Document Xz9aKELYDz167pXw7QkvkBamK
lInnlteerrnnaatliioonnaall RReesseeaarrcchh aanndd DDecvreell(oqp~mmeenntl CCoorrppovrra~ttiioonn
oT" 8
AX
sores SPONSOR: smazer: coCOuMzPoOrUDND::
SUBJECT:
p-- 3M Company pSriunneiteyt-ibayeiSuybacute hares okey FFlluuoorraadd? FFlluuoorraocchheesmiiccaal! SSeurrffaaccets~anrt FFCo--9355
Ninety-Day Subacu~e Rhesus Monkey Toxicity Study.
--Sa 0-20 Director of Reseerch
sifu Collaborators: 5e_0. Tessa, Phe, Associate D. C. Jessup, Ph.D., Associate ile Eimet Direc=or of Research ee pression: R. G. Gei!, D.V.M., Vice President ooand Director of Patho!ogy LT oe ot J. S. Mehring, Ph.D., Director of ffs anton Large Animal Toxicology
sates sucsrses 13. 197
Date: December 18, 1978
113377--009922
EExxhhiibbiitt 11119911
State of Minnesota v. 3M Co., Court File No. 27-CV-10-28862
11119911..00000011
33MMAA1100006655000044
| f | nierntional RRosecapreohn rantd D DeL veloC CpormR poerantiton _
| Page TABLE OF CONTENTS Page
FY Synopsis ..........................
i
IL Compound ieee II. Compound .......................... 33
IIL Clinical Stufes +s vv svn eau nana
llI. Clinical Studies ......................
b4
he eT + teenie &4
A. 1M.etGheodner.a.l .P. roc.ed.ur.e.... .+..s.i....u.u.. e.a......... .c4h
2i.. GCeonmeproaunldPArdomciendiusrter.at.io.n.... .os ..e..e..s..s.. e... 4
32. OCbovmeprovunadtloAndsmin+istrsattioen .v.e..r.r.a.n.e.e.e.r.r. e. e. s 8
43.. COlbisneircvaaltioLnasbor.at.or.y .Te.st.s..+.+..o.. o. ov.v.s.e..nS5
4. 8aCb.liniBHi cEeaBmlAaTto OoLLlaOobRgoyYrcat. o+r. h yL.tTLre.e sLit.se....m..a.a ...i ..i.l.a . .s .i..i..tia . .i. .ir. .i. . .iy . .i. .l S3
3obc&l..0 StUBUarirtioiincnahsaletlymiysicsisaistslr.y.mm. . Lsil. .y.s. .tis. ... .Li. .Li. ..e.. .e.. .i.. .i.. .i.. .i.. .i.. .i.. .i.. .i.. .l.. . 6656
Be Besuld.th Steatvisetincasl Antalaysriser.r.r.r.a.e.e.e.r.e.n.n.n.e. 86
B. R1.esulGtesne.ra.l.Be.ha.vi.or.,.A.pp.ea.ra.nc.e .an.d .S.u.r.v.i.+v.+a.+l.+,. + 66
I. General Behavior, Appearance and Survival ......
a5Vo.. oC0T .o5wntmrego3 /lk.lg/.a dsa.y . .g . . e..e. a f .a..i..a a..a..i. f .i..i.i a .i..i.. i. m. i.. l.. . i.. l. 767
A USmfaMer. sais c. 1.5 mg/kg/day ................. 4.5 mg/kg/day ..................
87 8
2 Bdo.dy HANES eee nina ana
88
32.. LaBbodoyraWteoirgyhtsTS.S .+..+ .e.e..e...a.u.a.e..e..a... 88
3. aLa5..0aboOrTOnhanereteoMerMoyonnMtotThnhetshtoossff ott.fhhee.thSS.ettuu.ddSy. ytu. d. y. ....LL..L..Lo...... ........ L.L. .oi. . .l. ... 988
19. Pathologi5.calThSrteuedieMsont+hs+ +of sthenStuady .. n.a.a.n.n..a.s.a.s. i1009
IV. APeathMoelhoogidcSael + vee e eae. Studies .................... 1i00
A. M1e.thGordoss.s .Pa.Ch.ol.og.ys.. . .. vv..s.sn..n.u. e .e.n..n.a... 1I00
2I.. HGroEss PSathotlogyo+.. +pv.e.an.t.ts.n.ha ..o.n.l.a.o.e.g.s . y. 1I00
2. Histopathology ...................
B. R1.esulGtrsos.s .Pa.th.ol.og.y.a.nd.O.rg.an.W..e.. i..g...-h.-. t...s.......
IIii
ii
2i. BGrosEs PaStholtogyoan+dpOsrgA nanetWseiaghhatsaO .e.el .e.eo .e.. ga.s. ye. 1ii
2. Histopathology ...................
113377--009922
11119911..00000022
33MMAA1100006655000055
||
Interntional esearch and Developrent Corporation
| taste or cowienis I
Teonctmued) TABLE OF CONTENTS (Continued)
PPaaggee
Table No. Table1 No.Individual Body Helghts ee uuta ea...
1
2. MIenadnisvidaunadlSBiogdnyifiWceaingchetsof.E.ea.ta.l. og. ic.al.V.al.ue.s..........
131-I5
14-15
3-52.. MIenadnisvidaunadlSHiegmnaitfoilcoagniccealofVHaelumetsalo.gl+ca+l +Voalusess.o..o.o .
16-18
16-18
6. 3-5. SIunmdmiavriyduaolf MHeeamnatoBlloogcihceanlicaVlaluVeaslue.s,..+ .+ .+ .+ .+ ..b..+.
1920
19-20
7-96.. SIunmdmiavridyuaolf MBeiaoncheBsitoecahlemiVcaalluesValues.+ .+ +. ses. s ns
223
21-23
7- 9. Individual Biochemical Values .....
PP 24-25
11-1I30.. ISnumdmiavriyduaolf MUerainnalUyrsiinsalyVsailsuesV.alues+ o u s esos oo
2628
26-28
Li. 11-13. NIencdriovpisdyualObsUerrivnaatliyosniss + + Values ...u ...s eesat
29
29
1145.. NAebcsorlouptsey OanbdseRrevlataitoinvse O.rg.an..He.ig.ht.s..+ + + oo +
30
30
1165..
Meroscopic Observations. + + tue e ease Absolute and Relative Organ Weights . .
Microscopic Observations ........
303
31-35
16.
137-092
137-092
11119911..00000033
33MMAA1100006655000066
1
|
ficial src and Descloptions Corpor ion:
b
|
PPaaggee 1|
1. sworsis
SYNOPFSlIuSorad Pluorochenical Surfactant 70-35 vas administered by gave
a5
age
to thesus monkeys ac dosage levels Fluorad Fluorochemical Surfactant
to rhesus monkeys at dosage levels
of 0, FC-95
of 0,
(distilled water was administered
(distilled water
only) by gay-
only)
0.5,
0.5,
1.5
1.5
and
and
4.5
4.5
amgg//kkga//ddaayy
ffoorr
090
ddaayyss..
TTeweo smaallee aanndd ttwwoo ffeemmaallee
mSoonnkkeeyyss wweerree iinniitciiaatteedd aact eeaacchh ddoossaaggee lleevveell aanndd aallssoo iinn tthhee ccoonnctrrooll
Soup. The sonkeys vere observed tuice daily for general physical
sgpropuepa.sancTeh,e mboenhkaevyisorwaerned pobhsaerrsvaecdotetxwiicce sidganisl.y foSrodygewneeirgahltsphwyesriecal
arpepceoarrdaendcev,eekbleyh.avioHremaatnodlopghiacramlacaontdoxibclocshiegnast.calBosdtyudiweesighatnsd wuerrienaly-
5r8e5corwdeerde wceoenkdluyc.tedHeamncaetoliongitchaelcoanndcrobliocphereimoidcalandstuatdietshe anedndurofinatlhey-
fsiisrstweraend cotnhidrudctesdontohnceof inthethestucdoyn.trol period and at the end of the
firstTheandmontiheiyrsd mtornetahtedofatthethest4ud.y5.-ag/kg/day dosage level died or
wereThseacmroinfkiecyesd itnresaxtterdeaatts thbeet4w.ee5n-mgw/eekkg/d3ayanddo7sagoef tlheevelstuddiye.d or
These were
These
sonkeys exhibited signs of toxiciy sacrificed i._9.n extremis between week
monkeys exhibited signs of toxicity
5
tn the and 7
in the
gascroincescinal of the study.
gastrointestinal
trace
tract
(smorexts,
(anorexia,
emesis,
emesis,
bbllaacckk
ssttooooll
aanndd
ddeehhyyddrraattiioonn))
fFrroomm
tthhee
Ffiirrsset
of second day of study.
or second day of study.
AAlLlL tthhee hhiigghh--ddoossee amoonnkkeeyyss hbaadd ddeeccrreeaasseedd aaccttiivv--
Sty and before death shoved marked to severe ripidicy, convulsions,
sietyneraanldizbeedforbeodydeattrhembslhionwge,d mparroksecdrattioonseavnedrelorsisgidoiftyb,odyconeviuglhsti.ons,The
scan body weight generalized body
mean body weight
decreased from 3.44 k trembling, prostration
decreased from 3.44 kg
at the begianing and !oss of body
at the beginning
of the weight.
of the
studyThe
study
0 2.70 kg a5 week 3 of study.
to 2.70 kg at week 5 of study.
AAtt I1 msoonncthh ooff ssttuuddyy aallll mmoonnkkeeyyss aatt tthhee
4.5-38/kg/dsy dosage level had decreased serus cholesterol values and
4c.e5r-unmg/aklgka/ldianye dopshaogsephalteavseel haacdtivdietcyr.eased serum cholesterol values and
serum alkaline phosphatase activity.
AAllll mmoonnkkeeyyss aatt tthhee 11..55--umgg//kkgg//ddaayy ddoossaaggee lleevveell ssuurrvviivveedd ttoo tthhee eenndd
of the study. The sonkeys exbibred sitghely decressed activity fron of the study. The monkeys exhibi=ed slightly decreased activity from the fires week of the study vhich occasionally becase soderate to the first week of the study which occasionally became moderate to
mmaarrkkeedd.. MMoonnkkeeyyss aatt tthhee 11..55--mmgg//kkgg//ddaayy ddoossaaggee lleevveell ooccccaassiioonnaallllyy hhaadd
black stools, diarches, sucous in the stool and bloody scood and exhib black stools, diarrhea, mucous in the stool and bloody stool and exhibited dahydration or general body trembling at the end of study. The ited dehydration or general body trembling at the end of study. The sonkeys fron this group had a slight decrease in sean body weight. monkeys from this group had a slight decrease in mean body weight.
