Diammonium [[N,N'-ethylenebis[N-(carboxymethyl)glycinato]](4-)-N,N',O,O',ON,ON']manganate(2-)

Neurotoxicity

Description of key information

Health Canada (2010) concluded that: "Although manganese can be toxic to a number of organ systems including the reproductive and respiratory 
systems, the critical target organ is the central nervous system (CNS), where manganese accumulates within the basal ganglia of the brain." Also SCOEL (2009), Rocks (2008) and ATSDR (2008) indicated that the critical effect in humans associated with exposure to manganese compounds is neurological.  
In the OECD 422 study with EDTA-MnNa2, using an extended pre-mating period (see for a summary section 7.5.1, 15375-84-5, Repeated dose toxicity: oral, Wolterbeek, 2010), detailed clinical observations, a functional observation battery (including grip strength and reaction to sensory stimuli) and measurement of spontaneous motor activity, did not show neurotoxicity at the highest level tested, viz. 1500 mg/kg bw.    

Additional information

According to Health Canada (2010):

"Toxicological studies of manganese have used animal models to investigate the neuropathological, behavioural, developmental, and genotoxic effects of exposure to this metal. In general, the majority of toxicology studies have been performed with rodents using

high exposure doses and small treatment groups. Some studies have used nonhuman primates, and an increasing amount of mechanistic in vitro work has been carried out with neural cell lines. The principal behavioural effect reported in manganese-exposed rodents is transient modification of spontaneous motor activity. Studies with nonhuman primates, though fewer, provide more detailed behavioural analyses, with symptoms of manganese intoxication often resembling those reported in humans. Hyperactivity is reported as a common early symptom, progressing to abnormal movements, muscular rigidity and limb flexion. Based on data from toxicology studies with nonhuman primates and rodents, it can be hypothesized that a number of interrelated processes are set in motion as manganese intoxication progresses: i) cellular energy supplies are depleted by mitochondrial disruption and interference with oxidative phosphorylation and the citric acid cycle; ii) oxidative stress is induced by interference with cellular respiration, the oxidation of dopamine, and/or reduced antioxidant function; iii) cellular iron and calcium homeostasis are disrupted;

iv) impaired astrocyte function leads to increased extracellular glutamate concentration and potential excitotoxicity; and v) apoptosis and/or necrosis is triggered in active neurons leading to cell death. The end result of these toxic processes is cytotoxicity and selective neurodegeneration in regions

of the brain that accumulate manganese, in turn leading to an alteration in CNS neurotransmission that gives rise to the behavioural effects associated with manganese intoxication." Also SCOEL (2009), Rocks (2008) and ATSDR (2008) indicated that the critical effect in humans associated with exposure to manganese compounds is neurological.

The manganese compounds in these evaluations are mainly inorganic, insoluble manganese compounds; the industries/jobs that were indicated in the SCOEL (2009) document are ferrous and non-ferrous alloy industries including steel making, welders exposed to manganese, grinding, power handling, founding, ore handling, production of manganese alloys, battery manufacturing, ferromanganese and silicomanganese plants, manganese metal (electrolytic) production, manganese smelters, and manganese mine workers, so generally metallurgic in nature. These reviews did not include EDTA-MnNa2, which is organic and soluble. As indicated above, the OECD 422 study with EDTA-MnNa2, in which male and female rats had been exposed for at least 12 weeks (males) and almost 14 weeks (females) no neurotoxicity was observed by performing detailed clinical observations and a Functional Observation Battery test (FOB; including measurement of grip strength and reaction to sensory stimuli) and measurement of spontaneous motor activity. In addition, histopathological examination of the brain did not show any histopathological changes. Thus, up to an oral level of 1500 mg/kg bw EDTA-MnNa2, no neurotoxicity was observed.

Justification for classification or non-classification

Based on the above indicated information, EDTA-MnNa2 does not need classification for neurotoxicity.