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

228
Blood chemistry measurements showed an increase in albumin and decrease in globulin
concentrations in males of the group at 2500 ppm, resulting in increased albumin : globulin ratios
throughout the study. Serum albumin concentrations were increased in females at 2500 ppm only in
week 28. There was a transient decrease in glucose and a transient increase in total cholesterol concentrations
in rats at 2500 ppm in week 28. Decreases in total bilirubin in males at 2500 ppm in week
28 and females at 2500 ppm in weeks 28, 53 and 79 were considered to be too small to be meaningful.
An increase in BUN in females at 2500 ppm in week 53 was considered to be incidental. ALT
activities were increased in males receiving 500 and 2500 ppm at week 53 but decreased in females
at 500 and 2500 ppm in week 28 and females at 2500 ppm in week 53. The inconsistency of these
changes suggests that there was no relationship to treatment. All other differences were considered
to be spurious owing to the low magnitude of the change, inconsistency across study intervals or the
lack of a dose–response relationship.
Urine analyses showed a slight increase in ketone bodies and decrease in pH in males at
2500 ppm at week 28, suggesting accelerated metabolism of lipids, which would be consistent with
the diminished nutritional status of these rats. Values for specific gravities, concentrations of protein,
urobilinogen and occult blood were comparable among the groups; bilirubin was not detected in any
samples and traces of glucose were found in only five rats. There were no apparent differences among
the groups in terms of microscopic examination of sediment.
In the females at 2500 ppm, absolute liver weights were 15.7% higher than those of rats in the
control group at 53 weeks, while relative liver weights of both males and females of the group at
2500 ppm were significantly increased by 14.2% and 48.2% as a result of significantly lower carcass
weights. Liver weights of the rats at 2500 ppm killed after 4 weeks of recovery were not different
from those of rats in the control group. At termination, absolute liver weights of the males and females
at 2500 ppm were 19.6% and 6% higher than those of their respective controls. The few other
statistically significant differences were considered not to be toxicologically relevant. These consisted
of increased relative brain and kidney weights in females at 2500 ppm at week 53 and relative
brain weight at week 105 that could be attributed to lower carcass weights; decreased absolute adrenal
weights at week 53 in males at 2500 ppm and spleen weights at week 57 in females at 2500 ppm
that were not seen at other times, and an increase in ovary weights at week 105 (500 and 2500 ppm)
that were attributable to one rat in each group with massive ovarian cysts. No differences were seen
between the groups of rats at 10, 20 or 500 ppm and the group at 0 ppm.
Autopsy did not reveal any treatment-related findings after 105 weeks. The most common
findings in the liver (target organ) were pale or dark areas and enlargement, but without any dose–
response relationship.
Microscopic examinations revealed an increased incidence and severity of hepatocellular hypertrophy
in males and females at 500 and 2500 ppm at 105 weeks (Table 7). These changes were not
evident in those rats killed at week 53, although ALT activities were increased in males at this time. In
contrast, however, ALT activities were significantly reduced in female rats at 28 weeks in the groups
at 500 and 2500 ppm and at 53 weeks in the group at 2500 ppm. The other liver findings, including
neoplasia, were considered to be incidental, owing to the lack of a dose–response relationship and/
or the low incidence.
The other histopathological changes that were noted are commonly seen in rats of this strain
and age and the incidence, distribution and morphological appearance of these findings did not
give any indication of a treatment-related association. There was no evidence for carcinogenicity or
o ncogenicity in rats.
The NOAEL was 20 ppm, equal to 1.0 mg/kg bw per day, on the basis of reduced body-weight
gain during the first year, reduced platelet counts and increased incidence and severity of hepatocellular
hypertrophy at 500 ppm, equal to 24.1 mg/kg bw per day (Cox et al., 1989b).
DIFENOCONAZOLE 201–272 JMPR 2007