Document b5b00YK8LDp6Mg1QJeZxEmadk
T 3253.5
Ore Teratology Study of mi-3422 in nats
Experinent Ko.: ---- Soatuatee Dosing Testes: study bisector:
ossoroo0 SSBattteBtayum dv,alWuiano tmieosnorsLaboratory August 19 to september 4, 1980 2 0. contnee
<A SeCnioSr Eesraeiscoh nTechnologis)t-282%-% AStianyaDRireecpeoertto rereieiagy
RLe seEaCaze0 nm4Vevp8 eorminrpaB, ruWyde,Pdat5choloh1g-is2tt2-9,)eE
HManaagesre,esPsathTOoleslet-etoxicolYog1y 3/541 Satery Prateneion beset
004233
1. Summary
Oral administration Sprague-Dawley rats
of FM-3422 at during days 6
t75h,rou3s7h.5 15anodf 25cesmtaa/tkigo/nday(pteoriopdreocfmant
iorngcalnuodgeedneasidse)velowpasmenttearlateoygeenaibcnotromarlaittyf,etucsleesf.t
Teratogenic changes palate, blood in the
kidney
parenchyma and appeared to be
asntearrnreebsrtaeinmaldfeovremlaotpimoennst. of Thtehedepvriemlaorpymenlteanls
eye abnormality fibers forming
tsheeconedmabrryyonlaenls lfeinbsernsucolfeusthefofleltoawlednubcylesuesc.ondaTrhye
aberrations proportions
of of
the fetuses
iwnitthhetheconlternoslchgraonugpe.s weCrleeftsipaanliaftiecsanwtelryehpirgohdeurceidn ainlltFhMe-375422andgr3o7u.p5s than
bmlgo/okdg/idnaythgeroukpisd.neyAlplartehnrceheymgar.oupTsherecsetiervnienbgraceomcphoaunngdesh,adalftehtouuscehs
with normally
considered skeleton aberrations, were viewed as compound-related
mianlfootrhmeartifoentsalbesckaeulseetonofabtehreriartisoenvse.rity. FM-3422 also produced an increase
FM-3422 was not eabryotoxic tract contents of the dams.
and
did
not
affect
the
ovaries
or
reproductive
FrMe-d3u4c2i2ngwatshemiartegrrnouapllmyeatnoxbiocdytowetihgeht75gaainnd d37u.r5inmga/tkhee/ddoasyindgoseintaenrivmaall.s in Tgrooxuipc. clinical signs and deaths occurred in only the 75 ma/ka/day dose
004234
2 Introtetion
CaTSonhpndiodsnutsceottrreeaerdtdaotbsobyelynotighcye seCftoSfuamefdmceyettrsycioaBiflvnaColrrhuaeetalmstliiycowanalasLdamcDbiioonvnriidassutitcooetrnrey,ed,dSttMRo.iakeevPiraascliuL.,aatbMeoTirahnttenhoeerssioteetamsedb,yrayvnaoedtcroevx,aisc
bDSerc.itnuccTieopnuat,lAuMpgiaunrsntteisc1oi9tpaaa.nntdstSweaopn.tdesmesbtuespreorfv4.iscoo1r9my0o0u:pnedrsTooaneennePisrnoitscoeucnrsalbteiaonnfdousnr1do1uspisnofwAeprptehe.enddiocseesd
Tana I respectively.
AOPLprLearcptaiotcrietnigo(nPGsLrEo)cofedxuterhmeiissats(itsouensdsyApavpneedrnetdhicexondST1ua1cfteerfdsorsPcvgoauoiarloidatitynigoAnstsLouarbtahoenrcaetGooroUynditSLeaabnosreartsory
prsFtioanvatlmiennrteg)p.ortTh1es
mstaoirnatgaei.neldockitniohneFoSrafestpyeciEmveanlsu:atiroan .
dLaatbaoraatndorya'scepryecoofrdthe
Methods
TBciraneneeddominantgmeuLdmabbeSropsrraatgtouarebyleD.aanwdlTehsyeardiergrantiesvsevdcearrceaetssthewanecreedoirvceihidaneidnFeeidnaefcroofmmopusCahtaegrrrl-oeusspesneRriofavteer3d2
CeaonnmispmieanrlgastuwFreaeidgmahniadnlgshu1n4si0taeiettdoyc2c4ao0n?tgrraoWmlIslt.ehdwiTrcohohem.SathsFaowSeirgeneahrnodu1wsaetdenrionwndeierveicuaaviaaiiylbilne
ad Tinie. Tne Tionts vere on a 12 nowt 1ian/dark crete.
Ta1h5benoarnadmnaila2a0l'csolfivnegirceeasltaotbsisioeanrnav.eadnddBatohidelyyrwaeftirsgonntdsodsaeywder3eactehrroeorcuaosirhndeddidyaoywn2i0dnagvoefag3ecsotn5asttia8onnt 1d5f.ooers
vF(o-Ll3ou4tm0e27284o)wfas5susmapige/nkniodneissotfdearbieolddyyGavinieldysiob.my
oiTlheatfou0,r 1s5osup5s7.5veerxe d25osnede/wriac/hayF:343 oral intubation with a syringe eniipped
VaGinetashlt'yaattiicboaanlll(c-ahtaaiyrpap0cetdienrdiiinsctauatbtiaeotdniobny(sneseepeedArlpmeppeontsdoiitxtihveIeV)rvatwasagsionnparldoavsvicedeed)5 .btyhroMvAe-h5C4o71m25ercial
Chemical Division, St. Eau, Minnesota.
