Document YG3KoZ27dkZR91V9oBqDDK7oy
AR 226. 0663
N-EtFOSA
Pharmacokinetic - [
000475
| 2 WISCONSIN TORI8I ISSR NE
Sponsor:
3M
St. Paul, Minnesota
+ CORNING Coram,
FINAL REPORT Study Title:
Single-SDtousdey IonftrTa-v5e9n0o4usinPhRaarbmbaictoskinetic
Author:
Steven H. Glaza
Study Completion Date:
October 14, 1994
Ha33z0l1etoKninsWniasnconBsoiunl,evaIrndc. Madison, Wisconsin $3704 aboratory Project Identification:
HWI 6329-117
Page | of 24
000476
Page 2 of 24
NI 6329-117 QUALITY ASSURANCE STATEMENT TWhiissconrseipno,rt Ihnacs. beiennacrceovrideawnecdebwyitthhethQeualFiotoyd AasndsurDarnucgeAdUaniitnisotfraHtaizolneto(n0A) GfoooldlowLianbgoraitnosrpyectPiroancsticweereRecgoulnadtuicotnesd,an2d1 CfFiRndi5n8g.s35re(pb)ort(e6d) t(o7).theThSetudy Dfiirndeicntgosr aarned miasnsaugeedmetnot.HazlWertiotntemnansatgaetmuesntrempoonrtthslyofacicnosrpdeicntgiontso asntdandard operating procedures.
Inspection Dates
Fron To _____ Phase
0033//0017//9944 0033//0071//9944 PBroodtyocWoelighRteview 0180//2161//9344 0180//2161//9944 DReaptoar/tRepRoer-tRevRieevwiew
RepoDratteed to
StudyDirector
0033//0072//9944 0140//2191//9944
Date
tMoanagement
0064//1100//9944 0151//1100//9964
FRaenpcryeseDniteddtriivceh, Quality Assurance Unit Date [0-14-54
000477
Page 3 of 24
STUDY IDENTIFICATION Single-SDtousdey IonftrTa-v5e9n0o4usinPhRaarbmbaictoskinetic
HHI 6329-117
Test Material Sponsor Sponsor's Representative
Study Director
Study Location StuEdxyperTiimmeenttaablleStart Date
Experimental Termination Date
71-5904
T3Moxicology Services 2St2.0-2PaEu-l0,2 M3NM Ce55n1t4e4r
J3oMhn L. Butenhoff, PhD T22o0x-i2cEo-l0o2gy3MSeCrevnitceers St. Paul, MN 55144 (612) 733-1962
HSatzelveentonM.WiGslcaoznasin, Inc.
MPa.0d.isoBno,x
7545 WI 53707-7545
(608) 241-7292
HBuaizlldeitnogn NWoi.sco3nsin, Inc. M3a8d0i2soPna,ckWeIrs 5A3v7e0n4ue
MMaarrcchh 97), 11999944
000478
MSSattnueadvgyeenrDi.recGtloarza Steven R. Sorenson
Study Coordinator
IPna-tTriifceiaSuPpaedrgvhiasnor RReopsoertM. `SBurpiedrgveisor
Quality Assurance HShaenrgreyrR. W. Petsel
Page 4 of 24 KEY PERSONNEL
: HI 6329-117
SDCuiippneldorymvaiJts.eo,rCaAryL,LApN w
AnatomicalPathology
SDJeuabpcoekrravShiesrofL.rosrtP/irkel Necropsy PASanuntpeheorlvMoiogssyohreDrata
000479
Page 5 of 24
CONTENTS
Quality Assurance Statement
Study Identification Key Personnel Summary Objective Regulatory Compliance Test and Control Material Test System Procedures
Results Discussion Signature Reference
Table 1 Individual Body Weights (g) 2 Individual Clinical Signs
AppPreontdoicxolA Deviations Protocol TP8084.PK
HWI 6329-117
2Page
3 4 6 7 7 7 8
109 n11
1
12 13
11s
16
-_-- 000480
Page 6 of 24
HNI 6329-117
SumHARY
aTdhimsinissttuedryedwasbydoinnetratvoenaosussessinjtehcetiloenveltoorfabsbyisttse.mic exposure of T-5304 when
ff{aepcmnoeay/lgeernHoirucaph:)e.([NDZiOWmn)eStPDhFayy1r0a,Sbublitfthseoxiawdneeirmea(lDasHsSsOir)ge]nceeaditveaadt 10.0, 50.0, or 10
daroassneidnogvmlaeituomienftirovafeve0gn.ro5ousu.mpLs/ikngjeocrtio1 n0.of
0.0 ng of T-5904/kg of body weight.
