Document RprN2j8kR19a6NM3J52w12Gkk

@ HpaazsLEsTeON ARN&-0323 FINAL REPORT =: : Roger G. Perkins, PhD 3M Toxicology Services Building 220-2E-02 St. Paul, MN 55144-1000 HWI Number: i 40200468 Stu Tite: Acute Oral Toxicity Study of T-5898 in Rats (OECD Guidelines) Signed: " Study Director Acute Toxicology 2.A 05742 EE TRRTSEWAT BELVERYSRT EWN ESTER TRS oR er Fe HHT Number: 40200468 Sample: T-5698 Acute Toxicology SSttuedvyenDiM.recGtloarza Manager SSttuevdeynCoR.ordSionraetnosron PIant-riifceiaSuPpaedgrhvainsor RReopsoert. `SBurpiedrgveisor Page 2 KEY PERSONNEL LaboratoryAnina)Medicine DCiipnldoymaJt.e,CarAyC,{AHDVM Supervisor Anatomical Pathology ATnhaotmoamsicEa.l PaPlamtehro,logPihsDt JDaecbkoraSherfL.ortPirkel/ SNeucpreorpvsiysors ASnunpeerMviossohrer Pathology Data CONTENTS Page ObKjeyecPteirvseonnel 32 TTeesstt MSaytsetreimal 33 SPurmomcaerdyureosf Results 45 DReifsecruesnscieosn 313 APpaptehnodlioxgy - ReRpaowrtD.ata 1 15 05743 - HHI Number: 40200468 Page 3 Sample: T-5898 OBJECTIVE The objective when the test of this material study was to assess is administered by the the acute oral oral route toxicity (gavage) produced to rats.' TEST MATERIAL Identification yTehellotwestliqmuaitde.rial was identified as T-5898 and described as a clear, 1ight- Purity and Stability T(hiencSlpuodninsgorunadsesurmetsestrescopnodnistiiboinlsi)t.y for purity and stability determinations StoanrdRa etegntieon wTihlel tebsetremattuerrnieadl towasthestoSrpeodnsaotr raofotmerteimspseuraantcuereo.f tAhenyfiunnaulsedreptoerstt to Hazleton Wisconsin (HI) Standard Operating Procedure (SOP). amactceorridailng safety Precautions The test material handling procedures were according to HHI SOPs and policies. TEST SYSTEM Test Animal ALadbuolrtataolrbiienso, raItncs. ofandthemaiCnrt1a:iCnDeOd(SDa)tBRthestrHaaiznlewteorneWipsrcoocnusriend ffraocmiliCthyarlaets38R0i2ver PcoamcpkleyrswiAtvhenuset,anMdaadridssono,utlWiinsceodnsiinn.theAn"iGmuaildehufosrbantdheryCaarned hanodusiUnsge aotf HWI Lteambpoerraattourrye-Aniamnadlsh*u.n"idiTthye-caonnitmraollslewderqeuasretpearrsa,tepdrobvyidseedx,cohnotuisneudouisn access to LaacbcolriamtaotriyonRpoedreintodDioeftat5l0e0a1s,t P7HIdayFse.eds,TheIncf.e,edanids wraotuetri,nelayndanhealldyzefdorbyanthe mSaamnpulfeasctuorfertheforwatneurtriatrieonpaelriocdoimcpaolnleyntsanaalndyzeednvibryonHmHeI.ntalThecroentwaemrienanntos.known cthoentarmeisnualntstsofinthtehestfuedeyd. or water that would have interfered with or affected 05744 HNI Number: 40200468 Page 4 Sample: T-5898 daToessnseigmnaleelvdeeltaoncdotnw1so0istfteremedaaltemoefnatfcicvgleriomuamptaselde ofarnadt5s0,0fivawenedigfhe5im,na0gl0e0 frmragot/msk.g22o5Afntiobmoad2ly8s0wewg,iegrhewte.grreouEpach othvhoerurosnuedigghhobtuytpseterhxieoadsntdubdeiyfd.oernetFiofteoisdetdamnbadytewaranitiaemlarlwaednrmueimnbieasrvtariaanldtaibolcneorwarhdeesnploinfboidotidun,ag, beueatxrcentpoattg wfaotrera,n wcaosndwiittihohneslde.xistIefd,vartiheaytiownesre fdroocmumtehneterdequanidredcontseimdpeerreadturteo