnrrrdooeooissmmummtaeeammdipneptpraerairnetaegtnduaraentt. rCdoToHoesmLsatCgtaDeerBmtigcBprlReeorufVaopAtrusFmr/[eueP.ilaIgTtUhitohSneDpes(prwSrgeperprroaaeugrepupder(eGvDpreaaohreuicwdples)dw|atiralhyastr.souwgehre FFVraaillfnlt)yoyd].-os0miypSxluetypshnraapoessssessseniuiismgnoginaonenteendusddsropa(tolfor0lfeyssttgh-heenbeevvareeenttenndetssfCtdteodaamrs:ratCtaiielcgcDsellee~eroBwgwfaterRe0osrrueo(eVpnVAasaedFddn[mam /eiPiycignislneuihi.ss&stttpi1ee.ernr(ere5Sod.dgupr1groooa0rhr,uagalpul12lly7ey0(.-G,vv0Di)2paraao3rawug9epnla2essv/dyua8)I gm0trhe5eartdoFosu1nwgCceheere dSg3S3 ae5Eeislagmytatigttooi/ockntngha/e((dyDsaDe.GyG.nsbsao6TT6tdhhuttyeeoroawddl11ley"7oo7i)-ss)bgaaaarhggtetseedddoorvfvesseoom aaclluogguamremldeseeedrowwafaiats0mssmo(5e5VndemmidhakLaitc/yseklselg,)y,6, aba1thded,jfrj5uouo,ssrutte1gee0hdad,d1m2ddi7a0aln,iliolyy2sft5opornnraaetntfsihdhuoeenmbDoeEafdSstCihs.eooff tttCCheehesshteteicnacarkkdrttssiiivcclfifledeoo.u.rravvliiaabbboiialldigttyyey.wwweeearirpgeephrtmmsoaxariddemeecaotttrwewdliiecycdeeoiddnmaaeilmilyhy.eo. duriCCalltiaiennflitiycceaarbllaeoodfbombsirseeneriravsvdatatmatiitoioinnnoisssntwwraaoentrirdoeentrrheoeecfcroothfrrdeodueerddto dCsSiaxteilayhookbuseerfafsoogrralaeeetteeddprroeo.srsiaTToodghhd.eees,ssaBeeanopoaddpbbyrsfsoeewexereridvmviagacalhtotiitoenosnlsnysswuomewwnpreeeterrieehrooenaacuilovsrsraooadlfrreuteeeedccrsodoawarrddiedlemreyddeidnuoorisrennitcccrnaoeegrtiddodieannadeiliay4on0ndddSuuD3rtnhiGn0eggSn (at0fhnno.eedu4.r 6to. postdosage period. Body weights were recorded daily during the D8e.e10d,os1a2,ge14.pe1n6, 18:2nd 20. postdosage periods and feed consumption values were recorded dosage on DGs and 0, 4, 6, 8, 10, 12, 14, 16, 18 and 20. JE 2 ODDeerttaatitloeevddidddeeesdsccririnippttthiioeonnassppoofrf osaapll.~lripparrDtooeeccveeisaeddtcuuitrroieenosssnsuufssoreefoddmthitiinnhs ettrhhePeeprooccrtootonncaddonuuldccattinnoodfSfthttthehaiisnas dtssaatutrcdhduyed aprBroreoettoopaccroonolvleidaannePdddroaiancmmetehednneuddrmameepsnpetnoroftspt.rhieaDtTeeevssitaeictintoigonnFsascfrioolfimttyhtiahsreerePaprvooartitoacabonlldeaininndtthSheetaarntatdawacrdhdaetda. Operating Procedures of the Testing FaciLity are available in the raw data. 10 171348 ---- 2788.0168 33MMAA1100008833228866 441188--001111::PPAAGGEEFF--77 418011 PAGE 418-0lIP:PAGE 7 AAolflllcrroaarttspsowwreaerrleeutsseaaac,crriiiffmiicpceleaddntooanntiDDoGGn s22i00tesaannlddiveeexaxanadmmiidnneeeadddffoforrettthuhseeensnuuammnbdbeeerraraalnnyddaddniidssttlrriaibtbueuttiioonn orpreeefssrcofoororprrptpmtioieoordnna.ss.l.uFtAAeeatgg,urrsioomessspsslwanneneertccaerrtooiwoppenssiyysgihootefefsdtthhlaeievnettdhhaooernrxaadcacimdiccie,,naaaedbbddfdeofotomumrisginenrasaollsaaasnnndeddxetppaeeerlmllvvyaiilccanavvldiistsecclraeeatrrteaiaownwsaa.ss and sex performed. and sex. Fetuses were weighed and examined for gross external alterations WL Results: III. Results: AAo i bservati -Table 1; MInodirtvaildituya,l CDlaintaica- lTaabnldesNe8caronpds1y0)Observations (Summary -Table 1; Individual Data -Tables 9 and 10) Ad. A.1. MMoortrtaalliittyy AAlll arattss ssuurrvviivveedd uunntitill sscchheedduulleedd ssaaccrirfifiiccee.. AA2.2.. ClCilniniiccaall OObbsseerrvvaattiioonnss Clinical observations during gestation considered treatment-related were limited 1C0lisniicnagll eobrastesrwviatthiocnhsrdomuorirnhgingoersrthaetaio,ncchornosmioddearcerdytorretahtmeaenort-reemlaacteiadtiwoenreatlitmhieted t2o0sainngdle35ramtsg/wkigth/dcahyrodmosoargheins.orrhea, chromodacryorrhea or emaciation at the 20 and 35 mg/kg/day dosages. AAblelllcooatuthhseeer:r ccllii1nn)iictcaahlleooibbnssceeirdrvveaanttciieoosnnsswewwreeerreenocctoondnsosisiddaeegrreee-dddeuupnnerrneeldlaaettneetdd;ttaoonttdhh/eeorttee2ss)tt taahrrtetiiycclloeeccurred buiinnnedoocenanrlulsyysioeod:enn,ee1br)raaatt.tch.keTTaihhnneecdsi/sdoeeernooncbbeesscesker.rwvvaeatrtieioonnnssotiindnccollusudadegeded-ldlooeccpaaelliinzzededednaatl;looappneecdci/ioaaroo2nn) the limbs, they occurred the limbs, underside, back and/or neck. AA3.3.. NeNcercrooppssyyOObbseserrvvaattiioonnss nCClelicinnriioccpaasllyoo.bbsseNerorvvaaatdtiidooinntissonooafflllooncceaacllriizozeepddsyaallooobppseeeccriivaaataainnoddnseemmoacaccuicraiartteiidoo.nn wweerree ccoonnffiirrmmeedd aatt necropsy. No additional necropsy observations occurred. B. MMaatteerrnnaalrlies BBood-dyy W Weeiigghhttss aanndd ;BBooddyyInWW dievieiduigaglhDhtattCCahhaa-nnTa_blge~eess ((FF1iigguurree 11;; Summaries -Tables 2 and 3; Individual Data -Table 11) : MdMeaactrteeerrannsaaelldb,boocddoyymwwpeeaiirggehhtdt ggtaaoiintnhsseiincnottnhhteero11l00grmmoggu/lpkkggo//nddaagyyesaatnantddiohhniiggdhhaeeyrrsddoo(DssGaasgg)ee 6ggrr1oo0uu8ppssanwwdeerr8ee 1tdo0e1c10r0.e. asBBeooddd,yycwwoemeiigpghahtrtssedwweteorreethddeeecccorreenaatrssoeel ddgrffooourr ptthhoeen22g55emmsgtga//tkkioggn//dddaaayyyaasnn(ddDGhhiisgg)hhe6errtoddoo8ssaaaggnedess8 oo10nn,DD2G0G,s211500a1tn0od11232,,511m22g/t1ok0g11/44daaaynndddo11s44attgooe11g66.r.ouMMpaastteewrrennraaell gbbeoonddeyyrawwleleiyigghchtotmggpaaaiirnnassbiilnnetthhteoe 11,, 55,, cc1oo0n,nttr2roo0l,l vv2aa5lluuaeenssd pp3oo5ssttmddogos/skaaggg/edea((yDDGdGosssa1188gettoog22r0o0)u)..ps were generally comparable to 10 171349 22778888..00116699 I3MMAAt100008833228877 441188-.001111:.PPAAGGEE FF--88 441188-001lI1PP:PPAAGGEES8 pRReeefrflileeocdctti(incngaglttchhuelesasteeedeeffaffeseccDttss ooGff6tthheteotte1e8ss)tt,aatrrthtiiecclleeen,,twwiereeiiggihnhttteggrvaaaiilnnssaffftooerrr ttihhneietieeannttitioirrnoeefddootssreaaaggteement p(1(De0DGrGmiossg6d/6k(tcgtooa/dl22ca00uy))laaaatennnddddhattihhsgeehDeeerGnntstdiirro6eestggaoeegss1ett8aa)gtt,riiotoohnunepppseee,rnriictoioroddem(p(iDnaDtGreGerssvda00ltttoaooftt22he00er))icnwwoineteitrarreetoiolrrnegedrdoouufuccptere.eddatiinmn ttehhneet 10 mg/kg/day and higher dosage groups, compared to the control group. gMMraatoteuerprnsnaalwlebbrooeddyygewwneeeiriagglhhlttyss caaonnmddpabbrooaddbyylwweeetiiogghhctotnggtaraioinlnssvaffoolrruetthsheeov11eaarnneddac55hmmgign/t/kkegrg/v/addlaatyyadbduoolssaaatggedee. groups were generally comparable to control values over each interval tabulated. C. Maternal Absolute (g/day) and Relative (g/kg/day) Feed Consumption VMaaltueernsal(SAubmsmoalruitees(c-~Tldaab)laen4sd aRnedla5t;iveIn(dqilvki(d=uladlavD)atFaee-dTaCbolnes1u2)mption Values (Summaries - Tables 4 and 5; Individual Data - Table 12) AAdbobsssoaolgluuetteegraaonnuddpsrreewllaaettriiveveedffeeeceerddeaccsooenndss,uummcpoptmtiipooannrvveaadlluuteoessthffoeorrcttohhneetr11ol00 gm mrggo/u/kkpgg/a/ddtaaayyll aatnnadbdulhhaiigtghehdeerr dii1nno6ttes.eaarrvvngaadellss1gddr6uour0uriipnn1sgg8)w.tthheeerMeaddtoodesseraacnggraeeelapfpseeeeredridi,oodcdcoo((nmDDsGpGuasmsrpe66tdittoo0ton88,,tvha88elt1uoc0eos11n00ft,r,oor11l t00ghtretooou1.11p22.5,a, t111a220,ltltoot2a0b11,44u,2,la511te44adnttodo 3156 amngd/k1g6ldtaoy1d8o).saMgaetegrrnoaulpfseewderceongesnuemrapltlioyncvoamlpuaersabfolrethtoe c1o,nt5r,ol10v,a2l0u,es25 and postdosage (DG 18 to 20) 35 mglkglday dosage groups postdosage (DGs 18 to 20). were generally comparable to control values cRReoefnflsleeuccmttpiinntggiotthnheevssaeelueeeffffseeccftotsrs toohffetthehenetittereessttdaaorrtstiiacclglee,e, paaebbrssiooollduutt(eecaaalnncddulrraeetlleaadttiivavese fDfeeGeesdd 6 to 18), the ecepneontrntiiirsroeeudmiin(npttDeetGirrovvsnaal0lvaaatffolttuee2err0s)iinnfiwiottieriaarttthieoieonnreeoondfftuittrcrreeeeadadttomimnseeatnnghttee((D1pD0eGGrmsiog66d/ktt(ogoc/a22dl00ca))uylaaaanntneddddtthhahieesgeheDnenGtrtiisrrdeeo6sggteaeosgste1taa8tt)ii,oontnhe groups, compared to period (DGs 0 to 20) groups, compared to the control group. were reduced in the the control group. 10 mg/kg/day and higher dosage dAAbobsssoaolgluuetteegraaonnuddpsrreewllaaettriiveveegffeeeneeeddraccloolnnysscuuommmppptatiirooannbvvlaaellutuoeesscoffnootrrrtothlheeva11laaunnesdd o55vemmrgg/e/kkaggc//hddaaiyynterval tdaobsualgateegdroups were generally comparable to control values over each interval tabulated. D. Caesarean-Sectioning and Litter Observations (Summaries - Tables ttChharroeousu,acglrhhea88n;; -IISnneddciivvtiiioddnuuaianllgDDaaatntada=-LTTiatatbebrlleeOssb11s33erttvhharrotoiuou.nqgshh 15)(Summaries 15) - Tables 6 . 8CCaa(ee1s0sa0ar%ree)a,ann-8s-se(ec1ct0ti0ioo%nn)ii.nngg8 oo(b1bs0se0er%rv)va,attii8oon(nss10ww0ee%rr)eeabbnaadssee8dd(oo1nn0088%)((11p00r00e%%g))n,,a77nt((8r8a77t..s55%%w)i)t,,h live l8liittt(et1err0ss0ii%nn )tt,hhe8e ss(1ee0vv0ee%nn )rr,ee8sspp(ee1cc0tt0iivv%ee),ddoo8ss(aa1gg0ee0%ggrr)oouuappnssd.. 8 (100%) pregnant rats with live RrReeeldadtuuiccveeetddoffteehttaeallcbbooontddryyolwwegeiriggohhuttpss (oo-cc8cc.uu5rr%rreeaddnadatt-tt1hh3ee.822%55,aarnneddsp33ec55timmvgegl/y/kk)g.g//ddTaahyyisddooossbaasggeeresvs,a,tion wwreaalsasticcvooenntssoiiddtheeerreecddoaannntroeeflfffgeerccottuoopff t(th-h8ee.5tte%essttaaanrrdttiicc-l1lee3.bb8ee%ccaa, uurseseespiiett cwwtaaivsselddyoo).ssaaTggheei-s-ddoeebppseeennrddveeannttiot n 10 17135O 22778888..00117700 MA10083288 3MA10083288 441188--001111::PPAAGGEE FF--99 18011 PAGE S 418-011P:PAGE 9 aa(nndeddcoorccecacusurerrrdeeddboaadttytthhweeeiddgoohsstaaaggneedss fiinenewwdhhiciccohhntsthhuemerpreetwiwoaanssvmm alaauteteesr)rnn.aall toxicity toxicity Gbserved observed (decreased body weight and feed consumption values). NNoo ootthheerr CCaaeessaarreeaann--sseeccttiioonniinngg oorr lliitttteerr ppaarraammeetteerrss wweerree aaffffeecctteedd bbyy ddoossaaggeess ooff tthhee tteesstt aarrttiiccllee aass hhiigghh aass 3355 mmgg/k/kgg//ddaayy.. TThhee lliitttteerr aavveerraaggeess ffoorr ccoorrppoorraa lluutteeaa,, iimmppllaannttaattiioonnss,, lliitttteerr ssiizzee,, lliivvee ffeettuusseess,, rreessoorrppttiioonnss ((eeaarrllyy aanndd llaattee)),, ddaammss wwiitthh aannyy TeSorptions and percent ive male fetuses were comparable among the resorptions and percent live male fetuses were comparable among the 0 Venlo). 1 5. 10, 20, 25 and 36 mgfkgkiay dosage groups. No dams had all 0 Vehicle), 1, 5, 10, 20, 25 and 35 mg/kg/day dosage groups. No dams had all resorbed Conceptuses, there were no dead fetuses and all placentae appeared resorbed conceptuses, there were no dead fetuses and all placentae appeared normal normal. Total of 109, 83. 116, 110, 118, 116 and 114 ive fetuses were evaluated for Totals of 109, 93, 116, 110, 118, 116 and 114 live fetuses were evaluated for external gross alierations in the seven respective dosage groups. No etal gross external gross alterations in the seven respective dosage groups. No fetal gross external alterations were observed at dosages up to 25 ma/kglday. One liter external alterations were observed at dosages up to 25 mg/kg/day. One litter ((1100665500)) iinn tthhee 3355 mmgg//kkgg//ddaayyddoossaaggee ggrroouupp ccoonnssiisstteeddooffttwwoo eeaarrllyy rreessoorrppttiioonnss. aanndd 1133 ffeettuusseess wwiitthh cclleefftt ppaallaattee ((ttwwoo aallssoo hhaadd wwhhoollee bbooddyy eeddeemma)a.). TThheessee ffeettaall findings were considered genetic origin and not test aricle-related findings were considered genetic in origin and not test article-related. IIVV.. CCoonncclluussiioonn:: BBaasseedd oonn tthhee rreessuullttss ooff tthhiiss ssttuuddyy,, ddoossaaggeess ooff 00 ((VVeehhiiccllee)),, 11,, 55,, 1100 aanndd 20 ma/kgiday of N-EIFOSE are recommended for the developmental toxicty 20 mg/kg/day of N-EtFOSE are recommended for the developmental toxicity Study in rats (418-011). The 1 mg/kg/day dosage s expected to be a no- study in rats (418-011). The 1 mg/kg/day dosage is expected to be a noobservable-efiect-evel (NOEL) for both maternal and embryo-fetal toxicy. and the 20 mg/kg/day dosage is expected to produce maternal toxicty (decreased observable-effect-level (NOEL) for both maternal and embryo-fetal toxicity, and the 20 mg/kg/day dosage is expected to produce maternal toxicity (decreased maternal body weight and feed consumption values) and minimal developmental maternal body weight and feed consumption values) and minimal developmental Toxicity (decreased fetal body weights and possibly delayed ossicatin). toxicity (decreased fetal body weights and possibly delayed ossification). "AM ee Alan M. Hoberman, Ph.D., DABT Date DDiirreeccttoorr ooff RReesseeaarrcchh o, ALPS 0-595 Study Director ond G. York| O.DABT Date "AAls~ sssooocciniaad ttee GDDi.irrYeeccotrt-ookrr,--t~8 ~PhRe.le~as.,erDacrAchBhTaannddD-~,--~ Study Director 10 171351 22778888..00117711 amAtoosa2se 3MA10083289 441188-001111::PPAAGGEE FF--1100 HB01PPAGE 10 418-011P:PAGE 10 A ---- 3 &e bg z z 3 3 3 3 8 EME of CER: TE mAE k ARR \. = " TE : =E "1- SJaalxa . = 2 oR s . =LU wh . 5% mck a 2 an 3 2 Q825 rwoxs =5z2 Z don," UJ oh I s<I-- L x -- ak - aK - 4 Wo 3 3 8 3 Soda g s2 f 22778888..00117722 MAT0083290 3MA10083290 441188--.001111::PPAAGGEE FF--1111 "1011p PAGE 11 418-0lIP:PAGE 11 .: =83 =& i si 2 P J oo mpel mml eeeo gd : JUROR 1 P: opey3e meee iii : o eeeee ooo fiz ix-izesses soos iE : 2 iis fia ecces oo o 2:% P3oi f= yik FiiE:l t$5ii8; gigi gpiigEft FR iE fz ie ff HPReo, Ld. [iIidR Ig . 38S:ig4lo;BEE Ri Fi fp2r0ggl 8 sjaiigl PRE. ritiin BIErRignigiEEd] iFi8g28 CiE.d 22778888..00117733 swatoosszst 3MA10083291 ;:: i 3 i I i iIi: E EERE Hii Pompe :: To wemwe ss 8 i: Emil; ee oe ~ 8% fHyN H3i tii HiHil L}] Ets Es3 Boiggog:t i:ii LPPiibEer i giz37 HBi?HRL a::g HLvEiaH pi 1 Hn i i: iSphoad ig $f P IEt THy ER ii iBlri [ER HERE EY 441188--001111::PPAAGGEE FF--1122 eee 418-0lIP:PAGE 12 28= e 22778888..00117744 antosszsz 3MA10083292 c3: o " fort E PFT 441188--001111:P:PAAGGEE FF--1133 anoiponcres 418-0lIP:PAGE 13 882 SiszzsrcezzseazenniYi= IIriiiiiiiiiin iii ii iiiiieeie I"ermgisrsoieoimoge IazoeIieIageIie : HERREREEERERRRRE F103 Siiiiiiiiiiiiiiaiio gi f ECC PJiLidididisidiiiYiiiiiraoiTiIiaidi it : $i30i LL I3EiEiEEEiRRiBRRREEiRERRIREIRRLi : iE a 30g i S fgPi oEg8 sgijiC5 eere E raenlaeiasaiizriaaizaE zinonaeasnaaonisiaiolnis8t FLEE i 22778888..00117755 -- 3MA10083293 441188--001111::PPAAGGEE FF--1144 4180119 PAGE 14 418-011P:PAGE 14 :Po 8& -: = b=] i E i TpiiriiiiiaGaiiii : : Pojmmlec Tjiiiiiiiiiiiiai; 22202933323 7%732; z iEsf osi-1? A porsriEA iAiLiSiEiArLA eEaLiEiLnEg friidifraigaiiaza giz if if iE Pin 3 $3333 3ii3iiiaasy:1 EEREEERERRRRRR EI 8 porvrccErzazzzizaal i iggtgisfdiyfrrrrrraaaaaaaaiagdi: 22778888..00117766 aMAtoosa2se 3MA10083294 441188--001111::PPAAGGEE FF--1155 rrr-- 418-0lIP:PAGE 15 x2 8is 3- hae. SSiEt2i3T2i2t:i3i3d%ag0 <= i iii iiig: [I i [EEEEEERERE i Fi33934444 ; Eo ALdiAdiRiEi EEs #i0i gE B[eREEBt 5i3i: 3 vIvXIrI eS nI ooin2iitAidge PSiRiiiiiiiiiiiaiiiinn ;i shi LL liiiiiiiiii E3N800 10 [EEREREREREIiNed : 0H 30F feesazrzraaaiil 1 Eiihgpe PpoicoilriiriEioeccaioth I piBaiellerpazinsiseliln 22778888..00117777 swatoosszss 3MA10083295 ::: *: : i 5 i : PORT i: Poses 441188--001111::PPAAGGEE FF--1166 4HB01IPPAGE 418-011P:PAGE 16 ! =288 = ~-- e "mms rma iii Giirpiriiil ii Bynes ii PIEiEiErErRrRiREiEiiRIbNd. +1 +1 +1 +1 1 1 +l 1 -vl 4-1 +t FfEi af3 gi LL SEiiiiiiiigiic 53: IEEREREERERIER : i$E1ii0sE ecrmzrriasaiiln Flip, SINE fEL icoei aai asezeeisid} HHH IRR HER] if: 22778888..00117788 SwAtooss296 3MA10083296 441188--001111::PPAAGGEE FF--1177 aoripPAGE 7 418-011P:PAGE 17 : = : i CTR LAGS ETS a I amie sevesmawpan = :i Tiiiiiiiiii e= EB i ow momma PEt or iiiiiiiid iEF gr By 23: 2 IE3E3E7E3E3R3E0R0E2E]3 : Pid FEREEiTEITC Ig 3: Bg 54 33 fspifg nie i PJaRdiEalEilEa iaaaid aeaa EiR +5 3 5 $5355 386 97s0q3 gf jigggggiiiggn iia groraizazaaainEg g4s EighEi iE crl esso issi eess oia nhis [tPiETaSlFARRERRRRRRI8 F 22778888..00117799 SwAtooss27 3MA10083297 :: - i i i [EEE 441188--001111::PPAAGGEE FF--1188 8011PPAG1E8 418-011P:PAGE 18 32 L~S =e 1333S RITIIN EE EE si B70 osmime IH vizzaaaiiad IyErRiErRiErE IiR iElE Rw] HiHi PBEeLL. Hgf H ii:t g3z ee $800 s1paig0 G12n3i2i3i3i33i3i3i3i0ol1e EEEEREERE : : R REE ERER RiRiRiRiR RiEiIlNC] 3 ifs prrrrrizoeasEyr 3;- iiH f jofoeoeszzazzzsoze-scois n BriggffliRRRRERIEEE irate if. 22778888..00118800 amAtoosa2se 3MA10083298 441188--001111::PPAAGGEE FF--1199 418.011PPA1G9E 418-011P:PAGE 19 so = io i = i ; iri iiiiiii e . i i EEEEEEEEE] 3 BHEgisinr fsiofriririririoisizzy Ey gros i fIgAIiIIN og i "Bvt rida iiiia B iiHH sisgisg3aiodoiiif HH Le BRRiEIiEaGE 5 i RERRRERRRRRIRE i27 :21g0F :1grerzrzozaaaiiEEsgguii qoikEi. Eos Siagdl tio Bigg JEPEiEoEciRiRsRsaEnEyEsIiCiEHf flint [Eo 22778888..00118811 MAt0083208 3MA10083299 I :: 1|od ": Po f PY 441188--001111::PPAAGGEE FF--2200 rrr-- 418-011P:PAGE 20 oo8~ ~ = = tii iiiicic Pir iiiiii: PETUT HiHd HH Pio. i! it OPEiiEiEE : eae 2ILIIIILLLE PiiiEiiiiiiaii 3 |1 iiii EidiEiE of Ff ig ifs si: 2 ifr TPeeleollE,E FL 2:i 3::i 23s 312i 3g2i0i30d Pyopifieeeiiaaieg 2 igs id: 22778888..00118822 swatoossa00 3MA10083300 441188--001111::PPAAGGEE FF--2211 pr418-011P:PAGE 21 A2 I. E8m or Liao oe | id 113% 33s EE 3 i f,oorrnronozoaa 4 poFITE TAS oTIIL TEE 5 ~ iors oi. i z mma mgue mmmoeeon3s3 iijis PIPE EEEEE IEEE img f * lois giif s18 2 i fl. dd 208 ah DIiEa dfireg3eic ffrf mie lmigilir li i iid 1.4.3 ii RI1EgLg ERIN 0 fz 0 s EgrBzHif ii riPHL 22778888..00118833 swatoossaot 3MA10083301 414188--001111::PPAAGGEE FF--2222 sopeaGe2 418-011P:PAGE 22 b-4 t 2= : o ii = e i : = 8 SLorrErcITIcyE cid Posed -iooareoeroeriid i : 1,0 i Fidos: i 28 iid EgoitRicg -rlarclTrcrs1.3238:43 i5 f : giz: sd es FE2 3%: tp ny i= F $i8i0 EC i: LOiTiHiE.EBIT.EiNaETpoeEiriTd: se r Fd al TEEpRp IREb El bj TaEoEpo adaib feareasl t e "07 Pf7s t5aa3as aeftidt 22778888..00118844 swar0083302 3MA10083302 i::: Crear: :2 z= ERI + & 2 dd. * p Titi ao t ',~ 1 { B5dfiairpie30r8 e iEEs oIpRIpOoZ Bog Tro IIlovg PEC iT ororanong: giii ssi]3 i PTT oy fp Pray pha! zo isd H=E = =,3 = Sik SET chili PPiyimfgihieass fp3u0; EHOY 441188--001111::PPAAGGEE FF--2233 awarraces 418-011P:PAGE 23 w888=n 22778888..00118855 Suntosssos 3MA10083303 441188--001111::PPAAGGEE FF--2244 asorpeace2s 418-011P:PAGE 24 Po = i:! 