Document J3Mx98JdDzeZvv8GQJmwB6X2
special Lane OralToTereattaoilnoggyofStuadvyeof T-2599CeC in
Sonnet a Experiment No. i
soning Period: stacy pirectors
0681TR0362
-
SCaaetayuelEe,vcaelMiuiaantrnietosenott.LaabTorhatory
osampteaarber5. 261,9811981 throvsh
5 6 Gartner
SAFil nAior aest esrch Technol2 ogie p a 2 FBri.4pesarinary
7-16-33 Pathologtet
SLT eratoton mpromction
T EMmae,re iPath7o) lGogoysToxicolVoisryles ey bvenoation Laboratory
wm illiame Esw o e7.e2002 e icoly oy services
004281
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1
Table of Contents
rage TableofContents + + + + sane s onenesees 1
FR |
FO
I
Results oe aneenene seas
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Discussion sss ea races eesacasaaess 8
i
References + sta a eee n eee ae ess 12
i
Tables
1. DMeeavniatMiaotnesrnLailstBeoddybyWeiGgehsttsati(og)n DWaiythinStTawnodaSrtdrains of Rats and Tvo Dose Levels of T-2995C0C + + + + 13
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2. NLuamnbserFinadndingPsercFeonrtIonfdivPirdeusahlanLdenSsecatnidonFeGrtousss Fetal
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DEoxspeerLiamveenltsalofUnTi-t2s99i9nC0TCo
Strains + + +s
of Rats and + ee sss
Two eo 14
!
3.
Ratios and Percent Findings Confirmed
of Freehand Section Microscopically for
Gross Lens Individual
ii
OLfensRaatsndanPdetuTsoEDxopseeriLmeevnetlasl oUfnitTs-29in9%CvooC St+ra+in+s + 15
4 LReantsiosPinadnidngPsercWeintth MAigcrreoesmceonpticofLeGnrsossFinIdnidnigvsiduianl ITv2o9S9t9CrOaCi+nos4f 4MbatsaasnedTewonDeosseeLesveelaosfs 6
:
S. FMiunmdbienrgsandLisPetrecdenbty LofensFeRteaglioLennsiensTWwiothStrMaiicnrsoscofopic
PTartosc,essTiwnogLePvreolcsedoufre7s-2W9i9t5hCoaCn aInnddexToofTiLsenssue
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SectioningProficiency + + + esse seen 17
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004282
2
Table of Contents (Concluded)
Appendices
rage
1. ofP7 roco- tol 2 fori9 SnpaTcw9 ioalSt9 LreanisnC sOroafo lRTaetC rsat+olo+gy+ +Stu+dy+ + 18
AStmuednydmoefntT-f2o9r99SCpoeCciailn TLweonsSOtrraalinsTeorfatoRlatosgy + + + 20
ProtocolDeviations + + + ss oes s2
I1. List of Principal Participating Personnel + + + 22
111. Statement of Quality Assurance + + + + + + ++ + 23
Iv. WIenidgihvtisduaalndBoSdtyanWdeairgdhtDsevi(ga)tiWointshfMoeranPreBogdnyant J
Vv.
GIrnodsisviadunadlMiPcertoussecsopiScecLteinosneOdbAscerrovsastitohnes
of Lenses.
.
28
V1. PmeitcursoesscopNoitc LSeencstiOobnseedrAvcartoisosnstohfe LIenndsievsidu+al+ + + + 36
VI. 7-2999CoC Composition, Purity and Stability . 44
004283
3
SUMURY
In a previous gestation day
2r0at gtreorssatolleongsy fisntuddiyngsofona
ufnlcuoodreodchefmrieceahlandalcsoehcotli,oneFdM-3fke2t2u,ses
vere this
ciunrtreernptretsetdudyasvacsomptoouncdompaanrdedotshee
related abnormalities. histological appearance
The objective of fetal rat
of
lenses lenses
that had been which had not
freehand sectioned to the been freehand sectioned.
hGirsotuposlogoifcatlhiartpypeatriamnec-emsotfed
Cmgr/1k:gC/DdOa(ySDv)iBtRhanTd-29C9D9FC(oFC-,34a)c/oCmrpiaBrRablreatsalcvoehroel,oraolnlydaydsose6dtshtrouOgahnd152o5f
-gestation. identities
Four fetuses from each of 20 of the fetuses vere concealed
litters per group vere from the investigators
selected. by coding.
The
Glriotstser.lensMicorbossecrovpaitcionlsenvseroebsemradveatioonnsfreveehraendmadseectoinonaslloffotuwrocofdeetdusefsetpuseers
folloving microtome sectioning and tissue staining.
7-2999CoC caused maternal of both rat strains. The
toxicity compound
(lov body weight gain) in did not affect either the
the pregnant gross or
dams
arleclraotsecdopoicccurlreensnceapopfearlaennscefoifndifnegtsusersepofrrtoemdtrienattehde
dams. The compoundprevious rat teratology
study could not be repeated when the fetuses vere coded before freehand
sectioning and gross evaluation.
The the
glernosssvefsiincdliengvoefstaigelenasreclaerfttifaacntds thceresmtiecdrosicnodpeipcendfeinntdliyngbyof fareeshpaancde
at and
microtome sectioning. They represent a separation between the embryonal
nucleus lens cells and the lens epithelium.
The gross finding of a lens dark streak is a normal observation of the
embryonal nucleus, The degeneration located in
etmhberycoennatlralnucrleeguisonisofanthaerelsenso.f
normal lens Lens cell
cell
degeneration was present microscopically in every lens sectioned across the
central region of the lens.
004284
4
Introduction
A Toxic Substances Control Act (TSCA) Section B(e) notice ves filed by the 34
eCfooorrrmaptaffoniapylueinnbndiagScsoetndhlceyhoanBni(ngere)atthbeentcoeattruriasecteaeotlmwLoeatgnsytvtehsgsetruofduooypbussn.edrrevsoaunTltlhtiyesonoibonnsoefcrFoMavm-ap3tof4iue2ont2nda8l,vtarlseenaPsartreetpdfloiyrndtdoeisrdenegsapgsworhnoaisupicsbhle
and had & dose-related incidence of occurance.
7-2999C0C (FM-3924) vas selected for use in the current study because it is
_PmootreenrtieaplrleysenptraetsievnetsofgreparteesrentripsrkodtuhcatnioFnM-t3hia2n2 bisecaFuMs-e342o2f. theFurstohmeerw,haTt-2h9i9g9hCeorC
Content of more soluble lover homologues.
ToSbrejeeacpttrmioevtneotsc.aonldTfhoterhetfhisertsrtcauirncrhejonfetctrisevtteudoyvnasvtahsteooirrniecgpiiodnretanlclteyheofdeesftifhegecnteldenowsfitTch-h2a9tnvg9oe9.0oCThe
SSrrepoonsdedoibjneucttievreo ernie with the
twiaonscidtdooesniccnoegmaponafdreleatnnhsiesaclihnachniagdneedsnlciienngotfhperolecCneDsdurccehosanntgureossledgofrionufpet.teursaetTsohleongoyt
aeTnebiaomoranalttsoorvfyerdegfaaicdnuoessdesdioinnasnsdigvhtithteh idnsatcsoisennvtoeirrsmetaslteafrnrmdoimnaabitnneoddru.msatlryD,ulernigsnogvederthvniemsleonpttoiemanent,d. tahceaAsdemtihae,
neretiflaecnte cohfanfgreeeohraingdinsaelcltyionrienpgo,rteanddintheprepvriootuoscolstuvdaisesamveansdedthotuoghttesttotbheisan
hypothests.
ToShfheengoepbsjtraoctctieiosvnseeddoafyfort2h0imsifcetrsaotlsucdyorpaytvastleoncshteahsengetmdhiactrtoohsaccvooepmipcabereeanptphefearrehaeinhscatenodloofsgeigccetasiltoantaeipdopneanadrdaanyce
20 fetal rat lenses vhich have not been freehand sectioned before being
processed for microscopy.
TTMhianevnoesrstaouttdoay.riveaasnsdInsvcaps.o,nscooStrn.edducPtbaeyudl,3byMCitonhmnemeseorStcaaif,aeltyTChhPeermaitlcwuaosltcioDoimnvpiolsuainbodonr,aatdoSmrti.yn,isPtaRurilak,teiron
GSrrooutposcowleraenddolsiesdt boeftwpereinnciSpeapltepaabretric2i8,pan1t9s81caanndbOectfoobunedr 8i,n A19p8p1e.ndicThees I and
11 respectively.
AOoPeLFprLearrcepatmiotecrinetncig.o(nPGsLrPoT)cohefedruestrghteeuosrl.aasgtteuidAoypnipsoewehneadrateinixdocnIoSInafIdfouerccttoysenpdteEacviiaanmclsecunossrtt,dhiieonnrgQeulvtaalobdioa`ttrtyaahteoaAGrnsyosdoudarSatLnacaconbepdoyarrUandOtifotrtyhe final report is mintained in the Safety Bralustion Laboratory's record archives.
