Document RpVBzqm1rKBm8N9DKbvNeQYO7
REPORT AE2201779
Stuy Tie ASSESSMENT OF ACUTE ORAL TOXICITY WITH
T7868 IN THE RAT (ACUTE TOXIC CLASS METHOD)
Author
Ors Ms. Teurissen
Studycompletioncate
20 April 2004
Tost Facy HambNaorToOmwXeBloVing 7 5231 hDeb &NHeetrhoagoenndgsosch
LaboratoryProjectIdentification
NONTOOTXOSXubPsrtojienccte318595290805A page tars -
3
T7868
NOTOX Project 389598
1. CONTENTS
21., SQTOANTTEEMNEYNSTo OF GLP Cy OMPLIAs NCE...t L er y s dn
3. QUALITY ASSURANCE STATEMENT...
rm
8
5. INTRODUCTION... orcs
atn--
--
55..32.. AGIUMISGOEIFItNhEESSA..Y..........c mnomes res ------ ------7
6. M5A.4T.EStRoIraAgLeSaAnNdDrMEeTlHOoeDfrSne.coi.rd.osannd Malerials................... m----"
61. T6.E1.S1L.SUTDeSsItASNUCBESIAN.G.E......c. ccoomnscn
rr--------------.--d
62. 6T.e1s.t2,SyTsesttemsu.b..s.t.a..n.c.e..p..reparation en------------------------
nndD
66..43.. AStnuidmyaldehsuisgbn.andry rrem------------------------
m---- ie
66..56.. TOrbesaelrmveantti.o.n..s........c..ooom- ---- r-------- ------------r"10
66.78.. LInteiOrfprPesrtoaItOtiCoDnI GVI..A..UONS...r.rvrrmormemvr----------rmmr--n----y
77..12..MColritnailciatlySi(Tganbsle(T1a)ble..2..)...... ovensne--------------------
11 1
77..43.. BMoadcyi0Wseciopgihct (FITnGaibngl3S)e(Ta.b.l_e.4_)_..__..._........................cn. emmA------ |
8 CONCLUSION...
wm----------
11
Tables
TTAABLBEL12E::CMLOIRNTIACLAILTSYIGNDSA..T.A
sp --
TTAABBLLEE 43:: MBOADCYRWOESICGOPHITCSF(GIRANM)D.I..N..G..S.... ress
ntmwmn--t m--------.4
lt
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Tras
NOTOX Project 389598
:
"2. STATEMENT OF GLP `COMPLIANCE
NOTOX B.'s Herogenbosch, The Netheriands
The study described inthis report has been correctly reported and was conducted in compliance
with:
>
The Organization for Economic Cooperation and Development (OECD) Good Labaratory
Practice Guidelines (1997).
Wich essentially conform 0
The Uni Sates Food and Drug Administaton Good Laboratory Pracice Regulations.
The Unie States Environmental Protsction Agency Good Laboratory Practice Regulations.
NOTOXBY.
OSrtsu.dyMsDi,reTcetournissen
DWiJvoAtMor.ofFTidoixnigloDgVyM
md
LD.
Date: ..20... 20M. 20Y................. Date: a1. lpnad REQA,
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NOTOX Project 389598
3. QUALITY ASSURANCE STATEMENT
NOTOX B.V., 's-Hertogenbosch, The Netherlands
"Tris report was inspected by the NOTOX Qualify Assurance Unit to confirm that the methods:
and results accurately and Completely reflect the raw data.
iTDnuhsrepiendcgattteehdse oofn-QsuiatleitpyroAcsessusrainnscpeecitnisopnesctpirooncseadrueregsivaepnplbielcoawb.le to this type of study were
inTsyppeectoifons.
OnPsroittoceol(P(rSotcuedsys)) Report (study)
Phase/Section PSaPtFhoUlnoigty
SItnasrptection
date(s)
O277UAUULGOO3S 0111DAEUCGOO33
EInndspection
date(s)
2117JAUULG0E3S O2051ADUEGCEO3S
Roporting date 1257.A4UUGL0O3S 0215DAEUCG0033
CH.eIaMdiocfhQeulalBi.tSycA.ssurance
a. {1 Gplsebd
outer Loy. au eh,
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NOTOX Project 389598
4. SUMMARY
`Assessment of acute oral toxicity with T-7868 in the rat (Acute Toxic Class Method).
