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    CANTHAXANTHIN

    1.  EXPLANATION

         Canthaxanthin is a diketo carotenoid pigment with an orange-red
    colour.  It occurs in the edible fungus, chanterelle  (Cantharellus
     cinnabarinus), in the plumage and organs of flamingoes, the scarlet
    ibis  (Guara rubra) and the roseate spoonbill  (Ajaja ajaja), and in
    various crustacea and fish (trout, salmon) (Haxo, 1950; Fox 1962a, b;
    Thommen & Wackernagel, 1963).

         Canthaxanthin has previously been evaluated for an acceptable
    daily intake at the tenth, eighteenth and thirty-first meetings of the
    Committee (Annex 1, references 13, 35, 77).  At the thirty-first
    meeting the Committee noted that canthaxanthin had been used as a
    direct food additive, as a feed additive, and as an orally-
    administered pigmenting agent for human skin in both pharmaceutical
    and cosmetic applications.  The previous ADI was reduced to 0-0.05
    mg/kg bw and made temporary pending submission of the the following:

    1.   further details of the long-term studies in rats and mice, for
         which summary data were submitted, including ophthalmological
         data where available;

    2.   clarification of the factors that influence pigment deposition in
         the eye, including the establishment of the threshold dose, the
         influence of dose and duration of exposure, the reversibility of
         pigment accumulation, and the investigation of potential animal
         models; and

    3.   clarification of whether pigment deposition is causally related
         to impaired ocular function.

         Since the previous evaluation, further data have become available
    and are summarized and discussed in the following monograph.  The
    previously published monographs have been expanded and are
    incorporated into this monograph.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1.  Absorption, distribution, metabolism and excretion

    2.1.1.1  Rats

         Adult rats were fed a range of oral doses of canthaxanthin (doses
    not specified) for 13 and 20 weeks respectively.  Canthaxanthin
    accumulated in fat and some organs, notably the liver and spleen. 
    Only slight depletion of canthaxanthin from fat occurred over a period
    of 1 month, indicating very slow elimination from this tissue
    (Hoffmann-La Roche, 1986).

         Groups of rats were given daily doses of 0.6, 6 or 60 mg
    canthaxanthin/kg bw daily for five weeks.  Highest organ
    concentrations were found in the liver and spleen, the tissue levels
    corresponding to the three dietary dose levels being 0.9, 12 and 125
    g/g in liver and 2.6, 50 and 67 g/g in spleen, respectively.  Levels
    in other organs were much lower (0.2-1.5 g/g at the highest dose
    level).  After discontinuing administration of canthaxanthin, tissue
    levels in the adrenals and small intestine fell to one-quarter and to
    one-third of their original levels over a period of 2 weeks (adrenals)
    or 1 month (intestine) (Hoffmann-La Roche, 1986).

         When rats were fed daily doses of 50-60 mg canthaxanthin/kg bw
    for 9 weeks, the concentration in the eye remained at approximately
    0.1 g/g with no further accumulation.  After administration of doses
    1.2, 2.0, 3.4, 5.6, 9.8, 16.7 or 28.4 ppm canthaxanthin (equivalent to
    1.4 mg/kg bw/day at the top-dose level) for 20 weeks, maximum
    concentrations in the eye were found to be about 0.01 g/g; the
    residual levels in the eye fell to 0.002 g/g over a 4-week period
    after removal of canthaxanthin from the diet (Hoffmann-La Roche,
    1986).

         Groups of 40 male rats were fed diets containing canthaxanthin at
    concentrations of 1.2, 3.4, 5.8, 9.8, 16.7 or 28.4 ppm.  After 96 days
    8 animals from each dose group were killed and the following tissues
    analyzed for canthaxanthin: plasma, liver, spleen, kidney, heart,
    testicular fat, adrenal fat, intestine, cerebellum, cerebrum, adrenal
    gland, thyroid and eyes.  A further 8 animals from each dose group
    were maintained on canthaxanthin-free diet for periods of 7, 15 and 29
    days respectively prior to analysis.  The remaining 8 animals per dose
    group were maintained on the test diets for a total of 137 days before
    examination.

         Tissue levels of canthaxanthin were more dependent on dietary
    concentration than duration of exposure over the period of 98 to 136
    days.  The highest concentrations reported in tissues in the highest
    dose group were found in spleen (3.2 g/g), small intestine

    (2.63 g/g), liver (1.56 g/g) and adipose tissue (0.79-0.91 g/g);
    levels in cerebrum, thyroid and eyes were low and close to the
    detection limit of the assay.  Depletion of canthaxanthin was obvious
    in most tissues during the withdrawal period except for fat, where
    levels fell slowly if at all.  In the spleen there was a rapid fall
    during the first seven days after withdrawal to about 20% of the
    original concentration but thereafter the depletion was very slow. 
    Conversely, liver concentrations fell quite steeply and continuously
    over the depletion period.  Because the maximum levels achieved were
    so low in brain, thyroid and eyes, it was not possible to follow the
    course of depletion in these tissues with any accuracy (Bausch
     et al., 1987); this appears to be a more complete report of the
    preceding summary (Hoffmann-La Roche, 1986).

         The distribution of the radioactivity derived from 6,7,6',7'-
    14C-canthaxanthin was studied in male rats after oral administration
    of 318-372 nmoles in about 2 ml of a liposomal preparation.  At
    intervals of 4, 24, 48, 96 and 168 hours after dosing, two animals
    were sacrificed and radioactivity was measured in liver, spleen,
    heart, lungs, thymus, kidneys, adrenals, testes, epididymes, skin,
    eyes and brain.  Samples were also taken from muscle, fat, pancreas,
    plasma and erythrocytes, and the contents of the stomach, small
    intestine and colon (including cecum) were also counted separately. 
    On the assumption that enterohepatic circulation had not occurred, the
    amount of the dose absorbed was calculated to be about 8% (range
    4-11%), based on the amount in the tissues and the amount excreted in
    urine.

