Document rB1ppgbwQoEYbm5QLjJN8OvvE

=E=3 consultationindrug safetyassessment " nay 24, 1ss1 Gfcr.oupC.uC.ompOllisaennce Manager flCionmnpeasnoyta Mining and Manufacturing S3t1. CePnatuelr.,'mNBldsg5.142-3100-0G0L-0% Re: F(NF-o3o3d24Add-itRievseponPseetittoionFDANosQ.uesOtBi4o1nSs7 oafndDe0c54e2m0b8e)r 10, 1390 Dear Craig: 1NiT4uhn0etfroiYDrtEmiAiavRotinisoiORnoaAntL reotflhDaeItTEioFTnxo)giocdotTloOaoXngIday RDIriKunEgRtAhLedambiCoenrniatstetorrraitFeiosron tFoohxoaidscirStaeyfqeutesystutdeaydndefnAutpripctlhiiemeedd IFCAL-392IN9RA4 TS CITY / (RIKER Exp NCoAROC2I8N1OCGREON0IICZI,TYApSrTiUlDY1SOSF1/FMLaUyORG15C8H3E)R.S ofIfunertthhleeirtsantiyundfyoorfmaanqtduieocsnotoiroondnisnraarttaiinslgeivdetrhbeychotarhnieggeiFsnDaAlobashreiersvtdeoidpraetdchutorelidonggtioctwhaerrdescuogulartissneing HwteiheathltNhatthiSeocindeainlacgenTsoo.sxtiiccoIlnocgardyidtiePtrriiooganr,apmu,tbhleiNsahtFeDiAdonaaillnso1I3nr8se6tqiuutenusdtteeredoftmhoeErneavuisriponinfcmoeersnmat.aolf pitucitaolenr rogan;tenecprooansttterdomlotridtsaetsmaueporncoocemhdpeuaprraeitsso,ocneslglruaolnsdasc/mlitaucbmorororasstc.oorpyicgecnoemrpaatriesdonhsi,stcoorm- 1aEa4c(rh2e)v:qi2ue6we3s-to2fi7;o3n,thhea15s8o6rb)ie,genineaxalidsdtrrieenpsgosretdd,ataantdheFialNeIrsPespartoenfsReeIrKeEndRcoecaunm(deTnotXxEeiNcdOoSlb.,asaePndadthoonl. Gdeiirle.ct Tchoemmduonciucmaetnitoantiwointhretshueltoirnigginfarlom rtehviisewirnegviepwathisoloegnicslto,sedD.c. R. orIretiqguhieanssatlebdedenibyagpntoohsessiisFbDlAeandatnodincttohemerppirrleeestuaeltstissoenndtoiofalnlottyhecahlllainvgeoerf itnheaniynfwaacym.atitohen Findings as pre- p2soesnssteiepbdalreai,tneBtuh(tecoamflipsnuaotlernortegpeonrreetraalltbyeyd)nDre.cgersGasesaisrl/y.m.icrTDhores.coFpGDieAiclrechqoaumsepsatrpirsetoseennptrieosdvimdboeotth cgglryuodssesdheaenstdummimanircyhriossicnaocpriiidgceinncFaeilndtriaenbplgoesrsto.nforeaIncbhotahdidnimdtaiicvorinod,usacloOrp.iacnGiemaianl)d hnaisstao1psa0thoiln-mictescopic Findings. P.0. Box 5008 North Branch, New Jersey 08876 003088 201/5262910 ffacy. 2C2.,u. `1O9l81san Page 2 qPuoTiocRkDl,y.8 not clear, let me know and corrections can be made very uith best personal regards, I remain, CCp6o7nrFsaudltTaDn. tKitnog,3nD.U.M., Ph.D. Enclosures 003089 an RESPONSE TO FDA LETTER OF DECEMBER 10. 