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

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Table 1. Key parameters of blood kinetics in rats given a single oral dose of radiolabelled
d ifenoconazole
Parameter 0.5 mg/kg bw 300 mg/kg bw
Males Females Males Females
C max
(ppm) 0.327 0.169 47.89 30.02
T max
(h) 2 0.5 4 4
T 1/2
1st phase (h) 6.2 4.4 22 24
T 1/2
2nd phase (days) 2.8 3.7 3.8 3.4
AUC (0–168 h) (µg
equivalents/h·per ml)
6.19 2.78 2460 1710
From Esumi (1992)
Tissue depletion results showed that at 2 h and 24 h after a dose of [ 14 C-phenyl]difenoconazole
at 0.5 mg/kg bw, only in the liver and kidney were concentrations consistently higher than those in
plasma for both sexes. Consistent results were observed in whole-body autoradiography sections of
similarly-dosed male rats, since at 2 h and 24 h after dosing most of the radioactivity was present in
the gastrointestinal tract contents and in bile, with lower concentrations in the liver and kidneys. Other
tissues with concentrations initially higher than in plasma were adrenal glands in both sexes and
Harderian glands and adipose tissue in females; however, these concentrations declined rapidly. After
168 h, [ 14 C-phenyl]difenoconazole residues in tissue were very low, with only fat showing concentrations
comparable to those present in plasma, while all tissue residues of [ 14 C-triazole]difenoconazole
were either below the limit of detection or below the limit of quantification. For both radiolabelled
forms of difenoconazole, residues in female tissues also tended to be slightly lower than those in
males and pre-treatment with unlabelled test substance had no effect on tissue d istribution.
Tissue depletion results showed that at 4 h after a dose of [ 14 C-phenyl]difenoconazole at 300
mg/kg bw, most tissue concentrations were similar to or higher than those in plasma in both sexes.
The highest tissue concentrations were present in fat in both sexes, with progressively lower concentrations
in the liver, Harderian glands, adrenal glands, kidney and pancreas. In all other tissues that
initially showed concentrations higher than those in plasma concentrations declined rapidly by 48 h
after dosing and by 168 h all tissue residues of [ 14 C-phenyl] difenoconazole had declined markedly,
only fat showing residues that were higher than in plasma. Tissue residues of [ 14 C-triazole]difenoconazole
were significantly lower than those of [ 14 C-phenyl]difenoconazole residues and by 168 h
were measurable only in the liver. Measurements in the contents of the gastrointestinal tract were
consistent with the observed absorption and elimination profiles.
After 14 days of [4-chloro-phenoxy-U- 14 C]difenoconazole at a dose of at 0.5 mg/kg bw per day
(Hassler, 2003a), the absorbed radiolabel was rapidly and almost completely excreted, predominantly
via the faeces. More than 90% of the total administered radiolabel was excreted within 24 h after the
last dose and 98.5% of the total radiolabel was recovered within 7 days. At that time, less than 0.5% of
the administered dose remained in the tissues and carcass. Metabolite profiles in the urine and faeces
were qualitatively similar at each time-point, although small quantitative differences were observed after
the administration of single and multiple oral doses. Concentrations of radioactive residues reached
a plateau in most tissues after 7 days. Residue concentrations increased with continued dosing in liver,
kidneys, fat and pancreas and did not reach a plateau during the dosing period; however, it was estimated
that residue concentrations would reach a plateau within 3 weeks. The depletion of radioactive residues
from tissues was moderately fast. Assuming first-order kinetics and monophasic depletion kinetics
for the depuration of radiolabel from tissues, the half-lives ranged typically from 4–6 days. Depletion
was more rapid in the liver, kidneys and pancreas, with half-lives of 1–3 days, and slower in fat, with
a half-life of 9 days. Experiments with position-specific radiolabelled compounds (Capps et al., 1988)
DIFENOCONAZOLE 201–272 JMPR 2007