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TRADE SECRET Study Title H-23004: SKIN IRRITATION TEST IN RABBITS LABORATORY PROJECT ID: HL-1997-01294 AR226-3085 AUTHOR: Tracy A. Filliben . STUDY COMPLETED ON: December 30, 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:!------fl& Page 1 of 10 Company Sanitized. Does not contain TSCA CB6 CERTIFICATION Study Director: KUibenDate C^JIU^^ ^dh^Juu^Q. ()Tracy A. Toxicology Associate /z/W^-7 " 'cwn, Banifced. Does not contain TSCA CBI STUDY INFORMATION Synonyms/Codes: H-23004 Haskell Number: 23004 Submitter's Notebook Number(s'):|^BBBJHI^ Physical Characteristics: Off-white 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 Font de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: November 25,1997 / (see report cover page) m-Life Initiated/Completed: November 26,1997 / November 29,1997 -3- Cofflipany 0^ not Mntain TSCA CBI STUDY PERSONNEL Managers): Judith C. Stadler, Ph.D. Study Director: Tracy A. Pilliben Primary Technician: Tracy A. Filliben Toxicology Report Preparations): Maryanne M. Wilford, B.A. Laboratory Veterinarian: Charles E. Cover, VMS. -4- Company Sanitized. Does not contain TSCA CB1 SUMMARY H-23004 was evaluated for acute skin irritation potential in 6 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 75 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. One rabbit exhibited no dermal irritation during the study. The remaining 5 rabbits exhibited slight erythema at 1 hour and no or slight erythema at 24 and 48 hours. All dermal irritation had cleared in the treated rabbits by 75 hours after test substance removal. No edema or clinical signs of toxicity were observed in any of the rabbits during the study. Under the conditions of this study, H-23004 was a slight skin irritant. -5- Company Sanitized. Does not eontain TSCA CB2 INTRODUCTION The purpose of this study was to evaluate the skin irritation potential ofH-23004 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 of Purina Certified High Fiber Rabbit Chow #5325 daily during the study. Water was available ad libitwn 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 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 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 1 week. 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 prior to treatment, the hair of 1 male and 5 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 2625 to 3128 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-23004 was -6- Compan^ Sanitized. Does not contain TSCA CB8 applied directly on the skin 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. Two other test substances were tested concurrently on separate, localized test sites on the backs of 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 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 75 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 DISCUSSION One rabbit exhibited no dermal irritation during the study. By 1 hour after test substance removal, the remaining 5 rabbits exhibited slight erythema. Three additional rabbits were clear of all dermal irritation by 24 hours. Slight erythema was observed in the remaining 2 rabbits at 24 and 48 hours and was clear by 75 hours. No edema or clinical signs of toxicity were observed during the study. Individual skin irritation scores are presented in Table 2. A summary of skin responses is presented in the following table. RESPONSE No Response Slight SUMMARY OF SKIN RESPONSES TO H-23004 1 hour 1/6 5/6 ERYTHEMA 24 hours 48 hours 4/6 4/6 2/6 2/6 75 hours 6/6 0/6 Ihour 6/6 0/6 EDEMA 24 hours 48 hours 6/6 6/6 0/6 0/6 75 hours 6/6 0/6 CONCLUSIONS Under the conditions of this study, H-23004 was a slight 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-23004 probably should not be classified as an irritant unless further data proves otherwise. -7- Company Sanitized. Does not contain TSCA CBI 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. L du Font de Nemours and Company Records Management Center). 8 - - Company Sanlfeed. Does not contain TSCA CM H-23004: Skin Irritation Test in Rabbits DuPontHL-1997-01294 TABLE 1 DRAKE3 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 praised 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 S = Bleeding Epidermal Scaling D = Desquamation L = R = X = SN = Sloughing Raw Areas Compound Adhered to Skin Superficial Necrosis 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. .9- Company Sanifeed. Does not contain TSCACBS H-23004: Skin Irritation Test in Rabbits DuPont HL-1997-01294 TABLE 2 INDIVIDUAL SKIN IRRITATION SCORES AND SKIN RESPONSES OBSERVED IN RABBITS RABBIT NUMBER 32186 32402 32381 32406 32407 32410 HOURS AFTER TEST SUBSTANCE REMOVAL ERYTHEMA EDEMA 1 24 48 75 1 24 48 75 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 1 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 -10- Compa"lf Sanitized. Does not contain TSGACB8