Oncogenicity studies of inhaled methyl tertiary-butyl ether (MTBE) in CD-1 mice and F-344 rats.

Oncogenicity studies of methyl tertiary-butyl ether (MTBE) vapor were conducted in CD-1 mice and Fischer 344 rats. Fifty animals of each sex per species per group were exposed for 6 h a day, 5 days per week to 0 (control), 400, 3000 and 8000 ppm MTBE vapor in air for 18 months (mice) and 24 months (rats). Both species showed reversible central nervous system depression at 8000 ppm for the first week of exposure, which continued for mice for the study duration. For the 8000 ppm mice, reduced body weight gain and early mortality prior to terminal euthanasia were exposure related. In the males, these deaths appear to be due to exacerbation of uropathy or dysuria, which occurs spontaneously in this strain. Increases in absolute and relative liver (both sexes) and kidney weight (males only) were seen at 3000 and 8000 ppm and decreases in brain and spleen weights were also noted (the latter decreases were without microscopic lesions and occurred at 8000 ppm only). An increase in hepatocellular hypertrophy occurred in both sexes at the two highest concentrations. The only neoplastic lesion found in this study in mice was an increased incidence of hepatocellular adenomas in females at the 8000 ppm exposure. In a follow-up study, a statistically significant elevation of cell proliferation in female mouse liver has been shown to occur following 5 days, but not 28 days, of exposure to 8000 ppm MTBE, suggesting that MTBE induces mitogenesis. For male rats, early euthanasia was required at week 82 and week 97 for the 8000 and 3000 ppm groups, respectively, due to excessive mortality from a severe progressive nephrosis. The end stage of this process appeared earlier in the male rats of all MTBE exposure groups; the incidence of this lesion and mortality for exposed females was comparable to control females. No exposure-related changes in hematological parameters were observed for any group at any time point, but a decrease in corticosterone levels was seen for male rats from the 8000 ppm group. Absolute and relative kidney and liver weight increases occurred in 3000 and 8000 ppm exposure groups, but the liver weight change was not accompanied by histopathological change. At study termination, increases in the incidence and severity of a chronic nephropathy in males from all exposure groups and in females exposed to 3000 and 8000 ppm was associated with secondary lesions of hyperplasia of the parathyroid and mineralization of tissues. Renal tubular cell tumors were increased in male rats exposed to 3000 and 8000 ppm. This may be associated with an accumulation of protein (stainable by Mallory's Heidenhain) in kidney tubular epithelial cells after 4 weeks of exposure. An increased incidence of interstitial cell adenomas of the testes was seen in males exposed to 3000 and 8000 ppm but was believed to be an artefact of an unusually low control incidence and not considered to be exposure related. Based on the above effects, the no-observed-effect level (NOEL) for chronic toxicity is 400 ppm, and the NOEL for carcinogenic effects is 3000 ppm (mice) and 400 ppm (rats).

Development of pituitary lesions in ND4 Swiss Webster mice when estimating the sensory irritancy of airborne chemicals using ASTM method E981-84.

This study determined the origin of pituitary lesions found in male ND4 Swiss Webster mice following a single head-only exposure to inhaled test materials using ASTM E981-84, standard test method for estimating sensory irritancy of airborne chemicals. Necropsy and histopathology data were evaluated due to the occurrence of unexpected pituitary lesions in sham control and exposure groups. Groups of four mice were restrained in body plethysmographs and exposed for 30 min to increasing dust concentrations of one of three test chemicals to assess the ability to cause sensory irritation. Sham control and test material-exposed mice were sacrificed after a single exposure and subjected to a complete necropsy and microscopic evaluation of the pituitary gland. Control mice remained in the animal room and were not restrained in the plethysmograph. Gross observation at necropsy showed pituitary lesions in one of seven unrestrained control mice (revised to zero of seven after microscopic examination). Seven of seven sham control mice had pituitary lesions, suggesting that the lesions were not related to test material exposure. Each test material-exposed group also had pituitary lesions with high incidence (52/60 for all groups combined), which was not exposure concentration-dependent. Microscopic evaluation of the pituitary glands revealed that darkening of the gland was due to hemorrhage and confirmed that the lesions developed with 100% incidence (19/19) in plethysmograph-housed animals. The rubber neck seal used to restrict animal movement in the plethysmograph appears to have caused an increase in pressure in the blood vessels in the pituitary gland; vessels then ruptured and hemorrhaged. This finding should not adversely affect sensory irritation responses evaluated with this method.

