Document 3NJ3QZpgZE9gGRDXJZyJN8gn
Oral Teratology Study of T-3141CoC in Rabbits
RECEIVED
FEliine
Experiaent Nou: Conducted at:
Dosing Period: Stuy director:
{LTICZXCICOOLLSIGTYY4 osarmsesse SRSeia.keetTryaLuae,bvoairlanutasoterisiooenrs,sLaTboocr:atory NSoevpetaebaebrer6,21,19811981 througn E.G. Gortaer
SantorrReo7 saaarch Technoloogi-st/5TFie2 Aninal Teratology Reproasesion
EREeGse.Mar.cLhanV4perteecSrhttu,nanryDpmPaatMkhDolo2g-is1t-p3ea
SHHMaaenfhaie.gleynsC,EassveaP,la7usahDtoGilEoosngyDL-aTbooxriactoolroya1y 3Sa2te
03082
1. Summary 5o0r,al5aadnmdini1s.5trmagt/ikogn/doafyditostpirlelgendanwtatNeerwsoZleuatlainodnsWhofiteT/-M3i1n4i1kCionC raatbbdiotssesduofrin0,g gestational days 6 through 18 (period of organogenesis) was not embryotoxic and c4o1mponuontdaf4f1edctnotthecauosvearigersosso,r irnetperrondaulc,tivoer tsrkaecltetaclontmeanltfsoromfatitohnesdooefs.theThe fetuses. T-3141CoC was not teratogenic in the rabbit. T-3141C0C administration was toxic to only the SO mg/kg/day dose group pregnant animals. The high dose does, as a group, lost significantly more weight than otchecur0rmegd/king/adnayy ogfrotuhpedcoeosm.pounNdo-tcroemaptoeudnd-grreoulpast.ed toxic clinical signs or deaths
03083
2
Introsuetion SE1aaagrtrnhgieeeiwniartthiidnnogcethselteuvFdeiylrsstdoefvfeour1rm00inGmeaadye/rtgohsfaatadybssveianngdS.emiahgsheeor5n0 muTshaesketvsoedcrniycyiycsyo.ubnbrievs4e4ulPiseuRervGiinvAed Sd1eaSrvaiutnrcyaioigonyttesrdvotasalidng{vdabasuytsse6lco-s5tacgaes50Staicgmin/oiNnf/)i.cdaanytThesa.amtoieugndhtonoofrtehbeodTyreevwsesueltrfsodrof+eartrlrayebbiisn the Tanderinding study.
Teratogenie effects of Orally administem red FanICor. p The seedy was' sp--on--s_or--ed
CBhyeS"HSaCtoarmymevrcailaulatCihoenmicLaalborDaitvoirsyi,on,RikSte.r LPaabuolr,atMoirnineess,oteInaensd Svtars Fcaosntd,ucted br
MSienpnveesmobtear, 21Twaond sNeetevenobfesCompou1n9d31:adaTihreisptrroassoivoenl garnodups1iowteroef dtohseedPrbeertewsepeenl
Pfeirrxeicctiipvaenltys. and supervisors personnel cun be found in Appendices s and 11
CPALrpLaecrtapitocirentgio(nFGsLrPo)coeftruetrgheiissiac(sistoeunedsyApawnpedernedtihcxeonSd1au1f1cettefydorBavGcaectaoluriadttiyingonAatLosaobrtoahrneactGeoorUonydisSL.taasbneotsratacetemoernyt)s
PTaheintsatoirnaegse. intoctahetiosnafefcoyr sEpveacliumaetniao,n LTaaubodracaetoarnsyd asoccoopmy oafrchtihevesF:inal report is
Hethoss
CDSoeumxcpucuahtlielaryn-dgnoaLnateburorraeatteeoswriTeZasen,adlonannedmei:shbieDtreesm/eMstian,bilkeFi.h,n
afnedmaalsesirganbebditscavvees.rsacocbotradiinnegd tfrnoam Tre fabbie; ranging. in vein foon
FTiobrsbirvee 2w0a1r3e pJroewmsae:d wienrdei.vitdhuenalldyiviitnedsta1i3n6i0erfsoiestegerloupceagoefs i1n6 s&nismetnrpeeraccaacrhe anmde
ELIhnuismoreinmdsiingtayvteicroeonn.tobrnolTaolhee1d2gdorheoosoumsT.wdeLriregFnoietoghsdeddhnaraokandrmeciiwyfaelilteceo.iraniwlegEyraechTinasvfaeaemmipialnlaaebivleesodabawdbiwietlnoivbmaibstou5mi.anljeTocfheeed
a
a Be Ee sar ot
ST5.hhenoorarmnails1a57lCsli1n8wiecraaenldohS39ai,emrav:heed.Bdoafdioyluyrwefgirrgoohmutpssdawvyeesrree3 drteherrceoodurgdhewdit2oh9nTosf3ersseeaistctioaoctnieSolinsssfaaorgrvsed'3. i6n, naGaldialtFyiiibnUbeseairngwcaatatehrceoranecsrta0onnt5y0d,eerste5avavinoodlnuam5ls doifbyae/1 ksaAdsnnkeyyo.ubiyhThoerraelsoliu"ntTtieuovbneesvriioovnnerevitshemisnissotreirmeede CMianrnaecstotaar.ic(eAspipoenndimxat10p1r.ovided by 3 Sommereiel Chemieal pevision, St. Paul,
B5RriRiokketerrhEExxppeerriimmeenntt
Number
Nunber
0681RB0331
0681770398
rina Rasbit Chow, Palston Purina Cor, St. Louis, Ho
03084
3.
