Manganese dioxide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.2 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.004 mg/kg bw/day

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

In genotoxicity studies with very soluble manganese dichloride, the manganese ion was not shown to be genotoxic. In a complete set of reproductive toxicity studies with manganese dichloride (inhalation OECD 416 2 generation reproductive toxicity study in the rat, an inhalation OECD 414 developmental toxicity study in rat, a subcutaneous OECD 414 equivalent study in the mouse, and an inhalation OECD 465 pre and post natal developmental toxicity study in rats), the manganese ion did not show intrinsically reproductive or developmentally toxic properties up to 20 mg/m3 (8.73 mg Mn/m3) and there were no signs of any pre or post natal developmental toxicity upto 17.6 mg/m3 (7.68 mg Mn/m3). The comparable respirable SCOEL (0.05 mg/m3, see below) from which DNELs have been derived, is protective of specifically of human neurotoxicity effects, and ca. 150 lower than the animal reproductive and developmental NOAELs which is considered an adequate margin of safety. The manganese ion was also non-carcinogenic in the rat or mouse in GLP and guideline compliant studies conducted by the US national Toxicology Program.

With respect to the SCOEL value, the following is taken from: Recommendation from the Scientific Committee on Occupational Exposure Limits for manganese and inorganic manganese compounds SCOEL/SUM/127 June 2011 (Doc attached). The values are also supportable from an independent review of the human data by Gut (2009) (See neurotoxicity data summary section. Gut also attached below)

"It is important that any metric(s) used for limit setting should be that most closely associated with the critical endpoint. The most sensitive endpoint for manganese exposure is neurological (i. e. systemic rather than at the principal point of entry, the lungs) and, for manganese, the respirable fraction is considered to be the best indicator of systemic availability. However, it is also appropriate to consider that every inhaled fraction reaching the respiratory tract contributes to workers’ exposure, being via rapid and complete absorption in the alveoli, dissolution in the airway mucus, some olfactory uptake in the upper airways or limited gastro-intestinal uptake after mucociliary clearance and deglutition. A large proportion of the inhaled fraction will, however, ultimately enter the gastrointestinal tract, yet gastrointestinal absorption is fairly low, even for soluble forms of manganese (~5%), and there is little evidence for manganese toxicity following dietary exposure. Uptake of dietary manganese is controlled by dose-dependent intestinal absorption, biliary excretion and intestinal elimination (Anderson et al, 1999, cited in IEH 2004). Adult humans normally maintain stable tissue levels of manganese regardless of intake; this homeostasis is maintained by regulation of absorption and excretion (ATSDR 2000). It is, therefore, recommended that the most biologically appropriate measure of exposure to airborne manganese for evaluating health effects and setting an occupational exposure standard is the respirable aerosol rather than total or inhalable aerosol. This approach is supported by data comparing the respirable and inhalable aerosol fractions in fields studies (e. g. Ellingsen et al. 2003).

Manganese dust may, however, vary in particle size depending on the industry sector and the process involved. The complex relationship and ratios between total, inhalable and respirable manganese particulates has been described and discussed in depth (IEH, 2004) in relation to most occupational scenarios that are likely to be encountered. The respirable fraction (hence the respirable to inhalable [or total] ratio) may, therefore, vary widely and it is recognised that this has practical implications for setting standards. In processes where the respirable to inhalable (or total) ratio is low, gastrointestinal absorption may not be, after all, insignificant, which may be the case in some processes. An inhalable limit is therefore also recommended. In support of this two-metric approach, it is useful to consider that Lauwerys et al. (1992) stated: “In industry, evaluation of individual exposure to manganese is thus best carried out by monitoring its concentration in total and respirable dust in the breathing zone of the workers. ”

The relative importance of cumulative versus current or peak exposure in determining risks is not exactly known. However, on the evidence available, including biological plausibility,cumulative exposure appears the best way to represent the time-relatedness of manganese exposure and effect for the purposes of setting an IOELV. It is also relevant as it may be that, as shown in some studies, not all the reported neurofunctional effects seen in longitudinal investigations of workers effects are reversible.

