Pesticide residues in food — 2007: Toxicological ... - ipcs inchem

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No treatment-related effect on survival occurred. Body-weight gain and food consumption
were reduced at 500 ppm. Reductions in values for erythrocyte parameters late in the study and a persistent
increase in serum cholesterol concentration occurred in females at 500 ppm. Histopathology
investigations revealed an increased incidence of pituitary gland adenomas in females at 500 ppm
(85% vs 45% in the controls) at termination (the control value appeared to be low in view of data
for historical controls, presented in the report, of 80–89%). The incidence of pituitary adenoma was
89% in the controls placed on diet containing atrazine at 500 ppm at week 65, and 75% in the females
at 500 ppm placed on control diet at week 65. All these incidences are reported among small numbers
of animals and the significance is therefore obscure. Controls and females at the highest dose
killed after 104 weeks had similar incidences of mammary tumours. A higher incidence of mammary
tumours occurred in females from the control group that were placed on diet containing atrazine at
500 ppm at week 65 than occurred in rats exposed in utero or in the females at the highest dose placed
on control diet at week 65. However, only 10 females per group were used in this part of the study.
There was no obvious effect of treatment on the proportions of prolactin-, LH- or FSH-reactive cells
in the pituitary.
Atrazine did not appear to be carcinogenic in female Sprague-Dawley rats in this study of
exposure in utero that was of supportive value (because of low numbers of rats at termination).
The NOAEL was 50 ppm, equal to 2.3 mg/kg bw per day in males and 3.5 mg/kg bw per day
in females, on the basis of body weight and haematological effects at 500 ppm (Rudzki et al.,
1991).
In a supplementary study of carcinogenicity, designed to investigate the effect of atrazine on
the estrous cycle, selected hormone levels and the development of mammary, ovary, uterine and
pituitary tumours, groups of 70 female Sprague-Dawley rats [Crl:CD BR] were fed diets containing
atrazine (purity, 97.0%) at a concentration of 0, 70 and 400 ppm, equivalent to 0, 3.5 and 20 mg/
kg bw per day, for 104 weeks. Interim terminations of 10 females per group were conducted at 1, 3,
9, 12, 15 and 18 months of the study, and all remaining survivors killed after 2 years. The terminations
were conducted at proestrus as determined by vaginal smear, unless this phase was not reached
within 7 days of the scheduled termination time-point. In order to avoid stress-related hormone
changes, rats were killed by decapitation without anaesthesia. Samples of blood were collected
post mortem for hormone analysis. The pituitary, mammary glands, uterus and ovaries from all rats
were examined microscopically. The study was conducted in compliance with GLP and OECD test
guidelines.
Statistical analysis indicated a significant trend toward early death at 400 ppm, since five deaths
in the group at this dose occurred before the earliest death in the control group. At termination,
however, there were no treatment-related differences in mortality. A decrease in body-weight gain
associated with decreased food consumption was observed at 400 ppm. At necropsy, the incidences
of fluid-filled uteri at 70 and 400 ppm and of mammary galactocoeles at 400 ppm were increased,
particularly during the first 12 months of the study (Table 6).
At 400 ppm, the onset-time for initial palpation of masses in the mammary region (confirmed
histologically as mammary fibroadenomas and/or carcinomas) was decreased when compared with
the control group. Because of early onset-time, there was a significant positive trend in the incidence
of mammary fibroadenomas or carcinomas analysed either separately or combined, and a
significant increase using pairwise comparison for onset rate of fibroadenomas and carcinomas
combined in the group at 400 ppm. The incidence of pituitary adenomas was increased at 400 ppm
after 12 months of treatment, but not at the end of the study, indicating that the onset-time was
shortened. No correlation between rats with mammary tumours and those with pituitary tumours
was apparent.
ATRAZINE 37–138 JMPR 2007