Naphthalene ingestion can cause severe toxicity in humans, especially in infants and individuals with a deficiency in the enzyme glucose-6-phosphate dehydrogenase. Since NAP readily crosses the placenta, it has the potential to be developmentally toxic. Accordingly, NAP (0, 50, 150, or 450 mg/kg/day) was administered by gavage to pregnant rats during the major period of organogenesis (gd 6-15). Dams and fetuses were examined for signs of toxicity and teratogenicity. Each group contained 25 to 26 pregnant dams.
NAP administration produced clinical signs of toxicity. All doses of NAP caused lethargy, slow breathing, prone body posture, and rooting, but the effects subsided in the 50 and 150 mg/kg/day groups before the end of the treatment period. Clinical toxicity persisted throughout dosing in rats treated with 450 mg/kg/day NAP.
Maternal mortality was low and limited to two animals in the 50 mg/kg/day group. Based upon the absence of maternal deaths at the higher doses, the association between NAP toxicity and maternal deaths at the 50 mg/kg/day dose is equivocal. Pregnancy rate, gravid uterine weight and liver weight (absolute and relative) were unaffected by NAP treatment. NAP caused significant deficits in maternal body weight gain during the treatment period. Relative to the control group, the 150 mg/kg/day group showed a 31% reduction in weight gain during treatment as compared to a 53% reduction in the 450 mg/kg/day group. Post-treatment weight gain from gd 15 through sacrifice on gd 20 also remained significantly below controls in these two groups. Body weights were correspondingly reduced from gd 9-20. Maternal body weights and weight gains were unaffected by 50 mg/kg/day NAP.
Maternal food and water consumption (absolute and relative) in the two highest dose groups were initially suppressed on gd 6 to 9. But unlike the effects on weight, the deficits in food and water intake were transient and confined to gd 6 to 9. Water consumption also displayed a transient increase on gd 9 to 12.
NAP was not fetotoxic or teratogenic. The average number of corpora lutea per dam, implantation sites per litter, and live fetuses per litter were within 95-102% of controls in all treatment groups. Average fetal body weight was similarly unaffected by NAP.
The results from this study indicate that NAP causes maternal toxicity expressed as central nervous system depression, decreased body weight, and altered food and water consumption. The maternal no observed adverse effect level was less than 50 mg/kg/day. Fetal growth, viability, and morphological development were not significantly affected by NAP, even at doses which caused significant maternal toxicity. However, statistically significant trends toward decreased fetal weight and increased malformation incidence suggest that the high dose (450 mg/kg/day) may be just below a significant lowest observed adverse effect level for developmental effects.