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D. Temporal association.
The few data that were available reflected a coherent temporal relationship in that enzyme induction
was observed within a few days and tumours were observed much later. This is a particularly
weak piece of evidence, since there has been no suggestion as to the intervening steps and when they
occurred.
E. Strength, consistency and specificity of association of tumour response with key events.
Although a phenobarbital-like MOA has been proposed, there has been only one key event
identified in the case of difenoconazole: induction of hepatic enzymes. While this shows consistency,
it is nevertheless considered weak in view of the absence of evidence for intervening steps.
F. Biological plausibility.
There has been no suggestion as to why induction of hepatic enzymes per se should have resulted
in a neoplastic response.
G. Possible alternative modes of action.
A genotoxic mechanism should always be considered. In the case of phenobarbital, there were
some data (usually weak and inconsistent) suggesting that it might have some genotoxic activity.
Nevertheless, a non-genotoxic MOA is generally accepted. In the case of difenoconazole, there is
no evidence for genotoxicity of difenoconazole or any of its metabolites. This MOA would therefore
appear to be ruled out. No other MOA has been proposed.
H. Uncertainties, inconsistencies and data gaps.
Within the dataset reported, there are uncertainties because so much relies upon a single experiment
on enzyme induction and a single experiment on carcinogenicity. On the other hand, the
results of several other studies are consistent with the conclusion that enzyme induction has occurred
because they show that treatment with difenoconazole produces hepatomegaly and hepatocellular hypertrophy.
An uncertainty, which applies even to the experiment with male mice, is that although the
dose and dose route were similar to the effective dose used in the study of carcinogenicity, the dose
rate would have been entirely different, since gavage administration was used in the 14-day study
and dietary administration in the study of carcinogenicity. The data available showed no inconsistencies;
however, large data gaps are apparent. Thus, there is no information to describe what happens
between the induction of liver enzyme activity and the emergence of tumours. An important data gap
regards the pivotal mechanistic study in male mice, which did not investigate whether similar results
would be found in female mice or how rats might respond to a similar treatment. In the case of phenobarbital,
there is evidence for a correlation between the magnitude of enzyme induction and the
tumour response in different rodent species and strains (IARC, 2001).
I. Assessment of postulated mode of acton.
The postulated MOA is weak because of the total lack of a description of events between enzyme
induction and the discovery of tumours.
2.4 Genotoxicity
Difenoconazole was tested for genotoxicity in a range of assays, both in vitro and in vivo
(Table 8). There was no evidence for induction of gene mutation in Salmonella typhimurium or Escherichi
coli in vitro (Ogorek, 1990). The dose range used extended into a range that was bacterio-
DIFENOCONAZOLE 201–272 JMPR 2007