Two-year toxicity and oncogenicity study with acrylonitrile incorporated in the drinking water of rats

Abstract

Sprague–Dawley rats (80 per sex per control and 48 per sex in each treatment group) were given drinking water formulated to contain 0, 35, 100, or 300 ppm acrylonitrile (AN) for up to 2-years. An additional ten rats per sex per group were added for a 1-year interim necropsy. The equivalent doses of AN consumed were 0, 3.4, 8.5, and 21.3 mg/kg per day for males and 0, 4.4, 10.8, and 25.0 for females. Rats were closely monitored clinically with body weight, feed and water consumption measured at numerous intervals. Hematology, clinical chemistry, and urinalysis were evaluated six times. All rats were necropsied when moribund, found dead, or at scheduled termination, with extensive histopathology of all rats. Numerous adverse toxic and oncogenic effects were observed in both sexes of all AN treatment groups. Decreased water consumption, feed consumption, and concomitant body weight suppression occurred within days of study initiation and persisted throughout the study in all treatment groups. An early onset of Zymbal gland tumors in high dose male and female rats, and in the mammary gland of all treated groups of females, was detected in-life. Hematology, clinical chemistry, and urinalysis, repeatedly evaluated, were without significant biological effects, except for an increased urine specific gravity due to the rats lower water intake. Organ weights at study termination were not significantly affected. Mortality was high in all female treated groups, with no surviving male or female 300 ppm rats during the last 2 months of the study. The most significant findings in this study were detected following gross and microscopic examination of an extensive list of tissues from all rats in the study. Nontumorous and tumorous lesions were found at an increased and/or decreased rate in a number of tissues of both sexes at all treatment levels. The primary nontumorous histopathologic effects of AN exposure occurred in the forestomach and the central nervous system of rats of both sexes and involved all treatment groups. A statistically significant increased incidence of tumors in one or more dose levels of either sex occurred in the central nervous system, Zymbal gland, forestomach, tongue, small instestine, and mammary gland. A no-observed-effect level (NOEL) was not identified in this study for toxicity or oncogenicity in either sex.