87To4ot-3h00e2G2a0rT1eshm0a0ai1tn0i)nlgeaasn1t1d5,796-t82h9Ce9O9FpC1eE7rSf0l(2uPNoi(r-Co3ao9lH2k54y))lCH1ZsgOrRaobuop(uRtickoen8rt8a%iEnxCspaePrtiih7mr8e0enoetN(tCoalslesve)nCHZcOaNrbon atoms. DFederal Register, Vol. 43, No. 237, December 22, 1978 pp 60013-60025.
004285
5
Materials aid Methods aNsisniegtnyedCrc1a:gCeDsB(SaDc)cBoRrdrinagtstco(aCDSc)omapnudters-igxetnyerCaDtPeed(F-r3aUndko)m/CrniusBbRerrsatatadbl(eC.DF)Thweyere VFeersepescetxiuvaelllyy (mAaptpuernedixtizIeV)-.mateTdhefermaatlsesvevreeighhoiunsgedbeitnwdeievnidu1a6l3l-y22i9n asnudspe1n2d7e-d1,63 Voiorme.mesThh,eysvtearienleisdsentsitfeieledcabygesearintaagstemvpietrhattuhraet ainddenhtuinfiidciattyionconnturaoblelred Iinddeinctaitfeidedonontlhyebyou&tsinduemboefr otnhethceageo.utsTidhee CoDfBtnheonc-atgree.atedFegerdosupanvdaswater vere available ad 1ibitus. Te lights vere on a 12 hour light/dark cycle. cThoendurcattedvasinchtohsiesnsbpeeccsiuess.e prTehveio2u5smgt/ekrga/tdoalyogydossetudlieevselonvasFMs-e3l2e2ctevderebecause it gave a positive response to the lens finding in the previous teratology study.
TCohmemeTr-c2i99a9lC0CChemciocmaplosigtrioounp, (pAuprpietnydiaxndVIIs)t.abilTihteytevsetreardteitcelreminveads bsyusptheende3dM in cVoerrne aodlmfinidsatileyr.ed bTyheortaelstianrttuibcalteionsoltuotiroantss oannddtahyes c6otrnhroouilghco1n5trofol article gestationk according to the following experimental design for dosing:
e Fat Strain and Dose Group 7-e 2990CcC Dose Level Group Size
Co corn ofl control article 0 mg/ke/dsy
30
CDP corn ofl control article O mg/ke/day
EY
be 7-29990oC tn corn oil
25 mg/kg/day
30
CDP 7-2995C0C 1a corn ofl
25 ng/Xg/day
3
CD Mon-treated group
rate not dosed
30
Supplied Gsupplicd
tbyy
CChhaarrlleess
RRiivveerr
BBrreeeeddiinngg
lLaabboorrasttoorriieess,,
IInncc..,,
FStoorntehriWdiglem,ingNtYo.n,
MA.
STohurpipnleiedLabbyorWaetolrcyh,ChHoovl,besMlasntdonClaPrukr,inaHarCroimspoann,y,NJS.t. -loNuFtsQ,ualMiD.ty.
Ebay sperm detected is day O of gestation.
004286
6
Tthhero7u-gh299d9aCyoC20troefatgeedstaatnidonconftorrolabngorromuaplancilmianliscalverseignosb.servTehde ddaamislyvefrreom day 3
avcecioghreddingontodaytshe 3,Bos6,t 1/kg of body veight.
9r,eTchee1n2,tCDb1o5dnyaonndw-etir2ge0hatotfedupsrigenrggonuaapnccwyoa.nsstoabTnseteyrvdovesedereonvldoyolsuefedoraof
5
1ive/dead check from days 3 through 20 of gestation.
.
oAfLLthdeainrs vfeerteusetsermveirneatefdixebdy cinervBiocuianl'sdisslolouctaitoino.n oAntdalyeas2t0 @roup had four or more fetuses. Four fetuses fron each of
o2f3 20
gdaemsstatiinone.achALL litters from the
CiHDedasednsatnidtofieCsvDPoofoTf-th2et9h9e9fCecotoCudseaednsdvfeectrouersnecsooinlcferacolomendteraocflhrooamfrtttihhceleein2v0geroslutipitsgtaetrvoserrseverbseyelesccoltdieicdne.gd. inTe
pforrotnitoanl-osfectthieonhetahdr.oughFretehehancdentseerctioofntghreosesyelebnuslgoebssearndvattihornosu,ghmatdhee wwiitdhestthe
abiidsecotfiang1t0h-eb0eXyedisbsuelcgteisngvermeicrporsoccoepses,edvefroer rheicsotrodleodg.icalTeobhseeardvatsieocntsionasfter
pParroacfersisningeabPerdodciendgurethe#2cuotf Tyaebleul5)e. suHrefadasceofdotmhe(rTaebmliensin2g 3t,wo|ceonddedTifsestuueses
bpfuralorgmaef--ercaiocnhnteaomifbneidtndhgeing2sp0etclhiiemtetbnersrasinvevreseruerpfrsaolccieecsedsdoendb.ehfionrTdhheitshstepoelceoiygemiecnbasullgbeoisbs.seecrtviTanhtgeiotenhyeebyeye
Beuvlagleuattyionfreofehatnhde ssalmiecinsgurvfearcee msiecernoutnomdeersethcetiodniesdsecttoinpgromviicdreoascohpies.toloTghiecal
"h#pi1esct0iofnleoTngasibclaselli5)ce.evdalbuTeahhetiinoedmnbteohdfedetdheveespcbeeuncltigemeresnsovfewreterheemislceercnotstioo(mnTeeidsssaeuctetiP5or-no6ecdmesitscoirnognpsroPvarinoddceedaure
stained Fetuses
vfirtohn
htheematCoDxBylnionn-atnrdeateeodsing.rouHpivsetroelognyotobevsaelruvsatteido.ns
vere
recorded.
Trheeporftoilnlgovifnegtalisleannseoxbpseerrivmaetnitoanls:design outline for tissue processing and
FO
Bat Strain coe
-- Z Fetuses of 2 Fet-- uses of
7D-o2s9e99LCe0veCl 2F0rLcihsatnedrs 2M0icLriotttoemres Fo. Lenses
mg/kg/day Sectioned Sectioned
Evaluated
Xooanmn-80
XemommaXamaoomn80
25
Pp --Y
core Bp(aAtpapenfdrioxm
iData from
25
FE
rr
Xommnon6a-
Xeooom-X-m-ob-a-t
25
Xewaoon-80
25
XeeoaeaXoaoana-t0
1f)e.tuses of dams NIRTS21, 7523 and 752k vere not evalusted
one fetus of dam NIRTS33 vas lost in transcription.
004287
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eMTomeepiattrnaeddiovfvidiattsnhle thfleeetnsur,sesrauslattsaheorpfostshtaihnebletihneedxipvfeiertduiusna,elntwlaeslns uthneeixtpeevrxeiprmeeerniatmalelnstoaulnrietpu.noirtt.eTdheaTned
i
bIyiTBgarrreoiasadsrelanetdnessemtsi.crwaoesTchouepseeDduonbtnoseettrs'vtsaattiiTosnttsiecstaalnldvyastcooumsepevadarleutaotteheevatlhieunactiaedfefnebccoetdy dofawteai1g-h2gt9e9n9ed0racataCt.ed
STreavtelistoifces:tatcoimsptairciaslonssignvierfeicamndcee vvaisthipn<ea0.c0h5.respective rat strain. The
Results
eSmThaietngenrrianfdaaimclciilanoynintstltoyrFxaoirtlciootvnhienerobfCtohDt2aSh5nsmtstgrth/raakatigin/nosdsfanyodcfonoonftrratogTsle-.ss2t9a9otT9nihCoeogniCersttdoaamteyiasponrne9g,bnodada1yny2t,sweadmianimgndshet1sv5uanstwiienlrethe COF
strain (Table 1).
1-2999C0C administration to pregnant dams did not affect the gross appesrance
OoFIFfnienretdehnicetnosgpsnrstetvr-ueadtrlyeermnr(oeTtgfaiebtolsaneilga2nn)li.defnisac.TahndetaGrlkrpyoesrdssctierfnfeftiaenkrdeoifninntglsebtnheestoefwsecaeennvtiletetnhrhsecolcfcelofetntfhtsterooalltrenasdtnhadervketrreesattrreeedapkorted
FgrooyupsPiefroerakthweasCvDisusatlraiizne.d siIngntihfeiccaanstelyomfor`tehe oCfDteFn 2t5hamng/ikng/tdhaeyCDgrFoupc,ontthreol
group.
TpIhenerdcievinintdduisov)fidutfaehlteustleinmfseo,rwtrsheepoarlteminonsrgeclgrerefoptsrsesaenlndetnsasttiorbveseaekrevxfapitenirdoiinmnseg.nstavleGrrueenaitrteerptohrtathneadntThhe
Peateraily in individual fetuses vithin each study group (Table 2).
TFhienidgirnnagnsgperwoopsforhatigigrohenleymoefnvtamribicearbtolwseec.eonpictIhnecgoegnnrfeoirsrasmla,tleintoshnesrfeiofnvdaiasngds&arwaknidtshtitrnheeasktmriaacnirdnosfctoorrpein&cd lfoovr
BDErooPpooar0toiCon44ofd cnoontfiarfmfaetcitontsheofratthieosleonfsccolneffitrma(tTiaobnleof3).groIssn uvtietrhomiexcproossucroepicto
findings in either strain of rat.
