Chronic toxicity and carcinogenicity to the urinary bladder of sodium saccharin in the in utero-exposed rat

In utero-exposed Charles River CD strain rats, the offspring of parents treated from weaning through mating, gestation and lactation, were fed sodium saccharin chronically at dietary levels of 0, 0.01, 0.1, 1.0, 5.0, and 7.5%. Calcium cyclamate was fed as a reference compound at a level of 5.0%. Groups of 48 male and 48 female weanlings were placed on the same regimen as their parents. The study was continued until the number of survivors in a group fell to 20% with the last survivors being killed approximately 28 months after the first weanlings were selected for the chronic study. Serial sacrifices were performed at 14 and 18 months. Treatment-related effects were not observed in hematological values, organ weights, and survival. Average weaning weights were decreased in litters from parents receiving 5.0 and 7.5% sodium saccharin and 5.0% calcium cyclamate. Some of the initial weaning weight depression was overcome, but the rats on these dose levels had lower average body weights throughout the study. The incidence and types of neoplasms and nonneoplastic lesions, other than urinary bladder neoplasms and hyperplasia, were typical of the aged rat and were not treatment related. A significantly increased incidence of urinary bladder hyperplasia occurred in female rats that received 7.5% sodium saccharin, but the lesion was not morphologically precancerous. A significantly increased incidence of urinary bladder neoplasms occurred in the males fed 7.5% sodium saccharin. A total of 11 bladder neoplasms was observed in rats on study longer than 18 months; nine in the 7.5% saccharin group and one each in the control and 5.0% saccharin groups. There were nine neoplasms in males and two in females. Histologically, six of the neoplasms were classified as benign and five as malignant. All the malignant neoplasms occurred in the 7.5% saccharin group. The occurrence of the urinary bladder neoplasms could not be related to such predisposing factors as gross calculi, parasites, or hyperplasia.