137-052
137-092
11119911..00000044
33MMAA1100006655000077
huersitioial Kescarelr wid Developimeni Corporation.
PPaaggee 22
In the laboratory tests, there was a decrease in the alkaline phospha-
In the laboratory tests, there was a decrease in the alkaline phospha-
tase activity and the concentration of inorganic phosphate in the
tase activity and the concentration of inorganic phosphate in the
sseerruusm aatt 33 mmoonntthhss ooff ssttuuddyy..
AALlLl mmoonnkkeeyyss aatt tthhee 00..55--magg//kkgg//ddaayy cdoossaaggee lleevveell ssuurrvviivveedd ttoo tthhee eenndd
ooff tthhee ssttuuddyy.. MMoonnkkeeyyss aatt tthhiiss ddoossaaggee lleevveell eexxhhiibbiitteedd aann ooccccaassiioonnaall
soft scool, diarrhea, anorexia and emesis. Slightly decreased activ-
istofytwasstoonlo,teddiairnrhtehar,ee amnoonrkeexyisa aatnd tehimsesidso.sageSlilgevhetll.y dAetcre3asmeodnthasctiofv-
ity was noted in three monkeys at this dosage level. At 3 months of
study a slight decrease in the serus alkaline phosphatase activity
wsatsudynotaeds.light decrease in the serum alkaline phosphatase activity
was noted.
NNoo ggrroossss oorr mmiiccrroossccooppiicc ppaatthhoollooggiiccaall lleessiioonnss wwhhiicchh, wweerree ccoonnssiiddeerreedd
ccoommppoouunndd--rreellaatteedd wveerree sseeeenn iinn ttiissssuueess ootthheerr tthhaann tthhee aaddrreennaallss,,
pancreas, and subbandibular salivary glands of male and female thesus
pancreas,
monkeys a
t
and
th
e
s4u.b5m-aangd/ibkugl/adray
salivary
dosage
glands
level.
Moifcrmoaslceopaincdalfleym,aletherheasdurse-
monkeys at the 4.5-mg/kg/day dosage level. Microscopica!ly, the adre-
nneallss ffrroomm msaallee aanndd ffeemmaallee mmoonnkkeeyyss aact tthhee 44..55--mugg//kkgg//ddaayy ddoossaaggee lleevveell
hhaadd ccoommppoouunndd--rreellaatteedd mmaarrkkeedd ddiiffffuussee lliippiidd ddeepplleettiioonn;; tthhee ppaannccrreeaass ffrroomm
mmaallee aanndd ffeemaaallee mmoonnkkeeyyss aatt tthhee ~4..55--magg//kkgg//ddaayy ddoossaaggee lleevveell hhaadd ccoommppoouunndd-
rreellaatteedd mmooddeerraattee ddiiffffuussee aattrroopphhyy ooff eexxooccrriinnee cceellllss;; tthhee ssuubbsmaannddiibbuullaarr
salivary glands from male and female monkeys had cospound-related
salivary glands from male and female monkeys had compound-related
mmooddeerraattee ddiiffffuussee aattrroopphhyy ooff tthhee sseerroouuss aallvveeoollaarr cceellllss..
No statistically significant variations in sex group sean weights
No statistically significant variations in sex group mean weights
ooff oorrggaannss ooccccuurrrreedd bbeettwweeeenn tthhee ccoonnttrrooll aanndd eexxppeerriimmeennttaal! ggrroouuppss..
113377--009922
11119911..00000055
33MMAA1100006655000088
hIn~tteerrmna.t,tiioonnaall RReesseeaarrcchh aanndd DDeevveellooppmmeenntt CCoorrppoorraattiioonn
PPaaggee 33
1. comonn
II. COMPTOhUeNDcompound vas received from IM Company, Saint Paul, Hinsesocs
on OcThteobecrom2p4o,und197w7asasrecsehiowvnedbeflroowm: 3M Company, Saint Paul, Minnesota
on October 24, 197L7avea:s shown below:
Descripston
TFFlluu5oorr5aadd5s FFllSuutooarLrcaookbccehholeernmiicc3aa8ll-02SS0uu7rr-ff0aa1cc0tt3aa.nn7tt
white powder Description
white powder
TFoCr-958403-MetStowec.k 5 ine: 22 kor No. 98-0207-0103-7
Lot 640 Net w~. 5 ibs. 2,2 kg.
137-02
137-092
11119911..00000066
33MMAA1100006655000099
International Research and Development Corporation
res
mn cme stems a vem: CLINICAL STUD!IS vI=.~HncDemsrat rrocature: i. GTeineenralmaiPsrocCeedeutraen:ins rom 2.35 5 353 kp) and eta fesade CuetgningEigfhrtomma2l.e75 (t~oeig3h.i75ngkaf)romth2e.s5e5s s=oom3e.r5s5 wkge)reanfdafseiigahc~ed fedmnalSehi s(uwaetiyg.hin~Toefrokma2y.7e:$ twoeve3.7p5urkcgh)aserdhesfursommoPnrkiemyasteweTraeporitnsi,tlaF=oertJ in this Ssatsuadyi.ngioTnh,e mSoernkeYyosrk.wereToepumrotshkaeserJs sferroem Pnroismsaetde nidmtpvoirdtusc,tiPsortfn hansina WLaisrheinmgetsohn,"aNqeewcsYeonrtku.pe"Thecompeosnkeaynsd wsearfeniahionuesded fnindaivSiadeuraalltyariens,hanhguimnigc wLiorme amnedsh g"hseqmuceoenzet-rtoylplee"d cae~vevsizoannsdanmta.intauirniedneinMoankteeympeSrhaotxu?res-a, fodhumidciitty-esanadns!ifzahyt-zanodntrFor!elsehd apepnlveisronwmeernat.fadPu3ritnian.eDsMoankweeyek.ChoFrdacewarssafsed at~viactetaelaecha2dayMoatnndumf.resh apples were fed 3 times a ~eek. Wa~er ~as availablebeardinglibtihteumc.ondiziontag serial, the senkers see taseseed 03 the tunerDursiunrgfacteheofcontdheiticohniignhganpderifoads,raptehelpemdonrkaelyssu~b-=e-=r~.s- uittaattotoeesdts on
the inner ~urface of the thigh and intrapalpebral tuberculin tests
wCerraeeinceonnsducpteerdi.od. TubCeormcplueltien sthe~rtssiesallsosw~a:seirneatcioonndsuctveedrs tc~iocneducdtuerding4 thhee
straeia?tmevne~sev;eirnieordi.en pCroimoprletteo pihnyfstiicaaslionexaofmincaotmipoonusndweardeuiactosnidruacLtieodn.by d~e
Ss.t=y~ sovnecteerrsinafrniagneodprihoeraictho vienristiasteiloenciaodf. compound administration.
Only Tats monkeTs sineugsoodwasheaflntihtie~ceerde osneleFcetberdu.ary 15, 1973. Terminal
sacrificeIsbiswersetudcyond"~uacsteidnitoniatYeady o17n, 1573. February 16, 1978. Yermina!
sacri3.ficeGsepwoerset caonddsuncitsecdraocnioMna:y 17, i978.
2. iCo=pSoheundadAdmoifnitshteractoinodni:sioning period the Somers sere diviisd
toto fouAr~ gr~hoeups~ndon &of ~rhaendocmonddies$iiso,nins~o ptehratiodthetheLamfoclnekleysavweerraege dbiovdiy!ed
sienttgohefsourser~erouspisattoans:a random basis, so that the ininial average body
,;eights ';era similar:
So[ sazs A teva: Dosage Level
wfv-uirsobbeer- ooff v~'on-i'i"ery"s~
3H0 (Ym((gGC.ao:nnkctger/oodtla))y)
>:ale
232
Female
::2
fi0h!.e.5d5
3:2 2
::22
~.5
2
o
137-392
11119911..00000077
33MMAA1100006655001100
Intersil Research and Development Corporation
Page
Page 5
i
The monkeys in the control group were previously esployed as
the
The
control
monkeys in the control
group fn an aborted 90
group were
day study
i
npremvonikoeuyssly
o
nempFlCo-y95ed
as
t(hsetudcyont1r3o7l-08g7r)o.up Tihne antesatborctoeadpou9n0ddasyuspsetnuddyed ininmodniksetyislleodn uFaCt-e9r5, vas
(study 137-087). The
administered 7 days a
test
week
cbyompgoauvnagde.susApLeLndeddoseisn
wdeirsetilglievdenwaitnert,hewas
administered 7
same voluse of
days a
water.
weTehiks byvolguavmaegeo.f
dAilsltildloesdeswawteerre
vgaisvengivienn thteo
the
csoamnetrovlolugmreoupo.f waItnedri.viduTahlisdaviollyumedosoefsdwiesrteillbeadsedwatuepronwatshegibvoedny to the
wceoingthrtosl ogrbotuapi.nedIwnedeikvliyd.ual daily doses were based upon the body
3. weights Oobbstearivnaetdiownese:kly.
3. TOhbesermvoantkieoynss:vere observed twice daily for general physical
The
appearance,
monkeys were
behavior and
observed twice daily
pharmacotoxic signs.
foIrndigveindeuraall
pbhoydysical
wapepiegahrtasncwee,reberheacvoirodredanwdeekplhya.rmaGceonteorxaicl psihgynssi.cal Ienxdaimviinduaatlionbsodywere con-
weights
ducted
were
in th
e
reccoonrtdreodl
wpeeerkiloyd. andGenmeornatlhlyphydsuircianlg
etxheamisntautdyi.ons Fwooedre ccoonn-
dsuucmtpetdioninwatsheesctoinmtartoe!d.period and monthly during the study. Food con-
sump~4.ionCwlaisniceasltimLaatbeodr.atory Tests:
4. BCBlllooioonddicaaalnnddLauubrroiirnneeatossraayzmppllTeeessstsww:eerree oobbttaaiinneedd ffoorr aannaallyyssiiss ffrroomm aallll
monkeys once during the control period and ac 1 and 3 monchs of
monkeys
study.
once during
The monkeys
vtehere cofnatsrtoeld
poevreirondighatnd partiori
atnod t3hemocnotlhlsectofion
of
study. The monkeys were fasted overnight prior to the collection of
bblloooodd aanndd uurriinnee ssaammpplleess..
a. Hematology:
a. HHHeeemmmaaatttooolllooogggyii:ccaall ssttuuddiieess iinncclluuddeedd:: hheemmoogglloobbiinnIl,, hheemmaattooccrrittc2?,,
eerryytthhrrooccyyttee ccoouunntt3d,, ttoottaall3) aanndd ddiiffffeerreennttiiaall lleeuuccooccyyttee ccoouunnttss,,
rreettiiccuullooccyyttee ccoouunntt4,, ppllaatteelleett ccoouunntc5d,, pprrootthhrroomsbbiinn ttiimmee6d aanndd
aaccttiivvaatteedd ppaarrttiiaall tthhrroommbbooppllaassttilnn ttiimmee7' ((AAPTTTT)).. MMeeaann ccoorrppuussccuullaarr
hemoglobin, mean corpuscular volume and mean corpuscular hesoglobin
hceomnocgelnotbriant,iomneawnerecocraplucsuclualtaerd.volume and mean corpuscular hemoglobin
concentrabt.ionBlwoecrheeatcsatlrcyu:lated.
b. BBiioocchheemaiisctarly:studies included: the deteratnations of
fasting
Biochemical
blood glucosed,
bsltouoddiesureianclnuidterdo:gendt,he tdheetearcmtiinvaittiioenssofof
fasting blood glucose8, blood urea nitrogen8, the activities of
sseerruumm aallkkaalliinnee pphhoosspphhaattaassee8,, sseerruumm gglluuttaammiicc ooxxaallaacceettiicc
.
