Tricarbonyl(methylcyclopentadienyl)manganese

Neurotoxicity

Description of key information

Six studies on rodents are available, covering several endpoints associated with neurotoxicity, such as: (1)  the levels of biogenic amines and GABA in the brain, (2) effects on a GABA receptor in the brain, (3) the destruction of dopaminergic nigrostriatal neurons as indicated by enzyme activity and levels of dopamine and metabolites and (4) tests for behaviour, motor nerve conductivity velocity, and effects on ATPase in sciatic nerves. .mmt was shown to: (1)  cause shifts in biogenic amines, (2) affect the GABA receptor and (3) decreases motor conductivity velocity.  The effects of mmt on these endpoints are summarized and discussed below under "Discussion"

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion

Dose descriptor:

LOAEL

50 mg/kg bw/day

Additional information

Six studies were summarized that address the possible neurotoxicity of mmt. They were prompted by the fact that manganese in inorganic form can have neurotoxic properties under certain exposure conditions. The main results of the six studies are concisely summarized below.

      Komura et al (1994) found shifts in the levels of biogenic amines in parts of the brain of mice after 12 months of continuous exposure via the feed. The manganese concentration in the feed was 0.5 g/kg (about 50 mg/kg bw/day). A notable effect was the significant increase of the normetanephrine level in the cerebellum, which correlated with the manganese level in that part of the brain.

      Another publication by Komura et al (1992) showed that chronic administration of mmt via the feed to mice (0.5 g Mn/kg) had no effect on spontaneous motor activity in rats.

      Fishman et al. (1987), treated mice with mmt by means of single intraperitoneal injection to investigate the mechanism of the seizures caused by mmt. Their data suggest that mmt (organic manganese) or a closely related metabolite and not elemental manganese itself is responsible for the seizure activity observed. The seizure activity may be the result of an inhibitory effect of mmt at the GABA-A receptor linked chloride channel.

      Gianutsos and Murray (1982) investigated the effect of repeated subcutaneous administration (11 injections, every other day a injection; 20 or 80 mg mmt/kg bw) to mice. This treatment caused decreases of the dopamine (DA) levels, striatal DA being more susceptible then olfactory tubercle DA. Effects on GABA content of the brain were only evident in the highest concentration administered, both in the striatum and substantia nigra. No effect was observed on choline acetyltransferase activity in striatum, substantia nigra, hippocampus or cerebral cortex.

      Yong et al. (1986) administered high doses (50 mg mmt/kg bw) by subcutaneous injection to female Wistar rats for up to 5 months (75 injections). This produced a substantial elevation in brain manganese content during the period of exposure (18%). Nevertheless mmt did not destroy dopaminergic nigrostriatal neurons as was demonstrated by measurements of tyrosine hydroxylase activity and contents of dopamine and its metabolites in the striatum, as well as by histological examination of the substantia nigra. Moreover, no effects on behaviour were observed.

      Liu et al. (2000) treated mice by three consecutive daily intraperitoneal injections with mmt (50 and 100 mg/kg bw). This resulted in a clear and dose-dependent decrease in motor nerve conduction velocity in the tail and a clear and dose-dependent decrease in ATP-ase activity in the sciatic nerve. The latter effect is probably the result of a decrease in one of the subunits of this enzyme (alpha1 polypeptide).

Based on these studies it can be concluded that mmt may cause effects in rodents that are relevant in an neurotoxicological context, i.e., increase of manganese levels in parts of the brain, shifts in levels of biogenic amines and related compounds, in particular decreases of dopamine levels, interaction with the GABA-A receptor in the brain, and a reduced motor nerve conduction velocity which is associated with reduced ATPase activity in the nerves. No effects on behaviour were seen after repeated exposure to high doses via the diet (12 months) or via subcutaneous injection (up to 75 injections). Moreover, nothwithstanding the effects on dopamine levels, 75 subcutaneous injections of 50 mg/kg bw did not result in the destruction of dopaminergic neurons. Nevertheless, together the studies indicate a neurotoxic potency of mmt.

In the context of the present REACH registration dossier it should first be noted that the effects were observed at high dose levels, in the sense that they approach LD50’s.

It is unclear, which compound (metabolite) is ultimately responsible for the neurotoxicity. Some studies point to an inorganic form, while other studies point to an organic form. In this respect, it is important to realize that toxicity of mmt varies with the biotransformation

Justification for classification or non-classification

Although there are indications for a neurotoxic potential of mmt, it is not justified to classify the compound based on neurotoxicity as a STOT. Most studies employed invasive exposure techniques (intraperitoneal or subcutaneous injection), with effects observed after exposure via non-invasive route (oral) occurring at the elevated exposure level of 50 mg/kg bw in feed.