Abstract
Tebuconazole (TEB) is a widely used triazole fungicide, but the toxicokinetics of its human metabolites are not fully described. For proper interpretation of biological monitoring data, knowledge on the metabolism and elimination of the compound is required. A human volunteer study was performed with the aim to describe the time courses of urinary excretion after controlled oral and dermal administration of TEB. Six healthy volunteers (three males and three females) received on separate occasions a single oral dose of 1.5 mg of TEB and a single dermal dose of 2.5 mg during 1 h. In addition to a pre-exposure urine sample, complete urine voids were collected over 48 h post-administration. The main metabolite hydroxy-tebuconazole (TEB-OH) was quantified in each urine sample. Peak excretion rates after oral and dermal administration were reached after 1.4 and 21 h, mean elimination half-lives were 7.8 and 16 h, and recoveries within 48 h were 38% and 1%, respectively. The time courses of excretion were compared to simulations with an established physiologically based toxicokinetic model for TEB that was extended with a parallel model for TEB-OH. Overall, TEB-OH was rapidly excreted into urine after oral exposure, and renal elimination was considerably slower after dermal exposure. Urinary time courses between individuals were similar. The model predictions were in good agreement with the observed time courses of excretion.
Highlights
Tebuconazole (TEB) is a widely applied triazole fungicide used against mildew, brown rot blossom, twig blight, dry rot, leaf spots, and as a growth regulator (Bowen et al 1997; Child et al 1993; Larena et al 2005; Mohapatra et al 2010; Rademacher 2000; Zhang et al 2010)
This study provides new insights into the toxicokinetics of TEB following controlled oral and dermal administration as determined by the excreted fractions and time courses of its main metabolite TEB-OH in urine, the accompanying toxicokinetic parameters, and a comparison with a physiologically based toxicokinetic (PBTK) model for TEB
The average fraction of the dose in humans excreted as urinary metabolite in our volunteer study was higher compared to that in animals, as only TEBOH was already recovered for 38% in urine after 48 h
Summary
Tebuconazole (TEB) is a widely applied triazole fungicide used against mildew, brown rot blossom, twig blight, dry rot, leaf spots, and as a growth regulator (Bowen et al 1997; Child et al 1993; Larena et al 2005; Mohapatra et al 2010; Rademacher 2000; Zhang et al 2010). TEB belongs to the group of triazole fungicides that interact with the enzyme 14-α-demethylase, which plays a role in the sterol biosynthetic pathways in eukaryotes (Bowen et al 1997; Sun et al 2011). TEB is one of the most frequently applied fungicides in the European Union (EC 2007). In 2009, TEB was approved in Europe, following a peer review of the risk assessment documentation by the European Food and Safety Authority (EFSA). EFSA stated that the risk assessment was incomplete, TEB is
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