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toxic for this compound, particularly for S. typhimurium TA1537 and TA98. A confirmatory test with
these strains used a highest dose of 1362 μg/plate. No significant response was observed in a single
study for mutations at the Tk locus in mouse lymphoma L5178Y cells in vitro, after exposure for 4 h
to difenoconazole at concentrations of up to 150 μg/ml or 50 μg/ml in the absence or presence of an
exogenous metabolic activation system, respectively (Dollenmeier, 1986a). Thus, difenoconazole did
not induce gene mutations in either bacterial cells or cultured mammalian cells.
Four studies on chromosomal aberrations were conducted, two in Chinese hamster ovary
(CHO) cells and two in human lymphocytes. The studies with CHO cells gave inconclusive results,
in that they were judged to be significant in one experiment in each study, but the result could not
be confirmed in independent experiments (Lloyd, 2001; Ogorek, 2001). On the other hand, the two
studies on chromosomal aberrations in human lymphocytes gave unambiguous negative results (Fox,
2001; Strasser, 1985).
No genotoxic activity was observed in a study for the induction of unscheduled DNA synthesis
(UDS) in primary cultures of rat hepatocytes exposed for 18–20 h to difenoconazole at concentrations
of up to 50 μg/ml. Higher concentrations were toxic (Hertner, 1992).
In a test for clastogenicity and aneugenicity, micronucleus formation was examined in bonemarrow
cells of Tif:MAGf (SPF) mice. Groups of five male and five female mice were given difenoconazole
at a dose of 0, or 1600 mg/kg bw orally by gavage on a single occasion and bone-marrow
cells were sampled after 16, 24 and 48 h. In a second experiment, groups of eight male and eight
female mice were given difenoconazole at a dos at 0, 400, 800 or 1600 mg/kg bw, and marrow cells
were sampled after 24 h. No increases in the frequency of micronucleated polychromatic erythrocytes
were observed in any group dosed with difenoconazole. Large increases in the frequency of
micronucleus formation were observed in both of the positive-control groups (Ogorek, 1991).
Table 8. Results of studies of genotoxicity with difenoconazole
End-point Test object Concentration/
d ose a (LED/HID)
Purity
(%)
Result
Reference
In vitro
Gene mutation
S. typhimurium strains TA100, TA1535,
TA1537, TA98; E.coli WP2 uvrA (± S9),
standard plate test
Gene mutation Mouse lymphoma L5178Y Tk locus 150 μg/ml −S9
50 μg/ml +S9
Chromosomal
aberration
Chromosomal
aberration
Chromosomal
aberration
Chromosomal
aberration
Unscheduled
DNA synthesis
In vivo
Micronucleus
formation
Chinese hamster ovary cells
Chinese hamster ovary
Human lymphocytes
Human lymphocytes
5447 μg/plate 91.8 Negative Ogorek
(1990)
34 μg/ml −S9
67 μg/ml +S9
59 μg/ml −S9
18 μg/ml +S9
40 μg/ml −S9
40 μg/ml +S9
75 μg/ml −S9, 3 h
10 μg/ml −S9, 20 h
62 μg/ml +S9
94.5 Negative Dollenmeier
(1986a)
94.3 EQ
EQ
94.3 Negative
EQ
Lloyd
(2001)
Ogorek
(2001)
94.5 Negative Strasser
(1985)
94.3 Negative Fox (2001)
Male Wistar rat, liver cells 50 μg/ml, 18–20 h 91.8 Negative Hertner
(1992)
Male and female Tif:MAGf (SPF) mice, bonemarrow
cells 16, 24 and 48 h after dosing
1600 mg/kg bw 91.8 Negative Ogorek
(1991)
HID, highest ineffective dose; EQ, equivocal response; LED, lowest effective dose; S9, 9000 × g supernatant from rat
livers.
DIFENOCONAZOLE 201–272 JMPR 2007