| Non-Human Toxicity Excerpts | /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In a study to examine the effect of repeated doses of erythritol on serum blood urea nitrogen and urinary excretion of electrolytes added to the drinking-water, groups of 12 female Wistar rats were given erythritol at 8 g/kg bw per day (purity, 99.7%) by gavage and given access to tap water containing sodium hypochlorite, a low-electrolyte solution (35 mmol/L sodium35 mmol/L potassium80 mmol/L chloride5 mmol/L calcium) or a high-electrolyte solution (70 mmol/L sodium70 mmol/L potassium160 mmol/L chlorine10 mmol/L calcium) ad libitum for four weeks. ... Almost all the treated rats had soft, muddy, or watery stools on the first day of treatment, regardless of electrolyte intake, and diarrhea was observed in some rats for the remainder of the study. ... Erythritol resulted in a slight decrease in feed consumption, which became more pronounced when the rats were also exposed to electrolytes. During the first six days of the study, erythritol caused increased water intake, which was further increased in groups exposed to electrolytes. During the remainder of the study, the water intakes of animals given erythritol in tap water were comparable to those of controls given tap water, while those in rats given erythritol plus low-electrolyte water or erythritol plus high-electrolyte water remained higher than those of groups receiving erythritol or electrolytes alone. This difference in drinking-water intake between erythritol-treated and control groups receiving supplementary electrolytes resulted in a higher net intake of electrolytes by the erythritol-treated groups. The hematocrit was unaffected by erythritol and/or electrolytes. Erythritol alone resulted in significant (p < 0.05) decreases in serum sodium and chloride concentrations, while co-administration of electrolytes significantly increased the concentrations to those observed in control rats. Erythritol caused a decrease in osmotic pressure that was unaffected by co-administration of electrolytes. Although exposure to erythritol alone resulted in slightly increased blood urea nitrogen, the difference was not statistically significant. When erythritol was administered with high-electrolyte concentrations, the blood urea nitrogen was reduced to concentrations significantly lower than those of animals receiving erythritol plus tap water or tap water alone. The total concentration of serum protein in animals given erythritol plus tap water was comparable to that of animals given tap water alone, but when erythritol was combined with electrolytes, the total serum protein concentrations decreased in a dose-related manner. The ratio of albumin: globulin was increased by erythritol and further increased by co-administered electrolytes. ... Although the urine volume was not affected by erythritol alone, it increased the specific gravity and osmotic pressure over those of controls receiving tap water. ... Animals treated with erythritol plus tap water had greater excretion of sodium, potassium, chlorine, and exposure to electrolytes further increased the urinary excretion in proportion to their increased intake, irrespective of erythritol treatment. ... Erythritol treatment alone increased both the absolute and relative kidney weights, although only the relative weight differed significantly from that of controls receiving tap water. Co-administration of electrolytes with erythritol did not affect kidney weights when compared with erythritol alone. Independent of electrolyte concentrations, dilatation of the renal tubules was reported more frequently in erythritol-treated rats. The authors concluded that the diuretic action of erythritol leads to hyponatraemia and the increase in blood urea nitrogen results from compensatory homeostatic mechanisms, since this increase was inhibited by addition of electrolytes to the drinking-water./LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Groups of four beagles of each sex were given 0, 1, 2.2, or 5 g/kg bw per day of erythritol (solution of 19.7 or 20.1%purity not stated) by intravenous injection for 180 days. Controls received physiological saline at the same volume as that received by the high-dose group. An additional two animals of each sex received 0, 2.2, or 5 g/kg bw per day by the same schedule and were allowed to recover without treatment for one month after treatment. As two bitches at the high dose had to be killed after dosing errors, a supplementary study was initiated in which groups of two bitches were given erythritol at 0 or 5 g/kg bw per day by the same protocol as used in the main study. The data from the two studies were combined such that there were 8, 4, 6, and 6 bitches in the treatment phase and 4, 0, 2, and 2 bitches in the recovery phase at 0, 1, 2.2, and 5 g/kg bw per day, respectively. ... A number of effects on general condition were noted in treated animals which included hypoactivity on the first day of dosing, increased frequencies of urination and vomiting during the first hour after dosing, and the appearance of red urine early in the study, particularly in animals at the higher dose. Salivation was also reported in bitches at the high dose. The incidences of diarrhea and soft stools were not increased by treatment. ... A dose-related increase in water consumption was seen during treatment that reached statistical significance (p < 0.05) in dogs at all doses and in bitches at the