1880 . Food Additive Petition Nos. DB%1S7 AND 0B4208 Toxicology Questions 2. oAfddittheionLailverexalmeisnioantsioni/nintfhiosrssattuidoyn poanrttihceuloacrcluyrreinnce cLliagshtsifoifcatthieonresccehnetmeNaotfionlailverTolxeiscioolnosgyinPrroagtrsam(sKaron- pot for Heetpaatla.,proNlaitfieornaatlivTeoxLiecsoiloongsy Progras, in Rats, Nomenclature Toxicologic PPlaetahsoelogpyr,oviVdole.a4d.isNco.uss2io(n19o86f),thepapgaetsho2g6e3n-e27s3i.s of ntohna-tneoofplhayspteircplalseisiaon(s",hyipnerrpellaasttiiocn ntoodulteh"e) neaonpdlaostthiecr Lbcihavasenirgse/ssd.uaptapoYriotnurftohsreubsmttihuesdsyoi.voenraslhloulidntearlpsroetiantciloundeofthethe plTeohrnegsppetacettrhmiovgereantweistishstudmoyeftautbnhodelerihcerpeaavntidoecwteolxlisiulcbaoerlsotgpircuonldipefrreosrftaioltoeidsvewohfleentshiiposlnasccelidansstihnoetfo gFoMm-p3o3u2n4ds(.N-EtThheylteFsOStE.artTiecclhenicianlthGeradteu,o y85e%a)r carcinogenic assay was Tianhmeitdhoaebesdtoihreaptnt.oilo.nwaso9f6%6.0N%-ECtFhAIyn-la3l4y2Ft2Oi)Sc)Ea-l1a4dCm(NiMn(Ri2)s-tNre-erEsetudhlytltspoeorrbfattlasuicnraeosdocaftrasonimensguellxeftordnao--cste-- aaetpdp4rr.oa8xt%imlaoitfveelrtyhet1uo0or%idgoaifynsatlhpeosstio-nrdgiolgseien,adloscecoanortfbaoiNnn-e-Ed1t%hpyaeldrmfiFlnOuSisEsc-to1eo4rcCet.daneHsouwlefvoenra,te pwarsesepnrtimaicniltyhevilaivetrhe32fecdeasy;s pio.se.t,-do6s2e%. atEl3i2midnaayst.ion(3oMf Itnhtweearsncaaslcthialnli4 Report, J.D. Johnson, FC-Experiment 11, 1881) apflneurlfatodirdpmiletediodnowaisltihng21N-bEydtahytyshleatFsOaSwmEhe-i1cr4hCo.utteimeFo,efceatshdemainrndaitssutrriawneterieownesrafeocrrciof7lilcdeeacdytseadnwdasfor ftarimosimsduoetshaecce2ot4li-lc4e8catcepiddo..st-wdOaonsseeemxetctroaalbclotelecidttieoa,nnd2pe-irNdi-eoendtt.hiyfli(pe3eMdrfIilnnutoetrrhnceaolcFteaRcneepesosruptlo,foolnJe.-dD. Johnsen, FC-Experiment 12, 1381) mtTuheleststiepsleuexbpsdetorasinemceensthasonrdtiecmrpolmybteirntmehdattowxitithcheirtemyorisspthueodnlitoeegsri,oc-hseeuvpgigadetesintccetrhepacrtiordctuuhcleeadtliiiovnnertohfe is actively involved in the detoxification process, 0603090 3n FDA PetTiotxiiocnoloNgosy. Q0u8e4s1t3i7ons& 084208 PAGE 2 In diet 90 day cat established trations of 30. totxhieciltiyverstuadsy,theN-EptrhiymlaryFOStEarg(eFtF-3o4rg2a2n). 100 and 300 ppm, there was a given At in the concen 1100,0b0e0anppBmodywerweeitgohot the termination of tgaoixnisc. andHigthheesre dgorsoaugpes gwreorudeposseteordfmeip1ne,an0t0d0ee,dntp3d,ie0oc0nr0emoaennsg tliivveer vauleuiegshtswhwielree thsteihgenfiesfmtiaucdlyae.ntvlaylAuteisn1c0rw0eearaseneddin3c0inr0eabpsopetm,hd terminal mate aibnsotlhueterealnadtivceela- fomparison oSlgesgiiocnasllayt, only at 300 1h0e0paatnodcy3t0i0c ppm. ppm, At but nneoctroipnsyt,he th3e0reppmwergerougpr.oss