         The distribution of the absorbed radioactivity was dependent on
    time after dosing.  Excluding the gastrointestinal tract and its
    contents, the highest levels of radioactivity were found in the liver. 
    Levels in the tissues were not reported if these were less than 1% of
    the dose, except for the eyes where the content never exceeded 0.05%
    of the dose.  After 24 hours, about 16% of the administered dose
    remained in the body (including gastrointestinal contents) and this
    fell to 0.3% after 7 days.  It was calculated that, of the absorbed
    radioactivity (assuming no enterohepatic circulation), about half was
    excreted in the urine in 24h and 96% in 7 days (Glatzle & Bausch,
    1988a).

         When rats were fed a diet containing 10 ppm canthaxanthin for
    13-14 weeks, the mean renal fat level was 0.43 g/g, falling to
    0.29 g/g during the four weeks after the cessation of exposure.  When
    administered at a dietary concentration of 100 ppm for 31 weeks,
    canthaxanthin levels in renal fat were 4.3 g/g and fell to 2.2 g/g
    over a withdrawal period of 31 weeks.  This study illustrates the very
    long half-life of canthaxanthin in adipose tissue (Glatzle & Bausch,
    1988b).

    2.1.1.2  Chickens

         Canthaxanthin was reported earlier not to exhibit provitamin A
    activity (Hoffmann-La Roche, 1966).  However, in recent studies in
    chickens, canthaxanthin was shown to be converted to vitamin A in
    small amounts.  Groups of 15 broiler chickens, 37 days old, were given
    diets containing 8.9, 18 or 35 ppm cantaxanthin along with 0, 300 or
    600 I.U. vitamin A/kg feed.  At each dietary level of vitamin A,
    canthaxanthin caused a dose-related increase in plasma and liver
    concentrations of both vitamin A and canthaxanthin.  The lowest level
    of canthaxanthin, in the absence of dietary vitamin A, yielded higher
    plasma and liver vitamin A levels than did a diet containing 600 I.U.
    vitamin A/kg in the absence of canthaxanthin (Hoffmann-La Roche,
    1986).

         When fed to chickens at a concentration of 70 ppm in a diet
    otherwise free of carotenoids, canthaxanthin was partially reduced to
    4-hydroxy-echinenone, with further reduction to isozeaxanthin.  Both
    metabolites and their ester derivatives were detected, together with
    unchanged canthaxanthin, in various tissues including intestinal
    mucosa, liver, serum, skin, claws, and feathers (Tyczkowski  et al.,
    1988).

         Two groups of 5 week old chickens were given diets containing 600
    I.U. or 12,000 I.U. vitamin A/kg; both groups were also given the
    equivalent of 10 mg 14C-labelled canthaxanthin/kg diet, in gelatin
    capsules, daily for four weeks.  At the end of this period,
    canthaxanthin administration ceased and one bird from each group was
    sacrificed after 0, l, 6, 10, 13 and 21 days.

         The total retention of canthaxanthin in the body at the end of
    the dosing period was approximately 6% in the low vitamin A group and
    10% in the high vitamin A group.  The radioactivity was similarly
    distributed in both groups, most of the retained activity being found
    in blood (approx. 20%), muscle  (20-24%) feathers (approx. 13%) and
    skin (8-12%). The highest tissue concentrations (as canthaxanthin
    equivalents according to radioactivity) were found in the retina
    (14-27 g/g), uropygial gland (13-35 g/g/), bile (approx. 10 g/g),
    toe-web (10-20 g/g) and, in birds of the high vitamin A group, liver
    (11-13 g/kg).  There was a continuous fall in the concentration of
    radioactivity in most tissues except for fat, feathers and retina
    after the cessation of exposure.  In fat, activity fell during the
    first 10 days of depletion and then plateaued.  With the small number
    of birds it was not possible to demonstrate any decrease in activity
    in the retina, the retinal activity of the high vitamin A group being
    similar after 0 and 15 days.

         The metabolites 4'-hydroxy-echinenone (4HE) and isozeaxanthin
    (IZX) were identified in muscle, liver and duodenum.  Conversion of
    canthazanthin to retinol occurred in the liver and duodenum, the main
    intermediates detected being 4-oxo-retinal and 4-Oxo-retinol.

    4-xo-12'-apo--carotenal was also identified as a metabolite (Schiedt
     et al., 1988).  Canthaxanthin can thus act as a precursor of vitamin
    A in the chicken (Schiedt, 1987).

         The distribution of canthaxanthin fed to laying hens differs from
    that of broilers; 30-40% of the dose was deposited in the egg yolk, 7%
    in body tissues and 42-54% was excreted.  During a 10-day depletion
    period after withdrawal of canthaxanthin, the body stores were
    reported to be mobilized and excreted via eggs and excrement;
    concentrations of canthaxanthin in fat were stated to be low and to
    remain constant (Hoffman-La Roche, 1986).

         15,15'-3H-Canthaxanthin was fed to two groups of 4 laying hens
    at dietary levels of 4 and 8 ppm, respectively, for up to 4 weeks
    followed by a 10 day withdrawal period.  One bird from each group was
    sacrificed after 15 days, two birds from each group after 29 days and
    one bird from each group after the withdrawal period.  During the
    period 15-28 days, about 40% of the ingested activity appeared in the
    egg yolk at concentrations (canthaxanthin equivalents) of 14 and
    29.3 g/g respectively in the low and high dose groups.  Of the
    3H-labelled  carotenoids in the yolk, about 97% was unchanged
    canthaxanthin, 2.3% was 4HE and 0.4% was IZX.  Only 0.2-1% of residual
    radioactivity was found in the pooled spleens and kidneys of all eight
    birds, of which canthaxanthin accounted for 60% and 80% in the
    respective organs.  4HE and IZX accounted for 6% and 5%, respectively,
    of the activity in the spleen and the remaining 28% was unidentified
    (because of the low residual amounts present);  the corresponding
    figures for the kidneys were 6%, 2% and 10%, respectively.  After 28
    days, canthaxanthin was present in peritoneal fat mainly unchanged at
    a concentration of 0.5 g/g.  In the liver, about 60% of the
    radioactivity was present as metabolites, mainly 4-oxo- and 4-hydroxy-
    retinol, and retinol, confirming that canthaxanthin can act as a
    precursor to vitamin A in the hen (Schiedt & Mayer, 1986).

