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

255
Table 21. Results of studies of reproductive toxicity with 1,2,4-triazolyl alanine
Study Species Dose NOAEL Adverse effects Reference
Two-generation,
feeding
Rat 0, 500, 2 000
and 10 000
ppm
Parental: 10 000 ppm, e quivalent
to 500 mg/kg bw per day
R eproduction: 2 000 ppm,
e quivalent to 100 mg/kg bw per day
Maternal: 1 000 mg/kg bw per day
Developmental: 100 mg/kg bw per
day
Reduced neonatal
weights
Milburn et al.
(1986)
Teratogenicity,
gavage
Rat
0, 100, 300 and
1 000 mg/kg
bw per day
Retarded
o ssification
Clapp et al.
(1983)
1,2,4-Triazolyl acetic acid was tested for mutagenic effects at doses of up to 5120 μg/plate in S.
typhimurium strains TA98, TA100, TA1535 and TA1537 in the presence and absence of an exogenous
metabolic activation system. There were no increases in the numbers of mutants per plate (Deparade,
1984).
(c)
Supplementary studies with difenoconazole.
Supplementary studies conducted with difenoconazole consisted of a mechanistic study, examining
biochemical and morphological changes in the mouse liver, to help elucidate the speciesspecificity
of the incidence of tumours seen in the long-term studies, and two studies (one in hens and
one in dogs) to help understand the finding of cataracts in a 6-month study in dogs.
A study with difenoconazole was conducted to examine the effects on selected biochemical and
morphological parameters in the liver, including activities of various drug-metabolizing e nzymes,
a fter repeated doses in male mice.
Groups of nine male TIF:Magf (SPF) mice were given difenoconazole technical (purity, 91.8%)
at a dose of 0, 1, 10, 100 or 400 mg/kg bw per day by gavage in carboxymethyl cellulose for 14 days.
Additional groups at 0 and 400 mg/kg bw per day were dosed for 14 days and then permitted to live
without treatment for another 28 days (recovery groups) (Thomas, 1992). Groups of male mice were
given phenobarbitone, 3-methylcholanthrene (3-MC) or nafenopin (NAF) as reference substances.
Mortality and clinical signs were checked twice per day during treatment and twice per week during
recovery. Body weights were recorded daily during treatment and twice per week during recovery.
From each group, six mice were killed for biochemical investigations of the liver and three were
killed for electron microscopy of the liver. The following parameters were measured: protein content
of supernatant, microsomal and cytosolic fractions; microsomal cytochrome P450 content; monoclonal
antibodies vs cytochrome P450 isoenzymes (immunoblot analyses); microsomal EROD and
PROD activities; region- and stereoselective microsomal testosterone hydroxylation; cyanide-insensitive
peroxisomal β-oxidation; microsomal hydroxylation of lauric acid; microsomal epoxide hydrolase
activity; microsomal UDP-glucronosyltransferase activity; cytosolic glutathione S-transferase
activity; spectral interaction of difenoconazole with microsome P450.
There was a marked increase in liver weights (+79%) in the mice treated with difenoconazole
at 400 mg/kg bw per day, relative to the controls. However, after a 28-day recovery period, liver
weights of mice in the control group and mice at 400 mg/kg bw per day were similar (1.41 g vs
1.40 g, respectively). Liver weights of the mice treated with 3-MC and NAF were also significantly
higher than those of mice in the control group, although they were treated for much shorter periods
of time.
The protein contents of the liver supernatant fractions were not affected by treatment, either
with difenoconazole or the reference substances. There was a moderate, dose-dependent increase in
the protein content of the microsomal liver fractions in mice treated with difenoconazole at 100 and
400 mg/kg bw per day; these increases were not apparent in animals which had a subsequent 28-day
DIFENOCONAZOLE 201–272 JMPR 2007