hypertrophy (megalocytosis) liver Histopath- cfoofrnetattaheiednitngrgreoauvtpaescduotglererosum,pisn,actherhdoonwieeacvrelriyn.hypHeerppaltaoscieallwualsarseceyntowopanlslayssmeiiencn tlhieinpiadil hepatocytes observed in and Kupffer cells anfdlahmempaatotroycelclelullsa,r dosage groups at 100 ppm and higher. pigment in bath necrosis was In the 300 ppm group, these renal tubular findings, the nephrosis was dietary dosage rat 2 year carcinogenic study were ca onpcreonmtirnaetnitonfsindsienlge.ctedBasfeodr 0, 10, 30 on the (FrI-3422 SO 11710/78) A cDoayrreSsupboancduitneg RaSOt Toxicity day oral Study, and 100 ppm IRDC, Pray. in the diet. 137-088, (gavage) toxicity study in chesus monkeys did not produce any evidence of hepatocellulas damage. gAploelsrefnolcfuioatrlholeoyctaabinodcveeantteid.ceaslcrAitlolbedtofhosstteuhdeireerspoodrwetenertde hfaeolprsaotocpeelrlfuolrmaerd fwiintdhingasmmowneireum ntoheevrihdeesnucse moofnkehyepaStOocdealylurleasruldtasmawgeer.e J.E., Am. Ind. Hyg. Assoc also sNim-iEltahry;l FOSE. i.e., tLhiekreewiwsaes, (Griffith, F.D. and Long, . J., %1:576-583, 1380) Having summarized tjeodityin stthuedi2esyeaanrd cthoempahreipnatgicthecsheangfeisndisnegesn in the shorter term directly with those oral Feeding of Fr-3524 (N-ethyl-2 toxrepor- tshualtfotnhaemyidaereetheasnsoeln;tiaNl-lEythyildenFtOiScE,al.TecFhunritchaelr)m,oriet, be-cpoemrefsluaoprpoaoccetnytlbased on the ab- aNs-foEfrtiphtnyiilotny,FOfSodErisrttarhteibursttaiutodnile,isv,emreittwaibtiohsliasalmsroealnacdtleieavxreclrytehtailtoonngthderaetctaoemndpteoiruinvdedhafsroman Finally, Species (irtodmeanyt) bespeacsisfuimce,d sthiantcethteheherphaestuoscelmlounkleayr alteratoinontsimea.re did not develop similar lesions stances. in 2 separate studies utilizing the same test sube TlThheeesriaeobfnossroeri,pntitrohanetsopfattrhtehoaegteentdeesswtiistharoftFiNc-tlh3ee324hisecpaaacnthoicbeeevleldduelsatcrhrriobpuergdohliastfheerfaotglialvoswetsr. Hienptaetsoticnealllultarracdtetvoixaiftihceatpioorntalprovcaesscsuelsar system inta ace activated the liver. ostimulating intracellular protein synthesis. rcCeeoslnultluitlniaunregd setinximpuotlhsaeutrifeoonlo,lfowetihxnecgeeldriievnaergctittvoheetmhloeirmpxihetonsloobogifioctnaiolcrmacilhnadnuhgcoeemsse:osathaecsphiarsto,nic cellular hypertrophy (megalacytosis), hepatocellular vacuolationo- G03091 an FDA PetTiotxiiocnoloNgosy. Gu0e8s41t3i7onsa OBY20s PAGE 3 m{osSeenatmsalindga,ris'eivicceEiosiunp.litceaaJltoisFotinr)sitmpaonprdhtaashneetploayft,octtehhleeluLlciaevrlelrusdleagrreenaehcrytapiteoirnotnrt.oopheyTxhcioosgmenreocpteioeneme