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.
8-Methoxypsoralen forms monoadducts and crosslinks with DNA, in conjunction with ultraviolet light irradiation. This forms the basis of its clinical use as an anti-proliferative agent in hyperproliferative skin diseases, but MOXY may also be mutagenic in the absence of light. Because of MOXY's potential to affect rapidly dividing cells, it may pose a threat to the developing conceptus. Accordingly, MOXY (0, 40, 80, or 105 mg/kg/day) was administered by gavage to pregnant New Zealand white rabbits during the period of major organogenesis (gd 6-19). Maternal clinical signs, body weight, and food consumption were monitored from gd 0 to gd 30. On gd 30, fetuses were removed from the does and examined for evidence of developmental toxicity.
There was no maternal mortality during the study and there was no dose-related increase in the incidence of clinical signs of toxicity. Maternal absolute and relative food consumption were suppressed during the dosing period (gd 6 to 19) by all doses of MOXY, but returned to control levels after the end of the dosing period. In keeping with the effects on food intake, maternal body weight gain (gd 6 to 19) was reduced in the 80 and 105 mg/kg/day dose groups, but that effect, too, was transient, as weight gain in those two groups was comparable to controls from gd 19 to 30. MOXY at 40 mg/kg/day also reduced maternal body weight gain, but the effects was not statistically significant. Although MOXY (80 and 105 mg/kg/day) decreased maternal weight gain, maternal body weights remained comparable to controls at all gestational ages because the changes in weight gain represented only 4-5% of total maternal body weight. Maternal relative liver weight displayed a rising trend, but the largest change was a 9% increase at the 105 mg/kg/day dose. These results indicate the lowest observed adverse effect level for MOXY-induced maternal toxicity was 80 mg/kg/day.
Gravid uterine weight was unaffected by MOXY administration. Examination of the uterine contents revealed MOXY did not cause developmental toxicity. Average live litter size, average fetal body weight (both sexes), and the incidence of external, visceral, and skeletal malformations or variations were comparable to controls at all doses of MOXY. The only significant difference observed was a decrease in the percent male fetuses per litter at 105 mg/kg/day MOXY. In the absence of an increase in the number of resorptions or fetal deaths at this dose, this result probably reflects normal variation in sex ratio. Based on the above results, the developmental no observed adverse effect level for MOXY was greater than or equal to 105 mg/kg/day. Thus, MOXY, at doses which cause minor maternal toxicity, does not affect fetal growth, viability, or morphological development.