Benzophenone occurs naturally in some fruits and is used commercially as a perfumery and flavoring ingredient. This study was performed in response to the potential for human exposure and the lack of pertinent developmental toxicity data.
Dose selection was based on a screening study in which Sprague-Dawley-derived (CD) rats were treated by gavage with benzophenone (0, 25, 50, 100, 200, or 300 mg/kg body weight/day) on gestational days 6 through 19 (NTP, 1998b). Maternal toxicity was found at all doses, but evidence of developmental toxicity was limited to a 6-8% decrease for average fetal body weight per litter (not statistically significant) at the high dose.
In this study, benzophenone (100, 200, or 300 mg/kg/day) or its vehicle (0.5% methylcellulose) was administered to female CD rats by gavage on gd 6 through 19. The dose volume was 5 ml/kg. Twenty-five to 26 timed-mated rats were assigned to each group. Dams were monitored at regular intervals throughout gestation for clinical signs, feed and water intake, and body weight. At necropsy on gd 20, the following were recorded: maternal clinical condition; body, liver, paired kidney 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 anomalies. Approximately one-half of the fetuses were examined for visceral anomalies, including internal head structures, and the remaining fetuses were examined for skeletal anomalies.
Confirmed pregnancy rates were 88-100% per group. No treatment-related maternal deaths occurred in this study. Clinical signs at all doses of benzophenone included lethargy, pilo-erection, weight loss and rooting in the bedding after dosing.
Maternal body weight was decreased at the low dose on gd 9, 12, and 15, at the mid dose on gd 9 and 12, and at the high dose on gd 9, 12, 15, 18, 19, and 20 at sacrifice. Decreased maternal weight gain was observed at all doses from gd 6 to 9, and at the high dose from gd 9 to 12. In-creased weight gain was noted at the mid dose (gd 9 to 12 and 19 to 20) and at the high dose (gd 18 to 19 and 19 to 20). Maternal body weight gain during treatment and gestation was decreased only at the high dose, while gesta-tional weight gain corrected for gravid uterine weight was reduced at all doses. Gravid uterine weight was not affected. Maternal liver and kidney weights (absolute and/or relative) were significantly increased at all doses.
Maternal relative feed intake (g/kg/day) was decreased at all doses from gd 6 to 9, and at the mid and high doses from gd 9 to 12. Rebound increases in feed intake were noted at all doses of benzophenone from gd 15 to 18, and 18 to 19. The high dose showed a significant decrease in relative feed intake for the treatment period as a whole. Maternal relative water intake (g/kg/day) was increased at the low dose (gd 15 to 18 and 18 to 19), and the mid and high doses (gd 12 to 15, 15 to 18, 18 to 19, and 19 to 20). Relative water intake for the treatment period as a whole (gd 6 to 20) was not affected.
Average fetal body weight per litter exhibited decreasing dose-response trends (males, females, and both sexes combined). At the high dose, a 6.5% decrease for male fetal body weight was statistically significant; a 5% de-crease for female fetal body weight was biologi-cally significant, but did not reach statistical significance. Benzophenone had no adverse ef-fect on prenatal viability or the overall inci-dences of fetal malformations or variations. The incidence of unossified sternebrae was increased at all doses of benzophenone, and the incidence of extra rib (full or rudimentary, combined) on Lumbar I was increased at the mid and high doses. However, neither of these skeletal varia-tions exhibited a significant dose-response relationship.
In summary, maternal toxicity was noted at greater than or equal to 100 mg benzophenone/kg/day administered on gd 6 through 19. Thus, the maternal toxicity lowest observed adverse effect level was 100 mg/kg/day and the no observed adverse effect level was not determined. Clearly defined NOAEL and LOAEL values for developmental toxicity were not achieved in this study. Slightly delayed skeletal development was observed at all doses, and male fetal body weight was significantly reduced at the high dose. Each of these effects has a high potential for early postnatal recovery.