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

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Inhibition of brain acetylcholinesterase activity and clinical signs consistent with neurotoxicity
were observed in rats exposed to profenofos at a concentration of 0.07 mg/l per day by inhalation for
21 days.
In three studies of dermal toxicity in rabbits, the overall NOAEL for inhibition of brain acetylcholinesterase
was 2.5 mg/kg bw per day on the basis of significantly reduced activity at 5 mg/kg
bw per day.
Three studies were carried out in dogs given profenofos orally for 90 days, 6 months, or 1 year.
Profenofos was given in the diet in the 90-day and 6-month studies, and daily in gelatin capsules in
the 1-year study. No clinical signs of toxicity were recorded in these studies, the 6-month and 1-year
studies including neurological examinations (NOAEL for clinical signs, 12.5 mg/kg bw per day).
Brain acetylcholinesterase activity was significantly inhibited in males at 5 mg/kg bw per day in the
90-day study, but not in either sex at 2.9 or 14.4 mg/kg bw per day in the 6-month study, or at 1 or
12.5 mg/kg bw per day (the highest dose tested) in the 1-year study. Hence, for brain acetylcholinesterase
inhibition, the overall NOAEL in these three studies in dogs was 2.9 mg/kg bw per day. Haematology
parameters (erythrocyte count, haemoglobin concentration and erythrocyte volume fraction)
were reduced; however, they were not considered to be toxicologically significant since there was no
clear dose–response relationship, and the small changes observed were within the range for historical
controls. Treatment of dogs with profenofos at 12.5 mg/kg bw per day for 1 year was also associated
with an increase in binucleated perilobular hepatocytes, bile-duct hyperplasia and an increase in bile
pigments in kidney tubules. These pathological findings were minimal in severity and were not observed
in the 90-day or 6-month studies of toxicity.
Profenofos was not mutagenic in an adequate battery of studies of genotoxicity.
The Meeting concluded that profenofos is unlikely to be genotoxic.
In long-term studies, treatment of mice and rats with profenofos did not adversely affect survival;
there were no clinical signs of toxicity, no increase in the incidence of tumour formation and no
treatment-related changes in either gross pathology or histopathology. Plasma and erythrocyte cholinesterase
activity were significantly reduced in mice given diet containing profenofos at 30 ppm,
equal to 4.5 mg/kg bw per day, and in rats at 100 ppm, equal to 5.7 mg/kg bw per day. In female mice,
there was a statistically significant inhibition of brain acetylcholinesterase activity (25%) at termination
of the group at 100 ppm, equal to 14.2 mg/kg bw per day, resulting in a NOAEL of 30 ppm, equal
to 4.5 mg/kg bw per day. The NOAEL in the 2-year study of carcinogenicity in rats was 100 ppm,
equal to 5.7 mg/kg bw per day, the highest dose tested. Profenofos was not carcinogenic in mice and
rats up to the highest dose tested. Although overt toxicity was not observed in the study in rats, the
Meeting considered that the available database was sufficient to evaluate the carcinogenic potential
of profenofos.
In view of the lack of genotoxicity, the absence of carcinogenicity in mice and rats, and any
other indication of carcinogenic potential, the Meeting concluded that profenofos is unlikely to pose
a carcinogenic risk to humans.
Multigeneration studies have shown that profenofos has no effect on reproduction at doses of
up to 400 ppm, equivalent to 35 mg/kg bw per day. The NOAEL for parental and pup toxicity was
100 ppm, equivalent to 7.0 mg/kg bw per day, on the basis of reduced body-weight gains and food
consumption at 400 ppm, equivalent to 35 mg/kg bw per day, and the NOAEL for reproductive toxicity
was 400 ppm, the highest dose tested.
Profenofos did not cause developmental effects in rats or rabbits. Clinical signs typical of
cholinesterase inhibition were noted in rabbits given profenofos at 175 mg/kg bw per day and approximately
50% of the animals died. There were no treatment-related effects on the mean number of
implantations, litter size, fetal body weight or embryolethality and there were no significant increases
in variations or malformations in the fetuses. The NOAEL for maternal toxicity was 30 mg/kg bw per
day and the NOAEL for developmental toxicity was 175 mg/kg bw per day, the highest dose tested.
PROFENOFOS 403–443 JMPR 2007