113377--009922
11119911..00000088
33MMAA1100006655001111
International Research and Development Corporation
Page 6
ttrraannssaamnitnnaasseegd~,
aanndd
sseerruumn
gglluuttaammiicc
ppyyrruuvviicc
cransasinased,
transaminaseg,
and
and
the
the
ccoonncceennttrraattiioonnss ooff cchhoolleesstteerrooll9?, ttoottaall pprrootteeiinn'9,, aailbbuuamitna8,,
sso0ddiuuamlI0,, ppoottaassssiivuamlI0,, cchhlloorriiddee?9,, iinnoorrggaanniicc pphhoosspphhaattee'9,, aass
wweellll
aass
cthhee
aaccttiivviittiieess
ooff
v~--gglluuttaamsyyll
ttrraannssppeeppctiiddaassee!IlI
and
and
creati-
creati-
nniinnee pphhoosspphhookkiinnaasseel1Z2,.
c. Urinalysis:
c. Urinalysis:
UUrriinnaallyyssiiss iinncclluuddeedd:: mmeeaassuurreemmeenntt ooff vvoolluummee,, ppH!1d3 aanndd
ssppeecciiffiicc
ggrraavviittyy;;
ddeessccrriippttiioonn
of
of
color
color
and
and
appearance;
appearance;
qualitative
qualitative
tteessttss ffoorr pprrootteeiinn1l3?,, gglluuccoossee1l33,, kkeettoonneess1!33,, ooccccuulltt bblloooodd1l33 aanndd
sicroscopic examination of the sediment.
4. microscopic eSxtaatmiisntaitciaoln Aonfaltyhsetss:ediment.
d. ASLtLatissttaitciasltiAcnaallyasniasl:yses compared the treataent groups
with the conAtlrlol sgtraotuips,ticbayl saexn.alyses compared the treatment groups
with the contBroodly wgeroiugph~tsby(ueseexk. 13), percent change in body weights bet=
ween controlBopdeyriowdeigahntds 1,(we2eaknd13)3,mopnetrhcsent(secxheasngecomibninbeodd)y, wehiegmhatcsolobgeit--
wcaele,n cbolnotcrhoelntcpaelrioadndanudrini,aly2siasndp3armaosnetthesrs ((seaxoensthscom1biannedd)3,) andhematologi-
acabls,olubtieochaenmdicraellatanidveuroirngaalnyswiesighptasram(etteerrmsina(lmonstahcsrif1icaen)d w3e)reandcompared
abbbyysoaalnnuaatlleyysstiassnd ooffrevlvaaartriiivaaenncceeorg((aoonnneew--evwiaagyyhtccsllaass(sstiieffriimcciaanttaiiloonns))a,,criBBfaairrcttell)eetttwt'e'ssre tteecssottmpaffrooerrd
hosogenetzy of vartances and the appropriate t-test (for equal or une-
hqoumalogevnaeriiatnyceosf) vaasriadnecsecsribaendd btyheStaepeplroparnidatTeorrti-etlest us(ifnogr equal or une-
Duqnuanletvta!raialn5ceusl)ttapsledesccormipbaerdisobny Sttaebelles antdo Tjourdrgiee1s4igunsiifnigcance of dif
Dunnett's15 multiple comparison tables to judge significance of dif-
f5.erenRceess.ts: B. RIE.SULGTeSn:era) Behavior, Appearance and Survival:
I. TGheenreeral#asBehnaovimoorr,caAlpipteyarianncteheancdontSruorlv,iva0l.:5- an 1.5-ag/kg/day dosage lTehveelrse. wasThrneoemowrontkaelyistyatin thtehe&.cSo-ntargo/lk,g/d0a.y5-doansdsge1.5le-vmegl/kgd/iedday dboestawgeeenlueeveelks.5 anTdhre6e ofmontkheeysstuadty.theTh4e.5-fmogu/rktgh/dmaoynkedyosafgreomletvheils dgireodup vbaestweseancriwfeiecked5 ianndex6troefattshe instuwdeye.k 7 Thoef fthoeurtshtudmyo.nkey from this group was sacrai.ficeCdontirnolesxtremis in week 7 of the study.
a. TChoentrsooln:keys from this group shoved an occasional soft stool or diaTrhreheamon(kseLyisghtfrotmo tsheivsereg)r.oup Fosrhowoende adnayoMcocnakseiyona7l358sohftad
stool or diarrhea (slight to severe). For one day Monkey 7358 had
113377--009822
11119911..00000099
33MMAA1100006655001122
Interasional Research and Developmen Corporation rage 7
Page 7
bBllooooddyy ddtiaacrtrhheesa,, sannoorreexxitas sanndd sslliigghhtt aattaaxxiiaa aanndd ffoorr 33 ddaayyss MHoonnkkeeyy 7368 had snorexts. Eeests vas noted rarely. 7368 hadbeano0r.ex5iam.aligE/maeasyl:s was noted rarely.
b. Y0o.5rkem~y/skg7/4d6a6y:and 7504 exhibited occasional diarrhea oc Soft stools. MonFkoerysMon7k4e6y6san7d463750a4nde7x4h8i3bittehde soocfctasisotnoaollsdianadrrhdeiaareohres wsaorfet fsrtoeoqluse.nt wFiorthMoonckceayssion7a4l63 aapnpdear74a8n3ce=hoef msuofctus sftnooltshe ansdtoodlisa.rrheOan waenereocfcraesquieonntbwliotohdyomcuccaussion1anl thaeppesatroacnlceandof fmnuctuhse r~nefutshee psatnoolssa.s On oonbeserovcecdasifoorn Nbolnokoedyy m74u8c3u.s inOcctahesiosntaololananodrexiinathaendreenfeussies pavnerewasnoted foobrserMvoendkeyfsor7M4o63n,key74674683a.nd 7O5c0c4a.sionSatlatlaanrolrye,xiaa asnldighetmestiasterweariettennotted dfoercreMaosnekeytsa 7a4c6t3i,vit7y466vasandnot75e0d4.forSMiomnikleayrsly,746a3,sl7ig4h8t3 ainndte7r5m0i4t.tent
decrease in activity was noted for Monkeys 7463, 7483 and 7504.
c. A1L.5L mmgo/rkige/ydsaya:t this dosage level exhibited a slight decrease tn Aalclcivmiocnykeydsuriatngthtihse fdiorssatgeweleekvelof esxthuidbyi.tedFoarsNliogahktey 7501 dtheecredaesceteaisnedactaicvtiitvyitydurfirnegquetnhetlyfirussst wneoetked ofthsrtouudgyh.outFotrheMosntkuedyy 7a5n0d1 btyhewedeekcre13asehdad abcetciovmietymofdreerqauteen.tlyAlwatshoungohtednotehareosuigsh,outsofthe sstotouldsy aanndd bdytarwecehkes13verhead mbeetceodmeformodtehriastem.onkeAyl,thosuigthghtnogeenmeersaisl, bosdoyft trsteomobllsingandand mduicaursrhe1an wteherestnoootledusfsorobthsiesrvemdonkieny,vesskilg1h2,t gaseneerlall absodyslitgrhetmbling and mduechuysdraitniotnhe instowoelekswas12 oabnsderv1e3.d iFnorweeHkonk1e2,y 7a5s01weallndas750s0liaghntorexia bdeechaymderatpieornsisitnenwteekdsuri12ngawndeek1s3. 12Foarnd 13.MonkeyF7or501Monakndey75705000andoiraerrxhieaa and bsoefctamestopoelrsisspteeanrtedduralionnggweweiktsh s12ucuasnd fn13.theFosrtooMlonkateywe7e5k002,dabrlrahceka and sstofotol sattoolveeakpp8earaendd aslloingghtwidtehhymdurcautsioninintheveesktoo1l2. atThwiesekso2,nkebylacekxhisiscteodol "abtruwieseikng"8 aanrdounsdligthhet drieghhytdraetyeionfolinlowweedekby12.bruTihsiisngm"onkaeryounedxhibbiottehd e"ybersulsatingv"eskaro1u2.nd the right eye followed by "bruising" around both eyes atFowreekYon12k.ey 7486 occasional soft stool and diarrhea were observed alonFgorwiMtohnkeaynor7e4x8i6aowchciacshionbaelcanseoftpersstioosltenatndindivaererkhea10.were Doubrsiernvgedweeaklsong10wistnhd a11norselxiigahtwhdiechhydrbaetciaomen vpaesrsiasltseontnotiend.weeMkonik0.ey 7462 Dhuadrinogccwaeseikosns]i0 saonfdt sIItoosll,ighetmesdieshydfroarti1ondaywaseacahlsoianowteeedk.s 1 Moannkdey3 a7n4d62 htahde doecccraesaisoendalacstofitvitsytoowla,s oebmseselrsvedforfn1 wedeaky e1 acohnlyi.n weeks i and 3 and
the decreased activity was observed in week I only.
11-002
137-092
11119911..00001100
33MMAA1100006655001133
.
International Research and Development Corporation
a 3 mginateas: d. S"e. a 6m .3=l m.<3Z./. kcga/yd: ay the onkers showed apparent sigms of
_-'_t /'.5 m.~/k~/dav the monkeys showed ag~aren: si~.ns
a"orxizoif:ythein sstuhedy ~aCsetnro~rienxtieasteinrd.a!per:trlaacl~ afnroormex:ihae, fiermsetsist,~ b:lheackse:s~sra.dcl
daany./oorf d~hsehpis~zuadcvi.on(anforroen~:isaliganh~t' ptoartsieadlaraatneo)r.exiaA,l1 had Zecressad emesis.. "~-~"~.~=~ anti
wanii.t"orfro/mehysiiriz~hteionto frsoevmersa~-.h*~_~3,_eftooremoddeersacthe)t.hey='si~howhe~dd miaercireedasaIio severe
vsiitsvtiifsryo,m csolnigvhutlsi~oonss,evseroed.eratBeefogreenerdaelaithzedtheSyodyshocwreadsb~l2irngkedasdto fsieavaelrley
ri~idiny, convulsions, moderate ~eneralized body ~re~bilng
drostratfon. Vonkey 7485 tad petachial hemorrhages on The
asnkdin offinally
ptrhoescfrnagtuifonns.l a~r'e[so,nkeyth7o4r8a5x haandd vfeacteechsinadlYohnekmaoyrrh7a4g3%esnaodn pthaele skgiunns ofafter
the inguinal area, thorax and face and ~o~kev 7484 had pale =~ _ after
week ....~_~'" 33 ooff tthhee ssttuuddyy..
