MALTITOL AND MALTITOL SYRUP
First draft prepared by
Dr J.L. Herrman
International Programme on Chemical Safety
World Health Organization
Geneva, Switzerland
1. EXPLANATION
Hydrogenated glucose syrups were evaluated at the
twenty-fourth, twenty-seventh, and twenty-ninth meetings of the
Committee (Annex 1, references 53, 62, and 70). A temporary ADI was
allocated at the twenty-seventh meeting, with the requirement that
the results of a lifetime feeding study be submitted. At the
twenty-ninth meeting the Committee concluded that the previously-
requested lifetime feeding study was not necessary because
hydrogenated glucose syrups are fully metabolized to natural body
constituents. An ADI "not specified" was allocated, which applied
to hydrogenated glucose syrups that met the established
specifications.
At the thirty-third meeting (Annex 1, reference 83) the
specifications for hydrogenated glucose syrups were revised and
retitled "maltitol syrup". The Committee confirmed that the ADI
"not specified" previously allocated to hydrogenated glucose syrups
applied to maltitol syrup meeting the revised specifications. In
addition, an ADI "not specified" was allocated to maltitol, which
was specified as having a minimum 98% purity.
A combined long-term toxicity/carcinogenicity study in rats
using a commercial product has now been completed, which is
summarized in this monograph addendum.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
No new information.
2.2 Toxicological studies
2.2.3 Long-term toxicity/carcinogenicity study
2.2.3.1 Rats
In a combined long-term toxicity/carcinogenicity study a
commercial preparation containing approximately 87% maltitol was fed
to Crl:CD(SD)BR male and female rats at doses equal to 0, 0.5, 1.5,
or 4.5 g/kg bw/day. [The highest dose corresponded to an average of
about 10% of the commercial product in the diet.] Rats were
maintained on these diets for 52 weeks in the long-term study (20
animals/sex/group) or for 106 weeks in the carcinogenicity study (50
animals/sex/group), after which they were killed.
In both experiments animals were examined daily for signs of
ill health or behavioral changes. Food consumption and body weights
were recorded immediately prior to the start of administration of
the test compound, at weekly intervals for the first 12 weeks, and
then every 4 weeks until the end of the experiment. Animals were
inspected twice daily for mortality, and those found dead or
sacrificed "in extremis", as well as those killed at the end of the
study, were subjected to complete necropsies and organs were
removed, weighed, and histologically examined. Caecum and colon
diameters were measured in the long-term study.
Ten animals/sex/group were subjected to ophthalmoscopic
examination prior to the start of treatment and at weeks 13, 26, and
52 in the long-term study. Haematological examinations, blood
chemistry tests, and urinalyses were performed on 10
animals/sex/group at weeks 14, 26, and 51 in this study.
Results of the long-term toxicity study
No animals in the mid- or high-dose groups died. Three animals
in the control group and four in the low-dose group died, most of
which were caused by accidents; none of these deaths was related to
treatment. No treatment-related clinical signs were noted.
Treatment had no effect on body weight. Sporadic differences in
food consumption were noted in males, with no apparent trend. Mean
food consumption was significantly less in high-dose females at 12
and 52 weeks than in the other groups. No treatment-related eye
abnormalities were observed. Sporadic differences were observed in
haematological parameters but, except for a decrease in leukocytes
in mid-dose females, none of these differences were observed at all
observation times. Occasional significant differences were observed
in blood chemistry and urinalysis parameters, but none of these
differences were major and most of them were not dose-related. No
treatment-related effects were observed after gross or
histopathological examination. A significant increase in the caecum
diameter of high-dose males was observed, which was due to higher
values in 3 out of 20 rats. A trend toward a decrease in caecum
diameter was observed in low- and high-dose females when compared to
controls. The NOEL in this study was the highest dose tested, 4.5 g
commercial product/kg bw/day (Conz & Fumero, 1989).
Results of the carcinogenicity study
Mortality was not affected by treatment. No treatment-related
clinical signs were noted. Body weights of all treated males and of
high-dose females were comparable to those of animals in their
respective control groups. Mean body weights of low- and mid-dose
females were slightly lower than those of controls, which reached
statistical significance only occasionally, including weeks 100 and
104. Food intake was not affected by treatment. No gross
pathological treatment-related changes were observed in any organs,
including the intestine and caecum. Occasional masses or nodules of
the adrenal glands were observed, but they were not dose-related and
the highest frequencies were within the control incidences observed
in 2-year carcinogenicity studies in rats of the same strain
performed in the same laboratory.
