Document YjM880dn6VYd96y44OnGZv5pV

AR226-2925 FOR DU FONT USE ONLY REVISED REPORT Copies to E. I. du Font de Nemours and Co., Inc. Haskell Laboratory for Toxicology and Industrial Medicine Elkton Road, P. 0. Box 50, Newark, Delaware 19711 HASKELL LABORATORY REPORT NO. 423-83 MR NO. Material Tested Haskell No. 15,048 INHALATION APPROXIMATE LETHAL CONCENTRATION (ALC) AND INTRAVENOUS AND INTRAPERITONEAL APPROXIMATE LETHAL DOSES (ALD) OF SUMMARY: A. Inhalation ALC: Groups of 6 male Crl:CD rats single, 4-hour periods to particulate atmospheres o: Lungs from rats which died were examined pathologica An ALC for----H^Bis 42 mg/m (paniculate co to Haskell Laboratory Toxicity Classifications,] toxic by inhalation. n). According s extremely i Pathological examination of rats which died after exposure to 73 ng/m revealed ele'.'ated lung weights, and severe pulmonary congestion, edema and hemorrhaga. These effects appe.ir to be caused by damage to Type I pneumocyfces, with consequent increased permeability of alveolar capillaries. B. I.P. and I.V. Injection: Groups of male Crl:CD rnts we dosed by either I.P. or I.V. injection with various concentrations of suspended in water. Rats which died were examined pathologica No deaths occurred in rats dosed intraperitoneally with up to 50 ing/kg. The ALD by I.V. injection is 500 ing/kg. The cause of death appears to be massive emboli formation in the alveolar capillaries. Rets surviving either I.P. or I.V. injection showed no significant adverse effects. Company Sanitized. Does not contain TSCA CBS :..' .s';. :--. ^.^^K:-;-- - ^.w. " :^;w??:T*s^''w:c????s?:^t:^^ ; . .. s . ^ ^ II. INTRODUCTION:,, The initial purpose of this study was to determine an inhalation^&LCfory----^J Secondarily, because^of the marked difference betweeE^^|B^ora^^^^^nalation fcoxicity U^Jhas very low toxicity by oral dosing;|B^IHH^R the -L.P. and I.V. routes were investigated. III. PROCEDURES; A. Animal; Male Crl:CD rats were housed singly in 5" x 11" x 7" stainless steel, wire-mesh cages. Purina Certified Rodent Chow )?5002 and water were available ad libitum. Rats were weighed and observed for general suitability for 1 week prior to testing. B. Test Material: Purity: UH^ Composition: Chemicals & Pigments Department Jackson Laboratory C. Inhalation Procedures: ofJUfJin 1. Protocol; Groups of 6 rats, /- to 8-weeks old and weighing between 228-267 grams, were restrained in perforated, stainless steel holders. Rats were exposednoag-only for one 4-hour exposure to paniculate atmospheres air. Rats were weighed and observed daily for 14 days post exposure, weekends included when deemed necessary. ^R------g& 2. Generation: Liquldy^ff^yas syringe-driven into a Spraying Systems nebulizer. Air introduced at the nebulizer aerosolized the test material and swept it into a cyclone. The cyclone removed nonrespirable particles by inertial impaction, whereas respirable particles passed through the cyclone and into the chamber. The cyclone andjiebuUzer were heated to 100C during the generation of the highest |B------RconcentraCion. ^^^^^^^9^ 3. Analytical: At 10- to 30-minute intervals, calibrated volumes of chamber atmosphere were drawn through pro-weighed, glass-fiber filters. Filters were weighed on a Cahn 26 Automatic Electro balance. Atmospheric concentration was determined from the filter weight differential before and after sampling. Company Sanitized. Does not contain T3CA CBl Chamber temperature was monitored with a thermometer. Particle size (mass median diameter) and percent of respirable particulate were determined with a Sierra Cascade Impactor during representative exposures 4. Pathology; Some rats which died after exposure to 73 mg/m were necropsied for examination of the lungs. Lungs were weighed at necropsy, then fixed and examined microscopically. D. I.V. and I.P. Procedures: 1. Protocol: The test material was suspanded in water and administered by incraperitoneal (I.P.) or intravenous (I.V.) injection to groups of 1-5 male Crl:CD rats. Eats were 7-8 weeks old and weighed between 213-251 grams. Dose levels were chosen based on the calculated body load at the inhalation lethal ^ concentration. This body load was determined to b& 6.5 ing/kg. Rats were held for 1 day after dosing, and were observed periodically for toxic signs. 2. Pathology: Rats which died after dosing were examined pathologically. Trachea, lungs, thyroid, parathyroid, esophagus, heart, kidneys, liver, thymus, and spleen were examined microscopically. IV. RESULTS A. Inhalation ALC: During exposures, a very slight mist was visible in a beam of light when the laboratory was darkened. Wet and dry filter comparisons .indicated that all water was stripped from the particles whenQilAwas aerosolized. Chamber temperature ranged between 24.8-25.5C'" TheBttljbody load at the inhalation ALC was calculated based on the atmospheric concentration, the typical average respiratory rate and volume for rats, the duration of exposure, and the rats' average body weight. One hundred percent absorption of the test material is assumed. Calculation: Lethal bods load (ing/kg) = (0.042 rn^Bl1' atmosphere) x (1.2 x 10 L/breath) x (120 breathsTmin.