Reproductive toxicity

Only one report of the reproductive effects of NMP in humans could be found in the literature. Intrauterine growth retardation and subsequent fetal demise at week 31 of gestation was attributed to dermal exposure to NMP at week 16 of gestation (Solomon et al., 1996). Animal data, although lacking and inconsistent in dosing regimes and routes of exposure, suggests that maternal exposure to NMP during organogenesis may affect fetal survival and growth, and cause subsequent delays in development. Fetal effects of NMP may be secondary to maternal toxicity (Becci et al., 1982), however, similar effects have been described in the absence of effects on exposed dams (Hass et al., 1994; 1995).

An increase in skeletal abnormalities was attributed to dermal administration of 750 mg/kg/day of NMP to pregnant rats on days 6 to 15 of gestation, inclusive (Becci et al., 1982). In other rat studies, inhalation of up to 165 ppm for 6 hours each day, for treatment periods throughout gestation, did not result in a similar increase in malformations (Lee et al., 1987; Hass et al., 1994; 1995).

The reproductive performance of rats exposed to 116 ppm (6 hours/day 7 days/week until end of mating in males or weaning in females) was not affected. Their offspring also had normal reproductive performance when mated with unexposed adults (Solomon et al., 1995). However, the incidence and numbers of pre-implantation losses in rats increased after inhalation of NMP on days 4-20 post mating (Hass et al., 1995).

In a study of the effects on rats exposed dermally, throughout organogenesis, to 75, 237 and 750 mg/kg/day NMP, fewer live fetuses, increased percentage of resorptions and skeletal abnormalities, and decreased fetal birth weights were reported at the highest dosage. Skeletal abnormalities were attributed to the teratogenicity of NMP. Other effects were indicative of delayed fetal development and considered likely to be secondary to the maternal toxicity observed at 750 mg/kg (evidenced by reduced body weight). Dose dependent brightly coloured urine and dry skin were also observed. No fetal or maternal toxicity was reported at 75 or 237 mg/kg (Becci et al., 1982).

Sporadic lethargy and irregular respiration on the first three days were the only effects observed in rats exposed to 0.1-0.36 mg/l (25-89 ppm) for 6 hours each day from days 6-15 of gestation. There was no effect on fetal survival, growth or development (Lee et al., 1987).

Brightly coloured urine, but no maternal toxicity was exhibited in female rats exposed to 150 ppm NMP for 6 hours daily from day 7 until day 20 of gestation. While significantly reduced bodyweights at birth and pre-weaning were observed in their offspring compared with controls, there was no decrease in viability. The weight reduction was recovered by five weeks post partum. Delays in achieving behavioural development milestones were attributed generally to delayed physical development (Hass et al., 1994).

Delayed fetal skeletal ossification and a significantly lower mean fetal body weight (4-5% less than controls) after adjustment for litter size were reported in rats exposed to 165 ppm, for 6 hours daily, on days 4 to 20 of gestation, when compared with controls. A significant increase in the incidence of pre-implantation loss (20 dams compared with 11 in controls) and an increase in pre-implantation losses were also observed in treated dams (20.5% compared with 13.4% in controls). These effects occurred in the absence of maternal toxicity (Hass et al., 1995).

In a two generation reproductive and developmental inhalation study, the reproductive performance of exposed rats did not differ significantly from controls. Slight decreases in fetal weights were recorded when both parental rats were exposed to 116 ppm NMP. This reduction in body weight was reflected at birth in offspring (particularly in females), and it persisted until 21 days post partum when maternal exposure ceased and the pups were weaned. Thereafter the body weights were comparable to controls. The reproductive performance of the offspring was not affected (Solomon et al., 1995).

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