Urinary excretion kinetics of the metabolite N-methylmalonamic acid (NMMA) after oral dosage of chloromethylisothiazolinone and methylisothiazolinone in human volunteers
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Methylisothiazolinone (MI) as well as the mixture of chloromethylisothiazolinone/methyl-iso-thiazolinone (MCI/MI, 3:1) are widespread biocides used in personal care products with potential consumer exposure. Their use is currently under discussion because of rising rates of skin sensitization against these substances in the general population. We have examined the human metabolism of methylisothiazolinone and chloromethylisothiazolinone after oral dosage of stable isotope-labelled analogues. Four human volunteers received 2 mg of labelled MI and MCI separately and at least 2 weeks apart. Consecutive and complete urine samples were collected over 48 h and were examined for the content of N-methylmalonamic acid (NMMA), a previously reported animal metabolite. NMMA represented 23.7 and 13.3% of the dose excreted in urine after dosage of MI and MCI, respectively, with more than 90% excreted within the first 24 h. Excretion of NMMA was rapid with mean half-lives of 6.1 and 7.6 h for MI and MCI, respectively. We have for the first time determined important human toxicokinetic data for the biocides MI and MCI that might be of relevance in future exposure and risk assessments.
KeywordsBiocide Human metabolism Human biomonitoring Toxicokinetics
The development of the analytical method and its first application in a human metabolism study are part of a large-scale 10-year project on the advancement of human biomonitoring in Germany. This project is a cooperation agreed in 2010 between the German Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety (BMUB) and the Verband der Chemischen Industrie e.V. (German Chemical Industry Association—VCI) and is managed by the German Environmental Agency (UBA). In this cooperation project, the analytical method development and the human metabolism study are financed by the Chemie Wirtschaftsförderungsgesellschaft mbH by a grant to the University hospital of RWTH Aachen University. Experts from governmental scientific authorities, industry and science closely accompany and advise the project in selecting substances and developing methods.
Compliance with ethical standards
The study design was in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Approval for the study protocol was obtained from the Ethics Commission of the Faculty of Medicine of the RWTH Aachen University, Germany (Reg. no. EK 336/14). Written informed consent was obtained from all individual participants included in the study.
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