毒理性
甲基异噻唑啉酮（MIT）形成无色棱镜。它被用作个人护理和化妆品产品中的防腐剂，例如驻留型产品，即手和身体乳液和保湿剂，防晒乳液以及一些冲洗型产品如洗发水、表面活性剂和调理剂。此外，MIT是一种抗菌剂，用于控制冷却水系统、燃料储存罐、纸浆和造纸厂水系统、石油提取系统和其他工业环境中的粘泥形成细菌、真菌和藻类。它还用于控制木材产品上的霉菌、霉斑和蓝变。它在美国注册使用，但批准的农药用途可能会定期更改，因此必须咨询联邦、州和地方当局以获取当前批准的用途。它通常与5-氯-2-甲基-4-异噻唑啉-3-酮结合使用。人类暴露和毒性：体外研究表明，短暂暴露于MIT对培养的神经元具有高度毒性，但对胶质细胞无影响。这种生物杀灭剂的毒性作用依赖于锌，并需要通过12-脂氧合酶介导的途径激活p44/42细胞外信号调节激酶（ERK）。细胞死亡过程还涉及NADPH氧化酶的激活、活性氧种类的产生、DNA损伤和聚(ADP-核糖)聚合酶过度激活，所有这些都在ERK磷酸化下游发生。化妆品成分审查专家小组注意到了体外神经毒性的证据，但得出结论，在许多体内研究中，包括亚慢性、慢性、生殖和发育动物研究，都没有发现任何神经毒性，这表明MIT在化妆品中使用不会具有神经毒性。尽管认识到MIT在动物和人体研究中是一种致敏剂，但专家组得出结论，存在阈值剂量反应，并且含有MIT浓度在100 ppm（0.01%）或以下的化妆品配方不太可能带来致敏风险。因此，MIT可以作为防腐剂安全地用于化妆品，直至该浓度。动物研究：将大鼠暴露于MIT，剂量水平高达2.64 mg/立方米，通过吸入方式持续90天，导致高剂量雄性体重下降，两性在高剂量水平下的体重增长减少。没有观察到与治疗相关的死亡，并且在血液学、临床化学、眼科显微镜检查和大体病理参数中没有观察到可归因于治疗的影响。当大鼠通过饮水暴露于这种化学物质（高达225 ppm）3个月时，也观察到了类似的观察结果。在大鼠的致癌性研究中，没有观察到任何性别肿瘤发生率的增加。MIT在大鼠中没有发现具有胚胎毒性、胎儿毒性和致畸性。MIT在TA100的Ames试验中，即使在低至0.0005 uL/板的浓度下，没有代谢激活也呈阳性。TA100有激活和所有其他菌株，无论是否有代谢激活，均为阴性。MIT在鼠标淋巴瘤基因突变试验中，剂量水平低至1 nL/mL（无代谢激活）和1.22 nL/mL（有代谢激活）时呈阳性。在果蝇性连锁隐性致死试验中观察到阴性结果。MIT没有显著增加小鼠骨髓细胞结构染色体畸变的频率，也没有在体外诱导大鼠原代肝细胞的不定期DNA合成。然而，在大鼠皮层神经元的体外研究中发现，MIT显著抑制了神经突生长，并得出结论，长期暴露于低剂量的MIT和相关化合物可能对发育中的神经系统产生有害影响。
IDENTIFICATION AND USE: Methylisothiazolinone (MIT) forms colorless prisms. It is used as preservative in personal care and cosmetics products such as leave-on products, namely hand and body lotions and moisturizers, sun tanning lotions and some rinse-off products like shampoos, surfactants and conditioners. In addition, MIT is an antimicrobial used to control slime-forming bacteria, fungi, and algae in cooling water systems, fuel storage tanks, pulp and paper mill water systems, oil extraction systems, and other industrial settings. It is also used to control the growth of mold, mildew, and sapstain on wood products. It is registered for use in the USA but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses. It is often used in a combination products with 5-chloro-2-methyl-4-isothiazolin-3-one. HUMAN EXPOSURE AND TOXICITY: In vitro studies show that a brief exposure to MIT is highly toxic to cultured neurons but not to glia. The toxic actions of this biocide are zinc-dependent and require the activation of p44/42 extracellular signal-regulated kinase (ERK) via a 12-lipoxygenase-mediated pathway. The cell death process also involves activation of NADPH oxidase, generation of reactive oxygen species, DNA damage, and overactivation of poly(ADP-ribose) polymerase, all occurring downstream from ERK phosphorylation. The Cosmetic Ingredient Review Expert Panel noted the in vitro evidence of neurotoxicity but concluded that the absence of any neurotoxicity findings in the many in vivo studies, including subchronic, chronic, and reproductive and developmental animal studies, suggests that MIT would not be neurotoxic as used in cosmetics. Although recognizing that MIT was a sensitizer in both animal and human studies, the panel concluded that there is a threshold dose response and that cosmetic products formulated to contain concentrations of MIT at 100 ppm (0.01%) or less would not be expected to pose a sensitization risk. Accordingly, MIT may be safely used as a preservative in cosmetics up to that concentration. ANIMAL STUDIES: The exposure of rats to MIT at dose levels up to 2.64 mg/cu m via inhalation for 90 days resulted in decreased body weight in the high-dose males and decreased body-weight gains in both sexes at the high-dose level. There were no treatment-related deaths, and no effects were observed in the hematology, clinical chemistry, ophthalmoscopic, and gross pathology parameters that could be attributed to treatment. Similar observations were made when rats were exposed to this chemical (up to 225 ppm) in drinking water for 3 months. In the carcinogenicity study in rats there was no treatment-related increase in the incidence of any tumor in either sex. MIT was not found to be fetotoxic, embryotoxic, or teratogenic in rats. MIT was positive in the Ames assay in TA100 at concentrations as low as 0.0005 uL/plate without metabolic activation. TA100 with activation and all other strains with and without metabolic activation were negative. MIT was positive in the mouse lymphoma gene mutation assay at dose levels as low as 1 nL/mL without metabolic activation and at 1.22 nL/mL with metabolic activation. Negative results were observed in the Drosophila sex-linked recessive lethal assay. MIT did not cause a significant increase in the frequency of structural chromosome aberrations in mouse bone marrow cells in vivo, and did not induce unscheduled DNA synthesis in primary rat hepatocytes in vitro. However, in vitro study in rat cortical neurons found that MIT induced a dramatic inhibition of neurite outgrowth, and concluded that prolonged exposure to low levels of MIT and related compounds may have damaging consequences to the developing nervous system.
来源:Hazardous Substances Data Bank (HSDB)
