Document 0Jmo2g7BRY5NJwvVO1J3ZnQYb

AR226-2912 -y^-f '"'"^^S^^S?^^^- FOR DU FONT USE ONLY Copies to Haskell E. I. du Pont de Nemours and Co., Inc. Laboratory for Toxicology and Industrial Elkton Road, P. 0. Box 50, Newark, Delaware 19711 Medicine HASKELL LABORATORY REPORT NO. 423-83 MR NO Material Tested Haskell No. INHALATION APPROXIMATE LETHAL CONCENTRATION (ALC) AND INTRAVENOUS AND INTRAPERITONEAL APPROXIMATE LETHAL~DOSES (ALP) OFl I. SUMMARY; A. Inhalation ALC: G^ups of 6 male Crl:CD rats single, 4-hour periods to partlculate atmospheres Qt\ Lungs from rats which died were examined pothologica. An ALC foroHHI^&is 42 mg/m (paniculate concentratj in). According to Haskell Laboratory Toxicity Classificationsj s extremely toxic by inhalation. Pathological examination of rats which died after exposure to 73 mg/m revealed elevated lung weights, and severe pulmonary congestion, edema and hemorrhage. These effects appear to be caused by damage to Type I pneumocytes, with consequent increased permeability of alveolar capillaries. B. I.P. and I.V. Injection; either I.P. or I.V. Injection Groups of male Crl:CD rats with various concentrations were dosed by ofJTBCU-ASa suspended in water. Rats which lied were examined pathologically. <^ No deaths occurred in rats dosed intraperltoneally with up to 50 ing/kg. The ALU by I.V. injection is 500 mg/kg. The cause of death appears to be massive emboli formation in the alveolar capillaries. Rats surviving either I.P. or I.V. injection showed no significant adverse effects. Company Sanitized. Does not contain T.^r'A c^-.f r iInI.halIaNtTlRAOnD^UJC^TI^OoNr: ] j j ^ ^ b e t w e e n f H ^ H r a J _ oral iln lii| ,ial purpose of t.iis study was to determine an Secondarily, because^of the marked difference Snalation toxicity --------I^a"s7 low toxicity by the I.P. and I.V. routes were investigated. III. PROCEDURES; A. Animal: Male Cr^CD" rats were Phuorulnsaed Cseirntgifliyedin R5o"dexnt 1C1"hoxw*7"ff5002 stainless steel, wire-mesh cages. and water were available ad libitum. Rats were weighed and observed for general suitability for 1 week prior to testing. B. Test Material: Purity: Composition Contaminants: Synonyns: Other Codes: Submitted by: Chemicals & Pigments Jackson Laboratory C. Inhalation Procedures: of^^fin 1. Protocol: Groups of 6 rats, 7- to 8-weeks old and weighing between 228-267 grams, were restrained in perforated, stainless steel holders. Rats were exDQag^OM-only for one 4-hour exposure to particulate atmospheres air. Rats were weighed and observed daily for 1A days post exposure, weekends included when deemed necessary. 2. Generation: LiquicQUkras syringe-driven into a Spraying Systems^ nebulizer. Air introduced at the nebulizer aeroaollzed the test material and swept it into a cyclone. The cyclone removed non- respirable particles by inertial impaction, whereas respirable particles passed through the cyclone and into the chamber. The cyclone and-nebullggr were heated to 100"C during the generation of the highest:--------lB:oncentration. 3. Analytical.' At 10- to 30-ninute intervals, calibrated volumes of chamber atmosphere were drawn through pre-weighdd, glass-fiber filters. Filters were weighed on a Cahn 26 Automatic Electrobalance. Atmospheric concentration was determined from the filter weight differential before and after sampling. Company Sanitized. Doss not contain TSCA CHf Chamber temperature was monitored with a thermometer. Particle size (mass median diameter) and percent of respirable paniculate were determined with a Sierra Cascade Impactor during representative exposures. 