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

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males (all litters) in the group at 125 mg/kg bw per day. In addition, small testes and epididymis and
undescended testes and epididymis were observed occasionally in both groups. These results were
similar to those seen with procymidone (Inawaka, 2005). A benchmark-dose (BMD) assessment of
the incidence of hypospadia (Table 30) was performed by the Meeting, using a nested logistic model
on incidences in individual litters. The 95% lower limit for a 10% response (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
(Izumi, 2005).
(e)
Interconversion of metabolites
The interconversion of metabolites of procymidone was investigated in female rats in vivo and
and in vitro. After the subcutaneous administration of [phenyl- 14 C]PA-CH 2
OH at a dose of 62.5 mg/
kg bw to a group of three Sprague-Dawley rats, imide-bond cleaved and uncleaved metabolites were
found in tissues and plasma (Table 31) (Tomigahara, 2005a), indicating reversal of the cleavage
reaction that produced PA-CH 2
OH from procymidone (see Figure 1). In an identical study but with
[phenyl- 14 C]PCM-CH 2
OH, both cleaved and uncleaved metabolites were seen in plasma and tissues
(Table 31) (Tomigahara, 2005b). A comparative study with oral and subcutaneous administration
showed that a subcutaneous dose of 125 mg/kg bw was equivalent, in terms of metabolite profile,
C max
and AUC, to an oral dose of 62.5 mg/kg bw (Tomigahara, 2005c). The variations in the relative
levels of metabolites between tissues (pH approximately 6.8) and plasma (pH approximately 7.4)
were investigated in vitro. [phenyl- 14 C]Procymidone and [phenyl- 14 C]PCM-CH 2
OH were incubated
at pH 2.0, 4.0, 6.8, 7.4, 8.0 or 11.0 at room temperature for 16 h. The reaction mixtures were analysed
by TLC and the ratio of procymidone to PCM-NH-COOH and of PCM-CH 2
OH to PA-CH 2
OH were
calculated. Under acid conditions (pH < 6.8), procymidone and PCM-CH 2
OH were stable, but under
alkaline conditions (pH > 7.4) the imide bond was cleaved to give PCM-NH-COOH and PA-CH 2
OH
(Tarui, 2005a). These studies indicated that procymidone metabolites have the potential to interconvert
non-enzymatically when transferred from plasma to tissues and vice versa.
4. Observations in humans
Annual medical records for workers involved with the packaging of procymidone were examined
for 1979–1983. A total of 20 workers was included in the survey. Of these, 16 had been engaged
in packing procymidone for more than 9 h per year for an average of 4 years. None of the workers had
any symptoms that could be associated with exposure to procymidone (Harada, 1983).
A further review was completed in 2001. The medical records and operational details of 15
workers who had been engaged in the manufacture and packing of technical-grade procymidone
into drums were examined. Operational details included number of hours spent packing per year,
number of years involved in packing, age and use of personal protective equipment. Annual medical
Table 30. Incidence of hypospadia in pups from studies of developmental toxicity with
procymidone and PCM-CH 2
OH
Dose (mg/kg bw per day) Day 22 (observation) Day 56 (gross examination)
Procymidone PCM-CH 2
OH Procymidone PCM-CH 2
OH
0 0/119 0/67 0/119 0/67
37.5 2/122 Not dosed 19/122 Not dosed
62.5 13/135 3/86 59/134 16/86
125 Not dosed 26/86 Not dosed 71/84
From Izumi (2005) and Inawaka (2005)
PCM-CH 2
OH, hydroxyprocymidone.
PROCYMIDONE 349–401 JMPR 2007