CtAoLh"Ledaostvuearrrvmiiievnsienganthaeentuntfaeolrlsulso,vwienriaen:clsaandcuirmnibgfeircietodaf conocnotrdepanoytrea2s0lwubatyornec:eremvviabcneailnreddiOfsslmovmcieaddtbiilseocnelaynd
BEfoeoutaiulsne'ssa,bnsoonrlumumatblieiortnioeffso,rressouArbpsppetrqiouoreninmtsaitteleryse,eonnpauenptdhWiSEreIecGtHoiSfontiahnnegd fbsyeexu,tsheeasndWwilaesnroynsFionesd in
SCpiaricezhsaneririqvnueesretidon tadoeltodeneronmleicntefosvrkiesclcleeetraaarllinaagbbnnaoonrdrmmaaslltiiattiiineeissn.:g ofSTheelsehecrteemsdakiefniisrnregeenhFavonicdtushessectwieorens
Vere processed for histolesical svalmstion
2 pRuirkienreELxapbeorriamteonrtytoC.how0,660RTaRlOs0t1o0n Purina Company, St. Louis, 0 004235
3.
Results and Discussion
FN-3422 was maternally ma/k/day) in reducing
toxic their
to the hich and group mean body
mid dose groups (75 and 37.5 weight cain during the dosing
interval. weighinas
All groups had lower mean during the dosing interval
wofeidaahyts g6ainthrtohuanahth1e5
ocfongterosltsatiaotn all
(Table 15 and
1). In the in the case
case of the high dose of the mid dose roup
group at gestation days at gestation days 9 and
9, 15,
12 and the
ogfrotuhpemceoanntrwoelighgtrougpain(s0 mwge/rkee/sdiamyi)f.icaTnhtelylowleorwemreatnhanweitghhet megaainnsweiofghttheqains
thhiecihr asnidgnmiifdicdaonstelygroluopwserdmuerainngbotdhye
dosing interval weights between
were responsible for the end of dosing and
the termination weight gains of
of the study the low dose
(Appendix aroup (25
V). The mean body weichts and mean mg/kg/day) were not significantly
different from the control.
dAobsneormaraolupc.linTihcraelesiraatnss
winerteheobshiegrhveddosaendgrdoeuapthsdieodc.currOneed
only in the high rat died without
clinical abnormal
csoimgnpso.und-Trweolaotfedtheclirnaitcsalthsaitgndsiewdhipclhusinonceludseudrvisovmienaofratthehad
following: and bloody
thin, nares.
lethargic, The onset
ataxic, blood in stool, urinary incontinance of abnormal clinical signs was on day 11 but
the signs remaining
d1i8sahpigpheardeosde inrattsheansdurtvhievimnigdraatndbylowdadyos1e9
of gestation. The rats did not have
abnormal compound-related clinical signs.
The compound reproductive
was not embryotoxic and did tract contents of the dams.
not affect the ovaries or The mean number of male,
female,
total sites
and and
dead fetuses, corpora lutea
the mean number of resorption sites, implantation of the three FM-3422 dose groups were not
significantly different from the control (Table 2, Appendix VI).
FM-3422 was body weight
gnaoitn fe(tTaalbletox1i)c.pluHsowehviegrh,er tnhuembceormsbionfatifoentusoefs riendutcheed
maternal treatment
wgerioguhptss tohfanaltlheFMc-o3n4t2r2olgrgoruopusp
(Table 2 Appendix VI) resulted which were significantly lower
in mean fetus than the
control mean fetus associated with an
weight. The increase in
reduced runting
mean fetus weights were not or other gross fetus findings
(Table
3.
Fcha-n3g4e2s2, aadlmtihnoiussthratnioornmalrleysuclotnesdidienremdalfsokremlaettoinonasbeirnrafteitoanls,stweerrneebrae. The
Tihnetersepvreertietdy asandcoomfptoeunndt-hreeliantceiddemnaclefoorfmatsitoenrsnebbreaceausmealfoofrmtahteiiornssewveerreity.
greater in the three treatment groups than the control group. These
mbailpfaorrtmiattei,onssterinnecblruadeedsctrhaembfloeldl,owisntge:rnebsrtaeerneebnrlaaergeads,ymmsetterrinceablr,aesmtiesrsnienbgrae
and sternebrae misshapen (Table 4). significantly higher proportions of
All three FM-3422 dose fetuses with sternebrae
groups had asymmetrical
than the control group. In addition, the hich dose aroup had a
004236
a
tshiegnciofnitcraonltlyarhoiuspher proportion of fetuses with bipartite sternebrae than
FnAUon-n3oi6sn2sc2irfeiaadcsmaeitniiionsntortcahhteainrognes.skeolfTehteotsnhee acsbrkeaernlrioaattloinonbsoanbeeasrlrsaaotnidoocncssutrerrienndecblruaadscedthpelusresoutlhterof
scshtiaegnrngnieefsbircatachnatnalnydthheriiccbheorncthraponrlgoepsoarrto(iTuoa.nbsleTohf4e).fmeitdTusheaesndhiwcilhotwhdoadsloeiseoafrgoruotpuhpessheahdasdkeleton
Rstihiesmsicifoningctaarnnotdllyg1r3ohuirpigsbhsernospptruaorbrpleoydr.tnioonnoTshsesioffsikcefaletetituoosnnesaofbweirttrhhaetsiocomrneasnioaffloutbnhodenseeasr,echsagtneedneresnreabltrlhayacn
cWiotnhsimdNe-r3e4d22mibneocraubsuet abnomalities.
otfheythearehigohf
parpopproerctiiaobnleofsiefneitutsiecsancweithinthtehis
study
dOTfihfeftehceroennvtcererotlevbagsrraoeuspibsihnpaiadfritcaiatnhetigthihnearnalplrthoepionrsttthiaroennecestofreeafxtecmteeupnstesfGorwroiuttphhseonf(eiTnadoviirnegt4w7oo.fboodTnhieiess body of the vertebrae bipartite in the low dose group.