T`ThoexisctuCdlayswsaMsetchaordr"i,edOoEutCDBaNsoed4o2n3 t(h1e99g6u)i;de"lAicnuetsedOersaclriTboxeidciitn:y';"AEcuCteCoTomxmiicislsyi-OornalD,irAeccuttieve `SG6uIiSd4e/lEiCne,sPOarPtP8T.S1 t8i7s0(.11919060);(1E9n9v6i)r,o"nAmceunttealOrParlotTecotixoniAc-gAiecntuctyye(TEoPxAi):c CHleaaslsthMeEtfhfeocdt"s aTensdt JMAFF Japanese test guidelines (2000).
Ibnoitdiyallwye,iTg-h7.86I8n waassteapdwmiisneisptreorceeddubryeoardaldigtaiovnaaglegtrooutphsreoeffaenmiamlaelsWiwsetraer draotsseadta2t020000m(gmkalges daentderfmeimnaalteiso)nmogf kbogdybowdeiygwheti.ghMta.crAlolsacnoipmiaclesxwaemrineastuibojnewctaesd ptoerdfaoilrymeodbsoenrvtahteiodnasyaonfddewaetehkloyr after terminal sacrifice (day 15).
`ocTcwuorfreemda.les dosed at 2000 mg/kg were found dead on days 1or2. No further mortality AuLnc2o0o0r0dimnagtkegd mtohevefmeemnatless, sflhatowgaetd,lsehtahlarlgoyw,rveesnptirroa-tliaotne,rpaillroeerceucmtbioenncayn,d hsualnicvhateidonpbosettuwree,en dmaoyvsem1eanntsd,4.piAote2re0c0timogn/kagndtohre fpetomsailseosnshdaoywsed1 laentdha2r.gyT,whounmcahleeds psohsotwureed, huuncnocohreddinpaostteudre. immediately after treatment only. b`Tehenobromadly,weight gain shown by the remaining animals over the study period was considered to dMiasctreonsdceodpwiicthpogsatsmaonrdtedmarekxarmedindaitisocnoolfoounreaoatnfiitmohaenl tmhuactoswaa.s fMoaucnrdosdceoapdicrepvoesatlemdoratsetmomach examinationof the remaining animals did not reveal any test substance related abnormalities.
``TmhgeikograbloLdDyggweviaglhute of T-7868 in Wistar rats was established to be within the range of 200-2000 rBeaqsueidreomnentthsesfeorrdesaunlgtesraonudsascucbosrtdainncgetsoatnhde pErCecprairtaetriioanfsor(CcolausnsciiflicDaitrieocntaivned6l7a/bSel4l8i/nEgEC), T-7868 should be labelled as: harmfulifswallowed (R22). - wAictchoirnd3i0n0g-t2o0t0h0emOgE/CkgDb4o2d3ytweesitgghu.ideline, the LDS0 cutoff values were considered to be. - AHcaczoarrddinClgastositfhiecasteioLnDSSyOsctuetmoffforvaHluumesananHdeablatsheadnodnEtnhveirOoEnmCeDntHaalrEmfofnecitzsedofICnhteemgriactaeld
oSruablsrtoauntec.es (OECD, 1998), T-7868 should be classified n Class 4 for acule toxicity by the
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T7868
5. INTRODUCTION
51. Preface
Sponsor
~
Study Monitor
Test Faciity
NOTOX Project 389598
3BuMilCdeinngte2r34-18-10 SUTS.AP.AUL, MINNESOTA 55144
3OrM. PCHor,poLriaetdeerToxicology
3P.MO.CeBnotxer3,3B2u2i0lding 220-202
ST. PAUL, USA.
MINNESOTA
55133-3220
HNaOmTbOaXkBe.nVwe.tering 7 5T2h3e1NeDtDhe'rsl-aHnedrstogenbosch
Study Director Study Plan
Drs. M.S. Teunissen StCaormptletion: + 3100 SSeepptteemmbbeerr 22000033
5.2. Aims of the study
a"Tshienogbljeecdtoisvee toof rtahtissosftbuodtyhwassexteosaastsoesnse tohremtoorxiecidteyfoifnetdhedtoessatgsesu.bstFaurntcheewrmhoerne,adtmhienriesstuelrtesdofin
the study currently
ianlulsoew.ed
the
test
substance
to
be
ranked
according
to
most
classification
systems,
TThhiesosrtauldryosutheouwladsprsoevliedcetead raastiiotniaslabapsoisssifbolrerrisokutaessofeshsummeannt einxpmoasnu.re during manufacture,
handiing or use of the test substance.
