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f FOR DU PONT USE ONLY AR226-2942 Du Pont HLR 466-89 Study Title Inhalation Approximate Lethal Concentration (ALC) of Author Rudolph Valentine Study Completed On September 6, 1989 Performing Laboratory E. I. du Pont de Nemours and Company, Inc. Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P. 0. Box 50 Newark, Delaware 19714 Laboratory Project ID Haskell Laboratory Report No. 466-89 Page 1 of 9 Company Sanitized. Does not contain T SC A C B I Material Tested: Medical Research No.: Haskell No.: Physical Form: Other Code: Synonyms; GENERAL INFORMATION 17,869 White aqueous dispersion Purity: Composition: Stability: Sponsor: Material Submitted By: The test material was assumed to be stable throughout the exposure phase of the study. Chemicals and Pigments Department E. I. du Pont de Nemours and Company, Inc. Wilmington, Delaware Cnemicais and Pigments Department E. I. du Pont de Nemours and Company, Inc. Jackson Laboratory Deepwater, New Jersey Com pany Sanitized. Does not contain T SC A C BI Du Pont HLR 466-89 GENERAL INFORMATION (Confd) In-L1fe Phase Initiated - Completed: 7/13/89 - 8/1/89 -3 Company Sanitized. D o ss not contain T S C A CB1 Du Pont HLR 466-89 Inhalation Approximate Lethal Concentration (ALC) of SUMMARY Groups of 6 male Cr1:CDBR rats were exposed for a single, 4-hour period to aerosols of M H f l i i n air. Test atmospheres were generated by atomization of the liquid t?st material 1n a high pressure air stream. Atmospheric concentrations o f l ^ l H M f e w e r e determined by gravimetric analysis. After exposure, rats were observed for clinical signs of toxicity during a 14-day recovery period. Deaths occurred following exposure t o M M f l f c at atmospheric concentrations of 590 mg/nf of greater; ell deaths were post exposure and occurred within 24 hours of exposure. Clinical signs observed immedi&.ely after exposure included red nasal and ocular discharges, lethargy, and compound-covered faces. During the 14-day recovery period, rats exhibited lethargy, hunched posture, labored breathing, red nasal discharge and wet, yellow stained perineum; these clinical signs had resolved by day 3 post exposure. Although slight to severe weight losses were noted in surviving rats 1 day after exposure, these rats began to regain body weight by day 3 post exposure. Under the conditions of this study, moderately toxic on an acute inhalation basis. considered t0 be Work by: C. W. Hutt Technician Study Director: Rudolph Valentine, Ph.D. Research Toxicologist Acute-and Developmental Toxicology Division Reviewed and Approved for Issue: RV:alr:HLR121.2 Rudolph Valentine, Ph.D. - 4- Company Sanitized. Does not contain T S C A CB? E9 Du Pont HLR 466-89 QUALITY ASSURANCE DOCUMENTATION STUDY: H# 17,869 Inhalation Approximate Leth mcentration (ALC) AUDITS: Items Audited Protocol, conduct Records, final report Audit Dates 7/13/89 8/24-25/89 SHORT-TERM AUDIT REPORT NUMBER: __ _ DATE FINDINGS REPORTED TO MANAGEMENT AND STUDY DIRECTOR! 8/25/89 Reported by: William J. Lynam Quality Assurance Auditor Date - 5- Company Sanllized. Does noi contain T S C A CBl Du Pont HLR 466-89 INTRODUCTION ^ ^ T h ^ u r p o s e of this study was to determine a 4-hour Inhalation ALC for male rats. Th ALC was defined as the lowest atmospheric concentration tested that caused the death of 1 or more rats either on the day of exposure or within 14 days post exposure. Except as documented in the study records, this study was conducted according to the applicable Good Laboratory Practice Regulations. MATERIALS AND METHODS A. Animal Husbandry Young adult male Crl:CD*BR rats were received from Charles River Breeding Laboratories, Raleigh, North Carolina. Each rat was assigned a unique 6-digit identification number which corresponded to a numbered card affixed to the cage Rats were quarantined for approximately one week prior to testing, ahd were weighed and observed three times during the quarantine period. During the test, rats were housed in pairs in 8" x 14" x 8" suspended, stainless steel, wire-mesh cages. The rat assigned the lower number in each cage was identified jy a slash in the right ear. Prior to exposure, rats' tails and cage cards were color-coded with water-insoluble markers so that individual rats could be identified after exposure. Except during exposure, Purina Certified Rodent Chow* #5002 and water were available ad libitum. Animal rooms were maintained on a timer-controlled, 12 hour/12 hour light/dark cycle. Environmental conditions of the rooms were targeted for a temperature of 23 + 2C and relative humidity of 50 + 10%. Excursions outside these ranges were judged to have been oT insufficient magnitude and/or duration to have adversely affected the validity of the study. B. Exposure Protocol Groups of 6 rats, approximately 7-8 weeks old and weighing between 242 and 271 grams, were restrained in perforated, stainless steel cylinders with conical nose pieces. The restrainers were inserted into a face plate on the exposure chamber such that only the nose of each rat protruded into the chamber. The rats jjereexposed nose-only for a single, 4-hour period