Abstract for TER99004

Developmental Toxicity Evaluation for Goldenseal (Hydrastis Canadensis) Root Powder Administered in the Feed to Swiss (CD-1) Mice on Gestational Days 6 Through 17

Report Date: July 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.

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 mice exposed to goldenseal root powder in the diet throughout the embryo/fetal period.

In this study, timed-mated female Swiss albino (CD-1) mice were given ad libitum access to NIH-07 ground feed containing 0, 3125, 12,500, or 50,000 ppm goldenseal root powder from gestational day 6 to 17. The calculated intake of goldenseal root powder was 0, 514, 2048, and 7738 mg/kg/day for the control through high-dose groups, respectively. Goldenseal root powder contained 5% berberine and 4.5% hydrastine by weight. Corresponding ingested doses were 0, 26, 102, and 387 mg berberine/kg/day and 0, 23, 92 and 348 mg hydrastine/kg/day.

Twenty-five timed-mated mice were assigned to each group. Dams were monitored in-life for clinical signs of toxicity, feed/water consumption, and body weight. At necropsy (gd 17), 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. The only dose-related clinical sign was discoloration of the fur, presumably from direct contact with the test chemical in the feed. Relative maternal feed consumption (g/kg/day) was significantly reduced at 50,000 ppm (gd 6 to 9 and 15 to 17). Relative maternal water consumption (g/kg/day) was increased at the low dose (gd 6 to 9 and 9 to 12), as well as the high dose (gd 6 to 9, 9 to 12, 12 to 15, 6 to 17 and 0 to 17). Increased maternal weight gain was noted at the low dose (gd 6 to 9 and 15 to 17) and the mid dose (gd 6 to 9). Despite intermittent reductions in maternal feed consumption during the treatment period at 50,000 ppm (see above), maternal body weight was not affected. Maternal body weight gain during treatment, gestational body weight gain, gravid uterine weight, and corrected weight gain were likewise unaffected. At greater than 12,500 ppm, significant increases were noted for maternal liver weight (absolute and relative), accompanied by significant dose-response trends. At the highest exposure (50,000 ppm), mean absolute liver weight reached 140% of the control value. Histopathologic evaluation of the ten heaviest maternal livers per group revealed no treatment-related lesions.

At scheduled necropsy, pregnancy was confirmed in 23-25 (92-100%) timed-mated females/group. Prenatal mortality (resorptions and/or late fetal deaths), average live litter size and percent male fetuses per litter were not affected. Female fetal body weight/litter exhibited a decreasing trend with a -6.5% reduction (not statistically significant) at the high dose. Fetal body weight/litter (males or both sexes combined) exhibited a significant trend test and a significant reduction (~8%) at the high dose.

There were no statistically significant increases in the incidences of malformations or variations when pooled by general type (i.e., external, visceral or skeletal). The incidences of exencephaly and cleft palate appeared to be slightly elevated at the high dose. Although, the incidence of exencephaly at the high dose was outside the historical control range (1.0% vs. 0.7%) this difference was statistically insignificant when compared to the concurred control group. Cleft palate is a malformation to which this species/strain is predisposed under conditions of maternal stress, suggesting activation of the hypothalamic-pituitary-adrenal axis at the highest exposure.

In summary, CD-1 mice were exposed to golden-seal root powder in feed (0, 3125, 12,500, or 50,000 ppm) from gd 6 to 17. The high dose yielded an average daily intake (7738 mg golden-seal root powder/kg/day) that was ~300 times the estimated human intake from dietary supplements (26 mg/kg/day). Maternal effects included intermittent reduction of relative feed consumption (50,000 ppm), possibly due to altered palatability, and increased water consumption. Maternal liver weights were increased at greater than 12,500 ppm, but in the absence of treatment-related histopathological lesions. At the high dose, definitive evidence of developmental toxicity was limited to a statistically significant (~8%) reduction in average fetal body weight per litter. Thus, the developmental toxicity no observed adverse effect level was 12,500 ppm and the lowest observed adverse effect level was 50,000 ppm.