Document 6RoxvQavVvKXb97qY9Bnk5M4
a
ore
Contains No Cpy
Ivo Viesk Oroerln-R3asn0gaecreicndiinngTTaotxsicity Study
g
E=R 2
Exportaent to.: Dosing seared:
Recovery Intervals Completed:
study Direotor: zesting Factitey:
vromsoz
october 3, 1979
November 15, 1979
6. n. stetfen, 35
S on J]
= 43
w>l
HsaoteesthyauitEa,veaclWauiuamntmritaoasnso:rLabTooreastory
sponsors
& EPA-OTS
vTf.onric.eecWieaegdcyomSiocrkvices
St. Paul, Minnesota
0008117964
S Spantoot r rno, xiycotbiat
bz/g1o02
A Mainnevr,esFa,thologGy-Tooxicolo2syis/es0e ts hvatancion Laboratory 03695
TAOFBCOL NTEE NTS Page
INLROBUCEION + + + shee e a eee.2 Methods . . + oui i ieee.2 RESULES + + vv ttt. 3 DASCUSSAON + 4 4 hh hh eeeaa h a.22 Appendices LL... i... 23
03696
1 Summary Tthweo oparratls.rangIenfPianrdterItotxheicaictuytestuordayloAfLDTS-O25w0a9sCcCdefininerdatsinwmasalecomCpDlreattesd. in Smiixnigsrtoeurpesd shianvginlge sdoisxesratrsa/nggrionugp,fro5m1-52950d-a1y0s,00o0f magg/ekgw.henIndoPsaedr,t wIeT,reTa-d2-509CoC Twavselvaedmirnaitss/tseerxe/dgrboyupd,ail5y1 dgaaysstroifc iagnetuobnatdioosnetdoamyal1e, waenrdefdeomsaelde CaDt r2a0t0s.or 7a5ndmgf/okrg/ndianye.dayDsosaitngthceontliownueldeveflor (f7i5vmeo/dkagy/sdaayt).theALhLighsurlveivevling(2h0i0ghmg/dkogs/eday) afnoilnlaolwsinagnddoshianlgf.ofSetlheectleodw dlooswedogsreoupanihmadalsa w1e4r-e15eudatyhanraetciozveedryonintdearyva1l0. All isnutrevrivvailn.g anBrianianl,s sintobmaocthh,grliovueprs,weardereneaulthaanndatkiizdendeyattithsesueesndweorfetheevalrueactoevdery microscopically. Tfhiedeanccueteliomritasl oAfLDS5O58o-f13T9-925mg0/9kCgo.C iGnasmtarloeinrtaetsstiwnaasl87i8rrmigt/aktgiowniwtahs95t%hecmoons-t cococmumrornedefifnectsomceausdoesdebygrohuipgsh a2c-7utdeaydsosefso.lloHwainndgldionsgi-npgr.eciTphietatleodwecsotndvouslesigonrsoup (250 mg/kg) was free Of treatment-related effects. aDnadilysexg-arsetrliactedintefufbeacttiso.n OfTheraptrsimwairtyh eTf-f2e5c0t3sCcwCerreesgualstterdicinirtrrietaattmieonnt,-,hadnodslaigneg-ptrreicbiuptietdatteoddocsoangveu-lsrieolnastedanddeamtihcsr.oscoSpeiccondlairvyerefcfheacntgess.at bTohtehseleevfeflesctwserceon-a tthueckdeods-iunpgapppereiaorda,nceh,eadanturnekmoermsptanadppheyarpaenrcaec,tivsiotfyt. feTcehse,hbiogdhydwoesieghgrtoulpo,ssbudturing wneortetnheo mliocwrdoossceopgircoucph,angheasd ihnisttohelogbircaienvisdeecntcieonsoffgraosmtreiictheirrrilteavteilont.o coTrherreelate wnietchrostihse aCNnSd effaftetcytsc.hangTehse. trTehaetmmeanlte-sregleanteerdallliyvehradeffeeacrtlsiercooncsciusrtreidnogfdefaotchasl, more convulsive episodes and more animals with liver changes. CRNeSveresfaflectosf dtihde tnootxioccceufrfecdtusrinogccurrecroevderayf.terThdeosgiansgtrsitcoppleeds.ionsSevaendreotdheelrayed sSaeicno.ndaTrhyeerfefceocvtesrysubasniidmeadlsdduirdinhgavreecmoivelrdy.fatAtlyllirveecrovecrhyangaensimbaults hnaodt wleiivsehrt necrosis.
03697
2
Introduction
The two
poarratls.rangPearftindIeervatlouxaitceidtythsetuadcyutoef
Tor-a2l509ALCDoSCO ininrmaatlse warsatsc.ompPlaerttedIIin
aevnadlufaetmealdetrhaetstouxsiicngeffdeocsetslaenvdelsrecsoevleecrtyedfoflrloowmintghedraeisluyltosralindoPsairntgI.in male
TThoexicsotluodgyywaSservciocnedsu,cte3dM
bCoymptahney,SafSte.tyPaEuvla,luMaitninoensLoatbaowraatsortyh,e
study Riker
sponsor. Laboratories,
rIencp.e,atSdt.osPeauplo,rtiMoinnnwesaostac.ompAlceutteed donosNionvgemsbtearrte1d5,on197O9c.tobeTrhe3,pro1t9o7c9olanwditthhe
amendments and a list found in Appendices I
of principal participants and II respectively.
and
supervisory
personnel
are
LSaibnocreattohreysPtruadcytiwcaes a(GLrPa)ngerfeigunldaetrioenxsp,erihmoewnetv,er,ittwhaessteuxdcyluwdaesd cfornodmuGcotoedd in arecqcuoirrdeamnecnetsw.ithThoeurstSotraangdeardloOcpaetrioantinfgorPrsopecceidmuerness,whriacwhdaitnacorapndoraftienalGLPreport is maintained in the record archives for the Safety Evaluation Laboratory. Methods
Part from
I: The Charles
RaipvperroxiLmaabtoreatoorrailesA,LDSIOnc.wasThdeeterratmsinweedreincomnadlietCiDonerdatsin-ohbotuasienedfor
approximately with food and
woanteerweaevkaiplraibolre toaddolsiibnigt.um. ThAenyimwaelreihdoeunsteidficsaitxi/ownirwea-stopbycaignedivi-
dual numbers and humidity
caonndtraolcloeldorancdodhiandg
asys1t2emh.ourThleigahnti/mdaalrkhcoyucslien.g
room
was
temperature
wSeirxera5t1-s5/9dosdeaysgrooludp waenrdewesieglheecdte1d79f-r2o6m2thgeramcsonwdhietniodnoesdeda.nimAalsc.onstThaentandiosmeals vthoelumteesotfar10timcll/ekgtowatsheusaepdproatprieaatceh cloenvecle.ntraDtiisotnisl.led water was used to dilute
T14hetaoni2m0aldsaysw.ereBoobdysewreviegdht3s-6wehroeursobtfaoilnleodwinjgustdopsriinograntdo ddaoisliyngtahnedreoanftetrhefdoary
Of necropsy. died or were
Gross killed
natectrhoepseyndabnoofrmtahelitoibesserwvearteionrepceorridoedd
for but
atlilssuaensimwaelrse tnhoatt
saved.
