Document Xn4v1q5K3aGb7kp66ybZv4OG
PREE T
serors 50. 1610 ores 2/18/60
Oral Toratelony Stuey of PH-3izz in Rats
Experteans No.:
Experiment No. :
contacted ac:
Conducted At:
IInnccliuussiivvee DDoossiinngg PPeerriioodd:
acsommooro
0680TR0010
sSRRaiaiktfkeeeerLrteyynLCEaaEhvbmvaooarltmlasuuavtaanaottnrriiiiooeaennrsss.,LLaabsItoonocrre.astsoorryy
St. Paul, Minnesota
Aust 19 to sepresves 4, 1900
August 19 to September 4, 1980
Study Director:
8Sorin J-23-77
~NSS-ae.i. nnniGiGt..aohrrGGPoRroerea~pts.toneneae~asrrrcuceshneiTTeoeccnhhmnTooellrooengtiiossttotsy DDaattee
Animal Reproducnion-Teratology Study Dir=c~or
E08, Fampudd 1222-8)
EEL .R.iGsGe.a .sscL~hs mVporetp cehrti,r nOorDvyVe M,,FPaPcc RhhDDalh ogit a GD, aattee Research Vet~rin-~ry Pathologist
HWaEaaagsens,stPatT,holsreopoxsolosYy13=/10 ST batuasion rates Manager, Pathology-Toxi=ology
Safety Evaluation Laboratory
11225511..00000011
Exhibit 1251
10 007777992244
33MMAA0000332266772222
GL
F -- y Oral administration of F~-3422 at ?5, 37.5 and 25 mq/kg/day tc ember mens Seems apes woe Sere pets Sprac~ue-Dawley rats durin9 days 6 th~ouuh 15 of ues~a~ion (period reanemsmenle) wus Soraestoms o on evubees Tereionnic chonees or~nogenes~s) wa~ t~ra~ouenic ~o rat fetuses. Teratogenic chan~es reese eee Shmssnation Shot. peters erect sorens mitner included a developmental eye abnormality, clef~ palate, ~lood in ~he kA~ne~ rena coe rites ASemamesane oe Senopoirees rt senarestis) parench~ ~d sternebrae ~Iform~tions. The d~velo~ntal eye abnor~li~y Tereurey te a sent: tu: skostosmem of the orien sont Eopere foreine appeared to ~ ~ ~rest in develo~ent of the Dr~ lens fibers fo~ino a hans ethesen by Seconiry smeretions oF ch the ~nal lan~ nucleus followed by ~econ~a~ ~rratlons of the ery en Eker at the Foci ions nt pooper of focuses secondary lens fibers of the fetal nucleus. The pro~rtions of fenuses prt I gk with ~e lens changes were si~ificantly higher in all FM-3422 ~oups Er Ch conceal `sey. "Clot malstes wire poosuces in che 5 ws 373 in the control group. Cleft palates were produced ~ the 75 and 37.5 aa eagce sresper ALL hres oop oeeivine compos 1d etunes with mg/kg/day groups. ~I three ~oups receiving com~und had fetuses with Three ta ame vets prensa: oe sreceebrer Sonate tiehoren normally b1~d ~n the ki~ey parench~. The 8te~ebrae chanqes, althouuh no~ally ivetoetes skeleton shores: vere vieces ot Someone relies considered skeleton ~rrations, were viewed as commune-related Eeforention. Pecos of foie sewers PHS res peossoes an incrosse malfo~ations ~=a~e of the~ severity. F~3422 also ~roduced an increase en erento ~n other f~tal skeletoo FS ------------------ FH-3422 was not embzyo~oxic and did not affeut ~:he ~arles or reproductive TI tract contents of the dam~3433 was maternadly orks to the 15 and 37.5 ae/ha/dey dose ants dn FH-3422 was maternally toxic to the 75 and 37.5 mq/k~/dey dose animals in jorioinipigrimy Arg rigvt rn yop ogtient re~ucin~ their group mean body welqht oaln durln~ the doslno interval. fpdreind Ait Arab pied Toxic clinical s~gns and ~eaths occurred in ~17 the 75 mq/k~/dsy dose
11225511..00000022
1100 007777992255
33MMAA000033226677223
Rbiios
-
simiticansiy hisher proportion of feshsse wich bipartite stesmebiss than
significantly higher proportion of fetuses wi~h bipartite sternebrae than
Atnheicnocnrtersoeln ~irnouoptoher skeleton sherrations sien occurred as the rest of
An increa=e in other skeleton aberrations also occurred as the result of
Toreseatasmuatm shesaes oF Shs eevLeE ons. meses FM-3422 a~inistration. These skeleton aberrations include~ other nonossification chanoes of the cranial bones and sternebrae plus other TTeiemeintaibioeuemisynahiabbercnapnrcoepseri(iRoensstsof1s.fotaTsoeeshviidthdoav1e aofroaunmem.e skeleton s~ernebrae and rib changes (Table 4]. The high dose oroup had
ShmcssFihiieranugsnnnrogiiiieffEspsSiicccrotaatanhhn~nttaattivnnyllyyTittohhhacheriiag~cgoShhchsemeeoenrrnrtatvarppmesporrekolooo.eeppPrroaoo~urrrrrototteouiiLmppooo..nnnoisssed.TooTorffhfoseeiafffmaeeerbiitttedauuuesssngeeeaansssnrdavwwsyeiiilhcttt~oihhhtwwapsdasSsoioloooolsmuimneessonfs2owfzriLootoyvuhvsteDeehhtsssaesevseeehhsaiasbdsdSckphheiaslvnneeuetmeesoessnLdetttoihhayasnn
the control ~roup; notably no~0ssiflcation of the cranial bones, sternebrae missin~ and 13 ribs spurred. ~ne skeleton aberratons foun~ are oenerally
onsiaaces ainor but Shey ave of sporecianle sionAELeance In Shit Sout considered minor bu~ they are of apprscla~is si~nlficance in this study Crionmiaitaieansbecavee of ine hon proportion of fetuses eich the w~nh FM-3422 because of the high proportion of fetuses with the
TohpSafhhbercenhtogahrcctremooeannrnlttvgcireetsosrrilttieevasbgrts.rr.ooaoweursspaebmhhigLapaEmdadirtctaaaiRnthhetiggthhIrnheearrn4pp1rr tr1hooeppioon~artattthalrineooiennen~ooo.ffresaffxtloecmctoauunnssteaessforwvyiittthhhoonnF(eeeiTnabboolirlxenettiuw4)ooo.fsbbooodTdneiheiieesss
S~o%lfsfer5entchee
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ksalvqinalsfib=iapna~rtiinteallin
to tov instances
dove arouncrroups except for the
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one
btFrEhhoH-rCed3-ey34s4hh22ioo22gfTnhouaats~hgaiemnnmddiigvnnesmeioii~ursapdattteererbeddurtoatasslieeeoohnnavb.~ipporpprroouiaoudordpsptuusiocctreeaaeednnddida~itnbnhBhselelotoohtotcdfeearriaIlantoantwocostuqmhoeedneesnoissicKkeciiiddaecsnntfrneeotfyyueepscc.ttpplaaarroonfsafnrcapcchnallyyjeemmetfsasttepbpinanaanlla1aaal~c1leeooiinnd
SittESn~hhoarannnen~eheaeiIlnndCkohhsitSea~hhenneeetgysCScro0oapuPnnlpao~tsrrere.eu0senn1tnuchhTc~yyFhTrmmeeOosamUumpppawvreneo((rsrpTTeeo.aa~ebbtkslsllaeiheno~ein51iLr1sfE+.aiLscoo.aafnnNRtEooflSeyytLculAsheMCeifoSstgshheewpprraialtlahbiintneeecssttlhheeevwfeetrrhPeeiopgoahhlpparreteddsesuoeecsenneattnd~sritonboulowpod
