Document qmVzzz1BO6QzyaRGgzbrYp3KG
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International Research and Development Corporation
SPONSOR: COMPOUND: SUBJECT:
34 Company
Fluorad Fluorochemtcal Fo-143 Ninety Day Subacute Rhesus Monkey Toxicity Study.
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VDiicreectPorresi8dinScusearnsden
Collaborators:
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D.DiC.recJteosrsupo,f RPhe.sDe.a,rchAssoctate
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JR.. PrSG..esMiGedeheirnli,tngaD,n.dVP.hMD..iD,r.e,cVtiDocirereocftoPratohfology
Large Antnsi Toxicology
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Dace:`NNoovesvber1e100,,m1199b7788er
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137-080
i 01723
International Research and Development Corporation
ToITAnBLtE tOnF uceondTENTS
Table Yo.
Page
5-7. Individual Hematological Values . . . ........... 8. Means and Significance of Biochemical Values . .. ....
1g20 2
9-11. Individual Blochemical Values . . . . ........... 12. Means and Significance of Urinalysis Values . . . . .. ..
22.2 25
13-15. Individual Urinalysis Values . .............. 16. Sumary of Gross Necropsy Observations . .. .......
26.28 29.30
17. Absolute and Relative Organ Weights . . . ......... 18. Microscopic Observations . .. ..............
3.3 3339
137-090
C01724
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International Research and Development Corporation
Page 1
I. sworsis
In a ninety day oral study in rhesus monkeys, Fluorade
Fluotocheaical FC-143 vas adsiniscered at created only with 0.5% Methocel), 3, 10,
dosage 30 and
levels of 0 (control, 100 mg/kg/day. Teo
sale also
and two female monkeys were initiated 10 a control group. The monkeys were
at each dosage observed tuice
level daily
and for
general physical appearance and behavior and pharmacotoxic signs.
uBroidnyalwyesiigshtsstuvdeirees rveecroerdecdondwuecetkelyd.oncHeemafntoltohgeiccaoln,trobliocpheernioidc,alatandthe
end of the first and third months of study.
durinTghewemeoknskey2sthtrroeuagthed 5 woifththtehesthuidgyh.er
dose,
Ac th
e
(100
30
mg/kg/day) all
mg/kg/day dosage
died
Level, three monkeys died during toxicity fn the gastrointestinal
veeks tract
7-12. They all showed signs (anorexta, emesis, sometimes
of
brown eves,
in color, slight to
black stools), pale face and gums, swollen severe decreased activity and prostration.
face The
and
monkeys of the 30 and
losses from the first
100 mg/kg/day dosage
week of the study.
level
showed
body
weight
dosagBeecaluevseel,ofthtehecleianrilcyaldealtahbsoraotfortyhe temsotnskeywsereat notthe co1n0d0ucmtge/dk.g/day
The
month of
monkeys at
the study,
the 30 mg/kg/day
slight increase
dosage level showed, in
in prothrosbin time and
the first
in acti-
vated partial thromboplastin time (A.P.T.T.) values, decreased alkaline phosphatase activity in the serus
as well as (statistically
significant). Only one monkey from shoved a lo albuain value. Ac the
this dosage level end of the study,
in this period the only
remaining monkey
aneata, lov blood
from the
glucose,
30 mg/kg/day dosage level showed apparent
alkaline phosphatase, total protein and
albuata values.
There vas no monkey had black
mortality at the stool on several
10 mg/kg/day days in week
dosage 12 and
level. One occasionally
137-090
C1725
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International Research and Development Corporation
Page 2
Lsenvoerlexttaheraendvaosneasvoenrkyeyseixighhitbitiendcrepaaslee
ifnacetheandsctgiuvmsa.vedABeme.hti,s
dosage ery
Cfnisttiheealfleymalseignsiofnikceaynst)d.uriTnhgerteheweFrieratnoscohnatngeosf itnhethseeastte(rountoasseenes
and no changes 10 the body weight. In single sonkeys from she 3 sos
P10hosmpgh/aktga/sdeaytndostahegeselreuvme.ls, there vere trends toward decreased alkaline
Tn Calicy,
the no
control changes
ainndthtehebo3dymgw/ekigg/hdtasy
dosage and no
Level signs
chore vas mo of coriatty,
more sure
stoolT,heGmioarrtcahleicyoranetmestihes avebroeveosbesnetrivoendedscsciagsntsonsoifnyw,oxicity in the 30
arnednd100cooua5r/dks/t2heaysdaoesagseignLsevoeflstvoexriecitcyomipnousnidnrgelleaceemdb.ersTheatrethseas10a
omfg/ksgi/gndsayofdostaogxeicilteyv.el.TheTrhee 3ismgan/kegv/iddaeyntdossaegleatiloemveslhiysesemesvosteonbeihefree
'
50 gross adainistered elated vere
soderoesenmsic(nranodscciaotsphueiecsdelogetrsheieeornsofhwahtnihechtthoevxeiarcdeiztecyro.antssi,derbeodne ccomaproeunnd.
