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EC number: 237-235-5 | CAS number: 13703-82-7
The qualitative assessment of the slides determined that precipitate was similar to thatvobserved in the Preliminary Toxicity Test and that there were metaphases suitable for scoring present up to the maximum dose level in all three exposure groups. Precipitate observations were made at the end of exposure in blood-free cultures and was noted at and above 40 pg/mL in all exposure groups. No haemolysis was observed in the 4(20)-hour exposure groups but was observed at and above 160 µg/mL in the 24-hour exposure group only.
The mitotic index data for the Main Experiment are given in Table 1 and Table 2. They confirm the qualitative observations in that no dose-related inhibition of mitotic index was observed in any of the exposure groups. Therefore, the maximum dose level selected for metaphase analysis was the lowest precipitating dose level (40 µg/mL) in all three exposure groups.
The chromosome aberration data are given in attached Table 4, Table 5 and Table 6. The assay was considered valid as it met all of the following criteria:
The frequency of cells with chromosome aberrations (excluding gaps) in the vehicle control cultures were within the current historical control data range.
All the positive control chemicals induced a demonstrable positive response (p<0.01) and confirmed the validity and sensitivity of the assay and the integrity of the S9-mix.
The study was performed using all three exposure conditions using a top concentration which meets the requirements of the current testing guideline.
The required number of cells and concentrations were analyzed.
The test item did not induce any statistically significant increases in the frequency of cells with aberrations either in the absence or presence of metabolic activation.
The test item did not induce any polyploid cells at any dose level in any of the exposure groups.
Table 1: Mitotoc Index - Main experiment (4(20)-hour Exposure Groups)
MMC = Mitomycin C
CP = Cyclophosphamide
P = Precipitate
NA = Not applicable
- = Not assessed for mitotoc index
Table 2: Mitotic Index - Main Experiment (24 -hour Exposure Group)
- = Not assessed for mitotoc index
The test item has been assed in an in vitro GLP-study in accordance with OECD Guideline 473 for structural chromosomal aberrations in cultured mammalian cells. It supplements microbial systems insofar as it identifies potential mutagens that produce chromosomal aberrations rather than gene mutations (Scott et al., 1991).
Duplicate cultures of human lymphocytes, treated with the test item, were evaluated for chromosome aberrations at four dose levels, together with vehicle and positive controls. In this study, three exposure conditions were investigated; 4 hours exposure in the presence of an induced rat liver homogenate metabolizing system (S9), at a 2% final concentration with cell harvest after a 20-hour expression period, 4 hours exposure in the absence of metabolic activation (S9) with a 20-hour expression period and a 24-hour exposure in the absence of metabolic activation.
The dose levels used in the Main Experiment were selected using data from the preliminary toxicity test where the results indicated that the maximum concentration should be limited on precipitate. The dose levels selected for the Main Test were as follows:
Group Final concentration of test item (µg/mL)
4(20)-hour without S9 0, 2.5, 5, 10, 20, 40, 80, 160
4(20)-hour with S9 (2%) 0, 2.5, 5, 10, 20, 40, 80, 160
24-hour without S9 0, 5,10, 20, 40, 80,160, 320
All vehicle (dimethyl sulphoxide (DMSO)) controls had frequencies of cells with aberrations within the range expected for normal human lymphocytes. All the positive control items induced statistically significant increases in the frequency of cells with aberrations. Thus, the sensitivity of the assay and the efficacy of the S9-mix were validated.
The test item was toxic at high doses but it did not induce any statistically significant increases in the frequency of cells with aberrations, using a dose range that included a dose level that was the lowest precipitating dose level.
The test item was considered to be non-clastogenic to human lymphocytes in vitro.
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