jaFPocdMioam--ntmi32trn44ri22oeas2l2btewevararantsesdydrwltChoiepeniwrrrcaaohttdhtoonisawossepespnee~mfAntsceuttdeu0tydvso.esttCohhiTeeehbxeeaeemyyeieetonneeoro~fafs.bttorttamhoheevetneirccauitntelfaaSfteteviecsaltllol)mbwaad~esoonssse,eae doLlrfeeevvveeehlllA esospmpernitmN aalcyeye
lSiSaaueibbemnntenreeshroceorranuafFmcatiiaainbbiloeeoiRnrrn+~issssyevnawfooorfhfomivi~eacttIatrhhhnyseenqaLospsfotTepechhceceeemoaeLnrnrosdeetpraamadhebrbrorydyrtlyyooootltsnnoebeisanencllsstahalaSnlffaeimlnssbaesepeer:eprressensesusuccoootclfaffhenieucntttnsehhh:,esee~esafFfFvoboereelLtalteliavoaoloo~wepresemnransdueestcsclbbeheynysoutofasnsSn.sveteichtteochnAMiidloHolnarnrywtsrheat
aDnormali~les were lo~allzed ~o the area of the embryonal lens nucleus
althouoh a variety oE morpholoulcal appearances were present within that
Socecion. The une of SOTPhoLosIELL Bppestonih me. soeetv snd. the 1ocatlun. The ran.me of morphological appearances as observed under the ShieStaecnesingLsheiareootsoravtairoinesoffrpoancka oLfihee Sletncashsoarsattieonprreosmeinoees oTfh5osuiete dissecting microscope varied from a slimht discoloration running throuuh
wetbBeheerreennrreeeeoaalutotdemvnhhueeseit~nhht~teeogoa atlLttheahhednneeeslsppb=rreseoeepnplssstioeeo~rnnnmesoccelcteeiiliiouooeonmnfmft..obl((eferTnnaassAp.pblalhvreevva~ee,5ss5)1loiS..fecolnleeetEhMHieirirmseseeimmtlvonneoiantalnsnnaoattc.qssialcncSdaaffolloolrlrtoymahyheiinntteghhpdeerioecvislsdbeeeiiefnfssiectcocsesoroslloroooofirrrroasnsttsiioocnnvlsseerfet
ppFFCsErrroueeieeiriEmsmrrnieeavoennreourtcynnmseadmlli`aenooamnffm~ssedpd~raeFhfuogegiiabeebsetennlrreeeesssrtnassawtewPvheshenoidiudwcccnihhleSonepPfeuaiLsansp~Cplt.prEpleiLeya=SserRhArceAilseodRaaxsm)lcodetcasooclrseoiylhnalaam~vsvrsese.eibdbeiunaratcSoSEttleceancetcooesliunlloydoontwannoisrggayauoatfttrheaerTlddseoonduinsaainneusiddfcbsnio.etbttlehhoraeerrshaeptpLeioonosvAensebslitbnolirweemesrle
development progressed normally except immediately murroundlno the abnormal embryonal nucleus. Prominant ~econ~ary aberrations of secondary lems
ESoihtahreetiiunnchu1d8e VJ-asmhapveerticclasfeFsembmeetrweesensrttheeinsdmiborynontshl mmoeciioocse-ot Lene fibers include V-sha~ed clefts between the embryonsl nucleus and
TThehpeeiitpphrreeoolppioounrrmttiiaeoonnndsoolffensfRfeeittvmuu~esssseeisscltwenviittrhh1e1mt~nhhareenotuslLseaenssssutraahrbbaonnnuoonrrdimmnlaanll~tiihttetyyhceoi1nnsntueoocsnnlteeeusoow.rxrobbuoos~uhh(TluLeebnntsseeess5)
was si~nlflcan~l~ hi~er ~n all groups than in the control ~rouD (Table 5 ).
11225511..00000033
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33MMAA0000332266772244
ER EET
5
Rneessusletss aennad oDsissccuussssiioonn mrFa~-/-3k34a42/2d22ayvw)aassinmmaaFtteeedrrunncaaillnllgyy Stthooenxriircc gttrooouttphheeaehhsiincqhhboaadnnydd vnmeiisddanddsoosseeasiaqnrrooduupsuserir((e7055thaaennddde33?r7.i.55ng
m~/ku/day} in reducing their group mean body we~,ht aain duri~.o the ao~ina
2wi1((eL5nrTi"taaa~aebbihnrlldivenenaeloi~1s.sn0).." tdahuiAerrlIIlinnincn~ign~~sTeeettohhuoeecpcfsaassddteeoohhrsaeiiodonfnfagslittodhhwiieneentdrteoheh.smcai-eevvh~aaanllsddrooowoffseoeel~sdhaaawonytyraasosug~p6pe6asi2tntta%h~ahetrtimoh~aoeauevnnaosehhitdaa~at~h11ivi~55oeonnoocff9ondda~aauenrvyevodesssi~ts9ae1,5t~,iiaoo~11nnr32 aeaallnndd D2ouc~1~i5rrooonttuuahhpnneeadnmmdceceioanaomnnnntitcrdhwvooeeellidiogoachvha.rcsteeoreuogggusaroapfioinun(~ssp~00shemnwvgaGee//mrurkkieeragdi//nsSddadiiaaogayystnn)}ehit..eficiedrcaToToanhhsunceeiptnllgyTyalotowwliLeeono~rrtwveeeesmmrrrteveaaaatttnlnihhoaewvwnnneeeird~clueahhdhyee:tsrm~eoeaus9aanmui~ananmnissdwwieesociiIfi[guSe0hhtt~thfhtee~osoeraaitnhes ShEtthhlhhieeeeoalihnre~teeaenrsrSdcmimii~iea~nnmnnaaliisttfdtiilioooccdfnnaaonsnco~ecofhflleyygttrhhlldoeeooouwvvpeesssrrdtuoudesmmduyeeeyraairnnn((~Apobbpeooptwtndheyyendd(ivwi3dx5eexoilsaV~aVi/)ihnno.~KegssTi/bnTbTae~teneetverwvr)eevmmeeaeensnalvnnerwttshebhbeerooedodnyyetnrevdweeessLiioopeffaoonhmnstiadssstooiissbeliiaamennnndnduacflmmaoayeenrnaaddnn trae ~e~ohn ualns gisele of ~he Io~ dose group (25 mq/k~/day) were non s~unificantly
different from the control-
SAAdCbboltnsnieeoonirrcmma~aaarrllloouupncsc..lliiiennkiTT.cchheraileleesvssoiirfoagaotnnvsfsas tvwiiheennerreetthhTeecaotbbehhasiieeggCcrhhhvvaeetddddoovseaaeelnneddso~-~drpoeeeulaavput~hshssddiioeenooddacc..ccsuurruorrOrmneeveeddivorroiaonnnttllyyddsaiiiirenenddhttwwehhiiedetthhdhooiluusuthth iSacfEnbbeolaalnlioolnirorbiomwmlcvalaaoilnllnnude:yccsroiomnmmempntpscohoi.euiunsnnn,.,dd--TrrwlseTeoeelhltteeahhotteafeerrsdadgn~iiahccccec,,klliironnamafiitttccaesaaxxAlllibrcc.mh,,ossariitaobmianmldolssoiooedcwdwdLhhiiiipinccnnlShhucsssettiiloononcocncklelEl,,uuids~eeuuusddrrriivcnssmieaaoevtrmrrieeyynomnooiiffnnrdccartoottyhnhneetthiia1nn3deabnnocctee aeChrtneheerdmemnamibsisanlniiioiolmnon.sgsd~ycod1d186niinassprhhuaoeippuisgppna.heedsa-rdrdreooeTesdshdaeeetiiernonrdanac~st~esehhcteelaiannsnosd~fivucrravattvlhihbieevnvsioimrnmniiimemmddaslFr:aaaantntcddlib5yJ7nloiouwcGdaaald~yyoosse11iee99crsroonaffsatcsweuaeesddstiitaddaoitninnoooodnntra,.yhhaaIvvTT~eehoeebut
abnormal compound-related clinical signs.
hTrCFheeeoeppbrccocoadtooiuummccponetouiiunvvnddeedeavdwttaarrssafacoctttnnuoontctcsooseenn,mmtnbberrntiyytheeosottoomoo~xeffiieaentthheemaaunndsdddbasemddssrii..ddofnnhooTtt~TeeesaamemfEerfefapeeactn~ntiomnnetushmhmeebbseeirrooevvnaaoo,fc~riicemmLssaaallpeeool,.rfAnCffReeLmmaisliOeen,, Sistiiota~teanesleiciatacnnnaddancdccieooyarrdppaooirrftaaettaullrsuaeettsnee,tsd ooCtffrheomttmhheeetahentthhcrnioeuenemstbreTForHMl--33o4f4(32S32raebhsddaooovrsepe3.tigSAorrpnoopuseppsnesidtievwsnee0rreViirmnn:oDottlan~a~ioq
siqnifLcantly ~iff~ren~ fro~ the control {Table 2o Appendix ~I).
