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

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mortality and morbidity. Changes in clinical condition and behaviour were recorded daily. Detailed clinical
observations were recorded weekly. Body weight and food consumption were measured weekly for
the first 13 weeks, then monthly for the rest of the study. Water consumption for each cage was measured
over 4-day periods ending on weeks 9, 16, 32 and 48 of treatment. An ophthalmoscopic examination was
performed before treatment, during week 50 and during week 104. Blood and urine were collected during
weeks 13, 26, 52, 78 and week 102. An additional bleed was conducted during week 72 for measurement
of thyroid hormones, thyrotrophin, thyroxine (T4) and triiodothyronine (T3). Haematological parameters
examined were erythrocyte count, leukocyte count, erythrocyte volume fraction, haemoglobin, platelet
count, differential leukocyte count and cell morphology. Standard clinical-chemistry and urine-analysis
parameters were examined. At week 52, 20 males and 20 females from each group were necropsied and
examined histopathologically. At termination, all rats were necropsied and examined histopathologically.
Liver, kidney, spleen, testes, ovaries, heart, brain and adrenals were removed and weighed. Selected tissues
were examined histopathologically.
Pyrimethanil was uniformly distributed in the diet and was stable at room temperature for 4
days (less than 11% of nominal dose lost over 8 days storage at room temperature). The measured test
concentrations ranged from –15% to +10% of the nominal concentrations, except for some results at
32 ppm and 400 ppm (Bright, 1993).
There was no treatment-related mortality or clinical signs of toxicity. A decreased incidence of palpable
masses (24%) in females at 5000 ppm was observed, and the mean time of onset was approximately
9 weeks later than that of controls. However, there was no indication that the delayed onset was caused by
treatment with pyrimethanil. Throughout the study, males and females at 5000 ppm consistently displayed
significantly lower mean body weights than did the controls. The body-weight gains of rats at 5000 ppm for
0–13 weeks were lower than those of the controls (males, 10%; and females, 16%). Overall body-weight
gains of rats at 5000 ppm were lower (males, 5%; and females, 42%) than those of the controls. There was
no significant difference in the mean body weights of rats at 400 ppm or 32 ppm. Food consumption was reduced
by approximately 5% in males and 11% females in the group at 5000 ppm compared with rats in the
control group. However, the food-conversion ratios were not significantly different between rats receiving
pyrimethanil and rats in the control group. There was no significant effect on water consumption. Ophthalmoscopic
examination did not revealed any treatment-related lesions at any dose. At 5000 ppm, statistically
significant d ifferences from control values were observed in several parameters at various intervals.
Leukocyte counts were decreased at weeks 78 and 102 for males only and erythrocyte counts
were decreased at weeks 13 and 26 for females only. Decreased MCH concentrations were observed
at week 52 and 78 for males and females, and also at weeks 13 and 26 for females. Increased platelet
counts were observed at weeks 13 and 26 for males and females, and at weeks 52 and 78 for females
only. At 400 ppm, a statistically significant increase in platelet counts was observed at week 26 in
females only, while a decreased platelet count was observed at week 102 in males. Other group mean
values for haematological parameters in rats at 32 ppm and 400 ppm were essentially similar to those
of the controls. All haematological data were within the range for historical controls, there was a lack
of dose–response relationship and effects tended to be transient and inconsistent over time. Thus,
these haematological findings were considered to be of no toxicological significance. At 5000 ppm,
slightly elevated gamma glutamyl transpeptidase (GGT) activity were observed after 78 and 102
weeks in males. There was slight to moderate increased in cholesterol concentrations in males at 13
and 26 weeks and in females at all sampling points. Decreases in serum phosphate concentrations
were observed between weeks 13 and 78 in males and females (at all doses in males and at the lowest
and highest doses in females). Phosphate concentrations were within the range for historical controls
and the noted decreases were transient and not always dose-related (Reader, 2003a). Concentrations
of thyroid hormones were normal at 72 weeks. There were no significant treatment-related effects on
urine-analysis parameters. However, a brownish-black urine coloration, which darkened on standing,
was reported in certain males and females at 5000 ppm throughout the treatment period.
PYRIMETHANIL 445–486 JMPR 2007