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NOTOX Project 389598
53. Guidelines
Aasgrreeqeudibryedtbhye AtrhtieclDeut1c4-hfuAnccttoionnAarnyimaanldEtxhpeerEitmhiecnatlatCioomnm,itthteeestoufdyNpOrTotOoXcol(DwEaCs rNeOvTieOwXed6a7-n0d3p1r4)ocaesdurreequsidreedscbryibtehdeDiun tthcihsArceptorotnwAenriemablasEexdpeornimtehnetaftoliloonwi(nFgebgruuidaerlyin1e9s9:7).Thestudy T`OersgtainnigsaotfiCohnefmoircEaclos,noSmeicctiCoon-4o,peHreaatlitohnEaffnedctsD.evNeol.o4p2m3e,n"tAc(uOtEeCODr)a,lOToExCicDityGu-iAdceultieneTsoxfiocr: Class Method", Paris Cedex, 1996. EDeutreorpmeiannatCioonmomfunTioxtiyci(tEy,C)a,sCloausntcaimleDnirdeecdtibvey6C7o/mSm4i8s/sEiECo,n ADinrneectxivVe,9P6a/r5t4B/,ECM,etAhnondesxfIoVr tBh,eB.1 rCiosm:m"uAnciuttieeTsoxNioc.itLy 2(O4r8a,l)19-9A6c.ute Toxic Class Method". Official Journalofthe European 8Un7i0t.e1d10S0t,atAecsutEenvOirraolnmToexnitciatly.PrOoftfeiccteioofnPArgeevennctyio(nE,PAP)e.stHiecaildtehs EafnfdecTtosxTiecsStuGbusitdaelnicneess,(7O1P01P)T,S EJaPpAan7e1s2e-CM-i9n6i-s1t9ry0,ofJAugnreicu1l9t9u6r.e, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000, incuding the most recent partial revisions. 5.4. Storage and retentionofrecords and materials. SRpeeccoirmdesnasnrdeqmuaitreirnigalrsefpreirgteariantiionng otro ftrheeezsitnugd)yainndcltudhienfginparlotroecpoolr,t raarewrdeattaa,insedpeicnitmheenNsO(TexOcXept arScphoinvseosrfwoirl abepecroinotdaocftaetd tloeadsett1e0rmyienaerwshaefttehrefrinraalwizadtaitoan aofndthsepreecpoirmte.nAsftsehrotuhlsd pbeeriroedt,urtnheed to them, retained or destroyed on their behalf. TthheosqueasltpyecoifmtehnessrpeeqcuiirmienngsrepferrimgietrsateivoanloufatfiroenezbiuntgnwoillbonegerrettahiannedtbhryeeNOmoTnOtXhsfoarftaesr flionnagliazsation of the report. NafOteTrOfiXnawliizlatrieotnaionfathteesrtepsourbt,stAafntecretshiasmppelreioundtitlhethseaemxpplierywdialteb,ebduetstnrooyleodn.ger than 10 years
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NOTOX Project 389598
6. MATERIALS AND METHODS
6.1. Test Substance 6.1.1. Test Substance
The sponsor is responsible for al test substance data unless determined by NOTOX.
IdMeonlteicfuilcaatriofnormula DeMsoclreicputlaironweight BaCotmcphosition Test substance storage EStxapbiirlytydautneder storage conditions SSpteacbiifliyc iGnravveihtiycle W1a%teArq. Carboxymethyl cellulose. CPormopoylene glycol MPeotlhyyeltheytlheynlekgeltyocnoel EtDhimaentohlyl sulphoxide AOcleivteonoiel Dimethyl formamide
T7868 3Li4g6ht yellow hazy liquid Lott A7t8r%oo(m22te%mpweartaetru)re in the dark S0t7abNloevember 2005 14 ANtolteiansdtic9a6tehd NNoott iinnddiiccaatteedd NNoott iinnddiiccaatteedd NNoott iinnddiiccaatteedd NNoott iinnddiiccaatteedd Not indicated
6.1.2. Tost substance preparation
Preparation 62. Test System
"The test substance was dosed undiluted as delivered by the. sponsor.
