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

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To investigate the significance of the label position for the outcome of studies of excretion and
metabolism, five male and five female Sprague-Dawley CD rats were given dimethomorph labelled
uniformly on either the chlorophenyl ring or the morpholine ring as a single dose at 500 mg/kg bw by
oral gavage. Chlorophenyl-ring labelled test compound (radiochemical purity, > 98%) had a specific
activity of 0.647 GBq/mmol and the E : Z isomer ratio was 45.3% E and 54.7% Z. Morpholine-ring
labeled test compound (radiochemical purity, > 98%) had a specific activity of 0.268 GBq/mmol
and the E : Z isomer ratio was close to 50 : 50 (mixed from separated isomers). The study complied
with GLP.
The excretion patterns of dimethomorph labelled at one of two different positions did not
exhibit significant differences (Table 6). Most of the radioactivity was excreted within 3 days after
administration, with faecal excretion being the major elimination pathway accounting for approximately
80% in females and approximately 90% in males. Urinary excretion was approximately
5% in males and approximately double (10%) in females. No difference in metabolite profiles
between the two test compounds was identified, although an additional very minor metabolic pathway
as cleavage of the amide bond was found with the chlorophenyl ring-labelled test compound
(Schluter, 1993).
To further characterize the faecal metabolites, the metabolism and excretion of [ 14 C]dimethomorph
was investigated in 10 male and 10 female Wistar rats (BRL-HAN) given a single dose at
50 mg/kg bw by gavage. Uniformly chlorophenyl-ring labelled [ 14 C]dimethomorph (radiochemical
purity, 99%) had a specific activity of 0.327 GBq/mmol and the E : Z isomer ratio was 51 : 49. Nonradiolabelled
dimethomorph was of 99.1% purity and the isomer ratio E : Z was 48 : 52. The study
complied with GLP.
Again, faecal excretion was predominant while urinary excretion was less than 20% of the
administered dose (Table 7). When compared with studies in Sprague-Dawley rats, rates of urinary
excretion seemed to be higher in male Wistar rats (17.1% of the administered dose).
In metabolite analyses, apart from the known degradation products (see Figure 2) an additional
metabolite (Z 98) was identified (Schluter & Grahl, 1994).
To investigate the pharmacokinetic features of dimethomorph, groups of four male and four
female Sprague-Dawley rats (Crl:CD BR) were given [ 14 C]dimethomorph as single oral gavage doses
at 10 mg/kg bw or 500 mg/kg bw, respectively. Test compound was uniformly chlorophenyl-ring
labelled [ 14 C]dimethomorph (radiochemical purity, 96%) with a specific activity of 0.363 GBq/mmol
Table 6. Excretion patterns in rats given dimethomorph labelled with 14 C in two different
positions
Position of
radiolabel
Day
Excretion (% of administered dose)
Males
Females
Faeces Urine Total Faeces Urine Total
Chlorophenyl ring 1 63.71 4.41 NR 34.08 6.13 NR
2 25.87 1.30 NR 36.21 6.26 NR
3 2.37 0.15 NR 11.63 0.87 NR
Total 91.95 ± 3.62 5.86 ± 2.01 97.80 ± 1.91 81.92 ± 6.94 13.26 ± 4.73 95.2 ± 2.92
Morpholine ring 1 76.71 3.24 NR 44.35 6.01 NR
2 13.89 0.86 NR 33.5 3.22 NR
3 1.09 0.17 NR 4.49 0.34 NR
Total 91.69 ± 1.50 4.27 ± 2.02 96.0 ± 1.54 82.34 ± 2.58 9.57 ± 1.10 91.9 ± 1.80
From Schluter (1993)
NR, not reported.
DIMETHOMORPH 273–315 JMPR 2007