INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
SAFETY EVALUATION OF CERTAIN FOOD
ADDITIVES AND CONTAMINANTS
WHO FOOD ADDITIVES SERIES: 44
Prepared by the Fifty-third meeting of the Joint FAO/WHO
Expert Committee on Food Additives (JECFA)
World Health Organization, Geneva, 2000
IPCS - International Programme on Chemical Safety
MISCELLANEOUS SUBSTANCES
gamma-CYCLODEXTRIN
First draft prepared by Dr P.J. Abbott
Australia New Zealand Food Authority, Canberra, Australia
Explanation
Biological data
Toxicological studies: Long-term studies
Observations in humans
Comments
Evaluation
References
1. EXPLANATION
gamma-Cyclodextrin is a ring-shaped molecule made up of eight
glucose units linked by alpha-1,4-bonds. The annular structure of
gamma-cyclodextrin forms a hydrophobic cavity that allows
incorporation and solubilization of a variety of organic molecules,
while the hydrophilic outer surface makes gamma-cyclodextrin
water-soluble. gamma-Cyclodextrin can be used as a carrier for
flavours, sweeteners, and colours. It is also proposed for use as a
carrier for vitamins and polyunsaturated fatty acids and as a flavour
modifier. The estimated three-day average daily intake of
gamma-cyclodextrin when used at a maximum level in 19 foods was 4 g,
and the 90th percentile intake was 7.5 g.
gamma-Cyclodextrin was evaluated by the Committee at its
fifty-first meeting (Annex 1, reference 137), when it concluded that
there were sufficient data to allocate a temporary ADI 'not specified'
but that the results of a study of adverse side-effects in humans
known to have been conducted should be reviewed in order to confirm
the absence of adverse gastrointestinal symptoms at normal levels of
intake. At the present meeting, the Committee reviewed the results of
that study and of a 12-month study of toxicity in rats treated orally,
which had also become available.
2. BIOLOGICAL DATA
2.1 Toxicological studies: Long-term studies
Rats
In a 12-month study of toxicity, four groups of 20 male and 20
female Wistar rats were fed a diet containing g-cyclodextrin at
concentrations of 0, 5, 10, or 20%, equal to time-weighted average
intakes of 2.1, 4.3, or 8.7 g/kg bw per day for males and 2.7, 5.4, or
11 g/kg bw per day for females. The animals were observed daily for
signs of toxicity, and ophthalmoscopic examinations were performed at
the start of the study and at 13, 26, and 39 weeks. Body weights were
measured weekly for 13 weeks and then monthly. Food consumption was
recorded weekly, and food conversion efficiency was calculated during
the first 13 weeks. The intake of gamma-cyclodextrin was determined as
a time-weighted average. Water consumption was recorded in weeks 1,
12, 24, 36, and 50. Haematological, clinical chemical, and urinary
parameters were measured in 10 rats of each sex per group at various
times during treatment. At the end of the study period, the animals
were killed, their organs were weighed, and their tissues were
examined by light microscopy. Groups of 10 animals of each sex were
screened for neurotoxicity by observation and in a battery of tests.
Indicators of immunotoxicity were derived from routine measurements.
No clinical signs of toxicity were seen during the study in any
group. One female rat at the high dose died under narcosis during
blood collection on day 95. The ophthalmoscopic examinations showed no
remarkable findings. The body weights of male rats at the intermediate
and high doses were slightly lowered throughout the study, but the
difference was statistically significant only in the first week. The
slightly lowered body weight of females at the high dose was not
statistically significant. The food intake of males was relatively low
only in the first week of the study and, overall, there was no
difference in food intake or food conversion efficiency among the
groups. All treated males showed a slight but significant decrease in
water consumption, but a significant decrease in females was seen only
at the intermediate and high doses at certain times. Haematological
parameters were not altered as a result of treatment, although some
sporadic changes were seen in prothrombin time and in differential
leukocyte counts. Some clinical chemical parameters showed
statistically significant changes that may have been
treatment-related, but they were not progressive and did not occur in
all animals. Males and females at the high dose had increased alkaline
phosphatase activity in week 14, and males at this dose had increased
alanine aminotransferase activity in weeks 14 and 26. Ornithine
carbamoyl transferase activity was increased in males at the high dose
in week 14. The creatinine concentration was increased in females at
the high dose in weeks 14 and 26 and in those at the intermediate dose
in week 14. The triglyceride concentration was decreased in males at
the high dose in week 14, while that of phospholipids was decreased in
males and females at the high dose in week 14. The changes in
triglycerides, phospholipids, and alkaline phosphatase may have been
due to fermentation of the unabsorbed carbohydrate. Overall, the
clinical chemical changes observed were considered not to be of
toxicological significance. Slight changes seen in renal urinary
volume were considered not to be related to treatment. A slight but
significant increase in the absolute and relative weights of the
caecum seen in males at the high dose was likely to be due to the
presence of incompletely digested carbohydrates in the gut. The
relative weight of the testis was also significantly increased in
males at the high dose, but gross and histopathological examination
revealed no treatment-related abnormalities. Screening for
neurotoxicity and immunotoxicity did not provide any evidence for such
toxicity. Thus, a dietary concentration of 20% gamma-cyclodextrin was
tolerated by rats with no toxic effects. The minor changes reported
were considered to be the result of incomplete digestion of
gamma-cyclodextrin in the gut (Lina, 1999).
