Chronic toxicity and oncogenicity of N-methylpyrrolidone (NMP) in rats andmice by dietary administration

A two-year feeding study in rats and an 18-month feeding study in mice were conducted to evaluate the potential chronic toxicity and oncogenicity of N MP in Crl : CD(R) (SD)BR rats and B6C3F1/Cr1BR mice. Groups of 62 male and female rats were administered diets containing 0, 1600, 5000, or 15 000 ppm of NMP for approximately 2 years. Groups of 50 male and female mice were a dministered diets containing 0, 600, 1200, or 7200 ppm NMP for approximatel y 18 months. In vivo parameters were evaluated weekly during the first 3 mo nths of the study, and every other week or monthly during the remainder of the study. For rats, an ophthalmoscopic examination was conducted prior to study start and near the end of the study. Periodically, blood samples were collected from rats and mice for determination of leukocyte differential c ounts, and from mice for red blood cell morphology. After approximately 2 y ears of dietary administration in rats and 18 months in mice, all surviving animals were sacrificed. Selected tissues were processed for morphological evaluation. Over the course of the two-year study in rats, test substance- related decrements in body weight and weight gain occurred in 15 000 ppm ma les and females, which correlated with decreased food consumption and food efficiency. A toxicologically significant, test substance-related increase in the incidence of severe chronic progressive nephropathy occurred in 15 0 00 ppm males. Several morphological changes noted grossly and/or microscopi cally were secondary to the increased severity of chronic progressive nephr opathy. NMP was not oncogenic in male or female rats at dietary concentrati ons of 15 000 ppm and below. A test substance-related decrease in the perce ntage of 15 000 ppm males surviving to the end of the two-year study compar ed to the control group resulted from the higher incidence of severe chroni c progressive nephropathy. However, a sufficient population of 15 000 ppm r ats were at risk for potential oncogenicity, so the lower survival did not impair the ability to detect an oncogenic response in this study. There wer e no adverse, test substance-related effects on the incidences of clinical observations, ophthalmic observations, or differential leukocyte counts in males or females, or on Survival of females at any dietary concentration. M ale and female mice administered dietary concentrations of 7200 ppm had sig nificantly increased liver weight, significantly increased incidence or hep atocellular adenoma, and significantly increased foci of cellular alteratio n in the liver. At 7200 ppm, male mice also had an increased incidence of h epatocellular carcinoma while the increased incidence of hepatocellular car cinoma in female mice fell within the historical control range. In addition , the incidence of hepatocellular hypertrophy was increased in 7200 ppm mal es. Liver weight and hepatocellular hypertrophy were also increased in 1200 ppm males. There were no adverse, test substance-related effects on the in cidences of clinical observations, food consumption, body weight, different ial leukocyte counts, red blood cell morphology, or survival in either male s or females at any dietary concentration. Under the conditions of the stud y, the no-observed-effect level for NMP was 5000 ppm for male and female ra ts, 600 ppm for male mice, and 1200 ppm for female mice.