Spleen and Lymph nodes for male and female monkeys au she 20 sng 100
efmlegm/aaktlgee/ddcamoyaircdkeoeysdsagdeaicflfteuhvseeels3.0LipatnMddicdr1eo0ps0lceomtpgii/ocknag;l/ldyat,yhe
dtohseagaedre1nevaellss bone sareon
fhroodm fram
cmoalmeonanntde sory wos
; |
eflemaatleed msolnikgehyts cca ale and
acto atnhdeer3a0teandbyp1o00cemlgl/uklga/rdiayy; female monkeys ac the 30 and
dotsheagesplleeevnelsandhadycnompsoourneds= 100 mg/ke/dey doers Devers
had compound related moderate atrophy of Lysphots oiiotes.
!
.
ThefsaevStvoaratgriaisnatstiicooanclscluywrersreiedgnboifeftinwceaenont mtvhaerbiicaootlniovognrisaclailannstsiegsxmxip8feTisooiumapmeenmsieeaatnnspweepiegarhstnsnoocf accompanied by morpholegie alterations.
i
157-090
601726
International Research and DevelopmentCorporation
Page 3
I. coon
on
The compound vas received from 3M October 24, 1977 as shown below:
Company,
Saint
Paul,
Minnesota
Label 3FluoStroacdk FNol.uor9o8c-h02e1n1i-c0a0l08F-C0-143
Description white pouder
Lot 340
137-090
C01727
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International Research and Development Corporation
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Page 4
11. cues stores i. emons: Te Sem Sate: Ten sale thesus monkeys (weighing fron 2.60 to 3.90 kilograms)
oanndth1i0s fsetmuadlye.s (Twheeighmionnkgeyfsrowmer2e.95purtcoha3s.e8d0 fkriolnogrParmism)atewerTenpoirntistiated
Corporation, individually
PinorthaWnagsihnigngwtioen,meN.sh,Y. "sq1u1e0e50z.e
tTyhpee" mocnakgeeyss anwderemaihnotuasiended
in a temperature, Monkey Chow was
humidity fed tice
eaancdh Ldiagyht ancdonftrreoslhledappelnevsirovmeerent.fod P3uritinnges
4 week. Vater vas avatlsble ad Libirus.
the tomerDursiuncfgacteheofconthdeititohniignhganpderitondc,raptahlepeabornaklevstuwbeerreculciancotoeesdts on
vere vals
conducted. during the
Tuberculln tests treatuent period.
were conducted at bisonthly fncerAlso a conplete physical examina
tion was compound
conducted by the administration.
staff veterinarian prior to Only monkeys n good health
initiation of were selected
P--
fioes
This study was initiated on January vere conducted on April 12, 1975,
11,
1978.
Terminal sacri-
7 SEA
ato
A the end of five groups on a
the conditioning randon bests, so
pthearttodthetheinimtoinakleysavevreargee dibvediyded
vetghts vere stutlers
Number of Monkeys
Yale
2
Female
2
Dosage Level
Control
2
2
3 mg/kg/day
2
2
10 mg/kg/day
2
2
30 wg/kg/day
2
2
100 mg/kg/day
137-090
co1728
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International Research and Development Corporation rege 5
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The test compound, suspended in 0.5% Nethocel, vas aden
!
Ciosntsetraende bvyolguamvea.ge,Al7 the vehicle control
sodaytshe group.
esaacmhe wveeekl.use Individual
afAll 0d.o5s%esHewtehroecegrisveananin daily doses vere beset
piaven seen
to coe
body veighes obtatned searly.