88= : E i : ix 2To7g 2ii3i9o%f3 1 1Ed FREE fffice corrorre Rni onoiood 1 PoE Prion du, path fi 3 ciaie ls3os3e3s3 sOlBC EiHiif 38 08 .88% 31;5] 2 ei [PE IH p Prh k a sy nBS 22778888..00118866 wA0083308 3MA10083304 := ; : t Po neepr 3 441188--001111::PPAAGGEE FF--2255 418..011P:PAGE 25 3=Ss == ib H HIN d TH: iE Hog al gE : 5% i iy i i 5 de i J Doan iggt AR HERI 22778888..00118877 -- 3MA10083305 : z: i ;; i i 2 ofso of po FEL E Posen 0 i: ii t oi,d 3 P8E , E BOND i: i i343 iE iid BE ses zz ozzifi: ii PROCTER pie U0 if ow i333 IPgERIBEE8E== aE e{ai e SHfE oHeEi3E f gLcd aI T ii H Tope et ph 22778888..00118888 4411884-301111::PPAAGGEE FF--2266 8011PPAG2ES 418-011P:PAGE 26 2 === =2 SwAtooss308 3MA10083306 .:i i: i : : Pio i! { go 1 :i Ei:li, : $ET1f0rgflEamnes sm nan n n Pg 2p0ipDH anIiaEn DdneReneEns $30 lal ig PP y30i id FiiH annIiH i-i i nifERREEEEEIDIBBEEENEE 2: 441188--001111':PPAAGGEE FF--2277 anortpaaG7e 418-011P:PAGE 27 48@ e==~ 22778888..00118899 st3MA10083307 II Eo gl i: Poi i 441188--001111':PPAAGGEE FF--2288 i : Pi : :! : aorprAGE 418-011P:PAGE 28 = = = i ; Eo I. ; iEo5D00 HiiD i P10 3 amma [EaRRRR nummy igREREEE! Piibniaasfa nan n B gSr 3 E0 s aiidPi iHisfH SLIing sFiagl iiss Ppidr mb is i28: isifEizErzEansz H fimmae zsmzy aist iid ii ia: 22778888..00119900 SwAtooss308 3MA10083308 =ii : i i i 441188--001111: :PPAAGGEE FF--2299 aoorpeace 418-011P:PAGE 29 : 5=eS = e ;: : : f i H Po EEET REHEBPEEHETLTDY To bin] mann 3% iig fin:i3s3es5s3i3e3saei:niHeeailgenisans ig H jo 6] man 3 - . i300 pn 8| 5 3: % : 3% fH Pooh Fon Bon El ocibamnnyemmy fi i he 22778888..00119911 wA10083309 3MA10083309 =:: !: i:: i : : Pi o ; i: : 441188--001111::PPAAGGEE F-30 F-30 asarieeace ~ 418-0lIP:PAGE 30 g 2= i E P 11 gHEma H PfsgihiEoonHnaERlaE n PHEEL minalii ji La s Eg- iigli EE FORE {2 h ii oi o aiB enon 2788.0192 surioassio 3MA10083310 i:: : : 5 bto u HHT m Eo, HiME Hal 2 A reer raaiaEEE. : [RE FEFEEEEREEEEFEEE s HI BE mmemmene mmmnensl :3 1g ' : 2 sf zazazesz zezsmeasi g 7 iz} sssesEes smemzEsE | 441188--001111::PPAAGGEE FF--3311 asonpeaces 418-0lIP:PAGE 31 -25 = e ih ii : 5 HE 5s bn i 22778888..00119933 staan 3MA10083311 xTo i: : E -: : i5 i: z sigdids diddidEE i HE : i fi HH ~so5osogo~g=s=e=s= 8~8~8o88o8=8=80 | z [gi FERRED REIRRIEL. DoE gaan am Pod : i g i 5 i azpazzza azssazss i : J sees meee : i2 1Iiadi)s}! ;saasamzssesaanzs msaemeamanaaznasiI]3 5: iE i0r (Ff gEEEEiEi diffs: faEcEf ii f fiit { = SEF Pin iff i 414188--001111::PPAAGGEEFF--3322 18011PPAG3E2 418-011P:PAGE 32 = S --= = 2 22778888..00119944 amAtoosss12 3MA10083312 441188--001111::PPAAGGEE FF--3333 i 3 i 5:i i Po i iPDoo gHHEiHgEhaHsE sEdinEas x | to HEE HEHE 0 somone 418-011P:PAGE 33 0 = ==2 id ; i ; # sscsasas asssscas : i: is) smmmssss mememems, | i i 5 (9% E23EIEER iii ii, 2 ~0 u i us : 3b [Hi] IM ih 28 ig H 1] ti i ia. 22778888..00119955 se 3MA10083313 .: ito ii i t : siddddidi { fi : gepresssi | Pop HERG DoE sama Etig HE PE 13HgE5RhiE} E Ei EE ERH Nsi ih sae 2: : eed [I]z wRazaTmazTai 3og a| 5 3fi Hii i af 0 iid li ht 3t2 higs' iii] 22778888..00119966 441188--.001111::PPAAGGEE FF--3344 418011P.PAG3E4 418-011P:PAGE 34 252 = ==2 amAtoos3ste 3MA10083314 i diszazs 441188--001111::PPAAGGEE FF--3355 3~=2 4B0nPRAGES ~=~ 418-011P:I#AGE 35 .= hal ig = grzdaeag 5 SRI HEE HH ii = did.iiieg!Pi ol igpare | : i SL oranigiis :i =olaiEgiizidfaisis EBEf sCipRREaRRRmRRL Le 2[HEgE iH E RT i i Pop TE if EsfLT [I iEgLaEgEgEiHdsHinElEg: gH giggEasili i "izspgsfsnis dmgrnaan ge 543 amma mem i 3 eisggiiigsiinisdegisigi ie i1 ihieees] Eg faneenana i? gc oipilEiszzsnal igaapna iE fpoETERRE EERE 22778888..00119977 MAT0083315 3MA10083315 3 i =izasaiasg i = igiadits ii =izazidaEE; i so sassan 441188--001111":PPAAGGEE FF--3366 [===J 418-0liP:PAGE 36 i Pein i - gegen if FE op -asaasn | i 1p EEE EEL iiasagssieissssaiie ie ik 1 is REESE EHECEEE gis i THIN [RPP a ii | $f 5 ii uf SHMob 3camimaens5iigdsaiad ifi: 2PE2 n Balisen eeees! lhaeSaemenssIiS Si oipiEfiEEEEEEEE:PiaEsassioi2e8s1 22778888..00119988 satonsssts 3MA10083316 Z Aid i =igizssangl i = 32RgRsRd Hi = gadsiidd. I 3 s gma 441188--001111::PPAAGGEE FF--3377 oa &===I= 441188-0-1011P1:PPA:GPEA3G37E7 ;i i: =iidfgsgds i -iiREseiad 2 POE mn ; Epon i SisE i [EEEsEEaE ciH IEE mer enn I Piifps memRmiEERELpiL r Pt: ilih obh:ssa n#iaL mann ina} i:Doig EER BREIEEEE: n(EBiEEaERnEIETg:s ii Hi i132 22778888..00119999 swato0sss17 3MA10083317 441188--001111::PPAAGGEE FF--3388 2v2 441188-001111P:PP:APGAEG33E88 == = sy = i: = igdgding i = ZERELR | IRE f saeiisss 3 sends i EEE : hti EgEiN5 iHE idRESIS is -- ~igRagEigs!i 5 ei-giansvgiiuinenseii ii PFFPITTFI ; PTET : -iFAREEiiic Rifas: ge F3irog Ha vsiziamaasdanaiciszessadidididss ugdis 5 EEE anise lipisan ul $3i tH 5: i} igs if=iprRammPiG E an n n5 22778888..00220000 amAtoosss1e 3MA10083318 : 2 igdgdgadd: { = aiisigdt] | Po : Io einen T:o e:luent 414188--0.01111::PPAAGGEEFF--3399 --3 asonpeaces o2xo 418-0lIP:PAGE 39 : e we i i P81 2elilE EE i, PE 0 PPiPiEEEpeLs co 2izAiiias -iiedaided : eiopimnsagnns iizi psn nisms} ii i -isessudndinigmnennasi]s m em e vl m n niTdHl pam aman PE= iB fEEe EEE amnaiaindmhal ii5 igiERiEEEiEEE:iPi(2EEEafEIiL3.E 22778888..00220011 swaro083319 3MA10083319 : olettests *iRFRRARAE 441188--,001111::PPAAGGEE FF--4400 8$2 s41t8e-00lI1P1:PPAPGAEG44E00 ==~ e 3 i ; ii = igrEndais! i ~gettene) : [ 1g R1 EmTeR i SIBE or {i5 PTioe iBTFfaEyd cigssessiiiieidageisssif{ gsspisiisesdsinsizmiasszndina ]loes -n ammssmnizeismsnenns BE i jamiimiiigsnislszaigiegnids iB Plan mani d$2e0i hg: i laassssnsii llEg i SPoeEIRTEIREEREEPlEERBIEEEILE:E: 22778888..00220022 stones 3MA10083320 H41B8-O01I1P:PAAGGEEFF-4H1 63 @ e~ sonPPAEY e= 418-011P:PAGE 41 =izzEianiel ; iEEE EH z P 10 o simi memn : i = faERER 5: ii i =gifaaadi sTveete i. f2 ligi (ET iri -isgsERasd : imm amae i [IE I FREE NE EHEERE reieies dEpss IIE; ) [PUSt emmsig a isnlliingadnsdaiagnds) fy i iE & P fo oph iETiiEe EEREEE eBEEeEEmnRE CE LE. Pi ix 22778888..00220033 satonss21 3MA10083321 i Ei 441188-001111:PPAAGGEEFF--4422 =E&=r] 441188-.00lI1P1:PPPAAGGEE4422 YeeT ] Tolisgadsdil lasdseid :5 . igesdigesi i dddsdddd : Hog hy pEihic,Dg amen fia g iIPyEFoPo oatfisinen 1yp sesnsnneifgtf: HE2E0R Ciissaui]t] ldsdunasei] :1 LsiEiEi. sseisine, 1 iesierenEefagl 85 ene daisies1 BS $BE5 faassieiegen] m baz ci B8Hh fy i 281 BiooinoiidfEBip-iEziEszRezEiiiiziEsEaEaiEiEiEiEc iAiiLHlE 22778888..00220044 satonsss22 3MA10083322 441188-001111::PPAAGGEEFF-4433 18 TM wsareercees ee= 418-011P:PAGE 43 : Po : Eo i Foigazased diddasis iD mes sam : Hop PHEoREg fy Fit Bie $Pi e. gPLi.Dp een epo anneBH g i icinaiaisensann : i sdddiisd (d4gisiiiifiocg iz eassiiss 5 8 ii Basisiasg Dasaners HY IP PLLB Emm ?; cennnn = BH Fiofen BEREEEEEIE HEHE 23 i i He1] 22778888..00220055 swatoossazs 3MA10083323 441188-001111PPAAGGEEFF,.4.4,44 $~B wnonpoaceu 2==2 418-011P:PAGE 44 i ii i i : Pi 3. 5 Tolimansizsl :5 Sp 7 semssmes fPEel,Tipieemvenes if simian madesaan l: assen i$ i ! Ji 0 jms meen ie FE i iisseses dessa BRE 1 HE id sigeesd araeens i HE ah FgEH id EfeasE ssansiisy 22778888..00220066 swaoossze 3MA10083324 ii 8 i 2 Po sien PD een EE. BE. Tg 2P l=i, ots :d iBy ioillig! i HE gif i & .i_ I: SgfE - sit iPotEh i JPi ods TEER ssasasis ffiii8 ceiil] aE onmunif3Ef LE 22778888..00220077 = 441188.-.001111::PPAAGGEE FF-4.455 ac) e= weaneonceis e 418-011P:PAGE 4,5 swaro0s3228 3MA10083325 441188--.001111::PPAAGGEE FF--4466 asorpeacses 418-011P:PAGE 46 : : .; =38 :Popp. eesPi mms i z= Pon eens DEE ees ene D Es ig mmeemeens lisx ssnneess ZT IoBiIlEs | eeemeseel ie seeees POLE emer eee 1 1 # essccsce o cccces POE == Eig B F1E0E0 F3E fLia cccccese eevee] eee o eee cocsocs fe eens ee Eg". B3 EEY lomceccscc! ie eeccocs oBiirg: Bii Ziccccccee: i io seseee - iiPo BEir EiTiecscoscoi iio soevant i i~ P PiliE. f1i. ceeeee : SE giiiaemszaer Sr ozamessl og Fr en : $3 3i4gh s o R wgonmangi i! nferences! i Hi i it Aloe + izDo -piig8iiEcBaRcEsSsEsRsEsidEissRaaIaaEcsi 22778888..00220088 swaro0s3320 3MA10083326 _ ::Dg .gl iPogie BIER i:Esi EBp FEE zmsaassi :i mezzmam eenii eee iregezeeel izeeeenae rREEeREeRRrRD; e pRRemEAeRR 441188--001111::PPAAGGEE FF--4477 HBOIPPAG4E7 418-011P:PAGE 47 =2S == e iPOdLiEg recor eecemeeed: TfEg 37 ceemeees eeeeen i FI3 dfFp crecoooe foomoonns! E PooBdlen Pid k i HERE HH H 5[EEBERT i i F2LE lvmemvenz) femegeneni 3 . ida i i sim zi ig Propo [EE i RB 22778888..00220099 aMAtoos27 3MA10083327 2: Ep bE FE 5 EE arms) eercaces. imi Bi [REEEESRRL rE en ::mssasem : : rresernz EERRASEEL es 441188--001111::PPAAGGEE FF-4.488 P-- 418-011P:PAGE 48 S =oeSo 2 Poi tBFEeil0dhF aerreene feeemnene E FEaCt leieees i leemeene PETE eee een 1 FE eeeeneeeenl pr RHobiH itf: LE : HL i i Bip eens deepen phigh rnernees gf gi 0d ie! ig 32 jp m=iFfmiEnzEaHsmcRaaac EiIcRmoEozmEeeEsEsiYng 22778888..00221100 stones 3MA10083328 . 2CE } i g i POLf E E eeseell n jE Bi 3 ERE til ajeenezmaaenams ferent eee 441188--001111::PPAAGGEE FF4.-3489 asoprAc4E8 418-011P:PAGE 49=a2-- z= BP80 hEEaegees FFhil eee pBiolEl00 Brg i i gI 1 E Ba ip1 iieeeem} eoni i| Ei 2i%izonzannni PEE een i . 3$ iil i i f30ronneidl 22778888..00221111 swaro083329 3MA10083329 441188--001111::PPAAGGEEFF--5500 z: ii ii ; } : i Pi iEo oipgiel J ffaamwemeasgazmeeln iisz woeawnaeams 1i i a] i Lovnansvel iLo wonaon i oi : 41B011PPAG5E0 418-011 P: PAGE 50 oS8r == e BE 5: i jIRaEnan: BF ogi i 3gERfg icoEdggyEE snisesarzuianzzaaneryl SP o xRF iE s if annem ai4a zsSeaasgapzasn osnaemn e Phat oT TTT i: I's. [NRL| NN,| 1dEreBET = TT is 3 oiagid irmeseenzi ieBaeewes FEF een een B } ito iH i$ Be HEHE INERT i FEI Boi Hi if Pd fe 22778888..00221122 aMAtoos3330 3MA10083330 441188--001111::PPAAGGEE FF--5511 arsarprAG1E 418-0lIP:PAGE 51 - :: !i 14 Z Z5Po if : e= Toye PPoOdL pd 8 iipifio JB1 immu mn eee] ferns i ELT soamnsmenmelmoimnsmneEnnses| F2EEysTl AETRRRUAL [RRR HT E3i 2i3mumeeenarfrEisnmeenaznannaasit Firdoxnd. i emrennsli= lgereeenel}: i1: 1ogf,t !Frenne}id : BiyE BETTIE i i ifyii iirEengEzanHziI0fiHgEEenEEaHaEsEEaEnis iIiH Piid iie 22778888..00221133 swatoosssst 3MA10083331 - 3: :i T oei gPsE ObHigh Li mrommiganmal ilrmsznnsnusmy : ee 441188--001111::PPAAGGEE FF--5522 wsortp ace 52 418-0lIP:PAGE 52 3= @ === I 3 igssesmns legesrersi E IRRIRCEN ARILRAG PE mmm mmm F i: Li iszmemEsna)n fceamnsesmnaemnes id 3 5 i 30 E%Eizezsnzesifiinemsznen)H Trg if . Hif 4i iH]: 1it7 Sfyi E xilE izssE szar EBizEmmpEminas fr Boi !i 2 is 22778888..00221144 smatonsss32 3MA10083332 .:i: o: -. i oad td gk th smn FIRE HREEEREEEE EjoL meme gE 3 2 i +i5 i P pei t yai 10 $dininmneennziid i500 i] si pdms jg [Rpg i i: ii:f 2: is 22778888..00221155 441188--001111::PPAAGGEE FF--5533 Jr418-0lIP:PAGE 53 =B2g8=s = e store 3MA10083333 441188--001111::PPAAGGEE FF--5544 r-- 418-011P:PAGE 54 5 1. s :i ai : i = == =2 gE 2 i2 Po = ix i= . 3: :3 i= % #2 Pole ee ile 2. Pol eid ef oe el ofl of i Toa ate a ef adele Pooiniloslefeleiene fByion elimmleelneie oR ofon le adele elRasend efell, oNhlRgEe gFEis; Releelbeleelle foff Eof gftel s2lteelleel efn2eedlihge Do iris eh ef nein gre B o iiignl eSloeAlTeelteAllaAltael eCaldgetde Sos2ltadAenl sitais n H P58oE oUlERSsE iaeiO indcF eegr I PERSTH slnileign dgteafsiagigniit}gk Jiit el eeteieeteeti aallel elE edela edadel g & vi 5 eiefeleleledalell 2B Toe CST al alelelefelelig 2 taorag gia 8 m0 elelelelelelalad 3 elelelaleleli? : 380 eieleiedeleiededl of] elelelelelelig Co R sisietefedadalelisiedl efafelzieded 5 si EIppatiriiiiisiiidgEl.ioisisiiissifsgg fs HEERREEERE EEEEREE BL z Po 3 22778888..00221166 swatoosssse 3MA10083334 :; is Pos 5 441188--001111::PPAAGGEE FF--5555 anarieracses 418-011P:PAGE 55 :: =52 = e E:ro oa aid2 i dHeE id2i Doe Por smeddeia esRaebela off of Ge lel alla alls Pps Bis esac sella Woo esanhiisddoeai,ib pla PE elisa slermideldaeds ellalddddd elisieladedia d Phe | Joo addiiadd chim gieiiadda dst Pio, Ppl Essien eld eed| added HI SET enka end HE sdeaeldel it To PE elie dddelad nly ei eleleleiden anedaia deiellaicdad Leip eledeleledelsdly deleleiaadaded fird geisgiiiansiS iago a iHE iE t EGiLiliiiitE iiierE iiz de 22778888..00221177 swntoszzas 3MA10083335 414188--001111::PPAAGGEEFF--5566 oo = o@ Jr---- 2 418-01 lP:PAGE 56 SeS i Le = Po 8 1 Foe i 2 : ios 23 Pi af Por Po eqf aale fal ae we elm og Pool amel lela aleladel dg FTIp | aelmelie sellsalieddsl aclneiialhd aais DEg ol chMeeRisefteediselbeeiissfieeds efssrfgaffreilgerlseiiesfdeelnebfirf PE Pp adel ddan hs eiiedades seit fBgEL sis iierei sterd itl, gizziiftaelcaeltaedfaeldasdiaeltifB=9=lrF~= Pati EEE ai, HER 5 IRE aH ERE Ei ing eleleleleladelois ielelelalelalele ly " ~ EPioEL G elmidaedmedledfadl edladlesledlealeadenided jE eleiededa dade 4 Lic eiiddpaddidadn PEoppEsiiiiiaiiiaiiag ig Se ER iarzae Bieozara:ist Bgo :y500 isfgisigii PiifiEiiiof3. 22778888..00221188 aMAtoos3336 3MA10083336 Is : i ois Poi ii 3I :Poa Poe Pos THE e om Bi o= BEPfEe.oz Cogometm agf aogil em afd steels elgg iosfstiedaelelel aeif,iigd shelsisfele gal fat PcsElPaeElPssElRaeElPdEePlEasPlEdeIlLdsElE BC4HU1E) 25 ie ow s3gigne afgigrivHE BifiEgLg R u nu Siem lS enaignga n HBEyET TBEiEf spinegaaaentanean dnHeiiEea B 5 eiL n ai S eleelelnelesdediEgiEs i 8 in : ss3lse3lee3lseifgatlaetlsetleatlitii ages pony celled gn Lo onp edna fi PEs IiiiiiEig pe Elioaisacgy ah 441188--001111::PPAAGGEE FF--5577 2a 2 waarporces I== 418-0lIP:PAGE 57 ~ 2oo 22778888..00221199 swntoszzar 3MA10083337 441188-.001111:.PPAAGGEE FF--5588 80NPPAGE 58 418-011P:PAGE 58 AAT'I-Ti'AACCHHMMEENNTT 11 PPRROOTTOOCCOOLL AANNDD AAMMEENNDDMMEENNTT 22778888..00222200 1100 117711440000 aMAtooss38 3MA10083338 441188--001111::PPAAGGEE FF--5598 8-011P:PAGE 59 " E ALSS Argus Research Laboratories, Inc. 905 Sh~ehy Dr~ve, Building A Argis RIE Homham, Pennsylvania 19044 As m= T: (215)443-8710 F: (215) ~43-8587 ovsons se mm T4347 PROTOCOL 418-011P SPONSOR'S STUDY NUMBER: T-6316.7 SSTTUUDDYYTTIITTLLEE:: PURPOSE: sm TESTING FACILITY: STUDY DIRECTOR: SSPPOONNSSOORR:: STUDY MONITOR: AALLTTEERRNNAATTEE `SSTTUUDDYYMMOONNIITTOORR;: OOrraall ((GGaavvaaggee)) DDoossaaggee--RRaannggee DDeevveellooppmmeennttaall TTooxxiicciittyy SSttuuddyy of N-EtFOSE in Rats The purpose of this study is to provide information for the selection of dosages to be used in the developmental toxicity (embryo-fetal toxicity and teratogenic potential) study ER of N-EtFOSE administered orally via gavage to CrI:CD~BR VAF/Plus presumed pregnant female rats. gg------ Argus Research Laboratories, Inc. 905 Sheehy Drive, Building A Horsham, Pennsylvania 19044-1297 Telephone: (215) 443-8710 Telefax: (215) 443-8587 Raymond G. York, Ph.D., DABT Associate Director of Research 33MM TTooxxiiccoollooggyy SSeerrvviicceess 3M Center, Building 220-2E-02 St. Paul, Minnesota 55144-1000 Marvin T. Case, D.V.M., Ph.D. Telephone: (612) 733-5180 Telefax: (612) 733-1773 AAnnddrreeww MM.. SSeeaaccaatt,, PPhh..DD.. Telephone: (612) 575-3161 Tetefax: (612) 733-1773 10 171401 22778888..00222211 3MA10083339 441188--001111::PPAAGGEE FF--6600 441188~.1011P1:PPPAAGGEE 6600 PPrroottooccooll 441188P--a00g11e11P?P Page 2 RERGEUGLUALATTOORRYYCICTITAATTIIOONNSS:: UUHFH.ea.aSSdv.mre.morFFmoaosolnaooiRstddeaigtaaoiionnnstndd:e;rDDGG,rruuuuySggidedepeAAltdldiimnenmiemenibniooesinnstrtrddr2aaee2tttt,iieeoocc1nntt9iio(9(o114nn99,89oo4Vf4)fo.)ltt.o.oxxiII5inccn8itit.tteyeyrNmnttoaoao.ttirrioe1oe8nnpp3aarr.lool ddCCuuooccntntfiifoeeonrnreeffnnooccrreemmeooednndiciciinnaall products. products. Federal I~egister, September 22, 1994, Vol. 59, No. 183. U.S. Food and Drug Administration. Good Laboratory Practice Regulations: Final Rule. 21 CFR Part 58. U.S. Food and Drug 21 CFR Part 58. Administration. Good Laboratory Practice Regulations; Final Rule. JfJoaafppSaaannfeeessteey SMMtiinunidissitterrsyyooofnf HHDereaualglttshh, aaMnnHddWWWeleOtfrfaadrrieena((1n19c99e977)N)..uGmGobeoorodd21LL.aabbMooarrraatctohorry2y6,PPrra1ac9ct9tii7cc.ee Standard Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. E`eEaaoucucmrcrcodeoepapppteettaiaaanonnncnceeEEoccbbnooyynncttooohhmmmeepiilcEEciuuCCarronooocmpmpemeemuaawnnuintinhEEtitcpycyrooi((nn1n1ooc99mi8m8pi99li)cc)e..sCCooCCofommogumuonmunconuicdilinlltiddatyyebecoocoirfifssaaaiitoonnonnrOOyoopEEnnrCCa22cDD88tiJdJdcueueelclc.yyiiss11Oiiof99ofn88ni/9c/9rireaooeclnncooJmttmohh-u-eernal of ne European mendation on the European Communes: Legislation. compliance with principles Communities: Legislation. 