Document YjQjezxerMrG4VK8XV7L3bj5E

-- Pathology and Toxicology RRR COMPANY CONFIDENTIAL Riker Laboratories, Ino, COMPANY CONFIDENTIAL Suid 703505. 0Corer n SP Building St. Paul, Mirela 551441000 270-3S-05, 3M Center Minnesota 55144-100(; ,| 1 TTWHOO YYEEAARR OORRAALL ((DDIIEETI)) TTOOXXIICCIITTYY // CCAARRCCIINNOOGGEENINCICIITIYY 1 SSTIUUDDYY OOFF FFLLUUOORROOCCHHEEMMIICCAALL FFCC--114433 IINN RRAATTSS 1 (RIKER (RIKER EExXpPeErRIiMmEeNnTt NNoO.. 00228811CCRR00001122)) un VVOoLuUuMrEe i1 oOFF 44 | | CCOoNnDoUuCcTteEnD DDUuRrIiNnGe I AAePRrIiLL,, 11998811 -- MMAaYy,, 11998833 |n RRIIKKEERR LLAABBOORRAATTOORRIIEESS,, IINnCc.. // 33MM Company COMPANY 1 Er SSTT.. PPAaUuLl,, MMIiNnNnEeSsOoTtAa 5555114444--11000000 UU..SS..AA.. Exhibit 1337 State of Minnesota v. 3M Co., Court File No. 27-CV-10-28862 11333377..00000011 3aMnAAo0o0c02277112266 I 1 TTWHOOSYYTEEUAADRRY OOOFRPAALLFLU((DGDRIIEOETTC)H)ETMTIOOCXXAIICLCIITTFYYC//-C1CA4AR3RCCIIINNNOOGGREAENTNIS[CCIITTYY I STUDY OF FLUOROCHEHICAL FC-143 IN RATS 1 ((RRIIKKEERR EExxppeerriimmeenntt NNoo.. 0022881]CCRR00001122)) I TTAABBLLEE OOFFCOCNOTNTEENNTT:S i 1 PAPGAGEE((ss)) 1 RERPEPOORRTT SSUUMMMAARRYY ....+.. ....o .....o ....o ...... .... I n IINNTTRROODDUUCCTTIIOONN .. .o.o..v.v.e.t..e ..e..e...e ....e ....e ... 33 1 MMAATTEERRIIAALLSS AANNDD MMEETTHHOODDSS .. .. .......................................... 44 | RERSESUULLTTSS .v ......i ......e ......t ....... ..... 100 1I DICSSION eee DISCUSSION ............................. 19 1 CCOONRCCLLUUSSIIOONNSS .+.+..o.v..e...e..e.e...e ...a ...e .... ... 28 25 I PPRRIINNCCIIPPAALL PPEERRSSOONNNNEELLLLIISSTT .... .. .. .................................... 2 ~6 1 SISGINGNAATTUURREE PPAAGGEE .+ ..+..+ .v.e.e...e ..e ..e...e.e.e....... 277 i RREFEERENFCESE..R..Eo..N.o.Co.t .E.So ...t..t ...u..s ...a..L........ 2B8 1 REPORT TILES LLL Be REPORT TABLES ........................... 29-92 i 1 TTAABBLLEE ]1 - AAnnaallyyssiiss ooff FFCC--114433 iinn tthhee DDiieet t...................... 2299 n TTAABBLLEE 22 - MSSauummlmaearrsyy.oo.ff.MMeeLaann LBBooddLyy WWeeiigghhttss -- Males ....................... 30 I1 TLE3 - Summary of Hean Body Vlght-s TABLE 3 -FeSFmuemmamallaeerssy of..M..ea..n..B.o.dy....We..ig..ht..s ..- ...................... 32 i1 WE+ ~ amary of fogs Fg Cop TABLE 4 - SPPueerrmmaKKriiylloogogrfraamMmeaBBnooddyyFeeWWdeeiiggChhottnsu--mpMMtaailloeenss .... .. .............. 3344 I 1 TTAABBLLEE 55 -- SSPeuurmmmmaKariryyloogorfaMMmeeaaBnnodyFFeeeWeddeigCChootnnssuu-mmppFtteiimooannles . . . . . .... 36 Per Kilogram Body Weight - Females ......... 36 TTAABBLLEE 66 --MSSauulmmmaearrsyy.oo.ff.MMeeaa.nn .AAbb.ssooll.uutt.ee .FFee.eedd.CCoo.nnss.uumm.ppttii.oonn.--.... 3 Males ....................... 38 i i TTAABBLLEE 77 --FeSSmuumammlaaerrsyy ooff.MM.eeaa.nn.AAbb.ssoo.llu.utte.e .FFee.eedd.CC.oonn.ssuu.mmpp.ttii.oonn..-- .... 4 Females ...................... 40 n TTAABBLLEE 88 -- EEssttiimmaatteedd MMeeaann FFCC--114433 CCoonnssuummppttiioonn IInn i 1 MMiilllliiggrraammss PPeerr KKiillooggrraamm PPeerr DDaayy .. .................. 442 i i 11333377..00000022 3MMA0A000002277112277 I i TTAABBLLEE OFOF CCOONNTTEENNTTSS -- CCoonnttiinnuueedd | 1 PPAAGGEE((sS)) i TTAABBLLEE 99 --MMoorrttalaitlyiDDtaattyaa...................................... 44 1 TTAABBLLEE 1100 -- SSuummmmaarryy ooff CClliinniiccaall SSiiggnnss .......................... 446 | TTAABBLLEE 1111 --SuSummmmaarryy ooff OOpphhtthhaallmmoollooggiicc CChhaannggeess .... .............. 4488 1I TLE 12- sn and Invicus) osogran Values- les... 50 TABLE 12 - Mean and Individual Hemogram Values - Males .... 50 1 TTAABBLLEE 1133 -- MMeeaann aanndd IInnddiivviidduuaall HHeemmooggrraamn VVaalluueess - FFeemmaalleess . ... 5577 i TTAABBLLEE 1144 -- MMMeeaaalnnesaannddo IInnddiivviidduuo aall SSeerruumn. CChheemmiissttrry. y VVaalluueess . -- Ea Males ....................... 64 i 1 TTAABBLLEE 1155--FeMMemeaaannleaasnndd I.InnddiivviidduuaallnSSeeirruumnaCCnhheemmiissttarryyiVVaaalluu.eess -- ea. 11 Females ...................... 71 1 TTAABBLLEE1166 -- UUrriinnaallyyssiiss VVaalluueess .. ................................ 7788 i i TTAABBLLEE 1177 -- WIIenniddgiihvvtiisdd,uuaallMeaOOnrrggaaOnnrgaWWneeiiggRhhettl,,atiAAvnnded AAPbbessrooclleuunttteeToMMeeaahnnolOOerrggaaBnnody i OWWWeneeiiiegggYhhhettt,s,a,rAA.nnMddeao nOOrrggOaarnnga. nTTooReBBlrro aaaiitnniveWWeeo iiPggehhrttcenRR. taattiiTooossW. hAAttole . Body 8 One Year ...................... 81 i 1 TTAABBLLEE 1188 -- WIIenniddgiihvvtiisdd,uuaallMeaOOnrrggaaOnnrgaWWneeiiggRhhettl,,atiAAvnnedd AAPbbersscooellnuuttt.eeToMMeeaahnnolOOerrggaaBnnody WWVeeeiiiggghhhttt,s,, AAnnMddeanOOrrggOaarnnganTTooReBBlrraaaiitnniveWWeeiiPggehhrttcenRRtaattiiTooossWhAAttole Body 1 Nora andOren To Bruin Neigh aries" Two Years ..................... 86 i 1 TTAABBLLEE 1199 -- FSSiuunmmdmmiaanrrgyys ooff- MMNaaejjoooprrlaMsMiticiccrroossLcceoospipioinccs . .......... Findings - Neoplastic Lesions ........... 91 i 1 TTAABBLLEE 2200 -- SFSuiunnmmdmaairrnyygsooff- MMNaaojjnoo-rrNeMoMipiclcrarosotssicccooppiiLccesions . .. ...... 9 Findings - Non-Neoplastic Lesions ......... 92 i RERPEPOORRTT FFIIGGUURREESS +..+ .+ ...e ...e ..e ....e ...e ...e .... ... 9933:-3966 1 FFIIGGUURREE 1I -- MMeeaann BBooddyy WWeeiigghhttss -- MMaalleess .. .. .. .....c..e.... o9w3 I FFIIGGUURREE 22 -- MMeeaann BBooddyy WWeeiigghhttss -- FFeemmaalleess ........................ 94 i1 FIGRE 3 - en Feed conseption er FIGURE 3 - KMKeiiallnooggrrFaaemmedMMeeCaaonnnsuBBmoodpdyytioWWneeiiggPhhettr -- MMaalleess .. ... ............ 9955 i i FFIIGGUURREE 44 -- MKMeeiaalnnogrFFaeemeeddMeCCaoonnnssBuuommdppyttiiWooenntgPPheetrr - Females . . ...... 9 Kilogram Mean Body Weight - Females ........ 96 I n | 11333377..00000033 M3MA0A000002277112288 | I 1 TC TAABBLLEOEOOFFNCOT NTENETS -N -CoCnoTnttiinnS uueedd PPAAGGEE((sS)) I AAPPPPEENNDIDXI.X...oo.t..........................S9T7-1223 i TITTEEMH AA -- AAilrr MMoonniittoorriinngg ooff AAnniimmaall RRoooommss .. .. .. ................ 9 98 I IITTEEMM BB -- DDiieett AAnnaallyyttiiccaall DDaattaa SShheeeettss ........................ 110033 I 1 IITTEEM CC -- AAPccaccteehppottlaaobbgllyee PRRaaarnnaggmeeessterffsoorr . C.Clliinniicc. aall............ ls Pathology Parameters ................ 116 i 1 IITTEEMM DD -- HbHyiissttDroo.ppaattRhhoobolelrootggiiccG. EExGxeaaimmlii,nnaattEiixootnnernaaannldd PCPoaanttshhuoolllotogagynytRReeppoorrtt VVbyeetteeDrrr.iinnaaRrroyyberPPtaatthGh.oolloGogeiiglsi,ts.tE.xt.. er.. na..l..C..on..su..lt..an..t .......... 111199 I 1 IITTEEMM EE -- BBiioossttaattiissttiiccaall AAnnaallyyssiiss PPrroocceedduurreess .... .. .. .. ........ 407 407 IITTEEMM FF -- SSuummmaarryy ooff MMeeaann BBooddyy WWeeiigghhttss aanndd IInnddiivviidduuaall AAnniinmaall 1 Body Weight and Feed Jar Height Data + 1. 411 Body Weight and Feed Jar Weight Data ........ 411 i 1 IITTEEMM G6 -- OODrpp.hhtthShatalelmpnhooessnccooppIii.ccBiEEsvvtaanlleuuraa,ttiiooEnnxteaarnnnddalDDaattCaaonsbbuyyltant ~ ` I VVDree.tteerrSitinenapahrreyynOOppI.hhtthhBaaillsmmtnooellroo,ggiissEttxte..rn..al.. .C. o.ns.u.l.t.a..nt.......... 11220033 1 IITTEEMM NH -- CCooppyy ooff tthhee SSttuuddyy PPrroottooccooll wwiitthh AAmmeennddmmeennttss.... .. .. .. 1206 1206 II IITTEEMM 1I .- QQuuaalliittyy AAssssuurraannccee UUnniitt SSttaatteemmeenntt .. .. .. .. ... ......... 11221I44 I 1 IITTEEMM JJ -- ACCnhheaemlmiiyccsaaells AAonnfaallFyyCss-ee1ss83ooffin FFDCCi--e11t4433 . aann.dd .SS.ttaa.bbii.llii.tt.yy .....I125 Analyses of FC-143 in Diet ............. 1215 i i i I i i i I 11333377..00000044 3MMA0A000002277112299 B R i TTWHOO YYEEAARR OORRAALL ((DDIIEETT)) TTOOXXIICCIITTYY//OONNCCOOGGEENNIICCIITTYY SSTTUUDDYY OOFF FFLLUUOORROOCCAARRBBOONN FFCC--114433 IINN RRAATTSS R 1 ((RRIIKKEERR EExxppeerriinmeenntt NNoo.. 00228811CCRR00001122}) 1i sus sums REPORT SUMMARY 1 TThhee ppuurrppoossee ooff tthhiiss ssttuudlyy wwaass ttoo aasssseessss tthhee ppootteennttiiaall ttooxxiicciittyy aanndd R oonnccooggeenniicciittyy ooff FFCC--114433 ((aammmaonniiuuam ppeerrfflluuoorrooaallkkyyll ccaarrbbooxxyyllaattee)) mmiixxeedd iinn tthhee 1 ddiieett aanndd ffeedd. ttoo 5500 rraattss ppeerr sseexx ppeerr ggrroouwp ffoorr ttwwoo yyeeaarrss.. AAnn iinntteerriimm | 1 ssaaccrriiffiiccee aanndd eevvaalluuaattiioonn wwaass ppeerrffoorrmmeedd aatt oonnee yyeeaarr oonn 1155 aaddddiittiioonnaall rraattss per sex fron the control and high-dose groups. per sex from the control and high-dose groups. B I 1 AA ttoottaall ooff 336600 SSpprraagguuee--DDaawwlleeyy mmaallee aanndd ffeemmaallee rraattss wweerree aassssiiggnneedd ttoo tthhrreeee experimental groups. The FC-143-treated groups were fed diets containing eeeixitptehhreeirrme33n00t00al oogrrro33u00ps.ppppmmThooeff FC-143-treated groups were fed FFCC--114433 ffoorr ttwwoo yyeeaarrss,, wwhhiillee diets containing aa ccoonnttrrooll ggrr6uupp B i rreecceeiivveedd oonnllyy uunnttrreeaatteedd ffeeeedd.. I i IInn--lTiiffee oobbsseerrvvaattiioonnss ppeerrffoorrmmeedd ddaaiillyy oobbsseerrvvaattiioonnss ffoorr aabbnnoorrmmaall dduurriinngg ssiiggnnss;; tthhee ccoouurrssee ooff tthhee ssttuudy inncclluuddeedd:: ppeerriiooddiicc pphhyyssiiccaall eexxaammiinnaattiioonnss;; bbooddyy 1 wweeiigghhtt aanndd ffeeeedd ccoonnssuummppttiioonn;; oopphhtthhaallmmoossccooppiicc eexxaammiinnaattiioonnss; aanndd cclliinniiccaall B ppaatthhoollooggyy iinncclluuddiinngg hheemmaattoollooggyy,, cclliinniiccaall cchheemmiissttrryy aanndd uurriinnaallyyssiiss.. B1 Wacrascopic postrorten examinations wers performed on 411 anisals that died oMorracrwwoeesrrceeopttieecrrmmpiionnsaatttmeeoddrteppmrriieooxrramttioonatttihhoeenseennwddereooffpettrhhfeeormsseccdhheedodnuulleeadldl animals ddoossiinngg.. that died SSeelleecctteedd 1 oorrggaann wweeiigghhttss wweerree oobbttaaiinneedd ffrroomn aallll ooff tthhee rraattss nneeccrrooppssiieedd aatt 1! yyeeaarr aass B 1 wweellll aass ffrroomn 1155 rraattss//sseexx//ggrroouupp,, rraannddoommllyy sseelleecctteedd ffrroonm tthhee ccoonnttrrooll aanndd bbootthh FC-143-treated groups, at the termination of the study. Selected tissue n FsspCpee-cc1iimm3ee-nntssreawwteeerrdee ghhraaorruvvpeesss,tteeddat ffrrtoohmne termination eeaacchh aanniimnaall of aatt the study. Selected tissue nneeccrrooppssyy,, aanndd pprreesseerrvveedd ffoorr 1 ffuuttuurree hhiissttooppaatthhoollooggiicc eexxaammiinnaattiioonn.. MMiiccrroossccooppiicc eevvaalluuaattiioonn wwaass ppeerrffoorrmmeedd I oonn aallll ttiissssuueess ssaavveedd ffrroomm aallll ooff tthhee ccoonnttrrool] aanndd hhiigghh--ddoossee rraattss,, wwhhiillee aa ssiinmiillaarr eevvaalluuaattiioonn wwaass ppeerrffoorrnmeedd oonn aa mmooddiiffiieedd l14isstt ooff ttiissssuueess oobbttaaiinneedd in from the Tou-dose animals. from the low-dose animals. I 1 TThhee mmaajjoorr iinn--1liiffee ffiinnddiinnggss aassssoocciiaatteedd wwiitthh FFCC--114433 aaddmmiinniissttrraattiioonn ccoonnssiisstteedd ooff:: aa ddoossee--rreellaatteedd ddeeccrreeaassee iinn mmeeaann bbooddyy wweeiigghhtt aanndd aa ttrreeaattmmeenntt--rreellaatteedd 1! n B 11333377..00000055 M3MA0A000002277113300 | 1 i iinnccrreeaassee iinn ffeeeedd ccoonnssuummppttiioonn ppeerr kkiillooggrraamm ooff mmeeaann bbooddyy wweeiigghhtt iinn mmaalleess;; aanndd | aa sslliigghhtt ttrreeaattmneenntt--rreellaatteedd iinnccrreeaassee iinn tthhee iinncciiddeennccee ooff aattaaxxiiaa iinn tthhee 1 ffeenmzalleess.. TThheerree wwaass nnoo iinnccrreeaassee iinn mmoorrttaalliittyy iinn tthhee hhiigghh--ddoossee ttrreeaattmmeenntt | ggrroouupp wwhheenn ccoommppaarreedd ttoo ssiimniillaarr vvaalluueess ffoorr tthhee ccoonnttrrooll ppooppuullaattiioonn.. 1| FC-163 related hanstologic changes in both treated groups consisted of 4 ddFeeCc-c1rr4ee3aasseereliinnaterrdeedd hematologic bblloooodd cceell]l changes ccoouunnttss,, in both treated groups hheemmoogglloobbiinn ccoonncceennttrraattiioonn consisted of a aanndd hheemmaattooccrriitt i vvaalluueess aatt vvaarriioouuss ttiinmeess tthhrroouugghhoouutt tthhee ssttuuddyy.. GGeenneerraallllyy,, tthheessee hheemmaattoollooggyy I ppaarraammeetteerrss rreemmaaiinneedd wwiitthhiinn tthhee aacccceeppttaabbllee rraannggeess ffoorr tthhee rraatt.. i 1 Tahleterpartiimoanrsy alterations FCww-ee1rr4ee3 associated changes were found in cchhaarraacctteerriizzeedd bbyy iinnccrreeaasseedd the liver. These lliivveerr wweeiigghhttss~, | hheeppaattoomneeggaalloaccyyttoossiiss wwiitthh vvaaccuuoollaattiioonn ooff tthhee ccyyttooppllaassmm,, aanndd ssoomnee eevviiddeennccee ooff i hheeppaattoocceelllluu]laarr ddeeggeenneerraattiioonn wwiitthh ooccccaassiioonnaall ssiiggnnss ooff nneeccrroossiiss.. TThheessee lliivveerr changes were found early in the study and showed very little evidence of i pcprhroaognggrreeesssssiiwooennreaattfottuhhneed early eenndd ooff in the study ttwwoo yyeeaarrss.. and showed very little evidence of :~ 1| TThhee iinncciiddeennccee ooff aallmmoosstt aallll nneeooppllaassmmss iinn tthhiiss ssttuuddyy wwaass rreellaattiivveellyy lTooww,, aanndd 1 tthhee ttyyppeess aanndd iinncciiddeennccee ooff nneeooppllaassmmss wweerree ggeenneerraallllyy nnoott ddiiffffeerreenntt ffrroomn | tthhoossee ccoommmmoonnllyy ffoouunndd iinn ggeerriiaattrriicc SSpprraagguuee--DDaawwlleeyy rraattss.. HHeeppaattoocceelllluullaarr 1 ttuumnoorrss vweerree vveerryy sslliigghhttllyy iinnccrreeaasseedd iinn tthhee hhiigghh--ddoossee mmaallee rraattss.. TThhee ootthheerr | nneeooppllaassamss iinn tthhiiss ssttuuddyy wweerree aassssoocciiaatteedd wwiitthh eennddooccrriinnee aanndd//oorr eennddooccrriinnee- i sisneennsstiihtteiivvheeigoohr-rggaaannnssd.. loTTwhh-eedoiisnneccrrgeeraaossueepdds iiwnnaccsiiddneeonntccee sootffatmimsaatmmimacararylylyoorrsittgeenssittfiiicccuuallnaatrr ttuumsoorrss and/or | vians was tsshiiemmiihlliaagrrh-ttooanttdhheelosswpp-oodnnottsaaenneeooguurssoupiisnncciiwddaeesnnccneeotrreespptooarrtttieesddtiffcooarrllSSypprrsaaiggguuneei--fDDiaacwwallneetyy and/or rraattss.. i 1 UUnnddeerr tthhee ccoonnddiittiioonnss ooff tthhiiss ssttuuddyy aanndd bbaasseedd oonn ttuummoorr iinncciiddeennccee,, ttyyppeess ooff 1 ttuunmoorrss,, ttiimvee ooff ttuummoorr aappppeeaarraannccee,, aanndd tthhee ssuurrvviivvaall rraattee aatt ttwwoo yyeeaarrss,, | FFCC--114433 iiss nnoott ccoonnssiiddeerreedd ttoo bbee ccaarrcciinnooggeenniicc iinn tthhee rraatt.. | 1 1| | 1 | 1 | 1 2. 11333377..00000066 M3MA0A000002277113311 1Ii TTWHOO YYEEAARR OORRAALL ({DDIIEETT)) TTOOXXIICCIITTYY -- CCAARRCCIINNOOGGEENNIICCIITTYY n SSTTUUDDYY OOFF FFLLUUODRROOCCHHEENMIICCAALL FFCC--114433 IINN RRAATTSS 1B IINNTTRROODDUUCCTTIIOONN 1 TThhiiss ssttuuddyy wwaass ddeessiiggnneedd ttoo eevvaalluuaattee tthhee cchhrroonniicc ttooxxiiccoollooggiicc aanndd B ccaarrcciinnooggeenniicc ppootteennttiiaall ooff FFCC--114433,, aann iinndduussttrriiaall ggrraaddee ooff aammmmoonniiuumm i ppeerrfflluuoorrooaallkkyyll ccaarrbbooxxyyllaattee,, iinn rraattss ffoolllloowwiinngg oorraall aaddmmiinniissttrraattiioonn iinn tthhee H ddiieett ffoorr aa ppeerriioodd ooff ttwoo yyeeaarrss.. TThhee ssttuuddyy wwaass ssppoonnssoorreedd bbyy tthhee CCoommmmeerrcciiaall 1 CChheemmiiccaall DDiivviissiioonn ooff 33MM CCoommppaannyy aanndd wwaass ppeerrffoorrmmeedd bbyy tthhee PPaatthhoollooggyy aanndd H TTooxxiiccoollooggyy DDeeppaarrttmmeenntt ooff RRiikkeerr LLaabboorraattoorriieess,, IInncc..,, 33MM CCoommppaannyy,, SStt.. PPaauull,, 1 WMiimnnneessoottaa,, UU..SS..AA.. TThhee ssttuuddyy aanndd ssuubbsseeqquueenntt rreeppoorrttiinngg wwaass ccoooorrddiinnaatteedd ffoorr n tthhee ssppoonnssoorr bbyy tthhee 33MH CCoorrppoorraattee TTooxxiiccoollooggyy SSeerrvviicceess ssttaaffff.. TThnee iinn--lliiffee oorr ddoossiinngg ppoorrttiioonn ooff tthhee ssttuuddyy bbeeggaann oonn AApprriill 2211,, 11998811,, aanndd wwaass ccoommpplleetteedd oonn i MMaayy 55,, 11998833.. AA ccooppyy ooff tthhee ssttuuddyy pprroottooccooll wwiitthh aammeennddmmeennttss iiss ccoonnttaaiinneedd iinn B tthhiiss rreeppoorrtt aass AAppppeennddiixx IItteemm HH.. :: i TThhee ssttuuddyy wwaass ddeessiiggnneedd ttoo eevvaalluuaattee ttwwoo sseeppaarraattee fflluuoorroocchheemmiiccaallss,, i FFM--33992244 aanndd FFCC--114433,, uussiinngg aa ccoommmoonn sseett ooff ccoonnttrrooll aanniimmaallss.. TThhiiss rreeppoorrtt 1 Wwiillll ddeessccrriibbee tthhee rreessuullttss ooff tthhee FFCC--114433 ttrreeaattmmeenntt wwhhiillee tthhee rreessuullttss i rreellaattiinngg ttoo tthhee FFHM--33992244 ssttuuddyy wwiillll bbee rreeppoorrtteedd sseeppaarraatteellyy.. TThhee ssttuuddyy wwaass ccoonndduucctteedd iinn aaccccoorrddaannccee wwiitthh tthhee DDeeppaarrttnmeenntt''ss SSttaannddaarrdd | 1 OOppeerraattiinngg PPrroocceedduurreess ((iiee..,, SSOOPPss)) aanndd iinn ccoommpplliiaannccee wwiitthh tthhee FFoooodd aanndd DDrruugg AAddmmiinniissttrraattiioonn''ss GGoooodd LLaabboorraattoorryy PPrraaccttiiccee ((GGLLPP)) rreegguullaattiioonnss ((2211 CCFFRR PPaarrtt B] Bre vatons hee of re Ho rs AA5s8s)ss.uurraannVccaeeriUUonnuiistt;;phttahhseeeiisrr of the study were inspected by the RIKER ssttaatteemmeenntt iiss pprreesseenntteedd iinn AAppppeennddiixx IItteemm II Quality ooff tthhiiss 1 rreeppoorrtt.. TThhee oorriiggiinnaall ssiiggnneedd pprroottooccooll wwiitthh aammeennddmmeennttss,, lTiisstt ooff ssttuuddyy R ppeerrssoonmneell,, rraaww ddaattaa,, ssttuuddyy ssppeecciimmeennss,, aanndd ootthheerr ppeerrttiinneenntt ssttuuddyy 1 ssaammpplleess//ddooccuumneennttss wwiillll bbee mmaaiinnttaaiinneedd wwiitthhiinn tthhee PPaatthhoollooggyy aanndd TTooxxiiccoollooggyy B DDeeppaarrttmreenntt aarrcchhiivveess ccuurrrreennttllyy llooccaatteedd aatt 33M CCeenntteerr iinn SStt.. PPaauull,, MMiinnnneessoottaa.. 1n iI R 1 B 1 in 3 11333377..00000077 M3MA0A000002277113322 I i MHAATTEERRIIAALLSS AANNDD MMEETTHHOODDSS I 1 TTeesstt SSyysstteemm:: TThhrreeee--hhuunnddrreedd aanndd ssiixxttyy SSpprraagguuee--DDaawwlleeyy rraattss [[CCrr1I::CcOoBBSsR I CCDD((SSDD))BBRR,, CChhaarrlleess RRiivveerr,, PPoorrttaaggee,, MMII]],, 3399 ttoo 4411 ddaayyss ooff gagee wwhheenn ttrreeaattmmeenntt bbeeggaann,, wweerree ddiivviiddeedd bbyy mmeeaannss ooff aa ttaabbllee ooff rraannddoomm nnuummbbeerrss iinnttoo tthhrreeee B1 rote. The control and high-dose groups. each contained 65 males and 63 gffreeommuaapllsee.ss,, wwThhheeerreecaaossntttrhhoeel llaoonwwd--ddoohssiegeh-ggdrrooosuuepp groups each ccoonnttaaiinneedd 5500 contained 65 males and 65 mmaallee aanndd 5500 ffeemmaallee rraattss.. 1 TThhee rraattss wweerree hhoouusseedd iinn hhaannggiinngg ssttaaiinnlleessss sstteeeell ccaaggeess wwiitthh wwiirree mmeesshh I fflloooorrss aanndd ffrroonnttss.. TThhee mmaalleess wweerree hhoouusseedd iinnddiivviidduuaallllyy,, bbuutt tthhee ffeemmaalleess B 1 wweerree roots hhoouusseedd ttwwoo fron those ppeerr ccaaggee.. TThhee ccoonnttrrooll which received FC-143 in aanniimmaallss wweerree hhoouusseedd iinn sseeppaarraattee order to prevent a possible cross 1 rccoooonnmttsaammiifnnraaotmtiiootnnhosbbeyy whppioocttheennttriieaaclleivvveaadppooFrrCii-zz1aa4tt3iiooinnn order to prevent a possible aanndd//oorr ssuubblliimmaattiioonn ooff tthhee cross tteesstt B aarrttiiccllee wwhhiicchh hhaass aa ffiinniittee vvaappoorr pprreessssuurree aatt rrooonm tteemmppeerraattuurree.. AAiirr ssaammpplleess wweerree ttaakkeenn ffrroonm eeaacchh ooff tthhee aanniimmaall ttrreeaattmmeenntt rroooommss ffoouurr mmoonntthhss aafftteerr tthhee i iinniittiiaattiioonn ooff tthhee ssttuuddyy iInn oorrddeerr ttoo aassssaayy ffoorr tthhee pprreesseennccee ooff aaiirrbboorrnnee n ccoonnttaammiinnaannttss.. TThhee ssaammpplleess wweerree aannaallyyzzeedd bbyy tthhee AAnnaallyyttiiccaall SSeeccttiioonn ooff ~thhee B 33MM CCeennttrraall RReesseeaarrcchh LLaabboorraattoorryy aanndd wweerree ffoouunndd ttoo bbee bbeellooww ddeetteeccttaabbllee lliimmiittss I ffoorr tthhee ssuussppeecctteedd fflluuoorroocchheemmiiccaallss.. IInn aaddddiittiioonn ttoo tthhee aaiirr mmoonniittoorriinngg,, 3300 1 uunnttrreeaatteedd sseennttiinneell rraattss wweerree ppllaacceedd iinn eeaacchh ooff tthhee ttwwoo aanniimnaall rroooommss.. FFrroonm i eeaacchh aanniinmaall rroooomm,, 55 mmaallee aanndd 55 ffeemmaallee sseennttiinneell rraattss wweerree eeuutthhaanniizzeedd dduurriinngg 1 tthhee ffiirrsstt wweeeekk ooff tthhee ssttuuddyy,, aanndd aatt I1 aanndd 33 mmoonntthhss aafftteerr tthhee ssttaarrtt ooff tthhee ! ssttuuddyy.. PPllaassnmaa ssaammpplleess oobbttaaiinneedd ffrroomm tthheessee rraattss wweerree aannaallyyzzeedd ffoorr oorrggaanniicc i Affpllpuueoonrrdiininexe taanenddn Aww)ee.rree ffoouunndd ttoo ccoonnttaaiinn lleessss tthhaann oonnee ppaarrtt ppeerr mmiilllliioonn ((sseeee H AppendEEiaaxcchh ItaaennmiimnAaa)ll. rroooomn wwaass tteemmppeerraattuurree aanndd hhuummiiddiittyy ccoonnttrroolllleedd wwiitthh tthhee 1 lTiigghhttiinngg oonn aa 1122 hhoouurr lliigghhtt//ddaarrkk ccyyccllee.. IInnddiivviidduuaall rraattss wweerree uunniiqquueellyy B iiddeennttiiffiieedd bbyy aann aanniimnaall nnuunmbbeerr oonn aa ccaaggee ccaarrdd aanndd oonn aa ttaagg aaffffiixxeedd ttoo tthheeiirr 1 eeaarr.. FFeeeedd ((CCeerrttiiffiieedd PPuurriinnaa LLaabboorraattoorryy CChhooww,, RRaallssttoonn--PPuurriinnaa CCoo.., SStt.. I LLoouuiiss,, MHOO)) aanndd ttaapp wwaatteerr wweerree pprroovviiddeedd aadd lib1iibtiutumn.. I1 Test Substance/Det preparation: FC-48 (Lot 37) vas analyzed by the CCoommmeerrTcceiisaatll SuCCbhhseetmmaiincccaaell/ssDieDDtiivviiPssriieoopnansrsat(i(CCoCCnDD:)) AAnnFaaCll-yy1tt4ii3ccaa(llLotLLaa3bb7oo)rraawttaoosrryyanapplrryiizooerrd by ttoo the tthhee i ssttaarrtt ooff tthhee ssttuuddyy,, aafftteerr aapppprrooxxiimmaatteellyy oonnee yyeeaarr ffrroomm tthhee ssttaarrtt ooff tthhee B ssttuuddyy,, aanndd aatt tthhee tteerrmniinnaattiioonn ooff tthhee ddoossiinngg ppeerriioodd.. NNoo ddeetteeccttaabbllee cchhaannggeess i wweerree ffoouunndd iinn tthhee tteesstt ssuubbssttaannccee dduurriinngg tthhiiss ttiimmee ((sseeee CCCCDD AAnnaallyyttiiccaall B RReeppoorrttss NNooss.. 330088,, 334488 aanndd 441133 iinn AAppppeennddiixx IItteemm JJ)).. IiB1 a 11333377..00000088 3MMA0A000002277113333 1I1 TThhee tteesstt ssuubbssttaannccee wwaass aa wwhhiittee ppoowwddeerr wwhhiicchh wwaass aaddddeedd ((iiee,, ssttrraattiiffiieedd)) I ddiirreeccttllyy iinnttoo aann aapppprroopprriiaattee qquuaannttiittyy ooff uunnttrreeaatteedd ddiieett aanndd mmiixxeedd iinn aa ] HHoobbaarrtt?R bblleennddeerr ffoorr aapppprrooxxiimmaatteellyy 2200 mmiinnuutteess ffoorr ecaacchh sseeppaarraattee bbaattcchh.. H PPrriioorr ttoo iinniittiiaattiinngg ccoommppoouunndd aaddmmiinniissttrraattiioonn ttoo aannyy aanniimmaallss,, tthhee tteesstt ssuubbssttaannccee//ddiieett mmiixxttuurree wwaass aassssaayyeedd.. FFCC--114433 wwaass ffoouunndd ttoo bbee uunniiffoorrnmllyy i blended and stable for ane to tuo weoks in the ground feed (see CCD blended and stable for one to two weeks in the ground feed (see CCD B AAnnaallyyttiiccaall RReeppoorrtt NNoo.. 220099 iinn AAppppeennddiixx IItteemm JJ)).. i TTeesstt aarrttiiccllee//ddiieett mmiixxttuurreess wweerree pprreeppaarreedd ffrreesshh wweeeekkllyy dduurriinngg tthhee B ssttuuddyy aanndd rreepprreesseennttaattiivvee ssaammpplleess ooff eeaacchh wweerree ccoolllleecctteedd aanndd aassssaayyeedd ffoorr 1 tteesstt aarrttiiccllee ccoonntteenntt aanndd hhoommooggeenneeiittyy dduurriinngg tthhee ffiirrsstt mmoonntthh ooff tthhee ssttuuddyy n aanndd aatt 33 mmoonntthh iinntteerrvvaallss tthheerreeaafftteerr ((sseeee AAppppeennddiixx IItteemm BB)).. TThhee rreessuullttss ooff tthheessee aassssaayyss iinnddiiccaatteedd tthhaatt tthhee lleevveell ooff FFCC--114433 wwaass ggeenneerraallllyy wwiitthhiinn aa ffeeww i percent of that desired (Tole 1) percent of that desired (Table I). B TThhee rraattss rreecceeiivveedd seiitthheerr FFCC--1]4433 ttrreeaatteedd oorr ccoonnttrrooll ((iiee,, uunnttrreeaatteedd)) B dhhiooelltees wwaaissn glass jars ccuutt iinn tthhee 10.2 cm high x ssttaaiinnlleessss sstteeeell 8.9 cm in diameter. A 1liidd.. OOnn aa wweeeekkllyy bbaassiiss 5.1 tthhee cm access ddiieett jjaarrss 1 wweerree rreemmoovveedd aanndd rreeppllaacceedd wwiitthh cclleeaann jjaarrss ccoonnttaaiinniinngg ffrreesshh ddiieett mmiixxttuurreess.l B 1 EExxppeerriimmeennttaall DDeessiiggnn:: TThhee ssttuuddyy ccoonnssiisstteedd ooff oonnee ccoonnttrrooll ggrroouupp aanndd i ttwwoo ttrreeaattmreenntt ggrroouuppss.. TThhee ddoossaaggee lleevveellss aanndd aanniimmaall ddiissttrriibbuuttiioonn aarree lliisstteedd i hheerreeiinnaafftteerr.. i B 1 GGrroouupp SSiizzee && AAnnitmnaall NNuummbbeerrss B 1 TTrreeaattmmeenntt. Groups. DDoossaaggee LLeevveellss (opm) MMaalleess (an. Nos.) FeFmemaalleess (An. Mos.) Groups (ppm) (An. Nos.) (An. Nos.) i I1 CCoonnttrrooll 0 o iH 5 igh 0 1 5 - High 66 - lLooww 3O300 30 B I 1 B 1 B i 65 (seas 6655 ((33551166--3358508)0)~ 6550 ((33568415--33664955))/ 50 (3646-3695)~ 6665s5 (((44655077166---4464745004)50)) 5605 ((44674016--4740755)5) 50 (4706-4755) 5. 11333377..00000099 M3MA0A000002277113344 n i AAnn iinntteerriimm tteerrmmiinnaattiioonn aatt oonnee yyeeaarr iinnvvoollvveedd 1155 mmaallee aanndd 1155 ffeemmaallee rraattss I ffrroomm bbootthh tthhee ccoonnttrrooll aanndd hhiigghh--ddoossee ggrroouuppss.. TThhee rreemmaaiinniinngg 5500 aanniimmaallss ppeerr 1 sseexx ppeerr ggrroouupp ccoonnttiinnuueedd oonn ssttuuddyy.. i IInn--LLiiffee OObbsseerrvvaattiioonnss:: AAlT]l aanniimmaallss wweerree oobbsseerrvveedd ddaaiillyy tthhrroouugghhoouutt tthhee 1 ttwwoo yyeeaarr ddoossiinngg ppeerriioodd.. eWeeekkllyy pphhyyssiiccaall eexxaamniinnaattiioonnss iinncclluuddeedd ppaallppaattiioonn i ffoorr tthhee pprreesseennccee ooff mmaasssseess aass wweellll aass oobbsseerrvvaattiioonnss ffoorr pphhaarrmmaaccoottooxxiicc ssiiggnnss;; i1 rortatity va recorded daly, Ooniry she studs mono sents woe mccollrootsseaelllyiytymmoownnaiisttoorrreeeddc,,ordaaennddd daily. During the eeuutthhaanniizzeedd wwhheenn iinn study, moribund tthhee jjuuddggeemmeenntt animals ooff tthhee were SSttuuddyy 1 DDiirreeccttoorr ddeeaatthh aappppeeaarreedd ttoo bbee iimmmmiinneenntt iinn oorrddeerr ttoo hhaarrvveesstt nnoonn--aauuttoollyysseedd I ttiissssuuee ffoorr ssuubbsseeqquueenntt hhiissttooppaatthhoollooggiicc eexxaammiinnaattiioonn.. 1 BBooddyy wweeiigghhttss aanndd ffeeeedd ccoonnssuummppttiioonn wweerree rreeccoorrddeedd oonnccee ppeerr wweeeekk ffoorr tthhee ! ffiirrsstt ssiixx mmoonntthhss,, aanndd tthheenn oonnccee eevveerryy ttwwoo wweeeekkss ffoorr tthhee rreemmaaiinnddeerr ooff tthhee ssttuuddyy.. i EEyyee eexxaammiinnaattiioonnss uussiinngg iinnddiirreecctt oopphhtthhaallmmoossccooppyy aanndd//oorr sslliitt llaammpp n bbiioommiiccrroossccooppyy wweerree ppeerrffoorrmmeedd oonn tthhee ccoonnttrrooll aanndd hhiigghh--ddoossee rraattss bbyy tthhee SSttaaffff i VVeetteerriinnaarriiaann pprriioorr ttoo ccoommppoouunndd aaddamifnniissttrraattiioonn aanndd aatt aapppprrooxxiimmaatteellyy oonnee i yyeeaarr.. TThhee eeyyeess ooff tthhee ssuurrvviivviinngg ccoonnttrrooll aanndd hhiigghh--ddoossee aanninmaallss wweerree 1 eexxaammiinneedd 22--33 wweeeekkss pprriioorr ttoo tthhee tteerrmmiinnaattiioonn ooff tthhee ssttuuddyy bbyy aa ccoonnssuullttiinngg I VVeetteerriinnaarryy OOpphhtthhaallmmoollooggiisstt ((sseeee AAppppeennddiixx IItteemm GG)).. 1 CClliinniiccaall ppaatthhoollooggyy ddeetteerrmmiinnaattiioonnss iinncclluuddeedd hheemmaattoollooggyy,, cclliinniiccaall ! ((sseerruumm)) cchheemmiissttrryy aanndd uurriinnaallyyssiiss.. TTeessttss wweerree ccoonndduucctteedd oonn ssaammpplleess oobbttaaiinneedd ffrroomm 1155 rraattss ppeerr sseexx ffrroomn eeaacchh ggrroouupp aatt 33,, 66,, 1122,, 1188 aanndd 2244 mmoonntthhss;; aanniimmaallss 1 wweerree rraannddoommllyy sseelleecctteedd aatt eeaacchh ttiinmee iinntteerrvvaell.. HHeemmaattoollooggiicc tteessttss iinncclluuddeedd | ttoottaall rreedd adnndd wwhhiittee bblloooodd cceellll ccoouunnttss,, hheemmoogglloobbiinn,, hheemmaattooccrriitt,, aanndd aa 1 ddiiffffeerreennttiiaall wwhhiittee bblloooodd cceellll ccoouunntt.. CClliinniiccaall cchheemmiissttrryy ppaarraammeetteerrss n iinncclluuddeedd ttoottaall bbiilliirruubbiinn,, ttoottaall pprrootteeiinn,, aallbbuummiinn,, bblloooodd uurreeaa nniittrrooggeenn [] ((BBUUNN)),, gglluuccoossee,, aallkkaalliinnee pphhoosspphhaattaassee ((AAPP)),, ccrreeaattiinnee pphhoosspphhookkiinnaassee ((CCPPKK)),, I aassppaarrttaattee aammiinnoottrraannssffeerraassee ((AASSTT--ffoorrmmeerrllyy kknnoowwnn aass SSCGOOTT)),, aallaanniinnee 1 aammiinnoottrraannssffeerraassee ((AALLTT--ffoorrmneerrllyy SSGGPPTT)),, aanndd ccaallcciiuumm.. UUrriinnee tteessttss iinncclluuddeedd I BpHH,, ssppeecciiffiicc ggrraavviittyy,, aallbbuummiinn,, gglluuccoossee,, bbiilliirruubbiinn,, ooccccuulltt bblloooodd aanndd kkeettoonneess.. i BBlloooodd ssaammpplleess wweerree ccoolllleecctteedd ffrroomm tthhee rreettrroobbuullbbaarr vveennoouuss pplleexxuuss ooff I aanneesstthheettiizzeedd rraattss wwhhiicchh hhaadd bbeeeenn ffaasstteedd oovveerrnniigghhtt.. BBlloooodd wwaass ggeenneerraallllyy i ccoolllleecctteedd ffrroomn tthhee rriigghhtt eeyyee.. UUrriinnee ssaammpplleess wweerree oobbttaaiinneedd bbyy ppllaacciinngg eeaacchh i rraatt iinn aann iinnddiivviidduuaal] mmeettaabboolliissmm ccaaggee ffoorr Z200--2222 hhoouurrss.. TThhee ssppeecciiffiicc mmeetthhooddss 11II 5 11333377..00001100 M3MA0A000002277113355 i i uusseedd ffoorr hheemmaattoollooggyy,, cclliinniiccaall cchheemmiissttrryy aanndd uurriinnaallyyssiiss aarree oouuttlliinneedd iinn | AAppppeennddiixx CC.. TThhee mmeeaann hheemmaattoollooggyy aanndd cclliinniiccaall cchheemmiissttrryy vvaalluueess ffrroomm tthhee 1 ttrreeaatteedd ggrroouuppss wweerree ccoommppaarreedd ttoo bbootthh tthhee ccoonnccuurrrreenntt ccoonnttrrooll ggrroouupp aass wweellll | aass nnoorrmmaall rraannggeess ffoorr tthheessee ppaarraammeetteerrss oobbttaaiinneedd ffrroomm hhiissttoorriiccaall ccoonnttrrooll 1 aanniinmaall ddaattaa ggeenneerraatteedd iinn tthhiiss llaabboorraattoorryy ((AAppppeennddiixx CC)).. | MMeettaabboolliicc EExxaammiinnaattiioonn:: OOvveerrnniigghhtt ((iiee,, aabboouutt 2244 hhoouurr)) uurriinnee aanndd ffeeccaall i ssaammpplleess wweerree ccoolllleecctteedd aatt 22,, 55,, 1111 aanndd 2233 mmoonntthhss ffrroomm ffiivvee rraattss ppeerr sseexx ppeerr | ggrroouupp ffoorr ttoottaall oorrggaanniicc fflluuoorriiddee aannaallyyssiiss,, aanndd ffoorr tthhee pprreesseennccee ooff FFCC--114433.. 8 AAtt tthhee sscchheedduulleedd oonnee aanndd ttwwoo yyeeaarr nneeccrrooppssiieess,, ssaammpplleess ooff lliivveerr,, bblloooodd,, i kkiiddnneeyy,, sspplleeeenn,, Tluunngg aanndd bboonnee mmaarrrrooww ((iiee,, ffrroomm tthhee ffeemmuurr)) wweerree ssaavveedd ffrroomn 1 Ffiivvee rraattss//sseexx//ggrroouupp.. AAfftteerr ccoolllleeccttiioonn,, aallll ssppeecciimmeennss wweerree ffrroozzeenn ppeennddiinngg | ssuubbsseeqquueenntt aannaallyyssiiss bbyy tthhee RRIIKKEERR DDrruugg MMeettaabboolliissmm DDeeppaarrttmmeenntt.. OOnnccee tthheessee ssppeecciinmeennss aarree aannaallyyzzeedd,, aa sseeppaarraattee rreeppoorrtt rreeggaarrddiinngg tthhiiss |1 Cxparinental ork will be prepared by the Drug Hetabolisn department. experimental work will be prepared by the Drug Metabolism department. i PPoossttmmoorrtteemn E~xxaammiinnaattiioonnss:: GGrroossss ppoossttmmoorrtteemm eexxaammiinnaattiioonnss wweerree | ppeerrffoorrmmeedd oonn aallll rraattss wwhhiicchh ddiieedd dduurriinngg tthhee ssttuuddyy aanndd tthhoossee wwhhiicchh wweerree 1 tteerrmmiinnaatteedd aatt tthhee aonnee yyeeaarr iinntteerriinm aanndd ttnwoo yyeeaarr nneeccrrooppssiieess.. AAtt nneeccrrooppssyy,, i aann eexxaammiinnaattiioonn wwaass mmaaddee ooff tthhee eexxtteerrnnaall bbooddyy ssuurrffaaccee aanndd bbooddyy oorriiffiicceess.. TThhee ccaarrccaassss wwaass tthheenn ooppeenneedd aanndd tthhee ccoonntteennttss ooff tthhee aabbddoommeenn,, tthhoorraaxx aanndd | 1 ccrraanniiuumm vweerree eexxaammiinneedd iinn ssiittuu aanndd ffoolllloowwiinngg rreemnoovvaall ffrroomm tthhee bbooddyy.. OOrrggaann wweeiigghhttss ((ifee,, wweett ttiissssuuee)) wweerree oobbttaaiinneedd aatt tthhee iinntteerriimm 1 tteerrmmiinnaattiioonn ffrroomm bbootthh tthhee ccoonnttrrooll aanndd hhiigghh--ddoossee ggrroouuppss,, aanndd ffrroomm tthhee | ccoonnttrrooll aanndd bbootthh FFCC--114433 ttrreeaatteedd ggrroouuppss aatt tthhee ttwwoo yyeeaarr nneeccrrooppssyy.. TThhee i wweeiigghhttss ooff tthhee aaddrreennaall ggllaannddss,, bbrraaiinn,, tteesstteess,, hheeaarrtt,, kkiiddnneeyyss,, lliivveerr,, sspplleeeenn | aanndd uutteerruuss wweerree rreeccoorrddeedd ffoorr 1155 rraannddoommllyy sseelleecctteedd rraattss//sseexx//ggrroouupp.. BBooddyy 1 wweeiigghhttss wweerree oobbttaaiinneedd jjuusstt pprriioorr ttoo nneeccrrooppssyy ffrroonm tthhee ssaammee rraattss iinn oorrddeerr ttoo | ccaallccuullaattee oorrggaann wweeiigghhttss rreellaattiivvee ttoo wwhhoollee bbooddyy wweeiigghhttss.. RReepprreesseennttaattiivvee ssaammpplleess ooff tthhee ffoolllloowwiinngg ttiissssuueess aanndd oorrggaannss ffrroonm eeaacchh |i at vere fixed fn 10% neutral, buffered formalin for subsequent hsteTogtc 1 prraotcewsesrieng:fixed in 10% neutral, buffered formalin for subsequent hlstologic processing: i soAorrttaa LLiivveerr ((22 SSeeccttiioonnss)) i AAddrreennaallss ((22)) LLuunngg ((22 SSeeccttiioonnss)) | BBrraaiinn ((33 SSeeccttiioonnss iinncclluuddiinngg LLyymmpphh nnooddee ((mmeesseenntteerriicc)) i11| 7. 11333377..00001111 M3MA0A000002277113366 i1!1 frontal frontal ccoorrtteexx aanndd bbaassaall ganglia, parietal cortex MMaammmmaarryy GGllaanndd ((ffeemmaalleess)) Pancreas i 1 gaanndgltihaa,lampuasr;ietcaolrecboerltlemx aanndd ptohnasl)amus; cerebellum PPPiaitntucuriiettaaasrryy Salivary Gland 1 GtoEyyneeassdasnd pons) SSSSpappiillnneiaaevllnaryCCoorrGddl/a/BnBdoonnee MHaarrrrooww ((vveerrtteebbrraaee)) B Gonadosvaries (2) SSptloemaecnh i i HeartTOevsartieess/Ep(i2)didynides Testes/Epididymides ((22)) STthoymraocihd/Parathyroid/Trachea/Esophagus Urinary Bladder Thyroid/Parathyroid/Trachea/Esophagus I 1 SHeaaarlt Intestine (3 Sections) LSmaarlgle IInntteessttiinnee (3 Sections) UUtreirnuasryorBlaPdrdoesrtate nUtyerutsissoruePmraosssteaste (suspected tumors) 1 KLiadrngeeysInt(2estSiencetions) Kidneys (2 Sections) AAnnyy gtriossssueTmeasstsoens (suspected tumors) Any gross lesion i 1 staineLLdii,gghhttpammrfiaccfrrfooissncc-ooeppntibcc.eddeeexxdaammiitnniaasttsiiuooenn wwaass ppeerrffoorrmseedd sections fron oonn all hheemmaattooxxyylliinn aanndd eeoossiinn tissues sted above, I 1 When available, and fron all rats stained, paraffin-embedded tissue when available, and from all rats (Group 5) populations regardless in the contral (Group 1) sections from all tissues in the control (Group ]) of the cause of death. and hih-dase listed above~ and high-d:se Microscopic i e(xGraomuipn,at5i)on poopfultaitsisouness teixsasmuiensatiolnistoefd taibsosvuees erffxerrcgooeammprtd:lttehhsees aollorooftwwa--,ddtoohsseeebrac((iaGGnurr,sooeuuppevoef66s)),derraaastttmhssa.lliinnMccaillncuudrddoeesddcloaPrttighhceee i htiiiinnsstttseeousspettasiitnnheeossll,,oigsitce.dLlyymmeppxahhabonvienanntooiddeeoex(n(csse))pa,,tn:d eaavnnaaddolrutaat,ssippoiinnnbaarlloafin,thcceoosrreeddy/e/sbbt,ooinnseesusemsalmmlaawrrarrsooawwnp..derfolrasTrTehhgdeee i 1 0bhb)yyi.sDtDrro..patRRhooobbleeorrgtticGG.. eGGxeeailmlli,,nacctooinnossnuullattniidnnggevVVaeelttueearrtiiinnoaanrryy oPPfaattthhhooellsooeggiitssittss((usseeesee wAAappsppeennpddeiirxxforIImtteeedmm D). i 1 1 w ei ghtBBsii,oossttfaaattiidssttciioccnaasllu MHeetthhooddss:: TThhee mption, absolute mmeeaannss organ aanndd ssttaannddaarrdd ddeevviiaattiioonnss weight, relative organ ffoorr bbooddyy weight to I 1 dWwwahhetioogallheetvsebb,rooeddyyfdeweweeetdiieggrchhnottin,,nseudoomrrpgsgtaaeinnpoanwr,weeaiitaggebhhlsttyoltftuoootrebberroaaarciighnnanwwseeewiixeggihhagttnhdtrr,daaottrsiieooelssagtraaionnvuddep.ooottrhhgeearrn llwaaebbioogrrhaatttoorrtyyo I These data wero analyzed data were determined separately These data were analyzed vardance. IF this test vas not uufsosriinnggeacBBhaarrsttellxeettattn''dss test for dose group. test for hhoommooggeenneeiittyy ooff significant at alpha = 0.001, the data vere i i avffauurrrtittwahhonee-crrtea.aatnnlaaelldIyyfzzDeetuddhmiasbbtyytt'cecosostmmpptaawerarsisitnnggnaotteeaactcshhhiegnttrirefeaaialtctoeaehdndatgg=rratoo0uu.ppa0l5ttpoohsaittghh=neei0f.cci0ooc0nn1att,nrroocllethlgegerrvoodeuualppt.auuwsseiTirnhnegeg i i rtraaeebsstluuwollostt-.sstaioolIffFedDDBuuaDnrmunteneltntetettt''ttss''ss tteetssettst test hhaaavvtee was thbbeeeeenn aliipnnhddaiicc=aattee0dd.05bbyysiaagssnttieefrriiicssakknssce aonlnevttehhlee. significant at alpha = 0.001, the data mmeeTaahnne were tables. If Bartlett's test was significant at alpha = 0.001, the data were I results have been indicated by the pound sign (F) on the mean tables. 1 rraannkkeedd aanndd aa ttwwoo--ttaaiilleedd DDuunnnneetttt''ss tteesstt wwaass ppeerrffoorrmmeedd oonn tthhee rraannkkss.. TThheessee results have been indicated by the pound sign (#) on the mean tables. IIii 5o 1337.0012 1337.0012 awacoozria? 3MA00027137 | 1 i IInn aaddddiittiioonn,, ffoorr eeaacchh oorrggaann//lleessiioonn ccllaassssiiffiiccaattiioonn tthhee sseexxeess wweerree | aannaallyyzzeedd sseeppaarraatteellyy uussiinngg aa ttwwoo--ttaaiilleedd FFiisshheerr''ss EExxaacctt TTeesstt ccoommppaarriinngg eeaacchh i ttrreeaatteedd ggrroouupp ttoo tthhee ccoonnttrroollss.. AAnn aallpphhaa ~= 00..0055 ssiiggnniiffiiccaannccee lleevveell wwiitthh i BBoonnffeerrrroonnii''ss aaddjjuussttnmeenntt ffoorr mmuullttiippllee ccoommpaarriissoonnss wwaass uusseedd wwiitthhiinn eeaacchh oorrggaann//lleessiioonn//sseexx ccaatteeggoorryy.. IIff tthhee eexxppeecctteedd vvaalluuee ooff eeaacchh cceellll wwaass ggrreeaatteerr 1 tthhaann 2200,, tthheenn YYaatteess'' ccoorrrreecctteedd CChhii--SSqquuaarree tteesstt wwaass uusseedd.. AAnn aasstteerriisskk oonn | tthhee ssuummmaarryy ttaabblleess iinnddiiccaatteess aa ssiiggnniiffiiccaanntt ddiiffffeerreennccee bbeettwweeeenn tthhee ccoonnttrroallss i aanndd tthhee ttrreeaatteedd ggrroouupp.. | IInntteerrnnaall RRIIKKEERR mmeemmoorraannddaa ppeerrttaaiinniinngg ttoo tthheessee bbiioossttaattiissttiiccaall pprroocceedduurreess | i aarree pprreesseenntteedd wwiitthhiinn AAppppeennddiixx IItteemm EE.. | 1 | 1 1| | i 1| 1| | 1 | i | 1 | 1 | 1 1| | i 9 11333377..00001133 MA00027138 3MA00027138 | 1 RREESSUULLTTSS | 1 IInn-:LLiiffee FFiinnddiinnggss:: BBooddyy wweeiigghhtt ggaaiinnss wweerree ddeepprreesssseedd iinn eexxcceessss ooff 1100%% iinn | tthhee FFCC--114433 hhiigghh--ddoossee mmaalleess ccoommppaarreedd ttoo tthhee ccoonnttrrooll mmaalleess tthhrroouugghh 6666 wweeeekkss ooff tthhee ssttuuddyy.. TThheerree wwaass aann aapppprrooxxiimmaattee 2211%% ddeeccrreeaassee iinn tthhee hhiigghh--ddoossee bbooddyy 1 wweeiigghhttss bbyy wweeeekk 66.. TThhiiss ddiiffffeerreennccee wwaass ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt ffrroonm wweeeekk | 22"" ooff tthhee ssttuuddyy uunnttiill wweeeekk 9988 wwhheenn tthhee hhiigghh--ddoossee aanndd ccoonnttrrooll mmaallee bbooddyy i wweeiigghhttss hhaadd ggrraadduuaallllyy eeqquuaalliizzeedd.. LLiikkeewwiissee iinn tthhee llooww--ddoossee mmaallee ggrroouupp,, aa 55%% | ddeeccrreeaassee iinn bbooddyy wweeiigghhttss wwaass oobbsseerrvveedd aatt wweeeekk 66,, hhoowweevveerr,, tthheerree wwaass lliittttllee 1 aaddddiittiioonnaall ddeeccrreeaassee tthheerreeaafftteerr ((TTaabbllee 22,, FFiigguurree I1 aanndd AAppppeennddiixx FF)).. TThhee | ooccccuurrrreennccee ooff aa nmiilldd SSDDAA vviirruuss oouuttbbrreeaakk aatt ddiiffffeerreenntt ttiimneess dduurriinngg tthhee ssttuuddyy 1 mmaayy hhaavvee hhaadd aa sslliigghhtt iinnfflluueennccee oonn tthhee bbooddyy wweeiigghhtt ddaattaa ((sseeee pp.. 1122)).. | MMeeaann bbooddyy wweeiigghhttss wweerree oonnllyy vveerryy sslliigghhttllyy ddeeccrreeaasseedd iinn tthhee FFCC--]14433--ttrreeaatteedd |1 females compared to the contra] female values through the first 18 months ooFffemattlhheees compared to the control female values through the first ssttuuddyy.. AAtt 1188 mmoonntthhss,, tthheerree wwaass aa ggrraadduuaall ddeeccrreeaassee iinn 18 months mmeeaann bba~ddyy i wweeiigghhttss ooff hhiigghh--ddoossee ffeemraalleess tthhaatt rreeaacchheedd aa mmaaxxiimmuumm ooff --1111%% aatt 9922 wweeeekkss.. | TThhee llooww--ddoossee ffeemmaalleess aallssoo sshhoowweedd aa ddeeccrreeaasseedd bbooddyy wweeiigghhtt,, bbuutt tthhee eeffffeecctt 1 wwaass nnoott ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt aanndd tthhee cchhaannggee wwaass ooff aa mmuucchh lloowweerr i mmaaggnniittuuddee ((TTaabbllee 33,, FFiigguurrae 22 aanndd AAppppeennddiixx FF)).. 1| ean feed consumption, presented 35 grams of Giet consumed per day per Mkkeiiallnooggrrfaaemmedoofcommneesaaunnmptbbioooddnyy, presented wweeiigghhtt,, wwaass as grams of diet iinnccrreeaasseedd iinn aallll consumed per day per ooff tthhee FFCC--114433--ttrreeaatteedd 1 mmaalleess tthhrroouugghhoouutt tthhee ssttuuddyy wwhheenn ccoommppaarreedd ttoo tthhee mmaallee ccoonnttrrooll ffeeeedd | ccoonnssuummppttiioonn.. TThhiiss cchhaannggee wwaass mmoorree pprroonnoouunncceedd iinn tthhee hhiigghh ddoossee ggrroouupp wwhheerree 1 tthheerree wwaass rroouugghhllyy aa 1133%% iinnccrreeaassee nnootteedd wwiitthh ssppoorraaddiicc vvaalluueess ggooiinngg aass hhiigghh | aass 2299%% dduurriinngg tthhee ttwwoo yyeeaarr tteesstt ppeerriioodd.. IInn tthhee ffeemmaalleess tthhee ppaatttteerrnn wwaass 8 lTeessss ccoonnssiisstteenntt,, bbuutt tthheerree wwaass aa ttrreenndd ttoowwaarrdd lloowweerreedd ffeeeedd ccoonnssuummppttiioonn iinn | bbootthh FFCC--114433--ttrreeaatteedd ggrroouuppss ccoommppaarreedd ttoo tthhee ffeemmaallee ccoonnttrrooll vvaalluueess ((TTaabblleess &4 aanndd 55 aanndd FFiigguurreess 33 aanndd 44)).. OOvveerraallll,, tthheessee vvaarriiaattiioonnss wweerree rreellaatteedd ttoo tthhee | i vvaarriiaattiioonn ooff bbooddyy wweeiigghhtt aasmoonngg ggrroouuppss.. 1 AAccttuuaall mmeeaann ffeeeedd ccoonnssuummppttiioonn ((wwiitthhoouutt rreeggaarrdd ffoorr bbooddyy wweeiigghhtt cchhaannggee)) wwaass | sslliigghhttllyy ddeeccrreeaasseedd iinn tthhee hhiigghh--ddoossee mmaalleess rreellaattiivvee ttoo ccoonnttrrooll mmaalleess,, ffoorr 1 tthhee ffiirrsstt yyeeaarr ooff tthhee ssttuuddyy.. FFeeeedd ccoonnssuummppttiioonn iinn llooww--ddoossee mmaalleess,, wwhhiillee | ssoommeewwhhaatt iinnccoonnssiisstteenntt,, wweass sslliigghhttllyy iinnccrreeaasseedd dduurriinngg tthhiiss ssaammee ppeerriioodd.. 1| i| 1l0O.. 11333377..00001144 M3MA0A000002277113399 i 1 i DDuurriinngg tthhee sseeccoonndd yyeeaarr,, tthhee ffeeeedd ccoonnssuummppttiioonn ooff bbootthh FFCC--114433--ttrreeaatteedd mmaallee | ggrroouuppss wwaass rreeaassoonnaabbllyy ssttaabbllee aanndd ccoonnssuummppttiioonn wwaass ccoommppaarraabbllee ttoo tthhaatt ooff tthhee 1 ccoonnttrrooll ggrroouupp.. AAllll ooff tthhee ttrreeaatteedd ffeemmaallee ggrroouuppss tteennddeedd ttoo ccoonnssuummee Tleessss | ffeeeedd tthhaann tthhee ccoommppaarraabbllee ccoonnttrroollss tthhrroouugghhoouutt tthhee ssttuuddyy.. TThhee ggrreeaatteesstt ddeeccrreeaasseess ooccccuurrrreedd ffrroomn 1188 mmoonntthhss ttoo tteerrmmiinnaattiioonn wwiitthh tthhee hhiigghh- aanndd | | lTooww--ddoossee ggrroouuppss bbeeiinngg eeqquuaallllyy aaffffeecctteedd ((TTaabbllee 66 aanndd 77 aanndd AAppppeennddiixx FF)).. i TThhee tteesstt aarrttiiccllee ccoonncceennttrraattiioonn mmeeaassuurreedd aass ppaarrttss ppeerr mmiilllliioonn iinn tthhee ddiieett | wvaass ddeetteerrnmiinneedd aatt 33 mmoonntthh iinntteerrvvaallss wwiitthh aa dduupplliiccaattee aannaallyyssiiss ppeerrffoorrnmeedd 1 wwhheenn aabbeerrrraanntt vvaalluueess wweerree ddeetteecctteedd.. TThhee mmeeaann ddeevviiaattiioonnss ffrroomm tthhee ttaarrggeett | ccoonncceennttrraattiioonn ooff tthhee hhiigghh-- aanndd llooww--ddoossee FFCC--114433 ggrroouuppss wweerree lleessss tthhaann 33%% 1 ((TTaabbllee 11)).. | | i AAccttuuaall tteesstt aarrttiiccllee ccoonnssuummppttiioonn wwaass ddeetteerrmmiinneedd ffoorr eeaacchh 22 wweeeekk ppeerriioodd ffoorr each sex and each experinental group, and expressed as ng/ka/day. The mean etaecsht test seaxrtiacnlde article eacccoohnnsseuuxmmpppettriiioomnnentwawaalss group, and eessttiimmaatteedd expressed ttoo bbee:: as mg/kg/day. mmaalleess,, 1144..22 The mean aanndd 1~.33 1 mmgg//kkgg//ddaayy;; ffeemmaalleess 1166..11 aanndd 11..66 mmgg//kkgg//ddaayy ffoorr tthhee hhiigghh- aanndd llooww--ddoossee | 1 ggrroouuppss,, rreessppeeccttiivveellyy.. MMeeaann tteesstt aarrttiiccllee ccoonnssuummppttiioonn vvaalluueess ccaallccuullaatteedd aatt 22 week intervals for the entire study are presented in Table 8. week intervals for the entire study are presented in Table 8. | 1 OOvveerraallll ssuurrvviivvaall rraatteess ffoorr tthhee FFCC--1l4433--ttrreeaatteedd rraattss wweerree ggoooodd dduurriinngg tthhee | FfUuTl1l ttwhoo yyeeaarrss ooff tthhee tteesstt ppeerriioodd.. TThheerree wweerree ffeewweerr ddeeaatthhss rreeccoorrddeedd iinn tthhee i thhhiiegghh--eddnoodsseeofmmaa1lleeysseaaarnn,dd 1ff5eemmaarllaeetsss/ttshheaaxnn fiirnnontthhteeheccoocmmoppnaatrrraaabbllleeanccdoonnthtrrioogllh-dppooosppeuullgaarttoiiuoopnnsss..werAAett i ttheermiennadteodf terminated tt]oo yffeuuallrff,iillll15 rats/sex from the control and high-dose groups were tthhee pprroottooccooll rreeqquuiirreemmeenntt ffoorr tthhee iinntteerriimm ssaaccrriiffiiccee.. 1 TThhee ffiinnaall ssuurrvviivvaall rraattee tthheenn bbaasseedd oonn 5500 rraattss//sseexx//ggrroouupp aatt tthhee eenndd ooff 110044 | wweeeekkss wwaass:: mmaalleess,, 7700%%,, 8888%% aanndd 7722%%;; aanndd ffeemmaalleess,, 5500%%,, 5588%% aanndd 4488%% ffoorr tthhee 1 ccoonnttrrooll,, hhiigghh-- aanndd llooww--ddoossee ggrroouuppss,, rreessppeeccttiivveellyy.. TThhee iinnccrreeaasseedd ssuurrvviivvaall | rraattee oobbsseerrvveedd iinn tthhee hhiigghh--ddoossee mmaallee rraattss ccoommppaarreedd ttoo tthhee ccoonnttrrooll mmaallee rraattss,, 1 wwaass ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt ((pp <~ 00..0055)).. MMoonntthhllyy mmoorrttaalliittyy ddaattaa aarree | pprreesseenntteedd iinn TTaabbllee 99.. i AA ssuummmaarryy ooff tthhee mmoosstt ccoommmoonnllyy sseeeenn cclliinniiccaall ssiiggnnss iiss ccoonnttaaiinneedd iinn TTaabbllee | 1100.. TThhee oonnllyy cclliinniiccaall ssiiggnn tthhaatt ooccccuurrrreedd mmoorree ffrreeqquueennttllyy iinn tthhee tteesstt B aarrttiiccllee--ttrreeaatteedd ggrroguuppss wwaass aa ddoossee--rreellaatteedd iinnccrreeaassee iinn aattaaxxiiaa rreeppoorrtteedd ffoorr | tthhee FFCC--11433-- ttrreeaatteedd ffeemnaalleess.. WWhhiillee tthhee aattaaxxiiaa wwaass mmoosstt ccoommmmoonn|lyy aassssoocciiaatteedd i|1i Inf. 11333377..00001155 M3MA0A000002277114400 i i wwiitthh mmoorrbbiidd aanniinmaallss aanndd wwaass sseeeenn iinn tthhee ccoonnttrrooll mmaalleess aanndd ffeemmaalleess,, oonnllyy tthhee I ttrreeaatteedd ffeemmaalleess sshhoowweedd aann iinnccrreeaassee iinn tthhee iinncciiddeennccee ooff tthhiiss cclliinniiccaall ssiiggnn;; 1 22,, 1155 aanndd 99 ccaasseess iinn tthhee ccoonnttrrooll,, hhiigghh-- aenndd llooww--ddoossee ggrroouuppss,, rreessppeeccttiivveellyy.. i TThhee iinncciiddeenncceess ooff aallll ootthheerr cclliinniiccaall ssiiggnnss iinn tthhee FFCC--114433--ttrreeaatteedd ggrroouuppss wweerree ggeenneerraallllyy Tleessss tthhaann oorr eeqquuaall ttoo tthhee iinncciiddeennccee ooff tthhee ssaammee ssiiggnnss iinn tthhee i1 control group, control group. 1 RRaattss aaddnmiinniisstteerreedd tthhee tteesstt aarrttiiccllee eexxppeerriieenncceedd aa ssuussppeecctteedd oouuttbbrreeaakk ooff n sstiaallooddaaccrryyooaaddeenniittiiss ((SSDDAA)) vviirraall iinnffeeccttiioonn bbeettwweeeenn tthhee ffiirrsstt aanndd sseeccoonndd i mmoonntthhss ooff tthhee ssttuuddyy.. CClliinniiccaall ssiiggnnss iinncclluuddeedd sswwoolllleenn ssuubbmmaannddiibbuullaarr I ssaalliivvaarryy ggllaannddss aanndd ooccccaassfioonnaall ooccuullaarr mmaanniiffeessttaattiioonnss.. TThhee ssuubbmmaannddiibbuullaarr 1 sswweelllliinngg wwaass rreessoollvveedd wwiitthhiinn 1100 ddaayyss,, aanndd tthhee iinncciiddeennccee ooff ooccuullaarr cchhaannggeess i wwaass eexxttrreenmeellyy llooww.. SSiimmiillaarrllyy,, tthhee ccoonnttrrooll aanniimnaallss hhaadd ccoommppaarraabbllee ssyymmppttoommss dduurriinngg tthhee ssiixxtteeeenntthh mmoonntthh ooff tthhee ssttuuddyy.. TThhiirrtteeeenn mmaalleess aanndd 1133 ffeemmaalleess iinn I 1 tthhee ccoonnttrrooll ggrroouupp ddeemmoonnssttrraatteedd ssiiggnnss ooff tthhiiss ccoonnddiittiioonn wwhhiicchh llaasstteedd ffoorr aabboouutt 1166 ddaayyss ffrroomm tthhee ttiimnee ooff oonnsseett.. OOnnee mmaallee aanndd 33 ffeemmaalleess ddeevveelloog~edd 1 ooccuullaarr ooppaacciittiieess dduurriinngg tthhiiss ppeerriioodd.. i 1 TThhee iinncciiddeennccee ooff ppaallppaabbllee ttiissssuuee mmaasssseess iinn FFCC--114433--ttrreeaatteedd ggrroouuppss wwaass i ccoommppaarraabbllee ttoo tthhaatt ooff tthhee ccoonnttrrooll ggrroouupp.. TThheerree wweerree mmoorree aanniimmaallss wwiitthh 1 mmaasssseess iinn tthhee mmaallee ccoonnttrroollss tthhaann iinn tthhee mmaallee ttrreeaatteedd ggrroouuppss;; tthhaatt iiss,, 1199,, | 1100 aanndd 77 aanniimmaallss iinn tthhee ccoonnttrrooll,, hhiigghh-- aanndd llooww--ddoossee ggrroouuppss,, rreessppeeccttiivveellyy.. LLiikkeewwiissee,, wwhheenn tthhee nnuummbbeerr ooff ppaallppaabbllee mmaasssseess wwhhiicchh rreeggrreesssseedd oorr rreessoollvveedd i bbeeffoorree tthhee tteerrmmiinnaattiioonn ooff tthhee eexxppeerriimmeennttaall ppeerriioodd wweerree eevvaalluuaatteedd,, tthheerree n wweerree ssttiillll ffeewweerr mmaasssseess ffoouunndd iinn tthhee FFCC--114433--ttrreeaatteedd aanniimmaallss tthhaann iinn tthhee 1 contro grap (Table 10). control group (Table 10). I 1 TThhee rreessuullttss ooff tthhee ffiinnaall oopphhtthhaallnmoossccooppiicc eexxaammiinnaattiioonnss wweerree nneeggaattiivvee I rreellaattiivvee ttoo aannyy FFCC--114433 ttrreeaattmmeenntt--rreellaatteedd eeffffeeccttss.. CChhaannggeess tthhaatt wweerree 1 oobbsseerrvveedd iinncclluuddeedd aa rraannddoomm ddiissttrriibbuuttiioonn ooff ccaattaarraaccttss bbeelliieevveedd ttoo bbee nnoorrmmaall I ggeerriiaattrriicc cchhaannggeess ooff tthhee lleennss aanndd ssoommee ccaasseess ooff cchhrroonniicc uuvveeiittiiss aanndd ssuuppeerrffiicciiaall kkeerraattiittiiss wwhhiicchh wweerree aallssoo ccoonnssiiddeerreedd ttoo bbee wwiitthhiinn nnoorramaall l1iimniittss i ffoorr aaggiinngg ppooppuullaattiioonnss ooff rraattss ((TTaabbllee 1111 aanndd AAppppeennddiixx GG)).. MMaannyy ooff tthhee rraattss I ffoouunndd ttoo hhaavvee ooccuullaarr lTeessitoonnss wweerree iiddeennttiiffiieedd aass rraattss wwhhiicchh wweerree uusseedd ttoo I i oobbttaaiinn bblloooodd ssaammpplleess vviiaa tthhee rreettrroobbuullbbaarr vveennoouuss pplleexxuuss.. | 1 1 1122.. n 11333377..00001166 M3MA0A000002277114411 I 1 RReedd bblloooodd cceellll ccoouunnttss,, hheemmoogglloobbiinn aanndd hheemmaattooccrriitt vvaalluueess wweerree mmiinniimmaallllyy I ddeeccrreeaasseedd iinn tthhee hhiigghh--ddoossee mmaallee rraattss ccoommppaarreedd ttoo ccoonnttrrooll vvaalluueess,, ffrroomm 33 1 tthhrroouugghh 1188 mmoonntthhss.. SSttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt ((pp == <<00..0055)) ddeeccrreeaasseess wweerree i sseeeenn aatt vvaarriioouuss ttiimneess iinn tthhee ffoolllloowwiinngg ppaarraammeetteerrss:: eerryytthhrrooccyytteess aatt 66,, 1122 1 aanndd 1188 mmoonntthhss;; hheemmoogglloobbiinn,, 33 zanndd 1188 mmoonntthhss;; aanndd hheemmaattooccrriitt aatt 33,, 1122 aanndd 1188 | mmoonntthhss.. WWhhiillee ssoommee ooff tthheessee ppaarraammeetteerrss wweerree aallssoo aalltteerreedd iinn tthhee llooww--ddoossee mmaalleess,, tthhee cchhaannggeess wweerree ooff 2a lleesssseerr mmaaggnniittuuddee aanndd iinn ssoommee ccaasseess,, wweerree iI rr a i eeirrnyycttrhherraooscceyydttee as well ccoouunnttss as decreased aanndd hheemmaattooccrriittss (Table 12). wweerree sslliigghhttllyy The female ddeeccrreeaasseedd aatt 33 high-dose mmoonntthhss,, bbuutt i wweerree sslliigghhttllyy iinnccrreeaasseedd aatt 66 mmoonntthhss ccoommppaarreedd ttoo ccoonnttrrooll vvaalluueess.. AAtt 1122 n mmoonntthhss tthheerree wwaass aa ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt ddeeccrreeaassee iinn eerryytthhrrooccyyttee ccoouunntt,, 1 hheemmoogglloobbiinn,, aanndd hheemmaattooccrriitt ((TTaabbllee 13). n MMeeaann lleeuuccooccyyttee ccoouunnttss wweerree iinnccrreeaasseedd iinn bbootthh mmaallee ttrreeaattmmeenntt ggrroouuppss ccoommppaarreedd 1 ttoo ccoonnttrrooll vvaalluueess,, tthhrroouugghh tthhee ffiirrsstt yyeeaarr ooff tthhee ssttuuddyy.. TThheessee cchhaannggeess wweerree i dduuee ttoo iinnccrreeaasseess iinn aabbssoolluuttee ccoouunnttss ooff llyymmpphhooccyytteess aatt 33 aanndd 66 mmoonntthhss,, d~nndd 1i in natroiis st 12 month. Statitiealy manic neers oe ooibnbsseenrrevvueetddr::ophiiilnns at 12 months. llyymmpphhooccyyttee ccoouunnttss Statistically aatt 33 mmoonntthhss significant increases were iinn tthhee hhiigghh- aanndd llooww--ddoossee 1 ggrroouuppss,, aanndd aatt 66 aanndd 1188 mmoonntthhss iinn tthhee llooww--ddoossee ggrroouupp;s aanndd iinn nneeuuttrroopphhiill i ccoouunnttss aatt 1122 mmoonntthhss iinn bbootthh ggrroouuppss ((TTaabbllee 1122)).. SSiimmiillaarr cchhaannggeess wweerree nnoott 1 sseeeenn iinn tthhee FFCC--114433--ttrreeaatteedd ffeemmaalleess wwiitthh tthhee eexxcceeppttiioonn ooff aa sslliigghhtt iinnccrreeaassee I iinn nneeuuttrroopphhiillss aanndd aa sslliigghhtt ddeeccrreeaassee iinn llyymmpphhooccyytteess sseeeenn iinn tthhee llooww--ddoossee 1 ggrroouupp aatt 1188 mmoonntthhss ((TTaabbllee 1133)).. i CClliinniiccaall cchheemmiissttrryy ffiinnddiinnggss aatt 33 mmoonntthhss iinncclluuddeedd sslliigghhtt iinnccrreeaasseess iinn i aallaanniinnee aammiinnoottrraannssffeerraassee ((AALLTT)),, aassppaarrttaattee aammiinnoottrraannssFfeerraassee ((AASSTT)),, aanndd I aallkkaalliinnee pphhoosspphhaattaassee ((AAPP)),, aass wweellll aass aa mmooddeerraattee ddeeccrreeaassee fiinn ccrreeaattiinnee 1 pphhoosspphhookkiinnaassee ((CCPPKK)) iinn bbootthh FFCC--114433-- ttrreeaatteedd mmaallee ggrroouuppss.. FFrroomm 66 uunnttiill 1188 i mmoonntthhss,, tthhee hhiigghh-- aanndd ll~oww--ddoossee mmaallee AALLTT,, AASSTT aanndd AAPP vvaalluueess wweerree iinnccrreeaasseedd 1 aabboovvee tthhee ccoonnccuurrrreenntt ccoonnttrrooll vvaalluueess,, wwhheerreeaass tthheessee vvaalluueess iinn tthhee hhiigghh--ddoossee I ggrroouupp wweerree ssttiillll eelleevvaatteedd aatt 224 mmoonntthhss.. AAllbbuummiinn vvaalluueess rreemmaaiinneedd vveerryy sslliigghhttllyy eelleevvaatteedd iinn tthhee hhiigghh--ddoossee mmaalleess uunnttiill tthhee eenndd ooff tthhee ssttuuddyy.. i SSiimmiillaarr cchhaannggeess iinn cclliinniiccaall cchheemmiissttrryy wweerree nnoott oobbsseerrvveedd iinn tthhee I 5 FFCC--114433--ttrreeaatteedd ffeenmaallee ggrroouuppss ((TTaabblleess 1144 aanndd 1155)).. I i i 1 ]13.. i 11333377..00001177 M3MA0A000002277114422 l 1 UUrriinnaarryy ffiinnddiinnggss iinncclluuddeedd iinnccrreeaasseess iinn iinncciiddeennccee aanndd sseevveerriittyy ooff aallbbuummiinn n aanndd ooccccuulltt bblloooodd iinn aallll ooff tthhee mmaallee aanndd ffeemmaallee ccoonnttrrooll aanndd FFCC--114433--ttrreeaatteedd 1 ggrroouuppss aatt 1122,, 1188,, aanndd 2244 mnoonntthhss.. TThheessee fFiinnddiinnggss wweerree mmoorree pprroonnoouunncceedd iinn l tthhee mmaalleess tthhaann iinn tthhee ffeemmaalleess aatt tthhee tteerrmmiinnaattiioonn ooff tthhee ssttuuddyy.. OOtthheerr tthhaann aann ooccccaassiioonnaall iinncciiddeenntt ooff sslliigghhtt kkeettoonnuurriiaa iinn bbootthh ccoonnttrrooll aanndd l1 FC-103-treated smimls, there vers no other remarkable urinary Findings 1 (Table 16) FC-143-treated animals, there were no other remarkable urinary findings (Table 16). I PoPsotsntmoorrtteenm_FiFninddiinnggss:: TThhee CCoonnssuullttiinngg PPaatthhoollooggiisstt''ss ccoommpplleettee rreeppoorrtt iiss I i llooccaatteedd interin iinn AAppppeennddiixx DD.. sacrifice were TThhee ggrroossss unrenarkable ppaatthhoollooggyy ffiinnddiinnggss seen at with the possible exception tthhee of a I1 yyeeaarr single 1 hhiiinggthhe--rddioomsseesacmmraaillfeeichheaavvwiiennrgge ssummnaarllllemattreekssattbeelsse with the aanndd 33//1155 possible hhiigghh--ddoossee exception of a single ffeemmaalleess wwiitthh mmaammmmaarryy ! mmaasssseess ccoommppaarreedd ttoo aann iinncciiddeennccee ooff 11//1155 iinn ccoonnttrrooll ffeemnaallee rraattss.. 1 PPoossssiibbllee FFCC--114433--rreellaatteedd ggrroossss ffiinnddiinnggss sseeeenn iinn mmaallee aanndd ffeemmaallee hhiigghh--ddoossee l rraattss wwhhiicchh wweerree eeiitthheerr ffoouunndd ddeeaadd,, eeuutthhaanniizzeedd iinn eexxttrreenmiiss,, oorr eeuutthhaanniizzeedd;iaatt i tthhee tteerrmmiinnaattiioonn ooff tthhee ssttuuddyy,, iinncclluuddeedd l1iivveerr aanndd tteessttiiccuullaarr oobbsseerrvvaattiioonnss iinn l tthhee mmaalleess aanndd oonnllyy aa vveerryy sslliigghhtt iinnccrreeaassee iinn tthhee iinncciiddeennccee ooff mmaammmmaarryy I 1 mmaasssseess iinn ccoonnssiisstteedd tthhee ooff aa llooww--ddoossee ffeemmaalleess.. sslliigghhtt iinnccrreeaassee iinn TThhee tthhee lliiver ffindings seeeen iinn tthhee mmaalleess iinncciiddeennccee ooff lliivveerr mmaasssseess,, nnoodduulleess 1 aanndd rraaiisseedd lleessiioonnss,, mmoottttlleedd lliivveerrss aanndd yyeellllooww oorr ppaallee lliivveerr ffooccii.. WWhhiillee l ssmmaallll tteesstteess wweerree oobbsseerrvveedd ggrroossssllyy iinn tthhee ccoonnttrrooll mmaalleess aass wweellll aass iinn bbootthh ttrreeaatteedd ggrroouuppss,, tteessttiiccuullaarr mmaasssseess wweerree ffoouunndd iinn 66//5500 hhiigghh--ddoossee aanndd 11//5500 I1 Tou-dose rats, but not in any of the controls. Mammary masses reported at nlneoecwcr-rodopopsssyey irinnatsI1, hhiibgguthh--ddnooosstee in any aanndd 22 of the controls. Mammary lTooww--ddoossee mmaalleess wweerree ffoouunndd masses reported mmiiccrroossccooppiiccaallllyy at ttoo 1 bbee nnoonn--nmaammmmaarryy lleessiioonnss.. MMaammmmaarryy mmaasssseess wweerree oobbsseerrvveedd iinn 2217//5500,, 2266//5500 aanndd l 1 3377//5500 ooff tthhee ccoonnttrrooll,, hhiigghh-- aanndd llooww--ddoossee ffeemmaallee rraattss,, rreessppeeccttiivveellyy.. NHoo remarkable FC-143-related liver changes were seen grossly in the fenale l vrraaettmssa..rkabOOlttehheerrFC-gg1rr4oo3sss-srepplaaattthheoodllooggliiiccverffiinncddhiiannngggsses were seen wweerree ttyyppiiccaall grossly in the ooff ffiinnddiinnggss iinn female aaggiinngg 1 rraattss ooff tthhiiss ssttrraaiinn ((AAppppeennddiixx DD)).. I OOrrggaann wweeiigghhttss pprreesseenntteedd aass eeiitthheerr aabbssoolluuttee oorr rreellaattiivvee ((rraattiioo ooff oorrggaann//bbooddyy i wweeiigghhtt oorr oorrggaann//bbrraaiinn wweeiigghhtt)) vvaalluueess aarree ccoonnttaaiinneedd iinn TTaabblleess 1]77 aanndd 1188.. AAtt ! tthhee 1I yyeeaarr ifnntteerriimn ssaaccrriiffiiccee wwhheerree tthhee oonnllyy ggrroouuppss eexxaammiinneedd wweerree tthhee 1 hhiigghh--ddoossee aanndd ccoonnttrroollss ((nn == 1155//sseexx//ggrroouupp)),, tthheerree wwaass nnoo cchhaannggee iinn mmaallee bbooddyy I wweeiigghhtt ((aabbssoolluuttee)) bbuutt aa ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt ((pp == <<00..0055)) iinnccrreeaassee iinn 1l1 1. I 14. 11333377..00001188 M3MA0A000002277114433 i| 1 rreellaattiivvee Tliivveerr aanndd kkiiddnneeyy wweeiigghhttss ((vvss.. bbooddyy wweeiigghhtt)) ffoorr tthhee FFCC--114433--ttrreeaatteedd i mmaalleess oonnllyy.. AAtt tthhee tteerrmmiinnaall nneeccrrooppssyy,, sslliigghhtt iinnccrreeaasseess iinn rreellaattiivvee ((oorrggaann 1 vvss.. bbooddyy wweeiigghhtt)) ilivveerr wweeiigghhttss wweerree nnootteedd ffoorr bbootthh tthhee mmaalleess aanndd ffeemmaalleess ooff i bbootthh ddoossee ggrroouuppss,, bbuutt tthhee iinnccrreeaasseess wweerree nnoott ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt.. 1 SSlliigghhtt iinnccrreeaasseess iinn rreellaattiivvee kkiiddnneeyy wweeiigghhttss wweerree oobbsseerrvveedd iinn bbootthh tthhee mmaallee | i aanndd ffeemmaallee rraattss iinn tthhee hhiigghh--ddoossee ggrroouupp;; hhoowweevveerr,, oonnllyy iinn tthhee ffeemmaalleess wwaass this finding statistically significant. this finding statistically significant. | CCoommpplleettee ddeettaaiillss ooff tthhee hhiissttooppaatthhoollooggiicc ffiinnddiinnggss aarree ccoonnttaaiinneedd iinn AAppppeennddiixx i DD aanndd aa ssuummmaarryy ooff tthhee mmaajjoorr nneeooppllaassttiicc aanndd nnoonn--nneeooppllaassttiicc mmiiccrroossccooppiicc i cchhaannggeess ffoouunndd aafftteerr 22 yyeeaarrss ooff ccoonnttiinnuuoouuss oorraall aaddmmiinniissttrraattiioonn ooff FFCC--114433 aarree 1 lTiisstteedd iinn TTaabblleess 1199 aanndd 2200.. | HHiissttooppaatthhoollooggiicc eevvaalluuaattiioonn ooff tthhee ttiissssuueess ffrroonm tthhee aanniimmaallss nneeccrrooppssiieedd aatt 1I i yyeeaarr iinnddiiccaatteedd tthhee mmaajjoorr FFCC--114433 eeffffeeccttss wweerree ccoonnffiinneedd ttoo tthhee lliivveerr.. i i DDiiffffuussee hheeppaattoonmeeggaallooccyyttoossiiss ((1122//1155 aanniinmaallss)),, hheeppaattoocceelllluullaarr nneeccrroossiiss ((66~/1155 animals), and portal mononuclear coll infiltration (13/15 aninals) were | asseneeeinnmaliisnn), tthhaeendhhiipggohhr--tddaoolsseemommnaaollneeussclewwahhirilleeceliilnncciiiddneefnniccleetssratiininontthhee(13cc/oo1nn5ttrrooallnimggarrloosuu)pp were wweerree i 00//1155,, 00//1155 aanndd 77//1155,, rreessppeeccttiivveellyy.. TTeessttiiccuullaarr ttuubbuullaarr aattrroopphhyy wwiitthh mmaarrkkeedd | aassppeerrnmaattooggeenneessiiss wwaass ffoouunndd ifnn 22//1155 hhiigghh--ddoossee mmaalleess bbuutt wwaass aabbsseenntt iinn tthhee 1 ccoonnttrrooll mmaalleess.. TThhee oonnllyy rreemmaarrkkaabbllee cchhaannggee sseeeenn iinn tthhee hhiigghh--ddoossee ffeemmaalleess | wwaass mmiinniimnaall ttoo mmiilldd hheeppaattoocceelllluullaarr vvaaccuuoollaattiioonn;; tthhee iinncciiddeennccee ffoorr tthhiiss 1 fFiinnddiinngg wwaass 1111//1155 aatt tthhee hhiigghh ddoossee aanndd 55//1155 iinn tthhee ccoonnttrrooll ggrroouupp.. |BR TThhee mmaajjoorriittyy ooff nneeooppllaassmmss oobbsseerrvveedd aafftteerr 22 yyeeaarrss ooff ddoossiinngg wwiitthh FFCC--114433,, involved either the Tiver or one of several endocrine or endocrine-related | ooirrnggvaaonnlssved((TTaaebbillteeher1199))t..he HHleeippvaaettrooccoeerllllouunlleaarrofccaasrreccviiennrooammlaassenwwdeeorrceeriffnooeuunndodr iinnend66%%o,,cri11n00%%e,,-reaalnnaddte22d%% i ooff tthhee mmaalleess ffrroomm tthhee ccoonnttrrooll,, hhiigghh--,, aanndd llooww--ddoossee ggrroouuppss,, rreessppeeccttiivveellyy.. i FFoorr tthhee ffeemmaalleess,, hheeppaattoocceelllluullaarr ccaarrcciinnoommaass wweerree ffoouunndd oonnllyy iinn tthhee hhiigghh--ddoossee 1 ggrroouupp wwiitthh aann iinncciiddeennccee ooff 22%%.. TThhee oorrggaann wwiitthh tthhee hhiigghheesstt iinncciiddeennccee ooff | ttuummoorrss wwaass tthhee ppiittuuiittaarryy ggllaanndd wwhheerree tthhee iinncciiddeenncceess ooff aaddeennoommasss iinn tthhee mmaalleess wwaass 3355%%,, 2288%% aanndd 3366%%,, aanndd iinn tthhee ffeemmaalleess aatt 7711%%,, 7711%% aanndd 8833%% ffoorr tthhee | i ccoonnttrrooll,, hhiicghh-- aanndd llooww--ddoossee ggrroouuppss,, rreessppeeccttiivveellyy.. 1 MMaammmmaarryy ggllaanndd aaddeennaoccaarrcciinnoomnaass wweerree pprreesseenntt iinn bbootthh ccoonnttrrooll aanndd ttrreeaatteedd | ffeemmaalleess aatt aann iinncciiddeennccee ooff 1155%%,, 1111%% aanndd 3311%% ffoorr tthhee ccoonnttrrooll,, hhiigghh-- aanndd | 11 15. | 15, 11333377..00001199 M3MA0A000002277114444 i 1 lTooww--ddoossee ggrroouuppss,, rreessppeeccttiivveellyy.. IInn aa ssiimmiillaarr ccoommppaarriissoonn,, ffiibbrrooaaddeennoommaass wweerree i sseeeenn iinn 2222%%,, 4488%% aanndd 4422%% ooff tthhee ffeemmaallee rraattss aatt tthhee eenndd ooff tthhee ssttuuddyy.. 1 MMaammmmaarryy ggllaanndd aaddeennoommaass ((77%%)) aanndd ccaarrcciinnoommaass ((22%%)),, wweerree sseeeenn oannllyy iinn tthhee n ffeemmaallee ccoonnttrroollss,, wwhhiillee oonnee hhiigghh--ddoossee ffeemmaallee hhaadd aa llyymmpphhaannggiioossaarrccoommaa.. AAnn iinnccrreeaassee iinn tteessttiiccuullaarr LLeeyyddiigg cceellll aaddeennoommaass wwaass ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt 1I (5 = 0.08 in the high-toe sale. Th Incidence for ths Teston wis Oh 11(p44%%=aa<nnd0d.0445%%) iiinnn ttthhhee e cchooinngtthrr-oodll,o,sehhiimggahhl--esaa.nndd The incidence for llooww--ddoossee ggrroouuppss,, this lesion was 0%, rreessppeeccttiivveellyy.. TThheerree i wweerree mmiinnoorr vvaarriiaattiioonnss iinn tthhee ttuummoorr iinncciiddeennccee ppaatttteerrnnss iinn tthhee aaddrreennaallss i ((pphheeoocchhrroomnooccyyttoomnaass)) aanndd tthhyyrrooiiddss wwhhiicchh rreepprreesseenntt ddeevviiaattiioonnss iinn ttwwoo ccoommmmoonnllyy i ooccccuurrrriinngg ssppoonnttaannceoouuss ttuummoorrss ooff tthhiiss ssttrraaiinn ooff rraatt.. OOnnllyy tthhee iinncciiddeennccee ooff I CC--cceellll aaddeennoommaass ooff tthhee tthhyyrrooiidd iinn mmaallee rraattss,, aappppeeaarreedd ttoo sshhooww aa sslliigghhtt ddoossee 1 ddeeppeennddeenntt iinnccrreeaassee;; nnaammeellyy,, 00%%,, 99%% aanndd 44%% ffoorr tthhee ccoonnttrrooll,, hhiigghh- aanndd i ] llooww--ddoossee ggrroouuppss,, rreessppeeccttiivveellyy.. HHoowweevveerr,, CC--cceellll ccaarrcciinnoommaass wweerree sseeeenn oonnllyy in the controls at an incidence of 54. in the controls at an incidence of 5%. i NNoonn--nneeooppllaassttiicc cchhaannggeess wweerree ffoouunndd aatt tthhee tteerrmmiinnaattiioonn ooff tthhee ssttuuddyy iinn Rthee i tateedssrtteeenssa,,ls,tthhhyyerraooriitdd,ss laainnvdder,uutteelrruuunssg, pancreas, ((TTaabbllee 2200)).. ovaries, salivary AAss nnootteedd iinn tthhee glands, 1I yyeeaarr spleen, iinntteerriimm i hhiissttooppaatthhoollooggiicc eevvaalluuaattiioonn,, tthhee lliivveerr wwaass tthhee pprriimmaarryy oorrggaann aassssoocciiaatteedd wwiitthh i FFCC--114433 ttrreeaattmmeenntt--rreellaatteedd eeffffeeccttss,, aanndd tthheerree wwaass aa rreemmaarrkkaabbllee ccoonnssiisstteennccyy iinn 1 tthhee ttyyppee ooff ffiinnddiinnggss oobbsseerrvveedd iinn tthhee mmaalleess aafftteerr tthhee sseeccoonndd ffuullll yyeeaarr ooff I tteesstt aarrttiiccllee aacdnmiinniissttrraattiioonn.. MMeeggaallooccyyttoossiiss,, ccyyssttooiidd ddeeggeenneerraattiioonn,, aanndd ppoorrttaall mmoonnoonnuucclleeaarr cceellll iinnffiillttrraattiioonn wweerree tthhee mmaajjoorr ddoossee--rreellaatteedd cchhaannggeess | sseeeenn iinn bbootthh mmaallee aanndd ffeemmaallee tteesstt aarrttiiccllee--ttrreeaatteedd ggrroouuppss.. MMeeggaallooccyyttoossiiss i 1 wwaass ffoouunndd aatt aann iinncciiddeennccee ooff 00%%,, 8800%% aanndd 1122%% iinn tthhee mmaalleess,, aanndd 00%%,, 1166%% aanndd 2 in the females fron the control, high- and low-dose groups, i rr2ee%ssppeeiccnttiivvteehlleyy.. females HHeeppaattiicc from the control, high- and low-dose groups, ccyyssttooiidd ddeeggeenneerraattiioonn,, aa ccoonnddiittiioonn cchhaarraacctteerriizzeedd bbyy 1 aarreeaass ooff mmuullttiillooccuullaarr mmiiccrrooccyyssttss iinn tthhee lliivveerr ppaarreenncchhyymmaa,, wwaass mmoorree ccoommmmoonnllyy i sseeeenn iinn mmaallee rraattss wwiitthh aa ccoonnttrrooll iinncciiddeennccee ooff 88%%,, wwhheerreeaass tthhee hhiigghh-- aanndd 1 lToowu--ddoossee mmaalleess hhaadd iinncciiddeenncceess ooff 5566%% aanndd 1144%%,, rreessppeeccttiivveellyy.. TThhee iinncciiddeennccee i ooff tthhiiss lleessiioonn finn ffeemmaalleess wwaass 22%% iinn bbootthh ooff tthhee FFCC--114433--ttrreeaatteedd ggrroouuppss.. HHeeppaattoocceelllluullaarr nneeccrroossiiss wwaass eeqquuaallllyy ddiissttrriibbuutteedd bbeettwweeeenn tthhee ccoonnttrrooll aanndd 1 FFCC--114433--ttrreeaatteedd ggrroouuppss.. TThhee iinncciiddeennccee ooff hhyyppeerrppllaassttiicc nnoodduulleess,, aa llooccaalliizzeedd i pprroolliiffeerraattiioonn ooff hheeppaattiicc ppaarreenncchhyynmaa!l cceellllss,, wwaass sslliigghhttllyy iinnccrreeaasseedd iinn tthhee 1 hhiigghh ddoossee ggrroouuppss wwiitthh aann iinncciiddeennccee ooff 66%% iinn tthhee mmaalleess aanndd 22%% iinn tthhee ffeemmaalleess I aass ccoommppaarreedd ttoo 00%% aanndd 22%% iinn tthhee ccoonnttrrooll mmaalleess aanndd ffeemmaalleess,, rreessppeeccttiivveellyy.. I11 16. n 16. 