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

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The Meeting concluded that the existing database on procymidone was adequate to characterize
the potential hazards to fetuses, infants and children
Procymidone has not been studied specifically for neurotoxicity, but there were no indications
from the results of conventional studies that it has significant neurotoxic potential.
A number of studies have been performed with procymidone metabolites. DCA was of
moderate acute toxicity in dd mice, having an oral LD 50
of approximately 850 mg/kg bw. PCM-
NH-COOH was also of moderate acute toxicity in dd mice, with an oral LD 50
of approximately
1450 mg/kg bw. DMCPA was of low acute toxicity in dd mice, having an oral LD 50
of approximately
4400 mg/kg bw and a subcutaneous LD 50
of approximately 2400 mg/kg bw. DMCPA
gave negative results in an Ames test and an assay for micronucleus formation in vivo. DMCPA
was rapidly absorbed and excreted with minimal metabolism. Retention of radioactivity in tissues
was low.
PCM-CH 2
OH was investigated in a modified study of developmental toxicity in which rats were
allowed to deliver normally. No abnormal findings were seen in dams or female offspring. In the male
offspring, a dose-related shortening of the anogenital distance was seen and there were increases in
the incidence of male offspring and litter with abnormities of the external genitalia. The incidence of
hypospadias was increased in pups from dams receiving procymidone at 62.5 mg/kg bw per day, the
lowest dose tested. In addition, small testis and epididymis and undescended testis and epididymis
were observed occasionally in groups treated with PCM-CH 2
OH. These results are similar to those
seen with procymidone at similar doses. The BMDL 10
for hypospadias was 43.8 mg/kg bw per day
for PCM-CH 2
OH and 23.7 mg/kg bw per day for procymidone. The Meeting considered the data
on the relative androgen receptor and plasma-protein binding affinities of hyroxy-procymidone and
procymidone, and the marked species differences in formation and elimination of procymidone and
its metabolites. The Meeting concluded that while PCM-CH 2
OH might be a significant contributor
to the effects seen in rats, due to the much higher systemic and fetal exposure, the contribution of
procymidone could not be discounted in other species, particularly due to limitations in the studies
in cynomolgus monkeys.
Surveys of the medical records of production-plant workers had not identified any symptoms
or diseases related to the manufacture of procymidone. There were no documented cases of procymidone
intoxication nor any significant effects associated with its use.
Toxicological evaluation
The Meeting established an ADI of 0–0.1 mg/kg bw based on a NOAEL of 12.5 mg/kg bw per
day in a two-generation study of reproductive toxicity and a study of developmental toxicity in rats,
on the basis of hypospadias and alterations in testes, prostate and epididymis weights, and a safety
factor of 100. The ADI was supported by NOAELs of 14 mg/kg bw per day in the 2-year study in rats
and 15 mg/kg bw per day in the 2-year study in mice.
The Meeting established an ARfD of 0.1 mg/kg bw based on a NOAEL of 12.5 mg/kg bw
on the basis of hypospadias, which might have been a consequence of a single exposure, in a study
of developmental toxicity in rats, and using a safety factor of 100. The Meeting concluded that the
effects on organ weights observed in the multigeneration study were largely a consequence of postnatal
exposure over a period of time and therefore not appropriate for the establishment of the ARfD.
The Meeting considered that, on the basis of the observed differences between species in terms of
kinetics, metabolism and toxicological sensitivity to procymidone, this ARfD might be conservative.
However, uncertainties regarding potential responses in species other than rats were such that it was
not possible to modify the default safety factor.
PROCYMIDONE 349–401 JMPR 2007