bf2Gre8aofinohnrioectuahrlestemsaoatfbrtsgmeeiarrntveairtniitaorlnasveandwomeuirsneiscitonrnjaedtcuitcoitonend.(DaatyBoa0dp)yp.rwoexiBiglmhoatotsdelywSearm0sp.l5,edset2,werrm4a,indc2'o4,lljeuasnnryded
Sp{uo4rs8vt-i-hvoiiunnrjgsectapinooisnmt.a-lai.lnjIenecAatlra]idodvnsie)atiminopanlo,eTfsaratwgtheeertevhaoenclieumtnmaielmseofoaftble2o-x,opder4wi-am,sen6to,ablta1it2n-e,erdmianFnadetmi9o4nmabcehre
Afneilmaaultsarsufrrvaicvtiinongs.to t`Thhee TheSshetized with sodium
eanndinaolf tfhoeund48-dhetoarduirfdupugoresidtn-gainndtjheescetspitaourndaytpeewdraisiondmteeccarsceehmneenreannd pentobarbital and exsanguinated wit
Tfhreozebnileto frthoem
Sepaocnhsoarnimaafltersutrevrimviinnagtitoon toefrmtihneatiionn-1wiafse
collechtoeudt phase.
anegcroopes)y.
dAdoodssueeinTilseevtverelasst,,ioahnnydpoofdaecTat-ti5hv9i0t4oyfrteihnseultahteneidnaanilinmatalrsedaetcterrdeeaatsateedtihnaet ft1oh0oed0.0c50o.mn0as./ukamgnpdtdiuoocneoatJnograd/l)lk"g
000481
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HI 6329-117
OBJECTIVE
tThhee toebsjtecmtaitveerioafl,thiTs-59s0t4u,dywhweans to rabbits.
atdomiansissetsseretdheasleavelsinogflesysitnetmriacveneoxupsosuirnejecttoion
REGULATORY COMPLIANCE ATLdhamibisonriasstttourrdyaytiwSotanus'disceosGn,odoud2c1teLCdaFbRoirn5a8ta.ocrcyo"rAdPllarnaccpetrioccweeidtuhRreegtsuhleautsUei.doS.nsinFofotohdrisNaonndsctluDidrnyuigcsarle in Spcrpoeomvnpislooiurasncawenodrwkis.tthudHytahzedlierAtenocitnmoarlW,sisctWohenelsfiasnrteud(yHAHcItd)idRdeongeoustlatnuionotnnesca.cecsespaItrnilatynhyeduropeplsiipncoiaontnseiboiaflniytthye pfroersetnhteedanailnystihsisofreptohret.samples collected in this study nor are these results
dentification
TEST AND CONTROL MATERIAL
TThhee St.
cLtooeunsittsr,omlatMeimrsaistaoelurriiaw;laswLaoistdeNDnoit.mieft5ih3eyHdl06a3Ss4u;l1f-o5Exx9pi0.d4eMaan(rdOcMhSdOe)s4,cr(i1Sb9i9eg5dn)aaCasnhdeamidyceeasllclroiwCboemsdpoalniayds,. a
clear, colorless Tiquid.
