Urinary excretion kinetics of the metabolite N-methylmalonamic acid (NMMA) after oral dosage of chloromethylisothiazolinone and methylisothiazolinone in human volunteers.

Abstract

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 2mg of labelled MI and MCI separately and at least 2weeks apart. Consecutive and complete urine samples were collected over 48h 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 24h. Excretion of NMMA was rapid with mean half-lives of 6.1 and 7.6h 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.