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

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s ystemic toxicity was 400 ppm (equal to 23.1 mg/kg bw per day) on the basis of decreases in bodyweight
(11–13%) and body-weight gains (11–17%). Offpring toxicity was manifested as a decrease
in pup body weights (17%) on postnatal day 21 at 5000 ppm, equal to 293.3 mg/kg bw per day. The
NOAEL for offspring toxicity was 400 ppm, equal to 23.1 mg/kg bw per day. Pyrimethanil was not
embryotoxic, fetotoxic or teratogenic at doses of up to 1000 mg/kg bw per day in rats. Pyrimethanil
was not teratogenic in rabbits. Decreases in fetal body weights were observed at 300 mg/kg bw per
day. These decreases in fetal weights (described as “runts” in the study report) were observed in the
presence of severe maternal toxicity manifested as a significant decrease in body-weight gain and
food consumption, reduced production and size of faecal pellets and death of three rabbits (moribund
condition) at 300 mg/kg bw per day. The NOAEL for maternal toxicity in rabbits was 45 mg/kg bw per
day and the NOAEL for developmental toxicity was 300 mg/kg bw per day, the highest dose tested.
The Meeting concluded that pyrimethanil is not teratogenic.
In a study of acute neurotoxicity in rats, transient functional observational battery (FOB) effects
(gait, ataxia, decreased hindlimb-grip strength in males, decreased body temperature) were observed
at 1000 mg/kg bw on day 1. Total motor activity was also decreased by ≥ 52% at 1000 mg/kg
bw on day 1 in males and females compared with controls. All rats appeared normal on days 8 and
15. As these transient and non-specific effects occurred at a high dose administered by gavage, the
Meeting concluded that they were not an appropriate basis for establishing an ARfD. The NOAEL
was 100 mg/kg bw. In a short-term study of neurotoxicity in rats, no treatment-related changes in
mortality, clinical signs, FOB, motor activity, brain measurements (weight, length, and width), gross
necropsy, or neurohistopathology were observed at doses of up to 6000 ppm, equal to 391.9 mg/kg
bw per day. In females, an overall decrease in body-weight gain of 21% was observed at 6000 ppm,
equal to 429.9 mg/kg bw per day. The NOAEL in females was 600 ppm, equal to 38.7 mg/kg bw per
day, and 6000 ppm, equal to 319.9 mg/kg bw per day, in males.
The Meeting considered that pyrimethanil is not neurotoxic on the basis of the available data.
No significant adverse effects were reported in personnel working in production plants.
The Meeting concluded that the existing database on pyrimethanil was adequate to characterize
the potential hazards to fetuses, infants and children.
Toxicological evaluation
The Meeting established an acceptable daily intake (ADI) of 0–0.2 mg/kg bw based on a NO-
AEL of 400 ppm (equal to 17.0 mg/kg bw per day) on the basis of increased cholesterol and GGT
levels, and histopathological changes in the liver and thyroid at 5000 ppm (equal to 221 mg/kg bw
per day) in a 2-year study in rats, and using a safety factor of 100. This ADI is supported a by twogeneration
study of reproduction in rats in which the NOAEL for parental systemic toxicity was
400 ppm, equal to 23.1 mg/kg bw per day, on the basis of decreased body weights and body-weight
gains at 5000 ppm, equal to 293.3 mg/kg bw per day. This ADI is also supported by the NOAEL of
160 ppm, equal to 20.0 mg/kg bw per day, in males in a 2-year study of toxicity in mice; this NOAEL
was identified on the basis of increased incidences of urinary tract lesions including bladder distension
and thickening seen at 1600 ppm, equal to 210.9 mg/kg bw per day.
The Meeting concluded that it was not necessary to establish an ARfD for pyrimethanil because
no toxicity could be attributable to a single exposure in the available database, including a
study of developmental toxicity in rats and rabbits. Observations in the study of acute toxicity in rats
and clinical signs of toxicity in the pyrimethanil database appeared at doses of 640 mg/kg bw per day
and greater were not considered to be relevant for establishing an ARfD since they were transient,
non-specific and occurred at high doses. The Meeting also considered clinical signs (vomiting) in
several studies of toxicity in dogs; these were considered to be local effects and therefore not relevant
in establishing an ARfD.
PYRIMETHANIL 445–486 JMPR 2007