The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program (NTP). The findings may or may not have been peer reviewed and were not evaluated in accordance with the Explanation of Levels of Evidence for Reproductive Toxicity criteria (see http://ntp.niehs.nih.gov/ntp/htdocs/levels/09_3566_NTP_ReproTOX_R1.pdf or with the Explanation of Levels of Evidence for Developmental Toxicity criteria (see http://ntp.niehs.nih.gov/ntp/Test_info/NTP_DevTox20090507.pdf) established by the NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the US Government.
Propylthiouracil was evaluated for potential reproductive toxicity using a two-generation study model. Beginning on Study Day (SD) 1, propylthiouracil was administered in the drinking water at dose levels of 0, 0.0001, 0.0004, and 0.0015 % (weight/volume) to adult male and female Sprague-Dawley rats (N=20). The F0 cohabitation period began on SD 71. Mating pairs were allowed to produce one litter. Dosing of the F1 generation was initiated on post-natal day (PND) 21 (i.e., at weaning). On PND 99 ± 10, F1 animals were assigned to mating pairs and allowed to produce one litter. Due to high mortality in the adolescent F2 0.0015 % animals, this group was not available for the F1 cohabitation. Endpoints evaluated included body weight, food and water consumption, clinical signs of toxicity, number and weight of pups, anogenital distance (AGD), sexual development endpoints, thyroid hormone levels, sperm parameters, vaginal cytology, organ weights, and gross and microscopic pathology.
For the F0 animals there were significant decreases at the 0.0015% dose level in mean body weights (6-23%), mean food consumption (3-35%) expressed as g/kg body weight/day and/or g/animal/day, and water consumption (13-38%) expressed as g/animallday. The pregnancy index was comparable in all groups, but the numbers of F1 female and total pups produced were decreased by 43 and 30%, respectively, at 0.0015%. Changes in estrous cyclicity were observed in the F0 females at 0.0015% but not at the lower dose levels. These changes consisted of a decrease in the number of females with a regular cycle and changes in the amount of time spent in the various estrous stages. Pup weights were comparable among groups but by PND 14 there was a significant decrease (15-37%) in the 0.0015% male and female pup weights. Survival was also comparable until weaning on PND 21, after which an increase in mortality was observed at 0.0015%. By PND 25, the 0.0015% pups were smaller with domed heads and misshapen snouts. During necropsy on PND 21 a delay in eruption of teeth was noted. Microscopically the jaws had damage (depletion and vacuolation) to the odontoblasts and ameloblasts resulting in a delay in cellular maturation and subsequent tooth eruption.
In the F1 offspring, eye opening was delayed by 1.9 days at 0.0015%. Prepuce separation was delayed by 2.0 days and vaginal opening by 1.4 days at 0.0004%. Because of the mortality observed in the F1 animals at 0.0015%, only the 0, 0.0001, and 0.0004% groups continued to produce the F2 offspring. For the F1 parents, no changes were noted in body weights, food consumption, water consumption, or reproductive endpoints. A decrease in anogenital distance was noted in the F2 male pups at 0.0001 and 0.0004%.
In the necropsy of F0 parents there were significant decreases at 0.0015% in absolute adrenal, brain, kidney, liver, ovary and spleen weights in female animals and significant increases at 0.0015% in relative right testis and seminal vesicle weights, and at 0.0004% and 0.0015% in relative pituitary weights in male animals. The absolute thyroid/parathyroid weights were increased 30-373% in the 0.0004 and 0.0015% males and females; relative thyroid/parathyroid weights were increased 34-443% in the 0.0004 and 0.0015% males and females and 18% in the 0.0001% females. In the necropsy of the F1 parents there were significant increases in the absolute and relative thyroid/parathyroid weights in the 0.0004% males and females and also in relative thyroid/parathyroid weight at 0.0001 % (males only). The findings in the F0 parents correlated with enlarged thyroids/parathyroids observed at necropsy in the 0.0004% males and females (seven of twenty and one of twenty, respectively) and 0.0015% males and females (twenty of twenty and eighteen of eighteen, respectively). There were no gross pathology findings in the F1 parents. Upon microscopic examination of the thyroid, follicular cell hyperplasia was observed in ten of ten 0.0015% F0 males and females, seven of ten 0.0004% F0 males, one of ten 0.0004% F0 females, one of ten 0.0004% F1 males and zero of ten 0.0004% F1 females. There was also degeneration of the germinal epithelium of the testes in three of ten, three of ten, and two of ten 0.0001%, 0.0004%, and 0.0015% F0 males respectively, and one of ten 0.0001% and 0.0004% F1 males. TSH levels were increased in the 0.0004% and 0.0015% F0 males and females and 0.0004% F3 males and females. T4 levels were decreased in the 0.0004% and 0.0015% F0 males and females and the 0.0004% F1 males and females.
Based on the findings of this two generation study with one litter per generation, Propylthiouracil would be considered a reproductive toxicant in females at dose levels greater than or equal to 0.0004% (based on decreased total pups per litter and pup mortality [at 0.0015%] ), a male reproductive toxicant at dose levels greater than or equal to 0.0001 % (based on degeneration of the germinal epithelium of the testes) and a general and endocrine modulating toxicant at 0.0015 and 0.0004% (based upon decreased body weight and food consumption [mostly at 0.0015%] and increased thyroid/parathyroid weights, changes in thyroid hormone levels, and/or thyroid follicular cell hyperplasia at 0.0015 and 0.0004%).
Report Date: September 2003