to aerosols of d B H f l P ^ i n air. Rats were weighed prior to exposure, and were observed for clinical signs of toxicity during and immediately after exposure. Surviving rats were observed daily; rats were also weighed daily for 14 days post exposure, weekends excluded when warranted by the rats' condition. - 6- Company Sanitized. Does not contain T SC A CB! Du Pont HLR 466-89 C. Atmosphere Generation Aerosol atmospheres of were generated by atomization. The test material was metered Into a Spraying Systems w^ h a Harvard Model 22 Compact Infusion Pump. Conditioned, filtered houseline air introduced at the nebulizer (approximately 40 L/min) atomized the test material and discharged the resulting aerosol directly nto a 38-L cylindrical glass exposure chamber. Test atmospheres were dispersed with a conical baffle within the chamber to promote uniform distribution. Chamber atmospheres were exhausted through a dry-ice coid trap and a MSA activated charcoal/HEPA cartridge filter prior to discharge into a fume hood. D. Analytical The atmospheric concentration of M H H a e r o s o l was determined by gravimetric analysis during each exposure. Known volumes of chaiiiber atmospheres were drawn through preweighed, Gelman glass fiber (Type A/E) filters at approximately 30-minute intervals. The filters were weighed on a Cahn Model 26 Automatic Electrobalance. The atmospheric concentration of aerosol was calculated from the difference in the preand post-sampling filter weights. Since the test material was supplied as an aqueous dispersion, filters were placed in a desiccator after sampling to remove residual water; the aerosol concentrations reported herein are based on the dry filter weights. Particle size (mass median aerodynamic diameter and percent less than 3 and 10 um) was determined with a Sierra Series 210 cascade impactor during each exposure1. Chamber temperature was measured twice per exposure with a mercury thermometer. Chamber oxygen concentration was determined with a Biosystems Model 3100R oxygen monitor once per exposure. Exposure chamber relative humidity was measured once per exposure with a Belfort Model 566 psychrometer. E. Records Retention All raw data and the final report will be stored in the archives of Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware, or in the Du Pont Records Management Center, E. I. du Pont de Nemours and Company, Inc., Wilmington, Delaware. 7 Company Sanitized. Does not contain T S C A C B I Du Pont HLR 466-69 RESULTS A. Exposure Conditions and Associated Mortality An aerosol readily observed during the exposures; during trial runs, the Aerosol coated the sides of the exposure chamber, preventing visual observation of the rats. Atmospheric concentrations of f l H B P H B n d rat mortality data for each exposure are summarized in the roil owing table. Characterization of .. . 11 and Rat Mortality Concentration 3^a Mean S.D. Range n 440 130 280 - 660 S 590 220 330 - 940 9 920 210 660 - 1300 7 % Particlesb <3 urn <10 um 78 96 76 95 79 97 MMDC (urn) 1.2 1.2 1.2 Mortality (# deaths/#exposed) 0/6 1/6 3/6 Values shown represent the mean, standard deviation (S.D.), range and number of observations (n) for each exposure. Particle concentrations were based on dry filter weights. Atmospheric concentrations based on wet filter weights obtained immediately after sampling were approximately 3-15% b greater. Percent by weight of particles with aerodynamic diameter less than 3 and 10 um. Mass median aerodynamic diameter. B. Clinical Observations The coating o f ^ H | m o n the chamber walls prevented visual observation of the ratsduring exposure. Upon release from the restrainers immediately after exposure, rats exhibi-ted lethargy, compound-covered faces, and red nasal and ocular discharges. No rats died during exposure. Deaths occurred among cats exposed t o j j ^ f l U ^ ^ a t atmospheric concentrations of 590 mg/nr or greater; a ^ c l e a t h ^ v e r e post exposure and occurred within 24 hours of exposure. Clinical signs of toxicity observed in surviving rats during the recovery period included lethargy, hunched posture, labored breathing, red nasal discharge, and wet yellow-stained perineum; these clinical signs were transient and had resolved by day 3 post exposure. Surviving rats also had slight to severe weight losses (up to approximately 16% of initial body weight) 1 day after exposure; these rats began to regain weight by day 3 post exposure. Transient, sporadic weight losses were also noted in some rats from the 440 and 590 mg/m groups during the second week of recovery. - 8- Company Sanitized. Does not contain T S C A CB1 Du Pont HLR 466-89 DISCUSSION AND CONCLUSION U n d e ^ h e conditions qf this study, the approximate lethal concentration f o r ^ H ^ ^ i s 590 m g / m . ,Based on the measured atmospheric concentration of % the test material Is considered to be.moderately toxic on an acute Inhalation basis (ALC between 200 and 800 mg/ni ). Calculation described in Sierra Instruments, Inc., Bulletin 7-79-219IM, Instruction Manual: Series 210 Ambient Cascade Impactors and Cyclone Preseparators. " Ii Company Sanitized. Does not containTSCA CB1