effect on the study outcome. haanvde hhuamdidniotyadverse Justification for Species Selection Hairestoprriecfaelrlrye,d bryatsvarhiaovuesbereenguluastedoryasagaenrceiperse.sentative of a rodent species and PROCEDURES Preparation and Adninistration of Test Material dTheeterumnidnialtuitoend An individual toefst1.m13ateg/rnilaLl twoasdetaedrmmiinniestetrheeddobsyegavvoalguemeusfiorngeaachbudloksedenlsevietly. dose was calculated for each animal based on its fasted body weight. ReasonforRouteof Adninistration Hkinsotwonriacmaolulnyt, otfhetesotralmatreoruitael.has been the route of choice for administering a Observations 2C.l5i,nicaanld 4obsheourrvsatiaofntseratnedstmomrattaelriitayl chaedcmkisniswterraeticoonn.ducAtdedditaitonaaplproclxiinmiactaelly 1, coobnsdeurcvtaetdiondsailayndtthweirceeaftaerdayformor1t4adlaiytsy. checks (morning and afternoon) were ABdoddiytiwoeniaglhtsbodwyerweeidgehttesrmiwneerde dbeetfeorrmeinteedstatmatDearyia7l, aatdmtienrimsitnraattiioonn o(fDaythe0). experimental phase (Day 14), or at death when survival exceeded 1 day. 05745 HHI Number: 40200468 Sample: T-5898 Page Pathology At termination of the experimental phase, surviving A11 animals, whether found dead during the study or animals wereeuthanized. euthanized, were subjected to an abbreviated gross necropsy examination and any abnormalities were recorded. After necropsy, the animals were discarded and no tissues were saved. Statistica] Analyses No statistical analyses were required by the protocol. ocation of Raw Data, Records. and Final Report Tahrechirvaews daotfa,HHIrecionrdasc,coradnadncaecowiptyhoHfNItheSOPf.inal report will be retained in the 05746 HHT Number: 40200468 Page 6 Sample: T-5898 SUMMARY OF RESULTS TSoeusrtceA:nimaClh:arleAslbiRnioverRatLsabo-raCtrolr:iCeOs(,SDI)nBc.R, Portage, MI Date Animals Received: 01/14, 01/28, 2/04, and 02/25/94 Experimental Start Date: 02/22/94 Experimental Termination Date: 03/23/94 Estinated Oral LD;: MFaelmeal-e B-etBweetewneen50050a0ndan5d,'050,000m0g/mkgg/kogfoBfodByodWyeiWgehitght Individual Body Weights (g) : Aninal Day 0 __Day7 Day 1a Number Weight Weight Gain* Height Gain* Males (500 ma/ka) c2299213812 227687 322042 2483 338129 10528 2299213844 225830 321824 3312 335940 11001 29130 257 289 32 353 9% Mean 266 282 16 360 93 Females(500na/ka) c2287064175 22310 222285 --153 226515 220 2288004730 223225 210870 -2-455 (123391) 7- 28050 238 225 13 250 12 Mean 233 23 -20 251 13 * Gain from the Day 0 body weight. () aVnailmuael iwnasparfeounntdhesdeeasd.is Sthueperbsocdryipwteignhutmbeart tihnedictaitmeesthdeay of mdeeaant.h. This number was not considered when calculating the - Not applicable. - COs747 HHT Number: 40200468 Page 7 Sample: T-5898 Animal Number Individual Body Weights (g) Day 0 Height Davy Height Gain* Day 14 Weight Gain Males (5.000ma/ka) c28621 269 (203) - - - C2288651983 22676 (2+28) -- -- -- 28619 267 (215)8 - - - 28625 mn (234)? - - - Mean 269 - - - - : Females (5.000 na/kg 28099 26 (209)% - 28117 250 (235)7 - - - 2288111084 226677 (2(23385))% -- -- -- c28120 255 (225) - - - Mean 257 - - - - * Gain from the Day 0 body weight. t Arneiqmuailredw.as found dead on the day of dosing. No body weight () aVnailmuael iwnasparfeounntdhesdeeasd.is Stuhpeerbsocdryipwteignhutmbeart tihnedictaitneestdhaey of mdeeaant.h. This number was not considered when calculating the = Not applicable. C05748 HAL Number: 40200468 Sample: T-5898 Page 8 Individual Clinteal Signs Animal Musber Ooservation sour Ws mw Day Iz1f358 B87 0 8 01 H Males(500sa/ke) 28161 TAphpienaraepdpenaorramnacle C EE r EE APA L A y M, A C2232 Appeared normal ClL llbl L dg 29184 Appeared normal Cl it ci ry 29234 SAopfpteasrteodonlormal EC ER l A A i . 29190 Appeared normal CL iilbL by C2765 RAepdp-esatraeidnneodrfmaacle ThAilonpaepcpei-aarance rear quarters 26047 Appeared normal 26043 RAepdp-esatraeidnneodrfmasc]e THhyiponacatpipveiatryance HaAnogcrheesdsipvoestbuerheavior Found dead 28070 Appeared normal 28050 "RAepdp-esatraetdnneodrfmaacle 7= CCoonnddiittiioonn neoxtisetveidd.ent, Fem(a50l0maekas) s-C osse t ti as r te iio ia e ioidiD oo 0DdCd Ss ses sdd dtd td SLi rbd gy C EA l I r S- ooososEE I L EE I o EI l RE S= oo<o<r- i - _t_ y _ 1 , J Vl Ltr i i bd C = osLre ll tlib no b iy d 05749 HWI Number: 40200468 Sample: T-5898 Page 9 nvidiia nClisent sans Animal Mumber Observation te aw Llzf ww I'z3 45851838 002 501 awn paren BFens 4 rE o 4MnaE les(n5,0R 0i 0Ema/kLEe e) L, cs RfJperrepsdenvotme 0 440- [ewSaoaepia EDT TDo o1r o11n n4 FoS [ndeia r ay so Rrapimesrtimvoe t 4T`y d:- Founndcdarnd .Shy ns ETmpaerceeotrsoemn fp) L t4t7.7l1tg Dooney, cmsfrprep oerssetiv)ona m) sN4 A. =o ! Founddead Doty 7LcontC tonmntti esvn [EE HHI Number: 40200468 Sample: T-5898 Page 10 IndividuCaolntCilnivnefdea)l Signs Msboienarl Oseration LW for WI 731i i1T 0A EEE Eemles (5.000parka) conuss ARpepdesatraeidnneodrmfaalce A- E LL E og. FHpoHoonascdttsdievsitty S S Eo o E o nE t iy C8117 AVSpoepfletlaorswetsodtoalntornmeadl S `o-ou l * Redw-osgteuniinteedlfracees Lacrination S == ~L = I -- /4 FHooupnodacdtoinvsity Sooo nldy U8 ReDdaarsrktoausintdavienediynegsface 4 4 44 EE) HToeptolaocwt-isvtiatiyned Sooo Fouwndgdeastd ] ares S - = I ~~I 4 28104 YdeRolepdlesaotrwaesidtnaenidonmefdiace v or1 7 7 7 Staugrsogeerneidtaglaitarea Hnched posture S = o L= oo =n.dd Foutndodrenctlinical abservations) EE] C2810. HRAapenpbceshateradeidpnoensdotrumfraalece o SoLoLa l7 7 HFyoHpiuoonsadtesdtievsidty S SL lL r Slbastetrevratliionnse)al See =7 CCoonnddiittiioonn nexottsteevdi.dent. 05751 HWI Number: 40200468 Sample: T-5898 Page 11 Animal Number c29181 29232 29184 29234 29190 c27615 28047 28043 28070 28050 Sex M M M M L} F F F F Individual Pathology Comments Dose Level: 500 mg/kg of BodyWeight Died - est Day Sacrificed 14 14 14 14 14 14 - 14 8 - - 14 - 14 NecropsyObservation No visible lesions. No visible lesions. No visible lesions. No visible lesions. No visible lesions. There is alopecia on both hind 1imbs, 60 x 35 mm. No visible lesions. Due to the animal being cannibalized the spleen, pancreas, left kidney, duodenum, jejunum, ileum, cecum, colon were not found at necropsy. No visible lesions. Each horn of the uterus is filled with a clear fluid . 