Part Inc.
II: and
cMoanldeitiaonndedfemianl-ehouCsDeraftosr
wtewroeweoebktsaipnreidorfrtoom
Charles dosing.
River Laboratories, The animals were
ainnddiwvaitdeuralwleyrehoauvsaeidlaibnlehaangdinlgibictaugne.s hAanviimnaglwiirdeenmteisfhicaftrioonntswaasndbybotitnodmisv.iduaFlood
ear had
tags a 12
ahonudr ca1gieghtc/adrdasr.k
cyTchlee.room
was
temperature
and
humidity
controlled
and
03698
3
Tawseslivgenedrattso/stehxe/l2e0v0elorwe7r5emgs/eklge/cdtaeyd fgrroounp.theOncondadyiti1ontehed aanniimmaallss waenrde 51144d-a1y8s5 gorladmsa.nd Tthhee mtaelsetsawretiigchleedso1l5u4t-i2o1n1sgrwaenrse parnedpatrheedfdeamialleysuwseiingghed duissetdilfloerdeawcahterdoasse tlehveeld.ilueDnots.ingAcocnotnisntuaendt dfoosrefviovelumdeaysofat10tmhle/hkigghwas d(o7s5emgl/evkegl/d(a2y0).0 mgT/hkeg/ldoawy)doasnedgrfoourpnhiande dsaiyxsaantimtahles/sleoxw rdoesteainleedvelfor areycov20e.ry aALfLtersudrovsievindgayan9imaanldsthien rtehemahiingihngdoasneimaglrsouwperweerecutrheatnaaitniezdedfoorn rleocwovdoesrey agfrtoeurp danodsin15g dsatyosppefdo.r tThehehriegchodvoesrey girnotuepr.val was 14 days for the
Tohbetaianniemdaplrsedwoesree,obbsiewreveekdlydadiulryingfodrossiignngsanodf toonxcieciotry.twicBeodya wweeieskhtdsuriwenrge rgercoosvsernye.croAplsly aanndimatlisssutehsatwedrieedsaovrewderfeoreuhtihsatnoaptaitzheodlowgeircealsuebvajleucatteidont.o a
TThhee d7o5smea/lkeav/edlasyfolrevePlartforIItwheererepseelaetctdeodseatporttheioncoomfplethteionstuodfyPwaarst sI.elected Tthoede2l0i0vmegr/kag/cduamyullaetvievlewa1s4 dsaeylecdtoesde atpopbreoxicmlaotseelytoeqtuhealactuotethenoA-LeDfSfOectvalue. ltheavneltahnedALtDoSOdelvialvueer.a cummulative 14 day dose at least two times greater
Results
P35a%rtcoI:nfidTehneceacultiemitosralofAL5D5S0Otoof1T3-9925m0g3/CkcgC.in male rats was 878 mg/kg having
CDloisnaigcea-lresliagtnesd ignacslturdoeidnteasttiuncakledt-ouxpicaiptpyearvaanscet,hesporfitmafreyce7s-/2d5i0a9rCrohCeaefafnedcth.yporoevaecrtniivgihtty/onhyptohaectdiavyitoyf d(oTsaibnlge 1()f.ounMdosdteaddeaotnhsstuadtytdhaeyhi2)ghwehrilleevetlhsoseoccaturrtehde ldoewaedrhaldeveglrsoswsereeviddeenlcaeyedofthrreodudgehnedstuodryhedmaoyrr8ha(gTiacblgeas2)t.roiMnotsetstiannailmalmsucofsoaund (rable 3).
Dtheelay5e00d0,CNS200t0oxaicnidty10w0a0smgev/ikdgenltevaetlssohmaed dcolsoangiec/tloevneilcs.conOvnuelsiaonnismalonatdayesach6,of
2 or were
f7 oruensdpedcetaidvewliyt.hin Ea2c4h hoeupriss.ode Hwyapsereparcetciivpiittyateodcobuyrrheadndtlhirnege
tanodnitnhee
daanyismals
cfoovlelroewdi.ng dThoesinobgseartvatthieon20p0e0,rio1d00w0asandext5e0n0dmegd/ktgo l20evedlasysbuatt tthheese10a0n0imaanlds5r00e-
mg/kg levels because of the delayed deaths but no additional effects occurred.
Tthheeseloawneismtaldsoseshogwreodupno(r2m5a0lmwg/ekigg)htwagsainf.reeAlolf tanriemaatlmsentat-reealcahteddoseeffelcetvselantdhat sofurvobivvieodusfogrrotshse dluersaiotnisonatofnetchreopsstyu.dy had acceptable weight gain and were free
03699
|
-- servation Appearednormal Salivaion Lcriaation poresctive
Tabte 1 oAfcu1t-e2o50r3a0CToxiincMiatlyeshtautdhy Nunbe1r0,o0f00Amn3i/mka3sGrAofufpe.cted
SBiamTooui asdw we
meee 733 3 aa Se eTyebiesowwn mmmm mm
2 3 2 ow. o- oo o-oo ooo oo
32 ow ow - - - - oo o.oo
W2 o-2 ooooo1 o. o
Wozoe ow o-oo. oo oo
Chrossdacryorzhea WE Ne 1 We = =. =. o-oo_ . o_o.
posctive
mows ao o-o ooo.
