Document YDRaMo30v9L13LzordyQr1bJ8

ARR26 _ 3251 = --_ --Tr TRADE SECRET ARR26 325] DluPiont11238 Study Title H-25357: Approximate Lethal Dose (ALD) by Skin Absorption in Rabbits Laboratory Project ID: DuPont-11238 AUTHOR: Carol Finlay, B.A. ~ STUDY COMPLETED ON: August 1, 2002 PERFORMING LABORATORY: E.L du Pont de Nemours and Company Haskell Laboratory for Elkton Road, P.0. Box Health 50 and Environmental Sciences Newark, Delaware 19714-0050 TT wan `Company Saniized. DenotecontsainTSCACB) --_ 52597:ApprosimatLetaDoss (ALD) bySinAbsorpioninRabbis Duron 11238 CERTIFICATION `We, the undersigned, declare that this report provides an accurate evaluationof the data obtained from this study. Reviewed by: eastd= haZT Lis ly"Jnee, acdbyStudyDist: lea hTFpi ileoy Ldeag-2002 ~ --_ o-- em --T-- ii---- ---- Company Santzed.Dossnot contain TSCACEI -- - = STUDY INFORMATION `Substance Tested: --') Synonvms/Codes; H-25357 A Submiter's Notebook Numb: [HNN Haskell Number: 25357 aS Regi Nome: [RNY nie Jig] Physical Chaacerstie: Amberliquid Sponsor: WE.iLlmdiungPtoonnt,dDeeNleawmaoruers19a8n9d8Company USA. Study Initiated/Completed: June 17, 2002/ (see report cover page) In-Life Initiated/Completed: July 2, 2002/ July 16, 2002 e-- e e----------rp-------- 3- Company Sanitized. Does not contain TSCA CBI -- H:25357: ApproximateLethalDose (ALD) by Skin Absorption in Rabbis DuPont 11238 STUDY PERSONNEL Study Director: Carol Finlay, B.A. Management: Scott E. Loveless, Ph.D. Primary Technician: James C. Mackay IT Toxicology Report Preparation: Sean M. Callaghan, B.A. Management: Nancy S. Selzer, M.S. Laboratory Veterinarian: William Singleton, D.V.M., A.CLLAM. --_ ee `C--ompa--ny --Sanit--ized--. Do--es n--ot contain TSCA CBI H:25357: Approximate Lethal Dose (ALD) by Skin Absorption in Rabbis DuPont-11238 SUMMARY 5H0-02053m5g7/kwga.s Taphpeliaepdpltiocatthieosnhsaivteedw,aisntsaecmtis-koicnoclfu2demdafloer aNpepwroZxeiamlataenldyW2h4itheourrasbbaifttseratwahidcohsethoef wteesitgshutbesftfaencctes,waansdrdeemrmoavle.effTechtesrfaobrbi1t4sdwaeyrsefooblsleorwivnegd rfoermocvlianliocafl tshiegntseostfstuoxbisctiatnyc,eb(owdeyekends excluded). aNpoprdoexaitmhaotcecluyrr2e%d.ofThineitraalbbwietisgehxthiobcictuerdrendoicnlionniecoalftsihgensrdabubriitnsgbtyhethsetuddayy. aBfoidyapwpeliigchattiloonsosfof the test substance. No biologically important weight loss substance produced no dermal irritation in either rabbit. occurred in the other rabbit. The Under the substance icsocndointsiiodnesroefdthtoibsetevset,rythleoAw LinDtowxaiscigtyre(atAeLrDthgarnea5t0e0r 0thmagn/5k0g0o0fmbgo/dkye)wewihghetn. This administered as a single dermal dose to rabbit. -- --_-- Company Sanitized. Does not contain TSCA CBI H-25357: ApproximsteLethalDose (ALbyDSk)inAbsorption in Rabbis Dupont 1258 INTRODUCTION o`fThHe-p2u5r3p5o7s.eoTfhtheiAs LstDudwyawsadseftiondeedtaesrmtihneelaonweasptpdroosxeiomfattehelettehsatlsduobsseta(nAcLeDa)dmbiynissktienraebdstohrapttion 5ca0u0s0edmgt/hekgdoefatthesotfasubtessttaannciemaanldwnietihtihner1a4ndiamyaslodfieesx,ptoshuerne.theId2feramnailmAalLsaDrweidlolsbeedrwepiotrhted to be greater than 5000 mg/kg. MATERIALS