05752 HHI Number: 40200468 Sample: T-5898 Page 12 Individual Pathology Comments Dose Level: 5,000 ng/kg of Body Weight Animal Number cgal Test Day Sex. Died Sacrificed 7 - Necropsy Observation No visible lesions. 28613 M 3 - No visible lesions. cogs98 mM 0 - Tehyeesr.e is red ocular discharge in both c28619 M 5 - tThheerdeorissala ctearn,vicmaolistregaiborna,ded15arxea10on mn. c28625 WM 2 - yTehlelopwe.rianTahlereregiisonredis nasstaalined odifscthhaergset.omacThhehansonmgullatnidpulleardmaurckosraed dairaemaest,erp.inpoint and up to 1 mm in 28099 F 5 - No visible lesions. ces117 F 2 - yTehlelopwe.rianTahlereregisionredis nasstaalined odifscthhaergset.omacThhehansonmgullatnidpulleardamrukcosraed dairaemaest,erp.inpoint and up to 1 mm in c2818 F 3 - No visible lesions. c28104 F 2 - yTehlelopwe.rianTahlereregisionredisnasstaalined odfiscthhaergset.omacThhehansonmgullatnidpulleardamrukcosraed haarseasm,ultuipplteo d3arxk1rmemd. areTahse, thupynutso 1 mn in diameter. c28120 F 2 - The perianal region is stained yellow. 60S 753 HWI Number: 40200468 Sample: T-58%8 Page 13 DISCUSSION Tvaehdiemgihnatic.sutteerBeoadrsaeldasatonoxitshcieintgoylbesoefgravvTea-dg5e8m9o8drotwsaealsiatetyv,alleuvthaeeltseedsotfiinm5am0t0aeldeandoarnad5l,0f0e10m0agnlgef/okrrgatmsoaflwehbeoandnyd fteomxailceityratisncwlausdeddettehirnminaepdpeatroanbcee,bethwuencehned500posatnudre5,,00h0ypomagc/ktgi.vity,Cliangigcralesssiivgnes of behavior, staggered gait, miosis, lacrimation, dark red-stained face, clear or red staining around eyes, dyspnea, nasal discharge, soft stool, yeliow- or dark-stained urogenital area, alopecia (rear quarters), and death. All mortality occurred 10 animals treated within at 500 8 days of test material administration. mg/kg exhibited body weight losses of 5 Six of the to 45 g during tphaethofliorgsitstw.eek of the study. Page 14 contains a pathology report by the study REFERENCES 1. "Acute Oral Toxicity," Organisation for Economic Cooperation and DMeavyel1o2,pme1n9t81')s. Guidelines for Testing of Chemicals, Section 401 (adopted 2. NIH Publication No. 86-23 (revised1985). C5754 HWI Number: 40200468 Sample: T-5898 Page 14 PATHOLOGY REPORT T50h0ereandwer5e,00100 nrga/tksg,(fnievcerompaslieesd.andAlfliveanifmeamallsesg)iveenach5,0f0r0ommgd/oksge alnedvelosneoffemale fanrionmaltshewegrreoupeutghiavneinze5d00amndg/kngecrdoiepdsieodn tatestthe(DOtTe)r.minaThteionreomfaintihengstsuudryv.ivinTghe dose the level, day Individual of death, Pathology and gross observations recorded for Comments that precede this report. each animal are in At necropsy, Brown stains most of the changes observed were in in the perianal region and red nasal the animals that died on test. discharge were indicative of acute death. All other changes in autolysis. The alopecia and fluid these animals were attributed filled uterine horns observed to in post mortem two of the females surviving to study termination unrelated to the test material. There were were considered no visible incidental lesions in findings and any of the - remaining animals in either group. ons o Palmer, Pathologist (40200468. 