Document 91k6bNVjxJror7zQdE7m5YVMe

P M A l - }J S O 432 TRADE SEC RET M M - D u P o n t- 11101 Study Title H-25357: Acute Dermal Irritation Study in Rabbits Laboratory Project ID: DuPont-11101 Test Guidelines: U.S. EPA Health Effects Test Guidelines OPPTS 870.2500 (1998) OECD Guidelines for Testing o f Chemicals Section 4: Health Effects, No. 404 (1992) Commission Directive 92/69/EEC EEC Method B.4 (1992) Author: Carol Finlay, B.A. Study Completed on: August 1,2002 Performing Laboratory: E.I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 Page 1 o f 18 Company Sanitized. Does not contain TSCA CBS H-25357: Acute Dermal Irritation Study in Rabbits DuPont-11101 GOOD LABORATORY PRACTICE COMPLIANCE STATEM ENT This study was conducted in compliance with U.S. EPA TSCA (40 CFR part 792) Good Laboratory Practice Standards, which are consistent with the OECD Principles of Good Laboratory Practice (as revised in 1997) published in ENV/MC/CHEM(98)17, except for the item documented below. The item listed does not impact the validity o f the study. The test substance was characterized by the sponsor prior to the initiation o f this study. Although the characterization was not performed under Good Laboratory Practice Standards, the characterization was done by an ISO 9000 certified lab and the accuracy o f the data is considered sufficient for the purposes o f this study. Applicant / Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U .S. A. Study Director: Staff Toxicologist Applicant / Sponsor: DuPont Representative Date Company Sanitized. Does not contain TSCA CI H-25357: Acute Dermal Irritation Study in Rabbits QUALITY ASSURANCE STATEMENT Haskell Sample Number(s): 25357 Dates of Inspections: Protocol: June 18,2002 Conduct: June 18,2002 Records, Reports: July 22-23, 2002 Dates Findings Reported to: Study Director: July 23, 2002 Management: July 23, 2002 DuPont-11101 Reported by: ML. Matthew Freni Quality Assurance uditor l ' / b a - 2 OL Company Sanitized, Does not contain TSCA C&l -3 - H-25357: Acute Dermal Irritation Study in Rabbits DuPont-11101 CERTIFICATION We, the undersigned, declare that this report provides an accurate evaluation of the data obtained from this study. Reviewed by; X L , /rr James C/Mackay II Associate Scientist Ml Issued by Study Director: ? A A aA - x j u ,. Carifl Finlay, B .^. Staff Toxicologist Company Sanitized. Does not contain TSCA cm 4- - H-25357: Acute Dermal Irritation Study in Rabbits DuPont-11101 TABLE OF CONTENTS Page G O O D L A B O R A T O R Y P R A C T IC E C O M PL IA N C E S T A T E M E N T ......................................... 2 Q U A L IT Y A SSU R A N C E S T A T E M E N T ..................................................................................................3 C E R T IF IC A T IO N .............................................................................................................................................. 4 ST U D Y IN F O R M A T IO N ................................................................................................................................ 6 ST U D Y P E R S O N N E L ................................................................................ ...................................................... 7 S U M M A R Y ..................................................................................................... 8 IN T R O D U C T IO N ................................................................................ .............................................................. 9 A . O b je c tiv e ............................................................................................................................................................. 9 B . P rin c ip le s o f th e M e th o d o lo g y ............................................................. 9 M A T E R IA L S A N D M E T H O D S ................................................................................................................... 9 A . T e st G u id e lin e s .................................................................................................................................................9 B . T e st S u b s ta n c e ........................................................................................................................................ 9 C . A n im a l H u s b a n d ry .........................................................................................................................................10 D . P ro to c o l..............................................................................................................................................................10 E . D a ta A n a ly sis a n d In te rp re ta tio n o f R e su lts......................................................................................... 11 R E SU L T S A N D D IS C U S S IO N ............................................................... 12 C O N C L U S IO N ............................................................................................... 12 R E C O R D S A N D SA M PLE S T O R A G E ...................................................................................................13 T A B L E S ................................................................................................................................................................ 