Document 0gm2R296j8mO2Opk80mne9X8M

ARRAE -- 3250 432 ARRRG - 3250 DuPont11101 -- TRADE SECRET Study Title H-25357: Acute Dermal Irritation Study in Rabbits Laboratory Project ID: DuPont-11101 TesT GUIDELINES: U.S. EPA Health Effects Test Guidelines OPPTS 870.2500 (1998) OSeEctCiDonG4u:idHeelailntehs EffofrecTtess,tiNnog.of40C4he(m1i9c9a2)ls CommissionDirective 92/69/EEC EEC Method B.4 (1992) AutHor: Carol Finlay, B.A. STUDY COMPLETED ON: August 1,2002 PERFORMING LABORATORY: EH.aL.skedlulPLoanbtodreatNoermyofuorrsHeaanldthCaonmdpEannvyironmental Sciences - NEelkwiaornk,RoDaedl,aPw.a0r.e B1o9x71540-0050 -- - Page 10718 Company Sanitized. Does not contain TSCA CBI 125357: Acute Del Iason Studyin Rabbis DuPont11101 ~ GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT "This studywas conducted in compliance with U.S. EPA TSCA (40 CFR part 792) Good Laboratory Practice Standards, which are consistent with the OECD Principlesof Good Laboratory Practice (as revised in 1997) published in ENV/MC/CHEM(98)17, except for the item documented below. The item listed does not impact the validityofthe study. `The test substance was characterized by the sponsor prior to the initiationofthis study. Although the characterization was not performed under Good Laboratory Practice Standards, the characterization was donebyan ISO 9000 certified lab and the accuracy of the data is considered sufficient for the purposesofthis study. Appli/Scpoansnort: E.L du Pont de Nemours and Company Wilmington, Delaware 19898 USA. StudyDirector: `Carol Flalay, BA. - dDu;s - 206 -- SafToxicologist Applican/t Sponsor: DuPont Representative Date --~ Company Saniized. Doss not contain TSCA CB - 1425257 ActDor non Sty Rais ~ QUALITY ASSURANCE STATEMENT Dini `Haskell Sample Number(s): 25357 DatesofInspections: Protocol: June 18, 2002 Conduct: June 18, 2002 Records, Reports: July 22-23, 2002 Dates Findings Reported to: ~ Study Director: July 23, 2002 Management: July 23, 2002 Reported: Matthew Fron Quality Assurance Auditor If=g - 2202 Ds Company Saniized. Doss notcontain TSCA G.:. - 125957: Acute Dermal naion Say n Rabbis Dupone1101 ~ CERTIFICATION rWeo,mtthheisunsdtuedrys.igned, declare tha tis report providesanaccurate evaluationofthe data obiained Reviewed by: m"AssociCtle SLacZierntT Lelymn suedbySugy Director: SeToiont3.h L-dug 108 v --_ -- -- Company Sanitzed. Doss not contain TSCA Cat --~ PS : ZHIe253,57: AAccuteeDDoerrvmaallIIfaattiioonn SSutdudyyiinnRRaabbbbiltes DuDuPpoonwt-i11l1i01l TABLE OF CONTENTS Page GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT .cnsnn QUALITY ASSURANCE STATEMENT wovsnsamsssnsnssmssssisssssssnsnd CERTIFICATION ccrrmsrmmsmmsmmsssssmssmssmsmssmssnssmsssmmmsmsssssndd STUDY INFORMATION worms STUDY PERSONNELccna] SUMMARYcourses INTAlROODUUCTIIO.N ors rsigrm upgmss mmmmmmmmasms mees eers ore) red B. Principles Ofthe MethOdOIORY cvs MATJ ERIALS AND METHODS cers) a C.. D, PAnIiSmaOl.HUSrDrErAeYrcrorrrnnnemsrnmsmosnsssmsssnmmsmsmssssemsemsseonenrsrnesenenrnernerereoeen1100 E. Data Analysis and Inferpretation OfRESUIS...........cvvomrecssvsosonr 1 RESULTS AND DISCUSSION vcs12 CONCLUSION ocomemmmsmsssssmmsmsmmsmssmssmsmsmsmmmmsssssimnd2 RECORDS AND SAMPLE STORAGE wns13 J 1. DRAIZE SCALEFORSCORINGSKIN IRRITATION.., . 