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

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In a 7-day feeding study, groups of six male Sprague-Dawley Crl:CD(SD)BR rats were fed diets
containing pyrimethanil (purity, 96.2%) at a concentration of 0 or 5000 ppm (equal to 1007 mg/kg
bw per day), or propylthiouracil at a concentration of 2000 ppm (equal to 353 mg/kg bw per day), or
phenobarbital at a concentration of 1000 ppm (equal to 217 mg/kg bw per day) for 7 days. On day 8,
the rats were injected intraperitoneally with radiolabelled 125 I; 6 h later, all rats were killed exactly 2.5
min after intraperitoneal injection of either saline or potassium perchlorate.
The rats were observed daily for abnormal behaviour and physical condition. Individual body
weights were recorded before treatment, at the start of treatment, on days 4 and 7 and at necropsy. The
weekly food consumption was recorded. At termination, all rats were necropsied and examined macroscopically.
The weight of the thyroid was recorded and radioactivity in the thyroid was measured.
The volume of blood was measured and radioactivity in the blood measured.
There were no mortalities during the study. Rats treated with pyrimethanil had no adverse
clinical effects. Rats treated with propylthiouracil showed reduced activity and piloerection while
treatment with phenobarbital resulted in reduced activity, unsteady gait, reduced muscle tone, piloerection,
and wasted body condition. Group mean body weights of rats treated with either pyrimethanil
or propylthiouracil were lower than those for the controls at days 4, 7, and 8 and total body-weight
gains (19.6% and 12.2%, respectively) were reduced compared with those of the controls (35.4%).
Food consumption was decreased by 36% at day 3 in rats treated with pyrimethanil compared with
those of the controls. Reduced food consumption in rats treated with propylthiouracil was seen at
days 3 and 7 (−46% and −26%, respectively). Uptake of 125 I was significantly increased in the thyroid
of rats treated with either pyrimethanil or phenobarbital (150% or 221% of the corresponding value
for concurrent controls receiving saline, respectively). There was no significant discharge of 125 I after
administration of perchlorate in either the phenobarbital or pyrimethanil group. The group treated
with propylthiouracil showed a significant reduction in uptake of 125 I uptake (65% of the value for
controls) and a significant discharge of 125 I (61%) after administration of perchlorate. At necropsy,
increased thyroid weights (+76%) and relative thyroid : body weight ratio (+113%) were seen in
rats treated with propylthiouracil when compared with the controls. No treatment-related effects on
thyroid weights were observed after exposure to pyrimethanil or phenobarbital. The results indicated
that findings in rats treated with pyrimethanil were similar to findings in rats treated with phenobarbital
and were different from those reported after treatment with propylthiouracil. The study results
suggested that pyrimethanil is not a direct-acting thyroid blocker (Healing, 1992a).
A 14-day feeding study in rats was conducted to characterize the thyroid effects seen in
short- and long-term studies with pyrimethanil at high doses. Groups of 10 male Sprague-Dawley
Crl:CD(SD)BR rats were given diets containing pyrimethanil (purity, 96.2%) at a concentration of
0 or 5000 ppm (equivalent to 378.5 mg/kg bw per day) for 14 days. Five rats from each group were
killed on day 15. The remaining five males per group received untreated diet for a further 14 days
before necropsy. Rats were observed daily for abnormal behaviour and physical condition. Individual
body weights were recorded before treatment, at the start of treatment, twice per week thereafter
and at necropsy. The weekly food consumption was recorded. Blood samples for clinical chemistry
were collected on study days 1, 2, 4, 8, 15 and 29. At termination, all rats were necropsied and examined
macroscopically. The weights of the liver, pituitary and thyroid were recorded and the organs
e xamined histopathologically.
There were no mortalities or treatment-related clinical signs reported. A reduction in bodyweight
gain (23%) was seen in treated rats at the first week only. Rats treated with pyrimethanil at 5000
ppm for 14 days showed a markedly increased activity of liver enzyme uridine diphosphoglucuronyl
transferase (UDPGT) (446% of the value for controls). Also, significantly increased concentrations
of TSH were seen at days 1, 4, and 15 of the study (162%, 155%, and 215% of values for respective
controls) while decreased concentrations of T3 and T4 (82% and 76% of respective c ontrols)
PYRIMETHANIL 445–486 JMPR 2007