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TRADESECRET AR226-3083 DuPont H L-1997-01226 Study Title H-22994: Eye Irritation Test in Rabbits Laboratory Project ID: HL-1997-01226 Author: Tracy A. Filliben Study Com pleted ON: December 19,1997 P erforming Laboratory: E. I. du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 Work Request Numb: Page 1 of 10 Company Sanitized. Does not contain TSCA CBS H-22994: Eye Irritation Test in Rabbits DuPont HL-1997-01226 Study Director: CERTIFICATION Issed b y Q.. (j Tracy A. Filliben Toxicology Associate /sin Ah Date -2 - Company Sanitized. Does not contain TSCA CB1 H-22994: Eye Irritation Test in Rabbits STUDY INFORMATION Substance Tested: DuPont HL-1997-01226 Composition: Known impurities: Physical Characteristics: Light tan liquid Stability: The test substance appeared to be stable under the conditions o f the study; no evidence of instability was observed. Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Initiated / Completed: November 24, 1997 / (see report cover page) Tn-TJfe Initiated / Completed: November 25,1997 / November 29,1997 -3 - Company Sanitized. Does not contain TSCA CBI H-22994: Eye Irritation Test in Rabbits DuPont HL-1997-01226 STUDY PERSONNEL The following individuals were responsible for conduct of the study: Manager: Judith C. Stadler, Ph.D. Study Director: Tracy A. Filliben Primary Technician: Tracy A. Filliben Toxicology Report Preparation(s): John D. Oldham, Jr., B.S. The following individual was responsible for assessing the health status of the animals on study: Laboratory Veterinarian: Charles E. Cover, V.M.D. -4 - Company Sanitized. Does not contain TSCA CB1 H-22994: Eye Irritation Test in Rabbits DuPont HL-1997-01226 SUMMARY H-22994 was evaluated for acute eye irritation potential in 2 New Zealand W hite rabbits. Approximately 0.01 mL of the test substance was instilled into the lower conjunctival sac o f the right eye o f 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 1,2, and 3 following treatment. H-22994 produced moderate conjunctival redness and slight conjunctival chemosis in the treated unwashed rabbit eye. Moderate iritis, mild conjunctival redness, slight conjunctival chemosis, and minimal discharge were observed in the treated washed rabbit eye. The treated washed and unwashed rabbit eyes were normal by 4 hours and 3 days, respectively, after treatment. No clinical signs of toxicity were observed during the study. Individual eye irritation scores are presented in Tables 2 and 3. Under the conditions o f this study, H-22994 was a moderate eye irritant. -5 Compdiiy Sanitized, woes iw i cjm aiu i S eA i/fll Company Sanitized. Does not contain TSCA CBI H-22994: Eye Irritation Test in Rabbits DuPont HL-1997-01226 INTRODUCTION The purpose of this study was to evaluate the acute eye irritation potential of H-22994 in young adult New Zealand W hite rabbits. MATERIALS AND METHODS A. Animal Husbandry Young adult male and female HM:(NZW)fBR New Zealand W hite rabbits were received from Hare Marland. 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 o f Punna Certified High Fiber Rabbit Chow #5325 daily during the study. W ater was available ad libitum. Haskell Laboratory has an animal health monitoring program. This program is monitored and administered by the Laboratory Veterinarian. W ater 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 ensure 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 o f 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 1 male and 1 female New Zealand White rabbit were examined using illumination, magnification, and fluorescein dye. Animals used on this study were free o f pre-existing comeal or conjunctival injury or irritation and were judged to be in good health. The rabbits weighed 2823 or 2716 grams on the day of treatment. Approximately 0.01 mL o f H-22994 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. -6 - not contain TSCA CBI Company Sanitized. D oes H-22994: Eye Irritation Test in Rabbits DuPont HL-1997-01226 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. Approximately 1 and 4 hours, and 1,2, and 3 days after H-22994 was administered, the rabbits were examined for evidence of eye irritation and for clinical signs of toxicity. At each o f 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 AND DISCUSSION H-22994 produced moderate conjunctival redness and slight conjunctival chemosis in the treated unwashed rabbit eye. Moderate iritis, mild conjunctival redness, slight conjunctival chemosis, and m in im al discharge were observed in the treated washed rabbit eye. The treated washed and unwashed rabbit eyes were normal by 4 hours and 3 days, respectively, after treatment. No clinical signs of toxicity were observed during the study. Individual eye irritation scores are presented in Tables 2 and 3. CONCLUSIONS Under the conditions o f this study, H-22994 was a moderate 