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Table 15. Scores for hindlimb grip in male rats fed diets containing difenoconazole for 90 days
Time-point
Dietary concentration (ppm)
0 40 250 1500
Week −1 571 573 600 481
Week 2 971 767** 844 752**
Week 5 833 856 831 806
Week 9 960 846 829 788*
Week 14 1131 1100 902* 823**
From Pinto (2006b)
* p ≤ 0.05; ** p ≤ 0.01.
highest dose tested at two consecutive time-points, it was considered to be a potentially treatmentrelated
effect at 1500 ppm in males only. Hindlimb grip strength was also significantly lower in the
group at 250 ppm in week 14, but in no other week (Table 15). It may be argued that this observation
was incidental to treatment or that it was a late development caused by treatment.
Hindlimb grip strength was significantly lower at some other observation times, but these
observations were considered to be incidental variations. In week 2, hindlimb grip strength was
statistically different from control values for males at 40 ppm and 1500 ppm. There was no difference
from control values at the intermediate dose of 250 ppm and, in addition, there were no
effects in any group at the next time-point (week 5). There were no treatment-related clinical abnormalities
observed in the FOB, with no treatment-related effects on landing-foot splay, time to
tail-flick, fore- or hindlimb grip strength (with the exception of males at 250 and 1500 ppm), or
motor activity.
Liver weight for rats at 1500 ppm was higher than that of controls. Brain weight was unaffected
by treatment. Microscopic examination of the central and peripheral nervous system showed
no effects of treatment with difenoconazole at dietary concentrations of up to 1500 ppm in males or
females.
The NOAEL was 40 ppm, equal to 2.8 mg/kg bw per day, on the basis of reduced hindlimb grip
strength in male rats at 250 ppm, equal to 17.3 mg/kg bw per day. It should be noted that no other
effects on neurobehavioral parameters (forelimb grip strength, motor activity, time to tail-flick, FOB)
were observed at any time point for males at 250 ppm, which argues for the reduction in grip strength
not being an expression of neurotoxicity, although it should remain to be considered an effect of
treatment. Furthermore, there were no effects considered to be caused by treatment in males at 40
ppm, equal to 2.8 mg/kg bw per day, or in females at any dose, including 1500 ppm, equal to 120.2
mg/kg bw per day. Thus, the observed grip weaknesses in both of these studies of neurotoxicity were
considered to be non-specific effects of difenoconazole, there being a lack of consistency (hindlimb
versus forelimb effects), a complete absence of effects at other end-points for neurotoxicity and no
neuropathology (Pinto, 2006b).
(b)
Toxicology of metabolites.
The following are plant metabolites of difenoconazole:
• CGA 169374: difenoconazole or 1-[[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-4-methyl-
1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole;
• CGA 205374 (1-(2-chloro-4-(4-chloro-phenoxy)-phenyl)-2-(1,2,4-triazol)-1-yl-ethanone);
• CGA 205375 (1-[2-chloro-4-(4-chloro-phenoxy)-phenyl]-2-(1,2,4-triazol)-1-yl-ethanol);
• CGA 189138 (2-chloro-4-(4-chlorophenoxy)-benzoic acid );
DIFENOCONAZOLE 201–272 JMPR 2007