Tucked-upsbdosen NE Ne We 1 = =. o-oo o_o_
D-- eachs rer-- e ereec ctt-- e0stta1t 0S -- overmig-- n te eraser e
Ne =votevident
23a
-
3S3
Ta1 b(conltinueed) AocfuTt-e2o5r0a9d0uTcoxiinciMtaylostRuadtys Number50of00Anmimaalgs Affected
O servato ion e-- s ------eTe T-- e --
ais 3a ET ew nm nw
| peedemal 4 4 1 3 2 2 2 2 1 ow = - - oo
Satsvation
30 wm a mow om oweow ow oo - o-oo
Bloody arescoun 2 Ww Nw 1 wowowow owow - - - -
Hyporeaceive
Zo ss mom ow ow ow ow - - = oo
Dyspnea
Poe ow ow owomow owow ow - - oo
Soft. feces
mass mowow ow owow - - - - oo
prosia
moo 1 mom oweow owow - - o-oo
Tokedwp bios MEN 2 3 Wow Wow ow ow - - - - - .
Clonic/tontcconmlston NE WE NE Ne wow ow we 2 we = - = o-oo -
Death
0 0 oo 3 1 0 0 1 1
2 =vot evident 2 precipitated by handling
2$a
-
3S8s
Re1 (continuo
AfWrcp toa Sr4aotoSTwhoexlntAesteeoutddeys
| --[T--TTTFE
it
=Se
=mTrSSe eme eewmat -- ----S e ---------- ------ --S ------ l --
wreoreemaecatoinet wow6 m2I : owowm ow ow - - -
oDronpty ares =mooww oma now hme wm ww
Fae mow om ow ow ow LL LLL sowow naaom oo LLL
oCtlotnueess conmtsio1=n8 0mow1a
rents
ow ow
Lemooww owow owow wowowow oLoLo L LLLLL mow ow oy owowow LLLL L
Hnpoenrsceive pesctive
wooew ooww ww ow
ommoowoowmowroowaowoew L LL L LLLLLL wow oy owow owoo LLLLL
se--ns_e ---- ooo Se nea 0a
1 = vo vigon,
reciente by anion
23
.
g32
Ta1(beonltinueea) AofcutTe-213o0r0a%0lc00cTnoaxi/ntveNatattyestautasy Wmber of Animals Affected
BObseE rvation
F=SoECamnm=Su=SM T BOBT Oe SESe STeOST RU eSeASwSwe n CTwm0
Aopeaced norma Clonic/tonicconvlsion NE
6 XE
66 WW
65 wow
6 ow
5s wm
4 ow
3
mom om ow
3 ow
3 ow
a ow
3 om
3 we
in pereactive
mow ow om mow ow ow
momomowow low mom om owowe ow 2
ow 3
ow ow wom
ow ow
ow ow
ow ow
enors
momom om mow ow ow ow ow 1 om ow ow ow ow
De_a--ths
0 0 0 0 0 1 10 10 0ro r o o o
2 =votevident
Bh
2 precipitated by hanating
22
-
33
8
-- observation Mpewedtorml Hrpereaceive De_at--hs NE =Not vident
Ta1 b(conlcludeed) Aofcu1te-2O5r0a5%l000cTnoaxiinycsHiatlyosRtautdsy Mbox of Anisala Affected
FBlFTzaai EwRs FF5 I We dse ee vs 5vwwonnn n nhmwmm
66 mow
66 Ew
66 wow
665 mow ow
5 wow 5s 5 5 5 ES 5s ow ow ow ow om
0 0 0 0 0 0 10 0 0r0 r o r o o o
Member of25A0nmimaalgs Affocted
`
O-- bserv-- ation
mes
FELTiSH= a=nes
opened normal 6 6
De_at--hs
o oo
seem SE53BO aWSSeSySU SOw SSnSw en Cw=m 6665656 5 & 5 o 0 0 0 0 0 0 0 0ro r o o o
2833
. Taste 2 hoefut1e-23o0r8aCl0CToxiincMiattyeStRuadcyh Death Pattern
BLlT oeeverl 3 TE 3 aeme a6wm7 e T4 rSeemm 5 omhrembpioemmeasams
10000 Bet 15 em em am en en en so0mat 0 3 1 0 0 1 1 ae em
es oe
2000ng/kg 6 3 0 1 0 1 0 1
os
soma 1000 mg/kg.
0o 0o 00 oo o1 11 0o 1o ooo
13/66
200=58708 nak . 250 mg/kg
Jooo0J00
0
0/6
95% Confidence Limits = 558 to 1399 mg/kg~
2 CfboamtepauetfartoimontshisbylbeuvleulthnoPtraubsietd AfnoarlyAsLiSsO, Bcavliczuolmamteinotnasl Research Laboratory
03705
ante 3
AofutToN-e2c5orr0oa5pl0s0yTcoxiRniecsiWatttysesatutdsy
usher of Andes Aefected
Gross Ghueevati"on
Tow
0Tow To05 7 Toon Em Ei
No. Dead/to. bossa No Visible Lesions
ws
os
ws
re
we
oe
BFuotuhnadnaDteiszaed
oo
o2
o1
15
s
.
Roddaned Stomach wicosa
Hesorehagic Stomach Mucosa
2
2 2
2
o
=
1
o
o
'
[a
Heamocrozrhnagic small Intestinal o
o
2
o
o
0
[R--
o
o
o
)
o
o
2with possible utcer
22
.5
83g
n
Part II: prominant
Terfefaetcmtencta-usaenddbydodsaagiel-yreorlaalteaddmgiasntirsitcratiirornitoaftioTn-2w5a0s9CotCh.e
most The
hgiagshtridcoseirgrriotuapt,ionb.ut Tnohtisthierriltoawtdioosnewagsrouppr,esehnatd hiinst11oloofgic12emvaildeesnceandof
8ulcofers12wefreemalfeosund(.TabCllein4i).calInsigsnosmeasisnosctiaantceeds weiatrhlyghaesmtorrirchaigrircitgaatsitornic
waeprpeearparnecsee,nt doinsabgoet-hredloasteedgrsoofutpsfeacneds infocrludtehde
maaldeosoangley-raelnadteadn
tucked-up unkempt
a(pTpeebalreasnc5eamnodre6).commBoentteirn tshuervilvoawldoastethgeroulpowtdhoansethleevehlighnododsoeubtgraolulpowed
Agbrdeoamtienralexpparienssi(otnucokfed-aupseacpopnedaarraynceef)feccto,ntsiuncuhedasforanthuenkefmiprtstapfpeewardaanycse.