1751 2. GLOOFSDESRMAALEFRFECYTS. pr------ frr-- 3. DERMALRESPONSES OBSERVED IN INDIVIDUALRABBITS... smmmmenm--tp 4. SUMMARY OF MEAN SCORESFOR DERMALRESPONSES... 11 S.. INCIDENCES OF DERMALRESPONSES (SCORES)..... smemm------ 6. BODY WEIANDG CLINHICATLSIS GNS OFTOXICITY OBSERVED IN RABBITS........ 18 Company Sanitized. Doesnotcontain TSCA CBI eeeTet B225957: AAcuesDDeevrmaallImmaitoonnSSuyyiRinaRbabiiss STUDY INFORMATION substance TesFT) Synonyms/Codes; + H-25357 Submitter's Notebook Numbers) JSST) Haskell Number: 25357 CAS Regisry Nomver: [SNE pwDeuwipneiror Physical Characteristics: Amber liquid Sponsor: E.L du Pont de Nemours and Company Wilmington, Delaware 19898 USA. Study Initiated/Completed: June 14, 2002/(see report cover page) In-Life Initiated/Completed: June 18, 2002 / June 21, 2002 - Company Sanitzed. Doss nal contain Tar rm OOOO H-25357: Acute Dermal Iiaton Study in Rabbits DuPont11101 --_ STUDY PERSONNEL Study Director: Carol Finlay, B.A. `Management: Scot E. Loveless, Ph.D. Primary Technician: EricaK. Pia, B.S. Toxicology Report Preparation: Sean M. Callaghan, B.A. Management: Nancy S. Selzer, MS. Laboratory Veterinarian: William Singleton, D.V.M., ACLAM. -- CompanySanitized. Doesnotcontain TSCA CBI r _----mm os EH:S25T57:: AAccueteDDeerrmmaallIImiatattiioonnSStudtyiiannRRadabtbibytiss DomDuPionnt-i11o101n SUMMARY AH-n2a5l3i5qu7otwoafs0e.v5almuaLtoefd tfohreatcesuttesusbksitnainrcreitwataisonapdomtiennitsitaleriend3tom2alleocNaeliwzeZdetaelsatnsditWehointteherabbbaictks.of ebaecthweaennimtahle.skTihneatnedsttessittessuwbestraencceo.veTrhede waintihmaalssewmeir-oececxlupsoisveeddtroestsheintgetsot seunbssutraencceonftoarct aapppprrooxxiimmaatteellyy 41,h2o4u,rs4.8,Tahnedf7e2sthsoiutresswaefrteeretvhaeleunadteodftahned s4c-ohroeudraecxcpoorsduirnegpteoriaomd.umerical scale No dermal iritation was observed observed, and no body weigh loss in anyofthe occurred. rabbits during the study. No clinical signs were Mqueaantnitvaatliuveesevwaelrueatciaolncoufltatheed f2ordeeramcahlarneismpaolnsseepsa(reatreyltyhefmraomanndumeedreimcaal) socbosreersveodbtianitnheed rfarbobmitsthaet 24,48, and 72 hours following test substance removal. These values are as follows: Rabbit Number Erythema Edema. 35554 0 0 35558 0 0 35555 0 0 ~ In accordance with Directive 67/548/EEC, H-25357 is not classifiable as irritant CompanySanitized. Does not contain TSCA -_-- En B21925335577::AAwcuteeDDeerrmmaallbIriatattiioonnSSttuuddyyiiRn aRabbbbiiss____ --_ INTRODUCTION DuDubPoonntt-i1u11i0o1n A. Objective rTehveerosibbjielcittiyoveoffdtehrimsalsteufdfyecwtsaosftoH-e2va5l3u5a7teftohleloswkiinngiari4t-ahtioounr/cdoerrrmoasliveexppootseunrtiealinaanldbitnhoe rabbits. TlahbeelriensgulrtesqoufitrheemesnttusdyinwaecrceorudsaendcteowdiettherEmEiCn.e the appropriate toxicity classification and B. Principles of the Methodology `rDeemromvaalleorfytthheemteastansdubesdtaenmcae