Toxicological Reasearch on Sorbitol

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INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

WORLD HEALTH ORGANIZATION

SUMMARY OF TOXICOLOGICAL DATA OF CERTAIN FOOD ADDITIVES

AND CONTAMINANTS

WHO FOOD ADDITIVES SERIES NO. 13

The data contained in this document were examined by the

Joint FAO/WHO Expert Committee on Food Additives*

Rome, 3-12 April 1978

Food and Agriculture Organization of the United Nations

World Health Organization

* Twenty-second Report of the Joint FAO/WHO Expert Committee on Food

Additives, Geneva, 1978, WHO Technical Report Series No. 631

SORBITOL

Explanation

Sorbitol was evaluated at the seventeenth session of the Joint

FAO/WHO Expert Committee on Food Additives in 1973. Since the previous

evaluation new data were made available and are summarized below.

BIOLOGICAL DATA

Long-term studies

Rat

A total of 75 male and 75 female Sprague-Dawley rats of the CD

strain were included in each dosage group. Each group consisted of 50

male and 50 female rats for tumorigenic evaluation, 15 male and 15

female rats for laboratory investigation, and 10 males and 10 females

for interim sacrifice of 5 male and female rats at 26 and 52 weeks.

All animals were derived from parents exposed to the respective test

diets. The test diets contained 0 or 20% sorbitol, or 20% sucrose. The

diet of all groups was maintained at 20% carbohydrate supplementation

through the use of rice starch in the 0% groups. Protein was

maintained constant in all groups through the addition of casein. For

the 20% sucrose groups, the carbohydrate was increased 5% per week

until the desired level was attained.

A lowered body weight gain was recorded through the first 78

weeks of the study for males and females in the 20% sorbitol group.

Coupled with the decreased body weight gain was an impairment of food

utilization efficiency for the 20% sorbitol group. A higher water

intake was seen in both male and female 20% sorbitol rats and was

associated with increased urine excretion. No other treatment effect

was observed on mortality, food intake, or clinical signs.

Urinalysis indicated increased urine volumes for the 20% sorbitol

All other urinalysis and haematological parameters, were within normal

limits for sorbitol, sucrose, or rice starch. Sucrose treatment

increased cholesterol in males at 52 weeks and males and females at 78

weeks. No increase in cholesterol was noted at terminal sacrifice for

the sucrose group. Both sucrose and sorbitol increased insulin levels

at 26 and 52 weeks but returned to normal at 78 weeks. At terminal

sacrifice the sorbitol group had normal insulin levels but the sucrose

males had elevated insulin levels. No other consistent treatment-related effects were noted on blood biochemistry for 20% sorbitol, 20% sucrose, or 20% rice starch.

At autopsy lower absolute and relative thyroid weights were

recorded for males and females in the 20% sorbitol and 20% sucrose

groups. Histological examination of the animals indicated no

treatment-related effects on the major organ systems. However, the

incidence of both unilateral and bilateral hyperplasia of the adrenal

medulla was increased significantly for both males and females in the

20% sorbitol group. Only unilateral hyperplasia was seen in the

controls. Macroscopic examination indicated that 20% sorbitol caused

caecal enlargement in both males and females. No other treatment-related gross pathological changes were noted (Hunter et al., 1978).

Dog

Sorbitol 0 or 20% was administered in the diet of pure-bred

beagle dogs (eight male and eight female animals per group). Another

group received 20% sucrose for comparative purposes. Rice starch was

included in the diets of the controls so that the diet consisted of

80% normal diet and 20% carbohydrate. After 52 weeks there was an

interim sacrifice of two males and two females per group. The study

was terminated at 104 weeks.

Mortalities, gross clinical signs, body weight, food consumption,

food conversion ratio, water consumption, ophthalmoscopic signs,

neurological signs and dental changes were determined. Haematology,

clinical chemistry and urinalysis were conducted at -1, 12, 26, 38,

50, 64, 76, 89 and 100 weeks.

There was an increase in total serum protein, body weight, and

organ weight in the 20% sorbitol groups as compared to the 0% group.

There was a slight increase in the utilization of food in the 20%

sorbitol group. There were no other significant findings (Heywood et

al., 1977).

Reproduction studies

Rat

A three-generation study was conducted in Sprague-Dawley (CD)

specific pathogen-free rats with 20 males and 20 females respectively

per group. Each group received the test material by dietary

administration. A control group received 20% rice starch. One group

received 20% sorbitol and another group received 20% sucrose

ad libitum.

The pups of the F1a, F2a, and F3a generations were weighed

and killed at four days and examined for sex determination of

abnormalities. The F1b, F2b, and F3b pups were weighed, sexed, and

litters culled to eight per dam. Pups were weighed at 8, 12, and 21

days post partum. Observations were made to determine litter size,

litter and pup weights, pup mortality, and gross abnormalities. Gross

and histopathological observations were conducted on rats of the F3b

generation, which were killed at three weeks of age. There were two

deaths of parent animals of the F2b generation, among nine deaths

which occurred in the study, which were attributed to chance

occurrence. Marked inhibition of food consumption occurred.

