SUCROSE ESTERS OF FATTY ACIDS AND SUCROGLYCERIDE
1. EXPLANATION
These substances were evaluated for an Acceptable Daily Intake by
the Committee in 1969, 1973, 1976 and 1980 (Annex 1, Refs 17, 32, 41,
53) and toxicological monographs were prepared on each occasion. In
1980, a Group Acceptable Daily Intake of 0-10 mg/kg bw/day was
allocated.
The present Committee considered the consequences of changing the
specifications to include the solvent residues dimethyl sulfoxide
(DMSO), isobutanol and methyl ethyl ketone. The Committee noted that
no ADI had been established for these solvents. (Isobutanol and
methyl ethyl ketone were reviewed by the twenty-third meeting of the
Committee in 1979; in both cases it was concluded that the data
available were insufficient for evaluation of the compounds for an
ADI. Dimethyl sulfoxide has not previously been evaluated by the
Committee).
Additional toxicological data on sucrose esters of fatty acids
were available and are summarized and discussed in the following
monograph addenda.
MIXED PALMITIC AND STEARIC ACID ESTERS OF SUCROSE
2. BIOLOGICAL DATA
2.2 Toxicological studies
2.2.2 Short-term studies
2.2.2.1 Dogs
Groups of three male and three female beagle dogs received in
their diet sucrose esters of mixed stearic and palmitic acids at
concentrations of 0.3%, 1% or 3% daily for 26 weeks. A separate
control group of three male and three female dogs maintained on diet
alone served as control. During the entire study, the group mean
daily intake of the esters was equal to 102, 345 and 1091 mg/kg bw/day
in male dogs and 104, 367 and 1139 mg/kg bw/day in female dogs in the
three corresponding treatment groups. No animals died during the
study. Body weights, food and water consumption, clinical chemistry,
hematology and urinalysis were essentially within normal ranges.
Gross and microscopic examinations of tissues and major organs
revealed no significant changes that could be attributed to the
ingestion of the esters (Chesterman et al., 1979).
2.2.3 Long-term/carcinogenicity studies
2.2.3.1 Mice
Groups of 21 male and 21 female ddY mice were fed on a diet
containing 0, 0.3 or 3% sucrose ester for 76 weeks. No significant
differences in average growth rate or food intake were found. Organ
weights and hematological indices of five animals of each sex of each
group showed no significant differences between test and control
animals. Serum alkaline phosphatase activity was higher in males on
the 3% diet and blood triglyceride levels were three times the control
level in males on the 0.3% and 3% diets. However, no such differences
were found in females and the significance of the findings is
uncertain in view of the small number of animals examined. Mortality
was said to be unaffected but data on this were not provided. Gross
and micro-pathological findings in three controls, three 0.3% and ten
3.0% animals showed no evidence of abnormalities caused by exposure to
the sucrose ester (Murata et al., 1976).
PALM OIL SUCROGLYCERIDE
2.2.2 Short-term studies
2.2.2.1 Rats
Groups of five male and five female CD rats were given diets
containing 0, 10% or 20% sucroglyceride for 13 weeks. The intakes
were equal to 5.38 and 6.15 g/kg bw/day for males and females of the
lower dose group, and 11.03 and 12.03 g/kg bw/day for males and
females of the higher dose group, respectively. In female, but not
male, animals of both treatment groups, food intake was significantly
lower than controls throughout the study. Weight gains were reduced
for rats of both sexes in the higher treatment group, and to a lesser
extent in the lower group but the decrease in weight gain was only
statistically significant in top dose group males. Water intake of
the high dose males during week 4 was significantly elevated relative
to controls but no such differences were apparent in weeks 8 or 13.
There was a dose dependent reduction in liver weight in animals of
both sexes. There were no histopathological changes related to
treatment (Hunter et al., 1980).
2.2.2.2 Dogs
A preliminary study was performed to establish suitable dietary
levels for a 13-week study in beagle dogs. Three pairs of one male
and one female dog received diets containing 0, 10 or 20%
sucroglyceride in their diets. Due to enforced variations in protocol
during the course of the study, direct comparison between pairs was
complicated by other variables but treatment with sucroglyceride in
semi-synthetic diet at 10 or 20% levels resulted in reduced body
weight gain or slight weight loss. Animals in the higher dose group,
whose treatment continued for a longer period, showed some signs of
recovery. Deterioration in coat condition was noted in both dogs in
the higher dose group but a marked improvement was apparent following
the addition of corn oil to the diet (Chesterman et al., 1980a).
