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

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a single dose, which produced overt maternal toxicity, was used in the study, and the fetal findings
were considered to be of uncertain toxicological relevance. The NOAEL for developmental toxicity
was 125 mg/kg bw per day, the highest dose tested. A NOAEL for maternal toxicity was not
identified (Inawaka, 2003).
Primates
Groups of four pregnant cynomolgus monkeys (Macaca fascicularis) were given procymidone
(purity, 99.0%) at a dose of 62.5 or 125 mg/kg bw per day by gavage in 0.5% methylcellulose during
the critical period of differentiation of the fetal external genitalia (days 20–99 of gestation). Monkeys
were observed twice per day during the dosing period and once per day thereafter. Body weight and
food consumption were measured at intervals up to day 100 of gestation. Blood was taken for clinical
chemistry and haematology on days 19 and 100 and 2, 4, 8 and 24 h after the first and last doses on
days 20 and 99 for analysis of procymidone concentration. Fetal heartbeat and size were monitored
by ultrasound at intervals during pregnancy. The fetuses and placentae were removed under anaesthesia
by caesarean section on day 100 or 102 of gestation. The dams were then terminated and selected
organs were removed, fetuses and placenta were weighed; the fetuses were then given an external
examination followed by an internal examination of visceral organs and internal genitalia.
None of the monkeys died in either group and there were no signs of toxicity or treatment-related
effects on body weight, food consumption, clinical chemistry or haematology. One dam in each
group aborted. The major organs were unaffected. Blood concentrations of procymidone reached a
maximum 2–4 h after dosing and C max
and AUC increased in a linear manner with dose on day 20 but
were equal at day 99 (Table 25). There were two male and one female fetuses in the group at the lower
dose and three males in the group at the higher dose. There were no effects on the weight of the fetus
or placenta and no increase in adverse external or visceral findings including external genitalia of all
five male fetuses treated with procymidone (Fukunishi, 2003a).
A more extensive examination of the fetuses was made in a second study in which groups of
16 pregnant cynomolgus monkeys (Macaca fascicularis) were given procymidone (purity, 99.0%)
at a dose of 0 or 125 mg/kg bw per day by gavage in 0.5% methylcellulose during the critical period
of differentiation of the fetal external genitalia (days 20–99 of gestation). Monkeys were observed
twice per day for clinical signs of toxicity during the dosing period and once per day during the nondosing
period; body weight and food consumption were measured at intervals. Fetal heartbeat and
size were monitored by ultrasound during the treatment period to confirm pregnancy status and fetal
Table 24. Findings in fetuses of female rabbits given procymidone by gavage
Finding a
Dose (mg/kg bw per day)
0 125
Males Females Males Females
Pup body weight (g) 41.5 ± 6.5 39.8 ± 6.1 40.5 ± 8.2 40.8 ± 8.3
Anogenital distance (mm) 1.48 ± 0.18 1.34 ± 0.23 1.41 ± 0.16 1.35 ± 0.10
Phallus boundary-genital distance (μm) 434 ± 94 286 ± 91 368 ± 113 259 ± 76
Preputial lamella diameter (μm) 940 ± 58 836 ± 59 934 ± 60 833 ± 70
Ventral gap of preputial lamella (μm) 46 ± 40 421 ± 114 38 ± 19 498* ± 71
Ventral gap : preputial lamella ratio 0.05 0.50 0.04 0.60*
Relative ventral gap : body weight (μm/g) 1.1 ± 0.8 11 ± 3.4 1.0 ± 0.6 13 ± 3.5
From Inawaka (2003)
a
Mean ± standard deviation.
* p < 0.05 relative to females in the control group.
PROCYMIDONE 349–401 JMPR 2007