         Day old chicks received a vitamin A-free diet supplemented with
    9, 18 or 36 ppm canthaxanthin and with or without small vitamin A
    doses of 300 or 600 IU/kg for 40 days.  In each case, canthaxanthin
    caused a dose-dependent growth promotion, better feed conversion and
    increased vitamin A levels in plasma and liver.  In chicks receiving
    600 I.U. vitamin A together with 0, 9 or 18 ppm canthaxanthin in the
    diet, the respective duodenal mucosal activities of -carotene-15,15'-
    dioxygenase were  74, 142 and  119 pmoles retinal/h/mg protein (Weiser
     et al., 1987).

    2.1.1.3  Dogs

         The tissue distribution of canthaxanthin was investigated in dogs
    which had received 50, 100 or 250 mg/kg bw/day canthaxanthin for 52
    weeks, corresponding to total doses of 200, 400 or l,100 g of
    canthaxanthin, respectively.  The highest mean tissue concentration
    was seen in adipose tissue (24 g/g in the top dose group).

    Relatively high concentrations were also seen in the adrenals
    (15.1 g/g), skin (9.62 g/g) and liver (8.1 g/g/) in the low-dose
    group.  The total amount of canthaxanthin extracted from 8 eyes of
    treated dogs was 0.1-0.4 g, but ophthalmological examinations were
    not reported, so it was not possible to determine whether crystalline
    deposits had formed (Hoffmann-La Roche, 1986).

    2.1.1.4  Humans

         A pharmacokinetic study was performed in which plasma levels of
    canthaxanthin were measured at intervals after multiple dosing of
    human volunteers.   Ten subjects were each given 1 mg canthaxanthin 6
    times a day for 5 days, corresponding to a total dose of 30 mg.  A
    further ten subjects received 8 mg canthaxanthin 6 times a day for 2
    days, for a total dose 96 mg.  Blood samples were taken at the start
    and at 12 hour intervals for 8 days, and canthaxanthin concentrations
    were determined by HPLC.  The elimination half-life was calculated as
    4.5 days in each group and the proportion of the dose absorbed was
    estimated to be 12 and 9% in each group, respectively.  The calculated
    steady state plasma concentrations of canthaxanthin after daily
    ingestion of 6 mg (6 times 1 mg) or 48 mg (6 times 8 mg) were 1,843 or
    10,346 g/1, respectively (Kubler, 1986).

         In a more detailed report of the above studies it was concluded
    that canthaxanthin was cleared from serum with a half-life of 5.3
    days, and after administration in multiple oral doses, steady-state
    serum concentrations were achieved after approximately 48 hours.  The
    absorption of canthaxanthin is incomplete, no more than 34% of a 1 mg
    oral daily dose being absorbed, with the proportion of the dose
    absorbed falling with increasing dose.  About 60% of the absorbed dose
    is transferred to fat tissue and remobilization is unlikely even under
    conditions of rapid fat utilization.  An intake of 30 mg
    canthaxanthin/day would lead to steady-state blood concentrations of
    approximately 6 mg/1 and a daily ingestion of 3.5 mg canthaxanthin,
    equivalent to the temporary ADI for a 70 kg person, would lead to a
    steady-state concentration of 1.1 mg/1 (Schalch, 1988a).

    2.2  Toxicological studies

    2.2.1  Acute toxicity

                                                              

    Species      Route         LD50          Reference
                            (mg/kg bw)
                                                              

    Mouse        oral         10,000      Hoffmann-La Roche,
                                                1966
                                                              

    2.2.2  Short-term studies

    2.2.2.1  Mice

         Canthaxanthin was fed to groups of 10 male and 10 female albino
    outbred mice at doses of 0, 125, 250, 500, 1000 or 2000 mg/kg bw/day
    for 13 weeks.  Males and females of the two highest dose groups showed
    the lowest body weight throughout, but the differences were not always
    statistically significant and in some cases they correlated with lower
    food intake.  Apart from a red discolour ation of some internal
    organs, no adverse effects were seen at autopsy and histological
    examination of the two highest dose groups and controls did not show
    any treatment related effects (Steiger, 1981).

    2.2.2.2  Rats

         Canthaxanthin was fed to groups of 10 male and 10 female albino
    outbred rats at dose levels of 0, 125, 250 500, 1000 and 2000 mg/kg
    bw/day for 13 weeks.  Organ function tests (BSP retention and phenol
    red elimination) were carried out at weeks 12 and 10, respectively, on
    animals in the control and top dose groups; comprehensive urinalysis
    was performed on all groups during week 11.  At termination, detailed
    ophthalmological, hematological and clinical chemical examinations
    were carried out, and a complete histological examination was
    performed on rats in the control and the top two dose groups.

         A small decrement of weight gain relative to controls was seen in
    animals of both sexes in the highest dose group only.  Values for
    plasma cholesterol were higher than controls in all treated groups but
    were within normal limits.  With this exception, all the other
    clinical, chemical and hematological parameters were unaffected by
    treatment and no abnormalities were detected in the organ function
    tests.  At autopsy, no gross abnormalities due to treatment were
    observed other than a red or orange discolouration of feces and some
    internal tissues.  Kidney weights of males from the highest dose group
    were significantly reduced relative to controls and the weights of
    adrenals from females of the 1000 mg/kg bw/day dose group also were
    reduced relative to placebo controls. No treatment-related
    pathological effects were seen on histological examination (Steiger &
    Buser, 1982).

    2.2.2.3  Dogs

         Canthaxanthin was fed to groups of 3 male and 3 female beagle
    dogs at dose levels of 0, 250 or 500 mg/kg bw/day for 13 weeks.  There
    were no effects on food and water intake or on body weight gain. 
    Apart from red/orange staining of the feet, muzzle, abdominal fat and
    the feces, there were no clinical signs related to treatment and
    ophthalmoscopic examination did not reveal any abnormalities related
    to the test compound.  At termination, organ weights were within

    normal limits and there were no histological abnormalities
    attributable to treatment (Chesterman  et al., 1979).

