Document OJzkqaMoj9Zwq7X6MMvneJ2gQ

AR a6 _ 124] Telomer Research Program FP AGC --_ ------ = Clariant. IPOD Report Title: 8.2 Telomer3 Alcohol: Subcionic Toxicity 90-Day Oral Gavage Study in Rats Author(s): Gregory S. Ladics, Ph.D Contractor: Ha1skdelulPLoanbtodreatNoerymofuorrsHeaanldthCaonmdpaEnnvyironmental Sciences NElekwtaornk,RoDaedl.aPw.a0r.e B1o9x71540-0050 Study Dates: Sudy nite: Februar7y, 2002 IInn-ilfifee ICnoimtipalteedt:ed:FebAruugaursyt1223,,22000022 Study Completed: April 1, 2003 8= J 3o8= = 5% Z=z 35 8 aSntdudtyheOrbejveecrtsiibviel:ityThofethobejeecftfiecvtesooffth8i-s2 sTteuldoymwearsBtoAelvcaolbuoaltewhtehenpaodtmenitniiasltesruebdchbryongiacvatogxeictioty dmeallievearnadnfaecmcaulreatreatsd.osaTghee. oral routeof administration was selected as he most efficient way to Mr1aa2tt5sewmreeirakelys/adadmnaidyniMfsoetrtearhpeopddrs3o-:x2imFTaietvleeolmgyre9or0u1pdsaAyolsfc.oyhoBoulondgdyaaiwdleuyilgbthymtasg,laevfaoagoneddacftoednmosasulamegpeCtsirol0n:,C,Dn*d1(.S5cD,l)i2nI5iG,cSaalnBsdRigns twheereenedvaolfutahteedthwreeeekl-ym.ontChlirneiccoavlepraytpheorlioodg.y eNneduprooibnetshawseiroeraelvaalsusaetsesdmeonntsweweekrse7a,s1o3.pearnfdonremaerd ppreirofrotromeddosoinnganainmdaldsuraifntgrwe10ekan1d3.apBpirooxcihmeamtieclayl 9e0vadlauaytsioofnsdo(hseipnagtiacndoxfiodlaltowiionng)thweertehrcemanodntshireencovgerroysspearniodd.micArfotsercoappipcropxaithmoaltoegliyca9l0edxaaymsinoaftdioosni.ngA,pp1r0orxaiimsasteevlidyotsherweermeonstahcrsifaifceerd hreeco9v0e-rdyoayfdooxsiincgepffeercitos.d. A10saunbigmraolousfpinrtxhsesecoxn/tdroosleawneriegdhesdiogsneatgerdoaupswaerteeelxabmcinded for afnoilmlaolwsi.ngAan1a0d-ddiatyioenxaplofsiuvreeatnoimtahlese/sstexs/udbossteanwceer.e designated for hepatic biochemical analysis "1T2he1a0n3g0emolf. mTehaen rdainlgyedaodsmeinviostleurmeedstooff2emalTeelaoimsewr aBs0A.l9cohol1.6admmlinistered to male ras was IFni-nLdiifnegsT:oxicology Parameters: No test substance-related mortality occurred in the study. A test sobusbesrtvaendcei-nrlthteed1,2t5oxmceolkogg/idcaayllmyalseiganinfdicfaenmtailnecdroeassee girnoutphse.mcOindetnocteodfays7i7s,temdatleeeth awnads 1feomhaeleteheithg.h dTohseereanwiemraelsnwoeersetpsluabcseadnocne-grreouandd,chtooxwicdluoegti0catleyt ssiugbnsitfiacnacnet-aildtuecraetdiosnhsenrabtoondsy Docs not contain TSCA CBI TT wean weight. female body weight dose groups. gain. food consumption, or food efficiency observed in anyofthe male or Netrotoxicology Parameters: No in male or female rats in any dose adverse group. changes in neurobehavioral parameters were observed BwiaoscshiegmniicfiaclanTtolxyicionlcorgeya:sedThienrfaetmeaolfeshaedpmaitincisBt-eorxeidda2t5iomng,/akgm/edaasyur8e-o2fTpeelroomxeirsBomAelpcroohloilferaantdioinn, mmaolnetsharnedcofveemraylepseraidomd,intihseterarteedo1f2h5epmagt/ikcgP/-doaxyid8a-t2ioTnelwoamserloBweArlcbouhtolst.il