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

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Table 4. Treatment-related histopathological findings in rats treated topically with difenoconazole
for 28 days
Site/finding
No. of rats or
weighted grade a
Dose (mg/kg bw)
Males
Females
0 10 100 1000 0 10 100 1000
Skin application site No. examined 10 9 10 10 10 10 10 10
Hyperkeratosis Incidence 2 4 2 6 4 7 6 10
Weighted grade a 1.0 1.0 1.0 1.1 1.3 1.0 1.7 1.2
Liver No. examined 10 10 10 10 10 10 10 10
Hepatocellular
hypertrophy
Incidence 2 1 2 7 1 1 1 7
Weighted grade a 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
Thyroid gland No. examined 10 10 10 10 10 10 10 10
Hypertrophy of
follicular epithelium
Incidence 8 6 9 8 7 6 7 9
Weighted grade a 1.6 1.5 1.7 2.0 1.3 1.3 1.4 1.7
From Gerspach (2000)
a
Weighted grade is Σ (severity grade × No. of rats with that grade)/total examined.
females at 1000 mg/kg bw. In the thyroid, the incidence of minimal to moderate severity grades of hypertrophy
of the follicular epithelium was slightly increased in the group of rats at 1000 mg/kg bw.
The observations in liver were regarded as adaptive responses and therefore not adverse.
Although the thyroid follicular-cell responses could also be considered adaptive, the reason for stimulation
of the thyroid to occur was not so obvious, i.e. whether it was the result of a direct effect of
difenoconazole delivery by a route where liver is not the first pass, or it was an indirect effect secondary
to a hepatic response. There were no other treatment-related findings.
The NOAEL in rats exposed topically to difenoconazole for 28 days was 100 mg/kg bw per
day on the basis of marginal effects on thyroid and the site of skin application at 1000 mg/kg bw per
day (Gerspach, 2000).
Dogs
Groups of three male and three female pure-bred beagle dogs were given diets containing
difenoconazole technical (purity, 96.1%) at a concentration of of 0, 100, 1000, 3000 or 6000 ppm,
equal to 0, 3.6, 31.3, 96.6 and 157.8 mg/kg bw for males and 0, 3.4, 34.8, 110.6 and 203.7 mg/kg bw
for females, for 28 weeks. The dogs were aged 5–6 months at the start of dosing. Dietary analyses
showed that the difenoconazole was homogeneously distributed in the diet and was present at the targeted
concentrations throughout the study. Analyses performed before feeding was started indicated
that the diets were stable for at least 15 days at room temperature. The state of health of the dogs was
checked and recorded daily. Daily measurements were made of food consumption and body weights
before the dosing period and weekly thereafter. Physical examinations, including heart rate, rectal
temperature and hearing tests, were performed before the dosing period and during weeks 13 and 28.
Eye examinations were conducted on all dogs before the dosing period and every 2–3 weeks thereafter.
Haematology, blood chemistry and urine analyses were carried out on all dogs before the dosing
period and during weeks 17 and 28. All dogs were subjected to gross pathological assessment after at
least 28 weeks, followed by microscopic examinations of selected tissues and organs.
There were no mortalities in the study and difenoconazole did not induce clinical signs of toxicity
at any dose. Body-weight losses occurred in all dogs during the first week of the study, except
for one male and one female at 100 ppm.. The losses were marked in the group of dogs at 6000 ppm,
DIFENOCONAZOLE 201–272 JMPR 2007