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

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still evident in the liver; however, no significant histopathological finding was reported at this dose.
This condition is associated with the nutritional and/or physiological status of the mice and has no
t oxicological significance. At 80 ppm, no treatment-related effects were detected.
The NOAEL was 900 ppm, equal to 139 and 203 mg/kg bw per day for males and females,
respectively, on the basis of decreased body-weight gains, slightly increases in cholesterol and total
bilirubin concentration, an increase in liver weight, and histopathological findings in the thyroid,
kidney and kidney stones seen at the LOAEL of 10 000 ppm, equal to 1864 and 2545 mg/kg bw per
day for males and females, respectively (Harvey & Rees, 1991).
Rats
In a 10-day dose range-finding study, groups of three male and three female CR1:COBS
CD(SD)BR rats were given pyrimethanil (purity, 99.7%) at a dose of 0, 10, 100, or 1000 mg/kg bw
per day by gavage in 1% aqueous methyl cellulose for 10 days. All dose suspensions were prepared
fresh each day. Stability and homogeneity were confirmed analytically. Rats were inspected twice per
day for signs of toxicity and mortality, with detailed cage-side observations performed once each day.
Body weight and food consumption were measured 3 days before start, at start and at 3-day intervals
during the study. At termination, blood was taken for haematological and clinical chemistry analyses.
Rats were killed and examined macroscopically. Selected tissues were collected for histopathological
examinations.
There were no treatment-related effects on mortality, clinical signs, food consumption or on
haematological parameters. There was a slight decrease in body-weight gain (10%) in males observed
initially at the highest dose only. At termination, the body weights of treated groups were comparable
to those of the control group. At 1000 mg/kg bw per day, the plasma cholesterol concentration was
slightly increased in males (2.86 vs 2.12 in controls) and moderately increased in females (2.92 vs
1.87 in controls). Necropsy findings were comparable in the control group and treated groups. The
highest dose of 1000 mg/kg bw per day for 10 days was tolerated by rats (Harvey, 1992b, 1992c).
At 1000 mg/kg bw per day, colloid depletion was seen in the thyroid gland (two out of three males
and one out of three females) and some follicular-cell hypertrophy was evident. At 100 mg/kg bw
per day, for one male only, some moderate colloid depletion was observed. Moderate follicular-cell
hypertrophy was evident in one out of three males. No histopathological changes were observed at
10 mg/kg bw per day (Harvey, 1992b, 1992c).
In a 28-day dose range-finding study, groups of five male and five female Crl:CD(SD)BR rats
were fed diet containing pyrimethanil (purity, 99.2–99.7%) at a dose of 0, 10 000, 15 000, or 30 000
ppm (equivalent to 0, 844, 1161 or 2701 mg/kg bw per day for 28 consecutive days. An additional
group of five males and five females received pyrimethanil at a dose of 1500 mg/kg bw per day in 1%
aqueous methyl cellulose by oral gavage for 11 days, after which the dose was reduced to 1000 mg/
kg bw per day owing to adverse clinical signs. Diets were prepared each week. Stability, concentrations
and homogeneity were confirmed analytically. Rats were inspected twice per day for signs of
toxicity and mortality, with detailed cage-side observations performed once per day. Body weight
was measured twice per week. Food consumption was measured each week. Ophthalmological examinations
were performed before the start of the study and at termination. At termination, blood was
taken for haematological and clinical chemistry analyses. All surviving rats were killed and examined
macroscopically. Selected organs were weighed. Selected tissues were collected for histopathological
examinations.
The diets were reported to be homogenous and analytical concentrations were within the
range -15% to +10% of the nominal. The study report containing the results of analytical measurement
was not available to the JMPR. There was no treatment-related effect on mortality in the group
treated by gavage nor in the groups given diets containing pyrimethanil. Two females (day 7 and
day 9) and one male and one female (day 15) in the group treated by gavage were killed in extremis.
PYRIMETHANIL 445–486 JMPR 2007