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

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examinations were carried out 8 days before the beginning of the administration period and on study
day 91. All dogs were subjected to gross pathological assessment, followed by histopathological
examinations.
The stability of boscalid in the diet was verified. The homogeneity of the mixtures and the
correctness of the concentrations were demonstrated.
There was no boscalid-related mortality or clinical signs of toxicity at any dose. The faeces in
all males and females at 25 000 ppm and transiently in three males and three females at 2500 ppm
were soft and light-brown discoloured.
Slight body-weight losses and retarded body-weight gains were observed during the initial
phases of treatment at 25 000 ppm in both sexes. Thereafter, body-weight gain was reduced in females
only. At the end of the study, females in the control group had gained 1 kg of body weight while
females at 25 000 ppm had gained only 0.2 kg. At the end of the study, in males at the highest dose
there was no difference in body-weight gain compared with controls. Food consumption in males at
the highest dose was 96% of the total food provided vs 100% in the controls. Food efficiency in males
and particularly in females at 25 000 ppm was reduced.
Ophthalmoscopy revealed no pathological changes in any dose group. Blood chemistry and
haematological examinations did show some test-substance related changes. In females in the group
at 25 000 ppm there was a significant, 11% reduction in erythrocyte counts and a significant, 11%
reduction in haemoglobin concentration at the end of the study. Midway through the study (week 6),
these parameters were also lower in dogs in the group at 25 000 ppm, but not significantly so. No
other haematological changes were recorded in either sex.
With regard to blood chemistry, alkaline phosphatase activities were significantly increased
by approximately threefold in males at 25 000 ppm at weeks 6 and 13. In females, alkaline
phosphatase activities were significantly increased at 2500 and 25 000 ppm by almost twofold and
threefold, respectively, but only at week 13. The activities of alanine aminotranferase and aspartate
aminotransferase enzymes were reduced at various times in the groups at 2500 and 25 000 ppm,
but reductions in these activities is not normally considered to be an adverse response. Alkaline
phosphatase activity is a sensitive indicator of hepatic enzyme induction in dogs and so the observed
increases, in the absence of increases in other hepatic enzymes in serum, can be interpreted as being
the result of enzyme induction rather than hepatotoxicity (Keller-Rupp, 1988). In reaching this
conclusion, the Meeting assumed that liver was the source of this enzyme.
Triglyceride concentrations were significantly increased after 6 weeks of treatment at
25 000 ppm by approximately 2.1-fold in males and 1.8-fold in females. After 13 weeks, triglyceride
concentrations were significantly increased in males at 250 ppm and greater and in females at 2500
ppm and 25 000 ppm. The increases were dose-related and reached approximately twofold in both
males and females at 25 000 ppm. Although the concentration of triglycerides at 13 weeks was
significantly higher in males at 250 ppm, the difference (30%) was no greater than in females (30%)
and could probably be viewed as an lowest-observed-adverse-effect level (LOAEL). However,
additional considerations included the fact that: (1) the control group concentrations appeared to be
particularly low in this study; and (2) apart from the group values for male and females at 25 000 ppm
for both sexes and for males at 2500 ppm at 6 weeks, all triglyceride concentrations were within the
range for historical controls (historical data were supplied in the report for the performing laboratory
for February 1995–January 1998: male beagles, 3-month studies: mean, 0.38; range, 0.24–0.45,
n = 10; and female beagles, 3-month studies: mean, 0.45; range, 0.38–0.51, n = 9). On the other
hand, assuming that there had been proper randomization, low concentrations of triglyceride should
be a characteristic of all these dogs and the dose-related concentration increases were monotonic
throughout the dose range in males and females at weeks 6 and 13. Furthermore, as in the great
majority of studies in dogs, the group sizes are small and therefore totally reliance on statistically
significant differences in pair-wise comparisons cannot be made.
BOSCALID X-X JMPR 2006