These compounds have been evaluated for acceptable daily intake
    for man by the Joint FAO/WHO Expert Committee on Food Additives in
    1969, 1974 and 1979 (see Annex I, Refs. 20, 34 and 48). Toxicological
    monographs were prepared in 1969, 1974 and 1978 (see Annex I, Refs.
    20, 35 and 49).

         Since the previous evaluation, additional data have become
    available and are summarized and discussed in the following monograph.
    The previously published monographs have been expanded and are
    reproduced in their entirety below.



         Curcumin at 0.1% in the diet lowered the serum and liver
    cholesterol levels of rats fed cholesterol at 1% in their diet for 7
    weeks. Faecal output of bile acids was increased in rats fed curcumin
    with or without added cholesterol. Cholesterol excretion was also
    enhanced by feeding curcumin (Rao et al., 1970).

    Absorption, distribution and metabolism

         Five male Sprague-Dawley rats were given by gavage a dose of
    1 g/kg of curcumin suspended in arachis oil. Between 67-87% of the
    dose was eliminated in the faeces within 72 hours. Excretion was
    highest in the initial 48 hours. Urinary excretion was negligible.
    Three hours after gavage, curcumin was detected in the plasma of 1 of
    4 animals. Biliary concentration of curcumin was 1 µg/ml after 30
    minutes and remained stable throughout the experiment. The amount
    collected in the bile during 3 hours was less than 0.0006% of the
    dose. About 0.015% of the administered curcumin was accumulated in the
    liver, kidneys and body fat after 3 hours. Perfusion of curcumin
    through the liver resulted in a transitory increase in bile flow; 10%
    of the dose was excreted in the bile within 3 hours. Of the curcumin
    excreted in the bile, 49% was in the conjugated form. Curcumin
    was rapidly metabolized when added to hepatocytes or microsomal
    suspensions - concentrations of up to 5 µg/ml were mostly metabolized
    within 30 minutes. The metabolites were not identified. Because of the
    poor absorption, rapid metabolism and excretion of curcumin it is
    unlikely that substantial concentrations of curcumin occur in the body
    after ingestion (Wahlstrom & Blennow, 1978).

         Male wistar rats weighing 150-200 g were given by gavage 400 mg
    of a suspension of curcumin in water containing 0.1% Tween 20. About
    40% of the dose was excreted unchanged in the faeces over a 5-day

    period; excretion tapered off after the first 3 days. The remaining
    60% of the curcumin was assumed to have been absorbed. Curcumin was
    not detected in the urine. However, the influence of curcumin
    administration was noticed in the increased excretion of conjugated
    glucuronides and sulfates. Negligible amounts of curcumin were found
    in the blood, liver and kidney. The authors concluded that curcumin is
    probably undergoing transformation even as it is being absorbed from
    the gut (Ravindrath & Chandrasekhara, 1980).

         Male Sprague-Dawley rats (250-300 g) were dosed orally with
    14C-labelled curcumin (0.6 mg in a 60% DMSO solution). Eighty-nine
    per cent. of the administered 14C radioactivity was excreted in the
    faeces and 6% in the urine within 72 hours. Biliary excretion of
    14C-labelled curcumin was measured after i.v. administration; 85% of
    the radioactivity was found in the bile from cannulated rats after
    6 hours. The major biliary metabolites were glucuronides of
    tetrahydrocurcumin and hexahydrocurcumin, minor biliary metabolites
    were dihydroferulic acid and ferulic acid (Holder et al., 1978).

         In another study, groups of 4 male albino rats of the Wistar
    strain were starved for 24 hours and then given oral doses of 400, 80
    or 10 mg of [3H] curcumin suspended in water containing 0.1% Tween
    20. The major route of elimination of the label was the faeces, the
    urinary excretion was very low (4-1% in 12 days) regardless of the
    dose. With 10 mg (50 mg/kg) and 80 mg (400 mg/kg) [3H] curcumin most
    of the label was excreted in 72 hours, while with 400 mg (2 g/kg)
    considerable amounts of the label were present in the tissues after 12
    days (about 60% of the label had been excreted). Regardless of the
    dose, the absorption of curcumin remained in the range of 60-66%. As
    the majority of the label was excreted in the faeces, biliary
    excretion is thought to take place. Furthermore, only about a third of
    the excreted radioactivity was present as curcumin, indicating
    biotransformation of the absorbed curcumin (Ravindranath &
    Chandrasekhara, 1982).

