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AR226-3114 DuPont-2121 TRADE SECRET Study Title H-23773 and H-23775: Skin Irritation Test in Rabbits Laboratory Project ID: DuPont-2121 A u t h o r : Carol Finlay, B.A. S t u d y C o m p l e t e d o n : February 19,1999 P e r f o r m in g L a b o r a t o r y : 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 Page I of 12 Company Sanitized. Do m not contain TSCA CBi H-23773 and H-23775: Skin Irritation Test in Rabbits DuPont-2121 C E R T IF IC A T IO N W e, the undersigned, declare that this report provides an accurate evaluation o f the data obtained from this study. Reviewed by: 0 ., ( j Tracy A. Filiiben Toxicology Associate /9 Date Issued by Study Director:---------- A t * f a f * . , ______________ _ Car^l Finlay, Toxicology Associate / 1- feh - /f f 7 Date -2 Company Sanitized D oes not contain TSC A CBI H-23773 and H-23775: Skin Irritation Test in Rabbits STUDY INFORM ATION Haskell Number: 23773 Submitter's Notebook Numberis): Composition: Known ImpufitiesT Physical Characteristics: White fabric DuPont-2121 Haskell Number: 23775 Physical Characteristics: White fabric } '.V -3 - C-\- SenRizsd. Doss m l saniein T3C.'. ..( H-23773 and H-23775: Skin Irritation Test in Rabbits DuPont-2121 Stability: The test substances 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: January 11,1999 / (see report cover page) In-Life Initiated/Completed: January 12, 1 9 9 9 /January 15, 1999 -4 Company Sanitized. Does not contain TSCA CBI H-23773 and H-23775: Skin Irritation Test in Rabbits STUDY PERSONNEL Study Director: Carol Finlay, B.A. Management: Judith C. Stadler, Ph.D. Primary Technician: Carol Finlay, B.A. Toxicology Report Preparation: Lisa G. Burchfield, A.A. Laboratory Veterinarian: Wanda L. West, D.V.M., A.C.L.A.M. DuPont-2121 -5 S-OtTrpany Sanitized. Does not co n tain 7SCA CBi H-23773 and H-23775: Skin Irritation Test in Rabbits DuPont-2121 SUM M ARY H-23773 was evaluated for acute skin irritation potential in 5 male New Zealand White rabbits. H-23775 was evaluated for acute skin irritation potential in 6 male New Zealand White rabbits. A 1-inch square o f each test substance was applied directly on the skin on opposite sides o f each rabbit beneath a 2-ply, 1-inch gauze square. The gauze square was held in place with non irritating tape for a 4-hour exposure. Approximately 1, 24,48, and 72 hours after test substance removal, the test sites were evaluated for erythema, edema, and other evidence o f dermal effects and were scored according to the Draize Scale. The adjacent areas o f untreated skin were used for comparison. H-23773 produced no dermal irritation in 3 rabbits throughout the study. The remaining 2 rabbits exhibited no dermal irritation at 1 hour and slight or mild erythema 24 hours after test substance removal. At 48 hours, all dermal irritation had cleared in 1 rabbit; slight erythema was observed in the other rabbit. No dermal irritation was observed at 72 hours. No edema was observed. H-23775 produced no dermal irritation in 5 rabbits throughout the study. The remaining rabbit exhibited no dermal irritation at 1 hour, mild erythema and mild edema at 24 and 48 hours, and no dermal irritation at 72 hours. Two rabbits exhibited a scratch on the test site during the study. No significant weight loss or clinical signs of toxicity were observed. Under the conditions o f this study, H-23773 and H-23775 were both mild skin irritants. -6 Company Sanitized. Does not contain TSC A CBI H-23773 and H-23775: Skin Irritation Test in Rabbits DuPont-2121 IN T R O D U C T IO N The purpose o f this study was to evaluate the skin irritation potential of H-23773 and H-23775 when applied to separate, localized test sites on the shaved, intact skin of New Zealand White rabbits. M ATERIALS AND M ETHODS A. A nim al H usbandry Young adult 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 o f PMI Nutrition International, Inc. Certified High Fiber Rabbit LabDiet 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 o f 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 o f this study. Rabbits were quarantined, weighed, and observed for general health for 14 days. Animal rooms were maintained on a timer-controlled, 12-hour light/12-hour dark cycle. Environmental conditions o f 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 6 male New Zealand White rabbits was closely shaved to expose the skin from the scapular to the lumbar region o f the back. The body weights o f the rabbits ranged from 2192 to 2512 grams on the day of treatment. -7 Company Sanitized. Does not contain TSC A C E 5 H-23773 and H-23775: Skin Irritation Test in Rabbits DuPont-2121 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. Both test substances were thoroughly moistened with deionized water prior to treatment. A 1-inch square of H-23773 and a 1-inch square of H-23775 were applied directly to the skin on opposite sides of each rabbit beneath 2-ply, 1-inch gauze squares that were held in place with non-irritating 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 substance was tested on a separate, localized test site on the backs o f 2 of these rabbits. Approximately 4 hours after application of the test substances, the rubber sheeting was loosened, and the skin at the comers o f 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. The skin was gently patted dry, and the animals were returned to their cages. The gauze square and square o f H-23773 became dislodged from