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AR226-3047 Study Title Eye Irritation Test with H-21951 in Rabbits Laboratory Project ID Haskell Laboratory Report No. 792-96 Author Tracy A. Filliben Study Completed On August 30, 1996 Performing Laboratory E. I. du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P. O. Box 50 Newark, Delaware 19714 Pape I of 12 Com pany Sanitized. Does not contain T S C A CBI Rye IrritationTest with H-2I95I in Rarbits-------- --------------------________________________ r.FNFR AL INFORMATION Substance Tested: DuPont HLR 792-96 1 Haskell No.: Physical State: rnmposition: H-21951 impurities: Punty: Submitter's Notebook , ^ TAS Registry No.: Sponsor: Study Initiated - Complet In Life Phase Initiated -^Complejed: DuPont Specialty Chemicals E. I. du Pont de Nemours and Company Wilmington, Delaware 7/12/96 - 8/30/96 7/24/96 - 7/27/96 Com pany Sanitized. Does not contain T S C C B I Eye Irritation Tea with H-21951 in Rabbits DuFtaMm * All raw d ataan d the final report will be stored in the archives o f Ha&kell Laboratory for Toxicology and Industrial M edicine, E. L du Pont de Nemours and Company, Newark. Delaware o r a t Iron M ountain, 200 Todds, Lane, W ilmington, Delaware (formerly DuPont Recoiris M anagement C ento'. -3- Com pany Sanitized. Does not contain T S C A CBI live Irriialion TeM with H-2I95I in kahhils SUM M M DuPont HLR 7 9 2 % H-2I95I was evaluated lor acute eye irritation potential in 2 rabbits. Approximately 0.01 mL of the test substance was instilled into the lower conjunctival sac of the right eye of each rabbit. Approximately 20 seconds after instillation, the treated and control eyes of 1 rabbit were washed. The treated and control eyes of the remaining rabbit were not washed. The eyes of the rabbits were examined on the day of treatment and on days I, 2, and 3 following treatment. H-2I95I produced moderate conjunctival redness and slight chemosis in both treated rabbit eyes. In addition, moderate discharge was observed in the treated unwashed rabbit eye. The treated washed and unwashed eyes were normal by 2 and 3 days, respectively, after instillation of the test substance. No clinical signs of toxicity were observed during the study. Under the conditions of this study, H-21951 was a moderate eye irritant. 4Com pany Sanitized. Does not contain T S C A CBI t.yc Imiai um Tesi with H 2 1`SI n Rabbiis SIGNATURE PAGE DuPont HLK 792-9h Report hy: Tracy A. Filliben Toxicology Associate Work by^ AAJaJLlA d 7\ Tracy A. Filliben ^ Toxicology Associate Reviewed and Approved for Issue: Study Director Acknowledgement: Carol Finlay and Barry Fritz also participated in the conduct of this study. tf/alw Com pany Sanitized. Does not contain T S C A CBI bye Iniuimn 'lost with H .21451 in Rabbits DuPont HLR 792-96 INTRODUCTION The purpose of this study was to evaluate the acute eye irritation potential of H-21951 in young adult rabbits. MATERIALS AND m e t h o d s A. Animal Husbandry Young adult male HM:(NZW)fBR New Zealand White rabbits were received from Hare Marland. Hewitt. New Jersey. The rabbits were housed singly in suspended, stainless steel, wire-mesh cages. Each rabbit was assigned a unique identification number which was recorded on a card affixed to the cage. The last 3 digits of the identification number were written on the inside of each rabbit's ear with a water insoluble marker. The rabbits were offered approximately 125 grams of Purina? Certified High Fiber Rabbit Chow? #5325 daily during the study. Water was available ad libitum. Haskell Laboratory has an animal health monitoring program. This program is monitored and administered by the Laboratory Veterinarian. Water samples are periodically analyzed for total bacterial counts and for the presence of conforms, lead, and othei contaminants. Additionally, samples from freshly washed cages and cage racks are periodically analyzed to assure adequate sanitation by the cagewashers. Data from this program are maintained separately from study records. Animal feed is certified by the manufacturer to meet specified nutritional requirements and to be free of a list of specified contaminants. On the basis of these analyses, there is no evidence suggesting that contaminants were present in the feed or water in amounts which may have interfered with the results of this study. Rabbits were quarantined, weighed, and observed for general health for approximately 2 weeks. Animal rooms were maintained on a dmcr-controlled. 12-hour light/12-hour dark cycle. Environmental conditions of the rooms were targeted for a temperature of 20"C T'C and relative humidity of 509? 109? . Excursions outside these ranges were judged to have been of insufficicn' magnitude and/or duration to have adversely affected the validity of the study. B. Protocol On the day o f treatment, the eyes of 2 male New Zealand While rabbits were examined using illumination, magnification, and fluorescein dye. Animals used on this study 6 Com pany Sanitized. Does not contain T S C A CB1 Kyc Irritation Tes with H-21951 in Rabbits DuPont HLR 792-% wereJreeofprerexistingcomealorconjunctivalinjuryorjrritationandwcrejudgcdto be in good health. These rabbits weighed 2829 or 2893 grams on the day of treatment. Approximately 0.01 mL of H-21951 was introduced into the lower conjunctival sac of each right eye. The left eye of each rabbit was not treated with the test substance and served as a control. Approximately 20 seconds after the test substance was administered, both eyes of I rabbit were rinsed for approximately I minute with room temperature water. The treated and control eyes of the remaining rabbit were not washed. Each rabbit was observed for approximately 30 to 60 seconds before being returned to its cage, and any abnormal