aopfperaerceovderuyn.kemTphtethsruoruvgihvoiuntg htihgehrdeocsoevearnyimianltservaanld.some low dose animals
Defofseacgtes-rweelraetedexpCNrSesseefdfecatsscooncvcuulrsrieodnsat anbdothisotlraetaetdmenitnstlaenvceless. ofThheesaed
tfroeumndorsinanadnimhaylpseraacttieviitthye.r lHeiveslt.opatThheolborgaiicnalsbercatiionnslewseiroensowbetraeinendotat
othcecurforreed-,inmitdwicaendthhiendnubmrbearinoflemvaellse.s coTmonpiacredortoclofenmiacl/etso:nicscioxnhviuglhsiodnosse
mTahleesl,essthrseeevehrieghCNSdoseeffefcetmsa,lesh,eadtwotrelmoowrsdoosre mhaylpeesracatnidviotnye, loocwcdurorseedfeimnale.
only one animal signs. One low
dionseeacfhemdaolseecognrotuipnueedxcetpotbethhaytpenroachtiigvhedodsuerinmagletshehraedcotvheersye
interval.
Tihnecrecaosnevulisnivfereeqpuiesnocdyesafwteerredgoesnienrgawlalsy sptroepcpiepdi.tatHeadndbylinhga-npdrleicngipaintdatdeiddconno-t vulsions started on dose day 5 at the high dose level and each animal that convulsed was dead within 24 hours. The low dose female convulsed on study day 9 and survived. The low dose males convulsed during handling just prior ttohiprldadnanyed (ndeacyro8)psiaefsteornddoasyisng8waasndst10o.ppeOdnebuthigthhedofsreeqmuaelnecycoofnvcuolnsveudlstihvee episodes were not increasing compared to the rats dosed acutely in Part I. All animals were handled (picked up) as much during recovery as they were while being dosed.
Treatment- and dosage-related deaths resulted from the treatment-related toxicities. Deaths occurred earlier in the study for the hich dose males wtehraen fdoeradtbhye hdiagyh6doasned bfyemadlaeys.8 alSlevetnheofmal1e2smaalnedsseavndentwoof o1f2 1f2emafleemsalweesre weiatdh.twoThesurhvigihvindgosethrfoeumgahleosutcothnetinrueecdovetroydiientetrhvraolu.gh Tdhaey o1n2ly(rterceoavtemreyntd-ay 7) related death at the low dose level was a female on day 9.
Tforlelaotwmienngt-rtehleatreedcovmeircyrosicnotperivcall.iveTrhetoxliicvietryefsfheocwtesd
evidence of reversal consisted of fatty
changes and focal areas of necrosis. Minimal to moderately severe fatty
03707
12
changes were present in five of 12 males and three of 12 females at the
hairgehasdoosfenelcervoeslisandocctuhrrereedofinfitvweo
males of 12
at the low dose level. Focal males and one of 12 females at
the high dose level and three of five males and two of five females at
the low dose level. These low dose effects reflect only those rats killed
for the
the interim necropsy. The recovery interval (died on
last days
three 9, 11
horigh12)dosheadfneomahliesstotphaatthodlioegdicdaulring
acnhiamnagels.witThheonltywofaftetmyalecshanignestheathingehcrodpossye. groThuep tlhoawtdossuervirveecdovheardy oanneimals
did not have focal liver necrosis but they still had minimal to mild fatty
changes in five of six males and one of six females. The greater number of
bleotwtedorsesurrvatisvalcomraptaeredattothehiglhowdodsoese raltesvewlitahnd ltihveersucbhcanhgreosnicrefnlaetcutreedofthethe
liver response.
gTarienatmoecnctu-rrreedlatdeudribnogdythweeirgehcotvelroyssinotcecruvrarle.d dTuhreinwgeidgohstinglosasndwbasodysiwmeiilgahrtat bAontihmaldsosein lbeovtehlsdobsuet tghreoupfsemaallseos alpopsteamroerdetwheini.ghtThtehansurthveivmianlgehsig(hTadbolsee 7). females and many of the low dose recovery animals continued to appear thin during the recovery interval even though they were gaining weight. Food consumption for all animals appeared normal throughout the study.
The only other treatment-related histopathological change was congested and hemorrhagic adrenals in one of 12 males and two of 12 females at the high dose level. The adrenal effect was probably due to stress caused by one or mroerleateodf ctlheinioctahleretfrfeeacttmweanst-ruerliantaerdy tionxciocnittiineesn.ce Ainn ifonufrrehqiugehntdotsreeamtamleenst.The incontinence occurred for several days prior to death but was not associated with microscopic kidney changes. One low dose male was euthanatized fonoradtaeyd8eshoapvhianggusa. soft subcutaneous lump caused by an intubation-induced per-
03708
My ITE: KPiodtnleo oyusi."ng c5om4pleCittaetnigteroIsitas mEiTmEi, OaW 200 220 water apmrierayes stom
shoe
sunshye Stomen ascents
psye 0 stomach anaarasye 7 [--.
smpirreayen
adeanaie [SR
Liver
axaraseer 0 Scone
re mh ir o --. mi irass frome
Liver
miireo Fo.
1 te + ntnooerGctrrMooTapnietsnyet.0de,dhi2s7K0t0corslsiooLgssnnciLiocffpiLtecosxuoannFmtiisnchaahstaaeinnoggnceebrrvsievawreovrrdaeeotfnisFoonuosonundt,sbdesbeieno,tnoibLyyiavieeso,mrmsetaonimtatcihns,eaaedrrseeeTnaitisLseeeasn?.d or ecy weat-- ion M[erroe--d--w--s
Smaellehnemorrhagic cess
Yo signiticant anges
Semmerttivaisaeckatayreus Duck rmorzhagicn Lahrsebemorhagtc acess tage blaocknyspore
Dark amorstagien Yo signicicant changes Dark Linus Oremcrchuge?)
