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

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treated rabbits showed slight erythema (score 1), which was not persistent. No irritation was observed
in the treated group during the challenge phase. No irritation was observed in the control group either
in the induction or challenge phase. Positive controls were treated using 1-chloro-2,4-dinitrobenzene
(DNCB), which indicated that the test system was capable of detecting a sensitizer (Davies, 1990a,
1990b). Thus pyrimethanil was not a skin sensitizer in guinea-pigs as determined by the Buehler
method (Davies, 1990a, 1990b).
In a study of dermal sensitization with pyrimethanil (purity, 96.5%), young male and female
Dunkin-Hartley guinea-pigs were tested using the maximization method of Magnusson & Kligman.
For the main study, five males and five females were assigned to the control group, and ten males and
ten females to the treatment group. The test substance was mixed with paraffin oil. In this study, the
test concentrations chosen were 20% for intradermal induction, 50% for topical induction, and 50%
for the challenge. Skin reactions at the challenge sites were observed at 24 h and 48 h after removal
of the patch. The positive-control group was treated with DNCB. No mortalities or clinical signs of
toxicity were observed. There were no signs of dermal reactions in any guinea-pigs in the induction
or challenge phase. Thus pyrimethanil was not a skin sensitizer in guinea-pigs as determined by the
maximization method (Clouzeau, 1994; Healing, 1996a, 1996b).
2.2 Short-term studies of toxicity
Mice
In a 28-day study of oral toxicity, groups of five male and five female Charles River CD-1 mice
were given diets containing pyrimethanil (purity, 95.3–95.6%) at a concentration of 0, 1000, 3000,
10 000, or 30 000 ppm (equivalent to 0/0, 167/236, 567/667, 1960/2357 mg/kg bw per day for males/
females) for 28 days. Mice were observed twice per day for mortality and moribundity and once on
weekends and holidays. Body weight and food consumption were measured each week. During the
study, diets were analysed for homogeneity, stability and concentration. Blood was collected from
the retro-orbital sinus of each mouse, under light ether anaesthesia, on day 28 for haematology and
days 29 (males) or 30 (females) for clinical chemistry. An ophthalmoscopy examination and urine
analysis were not performed. All mice that died or were sacrificed in extremis and those sacrificed
at study termination were given a gross pathological examination. Selected organs were weighed.
The selected tissues were collected from all mice, preserved in 10% neutral buffered formalin, and
stained with haematoxylin and eosin. Tissues from the liver, kidneys, thyroid gland, and urinary bladder
were examined in all groups (except mice at 30 000 ppm). A bone-marrow smear was taken from
all mice surviving until scheduled sacrifice.
Data on homogeneity, stability and concentrations were not provided in the study report (a separate
report that was not submitted. At 30 000 ppm, all mice died within the first week of treatment
(days 5–7). Before death, these mice experienced severe emaciation. Clinical signs such as altered
activity, prostration, ataxia, pallor and hypothermia associated with emaciation were observed. At
necropsy, the males exhibited the various macroscopic non-specific abnormalities. No tissues were
examined microscopically from these mice. At 10 000 ppm, emaciation was observed in two females
for an average of 5 days. Body weights were decreased by 7–19% in males and females throughout
treatment. Overall body-weight gains were decreased (46–55%) in males and females in 29 days.
Also in the first 2 weeks of the study, decreases of 17–28% were observed in food consumption in
the females, with correlating decreases in food-conversion ratio. Minor alterations in haematological
and clinical chemistry parameters were observed, but were considered to be not toxicologically relevant.
There were no dose-related macroscopic findings in the mice surviving to scheduled sacrifice.
Relative to body weight, liver weight was increased (+19%; p ≤ 0.01) in females, probably owing to
decreases in body weight. Increased incidence and/or severity of the following microscopic findings
PYRIMETHANIL 445–486 JMPR 2007