^ x (240 rnln.) (0.230 kg/rat) = 6.5 mg/kg Company SanifizeA Does not conta'r; TSCA CBl I* Data: Particulilte 3 a Conetntration (Bg/in ) Mean S.D. ^g 16 6.6 5.0-26 31 7.2 22-47 42 7.8 24-52 59. 26 73C 25 10-100 27-120 2 . Respirable 97 98 97 REVISED Mass Median Diameter of Bespirable Particulate 1.7 urn 1.6 urn 1.9 urn Mortality <',f Deaths/? Exposed) 0/6 0/6 3/6 6/6 6/6 jar^culate^ concentration represents combined| Percen^byweTgn^^^^Sticles with diameter less than 10 urn. During this exposure, the cyclone and nebulizer were heated to 100C 2. Observations; During Exposure; All exposed rats responded to a tail pinch throughout the exposures. When released from restrainers after 4 hours of exposure, some rats exposed to 42, 59 and 73 mg/m had labored breathing and decreased activity. Post Exposure: No adverse clinical signs were seen in rats exposed to 16 mg/m . Some rats exposed to 31 mg/rn had slight to moderate weight lose for 1 day post exposure, followed by normal weight gain. At 42 mg/m , 3 rats were found dead the morning after exposure; surviving rats had slight to moderate weight loss for 1 day. At 59 mg/m , 4 rats died within 1 day post exposure. The remaining 2 rats exhibited severe weight loss, red nasal, ocular and oral discharges, hunched posture, lethargy and rufflsd fur before they died 2 days post exposure. At 73 mg/m , 3 rats died within 1 day post exposure; the remaining 3 rats exhibited moderate to severe weight loss and lung noise until they died 2 days post exposure. 2 3 3. Pathology : The 3 rats exposed to 73 ng/m which died within 1 day post exposure had elevated lung weights, and severe pulmonary congestion, edema and hemorrhage. These effects appear to be caused by damage to Type 1 pneumocytes, with consequent increased permeability of alveolar capillaries. Lee, Ki Poong and James G. Aftosmis, "Pathology Report No. r--------------QH-15,0S4e8p,tember 26, 1983. 4 - Company Sanitized. Does not nmfam f^CA CBl ., . ;,- - -..^, c., . - . . . ---- . . ,-,.-v-^.%^y.--y,--,..; - - '^|S^^^";'": B. I.P. and I.V. Injections: 1. Data; Dose (me/kg) Dose (niL) Suspension (Bg/mL) Average Initial Body Weight (g) Mortality (tf Deaths/toosed) I.P. Injection: 5.0 0.46 2.5 231 0/5 50 0.47 25 234 0/5 I.V. Injection: 5.0 0.47 2.5 233 0/5 50 0.46 25 22? 0/5 120 0.24 125 237 0/1 250 0.49 125 244 0/3 500 0.47 250 237 1/5 i 960 0.49 480" 245 1/1 a , Concentration ot<^^frfff&^ 40% suspension as supplied 2. Observations: Rats dosed by I. P. inlection exhibited no adverse clinical signs at either dose level. Rats dosed with 5.0 and 50 ing/kg by I.V. Injection were hypersensitive for 2 hours after dosing. Rats dosed with 120 and 250 mg/kg by I.V. injection showed no adverse signs. At 500 mg/kg, 1 rat died 3 minutes after dosing. Surviving rats at 500 ms/kg showed no adverse signs. The 1 rat dosed at 960 mg/kg (test material as supplied) died within seconds after dosing. 3 3. Pathology : Pathological examination of the 2 rats which died revealed the cause of death to be massive emboli formation in the alveolar capillaries, which prevented gaseous exchange through the a(iinr-sbollouobdle bjfatrrHieAr. These emboli sre suspected to be undlssolved ' 3 Lee, Ki Poong and James G. Aftosmis, "Pathology Report ^Q---l^- ^^f,^\ 1 |tt^--------JH-15,048, September 26, 1983. ^-- -^ - 5 - Company Sanitized. Does not contain TSCA CB? ^ ^ !? ^ ; ""' ^^'^'^^S^' ' ^22^ ,:::. ^.^^^te^;:; '-^ipa REVISED foi_ V. CONCLUSIONS; An Inhalation Approximate Lethal Concentration is 42 mg/m" of paniculate. The cause of death after inhalation exposure appears to be damage to Type I pneumocytes, with consequent increased permeability of alveolar capillaries. According to Haskell Laboratory Toxicity Classifications, this material is extremely toxic by inhalation. In contrast ^f^pppears to have low toxicity by I.V. and I.P. injections. Deaths occurred only at concentrations of 500 and 960 ing/kg by I.V. injection, doses which are well above the calculated lethal ing/kg body load by inhalation. Furthermore, the cause of deslrh from I.V. injection appears to be physical blockage of alveolar capillaries due to the test material's insolubility. Work b ^.X.J --^/- ^ CZ^L Stewe / n J ; . / ^/Car kpe . n t e r - Technician -f^. l^rf-Z Scott E. Loveless Research Toxicologist Supervision and Report by : O.CU-V\.0\ I'r {v^1-r^-^\ Laura A. Kinne^U Chemist Study Director: Approved by: LAK:jrg:11.24 Date Issued: November 23, 1983 .Study Initiated/Completed; 8/12/83-9/1/33 naskenULab^^por^^o^^^^^P Number of pages in this reports Date Reissued: April 2, 1985 - 6 Gerald L. Kennedy, J Section Supervisor Acute Investigation' Company Sanitized. Doss not contain TSCA CM