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

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Analysis of dosing solutions indicated that the formulations were homogenous and the measured
concentrations were within 15% of the target concentrations. Maternal toxicity at 300 mg/kg
bw per day included significant decreases in body weight (6–8%), body-weight gain (29%) and decreases
in food consumption (35–42%). Decreased food consumption resulted in increased incidence
of rabbits with reduced production and size of faecal pellets. In addition, three rabits became emaciated,
due to the decreased consumption, and were subsequently sacrificed on days 24, 15 and 22 of
gestation. At 45 mg/kg bw per day, a slight increase in the number of dams with reduced production
and size of faecal pellets (less frequent and of shorter duration) was seen, but was not considered to
be an adverse treatment-related effect. At 7 mg/kg bw per day, no treatment-related maternal effects
were noted. Treatment-related developmental findings at 300 mg/kg bw per day, when compared
with those for concurrent controls, included decreases in fetal weight (10%), increases in fetal runts,
increases in the incidence of retarded fetal bone ossification, and increases in the incidence of extra
thoracic vertebrae and ribs. The increased number of fetal runts was outside the range for historical
controls. The Meeting requested a clarification on the criteria used by the study authors in describing
fetal runts to the submitter during the meeting. Fetal runts were defined based on reduced weights
only and not by fetal size. Since the decreased in fetal body weights were observed in the presence
of severe maternal toxicity (moribund condition, decreased body weights), the Meeting considered
that these effects were secondary to maternal toxicity and were not treatment-related. No treatmentrelated
developmental effects were observed at 45 or 7 mg/kg bw per day.
The NOAEL for maternal toxicity was 45 mg/kg bw per day on the basis of deaths in three
rabbits (kiled), decrease in body-weight gain (29%), a decrease in food consumption (35–42% and
reduced production and size of faecal pellets seen at the LOAEL of 300 mg/kg bw per day. The NO-
AEL for developmental toxicity was 300 mg/kg bw per day, the highest dose tested (Irvine, 1991).
2.6 Special studies
(a)
Acute neurotoxicity
In a study of acute oral neurotoxicity, groups of 12 male and 12 female non-fasted Sprague-
Dawley CD (Crl:CD [SD] IGS BR) rats were given a single dose of pyrimethanil (purity, 99.8%) at a
dose of 0, 30, 100, or 1000 mg/kg bw by gavage in 0.5% (w/v) methylcellulose (5 ml/kg). In a separate
study, the time of peak effects for pyrimethanil was estimated to be 1.5–4 h after dosing. Functional
observational battery (FOB) and motor activity were evaluated on days −6, 1 (approximately
1.5–2 h after dosing), 8, and 15. On day 16, five males and five females per group were perfused in
situ for neurohistological examination, and tissues from rats in the control group and group at the
highest dose were examined microscopically. Data for positive controls were provided and were
judged to be adequate, but were several years old.
No unscheduled deaths occurred. Clinical signs, body weights, body-weight gains, food consumption,
gross pathology, brain weights and measurements, and neuropathology were unaffected by
treatment. At 1000 mg/kg bw, the following transient FOB effects were noted on day 1: (i) slight to
moderate overall gait incapacity, indicated by slight to moderate ataxia; (ii) moderately dilated pupils
in females; (iii) decreased hindlimb-grip strength (24%; p < 0.01) in the males; and (iv) decreased
body temperature (0.56–1.49 °C; p < 0.01). Total motor activity was also decreased by 52–110%
(p < 0.001) at 1000 mg/kg bw on day 1 in males and females compared with controls. Habituation of
motor activity was unaffected by treatment. All rats appeared to be normal on days 8 and 15. These
effects were considered to be non-specific, transient and occurred at high doses.
The NOAEL was 100 mg/kg bw on the basis of decreased motor activity, ataxia, and decreased
body temperature in males and females, decreased hindlimb-grip strength in males, and dilated p upils
in females on day 1 seen at 1000 mg/kg bw (Beyrouty, 2001a, 2001b).
PYRIMETHANIL 445–486 JMPR 2007