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BITE ES Rr 9 EE ni Eg ore PARE Er A erirSari Sewi a FEE VE Forts i i aCA a So e ERs al 88 TREE ty be URdRhsAS E e Ehyn e ae dl os an Be REE Boll TORE nt SC Sep eia ad Ei te da e. oa fi nSh pis Re lSHS e U Se R S e e =5 3B io Es gir ig iSRE i 1 TRE pl EN aNeeLHaEs ges eb SE ou pe3el Uy TIE 3 eSe a en EE aTEEa he SD0 R r Baas lbiGene2 Poll eR RR SE Sie, eo 27k SR LE = 3 CE LE eel E EE m LiC rmen a Te EEE Alo ao Bo s Cael SCAR en FAR en AR eR Hite cee SC LETE Re CCol OC REA Shle, Sat guileaeSatie E roel Ee Socata EEE dike eh espas EE ia * 00061F soba ts Faanadmlanennn LAnaeES BsFBo Dai e i SH s e Red iTa eleb Ds pi 00 l TERe E. AR Ctl eeBE Hes 5e HE REGRE bitsll RS TT ER EpST ra pe r p bn yd Is RE a cre a 3 RnSESAenRTE REwTidT RE L HAh LSaEC eRA e eBe R<e a b haan f ga SR Se IS A he esse co a SEeE h EI 2 BOBi saaisSIN fon SaRe i pb ee el hae Giese Be eeBi Seareas fh uno BEEunryolpm BfoLe eeeet nLhE Seinese iee ee EEE iG Y liE ntE . enCe ORES ER n G PORR e CS o TT dn al ics bein Sa SeyeR, TETe bde e oi ia n Cores LTE a era in Ba SaSE eR iCaCl el a PERC SEST COPY AVAILABLE z 000018 i USEPA 16154 F CS eo nedeee sr EE Ce Re i ene prER ea R ati PTn T OL SL Tea LbiEogESoRA AELl he 2J A SUtUeE FdaEy {EhRIaE s LR PE OR teZ,3eLt| se el bu E Side Yra free sa Se Bs ame aa n eyi e ARr ae SH eCR EFle otchaibielialiS idn okE auld L Lthnai ara ira i gn Reng tSEe ER S th iSlaslIRsN wne Ts EE Ct mele geTy Lda ib i p Bro inne l ingadL r itl Loa na RL dSio S aae h boo Csiui oeme RRR Blam FhsmpeaR Mn a CS heraanaE ee [Se SEEe E n a a Sn eee RaeieEeR PRhNE et enSe e hae e Roel BH m Shg eRe He e A a R e RS A Lia Eg E e PsRpIl T S SEe rET i El e e Fie a ESi TE SSe RnL E RA e sehi CC LeeRSA Leha SnE iph STR Rea Ee ae Ce Wl we ' 000019 SEPA 1615 RvSan i a SEEt AR G ARSdI n TIEEE Sh SENT CE laitARSN Sv SOE bih tem:it ann a e : ehi S Es T To Cla e SO Tl RR L T e rr ER PEeT LPaEAkLEsIa See d ON LL CENTRE A EE a Ficamire ioe EL e e ais i ea r sHrEHsEe aDHEA en AeP ss E2l SEE Rr EE Eerste ars cb de EEE Ce HE ERE Ue al o Bae nT e Ciobanaea reDO 8 dees Te ie SEs Ge an ErRciauoshatemae resa vedlCei b ks ee e SR Nn L SE Ed poe ElEn E I Eb Si RaYsRS i EE LR Se aa riE ckiCagi Din CSoPITA S a Re e na SoREEe EjS Aot Ca ae n IR a Ft ara ae r lb e e feCLSR TtLR BR: Shield aaa aliens le SE eRdiatondmfl ge ES RETE a CLaTh TeEL E CRE S AyfAo i ee JE SpS LEe E Tea a ee EER ee EC TR CO EEERE A SE T CoaRETaR EERe nd TES Ad rE ENR | ES sie eA 000020 Tr p, bis a Hows sei so bal | suis FE oy andes aoa B . iw 1 E PED afm A = a ii A a a 3EST COPY AVAILABLE 7) : seca Bn 000021 USEPA 1615 pb? i rs APEwASnATe(Gm80)s(FoL)s a GE Ts HF 2 ag A oc HqY 4 E T i a we 0, ve, ffs ee, me snr 2 ren eaten SE, , 2630 23 150, 1% ana 670 mgfig deses. These deaths were due primarily w imyuy ol iret, and pancreas. Fosiomorten sucalysts partially obscured the effects fli the privsiste change was in the Lives which showed sorsrorcascer JOH] deviations and weight changes. The 12 mg/kg cose devel sppears to be the. (l troneition doe for this effect. Het Tg re 12 eft tres ie were accompanied ty an increase in weight nly g BEST COPYAVAILABLE RT -: " 900022 Hohe + USEPA 16158 So Liver weight. Ibis of doorest 33 oste 18% the Liv weight was % traverses eves cur if nie eeth dn Ps videh het Felavimely hig. { frente nine bady wedge, iver enlavgmart ups rab roted far ives i i Ship ts 8 cegre-, especially