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

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43%, 71% and 59% (control, lowest, intermediate and highest dose, respectively). The difference in
survival between males in the control group and males at the lowest dose was statistically significant.
The survival of treated and control females was similar (76%, 80%, 76% and 78% for control group to
group receiving the highest dose, respectively). There was no dose-related adverse effect on survival of
males or females and adequate numbers of male and female mice were available at study termination.
No adverse effects were observed on body weight or body-weight gain, food or water consumption,
clinical or haematological parameters, or organ weights. No treatment-related differences in palpable
masses were recorded. The incidence of macroscopic lesions was comparable among the groups (males
and females), with the exception of an increase in the incidence of urinary bladder distension in the
treated males. Males receiving pyrimethanil displayed a higher incidence of urinary bladder distension
at necropsy, and the incidence of lesions of the urogenital tract were increased at the highest dose compared
with the control values. In the first 52 weeks of treatment, an increase in the incidence of lesions
of the urogenital tract was seen in the treated males, 31% occurring in the groups at the lowest and
intermediate doses, and 57% in the group at the highest dose, while the incidence in the control group
was 18%. There was no evidence for an increase in the incidence of any tumour type in either sex.
The NOAEL for systemic effects was 160 ppm, equal to 20.0 mg/kg bw per day, on the basis of
increased incidences of lesions of the urinary tract, including bladder distension and thickening seen at
1600 ppm (210.9 mg/kg bw per day), in males. The NOAEL in female mice was 1600 ppm (equal to
253.8 mg/kg bw per day, the highest dose tested). The study authors (Clay & Healing, 1993; Clay, 1994;
Healing, 1995c; Clay, 1995; Clay, 1996; Patton, 1995) concluded that the NOEL for males and females
was 160 ppm, equivalent to 20.0 and 24.9 mg/kg bw per day for males and females, respectively.
A report on survival data for historical controls and, in relation to this, some necropsy/histopathology
findings (primarily concerning the urinary bladder) were provided to the country preparing the
EC draft assessment (Austria). The overall survival at 80 weeks was approximately 58% for males and
78% for females in the study of carcinogenicity in mice. The data for historical controls from the performing
laboratory for 1993–2000 indicate a mean survival of 66.5% for males and 73.3% for females
at week 80. The study author (Reader, 2003b) concluded that the overall pattern of mortality observed
in the study of carcinogenicity in mice would not suggest an effect of treatment with pyrimethanil compared
with data for historical controls. The slightly lower survival of male mice in the study of carcinogenicity
compared with females may have been primarily attribuatble to male aggression exacerbated
by co-housing. The study authors suggested that lesions in the urogenital region of males led to a large
proportion of the cases of morbidity and mortality. The incidence of bladder distension in the historical
controls for the male decedents was 40% at week 52 and 21% for the terminal kill compared with
43% observed in the study of carcinogenicity. The study authors suggested that the pattern seen in the
study of carcinogenicity was caused by an underlying inflammatory response in the male mice, which
was confirmed at terminal necropsy that showed more than 40% of the males in the control group had
inflammatory cell foci. The study authors further concluded that at the highest dose of pyrimethanil,
1600 ppm, the incidence of bladder distention slightly exceeded the value for historical controls and
may suggest an effect at this dose. The Meeting considered that, on the basis of study results, it was not
clear that the effects in males were treatment-related since values were within the range for historical
controls and the dose–response relationship could not be evaluated since tissues from the urogentital
tract were not examined in mice at the lowest and intermediate doses (Reader, 2003b).
Rats
In a combined long-term study of toxicity/carcinogenicity, groups of 50 male and 50 female Sprague-
Dawley Crl:CD(SD)BR rats were given diets containing pyrimethanil (purity, 95.5.2–97.6%) at a nominal
concentration of 0, 32, 400, or 5000 ppm (equal to 0/0, 1.3/1.8, 17.0/22.0, or 221/291 mg/kg bw per day in
males/females, respectively) for up to 104 weeks. Additional groups of 20 males and 20 females were sacrificed
at 52 weeks (interim kill). Diets were prepared twice per week throughout the study. Stability, homogeneity
and dietary concentrations were confirmed analytically. Rats were inspected twice per day for
PYRIMETHANIL 445–486 JMPR 2007