Dinoseb

Endpoint summary

Additional information

Animal data indicates that dinoseb is readily absorbed and metabolised via oral and dermal as well as parenteral routes of administration (Bandal et al. 1972, Hall et al. 1992, Shah et al. 1990). Signs of systemic toxicity, and deaths, were in fact observed early after dosing in the available acute oral and dermal studies. Absorbed dinoseb is extensively metabolised, and distributed throughout the body. The metabolite profile is similar in rats treated by the dermal route or injected i.v. (Hall et al. 1992). Dinoseb reaches the embryo in pregnant mice although the placenta acts as an efficient barrier leading to concentrations of 2.5% of those of maternal plasma levels. A similarly efficient barrier exists for the brain, where levels of radioactivity comparable to those noted in the embryo were observed (Gibson et al. 1972). Metabolic pathway involves oxidation of the side chain and reduction of a nitro group, and, mainly in rabbits, conjugation with glucuronic acid (Ernst and Bar 1964). Excretion is almost complete within 72 hrs, with urine being the main route of excretion (more than 70% in dermally treated adult rats - Hall et al. 1992; approx. 65% after a single oral dose in rats, a little less, ca. 40% in mice - Bandal et al. 1972). Less than 3% of unchanged dinoseb could be detected in the 24-h urine of treated rats and rabbits (Ernst and Bar 1964), and detection of dinoseb in urine from dermally or i.v. treated rats was minimal (Hall et al. 1992). Toxicokinetic data in mice and pregnant mice showed that Tmax in the embryo was much shorter when dinoseb was administered via intraperitoneal injection than by oral administration (8 minutes compared to 12 hours), with radioactivity (associated to dinoseb or its metabolites) already detectable in the embryo within 1 minuteafter i.p. injection, but not earlier than 30 minutes following oral administration. In the mothers, dinoseb administered i.p. was absorbed 40 times faster than after oral administration (Gibson et al. 1972). Differences in kinetics were considered to be a possible cause of the differences in findings in teratogenicity studies using different routes of exposure.  Dinoseb was found to cause specific teratogenic effects (microphthalmia) in rats and rabbits by dietary and dermal routes of exposure for the mothers (Giavini et al. 1986, Johnson et al. 1988), or transient nephropathies following i.p. injection on days 11-13 of pregnancy (McCormack et al. 1980). These effects were not seen following single daily doses by oral gavage (Giavini et al. 1986).