in tie second confirmatory est (Table 5) % Secssive veign: 3ncrosns far thu pancreas was demonstrated sven au tie i ; "wild be of interes. to sen 3 the change ia liver velgri Er } prograsees, os secured with A, sa Fe Co fas p i{ | B: ie e XESD Tevf I er A = BEST COPY AVAILABLE Feast oh 8 cs penta Coa pihin la ai A Tats eRRRre ji Po LEE: | EEPFFFRRERPER SIE EHH Tl Eke ob) TEE HEL BFor LIHTHEEL i & er {EEF iH f IN + hl E 1 Be ESTICOPY \ pate! | 11 FEE g 000028 TTT Ustea eis |{i SIEND FUR BLE! | be His Cores me ee Fo Semen mouse Una F Hmehs ! epsonryve GOIJCLOUENE for * 2-8-62 . : Fe a i i: 1 od Litas we 100002547 aren i661 = We foi aie aif | ll =% fre | | TEE Fn [i L |E TE R IT Tee sherri B FL i et ETETI | & 5 i ==EERE EATTET CFO iEE R Em EE m {8| = {ds E EEo E EEfbEE RE ET, EE ft | beprlcor AVAILABLE |} : Sey da i8 ge BSOBUG 1000027 USEPA 16163 thE oe tin 3 hE 4 5 . nha ae FRCRELS 2 - en Earl i Lin, 3 NEST ERIJC Ho. p= dee & 2 a Lo Es : Lg ; TET FatheSiogEie 55 3 2-8-2 al 1 ! : 3 ; BEST . COPY AVAILABLE E <2 i : A8 | : o% yyJ 000028 "*s*oFbowussieirlan1m6164 heer ! TH H III Ry To ENGINEERING lp COMPUTATION SHtcT NE a aes Tommi SS || rein ween pg A pa ~~ fia He ant bitte LaTie pegientid Ce ELL "IT Jo A pov oltmbnngis Caine mk Hsly whdha of abmglly wk] aCbee,l Ta Lien well i Ast okid fod rer Ar sainte hier So ilaiiisnly Kigl fost Se s5"y Jy weigh hh CB lant of Ae Coppin | binsin Am ART blll CA Hrd 4 connliil dudy ris | Lina 70 Aids ore ost Diclos 2h ng [fg nlagimint ear note gloimt i i Pid i. BEST COPY AVAILABLE BPyL : ; L Bsindnid, ee 006 : 09000003018' Ct ly sits at, pe og S SHaEs E g8 a bree USEPA 16167 ant A i di " SUBACUTE O%AL ToXLCIYY TEST 2 HASKELL MO._303 MATERIAL Curr morro oondnwor cpu dns, --4 DEPT.Krai. . coho. CxOTTu mudd ook Aen mardi mwas smngoioor, Moe eh Material given by stomach tube or = -An-orbginas z former ass Une SWIRL of Si ate oem 3 DOSE li esis No. TREAMETS_L0 HoRTALITY MATIO_s {io % i i wesc record 3 | EE EEEEE EE ee(1 x Crores eeTr eb hi ad q = ' | ps ol erm He ; ET | Ce aleebbelolol febebe em 52 bh LT TTTheale pt[ole LoLoloboablaclonua TTThssen)A Tes EE 8 Oe bi CErrr rrr r r he i HHH i i a 90 OF YE i EyLegrem, HSate ewanSgs? seen BEST COPY AVAILABLE 11-10-60 E00 po thay 900032 wFay aHiriEn oe Goi 2 Poa da 8 Lis dd LAE 2 ni USEPA16168  3 First Veek: Five oral 6.7 mp/kg Goses of H# 3035 administered over a one week i week produced nc clinical signs of toxicity in nll the treated animals. i First Mask: Three of the rats vers sacrificed four hours after the tenth treatment. i` urSetichoenn dSeWce eosnkd: vTehsek orfemaoibnrienrevattihorne.e animels oxhidited no clinical signs of toxicity ` {umes Summary and Conclusion 14 3035 produced no observable clinical signs of toxicity during tra treatnent or i i z g > $500 000033 retin Sn USEPA 16169 #5 - 2 Bat te. sory aa Liver it ery, x 30 Eoei H+l4 TsiaateT --3Tnes-- C18Br0o0e 1628 TE = saE pt) 5"i Soi 14 avs After Jot Ix 5. 2b27a 1r9a6k5e3 0 i Le 20.20 Lo97 am 28 5n.s5o2 Z&e| control Grows Lav of Jot Treatment a tt a i : 50e00t8 350%8 2~a 1 pes atten 20m 7 si oot 3356 37% 1160.9180 6 50002 Fi Cae 437 a Lan3d s0o Ed 4Co7t fEi7Ce sm wis Eo + hag Lad {ood pte BEST COPY AVAILABLE ir | Se : i Tdi 1g &2 2 USEPA 16170 i : JAONIUN PERFLUCKOCACRYLTE (Cgh2P0) i ; fee0s= Hex08y o Eef2ali i ; sumRY i 4 of ten success..e doses of . i { seks ven adtaomninsiissx1tirgraahtvsieosncmaiussgeedmemnotderoafteSheenlKairdgneemyse,nt of adr tne encis : i i nd cesces. Slmultensously ters wes slighs depression i of pancreatic weignt ard The lungs of the rats showed s1igatly ennanced pneumonitis. 