TBbFFooHModd--uys33p44swa22e22iitgwgwhhahaatstsn g9ntnaahooetiltnncffeoe{(tntTTaataallrbbollele~coog1Xni))iircCo.opupllpuu~Hsso(owTwhheaeivibvoael~rhreh..aezr2ttmnhhAe~emempbbacceenoorrhdmsasibbxiioontfVfaaEtt)iffiooeonvtnTuueessooeefufssitrreieiadnndsuuctciehhneeeeddmme~mcaararnce~eeaesr~~cfnnmeeaaemrllnnstt 5VwCc~eeoo1rlinno0e,ttucnhrrpitaoosssllc~emoomadeffenaannwaaiil~lclfhfheeePFttaMuucRns-so3nU4wivt2eenrEdic2oogrlhheggttarqr..soreuo0pTTusshhipneeww(rhhrrTeiieeacncddbhhtuuliccewneveedged2rreemomAfeepsaaspnnoiietgnmhfndfAeeiiefrtftxiuuicssVacazan)ovnwcseteisiilrydgyehhfsttdolussoroivow~eseewvrrdeerrfeet~iihhnnaagnsninomontteeattsnhneef(ebtulee 5associated wlt~ an increase in r~nting or o~her gross fetus findlnus (Table ciC7Fhh1nMaa-t-nn33ega44ree22pss22r.,eatadedaaaadliti~tlnhthnaotoIuecseotothhrmrapantnotooilu1roon~mnndna:alrrlrleeleyyssluuac~lltoottenneedssddilamdiieaenncsrefemmdodaarllmfsfsaokkotreerimllmoaeeanttttsoioinononnbsssaebbceeaiirrsnncreaaefftteoiiOtaoofalnnlssC0,sshteowweelaerrrrnneeeesbberrvaaeser..ity.TThhee MTTgaiahhrnrieeteeeads~~tCsoleeoem~rrvvareeterriitiinineottanyyt~shhaeaesan~iddn~ tchoolorme fufeptdte~eeeundnS~nrdeettt-ashhhr~eeetealeefaiinntonntteccl~iilrd~doeemooinnaauncclrepeefrssoorotfEm~h~aastssnntltt.aoearnrr~tmsnnheeeeebbb~rrrec~msaaonusen~stsrrommeooayalllmlfmofogf~toror~rm~iuathcpoteia.iiolorn,nssTTshhseevee~vseseeeererrmeeinteyb.iee mS2Bab1inali3dplmufi~cssotel~t~iieeac~trctaen,nin.eaotbbnlrs~esayteeee~Mimemanaeibichbslsreieusarshdheeaeappd~erssnnotccphrroe({a~rTTbtlraalibobeaolllddneel,,s.44i1o}s8n..fe~=re:fm~A~aeaLtihbIusrrstaeetteesshh~rerves~b~einlrtiaaPah~resH-qe-s3ee3at4dd4as2,,3r~22aees~thdditrrooeeassir~seecneaebseqlbrrer,raoyoaeueppcsssaim~tiserehse~iasdeicdlbnenrlnuae ~Chhaann tthhee c~onnt~roll G~rooUthp.. I~n 8aGdddiittiioonn,, ~thee hhiis~h G~osnee s~roouupn ohasd 3~
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11225511..00000044
10 077327
33MMAA0000332266772255
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archives.
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om Comercial FM-3422
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were
for hlstologi~al
svasoations abnormali~iee.
evaluation.
Selected free-hand .ections
processed
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TTLA Ie 0 TI TI AI 2--, No lens abnormalities occurred in the control ~roup. A no-effect dose
level for the teratoqenic abnormality was not established in this study.
res iscsi on ens rin Further Discussion on Lens Embr[olouy agate TE NCES 5a AOD SD Lens structural end functional requirements are met durino embryonic ane evra me font remem we tin born, ~evelopmen~ by the differentiation of highly specialized ~opula~ions of ahrr Ey cells from undifferentiated procursers and by ~he coordinated morphoqenesis SS JIA a BL Sr Coe of the resulting tissues- Both processes are ~ontrolled to a remarkable 5 fit Shame 0pent nt mercado s pil extent by interactions which occur among emsr~inq tissues. Each tissue of ATS Ey geri day the eye is broumht to its final state of differentiation, its cell Bat fp thsi, frwl, ~mpulation. size and i~s definitive ~eometry, not only by intrinsic prion, ti i be sninicive sume, vt lr in processes, but also by extrinsic influences exerted by nelqhborin,
~issues-.
rior edd The embryonal origin of ~he lens is undlfferentla~ea ectoderm- The tip of Or Sn rs tian ey Sa t~e optic veslcl~, presumably the neural renlna, plays t~ fnal role in BL TE reste ebmior Se fe hl em fe fe, ie inducinw lens from overlyinu ectoderm and in ali~n~nq ~he lens precisely A wi~h ~he rest of the eye. Additional action of zissues derived fro~ Oh iEa hacia SEL in LL SF TA ers endoderm (~ore~ut) and mesoderm (heart) on ~he eam~ tsr~e~ tlssue decreases ed a A EL Dn the probability that lens formation would b~ abort~ by a=clde,ts durinu a ed Sa aa) =he ~arly phases of induction. While the .nature of the inductive Influence ETT i, Wr hg ak si ri remains unknown, ~here are indications that substances may be transferred es, EF ee a from ~he p~esumptlve neural re~Ina to the overlylnc ectoderm durinm Te a a Los induction. A prolonqed period of indu~ive infarction no~ only increases BE Eo eT Harel Beran ~he probability ~lat lens induction will occur successfully in ~he face of igre Bsprod echnin T7 eavelpnpaly anhtie on any interference_, but provides a mechanism for continuously ad~ustinqzthe size,
sha~e, position and orientation of the lens ~o ~hat of ~he retina--.
a, Durino ~he early sta~es of the inductive process, the ectodermal ~ells re immediately overlying ~he ~Ip of ~he optic vesicle elonoate ~erpendi~larly Tr 1 fas T8 ios Sas reer ~o ~he body surface ~o form a ~hlckened disc (lens placo~e). The chan~e in TE tae cell shape is accomplished without change in cell volume. The number of BT onl Ine wom, cells, however, continues ~o increase durin~ 1:hla period. T~ward ~he end i) Tan jtSi Sade Ba vt, of lens placode formation, acidoph11c fibrils appear in the apices of the EE Ee So Ee i amar rT lens placode cells. At about ~hls time, the pleco~e Invao~na~es uo form a the lens cup. This invaqination is independent of ~he ~oncomi~ant SL invaglnation Of the ~mderlylng opUlc vesicle, and is probably due ~o forces op I opera%inq within the lens ectoderm. As the lens ~up ~eepens, its openin~ TrEe reg out Ti wie Te (lens pore) becomes proqresslvely constriet~ until i~ lIp~ meet and fuse, ro i a 2 ~utting off the lens vesicle internally ~nd re-eata~llehino continuity in in ot theJspeice aryl ed siting Sutin the ovsrlylnq ectode~. Closure of the lens pore is attended by, and ER ~ossibl accomplished by, a local and temporary restricted wave of cell hd aaa death. Followin~ closure of the lens por~, the cells et ~he back of the Ted hr Lom lens vesicle continue to elongate, under ~he Influence of the neural A Tht ioe retina, to form the lens fibers. As the fibors ~To~ the cavity of ~he lens BN i BL aa yee vesicle ~s obliterated. The lens cells ~o~ard ~he ectoderm, which do not Tee mede oe elongate further, form the ~ens epithelium-vt CSSEHE $8 HSA nF ee HY Co evo 23 The cuboldal lens epi~hellal cells which face ~le cornea continue ~o qro~
