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EC number: 430-380-7 | CAS number: 445409-27-8
No clinically observable signs of toxicity were detected in treatment groups from either the F0 adults or F1 adults throughout the study period. Bodyweight development, dietary intake and food utilisation were however adversely affect in 12000 ppm adult animals in both the F0 and F1 generation, resulting in a deterioration in physical condition of the animals. Haematological investigations of selected F0 adult animals revealed a normocytic, normochromic anaemia. This was probably associated with the bone marrow changes seen microscopically. Changes were identified as higher grades of severity of adipose infiltration of the marrow, indicating hypoplasia for adult females treated with 12000 ppm from either generation. Absolute and relative thymus weight was reduced in adult females from either generation at this dose level and microscopic examination of thymus sections revealed changes identified as a greater incidence of higher grades of severity of lymphoid atrophy. Sinus histocytosis was evident microscopically in the in the mesenteric lymph nodes for 12000 ppm adult females from either generation together with accumulations of yellow pigment also being observed in 12000 ppm adult females from the F1 generation only. Such effects in the thymus and mesenteric lymph nodes may possibly be associated with the reduced physical conditions seen in these animals, however the latter condition seen in 12000 ppm F1 adult females in the mesenteric lymph nodes may simply represent the accumulation of the coloured test material or coloured metabolite(s) and as such is of minimal toxicological significance.
Relative kidney weights were elevated for the F0 adult females treated with 12000 ppm and for F1 adult animals of either sex treated with 12000 ppm. Microscopic examination of kidney sections revealed basophilia of renal tubules in F0 and F1 adult females at this dose level. Further renal microscopic changes were evident in adult animals of either sex from both the F0 and F1 generations and were identified as accumulations of yellow pigment.
Microscopic changes were also identified in the ovaries. A lower incidence of fine cytoplasmic vacuolation of interstitial cells was observed for both F0 adult and F1 adult females treated with 12000 ppm and a greater incidence of higher grades of severity of yellow pigment accumulations (identified as haemosiderin) for F0 adult females at this dose level. Organ weight data supported these findings with reductions in absolute and relative ovary weight for adult females from the parental generation at this dose level. A reduction in absolute and relative uterus weight was also evident in these animals.
Toxicologically significant effects extended to the 6000 ppm dose group. F0 adult males showed a reduction in bodyweight gain and food consumption during maturation albeit to a lesser extent. F1 adult animals however showed a similar reduction in bodyweight gain and food consumption as observed in the 12000 ppm dose group.
A reduction in ovary, uterus and thymus weight was evident in F0 adult females together with the microscopic changes of sinus histocytosis in the mesenteric lymph nodes and a lower incidence of fine cytoplasmic vacuolation of intestinal cells in the ovaries. F1 adult females showed a reduction in absolute ovary weight together with microscopic changes of sinus histocytosis in the mesenteric lymph nodes and a lower incidence of fine cytoplasmic vacuolation of interstitial cells in the ovaries, while F1 adult males showed an increase in relative kidney weight together with microscopic renal changes of accumulation of yellow pigment.
Results for the functional observation are reported separately under Specific Investigations.
Changes detected in 3000 ppm were confined to the F1 adult animals. Adult males showed statistically significant increase in relative kidney weight together with microscopic changes of accumulations of yellow pigment in the kidneys while adult females showed a reduction in absolute ovary weight and a greater incidence and higher grades of severity of lymphoid atrophy in the thymus.
No such effects were detected in the F0 generation animals with 3000 ppm.
There were no treatment-related effects on reproductive performance in animals of either sex in treatment groups from either generation.
F0 adult females treated with 12000 ppm showed a reduction in live litter size at birth. A reduction in live birth index was also evident for F0 adult females together with a reduction in corpora lutea. There were no effect on intra-uterine embryonic deaths however, the reduced corpora lutea count may have resulted in the reduced live litter size at birth. F1 adult females treated with 12000 ppm showed a reduction in corpora lutea subsequently resulting in a lower number of implantations and litter size at birth. The toxicological relevance of these findings however is dubious given the absence of a true dose related response for corpora lutea and the deterioration in the physical condition of the animals. It should be noted that ovarian oocyte counts for selected F1 adult females was not affected by treatment at this dose level. Mean offspring bodyweights on Day 1 of age were unaffected by maternal exposure at 12000 ppm in either generation. However, litter weight was notably lower due to the aforementioned litter size at this dietary level. Subsequent bodyweight gain in either generation to weaning was progressively lower than concurrent controls, with differences being particularly marked from Day 7 of age. This may also have been a consequence of the offspring beginning to feed on the test diet rather than a developmental effect.
Selected F1 offspring treated with 12000 ppm showed an increase in age at completion of sexual maturation together with a reduction in bodyweight at sexual maturation. This did not effect the oestrous cycles of females prior to mating or the subsequent mating performance of these animals, and was most probably a consequence of the reduced offspring size.
Unselected F1 offspring and F2 offspring treated with 12000 ppm showed a reduction in absolute brain, spleen and thymus weight with the effect on brain weight extending to the 6000 ppm dose group.
No such toxicologically significant effects were detected in F0 or F1 generation animals of either sex treated with 6000 or 3000 ppm.
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