Document rBa9akRXmJBG8aaOqEvYVbX8v

Experiment No.: conducted at: Dates Conducted: Conducted By: Acute oral Toxicity Screen with 1-2574c00 in Albino ats RECEIVED OCT - 31379 TOXI3CmOLOGY 0979m80037 SRStia.kfeertPayuLlaE,bvoarlMauitanotnrieiosenost,aLabToncr.astory August 6, 1979 to September 6, 1979 DLDaLbWo.UratvaoMrriyeosTa,ench3k7n.oicgiahn- aDarteg : der mx.21.. cmabseens (2) WE.lo.. Gnreiceoerimtinck FSLlfobeens,e5s L SSteundiyordiTozxeicctoolrogist 7 FiBaste 7 004374 . 1. Summary An acute oral toxicity screen with T-2574CoC vas conducted from August 6, 1979 to September 6, 1979 at Riker Laboratories, Inc., St. Paul, Minnesota using male and female albino rats ranging in body weight from 203 to 300 grams. The test article was administered by gastric intubation at dosage levels of 5,000 and 1,000 mg/kg body weight with mortalities of 10/10 and 0/10 noted respectively. The untoward behavioral reactions which occurred during the stuly generally cone sisted of diarrhea, hypoactivity, lethargy, urinary incontinence and unkempt appearance with the onset of the reactions occurring from two hours to seven days post dose administration. ALL reactions subsided by day seven or death precluded recovery. Autolysis precluded gross tissue evaluation of the animals rom the 5,000 mg/kg dose group with the exception of one male which had heme orzhagic lungs while necropsy of the animals from the 1,000 mg/kg dose group revealed no visible lesions. The approximate oral LDSO of T-2574CoC is between 5,000 and 1,000 mg/kg in fasted male and female albino rats. Introduction The objective of this study was to approximate the acute oral LDSO of . T-257400C in fasted male and female albino rats. The study was initiated at Riker Laboratories, Inc., St. Paul, Minnesota on August 6, 1379 and completed on September 6, 1979. The raw data generated by the Study Director and final report are stored in the conducting laboratory's archives. 2 Riker Toxicity Experinent No.: 0373A%0037, Test Method GSA 004375 2. Hothod and nesuies Young albino rats vere used in this test. ALL animals were held under quarantine for several Gays prior totesting vith only annals vhich appeased to be in good health and suitable as test animals at the initiation of the study uasned.humTihdeityratcsonwterroellheoduzsoedomsinsanudsppeenrdmeidt,tewdirae-smteasnhdacradgeLsabionratteomrpyerdaiteurteplus Vater ad 1ibteum except during the 16 - 20 hour period immediately prior to sastric intubation when food vas withheld. The rats were adniniatered the test article at two dosage levels. ALL doses vere adainistered at a constant volume of 20 ml/kg into the stomachs of the xats using a hypodermic syringe equipped with a ball-tipped intubating neodeS, After gastric administration of the test article, the rats were returned 0 thelr cages and cbserved for the following 14 days. Initial, day one, seven and final body weights, mortalities (Table 1) and adverse reactions (Fable 2) were racorde A necropsy was conducted on all animals that died