Sodium chlorate is used as an oxidizing agent and bleach for paper pulp, to make chlorine dioxide used in water disinfection, in various manufacturing processes, and as a non-selective herbicide, defoliant, and harvest aid (Merck, 1996; HSDB, 1997; RTECS, 1997). This study was performed due to the potential for human exposure to sodium chlorate and the lack of pertinent developmental toxicity data.
Dose selection was based on a screening study in which New Zealand White rabbits were treated by gavage with 0, 100, 250, 500, 750, or 1000 mg sodium chlorate/kg body weight/day on gestational days 6 through 29 (NTP, 1998). Maternal toxicity was noted at greater than or equal to 250 mg/kg/day, with maternal morbidity and mortality at greater than or equal to 500 mg/kg/day. There was no definitive evidence of developmental toxicity at doses up to 500 mg/kg/day (NTP, 1998).
In this study, female NZW rabbits were dosed by gavage with sodium chlorate (100, 250, or 475 mg/kg/day) or its vehicle (deionized/distilled water) on gd 6 through 29. The dose volume was 3 ml/kg. The study was conducted in a two-replicate design. Twenty-four timed naturally-mated female rabbits (12 per replicate) were assigned to each group. Does were monitored at regular intervals throughout gestation for clinical signs, food intake, and body weight. At necropsy on gd 30, the following were recorded: maternal clinical condition; body, liver and gravid uterine weights; pregnancy status; and number of corpora lutea. In the gravid uterus, the numbers of resorbed, dead, or live fetuses were recorded. All live fetuses were weighed, sexed, and examined for external morphological, visceral, and skeletal anomalies. Approximately one-half of the fetuses were examined for anomalies of the internal head structures.
Confirmed pregnancy rates were 90-100% per group. One maternal death occurred in each dose group. Clinical signs associated with sodium chlorate exposure included urinary changes (orange or brown urine; and/or little or no urine) on one or more days of treatment. The number of animals affected showed doseresponse patterns across the control through high dose groups (i.e., 0, 0, 2, and 8 for color changes and 0, 1, 6 and 8 for urine output), respectively. Nevertheless, these changes in individual animals were transient and not clearly indicative of toxicity.
No significant treatment-related effects were observed for maternal body weight, body weight gain, or corrected weight gain. Maternal liver weight (absolute and relative to body weight) and gravid uterine weight were equivalent among groups.
Relative maternal food intake (g/kg/day) exhibited an increasing trend prior to initiation of treatment, but was reduced to 82-83% of control intake in the mid and high dose groups during early treatment (gd 6 to 9). Thereafter, no significant differences were noted among treatment groups for maternal relative feed consumption, suggesting that the decrease on gd 6 to 9 was related to initiation of treatment. A decreasing dose-related trend for the periods of gd 15 to 18 and gd 18 to 21 was observed, although no significant differences between the control group and treated groups were observed for these periods. These effects were not noted later in the treatment period.
Sodium chlorate exposure did not significantly affect any endpoints related to prenatal viability. Average live litter size in sodium chlorate treated groups was between 100-112% of the control mean, with no statistically significant difference among groups. There were no treatment-related effects on fetal body weight. There were no effects of treatment on the incidence of external, visceral, or skeletal malformations.
In summary, transient changes in maternal food intake, urinary color and/or output were noted at > 100 mg/kg/day in this study, but clear evidence of maternal toxicity was observed only at doses greater than 475 mg/kg/day in the screening study (NTP, 1998) Sodium chlorate did not cause any significant treatment-related developmental toxicity under the conditions of this study. Thus, the maternal and developmental toxicity no observed adverse effect levels were greater than or equal to 475 mg/kg/day.