Vol. 31, Issue 2, 168-178, February 2003

In Vivo Metabolic Fate of the Xeno-Estrogen 4-n-Nonylphenol in Wistar Rats

Daniel Zalko, Rémi Costagliola, Céline Dorio, Estelle Rathahao, and Jean-Pierre Cravedi

Institut National de la Recherche Agronomique, Unité Mixte Recherche Xénobiotiques, Toulouse, France

The distribution and the metabolic fate of 4-n-nonylphenol were investigated in male and female Wistar rats dosed orally with 1 µg/kg ("low-dose") or 10 mg/kg ("high-dose") labeled 4-n-nonylphenol. Following a 4-day metabolic balance study, neither the distribution pattern nor the residual levels of 4-n-nonylphenol were found to be different between groups, and no unexpected tissue-specific accumulation of 4-n-nonylphenol was detected. Most of the radioactivity was eliminated in urine, and consisted of hydrophilic metabolites very likely resulting from extensive -oxidation of the nonyl side chain and from the conjugation of the phenol to sulfate or to glucuronic acid. Traces of ring-hydroxylated nonylphenol were also characterized. Fecal excretion was mainly associated with unchanged 4-n-nonylphenol and with side chain hydroxylated 4-n-nonylphenol. Experiments carried out in pregnant rats exposed to a low-dose of 4-n-nonylphenol from day 3 to day 19 of gestation demonstrated similar metabolic pathways for this xeno-estrogen. Very limited amounts, if any, of non metabolized 4-n-nonylphenol did reach fetuses. The oxidative metabolism of 4-n-nonylphenol leads to the formation of both ring-hydroxylated and side chain hydroxylated metabolites. The latter metabolic pathway may be a major metabolic pathway for branched 4-nonyl-phenols and may be a clue to understand their biological activity.