AND METHODS A. Test Substance w`Tahse itensvtesrutbesdttaoncmei,xHb-e2f5o3r5e7c,acwhasamsouuppnltiefdorbdyotshiengspwoanssorremaosvaend.ambTehre tleisqtuisdu.bsTthaencteesatpspuebasrteadncteo be stable under the conditionsofthe or physical state, was observed. study. No evidenceofinstability, such as a change in color --~ B. Animal Husbandry RYeosuenagrcahduPlrtodmuacltes,HDMe:nv(eNr,ZWPe)nBnsRylNvaenwiaZ.eaTlhaendraWbhbiittsewrearbebihtsouwseerde sriencgeliyveind sftraoinmleCsosvsatneecle, ``wniurmeb-emrewshhiccahgewsassursepceonrddeeddaobnoavecacradgeafbfoiaxredds.to Ethaechcargaeb.biTthweaslasatss3idgingeidtsaoufnitqheueidiednetnitfiifciactaitoinon wneurmebeorffwereerdeawprpirtotxenimoantetlhey i1n2s5idgeroafmesaochfPrMabIbiNtu'streiatriownitIhntaemwaattieornailn,soIlnucb.lCeemrtairfkieerd.HTighhe Fraibbbeirts Rabbit LabDict 5325 daily during the study. Water was availableadlibitum. fAosllsopewciinfgipedroicnetdhuereHsasakreelpleLrafboorrmaetdorpyerainoidimcaalllhyeatlothenasnudreenthvaitrcoonmnetnatmailnamnotniltevoerlisnagrperboeglraomw, the those that would be expected to impact the scientific integrityofthe study: + aWnadteorthsearmcpolnetsamairenaanntasl.yzed for total bacterial counts, and the presenceof coliforms, lead, + Feed samples are analyzed for total bacterial, spore, and fungal counts + bSyamtphleecsagferwoamshferressh.ly washed cages and cage racks are analyzed to ensure adequate sanitation -- rCeerqtuiifrieemdeanntismaanldfneoetd tios eusxecde,edgusatraatnetdemedaxbiymtuhemmcaonnucfeancttruarteirontsoomfekeetyscpeocnitfaimeidnanunttrsi,tiionncalluding specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The _--_-- ep -s Company Sanized. Does ri cantain TSCA 0B ~~ 22p5re3s5e7nc:eAopfprtohxeismeactoenLettahmailnDaonstes (bAeLlDo)wbytShkeimnaAbxsiormpurimoncionnRcaebnbtirtast_ ion st_ ated b_ y the manuDfuaPcotunrte1r1238 `would notbe expected to impact the integrityofthe study. l`aTbhoeraantiomraylanheiamlatlhvaentedriennavriiarno.nmeEnvtaalluamtoinointoofritnhgesperdoagtraadmidisnaodtmiinndiisctaetreedanbyyctohnediattitoennsditnhgat affected the validity ofthe study. ARnabibmiatls rwoeoremswewiegrheemdaianntdaoibnseedrovnedaftoirmegre-nceornatlrohlelaeldt,h 1d2u-rhionugrthleig7h-td/a1y2-qhuoaurradnatrinkecypcelrei.od. rEenlvaitrivoenmheunmtiadlitcyoonfdi5ti0o%nsof1t0h%e.roExocmusrswieornestoaurtgseitdeed tfhoersae treamnpgeersawteurreeojfud2g0edCt+o h1avCeabneden of insufficient magnitude and/or duration to have adversely affected the validityofthe study. C. Protocol sOcnaptuhleardatyo tbheefolruemdboasrinrge,gitohne.furof each rabbit was closely shaved to expose the back from the o`fThbeotdesytwseuibgshtta.ncTehweaasmmoeuanstuorfetdesfotrseuabcshtaannciemdaelsoingntahteeddafyoorfeatcrheaatnmiemnatlawtaasdcoaslecuolfatSe0d0b0amsge/dkg --_ roanbbtihtestweestisguhbesdta2n2c6e6doerns2i1t6y4ofgr1a.m09sgo/nmtLheanddaythoefbtoredaytmweneti.ght collected prior to treatment. The d`Tohresaalresakitnoobfecatrcehatreadbb(iatppwriotxhiwmaatteerl-yin6s"oxlu5b"leorma1r9k0ers.quaItrweacsenntoitmefteaesrisb)lewtaosampaprlykethdeotnestthe ssupbrsetaadnocendtair2oectpllyy,to6t"hex