Purity and Stability
mdTaehteteerrSimpaiolnn/asvtoeirohniascslseu(mimeniscxlturuderisenpsgonfusonirdbeirclointtcyeesntftorcraotntideoisntt,iomnassto)el.urbiiallAitspyau,mrpilhteoymooagfnedntehsiettaytb.eisltsintdy
rsetqaubeisltietdy supplier,
dbaoyncaultmhyeesnetsSspownatsshoern.poturiTtthayekenCoferbtetihfefoircceoantatedrmooilfnimsaatntraelarytisiaiolsn,
aosbttahiinsedwasFrownot as 99.9% Tne
the
psutrapboisleis'tyofofthtihse sctoundtyr.ol material was considered to be adequate for the
Stoanrd Raetegntieon atTehcsectortdoeirsntgcoantntodroHclWoIntmraSottlearnidmaaalrtderwiiOalpllerawbteeirnedgisscPtarorordceededduartaeftre(orSoOPi)st.seumapnecreatuorfe.theAnfyinaulnusreedport
000482
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HMI 6329-117 Safety Precautions Tanhde tpoelsitciaensd. control material handling procedures were according to HHI SOPs
TEST SYSTEM
Test Animal
AKdaullamtazaolob,inoHI,raobnbitFsebroufartyhe23r,a:1(9N9Z4W)aSnPdFmasitnrtaaiinnewdereatretcheeiHveadzleftroonm HWRiPs,conIsnicn., hfoaucsiilnigty`aattHH3I802comPpalckyerwsithAvesntuaen,darMdasdisoount,iinWeidscoinnsitnh.e "AGnuiimdael fohrusbthaendCrayreandand Ubsoettoomf LstaabionrlaetsosrysAteneilmalcsa"g.es iTnheteamnpiemraaltsurew-ereandindhiuvmiidduiatlyl-ycohnotursoeldledin qsucarreteenr-s, DpireotvidHeFd #a5c3c2e6s,s PtHoI waFeteedrs,adInlci.b,itaunmdahnedlda mfeoarsuarnedacacmloiumnattioonf pLearbioordatoofryatRabbit nTuetarsitti7ondaalys.Comp`Tohneenftesedanids renovuitrionnemleyntaanlalyczoendtambiynatnhtes.manSuafmapclteusreroffwoarter are wpaetreiroditchaatllwyoualndalhyazveed biyntHeMrIf.eredThweirtehweorreafnofecktneodwnthceonrteasmuilntasntsofitnhethestufdeye.d or Amlalintaaniinmaeldsduwreireng itdheentoibfsieerdvabtyioannimpaelriondumbaser spaencdifcioerdresfporondtiheng acecarlimtaagtioannd prearnigoedd. froDmur2i0ngtothe23cCondauncdttohef trheelatsitvuedy,humtihdeittyempraenrgaetdurefroomf 4t8hetoani6m0a%l. roThoem aninals were housed under the required temperature and humidity conditions.
Selection of Test Animals Trheequiarneimmeanltss.were selected at random based on health and body weight
Study Desian
pFleancaelde ianntiomaltshewefioglhlionwigngfrosmtud2y,17g3routpos:2,386 g at initiation of treatment were
Group Treatment Dos_(ema/Lkegvel Dosel/kVeo)lume ofNAunmibmearls
1 (Co2ntrol) 7-_O5M9S0O4
01.00
00.55
11
34 T7-15-9590044 5100..00
005s
11
5 T-5904 100.0
05
1
000483
Page of 24 HHI 6329-117
ification for Specis Selection cHhiositcoericbaelclayu,sethoef tNheew lZaeragleandamoWuhnitteofalbbiancokgrroaubnbditihnafsorbmeateinontheonantihmiasl spoefcies.