11333377..00002200 M3MA0A000002277114455 B 1 1 NWoo hhyyppeerrppllaassttiicc nnoodduulleess wweerree ffoouunndd iinn tthhee llooww--ddoossee ggrroouupp.. TThhee iinncciiddeenncceess n 1 ooff ootthheerr hheeppaattiicc cchhaannggeess ssuucchh aass bbaassoopphhiilliicc hheeppaattooccyyttee aalltteerraattiioonn aanndd//oorr chronic inflamatory changes consisting of portal mononuclear cell I ciihnnrffoiinllittcrraattiiioonnnflawwmeemrraeetorssylliigghhctthllayyngeiisnnccrreecaaossneesddistiiinnng tthheeof hhiipggohhr--tddaoolssee mmmoaanlloeenssu,,clebbauurtt ocoennllllyy 1 aaggaaiinnsstt aa hhiigghh iinncciiddeennccee ooff ssiimmiillaarr cchhaannggeess iinn tthhee ccoonnttrrooll ggrroouupp.. B PPuullmmoonnaarryy cchhaannggeess tthhaatt mmaayy bbee aassssoocciiaatteedd wwiitthh tthhee aaddmmiinniissttrraattiioonn ooff FFCC--114433 1 iinn tthhee hhiigghh--ddoossee mmaalleess,, ccoonnssiisstteedd ooff aann iinnccrreeaassee iinn tthhee iinncciiddeennccee ooff R 1 aallvveeoollaarr mmaaccrroopphhaaggeess ((6622%4)) aanndd hheemmoorrrrhhaaggee ((4444%%)) ccoommppaarreedd ttoo ccoonnttrrooll incidences of 20%. However, the incidence of chronic interstitial B pinnecuitdoenncteas pneumonia aannddofppeerr2ii0vv%a.assccuullHaaorrwemmveoornn,oonnuucctllheeeaarr iiinnncffiiidllettnrrcaaettiiooonnf wwaacsshrggorrneeiaacttllyyinrrteeeddruusccteeiddtiaiilnn B i tthhee hhiigghh--ddoossee mmaalleess mineralization vas wwhheenn ccoommppaarreedd observed ttoo tthhee mmaallee comonly in ccoonnttrroollss.. both PPuullmmoonnaarryy vvaassccuullaarr control and test 1 mairnteircallei-ztarteiaotned article-treated mwalse male aonbdsefrevmeadle and female crroaattmssm;;onlhhyoowweevvieenrr,, ttbhoheteh control and FFCC--1L433--ttrreeaatteedd test ffeemmaalleess ! ddiissppllaayyeedd aann iinnccrreeaassee tthhaatt wwaass iinnvveerrsseellyy rreellaatteedd ttoo tthhee ddoossee.. i TThhee iinncciiddeennccee ooff cchhrroonniicc ssiiaallaaddeenniittiiss,, aann iinnffllaammmaattoorryy cchhaannggee ooff tthhee B ssaalliivvaarryy ggllaanndd aanndd oofftteenn aassssoocciiaatteedd iinn rraattss wwiitthh aann aanntteenmoorrtteenm vviirraall B 1 iinnffeeccttiioonn,, wwaass iinnccrreeaasseedd iinn bbootthh tthhee hhiigghh-- aanndd Tlooww--ddoossee mmaalleess.. B 1 HHteheemmoosssiipddleeerreiinnns,, the spleens oaafnn of iirroonn bbootthh hrrhiiiiccgghhhh--ddppooiissggeemmeennmmttaa,,lleesswwaassaannfdfdoouuffnneeddmmaaiillnneess,,ggrreebbaauutttteerriinnccooggnnrrcceeeeaannttttllrryyaattiirrooeennddssuucceeiisdnn i aammoouunnttss iinn tthhee llooww--ddoossee mmaalleess aanndd ffeemmaalleess aass ccoommppaarreedd ttoo ccoonnttrroollss.. R TTwoo cchhaannggeess oobbsseerrvveedd iinn tthhee ggoonnaaddss ooff bbootthh sseexxeess,, aappppeeaarreedd ttoo bbee rreellaatteedd ttoo ii the adsinfstration of FC-l2. Vascular mineralization of the testes atohcceccuurrarrdeemddiniiinnst1r188a%%tiooonff ttohhfee hhFiiCgg-1hh4--3dd.oossee Vmmaaasllceeusslaaarnndd m66i%%neroofaflittzhhaeetillooonww--ddooofssee the testes mmaalleess,, bbuutt i wwaass nnoott sseeeenn iinn tthhee ccoonnttrroollss.. TThhee iinncciiddeennccee ooff tteessttiiccuullaarr ttuubbuullaarr aattrroopphhyy B wwaass oonnllyy sslliigghhttllyy iinnccrreeaasseedd iinn tthhee hhiigghh--ddoossee ((2222%%)) aanndd llooww--ddoossee ((2200%%)) mmaalleess 1 ccoommppaarreedd'ttoo tthhee ccoonnttrrooll mmaalleess ((1144%%)).. i 1 IInn tthhee tteesstt aarrttiiccllee--ttrreeaatteedd ffeemmaalleess,, tthheerree wwaass aa ddoossee--rreellaatteedd,, n ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt iinnccrreeaassee ifnn ttuubbuullaarr hhyyppeerrppllaassiiaa ooff tthhee oovvaarriiaann 1 ssittnrrcoormmeaaa..se TTiuunbbuullsaatrrrahhnyyapp]eerrpptllaaabssuiilaaarfisseccleoomnnessniitddseerreewddhittcooh bbeefsaa dduiisffuffauulssleey,, nnbooinnl--atnneeerooapplllaassttaiinccd I ' aaissnsscoorcceaiisaaetteeddinwwiittshhtrddoeemcaclrreeaassteeuddbuoolrrarzabbessleeennmttenfftooslllliiwcchuuillcaahrr ddieesvveelluoosppummaeelnnltty.. bTTihhleeateiirnnaccliiddeennaccneed I 1 . B 17. 11333377..00002211 aMAooc27 146 3MA00027146 i 1 1 ooff tthhiiss cchhaannggee wwaass 00%%,, 3322%% aanndd 1144%% iinn tthhee ccoonnttrrooll,, hhiigghh-- aanndd llooww--ddoossee i ggrroouuppss,, rreessppeeccttiivveellyy.. CCyyssttiicc ggllaannddss ooff tthhee uutteerriinnee eennddoommeettrriiuumm wweerree ffoouunndd 1 aatt aa hhiigghheerr iinncciiddeennccee iinn tthhee llooww--ddoossee ffeemmaalleess ((2244%%)) wwhheenn ccoommppaarreedd ttoo tthhee i ccoonnttrroollss ((1144%%)) aanndd hhiigghh--ddoossee ffeemmaalleess ((1100%%)).. 1n Other seneneoplastic Testons (Tabla 20) are commonly associated with ther eOentndhdeeenrmiiccnodndii-ssneeeaaosspeelssastaainncdd//oolrresgigoeenrrsiiaatt(rrTiiaccblecchhaa20nn)ggeessareffoouucnnoddmmoiinnnlytthhiiassssosscttirraaatiienndoowffitrrhaatt..eithTTehhree n oofrrollwwoeewrrieenguusscuuhaaallnllgyyesddeecwcrerereaeasseecddonbbseeilldooewwredtthheeequccioovnnocccuuarrlrreenntttestiinnccaiirddteeinncccleee-irinnelacctooenndttrroofllindrraiattnssg..s 1 AAddrreennaall cchhaannggeess aarree ccoommmmoonnllyy sseeeenn iinn aaggiinngg rraattss ooff tthhiiss ssttrraaiinn aanndd tthhee i iinncciiddeenncceess wweerree iinnccoonnssiisstteennttllyy eeiitthheerr hhiigghheerr oorr lloowweerr tthhaann tthhee ccoonnttrrooll 1 vvaalluueess.. TThhee iinncciiddeennccee ooff ssiinnuussooiiddaall eeccttaassiiaa ((ddiillaattaattiioonn)) wwaass iinnccrreeaasseedd i vveerryy sslliigghhttllyy oonnllyy iinn tthhee hhiigghh--ddoossee mmaalleess ((3322%%)) ccoommppaarreedd ttoo tthhee ccoonnttrrooll 5 mmaalleess ((2222%%)),, wwhhiillee tthhee ccoonnttrrooll aanndd FFCC--114433--ttrreeaatteedd ffeemmaalleess wweerree aallmmoosstt eeqquuaallllyy aaffffeecctteedd ((8822 aanndd 8866%%)).. TThhee iinncciiddeennccee ooff cchhrroonniicc mmyyooccaarrddiittiiss wwaass i rreedduucceedd iinn aann aappppaarreenntt ddoossee--rreellaatteedd ffaasshhiioonn iinn tthhee ffeemmaalleess wwhhiillee bbeeiinngg i iinnccrreeaasseedd aabboovvee tthhee ccoonnttrrooll iinncciiddeennccee iinn tthhee hhiigghh-- aanndd llooww--ddoossee mmaalleess.. TThhee | iinncciiddeennccee ooff tthhyyrrooiidd CC--cceellll hhyyppeerrppllaassiiaa wwaass sslliigghhttllyy iinnccrreeaasseedd iinn tthhee hhiigghh 1 ddoossee ffeemmaalleess,, wwhhiillee oonnllyy tthhee llooww--ddoossee mmaalleess sshhoowweedd aa ssiimmiillaarr cchhaannggee.. TThhee i iinncciiddeennccee ooff aacciinnaarr aattrroopphhyy ooff tthhee ppaannccrreeaass wwaass vvearryy sslliigghhttllyy iinnccrreeaasseedd iinn 1 tthhee ttrreeaatteedd mmaalleess,, wwhhiillee bbeeiinngg sslliigghhttllyy ddeepprreesssseedd bbeellooww ccoonnttrrooll vvaalluueess iinn iIB tthhee hhiigghh--ddoossee ffeemmaallee.. 1i 1i 1| 1i | 1 n 1 1 1188.. i 11333377..00002222 M3MA0A000002277114477 I 1 1 DDIISSCCUUSSSSIIOONN i 1 TThhee ppuurrppoosseess ooff tthhiiss ssttuuddyy wwaass ttoo ddeeffiinnee tthhee lloonngg tteerrmm ttooxxiicciittyy aanndd I oonnccooggeenniicciittyy pprrooffiillee ooff FFCC--114433,, aann aannioonnficc fflluuoorroocchheemmiiccaall ssuurrffaaccttaanntt bbeelloonnggiinngg ttoo tthhee cchheemmiiccaall ccllaassss ooff aammmoonniiuunm ppeerrfflluuoorrooaallkkyyll ccaarrbbooxxyyllaatteess.. 1i The study vas successfully comsleted with sufficient nsbers of anfsals Tshuervisvtiundgy surviving iiwnnasaallsllucoocffesstthfheuelleeyxxppeecrroiimmmpeelnnetttaaelld with sufficient numbers of ggrroouuppss.. TThhee ssuurrvviivvaall rraatteess animals ffoorr tthhee 1 hhiigghh--ddoossee mmaallee aanndd ffeemmaallee rraattss wweerree aaccttuusallllyy hhiigghheerr tthhaann tthhoossee ooff tthhee i ccoonnttrrooll rraattss aafftteerr 2244 mmoonntthhss ooff tthhee tteesstt.. i 1 TThhee ggeenneerraal] hheeaalltthh ooff aa rraatt eexxppoosseedd ttoo tthhee eexxppeerriimmeennttaall ccoonnddiittiioonnss ooff aa 22 [] yyeeaarr ffeeeeddiinngg ssttuuddyy mmaayy bbee eexxaammiinneedd aatt tthhee bbeeggiinnnniinngg ooff tthhee tteesstt bbyy i eevvaalluuaattiinngg bbooddyy wweeiigghhtt ggaaiinnss aanndd ffeeeedd ccoonnssuummppttiioonn ccoommppaarreedd ttoo tthhee ssttuuddyy ccoonnttrrooll aanniimmaall ppooppuullaattiioonn.. BBooddyy wweeiigghhtt ggaaiinnss ooff tthhee FFCC--114433--ttrreeaatteedd mmaalleess I 1 ddeeccrreeaasseedd aass eeaarrllyy aass tthhee sseeccoonndd wweeeekk ooff tthhee ssttuuddyy,, ssttaabbiilliizzeedd aafftteerr 66 i wweeeekkss,, bbuutt rreemmaaiinneedd sslliigghhttllyy ddeepprreesssseedd iinn tthhee hhiigghh--ddoossee mmaalleess bbyy aatt lTeeaasstt 10% through 66 weeks. The treated females did not demonstrate any real I d1e0c%retahsreougihn decrease in 6bb6ooddyyweewwkeesii.gghhtt The treated uunnttiill tthhee females did 118tthh mmoonntthh,, not demonstrate ssoo tthheerree aappppeeaarreedd any ttoo real bbee aa 1 rraatthheerr oobbvviioouuss sseexx ddiiffffeerreennccee iinn tthhiiss ppaarraammeetteerr.. TThhee bbooddyy wweeiigghhtt cchhaannggeess i ddiidd nnoott aappppeeaarr ttoo bbee aassssoocciiaatteedd wwiitthh tthhee ppaallaattaabbiilliittyy ooff tthhee ddiieett aaddmmiixx i ssiinnccee ffeeeedd ccoonnssuunmeedd oonn aa bbooddyy wweeiigghhtt bbaassiiss wwaass aaccttuuaallllyy iinnccrreeaasseedd.. I FFuurrtthheerr,, ssiinnccee tthheerree wwaass aa mmooddeesstt ddoossee--rreellaatteedd eeffffeecctt sseeeenn iinn tthhee mmaallee FFCC--114433--ttrreeaatteedd rraattss,, iitt aappppeeaarrss tthhaatt tthheessee bbooddyy wweeiigghhtt cchhaannggeess ccoouulldd bbee 1i associated with a direct test article effect. associated with a direct test article effect. i TThhee ccoonncceennttrraattiioonn ooff tthhee tteesstt aarrttiiccllee iinn tthhee ddiieett wwaass wwiitthhiinn aa 33%% rraannggee ooff i tthhee pprrooppoosseedd Tleevveellss ooff 330000 aanndd 3300 ppppmm ffoorr tthhee ffuullll 22 yyeeaarrss ooff tthhee ssttuuddyy.. i TThhee aavveerraaggee ddaaiillyy ddoossee ooff FFCC--114433 ffoorr tthhee ssaammee ttiimmee ppeerriioodd aanndd ffoorr bbootthh I sseexxeess ccoonmbbiinneedd,, wwaass eessttiinmaatteedd ttoo bbee 1155 aanndd 11..55 mmgg//kkgg//ddaayy.. BBootthh iinn--lliiffee aanndd 1 ppoossttmnoorrtteemm rreessuullttss ccoonnffiirrmmeedd tthhee ssyysstteemmiicc aabbssoorrppttiioonn ooff tthhee tteesstt aarrttiiccllee I aanndd tthhee 330000 ppppmm ddoossaaggee lleevveell aappppeeaarreedd ttoo aaddeeqquuaatteellyy ccoommppllyy wwiitthh tthhee ccoonncceepptt i ooff aa mmaaxxiimnuumn ttoolleerraatteedd ddoossee ffoorr aa lToonngg tteerrnm ssttuuddyy iinn tthhiiss ssttrraaiinn ooff rraatt.. i TThhee oonnllyy cclliinniiccaall ssiiggnn sseeeenn dduurriinngg tthhee ssttuuddyy wwhhiicchh wwaass aassssoocciiaatteedd wwiitthh aa B tteesstt aarrttiiccllee eeffffeecctt wwaass aattaaxxiiaa.. TThhee iinncciiddeennccee ooff aattaaxxiiaa wwaass iinnccrreeaasseedd iinn aa i ddoossee rreellaatteedd mmaannnneerr iinn tthhee ffeemmaalleess,, bbuutt nnoott iinn tthhee ttrreeaatteedd mmaalleess.. AA 1I1 19. i 19. 11333377..00002233 M3MA0A000002277114488 1| i 0 bbaacckkggrroouunndd iinncciiddeennccee ooff tthhiiss ffiinnddiinngg wwaass sseeeenn iinn tthhee mmaallee aanndd ffeemmaallee ccoonnttrrooll ppooppuullaattiioonn.. | 1 DDuurriinngg tthhee eeaarrllyy ccoouurrssee ooff tthhee ssttuuddyy,, aa ddeeccrreeaassee iinn rreedd bblloooodd cceellll i ppaarraammeetteerrss wwaass oobbsseerrvveedd iinn tthhee hhiigghh--ddoossee mmaalleess.. WWhhiillee tthheessee hheemmaattoollooggiicc I vvaalluueess wweerree oofftteenn ddeeccrreeaasseedd bbeellooww tthhee ccoonnttrrooll mmaallee mmeeaassuurreemmeennttss aatt a ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt lleevveell ((pp ~< 00..0055)),, ggeenneerraallllyy tthhee ddeeccrreeaasseedd vvaalluueess | 1 wweerree ssttiillll wwiitthhiinn tthhee aacccceeppttaabbllee rraannggeess ffoorr tthheessee ppaarraammeetteerrss iinn tthhee rraatt.. 1 TThhee eelleevvaattiioonn ooff sseerruumm aallkkaalliinnee pphhoosspphhaattaassee,, aassppaarrttaattee aammiinnoottrraannssffeerraassee aanndd i aallaanniinnee aammiinnoottrraannssffeerraassee aaccttiivviittiieess oonnllyy iinn tteesstt aarrttiiccllee--ttrreeaatteedd mmaallee rraattss,, 1 ssuuggggeesstteedd tthhaatt FFCC--114433 aaffffeecctteedd hheeppaattooccyytteess.. TThheessee cchhaannggeess wweerree sseeeenn ffrroomm 33 i ttoo 1188 mmoonntthhss iinn bbootthh ooff tthhee mmaallee FFCC--114433--ttrreeaattnmeenntt ggrroouuppss,, bbuutt oonnllyy iinn tthhee 1 hhiigghh--ddoossee mmialleess aatt 2244 mmoonntthhss.. TThheessee Ffiinnddiinnggss wweerree ssuubbssttaannttiiaatteedd bbyy oorrggaann | wweeiigghhtt cchhaannggeess aanndd hhiissttooppaatthhoollooggyy oobbsseerrvveedd aatt tthhee 1i aanndd 22 yyeeaarr ssaaccrriiffiicceess.. i CChhaannggeess iinn tthhee cchhaarraacctteerr ooff tthhee uurriinnee ssppeecciimmeennss wweerree ssiimmiillaarr iinn bbootthh i ccoonnttrrooll aanndd ttrreeaatteedd rraattss eexxaammiinneedd dduurriinngg tthhee ccoouurrssee ooff tthhee ssttuuddyy.. TThheessee i ffiinnddiinnggss wweerree ccoonnssiiddeerreedd ttoo bbee aassssoocciiaatteedd wwiitthh tthhee sslloowwllyy ddeevveellooppiinngg I ddeeggeenneerraattiivvee cchhaannggeess ooff nnaattuurraallllyy ooccccuurrrriinngg cchhrroonniicc rreennaall ddiisseeaassee ccoommmmoonnllyy 1 ffoouunndd iinn rraattss ooff tthhiiss ssttrraaiinn.. I 1 TThhee lTiivveerr wwaass tthhee pprriimmaarryy ttaarrggeett oorrggaann aaffffeecctteedd aass sseeeenn bbyy aann iinnccrreeaassee iinn | rreellaattiivvee oorrggaann wweeiigghhttss,, ggrroossss ffiinnddiinnggss aatt nneeccrrooppssyy,, aanndd hhiissttooppaatthhoollooggiicc i aalltteerraattiioonnss.. TThheessee Tittle progression cchhaannggeess 1 year sseeeenn aatt later. tthhee 1I yyeeaarr nneeccrrooppssyy The FC-l43-treated sshhoowweedd males rreemmaarrkkaabbllyy were more | oolbibvtvtiilooeuussllpyyroaagffrffeeesccsttieeoddn I year later. The FC-143-treated males were tthhaann tthhee ffeemmaalleess.. TThhee sseexx ddiiffffeerreenncceess sseeeenn iinn more tthhiiss i ssttuuddyy wweerree ccoonnssiisstteenntt wwiitthh eeaarrlliieerr pphhaarrmmaaccookkiinneettiicc ssttuuddiieess uussiinngg ccaarrbboonn--1144 I lTaabbeelleedd aammmoonniiuunm ppeerrfflluuoorrooooccttaannooaattee,, iinn wwhhiicchh tthhee ffeemmaalleess dduurriinngg 2244 hhoouurrss 1 hhaadd eexxccrreetteedd eesssseennttiiaallllyy 110000%% ooff aann iinnttrraavveennoouuss ddoossee iinn tthhee uurriinnee wwhhiillee tthhee I mmaalleess eexxccrreetteedd oonnllyy 2200%%.. RRaaddiiooaaccttiivvee ttiissssuuee rreessiidduueess wweerree nnoott ddeetteeccttaabbllee s aafftteerr 1177 ddaayyss iinn tthhee ffeemmaalleess,, wwhhiillee aatt 3366 ddaayyss,, mmaallee rraattss hhaadd 22..88%% ooff tthhee | ccaarrbboonn--114 iinn tthhee lliivveerr,, 1]..11%% iinn ppllaassmmaa,, aanndd lloowweerr bbuutt ssttiillll ddeetteeccttaabbllee i aaammoouunnttss iinn ootthheerr oorrggaannss..I' SSiimmiillaarr rreessuullttss wweerree rreeppoorrtteedd bbyy HHaannhhiijjaarrvvii,, eett al 6 |1ii 2. 20. 11333377..00002244 M3MA0A000002277114499 I 1 HHeeppaattoommeeggaallooccyyttoossiiss aanndd hheeppaattoocceelllluullaarr vvaaccuuoollaattiioonn aarree cchhaarraacctteerriissttiicc ooff | iinnccrreeaasseedd mmeettaabboolliicc aaccttiivviittyy iinn tthhee rraatt.. FFoolllloowwiinngg cchhrroonniicc hheeppaattiicc 1 ssttiinmuullaattiioonn,, eevviiddeennccee ooff ccyyssttooiidd ddeeggeenneerraattiioonn aanndd,, ooccccaassiioonnaallllyy,, I hheeppaattoocceelllluullaarr nneeccrroossiiss mmaayy aallssoo bbee oobbsseerrvveadd.. SSiinnccee tthhee lliivveerr iinn tthhee rraatt 1 rraarreellyy rreeppaaiirrss ppaarreenncchhyymmaall cceellll lloossss wwiitthh fFiibbrroossiiss oorr ssccaarr ttiissssuuee,, tthhee mmoosstt B ccoommmmoonn ffiinnddiinngg iiss hheeppaattoocceelllluullaarr hhyyppeerrppllaassiiaa.. IInn tthhiiss ssttuuddyy,, tthhee iinncciiddeennccee ooff hhyyppeerrppllaassttiicc nnoodduulleess wwaass iinnccrreeaasseedd vveerryy sslliigghhttllyy iinn tthhee hhiigghh--ddoossee ggrroouupp,: i bbuutt tthhee iinncciiddeennccee wwaass nnoott ssiiggnniiffiiccaannttllyy ddiiffffeerreenntt ffrroomm ccoonnttrroollss.. IItt iiss I aallssoo iimmppoorrttaanntt ttoo nnoottee tthhaatt nnoo pprroolliiffeerraattiivvee hheeppaattiicc lleessiioonnss ((ii..ee.. nneeiitthheerr i hhyyppeerrppllaassiiaa nnoorr nneeooppllaassiiaa)) wweerree sseeeenn iinn aannyy ooff tthhee hhiigghh--ddoossee rraattss rreecceeiivviinngg B 1 FFCC--114433 ffoorr 1I yyeeaarr.. TThhee oobbsseerrvveedd hheeppaattoomneeggaallooccy~ttoossiiss wwaass ssiimmiillaarr ttoo tthhaatt reported by Pastaor et al in which perfluoroactanoic acid was administered reported by Pastoor et al in which perfluorooctanoic acid was administered I oorraallllyy ttoo mmaallee rraattss aatt aa hhiigghheerr ddoossaaggee ((5500 mmgg//kkgg//ddaayy))..22 IItt wwaass pprrooppoosseedd i tthhaatt tthhee hheeppaattooccyyttiicc eennllaarrggeemmeenntt wwaass dduuee ttoo pprroolliiffeerraattiioonn ooff ssmmooootthh,, n eennddooppllaassnmiicc rreettiiccuulluum,, mmiittoocchhoonnddrriiaa,, aanndd ppeerrooxxiissoommeess.. i TThhee oonnllyy hheeppaattiicc nneecoppllaassmnss ffoouunndd iinn tthhiiss ssttuuddyy wweerree hheeppaattoocceelllluullaarr n ccaarrcciinnoommaass.. TThhee iinncciiddeennccee ooff tthhiiss ttuumsoorr wwaass 66%%,, 1100%% aanndd 22%% iinn tthhee ccoonnttrrooll,, i hhiigghh-- aanndd lTooww--ddoossee mmaallee rraattss,, rreessppeeccttiivveellyy.. OOnnllyy oonnee hhiigghh--ddoossee ffeemmaallee wwaass I ffoouunndd ttoo hhaavvee tthhiiss lliivveerr ttuummoorr.. TThhee iinncciiddeennccee ooff hheeppaattoocceelllluullaarr ccaarrcciinnoommaass 1 iinn hhiigghh--ddoossee mmaalleess wwaass nnoott ssiiggnniiffiiccaannttllyy ggrreeaatteerr tthhaann tthhaatt ooff tthhee ccoonnttrrooll I mmaalleess aanndd wwaass ccoommppaarraabbllee wwiitthh tthhee rreeppoorrtteedd ssppoonnttaanneeoouuss iinncciiddeennccee oofF tthhiiss 1 ttuummoorr.?3 BBaasseedd oonn S~hheessee ffiinnddiinnggss,, FFCC--114433 wwaass nnoott ccoonnssiiddeerreedd ttoo bbee aa hheeppaattiicc I ccaarrcciinnooggeenn iinn tthhee rraatt.. 1 TThhee ootthheerr nneeooppllaassmmss oobbsseerrvveedd iinn tthhiiss ssttuuddyy oorriiggiinnaatteedd ffrroomm eennddooccrriinnee aanndd//oorr n eennddooccrriinnee sseennssiittiivvee oorrggaannss;; nnaammeellyy,, tthhee aaddrreennaall ggllaanndd,, mmaammmmaarryy ggllaanndd,, i ppiittuuiittaarryy ggllaanndd,, tteesstteess,, aanndd tthhyyrrooiidd ggllaanndd.. TThhee iinncciiddeennccee ffoorr eeaacchh ooff B tthheessee ttuumnoorrss aarree pprreesseenntteedd iinn TTaabbllee 1199.. n i Tcchooennttrrioonllc,,idehhniicggehh--ofaanmnddammllaoorwwy--ddgoolssaeend ffeeammdaaellneeocaggrrrcooiuunppossm,,as rrweeasssppeecc1tt5ii%,vveell1yy1..% and 31% WWhhiillee for the mmaammmaarryy B ggllaanndd ccaarrcciinnoomnaass aanndd aaddeennoonmaass wweerree ffoouunndd aonnllyy iinn tthhee ccoonnttrroollss,, tthheerree wwaass aann i iInnccrreeaasseedd iinncciiddeennccee ooff ffiibbrrooaaddeennoommaass iinn tthhee hhiigghh--ddoossee ((4488%%,, ssttaattiissttiiccaallllyy significant: p < 0.05), and the low-dose (42%) compared to controls (22%). I i sIItitgnssihhfooiuuclladdntaa:llssoop bb~ee 0nn.oo0tt5ee)dd, ttahhnaadtt t22h//e1133looowff-dttohhseee (42%) compared to hhiigghh--ddoossee ffeemmaalleess controls (22%). nneeccrrooppssiieedd aatt 1I a 1 2a1.. m 11333377..00002255 M3MA0A000002277115500 1I 1 yyeeaarr wweerree ffoouunndd ttoo hhaavvee ffiibbrrooaaddeennoommaass,, wwhhiillee 00//1155 ooff tthhee ccoonnttrroollss wweerree n ssiimmiillaarrllyy aaffffeecctteedd.. AAlltthhoouugghh tthhee iinncciiddeennccee ooff ffiibbrrooaaddeennoommaass iinn hhiigghh--ddoossee 1 ffeemmaalleess wwaass ssiiggnniiffiiccaannttllyy ggrreeaatteerr tthhaann tthhaatt ffoorr tthhee ccoonnttrrooll ffeemmaalleess,, tthhee I iinncciiddeennccee wwaass ssiimmiillaarr ttoo tthhaatt rreeppoorrtteedd ffoorr uunnttrreeaatteedd aaggiinngg rraattss..4 IInr aaddddiittiioonn,, wwhheenn tthhee iinncciiddeenncceess ffoorr bbeenniiggnn mmaammmsaarryy ggllaanndd ttuummoorrss ((aaddeennoommaa aanndd 1 ffiibbrrooaaddeennoomnaa)) aarree ccoonmbbiinneedd,, tthhee ttuummoorr iinncciiddeennccee iinn tthhee hhiigghh--ddoossee ggrroouupp iiss I 1 nnoo lloonnggeerr ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt.. I 1 LLeeyyddiigg cceellll aaddeennoommaass ((ii..ee.. bbeenniiggnn ttuummoorrss ooff tthhee tteessttiiccuullaarr iinntteerrssttiittiiaall B ttiissssuuee)),, wweerree ffoouunndd aatt aann iinncciiddeennccee ooff 00%%, 1144%% aanndd &4%% iinn tthhee ccoonnttrrooll,, hhiigghh-- 1 aanndd llooww--ddoossee ggrroouuppss,, rreessppeeccttiivveellyy.. TThhee hhiigghh--ddoossee iinncciiddeennccee ffoorr tthhiiss lTeessiioonn n wwaass ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt ((pp ~< 00..0055)) bbeeccaauussee tthhee iinncciiddeennccee iinn tthhee 5 ccoonnttrrooll ggrroouupp wwaass uunnuussuuaallllyy llooww ((00%%)).. IInn aaddddiittiioonn,, tthhee ssppoonnttaanneeoouuss iinncciiddeennccee rreeppoorrtteedd ffoorr tthhiiss nneeooppllaassmm iinn tthhiiss ssttrraaiinn ooff rraatt wwaass 77..44%% ffoorr i rraattss 2244 ttoo 2299 mmoonntthhss ooff aaggee aanndd wweass 1144..66%%.-aatt 3300 ttoo 3388 mmoonntthhss ooff aaggee3'.. BI a reas HHBaaaszzelldeettooonnn aLLnaaobbtoohrreaarttoorrsiieeetss,, of tthhSeeprassgppuooenn-ttDaaannweelooeuuyss two year study iinncciiddeennccee ooff data compiled by iinntteerrssttiittiiaall cceellll B i ttuumnoorrss wwaass 2288..77%%..5% i 1 TThhee rreemmaaiinniinngg nnoonn--nneeooppllaassttiicc ffiinnddiinnggss rreeppoorrtteedd ffrroomm tthhee hhiissttooppaatthhoollooggiicc eevvaalluuaattiioonn ooff aallll ooff tthhee aanniimmaallss oorriiggiinnaallllyy sscchheedduulleedd ffoorr tthhee 22 yyeeaarr pphhaassee iB of the study were mstly gertatric Teslons comon to this strain of rat. TTohhfee thooerrggaasnntssudyiinn wewwrhheiicchhmosttthhleeysseegellreeissaiitoornnissc wwleeerrseeionffsoouunncddommiionnncclluutddoeeddt::his strain aaddrreennaall,, of rat. hheeaarrtt,, B kKiiddnneeyy,, lTuunngg,, tteesstteess,, oovvaarryy,, tthhyyrrooiidd,, uurriinnaarryy bbllaaddddeerr aanndd uutteerruuss.. SSppeecciiffiicc I ddeevviiaattiioonnss ffrroomn ccoonnttrrooll vvaalluueess sseeeenn iinn FFCC--]14433--ttrreeaatteedd ggrroouuppss wweerree aaddddrreesssseedd i iinn tthhee rreessuullttss sseeccttiioonn ooff tthhiiss rreeppoorrtt;; hhoowweevveerr,, tthhee ffoolllloowwiinngg cchhaannggeess mmaayy ! bbee ccoonnssiiddeerreedd iinncciiddeennttaall oorr eeqquuiivvooccaall tteesstt aarrttiiccllee--rreellaatteedd eeffffeeccttss.. 1B TThhee iinncciiddeennccee ooff nnoodduullaarr hhyyppeerrppllaassiiaa ooff tthhee aaddrreennaall ccoorrtteexx wwaass iinnccrreeaasseedd 1 ((nnoott ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt)) iinn tthhee hhiigghh--ddoossee mmaalleess ((1188%%)) ccoommppaarreedd ttoo I tthhee ssaammee ffiinnddiinngg iinn tthhee ccoonnttrroollss ((44%%)),, wwhhiillee tthhee hhiigghh--ddoossee ffeemmaalleess sshhoowweedd aa 1 mmuucchh lToowweerr iinncciiddeennccee ((22%%)).. IInnccrreeaasseess finn tthhee iinncciiddeenncceess ooff aaddrreennaall ggllaanndd I ssiinnuussooiiddaall eexxttaassiiaa ((ddiillaattaattiioonn)) wweerree rreeppoorrtteedd iinn tthhee hhiigghh-- ((3322%%)) aanndd Ilooww-- i ((2266%%)) ddoossee mmaalleess ccoommppaarreedd ttoo mmaallee ccoonnttrroollss ((2222%%)) wwhhiillee tthhee iinncciiddeenncceess iinn I I 1 222.. 11333377..00002266 M3MA0A000002277115511 i 1 I 1 aallll tteesstt aarrttiiccllee--ttrereaatteedd ffeemmaalleess wweerree eeqquuaall ttoo ccoonnttrrooll vvaalluueess.. IItt sshhoouulldd bbee nnootteedd tthhaatt aaddrreennaall lTeessifoonnss aarree ccoommmmoonnllyy sseeeenn iinn oolldd rraattss.. a 1 TThhyyrrooiidd CC--cceellll hhyyppeerrppllaassiiaa wwaass sseeeenn iinn tthhee ccoonnttrrooll mmaalleess aanndd FFCC--114433--ttrreeaatteedd 1 ggrroouuppss wwiitthh aann iinncciiddeennccee ooff 1100%% aanndd 77%% ffoorr tthhee llooww--ddoossee mmaalleess aanndd tthhee high-dose i high-dose ffeemmaalleess,, rreessppeeccttiivveellyy., TThhee iinncciiddeenncceess wweerree nnoott ddoossee--rreellaatteedd oorr ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt aanndd wweerree lToowweerr tthhaann tthhee rreeppoorrtteedd ssppoonnttaanneeoouuss in incidence of this Tesion.? incidence of this lesion. i B CChhrroonniicc in the mmyyoocacradridtitiiss ((iinnfflalmammmaattiioonn)) wwaass low-dose (36%) and the high-dose sseeeenn aatt aa sslliigghhttllyy hhiigghheerr iinncciiddeennccee (34%) males compared to the control 1 i((n2286%%th))e low-dose (36%) and ggrroouupp.. TThhee ffeemmaallee the high-dose iinncciiddeennccee ffoorr (34%) males tthhiiss lleessiioonn compared wwaass 3322%%,, to the control 2200%% aanndd 1100%% iinn i tthhee ccoonnttrrooll,, hhiigghh-- aanndd llooww--ddoossee ggrroouuppss,, rreessppeecctitivveellyy.. IInnfflalmammmaattiioonn ooff tthhee hheeaarrtt iiss ccoommmoonn iinn oolldd rraattss.. TThhee llaacckk ooff aa ttrruuee ddoossee--rreellaatteedd eeffffeecctt iinn i i 1 eeiitthheerr sseexx ssuuggggeessttss tthhaatt tthhiiss ffiinnddiinngg i1ss pprroobbaabbllyy nnoott aa ttrreeaattmmeenntt rreellaatteedd phenomenon. phenomenon. n CChhrroonniicc rreennaall hhiissttooppaatthhoollooggiicc cchhaannggeess,, ccoommmonolnlyy oobbsseerrvveedd iinn aaggiinngg rraattss,, i i wweerree were nnoott mmeeanainningfgufullllyy aalltteerreedd apparently severe enoush bbyy to FFCC--114433 ttrreeaattmmeenntt.. produce pathologic NNoonnee ooff lesions tthheessee cchhaannggeess over a 2 year 1 wppeeerrreiioodda..ppaTTrhheeenrrteelyffoorrseee,,vernneoonneeenooouffghtthheteosseeprffoiindnuddciinenggsps ataahrroeeloccgooicnnssiildedeesrrioeednd s ttooovbebeer a 2 year ddiirreeccttllyy | rreellaatteedd ttoo ttrreeaattmmeenntt.. i 1 LLuunngg cchhaannggeess wwhhiicchh wweerree sseeeenn mnoorree ccoommmmoonnllyy iinn FFCC--114433--ttrreeaatteedd rraattss tthhaann iinn ccoonnttrroollss iinncclluuddeedd aann iinnccrreeaassee iinn aallvveeoollaarr mmaaccrroopphhaaggeess,, ppuullmmoonnaarryy hheemmoorrrrhhaaggee || ((aaggoonnaall)) aanndd vvaassccuullaarr mmiinneerraalliizzaattiioonn.. TThhee ffiirrsstt ttwwoo lleessiioonnss wweerree sseeeenn i pprreeddoommiinnaannttllyy iinn tthhee hhiigghh--ddoossee mmaalleess wwhheerree tthhee iinncciiddeenncceess wweerree 1 ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt ((pp <~ 00..0055)).. CCoonnttrrooll mmaalleess oonn tthhee ootthheerr hhaanndd,, hhaadd | hhiigghheerr iinncciiddeenncceess ooff iinntteerrssttiittiiaall ppnneeuunmoonntiaa aanndd ppuullmmoonnaarryy ppeerriivvaassccuullaarr 1 mmoonnoonnuucclleeaarr cceellll iinnffiillttrraattiioonn.. PPuullmmoonnaarryy cchhaannggeess aarree ccoommmmoonn iinn aaggiinngg I rraattss..3 OOtthheerr tthhaann tthhee ppoossssiibbiilliittyy tthhaatt aann iinnccrreeaassee iinn tthhee aallvveeoollaarr mmaaccrroopphhaaggeess mmaayy bbee aassssoocciiaatteedd wwiitthh FFCC--114433 aadcmniinniissttrraattiioonn,, aallll ooff tthhee 1I Pulbonary changes were no considered related to est article restau. pulmonary changes were not considered related to test article treatment. i i Chronic Chronic ssiiaallaaddeenniittiiss oorr iInnffllaammmmaattiioonn ooff tthhee ssaalliivvaarryy ggllaannddss wwaass i ssiiggnniiffiiccaannttllyy ((pp <~ 00..0055)) iinnccrreeaasseedd iinn tthhee tteesstt aarrttiiccllee--ttrreeaatteedd mmaalleess,, bbuutt I 1 2. i 23. 11333377..00002277 M3MA0A000002277115522 1i | 1 nnoott iinn tthhee oouuttbbrreeaakkss tteesstt aarrttiiccllee--ttrreeaatteedd ooff ssiiaallooddaaccrryyooaaddeenniittiiss females. vviirraall These changes iinnffeeccttiioonnss wwhhiicchh were attri ooccccuurrrreedd bute iinn d to bbootthh | tthhee ccoonnttrrooll aanndd FFCC--114433 aanniimmaall rroooommss,, but at different time periods and 1 aappppaarreennttllyy wwiitthh ddiiffffeerreenntt lleevveellss of intensity. 1 The incidence of splonic hemosiderosis, depositions of iron-containing The incidence of splenic hemosiderosis, depositions of iron-containing | 1 ppiiggmneenntt iinn tthhee ssiinnuussooiiddss ooff tthhee sspplleeeenn,, wwaass iinnccrreeaasseedd aabboovvee ccoonnttrrooll lleevveellss by approximately 12% in only the high-dose meles. However, the incidence by approximately 12% in only the high-dose males. However, the incidence i 1 iinn hhiigghh--ddoossee mmaalleess wwaass iinncciiddeennccee.. TThhee iinncciiddeennccee not significantly ooff tthhiiss lleessiioonn iinn greater than the control FFCC--114433 ttrreeaatteedd ffeemmaalleess wwaass | ssiiggnniiffiiccaannttllyy lloovweerr tthhaann tthhee iinncciiddeennccee ooff sspplleenniicc hheemmoossiiddeerroossiiss iinn ccoonnttrrooll 1 fefmemaalleess.. i AA ssttaattiissttiiccaallllyy ssiiggnniiffiiccaanntt,, ddoossee--rreellaatteedd iinnccrreeaassee iinn tthhee iinncciiddeenncceess ooff 1 oovvaarriiaann ((ssttrroommaall)) ttuubbuullaarr hhyyppeerrppllaassiiaa wwaass ffoouunndd iinn llooww aanndd hhiigghh--ddoossee i ggrroouuppss.. TThhee iinntteerrpprreettaattiioonn of these changes in the absence ooff aannyy i oobbsseerrvvaabbllee pprrooggrreessssiivvee ppaatthhoollooggiicc lleessiioonn aafftteerr 22 yyeeaarrss ooff ttrreeaattmmeenntt,, mmuusstt 111ii|| bbee ccoonnssiiddeerreedd aass eeqquuiivvooccaallllyy related to FC-143 treatment. 1i | 1 | i | 1 | 1 | i I 2. 24. i 11333377..00002288 M3MA0A000002277115533 I1I ous CONCLUSIONS l 1 TThhee rreessuullttss oobbttaaiinneedd uunnddeerr tthhee ccoonnddiittiioonnss ooFf tthhiiss ssttuuddyy wwhheen FC-143 was aaddmmiinniisstteerreedd iinn tthhee ddiieett ooff mmaallee aanndd ffeemmaallee rraattss aatt ccoonncceennttrraattiioonnss of 300 1 aanndd 3300 ppppmm ffoorr 22 yyeeaarrss mmaayy bbee ssuummmmaarriizzeedd aass ffoolllloowwss:: l 1 F-143related changes ere found sre coment in ules than fn 1 females of each of the two treatsent groups. FC-143-related changes were found more commonly in females of each of the two treatment groups. Thismales This finding than in finding I Sports aaron pharmacokinetic staies thi Commsirated 4 supports earlier pharmacokinetic studies that demonstrated a 1 increases FC-13 retention by trotad mals compared fo treated increased FC-143 retention by treated males compared to treated l ti female rats. I i 2. TThhee mmaajjoorr ddoossee--rreellaatteedd ffiinnddiinnggss wweerree oobbsseerrvveedd iinn the liver and l. ene activities. ccoonnssiisstteedd ooff mmeeggaallooccyyttoossiiss aanndd ccyyssttooiidd ddeeggeenneerraattion with only a i mmiinniimmaall pprroolliiffeerraattiivvee rreessppoonnssee aanndd rreellaatteedd eelleevations of serum enzyme activities. l 3. OOtthheerr nnoonn--nneeooppllaassttiicc ffiinnddiinnggss rreeppoorrtteedd iinn tthhiiss study were not 1 ccoonnssiiddeerreedd pprriimmaarryy tteesstt aarrttiiccllee--rreellaatteedd eeffffeeccttss,, bbuutt rraatthheerr wweerree l related to spontanecos changes curring aging res. related to spontaneous changes occurring in aging rats. l 1 4. BBaasseedd oonn tthhee iinncciiddeennccee,, ttyyppeess ooff ttuummoorrss,, ttiimmee of tumor Q aappppeeaarraannccee,, mmaalliiggnnaannccyy ppaatttteerrnnss ooff ttuummoorrss aanndd ssuurrvviivvaall rraate after l1 years, FC-165 1 ro considered ta be carnage in ha at. 2 years, FC-143 is not considered to be carcinogenic in the rat. l l l l l I 1 =. l 25. 11333377..00002299 ---- 3MA00027154 1B PRINCIPAL PISONEL IWVOLIED WITH THE CORLEY HO REPORTING OF PRINCIPAL PERSONNEL INVOLVED WITH THE CONDUCT AND REPORTING OF 'I SFIREH k Emenee,th,11 Cte] 0ero R]KER EXPERIMENT NO. 0281CR0012 - TWO YEAR ORAL (DIET) i H RN CNL TOXICITY/CARCINOGENICITY STUDY OF FLUOROCHEMICAL FC-143 IN RATS 1 --_ NNAeMEe B1 ah Seattr SS..1l.. BBiissttnneerr,, DD..VV..MM.. POSITIONN//FFUUNNCCTTION EExxtteerrnnaall CCoonnssuullttaanntt// Veterinary Ophthalmologist B WT. Cae, D0 Bh. Hager, Safety Evaluation M.T. Case, D.V.M., Ph.D. Manager, Safety Evaluation n1 RG. Geil, DV. External Consultant R.G. Geil, D.V.M. External Consultant/ VVeetteerriinnaarryy PPaatthhoollooggiisstt i Rl. kinon, 7.0. Servis, Statstica services R.W. Hawkinson, Ph.D. Supervisor, Statistical Services B i JJ..DD.. HHeennddeerrssoonn,, DD..VV..MM..,, MM..S. MMaannMaaeggdeeirrc,,ineLLaabbanoodrraattPooarrtyyhoAAlnnoiigmmyaall Medicine and Pathology Ii on an MM..KK.. HHoopppp,, AA..AA..SS.. SSeenniioorr LLaabboorraattoorryy Technician/ Study Assistant B1 pt ent CC..DD.. King, D.V.M., Ph.D. EExxtteerrnnaall CCoonnssuullttaanntt//DDrraafftt Report Preparation I ne Sore sons CC..EE.. LLuuddeemmaannnn,, BB..SS..,, M.T. SSeenniioorr Medical Technologist/ Clinical Pathology Determinations I ned Soe 1 LL..AA.. MMaarrsscchhkkee AAddvvaanncced Secretary/ Report Typing ii SLE. McCarville, B.5., KS. Advanced Biostatistician S.E. McCarville, B.S., M.S. |1 reditcmieaval WW..CC.. MMccCCoorrmmiicckk,, IIIlIl,, B..SS.. Advanced Biostatistician TTooxxiiccoollooggyy SSppeecciiaalliisstt//SSppoonnssoorr Representative and Project Coordinator i JJ..RR.. NNeellssoonn,, HH..TT.. Bi 6c. recone G.C. Pecore I SS..LL.. WWeessttmmaarrkk,, AA..AA..SS.. Spartan, Laboratory nie Gore HHiissttootteecchhnnoollooggiisstt//MMiiccrroossccooppee SSlide PPrreparation Supervisor, Laboratory Animal Care LLaabboorraattoorryy TTeecchhnniicciiaann B 1 LL..O0.. WWiisseetthh LT SSeenniioorr LLaabboorraattoorryy TTeecchhnniicciiaann// Assisted With Study Data B B 1 x. n 26. 11333377..00003300 3MA00027155 i | StawTuRE PAGE SIGNATURE PAGE 1 TTWHOO YYEEAARR OORRAALL ((DDIIEETT)) TTOOXXIICCIITTYY//CCAARRCCIINNOOGGEENNIICCIITTYY SSTTUUDDYY OOFF | FLUOROMENICHL Foo143 IN ARTS FLUOROCHEMICAL FC-143 IN RATS xiX RGR pein o, SRE RIKER Experiment No. 028]CR0012 | 1 FFrroomm tthhee PPaatthhoollooggyy and Toxicology Department RIKER Laporstories: ne. ot Company RIKER Laboratories, Inc./3M Company 1| SE. Pau Wimmasote 0.5.5 St. Paul, Minnesota U.S.A. | i SSttuuddyy DDiirreeccttoorr:: pushed: fo CRA "-L-~onard J. SiFb'inski, B.A. | EERE Senior Toxicologist 1i Report Reviewed by: ple. 2-atF7 Report Reviewed By: | i Jamds L. Allen, Ph.D. J DDiippla loommaamttee,,~AA. ..BB..TTD.. . DDaattee Research Toxicologist I Research Toxicologist []|| srs trot: PlPEL 5-217 Ebard - Ericson, FD. Tats Report Approved By: 1 LELadabwbaoorrrdaattooE.rryy EMMraaincnkaasggoeenrr, Ph.D. i | | 1| a. I 27. 11333377..00003311 swao0027150 3MA00027156 | | RREEFFEERREENNCCEESS | 1 1. JJoohhnnssoonn,, JJ..DD.. EExxtteenntt aanndd RRoouuttee ooff EExxccrreettiioon and TTiissssuue DDiissttrriibbuuttiioonn ooff i TToottaall CCaarrbboonn--1144 iinn MMaalle and Femmaalle RRaattss AAfftteerr aa SSiinnggllee IIVV DDoossee ooff B FC-143- C. Riker Laboratories, Inc., St. Paul, MN 55101, Internal DDFrCruu-gg14MM3e-ettaabCbo.olliissRmmikeRRereppoLoratrtb,,or11a--t22o00r,,ieJsa, nuuInaarcry., St. 300,, Paul, 1198800.. MN 55101, Internal 1 2. PPaassttoooorr,, TT..PP..,, LLeeee,, KK..PP.. aand GGililllifeess,, PP..Jj. MMoorrpphhoolologgiiccaall aanndd BBiioocchheemmicicaall I EEnnllaarrggeemmeenntt.. CChhaararactceteririssttiiccss ooff TThhee TTooxxiiccoollooggiisstt,, PPeerrfflluuoorroooocttaannoaattee -- IInndduucceedd 55((1!))::115555,, MMaarrch 11998855.. LLiivveerr i 3. Aver, M.R., Cohen, B.J., Lattuada, C.P. and Foster, S.J. Anver, M.R., Cohen, B.J., Lattuada, C.P. and Foster, S.J. | Age-Associated Lesions in Barrier-Reared Hale Spragie-Dawley Rats: A 1 AACCgogoimmenp-gpaAarsriRsisseooosc.nni,aBBte8eed(ttww1ee)LeePennasriotHHnaaps1p::: 3in-2((4SSB,DDa))rSrpiaaernnridd-nRgCCe,rarll:r:1e9d82C.OMBaSleCDSp((rSaSDDg)u) eSS-Dttooaccwkklses.y. Rats: EExxppeerr.. Aging Res., 8(])Part 1:3-24, Spring, 1982. B 4. E.K., and PPrreejjeeaann,, E.K., and Neisoureger, JJ..DD..,, PPeecckkmmaann,, Weisbureger, 'J.H.JJ..CC..,, J.H. Spontaneous Tumors in CCaasseeyy,, AA..EE..,, GGrriiswwoolldd,, Spontaneous Tumors in Sprague-Danley DD..PP..,, WWeeisisbbuurrggeerr,, Sprague-Dawley i RRaattss aanndd SSwwiissss MMiiccee.. CCaanncceerr RReesseeaarrcchh 3~3:32:2776688--22777733,, NNoovveemmbbeerr,, ]1997733.. B 5. HHFaaezzbllreeuttaoornny LL17aa,bboorr1aa9tt8oo4rriieess,, VViieennnnaa,, VVAA.. HHiissttoorriiccaall CCoonnttrrooll DDaattaa,, ppaaggee 1166,, February 17, 1984. BB 6. HDHaainnfhhfiiejjraaerrnvvciie,, EDxipfrf.ereBinocle. inHH..,,PeOOrppfhhlaauuuoggr,,docRR..tHHa..noaaatnnded iMnedP.erf1l71u:o5r0o.o5c5t,ano1a9t82e. SESEiixxnnccggrreeeerrtt,,iioonnLL.. iinn TThhtteehhee SSeeRRaaxxtt--..RReellaaPpttrreoeoccdd.. SSoocc.. Expr. Biol. Med. 171:50-55, 1982. I | B B I ! I I 1 28. I 28. 11333377..00003322 M3MA0A000002277115577 1iI mieTable I 1n Two Year Oral (Diet) Toxicity - Oncogeniclty Study eliotn Fi ee of Fluorocarbon FC-143 in Rats n I AAnnaallyyttiiccaall AAnnaallyyssiiss ooff FFCC--11443~% (% Above/Below Desired Concentration) (% Above/Below Desired Concentration) 1nB rEois 0 rr 1m Approximate CCD Analytical oe Study Month Report Numbers Dosage Levels (ppm) 300 30 R 1 0 ((IInniittiiaal)) 221133 I 229 I 4 250 ++ 00..66%0 0.3% + 5.0% -- 1o.0n% + 1.0% - 2.3% H 7 289 1.2% 10 319 ~ -34.0% 0.0% - 6.7% | B n11 312288 13 340 -- 66..11% - 2.3% an + 7.7% B 16 366 + 2.6% + 4.4% 19 384 n 22 395 + 2.0% + 3.0% + 2.2% + 3.3% 1 2244 440044 1InB - - Mean Deviation for the Study ++ 99..448% ~ nn + 1.6% ++1100..00%% + 1.9% n B -2a- CCoommmmeerrcciiaall CChheemmiiccaallss DDiivviissiioonn ((cCcCoD)) -2b- Itnncooorrzraecctt vvaalluueess ggiivveenn aatt tthhiiss lleevveell dduuee ttoo iinnssttrruummeenntt mmailffuunnccttiioonnt: this dosage level was reanalyzed after new detector was installed. 1B! -c- EExxcclluuddiinngg ffrroomm smeeaann ddeevviiaattiioonn tthhee percentages oovveerr ++ 2200%% aacccceeppttaabbllee lliimmiitt.. 11B a. B 29. 11333377..00003333 3MA00027158 | I 1 snes Table 2 Two Year Oral (Diet) Toxlcity-Oncogenicity Study of Fluorocarbon FC-143 in Rats | Smacy o un soy ize 1 2.4 steer toon Goes Summary of Mean Body Weights (g) + % Difference from Control |1 ass MALES | 1 SSttuuddyy Week | 0 1 2 44 | 6 8 | 10 12 14 i 111868 i 2o 22 1 2244 26 i 28 | 3o 32 34 i 333868 | 40 i i"42 44 46 | 48 5o 1| 352 1| i | 1I | CCoonnttrrooll Mean Wt, 330000 ppppam Mean Wt, % Diff. 165.3 162,1 270.9 333344,.00 234,3 227766.,77 390.7 308.6 429,2 353,2 456.2 380.1 475,5 398,0 493.2 412.8 555101525.,.933 444233566,..400 526.8 447,4 542.3 555500,.44 456,1 446644.,22 561,0 475.0 567.5 484,9 576,3 497.2 580.6 505,7 582,9 511,8 555999199.,.044 555122444.,.288 608.4 535.2 al 612,9 619.8 623.5 mmo 540.9 550.8 552.0 Gown 626,1 639.2 638,6 558.5 566,7 570,1 - 1.9 -13,5 -"1177,.22 -21.0 -17,7 -16.7 -16,3 -16.3 ---111555,..444 -15,1 -15,9 --1155,.77 -15.3 -14,6 -13.7 -12,9 -12.2 .---111322,.,044 -12.0 Gms -11.7 -11.1 -11,5 mm-10.8 -11,3 -10.7 3300 ppppmm Mean Wt. % Diff. 167,0 + 1.0 271,0 332288.,55 + 0,0 ~S1e.6 369,4 - 5,4 410,3 - 4.4 441,5 - 3,2 458,1 - 3.7 475.4 - 3.6 444989878...955 - 333.,.303 512,1 - 2.8 519.4 552266.,33 - 4,2 -- 44..44 538.9 - 3,9 546,2 - 3,8 558.6 - 3,1 566,4 - 2,4 571.3 - 2.0 555786544,..400 --- 222,..666 592,5 - 2.6 ems 600.5 610,4 612,1 Cin - 2.0 - 1,5 - 1.8 don 618.9 627,1 633.6 - 1,1 - 1,9 - 0.8 n30. 11333377..00003344 3MA00027159 B I i TTaabbllee 22 ((ccoonncclluuddeedd)) 1 Two Year OoorffalFFlluu(ooDrireootcc)aarrbTbooonxnicFFiCCt--1y14-43O3nciionngeRRnaaittscsity Study I ET Summary of Mean Body Weights (g) + % Difference from Control I1 wuss ~ALES 1B serStudy Week corer 000m Control 300 ppm Mean Wt. Mean Wt. % Diff. Py 30 ppm Mean Wt. % Diff. B 54 56 B 58 60 62 i 666664 I 68 7O 72 1 J74 B 76 78 80 I 82 i 888664 88 n 90 1 o994i2 B 96 98 n 100 102 104 I 654.3 661.6 668.0 673.2 674.4 666556004...885 656.6 Goa 661.9 658.3 660.8 667.7 668.8 670.6 663.1 666767585...616 678.9 Go 690.0 686.0 678.3 677.5 675.7 671.1 665.9 642.0 577.6 583.1 587.9 590.8 593.2 555999886...228 604.9 en 608.2 608.5 601.1 605.4 604.6 611.8 610.0 666111777...445 614.7 ome 624.6 621.8 627.6 621.0 627.2 625.5 629.4 613.3 -11.7 -11.9 -12.0 -12.2 -12.0 ---1808...112 - 7.9 lve - 8.1 - 7.6 - 7.6 - 9.3 - 9.6 - 8.8 - 8.0 --- 887...666 - 9.5 las - 9.5 - 9.4 - 7.5 - 8.3 - 7.2 - 6.8 - 5.5 - 4.5 641.9 646.4 652.7 656.8 655.7 666665228...553 666.5 ees 666.2 664.4 659.2 663.8 661.7 669.2 666.9 666666442...553 654.7 eee 662.4 652.9 660.0 653.4 659.7 660.0 664.0 650.8 - 1.9 - 2.3 - 2.3 - 2.4 - 2.8 +-+ 011...988 + 1.5 lod + 0.6 + 0.9 - 0.2 - 0.6 - 1.1 - 0.2 + 0.6 --- 011...966 - 3.6 Li - 4.0 - 4.8 - 2.7 - 316 - 2.4 - 1.7 - 0.3 + 1.4 I I B I 1 a I 3]. 11333377..00003355 3MA00027160 | | 1 Tames Table 3 | Two Year Oral (Diet) Toxicity-Oncogenicity Study of Fluorocarbon FC-143 in Rats 1| races Summary of Mean Body Weights (g) + % Difference from Control FEMALES | worStudy Week i 0 i 4.2 6 | 8 | 10 12 14 i 111868 i 20 22 1 2244 26 | 28 | 30 32 34 | i 333688 40 42 44 46 i 48 50 1| 352 con Control Mean Wt. 00mm 300 ppm Mean W%. % Diff. rm 30 ppm Mean Wt. % Diff. 138.2 138.1 221005099...552 221116337...883 238.7 237.4 256.9 254.6 269.2 263.3 279.5 274.2 289.7 286.4 233900166...888 222890599...444 311.6 307.6 3|9.1 323244..55 314.6 332222..55 327.3 326.0 333.7 331.6 338.3 338.6 345.5 344.1 350.7 352.8 333555599...533 333566722...133 363.2 366.0 371.2 373.2 380.1 380.4 385.7 385.9 yom 392.3 398.6 406.1 391.6 399.3 406.1 + 0.0 +++ 2252..111 - 0.5 - 0.9 - 2.2 - 1.9 - 1.1 --- 222...244 - 1.3 - 1.4 -- 00..66 - 0.4 - 0.6 + 0.1 - 0.4 + 0.6 +++ 000...858 + 0.8 + 0.5 + 0.1 + 0.0 - 0.2 + 0.2 + 0.0 137.2 - 0.7 221116446...990 +++ 422...366 235.7 - 1.3 253.8 - 1.2 261.3 - 2.9 275.5 - 1.4 282.8 - 2.4 222899588...900 -2- .22..909 304.1 - 2.4 309.9 331188..66 - 2.9 -- 11..88 323.6 - 1.1 330.4 - 1.0 339.0 + 0.2 344.9 - 0.2 353.5 + 0.8 333566383...110 +++ 011..|7 367.5 + 1.2 375.9 + 1.3 382.0 + 0.5 389.7 + 1.0 Wom 395.8 399.7 406.2 + 0.9 + 0.3 + 0.0 i | | | | i 3322. 11333377..00003366 3MA00027161 ii et Table 3 (concluded) I se se ey foe) STORE i Two Year OoorffalFFlluu(ooDrrieootcc)aarrTbboooxnnicFFiCCt--1y14-43O3nciionngeRRanatitscsity Study B Sms of an ody ite (9 2 Birence from Contest Summary of Mean Body Weights (g) + % Difference from Control 1B remus FEMALES 1 soar I Study we Week JE Control 300 ppm RNNR cee Mean Wt. Mean Wt. % Diff. wlorhm me 30 ppm Mean Wt. % Diff. | 54 56 B 58 6O 62 B 1 66664 68 70 H 72 74 76 B 78 8O 82 B 888664 I 88 90 92 i a94 I 96 98 1 fi100 i 102 I04 B 414.1 411.5 419.1 421.2 420.9 426.4 423.6 427.0 426.6 431.9 444222644..3|9 a4433545..50 427.5 433.0 431.4 429.1 435.2 432.8 446.5 444.6 455.2 447.4 464.8 452.7 474.9 457.0 484.0 461.8 444998224...778 444555887...226 499.1 456.6 San 500.6 512.5 505.7 Go 451.8 455.9 451.0 neon 506.9 500.0 501.2 464.5 468.0 464.2 503.6 462.8 502.0 450.3 - 0.6 412.6 - 0.4 + 0.5 420.7 + 0.4 + 1.3 427.3 + 1.5 + 0.8 430.0 + 1.5 + 1.2 435.7 + 2.1 +e+ a21..s59 4a443t69e..s59 +++s 3.2 5~I + 1.3 445.3 + 4.2 - 0.5 443.5 + 2.8 - 0.6 448.6 + 3.1 - 0.4 463.3 + 3.8 - 1.7 468.8 + 3.0 - 2.6 471.3 + 1.4 - 3.8 475.8 + 0.2 - 4.6 485.7 + 0.4 --- 775..006 444777996...773 --- 221...668 - 8.5 483.4 - 3.1 los - 9.7 -11.0 -10.8 wee 485.2 486.3 492.0 134 - 3.1 - 5.1 - 2.7 nomen - 8.4 - 6.4 - 7.4 504.3 505.5 505.6 - 0.5 + 1.1 + 0.9 - 8.1 503.3 - 0.1 -10.3 501.8 + 0.0 B H ! x| - B 33. 11333377..00003377 3MA00027162 I 1 ries i Table 4 B SO -- 1 Two Year Ooorffa!FFlluu(ooDrrioeotcc)aarrbTbooonxnicFPlCCt--11y44-33OnciionngeRRnaatitscsity Study Summary of Mean Food Consumption Per Kilogram Body Weight (g of diet consumed per day) + % Difference from Control I osMALES a I1 - M rr JE nn R oe Rpp e ee 1 Study WWeeeekk B I 2 4 B 6 1 1I080 B 12 14 16 18 B 20 22 24 n 26 i 2338O0 B 32 34 36 1| = we WDB oi 38 4O 42 44 B 46 1 54580O I 52 Control 300 ppm MMeeaann WWtt.. MMeeaann WWtt.. %% DDiiffff.. 102.0 85.2 76.4 69.4 655133...577 50.7 51.7 48.0 46.8 46.9 44.9 45.0 43.7 444233...822 42.9 41.8 38.4 40.7 39.5 39.3 38.9 39.0 333988...055 36.5 98.6 96.8 84.0 67.7 76603...060 58.1 59.5 55.2 52.6 54.5 51.9 52.0 49.2 444888...377 47.2 46.5 42.5 46.0 43.9 44.0 43.6 42.6 444333...322 41.1 - 3.3 +13.6 +10.0 - 2.5 +4+11747...383 +14.6 +15.1 +15.0 +12.4 +16.2 +15.6 +15.6 +12.6 ++4111222...977 +10.0 +I|.2 +I0.7 +13.0 +11.1 +12.0 +12.1 + 9.2 +++I11|22..202 +12.6 30 ppm MMeeaann WWtt.. % Diffff.. 103.8 85.0 77.0 61.2 655477...144 51.3 53.5 49.3 47.7 48.9 47.3 46.3 44.9 444343...757 44.0 42.8 39.7 42.2 41.8 41.3 40.5 39.7 333899...944 36.1 + 1.8 - 0.2 + 0.8 -11.8 ++4646...929 + 1.2 + 3.5 + 2.7 + 1.9 + 4.3 + 5.4 + 2.9 + 2.8 +++ 141..202 + 2.6 + 2.4 + 3.4 + 3.7 + 5.8 + 5.1 + 4.1 + 1.8 +-+ 202..333 - 1.1 I1 -_--m------ I H " B I 34. 11333377..00003388 3MA00027163 iI ie somernion Table 4 (concluded) i 1 Two Year OoorffalFFlluu(ooDrriooetcc)aarrbTbooonxnicFFiCC--t11y44-33OnoiionngeRKnaattisscity Study B mm of tous oud onsupein Fr Sisgeas ty wight Summary of Mean Food Consumption Per Kilogram Body Weight 1 IR A (g of diet consumed per day) + % Difference from Control B usMALES I wa 1 SWoetoeukkdy B 54 B 56 58 60 i 62 64 66 68 B 70 72 74 B 76 78 8O 1 888244 86 B 88 9O 1 292 B 94 96 98 n tO0 n i I02 1I0044 comers 0 0m Control 300 ppm MMeeaann WWtt.. MMeeaann WWtt.. % DDiiffff.. 37.0 36.6 36.1 35.4 35.9 31.0 36.3 32.9 32.6 33.0 34.4 37.1 36.6 34.6 33565...636 35.1 Ba34.8 34.9 35.1 38.5 37.1 37.3 36.7 35.0 3333..88 42.2 41.2 40.7 40.6 37.1 40.2 40.8 36.5 37.7 37.5 37.9 39.2 39.7 39.4 5 3368..75 38.6 ws33.0 36.3 37.3 40.5 40.1 38.9 38.1 38.3 3377..88 +14.1 +12.6 +12.7 +14.7 + 3.3 +29.7 +12.4 +10.9 +15.6 "!-13.6 +10.2 + 5.7 + 8.5 +13.9 +++881..212 +10.0 ses - 5.2 + 4.9 + 6.3 + 5.2 + 8.1 + 4.3 + 3.8 + 9.4 +1111..88 worm MM3e0eaanpnpmWWtt.. %% DDiiffff.. 36.3 - 1.9 37.9 + 3.6 37.5 + 3.9 37.3 + 5.4 37.1 + 3.3 34.5 +I I .3 36.4 + 0.3 33.5 + 1.8 33.0 + 1.2 34.9 + 5.8 36.7 + 6.7 36.9 - 0.5 34.9 - 4.9 36.8 + 6.4 33474..363 -3+- 337..67 35.4 + 0.9 sn ioe 33.0 34.7 35.1 - 5.2 - 0.6 + 0.0 36.8 - 4.4 37.5 + 1.1 37.4 + 0.3 37.3 + 1.6 37.2 + 6.3 3377..55 ++1111..00 I B | B i 5 I 35. 11333377..00003399 3MA00027164 1| es Table 5 | ve vou ops. ae) omen Sey 1 Two Year OoorffalPFlluu(ooDrrieootcc)aarrTbboooxnnicFFiCCt--y114-43O3nciionngeRRnaatitscsity Study | my of aa reco onsption so Cigna iy mio Summary of Mean Food Consumption Per Kilogram Body Weight 1 I SII Sree by ie (g of diet consumed per day) + % Difference from Control | FEMALE S | po i sSWeeteeukkdy | I 1 i2 4 | 6 8 I0 | 12 14 i 1166 18 i 2O i 22 24 26 B 233800 | 32 34 i 3366 38 i 4O 42 44 | 46 B 45508O i 52 corer CMMoeenaatnnroWWtlt.. 00 MM3ee0aa0nnpWpWttm.. % DDAiZZff.. si98.8 107.0 97.2 81.0 74.1 72.6 70.2 64.2 5577..22 64.3 63.4 58.6 59.5 57.0 565919...777 58.4 52.9 5656..77 56.8 58.4 54.2 54.7 48.5 455911...244 48.3 We96.6 101.6 81.8 81.1 74.9 72.5 70.4 62.0 5566..33 62.9 61.5 61.2 58.0 56.2 555817...144 56.1 51.4 5544..22 52.7 51.6 53.6 51.8 50.8 454505...113 48.3 lel - 2.2 - 5.1 -15.8 + 0.1 + 1.1 - 0.1 + 0.3 - 3.4 -- 11..66 + 2.2 - 3.0 + 4.4 - 2.5 - 1.4 --- 533...899 - 3.9 - 2.8 E- R4.Y4 - 7.2 -I I .6 - 1.1 - 5.3 + 4.7 +"-11222...323 + 0.0 wr 30 ppm MMeeaann wWEE.. %% DDiiffff.. lee96.1 103.0 83.6 82.8 73.4 73.5 69.7 64.9 5588..88 64.6 65.5 63.2 61.2 57.0 s5589e..l30 55.7 51.5 5577..00 54.3 50.3 52.9 53.9 52.1 555100...800 48.0 Lae - 2.7 - 3.7 -14.0 + 2.2 - 0.9 1.2 - 0.7 + 1.1 ++ 22..88 + 0.5 + 3.3 + 7.9 + 2.9 + 0.0 --- 511...522 - 4.6 - 2.7 ++00..55 - 4.4 -13.9 - 2.4 - 1.5 + 7.4 +-- 522...37 - 0.6 i | | | | i 3366.. 11333377..00004400 3MA00027165 i Table 5 (concluded) I 1 Two Two Year Year OOozrfaallFiu((obDriloeettc))arTbTeooxnxiiccFiiCt-ty1y4--3OOnnccioonggeeRnnatitccsiittyy SSttuuddyy of Fluorocarbon FC-143 in Rats I 1 SS(ugumsmomfazryydiocofft WMceeoaannnsuFmFeoodooddpCCeoornnssdauuymm)pptt+iioonn PDPeierfxfKKeiirlleonocggerraammfrBoSonoddyCyonWWteeriiogglhh (g of diet consumed per day) + % Difference from Control i ross FEM~tLES I 1 MssSteteaeuckdkyy Week i 55se4 56 i a56080 i 5666244 i 766a608 i 7Tn7e02 1 7777s4s6 i 275880O i 8888624 n 288a%68 90 ii 592 3a94 i 1 15990806 1 II1100002204 i 104 i WeMcCaoeonnnattnWrreooWell.. Mw33ee00a00nppWpWpeEm..%Aotbietr.. Mean Wt. Mean WE. % Diff. 4sw8i.s1 aa4a7l.a1 -cCae2.no1 51.5 48.4 - 6.0 Se o@s 46.3 ws a2 49.6 wh des 44578...144 al sels 41.0 as als 44.9 4 wh 46.1 3 all 45.3 44 ass 48.4 a3 sls 48.3 ah alo 44.1 7 wa 45.7 wo alo 4a443.s.05 wish 44.3 3 ea 45.3 Ww asle 46.1 47.6 49.2 441666...105 39.5 41.3 43.1 44.1 45.9 45.8 44.0 44.4 48329...808 39. I 42.3 45.6 45.9 ws as 46.9 wa sas 42.4 ws aw 46.8 als alo 41.5 ws ez 42.5 ale sis 41.6 43.9 47.5 44.4 44.2 44.0 46.2 50.9 on +Sl- to20..ss88 3 --- 441..838 --JCee38..so70 s--S262k..757 l--Cos55..li22 l--"aa02..ss28 nn ---848..565 Ca--Ie6In..s67 - 1.1 +vw- ea41..ra34 S-s+ se54..eo67 w+a+ m86el..a70 +22.4 MW33ee00anpppwmmWee. Mean Wt. 4aa7r.aa3 47.1 46.3 aa 47.7 ais 4a444.r.18 we 39.6 ame 39.8 ao 41.0 awd 44.4 ass 44.5 aaa 44.4 &7 43.7 ms 38.5 aw38398...212 aa 37.7 3a 37.2 es 38.5 BS39.9 a7 42.7 wa37.7 ae 41 .4 as 42.5 43 46.3 as 43.2 vb%oDpiiiftrfe,.. -asa1g.s7 - 8.5 In+ 0.0 tas - 3.8 las ---e48l..s99 Sa - 3.4 cna -11.4 on -11.1 Sal - 2.0 Can - 8.1 Cel - 8.1 los - 0.9 ose -15.8 na ---111122..:122 La -I 4.9 ne -21.8 ies -16.5 -13.1 Sao - 9.0 oa -11.1 ois -11.5 sa + 2.4 ass + 8.9 sa + 3.9 i n i i a I 37. 11333377..00004411 m3MAcA000002277116686 1I ames Table 6 R Two Year Oral (Diet) Toxicity-Oncogenicity Study aI meayrof oe ont cnpption < seit of Fluorocarbon FC-143 in Rats Summary of Mean Food Consumption - Absolute (g/rat/day) + % Difference from Control I MALES I wy commer 0m 0 pm Study Control 300 ppm 30 ppm Week Mean Wt. Mean Wt. % Diff. Mean Wt. % Diff. n I + 3.2 i 4 42 222535...155 222323...272 --- 991...007 222553...330 --- 000...884 I 6 27. | 20.9 -22.9 22.6 -16.6 8 26.4 24.9 - 5.7 26.3 - 0.4 R 1o 24.5 24.0 - 2.0 25.4 + 3.7 12 24.1 23.| - 4.2 23.5 - 2.5 14 25.5 24.6 - 3.5 25.4 - 0.4 I 1 111868 222444...111 222322...599 --- 525..050 222343...188 S+ i0.e0 - |.2 2O 24.7 24.4 22 24.3 23.7 - 2.5 24.6 + 1.2 H 24 24.8 24.1 - 2.8 24.4 - 1.6 26 24.5 23.4 - 4.5 24.2 - 1.2 28 24.3 23.4 - 3.7 24.3 + 0.0 B 3O 24.9 24.2 - 2.8 24.4 - 2.0 333424 222444...393 222333..889 --- 422...110 222444...595 F++ o00..s88 B 1 333688 222244...744 222144..119 --- 131..252 222424...787 +++101..242 4O 24.0 23 5 - 2.1 24.8 + 3.3 I1 hows Is ud ud 42 24.| 23.8 - 1.2 24.8 + 2.9 44 24.| 24.0 - 0.4 24.7 + 2.5 46 24.3 23.5 - 3.3 24.3 + 0.0 48 24.4 24.2 n 50 24.6 24.5 - 0.4 24.7 + 0.4 52 23.3 23.4 + 0.4 22.9 - 1.7 I I i B 2 a. i 38. 11333377..00004422 3MA00027167 '| rae o Table 6 i Two Year Oral (Diet) Toxicity-Oncogenlcity Study of Fluorocarbon FC-143 in Rats |1 A -- Summary of Mean Food Consumption - Absolute Tn so (g/rat/day) + % Difference from Control 1| uss MALES |1 cr ecm or moemm aom Study Control 300 ppm 30 ppm Week Mean Wt. Mean Wt. % Diff. Mean Wt. % Diff. | 54 24.2 24.4 + 0.8 23.3 - 3.7 56 24.2 24.0 - 0.8 24.5 + 1.2 i 58 24.1 23.9 - 0.8 24.5 + 1.7 i % Be me Im mn um 60 23.8 24.0 + 0.8 24.5 + 2.9 62 24,2 22.0 - 9.1 24.3 + 0.4 64 20.6 24.0 +16.5 22.7 +10.2 66 23.6 24.4 + 3.4 24.1 + 2.1 | 68 21.6 22.1 + 2.3 22.3 + 3.2 i 7?7202 222111..,677 222222...988 +++ 565...110 22223...202 +6I..99 6.9 | 74 22.7 22.8 + 0.4 24.2 + 6.6 76 24.8 23.7 - 4.4 24.5 - 1.2 1 a78 24.5 24.0 - 2.0 23.1 - 5.7 | Fos 20 is ns TEs 80 23.2 24.1 + 3.9 24.6 + 6.0 82 24.1 22.4 - 7.1 25.1 + 4.2 84 23.8 23.8 + 0.0 22.7 - 4.6 1 86 207 208 Tou 2s lok 86 23.7 23.8 + 0,4 23.5 - 0.8 | 88 23.6 20.3 -14.0 21.6 - 8.5 1 90 9922 24.1 22.7 2244..11 2233..22 - 5.8 23.0 --33..77 2222..99 - 4.6 - 5.0 - 5.0 | 94 26.1 25.4 - 2.7 24.3 - 6.9 96 25.1 24.9 - 0.8 24.5 - 2.4 98 25.2 24.4 - 3.2 24.7 - 2.0 100 i 110022 24.6 2233..33 23.8 2244..11 - 3.3 ++33.44 24.6 2244..77 + 0.0 T~ 66..00 I - nnn 104 21.7 23.2 + 6.9 24.4 +12.4 | | | 1| | 39. 11333377..00004433 3MA00027168 1l somes Table 7 l sv ve Sys. tee) onion Sensy i Two Year OoorffalFFlluu(ooDrrioeotcc)aarrTbhoooxnnlcFFiCCt--y114-433OnciionngeRRnaaittcssity Study i A -- 1 Su((mggm//arrraaytt//ddoaafyy))Me+a+n%%FDDoiioffdffCeerorenensncucemeptffirrooonmm CC-ooAnnbttsrrooolllute l ross FEMALES l wr omen worm or 1 WSWeteeuekdk y MCMeoeanatnnroWWtEl.. MM3ee00aannpWWpttm.. % Dpiifefr.. MM30eeaanpnpWmWeE.. _% Dpiifrfe.. l I 13.5 13.5 + 0.0 13.3 - 1.5 2 17.0 17.0 + 0.0 17.1 0.6 1 i Bd Ws Twa do ve 4 20.4 17.5 -14.2 18.0 -I I .8 l 6 19.3 19.2 - 0.5 19.5 + 1.0 8 19.0 19.1 + 0.5 18.6 - 2.1 1 io psooownnmoet Ih 10 19.5 19.1 - 2.1 19.2 - 1.5 l 12 19.6 19.3 - 1.5 19.2 - 2.0 l i 14 1166 18.6 1166..77 17.8 1166..11 - 4.3 - 3.6 18.4 16.8 - 1.1 +0.6 - 3.6 16.8 + 0.6 18 19.7 18.8 - 4.6 19.3 - 2.0 2o 19.8 18.9 - 4.6 19.9 + 0.5 l 22 18.7 19.2 + 2.7 19.6 + 4.8 24 19.3 18.7 - 3.1 19,5 + 1.0 26 18.7 18.3 - 2.1 18.4 - 1.6 I i 32308o 222000...622 191199...434 --Za64..o30 221090..003 I-- 61i..30 32 20.2 19.3 - 4.5 19.2 - 5.0 34 18.5 18.1 - 2.2 18.2 - 1.6 36 20.2 19.4 - 4.0 20.4 + 1.0 38 20.4 19.1 - 6.4 19.7 - 3.4 I 4o 21.2 18.9 -10.9 18.5 -12.7 42 20.1 20.0 - 0.5 19.9 - 1.0 44 20.8 19.7 - 5.3 20.6 - 1.0 l 46 18.7 19.6 + 4.8 20.3 + 8.6 i 4558o0 212009...535 181198...070 -1+-1222...212 222000,..050 +-- 262...424 l 52 19.6 19.6 + 0.0 19.5 - 0.5 l ! l l ' w. l 40. 11333377..00004444 3MA00027169 I I1 ses Table 7 So tone Genk 0iee) erioty-mcounttsy seu Two Year Oral (Diet) Toxicity-Oncogenicity Study I of Fluorocarbon FC-143 in Rats -- Summary of Mean Food Consumption - Absolute 1 a Sin et (g/rat/day) + % Difference from Control II2 - nn ross n FEMALES I 1 a MR cN ee Rh vee pees Meant. wean'ui. sour. eswm. ose. Study Week Control Mean Wt. 300 ppm Mean Wt. % Diff. 30 ppm Mean Wt. % Diff. 1III 6 2001 20.1 Too isis <3 1 7% 22.0 20.5 - 6.8 20.8 -5.5 54 19.9 19.4 - 2.5 19.5 - 2.0 56 21.6 20.4 - 5.6 19.8 - 8.3 58 19.5 20.3 + 4.1 19.8 + 1.5 60 21.0 21.0 + 0.0 20.5 - 2.4 62 20.1 20.1 + 0.0 19.5 - 3.0 64 20.6 20.0 - 2.9 19.4 - 5.8 66 17.4 17.2 - 1.2 17.7 + 1.7 68 19.2 17.9 - 6.8 17.7 - 7.8 70 19.9 18.5 - 7.0 18.2 - 8.5 72 19.7 19.1 - 3.1 19.9 + 1.0 74 21.6 20.4 - 5.6 20.6 - 4.6 76 22.0 20.5 - 6.8 20.8 - 5.5 I 78 20.5 19.9 - 2.9 20.6 + 0.5 8O 21.7 20.3 - 6.5 18.3 -15.7 1 o82 21.3 19.4 - 8.9 19.0 -10.8 I 3 wi Isa oes 098 84 21.1 18.2 -13.7 18.2 -13.7 86 21 .8 17.9 -17.9 18.1 -17.0 88 22.6 19.3 -14.6 18.0 -20.4 90 23.1 20.6 -10,8 18.7 -19.1 I 92 23.5 20.0 -14.9 19.4 -17.5 i 9994 6 222131...575 222010...646 - - - 494.,.722 2119..00 --1111..46 19.0 -11.6 I 98 23.4 20.7 -I 1.5 20.9 -I0.7 100 20.8 20.4 - 1.9 21.5 + 3.4 i I02 21.4 21.4 + 0.0 23.3 + 8.9 I Toi os ns tae man 15k 104 20.9 22.9 + 9.6 21.7 + 3.8 I 1 - I I I i a I 41. 11333377..00004455 3MA00027170 B i TTAABBLLEE 88 ! EEssttiimmaatteedd MMeeaann FFCC--114433 ((mmgg//kkgg BBooddyy WWeeiigghhtt)) H 1 CCoonnssuummppttiioonn PPeerr DDaayy 1 - nnn n B 1 We WSSeetteeuukkddyy eee eeHMeaallee r 330000 opppmmFeFemmaallee e MMaealeleem3e30r0ppopnm FFeemmaallee B1 , 5s a 0 2 :22i I 1 4658 1 1112800 n 1111s24 1 21110886 B 222220 1 2222846 B i 33333220208 B 3333846 n 1 a23408 1 a4a4524 B 8445608 I 1 555202 222299....2060 23209055..05 22221050...2323 222244:.5.335 1172183185..929 22p2211e..858 1117677...6959 21111868,,..1966 11116565.4..688 11116888..1.8999 11116555..6646 17118884..334 11118543..5868 1711667.4.994 111111444463:...652256 11111]677675:..2.84284 113112.32.8..898 15111665:...8334 13113332..228 11115655..5..158 11112333..8112 11115655....5125 1E11332X...008 1111305555...112 111223:..3 30 111443..555 3222..3616 3223..51195 2111...9838 2222...5255 1111..5797 2222....2212 1111'..ss56 22I2..0s10 I111..s854 2111..0989 j111..es45 2111..8s90 1111..3444 1111..8778 111111...333333 111111...8s7878 1111..3232 1111..7676 1111..2333 1111..6s56 1111..2222 1111..ss66 1111..2222 II11'..ss65 11I..12 111..445 | I B B 1 a. I 42. 11333377..00004466 M3MA0A000002277117711 I1 TLE (oni) TABLE 8 (Continued) R EEssttiimmaatteedd MMeeaann FFCC--114433 ((mmag//kkgg BBooddyy WWeeiigghhtt)) B1 Consusption par ay Consumption Per Day B i SsVtetuueddkyy B Week H1 5 i 55555a6864 I 66aa02 I i 6666676468 7777O2 I 777746 78 I1 3 1 888aaa2O4 I 889&0368O m i s599t%24 s99s68 B n 1 111110000040220 104 I B I B 1i B Hale 330000ppopnm Fenale Male Female 127 11 112112220...4274 1122:.22 1111444..s315 114.83 1Ii1I22.1.I12 11114483..0808 1211111221:.3..02120 11111212123l....4o9948 j111i11..at32 1111.74 1111332..2s29 1133.s8 1s11.7 ]I.9 111333..228 is 13 it111111''..s08 p11e.6 1111232..s36 111.79 1011915..9996 iz10.9 11112123..7777 1153.27 111122211l..1012 1111343..2322 1712.0 11.7 111333..333 11111111...s454 1111133335...93292 II.4 15.3 Hale 3300ppopmm Fenale Male Femal e 11 Le 11II 1111 1141..444 1I151111 1i 01 111111...433344 1111II 100001 111111...222322 11I1 101 1I 11 111111...333233 111 1 1 1 111..333 i 13 1111 1011 1111..2222 1111 1001 11 00 111111...112112 1111 1101 1111..2322 1111 1111 1111..1213 i11111 1i1111 111111..,343234 1 1 1.3 4a3.. 11333377..00004477 aMAo0c27172 3MA00027172 1 . | I 1 : biaonnon I1 ES te R1' Poe ces Hott cH TT TT TCT H I " PR Iino 'I Psi coc oe g 2X] B B B B ros CT c I 1 Poao-oeoe "= i : I1 i IJ IE 2 22 n | i : 2 g1y8 2 7f, iEuws I i o gigtharogigiR altieEiss 1 yf 2 n 1B 1 a4".4.. 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RE : (Ei ede ou El Led, Uf 1i 2 o#i1 n- l|pEsiBgEiBEEpes JiiTiigRgzdjeiiEise o--o- | i 1| a. | 87. 11333377..00009911 awscoczrzie 3MA00027216 n i i Po i 1i az | ogigTenn oigzlane R 1n 5 Ri-II z piiggEsl = ci3BEEl iB fe | } B 1 B N5,f pii, e oF BRIU si"31E3i2N2E3R3 s"iig3n3i3f GITITIET OL oGiTInnIT ss 5 I 82 , zi:It Eipgpast . Bigppipd 32 B I I! i 8$5y oi| r siizmnmsnzr oe saiznazsndr 2z:~ zz 1B $Be2 02% B=Ii" l RBlIa8se3a%s%r -[ RsiEgRhsfeesR: iI3d n 1 BEZ Y - A1 2I < 2z el gi pu, tev ! 2.J I10Plogiifs 9ibieczfis Ja: I Q.Q-Z _.If I <{ I :Z I I I I 1 8888., 11333377..00009922 suncoczr217 3MA00027217 1i 1| 1i i i 1I y | srp ase na san ng si i i i i i i | 1 " sarpeERsInBneRsesieneeInIBIAIEISENIOANIN i i i 1 HEMIIIu anna i i 1 Seeesetesseccccsiizrziziiissiisansassiiiasass g I i |i1 - | 89. 1337.0093 3MA00027218 1n I 1 i i I i i ii Prefers I i B 1i 1 EEE E EEE I i 1i - 3 smn nnn I 1n ' {E EEEPRER A LEMEEEE i 1 Either I 1n I 9900.. ' 11333377..00009944 3MMAA0000002277219 n1 vais TABLE 19 ! Tuo Two Year Oral Year Oral (Diet) (Diet) TTooxxiicciittyy - - OOnnccooggeenniicciittyy SSttuuddyy ooff i FFlluuoorrooccaarrbboonn FFCC--114433 iinn RRaattss I Summary Summary of of Major Major MMiiccrroossccooppiicc FFiinnddiinnggss - - PPeerrcceenntt IInncciiddeennccee aatt 2 2 YYeeaarrss i!1 sas ve | I. 1 Organlesion NEOPLASTIC LESIONS nel WMaal0leeCCoonntrtraolFlssFees mmallee s FMlaleeHHiigqhh FFe3em0amle Wale LLooww Female 5Male 50Female Organ/Lesion n : I 50 50 50 50 50 50 I 1 AdrPPPehrhneeeaaoolccchhhrrrooommmooocccyyytttooomnnaaa,,, mbbaeelnniiiggg.nn 044 4 40 808 00 2 828 0 00 Pheochromocytoma, malig. 0 i LLiiHvveeeprratocellular Carcinoma 6 0 CI 0 2 2 2 2 0 0 Hepatocel I ul ar Carcinoma 6 0 10 2 2 0 B I n oie MaAARmddemeeeannnroooymccaaaGrrlccaiinnndoonmaa B i FiACCdaaberrrnccooiismnndaooenmnaaona LFLyiymbmprphohaaandngeginiooomssaaarrccoonmaa :-s157 I : a227 : 22o0 :Sn110 S: we000 : 248* 2 :Sm310 D B-- w000 :- - 42o0 Ibo, Adenona Pituitary Adenoma 3x5 n72 ow28 7o2n 3o6w o8m3 H i Leydig' te! Adenoma TTeesstteess//EEppiiddiiddyymmiiss Leydig Cell Adenoma I Ccel] Adenoma i TThhyyrrooiidd C-cell Adenoma i 1 CC--cceellll CCaarrcciinnoommaa 0 Se14" 0 2 FR 0 2 9 0 5 5 00 00 00 4 4 - - 4 0 4 0 J0 J0 I i 1I == 5500 rraattss//sseexx//group were at risk, % values derived from actual tissues examined J i oey differ (0.08 fron controls * = Significantly different ( = 0.05) from controls I n I 5 a. ! 91. 11333377..00009955 a3MMAAc000c02277222200 | i TTAABBLLEE 22O0 | 1 Two Two Year Year Oral Oral F l((DuDoiireetot))carTTboooxxniicciFitCtyy-14--3 OOninnccoogRgeatnesinciciittyy SSttuuddyy ooff FTuorocarbon FC-143 in Rats | Summary Summary of of Major Major Microscopic Microscopic Findings Findings - - PPeerrcceenntt IInncciiddeennccee aatt 22 YYeeaarrss m1 nnn cos NON-NEOPLASTIC LESIONS i 1 Organ/lesion nel CCoonnttrroollss WalS e s Female Male Female MWaalsleeoHHiiqghh FFeemm5a0allee MMaalolees oLouw FFeemm5a0allee i Adrena] Orqan/Lesion n = I 50 50 50 50 50 50 i AdN~Sreoiudnnuuuausll~oarirdaHnlyyppeE~rcptrp laasi~siisiaa 244 os0[ITw i8 w22 s 22 s: i 1 HHeveaoMSearcirrtynatourcsdaoiirdtdaiitlsis,,EcCcthahrsrooisnniicc Bw ww % 22 84 32 82 26 86 28 32 34 20 i 1 LivCHHCHeyyeyespprspteatortaoipotidodlcaecslDDetleleliugugcleleaannrNereerdarAAaItultLiltio.oe.nn BBaassoophpihlil.. 88& 4 0 1080 216 s5126r* 612 232 44 36 10" 114222 2 0 016 i MHPHoeyergpgtaaeal]arlopccylMaytostonotsoiscinissucNloedaurle I PorCtoarll Taf: Mononuclear 7000 38002 8ws60rx* 4 3186" 611202 2202 74 38 96* 38 NNeeccrCrooessliliss Infil. s 6 w 1 64 22 sn on ii LLuunAnAHgglelvvreeoorolrlaahrargeMMaaccrroopphhaaggeess 1 HPeermiovrarsh.ageHono. Infi1. 10 20 2 0 m s28 2% 20 28 10 4 10 12 ea62rr* 3ow 8m m3o2m 220% 44* 3o8m 28La Vascular Mineralization 86 Perivas. Mono. Infil. 42 26 14" 28 26 6* 4* i 44 3 52 a 7a TesVPPtrnaieessuucn/muoElonpaniiraida,iM , dyiIInnnneittsreearrlsiszttiaitttiiioaanll 3286 32 1444 14 194 14 1s52 18 dors 86 76* ]0" 6 | i oTveaTVTVrsauyuatsb,ibsscucu/ulEullaalpararrirdAAitHMdtrriyonionmpeperhhiasryyal liizzaattiioonn 114o 0 -B 22w2 o - - 220 6 18" - 6 -- - - I i Ovary CTCyuysostutlar Hyperplasia ThyTruobiudlar Hyperplasia B 0 -- 1133 - 0 Sw - 111 32* Le -- 1]88 - 14" Cel Thyroid BouC-Cell HHyyppeerrppllaassiiaa 2 2 0 0 2 2 77 1 2 I UPatCeCnycryusrsstetiaiccs GGllaannddss FE - 14 - - 1100 13 2 Sow24 I 1 SPaalAAnicccvirineanaraasyrr AAGlttraronopdphhyy Bo 13 12 222 9sw20 1o2n SaSliivaalarydenGiltainsd, Chronic 2 EC I i SSppllSHeeeieenannolsadiedneirtoisss, Chronic EI2 2 30* 5 27* 2 Hemosiderosis 32 50 44 24* 8* 6* B50 50 raturseusarous rats/sex/group were were aatt rriisskk,, % % vvaalluueess ddeerriivveedd romfrom actu actual ttiissssuueess eexxaammiinneeds I 1 * = SSiiggnniiffiiccaannttllyy ddiiffffeerreenntt (( == 00.,0055)) fron controls from controls i 1 se. 92. 11333377..00009966 3aMAcAo00c02277222211 i 1 1 1 2 2 27 . 1 4 . i dh N %} : 1!3 % 3 ' EY : 1 2 $Y -5m 1 & -m i E x ) i2 : #8 3 --& - 2 (swiouB) Blom Apog UDON i I i =.93. 1337.0097 3MA00027222 i i1roy 13 1 yd 1 ' 1I Ai Hd i I ; : f B1 5 1B 3 r I E HBpn 2 p 2 xB : * ! 2 ts ston gon I n i 1337.0098 ba . . 8 8 g% 23 2 :s : : : 99%4.. 3MA00027223 i i ns ; ; 1I ef 1 53 oo LI 1i ng ro i' g | |' 3 | 1 38 ||1 2 i LlL2 fr . A 8 4 . Ho J g i d3 gb f4 5 = :i 8 8 s (Aop/AmApoqBoy/B) uoydumsuod pooy 9955.. 1337.0099 3MA00027224 I i iI ny, I iI Z :I 2 [J i LI ' : i i 83 i & p i g 1I og BF 1 2 i 1 1a} axa I2 i : fr 3 5. f 3 3 Z A F . > ) i== 3 :. (kop/im ApoqByy/B)uoydumsuogpooy 1337.0100 3MA00027225 BI 1I 1I l 1 l 1 l 1 1l 1 TTWHOO YYEEAARR OORRAALL ((DDIIEETT)) TTOOXXIICCIITTYY // CCAARRCCIINNOOGGEENNIICCIITTYY I I 1 SSTTUUDDYY OOFF FFLLUUOORROOCCHHEEMMIICCAALL FFCC--114435 IINN RRAAITSS I APPENDIX ITEMS l 1l 1l 1l I i I i I i il 1 I 9977 11333377..00110011 pee 3MA00027226 I I I1 ronments Internal Co~,,~espondence i Appendix Item A Appendix Item A I ce pon geen rem F. D. Grlfflth- 220-2E-02 IL EERE, W. C. McCormick- 220-2E-02 1 we J. Ke suas = 220-28002 rc: J. K. Sugg - 220-2E-02 I ILE ER F. A. Ubel, M.D. - 22C-2E-02 I 1 Lo%r'-.5M.1DT.. SCOARSEENSO-N PIKMEERDILAALB,OR0ATDO.RIERSG.- S2E1R8V-.3S- 220-2502 I 1 S. D. SORENSON - MEDICAL, IND. HYG. SERV. - 220-2E-02 Ssee hArugMeont27s,ori1n9e0,3 Protest s5noni0T Air Monitoring, Project 89007107 3M I o Augustr 27, 1981 e 0000000m 00 5I mary A= nonttoring has beer. onsuctad tn hres animal srassaens Air monitoring has been conducted in three animal treatment 35 manisering hasSeun, conducias tn wires snined resen room used in fluorochemical studies. The purpose of the I Sop TL TIERCE rusian The puryofetnhee" monitoring was to evaluate possible airborne contaminants. The sample resuits tnsicate that fruorocnemont snpasurac, if The sample results indicate that fluorochemlcal exposures, if 5 Top timele mati ngieate hae2 any, were below detectable amounts. I I, Detail I. DBoEliIngIves EconduRenad iMn shLe thres anim ees, Air sampling was conducted in the three animal treatment rooms used in the two year animal feeding studyof FM-3924 and FC-I~3. The study has been in progress since April 21, 1981. I fren samples vere collects in oton of the several trestosnt Area samples were collected in each of the several treatment Boone iP hetgtat Sobbastad fnmashofthesevered srcurn 1 SSrKKoCoCms ssibiylliiccmeaaanggseelllofssaaemmipptllhiiennrgg Ittumubbpeelssn..gersWWiittwhhithoonneemeteehxxaccneeopplttiioomnne,,diassaamomrppllees I Teh fii Fel tewiing ruben:win one greeption, Sample were located on top of the animal racks. The one exception LEE mie of the anita reeks he oneshesption was an air sampler located near the room air exhaust near the 1 Ha Mr reer dosaind rear tne eonaienters nea floor. The periods sampled are Judged representative of fie Te ne "usual" or steady state conditions. I1 TThHee.Flou iratne tof thhee asmammnpilee pumps vas checks spprestsately The flow rate of the sample pumps was checked approximately gue vas, cneckeuso every 30 minutes throughout the sampling period. I TThuen asiumreplleens evenre eannsviysed by ne Anaiiyteat Seceion of the 34 The samples were analyzed by ~he Analtyical Section of the 3M iedby oe draliyiaal sector of 1 aaCccecnctrrreeaddliittaaRtteiisooennarcaassh aLannaboIIrnnaddtuuossrttyrr.iiaall ThMHiyysgglieelnnaeeboLLraaabbtooorrrayattoohrraysy full bbyy tthhee I fooritierion oe, an Trseeieusypuone American Industrial Hygiene Association. I I 1 9988 11333377..00110022 wnongzrar 3MA00027227 I I I I Ii J Appendix Item A I I M. T. Case -2- August 27, 1981 I1 TTnee sIaPsRpia. resuiss tntcate that atrborne. consentrations of The sample results indicate that airborne concentrations of hat trierne sonceniraion the test fluorochemicals, if any, were below detectable TE EL Maen Tre Shots Sententnasion i pplooimttieetnnstt.iiaall Onbbyy thaaiiisrrbboobrrannseeis,mmeeaainntss isiiss Juuunndllgiiekkdeelltyyh..at cross contamination I Fiease call of there are any ussstons. Please call of there are any questions. I1 /0 Aeron Ii Ea SDS : c r I I I I I I I I 1 9999 11333377..00110033 awncoozrze 3MA00027228 | | i APPENDIX ITEM A APPENDIX ITEM A |1 wT. cane = M. Y. ~ase -3- i 1 BPBSsruaauoimmfjlppaedllicieentnggDDaastcm2saa1i0880--333ic7 i RPorgojueecst7,#891098013107 August 7, 1981 AruoggUuset 2277,, 1I0~0821 1| osNuSuasmmhbpeelrre DDeessccrriippttiioonn TTiimmee Compound Concentration, ng/a | 1 CIAL CCL81-20 SDDo-33p4400o..f zCaCcookmn.etrrooll fom, meus 922-1225 mesa ~cm~ound FM-3924 Com Concentration, mg/m3 < 0.003 top of rack. 1 oCL81-23 SSaammee aass aabboovvee 992222--11222255 rFeC--114433 o.oo | SA pa pede, dose mess mesa Coon D-332. FM-3924, dose 1 pind Rom. Sample on top of Room. SampZer on top of 926-1236 FM-3924 <0.003 high dose rack. | 1 CCCaL8s1-s25 rpCoDe-ou3aum3rst2.rfooT8~osmmSaeiamanmAtpcprxlheeerreesxxhasamhactuousvstet toss 1055-1236 FmMw-3a92s4 <C0o.o0n2s5 | re) about 18 floor. inches above | cmz CCL81-22 RobRDof-ooe3mm3i...8s.hsSFadraCmomes-ppe1lls4ee3rrr,,acookndnd.oosstteeoopp ses ren Loco 8 comes CCL81-24 of high dose rack. GSsapemmieescaaaesteCcCcLus8ma1im-ep2aaz2s,, sam 925-1228 931-1228 rn FC-143 PC-143 Coo < 0.001 40.002 | Sdusuaipnnlggicaastiiellis=csanampggelelel ttuubbee.. | 1 SNPLING METHOD: SAMPLING METHOD: FFTM1H--3439932244 SSmKEmCEptnasgsieiliirccaa= nggeeetl)hassnaaommrpp.lliinngg ttuubbeess.. | 1 AALYTICAL ANALYTICAL FC-143 ~pinger - methanol. ~M-E~TAH~HOODD:: | FFFMOH-1-3639392'244 = - gdgaeasrsivccahhtrrioczmmaaatttiooogsnre;aapphhsyya,,s ceehlleeeeccmttarrtooonngtccaaapppnttyuu,rreesdldeeetctet~crttooonrr..sapture FC-143 - ddeetreicvtaotrl.zatlon; gas chr~-~_tography, electron ~aptu~e | 1 rTICNL Regus 180246. detector. | ANALYTICAL REQUEST: #A80248 . | | | 1 100 11333377..00110044 aMA0c27229 3MA00027229 I B i IInntteerrnnaallCCoorrrreessppoonnddeennccee B h ApPENOIX ITEM A APPENDIX ITEM A B1 -- 5 L. 3. S ibinskl Fem 3. . ommsen Frem: J. D. Johnson I Sout Subject: LAAinnatalhlyysTsiuisos YooeffaPPrllTaaosmmxsaStSSuaadmmypp-ilReeasstsffrroo(nmniSSkeeenrnttilSnneaaaldlyRRNaaott.ss H0H3oo9uu1ssCeeRdd00ii1nn2)RRoooomm 3M !i---_-- Cae October 7, 1385 with Two Year Tox Study-Rats (Riker Study No. 0281CR00|2) Date: October 7, 1985 I1 have attached the one pape roteset asachmen x che us of i assIcCteeootnnhllatatllcivieehnencceeattdlleea)ddtrr~aaavactssethsraeedddiieennsstccrtrrRRhaiiienibbkseeetoksdrno..erSrStpetOaaOdundgndyeytJJoWuNp~oloVry...yotFOo01132ca5o,,R8ohI1laCC11pRRa99rO080taO011tg1T~,aa2Ec..dfo~aoresrnTT(y~hthooer.ssppfeeloaVarv)sssemutasamhibpenllsseeCueasnosnmmeppmvwileeeeeorsrsrfceei((assleeee I 1 baSCaChtihaaetie~kast~oiochcb~naeay.ldi)ssDDre.,wFffeoroVrrorem8a8a//ntnt32ahra44ila~/s/yns,28ssi11if..sseLrtrooAAcfefLladlLnoorrtssgogbaaaaamVnnb.pciillocceenPsscofFltlluvwhuudeeaooerrrrpiiedernnaeegJlh..aueasdstssa.TThhtht(eehhDeaarr.nnFroeeVoons)wnnteeeetisistppnaanrrovCweeteorrmae~pemi.oesrrrbssoceerinnnattel I ~f(Fll12uu15ooi0rro%iinnn.eeNorpparrFveerossooeemknnttth3i0tts5hh,3ea1tt,twwteassc.a53nAi.nntbteaecrffceeorrniicnnlggudwweiidtthhthtathhtiissthssettruueddyyw..as TTnhhoeessaeeirddbaaoct~eaeaarree in SJG Notebo~ 56531, p 53. I I 1 RaRRi~amksreeesrasrrTce0.ahhbohSrg.a~htdocoodrienainiealisiss,tt Tne. Riker Laboratories~ Ino. I l ! I I l 1I 110011 11333377..00110055 awacoez7z20 3MA00027230 R 1 Appendix trom a Appendix Item A B . Internal Correspondence Internal Correspondence I 1 cer mMW.TT!.. cGCaaessieettien FR.ED.. Ober Griffith B i RIAL wRi.lE.. W.LI. Prokop Opbeearrlson Pearlson 1 r -R-_._A. m Pr""ok~ op-- .... -'__ o-- q|l~~- _3_% B oTo:v.V. pPoottnhaapprraaggaaddaa i vm 3 stent From: J.D. Johnson I Sowct wAAinntaahllyyssIiivsso YoofefarPPllTaasosmxmaaStSSuaadmmypplleeRssatsffrro(~mRiSSkeeernnttiiSnntaauldlyRRNaaott.ss HH0oo2uu6s1seedCdRiin0n01RR3oo)co.am B ove: Jwuiltyh T1W5,o Y1e9a8r1 Tox Study Rats (Riker Study No. 0281 CR 0012). July 15, 1981 B 1 | iI . n 1 I R11 i FaFoonrrattlyyysippsll.aasssmTaahesssaamemppllseeassrplfferrsoommissneucnnlttuiidnneaall5 mrraaatltsse aa(rcIeeR ss3uu86bb1mm,iittttIeeRdd36ff6oo3rr, ffllIuunoorr3ii3nn63ee, 3IaInnnRdal33y88Ts66Ri44,,s4.92aa5nn)TddhewITshRneic33h88s66a55wm))eprleeaasnnddsaicn55rcilfff~uemidmacea_ellde5e mb((aeIIlfRReor44e99(22I11dR,,os3i8IIn6Rn1g,44w99a2ZI2s2R,, 3iI8In6RRi2t,i449a522tI33eR,,d.3I8I6Rn3T,h44e952244,, otaStnthhdaeertrtIeRdtt.h4h9ii2rr5Ttt)yyherpwpehlliaacssahhmraaewess5raaemmrppalltseesasscrowifwefoirreceeaecdhccoolblsleelxefecoctrtfeeerddomdoaastttihne33g0bcwddoaaansyytssroilaancfitttroeoirroamt,edddoo.ssfiirnnoggTnhe stittnhhaeerwthrreioodcoo.hmm siinTnthuwdewyhrhieirccahhatrsessttauu5rddeyyratrrcsaaettcsseofivaairreneeagchrfFeecsc3eeexii9vv4iifnnr.ggomFFCCt--h11e4433c,,ontaarnnoddl ffrrroooommm,tthheefrorrmoooomm in which study rats ane receiving FM-3924. The numbers for these rats are as follows: $5 mmaallee CCoonnttrrooll RRoooomm((IIRR 23886666,, IIRR 33806677,, IIRR 33886638,, IIRR 33886699,, IInR 32867700)) 55 ffeemmaallee CCoonnttrrooll RRoooomm ((IIRR 449922~6,, IIRR 44992277,, IIRR 44992288,, IIRR 44952299,, IIRR 44993300)) 5 male FC-143 Room (IR 3876, IR 3877, TR 3878, IR 3879, TR 3840) 5 male FC-143 Room (IR 3876, IR 3877, IR 3878, IR 3879, IR 3880) S5 ffeemmaallee FFCC--114433 RRoooomm ((IIRR 44993366,, IIRR 44993377,, IIRR 33883388,, IIRR 33883395,, IIRR 33884400)) 55 mmaalleo FFHM--33992244 RRoooomm ((IIRR 33868966,, ITRR 33888877,, IIRR 33088888,, IIfx( 23888899,, IIIi~ 32085900)) i S5 ffeemmaallee FFMM--33992244 RRoooomm ((IIRR 44994466,, IIRR 44994477,, IIRR 44994488,, IIMR 44994499,, IIRR 44995500)) I ] PtPlhleeaas~rseeesgugleetttsbbwaaicclkklttooLeauudss wwtiiot%hhspe~thcheeifiddaacttaaa..nalyIItstismmaayyofbbeetot~ahhnaaattlyiisnnittseerroppfrreetttiaasttsiiuooenn: ooff ~he results w~ll lead to specifc analysis or to analys~s of tissue. IB Suan .