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

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represented as equally as possible. Pups were selected on postnatal day 5 for the F1 generation; they
were separated on day 29 and allowed to grow to adulthood. Rats in the F1 generation were examined
daily, clinical examinations, food consumption and body weights were measured at intervals, and
evaluations of motor activity, auditory startle response and assessments of learning and memory were
also carried out. Rats were killed on postnatal day 63 and tissues were removed for neuropathological
investigations. Additional satellite groups (five dams per group, five male and five female fetuses per
group and five male and five female pups per group) were used to determine plasma, erythrocyte and
brain acetylcholinesterase activity in dams on day 22 of gestation and postnatal day 22, in fetuses on
day 22 of gestation and in pups on postnatal days 5, 12 and 22. The study was conducted in accordance
with GLP regulations and the protocol complied with US EPA OPPTS guideline No 870.6300.
The results of dietary analyses indicated that the test compound was stable in the diet for 27 days
when stored at room temperature or at nominally − 20 °C. The mean concentration and homogeneity of the
test compound in the diet were within limits of acceptability (± 9% and 3% of nominal, respectively).
Body weights were slightly reduced in the parent females during late gestation (15%) and early in
the postnatal period (5%) in rats at 600 ppm. Food consumption was also reduced during late gestation
and during late lactation in rats of this group. There were no treatment-related effects on clinical observations,
FOB measurements, reproductive parameters, litter losses or pup survival. On day 22 of gestation
and on postnatal day 22 there was a statistically significant reduction in plasma cholinesterase activity of
approximately 60% and 80% in the parental rats receiving profenofos at 60 and 600 ppm, respectively.
There was a similar reduction, of approximately 55% of values for controls, in erythrocyte acetylcholinesterase
activity in these groups at both time-points. At 600 ppm, brain acetylcholinesterase activity was
decreased by 44% on day 22 of gestation, and by 26% (not statistically significant) on postnatal day 22.
Pup and total litter weights were reduced on postnatal day 5 in the group at 600 ppm and group
mean body weights for F 1
rats in this group were lower than those of the controls from day 5 to day 29 in
males and until day 36 in females. In the F 1
rats, there were no treatment-related effects on motor activity,
auditory startle response, learning and memory or neurohistopathology. No statistically significant effects
were noted on cholinesterase activity in pups in the group at 3 ppm. In the group at 60 ppm, only plasma
cholinesterase activity was significantly inhibited (23%) at postnatal day 22. In males and females in the
group at 600 ppm, plasma cholinesterase activity was significantly inhibited by up to approximately 50%
at postnatal day 22 and erythrocyte cholinesterase activity was inhibited by up to 40% at the same sampling
time. There was a statistically significant difference in brain acetylcholinesterase activity in female
pups at day 5 (11% lower) but not at later sacrifice times. On postnatal day 12, absolute brain weight was
decreased (by 4%) in the males at the highest dose only. The differences were no longer evident when the
weights were adjusted to lower body weights of these animals. No treatment-related gross or microscopic
pathological findings were noted in any treated group. Significant differences in various morphometric
measurements were seen in males and females at the highest dose on postnatal days 12 and 63.
The NOAEL for maternal toxicity was 60 ppm, equal to 5.1 mg/kg bw per day, on the basis of
inhibition of brain acetylcholinesterase activity on day 22 of gestation and day 22 of lactation, and reductions
in body weight and food consumption at 600 ppm, equal to 50.6 mg/kg bw per day. The NOAEL for
developmental neurotoxicity was 600 ppm, equal to 50.6 mg/kg bw per day. The NOAEL for offspring
toxicity was 60 ppm, equal to 5.1 mg/kg bw per day, on the basis of inhibition of brain acetylcholinesterase
activity, reduced body weight, decreased brain weights in males on postnatal day 12 and changes
in the brain morphometric parameters at 600 ppm, equal to 50.6 mg/kg bw per day (Milburn, 2003).
(d)
Delayed neurotoxicity
A first study was conducted with three groups of two male and two female White Leghorn chickens
given profenofos (purity undefined) at a dose of 21.7, 46.4 or 60 mg/kg bw in polyethylene glycol
as vehicle. Surviving chickens (only in the groups at 21.7 and 46.4 mg/kg bw) were given a second dose
21 days later. For protection against the acute toxic effects of profenofos, atropine was administered intra-
PROFENOFOS 403–443 JMPR 2007