Autlelrussu,rviinvcilnugdianngimaitlss cwoenrteenetust,hawnearteizeedxamoinnegdesitnamteidoinaatleldyayto29d.eteTrhmeinoevatrhiees and
following: resorption
sintuemsb,erfeotfalcowrepiogrhatsluatenad, senxu,mbearnd ogfrovsissblfeetafletuasbenso,rmanluimtbieers.of
The
pfeertiuosde.s weFroellotwhienngplthaecedinciunbaatnioinncpuebraitoodr, aatll379fCetufsoersawe2rde-hokuirlleidncaunbdatieoxnamined
ffoorr
cilnetaerrinnagl
aanbdnorsmtaaliintiinegs.of
tThhee
sfkeetluesteosn wweirteh tahleinzaprrienserrevdedtoindeettehcytl
alcohol skeletal
abnormalities.
Results and Discussion
TohreganoorgaelneasdimsinciasutsreadtiomnateorfnaTl-31to4x1iCcoiCtytoonplryegninanttherahbibgihtsdodsuerignrgoutphe (p50eriod of
tmhga/nkg/tdhaey)c.ontrTohle
high dose does, as group (0 mg/kg/day)
a group, between
lost significantly more weight day 6 (the initiation of dosing)
aconmdpadraaybl9eofto tthheesctoundtyro(lTsabalefte1r,
Appendix day 9 of
Vg)e.statTihoen.highThedomseiddo(e5smeg/akion/eddayw)eigahntd
sliowgni(f1i.c5anmtgl/kyg/ddiafyf)erednotsefrgormoupthemeacnontmraotlerngarolupb.odyThweeigfhatilugraeinosfwethree nloewvedrose
d(o2e1s823t3o6)gawihnicbhodcyonwseiigshttantcloymplaorsatbleweitgohtthedurcionngtrotlhegdroosuipngwasintdeurevatlo aonnde aninal
Te-v3e1n4t1uCaolClytraebaotrmteendt aonfd pdrieedg.nantNoracbobmiptosu.nd-related clinical signs were unique to
tMeatrenrinnaaltiodnesathdsueoctocubrrroekdendubraicnkgs tohre wsetruedy.dueFtioveinoftubtahteiosnixerdreoart.hs Nwoeredeaths could be attributed directly to compound-related toxicity.
Rcoempprooudnudctiavdeminfiusntcrtaitoinono.f thTehedoceosncaenpdtiofnetailncisduernvciev,althweereinncoitdenacfefsectoefdabbyortions
or does treated
dgreoluipvseriwnegreeanrotly dainfdfertehent 24frohmourtheinccuobnattriooln gmrooruptal(iTtaybleinc2i).dence
of
the
Ttr-a3c1t41CcooCntweanstsnootf etmhberydooetso.xicThaendnduimdbernotofafmfaleec,t tfheemaloev,ariteostaloranrdepdreoadductive faentdusmeesa,n tfheetusmeawneinguhstbserofoftherestohrrepetiocnompsoituensd, doismepdlangtraotuiposnwesirteesn,otcorpora lutea significantly different from the control group (Table 3, Appendix VI). cNoompcooumnpdo-udnods-erdelagrtoeudp.majOonre grloowssdofseetalfetmuaslfhoardmaaticolnusbbweedrefoorbespearwved(Tianblean4y, vApipnen.dix VII). No internal fetal findings were observed (Table 5, Appendix
mTa-l3f1o4r1mCa0tCiotnrse.atmeThnet idindcidneontcecsausOef c13omrpiobusnd-inrelthaetedhigfhetdaolseskgerloeutpaland 13 ribs spurred in the mid dose group were significantly higher than in the control
G03085
a
group (Table 6, Appendix IX). The findings involving the 13th rib are
wniatthuraslkleyletoaclcurorsisnigficantdionwewreerenotnotcondsiifdfeerreedntmaalmfonogrmatthieonfso.ur
Findings associated treatment groups.