32 (No. L 315; 28 of good laboratory 32 (No. L 315; 28 pOcratocbteicre).. October): 1-17. Official 1-17. Journal of RERGEGUULLAATTOORRYYCCOOMMPLPILIAANNCCEE:: TTfOrehashiggeisusurlalssaatttttiuiuiondodngnyyssPwwccriiilloetlecbbddeeedaauccbbrooooennvvsddeeuufcociinrtnteetltdhdhaabaiitontntrtahtthhtheeeoerTTsyseeppsiosrilpritiiiettnnrooggafftFFttiahahoceencisilGlGittaoyyonooppdddeedrrLLassaatoobbannoonnrceroaealltlltoowweircrlityylllioPaPanrdd.raahhcceetTtririhceeceeettoo((TGeGtthsLLhteePPi))nSSgttaannddaarrdd POFrceappiceoiirrltiattyystoinQQrguuatlPahilrietotyyccerAAidsscussaurulerrsapanhnfocacreseelaUUsnboniofittrta((QteQoAAryUUst)o)updwwyei.illrlanntoioottnaasuudadintitdtthhdeeatpparrocotootllcoeocclt,oiottlhhne,e. raw data, the. The Testing raw data, the reports or the critical phases of the study. AADlilllreccchhtaaonnrggaeenssdootrrherreeSvvpiissoiinoosnnossro,offdttahhtiissedpprraoonttoodccomolal issnhhtaalallil nbbeeedddwooicctuhummtehenentpteerdodt,,ocssoiilgg.nneedd by by the the Study Study Director and the Sponsor, dated and maintained with the protocol. `SSTTUUDDYYSSCCHHEEDDUULLEE:: `See ATTACHMENT 1 o the protocol. See ATTACHMENT 1 to the protocol. 2277888..00222222 10 171402 33MMAA1100008833334400 441188-001111 PPAAGGEE FF--6611 a41i8B-o0r1i1PP:PPAAGGEES5!1 Procol Protocol 441188P0-a011g11ePs Page 3 TA TEESSTTRARTTICLIEAANNCDDVVL EEHHICIE CLLEE:: IIddeennttiiffiiccaattiioonn: TeTessttAArtriticcllee:: NaNPhamymseie:c:al Description: PLohvyBsaictacl hDNeusmcbreiprt:ion: WNNa--ExEtyFFOsOoSSlEEd. WFNaLx3~6s2o8lid(.30035, 30037, 30036). PuLSSporpetec/yBic:fiafiitccchGGrNraavuvimiyty:b:er: FM-3929 i20r.1% -1.7. (30035, 3003?', 30039). EPxupriitrya:tion Date: May, 2000. 99.1%. May, 2000. Expiration Date: Information on the entry, composition, srength and purtyofthe test artic is on fle With the Sponsor Information on the with the Sponsor. identity, composition, strength and purity of the test article is on file VVeehhicicllee:: 22B5%e%anTTiwwseeeeednnWat88e00r)ii.nn RRSeeuvvpeerprsseeerOOassnmmdoosositissenMMteeimmfbcbrartaainnoeenPPorfrooTccweesessseeenddDD8ee0iiooonniizbzeeedddWWoacatutemerer n((RRt.e.OOd..in tDheeiornaiwzeddatWa ater). Supplier and lot identification of Tween 80 to be documented in the raw data. 1NNeeibittehheeprrrtethsheeenSStppnoontnshsoeorrvnneonoircttihheeetSShatttuuddwyyouDDliidrrieenccttteororfiiessraeawwwaiarrtee toohffeaarnneyysupploottsteenontftitiaahllisccoosnntuttdaaymm.iinnTaahnnettrssefiliokkerelelyy, To analyses other than those mentioned in ti to be present in the vehicle that would interfere no analyses other than those mentioned in this protocol with the protocol wil be results will be conducted. of this study. conducted. Therefore, SaSfaefertyyPPrereccaauuttiioonnss: GfGollroomvvueelssa,,timmoanasskpk.r,epaaapprpparrtooipporrniiaaattenedeeyyadeemippnrrioosttteerccatttiiiooonnn.aannTddhaae uuMnnafitfooerrrmmia//lilaaSbbafcceootaaytt DaaarreteattooSbhbeeeewwtoo(mrMnSddDuuSrri)innggis anached to formulation attached to he protocel (ATTACHMENT 2} preparation and administration. the protocol (ATTACHMENT 2). The Material Safety Data Sheet (MSDS) is SSttoorraaqgee: VBBeuunlkikcTTieeessCttoAAmirptcioclnleee:nts: RRRoooooommmttteeemmmpppeereraarattutuurrreee... VPPPrrereeehpppicaaalrrreeeeddCd oVVFmeoenrhpimiocucenile:ae:tnitosn:s: RFRRrooooooozmmmenttteee(mmm2p0ppeeerCarr)aat.uttuurrreee... Prepared Formulations: Frozen (-20C). AAlllill aetesnsttGaaurlrttbiicicnlleeekssihh,iipMpmamneenantgtsse rttooottfhhFeeoTTreemsustatiitnniggonFFasac,ciilalitttyythssehhoopuurlelddv ibboeeusaalddyddirrteeessdsseeaddddttoro ettshhsee aaatntttdeennttiioonn of of telephone number. Julian Gulbinski, Manager telephone number. of Formulations, at the previously cited address and CSSahhriitppommnesennstthssossuhlhodouubkledd ilinnaccblleuuldedede iianpnfpfororormpmraaittaiitooennlycc.oonnTccheeermnifinneggcissitteoonrrtaagsgeheoccuoolndnddbiiteioonnnosstiaafinneddd ssihnhiiappdppviinnaggnce of Shipment cartons should be labeled appropriately. The recipient should be notified in advance of 10 171403 22778888..00222233 MAI0083341 3MA10083341 441188--001111::PPAAGGEE FF--6622 441188.-001111PP:PPAAGGEE 6522 PProrototoc~o1l441188P.00a11g11ePPs Page 4 FFOORRMMUULLAATTIIOONN: FFrerqueencqyoouffPPererepnparaarctaitioyonn:: pFFororermpmuaulraleatdtiiowonenssek((lssyuuasstppeetnnhsesiiooTnnesss)t)iwwniglilll Fbbaeecipplrryee.ppaarreedd daily at the daily at the Testing Testing Facility. Facility. Vehicle wil Vehicle will be be prepared weekly at the Testing Facility. DDeettaaiilleedd pprreeppaarraattiioonn pprroocceedduurreess are are attached attached to to this this protocol protocol (ATTACHMENT (ATTACHMENT 3) 3). AAddiujstumesnttffoomrrPePurunirtittyy:: TThhee tteesstt aarrttiiccllee wwiilll bbee ccoonnssiiddeerreedd 110000%% pure pure fo for the the purpose purpose of of dosage dosage calculations. calculations. `TTeessttiinnqgFFacaicliliittyy RReesseerrvvee SSaammplpeless:: TttTthhhhheeeeecvcSSeoohpupuiororcsnsnleseesoooocrfrfowwttmihhlipiillslsorrnsseetetssuuneeddtyrry.vsv.eeuTTaashhesseedaaTTmmdeueppsrlstlieteiinnng((g1g1tgFFhg)ae)aoccocifiiofleituteayyracswwcheihilllloloforretettosshofeiefsrrttvvshheeteeuaadbbyuss.ulaalkkmmSttpaepelsmsleettpla(a(5r5erttsiimmccLllwLee)i)luuloossfbfeeeeeddaasccddtuhhuorrrillieonondttggooff tuuhnneddeverer htthihceelepprcreeovvmiioopuuossnllyyencctiistteedudscceoodnndddituitidioonnnsgs..the course of this study. Samples will be stored AANNAALLYYSSEESS: tS`hSaeammcppollueerssseaaodddfdiitttiihooennaasltl uttdooy.tthhoossee ddeessccrriibbeedd below below may may be be takenif taken if deemed deemed necessary necessary during during the course of the study. BBuullkkTTeessttAArrttiiccllee SSaammp=lliinngl:: NNInoofoaarnnmaaaltlyyissoeenssooonff ttthhheeebsbutluablkitltetesystotfaartrtthiiccelleebuwwliklillltbbeseet ccaoortnniddculuecctiteseddodnduufririliennwggtithhheethcceoouuSrrpssoeenosofofrtt.hhiiss study. study. Information on the stability of the bulk test article is on file with the Sponsor. `AAnnaallyysseessooffPPrreeppaarreeddFForomrm ulualtaitioonnss:: AA`cttottnhhdeeucrrteeeqqduuedesustrtioonffgtththheeeSScppooounnrsssooerr,o, fnntooheaannsaatlulyydsyse.ess Hoooffwpperrveeeppraa,rreerddecttoeerssdttsaarwrtitiilccllleebeffoomrrammiuunlltaaattiiiononnessd wwtiolilll be be document conducted document hhdoouwwrintthgheethtteeesstct oaaurrtrtiisccelleeofffootrrhmmeuulslaatuttiidooynn.ss were prepared. However, records were prepared. will be maintained to DDIISSPPOOSSIITTIIOONN:: PaPrrrteeipcplaaerrweeiddll ffbooerrmmruuelltaauttriiononendss twwiolilltl hbbeeeSddtiiussdccyaarrMddoeendditaaottrtthahtee tTTheeesstptiirnneggviFFoauacscilliltyityyc..iteAAdllll arrdeedmmraeaisinnsii.nngg bulk bulk test test article will be returned to the Study Monitor at the previously cited address. 10 171404 2277888..00222244 33MMAA1100008833334422 441188--001111::PPAAGGEE FF-..6633 441188-001111PP:PPAAGGEE S6S3 PPrroottooccooll 441188P-0a01g11e19sP Page 5 TTEESSTTSSYYSSTTEEMM: `SpSecipesleStrcainiaanenddsRRee/aassoSonnftfoorrrSSeaelleecicttiiononn:: TTbbinehehdcceeuaasuCCutsrsdLeye.:CC:foDDr11B~))nEoB#itn1RRci5sliVVoonAAnniFceFea//lPmmPiaslautummsusmdmaiela((sSilSiaappofnrnraadssggeppuuveeeeecc--liDiDoeeaapsswwmlaaelececnyccyt)ee)applrrtatateettoddxwwiaaaacisnnstddyssee(wwleilieemddccbeetrtlleyeyydod-uuaafssseseetddttahhltteehhrTrToeoeuussggtthhSSooyuyutssttteemm ttdiFenooevdxxaviieucecdslilhttoyoyripy/hptmee;fmroreaaerntatnnootnaogtgdelnenttc4noio)licixxcnttiiinitnyhcyss)ea);;,;lt33e2s2))s)t)tuhhttdihaihssiiietstscoosrssreitiotccrrfaaaaildiilsnneddpavahhhtetaaaaalssroamapbbannmeecddeeeonneelnxoxtddapgpeeleiemmrtcrooiiaoexnelnnisncystccittareeyrcaaeeit(txeexveimidedssttbttionaoarytttbbottheeh-hefeeesssteeTTapneneelssscistitittiiiienvnvsgegeattonod strain. Facility(l"~); and 4) the test article is pharmacologically active in the species and strain. NNuummbbeerr: PIInnoiipttiiuaalllapptooippounullasatetiilooennctaaeccdcclfliiommraasttteeuddd::y: 577655 vmviiarrgtgiienndffefememmaaallleerraartatsst..s (8 per dosage group). Population selected for study: 56 mated female rats (8 per dosage group). `WBBooddyey WieiqghtaanhnddAAtggee:: wFwFDheeehimmicrcaheahlcleetioimrmrrdaaeeettssdtthhwwteiehilylyell wwbbdieealilllyoobbrraeeddfeeeeerrrxxeeppddreeecttccooteteiehhpddaattfvvaooeenbbdbbeeoowddaialytytlllwwebeeaeaeissitgdgthoh66tct00ssuomddofeaaf nyy22sst000e0oodffggaaittgngoeote.h2.2e22AA55rccatggtuwuaeeadlaalacctbbahhoo.addatyytrrwweeececeieiiggpihphtt.tt,ssaawwttiilll be recorded the day after receipt and will be documented in the raw data. soxSax; bFFeeemmuaasleleed rroaanttlssywwiaillsll bbbeereggeiidvveeernnsttahhneedtteeassrtteaarnrtotiitcclleec.o. nsMMiaadlleeererradatsspooaff otthrhfeethtsseaammTeeessstooSuuyrrcsceteeaamnndd strain strain wil will be used only as breeders and are not considered part of the Test System. SSoouurrccee:: Charles River Laboratories, Inc. Charles River Laboratories, Inc. TTLahhbeeoraraatttossriwweiislll. bbIeenc.ss.hhiitppoppteehdde iinTneffsiletteirrneegddFccaaacrrittloo.nnss by by air air freight freight and/or and/or truck truck from from Charles Charles River River Laboratories, Inc., to the Testing Facility. IIddeennttiiffiiccaattiioonn:: RCRoaa.ttss iaanrcre.e. ppNeeor.rmmaManSneePnntTtllyy20ii1dd0ee1nn)tti.iffiieeMddauulsseiinnrggatMMsaoroneneekgDli~vsesenleflf-u-ppniiieeqrrucceiinnpggeeeraamrranttaaeggnsst ((iGGdeeenyytiBBfiaacnnatddioaannndd Tag Tag CnFnFiduueeoemmmm.n,tbabaiIelnfelreeicrcss.a,rratauuNittppsosonoo.aannnrrMeueaaSmssaabPsssseiiTssgrgiings2ngmn0mnwee1eehdnd0net1tttne)tte.omomapMttsphohsoaereirlaageTTrnreeyyresasdtnnttisiuuonnmmgagbrtbeeFFheaeragrcscsisiavitlteaitutyyntd''rrsysueeoncbbceinrerqieeipupteethetddeaeaeprnnbredadmmrsmaggialisialvveeneoefenrrnaandltuutanppniydoioiqpeq0puuunuloeetalifatfppiitcpieeooarnrrnte.mim.osaanunnmeeenndtt gestation body weights. identification numbers when gestation body weights. assigned to the study on the basis of day 0 of presumed 10 171405 22778888..00222255 I3MMAAT100008833334433 441188--001111::PPAAGGEE FF--6644 418.011P PAGE 64 418-011P:PAGE 64 PPrroottooccsoll 441188P-.a00g11e11Ps7 Page 6 ANAINIMMAALLHHUUSSBBAANNDDRRYY.: AAallnl dccaaUggseeeossfiizzeLesasbaaonnrddathhoooruyussAiinnniggmccaoolnnsdd.iittiioonnss are are incompliancewith in compliance with the the Guide Guicle for for the the Care Care and Use of Laboratory Animals~4~. HHoouussiinngg: TTduhhreeinrrgaatttsshwweiliclllobbnaeebiiinntddaitivviiioddnuuaaplelllryyiohhdoo.uussDeeuddriiinnngsscttaaoihinnallbeeisstssatssittoeeenel,,l,ewwaicirrhee--pbbaoiotrttotomofmereaddtsccwaaiglgleessbeeexxhccoeeuppstted in tdbthhueeensnmmagacarltlieehfeirrcaaecttdo'sshbccaeaafbggoietre.ae.tiopNNanorotpunnereedtssoittodiinnn.ggisDmmeuaaxtrpietneergcriitaacellosdsh.wwaiibllliltbbaeetiossnuu,pppeplaliiecehdd pbaeicraoufsreattshwe ifllebmealheoruastesdwiilnl because the female rats will be sacrificed before l~arturition is expected. `RTRooooem mAAimrir,, pTemeperratuareatannddHuHumuirmdiidteityy:: T`fTrhheeeshaaanniiirmmtahalatrroohooamms biisseiiennnddeepppaeesnnsddeedenntttlhlyyrossuuugpphppll9iie9edd.9ww7iitt%hhHaaEttlPleeAaasstftittteeenrnscc(hhAaairnnoggCeelsseppaeenrrhhrooouuorrm)oo.ff 100% 100% fRCRroeoonssoohtmmanatttielreymtm.hppaeetrRrhaaotatuousrmrebe,ehwwueiminllil dpbbiaeetsymmsaweaiidinlnttthaaalriinsonoeuebdgdehaattm9o669n44.9i7tFFo%r((e11Hd88EcCCPo)nA)sttotfoialt7n7et99rlsyFF(aA((n2l2dt6o6mCCCa)il)enaaatnnnaddinmmeroodononiamittto)o3.rre0edd% to 70%. constantly. 70%. Room humidity will also be monitored constantly and maintained at 30% to Liigghhtt: `AmAanninaatuuattioonmmeadta.itcicaaElalllyychccoodnnattrrrkoollplleeedrdio11d22--whhilooluurbreliigggihhntt::a11t221--hh9oo0uu0rr hadoarurkrksfflEluSuoTorr.eesscceenntt ight light cycle cycle will will be be maintained. Each dark period will begin at 1900 hours EST. DDiieett: aRRadattlssibwwiiitlllulmbbfeerggoiimvveeinnndCiCveeirdrttufiafiileeddfeRRedooedrdese.nntt DDiieett~ ##55000022 ((PPMMII NNuuttrrittioonn Intemational) International) available available ad libitum from individual feeders. W Waatteerr: W Waanatateeurrtowwimilallltbbieec awavavataieillraaibbnllgee aaacddceilibstistusumysfftreromom.m iinnAlddliiwvviaiddtuueaarllwbbiolotltttblleeessfaarttottamacchaheelddocttaoolttshhoeeucrcacagegeeassndoorrpffarrososmmed . ttpahhrnrroooacuuueggsthohsmeaadarrtweeicavvteewerrasrsteeearoosinssamgmboaoascsciticesserimmsosesetmmsabytbsr.rtaaepnnrmoee.cbbeAeesflflsooewrrdeeawtuueassrtee.we.rillCCihbshieloeorfxdriponnemeectwwaeiidllllotlbbcoeeaclaaosddnotdduaeeriddcnetntooaonttmhhdeeo.praessed bttphahracoatncneer11si..as22leppdcppowmnmtaacctemhhirilnooaardsitnniaeeoanbatatatctnhhtedeerttttowiimsimtceaeeto;oaffpnaanrnounaacalleylylsssyissiesf.o.drWwWapotaasetsteeririrbilsisseeaacxnnhpaeaelmlycyiztzceeeadddltcmmooooncntnotathnhmltilayynifnafotorinrpooponso.mssiosbrilbeele. bacterial contamination and twice annually for possible chemical contamination. CCoonnttaammininaanntsts:: 1NN0eeibittehheeprrrttehhseeenSStpiponontnshsoeorrcnneorotrriftthiheeed SSditteuutddoyy DDiinirrteehcctetoodrrriiissnakaiwwnaagrwreeatooeffraaanntyy lppeoovtteeelnnsttitiaahlal tccoownontutaalmmdiinnianaennrttisserllieikkeellyy twwpoieittrbhhfettohhrpeemreerrsdeeessbunuyltltttsisnohoetfhffettehhieicssderssstttiuuufpiddepyydl..ideTTriehhoteerroretrefhfioonorsrteeeh,,emnnedoonritaaninnkoaainnllygyessdweeissanottotehhtrhiesaertprtrltehohvtaaoennclsottlhthhoowaisslteelwbrroooeuuutcltdiionnneeidnlluyytcetrfeedr.e performed by the feed supplier or those mentioned in this protocol will be conducted. 