ttFhher-e3eh6i2gd2hoasdeanndignrmtouispdtsr.daotsieTohnegrpopruropodspuocraetnddiotnhbseloootdferiafntootgtuhesenesiKciwdientfehfyeccptlaerfoetfnpccahltyeamftatepinaanlaaaitibeloiond ctiohnnatntrhoeilnkaitnhddeneycloopwnatrrdeoonslechGyrfmoeautupswee(srTeaebxlsaeing5ii)nf.eidc.aNnotlyClehfieshepralaitnesthewerheichpredseesnet.arinoun
aFd4n-i3n4i2s2tvearesd tienratthoigsenisctudtyo. abromality which appeared
thTeheeyteeroaftotsheenircatefaftecatllwadsosae to be an arrest. in development
dleevveellospmental eye of the primary
alabebnneosrrrmafatilibioetnrissesfofovremtrhieenglsoethcceaolnidezaaerbdyryotlnoeanltshefleianbrseerssnuocoflfeuttshh,ee
ffeotlailouemdaclbayses.ecoani1arayve eabryonal lens muclews
allotcahtoiuognh. a dissecting
Tmvhiaecrrioerstacynocpeoefofmvoarmrpoihreopdlhoofglrioocgmailcaalasplapipegpahertaarndacinesscceosvleorraseatiopobrnseesrervneetmdnwitinitgnhdisenrhrttohnueadt
tbheenealtehnsthteo were due to
alednsisceopliotrhaetliiounm the presence of
ol(feTnaspbalvreet5s)oi.cflethHeiresmtlneonalsnotgsiacnfadoltrlhayeintpghrecelsdeeifnseccseolooofrrat5iocnlseft
ppsrrueirsmzeaonrucynedlieonnfgsdtehfgeiebneleresrnastvehndiucchlsepuiastp.rpiecahrAeildaslotocceolhnlatsvr.eibnuotStiencegolnodtnaorgyattheeldenasainsdfcioblteoherrstpioosnsisblweere
edEeimvdbeerlryosopnmaielnnctl.nuupdcreloeugVs-r.sehsaspePedrdomnciolnreemfnattlslysbeeectxowcneedepantryithmaembeeerdmribaarttyieoolnnysalsoufnrurcosiueencwdosinndgaarnygthelleenmassbnormal
epithelium and lens vesicle remnants surrounding the nuciess.
vTahse psrioapnoirttiicoanntolfy fheitcuhseersiwnitahllthGeroulpenssthaabnnorimnaltihteycoinntornoel ogrrobuopth(Tlaebnlsees$).
004237
5
Nleovellensforabnthoermatleirtaiteosgenoicccurabrneodrmianlitthye
control was not
egsrtouapb.lishAedno-inefftehcits
dose study.
Further Discussion on Lens Embryology
dLeevnselosptmreunctturbaylthaneddifufnfcetrieonntailatiroenquiorfemheinsthslyarsepemceitalidzuerdinpgopeumlbartyioonnisc of
cofelltshefrroemsuulntdiinfgfetriesnstueisa.tedBoptrhocuprrsoecressseasndabrye tchoentrcoololreddinattoeda mroermpahrokgaebnleesis
etxhteenetyebyisinbtreoruagchttiotnosiwthsicfhinoaclcusrtataemonogf deimfefregrienngtitaitsisoune,s. itsEacchelltissue of
pproopcuelsasteiso,n, bustizealasnod byitsextderfiinnsiitcivienflgueoemnectersy,exneorttedonlbyy
by intrinsic neighboring
tissues.
The the
oepmtbircyovneaslicolrei,gipnreosfumtahbelyletnhse inseuurnadliffreetriennat,iaptleadysectthoederfmi.nal Threoletiipn of
inducing with the
rleesnts
offrotmheoveeyrel.yinAgddeicttioodnearlm
aacntdioinn
oaflitginsisnugesthdeerlievnesdprfercoimsely
tehnedopdreorbmab(ifloirtegyutt)hatandlenmsesofdoerrmnati(ohneawrot)uldonbetheabosratmeed tbayrgaectcitdiesnstuse
decreases during
ztehmeaienasrluynkpnhoawsne,s tohferiendaurcetioinn.dicWathiiolnesthtehatnatsuurbestoafncetshemaiyndbuecttirvaensifnefrlrueednce
inrdoumcttihoen.presAumpprtoilvoengendeuprearliordetiofnaintdouctthieveoveinrtleyriancgtieocntondoetrmondluyriniancreases
tihneterpfreorbeanbciel,itbyutthpartovliedness iandmuecctihoanniswimllforocccuorntisnuucocuesslsyfualdljyusitnintgh,ethfeacseizoef,
shape, position and orientation of the lens to that of the retinaZ.
Diumrmiendgiattheelyeaorvleyrlystianggestheofttihpeofintdhuectoipvteicprovceessisc,letheeloneacattoederpmearlpencdeilcluslarly
tceolltheshbaopdeyissurafcaccoempltioshfeodrmwaithtohuitckecnheadngedisicn c(ellenlsvoplluamceo.de).TheThneumbcehrangoef in
cells, however, of lens placode
cfoonrtmiantiuoens,toaciidnocprheialsiecdufribirniglsthiaspppeearrioidn. theTowaapricdestheofentdhe
tlheenslpelnascocdupe.celTlhsi.s iAntvagaibnouattiotnhisistiimned,eptehnedenptlacoofdetheinvcaoanicnoamtietsantto form
oipnevraagtiinnagtiwointhofinthteheunldenesrlyeicntgodeorpmt.ic
vAessitchlee,lenasndcuisp
probably deepens,
due its
to forces opening
(lens pore) cutting off
btehecomleesnsprvoegsriecslseivienltyercnoanlsltyriacntdedreu-netsitlablitisshilnipgs cmoenettinuaintdyfuisne,
ptohsesiobvleyrlyaicncgompelctiosdheerdm.by, Claosluocraelofandthetemlpeonrsarpyoreresistriacttteedndewdaveby,ofacnedll
dleeantsh.vesi"Fcollelocwoinntginculeosutroeelofongtahtee,leunsndeporret,hethienfcleulelnsceatofthtehebancekuraolf the
rveetsiincal,e
tios
foobrlmitetrhaetelde.ns
Tfhieberlse.ns
Acselltshe tfoiybaerrds thaerowecttohdeercma,vitwyhicohf
the lens do not
elongate further, form the lens epithelium.