Wihtehn tthhee Tesulted
tnoutmablernousfbgerroosfs (Table k). Two
mliecnsrosfcionpdiicngsobsceornvfaitrimoends,milcorwoscroaptiiocsalloyf avegrreeemceonatpared factors vere largely responsible for the lov ratios
SoBifrcos`rasogsroceobepemieecnrtvoabfisooernrstvhaetoifoentmshberyoofdnaartlkhantsutcrsletearuuksct(ufTriaenbdlie(nTg3a;)b.ltehebT)helaasnradgmeetnhuetsobsemrafslalcotfomrusmbevresreof
TCPeaeacrpeosnonaeivbeelrxeeceofpbotsrieortnvh.eedlTioenvntrhgaretoisoCssDFolefn2sa5gmcrlegee/fmkuegsn/tdaanyfdordeoitshgeehtgrlmoeuinpcs.rovsecsHoiopcwielcveerls,epnasocneVleyfsiintcdwloieng
of the gross observations vere confirmed microscopically.
eTYecemhsigeirsqousvesereefovrasleuacasttsiieoosnnseidnogfacrlfeornsessehamtnohdrephesoemlcbotrgiyyoo.nneadlInnfeuttcahlleeusClDen(sTeafsbeltheuasse5s),'lainomdivtearvteihroaenlsf oasf &the
Tet(hailenalrlbeelifeoSprom2er)a.tjaiotornAirtimoysfokrotofihfettyhhlaeevonilsfneegnslseeatnshtseevsregirrsreokespsorhraeodtpbeosdraetredtvdaoartabkiseosnhtnaorvoteifanksgaeconntdaoirgokrnvoeidssssitrbbelaeaesxkea.dscihnaoaOnnntgliegyornoass
observations had microscopic findings of sectioned lenses (Appendix V).
|
004288
{|
:
||EbtEe re eRscnSoRgceLpeet itnteeerBhtm hctggehaebnen
r TeeEwER nesRe aESvonmEw a SSReseSAeeevi,rFTeBrSHeEmren
I SF pri, h mSbRdiSlT onrSTnrIEe iEEeeehaSe t`trraannsseeccttiendgitnhethifsetasltudlyens(eTsa.bleB5e)t.weeTnhe85raenmadin1d0e0rpewrecreentloosft
the lenses in tissue
were
oiestme etenriSf ssecsiseiy nntLhRe e B0 pEeAteLrEs
FL5eIRTieTneBe SaEDeweiReEEReAlhWeelre Gna
fetuses (Table 5).
mShe rmEsh faiiitSoente nenyi tmferlealthsater tle2iey 1e a FS Toor E drimteiTmab0amheSSEn meibnheSsBten, (foregut) and mesoderm (heart) on the same target tissue decreasesthe EFoEeTpR Ap mIeL S i In, ae ri Senn prolonged period of inductive `interaction not only increases the maprobability peE Ef SrainLoeL m onSiysmT sEererA oA eheShTeEERetSretABshBle2m8tTSRwiEni edBSeErEr Behrme HBieE R Ep AeyTT i RnC e uRllemfye iPaE5BTEEeETeEbSeS hA
004289
'
CCpnorrlee,odnsuerteehoeoffcmtehhleelpseLaomtanethpeponobrraeecaLfkeedaotftetanhdeeds10tTey,eaasnidecpsohsoscinovinlyntehigsnercscseitdmoo.epvnluseirlseoachnoteeotdnhfteaeebt,yht,ebose8Jrtersnlrssocteh)e
Sn Tnfilenceofshe reured TEU 1 oamoss,
eeahfceetteorcdutbetoralhnan,eud wtLLheiectmnhenedsvoereplnpcioilthteheeeLllloioinaregll.atceeolSlfeesurIstwhhCeirco,,hr
fftIoahrcemetpttrhheoeevilncesgonhrsrn(oeieuavpteihcrtohtnmehteleisim.uicaealn.Tttohoergseorvecgeilolns, ascor and shone rapialy
drE Jiueffmyeewrrerineotnito ahtcaleledistnptrloaescnee2 rc:oonn1dthee
1LE ec0ee0ni0unE iiveeose:eaVirmcohrf,oowrnteehrairFcionbnevirescrliLnebnpeelcaoLnmoeews dtpostoes superticinily, he
of
olpoe roudesbgeimitsroidton,nbee Ddei|cvSoiemanrectaesdmnspkvOntrcehreniecBTlaeheencn decoEmree1Snetdlo)pLpSAeTaaEvrra.llaymaendtmhceaeerleelcnhrFseeifbceeserriirss)e,dsnFunotcdoualenevsddehrus,tiasnpaso7onfiosf
not broken dom andremoved bitTomsInDISS the amber sice
lens cellsl.
o`nhCTehhtaesnrlmaeeicrrctoeremorgcsioiczpooetnpdeibcasrpeacmoptepiareoreanagreEuadlen,acreihoteoynfCottfhreecugetreoeysrdctti,adtsTiiaootnEatdt,haiyeSncCe20mageutftetothnerae:lrLenreagehntitteownelc.esdannonsnttshtoehirseblodevcaneunspbd5eoniidds8eanlt
mTpcSooourenrmsteiarntmge noiinotng htehdreoenoeenfumegrHthoiheennrsCcaelntermleseesr, eWghomeeLanno,asecPEtCHLhieoOaanTeteadontrtcieharFodiiowbcreneerngsttirhoaaenilsseanoTdeodenroxtttntriheeioencncdariopernfsgeguigtolihneoe:n,
SAhbldteeehvSoeebulngosehpmftehehneetc,re8heLaer1sascEFotoerriLs1eedrBo8iToerutarTaa,pyaaceevmeanelccolthapeonautesponfasthnhateavhnteeepotenroLmiahtberrncyiopoootonmriaenplrtrgemesiidenc:nlteuasTteetnhde
abLenoctmauesreiboornopsoeclotnedabreey eLaueenneeoecfeetlhloeeoHf ethe [LeALtaNLofeJreinsorcellyl aenldongaaptpieotnr.s 1008
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oSsfT eemmcbdtreeiyogoaonnersanlsetrnhaurae ecotluiegonuhesne.thviteeninTchOeenner tlreeanRlsTbrIoeOwgLioinnTictCaohoynei.LtL.aeoSimnnbTsrosyttohentaaAlmnosvrneuecscetulmlireatgtusteasucrOaeerFp.ercoteghilrenTleessLaseriondivfseoenulsvteyhees4visnectdslaiegctelhsee
or Te etn the ssryom] macieus
| oJTLseeecennehissoacceedaeprniLo}rthyedeeolenigaeolnceicrntoeyhltuelisso.n,ofLrgmaeetesteaa etaironn, sdeeasyesdem2gne0e:rresefteiitooaTnlnoResWeLnsoaBfepsroLersdiesenaratpnofieannrfeeoasvremsreoyfrloylnfeonrtemhael
|
SLsCelirolnideroaerppdaleargreanroeaBrtnantgieevseeaLcohrnaeeTn[ogiteboser1ts1h,Se
3S,iCaorreHnreseronetrcihievoeesnras,nientsrrhfaepemuywLpsrroaO-ggtarepehpsneesdniroeintnrhgoerf ole)ns center 7, 13 Fimatined anh reporied on
i proxtaity ofthesecTteioen aia streak 10 the lena.
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004290
10
hSUepnruerrdiaiottsu.asrymiVocarrroyasircnoegpinscottaogbceassuesroefvdatlibeoynnsiscneofultlefredoteaglceonmelpreoanustnidofninedxhipanovgsesu,rbee,wehnhiacdhveeteabcreeteendnotrienpotrhteed
tCboeeimrnpngatSipcbrolaneggeunevi-itDtaahlvipeoeyragervsaetreolfetnynspo.ir"cmaallThrleeessnesponfdsieengsdeinnetgrosatvviaeorrnieoupsrienvtnieaortupusrrlaeyltedarfedtpooerbxtepeedriamsental
dileensvfselule`osnphciaennsg,brpaeTtrhcefeentitun.scidoerNnocnleeensor.feptohArete3d.f6inipndeirgncegesstnatvteirioennccioddaneysnicd1ee9roaefnddfde2et0luesfteeestruivsoieutssh vtaosthe
~ocCrohbnbsg:eeaTnlHi]OtMagr(odSuePpgF)senerorfaattliefvneestucsleeelnsls.s!fivTnihdteihnsgessveflvialnsidnignr,gespodriitsneicdnltuedinegdrgaetisintodanitviaiondnduadlfaoylrem1nts8iocnellosf
Jdaevceuloolpemsenti,n Findings of
tcthhheaeinsrgeectvyvothoiperlheapsoisrn.tistiaScliolnuycledochlcaeunvrsescbeeilenlnthdneoergmeeanmlebrrayotobinsoaenlrvanitusic&olnesunso,mrmdtaehleonlens
cLeonusleds rseesculttionferdonthmriounggh an increase in frequency
othbeseermvbartyioonnaslonnucolleduesr. gesAntatiinocnreaasgee of sectioning through the embryonal
ifnettuhsees ianncdidevnicteh nucleus. Both
pTGuebppvsoirotufesolllooapvbgiecnligetdypatorrhteuairnritofiiponandc.iintgysTethcaashtniccacaatlnalryabcettshseeveinttebhroymutcfaotscaaelreaicn1tgllaiusmtlraeanpstpilooipneadcviittotyhan&in
sit lamp.
