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


    First draft prepared by Dr P.J. Abbott

    Australia New Zealand Food Authority, Canberra, Australia

    Biological data
         Toxicological studies: Long-term studies
         Observations in humans


         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.


    2.1  Toxicological studies: Long-term studies


         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

         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).


         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

         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. 


         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


    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.


    See Also:
       Toxicological Abbreviations
       Cyclodextrin, gamma- (WHO Food Additives Series 42)