Subchronic Inhalation Toxicity and Neurotoxicity Assessment of Cumene in Fischer 344 Rats

Abstract

Male and female Fischer 344 rats were exposed to cumene vapor at 0, 100, 500, and 1,200 ppm for 6 h per day, 5 days per week, for 13 weeks; a satellite group received a single 6-h exposure. A subsequent 13-week study with a 4-week recovery period was conducted at 0, 50, 100, 500, and 1,200 ppm. Following the single exposure, the functional observational battery was altered at 500 and 1,200 ppm through 6 h postexposure. In the subchronic studies, there were no exposure-related changes in the functional observational battery, auditory brain stem response, brain measurements, or nervous system histopathology. Motor activity decreases seen only in male rats exposed to 500 or 1,200 ppm in the first study were not replicated in the second study. The 500andor 1,200-ppm groups showed transient decreases in body weight gain and food consumption, an increase in water consumption, and changes in several hematologic and clinical chemistry parameters. There were no exposurerelated ophthalmologic findings or effects on spermatogenesis. Weights of liver, kidneys, and adrenal glands were increased in the 500-and 1,200-ppm groups. Renal proximal tubular cell hypertrophy, hyperplasia, and hyaline drop formation were observed in the male rats at 500 and 1,200 ppm. In conclusion, exposure to cumene vapor resulted in mild toxicity at 1,200 ppm, minimal effects at 500 ppm, and no observable effects at 50 and 100 ppm. Cumene vapor exposure was neither neurotoxic nor ototoxic in these studies.

Characterization of the toxicological hazards of hydrocarbon solvents

“…Iso-paraffinic hydrocarbons including 2,2,4-trimethylpentane were the hydrocarbon solvent constituents most commonly associated with the induction of a2u-globulin (Aranyi et al 1986, Halder et al 1985, Short et al 1986), but these effects have also been observed in studies of cycloparaffinic constituents (Alden et al 1984, Johannsen andLevinskas 1987). Normal paraffins and aromatics are not commonly associated with a2u-globulin induction, although there is some evidence of weak induction in studies of n-butylbenzene (Izumi et al 2005) and isopropylbenzene (Cushman et al 1995, NTP 2009.…”

“…The toxicological significance of these data is unclear. Cushman et al (1995) reported that repeated exposure of rats to cumene vapor at levels up to 1200 ppm (approximately 6000 mg/m 3 ) had no effects on functional observations or auditory brain stem measurements and did not produce pathological changes in the central or peripheral nervous system. Changes in motor activity were reported in one study but not replicated in a second.…”

“…These results provide evidence that these CNS effects are acute and reversible. Cushman et al (1995) tested cumene for acute and subchronic neurotoxicity, and reported that acute exposure of rats to 500 or 1200 ppm (2500 or 6000 mg/m 3 ) resulted in an increase in motor activity.…”

“…The no observed effect concentration for systemic effects was 1230 mg/m 3 (250 ppm), the highest concentration tested. Cushman et al (1995) exposed rats to cumene (isopropylbenzene) in an initial study involving exposures for 6 hours/day and 5 days/week at levels of 100, 500, or 1200 ppm (500, 2500, or 6000 mg/m 3 ) for 13 weeks, and then in a second study in which the exposure concentrations were 50, 100, 500, or 1200 ppm (250, 500, 2500 or 6000 mg/m 3 ). Each study included an additional group of animals exposed at the highest level for 13 weeks and then held for an additional 4 weeks to assess recovery.…”

Disposition and Metabolism of Cumene in F344 Rats and B6C3F1 Mice

“…The LC 50 is 2000 ppm in mice that were exposed to cumene vapor for 7 h, and this exposure has been shown to cause various degrees of toxicity to the liver, spleen, and kidneys (Werner et al, 1944). Increases in organ weights are the most prominent effects in both male and female rats exposed to 500 or 1200 ppm of cumene vapor for 6 h/day, 5 days/ week for 13 weeks (Cushman et al, 1995).…”