Document M4675BzN8bQX3bwGvJ5oR1Oqk
| ? WSV2iA0e0nSa,HCLVEIaesNezUzGRiGeTa-OPeIsNKsE
E SpEe T Un,
MUTAGENICITY TEST ON
| APR 28 1593 ,
2 3M
coy=o
1.5710
IN AN IN VIVO RAT MICRONUCLEUS ASSAY
DATA REQUIREMENT U.S. EPA FIFRA Guideline 84-2
FINAL REPORT
AuTHOR Hemslatha Murli, Ph.D.
PERFORMING LABORATORY. Hazl9e2t0o0n LWeaesshbiunrggtoPni,keInc Vienna, Virginia 22182
LABORATORY PROJECT ID fA Study No.: 15516-0-454
suBMITIED TO 34 3CMorGpeonrtaetrion St. Paul, Minnesota 55144
STUDY COMPLETION DATE April 23, 1993
15516-0-454 '
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STATEMENT OF NO DATA CONFIDENTIALITY CLAIMS
No claim study on
otfhecobansfiisdenotfiailtistyfalislimnagdewitfhoirnantyhe inscfooprematofionFIFcRoAnta in1e0d(d)i(n1)t(hAi)s,
(), or ().
Company: Company Agent:
(Typed Name)
(Title)
Signature
Date
15516-0-454
2
01268
1 WASHINGTON
STATEMENT OF DATA CONFIDENTIALITY CLAIMS IofnfoPrImFaRtAion10c(lda)i(m1e)d(Ac)o,n(fBi)d,entoiral(C)onhatshebebaesnisreomfoveidts tofala licnognfwiidtehnitnialtheappsecno-pe Six, and is cited by cross-reference number in the body of the study.
Company: Company Agent:
(Typed Name)
ee e e-- (Titl-- e) ------ ees
Signature
Date
15516-0-456,
2
0i289
WASHINGTON
GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT
Fe Iheiisaecsituodnynsdwaapsarredcosn1d60ua.cstesdeAtnyinfoscriotgmhnpilfiiinacnaTcniettlwedietv4h0iatotfihoentshEePAfUr.FoSIm.FRtACheodGeopordooftoLcaFobelodreraaatnlodr/yor GLP
o BSi otnhen. eeIntdesrporsetraeantgiuolapnapteionfodnitwxhheitcorhesthuailfstfsecrteipenodrttht.ihse
qThuearleitwyeroec report.
niontedgerviitaytioonfs thferomstuthdey
Study Director: iNiemaslaathhsofHiarrll.HPoh.Di. DMeapmamratlmieanntCyotfogMeonleetciuclsar snd Cellular Toxicology Study Monitor:
Applicant [Submitters
4/22Di4r3e . Ta hw
15526-0-45
5 01270
@ HAZLETON WASHINGTON
.
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HAWZASLHEINTGOTONN
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WASHINGTON
QUALITY ASSURANCE STATRAENT
PROJECT TITLE: IN VIVO RAT MIGRONUCLEUS ASSAY
PROJECT NOL: 20996
AssaY No. 15516
PROTOCOL NO.: 36
Eprrion 10: 5
OqCueatlynittiyngAesqspuuriroraceneCmcdaeeurnreseinssncsepoodffectttpihhroeeonjseQacuptapolfriwoetptryhreeiaAtscsestouundrdGyauoncocdtaeenddL/UaonabricotcroraraetdnvoidirneygwacPocrtfooarcdttthihieencgefSitrtnaoeangldutalhreardteipoonrst.