Fsioglnlifoiwciannatglythirnecer-eased in in males administered female rats. 125 mg/kg/day 8-2 Telomer B Alcohol, and had returned to control levels SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN MALE RATS Hepatic Peroxisomal Beta-Oxidation (nmol/min/mg protein) Activity Dosage Group (mg/kg/day) _10-Day Time point _90-Day Time point 3-Month Recovery Time point | 0 148 10 2412 n2s18 me 1 14017 1B6x1s -- vt 5 159421 136430 oe vir 25 147211 34x21 or 1X 125 W537 206284 1494200 * SMaemapnle=swsetarnedarndodepvrieaptairone.dfoTheannalysisfofrrcoamcghrgroouup,ps,V and VIIat the 90-day recovery time points, * SSttaattiisiticcaallllyy ssiiggnniiffiiccaanntt ddiifffferreennccee ffrroomm ccoonnttrrooll ((>><<00..0055))bbyy JDouncnknhe'rcs'stesTt.end est Does not contain TSCA CBI 2 TRP (28-Apr-03) SUMMARY OF PEROXISOMAL BETA-OXIDATION ACTIVITY IN FEMALE RATS Hepatic Per(omxioslo/mmailnB/emtga-pOrxoitdeiant)ion Activity Group _ Dosage (mg/kg/day) _10-Day Time point __90-Day Time point 3-Month Recovery "Time point i 0 25:22 256433 28413 wh 1 02:15 254514 -- vit 5 238245 273221 ee vin 2 02:22 2972331 sen x 125 W52a4n 9047 270456 *#7 StSaeataimsnptli+ceaslslwytaesniedgannirfdoicdapenvrtieapdtiaiforfnerefnoTrcheeannfar=lyosmifscoorfnrtcooamlcgh(r7gor<u0opusp..I0V,b5VyI JaonndekVheIerIaet'tshTee9n0d-tdeaty.recovery time point mCloinntihcsalofPartehcoolvoegryy: fSoramhpelmeastowleorgey,ccollilneicctaeldcahtemmiids-tsrtyu.duyr.inaatlytshies,encdooagfultarteiaotmnen(te,ndaonfdsatfuedrythree only). and plasma and urine fluoride (end ofstudy and three-month recovery period). "There were no rats dosed with tuopxitc0ol1o2gi5cmalgl/ykgsi/gdnaiyfi8c-an2tTcehlaonmgeers in B clinical Alcohol. paOtthhoelrocghyapnagreasmedtuerrisngobtrseeartvmeedntinor amfagtneiartutdheroeef-cmhoantnhgerewcaovsesrmyalwle,rteracnosniseindt,eraendd/torreaitnmendti-rreecltaitoend nbouttansosno-caidavteedrsweitbhectaouxisceittyh.e. s"Tormeeaurmeedntc-elrlelmaaesdschpaarnagmeestoebrssearlvoendgiwnitahtsetaidcmuilnoicsytteorseids>an2d5imngc/rkegas/eddayseirnucmlucdheodledsetcerreoalses in (females only). 125 mg/kg/day iTnecsltudseudbsttraannsciee-nrtellytiendccrheaasnegdesaliknalcilnienipchalosppahtahtoalsoegy(omfarlaetssondloys)e,dinwcirtehased aplhbousmpihno.ruisnc(rmeaalseesd conallyc)i,udme(cfreemaasleedstornilgyl)y,ceirnicdersea(smeadluersinoenlvy)o,luimncere(amsaeldestootnallyp)r,oatenidndaencdreased urine ketone concentrations (males only). mPlkagsmdaayfl,uorbiudterleetvuelnsedwetroecosingtnriofliclaenvtellys ifnoclrleoawsiendg itnhrmeaelmeosnatnhdsoffermeacloesvedroys.edUwriitnhe 1f2lu5oride erxeccroevteiroyn, uwraisneinfclrueoarisdeed lienvmelasleisn faenmdalfeesmarleetsudmoesde1d0wciotnhtr>ol5lmegve/lksg,/dwahyi.le Alfevteelrstihnremeamleosntwherseo.f