2. 3odr eights (Zable 1:
2. CBhosdyzze~-s[eiignhtsths(Tbaobdlye wi)ai:ghes were sinlla: for serieys fn the
contral
Chan~as in
ead ot the
0t.he3-abgo/dyX
a/%-deaiy~hZdsos
were
ege
si~i!ar
level.
fBr
The
m~nkevs
ala mor
t
in
ars
the
fn
tchoentr1o.l3-asn3d/kaat/datyhe d0o.sa5g-emg/lkegviedlayhaddosaagdeecrlaeuvsele. fnYhtehemiralefomdonkweeysitin
the 1.5-mg/k~/day dosage leve! had a decrease in ~heir body
rom 3.13 kz 2t the beginalag of the study fo 2.93 k3 at the ead of
from 3.!5
the suey
kz at the beginning
mf fro 3.22 kg to
2of.75thke3 s[fuordy thteo
2f.e9m3alekgmoannketyhse. endTheof .
c~ ..h.a.ngsezuifvn.
=-B.a-.d;~r
frwoemigh3t._~_for'~.=o
to _9.75 kg for the female
This group of menkers was
fme:onksenyastisiieally
chan~e
signif
iciannth.ofdyronweitghhet
for this group
control group.
of
monkeys
was
not
3t~tiszica!!y
The significant fwroonmketrhse actonttrhoel&.g3r-Bump3./k3/dey dosage laval snowed 2 iss
The monkeys at ~he A.5-mg!kg/day dosage level sho~ed
of the bady seizht after 2 weeks of the study. Their svarazs bdr
oufatg~hhee bdoedcyreawseeid~h:froamfte3r.2%2 kwegeka~t otfhe :bheegi~n:nuidyn.g oTfhetihre asvieii=ya~e22 bo1d2y3 kz
weight deoreased from 3.44 kg
(sash 2) = 3.13 kg (soak 3) =
at the beginning of
2.97 kg (weak 2) =
the
2.70
skt'z;!y(week
3
Zor
(week 2) - 3.!B
Soth sexes. A:
kg (~-eek 3) - 2.97
week and 7 of the
kg (week &) - 2.70 k~ (week
stuiy thay dad, There vis
5)
20
for
bsottahtissteixcesa.l
eAv:alwueaet~i'on6
oafnd t7he ofBodtyhewesitguhdtys for .._.~.e.2
di=d.~ Yhere ~a~ no
conkers at the fu3-
Ssatfaetpii~dtiacya!isseavzae!ual~eivoeln, ofbectahuesebodtyheyweivgehrtss noftor almiovnekeyasc awtestthe13,4.w5h-en
mg/kgidav,. /o~aSe level, because they. were not a!i~-e a: w=~::__ 13, when
the siatissizs were done.
the statiszi.zs were done.
33..
LL~a-.v~:s..c.aa_z.oo.rr.}y
Tests
Tests
((TTaabblleess
22--1133])::
3. ne Month of the Study:
a.
One
3c
1
Month
month
of
of
thsetud~ytudtyh:ese
sere
no
pazhologizal
changes
in
7alues far oAk~evI smonftrhomofthestcudoyntr~ohleresad<-;eDr.a5n-omg/9iatshiodlsoygifzaa!s.uze:halne.=v==e_sl_. in
values for monkeys from the control and 0.5-mg/kg/day dosa~e lave!.
1[3377--009822
11119911..00001111
33MMAA1100006655001144
|
Internztional Resear i snd DevelopmentCorporation
Page 9
Page
AAtt tthhee 11..55--amgg//kkgg//ddaayy ddoossaaggee lleevveell oonnllyy MMoonnkkeeyy 77550011 hhaadd aa sslliigghhtt
ddeeccrreeaassee
tinn
tthhee
erythrocytes
erythrocytes
vwhhiicchh
vwaass
rreeccoovveerreedd
iinn
tthhee
tthhiirrdd
mmoonntthh
ooff
ssteuuddyy..
BBootthh tthhee mmaallee aanndd ffeemmaallee mmoonnkkeeyyss aatt tthhee 44..55--m2gg//kkgg//ddaayy
ddoossaaggee lleevveell hhaadd llooww vvaalluueess ffoorr sseerruusm cchhoolleesstteerrooll wwhhiicchh wweerree ssttaatt~issttli-
cally significance.
cally Monkey significance. 7484 had a decreased alkaline phosphatase activity
(312 untt/1),Monskeeryum74p8o4tahsasdiuma d(e3.c6remaesqe/dliatlekra)linaend pchholsoprhiad~ease activity
c(o3n12cenutnirta/tli)o,n s(e10r2ummepao/t1aistseiru)m a(n3d.6Mmoenqk/elyit7e5r0)3 aalndsochhaldorildoew serus
ccholnocreindteratcioonncen(t10r2atmieoqn/l(l1t0e2r)meqa/nlditMeorn)k.ey 7503 also had low serum
chloride conAcletnhtoruagthionthe(1502.6.m0e.q7/.lltaecrt)i.vity of male Monkeys 7484 and
7485 was in AtlhtehohuigghhesttheexSp.Ge.cOt.eTd. noarcstailvitryangoef m(a1l15e Muonnitkse)ys t7he484diafnd
7f4e8r5enwcaess binetwteheenhitghheessetvaelxupeescteadnd notrhamtalofrantghee c(o11n5troulnitvse)re thmeot disft-a-
,
tfiesrteinecaelslybetswiegennifitchaenste. values and that of the control were not sta-
tistically sTihgenifoinclayntu.nusual changes fa the urinalysis vere the
The only unusual changes in the urinalysis were the
aappppeeaarraannccee ooff gglluuccoossee ffrroomm MMoonnkkeeyy 77550000 ((11..55 mmgg//kkgg//ddaayy)) aanndd ffrroomm
MMoonnkkeeyyss 77448855 aanndd 77550033 ((44..55 mmgg//kkgg//ddaayy)).. HHoowweevveerr,, tthheessee mmoonnkkeeyyss hhaadd nmoo
ppaatthhoollooggiiccaall iinnccrreeaassee ooff tthhee bblloooodd gglluuccoossee..
bb.. TThhrreeee MMoonntthhss ooff ethhee SSttuuddyy:: There was a staciscically sigatficant decrease fn the
serum alkalinTeherpehowsapshataassetataicsctiivcicayllyforsicghneifmiaclaentsodnekceryesaseat intheth0e.5-
serum alkaline phosphatase activity for the male monkeys at the 0.5-
mmgg//kkgg//ddaayy ddoossaaggee lleevveell aanndd ffoorr ttwwoo MMoonnkkeeyyss,, 77550000 aanndd 77550011,, aatt tthhee 11..55--
mmgg//kkgg//ddaayy
values of
ddsooessraauggaee pollteeavveeslls..iua TThhceeossneecenlltaarttattteeirronmmsoo.nnkkeeyyMssorkaaellyssoo75hh0aa1dd
at 1.5 aa ddeeccrreeaasseedd
avagl/ukegs/daoyf bsaedrumverpyotalsowsiusmerucnonccehnotlreasttieornosl. anMdonMkoenykey75071500atat1.51-.5
mag8//kkgg//ddaayy bhaadd vaersyliglhotw dseecrruemasceholfensttehreolfaoarndgenMtocnkepyho7s5p0h0ateat (41..25-38/100
ma1g)/kgc/odnacyenthraadtiaons.light decrease in the inorganic phosphate (4.2 mg/100
ml) concentration.
119377--009922
11119911..00001122
33MMAA1100006655001155
e re | Imerniationad Research ae nd Developrizeri Corporationsome
PPaaggee I100
IIVv.. PPAATTHHOOLLOOGGIICCAALL SSTTUUDDIIEESS AA.. MmEoTHpOsDS:; 1i.. GGrroossss PPaatthhoollooggyy:: AAfftteerr ccoommpplleettiioonn ooff tthhee ccoommppoouunndd aaddmmiinniissttrraattiioonn ppeerriioodd aallll ssuurrvviivviinngg mmoonnkkeeyyss vweerree aanneesstthheettiizzeedd wwiitthh SSeerrnnyyllaann**,, eexxssaanngguuiinnaatteedd aanndd nneeccrrooppssiieedd.. AAtt nneeccrrooppssyy tthhee hheeaarrtt,, lliivveerr,, aaddrreennaallss,, sspplleeeenn,, ppiittuuiittaarryy,, kkiiddnneeyyss,, tteesstteess//oovvaarriieess aanndd bbrraaiinn wveerree wweeiigghheedd aanndd rreepprreesseennttaattiivvee ttiissssuueess vweerree ccoolllleecctteedd iinn bbuuffffeerreedd nneeuuttrraall 1100%7 ffoorrmmaalliinn.. EEyyeess wveerree ffiixxeedd iinn RRuusssseellll''ss ffiixxaattiivvee.. TThhee tthhyyrrooiidd//ppaarraatthhyyrrooiidd wwaass wweeiigghheedd aafftteerr ffiixxaattiioonn.. MMoonnkkeeyyss wwhhiicchh ddiieedd dduurriinngg tthhee ssttuuddyy wweerree nneeccrrooppssiieedd aass aabboovvee.. 22.. HBiissttooDpaatthhoollooggyy:: MMiiccrroossccooppiicc eexxaammiinnaattiioonn ooff ffoorrmmaalliinn ffiixxeedd hheemmaattooxxyylliinn aanndd eeoossiinn ssttaaiinneedd ppaarraaffffiinn sseeccttiioonnss wwaass ppeerrffoorrmmeedd ffoorr aallll aanniimmaallss iinn tthhee ccoonnttrrooll aanndd ttrreeaantmmeenntt ggrroouuppss.. TThhee ffoolllloowwiinngg ttiissssuueess wweerree eexxaammiinneedd;:
adadrreennaallss baarooarrittnaa ebserosaopiphhnaagguuss egyeaeylselsbladder hhgeeaaalrrlttbla((dwwdiiettrhh duovvdeeesssaseuellnss)) dliuleoeduwemnum jjeejjuunnuumm ccoceleccouunmm crroeelccotununm
ccoorroonnaarryy aanndd aannyy
kkiiddnneeyyss
ssaalliivvaarryy ggllaanndd
Llliuivnvegerr
plliuutsmubbiaatrrarssyppiinnaall ccoorrdd
sslkkuiningn
pssitttooummiaatccahhry
mmreeessteernnottpeehrraiirccynglleyyaomlpphhlnnyoomddpeeh tttehesystrteoesisd//oovvaerriieess
rcneantcoormddoaeeprhyargylnangdeal lymph ppttaahhrryyaamrttuohshiyydrrooiidd
mnear~vaery(wgiltahndmuscle) nseprlveeen (with muscle)
ttthrryaamccuhhseeaa tonsil
papsanpnlccerreeenaass
tctooonnnggsuuieel
prporsotstaattee//uutteerruuss bone/bone marrow (rib
uvurarigininanararyy bbllaaddddeerr
boJnjueun/ncbctotinioeonn))marrow (rib vttaaagttittnooaoo
ootthheerr ttiissssuuee((ss)) wwiitthh lleessiioonnss
113377--009922
p*SPhehe.enncJcyoycsclelipihdd,iinnMeeisHHsCCoLIur--i.BBiiooCCeeuuttiicc LLaabboorraattoorriieess,, IInncc..,, St. Joseph, Missouri.
