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Key value for chemical safety assessment

Additional information

As the required test battery for evaluating possible mutagenic/genotoxic effects of disulfiram in vitro and in vivo is not complete, read-across was performed using the surrogate substance thiram (CAS 137-26-8) (For detailed information on the justification of read-across, please refer to the analogue justification document attached in IUCLID section 13).

The mutagenicity of disulfiram in bacteria was assessed using bacterial reverse mutation assays (Ames test) with S. typhimurium strains TA 97, TA 98, TA 100, TA 1535, TA 1537 and TA 1538 (Debets, 1982, Hedenstedt et al., 1979, Jagannath, 1979, Rannug et al., 1984). In all except for one study (Rannug et al., 1984), which is not assignable, disulfiram was negative, with and without mutagenic activation. A mouse lymphoma assay performed without metabolic activation indicated that disulfiram causes gene mutations in mammalian cells in vitro, but only in concentrations which cause cytotoxicity (McGregor et al., 1991). Moreover, a HPRT test performed with the analogue substance thiram (CAS 137-26-8) failed to show genotoxicity in the absence of cytotoxicity (Debets et al., 1986). In addition, disulfiram was tested in an unscheduled DNA synthesis assay (McQueen, 1989). In this assay, no effects on the DNA repair in primary hepatocytes following exposure to disulfiram were reported.

In a GLP-guideline study, thiram did not induce micronuclei in bone marrow polychromatic erythrocytes in male and female CD-1 mice (Putman, 1987). Furthermore, in an in vivo gene mutation test (mouse spot test) and achromosome aberration test with mouse germ cells (spermatogonia) performed in mice (Völkner 1991 and 1990), thiram revealed no mutagenic capacities.

Classification for mutagenicity: None.

Short description of key information:

In vitro:

Gene mutation (Bacterial reverse mutation assay, comparable to OECD 471): negative with and without metabolic activation.

Mammalian cell gene mutation test (OECD 476): ambiguous; positive at cytotoxic concentrations only.

In vivo:

Mammalian cell chromosome aberration test (EPA OPP 84-2): negative.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

The available data on genetic toxicity is conclusive but not sufficient for classification according to the EU Directive 67/548/EEC and the CLP Regulation.