Methyl toluene-4-sulphonate

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Tosylates and other sulfonic acids should be regarded as possible mutagens due to their alkylating potential. The sulfonic acid, Methyl MethaneSulphonate (MMS), is often used as a positive control for mutagen studies in vitro. 

The alkylsulphonate, Busulfan (1,4-butanediol dimethanesulphonate), is an approved chemotherapeutic agent due to its alkylating effects. It's mode of action is to form DNA-DNA intrastrand crosslinks between the DNA bases guanine and adenine and between guanine and guanine. This occurs through an SN2 reaction in which the relatively nucleophilic guanine N7 attacks the carbon adjacent to the mesylate leaving group. DNA crosslinking prevents DNA replication. Because the intrastrand DNA crosslinks cannot be repaired by cellular machinery, the cell undergoes apoptosis.

Assessing the methyl tosylate structure through OECD toolbox pulls out the results of the Glowienke et al study and the Sobolet al study, which are summarised in Section 7.6.1 of this file.

The combined results of these studies show positive results for methyl tosylate in the Ames test (with and without S9 activation), and positive in vitromicronucleus (with and without S9 activation).

A computer-aided analysis using MCASE, also by Glowienkee et al, further indicates that methyl tosylate is an alkylating agent based on it's SO2 -O biophore, and as expected.  These data suggest that the classification of Methyl Tosylate under CLP should be Mutagen Category 2 with Hazard label H341 (Suspected of causing genetic defects). Signal word: Warning.

However, classification as a mutagen for different mutagenic categories always refers to germ cell mutagenicity. No germ cell assays or animal data indicating exposure/bioavailability of germ cells are available.

It is reasonable to anticipate that metabolism of MTS will mirror that of Busulfan, which is metabolized via glutathione conjugation in the liver to inactive metabolites after the administration of repeated large therapeutic doses.

Such high dose exposure to MTS is extremely unlikely. Accidental exposure through inhalation or oral exposure is likely lead to rapid inactivation through conjugation and clearance. Exposure assessment must also heed the high irritancy of the substance to mucous membranes. It is thus highly unlikely that germ cells far from the site of contact would be exposed.

Further evidence for metabolic deactivation comes from mutagenises studies in Drosophila where dosing was by feeding and injection. Injection lead to increased mutagenicity, whereas feeding showed lower activity, which has been shown to be due to considerable metabolic inactivation in the gut or tissues. Metabolic inactivation, to a lesser degree, was also observed in the injection experiments.

It is hypothesised that, after injection, the applied mutagens are still in close contact with the fat body which is distributed through the abdomen. The continued metabolic deactivation of Me-Tos after injection is also reflected in the disproportionate increase of their mutagenicity with increasing dose.

Zijlstra and Vogel consider the role of metabolic deactivation of MTS to rule as inconclusive any experiments with germ-line assays where negative results were obtained but where injection experiments had not been performed.

Further, because DNA crosslinking prevents DNA replication, the propagation of viable germ cell mutants is extremely unlikely.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (positive)

Genetic toxicity in vivo

Description of key information

The authors have established that application by feeding is not effective in producing genetic damage in the gonads, chemically unstable direct-acting mutagens; relatively stable direct-acting mutagens which are metabolically de-activated in the gut; and promutagens of the class of aromatic hydrocarbons.

We feel this is sufficient evidence for considering as inconclusive those experiments with germ-line assays where negative results were obtained but where injection experiments had not been performed.

The near absence of mutagenicity in the feeding experiments and the considerable mutagenic effect after injection, suggested a metabolic de-activation of Me-Tos somewhere along the route between the mouth and the gonads.

Two primary metabolic deactivation processes could be responsible. The first possible candidate, glutathione S-transferase, probably was not responsible, as depletion of glutathione with a sub-toxic dose of diethylmaleate did not influence Me-Tos mutagenicity. The second important de-activation, and activation, pathway involves cytochrome P-450-mediated oxidation. Phi is known to be a potent inhibitor of many isozymes of cytochrome P-450 in mammals and in Drosophila.

A clear increase of Me-Tos mutagenicity when the mutagen is applied in combination with this inhibitor, suggests metabolic de-activation of Me-Tos by cytochrome P-450. Inhibition of metabolic deactivation of Phi by Me-Tos is not probable as Phi is not mutagenic in both feeding and injection experiments.

Endpoint conclusion

Endpoint conclusion:

no study available (further information necessary)