Subchronic oral toxicity studies with alpha-cyclodextrin in rats.Regul Toxicol Pharmacol. 2004 Jun; 39 Suppl 1:S14-26.RT
The toxicity of alpha-cyclodextrin (alpha-CD), a cyclic polymer of six alpha-1,4-linked glucopyranosyl units with potential applications as a food ingredient, more specifically a water-soluble dietary fiber, was examined in a 4-week range finding study and a 13-week oral toxicity study in rats. In the 4-week study, the test substance was administered to groups of Bor:WISW(SPF;Cpb) rats at dietary levels of 0, 1, 5, and 15% (5 rats/sex/group). An additional group received a diet with 5% beta-CD. In the 13-week study, groups of Crl:(WI)WU Br rats received diets with 0, 1.5, 5, or 20% alpha-CD. An additional group received a diet with 20% lactose (20 rats/sex/group). Satellite groups of 10 rats/sex were attached to the control, 20% alpha-CD and 20% lactose group. Following the 13-week treatment period, these satellite groups were kept on a standard, cereal-based rodent diet for a 4-week recovery period. Parameters measured during the two studies included clinical signs, body weights, food and water intake, hematological and clinicochemical parameters, and organ weights as well as gross and histopathological observations at necropsy. In the 13-week study, ophthalmoscopic examinations as well as urine and feces analyses were also conducted. There were no treatment-related mortalities in either study. In the 4-week study, persistent diarrhea was the most prominent, treatment-related effect observed in the animals of the 15% alpha-CD group especially in the male animals. In association with this effect, food consumption and food conversion efficiency were decreased. In line with observations from studies with other low-digestible, yet fermentable carbohydrates, the weight of the full and empty cecum was increased significantly in the 5% alpha-CD, 5% beta-CD, and 15% alpha-CD group. The reduced relative liver weights (in males and females) and the significantly increased relative testes weight which were observed in the 15% alpha-CD group, were attributed to the impaired nutritional condition (due to diarrhea) and the reduced body weight of the animals of this group, respectively. Microscopic examination of the main organs did not reveal pathological alterations that could be attributed to the alpha-CD treatment. In the 13-week study, soft stool and infrequent mild diarrhea were observed only during the first 2-3 weeks in the 20% alpha-CD and 20% lactose group (mainly male animals). Accordingly, body weights were reduced in males of the 20% lactose group throughout the study and in the 20% alpha-CD group during the last week of the study. Food intakes were slightly increased in the 20% alpha-CD group and the food conversion efficiency, was significantly reduced in males, but not females, of the 20% alpha-CD and 20% lactose group. There were no treatment-related changes of hematological parameters. In line with similar observations from studies on other low-digestible carbohydrates, the urinary pH was decreased and urinary calcium levels increased in the 20% alpha-CD and 20% lactose group. Similarly, the fecal dry weight and nitrogen output was increased in these groups. At termination of the treatment, significantly in creased cecum weights (full and empty) were observed in the 5 and 20% alpha-CD groups and the 20% lactose group. The relative (not absolute) weight of the spleen was significantly increased in males of the 20% alpha-CD group. In the 20% lactose group, the relative weights of the spleen and liver (females) and the testes, brain, and adrenals (males) were significantly increased. The histopathological examination of these and all other organs and tissues did not reveal any abnormalities that could be attributed to the alpha-CD or lactose treatment. In conclusion, the ingestion of alpha-CD for 13-weeks at dietary levels of up to 20% (corresponding to intakes of 12.6 and 13.9 g/kg bodyweight/d in male and female rats, respectively) did not produce any signs of toxicity or adverse effects.