thsheeectiglorenonissnsgv.efsiincdTlihenegvseopsfatcieagselevanersreecalorebtfsitefravacnetddstmhciercermaoitscecrdoopsbicycoaplfilrcyeefhoainnnlddyinaignndosfaeicactrioostnposamceewhaitch
aeclaosbnorsyicosontnaetlnaciynnuebcdeltewtuehseenceelmtlhbseryotenomabltrhyneouncallleenusnsu.celpeiuTtshheealanibdussesnepclceuosnodfatrhayettldaeicnfhsfmeecrneetlnlcseof pitnrheedispose
tcShoeepnafrliearntmsitoinvosensisacunlgdegeasvgtersetteihmgaeetntttoheofsaergprtaoirsfasatciovtnitihosnmchieicgrthorlsaycnosspeucibtcjeedoc.ctcutroLroatvnicsresautoeiofsptrhooefcessing
as vell as being independently created by freehand and microtome sectioning.
fqIteutau1lsaleypsohshisogivhbelveleervtaeolreforufenesbpaartnoidfsifcaianecdntcomyri.ycroftoGorrmoseesvasoelbcustseitroivnnagttihtorhnoesuglohefnsfefvtraheleenhalnecdnosmespsaercetvdiitohnveidatnh
mGiectrionsecobpoitch otbhseerrveagtiioonnsi.n vOhriocshsloebnsseersvaatrieonssecatrieoneldimiatneddthine nmootrpbheoilnoggicaballe to
characteristics responsible for the lens findings reported.
Tciohnmeptoheuexnpdef:roilmleo1n)vtianalg1tdhefrseeitegunsveasfyosrverfeevraolcmuotadhteedionpbreeofvfoiroefuestfarlteeerhlaaetnnodsleossgeyicntsittohunidisyngsoftfuotdrhyegdrFiofs-fs3eLra2en2dd
mSeirxcaprleoirsaictmoeepdnitcailcorbuosnseictro.vpaitciaoClnol,myp,o2)unadnadllr3e)lfaettthuesedesgdrepomsrs,osvirldaeetndsherffoirtnhdaiinnngstahheveerpeervoatrroe,cpoolrnteveedrcehien the
r2Fe5entmdues/euxsnec/ovddeeardye. cdooTsdheeedsgebreocfuoopmrpeionufntrdhe-eerhepalrnaedtveisdoeucsotcictouenrrirsnetgnoclaeonsgdyvgersrotesusdynoetvvharelneupsettiahoetne.dfewthuesnesthveere
IRtker Experiment Nusber OS80TROOL0.
004291
n 7p4-r12ea9-9nto9etCr0saCffafeedtcmutisneise.sittrhaeTtrhiiostnhectoognrcpolrsuessgionoranntmiiscdracmoossncsoidpsuitrcainntgletnwhsietahppeptrehiaeordsaabcooeefncooerfgatonhfoegilerennessis Patnotrhmealsiatzieesdoosbeselrevveedl.in lactation day 21 pups similarly exposed to T-2999CoC
|
ERiker Experiment Number 0680TRO20.
|
|
004292
12 References 1. CNoeuwlaYomrbkr,e AHJo:lt TRhienehEayret, ainndDeWfiinasatnonR,L, 1U96r5s,prupnpg22H7-(2s3d2s.): Organogenests. 2. 1H5a3r(t1m)a:n HA8:32-8N4a0t,ura1l9l68y.occurring cataracts in the term fetal rat. JAVA 3. MLainpnpinI:cottDevCeorl,opm1e9n5t7Abnormlities of the Eye, 2nd ed. Philadelphia, JP "u. WTealtes,semiI,ceMagngdesrcahbubliztse. A,ASrtcohitvzerFiHe:r TSopxotnktoalnoegolues32c:onge1n9i9t-a2l07,cat1a9rTha.cts in wPira/26n
004293
1
RSattrain coe.
core
TABLE 1 Special Lens iOnraTlvoTeSrtartaoilnosgyofStRuatdsy.of T-299%CoC
GMeesantatMiaotnernDaaly BiondyIvVoeiSgthrtasi(ngs)oWfitRhatsStaannddaTrvdoDeDovsieatLieovneslsLisofted By
T-2999CoC.
(sg/Dxogs/eday) o
25
umDbaemrs Of 2
28
S Gestatioe n 202 226 27 2m 303 3@
a6 #6 #8 #9 21 30
97 ak
221 ss
237 2588 2802 35% a6 a9 21 #25
0
26
12 155 161 im
aT 209
$8 TH a6 #20
25
21
wo ask 156 1568 163% 200 a a a m2 oar
Sveeigthrtesatvmietnhtingreoaucph vsetirgahitns ovferreatsi(gDnuinfniectatn'tslyT lToewsetrpth<an0.t05h)e. control group WP:ra/26u5
004294
i
1
|
TABLE 2
|]
Special Lens iOnraTloTeSrtartaoilnosgyofStRuadtys of T-2999CoC
at
Strain
Coe
coe
core
core
coe coe
core
core
HIunmdbievridaunadl LPeenrscdgnatndofFePtruesghaEnxdperSiemcetnitonalGrUonsistsFeItnaTlvoLeSnstraFiinnsdinogfs RFaotrs and To Dose Levels of T-2999CoC.
Dose.
(mg/kg/day)
0 ng
25
[
25
0 25
TETxpeFRr E(EHlAei NnDsSmECTe ION n GRNOoStSViGFsaa IiiNbltDeI)lNGSS Lens
Lens Clersf Dark Strearf Change Not Sectioned
15 19;
3)
0 (75.
5
20 (25)
9 (11)
12 (53
15 (9)
6 (9)
5 (8)
0 (61)
15 (23)
10 (13)
17 (218
43 (54)
(18)
(Fetus Experimental Unit)
Fetuses With Dark Streak
11 (28)
_orLensCleft Findings
3 (8)
1 (28)
17 (43)
8 (20)
19 (48)
ot
5 (15)
5 (15)
25
8 (20)
14 (35)
8 (21)
18 (45)
2 Percent in parentheses ( ).
2 5 = 80 1enses.
S n= 40 fetuses.
2 o14ne1osrpboostshiblleensteoshaovfeanoneinodrivbiodtuhslgrfoestuss.findings (lens cleft or dark streak) in
21 = 66 lenses and n = 33 fetuses.
|
2
Ek
lens
aurk
cleft 1s a space
streak 10 & dari
catolotrheedaanrteenroctennttrhaelcernetgriaoln
of the
region
offetatlhe ldeenns.s.
2 tmhyee terxepaetrmiemnetntaglrouuapitwsandsigwniitfhiincantthleystdriafifnereonftraftrom(cthhie-scqounatrreolvigthrouYaptevsithin
correction p < 0.05).
i!
WPirm/26a2
oo4295
15
:
TABLE 3
Special Lens iOnralvo TeSrtartaoilnosgyofStRuadtys of T-2999CoC
! PMTewacotrioSostcsroapiainncsdalPotfeyrcRaFetonsrtIaonnfddiFvTrivedoueahDlaonsdLeeSnLesecvSteliasonndoGFfreotTsu-ss2L9d9e9BnCxsepCe.rFiignedinntgasl UCnointfsirmiend
ii
--losshFareeTnhaengd sSeeccutiioonnGGrroossSesP Fr inPidadirune akglT 1mIndkivi--dt ual
||
"SRtatrain (mDeo/sxge/day)
TnLdievnisdual 8s (53)
IndFeitvuisdual 611 (55)
InLdeivns WA (00)
Fetus 3/3 (100)
| coe
o
|
25
gio (us) 9AT (53) 6/9 (61) 6/8 (15)
core
oe
1
25
2/6 (33) 2010 (20)
2/5 (40) 2/8 (25)
2/5 0) 2/5 (40) 147 (65) 11/1k (19)
2 RReattioonsianrge tahnde cnounmfbierrmoefd mgircorsosscoobpsiecravlaltyi,ondifviinddiendgsby rtehceordneudsbefrololfowignrgossfreehand observation findings.
percent in parentheses ( ).
n= 80 lenses.
4 n= ho fetuses.
| Ba tens ches 10 an observe space tn he asterocenral. region of te (eal 5E14=e16a6pLTooesrnsssiebtslneanltdeonnshea=sveo3f3onafeentourisnebdsoi.tvhidguraolssfetfuisn.dingAsfe(tLuesnsvciltehftoneorordartkwossiiraetsl)ar
findings is counted only once.
||
& ST{incgehniit-frsieqcauatanmrteelnytvidgtirhfofuYeparteernsatticoofsrrroomefcttghireoonscsopntf<rion0ld.i0n5gg)rs.oucponrfatiiromsedVmAtihcirnosceoapcihcasltlryainveroef nroatt
|
A ns Ca*le confirmed microscopically by the presencreyonoaflanuscplaecues.betveca the
i
sMuibccraepsscuolpaircalelpyithteheliusmpaacned itshe& sleenpsar`acteilolns oaft tthhee elmebns vesicle vestige.
|
1pedrark streTiaakcoisnfainrmoebdsemrivcerdoscdoarpkicaclolloyrebdy atrheesprinestehnececeonftrtahle eremgbiroynonaofl the
nucleus.
