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

435
Studies of developmental toxicity in rats, maternal toxicity, which included clinical signs typical of
cholinesterase inhibition, and deaths were observed at the highest dose of 120 mg/kg bw per day.
There was no evidence for prenatal toxicity at either of these doses and the type and incidence of
fetal malformations and variations was unaffected by treatment. The NOAEL for maternal toxicity
was 90 mg/kg bw per day and the NOAEL for developmental toxicity was 120 mg/kg bw per day, the
highest dose tested.
The Meeting concluded that profenofos is not teratogenic.
The potential for profenofos to cause developmental neurotoxicity had also been investigated
in rats. In a preliminary range-finding study, rats were given diets containing profenofos at a concentration
of 0, 4, 200, 400 or 600 ppm, equal to 0, 0.7, 33.9, 66.0 or 97.6 mg/kg bw per day. In this
study, dose-dependent inhibition of the brain acetylcholinesterase activity was observed in dams at
≥ 200 ppm on postnatal day 22. The NOAEL for inhibition of brain acetylcholinesterase activity in
dams was 4 ppm, equal to 0.7 mg/kg bw per day. A statistically significant inhibition of brain acetylcholinesterase
activity of > 20% and 16% was found in female pups at ≥400 ppm and male pups at
600 ppm, respectively. In the main study of developmental neurotoxicity, rats were given diets containing
profenofos at a concentration of 0, 3, 60 or 600 ppm (equal to 0, 0.3, 5.1 or 50.6 mg/kg bw
per day). At 600 ppm in dams, brain acetylcholinesterase activity was decreased by 44% on day 22
of gestation, and by 26% (not statistically significant) on day 22 of lactation, and body weights and
food consumption were reduced. A statistically significant inhibition of brain acetylcholinesterase
activity was observed in female pups at 600 ppm compared with controls on day 5 (11% lower) but
not at later times. At 600 ppm, there was a statistically significant reduction in pup body weights
(11–12%). No effects on functional parameters or neurohistopathology were observed. 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 overall NOAEL for
inhibition of brain acetylcholinesterase in pups was 60 ppm, equal to 5.1 mg/kg bw per day. The
NOAEL for developmental neurotoxicity was 600 ppm, equal to 50.6 mg/kg bw per day, the highest
dose tested.
In two studies of acute neurotoxicity in rats, there were reversible signs typical of poisoning
with acetylcholinesterase inhibitors (diarrhoea, miosis, lacrimation, tremor), peaking 4 h after
administration of profenfos at 380 mg/kg bw by gavage. Lesser effects were seen at 200 mg/kg bw
(hypoactivity, soft faeces), and there were no effects in the FOB at 190 mg/kg bw (the NOAEL for
clinical signs). There was significant inhibition of brain acetylcholinesterase activity (by 37% in
males and 43% in females) at 4 h after dosing at 400 mg/kg bw, with a NOAEL of 100 mg/kg bw.
Inhibition was absent after a recovery period of 14 days.
There were also no clinical signs of toxicity, and no adverse findings in a FOB or effects on motor
activity in a 90-day study of neurotoxicity in rats. Pathological investigation revealed no evidence
of treatment-related toxicity. At the highest dose of 600 ppm, equal to 36 mg/kg bw per day, there was
a reduction of approximately 10% in body-weight gain. At 600 ppm, there was a statistically significant
inhibition of brain acetylcholinesterase activity of 12% in males and 20% in females at week 13.
The NOAEL for brain acetylcholinesterase inhibition was 135 ppm, equal to 7.7 mg/kg bw per day.
Profenofos did not induce delayed neuropathy in chickens given two doses at 45.7 mg/kg bw
(maximum tolerated dose) and then at 17.1 mg/kg bw, separated by an interval of 21 days (atropine
protection being given as soon as clinical signs appeared).
No cases of adverse effects have been reported among workers involved in the manufacture of
profenofos. In a biological monitoring study, whole-blood cholinesterase activity was inhibited by
less than 30% in six workers who were monitored daily for 4 days during spraying of p rofenofos.
The Meeting concluded that the existing database on profenofos was adequate to characterize
the potential hazards to fetuses, infants and children.
PROFENOFOS 403–443 JMPR 2007