11119911..00001133
33MMAA1100006655001166
|
interiational Rescarch and Developnieni Corporation
rage 11
Page ii
5. sam: B. 1. Gress .R_~SULTS: Pathoiosy (Isble 14) an orsen tielshes (Sable it):
i. GYroosgsrosPsathloeisoi~oyns (cToanbsleide14r)ed soandmpOorugnadn-sWeeiigshttesd w(eTraebls~eIe~n$:fn male and fematNeo Tghreosssus lmeosnioknesyscwohnsiicdherdeidedcoormowceurned-rsealcartiefdicweedrfenseeexncraicnismaloer waenrde fesmaaclreifircheedsusatcer 30 monkeysdwahysichofdisecdalyo.r were sacrificed in extremis or were sacrJiofiscteadtiasfttiecrall9y0 dsaiygsnifoifcesntutdyv.ariacions in sex group sesn wetghes Noof csrtgaatnisstciecsalelryretsibgenmimfiaceenntthevarciuantiiroenlsenidn esnepxergtreosunptemleangroups: 2. weights mofisccorgmaancsholoocscuyr(rTeadblbeet1w6e)en the control and experimental groups.
2. 1Hi1stomgalaethoanldo=yfem(aTlaebleso1n6k)e:ys at he 4.5 my/ka/day dosage level nad sasiedAlldimfalfeuseandpifedmaldeeplmeotnikeoyns iant thtehead4.r5enamlgs!.kg/dOaney dmaolseageandlevteol hfaedmslmeas~keadt dtiheff4u.s5e slgi/pikdp/ddaeypledtoisoagne inLevtehle haaddrenoadlesr.sieOnedifmfaulsee ansdcrotpwhoy offematlheespaantcrtehaeti4c.5exmogc!rkign/deayceldloss.ageThleevelleshiaodn mcoodnesriastteeddoifffudseecreastsreodphy ocfeithesipreancarnteatliocssexofocrsiynseogecnellgsr.anvTihees To lesionmecloensiasndtedoneof fami decreased
cell size and !oss of zymogen granules. Two male and one female
comofonnkkteehyyess saeattrouttshheea44l..v55eolmmaggr//kkagc/!eddllaasyy ddcoohssaaargBaeectellreeivvzeeleldhhabadyd mmdoeodcderereraaatsteeedddiicffeffluulsseesizaaertrrooeppndhhyy oLfosstheofseeryocuesplaaslmviecolagrrancuellelss. These micro characterizedscboypidcecrfeiansdeidngscewlelresizceonseindelroessd comaund-relaces. of cytoplasmic granules. These microscopic findings were considered Yo nisroseopis compound-related. changes which vere considered corpound-seleted "ere seenNo imnictrheoscaodpriecnalcsh,angpeasncrwehaisch owrerseubcsoannsdiidbeurleadr csoamlpiovuanrdy-rgelleantdesd wIenremalseeenandin ftehmealeadrseonnaklesy,s paatnctrheeas0.5oransdubm1.a5ndgib/uklga/rdasyaldiovsaargye gllaenvdelss. Jion mmai!cerosacnodpifcemalleesiomnosnkeiyns taitssutehse o0.t5herandcha1.n5 tmheg/ksgd/rdenaaylsd,osapgaencrleesvselsa.nd Nsoubmziacnriobsucloepric salleisivoanrsy ginlantdisssuoefs saolteherandthafnematlhee madormekmea!ss,atpatnhcere4a.s3 efand Ksugb/mdaenydidbouslaagre slaelveilvavreyreglacnodnssidoefremdalecoamnpdoinfde-mraelleatmeodn.keys at the 4.5 mg!
kg/day dosage level were considered compound-related..
7-002
137-092
11119911..00001144
33MMAA1100006655001177
|
International Research and Development Corporation
|
sefersaces
References
1.
HCCiooauulllettaeehrr, HHeeFmzioaagtg!iisooebb.iinnoomnestteerr,,
Coslier
Coulter
Tieccrontcs,
Electronics,
330
590
.W.
20ch
20~h
Strsec,
Street,
2.
HMCMiieoacrnlroeoohahnehen,,msattF5ao.lcaorrriiiisstdh,,a.. JJoohhnn
3.
B.
Male,
Miala,
3rd
3rd
Sd,Ed.,
1967,
~967,
The
The
C.
C.
T.
V.
Yosby
5.
CCSCo3oom0uuplla7tt.neeyrr,2JP0ea~h.rrs:iiS1cc1e!l5r4eea.ssSS,iizzeeHaCCtooeuunnstt,eerr,,FrMoMrooeddceeall.
7a,
ZB,
Coulter
Coulter
Slestronics,
Electronics,
4. R5GGe9rri0aatddmWwea.hhnoo,ll2''0sstEhiiCCtllSoitirrnnsetiecetasS,llthLHLiaa2abb0loo.erraaahtt1,oo9rr63yyF,!YoMreeTichtdehhaoo.ddCss. Vaa.nnddtaDDsiieaasggnnooCssoiimsspanFFyrrsaavnkkpeerll 11aa3nn5dd.
5.
R2CCeoo0iuuhtl!mt~aeeSnrri,rfPeeaErrd,itiiitoccHrlilsaeeteSS6aii~nzzh,eeEdFCC.loo,ouurnnitt1dee9arr6.,,3, fMooTddheeellC4.A,, V.CGooMuuollstibeeyrr
Elscsronics, 530 f. Company, p. !~32.
Electronics, 590 W.
5. G2e0ntehraSltreDeita,gmHoisatliecash,-- fFalroariedra.Chileort Laboratories Revised April 1965.
7.
General
Gfenreral General
Disgoscics Diagnostics
Di~Enostics
--
-
Harner Warner
Warner
Chicos Chilcott
Chilcott
Laborscories Laboratories
Laboratories
vised Revised
Revised
Januaty April 1965.
January
5. T1e9c67h.micon auto Analyser 6/60 Histo Vethodology.
5. MTeecrhoniAcuotnoAAuntoalyAsnearlyzIe1,r 66//6600 MMiiacrroo MNeetchhooddoollooggsy..
109.. MaciocsrtoeAuAtbossrApneailoynzerILIIY,ode6l/60393M.icro Metho~o!ogy.
I101.. AStiogmaiacTAebcshaoircpatlionSutIlLecMtondel3653,53.Signa Chem. Co., Sc. Louis, Missouri.
i1i2.. SSiiggemaa TTeeccthmniiccaall SBuulllleettiinn 552495,, SSiiggmnaa CChheemm.. CCoo..,, SStt.. LLoouuiiss,, Miissssoouurrii..
1132.. BSiigimlaabTsescihxnicCailmesBuRlelaegteinnt 52S0e,ripSei)g.ma Chem. Co., St. Louis, Missouri.
Leo13.
14.
BoSSftitee!eeSille!,,laebts~Ri..tciix6Gt..s(,DDA..mMeseaannaddRreaaTTngoonrreirrniiitLee,,,St.rJY.iepusH.).T.or((k11,996600.)),, T-PPrriisncciiool!eess
and
and
Procedures
Procedures
15.
15.
BDDofuounmenSmceternsrtit,,icsstCC,i..csWS5,.i,,peM.cNNGeers~1a9wT5T-0aa,Hbbillleelss,
forNew
for
Weitiple York, N.
>~ltiple
CCYoo.mmppaarriissoonnss
Wich
With
a
a
CCoonnttrrooll,,
Biometrics, Sept. 1964.
J 137-092
11119911..00001155
33MMAA1100006655001188
iI
!
Dl gizmag smaan sssns
li 38% 3amz sansa
Li gases seams asses
i lel s$s33s 33332 z333%
ol sasmz esssa ssa 1
| 7) Rid SERAFE addA a
z
$10 LU asses assez gmsse 31
PLLHBF HIfEA7) dHlipb)) PP3330E)b1 k
Bssmmes uoesmssmoosnmmamzo piagn?s wseEesomsmeers o smm n apans s3m3m3a8s1 EssMmnIc AraEmRs Eshasne mazEarr oEosmsmTag osmasta oagnen
200 LD gssza aman: sseas sama
i Piji lf| l| PPlRd] PDillgL]l
z#a2sz3z maazz m222E33
s#. s8e=3s oszaze so3s3mm:e
s2m m0sz3a r Bzsuasss amas ozmasz asgmmie:r os: mna
P1IE1Ph3y)! zRgE2m2man smamssme sossmsan:n ssaasmzss
les ddd 1|
g3
33g
33
HEF 12148 EHIeTn3t REonn PeyREIL FERP Nuves3 Hoven
11119911..00001166
Page 13 Page 13
i
1 !
i
|
i
! i: ii iii |i
I
1I11H Iis I5IHE
PIE
|
i|; 5
1[I %
33MMAA1100006655001199
ress
sesscstony Corgmereen,
[Th-- ea sem:pre, Pla1cghtecs, restestoerses, rrTasecoasia Tne, seEstSmeus rT -- Te =T,o "Te EiSon
Sinuca-Bur Subacute Shem Sooke Toxicity Sadr.
Ninety-Day Subacute Rhesus Monkey Toxicity Study.
MALF.~: .~eaus and Si~nflcance of Hematolozlcal Values.
