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

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Binding to plasma proteins
The plasma-protein binding of [phenyl- 14 C]procymidone (specific activity, 15.8 MBq/mg) and
its metabolite [phenyl- 14 C]PCM-CH 2
OH (specific activity, 3.3 MBq/mg) was determined in humans,
Sprague-Dawley rats, cynomolgus monkeys and New Zealand White rabbits; plasma from females
was used fo each species. Plasma-protein binding at pH 7.0 was investigated in vitro at concentrations
of 1, 3, 10 and 30 µg/ml using an ultrafiltration method. Both compounds exhibited a high level of protein
binding in plasma from all species (Table 8). Plasma-protein binding of procymidone was similar
in all species tested and ranged from 92% to 98% over the range of concentrations tested. The plasmaprotein
binding of PCM-CH 2
OH was slightly lower than that of procymidone; the value for human
plasma (90–91%) was slightly greater than that for rats (82–90%), monkeys (77–85%) and rabbits
(83–86%). Since rats make much more PCM-CH 2
OH (tenfold), these results indicated that there are
likely to be much higher levels of free PCM-CH 2
OH in rats than in other species (Matsui, 2005a).
2. Toxicological studies
2.1 Acute toxicity
(a)
Lethal doses
The results of studies of acute toxicity with procymidone administered by the oral, dermal,
subcutaneous, intraperitoneal (i.p) and inhalation routes, are presented in Table 9. Procymidone was
of low acute toxicity by all routes. All these studies were performed before GLP was instituted and
are limited in detail; however, there are no reasons to doubt the findings.
Clinical signs of toxicity were typically increased respiration and reduced motor activity.
These were evident at doses of ≥ 250 mg/kg bw orally and subcutaneously and ≥ 100 mg/kg bw i.p.,
but showed no clear trend with dose administered. There were no adverse findings at postmortem
examination.
Table 8. Plasma-protein binding in vitro and total and calculated plasma concentrations of free
procymidone and PCM-CH 2
OH (μg equivalent/ml) in female mice, rats, monkeys and humans
Concentration
(μg/ml) / dose
(mg/kg bw
per day)
Procymidone
Human Rat Monkey Rabbit
PPB
(%)
PPB
(%)
Total
(μg equivalent/
ml)
Free a
(μg equivalent/
ml)
PPB
(%)
Total
(μg equivalent/
ml)
Free a
(μg equivalent/
ml)
PPB
(%)
1 / 37 95.5 97.9 2.6 0.06 95.4 ND ND 97.6
3 / 67 95.5 97.5 2.6 0.06 94.6 3.6 0.19 97.3
10 / 125 95.5 96.9 6.4 0.19 93.9 6.6 0.4 97.4
30 / 250 95.4 96.3 5.1 0.15 92.4 6.8 0.4 97.1
PCM-CH 2
OH
1 / 37 90.9 90.4 9.9 1.3 85.3 ND ND 85.6
3 / 67 90.9 98.9 9.8 1.3 83.9 1.3 0.2 85.6
10 / 125 90.5 87.1 32 5.7 80.2 3.1 0.5 84.3
30 / 250 90.4 82.1 51 9.2 76.9 2.1 0.3 82.7
From Matsui (2005a)
ND, no data; PCM-CH 2
OH, hydroxyprocymidone; PPB, plasma-protein binding.
a
Concentration of free substance was calculated from binding percentage and total concentration.
PROCYMIDONE 349–401 JMPR 2007