- i 5. JoRgaon/mno - I B 1 110022 11333377..00110066 aMAc0c27231 3MA00027231 i I1 Appendix Tenn Appendix Item B CCD ANALYTICAL REPORT #213 i i 1 n1 --_-- | 8 CREEDEN\0C59E fom Fro~ P. J. Colbert - 236-28 SSuubjerc"l inGPS.tLLCCoJ.AAnnGaarCllooyyulssnbiidessrLtoao-bff C2FFh3MMo6--w-33.95222B44(Ri((kT1e--r2299S999t5CCuOodCCy)) fF0FCC2--811144C3R3O0((TT12--)22999988CCOCC)) BBlleennddeedd into Ground Lab Chow. (Riker Study #0281CROO12) 3 ueDa~e AApprriill 2299,, 11998811 7 Reference: RCCeooqmmuemersectriscaiall 17CC0hh7ee9mm,icica1al7lss080AA,nneal1yl7yt0ti3icc6eall LLaabboorraattoorryy Requests ~17079, 17080, 17096 | 1 WCCeootmmhemordceric#ai'alsl CC63hh0ee-nm0i4cic8aa1ll.ss AAG3nn1aa-l0ylytt8ii1ccaall LLaabboorraattoorryy Method #'s G30-0481. G31-0481 I i rCRehecofyee,fssryaaeeamanndlplcpoolelnneef;ggssromwowoiffittLh.hFFKMJff--o.o33uu992rS2r4i4bbbill((anWaWsnn..kkkRRi.. GGoErErnoLotFuFuOnOnd-SdS2EE0)LL)-aa8bbbb1lleCeCnhnfhdoodoewwreddassnaaiiantmmnytptsposoldlee.ssGG,rro,)uunrgAwe1re1 Tab n _sarnepcloerddyefrreomruLn. Ji.n tSriibpinlsikcieteo.n 4T-2h0e-8r1esuflotrsanaralys . All sample~ere run in triplicate. The results ~ Compound Theoretical AAvcactltueuaalmppsapr~e 1 ~BClaonmk_po_fuonrd co~n~ cen"~dgte T__heoretical__~_ ug/g FN,-3924 | BFF.I-(.lI.3ba-5l~38e9_2n24d4~eod[CCoo4nnc-cco1ee7nnn-ttc8rr1eaa)ttneet~~ ~ 220000 0 221s4 - (blended 4-17-81) 1i Pre3524 Top Sample 100 105) oo FM-3924 Top Sample I00 Mid Sam I00 n BBoottt:op Samp>ilee 10 i FFHM--33992264 SSaamrppllee 30 30 i HMiidd SSaammppllee 30 30 1| Sottan Sampte Bottom Sampl e 30 F-M3-9392244 TToopp SSaemmppllee 10 I0 |i wid Same Lo s\e BBMooitdtttooSmnamSSpaalmmeppllee I0 10 I0 \- 105\ ~ 1 05 ~/~,~ mIII / 2299 2277 \srEH 30 ' n 1ha 11333377..00110077 110033 m3MAcAo00002277223322 i 1 AepENDIX 178M 8 APPENDIX ITEM B i L. L, 3. J, SSiibbiinnsskkii i ACCpCCrDDilAAnnaa2ll9,yyttii1cc9aa8ll1 RReeppoorrtt ##221133 n -- a APPpaarggieel 22-- 29, 1981 r-- ee ----p ener | i 5~'~Compound Theoretical opn (AAuccstt/uugaa)llE pppmm _J~ Com~d Theoretical ppm {ug/g) F_]~4 | 0 1 Bllaannkk f for 30 poo n lov~ e>< I Blank for1s0pe-tevel 0 i i aTsoTacvheeclkeodf eatnhdanfoolundintoFH.b3e52l4essContcheanntr1atpepm((bulge/ngd)e.d 4-17-98) yaswa s . | i SSBiilxxankssaammGpprlloeeusnsdooffLabFFCC--C11h44o33w sbballmeepnnlddeeesdd wiienntrtooe ~GrrreoocuuenniddvedLLaabbfroCCnhhoowwL.,. aaJ.lloonnSggibwiwniisttkhhi ttwwoo 1 oobTnnhlean44/k/r,2e20sG0/ur188lo11utnsdffaoorrrLea:baannaaCllhyyosswiisss..amplAAlellls wsseaarmmepplleerssecweweievrreeedrruufnnromiinn L.ttrriiJ.pplliiScciaabttiene,ski The results are: | 5 Compound Theoretical pps (AAuccgtt/uugaa)llFe-pp1pom4n3 Compound Theoretical pp~a (ug/g)FC-%43 n FFCC--114433 TToopp SSaammppllee 330000 32266 i MHiidd SSaammppllee 330000 2w8e2 | BBoottttoomm SSaammpplle 300 297 300 297 i1 Stank for 300 pm Tevet 0 > Blank for 300 ppm level 1 7FC--114433 TToopp SSaammppllee 33O a24 i HMiidd Ssaammppllee 330 a 1 BBoottttoomn SSaammppllee 3300 28 1 I BBllaannkk ffoorr 3300 ppppmm leevveell 0 BR0 I1 Because tuo of the three 30 pm Tove) samples were Tou, another | |) 1 Bssfeeeottcrauooasffnealssyaatswmmioppsll.eeossf wTtwheheerereetrhrrereeseccueeelitivsv3ee0ddarpepff:mrroommlevLLe..l JJ..samSSpiilbbeiisnnsskkwiiereoonnlo44w//,2377//a88n11othe(r'.i...~"~ | for analysis. The results are: ~ ~. ! i I i 110044 11333377..00110088 3MMA0A000002277223333 n APPENDIX ITEM B i Lg. sibinski L. J. Sibinski CCD Analytical Report #213 i fori 3 1581 April 29, 1981 1 Beds Page 3 B 1 Compound Theoretical ppm AAtccittauiraoaln) ppBpomnes Compound Theoretical ppm (ug/9) FC-143 I Fe-143 Top Sample 50 a, FC-143 Top Sample 3O 31, I sotton sample 0 Mid Sampl e 3O Bottom Sample 3O \., 'q .. w28 l I .Blank for 30 ppm level 0 1R LissonModsA]AS " LJS/mao 1 cor wT. fa=s213e02 cc: M. T. Case - 218-2 B EC Camprecht - 218.3 E. G. Lamprecht - 218-3 WE MTEC Shocte-oz i WJJ... DCD... MLLcaaCZZeoerrrtmteeick-- 2-233662--2I10LL-2E-02 [ra R. A. Prokop - 236-2B i [RR V. Pothapragada - 236-3A H B n B | B R I B i 105 11333377..00110099 swao0027234 3MA00027234 | | 1 | i 1| |RB i | i| 1 || Fr 1| i| | 1| I| i| | | | 1| AAPPPPEENNDDIIXX 1T7EEMM BB InIntteerrnnaall CCoorrrreessppoonnddeennccee dei MT. Case dc: M T. Case Clie E G. Lamprecht 300] Lazerts J D. LaZerte WoC McCormick VWV. CPPo.otthMhaacppCrroaarggmaaiddcaak RR. AA.. PPrrookkoopp LID Winter L D. Winter 216-2 216-2 BOS218-3 2361 236-I 220-26-02 220-2E-02 223366--33AR 223366--22B8 236-28 236-2B a beard CCooimnueKr~crciiaal1 CChheevmscicaallss Ez Analytical Report i~229 TToo: FFreo~m: SSeuebejecctt Dale: ,~LL.. JJ.. Sibinski PP..JJ.. CCoollbbeerrtt 221188--33--33 223366--228B Into Ground Lab Chow (Riker Study f0281CR0012) GGLLCC AAnnaallyyssiiss ooff FF'MM--33992244 ((TT--22999999 CCooCC)) FFCC--114433 ((TT--22999988 CCooCC)) Into Ground Lab Chow (Riker Study #0281CR0012) JJuunnee 1155,, 11998811 BBlleennddeedd SRAE ALSSLIaiiaTxbxb All SssCsCaaahahmmmomopppwpwlllleeeessssssaanmwpwpooelelfferersseeFF,,CC--rrww1u1uenn4e4r33reeiinnbblrreeettnccrrdeieispeiillvdviieeccddiaantttffeeorr..aoGmmroTTLL..uhhuenenddJJ..rrLeLeasSasSbuibiublblititCCnnsshhssookkwwsaii,,rree::ooaannlloonn55gg-116w8w.-ii88tt1]hh sa~ammppllee TThheeoorerettiiccaall pp.ppmn BBllaannkk ffoorr 330000 ppppmm : 0 0 forttwwoo for snalysie. bbllaannkk GGrroouunndd analysis. AAccttuuaall pppomn ~ sa/gg FFCC--114433 00 Hid 300 FC-143 Top 300 Mid 300 sotton 300 Ze Nas Bottom 300 BBllaannkk ffoorr 3300 ppppmm 0 0 1 / us303 0 -~.~i ~ ~~" '~ 239055 0 cow 0 = FC-143 Top 30 31 MMiidd 3300 phr,~. .::."L ( Nn Sotton 0 "=z Bottom 30 < 31 .... 29 TThhee nneexxtt sseett August 17, ooff GGrroouunndd 81. LLaabb CChhooww SSeammpplleess wwiillll bbee ssuubbmmiitttteedd ffoorr aannaallyyssiiss oonn August 17, 19 PaC:da PJC:da 1I0066 11333377..00111100 a3MMAAc000c02277223355 | i erGonespont | APPENDIX ITEM B | i ACCnooanm~lmnyeetrriccciiaaalll RCCehhpeemomiricctaall4ss350 Analytical Report #250 i LJ. To: L. J. SSitbblinnsskkld -+ 221188--33-33 1| om 5.0. Gatbrs - 236.28 From: P. J. Colbert- 236-2B | i Sct SublecI: GCGLLhCEowAAnn(aaRlliyykssetirss SootffudyFFCC--41104423381C((RTT0--022199299)3GCCooCC)) BBlleennddeedd iinnttoo GGrroouunndd LLaabb pCuhgouwst(R2i0k,er19S8t1udy #0281CR0012) SRE {3ale: August 20, Ig81 | I Reference: Reference: RCCeooqmmumeeersrcctiiaa4ll178CC4hh3ee,mmiiccaaanlldss CACAnDnaallMyyetttiihccoaadll 63LL1aa-bb0oo4rr8aa1ttoorryy i 1 SSStr11wioobxxinBsBsslalakamaminpnpkklleeossnGG~rr,AooooRuuffuengnqdduFuFsCeCt-sL-L1ata1bb441337#,CC1h7hbb4ooll14wwe5e96nn,1ddss.eeaaddmmappnflldonieerntsstCo,,oaCnDawwGGleerrMyrrooeseeuutinnhsddorr.deeccLLeeaaGifbbA3Ivv1Tee-CCdd0hh4oos8wwaff1,,mrropomnraaellsoo1L..nnggweJ0.rwweiitthh | i sample Theoretteal spn rrSuuinnbiniisnnkittrriionpplliiAccuaagttuees..t 17TT,hhee1rr9e8e1ss,uullttfssoraarraeen::alysis. All samples were AAuccatt/uuaaallFepCpp1pma3 ~.ample Theoretical ppm ug/g fC-143 1| Sank for 300 ppm o 0 Fe183 Top 300 Blank for 300 ppm 0 2{ FC-143 Top MMiidd 333000000 | Hm = BY Bottom 300 30080 8. ... 33100 - + 328 | i BFBllCaa1nn4kk3 ffoorrTap3300 ppppmm FC-143 Top 000 1 MBMioiddtton 3033000 Bottom 30 1|| wesmo {el Golf--o 1 do: MEM.TG.T. 3E.00G.. LLLCCaaaaaznssmeepeprrrtae--ecchh22tt11+ 88--2-- 223226111880--33 | 1 WJHV..,.CCPD...otHMhLecaaCCpZoorerrarmgmtaeiidccakk- 2--- 322623-206I0-.L-2326AE--0022 VRo.AP.otPhraopkroagpad-a 23- 6-22386-3A | 1 RGRRLL1...OOAMWWD.... WWPKPPiiiaranryoyntskfftecoeeerhprrr----22233222366333.6-6662.2---8B32228B8B | G. W. KIrsch - 236-3A [00 I 0323080,. 30 ek | | 1 110017 11333377.0.10111 a3MMAAO000002277223366 R1 tcospniss Internal Correspondence n apemor 1ren 5 APPENDIX ITEM B B 1 AACNNOAAMLLMYYETTRIICCCIAAALLL RRCEEHPFEOoMRRITTCAL4#S328899 B LL.egJ.. SSIIBBIINNSSKKII -- 221188--33--33 1 ram Re Me PAYPER - 236-28 B n 1 SeosLTsAhBo R. M. PAYFER - 236-2B GLC ANALYSIS OF FG-143 (T2998 CHOGLWC : CHOW (RIKER STUDY ANALYSIS OF (RIKER STUDY 42081650012) FC-143 (T-2998 #2081cR0012) CCooGO))BBLLEENNDDEEDD IINNTTOO GGRROOUU3 NNDD M ~te: fovemver 30, 1981 ~ November 30, 1981 i i RReerfeerreennceeesss: GCoonmmmeerrcciiaall CChheemmiiccaallss AAnnaallyyttiiccaall LLaabboorraattoorryy Request #17779 n SSSiiuxx SssTaaammtppklleessgrooouffndFFCG--LI1aR4qbe33qcuhebbosllwteenndd#seea1ddm7p7l7Lie9nnstt,oo bggerrrooeuunnddreclleaaibbveccdhhoowwf,,romaalloobnneggd:wwiitthh i i Ten In Crip ioate with the following resuiis: tSSwiiobbiinnbsslkkaiinkoonngroNNuoonvvdeemmbbleearbr c11h66,,ow 11s99a8811mplffeoosrr, aawnneaarlleyyssiirsse..ceivAAelldll fssraaommmpplleeL.ss wwJ.eerree rSuenmpiien triplicate wTihtheotrheetfioclPlaoPlwMing resAuclttusa:l pew Sample Theoretical PPM Actual PPM i i Blank for 300 0 uugg/g/g 0FFCC--I1q433 II Beng, 2 2 . "oat Blank for 300 PPM FC-I~3 Top 300 300 i0 278 Middle 300 310 BBoottttoomm 330000 332233 B 1 BBllaannkk ffoorr 3300 PPPPMM 00 FEST, % FC-143 Top 30 MMiiddddllee 3300 1 Botton 30 Bottom 30 B1 apne RMP/hc 0 0 8 . 29 2288 333 nii Kde sMT. Case -AL212-2 GG.. WW.. KKiirtsscchh-- 223366--33AA Eom E. G. Lamprecht- 218-3 | 3.0. Lazerte - 236-1 J, D. LaZerte- 236-I U8 Wormick 2520-26-02 W. C. McCormick - 220-2E~02 5 UC Pothapregades 236. V. Pothapragada- 236-3A RR.. AA.. PPrrookkoopp-- 223366--22B8 B L. D. Winter - 236-2B8 (2 copies) I B 1 110088 11333377..00111122 swac0027237 3MA00027237 | 1| J, APPENDIX ITEM B | i iInntteerrnnaall CCoorrrreessppoonnddeenncte, I 1 ddec:: MGMGo..1TTWW6..... CCKLKaiaaisrmrsespsecrc-he-hc-h2=211~5_:.(33262-6'-.'~ 3 I J3WE.0L.0CDG.... LLWLaeaaZCmeeoprrmrttmeeeicchk--~--223362~.2-0-2-02 W.C. McCormick - 22G-2E-02 1| - othaprasads = 55.38 LV.D.PoWtihnatprearga-da236--22336-3A 1 i TTo:L.L. JJ.. SSIIBBIINNSSKKII -- 221188--33--33 . ACCNOOAMMLMMYEETRRICCCIIAAALLL CRCEHHPEEOMMRIITCCAALL4SS319 ANALYTICAL REPORT #319 i i Da Cron (kiien arin 2661 58 B19) i I -_-- FFrloomm: RR.. MM.. PPAAYYFFEERR -- 223366--228B Sioct GLC ANALYSIS OF FC-143 (T-2998 CoC) BLENDED INTO GROUND oe MARCH 5, 1982 GLC ANALYSIS OF FC-143 (T-2998 CoC) BLENDED LAB CHOW (RIKER STUDY #2081CR INTO GROUND 0012) MARCH 5, 1982 35 & i RReeffeerreennccee:: CCoommmmeerrcciiaall CChheemmiiccaallss AAnnaallyyttiiccaall LLaabboorraattoorryy RReeqquueesstt ##1188006699 Ii SSiixx ssaammpplleess ooff FFCC--114433 bblleennddeedd iinnttoo ggrroouunndd lTaabb cchhooww,, aalloonngg wwiitthh ttwwoo | Blank around 1ab Chow samples, vere received from LJ. Sipe on 1 wbFFileetabbnhrrkuuaatrrhgyyerou1f1n55o,d,llo1l199wa88bi22n.."gchorwTTehsheueslssateemsp:lsseaasmm,pplleewsserewweerrroeecaeaninavaelldyyzzeefddromiinn L.ttrrJii.pplliiScciaabttieneskffioorr onFFCC--114433 with the following results: | SaSammppllee TThheeoorreettiiccaall PPPPMM Actual PPM ug/g FC-143 4 |B || re , oat 30 po Mice 0 Blank for 300 PPM 0 333000000 PPPPHM PPM TToopp Middle 330000 300 1 333000000 PPPPPPMMM MBBioodttdttlooemn 303000 BBllaannkk ffoorr 3300 PPPPMM 3000 i 3300 PPPPMM TToopp. 320 0 30 PPM Middle 30 1 20 pm otton 5 a cl 30 PPM Bottom 30 (es. ra i as Aas J) TerA 0 2By ! N||n Aion ot RRUMPP::adff Y/ | | 1 110099 3133377..00111133 3mMAcA000002277223388 i 1 nena Correspondence | Internal Correspondence I i AvAePEPEwNDDIIXX ITTEEMM5B ||1 LO. SIGNS - 218-33 AcNoAmLeYTRIcCAALL RCEHPEOMRITCAL#S328 ~. J. SIBINSKI " 218-3-3 COMMERCIAL CHEMICALS ANALYTICAL REPORT #328 i wa oa + Tn Fro'n: R. M. PAYFER - 236-2B I 1 S~ubjjeecct~:: GGGGLRLRCCOOUUNNRRDDEE--LLAAAANNBBAALLCYCYHSHSOIOISWHS OO((FFRRIIKKFFEECCRR--114SS3TTUUDD(YYT-##222900988811COCCCRR)0O0011B22L))ENDED INTO oeDate: i wees 0 TF MMaarrcchh 3311,, 11998822 ME | i RReeffeerreennccee:: CCoommmmeerrcciiaall CHemicals Analytica]l Laboratory Request #18110000 i TThhrreeee ssaammpplleess ooff FFCC--114433 bblleennddeedd iinnttoo ggrroouunndd llaabb cchhooww,, aalloonngg wwiitthh oonnee i Blank ground 1ab chor sample, were received fron Lo J. Sipineti on arch blank ground lab chow sample, were received from L. J. Sibinski on March 88,, 11998822.. TThheessee ssaammpples were analyzed in triplicate for FC-114433 wwiitthh tthhee 1 Torlowing rosettes following results: | sample Theoretical ppH Actus) PPA ug/g Fe-143 Sample 5 Ti fo 0 om , 2 Blank for 300 PPM I 555"bon Ton a0 a, 333000000 PPPPPPMMM MMTiiodpdaGllee 5 300 pom Bogion 30 EH / 300 PPM Bol :om Theoretical PPM 0 333000000 30O Actual PPM ug/9 FC-143 0 23278 283 ~ ~' 284 |i he a RMP/hc i oc: MW. T. case - 218.2 i MGG... WWT... KCKaiisrtesscch-h--2122833-626--33AA | EE.. GG.. LLaammprecht --221188--3 500: Laterte = 2361 B J. D. LaZerte- 236-1 WW., CC.. MMccCCoorrmmiicckk =- 222200--22E--0022 V. othapragads - 536-34 V. Pothapragada- 236-3A | LC 0 Winter = 236.28 L. D. Winter- 236-2B I i | | 1 110 11333377..00111144 swac0027239 3MA00027239 i I -- Internal Correspondence B.I -- APPENDIX ITEM B 1 CCOOMMMMEERRCCIIAALL CCHHEEMMIICCAALLSS ANALTYICAL REPORT #340 I1 ge du SIBINSKI - 218-3-3 218-3-3 B R. M. PAYFER - 236-2B 1 Fume GGLLCC AANNAALLYYSSIISS OOFF FFCC--114433 ((TT--22999988 CCoocc)) BBLLEENNDDEEDD IINNTTOO GGRROOUUNNDD .I- Sar a ten ooo 30 ae MMaayy 2288,, 11998622 LAB CHOW (RIKER STUDY #0281 CR0012) k Reference: Commercial Chemica|s Analytical Laboratory Request #18320 R i SSiixx ssaammpplleess ooff FFCC--114433 bblleennddeedd iinnttoo ggrroouunndd llaabb cchhooww,, aalloonngg wwiitthh ttwwoo bbllaannkk ground lab chow samples, were received from L. J. Sibinski on May 17, 1982. These samples were analyzed in triplicate for FC-143 with the following results: :i teSample B Blank for 300 PPM 300 PPM Top 1 300 pow widate 300 PPM Middle 300 PPM Bottom n Blank for 30 PPM 3300 PPPPMM TToopp Bo Shi. 30 PPM Middle II1 lim A 30 PPM Bottom meen Theoretical PPM 300 300 300 2300 0 3300 30 30 wl Actual PPM ug/9 FC-143 3215000 . 280 i. 289, 0 3311 33 33 dc: M. T. Case - 218-2 G. W. Kirsch - 236-GB I E. G. Lamprecht - 218-3 JJ.. DD.. LLaaZZeerrttee -- 223366--I1 W. C. McCormick - 220-2E-D2 I VV.. PPootthhaapprraaggaaddaa -- 223366--GGBB L. D. Winter - 236-2B ! I I 1 I1 II 11333377..00111155 3MA00027240 I IiI I APPENDIX ITEM B I 1 I TL. J. SIBINSKI - 218-33 ANAACCNNAOOAAMLMLLMMTTTEEYYYRRIIICCCCCIIAAAALLLLRERCCEPHHPEEOOMMRRIITTCCAA##LL33SS665 REPORT #366 L. J. SIBINSKI - 218-3-3 i Fon RR.. MM.. PPAAYYFFEERR -- 236.28 236-2B I 1 Sect Subject: owe SGGeLLpCCt.AANNA1A3LL,YYSSI1I5SS82LOLOAFAFBB FFCCCHH--OO11W4W433((RR((IITTKK--EE22RR9993SS88TTUUCCDDooYYcc))##00BB22LL88EE11NNDDCECERRDDO00OII11NN22TT))OO GROUND GROUND Date: Sept. 13, 1982 i RReeffeerreennccee:: CCoommmeerrcciiaall CChheemmiiccaallss AAnnaallyyttiiccaall LLaabboorraattoorryy RReeqquueesstt ##1183660099 I i f1gFSfS9ooiraa8rlxogi2tluss.eonrsawdamimpnplTliTglaaaehelbbessIreseseccosoehhuffolosstwwaaFFsmmCC:pp--ssll11aaee44mmss33pplleebbwwssllee,,eerrnneeddwweeeedadarrnneeaaIillnnrryytteezzoocceeeeddggiirrvvooieieuunnddnnddfttfrrrrlloioiaampmpbblliiLLcccc..hhaaoottww3Jee,,.. ffaaSSoolliirroobbnniiggnnFFssECkkwwL-iiii1Ltt4ehh33oonn ttwwwwhAiioouutcgghh..bbllstaa1tnohn6okesk, following results: 1I ctu oon saSammppllee I i 3BB0ll0aannkkPPuffooTrrop330000 PpPuM I 1 B33333l00000a00000nkPPPPPPPPPAMMMMUforBMTMBoooiipttd3dt0tddoollmmeePP 333B000lanPPPkPPPMMH fMTToioorpdpd3l0e PPM 3300 PPPPMM BMoitds,dle 30 PPM B~ott~m Rul JB i Rb7he TThheeoorreettiiccaall PPPPMM 30000 333000000 330000o 330000 333000 uugg//AggctuFFaCel--114P63PM 3000o 333101309 304 . 3209400.5 29.5 335 2.5 2g. 5 + i des WM. T. Case - 218-2 G. W. Kirsch - 236-8 i== JEE...DGWG.... WJ.oCD.. MLLKLLcaiaaaCztmnZoespperrcrrrmhteetiecccehh-kt-t- 2223---33666-222--G211110B88--.3236-02 VW..CP.otMhcaCporramgiacdka _- 223260.-G23E-D2 LLVo.. D0P..otWWhiainpnrttaeegrra-d-a 223-366-2-232B86-GB 11333377..00111166 112 M3MA0A000002277224411 | | InenalConespondence Internal Correspondence ||a SEES APPENDIX ITEM B i 8. L Sbinakt = 218:3 % N. L. Slbinski - 218-3 | Fm 5s e Wires = T0 F,o~n. G. W. Kirsch - 236-28 CrCoovmmrmmeeirrccciiaaa)ll CCShhoeepmmeiirccaallasss Analytical Report #384 i Sublect: GLC Analysis of FC-143 (T-2998 CoC) Blended into C~-ound Lab Chow (Riker Study #0281 CR0012) Date: December 8, 1982 | Ratarences Commercial Crenicala Analytica! Laboratory Reference: Commercial Chemicals Analytical Laboratory Romans Thos Request #18855. | Six samples of FG-143 blended into ground ab crow, along wth vo Six samples of FC-143 blended into ground lab chow, along with two blank ground lab chow samples, were received from L. J. Sibinski on | Beran 3, 1583. hose angles re. cnstyied 1m $1aT oo for December 5, 1982. These samples were analyzed in triplicate for FET te Ciot roves enue: FC-143 with the following results: 1| ferust oom Actual ppm sonpie eoretical on aes i Stan for 300 pp 0 0 Sample | B33l00a00nkppppmmforTToopp300 ppm Theoretical ppm 3300000 Mgig FC-143 323, oe 00 Too tin whate Bw 300 ppm Middle 300 1 2 ne = # 300 ppm Bottom 300 | FE em > 5 Blank for 30 ppm 0 Soon To Be ee i 533000 pppppommm MMTiiopddddllee 353000 32 wb < | 30 5m Bottom 3 Be 30 ppm Bottom 30 |1 GGrekn GWK:ch 1 NT CC : M. T. Case - 218-2 | 3 Compan at-3 E. G. Lamprecht - 218-3 55 mee en B WWJ.,. CCO.., MMLcacCZCoeorrrmmteiicckk- 236-1L -= 222200--22E | 5 Fier Sse R. M. Payfer - 236-2B Votre Bea V. Prothapragada - 236-G8 1| be L, O. Winter - 236-2B 1I 13 113 11333377..00111177 awncoozrzez 3MA00027242 1iI tc Internal Correspondence I 1 aeeEvOX TEN 8 I APPENDIX ITEM B 1 | To wk. STBINSKI 3218-3 BBo omen Fro'n: G.W. KIRSCH- 236-2B ACCnooammleymrtceiriccaaialll CRCehhpeeommritcicaal#lss335 Analytical Report #395 Seiect Subject: i Due MGGLLACCRCHAANNAA7,LLYYSS1II9SS83OOFFRROOFFDDCCEE--NN11TT4433CCH((HOTTOW-2259((99RR88IIKKCEECRoRoCC))SSTTUUBBDDLLYYEENN#DD#EE00DD228811II--NNCCTTRROOO000GG11RR22OO))UUNNDD Date: MARCH 7, 1983 SM .-I Reference: m CommeT rcial Chetmeiceals Ae nTalEytiTcal TLaborratooryeRqeque ueesstt O #111951122T 11 n i SSiixx ssaammpplleess g1g6rr,oouunn1dd983ll.aabb ooff FFCC--114433 bblleennddeedd Tcchhheooswwe sssaaemmmpppllleeesss,, wewwreeerree iinnttoo ggrroouunndd llaabb cchhooww,, anrraeelccyeeziievvdeeddinffrrtoormmipLLl..icaJJt..e aalloonngg wwiitthh SSfiiobbriinnssFkkCii-14oo3nn ttwwoo bbllaannkk wFFieetbbhrruuaatrrhyye f1f6oo,lllloo1ww9ii83nn.gg rreeTsshuuellsttess::samples were analyzed in triplicate for FC-143 with the 1I scat gon saSammppllee I 3BB0ll0aannkkppmffooTrrop330000 ppppmm B 333000000 ppppppmnm MMTioipddddllee 300 ppm Bottom B 3BB3l0l0a0apnnkkppmpmffTooorrBpot33t00omppppmm 1 33330000 ppppppppmmmm BMMToioitdpdtadollnee R 30 ppm Bottom TThheeoorreettiiccaall pppomn 300o0 333000000 3300000 33E00d0 333000 uAugc~t//ug9alFFCe-p11pe4m33 La00 '~ 2317 286 3322033 7 2 3020 3. 3a310 T 1 aGnWeK//nhec Andy ,~.],\/ " ~ I 1 ddeci: EMM..TG.T.. LCCeaassmeepre--ch22t11s88--22- 218-3 E. G. Lamprechts - 218-3 RWWl.oCKC... MMPccaCCyoofrremmriicckk 23--6.22222800--226E B J2.00D.. LLaazZeerrttee -- 223366--1I WLRW..LIDMHH... WPPPieaenayatrrfellerssroo-n-n-2-2336622--2222338B--56S5E L. D. Winter- 236-2B B B I B 111aA 11333377..00111188 M3MA0A000002277224433 I i 1I IInntteerrnnaall CCoorrrreessppoonnddeennccee 1 mmm ns . APPENDIX ITeM B IR1 errs cen ACnoamlmeyrtciicaa|l CRheepomritcal5s404 Analytical Report #404 1B TT i Fam G. Wo KIRSCH = 236-28 ]o ~L. J. 5IBINSKI -218-3 FrOm G. W. KIRSCH - 236-2B I SSuubjeectl. GGLLCC AANNAALLYYSSIISS OOFF FRFRCOCO-D-D1E1E44NN33TT CC((HHTTOO--WW229999((88RRIICKKCoEoECCRR)) SSTBBTUULLDDEEYYNNDDEE4#DD002288II11NN-T-TCOCORRO0GGD0RR11OO22UU))NNDD 3N Date HAY 2, 1983 I 1 RReeffeerreennccee:: Comercial Crenicals Analytical Laboratory Request #19333 Commercial Chemicals Analytical Laboratory Request #19333 B 1 SGSiirxxousnsaad~mnppTl]aete.ss g$5r8o5u."nd Arat cocof"hfhSooawrFFmCpCl--sse11aas44mm33ppllweeebbssrll,,eeennddwwaeeeenddrraeeliiynnrrztteeeooccdeeiiggvvrrieeoondduunnddtffrrrioorrmpnaalttiLLco.ccahhtoo0Je.wr.,, Saaillbioonnnsggkiwwiittohhn SfiobrinsFkCi-14o3n AtAtwppwwirrootiihllbbllaa1t1nn33h,k,ke i 1F9o8l3l.owingAllressualmtpsl:es were analyzed in triplicate for FC-143 with the following results: 1 sample Tneoretical pon Sample Theoretical ppm i I i BS3lt0aa0nnkkpomffoorrTop330000 pom ppm 330000 pppomm MToapde 3300000000 330000 ppppmn MBiodtdtloen 303300000 B B 3B3B0ll00aannpkkpmpmffooTrroBpot33t00omppppmn 000 30 ppm Top 30 3300 ppppmm MMiiddddllee 3300 i 3300 ppppmm BBoottttoomm 3300 AAsccattluueaallFepptopenms ug/9 FC-143 23800 3yo EA 3.0328 0 3344.42= --o" 3322 Rn1 adc:meMT.GiCnasne - 218-2 RM. Payfer - 236:28 dc: M. T. Case- 218-2 R. M. Payfer- 236-2B | B JJW... DDC... LMLacaZCZeoerrrtmteiec-k- 22-33662--2110-2 W. C. McCormick - 220-2E WWL... HHD... PPWeieanartrlesrsoonn- --232622-22338--66SSEE L. D. Winter- 236-2B B n | 115 11333377..00111199 amAooo27244 3MA00027244 1n I i opens reese Appendix Item C i TTwwoo YYeeaarr OOrraall ((DDiieett)) TTooxxiicciittyy--OOnnccooggeenniicciittyy SSttuuddyy ooff FFlluuoorrooccaarrbboonn i FC-143 in Rats Noraes ange Sor espetagts us Sond Sse Yes o Sas Normal Ranges for Hematologic and Blood Chemistry Values of Rats I at Riker Laboratories, Inc., St. Paul, M~ n1gee E rythrocytes B Hemoglobin SR 5,000,000-8,000,000 cells/cu mm 11-17 g/dl Hematocrit I MMeeaann CCoorrppuussccuullaarr VVoolluummee ((MMCCVV)) |JI Mean Corpuscular Hemoglobin (MCH) 36-52% 1003 picogeaen 5577--7777 mmiiccrroonnss3d 18-24 picosrams n a Mean Corpuscular Hemoglobin Concentration (MCHC) Leukocytes I Neutrophils 2-22% n nner oc50 Lymphocytes 65-95% Monocytes 0-5% n cn en secs 0 Eosinophils 0-6% Blood Urea Nitrogen (~JN) I Glucose gees Total Bilirubin i Total Protein Boe Albumin n Calcium 1B Aissine noteanstorase (iE) Alanine Aminotransferase (ALT) 30-34% tons,338 vss mm 6,000-15,000 cells/cu mm 500-4,000 cells/cu mm soo astern =n 5,000-14,000 cells/cu mm 0-500 cells/cu mm toes0-500 cells/cu mm 10-30 mg/dl orators 120-160 mg/dl 0.I-I.0 mg/dl -- 5.5-7.5 g/dl 3.5-5.5 g/dl 10060 tacammacionas omsears 10.2-12.5 mg/dl 10-40 International Units/l n Aspartate Aminotransferase (AST) Alkaline Phosphatase | i CCrreeaattilnnee PPhhoosspphhookklinnaassee ((CCPPKK)) 20-60 International Unlts/l 50-200 International Unlts/1 5500--115500 IInntteerrnnaattiioonnaall UUnnlittss//l1 I 1 111166 11333377..00112200 3MA00027245 I1 mmenes Appendix Item C l: Nethods Ted tox Resntotosy on siendings Methods Used for Hematology On Bleedings Ige Parame ters lI ec Hematology l fotad Eryshssoyies Lewkooytes Total Erythrocytee & Leukocytes i l -- Hemoglobin 1l ---- Hematocrit 1l stttaransins Differential ne Units coli/eubic a cells/cubic mm arg/dl ST % packed cells VIO WE %/100 WBC l 4% 3 and & Home at 3 and 6 Months _--Me thods Gouieer Counter node Coulter Counter Model FN CCoouulltteerr EElleeccttrroonniiccss Sg Hemoglobinometer, Model 231, Jee Sav Instrumentation Laboratories Microhematocrit Centrifuge, Model MB rEionat westrmns co. International Equipment Co. micxoscape suite Microscope slide l I I ! I I ! l l 1l 11177 11333377..00121 wnonezre 3MA00027246 | i| seo men APPENDIX ITEM C | METHODS USED 1F122O,,R H1188EMAAATNNDODLO22G44YMMODONNETTTHHESSR.MINATIONS FOR |1 HTHODS USED FOR CLINICAL CHEVITRY DETERMINATIONS FoR METHODS USED F33O,R,6C6,,LIN11I22,,CALI18BCAAHNNEDDMIS22T34RYHMOONNDTTEHHTSSE.RMINATIONS FDR I 1 bPPaearnraaamtmeoetlteoergrssy Hematoloqy B ErEyrtyhthrrooccyytteess B i HeHHLLmeeeeamuumoktkogooogclccyolyortbtbieeiitsnsn Hematocrit |i Differential Differential Unniittss #7100 vec cceellllss((]1O0~y//mmm3~)) 4gcoc//eeddllllllss((1100/%r/amm) % %/100 WBC Methods Methods aanndd TTeecchhnniiqquueess Microscope slide UUlltrtaraLlooggiicc 880000 HHeemmaattoollooggyy CCAllaAaBnyyeanclatAAylodydznaaz,emmesrrs,D, icDDkiiivvniisssiiooonnn &oofCfo. Becton, Dickinson & Co. Microscope slide i CChehmeimsisttrryy B 1 TToottBaallloodBBiiUllriierrauubbiiNnni,,iroGGglleuunccoossee mmgg//ddll i 5 AAAlllbbkBuualmnloiiionnnd~, UTrPToeohtatoaasllpNhiatPptrrraooosgtteeeeniinn AlkASaTl,ineALTP,hoCspPhatase g/I/nddtllernational UInnittesr/n1ational ~|, TRRrooattvooeccnhhoeelmn 3L356abI1oI1AarataoriIensc,. : Travenol Laborataories,lnc. AST, ALT, CPK Units/l | rinalysis Urinalysis 1n Scie Gravity 15 eter, 10 astra co. Specific Gravity BpHH,,GluAAcllobbsuuemm,iinn,,Scc8Bu1i1llitirruuBbbliionno,,d n aGannldducoKKseeett,oonneeOssccult Blood TS Meter, AO Instrument Co. ABBniiellsiiLLaaCbbossmttpiiaxxny Ames Company B H I n B iH 111188 11333377..00112222 M3MAA000020727224477 iB I 1 i| 1Ini AAPPPPEENNDDIIXX ITIETEMM DD 1 PPAATTHHOOLLOOGGYY RREEPPOORRTT OOFF RRATS B RECEIVING FLUOROCHENICAL FC-143 RECEIVING FLUOROCHEMICAL FC-143 i1 IW DIET FoR Tho YEARS IN DIET FOR TWO YEARS 1I | i 1| 1R a 1 iB iB i! ii B 1 1B B i 19 119 11333377..00112233 swao0027248 3MA00027248 I oo H B METHODS B Gross Patholo$~ All rats which were sacrificed at the 1 year interim or the 2 year termina! I sacrifice or which died or were sacrificed in extremis during the course of study were necropsied. At necropsy, an examination was made of the external body surface and body orifices. The carcass was then opened and the contents of the abdomen, thorax and cranium were examined in situ and after removal from m the carcass. Representative tissues and organs from each rat were fixed in 10% B bbuuffffeerreedd nneeuurtacll ffoorrmmaalliinn ffoorr ssuubbsseeqquueenntt hhiissttoollooggiicc pprroocceessssiinngg.. AAtt tthhee 11 aanndd 23 I year sacrifices, wet weights were obtained on adrenals, brain, testes, hearl, n kidneys, liver, spleen and uterus from 15 randomly selected rats/~ex/group. Body weights were obtained prior to necropsy from the same rats for calculation B I a of relative organ Histopathology weights. Microscopic examination was made of hematoxylin and eosin stained paraffin tissue sections of th~ following tissues and organs, where available, from all I rats from the control group (0 ppm) and the 300 ppm group which were sacrifice~ 1 aatt [Laanndd 22 yyeeaarrss oorr wwhhiicchh ddiieedd oorr wweerree ssaaccrriiffiicceedd iinn eexxttrreemmiiss dduurriinngg tthhee ccoouvrrseee H of study. n aorta adrenals (2) brain (3 sections including liver (2 sections) lung (2 sections) lymph node (mesenteric) fronlal cortex and basal mammary gland (females) ganglia, parietal cortex pancreas H and thalamus; cerebellum pituitary i eevyeess and pons) sssppaiilnniaavllaryccoorgrdlda//nbbdoonnee mmaarrrrccwu ((vveerrtteebbrraaee)) B gonads spleen ovaries (2) stomach testes/epididymides (2) R heart thyroid/parathyroid/trachea/esophagus urinary bladder small intestine (3 sections) uterus or prostate I i kKliiaddrngneeeyyssint((e22stssieencctetiioonnss)) aaannnyyy oottithsheserureggmrraoosssssseslleess(iisoounnssspected tumors) I Microscopic examination of tissues from the 30 ppm group included all the above listed tissues except aorta, brain, eyes, small and large intestine, lymph node and spinal cord/bone marrow. I B ! 0281CR0012 (FC-143) 11333377..001124 112200 aor 3MA00027249 BBn ees RESULTS I Gross Patholosy There were no gross findings suggestive of a compound effect in any rats i B ffrroomm tthhee 337~00 ppppmm ggrroouupp wwhhiicchh wweerree ssasccrriiffiicceedd aatt tthhee 1i yyeeaarr iinntteerriimm.. AAtt tthhee 22 year terminal sacrifice and in rats which died or were sacrificed in extremis I during the course of study (TS/DOS), possible compound related lesions included an increased incidence of masses, nodules or raised lesions in the liver, an increased incidence cf yellow or pale liver foci or lesions and an increased incidence of mottled livers and testicular masses in male rats from the 300 I ppm group. There were no findings suggestive of a compound effect in TS/DOS female 1 rraattss ffrroomm tthhee 330000 oorr ~200 ppppmm ggrroouuppss oorr iinn mmaallee rraattss ffrroomm tthhee 3300 ppppmm ggrroouupp.. I Other gross pathologic findings were typical of findings in ageing rats of i tthhiiss ssttrraaiinn.. TThheessee iinncclluuddeedd mmaammmmaarryy mmaasssseess,, ppiittuuiittaarryy ffooccii aanndd mmaasssseess,, uullcceerrss i on the hind footpads, pale livers and pale, pitted and enlarged kidneys. at Orsan Weights B There were statistically significant (p 0.05) variations in absolute and relative w<ights (organ:body or organ:brain weight ratios) of a number of i organs in 300 ppm group male rate sacrificed st the | year interim. Except for organs in 300 ppm group male rats sacrificed at the [ year interim. Except for I an increase in the liver:body weight ratio, these variations were not considered B ttooxviiccoollooggiiccaallllyy ssiiggnniiffiiccaanntt.. TThhee iinnccrreeaassee iinn lliivveerr::bbooddyy ~w,e~ieigghhtt rraattiioo ccoorrrreellaatteedd i with compound related morphologic liver changes. The mean absolute liver i n wweeiigghhtt aanndd tthhee lliivveerr::bbrraaiinn wweeiigghhtt rraattiioo iinn tthheessee rraattss aallssoo wweerree iinnccrreeaasseedd bbuutt not to a statistically significant degree. There ~ere no statistically significant I variations in organ weights in 300 ppm females sacrificed at the 1 year interim. None of the several statistically significant organ weight variations in rats sacrificed at the 2 year termination occurred in target organs or showed a I dose response; none was considered toxicologically significant. Histopsthology Compound related microscopic changes were observed in the liver of male i rats from the 300 ppm group at the I year interim sacrifice and in liver of 1 mmaallee aanndd ffeemmaallee TTSS//DDO0SS rraattss aatt bbootthh tthhee 330000 aanndd 3300 ppppmm lleevveellss.. TThhee pprriinncciippaall n compound related liver change was megalocytosis, which was characterized by an ! increase in size of liver parenchymal cells due to increased cytoplasmic volume. The increased cytoplasm was of a finely granular "ground glass" appearance. The coarser cytoplasmic organelles were relatively decreased and were displaced 1| omens (ro-149 i. 0281CR0012 (FC-143) -2- 1I B 112211 11333377..00112255 wnonezrso 3MA00027250 l l to the cell membrane. The nucleus:cytoplasm ratio was decreased by the increase in cytoplasm in affected cells. In affected livers~ most or all lobules were l i iinnvvoollvveedd aanndd tthhee cceennttrriilloobbuullaarr cceellllss wweerree mmoorree sseevveerreellyy aaffffeecctteedd.. AAtt tthhee i1 yyeeaarr interim, megalocytosis occurred to a minimal to moderate degree in 12/15 males i I ffrroomm tthhee 330000 ppppmm ggrroouupp.. NNoo ffeemmaalleess wweerree aaffffeecctteedd aatt tthhee i| yyeeaarr iinntteerriimm.. IInn TS/DOS rats, megalocytosis to a minimal to moderate degree occurred in 40/50 ! males at the 300 ppm level and to a minimal to mild degree in 8/50 females at the same level. At the 30 ppm level in TS/DOS rats, megalocytosis to a mimima! degree occurred in 6/50 males and in 1/50 females. In more markedly involved l livers, fhe megalocytic hepatocytes were frequently vacuolated with multiple small spherical cytoplasmic vacuoles which in life probably contained lipid. - l 1 LLiivveerrss wwhhiicchh hhaadd aapppprreecciiaabbllee iinnvvoollvveemmeenntt wwiitthh mmeeggaallooccyyttoossitss aanndd ccyyttooppllaassmmiicc vacuolation also commonly had focal areas of necrosis. This association of l hepatocyte vacuolation and necrosis with megalocytosis suggests that the progression of lesions is megalocytosis to fatty degeneration to necrosis. Incidence ! of hyperplastic nodules was also increased at 300 ppm, indicating regeneration also occurred. The association of hepatocyte vacuolation and focal necrosis with megalocytosis was more clear-cut at the 1 year interim than in TS/DOS rats l because of the normally higher background incidence of the former in older rats. Cystoid degeneration, characterized by areas of multilocular microcysts I B iinn tthhee lliivveerr ppaarreenncchhyymmaa~, aallseo wwaass iinnccrreesasseedd iinn mmaallee TTSS//DDO0SS rraattes ffrroomm tthhee 330000 ppm group. Incidence of this lesion was 4/50, 28/50 and 7/50 in the 0, 300 and I 30 ppm males, respectively. The increased incidence of cystoid degeneration, megalocytosis and portal mononuclear cell infiltration in the 300 ppm dosage l group was statistically significant at the 5% level in male rats. In females from the 300 ppm level, only the increased incidence of megalocytosis was statistically significant. l Occurrence of these histomorphologic changes in the liver correlates with elevation of alkaline phosphatase, aspartate aminotransferase and alanine l aminotransferase levels observed in male rats. The markedly reduced incidence and severity of histomorphologic liver changes in females parallels the absence ! 1 ooff aalltteerraattiioonnss iinn lliivveerr ssppeecciiffiicc sseerruumm bbiioocchheemmiiccaall vvaalluueess iinn ffeemmaalleess.. There was no direct or indirect componnd effect in tissues other than l liver at the 1 year interim sacrifice. In TS/DOS rats, changes which were considered secondarily compound related, probably through to FC-143 altered liver metabolism of endogenous steroids, were observed in the adrenals, ovaries and iii 0281CR0012 (FC-143) -3- 122 11333377..00112266 J-- 3MA00027251 1I I lestes. In the adrenals, an increased incidence of nodular hyperplasia of the cortex occurred in males at the 300 ppm level. Incidence of this finding in I 1 mealleess wwaass 22//4499,, 99//5500 aanndd 11//5500 iinn 00,, 330000 aanndd 3300 ppppmm mmaalleess,, rreessppeeccttiivveellyy.. TThhee increased incidence of nodular hyperplasia in males at the 300 ppm level was I not statistically significanl, however. In females, lubular hyperp]asia of the ovarian stroma occurred in 0/48, 15/47 and 7/50 rats from the 0, 300 and 30 ppm ~ groups, respectively. This incidence was statistically significant at both the I 300 and 30 ppm levels. Tubular hyperplasia of the stroma was a non-neoplastic diffuse increase in tubular elements of the ovarian stroms which was usually bilateral and associated with absent or markedly reduced follicular development. I In male rats, there was a statistically significant, compound related i ooccccuurrrreennccee ooff bbeenniiggnn LLeeyyddiigg cceellll ttuumsoorrss ooff tthhee tteesstteess aatt tthhee 320000 ppppmm lleevveell.. I Incidence of Leydig cell tumors was 0/49, 7/50 and 2/50 at the 0, 300 and 30 I ppm levels, respectively. Although occurence of 2 Leydig cell tumors at 30 ppm is also suggestive of a compound effect, these neoplasms are not uncommon in untreated rats, although none were found in control rats from this study. The I occurence of Leydig cell tumors correlated with the observations of testicular masses at necropsy. Testes which contained Leydig cell tumors were usually I tolally aspermic. Mineralization of vessels within the testes occurred in 0/49, 9/50 and 3/50 rats from the 0, 300 and 30 ppm groups respectively. The I 1 iinnccrreeaasseedd iinncciiddeennccee ooff tteessttiiccuullaarr vvaassccuullaarr mmiinneerraalliizzaattiioonn aatt 330000 ppppmm wwaass ssttaattiiss-- tically significant. In female rats, there was a statistically significant i I iinnccrreeaasseedd iinncciiddeennccee iinn mmaammmmaarryy ffiibbrrooaaddeennoommaass aatt tthhee 330000 ppppmm lleevveell.. IInncciiddeennccee of this tumor was 10/46, 21/44 and 19/45 at the O, 300 and 30 ppm levels, I 1 oo Eoovesaes nGuseSER oF ORRR SSLESRSING 98 Sev STIR SHTINSS respectively. An increased incidence of focal accumulations of foamy alveolar macrophages occurred in the lungs of males from the 300 and 30 ppm groups. The incidence of this finding was 10/50, 31/50 and 16/50 at the 0, 300 and 30 ppm levels I respecitively. The increased incidence of alveolar macrophages at 300 ppm was J cociscicony ssgniticone Tn females, the cides of 4/50, 19/50 snd 10/5 statistically significant. In females, the incidence of 14/50, 19/50 and 10/50 I at the O, 300 and 30 ppm levels did not have a statistically significant increase I in treated animals. Other microscopic lesions in tissues from FC-143 treated rats were typical of naturally occurring inflammatory, degenerative and neoplastic I 1 {ofLumascory lesions fncluded chronic sonseppusative spocacditis, with sssceiated lesions in an ageing population of Charles River CD rats. Commonly occurring inflammatory lesions included chronic nonsuppurative myocarditis, with associated myocardial fibrosis, mononuclear inflammatory cell infiltrate into the portal II11 [ER - 0281CR0012 (FC-143) -4- 123 11333377..00112277 awozs 3MA00027252 lB lnc ct tr ser wien vn sesenty sts triads of the liver which was frequently associated with portal bile duct win portal bite duce proliferation and perivascular mononuclear inflammatory cell infiltrate and multifoca] chronic interstitial pneumonia in the lung. A high incidence of l HL sishdetet secured 0 mie set eon tk chronic sialadenitis occurred in male rats from the 300' and 30 ppm groups l i ssaaccrriiffiicceedd aatt tteerrmmiinnaattiioonn.. TThhee sappppeeaarraannccee ooff tthhee ssaalliivvaarryy ggllaannddss iinn tthheessee animals was typical of glands in the recovery stages of dacryosialadenitis, a common, highly contagious disease of laboratory rats. Its peculiar incidence l in this study was attributed to the housing arrangement. Both affected groups were housed in-the same room and the unaffected groups were housed in other B l n WT etd rooms. Although the incidence of sialadenitis in male rats from the 300 and 30 aoe ee rom the 300 nd 30 ppm groups was statistically significant, this increase was not considered compound related since it was explainable by the housing arrangement. Other lIi statistically significant variations in incidence of non-neoplastic lesions wvhhiicchh wweerree nnoott ccoonnssiiddeerreedd ooff ttooxxiiccoolloeggiiccaall ssiiggnniiffiiccaannccee ifnncclluuddeedddedeccrreeaasseedd chronic myocarditis in females from the 30 ppm group, increased lung hemorrhage in males from the 300 ppm group, decreased perivascular mononuclear cell infiltrate l rn Tm Stree in the lung in males from the 300 ppm group and in males and females from the sn esses fen the 30 ppm group and decreased splenic hemosiderosis in females from the 300 ppm B l T ns ten grove. group and in males and females from the 30 ppm group. Some of the more commonly occurring degenerative lesions in this study included adrenal cortical vacuolation and sinusoidal ectasia, focal mineralization i in large pulmonary artery branches in the lung, focal acinar atrophy in the | a ppaannccrreeaass aanndd cchhrroonniicc pprrooggrreessssiivvee nneepphhrrooppaatthhyy.. PPiittuuiittaarryy aaddeennoommaass wweerree the the most most common neoplasm in male and female rats. Overall, the health of the rats in this study was excellent, with organs free of lesions of common infectious diseases which would have had an impact upon survival or the validity of the study. . Robert G. Geil, D.~.M. Diplomate, American College of Veterinary Pathologists omens Grose - 0281CR0012 (FC-143) -5- 11333377..00112288 9 25 -- 112244 swonass 3MA00027253 l 1I otson contons TABLE OF CONTE]~S I TER escape Instanc Table Number Page e for Yates = 1 Yor oteetnserrreeressss.] I Macroscopic Incidence for Males - I Year Interim ............... 1 2 Macroscopic Incidence for Females - 1 Year Interim ............. 2 l 3 Macroscopic Incidencc for Males ................................ 3- i 455 MNNaoocnnr--noneseocoppollpaaisscttiiIccnciIIdnneccniicddeeennccfeeor ffooFrremMMaaallleeesss..--...I1 .YY.ee.aa.rr...II.nn.tt.ee.rr.ii.mm....................................e6--171 I Pen -Ii 3 s drei fori Se erie, 6 Non-neoplastic Incidence for Females - i Year Interim .......... 12-15 meimects eidems for towies = Sour frerineoonnn 12n1s 7 Non-neoplastic Incidence for Males ............................. 16-24 S g Non-neoplastic Incidence for Females ........................... 25-33 I To Tte fe irr 9 Neoplastic Incidence for Males - 1 Year Interim ................ 34 Ioopimmis ties fr Seles TerrTerie I0 Neoplastic Incidence for Females - I Year Interim .............. 35 1 H1 mMeomiariic hochimes for gamelan = 1 Year ceria ooo 11 Neoplastic Incidence for Males ................................. 3fi-37 m pe tr een 12 Neoplastic Incidence for Females ............................... 38-39 i _-- i ATTaapbbplleeendiNNxuummbbeerr PPaasgee I Ele}Ret te Ttates Anta Report 1 Yar Toseiaeeeeeerere2n0en} 1 Single Tabulated Animal Report - I Year Interim ................ 1-27 yDeives Teiaimed inet foro - 1 ten Twente BE 2 Single Tabulated Animal Report ................................. 28-214 e he TI 3 Tissue Inventory - I Year Interim .............................. 215-218 l 4 Tissue Inventory ............................................... 21o_2&2 I l I l l I l l I orenonnz reeteny 1l 0281CR0012 (FC-143) ,112255 11333377..00129 wnonezrse 3MA00027254 I H-=cr,~scopic Incide~c~ for ~,i.~!es Zi,~ar L~bor-.t,nrias, Inc. Zi,i T~ble: I FC-i43: Tao Ye~,r Oral Toxi=i~.y-Or~co~enici~y Study in Rats - Ona Year lqter~m 1l Si I De sc ri pti on Gro;~p I Group I i HNoo vviissiibbllee lTeessiotnuns Eye opacity I Pit.,itary m-~ss LiLvi veerr ; s 3 1 i : l pal s/ta, col~r l,;_~en =~_ ry fat necrosi ~ I i Ki aydrcrephrosis nydrene#hrosi cystic lesion l 1 po Tss~is sm~l 1 1 1 :i 1 l 1 Soft Tiss.~e (leg) n I l l l I I 1! NA Ti:les: Grou# i Group ~ l i Hacroscepic ]nsidence Po~e: 11333377..00113300 3MA00027255 | Macroscopic Incidence for Females Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim | Project Number: 02GICRDU12 Species: Rat || sorSi te/ Table: 2 Descri ption No visible lesions | 5Eye atartroopphhyy Pi tu i ta ry | enlarged Adrenal enlargeG 1 wrLiver | ppaallee//ttaann"* at rene, Lymph :i,~de (nes'enteric) 1 reorgte hemorri~a~ic | I,l:sentery Group 1 Group 5 5 9 1 1 22 3 1 : 1i I 1 1 Ill,IS S Kidney | hydronephrosi s B rUraetteerrcalculi dilatation;, calculi | Urinary B] adder 1 TE re di steaded, calculi ~tarJs i cystic lesion i| eddintltlaaattreagdde,,d ffluuitd ffiilllleeds F~.a~ary G1 ~nd | 1 SaSKiinn hair loss 1 1 1 1 ,1 1 i i 1 I 1 | | | | | Titles: Group 1 |i Ct as Group 5 CO~TROL FC-14J i| * includes "possibly" Macroscopic Incidence Pale: 2 127 11333377..00131 3MA00027256 i Macroscopic Incidence for Males 1 FFCC--114433:: TT~wYoo YYeeaaRrrikOOerrraallLaTTboooxxriiacctiiottryyi--eOOsnn,ccooIggneecnn.iiccii3tt1,yyI SSttuuddyy iinn RRaat~s Table: 3 B Project Number: 0231CR0012 Species: Rat 1 strSite! n Description Group i ~roup 5 Group 6 No visible lesions n Brain dar:: area Eye 1 = opacity/cloudy H hypopyon Pituitary i correnarsedyestod Tesien mass/enlarged/raised lesion I prose dark/hemorrhagic/red foci rl Thyroid 1 Faenlarged* I wr AdrenJl Sion enlarged/mass ge Throax (internal} pl fluid filled i Thymus a enlarged* hemorrhagic/hemorrhagic lesion B mass Lung 1 Simottled frothy tracheal exudate I consolidation* mass/raised lesion i origte its Tetons multiple white lesions B Heart cian flaccid/flabby enlarged* B pale on fn) i Abdomeggnaass,,(igngtaaessrttnrraoolii}nntteessttiinnaall ttrraacctt stomach empty of food B Sama mass, o~entum or fatty tumor i sen . Stomach I ay edema/thickened wall erosions/ulcerations* ge Small Intestine I enlarged, reddened Payer's patches a B LargeeennIllnaatrreggseetddi,,nerreeddddeenneedd PPeeyyeerr''ss ppaattcchheess I impaction B Titres Titles: H Group I i. Group 5 | Group 5 CONTROL FC-143 FC-I~3 0 ppm 300 ppm 30 ppm iB Ii 12 L8 1 i I D7yosronioim . 4NE2 2 :I Ioe .2 2 a I I 2 I . 1:. 1 i . i. 1 1 1 1 1 1 :1 .i . . 1 1 I 11 * includes "possibly" ems sien mt 1228 Macroscopic Incidence Page: 11333377..00132 noses 3MA00027257 l Macroscopic Incidence for Males Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats I Project Rumber: 02!IICR2012 Species: Rat Ii srSite/ pn Gori Gms wt Description rs Pancreas i saa : mdss/nodule I Liver ppa3l1ee//ppaalle Tloodbeess* ~ass/qod~le/raised l mottled* lesion Group 2 1i00 3 Group 5 Group 3 3 7 7 7 Table 3 i ayenenillalaorr.ggvee/sdpale loci/lesion possible congestion I Spleen enlarged i Tis ston raised lesion l pale loci pale, depressed area 1 jss~ll* l Lymph node {m~senteric/abdomi~al) i eennllaarrggeedd greeni~ col~r l Nes~ntery nodular/enlarged/thic~ened vessels 1 =~3SS l Kidney i 1 1 I 1 i :3 1 2 I : z 2 2 2 i od I 1 e:flarged, p~le, pitted i otaegns, pitted enlarged, pitted l pale, pitted - ppaallee,, eennllaarrggeedd*" I ppaallee pele are~ I hydronephrosis, pelvic dilatation ' 3 I 1 2 1 I I 1 3 1 1 ! cystic/polycystic Urinary Bladder l distended henaturia/filled ~ith 1 it hemorrhagic ~all Testis/Epididymis l sm~ll reddish/dar~ flui~ i entPenis l s~ollen l1 zs Mammary Gland 3 ,I 2 1 i 4 5 6 I LI oe I Titles: l Group I Group S l1 fe Group ~ COIITROL FC-143 FC-143 0 ppm 3JJ ppm 30 ppm l includes "possibly" Macroscopic Incidence P~O~_: 4 112299 11333377..00113333 3MA00027258 | I IBE | i| | i ||] | i I | | i i i i i | J Macroscopic Incidence for Males Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Onco~enicity Study in Rats .Projoct Number: O2SICROJ~2 Site/ Species: Rat Description SKin ulcers/inflamed/circular/raised lesions, hind footpads diinenfrfllmaaamnteeiddtisaa/rreuealsc"er/lesion/ moist area i~air loss mass/thickening abscess inflamed fat S~ft Tissue (neck) ~ass Soft Tissue (thorax) SSoofftt TmTiiassssssuuee ((lleegg)) s~311 en pad:s/feet Group 1 Group 5 Group 6 1 1 : 1 1 I I 1 1 I i I i Table: 3 Titles: Group I Group 5 Group 5 COIITROL FC-I~3 FC-1~3 0 ppm 300 ppm 30 ppm 11333377..00113344 * includes "possibly" Macroscopic Incidence 130 Page: 5 130 3MA00027259 ! Macroscopic Incidence for Females 1 : FFCC--114632:: TTu~oo YYeeaaRrrikOOerrraallLaTTboooxxrifacetiiottryyi--eOOsnn,ccooIggneacnn.iiccii3ttMyy SSttuuddyy iinn RRaattss. Table: B Project Number: 02~ICROC:12 Species: Rat 1 srSite/ I Description Group I Group Group 6 B No visible lesions Eye H i oiipnnaffcllaiamtmmymaa/ttciilooo~nudy atrophy Pituitary I mass/enlarged/raised lesion hemorrhasicidark lesion Adrenal B enlarged mass/raised lesion pale i LLuunngg small mottled B consolidaticm ponodule B =pale n Lymph ~ode (bro~ichial) enlarged B Heart enlarged* I Abdomen (internal) i 9g1as5,, ggaassttrrooiinntteessttiinnaall ttrrJacctt bloody flui~ filled nodular tissue, oment~m, mesentery | Stamach ulcerations/erosions red mucosal areas/redde:~ed Bi inflanee Sm~ll Intestine ~nflamed ulceration/ulcerated Large IntesZine outpouching | impaction Pancreas mass/nodule I Liver pale* mass/nodule/raised lesion mottled B circular Teston/pale foci/ circular lesion/pale foci/ pale lesion/yellowish lesion I enlarged* 3 i 1 I 2 3 7 1 :| : i 2 1 I 1 i I 1 2 1 1 i I 1 I I? 3 6 2 2 i I I 2 I 2 i I TiTittlleess:: Group 1 CO!iTROL 0 ppm 1 soem a, Group 5 FC-i~3 30~ ppm B Group J FC-143 30 ppm * includes "possibly" Macroscopic Incidence Page: 6 I| 113311 11333377..00113355 3MA00027260 | i | 1 I | | 1 i| | |1|| i B| 1i i | 1 | 1| | 1 | | Macroscopic Incidence for Females Riker Laboratories, Inc. 3M FC-143: T~o Year Oral Toxici~y-Oncogenicity Study in Rats arProject :lumber: 02SICR3012 Site/ Species: Rat Description Liver (continued) dark red area/lobe rough/~rregular surface Spleen enlarged* Lymph node (meSe;lteric/abdominal) reontleacrngeedd reddened cystic dt Kidney enlarged, enlarged* pale, pitted pale, pitted pitted pale* cyst UrineanrylaBrlgaeddder enlarged oi calculi thickened ~alls Ovary ~ass Uteros Filled vith enlarged filled ~ith ddaarre~//bs)l~ooaddyy fFlluaitdd I~ass dar~ are~/le~ion hemorrhagic lesion N~mary Gla,~d a mass!nodule mil~ cyst Skin raised/inflamed/ulcerated lesioa, footpad ramiasssed lesion raised lesion hair loss/thianin~ circular lesion Soft Tissues (neck) Group 1 Group 5 Group 5 I I 5 2 1 I 1 1 I iI I 2 1 I 1 I 11 I i 1 2 i 1 27 25 37 3 3 I 1II I 2 I ele . re~ened~ gia~d i~e s~r~c~res 1 Soft Tissues Ileg~ s~ellen foot i Table: 4 Tol, Titles: Group 1 Grmup 5 CO~TROL FC-143 0 ppm 300 ppm Group 6 FC-143 20 ppm * includes "possibly" Macroscopic Incidence Page: 7 113322 11333377..00113366 3MA00027261 a ses yo Non-Neoplastic Incidence for Males Riker Laboratories, Inc. 3M l FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: 5 !i tes as snr. sts Project Number: 0281CR0012 Species: Rat 8 TiTsisssauee// Diagnosis/ l Modifier i rent Adrenal I Within normal limits Cortical vacuolation 1 imild I pions ~odular hyperplasia, cortex GGrooupp i1 GGrroouupp 55 ...................... om ( 15} { 15) 12 15 i 0 A. I 0 I 3 1 0 1 Strusoimdoadleraetcteasta, cortex Sinusoidal ectasia, cortex moderate 1I1 0 0 I 0 I es a ob Aorta Within normal i Sone rr Gn Gm Bone Marrow l Within normal limits limits I 15) 15 (14) 14 (ii) 11 ( 151 15 wt dh dh Brain i rin amt is go Within normal limits ( 15 15 l conn IE Esophagus (15) { 15) Within normal limits BR EEryee Within normal limits I Cataract Retinal atrophy 1 has : minimal I Heart B MWMyiyotocchaairrnddiinaaollrmaffliibbrrlooissmiiistss minimal I mild 15 ((115s) 15 D 0 0 (15) 1o40 O 0 15 ((1155)) 13 1 I (15) 1222 1 1 Myocarditis, chronic nonsuppurative i ian 5 : minimal I mild 0 2 1 0 Kidney (15) (15) Within normal limits 5 4 l Calculus ] 0 cS HE i Chroniwcmiinnpiirnmoaagllressive nep~ropatby 8H5 1066 mild '3 4 l Cyst 1 0 Frets i Hydronephrosis ! 0 i ai : : moderate 1 O I Mineralization Nephriti~, interstitial, chronic I5 Se Pood mild 0 1 0 I 0 Titles: l Group 1 CONTROL 0 ppm Ii I mn Group 5 FC-143 300 ppm 1l () = Total Examined Microscopic Incidence Page: 133 11333377..00113377 3MA00027262 | Non-:leoplastic Inc~demce for Males (continued) Riker Laboratories, Inc. ~M 1| Table: 5 FC-I3: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interi~ Table: 5 Projec~ ~umber: O231CR]O12 Species: Rat I Tissue/ Diagnosis/ Group I Group 5 | Modifier K~dney (continued) 1 ninian Pye~itis, acute ~inimal nHld | Large Intestine Withi~ normal li:~Hts 1 pratt I~ematodiasis | Liver i 1 I ~ S( 1~] 15 0 ( 13} zI i |(!~) 14 ( i HWHieetppha~itonecey~ytozerm~aallltteelrriaamttiiitoo~nn,, vvaaccuuoollaa~teedd 27 2 0 | iai nimal I 0 i HHeeppaat~ooccmyyittldee vvaaczuuadllaattiioonn I 90 2 mi;Hmal 0 I | mi I d 0 i He~a] ocytosi s i we FE minimal 0 7 | mild 0 i HNeeccrraossii~ssmderate ,02~ 32S | minimal 0 mild 0 4 PigweedS, Kupfer cell 0 i ar : i minima] ~ I | mild ? i Portal bile Guct proliferation 5 I 1 ne Po minimal 1 | ~il d 4 I i mintnal 1 : Portal mononuclear cell infiltrate minimal 7 13 i nild i Lung { 15) [ 15) Within normal limit~ i Aveeno maton: 5 : Alveolar macrophages | mild 1 2 3 5 3 5 Atelectasis 1 He Po mild 1 Hemorrhage i i mm odiledrate moderate 6 ~ J 2 i 1 Hyperplasia, sep~al c~ll I 0 i mild 1 | i TTiittlleess:: Group I CO~:TROL ~ ppm | Group 5 FC-143 300 ppm I 1 () = Total Examined MMiiccrroossccooppiicc IInnccitddeannccea PPaageg:e: * 113344 11333377..00113388 3MA00027263 I Non-Neoplastic Incidence for Hales (continued) Riker Laboratories, Inc. 3~4 FC-143: T~#o Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim I Project Number: 0231CR3012 Species: Rat Table: 5 1 Toss Tissue/ I Diagnosis/ 1 A, Hodifier Ge 1 oan 3 Group i Group 5 I Lung (continued) 1 Perivaatsci~elar mcnonuclear infiltrate 2 2 I 1 mild 2 I I Pneumonia, interstitial, chro~ic 3 2 po Po minimal i mild Z 2 i Veto aeration ; : Vascular mineralization 7 8 I mi ni~al 4 1 mild 3 7 I pitied Lymph Node (mesen~eric) Within normal limits Hemorrhage Do(13) 13 0 (13) 11 2 I minimal mild ~amm~ry Gland 0 i 0 I { I ne po Within normal limits ~le~entery I~ecrosis, fat 1 Steatitmiasr,kedenronic Steatitis, chronic I fs moderate Pancreas Within normal limit~ i prhirnt Aci~r atrophy I mild Loii1 90 0 i 0 3 ; { 15) 11 3 (15) 15 2 moderate I Pancreatitis, chronic ~ild 1 ParaWtWihitythrhioinindnnoorrmaaall Vliimaiittss Pituitary I Within normal limits 1 4Cyst Prostate I Within normal limits I 3 . 3 7 ? ;(14) 13 I I 15) 15 O 0 33 (12) 12 0 (13) 12 Prostatitis, chronic I minimal Salivary G~aRd I i SSmmaallllWiIIthnnttineessttniionnrmee al limits Within normal limits 0 ~ (!5) 1155) 15 I 1 (14) (1154) 15 I Titles: Group I CONTROL ~ ppm 1I LEE Group 5 FC-1G~ 750 ppm I () = Total Examined Microscopic Incidence Page: 135 11333377..00113399 3MA00027264 ! Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M iR Table: 5 FC-143: Two Year 0ral Toxicity-0ncogenicity Study in Rats - One Year Interim Table: 5 Project Number: 02BICRO012 Species: Rat 1 Tons Tissue/ I Diagnosis/ 1 pe Modifier B -- Spinal Cord Gon 1 ws 3 Group ! Group 5 wm ( i SpSlpleeeeWnnithin normal limits Within normal limits I Hemosiderosis mild 1 Soman Stomach n Within normal limits Testis/Epididymis i rt ite Within normal limits | Tubule atrophy, aspermatogenesis pes 1 TThhyyrrooiidd marked nr its Within normal limits B rate Trachea 1(111854)) ((111555)) 15 14 ao on 0 0 (14) 1 1 (15) 14 (15) EA15 0 FEt(!Im0) PoE 11 dd (15) 15 (15) 13 2 ((1132)) 13 (15) | Within normal limits Urinary Bladder Within normal limits 15 (15) 15 15 (13) 13 B n | i i B n i Titles: Group I CONTROL D ppm n Group 5 FC-143 300 ppm B Total Examined Microscopic Incidence Page: 11 136 11333377..00114400 3MA00027265 1 AS SE eo Non-Neoplastic Incidence for Females B Riker Laboratories, Inc. 3M i ss ors sons, spire FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: 6 Project Number: O2BICRO012 Species: Rat 1 sr Tissue/ n Diagnosis/ 1 ie ~odifier i rnAdrenal on 1 ons Group i Group 5 mom (15) (15) i CWCoiortrthtiiicncaalnorddmeeaggleenneelrriaamttiiitoosnn mild n Sinusoidal ectasia, cortex mild Thmarked I Aorta Within normal limits 1 wn, Bone Marrow n Within normal limits 1022 11i1 2 I SI: 4 3 3 1 0 bh (14) ( 14 13 (15) ( 15 15 1 BrainWWiitthhiinn nnoorrmmaall Mliimaiittss Esophagus i Within normal limits 1 onEye Within normal limits i Atrophy femarked (115155 ) (1155 dh (15) 15 (15) (13) 13 (15) Po14 13 1 2 i 2 Panophthalmitis i 2 i marked 1 2 Heart i WWiitthhiinn nnoorrmmaall Vliimmiittss { 11154) (1u154n) Myocarditis, chronic nonsuppurative I | minimal 1 0 I mild Kidney Within normal limits 0 (15) ( 6 1 ata Calculus mild 4 I 1 2 I 1 Le bo moderate I 0 i rn pet eps bo Chronic progressive nephropathy I 3 mi]d 1 3 1 a Pood Cyst 1 0 I mild 1 0 Hydronephrosis I I 1 fon Lo moderate I 0 B pfer i att HboE marked 0 I I i Hyperpwlmiailsldida, pelvic epithelium 1I1 00 0 Mineralization 0 I mild 0 I ! Titles: I Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm i! () = Total Examined MMiiccrroossccooppiicc IInncciiddeennccee PPaaggee:: 1122 137 11333377..00114411 3MA00027266 'iB I n 1 I B 1 i I | iI B I 1 iB ii 1 B I i i1n I B n 1 || n eMusic etre or Fees contimed) Non-Neoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M Fo Tt ee nme St 3s - Oo ee Tn FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: 6 Project Number: 0281CR0012 Species: Rat ae Tissue/ Diagnosis/ Modifier ied Kidney (continued) Pelvic mineralization minimal mild Pyelitis, chronic momoddeerraattee Large Intestine Within normal limits ~ematodiasis Liver Within normal limits ale Hepatocyte mild alteration, vacuolated Hepatocyte vacuol ation mi ni real mild Portal bile duct proliferation mild Portal mononuclear cell wreminimal mild wyLungWithin nora Timits Within normal limits nS Alveolar macrophages pomild ris Hemorrhage imild infiltrate moderate Perivascular mononuclear Emild Pneumonia, interstitial, = Vasculm arildmineralization Vascular mineralization 2mild nt ric Lymph Node (mesenteric} Within normal limits Netra Hemorrhage amarked Man~nary Gland pap Within normal limits infiltrate chronic Galactocele Group I Group 5 To4 1 ~ 0 0 1 O 0 1 1 1 (14) (14) 12 12 2 2 (15) (15) 6 3 1I I 0 0 0 5 11 3 I 2 10 2 1 2 1 2 2 fd 1 0 1 2 Gh oh ( 1533} { 1555) yt 1 I i Pod 5 ; i I 1! 9 7 2 2 i 0 Pog 1 0 I 0 Pos 11 1 i I Pood I I po (12) ( 12 12 s : 0 I >0 I { 15) ( pe 13 10 2 i u1m600nom Titles: Group 1 CONTROL 0 ppm Group 5 FC-143 300 ppm 0 +ot cas () = Total Examined MMiiccrroossccooppiicc IInncciiddeennccee PPaaggee:: 1133 ~13388 11333377..00114422 3MA00027267 I B 1| I iR n i I|} I I i I n |i1 n I i n i B I i Bait Non-I~eoplastic Incidence for Females (continued) Riker Laboratories, Inc. 3M FC-Ii~: ~o Year Oral Toxicity-Onzogenicity Study in Rats - One Year Interiu Table: Project Number: 0231CR0012 Species: Rat Tot Tissue/ Diagnosis/ Nodi fi er _ Group i Group 5 Flesentery aoderate Necrosis, fat moderate Steati&is, chronic noderate Ov,~ry ls~Hthin Cys t Pancreas normal limits Pancreatitis, chronic ni I d PPaarraattihyyrrooitdd ~ithin nornal limits Pituit~ry Withi~ normal li~its S~I ivory Glan~ Wi~h~z~ normal linits S~:i n`WWiitthhiinn nnoorrmmaal lMianiisZss S,nal I Intestine Within normal li~izs Spin~1 C~rd Within ~:or~al limits Splee~ Within normal limit~ Hemosiderosis mild StomaWcihthin normal Within normal - Thyroi d Within normal ts Trachea lMiamiittes limits Wit~}in normal limits Ureter Cal cul ~s Dil~tation mar~ed Infl a`~n.~oadteiroan,techronic moderate (o) 1 o 1 I'3) (15) GhI~ 15 I 0 15) (15) I,~ 15 i [3G]) ~ 15) 14 15) 15 2 is) 15 i4} I; 15) 0 (99) 9 (14) 14 ( 15 < (is) (i~) 15 (15) 1 1 515) 15 15 (13) EE 14) (I~) JE is) (i~) 15 O) (i) ~ I 0 1 20~ 1 I 1 Titles: Group I CONTRDL J ppm Group 5 FC-143 300 ppm () = Total Examined MMiiccrroossccooppiicc IInncciiddeennccee PPaaggee:: 13 139 11333377..00114433 3MA00027268 i Non-Neoplastic Incidence for Females {continued) Riker Laboratories, Inc. 3M 1 i FC-143: Two Year Oral Toxiity-Oncogenicity Study in Rats - One Year InteriTTmaabbllee:: 66 Project Number: 0281CR0012 Species: Rat I1 Toss Tissue/ Diag~1osis/ on 1 Grow 3 Group i Group 5 Modifier n Urinary Bladder 1 CWCyiyststthiiittniissn,,ormccahhlrroonnliiiccmits a moderate I Epithelial hyperplasia, simple mild 1 PoUterus n Within normal limits (12) (15) Po12 14 0 0 I 1 0 l (nom 0 0 (15) I I (15) 12 13 ||] marked Cystic glands marked Endometritis, chronic 111 00o 0 I mild i HyHdydrroommeettrraa 0 I 0 0 2 re sd moderate 0 i I Hyperplasia, glandular epithelium 2 0 mild 2 0 1 J oo Metaplasia, squamous 2 0 i mild 2 0 n i I I i a I i Titles: n i GGGrrrooouuuppp 15 FCFCOC-N-1T16R43O3L3300000pppppmpmm i n (} = Total Examined MMiiccrroossccooppiicc IInncciiddeennccee PPaaggee:: 1155 140 11333377..00114444 3MA00027269 I1 alo Non-Neoplastic Incidence for Males Riker Laboratories, Inc. 3M ! FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: ~281CR0012 Species: Rat Table: n Tissue/ n 1 DiagnoMsMoiodsdi/iffiieerr Adrenal R Within normal limits Cortical degeneration moderate iR nininst Cortical vacuolation minimal mild i mammaorrdkkeaerddate Medullary cell hyperplasia ! minimal mild 1 mre moderate I Nodular hyperplasia, cortex minimal 1 nemild B moderate Sinusoidal ~ctasia, cortex ! minimal mild moderate n marked Aorta Within normal limits Mineralization i nile mild I Necrosis moderate 1 BBoonnee. Arthritis, synovitis; joints B moderate B marked Bone Harrow Within normal limits |1 rl i BraiWnWiitthbilnn nnoorrmmaall Mlimmiittss Abscess mild B Hemorrhage moderate Group I DDOsS SSAtC Group 5 D0O0S5 SSAACC Group 6 0D0OS5 SSAiCC 15) (34) 5 13 D 0 D 0 97 217 (6) (44) 2 12 0 0 O 0 21 2II (14) I 36) 8 I~ O 2 0 2 4a 05 4 13 03 02 0 0 i 5 0 40 O 0 3 5 0100 I 0 2 6 I 6 0 3 soe o O 3 I ,; 1 ~ 0 2 I 4 0 0 os 0 0 0 3 0 0 So 0 2 O D 3 1 I S I 0 0 7 00 i 0 0 0 0 O 1 0 I 0 1 4 7 0 16 5 8 0 2 O 2 0 i 2 3 0 13 4 5 2 2 O 3 I 2 3 O 0 I 0 0 15) (3~,) (6) [ 43) (0) (0) 13 34 6 43 0 0 11 00 I O 30O 000 a03 000 1 O O 0 0 0 1 O O 0 O 0 taO) t(Za) t (O)a( n1}tC oO) I I) 0 2 0 i 0 i 0 3 O i O 1 0 Z 0 0 0 0 15) (3Z) (6) { 4Z) (O) [ O) 15 32 5 z~2 0 0 11154) (333~3) (55)5 (44a44) (O3) [ 0 00I) AAA A 1 O 1 O 1 D 0 0 0 0 0 0 0 0 0 0 0 0 1 O 0 0 0 0 n i TiGGtrrlooeuuspp: 11 CCOONNTTRROOLL O0 ppppem nB1 GGGrrrooasuuppp 65 FFFCCC---111444333 3330000pprppampm {()) == TToottaall EExxaammifnneedd [r------ SDSAOACSC:e= UPPrrnoosttcoohcceoodlluleSSdcchheeDdeduautllhee{ddsS)SaaccrriiFFiiccee((ss)) 141 Microscopic Incidence Page: IG 11333377..00114455 3MA00027270 l Non-Neoplastic Incidence for Males (continued Riker Laboratories, Inc. 3M I simone spss ie FC-143: Two Year Dral Toxicity-Oncogenicity Study in Rats Project Number: 0281CR0012 Species: Rat Table: 7 I Tissue/ l re 1 DiagnoMsoidsi/fier Modifier Esophagus Group i Group 5 Group 6 MT D2O0S5 SSAACC 0D0OSS SSAACC DDOOSS SSAACC (15) (33) (6) (41) (13) (32) I Within normal limits Eye Within normal limits 15 33 5 41 13 32 ( 12) ( 33) ( 6) ( 44) ( 2) { 3) 12 32 ~ 41 1 0 I we Cataract Keratitis, acute marked Pili O O O O 0 3 O 0 I 0 I 0 1 2 0 0 0 0 1 Keratintiilse, chronic mild O0 O0O o 00 o0I 000 ii1 moderate O D 0 I 0 0 l Phthsis bulbi 0 O 0 I 0 0 La FE marked 0 O 0 I 0 0 1 tin sires oe 1a 1 0 1 Retinal atrophy 0 i 0 I 0 I l mild 0 i 0 0 0 0 marked 0 0 3 i 0 0 1 we Chie ome Heart (16) (34) (5) { ~) (14) { 36) l Within normal limits 8 23 G 27 9 19 1 Endocamrmdaairrtkkieesdd, chronic o 00 oO0 00 000 00o 1I1 Myocardial fibrosis 3 2 0 1 1 6 I mild 3 2 0 1 1 6 Myocarditis, chronic nonsuppurative 4 10 D 17 5 13 1 fh soso minimal 0 2 O 5 o 1 l 2 HE mild 4 7 O 12 4 12 i KKiiddnneeyy mode rate C(1160)60(334)I) ((860)) (C4a~O)) ((114I)90{ 33)~0} l W~h~n normal l~mi~s 4 0 1 2 3 2 Calculus 0 1 1 0 0 I minimal 0 1 0 0 0 0 1 he poss 8s mild 0 0 I 0 0 0 l Chronic progressive nephropathy 10 34 3 40 9 34 I mi ni real mild moderate marked i ost Cyst moderate I marked 1 4 5 16 2 Ii 211333 0 1 1 2 1 9 0 23 I 6 001 121 0 I 0 0 2 2 3 22 2 7 211 13I I 0 0 0 l Hydronephrosi s mild moderate 1 2 1 0 0 2 0 1 0 1 0 0 0 0 0 0 0 0 l I Een i TiGrtloueps : 1 CONTROL O pp Group i CONTROL 0 ppm Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm Be en (0)) == TToottaall EExxaammiinneedd DOS= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) 1421 4 2 I Microscopic Incidence Page: 17 11333377..00114466 3MA00027271 n Non-Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M I reset vers scons spies FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: D281CRODI2 Species: Rat Table: 7 I Tissue/ Group I Group 5 Group 6 1 DiagnMoosidsi/fier Modifier DDOOSS SSAACC DDOOSS SSAACC DDOOSS SSAACC | Kidney (continued) Hyperplasia, pelvic epithelium 1 he Co oo: o a mild I oi Sos tod moderate 0 0 0 0 0 0 0 3 0 2 0 i 0 0 0 0 0 0 Mineralization mild I Nephrosis ne 1 PPaappiillllaamrroyydernnaeectcreroossiiss. moderate i Pelvic mineralization minimal 1 "iremild i Te moderate on i Proteinmraerkseodrptiondroplets Protein resorption droplets mild n Pyelitis, acute i mild Pyelonephritis, acute mild 0 0 0 I 0 0 11111: 0 0 i 0 1 1i 80O 0 i 0 0 0 0 o0o 00 0 0 0 0 000 0 90 I 0 0 0 0 0 i 3 0 I Peo oz 3a i 2 Prose 0 0 FE O0 009 0 3 0 1 0 2 O 0 900 000 4 6 0 1 3 3 0 2 I1i 000 0 O 0 0 1 0 O D 0 0 i 2 0 O 0 0 1 2 I D 0 3 0 0 i O 0 2 0 0 moderate 0 O o I 0 0 Vacuolation, cony. tub. epitheium 0 0 0 0 i 0 n minimal 0 0 0 0 i 0 se A B LargeWWiittIhhniitnnesntnoiornrmmeaall lliinmiittss (11w44)o(3s24S) (~5) 6 (4@4~4) (i)I1 { 0O0 ) Nematodiasis 0 6 0 0 0 0 i tr Ch aw mm Liver (16) (3) (6) (~4) (14) (3~) 1 rans nie em egep ny Within normal limits 2 0 0 0 I 6 Cystoid degeneration 0 4 I 27 2 5 i minimal 0 I O 2 O i mild 1 on Tron moderate 0 2 o 1 I 22 o 3 2 4 o o i Hematopoiesis, extramedullary 0 0 0 0 1 0 i MHeeppaat~oocmcyiytltede aalltteerraattiioonn,,babsasoopphhiilliicc 00eo O22 0O0 &06 0I 011 minimal 0 0 0 1 0 0 I mild 0 1 0 2 0 1 fu sor on moderaZe 0 1 0 3 0 0 i Wsstogte Saaation, vaunted Ps ow iow Nepatocyte alteration, vacuolated I 9 0 13 i I0 i mild 1 7 0 8 I 9 moderate 0 2 0 2 0 1 i i TiGGtrrlooeuuspp: 1i CCOONNTTRROOLL 00 ppppemr | GGGrrrooouuuppp 665 FFCCE---111444333 3320000ppppompmm {()} == TToottaall EExxaammiinneedd DSOAS=CpUnrsocthoecdeuleSdchDeedautlhe(ds)Sacrificels) SAC: Protocol Scheduled Sacrifice(s) 143 I Microscopic Incidence Page: 18 11333377..00114477 3MA00027272 H Non-Neoplastic Incidence for Males (continued) I rics ers act ecies as wie 1 i FFCC--114433:: TTwwoo YYeeaaRrrikreOrraallLabTTooorxxaiitccoiirttiyye--sOO,nnccooIggnece.nniiccii3ttMyy SSttuuddyy iinn RRaattss Table: 7 Project Number: 0281CR0012 Species: Rat I iesTissue/ Diagnosis/ 1 tte Modifier I -- 1 LiverHHeepp(aactt~ooncctyyitnteueevdva)accuuoollaattiioonn minimal R ore e mild Gon 1 Group 1 ww DOS SAC wen 5 Group 5 ww DOS SAC somGroup G ww DOS SAC CPSadiorbodi 3 14 1 13 z2 1i0 1 1 0 8 s5 2 O I 3 I n ! i B ! : moderate marked [on Hyperplasia, Kupffer cell prt Hyperplmaosdteircatenoite Hyperplastic nodule ees Megalocytosis on omiilndimal mild -- moderato nn a1 ison Mononuclear cell infiltration 0 0 HE0 Se oioo ood 5 00 ~ Cota soe 0 coin od [I]O0 Cr oin os 0 Sfp o 0 1 1 0 0 0 0 0 3 0 0 0 3 2 33 02c 2~ I0 0 4 0 0 3 0 O 0 O I 0 0 0 1 O 0 0 6 00 69 0 0 0 I mild 0 0 0 0 1 Necrosis I 2 3 2 3 B vont PLE os minimal 0 0 i 0 i ne [EEE i mommidoldederraattee 10] 11 I 1I1 111002 ur ie es attests Pao obs Portal bile duct proliferation 21 I 14 5 13 I minimal 0 0 I 0 0 mild 21 1 13 5 10 ii po Phos s ok moderate 0 0 0 0 0 rwren wee P0%I5s8 a3 s4 Portal mononuclear cell infiltrate 30 5 43 7 25 minimal mild I wsLung wo rs ves i AlWAilvtveheoiolnlaarrnmoamrcmaarclorpohplhaiagmgeiestss. a minimal n nemild ne moderate i pemarked B wets Atelectasis pramoderate B caEdema | mild Tots B mammoardrkekeredadte ForoFibrosis Bi Thene mild i moderate 8 TGitrloews: 1 CONTROL 9 pn Group 1 CONTROL 3 ppm I or ar GGrroouupp 5 FFCC--114633 33003ppppm 1! Group 6 FC-I~3 30 ppm 2 0 2G 5 cha Ch an 34) (5) FRU 551 0co 5 4 Pooh is 2 0 c EArCis Sea 2 3 I 0 0 1 Soha id 0 0 PlLotosis 0 0 2 0 41 7 (44) (14) 6 9 1 27 6 0 0 aoe 25 6 2 0 0 O 0 1 0 I 3 25 (35) 10 0 8 o2t O 3 3 S 0 0 0 0 0 0 Pos E obs O00 o 00 o00 o 0O o00 HET0 0 1 0 0 PPeoosnioeboe 0 0 0 0 0 0 0 1 0 0 (0)) == TToottaall EExxaammiinneedd i eat nt) SDOcSo= PUrnostcohceodluleSdcheDdeualthe(ds)Sacrifices) SAC= Protocol Scheduled Sacrifice{s) 114444 Werte tres pg: 2 Microscopic Incidence Page: 11333377..00114488 surcozrzrs 3MA00027273 Non-Neoplastic Incidence for Males (continued) i Riker Laboratories, Inc. 3M 1 FFCC--1I3~33:: TTwvoa YYeeaarr ODrraall TTooxxiicciittyy--DOnrccooggeanniicciittyy SSttuuddyy iinn RRaattss Tabl ~: 7 ! Project Number: 02CICR3012 Species: Rat i Tissue/ Group I Group 5 Group ~ I i WMaoddiiffiieerr Lung (:on:inued) 0DO0SS SSACC 0D0O5S SSACC MDO5S SSAACC i Grandl om~ nild d J :; 4 2 1 ; 1 2 ~L~ ~ 5 u 3 3 ] moderate i marked H~dizl hypertr,)phy, arteri=s moderate I J 3 i 1 13 i 2 ..: 2 ] 0 :~ecr]~is marked I Peribronch~al lymphoid hyperplasia mi~d 1 [El Peso id merivass~lar nononaclear infiltrate n minimal mild 1 To Poly i moderate I Pneumonia, interstitial, acete l ~ I ~ ? 