Abstract
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 β-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.
Footnotes
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This study was partly supported by the “Environnement et Santé” program of the French Ministry of the Environment (EN97C17) and by the “Pôle de sécurité sanitaire des aliments” (Région Midi-Pyrénées, France).
- Abbreviations used are::
- NP
- nonylphenol
- NP-PE
- nonylphenol polyethoxylate
- 4-n-NP
- 4-n-nonylphenol
- HPLC
- high performance liquid chromatography
- LC
- liquid chromatography
- FAS
- formic acid solution
- ESI
- electrospray ionization
- MS
- mass spectrometry
- RT
- retention time
- ppb
- part per billion
- Received August 15, 2002.
- Accepted October 31, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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