10 1714O6 2277888..00222266 33MMAA1100008833334444 441188-.001111PPAAGGEE FF-6655 441188-.00111P1P:PPAAGGEES6S5 Protocol Protocol 441188P00a11g11eP7? Page 7 R RANADONMD IZAO TIOMNAI ANNDZ DCCOAOHAHTBAIBI TITAATOTIIOON NN:: cUUappmoopnnueaarrrrv-ivagale,ln, emmraaallteeeaadnnrddaffneedmmoaamlleeunrriatastt.sswwiAilflltbebereaaaccsslssiigmiangteindotentod,o viiinnrddgiiivvniiddfuueaamllalhheoouurssaiinsnggwioolnln btthehee bass basis of of +cwcSCooomlilnmhleaacacpboboriuninittsoeeseifdidrss-tttgwwhioeoeifttnfhvheaaabrbgmmairrtenaeaeaeexxdlddiimeercmaroruunnmmmmtdaeoaolonlmfeetffsfarviuvataenetsnsit,d,sddl.aoaooynynrsAsee.af.tmmecFaFroaleepaleemmucralcaraallaitltmeetpoproarraeyartittrfopssefnlewwu,mimgiavtthailhorlgebessisnpperaeeatrfrr.etv.mmmeaaTTdatthhlooieeenzzorosccaaiaootthshuooaawwbbbbiissiltlieeltaarrbbtvtveeiieoeodndn ippneerariioodd in a Comeidered to ba a day 0 of presumed smear of the vaginal contents andlor a considered to be at day 0 of presumed gestation and assigned fo individual copulatory plug observed in situ will gestation and assigned to individual bheousing housing. HHgeeeanaleltrthhayytemmdaat(tweeeddigffehetmmoaarlledeerrraaettdss)wwirillal nbbdeeoaamsszssaigitnogenndteptordoocddeoodssuaarggesee.ggrroouuppss based based on on computer computer- generated (weight-ordered) randomization procedures. AADDMMIINNIISSTTRRAATTIIOONN:: RR oRuoutteeeaannddaReass onffooo rrCChhon oiiccee": TGTihhoeeanooryraal1l0((0gg6aa,vvaatggheee))errxooauucttteedwwoaasssagsseeellececcattneeddbeffooarrccuuussreeatbbeeelccyaauausdseme:i:ni11s))teiirnnedcc;oommapnpadarri2iss)ootnnswwioitthnhetthhoeef the possible routes of human exposure. dietary route, the exact dosage can be possible routes of human exposure. accurately administered; and 2) it is one of the MMethe odat annddFh Frereqo quueend ncyc:y: ggfFFeoeeescsmtmotaaartaltidlieeooendn.rra,abttttsoshhdewweiylipplllweeebbrniieeoogddghgitivoovfeafennnoordrttgghhgaaeeinnvottoeegegnsesetntaneaatserrtiatsiispcics.plle.reoooDDxnniooccmsseeaaatgdgdeaeealisisyllyytwwihooillennl bsbddeeaaamyyaasseddjj66tuuitsstmhhtteeerroddoeuuffagogochhrrhtt1h1dh77eaeoyo.mfmfopopsrsrtetessrreeuuccmmeeenentddtllyy recorded body weight and given at approximately the same time each day. R Rata ionat leffoi orrDDo oossan aggeeSa eSleel lcetcite ioonn:: DwDoioshsaatggheeesstewwsiitlllabbrteeicssleeelleecctteedd by by the the Sponsor Sponsor on on the the basis basis of of previous previous studies studies conducted conducted with the test article. 22778888..00222277 10 171407 MAI0083345 3MA10083345 441188--001111::PPAAGGEE FF--6666 DCoDsosaoagqeneLLecevveelelss,, nContcerntraatiotnsaainnddoVVoolnluum mseess: 441188.-00l1IP1P:P.APAGGEE 8686 PPrroottooccoal 441188P.-a00g11e11Pt7 Page 8 Do.age Group Number of Do=age ConcenlTatmn Volume An~, us Batctl NumOer ~ 8 o C ToT T Tenmonammmenn | II 8 1 B-418-01 lP-A~Day.Month Year! 0.2 5 B-418-011P-BfDa~/.Month Year) CoToTeTTTsueomrcommmnmn | III B-418-011P-C~Da~.Month.Year1 oToTwT 2T= |eorouroommmu|n IV 8 10 2 B-418-011 P-DIDa~,Month Year1 TeTw[Te sasonmsommomen | V 8 20 4 B-418-011P-EIDa~/,Month Year) oeTw[T+ eosoneoommenan | VI 8 25 5 5 B-418-011 -P-FIDa'/Montl~ Year! CToTToSTSYE 1Pe2Fo1 ee+n|ese osonrcomumu|n -rrte test att~e ,~nll I)e B-418-011-P-G~Da~,Mont~. Yea? on~:l~r~;l 100% pure for the purpose of dosage catculat,ons. `A TTEESSTTSN S,, ANA ALYSL ESAANY NDDMMES EAASSUURE REEMMEES NNTTSS: Viability: Viability: Al Periods: All Periods: AAttlleeaasstt ttwwiiccee ddaaililyy.. ClO Cilniniicb caall Osbseervatrionsvaanndda lloorrGt Geennei erraall o AAppppen eaarraans nccee:: AAcccclliimmaattiioonn PPeerriioodd:: WWeeeeklkyly.. Predosage Period: Predosage Period: DDaayy 00 ooff pprreessuummeedd ggeessttaattiioonn.. DDoossaaggee PPeernioodd: TTpwowisiccteedoddsaalalilgyy.e, aOOnnndccteeheaanppppfrrooouxrxiitmmoaatstieexllyyhooounnrees hhloaotuuerrr postdosage and then four to six hours later. PPoossttddoossaaggee PPeerriioodd: `OOnnccee ddaaililyy.. CCalpliipnnriioccpaalrliooabbtseseebrrvyvaattthiioeonnSsstummdaayyyDbbireeecrreteoccroorraddneedddiommrooSrtreeudffryreeqMqouuneetnnitotllryy. than than Ged cited above. above, ff if deemed deemed appropriate by the Study Director and/or Study Monitor. . BBooddyyWWeiegiqhhttss:: AAcccclliimmaattiioonn PPeerriioodd:: WWeeeeklkyly.. PPrreeddoossaaggee PPeerriioodd:: DDaayyss 00 aanndd 44 ooff pprreessuummeedd ggeessttaattiioonn.. DDoossaaggee PPeerdioodd:: DDaaililyy.. PPoossttddoossaaggee PPeerriioodd:: DDaaililyy.. 10 171408 22778888..00222288 33MMAA1100008833334466 441188--001111::PPAAGGEE FF--6677 441188-001111PP:.PPAAGGEE 677 PPrrootoccooll 441188P0-a0111g1es Page EeFeaeddCConosnsuummptpitioonnVVaalluueess (recorded (recorded and and tabulated): taDulated): PPrreeddoossaaggee PPeerriioodd:: DDaayyss 00:aanndd 4 4 of of presumed presumed gestation gestation. Dosage Period DDaayyss 66., 88,, 1100,, 1122., 1144 and and 16 16 of of presumed presumed gestation. gestation. Dosage Period: PPoossttddoossaaggee PPeerriioodd: DDaayyss 1188 aanndd 2200 ooff pprreessuummeedd gestation. gestation. FrFeeepeelddencciooshnnsstuuhmmepfptetieioodnn. vvTaahllueueessse mminaatyyebrbveaeirsreewccioolrrddnoeetddbmmeoortraeebufflrreaetqqeuude.ennttllyy ftif it is is necessartyo necessary to replenish the feed. These intervals will not be tabulated. MaMtaitinngq PPeerrffoorrmmaannccee: oMMbaastteiirnnvggawtwiiliolllnbobeefeesvvpaaellruumaaatteetddozddoaaiaillyyinddauurrsiinnmggeatthhreeocfcoothhhaeabbivtiataagtitiinooannl ppceeornriitooeddntaasnnddanccdooinonfrfiirarmmceeoddpubblyyatory plug oobbsseerrvvaetdioinn situof spermatozoa in a smear of the vaginal contents and/or a copulatory plug observed in situ. `CCaa~s__s~a=_rreeaann--SSeeccttiioonniinngg OObbsseerrvvaattiioonnss:: RbRaeattrssewwmiliolllvbbeeed CCfaraeoesmsaartrheeeaaunni-e-ssreeuccsttiiaoonnndeeddplooanncedddaayyin22i00nodofif dppurreaeslsuucmomneetddaiggneeesrststa.attiiooTnnh._e TTrahhtees ffweielttluusbseeess wil will examined for number and distribution of: be removed from the uterus and placed in examined for number and distribution of: individual containers. The rats will be CCoorrppoorraa LLuutteeaa. I[ImmPplplalacanentntaattatiieoonnthSSaititteaesps.pear abnormal size. color or shape) will be noted in the raw data] [Placentae that appear abnormal (size, color or shape) will be noted in the raw data.] L(LAiivvieevaaennfddetDDueseaaidds dFFeeeftituunsseeedss.a.s one that responds to stimuli; a dead fetus is defined as. aea(Aatteledirvrmemfefffeetetuttuususssestitshhdaadettmeoddfinoonseeetssdrannatoosittnorrgneeesmsppatohornnakddterdtteoostospsttoeiimnmxudtulsrliietaaomnnedsdatiuttmhthaoaulttliy;iisssainsndooaettrammedacarfroekketneudsdslilyyidsaaeduurettteoofilodnlyyezzbdeeedda:;s iste resorption) dead fetuses demonstrating late resorptions.) marked to extreme autolysis are considered to be EE(aAarrcllyoynaacnneddptLLuaastteeisRRdeeessfoiropnrtpeidtioonansss..a late resorption ftis grossly evident that (ooaArnrggceaaoannrnoolcgygeeerpnneteuessossirisspisthhidaaoessnf)inooceccdcuurarrrseedad:;flafifttethhiirssesiisos rnnpoottitottnhheeif case, the conceptus is defined it is grossly evident that case, the conceptus is defined as as an eady resorption.) 10 171409 22778888..00222299 I3MMAAT100008833334477 441188--001111::PPAAGGEE FF--6688 418.011P PAGE 68 418-011P:PAGE 68 PPrroottooceoll 4411P88a-g00e11111PP0 Page 10 FFeettaall OObbsesrevrvaattiioonnss:: TaaFFnhneetddetuuddssbeeeeossaadddywwifwfilleelettibbuugeessheeteessxxoaawwfimmiellilainnbbceeeehddeefffexxootaarrummsssiieenwnxxieelddaabnnffdedoorrfrgfoogerrrcroooggsrsrrdssooeessdexss.xtteeeexxOmrttnnaeelalrmynl ataabllrloteaaadtrltyteaeirtwraiooaetntniiioosgsnhnstttso.os. tthohLLfeeaatteeveeexxttrreeefennesstottorurpppspootestsiissosoinwdinbilsslele.. TbaRabeeeehltpreeuurarseasbtseetoiieddoodnnnytttssooawtwwddeiieeiivllgtlteeehbbrrpteemmhoiffoifinnixtexeeeoeadgdllcirtehiitannerpfrBeBhffotsoeeuututisoaainflnlw''fbbssielootlssdadboolyylelwuguwterrtiieoieoocnsging;osh;hrtedaatxlelaaltdvvooe.etetmrhhraaOaeeglrgrneeafflsyesne.tet.buruosasFFdeteeeysisttouuwwwnssiseieellliwssgbbihwweeltisitbddhhieiossggfctcrrlaaaioovrkrssededssenefdedee.txxuttseeermnsaalwl ill Representative photographs of fetal gross external alterations will be taken. M METEHODT OOFFH SSAACRCOIRFIFIDCICEE:: aRRanattissnwwaiiplllebbreetossnaaeccrariliffiicicenejddebcbytiyoccnaoarfrbbeoounnthddaiionoxaxiisddieea aasssopplhuhytxyiixoainatit(iooBnne..utLLhiiavvneeaffseeittauuss-eeDss wwSiplielllcibbaeel.ssaaccrriiffiicceedd by by manufactured by Schering-Plough Animal Healt). an intrapedtoneal injection of euthanasia solution (Beuthanasia~-D Special, manufactured by Schering-Plough Animal Health). NNEECCRROOPPSSYY: vGGarrlooussasstlileeossniioo(nnasstwwaibilllllebbeoefrrreeattaaniidnnoeemdd "enviacluhaatliol nis(sauteasbleexoafmrianneddomat iuinnninnteesuuwritrlaalllbbbeuuffufeserereedtddo110s0e%%leffcootrrmamanaleliinncoffnootrrropploossgssriiobbulleep nuencitrsowpsilyl bweilulsbeedretotasieneled,ction noerdceorn1t0roplrgorvoiudpe ffruuatttuufrrereom craont tfrroolm wtSUipshsasiccueihehsscaalffllooltrriysaascnniuytyeesdppooebssexsslaiiobbmwll,eienehahlidilssottaototphpnaeatertnhctoorilolsoopsggsuiieyccsaawllwiieelllvvbaabelleuuraaedttitiiaosoincnnasserddoo,fef diggnrrooossrdsselleresstoiioonpnsrs)o.).vidUUennllceesossns.trol specifically cited below, all other tissues will be discarded. `SScchheedduulleeddSSacarcirfifiiccee:: GgOSOrronnoopssaddssraaeyynnnee22tcc00yrroooonppffossnppyyprrerooesfefsugttuhmnhmeaeeenddttthhooggrreraeaastsctcsitaiactcwti,i,ioolaann,bbb,dedffooeesmmmtmiaainanilalnaeeleldrraaaawnnttssddtwhwppielie1lllllvv0bbii%eecc vvCCaiiasmassccemseesoarraranareiewwauainillnm-l-sbbsseeeeuclctppftieieioodrrenfnfooeetrrddomm,,ceedoaad.nnn.fddiUUraatmteertrihi eooff absence of implantation apparently nonpregnant absence of implantation sites'. rats will sites<5~. be stained with 10% ammonium sulfide to confirm the RRaattssFFoouunnddDDeeaaddoorr MMoroiribbuunndd:; GRdoRebaealstltievssvreettvrhrhayyaattwwtiioddillniileebbisoeoerrmeeaaaxxdrraaeeemm.ssiiaanncTceerrhddfifeiifrcfcooeaerdtdttshhbbweeeeicccclaaaauubuusessseeeeeooxooffaff mmmddoieeornaarietitbhbhduuofonnorrddrmmcgcooorornornidisbdbisutiutininlooeddnns.i,ccooaoannsbnb.doodirrittttPiiiioooronnnnegoooonnnrrappttnhrrhceeeeymmddasaaatttyyauutrrttuehehsee oafp2pennbuutddpspuesssuuerwstvwtie.oalirrlltliiinobUnbetgneeeccrieestooxxnnomaattfmmeeaanindiptnntepssee.addoorTfefttnhoffoetteethlmmheyraeaalenlteseexorxtnwratepaetirnltsnlsetwtbgwipepnoilolaelssnsxbbstiaeeibbmrllrraeeeietn.,ccsueoousvdrriisddlnieflnegodgdb.rte.tghhersAAeotbbsassosoiararntmltmeeeedeseddiwommffineeetestthtu.tuhhs1sooePe0ddssr%sseaagndadnndeemda/ssimoncocorrcrriyinbddbieeeselutdldiiavmvtffeueoorrrsreedd sulfide to confirm the absence of implantation fetuses. Uteri of apparently nonpregnant rats sulfide to confirm the absence of implantation sites. will be stained sites~5~. with 10% ammonium 10 171410 22778888..00223300 IMAT0083348 3MA10083348 441188--001111::PPAAGGEE FF--.6699 441188-.001111PP:.PPAAGGEE 6689 Protcol Protocol 4411P88a-g00e11111PP1 Page 11 STSATTAITSISTTIICCAALLEEVVAALLUUAATTIIOONN.: AAapvvpeerrroaaprggieeassteaa.nnddAdppdeeirrtccieeonnnattalaggpeerssowcwieildllubbreeesccaaalnlccduullloaatrteedad.n.alLLyiitsttteeesrr vvmaaalluyubeessewwpielilllrbfbeeoruumsseeedddifwwdhheeeerreemed approprate. appropriate. appropnate. Additional procedures and/or analyses may be performed if deemed DDAATTAAAACCQCUIIUSIISTITIIOONN,,VVEERRIIFFIICCAATTIIOONNAANNDDSSTTOORRAAGGEE:: oDDDDriaaiirrtgteeaaiccnttwawooilrilrlllraaebbnnceeddo/r/hhoodaarrsnnaaddwpip--lpplraaronbnopdedprl/riosoiaatrrtoteccerooemmmdmapaipunnnueaatrtgehg-eerer-mermaeececrononrtcrdtdepphedeeid.ror.ssvfootRRennhennesceeecloolTrrwweddisissttthhiwwiinniniglll2211bbFaeecddirraaieetyyyvvss.iieaaewfwfAtteleeelddrroggbbreeygyninettnehrhaareelatitSSdiootatnunut.dda. yywAAilllll obbreereqigubbienoosatuu.lnnrddePcaaronnerddsdesiirnnwvddeeeilxdlxeebdtde.i.ssstAAuoerscceoodwppiilyynobotfehfaesaltllalorrrrcaaehwwdidvdaaetatsttaahoefwwitTlihllleesbbtTeeiensssguutpipnFppgallciieiFelddatcyttioolaittytth.hneeoASSclplphoooandnrsggsoieonrrafouul rppdoooannntae will Y1yree0eaqadrueretaasefftttr.eemrriPmmnraeeaislitleiihnnregvgdeoiodfsfptttohihsseesiutddierroasanfftwtofffiiilnltnaabhlleesrrseeetppomoorarertttd,eraaaifftattelethr.r ewwhhTiieccshhtittniimgmeeFatthhceeilitSSyppaootnnnssooorrchwwiaillrlgbbeeefccooornnottnaaecctteedd to determine the disposition of these materials. R RECOERDC STTOOO BBEEMR MAAIINND TTAAIINS NEEDD: PTPrerosotttooAccrootlilcaalenn,ddVAAemhmeiecnlndedmmeannedtnlsto.sr. Reagent Receipt, Preparation and Use. TAARnaeninsimmdtaoAalmlritAAizcccalqequt,iuisVioisnteitihiooSinccn.hl.eedaunldes/o.r Reagent Receipt, Preparation and Use. TRMMraaaetntaiidntngogmmeHHniizitssatt(ootrifroyyp.n.reSscchreiodeudlebsy. Staff Veterinarian). T`CGlGreieennnaieectrmaralalelOnCCbtoso(memifrmvmpearneettnsiscto.srni.Dseadndb/yorSGtaefnfeVreatlerAinppaeriaarna)n. ce. BFCBeooliednddiyycaWWCleoieOngisgbhuthssmtes.pr.vtaitoionnVsaaluneds/.or General Appearance. GCFCareaeoeessdsasarCrNeeoeaanncns-ru-SoSmepecspicytitiioooOnnbnsiiVnenrggavluaaatennisddo.nFFsee.ttaall OObbsseervrvataitioonnss.. OPGOhrrrooggtsaaosnngNWW reaeepicihrggoshhpt(sssfy((riiOeffqrrbueeisqqreueuirdirv)reea.ddt)i.)o.ns. `PSFSethtueuodddtyyoagMMnraadaipinnWhttaseetn(neiaafrnnreAccnqeeaul((irryroesoodeoms)m.. aanndd eennvviirroonnmmeennttaall records). records). FPPaeaceckdkiinnaggndaannWdda/ootrer rSSAhhinippammlyeesnnetts.LLiissttss.. 2277888..00223311 10 171411 33MMAA1100008833334499 441188--001111::PPAAGGEE FF--7700 441188-.001111PP:.PPAAGGEE T700 PPrroottooccaoll 4411P88a.-g00e11111P92 Page 12 KKPEEEYYRPSEORNSONNENLE:L: EADEDixsxiresreeecocccuctuttiootiarirvovteoeeffDDRDRiieirrreseeeescccaetttraooocrrrrcohooh:fff:RRReAAeeslslsaeaeenanaarrMrMccc.h.hh::HHaooMMnbbideielkrdrSrmmrteeauaddndn,ySS,..PDPinCChr.heh..rDci.rtis.so,trtii.DDaanAnA.R,BBaPPTThyh.m.DDo..n, dAATTG.SS York, Ph.D., DABT ADDMMMiasirarsnaeenoaccactgntgooiearerratreoooofofgffDfLLSAiSaartneebtbuiuocodmrrdtroyaayartltCCoooorOrofoyyporReOdOrredipapsneintareeitaaarioattrionictonioshon:nn:asas:nnVV:dadalJJMleSeooertdhhimuennebdeyAAFFr....D,BBSSirhaahIeamnracrnserttpeoptietretr,t:u,r,t,BBiRM.Mo..SnaS..SayS.l.m.AonnidmaGl.CYaorrek,aPndh.D., DABT MMCMoaaaUUnnnnsssaaaeetgggaeCCeenrorrotommo,omfffimRAVRteietntgetteiuegemeleru:aai:lantl taDDoOorreerypyynnePaaCCraaotoCCtmh.im.poollnLpLioseelgaibabynaono:cn,c,ede:VVW:.M..MMKKe..RaDmaDt.atb.hhyelleerB,eernnIonwAAsn.t..itMMuDotoiVrora.nanMan,.,l ,AMM.nP.SSih.m..aDl.CAaCreVPand Consultant, Veterinary Pathology: W. Ray Brown, D.V.M., Ph.D., ACVP RREEPPOORRTT:: AAimlmleeettdtteeirratrreeelppoyorrfttoffloolrrotwthihenegppcuuorrmpppoolsseeetioooffnddooofsstaahggeeeissne-eillfeeeccttpiihooannseffo.orr the the ful full study study willbe will be prepared prepared immediately following completion of the in-life phase. AAr`feeasnsssuduuullmitmtsnsmmdaiaaavnnrindayd]uccarroloeenppntcoocalrblrututlsseiwwsiiooli:nllnl;a;bbnetetadabppbrlrlreeeeoppeofaafcrrceoepoodndnftoiietnesnncucntllprtususp:ddo;iitrnccntgogoi::pspngyyaaobbosfdstftatrtrthahaaceectt(,,ppfrrssoaouutptommopcrmcomooalp:lra;niraaaieetmmesse)en.oonfdfdmttThmehheneeetnmmsters;eet;pthhossooruudtdmsmsw.m,mialarbryye taiinhnncecdlluduidrndaedefdditvriaadessupoaaarlnnttaaaabppnlppedeesntn;dwdaioinxxcdttooopreitthpehesoerofftusfullltohssfettsuuufddipnyyaplrroeerrppteoiponrotrgr.tt..dTTahthaee Sponsor will receive (if appropriate). The Sponsor will receive one copy report will one copy obfe of the draft report and two copies of the final report. ININSSTTIITTUUTTIIOONNAALLAANNIIMMAALLCCAARREEAANNDDUUSSEECCOOMMMMITITTTEEEESSTTAATTEEMMEENNTT:: TTtIInhnhhasseetttittpipuunrtrtvoiiooooccnlneevaaddelluuAsArrtneenuissimdmyddaaeelalssncCCciraramiirbrabeeelesddaannwiiinddnllhtUUhbisisesseeppcCCrrooooonmttdmoomuccimcoottliiltesthhedeaae.vvi.neeAaAbblllemlepepearnnronorcrcneeeevevddtiiueuroerwrweeaeessvddoddibbeedyysscocttrhfrhiieebmbeieTTdnedeissiimtnntiiinttnzhhggeiissFFappacrrciooiltltitootyycc''ososll tddhiisascctooimnmfvoforotlrv,te, ddsiitssuttdrreyessassnooimrrppaaalisinnwttiooll the anima. be conducted the animals. in a manner to avoid or minimize TTnehhceeesSSsppiootnynssfooorrY'cssossniidggunncaatttiuunrrgeebtbehelislooswwtdudodocycuaumnmedentnthtsse tfthahceetfftaaaccttt ttihhaastt information concerning the isnfonromt aatniounnnceocnecsesranriinlgythe dpGnruueoppcclelieccsdaasutittiryvueeefsossrwttuecurdodeyyndmamuvaacayytiinabbgbeelteohobibfstotaarsiitnmuneeededdytffiarrnonogmdmtttthhhheeeesfSStapacpottonetnsdhsoaportu.r.trhpiNNsosooiesaaslnlttooeeftrrntnaaahntetiiuvsventeund((eiiynn.cevvisittsrroao))rily procedures were available for meeting the stated purposes of the study. 2277888..00223322 10 171412 33MMAA1100008833335500 441188--001111::PPAAGGEE FF--7711 441188..00111P1:PPPAAGGEE 7711 PProrottooccooll 4411P88a--g00e11111PP3 Page 13 RREEFFEERREENNCCEESS:: 4. CCITThenehrsfsihtostssrst.mt.iiaaatnnEEi,n,novnMMvi.irrS.SSoeo.nr.nvmmaaienncenddent,taVValoUol.yPyPStr.tereookktDt,e,eccPPett..iiEEoop.n.n ((AAa11gg99e8e8r2nn2o)cc.)fty.y,C,ImIonW WnmaeVVamsisihevvhniroonicngRRtegete,tpooprnnrSo.o,pdrdDDui.ucn.CcCtg.tfi.iivveNNeelaadtaa,tiinnooVddnnAaaMMlluu2TtT2aetea1gcc6gehh1enn.niiniccciciaaitltlyy Information Service, U.S. Department of Commerce, Springfield, VA 22161. 