TOXICOLOGICAL EVALUATION OF CERTAIN FOOD ADDITIVES
WHO FOOD ADDITIVES SERIES 10
The evaluations contained in this document were prepared by the
Joint FAO/WHO Expert Committee on Food Additives*
Rome, 21-29 April 1976
Food and Agriculture Organization of the United Nations
World Health Organization
*Twentieth Report of the Joint FAO/WHO Expert Committee on Food
Additives, Geneva, 1976, WHO Technical Report Series No. 599, FAO Food
and Nutrition Series No. 1.
SUCROSE ESTERS OF FATTY ACIDS, AND SUCROGLYCERIDES*
Explanation
These substances have been evaluated for acceptable daily intake
for man by the Joint FAO/WHO Expert Committee on Food Additives in
1969 and 1973 (see Annex I, Refs No. 20, p. 115 and No. 33, p. 284).
Since the previous evaluation, additional data have become
available and are summarized and discussed in the following monograph.
The previously published monograph has been expanded and is reproduced
in its entirety below.
BIOLOGICAL DATA
SUCROSE MONOPALMITATE
BIOCHEMICAL ASPECTS
The ester linkage is only hydrolyzed with great difficulty by
pancreatic or intestinal enzymes in vitro (Berry & Turner, 1960).
The presence of sucrose monopalmitate had no effect on the absorption
of Ca45 from aqueous CaCl2 solution when given intragastrically to
six dogs. Estimation of blood activity up to six hours later showed
only a delayed peak in the activity/time curve compared with plain
aqueous CaCl2. Repetition in five dogs with induced impaired fat
absorption secondary to ligation of the pancreatic duct showed higher
Ca45 absorption postoperatively from the control solution and test
solution containing sucrose monopalmitate. Giving intramuscular
300 000 USP units of vitamin D decreased the blood levels in both
cases but less so for the solution containing sucrose monopalmitate
(Tudisco, 1961a, b).
* Sucrose fatty acid esters are the mono, di and triesters of
sucrose with edible fatty acids. They may be prepared as such from
sucrose and the methyl and ethyl esters of edible fatty acids usually
in the presence of a solvent. Another procedure is to react edible
fats or oils and sucrose to produce a mixture of sucrose esters of
fatty acids and mono- and diglycerides called "sucroglycerides". Both
are usually produced in the presence of a solvent. The article of
commerce may be further specified as to total fatty acid, total
sucrose, total glycerol, ash, chloride, soap and moisture. Two
different sets of chemical specifications have been developed by the
Joint FAO/WHO Expert Committee on Food Additives.
Everted rat intestine preparations were incubated in a medium
containing 5mM purified sucrose monopalmitate. Approximately 10% of
the ester in contact with mucosa was hydrolyzed. Only 0.2% of the
ester was detected in serosal fluid but 4% of palmitic acid penetrated
to the serosa (Murata et al., 1976).
The concentrations of sucrose monopalmitate and palmitic acid
were determined in arterial and portal vein blood of rats 30, 60, 120
and 180 minutes following an oral dose of 500 mg/kg bw of purified
sucrose monopalmitate. No ester could be detected in blood samples but
the palmitic acid content of arterial blood was raised between 30-120
minutes (Murata et al., 1976).
TOXICOLOGICAL STUDIES
Acute toxicity
Intragastric administration of 0.1 g to rats had no effect on
the osmotic fragility of erythrocytes but intravenous administration
to mice of 0.5 g/kg bw produced considerable haemolysis (Tudisco,
1965a, b).
An oral dose totalling 20 000 mg/kg, administered in 10 equally
divided doses at 30 to 60 minute intervals produced no deaths in five
rats (Tokita, 1958).
An oral dose totalling 20 000 mg/kg, in 10 equally divided doses
at 30 to 60 minute intervals, produced no deaths in 10 mice (Tokita,
1958).
Short-term studies
Rat
In another experiment groups of 10 male or female rats were given
0, 1, 2, 3, 5, 10 and 25% sucrose monopalmitate for 100 days. At the
2% and 3% levels (female rats used only) there was marginal reduction
in body weight gain of the test groups. At the 5% level there were
several deaths preceded by diarrhoea, weight gain was reduced but food
efficiency high compared with controls. The 10% and 25% groups did not
survive the first week and had white semi-soft faeces. Histopathology
showed nothing of note (Tudisco, 1961a, b).