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1100 007777992299
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etfCSEhlioiheobnbeineveirruersaxstnneuuiliccnanllnreeeappiiplliBaabbdnnoeeeleucscysooommuotoeteffovwapapJjrorouuadssnn.iicctttttiiiihoooeoSnnnnieenpddcoccelaaeaalltstt~lheeeaddoafbboonssuuuuetttthtueuuecrrtteehhlsseefe..nisbcceeernwnAAsts~hseeerrrsaseceeeooccfftoohnnsetddltyhhavseeraryyy~eeffeiifftbbdiieeebbrrpweessorirstsshiaatnnaaeddorrdtoofhfwoeorrr~m aa
uSsrcruuoeecppnffieveeeererrrifxrrtleeicddilc~neiant~altsoollhyyicbc,,sooowllll~rtheehoeegeuccitttowoo~inallvvrddeedbeell-essyyc~toaamssfSei~bbntteePchhr;eyeesscmtlloiheeirnnnneisscn~thnhenaeeuwunccedllrlleeeeuunnffssssii..nbaseclor~lmsWeyei~ctaAhhGrrioeotstiialaimmilpeeeewpaeyctccrshheeteennttdrrlelTaeaephnnllosesllsyyictcceeeaaeidlnnlllddl sarI~e
SnfFhuiiecbbleererssisi,.teinhhooavwnneedhvv~eessrrh,,irpeegaaircooeefnnntboohketecobbmrrleooeknkaeepnnycarnddeooouwmlnocnaatannrnddgdlrrifeeelmmdnooavvbleeylddyfbbuaudttcltsaorr~reepsmmeaaaiwirnhn.iciihnnTchppeollnaatcccerees.olll tTThhheuu~s
ntnihusembbeescri.,ze asliasznede
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ttlhheee~s L~eeannrsse
celiet contr~11ed
cellsUo
by
factors
which
control
the
To"oTffhhheeeoofrrttoqaeeraarrmnnaaaootttggooieaqgonneeneennss~iiioccsfsllseebbnneeesscttowwneeeedeeffannffreecycddt~iifflffoeofefenrsraeFPnfnMicit--ibi33aea44trt22isi22oonnpsprruooorofbbfraaobbullllneeyydnnssinoogccttcciitusushrsrseurureeeeeddaffbrdrdrououymr~rolinnnsesoooclttoottldhdheeeeenrrsnmppoorraancnnliddoann CtnnhuuheccelleeSfuubossnr..omramtTaiThloheinetyeoexfxwaaeccsrtteectotiannmmdeeeatrydooffetleet~rnhhsmeeintfteieedbrreaar~tisoon~seetsnhnueiirccroSuEiiunnnddssyiuu.llntt~ Ta~ahnhneded dtetehhmveeberlmymooooprnrmaopelhhnootsalaseelnn~eesssliiessnsooff ACactaobbohbmnnmenpoopoorrorauamumbnuaanndlildoi-ii-rtrrttmyeeyyalilhaaiaaatttppseeyppdeedaabwrreeaasserbbnennottorroonrmeoaaptbbaloeelir~ittUuetyennty-djie'.aqruumteeioAAnegbbdeeesscociiauanmiuurinisslleaeatsrhrp-e-oiiaanttpptsppahtheenauarssdasryro.iiunnnnsoogtgltyTsbbhsteeetireernunnudcceretedv~atueeerrlssasoccfll~rraniitebubllneseeennte~dssaslaahssultea+ns NwdGadAieebeCtgvnvhHeeoenlrle&omoarpa~evvmlaseeieeirrtnnvyyy~teaallhllaoposwrwllieennnIibssenneccceiiynaadd~beenlnrnneooeccnrrpeesmmoaarlltcooffiieettdlyy11l..ts2g~21o.7ff%.-~.ca4 cTTummhhruteetaasnnaaptnbbonnnaomo~croraumumntsaaeeelloiiuttsssyylti~rrareFiieeinnssnsemmwBrbbhailli~ceechsshfet~rtrhheueeesssueulslFFttrrssaabusstefefrrrroonm
degenerative primar~ lens cells~.
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RReefteorreenncceess
1. CiCnoouullWooimmlbbsrroeen AA3JJ,,, FCCrooauuslleoormmbbFrrCee (JJeLLd::s):AAbbnnNooarrnmmdaablleoOOkrrggaaonnfooggTeeennreeasstiiossloogoyff t2~rh-he:eMeEEcyyheea,,nisms ninaWPialtshoongeJn,esFirsa.serNeFwC Y(oerdks,):PleHannudmboFoeksso,f T1e97r7a,toBlpo~y3729:-3M4e5chanisms
and Patho@en=sis. New York, Plenum Press, 1977, pp 329-341.
2. COCofouauallnooommgbberrneesaAAiJJ:s:. ZThhNeeewEByyYeeo,,rk,iinnNODoaetlHiasaaRnninAeRLLn,,arcUUsrssappnrrduunWniggnsHHto((nee,ddss))19:65, pp 227-232. Or~ano~enesis. New York, Holt Rinehart and Winston, 1965, pp 227-232.
3.
M8MaanmnLipIX::pincDDoeetvvseellooCopprmm,eenntt195AA7~b-nnoorrmmaalliittiieess
of
of
the
the
Eye,
Eye,
2nd
2nd
ed.
ed.
Philadelphia.
Philadelphia,
JB Lippincott Co., 1957.
4. WWieeniissrssatees,II,,`mNWiiicggeggeeassnccdhh~ur!lazbzebeitAA,s,. SSttA~orttczsheeirrvHH::FuerSSp~oTnnottxaainnkeeoooluuossgieccoo3nn3gg:eenniittFaapll1c9ca9at-t2aa0rr7aa,ccttss1974. in ra~s, mi~e and rabbi~s. Archiv Fuer Toxikologi= 3_~2: pp 199-207, 1974.
5. NAHanammeailiecY,,troXKnotv~aambbiacaxrraoasTcT::opiBEcaarrstlluyydycc.yytcooTlloaogvsieicscciccghhaaatnngigeveses OoopffhtFFhrraaalssmeeorrloccgaayttaarr18aa.cctt..(7):
BpApnp
e53l11e77-c-55t22r77o,,n
1973. microscopic
1975.
study.
Investigative Oph~halm~logy 14
(7) :
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ies MMeeaann BBooddyy WWoOrereaailllgshhtTTeea GrrGaaaaiittnnoossllloogogoyyFf SPPTSoertt~seuuldogeyynhaannnoOIttZf FPaRMe aact--as3a4z2BBz2eatwiicennehntRaastmWeseeisghhiinngg:s
wi~h $~:andard Deviations
E = T T mEmR m Dose
Groum
Gestation Day
6
9 12 15 20
+ ears 0Smyg/skgz/day , - hid " Lid [--. 25 bs mg/kg/day
mn 3 ar a sn STAN LEV 5.% 7.5 58 4 Fai
mea de en ea mou STAN. DEV 14.2 24.6 15.6 47.0 4% 1
won zee ar am ee STAN DEV 5.4 10.9 5.8104 15 =
wen aoa om a on STA DEV 11.9133 |qI=I~I'.,I
27
11
~T~r-~. DEV 11. "~ 15. "~:
95~,.'-~
~:. 9
S416 ';'L:
~,. q 11 ,5
-2- S3iiggnniifiiccaannttlly lloowweerr ttahhaann t~.hhee coonn~trr~oll ({DDuunnnneetEtt''ss tE t~eesstt pp <,0-.O.0055))
11225511..00000099
1100 007777993322 33MMAA0000332266773300
WT Oral Tera~lo~y St~l~ of 151-3422 i~ l~at$
Heart Litter Data with FetuS ~;~igh~ ~d Standard
Devlatio~s
BE maven J me vom Gor med Dose
G~
~o. of VIRBLE FETU.~'~5
~i~Is M
F TOT~
~ERD RESO~PTIO~ IMF'LRNTATION CORPOPR ME~ WT.
FETUSES SI3ES
SITES
LUTE~ FETLE.~G)
0 ~day
Tews 7S M~g/d~ meee newer
~8
3. ~ 5.4 e. 9
e. e
e. 7
t.~ t,~ 2.~
v 17
5. I 4_ ? 9. 8
om 2.1 2.3 2.1
wo GiItof3o8W 2. t 2.1 1.9
0.2
~.6
9. $
9 ~
4. 4
u mUoT mw aRr 1.9
2.2
~.5
~-- SigniEtcantl~ 1o~ than the control (D~nnet~'s t test p ~ 0.05)
8
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.
rie 3 Table 3 ora Tesatolony ster of m-3z2 in rags Oral Teratology Study of FM-3422 in R~ts TL Number of Fetuse.'~ wi~h Gross Findings=-
Te 0 e 75 w37s.' 5 5 25
FFiinstdiinngg
mgm/g/kkg~//daaay mg/kg/day pa/kg/day moxg/day
Toned Facases rina 10 07 is as To~al Fe~es EMam~ned
161
167
195
213
fe - 2 - : R~ed
---
2
---
2
unniiient homia 3 -- = : O~ilical he~ia
]
......
