Document V36127mXDEKEx3nEe7Dkz58gp
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Oral Teratology Study of FC-95 in Rats
--
5 LopiXCa elerZere,bcZmloelou2 grpn0ts5s L ElClbkiSndN 52aAdmaampnpg, suneid i1u2l7s/=40 nar, Hote iceose
000615
1
Sumary
Oral administration Sprague-Dawley rats
of FC-95 at during days
doses of 10, 6 through 15
5 and 1 mg/kg/day to of gestation (period
pregnant of organogenesis)
resulted in teratogenic
fetuses with effect was a
dteevrealtoopgmeennitcalcheavnegesabninormthaelitlyenswhiocfhthaeppeeyaer.ed
Ttohebe
an
anurcrleesuts,in fdoelvleolwoepdmbeyntsoefcontdhaerypriambaerryratlieonsns foifbertshe fsoercmoinndgartyheleenmsbryfoinbaelrs loefns
the but
fetal nucleus. the proportion
oTfhefelteunssesawbintohrmatlheityleonsccucrhranegdesinwaasllsiFgC-n9i5ficdaonsetlygrohuipgsh,er
than the control group only in the 10 mg/kg/day group.
FAtC-9g5estaadtmiionnisdtaryastio12n
wtahsroumgahter2n0altlhyeitroxmiecanonmlatyertnoalthebod1y0
mg/kg/day group. weights were significantly
lower than the controls. groups.
FC-95 was not maternally toxic to the 5 and 1 mg/kg/day
FC-95 was not embryotoxic and did not affect the ovaries or reproductive nturmabcetrcoonrtepnrtosporotfiotnheofdanasb.normTahle fceotmaplousnkdeldeitdonnotabperrordautcieonsa.n increase in the
000616
.
2
Introduction Ta5nh4ai'sCtoetmreeraratitocosale)ongiyCsheesmftifuceyacltsoDofifviFsOoi-roa9nl5,lyinSiA.rmaitPnasiuslwi,aesrMecisomneFdsOuo-ct5t5ae.danthdo eweavsas.ltuceaodytnedwuectstheesSpebomyvb.erosyrhoeetsoxbiyc STPhraeot'teocccyoomlEpvoaualnnuddatsLiaiosmtniniLofasbtoetrahaettioporrnyi,npceirMpikaoeldrnpaaLsratsiofcrraiotpmoarnuitlesys:an1d4Intcsehu,epoewrSsta.hisoPJmeuaslly,pe2M4rsismom1me5es6ls0.tec.anThese Touma in Appendices I and 11 recpeckively: AOPLprLearcptaoitrcitenigo(nFGsrLoEc)oefdruterhgeisu.slats(itsouenedsyApawepnreaendtihcexonSd1au%fcetteyd0aBDvcuacaiolerisdttiiynognAstosLuarbtaohenrcateGoorRosdisLSvaabsnotdraaacrteeonreynt) TRhaeinsttaoirnaegeinLotchaetioSnafeftoyr sEpveacliummetniso,n Lraabordaattoarya'nsd areccoopryd oafrchtihveesf.inal report is ethos TLSiaanbbeloer.maattoTerhdyeaSpsnartaeqauswese-irDgeanveldtehyecnagddeesirviivAdecdeedoraditinsnkgwe5frhoeur5ogbceotomaupipunLseedro-ffsreo3n3mcrCaahntaiermdal.lessrawnRediivodemhsinnuBgsrbeee1rd7si5ng WCFoi.otoh2d6i1zangeraammwsea.stherTfhvleeoorrersatasavnawdielrafebrloehnotsuasdeindLinabdititevurimpdeeraTaihtieasreLiignahntPdsaRnvUieRnrLgeAieSoyneaiCnolm1e3csrhsooluisrotessLliFosochnae,g/edsark Crete. TS3h0henoorFamnaiGlmeaslCtslaitnviioecnraelanoabsisgetnrhsev.edradBtsoadiyldyoeseifdrgohamtcscdoayrwedri3engtlhryreocuousrshdiendgdaoy3nc2a0damvsoefiang5:test6dosastei.3.onvo13Lf,uomre15OFand dS5aaiutliy/uignintoufbsaobtmiooynGiluweiit8oh%hta0., sy10Is,hineg5efooSuxro1iSpmiEaoa/udkpes/idvtaehyr.sadhoFasOl.ei0d-5vtiiwtamhssedaTdmiCinnviibs(atLteoirwoen6d40dn)eaeidlslyuesbptyeonded VtSaHhgecionramalmtesrscomineaaldrasyCshemFioct5ah5lrouADsinhvailsy1itoinco,falgSSee.hsatraFatacsiitoe,nriMs(iaGntanyieosn0o.tian(:desiecastoepdebrysisapecopboossitSieveesided by AUELtoLelrluoasvn,innagil:nseTvuneturimenbgesraicosrfifccoiorcmpieoedrnaco.sn,LGiwnaeeynr,e20Smbnbydcecirenreovdifcmavelidaibdlaiestleoflceyattusiveoosn:deatnnedurmmtiehnree.oofvtaherrieessorparnd GtSrieeocnrttihosniiitrenasg,obfpyuttphheeweSAieigtlhostsosansavtnaaercsshenxFi,idreaendSdoiandnyaBtoegurrmoiisnnse fsveoitlsauclteirosanhlmofamobmrnaoiSriumbtasielegisit:einets.A:npFrrmoereeihmaanvdely CSkeemlaeitnoinngwiftehtusaelsizwaerrien prreedsettovedseteicntsSa ckoelneetalowrabnCoolremaarliintgieasn.d srSaeilneicntgedoffrtehce-hand
BiikneaExLpaebroirmaetnotryNoC.howo,sBs0aTtRs0t0o0n8 Purina Company, St. Louis, HO 000617
a
:
3
Results
;
FC-95 9oup
a(d1m0imngi/sktge/rdeady)dumriantgemtahle
period rats.