    2.2.3  Long/term carcinogenicity studies

    2.2.3.1  Mice

         In a preliminary report of an 80-week study in mice in which the
    animals received 0, 250, 500 or 1000 mg canthaxanthin/kg bw/day it was
    stated that no signs of systemic toxicity and no changes of tumour
    incidence were seen that could be related to treatment (Hoffmann-La
    Roche, 1966).

         When given orally, canthaxanthin exhibited no promotional
    activity in mice treated dermally with dimethylbenz(a)anthracene or
    benzo(a)pyrene (Mathews-Roth, 1982; Santamaria  et al., 1982).

         Oral doses of 6680 mg canthaxanthin/kg bw/day gave some
    protection against the skin carcinogenicity of regular exposure to UV
    radiation (Mathews-Roth, 1982).

         Groups of 60 male and 60 female CD-1 mice, approximately 4 weeks
    old, were given canthaxanthin by incorporation in the diet at levels
    calculated to achieve doses of 0, 0(placebo control), 250, 500 or 1000
    mg/kg bw/day for 90 weeks (males) or 98 weeks (females).  The
    canthaxanthin was microencapsulated in water-soluble beadlets
    containing 10% canthaxanthin and similar beadlets devoid of
    canthaxanthin ("placebo beadlets") also were prepared.  The test
    animals received a constant dietary concentration of beadlets, the
    different dose levels being achieved by mixing appropriate proportions
    of the canthaxanthin- and placebo-beadlets; one control group received
    basal diet and the second (placebo) control group received a similar
    concentration of placebo beadlets as was given to the test animals. 
    Throughout the study, the achieved intakes of canthaxanthin
    approximated the nominal value.  Ten animals of each sex per dose
    group were sacrificed after 52 weeks for interim examination.

         Food intake and body weight gain were similar in treated and
    placebo control mice throughout the study.  No clinical abnormalities
    other than a reddish discolouration of feces, fur and skin were
    observed and ophthalmoscopic examination did not reveal any
    abnormalities.  There was no indication of any treatment-related
    effect on survival and no factors attributable to treatment were among
    the assignable causes of premature death.  No treatment-related
    hematological abnormalities were observed and the only significant
    biochemical change was a higher blood cholesterol level in all groups
    of treated animals of both sexes at week 52 and females at week 98
    compared to placebo controls.  At termination, there were no effects
    of treatment on organ weights and the only gross observations at
    autopsy related to dosing were a generalized orange discolouration of
    fur/skin, subcutis, adipose tissue and gastrointestinal tract.

    Histopathological examination did not reveal any treatment-related
    effects on the incidence of any tumour type or on the total number of
    tumours per group.  Lipid positive granules were observed in the
    sinusoidal cells in the liver of all mice treated with canthaxanthin,
    the incidence varying in a dose-related manner.  Orange-brown pigment
    was present in sinusoidal cells and, to a lesser degree in macrophages
    and some hepatocytes, in treated animals.  Other histopathological
    findings were not treatment-related and were within the normal
    background range for mice of this strain and age (Rose  et al.,
    1987).

    2.2.3.2  Rats

         Groups of 25-30 male and female rats received 0, 0.5, 2 or 5%
    canthaxanthin in their diets for 93-98 weeks.  No adverse effects were
    noted on food consumption or weight gain.  Mortality and tumour
    incidence were not increased (Hoffmann-La Roche, 1966).

         Groups of 70 male and 70 female weanling CD Sprague-Dawley rats
    were given canthaxanthin by incorporation in the diet at levels
    calculated to achieve doses of 0, 0(placebo), 250, 500 or 1000 mg/kg
    bw/day for up to 104 weeks.  The canthaxanthin was microencapsulated
    in water-soluble beadlets containing 10% canthaxanthin and similar
    beadlets devoid of canthaxanthin ("placebo beadlets") also were
    prepared.  The test animals received a constant dietary concentration
    of beadlets, the different dose levels being achieved by mixing
    appropriate proportions of canthaxanthin- and placebo-beadlets; one
    control group received basal diet and the second (placebo) control
    group received a similar concentration of placebo beadlets as was
    given to the test animals.  The achieved dose was about 90% of the
    target dose for males while for females it was 100-10l% of the target. 
    Interim sacrifices of 10 males and 10 females of each group were
    carried out at 52 weeks and a further 3 or 4 animals of each sex per
    group after 78 weeks.  A further 10 animals of each sex per dose group
    were withdrawn and placed on a normal untreated diet at 78 weeks and
    maintained on this diet for up to 16 weeks (males) or 20 weeks
    (females).

         Overall food and water intake and body weight gain of placebo
    control and canthaxanthin-treated animals were significantly lower
    than untreated controls; body weight gain of canthaxanthin-treated
    animals was lower than that of placebo controls, especially for
    females, but did not vary in a dose-related way between dose groups. 
    Body weight gain of previously treated animals and placebo controls
    increased to a similar extent during the withdrawal period and it was
    concluded that the reduced food intake and body weight gain resulted
    from incorporation of the beadlets into the diet rather than from an
    effect of canthaxanthin  per se.  No clinical abnormalities other than
    reddish discolouration of feces, fur and skin were observed and
    ophthalmoscopic examination did not reveal any abnormalities.  The
    mortality among placebo and canthaxanthin-treated animals was much

    lower than in untreated controls.  The prolongevity was attributed to
    the reduced food intake resulting in leaner, healthier animals.  No
    treatment-related effects were seen in the hematological or urine
    analytical examinations.  The clinical biochemical examinations
    revealed treatment-related increases in the following parameters in
    females only:  AP and SGPT (weeks 12, 26, 52 and 78), SGOT and
    cholesterol (weeks 12, 26, 52, 78 and 104), gamma-GT (weeks 52, 78 and
    104) and bilirubin (weeks 26, 52, 78 and 104).