2
Tocat Norses eruses 10 1s ws TOtal No~l Feuuses
160
165
195
209
Tota Aonormal Fetuses 3 2 o . Total ~no~l Fetuses
1
2
0
4
(ieaare 0.05) 2a TTrreeaattmmeenntt ggrroouuppss wweerree nnoott ssiiggnniiffiic=aannt~llyy ddiiffffeerreenntt ffrroomm coonnttrrooll {Chi-squar p ~ 0.05)
PAINT TT
BO Els
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Tani 4 NasbesOOracnaadl TTPeeerrraactteoontllooggoyyf SSFtteuutdduyyscsooffwiFPMcA-h-334S:2rZ2eleiannconh~aatFc~eu.nding:
N~mber end Percent of Fetuses with Sk~]eton Findings
w sketeson Fining i mafxgscer s ma/nosesy ma/va/eey
Skele%on Finding
HFFooolnnetesaainneenilpllaeernniooetttaccllloosseedd
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FPHPraaoozrlniieteesattaalillnnopssnacccraasillsellitooappfleeidded
a1l ao(iw)n
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OoSIcctnccotiireppnriiepttbaearrslaicentneaonnlnooonsmnossosiinsofifsitiseeiiddefdied
14 (12)
0 on
SS5Sttttoeeemrrmmnneeeebbbbrrrraaaacseebnasiosspnyyamomrmsmt~sti%irtrfieiicceaadll
80
0210
(71)
@(9)
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2 (2)
SSOSn~tteeearrmnnseeetsbberzrmaaaeseebremaainieslssasmhrhiagasppeseedinnng
2 ao
OTTunhwoeioescssttt~eserztmnnae~embbberrrbaaare~esem~miiimsssissisiinsnngiggng
223 2
@(20)
(2)
OTO1nnh3eer'erbbeioonddssyy%evr~enerertbterebabreraaeemimsmisississniignngg
ow
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pnwPraroovotytrbruoursdsiiyiboosnnofoonnthreriibbwssrtabrae 9855 (((7274)))6)
On0eSbBiiobppoadadrriytteiisttoeefofT.thehe~evretretberbareas
29 {26)
17 Us)
TThwrobbeiiebppoaadbrr~tocideitisceeesofof~hsthevervteerbtreaberae (15)
TFhorbbueirieppaabrbrotocdidiiticeeeessofofthtehevveerrtteebbrrease
FFiovbuEeriippababrorodtediiiietcesees
of
of
the
the
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vertebrae
Fibvbieippaabrroetdiiicteaes of t~e vertebrae
TToottaall NNoorrmmaall FFeotcuusseess
s9 (S)
TToottaall AAbbnnoorrmmaall FFeettuusseess
W10e4 B(9D2)
Total Fetuses Examined
Total Fetuses Examined
u11s3
26Twe{2n2)
l (I)
325 ue
6@@2 us(5p3r):~ 56S42e1 oE((4w5n73))t~~ 1100200i ((wGi8)eo6)tta
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a1ear 37 (32)~ 1i a(i)
1 (i)
232 aa(28oe)r
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12
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GRE (51) ~
(33)K
11032 (ce74ao)d e1wa 34 (25)~
6 (4)
1 (i)
ow1_oan 3m 31 (22)
9 (7)
333 oa12)ma 28+54 @@((32)0)~ 2o1w5 a((41)m5)e
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22 (2) n11e4 o(9m8) n11e6
66 @(4) 11322 se 1I38
22~SSsiiiggsnnniiifstiiicccaaannncctlllyyy hhliioggvhheererrthtahannthttheheecoconootnntrUrozolull ((C(CGhuih-i.~s--qssuqqauuraaerreepp7<~<000..0.0505)5)) -((- 1S) i==gnppieefrlrcccsaennnu~tloofflttooowtteaarlltehexaxnaammitihnneeeddconnrol (Chi-square p ~ 0.05)
markasisr 2 an
1715 sGoodd
s57s94
(50) (40)
1w13m1% oo(75n)f
536 5
(24)~ (3)
13ow3 aCo2uu2n)s
16 (11)
855 (3)
2292 o5((i6w))
7
30
G((52)0o)
33 @(2)e~-
z2 w
irw
irw(1)
77 (5) a142 6(95%) 109
149
. zie
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FFeeGttiuusssecesoslwwoiirttahthioeenyveeraaubbnnnioonrrgmmaalltiihttriioeeusssh 0
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oarrnnuueennnneeiiyynneegg
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the lens of
in back of lens
BDBuuibbasbbicllsoeecloolroonnoatroiaouotutnitsosiniiddneerbuoaonf~fiknllgeeonnfssthlraearnonisduagh
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Bubbbroobuttlnhhenieoenyyngeeosztuhtrsoiudgeh
the lens
of lens
of
CBluabCctblltleeetfeiunoniintnhoeuttthheseliednlleseennssooffoofoflneeonosnneeeyeeeyyee
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CleSStmmaealllellnpsaleeayyoceefessone eye
EFECnonlllleaaafrrtrgggeepeddadlaaarttetenrraiiluwmspselvis ares fn 5 (10)
EBnlltcoahhderegiekKnaiidantnreheeeyyna!kidpneelyvis area in
ABblppdoaaoorrmdeeinnniccanhhlyytmmhcaaeavkiit~ynefyall of blood 1 (2)
Abdominal =avity full of blood 1
TTTooot~taaalll ANNboonrrommraamllalFFeePtteuutssueessses TTToootttaaalll APFbeenttouurssmeeass/ EEFxaeamtmiuinsneeesdd
@ 5 42 (87.5) 6 125) 6 (12.5) .48
a_ Ssiiggnniiffiiccaannttllyy ddiiffffeerraenntt frr~omm ~t/h~ee =coonn~trrooll
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16 (31)a-
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2292 o(G5w1n)ad-
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1 oan.
7 (12,~-a
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1 17 a,e
7 (14)a
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3 (5)
1i ((22)) . u11 et 1221a-
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8 ne 8 ~16) 4 60 43 (84) 551
222s5 w6(44e6> 532
57
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11 @(2) 13 (@5)
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AAopppeennadiinx 3 0Orraall TTeerraattoolloongyy 5Sttuudgyy ooff FMM2-4342Z22 iinn R~aat~s5
Protocol
ceive eAeCAfefctaeeeemcrrostaagszteoonolloafoeotggiyybonrr.assalttlluuyTyddoyyesavcwiihpimurlliiollnncieibsbdseesutorerueure.sseadeeCddTFoMmtt0-poo4l3i4ee2e2vv3s2aallwtuSuioaoatttheepprreotttghghhenneeaanneSeetmmebbnrrfryyaaeoottrststeoxx4driisueccrrciionnaamggnnetdnttdhhtea~eertrsippacoeetonrorssigieoeononddificcooffthe FEFEcSvoDvroaxAagllnaunuiSeoaasagttsmeiuiu1noeoe9endn7ds8ioioisfGfnn.ooJDJDardranaunTupguLhaesaaerrbyyopff,,rrooaorrtc11oe99HMrd6u6ayu6mm5raanenP{(r""UaUcGGscsouueetmii""ipdd])clee..eilleiisnnreeTTesshwhpeieutlff8hasoottrr5iutodhRR0nyeeesppwwrrgiiaooellnddnllduuecrcbabStteleaiifooennccrtooeynnScSddtcouuuumEccddmustltaeeeeelnssddsdnattaaffiiccoooocrcrnnoosrrSSddaaiioffnnefeggttyythe Ltoootrhaeco1r9y7'8sGoSotdandLaarbdoraOtpoerryatiPnrgactFircoessdruergeusl.ations and Safety Evaluation
LamDrato~!'s Standard Operating Procedures.
sSp~oo~nssoorr 3 Comezcial Chemical Division, St. Paul, Minnesota. T3eMstZionmgmeFrcaicailtiCyhyemlcal Division, St. Paul, Minnesota.
Tessin~ F~ility
SSaafteetsy Esvvaalluuaatciioonn LLaabboorraattoorryy,, RPiikkeerr LLaabboorraattoorriieess,, IInncc.., SSet.. PPaauull,, MKimnmneessoottsa.. seu pimetor
Study Director
E. G. Gortner
Start of sosing
~tart of Dosin@
HMiidd AAuugguusstt,, 11998800..
zest system
Tes~ System
EEfiirgdohhnttGyy--aeeciilogehhset sRsieevxxeuuraallllByyremmwaaittnuurrgee,,LatbtioimrreeatmomraaytteewddilSSlpprrbaaegguuehr--o~Dmaaewvdlleeyyinddeherarniiyvvieendds ffseecmmaaallieeniorrnaacstes
rCSscftotorenenoosettm]lrrloCothlScailaargegeSleeadeessessrrwovaoimiRmttn.i.hhdtzwucTiiTianrhrBeleierss~mcsmeaalsscstittehhnrrsa~aiiffnnLlfl~ooooo~bcmfzfe~lssrearrstaaaatotnnars~dayrwWeffiiwrrlliFoolllnenltsthshsaeebieliiynusnhseeeaaaov~d~ittelbbeesdeemmpccppieaeeieuurrn.nsaasetthouarrnoouee~gfriinhhaangiinnesdsdttsoMohL~reruaiiimmbnccLiolaaAdrellLiasetceyyory
CCcTrhoioonowwtnreoa/alnandndedhwawatatateeeyerratnewwd.iilltllimebbeemaaatvveaadiillaafbbellmeealeaasd
Mitibam. The Lignes will be cn 8 12 hour are readily avilable. Purina Laboratory
litibum. The lights will be on a 12 hour
light/dark cycle.
fest syscen Tones tication
Test System Identification
ESSaaicchhtaasnniiommaf~lltvwheiillllcabbgeee.seaaxr ctaaggggeedd aanndd tt.hhaatt unummbbeerr wwiilll bbee dinnddiiccoatteudd oonn tthhee
outside of the cage.