Histopathological changes related to treatment were observed in
the adrenal gland. The findings are summarized in Table 1. Both
benign and malignant phaeochromocytomas, when considered either
separately or together, occurred with higher incidence in both males
and females in the high-dose group when compared with the control
group. In addition, slight to moderate medullary hyperplasia
occurred at an increased frequency in all treated groups when
compared to controls. The trend test showed a significant increase
in females, with a significant difference between high-dose females
and the control group.
Table 1. Histopathological changes observed in the adrenal gland in
the carcinogenicity study in rats
Sex/ M F
Dose Level1 0 0.5 1.5 4.5 0 0.5 1.5 4.5
Phaeochromocytoma
Benign 8 4 10 20 2 2 4 10
Malignant 6 12 4 10 2 2 2 4
Total 14 16 14 30 4 4 6 14
Medullary
hyperplasia 24 32 38 32 14 22 24 34
1 50 adrenal glands/sex/group were examined except for the
mid-dose males, in which 49 were examined.
An increased incidence of mammary gland adenocarcinomas was
observed in females: 4/50 (8.0%), 2/43 (4.6%), 8/50 (18.6%,
P=0.054), and 10/50 (20.0%, P=0.044) in the controls and low-, mid-,
and high-dose animals, respectively. Although the trend was
significant (P=0.013), the incidences at the two highest doses were
barely significantly different than the controls. Increased
incidences of mammary gland adenomas or fibroadenomas were not
observed. The incidences of mammary gland adenocarcinomas were
within the historical control incidences of mammary gland
adenocarcinomas in female rats in the same laboratory in 7 studies
carried out between 1978 and 1989, which have ranged from 0 to 22%
(Conz & Maraschin, 1992).
3. COMMENTS
At its present meeting, the Committee reviewed a recently
completed combined long-term toxicity/carcinogenicity study, in
which a commercial preparation containing approximately 87% maltitol
was administered in the diet of Sprague-Dawley rats at levels equal
to 0, 0.5, 1.5, or 4.5 g/kg bw/day for either 52 weeks (toxicity
study) or 106 weeks (carcinogenicity study). No adverse effects
were observed in the toxicity study. In the carcinogenicity study,
histopathological changes related to treatment were observed in the
adrenal gland, which included increased incidences of both benign
and malignant phaeochromocytomas in male and female rats in the
high-dose group and an increased frequency of slight to moderate
adrenal medullary hyperplasia in all treated groups. A slightly
increased incidence of mammary gland adenocarcinomas was observed in
female rats at the 1.5 and 4.5 g/kg bw/day doses, however the
incidence was within the range reported in the historical control.
Increased incidences of mammary gland adenomas or fibroadenomas were
not observed, and the combined incidences of mammary gland
adenocarcinomas and adenomas were not increased. For these reasons,
the Committee did not consider the increase in mammary gland
adenocarcinomas to be related to treatment.
4. EVALUATION
Previous Committees have taken cognisance of adrenal medullary
lesions in rats associated with high intake levels of poorly-
absorbed polyols when allocating ADIs to them (Annex 1, reference
62). In line with earlier conclusions regarding the significance of
these lesions, the Committee confirmed the ADI "not specified" for
maltitol and maltitol syrup that meet the specifications established
at the present meeting. The Committee recommended that the
information database on adrenal medullary hyperplasia and
phaeochromocytomas associated with polyols and other poorly-absorbed
carbohydrates be reviewed and that mechanisms of the appearance of
these lesions and their toxicological significance be assessed at a
future meeting.
5. REFERENCES
CONZ, A. & FUMERO, S. (1989). Combined chronic
toxicity/carcinogenicity study in Sprague Dawley Crl:CD(SD)BR rats
treated with the test article MALBITR (crystal powder)
administered at the dosages of 0, 0.5, 1.5, and 4.5 g/kg/day in the
diet: chronic toxicity study. Unpublished report from RBM, Istituto
di Richerche Biomediche, Ivrea, Italy. Submitted to WHO by Cerestar
Research & Development, Vilvoorde, Belgium.
CONZ, A. & MARASCHIN, R. (1992). Combined chronic
toxicity/carcinogenicity study in Sprague Dawley Crl:CD(SD)BR rats
treated with the test article MALBITR (crystal powder)
administered at the dosages of 0, 0.5, 1.5, and 4.5 g/kg/day in the
diet: carcinogenicity study. Unpublished report from RBM, Istituto
di Richerche Biomediche, Ivrea, Italy. Submitted to WHO by Cerestar
Research & Development, Vilvoorde, Belgium.
See Also:
Toxicological Abbreviations