Tohfe omregaannobgoednyeswiesigwhatss toofxicalltodotshee
ghrioguhpsdose
gwleeerssestattsihioamnnildcaaorynstarto1l2gsestth(ar0toimugog/nhkgd2/a0dyastyh)et.hhriegTehhetdhmoresoeaunghgmranotiuepnrenraa(ltTsabbowldeeyig1wh,eeiAdgphpsteisngndoiiffxiVcm)ai.dntl(Ay5tme/kg/day)
tahned lstouwdy(.1 mgE/vkegn/dtahyo)ughdosPeC-9G5rowuapss mwearteemnaoltlyditfofxeriecntatfrthoem htihgehcodonsterollsevetlh,rounoghout
compound-related clinical signs were observed in any of the dose groups.
cFCo-n9t5entwsas onfottheemdbarmyso.toxiTche amnedandindumnboteraofffecmtalet,he foemvaalrei,es toortalreapnroddudcetaidvefettursaecst;
tfheetusmewaneignhutmsbeorfoftheretshorrepetioFnC-9S5itedso,seimgprlouapnstawteiroen nsoittess,igcnoirfpicoarnatllyutdeiaffaenrdenmtean
meraonm
ntuhembecronotrfolvsiab(lTeablmeale2,,
AfpepmeanledixanVdI)t.otalThefehtiugshesdotsheangrthoeupotdhiderhatvhereea
lower groups
wthriicbhutirnegsupliteecdesfroofm eavildoewnecrenutombetrheofloweemrbrnyuosmbeart otfhehisgthartdoosef tehmebrysotsudya.re Cthoen
low mean nurber absence of dead
offetuismepsl.antation
sites,
corpora
lutea,
resorption
sites
and
the
nFoCr-95aiddiFdC-n9o5t ctaruesaetmecnotmpporuonddu-creelaantedinacbrneaosremalingrtohessnufmebtearl ofrinpdrionpgosrt(iToanbleof3),
abnormal compound
ftertaelatesdkelgertoaulps abweerreratniootnss.igniFeftiaclantslkyeledtiofnferreenstultfsroomf thtehe cotnhtrreoel
garsosuopcia(tTeadblecha4)n.gesThoef sitnecrindeebnrcaeeanadsspyrmoeptorirctailo,nsstoefrnSetberrancebrbaieparntointoessianfdieodneand
stemebrae missing the control group.
were
unusually
high
in
all
dose
groups
of
this
study
including
FThCe-95tewraastogteenriactoegfefneicct inwasthea
dreavtelaotpmaelnltadloseeyeleaveblnsormaadlmiitnyiswtheircehd
in this study. appeared to be
annuclaerurse,stfoinllodweevdelboypmesnetcoonfdarthyeapbreirmraartyionlsensoffitbheerssecfoonrdmairnyg tlheensemfbirbyeorsnalofltehnes
lfeentsalnunculceluesus.althAlolugheyea avbanroiremtayliotfiemsorpwheorleoglioccaallizaepdpeatroantcheesawreeraeofpretsheenetmbwriytohinnal
dtihsastecltoicantgiomni.crosTchoeperanvgaerieodf mforropmhoalosgliicgahlt adpipsecaorlaonrcaetsionasofcbtsheerveldensunndeerarthtehe
anrtoemriboerneamtahrgitnhe toleansdaerpkitchoelloiruemdtoovahlalfa-rewaa,y
otfhtreonughcotnhteainlienngs
a cleft, extending posteriorly.
Hsuirsrtooulnodgiincgalltyhethaebnodrimsacloloermabrtyioonnaslwelreensduneuclteousp.resOenneceooffthleensmosvtesiscelveerlryemnaafnftescted
eryeedsblhoadodmocseltlso.f thAelseombcroynotnrailbutlienngs ntoucltehuesdirsecpollaocreadtbioynssiwneursesppraicmesaryconlteansinifnigbers
wnuhcilcehi apinpeaarendormtaol halveens nbotoweloofngnautcelde.i.
These lens Secondary
lfeinbsersfiwbeerredetvoertluoopumsentanpdrolgarceksesded
naobremrarlaltyionesxcoefptseicmomneddairaytellyenssurfriobuernsdinigncltuhdeedabntohermablendeimnbgryoofnalthneucfliebuesr.s arSoeucnodndatrhye
abnsourtmuarlesoovfaltahreeac,onvtehregisnugbsefqiubeenrts fanodrmalteinosnveosficplreomirneamnntantasntesruirroorunadnidngposttheerior
embryonal nucleus.
