Pesticide residues in food — 2006: Toxicological ... - ipcs inchem

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Chromosomal aberration in Chinese hamster V79 cells;
Unscheduled DNA synthesis induction in primary rat hepatocytes; and
Micronucleus induction in bone-marrow cells of mice treated in vivo.
Therefore, the available evidence indicated that genotoxicity is not an alternative mode of
action for thiacloprid.
Tests in vitro did not reveal any inhibiting effect on enzymes involved in steroid degradation,
so that an accumulation of estradiol was not the reason for the changes in serum hormone levels.
However, there was an induction of enzymes which catalyse the conversion of testosterone to
androstendione, which may have contributed to increased production of estradiol.
2.9 Uncertainties, inconsistencies, and data gaps
No inconsistencies were identified in the database for thiacloprid with regard to the postulated
mode of action for uterine adenocarcinomas in rats. However, the data indicating an increase in serum
estradiol levels as a result of exposure to thiacloprid are limited since this end-point was investigated
only in a mechanistic study.
2.10 Assessment of postulated mode of action
The data presented are considered, with a moderate degree of confidence, to be adequate to
explain that thiacloprid exerts its carcinogenic effect on the rat uterus secondary to induction of hepatic
aromatase activity leading to increased serum estradiol levels and prolonged uterine endometrium
stimulation.
2.11 Conclusion
There is experimental evidence that thiacloprid induces uterine adenocarcinomas in rats
by a process including induction of hepatic aromatase and prolonged stimulation of the uterine
endometrium by increased concentrations of serum estrogen. Although the postulated mode of
action could theoretically operate in humans, the particular sensitivity of rats for neoplasia owing to
increased estradiol levels over a longer period of time allows for the conclusion that thiacloprid does
not pose a carcinogenic risk to humans at exposure levels relevant to residues in food.
3. Ovarian luteomas in mice
3.1 Introduction
In the long-term study of carcinogenicity in mice, increased incidences of ovarian luteomas were
observed in females at dietary concentrations of 1250 and 2500 ppm, equal to 475 or 873 mg/kg bw per
day (see monograph section 2.3).
3.2 Postulated mode of action (theory of the case)
The postulated mode of action for thiacloprid-induced ovarian luteomas involves hormonal
disruption caused secondarily by effects on the liver. Specifically, thiacloprid is a strong inducer of
hepatic microsomal cytochrome P450 enzymes, including aromatase, a key enzyme in the synthesis
THIACLOPRID X-X JMPR 2006