Methyl toluene-4-sulphonate

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo insect germ cell study: gene mutation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1988

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 477 (Genetic Toxicology: Sex-linked Recessive Lethal Test in Drosophila melanogaster)

Deviations:

yes

Principles of method if other than guideline:

Recessive lethal tests and ring-X loss tests were performed as described in the review by Wiirgler et al. (1984), using Berlin-K and Rl(2), yB; y÷ Y B s. A brooding scheme of 3-2-2 days or 3-2 days was used for all experiments. The ring-X loss
frequency was calculated on the basis of all progeny carrying a ring-X chromosome or resulting from ring-X loss.

GLP compliance:

no

Type of assay:

Drosophila SLRL assay

Test material

Test material information

Constituent 1

Reference substance name:

Methyl toluene-4-sulphonate

EC Number:

201-283-5

EC Name:

Methyl toluene-4-sulphonate

Cas Number:

80-48-8

Molecular formula:

C8H10O3S

IUPAC Name:

methyl 4-methylbenzene-1-sulfonate

Test animals

Species:

Drosophila melanogaster

Strain:

other: Various strains

Details on species / strain selection:

Laboratory strains used: Berlin-K and Rl(2)

Sex:

male/female

Administration / exposure

Route of administration:

other: Oral and Injection

Vehicle:

The mutagenic effectiveness of DMBA is dependent on the route of administration, injection being far more effective when compared with feeding. The choice of the solvent is a crucial experimental condition. DMBA, when dissolved in oil/DMF, is ineffective whereas a special fat emulsion of DMBA gives high mutation frequencies.

Details on exposure:

Oral (feeding) of adults and larva (3 days) anf Injection of adults (single exposure)

Duration of treatment / exposure:

Single exposure or 3 days feeding.

Control animals:

not specified

Examinations

Evaluation criteria:

The ring-X loss frequency was calculated on the basis of all progeny carrying a ring-X chromosome or resulting from ring-X loss.

Statistics:

Statistical significance was calculated according to the Fisher exact test using pooled data from all available broods. For series with enzyme inhibitors, a comparison was made with a simultaneously executed series without inhibitors. For
experiments without pretreatment with inhibitors a comparison was made with the untreated spontaneous mutation frequency.

Results and discussion

Test results

Test results 1

Sex:

male/female

Genotoxicity:

positive

Remarks:

Injection

Toxicity:

not specified

Vehicle controls validity:

not specified

Negative controls validity:

not specified

Positive controls validity:

not specified

Test results 2

Sex:

male/female

Genotoxicity:

positive

Remarks:

Feeding

Toxicity:

not specified

Vehicle controls validity:

not specified

Negative controls validity:

not specified

Positive controls validity:

not specified

Applicant's summary and conclusion

Conclusions:

This paper shows the dependence in Drosophila of the route of administration on the mutagenicity of relatively stable direct-acting mutagens. Noticing the chemical similarity between MMS and Me-Tos, it was anticipated that Me-Tos, like MMS, would be mutagenic.

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.

The observations with the tosylates resemble very closely the mutagenicity of formaldehyde in Drosophila flies. This compound is not mutagenic when applied orally (Auerbach, 1952). Injection of formaldehyde does result in considerable mutagenicity but, similar to the p-toluenesulphonates, the mutagenicity increases disproportionally with the dose.

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.