Document KJonqBv2vn8GmNB25qyZzMmyK

ra_z 32e 54 "eo TRADE SECRET ARAZ6_ 3254 DuPonc11111 Study Title H-25357: Acute Eye lritation Study in Rabbits Laboratory Project ID: DuPont-11111 TEST GUIDELINES: U.S. EPA Health Effects Test Guidelines OPPTS 870.2400 (1998) -- SOeEctCiDonG4u:idHeelailntehs EffofrecTtess,tiNnog.o4f0C5he(m19i8c7a)ls Commission Directive 92/69/EEC EEC Method B.S (1992) AuTHOR: Carol Finlay, B.A. STUDY COMPLETED ON: August 9, 2002 PERFORMING LABORATORY: EL du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences . Elkton Road, P.O. Box 50 . Newark, Delaware 19714-0050 Company Saniized, Does not contain TSCA CBI AL 1.25357: Acute Eye Irtaion Study in Rabbis Dupont-1111 --~ GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT "This study was 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 done by an ISO9000certified lab and the accuracyof the data is considered. sufficient for the purposesofthis study. Applicant / Sponsor: E.L du Pont de Nemours and Company `Wilmington, Delaware 19898 USA. Study Director: C | Finlay, EA. Staff Toxicologist 9- 4-2002 Applicant/ Sponsor: DuPont Representative Date -- Company Sanitized. Doesnotcontain TSCA C51 125357: Acute Eye Imitation Study in Rabbits -- QUALITY ASSURANCE STATEMENT Haskell Sample Number(s): 25357 DatesofInspections: Protocol: June 24, 2002 Conduct: June 24, 2002 Records, Reports: August 1, 2002 Dates Findings Reported to: -- StudyDirector: August 2, 2002 Management: August 2, 2002 Reported by: -- Fren Quality Assurance Auditor DuPont11111 fha-2002 -- CompanySanitized. Dossnotcontin TSCA CBI ------ ere ---------- F-25357: Acute Eye Irttion Study in Rabbits DuPon11111 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of the data obtained from this study. Reviewsdby: Clare PTamuessC. zeyAlia z ot e IssuedbyStudyDirector: Fy i.B Saf Tosioiogit 9: dug Toi -- `Company Santizad. Does not contain TSCA CBI En $2535: AcEyueImtaieon Stayin Rabbis STUDY INFORMATION subsanss esc[ENN| Synonyms/Codes; j H-25357 1 Submilter's Notebook Number(s --] Haskell Number: 25357 CAS Registry -- | pJ uri i] DuPenci11 Physical Characteristics: Amber liquid Sponsor: E.L du Pont de Nemours and Company Wilmington, Delaware 19898 US.A. Study Initiated/Completed: June 14, 200/2 (see report cover page) In-Life Initiated/Completed: June 24, 2002 / June 27, 2002 - `Company Sanitized. Does not contain TSCA CBI 125357: Acute Eye miaton Study in Rabbits DuPont-11111 --_ STUDY PERSONNEL Study Director: Carol Finlay, B.A. Management: Scot E. Loveless, PhD. Primary Technician: James C. Mackay Il Toxicology Report Preparation: Sean M. Callaghan, B.A. Management: Nancy S. Selzer, M.S. Laboratory Veterinarian: William Singleton, D.V.M., A.C.LAM. --_ Company Sanitized. Does not contain =a Ry A-------------------------------------------- 125357: Acute Eye Imitation Study in Rabbis DuPont-11111 -- SUMMARY H-25357 was evaluated for acute eye irritation potential in 3 adult New Zealand White rabbits. Analiquot of0.1 mLoftest substance was administered to Ieyeofeach test animal. The eyes remained unwashed following treatment. The conjunctiva, iris, and cornea of each treated eye were evaluated and scored according to a numerical scale approximately 1, 24, 48, and 72 hours following administrationofthe test substance. Two rabbits paved the treated eye after instillationofthe test substance. The test substance produced conjunctival redness (score of 1) in the treated eyesoftwo rabbits and discharge (score of 1) in the treated eyes of2 rabbits. Fluorescein stain examinations were negative for comeal injury in the treated eyesofall rabbits. The treated eyesofthe rabbits were normal by 24 or 48 hours after instillation ofthe test substance. No clinical signs were observed. Body weight loss of approximately 4% of initial weight occurred by study termination (72 hours) in one rabbit. Mean values were calculated for each animal separately by using numerical scores