Tthhee odroasle aledvmeilnsisttreastteido.n of T-3141CoC to pregnant rabbits was not teratogenic at
03086
BESTCOPY AVAUABLE org e BBLEATET oA 1stn n , tpeave .
9/kesday
--
Bove LEY S03 20% 231 dea ub 3437. 6
ER bE ie oni ues
ms/ka/day
1.5 mo/ko/aay
ELT ELE ee Bint DEV S50 84.2 83.4 EL SLE a3 4
2 Significantly lower than the control (Dunnett's t test p < 0.05)
03087
mwome o maaan omsgar 5 waaranr Lemp
QRueaplroTbourtaioolnoneyctsoermunionf T-andFiaccee iMnccmuatbiireyh
oWehaeter of cmoimdaiptnicoen A
wa ow
asm
w
wt a
nw
eMIoeorscetmtoeornn Soorfolvaries
ns
"
nm
u
om
o
n
. ro24reoauttsy tTnoccbtasceinocen
ore va + om o ws 2
&o0Tr0neaootfmnm1t8ocasnoaiunapnsalwVsarseiCnoortmeisanrialgtyneidfiinbcaasineotrlyey
tndhidefeLprrneeengitnaatnficroionensotfhwodiocesoinntsgroocloasuotsweto(Fhhe+i-rasbqdu1acieeattihng
Yates correction conition
p
<
0.05)
8g g8
Op. o mr 30 maaan smi
eed
r---- 3fi9/isy
Hen LitoereoTteasaatnoaloFmetsatiushofcs3H1e4h 1Scianmmsbseosvtions?
sHoeOF VILEEFTEWSEES ALint
ECBTozI e 1sS an Awe
swieMyavTOzEe sOiDEDwi
Borer en ww
STAN LEY 17 14 Zz
au
Pose as se we
SIAN LEY Le 13 aa
we
WeSorllon u4r a0s ea
os
we
65
meSrEon ioe 5s: os
on Le
cCoemo aeteni
[tYiI !
c3o1 me:
as
?
2s
5%
ea
z
s
* Teeataent groups were not significantly different free control group (Dnett's test p 0.08)
8
E=
2
E
g&8
a.
Table 4 OralNunTebreartoolfogFyetuSsteusdyWiotfhTG-r3o1s4s1CFoiCndiningRsadbbits
Total fetuses examined small
Clubbed forepaw
Omdga/ykg/ 4
3
Dose Groups 50 dmagy/kg/ Sdmagy/ka/
7
7
Tw 2
175damva./ka/ as
2@ 1@
Table 5
Oral Teratology Study of T-3141CoC in Rabbits
Number of Fetuses With Internal Findings
Oma/kg/
Dose Groups 50 ma/kg/ 5 me/ka/
day
day
day
Total fetuses examined
a
7%
7
175damya/ka/ a
2 T(rDeuantnmeettn'ts grtoutpesstwepre< n0.o0t5)significantly different from the control group
2 No findings () = percent
owferetotoablserevxeadmininedthe
fetuses
examined
03090
5.
Table 6 OrNaulnbeTresratoofloFgeytusSetsudWyitohf TSk-e3l1e4t1aCl0CFiinndiRnagbsbits
No. of fetuses examined FHoolnetsaneilnlpearnioettacllosed Holes in both parietals One sternebrae missing SStteermneebbrraaee anostymomestsriifciaeld SEtxetrrnaebsrtaeemefbursaeed 13 ribs 1133 rriibbss sfpluorarteidng
0 dmayy/kg/ a
160 1@
7 a4 4 1@ 1@ 8 ae 13 o@e
50damya/kg/ 5 dmaay/ks/
7
7
16 e222 1m
Ga
16 22 3@ 1m 1m 28 Oo 12 as
1 ow ou as sm a Go) 11 8 es?