19 i) ? 2 14 0 3 9 O 0 b 0 J 9 7 9 a g 2 O 1 0 O O 0 ? O ~ 3 J I I 1 Preumntmao,defrnattaerstitial, chronic 0 2 0 1 O O 16 i3sO Pneumonia, interstitial, chronic 2 I~ l 6 o 5 mild 1 !1 1 5 3 5 moderate 1 3 ~ 0 0 I Thrombus Vascular mineralization minimal 19 33 ~ ~3 11 1 mmmiotldederraatts~ | nu in Lymph Node {mesenteric) Within normal limits a on Granuloma moderate i Hemorrhage 51~ O 31 O oz 4 ~1 0 2 TE ;2) (33) i0 29 0 0 (G) (44) 5 3B 3 1 9 O 0 1 2 4 0 4 0011 0 852 O (O) (~) g I O O 9 O 0 O minimal mild n Sinusoidal ectasia i HMaar~arryy GGllaamnniddld Within normal limits I I, Mesentery Polyarteritis iI pth marked 1 z 3 1 0 0 1 1 0 3 ~ O 0 0 0 i 0 O cheb Beh hed (F9O) I ( 0O}R(OE 0) (OE 1) E(~0)E(]~0) o o o o 1 o Sioa aoa o) ( 2} (o) (o) ( ~} (~) 0~ ~0 1i 02 00 11 I I i TiGGtrrlooeuuspp: 11 CCOONNTTRROOLL 0 ppppma GGGrrrooouuuppp 5~ FFFCCC---111443~3 3330O0Jppppompnm I (()) == TToottaal) EExxaamnifnneod DSSOAASCC-== PPUrrnoosttcoohcceoodlluleSSdcchheDadetuaulzehed(ds)SSaaccrriiffiiccse((ss)) 114455 Microscopic Incidence Pa~e: 2U 11333377..00114499 3MA00027274 I I I I 1 A { I] iI 1 I I i I I 1 I ' I 1 I 1I I i I I Non-~eoplastic Incidence for Males (continued) Riker Laboratories. Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0281CR0012 Species: Rat Table: 7 Tissue/ DiagnoosMiodsd/iffiieerr rn Pancreas Within normal limits Acinamrmiiannttirmoeapdlhy mild moderate marked Le HyperpIasia. acinar cell wmiilldd moderate ite Hyperplasia. islet cell mild moderate ppieee Polyarteritis minimal moderate marked ParaWWtiihttyhhriionnidnnoorrmmaall lliimmiittss. Pituitary Within normal limits Cyst esHyperplasia mild ProsWtWiaittthehiinn nnoorrmmaall1iIaiimt|sts. Edema moderate Prostatitis. acute minimal rp nemild moderate marked Salivary Gland pmoe h StWailtahidnenniotrimsa,l alciumtiets Sialadenitis. acute moderate marked Sialadenitis. chronic We minimal mild moderate Group I oDOsS SSAiCc Group 5 BD0OS5 sSAcC Group 6 D0O0sS SSAKCC SU. t Tegh Bs 13} ( 33} (6) (43) I0 24 4 27 02 040 & 00 11 12) ( 34) I0 21 1 I 1 I 2 0 6 0 5 1 1 0 4 0 2 0 ! 0 0 0 0 Pati, 0 0 00 00 1 1 0a11 0 0~ i Q 0 2 0 1i 1 L oo: 0 2 0 0 0 2 ois i 3 0 0 i 3 oa 1 1 i 0 S Sovt t S 4 0 0 0 2 0 2 0 2 0 0 0 2 0 0 s3 d3 I 2 0 ~55) (111666) ( 555 } ( 231 ) 29 ( 7 771 {%2266) 15) ( 33] (5) (41) 13) ( 3~) 7 ig 3 28 3 20 2 2 0 2 1 4 Ch Che Cho 0 2 0 2 w13)o( z33] I0 27 0 0 0 0 (6s)o (4@3) 5 40 0 2 0 1 uo 13) ( 35) 11 35 I 0 0 0 0 O I 0 0 0 0 O 3 5 1 3 2 1 0 0 0 I 0 0 BPikrhoedsdeed 1 2 i 3 1 1 12) (32) 0 0 0 I 1 1 (~) ( 4Z 1 1 .0 0 O 10) ( 34) S EEE E 0 00 0 0 0 0 [0 IY1 0 1 0 0 0 2111 O 0 0 1 0 I 0 14 0 12 Sronton 0 I 0 0 0 0 0 0 0 0 0 7 0 0 0 1 0 6 TEE TiGGtrrlooeuuspp: 1I CCOONNTTRROOLL O0 ppppm Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm TEE en {()) == TToottaall EExxaammiinneedd DOS: U,scheduled Death(s) SAC: Protocol Scheduled Sacrifice(s) 146 146 Microscopic Incidence Page: 21 11333377..00115500 3MA00027275 i iBN | ii 1 i n 1 i i I i n i 1i B 1 i i 1| =: Non-Neoplastic Incidence for Males (continued) FFCC--114433:: TTwwoo fYeeaaRrrikOeOrrraallLabTTooorxxaiitccoiirttiyye--sOO,nnccooIggneec.nnitccii3ttMyy SSttuuddyy iinn RRaattss Project Number: 0281CR0012 Species: Rat Table: 7 Tissue/ DiagnoNsMoiocsdi/iffiieerr Salivary Gland (continued) SStiaallaaddeenniittiiss,, cchhrroonniicc marked "Skin Abscess tts, wri Pododermatitis, ulcerative marked Ulcer mmaarrckiaad Small Intestine Within normal limits ou Polyarteritis moderate marked Spinal Cord Within normal )imits Spleen ire AAWttirrtohopiphnhyynormal limits moderate Fibrosis moderate Nestea, exrameatur, Hematopoiesis. mild Taee moderate extramedullary, marked Nemosiderosis i" NNeeccrroossiimssild moderate nenPolyarteritis moderate Stomach Within normal limits = Edema momoddeerraattee marked Gastritis, acute mild Ulcer marked wre increased Group i DDOsS SSAKC Group 5 0D0OsS SSACC Group 6 0DO0S5 SSAACC 0 0 Ch heh O) (7) 0 0 Pir 3 5 0 (O) 0 0 7 (2) O 1 hh 0 (5) (~) 1 0 2 2 3 5 0 i 2 2 111 9O0 0 oo 0 0 0 0 0 1 0 1 i~) (34) (6) { 44) I i) (O) 13 32 5 44 Pls 0 2 0 I 0 I 0 9 0 0 0 0 1 0 0 0 0 0 0 0 15) { 32) (6) (42) (O) (O) 15 32 5 42 0 0 16) (34) (6) (44) (14) (3~) Doorn 0S 22O0 0 0 I11 2050 I 0 o8 0 35 0 0 O 0 I 0 1 4 8 3 Lo 4 0 2 0 EEE I 0 Pesos I 0 0 0 0 0 I I 0 I 1 0 0 0 0 0 0 0 I 0 0 0 0 1 O 5 ii 3 19 4 0 Sos 5 II 0o 11 0 1 3 19 0[I]0 D 0 se 0 00 0 0 Gh hed ohh 0 0 0 0 16) (33) O 0 0 0 (5) ( 44} 0 0 1 (14) (35) Ii 33 5 43 II 35 EEEEE 3 0 22 0 1 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 I 0 0 0 O 9 1 0 0 0 i D O 0 3 0 i 0 O 0 3 0 For an Titles: Group 1 CONTROL 0 ppm Group ~ FC-I~3 300 ppm Group 6 FC-143 30 ppm E EIE NER ew () = Total Examined DOS= Unscheduled Death(s) SAC: Protocol Scheduled Sacrifice(s) a7 147 Microscopic Incidence Page: 22 11333377..00115511 3MA00027276 Non-Neoplastic Incidenoe for Males (continued) I Riker Laboratories, Inc. 3M 16 Te er To Sty 1 es FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats iI Tare7: Project Number: 0281CR0012 Species: Rat Table: 7 n Tissue/ 1 Diagnosis/ MoMdodiiffiieerr B Testis/Epididymis Group I D0O0SS SSAACC Group 5 0DO0SS SSAACC Group 6 DDOOSS SSAACC I~) (33) (6) (44) (14) ( I Within normal limits Granuloma, spermatic Leydig cell hyperplasia 13 26 0 0 0 0 5 23 0 0 O 1 7 26 1 0 1 1 I 1 nommodidleedrraattee Mineralization e 00 e00 0 1 o03o 201 0 2 011 00I 0 0 mild Polyarteritis i ie Lie o oot mild i moderate marked 1 ni, srs Pore od Tubule atrophy, n ee FO I mild aspermatogenesis 0 1 1 5 1 I 0 I 0 3 3 4 i I 0 2 O 2 0 0 0 2 0 0 1 i0 0 1 0 0 1 5 0 2 I 2 3 1 5 5 3 0 i B mmmaoadrrekkreeaddte Vascular mineralization i121 1 2 3 0 01s3 I 5 0 g I 1I I 4 3 0 Ii Tas mild moderate Thymus Hemorrhage O 0 (Dea 0 0 i) (O) 0 O 0 7 nen 0 2 (I) I 1) 0 I 3 neo 0 0 { I) (O) 0 0 marked Thyroid i Within normal limits Cyst, colloid 1 wmiilldd Follicular hyperplasia, cystic m moderate 0 0 12) (31) ii 25 0 1 00 I1 0 I 0 i 0 I (5) (42) 4 33 1 1 1 I 00 0 1 0 1 0 0 I 12) (35) I0 26 0 1 o0 90 1 1 0 marked Hyperplasia, C cell I mild i i UUllttiio~oobbmrroaadnneccrhhaiitaaell ccyysstt os Trachea i Within normal limits Urinary Bladder 1 i wre Within nom~al limits | Calculus Cystitis, acute 1 pry moderate 'B En Cystitis, chronic 0 0 0 0 1 1 0 I 0 i 0 1 0 1 Peon 11 0 0 1 1 00 0 30 3 Ghih Choad { 15) ( 34) ( 6) ( 42) 1 5 I 3 hom 1 2 0 2 1 2 ( 13) ( 35) Dheaih gus 15 34 { 13) (33) 13 32 G 42 (6) (44) 5 41 13 35 ( 14} (35) II 35 0 O i 0 Por odg i O Pil 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 I 0 minimal 0 0 0 O I 0 i Titles: Group I CONTROL O ppm ii Soy FE Tm GGGrrrooouuuppp 5 5 5 FFFCCC---1114~9332 30 pon 330 ppm 30 ppm es imenien ast) () = Total Examined SACDOS= SAC= PUPrrnoosttcoohcceoodlluleSSdcchheDededuautllhee(dds)SSaaccrriiffiiccee(ss)) 114488 I Microscopic Incidence Page: 23 11333377..00115522 3MA00027277 m Non-Neoplastic Incidence for Males Icoatinued) | S---------- 0 "FFCC--114433:: TTvw~oo YYeeaaRrrikOeOrrraallLabTTooorxxaiitccoiirttiyye--sOO,nnccooIggneec.nniiccii3ttMyy SSttuuddyy ifnn RRaattss Project Number: 0281CR0312 Species: Rat Table: 7 I Tissue/ Diagnosis/ I1 TeiModifier WW Group I DOS SAC WTR Group 5 DOS SAC wR Group 6 DOS SAC l 1 Urinary Bladder (continued) EEppiitthheelliiaall hhyyppeerrppllaassiiaa,, ppaappiill|laarryy 0oo0 o o 110 0 mild o o o I 0 Epithelial byperplasia, simple 2 1 3 3 o I minimal mild Hemorrhage iI sarced minimal marked o o 2 1 i Io oo 1 o I 1 2 o 1 0o o ooIa o o 3 o o o oooo 0o o I I | I l l I l l I i TiGGtrrlooeuuspp: I1CCOONTNROTL0R0pOppLpm I!1 GGGrrrooouuuppp 355FFFCC--E11443313330000p3poppmpum (0)) =+ TToottaall EExxaamnitnneedd Worse ete pg: 5 SDSAOACSC=== PPUrrnoosttcoohcceoodlluleSSdcchheDeeddauutllhee(dds)SSaaccrriiffiiccee((ss)) 149 Microscopic Incidence Page: 11333377..00115533 3MA00027278 B Non-Neoplastic Incidence for Females Riker Laboratories, Inc. 3M FC-I~3: Two Year Oral Toxicity-Oncogenicity Study in Rats i 1 PPrroojjeecctt NNuummbbeerr:: 00223911C0RR~I1122 SSppeecciieess:: RRaatt Table: Tissue/ i Saastss Diagnosis/ H hoe Modifier 1 woAdrenal I Within normal limits Cortical atrophy I moderate Cortical degeneration mild I moderate marked Cortical vacuolation i mmmoiodldederraattee Hematopoiesis, extramedullary I mild moderate prsmarked B Hemosiderosis mild Medullary cell hyperplasia | mild Te B Necrosimsoderate Necrosis i moderate marked ~odular hyperplasia, cortex phy moderate I Sinusoidal ectasia, cortex minimal 1 amild n Toe moderate go i Aaorrttaa marked Within normal limits B Mineralization mild Bone Marrow I Within normal limits wy i BraiWnithin norma Miaits Within normal limits I Esophagus Within normal limits ! Group I Group 5 Group 5 i WE "RRarWs R DOS SAC DOS SAC DOS SAC (mm (mm Coan 25) (25) (2~) (29) (25) (24) 2 0 4 2 3 I 0 0 1 2 0 0 O 1 2 0 0 2 5 I ~ I 0 0 0 I 2 i 3 0 9 3 2 0 2 1 0 O O 3 2 1 3 4 I 21to1I ro0I 121 331 001 4 0 0 0 1 i Prt 3 0 I 0 0 0 0 9 0 0 0 0 0 0 0 1 1 0 0 0 0 0 1 0 0 0 0 0 I 0 Prosi I 2 i 2 3 O 00 3 0 2 0 I 0 I 00 0 0 O 2 0 2 s0c 0O 0 0 1 0 0 0 0 O Pon 2 0 0 3 0 0 0 0 0 1 0 1 O 0 1 1 19 23 O I ore 08 ~ 4 P 11i1l.g 1 5 ~ 1~ 25 0 I 9 6 3 7 ~I 22 1 0 7 3 7 13 r2a15) e( 2d39) (n194)e~ mI2I7) n5 en 17 23 19 27 9 0 2 0 0 0 0 0 2 3 0 0 0 0 el { 25) (2S) 23 75 ( 22s55) w (2254) Ei ched (2~) (~9) 21 2g ( a2~} (229) 21 29 (O) ( O} 0 0 (o2) (o0) ~ 0 15) ( 21) ( 9} ( 15} ( 23) { 22) 14 21 9 15 23 22 Titles: n Group 1 CONTROL 3 ppm Group 5 FC-I~3 300 ppm B1 plndpgismnoias Group 6 FC-143 30 ppm B Shc rate Seated Serivice(s) () : Total Examine~ DOS: Unscheduled Death(s} SAC= Protocol Scheduled Sacrifice(s) 115500 Microscopic Incidence Page: 25 11333377..00115544 3MA00027279 i I l i I I 1 l 1l I I I|| iI iI i I I l 1 I I I I l NNoonn--NNeeooppllaassttiicc IInncciiddeenaccee ffoorr FFeemmaalleess ((ccoonnttiinnuueedd)) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toicity-Oncogenicity Study in Rats Project Number: 0281CR0017 Species: Rat vans Tissue/ Diagnosis/ - Modi fi er Eye Within normal limits Cataract Keratiti s, acute marked Panophtamhararklkeemddi ti s Phthsis bulbi moderate Heart Within normal limits Myocardial fibrosis minimal mild Myocarditis, chronic nonsuppurative ald minimal mild moderate Chrome prearessve septa Kidney Within normal limits Chronic progressive nephropat~y minimal Smoidledrate moderate marked Cyst momdoedrearattee Hydronephrosis moderate Hyperplasia, pelvic epithelium mild Mineral ization mmmooiddleedrraattee Nephrosi s mild moderate marked Pelvic mineral ization minimal mild moderate Group ] ny Group 5 Group 6 DOS SAC 20) ( 231 17 21 1 0 I 0 I 0 a00 i1I 0 1 0 I 25) (25) 19 I 0 2 0 0 0 2 6 I0 0 0 4 I0 2 0 pow 25) ( 25) 3 3 12 18 3 25 2 2i0 3 2 1 2 I 22 00 1 0 i 0 4 i 4 1 2 9 20 000 7 0 I 0 3 0 2 0 14 15 4 6 8 8 i 2 DOS SAC (16) (28) 16 28 0 0 o 0 0 0 6000 003 0 0 0 0 ( 21} (29) 15 2~ I 1 0 1 1 O 5 5 I aI 4 4 0 0 1m ( 21) ( 29) 7 ~ 7 19 5 4 01 0 212 2 i 1 0 0 0o 00 0 1 0 0 0 0 0 0 '3 0 000 000 0 0 0 0 0 0 0 0 I0 14 4 6 4 7 I 0 TTDOS SAC ( 2} (1) I I 0 o i 0 1 0 o00o 0o 0 0 0 0 (26) (24) 25 20 0 0 0 0 0 i 4 01a0 I 4 0 0 ow os ( 26) { 24) 5 5 12 9 4 5 80ac4 0 0 0 0 E0I 0 0 0 0 0 O 0 0 1 0 01I 000 I 2 0 1 0 I 1 0 12 15 4 6 6 6 0 2 Table: Titles: Group 1 CONTROL 0 ppm Grow F192 10 pm Group 5 FC-143 30'3 ppm Group ~ FC-143 33 ppm () = Total Examined SiewDOS= SAC= pUPrrnoosttcoohcceaodlluleSSdcchheDededuaultlhee(dds)SSaaccrriiffiiccee((ss)) 151 Microscopic Incidence Page: 11333377..00115555 3MA00027280 1 N~oonn--NNeeooppllaas~ttiicc IInncciiddeennccee ffoorr FFeemmaalleess ((ccoonnttiinnuueedd)) I Ri~er Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats I res Hers RGIZ spies at Project Number: DZ81CR~D12 Species: Rat Table: 1| tsar ny Tissue/ n Diagnosis/ CH ww ER WR Modifier 1 ony tmnt Kidney (continued) I Pelvic mineralization marked 1 Pass amr te soitetion soooao1 aoa Pigment, cony. tub. epithelium i minimal pl 113d moderate Group I DOS SAC Group 5 DOS SAC Group G DOS SAC 1 0 0 0 0 0 0 0 I I 0 1 0 I 0 0 2 1 0 2 0 0 2 Polyarteritis 0 0 0 i minimal 0 0 0 0 0 1 i Proteainimiilrddesorption droplets 00 000 Oa i 000 0v I 1I1 To I marked 0 0 I 0 I I Pyelitis, acute 0 0 2 0 0 0 mild 0 0 i 3 0 0 1 teats Soa oa moderate O 0 I 0 0 0 i Pyelon~phritis, acute I 0 0 0 0 0 Te Pir 1 B YVaaccuuoollaamttoiidooennr,,ateccoonnvv.. wtubb..eepptittabetiuunm T1 o0 1 0 00 00 0 00 9 I pra NER moderate i 0 0 oe rn heh hem heh LarGe Intestine { 24) (23) (17) (29) ( O) ( Within normal limits Nematodiasis i Liver W~thin normal limits 1 a Atrophy I - moderate 22 22 17 27 0 0 I I 0 2 0 0 P EEort (25) (25) (21) 1 0 4 4 0 0 0 0 0 0 0 0 7 7 1 0 1 0 1 animal Cystoid degeneration minimal 0 0 0 0 0 2D 0 I I 1 90 I 03 0 mild 0 0 0 0 1 0 i Hematopoiesis, extramedul]ary 3 0 1 0 5 2 minimal 0 0 0 0 3 1 i ne FE mild 3 0 O 0 2 1 n oe Psi 1 moderate 0 0 i 0 0 0 1 NoTvaos to, iti 1P1r1i1 1o1 d Hepatocyte alteration, basoph~lic I ~ 0 2 S 3 minimal O 0 0 I 0 0 i mild 1 5 O Ts Fiat i MHeeppaattooccmyyottdeeeraaaltlteteerraattiioonn,, eeoossiinnoopphhiilliicc 1 0i 222 a00 000 0a 60 mild O 2 0 0 0 0 i pi ge moderate 1 ~ O Hepatocyte alteration, vacuol~ted 2 11 2 4 I 5 i in shold minimal O g i 0 0 1 I mild 2 11 i i Titles: Group 1 CONTROL 0 ppm 1 GGrroouupp 55 FFCC--114433 320D0O ppppmm I PELE Group 5 FC-143 30 ppm B men DDIO)OSS=== UTUnontssacclhheeddEuuxllaeemddineDDdeeaatthh{ss}} SAC: Protocol Scheduled Sacrifice(s) 152] 52 Microscopic Incidence Page: 27 11333377..00115566 3MA00027281 n n aB B H iR H i iI i i |i| 1iI B B in 1R B 1 B i i B ~Jon-Neoplastic Incidence ?or Females (continued) es es es stsRiker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 02SICR0012 Species: Rat Table: 8 ne Tissue/ Diagnosis/ Modifier Liver {continued) Hepatocyte alteration, vacuolated marked Hepatocyte vacuolation ang minimal mild moderate Rraeyioss ~arked Hyperplastic nodule Megalocytosis minimal La MMiittoottiiccmsilcadcttiivviityy,, iinnccrreeaasseedd moderate Mononuclear cell infiltration amiilldd Ilecrosis rodrste mini~al mild moderate marked wie Pigment, Kupfer cell mild 2 Portal bile duct proliferation nd I d moderate marked Portal mono~uclear cell Se minimal mild moderate infiltrate nil Telangiectasis mild Lung frnc-- Within normal limits Abscess Alveolar macrophages Te minimal mild moderate Atelectasis mild [avg uEiietieol Titles: Group i CONTROL 3 ppm Groap 5 FC-143 330 pp~u Group 5 FC-143 30 ppm PeGroup ] DOS SAC Group 5 DOS SAC Group 5 DOS SAC 0 C 0 0 I 9 15 15 8 13 7 9 s I n131 05sn1~3 222 277 3 I 2 0 2 sooo 2 0 0 1 0 0 075 I 3 O 2 1 7 I 0 0 D i 0 0 1 6 o Poor 0100 0 I 0 00 0 0 I 0 O O 50 o 0 0 0 0 0 0 02 00 I 0 I100 0 0 o0 00 i 2 0 6 0 Leoooo 0 I I I 0 0 0 I 0 0 0 ss 1 0 3 0 0 0 I 0 2 005 000 1Ii 000 IE 4 13 3 12 I 5 ~ 5 .~ 0 i ,0o3o 0oSg I 4 i 4 0 0 0 0 0 0 I0 9 4 15 5 5 oo 0 9 1 O 0 ~ ~ 12 0 I tg O 2 5 4 0 0 II1c00 00 0 00 0 oo 0 0 0 0 (25) (21) { 29) (25) (24) few 2 3 I 0 9 I 3 O 0 6 13 os2 2 0 3 7 Sling I 0 S 0 2 0 4 12 0 i 0 1 3 5 0 O 0 0 0 i 0 0 0 0 0 1 S 05e VeIsretEotis)en (gs () = Total Examined DOS: Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) ] 5 ~icroscopic Incidence Page: 11333377..00115577 3MA00027282 | i BNoonn--Nteeooppllaassttiicc ITnncciiddeennccee ffoorr FFeemaatlleess ((ccoonnttiinnuueedd)) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxiity-Oncogenicity Study in Rats | Project Number: 0281CR0012 Species: Rat Table: 3 | Tissue/ Diagnosis/ Modifier Group I DOS SAC Group 5 DOS SAC Group 5 DOS SAC | Lung (continued) Edema 0 0 0 ~ 1 D mild Granuloma | mild marked ] dr Hemorrhage | minimal 0 0 0 0 0 0 0 4 Prose D 0 0 0 9 5 0 2 0 1 9 10 0 0 0 0 1 O 0 1 gt 0 1 0 0 9 0 1 | 1 mommiodldederraattse marked Hyperplasia, septal cell 81 31 I I 0 I 0 0 z 26 a46 1 0 0 0 ?8 0 0 2 2 I I 0 i | mild Perivascular m~nonuclear infiltrate minimal 0 0 4 9 0 I 0 0 5 9 3 4 0 I 0 2 0 0 mild 1 sodorats moderate | Pigment moderate 1 PPnneeuwmoonniiaa,, aaccuuttee eexxuuddaattiivvee mild | moderate a0 71I 0 i 0 I i1 00 0 0 i 0 902 005 0 0 0 0 0 00 0 0 0 0 000 00 0 0 0 0 11 0 I 0 0 | Pneumonia, foreign body marked Pneumonia, interstitial, chronic 0 0 0 0 ~ 3 0 0 0 O 3 6 ! 0 1 0 0 3 | 1 ammiilnldidmal marked Vascular mineralization +0 030 4 3 0 0 12 10 I1 0Is I 5 I 0 15 11 O930 0 3 0 0 IS 20 minimal mild i moderate Lymph ~Iode 1 ts, rin Hyperplasia, reactive | moderate 0 0 12 10 15 10 yee 0 0 0 I (O) ( D) ( O} (O) 0 0 0 0 0 0 0 0 11 12 er0 0 ( I) ( I) I 1 I 1 1 LympWhWiittNhhoiidnne nn(oomrremmsaaellntelTriimimicit)tss. Granuloma | Hemorrhage mild i ts moderate | feemarked ( w14 oz22 k14 oa21 0v00 0 0 0 1 0 0 P Peoots oe 2 i 1 i 1 0 0 0 0 2 0 0 0 1 0 1 0 0 0 0 0 0 0 0 | Titles: 5 om Group 1 CONTROL 0 ppm i GGrroouupp 55 FFCC--114433 330000 ppppm | Group 6 FC-143 30 ppm | past () = Total Examined DD0OSS== UUnnsscchheedduulleedd DDeeaatthh((ss)) SAC= Protocol Scheduled Sacrifice(s) 154 Microscopic Incidence Page: 29 11333377..00115588 3MA00027283 iB B I i 1I I 1 1 B i B B 1 1n i|] | n B B B B 5 | n ! i I Fes: ve ok See st 10 NNoonn--N~eeaoppllaassttiicc IInncciiddeennccee ffoorr FFeemmaalleess ((ccoonnttiinnuueedd)) Riker Laboratories, Inc. 3H FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Project Number: 0281CR0012 Species: Rat or Tissue/ Diagnosis/ ie Modifier i ee Cer tem Lymph Node (mesenteric) (continued) Pigment, brown minimal hemild pimoderate Sinusoidal ectasia fobmoderate marked MammaWWriiytthhiiGnnlannndoorrmsaall llimmiittss Fibrosis mild Galactocele Coir mest Lobular hyperplasia moderate soyDvaryWithin Within nnoorrmmaall lniimittss Cyst Tubular hyperplasia maillldd moderate marked Pancreas AAWcciiitnnhaairrnatantorrromopaphlhyy limits immiillnidmal moderate marked porn Cyst Edema moderate Hyperplasia, islet cell mild Pancreatitis, chronic ht PoPloylayratremtroeidrtieitrsias,te ptminimal ear Parathyroid Within normal limits on 1 Group I WE DOS $A3 on 5 Group 5 wR DOS SAC Table: 8 a 6 Group 6 DOS SAC 0 0 0 0 soo 4:5 ob 0 0 spool 0 0 i 0 Peston i 0 0 5 0 i 0 2 0 2 0 2 0 I 0 0 0 0 0 0 D 0 0 0 0 0 0 0 i 0 0 2434) (23g9) (1771 ) (9279) (23) 4 (2277) 0 0 0 I 0 0 0 0 I 5 4 2 1 Sahn 4 3 2 I 1 0 2 0 hh abo 25) 19 rom (23) ( 18} 17 11 ow(29) 16 0 0 7 2 ad 2 I 0 hoaon (25) ( 23 11 3 3 0 5 2 7 0 0 o 0 o0 7 8 00 22 0 7 0 11 0 0 6 6 0 0 0 i O 0 0 24) (25) (19) (2S) (22) (21) 20o2 1666~6 15~2 2242~4 1833 1728 00o 221 022 1I1 Ii1 0aI O 3 0 0 0 i 0 O 0 0 1 0 Elo 0 1 D 0 9 0 0 ~ 1 0 1 0 9 0 0 0 0 0 0 0 0 1 0 O O 0 HE 0 0 00 0 EEE 0 0 Cheb chon 5) (O) 0 1 I 0 021 000 0 0 (9) ( 14} 0 I 0 I 0 0 ohooh 000 011 0 (15) (15) 5 0 9 14 15 15 Titles: To oun om Group I CONTROL 0 ppm GGrroouupp 55 FFCC--114332 330000 pppam mien Group 6 FC-143 30 ppm AR() = Total Examined D0O0SS== UUnnsscchheedduulleedd DDeeaatthh((ss)) re even SAC= Protocol Scheduled Sacrificels) 155 155 Microscopic Incidence Page: 30 11333377..00115599 3MA00027284 1 N~oonn--NNeeooppllaassttiicc IInncciiddeennccee ffoorr FFeemmaalleess ((ccoonnttiinnuueedd)) I Riker Laboratories, Inc. 3M FC-143: T~o Year Oral Toxicity-Oncogenicity Study in Rats iI ragct Weber: CEICHIIZ Spates: Rat Project Number: 0281CR0012 Species: Rat Table: I Wie Tissue/ Diagnosis/ Modifier SW Group I DOS SAC WW Group 5 DOS SAC Group 6 DOS SAC Pituitary I Within normal Cyst 1 Peers Hemorrhage I er marked limits (22) { 24) { 21) (29) (23) 24) 5 7 0 0 Povo o uo I 0 ener 1 0 7 7 0 0 0 0 0 0 3 4 0 i 0 0 0 0 I soyNecrosis moderate Salivary Gland hh omoh omen 1 0 0 0 0 O 1 0 0 0 0 0 ( 19} (2~) { 15) (25) (22) 24) I i so Toe WSSiiitaahlliaanddeennniiottriimassl,, cclhhirrmooinntisicc mild moderate chTeeboirhehhed 131 I 02~0 0 0 i 0 150[I 23 2 0 0 0 2 220o 123 i 0 I 0 O I pode Skin Within normal limits Acanthosis FE ( 3} (3) { 2) { o) (6) 4) 0 0 0 0 2 2 0 i 0 0 0 0 I i PoPdooddoedremrsmiaalttdiittiiss,, uullcceerraattiivvee marked Ulcer 1 mmooddeerraattee semarked I Small Intestine Within normal limits i aEdema I mild BN Ucer Granuloma Ulcer I anemarked inSpinal Cord Within normal limits 1 Tos Nalacia I - ae moderate 00o 30i 01 00 I 0 0 0 0 0 0 0 0 0 'I 0 0 0 Lorn 21 i 000 1 0 00[EE0O 0 0 00a 00 0 0 0 LE on nr (2~) (25) { 1~) (29) ( I 24 25 17 28 0 0 0 0 I 0 0 0 0 0 I 0 0 0 000 000 000 0oIo 011 90 0 Prope i 0 0 0 0 1 0 mem heh ( 25} ( 23) ( 21) ( 29) ( 0 o} 23 23 21 29 0 0 TSN 0 I 0 0 0 0 0 hLehoreine i 0 0 0 0 0 Spleen (25) (25) { 21) (29) (24) 23) I Within normal limits Hematopoiesis, extramedullary, increased ~ It 7 ~ 12 23 2 I I0 17 ii 5 I 1 a mommiodldederraattee marked LoL + i 1I 4 1 2 0 1 II 900 0 I +5 22 4 2 2 i Ii we Hemosiderosis minimal mild moderate Suis 12 13 0 0 8 I~ l 5 0 i 6 3 0 I 1 o2 i 0 0 0 i I 0 I Titles: I 1 GGGrrrooouuuppp 5I5 FFCCCO--~11TR413O3L 3300000ppppmppmm Group 6 FC-143 30 ppm I D()0S=: DOS= UTUonntssacclhheeddEuuxllaeemddineDDdeeaatthhl(ss)) SAC~ Protocol Scheduled Sacrifice(s) Microscopic Incidence Page: 31 11333377..00116600 3MA00027285 1 Stas ste fr Fee (net Non-~eoplastic Incidence For Females (continued) Riker Laboratories, Inc. 3M | FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats | Project Number: 0281CR0012 Species: Rat Table: 3 1 TTihssssuui~e// i Diagnosis/ peModi fi er 1 hen fctimets Spleen (continued) | Hemosiderosis HWE Gop 1 Group 1 DOS SAC Grom 5 Group 5 DOS SAC Grow 6 Group 6 DOS SAC | marked Stomach Within norma7 limits 0 0 (25) (25) 20 25 0 0 (20) (29) 13 29 1 0 (26) (24) 20 24 i Edema moderate moderate | Hemorrhage mild fa moderate i Waerriacion Mineralization | mild 00eo 0O2 222 9000 I 0 0 0 Prone 1 0 Toso 1 0 0 0 0 0 0 0 0 0 1 0 0 0 000 O0 lg I D os I 0 D 0 0 D I Za Necrosis mild moderate SEE 2 0 1 0 1 0 I 0 0 0 0 0 0 I 0 1 0 0 O i Ulceramiitldd 1 0 00 00 0 0 o0 00 4 0 22 00 is i ed Thyroid (25) (25) (15) (25) { 23) (22) i Within normal limits 20 23 14 22 22 21 Follicular hyperplasia, cystic I 0 0 0 D 0 1 aie Too 9s mild I Hyperplasia, C cell i 0 0 0 0 0 I 2 ~ 0 I 0 mild 0 0 1 2 I 0 1 stadia ct Pog dd Ultimobranchial cyst 2 1 0 2 | Trachea (25) (25) (20) (25) (24) (23) | 1 UurriinnaWarirytyhiBBnllaaddnddoreemrral limits Within normal limits Calculus (2255) (2255) (25) (25) 17 25 1 0 (1260) (2263) (16) { 26) 15 25 0 0 (225~) ( 2232) (25) (22) 0 0 | Epithelial hyperplasia, papillary marked Epithelial hyperplasia, simple 1 0 1 0 7 0 0 0 O 0 0 1 0 0 9 9 2 0 i mmoidledrate moderate | Hypertrophy mild Uterus i j---- Within normal limits | Cystic glands 6I1000 000 02I 200 000 0 0 0 1 0 0 AEE 0 0 (25) (25) 21 17 0 1 (19) (29) 17 24 0 0 (26) (23) 17 17 2 5 1 4 7 5 | minimal mild moderate 0 0 0 1 2 1 0 1 1 2 0 1 0 0 I 1 2 1 1 nt Titles: i1 LGeLecaar 0m AiEoEn: 157 Group I CONTROL 0 ppm () = Total Examined i ' Group 5 FC-143 300 ppm Group 6 FC-I 3 30 ppm | Werte tee s1s572 DOS= Unscheduled Death(s) SAC= Protocol Scheduled Sacrifice(s) M~croscopic Incidence Page: 32 11333377..00116611 3MA00027286 B Neopiastic Incidence for Females I Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicit-Oncogenicity S~udy in Rats - Dne Year Interim Table: 10 Project Number: 0281CR0012 Species: Rat n Tissue/ B Diagnosis/ Modifier 'I pl i Ma,F~imabrryoaGclaenndcas fibroadenoma Pituitary Adenoma Group I Group 5 Yo0 { 15) 0 [ 15) I 2 (13) 2 (14) 0 | B B B H I n H B I I I Titles: i ioGroup I CONTROL 0 ppm H1 Group 5 FC-143 300 ppm B 110 0 som (} = Total Examined 116600 Microscopic Incidence Page: 35 11333377..00116622 3MA00027287 Do 00 Whe- -o J 00 -9 RVFEI 3 - ol ty 11333377..00116633 1I 1I 1B iH 1n I 1 B 1 I 1 1 I B B 1 n n 1 1 I 1 | 1 I 1 1n u 3MA00027288 I 1 Fort: Te teSRNRuiievkoeeeprrrlsaahsLLTtaisiboocorrraaIItetnnoocrerrit-iidaoeeressncc,,ceoeIIsnfnfeecoo..rrteaMan33l1l11eyessStuy fn fats FC-I~3: Two Year Oral Toxicity-Oncogenicity Study in Rats Tate: 1 Table: 11 1 as rs ETE cies: Project :umber: 0281CRO]12 Species: Rat l l 1 THiassssuSDeeih/aagmnoosswtiasss/ier OGGroouwpr11 Grom Group 5 5 oe es we Gon Group 6 oS Modifier DOS SAC DOS SAC DOS SAC I 1 aAdrreenCnaitlrctns, artic Gogttonsirons Carcinoma, cortical (1C ~C) ( 03O4) T C(6a)S(Ca44n) ce1 0oi0 ((140IR) (8(36) 0a 0a ! i PFGPPThrhhaeeeenetooogsrccclchhhiehrrroomooonmenmmeaooouricccreyyyyotittmtoiooaonmmnesaast,,,,aermabbaeellnsaiiiieggggmnnnniaaennst:n resent oo 0111~1 o0 o0 0o00 oo414 01 00 o0u000o o0aI Hemolymphoreticular neoplasm present yi Bone Marrow I arnearpmtorsticatar acalasn resent Hemolymphoreticular neoplasm present G1e50G) o(em0 (aPEtR4a02) (00D 0 0 (O) (O) C0 n0 Cac0 (o0 on0 . ! 1 BrainArOsertrctopsc/totoodmnaa,,noesbeoemntisagnnbenign SOleirgoodneyne4rroagtliioomaat,rbeenisgnpa present 16S0P) (oeI eo0 oo440) o1 o0 0ia dfo y (O) (i) 0 1 0a oe Hemolymphoreticular neoplasm present C0am0 aI ce0 (n0 ed0 iI I I 1 1 I A -- i 1 1I iI Eye `HHeemmoollyymapphhoorreettiiccuullaarr nneeooppllaassma [iHeart etyaprareticatar ssopasn Hemolymphoreticular neoplasm viens Kidney st soreticatar neplasn Hemolymphoreticular neoplasm ner Liver Tesstocetata carcirann Hepatocellular carcinoma A He~olymphoreticular neoplasm wosLung entymprerticatar mptase Hemolymphoreticular neoplasm Leon ote (ssaminal) Lymph Node (abdominal) emymanaretioar neslim Hemolymphoreticular neoplasm Lyon dade (reanteric) Lymph Node (mesenteric) enngtosareins Hemangiosarcoma enopanaretiesar necpias Hemolymphoreticular neoplasm Paras Pancreas Raancarctns Adenocarcinoma Ter een adams Islet cell adenoma Netymonareticsar septa Memolymphoreticular neoplasm Paotd Parathyroid [ey A4enoma Hiatt Pituitary pe Adeno:na Satuary Sand Salivary Gland Careinom Carcinoma inSkin riorom FiFFbiirbborroosmsaaarrccoomma ee} LL 11S prreesseenntt srssent present resent present present present present present present presers present present present 12o5) ( 3~o) 0 Cmpceea~) ( 61i } ( 00 Caatc ( 6) ( ~} 00 0 otmy ( I~') (36) G1o6p)r(es3s40} CI O0 C(D ~c)TE(eS440) C6i ao G(14i0IR) n(3o6) (101 (8o Sener ~) C 3) (6) ( 4~) ( 14} (36) I i Ch2DOoRmI Ca3 c CRireCes44i) ((1~40IIR) 080 ( 361 neo0 (n1 e 0 o) (i) ( o) ES I 0 0 I G5 as Cha 33) (G) ( 44) (I) ((OT)oen.i) (D1Pess0D C011asc10 Gmo00so 0 0 SSO133] 0(6L)S 0Po 0 ( 43) 51I I 12) 34) 00 aoo 0 1 C1om0 6} ( 16) C0Bs0 ((5n0E)R e( 3m10) Ch0 om2 ne0 e 0 (7) { om0 om0 33) Cnn Ii CSwECh GRn ~2) (32) (5) ( 41) 2 II (5) ( 41) (13) (34) CSg (meoyn (10) ( 3.~-) (h0BP) e(a7n0) tc(oa1)tc( ia02) ec(50)a(n40) 111 000 000 000 202 011 i Toes Titles: I GGrroowws 15 cF1o8m2o3003po3n 1 Grain 8 FCL183 20 om Group Group Ii Group 1 CONTROL 0 ppm 5 FC-143 300 ppm 5 FC-143 30 ppm 02()05=- TTtonotsatelheSEcxauamemdirnaeetdstn(z) DSOhSe=e pUrnostcohceodnuleSdensDseautlhe(ds)Surificels) 161 SAC= Protocol Scheduled MSaicerriefsiccpet(se) Tstaene p1ug6:135 Microscopic Incidence Page: 36 I 11333377..00116644 amAooo2728 3MA00027289 1B cpus Ictdee for aes (nina) Neoplastic Incidence for Males (continued) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats i Project Number: 0281CR0012 Species: Rat Table: 11 Tissue/ i Diagnosis/ 1 ie Modifier i Skin (continued) Ew Group 1 ........... DOS SAC Group 5 DOS SAC Group 6 DOS SAC Keratoacanthoma 1 2 0 1 0 0 Liposarcoma 1 D 0 0 0 0 i Papilloma 0 I 0 0 0 1 SaSmlal)lHemIIonnlttyeesmstptihinanereeticular neoplasm present ((14M1) E(3.M10) ({ B06H) 0 (44) ((Di0)L(OO) Hemolymphoreticular neoplasm present 1 0 1 0 0 0 | Soft Tissues (abdomen) (o) { o) (0) (o) (o) (i) Fibroma Soft Tissues {thorax) i HisLiocytoma, malignant Spleen i Hemangiosareons 1 oo 0 o Hemangiosarco~a I Hemolymphoreticular neoplasm present 0 (O) 0 16) 0 1 0 (~) 0 ( 34} I I 0 ( O} 0 (6) 0 1 0 ( ~} 1 (4~) 0 O 0 ( O} 0 (14) 0 1 I (O) 0 (36) 0 0 Stomach 1G} (33) ( G} (44) (~4) (35) | Adenocarcinoma He~olymphoreticular neoplasm present Testis/Epididymis O O I 0 15) (33) O 1 0 0 (6) (44) O O 0 O (14) (36) Leydig cell adenoma 0 0 0 7 0 2 Thymus 1) (O) ( I) { 1) ( ~} (3) i Hemolymphoreticular neoplasm present 1 0 1 0 1 0 Thyroid ( 12) ( 31) ( 5) ( 42) ( 12) ( 35} i cell adenoma oo 4 0 2 C cell adenoma C cell carcinoma 0 0 0 2 0 4 0 0 0 2 0 0 | Follicular adenom~ 1 UrUriinnaarryyBlBlaaddddeerr O 0 0 .,~ 0 C(1~33)) (033~)) ((66)) ((~284)) ((1~8)) ((3355)) Hemolymphoreticular neoplasm present 1 0 i 0 3 0 i Hemolymphoreticular System [# affected] [ 3] [ i] [ i1 [ 1] [ 1] [ O] Malignant lymp~oma, lymphocytic n 0 i I 0 0 i1 i i: IT Malignant Iymphoma, histiocytic 3 i I 0 0 0 Leukemia, myeloid 0 0 0 0 I 0~ I i i I Titles: Group 1 CONTROL 0 ppm i Gro 5 F010 0030 Group 5 FC-143 300 ppm n Group 6 FC-143 30 ppm i 205. isthe eves) () = Total Examined DOS= Unscheduled Death(s) SAC: Protocol Scheduled Sacrifice{s) Microscopic Incidence Page: 37 11333377..00116655 3MA00027290 Neoplastic Incidence For Females i Riker Laboratories, Inc. 3M FC-I~3: Two Year Oral Toxicity-Oncogenicity Study in Rats rs ses vz spt Project Number: 0281CR0012 Species: Rat Table: 12 1i _ -- Tissue/ i Diagnosis/ i rr WR t4odifier Group I DOS SAC Group 5 DOS SAC Group 6 DOS SAC i sr fim me Cpe Adrenal z5) ( ZS) ( (29) 25) (z~) I Po pe ey i CaACrdaerc,ci~ionnmooam,ma,,ccoorctorirtctiaiclcaall 500 000 000 00I 10 1 00 1 I a FE Pheochromocyto=a, benign 0 2 0 0 RE Poot Pheochromo~.ytoma, ~al i gnant 0 0 i 0 0 0 REE pe 1 0 L808 Hemolymphoreticu] ar neoplasm present 2 0 0 0 0 1 rt TIENTIRE TE Aorta 23) 19) (27) o) (o) i i pT I oh ah hh Hemolymphoreticul ar neoplasm present 0 0 0 0 0 Bone Marrow Hemolymphoreticul ar neoplasm present 25) ( 0 29) 0 0 o} O) o 0 I Br~in 29) O) ston,sre pean 1 EEssoopphhOalaggiuugssodendroglioma, benign s{ 15e0) a I (N 0 s0 (2392) 222) Hemolymphoreticul ar neoplasm present I o eh hem ah Eye 1 0 20) 23) 0 2~) 0 2} 1) Hemolymphoreticul ar neoplasm present 1 O 0 0 0 0 i adorn ane Coch aca chon Harderian Gland { O) o) o) o} 1) I ne pean cng Adenocarci noma 0 0 O 0 1 0 I hh hh Heart 25) 25} 29) 1 Simms L210 (D4 hi HemolymphDr~ticular neoplasm present 1 0 0 0 | Kidney 25) 29) 24) ersten somes (08 C20 i LaLrarggeeHemIIonnlttyeemsspttihinoneereticular neoplasm present (( m3 e 0 Z3) (m~70)em?9O) Co D) n0O) Hemolymphoreticular neoplasm present i 0 0 O 0 n Liver { 25) 21) 29) 24) n Hepatocel I ul ar carcinoma Hemolymphoreti cul ar n~opl asm present Lung 0 0 5 0 1 0 0 I 0 26) (24) i i LLyymmpphhHeNm~o.o!dlodeyemp((hmmoeersseeetnnittecerruiilcca))r neoplas:~ present (( ~95O) ( r230) ((14I)Ww290) 0oI) 0 (o0) HemoIymphoreticular neoplasm present 0 0 0 o 0 Lynph Node (thoracic) { o) ~ o) (o) ~) i} (o) i HHeemnoollyympphhoorreettiiccuullaarr nneeooppllaassma pprreesseenntt. 2 3 3 11 2 Nammary Gland i ee ep Adenocarcinoma Adenoma ( 23) (17) (27) ( 3 9 I 0 0 o 0 1 we long Carcinoma 0 o 0 i FLEree Drlorr og Fibroadenoma 4 5 16 11 i i HeLcyomplhyam:~hgoiroestariccoumlaar nesplasapresent Hemolymphoreticular neoplasm present :0 2 00 0 00i 00 0oo 000 B Titles: Group 1 CONTROL 0 ppm n Group 5 FC-143 300 ppm Group 6 FC-143 30 ppm (] : Total Examined DOS: Unscheduled Death{s) SAC: Protocol Scheduled Sacrifice(s] 163 I Microscopic Incidence Page: 11333377..00116666 3MA00027291 : - Wwe . _ ; Joo 3535 REE 1ssoter 1337.0167 n 1 Bi | i 1i n 1 i 1 H 1 i 1 i| I '1 :I I R 1i I 1 B i i 1 i 1- i sworrzr 3MA00027292 Neoplastic Incidence for Females (continued} | Riker Laboratories, Inc. ,a| we FC-143: Two Year Ora) Toxicity-Oacogenicity Study in Rats Table: 12 Project Number: 0281CR0012 Species: Rat 1... Tissue/ | Diagnosis/ a er Modifier | _ Mesentery 1 HeMHneeosmnooytlmhyepmlprihooormreaet,tiiccmuualllaairrgnnaneneotoppllaassm pprreesseenntt. | Ovary Granulosa cell tumor, benign i we Leiomyoma Tubular adenoma | EA ee Hemolymphoreticular neoplasm present isPancreas Islet cell adenoma i Islet cell carcinoma B PiPtiutuiiHtteaamrroyylymphoreticular neoplasm present Adenoma | wnSKin Fibroma 1 Farr Fibrosarcoma | Small Intestine oe te Leiomyosarcoma Spinal Cord | Hemolymphoreticula? neoplasm present i, i SpleHeHonemmoollyymmppnhoorreettiiccuullaarr nneesoppllaassam pprreesseenntt sonsStomach | He~Dlymphoret|cular neoplasm present Thyroid 1 Ce temo C cell adenoma | EE mp Hemoly~iphoreticular neoplasm present wT Unidentified Tissue 1 omLipoma | pn Urinary Bladder Hemolymphoreticular neoplasm present i UUtteerruuss Lam Adenoma | pee Hemangioma re Leio~yoma Polyp | Hemoly~phoreticular neoplasm present lI 1 HemoHMlaayllmiipgghnnoaarnnettticlTuyylmepaphrhoomSmay,,shteihmisstt[i#iooccayyfttfiiecccted] I Em Malignant lymphoma, lymphocytic wr 1 on 5s Group 1 ER WR DOS SAC Cama nta (o) C o) Group 5 Group 6 DOS SAC DOS SAC o} (o) (2) ( 5~ 00 000 900 11 0 1 0 (25) ( PTT YY i O 2 3 3540 2 hoe h (24) 3 4 (25) iG) (29) O 0 3 0 0 i 0 0 19) (2B) (2G) 0 0 0 I { 22) (24) 1 0 0 0 { 21) 0 1 0 I i 0 0 1 0 i 0 0 ((22t2)) (02240) 15 17 B Chh Che ( 3)(3) 1 2 Cs soo 1d 0 0 ( 24} ( 4 ao Be 0 oh em heh (25) (23) 1 hid dh ho (253) (250) BGhh Choa ~s) (2~) (22100) 0(2290)) 14 22 2) (O) i 0 0 0 18) (29) 0 3 21) (29) O 0 21F0) E(2]90) 20) (29) ((2231)) ((224)0) 20 19 ( 4 I i I (i) ( (O) (O) 0 0 (24I1) (023O) I 0 Son ere ge 0 I 0S 43 6 2 0 Chih heh chen o) (o) Geyer 0 0 eh ho hem 25} (25) 0 0 15) (25) 0 0 0 0 ~) (O) 1 0 16) (2~) 0 ( 23} 0 0 (O) 0 (zs) 0 (22) 0 0 (O) 0 (2~) ((2255I)) (( 228~0)} Dem she cn 0 i TPEor v 0 i O (1199)) ((2299)) 0 0 0 0 0 0 I 3 ((2266)) (23) 0 1 0 0 i 2 0 Sch choa hoa C 252] [ 000] EH 3 0 0 1 2 1 0 0 0 ~i13 [ 0O9] [ ~I13 [ 0OO] 0 0 O 0 i Titles: 5 ern Group i CO~TROL 0 ppm Group 5 FC-143 300 ppm | I= Re Group 6 FC-1~3 30 ppm B| TT () = Total Examined DOS= Unscheduled Death(s) Te SAC: Protoc31 Scheduled Sacrifice(s} MMiiccrroossccooppiicc IInncciiddeannccee 164164 PPaagRee:: 3 11333377..00116688 3MA00027293 d o S$ 3 D Y=o 2 133377..001169 n 1 1n 1i i 1 .ni iI i 2 :i n n :: i 1i n 1 I 1 I 1 I 1 I 1 i 1 I 1 3MMAA0000002277294 Susmarized Single Tabulated Animal Report Individual Macroscopic and Microscopic Observations i 1 FFLC--11443~:i TTwwoo YYeeaarr OOrraall TTooRrxiiikcceiirttyyL--aOObnnoccrooaggteeonnriiicceiistt,yy ISSnttcuu.ddyy 3iiMnn RRaattss -- OOnnee YYeeaarr IInntteerriimn Table: I i Re 7 Animal Number: IR-3516 Sex; Hale Group: I II CONTROL O ppm I Fate: {Wee~= 55) I Year Interim Sacrilice i i Macroscopic Observations; -NNoo vviissiibbllee Lleessiioonnss.. Microscopic Observations: kidney -Chronic progressive nepbropathy, mild n Lung Lymph Node (mesenteric} Pancreas -Vascular mineralization, minimal -Not examined, missing -Adnar atrophy, mild Parathyroid -Not examined, missing i Small Intestine Thyroid -Within normal limits Fewer than protocol number -Not examined, missing I The (ollowing tissues were found to be within normal limits( Brain, Spinal Cord, Bone Harrow, Spleen, Liver, Heart, Stomach, Large Intestine, Urinary Bladder, Aorta, TestislEpididymis, Prostate, Mammary Gland, Pituitary, Adrenal, Trachea, Esophagus, Salivary Gland, Eye. i Animal Number: 1R-3517 Sex: Hale Stoup: ( I} CONTROL 0 pps 1 a sa st Fate! (Week= 5~1 1 Year Interim Sacrifice i Macroscopic Observations: 1 -NNoo vviissiibbllee lleessiioonnss.. Microscopic Observations~ I Kidney -Chronic progressive nephropathy, minimal I Lung Parathyroid Thyroid -Vascular mineralization, mild -Not examined, missing -Not examined, missing 1 The following tissues vere found to be within sarsal Tints: The ~olloming tissues were found to be within normal limits: . I us emi Brain, Spinal Cor~ Bone Harrow, ~pleen, Liver, Heart, Stomach, Small Intestine, Large Intestine, Urinary ~Iadder, Aorta, TestislEpididymis, Prostate, Mammary 61and, Pituitary, 1 Addrreenna,l, TTrraacchheeaa,, EEssoopphhaagguuss,, LLyymwsphh NNooddee ((mneesseestneteririco)),, PPaannccrreeaass,, SSaalliivvaarryy GGllaanndd,, EEyyee.. .................................. . ............................................................... I Animal Number: 1~-~520 Sex: Na]e Group: (l) CONTROL 0 ppm Fate: (Week= 53) l Year Interim Sacrifice i Macroscopic Observations: 1 MMiiccrroossccooppiicc DObbsseervrvaattiioonnss:: -No visible lesions. Adrenal -Sinusoidal ectasia, cortex, bilateral, ii py 1 Kkiiddnneeyy moderate -"CChhrroonniicc pprrooggrreessssiivvee nneepphhrrooppaatthhyy,, smiinniismaall !1 -- Species: Rat ii Te: cng 1 Project Number: 0281CR0012 SSeuamnmarairizzeedd SSTTAARR PPaaggee:: |1 116655 11333377..00117700 3MA00027295 i Sunred Sie alte otal rt Cctv Suumarized Single Tabulated Aniual Report (continued) i Individual Ma:roscopic and Microscopic Observations Riker Laboratories, Inc. 1 FO Ts er it To Be Bs ri FC-14]: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim I Table: I i AAvniimnaall MNousmhbeerr:: I1RR--33552200 SSeexx:; MMeallee G6rroowusp:: (( I1)) CCOONNTTRROOLL 00 gpppma Fate: (Week= 53) l Year Interim Sacrifice | Microscopic Observations {continued): Liver -Hepatocyte alteration, vacuolated, focal, minimal 1 LLLyyusmngpghh NNooddee ((mneesseenntteerriicc)) --"NNVooatt.scueelxaaanmriinnmeeiddn,,ermamiliisszssaiitnniggon, minimal | Parathyroid -Not examined, not in plane of section Pituitary -Not examined, missing 1 he fellow iss ere fond Le be within sored iit: The following tissues were found to be within normal limits: I Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, i| SSUaralilinivvaaarryryy BGGllalaadndnded,r,, EyAyeoe.r. ta, TestislEpididymis, Prostate, Thyroid, Trachea, Esophagus, Pancreas, | B FFAaanttieem~:al ests Number: IWeek= 5$33I)R) -31I52Yf2eeaarr IInntSteeerxirm:i MSSaaalcecririffiicc6eeroup: ~ l) CONTROL 0 ppe Macroscopic Observations: | Liver Microscopic Observations= Kidney -Light (pale} tan in color. -Chronic progressive nephropatby, minimal ii LuLLnuignvger B | PPaarraatthhyyrrooiidd Thyroid "-Pfoarstcaullarmosnionvuecrlaelazratcieolnl, iwniflidltrate, minimal -Vascular mineralization, mild Hemorrhage, multifocal, mild Perivascular mononuclear infiltrate, mild N-Noott eexxaammiinneedd,, mwiissssiinngg -Not examined, missing | The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Testis!Epididymis, Prostate, Mammary Gland, Pituitary, Adrenal, Trachea, Esophagus~ Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. | Animal Number: IR-3527 Sex: Male 6roup: ( I} CONTROL 0 ppm Fate: (Week= 53i I Year Interim Sacrifice | Macroscopic Observations: -No visible lesions. | Microscopic Observations: Liver -Portal mononucIear cell infiltrate, mild Portal bile duct proliferation, mild Lung -Heworrhage, mu]tifocal, mild | The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stomach, Small Intestine, | | Species; Rat | 1 Project Number: 02BICRO012 SSuummmmaarriizzeedd SSTTAARR PPaaggee:t 2 16666 11333377..00117711 3MA00027296 1I Seid Sse alt lim ert nin Summarized Single Tabulated Animal Report (continued) Individual Macroscopic and Microscopic Observations i Riker Laboratories, Inc, 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: I ii Avian Nosber: IRIS Sex: Male Groups (1) CONTROL 0 pou ................................................................................................. Animal Humber: IR-3527 Sex: Hale Group: (I) CONTROL 0 ppm Fate: (Week= 53) I Year Interim Sacrifice 1I The Allon ists wr Fu ob afin corm Lint (ction Microscopic Observations (continued): The following tissues were found to be within normal limits (continued]: Large Intestine~ Urinary Bladder, Aorta, TestislEpididymis, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. I Animal Number: IR-3535 Sex: Hale Group: (I) CONTROL 0 ppm Fate: {Week= 53) I Year Interim Sacrifice i Macroscopic Observations: Mesentary -Area of fat necrosis, 2 x 3 x 0.5 ca. I Microscopic Observations: Lung -Alveolar macrophages, multifocal, mild ~.~Atellectasis, focal, mild 1 Mesentary I Parathyroid Thyroid -SNStteeecaartotisititisis,s,, fccahth,rroonnmiiaccr,,kedmsooddeerraattee. -Not examined, missing -Not examined, missing 1 he lio es mre od to 0 ihn srl Tits The following tissues were found to be within normal limits: i Brain, Spinal Cord, Bone MarrOw, Liver, kidney, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididymis, Prostate, Pituitary, Adrenal, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye, Spleen. n ow So ew 7 1 AFFnaaittmeea::l ((NMWueemeebkke=sr: S533I}1R-3I154YY~eeaarr IInnStteeexrr:iimnMaSSlaaeccrriiffiiGccreeoup: I I1 CONTROL 0 ppm I Macroscopic Observations: 1 [-- ee Microscopic Observations: I Kidney Liver I1 To ein fo, Lung -No visible lesions. -Chronic progressive nephropaLhy, minimal -Portal monnnuclear cell infiltrate, mild Portal bile duct proliferation, focal, minimal -Vascular mineralization, minimal i The following tissues were found to be within normal limits: SBrraaiinn,, SSppiinraall CCoorrd,, BBoontee HMaarrrrooww,, SSpplleeeenn,, HHeeaarrtt,, SSttoommaacchh,, SSmeallll IInntteessttiinsee,, LLaarrggee IInntteessttiinnee,, i Urinary Bladder, Aorta, TestislEpididymis, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary 81and, Eye. I I I Species: Rat I 1 Project Number: 02BICRO012 SSuummmaarriizzeedd SSTTAHB PPaaggee:: 33 116677 11333377..00117722 3MA00027297 | Summarized Single Tabulated Animal Report Icontinued] Individual Macroscopic and Microscopic Observations IBn FFCC-1I43:: TTwuoo YYeeaarr OOrraall TToouxRiiicckiierttyy--LDOannbccooorggaeetnnoiriicceiistt,yy SSIttnuutdodyy ii3nnM RRaattss ~- OOnnee YYeeaarr IInntteerriimn Table: I i 1 a tw nr Animal NumbPr: IR-3546 Sex: Male Stoup: (I) CONTROL 0 ppm Fate: (teek= 53) ! Year Interii Sacrifice | Macroscopic Observations: Microscopic Dbservations: -No visible lesions. 1 Adrenal ||1 Liver -Mmsoooddueelrraaartteehyperp]asia, cortex, unilateral, -Portal iononucIear cell infiltrate, mild uPortal bile duct proliferation, mild Hepatocyte alteration, vacuolated, multifocal, wild -Perivascular mononuclear infiltrate, mild -Not examined, missing i The following tissues were found to be within normal lieits: Brain, Spina! Core, Bone Metro#, Spleen, kidney, Heart, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididymis, Prostate, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Bland, Eye. | Animal Number: IR-3550 Sex: Male Group= ( I} CONTROL 0 |1 a Fo Sl Fate: (Week= 531 1 Year Interia Sacrifice | 1 Kidney Macroscopic Observations: kidney "-BBiillaatteerraall hhyyddrroonoeepphhrroossiiss Microscopic Observations; Heart -Myocarditis, chronic nonsuppurative, focal, Kidney | Liver 1 iorLung | Pancreas mild -Hydronephrosis, bilateral, moderate primp Calculus, pelvic -Portal mononuclear cell infiltrate, mild -Vascular mineralization, mild ii Ie eg Hos wre md wih wr Li Pancreatitis, chronic, focal, mild The following tissues were found to be within normal limits: Brain, Spinal Cord, ~one Marrow, Spleen, Stosach, Swell Intestine, Large Intestine, | Urinary Bladder, Aorta, Testis/Epididymis, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric), Salivary Bland, Eye. | I |1| giSpecies: Rat | Project Number: 0281CR0012 1 SSuummmmaarriizzeedd SSTTAARR PPaaggee:: 44 168 168 11333377..00117733 3MA00027298 I Summarized Single Tabulated Aniial Report (continued) Individual Macroscopic and Microscopic Observations I i FFCC--114433:: TTmuoo YYeeaarr OOrraall TTooxPxiiikcceiitrtyy--LODanabcocraoaggteeonnriiciceiistty,y SSItntuucdd.yy ii~nnH RRaattss -- OOnnee YYeeaarr IInntteerriimn Table: 1 .................................................................................................. 1 I AAnniimnaall MHuusmbbeer:r: 118R--33555510 SGeexx:: MMaallee GGrroouupp:: ((11)) CCOONNTTRROOLL 00 pgppma Fate: (Week= 53) l Year Interim Sacrifice I Hacroscopic Observations; Liver Hicroscopic Observations: -Pale tan I i Liver Lung -PPPooorrrtttaaalll ibboiinlleoenduduucclcettaprprrcooleliilffleerrianattfiiiolotnnr,a, tameii,lldemild -Pneumonia, interstitial, chronic, local, mild Hemorrhage, multi~ocal, mild I Hyperplasia, septal cell, focal, mild The following tissues were found to be within normal limits: I Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, TestislEpididymis, Prostate~ Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node <mesenteric), Pancreas, Salivary 81and, Eye. I i AAnniinmaall NNuambbeerr:: IIRR--I35555)g SSeecxt; MMaallee GGrroouupp:: {(I1)) CCOONNTTRROOLL 00 gppnm Fate: (Week= 53) I Year Interim Sacrifice I Macroscopic Observations: Microscopic Observations: -No visible lesions. I i Kidney -PNNyeeepglhbirrtiiittsii,ss,, aciiunnttteee,rrssbttiiilttaiitaaellr,,alcc,hhrroomnniiincci,,malffooccaall,, unilateral, mild I i Liver Lung -PPPooorrrtttaaalll bbmioillneeonduduuccclttearpprrooclleiilflfeerr(aaMttiiilooinnt,,atmaeii,lldd mild -Hemorrhage, molt(local, mild I The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididymis, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric], Pancreas, Salivary Gland, Eye. I Animal Number: IR-3568 Sex: Male Group: (I) CONTROL 0 ppm Fate: (Week= 53} I Year Interim Sacrifice 1I Kren Brian: Macroscopic Observations: -No visible lesions. I Microscopic Observations: kidney Pancreas -Chronic progressive nephropathy, mild -Pancreatitis, chronic, focal, mild I 8 PParaaraththyyrrooiidd -"ANNoocttinaeerxxaamnaitinrneoedpgh,,y,nnoofttociiannl,ppllmaainnleedooff sseeccttiioonn I I1 -- Species; Rat I 1 Project Number: 0281CR0012 : SSuummmmaarriizzeedd SSTTAARR PPaaggee:: 5 116699 11333377..00117744 3MA00027299 1 Sr -- Summarized Single Tabulated Animal Report (continued) | a an Individual Macroscopic and Microscopic Observations er ea Riker Laboratories, Inc. 3M 1 RC eT 3 orBen) Ss Be Tw ere FC-143: Two Year Oral Toxicity-OncogeniciIy Study in Rats - One Year Interim i es Table: I 1 AAnniimsaall NNuusmbbeerr:: IIRR--33556688 SSeerx:: MMaallee GGrroouupp:: ((I1)) CCOONNTTRRAOLL 00 pppomu Sw rie Fate: (Meek= b-l) I Year Interim Sacrifice I1 Was Bsentins ltind Microscopic Observations (continued): | Py ------ The following tissues were found to be within normal limits: i BBLrraaariignne,, ISSnpptiiennsaatllineCC,oorrcdU,,rinBBaoonrneye Large Intestine, Urinary N~BBaallrFaarFddoOdewWe,,rr,, SSpdpAloloereretetnana,,,, LLTTiieevvsseettrrii,,ss//HEHEeeppaaiirrddttii,,dfymaLLiiuussnngg,,,, PPSSrrtteooosswlttaaaacctthhee,,,, SPFutiiattluuliittaaIIrrnnyytt,,eessttM~iiddnsrreeee,,nnasll,, | re i Etro ot es oy a Thyroid, Trachea, Esophagus, Lymph Node (mesenteric~, Salivary Gland, Eye. i oe eo Cn Animal Number: IR-3570 Sex: Male Group; (I) CONTROL 0 ppm a Te Fate: (Week= 53) I Year Interim Sacrifice | sac atin: Macroscopic Observations: ni [i -- OariaRl vein, mi, i Microscopic Observations: -No visible lesions. 1 LALudunrngeg.nal I1 ti ae, sitei,ownisston Parathyroid -P-CPronereutusimcconaniliaa,,vaciiunnottleearrtssittoiintt,iiaallm,,ultccihhfrrooocnnaiilcc,,, mffioolccdaall,, miniial Hemorrhage, multifocal, mild -Not examined, not in plane of section I A ------ The following tissues were found to be within normal limits: a Gro a es or Bt, Sts, Sl Wt Brain, Spinal Cor~, Bone Narrow, Spleen, Liver, Kidney, Heart, Stomach, Small Intestine, 1 Lt hi: hams Bt os ts, ot, Boi Tore Large Intestine, Urinary Bladder, Aorta, Testis/Epididymis, Prostate, Pituitary, Thyroid, i Hr opr, op bk et, oc Bh Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. i AArniiaaall NNuusmbbeerr:: 1IR8--33557755 SSeexx:: MHaallee GGrroouupp:: ((11)) CCOONNTTRROOLL O0 ppppm ni Fate: (Week= 53) I Year Interim Sacrifice i rss tins Macroscopic Observations: Soft Tissues (leg) i Hast Bois Hicroscopic Observations: on A -------- Kidney !11 austa Traaslalsade wsihea raseintiomn simsd sit Lung -Swollen left hind foot at the hock joint. -Chronic progressive nephropathy, minimal -Vascular mineralization, minimal Alveolar macrophages, multi~ocaI, mild Hemorrhage, focal, mild Pituitary -Cyst, pars distalis i Ie ig mes wre od 0 be iis rd li: The following tissues were found to be within normal limits: ears Sos or ors Bont, al ttn Brain, )pinal Cord, Bone Marrow, Spleen, Liver, Heart, Stomach, Small Intestine, 1I CProait,eiteCsneBrty, toont,boensrRtee asssSRroycaoryt, Large Intestine, Urinary Gladder, Aorta, Testis/Epididymi~, Prostate~ Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary 81and, Eye. i I i ~pecies: Rat i ote: am 1 Project Number: 0281CR0012 SSuumamriarzizeesd SSTTAHRR PPaaggee:: 66 170 170 11333377..00117755 snooraon 3MA00027300 1 Sanit Se ti nd cnn Summarized Sing]e Tabulated Animal Report (continued) B a A wenn Bin Individual Macroscopic and Microscopic Observations i nee, i FFCC--114433:: TTwwoo YYeeaarr OOrraall TToorxRiiicckieirttyy--LOOannbccooorggaeetnonriiicceiistt,yy SItnuc.dy Study i3nM in RRaattss - - OOnnee YYeeaarr IInntteerriima i TaTable: Wi a ea 3 0 Animal N~mber: IR-35BO Sex: Male Group: I I1 CONTROL 0 ppi i Fi le D1 ox I Saris Fate: (Week= 53] I Year Interim Sacrifice I Herc aries Macroscopic Observations: 1 i pc i, 04 cai, Kidney I nih marion: Microscopic Observations: ra ot cn, a Bone Marrow pol a i api, wi Eidney I ws tsni a waaie, a Lung 1n f_ie ewRwnai tei,edrni,etfwo,niwt, Pancreas -Oark cystic lesion, 0.4 cm die., left. -Not examined, missing -Chronic progressive nephropathy, mild Cyst, cortical, unilateral -Alveolar macrophages, multifocal, mild Pneumonia, interstitial, chronic, aoltifocal, mild -Pancreatitis, chronic, focal, mild i PSSappriiannatalhlyrCCoooirrddd --NNNooottt eeexxxaaamsmiiinnneeeddd,,, namoiitssssiiinnnggplane of section B A -------- The following tissues were found to be within normal limits: Fn Lr eo, uh te ti, ir Bt, Brain, Spleen, Liver, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Tis on, Ray Wo yi, on, fo Testis/Epididymis~ Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, B firpapetiingditaie Lymph Node (mesenteric), Salivary Gland, Eye. 1 Sa BE ts Ses 1 0 Animal Number: IR-4578 SexI Female Broup: (I) CONTROL 0 ppm | Fi do en ei ai Fate: (Week= 53) I Year Interim Sacrifice i MMaaccrroossccooppiicc OObbsseerrvvaattiioonnss:: oats -No visible lesions. B -- Microscopic Observations: on ic aarti, wind Kidney -Pelvic mineralization, minimal 1 Li ot steric ot anne msi Lymph Node (mesenteric) -Not examined, missing | Woras EE Beno sei Parathyroid -Not examined, not in plane of section 1 pe ------ The followinQ tissues were found to be within normal limits: B Ct hee Lo stm, a tte Brain, Spinal Cord, Bone Narrow, Spleen, Liver, Heart, Lung, Stomach, Small Intestine, ins iy a, rt a is ih ota Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Mammary Bland, Pituitary, Adrenal, n TThhyyrrooiidd,, TTrraacchheeaa,, EEssoopphhaaggeuss,, PPaannccrreeaass,, SSaalliivvaarryy BGllaanndd,, EEyyee.. m Car i vos 1 0 Animal Number: IR-45B2 Sex: Female Broup: ( I] CONTROL 0 ppm 1 ana Fe a Fate: (Week= 53) I Year Interim Sacrifice n rc murs Macroscopic Observations: raky ole a, 143 i MMiiccrroosMscecosopepinictcarOOybbsseerrvvaattiioonnss:: -Yellow nodular mass, I x 0.5 I po i deste ree ft Heart -MyocardiLis, chronic nonsuppurative, focal, I -- B KKiiddnneeyy minimal -"CCaallccuulluuss,, ppeellvviicc,, uunniillaatteerraall 1Bn pan Species: Rat I ns ens i Project Number: 0281CR0012 SSuummmmaarriizzeedd SSTTAARR PPaaggee:: 7 171 11333377..00117766 asanzrsr 3MA00027301 2: o!r oo 1337.0177 :1i i 1 i 1 1I n 1 | 1 1| I 1 I 1 i 1 1I i I 1 I 1 i 1 | i 1| 1I 1| 3MA00027302 I i SSTuamemnairiiznaed SRSiai~gcleetuTTaaabp~llawatdetdriAnaaimslalaeRneepoGrttur((cacontnttiiionvunendt) I] FEL FC-143: Te Two Yi Tal ToRicker Lraorgieorss Snet,d 3in fats = Oe Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc, ~H Year Oral Toxicity-Oncogenicity Study in Rats - One Yer Year aInttreriiTamels 1 Table: I I i~Fnlnieelal fNHouamibbeeerr: 5RI9R4-4515Bf22er nSSeeiex:nFFeSomaaac|rleifiGScreoouupp: (1) I I) CONTROL CONTROL 0 0 po ppe Fate: I~eek= 53) I Year ]nterim Sacrifice I l i WMiccrhrossLLeccaororppggiecc tOuobasterirvntagitioonss Intestine tine): (conlinued): S-tNoontteeexsaom,inne,dt,rsimiisstisiinnaggl, craic, wife, 1 Lun~ -Pneumonia, interstitial, iemild SPervirsesc,aaacmlnrieosn, Hemorrhage, local areas, chronic, multifocal, amsiihlddltate, wile I Matar Besentary Perivascular mononuclear infiltrate, ASatartittiss, tvyice,trwyitretreate -Necrosie, lot, nodular, moderate mild l i FePaariastnthyersoBiatdttr Jtta wnainee,, oatssinosie of Steatitis, chronic, moderate -Not examined, not in plane of scion section 1 ass Urinary Bladder Uterus --pHeHoryttpieareap~platmaaiseni,ea,d,,ssgmyliahsnasdeiu,nllgaraeinptilhtaehlerlii,ounm,,wisd1 Hetaplasia, squaeous, glandular, mild I BTrRTrhaooaeiinnnafn,,oyllSplpoioiswnioaan,lg CCttoiPoirsrstdsts,ueeestBsfooannaweeserreHeFaairffrrrooouonuwn,,nd ,StStpoylrlebbeeeennd,,wwii,LtLtihhiviinennTere,,nacohSSrrtmsooas,mlnaccLslh,i,imhittSSsem:a!all,l nInLttsehtstiinnYee,o,kArowrttsa,,etOOvrayriy,,l i Fares Snr Bt Mammary Gland, Pituitary, Er.Adrenal, Thyroid, Trachea, Esophagus~ Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. l 1 iFAninitmeall eNNumsaberr:59BI)R-54155fB5er InSStueexsr:n FFSeamecarlmeificrSetonup: 1( II OOH CONTROL 8 0 pn ppm : Fate: (Week= 53) I Year Interim Sacrifice 1 [r---- Macroscopic Observations: Novis Lesion. I 1 HWiccrrossccoopp)icc sObeserrvvatiiosns:: -Ho visible lesions. Sint sti, crten, focal, wilt, Adrenal I LiitoKidney -FS-SmPsaaiieivnllreudvisaicocidmisainlnreaaercattliaiaaszitaati,ioocnncl,,olrtmaenixrni,iitmarfnloactale,, uniiilante]ral, 1 frLiver I Lung -Portal mononuclear cell infiltrate, "faerlrris,wnewsiisttsio,n,aaliel -Vascular mineralization, mild minimal russe NHeomorvrahamgae,e,eulatifo1csalh,ameildof section Parathyroid -Not examined, not in plane of section 1 FT ---- The following tissues were found to be within normal limits: ! Brin, Sin Cod, on Rrrmy Slee, ert Stowch, Sw Intestin, Lire testi, Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Btoeacb, Small Intestine, Large Intestine, rinry dtr tite War, Ory, Rowry Sia, Fata, Tyres, rach Ese Urinary Bladder, Aorta, Uterus, Ovary, Mammary Gland, Pituitary, Thyroid, Trachea, Esophagus, l1 Lhe seri Part, un BE 1, Lymph Node (mesenter~c), Pancreas, Salivary Gland, Eye, l I llLI-- Projet Ne: GICHOTZ Species: Rat I 5 Project Number: 0281CR0012 SSuumamrairizzeed SSTTAHR Page: Page: S 117722 11333377..00117788 aMAc0027303 3MA00027303 Ii Swit Sle Tittle cnt Tndiigusl Summarized Individual eMSaTiccnirrgkoloesesccoTLppaicibcrcusla1aontdrdeidMeMiAsinc,cirmorasIolcncoc,paRiepcporOBtbiseer(rcvvoaantttiiioonnnuessd) 1 FFCC-1A41:I TTwaoo Yeeaar rOraall Toicity-ncogmicity Riker Laboratories, Toxicity-Dncogenicity SSIttnuucdd. yy iIM in RRaattss =- Oenee YYeuarr nIntteerriiTnm ae | n Table: I i Afininmaall NHousmbbeerrs: RlRA-4B56E0 SSeecxt: FFeewmaallee GGrroouwp:: ((11)) CCOONTNROTL0R0pOppp.m Fate asks $31 1 Te tein Scrifice Fate: (Week= 53) I Year Interim Sacrifice I1 Hcroscpie Dserations: Macroscopic Observations: Sin Hui los, ec, Skin i rel Left wlared Adrenal Hicroscapic Btrvations: Microscopic Observations) 1 rent "Simsodal ctasia, corte, wilateral, Adrenal I1 iduey yrCpoiertreildcaasltdae,geprealtviicons,piutnhiellaitne,ralm,16wild Kidney i ner HCOesaltne,tcawy,ttlelpawarcryci,l,awtwioidnl,atemirtaifocl, wld Liver Lung i SSppiinnaall CCoorrdd. SpSlpeleeenn -Hair loss, neck. -Left enlarged -Sin~soidal ectasia, cortex, unilateral, marked Corlical degeneration, unilateral, mild -HyperpIaeia, pelvic epithelium, mild Calculus, pelvic, unilateral Cyst, medullary, mild -HepaLocyte vacuolation, multifocal, mild -Hemorrhage, diHuse, moderate N-Roott eexxaammiinneedd,, mwiissssiinngg --HHeomwoossiiddeerroossiiss,, maiilldd The following tiesues were found to be within normal limits: i Brain, Eee Parton, ert, Stonch, Sul Intestin, Lire Ttestie, riery Bae, drt, Brain, Bone Marrow, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, er, Dury, Yury Sli, Pititay, Troi, Fratyr, Traces, Espa, Uterus, Ovary, Mammary Gland, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus~ Lymn ode estar), Pascress, Salivary San, Ee, Skin, Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye, Skin. | .................................................................................................. foal sor: (F459 Sec Fels ro (1) COMOL pon Animal Number; lR-45B9 Sex; Female Group; (l) CONTROL 0 ppm Fate: (Week= 5)) I Year Interim Sacrifice i 1 RMauccrrFooisscicoippiticcarBOybusrervvtatiioonns:: Stigtly lured i MWiccrr[oePsrsciicotupaiiptcarGOybasrevrvtaitoionnss:: -Slightly enlarged feral armel eal infiltrate, ald Liver -Poorrttaal iboinloenudcaltearprocellilferiantfiiolnt,ratie,dmild Portal bile duct proliferation, mild ii Yar Gt Eas Farathyoid Mammary Gland Parathyroid et caine, -Galactocele -Not examined, noott iin pplaannee ooff sseeccttiioonn i BTTrheeioff,oolllSlpowiwiniannlgg Cttoisrsess,uoessBonwweeerreearafroouuwnd,d Stol3ebee,wwiiKtthhiiidnneynr,ormwoaaltLl,iimiLttns:g:, Sonsch, Sl Intestine, i 1 EBLLraogariggene,hInaSntpnteiesnstaLtilinineeCg,,ordbUU,rroiiBnnoaanrrseyy eMBaaldratrddodware,r,,,SpoAlorerFettnea,,,eksUWith,deenrreeeyssS,,,uHrOievavaarrriyty,,,aLPPnuiinttsgu,aitaaSrErtryyo.,,macrAhd,sreaSnmaal,!,l TThIrynrtooeiisdt,,ineTT,rraaccheesa,, I Esophagus, Lymph ~ode (mesenteric), Pancreas, Salivary Gland, Eye. i i R I Projet Nahr: OIRO? J SSppeecciieess:: RRaatt n 1 Project Number: 02BICRO012 SSuuamnmaarriizzeedd SSTTAHR Fuge: Page: 9 173 11333377..00117799 M3MA0A000002277330044 | Summarized Single Tabulated Animal Report (continued) Individual Macroscopic and Microscopic Observations i FFCC--114433:: TTwwoo YYeeaarr OOrraall TToorxRiiicckieitrtyy--LOOannbccooorggaeetnnoiriicceiistt,yy SSIttnuuc.ddyy ii3nnM RRaattss -= OOnnee YYeeaarr IInntteerriiam | Table: I i FAoniinmaall KNousmbheerr:: IIRR-44S59900 SSeexn:t FFeemmaallee GGrroouupps: (( I1)) CCOONNTTRROOLL 00 ppopnm | Fate: (Week= 53) I Year Interim Sacrifice | Macroscopic Observations: Microscopic Observations: -No visible lesions. |i Tie my Se wi ft fp SS Lung -Hemorrhage, local areas, moderate The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Liver, kidney, Heart, Stomach, Small Intestine, | Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Mammary Gland, Pituilary, AdrenaI~ Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. Animal Number: IR-4601 Sex: Fema3e Group: ( I1 CONTROL 0 ppm i Fates Heck SD) 1 Year Interin Sacrifice Fate: (Week= 53) i Vear Interim 8acrifice i Macroscopic Observations: i KKiiddnneeyy -~HHyyddrroanneepghhrroossiiss,, uunniillaatteerraall Microscopic Observations: i Kidney -Hydronephrosis, unilateral, moderate i Liver Lung Calculus, unilateral, mild -Hepatocyte vacuolation, multilocal, minimal -Hemorrhage, multifocal, mild | i TThhee ffoolllloowwiinngg ttiissssuueess wwaerree ffoouunndd ttoo bbee wwiitthhiinn nnoorrmeaall lliimmiittss:: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Mammary Gland, Pituitary, Adrenal, Thyroid, Parathyroid, | Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. Animal Number: ~R-4608 Sex: Female Group: ( I1 CONTROL 0 ppm | Fate: (Week= 53) I Year Interim Sacrifice Macroscopic Observations: |BR MMiiccrrooUsstcceoorppuiiscc OObbsseerrvvaattiioonnss:: -Left horn cystic looking lesion, ! ~ 0.6 cm. Liver -Hepatocyte vacuolar(on, multifocal, minimal Lung -Hemorrhage, multifocal, mild Lymph Node (mesenteric} Uterus -Not examined, missing -Cystic glands, focal, marked | The following tissue~ were found to be within normal limits: 1 ee me art a, ul tio Brain, Spinal Cord, Bone ~arrow, Spleen, Kidney, Heart, Stomach, Small Intestine, I LLairrggee IInntteessttiinnee,, WUrriisnaarryy EBllaadddteerr,, fAoorrttas,, ODvuarryy,, MNaemsmaaarryy GGllaanndt,, PPiittuuiittiarryy,, AMdtrreennaall,, TThhyyrrooiidd,, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. | I | Species: Rat I 1 Project Number: 0281CR00~2 SSuumamaaarriizzeedd SSTTAARR PPaaggeet: 1I00 t17744 11333377..00118800 3MA00027305 Summarized Gingle Tabulated Animal Report (continued) i Individual Macrosoopic and Microscopic Observations i FFCC--1|4433:: TTwuoo YYeeaarr OOrraall TToouxRiiickceiirttyy--LOOannbccooorgagteeonnriiicceiisIt~yy SSIttnuucd.dyy ii3nnH RRaattss -- OOnnee YYeeaarr IInnlteerriims I Table: ! | Animal Number: IR-4610 ex: Fomale Group: (i) CONTROL 0 ppm Fate: (Week= 53) I Year Interim Sacrifice Hacroscopic Observations: i Fititary "stigttly enlarges Pituitary -Slightly enlarged | Uterus -Slightly enlarged 1 MicrAorsAcdeornpeniaacll Observations: "-SSiinnuussooiiddaall eeccttaassiiaa,, ccoorrtteexx,, #miilldd Large Intestine -Nematodiasis I Lung -Alveolar macrophages, multifocal, mild | Pancreas Parathyroid Uteros -Pancreatitis, chronic, focal, mild -Not examined, not in plane of section -Hyperplasia~ glandular epithelium, mild Metaplasia~ squamous, glandular, mild | The following tissues were found to be within normal limits: Brain, Spina! Cord, Bone Harrow, Sp!een, Liver, Kidney, Heart, Stomach, Small Intestine, | Urinary Bladder, Aorta, Ovary, Mammary Gland, Pituitary, Thyroid, Trachea, Esophagus, Lymph Node (mesenLerJc), Salivary Gland, Eye. Animal Numbsr: IR-4620 ex: Female Group: (I) CONTROL 0 ppm Fale: (Week= 53) I Year Interim Sacrifice | Hacroscopic Observations: ] Be "raphy, right re, Eye Microscopic Observations: | Eye -Atrophy, right eye. -Panophthalmitis~ unilateral, marked | Kidney Lung Atrophy, unilateral, marked -Pelvic mineralization, minimal -Hemorrhage, multifocal, mild Urinary Bladder -Not examined, missing i i BLLaarrragginee, IISnnttpeeinssattiil nneeC,,orAdAo,orrttBaao,,ne UUMtteearrruuross,w, , DOrSvaaprrlyey,,enM,MaaLmmmmivaaerryyr, BGHllaaennad,r,t, PPSiitttouumiittaaacrrhyy,,, SAAmddarrIee! nnaaInll,,tesTThhtiyynrreooii,dd,, PPaarraatthhyyrrooiidd,, | Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Galivary Bland. | i Fs Mee 51 Te Trin Surfs Animal Number: IR-4629 Sex: Female Group: (I) CONTROL 0 ppm Fate: IWeek= 53) I Year Interim Sacrifice Macroscopic Observations: Skin -Hair loss, head, neck, face. | Microscopic Observations: | i Adrenal -iCmoitrldtdical degeneration, focal, unilateral, | | Species: Rat | Frome 1 Projecl Number: 028!CR0012 SSuummmaarriizzeedd SSTTAHR PPaaggee:: I1I1 175 11333377..00118811 3MA00027306 1i Src Sst Tate in ert ctv) Summarized Single Tabulated Animal Beport (continued) Individual flacroscopic and Microscopic Observations | ~iker Laboratories, Inc. 3M PC-143~ Two Year Oral Toxicity-OncogeniciLy Study in Rats - One Year Interim Table: 1 | i AAnniimmaall MNausehbeerr~: 1IR8--44662299 SSeexx:: FFeemmaallee GGrroouupp!: ((11)) CCOONNTTRRIOLL 00 ppppmm Fate: (Week: 53) ! Year Interim Sacrifice i Microscopic Observations (continued): Aorta Large Intestine -Not examined, missing -Nematodiasis i Liver Parathyroid -Portal bile duct proliferation, mild -Not examined, not in plane of section The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone ~aFFOW, Spleen, kidney, Heart, Lung, Stomach, Small Inteatine, Urinary Bladder, Uterus, Ovary, Mammary 81and, Pituitary, Thyroid, Trachea, Esophagus, | Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye, Skin. 1 i Vr 3 ra son 1 wv Animal Humber: IR-4630 Sex: Female Group: (I) CONTROL 0 ppm i Fate: (Week= 53) I Year Interim Sacrifice i i MMaaccrroossccooppiicc BOabsserrvvaattiioonnss:: Liver Microscopic Observations: -Possibly slightly pale in color. i Kidney Liver | Lung Parathyroid Thyroid -Calculus, pelvic, unilateral, moderate -Hepatocyte alteration, vacuolated, mu]tifocal, mild -Hemorrhage, multifocal, mild -Hot'examined, missing -Not examined, missing I B TThh~e ffoolllloowwiinngg ttiissssuueess wwaerree ffoouunndd ttoo bbee wwiitthhiinn nnoorrsmaall lliimniittss:: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, 5mall Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Mammary SlaM, Pituitary, Adrenal, Trachea, Esophagus, | Lymph Node (mesenteric), Pancreas, Salivary Bland, Eye. Animal Number: IR-4631 Se~: Female Group: [ I) CONTROL 0 ppm | Fate: (Week= 53) I Year Interim Sacrifice Macroscopic Observalions: | i MMiiccrroossccooppiicc OObbsseerrvvaaltiioonnss:: -No visible lesions. kidney Lung -Pelvic mineralization, minimal -Hemorrhage, local areas, Iild Lymph Node (Iesenteric) -Not examined, missing Parathyroid -Not examined, not in plane of section i Urinary Bladder -Not examined, missing i TThhee ffoolllloowriinngg ttiisssscueess wmeerree ffoouunndd ttoo bbee wwiitthhiinn nnoorrmmaall Lliinmiittss:: | Es ies oe Be, sl sin, Brain, Spinal Cord, Bone Barrow, Spleen, Liver, Heart, Stomach, Small Intestine, I 1| -- Species: Rat | i Project Number: 0281CR0012 SSounmmmarairizzeedd SSTTAARR PPaaggee:: 1122 117766 11333377..00118822 3MA00027307 I i SSuusmwmarairizzeedd SSiinnggllee TTaabbuullaatteedd AAnniimnaall RReeppoorrtt ((ccoonnttiinnuueedd)) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. ! FC-143; Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: I | Animal Humber: IR-46~I Sex: Female Group: (I) CONTROL 0 Fate: (Week= 53) I Year Interim Sacrifice i i TThhee ffMoaillcllrooownsiicnnoggpittciisssOsuubeessservmvaeetrrieeonffsoouunn(ddcontttooinbbueeedww)ii:tthhiinn nnoorrmmaall lliimniittss ((rcnonnttiinnuueedd)):: Large Intestine, ~orta, Uterus, Ovary, Mammary Gland, Pituitary, Adrenal, Thyroid, Trachea, B1 Cl av I A5Eer Feie Soar 1) COUR 8 Esophagus, Pancreas~ Salivary Gland, Eye. Anima] Number: IR-4632 Sex: Female Group: (I) CONTROL 0 ppm Fate: (Week= 53) I Year Interim Sacrifice B Macroscopic Observations: PiPtistiuittaarryy "Slightly enlarged with a dark red focus on 1 MNaanmwmaarryy BGllaanndd S-Sumslaul]rlfacssepphh.eerriiccaall mmaassss,, 11..22 ccma ddiiaa.,, ccoonnttaaiinniinngg dark red fluid, left inguinal. | Microscopic Observations: Adrenal -Sinusoidal ectasia, cortex, focal, u~ilateral, 1 bYmild I Kidney -Chronic progressive nephropathy, mi]~ Liver -Hepatocyte vacuolatian, multifaca], aild 8 Lng enrrhage, sltidocsl, wild Lung -Hemorrhage, multifocal, mild B Malmary Gland -Galactocele i OOvvaarryy. Chronic inflammation and hemorrhage in cysts. "-CCyysstt,, wunniillaatteerraall i Pituitary -Adenoma B The following tissues were found to be within norwal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Snail Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. | Animal Number: IR-4640 Sex: Female Group: (I) CONTROL 0 ppm Fate: (Week= 53) I Year Interim Sacrifice 1B sic Brion: Hacroscopic ObsErvations: -No visible lesions. Microscopic Observations: n Liver Lung Parathyroid -Hepatocyte vacuolation, multifocal, minimal -~emorrhage, mild -Not examined, not in plane of section B The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stomach, Small l~testine, n Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Mamaary Gland, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. i 1 f--_-- Bpe:ies: Rat n I 1 Project Number: 02BICRO012 SSuumamnarriizzeedd SSTTAHR FPaagge:: 13 117777 11333377..00118833 3MA00027308 & vm 300 pm - Bh 11333377..00118844 1I 1I 1I I 1 I.1 i I 1 I 1 I 1 11I I 1I I 1 iI I 1 I i 1I iI 1I amacooarite 3MA00027309 1 SSuummmaarriizzeedd SSiinnggllee TTaabbuullaatteedd AAnniimmaall RReeppoorrtt I Inividu hsm nk Rs Genin Individual Nacroscopic and Microscopic Observations ik avarie, Riker Laboratories, Inc. ~M 1 FEA: Ts er 1 Toepc ts Go er trie FC-14~: Two Year Oral Toxidty-Oncogenicity Study in Rats - One Year Interim I oir 1 Table: I i AAnnimiall NNuaeabbeerr:: IIRR--J3S5O804 SSeexx:: MMaallee GGrroouupp:: ((55)) FFCC--114433 330000 ppppe Fl these 5 1 Tow Ifrin rfie Fate: (Neek= 53) I Year Interim Sacrifice I [rp -- Macroscopic Observations: 1 [4 ie Liver I Wrens Garutions: : Microscopic Observations: on ot eine, sissioy Aorta 1 Key frog ---- kidney I Gow Tot men ch mart 014 Liver I = SbertcieehnnVeele,aaasttasrtemeennsiind, id Lung lr wae, iit, id Paralhyrod -Pale -Not examined, missing -Chronic progressive nephropathy, mild -Portal aononuclear cell infiltrate, mild Porta] bile duct proliferation, mild Hegalocytosis, moderate Necrosis, focal, minimal -Vascular mineralization, mild Alveolar macrophages, multifocal, mild -Not examined, not in plane of sectlon I he felon isms wre fou to bitin pr its: 1 TBBhrreaaiicnf,,ollSSoppwiiinnnaagll CtCoiorrsdds,,uesd8oownneeereKMaarrfrrooounwn,,d tSSopplleebeeenn,,witHHheeiaanrrtt,,norSSmttaoolmnaacclhhi,,mitSSsem:aalll] IInntteessttiinnee,, LLaarrggee IInntteessttiinnee,, I UUrriinnaarryy BBllaadddeerr,, TTeessttiiss/lEEppiiddiiddyyamiiss,, PPrroossttaattee,, PPiittuuiittaarryy,, AAddrreennaall,, TThhyyrrooiidd,, TTrraacchheeaa,, EEssoopphhaagguuss, yw bce ntti, Furie, Siar fd, Ee Lymph Node imesenteric), Pancreas, Sa|ivary Gland, Eye. 1 el a I So Ble Go (9) ts on Animal Number: IR-~588 Sex: Hale Group: (5) FC-14~ ~00 ppm I ater ee SD 1 oe Din uric Fate: (Week= 53) I Year Interim Sacrifice I1 WNeresccrc BGaerttioonn:: toile tse, Macroscopic Observations: -No visible lesions. i MicroKsKicidodnnpeeiyyc Observations: -"CChhrroonniicc pprrooggrreessssiivvee nneepphhrrooppaatthhyy,, wmiinniimsaall I pr "Feral stor col ie ad Liver -Portal mononuclear cell infiltrate, mild pisos, id Megalocytosis, mild 1 TM Aerrocs,amrisoo,nstdwld Lung I oe Seite wi pleen Necrosis, multifocal, mild -Vascular mineralization, mild -Hemoeiderosis, mild 1 he elo tess wre fd t be with srl iiss The Following tissues were ~ound to be within normal limits: I rin, io! Cor, oe Naren it Son Sl tie Luge esting Brain, Spinal Cord, Bone Marrow, Heart, Stomach, Small Intestine, Large Intestine, I ley Saar, rt eisai, Hebe, Paty, Ket, Trad, Pest i Urinary Bladder, Aorta, TestislEpidiCymis, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, TTrraacchheeaa,, EEssoopphhaagguuss,, LLyysmpphh NNooddee ((mmeesseenntteerriicc]),, PPaannccrreeaass,, SSaalliivvaarryy GGllaanndd,, EEyyee.. I I I I Species: Rat iI Fans Nahr: cs Project Number: 0281CR0012 SSuummnarriezedd SRSTAR Pugs Page: 14 14 117788 11333377..00118855 awacoezr3io 3MA00027310 I Summarized Single Tabulated Animal Report (continued} Individual Nacroscopic and Nicroscopic Observations Riker Laboratories~ Inc. ~M FC-141: Two Year Ural Toxicity-Oocogenicity Study in Rats - One Year Interim I Table: I .................................................................................................. 