2.2 Observations in humans
In a study of possible adverse side-effects, the gastrointestinal
response of exposure of two group of six men and six women aged 18-24
(mean weights, 73 and 62 kg, respectively) to gamma-cyclodextrin was
examined after they had eaten 100 g of plain yoghurt containing 0 or 8
g of maltodextrin or gamma-cyclodextrin within 15 min as a mid-morning
snack. The yoghurts bore only code numbers to identify the content,
and the design was a double-blind, randomized, controlled, cross-over
study. Information on the frequency of passing faeces, the incidence
of watery, normal, and hard faeces, and the occurrence of belching,
nausea, vomiting, abdominal distension, borborygmia, abdominal cramp,
and flatulence was collected 3-4 and 7-8 h after consumption. After
one week, the people in each group were given the alternative
substance in yoghurt and the information on symptoms was collected
again.
None of the subjects withdrew from the study because of
gastrointestinal symptoms or for any other reason. Dietary records
were collected for each person during each consumption period in order
to check that the dietary restrictions were being followed. None of
the participants drank less than 300 ml per day of milk or fresh
juice, and none had eaten products containing polyols or other
alternative sweeteners. None reported any change in their dietary
habits or smoking habits during the study. None reported taking
laxatives, anti-diarrhoetics, antibiotics, steroids, or any prescribed
medication during the study. The women continued to take contraceptive
pills if they were already doing so.
The participants were asked to note the number of visits to the
toilet after they had eaten the yoghurt and the consistency of the
faeces passed. No difference in the number of visits to the toilet or
in the consistency of the faeces after consumption of maltodextrin or
gamma-cyclodextrin was seen at either 3-4 h or 7-8 h. The faeces were
rated as normal, hard, or watery. Subjects were also asked to describe
any gastrointestinal symptoms that might have been related to
consumption of the yoghurt containing gamma-cyclodextrin or
maltodextrin and were told to rank their symptoms as normal (none),
slightly more than normal (mild), noticeably more than normal
(moderate), or considerably more than normal (severe). At 3-4 and 7-8
h after consumption, there was no difference between the subjects who
had eaten yoghurt containing gamma-cyclo-dextrin or maltodextrin in
the ranking of symptoms of belching, nausea, vomiting, bloating,
borborygmia, colic, or flatulence. After intake of maltodextrin, five
subjects reported a total of 12 symptoms, 11 of which occurred in the
first 3-4 h. After intake of gamma-cyclodextrin, five subjects
reported a total of seven symptoms, all of which occurred in the first
3-4 h. There was no statistically significant difference in the
incidence of the individual symptoms between those given maltodextrin
and those given gamma-cyclodextrin. The total symptom scores after
administration of gamma-cyclodextrin and maltodextrin were compared by
assigning a numerical value of 0-3 to gastrointestinal symptoms and a
numerical value of 1-3 for the number of visits to the toilet to pass
watery faeces. When the total symptom scores for 3-4 h and 7-8 h were
analysed by paired t tests, there was no significant difference,
although there was a trend towards an increase in total scores with
maltodextrin. Further statistical analysis of the data on symptoms in
the Fisher exact test for probability and the test for order effect
indicated no significant difference in total symptom scores at 3-4 or
7-8 h after consumption of 8 g maltodextrin or gamma-cyclodextrin
(Koutsou & Storey, 1998).
3. COMMENTS
In a 12-month study of toxicity, rats were given diets containing
up to 20% gamma-cyclodextrin. Minimal changes were seen and only at
the high dose, probably as a result of the presence of a large amount
of an osmotically active substance in the large intestine. These
changes were considered to be transient and not of toxicological
significance.
A study of adverse effects in humans indicated that
gamma-cyclodextrin was tolerated at concentrations up to 8 g per
serving, equal to 0.11 g/kg bw, which caused no symptoms of
gastrointestinal discomfort.
4. EVALUATION
On the basis of the studies described above and information
received at the fifty-first meeting, the Committee allocated an ADI
'not specified'1 to gamma-cyclodextrin.
1 ADI 'not specified' is a term applicable to a food component of
very low toxicity which, on the basis of the available chemical,
biological, toxicological, and other data, the total dietary intake of
the substance arising from its use at the levels necessary to achieve
the desired effect and from its acceptable background in food, does
not, in the opinion of the Committee, represent a hazard to health.
For this reason and for those stated in the evaluation, the
establishment of an ADI expressed in numerical form is deemed
unnecessary.
5. REFERENCES
Koutsou, G.A. & Storey, D.M. (1998) The gastrointestinal response of
young adults following consumption of maltodextrin and
gamma-cyclodextrin incorporated into plain natural yogurt. Unpublished
report from Nutritional Sciences, Department of Biological Sciences,
University of Salford. Submitted to WHO by Bioresearch Management and
Consulting Ltd.
Lina, B.A.R. (1999) Chronic (1-year) toxicity study with
gamma-cyclodextrin in rats. Unpublished study from TNO Nutrition and
Food Research Institute, The Netherlands. Submitted to WHO by
Bioresearch Management and Consulting Ltd.