1.d5aymg/kg/ 4s
nea 1@
10 22)
5 1
an @
9 (20) 1 7 @ ae)
2 significantly higher () = percent of total
etxhaanmintehde
control
(Dunnett's
t
test
p < 0.05)
G03091
10.
Appendix 1
TITLE: P(rRoitkoecrolExpfeorrimOernatl NTuemrbaetrolo0g6y817S5t0u3d9y8)o.f T-3141Coc in Rabbits
OBJECTIVE:
Atertaetroagteonliocgyefsfteudcytswiolfl obrealulsyedadmtoineivsatleuraetdeT-t3he141eCmobCryottoopxriecgnaanndt croambpbiltisesduwriithngthtehegpeenreiraold orfecoormgmaennodgaetnieosniss.of Tthhee pFDrAoceidsusrueed in JEavnaulaurayt,ion19o6f6 D(r"uGgusidfeolrineHsumafnorUsRee"p)r.oduTchteionstuSdtyudiweisllfobre Safety RcoengduulcatteidonsaccaondrdiSnagfettyo tEhvealu1a9t7i8onGooLdaboLraabtoorrayt'osryStParnadcatridce Operating Procedures.
SPONSOR: 34 Commercial Chemical Division, St. Paul, Minnesota. TESTING FACILITY: SSta.fetPyaulE,valMuiantnieosontaL.aboratory, Riker Laboratories, Inc.,
STUDY DIRECTOR: E. G. Gortner
START OF DOSING: September, 1981.
TEST SYSTEM:
SfreovmenDtuy-ttcwholansdexLuaablolryatmoartiuerse, NeIwnc.Z,eawlialnld Wbehihtoeu/sMeidnikininstraaibnblietsss cstoenetlrolclaegdesrowoimt.h wTihriesmsetsrhaifnlooofrsraibnbiat tweimlplerbaetuurseedanbdechauumsiedity whaitsetrorwiiclall bceonatvraoliladbaltea aids alivbaiitluanb.le.ThePulriignhatsRawbiblilt Cbehoownanad12 hour/dark cycle.
TEST SYSTEM IDEwNiTlIlFICbeATIiOnNd:icatEeadchonantihmealouwtislildebeofeatrhetacgaggeed. and that number RANDOMIZATION: coTmheputaenri-mgaelnserwaitleldberanadsosmignnuemdbecrasgestabalcec.ording to a CONTROL ARTICLE: Distilled water.
TEST ARTICLE: T-3141C0C.
ANALYTICAL SPECdIeFtIeCrAmTIiOnNeSd:byThteheteSsptonsaorrtic(l3eM CcoommmpeorsciitailonChaenmdicpaulrigtryouwpi)llprbieor 1t8o rtehseposntsairbtleoffotrheresttauidnyinagndaatreftehreenecned soafmpdloesinofg.theThetesstpoannsdor control article, as required, for GLP compliance.
2 re-143
03092
a.
DOSAGE LEVELS AadNriDtsitEciXllPelEeRdwIiMlwElaNtTebreDEdaSaIdGimNli:yn.istTeThrheeedtteebsytstoararartltiicclilenecuwbislaolttiuosbineonsaossseisghoelevvecdoeriirnmis
on days chroush 16 of gestation according to the foriemes
Dose Lever
croup size
5S0namkga/krea/nayny 1.5 ns,kayany
iiss
o nguasany
I
dThhaiesstaoBrreyaelncodrneocfuaitenniendoafnbtyasdataihrniesisktrnrooauwttneiotnionwiianltlrearbniegoerutssienwddietrbhecstaehueesne.tetsosxicity
ee
oOivnnujletachtteiioodnna.yofoTfh1ebmrgdeoeoedsfingup,iltlueiatctahhernyfeblmeaulteaeritnwiiifzlilicnigbaelhiotgryimveemnneseastnioniehnmteernsaveientohus
"0n.5ien/lMionfikpionolemdaledilruatbbeidtss:amen collected em an meron
grrTaeehbcsebotiraatdtnseiidomnadloosnsfeoddrwaiyalaslcbcnoob3,rredmaio6l,nbgsl5ec,yrlivnue1isd2,ciandlga1i5,4lsyigc1no8fenr.soatmnadndBta2o5yddyeo3sfwe'teshivreoessuumssamhnnwadisoaryea}2Lno9
of the
21/kg of body weet.