14 1. DRAIZE SCALE FOR SCORING SKIN IRRITATION.......................................................................................... 15 2. GLOSSARY OF DERMAL EFFECTS...................................................................................................................... 16 3. DERMAL RESPONSES OBSERVED IN INDIVIDUAL RABBITS..................................................................... 17 4. SUMMARY OF MEAN SCORES FOR DERMAL RESPONSES......................................................................... 17 5. INCIDENCES OF DERMAL RESPONSES (SCORES).......................................................................................... 18 6. BODY WEIGHTS AND CLINICAL SIGNS OF TOXICITY OBSERVED IN RABBITS................................18 Company Sanitized. Does not contain TSCA CBI H-25357: Acute Dermal Irritation Study in Rabbits STUDY INFORMATION Substance Tested: Svnonvms/Codes: H-25357 Submitter's Notebook Number(s): Haskell Number: 25357 CAS Registry Number: Composition: Purity: Known Impurities: D u P o n t-11101 Physical Characteristics: Amber liquid Sponsor: E.I. du Pont de Nemours and Company Wilmington, Delaware 19898 U.S.A. Study Initiated/Completed: June 14,2002 / (see report cover page) In-Life Initiated/Completed: June 18, 2002 / June 21, 2002 ^Company Sanitized. Does not contain 'r<ae.& H-25357: Acute Dermal Irritation Study in Rabbits DuPont-11101 STUDY PERSONNEL Study Director: Carol Finlay, B.A. Management: Scott E. Loveless, Ph.D. Primary Technician: Erica K. Pia, B.S. Toxicology Report Preparation: Sean M. Callaghan, B.A. Management: Nancy S. Selzer, M.S. Laboratory Veterinarian: William Singleton, D.V.M., A.C.L.A.M. Company Sanitized. D oes not contain TSCA CBl H-25357: Acute Dermal Irritation Study in Rabbits D u P o n t-11101 SU M M A RY H-25357 was evaluated for acute skin irritation potential in 3 male New Zealand White rabbits. An aliquot of 0.5 mL o f the test substance was administered to a localized test site on the back of each animal. The test sites were covered with a semi-occlusive dressing to ensure contact between the skin and test substance. The animals were exposed to the test substance for approximately 4 hours. The test sites were evaluated and scored according to a numerical scale approximately 1,24,48, and 72 hours after the end of the 4-hour exposure period. No dermal irritation was observed in any of the rabbits during the study. No clinical signs were observed, and no body weight loss occurred. Mean values were calculated for each animal separately from numerical scores obtained from the quantitative evaluation o f the 2 dermal responses (erythema and edema) observed in the rabbits at 24,48, and 72 hours following test substance removal. These values are as follows: Rabbit Number 35554 35558 35555 Erythema 0 0 0 Edema 0 0 0 In accordance with Directive 67/548/EEC, H-25357 is not classifiable as irritant. .Company Sanitized. Does not contain TSCA Cttt H-25357: Acute Dermal Irritation Study in Rabbits DuPont-11101 INTRODUCTION A. Objective The objective of this study was to evaluate the skin irritation/corrosive potential and the reversibility of dermal effects of H-25357 following a 4-hour dermal exposure in albino rabbits. The results of the study were used to determine the appropriate toxicity classification and labeling requirements in accordance with EEC. B. Principles of the M ethodology Dermal erythema and edema are evaluated and scored at 1 ,2 4 ,4 8 , and 72 hours following the removal of the test substance at the end of the 4-hour exposure in each o f 3 rabbits. The reversibility o f any dermal effects is assessed for up to 14 days, if necessary. Dermal effects are quantified according to the Draize Scale (Table 1). MATERIALS AND METHODS A. Test Guidelines The study design complies with the following test guidelines: Office o f Prevention, Pesticides and Toxic Substances (OPPTS) U.S. Environmental Protection Agency (EPA) (1998). OPPTS 870.2500 Acute Dermal Irritation. Health Effects Test Guidelines. Organisation for Economic Co-Operation and Development (OECD) (1992). 404 Acute Dermal Irritation/Corrosion. Guidelinefo r Testing o f Chemicals. European Economic Communities (EEC) (1992). Directive 92/69/EEC Annex V, Part B.4, Acute Toxicity (Dermal Irritation). Methodsfo r the Determination o f Toxicity. B. Test Substance The test substance, H-25357, was supplied by the sponsor as an amber liquid. The test substance was inverted to mix before each amount for dosing was removed. The test substance appeared to be stable under the conditions o f the study. No evidence of instability, such as a change in color or physical state, was observed. .Companj Sanitized. Does not confa? -9 - <nt?i H-25357: Acute Dermal Irritation Study in Rabbits D uPont-11101 C. A nim al H usbandry Adult HM:(NZW)fBR New Zealand White rabbits were received from Covance Research Products, Denver, Pennsylvania. The rabbits were housed singly in stainless steel, wire-mesh cages suspended above cage boards. 