1 Co Sie (3 7000 0m ~nimaI Number: IR-3589 Sex: Male Broup: (5) FC-143 ~00 ppm I Fate: (Week= 5~) L Year Interim Sacrifice I i MHaaccrroossccooppiicc OObbsesrevravtaitioonnss:: -No visible lesions. Hicroscopic O~servations: I Aorta Liver -Not examined, missing -Porte] mononucIear cell infiltrate, mld Hegalocytosis, mild iI PPLaaurrnagatthhyyrrooiidd Thyroid --NNVooattsceuexxlaaanmriinnmeeiedn,,erwamiliisszssaiitnniggon, mild -Not examined, missing I The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, TestislEpididymis, Prostate, Pituitary, Adrenal, Trachea, Esophagus, Lymph Node (mesenteric], Pancreas, Salivary Gland, Eye. I Animal Number: IR-~Sg2 Sex: Hale Group: ( 51 FC-143 300 ppm Fate: (Week= 53) I Year Interim Sacrifice 1 ec min: Macroscopic Observations: I Pituitary -Small dark red mass, 0.3 cm die. I Microscopic Observations: kidney Liver -Chronic progressive nephropathy, minimal -Portal mononucIear cell infiltrate, minieal 1I Lung HPPeiigpguametenonttc,,yteKKuupvpfafecerurolccaeetllilla,,n,mmulmltutiIiftfoiocfcaoalcl,a,l,bbrrmowoin,d, amiilld -Vascular mineralization, mild Alveolar macrophages, multifocal, mild I Parathyroid Urinary Bladder -Not examined, not in plane of section -Not examined, missing The following tissues were found to be ~ithin normal limits: I Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, Aorta, Testisl~pididymis, Prostate, Fituitary, Adrenal, Thyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. 1I ie om en 9 700 50 Animal Number: IR-~59B Sex: Hale Group: C 51FC-143 300 ppm Fate: (Week= 53) I Year Interim Sacrifice iI Baran rations Macroscopic Observations: -No visible lesions. Hicroacopic Observations: I Heart -Myocarditis, chronic nonsuppurative, multifocal, minimal I I Species: Rat I i Project Number: 02BICRO012 SSuummnmrairzizeedd SSTTAARR PPaaggee:: 1155 111799 11333377..00118866 3MA00027311 | i SSuummamrairzizeedd SSiinggllee TTaabbuullaatteedd Anininmaa]l RReeppoorrtt ((ccoonnttiinnuueedd)) Individual Macroscopic and Hicroscopic Observations Riker Laboratories, Inc. 3M | FC-143: Two Year Oral Toxicity=Oncogenicity Study in Rats = One Year Interim Table: I Animal Number: IR-~598 Sex: Male Group: (5) FC-143 300 ppm Fate: (Week= 53) I Year Interim Sacrifice i 1 Microtskicidodnpneieycy Observations (continued): -"CChhrroonniicc pprrooggrreessssiivvee sneepphhrrooppaatthhyy,, smiinniiamaall | LiLviveerr -~PFoorrttaall mwoonnoonauucc]leeaarr cceellll iinnffiillttrraattee,, mwiilldd Megalocytosis, minimal | Lung Parathyroid Necrosis, multifocal, minimal -Alveolar macrophages, mule(focal, mild -Not examined, not in plane of section | Pituitary -Not examined, missing The following tissues were found to be within normal limits: 1| BUUrrraiiinnnaa,rryySpBBillnaaaddldeerrC,,ordAf,oorrtBtaoa,n,e TTMeeassrttriiossw//,EEpgiiSddpiileddeyynam,iiss,,StoPPmrraoocsshtt,aatteeS,,malAMldrreeInnnaatlle,,stiTTnhheyy,rrooiiLdda,,rgeTTrraaIccnhhteeeaas,,tinEEess,oopphhaaggusss,, Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. I Animal Number: IR-~G04 Sex: Male Group: (5) FC-143 300 ppm Fate: (Week= 53) I Year Interim Sacrifice Macroscopic Observations; i ho visible lesions. -No visible lesions. | Microscopic Observations: 1 HAeoarrtta Heart -Not examine, mis~ing "-MMyysoccaarrddiiaall ffiibbrroossiiss,, Ffooccaall,, maiilld Kidney -Chronic progressive nephropathy, mild | Liver -Portal mononucIear cell infiltrate, mild | Lung |1 ternees ol wes, wit Parathyroid Salivary Gland 8egalocytosis, minima) Necrosis, mule(focal, mild Wascular mineralization, mild AlveoIar macruphages, multifocal, mild Nemorr~age, local areas, mild -Not examined, not in plane of section -Not examined, missing i he ong tsaes re fund 1 0 within er iis The following tissues were found to be within normal limits: | ~rain, Spinal Cord, ~one ~arrow, Spleen, Stomach, Small Intestine, Large Intestine, | ~rinary Bladder, Testis/Epididymis, Prostate, Pituitary, Adrenal, Thyroid, Trachea, ~sophagus, Lymph Node (mesenieric), Panoreas, Eye. | | I I| -- Species: Rat 1 Project N~mber: 0281CR0012 I SSuumnmaarriizzeedd SSTTAARR PPaaggee:: 1166 180 11333377..00118877 3MA00027312 i Summarized Single Tabulated Animal Report (continued) Individual Macroscopic and Microscopic Observations 1i FFOC--11433:: TTwaoo YYeeaarr OOrraall TToorPxiiikcceiitrtyy--LOlannbcocorogageteaoirniciceiistt,yy SSInttucad.yy ii3nnM RRaattss -= ODanee YYeeaarr IInntkeerriimn Table: ! i | AAoniinmaaIl NNuummbeerr:: IIRR--3~61I33 SSeexx:: MMaallee GGrroouupp:: |(5S)) FFCC--114433 33000 opppem Fate: (Neek= 53) I Year Interim Sacrifice | Nacroscopic Observations: Liver Kidney -Pale tan color. -Small depressed area, 0.2 CA dia., right | i MMiiccrroossccooppiicc OBbsseerrvvaattiioonnss:: kidney. Eye -Retinal atrophy, focal, minimal Liver -Portal mononucIear cell infiltrate, mild Lung | Parathyroid i = Testis/Epididymis Negalocytosis, miniaaI -Vascular mineralization, mild -Not examined, not in plane of section -Tubule atrophy, aspermatogenesJs, unilateral, marked I The following tissues were found to be within norea] limits: 1 BBrraaiinn,, SSppiisnaall CCoorrdd,, BGoonnee MMaarrrrooww,, SSpplleeeenn,, KKiiddnreeyy,, HHeeaarrtt,, SSttoosmaacchh,, SSmeaalll IInntteessttiinnee,, Large Intestine, Urinary Bladder, Aorta, Prostate, Pituitary, Adrenal, Thyroid, Trachea~ | Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Bland. | Animal Number: IR-3GI? Sex: Male Group: (5) FC-14~ 300 ppm Fate: INeek: 53) I Year Interim Sacrifice | i MMaaccrroossccooppiicc sObesrevravtatiioonnss:: Skin -Ulcerated nodule in the dorsal area, 1.5 cA dia. | Microscopic Observations: Kidney -Nineralization, mullifocal, cortical PPyyeelliittiiss,, aaccuuttee,, uunniillaatteerraall,, wmiilldd | Liver Lung Lymph Node (mesenteric) -Hegalocytosis, minimal -Alveoiar macrophages, multifocal, mild -Hemorrhage, minimal |1 To lone we es 1 1 wie st te Skin -keratoacant~oma The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone ~arrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, | Urinary Bladder, Aorta, TestislEpididymis, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye, | | | | Species! Pal |1 Project Number: 02BICRO012 Suanrized Sumlarized SSTTAHR Pages Pa~e: 1177 118811 11333377..00118888 3MA00027313 i Summarized Single Tabulated Animal Report (continued) Individual Macroscopic and Bicroscopic Observations i 1 FFCO--114433:: TTuuoo YYeeaarr UOrraall TTooxsRiiickceiirttyy--LOOannbccooorggaeteonnriiicceiistt,yy SSItntcuu.dyy liiMnn RRaattss -- nOnee YYeeaarr IInntteerriimn Table: I i Animal Number: IR-~20 Sex: Male Group: ( 5} FC-I 3 300 Fate: (Week= 5]) I Year Interim Sacrifice Bacroscopic ObsErvations: -No visible lesions. i Microscopic Observations: i KiAKdoirdotneaeyy --"NCCohhtrroonneiixcacmippnrreoodgg,rreemssisssiisvvieengnneepshhrrooppaatthhyy,, mmiinniimsaall I Liver -Porla] mononuclear :eli infiltrate, mild Hepalocyle vacuolation, multiiocaI, minimal n Parathyroid Negalocytosis, minimal -Not examined, not in plane of section The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Lung, Stomach, Small Intestine, Large Intestine, I Urinary Bladder, Testis/Epididymis, Prostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lymph Node (aesenteric}, Pancreas, Salivary Gland, Eye. 1 an No we Gon (3 700 50 Animal Number: tR-3~22 Sex: Bale Group: ( 51 FC-143 300 ppa n Fate: (Week= 53) I Year Interie 5acri(ice Macroscopic Observations: i Eye -Ocular opacity, bilateral. 1 MNiiccrroossTcceoospptiiiccs ODbisseerrvvaattiioonnss:: -Le(t testis small. i Eye -Cataract, bilateral Kidney -Chronic progressive nephropathy, mild 1 2 i Liver -Portal eononucIear cell infiltrate, minimal Megalocytosis, minimal i Pigment, Kupfer cell, brown, minimal Lung -Vascular mineralization, minimal Pneumonia, interstitial, chronic, auItifocal, i aild 1 PaPLrayarmtaphhthyyNrrooodiiedd (mesenteric) -"-NNNooettmoreerxxhaamaniginveee,dd,,minnloodtt iinn ppllaannee ooff sseeccttiioonn Prostate -Not examined, missing i Testis/Epididymis -Tubule atrophy, asperaatogenesis, unilateral, a femarked n The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, 1 San at Por os rh ice Sma, Poe, Urinary Bladder, Aorta, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Pancreas, ! Salivary Gland. I I I ~pecies: Rat | 1 Project Number: 02BICRO012 SSuumamnarriizzeedd SSTTHARR PPaaggee:: 1IB8 118822 11333377..00118899 3MA00027314 i Sanrio Sie Tilted im Bp nin) Summarized Sing]e Tabulated Animal Beport (continued) I Infviul Rrscopc sd Bice, Dsations Individua] Macroscopic and Microscopic Observations ir Liortrite oe, Riker Laboratories, Inc, 3M FC-I&3: Tun Year Oral Tnxicity-Onoogenioity Study in Rats - One Year Interim I Tole1: Table: I 1 inl rs Ser le op 9 F080 0 Aniial Humber: IR-3626 Sex: Male Group: (5) FC-143 300 ppm Ftd ther 01 Tor nein Sofie Fate: (Week= 53) I Year Interim Sacrifice l Rosie Guration: Macroscopic Observations: I1 Hermie Murution: Ho visite ies. Microscopic Observations: Gey ry------ Kidney 1 I= En Liver l ws Aeplicaiosnsi,paso,nsit, 16 Lung 1 Arthreid Ja cain, ote sha of sition Parathyroid Hit let eins ssn Piluitary l1 rate HJrsteatti, drone, foal, nersitital Prostate -No visible lesions. -Chronic progressive nephropathy, minimal -Portal mononuc]ear cell infiltrate, mild Hegalocytosis, minimal -Alveolar macrophages, multifocal, mild -Not examined, not in plane of section -Not examined, missing -Proslatilis, chronic, focal, intersititial, minimal l The flan tisas wee and ts be itis srl iit: The following tissues were found to be within normal limils: rin, in ad, oe Norton, Sle, er, Sonch, Sul Dtstin, Lire retin 1 BUUrrraiiinnnaa,rryySpBBillnaaaddldeerrC,,orddA,oorrttBaao,,neTTMeeassrttriiossw/l,EEppiiSddpiilddeyeynam,iiss,,HeaAArdrtre,ennaaSllt,,omaTTchhhyy,rrooiiSddm,,allTTrraIacnchhteeeaas,,tinEEess,aopphhLaaaggreugsse,, Intestine, l Uh ed einai, Faces, Slvr Sn, Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. oil ort AIT Sec We Soup 8) FOE 00 30 Animal Number: IB-3G27 Sex: Male Group: (5) FC-143 300 ppm i Fie tte 1 1 ow i Sif Fate: (Week= 531 I Year Interim Sacrifice l Brasic Duration: Macroscopic Observations: 1 A Liver I Neroscmic Baration: Microscopic Observations: Tor Artal wmesch col ifltrate, nied Liver 1 un Here, cl wis, wile Lung [ ne wt sh of section Parathyroid -Slightly pale tan in color. -Portal mononuc]ear cell infiltrate, minimal -Hemorrhage, local areas, mild -Not examined, not in plane of section I he folowing ius wre od to be ithe sored Lint: The following tissues were found to be within normal limits: i Eri, nl ary ie aro leks Kins Boar, Stoch, Sul ntti, Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stomach, Small Intestine, l Urge atin, awry Mader, fort, et adiae, rosa, stan, Mess, Large Intestine, Urinary Bladder, Aorta, Testis/Epididymis, Prostate, Pituitary, Adrenal, Ths, Traces Exh, Lh Nh eset], Faces, Sv Eady Ei. Thyroid, Trachea, Esophagus, Lymph Node (mesenteric], Pancreas, Salivary Gland, Eye. l Animal Number: IB-3638 Sex: Male Group: (5) FC-143 300 ppm Fike tke 5 1 er nein Suri Fate: (Heek= 53) i Year Interim Sacrifice 1 sic Burton Macroscopic Observations: l erase Gaarution: He vile nin, Microscopic Observations: i priv J -- Liver I ws Aieirsi,e,aictilfoarl,v,ldabate Lung I5 35% ts -------- Lymph Node (mesenteric) -No visible lesions. -Portal mononuclear cell infiltrate, minimal Necrosis, multifocaI, mild -Hemorrhage, local areas, moderate -Hot examined, missing l i Species: Bat ! Fee Nae, OSEAMIE i Project :Number: 0281CR0012 SSaumamnarriizzeesd SSTTARB PPaaggee:: 1199 118833 11333377..00119900 amAooo27315 3MA00027315 Summarized Single Tabulated Animal Report Icontinued) | IndividuaI Macroscopic and Microscopic Observations i FO-143: Tuo Year Oral TorRiickeirty-LOanbcooragteonriiceist,y SItncu.dy i3nM Rats = Dae Year Interis FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim | Table: 1 i| Fits te 5 1 ow tr Serie Animal Number: IR-3638 Sex: Male Group: ( 5t FC-143 300 ppm Fate: (Week= 53) I Year Interim Sacrifice Nicroscnpic Observations (continued): | Pituitary Prostate -Not examined, missing -Not examined, missing -Not examined, missing | The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stomach, Small Intestine, Large Intestine, Aorta, TesLisJEpididyeis, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. | Animal Number: ]R-3642 Sex: Male Group: (5) FC-143 300 ppm | a re ni Fate: (Week= 53) 1 Year Interim acrifice ! Observations: i --- Sein Microscopic Observations: Kidney Large Intestine -No visible lesions. -Chronic progressive nephropathy, mininal -Nematudiasis Liver -Megalocytosis, mild i Lymph Node (mesenteric) -Not examined, missing nl Parathyroid ThTyhryoroiidd -~ot examined, mi~eing N-~oott eexxaammiinneedd,, mmiissssiinngg | The following tissues were found to be within normal limits: Bra~n, Spinal Cord, Bone Marrow, Spleen, Heart, Lung, Stomach, Small Intestine, Urinary Bladder, 0 ra Tis Eins, Prat, Ptr, Bel Toe op Fre Aorta, Testis!Epi~id~mis, Prostate, Pituitar~ Adrenal, Trachea, Esophagus, Pancreas, | Salivary Gland, Eye. 1 Cine ar (5 Fm Animal Number: tR-3643 Sex: Male 6rout: ( 5] FC-143 300 ppe i Fate: (Week= 53) I Year Interim Sacri{ice | i MNaaccrroossccooppiicc OObbsseerrvvaattiioonnss:: -No visible lesions. Microscopic Observations: | Heart -Myo~ardia! fibrosis, Tocal, minimal Myocardit~s, chronic nonsuppurative, Focal, minimal Kidney | Liver i B LLuunngg. -Chronic progressive nephropat~y, mild a -Portal menonuclear cell infiltrate, mild MMeeggaallooccyyttoossiiss,, mmeoddeerraattee ~ecrosis, multifocal, mild -V~aassccuullaarr wmiinneerraalliiz~aattiioonn,, aeiill~d Pneumonia, interstitial, chronic, multifncal, ||1 in Species: Rat | Fe ers cn 1 Project ~ueber: 02BICRO012 Pe~ivascular mononuclear infiltrate, mild SSuumamwairiezesd SSTTARR PPaaggee:: 2200 118844 11333377..00119911 3MA00027316 Q Iva 3e0pm } roar.onee 1337.0192 I 1 | 1 1H 1H iH n i | 1 i B 1I 1H I i R 1 1I iB I 1 | 1 ! 1 I 1 I i awscoczrair 3MA00027317 Summarized Single Tabu]ated Anise1 Report {continued) I Individual Macroscopic and Microscopic Observations i FFOC--114433:: TTowoo YYeeaarr OOrraall TTooxRriiikcceiirttyy--LOOannbccooorggaeteonnriiicceiistt,yy SSIttnuuc.ddyy i~inn RRaattss -- OOnnee YYeeaarr IInntteerriiam Table: i n .................................................................................................. I ric Sarto lint Animal Wumber: IR-3643 Sex: Hale Group: (5) FC-143 500 ppm Fate; (Week= 53) I Year Interim Sacrifice Microscopic Observations (continued): Parathyroid -Rot examined, not in plane of section B 1 The following BBrraaiinn,, SSppiinnaall tissues were found CCoorrd,, BBoosnee NNaarrrrooww,, SStppolleebeeenn,,witBSthtoiomsnaaccnhho,,rmSaSlemaalllllimiIItnnstt:eessttiinnee,, LLaarrggee IInntteessttiinnee,, Urinary O]adder, Aorta, TeetislEpididyais, Prostate, Pituitary, Adrenal, Thyroid, Trachea, I Esophagus, Lymph Node (mesenterici, Pancreas, Salivary Gland, Eye. Animal Nomber: IR-4642 Sex: Female 6roup: (5) FC-143 300 ppm n Fate: (Week= 531 ! Year Interim Sacrilice 1 MMaaccrroossccooppiicc sObesrevravtaitioonnss:: ---- Eye -Atrophy, right eye. I Uterus -Both horns enlarged, filled with clear fluid. I Microscopic Observations: Eye -Panophthalaitis, unilalera], marked Atrophy, unilateral, marked Kidney -Chronic progressive nephropathy, mild Large Intestine -Neaatodiasis B Liver -Hepatocyte vacuoIation, mu]tifocal, mild Parathyroid 1 UUtteerruuss -"-HHNyyoddtrrooenmxeeattmrriaan,,ed,mwooddneoertraattieen plane of section Endoaetr|t~s, chronic, mild B The following tissues were found to be within normal limits: cn, i tiv, iy Hrs Brain, Spinal Cord, Bone Harrow, ~pleen, Heart, Lung, Stomach, Small Intestine, Urinary Bladder, I Aorta, Ovary, Mamnary Gland, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lymph Node Imesenteric), Pancreas, Salivary Gland. I ~ .................................... Animal Number: IR-4652 Sex: Female Group: (5) FC-143 300 ppm Fate: 4Week= 53) I Year Interim Sacrifice I ~acroscopic Observations: -No visible lesions. H Nicroscopic Observations: Kidney Liver -Chronic progressive nephropathy, mild -Hepatocyte vacuolation, multifocal, mild Parathyroid -Not examined, not in plane of section The following tissues were mound to be within norma] limits: I i Brain, ~pina] Cord, Bone UUrriinnaarryy BBllaaddddeerr,, A~oorrttaa,, Harrow, UUtteerruuss,, Spleen, Heart, OOvvaarryy,, NHaasmsmaarryy S8lL1auannngde,,, SPPtiiottmuuaiictthaa,rryy,,SmaAAlddlrreennIaanllt,,estTTihhnyyerr,ooiiddL,,argTTerraaccIhhneetaae,,stine, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary 81and, Eye. I ................................................................................................. H 1 -- Species: Rat nn ai TE 1 Project Number: 0281CR0012 S~uumnmaarriizzeedd SSTTARR PPaaggee:: 2211 118855 11333377..00119933 3MA00027318 B Soria Sie Tale bial for (cto Summarized Single Tabulated Animal Report {conlinued) i Individual Macroscopic and Microscopic Observations Riker Laboralories, Inc, 3M 1 E105 To ei Tce + t-te rie FC-143: Two Year Oral Toxicity-Onoogenicity Study in Rats - One Year Interim | Ys Table: 1 | nAniismall MNausmbheerr:: 1I8R--44665555 SSeexx:: FFeemaallee GGrroouuppt: ((55)) FFCC--114433 330000 pppomn Fate: (Week= 53) I Year Interim Sacrifice i Macroscopic Observations: MicrosEopic Observations: -No visible lesions. i LiALvoirveterar | Lung Pituitary --"NHHoeetpsaaettxoaaccmyyittneeedvv,aaccmuuioosllsaaittiniogonn,, meullttiiffooccaall,, maiilldd -Hemorrhage, local areas, mild -Not examined, missing 1 The Selle tng re fu 0b within sre Yitst The following tissues were found to be within normal limits: i Grain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Uterus, Ovary, Mammary Bland, Adreoa], Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Bland, Eye. i i FFAaanttieem::al M(NWeueemekbkse=r:S533I11R-I41 6YY5ee6aarr IInnttSeeexrr:iiam FSSeaamccarrliiefliiccGeeroup: (5) FC-143 300 ppm i Macroscopic Observations: Microscopic Observations: i KKiiddnneeyy 1 or oats vet, wire, i Liver | Lung Lymph Node (mesenteric) -No visible lesions. -CChhrroonniicc pprrooggrreessssiivvee nneepphhrrooppaatthhyy,, mwiilldd Mineralization, multifocal, cortical, mild -Hepatocyte vacuolation, muItifocal, mild -Hemorrhage, mu]tiFocal, mild -Not examined, missing 1 oe lin rs wr fn 2b tin rd Te The following tissues were found to be within norea] limits: | Brain, Spinal Cord, Bone Harrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, | Urinary Bladder, Aorta, Uterus, Ovary, Mammary Gland, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagua, Pancreas, Salivary Gland, Eye. 1 AFFnaaittmeea::l t(NhWueemsebtkes=r: 5593I))R-41I66YY4eeaarr IInnStteeerrxi:imnFSSemaucrarileiffiicGcereoup: (5) FC-143 300 ppm | Macroscopic Observations: 1 MMaasmnmaarryy BGllaanndd "-SSuubbccuuttaanneeoouuss amassss,, 33..55 Ccal ddiiaa.,, lfeefltt iinngguuiinnaall area. | MMiiccrroossccooppiicc OObbsseerrvvaattiioonnss:: : | Liver Mammary 81and -Hepatocyte vacuolation, multifocal, mild -Fibroadenoma ii TGBhrreaaiinnf,,ollSoppwiiinnnaagll tCCioosrrdsd,u,esGBoownneeereMNaarfrrorouownw,d, tSSopplleebeeenn,,witKKhiiiddnnneeyyn,,ormHHaeelaarrttl,,imiLLtuussn:gg,, SSttooamaacchh,, SSmeaalll] IInntteessttiinnee,, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Pituitary, Adrenal, Thyroid, | i1 3 Species: Rat |1 Project Number: 0281CR0012 Sonrized TH Pug:2 186 Summarized STAR Page: 22 11333377..00119944 3MA00027319 i| Sairizs Sige Tilated inl ep tied) Summarized Single Tabulated Animal Report (continoed) Individual Macroscopic and Microscopic Observations iI oy FFCO--114433:: TTwooo YYeeaarr OGrraal TTooxRuiic~caeitrtyy--LDOaonbccoorogagtenoniricicieitst,yy SSIttnacu.ddyy ii3nnM RRaattss -= OOnnee YYeeaarr IInntteerrinm Table: I | i AAnniinmaal] NNuummbbeerr:: I1RR--666644 SSeexx:: FFeemmaallee GSrroouupp:: |( 55]) FFCC--114433 330000 p~ppam Fate: (Week= 53) l Year Interim Sacrifice | Microscopic Observations (continued): The following tissues were found to be within normal limits (continued): Parathyroid, Trachea~ Esophagus~ Lymph Node ~eesenteric), Pancreas, Salivary Stand, Eye. 1i ASniinmaa]] NNuummbbeerr:: iBR--44i~h66 SSeenx:: FFeemmaallee G6rroouupp:: (( 55)1 FFCC--114433 330000 ppopnm Fale: (Week= 53) I Year InLerim Sacrifice | rms Beto Macroscopic Observationsl Microscopic . uos. erv.a~. zon.s; -No visible lesions. Liver -Portal mononuclear cell infiltrate, mild Portal bile duct proliferation, mild i 1 ~BTrrhaaeiinnf,,olSlSpopiiwnniaanllg CCtooirrsdds,,uesBoosnweeerN~eaarr~rrooouwwn,,d SStppolleebeeenn,,wiKtKiihddinoneeyyn,,ormHHaeelaarrttl,,imLLiuutnnsgg:,, SSttoommaacchh,, SSmmaallll IInntteessttiinnee,, ' Large Intestine, Urinary 81adder, Aorta, Uterus, Ovary, Mammary 81and, Pituitary, Adrenal~ | Thyroid, Parathyroid, Trachea, E~ophagus, Lymph Node (mesenteric), Pancreas, Salivary 81and, Eye. | Animal Number: IR-466~ Sex: Female Stoup: I 51FC-143 300 ppm Fate: (Week= 53} i Year Interim Sacrifice | B MMaaccrroossccooppiicc OGbhsseerrvvaattiioonnss:: Hicroscopic Observations: visible lesions. | Liver Lung ~ammary 81and -Hepatocyle vacuolation, muItifocal, mild -Hemorrhage, muItifocal, mild -Not examined~ missing | The following tissues were ~ound to be within normal limits: Brain, Spinal Cord, Bone ~arrow, Spleen, Kidney, Neart, Stomach, Small Intestine, | 1 PLPaaarrraagttehhyyIrrnoatiieeds,,tinTTerr,aacchhUeeraai,,narGEy~soopp~hhlaaaggduudsse,,r, lLyyAmsoprghtha,NNoodUeeter((umasee,sseennOtvtaeerrryii~cc)),,PiPtPauaninctcrareeraayss,,, ASSdaraleliniavvlaa,rryyTG8hl1yaarnnoddi,d,, EEyvee.. Animal Number: IR-4671 Sex: Female Group: (5) FC-143 300 ppm Fate: IWeek= 53) I Year Interim Sacrifice i Macroscopic Observations: Nammary 81and I1 ate Microscopic Observations: -Subcutaneous mass, 5 cm dia,, behind left shoulder, | i Kidney -PCCaealllvccuuiclluussm,,ineppreealllvviiizcca,,tiwmoiinll,dd eil~ i | Species: Rat i] Project Number: 02SlCRO012 [----- 187 ~ummarized STAR Page: 23 11333377..00119955 3MA00027320 Ii Sowing Se Tilt lil ect cuit Summarized Single Tabulated Animal Report (continued) Individual Macroscopic and Microscopic Dbservations Hiker Laboratories, Inc. IN n FC-14): Two Year Oral Toxicity-Dncogenicity ~tudy in Rats - One Year Interim Table: I i i AAnniimnaall MNousmhbeerr:: IRR--44867)1I SSeeaxt: FFeewmaallee GGrroouugp:: ((55)) FfCC--1l4l3 t3O000 pppoua Fate: (Week= 51) I Year Interim Sacri(ice I Nicroscopic Observations (continued): Liver Lung -Hepatocyte vacuolation, muItilocal, minimal -Hemorrhage, multifocal, mild | 1 PaMraamtmharyyroGildand Parathyroid -"-FKNiootbtroeeaxxdaaemmniionnmeead,, nmoott iinn ppllaanse ooff sseeccttiioonn The following tissues were found to be within normal limits: i Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach~ ~mall Intestine, Large Intestine~ Urinary Bladder, Aorta, Uterus, Ovary, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreae, Salivary Gland, Eye. .................................................................................................. i Animal Number: IR-467& Sex: Female Group: (5) FC-143 300 ppm Fate: (Week= 53) I Year Interim Sacrifice I i NMaaccrroessccoopaiicc GOobsseerrvvaattiioonnss:: -No visible lesions. Microscopic Observations: I Aorta Esophagus Large Intestine -Not examined, missing -Not examined, missing -Hot examined, missing Lung Parathyroid -Hemorrhage, muItifocal, mild -Not examined, not in plane of section I i BBTrrhaaeiinnf,,olSSlppoiiwnniaanllg CCtaoirrsdds,,uesBBoonw~eereFMaarrfrrooouwwn,,d SStppolleebeeenn,,wiLLtiihvvieenrr,,noKKriimddanlneeyyl,,imHHieetaasrr:tt,, SSttoomnaacchh,, S5eeaallll IInntteessttiinnee,, Urinary Bladder, Uterus, Ovary, Mammary Gland, Pituitary, Adrenal, Thyroid, Trachea, i Lymph Rude (mesenteric), Pancreas, Salivary Gland, Eye. i il ar IATL ele Go {51 FERS on Animal Humber: IR-467G Sex: Female Group: (5) FC-143 300 ppm I Fate: (Week= 53) I Year Interim Sacrifice 1 asic taro: Hacroscopic Observations: n Mammary Gland -Two subcutaneous masses in both inguinal 1 Wmaiirllekkas,ccyyss1tt.,,5 rraiinggdhhtt2 ssciimddeediecc.yysstt Lffeifiltllleesddidwewiitthh rruusstt colored fluid. I Hicroscopic Observations: Adrenal -Sinusoidal ectasia, cortex, mild 1 rt Sartitie, arc respons, ail, Heart -Hyocar~itis, chronic nonsuppurative, focal, i mild Kidney -Calculus, pelvic i Liver -Hepatocyle vacuolation, multifocal, mild I i Species( Rat i1 Project Number: 0281CR0012 [I -- Summarized STAR Page: 24 118888 11333377..00119966 3MA00027321 I Summarized Single Tabulated Animal Report (continued) Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M I Two Year Oral Toxicity-Oncogenicity Study in Rats - One Year Interim Table: I 1I AAnniinmaal] NNuusmbbeerr;s IRR4-466776 SSeexx:: FFeemmaallee rGroowups: {(55)) FFCC--114433 330000 ppopnm Fate: (leek= 53) I Year Interim Sacrifice Ii tn lr bos, wit, ie Microscopic Observations (continued): Lung Mammary Gland -Alveolar macrophages, multifocal, mild -Galactocele Galactocele I One cyst involved with chronic inflammatory process with extensive hemorrhage into cyst. I 1 TThhee ffoolllloowwiinngg ttiissssuueess wweerree ffoouunndd ttoo bbee wwiitthhiinn nnoorrmmaall lliimmiittss:: Brain, Spinal Cord, Bone Marrow, Spleen, Stomach, Small Intestine, Large Intestine, Urinary Bladder, ~orta, Uterus~ Ovary, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus, I do 5 ae (9 Rn Lymph Node (mesenteric}, Pancreas, Salivary 81and, Eye. Animal Number; IR-4687 Sex; Female Stoup: (5) FC-143 300 ppm Fate: (Week= 531 I Year Interim Sacrifice I Macroscopic Observations: Urinary Bladder -}isLanded with urine and containing greenish I Ureter spherical calcoli, 0.6 cm dia. -BiIaLeraI dilatation of ureters; filled with calculi near the end of the I Kidney ------ bladder. -Bilateral marked hydronephrosis with numerous calculi in the pelvic area. i MicroEEsscsoooppphihacaggeusOs.bservations: -"NHoo ddiiaaggneoossiiss,, iinnaaddeeqquuaattee sseeccttiioonn Kidney -Hydronephrosis, bilateral, marked I Pyelitis, chronic, moderate Mammary Gland -Not examined, missing 1 frien Kk ty we of scion Parathyroid -Hot examined, not in plane of section I Ureter -Calculus Inflammation, chronic~ diffuse, moderate O~Iatation, marked I UUrriinnaarryy BBllaadddeerr -EEppiitthheelliiaall hhyyppeerrppllaassiiaa,, ssiimmppllee,, ddiiffffuussee,, mwiilldd CCyyssttiittiiss,, c~hhrroonniicc,, ddiiffffuussee,, mmooddeerraattee i UUtteerruuss "-HHyycdrroosmeettrraa I The following tissues were found to be within normal limits: oy at tin, Brain, Spinal Cord, Bone ~arrow, Spleen, Liver, Heart, Long, Stomach, ~mall Intestine, I Large Intestine, Aorta, Ovary, Pituitary, Adrenal, Thyroid, Trachea, Lymph Node imesenteric), I I I Species~ Rat I Fat: S-- 1 Project Number: 02SICRO01~ SSuuammmaarriizzeedd SSTTAARR PPaaggee:: 2255 118899 11333377..00119977 3MA00027322 Summarized Single Tabulated Animal Report (continued) i Individual Macroscopic and Microscopic Observations i FFCC--1144)3:: TTuwoo YYeeaarr ODrraall TTooxrRiiikcceiirttyy--LODannbcocorogageteonnriiicceiistt,yy SSIttnuucd.dyy i3innM RRaattss =- tgnnee YYeeaarr IInntteerriima i Table: I i Afnniimnaall MNuumsbbeerr:: 1IRR--4468B99 SSeexx:: FFeemmaallee BGrroouupp:t ((55)) FFCC--114433 330000 pppoum Fate: (Week= 53) I Year Interim Sacri{ice | Macroscopic Observations: i sit ri, Eye | Liver -Right eye atrophied. -Pale tan in color. | 1 MMiiccrroossLcycomoppphiiccNosOdbeesrevr(avmtaetisieoonnntsse::ric) -Hemorrhagic Adrenal -~inusoidal ectasia, cortex, mild Eye -Atrophy, unilateral, marked i Liver Lung Panophthalmitis, chronic, unilateral, marked -Hepatocyte vacuolation, multilocal, mild -Hemorrhage, local areas, mild | Lymph Node (mesenteric) Parathyroid Thyroid -Hemorrhage, marked -Not examined, not in plane of section -No diagnosis, inadequate section |EB TThhee ffoolllloowwiinngg ttiissssuueess wweerree ffoouunndd ttoo bbee wwiitthhiinn nnoorrmmaall lliimniittss:: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart~ Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Overy, Mammary Gland, Pituitary, Trachea, i Esophagus, Pancreas, Salivary 81and. Animal Number~ IR-4692 Sex: Female Group: (5) FC-14~ 300 ppm Fate: (Week: 53) I Year Interim Sacrifice | Macroscopic Observations) -No visible lesions. i MMiiccrroossccooppiicc OObbsseerrvvaattiioonnss:: Lung -Hemorrhage, local areas, moderate I Lymph Node (mesenteric) -Not examined, missing I The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Liver, Kidney, Heart, Stomach, Small Intestine, 1 LTahrygreaidI,nteFsatrianteh,yrUcrii,narTyraBclhaead,derE,sopAhoratgau,s, UtPearnucer,easO,varSya,liMvaamrmyarEylanGdl,andE,re.Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. I Animal Number: IR-4699 Sex: Female Group: (5) FC-14~ 300 ppe 1 FFaattee:: ((WWeeeekk== 5533)) I1 YYeeaarr IInntteerriimn SSaaccrriiffiiccee | Macroscopic Observations: | Microscopic Observations: Adrenal -No visible leeions. -Sinusoidsl ectasia, cortex, mild 1| LiLvaergre Intestine Liver -H-HHeeeppmaaatttoooccdyyitlaeesivsvaaccuuosllaattiioonn,, mmullttiiffooccaall,, amilldd | | Species: Rat 1| Project Number: 0281CR0012 niet 5 pi 5 Summarized STAR Page: 26 190 190 11333377..00119988 3MA00027323 Sumaarized Single Tabulated Animal Report (continued) | ndoigunl ecroscpic ad Bcrasapic Drservations Individual Macroscopic and Microscopic Observations Tite Laorsorise, Ine, 0 Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rate - One Year Interia I Tate 1 Table: I Fier thes 50 1 Yeu Intern Scifice i Afnniimnaal! MNuusesbeerr:: I1RR--44~69%99 SSeex:: FFeeamallee GSrtoougps: (I 551) FFCC--114433 330000 ppppm | Fate: [Week= 53] 1 Year Interim Sacrifice Her[a4s Microscopic OBbsseerravattiioonnss ((coonnttiinnueedd):: Lung e-Hremaorgrhaege,, lloeccaall aarreeass,, mboedreraattee i 1 rTThaheeinff,oollSllpowwiiinnnagg Gttriasdss,ueesos ewwrereRerffroeaun,dd Stoolbebwe,wwiitKthiihdnosn,orrHmwaelrtlL,iimiSttts:o:ne, Sa Intestine, I UBUErrrsaiipinnhnaa~raryyeSspBB,ilanadadLldeiergrC,~hordANB,oaorrdttDeaao,,naesUWetMaeanrrrtureeso,,wr~iOOcvrS,aprrlyyeF,~ean~Mraaewmksmirda,nryeyyS,SSallaaHinnevdaa,,rrty,FPiSitStutnioiatt,aaacrfyylE,,,reSTTmhayhlrloiid,I~ntPPeasartriaanlteh,hyrroeiid,~ TTrraicchheesa,, ~sophagus, Lymph Node Imesenteric), Pancreas~ Salivary Siand~ Eye. | Fate: these 50 1 eur Intern Scifi ~nimal Number: IR-4704 Sex: Female 6roup: (5) FC-143 300 ppm Fate: (Week= 53) I Yeer Interia Sacrifice Macroscopic Observations: i Mcrescpic Bervations: fo visible esos. -No visible lesions. i Microhs~adcrroeepnniaacll Observations~ -"CCioolrrsttiiccaall ddeeggeenneerraattiioonn,, ffooccaall,, wuniillaatteerraall,, | ler Liver -FPhmuoierrltatdaatllsrwetooenonnvuucclilleeaaxrticcoeenll,ll iminnlfftiiillfttorrcaaattlee,,, imwiillledd wy | Lung "-bHVseaecspwacarutliloaaacrrygteems,iinveeawrcrlualtoliilisfazttaoitiaoiolnon,,n,,wmumw1lil6tlddifocal, mild 1 Tyrat cHtemorernheagien,dymulottifo1calp,lamnieldof section Thyroid -Not examined, not in plane of section | TSThhaeeinff,oolllSlopowininnnaglg tCtioirssdss,uueessSuwweerreearffrooounwnd,d tpoolbbeee,wwiittKhhiiidnnonn,oorrmmHaaellartlL,iimniiStttsso::mach, Sal Intestine, 1 LLTBiarrrraaggiceneh,sII,nnSttpeeiEsnspattliibnnaeeCe,,orsdiU,,rnianrBaorrnyhye ~aMlaNtarodrttdoerewr,,a,eSsAfpeoolsrrettteeasnr,,,icRkUltie,edsrnuesPsy,,,reOuHvesayarrsy,t,, SMMSaatalmosmmaaaarcryyhy, SSlthSanannadd,l,,lPPiEIintptt.ueistttaairrnyye,,~ Faathyoid, Parathyroid~ | Trachea, Esophagus, Lymph Nod~ imesenteric), Pancreas, Salivary Gland, Eye. I | | | | | | 1 PSSrppeoecjciieeets::NRFaaahttr: CBOE | 1 Project Number: 02BICRO012 SSuummmmaarriizzeedd SSTTAARR PPaaggee:: 2277 119911 11333377..00119999 M3MA0A000002277332244 Ca1 atmo C iL 137.0200 1337.0200 i 1 i 1 i 1 i 1 | 1 | 1 1i .1! I I 1 | i I 1 I 1 I 1 i i B 1 ii B 1 I 1 swacoczrszs 3MA00027325 Summarized Single Tabulated Animal ~eport I Individual Macroscopic and ~icroscop~c Observations Riker Laboratories, Inc. ~M FC-143: Two Year Oral Toicity-Oncogenicity Study in Rats Table~ 2 I Animal Number; IR-3518 Sex: Male Stoup: { 11 CONTROL O ppm Fate; (Week= IO&} Terminal Sacrifice I Macroscopic Observations; Skin -Raised inf~a~med lesion on right rear footpad, h Microscopic Observations: n Adrenal -Cortical vacuolation, multifocal, mild i H~ea~rrtt -MMy~yoeodccuaalrrlddaiirttyiissc,,ellcchhrrhooynnpiieccrplnnaaosnnissauu~spppuumrruaaltttiiivvfeeo,,cal, mild local areas, moderate i Kidne~ -Chronic progressive nephropathy~ min~ma! ~elvic mineralization, minimal 1 vr al tien sas mite, ssi Liver -Portal mononuciear cell infiltrate, mid~al | Portal bile d~ct proli~era~ion~ mild Lung -Vascular mineralization~ minimal i ! i PaPraartathhyyrrooiidd Pituitary Skin Pneusonia, interstitial, chronic, mdtifocal, mild -"PNNeoorttiveeaxxsaacmsuiilnnaeerdd,,mowmniiossnssuiicsnlggear in4iltrate, moderate -Adenoma -Pododermat~tis, ulcerative, hindleb marked Thyroid -Not examined, missing i The following tissues w~re found to bm ~it~in normal limits% 1 eA rs tity ri Eps Brain~ Spinal Cord Bone Marrow~ S~leen~ Stommch~ 8mall Intestine, Larg~ Intestine~ Urirary Bladde% Aorta, Testis/Epididymis~ Prostate~ Trachea~ Esophagus i Lymph Node (mesenterid, Pancreas, Salivary 61and, ~ye. I 1 Af,nn,~.imnaa,l' MNuusmtbeerr:: 1I8R--33551199 SSeexx:: M~aallee Fate: (Week= i0~) Terminal Sacrifice GGrroouupp:: (( 1i)1 CCOONNTTRROOLL 0n. pppgam I Macroscopic ObserYations: Microscopic Observations: -No visible lesions. i Adrenal I Esophagus Heart 1 Kidney n Liver -SCCioonrruttsiiocciaadllalvvaaecccu~taoallsaaittaii~oonn,,corsmtauellxtt,iivfoomccuaalllt,,ifoamciiallld, mild -Not examine~, missing -Myocarditis, chronic nonsuppurative, wmoilttiiffooccaall,, smiilld -Chronic progressive nephropathy, mild -Portal mononuc]ear ce!l infiit~ate, mild I Portal bile d~ct proliferation, mi1~ Hepatocyte alteration, vacuolated, multifocal, mild i i I Species: R~t Project Number~ 0281CR0012 Summarized STAR Page: 28 11333377..00220011 3MA00027326 I Summarized Single Tabulated Animal Report Icontinuedl i IInnddiivviidduuaall MMaaccrroossccooppiicc aanndd MMiiccrroossccooppiicc OObbsseerrvvaattiioonnss Biker Laboratories, Inc. 3M n FC-143: Two Year Oral loxicity-Oncogenicity Study in Rats Table; 2 B Animal Number: IB-3519 Sex: Male Group: (I) CONTROL 0 ppm Fate: (~eek= 106) Terminal Sacrifice I Microscopic Observations (continued): Lung -Vascular mineralization, mild n joel Perivascular mononuclear infiltrate~ moderate Pneumonia, interstitia], chronic, multifocal, moderate | The fo!1owing tissues were iound to be within normal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Stomach, Small Intestine~ Large Intestine, ! i LLUyyramippnhhary~NooddBeelad((dmweeerss,eennttAeeorrriitcca)~),, TPPeaasnntccirrsee/edEssp,,idiSSdaayll~iiivvsaa,rryy PBGrlloaasnntdda,,te,EEyyeeP..ituitary, Thyroid, Parathyroid, Trachea, Animal Number: !R-~521 Sex: Male Group: (I) CONTROL 0 pp~ Fate~ (Week= g2) Sacriiiced in extremis B Macroscopic Observations: Skin -Both hind footpads ~Icer~ted. 1 rol po Liver -P~le I Spleen -Enlarged i Microscopic Obsarvations: Ardernenaall -"CLoorrttiiccaall vvaaccuuoaIlaattiioonn,, dluoccaall aarreeaass,, mwiilldd Medullary cell hyperplasia, mu]tilocal, mild I Heart -Myocardial fibrosis, multifooal, mild I kidne~ Liver B 1 Lung -Chronic progressive nephropathy, moderate -Hepatocyte vacuolation, centrilobula~, moderate -PPVrnaeesuucmauoclneaiiraa,,miininentrteaerlrssittziiatttiiiaaolln,,, ccmhihrlrodonniicc,, llooccaall aarreeaass,, mild Edema, local areas, mild I Parathyroid Fibrosis, pleural, mild Thrombus -N~t e~amined, missing B Skin Spleen Stomach po -Podod~rmatitis, ulcerative, hindleg, ~ar~ed -Hem~to~oiesis, ~xtramedullarh increased, moderate -Edema, submucosal, marked B The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Small Intestine, Large Intestine, Urinary Bladder, Aorta, i Testis!Epididymis, Prostate, Pituitary, Thyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Sslivary Gland, Eye. i | I Species~ Rat Project Number: 0281CR0012 nee rg 193 Summarized STAB Page: 29 193 11333377..00220022 3MA00027327 B Said Sle Tanlated ial rt nto Summarized Gingle Tabulated Animal Report (continuedl oid Mosconi Res Gatos Individual Macroscopic and Microscopic Observations 1 te Corso, RiLer Laboratories, Inc. 3M B Fe: Te Your al i amici Sey is te ie2 FC-14~: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 I1 TTR Animal Number: I~-352~ Sex: Male Group: (i) CONTROL 0 ppm Fh ee 9 Suiscd in ross Fate; (Week= gSl Sacrificed in extremis 1 esas Gratis Macroscopic Observation~ n prt rss, 1024 in tails ilies Soft Tissues (thorax) -Mass, I0 x 9 ~ 4 cm in left axilla involving ike wa ih, wien ns muscle and rib, extendin~ into 1 Tek hrc city, solange 1s left thoracic cavity, collapsing left lung, | Yas st 8 nt Maes soft and fatty. sont Au) ito ath past scrtion is i Stomach -Waca!arlrtdieaad,.ematous with possible ulceration in rs Bertin: Microscopic Observations: n mt tical tation, witifc, ite Adrenal -Cortical Yacuolation, multifocal, mild 1 Seis ses, ren, be, W116 Sinusoida] ectasia, corte~, diffuse, mild i hort Atti rst, aio it Heart -Myocardial fibrosis, multifocal, mild ie ret press sip, wld Kidney -Chronic progressive nephropathh mild tw Fort natn cis lire we Liver -Portal mononuclear cell infiltrate, mild i Fatal bi dt rlisaion, Hid Portal bile duct proliferation, mild B epscte ssn eit, i Hepatocyte alteration, vacuolate~, mild oy She ieee, ws Lung -Vascular mineralization, mild 1 varie teh id Hemorrhage, ~ocal, mild Kne sromien 5i A~Yeolar macrophages, miid I esate Arabitin ate sapaive, vied Prostate -Prostatitis, acute, suppurative, marked J Firoawem, ars Skin -Fibrosarcoma, thorax i i rete, bis ala wit We!l differentiated, highly cellular with I ett ce i, moderate coIIa~en formation. 1 tos ee ret Stomach -Ulcer, marked I he aig ses wr fod tc 3 iin nd iit: The following tissues were found to be within normal limits: ie Si arty Ene baron, ees Sul ating Lge sin, ivr Sater, Grain, Spinai Cord, Bone Marrow, Spleen, Small Intestine, Large Intestine, Urinary Bladder, 1 Ee Toiihn, sti es srt Tran Ege Aorta, Testis!Epididy~is, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus, rk ie ester Peron, Slory Bt Be Lymph Node Imesenterid, Pancreas, Salivary Gland, Eye. n Ci Yas Set nls ran 1 BN0Oon Animal Number: I~-~524 Sex~ Male 1 Fits hae 0 Teast ce Fate: (Wee~= I061 Terminal Sacrifice Group: (i) CONTROL 0 ppm B [I -- Macroscopic Observations: 1 sat tt Pituitary | [er Microscopic Observations: Ho aly cll pti, itil, 16 Adrenal I fre ivi ras sor AE kidney B Le testes teist seaocso in ait Large Intestine in oe pPFrroa svweosaiteerl,ailrsaiiloain,dt,a,iedHeere Li~er -Small red lesion. -Medullary cell hyperplasia, multifocal, mi!d -Chronic progressive nephropathy, moderate Pelvic mineralization, mild -Nematodiasis, colon -Hepatocyte alteration, vacuolated, moderate Portal mononuclear cell infiltrate, mild Portal bile duct proliferation, mild | BI -- i SHpreocjieerst: eRart s O8ICHNI2 Project Number: 0281CR0012 [-- 194 Summarized STAR Page: 11333377..00220033 awaoooersze 3MA00027328 R Summarized Single Tabulated Animal Report (continuedl I Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc, 3M FC-143: Two Year Oral Toicity-Oncogenicity Study in Rats Tablel 2 I Animal Number; IB-3524 Sex: Male Fate: (Week= 106) Terminal Sacrifice Group: (i) CONTROL 0 ppm B Microscopic Observations (continued): Lung -Vascular mineralization, mild Lymph Node (mesenteric) -Not examined, missing Parathyroid -Not examined, not in plane of section B Fituitary -Adenoma 1 Thyroid -mFdoodelelrriaacttueelar hyperplasia, cystic, unilateral, Large cystic lesion occupying much of one n thyroid lobe. I The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Sma!1 Intestine, Urinary Bladder, Aorta, TestislEpididymis, Prostate, Trachea, Esophagus, Pancreas, Salivary Gland, Eye, I Animal Number: 1R-3525 Sex; Male Fate; (Week= I06) Terminal Sacrifice Group: (I) CONTROL 0 ppm | Macroscopic Observations: Bone -Joints of right forelimb and right hindlimb B Liver swollen. -Raised pale circular lesion, 2 cm dia.~ in medial lobe. n 1 MicroAAsdcrroeepnniaacl] Observations: -"CCoorrttiiccaall avar~suoollaattiioonn,, llooccaall aarreeaass,, mwosddeerraattee Bone -Arthritis, eynovitis; joints, foreleg, hindleg, marked I Heart Kidney -Myocarditis, chronic nonsuppurative, local area~, mild -Chronic progressive nephropathy, Boderate B Liver 1 B Lung 1 Prvaae Parathyroid I Spleen -Portal eononuc!ear cell infiltrate, mild Portal bile d~ct proliferation, mild Hepatocellular carcinoma iiLnnaffrigiell,ltrraapttoiiovvreel,.~ dAAiddfeefnneoariiedndtiaaarreteaeass~.,, Mlauntlaitpis!pallseetictt,uumsoerr embo!i in ee sae of ten -Vascular minerali(ation, m~Id Metastatic neoplasm -Not examined, not in plane of section -Hemosiderosis, mild Testis/Epididymis -Tubule atrophy, aspermatogenesis, mild I The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Stomach, Small Intestine, Large Intestine, Urinary Bladder, m B Species: Rat B Project Number: 02BXCRO012 SSuummmmaarriizzeedd SSTTIARR PPaaggee:: 3311 119955 11333377..00220044 3MA00027329 I Summarized Single Tabulated Animal Report (continued) I Individual Macroscopic and Microscopic Observations Riker Laboratories, !no, IN FC-143~ Two Year Oral Toxicity-Oncogenicity Study in Rats Table: l Animal Number; IR-3525 Sex: Ma!e Fate~ (Week= 106) Terminal Sacrifice 8roup; I !) CONTROL 0 ppm 1 sic Bates mies Microscopic Observations (continued)~ I The following tissues were found to be within nnrma] limits (continued): l Aorta, Prostate, Pituitary, Thyroid, Trachea~ Esophagus, Lymph Node (mesentericl, Pancreas, Salivary Gland, Eye. Anima! Number: IR-3526 Sex: Hale i Fate: is 108) Tersim] Sacrifice Fate: (Week= I06) Terminal ~acrifice Group: ( 1] CONTROL 0 ppm l Macroscopic Observations: i -NNoo vviissiibbllee lleessiioonnss.. Microscopic Observations: I Kidney -Chronic progressive nephropathy, mild l Li~er -Portal mononuclear celi infiltrate, mild Portal bile duct proliferation, mild Cystoid degeneration, focal, mild I i LLuunngg V-HVaeaspscacutulolacarrytewmiiasnleetrreaarllaiitzziaaottnii,oonn,,vace~uiiollldated, ~ild The following tissuee were found to be within normal limits: l Brain~ Spinal Cord, Bone ~arrow, Spleen, Heart, Stomach, S~all Intestine, Large Intestine, Urinary Bla~der, Aorta, Testis/Epididymis, Prostate, Pitoitar'~, Adrenal, Tflyroid, Parathyroid, Trachea, Esophagus~ Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. I Anima! Number: IR-~E2B Sex: Male Fate: (Week= I06) Termina! Sacrifice Group: ~ ti CONTROL 0 ppm I 1 MMaaccrroossccooppiicc OBbsseerrvvaattiiooenss:: Kidney -Hydronephrosis ~icroscopic Observations: Adrenal Kidney l Liver 1li Lung I Pituitary -Cortical ~acuolation, focal, mild -Chronic progressive nephropathy, moOerate eh, wie Hydronephrosis, unilateral, moderate -Portal mononuclear cell infiltrate, miid Portal bile duct proliferation, mild Hepatocyte vacuolation, mu]tifocal, mild -PPVrnaeesaucsmucolenaiiraa,,~iiinnnettreearrlssitt~iiatttiiiaaolln,,, ccmhhirrloodnniicc,, mmuilttiiffeoccaal1,~ mild -Hyperplasia, focal, pars distalis, mi1~ I The following tissues were found to be within normal limits; BBrraaiinn,, SSppiinnaall CCoorrdd,, BBoonnee M~aarrrrooww,, SSpplleeeenn,, HHeeaarrtt,, SSttoomsaacchh,, SSemaallll IInntteessttiinnee,, LLaarrggee IInntteessttiinnee,, Urinary Bladder, Aorta, TestislEpididymis, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, l l I Species: Rat Project Number: 0281CR0012 SSuummmmaarriizzeedd SSTTAARR PPaaggee:; 3322 1!9966 11333377..00220055 3MA00027330 | Summarized Single Tabulated Animal Report (continued) 1 Individual Ma~bciirkkoeesrrcoLLpaaibbcoorraaattnoodrriiMeeissc,,rosIIcnnocc.p.ic 3~O%Mbservations | FC-143: Two Year Oral To~icity-Oncogenicity Study in Rats J Table: 2 1 ie re en 1 Animal Number; IR-3528 Sex: Male | Fate: {Week= 106) Terminal Sacrifice Group: I 1) CONTROL | Microscopic Observations Kcontinued): The ollowing tissues were ~ound to be within normal limits Icontinued}: Lymph Node Imesenteric), Pancreas, Salivary Gland, Eye. Anima! N~mber: IR-3529 Sex: Male Group~ ( I] CONTROL 0 ppm | Fa~e: (~eek= 961 Sacrificed in exlremis |1 [-- Macroscopic Observations! -Areas of dermatitis with hair loss, some scabbed; back, side, abdomen. Liver -Raised pale mass, 1.2 cm dia. in left lateral i ilobe. Microscopic Observations: i HAidrreensa]l -"CCoorrttiiccaall Yvaaccuuoollaattiioonn,, mmuullttiif~ooccaall,, mwiilldd Kidney -Chronic progressive nephropathy, mild i Liver -Portal eononuclear cell infiltrate, ~ild | Hepatocellular carcinoma Trabecular pattern, f~irly ~ell differentiated. Lung | Parathyroid Prostate -Vascular ~ineralization, mild Edema, su~ple~ral, moderate -Not examined~ not in plane of section -Not examined, missing I ~a!ivary Gland Skin Urinary Bladder -Not examined, miesing -Ulcer, back, abdomen, marked -~pitheliaI hyperplasia, simp!e, di~use, mild The follo~ing tissues were ~ound to be within normal limits: i ~rain, Spinal Cord, Bone ~arrow, Spleen~ Heart, Stomach, Small Intesline, Large Inleetine, i APFo~urnntccarr,eeasssT~,eslEEiryese..!Zpididymis~ Pituitary, Thyroid~ Trachea~ Esophaqus, Lymph Rode (mesenter~c~ | ~nimal Number~ IR-3530 Sex; ~a]e Group: ( l} CONTROL 0 ppm i Fate: IWeek= 106) Terminal Sacrifice Macroscopic Observations: | ~icroscopic Observations; Heart -No visible lesions. -Nyocardi~is, chronic nonsuppurative~ local, minimal B Kidney "Dvanic progressive seghrapathy, wild Kidney -Chronic progressive nephropathy, mii( | Liver -Portal mononuclear cell infiltrate, mild Portal bile duct proliferation, mild Cystoid degeneration, ~ocal, moderate i Se Hepatocyte alteration, vac~olated, mild | .................................................................................................. | | i SPrpoejceicets: Projecl bNRuuasmtbbeerr:: (0228811CCRRI0001122 SSuummmaarriizzeetd SSTTARR PPaaggee:: 3333 1]9977 11333377..00220066 3MA00027331 I Summarized Single Tabulated Animal Report (continued) n Individual Macroscopic and Microscopic Observations Riker Laboratories~ Inc. 3M FC-143; Two Year Oral Toxicity-Oncogenicity Study in Rats I Table: .................................................................................................. Animal Number: 1R-~30 Sex: Male Group: (I) CONTROL O ppe Fate: (Week= 106~ Terminal Sacrifice I Microscopic Observations (continued): Lung -Vascular mineralization, =ild B Spleen Peribronchial lymphoid hyperplasia, mild -Hemosiderosis, mild The following tissues were found to be within normal limits: | Brain, Spinal Cord, ~one Marrow, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Testis!Epididymis~ Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteri~l, Pancreas, Salivary Gland, Eye. I Animal N~mber: IR-3531 Sex: Male Fate: (Week= 106) Terminal Sacrifice Group: (I) CONTROL 0 ppm Macroscopic Observations: B -No visible lesions. Microscopic Observations: 1 tn PO ---- Kidney -Chronic progressive nephropathy, mild B Liver -Hepatocyte vacuolation, mu]tifocai, mild i LLuunngg -VPVaoasrsctcaaulllaarrmons=oiinnnueecrrlaaellaiir~zaattcieiloolnn,, inmwfiiilllddtrate, minimal Pneumonia, interstitial, chronic~ loca] areas, B je moderate B The following tissues were found to be within normal Limil~; Brain, Spinal Cord, Bone Marrow, Spleen~ Heart, Stomach, Small Intestine~ Large Intestine, I 1 TTUreraaiccnhhaeersay,, BEElsasodopdphebarga,,gJssA,,orLtLay,mhphTeNNsootddiees/E((pmeiesdseiendntytemerirssic,c)),,PrPoPasarntccarrteeeas,ss,,PiStSuaailltiiavvraayrr,yy SGAladarnneddn,,al,EEyyeeT..hyroid, Parathyroid, Anima! Number: IR-3532 Sex: Male Group: (I) CONTROL 0 ppm B Fate: (Week= 106) Terminal Sacrifice Macroscopic Observations: Pituitary -Raised red mass, 0.4 cm dia. Kidney -Fluid filled cyst, ] cm dia., in right kidney B Microscopic Observations: Bn HHeeaarrtt --"RMoeyctoaicnraarldiiaaalltroffpiihbbyrr,oossiiFsso,,calff,ooccaaml!i,,ld meiillde Kidney -Chronic progressive nephropathy, moderate n Cyst, cortical, marked Liver BB1 Lung -Portal mononoclear cell infHtrate, mild Portal bile duct proliferation, mild is-Vascular mineralization, mild Pneumonia, interstitial, chronic, multifoca], mild Hemorrhage, local areas, mild Perivascular mononuclear infiltrate, mild B I 1 SSppeecciieess:: RRaatt Project Number: 0281CR0012 SSuumsmnarriizzeedd SSTT~RR PPaa~gee:: 3344 198 11333377..00220077 3MA00027332 | Summarized Single Tabulated Animal Report (continued) | Individual Macroscopic and Microscopic Observations Biker Laboratories, :no. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats | Animal Number: IR-3532 Sex: Male Fate: (Week= I06) Terminal Sacrifice Stoup: (i) CONTROL 0 ppm Table: 2 I Microscopic Observations (continued): Lymph Node (mesenteric) -Hemorrhage, mild | Pituitary Spleen -Adenoma -Hemosiderosis, mild 1 TShreainf,ollSopwinianlg tGiorsds,uesBewneereFafroruonwd, tSotobneichw,ithSianalnorImnatlestliinmiet,s:Large Intestine, rirary Bladder, Brain, Spinal Cord, Bone Marrow, Gtomach, Small Intestine, Large Intestine, Urinary Bladder, I Aorta, Testie/Epididymis, Frostate, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Fancreas, .... vary Gland. i Te a Animal Number: ~o.-o-oo~~ Ge~: Ma]e i Fate: (Week= I06) Terminal Gacri~ice Group: (I) CONTROL 0 ppm Macroscopic Observations: i Spleen -Pale circular depressed area, 0.4 cm dia. i ~iCFOEESyCeeOpiO ObeeFYations: "-NNoo ddiiaaggnnoossiiss,, iinnaaddeeqquuaattee sseeccttiioonn Heart -Myocarditis, chronic nonsuppurative, | multifocal, ~i!d i Kidney Liver -Chronic progressive nephropathy, mild -Portal mononuclear cell i~filtrate, mild Hepatocyte vacuolar{on, maltifocal, miid Lung 1| Prostate | otitis, ate, saprative, wil Prostate | Spleen -Vascular mineralization, mild Pneumonia, interstitial, chronic, multifocal, mi!d Per{vascular mononuclear infiltrate, ~ild -Prostatiti~, acute, suppurative~ mild -Hemosiderosis, mi!d Fibrosis, local areas, moderate | The following tissues were found to be within norma~ limits: Brain, Spinal Cord, Bone Marrow, Stomach, Sma!l Intestine, Large Intestine, Urinary Bladder~ Aorta, Testis/Epididymis, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, i Lyi Vote (nesnteric), Pancreas, Salivary Glan. Lymph Node (mesenteric), Pancreas, Salivary Gland. .................................................................................................. | Animal Number: IR-3534 Sex: ~ale Group: ( I1 CONTROL 0 ppm i FFaattee:: G{hWeeeekke= 110055)) SSaaccrriiffiicceedd iinn eexxt~rreenmiiss. | Macroscopic Observations: | Thymus Pancreas -Enlarged -Massive beige colored mass, 7.5 x 3 cI in area of pancreas completely i| aasrrueeraarssouoonffdirrniiggghhsttpleaaenndnd llaeeni~dtt alldaahtteeerrriaanllg to posterior | | Species: Rat Project Number: 02BICRO012 SSuunmwmaarriizzeed GSTTAARR PPaaggee:; 35 1t9999 11333377..00220088 3MA00027333 | Summarized Single Tabulated Animal Report Iconti~ued] Individual Macroscopic and Microscopic Observations ~iker Laboratories, Inc. ~M | FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Ii 2 Animal Number: 1R-~5~4 Se~: ~ale Group: I I) COHTROL 0 pp~ Table: 2 Fate: (~ee~: ~051 Sacrifice~ in extremis Macroscopic Observations icontinue~}: i Pancreas (continued] 1 on hives Kidney | ~estis/Epididy~is 1 i To he Li~er -liver lobes. -Pale and pitted. -Right testis small. -Pa~e with ~ellowi~h circular lesio~ 0.~ c~ diameter in right anterior lobe | | 1 A~rena~ -CMMoeerddtuuillcllaaalrryyvacccaellulloIahhtyyippoeunrr,ppllaadssiiifaaf,u,sell,ooccaamllodeaarrraeetaaess,, moderate -Chronic progressive nephropathy, moOerate | Liver Lung Malignant Iymphoma, histiocytic -Hepatocyte vacuolation~ di~fuse~ marked -Hemorrhage, diffuse, marked Malignant lymphoma, histiocytic i Ls ede laestateric) eerrhae, wild -Hemorrhage, mild | Malignant lymphoma, histiocytic i PPaarraatthhyyrrooiidd -Ma!ignant l'ymphoma, histiocytic "-Naot examineedd,, wmissing Pituitary -Adenoma | Small Intestine -Malignant lymphoma, histioc~tic I Spl~en ~to~a~h Testis!Epididymis -Malignant l~mphoma, histiocytic -Malignant lymphoma, histiocyt~c -Tubule atrophy, a~permatogeneeis, unilateral, 1 Thyeus -~mMHaaarllkiieggdnnaanntt ]Iyymapghhoomnas,, hhiis~ttiiooccyyttiicc Multiple sections of tumor from thymic and | ~edi~stinal a~eas. Thyroid -Not examined, mieeing |1 rs ae int ton sti Urinary Bladder -Malignant lyephoma, histiocyti~ | The following tiesuem were found to be within normal limits: Brain, Spinal Cord, Bone ~arrow, Heart, Trachea~ E~ophagus, Salivary 81and, Eye, Large Intestine, Aorta, Prostate. | | | i yas Species: Rat |1 Foe be sna Project Number: 0281CR0012 sans 200 Summarized STAR Pa~e: 16 200 11333377..00220099 3MA00027334 | Summarized Single Tabulated Animal Report (continued) | Individual Macroscopic and Microscopic Observations Piker Laboratories, Inc. 3M PC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats | Animal Number: 1R-S53B Sex: Bale Fate: {Week: 106) Terminal Sacrifice Group: ( I} CONTROL 0 ppm Table: 2 | Macroscopic Observations: Skin -Raised leaon, 1.5 cm dia., appears to be | Microscopic Adrenal i 1 TiKtindneeyy L~rge I~tes~ne abscess. -Cortical vacuolation~ ~ocal, mild -"CCShhirrnoounnsiioc[idapplrrooggerrceetssasssiiiavv,ee rnoeeopprhthrerwoo,piattfhhoyyc,,al,t~iinn~iiomndaaellrate . -Nematodiasis~ colon ii Li~er Pott src cat trate, ais -Portal bile duct proliferation, multifocal, Iild Portal iononuclear cell infiltrate, mild HHeeppaattooccyyttee vvaaccuuoollaattii~enn,, mmuullttiiffooccaall~, sBiinniismaall | Lung Skin -Vascular mineralization, mild Perivascular mononuc!ear infiltrate, ~ild -Keratoacanthoma Raised lesion from back. The following tissues were found to ~e within normal limits: I Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Aorta, Testis!Epi~idymis, Prostate, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus, 1 Do ees Par, Sn St, Bn, wr) ae Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye, Urinary Bladder. | Animal Nu~ber: IR-35~7 Sex: Male 1 a ot Fate: (Week= 73) Found Dead Group: (I) CONTROL 0 ppm | 1 Macroscopic Observations: LiLviveerr -"VVeerryy ppaallee LLyymapghh NNoodtee ((aabbddoommiinnaall)) -RReennaall Ilyymmpphh nnooddeess eennllaarrggeedd.. | Abdomen (internal} -MultilobularKfleshy mass, 4 x 3.5 x 3.5 | PPiittuuiittaarryy attached to omentum, left inguinal -eHsaeormeorarr.rhhaggiizc mmas~ss,, 00..77 ccmu ddiisa.. | 1 Mic[ros3copic Observations: -"NMoott eaxnamiinded,, imissisinngg Heart -Malignant lymphoma, histiocytic Li~er -Hepatocyte ~acuolation, dii{use, marked | Lung Malignant lymphoma, histiocytic -Malignant lymphoma, histiocytic Hemorrhage, loca! areas, moderate | Lymph Node (mesenteric) Pancreas Parathyroid -Not examined~ missing -Not examined, missing -Not examined, missing | | I Species: Rat Project Number: 0281CR0012 SSuumnmaarriizzeedd SSTTAHR PPaaggee:: 37 220011 11333377..00221100 3MA00027335 I Summarized Single Tabulated Animal Report (continued) I Ri~er Laboratories, Inc. ~M PC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats i Ca vr 7 on Animal Number: IR-3537 Sex: Male Pate: IWeek= 73} Found Dead Stoup: (I) CONTROL 0 ppm Table: 2 n Microscopic Observations (continued): Pituitary -Adenoma i Skin -Malignant Iymphoma~ histiocytic Mass from inguinal area ~as ma!ignant lymphoma. There ~as extensive necrosis in tu~or. i -Hem~iderosis, mild -Not e~ami~ed, missing i TThhee ffoolllloowwiinngg ttiissssuueess wweerree ffoouunndd tteo bb~e wwiitthhiinn nnoorrmmaall lliimsiittss:: Drain, Bpinal Cord, Bone Marro#~ kidney, Stomach, Small Intestine, Large Intestine, i Urinary Bladder, Aorta, Testie!Epididymis, Prostate, Adrenal, Trachea~ Esophagus, Salivary Gland. 1 ne a 5 ie os (ERR 0 n ~nima! Number; IB-353B Sex: Ma!e i Fate: (Week: i061 Terminal Sacrifice Group: (!) CONTRDL 0 ppm 1 Pacroscapc Ghservations: Macroscopic Observations: Pituitary -Sm~ll hemorrhagic area, 0.2 cB dia. i Liver i SSoplleaenn -Multiple pale ~oci, all lobee. E-Ennllaarrggeedd Microscopic O~servation~: i ~drenal -Cortical vacuolation, focal~ mi!d Kidney -Chronic progressive nephropathy, m~Id Liver -Malignant lymphoma, histiocy~ic I Lung -Vascular ~ineralization, mild i A~MlaavlleiiogglnnaaarnnttmalIcyyrmsoppphhhoaaemgsae,,s,hhiis~mtitliidooccyyttiicc Perivascular mononuclear in{iltrate~ mild I Lymph Node (mesenteric} -Hemorrhage, minimal n ~arathyroid Prostate Spleen -Not examined, not in plane o~ section -Prostatitie, acute, suppurative, marked -Malignant lymphoma, hi~tiocytic Urinary Bladder -Epithelial hyperplasia, simple, diffuse, mi!d i The following tissues ~ere found to be within normal limits; i 1 TBTereassittnii,ssl/EESpppiiiddniiaddlyymaCiiossr,,d, PPiiDttouuniiettaaMrrayyr,,rowTT,hhyyrrHooeiiaddr,,t, TTrrSaatccohhmeeaanc,,h, EEssScomppahhllaagguuIesn,,tePPsaatnniccnrreee,aassL,,argSSeaalliiIvvnaatrreyystGiGlnlaean,ndd,,AorEEtyyaee.,. I n 1i sp Species: Rat i Project Number: 02BICROOI2 SSuummmaarriizzeedd SSTTAARR Page: 36 220022 11333377..00221111 3MA00027336 | Samet Sige Telatd ial ert (contivnt i SIInnuddmiimvviiaddriuuzaael!d MMSaaiccnrrgoolsseccooTppaiibcculaaantnddedMMiiAccnrrimooasslccooppRiieccpoOOrbbtssee(rr:vvoaantttiiioonnnusesd) Riker Lorstoriss Int, Riker Laboratories, Inc. 3M | F-13: Te Your Gal oct Dogeicity Stay is Rats FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats 1 Tale: 2 Table: 2 ................................................................................................. I inl ars 5 Sec Mls rapt (1) CORO 0 an Animal Number: I~-3539 Sex: Ma!e Fite thet 08 Torsional Saerisice Fate: (Week= 106) Terminal Sacrifice Group~ (I) CONTROL 0 ppm | Macroscopic Observations: No visible esos, -No visible lesions. i i MMiiccrroosCKslcicarodonpnpgeieiycyc tOOebbsssteerrivvnaagttiioonnss:: lJ enses,-- colin -- -Chronic progressive nephropathy, mild i LiverLarge Intestine Liver -F-PNseoerrmataaatlloidimmsaosnoiossnn,uicislceotcalroinoccaenll,il iswnlifitllitaroattae,l, wsmiiil]ded | uaLung -sFVHcaerspaecauutllonayciryt,emHiasvneaesrcreuaarolls!iitazaitaitttoiainolo,n,,, mcummIihltladidsfocc,al,wimtlidfeal, i FPwmniieeleudmronbiae,rinsterrsctiltioalw, chronic, multifocal, niltrate, wild | fHaPtarruaaittthrryycroiied PeFivasoular mononuclear infiltrate, mild "Nyets,xairss ,is0a in pla f section -Not examined, not in plane of section Pituitary i sTireoe Spleen -"-HCHuyeUsimtoi,sttiedpiearrrasocsiidssai,,stamnlioiilsgsdt Thyroid -UItimobranchial cyst |1 er BrTTrhaaeieinnf,,oslSSltpopiwiniinanalgsCCtooi,rrsdes,yuersBFsoontweeetreMFeaa,rfrrooouFnwn,,rdaHbtmeoua,trb,teTwrSSicttthoheomisain,cchn,,oErxmSemapalllallgin,mIinttteseL:setininne,,SoUerianHarreysSBt!taedidrrer),, rAFotarstca,e,s, Testis/Epididymis, Prostate, Adrenal, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, i SSaalliivvaarryy lGlaanndd,, EEyyee.. .................................................................................................. | it Nave 160 Sent Te fro 1) COR 0g Animal Number: IR-~540 2 Fite ake 80 Fun Ie Fate: (Week= 64) Found Sex: Male Group: (I) CONTROL 0 ppm | Pcroscpic Oris: Macroscopic Observations: 1 rs Bien: pp-- Microscopic Observations: | re rr et earre, nisin Bone Marrow Liver paral wile cil efltrte, 18 Liver 1 ws irsctalsSlseeraaclispteiloinf,rstailodn, ais Lung i rotate att yinsdasishin,g a Prostate Spinal Cord | Tools ities ot Thyroid inky Batter Jt ante, wanes Urinary Bladder -No visible lesions. -Not examined, missing -Portal monon~cIear cell infiltrate, mild Portal bi!e duct proliferation, mild -Vascular mineralization, mi!d Alveolar macrophages, mild -Not examined, ~issing -Not examined, missing -Ultinobranchial cyst -Not examined, missing | 1 rBTTrhaeaeiisnnf,t,oilSSlipollcweeideennig,,itsKciis,adsnuyeeiy,sa,iwANeteriiaertytf,,,ouSSnMtdtosmotasowch,,b,e SFSwmieaatlrlhlslitnhaIonnttoiserdsmt,taiilneTe,lr,iamcaiLetarssr,:gee EIIsnptthesgtteisn,,e, LSAooprrttaa,Noe (sti, ure, Siliniy lestis/Epididymis, | Fancreas, Salivary Shand, Er. Pituitary, Adrenal, Gland, Eye. Parathyroid, Traohea, Esophagus, Lymph N~e (mesenteric), i | | i SSppeecciieess:: RRaatt fi:p Project Number: 0281CR00~2 SSuomnmrariiazeedd SSTTAAR PFaagee:: 33g5 220033 11333377..00221122 aMAc0c27387 3MA00027337 i 1n n i 1m 1I 1 i I iI B m Ii i n ii 'ii i ! i| Summarized Single Tabulated Animal Report (:ontinuedl Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. ~M FC-143: Two Year Oral Toxioity-Oncogenicity Study in Rats Animal Number: IR-3541 Sex: ~a]e Fate: (Week= 106) Terminal Sacrifice Group: I I) CONTROL 0 ppm joTable: 2 ~acroscopic Obeervatons: renSkin Microscopic Observations~ Adrena! isKidney Liver Lung Prostate Skin UUTrreiisnntaairrsyy/EBSplhiaaddtidtdeeyrr~is atin malatin, foc, mig -Raised lesion on left rear footpad. -Cortica! vacuolation, focal, mild a aie Sinusoidal ectasia, cortex, minimal -Chronic progressive nephropathy, minimal -Portal mononuclear cell infiltrate, mild Portal bile duct proliferation, m~id -PPVrnaeesuucsmuoolnnaiiraa,,~iiinnnettreearrlssittziiatttiiiaaolln~,, ccmhhirrloodnniicc,, mmsullttiiffeoccaall,, mild Hemorrhage, diffuse, marked Perivescular mononuclear infiltrate, mild -Not examined, missing -Pododermatitis, ulcerative, hindle~, marked -"-hN~ooottt eeexxxaaanmmiiinnneeeddd,,, wmmiiissssssiiinnnggg The following tissues were found to be within normal limits: ~rain~ Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, ~orta, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancqeas, Salivary Bland, Eye. Animal Number: ~R-~542 Sex: Male Fate: (Week= 106) Terminal Sacrifice Group: (I) CONTROL 0 ppm MMaaccrroossccooppiicc DOhbsseerrvvaattiioonnss:: Testis/Epididymis ~icrosco~ic Observations: Kidney Liver Lung Lymph Node (mesenteri~l Pancreas Teeti~/Epididymis Thyroid -Both testes small. -Chronic progressive nephropathy, moderate mHepatocyte vacuolation, multifoEal, mild -Vascula~ mineralization, minimal -Hemorrhage~ minimal -Hyperplaeia, islet ceIl~ moderate -Tubule atrophy, aepermatogenesis, bilateral, mPPaoar~lkyyeaedrrtteerriittiiss,, amiilld -Not examined, missing The following tissues were found to be within normal limits~ rch, Syn rs, or Bron po, er, nt Sul sie, Le tein Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine~ Large Intestine, Urinary Bladder, Aorta, Prostate, Pituitary, Adrenal, Parathyroid, Trachea, Salivary Gland, Eye, Ea Esophagus. ross rs CsCR1Z Species: ~at Project Number: 028ICRO012 SSuummmaarriizzeedd SSTTAA~R PPaaggee:: 4400 11333377..00221133 220044 3MA00027338 i 1 SSauemmmaarriizzeedd SSiinnggllee TTaabbuullaatteedd AAnniimaall RReeppoorrtt ((ccoonnttiinnuueedd!i Trib Ress ad some Gains Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M i E16 To Yer Bl Toe eit tty i us FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats aie 2 Table: 2 Animal Number: I~-~544 Sex: Male i Fie ei 16 Tria Surifc Fate: (Neek= I061 Terminal Sacrifice 8roup: (I) CONTROL 0 ppm 1 [re Macroscopic Observations: i Hout Src sin, 0.7 c din Pituitary Kite Si wire, ule wt pte. Kidney 1 Tetaitipis To tai TestisJEpididy~is i [a Microscopic Observations: Pe artical tation, wits, wnt Adrena] 1 ows GSriisapeteesa pfrien,aarteet Kidney i ve Sai lation, Atl ie Liver Je Sct iene, nd Lung 1ii rnaacetss AoF[terhlutprtoiyen,twainarepa of scion P~rathyroid Fite ry Pituitary i Sin Sires, ait Spleen i1 Tatts oFiiietesetsirs,,wsieess, wise, TestisiEpididymis -Hemorrhagic lesion, 0.7 cm dia. -Both en!ar~ed, pale and pitted. -Cortical v~cuolmtinn~ mul~i~ocal, moderate ~inusoid~I ectasia~ corte~ moderate -Chronic progressive nephropathy, marked -Hepatocyte vacuolation, mu!ti~ocal, -Vascular mineralization~ mild AiYeolar ~acrophages~ mild -Acin~r atrophy, mild Polyarteriti~ moderate -No~ examined~ not in plane o~ ~ection -Adenoma -He~o~derosis, mild -Tubule atrophy, aspermatogenesis, unilateral, mar~ed Polyarteritis, marked 1 The felon iss wre fond ob iti srl iit: The {of!owing tissues were ~o~nd to be within normal limits: | BBrraaiinn,, SSppiinnaall CCoorrdd,~ 8Boonnee MMaarrrrooww,, 5S1too~saacchh,, 5Smaaallll IInnt~eesstliinnee,, LLaar~gee IInnttee~sttiinoee~, UUrriinnaarryy B~llaaddddeerr,, re Hatt, Trt, Tran, Supe igh oe mic, Sey 1, 1 HH~eeoaarrrttta..