Comparative pharmacokinetics and subacute toxicity of di(2-ethylhexyl) phthalate (DEHP) in rats and marmosets: extrapolation of effects in rodents to man

Abstract

Certain phthalate esters and hypolipidemic agents are known to induce morphological and biochemical changes in the liver of rodents, which have been associated with an increased incidence of hepatocellular tumors in these species. There is evidence that hypolipidemic agents do not induce these effects in either subhuman primates or man. The oral and intraperitoneal administration of di(2-ethylhexyl) phthalate (DEHP) to the marmoset monkey at doses up to 5 mmole DEHP/kg body weight/day for 14 days did not induce morphological or biochemical changes in the liver or testis comparable with those obtained in rats given the same amount of DEHP. In the marmoset, the excretion profile of [14C]-DEHP following oral, IP, and IV administration and the lower tissue levels of radioactivity demonstrated a considerably reduced absorption in this species compared to the rat. The urinary metabolite pattern in the marmoset was in many respects qualitatively similar to but quantitatively different from that in the rat; the marmoset excreted principally conjugated metabolites derived from omega- 1 oxidation. The pharmacokinetic differences between these two species indicate that the tissues of the marmoset are exposed to a level of DEHP metabolites equivalent to the complete absorption of a dose of Ca. 0.1 to 0.25 mmole DEHP/kg body weight/day without significant toxicological effects. These exposure levels are at least 100-fold greater than the worst estimates of incidental human exposure (ca. 0.0015 mmole/kg/day). They are comparable with the human therapeutic dose of many hypolipidemic drugs (ca. 0.15 mmole/kg/day), a dose at which it is claimed that there is an absence of morphological or biochemical changes to human or subhuman primate liver.(ABSTRACT TRUNCATED AT 250 WORDS)