1hm) 041194 ateye22-F C5755 HWI Number: 40200468 Sample: T-5898 APPENDIX Raw Data Page 15 C5758 wi: 4030048 ; PERSOANCNUETLE STIOGXNIACTOULROEGYSHEET Name Job Title ay nits Rose M. Bridge Anthony Cass Report Supervisor Cedric, 8 Lab Animal Technician Gitlin, Cann ac Cindy J. Cary, DWH Lab Animal Veterinarian dp). Donna J. Clemons, DW, MS Lab Animal Veterinarian &. John A. Disch Lab Animal Caretaker Derch x0 Charles W. Fritz Lab Animal Technician (hands, W, ZZ 7 Kari Garfoot Lab Animal Technician i ie Steven W. Glaza Manager _se Kevin Grossman Jeff Hicks Lab Animal Caretaker N Lab Animal Technician 4A zl ) sharen L. Hovery Research Assistant Siler Su Wayne A. Madison Doug McConnell Supervisor Cpr2pal tem Lab Animal Technician Lesh (0 onal]Oren Efleen McConnell Bud Hebonald Staff Assistant Study Coordinator Be Phi loris e Lor Bodnal) sre Albert oleson Lab Animal Caretaker _COAAY) Goon AO Patricia Padghan In-Tife Supervisor Loic dl 2 Steven R. Sorenson Study Coordinator Se ALL SRS Annette R. Turner Staff Assistant Ley Tamra L. Walker Staff Assistant : 2) Lana M. Weeden hater 1.1eber Staff Assistant KpiNea cadH os ud) lahArintad Carder Aoathos)1.100bun) th] ) Tove GASILS LaloMuu Careleer T enr ol ge (62/10-06-53) CUS 757 rr mre hod `DOSEADNINISTRATION/BODYWEIGHT/MORTALITY RECORD wo HEOLYEE. Tn (imeey esaaade Sn fe<l7l3E 3ve)e eHS rE cTEaT ffmeeBa?Teel gy Lovet] | [[oorrc [omen {|3[ 7[S30o3ne aofp[To22p SH5AP|AjSe EC27--2|aS 2ice feaenmwinnnee| ons| e ves mmrg ale ] a [min [rosesworwos Tose |247|230 [2o2r5a]la23na]]2a3p8|A|<ce7o[ |reTarlo a] [oriTocFoeP| 2 NF (ifm .Lomme T-- P T w[uw] w | rE EE EEN 50rd e et 11 825 RerEry 15%Vo 2A 2k V1 7 1717 1% 2 Bl- 9 2 Flealeslin fez 7] Ble a3 em lrVl Pine 3 Bd 22] | o wos J0200448 Eee INDIVIDUALCLINICALSIGNS | von wt: Dolly vet mtentr: T5525 former @Eromte ---- =C[pe h ma Ser HpoPaRS Tt ITTAOA TE E UlEBEmTAa) 3 E E {mmE rssTA A r C=r = R r S>e 9338 Ee E = =e e e( Or EP EE A = E AT r AAA r A E A] SS] t2 SSerAHin EY Si 4 last >a = ie= A E E t= AZ AAZA ATA ATA AAAAATA swing ms treirrensd: or arin PU me 723 R PRAP APPR] = Er r EHH] nee. = sorting ams ama EE ERE E TDA EEAEAEEE AA=H] tb] 10 = nt= S H t ar dirmneesds TEhater WE E E e E = EASE |5 SvnaPndegn. E ada, 1% [313% 17% Be[220h Pet Pie t eye (026/09-22-93) Final data review by/Date: _/ _ Q3 c 494 | Cetus TOI nenL sie vos evel: _5pi0pl0hiy Tostmaterials T=5828 fRcioets?