liTtuhsteeacf,oenntnseulnmetsbserwwiiollfll fbebeetukseiexlsalmeid(nleiovdne tcoaanydde2td9eeraamdn)id,netrnhuembmoeveraeroirfes,osfeusoteeorrnuersoonand
asbinteosr,malniutmibeesr. De05 t&erm2i4nahtoeudr
sofurTvhiiemvpaplluapnscthaewtciiklo.ln bsehiteepsl,afcopeliudopviinenigagndneiynaaenmrameeetcmopsaoei3r70 and their viscera examines fos any oeerils
Hasbuinborsreemqaunleintrtieaesrsk.eletTahle peuxpasmiwnialtliontheanftebre Ecilxeeasrinign Lande' hstieetoomooelurfoorr
SMUPLES FOR FOSsCSSaaaIkmkDeeeLnnEspiSrxxPeoO-nrNdaSotbOshbReei,tCscOaoMmnaPetOdUraeNayaDbcbhL1iE8cdVsoaEsnLeodnAoNldneAavLyeYslSas3Iy9S:3oA9foSASfievbselsrroeaoctdseiarnmsirma.nimteplLetieowtnilloin?be
"11 be Labeled, froren and seansterren to tha sommaoSra eneples
03093
12.
tTheersaetolsoagmypleesvalaueatinoont ocfonTs-i3d1e4r1eCdoCanininrtaebgbriatls,partthatofisthethey are
not the
psepornssoer'asparretqueosft tbheecatuesreattohleoygymasytudsyu.pplyThuesyefwuelre
taken
at
sanuaplpylzeemde;ntatlhe ienxftoernmtatitoon.whicThhethseaymplarees
awinlallyzneodt
necessarily is a matter
be of
asncaileynsteisf,icifjuadngdemwehnetnbtyhetyhearsepocnosmorp.leteTdh,e wrielslultbse roefpotrhteesde in a
ssteupdayratdeirercetpoorrt.forAinccolpuysioofn suinchthreepSoarftetwyillEvableuasteinotn tLoabtohreatory
record Safety
Eavraclhuiavteiofnilet.hatAlthteernsaatmipvleelsy,wiltlhenostpobnesoarnaclaynzendo.tify
DATA ANALYSIS ANfoDrFaInNaAlLysRiEsPORoTf:theThdeatparoparoes:ed Dsutnanteitstt'iscatl mteestthodfsortodambeanudsepdup owfeigihmtpsl,antnautmiboenr osfitefsetuansdes,numnbuemrbeorfocforrpeosrpaorpltuiteoan; sCihties,squnaurmeber rfeoprorptercisent2-3abmnoonrtmhaslitaifetse.r deTthaeilperdoppouspedexdaamtienaftoirontshehafvienalbeen completed (approximately first quarter, 1982).
03094
13.
Appendix IT List of Principal Participating rersonnel
Nas
FuNcTIoN
Edwin G. Gortner Elden G. Lamprecht Gary C. Pecore Venkateswa Pothapragada Larry Winter Loren 0. Wiseth
Study Director Veterinary Pathologist
Supervisor = Animal Care Commercial Chemical - Analytical Commercial Chemical = Analytical Technician
03095
ApeENDTX "= RESTCOPY AVANABLE
STATEMENT OF QUALITY ASSURANCE
1a.
STUDY NUMBER: _oesitooase TITLE: Oral TrearattoollooggySSttuuddyooff TT3541411 CcooCciinn Rrabbbbitiss
ArCeuopdnoiprtltsieadnacnedto/Aourtdhieitnssutpnueidctytiodfniosrrecwttehorereapabnoedvrefotrotmiemtdalneadbgyesmtteuhndeyt,Raiskanegr follows:
Date Performed
Date Reported
14 october 1981 15 october 1981 19 October 1961 3 November 1981 November 1981 17 Novenber 1981 12 danvary 1982 18 February 1982
16 october 1981 21 october 1981 27 october 1981 11 Noverber 1981 11 Novenber 1981 1 December 1981 27 January 1582 19 February 1982
> RSiGrkepeaTrr{LaancbeoratAuodrTiEe2s, Inc. a2te/,/e
03096
15.
Appendix IV
OTreasltTeanrdatCoolnotgryolStAurdtyicolfeT-A3na1l4y1tCiocCalinReRsaublbtists 2-3141CeC Commercial Chemical Analytical Report #308
GLC of Methyl Esters
cg Acid Ce7hAcicdta(all isomers) CCigorAcciiad Cx Acid
Pre0s.2tuay 09.76.6 2 5
Posts2tuay a 96.4 2 I]
ALL values within experinental and integration parameters.