Suppression of weight gain was noted. Mating performance and pregnancy

rate were not affected. Gestation period was increased (23-24 days) in

36% of litters of the first mating versus 16.1% of controls and

23.2% of second mating versus 7.3% of controls. At terminal necropsy

caecal enlargement was noted.

Litter size was decreased (total and viable pups) as was litter

weight, but with increased mean pup weight. No terata were observed

grossly. Statistical analysis of organ weights showed a number of

statistically significant differences in absolute organ weights which

reflected body weight differences as shown by co-variance analysis.

Statistically significant decreased absolute thyroid weight did not

reflect body weight changes. There was also lower adjusted heart

weight and higher adjusted ovary weight. Distention of the caecum was

observed in the F3b generation. Two rats derived from the same litter

showed an absence of thymic tissue, cortical lymphocyte depletion and

changes in a number of other tissues. The relationship to treatment is

unknown. Two males and one female showed an absence of extramedullary

haematopoiesis in the liver (Palmer et al., 1978).

Special studies

Teratology

Rat

Groups of 31-33 CFT strain-specific pathogen-free female weanling

rats received test diets containing either/or 20% rice starch

(control), 20% sorbitol or 20% sucrose for comparison. The test diets

were administered for five weeks before mating. Parameters

investigated included food consumption, body weight change, and mating

performance. Litter data included implantations, pre-implantation and

post-implantation loss, litter and mean foetal weights, major

malformations and minor abnormalities, and skeletal variants.

There was a low overall pregnancy rate (approximately 50%) for

all groups. No major malformations were noted. No skeletal variations

were attributable to treatment. Other parameters were within normal

limits (Palmer and Bottomley, 1977).

Rabbit

Groups of 20 yellow-silver does of a closed, randomized, outbred

rabbit strain, aged three to four months (2.7-3.0 kg) received test

diets ad libitum containing 20% sorbitol or 20% sucrose baked into

the food pellets. Males were untreated. The test diets were

administered from days seven to 19 of gestation. Parameters

investigated were body weights of does, litter data including

implantations and pre-implantation loss, litter size and post-implantation loss, litter and mean foetal weights, major and minor

anomalies and skeletal variants. Young were incubated for 24 hours to

determine neonatal viability. Gross and X-ray examinations were

conducted to discover external and skeletal malformations. Alizarin

red technique was utilized where necessary. The Wilson technique was

used to examine for malformations of brain and skull. The incidence of

skeletal malformations was similar in treatment and control (sucrose)

groups. No major visceral abnormalities were noted. Food intake was

decreased during the period of sorbitol administration. No other

treatment effects were noted (Hummler, 1978).

REFERENCES

Heywood, R., Chesterman, H., Allen, T. R., Sheet, A. E., Kennedy, S.

J., Majerd, S. K. and Prentice, D. E. (1977) Xylitol toxicity studies

in the beagle dog. Unpublished report from Huntingdon Research Centre,

submitted to World Health Organization by F. Hoffman La Roche Co.,

Ltd., Basle, Switzerland

Hummler, H. (1978) Reproduction study in rabbits in oral

administration of Ro 06-7045-Xylitol, Phase II - Teratology study.

Unpublished company report submitted to the World Health Organization

by F. Hoffman La Roche Co., Ltd., Basle, Switzerland

Hunter, B., Colley, J., Street, A., Heywood, R., Prentice, D. and

Magnusson, G. (1978) Xylitol tumorigenicity and toxicity study in

long-term dietary administration to rats. Unpublished report from

Huntingdon Research Centre, submitted to World Health Organization by

F. Hoffman La Roche Co., Ltd., Basle, Switzerland

Palmer, A. K. and Bottomley, A. M. (1977) Effect of xylitol during a

modified teratology study in rats. Final report. Unpublished report

from Huntingdon Research Centre, Huntingdon, Cambridgeshire, England;

submitted to the World Health Organization by Hoffman La Roche Co.,

Ltd., Basle Switzerland

Palmer, A. K., Bottomley, A.M., Wight, D. G. D. and Cherry, C. P.

(1978) Effect of xylitol on reproductive functions of multiple

generations in the rat. Final report. Unpublished report from

Huntingdon Research Centre, Huntingdon, Cambridgeshire, England;

submitted to the World Health Organization by F. Hoffman La Roche Co.,

Ltd., Basle, Switzerland

See Also:

Toxicological Abbreviations

Sorbitol (FAO Nutrition Meetings Report Series 40abc)

Sorbitol (WHO Food Additives Series 5)

Sorbitol (JECFA Evaluation)