Nr Month Conceal C~n=rol
]
3
oct Control i1 33
Gn Control 7! ]3
ne ~onrrol 1 33
Conceal Control 7I
3
PR Con=rol 3T3
cme Control I 33
onceet Cou~rol 71
3
GaT mi 33
aol outrol T[ 53
cme Control +l 33
cemerel
Control
an~. 93
~,.67
~ .63
123~Z.3 jos12.& i12.3 3Hl35
37 39
129
i181 05205 osO. 5 oa0.3
0.2
ii
ii12 n29 i24 i25 v.007.03 wa 10.59
8.67
n379 "84 325 827 527 x%36
34
32
05 sires 0.5 mg/kg/day 5.26
5.36
:.81
:, .,~
112.7 i13.0 i12.~ 38 337 539 wo140 Ed226 Ed226 05O. 9 ao0.3
0.3
u!i iinzII 28 i25 i22 re10.29 toil I0.-~i
7.06
n777 80 x2~ 529 x26 xy. 37 333
Ls mialeer
1.5 mB/k~i~ay
so5.0~
~.66
4.45
us12.3 Jed13.2 ii11.6 37 37 336 1114 joy161 =223 0s0.6 a30.2
0.I
u11 iiII 29 i24 B28 oz8.22 ed8-'~9
9.0~
n~o =o25 a28 H26 x34 Hi36 i32
Page 14
Page 14
5 said ~.5 mg!k~iday sa
4.71
-
a!3.7 3i:12.8 uiw
177
oLfaI .{3 O.Z -
2ui:26 529 ?oa6.39 id i t .37
-
a78 5:25 327 *136 335 2-
137-092
- No~ available
11119911..00001177
33MMAA1100006655002200
Sone Tpzesasstony
poe a
ps
EE
hs
) =T,ow
rs ce pan sy cs ~inecy-Day ~ubacuce ~hes~.s Monkey Toxicity To: mo me psi Seog FE~.ALES: ~eans and $1gni~Icance of Hematological vaZues.
rTI EE Y~n~h
Control
1
ees Control
5.66 5.02
3
~ .71
Co~=rol
=1
3
Control ~
~
Control 1 3
1~, 1
1~.1 12.0
g39
~0
38
og1 ~ 6
, 151 232
oceiwin
0.5 mg/kg/d~
5.56 4.56 4.79
1~.6 13.~ 12.2
i38
38 39
#16~
177 236
issn i.5 ~,"k~iday
15. !i
5.~5
-~.37
12. 12.0 11.7
53~
35 37
%L 6~
15~ Z29
Control
0.4
O.S
O. 3
rul 8 4 ~
0.2
0.i
0.2
3
0.I
0.I
Co~tr~l
I i
I0
I i
I
II
II
II
Control
og i i 3 ra: i Control
I
27
~5 7.39 8.77
27
29 i0.31
7.82
~6
8. Sl 9.~4
3
~. 62
9.09**
Control
I
68
79
6=9
82
a67
88
3 3 3 Control
2~
23
25
rod i ~
28
30
31
)
26
26
27
ul x 3i 33 ~u=rol
34
33
37
I
36
36
35
3
32
31
32
re 5 Page 15
sie ~.5 mgikgi~ay
ig5.08
5.00 -
12.9
E3d182
194 O.S
40.~
ii 12 27
i112.71
I~.2S
E68E
75
223 325
-
5535
-
sr137-092
E rrS Ee IROEn TnEm A different from Control Stoup aean, p<O.05. different from Control Stoup ~ean, p<O.Ol.
1I 119911..00001188
33MMAA1100006655002211
| ! 2HH3) greaeze22 n wer snxonn RsRaAnasa snsexsa
| ED 88332 RARE 248A meanoe
| Tu sezza sssss massa seers
ETRE
I
d I) E Hel i hi oi l i$3;lkgu]
seems
22am:
eases 23ammmzam 2
-
sexs messe os sseee
2_RL7 R:RR A
1i5n:e
$148
SIE
sxx:
osmses
zazzz
ozzens
H|YgH]l sEaEssEy soymmenrs osemanmis oseness
PIiie# s S333: s3Eeld EEE R BEE:
TDlegede
HE
CEE
[D[I|liEEgsl|
mses sma amen sims
oz:ziomEni mio:
Emamnre mmem ine ssmsns asemas
Li Bee Feren {een FE
i2al5|i05 s3831 n1l)JaBdmaanrs$1:8asoanyn 11 3daBunsens 3 Haennes!
11119911..00001199
Page 16
Page 16
ii
i
|
| |:
|
||
|
i
i
:i
|
i|
|
|
|||
|
i| d#3
33MMAA1100006655002222
I Hy samza maga
i i) ARRAN ERE A hi LE EE TEI
ll
EE
a[1 Hal svenr comes
Hl $i] smsrc zsszs $| 0 TL
i j.|
ILHigsi)a
THHIiiE sEy|i
130150,
sssas
EseEsRsE
szema sess:
sams:
osgmnsi:
anus see 2
mess
a Bg
200 if] | |=
533 32233
233s RRIF
asa
=mRT I EE
sass
gEmaan TT
sewn sons sass aasas
assza ssn:
osgsemssEisoemsms
agaa menanes
seen
ossdsw smn: sIRER goEss
Le
iaHla) smrzomser mmr oma:
|] gd] ssa sssz osssza dss
H$E1H2E0 FTE ESIY. FH Homer I Mogee funn: J Ragec
11119911..00002200
Page 17
|
{ +
|
i
||
|
|
|
|
:
|1Ii1:
i[F
33MMAA1100006655002233
1IiB]T! sess amas meas
Fl osszes esses sssss
DPinE] ess sasee sess
sil]
HE i seams ssiRa =mase
RI FDEil3ill| cazmays mmsmszma mmaanggee
| ie] cover me sos HDiEgE! sssse maser mema
ih En
3p1i31e38 mzmza szzza ozzazs F iH d| oswmees mommssyn zozsems:
CPaYl maz: amar szzza
Dlgee] memes sxsnn mases
Hy SEEfd SEEIE ZEEE:
I fdgl)) smsma omoesrm aomsss: moumn
3 eld 33 i? $8... 0
HE
FETTERPRL PPT
11119911..000021
rage 18
Page 18
|
;
|
1
|
| i| iJ
:
||
||
i|
iPfi
33MMAA1100006655024
po~C-9~: som TABLE 6.
Bioche~.~s=~y
Gluco~e,
mg/l-O0 ~
B.CUma.zNsi.!i,0o0 ~at EEE .~llne ?hospda=~e,
i~'l un1=sil
5.G.O.T.,
In~'l ~i~s/l
ewxn. Cholesterol, m~/100 ~ aapn Total Protein, ~/I00 ~
sosg/l~o ~ _Sodi~,
meq/l
_ ?OCaSSI~,
meq/!
Chloride,
=meq/l ssgoon i~rga~e P~spha~e,
mE/100 ~
smn v - Glu~l Transpep=i~ase sam Si~ ~s/~ pi pepe, Creaci~ne Phospho~se, ro S~ ~=s/~
st cs sg sss ~Ine~y-Da~ Subacuce Rhesus Monke~ To~ic!~! Study.
Hom cmww H~L~S:
$ cudy
~on~h
S,~'r7 of ~un BiochenLlcal Valuee.
Control
0.5 ~g/kg/day
name ~.S m~/kgiday
Control
118
331
9"776
Canrirreml
n2233..y73
3
2B.2
v Conrro! l
pt 1070
1113
3
Control
Cd 3 Tg I
3
A ul SE Control l 3
wm w Eta Control ~ 3
ww l
3
3 Con=rol
1
3
ot ~CZOl
1095
22
56
42
35
183 198
162
8.38
8.46
7.85
4.75 4.70
LbO
161 153
4.9
1
4.9
3
~mcrol
TB l
3
[RA ~n~rol
~31
om~n~rol rodog 1
3
csoo Coa~rol
4.2
I12 117 112
6.8
8T7..e14
56
42
56
25
1
62
3
20
106
92
80
32n39..338
26.5
wr680
897
747*
23
349 i27
28
3172
200 152
ai8.74
8.59
8.07
im5.~7
4.69
5L56
160
151
25.6
&.6 4.2
~14
#LL8
~i0
ws~.4
&~3..~5
336 ii45
29
Hi44
34 40
I02
w1o1r5 107
33aI2..sA8
I~.6
i1I0ii3io50
89L
18
3g38
28
#@tSS
213
Lia8.68
8.74
.8.~8
in5.22
4.98
5156
160
150
5.4 ~.7
#~.8
116 iZl Iii
6.0
x86..~0
5~0 I855
45
3i1]
67 40
se 19 Pa~e 19
wwe ~,3 n~ikg/da?
--99
29.1
-
1T30e0
25
]:27 53190 ius8.90
8.90
-
"in160
153
us-
4.7
z.-
~i~ 105 -
4.-=9*
%46 326
-
2313
-
--137-092
i iS eTO e~sL~nlflcen~17 di~feren~ from Control
- = No~ available
Elgroup
mean,
p<O.O1.
11119911..00002222
33MMAA1100006655002255
renFC-95: We TABLE 6. Cont. -- 3iochem~s~ry -- Glucose, i =8/I00 =i seB.U.N., Simg.' :00 ~ site rospacte, .~i=e Phcspha~a~e,
ing'l uni~a/!
een S.~.O.T., Fi tn in~'l uni ts/i
Ee lesan 5.~.P.T., inc'l unlts/l
Cater, Chafes ~er~l, we mg/i00 m! fos proce, ~oral Proren, iiag/IO0 ml fr.~5~n, Ta gilO0 ~ fom, Sodi~, uameq/l rami, P= :assi~m, avierse, meq/l Sarsperce, ~eq/1
~=orga~= Phosp~e, ~/00 ~
Co Gum tian -, - Glut~l Transpe~tidase path Si~ u~s/~ Copnrcrisoeelmiomnpokisae, Creaul~ne Phosphoki~se,
acc Some Bane Soka Toney sr. Ninety-Day ~ubacuce Rhesus .~onkey Toxlc!t7 Study. run sm sven vem FLMALE$: S,-,mmr7 of Mean Biochemical Values.