3. Observations:
SPpearancTeheanmdonkbeeyhsaviwoerreanodbseprhvaerdmatceoiocreicdaisligynsf.or
general phyeient Inttvidont map
Seighis were recorded ducted 1n the control
wekly. General physical period and monthly during
examinations tne study.
sors
con
i. BClloiondteaalndLaurbionreatosrayaplTeesstsv:ere obtatned for analysts from ail
Sonkeys S5udy.
once during The sonkeys
the control vere fasted
period snd ac 1 overnight prior
and 3 enthy of to the sottaceton
of
blood and urine sssples,
o. Bematotogy:
Hematological studies included: hemoglobinl, hematocrit2,
erythrocyte count3, total? and differential leucocyte counts, reticulocyte count, platelet count, prothrombin tioeb, activated
bpianr,timaelanthrcoormpbuospclualsatrinvotliummee' centration vere caleulased.
a(nAd.Ps.eTa.nT.)c.orpuMsecaunlacrorhpeussocsutluanrt`yhepmoogelo-
b. Bocheotstry:
Biochemical studies included: fasting blood glucose8, blood urea nitrogen, serum alkaline phosphatase, serumglutamic oxalacetic and pyruvic transaminase activicies8, cholesterol?,
tthootralgapnrtoctepihno's,phaalcbeu?a,inYd-,glustoadmiyulml0t,eapnostpaespstiiudnals0e,llch(lyoorGi.dTe.?7,.) and
creatinine phosphokinase',
157-050 c01729
International Research and Development Corporation
Page 6
ec. Detnalyss: Urinalysis included: measurement of volume, pil? and
specific gravity; description of color and appearance; qualitative tests for proteinl2, glucosel?, ketones!2, occult blood? and Bicroscoptc examination of the sediment.
4. Statistical Analysis: Analysis of body weights and clinical laboratory tests
were performed. All statistical analyses compared the treatment groups with the control group, by sex. The tests were compared by analysis of variance (one-way classification) Bartlett's test for hosogeneity and the appropriate t-test (for equal or unequal variances) as described by Steel and Torrield using Dunnett'sl multiple comparison tables to judge significance of differences. 3. RESWIS:
I. General Sehavior, Appearance and Survival:
dosage
There was
levels.
no
mortality
in
monkeys
at
0,
3
and
10
mg/kg/day
did
not
The monkeys from
shou any unusual
the control
behavior or
and 3
signs
mg/kg/day dosage levels
of toxicity. Soft stool
or
moderate to marked diarrhea were noted occasionally. Frothy emesis
was also noted occasionally.
unusual
At the 10 mg/kg/day dosage level
signs of toxicity, except Monkey
the monkeys did not show any
7363. In week 7 its face
appeared swollen and pale. It had been occasionally anorexic in week
4 and black stools appeared for several days in week 12 of the study.
Ac the 30 3g/kg/day dosage level, three monkeys died during
weeks 7, 12 and 13 of the study. From week 4, the monkeys were
anorexic. Slight to moderate and sometimes severe decreased activity
was noted occasionally to frequently for the four monkeys. Emesis and
ataxia vere very rarely noted, for one monkey.
137-090
01'730
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International Research and Development Corporation
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rage 7
and
ms Ssuesrleietn efdac.e,
eves Fron
noted. Hankey 71987 shoved
waenedk v6a,lvef,or a5tenweslolntaesrep,allmoor aof sceherfaeceee siight So soterare dubmdrecios sup more:
of the eyersan.
S20entshe2prAceLhvLeioousugoshnke3gyrosoufpE,sctoubnudtyt.heheT1yh0e0yanpgsp/hokosgeesddayssohmedmoessseamgeiensLyeenevepeltosndosinetdofducroinngics
sbScretoeiwkvni1c)iyn1crnodolmovra)rSeUpasEloereftoascaesrekveaednrsde,gumspsnrm,onsetsrrsiaoet,iiioefnneoaftnandvyebsosotusyssteaeyrecern.otmtmomronemrrcsed
2. Control
CohdayngeHsetgihnesbodCyrawbetiegsht1-3e3:e siatlsr for monkeys from ant the 3 and 10ng/kgday dosage Sevets. mene ct
the mee
30
ofandst1u0d0y.mg/kThge/rdeaywasdosasgteattloetvieelastllyostsigbootdfyiowmenitghtdoearfetsesresthetn onfirstosweek
s1wo3enikg0eFhytshferorosmttuhdetyh.ema1l0eT0hemsognf/kekemaya/sldeaaystondtkohseeargs3e0
oL@fegv/tehkleg/asdearcyes
ddsoeesnratigneesnlersvooesslt
ms ces in week tn
3. Raborstory Test Chates 1830
S1505
sa3/Sklei/gdhety
TdhoesraegeerLeeve5l0s.notTensortheehyicrhaengmeosntihn osFonkneeyssefnrtoym tncresse (sot seaciaticalty sigattiounsy of smn
the 3 and nmneeneer.
