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

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cholesterol of females at the highest dose at different occasions. Gross pathology investigations
revealed a high incidence of enlarged pituitaries and of dermal/subdermal masses in females from all
groups including controls. Histopathology of mammary tissues showed a statistically significant, but
not dose-related increase in the incidence of benign fibroadenomas in females at the lowest (10 ppm)
and highest (1000 ppm) dose, but not at the intermediate dose of 100 ppm (incidences were: 11 out
of 54, 20 out of 52, 14 out of 54, and 22 out of 49 at 0, 10, 100 and 1000 ppm, respectively). Atrazine
gave positive results for carcinogenicity in this study, which is suitable to be used for supportive data
only. Because of data deficiencies (parameters not investigated in groups at the intermediate dose), a
NOAEL was not identified in this study (Spindler & Sumner, 1981).
In a combined long-term study of toxicity and carcinogenicity conducted in compliance with
GLP and EPA guidelines, groups of 70 male and 70 female Sprague-Dawley rats were fed diets containing
atrazine (purity, 95.8%) at a concentration of 0, 10, 70, 500 or 1000 ppm, equal to 0, 0.4, 2.6,
19.9 and 41.7 mg/kg bw per day in males and 0, 0.5, 3.5, 29.5 and 64.7 mg/kg bw per day in females,
for 2 years. Dietary exposure was verified by analysis. The control group and the group at the highest
dose contained an additional 20 males and 20 females for interim kill, 10 males and 10 females after
12 months and 10 males and 10 females after a further 1-month recovery period. For the long-term
evaluation of toxicity, 20 males and 20 females per group were used, and the study design contained
appropriate end-points to satisfy guideline requirements.
The males at the highest dose (1000 ppm) showed an increased survival (67% vs 44% in
controls), while a significantly decreased survival was recorded in the females at 1000 ppm when compared
with the controls (26% in the treated females vs 50% in the controls) at the study termination.
Increased irritability was seen in the males, and pallor in females, at 500 or 1000 ppm. An
increase in numbers of palpable masses was apparent in the females at 70, 500, and 1000 ppm. Bodyweight
gains of rats at 500 ppm (weight gain after 12 months, −10% in males; −23% in females)
and 1000 ppm (weight gain after 12 months, −22% in males; −34% in females) were significantly
decreased throughout the study. On the basis of these weight-gain retardations, doses of 500 and
1000 ppm were considered to be excessive for carcinogenicity testing. Food consumption was slightly
decreased. Haematology investigations revealed lower values for erythrocyte parameters in females
at 1000 ppm. Sporadic changes in some clinical chemistry parameters, namely lower glucose and
transient decrease in triglyceride concentration, were recorded in rats at 1000 ppm. The number of
females with mammary gland tumours was increased in groups at 70, 500 and 1000 ppm, confirmed
by histology peer review (Table 5). Time-to-tumour analyses are not reported.
Also seen was an increase in mammary acinar hyperplasia in males at the highest dose. Other
non-neoplastic lesions increased with treatment were confined to the highest dose and included renal
pelvic calculi, and prostate epithelial hyperplasia, in males; and urothelial hyperplasia in kidney and
urinary bladder, degeneration of the rectus femoris muscle, and hepatic centrilobular necrosis in
females. An increase in testicular interstitial cell tumours in males at 1000 ppm was not considered to
be treatment-related, since the increased incidence was within the range of spontaneous occurrence
and could also be attributed in part to the increased survival of the rats at 1000 ppm.
The 12- and 13-month interim kills were not considered for identification of the NOAEL, since
these comprised 20 rats in the control group at low risk of tumours and would dilute the number of
tumours in the controls relative to the group at the lowest dose, which had no scheduled interim kill. It
is noted that at 10 ppm the incidence of mammary tumours was also higher than that in controls (63%
vs 53%, excluding the interim kill), although not achieving statistical significance. This value was
outside the cited range for historical controls of 40–51%. However, the range of values for historical
controls (on the basis of four studies only) may be considered to be unusually narrow, a 40–60%
range being considered to be more representative.
ATRAZINE 37–138 JMPR 2007