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

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The dosing solutions were prepared the day before use. Aliquots of the dosing solutions on 1
day from week 1, 2, 3, 4, 5, 8 and every 4 weeks thereafter, were analysed. The mean results of all the
analysed suspensions used were in the range 76.6–116.1% of nominal doses (the study report was not
provided). There were no treatment-related effects on mortality, organ weights, necropsy findings, histopathological,
ophthalmological, electrocardiography, urine analysis or clinical chemistry parameters. At
400/250 mg/kg bw per day, there was an increased incidence of vomiting that occurred within 30 min to
6 h after dosing (35.7% of doses in all males and 75% of doses in females) during week 1 of the study.
When the dose was reduced to 250 mg/kg bw per day, vomiting was decreased to about 1% in all dogs.
Incidents of coloured faeces or diarrhoea occurred in most of the dogs receiving pyrimethanil at intervals
throughout the study. At 30 mg/kg bw per day, the overall incidence of vomiting was 0.4% of the
doses in males only, which was not considered to be a toxicologically relevant effect since it may have
been caused by local irritation of the gastrointestinal tract. No treatment-related clinical sign including
vomiting was recorded at 2 mg/kg bw per day. After treatment at 400 mg/kg bw per day, a slight mean
body-weight loss occurred in males (0.8%) and females (2.5%) in the first week of treatment. There was
also an overall very slight reduction in body-weight gain (males, 6%; and females, 17%) throughout the
study at the highest dose. Overall mean body-weight gain at the highest dose (400/250 mg/kg bw) was
reduced by 50% in males and 73% in females when compared with those of the controls. Overall foodconversion
efficiency was reduced in males and females at the highest dose by about 50% and 98%,
respectively. Overall water consumption at 400/250 mg/kg bw was significantly decreased by 35% and
26% in males and females, respectively, at the highest dose. There was a slight but statistically significant
increase in leukocytes (mainly neutrophils) in males after 3, 6 and 12 months after treatment at
400/250 mg/kg bw per day. After 12 months at this dose, a slight reduction in clotting time was recorded
in males and females. There were no significant treatment-related effects at 2 or 30 mg/kg bw per day.
The NOAEL was 30 mg/kg bw per day and the LOAEL was 400/250 mg/kg bw per day on
the basis of decreased in body-weight gains, food consumption and feed efficiency, water consumption,
reduced clotting times and increases in neutrophils. The study author concluded that the NOEL
was 30 mg/kg bw per day and the NOAEL was 250 mg/kg bw per day (Rees, 1992). The difference
between the NOAEL identified by the Meeting and that identified by the study author was attributed
to the fact that the study author did not consider decreases in body-weight gains, decreases in feed
efficiency and reduced water consumption as adverse effects.
2.3 Long-term studies of toxicity and carcinogenicity
Mice
In a study of carcinogenicity in mice, groups of 51 male and 51 female Crl:CD-1(ICR)BR mice
were given diets containing pyrimethanil (purity, 96–97.3%) at a concentration of 0, 16, 160, or 1600 ppm
(equal to 0, 2.0, 20.0 or 210.9 and 0, 2.5, 24.9 or 253.8 for males and females, respectively) for up to
80 weeks. Diets were prepared twice per week. Stability, homogeneity and dietary concentrations were
confirmed analytically. The mice were inspected twice per day for mortality and morbidity. Changes in
clinical condition or behaviour were recorded daily. Detailed clinical observations were recorded weekly.
Body weight and food consumption were measured weekly for the first 16 weeks, then every 4 weeks
until termination. Water consumption was not measured. An ophthalmoscopic examination was not performed.
Blood was collected from 10 mice per group during weeks 26, 52 and 80. All mice that died and
those that were killed on schedule were subjected to gross pathological examination and selected organs
were weighed. Tissues were collected for histological examination from mice in the control group and in
the group at the highest dose, mice that died prematurely, and mice that were killed in extremis.
Pyrimethanil was homogenously distributed in the diet and was stable for a storage period of 3
days at room temperature. The measured concentrations were within the range of 85–100% of the target
concentrations except on a few occasions. At the end of the study, the survival of males was 67%,
PYRIMETHANIL 445–486 JMPR 2007