The cuboidal lens epithelial cells which face the cornea continue to grow
004238
6.
after the lens vesicle forms. region, they take their places
As on
the the
cells rotate through the equator surface of the qrowing fiber mass.
These cells differentiate into secondary elongate rapidly toward the poles of the
lens lens
fibers at the equator and where they meet with other
fthiebierrsnuicnlepilabneecsomoef pjousnicttiioonnedcalatledabosuutturtehse.cenAtserseocfontdhaeryfifbiebresrsanrdowform a
scuopnevrefxiclieanlslyb,owthoeutwoalrdde.st
Since the fibers in
ntheewerlenfsibceormse atroe
always deposited lie centrally and
are
nruecfleeriredin tothicsollreecgitoinvebleycoamsetphyecnloetnisc nuacnldeufsi.nallWyithdistaipmpeeatrh.e
lens The
cell cell
tfhieberssi,zehoawnedvesrh,apearoefnothtebrleonksenardeownconatnrdglrleemdovbeyd bfuatctorresmawihnicihn pcloancter.ol Tthheus
number, size and shape of the lens cells.
oTfheotrgearnaotgoegneensiicslebnestweeefnfecdtiffoferFenMt-i3a4t2i2onproobfablleynsoctciussrureedfdruormineacttohdeerpmoratnidon
the formation nucleus. The
of secondary lens exact time of the
fibers surrounding teratogenic insult
the and
etmhberymoonraplhogleennessis
of
tahbenoarbmnaolrimtayliatpypeawresretnootbedeutnjeqrumeinebdecaiunsetheitsthuadsy.notThbeeednevdeelsocprmiebnetdalasleans
caobmnpoorumnadl-irteylahtaesdbeaebnnorrmeaploirttye'd. toAgsciumrilasrp-oanptpaenaeroiunsglystirnucrtautrafletulseness but
wdietvhelaopvmeernytallowlenisnciadbennocremaolfity1.p28f".a
mTuhteanatbnomromusaelitsytrraeisnemwbhliecsh
the Fraser results from
degenerative primary lens cells.
004239
7.
References
1.
Coulombre in Wilson
AJ, Coulombre J, Fraser FC
(JeLd:s):AbnoHramnadlbooOkrgoanfoTgeenreastioslogoyf
the Eye, 2:Mechanisms
2nd Pathogenesis. New York, Plenua Press, 1977, pp 329-341.
2. Coulombre AJ: The Eye, in DeHaan RL, Ursprung H (eds): Organogenesis. New York, Holt Rinehart and Winston, 1965, pp 227-232.
3. MJaBnnLipI:pincDoetvteloCpo.m,ent195A7b.normalities of the Eve, 2nd ed. Philadelphia,
4. Wienisrsaets,I,miNcieggeasndchurlabzbeitAs,. StAortczheirvH:FuerSpToonxtiankeooluosgieco3n2g:eniptpal19c9a-t2a0r7a,cts1974.
5. HAnamaeilecY,trKounwambiacrraosTc:opiEcarsltuydyc.ytolIongviecsticghaatnigvees oOfphFthraalsmeorlocgayta1raact.(7): pp 517-527, 1975.
004240
6
Table 1 Mean Body OWreailghtTerGaaitnosloogfy PSrteugdnyanotf FRNa-ts342B2etwienenRaWtesighings
with Standard Deviations
Dgorsoe
ma/kg/day 75 mafke/day
7.5 ass
bs y/xafey 25 mo/kg/day
Ces5 t1a2 mi15 onbay
nee zz 17 26 28 7a
STAN. DEY 9.% 7.9% S58 4.8121
MEFN STAN. DEY
MEAN
STAN. DEY
nem
STAN. LEY
za 14.2
28
5.4
27
11.9
ea ea 2a g3 14.6 19.8 17.6 15 1
e2as 17 1428 63
16.83 9 & 16.4 15 &
11 20 zz 7
16. % 89 5.4 11. 6
2 significantly lower than the control (Dunnett's t test p < 0.05)
004241
|
|
_-- Daose
Table 2 MeaOnralLiTtetreratoDlaotgaywiDStethvuidayFteoitofunssPHW-e3i4g2h2tsinanRdatSstandard aWvo.imaolfs MVIRFELE FET__UToStEelS_ reTOhEcReDs RESSiOrResPTION IWPSLiAtNeTsATION LCOTPEPRGRA FFEETRUNSCTEI)T
marasany w 1266 514s 2s6s 6a0a ar7e
2sse
25.19 oasa
Teo 1 2S114273 2s1s aezi aass
110.s4 12025 2BE 7a
2S wsmnwaw 5
24a12514 15s7 eaoe oasr
10T.e4 11075 o4s00
&B r-- Berm--aye--y ----a --14-- 53 -- 15s8 --110-- s1 ---- aese ----ooss------1-- 02.07----w-- 1ss----04--028 --
2 signiricantly lover than the control (Dumett's test p <0.05)
10.