EE OnRstfuaenndtteo tihnespescttudiyonsdiraendctofrinaoln trheeporftollroewviinegw wdeartees:reported to
DHIranarscvpteescRtt-ei3po/on4r//tD1a9tr9ee3view/d/14/1993
Findi3n7g0s471R9e9p3orted 412472993
5auhguilcloerce 5 Mulleee
Pinal Report review!d/23/1953 412312993
W. Mucphy
15316-0-45
QWuablsy FSesurencenUeM t
Bi2te3R-el9e3ased
. 601278
@HazLETON
STUDY COMPLIANCE AND CERTIFIGATION
TIBhheededeecsrcrie ibbeeddestt yue dy waan s ce Conduheceteed IisnnTobtchyoe;mo'fplccioGhaseaenocoerofgLwaaiFnbceiohdsraaartttaoihireoynGRoePfoprodrualcitELticaicoboenonorsmaCit(co3r1y)30
e EopoermahT omnean2Deeee Ee
TrEteeenrenpsicsToiiotgafneaiidetF.ciLtcipoovrnoenttoo1cf0do6el1.vt)ih,aetthiatotTenosswtotuhfreleodsmbteasctsthf.eecotfThttehheecaw
aeBya boetRee e ome SredsyooDnirteacdtorh,erwehion creerptriefsieenststahantapthperopriate
aeABetrem edrnds eaco an ee EeEAy Feor tTeieeLteiavstebn.odsoanreacbhyyLioovutambrda..offSoiltnlutodhtvyshienfDgii,srnieaosc]rutabogmrreei.psosfraiAtcoLinLliotfrieevs oLE feHazletonr e og oReT nEor averSieaallstiroeonntseaiynpoeeudrrio1dhperotifhoedt.isnteoh.reagoerSposfneasncottrii0rniaey4s ae fpnaved by the Sponsor:
J ,
Fernets
HEfoEprearnorcmaMaase rE eletaree and
celular
Toxicology
--dfoes[f23e/4s3 Fo#y[2fCo3smple[t43ion
COLl7a
: WASHINGTON
TABLE OF CONTENTS
Page No.
1. II.
III. IV. v.
VI.
VIL. VIII. IX.
x XI.
XII. KITT. XIV. XV.
SPONSOR + + vv eee manne2D
MAA.TERCIlAiLen(TtE'SsTAIRdTeInCtLiEf)ica ti on ov vv vow ov noone 11
B. Cc.
DPahtyessicaRleceDievsecdription
D. Genetics Assay No.
TYPE OF ASSAY . + oo eee e eee e eee
eee ee 1D
BROTOGOLNO. + + +e eee e eee eee
eeeeee AL
STUDY DATES + eee ee ene eee eee 1D
A. 5.
EInxipteiraitmieonntalDatSetart Date
C. Experimental Termination Date
SUPERVISORYPERSONNEL . . oo oooov oo ooo 11
A. B.
LStaubdoyratDoirryectSourpervisor
OBJECTIVE + + vv wvnev ee AL
MATERIALS + + + ov woo noe 12
AS. OLSoUluBbAiNlIDitSLyTAIaBnIdTLISYTtYabil. it. y ov vv vwwwoo ove ove 12
B. Cc.
MDoisceronSueclleecutsionAssay Dosing Information
BONE MARROW HARVEST, SLIDE PREPARATION AND ANALYSIS . . . . . . . 18
EVALUATION CRITERIA + vo vv vwwvon ooo oon oe 19
A. B.
GDaetnaeraPlresentation and Interpretation
RESULTS AND INTERPRETATION . oo + vv wwoooooo ooo 20
CONCLUSION + oo vv vv wev oooe 20
REFERENCES . + so esse eee e aceon
20
DEVIATION FROM THE SIGNED PROTOCOL . . oo ov ovo + oo 20
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somnry Mutagenicity Test on T-5710 in an in vivo Rat Micronucless Asssy
oIEhe NLobjectiEipviTe7a1p0uo,fs-bttahoiusiienyiduncreavtiemv.oicarsToshnaeuyctlweeasstinatoctboiencvelaelmuwaaatrserortshuepsoplaeybndcielhdirtoymiantoifccortnheeryoittlhe.rsot-
BT4Ae nEtehemEraeSdqeiuhFteiiasvcterbeyoFfeamnoadrtalhleepso)sgSipewotvneiasrvgoeeer,acftoaTnnrtd1ir2oao5nl0ll,yg1r2aoo5sf0us0pi,sgthneaeendudmtihtca5orn0oa0en0tauiccmzhlgee/ddkuogssa.ep/pshrtaoTuredxvnyiemvsaaatntsiemltaycilonsen2d4u(cftievde
Bi SBeEoinerfomErrorrceaiGxaoocttarisiacocgyttniwaoionnrwee.otrfheeintccahlenuuitdnhbeaaodlnnseatiiamnztaertdrhaoe1w1a.paspdsorasoDyexu.iemlaettoTvehelletsyh,ean2i4se,mxaacplee4s8scsivisaevlndreley 7ad2tosheotduhrewsi7ta2hfter
Hour harvest. this sassy vas repeated.