         At the interim sacrifices and at termination, liver weights of
    female rats receiving canthaxanthin were greater than those of placebo
    or untreated controls; no other treatment-related organ weight changes
    were observed.  Gross pathological examination at termination revealed
    orange discolouration of liver, intestinal contents, skin, fur,
    subcutis, adipose tissue and extremities in treated animals in all
    dose groups.  Histological examination of animals sacrificed at the
    interim and terminal sacrifices revealed treatment-related lesions
    only in the liver.  Male and female animals from all treatment groups
    showed hepatocyte enlargement and brown pigment deposition.  Females
    from all dose groups additionally showed eosinophilic hepatocellular
    foci, hepatocyte vacuolation, bile duct hyperplasia and cystic bile
    ducts; a few females from the top two dose groups also showed
    cholangic fibrosis and foamy macrophages.  At the terminal kill, there
    was a higher incidence of benign liver nodules in females of all
    treatment groups but this was not dose-related.  It was not possible
    to establish a no-observed-effect level in female animals in this
    study in relation to hepatic biochemical or morphological changes
    (Rose  et al., 1988).

         In a further review of the preceding study, a re-evaluation of
    the histological data and diagnoses and statistical analysis of
    non-neoplastic and neoplastic liver lesions in males and females was
    performed.  It was concluded that a toxic effect to the liver was seen
    at all dose levels in this long-term study.  Trend tests showed that
    the effect was much more pronounced in females, the dose-related
    response was flat, and no threshold dose could be determined for
    either sex.  The incidence of liver nodules was slightly increased in
    females but was limited to benign tumours only;  there was no
    indication of an increase in malignant tumours (Buser & Banken, 1988).

    2.2.3.3  Dogs

         Oral doses of 0, 50, 100 or 250 mg canthaxanthin/kg bw/day for 52
    weeks were well tolerated by dogs and no adverse effects attributable
    to treatment were observed (Hoffmann-La Roche, 1986).

         Groups of 4 male and 4 female beagle dogs were given
    canthaxanthin in beadlets in the diet at doses of 0, 0(placebo), 50,
    100 or 250 mg/kg bw/day for 52 weeks.  Canthaxanthin was micro-
    encapsulated in water-soluble beadlets in the same manner as described
    in the summaries of the studies in mice (section 2.2.3.1) and rats

    (section 2.2.3.2).  Detailed hematological examinations and blood
    biochemical and urine analyses were performed at weeks 12, 24, 39 and
    51 at which times an ophthalmoscopic examination also was carried out.

         There were no deaths and no indicative signs of systemic toxicity
    throughout, and there were no adverse effects of treatment on food
    intake and body weight.  Ophthalmoscopy did not detect any
    abnormalities due to the test material.  No significant intergroup
    differences in the hematological parameters indicative of a treatment-
    related effect were observed at any time.  Group mean values for the
    biochemical parameters showed occasional significant differences from
    placebo controls but these were not systemic or dose-related and were
    generally within normally acceptable limits.  Urinalysis did not
    reveal any treatment-related differences in any parameter measured. 
    At autopsy, reddish discolouration was observed in fur and hair,
    adipose tissue, aortic valve and right atrioventricular valve of
    selected animals; a cherry red discolouration was seen in the liver of
    one animal only from each of the 50 and 100 mg/kg/bw/day dose groups. 
    Organ weights were not affected by treatment.  Detailed
    histopathological examination did not reveal any dose-related
    pathological effects.  Moderate amounts of dark pigment seen in
    midzonal hepatocytes and in some Kupffer cells of one female from the
    50 mg/kg bw/day group and one male from the 100 mg/kg bw/day group
    were attributed to treatment but no such pigmentation was seen in the
    highest dose group (Harling  et al., 1987).

    2.2.4  Reproduction studies

    2.2.4.1  Rats

         In a three-generation reproduction study, canthaxanthin was given
    to male and female rats at doses of 0, 0(placebo), 250, 500 and 1000
    mg/kg bw/day in the form of beadlets in the diet throughout three
    generations.  Canthaxanthin was micro-encapsulated in water-soluble
    beadlets in the same manner as described in the summaries of the
    studies in mice (section 2.2.3.1) and rats (section 2.2.3.2).  In each
    generation, two litters were obtained and the second and third
    generations were produced from parents derived from the first litter
    in the F1 and F2 generations, respectively.

         There were no adverse effects of treatment or mating performance,
    duration of gestation, parturition or ability of dams to lactate and
    rear their offspring successfully.  Some treatment-related effects
    without consequences for reproductive performance were noted in the
    form of:

         a)   orange/red colouration of feces, fur, viscera and adipose
              tissue;

         b)   reduced food efficiency earlier than in placebo controls and
              a tendency for the growth curve to plateau at a lower value;

         c)   markedly increased levels of SAP, SGPT, SGOT and cholesterol
              in adult females;

         d)   significantly increased liver weights in culled weanlings in
              each of the six litters;

         e)   histological changes in the liver with foci of foamy
              macrophages in the liver sinusoids of F0 and F2 adult
              females and slightly increased hepatocyte vacuolation in F2
              adults at 500 and 1000 mg/kg bw/day;

         f)   decreased adrenal weight in adult females at all doses;

         g)   increased spleen weight in adult females of the top dose
              group.

         The above adverse effects were partially reversed during an
    eight-week withdrawal phase at the end of the study (Bottomley
     et al., 1987).

    2.2.5  Special studies on embryo/fetotoxicity

    2.2.5.1  Rats

         Groups of 40 pregnant FU-Albino rats were given canthaxanthin in
    the diet at dose levels of 0, 250, 500 or 1000 mg/kg bw/day on days 7
    to 16 of pregnancy, inclusive.  On the 21st day of gestation the dams
    of each group were divided into two subgroups, designated a necropsy
    subgroup and a rearing subgroup.

         Animals in the necropsy subgroups were sacrificed at day 21 and
    the uteri examined for the number and location of implantations and
    resorptions; the number of corpora lutea were counted and the fetuses
    were examined macroscopically, weighed and measured.  The fetuses of
    10 litters per dose group were examined for skeletal abnormalities;
    the fetuses of 7 litters were examined for soft tissue defects.

         Animals in the rearing subgroups were allowed to litter
    spontaneously and rear their young to weaning.  Litter size and
    weights, and maternal weights were recorded on days 1, 4, 12 and 23
     post partum.  At day 23 the offspring of 8 litters per group were
    necropsied and heart, liver and kidney weights were measured.