Study
BE owe Month 1 Courrol
TR l 8 3 Cot Control ; Bt 1 Pow 3 Cort Con~r=l
I
5 C~n~rol ol 1
Con=rol
107
163
88 25.6 25.2
28.7
1173 ~092
16 &6
3
36
ose 0.~ mg/kg/day wo119 %98 #97 io22.0 #325.5 i21.5 wn1013
942
bi39 355
36
swe 1.5 3g/kgiday PY113 Fe:19 f0d:20.7 a26.~ i22.6 =770
753
Hon20
~5
27
Control 1
PB i 3 co 0 on Control
om @ ! OW fi 3 Cra 0 Control i bo il I 3 5 i 3 et an pre ~==rol ; pe WW [ 3 pd i 3 et 1 Control Cl i [ 3 i 3 [ 22 Co==rol T i 3 I 5 1i" TM4] ~
o2Zh33
29
180 198 165
7.70
7.66 7.&9
4.71 &.86 &.77
156
155
152
4.8
4.7
4.6
342
37
27
208 221
169
8.77
8.47 8.02
5.27 5.&l &.82
158
162
~51
5.3
5.1
~.1
i32
35
334 Py204 i~69 4100 wio~ .67
8.63
isae5.20 pd5.42 fe5.21 pe157 i157 iI~9 55.2 i3.8 us33.7
i
3
4 is 3 Control
33I
ce 3 a ~=~rol ol 2 # 1 3s i 3 3
Goel 10 x Con=rol 3TR3 32 $}e 3
111 113
6.4
D66X..)55
38 41 32
I0
5
116 111
7.5
787..332
50 ~7 40
20
i0
113 109
5.4
p45x..]77
43 ~8
30
Z&
7
Page 20
Page 20
ewe 4.~ mBik~!day wjeo16,'. :aSei3[.6
-
os875
615
i57
75*
i37
45
ue2176 i112" 5is5a8.82* sae5. bE5.39
8ww159 #[56
-
55.3 ue350llO
6
5:5.=z6 i530
-
won !37-092
"mySH Iey E ry n ed ."Significantly different from Control ~zoup mean, p*O.O$.
eeSignlfican~ly differ~n~ from Com~rol Stoup ~ean, p~0.01. available
1119911..00002233
33MMAA1100006655002266
[| mere sme mre aes
[[EEiS seems smsss sma aes
P=]
THE zsavs maszs amin: sma
i {43}
U[liHssE]
|i i
$1.1 ol
HsEiB dHaEoE
HE
3P1 HE1S35)8]
PJoiIllaisy]l
sEmEs ozmmgs Emmzs zm:
smgmanos somas ss mso wamsiwmesss
83353 32333 3333 IEE
GERomI mD EE Ems
m 33338osm 3snz osmtEmny mgaEma
TssEsReEs
SsEsRmRaEs
sRzEsEtSrE
mess
REERR
$1355]
i187
iHolic|)
ammzs
$3ea83 A
mmees
AAs a
semen
AREER
zamss
RsEam
F185]
| |3ig|
sens
EERE
GsRmEsReEs
EsEeseEs asopsems
EE
I]
EEE EI HEI mn
Cl PPEE]E zmsez 3 osmsss 4 asses 5 amass
dPalorgi]a ee ETTeen ETJenn ETdames
HEHE EER EERE REFE
11119911..00002244
Page 21
Ta~,e 21
:
i
i
i
i |
|
i| i i | |i
Le
[IE
33MMAA1100006655002277
VLE] EIE}E
EE]
iHH i
2i 1:53]) IH
Ici
i De E| FE i i
F3iEglRiEieD|
33 HE
EEE a HieE
HEEL]
i 135)
isl
| Ha
Li EE3 D UEE
sesas samen somns meses
esses sspze amen mame
amor om: mma oma
zzz oszzza oma: asm:
menaonse ssemncse mcommmon osmmaonees
spas sass sERas sms
=
mmeommoamnnomus
s3m323zReE oeEsIaiioIsmanmiein 3 ozss
zi3ze g3%z: EEE: seme
RSTERm amRRE Ramm2 mmaza
sams ssssa wsszs 2fzsa
333F SIRE BBESR lugs
aErmRanIi omzaEziioommmaa:l omnmls:
pi ail sez: Soro sEges Yu zR@Ei EEE
RDEEEITEemRer LoaPneSe d|f qpF annAduSaOne?|
11119911..00002255
rage 22 Page 22
|
|
:i
i|
i
|
ii
|}
| |
| Ii
|
i
|
|| !i
|
[II E
33MMAA1100006655002288
Hi:_EH-_.] sens creza geen
3 saras smaza sees
LilHiH i iy. 1|4g5]%)]
Polis)
i5
J 13
HdHI HdEsH
UE Bfi il
HFiElMdSe)
HH
3h$11i1:1e5180
2) |g5|
IV| lIedS|s
mmr
mmr =B2RssEcE:
sure 23332
FREER
sss smemenr:
szzze
sens
ware:
Sgg3e3r2s
mann
mms 388R2I2i2
oman 3283
REERE
ame gmmmonrs
ossmss
amman
wares
sapnaszis a
mon
mm GI3EIEEEEE:S
amin PERIE
EEESS
aml omsoems
mame:
mames
samme
EssRssEz
rage23
PaSe 23
!
}
i
i
!|
|
|:
|
-
;
|!
i
||
PP| a30 ZEEE: ERIia ERRiz
I LB] zemze sesss ssszs 111
HBEERIGIEE PEAEERE NHOEISFENS E| RE HESEIT
PEi
11119911..00002266
33MMAA1100006655002299
FrCe--9955:: TTAHBLLEE 1I00..
UUreitnnaallyysstiss VVooollyuummee,,
mi
"pH
SGprSeapecvciiifcfiyicc Gravity
NNitnaeetcyy--DDaayy SSuubbaaccuuttee RRhheessuuss MMoonnkkeeyy TTooxxiicciittyy SSttuuddyy..
MMAALLEESS:: SS-u-m~,aarryy ooff MMeeaann UUrriinnaallyyssiiss VVaalluueess..
oSSttauutddhyy Control 0.5 mg/kg/day 1.5 mg/kg/day
Month
Con=rol
0.5 mg/kg/day
1.5 mg/kg/day
CCoonn=t1rrooll 33 1
CCoomnet1rrooll 331
CCoonmte1rrooll 31
3
232022 13i000
767..622 677...4000~ 11i ...000323282 Li.o02m8a
1.034a
2222 33235 885..s33 5T7..a52ea L1L.0o02a2r77 IL.o02n7e
1.033a
"2208 477s50 885.'s5s 885...900a0 11L..o00a3300 1t.o0a21
1.024
Page 2
44..55 mmeg//kkag//ddaayy 535888 38-p88..o44 6-.-4 IlL.oo03xx4 i. 0--33
137-082
137-092
a-2ssi=tggnaNlottffiicacavaanniccleeabnnlooect ddeetteerrmmiinneedd dduuee =too oonnllyy oonnee vvaalluuee iinn tthhee CCoonnctrrooll ggrroouupp..
- - Not availaSle
11119911..00002277
33MMAA1100006655003300
ze-95:
FC-95:
TTAABBLLEE 1I00.. rUrtinnaallyyssiiss VVoollauusmee,, pFHl
GesSappveeiccetityfiicc Gravity
Nisecy-day Subacuce Rhesus Monkey Toxicity Study.
Nine=y-Day Subacu=e Rhesus Monkey Toxicity Study.
CCoonntt.. FFEIMMAALLESSS:: SSuummmaarryy ooff MMeeaann UUrriinnaallyyssiiss VVaalluueess..
oSSetnuutddhyy Control 0.5 mg/kg/day 1.5 mp/g/day
Mon=h
Conmrol
0.5 mE/kg/day
1.5 mg/kg/day
CCoonntt1rrooll 331
cCoonnttIrrooll 331
CCoonntt1rrooll 33 1
233522 88205 885..811 885..080 111..000333211 L1i..o00z23i12
5533 33103 757.'.99s 995...005 LL1.000322277 Li1.l.0o02z3112
22200 "42008 ap8.3n3 06.~ L8.0031 111i...00002322s188
1.025
Page 25
Page 25
~4..55 amgg//kkagl/ddaayy 3330 23-886..s88 6.35 1.- 027 11i...00-0233766
-
137-082
137-092
- = Not avatlable
- - Not availaSle
11119911..00002288
33MMAA1100006655003311
IEe
La
CEE ee pepe ep ees
ELL LLL
iDUEi e5e et eee ee
J P1oE 8gB
Bly
Torem
ooip
or8 n p own
i How oor ow op
Fil $3 5F
#:
ITH
ee
if
FHMHEEI]IHH315]
sete
eer
tems
eee
were
eee
waiz
oem
:ilP| EHsl aete rene sess cous
UL sess sess szer sass
U[sa|] if3e2nn amteEs zszmaas nmaamm EOE ORR Bn By
| i|b sees Fass seer gas
[175 wenn aman een ee
IB
4
Hela 3
3
11119911..0000229
Page 26
I
ii
2
|
|
11[3i3Fs,E3E:
aii
|i! Lil
R[J ieiHtelit
|
|
[IEEH, Lud
1[8a8533 |
lz
33MMAA11000066550032
[|
Pillado
2:
Hep ee gp
i]PE
|
i
sD Ime mnrown pny
sSiedb oewesr ooops 1 zor oossne
fil
HE To op HE see ssn saan eens
iFE3I 00
HE PEL ID eeee eeee eeme are
is
o o
|} p| F "2 osgs yy sm: ms sweamee o29u5s8
iCBDR ONE sm onm
| 5 amzz mses =ssr sans
i 3| rr a res eens
SJ EE d3eers Jzaan di unn d: em
11119911..00003300
rage 22
Page 27
LE
iH H3H; HH |
A hn
[jEiE
:i
|
L| a2ala
{2582 loasiid
i
D| E3
[| iEtHhH
aisid
|
i:H
33MMAA1100006655003333
|J HEE ET
i lyad
iE) Car pee amg
EH fue gee eens
gl
$F0E3.Toon HE
HH # Fry Fer as
Tiger ao
1P H5E H rori eeeer oeese
iE3E70OH ver seer meee 2i
UH eet seen eee
i| i
i(|iBil E2 E2E2 O$E2E3E8E E35E:E3
Poel rao osm
ES EES &es2 2232 sgan 3II3
i i i Eras rEas rzas xzas
il NINE
i
i3
i3
E SlEaEnlHYE e BER eEe E EMRogsRBiOnEaEs
11119911..00003311
Page 28
PaEe 28
if o,
iit
it
;
i
L HHREM
je
Fi4H E
[[JnraEiei2EgsasEee
!
:
i| 3
[1]
HE
lesnss
|
i i
PiE
33MMAA1100006655003344
rage 29
Page 29
FC-95 :
sefue
Agrenals
enlarged
brown Ln color
Necropsy Observations, Ter~nel $~c~ce and Deaths.
_ Simi. deus dss fHilee:rz2r:23s:3e8 ss83ss35s3a83i3i83i2d:
Lun~ ~ellowish mi:e lesions dark red area
pleurel adhesions dark red raiJed focus
aodule
accessory splenic tissue
Thymus
x
x
S~omach raised edema,
nodules glandular
=ucosa
Sh ete, dar~ yei!ow ~.hick fluid,
VILL aie
void of on~en~s
IIeocoli~ orifice
ongestion
LAver
accea=uaced lobulacions yellowish focus/area brown Ln color
uo::Led
whhe~orrhaEe, bindli~bs
abscess, riEh~ hand
.