         Studies of the absorption of curcumin carried out in vitro
    with everted rat intestinal sacs indicated curcumin undergoes
    transformation during absorption from the intestine (Ravindrath &
    Chandrasekhara, 1981).


    Special studies on mutagenicity

         Extracts of curcumin, prepared by crushing the rhizomes of
    curcumin and diluting the extract with water, caused abnormalities in
    the metaphase state of division of root tip cells of Alluim cepa.
    The predominant type of aberration produced was chromosome breakage.
    In addition, other effects observed included C-mitosis, somatic
    segregations, binucleate cells and multipolar anaphases (Abraham et
    al., 1976).

         Studies on the effect of alcoholic extracts of turmeric on
    mammalian cells in vitro, using cells of the Chinese hamster
    (Cencetulus griseus), cell line Don of the cactus mouse
    (Peromyseus eremicus) and of the Indian munja (Muntiacus
    muntjac), and short-term human lymphocyte cultures, showed changes
    in chromosome morphology (chromatid separation, breakage and
    disintegration), as well as mitotic arrest. The incorporation of
    labelled nuclosides into Chinese hamster cells was greatly inhibited
    by concentrations of the turmeric extract that did not cause
    detectable changes in chromosome morphology (Goodpasture & Arrighi,

         Weanling Swiss albino mice fed control diets or diets containing
    0.5% turmeric or 0.015% curcumin for 12 weeks were used in the
    following genetic toxicity studies. Groups of 8 females given curcumin
    or turmeric exhibited no effect in the micronucleus test. Groups of 5
    males and 5 females given turmeric or curcumin showed no cytogenic
    effect on the bone marrow chromosomes. Similarly no effect of the
    substances was noted in a dominant lethal study in which 15 male and
    45 female mice were exposed to the test diets (Vijayalaxmi, 1980).

         In another study, groups of 5 male and 5 female rats were fed
    cooked diets containing 0, 0.05 or 0.5% of turmeric. A fourth group of
    rats was fed an uncooked diet with 0.5% turmeric. The feeding was
    carried out for 12 weeks. No effect was seen on the incidence of
    chromosomal abberrations in their bone marrow (Vijayalaxmi, 1980).

         Turmeric was not active in a test for induction of gene
    conversion in diploid yeast strain B234 (Murthy, 1979; Sankaranayavan
    & Murphy, 1979).

         Curcumin was studied in a battery of short-term assays of genetic
    toxicity. The compound was not active in the following systems:
    Salmonella/microsome test using strains TA-98 and TA-100, sister
    chromatid exchange using hamster lung fibroblasts and human embryo
    fibroblasts, and mutation in silk worms. Positive results were
    reported in the rec assay (B. subtilis) and for chromosomal
    aberrations in hamster lung fibroblasts (Kawachi et al., 1980).

         Neither curcumin nor commercial turmeric oleoresin (containing
    17.5% of curcumin) at the dose levels of 1.28, 6.4, 32.0 and
    160 µg/plate were active in the Salmonella/mammalian microsome test
    using strains TA-1535, TA-100 and TA-98 (Jensen, 1982).

         Turmeric did not induce sex-chromosome loss and dominant lethal
    mutations did not occur when hot water extracts of turmeric were
    administered to male Drosophila (Abraham & Kesavan, 1978).

         Curcumin was reported not to induce chromosome damage in Chinese
    hamster ovary cells in vitro (Au & Hsu, 1979).

    Special studies on pharmacology

         Curcumin administered orally was found to inhibit the
    inflammatory response in several test systems using mice and/or rats
    (Ghatak & Basu, 1972; Srimal & Dhawan, 1973). Oral doses of up to
    160 mg/kg of curcumin failed to prevent phenylquinone-induced writhing
    in mice. An oral dose of 80 mg/kg did not lower the temperature of
    pyretic rats, and blood pressure and respiration in anaesthetized cats
    were not effected by an i.v. dose of 10 mg/kg (Srimal & Dhawan, 1973).