Species :
Number of animals `Age and body weight Identification
Rat, Wistar strain Crl(Wi) BR (outbred, SPF-Quality). Recognised bOyECinDt,ernEaCt)i.onal guidelines as the recommended test system (e.0. 9`SAounricmea:lsC.haEralcehs dRiovseergDreouutspcchloannsdi,steSdulozffe3lda,niGmearlmsanoyf.one sex (females werenulliparous and non-pregnant). Young adult animals (approx. 8 weeks old) were selected. Body Ewaerimgahrtkv.ariation did not exceed +- 20%of the sex mean.
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NOTOX Project 389588
.
63. Animal husbandry
ACnonidmiatlisonwsere housed ina controled environmen, in which optimal conditions were considered 212b8eCap)p,roaxirmealtaetilvye 1h5umaiidricthyaonfg3e0s-p7e0r%h(oaucrt,uaaltreamnpgeer:a3tu4r-eo7f3%2)1.a0nd 31.20hCou(rasctauratlircaanlge: 18.5 Cfllueoarneisncgenptrloicgehtduarneds1i2 thhoeurrsoodmarmkingehstshpaevredacya.used the temporary fluctuations above the folputcitmuaaltimoansxwiemruemcloenvseildoefr7ed0%notfortorehlaavtieveafhfuemcitdeidtyt.heBastsueddyoinntelgarbioyr.atory historical data, these.
AGcrcooumpmhooduastiinognof3 animals persexper cage in labelled Macrolon cages (type IV; height 18 Ccemr)iccoantteasionifnagnpaulriyfsisedwsearwedeusxtamaisnebdedadnidngtmhaetnerrieallai(nSeAdWiIn,thJeelNuOWTerOkX, aRrocsheinvbeesr.g, Germany) Acclimatisation period was al least 5 days before start of treatment under laboratory conditions.
DFireete access 1 standard pelleted laboratory animal diet (fom Alromin (code VRE 1), Lage, Germany). Ceticofaantaleysiss were examined and then retained in the NOTOX archives.
WFareteeraccess to tap-waler. Certificates of quarterly analysis were examined and then retained in the NOTOX archives.
64. Study design
"TThhee ftiorxsitcgitryooufptwhaestetsrtesautebdstaatnacedowsaeslaevsesleosfse2d00b0ymsgt/ekpwgbisoedytrweeaitgmhetn.t Tofhegraobuspesnocfe3oarnimals. pprroecseednucreeodfemfoirnteadlliyntohfeagnuiimdaellisnedso.seTdheatoonsneet,stdeupradteitoenramnindesdetvheerlnyexotf sttheep,sibgansseodf otonxitchiteytest were taken into accountfo determination of th time interval between the dose Groups.
65. Treatment
aAnhiemaalltshwienrspeeicntiaongowoadsspteatrefoorfmheedalptrhior to commencement of treatment, to ensure that the
Method
Oral gavage, using a stainless steel stomach tube.
Fasting
dFoosoidngwaunstiwi3t-h4hehlodurosvearfntigrhatdfmionarisimraaxtoinmuofmtohfe 2te0sthosuurbss)tapnrcieor.to
Froquency
Single dosage, on day 1.
Dose level (volume)
2200000mgmlgkkgg(0(.11.443mimlikkgg))bbodoydywewiegihgth.t. Dose volume calculated as dose level : specifc graviy.
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T-7868
NOTOX Project 389598
ss. omsenvtons
Morais
JToudiecdil. Th timof death was recorded as redily as
Body weights
Giricat srs
ora Days 1 (pre-administration), 8 and 15 and at death (if found dead raAtepaetr3ei0r0o,6dssenarlna52ol7 1om5n.etThoafdasaryyaomshfp.tdogomsrisnogwsa(rdaaryfa1a)dveandodananrwcoeirdenay0 NTNeaicimmmoo agrrdasde3:. proaddoig ssiiggnh ((11)1o0vservseov(e9re ()
Maximum grade 1: presence is scored (1).