000618
In" ,
+a |
: 4
pThreopolretnsionabonformfaeltiutsyesocwictuhrretdheilnenasllabdnosoermaglriotuypsinexocneeptorthbeotchontlreonlsesgrwouaps. The sliegnnsifaibcnaonrtmlaylihtiyghreercorindedthefohriognhe docsoentrgorloupfetthusanuntdheer cotnhetrodliss(eTcatbilneg 5m).icroTshceope wdaosseanlevaerltiffaocrttwhheenteervaatlougaetneidc blyenstraabnnsmoirsmsailointylwiagshtnomticreosstcaobplyi.shedA inno-tefhfiesctstudy.
Discussion
tOhpetimdailffevriesunatliatfiuonnctoiofnahlighrleyqusirpeemceinatlsizaerdepompetuladtuiroinnsg oefmbcreylolnsicfdreovmeluonpdmiefnfterbeyntiated
pprroecceosusressersareandcobnytrotlheledcootordainarteemadrmkoarbplheogeexnteesnitsbyofitnhteerraecstiuolntsinwghitcihssuoecsc.ur Both
daimfofnegreenmteiragtiinogn,tisistusesc.ellBapcohpultaitssiuoen soifzetheandeyeitsisdberfoiungithitvetogeiotmsetfriyn,alnosttaotenlyof
by intrinsic tissuesl.
processes,
but
also
by
extrinsic
influences
exerted
by
neighboring
oThpeticemvbersyiocnlael, oprriegsiunmaObflythethelennseuriaslunredtiifnfae,repnltaiyastedtheectfoidnearlm.roleTheintiipndoufcintghe
olfensthefreoyme.oveArlltyeirnngateicvteodoerrmseaqnudenitniaalliagcntiinogntohfe tleinsssuepsrecdiesreilvyedwiftrhomtehendordeesrtm
t(hfaotregluetn)s fanodrmmaetsioondewromul(dhebaert)aboonrtetdhebsyamaeccitdaerngtest dtuirssiuneg tdheecreeaarslesy pthhaesepsroobfability
airneducitnidoinc.atioWnhsilethatthesunbasttuarneceosf
mtahye
biendtucrtainvseferirnfelduefnrcoem
trheemapirnsesuumnpkntoiwvne,
there neural
retina to inductive
ithneteroavcetriloyninngotectoonldyerimncdrueraisngesintdheucptiroonb.abilAilptryolotnhgaetdlpeensrioidndoufction
wfiolrl coocnctuirnuosuusclcyessafdujlulsytinign
tthhee
sfiazcee, ofshaipnet,erpfeorseintcieo,n
but and
oprrioevnitdaetsioanmeofchatnheism
lens to that of the retinal.
oDvuerrilnygintghe tehearltyipstoafgetshe oofpttihce
vinedsuicctlieveelpornogcaetses,pretpheendeicctuoldaerrlmyaltoceltlhse
immediately body
asucrcfoamcpelisthoedfowrimthaoutthicchkaenngeed diinsccel(llevnoslupmlea.codeT)h.e nTuhmeberchoafngecelilns,cehllowesvhearp,e cisontinues
atociidnocprheialsiec dfuirbirniglsthaipspepaerriiond.theToapwiacredstohef etnhde loefnslepnlsacpoldaecodceellfso.rmatAitona,bout
ithnidsepetinmdee,nttohef tphleacocdoencoimnivtaagnitnatiensvagtionaftoiromntohfe tlheensucnudpe.rlyiTnhgisopitnivcagivensaitciloen, is
and cup
diseeppernosb,abliyts duoepentiongfor(cleesns oppoerrea)tinbgecwoimetshinprotghereslseinsveleyctocdoenrsmt.rictAsed tuhnetillensits
lips meet and continuity in
fuse, cutting the overlying
eOcftfodtehrem.lensClovseusriecleofitnhteernlaelnslypoarned
irse-aestttaebnldiesdhibny,g
Fanoallpoowisnsgiblcylosaucrceomopflisthheedlbeyn,s paorleo,caltheandceltlesmpoatrattyherbeasctkricoftedthWeavleensofvceeslilcledeath.
cloenntsinfuiebertso.elAosngatthee, fuinbedresr gthreowinthfeluecanvcietyofofthetheneulreanls vreestiincal,e tios ofbolrimtetrhaeted.
lTheensleenpsithceellilusndt.oward the ectoderm, which do not elongate further, form the
000619
GE
do
5
The cuboidal lens epithelial cells which face the comea continue to grow after
<
tthaekeltehnseivrespilcalceesfoonrmst.he sAsurftahceecoefllstherogtartoewintghrofuigbherthmeasse.quatTohreseregcieolnl,s dtihfefyer-
entiate into poles of the
lseencsonwdhaerrye ltehnsey fmiebeetrswiatth tohetheeqruaftioberrsandineplloanngeasteofrapjiudnlcytiotnowcaarldletdhe
sutures. As secondary fibers grow their nuclei become positioned at about the
fciebnetresr aorfethaelwafyisberdsepaonsditefdorsmupaercfoincvieaxlllye,nstbhoewoloudtewsatrdf.iberSsincien tthhee lneenwsercome
ttioneliethecenltenrsallcyellannducalreeireinfetrhriesd rtoegicoonllbeecctoimveelpyycasnottihce alenndsfniuncalleluys.disaWpitphear.
TThheuscetlhle sfiizbeersa,ndhoswheavpeer,ofartheenoltensbroakreencdoonwtnroalnldedrbeymovfeadctbourts wrheimcahincoinntrploalcet.he
number, size and shape of lens cellsZ.