         No treatment-related effects were seen on the dams, and there was
    no indication of any embryotoxic or teratogenic action of
    canthaxanthin at any of the dose levels used.  The rearing experiment
    showed no evidence of effects on lactation nor of functional
    abnormalities in the offspring (Kistler, 1982).

    2.2.5.2  Rabbits

         Groups of 20 mated female Swiss hare rabbits were given doses of
    0, 100, 200 or 400 mg canthaxanthin/kg bw/day by gavage in rape seed
    oil on days 7 to 19 of pregnancy inclusive.  All the dams were killed
    on day 30 of gestation and examined for the number and location of
    implantations and resorptions; the number of corpora lutea were
    counted.  The fetuses were examined macroscopically, weighed and
    measured, then tested for 24h viability in an incubator at 34C.  All
    the fetuses were then dissected and examined for soft tissue
    abnormalities. All the fetuses were X-rayed and those which could not
    be judged definitely by radiography were cleared and stained with
    Alizarin red for skeletal examination.

         The test compound was well tolerated and no effects were seen on
    maternal body weight gain in any dose group.  The reproductive
    parameters measured were within the range of concurrent controls; a
    slight but statistically significant increase in resorptions was noted
    in the 100 mg/kg bw/day dose group but there was no such effect in the
    higher dose groups and it was considered not to be treatment-related. 
    Sporadic malformations of different types occurred in a few fetuses of
    all groups, including controls; because of their single occurrence and
    distribution in all groups, these abnormalities were not attributed to
    treatment.  In all treatment groups skeletal anomalies were in the
    control range.  It was concluded that, under the conditions of the
    study, canthaxanthin was neither embryotoxic nor teratogenic
    (Eckhardt, 1982).

    2.2.5  Special studies on genotoxicity

         Canthaxanthin did not induce mutations in  Salmonella typhimurium
    strains TA98, TA100, TA1535, TA1537 or TA1538 (Chtelat, 1981) nor in
     Saccharomyces cerevisiae (Chtelat, 1986).

         Canthaxanthin was negative in a mouse micronucleus assay after
    two-fold application of up to 222 mg/kg bw (Gallandre 1980),

         Canthaxanthin, in the presence of an activating system did not
    induce mutations to 6-thioguanine-resistance in V79 Chinese hamster
    lung cells (Strobel, 1986) and did not induce DNA damage resulting in
    unscheduled DNA synthesis in primary cultures of rat hepatocytes
    (Strobel, 1986).

    2.2.6  Special studies on effects on the immune response

         Male Wistar rats were fed diets containing either 2 g/kg
    -carotene or canthaxanthin, or basal diet for up to 66 weeks.
     in vitro immune responses of splenocytes to T- and B-lymphocyte
    mitogens were determined.  T- and B-lymphocyte responses were enhanced
    in the groups fed -carotene or canthaxanthin (Bendich & Shapiro,
    1986).

    2.2.7  Special studies on ocular toxicity

         (see also Human Studies)

    2.2.7.1  Rabbits

         Preliminary results of studies in rabbits on the ocular effects
    of canthaxanthin (dose not specified) did not reveal any deposits in
    the retina, but small alterations (prolongation) in dark adaptation
    were observed.  The significance of these results is controversial
    (Hoffmann-La Roche, 1986).

         In a 10-month experiment, three groups of chinchilla cross
    rabbits were fed diets containing approximately 200 ppm -carotene,
    canthaxanthin or -carotene+canthaxanthin.  Total doses of -carotene
    or of -carotene+canthaxanthin were approximately 11g; the total dose
    of canthaxanthin was approximately 8 g.  One of the canthaxanthin-
    treated rabbits developed a paracentral chorioretinal defect that
    increased under further treatment.  While electroretinography in the
    -carotene-treated animals showed slowly increasing scotopic a- and
    b-wave peak latencies, the rabbits treated with canthaxanthin alone or
    with -carotene showed hypernormal amplitudes at low cumulative doses
    (ca. 1 g) and reduced amplitudes at higher doses (ca. 5 g) and peak
    latencies increased remarkably.  Histology and transmission electron
    microscopy revealed a reduced retinal thickness in all carotenoid-
    treated animals but in the canthaxanthin-treated rabbits there were
    spotty degenerations and inclusions in the photoreceptor inner
    segments.  It was concluded that crystalline retinopathy may be a
    specific effect in primates but that the functional retinal
    alterations in humans that can be measured with the electroretinogram
    are reproducible in the  ERG of pigmented rabbits after canthaxanthin
    treatment (Weber  et al., 1987a; 1987b).

         Groups of two chinchilla cross rabbits, average body weight
    3.5 kg, were given intravenous liposome preparations daily for 19
    days; one group received control liposomes yielding a daily dose of
    13.7 mg of egg yolk phosphatidyl choline (PC), while the test group
    received similar liposomes containing a daily dose of 2.1 mg
    canthaxanthin.  Two further groups of two rabbits were given the same
    accumulated dose of 260 mg PC with or without 39.8 mg canthaxanthin,
    but as a single injection.  Electroretinography revealed that
    canthaxanthin caused a depression of the a-waves and prolongation of
    the scotopic a- and b-wave peak latencies.  The single high-dose
    injection of both control and canthaxanthin-containing liposomes
    caused a transitory reduction in ERG aplitudes; the canthaxanthin-
    containing liposomes also produced hypernormal a-waves within the
    recovery time.  Histologically, the canthaxanthin treated animals
    showed alterations in the retinal pigment epithelium and
    photoreceptors. It was concluded that an alteration in retinal

    function and morphology occurs in the rabbit even after relatively low
    doses of canthaxanthin (0.6 mg/kg bw/day for 19 days) (Weber  et al.,
    1987c).

