4-O-β-D-galactopyranosyl-D-glucitol

Toxicity to reproduction

Administrative data

Endpoint:

multi-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Multigeneration reproduction study of lactitol in rats

Author:

Sinkeldam EJ, Hollanders VM, Woutersen RA, Koëter HBWM, and Bär A

Year:

1992

Bibliographic source:

J. Am. Coll. Toxicol., 11(2): 233-248

Reference 2

Reference Type:

other: Published secondary source

Title:

Lactitol

Author:

WHO/FAO

Year:

1983

Bibliographic source:

WHO/FAO: Expert Committee on Food Additives Summary of Toxicological Data of Certain Food Additives Series 18 (http://www.inchem.org/documents/jecfa/jecmono/v18je10.htm)

Materials and methods

Principles of method if other than guideline:

In a multigeneration reproduction study, lactitol was fed to rats of both sexes throughout 3 successive generations at dietary concentrations of 0, 2, 5, and 10%.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

4-O-β-D-galactopyranosyl-D-glucitol

EC Number:

209-566-5

EC Name:

4-O-β-D-galactopyranosyl-D-glucitol

Cas Number:

585-86-4

Molecular formula:

C12H24O11

IUPAC Name:

4-O-beta-D-galactopyranosyl-D-glucitol

Specific details on test material used for the study:

- Source of test material: D.V. Chemie Combinatie Amsterdam (CCS), Gorinchem, The Netherlands
- Purity: The test material contained 9.67% water and had a purity of >98% on a dry matter basis

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Details on exposure:

- Diets containing 0, 2, 5 or 10% of the test substance over three successive generations.
- Because of the tendency of lactitol to induce diarrhea, animals of the F0 generation were adapted to the ingestion of the sugar.

Duration of treatment / exposure:

3 successive generations

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

2 other: %

Doses / concentrations 2

Dose / conc.:

5 other: %

Doses / concentrations 3

Dose / conc.:

10 other: %

No. of animals per sex per dose:

- Initially each group of parent rats consisted of 20 males and 40 females.
- Number of parent rats per group was then reduced to 10 males and 20 females for the second mating of the F1 generation and the same numbers were maintained in successive generations.

Control animals:

yes, plain diet

other: 20% lactose during F0 generation

Details on study design:

A multigeneration study in Wistar rats was conducted by feeding diets containing 0, 2, 5 or 10% of the test substance over three successive generations. Because of the tendency of lactitol to induce diarrhea, the animals of the F0 generation were adapted to the ingestion of this sugar. Initially each group of parent rats consisted of 20 males and 40 females. Weanling rats of the F1a litters were used to constitute the groups for a chronic toxicity/carcinogenicity study and for a teratogenicity study. The number of parent rats per group was then reduced to 10 males and 20 females for the second mating of the F1 generation and the same numbers were maintained in successive generations. One group of rats, fed a diet with 20% lactose, served as an additional control during the F0 generation.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Overall reproductive toxicity

Reproductive effects observed:

no

Lowest effective dose / conc.:

10 other: % (no reproductive effects at highest dose tested)

Any other information on results incl. tables

Body weights of the F1 male parents were somewhat decreased at the 5% and 10% lactitol levels. No unfavourable effects were observed in fertility, gestation period, gestation index, resorption quotient and litter size. Viability (day 4) and lactation indices were reduced at the 5% and 10% levels in most generations. F3b rats fed 5% or 10% lactitol for four weeks after weaning showed caecum enlargement, which is commonly seen in rodents fed polyols or slowly digestible carbohydrates and was attributed to poor digestibility of lactitol. Growth rate during and after lactation was decreased in pups of groups fed 10% lactitol, which was also attributed to poor digestibility. Treatment-related changes were observed in the livers of F3b males of all treated groups, characterized by a uniform and homogeneous cytoplasm of the liver cells. There was no dose-response relationship and was not accompanied by any other hepatic changes in the lactitol groups. Since this phenomenon was not seen in older rats or after chronic administration of lactitol, it was considered to be a transient manifestation of an altered metabolism in young rats. It is concluded that lactitol administered in the diet to three successive generations of rats at levels up to 10%, has no adverse effects on reproductive performance in either sex. The slight developmental delay which occurred in some generations, has been observed earlier with other polyols and may be attributed to the poor digestibility of these compounds.

Applicant's summary and conclusion

Conclusions:

The reproductive NOEL > 10% of the test substance with no adverse effects on reproductive performance.

Executive summary:

A multigeneration study in Wistar rats was conducted by feeding diets containing 0, 2, 5 or 10% of lactitol over three successive generations. Because of the tendency of lactitol to induce diarrhea, the animals of the F0 generation were adapted to the ingestion of this sugar. Initially each group of parent rats consisted of 20 males and 40 females. Weanling rats of the F1a litters were used to constitute the groups for a chronic toxicity/carcinogenicity study and for a teratogenicity study. The number of parent rats per group was then reduced to 10 males and 20 females for the second mating of the F1 generation and the same numbers were maintained in successive generations. One group of rats, fed a diet with 20% lactose, served as an additional control during the F0 generation. In each generation, two litters were reared until they were at least 3 weeks old.

 

Body weights of the F1 male parents were somewhat decreased at the 5% and 10% lactitol levels. No unfavourable effects were observed in fertility, gestation period, gestation index, resorption quotient and litter size. Viability (day 4) and lactation indices were reduced at the 5% and 10% levels in most generations. F3b rats fed 5% or 10% lactitol for four weeks after weaning showed caecum enlargement, which is commonly seen in rodents fed polyols or slowly digestible carbohydrates and was attributed to poor digestibility of lactitol. Growth rate during and after lactation was decreased in pups of groups fed 10% lactitol, which was also attributed to poor digestibility. Treatment-related changes were observed in the livers of F3b males of all treated groups, characterized by a uniform and homogeneous cytoplasm of the liver cells. There was no dose-response relationship and was not accompanied by any other hepatic changes in the lactitol groups. Since this phenomenon was not seen in older rats or after chronic administration of lactitol, it was considered to be a transient manifestation of an altered metabolism in young rats. It is concluded that lactitol administered in the diet to three successive generations of rats at levels up to 10%, has no adverse effects on reproductive performance in either sex. The slight developmental delay which occurred in some generations, has been observed earlier with other polyols and may be attributed to the poor digestibility of these compounds.