Because of the heterogeneity of the data (different types of industry, different manganese compounds and particle sizes, different study designs and different neurofunctional measurements), and the inherent limitations of every individual study, it is not possible to identify one single critical study that would be the best basis for setting the IOELVs. Some studies identified a LOAEL, other a NOAEL. Some studies relied on the respirable fraction; other on the inhalable or “total” (thoracic) fraction. A global approach using the most methodologically-sound studies, as used in the IEH Criteria document (2004) and a number of additional good quality studies published since this review was therefore considered to be the most robust and reliable approach. The studies by Roels et al. (1992), Gibbs et al. (1999) Myers et al. 2003b, Young et al. 2005, Bast-Pettersen et al. (2004) and Ellingsen et al. (2008) as well as Lucchini et al. 1999 in HC (2008) which showed adverse neurological effects and identified a point-of-departure (POD) in the dose-effect/response relationship may offer a basis for recommending an IOELV.

Thus, a reasonable respirable IOELV of 0.05 mg/m3 can be recommended, and a reasonable inhalable IOELV of 0.2 mg/m3 is also recommended. While recommending these values, SCOEL recognises that the overall systemic absorption of coarser particles (> respirable) is probably substantially lower than for the respirable fraction. Thus, SCOEL recommends both a respirable and an inhalable IOELV which would need to be observed conjointly. "

References

ATSDR Agency for Toxic Substances and Disease Registry September 2000 Toxicological Profile for Manganese, available athttp: //www. atsdr. cdc. gov/toxprofiles/tp151. html

Bast-Pettersen R, Ellingsen DG, Hetland SM, Thomassen Y (2004) Neuropsychological function in manganese alloy plant workers. Int Arch Occup Environ Health 77: 277-287

Ellingsen DG, Hetland SM, Thomassen Y (2003) Manganese air exposure assessment and biological monitoring in the manganese alloy production industry. J Environ Monit 5: 84- 90

Ellingsen DG, Konstantinov R, Bast-Pettersen R, Merkurjeva L, Chashchin M, Thomassen Y, Chashchin V (2008) A neurobehavioral study of current and former welders exposed to manganese. Neurotoxicology 29: 48-59

Gibbs JP, Crump KS, Houck DP, Warren PA & Mosley WS (1999) Focused medical surveillance: A search for subclinical movement disorders in a cohort of U. S. workers exposed to low levels of manganese dust. Neurotoxicology, 20, 299-314

HC 2008 Human Health Risk Assessment for Inhaled Manganese Draft Water, Air & Climate Change Bureau Health Canada, March, 2008 http: //www. hc-sc. gc. ca/ewhsemt/alt_formats/hecs-sesc/pdf/air/out-xt/_consult/draft_ebauche/manganese_e. pdf

IEH (2004) Occupational Exposure Limits: Criteria Document for Manganese and Inorganic Manganese Compounds (Web Report W17), Leicester, UK, MRC Institute for Environment and Health

Lauwerys RR, Bernard A, Roels H, Buchet JP, Cardenas A, Gennart JP (1992) Health risk assessment of long term exposure to chemicals: application to cadmium and manganese. Arch Toxicol Suppl 15: 97-102

Lucchini R, Apostoli P, Perrone C, Placidi D, Albini E, Migliorati P, Mergler D, Sassine M-P, Palmi S & Alessio L (1999) Long term exposure to “low levels” of manganese oxides and neurofunctional changes in ferroalloy workers. Neurotoxicology, 20, 287-298

Myers JE, Thompson ML, Ramushu S, Young T, Jeebhay MF, London L, Esswein E, Renton K, Spies A, Boulle A, Naik I, Iregren A, Rees DJ (2003b) The nervous system effects of occupational exposure on workers in a South African manganese smelter. Neurotoxicology 24: 885-894

Roels HA, Eslava MIO, Ceulemans E, Robert A & Lison D (1999) Prospective study on the reversibility of neurobehavioral effects in workers exposed to manganese dioxide. Neurotoxicology, 20, 255-271

Young T, Myers JE, Thompson ML (2005) The nervous system effects of occupational exposure to manganese—measured as respirable dust—in a South African manganese smelter. Neurotoxicology 26: 993-1000

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.043 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.002 mg/kg bw/day

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

exposure based waiving

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

As above for worker DNELs.