ASBCfneoteermlrencaricmomoenane1sashu.tolst(iatFnti1gin5oe0n1n-gavr5oti7ute1phs0. tbyhxdeVeohrSFaipiolcvnlesegoafrvea,amngadelTerpsiao)atsliwt3e1iIr2Ive.e5o,frcoann6tt2hd5ero,onlmliyscngtdraoosnus1spi2sc5gl0neeeumdusgc/htkaosgnt.auedtayiczAhwgeaadisn,
So Ema
immuhinoeurtsuyltahf7etetrhheaedroreessitanfgtaerfrtoircdloeesxitnargnadcwtewireoerne oifcnuctlthuheadendsbtoinieznedmtahrearpopawsr.soaxyi.nstTehley
a24n,ima4l8s
TIEEheerotmetssiete1rem.tataentraniabilos,neco1m-na3s7ri1rd0oe,wredipodlnyencgohatrtoimvisencdiuiccneetraheytshirragotnciybftoiencseantumnadrienrrcorvetsmhseiecrcooinnnudcilteiuosns of
test
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Mutagenicity Test on T-5710 in an in vivo Micronucleus Assay
I. SPONSOR: 3 Corporation
II. MATERIAL (TEST ARTICLE): A. Client's Identification: L-10059 (T-5710) B. Dates Received: February 2, 1993; March 11, 1993 . Physical Description: Cream-colored granular material D. Genetics Assay No.: 15516
III. TYPE OF ASSAY: In Vivo Rat Micronucleus Assay
Iv. PROTOCOL NO.: 454, Edition S
V. STUDY DATES: A. Initiation Date: February 24, 1993 B. Experimental Start Date: March 2, 1993 C. Experimental Termination Date: March 30, 1993
VI. SUPERVISORY PERSONNEL: A. Study Director: Hemalatha Murli, Ph.D. B. Laboratory Supervisor: Jos Arriaga, B.S.
VII. OBJECTIVE: Tteheresytthorbaojrcteyiccttleiesv,e ofo1f-5S7tp1hr0ia,sgueitn-oDaviwinlvdeouyceasrsmaatiysc.rwoansuTchlitesoiesvitanulduybaotwneeasmtahcerornaodbuwicltpieotdlyycuhosfrionmgtahteic modifications of the procedures suggested by Heddle et al. (1983).
15516-0454
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@ HAZLETON WASHINGTON vrs. verse: was maintained at 71.8 to 80.2F for Trial I and at 7246F for Trial IT
CO1279
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Dosing Scheme for Trial I of the Micronucleus Assay
4 total of 126 animals was used in this assay.
Number of Animals Assigned
Primary Dose Groups SecoGnrdoaurpys*Dose 26 Br 48 Hr 72 Hr
Treatment
M FM FM F Male Female ----
17-5720 1250 mg/kg 2500 mg/kg 5000 mg/kg
s 5 5s 5s 5S - ss 5 5 55 - -
ss 5s 5 5 5 8 8
Vehicle Control, Corn oil 20ml/kg
ss.
-
-=
-
-
Positive
Control, 60mg/kg
Cyclophosp5ha0midse .
-
-=
-
-
ee
+
Tohnelyanuismeadlstoasrseipglnaecde
atnoimtahles swehciocndhardyieddosien
groups were the primary
ddoosseedgranodupwearte the
hciugthhandaotseizeldevealt. theALLcomepxltreatiosnnimoaflsthenottriuasle.d as replacements were
The age of the animals at the time of dosing was =8 weeks.
Vboalsuemdesupodnoseidndwievriedua2l0
ml/kg (except for animal weights.
the The
positive positive
controls) and were control animals
were dosed at 10 ml/kg.
Animal Observations
ApLeLriaondiimcaallslywetrherouogbhseoruvtedtheimmdeudriaattioenlyofafttehre adsossaiyngfoarndtoxic
psoysmipttiovmes
acnodn/torrolmogrrtoaulpistiaepsp.eareAdLLnoernimmaallsaftienr tdheosivenhgicalned
and remained
hdeoasletdhygrouuntpisl aptpheearapepdronporrimaatle ihmamrevdeisatteltyimeasf.terAlalndteasptproarxtiimcalteely &
hours after dosing.
