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1,2,4-Triazole does not modulate ovarian estrogen biosynthesis in vitro. Rat embryos (aged 9.5
days) exposed in vitro to 1,2,4-triazole at concentrations of up to 5000 µmol/l showed a markedly
anaemic visceral yolk sac and visibly paler erythrocytes at 2500 or 5000 µmol/l.
The results from these studies are summarized in Table 18.
(ii)
Toxicology of 1,2,4-triazolyl alanine
1,2,4-Triazolyl alanine acid (Figure 5) is a significant residue in plants treated with
d ifenoconazole.
An initial study of absorption, distribution, metabolism and excretion and subsequent studies
of metabolism were conducted. Hamboeck (1983a) showed that the compound was rapidly absorbed
and readily eliminated, mainly via the urine, and that up to 86% of the administered dose was excreted
unchanged. There was no difference between the sexes with respect to excretion, the pattern of
tissue residues, or the qualitative pattern of urinary metabolites.
In the second study of metabolism (Hambock, 1983b), 1,2,4-triazolyl alanine and one metabolite
were identified: DL-triazolyl alanine was isolated and identified by nuclear magnetic resonance
(NMR) and mass spectrometry (MS) and represented 69–86% of the administered dose in the urine
and 1–2% of the dose in the faeces, while N-acetyl-DL-triazolyl alanine represented 8–19% of the
administered dose in urine and < 1% of the dose in faeces. Thus, absorbed DL-triazolyl alanine is very
rapidly and completely eliminated via the urine, predominantly in unchanged form. A pproximately
15% of the administered dose was excreted as N-acetyl-DL-triazolyl alanine.
Experiments on acute oral toxicity were performed in rats and mice. A test for acute intraperitoneal
toxicity was performed in rats. 1,2,4-Triazolyl alanine was found to be of very low acute
toxicity.
One 28-day study in rats was conducted in order to identify potential target organs after administration
of high doses of 1,2,4-triazolyl alanine. There were no treatment-related findings and the
NOAEL was the highest dose tested (400 mg/kg bw per day).
Ninety-day studies of toxicity were performed in rats and dogs. In the study in rats, the NOAEL
was 5000 ppm, equivalent to 500 mg/kg bw per day, on the basis of body-weight effects at 20 000
ppm, equivalent to 2000 mg/kg bw per day, the highest dose tested. There were no other treatmentrelated
effects. In the study in dogs, the NOAEL was 8000 ppm, equivalent to 200 mg/kg bw per day,
on the basis of reduced body-weight gain at 20 000 ppm, equivalent to 500 mg/kg bw per day, the
highest dose tested. There were no other treatment-related findings (Table 19).
1,2,4-Triazolyl alanine produced no evidence of genotoxic potential in assays for reverse mutation/DNA
repair in bacteria and in assays for forward mutation/DNA repair/cell transformation in
mammalian cells in vitro. No clastogenic or aneugenic effects were observed in tests for m icronucleus
formation in mice and hamsters in vivo (Table 20).
No studies of carcinogenicity with 1,2,4-triazolyl alanine have been identified
A preliminary study of reproduction in rats (Birtley, 1983) identified a NOAEL of 10 000
ppm for maternal toxicity and a NOAEL for fetal toxicity as 2500 ppm on the basis of slight reductions
in neonatal body weights of male and female pups at 10 000 ppm. The follow-up main study
also identified the NOAEL for maternal toxicity as 10 000 ppm, equivalent to an average intake of
Figure 5. 1,2,4-Triazolyl alanine acid or 2-amino-3-(1,2,4]triazol)-1-yl-propionic acid
N
N
N
NH 2
COOH
DIFENOCONAZOLE 201–272 JMPR 2007