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Table A2. NOAELs and LOAELs for key effects in the mode of action of thiacloprid in the thyroid
Effect
Liver
Induction of hepatic aromatase
Increase in liver weight
Hepatocellular hypertrophy
Hormones
Increase in serum estradiol
Uterus
Increase in uterine tumours
NOAEL/LOAEL
—/113 mg/kg bw per day (7-day mechanistic study)
—/60.4 mg/kg bw per day (one-generation study)
6.6/20.4 mg/kg bw per day (4-week mechanistic study)
20.4/47.5 mg/kg bw per day (4-week mechanistic study)
34/69 mg/kg bw per day (2-year study)
1.2/2.5 mg/kg bw per day (2-year study)
—/60.4 mg/kg bw per day (one-generation study)
3.3/34 mg/kg bw per day (2-year study)
2.5 Temporal association
The key events, such as induction of hepatic aromatase activity and increase in serum estradiol levels
were already observed after a 7-day or 9-week exposure to thiacloprid. In the 2-year study in rats, the first
uterine adenocarcinomas were observed at weeks 88, 77 or 67 at doses of 0, 34 or 69 mg/kg bw per day,
respectively. Thus, there was a logical temporal response with all key events preceding tumour formation.
2.6 Strength, consistency and specificity of association of tumour response with key events
Based on information from the studies described in the monograph, the weight of evidence that
the key events (as induction of hepatic aromatase activity, increase in serum estradiol level) are linked
to the uterine adenocarcinomas in rats was considered to be sufficient. The key events were observed
consistently in a number of studies with differing experimental designs. There was also evidence that
the key events (such as liver enzyme induction, increased liver weight) were reversible after cessation
of exposure to thiacloprid.
2.7 Biological plausibility and coherence
The relationship between prolonged stimulation of the uterine endometrium by increased
serum estrogen levels and an increased incidence of uterine adenocarcinomas is considered to be
biologically plausible and has been shown in some studies in laboratory rats. Increased serum estrogen
levels may result via different mechanisms including hepatic aromatase induction, as is the case with
thiacloprid. In rats that are normally exposed to relatively low estradiol levels, even a slight increase
in estradiol over a longer period of time may lead to a disruption of the estrous cycle. In contrast,
humans are able to handle much higher levels of estrogens than rodents.
2.8 Other modes of action
Genotoxicity is always one possible mode of action to consider, but no genotoxic potential was
demonstrated for thiacloprid in the following tests:
• Mutation in four strains of Salmonella typhimurium;
• Mutation at the Hprt locus of Chinese hamster V79 cells;
THIACLOPRID X-X JMPR 2006