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, Annex VI), H-22994 probably should not be classified as an "IRRITANT" until further data proves otherwise. RECORDS RETENTION All study records, raw data, and the final report are retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain, 200 Todds Lane, Wilmington, Delaware 19802 (formerly known as the E. I. du Pont de Nemours and Company Rcords Management Center). -7 - Company Sanitized. Doenot contain TSC CEI H-22994: Eye Irritation Test in Rabbits DuPont HL-1997-01226 TABLE 1 DRAKE3SCALE FOR SCORING OCULAR LESIONS (1) Cornea (A) Opacity-degree o f density (area most dense takenfo r reading) No opacity..........................................................................................0 Scattered or diffuse area, details of iris clearly visible....................1 (Slight) Easily discernible translucent areas, details of iris slightly obscured........................................................................................ 2 (Mild) Opalescent areas, no details of iris visible, size o f pupil barely d isce rn ib le ......................................................................................................... 3(M oderate) Opaque, iris invisible..........................................................................4 (Severe) (B) Area o f cornea involved One quarter (dr less) but not zero.....................................................1 (Localized) Greater than one quarter, but less than h alf..................................... 2 (Small) Greater than one half, but less than three quarters........................... 3 (Moderate) Greater than three quarters, up to whole area.................................. 4 (Generalized) (2) Iris (A) Values Normal............................................................................................... 0 Folds above normal, congestion, swelling, circumcomeal injection (any or all of these or combination of any thereof) iris still reacting to light (sluggish reaction is positive).............1 (Moderate) No reaction to light, hemorrhage, gross destruction (any or all of these)............................................................................................ 2 (Severe) (3) Conjunctiva (A) Redness (refers to palpebral and bulbar conjunctiva excluding cornea and iris) Vessels normal................................................................................... 0 Vessels definitely injected above norm al.........................................1 (Mild) More diffuse, deeper crimson red, individual vessels not easily discernible.....................................................................................2 (Moderate) Diffuse beefy re d ...............................................................................3 (Severe) -8 - Company Sanitized. Does not contain TSCA GBi H-22994: Eye Irritation Test in Rabbits DuPont HL-1997-01226 TABLE 1 (Continued) DRAIZE SCALE FOR SCORING OCULAR LESIONS (B) Chemosis No swelling......................................................................................... 0 Any swelling above normal (includes nictitating membrane).........1 (Slight) Obvious swelling with partial eversion of lid s..................................2 (Mild) Swelling with lids about half closed......................................................................3(Moderate) Swelling with lids about half closed to completely closed..............4 (Severe) (C) Discharge No discharge....................................................................................... 0 Any amount different from normal (does not include small amounts observed in inner canthus of normal anim als)............1 (Minimal) Discharge with moistening of the lids and hairs ju st adjacent to lid s .................................................................................................................... 2(Moderate) ; Discharge with moistening of the lids and hairs, and considerable area around the eye................................................. 3 (Copious) a D raize, J. H., "Dermal Toxicity." Appraisal of the Safety o f Chemicals in Foods, Drugs and C osm etics. The Editorial Committee o f the Association o f Food and Drug O fficials o f the United States, Austin, Texas, 1959, pp. 46-59. -9 - Company Sanitized. Does not contain TSC CBS H-22994: Eye Irritation Test in Rabbits DuPont HL-1997-01226 TABLE2 EYE IRRITATION REACTIONS OBSERVED IN THE RABBIT EYE UNWASHED AFTER TREATMENT RABBIT NUMBER 32411 CORNEA Opacity A rea IRIS CONJUNCTIVA Redness C hem osis Discharge 1 HOUR 0 0 0 2 1 0 4 HOURS 0 0 0 1 0 0 1 DAY 0 0 0 1 0 0 23 DAYS DAYS 00 00 00 10 00 00 TABLE 3 EYE IRRITATION REACTIONS OBSERVED IN THE RABBIT EYE WASHED AFTER TREATMENT RABBIT NUMBER 32392 CORNEA O pacity A rea IRIS CONJUNCTIVA Redness Chemosis Discharge 1 HOUR 0 0 1 1 1 1 4 HOURS 0 0 0 0 0 0 1 DAY 0 0 0 0 0 0 23 DAYS DAYS 00 00 00 00 00 00 - 10- Company Sanitized. Does not contain TSC CBi