behavior was noted. In the absence of visible evidence to the contrary, the test substance was assumed to be stable under the conditions of administration. Approximately. I and 4 hours, and 1,2, and 3 days after H-21951 was administered, the rabbits were examined for evidence of eye irritation and for clinical signs of toxicity. At each of these observation periods, eyes were examined using illumination and magnification and scored for ocular reactions according to the Draize scale (presented in Table 1). Eyes were also observed for any unusual responses to treatment such as pannus, blistering of the conjunctiva, ulceration, or other effects indicative of corrosive action. Control eyes were not scored. These untreated eyes were used for comparison and were considered "normal" relative to the treated eye. RESULTS H-21951 produced moderate conjunctival redness and slight chemosis in both treated rabbit eyes. In addition, moderate discharge was observed in the treated unwashed rabbit eye. The treated washed and unwashed eyes were normal by 2 and 3 days, respectively, after instillation of the test substance. No clinical signs of toxicity were observed during the study. Individual eye irritation scores are presented in Tables 2 and 3. 7 Compaty Sanitized. Does not contain T S C A C B i Eye Irritation Test with H-2I9SI in Rabbits CONCLUSION DuPont H L R 792-96 Under the conditions o f this study, H-219 5 1 was a moderate eye irritant. !f these test scores are to be used for EEC/OECD classification, according to the guide to the labeling o f dangerous substances published in the Official Journal o f European Communities (EEC Directive 93/21, Annex VI), H -21951 probably could be classified as NON-IRRITANT until further data is available. -8Com pany Sanitized. Does not contain T S C A C B I Eye Irritation Test with H-2I95I in Rabbits DuPont HLR 792-96 TABLE I n R A I7 F ' STALE FOR SCORING OCULAR LESIONS (1) Cornea (A) Opacity-degree o f density (area most dense taken for reading) N o o p a city ............................................ Scattered or diffuse area, details o f iris clearly v isib le.................................. Easily discernible translucent areas, details of iris slightly ob scu red ......................... Opalescent areas, no details o f iris visible, size o f pupil barely discernible.............. Opaque, iris invisible............................. (B) Area of cornea involved One quarter (or less) but not z e r o ................. Greater than one quarter, but less than ha l f . . . Greater than one half, but less than three quarters........................................... Greater than three quarters, up to whole area . . (2) Iris (A) Values N orm al................................................. Folds above normal, congestion, swelling, cincurncorneal injection (any or all o f these or combination o f any thereof) iris still reacting to light (sluggish reaction is positive) . . . N o reaction to light, hemorrhage, gross destruction (any or all o f th ese).............. (3) Conjunctiva (A) Redness (refers to palpebral and bulbar conjunctiva excluding cornea and iris) V essels norm al....................................... Vessels definitely injected above norm al......... More diffuse, deeper crimson red, individual vessels not easily discernible................ D iffuse beefy r e d .................................. 0 1 (Slight) 2 (Mild) 3 (Moderate) 4 (Severe) 1 (Localized) 2 (Small) 3 (Moderate) 4 (Generalized) 0 1 (Moderate) 2 (Severe) 0 I (Mild) 2 (Moderate) 3 (Severe) -9Com pany Sanitized. Does not contain T S C A C B I l-yc lmiuiion Tesi with H-2I95I in Rabbits DuPont HLR 792-96 -------------------------------------- TABLE 1(Cont'd)--------------------------------------DRA1ZE SCALE FOR SCORING OCULAR LESIONS (B) Chemosis No sw e llin g ...................................... Any swelling above normal (includes nictitating m e m b ra n e )...................................... Obvious swelling with partial eversion of ' d s ............................................... Swelling with lids about half closed............ Swelling with lids about half closed to completely c lse<J ......................................... (C) Discharge No discharge...................................... Any amount different from normal (does not include small amounts observed in inner canthus of normal anim als)............................... Discharge with moistening of the lids and hairs just adjacent to lid s......................... Discharge with moistening of the lids and hairs, and considerable area around the e y e ........ 0 I (Slight) 2 (Mild) 3 (Moderate) 4 (Severe) 0 1 (Minimal) 2 (Moderate) 3 (Copious) Draize. J. H., "Dermal Toxicity." Appraisal of the Safety of Chemicals in Foods. Drugs and Cosmetics. The Editorial Committee of the Association of Food and Drug Officials of the United States, Austin. Texas, 1959, pp. 46-59. - to - Com pany Sanitized. Does not contain T S C A CBI Eye Irritation Tesi with H-2I95I in Rabbits DuPom HLR 792 % TABLE 3 EYE IRRITATION REACTIONS OBSERVED IN THE UNWASHED RABBIT EYE 1 Rabbit Number 31052 Cornea Opacity Area Iris............. Conjunctiva Redness Chemosis Discharge 1 Hour 4 Hours 1 Day 000 000 0 0 .......o .... 222 ! 11 220 2 Days 3 Days 0 0 o .... 0 0 0 I0 10 00 -il Com pany Sanitized. Does not contain t s c a c b (i Kyc Irriialinn Test with H-2I95I in Rahhits DuPont HLR 792-% ----------------------------- t a b l e s ----------------------------- EYE IRRITATION REACTIONS OBSERVED IN THE WASHED RABBIT EYE Rabbit Numbe. 31057 Cornea Opacity Area Iris Conjunctiva Redness Chemosis Discharge 1 Hour 4 Hours 1 Day 000 000 000 2 11 10 0 000 2 Days 0 0 0 0 0 0 3 Days 0 0 0 0 0 0 - 12- Com pany Sanitised. Does sol contain T S C A C 8I