    2.2.7.2  Cats

         Cats were fed up to 16 mg canthaxanthin/kg bw/day for 6 months. 
    No changes in ERGs were observed after 2 months.  No crystals were
    seen, but an orange sheen was reported to develop over the tapetum. 
    Light and transmission electron microscopy revealed fewer mature
    pigment granules and more cytoplasmic vacuoles in the retinal pigment
    epithelium.  Electroretinograms performed at one and two months showed
    no significant changes from baseline examinations (Scallon  et al.,
    1987, 1988).

    2.3  Observations in man

         Six out of a group of 42 patients with a history of urticaria
    suffered a recurrence of their symptoms within 23 hours after an oral
    challenge with 410 mg canthaxanthin taken as three divided doses over
    3 hours (Juhlin, 1981).

         The ingestion of doses of about 30-120 mg canthaxanthin daily
    (approximately 0.4-1.7 mg/kg bw/day) for 3 months to several years in
    medicinal or oral sun-tanning preparations has been associated with a
    retinopathy in some individuals characterized by glistening, golden
    crystals in the inner layers of the retina, up to 10-14 m in size
    (Boudreault  et al., 1983; Cortin  et al., 1984; Ros  et al.,
    1985).  The crystalline deposits occur mainly in a ring between 5 and
    10 around the fovea, less numerous in the fovea and rarely in the
    foveola (Cortin  et al., 1982).  Occasionally, deposits have been
    reported nasally of the disc (Metge  et al., 1984) or scattered in
    the posterior fundus (cited in Daicker  et al., 1987) and in one case
    only in the periphery of the fundus in the inner layer of a
    retinoschisis (Cortin  et al., 1982).  A total dose of 75-178g
    canthaxanthin has been found to cause this effect in 50% of subjects
    and numerous cases have now been described (Franco  et al., 1985;
    Hennekes  et al., 1985; McGuiness & Beaumont, 1985; Meyer  et al.,
    1985; Philipp, 1985; Saraux & Laroche, 1983; Weber  et al., 1985b;
    Weber & Goerz, 1986).

         There are considerable differences among individuals in response
    to canthaxanthin and there does not appear to be a clear relationship
    between appearance of crystalline deposits and dose level or duration. 
    In one study, no crystals were detected in one subject after a total
    intake estimated at 132 g canthaxanthin over a period of 7 years while
    in another individual crystalline deposits were observed after an
    accumulated total intake of 67.5 g in six years; crystal deposition
    has even been described after exposure to 12-14 g canthaxanthin in 4
    months.  Canthaxanthin retinopathy was reported in 6 individuals who
    claimed never to have taken canthaxanthin as a drug or sun-tanning

    agent and  the source of exposure to canthaxanthin in these cases in
    unknown (Oosterhuis  et al., 1988).  Of 15 patients aged 9 to 72
    years receiving a total accumulated dose of 10-170 g canthaxanthin
    over a period of 1 to 10 years, six had crystalline retinal deposits
    (Barker  et al., 1987; Norris & Hawk, 1987).  Conversely, in 23
    patients receiving combined treatment with -carotene and
    canthaxanthin for up to 2 years (average 2-6 months), no coloured
    deposits were detected in the retina.  However, from the data given in
    this report it is not possible to determine the total doses involved
    (Raab  et al., 1985).

         In a biostatistical evaluation of 253 cases having received
    treatment with canthaxanthin, of whom 33 (15%) had retinal deposits,
    the median yearly dose in subjects free from visible retinal deposits
    was 5.3 g, whereas the corresponding figure for the group with pigment
    deposits was 14.4 g.  The lowest dose at which deposits were recorded
    was 7 g canthaxanthin/year and no retinal deposits were found in
    patients receiving less than 30 mg/day (Hoffmann-La Roche, 1986).

         In a review of 259 reported cases with overall doses ranging from
    3.6 g to 336 g over 3 months to 14 years, 92 patients showed crystals
    but with clear dose/duration relationship (Barker, 1988).  Maille
     et al., (1988) reported that the dose associated with appearance of
    crystal deposition in their patients varied from 7.92 g to 240 g but
    that numerous subjects having ingested between 3.8 and 7.7 g did not
    present with the retinopathy.

         In view of the large differences reported in the doses of
    canthaxanthin associated with crystal deposition in the retina, it has
    been suggested that there are predisposing factors, including
    co-administration of other carotenoids, age, intraocular hypertension
    and particularly pre-existing retinal pigment epithelial defects
    (Cortin  et al., 1982, 1984; Maille  et al., 1988; Metge  et al.,
    1984; Weber  et al., 1985a; Oosterhuis  et al., 1988, Pece  et al.,
    1988; Lonn, 1987).

         In most cases, pigment deposition is not associated with any
    detectable functional changes, but there have been occasional
    complaints of dazzle or blurred vision (Cortin  et al., 1984; 
    Hennekes  et al., 1985; Philipp, 1985); visual field defects have
    been described in only one report (Ros  et al., 1985).  The EOG is
    normal or subnormal and dark adaptation may be delayed; scotopic
    vision after exposure to glare may be reduced while the ERG is normal
    or displays b-wave changes (Boudreault  et al., 1983; Metge  et al.,
    1984; McGuiness & Beaumont, 1985; Weber  et al., 1985b; Hennekes
     et al., 1985; Philipp, 1985).

         No adverse influence on visual function was reported after
    treatment of 15 patients for up to 9 years (mean 4.9 years) with mean
    total doses of  75.5 g (11-170 g) canthaxanthin, although 6 of these
    patients displayed retinal crystals; dark adaptation was within normal

    limits.  EOG and PERG responses were not significantly different from
    normal (Norris & Hawk, 1987).  Similarly, 32 patients who had received
    canthaxanthin therapy for 2-13 years (mean 5.8 years) did not have
    visual symptoms, although 8 had retinal deposits.  No abnormalities
    related to crystal deposition could be found in visual field, dark
    adaptation and EOG; there was no canthaxanthin-induced degeneration of
    the retinal pigment epithelium (Nijman  et al., 1986; Oosterhuis
     et al., 1988).