during the study as well as those authanatized at the end of the 14 day observation period (able 1). The protocol, technical personnel involved in the study, composition char actertatics, and Quality Assurance statement are contained in Appendices Izv. =&ProCaphlpasertlroensaPnRudirviSeonrnasS,LraebIanodcri.an,tgoNrLeyawbCohMroyawdt,eornFiaaerisks,,toINnnecwP.e,YroiWrniklsmiSnrgtoan,uastsarcheusestts 004376 TABLE 1 ACUTE ORAL TOXICITY SCREEN - ALBINO RATS with 7-2574coc : Mortality, Necropsy and Body Weight Data C Dosee & AnimalTndTiesvt DiaysdoNduwmbwieer:igh (29/kg) Sex umber 0 1 7 1a Nunber ~ Dead Sumber Tested 5.000 M 99RRILLLIIEE?E 228580 ~.- (~5 Da(y8s)Day-s) 5/5 9SRRIILLLITE0Y 238070 ~-- ((76 pDaayyss)) -- SRILLTL 281 ~- (7 Days) - F9RI9R0I2026667 222240 ~-- ((35 Dpaayyss)) -- 5/5 99RRI100226698 224641 -~ ((76 DDaayyss)) -- 9R10270 264 ~ (4 Days) - 1,000 M 99RMI2233%767 221361 221388 129763 320520 ors 99R1I2237I8S 222043 222415 227135 236085 9R12380 233 256 280 317 FoSRl2a08 9RI2409 220283 222460 221530 222444 ors S9RRI1224411l0 221164 222372 223218 223320 SRI2412 214 229 233 2a1 3. -- PeDrecaednt 100 100 0 Note: Figures in parentheses indicate time of death TfaassetaegdurmaeleoraalndLDfSe0malaeppeaalrbsinotorabtes.less than 5,000 mg/kg and greater than 1,000 mg/kg in # he test article vas administered as a suspension in cottonseed oil. SNiecnro{psLyeFPirnedcinlgusd:ed gross {thheeh1,t0he00exncge/pktgion of one mtailsesuweheivcahluheadtihonemoorfrhaalglicanilmuanlgss. frNoencrtohpesy5,o0f00tmhge/ksgotadeorsee gLroou dose group revealed no visible lesions. 004377 ---------------- sCorien sex maori 500M Sawaltvhaaetcigyotn GunrkSieoanpepaytcaInncee mais 2 ACT: om TomzciTy scasm - Aamo wats wien r-zs7icse Summary of eacticns mt"imwbeee rbiAsttee etcTMted jFoorntoiTvSivnigGvaetsie GAenFiomlrlloewtioinragtetloosrne ,2 i7ys3s 772 oooaawrresss 7 on unTnoieutdr)sbbeeaaccnh frtegony os 20a owe . TEionbeloovfingteboase so: oo 5000p foBMaoncpieascciiaon sctivdey wis7sss 4 drsooeeurss 2 Howes 8g$ inathhhoeaprerasycance 757 Hoeu 3J ortcioanstyineInnce 5s oer 1000 n SnoIklpeemmcaepchtteisviey 721/s3 TT3oo toe Aopearance 1000 ontkSaecpmeesncance 7us T1oouurr mnneeeldsdst eDDeeseaenn FRET Sionenutadysseat ous . o32 0nouaas reeseeerrs =3aa rere 7r1iante RinAdLiCcaatteess hwhaenn nfioxsat.nianaimailn ttnhtdhoesedo3s1e0g0rpoeupdhebxihsisbithsetrheescseeisocntion . - oe = o-l APPorPoEcNoDrIIX Riker Experiment wo.: (AIGRROO. 5. TET Acute OarToaciry-SinceDose <Y SCPOONNDSUOCRT:ED 3B%Y:ComSpaafneyty_ B(vaolumatmieovnicLiaabeoratoCray,eaRiikaer Laboratories, Division mnc., St. Paul, Him TEST ARTICLE: T= 25 "Td (aC cwmoL mem: mane TPRSOPOsSEtD sSTARTI0NGs,oCmoweP:LeTQIeoNudoaiTePouFrTiestR:undgegLah/nc1to5n0g 0s SNeex:s.Ompm, ,5 -_ Weight Range: 200-300 acvms OBJECTIVE: Theaosbejaective of tT histRotxaeisdctsitwyi_llofwbeetrheetosteeclshetacrtaaecrdtteircasilezeainttheaesltbasicpnroeeten aTnodr greenperroadlucaivbaiilliatbyilGiFtyr.esponse, historical use, ease. in pempiing METHOD: qcTuhaeasreasanntiiinmnaeltseamwnpdierlaltteusbrteepheaornuidsoedhdsu,miinwdiisttthyaincflooenostdsgosaltnledeedwlartosseuersspoefdnfudereridendwgibraeo0tmhesthhe iLnigbitto wt.he correspond "0lEaabcahorcaaatnroidrmyal'asfwfiislxtleadnbdeatordidtheoenpteiSrufatitseiidndgebyproofccoetldhoeurrecc,aogdewi.nhgi,cAhawsciictnolgrlde s dc0oesiatvgheeedlroffrcoamgetsheORaT0nsApd0oSnod esbosaremn,rgv/ekadgfth wefriorlwli haibnceyhn uandtthmeoivnaisanrstidtamerabreleedshdawvttiiooloelrcaaaccblhheraeasnsneciivtmroaislmne.eed The frtooe;rcohtrehdaeerdtf,olAlluonGwgrison,sgs 1ln4ievecdrra,oysp.skyidnwIehnyiiscthiaawnlidlaglnednienfrcialnluadleg,baosbdturytovienniotstehsibtesinwa1ilitnstirtvaeecst wgtriholeslstebsaebtncooarsnmdawulecilttleideassonwthahielclhanainamrieamlaslosbssuwerhrvivicevhdinddgiusritnhdgeurttihenesgtctpoheenrdiucocodtn.doefsntyth.oef . snthieetcerRoipoksbesyrewrviLeladlb.orbeatAoLrrLeiceorsrawdAerddcahwtiiavtehasn,dspetSthc.eifPifaciunlma,elntMriiesopmnoersttootwait:lhle beergusntorsemda/oinr py 2 EB pGurreinmaalLsaboWreattoryhaChogwa,atRiaelsttopnouPur&inaM,ohSto. Louis, Missouri paste 4 Sag=ctaenr)daBp f F baind weit 00Lethen CChhaaneecGuuligung Ht Fepictlsy andilbovi)) - Ly ckllisrey done Leva will 62 odininitrid)| ReodlvH 004379 Ju20e1673 [Rp SWpwonO sor eThelori Tat2e/10 Seay biker1? Bae APPENDIX 1 (continua)*Fx POTirinmeenntt NoNo..:: (OIAR00C57YT] Amendment to Protocol 6. 1 bus bo OR mitidesof (fy teed pmadiniad (jolid) ib ums 00 0- CA- NA VS7eed=y D=s > S7 as 2. Dagon? body GALL we nantly omit) on tac ood alive out%otJ, Upecs Yi .e-- r ----------------|i She-- ds Dt-- ea ctor---- , 2-- at%e e-- rr----cere---- e. -- r --_--------------------n--T------ ES ----ee-------------------------- . s.S --_-- E Sree -- ET sc re r--------re------------ ._P -- L ---- . Study Director Date a.-- --_-- --------------Tre-- s ----ee == s.-0 _-- -- 000 FE0 wee 290090900 --_-- Sesto ee oo 004380 op . 004381 o . asemprx 11 TTeecchhnniicalPPeerrssoonnnneellInInvvoollvediinntthhee Ssteuudsy taNammee rwFuenscttieonn 5.- M. Markos, Jz., ALcaubtoeraBtolroycoTmepcahtniibciilainty XD. o'Malley, Bs TAedcvhannicceadlTWorxiitceorlogtst K. L. Ebbens, 35 SSteundiyorDTiorxeicctoolrogist G. c. recore ACnoiomradlinaLtaobroratory 004352 Aemprx111 s. Composition Characteristics This study ds not regulated by the Good Laboratory Practice Act of 1578 and therefore information pertaining to composition characteristics is not applicable for inclusion in this study. 004383 e eetsac . 10. APPENDIX TV Quality Assurance statement This study is not regulated by the Good Laboratory Practice Act of 1978 and therefore a statement signed and prepared by the Quality Assurance 9FOUp is not applicable. This study was, however, audited by the Quality Assurance group. In addition to the data audit, different significant phases for studies undervay in the Biocompatibility Laboratory are inspected weekly on a recurring cycle, and the facilities are examined by Laboratory Quality Assurance on a three month schedule. 004384