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

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but only at 6000 ppm after 13 weeks (131%). The assay in vitro showed that basal production of
testosterone was increased at all termination times at 6000 ppm. The hCG-stimulated production
of testosterone was elevated at all times in rats at 2000 and 6000 ppm and after 13 weeks in rats at
700 ppm. There were no treatment-related changes in the number of binding sites or the binding
affinity of hCG to the LH/hCG receptor (Murakami et al., 1988a).
Primates
In a dose range-finding study, no effects on ejaculate mass, sperm counts, testosterone and LH
concentrations or organ weights were seen in groups of two male cynomolgus monkeys (Macaca
fascicularis) that received procymidone (purity, 98.7%) at doses up to 1000 mg/kg bw per day by
gavage for seven consecutive days (Zühlke, 1991).
In the main study, groups of five male cynomolgus monkeys (Macaca fascicularis) received
procymidone (purity, 98.7%) at a dose of 0, 30 100 or 300 mg/kg bw per day by gavage as a suspension
in 1% sodium carboxymethyl cellulose for 13 weeks. Clinical signs and food consumption were
recorded daily and body weights weekly. Sperm was taken for analysis and testicular dimensions
recorded six times before dosing and in weeks 4, 8 and 13. Serum testosterone and LH concentrations
were measured in samples taken before dosing and weekly during the treatment phase. The monkeys
were necropsied at the end of the treatment period and the epididymides, prostate gland, seminal
vesicles and testes were weighed and examined microscopically.
All monkeys survived the study with no signs of reaction to treatment. Body-weight variations
were similar across the groups. There was no clear evidence of a treatment-related effect on food
intakes, testicular size or LH concentrations. Histopathology of the reproductive organs did not detect
any treatment-related change. There were indications of effects on ejaculate mass, sperm counts
(Table 28), and serum testosterone concentrations (Figure 2) particularly during the first 4 weeks,
and on testes weights (Table 28). There was no statistically significant change when compared with
values for concurrent controls, other than relative testes weights, which did not exhibit any dose–
response relationship. When values after dosing were compared with values before dosing for each
individual, using a repeated measures ANOVA with post-hoc comparisons using the least significant
differences (LSD) test, ejaculate mass was found to be statistically significantly reduced (p < 0.05) at
100 and 300 mg/kg bw per day. The small group size, absence of a clear dose–response relationship
and large degree of inter- and intra-group variation before and after dosing made it difficult to reach
firm conclusions on the findings of this study.
The NOAEL was 30 mg/kg bw per day on the basis of statistically significant effects on testes
weights and ejaculate mass at 100 mg/kg bw per day. The study contained statements of compliance
with GLP (Bee, 1992).
(iii) Fetal distribution
Groups of three pregnant rats (Crj:CD(SD)IGS), New Zealand White rabbits or cynomolgus
monkeys were given [phenyl- 14 C]procymidone (purity, > 97.5%; specific activity, 15.8 MBq/mg) at
a dose of 125 mg/kg bw on day 17, 21 or 54 of gestation, respectively. Groups of rats also received
doses on: (i) day 16; (ii) days 16 and 17; or (iii) days 16, 17 and 18 of gestation. Corn oil was the
vehicle in the studies in rats, for rabbits and monkeys the vehicle was 0.5% methylcellulose. The
rats and monkeys were killed 6 and 24 h after dosing, rabbits after 2 and 24 h. Samples of maternal
blood, amniotic fluid and fetal blood were taken. The maternal liver and kidneys, the placenta, fetus,
fetal brain, fetal heart, fetal lung, fetal liver and fetal kidneys were removed at necropsy. These
samples were analysed for radioactivity and the amounts of procymidone and its metabolites were
also determined.
PROCYMIDONE 349–401 JMPR 2007