Xylitol

Endpoint summary

Description of key information

3-Week feeding study; rat; NOAEL: 20000 mg/kg (highest dose tested). Reliability = 2

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

106-week oral diet study in mice

GLP compliance:

not specified

Species:

mouse

Strain:

other: CFLP

Sex:

male/female

Route of administration:

oral: feed

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

106 weeks or when 20% survival was reached

Frequency of treatment:

daily

Dose / conc.:

2 other: %

Remarks:

nominal in diet

Dose / conc.:

10 other: %

Remarks:

nominal in diet

Dose / conc.:

20 other: %

Remarks:

nominal in diet

No. of animals per sex per dose:

100/sex/dose level

Control animals:

yes, plain diet

other: 20% sucrose in the diet

Dose descriptor:

NOAEL

Effect level:

2 other: % in diet

Based on:

test mat.

Sex:

male

Remarks on result:

other: see "Remarks'

Remarks:

Macroscopic examination indicated a large increase in the incidence of urinary bladder calculi, urinary bladder nodules and masses, and urinary bladder distention for the 10 and 20% test substance males. Histological examination of the 10 and 20% test substance males revealed hyperplasia, metaplasia, and neoplasia of the transitional epithelium of the urinary bladder in male mice associated with the macroscopically observed calculi. No metastasis was observed in the bladder tumours.

Dose descriptor:

NOAEL

Effect level:

20 other: % in diet

Based on:

test mat.

Sex:

female

Remarks on result:

other: highest dose tested

Critical effects observed:

not specified

No diarrhoea was observed with up to 10% xylitol or sucrose during the first three weeks. During the fourth week, mice receiving 15% xylitol (male and female) exhibited diarrhoea. The males also had associated inflammation of the anogenital region. The 15% sucrose group also showed some evidence of diarrhoea. These mice were returned to 10% xylitol and sucrose until week seven when they again received 15% xylitol and sucrose. The same signs as above were again seen but were less severe. By week 11 the mice seemed normal and the 20% xylitol and sucrose levels were achieved by week 14. It therefore, took as long as 16 weeks to achieve dietary accommodation to 20% xylitol and sucrose.
An overall significant increase in mortality was seen for 20% xylitol males during the first year; however. Some increases in food intake was seen for males in the 10 and 20% xylitol groups between weeks one and 106 and for females in these groups between weeks one and 80. The 20% sucrose group showed increased food intake for the first year of the study. Males in the 10 and 20% xylitol groups as well as 20% xylitol females had decreased body weight gains. Water intake was increased for the 20% xylitol males.
Macroscopic examination indicated a large increase in the incidence of urinary bladder calculi, urinary bladder nodules and masses, and urinary bladder distention for the 10 and 20% xylitol males. No similar effects were seen in the 2, 10, and 20% females, 2% xylitol males, or the 20% sucrose group. Histological examination of the 10 and 20% xylitol males revealed hyperplasia, metaplasia, and neoplasia of the transitional epithelium of the urinary bladder in male mice, associated with the macroscopically observed calculi. No metastasis was observed in the bladder tumours. The incidence of treatment-related tumours, metaplasia or neoplasia was not increased for the 2% xylitol males nor the 2, 10, and 20% xylitol females. Analysis of the bladder calculi indicate they are composed of calcium, phosphate, and oxalate. In the 20% sucrose-fed males there was an increase in kidney lesions described as cellular infiltration. Macroscopic examination of mice dying during the study revealed a statistically significant, dose-related reduction in the number of male mice bearing liver masses treated with xylitol, as compared to controls. Among mice killed at termination a lower prevalence of liver masses was recorded for males treated with 10 or 20% xylitol and attained a level of statistical significance (P 0.05) when compared to controls. Histologically, the liver masses were mainly benign adenomas, a small proportion had a structure suggestive of carcinoma. The prevalence in the sucrose group was similar to controls. The differences were statistically significant when 10 and 20% xylitol males were compared to controls and when 2, 10 or 20% levels of xylitol compared to 20% sucrose group.
The incidence of hepatocellular tumours (benign) was increased for the 20% sucrose females. Male 20% sucrose mice also showed an increase in fatty degeneration of hepatocytes.

Executive summary:

Groups each of 100 male and 100 female CFLP mice per group were fed diets containing levels of 0, 2, 10, or 20% xylitol or 20% sucrose. The diet of all groups was maintained at 20% carbohydrate supplementation through the use of rice starch. Protein was maintained constant in all groups through the addition of casein. A group was terminated when 20% survival was reached. Initially the highest level of carbohydrate in any of the diets was 10%. Subsequently, desired levels of carbohydrate were obtained by increasing the amount in the diets by 5% each week.
No diarrhoea was observed with up to 10% xylitol or sucrose during the first three weeks. During the fourth week, mice receiving 15% xylitol (male and female) exhibited diarrhoea. The males also had associated inflammation of the anogenital region. The 15% sucrose group also showed some evidence of diarrhoea. These mice were returned to 10% xylitol and sucrose until week seven when they again received 15% xylitol and sucrose. The same signs as above were again seen. By week 11 the mice seemed normal and the 20% xylitol and sucrose levels were achieved by week 14. It therefore took as long as 16 weeks to achieve dietary accommodation to 20% xylitol and sucrose.
An overall significant increase in mortality was seen for 20% xylitol males during the first year. Some increases in food intake was seen for males in the 10 and 20% xylitol groups between weeks one and 106 and for females in these groups between weeks one and 80. The 20% sucrose group showed increased food intake for the first year of the study. Males in the 10 and 20% xylitol groups as well as 20% xylitol females had decreased body weight gains. Water intake was increased for the 20% xylitol males.
Macroscopic examination indicated a large increase in the incidence of urinary bladder calculi, urinary bladder nodules and masses, and urinary bladder distention for the 10 and 20% xylitol males. No similar effects were seen in the 2, 10, and 20% females, 2% xylitol males, or the 20% sucrose group. Histological examination of the 10 and 20% xylitol males revealed hyperplasia, metaplasia, and neoplasia of the transitional epithelium of the urinary bladder in male mice, associated with the macroscopically observed calculi. No metastasis was observed in the bladder tumours. The incidence of treatment-related tumours, metaplasia or neoplasia was not increased for the 2% xylitol males nor the 2, 10, and 20% xylitol females. Analysis of the bladder calculi indicate they are composed of calcium, phosphate, and oxalate. In the 20% sucrose-fed males there was an increase in kidney lesions described as cellular infiltration. Macroscopic examination of mice dying during the study revealed a statistically significant, dose-related reduction in the number of male mice bearing liver masses treated with xylitol, as compared to controls. Among mice killed at termination a lower prevalence of liver masses was recorded for males treated with 10 or 20% xylitol and attained a level of statistical significance (P 0.05) when compared to controls. Histologically, the liver masses were mainly benign adenomas, a small proportion had a structure suggestive of carcinoma. The prevalence in the sucrose group was similar to controls. The differences were statistically significant when 10 and 20% xylitol males were compared to controls and when 2, 10 or 20% levels of xylitol compared to 20% sucrose group.
The incidence of hepatocellular tumours (benign) was increased for the 20% sucrose females. Male 20% sucrose mice also showed an increase in fatty degeneration of hepatocytes  No diarrhoea was observed with up to 10% xylitol or sucrose during the first three weeks. During the fourth week, mice receiving 15% xylitol (male and female) exhibited diarrhoea. The males also had associated inflammation of the anogenital region. The 15% sucrose group also showed some evidence of diarrhoea. These mice were returned to 10% xylitol and sucrose until week seven when they again received 15% xylitol and sucrose. The same signs as above were again seen. By week 11 the mice seemed normal and the 20% xylitol and sucrose levels were achieved by week 14. It therefore took as long as 16 weeks to achieve dietary accommodation to 20% xylitol and sucrose.
An overall significant increase in mortality was seen for 20% xylitol males during the first year. Some increases in food intake was seen for males in the 10 and 20% xylitol groups between weeks one and 106 and for females in these groups between weeks one and 80. The 20% sucrose group showed increased food intake for the first year of the study. Males in the 10 and 20% xylitol groups as well as 20% xylitol females had decreased body weight gains. Water intake was increased for the 20% xylitol males.
Macroscopic examination indicated a large increase in the incidence of urinary bladder calculi, urinary bladder nodules and masses, and urinary bladder distention for the 10 and 20% xylitol males. No similar effects were seen in the 2, 10, and 20% females, 2% xylitol males, or the 20% sucrose group. Histological examination of the 10 and 20% xylitol males revealed hyperplasia, metaplasia, and neoplasia of the transitional epithelium of the urinary bladder in male mice, associated with the macroscopically observed calculi. No metastasis was observed in the bladder tumours. The incidence of treatment-related tumours, metaplasia or neoplasia was not increased for the 2% xylitol males nor the 2, 10, and 20% xylitol females. Analysis of the bladder calculi indicate they are composed of calcium, phosphate, and oxalate. In the 20% sucrose-fed males there was an increase in kidney lesions described as cellular infiltration. Macroscopic examination of mice dying during the study revealed a statistically significant, dose-related reduction in the number of male mice bearing liver masses treated with xylitol, as compared to controls. Among mice killed at termination a lower prevalence of liver masses was recorded for males treated with 10 or 20% xylitol and attained a level of statistical significance (P 0.05) when compared to controls. Histologically, the liver masses were mainly benign adenomas, a small proportion had a structure suggestive of carcinoma. The prevalence in the sucrose group was similar to controls. The differences were statistically significant when 10 and 20% xylitol males were compared to controls and when 2, 10 or 20% levels of xylitol compared to 20% sucrose group.
The incidence of hepatocellular tumours (benign) was increased for the 20% sucrose females. Male 20% sucrose mice also showed an increase in fatty degeneration of hepatocytes.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

20 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose studies with xylitol have been completed in several species of experimental animals. The subchronic toxicity of xylitol was examined in Wistar rats receiving either 20% xylitol in their diet or receiving the control diet. In a short-term (13 weeks) study four groups of eight female and eight male Charles River CD rats weighing 120-150 g, were fed 0, 5, 10 and 20 g dietary xylitol/kg/day. Groups of Wistar rats (70 rats/group) were allocated to diets of either 20% xylitol (two groups, one group was gradually adapted beginning with a 5% diet to prevent diarrhoea) or control diet (one group). In summary, except for transient diarrhoea in a number of treated animals in these studies, no other significant changes were observed and no significant histopathological lesions related to the xylitol administered were noted. In addition, xylitol has a long-standing history of daily consumption by the human population with no reports of systemic toxicity.

Justification for classification or non-classification

No effects were observed in repeated dose toxicity studies in multiple species. Therefore, the substance does not need to be classified for repeated dose toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.