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

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Table A3. 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
Decrease in serum estradiol/progesterone ratio
Increase in serum progesterone
Ovary
Decreased No. of old corpora lutea, activation of
i nterstitial cells
Increased No. of large, eosinophilic and luteinized cells
Increase in luteomas
NOAEL/LOAEL
18/139 mg/kg bw per day (13-week mechanistic study)
139/704 mg/kg bw per day (14-week study)
11/475 mg/kg bw per day (2-year study)
139/704 mg/kg bw per day (14-week study)
11/475 mg/kg bw perday (2-year study)
139/1101 mg/kg bw per day (13-week mechanistic study)
139/1101 mg/kg bw per day (13-week mechanistic study)
139/704 mg/kg bw per day (14-week study)
11/475 mg/kg bw per day (2-year study)
11/475 mg/kg bw per day (2-year study)
3.5 Temporal association
The key events, such as induction of hepatic aromatase activity and changes in serum estradiol
and/or progesterone levels (estradiol/progesterone ratio) were observed after a 13-week exposure to
thiacloprid. Increased estradiol and prolactin levels should already have been detected after shorter
exposure times; however, no earlier sampling times were included in the mechanistic study. In the
2-year study in mice, the first ovarian luteomas were observed at weeks 107 or 53 at doses of 475 or
873 mg/kg bw per day, respectively. Thus, there was a logical temporal response, with the key events
preceding tumour formation.
3.6 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 and
prolactin levels, precursor lesions in the ovarian tissues) are linked to the ovarian luteomas in
mice was considered to be acceptable. Some of the key events (as induction of microsomal liver
enzymes, hepatocellular hypertrophy, precursor lesions in the ovarian tissues) were observed
consistently in studies with differing experimental designs, while induction of hepatic aromatase
activity and changes in serum steroid hormone levels were investigated only in a mechanistic
study.
3.7 Biological plausibility and coherence
The relationship between prolonged stimulation of ovarian tissues by increased serum
estrogen and prolactin levels and an increased incidence of ovarian luteomas was considered to
be biologically plausible. This postulated mode of action would also give an explanation for the
increase of hypertrophy and vacuolization of the X-zone in the adrenal cortex of female mice, as
observed in the 13-week mechanistic study, the 14-week study and the 2-year study, since it has
been shown that lipid vacuolization of the X-zone is influenced by pituitary and gonadal function
of mice.
THIACLOPRID X-X JMPR 2006