TmTaoalEao3rciietlsyioeoyodfac0Sttkii,hdveeisrJteeaydg,ceatrshoeesntb,cheeantahceaamunasniaindfgjeasceteaanctthionl`etsousfrneaedcxatgiognve:eracLteielvdle:.r icinoneieraacrLono;elarotniss endoplasmic reticulun associatseudellwiintgh imsicdruoesomtaolanenziynmcereaismeauieneiooonoien CfSCe2gain0oi,au0sBl8ooecorugdtneedasslctrPeuihrebaaasetrediowmnhosir.cphholAFsoogliltchoeawlslmyectoanabtsoilneiuxcetadelnlshyeipoanotvsoecroewfolrltkuheledaraboonavcet.tievwaraterisoen,on: fS5Ylii0oe8attte,Usctuehalillslynteicimrneoc,sraieutoas,tsheaentrdih/neoforancuafamlopbcoeaprltoospfiastdteebgreengnieonrfsatedtidostborericboaumtterioospnpn.piaerdoEomcco,mhatar 22S15ietiziieo,tny, tht0eakcteheelolnsheamfaodtriofxmfyielcrirenonscce(obplhiuiecs)tseoixltaaonemdgsiinceoaaoftlsiiionnacprpCeeraeadsr)eadnscitenatidrnuaecwoetieoidiLiohnoo:icoaiocee slteration - basophilic, eosinophilic or cnl:eare.gG.e.il Froecsiceoieomceo.qlosos foHhymoepamoenar5)npeslaSsoaoiPfialyaetrchees(iwntohrecnoneotmurptatysctelsltposaceossthhrewirintkhsp(enacetiureoshpehpyoa)ftoaacnnyidmtaedlsise,((rinenegccelcmaucsdsiiesni)g,vethe PF(rfoaisrparppohesaeisse)o..f) =CSaycnedslvteeiartcrao-lsdvepeogartecyhneerlriacmtieitloelndulaceaxrnteendvtee,vnetlsFoipbmrayopursoadlusccooinnmbgeecttoshheooeovruicmshsaoscoro.ap- jPIhoregduecmeeatdqiUoslraootigdyalliovfefratshti-ssistocmrhoaisnnetggdeccsomepmlaolymnsog.neb,ley aPheitengtndmrcoeienbtutthededeptotesorimtaslstpeiornnagtmiieostsnaibseilnniecfpeaaietliyn. e3icino.ns offinnaolrlmya,l 2d congestion of vhdaeespgcarutalitacorryseincputrsaoosdiiudacst,sCtmeialnyangtgeOhicnescccuuftrsoarsamaisnsdo)fa roLehrepescmuefaiostceiannlteoci. sliesmobuosmn hfaeopuatocceysttersi.ction due to local sinusoidal compression by hucpeorftreannmieod 3f3Iphh9see0a,urlosaat,tsetaannHpcdehepaamsteooofcoyfitnictcrheeapsrpeoadltihfoeghreeanpteaistoionscytiisincvaolpvvreeorslyiftephrreaetdiiinoctntearbpilnreetrsaaettaicocenoixoioncfitityohe -athRaiossdeenftihnuLdpiievncegprlarNseuoipsdareuelsfleerisnov:tmesrSniaetgoonpmlaaajsoniroan,lientatnhearlpIrnethteearptnaiatvtoeitoonxpairlcoblSieynmmspoiottos.iudmifteeieumctoeimne-led Sffiooc0payllsalnsyetdiacdbdybroetdshsueletShoiwcsaisetiesysluioemf.iniTafotAixescidacanoaclseoregasitnucoltaHPcuacomtfahnolthoCigasinscSetyrmipRnoisc1ik9us6m2,umtstohespceocoin 