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

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was observed (relative to controls): (a) minimal to slight pigmentation of the follicular cells in the
thyroid in males (five out of five) and females (two out of five); (ii) minimal to moderate urothelial
hyperplasia (three out of five) and uroliths present in the lumen of the urinary bladder (one out of
five) in males; and (iii) minimal to slight basophilic tubules (two out of five) and slight tubular degeneration
(two out of five) in the kidneys in females. At 3000 ppm, relative adrenal weights in males
were significantly increased (+40–43%; p ≤ 0.05). But there were no significant effects at 10 000
ppm; thus the significance of this effect seems questionable. No other treatment-related effects were
observed at 3000 ppm. No treatment-related effects were observed in the group at 1000 ppm.
The lowest-observed-adverse-effect level (LOAEL) was 10 000 ppm (equivalent to 1960/2357
mg/kg bw per day for males/females) on the basis of decreased body weights, body-weight gains,
food consumption, and food-conversion ratio and on increased incidences of clinical signs (emaciation,
general pallor, and piloerection) and microscopic findings in the thyroid, kidneys, and urinary
bladder. The NOAEL was 3000 ppm, equivalent to 567/667 mg/kg bw per day for males/females. The
study author concluded that the no-observed-effect level (NOEL) was 1000 ppm (Harvey, 1991b).
In a 90-day feeding study, groups of 20 male and 20 female Crl:CD-1(ICR)BR mice were fed
diets containing pyrimethanil (purity, 97.7–97.9%) at a concentration of 0, 80, 900, or 10 000 ppm
for 13 weeks. Those doses were equivalent to 0, 12, 139 or 1864 mg/kg bw per day for males and 0,
18, 203 or 2545 mg/kg bw per day for females, respectively. Diets were prepared twice each week.
Stability, homogeneity and dietary concentrations were confirmed analytically. Mice were inspected
twice per day for signs of toxicity and mortality, with detailed cage-side observations were made
once per day. Body weight and food consumption were measured each week. At termination, blood
was taken for haematological and clinical chemistry analyses. Urine analysis and ophthalmoscopic
examinations were not performed. All mice that died and those sacrificed on schedule (10 males and
10 females per group) were subjected to gross pathological examination and selected organs were
weighed. Selected tissues were collected for histological examination.
The results on test article homogeneity were reported in a separate report (not submitted to
the Meeting). The test article was stable in the diet for 4 days at room temperature. The concentration
analysis of the test substance indicated that the measured concentration ranged from 87.1% to
100.8% of the target concentrations. There were no treatment-related effects on mortality, clinical
signs or water intake. The body weights measured each week did not show statistically significant
difference between groups. At 10 000 ppm, total body-weight gains were 12.4% lower in males and
7.2% lower in females than in the control group. There was an overall increase in food consumption
(14.1% in males, 9.8% in females) compared with controls, resulting in reduced food-conversion ratios
in treated mice. Clinical chemistry parameters showed significant increases in serum cholesterol
and total bilirubin concentration (in females only). No treatment-related effects on haematological
parameters were observed. Treatment-related necropsy findings included dark thyroid glands in eight
out of ten males and a bladder stone in one out of ten females. Significantly increased liver weight
in females and increased relative-liver-weight-to-body-weight ratios in males and females were observed
at the highest dose. Histopathological changes were detected in the kidneys, liver, thyroid
glands, and urinary bladder. Tubular dilation was seen in the kidneys of three out of ten males.
Uroliths were detected in urinary bladders of one out of ten males and four out of ten females (one
bladder-stone was detected at necropsy), with three out of ten females showing hyperplasia of the
bladder epithelium at the highest dose. There was marked depletion of glycogen in the liver of males
and females as indicated by decreased margination of cytoplasm and reduced intensity of periodic
acid Schiff (PAS) staining (performed for males only). In the thyroid gland, exfoliative necrosis of
follicular cells was seen in eight out of ten males and one out of ten females. Pigmentation of follicular
cells was seen in ten out of ten males and nine out of ten females at 10 000 ppm. Special staining
techniques indicated that the pigment was lipofuscin. At 900 ppm, some glycogen depletion was
PYRIMETHANIL 445–486 JMPR 2007