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Aragg - 3297. 479 ~ AR 226-3 297 `TRADE SECRET Study Title 'H-25499 and H-25500: Subchronic Toxicity 90-Day Gavage Study in Male Rats. Laboratory Project ID: DuPont-11671 AUTHOR: Linda A. Malley, Ph.D., D.A.B.T. ~ STUDY COMPLETED ON: September 4, 2003 PERFORMING LABORATORY: E.L du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 WonkRecussr Nuva {gull Newark, Delaware 19714-0050 SERVICE Cove Novefal} -- Coumpany Sentieed.Doesnot conte ene ssn sarn ~ potion We, the undersigned, declare that this report provides an accurate evaluationofdata obtained from this study. ivpiiaE raey2pE5Eit Esmst o0v9-iSseippfleioonr> rir JTEJoFcoh kosty oesayne _ Hse hPilttdp votbySod Diector:__ Zornoies 12 Pl ove 04=dyeb 2003 ~ ee tnes 910-D.ay2Gaanv5daHg-e42S5t5u90d0y:inSuMbaclhevoRnatisc Toxicity ~~ TABLE OF CONTENTS DuPont 11671 Page 1 PR S------------------ EE. | RISTOR TABLES. ...mmnmimmmmmssmmsnssmmmmmmmmssint LIST OF APPENDICES... STUDY INFORMATION... SUMMARY. am ----------_ INTRODUCTwIcON mms-------- OBIECTIVE consis and] MATERIALS AND METHODS... T A. TES SUBSHANCES rrr 7 B. Test SPECIES rrr ---------------- | ATIAYUBAIY cocummmmmmmmammmi------------"_ 3. entfication m-------- ~~ 4. Health MOBIONNE PROGRAM... D. QuaraandnPrettesitPenrieod. ' AD A-- F. Assignment to Groupsand Study Start... send GAT TorkSIS DR csmmnmmmmmmmmmm---------------- 1 Roly WhlSh mmm 10 IL Clinical ObSerVationsand MORAY sri 10 AA -- RESANUDDILSCUTSSISON mmm l RECORDS AND SAMPLE STORAGE sons |2 REFERENCE consumes APPENDICES ---- wn ~~ -- GommeSenized.Dossnotomel yscAcB! 9205-4Da9y9GaavndagHe.2S5t5u0d0yi:nSMuablcehvRonsc Tricity ~~ LIST OF TABLES DuPon-11671 Page `TABLE 1 INCIDENCES OF GROSS OBSERVATIONISN MALE RATS SUBSET ONE... 15 TABLE 2INCIDENCES OFGROSS OBSERVATIONSIN MALERATSSUBSET TWO... 16 TABLE 3 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS SUBSET THREE .... n `NTEAOBPLLEA4SITNICCIADNENDCNEOSNO-FNEMOIPCLRAOSSTCIOCPILCESOIBOSNESRSVUABTSIEOTNSONIEN MALE RATS smsmmmm-- TNAEBOPLLEA5SITNICCIADNENDCNEOSNO-FNEMOIPCLRAOSSTCIOCPILCESOIBOSNESRSVUABTSIEOTNSTWION..M.A.LE RATS wmmmm-- N`TEAOBPLLEA6SITNICCIADNENDCNEOSNO-FNEMOIPCLRAOSSTCIOCPILCESOIBOSNESRSVUABTSIEOTNTSHIRNEME.A.L.E RcAcTSc 20 TNAOBN-LNEE7OIPNLCAISDTEINCCLEESSAINONDSLSEUSBISOENTGORANDEES.O.F.MICROSCOPIC OBSERVATIONS IN MA- LE RATS 21 'TNAOBNL-ENEOIPNLCAISDTEINCCLEESSAINONDSLSEUSBISOENTGTRWAOD..E.S..O.F..MICROSCOPIC OBSERVATcIwONeSrINmMeAmLEmR--A--TS--"-- N`TOANBLEE9OPINLCAISDEEINCCLESENAONNDDLSEOSIIROENEGTREARDREES OF MIwrCsReOrSnCrOmPmImCmOsBeSoEmRmVmAaTsInOamNmSmIsNmMeAsLmmErReAsTmSimnlh ~ LIST OF APPENDICES Page APPENDIX A INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS aime AAFPFPEECTNEDDI.X..B INDIVIDUAL ANIMAL MICROSCOPIC OBSERVAT--IONS LISTINGwIeNDIVIDUAL ANIMAoLdS -- -- CompanySentizad. Dossnotcontain TSCA C81 a y-- s _ STUDY INFORMATION Test Substance 1 J sno occ m) Synonyms/Codes: + H-25499) + H-24616] puree Haskell Number: 25499 /24616 eo Psi] Charis: Opaque tan liquid `Stability: The test substance appeared to be stable under the conditionsof the study; no evidenceof instability was observed. --_-- "Test Substance 2 Substance Tested: Ssnonyms/Codes{pE inN Haskell Number: 25500 Phil Characters: Cleriuid Suiits The test substance apparetobe sable undethe ccoondviteidonsof the study; no evidenceof instability was Sponsor: W1i.midnugPioonns,dDeeNleawmaoruers19a8n9d5Company USA --_ Ea iv Initiated/Completed: November 5, 2002 /(see report cover page) ee eee e Gomnamy Sanitzed.Dossnotcontain TSCAC81 H90--Day2Gaa5nvdaH4g-e29S5t5u09d0y;iSnuMbaclhevoRnaitscToricity Dupont 11671 --_ SUMMARY A 90-day oral studyinrats was conductteod evaluate tJahndeHp-ot2ent5ia5las0al0 toxicity of H-25499" in oCfrtlh:eCvDeh(icSlDe,)B7R0 mragt/s.kgGrHo-u2p5s5o00f,1o5rm1a0l0e0rmatgs/wkegorefHad-m2i5n4is9t9erfeodr d1a4i,l2y8d,oosrag9e1sdbayys.oraBlogdayvage wAfetiegrht14w,a2s8,meaansdu9r1eddatywsiocefwtereeaktlmye.ntC,li5nircataslpoebrsegrrvoautpiopnesrwteirmee epovianltuawteerdethsarcoruigfhiocuetd tfohre study. evaluationofnasal histopathology. NraatssaaldmleisniiosntserweedreH-p2r5od4u9c9ewdeirneracthsaraadcmtienriiszteedrbedy Hd-eg2e5n4e9r9atainond/Ha-tr2o5p5h0y0o.ftThheeonlafsaacltolreysions in eafpfietchteeldiurmatasnwdasdelgoenwerfoartiaonni/mraelgsensearcartiifiocnoedftafhteerr1es4poirra2t8ordyaeypsiothfetliruema.tmeTnht,ehionwceivdeenrc;eaollfthe rats treated with H-25499 were affected after 91 daysoftreatment "wTihtehnHa-s2al54l9e9si,onwsitihn rtahtesaadddmiitnioinsatlerfeidndHi-n2g5t5ha0t0rwatesrteresaitmeidlawrittohtHh-o2s5e5o0b0sehravdedadihnersaitosntsreiantetdhe nasal turbinates. The lesions observed in this study were similar 90-day study with H-24616| to those observed in aprevious Based on the resultsofthis ~ swtiutdhy,a sthuerfnaacstaalntlecsainonbseoabtsterribvuetdedintothteheprseuvrfiaocutsansttucdoymwpiotnhenortgoafntofhleuomratiedreiaulr.ethane polymer --~ s* uDpuprliynogfth2e5c4o9u9rs,e ofthe stady, second lot (H-24616)ofthe same test substance was used due 10 an insufficient -- Comnany