41C05l:earf1e-c2d2oi7ms,mteinn1dc9e8td2i.)onprTbhoeevtiwdpeereonceexhecydepilenlrgepsnltaosftriectfheirasenndceSenynsmtepaoobopsnllisaustmthdiiisca(Tgonsnxouoibsmcjieoesnlcc.tia.nadtPauThtsaeheol. BSEg1ooO8on0Nxs,iect0nohs1leuS.s"noPdane0t-r8hni,oevloeN.TpdP,f1rf:oomm2e6rt3he-el2a7tS3uy,cmepo1s3g8iu8ui)mdelpiPrinocevtiodureeidraelthlecaetssecrceicepcnrotomimcfuiilicgoartoeepddi.snei.on lastic and neoplastic liver lesions deocesbon amove 005092 an FDA PetTiotxiiocnoloNgosy. QOuBe4s1tSi7ons& OBwa0s PAGE 4 r5%e: a1d3:mirAatbllays D-E. Prentice aopnfrdesEeDx.npJte.ecdimLeeiunnitsaa,l tNTeTxoPtxiPceroneltsoisgt,ilceaNdolr"uPCeaultrlhr.oelnotgyH.istcoopaGtohpoilnoagtyh,, Ma 197 SSYheioqtvuheeillnsPteohfecoctnhoesnitdreeexrpteldaocfeamstehnaitsreepprxaoprceaertsiismveeno,tf, `wroheregnpe-anoteuortcaetoliflveulafresphaynpeescpltarostiais a eSesn,EoaiWhSe.na aSesnidnegnlcey cencral core, hence Ffoocri thofe forming hheuppaetropclyatsitcicrergeeancetriaotniotnneeceieonoleeaissstghaaebplfaietshaoecsdy,what has been referce Sgmuoiiodeesleiironegegsii.ac ftLhiEeminiscsithiumipspeocspcelodnassitbdyiecrgeegdnreorwtaotlhlbyedoemasocnc-enhpoettedexdpcreaetcdotimtcehee,hydpoi.egeri.pi,liadsNtTiPc SfoemneieSipnneedoJfufdamgraelmheiyngptnearnpotlfasntiehaoe,plraetsvhmie.enwiinLtigkweipwlailtsheob,leotgchilesatssiotfphileoesdlteiascsi.onesrtHeioeewcseevecry, thiaft duct hyperplasia is classified in a similar mainntneerrpretation oe bile TibrraeesCedeCe3toPinno.ntSahbleseefrfavocertd atcihncatepratttihsneganftothnee-rnei2onptyleearasprtrsiectoifvpercoolsnittfaietnreuamoteuinsvtesdahbeopvaetocayretic ttrroeaatteead Tinn3%aR2s,imiwlearre measnsneenrtiafolrlyjunsot d9i0ffdearyesn.t than thoseiesceeerny infeeogr-s SSToneeioxiPpneoccoitddeiednngcebsatsouefddyloinvisertchoennesFoiipdnledarisenmdgs tooofbsbecerovneetdxitnruieonmuestlryheealtpoeawdt.oeryaTtthsisfrwoomultdheno2t P2oerdraoinoSaS,ltiohfroPutoigpmhuel,tahtepiaorngteiricisualtiarnridlcuycepdienritoooldddiofavgiedtdeheraarbtonsdo,ernmtathlsely1pirofoveecsrpiesann''peexoWtlheiansrdeends S2DdiEeagntyaicmstatnsicsawle2lryenenfooopunln-adssitgiincnif4ci/lc5oa0nnet(8i%is)ncgrhreieagashtelydoinseenhbaefnnecimegadnl.eheTpnabttahebiesirlilsttyeoydscgyo.r a i0hniYcs.itodoferniccteahleofcroetnmhtaerionlmianlgviagltnuraeensattefdfoorramntdhoi/fsortFhcieonndttirunmogolrr,aannigmeadlsfc.raatsm.Hoowboeovt.erm.ecTrtghien SsEtSaLtiiUs2tSi.ctaglyluyndsiignnibfoitchanctondtirfoflecaenndcetsr.eated grouhpesp,atoalcseolluwiistthooctapcaimnge SItSna2,tS7eu5dm,m0atrhaytataFndIth-e3b9a2ds%oesdaagdomenintlihesevteelirsnefdgoirvomeranat,liloynhastporterhseaetnstpeodtfeornatbioaavlep,eriietd coafn be o SilocfSaaonlntliyce,vsitndioemnnu-clneaetaefpolrraasttthiecheprianetdgoueccnytetireoasntivotfeo dcieslpllualyar bocthhangdeesgenwietrhattoinvomeecsaoinbggoeilf-hepatocellular neo plasia. 