Toxicity evaluation of main zopiclone impurities based on quantitative structure–activity relationship models and in vitro tests

化学 遗传毒性 毒性 杂质 急性毒性 佐匹克隆 斑马鱼 体外 数量结构-活动关系 药理学 毒理 环境化学 生物化学 立体化学 生物 有机化学 基因 催眠药
作者
Yin Jie,Hairuo Wen,Hua Chen
出处
期刊:Journal of Applied Toxicology [Wiley]
卷期号:43 (2): 230-241 被引量:1
标识
DOI:10.1002/jat.4376
摘要

Toxicity evaluation of main zopiclone impurities can provide a basis for safety assessment and quality standards of zopiclone. In this study, the impurity profile of zopiclone was analyzed using forced degradation and related substances of zopiclone tablets using high-performance liquid chromatography (HPLC). Furthermore, various quantitative structure-activity relationship (QSAR) models were used to compare the toxicity, especially genotoxicity of two main zopiclone degradation impurities, namely, impurity B and 2-amino-5-chloropyridine. The predictive genotoxicity results were verified using an in vitro bacterial reverse mutation (Ames) test. Meanwhile, using zebrafish embryos as an animal model, zopiclone and its main impurities were analyzed at different concentrations, and their effects on zebrafish development, including embryonic teratogenesis and lethality, were examined. The results showed that impurity B and 2-amino-5-chloropyridine were the main degradation impurities of zopiclone; the latter's content increased with increase in the solution storage time. QSAR prediction and in vitro test results confirmed that both impurity B and 2-amino-5-chloropyridine were non-mutagenic and classified in the fifth impurity category. According to ICH M7 guidelines, these could be controlled as general non-mutagenic impurities. The relative toxicity to zebrafish embryo development was the highest for 2-amino-5-chloropyridine, followed by impurity B and zopiclone, and the malformation rate and mortality of embryos were concentration dependent. In conclusion, an increase in the control limit of 2-amino-5-chloropyridine is recommended when the quality standards of zopiclone materials and preparations are revised to ensure safety and quality control. The specific limit value of this impurity should be determined through further evaluation and research.
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