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

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were noted at day 4. Liver weights of the treated rats were significantly higher (23%) than those of
the controls at interim kill, while thyroid weights were significantly lower (56%) than those of the
controls. After a 14-day recovery period, liver weight and plasma concentrations of T3, T4, TSH, and
reverse triiodothyronine were back to normal, while the UDPGT value remained elevated (163% of
that of the controls). There were no treatment-related gross pathological effects. Histopathologically,
14 days of treatment with pyrimethanil resulted in centrilobular hepatocyte enlargement in the liver
and colloid depletion, follicular-cell hypertrophy and follicular epithelial hyperplasia in the thyroid
gland. After a 14-day recovery period, these effects returned to normal.
It was suggested by the study author that the elevated level of liver enzyme (UDPGT) led to
increased clearance of thyroid hormones via enhanced hepatic metabolism. This in turn resulted in an
extrathyroidal, indirect effect on thyroid-hormone homeostasis, which via normal pituitary feedback
led to increased concentrations of TSH, and stimulation of the thyroid gland. Hence, the elevation of
TSH shown to result from treatment with pyrimethanil may be responsible for the histopathological
changes in the thyroid glands of rats (Healing, 1992b; Reader, 2003d).
Groups of rats were given pyrimethanil (technical) orally to investigate the effect on hepatic
mixed function oxidase system after 4 days dietary exposure. Groups of six male Sprague-Dawley
CD-1 rats were dosed orally with pyrimethanil (purity, 99.4%) at a dose of 0, 100 or 200 mg/kg bw
twice per day in 0.5% gum tragacanth for 4 days. Additional groups were given 0.1% phenobarbitone
in drinking-water for a minimum of 14 days, an intraperitoneal dose of phenobarbitone at 80 mg/kg
bw per day in water for 4 days, an intraperitoneal dose of β-naphthaflavone at 80 mg/kg bw per day in
corn oil for 4 days and an intraperitoneal dose of clofibrate at 400 mg/kg bw per day in corn oil for 4
days. Rats were necropsied 17 h after the last dose and microsomal suspensions prepared from their
livers. Activities of liver enzymes were determined.
Pyrimethanil had only a minor effect on the liver enzymes, showing very low levels of ethoxyresorufin-O-deethylase
and pentoxyresorufin-O-dealkylase. Pyrimethanil also led to a statistically
significant increase in liver weight (at 100 mg/kg bw per day only) and concentration of cytochrome
b5 (at 200 mg/kg bw per day only). The type of induction pattern was similar to that for phenobarbitone.
The increase in ethoxyresorufin-O-deethylase was not considered to be caused by an increase in
cytochrome P448. The magnitude of the increases with pyrimethanil was less than for phenobarbitone
and much less than for β-naphthaflavone. However, the increases in pentoxyresorufin-O-dealkylase
were less than for phenobarbitone but more than for β-naphthaflavone. Pyrimethanil did not increase
the activity of lauric acid hydroxylase and so was not considered to be a clofibrate-type inducer of
cytochrome P 452
. The study results suggest that treatment with pyrimethanil at 100 or 200 mg/kg bw
per day by gavage for 4 days resulted in a marginal induction of the hepatic mixed function oxidase
system, predominantly of the phenobarbitone type (Needham, 1991).
3. Studies with metabolites
Groups of five male and five female young adult Sprague-Dawley Crl:CD(IGS)BR rats were
given AE F 132593, 2-amino-4, 6 dimethylpyrimidine, a pyrimethanil soil-photolysis metabolite (purity,
98.7%) as a single dose of 0, 100, 200, 400, 800, or 1600 mg/kg bw by gavage in 1% w/v methyl
cellulose in distilled water. Treated rats were subjected to gross necropsy at the end of a 14-day observation
period. At 1600 mg/kg bw, all rats were culled owing to their moribund condition between
30 min and 4 h after treatment. At 800 mg/kg bw, three males and two females were culled between 1
and 6 h after dosing. At 400 mg/kg bw, one female was culled in about 5 h after dosing. No mortality
was observed in the groups at 100 or 200 mg/kg bw. Clinical signs such as salivation, prostration,
laboured respiration, unsteady gait, reduced activity, reduced muscle tone, occasional findings in the
eye (water, red discharge) and hair loss were observed in rats at 1600, 800, 400 and in females only
PYRIMETHANIL 445–486 JMPR 2007