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

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beet and several vegetable and ornamental crops. It is applied by foliar spray or seed treatment and acts
by interference with the synthesis of ergosterol in the target fungi by inhibition of the 14α-demethylation
of sterols, which leads to morphological and functional changes in the fungal cell membrane. Difenoconazole
is being reviewed for the first time by the present Meeting at the request of the Codex Committee on
Pesticide Residues (CCPR). All critical studies complied with good laboratory practice (GLP).
Evaluation for acceptable daily intake
1. Biochemical aspects
1.1 Absorption, distribution and excretion
The absorption, distribution and excretion characteristics of difenoconazole were studied extensively
in male and female rats (Esumi, 1992; Craine, 1987a, 1987b). The structure and positions of the
radiolabel are shown in Figure 1. A single oral dose of [ 14 C-phenyl]difenoconazole at 0.5 mg/kg bw was
rapidly and almost completely absorbed by male and female rats. A single oral dose of [ 14 C-phenyl]difenoconazole
at 300 mg/kg bw was less extensively absorbed since bile-duct cannulated male and female rats
excreted 17% and 22%, respectively, of the dose in faeces. Maximum blood concentrations were reached
within 2 h, followed by a rapid decline for the lower dose and after approximately 4 h, with an initial slow
decline up to 24 h, for the higher dose, after which the rate of decline was similar to the lower dose.. In females
the difference in area under the blood concentration−time curve (AUC) measurements between the
lower and higher doses matched the dose differential, while in males the AUC differential was 400-fold.
The systemic dose was eliminated predominantly via bile where it accounted for 73% of the administered
dose (0.5 mg/kg bw) in males and 76% in females. Urinary excretion by bile-duct cannulated
rats accounted for 14% of the administered dose in males and 9% in females, with faecal excretion
representing less than 4% of the dose and thereby confirming the almost complete absorption at the
lower dose. When bile from male rats at 0.5 mg/kg bw was administered intraduodenally to other bileduct
cannulated rats, 80% of the dose was re-eliminated via the bile and just 4% in the urine, thereby
demonstrating enterohepatic recirculation. Bile was also the major route of eliminryation at 300 mg/kg
bw, accounting for 56% of the administered dose in males and 39% in females, while urinary excretion
represented only 1% of the dose. In non-cannulated male and female rats given a single oral dose of [ 14 C-
phenyl]difenoconazole or [ 14 C-triazole]difenoconazole at 0.5 mg/kg bw, 13–22% of the administered
dose was excreted in the urine and 81–87% in the faeces. In non-cannulated male and female rats given a
single oral dose of [ 14 C-phenyl]difenoconazole or [ 14 C-triazole]difenoconazole at 300 mg/kg bw, 8–15%
of the administered dose was excreted in the urine and 85–95% in the faeces. There was no pronounced
difference in excretion profiles, either between the sexes or between the two radiolabelled forms at either
dose. When a similar dose of [ 14 C-phenyl]difenoconazole or [ 14 C-triazole]difenoconazole was given to
rats pre-treated with 14 daily oral doses of unlabelled difenoconazole at 0.5 mg/kg bw, there was neither
Figure 1. Position of the radiolabels on [ 14 C-phenyl]difenoconazole and [ 14 C-triazole]
d ifenoconazole
Cl
Cl
O
*
Cl
O
N
O N
N
O
Cl
O
N *
O N
N
[ 14 C-phenyl]difenoconazole [ 14 C-triazole]difenoconazole
DIFENOCONAZOLE 201–272 JMPR 2007