Assessment of Specific Target Organ Toxicity Endpoint for the Registration, Evaluation and Authorisation of Chemicals, Regulation (EC) No. 1907/2006 (REACH): Three inorganic Manganese Salts : August 2024

Manganese (Mn) is an essential trace element with multiple essential physiologic functions. Despite its essential nature, chronic exposure of humans to high levels of Mn leads to its accumulation in the basal ganglia resulting in a parkinsonian-like syndrome. Most cases of Mn neurotoxicity in the general population arise from repeated environmental exposure involving ingestion of the metal in drinking water. Occupational exposure to Mn generally occurs following chronic inhalation. For the purposes of classification of inorganic Mn compounds, there is an abundance of human data from occupational studies for hazard and risk assessment and from animal studies exposed to specific Mn compounds via oral and inhalation routes. Both human epidemiologic and experimental animal studies have identified neurologic effects as the most sensitive adverse health effect. There are inadequate human studies to assess the neurotoxicity of the chloride, sulfate, and nitrate forms of Mn. Therefore, this review summarises studies on nonhuman mammalian inhalation or oral exposure to these three forms of Mn.

Separate literature searches using PubMed were conducted for each chemical form and yielded 609, 33, and 33 unique citations in PubMed for the chloride, sulfate, and nitrate 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 Mn salts under review, and reported one or more neurotoxicity endpoints including neurobehavior, neurochemistry or neuropathology. Effects on behavioural endpoints were restricted to studies with Mn chloride. A total of 75, 6, and 0 studies met the inclusion criteria for this review for the chloride, sulfate, and nitrate forms of Mn, respectively. Unlike either the chloride or sulfate forms of Mn, Mn nitrate is corrosive, which may limit its use in neurotoxicity studies.

Studies involving manganese chloride (MnCl2) were performed in rodents and included drinking water, dietary, oral (gavage), and inhalation studies. The majority of these studies involved ingestion of MnCl2. No clear dose-response relationship between studies and neurobehavioural outcomes was observed with contradictory results reported by several laboratories using similar methods and MnCl2 exposures. Several studies showed that changes in distinct behavioural outcomes were reversible or transient during longer duration MnCl2 exposure. The weight-of-evidence suggests that most behavioural effects including changes in motor activity, acoustic startle, and balance or gait were transient and occurred at oral exposure dose of  10 mg MnCl2/kg/day. Effects on learning and memory were more persistent in some studies and occurred at oral exposure dose of  15 mg MnCl2/kg/day. Numerous studies evaluated changes in dopamine, gamma-aminobutyric acid (GABA), and other neurotransmitter levels in animals following MnCl2 exposure. These studies also yielded mixed results with the weight of evidence suggesting that neurochemical changes occurred at an oral exposure dose of  10 mg MnCl2/kg/day. Several studies evaluated neuropathologic outcomes following MnCl2 exposure. The most robust oral study exposed rats to MnCl2 by gavage at 0, 2, 5, 15, and 25 mg MnCl2/kg/d, 7 d/wk, for 30 days. Decreases in neuron numbers occurred following exposure to  10 mg MnCl2/kg/day.

The data available for Mn sulfate (MnSO4) is limited. Chronic (2-year) dietary studies conducted in both mice and rats failed to identify any treatment related evidence of neuropathology. Subchronic rodent and nonhuman primate inhalation studies were performed with limited neurotoxicity endpoints. In rodents, subchronic exposure to MnSO4 did not affect olfactory bulb, cerebellar, or striatal GFAP concentrations. Exposure or rats to MnSO4 at 0.5 mg Mn/m3 was also associated with reversible inflammation within the nasal respiratory epithelium, while the olfactory epithelium was unaffected by manganese inhalation. A near significant (p < 0.01) decrease in globus pallidal levels of both 5-hydroxyindoleacetic acid (5-HIAA) and GABA were seen in monkeys subchronically exposed to MnSO4 by inhalation.

Based on the REACH guidance provided in 3.9.2.: Classification criteria proposed for substances reviewed in this report, via oral or inhalation exposure is STOT RE 2 (Specific Target Organ Toxicity, Repeated Exposure Category 2) with the brain as the target organ. The classification for Mn nitrate is based on read across principles and data available from other Mn(II) salts

For the detail report contact reach@manganese.org