obtained from the quantitative evaluationofeach ocular response observed in each rabbit approximately 24, 48, and 72 hours following treatment. These values are as follows: RABBIT CORNEAL CONJUNCTIVAL CONJUNCTIVAL NUMBER OPACITY IRITIS REDNESS CHEMOSIS ~ 33553 000 0.00 033 0.00 35502 000 0.00 0.00 0.00 35566 000 000 0.00 0.00 In accordance with Directive 67/548/EEC, H-25357 is not classifiable as irritant. CompanySanitized. Does not contain TSCA CBI E -- 125357: Acute Eye mitaion Study in Rabbits Dupone11111 INTRODUCTION A. Objective `The objectiveofthis study wasto evaluate the eye iritation potential and the reversibility of ocular effects of H-25357 following a single ocular application to albino rabbits. The results of the study were used to determine the appropriate toxicity classification and labeling requirements inaccordance with EEC. B. Principles of the Methodology Ocular effects are evaluated and scored approximately 1, 24, 48, and 72 hours after instillation of 0.1 mLoftest substance (or a weight ofnot more than 100 mgoftest substance) into the lower conjunctival sac of1 eyeofeach of3 rabbits. The reversibility ofany effects is assessed for up 1021 days, ifnecessary. Ocular effects are scored according to the Draize Scale (Table 1). MATERIALS AND METHODS -- A. Test Guidelines "The study design complies with the following test guidelines: + Officeof Prevention, Pesticides and Toxic Substances (OPPTS) U.S. Environmental Protection Agency (EPA) (1998). OPPTS 870.2400 Acute Eye Irritation. Health Effects Test Guidelines. + Organisation for Economic Co-Operation and Development (OECD) (1987). 405 Acute Eye Initation/Corrosion. Guidelinefor Testingof Chemicals. + European Economic Communities (EEC) (1992). Directive 92/69/EEC Annex V, Part B.S, Acute Toxicity (Eye Irritation). Methodsfor the DeterminationofToxicity. B. Test Substance `The test substance, H-25357, was supplied by the sponsoras an amber liquid. The test substance was invertedto mix before each amount for dosing was removed. The test substance appeared to be stable under the conditionsofthe study. No evidence of instability, such as a change in color or physical sate, was observed. CompanySanitized. Does not containTSCACB _-- 25357: Acute Eye ImitationSudyin Rabbits DuPont-11111 -- C. Animal Husbandry Adult HM:(NZW)fBR New Zealand White rabbits were received from Covance Rescarch Products, Denver, Pennsylvania. The rabbits were housed singly in stainless stecl, wire-mesh cages suspended above cage boards. Each rabbit was assigned a unique identification number which was recorded on acard affixed to the cage. The last 3 digits ofthe identification number were written on the insideofeach rabbit's ear with a water insoluble marker. The rabbits were offered approximately 125 gramsof PMI Nutrition International, LLC Certified High Fiber Rabbit LabDiet 5325 daily during the study. Water was available ad libitum. 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: + Watersamplesare analyzed for total bacterial counts, and the presenceof coliforms, 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 manufacturer to meet specified nutritional ~ requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, 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 animalhealthand environmental monitoring program is administered by the attending Inboratory animal veterinarian. Evaluation of these 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. Environmental conditionsofthe rooms were targeted for a temperatureof 20C 1C and relative humidityof 50% = 10%. Excursions outside these ranges werejudged to have been of insufficient magnitude and/or duration to have adversely affected the validityofte study. D. Protocol On the dayoftreatment, the eyes of3 male New Zealand White rabbits were examined using illumination, magnification, and fluorescein stain. Animals used on this study were freeofpreexisting comeal or conjunctival injury