~ Prostate~ Thyroid~ Trachea, Esophagus, Lymph Node (mesenteric), Salivary 81and, Eye~ i ei Yas 6S Br 1) NTL 0 0 Animal N~er: 1R-3545 Sex: Male 1 Fae te 10) Fou ed Fate: (Week= 104) Found Dead 8roup: ~ 1) CONTROL 0 ppm i [---- Macroscopic Observations: on Src eins, 2.5 in. 0 st hit 1 Skin ootpats. -Circular lesions, footpads. 2.5 cm dia. on both hind i wr Shen ie Liver -Slightly pale [rp a-- i Microscopic Observa~ions~ hAddrreennaall -"5Siinnuussooiiddaall eeccttaassiiaa,, ccoorrtteexx,~ wmooddeerraattee i atic vals, aii, strc Cortical vacuolation, multi~ocal, moderate on a cies moi Eye -Nol examined, mis~ing rt eri vont, Toa wes, id Beart -~ocardial ~ibrosis, Inca] areas, mild 1 Tier vent egaive sara 11 Kidney -Chronic progressive nephropathy~ mild i Je Seat einen ad Lung -Vascular mineralization, mild vee seg 16 Alveolar macrophages, mild 1 Pocus Ar dri, oe Pancreas -Acinar atrophy, moderate i Pra Ter Pituitary -Adenoma i | cis at Species: Rat i Fes rs cena 1 :Project Number: 028]CR0012 Sawing ST Pig 41 Summarized ~TAk P~ge: 41 220055 11333377..00221144 awaooo2rsse 3MA00027339 | Sri ie Toate ial fet nel Summarized Single Tabulated Animal Report (continued) 1 oil Rosas rene Boman Individual Macroscopic and Microscopic Observations ir hres, en Riker Laboratories, Inc. IN i FEA Teo Yr ral TocoScie St i ts FC-143: Two Y~ar Oral Toxicity-Oncogenidty Study in Rats i1 i A rp nate 2 Animal Number: IR-3545 Sex: Male ie te 0 Fo Be Fate: (Week= 104) Found Dead Group: { I1 CONTROL 0 ppm Table: 2 I Microscopic Observations (continued): i ttt, awtive Ndi, Skin 1 -Pododermatitis, u!cerative~ hindleg~ Bbiillaatteerraall,, ~aaarrtkeetd Spleen I pim~id The follo~ing tissoes ~ere ~ou~d to be ~it~Jn normal limits: I Tit yn Ey oe Rare Ln, Sh Santi, Lge Tein, Brain~ Spinal Cord~ Bone Mmr~o~ Liv~r~ Stcma~h~ S~mi~ i~testine, La~e Intestine, Fin ar, Sete ai, Frosh, This Psat, Tie E6t Uri~aW Bladder, Aorta, Te~tisiEpidi~vmls, Prostate, Thyroid~ Parathyroid, Trachea. iI1 afCrmeehtetget0eii,iiyeniwviSeah res (11 G06 (Week= 851~ Sacdficed in extra,is B HeritsnSuna os, 04st, Pituitary -Mass~ 0,~ cm dia. 1 i pi Liver -Pale I ~i:ros:opi~ O~servations: i ABrdraraieinnna~ -"OQiiig~ootdeennddrrooggliiioon~sa,~ bbeenniiggnn ie gn sed of Lge, irs Large neoplasm compo~e~ of iar~e~ fairly I wen Seienpienne wiinesrnte i Se, ath le uniform polyhedral ca]Is in cerebral cortex. ,ya,o~ep,,ri,is, a~u~e, mii, B we En on a te wis Liver -Rortal mononu:lear cell infiltra(e, mild eis watt, rg, site Hepato:yte vacuolar(on, per(portal, moderate 1 io a vei wa Lun~ -Vascular mineralization, mild I fHooary rSiywna, ive -Adenoma -Edema, submucosa!, ~oderate 1 TO -------- The ~oilowing tissues ~ere found to be within normal limits: n i ob arom to es ol Tetons Lue etic, tiny hse, Spipal Co~d, Bone Maprow~ Sp!een~ Heart~ Small In~esdn., Large Intestine, Urinary Bladder~ a Tate ovat Itt, Fragrant Aorta, Testis!Epididymi% ~rostate~ Thyroid, Parathyroid~ Trachea~ ~sophagus~ 1 Cri ee wehy Poa Stir Gre Lymph Node (mementeric), Pancreas, Salivary Gland~ Eye. I i ers 1650S era |) ER Animal Number: IR-~54B Sex: Male 1 Ft cn ol Seo Sore Fate: (Week= I06] Terminal Sarrifice Group: ( II CONTROL 0 ppm n [r---- Macroscopic Observations: i N-~so vviissiibdllee lleessiioonnss,. Harouic uration: Microscopic Observations: B re totic calutis, wits, wld Adrenal -Cortical vacuolation, multifocal, mild B I1 cen at Species: Rat B roe baer: ET Project Number: O2SICRO012 swish Summarized STAR Page: 42 220066 11333377..00221155 swac0027340 3MA00027340 | I ] 1 i I | | i| | | | i i i| | | i| | | 1| | Sunarized IInnddiivviidduuaall Bingle Tabulated Animal Report (continued) MMaaccrroossccooppiicc aanndd MMiiccrroossccooppiicc OObbsseerrvvaattiioonnss Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats : Animal N.mber: IR-3548 Sex: Male Fate: (Week= 106) Termina! Sacrifice Stoup: (I) CONTROL 0 ppm TTaabbllee:: 22 Microscopic Observations (continued): Kidney Liver Lung LLyimspth NNooddee ((nmeesseenntteerriicc)) Parathyroid Pituitary Thyroid -Chronic progressive nephropathy, mild -Portal mononuclear ce!l infiltrate, mild oyHepatocyte vacuolation, periportal, mild Hepatocyte vacuolation limited to one area liver. -Vascular =ineralizatio~, mild Alveolar macrophages, minimal mHHPeeemaroairrvrrahhsaacggueel,,aramimlloddnonuclear infiltrate, mild -Not examined, not in plane of section -Cyet, pars distalis -C ce!I carcinoma The following tissues were found to he within norma! limits: Brain~ Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Testis/Epididymis, Prostate, Trachea, Esophagus, Pancreas, Salivary Gland, Eye. fAnniinmaall NNuumsbbeerr:: I1RR--~15S44g9 SSeexx:: MMaallee GGrroowusp:; ((1I)) CCOONNTTRROOLL 00 ppopum Fate: (Week= 86) Sacrificed in e~tremis Macroscopic Observations; Pituitary Liver -HemorrhaGic mass~ 1.4 x 0.8 cm. -Slightly pale MicroHsHeceoarrpttic Observations: -HMyaocrarddit[i,s, cchhrroonniicc rnoonsssuspppurrtaitivvee,, multifocal, mild Liver -Hepatocyte vacuolation, multifoca], mild Lung -Vascular mineralization, mild Alveolar macrophages, minimal Parathyroid -Not examined, missing Pituitary Spleen Thyroid -Adenoma -Hemosiderosis, mild -Not examined, missing TThhee ffoolllloowwiinngg ttiissssuueess wveerree ffoouunnd ttoo bbee wwiitthhiinn onorrmeal Lliismiittss:; Brain, Spinal Cord~ Bone Marrow, Kidney, Stomach, S~a]l Intestine~ Large Intestine, Urinary Bladder, Aorta, Testis!Epididymis, Prostate, Adrenal, Irachea, Esophagus, Lymph Node (mesenteric], Pancreas, Salivary 81and, Eye. srg Species; Rat Project Number; 0281CR0012 Summarized STAR Page: 43 207 11333377..00221166 3MA00027341 Summarized Single Tabu!ated Animal Report (Eontinued~ Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc, 3M FC-143: Two Year Ora! Toxicity-O~cogenicity Study in Rats Table: 2 Animal Number: 1R-3=5~ Sex; Male Stoup: 1 Peres erin: Fate: (Week: 106) Terminal Sacrifice Macroscopic Observatlons: Spleen -Circu!ar raised lesion,~.' 2 c~ dia. Microscopic Observations: Adrenal -Cortical vacuolation, ~ultifo:aI, mild Medullary cell hyperplasia, local areas, 1 Kidrey -~mCCohhdrrecoraniaictce pprrooggrreessssiivvee nneepphhrrooppaatthhyy,, mmooddeerraattee -Portal mononuclear ~el! infiltrate, mild 1 Lung Peas, Imari dre, stil Portal bile duct proliferation, mild -Vascular Bineralization~ mild Pneumonia, interstitial, chronic, multifoca!, mild 1 PPPaaarrnaacttrhheyyarr~ooiidd -o-NAotctinaeerxnaimaitnnrgeodp,,hy,sneottmi!iidnn ppllaanxe ooff secticn section Pituitary -Adenoma Prostate -Prostatitis, acute, suppurative, mild ~pl~en -He~ngioearcoma The following tissue~ were {ound to be within normal limits: Brain, Spi~al Cord~ Bone Marro,, Hear!~ Slo~ach, S~a!! Intestine, Large I~temt~ne, Urinary Bladder, ~orta, Testis/Epididymis Thyroid, Trachea, ~.~-oph=-~-,us, Lymph Node (me~enteric)~ Salivary B!and~ Eye, i moinsl Mater: 1R-ISED Sec Male Grasp: (1) CONTROL 0 psa .................................................................................................. ~ni~a! ~m~er: ~R-.>~=~ Sex: Ma!e Group: (!) CONTROL 0 pp~ Fate: (Wee~= BS) Found Dead Macroscopic Observations: Adrena! -Left enlarged by a I cm dia, mass, Microscopic Observations: Adrenal -Binusoida! ectasia, cortex, mild Pheochromocytom~, benign~ unilateral Eye -Not e~amined, mis~ing 1 Heart Kidney -Mwmyuioltctiaifrfidocicatalils,,~ wmciihllrddonic nonsuppurative, -Chronic progressive nephropathv, mild 1 tal be fo rors, brie Large Intestine Liver -Not examined, missing -Porta! mononuciear cell ~nfiltFate~ mi!d Portal b1e duct proliferation~ moderate Hepatocyte vacuolation, multifocal, mild Necrosis, multi~ocal, mild Lung Lymph Node (mesenteric) -Vascular mineralization, mild -Not examined, mimsing Species: Rat Project Number: 02BICRO012 SSuumnmaarriizzeedd SSTTAHBA PPaaQgee:s 4444 220088 11333377..00221177 3MA00027342 | Summarized Sngle Tabulated Animal Report (continued) | Individual Macroscopic and Microscopic Db~erYations Riker Laboratories, Inc. 3M FC-1431 Two Year Oral Toxicity-Oncogenicity Study in Rats | Animal Number: IR-3553 Sex: Male Group: (I) CONTROL 0 ppm Fate: (Week= BB) Found Dead Table; | Microscopic Observations (continued): Pancreas i Pituitary Salivary Bland Small Intestine -Cyst, pare dietalis -Not examined, eim~ing -Not examined, missing I FBTrrhaaeiinnf,,olSSlppoiiwnniaanllg CCtooirrsdds,,ueSsBoonnweeerNMeaarr~rrooouwwn,,d SStppolleebeeenn,,wiSSttthooismnaaccnhho,,rmaUUlrriinnlaairrmyyitsBB:llaacdddeerr,, AAoorrttaa, TTeessttiiss!/EEppiiddiidyye~siss,, Prostate, Thyroid, Parathyroid, Trachea, E~ophagus. Animal Number: IR-3554 Sex: Male i Fate: (Week= 106) Terminal Bacrific~ Group: ( 11 CONTROL 0 ppm i| [r---- -No visible lesions. | 1 MicroFsKicitdonnpeeiyyc Observations: -"CThrroonniicc pprrooggrreessssiivvee aneepphrreoppaacthhyy,, mmooddeerraattee Liver -Portal mononuc!ear cell infiltrate, mild Porto] bile duct proliferation, mild Lung i| = i PPPrraoorssatttaahttyeeroid Hepatocyte alteration, vacuolated, mild -AiveoIar macrophages, mu1ti~ocaI, moderate Per~vaecular mononuclear infiltrate, moderate Vascular m~nerali~at~on~ m~!d Pneumonia, ~nterstit~1, chronic, multi~oca1~ moderate -"-PPNrrootosstteaaxttaiimttiiinsse,,d, aacnuuottte,~insswuppplpauunrreaattoiifvYees,,ecwmtoisdote~rraattee i The following tissues were found to be within norma! li~its: I Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, Urinary BIadd~r, Ac.rt~, Te~tis/Epididyeis, Pituitary, Adrenal, Thyroid, Trachea, E~ophagus, Lymph ~ode (mesenteric)~ Pancreas, Salivary Gland, Eye. | Anieal Number: ,~on-,~~u:u= Sex: Male Group: (i) CONTROL 0 pp~ Fate: (Week= 102) Sacrificed in extremie | 1 MMaaccrroossccooppiicc ODbbsseerrvvaattiioonnss:: Kidney -Pale, enlarged; mild hydronephrosi~. Urinary Bladder -Enlarged, ~luid ~i!led~ wal! appears | Microscopic Observations: Adrenal hemorrhagic. -Cortical Yacualation~ local aream, moderate | | Species: Rat Project Number: 0281CR0012 SSuuammnaarriizzeedd SSTTHARR PPaaggee:: 4455 220099 11333377..00221188 3MA00027343 B Samion irl Talated ol prt conti ummarized Single Tabulated Animal Report (continued) 1 Tobit Mescns a aae Breion Individual Macroscopic and Microscopic Observations B tr Larvae, Riker Laboratories, :no. 3M FE: To You rl Toso apc Ss in ts FC-1431 Two Year Oral Toxidty-Oncogenicity Study in Rats n hae 2 Animal Number: IR-3555 Sex: Male Group: ( II CONTROL 0 ppm Fatt ase 0) Safe in ers Fate; (Week= 102) Sacri(iced in extremis Table: 2 I Microscopic Observatione (continued)i To -- Aorta nl wt Site, Gr eesgarative , Heart -Mineralization~ mild -Myocarditis, chronic nonsuppurative, I ner Awiirsl,ynlae, veterte K~ney multi~ocal, mi!d -Nephrosis, tubular, moderate 1 Pilly sree sors Papillary necrosis, moderate Heese i Hydronephrosis, mild B Tail at wih ton, asic Tubules dilated with low, .basophiIic thle, ated arte sole. i LiLviveerr epitheli~, scattered mineralized tubules. -"PPoorrttaall bbiillee dduucctt pprroollii(feerraattiioonn,, mwiilldd | rte astm, wit, 06 Nepatocyte vacuoIation, multioca], ~ild ws ict iit, ad Lung -Vascular mineralization, mild [] Seely, noma, ite Alveolar macrophage~, mild R rrttyois ASewkaa,easitsinheshe o section Parathyroid 1 ent "rosettes at, saps id Prostate Hemorrhage~ focal, mild -Not examined, not in plane o4 section -Prostatitis, acute, suppurative, mild I Sul testive MEioss, eintrere aitss, eeste Small Intestine Edema, intersititial, moderate -Within normal limits Siem fTreeotthttaagee ber Spleen n Sous Eire, stl wre Stomach Fray eter Serta set Urinary Biadd~r Fewer than protocol number -Hemosideroei~, mild -Edema, submucosal, moderate -Hemorrhage, marked n tli tsi, sie ifn, aie Epithelial hyperplasia, Bimp!e, diffuse, mild Citi, nt, mise Cystitis, acute, moderate IB TTrhiceial,lEoisciss ee fd tebe iti sora Lint: i BBTrrhaaeiinn~,,ol5Slppoiiwnniaanllg CCtooirrsdds,,ueBBsoonnweeerMMeaarr~rrooo~wwn,,d to be LLaarrggee within normal limits: IInntteessttiinnee,, TTeessttiiss//EEppiiddiidcyymuiiss,, PPiittuuiittaarryy,, TThhyyrrooiidd,, h, Lu Ke search, Pree Ss Bo, Tr~chea~ Esophagus, Lymph Node (mesenteric)~ Pancreas~ Salivary 81a~d~ Eye. Bil at R55 Sei Be roan |B) SOE 0 ~nimal Number: 1R-$556 Sex: M~le i Fier heh 11 Torinl Sie Fate: (Week= 106) Terminal Sacrifice Group: (I) CONTROL 0 ppm B [Er -- Macroscopic Observations: Adrena! n Hirst Gesration: Microscopic Observations: -Right enlarged by mass, 2 x I cm. rw "tariro, cart, wiles 1 Adrenal -LCaaLrragcriegneonmenaec~oppllacasosrsmt,,icammloo,ssttlulynyilnnaeetccerrrooattliicc.. CCeeilllss m [rispspt pertain foamy, polyhedra] arranged in cords and seis. Hh ioc sity. Mlbste sheets. High ~itotic activity. Multiple i tees raintwrasetvee agro, aie Kidney 1e Gr Foil odie et mee ats Liver lung metastases. -Chronic progressive nephropathy, mild -Porta] mononuclear cell infiltrate, mild I Faria il act efi vion, i Portal bile duct proliferation, mild -| spc mt Species: Rat ret Wer: ChNIZ - ilProject Numberl 02B!CRO0]2 Sunrize Summarized 56STAR Ppagee:t4s6 221100 11333377..00221199 amacoo2ses 3MA00027344 i Summarized Single Tabulated Animal Report (continued) | Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143~ Tmo Year Oral Toxicity-Oncogenicity Study in Rats Table; 2 | Animal Number: IR-3556 Sex: Male Fate: (Week= 106) Terminal Sacrifice Stoup: (I) CONTROL 0 ppm i MiCrOScopic Observations (continued): Lung -Pneumonia, interstitial, chronic, multi{ocal, | mild Metastatic neoplasm Perivascular mononuclear infiltrate~ mild I 1 PPaarraatthhyyrrooiidd -"VNNaoosttcueelxxaiaramiinnmeeiddn,,erannlooittzaiitnnioppnll,aanneemiloodff sseeccttiioonn The following tissues were found to be within normal limits: i Brain, Spina! Cord, Bone Marrow, Spleen, Hearts Stomach, Small Intestine, Large Intestines Urinary Bladder~ Aorta~ Testis/Epididymis, Prostate, Pituitary, Thyroid, Trachea, [sopha~us~ Lymph ~o~e (~eseoteric)~ Pancreas, Salivary B~and~ ~ye. | Fate: (Week= I06) Terminal Sacrifice | 1 MMa~ccrroosscoooppiicc OObbsseerrvvaattiioonnss!: -No visible lesions. Microscopic Observations~ I Kidney Liver -Chronic progressive nephropathy, mild -Portal mononuclear cell infiltrate, mild Hepatocyte alteration, vaouolated, mild 1 Lung i Thyroid -PFVnraeesuscmeuoalnnaiiraa,,miiinnnettreearrlssittziiatttiiiaaolln,,, ccmhhirrloo~nniicc,, mmuullttiiffooccaall~, mild -~yperplasia, C cell~ mild 1 A ---- Th~ following tissues were found to be within normal limits: | Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, I Urinar~ Bladder~ Aorta~ lestis/Epididymis, Prostate, Pituitary, Adrenal, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. I i FFAaanttieem::al W(NWukemekbs=er:110066~)1R-TTSeeurr~am8iinnaal! S5Seaaxcc:rriiffMiiaccl~ee Group: ( II CONTROL 0 ppm Macroscopic Observations~ I Pituitary Microscopic Observations: Adrenal -Sinusoidal ectasia, cortex, mild Kidney I Liver -Chronic progressive ne~hropathh mild Calculus, pelvic, minimal -Cystoid degeneration, focal, minimal I I Species: Rat I Project Number: 0281CRO012 Ssuumamrariizzeesd sSTtAiR pPaa~gee: 417 221111 11333377..00222200 3MA00027345 | Summarized Single Tabulated Animal Report (continued} Individual Macroscopic and Microscopic ObserYations i ne Coren Riker Laboratories, Inc. 3M | FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats i Animal Number: IR-3558 Sex: Male Fate: (Neek= I06) Terminal Sacrifice Group: (i) CONTROL 0 ppo Table: 2 Microscopic Observations <continued): | Parathyroid Pituitary |1 fie ors id Spleen -Not examined, not in plane of section -Adenoma -He~osiderosis, mild The following tissues were found to be within normal limits: | ~rain, Spinal Cord, Bone Marrow, Heart, Lung, Stomach, Small Intestine, Large Intestine, Urinary B!adder, Aorta, TestisfEpididymis, Prostate, Thyroid, Trachea, Esophagus, Lymph Rode (mesentericl, Pancreas, Salivary Gland, Eye. | Animal Number~ I~-3560 Sex~ Male Group: (I) CONTROL 0 ppm Fate: (Week= ~5] Sacrificed in extremis ||1 Lung a) sts it -Focal circumscribed dark area, dorsal surface, left cerebral hemisphere (0.2 cm dia.) and lateral surface of right cerebral hemisphere (0.2 cm dia, i -Dark red diffuse mottling, ali lobes; red | Spleen Lymph Node (abdomina!l frothy e~date at trachea. -Znlarged -Ne~ati~ and renal nodes enlarged. | Liver Microscopic ObserYations; Brain -Pale, appears enlarged. -Abscess, mild | i LLiivneer Lung -MMHaaellmiioggrnrnahanantgte,Ilyymmmppuhhlootmniasf,,ocahhlii,ssttiimoooccdyyettriiaccte -Malignant Iymphoma, histiocytic Hemorrhage, diffuse, marked | Lymph Rode ~mesentericl Small ~ntestine Recrosis, local areas, marked -Hemorrhage, minimal -Bi~hin normal limits Fewer lha~ protocol numbe~ | Spleen -Hematop~iesis, extramed~llary, increased, marked | i TThhee ffoolllloowwiinngg ttiisssseueess ewerree ffoouunndd ttoo bbee wwiitthhiinn nnaorrsmaall lLiimsiittss:: Spinal Cord, Bone Marrow~ Kidney, Heart, Stomach, Large Intestine, Urinary Bladder, Aorta, Testis!Epididymis, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Irachea, Esophagus, | Pancreas, Salivary Gland, Eye. | I I 1 age Yrs ERR Species~ Rat Project N~mber: 0281CR0012 SSummymrariinzeedd SSTTAHR PPaaggees: 488 2211122 11333377..00222211 3MA00027346 I Sarid Site Tite al Sept Gio Summarized Single Tabulated Animal Report (continued) 1 IInnddiivviidduuaall MPaaccrroossccooppiicc aanncd MMiiccrroossccooppiicc OObbsseerrvvaattiioonnss ar Lawrie oe, Riker Laboratories, Inc. ~M R FE To Yer alTo Bccty Say io ats FC-143: Two Year Ora! Toxicity-Oncogenicity Study in Rats 1 Tie 2 Table~ 2 n i Nar BES le ret ) CHL 0 pn Animal N~mber~ IR-3561 Sex; Male Fite tl 100 Terns Sri Fate: (Week= 106) Terminal Sacrifice Group~ I 11 CONTROL 0 ppm Macroscopic Observations: n Tine ep Sh nd 1 in an ih Fr Soft Tissues (leg) -Right and left hindpaw and right forepaw wile swollen. Kidney -Right kidney polycystic. | iron Brains Microscopic Observations: od Cortical vtatin, wtifal, ats Adrenal -Cortical vacuolation, multifocal, mild 1 Se i, aii, i Medullary cell hyperplasia, multifocal, mild B - iit, sme ots, bins Bone -Arthritis, synovitis; joints, hindleg, fay, rid 1 HBoonnee NMaarrrroow~ -"NHfooottreleeexxgas,maiinnmeeaddr,,kedmwiissssiinngg on' vei epi sate ald Kidney -Chronic progressive nephropathy, mild ! Si meetin, 18 Pelvic mineralization, mild Ge, cartial, ateial wkd Cyst, cortical~ unilatera1~ marked i Large ntetine Stein, fo Large Intestine -Nematodiasis, colon n iw rye ------ Liver -Portal mononucIe~r cell infiltrmte, miid Portal Ml at reins, 16 Portal bile duct proliferation, mild 1 - vista wwe EN 616 Lung -Perivascular mononuclear infiltrate, mild I Vora smarts, 1 Vascular mineralization, Pn rsh ror, witifcly Pneumonia, interstitial, chronic, multifocal, nemild 1 a ---- Hemorrhage, local areas, moderate B Parathyroid -Not examined, miesing Shiney fini Pituitary -Adenoma 1 a oe int, ssi Spinal Cord -Not examined, missing B fe niterin, a Spleen -Hemosiderosis, mild Teiseitimis Tie art, arwtapesis, strte i Testis!Epididymis -PPTooullbyyuaalrretteearrtiirttoiipssh,,y, maaaarrskkpeeeddrmatogenesis, moderate B Tid ant, svg Thyroid -Not examined, missing 1 ie flowing Hiss wre fat te be itis sel Lit: The fol!owing tissues were found to be within normal limits: in ers Sto Si) sin, ny airs rt, Frese Ths, Sapte, Grain, Heart, Stomach, Small Intestine, Urinary Bladder, Aorta~ Prostate, Trachea, Esophagus, B Co ek neti ees, ary Es Er Lymph Node (mesenteric), Pancreas, Galivary Gland, Eye. B ue et 180 Trin Saif Animal Number: IR-~562 Gex: Male Fate: (Week= 106) Te~minai Sacrifice Group: (I) CONTROL 0 ppm I MMaaccrroossccooppiicc OObbsseerrYvaattiiooness:: FH Sse sceates ame ein, righ re Skin -Raised ulcerated inflammed lesion, right rear H ost, footpad. ste Seed ple fc. Spleen -Several pa!e loci. Microscopic Observations: I rt sea bts, crt, wile, Adrenal -Nodular hyperplasia, cortex, unilateral, a a moderate | B m = SSppeecciieess:: RRaatt fm m Project N~mber: D2BICRO012 sSuumnmarriizseed sSTaARrPgagee: 849 213 11333377..00222222 amAooo27se7 3MA00027347 n SureSine Tilted inal eer, Contin Summarized Single Tabulated Animal Report (continued) i IInnddiivviidduuaall MMaaccrroossccooppiicc aanndd MMiiccrroossccooppiicc OObbsseerrvvaattiioonns.s ae Lorre, ey 1 Riker Laboratories, Into 3M H R10: To Yer a Toreit Sty i ats FC-143~ Two Year Oral Toxicity-Oncogenicity Study in Rats x ie 2 Table~ 2 | i Nos Swi le Bot 1) GOR 6 Animal Number: IR-3562 Sex: Male Fite te 106 Terwsl Sic Fate: (Week= I06) Terminal Sacrifice Stoup: (I) CONTROL 0 I Microscopic Observations (continued): Heart -Myocarditis, chronic nonsuppurative, Misc nie multifocal, mi!d nay rae ages sr, Hid Kidney -Chronic progressive nephropathy~ mild I Lr sine erating olf Large Intestine -Nematodiasis~ colon tn Fetal ie cll ete, als Liver -Portal iononuclear cell infiitrate, ~ild 1 = Sc wwintan wi Lung -Vascular mineralization, mild | Pewee, mers, ric, 16 Pneumonia, interstitial, chronic, mi!d Feira cio oie, 18 1 PPaarraatthhyyrrooiidd "-HNPcoettrieevx~aaasneciiunnleeaddr,, ~nnoaonttoniuincnleppallaranneeinoofffilstsreeaccttteii~oonn mild Hany rns Pituitary -Adeno~a B Sinn sg ot wri, sing Salivary Bland -Not examined, missing 1 Se sates sieativ, Noth, weed Skin -Pododermatitis, ulcerative, hindleg~ marked I he flan tists were fod 0 be itis sonal Lint: The following tissues ~ere found to be within normal liIits: in Se Cory os Tre oo Stow, nl esti, in isin, Ets, Brain~ Spinal Cord~ Bone Map~ow~ Spleen~ Stomach, S~all Intestine~ Urinary Bladder, Aorta~ n ei Yas Trt le Sos 1) GL Ge 1 iIBIBI1 PpwrPfrTsaioraneeae-- atraoSipFTirieenioettesrrsriyirtc1rsewe.tr,awm,henoaseealTthtevmoetoitotrinteeoiehnntnG,,and51ssamsiienItlbiaecwif,naeaiaeEls,,,asewat1We6ereSte i nI HToittee SrPeieseetlss, waotn,iisnpspaWtivte,tew,trsttes || Testis/~pidid~mis~ Prostate~ Thyroid~ Trac~ea~ Esopha~us~ L~mph AFFnaaittmeea!:l ((NWeuemeebkke=r:I10086I))~-3TT5eo6rr3maiinnaall SSSeaaxcc:rriiMffaiilcceee Group: ( I1 CONTROL O Macroscopic Observations: Thyroid Skin Microscopic Observations: Adrenal Brain Heart Kidney Liver LLuongg PPaannccrreeaass. Pituitary Prostate -One side enlarged~ ! x O.B cm. -~ass~ 1.7 x 1.4 cm, dorsa! area. -Cortical vacuolation muitifocal~ mild Binusoidal ectasia, cortex, minimal -Astrocytoma, beniBn Poorly defined lesion in be.a, area cerebrum. Tumor cells spindelate. -Myocarditis~ chro~ic nonsupporatiw, mu!ti~oca!, -Chronic progressive nephropathy~ moderate -Hepatocyte alteration, basophilio, moderate Portal mo~onuclear cell infiltFate~ mild HNeepcarotsoicsy,te laolctaleraatrieoans~, vearcuaotlaeted~ moderate -"NVWeaacssrccouuslliaasrr, wmiilnnoceearrlaalliiazzraaettaisi,oonn~,modwmieillFddate -"PAheceriiinnvaaarrscaauttlrraoorpphhyym,,onowmnaaurrckkleeeddar infiltrate, mild -Adenoma -Prostatitis, acute, s~ppurative, moderate .................................................................................................. B I i I SSppeecciieess:: RRaatt. Fa! e Nar Project Nuiber: eR 02BICRO012 SSumumarnizred iSTdAR gPagee: 5$00 221144 11333377..00222233 awacoo2ses 3MA00027348 | Summarized Single Tabulated Animal Report (continued) | Individual Macroscopic and Microscopic Observations Biker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats | Animal Number: IR-3563 Sex: Male Fate: (Week= I06} Terminal Sacrifice Stoup: ( I} CONTROL 0 ppm Table: 2 | Microscopic Observations (continued): Skin -Keratoacanthoma, back Thyroid cell carcinoma i The following tissues were found to be mithin normal limits: i SAApooirrnttaaal,, CTToeerssdtt,iiss//BEEonppeiddiiMddayyrmarioiwss,,, SPPpaalrresaettnhh,yyrraoSiitcdo,,macTThrr,aacchhSeemasa,,ll EEssIoonppthheaasggtuiunsse,,, LLLyyaamrppghhe NNooItdneetes((tmnieensseee,nntteUerrriiiccn))a,,ry Bladder, i Salivary Gland, Eye. i Animal Number: I~-~564 Sex: Male Fate: (Week= i06) Termin~l Sacrifice Group: ( II CONTROL 0 ppm Macroscopic Observations: Kidney -Pale area in cortex o~ one kidney. I Microscopic ObserYations: Adrenal i -Cortical ~acuolation, multifocal, mild MMeedduullllaarryy cceellll hhyyppeerrppllaassiiaa,, mmuullttiiffooccaail~, moderate I Bone Marrow -Not examined, missing i Heart | i Kidney | i LiLviveerr -Myocarditis, chronic nonsuppur~tive~ multifocal, mild Myocardial fibrosis, multifoca], mild -OCCyhssrtto,~nicuunmipilrlaostgterereraslls,,iYmesoodfneoerrpaahttreeopathy, ~oderate Area of multilocular cysts in cortex with lipid change in surrounding parenchyma. -PPoorrttaall bbiillee dduucctt pprroolliiffeerraattiioonn,, wmiilldd Hepatocyte vacuo!ation, m~]tifocaI, mild Portal mononuclear cell infiltrate, mild | Lung Pancreas Parathyroid -Vascular minera!ization, mild -Not examined, missing -Not examined, not in plane of section | 1 SaPSliaitluviivatararyryyS8l1aanntd -"-HANodottenoeemxxaaamniinneedd,, mmiissssiinngg Spinal Cord -Not examined, missing TestislEpididymis -Mineralization, focal~ mild | The following tissues were found to be within normal limits: Brain, Spleen, Stomach, Small Intestine, Large Intestine, Urinary B~adder, Aorta, Prostate, | Thyroid, Trachea, Esophagus, Lymph Rode (mesenteric), Eye. | | | Species: Rat Project Number: 0281CR0012 SSuammmaarriizzeedd SSTTAH~ pPaaggee: 3~1I 221155 11333377..00222244 3MA00027349 | Sunrise Sige Tht ial Set Contin Susmarized Single Tabulated Animal Report (continued} Tein secs rd Wirt Cations Individual Macroscopic and Microscopic Observations Sie Lire es 1 Riker Laboratories~ Inc, 3M 1| 0 Te eur a Tore ce tty i at ate 2 FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 | or Yor 155 Su ale ro: 1) CE4L0 Animal Number: IR-3565 Sex; Male Fb thle 4) Fo et Fate: IWeek= 841 Found Dead Stoup: (I) CONTROL 0 ppm 1 asic nation: Macroscopic Observations: | Son tage wey 27 ay stl rn Skin -Large mass, 7 x 7 cm, scrotal area. ve a Liver -Pale [te -- Microscopic ObserYations~ | tent to cnn weg Adrenal -Not examined, missing J "ut es sy A~Fta -Not examined, missing Esophagus -Rot examined, missing | or Cary iets cio -No diagnosis, inadequate section Vion rat wees art, id 1 klLaiardrngeey IInntteessttiinnee --"CNhhoorodanigiancgonsopsriiossg,,resiisniavdmeeqnueeaptherosspeeaccttthiiyoo,nn mild oe ean vals wif wi Liver -Hepatocyte vacuolation, m~Itifocal, =ild | Vers wif, wre Necrosis, multi~ocal~ moderate 1 Set ato 6 Lun~ -~ascular mineralization, ~ild i Lv tte tretricl ones sie L~ph ~ode (mesenteric! -Not examined, ~issln~ i [he ems sing Pancreas -Not examined, missing Jot et mies sien i PPPiiattruuaiittthaayrrryyoid -"-~NNooot~t eeexxxaaammmiiinnneeeddd,,, mmiiissstssiiinnnggg | Jo ot cones eng Prostate -Not examined, missing Lory fl ot mine, Salivary Gland -Nol examined, missing in Lan Skin -Liposarcoma 1 ea se come of The scrotal mass was composed of large, | aed rls cae Th epee of vacuolated monon~clear cells. The de~ree of i ah apis SAR an autolysis made diagnosis somewhat uncertain. -Not examined, missing | She ent, eraser, rns, -He~atopoiesis, e~tramedullary, increased, 1 yest ewteor, sain Thyroid | J Set ses ing Trachea freon an, sos Urinary Bladder -Not examined, missing -Not examined, missing -Not examined, missing 1 he felling iss were fo to be within srw lt The following tissues were found to be within normal limits: | rie, Sion Sty Eo Waren, er, Sto, TotFis. ~rain, Spinal Cord, Bone Narrow~ Heart, Stomach, TestislEp~didymis. Animal N~ber: IR-~566 Se~: Male i Fs ee 10 Tenn Sates Fate~ (Wee~= I~6] Terminal Sacrifice 1 Warsi trations: Macroscopic Observations: an [rp-- Pituitary | Wires Serio ~icroscopic ObservationsI tem vita at iis Adrenal |i oe 5 pur ret Kikdiodnaeyy Group: (I) CONTROL 0 ppm -Small dar~ lesion. -Within normal limits One of pair present "-CChhrroonniicc pprrooggrreessssiivvee nneepphhrrooppaatthhyy,, mwiilldd i | --_ Species; ~at |1 Foes er osc Project Number: 0281CR0012 SSuumamnaarriizzeedd SSTTAHR PPaaggee~ 522 221166 11333377..00222255 awaooo27sE0 3MA00027350 i Summarized Single Tabulated Animal Report (continued) i IT~uddiivviidduaaall MMaaccrroossccooppiicc aanndd MMiiccrroossccooppiicc OObbsseerrvvaattiioonnss Riker Laboratories, Inc. 3M I FC-143: Two Year Oral Toxicity-Oncogenidty Study in Rats II Animal Humber: tR-356G Sex: Ma]e Group: (I) CONTROL 0 ppm Table: 2 Fate: (Week= i06} Terminal Sacrifice | Microscopic Observations (continued): Liver -Portal monon~clear cell in{iltrate, mi!d | Lun~ Portal bile duct proliferation, mild -Vascular mineralization, mild Perivascu]ar mononuclear infiltrate, mild Fancreas I Parathyroid pleen -Polyarteritis, moderate -Nol examined, not in plane of section -Hemosi~erosis, mild I 1 TThhee {foelllloowniinngg ttiissssuueess wweerree ffoouunndd ttoo bbee wwiitthhiinn nneorramaall lliimiittss:: Brain, Spine~ Cord, Bone Marrow~ Large Intestine~ Urinary B1adder~ Aorta~ Testis/Epididymis~ Prostate~ Pituitary, Thyroid~ Trachea~ Lymph Node (mesenteric}~ alivary Gland, Stomach, | ~a]1 Intestine, Heart, Eye, Esophagus. Animal Number: ,-~,~, Sex: ~ale Group: (I) CONTROL 0 ppm Fale: (Week= lOG) Terminal Gacrifice | Macroscopic Observationsl Skin -Raised papilloma type mass on back; raised | ~pleen Microscopic Observations: lnflammed lesion, right rear footpad. -Two pale ~oci. | Kidney -Cortical vacuolation, mul{i{ocal~ mild Nodular hyperpla~ia, cortex~ focal, mild -Chronic p~o~res~Ye nephropathy~ moderate |i1 we 1 eLLuiynvger -"-VdPaiosrsctcauulllaarrmosnmioivnneeurrcaallleiiazzraattciieoolnnl,, ~tn~iilltrate, mild Rly Alveolar Bacrophages~ minimal Perva~cular mononuclear infiltrate, minima] -Pap11oma, back Podod~rmatiti~, ulcerative, hindle~, ~arked -Necrosis, loca! area~ moderate The following tissues were found to be within normal limits: i Brain, Spinal Cord, Bone Marrow~ Heart, Stomach, Small Intestine~ Large Intestine, | 1 UEErssioonppahhraaygguussB,,ladLLdyyemwrpp,hh ANNooor~etea~((mnTesesesentntiteserlriEicpc)i),d,idPPyaamnniccsrr~eeaassP,,rosSStaaalltiievv,aarryyPitGBulliaatnnaddr,,y,EEyveTe..hyroid, Parathyroid~ Trache~ I i |1 pio Bpecie~ Rat | Piroyject Rubber: 0281CR0012 SSuummmaarriizzeedd SSTTAARR PPaag~ee:: 553 221177 11333377..00222266 3MA00027351 | Summarized Single Tabulated Animal Report (continuedl | Individual Macroscopic and Microscopic Observations Riker Laboraturies, Inc. 3M FO-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 | Animal Number: I~-3569 Sex~ Male Fate: {Week= 106) Terminal Sacrifice Stoup: ( I~ CONTROL 0 ppm i Macroscopic Observations: Kidney -Bilaterally enlarged; pale, pitted. Microscopic Observations: Adrenal -Cortical vacuolation, focal, minimal | SinusoidaI ectasia, cortex, mild 1 HHeeaarrtt. "-MMMeyydooucclaalrraddriiyttiissc,e,llcchhhrryoopnneiirccplnnauosnnissai~,ppppuumrruaaltttiiivvfeeo,c,al, mild multifocal, mild | Kidney -Chronic progressive nephropathy, marked Liver -Portal mononucloar cell infiltrate, mild 1 mse vaso, aio, ad Hepatocyte vacuolation, multifocal, mild i Lung -Vascular mineralization, mild Perivascular mononuclear infiltrate, miid | Pituitary Testis/Epididymis -Hyperplasia, focal, pars distalis, mild -PoIyarteritis, moderate | i TThhee ffoolllloowwiinngg ttiissssuueess wweerree ffoouunndt ttoo bbee wwiitthhiinn nnoorrmmaall lliimniittss:: Brain, Spinal Cord, Bone Marrow, Spleen, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, i Lymph Rode imese~teric), Pancreas, Salivary Gland, Eye. Animal Number: IR-3571 Sex: Male Group: (I) CONTROL 0 ppm Fate: (Week= I06i Terminal Sacrifice | Macroscopic Observations: Liver -Pale | Kidney ~esentery Microscopic Observations~ -Pale, pitted, enlarged. -Mesenteric vessels thickened Adrenal Heart i | B LiLKviivedenrrey -Cortical ~acuolation, focal, minimal -Myocarditis, chronic nonsuppurative, multifocal, minimal -"-PPCoohrrrttoaanllicsmeoprnreoomnguurccellseesaairrvecceenllellphriionnpffaiitllhttyrr,aatteem,,arkmweiidlldd Portal bi!e duct prolferation, mild Hepatocyte vacuolation, multifocaI, m~Id | Lung Mesentery -Vascular Binerali~ation, mild PerivascuIar mononoclear infiltrate, minimal -PoIyarteritis, marked | Pancreas Parathyroid Pituitary -PoIyarteritis, marked -Not examined, not in plane of section -Not examined, missing | | | Species: Rat Project Number: 0281CR0012 SSoummnmaarriizzeedd SSTTAARR PPaaggee:: $544 221188 11333377..00222277 3MA00027352 | Su~arized Single Tabulated Animal Report (continued) | Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats | Animal Number: IR-3571 Sex: Male Group: (I) CONTROL O ppm Fate: (Week= 106) Terminal Sacrifi[e Table: 2 i Microscopic Observations (continued): Small Intestine -Polyarteritis, mesentery, marked | Gpleen Testis/Epididymis -Hemosiderosis, mild -Polyarteritis, marked | The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Stomach, Large Intestine, Urinary Bladder, Aorta, Prostate, Thyroid, Trachea, Esophagus, Lymph Node (mesenteric), Salivary Gland, Eye, | i Adnoiimnaall MNouambbeerrs: 1I0R--0~577~2 SSeexx:: MKaallee Fate: (Week= 106) Terminal Sacrifice Grroouupp:: (( 11)) CCOONNTTRRIO.L 00 pppome Macroscopic Observations: i te ese Microscopic Observations: -No visible lesions. I 1 LiKLviidvenerery --"CFPhoorrrttoaanllic amoporrncooagnuruceclsleseaiarvre ccneelelllphriionnpffaiit!lhttyrr,aatteem,,inimamiiallldd Portal bile duct proli!eration, mild Hepatocyte vacuolation, multifocal, mild | Lung Pancreas Parathyroid -Vascular mineralization, mild -Hyperplasia, ~let eel1, moderate -Not examined, not in plane of section | ~tomach -Not examined, missing ,,,e following tissues were found to be within normal limits: | 1 BrUrriaininana,rryySpBHilanatadtldeerrC,,ordAf,oorrttBsao,,ne TTMeeassrttriiossw/t,~EppiSidpti~ieddeyinmi~iss,,HeaPPrrrtoo,ssttaaSttmeea,l,l PPIiintttuueiistttaairrnyye,,, AKLdiarrreegnneaall,,IntTTehhsyytrrioaoiiedd~,, TTrraacchheesh, Esophagus, Lymph Node (mesenteric), Salivary Gland, Eye. i Animal Number: i~-3573 Sex: Male Fate: (Week= I06) Terminal Sacrifice Group: (i) CONTROL 0 ppm Macroscopic Observations: Pancreas -Small circular pa!e mass, 0.5 cm dia. i Microscopic Observations: i Adrenal -CPPohhreetooiccchharrloomaocvccayycttuooonmlsaa,,tioBbnee,nniiggmnnu,,ltiuufnnoiicllaaaltt,eerraamllild Kidney -Chronic progressive nephropathy, ~ild | Large Intestine -Nematodiasis, colon | Liver -Hepatocyte alteration, vacuolated, mild Hepatocyte alteration, basop~ilic, mild Portal bile duct proliferation, mild Hepatocyte vacuolation, multifocal, mild | Portal monon~clear cell i~{iltrate, mild .................................................................................................. | | Species: Rat Project Number: 02BICRO012 sri 219 Summarized STAR Page: 55 219 11333377..00222288 3MA00027353 n Sarin Se alate al ort cnet Summarized Single Tabulated Animal Report (continued) frown phony ai Individual ~acroscopic an~ Microscopic Observations ie Lote oe 1 ~iker Laboratories, Inc. IM B FAS Te Yo ol Tore Sich Sy in ts FC-143; Two Y(ar Oral Toxicity-Oncogenicity Study in Rats 1I er or SS We ro (11 RL 8 1 ate 2 Animal Number: IR-3573 Sex: Male Fe Tein Swi Fate: IWeek= 106) Termina! Sacrifice 8roup: (I) CONTROL 0 ppm Table: 2 Microscopic O~servations (conlinuedi: B jo I -- Lung 11I ureass HPTieieivaestarste,wontmiiipeaiotf seec,tionwid Parathyroid -Vascular mineralization, ~ild Perivascular mononuclear infiltrate, mild -Acinar atrophy, moderate Islet cell adenoma -Not examined, not in plane of section B he elon toms wre fmt te with nd iis The following tissues were found to be within normal limits; in Sah Et ov br, on ot Sent Sul sie Urry Hair, i ARBoarrrattiaan,,, TTSeepsistntaiil~si/EECppoiirdddii,deyyBmaoiinss~,, MPParrroorssottwa,atteeS,,plPPeieitntu,uiittHaaerrayyr,,t, TThhSyytrrooomiiaddc,,h,TTrrSaamcc~hhIeeIaa,,InEEtsseoosppthhiaanggeuu,ss,,Urinary Bladder, ke earls Soy Hos Er Lymph Node ~m~s~nteric)~ Salivary Gland, Eye. I en or YS We ro (1) ERLE Animal Number: IR-3~74 S~x: Ha!e Stoup: ( 11 ~ONTROL 0 ppm 1 ie ey Siti n tes Fate; (Neek= gg) 8acrificed in exlremis I ersaic rations i Sn Macroscopic Skin Observations; -"Uclrceartateedd rriigghhtt a1ndd lleeiftt ihinndd ffoaotspatdss; B eur wie cnr circular white subcutaneous m~ss~ rte mr van we 1.5 cm dia.~ in right i~uinal area. i TThhoorraaxx ((iinntteerrnnaall)) -"FFiilllleedd wwiitthh fflluuiidd., ot Sty ob cit Heart -Sli~htly pale and flaccid. n ve Siwy pie Liver -Sli~ht!y pale it Sd es 18 en rst i rig be Kidney -Pale and pitted; 1.5 cm cyst in right kidney. 3 Twisomis Tate Testi~/Epididymi~ -Teste~ small | ~icroscopic ObserYation~: a Gia latin, mit, ail Adrenal -Cortical vacuolation, multifocal, mild 3 pin ppp Aorta -Necrosis, local areas, moderate | Serre wnt is retin Uniform intimal necrosis with.~o:"~ ete pie cellular infiltrate. rt iin, tron sprtivg Heart -Myocarditis, chronic nonsupp~rative, i, mul~i~oc~l~ mild I tn ne pent eh, ees Kidney -Chronic progressive nephropa~hy, ~arked Cy ws wo Cysi~ unil~eral~ marke~ Liver -Portal mononudear cell infiltrate, mild B ee a team, ie Po~t~I bile d~ct proli~er~tion~ mild I Tame, aay ms 058, i L~ng w-moPonddeeeurmraoatnteiea~ interstitial, ch~onic~ eta wel nile, 14 PeriYa~cular monon~c!ear infiltrale, mild B Cio ea ry ot Edema, local areas, marked 5 ot te sre fp Rrmighis ,y~p, Node (me,enteric) -Not examined, mi~ing fi rare Pancreas -Acinar atrophy~ mild B Peat eet by poe of section Parathyroid -Not examined, not in plane of section B B I i fraprp-- SSppeecciieess;: RRaatt, Project Number: 0281CR0012 SSuumrmairzizeeed SSTTAR aPag~ee:: 5360 222200 11333377..00222299 swaco0zrsss 3MA00027354 I i SIIunnddmiimvvaiirddiuuzaaelld KMSaaiccnrrgoolsseccooTppaiibcculaaanntddedMMiiAccnrrioomsaslccooppRiieccporOOtbbssee!rrcvvoaantttiiioonenussed} B Riker Laboratories, !no, 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats B Animal Number: IR-3574 Sex: Male Group: (I) CONTROL 0 ppm Table: 2 Fate: (Week= 9g) Sacrificed in extremis | Microscopic Observations (continued): Pituitary i PPrroossttaattee -Cyst, pars intermedia P-rProossttaattiittiiss,, aaccuuttee,, ssueppppuurraattiivvee,, maocddeerraattee Salivary Bland -Not examined, missing | Skin -Fibroma, subcutaneous, inguinal B Tae lestis/Epididymis Pododermatitis, ulcerative, hindleg, ,marked -Tubule atrophy, aspermatogenesis, bilateral, moderate I 1 TThhee ffaolllloorwiinngg ttiissssuseess wweerree ffoouunndd ttoo bbee wwiitthhiinn nnoorrmmaall Lliinmiittss:: Brain, Spinal Cord, Bone Marrow, Spleen, Stomach, Small Intestine, Large Intestine Urinary Bladder, Thyroid, Trachea, Esophagus, Eye. B Animal Number; IR-3576 Sex; Male Group: (I) CONTROL 0 ppm Fate: (Week= 55) Sacrificed in extremis Macroscopic Observations: B Skio -Moist area around genital papilla, EB Abdomen (internal) -Lttarrraagccett;samnnooountffoooooddf iignnasssttioonsmaagccahhs.,trointestinal Microscopic Observations~ B Kidney -Pelvic mineralization, mild n Lung Parathyroid SpSlpeleenn -Hemorrhage, diffuse, marked -Not examined, not in plane of section m~HHeemaoossiiddeerroossiiss,, wmiilldd Urinary Bladder -Not examined, missing I The following tissues were found to be within normal limits: i BTTreeassittnii,ssl/ESEpppiiinddaiilddyymaCiiosrs,d,, PPBrrooonssettaattMeea,,rroPPwii,ttuuLiiittvaaerrryy,,, HAAeddarrreetnn,aal!,,StoTTmhhayycrrhoo,iidd,,SmaTTlrrlaacchhIeensat,,estEEissnooepp,hhaaggLuuassr,,ge !ntestine~ Aorta, n Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. Anima] N~mber: IR-3577 Sex: Male Fate: (Week= i06) Terminal Sacrifice Group: (I) CONTROL 0 ppz B Macroscopic Observations: 1 oe en, -No visible lesions. I Microscopic Observations: Kidney i LiLviveerr -Chronic progressive nephropathy, moderate f-Protrtaall maoonnoannuucclleeaarr cceellll iinnffiillttrraattee,, emiilldd Portal bile duct proliferation, mild I Hepatocyte vacuolation, multifocal, mild I Cystoid degeneration, multifocal, mild Hepatocyte alteration, vacuolated, mild m m 1 SSppeecciieess:i RRaatt Project Number: D2BICRO012 SSuummmmaarriizzeedd SSTTAHR PPaaggee:: 5577 222211 11333377..00223300 3MA00027355 B Summarized Single Tabulated Animal Report [c~ntinued) 1 IInnddiivviidduuaall MMaaccrroossccooppiicc aanndd MMiiccrroossccooppiicc DObbsseerrvvaattiioosnss. Riksr Laboratories, Inc. SM B FC-14I) Two Year Oral Toxicity-Oncogenicity Study in Rats | Animal Number: IR-3577 Sex: Male Group: (I) CONTROL 0 ppm Table: 2 Fate: (Week= I%) Terminal Sacrifice R Microscopic Observations icontinued): Lung i FMeesseesntteerryy -Vascular mineralization, mild -"PFoollyyaarrtteerriittiiss~, wmaarrkkeedt PancrBas -Polyarteritis, marked | Small Intestine -Polyarteritis, mesentery, moderate B Spleen Thyroid -Hemosiderosis, mild -Cyst~ colloid, mild 1 f~Trrhaeainnf,,olSSlppoiiwrniaanllg CCtooirrseds,,uBesDoosnweeerMMeaarr~rrooounwn,,d HHteeoaarrbtte,, wSSitttoohnmiaancchhn,,ormLLaaalrrggeelimIIinntttsee:ssttiinnee,, UUrriinnaarryy DBllaaddddeerr,, a~orrttaa,~ B Testis!Epididymis, Prostate, Pituitary, Adrenal, Parathyroid, Trachea, Esophagua~ Lymph Node (mesenteric), Salivary Gland, Eye. i nv Re em 1) SOL 0 Anita! Number: ~B-357B Sex: Male ! Pats: (Week= 106) Terminal Sacrifice Broup~ (I) CONTROL 0 pp~ B Macroscopic Observations: Pituitary -Hemorrhagic mass, 0.~ cm dim. i Skin -Rddaiiimsa.e.,d llueelffctterhahitinneddd ffioonoofttlppaaamddm,.ed lesion, 1.5 cm Microscopic Observations: B Kidney -Chronic progressive nephropathy, mild Hydronephrosi~, unilateral, moderate 1 te ess evar' meric Calculi present in ureter o~ hydronephrotic n kidney. Liver -Portal mononuclear cell infiltrate, mild Portal bile duct proli~eration, mild B Lung -VascuIar eineralizahon, mild 1 PiPtiutiuittaarryy Hemorrhage, local areas, moderate -AAddeennoommaa Prostate -Prostatitis, acute, ~up~uratiYe, moderate B Salivary Gland -Gialadenitis, chronic, minimal B Skin Very minimal lesion, only one duct a~fected. -Pododermatitis, ulcerat~w, hindleg, marked The foiIowing tissues were found to be within normal limits: I Brain, Gpinal Cord~ Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, TestisiEpididym~s, Adrenal, Thyroid, Parathyroid Trachea, Esophagus, Lymph Node (mesenteric), Pancreas, Eye. I I B I Species~ Rat Project Number: 02BICRO0~2 SSumomarrizied SSTEAR PPaaggee: 8 222222 11333377..00223311 3MA00027356  4 no C 13133737..00223322 I 1 I i I 1 1B | 1 1n I i I : I 1H i i 1B I 1 1I | 1 i 1 I 1 1I BI M3MA0A000002277338577 i Summarized Single Tabulated Animal Report !continued> | Individual Macroscopic and Microscopic Observations Riker Laboratories, Ind. SM FC-143: Two Year Oral Todcity-Oncogenidty Study in Rats i Animal Number: IR-3579 Sex; Male Group: (I) CONTROL 0 ppm !able: 2 i F~te: (Week= 86) Sacrificed in extrenis Macroscopic Observations; Pituitary -Raised mass, 0.8 cm dia. i LiVer Skin -Raised pale 2 cm dia. mass in right lateral lobe. -Mass seen clinicall~ on right side appears to be healed lesion. Microscopic Observations: | Kidney -Chronic progressive nephropathy, marked ii Liver -HHPeoeprpatatalotoccebelillllueullaadrruccctaarrpccriionnlooimmfaaeration, mild Portal mononuclear cell infiltrate, mild Lung -Perivascular mononuclear infiltrate, mild Parathyroid -Not examined, not in plane of section 1 rie Sion Pituitary -Adenoma i Skin -Keratoacanthoma i i SSmaaallll IInntteessttiinree -"WHSiikttihhniinnlennsoorirmomanallfrLloiimnmiirttissght side. Fewer than protocol number I 1 Spleen TTeessttiiss//pEipdiiddiydnyimsis -Hemosiderosis, mild -~TTuubbuullee aattrroopphhyy,, aassppeerrmmaattooggeenneessiiss,, uunniillaatteerraall,, mild Polyarteritis, mild i The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Heart, Stomach, Large Intestine, Urinary Bladder, Aorta, Prostate, Adrenal, Thyroid, Trachea, Esophague~ Lymph Node Imesenteric), Pancreas, 1 Salivary land, Eye. Salivary Gland, Eye. i Animal Number: IR457G Sex: Female Group: ( I1 CONTROL 0 ppm Fate: (Week= 25) Sacrificed in extremis i Macroscopic Observations: Liver -Enlarged; mottled yellow color. 1 we aa Ht Lymph Node (bronchiall -Enlarged i Lung -Pale he ee 1 SSSttpoolmaeaseccnhh -"-RREeenddlappraagtteccdhhyy aarreeaass oonn wmuuccoossha.. Lymph Node (mesentericl -Enlarged and reddened. | ~icroscopic Observations: i Adrenal Bone Marrow Kidney -Sinusoidal ectasia, cortex, mild -Malignant lymphoma, lymphocytic -Malignant iymphoma, lymphocytic i Nneralization, cortical, mild i Species: Rat lhe: cnn Project Number: 02GICRO012 SSuummmmaarriizzeedd SSITARR PPaaggee:: 59 222233 11333377..00223333 3MA00027358 I Su~arized Single Tabulated Animal Report (continue~} I Individual Macroscopic and Microscopic ObserYations Riker Laboratories, Inc. IM FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 I Anima! N~mber: IR-157G Sex: Female Group: Fate~ (Week= 25) Sacrificed in extremis Microscopic Observations (continued): n Liver 1 LLuunngg -Malignant iymphoma, lymphocytic -"MMaalliiggnnaanntt lIyymapphhoomsaa,, Ilyyemgphhooccyyttiicc. Hemorrhage, multi~ocal, mild i Lymph Node 4mesenteric) Pancreas -Malignant lympho~a, lymphocytic -~alignant lymphoma~ Iymphocytic Salivary Bland Spinal Cord n Spleen 1 Sin ste i pss, smi, dif id Stomach Urinary Bladder -Not examined, missing -Malignant ly~phoma, lymphocytic -Malignant lymphoma, lymphocytic -Ulcer -~pithelial hype~plasia, simple, diffuse, mild ii tes vt hie Fea, Bs, Ory, Kary ist, tut, The following tissues were fo~d to ~e within normal limits: Brain~ Heart, S~a'~~ In~e~+~~n.~~ Large I~testine, Aorta, Uteru~ Ovary, Mammary. Gland,. Pituitary, i Trachea~ Thyroid, Parathyroid, Esophagus, Eye. i rAnimlal NNa~aberr:~ IA~S-4T57]7 Ses Female Eros { 1) CORLL 0 gin Sex: Fem~le Stoup: (I) CONTROL 0 ppm i Fate: (Week= 99) Found Dead i i MMaaccrroossccooppiicc COhbsseerrvvaattiioonnss:: Pituitary -Hemorrhagic ma~s, O.B cm dia. Mammary Gland -Multilobular mass, 4.5 x 3.5 K 2 cm, in right axilla. Microscopic Observations: B Adrenal Kidney 1I Nepbrasis, tusalar, warked Liver -Sinu~oidal ecta~ia, cortex, moderate -Pel~ic mineralization, mild ~ephrosis, tubular, marked -Portal mononuclear cell infiltrate, mild Portal bile duct proli~eration, mild I Lymph Node (mesenteric) Mammary Gland Hepatocyte vacuolation, muitifocal, mild -Not e~a~ined, mis~ing -Cobular hy~erplasia Pituitary -Hemorrhage, ~arked I Spleen Uterus Necrosis, moderate -Hemoeiderosis, mild -Cystic glands, moderate | The following tissues were ~ound to be within normal limit~: Brain, Spinal Cord, Bone Marrow, Heart, Lung, Stomach, Small Intestine, Large Intestine, | Urinary Bladder, Aorta, Ovary, Tracbea~ Thyroid, Parathyroid, Esopbagus~ Pancreas~ Salivary Gland, Eye. | i i Species: Rat Project Number~ 02BICRO012 SSuummmaarriizzeedd SSTTAHR PPaaggees: 6600 222244 11333377..00223344 3MA00027359 | Soret Se Td fil rs Conti Summarized Single Tabulated Animal Report (continued) 1 IInnddiivviidduuaall MMaaccrroossccooppiicc aanndd MMiiccrroossccooppiicc OObbsseerrvvaattiioonnss. ie corr, es Riker La)oratories~ Inc. 3M | Fo: Tt a To cc Stk in Bt FC-143: Two Year Oral Toxicity-Oncogenicity Stu(y in Rats 1 ot 2 Table: | i es ns et a 1) SO 0 Animal Number: 1R-4579 Sex: Female Stoup: (I) CONTROL 0 pp= eh amie oes Fate: (Week: B4) Sacrificed in extremis | Macroscopic Observations: Pituitary 1 SSkeiinn -Raised mass, 0.5 cm dia. "-RRaaiisseedd tthhiicckkeenneedd lleessiioonn wwiitthh ssccaabb oonn rriigghhtt poyside. | or ny wie Liver -Slightly pale Homa 10. Stomach -Somewhat reddened Kidney -Fluid filled cyst in !eft kidney. | Warns Gertie: Microscopic Observations; oe -- 1 R~edrrteana! ~orta --~SMKiiinnnueesrroaailldiiazzlaaltiieoocnnt,,asimmauu,llttiicffooorctceaaxll,,, mmaiiilllddd o ns Heart -Nyocarditis, chronic nonsuppurative, | ir wits multi(oca], moderate io rie Kidney -Nephrosis, tubular 1 eine aren ate Pelvic minera!ization, marked | ah crs mi Cyst, cortical, moderate esi ie yn, de, 10 Hyperplasia, pelvic epithelium, diffuse, mild 1 ye ey wi rsh we Liver -Hepatocyte vacuolation, mdtifocal, m(ld i io rare mtn L~ng -Vascular mineralization, mild A nto wo Lymph Node (mesenteric) -Nol examined, missing i FaFraartahtyhryoriodid. -MNoott eexxaanmiirneedd,, nnoott iinn ppllaannee oof~ sseeccttiioonn a ro Pituitary -Adenoma i o erwin Skin -Ulcer, marked i beSpleen Stomach ws Skin lesion from side. -Hemosiderods, mild -~ineraliz~tion, mucosaI~ mild i TThhee ffoolllloawwiinngg ttiissssuueess wweerree ffoouunndd ttoo bbee wwiitthhiinn nnoorrmmaall lliimniittss:: | ie en Sen Su aie re tin, Winey Bt, es, B~ain, Spinal Cord~ Bone Marrow~ SmalI Intestine, Large Intestine~ Urinary Bladder~ Uterus~ Si: ory Bt oe Trt opin, ero, Sr Ss Bn Ovary, Mammary Gland, Trachea, Thyroid, Esophagus, Pancreas, Salivary Bland, Eye. 1 i oe Se ete fe 1 GL 7 Animal Number; IR-4~BO Sex: Female 8roup: (I) CONTROL 0 ppm i a eget Fate: (Week= 52) Sacrificed in extremis i [A -- Macroscopic Observations! i iy Ets ew rd mu, 08 Pitoit{ry -Enlarged( dark red ~as% 0.5 cm dia. Sr rion i Microsrcoepniacl Observations: "Sinusoidal ectasia, corter, sil Adreoa] -Sinusoidal ectasia, cortex, mild pet es Aorta -Not examined, missing i En es wy Esophagus -Not examined, missing ig A-- Nts wm Lymph N~de (mesenteric) -Not examined, missing Yaa Lo ~ammary Gland -G~!actocele | enn at gue in Parathyroid -Not examined, no~ in plane of section | |1 -- Speciesi Rat | five dp-- Project Number: 0281CR00~2 Snizes stipe 6 Summarized STAR Page: 61 222255 11333377..00223355 swa00027300 3MA00027360 B |1i| m B iR B iH i B H i m B B B n B i I I i I ISInnutd~iiavvriiiddzuuaaelld MMSaaiccnrrgoolsseccooTppaiibcculaaanntededMMiiAccnrriomosaslccooppRiieccpoOOrbtbssee(rrcvvoaantttiiioonnnusse.d) 8iker Laboratories, Inc. SM FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats to 2 Tablel 2 Animal Number: IR-4580 Sex: Female Group: ( I~ CONTROL 0 ppm Fate: (Week= 521 Sacrificed in extremis Microscopic Observations (continued): SSPppilteeueintary "--HHAeedmweocnesoiimdcaeerroassiiss,, amaotdeerraattee The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Liver, Kidney, Heart~ Lung, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Uterus~ Ovary, Trachea, Thyroid, Pancreas.~ Salivary Gland, Eye. FFAaanttieem::al G(iNWsoese~ikb=ser! 8855I]R-SS45aa8cc!rriiffiicceeddSexii:nn teFxertmoranelmeiics Group: [II CONTROL 0 ppm Macroscopic Observations: Mammary Gland Liver Spleen Microscopic Observations: Adrenal Liver Lung Mammary 81and Parathyroid Spleen -Ulcerated mass, 6 x 6 x ~ cm behind right shoulder. -Possibly slightly pale and swo!len. -Enlarged -Sinusoida! ectasia, cortex -HHPeeorpptaaattlooccyymttoeenovvnaaucccuulsoeliaaarttiicooesnl,,l smiuln!tftiiilffteorccaamtlIe,,, smmiiilllddd HHeeppaattooccyyttee aalltteerraattiioonn,, bbaassoepphhiilliicc,, amiilldd Hematopoiesis, extramedullary, mi!d -Uascular nineraIi~ation~ mild Pneumonia, i~ter~iitial, chronic, mu!tifocal, mild -Adenocarcino~a -Not examined, not in pl~ne of section -Hematopoiesis, extramedu!lary, increased~ marked The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Kidney, Hearl, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus, Ovmry, Pituitary~ Trachea, Thyroid, Esophagus, Lymph Node (mesen~eric), Pancreas, Sa!vary 81and, Eye. Animal Number: I~-45B~ Sex: Female Group: (I) CONTROL 0 ppm Fate; (Wee~= I05) Terminal Sacrifice MacrosrEcyeoepic Observations: -"EExxtteennssiivvee ppaosstt bMleeeetdiinngg iinnffllaammmaattiioonn ooff rriigghhtt Mammary Gland -Firm nodular mass, 6 x 5 x ~ om~ left inguinal, SSppeecciieess:: f~aatt Project Number: 0281CR0012 SSummrmairzizeetd 5STAR PPau~es: 622 222266 11333377..00223366 3MA00027361 I Sari Sie itd in pet Cnt SumIarized Single Tabulated Animal Report (continued) frmtwl mn mye I~dividual Macroscopic and Microscopic Observation~ Con 3 Riker Laboratories~ Inc. 3M ni Fe ee edna Ss nhs ae 2 FC-143; Two Year Oral Toxicity-Oncogenicity Study in Rats Table; 2 i one eS ee Gag 1 On Animal Number; IR-45S3 Sex: Female Group; ( I1 CONTROL 0 ppI ST a Si Fate; IWeek= 1051, Terminal Sacrifice 1 Ware Bratis lei Microscopic Observations Icontinued): I on Susi asa cot, it ~drena] -Ginusoida] ectasia, cortex, marked on mini isa, wri ~ye -Panophthalmitis, unilateral, marked n1 oes ene arti wid Kidney -Pelvic minera]iza!ion, mild CChhrroonaiicc pprrooggrreessssiivvee nneepphhrrooppaatthhyy,, mmiinniimmaall we Fringe Liver -Hepatocyte vacuolation, multi{ocal, mild 1 Se i Necrosis, ~o~al, ~ild | ns et ran, ait Lung -~iveolar ~crophages, mi!d a cose ie ie Perivasc~lar mononuclear infiltrate, mild i MMaaamnmaarryy BGllaanndd ~-FFiibbrrooaaddeennoonmsa br i, wa Ovary -Tubular a~enom~, unilateral I area tt sono tio Parathyroid -Not examined, not in plane of ~ec~ion fe on oa, Spleen -Hematopoiesis, e~Ira~eduIlary, increased, moderale I now Be, wie -Cystic glands, marked 1 TThhee ffolllloowvinngg tiissssuueess wwerree ffoounndd ttoo bbee wwiitthhiinn mnorrmeal lHiimtitss:! I Bb Cro Bos th, Be su bso, Le ie Brain, Spinal Cord, Bone Marrow, Heart, Stomach, Small Intestine, Large Intestine, 1 rttnh keyyhhet. h tng ch Fg be Arg SN Urinary 81adder, Aorta, Pituitary, Trachea, Thyroid, Esophagus, Lymph Node (mesenteric), Pancreas, 5allwry Gland. n Crave ie Best (on Animal Number~ IR-4584 Sex: Female Group~ (i) CONTROL 0 ppm 1 eh en Ss Pale; (~ee~: I05i Terminal Sacri{ice ! J Macroscopic O~servations: St rn th rd it it Eye 1i tit sfyv Pituitary a Bet vn Adrenal J -- Microscopic Observations~ i Wren snc tai, rte Adrenal i or ki ir Eye on bean re ert Heart 1 jo. oranmi e spit, ate Kidney i od a wae ah Liver 1 un A nts a weireesiaie, Lung iii rete LieErsha, 5eal et W--IwE i-- Parathyroid -Slight atrophy with corneal opacith right eye. -Enlarged -Left adrenal enlarged. -Sinusoida] ectasia, cortex -Phthsis bulbi, moderate -Myoc~rditis, chronic noneup~urati~e, m~itifocal, mild -Chronic progreesive nephropathh mild -Portal bile duct prolileration, mild Hepatocyte vacuolation, multifocal, mild -Pneumonia, interstitial, chronic, multifocal, mild Perivascu!ar mononuclear infiltrate, mild Hemorrhage, local areas, mild -Not examined, not in plane of section I B i SSppeecciieess:: RRaatt | Fk te: muons Project Number~ 0281C~0012 Corns 227 Summarized STAR Page: 63 11333377..00223377 suncozrsez 3MA00027362 I Summarized Single Tabulated Animal Report <continued) | Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M PC-143: Two Year Oral Ioxicity-Oncogenicity Study in Rats | Animal Number; 1~-45G4 Sex: Female Group: (l) CONTROL 0 ppa Fate: (Week= 105) Terminal Sacrifice | Microscopic Observations ~continued): Pituitary -Adenoma Table; 2 -Hemosiderosis, mi!d I The following tissues were found to be within norma] limits: Brain, Spinal Cord, Bone Marrow, Stomach, Small Intestine, Large Intestine~ Urinary B]adder~ 1 a at tr, ok i Aorta, Uterus, Ovary, Mammary Gland, Trachea, Thyroid, Esophagus, Lymph Node (mesenteric), | Pancreas, Salivary Gland. 1i Adnniinmaall NMausmhfeierr:~ 110R--445588~6 SSeexx~: FFeesmaallee GGrroouup~? |I 111) CCOONNTTRROOLL 00 ppppms ~ate~ I~eek~ 105) Terminal Sacrifice | Macroscopic Observations: Pituitary Uterus -Raised dark mass, 0.3 cm dia. -~ark area, Q.5 x 0.5 c~ in left horn near I 0 MMiiccrroossccooppiicc MObsseerrvvaattiioonnss:: cervix. Adrenal -Sinusoidal ectasia, cortex, mild Kidney -Chronic progressiYe nephropathy, mild i Liver Pelvic mineralization, mild -Portal mononuclear cell infiltrate, mild Portal bile duct proliferation, mild Hepatocyte alteration, vacuolaled, mild Lung i Ovary i PPParanracatrthehaayrsreoiidd Pituitary | Uterus -Perivascul~r mononuclear infiltrate, ~inima! -Not examined, missing --"ANHcootitnaeerxxsaaamtiirnnoeepddh,,y,nnoottmodiiennrapptlleaannee ooff sseeccttiioonn -Adenoma -Cystic glands, marked 1 The loo sms wr edt be wih sel lie The following tissues were found to be within normal limits( | Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, ~ammary Gland, Trachea Thyroid, Esophagus, Lymph Node (mesenteric), Salivary G!and, Eye. | i FFAaanttieem::al O(lNWeueeemkkbs=er:1I0055)I}R-TT4ee5rr8ma7iinnaall SSeaxc;rifFiecmeale Sacrifice Group: (I) CONTROL 0 ppm | Macroscopic Observations~ | Mammary 81and -Small nodular mass, 3 x 2 cm, axillary; large mass, 8 x 8 x ~ ca, throat area. | | | Species: Rat Project Number: 0281CR0012 masa 228 Summarized STAR Page; 64 228 11333377..00223388 3MA00027363 I Summarized Single Tabulated Animal Report (continued} B IInnddiivviidduaaall MMaaccrroossccooppiicc aanndd MMiiccrroossccooppiicc OObbsseerrvvaattiioonnss Riker Laboratories, Inc. 3M B FC-143: Two Year Oral To~icity-Oncogenicity Study in Rats B Animal Number: IR-4587 Sex: Female Stoup: ( II CONIROL 0 ppm Table: 2 Fate: (Week= 1051 Terminal Sacridce B Microscopic Otservations (continued): Adrenal 1 HeHaeratr.t -inusoida! ectasia, cortex, marked -"MMyyooccaarrddiittiiss,, cchhrroonniicc nnoonnss~uppppuurraattiivvee,, multifoca], mild n Kidney -Chronic progressive nephropathy, mi]d Pelvic mineralization, minimal Liver -Hepatocyte vaEuolation, mWtifocal, minimal B Mammary Glans -Lobular hyperplasia 1 SSPiaallriiavvtaahrryyyroBiBldlaasntd -"-NNNooottt eeexxxaaammmiiinnneeeddd,,, wmniiosstssiiinnnggplane of section Skin -Fibroma, su~cutaneous B pleen -He~osidero~is, mild Uterus -Within normal limits Fewer than protocol number B The fol!owing tissues were found to be within normal limits: i Th oa al a, Ls tt Brain, Spinal Cord, Bone Marrow, Lung, Stomach, Small Intestine, Large Intestine, B Urinary Biadder, Aorta, Ovary, Pituitary, Trachea, Thyroid, Esophagus, Lymph Node (mesenteric), Pancreas, Eye. B Animal ~ber~ IR-4591 Sex~ Female Group~ i II COntROL 0 ppm Fate! (Week= 105! Terminal Sacdfice Macroscopic O~servations~ I -No visible lesions. Microscopic Observations: 1 pro tial vu, tw, tee Adrenal -Cortical Yacuolation, local areas, moderate I Sinusoidal ectasia, cortex, minimal Kidney B LLiivveerr -Chronic p~ogressive nephropathh minimal ~-PPoorrttaall mmoonnoonnuucclleeaarr cceellll iinnffiillttrraattee,, wmiilldd Hepatocyte alteration, vacuolate~, mild I Lung -Vascular mineralizatioh mild B Lymph Node (mesenteric) Pancreas Parathyroid -~ot examined, mis~ing -Acinar atrophy, focal, minimal -Not examined, not in plane of section in ST -- Pituitary -Adenoma The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, I Urinary Bladder, Aorta, ~terus, Ovary, Mammary Gland~ Trachea~ Thyroid, Esophagus, Salivary Bland, Eye. B 1i iSpecies: Rat Project Number: 0281CR0012 ~Sucmamnasrriizzeedd SSTTAHR FPaagee:( 6635 222299 11333377..00223399 3MA00027364 I 1 SIIunncdmiimvvaiirddiuuzaaelld MMSaaiccnrrgoolsseccooTppaiibcculaaantnddedMMiiAccnrrioomssaclcooppRiieccpoOrObbtssee(rrcvvoaantttiiioonnnusse.d) Riker Laboratories, Inc. IM n PC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats i Anisal N~mber: IR-4592 Se~: Female Stoup: (1) CONTROL 0 ppm ' RUE Fate: (Week= $8> Found Dead I Macroscopic Observations: 1 MKiiccrrooPssiccteougpiiictcarOOybbsseerrvvaattiioonnss;: -Enlarged, 0.9 x I ca, Adrenal -Sinusoida! ectasia, corte~, moderate n Kidney -Chronic progre~siYe nephroFathh minimal Liver -Hepatocyte vacuolation, m~Itifocal, mild 1 = Site weit, aid Lung -Vascular mineralization, ~ild I Perivascular mononuclear in~iltrate~ mld i Manaary Eland Lymph Node (mesenteric) Mammary Gland -"CLoabbaullaarr hhyyppeerrppllaassiiaa,, mmooddeerraattee Parathyroid -Not examined, not in p)ane o~ sectio~ i Pituitary i SpSlpeleeenn -Adenoma -~HHeemwoossiiddeerrsossiiss,, maiilldd B The ~oilowing tissue~ were found to be wiihin normal limits: 8rain, Spinal Cor~, 8one Marrow~ Heart, Stomach, Small Intestine, Large Intestine~ n Urinary ~ladder~ Aorta~ Uierus, OYary~ Trachea, Thyroid, Esophagus, Pancreas, Salivary Gland, Eye, iI ~dnriimaall NN~amabbeerr:: 1I0R--0455g5S5 SSeexx:: FFeesmaallee GBrrouugp:: ((1!)) CCOONNTTRREOLL 00pppps~ Fate: (Week= I051~ Terminal Sacrifice | ~acroscopic Observations: ~icroscopic Observations~ -No ~isible lesions. Adrenal -Sinusoidal ectasia~ cortex, marked Liver n i PPaLaurrnagatthhyyrreoiidd -Hepatocyte alteration, vacuolated, mild Hepatocyte alteration, basophiiic, mild -"-NHVooattscueexlxaaanrmiinnmeeiddn,,ernanolottizaiitnnioppnll,aannee~ioolffd sseeccttiioonn B The followin~ tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stomach, Small Intestine~ i i ie rey ots vn, Urn, Sor, om Sr ttn Tihs Large Intestine, Urinary Bladder, Aorta, Uterus, Ovary, Mammary Gland~ Pituitary~ Trachea~ I Thyroid, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Gland, Eye. I 1 I I 1 R SSppeecciieess:: RRaatt Project N~mber: 0281CR0012 ~Suemamnaarriizzeedd SSTTAARR PPaaggee:: 666 223300 11333377..00224400 3MA00027365 I Summarized Single Tabulated Animal Report (continued) I~dividual Macroscopic and Microscopic Observations Riker LaboFatories~ Inc, ~M B F0-143: Two Year Oral Toxicity-Oncogenicity Study in Rats 'B CR oe Animal Number: IR-4594 Sex; Female 8roup: (I) CONTROL 0 ppm Table; 2 Fate: (Week= 7g] Found Dead Macroscopic Observations: | Kidney iB inn Str cg os 2a ed is tre wt Urinary Bladder -Right kidney appears slightly enlarged; tilled ~ith yellow milky ~luid. -Enlarged, 4.5 x 2 cml ~illed with large~ hard calculi. Pituitary -Hemorrhagic mass, 0.9 x 0.6 :m Microscopic Observations: B Adrenal -Sinusoida] ectasia, cortex~ =oderate i hots. One o~ pair present -NNoott eexxaammiinneedd,, maiissssiinngg Kidney -Pyelonephritis, acute, bilateral, moderate B HydrenephrosiB, bilateral~ moderate I Liver Lung Nephro~is~ t~bular, bilateral, ~oderat~ -Hepatocyte alteration, vacuo!ated, mild -Vascular ~ineraiization, mild m i O[Lvyam0rpyh Node (mesenteric) "--HWNiiottthhiiennxannmooirrnmseaadll, Llmiiinmsiisttissng One of pair present -Not examined, missing B Parathyroid Pituitary Small Intestine -Not examined~ not in plane of sectio~ -Adeno~a -Not examined, missing | Sp!ee~ Urinary Bladder -Hemosiderosi~, moderate -Epithelial hyperpIasia, papillary, marked B1 FE ---- CalculBs The ~ollowing tissues were (ound to be within normal limits: Brain, Spinal Cord, Bone Marrow, Heart, Stomach, Large Intestine, Uterus, Mammary Gland, n Trachea, Thyroid, Esophagus, Balivary 81and~ Eye. Animal Number: IR-4~91 Bex: Female 8roup: (I) CONTROL 0 ppm Fate: {Week= I05) Terminal ~acri(ice B Macroscopic Observations: Pituitary -Hemorrhagic mass, 0.8 cm dia. i MMaanmemaarryy EGllaanndd "-SSoaaalll Iloobb~uIlaarr mmaassss,, 22..77 xx L1.S5 x 1L.B8 cca~, llee(itt axilla. B Pancreas -SBa!I lobu]ar mass, i x 0.7 cm, in area of I Microscopic Observations: Adrena] pancreas. -Sinusoidal ectasia, cortex, moderate H B Species: Rat n Project Number: 0281CR0012 sSummiarizmed SsTAR rg Page: 607 223311 11333377..00224411 3MA00027366 | Summarized Single Tabulated Animal Repori (continued) I Individual Macroscopic and Microscopic Observations Riker Labor,tortes, Inc. ~M FC-143: Two Year Oral Todcity-Oncogenidty Study in Rats i Animal Number: IR-4595 Sex: Female Group: (I) CONTROL 0 ppm Fate: {Week: 105) Terminal Sacrifice Table: 2 Microscopic Observations (continued): i Kidney 1I ee ede rei +t Liver -Chronic progressive nephropathy, minimal -Portal mononuclear ce!l infi!tr~te, mild Portal ~i]e duct proliferaticn~ ~ild Hepat~yt~ alteration, vacuolated, ~ild Lun~ -Giveoiar nacropha~es, ~iId 1 Farsi Bard atalar dreplasia Mammary Gland -Lo~!ar hy~erp~sia -Islet cell carcinoma i Partially encapsulated with invasion of 1 ccaappssaul!ee.. WWeell]l ddiiffffeerreennttiiaatteedd.. -Not examined, not in plane of ~ect~on i , -Adenoma I Uterus -Adenoma ~all ciruumszri~ed papillary lesion, i BrTrhaaeiinnf,,oiSSipoiiwnniaanllg CCtaoirrsdts,,ueBsBoonvweeereaMarrfrrooouwwn,,d SStppolleebeeenn,,wiHHteehaairrntt,,noSr~qtmtooami~..a'.c.l~.h.i,m, iS~t:sma:al,~], IDnttsessttiinnee,, LLaarrggee eInsttesitrinze,, I Urinary Bladder, Aorta, Trachea~ Thyroid, Eso~ha~ue, Lymph Node (mesenteric), SaiiYa~y Gland, Fh Eye, Ovary. 1 POAnimel Number: 1R-45% Sex: Female Group: (i) CO~TROL 0 ppm i Fate: (WeeP= ~81, Sacrificed in extremls | M~croscopic Observations: Pituitary -M~ss, 0.8 x 0.6 c~= i LL~iimvvmeearrr~ Gland -"-VMHeaersrysy, ppaa2ll.ee5 x 2 x 1.5 cm, in left axilla. Kidney -Bilatera11y pale and pitted; si~htiy | erlarged; 0.4 c~ dia. cyst in right. Adrenai -Pale~ bila~erally i [i -- Microscopic Observations: I Adrena! -Cortica! Yacuolation, focal, moderate I Aorta Sinusoidal e=tasia, cortex, moderate Medullary cell hyperplasia, multifocal, mild Cortical dmgeneraHon, local areas, moderate -M~neralization, mild I i| Kidney Liver ~inerali~ation also in media of an elastic artery in section of mesentery submitted for [in iesenteric lymph node. -Chronc progressive nephropathy, marked Cyst, cortical, moderate -Hepatocyte ~acuo1~tion, diffuse~ marked | I | Species: Rat 3Project Number: 0281GR0012 Sorizes st age 46 232 Summarized STAR Page: 68 11333377..00224422 3MA00027367 | 1 I~Innodd~iiivvaiirddiuuzaaelld MMSaaiccnrrgoolsseccooTppaiibcc~!aaanntddedMMiiAccnrrioomssalccooppRiieccpoOrObtbssee(rrcvvoaantttiiioonnunsesd) Riker Laboratories~ Inc. 3M | FC-143: Two Year Oral To~icity-Oncogenicity Study in Rats | Animal Number: IR-45% Sex: Female Groupl ( II CONTROL 0 ppm Table: 2 Fate: (Week= 78} Sacrificed in extremis | MiErCSEOpiC Observations (continued): Lung 1 -Vascular AAllvveeoollaarr mn~aaiccnrreoorppahhlaaiggzeeasst,,ionme,iinnimimiaallld Lymph Node (meeenteric) -Not exami~ed~ missing | ~a~mary Gland -Fibroadenoma | Parathyroid Pituitary Salivary Gland -Not examined, not in plane of section -Adenoma -Not examined, missing | i UUSrrpiilnneaaerrnyy BBllaaddddeerr E--pEHpieimttohhseeilldiieaarllosihhsyy,ppeerrmppolldaaessriiaaat,~e ssiimappllee,, diffufsusee,, amii!dd The following tissues were found to be within normal limits: | Grain, Spinal Cord, Bone Marrow, Heart, Stomach, Smell Intestine, Large Intestine, Uterus~ Ovary, Trachea, Thyroid, Esophagus, Pancreas, Eye. Animal Number: IR-4597 Sex: Female Group: (i) CONTROL 0 ppm Fate~ (Week= ~05) Terminal Sacrifice | Macroscopic Observations~ 1 tAddrreennaall R-Riigghhtt aaddrraernaall eennllaarrggeedd.. Microscopic Observations; | Adrenal -Sinusoida! ectaeia, cortex, marked Kidney 1|| Liver Medu!lary cell hyperp!asia, focal, mild -Chronic progressive nephropathy, minimal en sid Pelvic mineralization, mild -Portal mo~onuclear ce!l infiltrate, Portal bile duct proliferation~ mild -A~veo!ar ~acrophages, mild | i LLyysmsphh RNooddee I(mneesseenntteerriiccl) Perivascular mo~onuclear -NNoo ddiiaaggenoossiiss,, iinnaaddeeqquuaattee issneefccittliitoornnate, mild Ovary -Tubular adenoma, unilateral Pancreas -Cyst | Parathyroid Spleen Uterus -Not examined, not in plane of section -Hemosiderosie, mild -Within normal limits Fewer than protocol number I The following tissues were found to be ~itNn normal limits: Brain, Spinal Cord, Bone Marrow, Heart, Stomach, Small Intestine, Large Intestine, | Urinary Bladder, Aorta, Mammary Gland, Pituitary, Trachea, Thyroid, Esophagus, Salivary Gland, Eye. | | | Species: Rat Project Number: 0281CR0012 SSuamnmrariizzeesd SSTT~R PPaageg: 6696 223333 11333377..00224433 3MA00027368 | | i | I ||] | 1 i | 1 | | i | | 1 | 1 | | 1 | i i | i Summarized IInnddiivviidduuaall MMSaicancrgrolosesccoToppaiibcculaaanntedddMMiAicncrirmoossacclooppRiieccpoOOrbtbsse(ercrvovanatttiiinoounnessd) Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 Animal Number: I~-4598 Se~: Female Group: (I) CONTROL 0 ppm Fate~ (Wek= 105) Terminal ~acrifice Macroscopic Observations: Pituitary Aadrreenaall Microscopic Observations: Adrenal Brain Heart Liver Lung Ovary P~ncreas PP~iiattruuaiittthaayrrryyoid U~erus -Massr 0,7 cm dia. L-Leefftt aaddrreennaa!l ggrreeaattllyy eennllaarrggeedd., -Sinusoidal ectasia~ cortex, marked -Oligoden~roglioma, benign -Myocarditis, chronic nonsuppuratiYe, multi~ocal, mild -CPherlovniicc wpnreorgarleiszsaitvieorn,ephariolpathy~ moderate Pelvic miner~lization, ~iid HHyyppeerrppllaassiiaa,, ppeellvviicc eeppiitthheelliisusm,, llooccaall aarreeasss,, ess wenn wi mild -Hepa~ocyte vacuolation, ~ItifocaI~ mild Hepatocyte alteratio~ basophilic~ mild -Vascular ~ineralization~ mi1~ Periva~cular mononuclear infiltrate, mild -Tubular adenom~ -Acinar atrophy, moderate ---AhNdodleennooe~a~asa~ined, not in plane o~ section -Cystic glands, moderate The ~oilo~ing +~ssues were f=u.