aartetheevaelnudaotefdtahned4s-chooruerdeaxtpo1,su2r4e, 4i8n,caacnhd o723fhoruabrbsiftosl.loThwei.ngthe reversibilityofany dermal effects is assessed for up quantified accordingto the Draize Scale (Table 1). to 14 days, ifnecessary. Dermal effects are MATERIALS AND METHODS A. Test Guidelines The study design complies with the following test guidelines: + POrfoftiecceotifonPrAegveenntciyon(,EPPeAs)ti(c1i9d9e8s).anOdPTPoxTiSc 8S7u0bs.t2a5n0c0eAsc(utOePTDeSr)maUl.SI.itEantviiorno.nmHeenatlatlh Effects Test Guidelines. + Organisation for Economic Co-Operation and Development (OECD) DermalIrritation Corrosion. Guidelinefor Testingof Chemicals. (1992). 404 Acute + EAucruotpeeTaenxiEcciotyno(mDiecrmCaolmImrurintiattiioen)s. (MEeEtCh)o(d1s9f9o2r).thDeiDreetcteirvmein9a2t/i6on/oEfETCoxAincintey.x V, Part B.A, B. Test Substance `wTahse tiensvterstuebdsttaonmcie,xHb-e2f5o3r5e7e,acwhasamsouunptpfolbriydoteshdiengspwoanssorreamsovaend.ambTehre ltieqsutids.ubsTthaencfeesatpspuebasrteadncteo be stable under the conditionsofthe or physical state, was observed. study. No evidence of instability, such as a change in color --_ _--_-- Company Sanitized. Does not contain Tara mms 5 12$925995577:; AAcucteeDDeerrmmaallIImiaattiioonnSSttadyyiinnRRaabbbbiiss _ --_ C. Animal Husbandry pwDuopmenntn1i11o0n1 Adult HM:(NZW)fBR New Zealand White rabbits were received from Covance Research cPargoedusctssu,spDeenndveedr,abPoevnnescyalvgaenbioaa.rdTs.heEraacbbhirtasbwbietrewahsouassesdigsniendglayuinnisqtuaeinildeesnstistfeiecla,tiwoinrne-ummebsehr `which was recorded on a card affixed to the cage. The last 3 digits ofthe identification number `were written on the insideofeach rabbit's car with a water insoluble marker. The rabbits were offered approximately 125 grams of PMINutrition Intemational, LLC Certified High Fiber Rabbit LabDiet 5325 daily during the study. Water was availableadlibitum. AfoslslpoewciinfgiperdioncetdhuereHsasakreelpleLrafboorrmaetdorpyerainoimdailcahletlaloytehnasnudreenthvaitrocnomnetnatmailna`nmtonlietvoerlisnagrperboeglraomw, the those that would be expected to impact the scientific integrityofthestudy: + 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 washed cages and cage racks are analyzed to ensure. adequate sanitation by the cagewashers. Certified animal feed is used, guaranteed by the manufacturtero meet specified nutritional ~ `requirements and not to exceed stated maximum concentrationsofkey contaminants,including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence ofthese contaminants below the maximum concentration stated by the manufacturer wouldnotbe expected to impact the integrityofthe study. `The animal health and environmental monitoring program is administered by thaettending laboratory animal veterinarian. Evaluationofthese data did not indicate any conditions that affected the validityofthe study. Rabbits were weighed and observed for general health during the 7-day quarantine period. Animal rooms were maintained on a timer-controlled, 12-hour light/12-hour dark