or imitation and werejudged to be in good health. The rabbits weighed from 2082 to 2592 grams on the day of treatment --~ r CompanyR Sanitized. Doesnnolt ecoan racas" H2:52593587:7AAccuteeBEyyeelImaittatoionnSSttouddyyiinnRRaabbbbiittss ____ DDuupPoenmti-1n1n11t --_ oAfneaalcihquroatbboitf.0.T1hmelloeff He-ye2o5f3e5a7cwhasraibbnittrowdauscendotinttroeattheedlwoiwtehrtchoenjtuesntctsiuvbasltasnacceoafntdhesreirgvhetdeaysea control. The treated and control eyesofall rabbits remained unwashed. Each rabbit was observed for approximately 30 to 60 seconds before being returned to is cage. Approximately 1, 24, 48, and examined for evidenceofeye 72 hours irritation after H-25357 was administered, and for clinical signsof toxicity. the At rabbits were each ofthese oobcsuelravrarteiaocntipoenrsioadcsc,oerydiensgwteoretheexDarmaiinzeedScuaslieng(Tialblulmein1)a.tiAonnyanodthmeargnaidfviecrasteioocnualnard rsecaocrteidonfso,r pTahretsiecuulnartlryeattheodseeyiensdiwceatrieveuosfedcofrorrocsoimvpeaarcitsioonn, awnedrewearlesocnoontseidd.erCeodn"inroolrmeayle"s rweelarteivneottostchoered. treated eye. evaluation. TFhleuorraebsbcietisnwsetraeinweexiagmhiendatoinontshewedraeyocfotnrdeuacttmeedntatatnhde 24-hourandeach subsequent at the last ocular evaluation. E. Data Analysis and Interpretationof Results rFeodrneesasc,haanndimcaoln,juanmcteiavnalvcahleumeowsaiss)cablycualvaetreadgifnogrtehaechscloerseiosno(bctoaimneeadlforpoacmittyh,e i2r4i-t,is,48c-o,njaunndct7i2v-al thhoeurgeonbesrearlvactliaosnssif.icTahtieonreasnudltlsawbeelrienginrteeqrupirreteemdenatcscofrodridnagntgoerDoiruescstuibvset6a7nc/e5s4.8/EEC relative to --~ `iTnhdeictaetsitosnuobfsdtaanncgeerwi"llIRbeRIcTlaAsNsiTf"iedinaasc"cIorRdRaInTcAeNwTi"thatnhde will require the criteria below. symbol "Xi" and the In addition, the following risk (R) phrases will be assigned to substances classified "IRRITANTS" as applicable, according to the following eriteria: R36 "IRRITATING TO EYES" `tThheetresitskanpihrmaasle,,tRhe36tes"tIsRuRbsItTaAncTeINcaGusTeOs EsiYgEniSf"i,canwtilolcbuleaarslseisginoends iwf,hiwchhenocacpuprliweidthtiont7h2e ehyoeurosf aifntdeirveixdpuaolsuarneimaanldmwehainchvapleuressiosfttfohreat2l4e-a,s4t82-,4ahnodur7s2.-hOocuurlaervalleusaitoinosnasirens2igonrifmicoarnetiafntihmeals comply with anyofthe following criteria: - comeal opacity - iridial lesion equa to or greater than 2.0, but less than 3.0 equal to or greater than 1.0, but less than 2.0 . -conjunctival redness equal to or greater than 2.5 - conjunctival chemosis equal to or greater than 2.0 -- - Company Sanitized. Does not contain TSCA CB H:25357: Acute Eye Iiation Study in Rabbits DuPont11111 --~ R41 "RISK OF SERIOUS DAMAGE TO THE EYES" T{ehset sruibskstpahnrcaesec,auRs4e1s s"eRvIeSrKe OocFulSarERleIsOioUnSs wDhiAcMhAocGcEurTwOitThiHnE72EYhoEuSr"s,afwlilelr ebxepaosssuirgeneadnidfwthhiech p2e4r-s,is4t8-f,oranadt l7e2a-stho2u4rheovuarlsu.atOicounslairnl2esoironmsorareeasneivmearlesifctohmeplinydiwviitdhuaalnyaonfimtahle mfeolalnowvianlguecoriftetrhiea: - comeal opacity equal to or greater than 3.0 -iridial lesion equal t0 2.0 R41 "RISK OF SERIOUS DAMAGE TO THE EYES" risk phrase is also required if: - othceultaerstlseusbiosntsanacree sctaiullsepsreisrernetve2r1sidbaleyscofloolrlaotwiionngotfrtehaetmeeynets -- Company Sanitized. Does not contain TSCA C81 --_-- Th H-25357: Acute Eye iaton Study in Rabbits DuPont-11111 --~ RESULTS AND DISCUSSION Two rabbits pawed the treated eye after instillationofth test substance. The test substance produced conjunctival redness (score of 1 in the treated eyesoftwo rabbits and discharge (score of 1) in the treated eyesof 2 rabbits. Fluorescein stain examinations were negative for corneal injury in the treated eyesofall rabbits. The treated eyesof the rabbits were normal by 24 or 48 hours after instillationof the test substance. No clinical signs were observed. Body weight loss ofapproximately 4%ofinitial weight occurred by study