Emodin is a naturally occurring and pharmacologically active anthroquinone found in the roots and bark of certain plant species. Other anthroquinones have been shown to be mutagenic, whereas allied synthetic compounds, i.e., anthracyclines, have been shown to be teratogenic. The wide availability of emodin in herbal preparations, coupled with the potential for mutagenic and/or teratogenic activity, suggested that ingestion of emodin by pregnant women might have adverse developmental effects. Estimated maximum human exposure to emodin is 3 mg/kg/day in a 70 kg person.
In the present study, timed mated Sprague Dawley (CD) rats (25/group) were exposed to emodin at nominal concentrations of 0, 425, 850, and 1700 ppm in NIH-07 ground rodent diet from gestational day 6 to 20. Average daily intake was 0, 31, and 57 mg emodin/kg of body weight/day for the control, low- and middose groups. Average daily intake for the 1700 ppm group was 80-144 mg emodin/kg of body weight/day, but could not be estimated more accurately due to scattering of the feed by the animals. Nominal concentrations of emodin (ppm in feed) and calculated intake of emodin (mg/kg/day) are expressed as the bulk test article (96.2% purity).
There were no treatment-related maternal deaths in this study. At termination (gd 20), 21-25 pregnancies/group were confirmed. Discoloration of the fur was noted primarily at 1700 ppm emodin (1-18 animals/day), and was presumed to be due to direct contact with the test material. Piloerection was noted primarily at the low and mid doses (1-10 animals/group).
Maternal body weight was decreased at the high dose on go 9 and 12 (94% of the control values) but this effect was not evident by gd 20 (in life). Maternal weight gain was reduced for gd 6 to 9 at the mid and high dose (44 and 12% of weight gain in the control group, respectively) and during treatment (gd 6 to 20) in the high dose group (86% of the control group). Maternal body weight during gestation and gestational weight gain corrected for gravid uterine weight exhibited a decreasing trend, but no pairwise differences were seen between emodin-treated groups and controls. Gravid uterine weight, maternal relative liver weight, and maternal absolute kidney weight were unaffected. Maternal absolute liver weight was slightly but significantly decreased at the high dose, whereas maternal relative kidney weight was increased (5-7%) at the low and high dose. The toxicological significance of these findings is unclear.
Compared to the concurrent control group, maternal relative feed intake was reduced on gd 6 to 9 (all treated groups), from gd 12 to 15 (low and mid-dose groups), and for gd 6 to 20 and gd 0 to 20 (mid-dose group). For relative maternal feed consumption (gd 12 to 15), the reduction at the high dose did not reach statistical significance (Mann-Whitney U test) even though feed intake was only 60% of the control group. The lack of statistical significance in the high dose group for relative maternal feed consumption on gd 12 to 15 was likely a result of the reduced number of data points for that time period. Data from the high-dose group were not used for comparisons after gd 15, since apparent palatability problems caused the dams to scatter the feed, making accurate measurement of the feed weights difficult. Relative maternal water consumption exhibited a transient increase in the mid- and high-dose groups on gd 12 to 15. Relative maternal water consumption also was increased in the mid-dose group for gd 15 to 18, but no other effects of treatment were noted.
There were no differences among groups for the number of corpora lutea/dam, number of implantation sites/litter, or percent preimplantation loss/litter. Postimplantation loss (resorptions or late fetal deaths), live litter size, percent male fetuses/litter, and average fetal body weight/litter (males, females or both) were likewise unaffected. Emodin did not affect the incidence of fetal malformations or variations.
In summary, the maternal lowest observed adverse effect level was considered to be 1700 ppm (80-144 mg/kg/day) based on maternal body weight and weight gain, and the no observed adverse effect level was 850 ppm (57 mg/kg/day). The developmental toxicity NOAEL was greater than or equal to 1700 ppm (80-144 mg/kg/day). A LOAEL for developmental toxicity was not established in this study.