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male pups at 250 ppm were significantly lower than those of male pups in the control group on day
21, but this difference was considered to be incidental in view of the absence of any effect in the
F 2
generation (see Table 13). However, there was no measurement of food intake at this age and no
detailed behavioural observations. There were no treatment-related clinical signs or ophthalmologic
findings and no treatment-related macroscopic findings were noted at autopsy of the F 1
pups.
There were no treatment-related clinical signs, ophthalmological findings or treatment-related
mortalities among the F 1
parental rats. One female at 25 ppm was found dead on day 2 of lactation,
one female at 2500 ppm was found dead on day 1 of lactation and a second female at 2500 ppm was
found dead on day 5 lactation. The timing of these deaths and the clinical signs associated with them
suggested that they were due to non-treatment-related difficulties in labour and delivery.
Body weights of the selected F1 parental rats were lower than those of rats at 0 ppm in the selected
males at 250 ppm and 2500 ppm and females at the beginning of dietary exposure (Table 12).
Males in the group at 2500 ppm tended to have lower body-weight gains throughout the treatment
period. The males at 250 ppm began the treatment period with body weights that were 8% lower than
those of males in the control group during the first week, resulting from a slight body-weight decrease
after lactation, but body-weight gains thereafter were sporadically higher or lower than those
of males in the control group. During the pre-mating phase, females in the group at 2500 ppm had
significantly lower mean body weights than did females in the control group and lower body-weight
gains during most intervals. Absolute body weights of the females at 25 and 250 ppm were not different
from those of females in the control group during pre-mating, although body-weight gains
were occasionally significantly higher or lower. Absolute body weights for the females at 2500 ppm
Table 12. Body-weight development of F1 generation in a multigeneration study of rats fed diets
containing difenoconazole
Time-point/phase Study day(s) Dietary concentration (ppm)
Males
Females
0 25 250 2500 0 25 250 2500
Body weight (g)
Start of treatment 0 237.0 235.5 217.6* 169.0* 178.2 177.3 166.5 138.2*
7 304.3 298.7 280.8* 225.9* 206.9 208.3 194.0 163.2*
49 525.4 517.6 504.0 432.8* 298.6 289.1 288.5 241.3*
End of pre-mating 98 641.6 619.5 611.7 534.3* 346.2 329.1 333.1 268.8*
Beginning of gestation a 101/121 — — — — 331.7 325.1 321.1 263.5*
End of mating 119 665.0 639.2 631.5 560.4* — — — —
End of gestation a 121/143 — — — — 452.6 439.3 446.8 375.6*
Beginning of lactation a 122/144 — — — — 371.3 365.0 358.3 290.3*
End of lactationa 144/165 — — — — 360.1 358.5 341.6 294.4*
Termination 145/169
(male/female)
683.1 653.0 647.6 572.6* 375.2 354.8 361.4 291.3*
Body weight change (g)
Pre-mating 0–98 404.6 384.1 394.1 365.3* — — — —
Gestation Approx. 110–132 — — — — 120.9 114.2 125.7 112.2
Lactation Approx. 132–155 — — — — −11.2 −7.3 −16.7 1.7
Full duration 0–145 446.1 417.6 430.0 403.6* — — — —
From Giknis (1988)
a
Days variable based on when each dam started/ended the phase.
* p ≤ 0.05, ANOVA + Dunnett test.
DIFENOCONAZOLE 201–272 JMPR 2007