To assess potential effect of "long-term" exposure to tamoxifen citrate prior to and including the first trimester of pregnancy in female Sprague-Dawley rats, tamoxifen citrate in 1% b-cyclodextrin was administered by oral gavage at dose levels of 0, 1, 3, and 10 mg/kg/day (1TAM, 3TAM, and 10TAM, respectively) to groups of 29 female Sprague-Dawley rats from six weeks prior to cohabitation to GD (Gestation Day) 7. The female F 0 generation began exposure as adults and were bred once to produce the F 1 generation. The F 1 adults were bred once to produce a F 2 generation. Parameters evaluated over the course of the study included body weights, feed consumption, clinical observations, estrous cyclicity, reproductive performance, anogenital distance, pup survival, sexual development, sperm analysis, gross pathology, organ weights, and limited/selected histopathology. An additional toxicokinetic phase of collection of blood and tissues was included at selected time points (data presented separately).
A dose-range finding study using a two week exposure prior to cohabitation and continuing to GD 7 at dose levels of 0, 3, 10, 30, 100, and 300 mg/kg/day tamoxifen citrate was conducted. Based on the finding of no live pups equal to or greater than 30 mg/kg/day tamoxifen citrate, dose levels of 0, 1, 3, and 10 mg/kg/day tamoxifen citrate were chosen for the main study.
In the F 0 and F 1 mating trials there were slight decreases (p > 0.05) in mating, pregnancy and/or fertility indices in the 10TAM group (high dose) compared to controls. In the F 0 mating trial, the pregnancy and fertility indices were decreased (13/29 vs. 19/28 and 13/23 vs. 19/23, respectively). In the F 1 mating trial the mating index and pregnancy indices were decreased (13/20 vs. 16/20 and 12/20 vs. 16/20, respectively). In the F 0 mating trial there was also an increase in the gestation length in the 10TAM group (22.3 vs. 21.8 days in controls).
There were several differences noted in estrous cyclicity. In the F 0 dams during dosing there was a difference in the time spent in the different estrous stages in the 3TAM and 10TAM dams compared to controls. After weaning when the F 0 dams were not dosed, estrous cycles were comparable. In the F 1 dams there were no differences except for a decrease in the number of females with regular cycles in the 10TAM group compared to controls (27/33 vs. 38/39).
The only difference in the reproductive and development parameters measured was a decrease (22%) in the sex ratio of F 2 pups born alive (male/total) in the 10TAM group vs control. Although not significant, the number of males was decreased (21%), females increased (25%), and combined males and females decreased (5%).
No treatment-related differences were noted in male sperm data in the F 1 males or in gross necropsy findings in the reproductive tract or organ weight data in the F 1 or F 2 males and females.
Results of this study suggest that tamoxifen citrate is a slight female reproductive toxicant at concentrations of 3TAM and 10TAM based on a changes in estrous cyclicity and a possible decrease in the number of male pups in the F 2 litter in the 10TAM group but did not adversely affect the F 0 or F 1 parents ability to reproduce and did not result in an increased incidence of reproductive tract abnormalities in F 1 offspring or in the F 2 offspring. The no observable-adverse-effect level (NOAEL) in this study was 1TAM.
NTIS #PB97-199723