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

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Microscopic examinations revealed initial changes in the lens, indicative of cataract, in three
out of five males and one out of five females treated with difenoconazole. The lesions comprised
slight swelling of the epithelial cells either at the equator or anteriorly, and/or necrosis of the lens
fibres posteriorly, under the capsule or in the outer cortex. Among the chickens in the positive-control
group, two out of three males developed changes indicative of cataract (necrosis of the lens fibres,
posterior under the capsule); one female in the positive-control group showed a slight swelling of the
lens epithelium at the equator. No changes were seen in the lenses of the chickens in the negativecontrol
group (Schoch & Schneider, 1989). The sponsor considered that, in the absence of dose–
response information, this high-dose phenomenon should be considered of no human relevance;
however, the experimental design was such that a dose–response relationship could never have been
observed.
Dogs
In a study of cataract induction, groups of three male and three female pure-bred beagle dogs
(KFM Kleintierfarm Madoerin, Füllinsdorf, Switzerland) were given diets containing difenoconazole
technical (purity 95%) at a concentration of of 0, 3000, 4000 or 6000 ppm for up to 18 weeks
according to a complex dosing schedule (Table 22).
Mortality was checked and clinical signs were recorded daily. Individual body weights were
recorded weekly and food consumption was recorded daily. Eye examinations were conducted on all
dogs before exposure and every 2 weeks thereafter. Haematology and blood chemistry investigations
were carried out on all dogs before the exposure period and during weeks 3, 13 and 19. Surviving
dogs were killed in week 19. All dogs were subjected to a detailed autopsy. Specified organs were
weighed. Eyes and tissues with macroscopic findings were examined microscopically.
There were no deaths in the test. The only clinical signs noted were vomiting in the male in the
reference group and a female in the recovery group during the first study week and faecal changes in
the female in the reference group during weeks 6 and 9, a male in the recovery group during week 10
and a female in the recovery group during week 14.
All dogs lost body weight during the first study week, 13–14% from initial values in the males
and 11–15% in the females. After the dietary concentration was reduced to 3000 ppm, all dogs began
to gain weight. The males in the reference and recovery groups gained weight at approximately
the same rate, but the female in the reference group gained weight at a slower rate than those in the
r ecovery group and lost weight again when the dietary concentration was increased to 4000 ppm.
Food consumption was markedly depressed in all dogs during the first study week, being between
72 and 85% lower than the last value recorded before dosing for males and 81–88% lower for
the females. Food consumption increased for all dogs when the concentration was lowered to 3000
ppm. By week 3, all males and the females in the recovery group were consuming all of the diet
o ffered. The female in the reference group consistently consumed less than the other dogs.
Table 22. Dosing schedule used in a special study of cataract induction in dogs fed diets
c ontaining difenoconazole
Time-point
Dietary concentration (ppm)
Group 1 (reference)
Group 2 (recovery)
Male No. 1 Female No. 1 Male No. 2 Female No. 2 Male No. 3 Female No. 3
Week 1 6000 ppm 6000 ppm 6000 ppm 6000 ppm 6000 ppm 6000 ppm
Weeks 2–3 3000 ppm 3000 ppm 3000 ppm 3000 ppm 3000 ppm 3000 ppm
Weeks 4–9 3000 ppm 3000 ppm 0 ppm 0 ppm 0 ppm 0 ppm
Weeks 10–18 4000 ppm 4000 ppm 0 ppm 0 ppm 0 ppm 0 ppm
DIFENOCONAZOLE 201–272 JMPR 2007