0 stgnitican chamses S[ma=ack=spucks nad ttnmn Yo significant anges Leoenegrbaiannetitirnas
aTeArraottcmihseectraoetuaaetaevrrieTtsshhuesfoiaosmouynrsshaesosastfmermetasnhteesoitfscosetnFeenotpsscoirsctmeoiaocornononsmaaonttssvhare Paricutar rectosty of the Sebcrie manos MrCmorpdErEecorraiutaiaemtlmyiaclssyaaetvrars-ehvivaahmfrsaieive,athsy.a.codhfao+ntgehceshLevreonersetoscpTsroeescoehnittnr,siefsaonome ination: rScatatazetd oect obf caonspeateion aanldpbeimsortehearsedvoereil Ratheeer asuckTed cTonTgestioBnevas presen, sexticutacly SFrceastatnesreidnfoocmk oeftecornseamteisononand hemozhace vere eDFCSeoPcecLaistttahtneehtIraieridinen'fvtoCasoantemvosoaouftmsoeccproemianengetecmsmoetaftiteoasn4ssasatntditMehroeensoopnbreeevrsheooaressresimmeavnnestrce Yo signtttcans changes taste ot processed tor exanination --KBAoLiA--staotFtyhcahahnegpeacoveeprieesinhdaiscapteedomatsananstosroxhtomstels FFBorcsatelantariTenesstohoeefiTpciouenrsgeeiwssiteionmnuseeoaemnsed-nheecmTrooocnoethosase8tivoenroee s f SaeteaLs epeitna)tim (hvelopmant oF an sort EKingsaayl faR tty che anges vfers peresei nt as ssppreoximnstiely 20 stsnicicans changes PForceaslentaceTsnstohfe Scoenvgeersiteioonnasnd.emorrhace vere Km ToMshtan otFtytchehahnagepsatoveeryeinsprmeasdenFoaen aSppvroseisaately fFocralyaceess of pcornogunagtion and esorshase vere
:
Table 4 (continued)
Grons an Microscopie Tissue Gervations
u
f A r ED Grows chesrvations Wieroscopic coeervations
20 ma/ig mates (con's
smsaay stomach
BLaercgoenbaigeeckstsypots
hf ers vep re focal axess of congestion and hemoesha
Liver
Mo signiticunt changes lInaotneiaocens mtheecrreaewiensre several smail fost of
mssay 0 --
No significant changes RTheemrteenvagee ifnocatlheagreassstriocf mcoonrgens.tion and
Liver
iTcaarabanTdoon dete
TaIdhoienlstaiiccoeunsd,tcoba"tlahaerarvreeevdsero--cefomscisonlaiypmvaislspcpifeaostnrteydneccthroousnbitese.sa asIn
rSrparexpinaaealyfat0vaocfwotihees:hapatooyies had Fine
Spleen
Aepears pate
Hasse not processed for exemtnation.
mdaanaer seomacn
Leaorgceenpiangcehesypots
eEForrcaeatleLntearneioantsttaohtfeecavuoirmttghreinceticmorncooraienssd oahfnedsotahrteehssaeegvveeevreaielereareas I Taine memmrmasie Sastric vice
200 msg vemsies
mTeahenaedey stoma
Laargee dark ares Gemor ADehceosorrsehoafstcheulscaerstvraise pSprietsmeenittiwmi:th localised
aacenats sack rmorzhagter) RReamtohteirnaegxetovnenrisveprceosnegnets.tion and some areas of
amehay seomach Dsemmcaeebnhaegcekstspots
Foctentofpceonrgepsotritonionandofhetmhecrgrhaasrterivcemruecopurse.sent
Liver
Mo significant changes arSecastetnPetec.iesdanifsonsgwtiiltoehcfianccioossnosmteoaftoifmomntohmonasecceiroocnsrtisocrvoelertesfoct.
mwrses
smn saver
Dark xed Linas Wo significant chnges
0 tmiicant changes KLLA fatty changes vere present as approximately
Ion of "a hepetaceien hat eviopiamiis Fat sales
medsadsay 1)
(none)
miarlaear stomacn
Dark rea streaks
Fock ofecorngesrteigoionnsanotfhetmheorsrhuasgierivcesruechperne:sent
mresye
stomach
Mo signiticant charges A anal, shallow bemorzhasic ulcer vas present.
pheea ay --
LCamrsgremmblaapceketsypots
Cmaeiprfeosceanltaicenssheofoceosntigieestmieotnonasn.a hemorshase
mersseo 0 stomach
hBienmodrutsnkagdiennes
wo sismiticant canes
03710
EEkEe orn 200 mig remstes (eons dmoanyrs,csomtgaoruninnda5ted Liver ayo) mtera's 51 stomach
arena aver sm{aonmacsoympound 5 Carminatad day 200 smtenas'eday 12) 25 mapag nates dmoanveu,coSmeproiunna9dted uve ay dmTyonns,ceotmhpeomuinnasated iver ayn smoinracsosmpound Liver dave,iorSerminated
smdoianrmea,cooomtpeoruminnda5ted Liver aio
arenas
smdoanrv'se,coomvpeoruend 5
Arenate + niver
alta 100
saovmne:coomspeoruminnda3ted Laver + wor
able 4 (continued) 15 Gross 4nd Kicroscoptc Tissue Corervations
rons comervations Wo significant changes
BOlraecmkoczthianzeesr?) EOnrloamrcgrerdhagaincd) duck Mo significant changes tone)
MeNircrwoswclopeichcmoesamrvtatiioonns
oFaFtttyhechheapnagteoscyvteerse hpardesecnyttopalsasampipcroxfiatastveacluyol3e0s-.40
Yo atanieicant changes Atoss of congestion and hemorzhage vere present. KhLeidhefpaatttoycyctheasnawhsadvecryesapprleasmemnitc aastabvoauctuol1e0s8.of
[==
RE Mo Hunificart charges Mo significant changes
Pale serous and foct [ep-- mtargea? Fae streak Mo significant changes
a10c-u30r0a"o:f the hepatacyses has -- cyeopiionic Far K1i0l8eoffatthtey hcehpaantgoecsytweesrehpardesceynttoplasasmaippcrofxaitmavtaecloyrle
psNlpoipdacesorixacitnefalatyteslveyavce3ur0oe%leofsfa.tttyheIcnhheaspndageetisocicoywnee,erseihnpraesnseceynttsoec.atnion ochroaaotpneiulcCalaterinoernscnueeviecrlrasolsicslsenvaaiinlti,hngiftonpcfaistlhtersaetcaiesorntuoofiafrSnlduiemcbekrriosu.s To0hnemsuuLlbeaastciiuootnesn ncIehncafrulorasvmiemsda.togrryAosrsMeliysmpdovtneesrseesvfaaosctalpreaosrfeensstscstoef adjacent to and vichin some Of hese Tock. Anreaes ofcorcvoenrgestion ant hesorehage vars resent Mo signiticant chases htLhieoaniatnraeedcsrsaomsociuhsne,tervofefrdeaqgcurueotnsetslly0ysvmceuobrosemcpuastntei.eemdsinobffylacmomnastuolrayvATpaiptcrtyoexsicmh:aantgeelsy a1s0-i2n0d8iocfatecdhebhyepEayttoocpyitaessaiehadfot
re oan 25 meg ates (conte) (moni%c0o3mpound "Liver adayys,aterminated sm{iornsc0o4sgoua + ver aayye,acarmimated dm oanys,cos mtpoocumin, nda3ted Lgver aay a amTo7yu3to0ha6natisea Becphagus
Adrenals
a{yons,conCgooruminnda9ted aay 5s) sm(ioznzc0o8mpound 3 dayLso,ver + terainited day 10) 25 mg remsten smC(oiornzmicsnosamtpoodundday3 d1a01ys, . s(amtasday 100 Aacenals + m{oan scosmgound 3 Liver + days, carminated day 10) m(onsceompoun9d Mer 0 anys. Carminaced aay 10) sda{aoynns;scoSnogromiwnaasted ain)
16 Table 4 (continued) Gross and Kicroscepic Tissue hrervations
Gross cbeervacions
fe --
Mo significant changes M1i-n2im0a0l tfhaettyhecphaatnogceystesverheadprceysteonptlasamsicappartoxvisaactuelo
Mo significant changes hWienpiamtaolcytfeasttyhadchasnygeeosplwaemrmeicprfeatsevnatcsaosle1r-21 of the
Mo significant changes EApEprvoaxciumoalteeslyin1d-i24catoifngthmeilhaepfaatiocrvyiecshahnageds.cyeoplas
apnutnecrtiuorre thoolethojruasctic Sets leads to large
in-
No tiasve saved
einctloattiecaxsiulblcauta-neionutsubaarteison
Deanrlkarg(erdemorzhagte), Congestion and hesorshage ere present.
