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EC number: 202-500-6
CAS number: 96-33-3
DISCUSSION:Moore et al have described a mutagenic effect of Methylacrylate in the TK assay. The induction of mutant colonies was also closely associated with the induced cytotoxicity. It has been previously reported, that Glutathione has a high affinity for Methylacrylate. This could lead to a depletion of the intracellular levels of Glutathione. In this study the cultures were treated with the same levels of the test substance as previously described to be cytotoxic and mutagenic. Furthermore, a group of the cultures were replenished with Glutathione in order to assess the impact of Glutathione supplementation on mutagenicity and cytotoxicity. The results in the absence of supplementary Glutathione confirmed the data from Moore et al. However, the addition of 1 mM Glutathione abrogated this observed cytotoxicity. Furthermore, according to the results of the present in vitro study, the test substance Methylacrylate did not lead to a relevant increase in the number of mutant colonies after the addition of 1 mM Glutathione The mutant frequencies at any concentration were close to the range of the concurrent vehicle control value and within the range of our historical negative control data without S9 mix.The mutant frequencies at any concentration were below the respective thresholds of 126 colonies per 10^6 cells (GEF) above the concurrent negative control values.The mutation frequencies of the vehicle control groups were within our historical negative control data range including all vehicles used in our laboratory and, thus, fulfilled the acceptance criteria of this study.The proficiency of the laboratory to perform the mouse lymphoma assay with L5178Y TK+/- cells was demonstrated by the laboratory’s historical control database on vehicle and positive controls and by X-bar chart to identify the variability of the vehicle control data.The increase in the frequencies of mutant colonies induced by the positive control substance MMS clearly demonstrated the sensitivity of the test method. The value was within the range of the historical positive control data. Thus, the acceptance criteria of the current OECD Guideline 490 were fulfilled.
The ability of the test substance Methylacrylate to induce gene mutations at the thymidine kinase (TK) locus or structural chromosome aberrations at chromosome 11 in L5178Y TK+/- mouse lymphoma cells in vitro with the microwell method in the presence of 1 mM.Glutathione was assessed. One experiment carried out without the addition of liver S9 mix from phenobarbital and β-naphthoflavone induced rats (exogenous metabolic activation), but with or without the addition of 1mM Glutathione.The following concentrations were tested. The test groups printed in bold type were evaluated for gene mutations.
Main Experiment:4-hour exposure period; without 1mM Glutathione0; 5.0; 10.0; 15.0; 20.0; 25.0; 30.0; 35.0 μg/mL
4-hour exposure period; with 1mM Glutathione0; 5.0; 10.0; 15.0; 20.0; 25.0; 30.0; 35.0 μg/mL
Cells were treated with the test substance for 4 hours in the absence of metabolic activation with or without the addition of 1mM Glutathione. Subsequently, cells were cultured for an expression period of about 48 hours and then only the cultures treated in the presence of Glutathione and the positive control MMS were cultured in selection medium for another approx. 10 days. Finally, the number of large and small colonies was determined for these cultures. The vehicle control and the dose groups without the addition of Glutathione were only assessed for the induction of cytotoxicity.The vehicle control with the addition of Glutathione gave mutant frequencies within the range expected for the L5178Y TK+/- mouse lymphoma cell line. The positive control methyl methanesulfonate (MMS) led to the expected increase in the frequencies of forward mutations.A dose-dependent cytotoxicity indicated by reduced relative total growth (RTG) of below 20% of control was observed in the absence of 1mM Glutathione at 30 μg/mL and above. At 35.0 μg/mL no RTG could be determined due to strong cytotoxicity. In the presence ofGlutathione, no relevant cytotoxicity was observed up to the highest tested concentration.Based on the results of the present study, the test substance did not cause any biologically relevant increase in the mutant frequencies without S9 mix after adding 1 mM Glutathione.Thus, under the experimental conditions described, Methylacrylate did not induce forward mutations or structural chromosome aberrations in vitro in the mouse lymphoma assay with L5178Y TK+/- cells in the presence of 1mM Glutathione without the addition of a metabolic activation.
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