2. `nCCnhSaahrcllirittirsesretnteixicaxaeoonnsnn,,,eeMMN(.(o.PSPSv.rr.oeo((ccm11eeb99eee88dd4r4i)in.)n7.gg,ssRR1eoo6epf8fpr3NNr)ooa,adldultJtu.crrecteCtxixilvovioneenn.eettooPSSxxsiyyiycccmmiihtptyipyoaoaastsnni.idduu4mm5tt,e(e,8rraNN)at7teeo-owwll1oo0gYYg.yoyorreekkvvaaAAllccuuaaaatddtiieoeomnmnssyy ooooffff Sciences, November 7, 1983). J. Clin. Psychiat. 45(9):7-10. 3 LLCICnaoacon.nngntg,tr,rWooiPlPllLmDD..Liaanttg((aa1t19o9ii8nn8n8,8)tt.h)h.MeeAEECCmhmha0babr1rrir8lyyee8ooss7-aaRR0inn6ivvdd3ee0rFFr.eeCCtrtaHat(ll:DCCDDaDetDeva~vBe)ebBllRaooRsppeRmRmaeapten.tr.ntotavaCClilhhdaTTearoodrxllxieebicsscyiittRRAyyiriv((vgTTeeuerersrrLLaaRalateboobolslooroeraggaatyyrto))orcrihieess,, ILLnaacbb.o,orW aratoitlormirieienssg,,toIInnncc,..)M) A 01887-0630. (Data base provided by Argus Research 4 LiInnassbttoiittruuattteeooorfyf LLAaanbibomoraralastt.oorryyNAaAtnniiiommnaaalll RARecesasooduuerrmccyeessPr((11e99s9s96,6).)W.asGGhuiuiniddgeetfofono.rrtthhD.eeC.CCaarree and and Use Use of of Laboratory Animals. National Academy Press, Washington, D.C. 5.o SISmaapllleeawwnstskakiti,,iEoE.n.s(s(11t9e96l64i4)e).n. aFFmi~rrUbbteeemmreuestthhdoooddreeRazztuutmem. mmaAarkckrhro.osskPkoaotpphioisslc.chhEeexnnp.NNaaPcchhhawwremeiaisskovvloonn 247.367. Implantationsstellen am Uterus der Ratte. Arch. Pathol. Exp. Pharmakol. 247:367. 2277888..00223333 10 171413 33MMAA1100008833335511 PPRROOTTOOCCOOLLAAPPPPRROOVVAALL: FFOORR TTHHEE TESTING TESTING FACILITY FACILITY f4`~Aocreagoaa~tEe.DDGiereaearcditooovrveeo,,f PPRhhe.s.DDe..a,rDDcfAhABBoTTe Associate Director of Research N `RayAmoslsociate GD.irYeorckt,o oPRfO. AResBgbrcTh Study Director Study Director ei lil VBDeeernnmaabCCs.r. LLIaenbbsoo,t,uVVio.AMnDa.Dl..Animal Care and Use Commitee Memi~er, Institutional Animal Care and Use Committee FOR THE SPONSOR FOR THE SPONSOR SMMtaaurrdvvyiniMTnTo.niCCtaaosrsee,, DVM. D.V.M., PhO. Ph.D. Study Monitor 441188-001111:PPAAGGEE FF--7722 418011PPAGE T2 418-011P:PAGE 72 Proce 41e6a.0e1119a Protocol 418-011P Page 14 10-Tn=gP Date Date fo-auue98 Date Date Fra Le Date DDaattee 10 171414 22778888..00223344 MAt0083352 3MA10083352 441188--001111::PPAAGGEE FF--7733 441188-001lIP1P:PPAAGGEE 7T3S AATTTTAACCHHMMEENNTT 11 SSCCHHEEMMAATTIICC OOFF SSTTUUDDYY DDEESSIIGGNN AANNDD SSTTUUDDYY SCHEDULE SCHEDULE 2277888..00223355 10 171415 33MMAA1100008833335533 AATI"TI'AACCHHMMEENNTT 11 441188--001111::PPAAGGEE FF--7744 441188.-001111PP:PPAAGGEE T744 PPrroottooccoolPl a44g11e88:-100011111PP2 Page 1 of 2 SSTTUUDDYYSSCCHHEEMMAATTIICC DDOOSSAAGGEE--RRAANNGGEE DDEEVVEELLOOPPMMEENNTTAALL TTOOXXIICCIITTYY STUDY" STUDY" FFeeRmmataasllee Rats DSsotusanartogofef. Dosage Gonapation Cohabitation PrDDeaasyyus6mooelfd Gestation Presumed Gestation CCSaeaceetssiaaorrneeiaannngDEEonnsadagcoSetf.ectioning= Dosage PDDraaeyys11u77meoodff Gestation Presumed Gestation PDDraaoy' c22u00m0eotdf P`Greesstuamtieond Gestation ma m DFDooorssaaadggdeetiPPeoernriaiooldd.d.etails see "Tests, Analyses and Measurements" seciion of the. : b. FppFreroootrtatoolaccdoeoldv.lia.tliounaatil odnesta(ialsl see "Tests, Analyses and Measurements" fetuses - extemal examinations) section of the Fetal evaluations (all fetuses - extemal examinations). 2277888..00223366 10 171416 33MMAA1100008833335544 AATTTrAACCHHMMEENNTT t 1 441188--001111::PPAAGGEE FF--7755 418.011P.PAGE TS PPrroottoo4cco1olPl8a44-g1018el8I-2P0.o1:0f1P1P1P2AGE 75 Page 2 of 2 SCHEDULE" SCHEDULE" 1166 JJUUNN 9988 2222JJUUNN998BPPMM--2277 JJUUNNG98BAAMM 2233 JJUUNN 9988-- 2277 JJUUNN 9888 2290 JJUUNN 9988-- 1144 JJUULL 9988 1133JJUULL 8988-- 1177' JJUULL 9988 2246J3UL9988 2299 SSEEPP 98 98 AArririvvaall DDaatte-e- AAcccclliimmaattiioonn Begins. Begins. CCoohhaabibtitaattiioonn Period. Period. DDaayy 00ooff PPrreessuummeedd GGeestsatatitioonn.. DpDrooesssaauggmeeePPdeergrieiosotddat((iDDonaa)yy.ss 6 6 through through 17 17 of of presumed gestation). pCCaraeeesssauarmreeeaadnn-g-SeSesectatctitiiooonnn)iin.ngg PPeerriioodd ((DDaayy 2200 of of presumed gestation). LLeetttteerr RReeppoorrtt. `SSuummmmaarryy RReeppoorrtt. a TThheessttuuddyyininititiiaattiioonnddaatteeiisstthheeddaatteetthhee SSttuuddyy DDirireeccttoorr signsthe protocol. signs the protocol. 10171417 2277888..00223377 33MMAA1100008833335555 441188--001111::PPAAGGEE FF--7766 "t8011PPAGE TE 418-011P:PAGE 76 AATTTTAACCHHMMEENNTT 2 2 MMAATTEERRIIAALL SSAAFFEETTYY DATA DATA SHEET SHEET 22778888..00223388 1100117711441188 aMAtoos3se 3MA10083356 441188-001111:PPAAGGEE FF--7777 N-E4F0SE 418.011PPAGE 77 MMAATTEERRIIAALL SAFETY SAFETY DDAATTAA SHEET SHEET 33SHtM.CePnautle,r Minnesota SS 5$58ti.1040aP4.s-31u160E0400,-003R5t7n7nesorota(612) 737-6501 (26 (24 hours) hours) C ACCA o~opYlpyyrTralrge igOgnnh~t,t,s, T1r1eer99ss9o9e8n1e8r,.,rv8vne0eRHde0di.i-nn.3nnp6eue4srCCs-opoo3otoptp5aasyy7eii7nnRHggioinnofiriaannnpnggdr(d6/o/1aopao2nrnerdo)rldO7yM Moo3awwa7nnUnn-luT6luofLo5aaLfa0adcid1ciztitnniuuggnrrgiinnoogfgafMCCTthhoBoimmirsspoDaganunycyt. s za1z1)s2n) foi aaze rnElmeEoaouwi~tezenae odg~noroprpemfrraoooanvvrmneiitdinodtahetnepedsyi1isTptssnhhuoarocacrptoboi:o:peTpsiahieeeieddneoodiirfnnipfgfrfriou ounpslalelllrOEM~wiy,i+iZthhuarnetdnnsiloooizldccin~haaognnrgg3eeoHsstnu~uenrrnolslaeeiussscsse~s 2) ted wien he snention of earning a prior agreemenz is oDZ~ned fro 3H, an~ neiZ~er zne copy nor the original is resoEd dzs~ribuZe~ ~i~h Z~e inZention o~ earning a Profit thereon. or oZher~lse profit ~emeon. DIVISION: 3M CHEMICALS DIVISION: 3H CHEHICALS TrAoeEnaFeLuoRAD Brand Fluorochenical Aleonol TRADE NAHE: FC-IO FLUORAD Brand FZuorochemical Alcohol 10 NOTMBERa/.Ps.C 00.51135-00495-2 96-0211-1183-0 IO NUHBER/U.P.C.: Ia] Sh Sis caias.a 9.0211-6620.6 95-0211-1113-7 9B-0211-~575-7 00.51135-09495-2 00.51135-02145-3 98-0211-1183-0 98-0211-6620-6 ooz-ceaz_ ZF-0002-0572-2 155080: vanuary 29, 1998 ISSUED: ~anuary 29, 1998 Supensiogs: Novemoer 05, 1857 SUPERSEDES: NovemDer 05, 1997 Document: 10-3778. DOCUHENT: 10-3778-7 000000.--555111111333555---010908545344822---323 00-51135-10439-2 + thcaeotent 1. INGREDIENT Cas. wo. C.A.S. NO. percent PERCENT PERFLUOROrOECTAAENSESUULLFFOONMAMMIIDDOO AALLGCOORWOOLL........... 31649518-:9099--23 820..00 - 79.00.0 PERFLUOROOCTANESULFONAHIDO ALCOHOL ...... nF LUPROVEPTANESULFONANIDD ALCOWOL. |... 8535-73-7 2.0 60 PERFLUOROHEXANESULFONAMIDO ALCOHOL ...... SROSUTAVESULFONANIOD ALCOHOL... 34449:88:3 2.0 =~ .0 PERFLUOROHEPTANESULFONA~ZDO ALCOHOL ..... OPENTANESULFONAIOO ALCOHOL... 68586:72:6 1.0 - 3.0 PERFLUOROBUTANESULFONAMIDO ALCOHOL ...... PERFLUOROPENTANESULFONAMIDO ALCOHOL ..... 1691-99-2 34455-03-3 68555-73-7 34449-89-3 68555-72-6 80.0 3.~ 2.0 2.0 1.0 90.0 7.0 6.0 6.0 3.0 1. bvsioa DATA 2. PHYSICAL DATA BOILING POINT: ....ovsssens SB+. m118Cno BOILING POINT: ................. VAPOR PRESSURE: oso os < 10 mmHg VAPOR PRESSURE: ................ VAPOR DENSITY:.....e.escasseses >ca1l:c0 AIP2E01 VAPOR DENSITY: ................. EVAPORATIONRATE: ............. ca1i:c0 B#U2O0ACCR. EVAPORATION RATE: .............. SSPoELCuITFLIICTYGRAaVnITwY:aT.EoR.}L.1oi1o1i1oi1e1. cnae.gli1o..7 waters! SOLUBILITY IN HATER: ........... SPECIFIC GRAVITY: .............. PERCENT VOLATILE:.......ooovees 0T%ot wert) PERCENT VOLATILE: .............. Pre III a pH: ............................ Wiseesiivi LILI wo VISCOSITY: ..................... MELTING POR1LTLLEI.LL NID HELTING POINT: ................. ca. 118 C ~ 1 mm Hg < 10 mmHg Ca~c @ 20 C > 1.0 Alr=l Calc @ 20 C. < 1.0 BuOAc=I negEig. ca. 1.7 Nater=l (of meet) 0 ~ N/A N/D N/D 10 171419 III I RII A her Aeelicabie CA - Approximately 22778888..00223399 MAI0083357 3MA10083357 441188--001111::PPAAGGEE FF--7788 JMRSaSDnDSuS:a: ryFFCC-2-81IO,0 F1FL9LU9UO8ORRAADD Brand Brand Fluorachesical Fluorochemical Alconol A.lco~ol January 29, 1998 4411&8O0l1IPI:PPPAAGGEE T7S8 PPAAGGEE 22 3 PWSICAL DATA 2. PHYSICAL DATA (continued) (continued) AAPPP`PaEEmAAvRReAArNNCCwEEaxAyNN~DDsoOlODiDOcORR:: Amber waxy solid "3 FIRE Mb EXPLOSION WAZARD DATA 3. FIRE AND EXPLOSION PLOD DATA FFFFFLLrLA~AiAMJSoSM~HmHPAaP~BBBPOLLLOIEeENINTLLTL:II:IMkM..iII..TTT..SSS.....-..Uo.LE Es.ELo.L:.s: .L oL..n.L..n...s.I ..e...e..s.. >WA114488 NWI/AA C C SeTaTlash Setaflasb TFLOATJMOMNAIBLTEIOLNIMTITESMP-ERUAETLU: R..E.:....|.... NIAN/A N/A AUTOIGNITION TEMPERATURE: ...... EEXXaTTItINNeGGrUU,IISSHHCIIaNNrGGboMnMEEDdDIiIAoA:x:ide, Dry chemical, Foss Water, Carbon dioxide, Dry chemical, Foam SSPPENHE~IHoCnCeoaIaeanIsAA"rLLilptffiavu FuenFeIelIRlsR]lE,EDopprrFrFeberIoIoaasGGtnsstHHeeduuTcTerrcetIIetNiNiavGvGooreeforPPuRRncppcOdOlrrloCeoeCEtstsEahDhssrDUiiuumUnRnsrrREgge,eES,,S:Wdd: eaieinmimncsdcaltnlnudduddainibbndnrrggeealatehhthhgeesililnm ,nmgegetrt,,aaacppepsspaeearlslrafafa-ts-ctukucos,os,nn, ttaaabnbiiduunnnneekkddee,,rr coat coat Banrdatepcatnitvse, bcaonvdesrinagroufnodr aexrmposs, edwaairsetasandof the Legs, hefaacde. mask, and protective covering ~or exposed areas of the head. UUNNUoUSSyUUAALaLrFFaIIrRRaEEouAAsNNDDDEEeXcXPoPmLLOpOoSSsIIOiONtNioHHAnAZZAAsRReDDcStS:i: on for Products of compusTion. See HazarOous Oecomposi%ion section for products o~ combustion. i ReAcTiviTY DATA 4. REACTIVITY DATA : :: stasLITY: Stasle STABILITY: Stable IINNCNCoO OtMHPPAaApTpTIlBIBiIcILLaIIbTTlYYe. - - WATERTALS/CONDITIONS MATERIALS/CONDITIONS TO TO AVOID: AVOID: Not appllcable. JAZARDOUS POLYMERIZATION: Hazardous polymerization will mot ocour. HAZARDOUS POLYMERIZATION: Hazardous polymerizaton all1 not occuF. HHAA~aZ.AArRRoDDoOOnUUSS CGuasrbfounr, M MnDoDonyEEnooCCoxrOOxioMMiddgPPeeeOOnSSIaaITnnFTddIlIOOuNNoCCraaiPrPrdbRbReoOoO,DnnDUUCD TDCTioTiSoxoS:xi:xiciddeeV,a, poOOrxxsi~,dOeessGa soof~e s WNio%trrtrooPggaeerntn,i, c uOOlxxaiitddeeesss. of of Sulfur, MyOrogen Fluoride, Toxic Vapors, Gases or Particulates. 5 EMVIROWHENTAL INFORMATION 5. ENVIRONMENTAL INFORMATION LIONEL oy coe vi ror sven rograng 10 171420 10 171420 soiLL RESPONSE: PRpPneheyryfeaessorcrcaataolll pPeeerisdounea.l oapapnn"rtrhPddoolettaehehrcececeatstaliieivltvntcehhetiaohehenaUqaqs.zuuz5aiaip.rpordm mafseOse,nOt,nhtTt.-ri.rseaepssCpMpCporiSiolorDrallvaSleetetocodfcortrtyyrcsospppipnnritrf1olaoo1tlitreeeenmdcdectratimimtooaiaonnttn,ee,rriivvraeaeellgmn..attiriZal~aaCCnttll~iegeooaannnn,, uapanndd up resiQue. PEace 1n a U.S. DOT-~pproved container. : STINT Raorexinatedy 22778888..00224400 I3MMAAT100008833335588 441188-.001111::PPAAGGEE FF--7799 MSDS: FC-10 FLUORAD Brand Fluorochemical Alcohol RJJaaSnnVuuPa:arryyFC22-019,0, F11L99U89O88RAD Bran~ Fluoro~e~zl kJ,cohol 418011PPAGE 78 418-011P:PAGE 79 P~AAGGEE 33 "5. ENVIROWENTAL INFORMATION 5. ENVIRONHENTAL INFORNATION (continued) (continued) REE COMENE DED DISPOaSAcLa:itted hazardous waste incinerator in the presence RECOHHENDED DISPOSAL: TTae arrorasl. Cospustion products will include HF. Incinerate in a permitted hazardous waste incinerator in the presence OE rset in 4 facility persited to accept chesical of a combustible material. Com~ustion products will include HF. Dispose of waste product in a facility perm~tted to accept chemical Naste. ENVIROMENTAL ENVIRONHENTAL EeA Laboratory oteDeDpArsrATeotTAs'mA:s: issahhsoo)wweedd Nnnooo aniicant efbmbfioioeordcdtteaegigrioratnadyda%atatithiooannwt.a.et,er9$6\6-s-HHaSrtur.u.rrvaLLitDDviSa5oO0ln,.FFawatethhiWegeoahadtd, Minnow and Rlnnow (plmepnales promelas) No mortality at water saturation. No e Se rcay Fithesd Manno egp Try Study. Lab tests snowed 200 statistically significant effect on hatch, survival, weight, and aemaracion of Fo.1 inte muscle fillets of chanel catfish. length in 30 day Fat~ead Hlnno~ egg fry stuOy. Lab tests snoHe~ 200 fold bioconcentratzon of FC-IO into muscle fllets of c~anne; catfish. RREESGGeUUiLLAaATtTOiORaRYeY Vt tase Volatile zIOIONrNroFgFgOaOaRn4RniHMiccEAAxTTCeCIIOomoOmpNmNpt:poouSunondldsvs:e:ntNNsI/A:A.. NIA VnT6OihcCiss,LeppsrrEsooIddNHuEuCc2cS0tt,&ccoCoEDmmSpxpLel,milieepssAt ISww CiSoittlhhvaend~TnhteseK:orcceNhhae/e.Asmi. cicaall registration registration requiresents requirements of o~ TSCA, EINECS, CDSL, AICS and Korea. EvchA EPCRA HAZARD HAZARD CCLCLArASSSS:b: RESSURE: No REAGTIVITY: No AGUTE: Yes CHRONIC: Yes FIRE HAZARD: No PRESSURE: No REACTIVITY: NO ACUTE: Yes CHRONIC: Yes & SuccesTED FIRST AID 6. SUGGESTED FIRST AID eEvYeEaImeSaCcm OsoOcneNTtadTalaiAacvCtteaTe:it:lyyteffn~ltuiusoshnh eyes eyes with with large large amounts amounts of of water. water. Get Get ismediste immediate medical attention. SSKaIr IIcwm NonmcCCtaoeu OOwm NdeNTTiTiamAnAACtc GaCaeTLtTl:neyy: dawwtacsasesalohhodtt~mssiikCknni1inggno..twwniiaI1~ttn1hhg sssisbigooegnasfnsppos/r/saesaynnymddarppettlluoaoasmrnregssgeeaooncadaccmmcuoduoruiru,n,sntptsscocasaoleolffll ofww8aaattppceehorhr.yny.stsiaiRcRmceiieiasamnnonaovt.veees Nash contaminated clot,zng Defore ~euse and dispose of con~amZnate~ shoes. : IINNHHIiAfAoLLAAnAsTTiIogIOaOnmNysN:sa/:sypytamoppnttsoomscssontooaccnccvuuerr,,, rcreeammlolovveea pppeheryrsssooinnciattono.f~rreesshh air. aEr. If If signs/symptoms continue, caE1 a physEc~an. IFAStAAiLLOApEhDy:sician THHEDIATELY. If ssallowsd, induce vomiting IF SNALLONED: CE Feted by medical peraomiel. Never give anyening by Call a physician IMMEDIATELY. If swallowed, Enduce vomitEng Zmmedately as directed Dy medical personnel. Never gve anything by South Ta" un Unconasiove parson. mouth ~o an unonscous person. ITI 10 1"/1 ,21 Aeerexinately 22778888..00224411 MAI0083359 3MA10083359 441188--001111::PPAAGGEE FF--8800 Jaruary 29, 1998 MSDS: FFCC--1IO0 FFLLUUOORRAADD BBrraanndd Fluorochemical Alcohol Fluoroche~~l. ~0t~01 jaP.uary 29, 1998 reo INFOMATION PRECAUTIONARY INFORMATION so eacEs 418-011P:PAGE 80 PPAAGGEE 44 evePsRmOoTrEeCcTrIiOoNn | pur savory chasses wien sion smaedes. EYE PROTECTION: AvoZO eye contact. Near safety glasses VLtth sde shzelas. scaOnM PmRrEOcTTEiOCnT:ION ear appropriens gloves shen handling is SKIN PROTECTION: A CT Ce Tatiaany serials) are Avoad skin contact. Near appropriate gloves ~hen handlng thls A ee Lo sare of the Felson mater~al. A paar of gloves meOe from the follo~ng mater~a~(s) are recciniee: BLL CUI aseeuary to provers skin somtact recommenOe~: Duty~ ruDDer. Use one or more of the foZlo~ng persona~ protection toms as necessary to prevent skin contact: rp covera1~s. recomEIoED VENTILATION: RECOHNENDED VENTILATION: UreaT TOT dee aaminaes spots Limits Use ~Zt~ agpcoprzate local exhaust ventlat~on. Prov&de su~#aczent ven~alatzon to m~zntazn emzsszons DeZo~ recommended exposure If exhaus~ vent~lataon ~s no~ adequate, use appropraate resDiratory peSsTpIiRnAaTTOoNnYy PPRROTTEECTCITONI.ON ne material. Select on of the following protection. RESPIRATORY PROTECTION: Avoid breathing O~ aZrDo~ne mater~a1. Select one of the foZlo~ang NIOSH aDproved ~esgzrato~s based on arbo~ne concen~ra;~on of contaminants and ~n accordance w~t~ OSHA regulations: ha!f-mask ~us~ ST A ometien Sir respirator respirator, full-~ace su9pZ~ed ar respirator. oreEvveerTuiToinonofoF AACCTCIIODBETNATLAL DIGEGSETSITIOONN, ry ths sroce. an emotes PREVENTION OF ACCIDENTAL INGESTION: Do not eat, drink o~ smoke ~hen using this product. Hash exposed areas thoroughly ~th soap and ~ater. Nash han~s after ~andlang and [rs Defo~e ea~zng. RECOMHENDED STORAGE: Fire ao EXPLOSION AVGIONKEE: Store away ~rom neat. Keep container closed ~hen not in use. FIRE AND EXPLOSION AVOIDANCE: even sREcAUTIOWNY INFORMATION: Nonflammable. OTHER PRECAUTIONARY INFORMATION: No smoking: SmoKang wh~le using this proOuct can result contamanatzon of the ~oDacco and/or smoke an~ Zead to the formation of the hazar0ous decomposition proaucts mentioned an section 4 of iTS WrAZAeRD RATINGS: WEALTH | FLAWBLLLIITTY:e|e RpErAoCoTuIsViIaToYn:t. 0 ection 117.00) 117711442222 HH~S HAZARD RATZNGS: HEALTH: 1 FLAMf4ABEL[TY: 1 REACTZVZTY: 0 PERSONAL PROTECTZON: X (See precautions, cxvosune Lins EXPOSURE LZRITS -- we ee am sae INGREDIENT SToeTiLnCeMEsILiIoOnWsI eASaL 0BL h Me ete amYTY PERFLUOROOCTANESULFONAHIDO ALCOHOL... ona PERFLUOROHEXANESULFONAHZDC ALCOHOL... VALUE UNIT 0.1 MGIM3 0.1 MG/M3 TYPE TNA TNA AUTH SKIN* 3M Y 3H Y PERFLUOROHEPTANESULFONAHIDO 0.1 HG/H3 TNA 3M Y ALCOHOL ............................ ......................... ~'''''~ ..... =. ~..~*.=h]~ CA - AOgrox~mateZy 22778888..00224422 MA10083%0 3MA10083360 441188--001111::PPAAGGEE FF--8811 441188.-0Q1l1lPP PPAAGGEE8811 JsRaoSrDsu$:a: ryFFCC2--51IO,0 FF1LL9UU9O8ORRAADD Brand Brand Fluorochemical Fluorohemi=~ Alcohol A~oho1 PPAAG~EE 55 Jar.uary 29, 1998 EXPOSURE LINITS ((ccoonnttiinnuueedd)) INGREDIENT EXPOSURE LIRITS ae wT VALUE UNIT TPE AUTH SKIN AUTH SKIN" TYPE INGREDIENT SERFLUGORTAVESULFONANIDO ALCOROL... 0.1 0.1 MG/M HG/M3 TWA 3 TNA 3H Y PERFLUOROBUTANESULFONAMIDO ALCOHOL... PEE RFLUOE ROPENTANESULFONAHIrOrO eensss PERFLUOROPENTANESULFONAHIDO 010.1 HONS ~!H3 TWA MY 3M Y TNA -rtohneeeSASRKLKCiIcpINONeonHntONNgetOLOnTs.TAtm.AaiTua.TlIc.lIOOo.NuNc.c:so.:o.nnm.tte.rLLrm.iiibb.sbs.rutute.aettd.indio.eon.nss.uua.Tbtnbo.osds.tt.aatteh.nnhy.eccee.e,e.ssoo.vev.ieeiinrntradadhZliiec1lcraatteebeexyxddppooEsN wisuiruirttbrheehornbD'Y eyYy'' TnuuennddecerurtSSaKnKIeiNNousrreefrfeeorurtettoo tohre, cBuortaenepoaursticrouluaterly, HC vract /ncluding mcounctoaucstmweimtbhranteheansdubsetyaen,cee.itheVernsbcyleasirbcoarnnealtoerr, =sokiren sosorpLion particularly, by direct contact ~ith t~e substance. Vehicles can otter skin adsorption. SSOOUUaRR:CCEE OF OF a EEXXPPROOeSScUUoRRsEEmenLLdIIHeMcIITT EDxDApAToTAsA:u: re Guidelines 3H: 3H Recommende~ Exposure Guzdelines 5. WEALTH HAZARD DATA - EEvYeENoCCOOaNdNTvTAeACrTCs.Te: health effects are expected from eye CONTact. No adverse heaZth effects are expected ~ro~ eye contact. SSKKI`INNbroCCaOOuNcNTtTAACC1TsT:: not expected to be irritating To the skin Product ks not expected May be absorbed through to be irritating to the the skin and persist in sthkein.body for an extended Time. Hay De adsorbed extended tame. through the skin and persist An the body for an IINNH`HhAAaLLyAAT5TI6IOONNa:b: sorbed by inhalation and persist in tne body for an extended May Oe absorbed by inhalation and persist in t~e body for an extended ~zme. IIFF ISnSHWgAeALsLLLtOOiWWoEnEDD:1: s not 3 Likely route of exposure To this product. Ingestion ks not ~iKely route of exDosure to this product. aIIlullniinnetessasstiemmsaayy oofocccctuuh~risaamt~attteeerrriaaalss.iinnggllee swallowing s~alloNing of of relatively relatively large large quantities of this material. MMUUTNTAoAGtGENEmINuCtICIaITgTYeY:n:ic in 1n-VATro assays. Not mutagenzc in in-vitro assays. RREEPSRSPRiuRuOlbObDissDUittUCagaCTnrnITcacVIeneVEsEnH//DaDpaEseEsVrVEEnnLLoKoOOtitPPlHMottEeEgeNrrNrTaaaTAtmAtoLoLggpeTTeeOOnrnXiXicIcdINNaSSyiin:n: vitthahee orrraaatlt asrtot udtdeoo.sseess as as high high as as 30 30 mZligrams per ~Zogram per ~ay via oral route. OOTTHHThCEEahiRRlissitHHopEpErArAronLoLTsTddHaHuucctHHPtAArZZao1AAspRRoDDsnnoiottIItNiNFoFkkOnOnnoRRowMa6H5AnnA.TTItTIOoOoNN:cc: oonnttaaiinn any any substances substances regulated regulated under under California Proposition 65. A Proguct Toxicity Summary Sheet is available. A Product Toxicity Summary Sheet ks available. 10 171423 10 171423 IIIS inrornately 22778888..00224433 M3MATA010008833336611 i 441188-.001111::PPAAGGEE FF--8822 JIJ~aoDnsSu:a' ryFFCC-2-11,00 FF1LL9UU6O8GRRAADD Brand Br|nd Fluorochemical Fluorochem~~l. Alcohol A~ohol JanUary 29, 1998 Section crane DATES SECTION CHANGE DATES reHEADING SECTION CHANGED SINCE November 65, 1997 ISSUE SECTION CHANGED SINCE November 05, lg97 ZSSUE 18.011PPAGE 82 418-0lIP:PAGE 82 PpAaGceE 66 Sonreviationsi Abbrev~atZons: WbN/D - hotNot bevermines Determined NIA Not Applicable NIA - Not Applicable GA - Approximately CA - Approxzmately TTbST EnheneeeCcrihZoenenrfwnrfoeoH~rAE cmmBItaLNatLaEtziLsLoo7UnnYD~INiOGnnnRth,tettFhBhIUaiiOTskTsNacEe;MeM NS.aOSatTZseteFsersLOsirsRuIiaeNeadlAIdl.T. SSEPaDAaf30RfHeTeTtOIty,yWHCAUADKDKLAaEEANaStSRYtaa1NIPOSSNUhPRhWeNLPeAeIOAetRESRtRDERAA((NHWO4NTSASRTIRDDZESRSECS)A)OS,NU,T~iRYssESEEXXbODPPFeRROelEFE1iSS~eSSeEvEvDeeDdsOOtRtRoo TH~E PZEEEHhRRoePFCmLtOhrHIwEReAe ADHarNAo,CTNttAEhCZB:enENZCLtOZOoL3nUnTR~heYDoUUZfppuSNOsSereAoARGos.GGsd,eEEueFuacBZncTeUOOdotNTFrFE1~aSTNTssapSRROppAATFfpaDiDFiliEOt%LiEc.RIc.aHafftZotAoiTirUUroEosPnsDneAaae.rRorTTpfpOZiaZaCars,aGrUtitALirr3viAceNcMeeRYsuusnlppplaaoIPrtoHUrnhornPsRedsiLPuppiObIcuvbuEltSrarlDepe,EprooiNsfsOfesoeoeARtoRryrmRCeaaAOadnnoNeddUfeoTtRfteYeSssfrEruwam usOihciZiOFttitanFnacoib*bhrnnlsleggeatrffheooartr user's method of use or application. G~ven the varety of factors that eens Simin the user knocledge and conerod, At 18 essential that can affect the use and applcatZon o~ a 3R product, some of Nhich are EE Tans the on product fo detarasne unether it 1s it for & uniquely ~t~n the user's knowledge and control, i~ s essen~al that ee ine wukvasie for users method of use or application. the user evaluate the 3R product to deter=ins N~ether it is f~t for a p3DBSMoapuerrtepe~o~rrcvooouoivZrtoisaheaeeee,"rssporreuieemnrnrnpaf~oeotooteseir~eomnnpapaeaototnbisdoeoosnlnrosbtaiuinin~lititlaiteeetbyylrZelaeecttTchtihtrrfoaaooonttnnsrieecculileenscffceootttrrrrrho'~saionsnmiaaccissenthftatarooradrassnaneeassrortivfvfeiaiicorrcu,enes,eamatTaoyooIy~thihttasaassvavpeekpecclsuuirrcesseasttsnotuouommZloetteenrerdsa.s. ir~HCrnerentpeofooeorrrrererm earrsaoaeaettnrtn~isittooo,iannnttiiooooomonpnbnessttasaishaianineoeseendds.ttwooadfofrsriroottmssnaavltca&caeoiorlGdmmaaApaptbTltiallseoebetbtneaeasnsnsdeeesissr~ssmenmacattyooyhrlrynnsaaooctfctc~rcuobbnurmeefroaacrac3a~yMEsya...~ccuuorIIrnnnrree, nsnat3dtd~adiaaitsmstiiaoohtkhnneee,s, no information in the RSDS available d~rec~ly from 3M. 100117711424 22778888..00224444 amAtoosze2 3MA10083362 441188--001111::PPAAGGEE FF--8833 418.011P PAGE 83 418-011P:PAGE 83 AATTTTAACCHHMMEENNTT 33 TTEESSTT AARRTTIICCLLEE AANNDD CCOONNTTRROOLL AARRTTIICCLLEE PPRREEPPAARRAATTIIOONN PROCEDURE PROCEDURE 2277888..00224455 10 171425 33MMAA1100008833336633 441188--001111::PPAAGGEE FF--8844 441188.-001111PP:PPAAGGEE 8844 AATTTTAACCHHMMEENNTT 33 Version: 41P8r-Po0rt1oo1toc7c(oo0ll844J1188U.-N00119178P7) TEST ARTICLE AND CONTROL ARTICLE P REP AR ATVIeOrsNionP: R41O8C-0E11DPU(RP0P9aEagJgeUeN1 190813) of 3 TEST ARTICLE AND CONTROL ARTICLE PREPARATION PROCEDURE TTeesstt AArrttiiccllee:: NN--EEtIFFOOSSEE Vehicle: 2% Tween 80. in R.O. Water 2% Tween 80, in R.O. Water Vehicle: A. PPuurrppoossee:: oTTfhhdeeoppsuuarrgppeoossseeuoosffpttehhinisssppirroooonccsefeddNuu-rreeEiXsisFOttooSpEprrooavvniidddeethaae mmcoeenttthhrooolddfafoorrrttithhceefopprrreeoppraaalrraattiioonn `oaafddmdmioinnsiiassgttrreaattsiiouonsnpttoeonrrsaaittossnoosnnoAAfrrNgg-uuEsstFSSOttuuSddEyy 418-011P. and the control 418-011P. article for oral BB.. General Information: General Information: 1. A`ASllplesscuuifssyppteehnnesspiirooonntocccooonntltaaniinnueemrrbssewrwi,lillltbebseet llaaarbtbieecllleeeddidaaennntddifcciocolaltooirroncc,ooddAeerdd.g.u sEEbaaaccthhchllaabbeell will will usnapnmuedmbcebsifretyo,r,trhaccegooennpccrceooenntntodrticrataotitlioioonnsnnu.,,mddbooessraa, ggteeesllteevaverelt,li,clpperreeidppeaarnraatitftiiicooanntidodaantt,ee.A, reegxxuppisirraabttaiiotocnnhddaattee. and storage conditions. 2a28. a SSuussppeennssiioonnss wwiilllbbee 7pprreeppaarreWedd:ey X Daily m Weekly For daysofuse __ For days of use 22bb.. --VVeehhiicclleeDawwiilillyl bbee pprreeppaaXrree_dd:: Weekly _For__daysofuse m Daily X Weekly __ For days of use 3. Suspensions wilbeprepared at a final dosage volumeof 5 mks. Suspensions will be prepared at a final dosage volume of 5 mL/kg. a XSsaa_tfeety::Gloves, ab coat, goggles or safety glasses and faceshiekd XXXC GDDHuluoasslvttfe-MMFsia,sicstletabRRReeecssosppapiitrirr,aaatgttoooorrrggles or safety glasses and faceshield TZ THFFyuauvlfllt-e-kFFkFaSaaccuceeeivRRRAeeespspsripporiirnaraattotoorrr/lPPoossiittiivvee Pressure Pressure Hood Hood __ Tyvek Suit/Apron 5. DoDsoasaggeeYsesosolluuttiioonnss aaddjjuussX_tteeddNffooorr(FFCrareeleceubblaaastsieeoaannnsddba%%sePPduurrotiytny..100%) _T_ YFFrereeseeBBaassee __X Pury No (Calculations Purity based on 100%) 66. SSaammpplilinngg rreeqquuiirreemmeenntsts:: Cited in protocol. Cited in protocol. 77.. SSttoorraaggee:: Cited in protocol Cited in protocol. 10 171426 2277888..00224466 33MMAA1100008833336644 441188--001111":PPAAGGEE FF--8855 418.011PPAGE 85 416-1311P:PAGE 85 ATTACHMENT3 A't-TACHMENT 3 Version: Version: 418-PP0rro1ot1too7ccoo0ll944J118U8-0N0119118PP) 418-011P (0P9agJUe2N09183} TTEESSTT AARRTTIICCLLEE AANNDD CCOONNTTRROOLL AARRTTIICCLLEE PREPARATION PREPARATION PROCEDURPaEge PROCEDURE 2 of 3 NNOOTTEE.: TetTt`heaseetsttelloaoadwrwtrttioiddcctoollesehswaeawiggeilcle.lob.nbOteeOanpiprcnnreceeeprepstaa;thrhreeeemfdidfixainniasanaslglaavvssooeshrlleouiuurmaimlaldeel sdsdoiicaaltucrritueeoiornaandccfuhfhrrriiooieemnmvvgeettddhsh.,eaemssphhtiiilirggibbhhnaadgdrrossoasnsaaadagrr/egeeoettbrtootooebe `administration. added to the containers; administration. mixing should occur during sampling and/or C. PPrreeppaarraattiioonnooff VVeehhiiccllee 1. AAl`laaaddbbmddeeolluttehenhddete ccorroofeennqqTtutuawaiiiirnreneeeeedrd.rn.aammHHo8oe0uuanenatttnttohhdofeeafmwRRwia..xtaOtOe.tu.ernrtddiettelooiioou55nnn00iiizfzCeCoe,drd,mww+(a55aStteeCCeer.r, 1tTaao0ddEaaddSnnTtthhaaeAepppRprrrTereooqIqppuurCiriiLriraaeEettddeellyy CaCmAALoLCuCUnULtLAoATfITTOIwONeNSe)Sn.). 80 and mix until uniform (See TEST ARTICLE D. TTeessttAAtriticcllee Suspension Suspension Preparation Preparation: Do + T`oTofaofoppttperpersseroettpppraaaiarrraltretieccetllletehyhee((sSiS77zeee--eedmm.TTggiEEl/mmaSSbLLTTe.,lAAeGGdRRrrToocToIuuInCppCtaLLVViEEinIlIeCCrss.AuuAsLsLpApCCeeUnGUnsLLsiAtoiAoThnTne,II,OOraaeNNddqSudSd)i)trthehiinednettoaorreemaaqqonnuuuiinrreteddoaafmmoouunntt Vehicle and heat the mixture to 80C, appropriately sized, labeled container. vehicle and heat the mixture to 80C, +5A5dCCd fthore for arpepqruoixreimdaatemloyu3n0t approximately 30 omif nutes. minutes. 2. cOOononlccsee. tthh(eeB etteessstut raaerrtttiichcleleerehhiaasssaddiivssisssiooblllvveeeddv;o;rsstppeixinn, oothvvieesrrwinnliilgghhatct hwwihhieilvleee the tthhee ssdooelsluuittriioeodnn ecmouollss.io(Bn)e sure there is a visible vortex, this will achieve the desired emulsion.) 3. TTaoompoprureneptpaaorrfeetstthhoeeckS5-s-mmuosg/p/mmeLnL.s,iGGornroo(uuGpproVVuiIpssVuuIssIpp)ee(nnSsseiieoonnT.,ErrSeemTmooAvvReeTttIhhCeeLrrEeeqquuiirreedd aCCmAALoLCuCUnULtLAoATfTIsItOOoNcNSkS)s).u, saapddeddnttshhioeenrree(Gqquurioirrueepdd VaImI)ou(SneteofTvEeShiTclAeRaTnIdCLmiEx. amount of vehicle and mix. 4 TTaoomoppurrneetppaaorrfeesttthhoeeck4ms-gmu/sgpm/meLnL.s,iGGornroo(uuGpproVVupssuuVssIpp)een(nsSiseoieonn.T,ErrSeemTmooAvvReeTttIhhCeeLrrEeeqquuiirreedd . aCCmAALoLCuCUnULtLAoATfTIsItOOoNcNSkS)s),u, saapddeddnttshhioeenrree(Gqquurioirrueepdd amount VI) (See amount oTfEvSehTicAieRTanICdLmEix. of vehicle and mix. 5. o TTaCaoommApoLopruCureneUnptpLtaaAoorrfTfeeIssttttOhohoNeeccSkkm2)ss-g,muu/ssgapmp/dmeeLdnnL.sts,ihioGGoennrrroo(e(uuGqGppurriooIIruVuVeppdssVVuua)ss)mppo((eeSuSnnenesseteiiooToTnnfEE.,vSSrreeTThemimAAcoolRRvveTTeeaIItntCChhdLLeeEEmrrieex.qquuiirreedd CALCULATIONS), add the required amount of vehicle and mix. 10 171427 2277888..00224477 33MMAA1100008833336655 441188--001111":PPAAGGEE FF--8866 18011PPAGE 86 418-011P:PAGE 86 | AriachmenTs Versan 1Pr6otoDsS9a1A0o.N01S1a1E8 A'I-rACHMENT 3 Protocol 418-011P Version: 418-011 P {09 JUN 98} Page 3 of 3 TEST ARTICLE AND CONTROL ARTICLE PREPARATION PROCEDURE TEST ARTICLE AND CONTROL ARTICLE PREPARATION PROCEDURE 6 Toprepare the T.mgimL. Group ll suspension. remove th required To prepare the 1-mg/mL, Group III suspension, remove the required moun of stock suspension (Group IV (See TEST ARTICLE amount of stock suspension (Group IV) (See TEST ARTICLE CALCULATIONS). dd the required amount of vehicle and mix CALCULATIONS), add the required amount of vehicle and mix. 7. To preparetne 0.2:mgimL. Group suspension,removethe required To prepare the 0.2-mglmL, Group II aammoouunntt ooff ssttoocckk ssuussppeennssiioonn ((GGrroouupp sIlul)s(pSeenesiTonE,SrTemARoTveICthLeE required III) (See TEST ARTICLE CALCULATIONS). 4d th required amount of vehicle and mix CALCULATIONS/, add the required amount of vehicle and mix. Vinten by: _s. . Approved by Claricaton: +ZN7]o enlace Hn ves (Seo atached claication form) Inttials/Date: (lft, I Epp oppofor 22778888..00224488 10 171428 aMAtoos3es 3MA10083366 Arg2s -- " Abonrones 441188--001111::PPAAGGEE FF--8877 418011 PAGE 87 418-011P:PAGE 87 `Argus Research Laboratories, Inc. Argus Research Laboratohes, Inc. S05 Shea Ove BldA SOS She~hy Ori~e, Building A Horsham, Pennsylvania lS044 epaeses apcaston T: (215) ~1,~3-~710 F: (215) 443-~587 PRPORTOOTOCCOOLL441188:-001111PP OORRAALL ((GGAAVVAAGGEE)) DDOOSSAAGGEOE.F-RRNAA-NNEGGFEEODDSEEEVVIEENLLROOAPPTMMSEENNTTAALL TOXICITY TOXICITY STUDY STUDY OF N-EtFOSE IN RATS SSPPOONNSSOORR''SS SSTTUUDDYY NUMBER: NUMBER: T63167 T-6316.7 Amendment1 - June 18, 1898 e--re--re---- Amend-- ment I-- - June-- 18, 19-- 98 ----e-- nt 11 . ClO Cilniniicb caall Os bsee rvatr ionsv aanndd/a /oorrGGt eenneeri raall Ao Apppl:e)n eaarraas nnccee ((ppaaggee 88oofftthhee pprroottooccolo)l):: Cinical observations during the dosage periodwillbe taken wice daly. prio 10 Clinical observations during the dosage period will be taken twice daily, prior to Sovags aamintraton and once approximately one hour postdosage. rather than dosage administration and once approximately one hour {~ostdosage, rather than re pronimatel ane nour posidosage and hen four to six hours ater. once approximately one hour postdosage and then four to six hours later. RReaesonaffoosrr CChohaanngnqee:: TiThhniissscchhoaainngsgeerwweaapssrommgaauddceeivaatettethhveerlreeoqqpuumeeessntttooaffttthheeoSStppoosnnshsoiorer tstoo smmiaanctgchhitteheesttaiimmmeee ftfrleaasmmeess pind of the other reproductive/developmental toxicity studies using the same test ~.,ticte. / 7) [tog & fae asst he E Josarore. PhD. DAB Date Raymond, z vark Pn. ORT Associate Diecirof Research ~eo~Je E~;adove,-Ph.D., DABT Date Associate Director of Research AARasnsasdsoyoc~Scitniaau~tdteeLy~DDDi.iirrrYeeeccoctttrookorr,rooPfRfhRe.l~ee.s,a~Ira~crBcnhT and Study Director RE Date Date LDDMeeehmrnibaaewCrC..a. LLIeenCbbsoob,u,VhtViM.oMnia..Dl.Animal CsaprdeuDDauanatndeted.y MaInien..Case,[DGVnM. PhD. SMtaurdvyinMTo.niCtaosre, D.V.M., Ph.D. 22%D.at9e% Date Ue Commitee Member, Institutional Animal Care and Study Monitor Use Committee 10 171429 22778888..00224499 SwAtooss3s7 3MA10083367 AAPPPPEENNDDIIXX GG HHIISSTTOORRIICCAALL CCOONNTTRROOLL DDAATTAA 2277888..00225500 1100 117711443300 mAtoc83388 3MA10083368 441188--001111':PPAAGGEE GG--11 SSOTMIMAARRYY OOFF RREEPPoRROOmDDUUrCCTTIIVVEE INDICES INDIC~S CD RAT sPEERRIIOODD NWEOMMEBEERR OOFF SSTTUUDDIIEESS SJoUnNEe 11999955 --JuUNxE 11999977 907 NNOEMME~EERROOFFRRAATTSS=: rTmTeEosSTNTEETDD 2291633722 FrOoUp`NRAmDesgoDDNREEATAANEDDTD 1967o33 DDEELALIBIVOVERETRREEEDDD o0 0 NNCUEAMMBBBSEERRAROOEPFANRR-AASTTESSCTPPIRROEENGGINNNAAGNNTT AT AT 11995577 CAESAREAN-SECTIONING MNNUO`MMCBBoEERRRCEOOPPFTURRSAATTLISSTTWWEIIRTT:HH SINGLE SINGLE CONCEPTUS LITTER: Love s `RR`EAEASBssOOooRLRRRBITsTEVEEEDEDDD 0500 MEAN orn % PeRrEEGcNAnNTT 52.8 92.8 AAVVEERRAAGGEE # # CORPORA CORPORA LUTE LUTEA 117..33 AAVVEERRAAGGEE ## INPLANTATIONS ZMPLANTATIONS 115..66 aAvVeERRaAGGEE LLIITTTTEERR SIZE SIZE RAVVEERRAAGGEE ## LLiIvVeE FFEETTUUSSEESS w14e.8 AAVVEERRAAGGEE # DDEEAADD FETUSES FETUSES o0.aI AAVVEERRAAGGEE ## RREESSOORRPPTTIIOONNSS 00..88 AAVVEERRAAGGEE # EEAARRLLYY RESORPTIONS RE~ORPTIONS 00.77 AAVVEERRAAGGEE ## LATE LATE RESORPTIONS RESORPTIONS 00..00 RRAMAEnNAGGNEE//SSoTTfUUDDVYY MEAN or % ((6644..00--1I0000)} (@15s.2a-2-1.00) ((122..99--1188..00)) a(1u1.s8a-1r7n.0o) ((o0-z-.11) ((00--11.66)) ((o0-11..66)) ((o0--o0.22)) 2277888..00225511 10 171431 33MMAA1100008833336699 441188--001111::PPAAGGEE GG-22 SSUUMMMMRARRYY OOPF RREEPoPRROOmDDUaUCrCTTIIVVEE IINNDDIICCEESS CD RAT Mean or v `mMaEvAcNe/osrToADY AAVV`EERRREAASOGGREEPT%IODDNAASMM.SS WITH WITH ANY ANY RESORPTIONS w48a. 4 ((00-7755..00)) AAVVEE`cRRoAAnGGcEEarqrUDDsAAEMMsSSRWEWISITOTRHHBEAADLLLL 01 (0-65) | CONC~PTESES R~SOI~ED 0.1 (o-4.$) AAVVEEHRROAARGGEEEL3IVDDEAAMMrSSrTWWUIIsTTEHHS OONNEE OORR MORE LI'V~ FETUSES 9999.99 ((9955..44--120000)) AAVVEE(RR8AAGGAEELEsSSEE/XXLrRRTAATTTEZIROO)~, ( MALES/LITTeR) AAVVEERRAAGGEE FFEETTAALL BBOODDYY WWEEIIGGHHTT {(UG)} 5500..22 ((4422..21--5577..00)) 33..4477 ((33..1100--33..7788)) AAVVEERRAAGGEE FPOORR MMAALLEESS ((3G)) 33..5565 ((33..1177--33..9900)) AAVVEERRAAGGEE FYOORR FFEEMMAALLEESS ((6G)) AAVVEE`RRcAAoGGnEEcz\PrDDuEEsAAEDDs/OOLRRITRRTEEESSROORRBSEEDD CONCEPTUSES/LITTER 33..3377 ((22..9988--33..6666)) 55 .. 