Kinetics of di-(2-ethylhexyl) phthalate in immature and mature rats and effect on testis

Abstract

The testicular response of di-(2-ethylhexyl) phthalate (DEHP), as well as the kinetics of DEHP and its primary metabolite mono-(2-ethylhexyl) phthalate (MEHP), were studied in immature and mature rats. After 14 daily oral doses of 1.0 g DEHP/kg body weight to 25, 40 and 60-day-old rats, testicular damage was observed in the youngest age group only. DEHP was not found to any significant extent in the peripheral plasma after an oral dose of 1.0 g DEHP/kg body weight. High plasma levels of MEHP were found, with maximal plasma concentrations ranging from 48 to 152 micrograms/ml. The in vitro plasma protein binding of MEHP was extensive, approximately 98%, in all age groups and no age-related difference in the elimination half-life was observed. The amount of DEHP-derived material excreted in urine was twice as high in 25 as in 60-day-old rats. The mean area under the plasma concentration-time curve of MEHP was also significantly larger in 25 than in 40 and 60-day-old rats. These observations suggest that the extent of absorption, and hence total exposure to MEHP and its metabolites, is higher in young than in more mature rats after oral administration of DEHP. It seems probable that this finding is relevant to the age-related difference in the toxic effects on the testis.