         Groups of 10 albino Porter strain rats received oral doses of 50
    or 100 mg/kg of curcumin administered as a 2% suspension in gum arabic
    daily for 6 days. At the high dose, gastric erosion was reported.
    Changes in the mucin content were reported to be the cause of the
    ulceration. Pretreatment with adrenergic, cholinergic, tryptaminergic
    and histaminergic receptor antagonists provided partial protection
    while metiamide pretreatment completely prevented the development of
    the lesions (Gupta et al., 1980).

         In vitro lipid peroxidation of rat brain preparation showed a
    95% inhibition in the presence of 5.15 × 10-3 M curcumin (Sharma,

    Special studies on reproduction

         The petroleum ether, alcoholic and aqueous extracts of rhizomes
    of Curcuma longa inhibited fertility when administered by gavage on
    days 1-7 of pregnancy at doses of 100 or 200 mg/kg to female albino
    rats. Studies in rabbits indicated doses of up to 200 mg/kg of the
    extracts did not produce anti-ovulatory effects (Garg, 1974).

         Groups of 10 male and 20 female albino rats were fed either
    500 mg/kg/day of turmeric or 60 mg/kg/day of an alcoholic extract of
    turmeric; two comparable groups of rats were used as controls. The
    feeding of this F0 generation was started when the animals were 28
    days of age. The first mating was initiated (1 male + 2 females) after
    12 weeks on the test diet. Lactation was permitted for 3 weeks.
    Following weaning the females were allowed a 2-week rest period before
    remating. The first litters were discarded at weaning. From the second
    litters 10 males and 20 females were selected from each group. This
    F1 generation was raised to maturity and mated like the parent

         The study will be continued up to the F2 generation. So far,
    only results from the first 2 matings in the F0 generation are
    available. There were no significant differences in fertility,
    gestation, viability and lactation indexes, weight and numbers of pups
    in the different groups (WHO, 1980).

    Acute toxicity

    Animal     Route     (g/kg bw)         Reference

    Mouse      Oral          2        Srimal & Dhawan, 1973

    Rat        Oral          5        Wahlstrom & Blennow, 1978

    Short-term studies


         Groups of 5 male and 5 female Wistar rats were fed a diet
    supplying 2.5 g of turmeric/kg bw or 300 mg/kg bw of an alcoholic
    extract of turmeric for 1 day. The animals were then put on control
    diets and observed for another 3 weeks. Compared to controls, no
    effect of treatment was observed on mortality, body weight or weight
    or gross or microscopic pathology of the heart, liver or kidney
    (Shankar et al., 1980).

         Groups of 7 male and 7 female albino rats were fed either basal
    diet or basal diet containing turmeric corresponding to a level of
    500 mg/kg bw per day for 3 months. There were no statistically
    significant differences between the groups as regards gain in body
    weight, haematological parameters studied and relative weight and
    histopathology of liver and kidneys (WHO, 1980).

         Turmeric at 0.3, 1.0 and 10% and curcumin at 0.1, 0.5, 1.0 and
    2.0% were included in a synthetic diet and fed to groups of 10 male
    Wistar strain albino rats for a period of 8 weeks. Ten per cent. of
    turmeric lowered the food efficiency ratio, probably because of
    reduced food intake. No effects were seen in the other dosed groups as
    regards growth, haematological values, total serum protein, albumin,
    globulin and cholesterol. No mortality was seen and no histo-
    pathological changes were observed in the gastrointestinal tract,
    liver, spleen and kidneys (WHO, 1980).


         Groups of 5 male guinea-pigs were fed a diet supplying 2.5 g of
    turmeric/kg bw or 300 mg/kg bw of an alcoholic extract of turmeric for
    1 day. The animals were then maintained on a control diet and observed
    for an additional 3 weeks. Compared to controls, no treatment-related
    effects were observed with respect to mortality, body weight or weight
    or gross or microscopic pathology of the heart, liver or kidney
    (Shankar et al., 1980).

         Groups of 5 adult male guinea-pigs were fed 500 mg/kg bw turmeric
    or 60 mg/kg bw of an alcoholic extract of turmeric along with basal
    diet for 3 months. No deaths were reported during the observation
    period. The test substances did not affect weight gain or the
    haematological parameters studied and relative weights and
    histopathology of liver, kidneys and heart (WHO, 1980).


         Groups of 3 male pups were fed 500 mg/kg bw turmeric or 60 mg/kg
    bw of an alcoholic extract of turmeric in milk for 3 months. No deaths
    were reported during the observation period and the test substances
    did not affect weight gain or the haematological parameters studied
    and relative weights and histopathology of liver, kidneys and heart
    (WHO, 1980).