Santon zation
Randomization
hiThmeeoeaarnnsiimsaatllasnstaww.iidl)l
bbee
aassssiiggnneedd
ccaaggeess
aaccccoorrddiinngg
to
to
aa
ccoommppuutteerr--ggeenneesraacteedd
rsainnddoomm
numbers table.
11225511..00001144
10 077937
33MMAA0000332266773355
finin
In14. [Ep -- Appendix I (Concluded) contro arsiste com oat. Control Article
Corn oil.
sean.Article
sFaMs-3t4y2s2i.ent specifications
aAT3hnx~alyCttteoesimstcmt.aelnaacrrictSaiipctcellceeiS,,fhiecmcciaooetmmcippsooonsssiisttriiooonn) aapnnrdioppururriitttoyytwwhieillllBabbreseddoeefsteerrmmmeiinnaesddeubblyy wint},~. SwStppoonnthsseoorr
a(n3iM oCof~ndwe~vricniea,l Chemical group) prior to the star~ of the study and at the
eSnodsagoef ovals dosing. wd Beperirens vosion
amTsDIhuoieessEpapn@ectIesnoesssiiTetLooennvaaEerrlcitaEsiinnccddllaeencDcdooivwnniittEollrrxo)lopnllebrbeeiaa1mrr5esttsnuiiu5tcscslippseeeDeoennwwvsddiicieelalgddlclnti$obnnnneeccsaaoocir~mcnnmoiiroonmdliiiialssnttgeeddaarriiee0llddyy..bbthyyeoToT1trhh9aaee1lltZtoeimevsnsbitttinubebaaa:arrrtttiiiiococnlnleettoo
he
the
rats on daysDo6sethrcoruoguhp 15 of sate teva gestation according to the focllroowwings:ize
nwodn Dose Grou~ High
D7C 7o55smemgaa/Lukeagv/ealdy aarz
zayy Group Size 22 ~
oMLiohrdwerr
2hmaamanria 37.5 mg/kg/day
25 mg/kg/day
1ay22
22 ~
ThGhRoetionorrtaaallbyrroouuhttieescooonffftoraauoddslmmiiinnniisstt+rraarttaiinoosnnucwviiinlldlle0sbmbsegot/ukuuagssr/.eedddabybeuNccoaauudsiieeetactrooyxxiicccsiostmyy2a2mhhiaa~nssanbbeeeseennazo
idnetfein:ned bynttahritserreouwteithinhea' tems article. rangefinder study. No dietary contaminants are
akThT3bhnoe3enomowo7rnarammmnnaaitnllmkoaeallScissLlnoiitrvwnneiiipirLclerLalaeellgrbnbeaeessniiwgcgoicnyntbbeshsm..aeenrrtgvvheBeeBdodocddhtyydedenaswwiitceellaLiyycadhgrhhtffitidrrescooolsmnVwee.AidddLlaal)yyacbbc33eeottshiTrhrieeronccougoouglrrhhyideeddsddeeaaoyiynnns2200ddai8yvooseffcongg33ui,eeissabct6r,raaettiiB9u,oodnno11e32ff.,oorr
weiime 15 and
volume
of20
of
3'ab/kg of boar else: or pregnancy and ~he rats
5 ml/kg of body weight.
dose~
accordingly
using
a
constant
dose
hCwT(heilevleeffbeeemmnasdalleeexssSnamewwiininialeai,ld Sein ana 370s
mbbttseeooahsmdKkdoeeieierctllLeellrAreeommfdCdiiLnnooreeanner::s:ddoaaryynpmtuAim2e2P0o0bPnerRaraOnnrCoddoiAfsfRetcGshchcC:eeoAoLrmYpoopovvouotaarmsnrxaeiiereelwCssuiR,,oteAfenEauu,,EttieemrornpmuuFuhbssmabnacetaharernnaddciooPoffuiinptcsssffsoecKucctoicuountesnssecste.resennBtceYssP
wSf(eile2ixii2gveahe0dtn3aii0nnaednBdSoodtuteogiairndnod')s'e,sssxernasSaubooimnllnbouueerctmriiaaoolnnnoifytf(ivrooeireFscs.seoseruurpbbatAsalipecopqanruBueoonnxsnttiiotmreamffsterr,eieelieeycn-hiuhaeomansnbnseedu-rsts~hioeifnc~rgkidiiooamnonpiSfliniangangtsth7ebeacyttipiouc~nnphhgseeswHMWiiiitielollsrlss,ooosnnbcepoupps:
TrtTheoeecrhnTrriemeqsi~useieiqnnuiitenonnggtdaesTtppiepperrrtmeooisxtniisen~]attaeensllyryyamvtiitenswaeoosce-irtoahinlirridaassbfntoooeFfrrmattchlhheieetsiipseuipspnssguwswaiiinlnldlglsbbtaeea.idniffisiinsxregeedodtwiiiIntnnhgeemtscihiychslraorssaictlnoecpsoemhr.ooedll.
for subsequent skeletal exam~ation after clearing and staining with alizarin red.
2550 Anaiysse an pina) razors
hDSDTDahuuie~enmaanmnppec.rtrAeotonr'papaesoolbssyeese~didrsC~aesssosttatftaan.dttiififFssoomittrrpniilaccdmalaaannlltmaRsataemienn~pottddonnhrpPootduudsspisptVwetteesooiiogbbahheentedshuu,,ArseeuPdndUeummffrbbooAerrorZfaannooaSfaflolymyfFsmseeiiottssrusaeeoossLff,,utttemhnhseuue:smbbddceeaarrcthaaiooaafafdrrieerFe:seerssoeGrEppf~oL-ritoonn
pPCseieRrtrTeceseTn,nestsnusauobmmnbpooerzra~eaaoxilfai~mttiii~nmeeapsstl..iaonntsaTTthnhieeaonpvpreroosbppieotoesesnseeddaCddnoadamttpneeluemtffbeo~esrrrtt(chhseefppcfFrioionrnvakpIlsoRrSarrteeeppLloouytrrettFdA;iirsseCch32qi--u3-3esrmqmeouoenanrtrt,hhess1faso9frt6t1ee)rr
de~ailed pup e*ami~ations ha~e been completed (approximately first quarter, 1981).
11225511..00001155
10 07793
33MMAA0000332266773366
aT
i
15.
Oral Turatoton seuss of Pues in ate Appendix II
Oral Teratology Study of FM-3422 in Rats List of Principal Participating Personnel
we BNAi~En. Gortner BEdiwdiennG.. Gsoarstpnreercns GEladcehn G.. ZLaadmepmraencnhn Gcaartyhyc.E. BLaucdoreem=nn sGaorr~e"n oC.. Pseceoeren
Loren O. Wiseth
cron SFeUaNtCyTIDOiNrector
Study Director
Veserinary Facnoloziss Cvoeoterriinnaatroyr-Puaitshtoelioogniyst SCuoopzedrivniastoorr--a~niisatnolocgayre Tecmician Supervisor-Animal Care
Technician
11225511..00001166
1100 007777993399
33MMAA0000332266773377
STATEMENTJA~ppOpeFennrdQ]iUi xxALI11T11Y11 ASSURANCE
sw.
STATEMENT OF QUALITY ASSURANCE
SSTTUUDDYY NNUuMMBBEERR;: Tne:
TITLE:
_00688800T7RAO00011C0, Oorraall TTeerraattoolloogg~y. SSttuuddyy oof FFMM--334a2:2 iinn Rmaattss
UAAnuuiddtiittssforaannddth//eoorrabiionnvsseppeetccitttiiloonensds tUonitmanfaogremtehnet abaso. vefo~llio%w1se:~
swwteeurrdeey,ppaeenrrdffoorrrmneeepddortbbeyydttthhoee
s%ud~,and repor%ed ~o
tRRhiiekkeerrstuQQduuyaalliidttiyyrecAAtssossruurraaannnccdee
:he study director and
to management as follows:
DDaattee PPeerrffoorrmneedd
2200 AAuugguusstt. 11998800 22 SSeepptteemmbbeerr 11998800 2200 aanndd 2221 JJaannuvaarryy 11996811 2222 JJaannuuaarryy 11998811
Date Reported
Date Reported
2211 AAuugguusstt 11998800 44 SSeepptteemnbbeerr 11998800 2222 JJaannuuaarryy 11998811 2222 JJaannaauurryy 11998811
ar #
C kbeoraotrotreyraQtuhaolnity Assurance Riker Laboratories, Inc.