Table 3 Oral Teratology Study of FM-3422 in Rats
Number of Fetuses with Gross Findings
rr ising
--
Total Fetuses Examined Runted umbilical hernia Total Normal Fetuses Total Abnormal Fetuses
-_--
ows mg/kg/day ma/ke/day ma/kg/day
161
167
195
---
2
=
1
=
=
160
165
195
1
2
# Treatment groups were not significantly different from control (chi-square p < 0.05)
3m mg/ka/day
213 2 2
209 4
004243
n.
Table 4 NusberOraanld PTeerrcaetnotloogfy FSettuudsyesofwiFtMh-34S2k2eleitnonRaFtsindings
Skeleton Finding
mg/ka5/dsy __ ma/kwam/day maw/ks3/dsy
HFoolnetsaneilnlpearnioettacllosed Parietal scalloped
271aea 1
%1m@2 25 as
FPraorniteatlalnnoonnoossssiififeided
22a a99)) 6622 G(ENW0 ((sDn2a
OIcnctiepriptaarlientoanlosnsoinfoisesdified Stemebraenonossi tied
14 (12)
541@n2 46 (338
N10 602 102 7a
SStteermmeebbrraaee baispyamrmteittreical 02 ) Stemebrae scrambled
32 GGaez 3es sa 1a) 1
SStteermmeebbrraaee meinslsahragpeedn One sternebrac missing
23 0)
1 2 ee
a1(2
TTwhoreestsetmeerbnreaberaemimsissisnigng 2 2
11aa) ms (0
O1n3eribbosdy vertebrae missing 1a
13 ribs spurred
3 3)
130a) 3 2 2 ea 28 Goa
pWraovtyrursiibosn on ribs
55 @(7)
128 an 5ao
Onbeipbaordtyitoef the vertebrae 29 (26)
15 nk 2a as
Wobibpoadriteitseof the vertebrae 17 (15)
4 2 5 WR
Thrbeieparbtoidtiees of the vertebrae
1
Fobuirpbaortdiitees of the vertebrae
Fibviepabrotdiitees of the vertebrae
Total Normal Fetuses
5 (
2@ 6
Total Abnormal Fetuses 14 0 14 68) 12 08
Total Fetuses Examined 13
16
138
23Sisgionniiftiiccaanntcllyy hliogvehrerthtahnanthtehecocnotnrtorlol (C(hCih-is-qsuqauraerepp<<0.00.50)8)
() = percent of total examined
me/ka/day 2 a9
77%5 ((ss0)ad
59 (40)
aas aGs)d 5
136 a22n)e
5so( 27 m(5)
30 (20) 3 @k
zw Tw Tw 7 12 65) 109
004244
12.
--
Table 5
Oral Number and
Teratology Percent of
FSettuudsyesofwiFtMh-34I2n2terinnalRaFtisndings
Eovesnal Findiingtn
T mg/kg/dao y mg/m kg/day
msm mo/ko/day mg/kg/day
FetDuissecsolwoirtahtioeyneraubnnnoirnmgaltihtrioeusgh 0
Ditshceololreanstioonf
one eye running
through
Disthceololreantsioonf
both eyes running 1/2
to
o3n/e4
through eye
the
lens
of
Discoloration 3/4 through
trhuennlienngs1o/2f
to
Dibsoctohloreayteison in back of lens
Bubdbilsecolonoraotuitosniderunonfinlgensthraondugh
the lens of one eye
Clerfutnniinngthtehroluegnhs tahned dleinsscoolforation
Cloenfet einyethe lens and discoloration
broutnhnineygesthrough the lens of
Bubcblleeftoninoutthesidleensofofleonsne eye
OCpleenftspiancetheinltehnes orefaroneofeythee
Smallelnseyoefsone eye
ECnlleafrtgpeadlaatteriuns
Enlthaergkeiddnreeynal pelvis area in 5 (10)
Blood in the kidney
Abpdaormeinncahlymcaavity full of blood 1 (2)
3 emt 7 a3 16 6D 5 ao 1@
5 10)
1@ 1@ 7 ant 1 (2) un et. TE
29 (snd 2@ 13 ea? 1@
7 ant
1@ 1@ Ec 35 3s
TToottaall ANbonromramlalFeFteutsuesses Total Fetuses Examined
426 ((8172..55)) 438 1(884))
a8
51
2352 ((5464)) 57
2 significantly different from the control (Chi-square p< 0.05)
27 wd 1@ 1@ a ae? 5 (8) 2
4 (8
1@ 3 1@
2 1@ 1@ 3322 ((5500)) 64
004245
13.
Appendix I
Oral Teratology PSrtoutdoycoolf FM-3422 in Rats
Objective
AeffteecrtastoolfogoyrasltluydyawdimlilnibseteruesdedFMt-o34e2v2alutaotperetghneanetmbrraytostoxdiucrinagndthteerpaetroigoedniocf FoDrAganiosgseuneedsiisn. JanTuhaeryp,roc1e9d66ure("cGoumipdleileisneswitfhortRheeprgoednuecratlionrecStoumdmieensdatfioornsSaofeftythe Etovatlhueati1o9n78ofGooDdrugLsabofroartoHruymaPnrUascet"i)c.e reTgheulasttiuodnyswialnld bSeafectoyndEuvcatleudataicocnording Laboratory's Standard Operating Procedures.
Sponsor
34 Comercial Chemical Division, St. Paul, Minnesota. Testing Facility
safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota. Study birector
E. G. Gortner
Start of Dosing
Mid August, 1980.