Cally valuessiignnitfheicafnetmalienscreaatsetheof10the# AbeT.1. g/kg/day dantosageprolmemveelnmnannyd Lime on a statisti-
atF iihnnekmeooynnek(ePsy7us4r5va3it)vithnhageds3ap0rnokwmegmy/iknrge/ondndaynchdeeoas3at0gt egasl/esvdeolra..yIdnovtahgee trheinrsdt.monmtheopf n
137-050 01731
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International Research and Development Corporation
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rages
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nin smoonnkkeeyyss "ithin the
satt tthhee noreal
310mgm/gk/gk/gd/adyaydodsoasgaege Lelveevlel 55and3 ystologiear tintcs.
mienncthhse
opflatsetldest,
see count
)|
b. Bocheststry: These vere no noteworthy changes in monkeys from the
control, 3 and 10 mg/kg/day dosage level. Only one monkey from the 3
mLge/veklg/dsahyoveddosatgreendlseveclovaarndd 474 unste/1, respectively),
dowenicetrhemoaousntekseyseofaftriaosmltkiatcihatelne10ipgmhgon/sikpght/aidtaaoysendo(s43a5ge
a
nd
Line
phosphatIaasethesasfixnees dmonitnhsoofnkecyhse
study, at che
3d0ecargo/nksee/dInny sfeorrvaegealtkvael
(stattsescally significanc) and to one monkey in the same donege
level, the albumin in the serum was lower (3.22 8/100ml). The one
dseucrrveiavsiinngg moofn:keybl(o7o4d55)sugfarrom (6t6hesg3/010m0g8/1k)g,/datyotadlosapgreaceltenvel(5.s5h2owoe/d10081)
with albumin (2 g/100m1) and alkaline phosphatase (360 units/1) and
c. mrtastyess: slightly elevated cholesterol (240 mg/100ml).
In
the
Yo changes considered urinalysis seudtes.
to
be
related
to
compound
were
seen
137-00 01732
International Research and Development Corporation
Page 9
TV. PATHOLOGICAL STUDIES
A. YETHODS:
1. Gross Pathology:
After completion of the compound administration period all
surviving monkeys were anesthetized with Sernylan, exsanguinated
and necropsied. At mecropsy, the heart, liver, adrenals, spleen,
pituitary, kidneys, testes/ovaries and brain were weighed and repre-
sentative tissues vere collected in buffered neutral 10% formalin.
Eyes were fixed in Russell's fixative. The thyroid/parathyrotd vas
weighed after fixation.
Monkeys which died during the study vere necropsied as above.