PROCEDURES DPoserepaarndaAdtminiistoratnion fTohre etaecsht dmaotseerilaelvelw.as Adniluitneddiviwdiutahl DdHoSsOetoofaecahciheveresapescpteicviefictesctoncseonlturtiaotnionor ctornetartomlentw.as Tchaelcurleastpeedctifvoer etaecsht asnoilnuatlionbasweads oandmiintisstbeordeydwebiyghitntroanvetnhoeusday of (idnujreacttiioonn rianntgoinagmafrrgoimna3l5 teoar63veisne.condTsh)e. doTsheewapsrepgairveedn tasesta ssloolwutipounssh were rsetmoariendinagt treosotm tsoelmupteiroantsureweruentidliscaadrmdiendi.stered. After administration, any Reason for Route of Administration Intravenous injection is an acceptable route to assess systemic exposure. Observations of Animals Chloiunriscaalfteorbseirnvtartaivoennsouswerienjeccotnidounc.ted at approximately 0.5, 2, 4, 24 and 48 Body weights were determined just before test material administration (Day 0). sample Collections Boflooadll saanmipmlaelss (aatpp2r,ox4i,matanedly62homLu)rsweproest-cionljleeccttieodn.fromSubtsheequmeanrtgincaollleecatriovneinof Abtlootdhe ftrionme soufrvinveicnrgopsaynim(aalpsprwoaxsimactoenldyuct4e8d-hoautrs12 poansdt-i24njehcotuirosnp)osst-lairngjeectvioolnu.ne AoTf1 blsoaomdple(sapwperroexicmeantterliyfu4g5edtoan6d0 msle)pawraastedobtianitonedserfurnomanedachcelsluurlvairvinfgracatniiomanls:. TSphoensbolro.od samples were then stored frozen (-20C 10C) until shipped to the
000484
|
Page 10 of 24
i Pathology
HW 6329-117
Tnthheeecreoaxpnpismeyarliemxeafnmotiuannladtidpohenaasdea,nddusruiarnnvgyivtaihbnengorsamtnauildniyatliwseasswewsreuerbejeacnrteeecsdotrhdetetodi.zaendAatwbibtrtheevrimsaiotndeaidutmiognrososf psfreuonrztveoinbvairnbbgyitptalolactieannrgdmineianxtsiaaonngfuriwenaesazterecdolswleteictthteoodumtaainnndetcariiomnpmseyad.itaetmeTplhyeerapbtliualrceeedforfoonm -d7er0aycCh icae1n,0imCat.lhen After necropsy or bile collection, the animals were discarded.
hi f Blood and Bil D5T.5h1e0J6ob)hlnosoaodfnt,esra3m4cpolmeEp.sEl.eatnid&onPb.ioCl.fe,wteBhelrdegi.ns-e12nit-f3efr-po0hz,aesne9.3(5onBudsrhy Aivceen)uet,o Stth.e PSapuoln,soMrN,(James
Statistical Analyses No statistical analyses were required by the protocol.
ocation of Raw Data, Records. and Final Report aTrhcehirvaewsdaotfa,ANIrecionrdasc,coradndancaecwoiptyhoHfHItheSOPf.inal report will be retained in the
RESULTS Body Weights Individual and mean body weights are in Table 1.
Clinical Observations a1In0ni.d0mi,avlidauntadrlea5t0ce.ld0inmiacgta/lk0g.0siamgpgnp/sekagraerdeexhniionbrmiTatalebdleata2.0de.c5rTehaaensdea2niinmhaoulfrsosodtprcoeosantts-euidnmjpaettcito0in.o0n,a.t 14.,0T,he24, taIhnnedf4o48o8-dhhocouuorrnss.uobmspetTrihvoeantaianotinm.a4lsaTnhdter2e4aantiehmodaulrast,tr1et.ah0teneadndraett1u0r5.n00e.d0mgm/tako/gkagexneohrximhbaiilbtietdaepdpaeadreacnrceeaseat 7ha.ny5dpoh4a8ocutrihsvouirtpsyo.sta-tiTnh4jeeacantndiiom2an4l hfootlurlreosawtieandngdastaigd1ne0sc0.r0eofamsahe/ykpigonacwftaoisovdiftcoyuonnds(uatdmepat2dioannadppart4oxh4,oiumra2s4t),ely and decreased food consumption (at 4 hours).