Four groups of five male and five female beagle dogs received
sucroglyceride in the diet at levels of 0, 5, 10 or 20% for 132 weeks;
two animals of each sex were observed for a further 8 weeks after
cessation of treatment. At termination, a bone marrow smear was
prepared from each animal and organs were weighed. Comprehensive
histopathological examinations were performed on all animals.
Animals in the 20% dose group showed adverse effects on body
weight and two males in the 10% group also showed adverse effects on
body weight which were probably treatment-related. During the post-
treatment observation period some animals from the treated groups
showed an increased body weight gain, most marked in the animals which
had received 20% sucroglyceride. No ophthalmological or hematological
changes due to treatment were observed and no abnormalities were seen
on urinalysis. Elevated alkaline phosphatase activity was seen in a
number of animals of the 20% dose group, returning to normal 4 weeks
after treatment ceased. SGPT levels were increased in the highest
dose group but fell during the post-treatment period. Cholesterol
values for control animals were higher than usual but treatment with
20% sucroglyceride led to lower cholesterol levels, and cholesterol
values in previously treated animals tended to rise when treatment was
discontinued. No gross abnormalities due to treatment were seen at
autopsy and all organ weights were within normal limits although, when
adjusted for final body weight, the mean kidney weights for all groups
receiving sucroglyceride were significantly greater than control
values. In addition, the mean heart weights of the 10% and 20% groups
were also elevated after 13 weeks dosing but no significant
differences remained in animals 8 weeks after treatment was
discontinued. The only histopathological effects noted were in the
livers of female animals treated with 20% sucroglyceride. After 13
weeks marked numbers of vacuolated centrilobular hepatocytes were
observed, all of which showed moderate to marked fat deposits. The
liver of one female killed 8 weeks after cessation of treatment with
20% sucroglyceride showed a minimal number of vacuolated centrilobular
hepatocytes with trace fat deposits (Chesterman et al., 1980b).
2.2.3 Long-term/carcinogenicity studies
2.2.3.1 Rats
Four groups of 50 male and 50 female CD weanling rats were given
diets containing 0, 5%, 10% or 20% sucroglyceride for 106 weeks
(females) or 108 weeks (males). The intakes averaged over the whole
treatment period were equal to 1.59, 3.37 and 7.70 g/kg bw/day for
males, and 1.86, 4.01 and 9.25 g/kg bw/day for females in the three
respective dose groups. Satellite groups of 15 animals of each sex
were included for interim blood anlaysis; these animals were
sacrificed after 78 weeks.
All rats killed in extremis or found dead during the course of
the study were subjected to macrosocopic autopsy examination and,
where possible, tissues were examined histologically. At terminal
autopsy, organ weights were recorded. Complete histopathological
examination was performed on each group.
Food intake in rats receiving 20% sucroglyceride was greater than
controls, particularly during the first 52 weeks but body weight gain
of treated male, and to a lesser degree female, animals showed a dose-
related decrement in the early part of the study and up to week 78 in
the top dose group. Food efficiency was significantly reduced in the
20% dose group and in males of the 10% dose group. Water intake in
the highest dose group was elevated during weeks 5, 13, 26 and 40 and,
for females only, during week 51; thereafter no treatment dependent
difference was observed. Clinical signs during the study included
brown staining of the fur, pale fecal pellets and poor grooming in all
treatment groups. Mortality in the treated animals was lower than in
controls, probably associated with the reduced body weight. The only
consistent difference in hematological parameters between control and
high dose animals was a marginally elevated platelet count at weeks
25, 51 and 77; subsequent (week 78) examination of all dose groups did
not conclusively indicate any treatment-related effect and no changes
were seen at week 102. During weeks 6, 12 and 25, serum alkaline
phosphatase and SGPT were higher in the top dose group than in
controls but the levels were similar to controls at subsequent
analyses. A transient elevation of SGPT was observed in the
intermediate dose group only during week 6. Treatment-related
elevated serum potassium concentrations were observed at weeks 25 and
51 in females of the top dose group and in both sexes at week 77, but
the differences were small and were not noted in week 102. Urinalysis
did not reveal any treatment-related changes other than a decrease in
urine volume, which was possibly related to treatment in female rats
of the top dose group during weeks 51, 77 and 78.
