TOXICOKINETICS OF P-TERT-OCTYLPHENOL IN MALE WISTAR RATS

Only weak oestrogenic activity has been reported for p-alkylphenols co mpared with the physiological hormone 17 beta-estradiol. Despite the l ow potency there is concern that due to bioaccumulation oestrogenicall y efficient blood levels could be reached in humans exposed to trace l evels of p-alkylphenols. To address these concerns, toxicokinetic stud ies 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 singl e 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 similar to 1970 ng/ml immediately after a single intravenous appli cation, 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 r apid initial uptake from the gastrointestinal tract; maximal blood lev els reached 40 and 130 ng/ml after applications of 50 and 200 mg/kg, r espectively. Using the area under the curve (AUG) of blood concentrati on vs time, low oral bioavailabilities of 2 and 10% were calculated fo r the 50 and 200 mg/kg groups, respectively. OP toxicokinetics after r epeated administration was investigated in male Wistar rats receiving daily gavage administrations of 50 or 200 mg OP/kg body wt for 14 cons ecutive days. Profiles of OP blood concentration vs time determined on day I and day 14 were similar, indicating that repeated oral gavage a dministration did not lead to increased blood concentrations. Another group of rats received OP via drinking water saturated with OP(similar to 8 mg/l, corresponding to a mean daily dose of similar to 800 mu g/ kg) over a period of up to 28 days. OP was not detected in ally blood sample from animals treated via drinking water (detection limit was 1- 5 ng/ml blood). OP concentrations were also analysed in tissues obtain ed from the repeated gavage (14 days) and drinking water groups (14 an d 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 an d 7 ng/g tissue, respectively. OP was not detected in the other tissue s analysed from this group. In the 200 mg/kg group. OP was found in al l tissues analysed except testes (fat, liver, kidney, muscle, brain an d lung had average concentrations of 1285, 87, 71, 43, 9 and 7 ng/g ti ssue, respectively). OP was not detected in tissues of animals receivi ng OP via drinking water for 14 or 28 days, except in muscle and kidne y tissue of one single animal receiving OP for 14 days. Using rat live r fractions it was demonstrated that OP was conjugated via glucuronida tion and sulphation in vitro, A V-max of 11.24 nmol/(min mg microsom al protein) and a K-m of 8.77 mu mol/l were calculated for enzyme-cata lysed OP glucuronidation. For enzyme-catalysed sulphation, a V-max of 2.85 nmol/(min mg protein) and a K-m of 11.35 mu mol/l were calculat ed, The results indicate that OP does ndt bioaccumulate in rats receiv ing low oral doses, in agreement with the hypothesis of a rapid first- pass elimination of OP by the liver after oral ingestion, via glucuron idation and sulphation. Only if these detoxification pathways are satu rated may excessive doses lead to bioaccumulation.