Riker Laboratories. Inc.
weJJaaennuuaarryy 2222,, 11998811 Date
11225511..00001177
1100 007777994400 33MMAA0000332266773388
AAppppeennddiixx IIVV
1B7.
<
rent and/or Contre Areicia arseserisation
Test and/or Control forArticle Characterization
i:3920 cfoorz 384
3.
i.
hBoTtheierenseeentimtdaeeScnnhhtiaaisrtryayicctsstettaarrrieieanzngggattttidhhii,,oonnosssumnnioioffffoomrttmmhoiieettayyvtH,,eesr1tec~o~SpmdoeeBs[sgiii~rttzaeiiooccnnoo,,nBntrppvouuolrrEiictsSyy~sseootsrranneoectteehhsseerrMpopeverec: -:
5. fthermernoeoof anlsseriis ogx cxoisinlof he rteastdaine concei or swrn ances,
Inclu~ng ~e~ ~t ~ ~e ~t~d of b~oa~a~ {if applic~le) is
d~ent~.-
yoo XY mo
5.
3.
ShThieenessttaabbiiwlliiittyy booeff atthhee ntteesxtttaunnedt/eorrncoonnnttrroael smupsbasctaannc8cseys Bh~ aove FbeEebennAdeResteorws-ecasrasy
heThe
shove
~e
information
~fo~
and
docmentation
axe
located
in
Se
sponsee's
fer
cords.
SDDon. oRr L
St lpo
Tate
S~o~or
Da te
Be fo ares cecmseromma------ rt 2
11225511..00001188
1100 007777994411
33MMAA0000332266773399
1. pendixv OOLzraaadl)iviTTeceroranatltoollaoonggd%y'HSeStitnuuddyyBoodofyf FWFNeM-i-3g34h42t22s2 oiifnn RFRaaattsss Individuaweli~hahndSSetMaaennaadnsarrBddOdDDyeevvWiieaaittgiihootnnsss of Bats
S ee ew
mDaionsdme ReaGtrnouNeop..T3 E6
9 wp Stuffy 9 12
Da~
I15so2m0
manga
nNWNooOPweR 1ad344s7a75i5ErnS.
NNNOoo~ww' 1aa4ad77?e6
NWNooo. ekw. 9A233777iT6E-
NNNI-oJoOerkK 1221455S73q7i6~257E__
fWNOOeRR S2iaR =-....a
NnOomFNOR
r.40~+
13115543440000E%70.
WNNGOOPRR 31175%a4a00o58s
WNeOkR 1%et 15409
NOF' 15425
STAvIMEeRDnl'.Ei V
STRt.~. [:,E'.,.'
2i12008T44d ZaZ21e.on6 225d44ep88x
131885442 BZ2e0xa9 e=g~<r"p~a'2
Gi1i6W ZSi5eso~ s22ihp
11219e%50r 2fzS2ri0ee m2Z~'3ak:2
dE19e321n1 iezs.?, >7, MHzs
D1e31~;,I
195
2~:+~
a25erZaen 220
21~
24~+
221:~8:96 Z22h518e8 zreen~,~"="
11%9:3 im218 ze248
154 17t 2E~6
2122.0000232222490 2622.44655
21. 8 '22. 4 20. ~
2e rZ7ee6 oo42,.n",4 I-Il-inoen
20aiq7n3 2a27:1h; aL__io.
mefeaoa e2~r:82ee75 4Linn
h~sz"=eom'_a,4 aZo2~fm:e~, aLLiwed
ZS26nR9 Icow fLaee
22:L,
6lzera261
2~.~:,
3Die1oe2 '9 '3
0~In1bne'-,
206
f26r32~3:
3.31
22837%297
4ioi0wt1
2~2 255
2222,7"1.a1 22330600302I7n1
22. :1. 2:2. 6 2~0 7
HOH PREGHANT AINALS
NAN PF:E.,'~t+,IRNT RII I I'II'3LS
WtNWoOOOkRRR 11a144447777557st9s 1iE281za84 22324322~s32 222232756 222249752%32 222s4a4s'3se9 r22Zi65es40
NNoOkk 31552:.6866
115922
222255
2.2.44.23.
ze~=
244
32432:
en250
28A_
=_,=""
11225511..00001199
I100 007777994422
33MMAA0000332266774400
1.
19.
AApppendpixeVV (n(cCoondnttiiinnuueexdd)) OOTrrnaagllivTiTdeeurrsaalttoollaoong~gyyeSSattnuuddyyJodooyff eFMMiN-s-3h34t42s32 ioinnf aRR~avtcsse
Individual and Mea~ Body Weights of Rats With Etandard Deviations
mT emBeeowmw. ma e 3 wn ooy wow
and Rat No.
3
6
9 12 15 20
75 no
oSGooFkp aaaaaaTrEey:i 1iai:ni mizir 2h2es3 2i23r0 zs2eemer iivonor
:
OOoooFkk
a1r3e7in 1475:
i15o: Zo:
ii2io Ii
z2or 20s
zaen: 204
d2e5n6 210
i30es 287
OOuo 223a7t5s3h fZooer DZaa:n 223a7 2ed mZeer iftia
COGoOFrF 232a337:a30T Zi1o8v:ie mfaeer i221am0 xa2m3i is2ee2se5 aza,et
SooeRR 1aAs3Ti3aEi: naioii iaamxvi 22s3ai3 ELgehkr s2zae3sn lfioib
OOoFouk 11z5Sa4ai1o4 2111e8s03 221aam sZ2ea1im5 2mi9em% 2oie8vr6 tZihatin
O6F 1842 138 2: 243 Za Ze tae
EA zon zn 232 3b 2d iu MEAN
201 231 232 D-._g.~b_. 240b -..__b
STAI DEV 22. 166 47.6 25 35.7 40 ~;TRI',I. DE'," ~. 1 16. ,5 17. 6 2~.:. ~ ~"~,. 7 40 ,.."
NON PREGHANT ArINALS NON PREGNRNT RI'.I! I.IRL_~.
OcO0Ooo08rRk~~ a311da454at74r7e~e1~:ss:41
z210o9~:5: 212945
222a413i 2224s1
2a2s00s~8 21~242
111~5753 a1t77e
20%0O 210442
2os,o,~fa | of 2~'~
(
Ook 33413 OGF: i~412 00R 1541~
223224
~3
2z4ai5
2~ 46
214796
1244~2
2560~
241 24~ 240 24~ ~5.""::
ErsRaiaegtnaidtfieeidacantly lover than the control (dumnect's ost p <0.05) SLgnificantly lower than the ontrol (Dunnett's t test p < 0.05)
11225511..00002200
1100 007777994433
33MMAA0000332266774411
20.
Appendix (Continued) oOTrraaadllivTiTdeeurraaalttoollaoong~dy"eSSactnuuddyyBooodfyf WFFHeM-i-3g344h22t22s oiifnn R~Raaatttsss ladividuaWlit~hndStMaenadnar~dodDyevWieaitgihotnss of R~ts
With Standard Deviations
Ee
-- a ----
mdmthe. Dose Grou~ and l~t No.
T3 E6
5 W@W Tow Stud7 Day
9
]2
15
20
3377..55 MGAGA PFeerr 2sa4v7e6s7 G1e5: Z21ws iEdEo e23s7 z25i4 in FFooRk 144477665x iZee: a21ss 2Iaime 2zesa gsemr zien FOFORR 114477e7T0 1i8z7 2a0r5 2I2m 2z5ea e2%T LIxr FPoORF 114877E6es 11772 G20e4s sfiozs cZai s2d4s5 G3eho FFOoPR adaaT7e3ee 1ass: GIohv aofaann Zsen aIre Din FFooRR 2a5s3i9s5h 1i8e1r 2210:a 3ca:r 2sa5n 2z4z fGiien PFOoRR 3aZ%33w%sr 3a17 2a4s3 2zim: zere vewr edwe FFOeSs 115543195s 2i0s5s 22137% 222486 22s3%7 22940s otta POPSS 135%4a1i5? 221202 22443a 22944% oZ7vw 2265x% aInwa PPOORR 233541133 214506 222331 225972 224657 22e3r7 G34%0 FOR 13427 132 215 231 235 245 zed
STANMI',lEEFDilA'.E~ V 162z8o.-r.8.: 42s23e70 2522.~3877 472o..~,3h,~_22z267e8]Pe3.. 1Si3i;-bb_
STRN. DE'.,.' 16. e: 16 7 ~6. ~ "~T. ; -~2, 7 _-.-#~ :
NG PREGNANT ANINALS. PREGNRNT RNI r4RL5
FOR 1144778866
288
188
206
206
213
213
214 222 214:--'=~.'"~
2 226
2siguiticantly lover tthhaann ~thhee c~onnUtzrooll ((DDuumrmneett~t:''ss tt t~:eesst~ pp << 00..0055))
11225511..00002211
1100 007777994444 33MMAA0000332266774422
21.