Element cF 8 BoSby aire. Mo = 431
Elemental Analysis
Theo. 6.13
Prestuay 6.2
22:27 3.2
223..25
07.:422
07.74
0
68 ppm
Po6s5t.s5tusy 223:62 70..67 68 ppm
Spectroscopic
Infrared spectra.
spectra
#16474-1
and
17958-1
are
identical
and
match
reference
Nr1eM2%fRebrsaepcnekccetbrosanpeeHctb6r3ra8a.6n,cheFTdh.e83c8h6a-i9n (iPsre)79%ansdtrFai1g0h1t63c-h4ai(nP,ost9)% a(rCeF)igdCePn-tibcarlancahnidngmastecdh
Conclusions
rTe-p3r1e4s1eCnotCathiavseaonfacnoamlmyesricsiawlitmhaitnersipaelc.ifications, is stable and is
Roststudy Control Article Commercial Chemical Analytical Report #294
Control Article Distilled water
2T-h3e1o4r1ect0ical mg/ml 0.0
TA-c3t1u4a1lc0mcg/m 0.0
03097
BESTCOPY AVAILABLE,
Oral
Teratolony
repens v Study of T-s1aicoc
in
Rabbits
NeishtsI andndividSutaalndaBroddyDaWveiigshttiso(ngs) fWoirthBroMsenaann.Bodsyaisals
ve 3s 3 az as as zs 0 Haat wwNaeeE CS2.i3EnL Eo16Rh70 A E4sNs7 NE155R3EEa7DEed E1D7SEPiSdUs E2 issYn mwweee ZEZhIRIGREEOmURTEaPEdEILESEEEEnRNRh ROEREEE MWwEEr SE CitHe Ui deBsn iIomUHiuZmEaSGna EHERRSEEEEaEEsS wi SH ET mn Edam EiET an MMEE CooBo LImmInmoiSdEnSaSrRanEaEsaAnS EEMEAN 4elessistabitAJoieoifuserHiS a
Na EEG Friis nMHAIiEE HEiIaiSn f1U5ieIsd i4Loahr i1A2SiaS 1f15asseti: li15of0an5 1f4H9i]%s Pb1a5En3d
03098
Appendix V. (continued) OraIlndTievriadutaollogByodyStWuediyghotfsT(g-)31W4i1tchocMeiann RBaobdbyits Weights and Standard Deviations for Pregmant Animals
cr Sos ow az as as os
So MaAG DAY
G4L6E die
1G11133 IT
1SiItih2 ETTN
l23o9e3s H18I5E% AEDS
2100402% 107
2iv0e8s4 feo
1227344 avs
2Z9o5i4d ised
Gfuee Gap
I01DDe 1100
JDiIeNd KiEw
HLaOiTe isis
dIeIerR Le
EdAeTw tl
H15i2e0 ses
I13A3N% ibaa
iasnd 213:
Gfeer TIE
ISeteTibiI Sien anee
IdriNer tebe
EN tums
BRriLereSfFel ders sow
AONdeGrE tin Tov
tCSieEE DLTealOl LLEOeDSDWNubNsIAuTsGd ESobNoVl ACILNNES ZEEidNNs EaZuDnlh me TE ILI ILA DU SN ERI
CIE Dik hess hows deob Aver sted Lew iii
STRNERCn thiaswaltStGaLreadALeoinRi0es34$IhhasieZL:
rs EERE RLS GLE lib idSe BNET AUR Ele ZIAD MWD 2226
ABLE
2 animal died - intubation error
03099
BESTCOPY AVAIL BLE,
oraIlncTievisaautaollAoBpnpyhednStdvuiedxiysvhoif(sC75oonatniRdniruccehodcHaiannRaBbodbyics PINES Sto Jhon
we 3 ss az us as a ee mMSie mEcmRe sEEaremime 2mamsnersisnmeekmEZeune n2eisse mmWnooonrnsnnmRLiEmanmnnInonmmintEmEaLnnnaaiunnooannnnraaaanew mHooNHrRnnLmiiEnnLRaERrsIaaCn annennaan aa=
EeO n ELL -- A--
,
TMSioOoInED iN. hom
mm 4DEem rs asa s a3e4 mmm an am
osouns aZuno aman
mFTleoOncIenwd 2007 R204R2 tLnad la nd@ ida und@
2 Animal died - intubation error
603100
AVAl apy, oraElnaiTveiraauteodi[onBRyodySStWuedlysho-- efs T(-3)snWiiccehsMeiann Rsabobsits Vasohts and Standase Devistions for Pramant avimals
