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

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procymidone (18–27% of the administered dose). Only low concentrations (< 0.3%) of radioactivity
were retained 168 h after oral administration; the highest concentrations were found in fat. The major
metabolic pathway for procymidone in mice and rats involved the oxidation of the methyl groups
to hydroxymethyl or carboxylic acid derivatives, cleavage of the imide, and glucuronide formation
of the resultant metabolites. In cynomolgus monkeys, rabbits and chimeric mice with humanized
livers (i.e. liver repopulated with human hepatocytes), there was more extensive urinary excretion
of glucuronide conjugates than in rats or normal mice. In rats, the glucuronides were formed, but
were present in the bile and appear to be deconjugated and the aglycone was reabsorbed giving a
prolonged elimination phase and relatively high AUC. Studies in vitro with liver preparations from
humans, rabbits, cynomolgus monkeys and rats showed that the rate of metabolism of procymidone
and PCM-CH 2
OH was significantly lower in rats than in the other species studied.
In female cynomolgus monkeys, there was an increase in C max
and AUC values after repeated
doses. In other species, the routes and rates of tissue distribution, biotransformation and excretion of
procymidone were similar in males and females and after single or repeated administration.
Procymidone has a high binding affinity in vitro (92–98% bound) for plasma proteins when
incubated with plasma from female rats, cynomolgus monkeys, rabbits and humans. The alcohol
metabolite PCM-CH 2
OH had a slightly lower binding affinity (77–91% in all species) than procymidone,
with the highest affinity being for human plasma proteins.
Kinetic studies in rats, rabbits and cynomolgus monkeys (dams and fetuses of each species)
have been performed as part of investigations of the effects on male rat reproductive tissues. After a
single dose, cynomolgus monkeys had much lower C max
values for total radioactivity than did rabbits
and rats, but at doses of up to 125 mg/kg bw rabbits had relatively low AUC values owing to rapid
elimination. In cynomolgus monkeys, the predominant compound in plasma was procymidone; in
rabbits, acid metabolites and glucuronides of alcohol metabolites were the major components in
plasma; in rats, free alcohol metabolites predominated. After 14 doses at 37.5–500 mg/kg bw per day,
C max
and AUC values for total radioactivity were similar for rats and cynomolgus monkeys. These
findings show that the doses used in the studies of developmental toxicity in cynomolgus monkeys
would have produced similar plasma concentrations of total radioactivity, but with different metabolite
profiles, to those in rats at doses resulting in hypospadias. The investigations of the transfer of
procymidone and metabolites to fetuses again showed species differences. After dosing at 125 mg/kg
bw per day, the concentrations of procymidone and metabolites in the fetus were significantly greater
(10-fold or greater) in rats than in rabbits or cynomolgus monkeys. In rats, the relative concentrations
of PCM-CH 2
OH in the fetus versus the dam were much higher than in rabbits or cynomolgus
monkeys.
Toxicological data
Procymidone was of low acute toxicity by the oral (LD 50
> 5000 mg/kg bw) and dermal
(LD 50
> 2500 mg/kg bw) routes, and after a 4-h exposure by inhalation (LC 50
> 1.5 mg/l). Procymidone
is not an eye irritant, but is a slight, transient skin irritant. Procymidone did not produce delayed
contact hypersensitivity in guinea-pigs in either the maximization or repeat-injection tests.
The primary target organs in rats and mice exposed to procymidone in repeat-dose studies were
the liver and testes. The major effect of short-term dietary administration of procymidone in ICR mice
was on the liver. Centrilobular hepatocyte hypertrophy was noted in male mice and hepatocyte granuloma
in females that received procymidone at 500 ppm, equal to 71 mg/kg bw per day, for 13 weeks;
the NOAEL was 150 ppm, equal to 22 mg/kg bw per day. In a subsequent study with B6C3F 1
mice,
multifocal coagulative necrosis of hepatic parenchyma, centrilobular cytoplasmic swelling, nuclear
enlargement, coarsely-dispersed chromatin and multinucleate hepatocytes were noted in mice receiving
procymidone at 10 000 ppm, equivalent to 1430 mg/kg bw per day. This was accompanied by
increased liver weight and serum ALT activity in males and higher cholesterol concentrations in
PROCYMIDONE 349–401 JMPR 2007