s5k"ing.auTzheepaadl.iquTohtoefgatuezetepstadsuwbasstapnlcaecdeedsoingtnoattehdefotersatnsitaen.imTahlewraabsbits r`waebrbeittshweenrwerafiptpteeddwwiitthhpslausctciecscsoilvlearlsayteorsporfesvternetticnhgegsatuizoenofbatnhdeagteestansdubasdthaenscieveorbdainsdraugpet.ionThoef othbesewrrvaepdpifnogrs.clinAifciaelrswirganspopifntgo,xitchietyraabpbiptrsoxwiemraetreeltyur2nheodturostahfetirr cdaogseisn.g.The rabbits were wArpapprpoixnigmsataenldyc2o4llahrosurwserafelerretmroevaetdm.entE,xctehessratbebsittssuwbesrteanrceemwoavsedwafsrhoemdthferiormcathgeesanainmdaltsh'e backs with Lander soap and retumed to their cages. wAaprprmowxaitmeart,ealnyd|thheousrkianftdrriteedstwsiutbashtapnacpeerretmoowevla.l,Tthhee rabbits were then animals were dweerimgahledirarintdatoibonsewrevreedmfaordeclianciccoarldsiinggnstoofthteoxDircaiitzyeanScdadleer(mTaalblierri1t).atAion.glOobsssearryvoatfidoenrsmfaolr defefremcatls ainrrditaabtbiornevwiearteiomnasdies pdraeisleynftoerd1a4s dTaaybsleaf2t.eOtbrseeartvmaetnito(nwsefeokrecnldinsiceaxlclsuidgendso).ftOobxsiecrivtaytainodns sftourdym.ortTahlietyanainmdalssigwnesroefwiellingeshse,dinojnurtyh,eodraaybonfortmraealtmbeenhtavainodrownerdeaymsad1,e7,daainldy t1h4rfooulglhoowuitntghe treatment ~~ * tOontaelhbuonddyresudrnfianceeotyfrsqaubabrietsceinnttihmee2t-e3rskoerboapdpyrwoexiimgahtterlayng6e. 5is approximately equal t 10percent ofthe -_-- Cornpany Sanilized. Does rot contain TSCACail 125357: Approximate Lethal Dose (ALD) by Skin Absorpion in Rabbits ~ RESULTS AND DISCUSSION DuPont11238 A. Dose Information and Mortality No death occurred. detailed below. The dose regimen and the mortality resulting over the 15-day test period are "Animal Number g/kg] Amount | Initial Body (nL) Weight (5) | Morality [sss| soo | ioa | 2266| No | 35561 | S00[99[a1 | No | B. Clinical Observations, Body Weights, and Skin Responses o"Tfhienirtaibabliwtseiegxhhtiboictceudrrneodcliinnoicnaelosfitghnes druarbbiintgstbhye tsthuedyd.ayBaofideyr awpepilgihctatlioosnsooffthapeptreosxtismuabtsetlaync2e% dNeormbaiolloigriictaatliloyniinmepoirtthaenrtrwabebiigth.t loss occurred in the other rabbit. The substance produced no Individual Individual body weights and dermal responses individual clinical signsoftoxicity are presented inTable 4. are presented in Table 3. CONCLUSIONS sUunbdsetrantchee icsocndointsiiodnesroefdtthobsetevset,rythleoAwLinDtowxaiscigtrye(atAeLrDthgarnea5t0e0r0thmagn/5k0g0o0fbmeo/dkye)wewighhetn. This administered as a single dermal dose to rabbits. RECORDS AND SAMPLE STORAGE NSpeewcairmke,nDsel(iafwaapprlei,caobrlaet),IrronawModuatnat,aainndRtehceofridnsalMraepnoargtewmilelnb,eWrieltmaiinnegdtoatn,HaDseklealwlarLea.boratory, ~~ -- = `Company Sanit} ized. Does not--contain TSCA Gat --~ 2H:255 357: SAppperorxoimnateeLLeetahall DDoossee((AALLDD))bbyySSkkiinn AAbbssoorrpprtiioonniinnRRaabbbbitiss DDuuPoPnotn1t112132388. --~ TABLES _-- 0 Company Sanitized. Does nt contain TSCA Caf -- S 125357: Approximitee Lethal DEosSe (ALD)byr Skin Absorpion in Rabe bits n Du2 pont18 1238 TABL|E DRAIZE* SCALE FOR SCORING SKIN IRRITATION EvaluationofSkin Reactions Score Erythema and eschar formation: NVOerCy slOighVt erEythec ma(Barely POrCEPHDr IE)...........cors ermrmrerenrreeen 0 1 (Slight) MWeOlGlE-TdeAfEin1e0dSEeVrERyEtEhreYmIaN.EM.R.vrses nses 2 (Mild) 3 (Moderate) Severe erythema (beet redness) to slight eschar formation (injuries in depth) .. 