000485
Page 11 of 24 HHI 6329-117
| pathology oTfhethaenimeaxlpseritmreenattaeld apthas0.e0,and1.w0,ere10.n0o,t naencdro5p0s.i0edm.g/kTghesuarnviimvaeld ttroeatteerdminatation v1i0s0ibnlge/kglesdiioendsoninthtehisdayaniomfalt.reatment and was necropsied. There were no
DISCUSSION Trahbebiltesvelwheonf saydsmtienmiisctereexdposasurea soifngTl-e590i4ntrwaasveneovuasluaitnejdectiinonfeamtalelevaellbsinoof 0.0, t1h.0i,s m1a0t.e0,ria5l0.0r,esualntded100i.n0amdge/ckrgeausseinginDHfSoOodascontsheumpvteihiocnlea.t alAldmidnoissetrlaetvielosn, of htryepaotaecdtivaittytheat10t0h.e05m0g./0kganddos1e00l.e0venlg./kg dose levels, and death of the animal
SIGNATURE
SSttuedvyenDiW.recGtloarza Acute Toxicology
Date 14-04
REFERENCE 1. NIH Publication No. 86-23 (revised 1985).
000486
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Individual TaBboldey
1 Weights
(g)
LeDovseel
Animal
Group (mo/ka) Sex Number Day0
1
0.0 Female F50169 2,231
2
1.0 Female FS0170 2,386
3
10.0 Female F50171 2,176
4
50.0 Female F50097 2,173
H
100.0 Female F50098 2,300
HHI 6329-117
000487
Page 13 of 24
Table 2 Individual Clinical Signs
HWI 6329-117
Grow L(neDoov/sekela) Sex AnMimmbaelr Observation GF 2Hd ow ZI 1 0.0 Female FS0169 ADepcpreeaarseeddnfoomoadl 4s. . consumption = =, 4
consumption. yy. 2
1.0 Female F50170 Appeared normal 4 4 - - 4
Decreased food
3
10.0
Female
F50171 ADepccpreoeaarnseedsd nuofrommoadpl tiJov n.J
-
,
-
,
4
4 0.0 Female F50097 HyAppopaeacrteidvimtoymal +E4A...
Deccroenassuemdptifoonod ~~, yy
5
100.0 Female F50098 Appeared normal 7 - -
Hypoactivity
- /J
Decreased food
Fouc(no=d7n.s5udemahpdotuirosn - - J
post-injection) - -
/ Indicates condition exists. = Not applicable.
000488
Page 14 of 24
APPENDIX A Protocol Deviations Protocol TP8084.PK
HWI 6329-117
000489
Page 15 of 24 Protocol Deviations
HI 6329-117
Protocol CP.agDeos6,ing7. PrEoxcpeedruirmeesn,tal(1)Design, DionsjiencgtioRnoutien.to aInmtarragviennaolusear 3v0einsecoovnedrs.approximately
Actua) Procedure fThreonr3a5tetoof63insjeeccotnidosn. ranged
DP.agOebs7,erv7a.tiEoxnperoifmeAnnitmaallsD,esi(g3n), oSfampCloelleCcotliloenc.tionBsl,ood(c)samMpeltehsod t(h2emm)argwiinlall beearcovlelienc.tedInfrom nadedcirtoiposny, apatprotxhiemattiemleyof50 f7r0onmLeaocfhblanoiomdalw.ill be obtained
bAlosoedpawraasteno2t-nLtakseanmplaet tohfe (t4i8mehooufrstheposstc-hiendjuelcetisoanc)rifice psoisnscieblaes m(uacphprobxliomodatevloylu4m5e taos 6a0nimnall). was obtained from each
EP.ageTer8,min7a.tiEoxnp,eri(m2e)ntSaclhedDuelsiegn, CSoalclreicftiicoen,. (a)Thesabmipllee from each wainlilnalbe scuorlvlievcitnegd toandtermination tihmemnedifarotzeelny bpylacpeladcionngdriyn aice tfermepeezerratusreet otfo m-a2i0nCtai1n0aC.