         Groups of 4 male and 4 female pigs were given 57, 286 or
    1430 mg/kg bw per day of turmeric oleoresin (curcumin content 17.5%)
    for 3 months. Six male and 6 female pigs served as controls. No
    changes were noted on autopsy. Detailed biological, biochemical, and
    histopathological reports are not yet available (Poulsen, 1982).


         Groups of 3 adult female monkeys were fed a diet supplying 2.5 g
    of turmeric/kg bw or 300 mg/kg of an alcohol extract of turmeric for
    3 weeks. Compared to controls, no treatment-related effects were
    observed with respect to mortality, body weight or gross or
    microscopic pathology of the heart, liver or kidney (Shankar et al.,

         Four male monkeys were given 500 mg turmeric/kg bw per day
    concealed in a banana for a period of 9 months. A similar group served
    as a control. No effects were seen in blood and urine analysis and
    histopathology of liver, kidneys, heart, brain, spleen and testes.
    Details are not available (WHO, 1980).

    Long-term studies


         Groups of 20 male and 20 female rats were fed for 420 days on a
    diet containing 0.5% of commercial turmeric with a control group of 15
    males and 15 females. The average life span of the test animals was
    16-1/2 months compared with 17 months for the controls. Growth,
    haematology or reproductive function were undisturbed as well as

    survival of the pups. Passive congestion of the liver was seen equally
    in test and control animals. No tumours were found. A follow-up of the
    first filial generation for their life span showed no abnormalities
    except for 1 benign tumour in a female rat (Truhaut, 1958).


         Two dogs were fed for 1 year on a diet containing approximately
    1% commercial turmeric. No adverse effects were noted compared with 2
    controls (Truhaut, 1958).


         Metabolic data from studies in the rat suggest that some 60% of a
    dose of curcumin suspended in water is absorbed. Suspension in oil may
    increase the absorption. Unchanged curcumin is not detected in the
    urine or blood and does not accumulate in the tissues or fat. Curcumin
    undergoes rapid metabolism and although the metabolites have not been
    completely identified, use of 14C-labelled curcumin has shown that
    major biliary metabolites are glucuronides of tetrahydrocurcumin and
    hexahydrocurcumin; minor biliary metabolites are dehydroferulic acid
    and ferulic acid. Metabolic studies have not been carried out in man.

         Curcumin was shown to be non-mutagenic in a battery of short-term
    genetic assays (including the Ames test, sister chromatid exchange
    using human lung fibroblasts and human embryo fibroblasts). It was
    inactive in a dominant lethal study in mice, and in Drosophila.

         Short-term studies have been carried out with turmeric and an
    alcoholic extract of turmeric in rats, guinea-pigs, dogs and monkeys.
    Although the studies have only been presented in summary no adverse
    effects were apparent. The Committee was informed that the adequate
    short-term feeding study with turmeric in a non-rodent specie
    requested in 1980 is under way, and that a long-term study on curcumin
    is being planned.

         The long-term study in rats, in which single dose levels of
    turmeric were fed, provided the basis for the previous evaluation.

         The single level tested revealed no adverse effects and the true
    no-effect level may well be higher than the test level chosen.
    Turmeric is known to contain an average of 3% curcumin. On this basis
    it is possible to evaluate both turmeric and curcumin temporarily
    until the results of the further studies requested are made available.



    Level causing no toxicological effect

    Rat: 0.5% (= 5000 ppm) in the diet equivalent to 250 mg/kg bw.

    Estimate of temporary acceptable daily intake for man

    0-2.5 mg/kg bw.

    Curcumin (considered to be present in turmeric at 3%)

    Estimate of temporary acceptable daily intake for man

    0-0.1 mg/kg bw.


    Required by 1986


    (1) Adequate short-term feeding study in a non-rodent species.


    (1) Adequate long-term feeding carcinogenicity study in a rodent

    (2) Multigeneration reproduction/teratology study.