I.
.
-
sacrificed in excre~is.
11119911..00003322
33MMAA1100006655003355
| | 323333 3832223 ssanag id
{| IND HIND Bind bd
i 522324 f3sEeR 224323 z3az
LY| lE)=! Ec HegIrNesDs NnezIasIz msaiznasts = uczmez
rage30
Page 30
HE fl 234223 s3zags gaaszs
Hg ay
oaag|B
i
Hi:AA) sSsEzNemDs sZzEzNenEs h wssE enn RomneEs L|if
{ iy
iH]
i|
I
355332
s3sass
SERSER
2233828
2333s
szszze
ddddid
231313
ssasms
sassas
did4ssd
zzsazy
gas [EDF
mess|i
EEE1 i:
grag (EL
| $$ii) 392333:313 3sIzAsaInE: ssIsMan:s osw3ang
0s ar EE J ; El lgmratgntag
4; 5 ian inindus
5 3
11119911..00003333
33MMAA1100006655003366
Page 1
Page 31
TA3LE 16.
H~c~os~op~ Observations.
SpE ipa shy
-itn
i$H1 232335%2 3353%F TF2i32z2 $Erii:st
~razn
Peripheral Ne.-ve
Sn Eye
f~c~ of l~hoid ~f~ra~es ~!an/
~ys~ic ~arsal ~l~ds
Piiuip i=aryToac ot tras mtsence a ~ar~ =e~osa
~renals
focus of i~pnoid ~filtra~e /Lffuse ~on~es~ion aci/o?h~ic desenera~on of
Sy see ~ s~l! ~roups o cells
Eseir -- diffuse lipid depletiou
focus of In~mrs~itla! lymphoid
sien:
:
>
sas a : riCsaasa
TTT I rr Ti as
Parathyroid
Tongue
Terps, oca_i hzalin de~enera=iou o muscle
focl of i~fi~anor7 cell infil~raues ~ ~ osa! epi:he!i~ and l~i~ ~ropr~
SEE arin loci of ~fi*~o~ call
~ muscle ~nEylo~ s~. i~ ~ucosal epi~heli~
1 1 i
3114
3 2 2
1 1-
'3
,
:
2
2 x
- -1
3 '
R
:
1 !1
`
,
3
GREED wn. 000 rr re : loci of iafl:-~=~ory cell
a --atl he shat > i Esophagus TEE ttm cnt tics in fccl of i~flam=a=or7 cell ~-f!i'~ra~es in
4 3 2
3
1 1
2 2 ~ 2
222 3
!
1 1 1 2
1 1 ! I
lamina ;r~pria
3 2
3 3 2 2
4 32
EE ~ear: loci of ~nters=tial lymphoid iufil~rates small focus of myocardial necrosis
I 2 3 3
I 3 2 3 2
1 3 2
2
2
apSim es Code:
x - condition present 1 - not remarkabie
2 - very. sii~ht
ame 3 - slight
& - moderate
Ee 5 - marked
usm 6 - ~treme
- - nc~ available
ET... ome * - died or sacrificed in
!37-092
11119911..00003344
33MMAA1100006655003377
nage 32
Page 32
te
TTT ~aivary ~$and 7 -- foc~ of in=srs=i:ial L~phoi~ md ss infiltrates
decreased cell size, loss of ~ycoplasmic Ecanules
dila=ed duc:s
fm eye raw ssa
ff sz: 33s
TTT
ress 2 2 3 2
ICo soI a
3
2
sss iii
TT
av1os l
:
2
2
4 ~ 3
1fo5ca1! preertivvuassctualiatrsnepecurtoroppsshlll isnafuitlctrrsacteess
re ~oca! aggregates of alveolar ~rop~ges
acarlan ~i~e~= (peri~ronchlclar,
Serenata, Bertvaseutae ~erib ronchi~, perlvascular
a,Rl pes loci of per~vascular l~pho~4 ~f~ra~es a a snp Zhe1Srekthola 1aen foot of perlbronchial/peribronchiolar
i~phold aggregates
lun~ mica in bronchlolar l~en acute focal brouchcpne~on~ =hroRic focal plauri=is
STaINnEiahet 1 seri focal acc~lation of blood and n~roph~s
~ alveoli
coin emia, foe tszemaisial tibeonss focal n~rrhase, focal ~uersi~ fibrosis
p21
z 2 2 2
EE 3 3 3 3
Tonsil
ksracin-fi!!ed cyet
BITES wn ween fo~ of ~nfl=~:ory cell infil=ranes in
muoosal epithelium and lamina proprta
LR Sm e m focl of !nfl~m~ory c~ll ~~tra~es
nielemn mai, surface epi~he!i~ and ~ons~la~
3 4
mE Th.~-~u~
Lye.oh Nodes
diffuse re=iculoendo~hellal ce!l hyp erp las ia
ir
EEE Fa Stomach totiamaceny cot atti tn
toci ko~ f Spriopra~ r wit tattieaces dn
"lasine propriasod subsucosa
~oci of infl~=~o~ call ~f~raues
LEN ei ctsnion of mtn l~a ~ropria and serosa
S~II mui~ifocal cystic d~ata~io~ of glands
' `4 23 35
J?3
,3
2122
! 3 Z 2 Z 3 3 3 2 3
3 :
:
: ni
222:
222 2 3 3 3 3 3
:
22 22 22 22
3i+2 ?2
s
s
3
ss ia
2P3rone
.
,
3
:
Pr
3
.
aeCode: won 137-092
pigemepe x - condi:iou present
i - not r~markable
EES 2 - very slight
giage slisht EEE marked
time not available Elena died or sacrificed in extramls
11119911..00003355
33MMAA1100006655003388
-
TAz~L~ ~6. Con.
at th vor 4 nS
Microlcop~c Observations.
raze 3 Page 33
SEL ewe Lie i. 5 mglk~Iday see &.5
",,
HY z23s gees pss 3iii
i np
-x ,
x X x
CoiDn
1 11
1
1 1
focal mucosa! hemorrhage
3
paras&t!c ~ranuloma Ln muscularLs and
EE rr-- : parasitic ~ranulo~a in serosa and
f~ci of inflammatory cell Infil=races Ln muscularis and serosa
loci of inflammatory cell n11tra~es
loci of in1=~ory cell i=~il=rates
i Em , in muscularis, serosa and mesen=e:'y
parasitic granuloma in mesen=er7 parasitic ~ranulo~.a in =uscuiaris
FEES RR : chronic focal seros~=is a rl TT ETE ETET fool of Infl=--'~:o~T, cell infilcra~es TE EooTsE tpLiE i mtRoE t. res F:;1e,: oa f:: + 3tesCo , A, tn ~uscularis
I i 1 i
3 2 2 3
1 1
3 3
1
1 1
x xx
x
2 3
3
2
3
Een L amT e
Cn0
in roams amt a arin
ety
3 3
E3 L3 3E2 ES2 EE3 3
.
IRE 3
2 2
5 & 4
4
3
3
=
3 3
rT focal ly~phold infll:rates i~
~eripanc~eatic fat ~issue
Je : decreased cell size, loss of z~aogen te ST . Lots ~ranules
i i 1 3
1 4 4
focal ince~s=i~ial izmphold infiltrates
3 2
3
P PDoEmEmST e CmET Be E tse ee i - ~o: r~mar~able
3 - sll~hc 4 - moderate
- = not available
2 - yew s!iEh
* - died or sacriced in exCr~mis
137-092
a - autolyzed
11119911..00003366
33MMAA1100006655003399
roFC-95:
T.~LE 16. C~nc.
oy ip pin wn ou ey Hp Niuer7 Day Subacuts Rhesus ~nkey Toxiclcy
~croscopic Observations.
Page 3
Page 34
Es Samer lgser sie
~idney
LC ---- m~l;inuclea=ed iL~ epi;~e!i~m
L~ papillar> ducts
LE amen f~al interstitial iTmphoid
focus of g!omeru!ar fibrosis
nn Be ~icroli~h in rerml tubules ill we cystic ~lomerull
Tage :
113s .
aaa s
Co
a as i2 e2s2
4 3 3 3
fy wt atten Urinary ~ladder in lamima prcpria of SmI. loci of inf!=~-cory cell loci of ~fi=~ory cell
ss 1 3 3 3 :
ars 2 2
]
aaa
2 3 2
1 1 s
4
omnes 2 1
loci of interstitial 17~phoid infil=Tates
3 3
LF~phoid modules/infilc:a:es in corpu~
3 2
Sa~ ocys~is sp. ~n =uscle
1
uUer~ne ~lands smal! ~oci of hemorrhage
smn endomecri~ ne sim 5 is focus of
L BTT st sr pa prepuberal development
2 : 3 : " tI s
3
:
" ig
: i K X
:
2
p vr
EE of eis ations a meen i i . epi=helium and lamina pr~ri~
4 3
pry -- i $1 1 3 loci of lymphoi4 infil~ra~es in musc'olarls
2 2
~ocus of ~ucosal epi~hellmm
2
r Meme ar in ~kel~al muscl~
Sar=ocys~is sp.
Eea ramen eit : fool of in~ers=l~lal i~i=.-~=~ory cell SL sci 1: i : infil~rates
i 1
1 1
!
1
3 2
3 4 i 1
small loci of necrosis
: me omens NEE. NEE C~de:
27 vnveeorr:yys:s~ilmLgagrnhkueable
3 - slgh:
~55 -- s~~aoardr~eeredace
-+== tnoitedaovrailsaabclreifices fo mezents
137--092
11119911..00003377
33MMAA1100006655004400
FC-95: TASLE 16. Cont.
N~necy Day Subacute Rhesus ~onkey Toxicity Study. Microscopic.Observatlon~
page 35
Page 35
Sm nage Lise sae
Site
BY raz zzz: ssi: id
EE Pe i ki EAoreaime
.x
C2it 2
"
7?3
2
ro i3
3
M=~ry Gland dermal nflan=~=ory cell infla~r~cory ~xuda~e in d~c~s
32 3
2
2
~i!a~sd ~uc~s
ETE se 1535 fsey Qr,r ges hyperkera~osis
ET TTT TT T TTT ~one/3one ~rro~ (R~b ~ :Lou) TEL St h~ocellular ~ov
~Lff~e conEesclon
L37-092
TRImERSOIIINDY Coda:
~ - condition present ~ - ~oc :emarlu~le 2 - very slight
~ - ~dera~e 5 - ~arked
STILT wees - = uoC available
* - died or sacrificed n ex~reeis
i
11119911..00003388
33MMAA1100006655004411