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

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of the test article on microsomal cytochrome P450. All spectra indicated low- and high-affinity microsomal
binding sites for difenoconazole, with approximate spectral dissocation constants K S1
and
K S2
between 0.22 and 0.43 μmol/l and 1.73 and 5.27 μmol/l, respectively. A unique binding site for
difenoconazole (K S1
= 1.99 μmol/l) was identified in mice treated at 400 mg/kg bw per day.
The ultramorphological analysis of liver sections from the mice treated with difenoconazole
at 400 mg/kg bw revealed a distinct proliferation of smooth and rough endoplasmic reticulum membranes
and a disorganization of rough endoplasmic reticulum membranes, leading to a mixture of
smooth and rough endoplasmic reticulum elements, mostly in vesicular form. After the 28-day recovery
period, hepatocytes from mice in the control group and mice treated with difenoconazole were
essentially the same (Thomas, 1992).
Difenoconazole is considered to be a reversible barbiturate-type inducer of metabolizing enzymes
in the mouse liver. No peroxisome proliferation was observed. The dose of 10 mg/kg bw per
day was a no-observed-effect level (NOEL), without an inductive effect on metabolizing enzymes
and other parameters in the mouse liver.
(d)
Cataract induction
Chickens
In a study of cataract induction, a group of five male and five female Hisex chickens were given
diets containing difenoconazole technical (purity ≥ 95%) at a concentration of 5000 ppm for 8 weeks.
An additional three male and three female chickens received the basal diet only and three male and
three female chickens received the diet admixed with 2,4-dinitrophenol at 2500 ppm as a positive control.
Mortality was checked and clinical signs were recorded daily. Eye examinations were conducted
on all chickens twice per week. Individual body weights were recorded weekly and food consumption
was recorded daily. Surviving chickens were killed on study day 57. The eyes were removed and fixed
in buffered 10% neutral formalin and subsequently processed for histopathological examination.
There was no mortality among the mice in the negative- or positive-control groups or among
the male treated with difenoconazole. One female receiving difenoconazole died on study day 36.
The clinical sign of ruffled feathers was seen in all test groups and all hickens in the positive-control
group from day 7 until study termination; reduced locomotor activity and ventral recumbency were
also noted for the female that died. There were no clinical signs among the chickens in the control
group. Body weights of the males receiving difenoconazole were significantly (p < 0.05) lower than
those of the chickens in the control group from day 14 onwards; body weights for females receiving
difenoconazole were significantly lower from day 7 onwards. Mean body weights of males and females
in the positive-control group were also consistently lower than those of chickens in the control
group and slightly higher than those of the chickens receiving difenoconazole. Food consumption by
the difenoconazole-treated chickens was markedly less than that of the chickens in the control group
throughout the study. Food consumption by chickens in the positive-control was also lower than that
of the controls, but higher than that of chickens receiving difenoconazole.
Ophthalmoscopic examinations revealed lens alterations in all males treated with difenoconazole,
two out of five females treated with difenoconazole, all chickens in the positive-control group
and one in the negative-control group. Slight lens alterations were seen between days 24 and 35 in
three males and one female treated with difenoconazole. Slight to moderate but irreversible lens
alterations developed between days 45 and 56 in one female and four males treated with difenoconazole.
In contrast, all chickens treated with 2,4-dinitrophenol showed marked lens opacities on day
3, which diminished in severity on day 7 and persisted as slight alterations through study termination
(except for one female for which there were no findings after day 38). Yellow/grey discoloration
was also observed in the eyes of chickens in the positive-control group from day 31 onwards. The
slight, transient alterations seen in the one male in the negative-control group were considered to be
s purious.
DIFENOCONAZOLE 201–272 JMPR 2007