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

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on control diet for a 39-week recovery period, while four males at the highest dose were placed again
on a diet containing DACT at 750 ppm until termination at 52 weeks. The mean daily intakes at 0, 5,
100 or 1500/750 ppm were equal to doses of 0, 0.2, 3.5 and 23.8 mg/kg bw per day for males and 0,
0.2, 3.3 and 29.9 mg/kg bw per day for females, respectively.
Five males and two females in the group at the highest dose were kiled in a moribund condition,
mainly during the first 9 weeks. Clinical observation revealed tremors in all dogs at the highest
dose during weeks 5–15. Additionally, inactivity, paleness, abdominal distension and emaciation
were noted. Dogs that were killed moribund displayed inappetence, hypothermia, laboured breathing,
hunched posture, and abnormal gait.
In the group at the highest dose, treatment-related physical examination findings consistent
with impaired heart function occurred from week 6 onwards and included irregular (rapid) heart
rate, pericardial thrill, pulse deficit, abdominal ascites and emaciation. Electrocardiographic abnormalities
(atrial fibrillation) ocurred in three males and two females at week 5, the first electrocardiographic
evaluation during the treatment period, and were diagnosed in a total of six males and four
females in the group at the highest dose. Ophthalmological examinations revealed no treatmentrelated
findings.
Dogs in the group at the highest dose lost weight during the first 6 weeks of treatment. After
the concentration of DACT in the diet was reduced to 750 ppm, the dogs maintained their body
weight. Body-weight gain of females in the group improved after cessation of test article treatment
and was greater than the body-weight gain of females in the control group for the same period. Food
consumption was decreased in males at the highest dose during the first 6 months of the study, except
during the period when the dogs were fed the control diet. In females at the highest dose, the reduction
of food consumption was not as pronounced as in males and was comparable to that of controls
from week 18 onwards.
Moderate anaemia accompanied by an increased number of reticulocytes indicating an increased
erythropoiesis was noted in dogs receiving the highest dose. The decrease of erythrocyte counts,
erythrocyte volume fraction and haemoglobin concentration was significant in females at weeks 13
and 26. By week 52 the number of reticulocytes was within the normal range and the erythrocyte
parameters had returned to nearly normal levels. Decreased calcium and increased lactate dehydrogenase
and albumin concentrations were observed in the group at the highest dose. There were no
effects of treatment on urinary parameters.
Mean absolute and relative liver, spleen and kidney weights were increased in dogs at the
highest dose when compared with those of the controls at 13 and 52 weeks. At necropsy, heart and
liver lesions were observed in dogs at the highest dose. Accumulations of fluids in the abdominal or
thoracic cavity or the pericardium were secondary to the impaired heart function. Histopathology
revealed chronic myocarditis in several dogs at the highest dose. The right atrium was most often
affected, although the ventricles and papillary muscles were also affected in several animals. Males
were more severely affected than females. Liver lesions included centrilobular fibrosis/atrophy, bile
stasis, necrosis, haemorrhage, haemosiderosis and inflammation. Hyperplasia of the bone marrow,
thymus atrophy and hypospermatogenesis of the testes were recorded at the interim kill, primarily in
male dogs receiving the highest dose.
The effects observed in females at the highest dose were reversible 3 months after the cessation
of treatment. The two females in the recovery group did not exhibit any clinical, electrocardiographic,
gross or microscopic evidence of cardiac abnormalities. Likewise, no effects on haematological or
biochemistry parameters were recorded at termination.
The NOAEL was 100 ppm, equal to 3.5 and 3.3 mg/kg bw per day in males and females, respectively,
on the basis of clinical, electrocardiographic, gross and microscopic evidence of impaired
heart function at 1500/750 ppm (Thompson et al., 1990).
ATRAZINE 37–138 JMPR 2007