15516-0-454
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Dosing Scheme for Trial II of the Micronucleus Assay A total of 130 animals was used in this assay.
Number of Animals Assigned
. Treatment ee
Primary Dose Groups SecoGndraoruypsDose 24 Be 48 Be 72 HE M FM FM F Male Female
17-5710 312.5 mg/kg, 625.0mg/kg 1250 mele
ss ss 5s - ss ss 55 - -
ss ss 5s 5s 10 10
vehicle 1Co0ntrmoll/,kgCorn oil ss. o- = - - -
Positive C6o0ntmrgo/lk,g Cyclophosp5h0em5ide - - = = - -
----
+ Thohnielgyhanduisomesadelsltoeavesrlse.ipglnaecAdeLLatnoeixmttarhlaessawnehicimocanhldsardyineodtdosiuensedgtrhoeausppsrriewmpealrraeycemddeoonssetesdgawrneodruepweartethe cuthanatized at the completion of the trial. The age of the animals at the time of dosing vas =8 weeks. Volumes dosed were 10 ml/kg and were based upon individual animal weights.
nina) Observations ApSLeyLrmipoatdoniniscnaallaslnydw/eotrrhermooourbgtshaeolruivtteidtehsei.mmdeuAdrLiaaLttieoalnnyimofaalfsttehreindaostsshieanygvefhaorincdlteoxiacnd Ppoesailttihvyeunctoinltrotlhegraopupprsopraipapteearehdarvnoersmtaltimaefst.er dALoLsintgestandartriecmlaeined dosed groups appeared normal immediately after dosing.
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A6p55p.r0o,ximaantdel1y2505 mhogu/rksg daofsteergrdoosuipnsg,inacllludainnigmatlhse sfreocmondtahery31d2o.s5e,
group were ataxic.
a1p5p5roxmigm/aktgeldyose23 ahnodur2s4 remaining animals from
ahofutrerhadorsviensgt, gr1omuapleapp(e#a6r5e57d) lafnrgoumidt.he All the 1250 mg/kg dose group including the
Secondary 2nd 625.0
mdogs/ekggdroosuep
garpopuepasredappateaaxriecd. norAmLaLlanaitmatlhsis frtiomme.the
312.5
A1ap3t2pa0xriocmx.gi/mkagtAellldyosae4n7imgahrloosuurpsfirnaofcmtleutrdhiendgo3s1i2tn.hg5e, asnaeldclon6da2an5ri.y0maldmsogs/ekfgrgordnoosutepheagprpoeuaprsed
appeared normal at this time.
Adgproposruepo)xainmdwaetr7ee2lyhfoou7ur1ndhhoaduerravsde.staftgAerLroLupdrsoesmia#ni6g4n,5i4ng2 fmraaonlmiemsatlhse(#6sf4re8oc1mo,ndtah1re2y5012dm5og0s/ekmgg/kg
oALsLe angirmouapls infcrloumditnhge
t3h1e2.5secaondnda6r2y5.0dosmeg/kggroudposeappgeraoruepds
ataxic. appeared
normal at this time.
X. BONE MARROW HARVEST, SLIDE PREPARATION AND ANALYSIS:
AaTtnhde tmhteaherarpoapwdrhoveparrsiinagatsepsoihfrtaartvetedisstsfuretoimmaent,dheethpbeiopnehaynsiamenasdlsmoifwxeebrdoethienuttaihbiasanyeartiwinezgreeedwwiritethmhoveCdO.;
lVPoalcya1c-'eGmdrlunofwneatlsadllidsceoasllufatnisdoenrauifmro-ltdloroiwefedod,rmbyfaiGxsieuedsmpsieannsm(ieSotcnhh.amniodlT,,he1e9cn7e5dl)l.sstavTiehnreeedatiihnre-ndried
slides were coverslipped using Depex mounting medium.
Tf(hoPecCEo)rcdodteotdhnesoselrimdodeacsthar.woemraetOincethet(nhNCoEus)scaoncrdeedllPfCoErrsatimpoie.crroannSuitcmalaneldiarwdearnedfortsmhcseorewpdeo.rleychuTrshoeedmafttrioec
qneuolerlnmscayl baoffsreemdqiuceornnocnytuhceolfetamotiteacdlroncBuCecElsllseipwraeissnenettxhpisriensrstaethde satssrcaoiprneedrcieosnpttaibcmoiuctfrioe0ln.du0.c-l0e.sT4th.eed
Tohfe BCfErsequanedncyNCEosf
PoCbEsservveerdsuisn
NtChEes owpatsic deftieerlmdsinwehdilbey
scoring scoring
the the
number first
1000 erythrocytes.