4. Pathology: Some rate which died after exposure to 73 mg/rn 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 suspended in water and administered by intraperitoneal (I.P.) or intravenous (I.V.) injection to groups of 1-5 male Crl:CD rats. Rats 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 be 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, tnymus, and spleen sere examined microscopically. IV. RESULTS A. Inhalation ALC- D . -^ -.,,osures, s very slight mist was visible in a beam of light ' l ^r , laboratory was darkened. Wet and dry filter compansonsindicated that all water was stripped from the particles when||HBHwas aerosolized. Chamber temperature ranged between ThejUbody load at the inhalation ALC was calculated based on the atnosp*- -ic 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 bodv load (mg/kg) '= (0.042 mg^^U^ atmosphere) x (1.2 x 10 L/breath) x (120 breatheTmin.) x (240 min.) (0.230 kg/rat) = 6.5 mg/kg Company Sanitized. Does not contain 7SCA ( 1. Data: Particulate , Concentration (mg/m )a Z . Mean S.D. Range Respirable 16 t.6 5.0-26 97 31 7.2 22-47 42 7.8 24-52 98 59 26 10-100 73C 25 26-120 97 Mass Median Diameter of Respirable Particulate 1.7 urn 1.5 urn 1.9 urn Mortality (.ff Deaths/ f Exposed) 0/6 0/6 3/6 6/6 6/ft represents combined) . ^^^^v__----^----i^wi^:oncentration. Percent by weight of particles with diameter less than 10 urn. During this exposure, the cyclone and nebulizer were heated to 100-C 2. Observations: During Exposure; All exposed rats responded to a tail pinch throughout the exposures. When released from res trainers 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/m had slight to moderate weight loss 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 ruffled 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 mg/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. --* H-15,048, September 26, 1983. Comasnv Sanitized. Does no? contain TSCA CBf &&,: It s^; B. l.P. and I.V. Injections; 1. Data: Dose (-g/kg) Dose (mL) Suspension (mg/inL) l.P. Injection; 5.0 50 0.46 0.47 2.5 25 I.V. Injection; 5.0 50 120 250 500 960 0.47 0.46 0.24 0.49 0.47 0.49 2.5 25 125 125 250, 480 Average Initial Body Weight (g) Mortality (<' DeatWtoosed) 231 0/5 234 0/5 233 0/5 229 0/5 237 0/1 244 0/3 237 1/5 245 1/1 of^^Hf Concentration 40X suspension as supplied 2. Observations; Rats dosed by l.P. injection exhibited no adverse clinical signs at either dose level. Rats dosed with 5.0 and 50 nig/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 mg/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 ) f | alveolar capillaries, which prevented gaseous exchange through the air-blood barr^ar. These emboli are suspected to be undis solved ( insoluble Lee K^Poong and James G. Aftosmis, "Pathology Report No. H-15,048, September 26, 1983. Company Sanitized, Does w--i-w-..w._.^.. T<?<- . ^^,_, ,-'.,-. ^_._, V. CONCLUSIONS; An Inhalation Approximate Lethal Concentration fox is 42 mg/o of particulate. The cause of death after Inhalation expo 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 con eras t,^BIfppears to have low toxicity by I.V. and I.P. injections. Deaths occurred only at concentrations of 500 and 960 mg/kg by I.V. injection, doses which are well above the calculated lethal mg/kg body load by inhalation. Furthermore, the cause of death from I.V. injection appears to be physical blockage of alveolar capillaries due to the test material's insolubility. Work bi<: Stev^n^C./Car-pen ter Techni cian }^f /^ '^r&^A Scott E. Loveless Research Toxicologist Supervision and Report by dLojLV\0< ft r<-<^-K^-~-ji---\ Laura A. Kiaae*,J Chemist Study Director; Approved by: LAK:jrg:11.24 Date Issued: November 23, 1983 Elated/Completed: 8/12/83-9/1/83 iskell Lab. Report No. Number of pages in this report: 6 6 - Section Supervisory Acute Investigation' 'HK Company Sanitized. Doss not contain TSCA CBi