Pesticide residues in food — 2007: Toxicological ... - ipcs inchem

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cell hyperplasia. The testes tumour incidences of 16% at 750 ppm and 20% at 2000 ppm are at the
upper bound of the range for historical controls (range, 4–20%; mean, 10.4 ± 6.6%; control groups
from studies performed 1986–1992) and statistically significant at the highest dose. The incidence
of benign adrenal medulla tumours of 16% in males is at the upper bound of the range for historical
controls (range, 1–17%; mean, 12%; control groups from studies performed 1997–2002).
The NOAEL was 750 ppm, equal to 33.9 mg/kg bw per day, on the basis of reduced body-weight
gain in both sexes and histological changes in the liver of females at 2000 ppm (Everett, 1991).
2.4 Genotoxicity
Dimethomorph was tested for genotoxicity in assays for reverse mutation with Salmonella
typhimurium and E. coli, an assay for HGPRT forward mutation assay with V79 cells, two assays for
chromosomal aberration in vitro with V79 cells, one assay for chromosomal aberration in vitro with
human peripheral lymphocytes, an assay for cell transformation, an assay for unschedulaed DNA
synthesis in vitro and an assay for micronucleus formation in mouse bone marrow in vivo. All studies
complied with GLP.
The summary of results is given Table 31. Except for the test for chromosomal aberration, all
tests for genotoxicity gave clear negative results. In the first of two assays for chromosomal aberration
in vitro with V79 cells (Heidemann & Miltenburger, 1986), at the first time-point of collection at
7 h an increase in the percentage of aberrant cells was observed at the highest doses with (8%) and
Table 30. Results of tests for chromosomal aberration with dimethomorph
Concentration (μg/ml) Percentage of cells that are aberrant, including gaps (excluding gaps)
Harvest at 7 h Harvest at 18 h Harvest at 28 h
+S9 −S9 MI +S9 −S9 MI +S9 −S9 MI
Heidemann & Miltenburger (1986)
0 (solvent) 3.0 (0.5) 2.0 (0.5) 100 2.5 (1.0) 7.0 (3.0) 100 2.5 (0.5) 3.5 (0.5) 100
12 — — — 7.5 (3.5) 3.0 (2.5) 157/159 — — —
60 — — — 1.0 (1.0) 2.5 (2.0) 177/138 — — —
160 (−S9); 170 (+S9) 8.0 (3.5) 8.0 (4.0) 26.2/47.6 1.5 (1.0) 5.5 (4.0) 243/212 4.5 (1.5) 4.5 (1.5) 74/97
Heidemann & Miltenburger (1987)
0 (solvent) 3.75 (1.25) 4.25 (1.25) 100 — 4.0 (1.25) 100 — — —
12 — — — — 4.0 (1.75) —/75 — — —
60 — — — — 5.0 (1.25) —/64 — — —
160 (−S9); 170 (+S9) 9.5 (6.75) 6.25 (3.5) 73/76 — 7.0 (3.5) —/77 — — —
van de Waart (1991a)
Harvest at 24 h
Harvest at 48 h
+S9 −S9 MI +S9 −S9 MI
0 (solvent) 1.5 (1.0) 0 (0) 100 2 (0.5) 3 (3) 100
1 2 (1.5) — 94/— — — 104/—
10 1.5 (1.5 0.5 (0.5) 86/79 — — 105/70
100 — 2 (1) 62/66 — — 71/65
333 2 (0) 2.5 (1) 61/53 — 1.5 (1) 83/74
422 a 18 (16) — 32/24 2 (1.5) 5.5 (3.25) 87/43
MI, mitotic index; S9, 9000 × g supernatant from rat livers.
a
Slight precipitation observed.
DIMETHOMORPH 273–315 JMPR 2007