The teratogenic effect of FC-95 probably occurred during the portion of organo-
ogfenesseicsondbaetrwyeelnensdifffieberresntisautriroonundofinglentshe teimsbsruyeonfarlomleecnstodneucrlmeuasn.d
the formation The exact
tine of the teratogenic insult and the morphogenesis of the abnormality were
nuontiqudeetbeercmaiunseed iint htahse nsottudyb.eenThdeesdcerviebleodpmaesntaalcomlepnosunadb-nroerlmaatleidtysbanpopmeaalristytdo.be
sAposnitmainleaoru-salpypeainrinrgat stfreutcusteusr,albultenswitahbnoarvmearlyitylowhasinbceiednencreepoofrte1d.2t4o. occThuer
abnormality resembles the Fraser developmental lens abnormality of a mutant
mouse strain which results fron degenerative primary lens cellsS.
References 1. iCnouWliolmsborne JA,J,, FCorualsoemrbrPeC J(Le:ds)A:bnorHmaanldboOorkgaonofgeTneersaitsoloogfy:t2heMeEyceh,anisms
and Pathogenesis. New York, Plenum Press, 1977, pp 329-341. 2. OCrogualnoomgberneesAiJs:. ThNeewByYeo,rk,inHoDletHaaRnineRhL,artUrsapnrdunWginsHto(ne,ds)1:965, pp 227-232. 3. MIaBnnLipI:pincDoetvtelCoop.m,ent195A7b.normalities oftheEye, 2nd ed. Philadelphia, 4. Wienisrsaets,I, miNcieggaensdchurlazbebitA,s.StAortczheirvH:FuerSpToonxtiankeooluosgieco3n2g:eniptpal199c-a2t0a7r,act1s974. 5. Hamai Y, Kuwabara T: Barly cytologic changes of Fraser cataract.
An electron microscopic study. Investigative Ophthalmology 14 (7): pp 517-527, 1975.
000620
6
Table 1 Oral Teratology Study of PC-95 in Rats Mean Maternal Body Weights with Standard Deviations
Gbroouse
mg/kg/day,
10 mg/kg/day
5 mg/kg/day
1 mg/kg/day
5 17Gemueidy 15%
STAI MDERENV 162.070 1722.36 2024.79 202.752 242.04U 322.808 VERN 19% 223 243 2573 2prR 3432
STH DEV 11 8 15 8 18 2 16.2 18.6 34.6 STAN MDEEAVN 202.06% 152.248 122.46% 122.2S 17Z.sa 25X.783
MEAN Zan 226 252 272 Fas 37m SIM DEV 1% % 1304 187 1205 24.8 318
2 significantly lover than the controls (Dunnett's t test p <0.05)
000621
bia 2 oMreaaln TLeirtatteorloSbgattyaan.sdtaaurndddyDPoeofvpiWFaCet-ii9go5hntss'inwiRtahts
o2 e
Mwiesetrs VIMRLFE FlEToUSwES eeTElACs WSEnCeHsRTIN TRPSLIRTIETST ION CLOeRFnORR eTeETr)IT
omaway wm nTzea4rs w2etoawne ourd
w2ss rwizd Puea
2 WmAwey 1 I8sIidsolcro oowue ea
aa:1 5I2% uai:
2 5mnver 8
vseYesos hw:s en or
niec wZau uaiz
3 marasany
ai7r s2e1 12s a0:1 aeas
wFeH wPeH aI2
rrcateent groups vere not.signiicantly different from controls (mmett's test p <0.05)
Ta
8
Table 3 NOurmalberTeorfatFoeltougsyesStwuidtyh oGfroFsCs-95FiinndiRnagtssd
TT a T
Binding
mg/kg/day my/ka/day mo/kg/day _ma/kg/day
No. of fetuses examined
201
131
178
192
umbilical hernia
1
-
1
--
Runted
---
1
--
1
Total Normal Fetuses
200
130
177
191
Total Abnormal Fetuses
1
1
1
1
_--
:
2 T(rCehait-mseqnutaregrpoup<s0.w0e5r)e not significantly different from the control
000623
1. 5 oe
} |
s
Table 4
Ora reracolony seuty of FG-95 in mats
Number and Percent of Fetuses with Skeleton Findings
_ Skeleton Pinding -- ma/ka/any mpia/any -- _mjea/any myiasis
FF[ raorniteatral-- nneonvoeeseis-- tiifeiedd wi"oo0 wi1aomn JTa w 11 swH
GSTenrctetemrreipbeararalieornanossecsossroiinFofisiesedidtied 1413 0(63)0 7Txw(6h aoLZeZen 107L1e(6
SGermeaermmbeibireeees bsnippamretoicvtieinge 0B70G58D naiaamn RSeGoyh 2NCHoGb
3Tf3oreFrsieeeemeapbuersreeacesing 105[(1 iT>i o ia CoG `PR oet
CFarrvaoytbrosrdsiyibosnofontheribvsertebrae 3s1omGH aS2 hGeoy9 2osdGw0 3%H1BG]h
vToiHibbBeeorrdssiiiezcseeof the vertebrae 18 43 7 1 so
FMoauSenisnbaobrdoeidieisseesofofthtehevveerrtteebbrraeae
4 (3 =
Tw -
Law --
sw ra
Siversive
Tota vo. Normal Fetuses 7 (5) se we we
Total No. Mbnomai Fetuses 133 95) 8 7) 13 0 123 02)
Total o. of Fecuses Dramines 140
a
123
1
2(5PTr%eeatpomaernnetntgroofupsorwaelreexnaomtinseisgnificantly different from the control (Chi-square