Test system
Eighty-eight 7om Charles
sReixvuearllByreemadtiunrge,LabtoirmaetomraytewdilSlprbaeguheo-uDsaewdleyindhearnigviendgfsetmaailnelersasts
cstoenetlroclalgedesrwooimt.h wiThriesmessthraifnlooorfsraatnsd wfirlolntbseinusaedtbeemcpaeursaeturofe hainsdthoruimciadlity
Cchoonwtroalnddwaattaeranwdiltlimbeemaavtaeidlafbelmealeasd alirteibruena.dilTyheavilliagbhltes.wilPlurbienaonLabaor1a2thooruyr
light/dark cycle.
Test system Identification
oBuatcshidaeniomafltwhiellcagbee. ear tagged and that number will be indicated on the
Randoni zation
nThuembearnsinatlabslew.ill be assigned cages according to a computer-generated random
004246 ey
1a. Appendix I (Concluded)
contro article
Com oil.
Test Article
Fw-sa2z.
Anatytical specifications
The test article, composition and purity will be determined by the Sponsor e(n3dM oCfomdmoesricniga.l Chemical group) prior to the start of the study and at the
Dosage Levels and Experian Design
TsTahutesspetnoesnsitodnaayrstaincdletchornwotiurllgolhbea15rstuoicsflpegeenwsditeladltiiobnnecaaocdrcmoirnodiilisntgdeariesldoy.tbhyeoTrhFaeolltlseeasittnusah:ratciicolneto the
Dose Grow
Dose Lever
crow size
High
75 mg/kg/day
229
Mid
37.5 mg/kg/day
22g
Low
25 mg/kg/day
22%
Control
0 mg/kg/day
22g
KTdnheoefwinnoreadtlobyirnottuehteirsfeorfreouawtdiemtihinnitshtaerarttaeinsogtnefawirineldileerlbese.tuudsye.d bNeocaudsieetetrosxicciotmyamhiansanbceeenare
a1T5hbenoarnadmnailm2a0lcslorinwpiirclealglnbaesnicgonybss.aenrdvBeotddhyedawirlaetyishftdrsoosmweiddlalaycbc3eortdhrirenocguolgryhdedudasuyinng2d0aavoecfogonoetsebtnattsiodno1sf3or
Volume of 5 m1/kg of body weight.
TVihlel fbeemaelxeasmwiinleld (Live and dead),
bnteuombkdeeirtlelroemfdinorene:sodraypntuim2o0bnearsniOdtfetsch,eorpnovouarmrabieeurst,oefsu,itmemprlubasanearantdoiofintsfoerciuoemneet.senptusp
wteeiicxghehnditqiunaenBdotuogirnod'sessterasmboinlnouertmiaoalnniytfivoeirss.cSeurbasAlpepqrauobexnniotmramftarelelieyt-iheoasnndeu-Ssteihcnitgridoanoidfnigstshoeeyc.ptuispnhegs
AWiislisonhi mievescope.
Tfhoer rsuebnsaeiqnuienngtaspkperloextiamlateexlaymitnwaot-itohnirdasfteorf cthleeaPruipnsg awinld)stbeainfiinvgewiitnheoriimsarsiinoinroeld.
Data Analysis and Final nepore
sDTiuhtneenspe,rtotnp'uosmsbeedrtesostftatiifmsoprtliadcnaatlmatamineodtnhpoduisptewtseoigbahentdsu,nsuemndbuemfbroerorfanofacolryfpseoitrsuas.eosfT,uttenhnue:mbdeaerthaio-fsardeir:eerseorpftoiron Pdeertcaeinltedabpnuoprmeaxlaimtiineast.ionsThehavperobpeoesnedCodamtpeletfeod t(haeppFrionveidnatreepsoyref.irisst3auarmcoenrc.hs1e9t6t1e)r
004247;
15.
Appendix IT
Oral List
oTferaPtroinlcoigpyalStuPdayrtiocfipFaMt-i3n4g22PeirnsoRnantesl
nave Bawin G. Gortner Elden G. Lamprecht Cathy E. Ludemann Gary C. Pecore Loren 0. Wiseth
FUNCTION Study Director Veterinary Pathologist Coordinator-Histology Supervisor-animal Care Technician
004248
Appendix 111
STATEMENT OF QUALITY ASSURANCE
16.
STUDY NUMBER: _0680TR0010
TITLE:
SO=rawlTTiero aytolw oogyfStrudywofdFNz-34z22 iin nratms ats
AUnuidtitsforantdh/eorabionvsepecttiitolnesd to management as follows:
wseturdey,peanrdforrmeepdortbeyd tthoe
tRhiekerstuQduyalidtiyrecAtsosruraanncge
Date Performed
20 August 1980 2 September 1980 20 and 21 January 1981 22 January 1981
Date Reported
21 August 1980 4 September 1980 22 January 1981 22 Janaury 1981
( LhabeoraotrotreyrsQtukaolnity Assurance Riker Laboratories, Inc.
January 22, 1081 te
004249
--------
Appendix IV 17.
Test and/or Control Article Characterization for
EM-3422 Cor 384
b
Cimetentiey
tinent chara
strength,
uniformity,
comosicion,
purity
or
ther per-
-
been determincetderainzdatdioocnusmeOnftetdheasteosft
) control substances have
G[hoe rmeethnodhoefLEanmtohuensits4oxx
otrhieg'mienthoof
the
/4,
tat.
and
.
controrsubstances,
documented.
veo
X_
n of biosssay (oF sonitoniaes no
CordmTiehnare"dgFfoaoxABrvLmiLalLtlYibooefndtaehntedertdmeoiscntuemdaennsdts/aoorfcoCnatrnolpesutbsitannceds Bhaovee FpeandeterH Wecesea,
cords.
tion are located tn the sponsors er.
o
SpDons2or .A
ShDaitelo
004250
a [-- ----,
18.