    *    Using an oleoresin of turmeric with a well-defined curcumin


    Abraham, S., Abraham, S. K. & Radhammany, G. (1976) Mutagenic
         potential of the condiments, ginger and turmeric, Cytologia
         (Tokyo), 41, 591-595

    Abraham, S. K. & Kesavan, P. C. (1978) Evaluation of possible
         mutagenicity of ginger, turmeric, asafoetida, clove and cinnamon,
         Mutat. Res., 53, 142

    Au, W. & Hsu, T. C. (1979) Studies on the clastogenic effects of
         biologic strains and dyes, Environmental Mutagenesis, 1,

    Garg, S. K. (1974) Effects of Curcuma longa on fertility, Planta
         medica, 26, 225-227
    Ghatak, N. & Basu, N. (1972) Sodium curcumate as an effective anti
         inflammatory agent

    Goodpasture, C. E. & Arrighi, F. E. (1976) Effects of food seasonings
         on the cell cycle and chromosome morphology of mammalian cells in
         vitro with special reference to turmeric, Food Cosmet.
         Toxicol., 14, 9-14

    Gupta, B. et al. (1980) Mechanisms of curcumin induced gastric ulcer
         in rats, Indian J. Med. Res., 71, 806-814

    Holder, G., Plummer, J. & Ryan, A. (1978) The metabolism and excretion
         of curcumin (1,7-Bis-(4-hydroxy-3-methoxyphenyl-1,6-heptadiene-
         3,5-dione) in the rat, Xenobiotica, 8, 761-768

    Jensen, N. J. (1982) Lack of mutagenic effect of turmeric oleoresin
         and curcumin in the Salmonella/mammalian microsome test.
         Unpublished paper submitted to WHO

    Kawachi, T. et al. (1980) Cooperative program on short-term assays for
         carcinogenicity in Japan, IARC Sci. publ., 27, 323-330

    Murthy, M. S. S. (1979) Induction of gene conversion in diploid yeast
         by chemicals: Correlation with mutagenic action and its relevance
         in genetoxicity screening, Mutat. Res., 64, 1-17

    Poulsen, E. (1982) Personal communication to WHO

    Rao, D. S. et al. (1970) Effect of curcumin on serum and liver
         cholesterol levels in the rat, J. Nutr., 100, 1307-1315

    Ravindrath, V. & Chandrasekhara, N. (1980) Absorption and tissue
         distribution of curcumin in rats, Toxicology, 16, 259-265

    Ravindrath, V. & Chandrasekhara, N. (1981) In vitro studies on the
         intestinal absorption of curcumin in rats, Toxicology, 20,

    Ravindaranath, V. & Chandrasekhara, N. (1982) Metabolism of curcumin -
         Studies with [3H] curcumin, Toxicology, 22, 337-344

    Sankaranayavan, N. & Murthy, M. S. S. (1979) Testing of some permitted
         food colors for the induction of gene conversion in diploid
         yeast, Mutat. Res., 67, 309-314

    Shankar, T. N. B., Shantha, N. V., Ramesh, H. P., Murthy, Indira A. S.
         & Sreenivasa Murthy, V. (1980) Toxicity studies on turmeric
         (Curcuma longa): Acute toxicity studies in rats, Indian
         J. Exp. Biol., 18, 73-74

    Sharma, O. P. (1976) Antioxidant activity of curcumin and related
         compounds, Biochem. Pharmacol., 25, 1811-1812

    Srimal, R. C. & Dhawan, B. N. (1973) Pharmacology of deferulolyl
         methane (curcumin) a non-steroidal anti-inflammatory agent,
         J. Pharm. Pharmacol., 25, 447-452

    Truhaut, R. (1958) Resultats des expériences de toxicité à long terme
         effectuées avec les colorants d'origine naturelle, le curcuma et
         l'orseille. C.R. du 18ème Congrès de la Féderation Internationale
         de Pharmacologie, 8-15 September 1958

    Vijayalaxmi (1980) Genetic effects of turmeric and curcumin in mice
         and rats, Mutat. Res., 79, 125-132

    Wahlstrom, B. & Blennow, G. (1978) A study on the fate of curcumin in
         the rat, Acta Pharmacol. et Toxicol., 43, 86-92

    World Health Organization (1980) Unpublished report from Central Food
         Technological Research Institute, Mysore, and National Institute
         of Nutrition, Hyderabad, India (1978), submitted to WHO by Chr.
         Hansens Lab., Copenhagen

    See Also:
       Toxicological Abbreviations
       Turmeric and curcumin (WHO Food Additives Series 6)