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EC number: 212-039-2 | CAS number: 753-73-1
Table 1: Summary of Definitive UDS Assay
-6.8 ± 0.7
1 ± 0
8.0 ± 1.6
-7.4 ± 1.0
2 ± 1
6.6 ± 0.8
-9.0 ± 0.4
0 ± 0
--- ± ---
-7.7 ± 0.5
7.2 ± 0.8
-6.5 ± 0.4
6.4 ± 0.0
-8.9 ± 0.2
-6.1 ± 0.4
9.1 ± 2.7
28.4 ± 6.0
93 ± 2
30.8 ± 5.9
Standard errors (S.E.) represent variation among animals
n = Number of animals
NG = Net grains/nucleus
% IR = Percentage of cells in repair (with at least 5 NG)
NGIR = Average net grains/nucleus of cells in repair
The purpose of this study was to evaluate the ability of a mixtures of methyltin chloride compounds (methyltin chloride) to induce unscheduled DNA synthesis (UDS) in male Fischer-344 (F-344) rat hepatocytes after a single oral administration 16 or 2 hours before collection of liver specimens.
A dose range-finding assay was conducted to determine dose levels for the definitive UDS assay. Male rats approximately 8 weeks old (162-200 g) were dosed at 25, 50, 100, 200 or 400 mg/kg bw with a single oral dose on day 0 and were observed daily for morbidity or other clinical signs. No animals died within the first 24 hours so two more dose groups were added to the range-finding assay on day 1 (600 and 800 mg/kg bw) to ensure that animal death would be observed in the range-finding assay. On day 7, the surviving test animals were sacrificed and their internal organs were examined. One rat from the 400 mg/kg dose group and three rats each from the 600 and 800 mg/kg dose groups died before their scheduled sacrifices. The LD50 was estimated to be approximately 443 mg/kg bw.
Dose levels for the definitive UDS assay were set at 90, 175 and 350 mg/kg bw (approximately 20, 40 and 80% of the estimated LD. Male rats approximately 9 weeks of age (196-228 g) were dosed 2 or 16 hours before sacrifice with test material, vehicle control or the positive control (dimethylnitrosamine given 2 hours before sacrifice). All dose groups contained three rats except the 16 hour 350 mg/kg dose-group, which contained four rats. One extra rat was dosed to avoid loss of data because of animal death. Three rats from the 16 hour 350 mg/kg dose group were found dead on the morning after dosing. This experiment was terminated after the first eight test animals yielded insufficient viable hepatocytes to evaluate for UDS probably because of a technical error in the preparation of the cell culture medium. A second UDS assay was conducted using new cell culture medium.
Another LD50 was estimated to be approximately 280 mg/kg bw based on the pattern of death observed in the first UDS assay. Dose levels for the second UDS assay were set at 50, 110 and 225 mg/kg bw (approximately 20, 40 and 80% of the LD50). A second definitive UDS assay was conducted as described above using the lower dose levels. Male rats approximately 9 weeks of age (175-208 g) were given a single oral dose of the test or control articles 16 or 2 hours before sacrifice. All dose groups contained three animals except the 16 hour high-dose group, which contained five animals Two extra animals were dosed to avoid loss of data because of animal death. One rat in the 110 mg/kg 16 hour dose group was found dead the following morning and could not be evaluated for UDS.
Primary cultures of liver cells on coverslips were obtained from these rats and labelled in vitro with 3H-methylthymidine for 14 to 18 hours. These culture coverslips were coated with Kodak NTB-2 emulsion, exposed, developed, and stained, and the autoradiographic grain counts were quantitated. The net grains/nucleus and percentage of cells in repair were determined. The test article was considered positive if the mean net grain count (NG) was greater than zero and the percentage of cells in repair (IR) for that group was greater than 20%.
Hepatocytes from male rats given up to 225 mg/kg mixtures of methyltin chloride or the negative control 16 or 2 hours before evaluation of UPS yielded NG between -9.0 and -6.1 and ≤2% ER. In contrast, positive control rats given DMN two hours before liver collection yielded 28.4 NG and 93% ER.
Liver cells from male rats were monitored in vitro for unscheduled DNA synthesis (UDS) after these rats were given oral doses of methyltin chloride (50, 110 or 225 mg/kg) 16 or 2 hours before collection of liver specimens. Results indicate that methyltin chloride is not genotoxic in male F-344 rat hepatocytes.
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