Rats given daily oral doses of 100, 200, 1000, 2000 mg/kg for
60 days grew normally and had normal organ weights (brain, heart,
stomach, liver, spleen and kidney) at necroscopy (Hara, 1959).
Dog
Twelve male and 12 female young beagles were divided in four
groups of three male and three female animals and fed a diet
containing 0, 0.3, 1.0 and 3.0% sucrose monopalmitate for two years.
Appearance, behaviour, appetite, elimination, body weight gains,
urinalysis, organ weights, histopathology and organ function studies
revealed no gross abnormalities or differences between test and
control groups related to the compound (Paynter & Crews, 1966).
Long-term studies
Rat
Groups of 25 male and 25 female albino rats were fed dietary
levels of 0.3, 1 and 3% sucrose monopalmitate for two years. The
control groups consisted of 50 males and 50 females. There was one
death in the first six months, a male in the 3% test group, apparently
caused by bilateral pyelonephritis. Periodic records of body weight
and food consumption disclosed a suggestion of lowered bodyweight
gains in the 3% test groups. The first half-year growth rate and the
78-week mean body weights of the 3% group females were significantly
lowered; food consumption in the 3% group males was significantly
lower at 26 weeks and slightly below that of controls in the first
year; and the food efficiency of the 3% group females was slightly
lowered in the first quarter year. No other differences were noted
between the groups on the basis of observation of general appearance
and behaviour, mortality and tumour incidence, haematology and
urinalysis of pooled samples at 1, 3, 6, 12, 18 and 24 months, and
sacrifice with necropsy, organ weight measurement and histological
examination of tissues of five males and five females from each group
at three months and of all survivors at 24 months (Paynter, 1966).
A concurrent reproduction study over three generations was
carried out on groups of eight male and 16 female rats over 22 months
using sucrose monopalmitate at 0 or 1% of the diet. The parent
generation (P) was kept for the whole study. Mean body weight gain,
survival and food consumption of the P generation showed no
significant differences between controls and test group. The P
generation was mated twice to give F1A and F1B filial generations.
Of the F1A generation 10 male and 10 female pups were sacrificed for
autopsy and the rest discarded. No significant findings were detected.
The fertility index of the F1B test groups was significantly lower
than that for the control groups due to adverse environment and
unrelated to the test substance. Gestation, live birth and lactation
indices were comparable between test and control groups. The F1B
litter had slightly more frequent small weak pups with blue marks on
the body but all survivors later developed normally. Sixteen F1B
females and eight F1B males were mated twice to produce F2A and F2B
filial generations, all other F1B animals were discarded including
the 24 F1B animals used for mating. The F2A and F2B generation
developed normally both in control and the test group. Growth of the
males in the test group was slightly higher and for the females
slightly lower otherwise control and test group showed no significant
abnormalities. The F2A litter and all animals of the F2B litter
except 16 females and eight males were discarded, the latter being
mated twice to produce the F3A and F3B filial generations. Five
males and five females of these 24 F2B animals were sacrificed. Gross
and histopathology of all major organs revealed no significant
abnormalities. The F3A and F3B litters showed no difference from
previous generations or between the test group and controls. Mean
litter size, physical appearance and growth of litter were comparable
among test and control groups for each generation and among the three
filial generations. The autopsies and histological examinations were
normal (Paynter, 1965).
SUCROSE MONOSTEARATE
BIOCHEMICAL ASPECTS
Surviving intestine has been shown capable of hydrolyzing the
glucosidic linkage of sucrose monostearate to glucose and fructose at
one-quarter of the rate of sucrose hydrolysis. alpha-amylase and
gluco- or fructo-invertase were unable to hydrolyze sucrose
monostearate. Liver homogenate, but not intestinal mucosa homogenates,
could oxidize sucrose monostearate. Only pancreatic juice was able to
hydrolyze the ester linkage to a moderate degree (Berry & Turner,
1960).
TOXICOLOGICAL STUDIES
Acute toxicity
Mouse
An oral dose of 20 000 mg/kg, administered in 10 equally divided
doses at intervals of 30 to 60 minutes, produced no deaths in 10 mice
(Tokita, 1958).
