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Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
5
Absorption rate - dermal (%):
1
Absorption rate - inhalation (%):
5

Additional information

TOXICOKINETIC ASSESSMENT

TEST MATERIAL: Manganese Dioxide (MnO2); (EC Number 215-202-6, CAS Number 1313-13-9)

 

The test material, manganese dioxide, occurs naturally as the mineral pyrolusite which is the main ore of manganese. It is also present in manganese nodules. Pyrolusite is a soft darkish black/grey/blue amorphous appearing mineral, often with a granular, fibrous or columnar structure. Particle size analysis of manganese dioxide powder has shown that 35% of the particles were smaller than 1 µm diameter.   

 

Absorption

The test material, manganese dioxide, has an exceedingly low water solubility of 4.6 x 10 -5 g/L of manganese in solution at 20.0 oC, which is equivalent to 7.3 x 10-5 g/L of the test material in solution at 20.0 oC based on the manganese content of the test material (Butler and O'Connor, 2009). Manganese dioxide also has an extremely low solubility (0.092 ± 0.016%) in artificial gastric juice (Anderson, 2009). As the oral absorption of even soluble manganese salts is still relatively low, typically less than 5%, this means that manganese dioxide has an exceedingly low potential for substantial oral absorption (<0.01%). In a study investigating the influence of the route of administration and chemical form of manganese in rats, it was concluded that a suspension of manganese dioxide powder had low bioavailability due to the lack of intestinal absorption (Roels, Meiers et al., 1997). The acute oral median lethal dose (LD50) of the test material in the rat was estimated to be greater than 3000 mg/kg bodyweight. As such the test material has a very low potential for toxicity by oral absorption. As the test material has a very low solubility in water coupled with its physical inorganic nature (powder) means that it is unlikely to be readily absorbed through the skin. 

 

The test material was so poorly solubility (<0.00005%) in artificial alveolar based upon the extractable manganese (Anderson, 2009) that it was below the detection limit for the procedure. Particle size analysis of a sample of manganese dioxide powder showed that approximately 80% of the particles of manganese dioxide powder were < 10 µm diameter (inhalable) and approximately 50% were < 2.5 µm diameter (respirable). As such, manganese dioxide powder has a very high potential to be inhaled and respired due to its particle size distribution. Since the test material is virtually insoluble in artificial alveolar fluid it would not be expected to be readily absorbed by the lungs and is likely to be slowly cleared from the lungs by the mucocilliary elevator into the gastrointestinal (GI) tract. However, animal studies have shown that significant amounts of manganese are still absorbed by the lungs following manganese dioxide exposure, albeit at a much slower rate than from a soluble form of manganese (Roels, Meiers et al. 1997). The absorption of manganese dioxide from the lungs was most probably mediated by peritoneal and alveolar macrophages through phagocytosis.  As such, manganese dioxide powder poses a considerable hazard by inhalation due to its particle size distribution and its low solubility which is likely to hinder its clearance.

 

In conclusion, the test material has a low potential for any absorption by oral ingestion or dermal absorption. However, due to the small particle size, slow absorption and clearance from the lung, and uptake through phagocytosis means that the substance poses a hazard following exposure via the inhalation route. 

 

With respect to absorption values to be used in risk and exposure assessments, those for the soluble manganese salt, manganese chloride, are adopted as a worst case, although the figure for inhalation absorption is adjusted downwards (absence of solubility in Anderson, 2009) to match oral absorption as a worst case (inhalation 5%, oral 5%, dermal 1%).

 

Metabolism, Distribution and Excretion

 

The majority of any test material that is ingested orally is likely to pass through the GI tract unchanged and be excreted in the faeces. 

 

It is generally thought that manganese is metabolised by the body in the form of converting manganese from the Mn2+ valance state to the Mn3+ valance state, and that ingested manganese is absorbed as Mn2+ possibly bound to alpha 2-macroglobulin or albumin. In transversing the liver it is removed nearly quantitatively, but a small proportion is oxidised to the Mn3+ valance state, bound to transferrin and enters the circulation to be transported to tissues. The circulating amount of manganese will be controlled by the normal homeostatic mechanism provided by the liver that controls the manganese balance.  However, manganese dioxide has manganese in the Mn4+ valance state and there is no specific information on the uptake and metabolism of Mn4+. In addition, test material that is inhaled can be taken up in the lungs, probably by phagocytosis, and thus will enter the blood stream initially bypassing the liver and its hepatic control of manganese homeostasis. 

Manganese was widely distributed and evidence of manganese accumulation in the brain was seen following repeated exposure by inhalation (22 hours/day for 10 months) to manganese dioxide dust at a concentration of 3 mg/m3 manganese (Nishiyama, Suzuki et al. 1977). Mild, but definite neurologic signs were reported for 2 out of the 3 monkeys after 3-4 months of exposure.

 

As such, the test material, manganese dioxide, presents a hazard by inhalation of the powder, whereupon it can be absorbed and widely distributed throughout the body, including the brain, where evidence of neurotoxicity has been seen following repeated high dose exposures in both animals and man.

 

Further information

A comprehensive toxicokinetic assessment has been made on manganese and its inorganic compounds, the full report is attached to this endpoint summary (Bounds 2009).

 

References

 

Anderson, K. A. (2009). Bioaccessibility of manganese from manganese Materials in Gastric and Lung (Alveolar) Biofluids, Oregon State University.

Bounds, S.V.J (2009). A toxicokinetic assessment for the Registration, Evaluation and Authorisation of Chemicals, Regulation (EC) No. 1907/2006 (REACH), Manganese and it inorganic compounds, Bounds Consulting Ltd.

Butler, R. E. and B. O'Connor (2009). MnO2 (Erachem): Determination of Water Solubility. Project Number :2702/0002, Harlan laboratories Ltd.

Nishiyama, K., Y. Suzuki, et al. (1977). "Biochemical changes and manganese distribution in monkeys exposed to manganese dioxide dust."Tokushima J Exp Med 24 (3-4): 137-45.

Roels, H., G. Meiers, et al. (1997). "Influence of the route of administration and the chemical form (MnCl2, MnO2) on the absorption and cerebral distribution of manganese in rats."Arch Toxicol 71 (4): 223-30.