WP:rm/26ml
004296
16
+
TABLE k
Special Lens inOralvo TSetrraationlsogyofStautdey of T-2999CoC
MRiactrioosscopoifcanLdensPerFicnednitngsAgrienemTevnot StofraiGnrsossof IRnadtisviadnudalTLoensDosFeinLdeivneglssS
With
of
T-2999CoC.
Rat
_Stratn
coe.
core
(mgD/oksge/day) ~~IemsTVeeIsnirdcileviduanlace Lens HMeicrrrosecopicbryF.indingscrleeus!t
o
8/27 (30)
4/40 (10)
25
9/27 (30)
6/hk (1k)
od
2/10 (20)
25
2/8 (25)
2/20 (10)
11/28 (39)
2 Rfarteieohsandaresetchteionniunmgbearndofmaigcrreoesmceonptisc bfeitnwdeienngsgrdoisvsidefdinbdyingtshe rneucsobredredoffollowing microscopic findings.
2 Percent in parentheses ( ). <n = 80 lenses.
4 n= 66 lenses.
2 hfienditnrgesatvmeernet gnortoupsigrnaitifoiscaontflaygrdeiefmfeenrtenbtetfwreoeanthgeroscsonatnrdolmigcrroouspcorpaitcioslewnisthin each strain of rat (chi-square with Yates correction p < 0.05).
Anulcelnesusvelseincslecelslpsacefriosm atnheopseunbcsappascuelacrreesptietdheblyiuas satepatrhaetiloennsofvesthiecleembvreysotingael. Tahned trhaetimoic1rsostchoepincumbfeirndoifngagorfee&melnetnss bveetsviecelne tshpeacgerodsisvidfeidndibnygtohfe &malbeenrs colfeft lens vesicle spaces observed.
& FcAneinntdeeimrnbgrOyfoonftahlaendluaecrnlkse.usstreTihesekarannadtairotehaeisomftihcneroorsmncauolmpbiedcregofefinneadrgiarntegievmoeefnctahsnanbgeeemtbwrleyoeocnnaatletdhemiicgnlreotushsse divided by the nusber of embryonal nuclel observed.
WP:rm/26m3
004297
mae 5 Special Lens1aOrvaloTerraaitonlsogyofStMuadtevor 72999000
ousmheTriveainsd P7erHc1e3n5t05o05fcPaentadlTLeenFsleassuWeitPhroMsiecsrsoisncgopPircoceFdiunrdeisngsWhLisatnedInbydexLeonfs RLoengeionSecitnioTnwiongStrParionfsicioefncRya.ts,
Me
Dose
Praoceessding
CorerMtcronchogoerpte " Vesiciey Brye onuif
Findings dcentric
nd Lens Region Sectioned Bystorial Law Lenosf hFoaretigenrs
ISnedecxtioonfinLgena.
rate (a/valiny) Procesure" Space mciews Begion Region Missing terial Proficiesey
on
1DomaEn nboyn s2Od 2L6m) 010G 23)
(G03)
< ER
1PAmeR) EwaDs BmnE,R LG) 280) 6wat 35)
8Bo com
1E 9D(1n3) 2m0 (E29) Mwk o(6h5) 6 2 (3) 02(m0) 150 (015)
2(100)
Com
IPoAoGl)e aBOE B AEri56a) 2s)@ mwaewd
(596))
BeO5eT1e6.dto1em2nseepenan,rentheses ( ). E3ima%e Hrotersing Procedure
#1
tiswues
vers
processed
for
microscopy.
The lenses vere not freehand sectioned:
oTreees PrroceessinPg Poocartira 2 aneaess ere hesmamEsecAtioTned boerfoorhem daerinoeupnrocemsosreodn.orLeintcroooetcIoersr.om the
18
Appendix 1
TITLE: Protocol for Special Lens Oral Teratology Study of T-2999Coc" in Two
Strains of Rats (Riker Experiment
Number
0681TRO362).
.
OBJECTIVE:
TCahtasngeisn tweerraetodleotgeyctsetdudiinesdayrun20onfeTta-l299l5eCncsCe.s ofTheSprSapgruaeg-uDea-wDlaewyley
"train of addition,
rat the
mtahyresbheoplrdedfiorspodseveedlotpomednetveolfopthtehe lelnesns chcahannggee.may Inbe
sJtouwdeireesd. by Onheanodbljiencgtipvreocoefdurtheissussteuddyin iscotnoducctoimnpgareterthaetoliongcyidence
otfreattheedlSepnsragcuhea-nDgeawlienyfaentduseFsishoferbostthraicnontdarmosl. anTdheT-2s9e9c5oCnodC
onbotjecetxipvoesed1sintoutceormopatroe dthoesinigncainddenhcaenodflinlgenpsroccheadnugreessofusefdetuinses
tinecriadteonlcoegyofstulednisesch(aSnpgreasguien-DtahweleySprnaognu-et-rDeaawtleedy gcroonupt)rolwitghroutph.e
TPhreactsitcuedyRewgiulllatbieoncsonadnucdteSdafeatcycorEdvianlguattoiontheLab1o9r7a8toGroyo'dsLaSbtoarnadtaorrdy
Operating Procedures.
SPONSOR:
3 Commercial Chemical Division, St. Paul, Minnesota.
TESTING PACILITY:
Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota.
STUDY DIRECTOR: EB. G. Gortner
START OF DOSING: Fourth quarter, 1981
TEST SYSTEM:
Nriantestyansdexsuiaxltlyy Fmiasthuerre,rattismefrmoamtCehdarSlpersaguRei-vDearwBleryeeddienrgiveLdabofreamtaolery
Wfillolorbseahnodusferdontisn hianngaintgemspteariantluersesasntdeehlumciadgietsy wciotnhtrwoilrleedmersohom.
rTheeasdeilystraavianislaobfleraatnsd
will they
bweilulsepdrobveicdaeusae ctoimmpearmiastoendbfeetmwaeleens tawroe
strains. 1ibitus.
TPhuerinlaigLhtasborwaitlolrybeChoonwaan1d2 hwoautrerlwiiglhlt/bdearkavaciylclaeb.le ad
TEST SYSTEM IDENbTeIFiInCdAiTcIaOtNe:d onBacthheanoiumtaslidewilolf bteheeacraget.aggeTdheanSdpratghuaet-Dnauwmlbeeyr will non-treated group will be identified only by & nusber on the outside of the cage.
RANDOMIZATION: geTnheeraatneidmalrsandwoimllnubmebearsssitganbelde.cages according to a computer-
CONTROL ARTICLE: Corn oil
TEST ARTICLE: 7-2999CoC
u-3924
004299
19
Appendix I (Continued)
ANALYTICAL SPECIFICATIONS: The test article composition and purity will be
deternined Sponsor 1s
rbeysptohnesiSbploensofror (r3eMtaCionmimnegrciaalrCehfeermeinccaelsgarmopulpe).of
Tie the
test and control articles, as required, for GLP compliance.
DOSAGE LEVELS ANcDornEXPoiElRIMdEaNilTy.DESITGhNe: teTshteartetsitcleartaindcleconwitlrlolbearstuiscpleendweidllinbe
administered of gestation
bayccoorradlinginttuobatthieonfotlolowtihneg:rats
on
days
6
through
15
strain
Dose Level
Group size
Sprague-Davley 25 mg/kg/day
30
Pisher Sprague-Dawley
25 mg/kg/day 0 mg/kg/day
30 30
SFpirsahgeure-Dawley
0 mg/kg/day No treatment
30 30
The oral route of
route of exposure
administration will in previous studies
be in
used because it is which lens changes
the were
observed. No dietary the test article.
contaminants
are
known
to
interfere
with
TdhaeilyT-2f9r9o9mCodCaytr3etahtreodugahnddacyon2t0roolf ggreosutpatainoinmalfsorwaiblnlorbmealobeerved
c1l2i,ni1c5alandsig2n0s.of pBroedgynawneciyghtasndwithlel braetsredcoosreddedacocnorddaiynsgl3y, 6u,sin9,g a
cSpornasgtuaen-tDadwolseeyvnoolnu-mtereoafte5dmlg/rkogupowfilblodoynlwyeigbhet.obseTrhveed for a
wliilvle/bdeeakdilclheedckonfrdoamyd2a0ysof3 tgehsrtoautgihon2.0 oAfLLgeosftattihoeni.r puTphse wfielmlalebse
fixed in Bouin's sectioned by the
Wsiollsuotniotnecahnndiqtuhee. heTahdes
will be free-hand presence of eye
Saeblneocrtmaleiyetiessectwiiolnls bceoudledtebremisneendt utsoinghistthoepadtihssfeocrtimnigcrmoisccroopsciocpe.
exanination.
DATA ANALYSIS ANfoDrFaInNaAlLysRiEsPORoTf:theThdeaptaropiossethdestPiasthiesrtiecxaalctmeptrhoobdabtiolibteyusaendd Cthhie-sfqiunaalrerefpoorrtpericsen2t-3omfonatbhnsormaaflteirtietsh.e puTpheeyperopeoxasmesd hdaavtee bfeoern completed (approximately fourth quarter, 1981).