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XII. RESULTS AND INTERPRETATION:
uhceletaetsetdarptoilcylceh,romTa-t57i1c0,eryitnhdurcoecdytenso Tehicle controls in either sex or at
osviegrniftihecanlteveilnscreoabsseesrveidn miincrtoh-e any of the harvest times. The
Bp0oEssitiivne bcootnhtrsoelx,es,CP,witihndumceeadns siagndnifsitcaanndtardinecrrreaosress ofin4m.i6c4Iron#uc0l.e6a4t1edand
s3.u1m2m7arize0d.70b1y dfoorsetgheroumapleasreanpdresfeemnatleeds,inrTeasbpleecti1vealnyd. indThievidduataal animal
data are found in Tables 2 through 4.
XITI. CONCLUSION: mTihcerotneusctlemiateirniablo,neTm-a57r1r0o,w pdiodlycnhotromiantdiucceearytshirgonciyftiecsantundienrcretahsee in mCaornrdiotwiomniscroonfuctlheiussastsesaty. and is considered negative in the rat bone
XIV. REFERENCES: HNeedwdellel,, GJ..WA..,, Haintde,SaMl.a,monKei,rkhMa.rFe.,: B.T,heLairnsdeunc,tiKo.n, oMfacmGircergoonru,cleJi.T.a.s a measure of genotoxicity. Mutation Res., 123:61-118, 1983. Schmid, W.: The micronucleus test. Mutation Res., 31:9-15, 1975. CSchhemmiidc,alW.M:utagTehnes:micrPorniunccliepulsesteasntd MfeorthocdystogfeornetTihceiranaDleytseicst.ion,In,Vol. & (A. Hollander, ed.). Plenum, pp. 31-53, 1976. Sokal, R.R. and Rohlf, J.J.: Biometry, Freeman, 1981.
XV. DEVIATION FROM THE SIGNED PROTOCOL: The following deviation was made from the protocol. mTthieeccrhontnieucmcaplleeruadstiufrfaeiscsauvylatsiaemnsadinnaotttaitnmheeadinatnaatiimna7le1d.8faatctiol7i82t0#y6..2F.F ThfiTosrhisTsrlwiiaagslht dIudeeofvitoathteion 41d not affect the animals in any way.
15516-0-454,
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01287
@ HWAASZHLIENGTTOONN
01288
J--
MICRONIGLEDS DAT SVARY TABLE
<T
>
z
E sseeotnesons20371scorporation
mm
test ATIOLE: 15720 oN
Tamme
H=- Y
Toom n Twn E reIT nEt e wm emems wwew |T| WmRm mntmes 222
gsaww 10mig
un 0a2k0.08 0.1240.00 0a240.03 jomson 0.39 0.05
TE POSITIVECONTROL 60 gli. a awetosw 2200 -- | Jmsose | omsoo 0.42 20.08
meas
@ omeom Sams 6 oom
omioe O0S0K
02i0m | 0maew 000m | OEom
oso 08400
7 oooh 0.12 0.04 1320.03 || 0720.08 0.490.09
o omiom asomiy oro
omsow omiom
omsos | osioes omioi 0a208s | 0miol 03:00
n
o
Mo0em16i%0om.0m7 e0m .o2m4ss0.v0e5
ee 01420.00
omio;
| 0.74008
| omioss
marsn on
oseos
oLon m 8u w0t.mm00i2e0t.n0m2 we0.e0e4o2s0no.0w2 wo0.em04e4n0o.0nm2 lj|ooammeigoons 024s7ms02.e06n
5B2 o.w
WASHINGTON
.
