Metabolism and disposition of [¹⁴C]n-butyl-p-hydroxybenzoate in male and female Harlan Sprague Dawley rats following oral administration and dermal application

Abstract

n-Butyl-p-hydroxybenzoate (n-butylparaben, BPB) is an antioxidant used in foods, pharmaceuticals and cosmetics. This study investigated the disposition of ring-labelled [(14)C]BPB in Harlan Sprague Dawley rats, and in rat and human hepatocytes. BPB was rapidly cleared in hepatocytes from rat (t(1/2) = 3-4 min) and human (t(1/2) = 20-30 min). The major metabolites detected in rat hepatocytes were hydroxybenzoic acid and in human hepatocytes were hydroxybenzoic acid and hydroxyhippuric acid. [(14)C]BPB was administered to male rats orally at 10, 100 or 1000 mg/kg, intravenously at 10 mg/kg and dermally at 10 and 100 mg/kg; female rats were administered oral doses at 10 mg/kg. Oral doses of BPB were well-absorbed (>83%) and eliminated chiefly in urine (83-84%); ≤ 1% of the radioactivity remained in tissues at 24 h or 72 h after dosing. About 4% and 8%, respectively, of 100 mg/kg dermal doses were absorbed in 24 h and 72 h, and about 50% of a 10 mg/kg dose was absorbed in 72 h. Metabolites detected in urine included those previously reported, BPB-glucuronide, BPB-sulfate, hydroxybenzoic acid and hydroxyhippuric acid, but also novel metabolites arising from ring hydroxylation followed by glucuronidation and sulfation.

Considerations for estimating daily intake values of nonpersistent environmental endocrine disruptors based on urinary biomonitoring data

“…By oral gavage, Mathews et al (2012) exposed rats to 14 C-BuP at three dose levels and recovered 83-85% of the radioactive dose in urine and 3-6% in feces within 72 h. Faster excretion but similar levels of recovery in urine and feces were observed 72 h after i.v. exposure to 10 mg/kg.…”

“…administration and HBA and butyl-containing metabolites being the major metabolites following oral exposure. Apart from HBA and HHA, several other urinary metabolites were identified, but the amounts of these metabolites including free, sulfated, and glucoronidated BuP were not quantified (Mathews et al 2012). A similar study in rats using 14 C-MeP, -nPrP, and -BuP has recently been conducted (Aubert et al 2012): following oral exposure by gavage, recovery of the administered dose was found to be similar for the three compounds and the results was comparable to the findings of Mathews et al (2012) with complete recovery (urine, feces, and cage wash) after 168 h. Following dermal administration, systemic exposure was found to be highest for the short-chainlength MeP and lowest for the long-chain-length BuP.…”

“…Apart from HBA and HHA, several other urinary metabolites were identified, but the amounts of these metabolites including free, sulfated, and glucoronidated BuP were not quantified (Mathews et al 2012). A similar study in rats using 14 C-MeP, -nPrP, and -BuP has recently been conducted (Aubert et al 2012): following oral exposure by gavage, recovery of the administered dose was found to be similar for the three compounds and the results was comparable to the findings of Mathews et al (2012) with complete recovery (urine, feces, and cage wash) after 168 h. Following dermal administration, systemic exposure was found to be highest for the short-chainlength MeP and lowest for the long-chain-length BuP. Urinary excretion of radioactivity following dermal application of 100 mg/kg was around 20% for MeP and nPrP and around 26% for BuP after 168 h. Also in human, parabens are readily hydrolyzed to HBA and HHA and conjugated with glucoronic and sulfuric acid before excretion, as reviewed by Soni et al (2005).…”

“…In this study, only 0.32% of the dermally applied dose was recovered in urine as the free and glucoronidated compound. However, as shown by Mathews et al (2012) in rats, a large fraction of a topically applied dose corresponding to the dose used by Janjua et al (2008) was recovered in skin as unabsorbed dose (21%), and thus, this needs to be taken into account when trying to back-calculate the concentration of paraben found in urine into an estimated intake/uptake. To obtain valuable knowledge for doing this back-calculation, a study using realistic concentrations of parabens in various topical dosage forms applied to healthy volunteers could be carried out.…”

“…Subsequently, quantification of free and conjugated parabens in urine should be done, as well as quantification of unabsorbed parabens at the dose-site (appropriate use of an animal or an ex vivo model could prove useful for this part of the study). To obtain information about the ratios of metabolites in urine, studies such as the ones performed by Aubert et al (2012) and Mathews et al (2012) but with detailed quantification of the excreted metabolites would be very useful.…”