Final Study Report: Developmental Toxicity Evaluation for Berberine Chloride Dihydrate (CAS No. 5956-60-5) Administered in the Feed to Sprague Dawley (CD) Rats on Gestational Days 6 Through 20
Report Date: April 14, 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.
Berberine is an alkaloid isolated from plants in cluding Hydrastis canadensis L., and the Berberidaciae family, and many other plants, including the Oregon grape root. It is the major alkaloidal component of Coptis chinensis used in Chinese herbal medicine. It has also been produced synthetically. Berberine is found in tea, herbal dietary supplements, and over-the-counter health-related products. This developmental toxicity study was designed to evaluate potential maternal and developmental toxicity in timed-mated rats exposed to berberine chloride dihydrate in the feed throughout the embryo/fetal period.
Female Sprague-Dawley-derived (CD) rats were dosed through ground feed (NIH-07) containing BCD (0, 3625, 7250, or 14500 ppm) on gd 6 to 20. The calculated average daily intake of BCD at these concentrations in the feed was 0, 282, 531, and 1313 mg/kg/day. When berberine chloride intake was calculated, animals in the control through high-dose groups ingested 0, 223, 420 and 1040 mg berberine chloride/kg/day. The oral route of administration conforms to one of the expected routes of exposure in the human population. Dose range selection for this study was based on information obtained from the literature as well as two earlier screening studies in rats.
In this study, twenty-five timed-mated rats were assigned to each group. Dams were monitored inlife for clinical signs of toxicity, feed and water intake, and body weight. At necropsy (gd 20), the following determinations were made: maternal clinical condition; body, liver, and gravid uterine weights; pregnancy status; and the number of corpora lutea. In the gravid uterus, the numbers of resorbed, dead, and live fetuses were recorded. Live fetuses were weighed, sexed, and examined for external, visceral, and skeletal morphological anomalies.
No maternal mortality was observed in this study. Yellow discoloration of the fur was noted with an increased incidence at 14500 ppm, and was considered due to direct contact with feed containing the test chemical (yellow powder with an orange cast). There were no other remarkable clinical signs related to BCD exposure.
At 14500 ppm, BCD exposure was associated with significant decreases (-4-10%) in maternal body weight on gd 9, 12, 15, 18, and 20. The 7250 ppm group gained less weight than controls during the gestation period (gd 0 to 20). In the 14500 ppm group, maternal body weight gain was lower than controls from gd 6 to 9, 9 to 12, 12 to 15, 15 to 18, and 18 to 20 and during treatment (gd 6 to 20). Gestational (gd 0 to 20) and corrected weight gains were also reduced at 14500 ppm. Maternal liver weight (absolute and relative) was reduced at 14500 ppm. Gravid uterine weight showed a decreasing trend.
At 14500 ppm, maternal relative feed consumption (g/kg/day) increased (gd 6 to 9; 12 to 15) or decreased (gd 9 to 12) during specific measurement periods, but was significantly increased for the treatment period (gd 6 to 20) and the gestational period (gd 0 to 20). Maternal relative water intake (g/kg/day) showed a decreasing trend during early treatment (gd 6 to 9). At 3625 ppm, relative maternal water consumption was reduced (gd 12 to 15; 18 to 20). For the treatment period (gd 6 to 20) and the gestational period (gd 0 to 20), maternal relative water consumption was not affected by BCD exposure.
At scheduled necropsy, pregnancy was confirmed in 24-25 females/group (96-100%). Prenatal mortality and average live litter size did not differ among groups. In addition, incidence of fetal morphological anomalies (external, visceral or skeletal malformations or variations) was unaffected. However, average fetal body weight per litter (males, females or both sexes) was reduced by ~6% at 14500 ppm.
In summary, CD rats were dosed through ground feed with BCD (0, 3625, 7250 or 14500 ppm) from gd 6 to 20. Maternal toxicity was found at ≥7250 ppm BCD in feed and developmental toxicity was noted at 14500 ppm. Thus, the maternal toxicity lowest-observed-adverse-effect level was 7250 ppm (531 mg BCD/kg/day or 420 mg berberine chloride/kg/day), and the no-observed-adverse-effect level was 3625 ppm (282 mg BCD/kg/day or 223 mg berberine chloride kg/day). The developmental toxicity LOAEL was 14500 ppm (1313 mg BCD/kg/day or 1040 mg berberine chloride/kg/day). The developmental toxicity no observed adverse effect level was 7250 ppm (531 mg BCD/kg/day or 420 mg berberine chloride kg/day).