Neary
ToSfhiesmesspuhrsiisnetgosnosuhooergnheds oSof yhhe ewcebresearnavaciGoenatspearsiordrowamessrp.syaaAcnlrded
Senaions 3al rl arscsses somarraties rend.
67. Intorprtation
Toe201.200400smvkolsebotf.hotf 3t5 xscuobesdtnagn3w0a0s0rmaakkeadownith thlowing ranges: 025, 25200
No statistical analysis was performed (The method used is not intended to allow the calculation
of a precise LD, value).
TCEhiaecnra.etsuTos5n%wS0eyrmosieevmmalauoa2tt6erdcaocvnosrdHionorgdsactnhedaOEEnnCtDoarHnnaremlnoianinSzegedcogsfrsoaafnthsetoseusHrazuabrSaduobrsteannsceosrd SapeanritmoannesCofoomsetriasccoiSnSSeSEECatFllpuoranoofvseEtroemroCsoemsmaunni) 63. Listof protocol deviations No protocol dovainswere made during is pre.
"page t0-
7-7
7.7868
NOTOX Project 383598
7. RESULTS
7A. Mortality (Table 1)
TDhoeseinlceviedlence of mortalitMyowrtaasitays follows, preseSnteexd in chronological oderDaotfetorfeavtemaetnmtent
2200000mmghgkkgg
233
fofemmaalleess
1102 SSeepptteemmbbeerr 22000033
200 mghkg
os
males.
16 September 2003
The decedents were found on days 1 or 2
72. Clinical Signs (Table 2)
DCioisceallevseilgns observed dCulriinnicgalthsesigtnusdyperiod were as follows 2000 mg/kg (females) ~ Lmeotvheamrgeyn,tsv,enftlraot-gaatie,raslharlelcouwmrbeesnpcirya,tihoun,ncphlecedrepcotsitournea,nudnlcoorosradliinvaattieodn 200 mg (females) aLentdhlaorrgpy,oshusnched posture, uncoordinated movements, pierection, 200 mg/kg (males) ~~ Hunched posture.
`The surviving animals had recovered from the symptoms by between days 1 and 5.
7.3. Body Weight (Table 3)
b`Tehesibmoildayrwteoitghhatt egaxipnecstheodwonfbnyortmhaelsuurnviirveiantgedanainmiamlaslsovoefrtthheessatmudeyapgeeriaonddwsatsracinonsidered to
7.4. Macroscopic Findings (Table 4)
Aditsmcoalcoruorsactoiopnicofptohset gmloarntduelmarexmaumcionastaiownasa fsotuonmdacinhodniestaennidmeadlwtihtahtgdaisedadnudridnagrkthreedstudy. aMnaicmraolsscoaptitceremxianmaitniaontidoindonfothreevoetahlerananyifmeaslt sthuabtsitaendcedurreilnagtetdheabsntourdmyalaintideso.f the surviving
Severe autolysis was noted in one animal that died during the study.
8. CONCLUSION ``TmhoekograbloLdDyswoeviaglhut.e of T-7868 in Wistar rats was established to be within the range of 200-2000 Breaqsueidreomnentthsesfeorrdeasunlgtesraonudsascucbosrtdainncgeos atnhde pErCepcarritaetriiaonfsor(cCloausnsicfiicDaitrieocntaivned6l7a/b5el4l8i/nEgEC), T7868 should be labelled as: harmil f swallowed (R22). - wAictchoirnd3i0ng0-f2o0t0h0emOgE/CkgDb4o2d3ytweesitgghu.ideline, the LDSO cut-off values were considered to be: - AHcaczoarrddinClgastositfhiecasteioLnDSSyOsctuetmofforvaHluumesananHdeablatsheadnodnEtnhveirOoEnmCeDntHaalrEmfofnecitzseodfICnhteemgriactaeld
`orSaulbsrtouatnec.es (OECD, 198), T-7868 should be classified in Class 4 for~acute toxicity by the
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NOTOX Project 339598
TABLE 1: MORTALITY DATA
I TESTORo Y wRSE0R 121.T 1423RC 4E 56C 7N 8C 0M 9 C 0 E F2 N Ts CT
FFEEMMAALLEESS2200000GMIGIGKG.. MALES 200 MGS
r er[l ERe i G cel r T 4 l a
TABLE 2: CLINICAL SIGNS
HOTEUSRTSOAAFYTER TREATMENT _--
Max 012141234587809 0nREMS ome
BAFeENrMIAAMvLAiELo1SR2000 MGIKG.