Santized,Doesnotcontain TSCACBI 9205-4Da9y9Gaavndag2e5S5u0d0y;inSMulbcehvRoaisc Toxicity Duront-11671 --_ INTRODUCTION hiseuseesdtassaucbarepert pcrootenctsantS .10 a previous 90-daS y oral study, rats wereE administeredda5i0ly) 1 dosagesof0, 50, 250,qf 1000 mg/kg/day(based on active ingredient) ofthis same C-- was obse-- rved in male and femalebaytgsaavtaaglel.d"osNaagsesa,laonlfdacitnofrlyamepmiatthieolniuofmthdeegeonlefraacttioorny/necrosis tephitthtehelisuumrfwaactsaontbsienrtvheediprnomdaulctemraatys ahdamvienicsontterriebdu2te5d0toort1h0e0n0asmga/klegs/idoanys.. It In was hypothesized ordero est this h(yGponthieseids,witn ethye c1ur0r0entmsytusdy,imyaloepismere administered daily dosagesofthe vehigle formulation (H-25499), or 70 mg/dayofthe surfactant alone (H-25500). The dosage for the surfactant was based on the concentrationofsurfactant in he fmmglormuiaiion. dTuhreinsgtutdhyewcaousrosreiogifntahlelystiunidtyi,attehdeuasmionugntteosfsHub-s2t5a4n9ce9lwoatsiddeenttiefrimeidnaesdHt-o2b5e49i9ns.ufHfiocwieenvterfo,r the `rceommapilnedteertoheft9h0e-dsatuydtyr.eaTthmeernetfopreeri,odH.-24Al6l1r6ef(aerseenccoensdtolotthoeftetshtestuebststsaunbcsetainnceth)iwsarsepuorstedwitlol use H-25499. --~ OBJECTIVE H"T-h2e5o5b0j0e,ctwihveenoftahdimsinsitsutdeyried tboycgoamvpaagreetothmeaploeternattsi.alTnhasealortaolxircoiuttyeooffaHd-m2i5n4is9t9raatnidonsuwrfaasctant, selected because it was the routeofexposure in the previous studies MATERIALS AND METHODS A. Test Substances tTehstedtaesyt 5s2u,bstthaencqeu,anHti-t2y5o4f9)H-25499 was supplied by fheas5pdoenstoerramsineaodptaoqbueeintsaunffliicqiueindt. fOorn p= the reminderuosfedthuentisltusdyt.udyThteerremfinoartei,oan.second lot ofthe same test "san Twhaes uarsstiugcnaendY Haskell LaY boratory NumbseurppHl-i2e5d5b0y0t}he sponsoargaclear liquid. The surfactant "iTnshteabtielsittsy,ubssutcahncaessaacphpaeanrgeeditnocobleosrtoarblpehyusnidcearltshteatceo,nwdaitsioonbssoerfvtehd.e study. No evidence of --_ --e -- e ---- Comonm Sanired, Does net corain TSCA ST H-25499 and H-25500; Subehvonic Toxicity 90-Day Gavage Study in Male Rats --_ B. Test Species DuPon-11671 MCaarloeliCnralw:eCrDe(uSsDed)IoGnSsBtuRdyr.ats received from Charles River Laboratories, Inc., Raleigh, North `The rat was selected for ths study because it is the recommended species specified in the igunifdoerlmianetsi.onTisheavCairlla:bCleD*f(rSoDm)tIhGeSliBteRratsutrrea,inthweassupcphloiseernabnedcparuesveieoxutsesntsuidvieesbaactkHgarsokuenlld Laboratory. This species/strain also is considered suitable relative to longevity, hardiness, sensitivity to the test substance, and low incidenceof spontaneous diseases. C. Animal Husbandry 1. Housing All rats were housed in stainless steel, wire-mesh cages suspended above cage boards. Rats were housedonepercage. Cage racks were relocated within the animal room each week and cages were repositioned on the racks every 2 weeks. Animal rooms were maintained on a 12-hour light/dark cycle (fluorescent light) and at a temperatureof22 3C and a relative humidity of 50-20%. 2. Feed and Water ~~ `Tap water was provided ad libitum. All rats were fed PMI Nutrition International, LLC CwearstiifniceodrRpoordaetnetd LiantboDitheetfo5o0d02atacdonlciebnitturma.tioDnusrisnpegcitfheietdesbty(setxupodsyudrees)igpne.riod, test substance 3. ldentification Priorto assignment to groups,eachrat was temporarily identified by cage identification. After assigament to groups, an individual identification number was tattooed on the tailofeach rat. `The information on the cage labels included the unique 6-digt Haskell animal number and the individual identification number assigned to each rat. 4. Health Monitoring Program As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impact the scientific integrityofthe study: + Water samples are analyzed for total bacterial counts, and the presenceofcoliforms, lead, `and other contaminants. + Feed samples are analyzed for total bacterial, spore, and fungal counts. + Samples from freshly washedcagesand cage racks are analyzetdo ensure adequate --_ sanitation by the cagewashers. _-- Company Santtzod. Doss not contain TSCA CBI H90-.Day2Gao5nvda4gHe25S9t5u0d90y:inSMuablcherRoantisc Toricity Dupont 11671 -- Certified animal feed was used, guaranteed by the manufacturer to meet specified nutritional requirements and not 10 exceed stated maximum concentrationsofkey contaminants, including specified heavy metal, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presenceofthese contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrityofthe study. `The animal health and environmental monitoring program was administered by the attending laboratory animal veterinarian. Evaluation ofthese data did not indicate any conditions that affected the validity ofthe study. D. Quarantine and Pretest Period Upon arrival at Haskell Laboratory, the rats were quarantined for at least days. The rats were observed daily for any clinically apparent signsofdisease or injury and weighed 3 times. On the basesofacceptable body weight gains and clinical