1 G2U-H5S-/6a2n D7D ondef-- G. W. i. Schepers, M.D. E! :J Bieneionias : : : - ixn :. i L Bho alist 2 g 00w0o035 a 2 ohuidi LdE 8peo g aldose USEPA 16171 |id TT i A o . 4 t SER URAL (RARE) {rit 4 ID pire ferme Falling Busetas Grad hintedseria: 3 = x Yale RCD Ree Wet wr ren i3 i 1 chmics) us atmiedetared by Antragasiric Srvibesion 35 i : + ag 5 ion. Tach of 4 rave veesived 16 dutydus of .1 refi : wo dn ba and he eae vere Kidd 1 days deter. Str arsed cE i 1 ble} an agen weirs ave pressed in TekLE 2 958 3 i | what loss since 1h days ator the livers wers only 20F hescier than tose at so sees 11e pe ae sa Ihe renal weights were Z0f hesvier than those of the correspentinSgASH i i . | 2 snore st of the control vats 1 dys ater, These weight hangs = vars vol sessmpanted by morphological changes. .: h106 ouwe Ttnrerpar.ncereatoifcoseepiisrgens Ws aeisSeslie ngdhtiovfrtdevprevssessedi,anrbelvone cgidf ae nd IYTWe,E . BEST COPY AVAILABLE 000036 ed . . RE isn GRRE. USEPA 16172 1+ to robclear why a dice 37 6.7 nelkg ves Aucred for LASS corre. ore Lily S Cod honinT , (Opler Tirotorses iH : BEST COPY AVAILABLE E: : ; EB Ea] p= 00003? bum sais 4fs 10 ob SERA SURSEPAS1d6173 pa: Tiivrerer| 3 [= E ; A D PEEE TEREERRIR IeTIeE TI IHAE] 3 ULE EERRERERETE BRE b g i LR, IE 2 i bl z Ea iE Lb SE t fa = | UPR EE a Cb +| i |i g ii E iF hdd Ji L sf ol fF 2 2 C PORER AO 1| He lb L[boEolYRS i etme . FRI R EeesSidhe : i esticory AvkiagidA | | A1EcR=RGEv S hh Ther 2 whoo 000038 USEPA 16174 bSoE TaRncIaaMnaEnaRzrzat |! 8 C[FEGTEREREPLTETREEAlEEELE|iGet | os8 [H LEE R R IleBi EEE 1] CEBLLEEE ELFE SEE FL [EBLLBEEEE R | ||I.L 1) 8 4 hii0 HERES E lesaners gd Eid oF F||L CE LRpRIbEE Rl = Eo eeRE 0001S USEPA16175 bo TEER ERRlE | fr ;{[Err moi . h Ei Fito OLg LJF=RoEG g 1s1s7s8To eR4e42 ; | bo TETERRTRRN H i ; | 8 CO Fee |DS5 Fog SU Fo " I DEE LL EEEEEE (EH WR = J od TERETE ere GER] El el lElklEL arRr] ee EE fois Eo Tae F LER as [r E br ERlEl EERE e|Elk S| = Sls? re lCp e a rl dk eh EE he ie Lhe Sine lads Sle bl. fai ik athpeElpoan oe ee ve Tek ies Se [VO ve v1 deeded ted tToRi FETERETE Ebel | [LEEee | [ELFEE] Fa aan Foes ly betta i a] BF user te wT rosin ACUTE ORAL TOKIGTSY 7867 4 DA&T ppeErane, 2 (90H tE ani,E Se t Earp t ed s 0 het E be 7 Toe br 1i DEPT. SANPLE NO. FASK. NO, zn2% DEVSTY 4 4 ;1 LU sioqluaiai PY yy (J - L TasteE powder () (1) m 57100 pmTre(()3 tn_awun | T2E) mom () 6 ;L Material given by: orm-on 8s 85.5" stomach tube oF-bY_: topo5s solution of <etive-ingredtenta in dn-origimet ous #2Si:i t Suspensies original sample EZ EN pt :: : satel BAuIsEoRrI| vTeTeY] (aDorgbe)] (mDajao)|7ssol[Toerghe Ttomhaane lemallaoosll co fho obalslsmisivniushinly Results PRT 5 des aman hJkt o PE |i lwasluneu sen] Teltfbb] boon ad amen odes D2 lanl ashes Co bald sea sa +g | LH Let E 1 3d ali LE br 11 be [1] Ee L TTT 1 Tr |e A ih g ia brea ' FE SoH a DNG 0 m. e/ke RRS: Toa (te neem a aE . ona, 3XaoS a RR EIA T i: :4 e T:C T TY L Naixgurcsoya0a0raetnig+Fre|tRT= SSJn SELiA dh ET EaR . edramaperilooml 081 tk Aiea ROG USEPA 16177 Ep. ho OUTVTTY STUDIES OB FIGEOUARRON DITERSTD ANTS Vetter oameresh Profect Nos. 18-479 wd 10-0-1 Brom Joemontim perfluorossprylate (CGFA), smmmive -hydeoberadecaflsoro- consroste (CFDA) and avmonbun-3y6-dtona-2,S-(trifisoronathyl