significantly reduced compared to those at the end ofthe exposure period. Does not contain TSCA CBI 3 TRF (28-Apr-03) Red cell mass parameters and reticulocytes (expressed as a perocfceonntrtol group mean)* Males Dose mgkeidayy 15 25 13s Females Us as ms RBC TaegDaagy 9% 9h osm 9am os oh oma 9% over 100% OM 9% 1% FE 100% 10% ox 93% ee om GB gag 101% 100% owe 96% vos 100% 9% ow 94% 9% 99% on 91% 0% wn 98 9% We ee ow HOT aay 100% 100% 97 96% oor 101% 99% ow 95% os sen oi 01% 102% 97% 90% ws me om ee ew ARET gag OTE 1% 13% 123% ss ome ssw oa oes 108% 11% 126% ow 110% 99% 125% Sua neW anee s mee dbybo aes plseu ES ABRERVUICATIOtNeSdboellcdount HHGTB hheemomgloobrin ARET shackmtiuloecyotunct Fluoride (expressed as mean and as percent of control group mean)* Parameter Sex TetDay UI ny vw mg0 d 1 mekgday 5 mgkgdsy PLUG) Males 93 0d w0o1k 0010 mo~ =- = PFLU (uml) Females 94 0-1 0001% o01s woo ~ ~ viv 25 mekeldsy 0001% pa 0-2 20! % xx 125 mekalday g0o4 01 10050% soooos UU) Males 93 1-07 w5i ewws aanse snez we" po- -~ -- 2277965 URLU Gg) Females 94 -` D 5 E1N 1 R3 702 wo ne - = 7 fi SE mR by Wer- e = = - 12% ABBRUPEVLUIUATIONpSrli:ansemaBoflruioreide Does norconain TSCA CBI 4 TRE (Apd) dAinsaotrogmaincizaaltPioantohfoleognya:melTeosrtgsaunbsatmaenlcoeb-lraelsattecedl,lstooxciccuorlroegdicainllmyasliegnriaftiscaandtmidneigsetneerreadtion / 125 mg/kg/day 8-2 Telomer B Alcohol, wAatsesotbssuebrsvteadncien-rmeallaetseda,damdivneirssteeriendcr2e5asaendin1t2h5e mign/ckigd/ednacye.andAnseivnecrrietyasoefdfionccaildheenpcaetiacndnescervoesriisty of chronic progressive considered adverse. nephropathy occurred in the 125 mg/kg/day female group and was pTreesste-nstubisntmaanlceesrealnadtefdeamnadlesstaatdismtiinciaslltyerseidgn2if5icoarnt12i5ncmrgea/skegs/idnaylivfeorr waepipgrhotxipmaartaemleyte9r0sdwayesr.e The i1n2c5rmeea/skeg/lidvaeyr wmeailgehtdsosceorgrreoluapt.edLwiivtehrmwiecirgohstcocphiacngheespaatoncdelmliuclraorschoyppiecrthryoppehrytrinopthhye were acdovnesrisdee.redTetsotb-seuabspthaynscieolreolgaitceadlaanddapsttiavtiestriecsaplloynsseigtnoifmiectanatboilncirsemaosfetshien kteisdtnseuybwsetiagnhcte and not pkairdanmeeytweerisgohctcsucrorrerdeliantmedalweisthanmdicfreomsacloepsiacdrmeinnailstteubrueldar25hyoprer1t2r5ompghy/kign/dtahey.25Tahnedincreased e1v2i5demnec/ekoef/rdeanyamlatloexigcriotyupwseronelyp.reseHnotw.evTehre,renfoorceo,rrkeildatnievyewmeiicgrhotsccohpaincgeorsclainndicmailcrpoastchoopliocg.ical stupbounltaarnhcyopuesrftirnodpihnyg winerreatsn,otwacsonisnicdreeraesdedadivneirnsceidfienndciengas.ndoArltseerveedrictoyllionidt,reaatceodmmmaolengroups. cTohnissicdhearendgeanwaasdvneortseasfsioncdiiantge.d with other findings in the thyroid gland and was also not eAfffteecrts.thrTeehemoanmtelhosbloafsrteiccovdeergye,nerraattsidoon/sdeidsowrigtahni1z2a5timogn/pkegr/sdiastyedshwoiwtehddercevreerassiebidliitnycoifdenscoemaend