observations, all rats were released from quarantine by the laboratory animal veterinarian E. Study Design Male NumberofMales Daily Dosage Dose Volume (mLkg) ~~ 1 15 0 (Control)* 408 m 1s 70 meg Surfactant H-25500 1.00 bvee 15 1000mg /kg H-25499" 4.08 -GroupVreceived asecondlot(H:24616)ofthesumetest substancebeginingontestday52. `Study animals consistedofthree subgroups: Subset | was sacrificed on test day 14 (5 rats/group), Subset 2 was sacrificedon est day 28 (5 rats/group), and Subset 3 was sacrificed on test day 91 (5 rats/group). F. Assignment to Groups and Study Start The rats were selected forstudyuseon the basesofadequate body weight gain, freedom from any clinical signsofdisease or injury, and a body weight within + 20%ofthe mean. The selected rats were distributed by computerized, stratified randomization so that there were no statistically significant differences among group body weight means. Administrationof test substances beganontest da0y. The rats were between 6 and weeks of age on test day 0. -- `Company Sanitized. Dossnotcontain TSCA CBI 9H0-.2D5a4y99GaavndagHe-2S5t5u0d0y;inSMuablcehrRoantisc Toriciy DuPont11671 -- G. Administrationof Test Substances H-25499 was administered undiluted, once daily by gavage to the study animals. Starting on test day 52, H-24616 replaced H-25499 and was administered daily to the study animals. H-25500 was diluted with deionized water and administered once daily by gavage. Animals designated for Subset 1 were dosed for 14 days. Animals designated for Subset 2 were dosed for 28 days. Animals designated for Subset 3 were dosed for 91 days. The volumeofthetest substances given to each rat daily was based on the most recently recorded weight. Control animals were similarly treated at the same dose volumeofdeionized water as the 1000 mg/kg H-25499 group. H. Body Weights All rats were weighed twice per week. I Clinical Observations and Mortality `Cagesite examinations to detect moribund or dead rats and abnormal behavior and appearance among rats were conducted at least twice daily throughout the study. At every weighing, each rat was individually handled and examined for abnormal behavior and appearance. J. Pathology Evaluations ~ Five animals from each group were sacrificed on test days 14, 28, and 91. Noses from all sacrificed animals were processed and microscopically evaluated. -- vo `Company Sanftized. Doss RotcontainTSCA CBI S4o2yC5rodn10g2e5s500t: SciToi Durr11 ~ RESULTS AND DISCUSSION CtOiMrBwiersirs aodmcirnetdsHn2s55o0E iat on-- y). Theser eiar| nmms r "Text Table 1. TEXT TABLE 1 INCIDENCES OF COMPOUND-RELATED MICROSCOPIC LESIONS IN THE NOSE OF MALE RATS* TDTare vem _amw No abnormality detected Degeneration/atrophy, olfactory mucosa Degeneration/regeneration, respiratory mucosa. Control 3 1 1 70 mg/kg/day 3 1 1 aE 1000 mg/kg/day 1 3 2 Adhesion, turbinates. - 1 - Exudate, nasal cavity - 1 1 28 Days No abnormality detected ~ Degencration/atrophy, olfactory mucosa 4 2 1 1 2 2 Degeneration/regeneration, respiratory mucosa - - 1 `Adhesions, turbinates - - - Exudate, nasal cavity - - 1 No abnormality detected ` - - 91 Days Degeneration/atrophy, olfactory mucosa 1 5 s Degeneration/regeneration, respiratory mucosa. - 1 - Adhesion, turbinates. - 5 - Exudate, nasal cavity - = 1 *5 rats/groupitime point `The primary finding in the nose ofmale rats administered 1000 mg/kg/day H-25499 by gavage `was degeneration and atrophyofolfactory epithelium. Degeneration or regeneration of respiratory epithelium and exudates within the nasal cavity (composedofproteinaceous material and neutrophils) were also present in a few affected animals. Olfactory lesions were present in low incidences at 14and 28 days, but all animals were affected after 91 days exposure. These lesions were characterized by disorganization and thinningofthe olfactory epithelium especially along the ventral one-hoaftlhfe nasal septum in the posterior nasal sections. Other areas more commonly affected included the medial extentsof the ethmoturbonates. Minimal focal olfactory --~ degeneration was noted in some controls; however, these lesions wererandomlydistributed and ee TT -- Company Sanitized. Does not contain TSCA CBI 9102-5D4a9y9GaavnadgHe-2S5t5u0d0y:inSMuabclherRoantisc Toxicity Dupont 1671 ~ thus distinguishable from the compound-induced lesions.* The compound-related lesions observed in the current study following exposure to 1000 mg/kg/dayof the Lt`material. aresimilar to those produced in a previous study with this. ItnhoasneiombaslesravdemdinwiisttheHre-d257409m9g/wkegr/edoabysesrurvfeadctianntthaelnoonsee.