JmlecaSioro- sonsnoate (ABT) sre dispersing roteariuoroetiviane, In acute agents used in. tw `polymerization of taxicity studi with these compounds, the mast | --el rtargement, of the Yiver. A sintler but less skad effect vas obaervod rabbtta that had sbsorbed ET through the skin. vepeersmtoney experisents repaid hare wees doatgaed to saseiEs a tr 3 } mer-- er Laimvterssietotedetsehramriene12vh8otshpemrctfeusncdtiifofnaelreSnspstinrarapnttiofblthteyyli,verToooocuMres rosfweelli; n ; na to adios supervision in detecting flisrocashon iver injury. The i Lutter hase of the work vas supported by the Plastics Department coder Medical 0 masearch Project Yo. MR-63. ee 1. DO3s Te 3 : | ie }b A4 2 2b E: Gf a E "En " 5 d6ad-of MT, equivalent to Ly 6, or 9 mg/kg. Samples of blood vers taken st TR 5 peoquent. Anterrals for times yosks and then veskly theresfter until the witmls i Hh fli: mgperitice ox gina in sitions doe of he compmad. Toe 4, pligieswire, givea a single oral dose of either CGFA or OgfDA, or CFDA; Aqidve~ Ene Ey "Alsink 6 150 re/kg mds similar serios of measmemmts madi. Since bith,Gogoriseeiyl BIR Foo aed cn shin18 nee, the perio me SrpiRd sistas dob BI iaipborsfis) wt thtsaisperetie spmt. The $40 dogs hit usivadethe 5 3 = ke + miaure ta thn CPD were gtran addition trad dase, a5 : BEST COPY AVAILABLE 000082 50h 5 2 F - USEPA 16178 Rm EE ------TE - Eid ps + Jt tate tim. Hood mger and Eplase activity were messed om these cogs <aan stort odetoctanatfectonthepmcress. : ! he folowing blochazical messurwmznts vers wads routinely on the 3 Wood: APase). sWugaanr,huirgehadmoigtsrogoefn,thetotdailspecrhsoilnegstargoeln,tsawnedraelkdasliinniestpohroaspdh,attahsee - | L(amvoem)),of aslcdtoilvasiet,y ogflultaacmtiicccdxeallyodwrcoegtTeihnsassf(erOeT(e)10a8an)dd, eigssitosectrieitafrtiiaecdpdcyehhoryldaersotge(er3ns7als),e & 3 ransaninases vers also masured. phospbolipids, demsstarol (u-dehydrocholusterol), tigmsl Surbidity, albemin i astglobalin wore alsodeteratned on oneoF wore semplesof blood from the 7 dogs given low doses of AHT. In 2ddition a Toutine hematological examination and analysis of a 2u-hour urice specimen vas made ct intervals on these 5 3% ata. i The level of the various camponents of the blood following the dose of Flucrocarbon dispersing agents as cumpered with an average value #5 4 a samo wh snes srr se 00 saa +13 on spectaens fren stock colony dogs. Fo Por the amet mada exgme activities, a on 3 mbar of stock normal dogo. rEg vas. srtablished The activity yas slic from meirred 33 a at Joost, ones, Jrior to treateant, ou the dogo dosed With the dispersing Joi 1 Remit) Toesignificant bochemicelandclintarl findingssremmemrind Bi eg 8 brisfly in Tabs 1. har prinatpel. Binding ntteativ of some dafuryordystastioin ge | tbe dogs taut received AFT wns + 3 dacrease x the FAG CROTSMAIRArAC {areas 4abrossilfulatnretention (26?)md4Pamsctivlty, WEEe we iHo E- |i ` {5000 : 000043 oo EE fii : 2 g vine pstmt cenoepasepipi on USEPA 16179 i 3 { chaogni gtoe00s6 thincnaweak aftesthadoseVAY adainistarsd. i Ihe changes 4a cholastarol and APane became "abmoraal, i.e. exceeded 1 an arbitenry 1ntt of tro standard devistics from tha Fre-exporie mow, f one or two weeks later. The increase in dys retention occurred drt i the firstweekor tendaysendthenbegen toreturnto moral. Ts - dapressionofplasms cholestarol &n allthreedogs ccouredserliermd 3 sogan to return to normal sooner