~ to be within normal limits~ S~nal Cor~ ~on~ ~arrow~ 5pl~en~ Stomach, Small Intestine~ Large Intestine Urinary Bladder, Aorla~ Ham~ary Glaod, Trachea, Thyroid, Esophagus, Lymph Node (=esenteric), Salivary Gland, Eye, fAnriimael NNuambbeerr:~ I(~0-445599~ SSeext: FFeemmaallee rSroouuppt~ ((I1)) CCONTRNOL 0Rppopnm Fate: (Neck= i02i Found ~e~d MMaaccrroossccooppiicc OObbsseerrvvaattiioonnss:: Mammary Gland Liver Stomach Urinary Bladder oEyee Microscopic Observations: Adrenal fAaorrttsa Esophagus Eye -Subcutaneou~ mass~ 2.5 x 2 x I c~ i~ perinea! area, -Appe~s mott!ed -Areas of enlongated ulceration, -Thickened walls; mass 1.5 x ! c~, with -"NAoaodhtteiisssissouunees tttaaokkeennabdt~ouemeinttaool ppwooass!tt1am.corriteemn cchhaar~gee~s -Sinusoidai -"MMaalliiggnnaanntt lleyycmstppahhsooieraaa,,, chBoiirssttteiixoo,ccyyttmiiaccrke~ -Ma!ignant lymphoma, histiocytic -Not examined, missing Species: Rat Project Number: 02BICRO012 nein 234 Summarized STAR PaQe: 70 234 11333377..00224444 3MA00027369 m Sulmarized Single Tabulated Animal Report (continued) 1 IInndciivviidduuaall MMaaccrroossccooppiicc aanndd MMiiccrroossccooppiicc OObbsseerrvvaattiioonnss. m Riker Laboratories, Inc. !M FC-143: Two Year Ora! Toxicity-Oncogenicity Study in Rats 1 2 Table: 2 I Animal Number: IR-4599 Sex: Female Group: ( I} CONTROL 0 ppm Fate: (Wee~= 1021 Found Dead I Microscopic Observations (continued): Heart -Myocarditis~ chronic nonsuppurative, l Kidney multifoca!, mild -Malignant lymphoma, histiocytic Pelvic mineralization, mild Hypsrplasia, pelvic epithelium, local areas, l m[id Nephrosis, tubular, mild 1 LLLiianvreegrre Intestine -"-MMMaaallliiigggnnnaaannnttt Lllyyummppphhooommaa,~, hhhiiissstttiiisooeccyyytttiiiccc Necrosis, local areas, marked l Lung -Malignant lymphoma, histiocytic Hemorrhage, multifocal, mild 1 yt tts tric eet an, BE Lymph Node (mesenteric) -Malignant iymphoma, histiocytic l Mammary Bland -Malignant ]ymphoma, histiocytic Ovary -Malignant lymphoma, histiocytic Pancreas -Malignant lymphoma, histiocytic l Parathyroid -Not examined, not in plane of section i PSiltueitary -~-AHHdeeenmncoossmiiadduerraos~iiss,, amiilld Stomac~ -Necrosis, mucoaal, moderate l Thyroid -Ma!i~nant lymphoma, histiocytic Urinary Bladder -Ma!i~nant Iymphoma, histiocytic 1 hs opwsiin, oe, its, 1s Epithelial byperp1~sia, simple, diffuse, l Uterus -Malignant lymphoma~ histiocytic il TThhee ffeolllloonwiinngg ttiissssuueess wwerree fFoouanrdd ttoo bbee wwiitthhiinn mnorramadl lJiimiittss:t BBrraaiinn~, SSppiinnaall CCoorrdd,, BBoonnee MNaarrrrooww,, SSemaallll IInntteessttiinnee,~ TTrraacchheeaa,, SSaal!iiv~aarryy 8B1laanndd.. i l AAnniinmaall MNuusmtbeerr:: 1!8R--44460000 SSeexs:: FFeesmaallee GGrroouupp:: ( I1)) CCOONNTTRROLL 00 pppomn Fate: (Week= 99! Found Dead I Macroscopic Observations: Mammary Gland -Gubcutaneous cystic mass, 4 ~ 3.5 x 2 cm, in region of throat; subcutaneous 1 mwauxililtlllisal,.obular mass, 5 ~ 4 x 2 cm, in right l Liver -Appears mottled Microscopic Observations! i AAddrreennaall -NNeeccrroossiiss,, uunniillaatteerraall,, emaarrkkeedd Eye -Not examined, missing ! Heart -Myocarditis, chronic nonsupp~rative, 1l pie m~Itifoca], mild ! l Species: Rat Project Number: 0281CR0012 SGuumnmnaarriizzeedd SSTTAARR PPaaggee;: 774! 223355 11333377..00224455 3MA00027370 | Summarized 5ingle Tabulated Animal Report (continued) | IBdividual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3N FC-143: Two Year Dral Toxicity-Oncogenicity Study in Rats | Animal Number: IR-4600 Sex: Female Group: (I) CONTROL 0 ppm Fate: IWeek: 99) Found Dead Table: 2 | Microscopic Observations (continued): Kidney -Chronic progressive nephropathy, mild | Liver Pelvic mineralization, mild Nephross~ tubular, ioderate -Portal mononuclear cell infiltrate, moderate Portsl bile duct prolileration, mild Hepatocyte vacuo!ation, multifocal, mild | Hepatocyte alteration~ eosinophilic, moderate i Lung. Teiangiectasis, mild V-Vaassccuullearr wniinneerraalliizzaattiioonn,, wmiilldd Mammary Gland -Adenoma, papillary | Lobular hyperpIasia | Ovary Perathyroid Pituitary Spleen -Cyst, unilateral -Not examined, not in plane of section -Adenoma -Hemosiderosis, mild | The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Stomach, BmaI1 Intestine, Large Intestine, Urinary Bladder, i Afoorrttae,, UUtteerruuss,, TTrraacchheeas,, TThhyyrrooiidd,, EEssoopphhaaggauss,, LLyyampphh NNooddee ((ameesseenntteerriicc)l,, PPaannccrreeaass,, SSaalliivvaarryy B8l1aanndd.. | Animai N~m~er: IR-4~02 Sex: Female Group: { I) CONTROL 0 ppm Fate: (Week= 105) Terminal Sacrifice | Macroscopic Observations: i PEPiyitetuuiittaarryy -Cornea appears cloudy. -RRaaiisseeddasmass,s, !| ccbm idias.. Adrenal -Right adrenal enlarged. | Kidney -Pale and pitted. | Microscopic Observations: Adrenal -Sinusoida] e:tasia, cortex, ~arked Cortical degeneration, diffuse, marked Eye Neart I Kidney 1 | Liver -No diagnosis, inadequate section -Myocarditis, chronic nonsuppurat~ve, multifocal, mild -CPPheerllovvniiiccc mapiirnnoeegrrraaellsiiszziaatvtieioonnn,,ephmmriiollpdathy, marked Cyst, cortical -Hepatocyte alteration, basophiIic, mild | Parathyroid Pituitary -Hemorrhage, local areas, moderate -Not examined, not in plane of section -Adenoma | | | Species: Rat Project Number: 0281CR0012 SSoummmnarriizzeedd SSTTARR PPaaggee;: 272 223366 11333377..00224466 3MA00027371 I i IISnundmcimivaviridituzuaelld MMSaaiccnrrgoolsseccooTppaiibcculaaanntddedMMiiAccnrrioomsasclcooppRiieccpoOrObtsssee(rrcvvoatntiticionnnusse.d) I Piker Laboratories, Inc. IM To oY eeoy ty FC-143: Two Year Oral Toxicity-Onco~enicity Study in Rats 1 ws Table: 2 I Animal Number: IR-4602 Sex: Female Group: ( I} CONTROL 0 ppm Fate: (Week= I05i Terminal Sacrifice I Microscopic Observations (continued): pi -- i UUSttpeelrreuusesn "--HWHiiettmhhoiisnnidennroaorrsmnaialls, lLiimmniii]ttdss I Fewer than protocol number I1 in a Crs Bn rn, Seth Sel ation, re Toten, in Ptr, The following tissues were found to be within normal limits: Brain, Gpinal Cord, Bone Marrow~ Stomach, Gmall Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Mammary Gland, Trachea, Thyroid, Esophagus, Lymph Node (mesenteric), Pancreas, l Salivary Gland. Animal Number: IR-4603 Sex: Female Group: ( I1 CONTROL 0 ppm Fate: (Week= I05) Terminal Sacrifice I Macroscopic Observations: Liver -Circular raised lesion, 0.6 ca dia., left Skin I Microscopic Observations: Adrenal 1l a ein oe Heart lateral lobe. -Hair loss on forelimbs. -Ginusoidal eotasia, cortex, moderate Cortical degeneration, diffus{, moderate -Myocarditis, chronic nonsuppurative, multifocal, mild Kidney Liver lI as Mammary Bland -Pelvic mineralization, mild -Portal mononuclear ceil infiltrate, m~!d Portal bile duct proliferation, mild Hepatocyte alteration, vacuolated, mild -Perivascu!ar mononuclear infiltrate, mild -8alactocele i PiPPtiautriuaittthaayrrryyoid I Skin Spleen H--ANedonetncoeemxaamined, not in plane o~ section -Acanthosis, mild -Hemosiderosis, mild i he ning sas re fn 0 be the rt ts: The following tissues were found to be within norma! limits: l Brain, Spinal Cord, Bone Marrow, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Uterus~ Ovary, Trachea, Thyroid, Esophagus, Lymph Node (mesenteric!, Pancreas, 1I Lt Salivary 81and, Eye. l l I i SSppeecciieess:: RRaatt I it NO Project NumberI 0281CR0012 Ssuumwmrariizzeesd sSTuARppPaeger: 713 223377 11333377..00224477 3MA00027372 n Summarized Single Tabulated Animal Report (continued] i IInnddiivviidduuaa!l MMaaccrroossccooppiicc aanndd MMiiccrroossccooppiicc OObbsseerrvvaatliioonnss. Riker Laboratories, Inc, 3M B FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats I Animal Number: 1R-4604 Sex: Female Stoup: (1) CONTROL 0 ppm Table: 2 Fate: (Week= 105) Terminal Sacrifice I Macroscopic Observations: Adrenal -Left adrenal enlarged, i MMiiccrroossccooppiicc OObbsseerrvvaattiioonnss:: Adrenal -Ginusoidal ectasia~ cortex~ marked i Aorta -Not examined, missing Esophagus -Not examined~ missing Kidney -Chronic progressiYe nephropathy, mild i Pelvic mineralization, mild 1 Live Large Intestine Liver -"-PPNooerrtttaaellxabmbiiillneeed,dduuccmttisppsrrioonllgiiffeerraattiioonn,~ msiilldd Hepatocyte vacuolation, multifocal, mild I Hfperplastic nodule Ovary -Cyst~ unilateral i jt Niet i sae of sti Parathyroid -Not examir, ed not in plane of section i Uterus -Within normal limits Fewer thor protocol number I The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Heart, L~ng, Stomach, Small Intestine, Urinary Bladder, i MMaammsmaarryy GGllaanndd,, PPiittuuiittaarryy,, TTrraacchheeas,, TThhyyrrooiidd~, LLyymapghh NNooddee ((neeesseentteerriicc)),, FPaannccrreeaass,, SSaalliivvaarryy SGllaanndd,, i Eye, AoimBl Nu~er: IR-4605 Sex: Female Group: (i) CONTROL 0 ppm Fate: (Wee~= 77} Sacrificed in extra,is i Macroscopic Observations: 1 pr pr Kidney I Lung -1ightly pitted -Right apical lobe consolidated and somewhat enlarged; possibly tumor, mass, 1 cchhrroonniicc ppnreeuumeocnniiaa.. Microscopic Observationsl n Adrenal -Necrosis~ local areas, moderate Hematopoiesis, extramedu!lar~, multi~ocal, 1 mild i Heart -Myocarditis~ chronic ~onsuppurative, 1i Kidney m~Muaallltiliggfnnoaacnnattl~lIyymmsopphdhoeo~nrasa,,te lLyymapphhoeccyyttiicc -Chronic progressive nephropa~hy~ moderate Pelvic mineralization, minim~I i Liver Lung -Hepatocyte vacuolation, midzonal~ moderate ~alignant lymphoma, lymphocytic -Uascular mineralization, mild ! ~alignant lymphoma, lymphocytic Large circumscribed mass with extensive necrosis, .................................................................................................. I 1 I GSppeecciieess:~ fBaatt Project N~eber: 0281CR0012 SSumomarrizied HSTiApR Page: 74 238 11333377..00224488 3MA00027373 | Summarized Single Tabulatsd Animal Report (continued) | Individual Macroscopic and Microscopic Observations Riker Laboratories, ;no, 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats |i a ag CR Fate: (Week= 771SacriTiced in extremis Table: 2 I Microscopic Observations ;continued): Ovary -Cyst, unilateral Parathyroid -Not examined, not in plane oT section Pituitary -Adenoma i Spinal Cord -Malacia, local areas, moderate 1 SUUprrliienneaanrryy BHlaatddeerr --"HEEeppmiiottshhieedlleiiraaollsihhsyy,ppeermrippl!ldaassiiaa,, ssitmpele,, ddiiSfffuussee,, | Er moderate NE -- The foIlowinq tissues were found to be within normal limits: Brain, Bone Marrow~ Stomach, Small Intestine, Large Intestine, Aorta, Uterus, Mammary Gland, i Trachea, Thyroid, Esophagus, Lymph Node (mesenteric], Pancreas, Salivary 81and, Eye. | Animal Number: I~-4606 Sex: Female Group: ~ I) CONTROL 0 ppm Fate: (Week= 105) Terminal Sacrifice i MMaaccrroossccooppiicc OObbsseerrvvaattiioonnss:: ~ammarl Gland -Smal! mass, 1.4 cm dia., left ]ster~! area. | Pituitary -Enlarged; circular dark lesion, 0.4 cm dis. Uterus -~ark fluid filled lesion, 0.5 x 0.6 cm, right 1 ihorn. | Microscopic Observations: Adrenal -5inusoi~al ectasia~ cortex, m~Id 1 nl kind, wee Cortical dsgeperation, bilateral, moderate | Pheochromocytoma~ benign, unilateral Heart 1 KKaitdonaeyy -Myocarditis, chronic nonsupp~rative, mwuilttiiffooccaall,, wgiilldd C-Chhrroonniicc pprrooggrreessssiivvee nneepghhrrocppaatthhyy,, amiilldd I Pelvic mineralization, mild Liver -Nepatocyte vacuolation, multifocal, mild 1 Yotogts svesion wasatet, ae Hepatocyte alteration, vacuolated, mild | Lung -Pigment, moderate |Bi Sppciiaggtemteeesnrtte--dllaatdsmeeannllmmaalccorrcoeipphhaaofggeessdarwwkiitthbhirieo~wnaallveooieio Lymph Node (mesenteric) -Hemorrhage, mild Mammarl G1und -Adenocarcinoma | Ovary Parathyroid Pituitary -Not e~amined, missing -Not examined, not in plane of section -Adenoma | Uterus -Hydrometra, marked The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Spleen, Stomach, Small Intestine, Large Intestine, i | Species~ Rat | id 3Project Number: 0281CR00~2 SSuummmaarriizzeedd SSTTA~ PPaaggee:: 755 223399 11333377..00224499 3MA00027374 - I I I |I| i ! i ii | i BI iI I i I n Summarized Single Tabulated Animal Report (continued) IndiYidual M~croscopic and Microscopic Observations Riker Laboratories, Inc. 3M FO-143~ I#o lear Oral Toxicity-Oncogenicity Study in Rats Table: 2 Animal Number: I~-4~06 Sex: Female Group: (I) CONTROL 0 ppa Fate: (Week= I05) Termina! Sacrifice MMiiccrroossccooppiicc OObbsseerrvvaattiioonnss ~(ccoonnttiinnuueedd)):? The following tissues #ere found to be within normal limits (continued): Urinary Bladder, Aorta, Trachea, Thyroid, Eso~hagus~ Pan~reas, Salivary Gland, Eye. Animal Number: IR-4607 Sex: Female Group: ( l! CONTROL 0 ppm Fate~ (Nee~= 40) Sacrificed in extra,is Macroscopic O~servations: So{t Tiseues (neck) Lymph Node LLivrer Spleen Microscopic Observations: AAddrreennaall Aorta Bone Marrow Esophagus Eye Kidney LiLLiu~gnegr Lymph Node (mesenter~c] Mammary Gland PaOPrvaaarrtaythhyyrrooiidd Salivary Bland Spleen Stomach Thyroid Uterus -Reddened gland li~e structures, ~ossibly enlarged lymph nodes or ealivary glands. -Enlarged axillary, hEpatic~ mesEnteric and -FPoiosnsstsieirbbnllayyl ssillliiiggahhcttllylyympp~aahllee..nodes. -Considerably enlarged. ~-KMaalliiggrnaanntt llyymspphhoosmsa,, lIyymspphheoccyyttiicc -Malignant ly~pho~a, lymphocytic -Malignant lymphoma, lymphocytic -No diagnosis, inadequate section -Malignant lymphoma, lymphocytic -Malignant lym~homa, lymphocytic -a-MMlaaillgiigrgnnaaannnttt liIyyymms~phhhooosmmaaa,,, lLyymapphhoeccyyttiicc lymphocytic Hemorrhage, local areas, mild Abscess -Hemorrhage, moderate ~a!ignant lymphoma, lymphocytic MassiYe e~largment of node by mature a~pearing lymphocytes. All other nodes e~amined were similarily invol~eO. -Malignant lymphoma, lymphocytic -o-MNatoltigeen~xaaanmmtiinneelddy,,mphnnooomtta,iinnlyppmllpaahnnoeecyootfficsseeccttiioonn -Not examined, missing To itn Tie -Malignant lymphoma~ lymphocytic -Hemorrhage, eubmucosal, moderate Malignant !ym~homa, lymphocytic -Malignant lymphoma, lymphocytic -Malignant lymphoma, lymphocytic The following tissues were ~ound to be within normal limits: Brain, Spinal Cord, Heart, ~mall Intestine, Large Intestine, Urinary Bladder, Pituitary, Species~ Rat ~roject Number: 0281CR0012 SSuuamnmaarriizzeedd S~TTAARR PPaaggee:: 7766 224400 11333377..00225500 3MA00027375 I Summarized Single Tabulated Animal Report Icontinued) I Individual Macroscopic and Microscopic Obeervations Riker Laboratories, Inc. 3M FC-I(3: Two Year Oral Toxicity-Oncogenicity Study in Rats I Sa lease Animal Number( IR-4607 Sex: Female Stoup: (I) CONTROL 0 ppm Tatle: 2 Fate: (Week= 40) Sacrificed in exlremis I Microscopic Observatione (continued)( The following tissues were found to be within normal limits (continued): i TTrraacchheeaa,, PPaannccrreeaass.. I Animal Number: IR-4607 Sex: Female Broup: ( I} CONTROL 0 ppm Fate: (Week= I05) Termina] Sacrifice I Macroscopic Observations: I Pituitary -Raised mass, I cm dia. 1 ~Faama~saarryy EGllaanndd H-Maassss,, 55 xx 44 ccom,, tthhrrooaatt aarreeaa; 3I Ccme dd~iaa.,, l!eeiftt axilla. Microscopic Observations: I Adrenal Heart -Sinusoidal ectasia, cortex, moderate -Myocarditis, chronic nonsuppurative, multifocal, mild 1 Kidney -PPCeehllrvvoiinccicmmiipnnreeorrgaarlleiiszzsaaittviieoonnn,,epsmhoorfdoueprraaatttheey, mild I Large Intestine -Not examined, missing Liver 1 -Portal mononuclear cell infiltrate, mild FPoorrttaall bbiillee dduucctt pprreolliiffeerraatliioonn,, mwiillde Hepatocyte vacuolation, multifocal, mild I Lung -Pnecmonia, interstitial, chronic, eultifocal~ I Mammary Gland mild -Carcinoma Highly cellular very ~ndifferentiaied tumor. nI1l PPPaaarrnaacttrhheyyarrsooiidd odPituitary Spleen -"-~Aoocttineaexrxaammaiitnnreeosdp,~hy,onottmioidnnerppalltaaennee ooff sseeccttiioonn Te, -Adenoma -Hemosiderosis, mild I Thyroid Uterus -C cell adenoma -Within normal limits Fewer than protocol number I The following tissues were found to be within normal limits: BGrraaiinn,, SSppiinnaall CCoorrdd,, BBoonnee MMaarrrroonw,~ SSttoommascchh,, SSemaallll IInntteessttiinnee,, UUrriinnaarryy BBllaaddddeerr,, fAoorrttaa,, DOvuarryy,, Trachea, Esophagus, Lymph Node (mesenteric), Sa!ivary Gland, Eye. I I I I S~ecies: Rat I T"ate: cnn Project Number: 0281CR00!2 ws 241 Summarize~ STAR Page: 77 241 11333377..00225511 3MA00027376 I Summarized Single Tabulated Animal Report (continued) Individual Macroscopic and Microscopic Observations 1 ie a aie, 1 Riker Laboratories, Inc. ~M | FC-1431 Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 | .................................................................................................. Anilal Number: IR-4~11 Sex: Female Group: (i) CONTROL 0 ppm Fate: (Wee{= 105) Termina! Sacrifice Macroscopic Observations: I Mammary Gland Microscopic Observations: 1| tr: ---- Adrenal -Large Inbular mass, IO x 7.5 x 5 cm. -Sinusoida! ectasia, cortex, marked Cortical degeneration, local areas, moderate BR Liver -HHHeeepppaaatttooocccyyyttteee vaaallcttueeorr!aaatttiiiooonnn,,, semooussliitnnioofppohhciiatllii,cc,,mimaliidltdd | -Hemorrhage, multifocal, mild 1 MRaamsmaarryy 8G1laanndd F-AiFlbvbreroooslataderennaomnmasac.rophages, multifocal, mild Parathyroid -Not examined, not n plane of section i Pituitary -Adenoma | The following tissues were found to be within normal !imits: Brain, Spinal Cord, Bone Marrow, Spleen, Kidney, Heart, Stomach, Small Intestine, I i LLLayyrmgpeeh IN~nootddeestI(imeneeess,eennUttreeirrniiacc)r),y, BPPlaaanndccdrreeeraa~ss,, AoSSraatllaii,vvaarrUytyerBBullsa,andn,OvaEEyryeye.,. Trachea, Thyroid, Esophagus, Animal Number: IR-4612 Sex: Female Group: { I) CONTROL 0 ppm | Fate: (Neek: I0~) Terminal Sacrifice Macroscopic Observations: Pituitary -Raieed mas~, 0.7 cm di~. Mammary Gland | right axi!la; i KMiiccrroossccooppiicc OObbsseerrvvaattiioonnss:; 7 x 6 x 2 cm, right side. Adrenal -Sinusoida! ectasia, cortex, moderate | Eye -No diagnosis~ inadequate section Liver -Hepatocyte vacuolation, multifocal, mild 1 - eri tons Lung -Hemorrhage, diffuse, marked I Alveolar ~acrophages, mild Mammary Gland -Gala~tocele i Fibroadenns Fib~oadenoma | Fibroadenoma i PPaarraatthhyyrrooiidd Two t~mors present. -"NMoott eexxaammiinneedd,, nnoott iinn pp]laannee ooff sseeccttiiocnn Pituitary -Adenoma | Uterus -Within norma! ]~ts | Fewer than protoco! number The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Harrow, Spleen, Kidney, Heart, Stomach, Small Intestine, I | Species: Rat | ES ees Project Number: ~281CR0012 SSuommmaarriizzeedd SiTAkR rPaaggee;s 77B8 242 11333377..00225522 3MA00027377 | Summarized Single Tabulated Animal Report (continuedl | Individual Macroscopic and Microscopic Observations FlEer Laboratories, !no, 3M FC-143; Two Year Oral Toxicity-Oncogenicity Study in Rats Table: i Animal Number: IR-4612 Sex: Female Stoup: ( ii CONTROL 0 ppm Fate= IWeek= I05) Terminal Sacrifice i Microscopic Observations (cnntinued): The follo~ing tissues were ~ound to be within normal limts ~continued!~ i Large Intestine, Urinary Bladder~ Aorta, Ovary, Trac~ea~ Thyroid, Z~ophagus~ Lymph Node !me,enteric}, Pancreas, ~alivary Gland. Animal Nu~er~ I~-4613 Sex: Female Group: ~ i) CONTROL 0 ppm Fate: IWeek= 89) Sacrifice~ in extremi~ | i MacrPoPsiicttoupuiiit~taarrOyybservations~ "-SScoameewshhaatt eennllaarrggeedd Ma~ry Gland -Mass, 10 x 8 ~ 5 cm, inguinal area; surface i ulcerated. | Liver ~icroscopic Ob~ervations~ Adrenal -Appears pile -Hematopoiesis~ extramedu!!ary, mild Sinusoidal ectasia, cortex, mild Cortical vacuolation~ focal, mild | Esophagus -Nct examined~ missing Kidney 1 -Pelvic mineralization, mild MHyyppeerrppllaassiiaa,, ppeellvviicc eeppiitthheelliiuusm,, llooccaall aarreeaass~, mild | Large Intestine -Not e~amined, missing Liver -Hepatocyte vacuoletion, periportal, mild Necro~i% m~Iti~o~al, aild | Hematopoiesis, e~tra~edullary, mi!d i Lung -PFHneremeuosmraornnhiiaaag,~e, iinnmttueelrr~ssitt{iiottciiaaalll~~, acihlrdonic, chronic, mmullttiidfooccaall~, m1d | ~ammar? Gland -Lo~ular hyperplasia ~ Parathyroid -Not examined, not in plane o{ section i ow Hm ~ituitary -Adenoma | Spleen -Hematopoiesis, extramedullary, increased, moderate | Urinary Bladder Uteras -Epithelial hyperplasia~ sim~le, diffose~ mild -Within normal limits Fewer than protocol number | The following tissues were found to be within normal limits: HDrraaiinn,, SSppiinnaall CCoorrdd,, BBoonnee MMaarrrrooww,, HHeeaarrtt,, SSttoowmaacchh,, SSmmaallll Iinntteessttiinnee,, AAoorrttaa,, OOvvaarryy,, TTrraacchheeaa,, | Thyroid, Lymph Node (mesenteric), Pancreas, Salivary Bland, Eye. | |1 pt Species: Rat | Project Number: 0281CR0012 sSuummmrairizzeedd SSTtAR bPaaggse:: 759 224433 11333377..00225533 3MA00027378 | Sized Sage Tilated inl et (nti) Summarized Single Tabulated Animal Report (continued) Irivital crs and Mersin sation Individual Macroscopic and Microscopic Observations i he Lasoo, Riker Laboratories, Inc. ~M | FE To er a Tee icy Stay i is FC-14~: Two Year Oral Toxicity-Oncogenicity Study in Rats I1 i Yr: TRE fet Foie Sot {1 GURL 6pm ate 2 Animal Number: IR-4614 Sex: Female Group: i I} CONTROL 0 ppm Fe ee 19 Torna Suifce Fate: (Week: 105) Terminal Sacrifice Table: 2 Macroscopic Observations: | rr i tase in pried wat seit ail ct. Mammary Gland -Mass in perineal area; possible milk cyst. 5 ew ie rin cri sas 2 fe Uterus -Large gelatinous cervical mass, 2 cm die. Microscopic Observations: i ra Siu eta, corten, strate Adren~l -Sinusoida! ectaaia, cortex, noderate iow ai ration writ Kidney -Pelvic mineralization, minimal 1 vec weg wri, Chronic progressive nephropathy, mild | tr Saari webrin mito, ld Llver -Hepatocyte vacuolation, m~Ittfocal, mild Yory ht Proiiy Mammary Gland 1 PPaannccrreeaass -Adenocarcinoma -~Ahcciinnaarr aattrroopphhyy,, wmiilldd jt roe vt ipl 8 scion Parathyroid -Not examined, not in plane o~ section | Hey ry Pituitary -Adenoma Si ort apts, tte ection -No diagnosis, inadequate section i She Sits, a Spleen -Nemosideros~s, mild | Trt rain oat Thyroid -Ultimobranchial cyst Jae Fin Uterus -Polyp 1 he ws th aes at erie mt This was the mass at cervix noted at necropsy. |1 The flag tists wre fat fob tis crm Lit: The foilowing tissues were found to be within normal limits: Hin Fone Rarrng str, uy ouch, Sul nesting tats, Uri Baer, Brain, Bone Marrow, Heart, Lung, Stomach~ Small Intestine, Large Intestine, Urinary Bladder, | in Darn, en Ean, rh oe seach nh, Aorta, O~ary, Trachea, Esophagus, Lymph Node (mesenteric), Salivary Gland, Eye. 1 i es rs So rote Son 1) Gn Animai Number: IR-&615 ~ex: FemalB Group: i I) CONTROL 0 ppm | Ft ee 109 Tein agin Fate: (Week= I05) Terminal Sacrifice 1 MMaaccrroossccooppiicc OObbsseerrvvaattiioonnss:: P---- -No visible lesions. | Microscopic Observations: ret J -- Adrenal -Sinusoidal ectasia~ cortex, marked 1 po x wane, nsw Aorta -Not examined, missing I jr Fe vireo, sist Kidney -Pelvic mineralization, minimal le Fark sie ek lint, wig Liver -Portal bile duct proliferation, m~id Hepatoeyte alteration, vacuolated, mild | Wsete altwatio, Lt, 11d Hepatocyte alteration, basophilic, miid os rein eae, Sih wd Lung -Pneumonia, interstitial, chronic, mild 1 esr rs, 16 Alveolar macrophages, mild rr ieee Mammary 81and -Galactocele | Pera ere, wt i sae of cic Parathyroid -Not examined, not in pl~ne of section Sie Smtr i Spleen -Hemosiderosis, mild i fed frre) Uterus -Within normal limits | Fer ths rota nutter Fewer than protocol number | |5 Spies ht Sppcies: Rat | hes ers ccz !Project Number: 0281CR0012 sai ngs 244 Summarized STAR Page: 80 244 11333377..00225544 awaooo2rs7e 3MA00027379 | Summarized Single Tabulated Animal Report (continued> |a as Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rate Table: | Anima! Number~ IR-4615 Sex: Female Group: I 11 CONTROL 0 ppm Fate: IW~ek= 105) Terminal S~crifice | Microscopic Observations (continued): 1| Fin on dy Fv ron, Her, mc Sl Dian, Lr testi The following tissues were found to be within normal limits~ Brain, Spinal Cord~ Bone Marrow, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Ovary, Pituitary, Trachea, Thyroid, Esophagus, Lymph Node (eesenterid, Pancreas, SaliYary Gland, Eye. | Animal Number: IR-4616 Se~: Female Group: (I) CONTROL 0 ppm Fate: iWeek= 105) Termin~I Sacrifice Macroscopic Observations: | Microscopic Ohservations~ 1 Teen tetiol apnation, silts, aris Adrenal I Heart -No visible lesions. -Cortical degeneration, unilateral, marked -Myocardial fibrosis, focal, mild i | Kidney | Liver Mmmyuioltctiairffdocicatalil,s,, amcilhldrdonic nonsuppurative, -Chronic progressive nephropathy, mild To rein ie Pelvic mineralization, minimal -Portal mononuc]ear cell infiltrate, mild Portal bile d~ct proliferation, mild Hepatocyte vacuolation, multifocal, mild HHeeppaattooccyyttee aalltteerraattiioonn,, vvaaccuuoollaatteedd,, wmiilld Lung -Perivascular mononudear infiltrate, moderate | Vascular mineralization, mild 1 MMaasmumaarryy GBllaanndd Alveolar macrophages~ mild -HNoott eexxaamniinreedd', mmiissssiinngg Ovar~ -Cyst, unilateral | Parathyroi~ -Not examined, not in plane of section a Fm Bk Spleen -Hemosiderosis, mi1~ | The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Stomach, Small Intestine, Large Intestine, Urinary Bladder, | Aorta, Uterus, Pituitary, Trachea, Thyroid, Esophagus, Lymph Node (mesenteric), Pancreas, Galivary Gland, Eye. | | | | | 1 SSppeecciieess:: RRaatt Project Number: 0281CR0012 metre 245 Summarized STAR Page: 81 245 11333377..00225555 3MA00027380 I Summarized Single Tabulated Animal Report (continuedl i Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Onco~enicity Study in Rats I Ani~aI Number: i~-4617 Sex: Female Group: (i) CONTROL 0 ppm Fate: (Week= 73) Sacrificed in extremis Table: 2 Macroscopic Observations: I Ovary Liver 1 Wrssoe aration Microscopic Observations: n Adrenal -Hemorrhagic mass, 5 cm dia., left ovary. -Pale; left lateral lobe dark rmd. -Sinusoidal ectasia, cortex, mild n 1 Liver Liver i 1 Lung -"PaOonrrettaaollf ampoam~iaronnupccrlleeesaenrntcceellll iinnffiillttrraattee,, mniildd Necrosis, diffuse, marked Massive necrosis of one lobe with ccoommppeennssaattoorryy iinnccrreeaassee iinn mmiittoosseess iinn aannotthheerr lobe. -Vascular mineralization, mild n Mammary Gland Ovary I i PPaarraatthhyyeraoiidd Pituitary -Not examined, missing -Leiomyoma Large well differentiated neoplasm, mostly -"NNeonttecereoxxtaaimncii,needdp,,ronbnooattblyiinnapprlliaasnneees oofffromsseeccattniiooonnviduct. -Not examined~ missin~ i The following tissues were found to be within normal limits: Brain, Bpinai Cord, Bone Marrow, Splemn, Kidney, Heart, Stomach, G{a!l Intestine~ Large Inlestine, Urinary Bladder, Aorta~ Uterus, Trachea, Thyroid, Esophagus, Lymph Node (mesenteric), Pancreas, Salivary Bland, Eye. i Animal Number: lR-461B S~x: Female Group: ~ I1 CONTROL 0 ppm Fate: (Week= 931 Sacrificed in extremis I Macroscopic Observations: Pituitary -Raised mass, 1.1 ca din. | Mammary Gland Microscopic Observations: -Large ulcerated mass, 10 x 7 x gcm, right axilIary area. Adrenal Esophagus | Kidney | 1 LLLuuinnvgger 1I Fores Mammary Gland Parathyroid Pituitary -Sinusoida] ectasia, corte~, mild -Not examined, mis~ing -Pelvic mineralization, minimal -"-VPaaossrcctaualllaarrmowwniionnneeurrcaallleiiazzraattciieoolnnl,, iamniiflliddltrate, mild Alveolar macrophages~ mild Mt ryt ae of scion Perivascular mononuclear infiltrate, mild -Not examined, missiog -Not examined, not in plane of section -Adenoma | i i ySpecies: Rat Project Number: 02BICRO0]2 Ssumamarrizied SsTARrPagge: 82 224466 11333377..00225566 3MA00027381 i Summari2ed Single Tabulated Animal Report (continued) | Individual Macroscopic and Microscopic ObserYations Piker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats i Animal Number: 1~-461B Sex: Female 6roup: (I) CONTROL 0 ppe Fate: (Week= 93) Sacrificed in extre~is Table: 2 | Microscopic Observatious (continued): Skin -Fibroma, subcutaneous I Large neoplasm with extensiYe collagen formation, large portion necrotic. Described as ~ammary lesion but no mammary tissue present in section. Thyroid Urinary Bladder -U!timobranchial cyst -Epithelial hyperplasia, simple, diffuse, mi!d 1i Th following issues ware Foust to be within norm] Limits: The following tissue~ were found to be within normal limits: Brain, Spinal Cord, Bone ~arrcw, Spleen, Heart, Stomach, Small Intestine, Large Intestine, i Aorta, Ovary, Trachea, Lymph Nede (mesenteric], Pancreas, Salivary Gland, Eye, Uterus. I Anima! Number; i~-46!9 Sex: Female Group: (I) CONTROL 0 ppm Fa~e: (Week= 641 Found Dead I wo --_-- i MMaaccrroossccooppiicc BOhbsseerrvvaatliioonnss:~ Spleen -Slightly enlarged Liver -Pale with an irregular surface on all lobes. i Pit~it{ry Microscopic Observations: Adrenal -Enlarged ~ith heeorrhaQic fool. -Necrosis, diffuse, marked I Eye n i LiLKviivdeenrrey Malignant lymphoma, histiocytic -Not examined, missing -Not examined, missing --"PFNooerrptthaarllosibbsii,lleetdduuubccuttlarpp,rroollmiiaffreekrreaadttiioonn,, mearrk~eecd Necrosis, local areas~ moderate Malignant lymphoma, histiocytic n Lung Lymph Node (meeenteric) -Vascular mineralization, mild Malignant Iymphoma, histiocytic -Hemorrhage, mild Mammar~ Gland -Salactocele Parathyroid -Not examined, not in plane of section i Pituitary -Adenoma i SpSSplalleeieevnnary Bland -"-~BSaaillaii!ggaandaaennnttitiIIsyy,mspshchohomrsao,,nichh,iissttmiioosdcceyyrttaiitcce Hematopoiesis, extrameduIiary, ~ncreased, I fers moderate Stomach -Necrosis, mucosa!, mild ii ri ater Enea massa ste athe, we Urinary Bladder -Epithelial hyperplasia, simpLe~ diff~s, mild The following tissues were found to be within normal limits: I Brain, Spinal Cord, Bone Marrow, Heart, Small Intestine, Large Intestine, Aorta, Uterus, 1i -- Species: Rat i Project Number: 0281CR0012 senses 247 Summarized 5TA~ Page: 83 247 11333377..00225577 3MA00027382 n Summarized Single Tabulated Animal Report (continuedl Individual Macroscopic and Microscopic Observations ii oe orn Riker Laboratories, Inc. ~M FC-14~: Two Year Oral Toxicity-Oncogenicity Study in Rats I Animal Number: 1R-4619 Sex: Female Stoup: (I) CONIROL 0 ppm Table: 2 I1 ras Surat tio Fate: (Week= 64) Found Dead Microscopic Observations (continued): The following tissues were found to be within normal limits (continuedl: I Trachea, Thyroid~ Pancreas. Animal Number; IR-4621 Sex~ Female Stoup: (I) CONTROL 0 ppm Fatel (Week= 99] Sacrificed in extremis B Macroscopic Observations: Pituitary -Slightly enlarged 0 MMaamnmtaarryy GGllaanndd -SSuubbccuottaanneeoouusm uullcceerraatteedd mmaassss,, S5 zx 44 xx 11..55 coma,, in right axiI[a. R Liver -Appears mottled. B Adrenal Microscopic Observations: Adrenal -Slightly enlarged. -Cortical ~acuolation, foca!~ mild INn ESswoppthaagguuss Heart B Kidney Pr) H-NSooittnuseeoxxiaadmsaiiinneedde,,ctawmsiiissass,iinnggcortex, marked -Myocarditis, chro~ic nonsuppurative, multifocal, mild -Chronic proQressive nephropathy, mild Pelvic mineralization~ mild Nephrosis, t~bu!ar~ moderate I Liver Lung -Portal mononuclear cell infiltrate~ minimal Hepatocyte ~acuolation, peripor[al, mi!d -Alveolar macrophaBes~ miXd i PHWeeermsioovrrarrhshacigg~eel,,ar llmoooccnaalolnuaacrrleeeasas,,r imwniifll~ieltrate, mild | Mammary Gland -Fibroadenoma Galactoce!e Pa~afhvroid -Not examined, not in plane of section 1 Hier py Pituitary -Adenoma I Spleen -~ematopoiesis~ extramedollary, increased, 1 gimild n The following tissues were found to be within normal limits: | n BfArooarrittnas~~, SUUpttieenrrauulss,,CoOOruvdaa,rryy~,BonTTerraaMccahhreeraao,,w,TThhySyrtroooimidda,,ch,LLyymSsmppahhllNNooddIeenteI(smmteeissneeenn,tteeLrraiirccgi)e,, IPPnaatnneccsrrteeiaansse,,, SSUaarlliiinvvaaarrryyy BGGlllaaadnnddde,,r,EEyyee.. B B B I 1 SSppeecciieess:: RRaatt Project N~mber: 0281CR0012 SSuummmmaarriizzeed SST1A8~ rPaaggee~: 084 224488 11333377..00225588 3MA00027383 m Summarized Sing!e Tabulated Animal Report (continued) B Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc, 3M FC-14~: Iwo Year Oral Toxicity-Oncogenicity Study in Rats I Table: 2 ................................................................................................. Animal Number: IR-4~22 Sex: Female Group: l) CORTROL 0 Ope Fate: (Week= 62) Found Dead B Macroscopic Observations: 5kin -Small circular lesion on back; slight hair | Mammary Gland loss on left latera! side, -Mass, 2 ce dia., right axillary area; 1.5 ca dia,, left inguinal area, B 1 Kidney Pituitary Lung -Rabkiiisgdenndeeys;sareaaapp,ppee0ar.'s3s off~lluuiidddia.ff,iilllloenetd,.surface of right -Dark red gelatinous ease. -Slightly mottled B Microscopic Observations: Adrenal Aorta -Ginusoidal ectasia, cortex, marked -Not examined, missinQ B Kidney -Chronic progressive nephrooathy, ~oderate Pelvic ~ineralization, mnderat~ Hyperplasia, pelvic epithelium, local areas, i LiLviveerr Lung H Mammary Gland Parathyroid i Hater Pituitary n Skin -"HHmeeippladattccceyrttee vvaaccuuoollaattiioonn,, ppeerriippoorrttaall,, wmoidrearattee -Alveolar macropha~es, m~!d ripe -Galactoce!e -Not examned, not in plane o{ s~cton -Not examined, missing -Ulcer, focal, moderate The followin~ tissues were found to be wk~h~n normal l~mits: I Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Btomach~ Small Intestine, Large Intestine, i SUSraBil1niiavvraayrryyBlGSalldaadnnegdr,,, EEUyvteee..rus, Ovary, Trachea, Thyroid, Esophagus, Lymph ~ode (mesenteric}, Pancreas, B Animal Number: IR-4623 Bex: Female Group: (I) CONTROL 0 ppe H Fate: (Week= 96) Bacrificed in extremis Macroscopic Observations: Eye -Opacity, right eye. i Nanny Bland "Hltilobuler mass, 10x 123 ab, rit Mammary Bland -Multilobular eas~, II x 12 x 3 cm, riQht I axilla. Adrenal -Appear enlarged i MMiiccrroossccooppiicc OObbsseerrvvaattiioonnss:: Adrenal -8inusoida! ectasia, cortex, arked n Esophagus -Not examined, missing I Eye Kidney Liver -Cataract, unilateral -Pelvic mineralization, ~inimal -Portal mononuclear cell infiltrate, e~Id Hepatocyte alteration, Yacuolated, m1d B I B Species: Rat Project Number: 02BICRO012 sSumomawriizeed SsTAw~rPgagee: s8s5 224499 11333377..00225599 3MA00027384 l iI l I 1l 1 l l I I I l iI 1n I = ar stories, he 1 Summarized Single Tabulated Animal Report (continued) Individual Macroscopic and Microscopic Observahions Biker Laboratories, Inc. ~M FC-143; Two Year Oral Toxicity-Oncogenicity Study in Rats Animal Number: IR-462~ Sex~ Female Group: I I) CONTROL 0 ppm Fate: (Week= 961 3acrficed in extremis Table: 2 Microscopic Observations (continued): Lung br Lymph Node (mesenleric) Mammary Gland Pituitary Thyroid Uterus r---- -Pneumonia, interstitiaI, chronic, multifocal, mild Alveolar macrophages, mild A Perivascular mononuclear infiltrate, mild -Sinusoidal ectasia, moderate -Fibroadenoma -Adenoma -Follicular hyperp!asia~ cystic, unilateral, mild -Within normal limits Fewer than protocol number The following tissues were found to be within oormal limits; Brain~ Spinal Cord~ Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine~ Urinary Bladder, Aorta~ Ovary, Trachea, Parathyroid, Pancreas, Salivary Gland. Animal Number~ 18-4624 Sex: Female Group: (I) CONTROL 0 ppm Fate~ (Week= I00) Sacrificed in extremis Macroscopic Observations: Pituitary Mammary Gland LLuunngg Tow Microscopic Observations: Adrenal Kidney Liver Lung Mammary Gland Ovary -Hemorrhagic mass, 0.6 cm dim. -Ulcerated, cystic mass, 4 x 4 x 5.5 cm~ in left axiIla-throat area; multilobuIar mass, 8.5 x 5.5 x 3 cm, in right nt"-~Raianiigss~eeiddnacc!iirrccaruuellaaa.rr nvoodduellee,, 00..66ccomcdiim,., iinn lleefitt lobe. re asin -Sinusoidal ectasia, -Chronic progressive somepny sin cortex, moderate nephropathy, minimal PeI~ic m~neralization~ mild mPortal mononuclear cell infiltrate, mild Portal bile duct proliferation, mild onHepatocyte vacuolation~ mu]tifocal, m~]d -Pneumonia, interstitial, chronic, multifocal, mild Metastatic neoplasm Large metastasis of mammary aOenocarcinoma. -Fibroadenoma Adenocarcinowa -Cyst, unilateral Species~ Rat Project Number: 0281CR0012 Sani rs 250 Summarized STAR Page: 86 250 11333377..00226600 3MA00027385 n Summarized ~ing]e Tabulated Anima! Report Icontinued) Individual Macroscopic and Microscopic Dbservations i Piker Laboratories, :no, 3M FC-143: Two Year Oral Toxicity-Dncogenicity Study in Rats Table; 2 i Animal Number: IR-{624 Sex: Female Broup: (i) CONTROL 0 ppm Fate; (Week= I00) Sacrificed in extremis i Microscopic Observations (continued): Parathyroid -Not examined, not in plane of section Pituitary i Spleen -Adenoma -Hematopoiesis, extra~edullary, increased, moderate I i TThhee ffoallltoowiinngg ttiissssuueess wweerree ffoouunndd ttoo bbee wwiitthhiinn nnoorrsBaal! lliiamiittss:: Brain, Spinal Cord, Bone Marrow, Heart, Gto~ach, Small Intestine, Large Intestine~ Urinary Bladder, Aorta, Uterus, Trachea, Thyroid, Esophagus, Lymph Node (mesenteric}, Pancreas, n Salivary Gland, Eye, ~ni~al N~ber: I~-4625 Sex: Female Group: ( i1 CONTROL 0 ppm Fate: (~eek= I00) ~acr~iced in extremis i Macroscopic ObserYations: Pituitary -Enlarged d~e to raised mas~, 1.2 cm dia. i MMaasmmsairryy BGllaanndd "-CCyyssttiicc maaeess,, 22 ccam ddiiaa..,, lleefftt aaxniillllaa., Adrenal -Both appear enlarged. | K~dney -Somewhat pitted Microscopic Observations: Adrenal -Ginuso~dal ectasia, cortex, marked i Cortical degeneration, local areas, mild Esophagus -Not examined, missing B by 30 pen, its wet Eye -No diagnosis, inadequate i Heart -Myocarditis, chronic nonsupp~rative, B KiKdindneeyy multifocal, ~ild -C~hhrroonniicc pprrooggrreessssiivvee nneepphhrrooppaatthhyy,, mmaarrkkeedd Liver -Portal mononuclear cell infiltrate, n Hepatocyte vacuolaton, mult~ocal, minimal I Lung Mammary ~land Parathyroid -Hemorrhage, local areas, moderate -Fibroadenoma -Not examined, not in plane of section i B PSSipetleueeinntary --AHdeesnoosmiaderssis, ail -Hemosiderosis, mild The following tissues w~re found to be within normal limits: i Brain, Spinal Cord, Done Marrow, Stomach, Smal! Intestine, Large Intestine, Urinary Dlad~er, Aorta, Uterus, Ovary, Trachea, Thyroid, Lymph Node (mesenteric}, Pancreas, ~a!i~ary S!and, i i i i SSppeecciieess:: RRaatt i Project Number~ 02BICROOI2 sSuamwmairzizeetd 8wTAeR rPaiggee; 877 225511 11333377..00226611 3MA00027386 I ~um~arized ~inqle Tabulated Animal Report (continued) I Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc. ~M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: I Anima! Number: IR-4626 Sex: Female Group: (I) CONTROL 0 ppm Fate: (Week= ~05i Terminal ~acrifice 1 [-- Macroscopic Observations: I Pituitary -Raised mass, 0.9 cm dia. Microscopic Observations~ I Adrenal Kidney -Pheochromocytoma, benign~ unil~teral -Chronic progressive nephropathy, moderate 1 LiLviveerr I LLuunngg Parathyroid Pituitary 1 Sin tos Spinal Cord I Spleen -"PHHeeelppvaaittcoeccymyittneeervvaealccisuznoalltaaittoiinoo,nn,, mommduleltrtiaiftfeeocceall,, 8miilldd -"VVaassccuullaarr mmiinneerraa!liizzaattiioonn,, mmilled Jog-Not examined, not in plane of section -Adenoma -Not exaained, missing -Hemosiderosis, ~ild I The following tissues were found to be within nor~,al limits: Brain, Bone Marrow, Heart, Stomach, Small '~n~~es+~~n~~,. Large Intestine, Urinary ~ladder, Aorla, I 1 SSUaatlleiriuvvsaa,rryy OGlwlaranyne,d,, MEE~vymeea..ry Gland, Trachea, Thyroid, Esophagus~ Lymph Node (me,enteric], Pancreas, Animal Number: ~-~627 Sex: Female Group; (I) CONTROL 0 ppm I F~te~ INeek= I051~ Terminal Sacrifice Macroscopic Observation~ 1 PMiatsutiatrayrySlant --"~FFaiisrrsam, mwIaasssx~, 0.556..55c2m~. &4xx 3~..55 ccam,, rriigghhtt llaatteerraa!l I area; Iobular 1 MMiiccrroossccoeppiicc OObbsseerrYvaattiioonnss~: left a~i[la. Adrenal -3in~soidal ectasia, cortex, moderate I Medullary cell hyperplasia~ multi~ocal, mild I Heart Kidney -~yocarditis, chronic nonsuppur~ti~e, m~Itifoca~, mild -Chronic p~ogressive nephropathy, moderate I i Liver Lung -PPPooorrrtttaaalll bimiollneeonuddiuccc!ttearpprroocllei!i1ffeerriaantt{iiioolnnt,,ratmweod,deerrmaaittleed He~atocyte alteration, basophil~c, ~od~rate -Vascular ~inera1~a~ion, mild I ~ammary 81and In te Ovary A~veclar macroghag~s, mi1~ Perivascular mononuc!ear infiltrate, mi~d -Ade~ocarcinoma Neoplasm arises in several places in a fibroadeno~a. -Tubular adenoma~ ~nilatera] Cyst~ bilateral I I Species: Rat 1I dr Project Number~ 0281CR00~2 SSuumnmrairizzeedd SSTTAR PPaageg: 888 225522 11333377..00226622 3MA00027387 n Summarized Single Tabulated Animal Report (continued} B Individual Macroscopic and Microscopic Observations Riker Laboratories, !no, 3M FC-143; Two Year Oral Toxicity-Oncogenicity Study in Rats B Animal Number: IR-4627 Sex: Fe~a!e Group: (I) CONTROL Fate: (Week= 105) Terminal Sacrifice Table: 2 Microscopic Observations .(continued)~ I Paocreas Parathyroid 1 rary eo Pituitary a Skin -Islet cell adenoma -Not examined, not in pl~ne of section -Adenoma -Fibroma, subcutaneous Uterus -Cystic glands, mild B The following tissues were found to be within normal limits~ Brain, Spinal Cord, Bone Marrow, Spleen, Stomach, Smal! Intestine, Large Intestine, i UUrriinnaarryy BBllaaddddeerr,, AAoorrttaa,, TTrraacchheeaa,, TThhyyrrooiidd,, EEssoopphhaagguuss,, LLyymapshh NNoeddee ((meeesseenntteerriicc)),, SSaalliivvaarryy GGllaanndd,, i Eye. B Animal Number: I~-4628 Sex: Female Group: (I) CONTROL O ppm F~te: ~Week~ ID5) Terminal ~acrifice I i MacPrioPsticutoiuptiiatcrayrOy.bservations: -"MHaissss,, 11..22 ccmo diina,. Mammary Gland -Small nodule, 1.5 cm dia., right ~xilla; possible milk cyst. B Microscopic Observations: Adrenal Esophagus -Sinu~oidal ectasia, cortex, mod~rat~ -N~t examined, missing B Kidney Liver i Lng 1eI Parathyroid -Pelvic mineralization, minimal -Portal bile duct proliferation, mild Hepatocyte alteration, vac~oIated, m~Id "-VHVaaesspccauatlloaacrrytemsii~nnaeecrruaaollliiazztaaittoiinoon,n,, m~m#Iiitllddifocal, mild pee -GaIactocele Adenoma, papillary Small highly cellular neoplasm lying adjacent to several large galactocoels. -Not examined, not in plane of section Pituitary -Adeno~a B The following tissues were found to be within normal limits: i UUBrrriai~nnnaa,rryy SBBplliaanddaddleerrC,,ordAA,oorrttBaao,,neUUttMeearrruursso,,w,OOvvSaaprrlyye,~en,TTrraaHccehhaeeraat,,, TTShhtyyorrmooaiicddh,,, LLSyymamapplhlh NNIoonddteeest((immneeess,eennttLeearrriigcce))~,InPPtaaennscctrrieenaaes,s~, II Salivary Gland~ Eye. B n I 1 I >SSppeecciieess:: RRaatt Project Number: 0281CR0012 sme 253 Summarized STAR Page: B9 253 11333377..00226633 3MA00027388 m Sie Sie Tf pet Gentine Summarized Single Tabulated Animal Report (continued) | Individual Macroscopic and Microscopic Observations Riker Laboratories~ Inc. IM FC-143: Two Year Oral Toxicity-Oncogenicity Gtudy in Rats Table: 2 | Animal Number: IR-4633 Sex: Female Group: I I) CONTROL 0 ppm Fate: INeek= 63} Sacrificed in extremis 1 [EE -- Macroscopic ObserYations~ I Liver -Very pa!e Spleen -Slightly enlarged Mammary Gland -Large subcutaneous mass, 6 x I0 x 2.5 | with necrotic areas, containing dark brown fluid, ventra! abdomen. i FMiiccrroossccooppiicc OOb~seerrvvaattiioonnss:: A~renal -Hematopoiesi% extrameduIlary, cortica!~ mild | Sinusoidal ectasia, cortex, mild Aorta -Not examined, missing Esophagus | KKiiddnznyey -Not exami~ed~ missing "-CChhrroonniicc pprrooggrreessssiivvee nneepphhrrooppaatthhyy,, wmiinniismaall Vacuolation~ conY. t~b. epithei~m, moderate 1 i Prrenghribanad Liver -Nepatocyte vacuolation, centrilo~u!ar, marked i Lung -Uascular mineralization, mild Hemorrhage~ multifocal, mild i Maaammmaarryy BBllaanndd -~AAdeennooccaar~cciinncoemsa Well dif~erentiated~ ductular pattern, areas | oT moderate mitotic actiYity, ]arge areas of necrosis. 1 rev ig, wt on ft Parathyroid -Nol examined, not in plane of section | Salivary Gland -Not examined, m~esing | i Spleen -wmHoetdmemarrtaaottpeeoiesis, extramedullary~ increased, The ~oilowing tissues were found to be within normal limits: | Brain, Spinal Cord, Bone Marrow~ Hemrt, Stomach, Small Intestine, Large Intestino~ Urinary Bladder, Uterus, OYary, Pituitary, Trachea, Thyroid, Lymph Node (~e~enteric)~ Pancreas, Eye. | Animai Number: IR-46~4 Sex: Female Group: (I) CONTROL 0 ppm Fate: (Week= 105) Terminal Sacrifice i MMaaccrroossccooppiicc OObbsseerrvvaattiioonnss:: Pituitary -Mass, 0.7 cm dia. | ~ammary Gland -Lobular mass, 8 x 6 x 4 cm, right axi!la; lobular mass, g x 7 x ~.5 cm~ left i pray inguinal. | Ricroscopic Observations; | Adrenal Esopha;us Heart -Sinusoidal ectasia~ cortex, moderate -Not examined, missing -Myocarditis, chronic nonsuppurative, muItifocaI~ mild | | i| PPSrrpooejjceeiccetts:MNuuRsmatbteerr:: 0G2Z8B1ICCRR0I0C1I2Z GSumimazriezedd STAR PPagge: 90 225544 11333377..00226644 3MA00027389 i Summarized Sinle Tabulated Animal Re~ort {continued} Individual Macroscopic and Microscopic ObserYations 1 ow Lire oe, 1 Riker Laboratories, Into 3M | FC-143~ Tmo Year Ora! Toxicity-Oncogenicity Study in Rats | Animal Number: IR-4634 Sex: Female 6roup: (I) CONTROL 0 ppm Fate: ~Week= 105) Terminal Sacrifice Table: 2 I ~icrosoopio Observations (continued): Kidney -PelviE mineralization, minim~! | Liver -Portal mononuclear cell infiltrate, mild Portal bile duct proliferation mild Hepato~yte alteration, vacuolated, mild i HHHeeepppaaatttooocccyyyttteee aaalllttteeerrraaatttiiiooonnn,,, beeaoosssoiipnnhooipplhhiiicll,iicc,,modmaeiirlladdte ||1 w[r------ A Favete Mammary Gland Perivasc~l~r monon~clear infilt~mte, mild ~e~orrbage~ =~]tifoca]~ mild -FiSroadenoma Fibroadeno~a | i P~rathyroid Bnnoeetcchrroamsiaisssseaasnnddweccryyessttiifccibraaorraeedaaessnoiimnnastt.uemrorAssr,.eas of -Not examined~ not in plane of section |1 shen Swonototssis, wtraseeltey, toressel, Pituitary -Adenoma -Hematopoiesis, extramed~!!ary, increased~ mild Hemosiderosis, mild i he eleifend iiss The foIlowi% tissues were ~ound to be within norma! limits: | Brain, Spinal Cord, Bone Marrow, Stomach, Small Intestine, Large Intestine, Urinary B!adder, | Aorta~ Uterus~ Ovary~ Trachea, Thyroid, Lymph Node (mesenteric), Pancreas, Salivary Glan~, Eye. Animal Number: IR-4635 Sex: Female Broup: (I) CONTROL 0 ppm Fate; (Week= 94) Found Dead I Macroscopic ObeervationsI Small Intestine -Oejunum appears infIammed with reddish fluid; 1i| Hi, ri 2 Mammary Gland ileum appears inflammed near -Mass, 7 x 7.5 ~ 2 cm, multilobular and ulcerated, right inguinal; mas~, light beige in color, spherical, 2 c~ dia., in left axilla. | Microscopic Observations: i #aArdreennaall -"SSiinnuussooiiddaall eecottaassiiaa~, ccoorrtteerx,~ maiilld Hematopoiesis, extramedu!larh cortical, moderate | Esophagus Eye Kidney -Not examined, missing -Not examined, missing -Chronic pro~ressiYe nepbropathy, mild Pelvic mineralization, minimal i i | Species: Rat Project Number: 0281CR0012 SSuumwmrairizzeetd SSTTAR PPai;see: 391 225555 11333377..00226655 3MA00027390 I Scmmarized Single Tabulated Anima! Report (continued} I Individual Macros{opic and Microscopic Observations Riker Laboratories~ Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 B Animal Numbr: IR-46~5 8ex: Fema!e Group; ( II CONTROL 0 ppm Fats: (Wsek= 94) Found Oead n Microscopic Observations (continusd): Liver -Hepatocyts vacuolstion, diffBse, mild Hematopoiesis, extrameduIIary, mild Mitotic activity, incrsassd, moderats n Lsng -Vascular mineralization, mild M,as,a,~c neoplasm i NMaamsMsaarry BSllaanntd -hAednencoeBa Adenocarcino~a R Extensive necrosis. Parathyroid Pituitary B Salivary Bland Splesn B1 pe Thyroid -Not examined, not in pIsne of section -Not sxaMined, missing -Not examined~ missing -Hsmatop~iesis, extraMedul]ary, increassd, marksd -Ultimobranchial cyst B i T,,h,ee f~oolllloowwiinng~ ttissssuuee~s wweerree ffoouunndd ttoo bbee ~wiitthhiinn nnoorramaall lliismiittss:: Brain, Spinal Cor~, Bone ~arrow, Heart~ ~toMach~ 5mall Intsstine, Large Intestins~ Urinary Bladder, Aorta Uterus, Ovary, Trachea, Lymph Node (mesenteric), Pancreas. B Animal Nu~b~r: I~-46~6 Sex: Female 8ro~p: (I) CONTROL 0 ppm Fate: (Week= IOS) Termins! Sacrifice i FMaatcrroossccooppiicc DObssaerrvvaattiioonnss:: B Mammary 81and -Mass in right axilla a~pears to be milk cyst. Liver i -Slight!y raised dark mass, 0.6 cm dis., left llaatteerraall lloobbee.. Microscopic Observations: I Adrenal -Cortical vacuolation, ~ocal, mild I Heart Kidney Sinueoidal ectasia, cortex, mild -Myocardia! fibrosis, multifocal, mi!d -Chronic progressive nephropathy, mild I i LiLLvairvegerer Intestine -"-NHHeaemgpaaatttooodcciyyattseeisvv,iaccuucoool!losanttiioonn,, emuullttiiffeoccaalI,, wmiilldd Hepatocyte a!teration, vacuolated, mild Hepato:yte alteration, basop~i!~c, Mild B L~ng ~amMary Gland -Vascular ~inera!ization~ mi!d AIveo!ar ~acrophaBes~ mild -Lobu1~r hyp~rp|asia B P&ncreas Parathyroid Pituitary -Acinar atrophy~ mild -Not examined, not in plane of section B I Species: Rat I1 i ob: anon Project Number: 0281CR0012 sSuamwmrairizzeetd SBTAWR PPagge: 922 256 11333377..00226666 3MA00027391 R Summarized 5ingle Tabulated Animal Report (continued) Individual Macroscopic and Microscopic Observations 1 ie Leste, re 1 Riker Laboratories, Inc. ~M I FC-~43: Two Year Oral Toxicity-Oncogenicity Study in Rats I Animal Number: IR-4636 Sex; Female Group; (I) CONTROL 0 ppm Fate: (Neek= I051 Terminal Sacrifice fable: 2 ~icroscop~c Observations (continued)% n Spleen -Hemosiderosis, mild 1 he elm tos re fd te with sr iis The following tissues were found to be within normal limits: B Brain, Spina! Cord, Bone Marrow, Stomach, Smal! Intestine, Urinary Bladder, Aorta, Uterus~ Ovary, Trachea, Thyroid, Esophagus, Lymph Node (mesenteric), Salivary Gland, Eye. n Animal Number: IR-4637 Sex: Female Group: (I) CONTROL 0 ppm Fate: ~Week= 82) Sacrificed in extremis I Macroscopic Observations: Pituitary -Reddened mass, 1 cm dia. Lung -Focal areas of consolidation in anterior part of right and left lung, n Liver -Possibly pa!e 0 MicrosEfcyeoepic Observations: "-HKeerraattiittiiss,, aaccuuttee,, nmaerkkeod Kidney -Pelvic mineralization, mild n Minerali~ation, cortical, mild B Liver Lung Chronic progressive nephropathh mild -Hepatocyte vacuolation, periportal, moderate -Pneumonia, acute exudative, local arems, i I Mammary Gland i SP~liptleueieetnary n Uterus HmHaoendmgeorrrrrahhtaaeggee,~ meue!lttiiffoeccatl,, mwiiled -Galacto:ele --"AHHdeeemanososs~iiadceerraossiiss,, moofdeerraattee -Cystic glands, moderate | ~,,~ tissues were found t~ be ~ithin normal limits: Brain, Spinal Cord, Bone Marrow, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Ovary, Trachea, Adrenal, Thyroid, Parathyroid, Esophagos, Lymph Node (mesenteric), Pancreas, Salivary 81and. I Animal Number: !R-4638 Sex: Female Group: (I) CONTROL 0 ppm Fate: (Week= I05~ Termina! Sacrifice 1 resis Bots: Macroscopic Observations: I Pituitary -Mass, 0.5 cm dia. B Microscopic Observations~ Adrenal Esophagus -Sinusoidal ectasia, cortex, mild -Not examined, missing n i I Species~ Rat Project N~mber: 0281CR0012 SSuummmarriizezd SSThA~ Praaggee:: 593 225577 11333377..00226677 3MA00027392 m ShSuumiamranirizzaeedd BSSiinnggsllee TTcabuula1tt:edreAnianmalsRReespoorrDttrac(ctointtoinnuused) m i FCInd:ividTuoal YoMuaeRrcir~eomrsracloLLpTaiibconrraaetnodtariMreisc,c,raosrmIcneoic:p.cictIOyMbsSeravattioisnsut FC-143: Tmo Year Ora! Toxicity-Oncogenicity Study in Rats Tae: 2 Table: 2 I Animal Number: IR-4638 Sex: Female Stoup: (i) CONTROL 0 ppm Fate ask 109 Terao Sirifice Fate: (Week= 105) Terminal Sacrifice 1 [---- Microscopic Observations (continued)I R KiKdidoneeyy "-CChhrroonniicc pprrooggrreessssiivvee nneepphhrrooppaatthhyy,, m#iilldd. tier Fatal bie tact rlfrstion, ale Liver mPortal bi{e duct proliferation, mild 1 toot waa, mit, iets Hepatocyte vacuolation, multifocal, moderate B TM alr smraintio ia Lung -Vascular mineralization, mild per ot ninety asses i PMPaaarmramatathrhyyyrrooGiilddand --"NNHooottt eeexxxasamamiiinnneeeddd,,, mnnioosttsiiinnng ppllaannee ooff sseeccttiieonn Fititiy J gross, atraats section Pituitary -No diagnosis, inadequate section B Sli Heasidersis, 4 Spleen -Hemosiderosis, mild 1 tars rsa gine, arise Uterus -Cystic glands, marked B The felon tsses were fod oe within asl Lit: The following tissues were found to be within normal limits: rain, Sisal Cord, Bo Rrron, ear, Stonsch, Sell ttn, Large Itatin, Brain, Spinal Cord, Bone Marrow, Heart, Stomach, Small Intestine, Large Intestine, i inary Bue, forte, Techs, Troi, Lys Noe (aseterc, Focress, Salivary San, Urinary Bladder, Aorta, Trachea, Thyroid, Lymph Node (mesenteric), Pancreas, Salivary Gland, B fe, ar, Eye, Ovary. 1 J Fy Animal Number: IR-46~9 Sex: Female Group: (I) CONTROL 0 ppm i Ft ele 58 Swifced in res Fate: (Week= 56) Sacrificed in extremis i MKaccrroossictornpiicc Bserativs: Observations: ten satis ws, 3653 cn B HotSiLskieivneprr Gavin: Stig pale -Midsternal subcutaneous -Slightly pale i MicrtoisKcdiodrpneieycy Observations: -"PeCelrlviviilcceamiionsreereraaellsiizinanatteiioonr,, awmiitlledh, ald B tLLarrrgge IInnteessttiionne Sm-NaCehrmrtcaoat~loikdcisapsor,iosgr~retsccsoleilovonnecenlelphrionpfaitlhtyr,atem,ilwdild Liver -Portal mononuclear cell infiltrate, mild 1 or Trt ts wid LunB I fr Fires Mam~ar~ Bland Siar He "tot anon, ising Salivary Gland 1 sie Sessderest, nt Spleen n jet tFhontrhonartls,ste Uterus -Hemorrhage, multi~oc~l, mild -Fibroadeno~a -Not examined, miesing -He~osiderosis, mild -Within normal limits Fewer than protocol n~er I The following tissues were found to be within morea! limits: tain, pn Cord Boe Baron, at, Stes, Sn] tein, Gin Sct, bts, Ss, Brain, Spinal Cord, Bone Marrow, Heart, Stomach, Small !ntestine, Urin~ri 1 PPiittuuiittaarryy,, TTrraacchheeaa,, AAddrreennaall,, TThhyyrrooiidd,~ PPaarraatthhyyrrooiidd,, EEssoopphahgau~ss,~~Lyy~n. Nude (reserteric), Panireas, i fe.Zye. I i 1m Seo ft I rage emer: HELEONZ y Soni Sf Summarized STAR Fa~e: 94 225588 11333377..00226688 aMAc0c27363 3MA00027393 & tuo 3e0ppn Bn -- 133377..002269 1i i! in ii in iI I . i ! 1 i 1 I 1 I 1 i 1 I 1 I 1 I 1 n 1 I 1 I i 3MMAA0000002277394 S~mmarized Single Tabulated Animal Report i Individual Macroscopic and Microscopic Obeervations oe Laie, 8 Riker Laboratories, Inc. 3M ii Ft: Te Yer rk Toi est Sun in ots 1 FC-143: Two Year 8ral Toxicity-Oncogenicity Study in ~ats Table: 2 i Ei en 0 Tei vine Ani~a! Number: IR-3581 Sex: Male Fate: (Week= ~06) ~erminal Sacrifice Stoup: I 5) FC-143 300 pp~ 1 MMaccrraossccaoppiicc OBbsseerravtatiioonnss:: Hin Siew 03 i Pituitary -Raised mass, 0.5 cm dia. | Microscopic Observations: po strocton, via A~renal -Pheochromocytoma, benign 1 bn re ea st, 4 Kidney -Chronic progressive nep~rmpmthi~ ~ild | jo So ion at ie wis Liver -Portal mononuclear cell infiltrate~ mil~ Hepatocyte va~uola~ion, multifocal, mild 1 . eae wat wig at Hepatocyte mltermtion, vacuolmted, mild | te wid Me~alocytos!s~ minimal 1 1| FTiarretes efh onwdlyea, ie Splee~ -Vascular ~ineraliz~tion~ mild HHeemmoo~rrrhhaaggee~, mmucllttiiffooccaall~, mmooddeerraattee -Adenoma -Hmmosideroeie, mild -C ce!l adenoma | The foiio~!ng tissues were found to be within normal limits: Tie ra oy Eo Mon ar, has, Sl Tiss, Lore tation Brm~n, Spinal Cood~ Bone Marrow, Heart, Stomach~ Small Intestine, Large Intestine, 1 hey tes stn, wei Prose, Prot, Tbe tai ~n~ry B~B,~ ~orta, TestisiEpididymis, Prostate, Parathyroid, Trachea, Esophagus, | phi vd i eon Lymph Node (mesenteric), Pmncreas, Salivary Bland, Eye, .................................................................................................. Nine or 1 fe ie ran 9 6 Animal Number: IR-3582 Sez: Male Fr deo Seas Susie Fate: (Week= 106) Terminal Sacrifice Stoup: (5) FC-14~ 300 ppm | [---- Macroscopic Observations: Skin -U]cerated ma~s~ 2.8 cm dia., dorsal. | Hh eerie in 01 cin. Pituitary -Hemorrhagic lesion, 0.2 cm dia. Jie he B KAirddrenenenaayll -L-PLeaeflftet aadgrreannaall eennllaarrggeedd,, 00..77 ccam ddiina,. mmaassss., Tenis Tots lh, wien Testis!Ep~did~mim -Teste~ s~all, bilateral, | roa Gammon Microscopic Obeervations: pr tanto, bi, wilt Adrenal -Pheochromocytoma~ benign, unilateral i Be Sia sy ue wed Eye -Retinal atrophy~ diffuse, marked | ot eit cuit pane Heart -Myocarditis~ chronic nonsuppurative~ Wikre nie mu]tifocal, mild 1 ier roe gain rath, ite Kidney -Chronic progressive nephropathy~ moderate | ie attisegoeranionh,tflsy 1e6 wie Liver -Portal mo~onuclear eel! infiltrate~ mild 1 LLiunngg -"OViyahssstceo~cilldaarrdemsgiiennneeerrraaaIltiiizzoaantt,iioonnf~,ocaimiil~ldmil~ Hebd propel Parathyroid -Nol examined~ missing i Hhitry em Pituitary -Adenoma Sir st Se wine, sey Salivary Gland -Not examined, miasing |1 or emetion we -Keratoacaothoma~ back | | Species: RRaatt |1 fitsProaect Number: 0281CR0O12 mi srs Summarized STAR Page: 95 225599 11333377..00227700 swac00z7ses 3MA00027395 1I Sa Sr Fe Gt 5uwmarized Single Tabulated Animal Report (continued) in Te Individual Macroscopic and Microscopic Observations i RRiikkeerr LLaabboorraattoorriieess,, TIancc., 33M I so er Ce ore J FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats i Animal ~umber: ,R-o58~ Se~: Male SAT. Fate: (Week: I06) Terminal Sacrifice ~roup: < 5) FC-I~3 300 ppm 1 nis Grins (tnt Microscopic Observations (continued): I wn I Spleen Ss iii ON Testis/Epididymis 1 ns A "= ThyroiO -Nemosiderosis, ~ild -Tubule atrophy, aspermatogenes~s, bi!ateral~ mild -Not examined, m~ssing B A a ipo ar ate The ~ollowing tissues were found to be within norma! limits; 1 Lz pin wir ti Brain, Spinal Cord~ Bone Marrow, Stomach, Small Intestine, Large Intestine, Urinary Bladder, B ESi Tam py Aorta, Prostate, Trachea, Esophagus, LymFh Node (mesente~ie)~ Pancreas. 1 RAeniin~sm!~ MNuurmdebre:r: 1IR8--~35B8~3 SSeexx:: MMaallee GGrroouupt: (( 55!1 FFCC--114433 330000 ppopnm eA sid Fate: (Week= 106) Termina! Sacrifice I Macromcopic Observations: ie pa 350 i Live~ -~ale raised masses, 1.3 cm dim., right B Ln lateral lobe; 0.6 cm dim., left ier lateral lob~. Microscopic Observations: n pi I Adrenal -Sinusoidal ectmsia, cortex, moderate ta pal se el, 1 LiLKviivedenrre7 -Chronic progressive nephropathy~ mii~ H-eHeppaattoocceelllluullaarr ccaarrcciinnoomna Megalo~tosis, mild I pn Portal monon~c!ear cell infiltrate, ~ild Fl pm Cystoid degeneration, focal, mild Hepatocyte alteratio~ ~acuoiated~ mild I i. Lt Lung -Vascular mineralization, mild ee Alveolar macrophage% mild i -- Sr -Leydi~ cell adenoma, ~n~latera! B Seis Soh Vascular mineralization, mild 1 TThhee ffoolllloowwiinngg ttiissssuuerss wweerree ffoouunndd ttoo bdee wwiitthhiinn nnoorrmeaall lliimniittss:: i irs tt, Lrg in, Br~in, Spinal Cord, Bone ~arrow, Spleen, Heart, Sto~ach~ Small Intestine, Large Intestine, I Ee Urinary Biadder~ Aorta~ Prostate, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus, i ny br fet Ri et! Lymph Node imese~teric), Pancreas, Sa1~vary Gland, Eye. n RL ~nima~ N~mber: I~-~85 Sex; Male gb Fate: (Week= 106) Terminal Sacrifice Group: (~) FC-14~ 30~ PF~ 1 rR Macroscopic Observations: i wo de pie 05d, Lung 1 hohe ein Microscopic Observations: B wo J-------- Kidney -Rased pale lesion, 0.5 cm dim., left lobe. -Chronic progressive nephropathy, mild i B i Species: Rat B1 St Project Number: 0281CR0012 wrens 260 Summarized STAR Page: 96 260 11333377.100227711 nonczrse 3MA00027396 | Summarized Single Tabulated Animal Report (continued) Hine eee, ton Individual Macroscopic and Microscopic Observations i ie hen Riker Laboratories, Inc. 3M | 6 To or ed Tone Sc Ss 0s oie 2 FC-143: Two Year Oral Toxicity-Oncog~niMty Study in Rats Table: 2 I a Animal Number : 1~"-.~.uBu~ Sex: Male Fate: (Week= I06! Termin~1 Sacrifice Group: (5) F~r-14~~ 300 ppm 1 KMiiccrroossccoonpiicc GOhbsseerrvvaattiioonnss ((ccoonnttiinnuueedd):: I us FO Liver -Portal mononuclear cell infiltrate, mild rd em what a Cyetoid de~eneratio~ multifoca1~ mild 1 Dn Malignant lymphoma~ lymphocytic Hepatocyte alteration, basophilic, moderate i ranked Megalocytosis, minimal - 4 Lung -Vascular ~ineralization, mild 1 Finn hotel Bite Fibrosis, pleural, moderate I ore oti Pancraas ees a, as Hyperplasia, acinar cell, mild 1 FE ---- The following tissues were found to be within normal limits: | Be oe a as at Wi, Lng tion Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Smal] Intestine, Large Intestine, i me Riamyoe Tr Sovmott Urinary B!adder, Aorta, Testis!Epididymis~ Prostate~ ~ituitary~ Adrenal~ Thyroid~ Parethyr~id, Bi Traae, Expt rh ote esac, Sivas hn Be. Trachea, Esophagus, Lymph Node (mesenteric}, Salivary Gland, Eye. a Animal Number: IP,-3586 Sex: Male Broup: ( 51 FL~-,4J 300 ppm in et et Fate: (Week= I06', Terminal Sacrifice | area tte: i MacroLsLicivoveeprric Observations: -"PPooss_s~ibb~lee gpaallee flooccii oona oonnee lioosbee.. TTeessttiiss!/EEppiiddiiddyy~eiiss -"PPaallee mmaassss,~ i| ccme ddiiaa.. | es Sots Microscopic Observations: psd tn esti, fi, wid Adrenal -Cortical vacuolation, foc~l~ mild Binusoidal ecta~ia, cortex, ~i~d | rt tlh Heart -M?ocarditis, chronic nonsup~urative, ~ild tr ne Kidne~ -Chronic progressive nephropathy, ~oderate 8 im ar Liver -Portal mononuclear cell infiltrate, mild | mes wh os Cystoid degeneration, multifocal~ moderate i i LLaunng~. Megalocytosis, mild -"VVaassccuullaarr wmiinneerraalliizzaattiioonn,, #miilldd fa en wi Pancrea~ -Acinar atrophy, mod~rat~ | aus ets Salivary Gland -Sialadenitis, chronic, moderate Bb as inn TN TestisIEpididy~is -Tubule atrophy, aspermatogenesis, moderate Mineralization, tubular~ mild | as Leydig cell adenoma, bilatera! 1 TThhee ffoolllloonwiinngg ttiissssuueess wweerree ffoouunndd ttoo bbee wwiitthhiinn nnoerrmsaall !Liimniittss:: | rr ee So enn gt oy SE, rh, rin, Spleen, Stomach, Smali Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Pituitary, rt Eu vr Tor esr an ns Brain, Spinal Cord, Bone Marrow, Thyroid, Parathyroid, Trachea, Esophagus, | i LLyymapshh NNaocdee i{mnesseerntteerriicc)),, EEyyee.. | | --_-- Species: Rat I1 ose: coo Project Number: 0281CR0012 sain 0 261 Summarized STAR Page: 97 261 11333377..00227722 awncoozrosr 3MA00027397 | 1| I 1| | i I 1| ii |un 1I : | i| 1I 1| 1| 'i1 | i 1| Sunwin Sia Tilted final feet. ctr) Sum~arized Single Tabulated Animal Report (continued) Tobit Rates 1s recon ation Individual Macroscopic and Microscopic Observations Sia Lora, es Riker Laboratories, Inc. FEE To Yew TorBic Std i ot FC-143~ Two Year Oral Toxicity-Oncogenicity Study in Rats ste 2 Table: 2 Animal Number: IR-35B7 Sex: Male Fate: (Week= 1061 Terminal Sacrifice [------ Macroscopic 0bservations: toEye J-- Microscopic Observations: Adrenal tEye JsKidney Liver / Lnungg PPaannccrreeaass HTeiot ts Pituitary Sty nt Salivary Gland SSpplleeeenn Group: (5) FC-143 300 ppm Are, it a. -Hypopyon, right eye. -Sinusoidel ectasia, cortex, ~inimal five in -Phthsis bulbi, unilateral, marked eso carstiae e ses, Lesion characterized by retinal atroph~ ccaattaarraacctt,, aanndd ccoorrnneeaall vvaassccuallaarriizzaattiioonn wwiitthh Shs f he te collapse of the glcbeo -Chronic pr%~.re~~.ve nephropathy~ mild "Rrkl svamsin i Trois, as -Portal mononuclear ce!1 infiltrate~ mild se spare, iti 1 Cystoid degeneration~ multifocal~ mild tie sion bs, mil Hepatocyte alteration, bascphilic, minimal Rents, main H-VMaaessgtcaaullloiacrrytosmsiiinnsee,raallmiiisznaaittmiiaoolnn,~ imilled Sila ston, ale Alveo|ar macrophages, mild Feat soins le, wie Perivascular monon~clear infiltrate, minimal H-yHyppeerrppllaassiiaa,, iisslleett cceellll,, mmoaddeerraattee tine, 1 in sho of ston -Not examined, not in plane of section Its us hs -Cyst, pars distalis Shite, coi, wre -Sialadenitis, chronic, moderate Hse recive sets of ict Moderate ~eactive hyperplasia of included msIymph node. -HHeewmoossiiddeerroossiiss,, wmiillde The following tissues were found to be within normal limits: Brin, Sin Lr, Fo Rrrw bss, Stn Sa] Iestie, Luge Itt, Brain, Spina! Cord, Bone ~rrow, Heart, Stomach, Small Intestine~ Large Intestine, rin Bae, its, Tis Eidii, Hsiats, Tors, acon Euros Urinary B.a~e., ~orta~ Teetis/Epididymis, Prostate, Thyroid, Trache~ Esophagus, Ur ke meri Lymph ~ode (mesenteric~. ial at D0 Se ie Bg (5 F003 Pe Animal Number: IR-3590 Sex: M~Ie Group: ( ~v Fue hea 15) Surifics 1 mois Fate: (Wmek= 19) Sacrificed in extremis [--r-- MacrTohTsyhcyeompsuissc Observations: le Bure, Gowrie wiih Liver Sin Kota ses 3 341 on Spleen Tn tate steric pr] Lymph Node (mesentmric) great Spat tt rds are Lymph Node (abdominali Sl stn Tors hs lige wt rete, Small Intestine Gre nestine Fess chs alge wt ren, Large Intestine i dtr of ek Bt Kidney iy tr Biles nih ive Urinary Bladder ois Sain Penis "-E[nnllaarrg~eedd~, 11..55 xx 11..551x 00..33 ccma~y ddaarrkk rreecd.. -Enlarged, brown/yellow mottling. -Markedly enlarged, 8 x 2 x i cm. -[nlarged -Hepatic lymph nodes enlarged. -Peyer~s patches enlarged and reddened. -Peyer's patches enlarged and reddened. -Slight dilatation of renal pelvis~ bilateral. -~istended with urine. -Swollen Scie at Species: Rat Fae er: ECH2 :Project Number: 0281CR0012 11333377..00227733 Swiss Summarized STAR gePage: v98e 226622 awaoooersse 3MA00027398 I SuImarized Single Tabulated Animal Report (continuedi 1 Individual MRaRicikkreeorrscoLLpaaibbcoorraaattneodrriiMeeissc,,rosIIcnnocc.p.ic 3IOMbservations FC-143~ Two Year Oral Toxicity-Oncogenicity Study in Rats | Table: 2 1 vt art B50 See Me Gop 8 FOS 00 Animal Number: IR-3590 Sex: Male Group: (5) FC-143 300 ppm | Fate: (Week= 19) Sacrificed in extremis Microscopic Observations | Adrenal Bone Marrow 1 Frain "nalignat yin, Iymocrtic Brain Eye I Kidney {continued): -Malignant iymphoma~ lymphocytic -Ma!ignant Iymphoma, lymphocytic -Malignant Iymphoma, lymphocytic -Malignant lympho~a, lymphocytic -Malignant Iymphoma, l~mphocytic I Liver -Malignant Iymphoma, lymphocytic Parenchyma almost completel~ replaced by diffuse ~oeplastic cell infiltrate. i Lung -KH~eelsmioogrrnrrahhaanggtee,,Iymllopocchaaollma,aarreelaa~ssm,,phmmooocddyeetrriaacttee | Lymph Mode (abdominal) -Malignant lymphoma, histiocytic Extensive neoplastic involvement of hepati~ node. 1 wh et ate ep ---- ~m~h Mode (mesentenic~. -Malignant lymphoma, lymphocytic I Parathyroid -Mot e~amined~ missing Pituitary -No diagnosis, inadequate section Small Intestine -MaliBnant lymphoma~ lymphocytic I Spleen -Malignant ly~phoma, l~mphocytic i TTThh~yyyrmreuoisitd --"MNNaootltigeenxxaaanmntiinreelddy~,mphmaoiimssass~iinngghistiocytic | UUrriinnaarryy BBl!aaddddeer~ M-Maalliiggnnaanntt l!yysasphhoomsaa~, Ilyymmpphhooccyyttiicc Epithelial hyperplasia~ si~p!e~ diffuse, miid i The fling ens ee dt 105 iti sre! ist The fo!io~ing tissues were founO to be within normal limits~ I Heart~ Stomach Large Intestine, Aorta~ Testis!Epididymis~ Prostate, Trachea, Esophagus, | Pancreas, Salivar? Bland, Spinal Cord. Animal Number: IR-ou~ ~x: Mal~ Broup: (5) FC-14$ 300 pp{ Fate: iWeek= I06) Terminal Sacrifice i Macroscopic Observations: -No visible les~ons. Microscopic Observations: Adrenal | Esophagus Kidney 1| i probe Liver -Binuso~dal ectasia, cortex~ mild -No diagnosis, inadequate section -Chponic progressive nephropathy~ minimal -Portal mononuclear cell infiltrate, mild Cystoid degeneration~ moderate | i Lun@ MMHeeegQpaaalltooocccyyytttooessiiassl,,tesrmiainntiiimnoaanll, basophilic, moderate -Vascular mineralization, Alveolar macrophages, mild | Hemorrhage, local areas, moderate .................................................................................................. i Species: | FI ne 1 Pro~ect N~ber: SSuumnmrarriizzeedd SBTRAR PPaaggee:: 9 226633 11333377..00227744 3MA00027399 | 1 1 | | i | i | | | i | iI | | i | | | | i | | I i i Crevn `SSuummmnaarriizzeedd SSiinnggllee TTaibduullaatteedd AAnniinmaall RReeppoorrtt ((ccoonnttiinsuueedd)) Individual Macroscopic and Nizroscopi~ Observations Riker Laboratories, Inc. ~M PC-143: Two Year Oral Toxicity-Oncogenidty Study in Rats Table: 2 .................................................................................................. Animal Number: IR-~Sgl Sex: Male Fate: IWee~= 1061 Terminal Sacrifice Group: ~ 5) FC-143 300 ppm MiCrOScopic Observations Icontinued): Pituitary -Adenoma TThhee ffoolllloowwiinngg ttiissssuueess wweerree ffoouunndd ttoo bbee wwiitthhiinn mnoorrmaanl! lTiigmiittss:: BrAin, Spinal Cord, Bone ~arrow, Spleen, Heart, Stomach, Sma!l Intestine, Large I~testine~ Urinary Biadde~, Aorta, TestisiEpididy~is, Prostate, Thyroid, Parathyroid, Trachea~ Lymph Node [mesenter~c), Pancreae, Salivary S!and~ Eye. .................................................................................................. Animal N~m~.r. ~R ~,<. Sex: Male Fate: (Week= I~6) Terminal Sacrifice Group: ( ~i F~-,4~. ~00 ppm Macroscopic Observations: Liver Microscopic Observations: Kidney Liver Lung Parathyroid Thyroid -Raised pale lesion, 0.6 cm dia.