00 ((00-2100..99)) 2277888..00225522 10 171432 33MMAA1100008833337700 441188--001111P:PAAGGEE GG--33 SSUDMIMAARRYY OOFF HMAATTEERRNNAALL NNmEEaCCRrROOPPSSYY OOBBSSEERRVVAATTIIOONNSS CDRAT PE+ ERRsIItOoDres +# SrTaUsDIETSESTED eJUeNE 11999955 - - oNE JUNE 11991992770 2517290 ##++ RRrrAAaaTTztSSss TPppER1RSEEETGG>ENNDAANNTT #+ RRAaTsS DAIBEODRTED 222353878797 4 o ##+# RRrRAAaATzTTsSSS ADWDBEIEOLTLRIIHTVVEEE1DRR0EE0DD% RESORPTION 4a39901 # RATS WITH 100% RESORPTION 1 EOEOTBBXSSTEEEERRRVVNAAATTLIIOONNSS`had substance asound RIen`dncnoiomssseouerbssaantndadm/n/iocosreralmimaogoxunuoettudhhnd cIhnrbbcorrimosookokdereasnncrma~yinnomddr/a/solohrlregmsmniiesmdssilnngg AAcWllhhooirpptoeeemcocidisaaaucbrsytoanrcreheapresent in anterior chamber of oes in anterior ch-m~er of oMMee~aAnN N 110.0.0064 222 0o0..i00s88 233 000..11O22S 11 00..0048 mRaAw NnGcEe s //sSTTUoDD~Y N 00---1i ((00-33..33)} 000---222 (((000--.-666...777))) 000---233 (((000--1610.0.7.0}0)) 00--I1 ((00--44..22)) Gross LEsTONS GROSS LESIONS SSUUBBMMARNNDDIIBBUULLAARRDaLLrYTkMNPPrHEedNNOODDEESS Dark red JJUuGoUuLLAaRR vVEIInNDistended with blood Distended with blood 11 00..0084 00--1I ((00-33..33)) 11 00..0048 00--11 ((00--33..33)) CHEST TmHoOmReACrIeC mTHoYMsUS SSuuzbbeccduutotaannneeoovuuesnstrffaaattl,, sddiaadrrekk red on ventral aide eCaAvViIFTTi~ylled wich Ligh rea Filflleudidwith light red fluid LDDaiirssgcceoolloorreedd aarreeaass L~go 1 00..0046 00--1I ((00--33..33)) I1 00..0084 00--11 ((00--44..00)) 212 00o..l00s88 000--221 {((000---646...707})) 1 0.04 0-I (O-4.0} Mase present. 1 00..0084 00--1i ((00--64..00)) 10 171433 2277888..00225533 33MMAA1100008833337711 441188--001111::PPAAGGEE GG-44 SSUUMMMMAARRYX OOFF NMAATTEERRNNAALL NNEEmCCzRROOPPSSYY OOBBSSEERRVVAATTIIOONNSS CD RAT rGRoOsSsS LLEzSsItOoNNsS Liver LIVER Adhesion between lett AdhLlleaaamtttieeeorrrnaaalllbaellbtoodwbboeeemeinaannnddlaelfllteevffattll lateral abdomlnalwall `STsOrMoAsCaHc/nI/NTTEESSSTtTIoINmNaEEch, fluld-filled SSttyao-lmJsaotcbeh,ndaenfddluwiiidnt-thfeisgltalisendes ICnotcdeuis~ntti~cnoden~st,daiwneiemtpdhtyagabslack ~ `subst~aoncneta~ a black mex SSppii`onnnee,,dorppsrraoolttrrutushsioioronancoioffc bone ~one ppooonrrttdioioronsnal thoracic Kuowzx(s) PPeellavviiilssa,,tiossnlliiwggihhttth//mmooorddeerraattee Pewwldviiiittlshha,ootuuittmoanrfekwllieuutdiihd/deoxrtreme MPoeltdavtilil1lsaae,ttdii~oonnarked/ex~r~ Mottled Lsaezagl)s Lsxge SCLCaoomtrraettl)eelxxpppeiilttvtitseeddcontained Lefyytee;llllopoewwlvffillsuuiiddcontained AASBoDoOKMIINNAALL CCAAVVPIIiTTlYYled with light red Filffllaeutdiadwith light rod seuzmn SPLEEN Two`sewrhoistale ascuersfsacoen leEo,al ,ttEface BBLLAADDDDEERR PWFallluuldd--tfhfiiilcllkle,edd contained Waolonlneethcciaacllkcc,uullicontained Bm~ oaxaoRmAaNnGoEr /sToaDE N % N 11 00..0044 00--11 ((00--44..00)) 11 00..0044 00--11 ((00--44..00)) 111 000l..o00s64 000-1-11i (((000---444..000))) 1 0.04 0-1 (0-4.0) 11 00..0004 00--1I ((00--46..00)) 1 00..0048 00--11 ((00--44..00)) 1177 00..6666 00--22 ((00--1122..355)) 25 000...110598 000---111 (((000--.444...000))) 12 0000....00008888 00O0----ii11 ((((0000---.4444..1.0000)))) 1 000..000444 0O0--11I (((000--3430..404))} 11 00..0046 00--11 ({00--44..00)) 11 00..0084 00--1I ((00--44..00)) 11 00..0084 00--11 ((00-44..00)) 11 0.0.0044 00--1i ((00--44..00)) 11 00..0084 00-1i ((o0--1122..55}) 10171434 2277888..00225544 33MMAA1100008833337722 441188--001111::PPAAGGEE GG--55 SSUUMMMMAARRYY OOFF MMAATTEERRNIAELLEXNNEECCRROOPPSSYY OOBBSSEERRVVAATTIIOONNSS CDRAT rGRoOsSsS LLEESSIIOONNSS omerEns DDiisspttaeennddeedd wwiitthh clear clear f~uid VvAAGGIInNAA//CCEERRVVIIXXCorvix distended with CCeerrflvvlaiiutxxieddcionsttaeinndeedd with a thick, CCaer`rbbvvrriiooxxwwnnccoosmunnu.ttbbaasmiittnnanzene~dcdceoaa thick, dark Cerrzseevudaib,,xstcaggoenenllctaaea=tiiinnneooudussa d~k ~ Cevrviisxcocucosonnttfaaliiunnieeddd g~renen,, VVaavvggiiiissnn=caaoouuccsosonntff~allaiuuiniinedd~d b~rrow~n,, NoMMEevRa~on oRRwAANNGGEE //SsTTOUaDDYY 11 00..0048 00-1I ((00--44..00)) 11 00..0046 00-1I ((00--44..00)) 11 00..0044 00--I1 ((00--44.o00}) 11 00..0044 00--11 ((00--44..00)) 11 00..0044 00--1i ((00--44..00)) 110.0.0044 00-1i ((00-22..31)) UTERUS FrOoRrEzLLIIMNBG Ccoonn`attnaadiinnoeendde drreeeaddd--,bbrrboorwwnonwnfflluuiidd Rigaffnheedtttuussohnoren,deaadb,sebnrtown 211 o00..l00s44 0o0--a11 (((000---441..600.))7) RLRReiiifgggthhhttthhhohoorornrrn,nn,,, lttauhsbhersrneeenastddallbiiskekenet 211 000...000844 000---ii1 (((O00---1226..1.1}7)) Lefoootnnvahr=coeierrranvvn,iiccenaaldllu,meeennndddi;as; btseenndted Rigow"hviitattrhhihacocrnllnee,eaanrrdC,lffelldauuiriisddmtaesnsdeesd, 11 00..0044 00--1I ((00--24..00)) Rigccshooutnnbttsaathiioarnnnneec,dde cggleeellaaarttiimnnaoosuussses, 1 0.04 0-1 (0-0.0) 1 0.04 0-1 (0-4.0) LLeessiioonn pprreesseenntt 110.0.0084 00--11 ((00-33..33)) 2277888..00225555 10 171435 33MMAA1100008833337733 441188.-001111::PPAAGGEE GG-66 SSUGMAMRARY~OOFF FFEETTAA@LLmEEXrXTTEERRNMAALL ALTERATIONS ALTERATIONS CDRAT renzo JUeNEe PERIOD i+ CsStoTurUpDrzIezEssS mImNCoeLUDeuED + Lave rerosss Exe LITTERS EXAMINED LIVE FETUSE~ EXAMINED AuLrTEEmRaATTIIOONN wo Exencepnaly Exenceph&ly HHoemmaattoon~sa uMiic=rrooc=eepphhaallyy seas EYES sEvyGeeopbbruuellnggseessed LLiidddsseporopepesesnned MMiiccrroopphhtthhaallmaiiaa 11999955 --J JUNEE 11999977 1784a65 2a51s676411533 LFoo:s 0o0.la2em9 LFo%l 0oo0..0oe026 IFoi1 o00o..le00e06 O.O0 LFLo oi14 0o0..l80s0 FLFI i1511 oo00..lo00so66 LFFFL i1111 0o000.l...00e0006s80 mRaAsNcGeE N 0o0-aa1 o00o--aa1I 00oo--anI1 0-1 000-222 0-2 ooaa0-1 o000---a111 0-1 //sSTToUoDrY (((000-40a.5))) ((((0000--2002...2242)))) ((((0000---00440..0320)))) (0-0.3) (((000-011.229..)55)) (0-0.9) 000432)) (0-4.2) ((((0000---0044...3300)))) (0-0.3) EARS awour SNOUT Low set Lo~ seT. sShhoorret LLFd33 0C01.l1l7 F 3 0.01 1LFo2:2 0oo.1mo1 F 2 0.01 0oo-aai (((0o-o1z2os.5)) 0-1 (0-0.9) oo0-ani (((00o--46o.22n)) 0-1 (0-0.3) Avaanc LFLa11 od0.weOss6 oo0-aa1 (((o0o-64o..0ol)) F 1 0.00 o-i (0-0.3) . enuare PALATE rere Cleft LLFoLe4 oc0.me23 oo0-aa-I ((04o-45s.5))) F 4 0.02 o-i (0-0.4) L7L::o LrrIeTrATLErRTIaeNwTCcDIiDomEmNNvECeEr F: FETAL INCIDENCE 10 171436 22778888..00225566 MAI0083374 3MA10083374 441188-0-101 1:P1A:GPEAGGG--E77 SSTUIMMMAARRYYOOFF P~EETTAALLEmEXrXTTEERRNNAALLAALLTTEERRAATTIIOONNSS CDRAT auALTTEERRAATTIIOONN aJAvWsS Micrognathia Micrognathi& AAggnnaattnhiiaa BsOo0DYY dean Ed~ GUembbiilliiccaallheherrantiaa GaGassttrroosscchhiismiiss TTrruunnkk mshhoorrt~. sSppiinnaa bbiitfiiddaa EExxtttrrraaadil1ni~gmmbbfrpporroom--back MHe-mmtaarttuodonimana.g from back PPLLAACCEENNTTAA Ealarged Enlarged rFOoRrEeLLInMmBSSTwodigits presse Two~onndfifogorire~epmpeapwrrement NoamaRAvNGaE N % N LLrss5 000.202929 000-11i FLFLFr 51111 00000...0000060260 00000---11IiI LLr o222 0oo.Immi 000-11i LFLFI 2777 0000...00443100 0000---a1I1 LFFL 1171 0000..00000636 00o0--1aii LLFroa313 0o00..1o107l70 0000--222i LLFFP 1131 0000..00000616 0000--112i 1LF7 1111 0000....00000606 0000----111i LFFL 1111 0000..0000s006 0000--11ii F 1 0.00 0-1 LL i11 o00.o00os6 00o-aai F 1 0.00 0-1 LLFP 111 000..000066 000--1I1 F 1 0.00 0-I //SsTTUaoDDYY % (((00a-04.5.35))) ((((0000---0011.22.3..9)55)) (0-0.9) (((00-044...455))) ((((000O---1011.6614..))77)) ((((0000--044i....200I))}) ((((000--9-09.0..3721)))) ((((0000---4040...10702)))) ((((0000----0064..0.2545)))) ((((0000--0202....2444)))) (0-0.2) (((00o-1o166d..)77)) (0-1.1) (((000--044...333)}) (0-0.3) HINDLIMBS RRoottaatteedd LL 111 00o.0o06o6 0o0-1ai (({000--044..200))) F 1 0.00 0-I (0-0.2) ANUS NNoo ooppeenniinngg pprreesseenntt rLL 222 0o0..o11n11 0o0--a1i (((000---480..455))) F 2 0.01 0-i (0-0.4) LL7+:: LLFIIETTTTTALEERRINIINCNCICIDIDEDEENNNCCCEEE F: FETAL INCIDENCE 10 171437 2277888..00225577 33MMAA1100008833337755 441188--001111::PPAAGGEE GG-88 SSUTMAMMAARRYY OOFF FFEETTAALL EmEXaXTrTEERRNNAALL AALLTTEERRAATTIIOONNSS CDRAT AAuLTTEERRAATTIIOONN = TAIL Threadlixe genesis pe Sshhoorret. constricted BN oy% rL s5 o00..z2259 LFr 33 00o0..011o27 L 11 000o..l000o016s 1r 22 00oo..oiu0ri0 r 11 00oo.ol00os16 0.00 RANwGE w /sTUDY N 000-111 (((000---550..1338))) 000o--1a1i ((((0000---0044...5345)))) 0000--11Ii ((((0000---.0404...5354)))) 000o--1a1i ((((000-o---04l0..343y))) 0000--11Ii ((((0000---2020....4342)))) 0-i (0-0.2) LLF::i LLFIIETTTTTAEELRRINIICNNICCDIIEDDNEECNNECCEE F: FETAL INCIDENCE 2277888..00225588 10 171438 33MMAA1100008833337766 441188-001111::PPAAGGEE G-9 | STORY OF PETAL@SOFmaTrTISSUE ALTERATIONS rP+aEzRsIotOonDnes nczoDEDsJUoNeE 11999955 -- sJUoNwE 1199939767 +### LSLrITIeTUTTTDToEIEsREReSSSs EEEIXXNAArCMNLIInONNDEEe~DDD e8oo4e315s6 # FETUSES EXAMINED 6091 AAuLTTEERRAATTIIOONN ovo RRAawNoGEE//SSTTOUDDYY mam BRAIN Lateral vemtricles, LatmeordaelratveentdriIlcslteieo,n N N IF 11 000o..110222 000---11i (((000--330.o.446))) LLaammttoeaedrrreaakrlleadtvveedenintdtlrriaiiltccailltoeeinsso,,n PL 1100000...2011222 0000---1Ii ((((0000----0044.1..6262)})) hThim`irmaraerdrkkevveedednnttddrriiiillccaalltteeii,,oonn LFo1l 0000...2100222 0000--11i ((((0000----0044...2662)))) LLaatmtieaecrrrlakaellesd,aandnddiilrtatrhtheiiigrocudndlavrvelenyntt--| L 0.02 1 0.12 orhiecpleesd, irregularly LF11 00.212 0-I (0-0.6) 000--a11 (((000---044...622))) shaped F 1 0.02 0-1 (0-0.6) pes EYES Microphenaiata Microphthalmia LLr 333 000..033s66 000---1I1 (((000---440...006))) F 3 0.05 0-i (0-0.6} PALATE ronauE TONGUE cCllaerfet saat Absent LLr oz22 o00..o2264 F 2 0.03 LFL 11010.2212 LFLro11 0000..2001222 F 0.02 000--111 (((000----04.8.600)) 0-i (0-0.6) 000-121 (((000---404.633))) 00o0--aaI1 ((((0000----0044...0660)))) 0-1 (0-0.6) JAW nicrognathia LLro1i 0o0.21z2 00o--ai1 (((000--04.0.006} F 0.02 0-i (0-0.6) . marr HEART septal defect L102 0-1 (0-00) Sepia1 defec~ ro1 000..001222 000--111 (((000---040...606))) LLF:i: LvLEIITTTATTLEERRIIINNNCCCIIIDDEDENENCNCECEE F: FETAL INCIDENCE 10 171439 22778888.00225599 I3MMAAT100008833337777 441188--001111':.PPAAGGEE GG--1100 SST~I0U~RRYY OOFF FFEETTAALL@SSOOmPFaTTrTTIISSSSUUEE AALLTTEERRAATTIIOONNSS CDRAT VvEeSssSeELLsS AALLTTEERRAATTIIOONN Inncainate, absent IInnnlsoaatmieinnaattee,, aarriisseess oonn sSuuabblbccesflletaanvvtiiaann aarrtteerryy,, DDuu`ccat~buussesntaarr~teerriioossuusa,, Ubmedbabiibislslpieilcncaataclleadarrtteerryy,, Ssiittduuissspliianncvveeedrrssuuss AAoorrttaa,, d~essoceennddss ttoo rriigghhtt PPuudllemssoocnneaanrrdyysaatrrttoeerrzyyi,,ght bdbeeesnhciiennndddsasootrrottaaright NovoRwaNGE/sTUosDY N N LLr 888 000..199355 LFrI 8111 0000...1132223 FLLF 11i1 0000..2001222 LFL7 1111 0000..2001222 LLFro21a001 0101...0118288 FLL II111 0000...1120228 LFFL 1111 0000...00112222 F 1 0.02 000--222 (((000--188...200))) 0000---1211 ((((0000---0414....6020)))) 0000----1111 ((((0000----0303..1.6464}))) OO00---11i1 ((((0000---0303.i..6464)))) 0000---2221 ((((O000--8108....3263)))) 0000--112i ((((0000---0144..1.6222)))) 0O00----Ii11 ((((0000---0404....660O)})) 0-1 (0-0.6) FLL 111 000..011222 000--11i (((000--044...600))) F 1 0.02 0-1 (0-0.6) LUNGS RRiiggihhnttd aadppliiaccpaahllr,,agcmcaeatrriddciiaacc Inaltlnoeodbbreemssdeldaaaipppaptpheeeraaerr~lmoabaaetss,icoonnee I`naatbbeasreemnnettdiate lobe, LPLF 111 000...110222 000---111 (((000--440...006))) FLLr 111I 0000..220122 0000---1111 ((((0000---0044....6600)))) F I 0.02 0-1 (0-0.6) BODY dens LLr 111 00o.21z2 0o0-a11 (0(000--.40..600))) F 1 0.02 0-1 (0-0.6) AAmBpDoOwMIINNAALLsCCiAatuvVsIITTYYinversus of liver, Sits~iupnnsltteeeeBsinttn,Eivnnepeera8ssn,,uc8rsseottafoosmmaaalccinhhv,,edr, IL Kksipidldneneeenyy,ss pancreas and L*F 111 O00..011222 000--1i1 (((000--044...600))) 1 0.02 0-1 (0-0.6) . KxIzDoNnEErYsS Pelvis, slight dilation L 1 0.12 0-1 (0-3.7) Pelvis, slight dilation LFF111 000..21022 000--1i1 (((000--030...676))) L7L::: LFLIEITTTATTLEERRIIINNCNCICDIIEDDNEECNNECCEE F: FETAL INCIDENCE 10 171440 2277888..00226600 33MMAA1100008833337788 441188--001111::PPAAGGEE GG--1111 SST~IMGMAORRYY OOFF FFEETTAALL@SSOOmFFaTTrTTIISSSSOUEE AALLTTEERRAATTIIOONNSS CDRAT AALLTTEERRAATTIIOONN SsPpLeEEwN Avmane. Absent nerRs Distanded Noyoo`RRAmaNNGGEE//SSTTUUDDYY N % N LL7 121 000..101222 000---I11 (((000---440..500))) F i 0.02 0-i (0-0.5) L* 223 00o..l22s64 000-232 (((000-887..77))) 3 0.05 0-3 (0-1.7) LL7:e: LLFEIITTTATTLEERRIIINNNCCCIIDIDEDENENCNECCEE F: FETAL INCID~C~ 2277888..00226611 10171441 33MMAA1100008833337799 441188--.001111::PPAAGGEE GG--1122 SSTUIMGMMAARRYY OOFF FFEETToAALL SmSaKKrEELLEETTAALL AALLTTEERRAATTIIOONNSS CD RAT pPrERRsIIroOmDDizs mcLoDED ##++ LLrSIreTTTrDTDruEIEsERReSSss EEEIXNxA~mxMLaIENNDeEEEDDD # FETUSES EXAMINED JJUoNnEe 11999955 -- TJOENNEE 1199993775 a882823005 6318 AuTERATION Xoaoawnor/STUaDY SsKUxLFFLrroonn~taall((ss}):A:LTEiIRnnAc=TooImmOppNlleet~eellyy oorr not ossitied LL r N 222 000..022364 000--11I (((000-40-.4..262))) PPaanrroii~eettaaolls((smsi))f::iednnoott oosmssiiffiieedd FLrI 2222 0000...00223344 0000---1Ii1 ((((0000---0-440....6226)))) NNaassaall((ss)):: smhhoo~rtt LLFr 3233 0000..0033s36 0000--1ii ((((0000--40-04:...2662)))) BBaasominisssippfhhieeenndooiidd:: iinnocoommpplleetteellyy ILFrL 3111 0000...00112522 0000---11i1 ((((0000----0440...5600)))) Sspphoheesnnsooiiifddi::ed iirrrreegguullaarrllyy sshhaappeedd LFTL 111100000...2101222 0000---11Ii ((((0000---0046...5500)))) _"_ o4r~b,~i-t~s-- emalk -S~a-1--1- ....................... 1LF -221 0 00..0023.000--2 13i(0((0044 -0.0..065))) MMaaxxniiollrlleaaee aanndd Pprre@mmaAx~iillllsaee:: LF 2333 00O0..03O3s636 0O00-.-111i ((((0000-----0046...2662)))) SSkkuu`snllhollot::rtossiiinntcciooemmdpplleetteellyy oofr ILF7 3232 00o0.l.20o26s54 0000--21iI ((((0000----4041.1.2622)))) SSkkuunllollts: ommffiuufsseiededd FLL 1311 0o00..201z52 0000--112i ((((0000--4014....0520)))| F 1 0.02 0-1 (0-0.5) VVEERRTTCEEeBBrRvRiAAcEEal: Cervical: Thoracic: Thoracicz . AArrcchh,, ooppeenn Fruumseedd CCeennttrruumm,, bbiffiidd CoCeesnns~tirrfaai,,cautuniniiollnaatteerraall ossification LLr 111 000.20122 LFL 1111 0o00..20z122 F 1 0.02 1LPo77m11 oa88..6666 LFL 77888 1000...12993288 F 8 0.13 000-11i (((000-404...050))) 000o--1ai1 ((((0000----0440...5500)))) 0-1 (0-0.5) 000--988 (((000---224997..)66)) 0000----9222 ((((0000----8481....0700)))) 0-2 (0-I.0) Cinieonnntcctoozom%msp~slp,eiltteeitleydeoloyrr not ossified LL 33& 000..36366 000--322 (((000---881..833))} F 4 0.06 0-3 (0-1.8) LL7e:: LLFIIETTTTTAELERRINIICRNICCDIIEDDNEECNNCEC~E F: FETAL IMCIDENCE 10 171442 2277888..00226622 33MMAA1100008833338800 441188-001111:PPAAGGEE G13 G-13 SSUTMOMARRY~ OOFF FFEETTAA@LL SmSaKKrEELLEETTAALL ALTERATIONS ALTERATIONS CDRAT savas/sTooe vemonraacis(c(AocuLzorTE)nEstRa)ATTIIoONN 1 Gti) tases FN EE 11a oa 0-2) + acon, open Thoracic {cent- } Centra, fused LLIPFPoio1111clo000...aom101222 oooo--aaI1 oo-a1 o(((aoo00---oo404o...mm250))) : Arch, open + acon, small : Arch, small FLIPodl11 o0o0a..0n1m22 o0oo--a1ih(a(00o--03e.os54)} [ALumbar~ Can=rum, --bifld + concen, fused F 1 0.02 LFLLoolz22io000o..ena20s43 o-1 o0o-1a1 ((0oo3--0.o3..8m58))) 0a-1d(oe-o.n5) : : . CCcCeeonnnntttrrrauu,mn,,tfuiiesnneccdooammpplleetteellyy LFLTI ol11223 Le mimmecely FI 153 0o000a....a1022sm224 01..0853 0oo000----32i21 i((((o0000-----4L808e...w3633))))) 00--33 ((O0-1Z2..S0)) or not ossified : Arches, inco~pl~cely oTAchpreesetntrea or not ossified LFFLLPoMh21l511 0100oS...3831em3332 0-3 (O-12.0) 04 (02.1) 0-4 (o-2. z) eoi aoome o-i (0-4.3) : + IA,cehp,resoepnetn : ACcroecnihtf,einc.oaptewinnoilnaterat FLIFTI oi1112lto0000....eE01022228 HE 2 0.24 o-i (o-o. 5) odie o-1 (0-4.0) ou ioas o-z (0-0.5) 0p-1 e(08e.2) 0--I (0--4.2) : [IR Centra, unilateral -- ossification L F 2 0.03 LLPooa1 l0o.oa12 o-I ooo-aaI (e(i0oe--a04o..d63e)) +.- Aarccohn,, open open DPooEm F 1 0.02 L 1 0.12 ooood--ii1e a((00--40n..06)) CCaausdaalls: None present None present + 1, present F 1 0.02 LLFPLolao11 o0o0h..wo10a22 o-i (0-0.5) oa 0a 0-1 (0-4.3) ooaa (ooees 0-1 (0-0.6) : l, present Pola L 1 0.12 1 0.02 on woe 0-1 (0-4.3) o-'z (0-0.6) F RIBSServet mice) present Cervical Rib(e) preaant one ox more, vivy Oonneeor osoosrrxife emmiooerrdoees,,sp(ihifiyoninpcsoeropedmlaaappsltlteelettcee),ll,yy L1F:.i LwrIeroTarTesEnnRom~IceNrooCsIomsDmiEiefNziCceEd F: FETAL INCIDENCE Lm sre os (020.0) L 31 3.78 0-5 (0-20. O) Dhoom os oz) F 32 0.51 I 230 oo osm L 44 5.36 0-5 (0-2.7) 0-7 (O-31.8) HE rete F 73 1.16 0-15 (0-8.3) 3) 402 0-5 (0-227) L 33 4.02 TS da os oso F 53 0.84 0-5 (0-22.7 } 0-9 (0-5.0) 10 171443 2788.0263 2788.0263 3aMMAAt1o0o0e8a3s3s8:1! 