Metabolism and elimination of methyl, iso- and n-butyl paraben in human urine after single oral dosage

Abstract

Parabens are used as preservatives in personal care and consumer products, food and pharmaceuticals. Their use is controversial because of possible endocrine disrupting properties. In this study, we investigated metabolism and urinary excretion of methyl paraben (MeP), iso-butyl paraben (iso-BuP) and n-butyl paraben (n-BuP) after oral dosage of deuterium-labeled analogs (10 mg). Each volunteer received one dosage per investigated paraben separately and at least 2 weeks apart. Consecutive urine samples were collected over 48 h. In addition to the parent parabens (free and conjugated) which are already used as biomarkers of internal exposure and the known but non-specific metabolites, p-hydroxybenzoic acid (PHBA) and p-hydroxyhippuric acid (PHHA), we identified new, oxidized metabolites with hydroxy groups on the alkyl side chain (3OH-n-BuP and 2OH-iso-BuP) and species with oxidative modifications on the aromatic ring. MeP represented 17.4 % of the dose excreted in urine, while iso-BuP represented only 6.8 % and n-BuP 5.6 %. Additionally, for iso-BuP, about 16 % was excreted as 2OH-iso-BuP and for n-BuP about 6 % as 3OH-n-BuP. Less than 1 % was excreted as ring-hydroxylated metabolites. In all cases, PHHA was identified as the major but non-specific metabolite (57.2–63.8 %). PHBA represented 3.0–7.2 %. For all parabens, the majority of the oral dose captured by the above metabolites was excreted in the first 24 h (80.5–85.3 %). Complementary to the parent parabens excreted in urine, alkyl-chain-oxidized metabolites of the butyl parabens are introduced as valuable and contamination-free biomarkers of exposure.

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Correspondence to Holger M. Koch.

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Fig. 1

ESI-negative Q3 mass spectra of D4-2OH-iso-BuP, D4-3OH-n-BuP, 2OH-iso-BuP and 3OH-n-BuP. (PDF 22 kb)

Table 1

Gradient program for cleanup and enrichment and chromatographic separation, solvent A: 99.95 % water and 0.05 % acetic acid, solvent B: 99.95 % acetonitrile and 0.05 % acetic acid, solvent C: ammonium bicarbonate buffer 3 mM. (PDF 85 kb)

Table 2

MRM parameters for mass spectrometric detection. (PDF 157 kb)

Table 3

Intraday and inter-day precision of the method calculated by analysis of self-prepared quality control materials with two different concentration levels and quantification limits of this method. Precision and accuracy calculated from analysis of eight different urine samples with varying creatinine concentrations and two or three different spiking levels. (PDF 120 kb)

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Moos, R.K., Angerer, J., Dierkes, G. et al. Metabolism and elimination of methyl, iso- and n-butyl paraben in human urine after single oral dosage. Arch Toxicol 90, 2699–2709 (2016). https://doi.org/10.1007/s00204-015-1636-0

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Keywords

  • Parabens
  • Human metabolism
  • Urinary metabolites
  • Human biomonitoring