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

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Procymidone induced liver tumours in mice and testicular tumours in rats. No specific
mechanistic studies have been performed to investigate the liver tumours; however, hepatocellular
hypertrophy was present in shorter-term studies, and mice are sensitive to the production of liver
tumours in response to such effects produced by high concentrations of xenobiotics. Procymidone
gave negative results in assays for genotoxicity in vitro and in vivo. A clear threshold for induction
of liver tumours was identified in the study of carcinogenicity in mice. Investigative work on the
endocrine effects of procymidone indicated that it binds to the androgen receptor with a similar
potency to that of the prostate-cancer drug flutamide, and that in rats the mechanism of hormonal
action appeared to be via binding to the androgen receptor, disrupting the feedback controls on LH
and testosterone concentrations. Overall, the data suggest that procymidone may induce testicular
interstitial cell tumours via an endocrine-mediated mechanism. Although this mode of action is
relevant to humans, there is good evidence to suggest that humans are less sensitive to chemicallyinduced
interstitial cell tumours of the testis than rats, owing to differences in sensitivity to LH on
the basis of Leydig-cell receptor number and control of LH-receptor expression (e.g. via prolactin
in rodents but not in humans).
The Meeting concluded that procymidone was unlikely to present a carcinogenic risk to humans
at typical levels of dietary exposure.
The reproductive toxicity of procymidone had been investigated in two studies in rats. The
developmental toxicity of procymidone had been studied in conventional studies in rats and rabbits
and in special investigative studies in rats, rabbits and cynomolgus monkeys.
In the first generation of the two-generation study in rats, there was no effect on mating and
reproduction, but at 750 ppm, equivalent to 50 mg/kg bw per day, there was an increase in the number
of male pups with hypospadias and reduced anogenital distance. In the second generation, male fertility
was reduced and the incidence of hypospadias was increased at 750 ppm. In parents and pups,
there were increases in testes weights and decreases in body-weight gain, prostate and epididymis
weights at 750 ppm, with the organ-weight changes also present in pups at 250 ppm. There were no
adverse effects on female reproductive performance or on female offspring. The NOAELs for effects
on parents and on reproduction were 250 ppm, equivalent to 17 mg/kg bw per day. The NOAEL for
pup development was 50 ppm, equivalent to 3 mg/kg bw per day, on the basis of the alterations in
weights of the testes, prostate and epididymis at 250 ppm. In a subsequent one-generation study,
designed to investigate the effects on male pups in the previous study, there was a reduction in bodyweight
gain and reduced litter size at 37 mg/kg bw per day. Increases in the incidence of hypospadias
and in testes weights, and decreases in weights of the prostate and seminal vesicles were seen in pups
at 37 mg/kg bw per day. The NOAELs for parental toxicity, pup development and reproduction were
12.5 mg/kg bw per day.
Studies of developmental toxicity with procymidone have been performed in rats, rabbits and
cynomolgus monkeys. In a conventional study of developmental toxicity in rats, there were significant
(60%) reductions in maternal body-weight gain during the first 6 days of dosing at 300 mg/kg bw per
day, but no adverse findings in pups. This study did not include specific investigations of anogenital
distance or the external genitalia. The NOAEL for fetotoxicity and teratogenicity was 300 mg/kg bw
per day, the highest dose tested. The NOAEL for maternal effects was 100 mg/kg bw per day. In a
modified study of developmental toxicity, pregnant rats were dosed with procymidone on days 6–19
of gestation; on day 20, half the dams had caesarian sections and the other half were allowed to deliver
normally. Examinations focused on the male reproductive tract. Maternal toxicity (body-weight loss
and poor appearance) was evident at doses of 125 mg/kg bw per day and greater. A range of effects
was seen on male fetuses and offspring from dams receiving doses of 125 mg/kg bw per day and
greater: reduced anogenital distance, undescended testes, hypospadias, testicular atrophy, distended
preputial gland, inflammatory changes in the accessory sex organs (seminal vesicles, prostate and
coagulating glands), and lower organ weights of testes and prostate. At 500 mg/kg bw per day, there
PROCYMIDONE 349–401 JMPR 2007