441188--001111::PPAAGGEE GG--1144 .Sq UM~AY RY OOFF FBEETTAELL SSKKEELLEETTAALL mar AALLTTEERRAATTIIOONNSS Rass (cont.auALTTEERRAATTIIOONN used R~BS (CONT.) Fused Ssppaltiet vo segments NovoRRwAANNNGGEE//SSTTUUaDDYY LL 333 000..033s65 LLFr 2322 00o0..l202o6543 LFrL1211 0000..220132 F 1 0.02 000--.I11 (((000--.440...336))) 0000---a1i1 ((((0000----0404..0.6050)))) 0o00--aii ((((0000---0033..5757)))) 0-1 (0-0.5) MMAANNDUUuBBpRRlIIiOUcNMated Duplicated LL? o111 000a.01222 000--111 (((000--303...848))} F 1 0.02 0-1 (0-0.4) sSTTEE`RRoREnEeBBRRoAArEEmore Lncompletaly DOunpGeolesissociriafftmiieoeerdddeoorrLncnmooottmpolosesstsieilffyiieedd Dupli=ated rFuusseedd AAeeyymmomeettrriicc LLF111161644 211.336..09900 00-0-1-771 (((000---633.332..)33)) LFLr1o1641 0020..2016220 000-0-1-1111 ((((0000----6303...8428))}) LFL1111 0000.2. 02122 0000--a111 ((((0000--03301...7547)))) LLFF 1111 0000..2001222 0000--a1iI ((((0000---0044...2552)))} F 1 0.02 0-I (0-0.5) PseErLvVFiIusSbis(es) and/or Tachium(a): Pubiinsc(oemsp)leatneldy/ororInmoothiuoms(sai)f:ied LFL121323949 PPuubbciiinuemcsc(oieemfsmpi))le::edteliiynncoooormmppnlloeett~eelolyyssified FLL7112128214s44 Psuuobbimissm((ieefsmi))e::d nonott oosmssiiffiieedd FLFLo18s588 ZIas`ccohhxiiuunamo((ta&})c=:esifiiinneccdoommpplleetteellyy LFrL o55008 or not ossified F 70 311.665..49955 00-0-1-996 (((000---933.990..)11)) 3112.3.359..439900 00-00-1--16996 ((((0000--38935..9.90.1))1)} 2000..19993838 0-000-1--3363 ((((0000---1-1183.3..6.96)}6)) 0661...11111300 0000---0344 ((((0000---6111..6676..))77}) i.ii 0-9 (0-47) rFOoRrENsLeLIt1MamBcsSarpale: 1, present MetaoarlDalB= I, present += 22,, ppEreessesnntt Froorreeddiigglittse:: 22,, pprreesseenntt FPoorreepphhaall~annggeess=: I1,, pprreesseesntt LFL11 000.20122 LFL* 23 0000..2001222 LLFFo1: 0000..2101222 LrL 11 00000....0010122222 00O-a1I (((000-0-4.6.633))) O000--11ii ((((0000---0404.0..6363)))) 0000--11iI ((((0000-----0044...3663)))) 0000---1111 ((((0000---0044....6363)))) 0-1 (0-0.6) LL7i:: LLFIIETTTTTALEERRINIICNNICCDIIEDDEENNNCCE~E F: FETAL INCIDENCE 10 171444 2277888..00226644 33MMAA1100008833336822 441188--001111::PPAAGGEE GG--1155 SSTUMMMMAARRYY SOOKFFELFFEEETTTAAALLL OAOVSSESSRIIAFFGIIECCSAATTIIOONN SSIITTEESS (CABSAREANS-KSEELCETTAICLDOEARmDVAaETDrRAAYGE2S0 GESTATION) (CAeSAREAN-SECTIONED DAY 20 GESTATION} PP+EERRsIITOOuDDp::rEs mrcLuJoDUEnNDeE 11999955 -- JJUUNNEE 119999377 ##*+ LLSrrITETTUrTTDUEEIsREREsSSs BEEIXNOoACMMLIvIUNNDEaEEDDD 977763223 # FETUSES EXAMINED 5944 SSK~ErL.ERTTAALL AAVVEERRAAGGEESS saVHvYEoORrITDEBRAE VER`TTCcHEEaOBRmRRVvAAIiCECeIAaCLL sLTLaoHUcwOMrmRBaaAACRRLIC RIcBaSSCuAACUb(RDpAAAaLLLirs) R`SITSBHETSRAENRRUU(NMpBaRiIrOsH) MSxSAzTTNpEEUHRRoBNNIRAADILLUMCCEE/NTTTEERRSS FFoORREEXPPIAAPRHWSOSIDa((vCCeaarllaccguuellaattpeeedrd aalmsimb) McEaCATnRAsPCaAAzLRsSaP.vAeLrSa.ge per limb) PbMDuiEInaTGLrAIAzCTNsASGREPSALS HHIINXDPDPHPAAALWNASSNGa((EvCCSe~arilaccguuellaaptteeerdd aalsmimb) MTETaATRRASsTAaALLRSasSvAeLraSge per limb) MDPoErIEGTGAIAILTTTASASR.RGSEASLS PHALANGES hraaanTos/uRxATNTGEER/STODY 0.86 (0.69-0.95) 0.84 (0.69-0.95) 1737.0.000003 1s353i..09090377 1d342..e080s230 13.02 (12.9-5----13.15) (((15(252.:5.9.895659---63-61...o030o00.1))) 5) ((((4218..2339.55695--953.-..12203110.)0)) 8) (12.99-13.o8) 311..500700 (((o30...929868---131...o80o50))) 30i..s59s79 (0l94-1.00) (3.26-3.85) (o.94-1.oo) 0F0..0C000 -- 3555....40009005 ((34..3930-=3..2672)) 5.05 (4.90-5.27) 0a0..i00s00 -- (3.90-4.00) s355...9e00900 (e37.9r3=-s4.a04n) 4.96 (4.77-5.13) 2277888..00226655 10 171445 33MMAA1100008833338833 441188--001111::PPAAGGEE GG--1166 $S0TMIMMAARRYY OOSFFKEFFLEEETTTAAALLL AOOSVSSESIRIFAFIIGCCEAASTTIIOONN SSIITTEESS (CAZSAREAN-SSKEELCETTIAOCLNDERmADAaVTErDRAAYGE2S1 GESTATION) (CAES~-SECTIOII~D DR~Y 21 GESTATION} pP+rERRszIToOoDDo::rEs 1RCLODJsEOoDnNe~ 11999955 -- JJOUINTEE 119999772 ##++ LLSrIITeTTUrTTDoIEEsERReSSSs EEEIXNxXACuNMLaCUIiNDNEEEEDDDD E34n82 # FETUSES EXAMINED 374 sSxKmeLLEeTTAALL AAVVE~RRA~GEESS avHoYROrTIRDSRAR VERcmTCao~EmERBRvRaVAicIEeICAacL: sTLLaBUocOMwrRBmaAAaLCRnIC RIcBSSCaAACUm(RDpaAAaLiLrs) RsSITeHBESARmNNU(TiMpBaRiIrOs)N MSxSAzTTNpEEUERRBONORIALIDLUcMCoEnNTTEERRSS FFOORRXEEPIPAAPWWHSSOIDa((vCCeaarllaccguuellaattpeeedrd alassish) McaECArTReAPaCALALsRSa.ZvAeLraSge per limb) PMDbHEIrATGeLAIIATCTNsSAGREPASLS HHIINNDPDPPHAAAWWLSSANGa((ECvCSaealrlcacugulelaatpteeedrd aa1ssisb) KTTEaATnRAsSTaAAzLRsSaSvAeLrSa.g~ per i ~ mh) spuMDrAI~eGTzrIATaTTsNSAGRESSALS P~J.ANGES mFrn~rTrUuSs//LLRITATTNTEG~RER/STUDY RANGE/STUDY 0.97 (0.96-0.97) 0.97 (0.96-0.97) 1773..000O00s 13355...0099046 12373...44006603 13.03 11s..00e00 311..090080 ((1(1533...900422---511.339.8.00)66)) = (5.94-5.98) (((7113..2.33017-7-.1.6637.7)0) 8) (13.01-13o05) -- ((33..9977---33..9988)} 003..00800 -- (3.98-3.99) 3T55...e900e080 ((31..9883-----73..7959)) 7.64 (7.53-7.75) 004..600122 (4.60-4.62) 455s...e600e100 = (4.60-4.62) (5.78-5.89) 5.84 (5.78-5.89) 2277888..00226666 10 171446 33MMAA1100008833338844 AAPPPPEENNDDIIXX HH SSTTAATTEEMMEENNTT OOFF TTHHEE SSTTUUDDYY DDIIRREECCTTOORR 2277888..00226677 1100 117711444477 33MMAA1100008833338855 rPri O2PRIMFREIMDEIDCICAA -_ PPRROOTTOOCCOOLL 418.011: 418-011: 441188--001111:PPAAGGEE HH--11 Se cn,PA 19080 AArmg0us5s RReesSsheeeaashrrycchh DLLraaibbveoo,rraBatuoitlrodiicnegsi,cIsn,cA. 905 Sheehy Drive, Building A Hotsham, PA 19044 Telephone: @15) 443-8710 Telephone: (215) 443-8710 Toefax: (215) 43-4587 Telefax: (215)443-8587 OSORTRAUALDLY((GGOAAFVVNAA-GGEEEI))FDDOSEEEVVEEINLLOORPPAMMTSEENNTTAALL TOXICITY TOXICITY SSSPTPUOONDNSYSOOORRF''SSN-SSETTtFUUODDSYYENNIUUNMMRBBEAERTR:S: T-6316.7 T-6316.7 SSTTAATTEEMMEENNTT OOFF TTHHEE SSTTUUDDYY DIRECTOR DIRECTOR TTofhhitissheffiinsnatalul drryee.ppoorNrttoaacsciccguunriraaftitecelalnyyt rrdeeefflvleeiccatttssiotthnhese raw data frarowmdtahtea Uoo.bbStt.aaiiFnnoeeodddddauurnriidnnggDrtthuhege performance performance `oAJAfaddtpmmhaieinnniesissstttuerrdaayttMii.ioonnniNs((otFFrDysDiAAgo)fn) iGHGfieocoaaoolnddtthdLLaaeanbvbdoioarrWtaaieottloonfrrsayyrfrPPeorrmaa(ccMtttHihicceWee)URRe.GSegog.uoulFadlaottoLiiodoannbasos;nr; daFFtiiDonnraarluyl gPRRruuallece"t",i, cttehhee J(S`aSEttapEanaCndn)daeaCrrsoddeuffnoMocrriinSSliasadftefreecyttiyyosifSSotHtnuueddoaiinelethss28ooannnJduDDlrWryuugge1ssl9fba8r9aaennodd(nMttthHhheeWe EEa)ucuGrcrooeopppoeetdaaaLnnnacEEbecocbooryanntootomhmreiyiccEPuCCrraooocmmtpmicemueanunintityy Ep(EErcciEoonCncnioo)pmmlCieiosccouCCfnocogmimlomdomuednucilnisatiitboyyonrooafoftnaaonnr2y8OOpErJEauCCclyDDtid"dce!9eec8ico9sicsicoioounnnr/rt/hrreeeedccaotohcmmacmtmeeapenftndafdeancatctiteeioodbnntyohotennheqccuooaEmmlupirptloyliipaoaenrnaccnee with with piinnrttieneggcriripittlyyeosoffottfhhgeeossottduuddlyay..boratory practicec occurred that affected the quality or JA AN 1z-pese nd G. York, Php. DABT Date AasnsdocSitautdeyDDiirreeccttoorrof Research and Study Director 1100 117711444488 aao URUeS.Sg.u.lFFatooioooddnsaa;nnddFinDDarrluuggRuAAldedm.min2iin1sitsrCtarFatitRioonnP.a. rtGGo5o8oo.dd Laboratory Laboratory Practice Practice b. JRPJraaeappgcaautnnilaeectessioeeSntMMsai;nninFidisisanttrrandylj fRoooffurHHleSeea.afale2ltt1thhy CanFdRWePlafratr5e8.(1988). Good Laboratory aSntdudWieeslfoanreD(r1u9gs8,8)M. HGWooOdrLdainbaonracteory PNNEuuruarmmcobtbpieceereran22S11tE,a, cnMModanaarorrccmdhhifco2266rC,,So11am99fm9e9u7t7.yn.iSttuyd(i1e9s89o)n. Drugs, MHW Ordinance Council decision on 28 July co EO1199uE88rCo99pDooennadenttchhiEeescaaiococncnco/eemrppetticacanonCmccomeemebbnmyydauttthnhieeitoynEEu(uo1rrn9oo8ppc9eeo)aam.nnplCEEiocacuononcnnecooimlmwidiitccehcCCipsoroiimomnmncmuionpunlinet2isty8yoofoJfugfalaoynnod llOLaaebEgbiooCsrriDaaatttooidorrenyyc.ppisrriaa3oc2cnt(ti/iNcrceoee..c.oLmOOf3fmffi1icce5ii;naaldl2aJJ8ootiuoOurcnrtnnoaoablnlerooc)ffo:ttmhheep1-lEEi1a7uun.rrcooeppeewaaintnh CCpoormimnmcuminpiultenisiteiesos:f:good Legislation. 32(No. L 315; 28 October): 1-17. 22778888..00226688 33MMAAT100008833338866 AAPPPPEENNDDIIXX |I QQUUAALLIITTYY AASSSSUURRAANNCCEE UUNNIITT FFIINNAALL RREEPPOORRTT STATEMENT STATEMENT 2277888..00226699 1100 117711444499 amAto083387 3MA10083387 441188--001111::PPAAGGEE 1I-11 PPRRIIMMEEDDIICCAA HS Se Ses Argus Research Laboratories, Inc. 905 Sheehy Drive. Building A Horsham, PA 19044 Telephone: (:215) 443-8710 -- Telefax: I215) 443-8587 QQUUAALLIITY ASSURAANNCCEE UUNNIITT FFIINNAALL RREEPPOORRTT SSTTAATTEEMMEENNTT Sty Director RaymonGd. York, Ph. DABT Study Director: Raymond G. York, Ph.D., DABT EExxeeccuuttiivvee DDiirreeccttoorr ooff RReesseeaarrcchh:: Mildred S. Christian, Ph.D., Fellow, ATS Mildred S. Christian, Ph.D., Fellow, ATS protoco1 416.017 Oa ral (GavagSet)uDy NeumvbereTl9T1oox6ic7pitySmtuedyonf Nt-EaIFOlSE Protocol 418-01 "~: Oral (Gavage) Developmental Toxicity Study of N-EtFOSE iinn RRaattss. Sponsor's Study Number: T-6316.7 DIrmeo crt prtd ofocr neisstucyLwaabosraatuordyePrfaocriacdshRereegnucieto0nUsS,.JapFaonoedse The draft protocol for this study was audited for adherence to U.S. Food a0 DrugAer vy ood Laperaary Pras Standard fo and Drug Administration (FDA) Good Laboratory Practice Regulations, Japanese a a nagean Seonom Conmunty (1968) coun Ministry of Health and Welfare (MHW); Good Laboratory Practice Standard for Beon I echamontaton on cmpiancs wih princes Safety Studies on Drugs, and European Economic Community (1~)89) council decision on 28 July 1989 on the acceptance by the European Economic Community of an OECD decision/recommendation on compliance with principles of good laboratory practice on 13 JUL 98. Crtiont phases of te study wera nspeced ve mos; suey formation Critical phases of this study were inspected five times; study information re ase ep and 2 of dates nd shasesiiae) and raw data were audited twice (see tables 1 and 2 for dates and phases/data). he draft report ae th ra data for is sudy except or The draft final report and the raw data for this study [except for pBeD ES wewehocsomwpaatrecdonadnacaedusheorsaccpourfaGcroy,odor Appendix F, the Pilot Report, which was conducted in the spirit of Good Laboratory ee ry Proc Regulation. Japanese Mini aaddhheerreennccee ttPoorappcrrootittcooeccoo(lGl rrLeePqq)uu]iiwrreeemmreeenntcstos,m, aapnnaddreffdoorraaandddhhaeeurredenintccedee tfoo rUa.Sc.cuFraocoyd, to U.S. Food afonrd and Drug Drug Bo as ons Laverton Prcien Sanaa for Sey Administration (FDA) Good Laboratory Practice Regulations, Japanese Ministry ea a a rome Commanty (1659) sound deciin of Health and Welfare (MHVV); Good Laboratory Practice Standard for Safety Se oe EO re Europea Evaro Commun of an Studies on Drugs, and European Economic Community (1989) council decision ED Wo 58 an 02 DEC 56, and or tevons on 28 July 1989 on the acceptance by the European OECD ddeecciissiioonn//rerceocmommmeennddaattiioonn oonn ccoommpplliiaannccee wwiitthh Economic pprriinncciipplleess Cofogmomodunity of good of an laboratory practice between 12 NOV 98 and 02 DEC 98, and for revisions ; rreequestteedd by tthhee SSppoonnssoorr oonn 1100 DDEECC 9988 aanndd 1177 DDEECC 9988.. 22778888..00227700 10 171450 3MA10083388 441188--001111::PPAAGGEE II--22 AdminisTTthrhiaisstissottnuudd(yyFDwwAaa)ssGccoooonnddduuLccattbeeoddraaatccoccrooyrrddPiirnnaggctttiooceUU..RSSe..guFFlooaootddioaansnn,dd JDDarrpuuaggnese Ministry Administration (FDA) Good Laboratory Practice Regulations, Japanese Ministry SoooSftnftuuHH2ddeie8iaeealJsslttuhhoolynnaann1DDdd9rru8uWWg9gesosel,,fnlfaaaartnrnehedde((EEMaMuucHHrcrWoWoe)ppp):eet; aaaGGnnnoocEEooecddcbooyLLnnaaootbbmhmooeirirccaEatuCtCoorororomyympmPPemurarnauancincttEtiitiyccyceoe((n11SSo99ttm88aai99nn)c)ddaaccCroroodudumnnffcmoociurrillnSSddiaaeetfcfceyeiitstsyoyiifoonan n on 28 July 1989 on the acceptance by the European Economic Community of an (lOaOEbEoCCrDaDtoddreeyccipisrsiaiocotnni/cr/eer.ceocmommmeennddaattiioonn oonn ccoommpplliiaannccee wwiitthh pprriinncciipplleessooff ggoooodd laboratory practice. 2 3 `Barbara J. Peklefson, BA. DainredctCoormopfliOpaenrcaetions. and Compliance Ie ars:wu' [7bdesc Date HeatheLr Rabuttino, M.S. Date and Principal Auditor QQuuaalilittyy AAssssuurraannccee SSuuppeerrvviissoorr and Principal Auditor 22778888..00227711 10 171451 MAI0083389 3MA10083389 TTAABBLLEE 11 CCRRIITTIICCAALL PPHHAASSEESS IINNSSPPEECCTTEEDD 441188--001111::PPAAGGEE II--33 CCoohhaabibtitaattiioonn DDaattee ooff iinnssppeeccttiioonn:: 2211 AAUUGG 9988 DDaattee rreessuullttss rreeppoorrtteedd ttoo tthhee SSttuuddyy DDiirreeccttoorr aanndd MMaannaaggeemmenetn:t: 2211 AAUUGG 9988 TTeesstt AArrttiiccllee PPrreeppaarraattiioonn DDaattee ooff iinnssppeeccttiioonn:: 0022 SSEEPP 9988 DDaattee rreessuullttss rreeppoorrtteedd ttoo tthhee SSttuuddyy DDiirreeccttoorr aanndd MMaannaaggeemmenetn:t: 2288 SSEEPP 9988 TATeesdstt AAmrritiicclleenAidmsintistrratiaont--GGiaavovaagngee DDaattee ooff iinnssppeecctitioonn:: 0033 SSEEPP 9988 DDaattee rreessuullttss rreeppoorrtteedd ttoo tthhee SSttuuddyy DDiirreeccttoorr aanndd MMaannaaggeemmenetn:t: 2288 SSEEPP 9988 BBllooooddCColollleeccttiioonn DDaattee ooff iinnssppeeccttiioonn:: 1100 SSEEPP 9988 DDaattee rreessuullttss rreeppoorrtteedd ttoo tthhee SSttuuddyy DDiirreeccttoorr aanndd MMaannaaggeemmenetn.t: 1100 SSEEPP 9988 GCaaeessaarreeaann--SSeeccttiioonniinngg DDaattee ooff iinnssppeeccttiioonn:: 1100 SSEEPP 9988 DDaattee rreessuullttss rreeppoorrtteedd ttoo tthhee SSttuuddyy DDiirreeccttoorr aanndd MMaannaaggeemmenetn:t: 2288 SSEEPP 9988 22778888..00227722 10 171452 MAI0083390 3MA10083390 441188-.001111:.PPAAGGEE 1I-44 TTAABBLLEE 22 RRAAWW DDAATTAA AAUUDDIITT((SS)) 0n 0TT8hhOeeCffooTlllol9ow8w,iinnaggnssdttuu1dd5yyOiinCnffToorrm9m8aatttiiooonn17aannOddCrrTaaww98:ddaattaa wweerree aauuddiitteedd on 08 OCT 98, and 15 OCT 98 to 17 OCT 98: PPPrrroootttooocccooolll. amendments. LELPirirssrottotrooofcfcopoplederaerssmsooenannnnneddelml caaeonnndddtescsc.oomfmoprupctulietenrircoaoplpeseriragatntoororbcsceoorddveeasst.ions. AAEInnnr-iriiommfreaacltlorrrdaeeneccseseaiipcpatttn,,idorrnaacnnroedddcooeomm rsidz.ifzaoatrtiicoolninn,,icppahhlyysssiigiccnaalloeebxxsaaemmrivinanataitotiinoosnn. aanndd aacccclliimmaatitioonn.. FCIFnoee-heelaifddbeitcctraooatnninssosuunam.mcpttpioitiononnr..ecord. CMCCaaoateheesasraabnrraeitelaaantgin-ors-nose.secscttioioobnnsieinrnvgga.tions. FFMFeeeatttaataelllrggfnirraxoolasstgsisrvoeoosbbasssseesorrvibvagsatneitmiroovennanss.tti.ons. FFFFeeeettttaaaallll sfvvikiixsesaclcteeeivrtraaealllaeeesxxxsaaaimmgmiinnnimnaattaeiitniooonntn.... TFNNieeesctcasrroulopespskspyey.al.cektailngexlaismts.ination. GTMMeaisanlsteeeurebbarlrpeeaceecoddkmeeimrnregccnootllilssoo.tnnsy.y rreeccoorrddss.. STGSteteuumnddpeyyerrammalataciuionnrmtteeemnnaaanenndncctsreee.lrraeetccioovrerddshs.u.midity reports. TFEFdeeeieemtddpreeaaqrnnuaddetsuwwtrsaea.tteaernr daannraealllyayssteievses.. humidity reports. DDDEeodovsisitaaartggeieeqonuvvse.oosllutusmm.eess.. DKDDaeaetytvaaifaorrterieovvtniieessew.twfppaacagigelet.y. computer back-up record abbreviations. Blood collection data and packing lists Key for test facility computer back-up record Blood collection data and packing lists. abbreviations. ManT"aThgheee mrreeessnuutllttsosnooff21tthhiiOssCaaTuuddi9it8t.wweerree rreeppoorrtteedd ttoo tthhee SSttuuddyy DDiirreeccttoorr aanndd Management on 21 OCT 98. 22778888..00227733 1100117711445533 MAT0083391 3MA10083391 441188--001111P:PAAGGEE II--655. T"Thhee ffoolllloowwiinngg ssttuuddyy iinnffoorrmmaattiioonn aanndd rraaww ddaattaa wweerree aauuddiitteedd oonn 0088 OOCCTT 9988 aanndd 1100 OOCCTT 9888:: VVeehhiiccllee rreecceeiipptt,, pprreeppaarraattiioonn aanndd uussee.. TTTeeesssttt aaarrrtttiiicccllleee rpreeaccceekiiippntt,g, pplirrseetspp.aarraattiioonn aanndd uussee.. Test article packing lists. TThhee rreessuullttss ooff tthhiiss aauuddiitt wweerree rreeppoorrtteedd ttoo tthhee SSttuuddyy DDiirreeccttoorr and and MMaannaaggeemmeenntt oonn 2211 OOCCTT 9988.. 2277888..00227744 10 171454 33MMAA1100008833339922