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TOXICOKINETIC ASSESSMENT

TEST MATERIAL: Manganese Sulphate (MnSO4); (EC Number 232-089-9, CAS Number 7785-87-7)

 

The test material, manganese sulphate, is a deliquescent solid and commercially significant manganese salt. It forms a variety of hydrates: monohydrate, tetrahydrate, pentahydrate and heptahydrate. Manganese sulphate monohydrate, the most common form, is a pale pink powder with less than 10% of the particles smaller than 10 µm diameter.   

 

Absorption

The test material, manganese sulphate, is exceedingly soluble in water with a water solubility in the range of 42.5 to 45.0% w/w of solution at 20.0°C (O'Connor and Woolley 2009). As such, manganese sulphate would be expected to be readily bioavailable after oral administration, which for soluble manganese substances is around 5% (3-13%) in humans. Several factors influence the oral uptake of soluble manganese substances, including iron status, dietary matrix, fasted status and existing body burden of manganese. After an oral dose of 50 mg of test material to humans increases in plasma manganese levels were measured, however at this dose level gastric discomfort was reported (Bales, Freeland-Graves et al. 1987). The acute oral median lethal dose (LD50) of the test material in the mouse and rat was estimated to be greater than 2000 mg/kg bodyweight (Singh and Junnarkar 1991). As such, although the test material is orally bioavailable, it still has a low potential for toxicity by oral absorption and good hygiene practice should limit exposure. The test material is not a skin irritant (Pooles 2010) although it may have some potential for skin absorption due to its deliquescent nature.

 

Particle size analysis of a sample of commercial manganese sulphate powder showed that approximately 90% of the particles of manganese sulphate powder were > 10 µm diameter and approximately 80% greater than 100 µm diameter. As such, commercial manganese sulphate powder has a low potential to be inhaled and respired due to its particle size distribution. However, there has been a considerable interest in the toxicity and toxicokinetics of manganese sulphate by inhalation, primarily due to it being present as a combustion product from automobiles where methylcyclopentadienyl manganese tricarbonyl (MMT) is used as a fuel additive(Dorman, Struve et al. 2001). The particle size of the manganese sulphate used in animal inhalation studies is typically around 2μm mass median aerodynamic diameters (MMAD) so as to optimise respiration of the particles and absorption by the lungs. This situation is presumably to reflect the small particle size of the test material that is seen in automobile exhaust fumes as opposed to the commercial product. Using this small particle size means that the soluble test material is readily absorbed by the lungs and distributed around the body.

 

Metabolism, Distribution and Excretion

The majority (~95%) of any test material that is ingested orally is likely to pass through the GI tract unchanged and be excreted in the faeces. 

 

A 14-day (6 hours/day) repeat dose inhalation study of manganese sulphate (MMAD 2.1 μm) at 3 mg Mn/m³ in rats lead to significant increases in manganese levels in many tissues including the femur, liver, bile, lung, testes, olfactory bulb and striatum (Dorman, Struve et al. 2001). In this study, the authors compared the distribution of manganese following the inhalation of either manganese sulphate or a non-soluble manganese substance, Mn3O4. They concluded that inhalation exposure to soluble forms of manganese results in higher brain manganese concentrations than those achieved following exposure to an insoluble form of manganese. Following a subchronic inhalation study with manganese sulphate (MMAD 2.1 μm) in Rhesus monkeys, it was found that the tissue manganese concentrations depended upon the aerosol concentration, exposure duration, and tissue (Dorman, Struve et al. 2006). Monkeys exposed to MnSO4 at ≥ 0.06 mg Mn/m³ for 65 exposure days or to MnSO4 at 1.5 mg Mn/m³ for ≥ 15 exposure days developed increased manganese concentrations in the olfactory epithelium, olfactory bulb, olfactory cortex, globus pallidus, putamen, and cerebellum. The olfactory epithelium, olfactory bulb, globus pallidus, caudate, putamen, pituitary gland, and bile developed the greatest relative increase in manganese concentration following MnSO4 exposure. Tissue manganese concentrations returned to levels observed in the air-exposed animals by 90 days after the end of the subchronic MnSO4 exposure.

 

In conclusion, the test material has a small potential for absorption by oral ingestion, although it has a low potential for toxicity by this route. It may have some potential for skin absorption due to its deliquescent nature.

 

However, exposure by inhalation to the test material in as a fine particle aerosol (MMAD ~2 μm) means that it is a hazard by the inhalation route. 

 

As such, the test material, manganese sulphate, presents a hazard by inhalation of the powder as a fine particle aerosol (MMAD ~2 μm), whereupon it can be absorbed and widely distributed throughout the body, including the brain, where considerable scientific focus is investigating the potential of the neurotoxicity of manganese.

 

 

References

Bales, C. W., J. H. Freeland-Graves, et al. (1987).Plasma Uptake of Manganese - Influence of Dietary factors. Washington DC, American Chemical Society.

Dorman, D. C., M. F. Struve, et al. (2001). "Influence of particle solubility on the delivery of inhaled manganese to the rat brain: manganese sulfate and manganese tetroxide pharmacokinetics following repeated (14-day) exposure."Toxicol Appl Pharmacol170(2): 79-87.

Dorman, D. C., M. F. Struve, et al. (2006). "Tissue manganese concentrations in young male rhesus monkeys following subchronic manganese sulfate inhalation."Toxicol Sci92(1): 201-10.

O'Connor, B. and S. M. Woolley (2009). MnSO4 (Erachem/Eramet): Determination of Water Solubility. Report No. 2702/0006, Harlan Laboratories Ltd.

Pooles, A. (2010). MnSO4: Acute Dermal Irritation in the Rabbit. H. L. Ltd., Harlan Laboratories Ltd.

Singh, P. P. and A. Y. Junnarkar (1991). "Behavioural and toxic profile of some essential trace metal salts in mice and rats."Indian Journal of Pharmacology23(3): 153-159.