004300
20
Appendix 1 (Continued) Amendment for Speciailn TLweonsStOrraailnsTeroaftoRlaotgsy Study of T-2999CoC
The subject of strain-related
pthhiesnomsetundoyn, haicfhetawlaslepnossscihbalnygep,revcaispitthaotuegdhtbytostbreessa
of
handling
procedures laboratory
uhsaesd gaininteedraitnosliogghyt
sitnutdoietsh.e
dSeivnecleoptmheentoroifgitnhael lpernostocchoalngei.ssueTdh,e
the
Tcheacnhgneiquies.nowThtihsouagmhetndsto tbhee
apnroatrotcioflacctonosfistfarnetehawnidthsescttuidoyniinnggthbey
the Wilson lens change
as an artifact.
OBJECTIVE:
C(hAamnegnedsmewnetreredpeltaeccetsedtheinObgjeescttaitvieonaslecdtaiyon 2o0f fetthealprloecnosteosl.o)f Sobpjreacgtuiev-eDawofleythirsatsstuidnyteisrattoolroegpyorsttutdhieescormupnaroinsoTn-29of99CtohCe. The hthiasttohlaovgeicabelenappferaersahnacned osfectgieosnteadtiboynatlhedayWil20sonfettaelchnriaqtueleannsdesthen pgreoscteatsisoendalfordayhi2s0tolfoegtaylwirtath tlheensehsiswthoilcohgichaalveanpopteabreaenncefrofeehand WsielcltiboeneddonbeefoonreSbperianggue-pDraowcleesysedandforFishhiesrtolroagty.straTihnes.comparison
DOSAGE
LEVELSseAnNtDenEcXePsE.R)IMEANlTlALofDEtShIGeN:fetu(sAemsenwdimlelntberefpilxaecdes intheBoulians'ts thsroeleution.
FPoiusrherfeTt-u2s9e9s9CforComanedacchonotfro2l0
litters vehicle
tfrreoamtetdhegrSopurpasguew-iDlalwlbeeycoadnedd
before being evaluations.
pTrwooceosfsedtheforcoddeidssefcettuisnegsmifcrromosecaocphicofandthehisltiotltoegrsical
uthnederWilcsoonnsiTdeecrhantiiqoune.wilTlhehavfereethhaenidr hseeacdtsionfreleenhsanodbsseercvtaitoinoendsbwyill
bperocreescsoerddedf.or Thhiesthoelaodgicsaelctoibosnesrvbaitsieocntianfgtetrheeemybeesddwiinlglwitthhenthbee
bLriatitnerssiduendedrownc.onsTihdeerarteimoaniniwinlgl thwaovecotdheedirfehteuasdess
from each freshand
of
the
hsiescttoiloongeidcablehoibnsdertvhaetieoyness. byTphaerasfefcitnionesabweidldilngbewpitrhocetshesedbrafionr
msiicdreondsowna.nd sTthaeineemdbewdidtehd hsepmeactiomxeynlsinwialnldbeeossienc.tionHeidstaotlog5y-6
observations will be recorded.
DATA
ANALYSISprANoDtocPoIlN.A)L
RETPhOeRTe:xper~i(mAmeenntdaslentunrietpliascetshethiinsdisveicdtuiaoln
of the lens. The
TshteatipsrtoipcoasledtedsattefofrorinthceidefnicnealdarteapowritllisbethethefiCrhsit-sqquuaartreer,tes1t9.81.
004301
2
Appendix 1 (Concluded)
Protocol Deviations
CoVOteFre25'asnneotla/eahclats/eddNaIyfRo7orSn2l1ga,enest7a5e2tv2ia,olnua7t5di2ao3yn.a1n3.dS7i5nF2ce4etusvteehsreeyofmweiarsnetiamkcaeolnnsltyrNoIldRoTsgSer2do1u,wpi7tf5he2t37u-sa2e9sn9d9aC7n05dC24
nhaelyyshiasd.beahneexfpeotsuesdestaoffTe-c29t9e9dCobCy iTnhiusteprroo,totchoelirdedvaitaativoansareexclluidsetdedfbryomdam as
follower
wiwriirss2231 as] wIxs2e os
2%20 86
22917 0
2002 0
||| mm2au/s3emoseadvaiyaTtgiiroonuSpslreaftTtlaeb6cl8telt5ehnesrieersfleascbutsbsejnecctetheptolaubmssiectnrhcoeescaoofbpsietcnhceeseevaofltuwaeftleivtoeunsf9ien4tutsfhereso.mCOthTPeaYbl0es
| Cor 0 ma/xa/aay group hose gross chesrvation data were lost in transcription.
|| Gfertousssesa.nd microscopic lens obasrvations were not made on CO non-treated group
|
004302
2
Appendix 11
-
Special Lens Oral Teratology Study of T-2999CoC in vo Strains of Rats
List of Principal Participating Personnel
Nase Zovin G. Gortner Elden G. Lamprecht Wa. C. McCormick Gary C. Pecore Inara Porietis Loren 0. Wiseth
Function study Director Veterinary Pathologist Toxicology Services Representative Supervisor of Animal Care Histopathology Technologist Technician
004303
APPENDIX 111
2
STATEMENT OF QUALITY ASSURANCE
STUDY NUMBER: _ 0681TRO362
\
* TITLE: speciTawlo LSetnrsainOsralofTeRratastology Study of T-2999CoC in
ACTueodpmioptrlstieadnacnedt/oAourtdhieitnssuptneuicdttyiodfniosrrewctethroeer apabenorvdfeotrtonietmdlaendbaygesmttehunedty,Riaksaenrd
follows:
Date Performed
Date Reported
October 7, 1982 October 12, 1981 March 22, 1982 June 4,7,8, 1982 June 28-29, 1982 July 15, 1982
October 14, 1981 October 21, 1981 March 29, 1982 June 17, 1982 July 15, 1982 July 16, 1982
RlikherewLl haebeoraAtuore ies, Inl c.
m a Slstre
004304
2
Appendix IV
Special
Lens
Oral Teratology Study of Two Strains of Rats
T-2999CoC
in
.
Individual Body Weights (g) with Mean Body Weights and Standard Deviations for Pregnant Animals
co
OAY
3 6 5 12 15 28
MG/KGDRY NiF 7ED2 194 218 234 268 298 379 NiF 7EOL 181 203 216 247 273 337 NiF 7EB4 199 221 23% 271 303 380 NiF 7EBL 196 223 257 274 306 IES NF 7815 175 20 218 248 272 34% NF TELS 201 229 25% 285 27 422 NF 7EL5 201 219 237 264 292 351 NiF 7820 178 198 221 243 255 325 NIE 7631 229 258 284 318 345 451 NiR 7832 206 234 297 23% 304 38% NAR 7833 215 241 264 293 321 396 NAR 7834 176 207 232 266 290 363 NiR 7SIS 198 222 258 265 300 38% NiR 7845 204 221 240 266 290 335 NiF 7E47 182 215 240 271 302 373 NiF 7E4E 213 247 270 299 315 347 NiR 7Ee3 214 231 255 231 299 377 NiF 7850 220 246 270 302 321 33% NF 7861 212 244 264 303 333 41d NF 7862 219 246 262 289 317 400 NIR 7863 20% 237 266 288 320 415 NiR 7864 182 209 225 254 279 363 NiR 7879 202 222 243 272 299 371 NiR 7880 225 233 261 292 317 391
MEAN 202 226 247 277 303 378 STAN. DEV 15.716.3 18.2 19.4 20.9 29.6
NON PREGNANT ANIMALS NiR 7801 171 201 214 21@ 224 237 NR 7E17 212 241 256 276 27@ 286 Ni 7965 203 215 224 236 238 253 NiR 7876 208 229 253 ri 262 284 NAR 7877 210 230 243 259 271 291 NiIR 787 209 233 24z 245 252 258
004305
25
Appendix IV (Continued) Special Lens OralTwToerSattroaliongsyofStuRdaytsof T-2999CoC in IndividuSatlanBdoadryd WDeeivgihattsion(sg) fWoirthPrMeegannanBtodAyniWmeailgshts and
coe vRY 3 6 9 12 15 20
25 MG/KG/DAY
OO1iFk 7EEO0?6 2181%0 221332 225245 229820 320799 334940
0O1lkR 778g6e3s 11354: 221126 222247 224498 226568 333%6
O1R 01
7810 7822
211 210
23% 236
264 251
283 277
307 308
388 38
01f Cif
7823 7824
180 163
205 181
219 197
2408 217
263 237
334 297
O011kF 77e823s6 11587% 220088 223322 224613 225840 336118
O1R O1R
7837 7836
215 ws
224136
222641
225941
237256
333897
01R O1F
7839 7846
187 132
208 207
222 216
249 233
269 255
329 316
01f 01k
7851 7852
205 191
223142
223560
226522
227749
33S4T%
01k 01k
7853 7854
216 133
34 213
259 238
281 252
306 275
382 343
O1R Oi
7855 7866
198 211
223 244
241 237
257 203
270 312
344 388
0O11Rk 77886687 210918 222277 223440 225604 227710 335448
O011RR
7788760s
222173
225329
225628
227828
305 290
36 37@
O1R O1R
7881 7832
203 198
222169
224413
226600
227671
334625
O011kR
77888635
119817
221132
222364
223415
266 263
326 348
STANM.EANDEV
143.577
152.231
162.372
182.568
280 21.6
351 25.3
NON PREGNANT ANIMALS
01R O1F
7821 7884
197 207
223226
223478
224346
224552
225539
004306
2
Appendix IV. (Continued)
Special Lens OralTvToerSattroaliongsy ofStuRdaytsof T-2999CoC in
Individual Body Standard
WDeeivgihattsion(sg) fWorithPrMeegannantBodAyniWmeailgshts
and
cor oAY x 6 = 12 15 0
@ MG/KG/DAY
