Toxicology and carcinogenesis study of ethinyl estradiol (CAS No. 57-63-6) in Sprague-Dawley rats (feed study)

Ethinyl estradiol is a potent synthetic estrogen that is widely prescribed in oral contraceptives and is also used in the treatment of breast and prostate cancer. Ethinyl estradiol is one of a class of chemicals known as"environmental estrogens" that can affect the hormone activities and possibly reproductive function of wildlife and humans through exposure. The NTP conducted a series of studies on three such chemicals to detect if exposure over the course of multiple generations could have any cumulative effect on animals' reproductive systems or development of cancers. This report describes the results of a set of studies in which rats were exposed to ethinylestradiol for part or all of the study period and examined at the end of two years.

The study consisted of three separate study components; in each, animals were exposed to ethinyl estradiol from the time of conception and through weaning through their mothers, who were given ethinyl estradiol in their feed.In one study we gave feed containing 2, 10, or 50 parts per billion (ppb) of ethinyl estradiol to groups of 50 male and female rats from conception through two years. In the second study, groups of 50 male and female rats were given the same feed concentrations up to 20 weeks following birth, followed by untreated feed for the remainder of the two years. In the third study groups of 50 male and female rats were exposed from conception through weaning, and then given untreated feed for the duration of the study. Control animals received the same feed with no ethinyl estradiol added. Enthinyl estradiol is known to cause cancer at higher dose levels; the concentrations given in this study were below the levels of detection by chemical analysis, to determine the possible effects of trace amounts in the environment. At the end of the study tissues from more than 40 sites were examined for every animal.

In all three study sets effects were seen in the uterus of female rats. The rates of squamous metaplasia increased in females exposed for two years and in females exposed from conception through weaning; endometrial hyperplasia and atypical focal hyperplasia of the uterus also were increased in females exposed for two years. Uterine stromal polyps were increased in female rats exposed from conception through 20 weeks after birth or from conception through weaning. Male rats exposed from conception through weaning had small increases in the rates of preputial gland tumors and three male rats in that study had rare mammary gland adenomas or carcinomas.

We conclude that exposure to trace amounts of ethinyl estradiol during the period from conception through weaning may have been related to development of uterine stromal polyps in female rats and to preputial gland tumors and mammary gland tumors in male rats.