(H-H2o5w5e0v0e)r,,oilnfatchteorsyurcfhaacntagnetsosnilmyilgarrotuop, obleftawceteornytcuhrabinngaetseswaenrde tahlesonaassaslocsieaptteudmw.itThhfeisberoaudsheasdihoenssiownesrbeeltiwkeeelynainsdeiqvuiedluaaloftufrobcianlaltyesmoarned sinevtehreesoulrffaaccttoarnyt-eopniltyhegliraolupnecwreorseisquaanlidtaultcievrealtyiosni.milTahruos,tmhiocsreoosfcroaptiscicnhtahnegpeoslyinmtehresnuorfsaecotfanrtats `cgornosuips,teanltthporuegshenlceesoiofntsuirnbitnhaetseurafdahcetsainotn-so.nlTyhgeromuepchaappneiasrmsuonmdeerwlhyaitngmothries aspepvaerreenbtalsyegdreoantetrhe severity is not known. No studies have been conducted with potentialfornasal toxicity has not been determined. Nevggtheless,based onotnhee,reasnuldtsthoufsthitiss study, the nasal lesions observed in a previous study wi CS<1 be largely,ifnot completely, attributed to the surfactant componenofthe `material _ RECORDS AND SAMPLE STORAGE Ahlel dspaotnasaorn.d rLeacboorrdastofroyr-asnpaelcyitfiiccalocrhsairtaec-tsepreicizfaitciornaswcdoantdau,cstuecdhbaystpheerssopnonneslorfiwlielslabnedreeqtuaiinpemdenbty records will be retained by the facility where the work was done. A sampleofthe test substance will be collected for archive purposes and retained at Haskell rLeatbaoirnaetdorayt,HaNsekwealrlkL,abDoerlaatwoarrye,.NeSwpaercikm,eDnesl(aiwfaarpeploircaabtleI)r,onraMwoudnattaa,inanRdecthoerdfsinaMlanreapgoermtewniltl,be: Wilmington, Delaware. REFERENCE 1. DRautPsownittHhaOsnkeel-lGeLnaebroartaitoonryRe(p20r0o1d)u.ctiHo-n24E6v1a6lu:atSiuobnsc.hrUonnpiucbTloixsihceidtyre9p0-oDratg Gavage Study in Fdaoycsa(lanmiimnailma#l66d5e9g6e5n)erwateisosnoimfiloalrfocotrhaytespeietnheilnicuomnitnroolnasnnthlus amdamyinriesptreerseednt1a00s0pomngta/nedoausyocHc.u2r5r4e9n9cefoorft2h8is -- sepiiotnh.eliIunmaidndtihtiiosna,nismrailf.actual disruption ofthe olfactory mucosa precluded citical evaluation ofthe olfactory --_-- `CompanySanized. DoesnotcontTSaEAiCna H90.-Day2Gaa5nvdaH4g2e59S5t0u90dy:iSnuMbaclheroRnatiscToxicity DuPont 11671 TABLES --~ -- EY Company Sanhized. Does not contain TSCA CBI 01.-2D5a4y99GaavnadgHe.2S5t5u0d0y:inSMuablcherRoantisc Tonicity --~ TABLES Dupont 11671 EXPLANATORY NOTES STUDY DESIGN Male Number ofMales Daily Dosage Dose Volume (mL/kg) 1 1s 0 (Control)* 408 m 1s 70 mg/kg Surfactant H-25500 1.00 SVv.eema 15 1000 mg /kg H-25499" 4.08 b Group V received a second lot (H-24616) ofthe same tet substance beginning on test day 52. Study animals consistedofthree subgroups: Subset 1 was sacrificed on test day 14 (5 ratsgroup), Subse2t was sacrificed on test day 28 (5 rats/group), and Subset 3 was sacrificed ontest day 91 (5 rats/group). --~ ~~ -- CommanySenflized. Does not containTSCAcaf ~ i 2 --_ i &i i on igh Fp i CT EBiiEsieigeE ia 0 Td fei Tris g Eid 8 tofu IT 13 i 5 0 iF is Soil it T | i ii gz } i533 8= 28g8 i z 28 ii| E18E3 if som ; iif ga | | [EE &Soa : ;i fPu3n2 :| ; ii; 8| [og iad i OEE i; i I EE] A ~ i4 mss mtorr 8 3 i :z i | :5 i 2I2 ~ i3 ~ 5i i2 ee MELEE Hilaio EIRIERE GC ET @ |EP iGZERG } E, ia3 EZ L: iE ig : PEuLg z i| iiEg | E18Ng i 2x i ia g2<<8e!| EERoIg i 2283 gz |i 5i gZz Zg || i Pog il : i 15g {no {i iied ii i188 jg :|; EFEH] [5% || ii9d% || i1f2y2 P Logfid PE iad P | F g i dg sia EH 8 i i i2 ] I . : E&N 8 ~ 3 | 2 ~ iis 4] E8H 4 ~ #2E42s] 22 GE 151Ts% 1 ao oi iE ee PELEIEER Fm , idgli ieE2. ligi. di S EoTTT T Te iE 0 33 CE z3 gE58S | 25 | 828 | 57 1 ii :|I i3E23 : (28 :: I14g%a | IM | Coil Z8 |i sg ii ii ifta :: 8 8P233 iPoE HE i i 7 ist :i a I : w 2 a ial :fen: d [1 R2Ea 8 ii i i < 32 iz 2ii%zf 2 ~ Z3 - i5.3 : ioi i i _ ii 22 g5h777S87E1 6ven | EHireiged TTT oT ffgg feEim t tid gh 2 Fie i13 igzg 01 iiFE f3a3 2g2e P|o ; 35s% 2222% i| ,5 2 BEE2E0 || 20 i] iiin:a ii :i i: iiif l i iE Lop ig ln 2gCeE2e38 | 2Ei 88 gg E ii $ ;i i;; ; Pi ]};i 5gL ie iL iitisd ;; 883 iiv%, ; did jP|o 8BEBgBg.iE8g.igi1tf82% ii, FEELSEEERTE:HCRS iP[i BE oEfpsodrgsisisfdieiisc Pog fianaidt 08, eREEEEI] | E 8% RE iE; f: i | ii 2 - : 3t i E2E % :5 ~ I: 8 ~ ~ i5 i ii 73% is 2i9f) B igi I g ii ilms aadi HieiT BET iigBiiEfiiergpEHl} 2 Tt J g i iB jt emi i s"it 8= , | iiEE i i3t $2 0 if 8 28 1 itd ig} 5 Eh 2E2g8g || FE] i o 58g 8 | 5322 E520 2g2i2g || 5g5e? | 53 | gg%g || g z| ii :i : f]om |; iPengg ||i , 1g541g3 | 3 iE i g iid ii 5B4ia1s% :i co Begiiiiss i| iLIS iIis Po YBLBR LEiHE Po, HEEBESICE iL E E poogeE fiis ggE | EaEgeiBRini, | FE, oEERERI: | E8R2 FiBR 8 f i : | I s ' . is 338 i 3? ~ i --~ 3 2g i:2 izz i: | 1BHg ~ i#4 BET 5. iHgliiiEimil Cd LIES gi iig o feB2a4i - TT i "i 3 is 8, 1 iE iisty 22001 i SivHi sg_ | i 1 E3G2S | i; j(82%3 .2 B28 828 | i iz : gi if =Z 5oZ3Ef | i: Efi8s 228 | : 5 i%g goE<esNi| ii Pl Eig8 Ti1]d43 25x8 i 82 i: EE2RE 1i3igd LN EEE 8g ii |} H gesnEiliRey z ii iiBg oHpEoBgEiRsEgIiLiZl i]ii Pi oa2 f5 ang a13.F gy }ik4 LEFEREEEIEENy Pi oE Ld SLEH VEIEE :i 1 i gf E TTRRRRiIg | i } ki: 7gi ii2i 23: ~ if F 3 g iET %iT igees T| T os. ans amo. i ; H igi oiRER ; ihe eT f g Eten 0 0TTT 3 8ZOHiEgDi i fLpy . i Eom meen i i FA E ; | 8 i if i =i {PF i z= Pee ZZ o :i 2| i ~ 2c28&Zs28!