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

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(b)
Short-term studies of neurotoxicity
In a short-term study of neurotoxicity, groups of 12 male and 12 female Sprague-Dawley CD
(Crl:CD[SD]IGS BR) rats were given diets containing pyrimethanil (purity, 99.8%) at a concentration
of 0, 60, 600, 6000 ppm (equal to 0/0, 4.0/4.6, 38.7/44.3, or 391.9/429.9 mg/kg bw per day for males/
females) for 13 weeks. FOB and motor activity were evaluated during weeks −1 (before dosing), 4, 8,
and 13. At termination, five males and five females from each group were perfused in situ, and tissues
from rats in the control group and in the group at 6000 ppm were examined microscopically. Data for
the positive controls were provided and were judged to be adequate, but were several years old.
No treatment-related mortalities were observed. Clinical signs, FOB, motor activity, brain
measurements (weight, length, and width), gross necropsy, and neurohistology were unaffected by
treatment. In females at 6000 ppm, there were decreases in body weight of 8% at the end of the study,
an overall decrease of body-weight gain of 21%, and corresponding decreases in food consumption
(9–15%) in many weeks throughout the study. In males, significant decreases in body-weight gain of
21% and food consumption of 12% were seen only in the first week of the study. No treatment-related
effects were observed at 600 ppm or less.
The NOAEL for males was 6000 ppm (equal to 391.9 mg/kg bw per day, the highest dose
tested). The NOAEL for females was 600 ppm (equivalent to 44.3 mg/kg bw per day) on the basis of
decreased body weight (8%), body-weight gain (21%), and food consumption (9–15%) seen at 6000
ppm (equal to 429.9 mg/kg/day, the highest dose tested) (Beyrouty, 2001c).
Mice
A study in mice was designed to investigate the effect of pyrimethanil on the activity of hepatic
enzymes and the estrus cycle of female mice after 4 days dietary exposure. In a 4-day feeding
study, groups of 15 female Crl:CD-1(ICR)BR mice were given diets containing pyrimethanil (purity,
96.2%) at a concentration of 0 or 900 ppm (equal to 162 mg/kg bw per day) for 4 days. All mice
were weighed and killed on day 5. Livers were removed, weighed and five sets of three livers were
pooled and used to prepare microsomes. The protein content and a measurement of the concentration
of cytochrome P450 were carried out. The microsomes were then used to determine the level of the
activity of 7-pentoxyresorufin-O-depentylase (PROD). Vaginal smears were prepared on day 1 and
on day 4.
Treatment with pyrimethanil for 4 days did not affect the terminal body weights, or the liver
weights. The concentration of microsomal protein/g liver rose by 8% in the treated mice and the level
of cytochrome P450/mg protein rose by 5%. Each of these results was statistically significantly as
was the increase in the activity of PROD (38% when expressed per mg protein). There were no overt
differences between the cell types or the stages of the estrus cycle between the treated and control
groups over the treatment period. The study author concluded that treatment with pyrimethanil at a
dietary concentration of 900 ppm for 4 days resulted in a low potency induction of cytochrome P450,
including the Cyp2b subfamily, with a profile of induction that was similar to that expected with
phenobarbitone (Barker, 1998).
Rats
A study in rats was conducted to investigate whether the thyroid effects (colloid depletion,
follicular-cell hypertrophy and follicular epithelial hyperplasia) seen after dietary administration of
pyrimethanil at repeated high doses occurs via a direct effect on the thyroid or an indirect extrathyroidal
mechanism (mediated by the liver). These two mechanisms can be differentiated by implementing
the perchlorate discharge test, which is based on: (a) the uptake of radiolabelled iodine;
and (b) the ability of perchlorate to discharge any non-organified thyroidal iodine into the circulation.
Normal uptake of iodine will be inhibited by a direct thyroid-blocking agent. Propylthiouracil
(known to inhibit thyroid function directly) and phenobarbital (acts indirectly) were used as positive
controls for each type of mechanism, respectively.
PYRIMETHANIL 445–486 JMPR 2007