Tinneabiflreeezsearmplseest wteoremaipnltaaciend a temperature of -70C 10C.
oTuhtecsoenedeovfiatthieonsstuadrye. not considered to have had an adverse effect on the
000490
! R RAA SEE O NLSR N
Page 16 of 24 Comm mtr
Sponsor:
St. Paul,mnMinnesota PROTOCOL Teg084..pK
Stugy Title: Single-Dose Intravenous Pharmacokinetic Study
of T-5904 in Rabbits
Date: March 4, 1994
MHa3ad3zi0ls1eotnKo,innWsWimisascncoonnBssoiiunnl,ev5aI3rn7dc0.4
LaboratoryProject Identification:
WE 6329-117
Or IS ne en sussunnn wn a LT 000491
Page 17 of 24
-
STUDY IDENTIFICATION
Single-Dose IonftrTa-v5e9n0o4usinPhRaarbmbaictoskinetic Study
HHI No. Test Material Sponsor
Sponsors Representative
Study Director
Study Location
ProEpxpoesreidmeSnttuadly
Timetable Start Date
Experimental Draft Report
Termination Date
Date
6329-117
T-5904
TMomxicology Services S1t2.20-P2a6u-l0,2 H3NM Ce5n51t4e4r
J3Hohn L. Butenhoff, PhD T22o0x-i2co-l0o2gy3HSeCrevincteesr S(t6.12)Pau7l3,3-1H9N62 55144
HSatzelveetnonM. WiGslcaoznasin, Inc.
MPa.d0i.soBno,x
7545 WI 53707-7545
(608) 241-7292
HBuaizlldeitnogn WNoi.sco3nsin, Inc. M3a8d0i2soPna,ckWeIrs A53v7e0n4ue
WWeeeekk ooff MMaarrcchh 77,, 11999944 Week of April 11, 1994
PPa8ge082 4P.K
000492
Page 18 of 24
PTa8ge0834P.K
4. SSitnugyle-Dose Intravenous Pharmacokinetic Study in Rabbits
2. piTtourpaissosseaesdsaintihestelreevedlasofassyisntgelmeicienxtproavseunroeustointjheecttieosnt mtoatecruisamlitwhen
3. ReTahiuslasttourdyyCwoimlpllibaencceonducted in accordance wi,th the following Good
Laboratory Practice Regulations/Standards/Guiindees):
[{xC]o2n1duCFcRt83s(2FAH)onregulated Study
[{1] 1 {1
4400 CCFFRR 716502" ((epPAA--TFsICFAR)A) C(81)30 (Final) (OECD)
[]
[1]
Notification
Notification
Ko.
No.
331835,0, MaArucghust31,10,198129,84an(dJaapsaneasmeendHeAdFF)by
Notification No. 870, October 5, 1988 (Japanese MOHW)
WAeIlfaprreocAecdtureRseguilnattihoinss.protioncotlhe aorpeiniinoncoomfplitahenceSpownitshor taheedAnmiommaa]y
director, the study does work. Hazleton does not
not unnecessarily duplicate accept any responsibility
any
previous
roefsutlhtes sbaemplperseseonrtetdissinuesthecolrleepocrttedofinthtihsisstsutduyd.y
for the nor will
analysis these
4. Quality Assurance
Tthhee Qpuraoltoictoyl,AsssutruadnyceconUdnuictt,in anadccotrhdeanfcienalwitrhepHoarztlewtiloln bbersaumdoittceed by
5. Test Material (HWI) Standard Operating Procedures (SOPs) and policies.
A. = Identification
8. PhVyelsoicwalsaDletsdcription
C. Purity and Stability dTehteerSmpionnastoironasssu(miensclurdeisnpgonusnidbeirlittyestfocronpduirtiitoynsa)n.d s*taSbaimlietcyof ctoensctenmtartaetriioanl,/veshoilcublielimtiyx,turheo(mso)gen(eiiftya,ppalnidcabsltea)bi]fostry analyses WSapifoltnlesrobree.xptearTkihemenesnebteafsloamrpetleerasmdimn(iaintfiisottnarkaetfnio)ronpwoiislfslirbbeleeq.uesessntpteedltsobsyitshteheSponsor
0. Rsotoomragteemperature
000493
Page 19 of 24
TPaPg8e0484P.K CE. RReesseerrvvee Ssaammplleess will not be required for this study.
F. Retention tAhney fuinnuasledretpeosrtt,matuenrlieasls dwiilrlectbeeddoitshcearrwdiesde abfytertheisSspueanncceer.of
6. SaAsferteyqupirreecdaubtyioHnIs SOs and policies 6. Vehicle
A Identification Dimethyl Sulfoxide (DMSO); report. date to be recorded in the
Lot number, source, and expiration data file and included in the final
8. Ph(yTsoibcealdoDceusmcernitpetdioinn the raw data) C. puarndiStatbilyity
To be documented by HWI (information from the supplier).
