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

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The LOAEL was 8000 ppm (529.1 and 625.9 mg/kg bw per day for males and females, respectively)
on the basis of decreased body weights, body-weight gains and food consumption; brown urine
and increased urinary protein in males; decreased absolute heart, adrenal, spleen, thymus weights and
increased relative liver, kidney, gonad weights and hypertrophy in the liver and thyroid. The NOAEL
was 800 ppm (54.5/66.7 mg/kg bw per day in males/females). The study author concluded that the
NOEL was 80 ppm (5.4/6.8 mg/kg bw per day in males/females) (Higham, 1990; Harvey, 1994;
Reader, 2002).
In an amendment to the study report, the study author concluded that the treatment-related
changes in the incidence and severity of follicular epithelial hypertrophy and incidence of follicular
epithelial brown pigment observed at 8000 ppm that stained positively for lipofucin by the
Schmorl method. No treatment-related findings were apparent in either males or females at 800 or
80 ppm. After a 28-day recovery period, treatment-related findings were no longer apparent, indicating
r eversibility of the effects (Husband, 1992).
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 (Austria) requested a statement regarding the thyroid changes seen in the 90-day and
104-week studies in rats and their possible relevance to man. The study author suggested that changes
in the thyroid pathology (e.g. minimal to slight colloid depletion, hypertrophy of the follicular epithelium
and deposition of intra-cytoplasmic brown pigment in the follicular epithelium) were noted at
high doses of pyrimethanil. Mechanistic data suggested that an imbalance in thyroid hormones due to
increased thyroid-hormone clearance by the induction of liver enzymes resulted in increased thyroidstimulating
hormone (TSH) activity and persistent thyroid stimulation. Such effects may lead to
changes in thyroid functionality and morphology. Since rodents are known to be particularly sensitive
to this effect, it is considered that this mechanism has little relevance to humans (Reader, 2003a).
Dogs
In a 13-day dose range-finding study of oral toxicity, groups of one male and one female beagle
dog were given pyrimethanil (purity, 98.5–100%) at a dose of 10 mg/kg bw per day by gavage in 1%
methyl cellulose in distilled water, the dose being increased each day up to 2000 mg/kg bw per day in
this the first phase of the study. No treatment was administered on days 6, 7 and 13–15. In the second
phase of the study, the male, after a 4-day period without treatment, was treated with pyrimethanil at
a dose of 1200 mg/kg bw per day for 3 days (days 24–26) then at 800 mg/kg bw per day for 10 days
(days 27–36). The female, after a 4-day period without treatment, was treated with 1200 mg/kg bw
per day for 14 days (days 24–36). A previously untreated male (number 1602) was treated with pyrimethanil
at a dose of 1200 mg/kg bw per day for 3 days (days 29–31) then at 1000 mg/kg bw per day
for 5 days (days 32–36) and a previously untreated female (No. 1604) was left untreated. Dogs were
inspected twice per day for morbidity or mortality, with clinical signs being checked daily. A detailed
physical examination was performed before commencement of treatment and at the end of treatment.
Body weight and food consumption were measured daily during the treatment. Electrocardiograms
were made on all dogs pre-test and at the end of the study. Blood was collected from all dogs at pretest
and at termination for measurement of haematological and clinical parameters. At the end of the
study, a complete gross postmortem was performed. The adrenals, brain, kidneys, liver, thyroid and
parathyroid, heart, and gonads were weighed. The organs specified were examined microscopically.
All dosing solutions were prepared daily. The dosing solutions were analysed for concentrations
and homogeneity on days 24, 29 and 32. However, the results of the suspension concentrations and
homogeneity were not provided in the study report. No deaths occurred during the study. Salivation
was observed from dosing for 6 h in the male dog at 800 mg/kg bw and greater during the first phase
of the study, and liquid faeces were recorded. The male dog vomited within 1–3 h after dosing after
treatment at 640 mg/kg and greater. Vomiting also occurred in males treated in the second phase of the
study at 1200 mg/kg bw per day, although this ceased when the dose was reduced to 1000 mg/kg bw
PYRIMETHANIL 445–486 JMPR 2007