000624
|
1Q
10
t
Table 5
NumobrearlaTnedraPteorlcoegnyt SoftuFyatuosfes7Cw-i9s5hinIntaetrsnal Findings
w Tnm cemala FindiT ng Tyan s i ", Tre
TByheooFraabcblinocoomdcaatviittyy full
=2a a1ns E=m 2=03)
sEnrllaarrgeeedd arterniaa pelvis area 13 (a8) -=--
--=
--Te
AodionmitnhaelKicdanveiyty fall
im
2
so
2m
oF blood
Total No. Normal Fetuses 52 (85) 23 61 47.) 53 (00)
Total No. Abnoma fetuses 9 QS) 17 (43) oa i)
Total No. of Fatuses Bxanined 61
w
ss
5
2 Eye abnormality was an artifact and was not considered for statistical Eye abnormalities were developmental lens abnormalities with secondary
(3Tenspearbceernrtatiofonstotal examines significantly higher than the control (Chi-square p < 0.05)
000625
Peo
:
n
Appendix
Oral Teratology Study of FC-95 in Rats Protocol
Objective
AeffteecrtastoloofgoyrasltluydyawdimlilnibseteurseeddFCto-95evtaoluparteegntahnetemrbartsyotdouxriincgatnhdetpeerraitoodgenic
of of
organogenesis. the FDA issued
iTnheJapnruaorcye,dur1e966com(p"lGiueisdewliitnehs thfeor geRneeprraolducrteicoonmmeSntduaditeisons
afcocrorSdaifnegtytEovatlhueat1i9o7n8 oGofodDruLgasborfaotrorHyumaPnraUcstei"c)e. reTghuelatsitoundsy awinldlSbaefetcyonEdvuacltue-d
ation Laboratory's Standard Operating Procedures.
sponsor
3M Commercial Chemical Division, St. Paul, Minnesota.
Testing Facility
safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota.
Study Director
E. G. Gortner
Start of Dosing
Mid July, 1980.
Test system
Eighty-eight from Charles
RsievxeurallByremeadtiunrge,LatbiomreatomraytewdilSlprbaeguheo-uDasweldeyin dhearnigviendg fsetmaailenlersasts
sctoenetlrolcalgeedsrwooimt.h wiTrhiesmessthraifnlooorfsraatnsd wfirlolntsbeinuseadtbeemcpaeursateuroef hainsdthourmiciadlity
Cchoontwroalnddwaattaeranwdiltlimbeemaatveadilafbelmealeasd alriebitruena.dilyTheavaliilgahbtlse.willPurbeinoanLaab1o2rahtoourry
light/dark cycle.
Test System Identification
oBuatcshidaeniomafltwheillcagbee. ear tagged and that number will be indicated on the
000626
IR
i. :
2
Appendix I (Continued)
.
Randomssation
Tnhuembeanrismatlasblew.ill be assigned cages according to a computer-generated random
control article
com oid.
Zest article
ross.
Analytical specifications
T(h3e4 end
CtoemsmteracritailcleC,hemciocmaplosgirtoiuopn) of dosing.
aPnrdipourriftoytwheillstbaertdeofterthmeinsetdudbyy
atnhde
aScponthseor
Dosage Levels and Experiment design
TTshauetsspetnoenssitodnaayrsatnicd6letchorwnoitulrlgohlbea15rtsoiucfslpegeenwsditeladltiibonencaaocdmcnoiornidilisntgdearietldoy.btyheoThtfeaollltoeiwsnittnugba:arttiiocnleto the
Dose Grow
Dose tevel
croup size
High
10 mg/kg/day
229
CmLoiondwtrol
51 mmnoga///Kksag///aadaaayyy
2 22s%
TshheoweodralradziouotleaboefledadFmCi.n9i5stwraastiownelwlilalbsobrebeuds.ed Known to interfere with the test articie.
bNeocaduiseetasoyf
mcoenttaabmoilniasnntsstuadriees
T9fho,er12aa,nbinr1o5amlasalnwdicll2l0inboifecaplorbessgiegnrnavsne.cdydaaBinolddyytwhfeeriog7mhattdssaywdio3lsletdhbreoaucscrhoercddoiarnydgeld2y0onoufsidngugesstaa3t,cioon6n,stant dose volume of 5 ml/kg of body weight.
TWhiellfbeemaelexsanwiinleld tbeo kdieltelremdinoen: daynum2b0eranodfthceoropvoarraielsu,teau,tenruusmbearndofitsfetcuosnetsents Db(eulpivfweiexieagndhdtindaeBnadodu,)ignr'onssusnbseoarlbunootrifmoanrleisftooirrepsts.iuobnsAepsqiputreeonsxt,imfanrtueemelb-yehraonnodfe-steihcmitprildoannitonafgtitbohyne pstuihpteess.Kill Wilson technique to determine any visceral abnormalities ueing a dissecting
000627
13 Appendix I (Concluded)
mfiicxreodscionpee.thylThaelcorheomlainfiorngsuabpsperqouxeimnatteslkyelettwaol-tehxiarmdisnaotfiotnheapfutpesr wcillelarbieng and staining with alizarin red.