D. SRtooornagteemperature
E. SReeeserSevcetiSoanm,pl5e.s E. Reserve Samples
F.
ARneytenrteimaoinning Final report:
vehicle
will
be
discarded
after
issuance
of
the
6. SaAsferteyquPirreecdaubtyioHnIs SOPs and policies 7. Experinenta)Desian
A. Animals
(1) SRpaebcbiites
@) sHtraii(NnD/Wrs)oSuParFcHeR:P, Inc.
3) AsIenaittiation
Adult
(4) sZeloahtt 3at0kInitiation
000494
Page 20 of 24
- (5) 5Numfebmearleasnd Sex
PTapgae0845 PK
(6) InIddeinvtiidfuiaclatniuonmbered ear tag
(7) Husbandry
a) Housing A
Individually, (heavy gauge)
in
screen-bottom stainless
steel
cages
(b) AF(oPmoHIdeasFeuerdesd, anIoncu.n)t. ofAnLiambaolrsatwoirlyl RnaobtbitbeDifeatsteHdF b#e5t3o2r6e ebdynosveithreaodmmmeainnntuiasfltarcacttouinrotenar.mifnoarTnhtnesu.tfroiotdioinsalrocuotmipnoenleyntasnatlaygzed
(c) M4adteTribitua from an automatic system. Samples of the
water are hardness,
aanndalsyzpeedcifbiyedHWmIicfroorbitooltoaglicdailsscoolnvtedentsolaindds,
for selected elements, heavymetals,
organophosphates, and chlorinatedhydrocarbons.
(d) CThoenrteamairneanntos known contaminants in the food or water that would interfere with this study.
(e) EEnnvviirroonnmmeennttal controls for the animal room will be rseetlattiovemahiuntnaiidnitya otfem5p0e%ra2tu0r%e, of`an1d9a to122-3hoCu,r a
Vight/12-hour dark cycle.
(f) AActclTiemaasttio7ndays
(8) SeleofcTetstiAnoinanls
Based on adequate
health number
and body of extra
weight animals
according to HWI SOPs. will be purchased so
An that
no animal in obviously poor health is placed on test.
(9) Justification for Species Selection
bHtahicesktgoarrnoiicumaanlldlyoi,fnfcothrhomeiatcNieeownbeZcoenaaultsahneidsofWshipttheeecilaealsrbgienoamroaubnbtitohfas been
0004395
Page 21 of 24
B. Dose Administration
PPa8ge084P.K
.
(1) Iest Groups
Group
DoseLevel
Ama/ka)
Number of
[Females
1
0 (Control)
1
452
105010..000
5
100.0
i11 1
a wTehieghdtose volume will be 0.5 mL/kg of body
C. DosingProcedures
(1) DoIsntirnagveRnoouusteinjection into a marginal ear vein over approximately 30 seconds.
(2) R sIynsttre eanviefcnoa oruesDxpos oissniujnreo gec.tRioon unt1es an acceptable route to assess (3) DoSsinignlge udorsaetion
(4)
DoPT(hDsreHeSeDTp)easttroamaattciehrioienavle Tevel. Individual
dwaoislslepsecbwieiflidlcilbcueotneccdaelnwctiurtlahattideoidmnetbfhaoysxledeascouhnlfgtohaxeri.ede
animal's body weight taken just before test material
gtaredommuippnesir.sattruTarhteeioupnn.rteiplarTeahddemitdneoissstetrmvaiotxlituoumnre.eswiAwlilfltlebrebeaeqdusmatilonriebsdettrwaateteinroonoamll
any remaining test mixtures will be discarded.
0. ObservoafAtniimoalns
(1) ClinicalObservations
-
after treatnent. The animals
toxicity at
waiplplroxbiemaotbesleyrve0.d5,for2.0c,lin4i.0c,al 24s,ignasndo4f8
hours
(2) Body Meights Just before test material administration.
