INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
SUMMARY OF TOXICOLOGICAL DATA OF CERTAIN FOOD ADDITIVES
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 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.
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
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
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
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).
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).
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).
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