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EC number: 700-111-0
CAS number: 148528-05-6
weight of evidence approach based on in vitro data and QSAR predictions
Additional information from genetic toxicity in vitro:
Four in vitro genetic toxicity studies are available for the mutagenicity endpoint of MODA and were used for the assessment:
One in vitro gene mutation study in bacteria (Kazuhiko Saigo, 1997;equivalent/similar to OECD 471), one in vitro gene mutation study in mammalian cells (TÜV SÜD, 2012;OECD 476), one chromosome aberration test (Kazuhiko Saigo, 1997;equivalent/similar to OECD 473) with Chinese hamster lung (CHL)/IU) cells and one in vitro micronucleus study (B. Usta, BSc, 2015;OECD 487) with cultured human lymphocytes. Additionally, three QSAR calculations were conducted (OECD Toolbox, Vega and Test).
An in vitro gene mutation study in bacteria (Kazuhiko Saigo,1997) was conducted using five bacterial strains (Salmonella typhimurium TA98, TA100, TA1535 and TA1537 and E. coli WP2urvA) to evaluate the mutagenic potential of the substance. Six different doses, 156, 313, 625, 1250, 2500, and 5000µg/plate, were used in the main study with and without metabolic activation. Cytotoxicity was observed at concentrations of 2500 and 5000 µg/plate. In this test, the substance did not show mutagenic potential with and without metabolic activation.
In an in vitro mammalian cell gene mutation study using mouse lymphoma L5178Y cells (TÜV SÜD, 2012; OECD 476) cytotoxic effects (cell growth inhibition) were observed at 2.5µg/mL and above concentrations in a pretest. Concentrations of 2.5µg/mL, 1.25µg/mL, 0.625µg/mL and 0.3125µg/mL were used for the main test. In this test the substance was determined to be non-mutagenic to the L5178Y TK+/- clone, both in the absence and presence of metabolic activation.
In the chromosome aberration study using cultured Chinese hamster lung-derived fibroblast cells (Kazuhiko Saigo, 1997) a positive result was concluded for the substance. The test was carried out with 12.5, 25, 50, and 100 µg/mL in the absence of metabolic activation with the treatment periods of 24 and 48 hrs, and with 44.4, 66.7, 100, and 150 µg/mL in the presence of metabolic activation without S9 Mix, and at 444, 667, 1000, and 1500 µg/mL in the presence of metabolic activation with S9 Mix. Doses were set so that the cell survival rate ranged between 20% and 80% based on the results of a range finding study. Cytotoxicity was not evaluated during the main study. Positive results were observed at concentrations of 50 and 100 µg/mL in the absence of metabolic activation with the treatment periods of 24 and 48 hrs. Both concentrations were above the 50% cell growth inhibition concentration (GI50) of around 48 and 35 µg/mL, respectively, as determined in the pretest. With metabolic activation a positive result was observed with S9 Mix at 1000 µg/mL. Here, a GI50 of 610µg/mL was calculated from the range finding study. With metabolic activation without S9 Mix positive results were observed at all four concentrations (44.4, 66.7, 100, and 150 µg/mL). For this method, a GI50 of 80µg/mL was calculated from the range finding study. As most of the positive responses were observed at doses above the GI50 value the study is considered of limited value because the observed chromosome damage may be induced as a secondary effect of cytotoxicity (ECHA guidance R7a, 2015 section R.188.8.131.52). Also cytotoxicity was not determined in the main study but in a separate test.
As the positive result of the chromosome aberration test (equivalent/similar to OECD 473) with Chinese hamster lung cells was considered to be questionable a follow up study was carried out to determine the potential for chromosome damaging of the substance. Due to the observed high cytotoxicity in the first chromosome aberration test using Chinese hamster lung cells, the follow up test was conducted with cultured human lymphocytes in a micronucleus test according to OECD 487 (B. Usta, BSc, 2015) with the following concentrations: Experiment 1: 1266, 633, 317, 158, 79, 40, 20, 10, 5, 2.5 µg/mL (pulse treatment method with and without metabolic activation; Experiment 2: 1266, 886, 620, 434, 303, 213 µg/mL (pulse treatment method without metabolic activation); Experiment 2: 1266, 886, 620, 434, 303, 213, 149, 104, 72.8, 51.1, 35.8, 25.0, 17.5, 12.3 µg/mL (continuous treatment method without metabolic activation). In this test the Cytotoxicity was determined from the Cytokinesis-Block Proliferation Index (CBPI) and three test concentrations (not including the solvent and positive controls) that meet the acceptability criteria (appropriate cytotoxicity, number of cells, etc) could be evaluated as required according to the test guideline. From the results obtained in this in vitro micronucleus test it was concluded that, under the reliable conditions used in this study, the test substance MODA was not clastogenic and/or aneugenic to cultured human lymphocytes.
In addition three independent QSAR studies were conducted using different models. All three models predict that primary amines do not have a genotoxic potential.
The available data were used in a weight of evidence approach to determine the potential of the substance for genetic toxicity. It was concluded that the substance has no mutagenic potential and further in vivo testing was not deemed necessary.
Justification for selection of genetic toxicity endpointThe mammalian cell micronucleus test (OECD 487) is the most recent study.
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