Absorption, bioavailability, and metabolism of para-nonylphenol in the rat.
To better interpret the responses to para-nonylphenol (NP; CASRN84852-15-3) in in vivo toxicity studies, including estrogen-like activity, the bioavailability of 14C-radiolabelled NP has been determined in male and female CD rats following either single oral doses of 10 and 100 mg/kg, single i.v. doses of 10 mg/kg, or repeated daily oral doses of 10 mg/kg for up to 14 d. Up to 80% of an oral dose of NP was rapidly absorbed, the remainder being excreted unchanged in faeces. Excretion was largely complete within 24 h of dosing. Following absorption, NP was metabolised in the liver, with the majority of the metabolites excreted in bile, mainly as glucuronide conjugates. Unchanged NP was found only in bile and urine from female rats given a 100 mg/kg dose, indicating that metabolic saturation occurred. Following repeated dosing, steady state was reached within 7 d. There was no evidence of significant accumulation into tissue compartments nor of a significant change in clearance or the metabolite profiles in urine. These data suggest that the estrogen-like effects observed in toxicity studies with female rats at oral NP doses of approximately 50 mg/kg/d and greater are a result of the increased bioavailability of NP which occurs following metabolic saturation.
Green
Trevor
T
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK. trevor.green@syngenta.com
Swain
Cindy
C
Van Miller
John P
JP
Joiner
Ronald L
RL
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D010636:Phenols / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D010636:Phenols; C041594:4-nonylphenol