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

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day during gestation and 0, 0.7, 33.9, 66.0 and 97.6 mg/kg bw per day during lactation and weaning.
Day 1 of gestation was the day of confirmation of mating and postnatal day 1 was the day of littering.
Rats were examined daily, clinical signs of toxicity and body weight were recorded on days 7, 8,
15 and 22 of gestation and on postnatal days 1, 5, 8, 12, 15 and 22. Food consumption was recorded
at 3–4-day intervals during gestation and lactation. Concentration, homogeneity and stability of the
test compound in the diet were confirmed. The sex, weight and clinical condition of each pup were
recorded on postnatal days 1, 5, 8, 12, 15 and 22 . Plasma, erythrocyte and brain acetylcholinesterase
activity was determined in dams on day 22 of gestation and postnatal day 22. Cholinesterase activity
was also determined in pups on day 22 of gestation and postnatal days 5, 12 and 22. Staements of
compliance with GLP and QA statement were provided, but as this was a preliminary study compliance
with a regulatory guideline was not applicable.
Profenofos was stable in the diet at room temperature for 13 days and in the freezer for 28 days.
The test compound was homogenously distributed in the diet. The mean concentrations were within
8% of nominal concentrations.
During gestation, body weight was slightly reduced (6%) in rats at 600 ppm and food consumption
was reduced in rats at 400 or 600 ppm. On postnatal day 22, decreases in male (13%) and female
pup weights (9%) and total litter weights (13%) were evident in the group at 600 ppm compared with
values for controls. There were no other effects on litter or pup parameters.
In the parental rats, there were statistically significant reductions in plasma and erythrocyte
acetylcholinesterase activity in rats at 200, 400 and 600 ppm at day 22 of gestation and postnatal day
22 . The inhibition was not dose-dependent and ranged from 76–86% for plasma cholinesterase and
42–53% for erythrocyte acetylcholinesterase activity. Brain acetylcholinesterase activity was significantly
inhibited in the groups at 200, 400 and 600 ppm on postnatal day 22. The inhibition appeared to
be dose-dependent and ranged from 21% at 200 ppm to 52% at 600 ppm. On day 22 of gestation, there
was an 18% and 17% inhibition of brain acetylcholinesterase activity in rats at 400 and 600 ppm,
respectively, but the reduction was not statistically significant. In pups there were no statistically significant
effects on plasma, erythrocyte or brain cholinesterase activity on day 22 of gestation. A statistically
significant inhibition of erythrocyte and brain acetylcholinesterase activity was only found
on postnatal day 22, but there was no clear dose–response relationship. Brain acetylcholinesterase
activity was inhibited by 25% in females in the group at 400 ppm and by 16% in males in the group
at 600 ppm; erythrocyte acetylcholinesterase activity was inhibited by 33–46% in pups in the groups
at 400 and 600 ppm. Inhibition of plasma cholinesterase activity increased during weaning and there
was a 36–65% inhibition in pups exposed to profenofos at 200–400 ppm by postnatal day 22.
The NOAEL for parental toxicity was 4 ppm (0.3 mg/kg bw per day) on the basis of significant inhibition
of brain acetylcholinesterase activity at doses of 200 ppm (15.5 mg/kg bw per day) and greater,
and reduced body-weight gain and food consumption at 400 and 600 ppm. The NOAEL for offspring
toxicity was 200 ppm (33.9 mg/kg bw per day) on the basis of reductions in brain a cetylcholinesterase
activity at doses of 400 ppm (66.0 mg/kg bw per day) and greater (Milburn, 2002).
In the main study of developmental neurotoxicity, groups of 30 mated Alpk:APfSD Wistarderived
rats were fed diets containing profenofos (purity, 91.8%) at a concentration of 0, 3, 60 or
600 ppm from day 7 of gestation to postnatal day 29. These dietary concentrations corresponded to
daily doses of 0, 0.3, 5.1 and 50.6 mg/kg bw per day during gestation and 0, 0.5, 10.7 and 103.4 mg/
kg bw per day during lactation and weaning. Concentration, stability and homogeneity of the test
compound in the diet were determined. Rats were examined daily; clinical signs of toxicity, body
weight and food consumption were recorded at intervals during gestation and up to termination on
postnatal day 29. The parental animals were assessed in a FOB on days 10 and 17 of gestation and on
postnatal days 2 and 9. The sex, weight and clinical condition of each pup were recorded on postnatal
days 1 and 5. Where possible, litters were culled on postnatal day 5 to eight pups per litter with sexes
PROFENOFOS 403–443 JMPR 2007