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m m m sm -, AR226-3024 Study Title Bye Irritation Test with H-21209 in Rabbits Laboratory Project ID Haskell Laboratory Report No. 602-95 Author Tracy A. Filliben Study Completed On August 28. 1995 Performing Laboratory E. I. du Pont de Honours and Coapany Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road P. 0. Box 50 Newark, Delaware 19714 1 Substance Tested; Synonyms/Codes : Physical Form; Composition: GENERAL INFORMATION DuPont BUI 602-95 Whitish liquid Contaminants: Purity: Submitter's Notebook No.: CAS Registry No.: Sponsor: Study Initiated - Completed: In Life Phase Initiated - Completed: DuPont Specialty Chemicals E. I. du Pont de Nemours and Company Wilmington, Delaware 8/7/95 - 8/28/95 8/8/95 - 8/11/95 -2- tt DuPont HUI 602-95 Eye Irritation Test with H-21209 in Rabbits SUMMARY H-21209 was evaluated for acute eye Irritation ^ t e n t l ^ in 2 raWits. S S S S -S h 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 ays , , and 3 following treatment. H-21209 produced mild conjunctival redness in both `reat*d In addition, slight chemosis was observed in the treated washed rabbit eye. he treated unwafhed and washed rabbit eyes were n o r m a J ^ v We r e ' respectively, following treatment. No clinical signs of toxicity were observed during the study. Under the conditions of this study, H-21209 was a mild eye irritant. Report by: Work by: " Q Amy L. Williamson Secretary Tracy A. Filliben Toxicology Associate Reviewed and Approved for Issue: --- -- Tracy A. Filliben Study Director // Bryan W. Crossley and M. Scott Karr also participated in Acknowledgement : the conduct of this study. TF/alw -3- DuPont HLR 602-95 INTRODUCTION The purpose of this study vas to evaluate the acute eye irritation potential of H-21209 in young adult rabbits. MATERIALS AND METHODS A. Animal Husbandry Young adult female 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 coliforms, lead, and other 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 timer controlled, 12-hour light/12-hour dark cycle. Environmental conditions of the rooms were targeted for a temperature of 20C + 1C and relative humidity of 50% 10%. Excursions outside these ranges were judged to have been of insufficient magnitude and/or duration to have adversely affected the validity of the study. B. Protocol On the day of treatment, the eyes of 2 female New Zealand White rabbits were examined using illumination, magnification, and fluorescein dye. Animals used on this study were free of pre-existing corneal or -4- DuPont HLE 602-95 conjunctival injury or irritation and were judged to be in good health. These rabbits weighed 2360 and 2464 grains on the day of treatment. An aliquot of O.Oi mL of H-21209 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 1 rabbit were rinsed for approximately 1 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 1 and 4 hours, and 1, 2, and 3 days after H-21209 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 m 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. C. Records Retention All raw data and the final report will be stored in the archives of Haskell Laboratory for Toxicology and Industrial Medicine, E. I. du Pont de Nemours and Company, Newark., Delaware or in the DuPont Records Management Center, Wilmington, Delaware. RESULTS H-21209 produced mild conjunctival redness in both treated rabbit eyes. In addition, slight chemosis was observed in the treated washed rabbit eye. The treated unwashed and washed rabbit eyes were normal by 1 and 3 days, respectively, following treatment. No clinical signs of toxicity were observed during the study. Individual eye irritation scores are presented m Tables 2 and 3. -5- Under the conditions of this study, H-21209 was a mild eye irritant. If these test scores are to be used for EEC/OECD classification, according to the guide to the labeling of dangerous substances published in the Official Journal of European Communities (EEC Directive 93/21, m e x VI), H-21209 probaoly could be classified as NON-IRRITANT until further data is available. * -fi la DuPont HLR 602-95 EYE IRRITATION TEST WITH H-21209 TABLE 1 DRAIZE1 SCALE FOR SCORING OCULAR LESIONS (1) Cornea (A) Opacity-degree of density (area most dense taken for reading) No opacity .................................... Scattered or diffuse area, details of iris clearly visible ............................ Easily discernible translucent areas, details of iris slightly obscured .................... Opalescent areas, no details of iris visible, size of pupil barely discernible .......... Opaque, iris invisible ........................ (B) /rea of cornea involved One quarter (or less) but not zero . . ........ Greater than one quarter, but less than half . . Greater than one half, but less than three quarters ................................... Greater than three quarters, up to whole area . 1 (Slight) 2 (Mild) 3 (Moderate) 4 (Severe) 1 (Localized) 2 (Small) 3 (Moderate) 4 (Generalized) (2) Iris (A) Values Normal .......................................... Folds above normal, congestion, swelling, circumcorneal injection (any or all of these or combination of any thereof) iris still reacting to light (sluggish reaction is positive) . . . No reaction to light, hemorrhage, gross destruction (any or all of these) ............ 0 1 (Moderate) 2 (Severe) (3) Conjunctiva (A) Redness (refers to palpebral and bulbar conjunctiva excluding cornea and iris) Vessels normal . . . . . . ........ ............ Vessels definitely injected above normal . . . . . 0 1 (Mild) More diffuse, deeper crimson red, individual vessels not easily discernible . . . . . . . . Diffuse beefy red .................... ......... 2 (Moderate) 3 (Severe) DuPont HLR 602-95 EYE IRRITATION TEST WITH H-21209 TABLE 1 (Cont'd) DRAIZE SCALE FOR SCORING OCULAR LESIONS (B) Chemosis No s w e l l i n g ...................... ; Any swelling above normal (includes nictitating membrane) ..................................... Obvious swelling with partial eversion of l i d s .......... .............................. Swelling with lids about half closed ............ Swelling with lids about half closed to completely c l o s e d ................................ . . . 0 1 (Slight) 2 (Mild) 3 (Moderate) 4 (Severe) (C) Discharge f ^ No d i s c h a r ^ / ............................. * Any amount different from normal (does not include small amounts observed in inner canthus of normal a n i m a l s ) ........................ . * (Minimal) Discharge with moistening of the lids and hairs just adjacent to l i d s ........................ 2 (Moderate) Discharge with moistening of the lids and hairs, and considerable area around the e y e ........ ^ 3 (Copious) i 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. -8 - DuPont HUI 602-95 EYE IRRITATION TEST WITH H-21209 TABL 2 EYE IRRITATION REACTIONS OBSERVED IN THE UNWASHED RABBIT EYE Rabbit Number 30414 Cornea Opaci ty Area Iris Conjunctiva Redness Chemosis Discharge 1 4 12 3 Hour Hours Day Days Days 0 0 00 0 0 0 00 0 0 0 00 0 1 1 00 0 0 00 0 0 0 00 0 DuPont HUI 602-95 BYE IRRITATION TEST WITH H-2i 09 TABLE 3 EYE IRRITATION REACTIONS OBSERVED IN THE WASHED RABBIT EYE ... Rabbit Number *0415 Cornea Opacity Area Iris Conjunctiva Redness Chemosis Discharge j 4 1* ' Hour Hours Dav Days -- ----- o oo o oo o oo o oo oo i i i1 ; 1 1 oo o o o oo o - 10 -