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

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At interim kill, no significant treatment-related effect was reported for rats at 400 or 32 ppm.
At interim kill, the absolute liver weights were 13% higher in males and 5% higher in females in
the groups at 5000 ppm compared with controls. At interim kill, at 5000 ppm, minimal to moderate
hypertrophy of centrilobular hepatocytes were observed in all males and 1 out of 20 females, but was
not seen in the control group of either sex. A significantly higher kidney to body-weight ratio was
observed in males only at 5000 ppm. At terminal kill, the absolute liver weight of males (22%) at
5000 ppm was higher than in the controls. The relative liver to body-weight ratios were significantly
increased in males (26%) and females (21%) at 5000 ppm. At 5000 ppm, dark thyroids were observed
in 1 out of 20 males and 4 out of 20 females at the interim kill. At this dose, dark thyroids were also
observed in 6 out of 50 males and 17 out of 50 females at terminal kill. In the thyroid gland, there
were minimal to moderate intra-epithelial depositions of brown pigment (which stained positively
for lipofuscin by the Schmorl method) in 18 out of 20 males and 19 out of 20 females compared with
1 out of 19 in the controls for males and females. There were higher incidences of colloid depletion
and hypertrophy of the follicular epithelium (males, 18 out of 20; and females, 13 out of 20) than
controls (males, 9 out of 19; and females, 6 out of 19). At terminal kill, minimal to slight hypertrophy
of centrilobular hepatocyte were observed in rats at 5000 ppm only (males, 32 out of 50; and female
6 out of 50). Also, there were higher incidences of minimal to severe eosinophilic foci (males, 19 out
of 50; and females, 12 out of 50) than in controls (males, 2 out of 51; and females, 7 out of 51). In
the thyroid gland, minimal to severe colloid depletion and hypertrophy of follicular epithelium were
observed at 5000 ppm in males and females at higher incidences (males, 36 out of 50; and females,
38 out of 50) than in the controls (males, 25 out of 51; and females, 15 out of 51). Focal hyperplasia
of the follicular epithelium was seen at 5000 ppm in 9 out of 50 males and 7 out of 50 females, but
in the control group in 2 out of 51 males and 1 out of 51 females). Minimal to moderate depositions
of intra-cytoplasmic brown pigment (lipofuscin) in the thyroid follicular epithelium were detected at
5000 ppm in males and females (males, 38 out of 50; and females, 47 out of 50), but was not present
in the control group for either sex. No treatment-related effects on microscopic findings were noted
in rats given pyrimethanil at 400 or 32 ppm after 52 or 104 weeks.
Overall, the only tissue showing a higher incidence of tumours than did the controls was the
thyroid gland; benign follicular-cell adenomas were observed in 9 out of 70 males and 7 out of 70
females at 5000 ppm, compared with 3 out of 70 males and 0 out of 70 females in the control group.
A pair-wise Fischer test indicated that the incidence of tumours in males at the highest dose (9 out
of 70) was not statistically significant (p = 0.06) when compared with that of males in the control
group (3 out of 70). However, the incidence in males at the highest dose (12.9%) was higher than the
upper limit of the range for historical controls (1.5–5.9%). In females, the incidence of tumours at
the highest dose (7 out of 70, or 10%) was higher than that of females in the control group (0 out of
70) and exceeded the uppr limit of the range for historical controls (0–3.0%). A positive trend in the
incidence of these tumours in males and females was also noted. In addition, thyroid follicular-cell
adenocarcinomas were seen in male rats at 32 ppm (males, 1 out of 70) and at 5000 ppm (males, 1
out of 70); however, the incidence (1.4%) was within the range for historical controls.
The NOAEL was 400 ppm, equal to 17 and 22 mg/kg bw per day for males and females,
respectively. The LOAEL was 5000 ppm, equal to 221 and 291 mg/kg bw per day for males and
females, respectively, on the basis of decreased body-weight gains, increased serum cholesterol concentration
and GGT activity, necropsy, and histopathological findings (Rees, 1993; Simpson, 2003;
Healing, 1994). In a position paper (Reader, 2003a) prepared as a part of the ongoing review of the
Toxicology and Metabolism Tier II dossier for pyrimethanil (under EC directive 91/414/EEC), the
Rapporteur Member State requested additional information on the 104-week combined long-term
study of carcinogenicity and toxicity in rats regarding historical data on survival and some clinical
chemistry parameters (phosphate and urea). The author concluded that the data on survival, blood
phosphate and urea concentrations were essentially similar to those for historical controls.
PYRIMETHANIL 445–486 JMPR 2007