No treatment-related abnormalities were seen in the
ophthalmoscopic examinations or at autopsy. Small but statistically
significant differences were seen in some organ weights but these were
generally not dose dependent and histological examination did not
reveal any abnormalities related to these differences. A dose-
dependent increase in the incidence of basophilic hepatocytes was
observed in females only. These changes are commonly observed in old
rats of this strain. There was no treatment-related effect on the
incidence of any tumour type or on the total number of tumours per
group (Hunter et al., 1982).
3. COMMENTS AND EVALUATION
Modifying of the specifications was considered by the Committee
for these substances manufactured by a process using the solvents
DMSO, isobutanol and/or methyl ethyl ketone. It was noted that an ADI
(or provisional intake) had not been established for these solvents
but that DMSO and isobutanol occur naturally in the diet and methyl
ethyl ketone has been identified as a product of intermediary
metabolism. The levels of these solvents in foods as consumed arising
from residues in sucrose esters of fatty acids which comply with the
revised specifications are insignificant relative to naturally
occurring levels in the diet, and there is no reason to suppose that
they present a hazard.
The Committee also reviewed new toxicological studies on a palm
oil sucroglyceride, including a long-term carcinogenicity study in
rats and short-term studies in rats and dogs.
It was concluded that sucrose esters of fatty acids manufactured
by a process using DMSO, isobutanol and/or methyl ethyl ketone as
solvents, and the palm oil sucroglyceride, could be included in the
previously established group ADI of 0-10 mg/kg bw/day for sucrose
esters of fatty acids and sucroglycerides.
5. REFERENCES
CHESTERMAN, H., ANDREW, J.E. & HEYWOOD, R. (1980a). Celynol MSPO 11
preliminary dietary toxicity study in beagle dogs. Unpublished Report
No. 2307 from Huntingdon Research Centre submitted to WHO by Rhône
Poulenc, Paris, France.
CHESTERMAN, H., BROWNING, J., HEYWOOD, R., JAMES, R.W., STREET, A.E.,
PRENTICE, D.E., OFFER, J.M. & JOLLY, D.W. (1980b). Celynol MSPO 11
oral toxicity study in beagle dogs. Unpublished Report No.
RBNP/141/80255 from Huntingdon Research Centre submitted to WHO by
Rhône Poulenc, Paris, France.
CHESTERMAN, H., HEYWOOD, R., ALLEN, T.R., STREET, A.E., READ, R. &
GAPINATH, C. (1979). Sucrose ester of mixed stearic and palmitic acid
dietary study in beagle dogs. Unpublished report from Huntingdon
Research Centre submitted to Ryoto Company Ltd., Tokyo, Japan,
submitted to WHO by Rhône Poulenc, Paris, France.
HUNTER, B., RICHMOND, G., WATSON, M., HEYWOOD, R., STREET, A.E.,
GIBSON, W.A., PRENTICE, D.E., READ, R.M., CHERRY, C.P. & GAPINATH, C.
(1982). Celynol MSPO 11 igenic and toxic effects in dietary
administration to rats. Unpublished report No. RNP/139/82995 from
Huntingdon Research Centre submitted to WHO by Rhône Poulenc, Paris,
France.
HUNTER, B., WATSON, M., OWEN, R.A., GIBSON, W.A., PRENTICE, D.E., &
WOODHOUSE, R.N. (1980). Celynol MSPO 11: Preliminary assessment of
toxicity to rats in dietary administration for 13 weeks. Unpublished
Report No. RNP/138/79689 from Huntingdon Research Centre submitted to
WHO by Rhône Poulenc, Paris, France.
MURATA, T., KIMURA, R., AKIMOTO, T., SATO , M. & ITO, K. (1976). Study
on chronic toxicity of a sucrose ester of fatty acids. Unpublished
report of the Shizuoke College of Pharmacy and Hokkaido Institute of
Pharmaceutical Sciences, Japan, submitted to WHO by Rhône Poulenc,
Paris, France.
See Also:
Toxicological Abbreviations