Maternal-fetal distribution and prenatal toxicity of 2,2,4-trimethyl-1,2-dihydroquinoline in the rat.

BACKGROUND

Polnoks R (poly-2,2,4-trimethyl-1,2-dihydroquinoline) is used as an antioxidant in elastomer processing. It is an embryotoxic and fetotoxic agent. This chemical given per os to female rats induces also teratogenic effect but only at doses toxic to the mother. The aim of the study was to evaluate prenatal development and tissue distribution in rats exposed to 2,2,4-trimethyl-1,2-dihydroquinoline (TMDHQ), a monomer of Polnoks R.

METHODS

Females were exposed orally to unlabeled TMDHQ during organogenesis at doses 50-400 mg/kg to asses prenatal toxicity and to radiolabeled 14C monomer at a dose 210 mg/kg to evaluate tissues distribution.

RESULTS

TMDHQ administered to pregnant females per os at doses 100 mg/kg and higher produced teratogenic effect (cleft palate, wavy ribs, kyphoscoliosis, exencephaly, external hydrocephalus, hydronephrosis, and renal hypoplasia). Peak 14C-radioactivity was found in mothers' plasma about 10 hr after administration of this compound at dose 210 mg/kg. The accretion of 14C proceeded with a kinetic constant of 0.35 hr(-1) and a half-life of 53.3 hr. Kidneys are the main organs of monomer excretion. The highest concentration of 14C in maternal tissues 24 hr after oral dosing was found in adipose tissue, sciatic nerve, muscles, kidneys, and liver. Radiocarbon retention in fetuses was the highest in kidneys at all time points after dosing.

CONCLUSIONS

This study has demonstrated that transplacental exposure to Polnoks R monomer is teratogenic in rats. 14C retention in placenta, amniotic fluid, and fetal tissues indicates that this compound or its metabolites penetrate into placenta to the fetus.