Rat
An oral dose totalling 20 000 mg/kg administered in 10 equally
divided doses at intervals of 30 to 60 minutes produced no deaths in
10 rats (Tokita, 1958).
Short-term studies
Rat
Rats were given daily oral doses of 100, 200, 1000 and 2000 mg/kg
for 60 days without deleterious effect on weight gain or relative
organ weights (brain, heart, stomach, liver, spleen, kidney) (Hara,
1959).
Long-term studies
None available.
MIXED PALMITIC AND STEARIC ACID ESTERS OR SUCROSE
TOXICOLOGICAL STUDIES
Short-term studies
Rat
Daily doses of 3000, 4000 and 6000 mg/kg were administered orally
to rats in groups of six for 33 days. There were no effects on weight
gain and no histopathology (Tokita, 1959a, b).
SUCROSE MONOOLEATE
BIOCHEMICAL ASPECTS
Rat liver homogenates hydrolyzed the ester bond almost completely
in 60 minutes without attacking the glucosidic linkage. alpha-amylase,
lipase and dog pancreatin are similarly effective. Invertases only
released 3 to 6% of the existing glucosidic links. Intestinal mucosa
and liver homogenates were able to oxidize 0.1% of the substrate
(Berry & Turner, 1960).
TOXICOLOGICAL STUDIES
Acute toxicity
No data available.
Short-term studies
Rat
Groups (unstated number) of rats received 0, 2, 5, 10 and 20% of
ester in their diet for six months. Only at the 20% level (0.09%
dimethylformamide) was there retardation of growth compared with
controls. Soft faeces or mild diarrhoea occurred initially with 10%
and 20% test diets but animals later become tolerant. On return to
normal diet there was rapid regaining of full body weight (Oshima &
Kajiwara, 1960).
Long-term studies
None available.
SUCROSE MONOLINOLENATE
BIOCHEMICAL ASPECTS
Five rats with either their thoracic duct cannulated or having a
bile and lymph fistula were given intragastrically an aqueous
suspension of sucrose ester or linolenic acid. Linolenic acid
increased in the lymph within 24 hours. No linolenic acid was found in
the bile of animals given the ester during 48 hours and it appeared
only slowly after 72 hours in controls given linolenic acid. Rats with
both bile and thoracic duct fistula showed a rise in the lymph content
of linolenic acid within 24 hours and none in the bile even after 72
hours. Thus lymphatic absorption of the linolenic acid moiety was
demonstrated. The percentage linolenic acid absorbed was the same
whether the sucroester of the free acid was administered (Tudisco &
Turner, 1963).
TOXICOLOGICAL STUDIES
Acute toxicity
None available.
Short-term studies
None available.
Long-term studies
None available.
PALM OIL SUCROSE ESTERS
BIOCHEMICAL ASPECTS
When aqueous suspensions of palm oil sucrose esters were given
intragastrically to rats after pyloric ligation there was no evidence
of digestive hydrolysis up to eight hours. In vitro use of
intestinal juice on a substrate containing 1% palm oil sucrose esters
for six hours produced only negligible hydrolysis of the ester and
glucosidic linkage. A metabolic balance study on 35 male and female
rats using food containing 5% palm oil sucrose esters and determining
the amounts of ester given, the residue in stomach, gut, excreta and
left over in food showed some 75% as unaccounted and, therefore,
metabolized. Skeletal development as a measure of calcium absorption
was determined by measuring growth of rat tails in two groups of 10
rats receiving daily 1 ml of 50% palm oil sucrose esters suspension
for 10 weeks. Tail growth was more rapid in the test group during the
first four weeks but later was not significantly different from
controls (Balea et al., 1966).
TOXICOLOGICAL STUDIES
Acute toxicity
Animal Route LD50 mg/kg bw Reference
Rat Oral >30 000 Balea, 1963
Mice receiving intravenous doses of 1-2 g/kg bw showed no
haemolysis (Tudisco, 1965a, b).
