Hazard classification of manganese salts based on animal neurotoxicity data: case study for specific target organ toxicity – repeated exposure (STOT-RE)

Specific Target Organ Toxicity – Repeated Exposure (STOT-RE) is a hazard class in both Globally Harmonized System and Classification, Labelling and Packaging (CLP) Regulation in the European Union (EU) legislation on hazard classification labeling and packaging of substances and mixtures. This legislation, used for the chemical safety assessment under the EU Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), evaluates long-term exposure of chemicals on human or animals and designates three categories of classification – STOT RE 1 (potential to produce significant toxicity to humans); STOT RE 2 (presumed to be toxic to humans), or not classified. Human epidemiologic studies identified neurologic effects as the most sensitive adverse health effect following repeated manganese (Mn) exposure. However, there are inadequate human studies to assess the neurotoxicity and STOT-RE classification of the chloride, sulfate, and nitrate forms of Mn. This review summarizes peer-reviewed studies with original data identified from searches of PubMed and OECD studies submitted as part of the REACH information requirement. This review included peer-reviewed studies that exhibited a duration of ≥21 days, including oral or inhalation exposure, and reported neurobehavioral, neurochemical or neuropathologic outcomes. A total of 75, 6, and 0 investigations met the inclusion criteria for this review for the chloride, sulfate, and nitrate forms of Mn, respectively. Based upon retrieved data or read-across principles a proposed classification of these Mn salts, following repeated oral or inhaled exposure, is STOT RE 2, target organ, the brain.

特定靶器官毒性-重复暴露（Specific Target Organ Toxicity – Repeated Exposure，STOT-RE）是《全球化学品统一分类和标签制度》（Globally Harmonized System，GHS）与欧盟《化学品分类、标签和包装法规》（Classification, Labelling and Packaging，CLP）这两部规范物质和混合物危害分类、标签与包装的立法所界定的危害类别。该法规用于欧盟《化学品注册、评估、授权和限制法规》（Registration, Evaluation, Authorisation and Restriction of Chemicals，REACH）框架下的化学品安全评估，用于评估化学品对人类或动物的长期暴露危害，并划分三类危害等级：STOT RE 1类（对人类具备显著毒性潜能）、STOT RE 2类（推定对人类具有毒性），或未分类。人群流行病学研究显示，反复暴露于锰（Manganese，Mn）后，神经系统损害是最敏感的不良健康效应。然而，现有针对锰的氯化物、硫酸盐及硝酸盐形态的神经毒性与STOT-RE分类的人群研究证据仍不充分。本综述汇总了从PubMed数据库检索得到的同行评议原创研究，以及作为REACH信息要求提交的经合组织（Organisation for Economic Co-operation and Development，OECD）研究。本综述纳入的研究需满足暴露时长≥21天、暴露途径为经口或吸入，且报告了神经行为、神经化学或神经病理学相关结局指标。针对锰的氯化物、硫酸盐及硝酸盐形态，分别有75项、6项及0项研究符合本综述的纳入标准。基于检索到的试验数据或交叉参照（read-across）原则，经反复经口或吸入暴露后，建议将此类锰盐的STOT-RE分类定为STOT RE 2类，靶器官为大脑。