Data Analysis and Final Report
The proposed statistical methods to be used for analysis of the data are:
zDuensnoertptt'isonsitteesst,
for dam number
and pup weights, number of fetuses, of implantation sites and number of
number of corpora lutea;
iCshi2-s3qumaroenthfsorapfetrecrendtetaaiblneodrmapluiptieexsa.minaTtheionpsrohpaovseedbedeantecofmoprlettheedfi(naaplprroexpiomrattely
fourth quarter, 1980).
000628
IS |
x
:
14
Appendix 11
1
LisOtxalofTePrraitnocliopgayl PSaerutdiyciopfatci-n9g5PeinrsoRnantesl
:
we
Foscrzon
Savin 6. cortaer
Stuy Director
Elden G. Lamprecht
Veterinary Pathologist
Cathy =. Ludemann
Coorainacor-istology
Gary c. pecore
Supervisor-Aninal Care
Loren 0. Wiseth
Technician
000629
fo
fo.
Appendix 11x
:
STATEMENT OF QUALITY ASSURANCE
15
STUDY NUMBER: oseomeooos
TITLE:
Oral Teratolocy Studv of FC-95 in Rats
AUundiittsforantdh/eorabionvsepetcittiloends wseturdey,peanrdforrmeepdortbeydthteo tRhiekerstuQduyalidtiyrecAtsosruraanndce to management as follows:
Date performed 1286 Jguullyy 11998800 1175 DDeecceerrbbeerr 11998800
Date Reported 21 guy 1080 1278 DJeuclyemb1e9r801980 17 Decenber 1980
C gi E. orterstzom RLiakbeorratLoarbyoraQtuoarliietsy,AsIsncu.rance pepgmerin2 ten
000630
Io
APPENDIX Iv
16
Sort and/or Contest asticte Chasactastzation
FC -95 Lot 640
1. TThoenersstenatcithyetsetrrengtthTo,newnoietforomheritfyHe,onngscomponriajrcvtoicoTonmo,errptuerityooxrootthheerrppeerr:2. Tm he metha od of syTnthnesis or oarishineoaf hTeE tHessLst contrTol RsdbeItaneess
ya
soipegers Soest 278 SORORIENSST S50 TSHR 1 The err oe 3. mThienedstoarbiwliiltly boef dtheetertmesitnedanads/oorfcCoonntrpollefsiubesntanocfesThoanveJobseteniudseteTr-F Mecesiany,
oB-lReke
st2oilse
000631
1
=
Appendixv.
tn
oral TeIxnadtivoitdousaylSBtoudyy woefig7het-s5.s (i3)n nats
4",4,
mmiamteNee..3 T 6-- 5 ie rrr-- ma m---- --
E NNoOrR 1L7i5S5s7e T Zloed Gieel
2a3e%
sceoa
a san 44 Gan Ser
NNookk d13Soaw0es Nok Lae
cDeid lhc
snoioe sav
chaan sed
Seaa oh
idveee sea
aiei sa
Nok r1e0r1es New La
Lh Led
ogiirl Lhd
boeei
sLaie cor
3A0 45
sd son
Nneokk Nok
DLLaaaailne
1dd5moh
cdseeleea
2cGoeo
Gsbeeonr
esioioe
i5ao4e
NNookw wADiwds: Nok Loew
Coasr Zs
sSieew se
ioi Lb
esrn She
sSaeme 4s
aoome aes
NNoekk Nom
1L0b5m.n 13oc:
Z1ahb 18h
adies Gon
saele 47
icreo or
sleeer os
bbeer sas
NNookk 1L360t6s4 l10ns: i18i4 ccooee ccoien ssoee eonh
STHeRDEV a5cus 47sox6 czoakr Zoz7c4 aeand iiomea
NOM EREGHINI FACS NNeokk aT3aedn:7 alsoek caesse eere c2i1rs S2eb ouer
000632
in .
BEsrgy
1.
Appendix V (Continued)
oral
TeIrnadtiovliodguyalStBuoddyy
of FC-95 Weights
in (g)
Rats
DaonsdemGartouNop.
36
Stay pay 51
35
wm
16 MG/KG/DAY
ODUoRk 11TZeoeu1 1i8sFs 221a7 22:330 228918 2288x 334576
DR 1300. 182 2uc 224 zen Ze 381
OCaOkR 11330600S3 2103:1 2i2z5 22610% 2i6i1 2289%% l2e1sm
0Q6uk 1133002212 2221;2 225404 224471 2zmr 32181: dl6e2w
OBR 1202: 188 205 258 22; du 2un
UOBOFF 1133003275
Z1sey
22i1r4
2Zoaw
zZaens
22s7;4
Gaz 380
OGookk 112Z0o3d0n l1e5e0 z21ean 2Z2e6w Zgiue ZZaewd 1 fl
OQuuk LLioemwe 2Zo0d7 z22o:e 22774h zzee:. 2L6i2s 31998d
wok Aes? zie 2:4 222 268 278 iZz
OOoOkF 1133003614 1Z3uai z2e28s e23ss z26z2; 2Z5e1n 2G8I1R
STRIMLERDNEV 4i1s%s 13Zgz8 1324.32 152872 152.76 343.a8
NON PREGNANT ANIMALS
0QB0R 1133002445
113s%
Ziv zea
23r az
zee zze
Zaz zz
Zhe 2i1
Ook 13047 134 201 zed 221 233 23%
OOookk 1133e9e4s5 221163 22332 z234e3 2Th3e% 225910 2z6e1n
000633
Is
BESTCOPY AVAILABLE
epentin conse ora eTstaRte LSty of ress in use
a...
