A combined chronic toxicity/carcinogenicity study of sucralose in Sprague-Dawley rats.

The chronic toxicity and potential carcinogenicity of sucralose was evaluated by exposing Sprague-Dawley rats to dietary concentrations of this low-calorie sweetener both in utero and for up to 104 weeks following parturition. The rats assigned to the toxicity phase of this investigation were administered diets containing either 0% (control), 0.3% (3000 ppm), 1.0% (10,000 ppm) or 3.0% (30,000 ppm) sucralose. Each treatment group comprised 30 male and 30 female rats, of which 15 males and 15 females were sacrificed after 52 weeks of treatment. The surviving rats were killed following 78 weeks of sucralose administration. In the carcinogenicity phase of this investigation, groups of 50 male and 50 female rats were administered dietary sucralose at concentrations of 0% (control 1), 0% (control 2), 0.3%, 1.0% or 3.0% for 104 weeks. Evaluation of the data obtained from the two phases of this study showed that sucralose was not carcinogenic. Sucralose did not adversely affect the survival or clinical condition of the rats, and there were no toxicologically significant findings. Group mean body weight gain and food consumption were significantly decreased in a dose-dependent manner in sucralose-treated rats throughout the treatment period as compared to the controls. The primary effect of sucralose on food consumption, and secondarily on body weight gain, was established in later studies to be due to the fact that diets containing high concentrations of sucralose are unpalatable to rats. These subsequent studies established that the reduction of body weight gain seen in previous rat studies using sucralose in the diet at concentrations of 1% and below resulted from reduced food intake as a direct consequence of the unpalatable nature of sucralose. Similarly, at concentrations of 3% in the diet, it was shown that approximately 95% of the effect on body weight gain could be attributed to the reduction in food intake due to the reduced palatability of the diet, the remainder apparently due to a physiologic response to the high concentrations of non-digestible sucralose in the rats' diet. Complete toxicological evaluations of gavage studies with histopathological evaluations demonstrated that even at the 3% dietary level, toxicity was not responsible for the small body weight gain decrement. Gross and histopathologic examinations revealed that the administration of sucralose affected neither the types nor incidence of the tumours observed. The incidences of some non-neoplastic findings were statistically significantly increased in the sucralose treated groups relative to the controls. These included: renal pelvic epithelial hyperplasia in all female treatment groups, renal pelvic mineralization in females administered the intermediate or highest dietary concentrations of sucralose, adrenal cortical haemorrhagic degeneration in high-dose group female rats, and the histopathologic incidence of cataracts at necropsy in high-dose group male rats. The non-neoplastic findings that occurred were of no toxicological significance since they were either spontaneous findings commonly observed in aged rats of this strain or the physiological response to high dietary levels of a poorly absorbed compound.

A carcinogenicity study of sucralose in the CD-1 mouse.

The potential carcinogenicity of sucralose was evaluated by feeding groups of 52 male and 52 female CD-1 mice a diet containing sucralose at 0.3% (3000 ppm), 1.0% (10,000 ppm) or 3.0% (30,000 ppm) for 104 weeks. A group of 72 male and 72 female mice received diet without sucralose and served as controls. Week 1 achieved doses ranging from 543 to 5870mg/kg body weight/day in the low-dose males and high-dose females, respectively. Sucralose had no adverse effect on survival. No significant changes attributable to sucralose were found in the clinical condition or behaviour of the mice. Organ weights and the gross appearance of tissues were unaffected by treatment. The mean erythrocyte counts of females receiving the highest dietary concentration were slightly, but statistically significantly, lower than those of the controls after 104 weeks of treatment. Group mean body weight gain at the highest dietary concentration of sucralose was significantly less than that of the control in mice of both sexes. Food consumption, after correction for sucralose content, was lower for female mice, but not statistically significant. Water consumption for male mice receiving the highest dietary concentration was approximately 9% higher than that of the controls. There were statistically significant increases in the incidence of several non-neoplastic findings, but these were not considered to be related to sucralose administration. Treatment with sucralose did not increase the incidence of any tumour or influence the types of tumours observed. It was concluded that sucralose is not carcinogenic in CD-1 mice. The body weight gain and erythrocyte observations at the 3.0% dietary level were of limited biological significance as they were not accompanied by any histopathologic finding and had no impact on survival. The remaining dose levels were judged to have no effects.

Safety evaluation of amino peptidase enzyme preparation derived from Aspergillus niger.

An amino peptidase enzyme preparation obtained from Aspergillus niger was subjected to a series of toxicological tests to document the safety for use as a processing aid for food. The enzyme preparation was examined for subacute and subchronic oral toxicity, and mutagenic potential. No evidence of oral toxicity or mutagenicity was found. Administration of the amino peptidase enzyme preparation at doses of 500, 1000 and 2000 mg/kg body weight/day for 90 days did not induce noticeable signs of toxicity. The no-observed-adverse-effect level (NOAEL) of the enzyme preparation in the subchronic toxicity study was 2000mg/kg body weight/day (equivalent to 1152 PHEA units/kg body weight/day). It can be concluded that no safety concerns were identified in the studies conducted with this amino peptidase enzyme preparation derived from Aspergillus niger and produced under controlled fermentation conditions.

Safety evaluation of lipase derived from Rhizopus oryzae: summary of toxicological data.

A lipase enzyme, obtained from Rhizopus oryzae produced by a fermentation process was subjected to a series of toxicological tests to document the safety for use as a food additive. The enzyme product was examined for acute, subacute and subchronic oral toxicity, and mutagenic potential. An extensive literature search on the production organism has also been conducted. No evidence of (sub)acute oral toxicity or mutagenic potential was found. Administration of the lipase at dosages of 50, 200 and 1000 mg/kg body weight/day for 90 days did not induce noticeable signs of toxicity. A few minor changes in the chemical composition of the blood in the highest dose group were of no toxicological significance. The no-observed-adverse-effect level of the tox-batch in the subchronic toxicity study was 1000 mg/kg body weight/day. It can be concluded that no safety concerns were identified in the studies conducted with this lipase preparation derived from R. oryzae and produced under controlled fermentation conditions.

Oncogenicity studies of taltirelin tetrahydrate (TA-0910) by oral (GAVAGE) administration in CD-1 mice and CD rats.

Oncogenicity studies of taltirelin tetrahydrate (TA-0910), a new thyrotropin-releasing hormone (TRH) analogue, were carried out on CD-1 mice and CD rats. Groups of 60 male and 60 female CD-1 mice received TA-0910, by oral gavage, at dosages of 5, 15 or 50 mg/kg/day. Treatment continued for a minimum period of 104 weeks. Groups of 55 male and 55 female CD rats received TA-0910, by oral gavage, at dosages of 20, 60 or 200 mg/kg/day. Treatment continued for a minimum period of 90 or 94 weeks for males and females, respectively. Of the treatment-related behavioral changes noted, the majority were considered to be directly related to the known pharmacological activity of the test substance and, as such, to be of questionable direct toxicological significance. In mice, there was no evidence of a treatment-related effect on the incidence of neoplasms. In rats, slightly higher incidences of pituitary adenoma, in males given 60 or 200 mg/kg/day, and thyroid follicular adenoma, in females given 200 mg/kg/day, were noted. However, in neither case was statistical significance attained in pair-wise comparisons, and the incidences were within expectation from background data. There was no evidence of any oncogenic potential of TA-0910 in these studies.