cycle. rEenlvaitirvoenmheunmtiadlitcyoonfdi5ti0on%s of1t0h%e. rEoxocmusrswieornestoaurtgseitdeed tfhoersae treamnpgeersawteurree ojufd2g0edCto+ h1avCeabneden of - insufficient magnitude and/or duration to hav adversely affected the validityofthe study. D. Protocol Approximately 24 hours prior to treatment, the fur of3 male New Zealand White rabbits was closely shaved to expose the skin from the scapular to the lumbar region ofthe back. The rabbits weighed from 1914 to 2358 grams on the dayoftreatment. ~. `The area to be treated (approximately 6 cn) was marked on each rabbit's back with a water- insoluble marker. An aliquot of0.5 mLof H-25357 was applied to the test site and covered with -- ECE CompanySanit-- ized. Dosnotcontai-- n Tsca car HL:22593577: AAccwutteeDDeerrmmaallIImmiattaitioonnSSutdudyyiinnRRaabbbbiitss ___ DuDubPoowntt1r1i1o0r1 --_ oaf2e-palcyh,rla-bibnicthwsaqsuawrreapgapuezdewpiatdh.pTorhoeupsatdawpea. sThheeldtaipnepwlaacsefwuirtthhenrosn-eicrurrietdatwiingthtawpaet.erTphreootfrufanpke, `tThheeserarbabbibtiss.were retuned to their cages aftr treatment. No other substances were tested on Athpepirrocxaigmeastaenldy t4hehowurrasppafitnegrsapapnldicgaatuizoneofpatdhsewteerstesruebmsotvaencde., tThheertaebsbtitssitweserweerreemgeonvteldy wfarsomhed with Lander rabbits were Sthoeanpreatnurdnewdartomtwheaitrecratgoesr.emove excess test substance and gently patted dry. The eArpyptrhoexmiam,aetdeelmya1,haonudroatfhterr reevmiodevnacleofoftdheertmeaslt peaftfcehcetss,atndhwteesrtesistceosrweedraecceovradliunagtetdoftohre Draize SAdcdailtei(oTnaablleeva1)l.uaAtigolnosswsearryeomfaddeermaatlapepfrfeocxtismaantdelayb2b4r,ev4i8a,tiaonnds 7is2phroeusresntaefdteirnrTeambolveal2.ofthe praatbcbhietss.weTrheeeaxdajmaicnenetdfaorrecalsoifnuicnatlresiagtnesdofsktionxiwceirteyautseeadcfhorobcsoemrpvaartiisoonn.perAidoddi.tiTonhaellrya,bbtihtes were weighed on the dayoftreatmeandtatthelastdermal evaluation. E. Data Analysis and InterpretationofResults Mfreoamnnvuamleureiscaflorsecaocrehsloesbitoanin(eedryatthtehmea24a-n,d4e8d-,emaan)d w7e2r-heocuarlcoublsaetrevdatfioornse.acThhaenriemsaulltssewpearrea:tely ~ interpreted according to 67/548/EEC relative requirements for dangerous substances. to the general classification and labeling Corrosive "tThheeitnedsitcsautibosntoafncdeanwiglelrb"eCcOonRsRiOdeSrIeVdEto"biefi"t CprOoRdRuOceSsIfVuEll"thaincdknweislsl rdeeqsutirruecttihoenosfytmhbeolsk"iCn" and tissue on at least | animal during the skin iriation test. Risk phrases will be assigned in accordance with the following criteria. R35 "CAUSES SEVERE BURNS" rIef,suwlhteonf uappptloie3dmtionhuetaelstheyxpinotsaucrteaonriimfatlhisksrien,suflutllcathnicbkenepsrseddiecstterdu.ctionofskin tissue occurs as a R34 "CAUSES BURNS" If, when result of applied up to 4 to healthy intact anima hours exposure orifthis skin, full thickness can be predicted. destructionof skin tissue occurs as a _-- ETH Eginegeany Sanitized. DossnoltccoonmtaainnT=mmay 121925933577:; AAcceeDDeerrmmaallllaattiioonnSSutddyiinn RRaabbbbiiss___ ~ Lritant DuDubpoonit.t1i11o0r1 `The test