(nena)
"Mo aigniticant changes 1K0i014offtahtetyhcehpaantgoecsytveesrehadindciyceaotpeiadsmaiscapfourrovxaicnuaetteelsy
(none) endacgear Soasible pale ares
pale stress
(sone)
iConngTehesticoonrtaexndanfaocmaledhiensao.rehages were present No significant charges
h`ceougluelsaitoinosn OF in acute
ctnboescersrouvsbeisdscutagecrcoiosmsnplfayinuivmeeardteobryfyociaenlxfuidlaatrteresastioonf
3 Tobe 4 (comciotess rons nd Micrncepc Tansn comrvasions
Ei ow
emai mene
25 maa vemos com
T mfionrsseooE on 3
saver ear 11
RA.
S my aceeveree focat eaT as of ch oupleteseucerote
adeannie dP oonreoT 3
Novas aniarges Ro Hioniticunt chugs
Yo ianiticans ahargn TThaozervase mpinieasltfaattyachaTnrgees asTapprosimetely
a
mn
moinknoseanscsverunrdh9sass,.
[--
fra mayL o tam Ce
. aS mroayrseeL
ener
-- SonIcomEgenna sw+f
[--
SmonnsIomonTna 3
one
03713
ste vo WeeoRkkepaOeartasbroonasng%1Eeeatf0iamncaiktntsga Study
imate teceessouy
-- Ce SI em teet B e ---- 1 O e ----a --n ----e ----a--CR--aT--Rn
`-- ScEkedeu-- pespeacance
wE 2w23iE o4lmrmE dioma e
HUiormininearyfosamcaotnatiionnetnce
Ek wwo eeeddmeSee5w3wom1
Unkenoe. appearance Deaths
W w0w0e0w16331 2
200 my/xq/eny vemos
ANJ ipcpnkeeaar-er udpnsoprpmea-- nlcance TiBonlnkokeocsspySrnoorseveseansinaodmnmteouth Tupersctive suathe 25sapa/enywares feoSFreo-- cnkediue-- epesppencance Bevoravseont tem
mWm12o1me1m2 moo1l1wE6 6 wNwE rNE2 Nm 6E6 N4lE5 m1NE4 omO h 2om3N o3eE o11 m mC owCm1oTCN ww1Nm oWE wEEewWNC E TWm wN E TNwEE YwWE A
WmEEE EE mwmo1Wwom2 fwmedm e WwdmNmomweema owwn mEoi Emma hea
WW
mw ew
0000 2411
13 mm a Ne ee 01100000000
mW 2w2smw 9w39 27lw 4sism4]31 1 l 31e1 Twme1sm1 eece1 we1 eEw Se1 e ee
rr
5
Table 5 (concluded) v0 MeaRk 0Sex1hpbomoraeenEnoieanfnieonctmitannsrgs sy
i Rerertearey
-- Retest
T1 S 7 34 5E6T7T8 ST5 1Rm0 Nm11 1P2 T13 W14 E15 R16 E17 E16 1E9 E30 TFEB
ES
w[in ----
E mw ssm w 223 5e 3 53 3d0wme 0w 3i3a 3w 2323232e 212220:
iTTSnoiokcsnoeissmcytpcroenAnmopvousurselsssatinadonnmcsoeuth impon Tortside
NE E WEE mNEE EE NEEENwEmENA EweENEeNEeE TeWE1oNwE1E R 1lENdmEm NwwEoNmmE E NREERMwNREMwNE NbEe wNbA EeA NmE NE aNE NE
seats
0 000 00 Bo Ro 00000000o0o
25 ma/kg/day Females
Aeepkaneairea naoprpmeeadrence Eerpicatory congestion
mE WB oEwEmoEmwmmmr oEe3 7w45w45a416 e w 4552o 14 1w 3 i 23ww 3 mm 2w 2To 2T w 2s m E 2aw Tm aa!