Short-term studies
Rat
Groups of eight rats received 5% or 10% palm oil sucrose esters
in their diet for 150 days without showing any deleterious effect on
body weight gain (Tudisco & Chiancone, 1965). Three groups of 10 rats
were fed diets containing 10 g/kg bw lard with either 0, 50 ml/kg bw
10% palm oil sucrose esters and 10 ml/kg bw 50% palm oil sucrose
esters for six weeks. No gastrointestinal disturbances were seen. Test
groups showed a slightly greater body weight gain and slightly larger
fat deposits in their carcass compared with controls (Balea et al.,
1966). When the compound was fed to groups of eight males and eight
female rats at 0, 3, 5, and 10% levels of their diet for 100 days no
difference was noted between tests and controls regarding general
condition. Test groups showed a slightly greater weight increase.
Haematology, organ weights and gross autopsy were comparable in tests
and controls, while histopathology revealed no abnormalities in the
test group (Balea, 1963). In a similar experiment with 8-10 female
rats per group, these received 0, 5 and 10% of the compound in their
diet for 100 days. No abnormalities related to the test substance were
detected in general appearance, food consumption, body weight gain,
food efficiency, haematology, gross autopsy findings, histology
(thyroid, liver, adrenal) and biochemistry (plasma and liver
cholesterol, phospholipids, total lipids) only the liver lipids of
test animals were significantly raised (Tudisco, 1963a).
Two groups of 10 rats received 0 or 2% palm oil sucrose esters in
their diet for three-and-a-half months. No deleterious effect was
noted in mating, reproduction, litter number and litter size. Pups
gained weight satisfactorily during weaning with better performance
in the test group. Lactation was unaffected and no external fetal
abnormalities were seen (Ferrando, 1964).
Long-term studies
Rat
Groups of 15 male or female rats were fed diets containing 0 or
0.5% of the compound for 14 months. No tumours were seen at the end of
13 months nor any growth abnormalities in male rats. Female rats
showed a temporary lowering of growth rate during the eighth to tenth
week. Three animals were examined histologically and no evidence of
abnormality attributable to palm oil sucrose esters was found.
Haematologic finds and blood proteins were comparable in test and
control groups (Chiancone et al., 1963).
Groups of 12 male rats were fed 0 or 10% of the ester as only
source of lipids in their diet for 25 to 28 months. No abnormalities
were found with respect to body weight, general health, mortality,
haematology, plasma proteins and food efficiency. Tumour incidence was
similar in test groups and controls. Visceral abnormalities were
equally distributed (Tudisco & Chiancone, 1965).
A two-generation study was carried out on 15 male and 15 female
rats given 0 and 5 g/kg bw palm oil sucrose esters containing 68 ppm
(0.0068%) of dimethyl formamide daily. The parent generation (P) was
observed for two years. Body weight gain, external appearance and
incidence of tumours were identical to controls. Three male animals
died from intercurrent respiratory disease, three female animals
either died or were sacrificed, the remaining 12 animals survived
24 months. No haematological abnormalities were detected and blood
proteins had a normal electrophoretic pattern. At autopsy no
significant lesions were found in the test group which were not also
found in the controls. Histology was similarly comparable for tests
and controls. Five male and five female rats (P generation) were mated
after nine months' treatment to produce 23 F1 generation animals. The
F1 generation was observed for 21 months. Body weight gain was
similar to controls and no spontaneous deaths or illnesses occurred.
Five male and five female survivors were autopsied after 21 months. No
evidence of malignant tumours or other significant abnormalities was
found which differed from the controls. Five male and five female F1
animals were mated after nine months to produce 30 F2 generation
animals. The F2 generation was observed for 14 months. All litter
mates gained weight identical to controls. Five male and five female
F2 animals were autopsied after 14 months. No malignant tumours or
other pathological conditions were found which did not also occur in
the controls. No other significant abnormalities were seen. Seven from
50 animals examined showed hepatic hyperfunction. No evidence of any
adverse effects on fertility and fetal development was seen (Mosinger,
1964a).
LARD AND TALLOW SUCROSE ESTERS
BIOCHEMICAL ASPECTS
Each of four dogs aged five to six years were given
intragastrically 1131-labelled triolein in olive oil, oil/water
emulsion and oil/water emulsion containing lard sucrose esters and the
plasma activity determined as a measure of absorption. Each animal
served as its own control, the administrations being separated by
seven-day intervals. With olive oil peak absorption occurred after six
hours with a fall between six and eight hours. The oil/water emulsion
gave inconsistent patterns while oil/water emulsion with lard sucrose
esters had a peak absorption of four hours and less abrupt fall during
four to eight hours. Lard sucrose esters did not appear to interfere
with intestinal fat absorption (Tudisco, 1961a, b).
