Final Study Report: Developmental Toxicity Evaluation for Emodin Administered in the Feed to Swiss (CD-1) Mice on Gestational Days 6 Through 17Report Date: Aug. 30, 2002
The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings may not have been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. For more information, see the Explanation of Levels of Evidence for Developmental Toxicity. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.
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 Swiss albino (CD-1) mice (25/group) were exposed to emodin at concentrations of 0, 600, 2500 or 6000 ppm in NIH-07 rodent diet from gestational day 6 to 17. Average daily intake was 0, 94, 391, and 1005 mg emodin/kg/day. 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) unless otherwise noted.
There were no treatment-related maternal deaths in this study. At termination (gd 17), 24-25 pregnancies/group were confirmed. Discoloration of the fur was noted at greater than or equal to 2500 ppm emodin (greater than or equal to 3 females per group), attributable to direct contact with feed containing the test chemical. At the high dose, discolored feces (also presumed due to the test chemical or its metabolites), and soft or loose feces were noted in 0-7 females/day.
On gd 17 (in life), maternal body weight exhibited a decreasing dose-related trend accompanied by a 7% reduction at the high dose. At 6000 ppm, maternal weight gain was decreased from gd 6 to 9 and 15 to 17, but was equivalent among groups from gd 9 to 12 and 12 to 15. At 6000 ppm, the following weight gain parameters were also significantly reduced: maternal weight gain during treatment (gd 6 to 17), during gestation (gd 0 to 17), and gestational weight gain corrected for gravid uterine weight.
Maternal relative liver weight, paired kidney weights (absolute or relative), and gravid uterine weight showed no differences among groups. A significant trend test was noted for maternal liver weight (absolute), but in the absence of a systematic dose-response relationship or any pairwise differences between emodin-treated groups and the control group.
At the low and mid doses, maternal relative feed intake (g/kg/day) was transiently decreased (gd 6 to 9), but was comparable to controls for the remainder of the study. At the high dose, maternal relative feed intake was increased (gd 12 to 15), and later decreased (gd 15 to 17). At 6000 ppm, maternal relative water intake (g/kg/day) was increased from gd 9 to 12, 12 to 15, 15 to 17, and 6 to 17 (treatment), but at 2500 ppm, maternal relative water intake was increased only from gd 12 to 15. Increased drinking water consumption may compensate for increased fluid loss via the lower gastrointestinal tract (i.e., associated with the laxative effect of emodin).
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, and percent male fetuses/litter were likewise unaffected. At 6000 ppm, average fetal body weight/litter (males, females or both) was reduced by 10-11%, and this effect was statistically significant.
Ingested emodin failed to significantly affect the incidences of fetal malformations or variations. At 2500 ppm, external malformations included exencephaly (3 fetuses in 3 litters) and cleft palate (2 fetuses in 2 litters). However, this increase in external malformations was not considered to be treatment related due to the clear absence of a dose-response relationship. At 6000 ppm, no external malformations were found among 302 fetuses (24 litters), nor had any been observed among 161 fetuses (13 litters) at 6000 ppm in the screening study (NTP, 2000).
In summary, the maternal toxicity lowest observed adverse effect level was considered to be 6000 ppm (1005 mg/kg/day) based on reduction of maternal body weight and weight gain, and the no observed adverse effect level was 2500 ppm (391 mg/kg/day). The developmental toxicity LOAEL was 6000 ppm (1005 mg/kg/day) based on reduction of fetal body weight, and the NOAEL was 2500 ppm (391 mg/kg/day).