Assessment of Specific Target Organ Toxicity Endpoint for the Registration, Evaluation and Authorisation of Chemicals, Regulation (EC) No. 1907/2006 (REACH): Four inorganic Manganese Oxides : August 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 nervous system is the target organ. This review focusses and summarizes studies on nonhuman mammalian inhalation or oral exposure to the following four forms of manganese: manganese monoxide (MnO), manganese dioxide (MnO2), manganese tetroxide (Mn3O4), and manganese carbonate (MnCO3).

Separate literature searches using PubMed were conducted for each chemical form and yielded 49, 245, 33, and 2 unique citations in PubMed for the monoxide, dioxide, tetroxide, and carbonate forms, respectively. 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  21 days, included oral or inhalation exposure to one of the manganese compounds under review, and reported one or more neurotoxicity endpoints including neurobehavior, neurochemistry or neuropathology. A total of 1, 4, 2, and 1 study met the inclusion criteria for this review for the monoxide, dioxide, tetroxide, and carbonate forms, respectively.

The data available for each of the forms of manganese forms addressed in this review is limited, and robust studies exploring a wide range of relevant neurological outcomes and dose-response relationships are sparse. Most changes seen in the reviewed studies involved alterations in spontaneous motor activity or changes in regional brain dopamine concentrations. For example, rhesus monkeys exposed to either air or MnO at 30 mg Mn/m3 for 6 hrs/day; 5 days/week for 2 years was associated with reduced caudate and globus pallidal dopamine concentrations and increased putamen and globus pallidus manganese concentrations. Dietary exposure to MnO2 was associated with increased cerebral cortex manganese concentrations, reduced growth rate, decreased end of exposure spontaneous motor activity, and reduced striatal, hypothalamic, and midbrain dopamine concentrations. Two rodent inhalation studies with MnO2 also reported altered motor activity and brain manganese concentrations in manganese-exposed animals. Motor activity was reduced in mice given Mn3O4 in the diet. Subchronic (9-month) inhalation Mn3O4 did not affect electromyographic activity or limb tremor in either rats or monkeys. Limited evidence of MnCO3-induced neurotoxicity in mice is provided by one year-long dietary study. Exposure of mice to MnCO3 was associated with increased cerebral cortex manganese concentrations, reduced growth rate, decreased spontaneous motor activity, and reduced hypothalamic dopamine concentrations.

Data available for manganese dioxide is limited, however, the number of studies evaluated meet the criteria for classification by weight of evidence (i.e., a minimum of two separate study records for the property). Depending upon the neurologic outcome examined, the individual studies provided conflicting evidence for an effect, making it difficult to draw a clear reliable classification with regards to neurotoxicity.

Insufficient studies were available for either the oxide, tetroxide, or carbonate forms of manganese to classify these compounds. Some of the outcomes reported for these compounds are cause for concern, though in some cases effects did not reach statistical significance. 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. This has not been met for the oxide, tetroxide, or carbonate forms of manganese, hence data for these substances are insufficient for a classification via the weight of evidence approach. Therefore, using the data available for these 3 oxides, a STOT classification of any kind cannot be assigned. However, using a precautionary approach could be used alongside the REACH Guidance and CLP guidance on classification by weight-of-evidence, to classify a Specific Target Organ Toxicity Catego