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

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gavage for 4 weeks; a group of 40 females served as a control group for the vehicle (0.5% carboxymethyl
cellulose). The study was conducted in compliance with GLP guidelines. On day 22, all rats
were ovariectomized, and on day 28, a capsule releasing E2 was implanted subcutaneously. On day
31, all rats were dosed at about 06:30 (10:30 biological time), and serial blood samples were collected
from each rat at designated time-points (13:00, 16:00, 18:00, 20:00, 22:00 and 24:00 biological time)
for analysis of LH. The maximum LH amplitude (LH max
), the time to maximum concentration of
LH (T max
), and the area under the LH curve (AUC) were evaluated. After the final blood sample, the
rats were killed and mammary tissues, uterus, vagina and pituitary were examined and preserved.
Administration of both atrazine and DACT was associated with body-weight losses during the first
week of treatment at doses of 40 mg/kg bw per day and greater, while body-weight gain during the
study was decreased at doses of 40 mg/kg bw per day or greater for DACT and 200 mg/kg bw per
day for atrazine, respectively. Both LH max
and AUC were significantly decreased in rats given DACT
at 200 mg/kg bw per day, but not in rats given atrazine. There was no effect of treatment on T max
for
either substance (Minnema, 2001).
In a subsequent study designed to compare the effects of atrazine and its metabolite DACT on
the the pre-ovulatory LH surge, groups of 16 (dose groups) or 32 (control group) female Sprague-
Dawley [Crl:CD BR] rats received diets containing atrazine (purity, 97.1%) at a concentration of 0,
25, 50, 70 or 400 ppm (equal to 0, 1.8, 3.4, 4.9 or 28.2–29.1 mg/kg bw per day) or DACT (purity,
96.8%) at atrazine molar equivalent concentrations of 0, 17, 34, 48 or 270 ppm (equal to 0, 1.2, 2.4,
3.4 or 18.8–19.7 mg/kg bw per day), respectively. Sixteen rats in each treatment group and 32 rats in
the control group were designated for assessment of the plasma LH surge during weeks 30–31 (after
at least 29 weeks of treatment). Fifty rats in the control group and 20 rats in each of the groups at the
highest dose were designated for histopathology examination after 52 weeks of treatment. The study
was conducted in compliance with GLP guidelines. During weeks 30 and 31, all surviving rats designated
for plasma LH-surge assessment were ovariectomized. Six days later, a silastic E2 capsule was
implanted subcutaneously; the LH surge was examined 3 days later. For the LH-surge measurement,
blood samples were collected from each rat at designated time-points (13:00, 16:00, 18:00, 20:00,
22:00 and 24:00 biological time). At the highest doses of atrazine or DACT, the mean body-weight
gains were 72% or 84% of those in the control group after 29 weeks of treatment, respectively, and
65% or 95% of those in the control group after 52 weeks of treatment, respectively. Exposure of rats
to DACT at the highest dose resulted in a significant reduction in the estrogen-induced LH surge,
while there was no such effect for atrazine.
The NOAEL for effects on LH was 400 ppm (equal to 29.1 mg/kg bw per day) for atrazine and
48 ppm (equal to 3.4 mg/kg bw per day) for DACT (Sielken & Holden, 2002).
On the basis of the analysis of the vaginal smears (percentage days in diestrus, percentage days
in diestrous blocks, percentage days in estrus, and percentage days in estrous blocks), treatment with
atrazine or DACT did not affect the estrous cycle. Microscopic examination of the female reproductive
organs revealed no effects associated with treatment with atrazine or DACT, although a nonsignificant
increase in the percentage of pituitary adenomas was noted at the highest doses of atrazine
and DACT when compared with controls (19% and 22% vs 8%, respectively). Statistically significant
increases in the incidences of mammary carcinoma and mammary fibroadenoma-carcinoma were
noted at the highest dose of DACT (17% and 23%, respectively), when compared with those for the
controls (5% and 7%, respectively).
Overall, the NOAEL for atrazine was 70 ppm, equal to 4.9 mg/kg bw per day, on the basis of
decreased body-weight gain at 400 ppm. The NOAEL for DACT was 48 ppm, equal to 3.4 mg/kg bw
per day, on the basis of decreased body weight, attenuation of the LH surge and increased incidences of
mammary carcinoma and mammary fibroadenoma-carcinoma at 270 ppm (Minnema, 2002; Sielken
& Holden, 2002).
ATRAZINE 37–138 JMPR 2007