Analysis of available literature for the purposes of the evaluation of Neurotoxicity Potential - Four inorganic Manganese Oxides

The publication of the ECHA Assessment of Regulatory Needs Report and the European Commission’s Restriction Road Map Report, triggered a thorough investigation on the Neurotoxicity potential of 4inorganic manganese oxides -manganese monoxide (MnO), manganese dioxide (MnO2), manganese tetroxide (Mn3O4), and manganese carbonate (MnCO3).

Five Manganese Scientists were commissioned to obtain and review available Literature - Prof David Dorman; Prof Michael Aschner; Dr Doreen McGough, Prof Len Levy and Dr Ruth Bervan.

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. This is the largest literature review there has been on this endpoint since the REACH 2010 registration deadline.

Data was analysedvis-à-vis the REACH regulation and the EU Classification and labelling regulation, taking into account the essentiality aspect of manganese and its toxicology.

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.

The Experts concluded that, using the data available for theoxide, tetroxide, or carbonate, a STOT classification of any kind cannot be assigned. However, 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 Category 2, Repeated Exposure with the brain as the target organ for MnO2.

The report was finalised in August 2024 and the REACH dossiers for 4 oxides are being updated accordingly.