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, LLC Certified High Fiber Rabbit LabDiet 5325 daily during the study. Water was available ad libitum. As specified in the Haskell Laboratory animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impact the scientific integrity o f the study: Water samples are analyzed for total bacterial counts, and the presence o f coliforms, lead, and other contaminants. Feed samples are analyzed for total bacterial, spore, and fungal counts. Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation by the cagewashers. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations o f key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence o f these contaminants below the maximum concentration stated by the manufacturer would not be expected to impact the integrity o f the study. The animal health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluation of these data did not indicate any conditions that affected the validity o f the study. Rabbits were weighed and observed for general health during the 7-day quarantine period. 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 o f 20C 1C and relative humidity o f 50% 10%. Excursions outside these ranges were judged to have been of insufficient magnitude and/or duration to have adversely affected the validity o f the study. D. Protocol Approximately 24 hours prior to treatment, the fur of 3 male New Zealand White rabbits was closely shaved to expose the skin from the scapular to the lumbar region o f the back. The rabbits weighed from 1914 to 2358 grams on the day of treatment. The area to be treated (approximately 6 cm2) was marked on each rabbit's back with a waterinsoluble marker. An aliquot of 0.5 mL o f H-25357 was applied to the test site and covered with -10- StempmgSmze i Does not contain TSCA CBI H-25357: Acute Dermal Irritation Study in Rabbits DuPont-11101 a 2-ply, 1-inch square gauze pad. The pad was held in place with non-irritating tape. The trunk o f each rabbit was wrapped with porous tape. The tape was further secured with waterproof tape. The rabbits were returned to their cages after treatment. No other substances were tested on these rabbits. Approximately 4 hours after application of the test substance, the rabbits were removed from their cages and the wrappings and gauze pads were removed. The test sites were gently washed with Lander Soap and warm water to remove excess test substance and gently patted dry. The rabbits were then returned to their cages. Approximately 1 hour after removal of the test patches, the test sites were evaluated for erythema, edema, and other evidence o f dermal effects and were scored according to the Draize Scale (Table 1). A glossary o f dermal effects and abbreviations is presented in Table 2. Additional evaluations were made at approximately 24, 48, and 72 hours after removal o f the patches. The adjacent areas o f untreated skin were used for comparison. Additionally, the rabbits were examined for clinical signs of toxicity at each observation period. The rabbits were weighed on the day o f treatment and at the last dermal evaluation. E. Data Analysis and Interpretation of Results Mean values for each lesion (erythema and edema) were calculated for each animal separately from numerical scores obtained at the 24-, 48-, and 72-hour observations. The results were interpreted according to 67/548/EEC relative to the general classification and labeling requirements for dangerous substances. Corrosive The test substance will be considered to be "CORROSIVE" and will require the symbol "C" and the indication o f danger "CORROSIVE" if it produces full thickness destruction o f the skin tissue on at least 1 animal during the skin irritation test. Risk phrases will be assigned in accordance with the following criteria. R35 "CAUSES SEVERE BURNS" If, when applied to healthy intact animal skin, full thickness destmction o f skin tissue occurs as a result o f up to 3 minutes exposure or if this result can be predicted. R34 "CAUSES BURNS" If, when applied to healthy intact animal skin, full thickness destruction o f skin tissue occurs as a result of up to 4 hours exposure or if this can be predicted. Sanitized. Does not contain -n - H-25357: Acute Dermal Irritation Study in Rabbits Irritant DuPont-11101 The test substance will be classified as "IRRITANT" and will require the symbol"Xi" and the indication of danger "IRRITANT" in accordance with the criteria given below. In addition, the following risk (R) phrase will be assigned to substances, if appropriate, according to the criteria indicated below: R38 "IRRITATING TO SKIN" If, when applied to healthy intact animal skin for up to 4 hours, significant inflammation is caused and is present 24 hours or more after the end of the exposure period. Inflammation is significant if the mean values of the scores for either erythema and eschar formation or edema formation corresponds to one or more o f the following mean values calculated for each animal separately and has been observed in 2 or more animals: - Erythema and eschar formation 2.0 or more - Edema 2.0 or more All scores at each o f the reading times (24,48, and 72 hours) for an effect should be used in calculating