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

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Long-term studies of toxicity and carcinogenicity were conducted in mice and rats. As in shortterm
studies, the liver was the primary target organ, with induction of liver enzymes being the most
sensitive end-point in both rats and mice. Effects on other organs, such as thyroid, adrenals, ovaries
and uterus were considered to be secondary to the increased liver enzyme activities and the subsequent
hormonal imbalances. The increased incidences of lens fibre degeneration and retinal atrophy in
female rats at the intermediate doses (50 and 500 ppm) were not considered to be treatment-related
when compared with the data for historical controls, rather they were caused by the low survival rate
of females in the control group. The increased incidences of degenerative changes in the nervous
system and skeletal muscles in females at 500 ppm and higher were considered to reach statistical
significance owing to increased survival at the highest dose compared with the concurrent control
group, resulting in a seemingly increased incidence of age-related findings.
In the study of carcinogenicity in mice, the NOAEL for systemic toxicity was 30 ppm, equal
to 5.7 and 10.9 mg/kg bw per day in males and females, respectively, on the basis of effects in the
liver (increased weight, hepatocellular hypertrophy, fatty change, degeneration) and lymph nodes
(vacuolization) in both sexes and in the adrenal cortex (vacuolization in the X-zone) in females at
1250 ppm and higher. There was no evidence of oncogenic activity in males. In females, the incidence
of benign ovarian luteomas was significantly increased at 1250 ppm and higher.
A 13-week mechanistic study on ovarian tumorigenesis in mice showed increased hepatic
aromatase activity and vacuolization in the X-zone of the adrenal cortex at 250 ppm and higher,
while plasma estradiol/progesterone ratio was decreased and plasma progesterone and liver weights
were increased at 2500 ppm. Co-treatment with mecamylamine (a nicotine mimic) did not abolish the
effects of thiacloprid on the estradiol/progesterone ratio.
The Meeting concluded that the increased incidence of ovarian luteomas in mice was a secondary
consequence of liver enzyme (especially aromatase) induction, resulting in increased estradiol
synthesis. Increased estradiol levels in mice but not in rats produce a positive feedback response with
an increased prolactin release which consequently stimulates ovarian tissues and may explain the
increased incidence of ovarian tumours. Based on application of the IPCS Framework for Analysing
the Relevance of a Cancer Mode of Action for Humans to the limited available data, the Meeting
concluded that the probable mode of action for the luteomas seen in mice is exclusively a high-dose
phenomenon that is not relevant for human exposure at the levels of residues found in food.
In the long-term study of toxicity and carcinogenicity in rats, the NOAEL for systemic
toxicity was 25 ppm, equal to 1.2 mg/kg bw per day, on the basis of liver toxicity (increased mixed
eosinophilic-clear cell foci) and thyroid effects (follicular epithelial hypertrophy) in males at 50 ppm
and greater. There was also evidence of increased thyroid hyperplasia at 500 ppm and greater. The
NOAEL for oncogenicity was 50 ppm, equal to 2.5 mg/kg bw per day, on the basis of the increased
incidences of thyroid follicular cell adenoma in males and uterine adenocarcinoma in females at
500 ppm and greater.
Mechanistic studies on thyroid tumorigenesis in rats showed increased liver weights and
increased UDP-GT activities at 400 ppm and greater, with the consequence of a decrease in
T4, increase in TSH and thyroid follicular cell hypertrophy. The NOAEL was 100 ppm, equal to
9.0 mg/kg bw per day in males and females, respectively. Thiacloprid or its hydrolysis products had no
inhibitory effect on thyroid peroxidase activity in vitro (IC 50
> 870 μmol/l). Also, plasma extracts from
rats treated with thiacloprid had no inhibitory effect on the activity of thyroid peroxidase in vitro.
The Meeting concluded that the increased incidence of thyroid adenoma observed in male rats
was a consequence of liver enzyme induction, leading to increased clearance of thyroid hormones and
increased levels of TSH. Based on application of the IPCS Framework for Analysing the Relevance
of a Cancer Mode of Action for Humans to the available data, the Meeting concluded that the mode
of action for the thyroid adenomas seen in rats is exclusively a high-dose phenomenon not relevant
for human exposure at the levels of residues found in food.
THIACLOPRID X-X JMPR 2006