NNIAPP
7S21 7522
131 136
148 433
152 147
164 158
11 158
222 168
NNiIFE
7S2z 7524
152 144
170 159
172 163
184 177
196 182
224 204
NNAAFP
7525 SIL
136 143
148 163
15S 168
162 178
146 185
166 22%
NIP NIP
PSI 7533
435 142
145 458
151 467
15% 177
171 191
201 218
NNIiPF 77553345 114362 116428 116S88 118710 4198%3 1218d0
NIP NiF
7541 7543
144 138
157 154
165 160
178 175
164 186
214 218
NIF NAF
7544 7545
145 144
161 159
166 161
185 168
196 178
229 217
NLR NAF
7SS1 7952
132 143
45a 154
158 160
168 160
182 161
226 164
NNIAPF
7TS3 7554
140 147
453 158
157 161
172 171
184 167
226 201
NIR NIP
755% 7561
144 135
157 143
162 151
171 159
179 154
203 165
NIR NiR
7552 7564
140 152
153 166
155 173
148 179
138 192
163 228
NIR NIP
7565 7571
146 120
158 142
162 150
172 158
17 156
21% 162
NIR NIP
7572 7572
148 148
161 160
166 166
174 18@
18% 188
226 231
NiP NLR
7574 7575
136 148
153 159
1@ 165
172 177
18% 183
247 222
MEAN STAN. DEV
142 6.2
155 80
461 67
471 4177 209 S@156203
NON PREGNANT ANIMALS
NR NiF
74D 7563
427 125
134 14a
142 153
144 157
142 150
147 14%
004307
2
Appendix IV (Concluded)
Special
Lens
Oral Teratology Study of Two Strains of Rate
T-2999CoC
in
-
Individual Body Weights (g) With Mean Body Weights and Standard Deviations for Pregnant Animals
cor
pay
2 6 2 12 15 20
2% MG/KG/DAY OLR 7S2E 447 161 160 1% 1% 200 01F 7527 127 143 141 130 138 142 01F 7528 142 45% 166 171 177 210 01F 7528 135 451 150 156 160 202 01F 7530 133 151 153 155 165 200 01P 7936 141 1ST 157 166 170 21% 01R 7537 140 152 157 1% 168 208 04F 7I3e 438 451 157 453 166 211 O1F 7538 148 163 163 162 17@ 216 O1F 7540 139 155 162 166 180 213 01F 7547 129 144 148 151 161 152 01F 7548 127 14% 152 155 461 186 01F 7543 134 148 145 150 162 157 01F 7550 131 146 1T1 148 160 203 01F 758 142 156 1%e 156 161 18% 01F 7553 163 177 178 17@ 182 233 01F 7560 142 154 153 155 166 214 01F 7966 137 451 156 155 1%6 201 01R 7367 146 158 160 158 161 206 01R 7568 146 159 164 142 155 165 01R 7363 137 150 152 152 174 201 01P 7570 143 153 149 157 165 208 01F 757 151 163 166 164 172 213 01P 7577 137 447 152 162 474 21% 01P 7576 138 4ST 153 453 451 186 01F 7579 134 147 152 155 165 20% O1F 7IE@ 143 173 157 140 137 174
MEAN 140 154 156 1% 163 201 STAN. DEY 7.3 7.1 7.4 89115165
NON PREGNANT ANIMALS 01R 7T46 141 1T2 1%e 141 138 1m 01P ?7STE 13% 148 146 146 148 1%6 01P 75ST 148 15a 152 150 1%2 158
04308
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rT
arm prcening proce 418 Tle
some STESr ersten Sey of
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mo-uir ars pinion. Coon en microscopic intone py WraE NoRneER ee TEThee mieaer RmeTrTon OmeEmRctCeOMsIaStMel EteD, LorOenIim
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o
r--m_----
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.
%
STpe2c5i9a5lcaLtensinroerTpawelondiSTxterrvaazitnosloogfy speteusdy of
Microscopic Lens Observations? of Individual Fetuses
Not Freehand Sectioned Across the Lenses
-
w/xa/tay TSU-eL
. : n 2 @a w " 55 5 @ w0 2
central tans
nagion
tVSpeeiscieecl|e NEecbirlveeowmssal
ww
x
ne x
x wom 5nomx xx :. m: om. xx
MRAescgeinotnnric RhEeeqpusiaiotnonrial
. . nw w u.
: w= . xww x u .
WsLMewenissinngg
rane MhSoarhtaaertvrceieeasralseat x
a i2siHnonbeeomTeonmeting Procedure 1 of Tele 5
OOOOoo
004317
.
:
Avpendix VI (Continued) STpe-c2i9a9l9CcLCensinOrTavlo STterraaitnoslogofy RSattusdy of MicrosNoctopiFcreeLheannsdOSbseecrtviacteidonAscroosfs ItnhdeivLiedunaslesFdetuses
. ss/xg/day avtuesr 1 20 sa 5 EY "61 6139 200 02 84 6 a 3 294 298 299 nr ne
Central Ragion
_n
LVeenssicle Space
NEuscblreyuosnal
ReAgcienotnric ERqeugaltoonrial
MLiesnssing
oSrhaFtotreeriegdn Material
L
L
mn n
L
L L
ne
L
:
L
L
L
L
L
L
L
RL n L n n n L u
RL=e rliagthet rleennes Tissue Processing Procedure 1 of Table
004318
Po
3%
Aopendix VI (Continued) Special Lens Oral Teratology Study of T-2999CoC in Two Strains of Rats Microscopic Lens Observations of Individual Fetuses Not Freehand Sectioned Across the Lenses2
.
5 mg/kg/day
"cus aber
6 8 10 12 25 2 3 EX) 7 80 9 100 109 110 13 ns 121 123 102 144
Central Lens VSpeasciecle
L "
Region
ENumcblreyuosnal L EA L
L
L
L
L
R
RL
Rr
mw
"
"
=
Rr
Ro
RL Ea
ARceegnitornic ERqeugaitoonrial Rr
Rr Ea Rr m
Rr
L [a n m
un no
=
MLiesnssing
Lens Shattered oMrateFroiraelign
Rr mn
LR== lreifgthtlelnesns Tissue Processing Procedure #1 of Table 5
004319
.
SpecialALoeonesndiOrxalVITe(rCaotnotlionguyed)Study T-29930C in vo Strains of Rats
of
MicrosNcootpiFcreeLheannsd OSbescetrivoanteidoAncsroosfs ItnhdeivLiedunaslesFbetuses-
we 25 ma/kg/aay
-- sFuentbu-- esr 174 1s 179 100 197
200 205
206
23 24 22 24 250 m2 201 208 205 307 wm a2
Central Region LVaenssicle Embryonal Space Te Nuclweus
L
L
x
L
1
L
L
nw
L
L
Rr
rw
L
L
L
L
n rw L L L Ru
L Rr
RReAedcgelineotnnricReREeqgguiatotnnorial ne L
MiMLisesnsssiinngg mw
. oSrhaFtteermedi MaMatteerriiaall L
Rr
rn su
Rr x
--mm LR e= rleifgehtlelnesns Tissue Processing Procedure #1of Table 5 :
004320
` 40
Appendix VI (Continued) STpe-c2i9a9l5CcLCensinOrTaol STterraaitnoslogoyf RSattusdy of MicroNsoctopiFcreeLheannsdOSbescetrivoanteidonAscroosfs InthdeiviLdeunaslesFetuses
core 0 ma/kg/tay aF_em--tbuesr 1 20 4 36 50 5 ore eS 908 928 9 95 101 104 n7 120 129 m 13 136
Central LVaenssicle 7 Space
Region ENmubcrleyeoSunsal L
L L
ToARcetegenitonrnic nw mw nn ww L Rr L
rn
mn
mn Rm nw
L
L
nn
L
REReeqgusiaoitnonrial
L
Lens
Mliesnssing
oSrhaFtetreerieedm Material
Missing Material
mn
_-- AL== rliegfhtt lleennss TDiastsaueexcPlruodceedssifnrgomParnoacleydsuirse i#nloTfabTlaebleac5cording. to a Protocol Deviation (Appendix 1)
004321
:
a
Spectal
Appendix Lens Oral
T-29990oC in To
VI (Continued) STterraaitnosloogfy SRattusdy
of
MicrosNocto.pFirceeLheannsdOSbescetrivcanteidonAsc?roosfs ItnhdeiviLdeunaslestFetuses
core 0 ma/kg/tay
-- vFeitnubser 138 10 158 159 166 168 150 th
190 196 m 212 258 208 29 230 265 267 273 27
central LVeenssicle Space
L L
L L L
L
Region NEoumcbllreeyuonsnal L L L n
L mn un mn L
L
TcReeeggnitornic n nn L mn
L L n n mn n
RREeeqgusiaotinonrial
MMiLiesnssssiinngg
one oSrhatFeoreeriagan MMaatteerriiaal mn mn L
ne
-_-- SLR= ilegfhttlelnesns DTaitsasuemxcPlruodceedssfirnogm Parnoacleydsuirse i#n1TaobfleTaSblaecscording'|to a Protocol Deviatien (Appendix I)
004322
Aopendix VI (Continued)
SpTe-c2i9a9l9C0LCensin OTrwaol
Teratology Strains of
Study Rats
of
MicroNsoctopiFcreeLhenasndOSbescetrivoanteidonAsc?roosfs ItnhdeivLiedunaslesFRetuses
ore 5 mg/kg/day
etus amber
13 16 2 22 4s a se s6 63 6 6 6 6 72 7 7 a 82 os "06
Central Region
Lens
Vesicle Space
Embryonal Nucleus
L
L
L
L
L
L
L
r Rm =
RAecgeinotnric ERqeugaitoonrial
L
Rr
n
Rr
"
3
"
L
Rr
mn
L
Rr
"
rR
L
n m
L
MLiesnssing
Lens Shattered MoarteFroiraelign
nu n
L = lefe lens R = right lens Tissue Processing Procedure #1of Table 5
.
