Document jL6MOrRDg9RjBa3RvZpKEeEk
EH.aI.skdeulPl oLnatbdoerNateomryofuorrsHanedalCthoamnpdaEnnyvironmental Sciences
2 December 2004
Toxicokinetics in the Rat: Pilot results
Study Director: W.J. Fasano, Sr.
AR226-3394
DuPont Haskell Laboratory
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Tpihloetreesxupletsripmreensetsntwederheeareliamreitepdreelixmplionraartyorayndexsahmouinldatnioont boef cthoensaibdseorerpdticoonn,cdluisstirvieb.utiTohne, manedtatbhoelsiesmre,saunltds ealriemsitnraictitolyntoofbe used for establishing robust teinstmroauletinaensd ffoermthaleemraatisn, study experiments.
Summary of pilot experiments
Aekaliisnmpienitilginoclatestsioootrufnadl(yAdwoDsaMesaEcn)odnodafu6c-theodutrodderemtaenardml esinexlepeoctshteuedreambasetot1ar2pb5toilomintemg,s/dkawilgsee.trraieAnbddudetdiftoeietnmriom,anmliaenleelrtydaa,tbfstoohflleoilsolmplwol,awinsaimgnngdaa fsaainnta,gllyaezneoddraplblydasormsaedatioof-rmcohmarloemraaatnstdoigfneramtphahelye oraarcatcsloamAt Dp1a2Mn5iEemdgab/nkydg.lpiqlSauseimdlecacthekdrionsmeatmaitcopgleerxsappoehfryiumr(ieLnnCet,s)fmewcaeesrses, spectrometry (MS) and/or gas chromatography (GC) MS.
1. Oral dose, 125 mg/kg of|
p(ADME)
Fmoaljloorwitiyngofatshiengaldemoirnailsdteorseedadto1s2e5wmags/kelgimanindaated16i8n-hthoeurfeccoellsec(>ti6o5n%-re),cowvheircyhpceorinotda,inthede p rim a rily M H B M flH H flH l along with minor amounts of|
....-- |a n c [
an unknown metabolite mass 559 Daltons (Da). Numerous low concentration fluorinecefeolimnmtaailnienaitrniaogtnsmp(1eat.ta8hb2wo%aliy)tewcsoiwmtheprgaerreeaadltseotrodthmeateanlcet3e-rdfaotislnd(fm0e.co5e3rse%. r)aE.dxicoAraenctatiilovynistivysiraoeftchouevrieunrreeindsehinwowuasreidnaetmhfairnotomirt mcoenttaabionleidteps with mrolecuilar wmeights of 202a and 2r56 Dai. Ulrine yfrom fem*"al0e urnatksnoawlson Dcatf(tehe1osarmy5nm,rl.t4a4oaaiCl)nniie,dnad-ecllris(daavt2ertie1sbvsrs.oe2(urn(4)ae82l.dh.6co2iao)ot9,dhnxecaiptrednhgnemdetreitwanhhqtoaiyuigosrrihvonmne/isgdsee)twgt.(alt7ebiig.rsoT8eislb)iui.shtleesei-usgWt.eho(<-e-hEtb0soiltll.-io3embio0n3li1%dion1nfoaa)urfd.tatenitmokrfiooanAnatrsoilot.oebwfssto,htnLhtfehfeoCmaretm/deMnmo(tada6sSlab1eeloo.ea6a(lfss2i)nt,3taeawh.aln9yweed5sorriiee1rtshgpn6gagao8arnl-feseihmacqfo(taauv2eutssi3orvst.le1/apoxgf)teot)if,rrlriea5aaocf9nnodat0ddsr,t breeveaatlehdigthheerprleesveenlsceinoffaatndfroanmunfekmnoawlens ccoommppoaurendd mtoasms a4l1e3s.DaAwdedrietioonbasalelPryvP,eedasereivn^era1alll fat extracts and at approximately the same levels in control rats and rats dosed wif
Fthoellaopwpilniegdadsoisnegl(e>2d3e%rm)awl aesxproemsuorevetdo from the application skin saitseigantitfhiceanent damoof uthnet o6-f
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hour exposure. Greater than 27% of the applied dose volatilized from the application site mdaapnuapdrjilonitregiisdtsytudheooesfseettahxwkepeoeenrsleuiamrrteeitnceiaonrtvmtieoerirnnveaadoll;ciscnauc<rtrhr2iief.n0icg1ee%x1c(81r-ew6ht8aaosuh(r<ose0lupi.rm1os%sipnt-)oaetsxoetpr-ddoaosasusser1e)4aC.nd-icdoNarrgnebagoonltniigccidobvinlootexaliialndetievldeee(,l<stew0oc.it2fta%htbhl)eea, levels of radioactivity, with the exception of the dose skin, which contained ~2 pg equiv/g.