000634
ls
SESTCOPYAvAapy ~~ st TPHRREI .ES re
1 MG GAORY
000635
BESTCOPYAvpiagre
TT some A Oral Teratology Study of FC-95 in Rats
Dore STOW VIRELE FETUSES OER
cam
RESOR INFLAN CORPRM MEAN Feri M1i0r
000636
|e"
:
rg
n
eoravl aTeArrpaptoelnTodgieyxsVSItboed(ytCaoonwfteienFuneEdp)epinmReatks
BoneCN VIRELCEFETISRES FeDTEuRsGes
10 so/xa/eay
rbnooorredtszsmeenes P3F4 EE6roWWu16 oeo@w
vr bor
dhdeeers
a15 2PFo Na}
8 oe
trGtoenri3d7tel0ecsarnMYBsMoe-oREEoHAnNVTMd
FBnorredtrheeesse inihi3vcieasnofciodlw m a
roreaBrfelew a]MIrTReElMMaM
bbOooaxk lAd3leoccsss Ook djs
won3z 1Pr4E5un%enas s too@
aE dif 8
swei n 2t i6e y z3os . avi7 seew
KETErSirOoRn ImI anriiotn nCoernen pmoenm rionos n meer
EP4 oonn1m o81u eSONN8om20% eeaolM aom P0ooaE12 EO1HB is 8 He PV01%IR o&Su R serf8 eeee 831% Isiz
a t f45ar u are a say EaLSriaaaafdnaaar aasraaavnlaaa:sa az oaz ois fS az ietA w sa: g2s rozzaoad a:
000637
ia
5
23
Appendix VI (Continued) oIrnadliviTdeuraaltolLoigtyterStuDdaytaowfitFhC-9P5upiWneiRgahttss
Dose SOW and Fat No.
5 ma/ka/day FFuukk sLaoee FFoobk L1i0ewss FFuokk LL7i0e6s FFookk Z12e2;s bboopr Afwezns [POrRe diese FFookk 3L0i%b FFookk L13o0u0i4 FFookR 113x0o7t1e FFookk t12iuecrcs FPookek 1133600542
STRMEALNEV
jElE FETUSES DEAL WF TOTAL FETUSES
xo:ox az0s a 05 47 12@ a NOT4 PRE7GNANaT1 84 35 A1L2 ao 44 c 5 vax 54 58 1b= oo NUL4 PRE7GNANoTan "iofn a1w4 5EE8 1% oo NOTGP4REGNANT= o NNOOTT PERREEGGNNAANNTT f1e8 S2G0 1282% awae
RFTEISOUNR TIANTFILOANN LCOURTPERWR SITES S17Es
8zs12 az ae 123 i5z e 11 az
2 1132 1a8z a1 a47 1164 B1 18ae 18a @ 1x az
6 1a64
a4 11
21 aaws 1a=
CR
3
187 1z2z az1a
RFVEGRN FEH TUSFW1oon
Adie 4aaz daae 33:c 44016 sIss
= 46 iw a43e 44a1 za s a45 5425 o4ab: a44e a4 z s4w2 43 4a az Te 27 3s 4422 aaz: 4a1z 4a:8 44a7 4a3z
64:2
000638
lo"
BESTCOPY AvAILARLE
.
:
Appendix VI (Concluded)
IOrnadlivTiedruaatlolLoigtyterStDuadytaofwitFhC-9P5upiWneiRgahttss
Dose GROW and Rat No.
1 mg/kg/aay
owookr 11x3e01121
CBuabk 1i3n01s4
Geokk 1Txu0l1
Bulkaek 1L3u0z3
awokk 11i300isd
Gib bak
11330s0
fuikn 1L3i0o5n7
GDoukk 1T3s0e5t0s
oUBekr 1133667765
faokr 1132e0r0s7
DGakk 11Z2o6s7s
SIANMEADENY.
yGTEipE FETOUTSEAS FEDTEUASLES
5voz8 1a1w o
Sovoem12
0
4oeoe
am 1:
a o
a11= a32 oou
25 a 5 s10 oo
Ee az o
57 64 1111 1a
i NOT
PRE5GNANICw
&
4 4
1168
a a
NOD PREGNANI
5 5os awos @
NOT PREGNANT
4 11 as a
4.7 5.4101 1.7 21 28
8a12
RPETSIOORN TIAMTFILOANN LCUOTREFWkm S1ES S1IES
e 1101 1azs
@ 6
1z=
11%1
wa az1a 14=
B azES 24a
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B12 1z
11 1saz 1112
1 18 1z
Eo RT10 1111
E1 RTa 15=
o 1s 15
o0s4 12075 1z6e8
AMVEGAN FEMLFWii)
4a14 4a1s daaw
44 4
za4e
sacs
AIws nXee oiawd
aDne aoa E asnz
Se Sa daw
aazE aaa aaza
a4x1 a4z: a43b
Is ie i
a4z1 4432 az1s
a4.E4 444s daaq
41 42 an
a4a2
000639
von.