------ Appendix V (Concluded) ath apa gE EE 4 Bure Oral Teratology Study of FM-3422 in hi5 TAT eet weionis of hans Individua] and Mean Body Weights of Rats
Ane With Standard Deviationsc
. BDoossee GG_ roowup_ |___S_ Sttuudy_ ybDaayy
aanndd BRaattMNoo.. 3 -3 66 59 1172 1155 2200
5 mortar
rGfRoauart or fm
sR AzE IaEeEIzOTm EiO peEs Eam :ionke
.
foGroraidan l BBe lEfm Ide sEoeEin
GGaarrMddEvuEes EH EaOOEE EE EEo foRErn MRaT Dm
GFdoo rddiieee:s d1ge5r eiBhiiogSeu eassi lfspe
on in
GEGoraEtSiiEetne o m hi kcam p S oe E E se M a4 I n
StGiepnimin ao3Rm% E RTT oImeHEn I Wom Eom
or in of a ENE
SrneMvEbeRNev 3a25@ns1 2z262s8 5a2.4e58 22s5s95 EzLaEZ~"l" omss2:'~5=,:
STRN. DEV 19. 8 28. 8 19. 9 21...,~. 2t. 6~,'~"- "~
on PREGHANT ANNALS NON PREGNRNT RNIMRL~ oor asze 156 zs wn ze se i QOR 1~=~t28 196 225 231 22::4 236 271 meres eens 0.09 Means not significantly different from control
(~t's ~ ~st p ~ 0.05)
SnLE
11225511..00002222
1lO0 0077779944S5
33MMAA0000332266774433
22.
AApoppeenn~dliixx VviI IndiOOvrriaadlluaTTleerrLaaitttooclleoorggyyDaSSttteuuddWyyicoohff MFFeM-a-3n3442F21a22ceiisnn H~Keaaittossnes
Individual Litter Da1~a With ~4~an Fetus Weights
r~ ~esee nGGaerroauvnopy.
,hd R~ NO.
eaves (~ mg/k g/day
VIELFE ETUUEAS L_ERES SOR INFLANCOFPrm VlI%:LE FETU'E,E3 DER[:,
WF TOTAL FETUSES STiItOeNs TAsTiItOeNs LUTEm I1
F TOTRL FETUSES
RE:5OF:
PT]Ohl
SITE~
IHF'LRr.t
TRTION
SITE'--.
COI~'F'I-Tt~ LU]EM
FER FETUSHIG: 1.1E~t.I FETU:: NI',G,
nih hb t-+',..'G
I'.1
F
sweha3sTiIeEs oT44 PRE27GNAaN1T1
oe
0
omwaesaseEss
NOT PF:EGNRI'.]T
3a8oe oau zo 4. 8 12
O
wweeaagsseesR
2.:
6:
133: 1
3
1144eeOo0e
wmrhamaen:3sos == 0
owrw aassiiees 4430735 ag95 o
h aewasa aeedsa:244:_.-3:: oso4?77a ai1l077 eo 8000o
iIniie 1144775555 NNNOOOTTT PPPRRREEEGGGNNNAARNNNTTT
wwoke earse NOT13 P2RE7GNHHaTF e e6
iIweFer
aae4r777ze 34775
77 6ao2ar NOT7 PREWGNAN1T1
eoe
8
Hwkeaarssee
NOT F'REGNRt~T
s4oa46S@oe 4 4
~
0
e wm 7 Ii onioa e a6 a1a2z ia LIacoiniisEsi4aes 6Taeoe a aawEdi4i ib sa44idasd3e 6 a5 aaxe 1as:oaoairoaazs s 6N1o R11 aLaiiaa d asuse
1 61 416~ az8~:
1e1 111ia4~4.
.1.2
1aa14
1"1.
11
i1 1 osw oonm
1
aa~1. z77 aa4.335 a44.i77
4. 2
at0iona6zoa3es 4 i/1
4. 3 4 0
4. 1 ~.. 9
5. 1 5. 2 4. I~:
zIsIoEp? dosE:
11225511..00002233
1100 007777994466
33MMAA0000332266774444
a.
23.
AAppppeennddiixx VVII ((CCoonnttiinnuueedd)) Ora) Teratology Study of BIZ in Rats IndiOvriadluaTlerLaircocleorgyDaSttaudWyitohf MFeMw-s34F2e2tuisn HReadtgses
In~ividua! Litter Data Wi~h Mea,, F~ W~ight'-
rneGreo,w VIWMELEE FETTiUoSTEeSl reTvEiMsGes No.
~msprs/any
D mg/kg/day
cwwwoaaa15z2ezE9e0 comaCmE e 3as7
weraa1g5-me'-'9er3: 4243 eo&
Lo wweea1a5m4l1e0 45 73soa 6
TO"uiL411555: 44#111:512 NcOeTnPREGRANT
Gwhw od1a5es4a1as4s 25 arazaz 1e
1~,4~.
waagae: 14761
68 3oz aaze
o6
mweea111s4437Tt766"e~E-s:" ffzas5
hGwE 1d134a77t66e14s oER7C 3 oan o
Df , oWuuFeE,' 21l1e 34a4777782e8~32z:
6A 5I]a1 NOT PREGNANT
uoFe 111244447777886745s 5787 aa1z eoe
14797
ERrEiSoGnR TIeFmlLoAw CLUOTREFREm MAEvnie FETnUSFWIG sires Sites
2s 1a7ae 1FI a0 a1
sie ois ze s 1i3i3s3z3e s iIsIIis iiae az ia 7 33
e 4a4z 2a3r 6e iazw aaz 6aoassoa. HOP 17a om 61 aizz aomz
a1IoI3l%oaaaa 3Z:a Iaiziz: 3i7 iEsdsa
3a7:3553 3s1e aZ4e a338 3e8S
11225511..00002244
11103 807777994477
33MMAA0000332266774455
Hi 2
Appentix VI (Continued)
Appendix Vl (ConUinued)
OOrraal! TTeerraatcoolloogmy SSttuuddyy ooff PIH~--33462222 iinn RRaattss IInnddiivviidduuaall LLiitttteerr DDaattaa WWiitthh ~Hoew~ FFee~tuus~ s~iugihgths~
\ocavte GGrroowwuops.| Rat No.
VVIIR~EE:LLEEFEFETTUUES,EES~ DDEE~R[,G RREESSOGFR: IINHEPLLFAiNNCCO:OR~:FF'FF:FA~ MHEEARNNFFEETTUUSS Wi 0
MF TOTAL FETUSES PTION TATION LUTER fv hE H
F "TOTF~L FETUSES PTI,'~N "TBTION.LUTFF~
~'v'G
I'!
F
Sires `Sites SITE~ SITE5
2.5ma/xa/any .:;7.5 m~/k~/day
E rec E WE aziEe 5 6 an
wCisEe 3E 0sy o
wpeee 1ti5sa4a1dn5 wir
E 688 3o3s 0a1z2
Efaueers1155a:44a11s89
528
88 3
aa4ele
biwioal!aa4a7ees6sr~ 54 3 248 .a1 8
IIrF 124477S7E0 NOT5 PRE4GNA5NT e
a vb a14d7r~e6s NOTi4 7 a1 te a1a4r7sBs~ 14 6 8
eo e
wtooee aaaarrssee 17 72 8 6e
~4798
o e + a1
a==
Z3e73Z%e3:s 33 35 4:
z 1 aaz 2e1 ae31 3a43 iies
ia12 aa 3Zse 4z6s 336s
1 aam ai
aaz ai
4iI7zg
sa3o 3a
az4e61
z 3 e a: ea3 i3o7 33s133sS
18[FE 2a
asi2as 1 a1
330s 43
33zs7s
1 225 1 28
a1e2 1
4a41 aa32 4as1 5s 38 3%
i es s 3Te a433 333Iasse
11225511..00002255
1100 007777994438
33MMAA0000332266774466