Calcium absorption using Ca45Cl2 was tested in eight dogs using
aqueous CaCl2 solution. CaCl2 in oil/water emulsion and CaCl2 in
oil/water emulsion with lard sucrose ester. All doses were
administered intragastrically and blood activity determined
subsequently. Each dog acted as its own control. The presence of lard
sucrose ester had no consistent effect on Ca45 absorption (Tudisco,
1961a, b).
Each of four dogs aged one year received simultaneous
1131-labelled triolein and Ca45Cl2 either in oil/water emulsion and
oil/water emulsion with lard sucrose esters. All doses were given
intragastrically. Lard sucrose esters had no effect on the pattern of
absorption. Experiments were repeated in young and old dogs with
ligated pancreatic duct and administering intragastrically
1131-labelled triolein in oil/water emulsions or oil/water emulsions
with lard sucrose ester. Pre- and post-operative blood samples showed
that no significant effect was exercised by the ester (Tudisco, 1961a,
b).
As much as 100 g fat as lard sucrose ester may be administered to
dogs and human subjects without producing plasma turbidity or an
increase in excreted faecal fat (Berry & Turner, 1960). Humans have
been maintained for short periods on this material as the sole source
of dietary lipid (Tudisco, 1965a, b).
TOXICOLOGICAL STUDIES
Acute toxicity
Rats tolerated doses of 5 g/kg bw lard sucrose ester every two
hours up to a total of 15 g; 10 g/kg bw every two hours up to a total
of 30 g produced diarrhoea and death from overdistension. Single doses
of 3.8 g/kg bw in dogs had no effect. Rabbits tolerated 2.0 g/kg bw
single doses without deleterious effects (Tudisco & Chiancone, 1965).
Intragastric administration of 1 g to rats or 20% of the ester in
their diet produced no osmotic fragility of erythrocytes. Rabbits
given 3-6 g intragastrically also showed no osmotic fragility rise.
Intravenenous administration of 1-2 g/kg bw to mice had no haemolytic
effect (Tudisco, 1965a, b).
Single oral doses of lard sucrose ester (48% sucrose ester, 12%
triglycerides, 21% diglycerides, 19% monoglycerides) were administered
to four adult dogs aged four to six years as follows: 56 g lard
sucrose ester, after a long interval 40 g refined lard, after a long
interval 56 g lard sucrose ester and 40 g refined lard. Thus each
animal served as its own control. No gastrointestinal disturbances,
toxic symptoms or abnormal findings were discovered when blood sugar,
total lipid, glyceride, cholesterol, phospholipid and percentage fatty
acid composition were estimated. Plasma turbidity was lowest in the
dog receiving the ester alone (Tudisco, 1963b).
Short-term studies
Rat
Groups of 12 animals received 0, 5%, 10% and 25% lard sucrose
ester daily in their diet for 15 days without adverse effects except
that the test group at the 25% level showed reduced body weight gain
(Tudisco & Chiancone, 1965).
In another experiment groups of 12 rats each received for 200
days 5%, 10% and 25% lard sucrose ester in their diet while controls
received 3.6%, 7.7% and 18% lard. Body weight gain was reduced at the
10% and especially the 25% levels. Food consumption and food
efficiency were reduced at both the 10% and 25% level. No abnormal
findings were seen in haematology, and clinical tests (blood glucose,
plasma lipids, plasma proteins, liver lipids). There were no undue
gastrointestinal symptoms. Only test animals at the 25% level were
autopsied; there were no significant abnormalities in organ weights or
histology of kidney, spleen, thyroid and adrenals. The liver showed
frequent "steatosis" (Anonymous, 1961). When male rats were given a
diet containing 25% lard sucrose ester or 18% lard and 7% sucrose for
200 days there was no adverse effect noticeable in body weight gain,
food consumption, survival. Clinical findings which could not be
ascribed to high fat diet were absent. Only the total liver fat of
tests and controls was raised while the blood cholesterol of controls
was also higher. Autopsy revealed no significant organ changes
(Tudisco, 1967).