| ::; 85o2F | |; 8% i 23 | : iz I 1a 1I5Hg 38 IH 2i iiRzgH3t =. Eo 3 i3y " if z iiei 35 ii sl 2& i :PoEEEy E 38 E0% [POoBpRs BBGEF 4BpS 5opo3iiins 4OFg HBiidl 2 223g g48g 32 a sipiP(gE8 BOEBEEgE.Ei.ABi8.i2T.ElE8Ra%AEy,ETL8sES5EEA.i8USl8EEE8EEEFfSIiiI8iiTiCgCd |B $43 2 8 0%i oigpgewFoEiF2 8 i8 isnf 532 z oF i i 8 E i1h87 [|33% ~ ig 2 1 T 3 E g5 Hg RizTTiae TT omImm aed i IR C z t gr J re eea} : i 2 i z (AL Logal| & - mm -- z ETE -- is io pF fend| ii33 IEia I 2z | ot i: Z ig ig igza: ; | i 1i1:3 188 ~ EgE8eSs2d| ;: oF i| 28 x53: LEif i. 2gF3Es!Ri g P;[oos isEs osHskaik;gb gdiid 5I PiPPoooeeElglaB 38tr48kigPEf- iad 33 F8Rn1Ei3Tl]8 alts H g:l 2a& ; E ii[goIk.5sE8 E ii5fs8 B i iEE E E nisgAJGFiiEes i3g o5z a 2% 9 R iHzi SiBEEiEucS3aii2nE3sEdNiiiEEna7LEi8eLRi8Es5Ei8Rt8EE0EE3ExR8RE1INii:EfStsS (|8B 8323 Z2<z i 2 i i E 8 iiPiE Eff,08ok g 1i:d gary [123 128?2 eee hir | |3%B ~ i3g3 2& eh i i ig og if Bandeo oh n ti ol 2 PREG dEg 4 fi ~ gf 2 REESE Be pamcoereeemetsmn a ott ie ! : ggigiigi i351 or oe i 8 g g 8o 1% eBud lTg TeaTa yTvt To wie wmaTH f 32 iigEi fIToFe.iT Eo ct i z ZEzE TRL i i : FEE is ] a= |i ii g i iH3E =El -- iE EizS Zz i i isc I g20i | iigni ~ SEE2ErgR ii i ifz3 in SSoOpF!| }i E8o {185d% * 2E2R ii 585i8f 5 gi(t3;d gi Pog i EE Ey 3 gia 5s g| P} oggyEEuE iige b BPREE Does BoiR Ep zi < ogz zz g BCoRnoEE8. iB pl 82 BEERDBEEiE 8% 44. 83. 2FBi%,i: #0, 5 inna 5 2<;| ogz | iy 8 | ggiif ok g gE FFB [EgER 5A iisfiy [32 } Poh | E83 g3:f zBe 188 i1E5% [[E32S gl f 2: H-25499 and H-25500: Subehronic Toxicity D 90-Do ay Gay vageG Studyuin Mv ale Ra ats geSudyinMaleOR wDuoPe ownnte 1e167n1 --_ APPENDICES --_ _--_--nTemm,---- Compeny Sanitized. Doesnotcontain TSCA cal 9H:0D25a4y99GaavndagHe-2S5u5d00y:inSMuablehevoRnaisc Tosicty _ APPENDICES EXPLANATORY NOTES Dupont 11671 STUDY DESIGN Male NumberofMales Daily Dosage Dose Volume (mL/kg) 1 m 1s 15 70(0Cmongt/rkogl)S*urfactant H-25500 408 1.00 Tvbe 15 1000 mg /kg H-25499" 4.08 GrVorecueivpeda second lo H:24616) of he same est substance beginnoninesgtday 52 (S5turdatys/agnriomuapl)s, cSounbssiestte2dowfasthsraecreisfuibcgerdoounpst:estSduabyse2t81(5warsatss/agrcourp)i,faoinndcteeSsudtbsdeaty31w4as sacrificed ontestday 91 (5 rats/group). - -- Tm ------ `Company Sanhizod. DoesnotcontainTSCA CBI H-25499 and H-25500: Suberonic Toricity 290D0ay GDavagoe StyudyGin Maole Rvats ageSuudyinMaloDRuDbuaoPownltti.e1s1n67n1 --~ APPENDIX A INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS --~ -- --- = Company Sanhized. Does not contain TSCA CAI H90--2D5a4y99GoavnadgHe-2S5t5u0d0y;inSMuableehrRoantisc Toxicity DuPont 11671 -- INDIVIDUAL ANIMAL GROSS AND MICROSCOPIC OBSERVATIONS EXPLANATORY NOTES Lesion Grading aHnisdtsoepvaetrhiotyl.ogiTchael dcihsatnrgiebustairocn d(eexstcernitboefdtiascscourediinnvgotlovethmeeinrtm)oirspihnodliocgatiecd,chwahreacrteera,ppdriosptrriiabtuet,iobny `modifiers such appropriate, is aalssofoacsasl,igmnueldtiafsocfaoll,lodwisf:fuse, unilateral, bilateral, etc.; A severity score, if Minimal: the normal limits amountof change present barely exceeds that which is considered to be within * Mild: in general, the lesion is easily identified butoflimited severity. does not produce any functional impairment. The lesion probably * MLoidmeirtaetdet:isstuheeolresoirognainsdpyrsofmuinncetnitonbuits ptohsesrieblies.significant potential for increased severity. * Severe: intensity the or edxetgernetetoofecxhpaecntgesiigsniefiitchaenrtatsiscsoumepolretoergaasncodynssfiudnecrteidonp.ossible or great enough in ~ Comment: `gcroandteisnmuuimniwmiatlh tmhirnoiumgahlsleevseiroensrebperiensgenttheprloegarsetssseivveereinavnodlvseemveenretsleevseironistybeailnogngthae mthoesytaslesvoerien.dicWahtieltehetihrergelraatdievse rbeifoelrogtioctahlesimgonripfhiocalnocgei.cal characteristics of lesions, dGroestcs)observations listing multiple masses for a tissue are distinguished with letters (i.e. 3, b,c, Neoplasm Designations *B: Benign neoplasm, primary site *M: Malignant neoplasm,primarysite -rm `Company Sanitized. Doss not contain TSCA CBI H90--2D5a4y99GaavndagHe.2S5t5u0d0y:inSuMbaelleroRantisc Toxicity DuPon.11671 Showing anIinrdailvidduaatla AfnoirmailndiLviisdtuianlg animals sDtoospeyGroup: 1 0 ma/kgle (+ SAePxP:ROVMEaDlesPROTOCOL +) Aninal Ret Microscopic & Macroscopic Findings ess927 TKeirlmliendalonSaDcaryif: ic1e4 AEnxipmoaslureisGrsoiugpne:d oSfufbseftrom1 necropsy Grose Pathology : Yo MaNcOrSEoscopic Abnormality Observed : Histopathology No Mircorsoescopic Abnormality Observed : ssss28 TKeirlmliendalonSaDcaryi:fic1e4 ABnxipnoaslureisGrsoiugpned: oSfufbseftrom1 necropsy ~~ Gross pathology No MaNcorseoscopic Abnormality Observed : Histopathology nose 'DEGENSRATION/ATROPHY, OLFACTORY, MUCOSA, minimal. 6ss929 TKeirlmliendalonSDaacyrif: ic1e4 . AEnxipnoaslureisGrsoiugnpe:d oSfufbseftrom1 necropsy Gross Pathology : No MNaOcSrEoscopic Abnormality Observed Histopathology + No Mircosreoscopic Abnormality Observed : --~ Te Company Santtized. Donotecontsain TSCA Cal -- 9H0.-Day2Gaa5nvda4Hg-e29S5t5u09d0y:iSnuMbaclheroRnaE tisc Tox-- H icity a DuPont. 