es ss ax us as a is waren woaSdieEEmmn SBLmomlneIEDSm0n VGmIBEB2R0n0Id 7 sEEZemmBd.EEE E1EmRSilTg Iueel0NE a a1aN623on anyold aToSIhoeRkIhISssESiEcRhsESeEEipkmSLNe CaSiimnedmsasir Taan cm en REEL
ne Esa Aes
ae PGrEd
OI CIEhI e RIAT ABahaI ri Ev
ORmREleA nOLgWM
aGmeEh aHeeEy aeEen SLI
CO EAiR.SE
ER LR SOF
IT O52
E Aviimal idileides- abhorrotneednfSouarndays before death
03101
20. Appendix VI InOrdailvidTuearlatoLliotgtyerStDuadtya WoifthT-3Me1a4n1CFoeCtuisn WReaibgbhittss 0 mg/kg/day
ANTAL
ue as
riz Zikz
we ae
Zain ia
awsE Ziilmi
SsEe ZLEAwDh
iLe mCiman
8BleLsDsL
t= ie
2000k0
i1e6 Zzeonud
ie Zils
VIMABLFE FETTUOTSAELS FEDTEUADSES
iz 1
os 3
uaw
"or Lau
aa
wa EE11
aa
wWLdI FERrEESeHbEeRn)t
puoPzREGNANT
o
AedEoEmiIsEcL
Delsivewred Earl4y o
Tris
oa
oa a
FFIELSOONR T[WMTPILOANN LLUOTREPRRR sMvEeAN FETHUSFMTG) SIiEs 217es
a1 35 1u 27 o1 2;
a`
=B42az iGaalz:aoda4siez G4 BiZazzeladzeaasn G3E:EEeaEsY]
Bama 5 ms
aP "`
2
5 5
5 ISmLaEullmsaoaBnas # 38m7ziam4ziimaea
03102
50 m/xg/day
Appendix VI (continBueEd)STCOPYAVAILABLE -.. IOnxdailvidTuearlatLoilcoeseyrSbtaurday woifen1-n3a1a4n16BCotninn mRoanbiieess
MINA VIHSLFE FETTUOSMERCS FECTEURSUES
SwwEiiDnm nnn
se$lze0n3dou op , mee
EFoaa:roDfooL: 0%o: o0ed
Zona ptr
SSER E EPL:r ok
PFRelsiEimm RIinNiEoLn CLourfernen WLeSs FEFTETUSUS wrWrees i s Fo3 Baianngge Ze 18 seria F[O ET SEV 5 Pf Lragaps PeooEs 7D Raiindian:s
F3 OEi2LrnaEm e wToeh een3 dsS a
@
5
=
AEB 45. 7 ag 2
03103
Aopentix VE (GoncinBsEedS) TCOPYAVA ABLE = IOnraailviaTueersatoLlioegeyrStDuodcye WoifthT-d3e1a4n1cpeceicn mRearbmbeircye
5 mg/kg/day
AMAL VISELEEFIETUTSES ECTEsROes
E ie r ZEEnSnSiPLrooio:r 33
OEE edo
ESEERNNE w orTeEe en
aEi RBoSEEni
welmei aese ower,
S m BsaE imoo sI Lr o ordd2
BOE wel endow
ESRrEieSoGnR tIeENrFiLhoAnM nCOeRPnER mMeEaAnN FEFTESUS WTMTi3>
F5 5O:E;7 Tf 1
gmsriizimmmiiznaigte4
67 5 fs S:oFz:sofo P50Fs dlhn
esizins asiaezias oS amszio ansIsm asnlr WSeiaanad
03104
1.5 ma/xg/cay
BESTCOayPaYABLE--
InOdriavlidTuearlatLoiltoAtgpeypreSntDduaidtxyaVWoIift(hTC-oM3ne1ca4ln1ucdFeeedCt)uisn WReaibgbhittss
THINAL VIMFELFE FETTUOTSAELS FDEETURSDES
S"E6 22333353 = E55
oNNOOaTTr FPRREEGGHNAANNTT
EE2s3Z5ie1a
soaTu rrecNAnT NOT PREGNANT
E2o3m5sss2 NOTisPRs1EGNs ANT5 a
rme8e Zaz
4zzzg ced
3
&so2ys & riz
4zo:os 77 ss 3 a
@2 @
&s iEEtemenoRTeC
SFKiTEtISeOOsNR
ITNAFTLIAONN sites
LCuOrReFmER
MAvEeAN FEmToUS WT(os
e FO a i
2F5 elsaEdeFzd3dseIaLiuaasnlss
55 7 ocEsae sina
@2 sh zFazT oEimru soiicEe aalaiaia1 nnnaaz
03105
Dosa Group = 0 ma/ka/day
Total
fetuses
oto. examined
Seat
Dose Group = 50 ma/ka/any
Br
Dito.