two higher doses. ... Some minor changes in electrocardiographic parameters were observed in treated animals, but the responses were inconsistent and the values of the affected parameters were within normal ranges. ... Treated bitches showed a dose-related increase in blood urea nitrogen at three and six months which was statistically significant at the intermediate and high doses at three months and at all doses at six months. Since there was no evidence of impaired renal function and no histopathological evidence of renal damage, the toxicological significance of the increased blood urea nitrogen is questionable. Treatment resulted in a dose-related increase in urine volume which was statistically significant at 2.2 and 5 g/kg bw per day in dogs and at 5 g/kg bw per day in bitches, and a dose-related decrease in the specific gravity of the urine which was statistically significant (p < 0.05) in dogs at the intermediate and high doses. There were no differences in urine volume or specific gravity at the end of the recovery period. Controls, given physiological saline, excreted more urinary sodium and chlorine during treatment than before administration or during recovery, while potassium excretion was unaffected. In comparisons with pre-treatment urinary excretion of sodium, ... erythritol was found to increase excretion in animals of each sex at the intermediate and high doses. These doses also tended to increase the chlorine excretion over that before treatment, most markedly in males. Urinary excretion of potassium was decreased in dogs at both three and six months and in bitches at the high dose at three months. Urinary excretion of sodium, chlorine, and potassium was comparable in all groups during the recovery period. ... Hemorrhages were observed in the urinary bladders of animals that had reddish urine during treatment, but there were no other gross or histopathological findings which could be related to treatment. There was no NOEL in this study. The LOEL was 1 g/kg bw per day on the basis of increased blood urea nitrogen and vomiting in bitches and increased water consumption by dogs at this dose. Higher doses were associated with vomiting, increased water consumption, increased urine volume, hemorrhage in the urinary bladder resulting in reddish urine, increased urinary sodium excretion in animals of each sex, and increased urinary chlorine excretion, decreased urinary potassium excretion, and atrophy of the acinar epithelium and foliate interstitial fibrosis of the prostate in dogs./LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Groups of three beagles of each sex were given erythritol (purity, 99.7%) by gavage at doses of 0, 1.25, 2.5, or 5 g/kg bw per day, on seven days per week for 13 weeks. An additional two animals of each sex receiving the 0, 2.5, or 5 g/kg bw per day were treated for 13 weeks and then allowed to recover without treatment for four weeks. ... Changes in general condition that were associated with treatment were seen in animals of each sex at the intermediate and high doses and to a lesser extent in those at the low dose. ...These were transient effects which were resolved within 24 hrs and may have been due to increased plasma osmotic pressure. ... Erythritol caused dose-related increases in water consumption in animals of each sex during treatment, but because of large individual variations in water intake, consistent, statistically significant increases were observed only in dogs at the intermediate and high doses and bitches at the high dose. Animals of each sex at 2.5 and 5 g/kg bw per day showed a gradual increase in water intake during treatment. ... The urine volumes of animals at the high dose were significantly higher than those of controls during treatment but returned to pre-treatment concentrations during the recovery period. The urine of bitches at the low and intermediate doses had a significantly higher specific gravity and osmotic pressure than that of controls during treatmentalthough the specific gravity of the urine of bitches at the high dose was also higher than that of controls, it was significantly so only at week 13. These differences probably reflected the urinary erythritol concentrations. The urine became paler with the increased volume associated with erythritol treatment. During weeks 7 and 13 of treatment, diarrhea was observed more often in animals at the high dose than in controls, and occult blood was observed in the feces of three of four dogs at this dose that had diarrhea at the end of treatment. Occult blood was a more frequent finding in dogs at the high dose because it was often observed in association with diarrhea. During the recovery period, occult blood was observed only in the feces of the one bitch at the intermediate dose that was affected during treatment. ... A variety of histopathological changes were seen in the renal tubules of two dogs at the high dose at the end of treatment, which included desquamation, eosinophilic degeneration, hydropic degeneration, pyknosis, slight dilatation, and slight necrosis. At the end of the recovery period, hyaline casts were observed in the kidneys of one dog at the intermediate dose and eosinophilic degeneration and pyknosis of the tubules of one dog at the high dose. ... The NOEL was 1.25 g/kg bw per day on the basis of increased incidences of vomiting, diarrhea and/or loose stools, increased water consumption, and atrophy of the thymus in animals of each sex at