Abstract for TER98007

Developmental Toxicity Evaluation for Goldenseal Root Powder (Hydrastis Canadensis) Administered in the Feed to Sprague Dawley (CD) Rats on Gestational Days 6 Through 20

Report Date: April 3, 2003


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.

Goldenseal (Hydrastis canadensis) root powder is readily available in OTC dietary supplements. Thus, the potential hazards of oral exposure during pregnancy warranted further investigation. The present study was designed to evaluate potential developmental toxicity in timed-mated rats exposed to gold-enseal root powder in the diet throughout the embryo/fetal period.

In this study, timed-mated Sprague-Dawley (CD) rats were given ad libitum access to NIH-07 ground feed containing goldenseal root powder (0, 3125, 6250, 12500, or 18400 ppm) from gestational day 6 to 20. Calculated intake of goldenseal root powder was 0, 207, 415, 841, and 1215 mg/kg/day for the control through high-dose groups, respectively. Goldenseal root powder contained 5% berberine and 4.5% hydrastine by weight. Thus, ingested doses of these constituents were 0, 10, 21, 42, and 61 mg berberine/kg/day and 0, 9, 19, 38 and 55 mg hydrastine/kg/day.

Twenty-five timed-mated rats were assigned to each group. Dams were monitored in-life for clinical signs of toxicity, feed/water consumption, and body weight. At necropsy (gd 20), the following were evaluated: maternal clinical condition; body, liver, and gravid uterine weights; pregnancy status; and number of corpora lutea. In the gravid uterus, numbers of resorbed, dead, and live fetuses were recorded. Live fetuses were weighed, sexed, and examined for morphological anomalies [external, (including cleft palate), visceral and skeletal].

No maternal mortality was observed in this study and there were no remarkable clinical signs. Maternal body weight was unaffected. Likewise, there were no significant effects on maternal body weight gain across the treatment (gd 6 to 20) or gestational (gd 0 to 20) periods. Gravid uterine weight and maternal corrected body weight gain were likewise unaffected. At 12500 and 18400 ppm, maternal relative feed consumption (g/kg/day) and maternal body weight gain were transiently reduced during early treatment (gd 6 to 9). Maternal relative feed consumption was also reduced from gd 9 to 12 at 6250 and 18400 ppm, but there were no significant effects on maternal body weight or weight gain during the same measurement period. Effects during early treatment were probably due to altered palatability of the dosed feed, as suggested by the absence of persistent effects on maternal relative feed consumption, body weight or weight gain. At 6250 and 12500 ppm, relative maternal water consumption (g/kg/day) was increased from gd 18 to 20. At ≥6250 ppm, significant dose-related increases were noted for maternal liver weight (absolute and relative). At the highest exposure (18400 ppm), average absolute liver weight reached 113% of the average control weight.

At scheduled necropsy, pregnancy was confirmed in 22-25 (88-100%) timed-mated females/group. The following endpoints were unaffected: prenatal mortality (resorptions and/or late fetal deaths), average live litter size, average fetal body weight per litter (male, female or both sexes) and percent male fetuses per litter. Likewise, there were no statistically significant or otherwise distinctive dose-response patterns for malformations or variations whether pooled by general type (i.e., external, visceral or skeletal) or considered individually. There were a limited number of fetuses with multiple malformations, but based on the absence of a dose-response relationship, these findings did not appear to be treatment-related.

In summary, CD rats were exposed to goldenseal root powder in feed (0, 3125, 6250, 12500, or 18400 ppm) from gd 6 to 20. Higher concentrations of goldenseal root powder appear to be unpalatable to the CD rat (NTP 2001h) and were not included. In this study, the highest concentration yielded an average daily intake (1215 mg goldenseal root powder/kg/day) that was ~47 times the estimated human intake from dietary supplements (~26 mg/kg/day). Maternal effects included transient reduction of relative feed consumption and body weight gain during early treatment, possibly due to altered palatability, and increased water consumption at the end of gestation. Maternal liver weights were increased at ≥6250 ppm, suggesting possible enzyme induction. There was no definitive evidence of developmental toxicity in this study. Thus, the developmental toxicity no observed adverse effect level was ≥18400 ppm, and the low observed adverse effect level was not determined in this study.