Document RaNr4V7N9xqLv13JaojGjNDnn

AR226-3036 Study Title Approximate Lethal Dose (ALD) of H-21333 in Rats Laboratory Project ID Haskell Laboratory Report No. 649-95 Author M. Scott Karr Study Completed On January 23, 1996 Performing Laboratory E. I. du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P. 0. Box 50 Newark, Delaware 19714 Page 1 of 8 eowspwf M M . Boml tain T8CA CBI DuPont HLR 649-95 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT This study was conducted in compliance with EPA TSCA Good Laboratory Practice Standards (40 CFR 792) with the following exceptions: 1. The dosing preparations used in the study were not analyzed for stability, homogeneity, or accuracy of concentration. The procedures used by trained staff to prepare the dosing preparations ensured: the accuracy of concentration because the test substance was weighed on an analytical balance accurate to 3 decimal places and the vehicle in which it was suspended was accurately measured in a flask graduated in 1 mL increments, homogeneity because the mixture was stirred prior to dosing and while portions were removed for dose administration, and stability because the time between dose preparation and administration was kept to a minimum (less than 1 hour). 2. H-21333 did not undergo GLP analysis to determine purity. The deviations did not affect the validity of the study. Submitter: E. I. du Pont de Nemours and Company Sponsor: DuPont Specialty Chemicals E. I. du Pont de Nemours and Company Study Director: Tracy A. Filliben Toxicology Associate Company Sanitized. Does not contain TSCA CBS -2 Substance Tested; Synonyms/Codes; Physical Form; Composition; GENERAL INFORMATION DuPont HLR 649-95 Contaminants; Purity; Submitter's Notebook No.; CAS Registry No.; Sponsor; Study Initiated - Completed; In Life Phase Initiated - Completed; DuPont Specialty Chemicals E. I. du Pont de Nemours and Company Wilmington, Delaware 8/8/95 - 1/23/96 8/9/95 - 8/28/95 -3- DuPont HLR 649-95 Approximate Lethal Dose (ALP) of H-21333 in Rats SUMMARY H-21333 was administered as a single oral dose by intragastric intubation to male rats. Rats were found dead up to 7 days after dosing. Clinical signs of toxicity were observed in lethally and nonlethally dosed animals. Under the conditions of this test, the ALD was 2300 mg/kg of body weight. This substance is considered to be slightly toxic (ALD 500 - 5000 mg/kg) when administered as a single oral dose. Work by: Reviewed and Approved for Issue: M. Scott Karr Toxicology Technician ^DLIk a J ________ f /.Z3/9 Tracy A. Filliben Study Director TAF/lmp/alw Sanitized. Does notcontain TSCA CBt DuPont HLR 649-95 QUALITY ASSURANCE DOCUMENTATION (H-21333) Date(s) of Inspection: Conduct - 8/9/95 Records, Report(s) - 1/22,23/96 Date(s) Findings Reported to: Study Director - 1/23/96 Management - > 1/23/96 Reported by: Ronald B. Macturk Quality Assurance Auditor //2i?/9 Date -5- Cwmpawip anifeed. Does not contain TSCA CBI DuPont HLR 649-95 INTRODUCTION The purpose of this test was to determine an approximate lethal dos of H-21333 when administered as a single oral dose to male rats. The ALD was defined as the lowest dose administered which caused death either on the day of dosing or within 14 days post exposure. MATERIALS AND METHODS A. Animal Husbandry Male Crl:CDBR rats, approximately 7 weeks old, were received from Charles River Breeding Laboratories, Raleigh, North Carolina. Rats were housed singly in suspended, stainless steel, wire-mesh cages. Each rat was assigned a unique identification number which was recorded on a card affixed to the cage. The rats were tail-marked, using a water-insoluble marker, with the last 3 digits of the animal number. Purina Certified Rodent Chow #5002 and water were available ad libitum. 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 assure 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. Rats were quarantined, weighed, and observed for general health for approximately one week prior to testing. 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 23C 1C and relative humidity of 50% + 10%. Excursions outside these ranges were of small magnitude and/or brief duration and did not adversely affect the validity of the study. B. Protocol The test substance was suspended in deionized water and administered *"? \ rat Per dose rate by intragas trie intubation. In the absence of visible evidence to the contrary, the test substance was assumed to be - 6- Companf SwSteeA 0@nel contain TSCA evu DuPont HLR 649-95 stable under the conditions of administration. Dose rates administered ranged from 450 to 3400 mg/kg of body weight in increments of approximately 50%. The dosing day was test day 1} postexposure day 14 was test day 15. Following administration of the test substance, rats were observed for clinical signs of toxicity. Surviving rats were weighed and observed daily until signs of toxicity subsided, and then at least 3 times a week throughout the 14-day observation period. Observations for mortality were made daily throughout the study. Pathological examinations of test animals were not performed. C. Records Retention All raw data and the final report will be stored in the archives of Haskell Laboratory for Toxicology and Industrial Medicine, E. I. du Pont de Nemours and Company, Newark, Delaware or in the DuPont Records Management Center, Wilmington, Delaware. RESULTS A. Dosage and Mortality Data The dosage regimen and the mortality resulting over the 15-day test period are detailed below. The lowest dose of H-21333 which resulted in the death of a test animal was 2300 mg/kg. Rats were found dead up to 7 days after dosing. Dosage (mg/kg) 450 670 1000 1500 2300 3400 Dose Volume (mL) 0.55 1.2 1.3 1.9 3.9 4.2 Suspension Concentration (mg/mL) 200 150 200 200 . 150 200 Initial Body Weight (g) 243 264 250 247 257 246 Mortality No No No No Yes Yes - 7- Company SwitteeA Bees m i tifate C A CBS B. Clinical Signs Nonlethal Doses DuPont HLR 649-95 The rats dosed at 450, 670, 1000, and 1500 mg/kg exhibited continuous weight losses of up to approximately 26% of initial body weight 2,3,or 6 days after dosing. Clinical signs observed in these rats included ruffled fur, lethargic behavior, hunched over posture, wet perineum, or alopecia of the underbody. Most clinical signs of toxicity had subsided by 7 days after dosing. Lethal doses dosed at 2300 mg/kg exhibited a weight loss of approximately 39X of initial body weight by 6 days after dosing and was found dead by 7 days after dosing. The rat dosed at 3400 mg/kg exhibited a weight loss of approximately 22% of initial body weight by 3 days after dosing and was found dead by 4 days after dosing. Clinical signs of toxicity observed in these rats included lethargic behavior, ruffled fur, hunched over posture, or dry red nasal or ocular discharge. CONCLUSION Under the conditions of this study, the ALD for H-21333 was 2300 mg/kg of body weight. This substance is considered to be slightly toxic (ALD 500 5000 mg/kg) when administered as a single oral dose to male rats. -8 - Company Sanitized. Does not contain TSCA CBJ