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

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Table 16. Results of studies of acute toxicity and genotoxicity with metabolites of difenoconazole
found in plants and rats
Metabolite Assay HID/ concentration Result Reference
CGA 189138 Reverse mutation 2000 µg/plate, ±S9 Negative Nakajima (1991a)
CGA 205374 Study of acute oral 0, 5000 mg/kg bw LD 50
> 5000 mg/kg bw Ohba (1991a)
toxicity in mice
Reverse mutation 5000 µg/plate, ±S9 Negative Nakajima (1991b)
CGA 205375 Study of acute oral 0, 1000, 1300, 1600, LD 50
> 2309mg/kg bw Ohba (1991b)
toxicity in mice 2000, 2500 mg/kg bw (male mice)
Reverse mutation 320 µg/plate, ±S9 Negative Nakajima (1991c)
HID, highest ineffective dose, in the bacterial mutation tests; S9, 9000 × g supernatant from rat livers.
•
•
•
CGA 71019, (1,2,4-triazole);
1,2,4-triazolyl alanine; and
1,2,4-triazolyl acetic acid.
• All these metabolites, except for 1,2,4-triazolyl alanine and 1,2,4-triazolyl acetic acid, are
also found in the metabolism of rats.
The acute oral LD 50
values for metabolites CGA 205374 and CGA 205375 in mice were in
excess of 2000 mg/kg bw. In addition, none of these metabolites was mutagenic in S. typhimurium
strains TA100, TA98, TA1535 and TA1537 and E. coli WP2 uvrA (Table 16)
(i)
CGA 71019 (1,2,4-triazole)
In three studies of metabolism and toxicokinetics (Lai & Simoneaux, 1986a; Weber et al.,
1978; Ecker, 1980), 1,2,4-triazole was shown to be rapidly absorbed and readily eliminated, mainly
via the urine. In the study of biokinetics (Weber et al., 1978), elimination was shown to be proportional
to dose and independent of the route of administration. The bioavailability of the oral dose
was virtually 100%, and the bulk of the amount excreted via bile was reabsorbed. In the study of
biotransformation (Ecker, 1980), 1,2,4-triazole was rapidly eliminated via the urine, predominantly
in an unchanged form.
1,2,4-Triazole is of low acute oral and dermal toxicity in rats (oral LD 50
, 1650 and 1648 mg/
kg bw for males and females, respectively; dermal LD 50
, 4200 and 3129 mg/kg bw for males and
females, respectively). No dermal irritation and only moderate ocular irritation were noted after
application to the skin and to the eye of rabbits. The studies of acute toxicity after inhalation in
rats and mice were deficient in that exposure to the test substance was not demonstrated, and classification
was not possible. In a Magnusson & Kligman maximization test, no signs of allergic skin
reactions were observed. There was no evidence of genotoxicity in two assays for reverse mutation
in b acteria.
The results from the short-term studies of toxicity are summarized in Table 17.
In an older 90-day feeding study in rats, 1,2,4-triazole caused retarded body-weight development,
temporary slight effects on the central nervous sytem (convulsions), slight microcytic hypochromic
anaemia (males only), and accumulation of hepatocellular fat (males only) when administered
at a dietary concentration of 2500 ppm, equivalent to an average test substance intake of 212
and 267 mg/kg bw per day for males and females, respectively. Comparable results were obtained in
a more recent short-term study in rats that included additional specific neurotoxicological investigations.
In this study, a retardation of body-weight gain and clinical findings, such as tremor, muscle
fasciculations and uncoordinated gait, were seen at 3000 ppm (equivalent to 183 mg/kg bw per day in
DIFENOCONAZOLE 201–272 JMPR 2007