~ interior ccaauuddaattee lloobbee.. -Chronic progressive nephropathy, mild -Megalocytosis, ~inimal Porta] mononuc!ear cell infiltrate~ mild Cystoid degeneration, m~itifocal, mild HeWMpealLltocddeiiIfflffueelrraeernntticiaaatrtecedi,,nomttarraabbeeccuallaarr ppaatttieerrne,, moderate mitotic activity, vascular invasion. -VascuIar ~ineralization, mild AIveolar macrophag~s, mild -~o~ examined, not in plane of section -C cell adenoma ,,_ fo~ow~ng tissues were found to be within normal limits: Braip, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large I~testine, LLUyyrmsippnhharx~KodtBeeladi(dnmeeersseenntt~eeorrritcca)),,, Testis/Epididymis~ PPaannccrreeaass,, SSaalliivvaarryy Prostate, Pituitary, BBllaanndd,, EEyyee.. Adrenal, ~rachea~ Eeophagus, Animal Number: IR-~5~4 Sex: Male Fate; (Week= 106) Terminal Sacrifice Group: ( 51 FC-143 300 ppm Macroscopic Observations: Liver Microscopic Observations: A~renal Heart Kidney -Pale loci throughout. -BinusoidaI ectasia, cortex, moderate -mwMuyllottciiaff~eodcciaatl1i~,s~ wmiicnnhiirsmoaanllic nonsuppurative, -Chronic progressive nephropathy, mild Species: Rat PPrroojjeecctt NNuumabbeerr:: 0022681|0C8R0~001122 SSuumomnawriizzeedd SSTTARR PFaeges; i10000 226644 11333377..00227755 3MA00027400 | Summarized Sing!e Tabulated Animal Report (continued) Tt te eon i Individual ~aR~ciirtkeeorrscokLpaiibbcoorraaattndoerriiMeeissc,,rosIIcnnoccp..ic 33OM1bservations I oo EE ates FC-143: Two Year Oral To~icity-Oncogenicity Study in Rats J Ta~le~ 2 i Pr PT Animal Number: IR-3594 Sex: Male | aE Fate: (Week= 106) Terminal Sacrifice Stoup: { 5) FC-143 300 ppm Microscopic Observations (continued): | wo pt ttn, wii Liver 1I|1 . E D S Teresendn m T ieE in, L rtetewtaesle Lung 1| irree nwuwes,rwtise. Parathyroid -Hepatocyte vacuolation, diffuse, moderate Cystoid degeneration, mild Hepatocyte alteration, vacuolated, moderate Megalocytosis, moderate Centri|obular cells enlarged with finely yanular, eosinophilic, 'ground glass" appearing cytoplasm. -Pneumonia~ interstitial, chronic, muI[i4ocal~ mild ~heolar ~acrophages, moderate -Not examined, not in plane of section 1 Pituitary TTesetsitsis/EEppidiiddiydeyimsis -Adenoma ~-Vaassccuullaarr mmiinneerraalliizzaattiioonn,~ smooddeerraattes | he ER Thyroi~ -Hyperplasia, C cell~ mi!d ST eat lg od Tn The following tissue~ were found to be within normal limits: Brain, Spinal.ford,. Bone Marrow, Spleen,. Stomach,. Small htes~ine~ Large | Seer sosSea to we, Urinary Biadder~ Aorta~ Prost~te~ Traches, Eso~hagus~ Lymph Node (mesenteric!,oPancreas, Fo eo Salivary Gland, Eye. 1 mE Te aT Anima: Number: IR-..~% Sex; ~ale i Sra Fate: iW~ek= i06) Terminal Sacrifice Broup: ~ 5} F~-I4~ 30~ ppm i f---- Macroscoplc Observations: | ng acm aie she Ma~may Gland ne Tm iat Pituitary N~croscopic Observations! | pi Sie ston, a Adrena! -Firm mass, ~ x 2 x 1.5 cm, right axiiIa. -Hemorrhagic mas% 0.5 x 0.7 cm. -Sinusoidal ectasia~ cortex~ mild i KiKBdiondnneeeyy~arrow "--FPNeeolltvviiec~xasmmiiisnneeerdra,alliimzziaasttsiiioonrng,, amiilldd | a Pyelonephritis, acute, mild HHyyppeerrppllaassiiaa,, ppeellvviicc eeppiitthheelliiuumm,, ddiifffuussee,, mmiil!dd oe Tn in tr Liver -Portal mononuclear cell infiltrate~ mild i Tora bie ch etersien, mic Portal bile duct proliferation, mild | i Cyetoid degeneration, mu~tifocal, miid - a Lung -Vascular mineralization, mi1~ Alveolar macrophages, mild | ite A Pituitary -Adenoma ne HO stn tre Salivary Bland -Sialadenitis, acute, moderate 2 LS ee Mass described at necropsy as mammary gland | Es was apparently the enlarged, inflammed Eh salivary gland. No mammary tissue was 1 yen presenl on any slide. I .................................................................................................. | on Species; Rat 1| Er Project Number: 028!CR0012 Corsi 0 Summarized STAB Page~ 101 226655 11333377..00227766 ari 3MA00027401 B | i I I I B iB i B B iB i a | B 0 B B | 1 I R i I Summarized Single Tabulated Animal Report (continued) Individual MaRickreorscoLpaibcoraatnodriMeisc,rosIcnocp.ic 3O0bservations Riker Laboratories, Inc. SM FC-14S: Two Year Oral Toxicity-Oncoge~icity Study in Rats Animal Number: I~-SSg5 Sex: Male Fate: (Week: 106) Terminal Sacrifice Group: (5) FC-143 30~ ppm Table: 2 Microscopic Observations (continued)I Spinal Cord Spleen -Not examiF~ed~ missing -Hemosiderosis, mild The followino, tissues were found to be within ..orma~' limitsI Brain, Heartr Stomach, Small Intestine, Large Intestine, Urinary Bladder~ Aorta, Testis/Epididymis, Prostate, Thyroid, Parathyroid, ~rachem, Esophagus, Lymph ~ode (mesenteric), Pancrems, E~e. FFA~inttieem~:al e(NWsuemiebks:er:110068I))R-TT~eeSrrgam6iinnaa!l SSSaaeccx:rriiffMiiaccleee Group: (5) FC-14S 300 ppm Macroscopic Observations: KKiiddrneeyy Microscopic Observations: "-PPaallee,, eennllaarrggeedd aanndd ppiitttteedd,, bbiillaatteerraall.. Adrenal Heart -~o.,~ca~ vacuolation, multifocal minimal Medullary ce!l hyperplasia, (ocal, mild -Myocarditis, chronic nonsuRpuratiYe, Kidney Liver Lung Pituitary Testis/Epididymis multifoca], mild -OCChysrstto,,nicccoorrpttriioccgaarlle,,ssimavaoetdeernraeatptehe.ropathy~ marked -Portal mononuclear cell infiltrate, mild Hepatocyte vacuolation, m~Itifocal, mild HHeeppaattooccyyttee aalltteerraattiioonn,~ vvaaccuuoollaatteedd,, mwiilldd Megalocytosis, ~ild -Vascular mineralization, mild Hemorrhage~ local areas~ ~arked -Ad~noma -Pelyarteritis, moderate TThhee ffoolllloowwiinngg ttiissssuueess wveerree ffoouunndd ttoo bbee wwiitthhiinn nroorremsa!l ltiismi!tiss:: Brain, Spinal Cord~ Bone Marrow, Spleen, Stomach, Sma]] Intestine, Large Intestine~ Urinary Bladder, Aorta, Prostate, Thyroid Parathyroid, Trachea~ Esophagus, Lymph Node (mesenteric)~ Pancreas, Salivary 8]and, Eye. Animal Number: IR-35~7 Sex: Male Group: (5) FC-14T 300 ppm Fate: (Week= 106) Termina] Sacrifice Macroscopic ~servatio~s: MMiiccrroossccooppiicc OObbsseerrYvaattiioonnss~: Heart -No visible lesions. -~yocarditis, ~hronic nonsuppurative, ~ultifocal, mi]d Species: Rat PPrroojjeecctt NNuumsbbeerr:: 00228811CCRR00001122 Summarized STAR Page: 102 266 11333377..00227777 3MA00027402 B x i 1i 1i i I! B xi B ! 1 i I i i i I i | inl | i Ii Summarized Single Tabulated Animal Report (continued) Ae sad ret eis Individua] Macroscopic and Microscopic Observations Pe Riker Laboratories, Inc. 3M Re Tee a icy iy ns FC143~ Two Year Oral Toxicity-Oncogenioity Study in Rats oa d RB ~nimal Number: IR-35g? Sex: Male Fate: ~Week= 106) Terminal Sacrifice Group: (5) FC-143 300 ppm ns Table: Microscopic Observations (continued); po ot rope ly Kidney a EL Liver wr i ptreiemtate e e Lung Ee i Pancrems fo Hn apt, ss Prostate -Chronic pFogressi~e nephropathy, mild -Rortal mononuc]ear cell infiltrate, milO Portal bile duct proliferation, mild Hepatoc~te alteration, vacuo!ated, ~ild Megalocytosis, minimal -Vascular mineralization, mild -Acinar atrophy, mild -Prostatitis, acute, suppurative, minima! is ti The following tissue~ were found to be within normal limits: Eii r Sos ms So Bt, Ln tine Brain, Spinal Cord, Bone Marrow, Spleen, Stomach, Small Intestine, Large Intestine, Bt ae etn Su its te, Urinary Bladder, Aorta, TestislEpididymis, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, EEssoopphhaagguuss,, LLyyimpghh NNoocdee ((smeesseeantteerriicc)),, BS~illiivvaarryy GGllaanndd,, EE~yee.. .................................................................................................. ii Bn Be To Animal Number: IR-~599 Sex: Male i Fate: (Week= 106) Terminal Sacrifice Group: (5) FC-143 ~00 ppm -- Macroscopic Observmtions( wer ri vapess i io Kidney on Microscopic Observations) I Kidney we i ro mi et at tne i Liver i" rinrege eetaeit Lung fr-- BA in a rea, weatee Salivary Gland = kl Spleen -Hydronephrosis, right kidney. -Chronic progressive nephropathy, mild Pelvic mineralization, mild HHyyppeerrppllaassiiaa,, ppeellvviicc eeppiitthheel]ium, meualtifocal, moderate -Porta! mononuc!ear cell infiltrate, mild Portal bile duct proliferation, mi!d Cystoid degeneration, multifocai, mild Megaloc~tosis~ mild -PPVrnaeesuucemucolnnaiiraa,,Biiinnnettreearrlssittziiatttiiiaaolln,,~ ccmhhirr!oodnniicc,, mmaullt~iiffeoccaall,~ mild Alveolar macrophages, mild Hemorrhage~ local areas, moderate -Bialadenitis, chronic, moderate -Hemosiderosis, mild Tii binsGo frna t i ELsr tI in n The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Heart, Stomach, Small Intestine, Large Intestine~ TTUrrraaiccnhhaeersay,, Bladder, Aorta, TestislEpididymis, Prostate, Pituitary, EEssoosphhaaggeuss,, LLyyimpshh NNooddee ((nmeesseenntteerriicc)),, PPaannccrreaass,, EEyyee.. Adrenal, Thyroid, Parathyroid, ................................................................................................. T see h cn Species: Rat Project Number: 02BICRO012 11333377..00227788 Seis rs 10 267 Summarized 5TAR Page: 103 -- 3MA00027403 I Summarized Single Tabulated Animal Report (continued) SL natpt i Individual MRaictreorscLoapbicoraatndoriMeisc,rosIcnocp,ic 3Observations Ri~er Laboratories, Inc. 3M ots sor FC-H31 Two Year Oral Toxioity-Oncogenicity Study in Rats I ez Table: 2 i et a Se We Sogn (9 E10 50 Animal Number: IR-360~ Sex: Male i Sr Fate: I~eek= 106) Terminal Sacrifice Sroup: (5) FC-143 300 ppm Macroscopic Observations: I pe -- Liver -Mottled Microscopic Observations~ 1 Addrreenaadl "-CCoorrttiiccaall Yvaaccuuoollaattiioonn,, wmiilldd Fara Ps Bone ~rro~ -Not examined, m~seing i Heart -Myocarditis, chronic nonsuppurati~ ra ~ultifoca!, ~ild -Chronic progressive nephropathy, ~ild i i ne -Portal mononucle~r cell infi~trate~ ~ild TE ty Porta! bile duct proliferation, mild 5 En Cystuid degeneration, ioca1~ mild Fook Megalocytosis, moderate I i" oa, att L~ng i -Vascular mineraiization~ ~ild AAllvveecollaarr smaaccrroopphhaaggeess,, mniilld on Hemorrhage, local areas, eoderate n te tei fond Lymph ~ode (mesenteric) -Hemorrhage, minimal Pituitary -~ot ea~ined, mis~ing 1 nl rw Spinal Cord -Rot examined, mis~ing n bon btn -Hemosiderosi~, mild CL -- SET vit Testis!Epidi~ymis -Vascular mineralization, mild 1 A ------ The following tissues were found to be within normal limits~ i estoy Br, ds, rn, Trt Brain, Stomach, ~oma,~' !ntestine, Large Intestine, Urinary Bladd~%.. Ao,ta,. Prostate~ Thyroid,. 1 a Parathyroid, Trachea, Zsophagus~ Pancreas, Salivary Gland~ Eye. i PE e---- Animal ~mber; I~-3601 Sex: ~a!e i a ae Fate; (Week= 1061 Terminal Sacrifice 8roup: (5) FC-!43 300 ppm | [-- Macroscopic Observations: fe tt ie E67 E47 i Liver -Mo<ctmtlddeiidaa;.,, yepploolssottweerriirooarriseccdaasulddeaasttieeonllsoo,~beess0...7 and O.g JAN a Lymph Rode (me,enteric! -Enlarged i J.o..t bo -- Stomach -Enlarged gastric rugae Microscopic Observations: Adrenal -Cortical vac~olation, multifocal, moderate i pas i Heart -~yocardi~is~ chronic nonsupp~rative, Sn multi(ocal~ minimal 1 po it Kidney -Chronic progressive nephropath~ mild I = hes Liver -Portal mononuclear cell infiltrate, mild Tt a mito, oe B HHCeeyppsaatttoooicdcyyttdeeegaaellntteeerrraaatttiiiooonnn,,, mvvuaalcctuuiooflloaacttaeeldd,,, mmwoiidlleedrate bh MeQalocytosis, moderate n a: oi, wee Hepatocyte alteration, basophilic, moderate i I I Species~ Rat |i ! on? Project Number~ 0281CR0012 soci ro 268 Summarized STAB Page: I{14 268 11333377..00227799 -- 3MA00027404 . iB one Tf in Summarized Single Tabulated Animal Report (continued) Stein Td foSd i Individual MaFcirkoesrcoLpaibcoraatndoriMeisc,rosIcnocp.ic 3O%bservations ~iker Laboratories, Inc, 3M LE FC-143: Two Year OFal To, icity-Dncogenicity Study in Rats n --Table: 2 1 Eevee wn ee 9 716 on Animal Number: IR-3&O! Sex: Male | a Se Fate: (Week= lOG) Terminal Sacrifice Group: (5) FC-143 300 ppm Microscopic Observations (continued): n Lung 1 a ta Ss r, e Lymph Node (mesenteric) B re toa, ee Pancreas 1 a te Pituitary IRH ww brS enris n stuntTusysast Stomach -Vascular rineralization, mild Hemorrhage, local areas, marked -Hemorrhage, mild Hemangiosarcoma -Acinar atrophy, moderate -Cyst, pars distalis -Adenocaroinoma Extensive infiltration into submucosa and muscolaris. Well differentiated, high mitotic index. Probably parietal cell origin. Tumor cells in lymphatics. i1 uEa oSli oesfSatSiMSItNey S ovie,Snr, i TThhee ffooillloowwiinngg ttiissssuuesss wweerree ffoouunndd ttoo bbee wwiitthhiinn nnoorrmmaall lliiamiittss:: Brain, Spinal Cord, Bone Marrow, Spleen, Small intestine, Large Intestine, Urinary Bladder, Aorta, TestisiEpididymis, Prostate, Thyroid, Parathyroid~ Trachea, Esophagus, SaliYary Gland, Eye. n I I Animal Number: I~-~602 Sex: Male fr F~te: iWeek= i06) Terminal Sacrifice Group: ( 51FC-145 300 ppm i I Macroscopic Observations: n I -No visible lesions. 3 J Microscopic Observations: pn i Adrenal -Nodular hyperp]asia, cortex, foca!, mil~ n SL Medullary ceil hyperplasia, ~ocal, mild nt J Heart -Myocarditis, chronic nonsuppurative~ I KKiiddnneeyy multifocal, mild "-CChhrroonniicc pprrooggrreessssiivvee nneepphrrpopaatthhy,, emilldd on em pee et 1 Liver -MMPeeoggraatlallaoccyymttooonssoiin~su,,clesmaiirnniimcnaellll infiltrate, mild tose L~ng -Vasc~lar mineraization~ mild n ob a Alvenlar macropheges, mild 1 ts ii fs Lymph Node (mesenteric) -Hemorrhag~ mild i Fr de P~oreas -Icier cell adenoma B Go Spleen -Hemosi~eresis, mild Epos Tt Testis~Epididymis -Vascular mineralizaton, mld 5 fs os Thyroid -C eel! adenoBa i ei ss art tir i i TBBhrreaaiinnf,,oIlSSoppwiiinnnaa~ll tCCioorsresd,,uesBBeowsneeereMFaafrrorruoonww,d, tSSottoombmaeacchhw,,ithSSimmmaellllnorIImnnattleessttliiinnneie,t,s:LLaarrgQee IInntteessttiinnee,, UUrriinnaarryy Bladder, Biadder, i i drermh, i ai, i Aorta, Prostate, Pituitary, Parathyroid, Trachea, Esophagus, Salivary Gland, Eye. B B 1B pneit Species~ Rat Project N~mber: 02BICROOI2 vis 269 Summarized BTA~ Page: 105 269 11333377..00228800 -- 3MA00027405 I Summarized Single Tabulated Animal Report (continued) ts ac rs Asai Individual Macroscopic and Microscopic Observations i RRiikLeerr LLaabboorraattoorriieess,, IInncc.. 3IM FS Te Ye rd Toor cy Sty in ts FC-I(I: Two Year Oral Toxicity-Oncogenicity Study in Rats I ai 2 Table: 2 i i To ae oy (1 Animal Number: IR-!60l Sex; Male I oe te ty Tria Sree Fate: (Wee):= 106) Terminal Sacrifice Group: (5) FC-14S iO0 ppm l [---- ---- |} ilIllI5 CrWohieinneeytvSiHyJcSwnltiyos,Cmtrorsmatso,eswroea rotfnid,esStclbeo,wwatatttn(esd8,eEmRtehimiaeiiptsSisuintlpa!sbetanTneisnsrtieaeinsyssa,,oTLfrSgiiohels,ibe,wtStnt,n1o,daitsse i Macroscopic Observations: Microecopic Observations: Arenal Kidney Liver PPaarraatthhyyrrooiidd -No visible lesions. -~SSiinruussooiiddaall eeccttaassiiaa,, ccoorrtteexr,, mmiinniimmaall -Chronic progressive nephropathy, mild -Portal mononuclsar cell infiltrate, mild Cystoid degeneration, focal, mild Megalocytosis, minimal Hepatocyte alteration, basophilic, mild -"-NHVooattsceuexlxaaammriinnmeeiddn,,ernnaoolttizaiitnnioppnll,aanneemioolffd sseeccttiioonn The followin~ tissues were found to be within normal limits: Brain, Spinal Cord~ Bone Marrow~ Spleen, Heart~ Gtomach~ Smali Intestine~ Large Intestine~ Urinmry B~adder~ Aorta~ Testis/Epididymis, Prostate, Pituitary, Thyroid~ Trachea, Esophago~ Lymph Rode (mesenterc)~ Pancreas, Sa{ivary GIaod~ E~e, Animal Rumber: 1R-~605 Sex: Mmle F~te: (Week= 106) Terminal Sacrifice Group: (5) FC-14~ 300 ppm i MMaaccrraossccaoppiicc OObbsseerrvvaattiioonnss:: [4 sa, tte Liver -Pale, mottled n Microscopic Observations: pi -- Heart -Myocarditis, chronic nons~ppurative, I sites Se aut at Kidney multifocal, minim~l -Chronic progressive nephropathy~ mild lv rt wen ch an 14 Liver -Portal mononuclear cell infiltrate, mi!d 1 es Portal bile duct proliferation, mild I ene eal ie, 4 Hepatocyte vacuol~tion, m~itifoca!, mild Erte bon, wie a4 Cyetoid degeneration, m~tifocal, mild i MMeeggaallooccyyttoaesiiss,, maiinniimaaall wn re wa 14 Lung -Vascular minera!ization~ mild I ess tsi vic sito Pneumonia, interstitia1~ chronic, multi~ocal, jomild Alveoiar macrophages, moderate l ta meio rt, tele Perivascular mononuclear infiltrate, moderate Soy ad Evin rms whe Salivary Gland -Sialadenitis, chronic, moderate 1 See toi, ect wrath Spleen -~ematopoiesis, extrameduIIary, increased, l Imild [= Hemosiderosis, mild 0 TeTsetsitsi/sE/pEiptiiddiydnyimsis -~TTuubbuullee aattrroopphhyy,, aassppeerrsmaattoog~eenneessiiss,, uunniillaatteerraall,, marked I [re-- Vascular mineralization, mild I I ces at Species: Rat 1l F!e vr cz Project Number: 0281CR0012 Sanit 56 rs 66 S~mmarized STA~ Page: 106 227700 11333377..00228811 swao0027406 3MA00027406 | Summarized Single Tabulated Animal Report (continued) Saris be tf Jd Individual Macroscopic and Microscopic Observations i RRiikkeerr LLaabboorraattoorriieess,, IInncc.. 3~M a by ty FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats I roTable: 2 1 i os Bs Sor Me Boge 9 FOS 0000 Animal Number: IR-~605 Sex: Male I i Fate: I~eek= 1061 Terminal Sacrifice Group: ( 51FC-14T 300 ppm i eet anon nt Microscopic ObserYations (continued): | HE EB LS i BBTrrhaaeiinnf,,olSSlppoiiwnniaanllg CLtooirrsdds,,ueBsBoocnweeerMMeaarrfrrooouwwn,,d SStttooomabaaecchhw,,itShSemiaanllllnorIImnnattleessttliiinnmeei,,ts;LLaarrggee IInntteessttiinnee,, UUrriinnaarryy BBllaadddteerr,, rh Se Sl er Aorta, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, i En Lymph Node (mesenteric), Pancreas, Eye. Animai Number: IR-~606 Sex: Male I Sasa Jee Fate: (Week= 106) Terminal Sacrifice I1 I Be Macroscopic ObserYations: Group: 1 51FC-14~ 300 ppm -No visible lesions. Microscopic Observations~ i hdAdrreennaall -"NNoodduullaarr hhyyppeerrppllaassiiaa,, ccoorrtteexx,, ffooccaal!,, wmiilldd i fi a Kidney -Chronic progressive nephropathy, minimal Pyeloenephritis, aaccuuttee,, wmiilldd or SeSE vn win Liver -Portal mononuclear ce!! infiltrate, mild 1 TEMega!ocytosis, minimal | ws I Lung -Vascular mineralization, mild hart DL F'arath~oid -Not e~a~ined, not in plane of section 1 wi frat Spleen -Hemosiderosis, mild | 0 LE The following tissues were found to be within normal limits; ey us tsi, Brain, Bpinal Cord, Bone Marro~ Heart, Stomach~ Small Intestine, Large Intestine, nH STehByJ nC Urinar~ Bladder, Aorta, TestisiEpididymis, Prostate, Pituitary, Thyroid, Trachea, Esophagus, | ban fr I Lymph Node imesenteric), Pancreas~ Salivary 81and, Eye. 5 Se Animal Number: IR-3607 Sex: Male Group: ! 5) FC-143 300 ppm | Sane, wi Fate: (Week= 106) Terminal Sacrifice 1 MMaaccrroossccooppiicc OObbsseerrvvaattiioonnss:: Rs wr Pituitary -Hemorrhagic mass, I ~ ~.7 cm. | Ne ti: Microscopic Observations: wm tit vette, Adrenal -Cortical vac~olation, mullifocal, moderate 1 esaretsrinn, sie m1] Fheochromocytoma, benign, uniiateral | . mmte Kidney -Chronic progressive nephropathy, miI~ a Pyelonephritis, acute, moderate 5 a SY Hyperplasia, pelvic epithelium, diffuse, mild | oeLiver -Porlal mononuclear cell infiltrate, mild or Te pm Lung -Vascular mineralization, mild |: T eyT, ware PPaannccrreeaass Alveolar macrophages, mild A-cAidnar atrophy, wmild HyperpIasia, islet cell, moderate | | -- Species: Rat |1 Se he cms Projecl Number: 0281CR0012 sear 271 Summarized STA~ Page: 107 11333377..00228822 nonce 3MA00027407 I Summarized Single Tabulated Animal Report (continued) et et aa es Brenton Individual Macroscopic and Microscopic Obsarvations 1 tone 8 Riker Laboratories, Inc. ~M I 0 To Sal To Seni Sas ps FC-1431 Two Year Oral Toxicity-Oncoganicity Study in Rats 1 on oa ae 13 7 2 A~i~al Number: IR-3607 Sax: Hale I an no on tin Fate: (Week: 106) Terminal Sacrifice Group: (5) FC-143 300 ppm Table: 2 Microscopic Observations I Totnes Pe Parathyroid Thar frie Pituitary 1 ined Toate, st, spat, rie Prostate I J Ein, eh Salivary Gland He Sars Spleen Hires a Thyroid 1I Vor se Spiet waht soe, Ts ven Urinary Bladder (continued): -Adenona -Adeno~a -Prostatitis, acuta, suppurative, marked -Sia!adenitis, chronic, moderate -He~osiderosis, mild -Ultimobranchia] cyst -Epithelia1 hyperplasia, simple, local areas, mild 1 De lig ses re fm to a srl nts The following ti~sue~ were ~ound to be within normal limits: I Ti she tr bs ov sl) pte re tin re Brain, Spinal C~rd, Bone Marrow, Heart, Stomach, S~all '.n.~e.~tl"ne, Large Intestine, Aorta, ee es Foon on nc Er Testis/EpididyBi~, Tracha~, Esophagus, Lymph Node (me~entBric), Eye. 1 Pr pe. Animal N."m~..o.'. l~_~~ ,.o Sex: ~ala I Fe Sok i Fate: (Week= 106) Terminal Sacrifice 8roup: ( 5> FC-14~ 300 ppm Hacroscopic Observations~ I a hide si, Ni ct Skin -Raised inflammed lesion, left hind footpad. re Brion: Microscopic Observations~ 1 pu Sal eas cre, wi Adrenal -Sinusoidal ecta~ia, cortex, mild I er per sav mil, wie Noduiar hyperplasia~ cortex, multi~ocal, mild im sit Kidney -Chronic progreaaive nephFopath~, minimal 2 to pola Liver -Portal mononuclaar call infiltrate, mild Tet ie asin, wid Portal bile d~ct proliferation, miid I Eis ito i Cystoid dageneration, ~ocal, mild se eas sie, 414 i Fealuctoss, sild Hepatoc~ta alteration, Me~alocyto~is, ~ild vacuolated, mild I - ne ten, sd Lung -V~cular minera!ization, mi|d he wei a Alveolar macrophagas, mild 1 Feats sates wie, vis PeriYascular mononuclear infiltrate, mild I sie in deat ae sr Skin -Pododermatitis, ulcerat~w, hind!eg, marked Toston an vai: se woe Testis/Epididymis -Tubule atrophy, aspermatogenesis, moderate 1 TThhyyrrooiidd -~UUllttiimnosbbrraanncchhiiaa!l ccyysstt I oe on oes wre fod fb it rd Ts The follo~ing tiesues were found to ba within normal limiLs: ae Sv bs Ey So ei re ei Brain, Spinal Cord, Done Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intastine, Urinary Bladder, Aorta, Prostate, Pituitary, Parathyroid, Trachea, Esophagus, I Cat ke ets Poe, Sey St Lymph Node ~me~antericl, Pancreas, Salivary Gland, ~ye. I I I -- Spacies: Rat I Ft: ams 1 Project Number: 0281CR0012 SSumomaraizend5rS1TAiR aPzgageee:! 1di0088 227722 11333377..00228833 sunconzrion 3MA00027408 I Summarized Single Tabulated Animal 8aport (continued) i Individual MaR~ciirkkoeersrcoLLpaaibbcoorraaattndoorriiMeeissc,,rosIIcnnoccp..ic ~30OMbservations FC-143: Two Year Oral Toxicity-OncogeniciIy Study in Rats I Table: 2 1 ve nr (9 546 9m Animal Number: 1R-360g Sex: Male I Fate~ IWeek= 106) Terminal Sacrifice Group: (5) FC-143 300 ppm I Macroscopic Observations; -No visible lesions. 1 MicroAAsdcrroeepnniaacll Observations: ~-NNooddsullaarr hhyyspeerrppllaassiiaa,, ccoorrtteexr,, ffooccaa!l,, wmiilldd Kidney -Chronic progressive nephropathy, minimal I Liver -Portal mononuclear ceH infiltrate, mild Porta! bile duct prolileration, mild 1 Jb Megalocytosis, mild I Lung -Vascular mineralization, mild Hemorrhage, local areas~ modmrmte 1 tk ri Se sta wh Lymph Node (mesenteric) -Sinu~oidai ectasia, mild I Pancreas -Acinar atrophy, moderate 1 PaPraartahkhyyrrooiidd "-NHPoeott~yeaexrxatanemirinnieetddi,,s,nnoomttodieinnraptplelanae ooff sseeccttiioonn I TTeestsitsi/sElpEipdiiddiyduyimsis --LLeeyyddiigg cceellll hhyyppeerrppllaassiiaa,, ffoocuaall,, wmiilldd The following tissues were found to be within norma! limits; I Brain, Spinal Cord~ Bone Marrow, ~pleen, H~art, Stomach~ ~m~ll Inte~tine~ Large Intestine, Urinary Bladder, Aorta, Prostate, Pituitar~ Thyroid, Trachea, Esophagus, Salivary Gland, Eye. I 1 nAniiamal! NNuambbeerr:: I(RR-T365i00 SSeoxc: MMaallee Fate~ iWeek= 106) Termin~ Sacrifice oGruosupt; ((15} FFEC--L1A4D3 130000 pppnm I 0 MMaaccrroossccooppiicc OObbsseerrvvaattiioonnss:: Li~er -Few pa!e loci. Testis!Epididymis -Testes appear somewhat ~icroscopic Obaer~ations: I Adrenal Kidne~ -Pheochrom~yto~a, benign, ~nilateral -Chronic progressive nephropathy, mild I i Liver iI Lung -PHHoeerpptaaattlooccymyottn~eonvvuaicccluueolalarattiicooennl,l, ismniufl!ittliitffreoacctaaeli,,, mmaiiillldd Cystoid degeneration, multifocal, mild ens, Train comic, mito, ~egalocyt~sis, minim~l -Vascular ~ineralization, mi!d Pneumonia, interstitial, chronic, multifocal, mild Perivascular mononuclear infiltrate, minimal I P~aannccr~eeaass Hemorrhage, local areas, moderate ~-AAcciinnaarr aattrroopphhyy,, wmiilldd I 1 Testis/[pididy~is -MTTiubnbueulrleaeliaazttarrtooippohhnyy,,, taaussbppueelrrasmraa,ttcosgmeienlndeessiiss,, bbiillaatteerraall~, ma~ked I ~|I,Ii SPPprreoocjjieeeccstt~ NNRuuammtbbeerr:: $02Z8811CCRR0001122 swe 473 Summarized STAR Page: 109 275 11333377..00228844 3MA00027409 | | SSuusmsmarariizzeedd SSiinnggllee TTaabbuullaatteedd AAnniinmaall ~Reeppoorrtt ((ccoonnttiinnuueedd)) i a Individual Macroscopic and Microscopic Observations 1 a i Riker Laboratories, Inc. IM I ates FC-143: Two Year Oral To~icity-Oncogenicity Study in Rats 1 RT pa ran ns Animal Number: IR-3610 Sex: Male I nr Pate: (Week= I061 Terminal Sacrifice Stoup: (5) FC-143 300 ppm i [A -- Microscopic Observations (continued): 1B 7s catkisounte, ite, iin Thyroid -C cell adenoma Follicular hyperplasia, cystic, unilateral, moderate I i pn ot ad The following tissues were found to be within normal limits: Ls ttn ors vit Brain, Spinal.Cord, Bone Marrow, Spleen, Heart, Stomach, Bmall Intestine, Large Intestine, 1 iva Fs, tn, roan, Fishin, Fetal, ate Esmi Urinary Bladder, Aorta, Prostate, Pituitary, Parathyroid, Trachea, Esophagus, B Gari fo ie hte Lymph Rode imese~teric), Salivary Gland, Eye. 1 TEI pe eR Animal Number: IR-3611 Bex: Ma!e | er Fate: (Week= I06) Terminal Sacrifice Group: ( 51FC-14~ ~00 ppm i MMaaccrroossccooppiicc COobsseerrvvaattiioonnss:: B on te it ts st 17. Liver -Few pale loci; raised pale lesion, 0.7 cm crc Gratin ph, Microscopic Observations: dia., in median lobe. i pe Fp ------ Adrenal -Sinusoidal ectasia, corte~, ~ild B gan arlesn Esophagus Cortical vacuolation, focal, minimal -Not examined~ missing 1 i LEE Sein, Heart -Myocarditis, chronic nonsuppurative~ B . RLi it, mi Kidney 1 te Jae ne Li~er mo]ti~ocal, ~ild -Chronic progressive nephropathy, mild PPeellvviicc maiinneerraalliizzaattiioonn,, ~siiotiimmall -Portal mononuclear cell infiltrate, ~ild B folderlh hi we Hepatocyte vacuoletion, multifocal, mild on pl, Cystoid degeneration, m~Itifocal, mild Hepatocyte altermtion, vacuolated, mild n fai Megalocytosi~, minimal Hyperplastic nodule 1 EE ect os, ny Cells in cords of single cell thickness. Many B A cells vaouolated. Large central blood filled ol~pace, - ---- Lung -Vascular mineralization, ~ild i pr A Hemorrhage, local areas, moderate | i Jom be Pancreas be rene Parathyroid -~cinar atrophy, mild -Not examined, missing Salivary Gland -Sialadenitis, chronic, marked I Ln SE a Extensive squame~ metaplasia of duct na n B ra TE Thyroid bherypppieetrrhppelllaaissuttmiiccw,,itsmheettsu~oppmlleaassdttuiiccctseeppoiicttchhleeulldiieuvdme.,by -Not examined, missing ! I Species: RRaatt 1I BE co Project ~umber: 0281CR0012 Sui re 227744 11333377..0022885 wnonezrao 3MA00027410 | Summarized Single Tabulated Animal Report (continued) frothing Individual Macroscopic and Microscopic Observations Riker Laboratories, Inc, ~M | TAT Ye ity Sty i ft ie:2 FC-14SI Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 i im Yous R01 Ser Mle Sgt (9) FG 0 oe Animal Number: IR-3SII Sex: Male | Bo wn iin Fate: ~ee~= 1061Termina! Sacrifice Group: (5) FC-H3 300 ppm 1 re Microscopic ObeerYations (continued): i Aol is Trachea -Not examined, missing i he tg a en bb on el The foiiowin~ tissues were found to be within norma] limits: LL ony sage tissin, Brain, Spinal Cord~ Bone Marrow, Spleen, Stomach, Small Intestine, Large intestine, | eae ste Hn oh it re), Urinary Gladder, Aorta, Testis/Epididymis, Prostate, Pituitary, Lymph Node imesenteric)~ Eye. | no ot Anim~I Number: I~-~612 Sex~ Male Fate~ IWeek= ~g) Found Oead Group: (~) FC-14~ ~00 ppm 1 MMaaccrroossccoappiicc OObbsseerrvvaattiioonns~! fi Rd sn L814 cn Liver -Multilobu!ar mass, 4.5 ~ 4 x Z cm in area | a ta iy hte right lateral lobe~ attached to wn caudate lobe. Sg Set Microscopic Observations~ | ie etc west, ec, vis Adrenal -Cortical vacuolation, focai~ minimal So ret meg aan we Kidney -Chronic progressive nephropathy, mar~e~ I hs Blip fg) Liver -Porte! ~ononudear ce!l infiltrate, mild | To Brest tion mid Portal bile duct pFoiifer~tion, mild ea on 1 HeNWpeea1l1ltocdd~iilfflffuee~rraeernnttiicaaattreecddi,,nomttarraat~eeccaullaarr ppaatttteerrnn,, ee ot sa or large area~ of necrosis within tu~or. | Lung -Vaacular mineralization, mild eis an et A1veoiar macrophages, marked Medial hypertrophy, artere~ moderate | tues Ta -Hyperplasia, islet ceI!, moderate Tos PURER Thyroid -Cyst, coiloid, mild | The foliowin~ tissues ~ere found to be within normal limitsi wea oe wats vag dul Inti, re eto Brain, 5pin~l Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large ~ntestine, um, Urinary Bladder, Aorta, TestislEpididy~is, Prostate, Pituitary, Parathyroid~ Trachea~ Esophagus, Sites Soe ey eee ee Salivzry Gland, Eye, Lymph Node Imesentericl. | es Be pe 1 Fo Animal Number: I~-$614 Sex: Male Fate: IWeek= 106) Terminal Bacrifice Group: (5) FC-I4S SO0 ppm | -- i MacrToTesescstotipisis/clEEpOpibidsdieidrdyYyanmtiiisos.ns: "-FPaallee smaasssseess oo~f vvaarriioouuss ssiizzeess iinc bbootthh tteesstteess.. We Microscopic Observations: | yori A ---- Kidney -Chronic progressive nephropath~, mild oe a Liver -Portal monon~clear ceil infiltrate, mild | ia, Cystoid degeneration, ~ocal, minimal | I SSppeecciieess:: RRaatt |i Fo ie: cons ~roject Number: 0281CR0012 Sores pu 11 275 Summarized BT~ Page: 111 275 11333377..00228866 wncoozrars 3MA00027411 n Summarized Single Tabulated Animal Report (continued~ Individual Macroscopic and Microscopic Observations | Riker Laboratories, Inc. SM FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: Animal Number: IR-~614 Sex: Male I Fate: (Week= I06i Terminal Sacrifice Group: (5) FC-14S 300 ppm i [I ------ Microscopic Observations (continued): B Lung -Vascular mineralization, mild Alveolar macrophages, mild Prostate B Spleen 1i ean em, iis Testis,~Epididy~is -Rot mxamined, missing -He~osiderosis, mild -Tubule atrophy, asper~atogenesis, unilateral, moderate Leydig ce]l adeno~a, ~nilateral B The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Heart, Stomach, Small Intestine, Large Intestine~ Urinary B1adder~ Aorta, Pituitary, Adrenal, Thyroid, Parathyroid~ Trachea, Esophagus, Lymph Node (mesenteric), Pancreah Salivary Gland, Eye. H Animal Number: IR-3615 Sex: Male F~te: (Week= 106) Terminal Sacrifice i TO ---- Macroscopic Observationsl I Pituitary Group: (5) FC-143 300 ppm -Mass, O.B cm dia. i Testis!EpididyBis Microscopic Observations: Adrena] -Right testis sma11. -Sinusoidal ectasia, cortex, mild i I LiLKviivdeenrrey iI Lung -"-FPCeohrrrttoaanllicmaospnrroeonng~urccellseesa~irrveccean!le1lphriionnpffaiitllhttrrm,attee~~,ode~miirlladdte Cystoid degeneration, multifocal, mild iv comin, 14 Megalocytosis, minimal -Vascular ~nera!ization, ~ilJ Alveolar macrophages, mi!d Hemorrhage, local areas, mild Parathyroid -~ot examined, not in plane of section Pituitary -Adenoma I Salivary Bland -Sialadenitis, chronic, marked i eeEppxiitttehhneesliiivnueam..hyperplasia and metapla~ia o{ duct Spleen -Hemosiderosis, mild I TestisiEpididymis -Tubule atrophy, aspermatogene~is, uoil~teral~ 1 --marked B The following tismues ~ere found t~ be within normal limits: Brain, Spinal Cord, Bone Marrow, Heart, Stomach, Small Intestine, Large Intestine, B Urinary Bladder, Aorta, Prostate, Thyroid, Trachea, Esophagus, Lymph Rode (mesenteric), Pancreas, Eye. .................................................................................................. I I Species: Rat I1 es asco Project Number: 0281CR00~2 wisn 276 Summarized STAR Page: 112 276 11333377..00228877 3MA00027412 | Summarized Single Tabulated Animal Report (continued] Ln a Individual Macroscopic and Mioroscopic Observations 1 et on Riker Laboratories~ Inc. 3M i Fo Te on St et FC-143~ Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 1 rar TL Sr rR Animal Number: I~-3&16 Sex: Male i i Pate: (Week= 721 Found Dead Group: (5) FC-143 ~00 ppm 1 Rersosc Bertions: Macroscopic Observations: I pitt ret oats Pituit~ry A Microscopic Observations: 1 os ric pegs pity, sn Kidney I is rei rere rnwn Liver 1| I. Jtereenpimrlema wees, Lung | us e ee r Pancreas fees ar Pituitary I i win Salivary Gland SpSlp!eeeenn -Enlarged, 0.~ cm dia. -Chronic progressive nephropathy, minima1 -Portal mononuclear cell infiltrate, mild Hepatocyte vacuolation, m~Itifocal, minimal Cystoid degeneration, multifoca~ mild Necrosis, multifocal, moderate -Vascular mineralization, mild Al~eolar macrophages, mild Hemorrhage, diffuse, ~ar~ed -Hyperplasia~ acinar cell, moderate -Adenoma -Not examined, missin~ H-Heeamcossiiddemrrcossiiss,, x~iilldd i ---- Ths following tissues were found to be within normal limit~: i Fain Spe uty oe oro Hers Soi Sn Wbstine, Lire Intestine, Brain, ~pinal Cord, 8one Marrow, Heart, Stomach, ~mall Intestine, L~rge intestine, | Urinary ~B!laddeur, f~ortsa~, Te~stis[/Epididyw~ais, Prostate,~ R~drenal, Thyroid, Parathyroid, Traces, ' a, i ea Esophagus, Lymph Node imesenterici, E~e. i Cavan an ee ~nima! Number: ~8-~618 Sex: Male Sasa ni Ju . Fate: (~e~k: 106) Terminal Sacrifice Group: ( 51FC-!4~ SO0 ppm 1 sc ratios Macroscopic Observations: | io prs it it it i Liver -Appears pale; pale raised mass, i cm dia., i caodate lobe. 1 Wersos Gherations Microscopic Observations~ | wo ---- Adrena! -Cortical vacuolation.~ multifocal: mild frente Binusoidal ectasia, cortex, mild 1 wor a Kidney -Chronic progressive nephropathy, mild | ge nL Liver -Portal mononuclear cell infiXtrate, ~ild a, Hepatocyte vacuolation, mul~fo~a., minimal i NNeeccrroossiiss,, ffooccaall,, smiinniimeaall ants, Megalocytosis, minimal | oe Hepatorel luIar carcinoma Cn Trabecular pattern, many tumor ce!ls vac~oiated, moderate mitotic activity. | " nn Lung -Vascular mineralization, miId To Alveolar macrophages, mild 1'| ei ts ws ot 1 itn cn tn The following tissues were found to be within norma~ limits: Dale od EE US, re tin, Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, | I Species: RRaatt 1I aid Project Number: 0281CR0012 sori sp Summarized STAR Page~ II~ 227777 11333377..00228888 wnonezraa 3MA00027413 i Summarized Single Tabulated Animal Report (continued) B Individual MaRRciirkkoees~rcoLLpaaibbcoorraaattndoarriiMeeissc~,rosIIcnnoccp..ic ~3OMbservations FC-143: Tmo Year Oral Toxicity-Oncogenicity Study in Rats | Table: 2 i rl ha To eat (51 Fe Animal Number: IR-3618 Sex: Male Group: (5) FC-143 300 ppm i Fate: (Week= i061 Terminal Sacrifice Microscopic ObserYations icontinued): I The following tissues were found to be within normal limits (continued): 1 UEErssioonppahhraaygguussB,,ladLLdyyesmrsp,hh ANNooordtteea,((nmTeeessseetnnittseetrrEiipcci)),d,idPPyaamnniccsrr,eeaassP,,rosSStaaalltiievv,aarryPyitGGulliaatnnaddr,,y,EEyyeeT..hyroid, Parathyroid, Trachea, | Animal Number: IR-3619 Sex: Male Group: I 5) FC-143 300 ppm | Fate: ~Week= !06) Terminal Sacrifice Macroscopic Observations~ | net i LKdiivedeneresy ---RHHayridtsrreoadnneeplpheirsrioaossnisss,,, 2Lleexfit1.ik5iddacnsmey,y.. ~edian loses. Urinary Bladder -Distended into abdomen, filled with dark colored Fluid. Microscopic Observations~ Adrenal -Sinusoida] ectasia, cortex, mi!d i Nodul~r hyperplasia, cortex, focal, moderate Kidney -Chronic p~ogressive nephropathy, minimal 1 ma Hydronephrosis, bilateral, mild i Liver -Portal mononuclear cell infiltr~te~ mild Cystoid degeneration, multifocal, mild 1 MMeeggaallooccyyttoossiiss,, maiilld Hepatocellular carcinoma i Poorly differentiated, adenoid and trabecular | Lung patterne, moderate mitotic actiYity. -V~ecular mineralization~ mild Hemorrhage, local areas, moderate Salivary Gland -Not examined, mis~ing | Urinar~ ~iadder -Epithelia1 hyperplasia, simple, diffuse, mild Hemorrhage, focal, minimal | i TThhee ffoelllloowxiinngg ttiissssueeess wweerree ffoouunndd ttoo bbee wwiitthhiinn nnoorramaall lliimmiittss:: Brain, Spinal ~ord, Bone Marrow, Spleen, Heart, Gtomach, Small Intestine, Large Intestine, Aorta, Testis/Epididym~s, Prostate, Pituitary, Thyroid, Parathyroid~ Trachea, Esophagus, i Lymph Node (mesenteric}, Pancreas~ Eye. Anima! Number: IR-~621 Sex: Male Group: ( 5] FC-143 300 ppm Fate: (Week= 106) Terminal Sacrifice | Macroscopic Observations: -No visible lesions. i MMiiccrroossccooppiicc OObbsseerrvvaattiioonnss:: | Kidney -Chroni~ progressive nephropathy, minimal i i Species: Rat |i Ep Project Number: 0281CR0012 seis 10 278 Summarized STAR Page: 114 278 11333377..00228899 3MA00027414 | Summarized Single Tabulated Animal Report (continued) | i Individual MaRBciirtkoeersrcoLLpaaisbcoorraaanttdoorriiMseissc,,rosTIcnooccp,,ic 33OMbservations FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 i Animal Number: I~-3621 Sex: Male Fate: (Week= I06) Termnal Sacrifice Group: (5) FC-143 300 ppm- | Microscopic Observations (continued!: Liver -Portal mononuclear cell infiltrate, ~ild | i Lung Parathyroid MRCeeygsgataloloiscdcyptdtoessgiiessn,,eramatiiillodn, multifocal, miXd -Vascular mineralization, ~ild -Not examined, not in plane of section | Salivary Gland Spleen -Sia!adenitis, chronic~ moderate -Hemoeiderosis, mild | The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, HeBrt, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, TestislEpididymis, Prostate, Pituitary, Adrenal, [byroid, Trachea~ Esophagus, Lymph Node (mesenteric), Pancreas, Eye. | .............................. T ................................................................... Animal Number: IB-~623 Sex: Male Group: (5) FC-14~ 300 ppm Fate: (Week= 106) Terminal Sacrifice Macroscopic Observations: i -No visible lesions, i MicroSAsadcrorepmniaca! Observations: -"CCoorrttiiccaall vvmacs~loaltatiieonn,, ffoeccaall,, mlildd | Sinusoida! ectasia, cortex~ moderate Kidney 0 LiLviveerr -Chronic progressive nephropathy, mild ~-PPaorrttaall amcorncoonuucclleeaarr ccee!lIl iinnffiillttrraattee,, maiilldd Hepatocyte vacoolation, mild | Necrosis, multifocal, mild | Lung Megalocytosis, minimal -Vascular mineralization, mild Pneumonia, interstitia], chronic, multifocal, | 1 AHmliivvleedosllaarr s~aaccrroopphhaaggeess,, maiilldd Lymph Node (mesenteric) -Hemorrhage, m~Id Pituitary -Not examined, missing Prostate Salivary Gland | lestislEpididymis -Prostatitis, acute, s~ppuratiw, ~od~rate -Sia!adenitis, chronic, marked -Vascu!ar mineralization, mild 1 Ie gts rt 03 it srl ns: The following tissues were found to be within norma! limits: | Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, ~rinary Bladder, ~orta~ Thyroid, Parathyroid, Trachea, Esophagus, Eye, Pancreas. | i | Species: Rat |1 Project Number: 02BICRO0]2 Sass 1 279 Summarized STA~ Page: 115 279 11333377..00229900 3MA00027415 | Summarized Singls Tabulated Animal Report (continued) frm sim ig Soins i Individual MRRaiickkreemrrscLLoaapbbicoorraaatntdoorriiMeeissc,,rosIIcnncco,.pic 3~OM bservations FE TY BlTo ete Sty ts FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats | ae2 Table: 2 Animal NumBer: 1R-3624 Sex: Male Group: (5) FC-143 30~ ppm | tr awit Fate: IWeek= gO~ Sacrificed in extremis 1 Pans iio: Macroscopic Observations; i i re wn 1403 8 Pituitary -Hemorrhagic mass, ! x 0.5 cm. js Fait Liver 1 KKiiddnneeyy -Possibly pale ~-SSl~iigghhttllyy eennllaarrggeedd aanndd ppiitttteedd., sons er a, Testis!Epididymis -Both testes appear somewhat sm~ll. I Oo Microscopic Observations: on FE ---- -Cortical Yac~olation, multifoca!~ mild Medullary cell hyperplasia, mo]tifocal, mild | or ] ~oney -Chronic progressive nephropa~hy~ moderate a i Th Liver -Portal mononuclear ceil infiltrate, mild 1 en Hepatocyte ratio|alton, periporta!, moderate | - sm -Vascular minerali~ation~ mild rears rsh, rie, wit, Pneumonia, interstitia1~ chronic, multifoca1~ poymild i het whe, itil, id Alveolar aacrophages~ m~Itifocal, mild | nasty ov Pituitary -Adenoma ra Sresitn, uate, sarin, rie Prostate -Prostatitis~ acute, suppurative, marked | Tetsaenis Tie tn, svg later Testis!Epididy~is -Hemosiderosis, mild -Tubule atrophy, aspermatogenesis, bilatera]~ --marked 1 I A Si A SAL The following tissues were found to be within normal limits: | ine Soe ns ov rn i, Soy ul} pine, re sie Brain, Spinal Cord~ Bone Marrow, Heart, Stomach, Small Intestine, Large Intestine, ry His te opt, Fes Fan Ein ol teil Urinary Bl~dder, Aorta, Thyroid~ Parath?roid, Trachea, ~sophagus, Lymph Node 4mesenteric)~ i Furies, Salivary Sit, re. Pancreas~ Salivary Gland, Eye. | en a ern (9 7 Animal Number: IR-3625 Sex: Male Group: (5) FC-143 300 ppm 1 tins aa F~te: (We~k= 27) Sacrificed in extremis | [-- Macroscopic Observations: 1 Lie: ag iti i, 7183 ct, Soft Tissues ~neck) i| sien rToTooiykitoyntso oomiiyesn osoiot Spleen Nees Gunton: Microscopic Observations: 1 i PO -- Liver |II - re eeyainn tsao--na--ayaonneni.r ly Lung -Large multinodular mass~ g x 8 x 6 c~ in left neck a~d throal region. Possibly of mammary gland or salivary g!and origin. Mass contained severai cystic areas that w~re fi!led with dark ~i~id. -Possibly ~light!y enlarged. -Portal mononuclear cell in{iltrate, mild Necrosis, focal, mild Mega]ocytosis, minimal -~etastatic neoplasm Thrombus Large thrombus containing t~mor ceI1~ ~rom salivary gland t~mor. ~ultiple small metastases of salivary tumor throughout lung. I --_---- S~ecies: Rmt Ii Eo' -- Project Number; 0281CR0012 Sourirs st a 116 228800 11333377..00229911 awncoozrars 3MA00027416 Summarized Single Tabulated Animal Report {continuedi fraying Individual Macroscopic and Microscopic Observations B RRiikkeerr LLaabboerraattoarriieess,, IInncc., 3~ FEA: Ts Yor al To nei Sy Bt FC-I 3; Two Year Oral Ioxicity-Oncogenicity Study in Rats ie:2 Table: 2 Animal Number: IR-3625 Sex: Male Group: (5) FC-143 300 ppm Be tc iets Fate: (Week= 27) Sacrificed in exbremis 1 ye retin tint Microscopic Observations (continued); pth wei Salivary Gland -CarcinoMa ie ihr, tc tr. ors Highly cellular, anaplastic tumor. ~ppears to i Mhaavvee aarriisseenn iinn ppaarroottiidd ggllaanndd dduucctt.. SSmmaallll rriime Patra did bey of salivary gland tissue around mass. Siew ce sy Spleen -Hematopoiesis, extramedullary, increased, 1 -- moderate ia iy st AO AL The following tissues were found to be within normal limits: Be a tae we, Si Wie Lg en, Brain, Spinal Cord, Bone Marrow, Kidney, Heart, Stomach, Small Intestine, Large Intestine, 5 in ts wt on apn, abt, ort, sony rt Fast Urinary B1adder~ Aorta, Teetis[Zpididymis, Prostate, Pituitary~ Adrenal~ Thyroid~ Parathyroid, ee a Cama a Tr~chea~ Esophagus, Lymph Rode (mesenteric), Pancreas, Eye. I a ---- orn Ankma~ Number: I~-362B Sex: Male Group: (5) FC-i43 300 ppm el ra en Fate: (Week= 106) Terminal Sacrifice Nessa Bertin: Macroscopic Observations: B ---- -No visible lesions. Microscopic Observations: gL totic citi fc, ste i Adrenal KKiiddnneeyy -Cortical vacuo]ation, focal, moderate ~-CChheraonniicc pprrooggrreessssiivvee oneepphhrrooppaatthhyy~, m~ooddeerraattee or eon Liver -Portal mononuclear cell infiltrate, mild eth roi it Portal bile duct proliferation, mild a dpm rh ss i CMRyeesgtagolioadclytdooesgsiesn,,erammtiiinnoiinmm~aallmultifocai, mi!d - iin, wis Lung -Vascular mineralization, moderate oh et Alveolar m~crophages, mild 1 em te Hemorrhage, local areas, moderate ras et veo ion Parathyroid -~ot examined, not in plane of section fe Tonio Spleen -Hemosiderosis, mild 1 SO -- The ~oilo~ing tissues were found to be within normal limits: in ser an onc a tiv, Lr ti Brain~ Spinal Cord, Bone Marrow, Heart, Stomach, Small Intestine, Large Intestine, Sy Sa te ei se on an Ton sn Urinary B1adder~ Aorta~ Testis/Epididymis, Prostate~ Pituitary, Thyroid~ Trach~a~ Esopnagus~ Lymph Node (mesenteric), Pancreas, Salivary Bland, Eye. 1 cFienautr 2 Species: Rat Project Number: 02BICRO012 11333377..00229922 Sie 5 ie 17 281 Summarized STAR Page: 117 281 awncoozrarr 3MA00027417 I Summarized Single Tabulated Animal Report (continued) Be i Individual Macroscopic and Microscopic Observations i FRiikkeerr LLaabboorraattoorriieess,, IInncc.. 3SM1 5 To a eo ey Ss ts FC-143: Two Year Oral Toxicity-Oncogenioity Study in Rats I oe 2 Table: 2 I1 it eesoBeSn Sterielne og (9) FOE 90 .................................................................................................. Animal Number: IR-3629 Sex: Male Fate: (Week= I~6) Terminal Sacrifice Stoup: (5) FC-143 300 pp{ 1 MWaaccrroossccooppiicc sObesrevraYtatiioonnss:l I I -No visible lesions. gi Microscopic Observations: 1 HHeeaarrtt "-MMyyooccaarrddiittiiss,, cchhrroonniicc nnoosnssz~ppppuurraattiivvee,~ as multifocal, mild I ior Bn Wn -Chronic progressive nephropathy, ~ild i rn tt -Portal mononuclear cell infiltrate, mi!d Megalocytosi~, mild I - ton 34 Lung -Vascular mineraIization~ mild pres Alveolar macrophages, mild 1 tts Hemorrhage, local areas, moderate I po tir rors we 5aliwry Gland -Bialadenitis, chronic, ~arked Hoo Jick ion Thyroid -U1timobranchial cyst 1 he lig ttt re fd 1 with srl ls The following tissues were found to be within normal limits: I Edt warn Ses a ul tine ure ttn, Brain, Spinal Cord, Bone Marrow, Spleen, Stomach, Smal! Intestine, Large Intestine, int rte Tosti esto He, ins Peabo Urinary Bladder, Aorta, Testis/Epididy~is, Prostate, Pituitary, Adrenal~ Parathyroid, Trachea, Esophagus, Lymph Node (mesenter~c), Pancreas, Eye, I re ve wep (8 on Animal Number: IR-36S0 Sex: Male Stoup: (5) FC-143 SO0 ppm i FFaattee:: ({MWeeeekks= 110068)) TTeerrmiinnaall SSaaccrriiffiiccee I se Bm Macroscopic Observations: 1 [-- oie Microscopic Observations: I oa ---- Adrenal - i Sot, Two 6 Heart 1I ur SHe eaenerelet wats, id Liver 1I wr e reetartn na,pn) m1o4s st Lung Pty a ty Pituitary TestisiEpidldymis -No visible lesions. -Sinusoidal ectasiB, cortex, mild -Myocardial fibrosis, local areas, mild Myocarditis, chronic nonsuppurative, local areas~ mild -Portal mononuclear cell in~i]trate, mild Cystoid degeneration, multifocal, mild Megalocytosis, minimal -V~scular mineralization, m~Id -Not exa~ined~ ~issing -Vascular mineralization, mild I he lig tes re tt ee mit srl ts The following tissues were fouod to be within normal limits: 1 or Bor L an stn, Lge he, Brain~ S~inal Cord, Bone Marrow, Bpleen~ Kidney, Stomach, Small Intestine, Large I a en, Urinary Bladder, Aorta, Prostate, Thyroid, Parathyroid, Trachea, Esophagus, 2 ee He Lymph Node {mesenteric), Pancreas, Salivary Bland, Eye. I I I -- Species: Rat Ii ee oer: zon2 Project Number: 02BICRO012 Sunrises ue 1 Summarized STAR Page: 118 228822 11333377..00229933 awncoozrars 3MA00027418 I Summarized Single Tabulated Animal Report (continued] Ste Individual Macroscopic and Microscopic ObserYations i RRaitkeerr LLaabvoorraattoorriieess,, IInncc.. 33M es st 1s FC-143~ Two Year Oral Toxicity-Oncogenicity Study in Rats B et Table: 2 Animal Humber: IR-3631 Sex: Male H great ak Fate: (Neek= I06) Termin~l Sacrifice Group; (5) FC-143 30(~ ppm 1 I Macroscopic I A -No visible lesions. seh ania i Microscopic Observations: kAddrreennaall -"NMoodduullaarr hhy~ppeerrppllaassiiaa,, ccoorrtteexx,, ffooccaal!,, wmiilldd ed veep soi Medullary cell hyperplasia, focal, minimal I weer ther ll ans fo, Kidney -Chronic progressive nephropathy, mild on I Liver -Portal menonuclear cell infiltrate, mild Portal bile duct proliferation, mild B Le Hepatocyte ~acuolation~ local area~, mild ig i Lunngg -"MVdeaa~ssacc!uaollcaiyrrtomwsiiinn~ee,rraamlliiinz~iaamttaiiloosn,~ msooddeerraattee ls pn AIYeolar macrophages, mild m iho ng He~orrhagh local areas, moderate ---- rn rl, i Salivary 61and -~ialadenitis, chronic, marked 1 hee ave bo sci of shin on the There were two sections o~ gland on the I ae slide, on]~ one was invoIYed. ' i. Feit -Hemosiderosis, mild B SP ------ The follo~i~ tissues were ~ound ~o b~ within normal limits~ no nin, i UBrrianian,ry SpBilnadadlerC,ordf,ert8ao,neTeMsatrriosw/,EpiHdeiadryla,isS,~oP~racohs~tat~em,allPitIunitteasrtyi,ne,ThyLraorigee, IPnatreastthiynreo,id, Trachea, Urinary ~ladder, Aorta, Testis/Epididymi~, Prostate, P~t~itary, Thyroid, Paraihyroid, Trachea~ er Esophagus, Lymph Node (mesenteric), Pancreas, Eye. I PRERTEN Pp Animal Number: IR-~632 Sex: ~ale Fate; (Week= 106) Terminal Sacrifice Group; I 5) FC-143 300 ppm B asic tanto: Macroscopic Observations; 1 wr wn, Liver | OSWons Tn Testis/Epididymis -Few pale foci. -Pale mass, ].5 cm dia. ~icroscopic Observations~ 1 iKiddnneeyy -"CChhrroonniicc pprrooggrreessssiivvee nneesphhrrooppaatthhyy,, wmooddeerrattee ie rk rere Liver -Portal mononuclear cell i~filtrate~ mild B a wars whe Hepatocyte vacuolation, moltifocal, mild ter peels Megalocytosis, mild Hepatocyte alteration, basophilic, mild B pe devi,bets a Single s~bcapsular area of basophiiic LS 1 wamlautllettriiapptllieeoncc.yyttoopAplbloaausstamiicconevvaahccausloc~lleesso..~ ~he cells have ws le ctelis ce Lung -Vascular mineralization, ~ild I TE Alveolar macrophages, mild 1 i eo Hemorrhage, ~ocal~ ~ild i J mr, 2 ene Pancreas -Hyperplasia, islet cell, ~oderate B n Species: Rat 1n SEProject R~mber; 0281CR0012 wisn 283 Summarized STA~ Page; I19 11333377..00229944 wnonezrae 3MA00027419 I Summarized Single Tabulated Animal Report !continued) I Individual MacrosEmpic and Microscopic Observations Riker Laboratories, Inc. 3M FC-143~ Two Year Oral Toxicity-Oncogenicity Study in Rats Table: 2 B Animal Number: IR-3632 Sex~ Male Fate~ IWeek= I06) Terminal Sacrifice Group; I 5} FC-143 500 ppm 1 Karenos Bertin tins Microscopic Observations (continued)~ 1I 3 sn Testis!Epididymis -Tubule atrophy, aspermatogenesis unilateral, marked Leydig cell adenoma~ unilateral I The following tissues were found to be within normal limits: i Brain, Spinal Cord, Bone Marrow, Spleen, Heart, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenkeric), Salivary Gland, lye. I Animal Number:...-~ ~c~ Sex: M~le F~te: IWeek= 106) Terminal Sacrifice group: (5) FC-143 300 ppm i MFaaccrroossccooppiicc sObesrevravtatiioonnss:~ Eye -Opacity, right eye. i Kidney -Bilaterally pale and pitted. Microscopic Observations: a [re Sait ati, contr, wie Adrenal -Sinusoidal ectasia, cortex, mild / 8anglioneu~oma Large, well differentiated tumor arisinB in ' Se medulla o4 one gland. Composed of nerve i fibers and large ganglion ceils. i HeHEaeyraetr.t -"-MBKyyeoercc~aatrriddtiiittsii,ss,,chcrchohrnrioocnn,iicc msnooodnnesrsuauptppepuurraattiivwe~, i Kidney local area~, mild -Chronic progressive nephropathy, marked B Liver One of pair present -Portal mononuclear cell infiltrate, mild Portal bile duct proliferation, mild n 1 Lung CHHyeespptaaottioodrcyytdteeegeaanllettreearrtaaittoiinoo,nn,,muv~!aitcciuwfololacatatelet,d,, mim3li1dl0d Megalocytosis, moderate -Vascular mineralization, m~Id | Alveolar mmcrophages, mild Perivascular mononuclear infiltrate, minima! Hemorrhage, local areas, mild i Thyroid -Cyst, co!!mid The following tissues were found to be within normal limits: I i UUBrrriianinana,rryySBBplliaandatdlteerrC,,ordAo,orrttBaao,,nTeTeeMssattriirsso/wE,EppiidSdipilcdeyyeamnii~ss,,StPoP~mroaocsshtt,aatteeS,,maPPli!ittuuIiintttaaerrsyyt,,inePP,aarraaLttahhryygrreooiiIddn,,teTTsrrtaaiccnhehe,eaa,, EEsxocpihhaa~guuse,, Lymph Node (mesenteric], Pancreas, Salivary 81and. i I Species: Rat | iste AN 1 Project Number: 02~ICR0012 SSuumnmearriizzeedd S~TTA~ PPaaggee:: 11200 2~844 11333377..00229955 3MA00027420 I | i B 1 i iI | i I 1 B B 1 n B 1 n |B| B B | I B B 1 Summarized Sing]e Tabulated Animal ~e~ort (contin~edl ~ndi~id~al MaRSciirkkoeesrrcoLLpaaibbcoorraaanttdaorriiMeeissc,,rosTIcnooccp,,ic 33OMbservations FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Ra Animal Number: 1R-3634 Sex: Ma!e Group: (5) FC-143 300 ppm Fate: (Week= I~6) Terminal Sacrifice Table: 2 Macroscopic Observations: TestisiEpididymis -Pale masses, tcm dim., in each testis. MMiiccrroossMcceoosppeiinccteDOrhbysseerrvvaattiioonnss:: -Mass, 3 x 1.5 cm in area of pancreas. Liver -Portal aononuclear cell infiltrate, mild a Cystoid degeneration, multifocal, mild Hepatocyt~ alteration, vacuolated, moderate Megalocytosis, minimal - Lung Ay ne -Vascular mineralization, mi!d Alveolar macrophages~ mild -Adenocarcinoma Large, highl~ cellular, well differentiated neoplasm with high mitotic index. L~mphatic invasion. Parathyroid -Not examined~ not in plane o~ section Spleen -~emosiderosis, mild Testis/Epididymis -Tubule atrophy, aspermatogenesis~ bilateral, marked te tn sr to 30 i sd nt: Leydig cell adenoma, bilateral The following tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow~ ki~neh Heart~ Stomach, Small Intestine~ Large Intestine, LLUyrimigpnhhar~cNoedBeiadl(dnmeeerss~eenttAeeorrriitccah},,, PSSraaollsiitvvataaerr,yy BGPlilatanudi,,tarEEyyye,e., AdrenaI~ Thyroid, Trachem, Esophagus, Animal Number: IR-36~5 Sex: Male Fate: (Week= 106) Terminal Sacrifice Group: (5) FC-14~ 300 ppm Macroscopic Observations: MMiiccrrooPssicctoouppiiictcarOOybbsseerrvvaattiioonnss:: Adrenal Kidney Liver Lung Pituitary Salivary Gland -Hemorrhagic area, 0.5 x 0.2 cm. -Medullary cell hyperplaeia, focal, mlnimal -Chronic progressive nephropathy, mild -Portal mononoclear cell infiitrate~ Megalocytosis, minima] -Vasculao mineralization, mii~ Alveolar ma~r~pha;es~ mild Pe~ivasz~la~ mononucl~ar infitrate, ~i~imal -Sialadenitis~ chronic, marked The following tissues were foL~d t~~~=" within norma! limits; Brain, Spinal ~or~, Bona Harrow~ ~=~'ee,,~, Heart,. Stomach,. SmaI! Intestine,. Large Intestine, SPFprreoocjjieeeccstt~ NNRusambtbeerr:: 0$228811C0R800001122 Summarized STAR Page: 121 285 11333377..00229966 3MA00027421 R tn i ti i gt tit Summarized Single Tabulated Animal Report (continued) Sr poe i an el ns Indiddual Macroscopic and Nicroscopic Observations 5 ei Riker Laboratories, Inc. 5M | eats re SR ty FC-14~1 Two Year Oral Toxidty-Oncogen~city Study in Rats 1 Pa wt Animal Number: i Eee Fate: (Week= ~6, Terminal Sacrifice Group: (5) FC-143 300 pp~ Table: 2 1 [A ---- Microscopic Observations (continued)I I ne BETTIEEE nts rat: The foiio~ing tissues ~e~e found to be within noted limits (conti~uedi: 5 E DEITA IES I Sine Urinary Bladder, Aorta~ ~est"i"e.'Epi' dl"dv~,~s, Prostate, Thyroid, Parathyroid~ Trachea~ Esopha~u% | i p-- Animal Number: IR-363~ Sex: Male a Sl F~te~ !Week= 106) Te~m~nml Sacrifice Group: (5) F0-143 300 ppm i po Rp: Bone -Swollen metatarsal joint~, bilateral hind lim~s. I -- Zum -Both testes a~pear ~icroscop~c Observations: i Sone. ~-Arrtthhrriittiiss,~ ssyynmoovviittiisss; jjooiinnttss,, hbiinnddlleegg,, po moderate I wt Te re meetin, Heart -Myocarditis~ chronic nons~ppurative, food, minima! 8 tity <r pregremive syrepthy, wives Kidney -Chronic progressive nephropathy, minimal i er rm pe vy Liver -Portal mononuclear cell infiltrate, mi!d To ah le Portal bile duct pro!i{eratio% Gild 5 ee pai Cysboid de~eneration~ {oca!~ minimal men Megalocytosis~ minimal i I. JBL ne 1 Lun~ -Vascular mineralization, mild AAllvveeoallaarr msaaccrroopphhaaggeess,, mwiilldd i i ts tr ote Lymph Node {~esentedc) -Granuloma~ mult~{ocal, ~oderate me Sle Pancreas -Polyarteritis, moderate 2 sans Tr pes, st, Testis!Epididy~is -Tubule atrophy, aspermatogenesis, bilatera!~ | ioe A marked Vascdar mineralization, mild |1 loi ssn a tite cd tin The following tissues were found to be within normal limits: De ee Uy ee Brain, Spinal Cord~ Bone Marrow~ Gpleen~ Stomach, Smal! Intestine~ Large Intestine~ Dn mL Tm So SU nt WR SU on Urinary B~adder~ Aorta~ Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, | Sin sr i Salivary Gland, Eye. i n n | yi Species: Rat 1i Jn cn Project ~umber: 0281CR0012 Souci rem 28.6 Summarized STAR Page: 122 286 11333377..00229977 nonce 3MA00027422 i Summarized 5ingle Tabulated Animal Report (continued) I Riker Laboratories, Inc. 3M FC-14~: Two Year Oral Toxicity-Oncogenicty Study in Rats Table: 2 | Animal Number: IR-~6~7 Sex: M~le Fate: IWeek= 106) Termina! Sacrifice 1 J Macroscopic Observations: i Thyroid Group: I 5) FC-14~ ~00 ppm -Possibly ~li~htly enlarged. Pituitary -Hams, 0.5 c~ dia. Thymus -Slightly enlarged and h~morrhagic. i Microscopic Observations: 1 Heart -Mwm~iuollcttaiirffdooicctaail~~,,, mwciihnnriiomsnaail!c non~uppurativm, -Chronic progressive nephropathy~ minimal a Liver -Portal mo~onuclear cell infiltrate, mi!d Portal bii~ duct proli~eration~ ~ild i rei, wn, wie Ne~ro~is, multi~ocal, moderate | Lung -Vascular ~inerali~ation, ~iid Hemorrhage, !ocal areas, moderate 1 ves provipogbint Pancrea~ -Acinar atrophy, minimal i Pituitary -Aden~ma | Salivary Gl~nd -Not examined~ missing i TThhyysmuuss -HHeeamoorrrrhhaaggee,, mmaarrkkeedd The ~ollo~ing tissues were ~ound to be within normal limits: ! ~rain, Spinal Cord, Bmne Marrow, Spleen, Stomach, Sma11 Inte~tine~ Large I~te~line, Urinary ~iad~er~ Aorla, TestislEpididy~is~ Prost~te~ Adrenal, Thyroid, Parathyroid, Trachea~ Esophagus, Lymph Node (mesenteric)~ Eye. I i dial Nother: (IT Ser: Male GBrroeuappt: ((55)) FFLCA-L1G433 33000) ppppm I i Macroscopic Observations! Pituilary -Raised dark mass, 0.7 cm din. Adrenal -Enlarged~ right adrenal I Microscopic Observations: Adrenal -Cortical vacuolation, local areas~ ~oderate Sinusoidal ectasia, cortex, marked B FiKtidnneeyy Liver i|1 Lung -H.MiMenidenurelarllaalirizyzamtctieiolonln,,hyccpooerrrttpii1cc~aaslli,,a~maiiflloddcal, mild -Portal mononuclear cell infiltrate, minimal Piva samo ile, wi -U~mcular mineralization, ~ild ~!ven!ar macrophages~ mild Periva~cular mononucle~r infiltrale~ mild Hemorrhage, local areas, moderate I Sranuloma Fragment of unidentified foreign material in granuloma. I | Species: Rat I Proj; ect Number: 0281CR0012 BSumamarriczeod STiAtR ages Page: 111 !23 228877 11333377..00229988 3MA00027423 ! BI il l i I | l l t - Summarized Single Tabulated Animal Report Icontinued) Individual MRaickreorscLoipdiocraatnodrdMeisc,rosIcsco,pic3Observations Riker Laboratories, Inc. ~M FC-14~: two Year Oral Toxicity-Oncogenicity Study in Rats Fate: ~Week: 1061 Terminal Sacrifice enGroup: TER 5} FC-143 300 Microscopic Observations (continued): Pancreas PiPtauriatthayrryoid Spleen -Not examined, missing --"NAdodeternooenmxeaamined, not in plane of section -Hemosiderosis, mild The fo]~owin~ tissues were found to be within normal limits: Brain, Spinal Cord, Bone Marrow, Heart, Stomach, Small Intestine, Large Intestine~ Urinary Bladder, Aorta, Testis/Epididymis, Prostate, Thyroid Trachea, Esophagus, Lymph ~ode (mesenteric), Salivary 81and. Eye. Macroscopic O~servations: SpSlpleeeenn ~bdomen (internal] Eye Microscopic Observations: AAddrreennaall Eye P-PoossssiibblIyy ssmeaallleerr than noorremaall.. -Gastrointestinal tract from stomach to cecum distended with gas. -Right eye slightly atrophied N-Noodduul!aarr hhyyppeerrplasia, corrtteerx,, ffoozcaall,, msiinniismaall -keratitis, acute, marked Lesion in right eye. Extensive cornea1 Kidney Liver ulceration. -Calculus, pelvic, mild -Portal mononu~lear ce!l infiltrate, milO Lung Spleen Stomach ~egalocytosis, minimal -Vascular mineralization, mild Alveolar macrophages, ~iid -Hemosiderosis~ mild Atrophy, moderate -Gastritis, acute, diffuse, mild The following tissues were found to be within normal li~its: Brmin, Bpinal Cord, Bone ~arrow, Heart, Smail Intestine, Large Intestine, Urinary Bladder, HAoorrtaa,, TTeessttiiss/EEppiiddiiddyyn~is, PPrroossttaattee, PPiittuuiittaarryy,, TThhyyrrooiid,, Lymph Node (mesentericl, Pancreas, ~ali~ary Gland. Parathyroid, Parathyroie, Trachea, Trachea,' Esophagus, Esophagus, Bpec~es: Rat yPro~ect Number: 028~CR0~2 Suanrized ST ppg: 1 Summarized STA Pa~e: 12~ 228~ 8 11333377..0299 3MA00027424 | Summarized Single Tabulated Animal Report (continued) rit ae tn re i Imdivid~al Macroscopic and Microscopic Observations 5 i Riker Laboratories~ Inc. 3M | Rae aR _ FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats ii L fC r i TR Animal Number: 1R-3641 Sex: Male Fate~ IWeek= 106) Terminal Sacrifice Group: (5) FC-!43 300 ppm Table: 2 Macroscopic Observations: ,i is -- Liver -Yellowish foci, 0.3 cm dia., median lobe. J Microscopic Observations: 1 pa di al 2 8 Adre~a~ -Medullary cell hyperplasia~ local areas, mild | EL, i gia Heart -~yocarditis, chromic nonsuppurati~e, Ta i KKiiddnneeyy multifooa3, mild -"CChhrroonniicc pprrooggrreessssiivYee nneesphhrrooppaatthhyy~, mtooddeerraattee hi rere, Liver -Portal monon~ciear cell infiltrate, mild | i i Crstoid degeneration, ~Itibca!~ mild Lt Megalooytosi~, minimal 1 a Hyperplastic nodule | sim Circum~cribed~ expansive ie~ion with SP ena i aaprrreeeaae~serppvraretesiseoenntt..ofCCaenl!ol1rs~~aliinnantroocdth~aillt~eectsmuoorrreee. Portal a basophilic, vacuolated. | w ry i -V~scular ~inerali~ation, mild Hemorrhage, focal, mild -Acinar atrophy, moderaW | ii he-Hemoeiderosi~, mild : EA i -- -Leydig ce!] adenoBa, unilateral | eo sn er fot i rt it The foilowing tissues were found to be within normal limits~ . Ey on uo wiry By 3 R8erratian,~ Po~rpo~.sm.t,~ateC,ordP,itu~iotnaery~,rrToowy~roiSdt,omaFcahr,athSymraolile,InTtreascthienae,, ELsaorpgheagIunst,e~Ltyiengeh~ NUorcienar(yses8e1natdedreirc~), ~orta~ Prostate~ Pituitarh Thyroid~ Parathyroid, Trachea, Esophagus, Lymph No~e (~esenteric)~ nn Salivary Gland, Eye. | ET Te ee Animal Number: I~-3644 Sex: Male i Fie me 0 eet Stee Fate: (Week= I06] Termna! Sacdf~ce Group: (5) FC-143 300 ppm II sing m---- Macroscopic Observations: LiYer -Appears mottle~; small p~le are~ in media~ | fotlobe. FR Microscopic Observations: B fAddrreennaall -"CCoorrttiiccaall vvaaccaucollaattiiconn,, ffaoctaall,, smiilld Nodular hyperplasia~ cortex, focal, mild | - a ce Heart -M)'ocarditis, chronic nonsuppurative, ri multifocai, mild Kidney -Chronic progressive nephropathh minimd | is er Liver -Portal mononuclear cell idiltrate, miid nL Portal bile duct proliferation, mild 2 Lr Megalocyto~is, minimal | en Nyperplastic nodule Ee tly or aii Cells of nodule have slightly more basophilic 1 a oe a cytoplasm; many are vacuolated. | .................................................................................................. | nn Species: Rat |i Eos"ProjectNumber: 0281CR0012 conc re 1 239 Summarized STAR Page: 125 2~9 11333377.100330000 wnonczrcs 3MA00027425 B SSuumemmarriiazeesd SSiinnggllee TTaabsuallaatteedd Ainniamall eRerpotrt ((ccoonnttiinnuueedd)) Individual Macroscopic and Microscopic Observations | saan Riker Laboratories, Inc. 3M FC-143: Two Year Oral Toxicity-Oncogenicity Study in Rats Tab1e: 2 i Animal Number; IR-3644 Sex: Male Fate: (Week= 106) Terminal Sacrifice Group: [ 51 FC-143 30{~ ppm Microscopic Observations (continued): i Lung 1 _-- Ae oes Salivary Gland i TestislEp~didymis -Vascular mineralization, mild Alveolar macrophages, mild -Sialadenitis, chronic, marked -Vascular ~ineralization, moderate a i TThhee ffoolllloowwiinngg ttiissssuueess wweerree ffoouunndd ttoo bbee wwiitthhiinn nnoorrmmaall lliimaiittss:: Brain, Spinal Cord, Bone Marrow, Spleen, Stomach, Small Intestine, Large Intestine, Urinary Bladder, Aorta, Prostate, Pituitary, Thyroid, Parathyroid, Trachea, Esophagus, Lymph Node (mesenteric]~ Pancreas, Eye. n Anima! Number: IR-3645 Sex: ~ale Fatal iWeek= 106) Terminal Sacrifice B I Macroscopic Observations: I Testis/Epididymis Group: ( 5] FC-14~ ~00 ppm -Pale mass, I.~ cm dia., in left testis. Microscopic Observations: Adrenal -Nodular hyperplasia, cortex, moltifocaI, mild Aorta -Metastatic neoplasm Esophagus Kidney l Liver l1 Lung -Metastatic neoplasm -Chronic progressive nephropathy, mild a oa -Portal mononuclear cell infi!trate, minimal Portal bile duct proiiferation~ minimal Mega]ocytosts, minima] -Vascular minera]ization, mild Pneumonia, interstitial, chronic, multifocai~ I mild Alveolar. macrophages, mild Hemorrhage, focal, ~iId PanEreas -Acinar atrophy, mild Parathyroid I Salivary Gland li ey Soft Tissues (thorax) -Adenoma -Sialsdenitis, chronic, moderate -Histiocytoma, malignant ~iffuse infiltrate of histiocytic cells in mediastinal tissues. Moderate number of multinucle~te giant cells. Infiltrate I Spleen TestisiEpididymis extends into musc]e around bone. -Hemosiderosis, mild -Leydig ceil adenoma, unilateral Trache~ -Metastatic neoplasm I Urinary Bladder -Epithelial hyperplasia, simple, diffuse, minimal l I i Species: Rat I1 Project Number: 02BICRO012 vir 290 Summarized STA~ Page: 126 290 11333377..00330011 3MA00027426 - anes Sie oe bd Summarized Single Tabulated Animal Report (continued) - Jtdr ee Individual Macroscopic and Microscopic Observations wn en Riker Laboratories, Inc. 3M _ es: vo od ey so 0s FC-143: Two Year Oral Toxicity-Oncogenicity StBdy in Rats -- Tr oe Animal Number: IR-3645 ~ex: Male bi hr Fate: (Week= 106) Terminal Sacrifice Group: (5) FC-143 300 ppm Table: 2 Microscopic Observations (continued): I--I Selig pr LSA The following tissues were found to be within normal limits: nFnoemysor IA rs Brain, Spinal Cord, Bone Marrow, Heart, Stomach, 5mall Intestine, Large Intestine, Prostate, Pituitary, Thyroid, Lymph Node (mesenteric), Eye. Ei Lara ET Animsl Number: 18-4641 Sex: Female Group: (5) FC-14~ 300 ppm sm ee Fate: IWeek= 7~) Sacrificed in extremis | ere ours Macroscopic Observations: 1 de i sires Mammary Gland -Large multilobular subcutaneous mass, left | pry inguinal and perineal area, avin 10 ~ 7 x 3.5 cm. Mass ulcerated on the dorsa! i ssuurrffaaccee;s iinnssiiddee ccyyssttiicc w~iitthh mwiillkkyy Fel fluid present. | rrr is Microscopic Observations: 2 HT .I Adrenal -Sinusoidal ectasia, cortex~ mar~ed Soar es Esophagus -Not examined, missing Ft FL Kidney -Chronic progressive ~ephropathy, minimal ten yn i Live~ -HHPeeoppraatattlooccyybttieeleaalldttueecrrtaattpiirooonnl~,ifevvraaacctuuioolloaantt,eeddm~,ilffdooccaall,~ l pyminimal w RC -- Lun~ -Hemorrhage, local areas~ mild i we Alveolar macrophages~ m~!tifocai, mild A A MamBary Gland -Fibroadenoma l Joo ER Ovary -Not examined, missing : ert Hn Sa[ivary Gland -Not examined, missing l A The foiio~ing tissues were found to be within normel limits: re ane B UUBrrriianniaanrr,yy SBBplliaanddad!deerrC,,ordAR,oorrttBaao,,neWUteMearrruursso,,w,PPiiSttpusliietteaanrr,yy,,HeaTTrrrtae,cchheeSaat,omaTTchhhyy,rrooiiSddm,,allPPaarrIaanttthheyysrrtooiiindde,~, Large intestine, tp Lymph Rode Cmesenteric], Pancreas, Eye. l ST a Br ST Animal Number: ~B-464~ Bex: Female Group: (~) FC-14~ ~0~ ppm He Fate; (Week: 78) Sacrificed in extremis l Nese saris Macroscopic Observations; 1 7 nn Pituitary l Siemit -- Microscopic Observations: -Hemorrhagic mass, 0.8 cm dia. B l irXEKisidodopneheyaygus Liver J --"NPfoeetllvvieicxcamamiiinrneeedrr,aalliimzziaasttsiiinoognn,, amiilldd -Hepatocyte vacuolation, diffuse, mild l l -- Species: Rat 1l SE cnn Project Number~ ~281CR0012 swt stm 291 Summarized ~TAR Page: 127 291 11333377..00330022 sworn 3MA00027427