Toxicokinetics of p-tert-octylphenol in male Wistar rats

Only weak oestrogenic activity has been reported for p-alkylphenols compared with the physiological hormone 17 beta-estradiol. Despite the low potency, there is concern that due to bioaccumulation oestrogenically efficient blood levels could be reached in humans exposed to trace levels of p-alkylphenols. To address these concerns, toxicokinetic studies with p-tert-octylphenol [OP; p-(1,1,3,3-tetramethylbutyl)-phenol] as a model compound have been conducted in male Wistar rats. OP blood concentrations were determined by GC-MS in rats receiving either single oral (gavage) applications of 50 or 200 mg OP/kg body wt or a single intravenous injection of 5 mg/kg body wt. The OP blood concentration was approximately 1970 ng/ml immediately after a single intravenous application, decreased rapidly within 30 min, and was no longer detectable 6-8 h after application. The curve of blood concentration vs time was used to calculate an elimination half-life of 310 min. OP was detected in blood as early as 10 min after gavage administration, indicating rapid initial uptake from the gastrointestinal tract; maximal blood levels reached 40 and 130 ng/ml after applications of 50 and 200 mg/kg, respectively. Using the area under the curve (AUC) of blood concentration vs time, low oral bioavailabilities of 2 and 10% were calculated for the 50 and 200 mg/kg groups, respectively. OP toxicokinetics after repeated administration was investigated in male Wistar rats receiving daily gavage administrations of 50 or 200 mg OP/kg body wt for 14 consecutive days. Profiles of OP blood concentration vs time determined on day 1 and day 14 were similar, indicating that repeated oral gavage administration did not lead to increased blood concentrations. Another group of rats received OP via drinking water saturated with OP (approximately 8 mg/l, corresponding to a mean daily dose of approximately 800 micrograms/kg) over a period of up to 28 days. OP was not detected in any blood sample from animals treated via drinking water (detection limit was 1-5 ng/ml blood). OP concentrations were also analysed in tissues obtained from the repeated gavage (14 days) and drinking water groups (14 and 28 days). In the 50 mg/kg group, low OP concentrations were detected in fat and liver from some animals at average concentrations of 10 and 7 ng/g tissue, respectively. OP was not detected in the other tissues analysed from this group. In the 200 mg/kg group, OP was found in all tissues analysed except testes (fat, liver, kidney, muscle, brain and lung had average concentrations of 1285, 87, 71, 43, 9 and 7 ng/g tissue, respectively). OP was not detected in tissues of animals receiving OP via drinking water for 14 or 28 days, except in muscle and kidney tissue of one single animal receiving OP for 14 days. Using rat liver fractions it was demonstrated that OP was conjugated via glucuronidation and sulphation in vitro. A Vmax of 11.24 nmol/(min * mg microsomal protein) and a Km of 8.77 mumol/l were calculated for enzyme-catalysed OP glucuronidation. For enzyme-catalysed sulphation, a Vmax of 2.85 nmol/(min * mg protein) and a Km of 11.35 mumol/l were calculated. The results indicate that OP does not bioaccumulate in rats receiving low oral doses, in agreement with the hypothesis of a rapid first-pass elimination of OP by the liver after oral ingestion, via glucuronidation and sulphation. Only if these detoxification pathways are saturated may excessive doses lead to bioaccumulation.