Can Inorganic Mn Substances cause Endocrine Disruption : What does available data say?

In the assessment of regulatory needs report by ECHA, it is stated under the section detailing the justification for the need of regulatory risk management action that ‘For all substances in the group I (several inorganic manganese substances in the list), there is inconclusive evidence on human health ED hazard due to very limited relevant findings.

To this end,experts  from Exponent werecontracted to review available literature vis-à-vis the joint guidance issued by ECHA and EFSA on how to identify endocrine disruptors (EFSA Journal 2018; 16(6):5311, hereafter referred to as the Guidance)3 and also, OECD Guidance Document 1504 which documents the standardised endpoints for evaluating chemicals for endocrine disruption.

The thorough literature review process yielded 29, 153 publications – the biggest review ever carried out for this endpoint.Upon the evaluation of the titles and abstracts only 50 articles met the endpoint eligibility criteria.

The review concluded that,

1. There is no evidence of EATS mediated adversity in rodents.
2. In vitro activity prediction data did not indicate antagonistic or agonistic activity at the estrogen or androgen receptor.
3. Steroidogenesis-mediated activity is unlikely given a lack of toxicological effects to indicate any S-mediated adversity.
4. With regards to parameters ‘sensitive to, but not diagnostic of, EATS’, the effects observed in the relevant studies were not consistent across the data package, without a clear dose-response relationship and/or observed in the presence of maternal toxicity.

Whilst some publications have indicated potential findings of endocrine relevance due to effects on thyroid function and sexual development and fertility, these publications have design limitations in comparison to regulatory standard study designs and therefore are of limited weight in the overall evaluation

The experts suggested that, despite the lack of reliability in these publications when evaluated against the ECHA/EFSA criteria indicated in the ED guidance and given the keen focus on the endocrine modality across regulatory agencies, this large body of research is likely to heighten regulatory concern, especially in the knowledge that manganese is an essential trace element for thyroid and reproductive development and function. The lack of regulatory data on thyroid hormone or endocrine activity may be considered a key data gap despite no clear adversity in the existing studies.

The literature review carried out for the most part of last years was concluded early this years (2024) with Charles River Labs taking the baton to complete the proposed Invitro testing to fill up these data gaps.

All Dossiers being updated carry  the required information on ED, emanating from this review