2. Histopathology:
Microscopic examination of formalin fixed hematoxylin and
eosin stained paraffin sections was performed for all monkeys in the
control and treatment groups. The following tissues were examined:
aaodrrtenaals bone
kliidvneerys lung
pLiutsubiartarsypinal cord scomach
eebsyroeapsihnagus
srmeketisrneonpchearircyngleyamlph lynmopdhe
ttheysrtoeisd/ovaries parathyroid
ghaelalrbtlad(dveirth coronary vessels)
mamnmoadery gland nerve (vith muscle)
ttrhaycmuhsea tomsil
diuloeduennun
psapnlcereenas
utroinnguaery bladder
cJeecjuunnua colon
prToibscajutnec/tuitoenru(sbone vtaagtitnoao marrow)
rectua
salivary gland
and any other tissue(s) with lesions
_--_--
#SPth.enJcoyscelpihd,ineMisHsCoLur-d.Blo-Ceutic Laboratories, Inc.,
137-090
01733
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International Research and Development Corporation
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5 mus:
Page 10
,i
and
f1.eanlYGeorossghsreassPuastshoLlmeoosgniykoenyss(cTvoahnbislcechie1cd6et)dedasnodonmOosrutgnuatdnyWreoeifl;iwveetrssemos(Tasacbeliefrie1o7ee)t:
sate aries
90
of
fdaeyvsorSogtfaantssitsutdoyic.ccuarlrleyd sbiegtnwiefeincantthe vcaornitartoilonsandinexspeexrigmreonutpersesanouvsei.ghes
The following statistically significant organ weight variations seurred:
DTosoage
Osregaatn mg/1k0g/daxy absolWuecieg,hctelacive san 10 passes
decrcehmasne.gdeecrense 0.a00x.01 seseien 0.00
Piicary 3% elacive
rcasen 0.05
vTehieghbeiovlaorgiiactailonssigvneirfeicannocteacocfomtphaensieedvabryiatsioornpsholiosgiuenkncohwanm,esTsheircehosrgeasn
considered compound related,
Level2. anHdCirseatlolpsaatmlheeolleoagnydandtu(foTefamebamllaeele1r8hc)eh:seussusmormkoenykseysac attheche10030apa/gk/akred/edyayddooesrasse
Level had aecked diffuse female thesus sonkeys ac
tLhiepid30deanpdlet1i0o0nugt/nkst/hedayaddroesnaalgse. LeAveLlLsmhealse
wus
siighe female
to moderate hypocellularicy thesus monkeys ac che 30 asd
of100cheug/bkogn/edamyardroons.ageALLLevestasleheasnt
sederate atcophy of 50 ag/ka/day dosage
lysphoid follicles Level and all cate
atnndthSeemeslpeleesnh,asusonesonfkeemraslestatthcehe
I1n00thmeg/Lkygm/pdhaynoddoessa.ge level had moderate atrophy of the lymphoid follicles
the zenNos,atcrboosnceopmiacrrocwh,angsepsleceonnsaindderLeyderchomnpuoduensdorfelsaatleedavnetrefesmeuerns fa
rhesus monkeys at the 3 and 10 mg/kg/day dosage levels. No microscopic
157050
01734
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International Research and Development Corporation
I| rape 1
Lesions in Lymph nodes
tissues a She
other 30 and
than 100
mchge/addareynaldosr,agbe.oneLemvearrscosw,erespsloenenntoaenodns
Ny
157-080 01735
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International Research and Development Corporation
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rage 12
I.
SCoiurlete,r HHiesstoigalno,binPormoescseerr:.
-- Coulter Electronics, 390 4. 00h
2. MCcoromhepmaettocertse,, Joh 3. Mile, 3nd 5., 1967, The C. 7. Yosby
3. 2Co0uhlteSrtrePeatr,edcHlaeloSainz,e FCroaurnitoenr,, Model 23, Coulter Electronics, 39 5.
4. 5.
2CRG0eortiuahtldatuaeShnrto,elePrsaS,rdtiCiBclcioilarntesiecsaSSnltt:heLFaBoCaboo.ovu)rinaett1eeo9:r6r,3y,YeoTtdhheelocs:A, a.nCdouHlDotineasrgnEoolesoiecm,earaaFrnrtaonenke,ell,332a02ndd5.
6. 7. 8.
General General
Diagnostics Diagnostics
=
Warner Hacner
Chilcott Chilcott
Laboratories Laboratories
Revised Revtued
JAepnrmiilar1s9651.967.
Techntcon Auto Analyzer, 6/60 Hicrs Hethodotogy.
109.. HL.
SAMcipocanrstoeGAOAuTbtPsoorPAprntoaicleoydnzuerr1e1,IBI,uYlodl6ee/lt6i0n35M63i3c6r5o.MeStihgondsolCohgeym.. Gov, St. Louie, vo.
12. 13.
oSfSBttieliedsllt,aabRec.tiicGc.s(,bm.eWsaenldRreTsaogmreirnitle,,scJRr.oiwpsA),T,or(k1,960v,),YioPrineciplies aEanndtlPPrrooceceedduusrreess
4: BDiuommmeettrti,caC,. MVe.,raewtiTianbslesouforvotarltiple5, Comparisons 4th a Conrot,
137-00 01736
ar
Tan
= Ecoonoenisly
".