than the rise in plassa APase activity. i ho dogthat received thehighestdoseofARTshowedthegreatest change fran the ro-czposure wean. or doses of AST up to 26 ng/ks, hoverer, ihe actus) values observed for 11 three dogs did not differ greatly. | ! (Gon figures 2 and 2.) Some qualitative and quntitative changes in the ser: protetss of ons of the twee dogs were noted. ALL three showed decreases in the 5 lass phombolipids. There vere lao sae Chuiges in Ted Cell morphology and adocresse inthomsber ofTedbloodcellsofthedogsreceiving lov 2oses of MIT. A11other messuremants Eade oathebloodorurineshoved no signtticant deviation from the mrml. Vien highdosesofANT, CEFDAor O57DAwere administered the J activityof &mbarofenzymes,reportedtobesensitiveindtastorsof i: clmivsemrodsnejtorey-,aweesrepmeeasstureedi1anSth2e0pl2a.sms. Thereosftu hebl loct hmxis cal > Vor highc(60oMs/Se, oquivalact totherat, tbldose) 37 afaim ameadntutstaredto theons dog taKthad pravionalyiracetand dyn Go BE the Fiaow saysmessed re:arsteditattha #r2y re aayta he:doma evue fives. hegrater argensnsiiim ore (as)asa.dpase (100). WARSomeesi 1 tut pam te : ? ; : : : : ! 3i 3 i z g ers : 3 BR 8 USEPA 16180 pi ; +e ? : soeosh ange. The depression of the plarea cholesterol occurred ore TE :Donsluoviyts bast thevrse vsesoomecevbidrence of 8 Tetum to morsel sfter three veeks. i Vth the Lover dose of the CED (30F of rut, lathal dove) the uf 3 transaminases were elevated in both dogs within LS hours and contimed to & [ERE # i retarm to nome3. The dog that sppeared to have retained Wo largest 2 oom it toe atte te Toews sims ars 7B in this dog esd perakielod the OFT. The cholesterol was morsel or only al rigohntyvisettevastaedewiatnhin+ ons week dase aftar the sane trastzant. scbiviy. There yas no effect ha a Sigh ase i 7 of tnis compound was administered (2/3 of the rat lethal dose) ail of the es ensymen henges masirad occuceed were meskedly slavated within 2 dn the GFF and TUTH. Thera vas to LS hours. io change in The greatest the plasms 2 re cholesterol. Both animale expired Fw dom of 0h cf within LY hours after dooing, a 0 A tis | oe "= po SA clevated values of re malaltienzeymresamteaswuread ocmcursredgwithtin LaB houwrsrin one of wn. the + So 2 aye. The plasma cholesterol vas normal or only sghtly elevated after after SE ve weak, The other dag shoved fo effect fron the traatnent. Ab the higher YER . dose (LSS of the rat lethal dose) of this compound.the more mssapiible dog SG sgotn showed a rise dn OT and OFF during the first Ld hours md a vetura:td So oe vithin rm vas, There wah & ALAS rise 1a APase nddnhwcpiased"SHOES chclesteral. Sintlar, but less marked changes occurred intheSedo. pa g The ylase activity vas lover than normal during the rene 8 esd = rise 414 occur during on the Sion ageart the week following Sts tine: Within tthheonexvpeoerkarasS.2pmeir rSahwaeHdHEaEEtRh.eTl % | BESTCOPYAVAIoLABnoLrmalE. o00s0es |eAcySaInrSdEdeEr PERSE sepa 16181 a-- E -- - The blochasicel date have shown thet the three flucrocerbon } Atspersing agmts affect the Liver. VeryhighdosesofART orthe Cid that are Lothal or pear lethal for dogs, produce elevated plasua levels ho of come activity indeutios of cellar dasiructdan. The digression 3 ofcholseeemstsobt epee culirartcoAl FT. Tha Oy dleperageenitnmagy also affect the pancreas but this follows the liver lsjury.Tow doses of TT a aoe, meme e1} APase and OFF sem bo be the most sensitive