ClTnrokEneoicrT/etosornnpisecncrodanenvncuslesnion M[EW E NEEEmEEWEEENmEEEmNEEENE mEEwNEENmEEwI1 NH wE NwEE NwE NEA1 NEH AN1 E NE1E NE N1 AEH hNE1 wNEoN1 E NE
-- Deaths 00000000 6r0r0r000000000
BS 3e cE=omvmmoie tsmeivvie.daenpsisodes geerally cccureed ducing banding (dosing, weighing, ote.)
ie
IEpive outhanatized, one found dead
"
20
Table & Two Week Oral Rangefinding Study
of 7-2509C0C in Rats Summary of Clinical Observations
Number Affected/Group
Csliignnical
204
No signs through study onz
Treatment-related deaths 12/12
Soft feces
8/12
Tucked-up appearance
1/12
hin
6/12
unkempt appearance
4/12
Tonic or clonic/tonic convulsions
6/12
Hyperactive
0/12
Head tremors
0/12
Urinary incontinence
112
Respiratory congestion 0/12
Bloody nose and mouth
0/12
Lump on left side
on2
Hair loss on abdomen
0/12
D2o0s0eG row(mg/k7g5/4day
TE
0/12
112
112
10/12
0/12
112
0/12
2/12
oz
12/12
6/12
6/12
1/12
e/12
8/12
312
8/12
6/12
312
2/12
112
112
o/12
112
0/12
112
0/12
312
0/12
0/12
0/12
712
1/12
112
1/12
0/12
0/12
112
0/12
o/12
012
1/12
03716
able 7 No okof O7r-a2R5an0go5ifni0nRd0aitnsg stucy
Group Mean Body Weisnts
Gar.ow
e = T m5y mm = To T LaeomSs noEot
20mm S1sn aamwen m1eMe ae en
an
-
20mAg/eys 1304 169.208 m1o4s2 aMomoes Hidsde wsoeosn
oy an
Teeny 1f1m3 awame 1w0e9n smeRm uHseam aaaram ahessae os an
T-- Smafosday Se17356 1d6o3e.7s Quneo 1n2s9.e5-- % heeass rdemear s10s.7i oa ae |:
2 vDoosisntg ddiissccoonnttiinnuueedd ffoollltaodtnngg adaayy 5
2
8
Sg
2
Discussion
Ddoasialgye-gasatndricsexi-nrteulbaatteidonefoffecrtast.s
with The
Tp-ri2m5a0r9yCoCeffreecstusltweedreingatsrteratimcenitr-r,itation,
handling-induced responses to the
convulsions and gastric effects
mwiecrreosacotpuicckedl-iuvperapcpheanagreasn.ce, Doasnaguen-kreemlpatted
raepsppeoanrsaenscetaondthseofgtastfreciecs;effoencltystwheermealtehsinhneasdssaonfdt bfoedcyes.weiTgrhetatlmoesnst-druerliantged
dosing. stomach
iTrhreitafteimaolneswhilcohstimnocrleudweedigahtfewtheaanrltyhehmeamloersr.hagGircosgsastarnidcmiuclrcoerssc,opwiacs
porcecsuernrtediinntmhoerehigahnimdaolsse
girnoutpheonhliyg.h
Convulsive episodes (CNS stimulation) dose group than the low dose group and
meofrfeectmsalweesrethahneafdemtarleemsorshaadncdonhvyuplesriaocntsi.vityL.essDofsraegqeu-entandtresaetxm-ernetla-treedlatleidveCrNS
cthoaxnigceistyooccccuurrrreeddininmotrhee mfaolremsofthafnocaflemanleecsr.osis and fatty changes. The liver
Dosage-related deaths were caused by T-2509CoC treatment. More high dose
males died study.
than
high
dose
females
and
the
males
started
dying
earlier
in
the
The recovery interval resulted in reversal or cessation of the toxic effects. Gastric lesions were not present in the two surviving high dose females. Gastric pain (tucked-up appearance) continued for the first few days of raneicmoavlesr,y haonwdevaerf,ewhaadnibmoadlys wceoingthitnugeadintotahprpoeuagrhouutnketmhpetreancdovetrhiyn.intAelrvlalr.ecoTvheery later-occurring deaths in the high dose female group were probably due to a generalized debilitated condition because none of these animals had microscopic cLhiavnegresn.ecroSseivserweasdenlaoytepdrecsoennvtulsiinontshedirdeconvoteroycacnuirmadlusr.ingTrheecolvoewryd.oseForceaclovery group had more males than females with mild fatty changes in the liver.
03718
23 Appendix I Two Week Oroafl7-R2a5n0g9eCfoiCndiinngRTaotsxicity Study Protocol
TITLE: P(rSottuodcyolNumfborera1T7w9oRR0W2e3e)k Oral Rangefinding Toxicity Study in Rats
TEST ARTICLE:
A clear, chemical
pale will
byeellsouwpplsioeldutbiyonToixdiecnotliofgiyedSeasrviTc-e2s5,09C3o4C.CompTahniys,
st. Paul, Minnesota.
OBJECTIVE:
Tihneraptrsimadurryinogbjetcwtoiwveeewkisllofbedaitloyigdaesnttriifcy ainnytumbaajtoirontoofxiTc-2e5f0f9eCcotCs.
hBoewfeovreer,thethedosaecsutweilolrableALsDeSlOecotfedT-t2o50c9oCmopCletien
the above rats will
objective need to be
dseutpeprlmiiern,ed.straTihnisanadcuatgeeporratnigoenowfilrlatsusaesmadleesscroinbleyd
from the same below for the
rEveapleuaattidoonseMepotrhtoidon6.05ATwhiellgenbeeraulsedprofcoerdutrheesacfuotreadoRsikienrg
Safety except
that
susiex mtahleesa/cluetveeldawtialltobeseldeoscetd.theThdeosasgpeonsloervelasndfosrtutdhyedtiwroecwteoerkwill
repeat dose study.
Atthethsetudcyondcilruescitoonrofhavtehethtewoowpetieokndoosficngontiinnteurivnagl,thetheobsspeornvsaotrioannd
pexetreinoddedfoorbsaebrovuattoinoen-phearlifodthweilmlalebse
and two
wfeeemkaslesinatleenagcthh
level. The and dosing
will not occur during that interval.
CONTROL ARTICLE: None
SPONSOR: Toxicology Services, 3 Company, St. Paul, Minnesota
TESTING FACILITY: Ssta.fePtayulE,valMiunanteisoontaL.aboratory, Riker Laboratories, Inc.,
DOSING INTERVAL: September-October, 1979
DOSAGE LEVELSb,ecaRuOsUTeE,itGRaOpUpPe,arsSIZtEo,beEICa.n:appOrraolprigaatsetrriocutientfuobrateivoanluwialtlinbgetuhseed systnic toxicity in rats. The rats will be dosed daily for two weeks (1)
Alevceoln.staDnitstdoislelevdowlaumteerowfil1l0 bmel/kugsewdilflorbeallusnedecfeosrsaeraychdilduotsiagoens of the test article.
