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

220
3000 ppm and 6000 ppm, but these changes were not statistically significant. Kidney weight relative
to body weight was also increased in the female group at 6000 ppm. Reductions were observed in absolute
weights of heart, prostate and salivary gland in the male group at 6000 ppm. No organ-weight
differences were seen among the groups of males and females at 100 or 1000 ppm or in the group of
males at 3000 ppm. At autopsy, treatment-related bilateral ocular opacity was observed in one female
at 3000 ppm, one male at 6000 ppm and one female at 6000 ppm. No other treatment-related observations
were made. Microscopic examination did not reveal any treatment-related changes other than
to the eyes, which confirmed the observations made in vivo. Moderate to severe cataracts were seen
in the left lens of all animals at 6000 ppm and minimal to severe cataracts in the right lens. Cataracts
were noted for one male at 3000 ppm (bilateral) and two females at 3000 ppm (both unilateral) which
were not seen in the ophthalmoscopic examinations. Differences in observations between the left and
right lenses were attributed to the use of 10% neutral buffered formalin as the fixative for the right
eye and Russell’s fixative for the left eye.
The NOAEL in dogs given diets containing difenoconazole for 6 months was 1000 ppm, equal
to 31.3 mg/kg bw per day, on the basis of decreased body-weight gain in males, cataracts in males
and females and significantly increased serum alkaline phosphatase activity in females at 3000 ppm,
equal to 96.6 mg/kg bw per day (O’Connor et al., 1987).
Groups of four male and four female pure-bred beagle dogs were given diets containing difenoconazole
technical (purity, 96.1%) at a concentration of of 0, 20, 100, 500 or 1500 ppm, equal to
0, 0.7, 3.4, 16.4 and 51.2 mg/kg bw for males and 0, 0.6, 3.7, 19.4 and 44.3 mg/kg bw for females,
for 52 weeks. The dogs were aged approximately 5 months at the start of dosing. Dietary analyses
showed that the difenoconazole was homogeneously distributed in the diet and was present at the targeted
concentrations throughout the study. Analyses performed before feeding was started indicated
that the diets were stable for at least 46 days at room temperature. The state of health of the dogs was
checked and recorded daily. Measurements were made of food consumption daily and body weights
before the dosing period, weekly for the first 13 weeks and monthly thereafter. Physical examinations,
including heart rate, rectal temperature and hearing tests, were performed before the dosing period
and during weeks 14, 25, 39 and 52. Eye examinations were conducted on all dogs before the dosing
period and during weeks 11, 27, 39 and 51. The eyes of dogs in the control group and dogs at 1500
ppm were also examined at nine additional times during the study. Haematology, blood chemistry
and urine analysis were carried out on all dogs before the dosing period and during weeks 13, 26 and
52–53. All dogs were subjected to gross pathological assessment on days 365–367 (during week 52),
followed by microscopic examinations on selected tissues and organs.
There were no mortalities in the study and difenoconazole did not induce clinical signs of toxicity
in any of the dose groups. Absolute body weights were not significantly different among males
or females of any the groups during the study and body-weight gains of male dogs were not affected
by any of the treatments, but while body-weight gains among the females receiving 100, 500 and
1500 ppm were not significantly affected by treatment, they tended to be lower relative to values for
females in the control group at some intervals during the study. There was no effect on body-weight
gain in females of the group at 20 ppm. During the first 3 months of the study, percentage body-weight
gains of the females at 100, 500 and 1500 ppm were slightly lower than those of females in the control
group. During the intermediate 6 months, this reduction continued for the group of femaless at 500
and 1500 ppm, but during the last 3 months, body weights were relatively stable or decreased in all
groups, particularly in the females at 500 and 1500 ppm. The terminal body-weight gains for females
in the groups at 0, 20, 100, 500 and 1500 ppm, respectively, were 42%, 45%, 43%, 25% and 29%.
Food consumption by the group of females at 1500 ppm was reduced throughout the study.
Across all measurement intervals, the females at 1500 ppm consumed about 20% less feed than did
the females in the control group; statistically significant reductions were recorded on days 7, 35, 70
DIFENOCONAZOLE 201–272 JMPR 2007