4 (Severe) Edema formation: `SVleirgyhstleigdhetmead(eemdage(saorfealryeaPEwreClelpHdBeIfEi)n.ed.b.y deefrinintesrmissinog)n.n..s..o.e..e..o..e..n 1 2 (Slight) (Mild) MSeovdeerreateedeemdaem(arai(siesdemdoraepptrhoaxni1m.a0tmelmy 1.e0xtTemnd)in.g.b.e.y.on.d.tohreeanreoaronfreorrer 3 (Moderate) --r ~ ee EXPOs SUE)e er ------r ----a ----n eeet i ---- (-- SEVETE. ) a DEPpd.oitzo4r6ei.a5,Jl9..CHo,mm"iDtemenealofTtohxeicAistsy.o"ciAaptoonmoifsiFooofdhaenSdafDertuygoOffCfihciialcssofthienFUonoitdesd,SDarutgs,aAnusdtCions,mTeetxiacss,. 1T95h0e, - TT CompanySeized. Doesnotcontain TSCACBI --~ LH2:2553357:: AApppprrooxviimmaatteeLLeetthhaallDDoossee((AALLDD))bbyySSkkiinnAAbbssoorrppttiioonninnRRaabbbbiittss___DuDuPPoonntt111223388. TABLE 2 GLOSSARY OF DERMAL EFFECTS Blanching Eschar white appearance to skin scab on the skin that is more superficial than necrosis. This is Desquamation considered to be severe imitation. dry, flakingofthe skin Fissuring Fissuring with Bleeding aa sspplliitt oorr cclleefft inn tthhee tskoipnlwayietrhobflsekeidninwgithout bleeding Hyperkeratosis tchoilcokr,)orfythdeistcooplolraayteironof(usskiuna.llyThbiust nisotcolnismiidteerdetdotborboewsneovrerwehite in imitation. Sloughing peelingofthe detached top layerofskin, and epidermal scaling that has Necrosis a`Trheiasoifs croonusgihdvehraerdd/tcorbyeblcaocrkroosriodnarakncdoalnorierdresvkeirnsitbhlaetemffaeyct.crater. Epidermal Scaling parleatseillilkeatatraecahsoedfttohevitaobplelsakyienr.ofTshkiisnmtahaytphraovgeressespatroastleodufghrionmg.but Thickening --_ Ulceration skin is firm and/or dense to the touch. `open sore representing lossofsuperficial tissue: ABBREVIATIONS OF OTHER DERMAL EFFECTS - = NoEffect A = Abraded B = Blanching C = Eschar D = Desquamation F = Fissuring G = Fissuring with Bleeding H = Hyperkeratosis I= Intact L = Sloughing N = Necrosis R = Raw Areas S = Epidermal Scaling T = Thickening X = Compound Adhered to Skin --~ eT ------ Company Sanitzed. Doss not contain TSCA Ca 12H5:23553577:: AApppprrooniimmaatteeLLeetthhaallDDoossee ((AALLDD))bbyySSkkiinnAAbbssoorrppttiioonniinnRRaabbbbiitss DDuuPpoonnet1111223388 RABBIT NUMBER| (mg/ke 35563 | 5000 3ss61 | 5000 TABLE 3 INDIVIDUAL BODY WEIGHTS (8) INITIAL DAYS AFTER APPLICATION. WeGHT 2266 [1 20 TT 7 3562Ti268a 7 | 2164 2143 2458 2562 CLINICAL SIGNS OF TOXICITY OBSERVED IN RABBITS No clinical signsoftoxicity were observed in any ofthe rabbits during the study. e Companr ySankized.Dos. snctcontainTSCA Cal -- 1L12553537,: ApApprrooxxiimateLethalDDoosse((ALD)bbySSkkinAbsoorrpptoionniinRRaabbbiits TABL4E INDIVIDUAL DERMAL RESPONSES DuDbuopnotn-t1111223388 ERYTHEMA RABBIT DAYS AFTER APPLICATION NO3M5B56E3R[ TTT5776 17 |80 [o[0 [To [15[ 1a] 35561 0| o EDEMA RABBIT DAYS AFTER APPLICATION NO3M5B6E3R[|TT0 T|50716 170 [8[0 [9[10 [15|1a] ssl | 0 | 0 o |oo ~ --- CompanySanitzed.Does noteontainTSCAcar