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TRADE SECRET AR226-3076 Study Title H-22762: SKIN IRRITATION TEST IN RABBITS LABORATORY PROJECT ID: HL-1997-00716 AUTHOR: Carol Finlay, B.A. STUDY COMPLETED ON; August 8, 1997 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 19714-0050 WORK REQUEST NUMBER: f--Q ^P^SaflfH^ ^^TSOA^ Page 1 of 8 GENERAL INFORMATION ni 1111 111 ^imfff^mi^^^mmi Synonyms/Codes: ^ H-22762 Haskell Number: 22762 Physical Characteristics: Clear yellow liquid Stability: The test substance appeared to be stable under the conditions of 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: July 18, 1997 / (see report cover page) In-Life Initiated/Completed: July 22, 1997 / July 25, 1997 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 Records Management Center). Corop^T' -2- SUMMARY H-22762 was evaluated for acute skin irritation potential in 2 male and 4 female New Zealand White rabbits. Approximately 0.5 mL of the test substance was applied to the shaved, intact skin of each rabbit and covered with a semi-occlusive dressing for a 4-hour exposure. Approximately 1,24,48, and 72 hours after removal of the test substance, the test sites were evaluated for erythema, edema, and other evidence of dermal effects and were scored according to the Draize Scale. The adjacent areas of untreated skin were used for comparison. Although the test substance adhered to the skin of the rabbits during the study, the test sites could be evaluated. No edema or clinical signs oftoxicity were observed during the study. H-22762 produced no dermal irritation in 1 rabbit, slight erythema in 4 rabbits, and mild erythema in 1 rabbit by 1 hour after test substance removal. At 24 hours, no dermal irritation was observed in 3 rabbits and slight erythema was observed in 3 rabbits. No dermal irritation was observed at 48 or 72 hours. Under the conditions of this study, H-22762 was a mild skin irritant. Company Sanhizod. Does not contain TSCA CBI 3- SIGNATURE PAGE Reviewed and Approved for Issue: L(U^^)JUI^. CaroKFinlay, B(h. Study Director ^/s^7 STUDY PERSONNEL The following individuals were responsible for conduct of the study: Manager: Study Director: Primary Technician: Assisting Personnel: Toxicology Report Preparations): Nancy C. Chromey, Ph.D. Carol Finlay, B .A. Carol Finlay, B.A. Craig M. Lightcap Maryanne M. Wilford, B.A. The following individual was responsible for assessing the health status of the animals on study: Laboratory Veterinarian: Charles E. Cover, V.M.D. I .4- INTRODUCTION The purpose of this study was to evaluate the skin irritation potential ofH-22762 when applied to the shaved, intact skin of New Zealand White rabbits. MATERIALS AND METHODS A. Animal Husbandry Young adult male and female HM:(NZW)fBR New Zealand White 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 ofPurina Certified High Fiber Rabbit Chow #5325 daily during the study. Water was available ad libitum except during the exposure period while the animals were in stocks. 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 ofcoliforms, 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 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/I 2-hour dark cycle. Environmental conditions of the rooms were targeted for a temperature of20C 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 prior to treatment, the hair of 2 male and 4 female New Zealand White rabbits was closely shaved to expose the skin from the scapular to the lumbar region of the back. The body weights of the rabbits ranged from 2350 to 2768 grams on the day of treatment. Each rabbit was placed into a stock which had been fitted with a piece of rubber sheeting, approximately 8" x 18". The rabbits remained in the stocks throughout the exposure period and during that time did not have access to food or water. Approximately 0.5 mL ofH-22762 was -5- Company Santtteod. Does not contain TSCA Cffl applied directly on the test site beneath a 2-inch gauze square that was held in place with nonirritating tape. The rubber sheeting was then wrapped around the animal and secured with clips to retard evaporation and to keep the test substance in contact with the skin without undue pressure. One other test substance was tested concurrently on a separate, localized test site on these rabbits. Approximately 4 hours after application of the test substance, the rubber sheeting was loosened, and the skin at the comers of the gauze squares was marked with a waterproof pen; wrappings and gauze squares were then removed. The test sites were gently washed with Ivorysoap and warm water to remove excess test substance. The skin was gently patted dry, and the animals were returned to their cages. Approximately 1, 24,48, and 72 hours after removal of the test substance, the test sites were evaluated for erythema, edema, and other evidence of dermal effects and were scored according to the Draize Scale (Table 1). The adjacent areas of the untreated skin were used for comparison. The rabbits were also examined for clinical signs oftoxicity at every dermal evaluation. RESULTS AND CONCLUSIONS Although the test substance adhered to the skin of the rabbits during the study, the test sites could be evaluated. No edema or clinical signs oftoxicity were observed during the study. H-22762 produced no dermal irritation in 1 rabbit, slight erythema in 4 rabbits, and mild erythema in 1 rabbit by 1 hour after test substance removal. At 24 hours, no dermal irritation was observed in 3 rabbits and slight erythema was observed in 3 rabbits. No dermal irritation was observed at 48 or 72 hours. Individual skin irritation scores are presented in Table 2. A summary of skin responses is presented in the following table. SUMMARY OF SKIN RESPONSES TO H-22762 RESPONSE No Response Slight Mild ERYTHEMA EDEMA Ihr 24hr 48hr 72hr Ihr 24hr 48hr 72hr 1/6 3/6 6/6 6/6 6/6 6/6 6/6 6/6 4/6 3/6 0/6 0/6 0/6 0/6 0/6 0/6 1/6 0/6 0/6 0/6 0/6 0/6 0/6 0/6 Under the conditions of this study, H-22762 was a mild skin 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-22762 probably could be classified as "NON-IRRITANT" until further data is available. Company SanHlzed. Does not contain TSCA CBI -6- TABLE 1 DRAIZE8 SCALE FOR SCORING SKIN IRRITATION Evaluation of Skin Reactions Score Erythema and eschar formation: No erythema....................................................................................................... Very slight erythema (barely perceptible).......................................................... Well-defined erythema....................................................................................... Moderate to severe erythema.............................................................................. Severe erythema (beet redness) to slight eschar formation (injuries in depth).. 0 1 (Slight) 2 (Mild) 3 (Moderate) 4 (Severe) Edema formation: No edema................................................................................ Very slight edema (barely perceptible)................................... Slight edema (edges of area well defined by definite raising) Moderate edema (raised approximately 1.0 mm)................... Severe edema (raised more than 1.0 mm extending beyond the area of exposure). . 0 1 (Slight) 2 (Mild) 3 (Moderate) 4 (Severe) Abbreviations of other dermal effects are: A = Abraded F = Fissuring I = T = Intact Thickening N = G = Necrosis Fissuring with C = - = B = Eschar No Effect Blanching Bleeding S = Epidermal Scaling D = Desquamation L = R = X = SN = Sloughing Raw Areas Compound Adhered to Skin Superficial Necrosis a 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. Company Sanitized. Does not contain TSCA CBI I .7- TABLE 2 INDIVIDUAL SKIN IRRITATION SCORES SKIN RESPONSES OBSERVED IN RABBITS Rabbit Number 32043 32045 32085 32075 32077 32081 Hours After Test Substance Removal Erythema Edema 1 24 48 72 1 24 48 72 1 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 Rabbit Number 32043 32045 32085 32075 32077 32081 Hours After Test Substance Removal Other Dermal Effects 1 24 48 72 XXX - X X - - XX - - X X - - X - - - XX - - Symbols are defined on page 7. fCompcmySanNbed. Does not contain TSCA CBI 8-