Respiratory peripheral sensory irritation and hypersensitivity studies with glutaraldehyde vapor.

Overexposure to glutaraldehyde (GA) vapor (CAS No. 111-30-8) is known to cause peripheral sensory irritant effects in humans. Respiratory sensory irritation was investigated in male ND4 Swiss Webster mice to quantify the effect, and also as a preliminary to a study of the respiratory sensitizing potential of GA. For the irritation study, groups of four mice were exposed to seven different GA vapor concentrations in the range of 1.6 to 36.7 ppm, while respiratory rate (RR) was measured by plethysmography. Concentration-related decreases in RR were measured, with a maximum decrease at 3 to 20 min, which was sustained, indicating an absence of desensitization. The 50% decrease in RR (RD50) was calculated to be 13.9 ppm, which accords with the known sensory irritancy of GA and other aliphatic aldehydes. In a separate study, the respiratory sensitizing potential of GA vapor was studied in male Hartley guinea pigs, who were exposed for one hour per day for five consecutive days to an inducing GA vapor concentration of 13.9 ppm. Subsequent challenge exposures to 4.4 ppm at 14, 21, and 35 days after the final induction exposure did not produce any evidence of respiratory sensitization. The above findings confirm that GA vapor is a moderately potent peripheral sensory irritant, and does not produce respiratory sensitization in the guinea pig at the concentrations tested.

Isopropanol: acute vapor inhalation neurotoxicity study in rats.

Five groups of 25 Fischer 344 rats of each sex were exposed for 6 h to isopropanol vapor at 0, 500, 1500, 5000 or 10,000 ppm. Behavioral observations for 10 rats of each sex were made prior to and 1, 6, and 24 h after exposure. Motor activity was evaluated for 15 rats of each sex prior to and immediately following exposure. Exposure to isopropanol caused a spectrum of transient effects indicative of narcosis at 10,000 ppm and sedation at 5000 ppm. Prostration or severe ataxia, decreased arousal, slowed or labored respiration, decreased neuromuscular function, hypothermia and loss of reflex function were observed 1 and 6 h after exposure to 10,000 ppm isopropanol vapor. Similar, but less severe, alterations were observed in animals in the 5000 ppm exposure group 1 h after exposure. Exposure concentration-related decreases in motor activity were observed in males and females in the 5000 and 10,000 ppm groups and slight decreases in motor activity were observed in males in the 1500 ppm group. Animals in the 1500 and 5000 ppm exposure groups recovered from these motor activity effects within 5 h. Based on this study, exposure of male and female rats to isopropanol vapor produces transient, concentration-related narcosis and/or sedation at concentrations of 5000 and 10,000 ppm and minor decreases in motor activity in males at a concentration of 1500 ppm. The no-observed-effect level (NOEL) for this was 500 ppm isopropanol.

Isopropanol 13-week vapor inhalation study in rats and mice with neurotoxicity evaluation in rats.

This study was conducted to evaluate the possible subchronic toxicity as well as neurobehavioral effects of isopropanol, a widely used industrial and commercial solvent. Five groups, each containing 10 Fischer 344 rats/sex and 10 CD-1 mice/sex, were exposed for 6 hr/day, 5 days/week, for 13 weeks to isopropanol vapor at concentrations of 0 (control), 100, 500, 1500, or 5000 ppm. An additional 15 rats/sex were assigned to the 0, 500, 1500, and 5000 ppm groups for assessment of neurobehavioral function. No exposure-related mortalities occurred during the study. The narcotic effects of isopropanol were noted only during exposures at 1500 and 5000 ppm. These signs, noted during exposures, were typically absent following exposures. The only clinical signs observed following exposures included swollen periocular tissue, perinasal encrustation, and ataxia for rats of the 5000 ppm group. Neurobehavioral evaluations indicated no changes in any of the parameters of the functional observational battery; however, increased motor activity for female rats in the 5000 ppm group was noted at Weeks 9 and 13. Decreases in body weight and body weight gain were observed for rats of the 5000 ppm group at the end of the first week of exposure. During the remaining weeks, increases in body weight and/or body weight gain were observed for rats of the 1500 and 5000 ppm groups. No exposure-related effects on body weight were noted for male mice; however, increased body weight and body weight gain were observed for female mice of the 5000 ppm group.(ABSTRACT TRUNCATED AT 250 WORDS)