termination (72 hours) in one rabbit. `The ocular scores from individual animals withrespectto observation time are presented in Table 2. Mean ocular scores calculatedinaccordance with EEC are presented in Table 3. Individual body weights and clinical signsoftoxicity are presented in Table 4. CONCLUSION In accordance with Directive 1999/45/EEC, H-25357 is not classifiable as irritant. --_ RECORDS AND SAMPLE STORAGE All data and records for analytical characterization conducted by the sponsor will be maintained at Chambers Works, Deepwater, New Jersey or at Iron Mountain Records Management, Wilmington, Delaware. Specimens(if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware. Company Sanitized. Doesnot contain TSCA CAI - 125357: Acute Eye maton Study in Rabbis --_ Dupone1111 TABLES - `Company Sanitized. Does not contain TSCA 651 H25357: Acute Eye Iiaton Stuy in Rabi Duponeni --_ TABLE | DRAIZE* SCALE FOR SCORING OCULAR LESIONS Cornea (3) NOpOacOiBtCy-HdYegc ree ofdensity (ars ea most dense takec nfor reading) 0 ESacsaitltyerdeidsocremdiibflfuesteraarnesal,ucdeentatialrseoafsi,idsetacillesaorlfy iVsilsiighbtllye... OpalOeDsScCeUntTEaAreasv , no detailsofiisc visible, sizofs pupil barely 2 OPAGGUSEC,EIiIDIVEISIBLEo . ree rrs or 43 (B) Areaofcornea involved. GOrneeatqeurartthearn(oorne16q5usa)rbteUrt, BbOuLt28le1s0v thas Balfc ..coror vcrorr. 2| Greate than one half, ut less than three GUATIEES errr. 3 Greaterthan three QUELETS, Up 10 WhOIE A7C....rovrorocror 4 mis ~~ (A) N Values OL. Foldisnjaebcotivoenn(oarnmyaolr, aclolnogfetshteiosne,osrwceollmibnign,actiirocnuomfcaonrnyeatlhereof) No rierasctstiiollnrteoaclitgihntg, htoemloigrhtth(asgleu,gggirsohssredaecsttirounctisiopno(saintyiovrea)ll.o.f. | @) (3C)onjuRnecdtnievsas (refers topalpebral and bulbar conjunctiva excluding RcoE rnea and iis) . MVeosrseeldsidfeffuisnei,tdeeleypienrjeccrtiemdsaobnorveed,noinrdmiavlid.u.a.lovre.s.s.el.s..n.ot asily 1 J J `Company Sanitzed. Doss not contain TSCA CBI Te DHT :25357:AAccueteBByyeelImmiittatoinonSSutduyyininRRaabbbbiittss -- DDuuopmoenitn11n11n1 TABLE I (Continued) DRAIZE SCALE FOR SCORING OCULAR LESIONS ) Chemosis ANnOySsWwEeIllNiGng ac bove noo rmal (ir ncludes n nictitatis ng membranc)....... | Obvious Swelling swelling With partial eVersion ith lids 8bOut halfc10d of ids.............. corer 2 3 Swelling with lids abouthalfclosed to completely closed .......... 4 () Discharge NO BSCR. rss 0 Anyaammoounutnst odibfsfeerrveentdfirnoimnnneorrcmaanlth(udsoeosfnnootrmianlclaundiemaslmsa)l..l........ 1 DiscF harge with moisteningofE the lids and hairs just ad-- jacent to Discharge with moisteningofthe lids and hairs, and considerablearea around the Ye........evnninns 3 -_-- -- @ EDdriatiorziea,lJ.CHo,mm"iDtetrmeoalftThoeicAistsyoc"iaAtpipornoaifsFalooofdthaendSaDfreutgy oOffCfihceimailscaofltsheinUFnoiotdesd,SDartueg,s AaunsdtiCno,smTeetxiacns,,1T95h9e, Pp. 46-59. --_ _--_-- `CompanySaniized. Does not conn vag op Te 7TTT Te - ~ zi3z --_-- 4 EH %5 2 :3 33 ~ i28 Zz 3SEBE zgss=ss=B22E90g282s0e8s82s803 5 |S3B EZ = =) Elz g2 coolecs [3 2z gc B9a3 Z (52 oo sleool z a 3E)3 2 E | |g : 228 Oo 32 cooloool 2; = ogz | (2 g E 2 % Ms g8 zIg 322|E8E8 soof - 2 2 : 19 E= fassgosyasslasy Eg | 2g EEE 232554552555855888 Zo zz |3: | g2 2-&l8=)sl=8) |8 = 4|8 CompanySante.Doss notcontainTSCA i. B2983757AMeewpBeemIinmtiaioonnSSuyintaRbalies ~ oDuwpoennt TABLE 3 MEAN SCORES" FOR OCULAR RESPONSES FOR INDIVIDUALRABBITS 4 Mh Ash 72h. Clete scoring BEC RABBIT|CORNEAL NUMBER| OPACITY| IRITIS 35553 0.00 0.00 35502 0.00 0.00 35566 0.00 0.00 CONJUNCTIVAL| CONJUNCTIVAL REDNESS CHEMOSIS 0.33 0.00 0.00 0.00 0.00 0.00 TABLE 4 INDIVIDUAL BODY WEIGHTS OF RABBITS RABBIT INITIAL WEIGHT| FINAL WEIGHT (72 HOURS) NUMBER SEX 2) 2 35553 M 2082 1989 ~~ 35502 M 2592 2604 35566 M 2110 2120 CLINICAL SIGNS OF TOXICITY OBSERVED INRABBITS No clinical signsoftoxicity were observed in anyofthe rabbits during the study. -_-- Company Setted.boss not conn 3