the test site of 1 rabbit. This test site was not evaluated. Approximately 1, 24, 48, and 72 hours after removal o f 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 o f the untreated skin were used for comparison. The rabbits were also examined for clinical signs of toxicity at every dermal evaluation. RESULTS AND DISCUSSION H-23773 produced no dermal irritation in 3 rabbits throughout the study. The remaining 2 rabbits exhibited no dermal irritation at 1 hour and slight or mild erythema at 24 hours after test substance removal. At 48 hours, all dermal irritation had cleared in 1 rabbit; slight erythema was observed in the other rabbit. No dermal irritation was observed at 72 hours. No edema was observed. H-23775 produced no dermal irritation in 5 rabbits throughout the study. The remaining rabbit exhibited no dermal irritation at 1 hour, mild erythema and mild edema at 24 and 48 hours, and no dermal irritation at 72 hours. Two rabbits exhibited a scratch on the test site during the study. No significant weight loss or clinical signs of toxicity were observed. Individual skin irritation scores are presented in Tables 2 and 3. A summary o f skin responses is presented in the following table. -8 Company Sanitized. Does not contain TSCA CBI H-23773 and H-23775: Skin Irritation Test in Rabbits DuPont-2121 SUMMARYOF SKIN RESPONSES TO H-23773 RESPONSE 1 No Response 1 5/5 Slight 0/5 Mild 0/5 HOURS AFTER TEST SUBSTANCE RFMDVAT ERY1'HEMA EDEMA 24 48 72 1 24 48 3/5 4/5 5/5 5/5 5/5 5/5 1/5 1/5 0/5 0/5 0/5 0/5 1/5 0/5 0/5 0/5 0/5 0/5 72 5/5 0/5 0/5 SUMMARY OF SKIN RESPONSES TO H-23775 RESPONSE 1 No Response I 6/6 Slight 0/6 Mild 0/6 HOURS AFTER TEST SUBSTANCE REMOVAL ERYI'HEMA EDEMA 24 48 72 1 24 48 5/6 5/6 6/6 6/6 5/6 5/6 0/6 0/6 0/6 0/6 0/6 0/6 1/6 1/6 0/6 0/6 1/6 1/6 72 6/6 0/6 0/6 C O N C L U SIO N S Under the conditions of this study., H-23773 and H-23775 were both mild akin irritants. 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 o f European Communities (EEC Directive 93/21, Annex VI), H-23773 or H-23775 probably should not be classified as irritants unless further data proves otherwise. RECORDS AND SAMPLE STORAGE Specimens (if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware (formerly known as the E. I. du Pont de Nemours and Company Records Management Center). -9 Company Sanxsd. Doss r. confair TSCCHt H-23773 and H-23775: Skin Irritation Test in Rabbits DuPont-2121 TABLE 1 DRAIZE3 SCALE FOR SCORING SKIN IRRITATION Evaluation of Skin Reactions Score Erythema and eschar formation: No erythema.................................................................................................................. 0 Very slight erythema (barely perceptible).................................................................. 1 (Slight) Well-defined erythema...................................................................................................2 (Mild) Moderate to severe erythema.......................................................................................................... 3(Moderate) Severe erythema (beet redness) to slight eschar formation (injuries in depth).......4 (Severe) Edema formation: No edema...................................................................................................................... 0 Very slight edema (barely perceptible)...................................................................... 1 (Slight) Slight edema (edges of area well defined by definite raising)................................ ; 2 (Mild) Moderate edema (raised approximately 1.0 m m )..................................................... 3 (Moderate) Severe edema (raised more than 1.0 mm extending beyond the area o f exposure)................................................................................................................ 4 (Severe) Abbreviations of other dermal effects are: - = No Effect I = Intact A = Abraded L = Sloughing B = Blanching N = Necrosis C = Eschar R = Raw Areas D = Desquamation S = Epidermal Scaling F = Fissuring T = Thickening G = Fissuring with Bleeding X = Compound Adhered to Skin H - Hyperkeratosis 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. - 10 - Company Sanitized. Does not contain TSCA CBI H-23773 and H-23775: Skin Irritation Test in Rabbits DuPont-2121 TABLE 2 INDIVIDUAL SKIN IRRITATION SCORES AND SKIN RESPONSES OBSERVED IN RABBITS H-23773 RABBIT NUMBER 33354 33355 33358 33359 33360 33361 HOURS AFTER TEST SUBSTANCE REMOVAL ERYT HEMA EDEMA 1 24 48 72 a aa a 1 24 48 72 a aa a 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 00 0 0 10 0 0 0 0 0 0 210 0 00 0 a The patch became dislodged during the exposure period. RABBIT NUMBER 33354 33355 33358 33359 33360 33361 HOURS AFTER TEST SUBSTANCE REMOVAL OTHER DERMAL EF FECTS 1 24 48 72 -- - -' - - - ---- -- - - - --- -- - - Symbol is defined on page 10. fflftjoany Sanitized, s :- cer ^ H-23773 and H-23775: Skin Irritation Test in Rabbits DuPont-2121 TABLE 3 INDIVIDUAL SKIN IRRITATION SCORES AND SKIN RESPONSES OBSERVED IN RABBITS RABBIT NUMBER 33354 33355 33358 33359 33360 33361 H-23775 HOURS AFTER TEST SUBSTANCE REMOVAL ERYT HEMA EDEMA 1 24 48 72 1 24 48 72 0 0 0 0 0 0 .0 0 0000000 0 0 000 00 0 0 0220022 0 0 000 0 0 0 0 0 0000000 RABBIT NUMBER 33354 33355 33358 33359 33360 33361 HOURS AFTER TEST SUBSTANCE REMOVAL OTHER DERMAL EF FECTS 1 24 48 72 -- - - -- - - -- - - -- - - - aaa - aaa a Scratch on test site. Symbol is defined on page 10. - 12 - Company Sanitized. Does not contain TSCA CBI