in datectisg on effoct from S11 Anes dispersing agents. Of these, the latter may be more usaful in that i thors 15 a narrower range of normal values. Depraseed cholesterol levels ayba useful indatecting anexpomretoALT. i "i F * i L. b iE i Pt 2. RATS : heexperinemtsvithratsverecondustedwith onlyoneofthe 4 twee fluorocarbon The first partves daisstpuedrysionfgtshgenbtiso,chAeSmTi,caalndcvehreadniivnigdLeiedvesirntotistswouepMaritcsh. m1i5g7htonredfelgeecnterfautnicntgioonxalropiumapeariamteinntg)lithvee`rsetcsonadd.atwith the effects of 1. Piochesical Changes Procedures Thirtyyoung albinorate(CHR-CD)weregiven asingle oral dose, squti o 12vng/atkegrolfeibga ohdtyon wfetihgt ahtts, woefrAeNsTabcyrisftiocmeadcehxtutbhee.t LriizrteamcetcoaGmtanteydeftorivMeoschGaanytsclaal evidenceofaboormality. Asedis muber 5 ratrested control animlsdere eumined to establish a poral Feng of lies.Zur-tba reriosn Blochemtoal measriments a rota ofthisagvandgrain, g 2B & a Es L Es a = 4 : I 000026 d4Ea rit ET i ssa BEA es g 2 aTo GOUL USEPA 16182 ? BEST COPY AVAILABLE *| ; = 4 Sixty to sixty-olght days after the single dose, a second group of 3 elght AST-trosted ate and eight controls vere sacrificed and the ese measure- i: ants sade. At this tins, eemples of blood vers also taken for mesecresent & of the passa alkaline phosphatase activity (sPase) md cholestercl conoon- <3 tration. Apprasinately 5 1/2 nonths after tho AMT trestamt the ressining entre vere critices. is 4 a meme 4) Besults: The results of the bochexicel examination of tha lirers fa rn gape ater sie cre dose of Af he principal changes 12 ha Mver, 50 i vamos ata cea re. se is = increase tn alkalina phosphatase activity, mombolipids end 4 duceise 4a By Gaycogen, nen-proteln attrogen (FH), ad demcyribomscleto acid (NA). Onell nt atgaiicant increase in cxypn Consumption, Vater ed protetn ocrurred we B= and a slight but significant dacresse in respiratory quotdent (RQ), choline EE oxidase and ribemciedc acid (RGA). AL other meeseresents vere in the Cm, hs A i Sixty days after the single dose, tho livers of the AHT-treated sR i ets are Gill quite lange, although they were spparertly mo longer GrOWiRE el : at tho accelerated rate. The growth depression as measured by live body "SE | however, was grester then charred previously. a i The increase in phospholipid and decreas in giyoogen were still pe } om most, outstanding change. Seal bub ofgaiticent decresses in Bl, TW wa : 70 eget ocourral. The alialine sharphatese sas 0 Longer sige ARH i aitfarent fron the controls, While the choline oxides hasd narsy dpsties - ki aalndikaertihcee rdoagtshetrhtehsaenr3atFealshoivne`dPlpaosimnacrcehaosleestienropll.ama slkalivecEURaRLENS as2t E AppraxinFaitveaalnyd oescabtha yXilaithe th Livers vere SHI M14gly Larger fomnSn REIS pl sige i El = z 000047resi IRGL5 ARTERIES USEPA 16183 . a. size of the Liver had decreased appreciably, Although small differmces ere st411 charred between the control and treated aninals, all of these rere within the range of normal for rats of this sge, sex md strain 83 astabliched by the untrested controle. Ihe results intoete that the enlarged vers resulting from 8 single dose of ANT are biochemically as Well aa anatomically sonormai. Toe rise in 0p consumption ov decrease in C0 productien snd BY reflect some change in the metabolic behavior of the liver, for-theoe--ere--e-messure--st Aihontogrotedth_at mgooonsincltiviingctaamas. The