Assessment of Specific Target Organ Toxicity Endpoint for the Registration, Evaluation and Authorisation of Chemicals, Regulation (EC) No. 1907/2006 (REACH) MetallicManganese : October 2024

Manganese is an essential trace element with multiple essential physiologic functions. Despite its essential nature, chronic exposure of humans to high levels of manganese may lead to its accumulation in the basal ganglia, resulting in a parkinsonian-like syndrome. Most cases of manganese neurotoxicity in the general population arise from repeated environmental exposure involving ingestion of the metal in drinking water. Occupational exposure to manganese generally occurs predominantly following chronic inhalation. For the purposes of classification of inorganic manganese compounds, there is an abundance of human data from occupational studies for hazard and risk assessment and from animal studies exposed to specific manganese compounds via oral and inhalation routes. Both human epidemiologic and experimental animal studies have identified neurologic effects as the most sensitive adverse health effect. Thus, for purposes of classification under REACH the Brain is the target organ.

A literature search using PubMed was conducted. Studies were screened initially using titles and abstracts followed by full text review. Studies were included if they reported original data, were peer reviewed and published in English, had a non-exposed control group, had a duration of greater 21 days, included oral or inhalation exposure to metallic manganese, and reported one or more neurotoxicity endpoints including neurobehavior, neurochemistry or neuropathology. A total of three studies met the inclusion criteria for this review.

The data available for metallic manganese is limited.  Three inhalation studies (Envigo, 2016; Normandin et al. 2004; St-Pierre et al. 2001) met the inclusion criteria for this review. The studies conducted by Normandin et al. (2004) and St-Pierre et al. (2001) were performed by the same laboratory and shared many experimental design features. Adult male Sprague-Dawley rats were exposed to either air or 3750 µg/m3 of manganese dust for 6 h/day, 5 days/wk for 13 consecutive weeks. After the end of the 13-week exposure, spontaneous motor activity and tissue manganese concentrations were assessed. In both studies inhalation of manganese dust resulted in elevated manganese concentrations in some brain regions. Effects on motor activity were mixed with one study reporting transient changes in motor activity (St-Pierre et al. 2001) with no treatment related effect on activity reported in the other subchronic inhalation study (Normandin et al. 2004).

A third subchronic inhalation study (Envigo, 2016) was also identified. This 13-week inhalation rat study was performed under Good Laboratory Practices (GLP). In this study, male and female Wistar rats were exposed nose-only to metallic manganese at 0, 0.5, 5, and 20 μg Mn/L (nominal concentrations) for 6 h/day, 5 days/wk for 13 consecutive weeks. A four-week recovery group was also included in this study. Neurologic endpoints of interest in this study included performance of a neurologic examination using a functional observational battery (FOB) evaluation of spontaneous motor activity. Measurement of brain weight, and perfusion neuropathology. Regional brain manganese concentrations were also evaluated at the end of the exposure and after the 4-week recovery period. However, controls were not included in these measurements. No treatment-related changes in grip strength or foot splay were noted in the manganese-exposed animals during the FOB. Likewise, manganese exposure did not affect motor activity, brain weight, or resulted in histologic evidence of neuropathology. A trend, of unknown statistical significance, towards a dose-response increase in cortical, pallidal, and striatal manganese concentrations were seen at the end of the exposure in the three manganese exposed groups.

To conclude, with regards to available published literature, insufficient studies were available to classify metallic manganese. REACH Guidance and CLP guidance on classification by weight of evidence suggests a minimum of two separate study records for the property is required for weight-of-evidence classification purposes. However, based on the 13 weeks inhalation exposure study in accordance with GLP and OECD guidelines, a study that met the REACH requirements for classification, no robust treatment related effects were reported. Based on this, metallic manganese cannot be classified for Specific Target organ toxicity.

For more information contact reach@manganese.org