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EC number: 216-407-3
CAS number: 1576-35-8
TABLE 1 - Mortality and Toxic Signs in the Dose-range Finding Study:
TABLE 2 - Mortality and Toxic Signs after Treatment in the Main Study
TABLE 3 - Overview Tail Intensity in Liver Cells of Males Rats
TABLE 4 - Overview Tail Intensity in Duodenum Cells of Male Rats
TABLE 5 - Overview Tail Intensity in Glandular Stomach Cells of Male Rats
The study procedures described were based on the most recent OECD 489 guideline.
Based on the results of the dose-range finding study test concentrations of 250 mg/kg/day for male animals was selected as maximum dose for the main test (maximum tolerated dose). Since there were no substantial differences in toxicity between sexes only males were used in the main study.
The concentrations analyzed in the formulations of Group 2 (62.5 mg/kg), Group 3 (125 mg/kg) and Group 4 (250 mg/kg) were in agreement with target concentrations (i.e., mean sample concentration results were within or equal to 90-110% of target concentration). No test item was detected in the Group 1 (control group) formulation. The formulations of Group 2 (62.5 mg/kg) and Group 4 (250 mg/kg) were homogeneous (i.e., coefficient of variation ≤ 10%).
In the main study male animals were dosed with vehicle (propylene glycol), test item (at 62.5, 125 and 250 mg/kg body weight) for two consecutive days. A positive control group was dosed twice by oral gavage with 200 mg Ethyl Methane Sulfonate (EMS) per kg body weight.
Clinical signs of toxicity were limited to the middle and high dose group and included convulsion, lethargy, hunched posture and paralyzed hindlegs. In the highest dose-group 1 animal was found death on day 2.
Approximately 3-4 hours after the last dose the animals were sacrificed by abdominal aorta bleeding under isoflurane anesthesia tissues were isolated. Single cell suspensions from liver, stomach and duodenum were made followed by Comet slide preparation. The slides were analyzed and the Tail Intensity (%) was assessed.
No statistically significant increase in the mean Tail Intensity (%) was observed in Liver, Duodenum and Glandular Stomach cells of test item treated male treated animals compared to the vehicle treated animals. A statistically significant increase was observed in Duodenum cells of the animals treated with 62.5 mg/kg compared to the vehicle control treated animals. However, no significant concentration-related increase was observed, and the results are within the 95% control limits of the negative historical control data range. Therefore, the increase was considered not of biological relevance.
The mean Tail Intensity in Liver, Duodenum and Glandular Stomach cells of vehicle-treated rats was 4.54 ± 0.32% (mean ± SD), 5.88 ± 1.86% (mean ± SD) and 6.33 ± 2.80% in male animals, respectively, which is within the 95% control limits of the distribution of the
historical control data for the vehicle control. The positive control EMS induced a significant increase and showed a mean Tail Intensity of 95.72 ± 1.48% (mean ± SD), 62.31 ± 4.59% (mean ± SD) and 66.46 ± 1.81% (mean ± SD) in male animals in Liver, Duodenum and Glandular Stomach cells, respectively. The mean positive control Tail Intensity was within the 95% control limits of the distribution of the historical positive control database. Adequate numbers of cells and doses were analyzed, and the highest test dose was the MTD. Hence, all criteria for an acceptable assay were met. There were no hedgehogs observed in any of the slides.
In conclusion, under the experimental conditions described in this report, Toluene-4-sulphonohydrazide has not shown any evidence of causing an increase in DNA strand breaks in Liver, Duodenum and Glandular Stomach cells when sampled approximately 3-4 hours post dosing, of male rats, dosed via oral gavage for two consecutive days up to a dose of 250 mg/kg (the maximum tolerated dose in accordance with current regulatory guidelines). Thus, Toluene-4-sulphonohydrazide was found not to be genotoxic in the Comet assay (OECD 489). The results obtained with the positive control substance EMS confirmed the validity of the test.
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