difference in respiratory quotiant vas sll and after vo mouths greater voriation vas sou in the AiT-trested grovp 8s mre of ihe animale spprosciad the moras range. Some individual onsyses were affected to u greater degree than ihe RQ botween 15 apd 23 days. After tv months, hoverer, bro of the nye sctivitias wero in the noreal rxvia, and the third vas actually | more active than the controls. These chongos, together With the respiratory changes in the tissue, suggest that sone mdificotion in the effect of LT | a 2 min som soe mt ore Sm. on hed oncurred. aLiver vasdeploted ofglycogenobboth tuo vaeksandtwo 4 na peplaced by ates snd protein iathesesly stagesofteLiversalisgea = Tho.decrease 4 DHA and HRA probablyremiltedfrom 8decressein sa donstty as themaber of sells in & piven amount of Liswiedocrannod. SL mite agresviththe sberrvationthatthe surly emlargeimsdcute i! Etretpally to collslaryperteopty rather thin proliferation: After to Ls : = g 8 ies Er oils 0p0043 : AS al EELSo mn tlieraatPA etite es USEPA 16184 BEST COPY AVAILABLE on 3 eri the wn Lass 55Eren ese cnt. 4nd FEArsted ote a suggesting either a decrease in the size of the cells or an tacresse in E ritosts. he romitn reporiad suem to Snticate that the Livers of rata 3 & atimdlated by a single oral dose of ART undergo slteration in their bio oF chemical behavior and metabolism during the period of rapid growth, later, = tet toe sev oo ct sre 2 aberrations also cand to dissppesr. The greatest changes occur during the fret few weeks or month after the exposure. By the end of two ronths some % evidence of a roverasl of these effects is already apparent; between five a and six months recovery of the orgen is virtuslly complete. vr 2. Regenerating and _Dogenerating Liver 3 Procedure: Regenerating Lover tissse vas induced by pertial LE vepatactony (60-TOF) tn six ale rata fron the stock colony. Forty-eight 8 hours after the sperstion a single oral dose of ART, squivslent to 12 re/ks Ee t oe vemiomm ee tantw ine Fe orcmese Wtoi isme-- aes iht a its LL i i } i F 3 som a0 mepeated 3 sscond tine, reversing the procedure by performing the partis hopatectony forty-sight hours attar the dogs of AUT had bem administered. Degenerating liver tiseus was induced chemically by administering, A :T Sis 40 rats 1 hours after intubatingthem with 12 mg/kg of ANT. Animals hich hdbs received anly carbon tetrachloride served as controls. fie i Besultsr The results are mumarizsd in Table b. Hepstastomr-ilend,. dis: Tk prodced in accelerated grovth of the Liver tare tos witidh wijeceint oe nearly o12 of the tiasorves Testorsd. The Dik,Rk ot 448 Spt ih iy - than innormal tissue. . Lat J ids i ARE:gaised ja accslerated growthof Hho Hires soba |g them tuice porsal size tav-wsksafter stapes Eien d 2 nm HSee ER Pel ) 000049 USEPA 16185 ' a 4n DHA and glycogen as vell as an increase in APase and prospioliptd, These 7 changes occurred regargless before or after the dogo of of whether two-thirds of AH, although thero vas the liver was removed somewhat less of an effect : on the mclete acids, hospbolipide and APeas when bepatectory fotleved trout- fi ent. wlth AB. K This remsrkable growth of the liver even efter "wo-thirds of it has gi been surgicslly removed, {be affected tissue doss is quite imteresting. mot appreciably alter Apparently the wml removal of mich grvith Tate of of at,pematntng, Prom nother pooifvnietw, ANT wuld apesrt have an b oven greosftvesesrtiemmlauisniazngreagfetneerraptairntgialtibsseupea,tectIfosoynewuasssbuemtewseetnhaklatnhde gars, E aunt, 46 tncreased 2 to 3 01d within two Ueeks after hepatectaryy ebavt the sare aooslersced growth thot occurred in normal tissue after trestrant ith MT. The k or 5 grams of tissue remaining after partial bepatoctumy, however, had + is! i> Le : . 