Es
Dore Group = 5 maya. Dm.
TotSaeafletuses examined
Dose Group = 1.5 sg/ks/ay
Total
fetuses
Dano. examined
aEarp--
OHruamlberTeoxfatoFlootussyesS-- tubdyyDoufn TW-i3tLh4r1cooncsiFninrdaibnbgists
aL 22 S03
am 72
a4 a
2 ia
2 es aa
203 a
20s 37 ame ess
225 226 18 241 204 2043 24 20 0 291 292 0s 2706 2708 1
229 20 am 1P28
dw 1
:er a
295 6
209 a
amo a
2m ama 5s
am
3
2697 2698 6s
299 6
a0 os
ama ms 1g
ame 4
1
:
4388S
3
Dose Group = 0 my/ka/day
Total
fetuses
Dude examined
Dose Grow ~ 50 ma/kg/day
Total
fetuses
Dl. examined
Dos Group = 5 myka/ay Do
Totalfetuses examined
Dose Group = 1.5 ma/kaycay Damo.
Total fetuses examined
HOurmabelrFOoFratPoaltoisaydssAbteyupdebynodmoifWviTit-zhazlIncteecrnaitn RFianbdiiensgs
22 53
23 7
am a
2m a
am 2 aa
203 208 ae
mr ame ss
32226 Sf
a0 7
241 8
202 34 4s
24s 20 as
30 20 as
269 5
205 4
206 5
208
2m a0 20 Bors
233
29 0
9 6
200 a
Mo 2m a,
me
zm
2697 2098 Ss
2699 2300 es
ama a
zs me a,
3
8
3
#
0010 Group = 0 maga biengr SOAfALFOeLtOuMsYesSbtyudyDuOnFWiTt-h24S1hCeOteCcafrn FRabibitms
:
eFonrtarnelolCe fmiotnecslosceadonpineer Holes inthe parie
Pr5oHBEyDNy5030a 2m seTs 1a0s e20s amosy me
SESxttteerrranneasbbtrroaarecnsanoboyrtmaenonscsttiiaiolensa 1
! 11
2
a
1
I
1
Sternebras 13 cine
fuses
1
:
2
113 riivbes sCpouactriendg
aa1, 1 FE
1 :2
:
D080 Group - 50 mg/kng/doayr
HrFooolneatsarnienlethfenooptrarceileoeseaextgamine
ESSxttteertranmaesbbtrieaarennansboartyameoosnstiifoinesq
Sternebras 13 rion
fused
[Erepe--
W126 5
300
But Bur NE
3343
ER i
2
) 2
30Tod
Tfogo i sE,EN
an zee 20 Toes
1 [a
soai
00 292 se 1 a
205 2706 200g
Ty sa
TY
roa,
1
i>
2 8g 3
Dose Group = 5 mg/kg/day HrumablerToefratPoeltoigayasSbtyudSyoomfWTi-t3h14S1rectoaCteisn Friasbtbiitesge
2
uber
of
totes
Damo examined
Pontanelie not closed
28220 8207132
290 3
9 205 gy
mo gy
2m a
mz a
am
20s 2s
OSSntteoerrSnmteaobbrirnnaanebranaeosytmemonistssrsiiifcniagln 1
0 soa3
qa gg, 3[IOi
111333 rreiintbees sCpluorstriendg
iTosEI aa,1
12
5
:21
i
Dose Grow = 1.5 ma/Dxae/naony. HMFoomlnbetesarnieolnifeboftnehottupsaecsrlioeesrexadmtisned SEStxtaterrtmanaesbbtrraaarssnconbeorytassmoantsriifcianld 111333 iciibbbsee sBpluorarteidng
2697 2098 65
2699 4
200 5
ama ms 5;
ame a
EE
2aaaa
2
i a
1
1 2ro2a oasog,:
Lb
83
3
38
DISTRIBUTION LIST No. case E. G. Gortner (Original + 1) Be Keller (ga File) E.G. Lamprecht EeLe Muts+cRh. A. Nels+oRn. E. Ober We C. McCormick + F. D. GEAffith (2) HH. Pearlson G- Re Steffen =J. D. Henderson K. L. Ebbens
03110