Appendix v
OIrnadliviTdeuraaltoalnodgyMeSatnudByodoyf
FM-3422 Weights
in of
Rats Rats
With Standard Deviations
mDadnodsReaRGaetNrNeo.o. w336655m gr1may4155 wm
B MG/KG/DAY
NNOORR 1144778557 NOR 14760
120346 213
223346 28m
d24z8 257
227768 2m
ozedd 21
33767 es
NOR Nok
14776 14777
NOR 14775
184 232 186
us 2z 213
222 274 232
24x 307 284
ra 341 237
iim 4ze arr
NNOoRk 1144775860 NOR 1538S
122560 157
2252%6 23
227312 251
z25ean 271
3z2o6e zen
s2a4nzea
NOR NOR
15367 15388
NR 45383
188 113363
216 Z22e2
23% 2Z6a4z
264 2z8e6a
232 32322
Gre daoee
NOR NOR
15465 1840
Nek 15467
184 15% 238
2Z2e0a 267
224103 272
226315 287
22aam 342
tipisp ten
Nor NOR
15483 15403
NER 15425
233 193 454
258 218 171
275 248 Zee
ee 263 232
331 287 258
401 ara 13
VERN STAN. DEV
200 21.8
229 23.4
245 20.0
274 22.1
zem 22.
371 26 7
NON PREGNANT ANIMALS
NNOERR 1144775538 221102 222434 222568 224723 224638 e2e9d%
NNORR 114573785
113342
222225
224237
224545
243 252
280 20
004251
. Aependix V (Continued) OInadiviTdeuraaWltiocl1hongdSyteaSantdnuadzyBaodoDyfevWPie-ait3di4ho2tn2es oifn Raatcse
mmmewmBrnee..n TT UTg 5eG mp mym
75 Hakoe
OOOOooFkk 1s14a47v76e6::1 OU 147s
1i251a%8 13:
2b21i41e7 220
0am0ie aon
gSaiisops G45
fbzaasi Sus
oazoner ses
OOO0OOo6KFkk s11144a477v766e:25 Oo 1477
Gc2Zou2obp:0 1g:
2Z22a36an30 21a
a2IZ6o;o7 ia
Sa2cgo3ead2 237
oe3261ss36 So
e3as8aew4pr hos
Ook 1530 ire Lui i: seo ioe oa
OOOOoooOkkkF 1311555%33:39:341 Ook 15410
12Z233a04a4z iss
c2o23o88so33 zi
Zn22a2a:r8 215
Sg215e9a7s1 1s
fsz1eo6ann8 155
oazabeaod ses
OOObGORFK 41155544421164 121314%30 222142a01 2s2e34d13 2cZ4oi3sp ss2r3se0 soseasns
STANM.EADNEV 22z.o1n 422361 172.32 26a.n6id25ec7ka6ii%d
Non pect snes BESTCOPY AVAILABLE
OQODBOoFKRF 1411554a4477118e321i 2122220%438% 222a444i153 s2iaai0nsa8 f11ia67rb97e Gaiaeeodsa 2e4s0eda,dl B8siagtnisciiecnantiy lower than the control (Dummett's test p <0.05) eeeeT004252
Aopendix v (conimsed OTrreeltvTiutraailtoatnodsSswtesantnuidnoynoptf rTei3-4ss42z22 t0n nmaaccee mT imEeee. e
MEAN 203 230 237 sdb 26d ub
Non PREGNANT smALs BESTCOPYAvAILABLE
2 Significantly lower than the control (Dunnett's t test p < 0.05)
oT004253
2.
Appendix V. (Concluded) IOrnadlivTideuraaltolaongdyMeSatnudByodoyf FWe-i3g4h2t2s oifn RRaattss
With Standard DeviationsS
fmemaammetvveo.. F6 T0 er 9 -- 1 i am -- m 25 neoka oR
CGOFR 1144777712 ok 14773
221322 1532
222264310
222264557
Z2es:z 2%
253m3m ave
ierre ab
OOORF 114477774S OOF 147S1
Z1e8:2 217
2Z3i5p 281
224118 zes
22z53e16n
ss9e8e 318
soarg due
GGOORR 1143775532 GOF 14754
222011 215
22524% 248
3a5z1 264
2r6a1 2e4
sseess 331
aaed oe
OQOaFk 1144775535 Q6F 15400
118573 153
22122: 131
Z2o2%r Zor
2Z3a6 14
a2p9e5 a4e
daaee ao
OGUSRR 1155446612 OF 15403
z1o5s1 17S
223167 212
2253%% zoe
c2e4s8 208
seasr 247
ahge 314
OGOOFR 1155442604 G9F 15421
211932 183
224210 207
222155346
e27z4 234
239610 295
sseors ses
GOOFF 1155442232 OOF 15424
212885 27
225136 257
z23e1 25a
caapr sme
sZaen ses
deenn See
STANV.EDRNEV 152.081 225208 122.4502129%=212e61 253m=
Hen peanut ants BESTCOPY AVAILABLE
OF 15428 156 225 23: 234 2ze 2m MGeuamnnsetntot'.sstigtneisfticpan<tly0.0d5i)ferent from control
004254 ---- ee, , --
22.