2: Ausgedlosisnardye/sdcersicbirnigptiloinverofletsheionhsistionpartathso.logic teras gCCiroDoam.mmaJaascbulegeedf1.oinathetlhiensotmFieinnngaclloaftruetrpheoertoprrifoogprionsaetldhe hbyFeMp-ta3hte8o2c4Nealt2liuoylmeaaarlr hrTiaostxtiocspotalutdohygoyloagcPieeco(Toxicol. Pathol. 14(2): 263-273, isse). 6030923 an FDA PetTiotxiiocnoloNgosy. Q0uBe4s1tSi7ons& OB4208 PAGE 5 Tthhee plaepseironsby refapcoorntpeodt,by etOr.al.G,eilcleianrltyhe de&fiyneeasr asntdudyd.escribes 4 all of vIrihoeeuw,tNeTtrEshmees,y uoasureeedvebiryd,enDtrFi.rcoamGle.ialdairaegnonsotticidaenndticianltewriptrhetatthiovses phraoipnoeseodf by 3. aYtoiuornscuobnmciesrsniionngsthhoeuldexaimnicnlautdieonthoef ftohlelowliinvgersi:nfora- 2: The cat ssucrofpaeceosf).the gross examination (external and b. tMheethostdudoyf. sampling the livers from ati animals in - 9Irnofsosraalteisoionnsonobasneyrvaeddditaitontahle stiescetioofnsnetcarkoepnsyf.rom d- Hfarxobsereacohf aLniivnearl.sections examined microscopically . lCeosriroenlsati(ofnorofeacghroasnsinfailndiinngsthewistthudtyh)e. nicroscopic fe A1nindeixnpglsanaatreionnotfoarcctohuonsteedcasfeors findings. biyn wthheichmictrhoescgorpoiscs 9+ SyIaefrspturhsoevmitidecesrtoiasncgcooprliracebloarrteasituoolnrtys'r)es,pocrtothmepu(igtrneofrsosrssyasfttiienosdninigssshoaubllde bLeivenradelesaivoanisl.able for further assessaent of the @ EFgioxrragmoieinaoacgthiisoatnn.imwaalsALLnpeecartbfonoporsrmimeeaddl,iUtnidaeesrcoFmtophulenedtseuwpeeerxretveircsnioaonlni and of tihneteartntaelndgirnogss NNUoLrfoPrathtohlatogiosrtg,an raencdo/rodredtiasnsdueifwansonmeadwee.re seentmeadremycortdhiengoeroofn- b: oL2kisv.elfrefsaosntwetrtheueo Frilirogsbhtetselxwaaetrmeeirnaeeldxalmioinbneesditayno,dn rcuetmovSeurdfaicnet.acttuaendseemxraimmiinnedd, one from the m hfnroeeediffraaekkceetnnioffnroormofhaitlslhteopgaarttotshesonldoligenisgcionepsaxtahmnoiolntoaegdtiisoitnn',. thoemIengroarddemidetiisaos:n.Sleacbmtedieo-cns Tthiemetseirzse ogfivitnisgsueeithmearssetshe(dsiuasmpeectteerdortumiotrss)outweseisdeosssoSciomoerbnisceeincoumssste.ioonnsa.l 0603094 an FOA PetTiotxiicoonloNgesy. G0uBe4s1tSi7ans& OE4208 PAGE . ApfLorLrotmisgnhrfeooesrtsmsa.tlieosSniionnoscn,etgharecoesrsecloaannttdiaviemnlieycdrofisencwotpshiuecppilFneidmniedvniintdgausraylatpteaicshsceuolerosrgeyltaatkceeodnc