77 ie ions Ancressed 5 or 6 fold when trotted with AMT. Ope of the ssiixxrraattes ddoossesddwwiitthhAcNaTrbporniortettoracthhelorciadrebodnietdetoriagchhtloride dye Later, but 411 ted within 8 hours. No analysis of the Liver was poceidle for all of the animale were found dead and post-zortes chengea had begun. When eined grossly, however, the Jivers vere massive in size (Lie. 30 to LO grams} and yellow ta color probably from scute fatty intilizetion. Plochemdcal mesmrwiants on the marviving carbon tetrachloride ats shoved m0 sppFeciable (iffereaces fromcotesls aside frensmell changssin the mmeleda acids. Tho bochemical. data. waggest that Whee tre FOIAILY QRARLLTS +; utramees tn the atraciotAFT Pluordearbon Biepebstng wgoneninteEynd ) REtue } AQo0S0 ons rien oc oes . E wl 8 ds, USEPA 16186 : 3 "10 # dogs. Liver enlargement oncure tn Tats but. in dogs, hypocholestorolents 15 the most unusuol uding. Tt would be useful to investigate these in several i other species --- nice, guinea pigs, rabbits. The combined effect of carbon 3 tetrachloride and AUT rey be of practical significance since mich mtiple <3 exposures coiid conceiahly be experienced by persomnel hmdling AT. i Further stady of this problem is recomended. i & I Fa Scngof] * io X eh . VEO0G0 000054 ae Feee nL i Ei sDOT ngay AE E= niin By g aaSdRVNeeeubsey USEPA 16187 rer 7 Wade i aoa E PE | FHrit Hlle \L(Eu CogH1a1i9n5bE41 PiliGe |a5.8 [ii F a BE (use i . ; hod J | ] 1 fpr dit|EaBig 1 i i. 31 1d Bf Rill / Fleoweoa 8 R 5 2 : ? a - gl F jfeo-aes |g 8 |8 3 : [EL a . at ond Woe = I Te tt si eo 1a ; IR 000052 Led ai USEPA 16188 { TR TABLE 2 ' + 3 PLASMA LEVELS OF BLOOD CONSTITUENTS AFTER hy EXPOSURE 0 FLIOIOOAREON DISWIRSIIO AGES # a |.Det pom Do PB 1. mr g AEE After F Cholee sterot l e BAodP:alsUeun.ittse Uanrirts DUomeoitree uB Unmits l &dmoett aase i4.% o* 33 2.3 3s m0 ow 20 og 8 & 5.5 CE 15 uw 5.5 Cg 22 wr 7.3 vr [ c------n --------86--------e1.r2 es ees ------ 3 n 2.7 850 350 360 | ow 1 n 1.7 20 us & 8 10 ob Ww 50 2 18 13k 135 - Lo Ba a 20 10 wh nous - 0 ey wr In n w4d 0 43 uv EE - wig AE - ji* Be L gviaei | : C3 il i Ec 2 eral BE 000053 | weds USEPA 16189 Eo33% 5s 3: 2" jgsssxeg23 gS MSs 53d 5a 2g. IE8% i 3 ul maguszaz 2s i 8.& ~jegasx=2sax 1 -- | [{rssszees 5% a382%%A9 a|2s8. 0 al[zrzasans 723 : ifsil beceneans (nn. : IB EEEEEEEE: 33 ; y i BE eeho lb] 8 8888888 HE. : erBl gles. 5 ceibps bmE aboLf hLeS oc addi feng eS pcan dete ia aii 000054 USEPA 16190 Pil. | pracsture Supmary and Conclusion 1f0orSa14mSpidanrigevlsero4onosduailiss1o2-rLimiftahi/ckeaolt,hdeorsTeShsiissopfeprrHeoHicne3gd0u3ra5erwiavresye iaapevhteenrpiettsoerwtanhtrean(3sb)h ASraeotrasri,ieyuhLriACcHhoaasbbeonrrentt Qnteny #83035 Conclusion piven in single oral 12 nefke dosen produces no Sliniced signe of Soxierty. Grad d#a#sa3n035ofma1y3 mbee/kcso,nsihdaevriende prreoltautcievtelyno hearrmilmeesnst soma mister when adninistersd to rate in sinsle Tuleof Liver Hesents wt ve. -- 2 Liv=er we. BLRev, , 10 3ipso5te: (503 11o5ss iPpret - * . z5 ie : 00005S B g BAGO REA 2d USEPA16191