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

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Table 7. Incidence of hydrocephaly in rabbits exposed prenatally to flusilazole
Study a Dose (mg/kg bw per day) Total No. of fetuses (litters) affected
Alvarez (1990) 0 —
7 —
15 1 (1)
30 1 (1)
Alvarez et al. (1985b) 0 —
8.9 —
21.2 —
37.8 —
Solomon et al. (1984) 0 1 (1)
1.9 2 (1)
4.8 5 (3)
10.1 4 (3)
Zellers et al. (1985) 0 —
11.2 —
31.5 1 (1)
—, no incidence.
a
Purity of flusilazole: Alvarez (1990), 93.8%; Alvarez et al. (1985b), 94.8%; Solomon et al. (1984),
96.5%; Zellers et al. (1985), 96.5%.
per day (given as two equal half-doses, twice per day) for 14 days. The control group (0 mg/kg bw
per day) and group at 200 mg/kg bw per day each contained an additional subgroup of 10 male rats
that were treated with hCG 1 h before killing. All surviving rats were killed on day 15 of treatment
and necropsied. Samples of testicular interstitial fluid and serum were collected from rats that were
not treated with hCG; interstitial fluid was analysed for testosterone and serum was analysed for
testosterone, estradiol, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Serum
samples collected from the rats treated with hCG were analysed for testosterone, androstenedione,
17 α-hydroxyprogesterone and progesterone.
At the lowest dose of 20 mg/kg bw per day, and greater, increased absolute and relative liver
weights and a dose-related inhibition of serum testosterone (statistically significant at 150 mg/kg bw
per day and greater) and estradiol (statistically significant at all doses) concentrations were observed.
At the two higher doses (150 and 250 mg/kg bw per day), clinical symptoms of toxicity (sores, stained/
wet fur, dehydration and diarrhoea), decreased body weight and body-weight gain, and reduced food
consumption were evident. Increased mortality (8 out of 10) also occurred at the highest dose of
250 mg/kg bw per day. At 250 mg/kg bw per day in the rats treated with hCG, serum testosterone
concentrations were significantly lower than in the controls; no other significant differences in
hormone levels were noted in rats treated with flusilazole. In the positive-control group treated with
ketoconazole, rats showed significantly lower concentrations of testosterone, androstenedione and
17-hydroxyprogesterone, and higher concentrations of progesterone, indicating inhibition of 17αhydroxylase.
On the basis of the results, no NOAEL for the portion of this study that was carried out
in vivo could be identified.
In a GLP-compliant study in vitro, Leydig cells were collected from rat testes at termination
of the study in vivo and cultured in microplate wells. The cells were then incubated with either
flusilazole technical or ketoconazole at doses of 0.05–100 μmol/l (in 70% ethanol) for 2 h. Culture
media were sampled and analysed for testosterone, androstenedione, 17 α-hydroxyprogesterone
FLUSILAZOLE 317–347 JMPR 2007