         In a study of 29 erythropoietic protoporphyria patients who had
    received canthaxanthin for up to 10 years in daily doses of 30-150 mg
    (total dose up to 170g canthaxanthin), dark adaptation and PERGs were
    unaltered, but there was a slight decrease in the amplitude of the
    scotopic b-wave in the ERG over the summer months.  During the winter
    this change was found to be reversible and, judged from this
    parameter, it was reported that the no-effect-level appeared to be a
    daily dose of 60 mg canthaxanthin (Schalch, 1988b).

         Minor ERG changes (reduced b-wave amplitude) observed in EPP
    patients, with or without crystalline deposits, did not cause symptoms
    even after several years of therapy.  The observations in this study
    led the authors to conclude that the reduced b-wave is unlikely to
    result from canthaxanthin acting as a filter reducing the number of
    photons absorbed by photoreceptors as this would have caused
    additional changes including increased latency and reduced amplitude
    of the a-wave (Norris  et al., 1987).

         Evidence on the reversibility of retinal pigment accumulation is
    controversial.  Some workers have evaluated patients with retinal
    crystals for up to 3 years after administration of canthaxanthin
    ceased and reported no decrease in crystal deposits (Boudreault
     et al., 1983; Weber  et al., 1985a; Goerz & Weber, 1988; Weber &
    Goerz, 1986; Lonn, 1987).  Conversely, in a follow up over a mean
    period of 47 months, retinal deposits in 7 out of 9 patients   
    decreased by 6713% but no reduction was seen in the other two
    patients (Malenfant  et al., 1988).  The number of retinal deposits
    was evaluated in 9 patients, 2 to 4 times over a period of 55 months. 
    There was no significant difference observable after 9 months, but a
    significant decrease in the number of retinal deposits was found after
    26 months.  The deposits disappeared slowly but some remained even
    seven years after canthanxanthin was discontinued (Harnois  et al.,
    1988).  Other workers have also noted some reversal of crystal
    deposition after long recovery periods of up to 4 years (Oosterhuis 
     et al., 1988).

         The eyes of a female patient, aged 72 years, who had retinal
    deposits and who had died under anaesthesia, were examined by light
    and electron microscopy, and the extracted pigment was examined by
    mass and proton magnetic resonance spectroscopy.  There were red,
    birefringent crystals in the inner layers of the entire retina, which
    were particularly large and numerous perifoveally where they were

    clinically visible.  The crystals were located in the inner neuropil,
    where atrophy of the inner parts of the Mller cells was observed. 
    The compound was identical to canthaxanthin, and was present at up to
    42 g/g in the retina, along with a minor amount of other carotenoids. 
    Of the other ocular tissue, only the ciliary body contained measurable
    amounts of canthaxanthin (Daicker  et al., 1987).

         Canthaxanthin was measured at autopsy in the tissues of 38
    people, aged 22 to 96 years, none of whom were known to have received
    canthaxanthin therapeutically or in sun-tanning preparations.  The
    tissues examined were mesenteric and sub-cutaneous fat, skin, liver,
    spleen and blood serum.  The highest concentrations were found in
    omentum and sub-cutaneous fat (mean concentrations 0.2 and 0.3 g/g
    respectively).  The mean concentrations in other tissues were: liver,
    0.08 g/g; skin and spleen, 0.04 g/g; and serum, 0.024 g/ml
    (Hoffmann-La Roche, 1986).

         Fat samples from mesenterium and omentum and a liver sample were
    taken at autopsy from a 71-year old woman who had died from bronchial
    carcinoma. The patient had previously ingested approximately 45 mg
    canthaxanthin/day for four years (total dose approximately 65 g) in a
    sun-tanning preparation.  The concentrations of canthaxanthin in
    omentum and mesenteric fat were 270 g/g and 158 g/g, respectively. 
    Lower levels of 5 g/g were found in the liver (Hoffmann-La Roche,
    1986).

         Biopsy samples of orange-coloured fat (omentum) were obtained
    from two patients undergoing surgery.  In one case, the woman had
    taken a total dose of about 6g canthaxanthin in a tanning preparation
    during 1983/84 and had stopped this intake 1-1 years before the
    biopsy; fat and serum canthaxanthin levels were 49 g/g and 69 g/1,
    respectively.  In the second case, the patient had taken a total dose
    of approximately 16g over 2-3 years and the concentration in omentum
    was 34 g/g (Hoffmann-La Roche, 1986).

    3.  COMMENTS AND EVALUATION

         In reviewing the results of two long-term/carcinogenicity studies
    in mice and rats, the Committee noted that these did not provide
    evidence of carcinogenicity but, at high dose levels, canthaxanthin
    produced liver damage in the rat (with a non-dose-related increased
    incidence of benign nodules in female rats); the mouse appeared less
    sensitive to hepatic injury.  It was concluded that, in addition to
    the eye, the liver was a target organ for canthaxanthin.

         In the long/term studies in rats, it was not possible to
    establish a no-effect level, but the Committee was informed that
    another long/term study in rats was in progress aimed at establishing
    a no-effect level with respect to hepatic pathology.

         On the basis of distribution studies using radiolabelled
    canthaxanthin, relatively high concentrations accumulated in the eye
    in all mammalian species studied.  However, to date, crystal
    deposition has been observed only in the human retina.  Therefore, the
    animal species studied did not provide a suitable model for the study
    of the pathogenesis and reversibility of this phenomenon.  However,
    changes in ERGs in humans were reproduced in the ERGs of pigmented
    rabbits.

         Although the Committee concluded that the long/term toxicity in
    rats raised questions of potential hepatotoxicity, these may be
    answered by obtaining clinical data derived from human subjects
    showing retinal pigment deposition.  However, the Committee considered
    that the primary problem related to canthaxanthin is its crystal
    deposition in the human retina.

         In view of the irreversibility or very slow reversibility of the
    retinal crystal deposition, the significance of which is not known,
    the Committee was unable to establish an ADI for canthaxanthin when
    used as a food additive or animal feed additive.  Therefore, the
    previous temporary ADI was not extended.

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    See Also:
       Toxicological Abbreviations
       Canthaxanthin (WHO Food Additives Series 22)
       Canthaxanthin (WHO Food Additives Series 35)
       Canthaxanthin (WHO Food Additives Series 44)
       CANTHAXANTHIN (JECFA Evaluation)