Repeated dose toxicity study (28 days) in rats and mice with N-methylpyrrolidone (NMP).

Twenty-eight day feeding studies were conducted to evaluate the repeated dose toxicity of NMP, a widely used industrial solvent, in Crl:CD BR rats and B6C3F1 mice. Groups of 5 male and 5 female rats each were fed either 0, 2,000, 6,000, 18,000, or 30,000 ppm NMP; similar groups of mice were fed either 0, 500, 2,500, 7,500, or 10,000 ppm. In vivo parameters, hematology and clinical chemistry parameters, and complete pathology evaluations were conducted after approximately 28 days. Decrements in mean body weight gains, reflecting decreases in food consumption and efficiency, were seen in male rats fed 18,000 ppm and in both sexes fed 30,000 ppm. In rats, clinical chemical changes, indicating possible compound-related alterations in lipid, protein, and carbohydrate metabolism, occurred at 18,000 ppm in males and 30,000 ppm in both sexes. No histopathological changes in rats were judged to be directly related to NMP exposure. Hematological (mild to moderate leukopenia) and histopathological alterations (hypocellular bone marrow, testicular degeneration and atrophy, and thymic atrophy) were judged to be secondary to nutritional and body weight effects in male and/or female rats at 30,000 ppm. In mice, cloudy swelling of the epithelia of the distal parts of the renal tubuli was observed in 4 males and 3 females at 10,000 ppm and in 2 male mice at 7,500 ppm. For both rats and mice, abnormal urine coloration was observed (in mice at 2,500 ppm and above, and in rats at 18,000 ppm and above). The discoloration was interpreted as a sign of systemic availability of the test substance, but not as an adverse effect. The NOAEL was 6,000 ppm for male rats and 18,000 ppm for female rats. In mice, the NOAEL was 2,500 ppm based on the kidney histopathology.

Ergometer within a whole-body plethysmograph to evaluate performance of guinea pigs under toxic atmospheres.

A guinea pig ergometer was constructed within an enclosure, with inlet and outlet ports for continuous ventilation, designed so that the enclosure would work as a whole-body plethysmograph as well as an inhalation exposure chamber. This system provided continuous measurement of tidal volume, respiratory frequency, oxygen uptake, and carbon dioxide output which enabled an evaluation of performance in terms of distance traveled over time with the animals running at a known speed and constant oxygen uptake. The effects of CO or HCl in running versus sedentary animals were investigated using this apparatus. For CO, exercise increased the rapidity of the onset of incapacitation as would be predicted by the increase in metabolic rate. HCl produced a more severe incapacitating effect in exercising animals that was out of proportion with the increase in minute volume induced by exercise.

Performance evaluation under intoxicating atmospheres.

A new behavioral model has been developed and used to assess the performance of mice during exposure to carbon monoxide, hydrogen chloride, or subambient levels of oxygen. The apparatus is a ventilated 150-ft series of glass tubes forming an S-shaped exposure system. Performance evaluation was obtained for two sublethal responses: distance traveled/time and incapacitation. Performance of normal mice (Type I) or mice previously fitted with a tracheal cannula (Type II) was very reproducible and similar. Concentration-response relationships were obtained showing the deterioration of performance with exposures to CO from 2500 ppm, HCl from 1095 ppm, and below 8.8% ambient O2 level. This model is likely to be sensitive to other asphyxiants and irritants. It includes both distance traveled and time of performance prior to incapacitation. Both are critical parameters to be included in escape hazard analysis in fire situations and possibly in other accidents involving chemical spills.

Evaluation of the pulmonary effects of wood smoke in guinea pigs by repeated CO2 challenges.

Male, English smooth haired guinea pigs were exposed to thermal decomposition products, i.e., smoke, generated by heating Douglas fir in an open system. Various amounts of Douglas fir were placed in a furnace, at room temperature, and heated at a rate of 11 degrees C/min until completely decomposed. Major decomposition occurred between 160 and 490 degrees C, and the animals were exposed during this time for a period of 30 min. Immediately before exposure and at various times after exposure, each animal was evaluated by whole-body plethysmography to measure tidal volume and respiratory frequency during air breathing as well as during challenge with 10% CO2. Exposure to smoke from Douglas fir resulted in a diminished ventilatory response to 10% CO2. Comparing the effect of wood smoke to the effect of smoke from polyvinylchloride from previous experiments wood smoke was found to be 10 times less potent than smoke from polyvinylchloride and animals recovered much more rapidly than with smoke from polyvinylchloride.

Pathologic findings in rats following inhalation of combustion products of polytetrafluoroethylene (PTFE).

Adult male Fischer 344 rats received single 30-min exposures to the aerosolized products of polytetrafluoroethylene (PTFE) heated to 595 degrees C. The concentrations of thermal degradation products of PTFE were at the LC50 dose of 0.045 mg/l for most rats, but some rats received doses ranging from 0.005 to 5.025 mg/l. Serial measurements of cardiopulmonary function were obtained and will be published subsequently. Necropsies were performed at 0, 2, 12, 24 and 36 h post-exposure, and a few rats were killed between 2 and 17 days. Signs of respiratory impairment were followed by death in some rats. Pathologic findings included focal hemorrhages, edema and fibrin deposition in the lungs. With time focal interstitial thickenings developed due to hypertrophy and hyperplasia of alveolar cells, and macrophages accumulated in alveoli. Thrombosis of pulmonary capillaries was common. Disseminated intravascular coagulation (DIC) occurred in 53% of test rats; its incidence and severity were positively related to the degree of pulmonary damage. Renal infarcts were common due to DIC. No lesions were seen in kidneys or other tissue (except lung and thymus) unless they were affected with DIC. Thymic lymphocytes underwent necrosis in many test and some vehical (warm air) control rats, possibly due to stress. The finding of DIC in PTFE combustion product exposure has not been reported to our knowledge. The toxicity of the thermal degradation products of PTFE requires further study, especially relative to induction of DIC.