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

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muscularly 60 min before the second dose. Tri-orthocresyl phosphate was given to chickens in a positivecontrol
group. Clinical signs of toxicity and mortality were recorded up to 42 days after the second dose.
At the end of the observation period, the remaining birds were killed and samples of muscle and spinal
cord were taken for histopathology. The study was not conducted in accordance with GLP requirements,
but the procedure used was as recommended by the United Kingdom Ministry of Agriculture, Fisheries
and Food (MAFF), Pesticide Safety Precaution Scheme, working document No 2, appendix B, 1967.
All the chickens at 60 mg/kg bw died after the first dose and only those in the group at the lowest
dose survived the two treatments. Clinical signs of toxicity were salivation, asynchronisms of the
extremities, curved position, apathy and ruffled feathers. Neither symptoms of delayed neurotoxicity
nor histological changes in spinal cord or peripheral nerve could be detected. The birds in the concurrent
positive-control groups treated with tri-orthocresyl phosphate showed the expected reactions
(ataxia, deterioration of the reflexes, swelling, fragmentation and disruption of myelin sheaths) by
day 18 after treatment and the histopathology findings were also as expected (Krinke et al., 1974).
In a second study, chickens of the White Leghorn strain (sex not specified) were given profenofos
(purity, 89.5%) at a dose of 30 or 45.7 mg/kg bw. The doses were based on an initial assessment of the
acute toxicity of profenofos, which showed the LD 50
to be 45.7 mg/kg bw. Surviving birds were given a
second dose 21 days after the initial dose, but owing to the unexpectedly high mortality after the first dose,
the second was reduced to 17.1 mg/kg bw, which was the revised LD 50
on the basis of mortality after the
first dose. Birds in a positive-control group were given tri-orthocresyl phosphate. The birds were observed
daily for mortality and possible neurotoxic signs for up to 21 days after the second dose. Body weight was
measured on days 0, 21 and 42 and food consumption was measured weekly. All birds that died during the
study were given a gross necropsy. At the end of the study, the sciatic nerves, brain and spinal cord were
examined in surviving birds. The results of this study had not been independently validated.
Forty-one of the 50 birds at 45.7 mg/kg bw and 28 of the 40 birds at 30 mg/kg bw died within
21 days of dosing, mostly within 24 h. There was only one further death when surviving birds of both
groups were given the second dose 21 days after the first, even without pre-treatment with atropine.
Clinical signs noted after the first dose were lethargy and salivation. Slight lethargy was also apparent for
24–48 h after the second dose. There were no behavioural signs of delayed neurotoxicity. In particular, no
signs of locomotor disturbances were observed. Reduced body-weight gains and food consumption were
apparent in treated birds, particularly after the first dose. Gross and histopathological studies of neural
tissues from these birds did not reveal any treatment-related findings. The concurrent positive-control
group showed the expected established signs of neurotoxicity by day 8 of study (Reinart, 1978).
These studies demonstrate that profenofos caused no delayed neurotoxic effects in adult
c hickens even at very high (sublethal) doses.
(e)
Antagonistic agents
A protective effect of atropine given early after the oral administration of profenofos in rats
or intraperitoneal administration in chicks and mice was demonstrated by a reduction in mortality
and signs of toxicity (e.g. salivation, tremors, sedation, and convulsions) typical of exposure to anticholinesterase.
The effect of oximes was limited, probably due to rapid ageing (Sachsse & Bathe,
1976; Gfeller & Kobel, 1984; Glickman et al., 1984). These investigations were not conducted to
GLP or to any regulatory guideline.
(f)
Potentiation studies
Potentiation studies were divided into two phases. First, the oral LD 50
for each compound was experimentally
determined in rats. In the second phase, the LD 50
values for the equitoxic mixtures of the
insecticides were evaluated and compared with the theoretical LD 50
values derived from an assumption
of strictly additive toxicity. The procedure for the determination of the acute oral LD 50
for each com-
PROFENOFOS 403–443 JMPR 2007