03719
Appendix I (continued)
2
Dose Group. High Low
Dosage Levels (2) a(fttoevre tsheeleacctuetde pcoormtplieotnedh)as been
Group size 124,129 124,128
ANALYTICAL CHARACTERIZATIONS: The sponsor has on file one or more of the following or other pertinent characterizations of the test article: identity, synthesis, strength, purity, stability. Ptrheepatreasttioanrtiacnldemweaislulrbeemenctonsriecdoerrdesd afdoerqutahteevavreiroiufsicdaitliuotnioofns of croanntgeenftindainndgcsotnucdeyn.tration of the dosing solutions for this
TEST SYSTEM:01dTwoenntdyo-sfeoudramyal1,e wainldl2b4efuesmaeldefCohrartlheesreRpievaetr CdDosreatsst,udy4.5-55Thedays (3) acangiemsalswiwtihllwibree mheosushedfloionrdsiviadndualflryontisn.haTnhgeinrgosotmawiinlllesbsestteeemlperature and humidity controlled with the lights on a 12 hour light/dark cycle.
JUSTIFICATION FOR SELECTION OF TEST SYSTEM: Charles River CD rats will be used because of historical in-house data on the strain.
TEST SYSTEM IDENTIFICATION: Each animal will be assigned a number which will be indicated on the outside of the cage and on an individual ear tag.
RANDOMIZATION OF TEST SYSTEM: The animals will be indiscriminately removed from otfhecasgheisppifnrgombolxeefst btyo ArniigmhatlsCtaarretipnegrsaotnntehle atnodp palnadcweodrkiinngthedowrna.ck The study director will assign dose groups by vertical rows.
DIET SPECIFICATIONS: Purina Laboratory Chow and water will be available ad libitun throughout the study.
BIOAVAILABILITY OF TEST ARTICLE: During previous acute toxicity studies in rats, systemic absorption of the test article appears to have occurred in the form of delayed CNS effects.
CLINICAL OBSERVATIONS: The animals will be observed daily throughout the dosing interval for evidence of treatment-related toxicity. Body weights will be recorded approximately one week prior to dose day 1, on dose day 1 and biweekly thereafter. Food consumption will be eresttaiimnaetdedfwoerektlwyo atdhdriotuigohnoault wteheeksdosfionlglowiinntegrvdaols.ing,Ifthaenyimwaillslarbee observed and weighed as indicated above (4).
03720
Appendix I (continued)
25
TISSUE
PATHOLOGY: during
Gtrhoessstundeyc.ropsIineasniwmialllsbweitchonaduutcotleydsiosn, alals
rats which a minimum,
die
bseamfpliexsedofinlfuongr,malliinv.er,Mikicdrnoesyc,opibcraiexnamaindnatainoyngwriolsls dleetseiromninweillif
itnheatmiosrsiuebsundareconsdaittiisofnactsohroyuldfobrehitsetromliongaitcedditoagnionssiusr.e sAantyisfraacttory
tthiesssueelescatmpeldess.urvAivpoprrsoxiwimlaltebley k2i4llheodursforfoglrlooswsinngectrhoepslyastexdaomsien,ation.
The any
aarneimasleslecsteelde,ctweidllforbeadkdiiltlieodnaflorobgrsoesrsvatnieocnrowpisythoeuxtamidnoasitnigo,n
if at
tfhoermeanldinofarethaltisitendtebrevallo.w. Samples to be fixed in 108 buffered
12.. EMyaemsmar(y2) Gland (female)
3. 4.
TThhyymruosid/Parathyroid/Trachea/Esophagus
65.. HLeuanrgt
7. Liver
6. 9.
AKiddrneenyasls (2()2)
1101.. UTreisntaersy/EpBildaidcdyemris or Ovaries
12. 130
Uterus or Prostate spleen
.
1154.. sPtaonmcraecahs
16. 17.
SLmaarlgle IInntteessttiinnee (at least two areas)
11980. MsecsieanttiecriNcervLeymph Node
22100. SBrpaiinnal Cord/Bone Marrow (cervical and thoracic)
22. 23.
pAintyuiGrtoasrsy Lesion
Tsheeletcitsesduebsy tthoebepaptrhoocleogsissetd aantdtheexamcionnecdlushiiosntoolfogithceallgryoswsillnecbreopsy. pTrhoecetsissisnuge s(5e)l.ections will be reviewed with the sponsor prior to
DATA ANALYSISwiAlNlDbFeINsAeLleRcEtPeOdRTa:t tThheecoanpcplruospiroinatoefsttahetissttuidcya.l aTnhaelysperso,posiefdadnya,te f(oarpptrhoeximfaitnaellyre2p-o5rtmonitshs1-a2fmtoenrthnsecraofptseyr).slide reading is completed
03721
2 Appendix I (concluded)
AMENDMENTS: 1.
2. 3. 4. 5.
The was
last day of dosing day 5 and the last
for the high dose day for
dose group (200 mg/kg/day) the low dose group
w(e7r5emgo/bksge/rdvaeyd) fwoars adpapyrox9.imatAelllysutwroviwveienkgshifgohlldoowsiengantihmeallsast
dtohsee.apprFooplrlioawtiengnucmobmpelreotfiomnaloefsdoasndingfemataletshewelroew dkoisleledletveol
reach a total of 6/sex dead. served for approximately two
moTrhee
wreeemkasi.ning
6/sex
were
ob-
The selected selected low
high dose
dose level was 200 mg/kg/day level was 75 mg/kg/day.
and
the
Age day
range for the of dosing.
acute
rats
extended
to
59
days
old
on
the
Body weights obtained rather than biweekly.
once
or
twice
a
week
during
recovery
The tissues processed for liver, adrenals, stomach,
hkiidsnteoypsatahonldogbiracianl. evaluation
were
03722
2
Appendix IT
To Week Oroafl7-Ra3n5g0e5f0i0ndiinngFaTtoexicity Study List of Principal Participating Personnel
Nene Marvin 7. Case ames D. Henderson, Ir. Cathy 2. Ludemann Gary c. Pecore Tnara Porietis Jan H. Skeons G. Ray Steffen
Function Veterinary Pathologist Stat veterinarian Coordinator - Clinical Pathology Coordinator - Anisal Care Histopathology Technician Toxicology Technician Study pizector
03723
DISTRIBUTION LIST M. 7. Case X. L. Ebbens F. Db. Griffith W. C. McCormick R. A. Nelson G. R. Steffen (2)
03724