Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labeling and/or risk assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1970

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
not specified
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Purity: not reported

Test animals

Species:
rat
Strain:
other: Charles River CD
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13-weeks
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 5, 10, 20 g/kg/day
Basis:

No. of animals per sex per dose:
8/sex/dose level
Control animals:
yes, plain diet

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Parameters examined: physical condition and behaviour

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean weekly diet consumption calculated as g food/kg body weight/week: Yes
- Compound intake calculated as averages from the consumption and body weight data: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: 4, 8 and 12 weeks
- Dose groups that were examined: all
- Parameters examined: eyelids, conjunctiva, and sclera, as well as examination of cornea, iris, lens, and fundus with an ophthalmoscope

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 4, 8, 12 weeks
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5/sex/dose group
- Parameters examined: haemoglobin content, haematocrit, total and differential leukocyte counts, and coagulation time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 4, 8 and 12 weeks
- Animals fasted: No data
- How many animals: 5/sex/dose group
- Parameters examined: blood glucose. In addition at the time of sacrifice, blood was taken from 5 male and 5 female rats of each group for determination of serum alkaline phosphatase, serum glutamic pyruvic transaminase, serum glutamic oxalacetic transaminase, blood urea nitrogen, serum
bilirubin and uric acid values.

URINALYSIS: Yes
- Time schedule for collection of urine: 4, 8 and 12 weeks
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked examined: color and transparency; pH and specific gravity; qualitative tests for glucose, albumin, ketones, bilirubin,
and occult blood; and urine sediment examined microscopically

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: prior to treatment and at 4, 8 and 12 weeks
- Dose groups that were examined: all
- Parameters examined: gait, body position, muscle tone, behaviour, movement of legs, and reflexes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- Gross autopsies were performed on all animals found dead or sacrificed at the end of the study. The extent of autopsy and histologic study was limited to grossly abnormal organs in the animals found dead or sacrificed prematurely. For animals sacrificed at the end of the study, the cervical, thoracic and abdominal organs plus the pituitary and brain were examined grossly. The heart, lungs, liver, kidneys, spleen, brain, ovaries, testes, uterus, thyroid gland, adrenal glands and pituitary gland were weighed for rats sacrificed at the end of the study. Of these, the thyroid glands, adrenal glands and pituitary glands were weighed after fixation in 1070 formalin. The other organs were weighed prior to fixation.

HISTOPATHOLOGY: Yes
- Portions of all the organs and other tissues observed at gross pathology were fixed in 10% formalin containing 2% acetate for histologic sectioning. Haematoxylin and eosin stained sections prepared included liver, spleen, kidney, heart, lung, adrenal, thyroid, pituitary, gonads, intestine, pancreas, urinary bladder, brain, bone marrow, and eye. Additional sections of liver and kidney were also stained with the P.A. Schiff stain. Frozen sections of liver were stained with oil red 0 stain.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: Except for transient diarrhea in a few of the treated animals, no clinical abnormalities that were related to treatment were noted. During the first week 10 animals fed compound at the level of 10 grams/kg/day showed some diarrhea. The diarrhea noted during week one cleared and did not recur except in one animal that had diarrhea during week 4. Animals fed at higher and lower levels did not have diarrhea except one high level animal had diarrhea during week 7. One rat in the low level group (5 grams/kg/day) died during the 6th week of the study with chronic pneumonia and a lung abscess. All rats in the 10 and 20 grams/kg/day groups survived for the entire study.

BODY WEIGHT AND WEIGHT GAIN: Body weight gain of treated animals, particularly the males was slightly less than that of controls at the end of the study. At the end of the study, the mean body weights of male and female rats fed the compound at the high level of 20 grams/kg/day and the mid-level of 10 grams/kg/day were significantly less than that of control animals.

HAEMATOLOGY: Some variations were observed; however, these did not persist for more than one time period or show any relation to dose level.

CLINICAL CHEMISTRY: Blood glucose values of treated and control animals showed no persistant difference. Except for slight elevations of the blood urea nitrogen and bilirubin in individual treated animals, none of the determinations performed on blood obtained at the time of sacrifice showed increased values for treated animals. In no animal was the blood urea nitrogen greater than 30 mg %. All bilirubin values were less than 0.8 % with the range for treated and control animals being the same. No animal had a uric acid level greater than 3.0 mg %.

GROSS PATHOLOGY: As a reflection of decreased body weight there was a slight increase in the weight of the brain, liver, kidney, heart, spleen, and testes when expressed as a percent of body weight. Only the mean weight of the liver of treated female rats was absolutely increased over that of the controls; however, this was not numerically significant.

Effect levels

Dose descriptor:
NOAEL
Effect level:
20 other: grams/kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Highest dose level tested

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Rats fed xylitol as a dietary admix at levels of 5, 10 and 20 grams/kg/day for 13 weeks tolerated the feeding well except for transient diarrhea and slightly reduced weight gains. This study and the conclusions which are drawn from it fulfill the quality criteria (validity, reliability, repeatability).
Executive summary:

In a 13 week study four groups of eight female and eight male Charles River CD rats were fed 0, 5, 10 and 20 g dietary xylitol/kg/day. Each rat was observed daily to determine general condition and behaviour. Food consumption and body weights were measured weekly and the test material intake calculated. Ophthalmic and neurologic examinations were performed on all rats prior to treatment and at 4, 8 and 12 weeks. Haematological studies, blood glucose determinations and urinalyses were performed on specimens from 5 male and 5 female rats from each group at 4, 8 and 12 weeks. Serum alkaline phosphatase, serum glutamic oxalacetic transaminase, blood urea nitrogen, serum bilirubin and uric acid were determined on blood from 5 male and 5 female animals of each group at 13 weeks. Each surviving animal was autopsied at that time.
All animals fed compound at the level of 10 and 20 grams/kg/day survived the entire period of the study. One rat fed the low level of 5 grams/kg/day died during the 6th week of the study with chronic pneumonia and a lung abscess. Body weight gain of treated animals, particularly the males was slightly less than that of controls at the end of the study. At the end of the study, the mean body weights of male and female rats fed the compound at the high level of 20 grams/kg/day and the mid-level of 10 grams/kg/day were significantly less than that of control animals. As a reflection of decreased body weight there was a slight increase in the weight of the brain, liver, kidney, heart, spleen, and testes when expressed as a percent of body weight. Only the mean weight of the liver of treated female rats was absolutely increased over that of the controls; however, this was not numerically significant. Except for transient diarrhea in a few of the treated animals, no clinical abnormalities that were related to treatment were noted. Clinical laboratory studies did not distinguish treated animals from controls. Autopsy of all animals failed to demonstrate any lesions related to the level of compound given in the diet. Incidental inflammatory lesions were noted in rats of all groups.
Rats fed xylitol as a dietary admix at levels of 5, 10 and 20 grams/kg/day for 13 weeks tolerated the feeding well except for transient diarrhea and slightly reduced weight gains.