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.