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Abstract for RACB83073

Reproduction and Fertility Assessment of Theobromine in CD-1 Mice When Administered in Feed

CASRN: 83-67-0
Chemical Formula: C7H8N4O2
Molecular Weight: 180.16
Report Date: August 1984


The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings were not evaluated in accordance with the levels of evidence for reproductive or developmental criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.

The reproductive toxicity of theobromine was evaluated according to the Reproductive Assessment by Continuous Breeding protocol. Based on the information available in the literature, the following dose levels were selected for Task 1: 0, 0.1, 0.25, 0.5, 1.0, and 2.0% administered in feed. The dosed/undosed feed was available ad libitum. During the two weeks of treatment, 63% of the males and 50% of the females ingesting diet with 2% theobromine died. There was no mortality in the control or the remaining dose groups.

To evaluate reproductive performance (Task 2), dietary levels of 0, 0.10, 0.25, and 0.5% theobromine were tested. Breeding pairs were housed together for 14 weeks after one week of pre-mating treatment. During this period, the following parameters were monitored: fertility, number of live and dead pups, average pup weight, and sex ratio.

Theobromine treatment adversely affected at least one or more reproductive parameters in all three dose groups (p<0.05). Furthermore, in the 0.5% dose group, the proportion of pups born alive per fertile pair was 0.64 as compared to 0.98 in the control group suggesting that theobromine may be a fetotoxicant. The study was extended to determine the affected sex in the high dose (0.5%) group (Task 3).

The crossover mating trial demonstrated that reproductive capacity was severely impaired in female mice ingesting theobromine. More specifically, the number of live pups per litter, proportions of pups born alive, and pup body weights were significantly reduced. Males ingesting 0.5% theobromine revealed a significant increase in the incidence of abnormal sperm. The liver in both male and female mice was significantly enlarged. The testicular weight in males and brain weight in both male and female mice were depressed. No morphological changes were seen in the reproductive organs. Hormonal patterns in both male and female mice were unaffected by the theobromine treatment.

Thus, under the conditions of the study, theobromine ingestion had adverse effects on various endpoints of male and female reproductive functions without significant effects on general health and growth.

NTIS# PB85120368