Analysis of available literature for the purposes of the evaluation of Endocrine Disruption Potential

In this 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 substance in the list) , there is inconclusive evidence on human health ED hazard due to very limited relevant findings.

To this end Exponent Dr Emily Richmond was contracted to collect and review available literature vis-à-vis the concern raised. Seventeen different inorganic Mn-based substances were evaluated for endocrine disruption potential from available literature.

The thorough literature review process yielded 29, 153 publications – the biggest review ever carried out for this endpoint. Upon the review of the titles and abstracts on 50 articles were eligible for further consideration and these were assessed in line with 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 highlighted that at the time of issuance of this evaluation, there are no standard information requirements for ED testing under REACH annexes VII-X to inform on this assessment.In the absence of data for the assessment for endocrine disrupting properties in the environment, this review focused on the weight of evidence for determining endocrine disrupting properties in humans.

After thorough review of all the available regulatory study data for substances in sub-group I, the review concluded that, there is no evidence of EATS mediated adversity in rodents. Furthermore, the limited in vitro activity prediction data further substantiate this since there is no indication of antagonistic or agonistic activity at the estrogen or androgen receptor. Steroidogenesis-mediated activity is unlikely given a lack of toxicological effects to indicate any S-mediated adversity. 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. In the absence of consistent changes across thesedata sets for the different substances in sub-group I, and when compared with the more reliable conclusions from the extensive regulatory data sets, the regulatory weight of evidence would suggest no adverse effect on endocrine modality.

Regardless of the regulatory data, it has to be acknowledged that during the systematic literature review there were 50 publications identified which indicated manganese adversity on endocrine function of thyroid or estrogenic, androgenic or steroidogenic modalities. These changes for both EAS, or T modality were consistently due to neuroendocrine disturbance but there were some suggestions of potential direct endocrine disturbance. Despite their lack of reliability when evaluated against the ECHA/EFSA criteria indicated in the ED guidance, 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. In particular, the lack of regulatory study thyroid hormone data or endocrine activity data may be considered a key data gap despite no clear adversity in the existing studies.

The Experts proposed generating invitro data to strengthen the data set that explore potential direct effects on endocrine activity. If these newly generated data show absence of direct effects, industry could more robustly defend that changes seen in literature are due to a secondary consequence of neurotoxicity (i.e. neuroendocrine change).

For the full report contact reach@manganese.org