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

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In a 90-day feeding study, groups of 10 male and 10 female Crl:CD(SD)BR Sprague-Dawley
rats were fed diets containing pyrimethanil (purity not stated) at a concentration of 0, 80, 800, or
8000 ppm for 13 weeks (equal to 0/0, 5.4/6.8, 54.5/66.7 or 529.1/625.9 mg/kg bw per day, for males/
females, respectively). Additional groups of 10 males and 10 females were given diets containing pyrimethanil
at a concentration of 0 or 8000 ppm, the highest dose, for 13 weeks, and then maintained
on diets without pyrimethanil for 4 weeks to investigate the reversibility of any findings. Diets were
prepared each week. Stability, homogeneity and dietary concentrations were confirmed analytically.
The rats were inspected twice per day for signs of toxicity and mortality, with detailed cage-side
observations performed once per day. Body weight and food consumption were measured before
treatment, at start of treatment, each week during treatment and at necropsy. Ophthalmoscopic examination
was performed on all rats at start of treatment and on the rats in the control group and at the
highest dose at termination (91 days). Urine analysis was performed on all rats after 90 days and also
during the first week for rats in the reversibility group. Blood was taken for haematology and clinical
chemistry measurements at week 4 and 13, and during the final week before termination for groups
in the reversibility study. At termination, all rats were necropsied and examined histopathologically.
Selected organs were weighed. Selected tissues were collected for histological examination.
Test diets were stable for 4 days at room temperature, so diets were deep-frozen and thawed before
use. The analytical concentrations were in the range of −15% to +10% of nominal concentrations.
Results on homogeneity were reported elsewhere and were not submitted to the JMPR. There were no
treatment-related effects on mortality, clinical signs, water intake, ophthalmology, haematology, clinical
chemistry or macroscopic findings. Mean body weight and body-weight gains of males and females
at 8000 ppm were consistently lower than those of the controls. The overall decreases in body-weight
gains were 28% in males and 33% in females. Body-weight gains of rats at 80 or 800 ppm was similar
to those of controls. During the reversibility period, increases in body-weight gains were apparent in
males and female previously given diets containing pyrimethanil at 8000 ppm. However, the total body
weights were still lower than those of the controls (15% in males and 13% in females). During the first
week of treatment, marked reductions (33%) in food intake of males and females at 8000 ppm were noted
when compared with those of rats in the control group. From week 2 of the study onwards, the food
intake of males and females at 8000 ppm was slightly reduced (overall, by 16% in males and 17% in
females) when compared with those of controls. Food intake of rats at 80 or 800 ppm was comparable
to that of controls throughout the study. During the reversibility period, rats previously at 8000 ppm ate
similar amounts to rats in the control group. Food conversion efficiencies were similar between treated
and control groups, except for the first week when they were decreased for rats at 8000 ppm. Urine
analysis showed dark brown coloration in males and females at 8000 ppm and 800 ppm. At 8000 ppm,
the group showed increases in urinary protein compared with the controls. At the end of the reversibility
period, the urine samples of males and females previously at 8000 ppm were comparable to those
of controls. Significantly lower absolute weights of the heart and adrenals in males and females, and
the spleen, kidney, and thymus weight in females were observed at 8000 ppm. Significant increases in
relative organ weight to body weight ratios were seen in the brain, liver, gonads, and kidneys for males,
and the brain, liver, and kidney for females. These changes could be considered to reflect the growth retardation
observed in rats at 8000 ppm. No changes in organ weights were apparent in rats previously at
8000 ppm and killed at the end of reversibility period. It was stated in the study report that organ-weight
changes in the groups at 800 and 80 ppm were within the range of values for control groups (although
ranges for organ weights of rats in the control groups were not presented in the report). At 8000 ppm,
microscopic pathology showed an increased incidence of liver hypertrophy in centrilobular hepatocytes
(males, nine out of ten; females, three out of ten), increases in the incidence and severity of follicular
epithelial hypertrophy (males, nine out of ten; females, six out of ten), and epithelial brown pigment
(males, eight out of ten; females, seven out of ten) were seen. At 800 ppm, an increased incidence
(two out of ten) of centrilobular hepatocyte hypertrophy was seen. After the 28-day recovery period,
c entrilobular hepatocyte hypertrophy was not apparent in rats previously at 8000 ppm.
PYRIMETHANIL 445–486 JMPR 2007