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

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In another study, groups of four male and four female beagle dogs were given gelatin capsules
containing profenofos (purity, 91.2%) at a dose of 0, 0.015, 0.05, 1 or 12.5 mg/kg bw per day mixed
with lactose for 1 year. Six mixtures of each concentration were prepared for the 1-year period and
were stored at 0–5°C. Clinical signs and food consumption was monitored daily and the dogs were
weighed weekly. Eye examinations were conducted and tonometry measurements made before testing,
and at weeks 7 (tonometry only), 13, and 26, and towards the end of the treatment period. Neurological,
clinical and haematological investigations were made at weeks 13, 26 and 52. This included
determination of acetylcholinesterase activity in erythrocytes and butyrylcholinesterase activity in
plasma. The dogs were given a gross examination at necropsy and selected organs were weighed.
A microscopic examination was also conducted and acetylcholinesterase activity was determined
in brain. Cholinesterase a ctivity was analysed statistically and inhibition calculated relative to the
values measured before t esting.
The analyses of dietary concentration were performed at higher concentrations. The results
showed that the mean concentrations at 1000 and 50 000 ppm (29 and 1450 mg/kg bw per day, respectively)
were 90% and 97.6% of the nominal concentrations, respectively. The test compound was
homogeneously distributed and was stable in lactose powder (bulk or in capsules) for 10 weeks under
the conditions of the study.
There were no treatment-related deaths in this study. No treatment-related changes were observed
in behaviour, food consumption, eye examination, intraocular pressure, neurological examination,
urine analysis, organ weights, and macroscopic examinations at necropsy. Mean body-weight
gain was slightly depressed at 12.5 mg/kg bw per day, mainly due to results for one female.
Haematology parameters, namely erythrocyte count, haemoglobin concentration and erythrocyte
volume fraction, were reduced in males and females at 12.5 mg/kg bw per day and in males at
1 mg/kg bw per day. Mean erythrocyte volume was elevated in males at 12.5 mg/kg bw per day. At
weeks 26 and 52, a slightly higher platelet count was recorded in males at 1 and 12.5 mg/kg bw per
day. The changes in the haematological parameters were not considered to be toxicologically significant
since there was no clear dose–response relationship and the magnitude of changes observed
were within the range for historical controls. Small changes in blood chemistry were noted in the
groups at 1 or 12.5 mg/kg bw per day. They included reduced concentrations of plasma protein and
albumin and, as a result, a reduced albumin : globulin ratio. Reductions in calcium concentration paralleled
those of plasma albumin owing to its calcium-binding properties. Plasma glucose concentrations
were decreased, and alkaline phosphatase activities increased. Changes in the clinical chemistry
parameters were not considered to be toxicologically relevant.
There was a 54–68% inhibition of erythrocyte acetylcholinesterase activity in dogs at 1 mg/
kg bw per day and an 82–86% inhibition at 12.5 mg/kg bw per day. At both doses the inhibition was
statistically significant. There was no sex difference in cholinesterase inhibition and no significant
change in inhibition after the first determination in week 13. There was also a dose-dependent inhibition
of plasma cholinesterase activity in all groups; at the lowest dose; the inhibition was 26–55%
in males and 13–42% in females, although the group mean differences did not achieve statistical
significance. Brain acetylcholinesterase activity in the group at the highest dose was slightly (not
statistically significantly) lower than that of dogs in the control group (males, 11%; and females, 6%).
Neurotoxic esterase activity was not affected by the treatment.
Microscopic examination revealed an increased number of binucleated perilobular hepatocytes
in males and females at 1 and 12.5 mg/kg bw per day, accompanied by hyperplasia of bile-duct epithelium
in the males. Concentrations of bile pigments were increased in the convoluted renal tubules
in dogs at 12.5 mg/kg bw per day. These pathological findings (Table 2) were minimal in severity and
were not observed in the 90-day or 6-month studies of toxicity in dogs given similar doses. In addition,
they were not associated with any biological correlates. Therefore, a NOAEL was not identified
on the basis of these findings.
PROFENOFOS 403–443 JMPR 2007