3. Panlaosrmaladkoinsee,ti1c2s5o:mg/kg of
and selected metabolites following
Foiinnof lmf1leo2maw5leaimslnegg(r/5aka4tgs1s,i.n2(tThg5melenamXgoa/=rmaxl2iLmdd)hoeuocscmueolrimnosp)elpfad^casorjrmemamdpapUitcdaoorlHyenfdecHamentnofdatllrmwMeastaeiMlro(ee2n4rMn(a8oCt.st9Lmd5(aTxeto)ntm,egmawc/xtmahe=ldiLec4b)ha,ehnwoyodcoaucnsfruesdnm)r.er2eaa4dlPrelhlysarolas2iutmg-rshfsaoatlfltlyodearvheteeaiaiglrrtslhhgioeeeerrrtf sfoexld. gTrheeatteortafol rsymstaelme ircatesx(p4o4s5u5re.0o9rhAr*UnCg/m(0L-1)2thhaonurfso)rwfeams naloeterdattso(b2e07a5p.p9r4oxhirm-nagte/mlyL2), and the terminal elimination half-life ranged from 2.52-3.68 hours.
Fomocofacll1lueo2rsw5re(i3dmn.g4ge2a/akrplsgiig,en/rtgmhilneeL)ofmercmaaolxamdlieopmsareuraetmsd f(tTjoBmfPaexmrp=alla5esshmo(1au.r8sc9)oncpocgem/nmptLraar)te,idoanmntoda(Clmtehmaeaalxnte)idmrwafeetasmsto(asTmllemigaarhxxatt=ilsmy^au^htmniagrohtleauevrrrgeseil)nst. s<Ot1injl0lahdv.oeewturearacsgsteafn,bootlrehtfeedinmetetpearmclleateisrndmaatialsn,efpalriolnmamdsimnthmaaetaiboAleenUyrhoaCantsldvf-aa7ltli2ufteehhseoowufer(ensrdef(oonrfofwttehemdeaastsloae>mbr7ae0ptls1ih.n0og-Hufroposledwrfiogoerrdvemea(rta1e,l6Bre8froahrPtosmuwarasnal)des. rats (352 hr-pg/mL) than for female rats (32.8 hr*pg/mL).
Fooopcogffcl/fl1muol2rHwLr5eidBnmfogsgfroa/wokmsngeiae,nrlregethilnneeaonoftmedrdmaaelfxatedeilmmeoctsareuealdmetosbri(ea1fyt.lso5B,nhdrMoe2sup4rHseph)clotBcaiuosvmrmeMslaypf.oafcrrloeBendiTctVthehoenemrttrotsaaietmmlxieo,earnlaaetnto(sadCn(mmt6dhaaxehf)xeotimeuwmrramasuls)mei.n2raPa.ll4telsa8evsleaimalmtsnaaidn(tlTaea3vrtmi.ge8oaelx6ns)t hvaallfu-elisfewweraess2li.g2h4tlyanhdig7h.8e0r fhoorufresmfaolre mraatsle(3a9n.d3 fherm*pagle/mraLt)s,croemsppeacrteidvetloy.maLlaesrtlayts, A(2U4.C5 hr*pg/mL).
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d. Additional plasma metabolites QRCeo0mmRapiianariinnsdgontwpoloafsntmheewatouftrnaoildmeionndtiofcisheedrdommreaatttasobgowraleimtreess wfprooitomhlemddooslaeencddurlaaftruswrtthoeeigcrhoetnsvtraoolflu4as7tae2mdapnbledys4rL4e2Cve/DMaale.Sd.
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Conclusions and conduct of main study pTmiheloetatrbeeosxlupilsetmsri,pmraeennsdetsnewtleiedmrheineaarteliioamnreitepdreelixmpilnoararytoaryndexsahmoumldatniootrubref c%onisnaibdmseoraerlpdeticaoonnnd,cdflueismstirvaibele.utriTaothnse,, and these results are strictly to be used for establishing robust test routines for the main study experiments. WTraechsieudlsrtlesasinausdllstoosstoshyhfesottrehwymeestitehctaaloitlmlbyeiatedvdeatipelairlbmolteineafexroedpllesmorhiweomtriatenb-ngloitbvlsioethedtahsva.moneTerdadthalteebhmdopoaollstianzi^nsseMmtgdraaattIonekhddninaudteshmetairaecmnrsdoaiagul tnseaixpfspiehcoroafswlnuutrloteyhr.ilanoTtan(htHgeeedPr terminal elimination half-life in male rats. Further, examination of plasma revealed the presence of two major metabolites of unknown structure. Csbosstuyryuodbndndejtideharecuettstasoc,sit,frzmreoteohqedfmeuet(htiatrteothdeh-semdebiapetaoi-rimobponnjrpoeiooroncpestfoviervrisdoeveebpsosdueu)oeaspmxfttptposelhteertuearmadilbmmeyaonaenldtiindatenetlssdssi,iegtnfuirnonmdvrchyiaotqa,rlruvotpdhaionmoenrgsteiaiintnttaaiagtnvtbi,lgiovevaaeltonihssdaetrmnettkwdsheeueoqxyltuapdslvaeeoslaraishiitremlaonatuliebienvlnivdgletiesstbluysufesr,soeoami.fnmcnogcAeortrhelwmaseotlpyp,aaniinlndoietd human microsomes and hepatocytes.
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