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In vitro genetic toxicity:

A large number of publications are based on gene mutation tests in Salmonella typhimurium, most of them used the strains TA98 and TA100. The assessment of the cytotoxicity is not always taken into account in these tests. However, the results on TA100 are quite obvious and were obtained in a lot of different laboratories: quinoline induces gene mutation (missense mutations, by base pair substitution) with metabolic activation from liver of rat, mice, human or hamster. In addition, metabolic activation of rat gut and lung was also used. In these cases, quinoline doesn't induce mutations in the tester strains.

The results on TA98 are more ambiguous and are most probably, more dependent on the metabolic activation (i.e.enzyme inducer used).

Only one test about the gene mutation properties was performed on mammalian cells (mouse lymphoma assay) and considered reliable. Unfortunately, it was only performed without metabolic activation. However, in the conditions of this test, quinoline induced forward mutations. This is the only test showing a mutagenic activity of quinoline in absence of metabolic activation.

A HGPRT test is also available but the publication gives too few details to be evaluated, however, the results are consistent with the other tests: negative without activation and positive with activation.

Several tests about the clastogenicity of quinoline have been published using mainly the chromosomal aberrations assessment, one test was based on micronucleus determination. Among the valid tests, it can be concluded that quinoline is clastogenic only in presence of metabolic activation.

Regarding DNA repair tests, some results on sister chromatid exchanges and unscheduled DNA synthesis are available and are considered as valid. In addition, one single breaks test and a test on yeast are also valid.

Except the test on yeast, all other are consistent and give the same result: quinoline induces DNA repair in presence, but not in absence, of metabolic activation or when tested in hepatocytes.

A test of genome mutation (cell transformation) was also performed and was positive with quinoline.

Quinoline was tested for its ability to produce cross-link between DNA interstrands and DNA proteins. In presence of metabolic activation, the results were positive.

Quinoline was shown to produce adducts with nucleic acids in vitro in presence of metabolic activation. The quinoline metabolite recovered by hydrolysis of these adducts is 3 -hydroxyquinoline.

In vivo genetic toxicity:

The chromosomal aberrations have been studied in vivo in rat and mice using the chromosomal aberrations test and the micronucleus test. In addition to the usual target tissue (bone marrow), hepatocytes were sometimes used in the test because the liver is the target organ for the carcinogenicity of quinoline . The test substance was administered mainly by ip injections and by gavage in 2 studies.

Among the 5 valid studies, 2 gave positive results and 2 gave negative results and in the last one which was performed in 2 laboratories, quinoline was positive in one lab and negative in the other lab. The positive results are observed only in hepatocytes. So, quinoline was able to induce chromosomal aberrations in vivo, when the examined organ is the liver.

3 DNA repair studies were performed (SCE and UDS) on rat and mice by gavage or ip injection. Only one was clearly positive in hepatocytes of rat by gavage another test in hepatocytes was ambiguous. When the target tissue is the bone marrow, the results are negative. So, in the liver, quinoline produces genotoxicity effects in vivo.

Gene mutations induction in vivo have been studied using a transgenic mouse test. Differents target organs were used (testis, bone marrow, spleen, kidneys and the liver) with a treatment by ip injection. Mutations were only observed in the liver. Unfortunately the relevance of the results on liver with ip injection is questionable.

Based on these tests, quinoline didn't induced gene mutation in testis, spleen, kidneys and bone marrow of the mouse.

In addition to these genotoxicity/mutagenesis tests, some mitogenesis tests (replicative DNA synthesis, and S-phase induction) have been carried out on hepatocytes of rats, mice and guinea pigs. Quinoline was mitogen in rat and mouse and could consequently induce cell proliferation.

Conclusion:

Quinoline is considered as genotoxic and mutagenic in vitro and in vivo only after metabolisation by the liver. In vitro, the positive results are highly dependent on the metabolic activation system used and on the enzyme inducer chosen.

In vivo, the mutagen activity seems to be limited to the liver, probably due to the production of very reactive metabolite (epoxide) in situ. The other examined tissue/organs (bone marrow, testis, kidneys, spleen, lung) give negative results.

Based on these observations, the ability of quinoline to produce heritable mutations is unlikely. So it's not deemed necessary to propose any germ cell mutation test.


Short description of key information:
Quinoline is genotoxic and mutagen after metabolisation by the liver.

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

Quinoline is currently classified as mutagen cat 3 R68 according to the 31st ATP of the directive 67/548/EEC. This classification is not to be changed as no germ cell test is available and it is not necessary to perform this kind of test.

The corresponding CLP classification is muta cat 2.