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

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Three groups of five male and five female Crl:CD®(SD)BR rats were given a single oral
dose of [phenyl- 14 C]procymidone (radiochemical purity, > 98%; specific activity, 242 μCi/mg
(8.95 MBq/mg) at 1 or 250 mg/kg bw in corn oil. An additional group of rats received 14 consecutive
daily doses of unlabelled procymidone at 1 mg/kg bw before receiving [phenyl- 14 C]procymidone
at a dose of 1 mg/kg bw. Urine and faeces were collected for 7 days after dosing, after which
the rats were killed and tissues removed for analysis. Samples were processed, including incubation
with glucuronidase. Metabolites in excreta collected for up to 48 h (for rats at 1 mg/kg bw) and to
72 h (for rats at 250 mg/kg bw) after dosing were isolated by TLC and identified by co-chromatography
with standards by mass spectral analysis. Overall, up to 42 urinary and nine faecal metabolites
were found. Unchanged procymidone in the faeces accounted for < 5% of the administered dose
in the group at 1 mg/kg bw, but was a major faecal component (18–27% of the administered dose)
at 250 mg/kg bw. There were no significant differences in metabolism between the sexes, or after
repeated dosing (Table 4). The findings were consistent with the results of earlier studies, with acid
metabolites predominating in the urine (Struble, 1992b).
The proposed metabolic pathway is shown in Figure 1. The major metabolic reactions for
procymidone were oxidation of the methyl groups to hydroxymethyl or carboxylic acid derivatives;
cleavage of the imide; and glucuronide conjugation of the resultant metabolites.
Human-derived tissues
In an initial study, [phenyl- 14 C]procymidone (purity, > 98%; specific activity, 15.6 MBq/mg)
at a concentration of approximately 1 μmol/l was incubated with human hepatocytes at 37 o C for
46 h . The reaction was terminated by the addition of acetonitrile. Metabolites were identified by
Table 4. Metabolites in excreta from rats given [phenyl- 14 C]procymidone at a dose at 1 or
250 mg/kg bw
Metabolite a
Recovery (% of administered dose)
Dose
1 mg/kg bw 250 mg/kg bw
Single dose Fourteen doses
Male Female Male Female Male Female
Urine 71 70 67 75 58 61
PCM 0 0 0 0 0 0
PCM-CH 2
OH < 1 < 1 < 1 < 1 < 1 1
PCM-CH 2
OH-glucuronide 2 1 2 3 — —
PA-CH 2
OH < 1 1.8 < 1 < 1 < 1 < 1
PCM-COOH 2 0 3 1 2 1
PA-COOH 50 48 45 56 44 44
DCA 0.3 0.5 0.1 1 0.8 0.5
Unknown/unextracted 10 11 11 19 11 11
Faeces 15 10 11 6 32 23
PCM 3 1 < 1 < 1 26 18
PCM-CH 2
OH 2 1 1 < 1 2 1
Unknown/unextracted 10 7 8 6 7 6
From Struble (1992b)
DCA, 3,5-dichloroaniline; PA, procymidone acid; PA-CH 2
OH, hydroxyprocymidone acid; PA-COOH,
carboxyprocymidone acid; PCM, procymidone; PCM-CH 2
OH, hydroxyprocymidone; PCM-NH-COOH,
carboxyprocymidone.
PROCYMIDONE 349–401 JMPR 2007