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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978
Report date:
1978

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: Food and Drug Administration (1966). Guidelines for Reproductive Studies for Safety Evaluations of Drugs for Human Use.
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Committee on Safety of Medicines. Guidelines on Reproduction Studies for the Guidance of Applicants for Product Licences and Clinical Trial Certificates, June 1974.
Deviations:
no
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Xylitol
EC Number:
201-788-0
EC Name:
Xylitol
Cas Number:
87-99-0
Molecular formula:
C5H12O5
IUPAC Name:
(2R,3r,4S)-pentane-1,2,3,4,5-pentol
Details on test material:
- Purity: not reported

Test animals

Species:
rabbit
Strain:
other: Yellow-Silver
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Animal Farm Füllinsdorf (BL), Switzerland
- Age at study initiation: 3-4 months
- Weight at study initiation: 2.7-3.0 kg
- Housing: housed in individual stainless steel cages
- Diet (e.g. ad libitum): For all dose levels portions of 150 g food per day were given from 1st to 30th day of gestation.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: acclimatized for a period of at least four weeks prior to the experiment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): fully air-conditioned rooms at a temperature of 18 ± 1ºC
- Humidity (%): 50-60 %
- Photoperiod (hrs dark / hrs light): 12 h/day light

Administration / exposure

Route of administration:
oral: feed
Details on exposure:
DIET PREPARATION: The test substance, sorbitol, or sucrose was baked into Nafag 814 food. Control were fed Nafag 814 without addition.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: 10-15 healthy untreated Yellow Silver bucks of proven fertility were employed. Each doe was caged with a buck for one to three hours and copulation observed. Ideally following two copulations with the same male, the fertilized females were distributed to the experimental groups according to a table of random numbers.
Duration of treatment / exposure:
Gestation Days 7 to 19
Frequency of treatment:
Daily
Duration of test:
Surviving does were sacrificed on the 30th day of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
2 other: %
Remarks:
nominal in diet
Dose / conc.:
5 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:
20 females
Control animals:
yes, plain diet
other: Further groups received diet containing 20% of either sorbitol or sucrose.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: changes in appearance, behaviour and pharmacological effects

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 30
- Organs examined: Mothers were examined for possible malformations.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter, including crown-rump length
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter
Statistics:
Statistical analyses were performed using Student's "t" test for independent samples and the chi-square test (Fisher's exact probability test).

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Body weight was reduced during the treatment period at 20% xylitol and 20% sucrose.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The average daily feed intake in the control, 2, 5, and 10% xylitol groups varied between 100 and 144 g per doe from days 2 to 28 of pregnancy. In the 20% xylitol, 20% sorbitol, and 20% sucrose groups the feed intake decreased to less than 100 g/day/doe during parts of the period of treatment but returned to normal when the diet was no longer supplemented with xylitol or other sugars. The average daily uptake of sugars (g/kg) in these groups with 10% admix to the feed showed a tendency to decrease during the treatment period. The daily uptake I the various dose groups was on average (g/kg): 0.94 (2% xylitol), 2.33 (5% xylitol), 4.17 (10% xylitol), 6.77 (20% xylitol), 7.74 (20% sorbitol), and 7.37 (20% sucrose).
Behaviour (functional findings):
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
4 170 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Remarks on result:
other: 10% in diet
Dose descriptor:
LOAEL
Effect level:
6 770 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Remarks on result:
other: 20% in diet

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in litter size and weights:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
no effects observed in crown rump length

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
6 770 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: no effects at 20% (6770 mg/kg), the highest dose tested

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Maternal NOAEL: 4170 mg/kg (10% in diet) based on reduced body weights at 20%
Foetal NOAEL: 6770 mg/kg (20% in diet), highest dose tested
Executive summary:

Xylitol was investigated for embryotoxic and teratogenic action on the rabbit according to the guidelines of the American FDA and of the British CSM. The substance was administered orally to rabbits from the 7thto the 19thday of gestation (day 1 = the first 24 hours after copulation) by incorporation into the diet. Dietary concentrations of 2, 5,10, and 20% xylitol were employed, and further groups of rabbits received diets containing 20% of either sorbitol or sucrose, for comparative purposes. 20% feed admix corresponds to an average daily intake of 6.8-7.8 g/kg bw.

 

All doses of xylitol as well as sorbitol and sucrose were well tolerated by the pregnant does. The reproductive process was not impaired in any of the experimental groups. The measured parameters (litter size, foetal weight, resorption rate, etc.) were within the normal range and showed no difference between he treated groups and controls which could be attributed to the treatment of xylitol or the other sugars. Detailed examination for skeletal and other abnormalities showed no indications of any embryotoxic or teratogenic effect of xylitol in the rabbit at concentrations up to 20% in the diet. This corresponds to an average daily intake of 6770 mg/kg bodyweight, approximately, during the period of treatment. Weight development during the treatment period was retarded in the does at 6770 mg/kg. The maternal NOAEL is 4170 mg/kg and the developmental NOAEL is 6770 mg/kg, the highest dose tested.