004323
:
a
Aopendix VI (Concluded) SpTe-c2i9a9l3CoLCensinOTrTMaol STterraaitnoslogofy RSattusdy of MicrosNoctopiFcreeLheannsdOSbescetrivoanteidonAscroosfs InthdeiviLdeunaslesFbetuses
core
25 mg/kg/day Central Ragion
Lens
NFuemtubser
LVeenssicle Space
ENmubcrlyeounsal
RAecgeinotnric REeqguiaotnorial
MLiesnssing
Shattered MoarteFroiraelign
S AO l iOcS. Os,MtBO
125
n
126
mn
146
n
148
L
202
Rr
200
L
238
rn
239
n
200
"
202
L
207
v
L
208
mn
250
L
21
mn
255
n
256
L
270
n
m
ne
as
L
x
216
L
x
2, 1R=lreifgthtlelnesns Tissue Processing Procedure #1 of Table S
004324
Lo
a"
Appendix vI1
Sp7Te-c2i9a9l9CL0CensinOrTawlo TSetrraatinoslogoyf SRattusdy of
7T-2999CoC Composition, Purity and Stability
.
"References: ACnoamlmyetricciaall CRehpeomritcal#s318Analytical Requests #16474, 16319,
Aforliagnhta,lyssitsrawfo-rcolRoirkeedr been analyzed with the
twaexryatosloolgiyd sltaubdeyled#06F8N1-T3R502346,2.LotTh5e47mawtaesriraelcehiavsed following results:
Gas Chromatography of Sample As Received
All in Area 3
(14310 12/3/80 3/31/81 3/5/82 S/21/82
AInniedrets
0.5 [X0]4
0.7 0.6
0.4 0.6
0.7 0:2
[[31
.
10.6 for
12 1.8
13 17
12 1.8
13 2.2
CCss
baollilelrws
1s 4.8
1.6 4.3
15 48
19 4.9
W7a.nCsgotters 8- .9 880.69 8(.X9] 880..96 80..92
mAelletvCalsuepsecaireficwaittihoinns.experimental and integration parameters. Values
c HN Fs 0 by difference
Elemental Analysis
% Theor. 3 Found 3/5/82
2.2
2.6
21..4755
21.56
565..666
575..03
8.4
9.0
1 Found 5/21/82 251..08 62..17 59..31
004325
:
"
Appendix VII (Concluded) S7p-e2ci9a9l9CLoeCnsinOrTawlo TSterraaitnosloogfy RSattusdy of 7-2999CoC Composition, Purity and Stability
ue S71
:
Melting Pont: Inftial 38-48C R5e/c2h8e/c8k2 3388--4488CC
Spectroscopic:
mIantfcrharerdefesrpeenccterasp1e6c4t7r4a-.2,3,4 and 18318-1 are fdentical to each other and
1166447744-32 wwaass oobbttaaiinneedd 1186341784--14 wwaass oobbttaaiinneedd
31/13/11/48/180 35//258//8822.
1N2M/R2/s8p0e.ctraThHes8e385w,areHB3t8o7,ConFf3i9r0m, stFr8u3c9t]urweereandobntoatinreedpeoante1d2./1/8S0truacntdure wcahsatnc,onf1i0r.m9e%d.(CFT3h)ezCFfsbormaenrchdeids,trainbduti1o9n.5w%absacfkobuonndetborabnech6i9n.g6.% straight
Conclusions:
FS N-3924, e Lot 547 hcaqsmeaenrcainaallymsaitserwiiatlh.in specifications, fs stable and is
wh
of
004326
Gen Mt Case
"
Jiri | EEe.DrG.GrGAofrEtEnetrhA(Wo.riCg.inaMlcCo+rm1i)ck
+
EFl.GK.ellLearmprecht
Swen -- 22 Re A. Prokop
_--
V. L.
0P.otWhiaspertaghada/L.
Winter
TITLE:
SPtrroationcsolofforRatSspecial Lens Oral `Teratology Study of T-2999CoC in Two (Riker Experiment Number 0681TRO362).
OBJECTIVE:
sFCathtrasanigneisnoftweerrreaattdomelatoyegcytbeesdtpurdieindeisdsapyrousn2e0donfteo7t-al2d9e9vl9eeClnoosCpe.sthoefThleSepnrSsapgrcuahega-unebg-aebw.alweiyeIyn
ladodwietrieodn,bythhaendtlhirnegshporlodcefdourredsevuesleodpmienntcoofndutchetinlgentsercahtaonigoegymay be
tOsfrteuadtitheeesd.leSnpsrOancgehuaeon-bgDjeaewcltineiyvefaentodfuseFtsihsihsoefrsbtosuttdhryaicionsntdtraomoslc.oamnpdTahreTe-2st9eh9ce5oCniodn0cidence
otnbeojrteactetoxilpvooegsyedisstiutndoiuectsoemrpo(aSrtpeoratdghouese-iDinangwcliaednyedncnheoann-odftlrielnaegtnepsdroccgheradonuugpre)esswoiuftshefdetthuienses
PTirhnaeccitdsietcnuecdeyRewoigflulllaetbnesiocncsohnadnagunecdsteSdaifneatctychoerEdvSiapnlrguaagtutioeo-ntDhaLewalbe1oy9r7a8ctooGnrotyor'doslLaSgbrtooaurnpda.atvodry
Operating Procedures.
|
SPONSOR:
34 Commercial Chemical Division, St. Paul, Minnesota.
TESTING FACILITY: sSta.fetPyaulE,vaMliunanteisoontaL.aboratory, Riker Laboratories, Inc.,
STUDY DIRECTOR: E. G. Gortnmer
START OF DOSING: Fourth quarter, 1981
TEST SYSTEM: wTNiailtnlsetbyaendsheoxsuuisaxeltdlyyiPnmiasthhuaerrneg,irnagttsismtefarimonamlteeCsdhsarSslpteresaeglRuiecv-aeDgraewsBlreewyietddhienrgiwivrLeedabmoferesamhatloery Thleosoersstarnadinfsroonftsraitnsawitlelmpbeeratusuerde baencdauhsuemidtiimtey mcaotnetdrolfelmeadlersooma.re srteraadiinlsy. avaPuirlianbaleLaabnodratthoeryywCihlolwparnodvidwaetearcwoimlplarbiesonavabieltawbeleen atdwo libitun. The lights will be on a 12 hour light/dark cycle.
TEST SYSTEM IDEbNeTIFiInCdAiTcIaOtNe:d onEacthheaonuitmsaildewilolf tbeheeacraget.aggTehdeanSdprtahgaute-Dnauwmlbeeyr will onuotns-itrdeeatoefdtgheroucpagew.ill be identified only by a number on the
RANDOMIZATION: geTnheeraatneidmalrsandwoimllnubmebearsssigtanbelde.cages according to a computer-
CONTROL ARTICLE: Corn oil
EST ARTICLE:
2 ru-3924
1-2999CoC
004327
ANALYFICAL SPECIdSFpeIotCneAsrTonIriOnNeiSda:bryesThpteohenstiSebpslotensaorfrotric(lrIeetaCcioonmmimpenorgsciitaailorneCfreaernadeinopceeulristssymepohwwsisl)lofbemihee
Cost and Gonro articles, ae requised: for Lb commiences
DOSAGE LEVELS AaMCdoDmrniEnXioPisE1tReIrdMaeEidNlEyb.yDEoSIrTGahNle: itensTtthuebaartttieioscntletaoratnitdhcelceosnawttisrlollonbrenestuissprenwdtiehldelsienmse 15
of gestation according So the foliowing:
strain
bose Lever
croup size
SFSproranageguruee--bbaavlleeyy
2355 mmea/rkvaa/rdianyy 0 mashorany
303%
FSlparnaegrue-bavley No tnrge/atgaadnaty
34
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The test article:
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