11671 --~ howing anIinmdailvidduaatla AfnoirmailndLiivsidtuianlg animals DsoTsoeoyGroup : I 0 hg/kgle (+ ASePxP:ROVMaElDesPROTOCOL *) Animal Ref Microscopic & Macroscopic Findings 665930 TKeirlmliendalonSaDcaryif: ic1e AEnxipmoaslureisGrsoiugpned: oSfufbseftrom1 necropsy Gross Pathology : No MaNcosreoscopic Abnormality Observed : Histopathology No Moicsroscopic Abnormality Observed : 665931 TKeirlmliendalonSDaacryif: ic1e4 AEnxipmoaslureisGrsoigunpe:d oSfufbseftrom1 necropsy Gross Pathology : No MaNcosreoscopic Abnormality Observed : Histopathology : nose INFLAMMATION, SUBACUTE/CHRONIC, minimal DEGENERATION/REGENERATION, RESPIRATORY, MUCOSA, minimal -_-- Te `CompanySenhized.DossnotcontainTSCAcal 9H0--2D5a4y99GaavnadgHe-2S5t5u0d0y:inSMuablcehrRoantisc Toxicity Dupont 11671 --_ spy haloeuin(g+ anIinmdailvidduataal AfnoirmailndiLviisdtuianlg APPROVED PROTOCOL +) animals Dose Group : 11190 mg/kg Surfactant H-25500 Sex: Males Animal Ref Microscopic & Macroscopic Findings 665942 TKeirlmliendalonSDaacyri:fic1e4 AEnxipmoaslureisGrsoiugpne:d oSfufbseftrom1 necropsy Gross Pathology No MNacorsoscopic Abnormality Observed : Histopathology No MNicorsoscopic Abnormality Observed : s65943 KTeirlmliendalonSDaacryif: ic1e4 AEnxipmoaslureisGrsoigunpe:d oSfufbseftrom1 necropsy --~ Gross pathology No MNacorsoscopic Abnormality Observed Histopathology : No MNiocsreoscopic Abnormality Observed : s65944 KTeirlmliendalonSDaacyrif: ic1e4 AEnxipmoaslureisGrsiogunped: oSfufbseftrom1 necropsy Gross Pathology + No MNaocsreoscopic Abnormality Observed : Histopathology wos D: EGENERATION/ATROPHY, OLFACTORY, MUCOSA, moderate. A'DDEHGEESNIEORNR,TITOONR/SRTENGAETNEESR,ATImiOlNd,. RESPIRATORY, MUCOSA, mild. EXUDATE, `NASAL CAVITY, minimal. -- meee Company Seniizsd. Doss not contain TSCA Cal S0.D2a5y49G9aaangde25S5t0y;inSiclhoRnts.Tovey Dupo 11671 ~ moving anIinndailvidduaatla AfnoirmailndiLviisdtuisnlg animals stDoospeyC Groupo : TXn M0 m/kg Sa urfactr ant #2o 6500 ax Sex: Males Saint ret Wicroscopic & Macroscopic Findings pores KTeirimliendalonsDaacyrit ic1e4 AEnxipmoaslureToGrsiogunped: oSfutbssttrom1 necropsy Gross rathotosy Yo Moacrrsoscopic Abnormality Observed : Histopatholony + wosz INFLAMMATION, SUBACUTE/CHRONIC, minimal cessae TKeirlmliendalonSbaacryific1e4 iExmpaoslure5sGrsoiugpned+ oSfufbseftrom3 necropsy --_ Grose pathotosy Yo Maocsreoscopic Abnormality Observed sistopatholosy No Moicsrsoscopic Rmormality Observed _ reree-- =e-- eet-- osmm-- e------ ----e-- eee "pany Sanitized. Does otcontain TSCA cBf R 9HL025D09G9P osvdag2e5Sy 50y0,nSG iuebRuare i Toxs ic uaMicroe Dwwronns -eitern --_ sroor noTav.inSg AaenIrinmmdoaivlveiodd.uaatplaRoArFomorir.noasi)n+d)Liivsidteinntg animals Dore Gra IO ark Heston oe Watas raid net Microscopic 4 Waeroreopis Finings Gases EKTerirplmolirenadardeonGsrDaoacyurpifi: c5e1Subset 1 RoEoal Ss some off from necropsy Grose pathology : No Moacmreoscopic Abmormaicy observed nistopatholosy ose D+RGRNERNTLON/ATROPIY, OLPACTORY, MUCOSA, miniral. cassss EKTreiprtomenisinraelonGsrDaoacyurpit+i+c1e4Subset 1 Robo 1s Sioned off from necropsy ~ Gross pathology : No Maocsxeoscopic Abnormality Observed : Histopathology oseDEDGREGNEEERRAATTIIOONNRNETGREGNPEHRYA,TIOOLNT,ACTROERSYP,IRANTOOCROYS,h, MUmCiOnSiAm,al,minimal. EXGONTS, NASAL CAVITY, minima cassss EKTxelpromonisuncaelonGsraDocaurypi:ti+c1S1eubset 1 foal Lo siomed oft trom necropsy Gross Pathology : No Maocoroscopic Abnormality Observed : Histopathology oss SEGREGATION REGENERATION, RESPIRATORY, WOCOSA, minieal ~ e--e --s ------------ ro ------ sees e--eee Company Sanz. Dossnot conten Tsca cal 9F0--Day2Gaa5nvadg4Be-29S5t5u09d0y:iSnuMbaclheroRnaitcs Toxicity DuPont 11671 --~ stupy wing anIinmdailvidduaatla AfnoirmailndiLviisdtuianlg animals le (+ APPROVED PROTOCOL *) Dose Group: V 1000 mg/kg H-25499 Sex: Males Animal Re Microscopic & Macroscopic Findings se5960 TKeirlmliendalon SaDcaryif: ic1e4 AEnxipmoaslureisGrsoiugpned: oSfufbseftrom1 necropsy Gross Pathology : No MaNocsreo.scopic Abnormality Observed : Histopathology sess61 Nos DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, minimal. KTielrlmiendalonSaDcaryif: ic1e4 AEnxipmoaslureisGrsoiugpned: Sofufbseftrom1 necropsy --~ Gross Pathology No MNaocsreoscopic Abnormality Observed : Histopathology No MNiocsrsoscopic Abnormality Observed --~ Tee. `CompanySentized. Doesnotcontain TSCA CBI 910.D2ay5Gaanv4dagHe-92S5u590d0y:iSnuMbiclheroRnaisc Toxicity Dupont 11671 ~ roving anIinndailvidduaatla AfnoirmailndiLviisdtuianlg anieals Dsoosoe:GSroupo: m1 0mma/ekg ( ASrexp:novHealnesshores) Animal Ret Microscopic & Nacroseopic Findings Pree KTeirlmliendalonsbaacyrif: ic3e8 AEnxipmoaslureisGrsoiguhped Sofufbseftrom2 necropsy Gross Pathology Yo MaNcorssoscopic Abnormality Observed sistopathology : Yo Miocsrsoscopic Abnormality Observed sess KTeirlmliendalonSDaacyrif: ic2e6 AEnxipmoaslureisGrsoiugpned: oSfufbseftrom2 necropsy . Gross pathol.ogy Yo MaNcorsosscopic Abmormality Observed : Histopathology : soss DEGENERNTION/ATROPHY, OLFACTORY, MUCOSA, minimal. sess KTielrlmeidnalonSDaacyrif: ic2e6 AEnxipmoaslure1sGrsoiugpned: oSfufbseftro2m necropsy Gross pathology + Yo Moacsrsoscopic Abnormality observed : Histopathology : No Moicsrsoscopic Abnormality observed eee CompanySanitized. Dossnotconta TSCA CBI 9H0--2D5a4y9G9aavnadgHe-S2t5u50d0y:inSMubaclheRroRenatiesc Toxicity DDuupwoonwtn1i1e67n1 ~ sTopy howing anIinmdailvidduaatla AfnoirmailndiLviisdtuianlg animals ale (* APPROVED PROTOCOL +) Dose Group: 1 0 mg/kg Sex: Males Animal Ref 565935 Microscopic & Macroscopic Findings KTeirlmliendalonSDaacyr:ific2e8 ABnxipnoaslureisGrsoiugpned: oSfufbseftrom2 necropsy Gross Pathology No MNaocsreo.scopic Abnormality Observed : Histopathology No MiNocsreo.scopic Abnormality observed 665936 KTeirlmliendalonSDaacyrif: ic28e AEnxipmoaslureisGrsoigunped: oSfufbseftro2m necropsy ~~ Gross Pathology No MNaocsreoscopic Abnormality Observed : Ristopathology No MiNcorsoEscopic Abnormality Observed : -- -_-- TT Company Santtized. Does not contain TSCA cB 02-5D4ay59GaavnadgHe.S25t5y00:inSMulbecvoRntise Toxichy Duron Ps sroor Com roving anIiondaslvidcautaal afnoirmailndiLviisdtuianlg animals AerroveD sRovocor +) Dose Group + TTT WF mg/kg Surfactant N-7350 Sex: Males minal nef Microscopic & Nacroseopic Findings cesar TEKexirplmolisenudarleonGsrbaoacwrypif:i+c3e8Subset 2 Simal 55 siomed off from necropsy Gross pathology No Moacrrsoscopic Abnormality Observed siscopathology woss C NFLNBATION, SUBACUTS/CHRONIC, minimal sassas EKTxeigrlomlnieandraelonGsrDaoactyreifi+ c3S3eubset 2 Animal 53 siomed off from necropsy Ps Gross pachotoay + No Maocsrsoscopic Amommality Observed Histopathology ose INFLATION, SUBACUTE/CHRONIC, TOOTH, mild. 665949 ASTKnxeiiprlmomlanielundzaelo55nGSaSDrciaoorywnief+di+ c3S3oefufbseftrom2 necropsy - Gross pathotony No Maocsreoscopic Abnormality Observed Atstopathotosy oss:DEGENERATIONATRORIY, OLEACIORY, WICOSA, mila reese------=eieemesimre------ `Compeny Sentzad. Doss not contain TSCA Ca 5205-0Da9y9Ga1v0adg1e.2S5t5u0d0y,inSiubltrRotisc Tovcy Dupont 11671 ~ orCom}!houin&g anIinndailvidduaatla afnoirnailndiLviisdteisntg ApeRovED sRoTOCOL +1 anisals Dose Group 1 TIT 0 %a/kg Surfactant Bosses | Sex: Males Aninal Ret Microscopic & acroseopic Findings cosas KTeirlmliendalonsbaacyrif: ic3e0 AEnxipmoaslure55Grso3u9p00d+ OSFuFbseFtrom2 necropsy axoss sathology Ho Maocsrsoscopic Abmomality Observed Histopathology : No Miocsrsoscopic Abnormality Observed cases TKeirlmliendalonsbaacyrif: ic3e6 AEnxipmoaslure53Gr3o1wp0d+ SOFuFbseftro2m necropsy --_ Gross Pathology No Maocsreoscopic Abnormality Observed itatopathology : No Miocsreoscopic Abnormality Observed : -- -_------ `Company Sanitized. Does not contain TSCA CBI 9H0-D-ay2Gaav5nadgH4e-2S95509t0i:nuSMuabldcehRroayntiscToxicity DuPont11671 -- howing anIinmdailviddautaal AfnoirmailndiLviisdtuianlg animals DsotsuepyGEOUP: V 1000 magl/ekg(+HA-P2P54R3O5VED PRSOeTxO:COMLal+e)s Animal Ref Microscopic & Macroscopic Findings sesss2 KTielrlmeidnalonSDaacyrif: ic2e8 AEnxipmoaslureisGrsoiugpned: oSfufbseftrom2 necropsy Gross Pathology : No MaNcorsoescopic Abnormality Observed Histopathology Nose D: EGENERATION/ATROPHY, OLFACTORY, MUCOSA, 'DECENSRATION/REGENERATION, RESPIRATORY, MUmCodOeSrAa,tem.inimal. EXUDATE, NASAL CAVITY, moderate. 665963 KTielrlmeidnalonSaDcaryi:fic2e8 --~ . AEnxipmoaslureisGrsoiugpned: oSfufbseftrom2 necropsy Gross Pathology : No Moacsrzoscopic Abnormality Observed : Histopathology No MNicorsoscopic Abnormality Observed : 665364 TKeirlmliendalonsDaacyr:ific28e AEnxipmoaslureisGrsoiugpned: oSfufbseftro2m necropsy Gross Pathology : No MaNocsreo.scopic Abnormality Observed : Histopathology : NoSE I: NFLAMMATION, SUBACUTZ/CHRONIC, minimal --_ - Company Sanitzed.Doos not contenTscAca 0H--2D5a4y99GaavnadgHe-2S5t5u0d0y:inSMuablcherRoantisc Toricity DuPont11671 --~ bowing anIinmdailvidduaatla AfnoirmailndiLviisdtuianlg animals sDtouspeyGroup: V 1000 mgl/ekg(+HA-P25P4R9O9VED PRSOeTxO:COLMal*)es Animal Ref Microscopic & Macroscopic Findings ses96s TKeirlmliendalonSDaacyrif: ic28e AEnxipmoaslureisGrsoigunped: Subset 2 off from necropsy Gross Pathology No MaNcOrSEoscopic Abnormality Observed : Histopathology + Noss : DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, minimal sessss TKeirlmliendalonSDaacryif: ic28e AEnxipmoaslureisGrsoiugpned: oSfufbseftro2m necropsy --_ Gross Pathology : No MaNcOrSoEscopic Abnormality Observed : Histopathology No MiNcorsoescopic Abnormality Observed : --_ _--_-- Te `CompanySanftized.Doesnot contain TSCA CBI 9H0--2D5a4y99GaavnadgHe-2S5t5u0d0y:inSMuableterRoantisc Toxicity DuPont 11671 -- howing anIinmdailvidduaatla AfnoirmailndiLviisdtuianlg animals Dsmoospey Group: I 0 WG/kgle (+ ASPexP:ROVMEalDesPROTOCOL +) Animal Ref 665937 Microscopic & Macroscopic Findings KTeirlmliendalonsDaacry:ific91e AEnxipmoaslureisGrsoigunped: oSfufbseftrom3 necropsy Gross Pathology No MNaocsrgoscopic Abnormality Observed : Histopathology : No MNiocsrgo.scopic Abnormality Observed ses938 KTeirlmliendalonSDaacryi:fic9e1 AEnxipmoaslureisGrsoigunped: oSfufbseftrom3 necropsy ~~ Gross Pathology No MaNcosrEoscopic Abnormality Observed : Histopathology No MiNocsreo.scopic Abnormality observed : 665935 TKeirlmliendalonSaDcaryi:fic9e1 AEnxipmoaslureisGrsoiugpne:d oSfufbseftrom3 necropsy Gross Pathology : No MaNcosreoscopic Abnormality Observed : Histopathology No Moicsroscopic Abnormality Observed --_ me Tiree `Company Sanitized. Doss not contain TSCA CBI / H90--Day2Gaa5nvda4Hg-e29S5t5u09d0y:inSMuabclherRoantisc Tonicity DuPont.11671 - howing anIinmdailviddautaal AfnoirmailndiLviisdtuianlg animals sDroospeyGroup : I 0 mg/kagle (x ASePxP:ROVMEalDesPROTOCOL +) Animal Ret Microscopic & Macroscopic Findings ses940 KTielrlmeidnalonSDaacyrif: ic5e1 AEnxipmoaslureisGrsoiugpned: oSfufbseftrom3 necropsy Gross Pathology : No MaNcosreoscopic Abnormality Observed : Histopathology No Microscopic Nose Abnormality Observed : sessa1 TKeirlmliendalonSaDcaryif: ic5e1 AEnxipmoaslureisGrsoiugpned: oSfufbseftrom3 necropsy --~ Gross Pathology No MaNcosrzoscopic Abnormality Observed : Histopathology Nos D: EGENERATION/ATROPHY, OLFACTORY, MUCOSA, minimal INFLATION, SUBACUTE/CHRONIC, `minimal ~~ T ee r ------ CompanySanitized.Doesnotcontain TSCACBI 0H-D-ay2Gaanv5dagF-e42S5t5u90d0y:iSnuMbaclheroRnaitsc Tonicity DuPont 11671 sTopy holewin(g+ anIinmdailviddauatla AfnoirmailndiLviisdtuianlg APPROVED PROTOCOL +) animals Dose Group: III 0 mg/kg Surfactant K-25500 Sex: Males Animal Ref Microscopic & Macroscopic Findings ses9s2 KTeirlmliendalonSDaacyrif: ic9e1 AEnxipmoaslureisGrsoiugpned: oSfufbseftrom3 necropsy Gross pathology : No MaNocsreo.scopic Abnormality Observed Histopathology Noss:DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild ADHESION, TURBINATES, minimal cases KTeirlmliendalonsDaacyrif: ic9e1 AEnxipmoaslureisGrsoiugpne:d oSfufbseftrom3 necropsy --~ Gross pathology No MaNcorsoescopic Abnormality Observed : Histopathology : Nose. 'DEGENERKTION/ATROPHY, OLFACTORY, MUCOSA, mild. ADHESION, TURBINATES, mild ses950 KTeirlmliendalonSDaacyri:fic5e1 AEnxipmoaslureisGrsoiugpned: oSfufbseftrom3 necropsy Gross Pathology : No MaNocsrso.scopic Abnormality Observed : Histopathology : Nose ':DEGENERATION/ATROPHY, ADHESION, TURBINATES, OmiLlFdA.CTORY, MUCOSA, mild. --~ - `Company Sanitized. Doesnotcontain TSCA CBI 9H0--2D5a4y99GaavnadgHe-2S5t5u0d0y:inSMuableherRoantisc Toricity DoDumPonnt11e671 --~ stupy ahloeuin(g+ anIinmdailvidduaatla AfnoirmailndiLviisdtuianlg APPROVED PROTOCOL +) animals Dose GFouwp : III70 mg/kg Surfactant K-25500 Sex: Males Animal Ref Microscopic & Macroscopic Findings ses95s KTeirlnliendalonSDaacyrif: ic9e1 AEnxipmoaslureisGrsoiugpned: oSfufbseftrom3 necropsy Gross pathology : No MaNcorsozscopic Abnormality Observed : Histopathology : nose D: EGENERATION/ATROPHY, ADHESION, TURBINATES, mOiLlFdA.CTORY, MUCOSA, mild. 665956 KTeirlmliendalonSaDcaryif: ic5e1 AEnxipmoaslureisGrsoiugpne:d Subset 3 off from necropsy ~ Gross Pathology : No MaNcorseoscopic Abnormality Observed : Histopathology Noss I: NFLAMMATION, SUBACOTS/CHRONIC, minimal. A''DDDHEEEGGSEENINEOSRRNAA,TTIITOOUNNR//BARITENRGAOETPNEHESYR,,ATIOmOLiNFn,AiCmTaROlER.SYP,IRAMTUOCROYS,A, UmCiOlSdA., mild. ~~ - `Company Sanitized. Does not contain TSCA CBI S 9H0--2D5a4D y99Gaavnw adgHe-2S5O t5u0d0y:iw nSMuabcli heroRaniiscgTorice ity SudvinMaer DDuuoPs owntn-i1s 1e67n1 --~ howing enIinmdailvidduaatla AfnoirmailndiLviisdtuianlg animals DsorsuepyGi%p: V 100 magl/ekg(+HA-P2P5R49O9VED PRSOeTxO:COMLal*)es Animal Ref 665967 Microscopic & Macroscopic Findings KTeirlmliendalonsDaacyrif: ic9e1 AEnxipmoaslureisGrsoiugpned: oSfufbseftrom3 necropsy Gross Pathology : No MNaocsrEoscopic Abnormality Observed Histopathology ses968 nose ':DECENERATION/ATROPHY, OLEACTORY, MUCOSA, mild. TKeirlmliendalonSDaacyrif: ic9e1 AEnxipmoaslureisGrsoiugpned: oSfufbseftrom3 necropsy -- Gross Pathology : No MaNcorsoescopic Abnormality Observed Histopathology : Nose D: EGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild. 665965 TKeirlmliendalonSaDcaryif: ic5e1 : AEnxipmoaslureisGrsoiugpne:d oSfufbseftrom3 necropsy Gross Pathology : No MaNcosreoscopic Abnormality Observed : Histopathology NosE : 'DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild ~~ FE Ere `CompanySanitized.Doesnotcontain TSCA GBI 9F0--Day2Gaa5vnadg4He-S29t5u5d090y:inMSuablcehRroantisc Toxicity DuPont11671 --~ stop howing anIinmdailvidduaatla AfnoirmailndiLviisdtuianlg animals ale (+ APPROVED PROTOCOL +) Dose GYoup : V 1000 mg/kg H-25439 Sex: Males Animal Ref, Microscopic & Macroscopic Findings ses970 KTeirlmliendalonSDaacyrif: ic9e1 AEnxipmoaslureisGrsoiugpned: oSfufbseftrom3 necropsy Gross Pathology No MaNocsreo.scopic Abnormality Observed : Histopathology + oss DEGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild. sess71 TKeirlmliendalonSDaacyrif: ic9e1 AEnxipmoaslureisGrsoigunped: oSfufbseftrom3 necropsy --_ Gross Pathology No MaNocsreo.scopic Abnormality Observed Histopathology Nos D: EGENERATION/ATROPHY, OLFACTORY, MUCOSA, mild EXUDATE, NASAL CAVITY, mild. -- -_-- Te `CompanySanitized. DossnotcontTSaCAiCBnI 91D0.-2uD5ya4y9G9Gaaonvvdag2ee5SS5tu0udd0yy:innSMMuaablctheerRoRantaiscsToxicity -- DDuuPmonto-1n167t1 APPENDIX B INDIVLIISDTUIANLGAINNIDMIAVILDMUIACLRAONSICMOAPILCS OABFSFEERCVTAETDIONS --~ --_ Teams CompanySanitized. DoesnotcontainTSCA CBI rs 1 Ei T T gyo| T s UEEE3E2RE3E:E | 2 igi iE 41 3 ; 5agz 7 8 | ;52 -- gfiE; | || af Iiiae: :. iy 3: ~i : oBeig og iit PEoBogdig fin 2 i ~ : Ee 1s i Toe Hi Tzggaz | Lia as : HILL ih 8 A eR. EEE 8 : EB 3F oo: bHiyi ~ |i | i i i FPo o fr jB=s : ~5 if | 0 gE 4 Pom PfeoEE a Ei iig:: i gh ia EE TTT OE | 2 3i | 5; : if WO BET DHE | ] ERE Cf RHEEEECEE 8 eRe CESE EF EE L i lih a gg; | | i PFgoog | : Po, i R iBE F1 I i i Hi(l5t]3 i