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首页> 外文会议>Annual conference of the International Society of Exposure Science >Human metabolism of the biocidal compounds methylisothiazolinone and chloromethylisothiazolinone: excretion kinetics of N-methylmalonamic acid in urine
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Human metabolism of the biocidal compounds methylisothiazolinone and chloromethylisothiazolinone: excretion kinetics of N-methylmalonamic acid in urine

机译：人体杀生物化合物甲基异噻唑啉酮和氯甲基异噻唑啉酮的人体代谢：尿液中N-甲基丙二酸的排泄动力学

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Introduction: Methylisothiazolinone (MIT) and the mixture of Chloromethylisothiazolinone (CIT) and MIT (CIT/MIT (3:1)) are important biocidal active substances (ASs) and are used widespread as preservative agents in industrial applications, cosmetic and household products. Both substances have skin-sensitizing properties and are well absorbed orally and dermally. An increasing frequency of contact allergies to both MIT and CIT/MIT (3:1) in recent years has raised concerns about the use of these biocides. Human biomonitoring might help to evaluate the extent of exposure to MIT and CIT/MIT (3:1) in the general population and to elucidate main exposure pathways. The main urinary metabolite of MIT and CIT in rats was reported to be N-methylmalonamic acid (NMMA). However, data on human metabolism of both substances and kinetics of urinary excretion of NMMA are lacking. Therefore, it was the aim of the present study to fill this gap by the investigation of the urinary excretion of NMMA after oral dosage of isotopically labelled MIT and CIT to human volunteers. Methods: Four volunteers (2 m/2 f) received one dosage (2 mg) of 13C3-MIT and d3-CIT separately and at least 2 weeks apart. Consecutive urine samples were collected over 48 h. For the determination of urinary NMMA, a previously developed GC/MS/MS-method was applied. The study has been reviewed and approved by the institutional review board of the RWTH Aachen University (EK 336/14). Results: Both substances are rapidly metabolized in humans. The mean creatinine-corrected peak excretions of urinary NMMA from four dosings were 2.5 h and 2.9 h after oral dosage of 13C3-MIT and d3-CIT, respectively. The mean urinary half-lives of excretion of labelled NMMA were determined to be 6.1 h and 7.6 h for 13C3-MIT and d3-CIT, respectively. With respect to MIT, mean excretion of NMMA within 48 h accounts for 23.7 % (18-30.9%) of the dose. Concerning CIT, urinary NMMA accounts for 13.3 % (10.9- 15.9 %) of the dose with more than 90 % excreted within the first 24 h. No gender differences in toxikokinetics were observed. Conclusion: The present study is the first to investigate human metabolism of the biocidal compounds MIT and CIT. The results of this study confirm rapid metabolism of both substances and the urinary excretion of NMMA as major human metabolite and potential biomarker of exposure. The kinetic data obtained in this study might be useful for exposure assessment in the general population.
机译：简介：甲基异噻唑啉酮（MIT）以及氯甲基异噻唑啉酮（CIT）和MIT的混合物（CIT / MIT（3：1））是重要的杀菌活性物质（ASs），在工业应用，化妆品和家用产品中广泛用作防腐剂。两种物质均具有皮肤敏感特性，并且可以通过口服和经皮肤很好地吸收。近年来，对麻省理工学院和CIT / MIT的接触过敏的频率越来越高（3：1），引起了人们对使用这些杀生物剂的担忧。人体生物监测可能有助于评估普通人群对MIT和CIT / MIT（3：1）的接触程度，并阐明主要的接触途径。据报道，MIT和CIT在大鼠中的主要尿代谢物是N-甲基丙二酸（NMMA）。但是，缺乏有关人类体内两种物质代谢和NMMA尿排泄动力学的数据。因此，本研究的目的是通过对人类志愿者口服同位素标记的MIT和CIT后研究NMMA的尿排泄来填补这一空白。方法：四名志愿者（2 m / 2 f）分别接受一剂（2 mg）的13C3-MIT和d3-CIT，间隔至少2周。在48小时内收集连续尿液样本。为了测定尿液中的NMMA，使用了以前开发的GC / MS / MS方法。这项研究已经亚琛工业大学的机构审查委员会（EK 336/14）进行了审查和批准。结果：两种物质均在人体中快速代谢。口服13C3-MIT和d3-CIT后，四个剂量的尿NMMA的平均肌酐校正峰值排泄分别为2.5 h和2.9 h。对于13C3-MIT和d3-CIT，标记NMMA排泄的平均尿半衰期分别确定为6.1小时和7.6小时。对于MIT，NMMA在48小时内的平均排泄量占剂量的23.7％（18-30.9％）。关于CIT，尿液NMMA占剂量的13.3％（10.9-15.9％），在最初的24小时内排泄了90％以上。没有观察到毒代动力学的性别差异。结论：本研究是第一个研究杀虫剂MIT和CIT对人体代谢的研究。这项研究的结果证实了这两种物质的快速代谢和NMMA的尿排泄是人类主要的代谢产物和潜在的生物标志物。在这项研究中获得的动力学数据可能对一般人群的暴露评估有用。

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