higher doses. The dose of 5 g/kg bw per day was associated with increased urine volume, the presence of occult blood in urine, and histopathological changes in the kidneys of dogs. While the clinical signs and clinical biochemical and urinary parameters had disappeared by the end of the four-week recovery period, thymic atrophy and renal abnormalities were still apparent./LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Groups of 22 Slc:Wistar rats of each sex received erythritol (19.7% solutionpurity not reported) at doses of 0, 1, 1.73, or 3 g/kg bw per day by intravenous injection for 180 days. Six additional rats in each group except that receiving 1 g/kg bw per day were allowed to recover without treatment for one month. Control animals received physiological saline at a volume corresponding to that received by animals at the high dose. The rats were observed for deaths and clinical signs of toxicity at least once a day during both treatment and recovery. ... After three and six months of treatment, urine was collected from six rats of each sex per group in metabolism cages. ... Before necropsy at the end of treatment or recovery, blood samples were obtained for assessment of hematological and biochemical parameters. All animals were examined externally and then sacrificedtheir organs and tissues were examined grossly. ... No unusual clinical observations or deaths related to treatment were found during the study. The mean body weights of males at the high dose were lower than those of controls during most of the treatment period through to the end of recovery, and at the end of treatment the difference from controls was approximately 6%. ... Average feed consumption during treatment was unaffected, but the treatment resulted in dose-related increases in the water intake of animals of each sex at all doses, which were more often statistically significant ( p < 0.05) in males than in females and increased with dose. As the water intakes of controls tended to be higher during recovery than during treatment, the water intake of treated rats did not change during the recovery period. Erythritol treatment resulted in a dose-related decrease in the erythrocte and hemoglobin counts and in the hematocrits of animals of each sex, which were statistically significant in males at all doses and in females at the intermediate and high doses, although these parameters remained within the reference ranges reported in the literature. The number of reticulocytes was reported to be significantly higher in females receiving 1.73 or 3 g/kg bw per day and in males receiving 3 g/kg bw per day than in controls. At the end of the recovery period, the hematological parameters in treated animals were comparable to those in their respective controls. Females showed a dose-related increase in serum blood urea nitrogen that was significant at the high dose. Significantly lower serum sodium and calcium concentrations were seen in all treated males than in controls, and males at the high dose also had significantly higher serum potassium concentrations. ... At three and six months, the urine volumes of animals of each sex at 1.73 and 3 g/kg bw per day were significantly higher than in controls, the increase in urination being evident in rats at the high dose within the first hour of treatment. The urine density decreased with increasing dose of erythritol but at neither time were the decreases statistically significant. ... The urinary pH of females at the high dose was significantly decreased (p < 0.05), although the values remained within the reference ranges. After the one-month recovery period, urinary parameters in treated males were comparable to those in controls, but erythritol-treated females continued to excrete significantly more urine of a significantly lower density. Urinary electrolyte excretion was comparable in all female groups at the end of the recovery period. Treated rats of each sex had dose-related increases in the absolute and relative weights of the kidneys, which were statistically significant at 1.73 g/kg bw per day. No difference in absolute or relative kidney weights was observed at the end of recovery. The absolute and relative weights of the thymus were lower in males at the high dose but only the absolute weight differed significantly (p < 0.05) from that of controls. The absolute and relative weights of the left and right adrenal glands were higher in rats of each sex at the high dose than in their respective controls, but only the relative weights differed significantly from those of controls. Consistent with the known mode of action of erythritol, no increase in caecal weights was reported in this study. No abnormalities were observed during histopathological or electron microscopic examination conducted at the end of the treatment and recovery periods. The NOEL was 1 g/kg bw per day on the basis of increased water intake, urine production, reticulocyte count, and adrenal and kidney weights in animals of each sex, decreased body weight and serum potassium in males, and increased blood urea nitrogen in females at higher doses. At the end of the one-month recovery period, the body weights of males at the high dose remained depressed, and diuresis was still present in females at the intermediate and high doses.For more Non-Human Toxicity Excerpts (Complete) data for Erythritol (22 total), please visit the HSDB record page. |
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