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prsmsuron ust X. L. Sbbons + 3. D. Henderson + G. R. Steffen + K. 7. Case 5. G. Gortner (original +1) 5. xelter (on tite) 5m . G. c tarprecnt Re A. Nelson = E. i. Hutsch + R. B. bor
000640
a
BEST COPY AVAILABLE
EL. Gortner (original + 1) (R yy T YETTry
F AE AA
EESE Le E niee s vote,oBANoE SsSe-- ohn -- ant-- egos we
E rE yG pecGrs SPilobtuioupd 77220632 L TDerimsees, f7raboerseceotDoossriinn
000641
Cen io
BEST COPY AVAILABLE
Aoended summacy (pe 1)EvtpoertihneenOtralho.TeroaetboolToROgSy08Study of FG-95 in Fate oCorxraer1amgeaepceenrnibenonsrisiste)ryatrvieacosenmodouftrisFneCg.s-aSt5doapyaaetnidcosisnesiouotfh 101,5 o5fangdest1amtaio/nka/(dpaeyriotdo opfregmant BeF-re3a5tiaoodnnmiinSaiiyTseat.nrta1it5yiocnhtoevwoaeusrhmta3r0tanerchntehaelalycconotcorrxoinlcs.boondlyyFOvt-oe3i5sthaheess 1on0toatgcr/maektge/mrdiseseyhlldgyor.eosuspo:enmetAtteos
sane mavalday soup. oCFeoo-mp9ar5natrveoarsoefinootntheoefmbdarfsyeeot:atloxiTechleeavncdoemnpdoiudvnadrnioa4tt1iaaofnfnesoc:rt.Brtehdeteoevaarieisncorrearsee.proinducthteivemimtbrearct
000642
nol
Amendmeofntthteo OtrhaelReTseurlattsoloagnyd DStiusdcyusosfioFnC-S9e5ctiionnsRat(sp..3-5) Experiment No. 0680TRO008
(This amendment addresses the last two paragraphs of the results section and the entire discussion section.)
FC-95 was labeled a teratogen Of the lens because apparent lens abnormalities
wsetrudeieosb,sepravretdicautlatrhley 10R,ike5raEnxdpe1rmigm/ekngt/Ndoa.y 0d6o8s1e7Rl0e3v6e2l,s.theBaisnetderopnrestuabtsieoqnusenotf
these observations have been extensively modified. The lens findings observed
under the artifacts
dorissaecntoirnmgalmiacrreoascoofpeleanrse cneolwl
kdneogwennertaotiboen.eithTehre
ffreetealhanrdatselcetnsioning
findings were incorrectly interpreted as a teratogenic change in this study.
The gross finding of a lens cleft was an artifact created by freehand sectioning. It represents a separation between the embryonal nucleus lens ncoerlmlaslaonbdsetrhveatlieonns oefpitthheelieummb.ryonTahle ngurcolsesusf.indiThneg eofmbrayolneanls nduacrlkeusstreisakanvasareaa of normal lens cell degeneration in the gestation day 20 fetus.
The gross appearance of the rat lens at day 20 of gestation is determined by the region of the lens which is transected by freehand sectioning. In a oscucbusreequnecnetofstutdhey l(eRniskerfiEnxdpiengrsimecnotuldNo.not06b8e1TRrOe3p6e2a)tetdhewhecnomptohuendf-erteulsaestedwere ocobdseedrvabteifoornes afnrdeehtahneddsiefcfteiroennicnegs aanmdonggrotshse devoasleuagtrioounp. inTchiedenrcanegseweorfegrdouesstolens the manner and frequency in which the lens cleft artifact was created by nfurceleehuasn.d sectioning and the limitations inherent in visualizing the embryonal
In summary, FC-95 in utero exposed fetuses did not have compound-related changes in their lenses.
000643
a ! ..
2
Amended Table 5 (p. 10) Nusber Oarnad)PeTrecraetnotloogfyFSettuudsyesofwiFtCh-9I5ntienrnaRlatsFindings
Internal Finding LTehnosracfiicndcianvgiatdy full Enolfarbgleododatria AEbndloamrigneadlrecnaavlitpyelfvailsl
of blood No. of Fetuses Examined
mo/kg/eay -1--2) 315@) "a
61
ma/1ko/dsy 14T(a35) ---- 2 (5)
w
ma/ksa/tsy --am ------so
ss
mo/k1a/day --23) -3--s) 23)
so
2, Tfhreeehlaennsd fsiencdtiinognsinogbsaerrtviefdactusndeorr tahenodrimsaslecatrienagomficlreonsscocpeellwedreegeeneirtahteiron 2 signicicantly higher than the control (chi-square with Yates correction
(1) < 0=.'0p5e)rcent of total examined
000644
jE I
XK. L. Ebbens
:
eetettrnut nt
R. E. Ober + R. A. Nelson + E. L. Mutsch
:
vin
000645
oo
inns erie rx 51COPY AVAILABLE
:
STATEMENT OF QUALITY ASSURANCE
STUDY NUMBER: _Amendment to 0680TR0008
)
TITLE:
Amendment to the Pinal Report of the Oral Teratology
Audits and/or inspections were performed by the Riker
Compliance
reported to
Audit
the
unit
study
for the
director
above
and
totimtalnedagesmteundyt,
and
as
follows:
Date Performed
Date Reported
Riker Laboratories, Inc.
fg 23 (182
)
000646
fo
rere
:
}
BEST COPY AVAILABLE
prsragauTion ser X. Lr bens + 3. D. Henderson + G. . Steffen + K. 7. Case 5. c. Gorener (original +1 P. Xeller (@ tiie) 5. G. Lamprecht
R.A. telson + . 1. Hussch + B. B. oer
000647