[|R5aenlasrotsF sgae Ei eL r tours E e AEStEA o III 08 saccoutt6e2a 415 {alressree imma r e iE AEaSa 2IESIEaEIEXEE o oTrAPoEBoordRrsarsi or 41 EEEeA eEe iti iAH | J3 BE|edEsiiEnid face |I T E TrIr DE AA TA===E InNEeITH = Seym0otTa 4ershiedxasnEY | j&oE 908-- |a eiE sedapmoste A = {T TH A =HH ST E T H SRo E iT R TNS OSH][EssTeur1eviitvt0iendg AanLtsLL o$Yf opo -- e [P r aarraa rAe AAy] r74ere I E E --eE t otoe 2A AAT 4A 3 4PtAEoA 4E4E4]4 1 dseesrivmotseadniSm O LR EE] eo EEE EH Enici e [AEAmdmeiI == A om T ttt] | o5Font0eam0aitncSsastee. , 72 13813% 130 174Fab (ip 0p0s tp le (26/09-22-99) Fina data review by/utes__OC394.99 so gi ~ ost AowsTONTIerTa IoOrNn recor" + HALE -------- oo ogi em Tr ea A | ooie vole: HG (aha) syrinoe saedssioe: of pasate es SAT nmiTeSavy age NTeetnhendostdoan: Balgl-ytizo[nd sotaienlesssien)swOeEoaesrdlye/er3nIncy[a6sauyem CeF ri m a7 4a Ee neea 7eFoa INa omr P eee=l e| CELI eSroe] seer NH rC SeeToO=115h T2a7 a T=hBahllIINTeers Jando, Lote To TA rSaLN ,o] X3p =EIrEr Ee Eee a ee H| (oI bedebhbidfLalo bended TT TH Fecmician lezleer sale calad lo pdealealealTrt LTTT [111 Jeg] Leeroy aBlt Ta te EA 11 Tt TT Fit te reve btn: 17] nf3eSO o o - Da ow mo sis wiv. 4- 02 #120 468 00468 Pyel sos ever: 5000, Test materia; 7=5898 Cmfiosmre|boebsEedhrmDanriestetot em [soel HIRc SP EATT EE rLeTErp HIaEaEyNfsroeTlmEyy | $e | e EE niSeE E ea eS ==N e n e B N E H SP 8413 [E fod mms ticlea aiene a7e4S= ES L TE hongePtaE R sicaitsaidm mT nm ET S 4o =I T oF rH T PEFS H H] ijn ofianng tes GrToupoand separated BB E 57 CBeA ardnae salTiadaza7lr _INLEZo Tm E=mT ont T HeEoFP P HS LT ] 1 sstveinn = wesne boadsmaiedtoca TT rePeAH TA S PP EHa] rf[eee 0r, 641 mrrea s EE EEoe E EE S TSIE nSsdurvivRiBinngagcaTaarnimatreica | Paalo TFee ELdeasdieS uioted face -- Im TWH IeE ZmT27e 147e oa 1TtLT m m LLm ] I PaE e T Nn ED T 44Technician i ir re, at, atin leet)ESI C | + iriestaeny Pa lala Ba EZ ody|| | | TS (026/0-22-93) Final data review by/Date: Ko /\3 500 ~ ronc~ nsas ie 1402009o 68 r oes evel:_S0000gplky Test tartar: T=5E98. -- FE PEoDnyiremte Ft reer p Pee L = E EE E E -- ee e e---- -- -- -- ---- H -- e e EeEe=e a -- ee ~~= ---- E EE EE E ER EE , =3-- P-- e= e--= E EE EE E | E E E E H E eE e wan, s-- i orm ---- TS SNRET RAT BRT E=] =EE +J FCondoitioen maoneevihdenkt. i tervs byes 25.90 ~, J-- Ne.H020p0e%l8a voselevel: 5000nglfs nies? nem Test matertat: T= 5898 [rr Shuey - Co90Th17R at2 sem E e P SEDe C7E74EE4e 5M EN T fTs 5TPH oy Maa Eo toe F~o a a r[Cr ahe mn S n AIESE I1I 2ES F =E H et|| MA O arI a Siig bedsmiedface TIet TTAA4Z2IP a IeTeH Gn E r t 7 o HH re4omiaTMen c = i eFYWSENO NZ CdEeE E sn a trt 7 ar ys ld 2 At -- reE eT]a tH s = eStS Entmm I nTSaeoclmiecEniitcaanre!er rtrice 9120 Efad Ame m f-- r aa 74 == a tS == Wot ap-- pa T EET E Tr] onion sis, g LC ShefETa IA ARICEIE 1c im ee mm Ei R OP [a halal PLZZ 1 1 | TTF1] Hoey 4 Fin Gt review byte: sg3o,-5.90 \ : | ~ ; we tozootey " Page "of 3 INDIVIDUALCLINICAL SIGNS vos eve: LOugplhy test tartar, T=. :Jiie oewre--st-- o aH t etre H a | EmrH = E r E e e e e H HH e e H 7 i P ---- = e == i P ---- F =e E E P E I-- ------ -- = r E T rr= -- E nH H m e=F E H --~: ---------- e= E T E e E H m E E ------ e E Pe E H < TE TSC E TT = HT e][TY 0 i iRtLTamOd,a, a Final data review by/oates /K3n-SQY