90-day subchronic toxicity study in rats and mice fed N-methylpyrrolidone (NMP) including neurotoxicity evaluation in rats

Ninety-day feeding studies were conducted to evaluate the repeated dose toxicity of NMP, a widely used industrial solvent, in Crl:CD^(R)BR rats and B6C3F1 mice. Groups of 20 to 26 male and female rats each were fed either 0, 3,000, 7,500, or 18,000 ppm NMP for 90 days. Groups of 10 male and female mice were fed either 0, 1,000, 2,500, or 7,500 ppm NMP for 28 or 90 days. In vivo parameters, hematologyand clinical chemistry parameters, ophthalmologic examinations, functional and histopathologic neurologic parameters (rats only), and complete pathology evaluations were conducted after 90 days. Decreases in mean body weights, reflecting decreases in food consumption and efficiency were observed in male and female rats fed either 7,500 or 18,000 ppm NMP. A change in urine coloration was observed at 3,000 ppm and above in both males and females. This was considered to be evidence of systemic availability since it was not associated with any functional or pathological changes. Of 36 neurobehavioral parameters investigated, male rats in the 7,500 and 18,000 ppm groups showed an increase in foot splay, and 18,000 ppm males had a higher incidence of lowarousal and slight palpebral closure suggestive of a sedative effect. Absolute and relative liver weights were increased in 18,000 ppm females which were associated with an increased incidence of centrilobular hepatocellular hypertrophy and were considered to be an adaptive/physiological response. Absolute and relative kidney weights were increased in 18,000 ppm males and females, however, there were no pathological or functional changes associated with the increases. In mice, there were no effects on body weight or food consumption. As observedin rats, mice fed 2,500 or 7,500 ppm exhibited a change in urine coloration which was not associated with morphological changes in the kidney. In 2,500 and/or 7,500 ppm mice, changes in cholesterol, triglycerides, calcium, and alkaline phosphatase occurred at 28 days but not90 [ABSTRACT FROM AUTHOR]