Thionyl dichloride

Endpoint summary

Additional information

There are 3 different Ames tests from 2 reports available. In the study of Herbold (1988, Klimisch 2) the Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 were tested with the hydrolysis products of thionyl chloride (sulfur dioxide and hydrogen chloride) up to a concentration equivalent to 10,000 µg/plate of thionyl chloride with and without metabolic activation (30 % rat liver S9), which is acceptable as the test substance undergoes immediate disintegration upon contact with the aqueous culture medium. Up to the highest test concentration there was no cytotoxicity or increase in revertant numbers observed, this test was negative.

In contrast, in another test, suffering from very limited documentation (NCI, 1981 and 1984, included in the report on the mouse lymphoma assay by EG&G Mason, 1981, Klimisch 4), but performed with the S. typhimurium strains TA102, TA98, TA100, TA1535, TA1537 and TA1538 (all up to 450 µg/plate except TA102: up to 3,333 µg/plate) with and without metabolic activation, the test substance induced an increased frequency of revertants in TA 102 with 10 % rat liver S9 at 1,000 µg/plate (2.3-fold of solvent control, dose-response related, cytotoxicity at 3,333 µg/plate).

In the corresponding retest with TA98 and TA100 with metabolic activation (hamster liver S9 at 2.5, 5, 10 and 20 %), included in the same report, the test substance induced a maximum increase of revertant numbers in TA100 with 10 % S9 at 1,000 µg/plate (10.3-fold) and in TA98 at 333 µg/plate (2.6-fold) in a dose-related fashion. Other configurations with different S9 concentrations were positive, as well.

Taking the results from all available Ames tests into consideration it cannot be explained why there was no mutagenicity or cytotoxicity observed at a 3-fold higher test substance concentration in the study by Herbold, this is not feasible, therefore, the genotoxicity in bacteria should be considered ambiguous.

The mouse lymphoma assay, reported from EG&G Mason (1981), was considered positive by the authors without metabolic activation and negative with metabolic activation. However, although a significant increase of mutant frequency without metabolic activation is claimed (3-fold of control mutant frequency), the criteria used as basis for this evaluation and the underlying statistics were not provided.

Besides, the observed increase in mutant frequency is rather low, actually the highest observed mutant frequeny considered positive in the trial without metabolic activation is identical to that considered negative in the trial with metabolic activation. From a toxicological point of view it is not feasible that a substance has a relevant tocicological effect without metabolic activation, but then will be inactivated by the metabolic system.

Further, information on historical controls is missing to get an impression of the biological relevance of the observed effect, and possible pH-effects due to the corrosive nature of the test substance have not been considered, at all, in the evaluation of the results.

Taking all these flaws together, the study (Klimisch 3) should be considered as negative or, if at all, borderline for mutagenicity, but not demonstrating mutagenic characteristics of the test substance.

A classification of the test substance as mutagenic based on the results of this study cannot be justified.

Considering all available information there cannot be an unequivocal decision on mutagenicity in bacteria and mammalian cells, and data on cytogenicity in mammalian cells was not available, at all. However, a possible potential for genotoxicity cannot be excluded.

Nevertheless, further in vitro testing is scientifically not justified, as the substance hydrolises rapidly in the aqueous media used for mutagenicity testing in vitro, any observed effect would have to be attributed to the hydrolysis products sulfur dioxide and hydrogen chloride. In the aqueous cell culture medium the sulfur dioxide will form an equilibrium with the sulfite ion, which is further oxidised to sulfate by sulfite oxidase in the mitochondria of eukaryotic cells. Inorganic sulfate also occurs endogenously and plays important roles in physiology. Hydrogen chloride will dissociate in an aqueous milieu, as well, the resulting chloride ion also plays an important role in physiology. Therefore, a mechanism of mutagenicity induced by chloride and sulfate ions is not feasible. Although cell culture is performed in buffered media, pH-effects due to the formation of 4 hydronium ions upon dissociation of the test substance in aqueous media, exhausting buffer capacity and leading to acidification, could be expected, however, such effects would be secondary and not toxicologically relevant for assessment of cytogenicity, anyway.

Due to the highly corrosive characteristics of the test substance, testing in vivo cannot be recommended due to animal welfare reasons. Besides, in the aqueous milieu of the body the test substance would immediately disintegrate into sulfur dioxide and hydrogen chloride, as well, and the same processes as described above will take place. As the metabolism of vertebrates is maintained under well buffered conditions, pH effects due to the formation of hydronium ions should not be expected, however, these would have to be considerd as secondary and, therefore, not toxicologically relevant, either.

SOCl2 is hydrolyzed rapidly and completely by water in an exothermic reaction with formation of HCl and SO2. Therefore the mutagenicity of the hydroysis products(HCl and SO2) is also considered.

HCl:

For genetic toxicity, a negative result has been shown in the Ames test. A positive result, which is considered to be an artifact due to the low pH, has been obtained in a chromosome aberration test using hamster ovary cells. The effects of low pH in in-vitro studies are not a problem in vivo as the proton level is regulated systemically (OECD SIDS for HCl).

SO2:

The available Ames test was negative and no DNA strandbreaks were found in hamster lung cells and primary rat hepatocytes.SO2 was also negative in a micronucleus assay in NMRI mice according OECD 474

In conclusion, from the available data of HCl and SO2 a genotoxic potential of SOCl2 is not expected.

Short description of key information:
In vitro gene mutation (Bacterial reverse mutation assay/Ames test): ambiguous;
In vitro gene mutation mammalian cells (Mouse lymphoma assay): ambiguous;
Waiving: In vitro cytogenicity in mammalian cells

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

The data for SOCl2 are inconclusive, the available information is not sufficient for assessment. However, taking all available information and underlying physiological and chemical processes into consideration, the test substance should not be considered as mutagenic.

For the hydroysis products of SOCl2 (HCl and SO2) no mutagenic potential is obvious. Therefore a classification is not justified for SOCl2.