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 antiproliferative agent in hyperproliferative skin diseases. MOXY may also be mutagenic in the dark. Because of MOXY's potential to affect rapidly dividing cells, it may pose a threat to the developing conceptus. Accordingly, MOXY (0, 20, 80, 120, or 160 mg/kg/day) was administered by gavage to pregnant rats during the major period of organogenesis (gestational day 6-15). Maternal clinical signs, weight, and food and water consumption were monitored from gestational day 0 to gestational day 20. On gestational day 20, fetuses were removed from the dams and examined for evidence of developmental toxicity.
There was no maternal mortality during the study. Maternal relative food consumption was suppressed by MOXY administration. Maternal food intake in the 160 mg/kg/day group was decreased 44% relative to controls on gestational day 6 to 9 and 64% on gestational day 9 to 12. By gestational day 15 to 18, maternal food consumption had reached control values and on gestational day 18 to 20, food intake was 55% greater than controls. A similar pattern was observed in the 80 mg/kg/day and 120 mg/kg/day MOXY groups. Maternal relative water consumption on gestational day 6 to 9 in the 120 mg/kg/day and 160 mg/kg/day groups displayed significant 23% reductions. By gestational day 12 to 15, water consumption was near or above control values in all MOXY groups. Water intake was elevated in the three highest dose groups from gestational day 18 to 20.
MOXY significantly reduced maternal body weight 6%-13% by gestational day 9 (80, 120, and 160 mg/kg/day groups). Dam weights in all three groups remained significantly subnormal through sacrifice on gestational day 20. During the dosing period, maternal weight gain was decreased 162% in the 160 mg/kg/day group, 114% in the 120 mg/kg/day group, and 44% in the 80 mg/kg/day group relative to control values. Significant deficits in corrected maternal weight gain were also observed for dams in the 120 mg/kg/day (42%) and 160 mg/kg/day (66%) groups. MOXY treatment also significantly reduced gravid uterine weight in the 120 mg/kg/day (15%) and 160 mg/kg/day (40%) groups. Relative maternal liver weight was significantly increased 7%, 17%, and 26% relative to controls in 80, 120, and 160 mg/kg/day groups respectively. No maternal measure was significantly altered by 20 mg/kg/day MOXY.
Results of the uterine examination revealed that MOXY caused significant fetotoxicity. MOXY at 160 mg/kg/day increased the percent resorptions per litter. Live litter size and average fetal body weight in the 160 mg/kg/day group were both significantly reduced by 19%. A significant trend toward an increase in the percent fetuses with malformations per litter and the percent litters with malformations was noted. Enlarged lateral ventricles of the brain was the major contributor to this increase. However, the overall incidence of malformations was not significantly increased relative to concurrent controls, and was within the historical control range, except at 160 mg/kg/day. The percent fetuses per litter with variations was significantly increased in the 120 mg/kg/day (217%) and 160 mg/kg/day (320%) groups. The incidence of a rudimentary lumbar I rib was the only variation which showed a dose-dependent increase. MOXY at 20 mg/kg/day or 80 mg/kg/day did not adversely affect fetal development.
The developmental lowest observed adverse effect level was 120 mg/kg/day and the no observed adverse effect level. 80 mg/kg/day. The LOAEL for MOXY-induced maternal toxicity was 80 mg/kg/day and the NOAEL 20 mg/kg/day. The results from this study indicate that MOXY adversely affects fetal growth, viability, and morphological development at doses which caused significant maternal toxicity.
|Pregnancy rate (%)||92||92||100||96|
|Body weight change|
|(gestational day 6-15)||⇓||-||⇓||⇓||⇓|
|Relative food consumption|
|Relative water consumption|
|No. corpora lutea/dam||⇓||-||⇓||-||⇓|
|Gravid uterine weight||⇓||-||-||⇓||⇓|
|Relative liver weight||⇑||-||⇑||⇑||⇑|
|% litters with resorptions||-||-||-||-||-|
|% litters with 100%|
|Avg. female body wt/litter||⇓||-||-||-||⇓|
|Avg. male body wt/litter||⇓||-||-||-||⇓|
|% malformed fetuses/litter||⇑||-||-||-||-|
|% litters with|
|% fetuses with ELV/litter||⇑||-||-||-||⇑|
|% litters with ELV||⇑||-||-||-||-|
|% fetuses with|
[a] The vehicle control group contained 25 timed-mated females: one female was removed because of a dosing error, and 22/24 (97%) were confirmed pregnant at necropsy.
[b] Arrow in Trend column indicates direction of trend.
⇓ indicates significantly greater (p<0.05) than controls;
⇑ indicates significantly lower (p<0.05) than controls;
- indicates not different from controls.