22
Hine Day Hern Body
Subacute Rhesus Noskey Noth of Warkeys veek
Toxicity Seady. 13 of seury
eeo at1i1 n 230
ocserea t11i1 a vis
Soocecaa1t 2.300
sa
a
pi
nCgya epsyd
2
5a8
13-090
"statistical significance
y
I
=
Feta:
Ninety Day Subacute Rhesus Nonkey Toxicity Scudy.
ie 2. Grown,
Individual Body Weights, Kilograms.
E Honkae y control
Mek of stu TT
onerols
ete
hA e hM Roam TT em aN MR OMB
de am
N G3 SR l EOEET an sms am 31s
E0L
EET m
de
2A20
w36o0
dasse
Hen
TOMRON HOM
2exfintay:
om Se 3030
am 2
S030 328 21
NONsEm Am 2%
1sBw 3a
yaee us
xan aw
M303333% re ae
3as0 2.66
e BN k ID OZR TH e PTEMRR OZR
aOMmE OME
o2a%w NR
aalme Mm
2a5m um
aanm oan
Danm 3m
N ams faio se
wLSn
e4oms
4t0e
2e5m0
aonx
Hen 10sah day:
THO
Om
ae se BONE
3h 0
38 a
3G 0
MRM 30 3x
1sm ks
ioem ss
uame as
a2p0 oe
3a0s ae
3ask 359
eMeeNMDIE TBo. ET IB
SOIwD IER
aOImD ME
s3k 30
dahee 20
d1e6 50
3a6 am
NnEw am
Jaem
M0R
Jaees
iarns
322835
3323s
a39s0
Hesn
TOM ae amos BIOMOL
od 3 un
dn a Mahz NsSe ayee ae am 4 3% a us ase
324s0 oe
a36s0 ve
as 37
e
3
Fron
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|
--
-
wien a
Hoey ouy StacoeEnesresnerToseetey Sent.
horeotbs y econtroTM A TT y wes at se t.
Bw TtEwNn BEL
MdE0 OIR
aSSaE1 OME IR
uRa EaI0 Dnas 2m am ve
sIaRs am
aEmD im
M or Nme
LL
ie aw aa
BT roE d GE 0 mtn:
SF RR ON SE IN I l oirem iIRe swworreae eiwe are
aea
E m WToEYwNRw3MoRImOmmJ waam0orrammm avewe 3 rae bee
Wn An 0 ae am ase ae
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| Uren
Ninety Day Subacute Rhesus Monkey Toxicity Study.
Page 16
TABLE 3.
T-Test Comparison of Body Weights.
-- MSeteukdy Sex Coaerol 3 ma/kg7 /dey T 10 msy /ks/day 3NO0 meg//kkea//ddaayy 101000emgg//kksg//ddaayy
13 MFo osas7
33.6580
33.688
2.3=08
--
237-020
#4#pp<<00..0015 Moonte isnucrlvuidveidnginanismtaalt.istical analysis due to only - Line indicates animals had died prior to week 13.
01'740
FC-143:
Vinety Day Subacuce Rhesus Monkey Toxicity Study.
TABLE 4.
Means
--ee
and
Significance
of
Hematological
Values.
Hematology Study
Control 3 ms/kg/day 10 mg/kg/day
106/cam
3
He8m/o1g0l0oab1in,
1 3
Hemat5ocrit,
1 3
Platelets, 1
103/crm
3
ReticuFlocytes, 13
PrTiozteh,rosaebcin 31
PAcTtTivLa,tedsec 31
Leuc10g%/ecycoems, 31
Neutro%phils,
1 3
Lyspno%cyces, 13
Eosino%phils,
1 3
Monoc%ytes, 13
Basop3hils, 31
Me3v,
31
au, wig
1 3
M8e/H1C0,0 m1
1 3
4.90 7
12.9 3378 253
210
00.32 1u2 228 99..4490 2 16 87s 1 3 01 00 87s 27 2 3a%
Wn 1.4 127 337 233
285%
00.25 u12 2268 99..7883 19 1 77% 53% 02 00 878 2277 3Esl
5.47 12.1 133 3d9own 210
216
00..25 1u3 an 91.1.9936 2265 6772
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Page 17
30 mg/kg/day pe) uy 9.78 3308
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control 8& 2237.60
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Page 21
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Page 25
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