Abstract
Methylisothiazolinone (MI) as well as the mixture of chloromethylisothiazolinone/methylisothiazolinone [MCI/MI (3:1)] are biocides that are used in a variety of products of every-day life. Due to the skin sensitizing properties of these biocides, their use has come under scrutiny. We have previously examined the human metabolism of MI and MCI after oral dosage of isotope-labelled analogues in human volunteers and confirmed N-methylmalonamic acid to be a major, but presumably unspecific human urinary metabolite. In the present study, we have investigated the urinary kinetics of a mercapturic acid metabolite of MI and MCI using the same set of samples. Four human volunteers received 2 mg of isotopically labelled MI and MCI separately and at least 2 weeks apart. Consecutive urine samples were collected over 48 h and were examined for the content of the (labelled) 3-mercapturic acid conjugate of 3-thiomethyl-N-methyl-propionamide (“M-12”), a known metabolite in rats. On a molar basis, M-12 represented 7.1% (3.0–10.1%) of the dose excreted in urine after dosage of MI. Excretion of this mercapturate was fast with a mean half-life of 3.6 h. Surprisingly, for MCI the mercapturate M-12 represented only 0.13% of the dose excreted in urine. Thus, this biomarker is highly specific for exposures to MI and might be used to distinguish between different exposure patterns of these biocides [use of MI or MCI/MI (3:1)] in the general population.
Highlights
Methylisothiazolinone (MI) and the mixture of chloromethylisothiazolinone/methylisothiazolinone [MCI/MI (3:1)] are biocides that are used for preservation of cosmetic products, water-based paints, cleaning agents, wet wipes or cooling lubricants in occupational settings (Scientific Committee of Consumer Safety 2009, 2016)
In the search for a biomarker of exposure to MI and MCI, we have developed a method for the quantification of N-methylmalonamic acid (NMMA) as the main urinary metabolite of MCI and MI in animal experiments (Schettgen et al 2017) and investigated excretion kinetics of NMMA after oral dosage of isotopically labelled MI and MCI in a human volunteer experiment (Schettgen and Kraus 2017)
While 13C3-M-12 could be quantified in all urine samples obtained after dosage in the 48-h time frame, D 3-M-12 surprisingly could only be determined in the urine samples collected within 24 h after dosage
Summary
Methylisothiazolinone (MI) and the mixture of chloromethylisothiazolinone/methylisothiazolinone [MCI/MI (3:1)] are biocides that are used for preservation of cosmetic products, water-based paints, cleaning agents, wet wipes or cooling lubricants in occupational settings (Scientific Committee of Consumer Safety 2009, 2016) These biocides can both be taken up via skin contact by cosmetics or wet wipes as well as inhalative, e.g. after application of cleaning agents or paints indoors (Lundov et al 2014). Dermatologists have reported an increase in skin sensitizations against MI and MCI/MI (3:1) in the general population in various countries (Schwensen et al 2017) This led to stronger restrictions in the cosmetic use of MI and MCI/MI (3:1), which ended up in a ban of both compounds in leave-on cosmetics (Regulation (EC) No 1003/2014; Regulation (EC) No 2016/1198) and a maximum content
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