toihnse ctgohrueonsstesedsalomenescieoSnhefscotarsn,ebaecahnyiadneainbmteaiclfc,iaendtr.egFaiSrniddnlicenesgs ssaopfcehciimtdiieccncatalislfycyoipnrigeclaa tleeSdsiimoitnno lac lesion in other sections fram the same organ, the Final imcie ccrdeeeornvrtcir.eeewlattToahfibeolnetrheeowfviilielntwduioidvdiioeddrnutainmlofotyrearnueinlmvuiaesvlaeulralpaalnteoyhrsoilroaoenbgmseyarrrwksahahnibetcelhtefsmicanoyadrlienlaegopiswpa.eetdairofAnoisrncuwccrhhoriemecenht tuaebrleesd.ifferent from those documented in the pathalogy incidence d. TilwniosThalebdilveefro2rsaetschettioostntasuldyp.elriveaUrnsirmsiaealcttiiwoaonsnsstfhhreiosmtsottpahanitdshaorpldroogpcirecodaculerldsyuraeerxeaemslitinasebtd-edby Lgirvoeurp taissswueelsl vaasritehde Firdoemnttihfeicsattainodnarodf parnoitmoaclosl.were the momber of e. cwTiohtmehpafrtiihnesaolnmisctirsuodyspcroerpseiepcnotretldesciooonnntstahieFnasrintedhaeicvhicdouaranrliemlaapltaitohionnlotoghfyegrssthouesdesyt.sf.inTdhiinsgs . csToahrreyrreestpwooenrqdeuentsootiraoencroetgchnoeirzdaeebddsegnircnoesstsaofnFcieansdmininocgtr.eodscAwoepmrieacjolirtivwreroeualsldoensbifeoonrnetcothees- tSethfuefdiycg,ireonsuscaysotbohfsaetctvhaeatiqgournaoslsisf/uimeecidecrmpoaasdtceho.opliocgicsotrrwealsatiProensepnrtocaetssthien ttihmies g. atItocomumoipucalrrdoisscaoopnpp.iecarSciotnrhcaretelattthhiiesonrceoarmsepopnaorrittsoownohuavleedxisbatescoimninputttheherearbgesepenonercrteatefOdoFrgsreuoacschsh raneidmuanld,anti.t would appear that any additional documentation would be 4. ccIionnnfotonrraon)la.tidohanytpaesrohpnolualhsdeipaba,etohcpyerploelvruipldlaeardsttoinucrotrnhsoeduh(ilasedtesonoraminacd.aloctahre-r ShLteerpcaatitenodceautlsleudtlhaeirnspptorhenosloiprfr'eessreantltiavbeofrlalutesosrroiycahnesanvieicrnalrtahetstupodafys,tthefciovlercyioetnairdcsu.ecdt.ed"praosvindeelltheasdattheesagdeuroifngthheicahnineaalcsh wshteundysaecs- Nsoaneeddfiatciiolniatlies2 two similac tuo yyseeiaanrrcetceatsrhtcesincwooegmrepenliecctoimospntluedotifeedsthephraivFeorir-b3et5oe2n4thapesesrasfyto.arrmtedHoofwienvtehtreh,e current study. : 003095 an FDA PetTiotxiiocnoloNogsy. GuOeB4s1t9i7cns& 0B4206 PAGE 9 \ csTahatemsesutseuocudericeeasppawrneodrxeiwmeiarnetietlhiyoautse&eddweienikns1t3oh7fe7 saaganemdew1hF9e7a3nc,ilpilrtaeycsepdeonctointvheeflays3,tM. caanmdputdh.e sTthuediceosntarroel adsatFaolfloorwsl:iver proliferative lesions from these tuo Study No. 277CRO01 HHeeppaattoocceelllluullaarr caadrecnionmoama ralNeescropsy 18F7e8male