LPEVOETSNHTTUARRROEGLYATERAL RECUMBENCY
@ ae @ re
BHREUANTCHHIENDG.POSTURE
EE
ASNHIAMLALL2OW RESPIRATION
@1
LBPEEOTHSAHTVAUIRROEGRY
@ -a3e
VBERHENUATNTCRHHOIENLGDA.TPEORSATULRREECUMBENCY
W[LEtIre
SSHAKLFLUOIRW RPELNSUPMIRA/AGTEION
@ -1ae
S"PSIAELLOVECARTERICOTE/NIEOTXNCIREOTINON
m ae @ 1.
BAENHIAMVAILOSR
PLOESTTHUARREGY
B) streerettaatecena
G`HUUNNCA/COMOHORTETDIDILNITPATOYTS.ETDURMEOVEMENTS
MTree @ cfrrrrerscrnrcnas
SKFILNATFGUART) PLUMAGE
Barri:
PILOERECTION
Wh +4 Vhs sssanttenma
AFENMIAMLAEL&S 200 GIG.
LPBEOETSHAHTVUAIRROEGRY
B ~trrrerissrnncnna
SKHIUNN/CFHUERD)PPOLSUTMUARGEE
MD 1 ee
-= PSIILGOENRNECOTTIOOBNSERVED|. = OBSERVATION NOT PWERFa ORMt ED+ =e ANIMAL DEAD
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7.7868 TABLE 2: CLINICAL SIGNS.
NOTOX Project 389598
HTEOSUTRDSAAYFTER TREATMENT
wx 01214123458789 0NRBRS
T ewess
FANEIMMAALLE'SS200MGIKG LBEETHHAVAIROGRY GPAHOTUSTNTCUHMREoEDTLPUOTSYTURE SUNKCOIORNDI/IPNLAFUTMEUADGMREO.VEMENTS PABIENLHIOAMEVRAIEOL&CRTION PLOESTTHUARREGY SHUNKCFHUEIRD PPLNOSUTMUA/RGEE VPAIRLIOOEURSECTION `Prosi
@ hee eee @ eee @ tee Meee
@ tee M4 Mc tee @ hee
MAPONSMATAULR2LTE00EMGSI
NAOHNUCILNMICANHLIESCDALPSOISGTNUSRNEOTED.
Meee tettre restates
APNOISMTAULRSE HUNCHED POSTURE
@ 4 eee
SIGNNOTO3SERVE/D.=OBSERVATION NOT PERFORMED/ + =ANMAL DEAD
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TABLE 3: BODY WEIGHTS (GRAM)
sExosE LeveL FEMALES 2000 HGIKG.
FEMALES 200 MGIKG
MALES 200 MOG
animal found dead on day 2.
Anna z13 SwTeoeav. N 5s 5 STeNoaEvn. 57 s NeSTaoEV.
NOTOX Project 389598
Avi OAY2 DAYS Davis
w 18821 ow 20 5
=- =nw fia7s =azw
1e9s9
223 a2m
3
wr ws
3318
[23Ol
2a 3
22023
m ws ma
2
3
32i
w va on m 33
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NOTOX Project 389598
TABLE 4: MACROSCOPIC FINDINGS
AMAL ORGAN
"ENDING.
TFA EMALESa2m00e0nMGIKG. GDaisntedndaedmwuictos0a2s:.discolouration, dark red
2 General chsenvatons Severs susysis
3
No findings noted
4FEMALES 200 MGIKG.
5 5
No findings noted
No. findings noted No findings noted
7MALES 200MGKG 5 s
No ficings noted No fdings noted No. fciogs noted
DAYOF DEATH
SDpooyn1tasneeoruessdemaetns t DSpyon2taafneeoruvsoadteamtesnt SDcahyec1u8aiefdtrnevcoraotpmseynt `aSyche1d5ualfedernevcaraoipmseynt `aSyche1d5ulaefdrnevceraoipmseynt Sacyhe1d5ualefdrnevceraoipmseynt SDcanyeg1u5iaefdrnewceraoupmsaynt SDcahyed1 ulaefdrnewcarmopismya.nt SDcahyed1u5lsehdornevcoraopismya.nt
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