substance will be classifiaesd "IRRITANT" and will require the symbol "Xi" and the indicationofdanger "IRRITANT"inaccordance with the criteria. given below. Itno athdedictriiotne,ritahienfdoilcaltoewdinbgelroiswk: (R) phrase will be assigned to substances,ifappropriate, according R38 "IRRITATING TO SKIN" If, when applied to healthy intact animal skin for up to 4 hours, significant inflammation is caused and is present24 hoursor more after the endofthe exposure period. Inflammation is significantifthe mean valuesof the scores for either erythema and eschar formation or edema formation corresponds to one or moreofthe following mean values calculated for each animal separately and has been observed in 2ormore animals: - Erythema and eschar formation 2.0 or more - Edema 200r more All scoresat eachofthe reading times (24, calculating the respective mean values. 48, and 72 hours) for an effect should be used in -- An R38 "IRRITATING TO SKIN" phrase should also be. assigned if: i`enfTtfhoeecaitcsncfsoluuacnmthm,aastihoynpepreprlsaissitsa,inscaatlilnega,std2isaconliomraaltsiaotn,tfhiesseunrdeso,ftshcaebso,basnedrvaaltoipoencitaimse.houPlardtibceultaarken RESULTS AND DISCUSSION No dermal irritation was observed in anyofthe rabbits during the study. No clinical signs were observed,and no body weight loss occurred. `The dermal scores from individual animals with respect tg observationtime are presented in `Tabl3e. S Incidences ummaryofmean scores calculatedinaccordance `with ofdermal irritation responses (scores) are summarized EEC are for each presented observati in on Table period 4. in Table S. Individual rabbit body weights and clinical signsof toxicity are presented in Table 6. CONCLUSION In accordance with Directive 67/548/EEC, H-25357 is not classifiable as irritant, - EottpanySanitized. Donotecontsatn wera og; 121529553577:AAccutoeDDoerrmmall IiwtioonnSSutuddyyiinnRRaabbbbiise ~ RECORDS AND SAMPLE STORAGE pwDounpenn1ii0o1 All at C data and hambers records Works, for analytical characterizat Deepwater, New Jersey or ion at conducted by Iron Mountain the spons Records or will be maintained Management, `Wilmington, Delaware. Specimens(if applicable), raw data, and the final report will be retained at HaskellLaboratory, Newark, Delaware, or at Iron Mountain Records Management, `Wilmington, Delaware. ~~ - Company Sanitized. Doesnot contain sca oat --Hh -25357; AAvcuteeDDeormmaelIInmfietartiioornSSttuuddyyiinnRRaatbbbiitess --~ DDuuPoonmt-i111i01l --~ TABLES `Company Sanitized. Does not @antain Tema nr ws 22H-920533577::AAccuuiteeDDeerrmmaallIInittaattiononSStuuddyyiinnRRaabbbbiiss __ -- TABLE 1 pDuuppoonw-i1n1i1o0r1 DRAIZE* SCALE FOR SCORING SKIN IRRITATION EvaluationofSkin Reactions Erythema and eschar formation: VNeOryCsIligVht.ery.t.hcecmrave(rbsarreerlryspssesrscsempesteisbsleesm)s.s.e.smssssmsss ---- wrssisssssssrnresnns Moderate {0 SVEIE eIVIICINA .......cvevevesesereseresoseseesesnssrin ET ---- Severe erythema (beet redness) to slight eschar formation (injuries in depth)............... [Edema formation: VNeOrCyEsIliIgRht .ecd.ceomcacr(rbvarrrerlreysPEmrceepstisblee)sneee ssesm s-------- cersssnssnsnsanin MSloidgehrtaetdeeemdae(meadg(ersaoisfeadraepaprwoeXlIlmdaetfeilnyed1b.0yIdeIf)incite.ra.iScingc) o vvv. sro soo om. ns Severe -_-- edema (raised more than 1.0 mm.extending beyond the areaofexposure) ......... Score 0 1 4 0 1 2 3 4 ~~ a PEDdr4iat6oir5ziea9J,l..CHo.m,m"iDteremeaolfTtohxeicAistsyo.c"AipatpiroanoisfaFlooofdthaenSdaDfreutgyoOffCihceimailcoaflsthienFUoniotdesd,DStrautegss.aAnudstCion.smTeotniecss,.19T5h5e, _ - CompanySanitizee. Dass not contain ran mr us =1253=57:fAocuoteDDoerrmalIImvattaitoonnSSutddyyiinnRRaabbbbiitss ~~ TABLE2 bDwupeowntn1o110n1 GLOSSARY OF DERMAL EFFECTS Blanching Eschar `swchaibteoanptpheeasrkainncethtaotsiksimnore superficialthan necrosis. This is Desquamation cdroyn,sifdleakriendgotfotbheesesvkeirne irritation. Fissuring Fissuring with Bleeding aa sspplliittoorrcclleefftiinntthhee stkoipnlwaiyetrhobflsekeidninwgithout bleeding Hyperkeratosis ctohliockr,)odfrtyhdeistcooplolraayteiroonf(suksiunal.lyThbiust insoctolnismiidteerdetdotborboewsnevoerrew.hite in Sloughing imitation. peelingofthe top layerofskin, and epidermal scaling that has Necrosis detached areaofrough/hard/cry black or dark colored skin that may crater. Epidermal Scaling plTahtiesliiskecaornesaisdoerfetdhteo tboepcloaryreorsoifosnkainndtahnatihrraevveersseipbalreaetfefdecft.rom but Thickening sakrienstiisllfiarttmaacnhde/dtorovdieanbsleetosktihne. tTouhcihs.may progressto sloughing. pe Ulceration open sore representing lossofsuperficial tissue. ABBREVIATIONS OF OTHER DERMAL EFFECTS - = No Effect 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 T = = Epidermal Scaling Thickening X = Test Substance Adhered to Skin -YYYYY CompanySanitized. Doesnot contain Ta 2 125957 AhcouwteePDeormlalmIiaattioonnSSutduyyininaRbabbibtiss pwDoupwoirusi11o0r1 TABLE 3 DERMAL RESPONSES OBSERVED IN INDIVIDUAL RABBITS ERYTHEMA RABBIT NUMBER 35554 35558 35555 HOURS AFTER REMOVAL OF gs TEST ---- SUBSTANCE 1 F) 48 72 0 0 0 0 0 0 0 0 0 [J 0 0 EDEMA RABBIT NUMBER 35554 35558 35555 HOURS AFTER REMOVAL OF TEST SUBSTANCE 1 A 48 72 0 [ 0 J 0 0 0 0 0 0 0 0 TABLE 4 SUMMARY OF MEAN SCORES FOR DERMALR|ESPONSES RABBIT NUMBER ERYTHEMA* EDEMA 35554 0 0 -- o 33s5555s5585 00o 00 + Calalted rohe2m4, 48,and 72 hourermal responses (BEC). `Company Saniized. Doss not contain TS ~F EE ~ : H-25357: AcutemDermral Ie rritationSSteudby binRRaabbibtss --~ DDwuepomnta-1n11o01r TABLE INCIDENCES OF DERMAL RESPONSES (SCORES) ERYTHEMA SCORE 0 1 2 3 4 IHOUR 37 on o3 3 03 24 HOURS 33 03 3 o3 o3 _48 HOURS 373 on 3 3 o3 72 HOURS 33 o3 3 3 on EDEMA SCORE 0 LHOUR 37 24 HOURS 33 _48 HOURS 373 _72 HOURS 33 1 2 03 o3 03 3 on [3 3 03 3 4 03 o3 03 on 3 3 3 03 _-- --_ TABLE 6 INDIVIDUAL BODY WEIGHTS (g) OF RABBITS RABBIT NUMBER SEX 35554 Male 35558 Male --= 35552 5 MaMallee INITIAL WEIGHT 1914 FINAL WEIGHT (72 hours) 222 2051 22335%8 00 2311 a2e627 CLINICAL SIGNS OF TOXICITY No clinical signsof toxicity were observed in anyofthe rabbits during the study. --~ -YYY CompanySanitized. Doesnotcontain TSCA Gat