Appendix VI IndiOvriadluaTlerLaittotleorgyDaSttaudWyitohfMFeMa-n34F2e2tuisn WReaitgshts
aDnodseRaGtroNwo. --_-- 0ng/ka/day
VIRMELFE FETTUOTSAELS FOEETRULSES
FRTEISOONR TIANTFILOANN LCUOTREFRRA SITES SITES
fMEuANorFEiTUS IfID
SUEeve"
NNEORR 115S3I8S5E NOT4 PREpGNaANgT
NNoekk S1T5E3E5R7 Mek 1538s
z4ose a1)z 1 zg
a a
Nneokk 1155di06es Nok 15467
is3sog oss
o@ a
NNoik 1155440 62:4 Nef 15425:
75 4
ge@ 7
0a
NNoEkR 1144775576 NOR 14755
2a 67 a1og NOT PREGNANT
o
NNOoEk 1144776505 NOT1 PRE2GNANT3 Ne 14776 3 7 aa
e
NNeekk 1144777787 Nok 14773
77 46 aaz1 NOT PREGNANT
ea
NNookk 1144779856 54 44g9 @
01 i 11122 4a 10a 2es11 183 8a 117 1s
1 18a 1e 1411 11408s
7 33% nz za 1au8 axs7 dzee azea & 4414 4a55 az4g a118 aalds aalza 4aas 1182 a4zg 44:7 44:s a174s az Sasb a4sa 5 44 4a aa
12 4427 a453 4a17 111a 4slai 4s0z zies oau1 Isss Yose? zsiz
ese--ececees
004255
Co
23.
Appendix VI (Continued) Oral Teratology Study of FM-3422 in Rats Individual Litter Data With Mean Fetus Weights
Dose Grow oad Rac No.
VIMRELFL FETTUOTSAELS FEDTEUDSES-- FRUEISoONR TIRNTFILOANN LCUOTREFRRM SITES sites
fMEvR|FEnTesUS Ti)
25 ma/ka/any
OoBokR 1158335%1 DEA4D 3p a
CeOkR 11553355:2 COR 15384
62 43g 4 sg
a
00O6R% 115544161 45 7xga1 00k 15412 DERD
a
OCOOFR 1155441134 eR 15426
NOT2 P1R1EGNAN4T% 5 7 12
a1
0O6Rk 1144776621 ook 147eX
&5 23 112g & 2 1g
aa o
OCBORR 1144776654 oR 14781
75 44 43 DERD
e@
COOORF 1144776532 OBR 14764
1 5 5 g11 NOT PREGNANT
e
OOBoRk 1144776557 57 47 4112 ae
zs 11 107 s i s10 @ 41
8 1124 @@ 1182 a is a 142 1@ 417 11212
* zs 23 ze
#3 36 5 5 ze
izas x7
lzes 3a
az8 F3i3 3i;s ozze:
a424 aaz1 35s4 aag1 aaz I3z4 zigz o:z:: a2 3F6r 3xsg zosg a3 a1 4 41 ua5 4z7z 5oz3s s3eg 1113 aze4 3433 atag
004256
i
2.
Appendix VI (Continued) Oral Teratology Study of FH-3422 in Rats Individual Litter Data With Mean Fetus Weignts
DanodseRaGtroNuop. --_--
VIFMELFE FETTOUTSAELS
37.5 ma/xa/sey
PPeOkR 1155335565 43 5 5g g
PFOoRk 1155338557 53g& FOR 15353: 5
111
PFOORR 1155481165 POR 15417
5& 3& 4102 & 3 11
PPOORR 1155441138 Pek lives
&2 &3 114a 53 g
FPeOkR 114477667 POR 14763
4zg> a1 54 3
PPOORR 1144776750 POR 14787
NOT5 PRE4GNANT 45 5
PPGORR 1144776638 POR 14750
14 7 415 17 g
POR 14738 7 zg
FEDTEUFSOES iFSRITeETISEOsOSNR sTISAMeITFTILEOAsSNN CLUOTREFRRR MfEvAgN F Eh TUSp1171:
a e
e a s5 @1
2s 16
3 37 z3gs z3s3 az 4s 4:
o e
1z 221a i043
a1 az
4461 4443 3a4 zs 4p zg
@e a
e@ 1112 111
aa11 22
aIze 3z3g 4z1g 47 sa 48
@a a
cezat14 zs
aazs 8
3zi7s 43gg izose 40 a1 za
aa a
8esat 148
a51 18
4 zs a3pa iiao 41 43 ia
@e
18 125 1 28
10 1112
4441
42 43
a1 44
ze 33 1s
ee
1 a s5 a1E43 34 4413 ases
00425, BEST COPY AVAILABLE
--_--
25.
Appendix VI (Concluded) Oral Teratology Study of FM-3422 in Rats Individual Litter Data With Mean Fetus Weights
Dose Group -a_nd Rat No. 25 mo/kg/aay
VIMFELFE FETTUOSTEASL FDEETUASDES FRTEISOONR TIAMTFILOANN CLUOTREFRRM SStITeEsS sse1TesEs
MAvEeAN FETMUSFWTi0)
GGEERR 1155440010 66 4& 112a
o
GGOERR 1155440832 2ze7 118
a
GOR Ger
15484 15420
5s Ss
7 7
12 12
GOR GR
15421 15422
26 10
3 13
a a
Gor GR
15423 15423
s 3
7
11 1a
@
GOR GOR
15428 14771
NOT PREGNANT Ss 6 11
Ger GOR
14772 14773
Ss 2
4s 3 0s
e
GOR 14774 GOR 14775
3a 63
7 5
@
QGR 14791 GER 14752
5s & 11 zs 11
2
GQ6RR 1144775543 42 58 12
oo
GGEERR 1144779555 77 43 111s @
1 1112 12s L3E3 s3es 3372
81 1118 1101 4337 4a.14 a335
1 o
az 12
14 12
45 48
aE 48
aa 48
as 12
3 13
26 a8
38 az
zs ao
11 a112 1116 44.83 4448 zasz
1
az 3
13 3
41 48
az 41
am zs
1
&5
10 8
IE 3s
3s az
38 37
11 1210
12 1z
29 41
38 23
a2 a2
8 1
a1 az
1z 1z
37 45
3s 48
37 43
8 11
10 11
3S 48
46 47
335 aa
o 11 1z 45 45 45
------------------ Co
004258
LABLE