Long-term studies
Rat
Groups of nine to 11 male rats were fed 3.6% lard, 5% and 10%
lard sucrose ester in their diet as only source of lipids for 24 to 28
months. No abnormalities were found with respect to body weight,
general health, mortality or haematology. Tumour incidence was similar
in test groups and controls. Visceral abnormalities were equally
distributed (Chiancone et al., 1963; Tudisco & Chiancone, 1965).
A two-generation study was carried out starting with 15 male and
15 female rats receiving 0 and 5 g/kg bw lard sucrose ester containing
52 ppm (0.0052%) of dimethyl formamide for two years. The parent
generation was observed for two years. Four females died or were
sacrificed for reasons unrelated to the test substance while 11
animals survived. Three males died from respiratory disease. After 24
months autopsies showed no malignant tumours or other conditions to be
present which did not also occur to a similar extent in controls.
Haematological findings were normal and electrophoresis or plasma
proteins showed nothing unusual. Five males and five females were
mated after nine months to produce 35 F1 generation pups. All F1
animals gained weight satisfactorily without spontaneous deaths and
were kept for 21 months. Five males and five females were examined
after 21 months without showing any malignant or other tumours not
also present equally in the controls. No abnormal findings were seen.
Five males and five females of the F1 generation were mated after
nine months to produce 32 F2 generation animals. The F2 generation
survived for 14 months without showing any abnormalities as regards
body weight gain or mortality. Five male and five female F2 animals
were autopsied at 14 months without showing any unusual tumours of
benign lesion or other condition not occurring equally frequently in
the controls. No adverse effects were seen on fertility or fetal
development (Mosinger, 1964b).
Groups of 15 male or female rats were fed diets containing 0 or
0.5% tallow sucrose ester for 14 months. No tumours were seen at the
end of 13 months nor any growth abnormalities in male rats. Female
rats showed a temporary lowering of growth rate during the eighth to
tenth week. Three animals were examined histopathologically and no
evidence of abnormality attributable to the ester was found.
Haematology and blood protein investigation showed comparable results
in tests and controls. No animal died (Oshima & Kajiwara, 1960).
MIXED PALMITIC AND STEARIC ACID ESTERS OF SUCROSE
TOXICOLOGICAL STUDIES
Long-term studies
Mouse
Groups of 21 male and 21 female ddY mice were fed on a diet
containing 0, 0.3 or 3.0% sucrose ester for 76 weeks. No significant
differences in average growth rate or food intake were found. Organ
weights and haematological indices of five animals of each sex of each
group showed no significant differences between test and control
animals. Serum alkaline phosphatase activity was raised in males on
the 3% diet and blood triglyceride levels were three times the control
level in males on the 0.3% and 3.0% 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 micropathological findings in three controls, three 0.3% and 10
3.0% animals showed no evidence of abnormalities caused by exposure to
the sucrose ester (Murata et al., 1976).
Comments
In evaluating these compounds, their metabolic fate in animals
and probable metabolic fate in man were considered. Studies on sucrose
monopalmitate have demonstrated it is likely to be completely
hydrolyzed in the lumen and mucous membrane of the gastrointestinal
tract. Palmitic acid but not unhydrolyzed ester was found in arterial
blood following a massive oral dose of the ester. However, the
available metabolic studies are not adequate to reveal the pathways of
all products. The long-term feeding studies in rats on some
representative compounds are adequate. A two-year study in dogs has
been reported on sucrose monopalmitate. A long-term study in mice on
mixed palmitic/stearic acid esters of sucrose was inadequate for
evaluation.
EVALUATION
Level causing no toxicological effect
Rat: 10 000 ppm (1%) in the diet equivalent to 500 mg/kg bw.
Estimate of acceptable daily intake for man
0-2.5* mg/kg bw.**
* In sucroglycerides, dimethyl formamide (DMF) should be limited to
10 mg/kg. DMF should not be detected in sucrose esters of fatty acids.
** Temporary.
FURTHER WORK OR INFORMATION
Required by June 1979.
1. Studies on individual sucrose esters to demonstrate their likely
sites and degree of hydrolysis.
2. A six-month toxicological study in a non-rodent species on a
sucrose ester other than sucrose palmitate.
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Sugars Co., Gramercy, La., USA
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report from Dept of Pharmacology, Toho University, submitted to
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Co. Ltd, Japan
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acid ester 80% and sucrose palmitic acid ester 20%). Unpublished
report from Dept of Pharmacology, Toho University, submitted to
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