History/Summary of Dossier

The lead dossier was submitted in 2010 with no testing proposals.

In 2013 a compliance check was initiated, requesting more details with regard to the following information requirements/updates:

• Annex VI, 2.3.7 ( description of the analytical methods for the identification of the substance)
• Annex IX, 8.6.2 (Sub-chronic study - 90days, Oral route, OECD 408)
•  Annex IX 8.7.2 (pre-natal developmental study, oral route, OECD 414)
• Annex X, 8.7.3 (two-generation reproductive toxicity study, oral route, OECD 416 or an extended one generation reproductive toxicity study, OECD 443) 
• Annex VI, 4.1 & 4.2 (hazard classification and resulting hazard label for chronic aquatic toxicity)

By Q4 2013 the consortium secretariat on behalf of the lead registrant had responded to the ECHA’s draft decision concerns, highlighting the lack of need for such animal-intensive studies for this substance and the importance of using available literature and readacross. More information was provided in the updated dossier using available literature to comply with the OECD 408 and using studies from MnCl2 - a more soluble salt as a worse-case analysis to comply with the OECD 416 studies. The chronic environmental classification was revised and considered acceptable.

After a second correspondence between ECHA and the lead registrant, the third conrrespondence was the compliance check final decision concluding that the following studies should be conducted:

•  Pre-natal developmental toxicity study (Annex IX, 8.7.2.; test method: EU B.31/OECD 414) in rats or rabbits, oral route 

In Q4 2017, the dossier was updated and submited with the OECD 414  in the rat study from readacross substance - MnCl2.  

 ECHA's request to update this dossier in January 22, 2018 http://consortium.manganese.org/news/article/four-manganese-substances-short-listed-by-the-echa-as-substances-of-potenti  with repect to reproductive toxicity endpoints triggered a further reveiw of these endpoints.

In 2018 - 2019: Outcome of reveiw - in summary

Developmental toxicity data  and the two generation reproductive toxicity data in the rat on the read-across substance manganese dichloride resulted in no classification. Although readacross is acceptable, there was no second species data for these endpoints on any inorganic Mn- based substance. A pilot study was therefore initated in the rabbit. Although the total number of rabbits used was very small, it identified  that exposure up to the limit dose of 1000 mg/kg/day in non-pregnant rabbits was generally well tolerated for 14 days. However, this was not the case for pregnant rabbits. Embryo-foetal toxicity  was observed at dose levels ≥ 150 mg/kg/day (decreased embryo-foetal survival) but only in the presence of overt, excessive maternal toxicity which manifested as premature mortality, with an associated decline in clinical condition, body weight loss and inappetence (150 mg/kg/day was associated with maternal mortality of 50 %). ECHA CLP guidance1 (Annex I:3.7.2.4.4) defines that “maternal mortality greater than 10 % is considered excessive and the data from that dose level shall not normally be considered further for evaluation”.

Hence, it is justified to consider that although identifying findings of concern in a limited data set, the preliminary study does not provide sufficient data for basis of classification owing to the excessive maternal toxicity apparent at all dose levels where embryo-foetal effects are apparent.

In order to clarify this concern it is recommended that a full OECD Guideline 414 study is conducted in the rabbit - based on this, an appriorpiate testing proporsal will be submitted in the next dossier update - Q4 2020

For more information contact: reach@manganese.org

Note: Post 2018, the consortium will no longer invoice co-registrants  for ECHA requested studies retrospectively. All compliance check related work will require co-registrants to contribute their share before any dossier update work can begin.