Be
----
000496
'
Page 22 of 24
(3) Sample Collections
PPa8ge0874P.K
(2) E2r,e4q,uen6c,y8, 12, 24, and 48 hours post-injection (b) aMunsber of Animals
(c) BMleotohdodsaomfplCeoslle(2ctailo)n will be collected fron the mnaercgrionpasly, caarppvreoixni.mateIlnya5d0dit-io7n0,'nLatofthbelotoidnewiolfl be
obtained from each animal. The samples will be
tshteoresdepaartatreoomsertuenmpaenrdatucreellualndarthfernactcieonntsrifsutgoerde,d aatnd e=fx1rp0aecrCtiinotenonst-aw3li0llCt.erbemiTnshaeetnitsoenpfarforozaretnedpotsosseitrbhuleme Safnpduotnuscroeerllualfatrer analysis.
Samples will be shipped to:
BMJladmEge.sE3D.-3E6JP-oC0h9n.son 935 Bush Avenue
St. Paul, MN 55106
James 0. Johnson will be notified by telephone at
(612) 778-5294 prior to the shipment of the samples.
E. Termination (1) UnscheduledSacrifices and Deaths mAnoriabbubnrdevicaotndeidtigornosswilnlecrbeopsayneswitlhletibzeeddonwei.th Asnoidmiaulms in a
pentobarbital and exsanguinated without necropsy.
(2) ScheduledSacrifice At approximately 48 hours post-injection, animals will be waintehsotuhtetinzeecrdopwsiyt.h sodium pentobarbital and exsanguinated
000497
Page 23 of 24
PPa8ge0884P.K
-
(a) Sample Collection
wTihlel bibelecoflrloencteeadchanadnimiamlmesdiuartveilvyinpglatcoedteornmidnraytioince
ttehmepnerfartouzreen obfy p-2l0acCing10inC.a freezer set to maintain a
eTxhpeerbiimleent(aflrozteenr)miwnialtlionbefsorentpososnibdlrey samples will be shipped to the person
fiucteurteo listed
tanhaelySspiosn.sorThaefter in Section
7.0.3).(0).
F. SNotatsitsattiicsatlicaAlnalaynasleysses are required.
8. ARepfoinratl report including those items listed below will be submitted.
DDeessccrriippttiioonn ooff tthhee tteesstt smaytsetreimal DPartoecsedoufresexperimental initiation and termination Description of any toxic effects
9. LOforacicgaiitlniiaotlnateodaftaauR,daiwtoirDantgcao,tphieeRsecsottruhddesyr,eodfua,rndinwgiFlilniatlsbepRraeovpgaorireltsasbleandatbHeHfIoreto raalecltcaeiopnrteiadgnicneianloftpheatpheearrcfhdiiantvalae,s reoipfnocrHltWu.IdinagcWchoetrnhdoistnehgeitftoienmaHlWlIisrSteOepPdo.rtbelioswcwoimlplletbeed,
DPorsoetocporlepaarnadtipornotorceoclordasmendments InB-oldifyeweriegchotrsds
DOobsseervaadtmiionnisstration SStaumdpylecocrorlelsepcotnidoenncreecords Final report (original signed copy)
The not
bfeolalrocwhiinvgedsuwpiptohrttihneg
rsetcuodrydsdatwai.ll
be
retained
at
WWI
but
will
WAnaitmearl anraelcyesiipst/arceccloirmdsation records ARneifmrailgerraotoomr taenmdperfarteuerzeerantdemhpuemriadtiutrye rreeccoorrddss Instrument calibration and maintenance records
000498
Page 24 of 24
PROTOCOL APPROVAL
TPoaegoes'es px
edBtd Joh L." Butenhoff, PhD
shSponsor's Representative
IW.L craze NW Study Director
Acute Toxicology Hazleton Wisconsin, Inc.
Cor esLeendtitive HQauzalleittoynAWsissucroannscien,Unintc.
(6329-117.PK,dsk2)
ancl 7, 974
Date
Bp ate ea Tate ogJos
-
A--
.
1
SY000499 |