the respective mean values. An R38 "IRRITATING TO SKIN" phrase should also be assigned if: The inflammation persists in at least 2 animals at the end of the observation time. Particular effects such as hyperplasia, scaling, discoloration, fissures, scabs, and alopecia should be taken into account. RESULTS AND DISCUSSION No dermal irritation was observed in any o f the rabbits during the study. No clinical signs were observed, and no body weight loss occurred. The dermal scores from individual animals with respect to observation time are presented in Table 3. Summary o f mean scores calculated in accordance with EEC are presented in Table 4. Incidences o f dermal irritation responses (scores) are summarized for each observation period in Table 5. Individual rabbit body weights and clinical signs o f toxicity are presented in Table 6. CONCLUSION In accordance with Directive 67/548/EEC, H-25357 is not classifiable as irritant. ISlip'if .S'hffeea Does noi coni* -12- H-25357: Acute Dermal Irritation Study in Rabbits D u P o n t- 11101 RECORDS AND SAMPLE STORAGE All data and records for analytical characterization conducted by the sponsor will be maintained at Chambers Works, Deepwater, New Jersey or at Iron Mountain Records Management, Wilmington, Delaware. 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. Company Sanitized. D oes not contain t sc a ct*f H-25357: Acute Dermal Irritation Study in Rabbits DuPont-11101 TABLES .Company SanfHzed. Does not dont Ter** -14- H-25357: Acute Dermal Irritation Study in Rabbits DuPont-11101 TABLE 1 DRAIZE3 SCALE FOR SCORING SKIN IRRITATION Evaluation of Skin Reactions Score Erythem a 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 2 3 4 Edem a formation: No edem a.......................................................................................... Very slight edema (barely perceptible)................................................................................... Slight edema (edges of area well defined by definite raising)............................................. Moderate edema (raised approximately 1.0 m m ).................................................................. Severe edema (raised more than 1.0 mm extending beyond the area o f exposure)........... 0 1 2 3 4 a Draize, J. H., "Dermal Toxicity." Appraisal o f the Safety o f Chemicals in Foods. Drugs and C osm etics. The Editorial Committee o f the Association o f Food and Drug Officials o f the United States, Austin, Texas, 1959, pp. 46-59. .Company Sanitized. Does not contain tsc - 15- H-25357: Acute Pennal Irritation Study in Rabbits DuPont-11101 TABLE 2 GLOSSARY OF DERMAL EFFECTS Blanching white appearance to skin Eschar scab on the skin that is more superficial than necrosis. This is considered to be severe irritation, Desquamation dry, flaking o f the skin Fissuring a split or cleft in the top layer o f skin without bleeding Fissuring with Bleeding a split or cleft in the skin with bleeding Hyperkeratosis thick, dry discoloration (usually but not limited to brown or white in color) o f the top layer of skin. This is considered to be severe irritation. Sloughing peeling of the top layer of skin, and epidermal scaling that has detached Necrosis area of rough/hard/dry black or dark colored skin that may crater. This is considered to be corrosion and an irreversible effect, Epidermal Scaling platelike areas of the top layer of skin that have separated from but are still attached to viable skin. This may progress to sloughing, Thickening skin is firm and/or dense to the touch, Ulceration open sore representing loss o f superficial tissue ABBREVIATIONS OF OTHER DERMAL EFFECTS - = No Effect A = Abraded B = Blanching C = Eschar D = Desquamation F = Fissuring G = Fissuring with Bleeding H = Hyperkeratosis I = Intact L = Sloughing N = Necrosis R = Raw Areas S = Epidermal Scaling T = Thickening X = Test Substance Adhered to Skin fpfnpafi Sanitized. Does not contain m H-25357: Acute Dermal Irritation Study in Rabbits DuPont-11101 TABLE 3 DERMAL RESPONSES OBSERVED IN INDIVIDUAL RABBITS ERYTHEMA RABBIT NUMBER 35554 35558 35555 HOURS AFTER REMOVAL OF TEST SUBSTANCE 1 24 48 72 00 00 0000 00 00 EDEMA RABBIT NUMBER 35554 35558 35555 HOURS AFTER REMOVAL OF TEST SUBSTANCE 1 24 48 72 00 0 0 0000 0000 TABLE 4 SUMMARY OF MEAN SCORES FOR DERMAL RESPONSES RABBIT NUMBER 35554 35558 35555 ERYTHEMA" 0 0 0 EDEMA" 0 0 0 a Calculated from the 24-, 48-, and 72-hour dermal responses (EEC). Company Sanitized. Does not contain trca - 17- H-25357: Acute Dermal Irritation Study in Rabbits DuPont-11101 TABLE 5 INCIDENCES OF DERMAL RESPONSES (SCORES) ERYTHEMA SCORE 0 1 2 3 4 1 HOUR 3/3 0/3 0/3 0/3 0/3 24 HOURS 3/3 0/3 0/3 0/3 0/3 48 HOURS 3/3 0/3 0/3 0/3 0/3 72 HOURS 3/3 0/3 0/3 0/3 0/3 EDEMA SCORE 0 1 2 3 4 1 HOUR 3/3 0/3 0/3 0/3 0/3 24 HOURS 3/3 0/3 0/3 0/3 0/3 48 HOURS 3/3 0/3 0/3 0/3 0/3 72 HOURS 3/3 0/3 0/3 0/3 0/3 TABLE 6 INDIVIDUAL BODY WEIGHTS (g) OF RABBITS RABBIT NUMBER 35554 35558 35555 SEX Male Male Male INITIAL WEIGHT 1914 2051 2358 FINAL WEIGHT (72 hours) 2222 2311 2627 CLINICAL SIGNS OF TOXICITY No clinical signs o f toxicity were observed in any of the rabbits during the study. Company Sanitize!. D oes not contain TSCA Cifri