o1//5s00 20//5500 Study No. 273CROZR HHeeppaattoocceelllluullaarr caadrecnionmoama Hepatocellular hyperplastic nodule MaleNsecropsy 1F3e81male 03//5500 21//5500 1/50 0/50 niTefheidsanywfiuolrflthetcrhoemspeexlpealtanensawttehireosnr,aersepwoeunnswceilleltaorbetohreavaitfiolxaainbcyloeloofagtitchyeoquuraesbtocivooennvseq,nuieeshntociueos,nvser tiossdueisscuwshsichthemsaey obre arneylevaadndtititoonaylourexpreerviiemwe.ntal or interpretive Conrad D. King, D.u.n{ Pha. ray 24, 13 0603096 TABLE 1 TWOS_TYUEDRYR OOFRAFALpLrUDiOIlREOTC1)H8E61MTIOC/XAILMCaIyFThY-1/33C38A32R4CININGGREANTISCITY A i losssacty oo f Ro atLaivt er hologi Tercms Qrivsg NTPiNomn enca latulre HON-HEOPLASTIC TERNS ORIGINAL D1asHoSIS FiC#bytsrrtooposhiiydsdegeneration HHHeeepmpaaatttooocpcyoytiteeesiaasll,tteerreaaxtttiirooanns,,edeubolaslsioanprohypihliilcic HHHyeepppeaarttpoolccayysttteeicavlantcoeudroualltaietoino,n vacuolated NMietgoatlioccytaocstiisvity, Necrosis increased PiPiggnreenntt, brown PPPoiirggtnnaeelnntt,,bilKheueppfdaeutrcotccyeptlreloliferation TePloarntagliecmtoansoinsuclear cell infiltrate HTPe HONENCLATURE/DESCRIPTION +# HCIynescptraietcaoscedeelgilenunleafrriabtrdioeougnse,nceosrnpanotenicgotinoisviestihsespuaetsis * FFRooeccdii boolffoocdceellclleululllaarrpraoalldttueecrrtaaittoiinoonni,,n btahseop1hiivleirc easinophisic * # HCfreoctpioaptlooacfsenlcileculllauvrlaachruyoplaealrttpieloranastiioan, clear coll * HIenpcarteaosceedlluclelalr Hecrosis hdyipveirstiroonphy PBHirogonrwdenenstpcirgiianpetnltip;viegren.egnc.to,ll(hse)sosiderin * APBaiiglgerreengdtautcetisnporpfohlacighforecoryntaiitccionicnefllla(msm)atory cells * Localized vascular ectasia HEOPLASTIC Terns HHHeeeprpaoatltoyocmcepelhllolurulelatarircucaladarercnionnnoeanoaplass +* DHHeiepspasatetoxocicenelalltlueuldlaarrlycmaapdrheconironenotsmiacular cell tusor 003097 TABLE 2 TWO YEAR ORAL (DIET) TOXICITY/CARCINOGENICITY A STUDY OF FLUOROCHEMICAL FR-3824 IN RATS HCiognhtrDoolsse Lroiud DDoossee IntecOinne SYaecarrifice tal3e0Cs15/sexE/sgomp3a)2les =30 3=2 - - TermiTnuaol YSeaacrrifice 1ta0l0e(s50/sex/gErepm1)a08les 111013 13133 10% 101 fuahanat Live Seesigns sor anizal Sections/Rat Group 1 Contral nia Low a Control High nia Lou 4 Control High Low alesAnimal 3540 3842 3534 33773087,, 33773038 374s, 3750 3753 33870708, 3802 3724, 3748 3831 NumberEsemales use 4875, 4a1s 4823, usu 459S, 45396 4603, 4618 44777715), 44777822 4781, 4784 44880179, 4813 4438073s, ues1 usaz 4762, 480% 4803, 4820 Ss Low 3815 8 High 003095 1802