TABLE 2
MICRONUCLEUS TEST - INDIVIDUAL ANTMAL DATA
SPONSOR: 3 Corporation
TEST ARTICLE: T-5710
ASSAY NO.: 15516
MALES
1
FRUALES
TREATVENT
ANDAL
Wo. BCBS
RATIO |
NMBER (1000) PCE:NCE |
--
To. ANNMDBWELR (C10E0s0)
V(e2h4ichloeurChoanttvroelst)
477 sua
6508
1 13
00..7686
| |
64667867
0.99} 6497
1 2 o
66550283
1
01.0682 || 66553292
1 2
P(o2s4ithiovuer hCoanrtvreoslt) 66551072
36 Ww
66552546
2 65
6582 55
00..6792
1 1
66447627
20 15
00..4688
| |
66542779
5 26
0.95} 6578 ww
T(e24sthAorutrichlaervest) 66552286 312.5 ng/kg 6561
o 2 1
00..699
|
6654182
0.48 | 6536
2 2 1
66556619
2 1
00m7} 66558742
1
625.0 mg/kg,
6s4u6s2
0
00..6748
| |
66553010
3 o
6s4i7s31 6571
2 o 2
00..4759}1 66556678 0.64 | 6583
13
1250 rgfig 65654660.
13
00..5689 1 6s5u5s8e
1 2
66555770
1 o
00..3692
|
66557775
0 2
6579
2
0.62} 6580
1
MPNCE==MiPcorloyncuhcrloemuastic erythrocyte
No. NCE
M=NNoPCrEmsoch=roMmiactriocnucelreyattherdocPyOtEes
BRCAET:INOCE
00..5382 00..4321 0.31 00..4398 00..323 0.68 00..6625 00..5410 0.67 00..4112 00..3602 05 00..9285 00..5679 oz
15516-0-454
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TABLE 3
MICRONUCLEUS TEST - INDIVIDUAL ANIMAL DATA
SPONSOR: 3M Corporation
TEST ARTICLE: T-5710
ASSAY NO.: 15516 TREATMENT T(e4s8thAorurtichlaervest) 312.5 ng/kg
J HALETSo, WY t1SN FRuLWEoS. M
DNRABELR (C10E0s0) PRCAETNICOE || ANNMDBAELR (C10E0s0) FRCAET:INOCE
= s6u4s8k 1o
00..6203 | ee511931
20
00..4470
6e5s5e9 e573
1 1
00..7802 1| 6e5s5ts0 0.69 | 551
2 1
00..6676 0.80
625.0 malig su7s0? ego
o1 5
00..6303 | 6su4e9s
0.80
6532
0 3
00..2346 0.67
66039695 o2 00..7369 | o6s5u2 1o 00..6588
1250 mg/kg eeess 6is6
1
00..6180 1{ s65s0s5 0.20 6500
o1
00..2128 0.31
66551483 1 ovoez |i 6ss5622 1 00..589
MBNyoC.E=M=mNiPcoPrCloEynscuhcr=loemMuaistcirconuecrlyetahtroecdytPeCEs NCE = Normochromatic erythrocyte
15516-0-454
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.
TABLE 4
MICRONUCLEUS TEST - INDIVIDUAL ANIMAL DATA
SPONSOR: 3M Corporation
TEST ARTICLE: T-5710
ASSAY NO.: 15516 TREATVENT
MALES
1
FEMALES
Aa NTAL F(OP1.C0E0sM0W) PRCAET:INOCE 11}| ANMMTBMEARL w(oP1.C0E0Ms0N) PRCAET:INOCE
NRMBER
H
T(e7s2thoAurrtichlaervest)
6456 6503
2 1
0.7} 6463
0.66 1
6489 6490
1
0.67
2 2
0.31 0.35
312.5 ng/kg 65653643 6581
2 2 0
00..5808}| 6507
0.9 1
6565
1 0
0.37 0.73
625.0 mg/kg.
6465 6468
2 "
0.58 1.00
6455 6485
0.58 |
6498
1 3 1
0.83 0.29 0.43
6513 6545 6574
1 1
0.65 1 0.89}
6524 6533
0 1
0.22 0.27
1250 mg/kg
6s4u5i2s
2 2
0.46 } 0k
6495 6519
0.54 | 6548
o 0
1.00 0.40 0.20
6492 6529 6564
2 3 2
0.53} 0.68
6555 6585
1 1
0.55 0.43
MPNCE= =MiPcorloyncuhcrloemuastic erythrocyte
No. NCE
M=N NoPCrEmsoch=rMoimcartoincucelreyattherdocyPtCEes
15516-0-454
25 C0192