sIenvcerreiatsyedinltihveer1w2e5igmhgt/kpga/radmaeytmerasleangdrouhpe.patAolcteelrlautliaornshyipnertthryroopihdyc(omlalloeids poenrlsyi)stweedriennmoalleonrgatesr, hoebpsaetrovceedlliunlatrhene1c2r5osmigs/ikng/thdeay12m5almeg/akngd/dfaeymamlaelgerogurposu.p iHnocwreevaesred,atfhterintchirdeeenmcoenotfhs of nreoctoovebrsye.rveIdncirnearastesdskaicdrinfeiycewdeaifgthetr tpharreaememtoenrtshasondfrreecnoavletruyb.ulaIrnhcyopnetrratsrto,phthye(imnacliedsenocnelya)nwdere sfeovlelroiwtiynogfcthhrreoenmiocnptrhosgorfesrseicvoevenreyp.hropathy were increased in the 125 mg/kg/day female group Does not contain TSCA CBI 5 TRP (28-Apr-03) Sl . sii LL z =N F=z BHiii ,m Eg: gs 5 8 B #5788EI3Z G2ed 8 4: ZH5.. 2$83):d 5 23g0: gd zz 3: z 22 2 B 35E3 Guf " 18 3 H iiEa Hoad : 38 3 2 3 3% = - g BF FI | aE FE FSEgR. RE 3H3E% ora3 7: 2 2g FR sEE g:FREE3% 23 g5& 22g78i}: s 3 N239E5. E sf os g | zZz gg z 25 2 = ii5 ii god Ja 2 $5 i83s 38 zz |g 12 (] " IE 3 . 2 BB 3 Eoi ZBE gg; l:.m8E2 s5rE 8a5 os88o=s 423g i EI --- iz F8E8 E55,EE3 OE RB F 0E 85:. 2z [gE za a;H. 2302 3382 OG32i0% gEEZRaE d:HE3I53| 1=3 $g y:8: $g8q:: | g 2g 3: 0 si3ege3 3 52P 1 82 i7 2Sg!: 5Sie 43 43 oi [ E 8Fl E4: 383 2 gg 3 Z FI | zzgz =4 35HE52 23i zzz g . i EE HBE 33 i ELx Hit [3 EE8 2 =g E Pg i z3 HE & 2 4 $3 fncidences and Average Lesion GradesofTFeestmaslubestRaatnsce-Related Microscopic Findings In Male and Dose (ngkgidayy 0 ' 5 3s 12s Liver: To Males: 90-Day Exposure = NeHcyrpoesritrso,pfhoyc.alhepatocellular OI00C0O0O)" 0011000000)) 011000000)) 0$11000000)) 1010016) 3100.0) KHyipdenneryosp:hy.tbr 01000 01000) 01000) 91010) 101000) TAlheyrratoiiodn.gcloalnlodi:d 00) MOAN 00) 101000) I0E3) DTeegeetnhc:rtion, amcloblass (nose) 01000) 010 (00) 01000) 01000) 10016) NLeicvreorsi:s. focal Moan Males: Three-Month Recovery wa NA NA 00.1) TAhlyerraoiiodn,gcloalnldoi:d moa Na NA NA 1010016) DTeegeentchr:ation, ameloblasts (bose) ~~ 01000) NA NA NA 2100.0) Kidneys: Chronicprogressive nephropathy WOO Females: 90-Day Exposure 2000) MMe) 000) 000 Females: Three-Month Recovery CKhirdonneiycpsr:ogressivenephropathy 9.10 Na NA NA 8100.8) a. NNuummerbaetiornrpianrdcicnahteesseisnciinddeicnacteoesfarvtesrawgietshevmeircirtaysocfopsiiolnesion. Denominator indicates numberof ats n group. NA Tissue notavailabe because therewere no intermediate recovery groups. CAlocnochloulsiboans:edTohnetnhoe-oibnscerrevaesde-deifnfceicdtelnecveeolf(NheOpEatLi)c fnoercrmoasliessowbasesrSvemdg/ikngm/adlaeys 8a-d2mTineilsotmereBe>rd 25 mg/kg/day. The increased incidence NOEL for females was and seveofrcihrtonyic 2pr5omgrge/sksei/vdeanye8p-h2roTpealtohmyeorbsBeArlvceodhionl fbeamsaeldeson the. administered 125 mg/kg/day. Publications / Presentations: None Does not contain TSCA CBI 8 TRP (28-Apr-03)