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    ALLURA RED AC

    Explanation

         This food colorant was first evaluated by JECFA in 1974 (see
    Annex I, Ref. 34). At that time the Committee decided not to set an
    ADI for this substance because of a lack of metabolism studies and the
    unsatisfactory nature of the only long-term study in rats available
    for evaluation; too few animals remained at the end of the study to
    allow a satisfactory assessment to be made. Additional studies in
    these areas were found essential to be carried out before a definite
    evaluation could be made. A short monograph was published (see Annex
    I, Ref. 35). The substance was re-evaluated subsequently when some
    metabolic studies using radio-labelled materials were made available
    (see Annex I, Ref. 43). These studies demonstrated that the metabolism
    of this colour was similar to that of other members of the azo dye
    class. No monograph was prepared and no acceptable daily intake (ADI)
    was allocated. JECFA in 1979 had again re-evaluated this compound (see
    Annex I, Ref. 51).

         Since the previous evaluations additional data have become
    available and are summarized and discussed in the following monograph.
    The previous monograph has been expanded and is reproduced in its
    entirety below.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         Rats were fed a diet containing 5.19% of Allura Red (White,
    1970). It was observed that 0.1% and 29% of the intact dye was
    excreted in the urine and faeces respectively. In later studies, rats
    and dogs were pretreated daily with nonradioactive Allura Red.
    Subsequently, the animals were dosed with the 35S labelled compound
    and studied for up to 72 hours for excretion and distribution patterns
    of the colour. Both species showed limited absorption of the compound
    with the major route of excretion being via the faeces. In the dog 92
    to 95% of the recovered radioactivity appeared in the faeces within 72
    hours while in the rat 76 to 92% of the recovered radioactivity
    appeared in the faeces within this time period. Urinary recoveries of
    the colour in rats and dogs, respectively varied between 5.7 and
    19.8% and 2.7 and 3.6%. After sacrifice, significant retention of
    radioactivity was located in the intestinal contents of both species
    and in the washed intestines of the rats. This was thought to be due
    to adhesion of the compound to the intestinal wall, since the total
    carcass and viscera of these animals contained less than 0.4% of the
    administered dose (Guyton & Reno, 1975).

         Cresidinesulfonic acid was found to be the major metabolite of
    Allura Red in the urine of these two species, whereas the parent
    compound was not measurable. In addition, two other unidentifiable

    metabolites were found in the urine of the rats. In the rat faecal
    extracts, cresidinesulfonic acid was a major metabolite along with two
    unknowns and the parent compound. The dog faecal sample revealed an
    identical metabolite pattern as seen in the rat, and in addition, a
    third unknown was discovered. One of the urinary unknowns demonstrated
    an Rf value which was identical to that of the one of the faecal
    unknowns suggesting that they were one and the same. The other
    unknowns exhibited distinctive Rf values which indicated that these
    metabolites were different (Guyton & Stanovick, 1975).

         It has been postulated that azo reduction by gut flora of the dye
    will yield the two components of the parent compound:

    2-methoxy-5-methyl-aniline-4-sulfonic acid (cresidine-4-sulfonic acid)

    CHEMICAL STRUCTURE

    and 1-amino-2-naphthol-6-sulfonic acid

    CHEMICAL STRUCTURE

    (White, 1970)

         It appears that negligible quantities of intact Red are absorbed
    and excreted in the urine, and that the major portion of the colour is
    excreted as metabolites in the faeces.

    TOXICOLOGICAL STUDIES

    Reproduction

    Rat

         Groups of 10 male and 20 female rats received 0, 0.37, 1.39 or
    5.19% of Allura Red in their diet through two parental (F1A was the
    P2 generation) and two filial generations. Mating occurred after 27
    weeks on either the control or test diets for both the P1 and P2
    generation. The fertility indices were low for the controls and test
    animals in the F1A and F1B generation as well as in the low test
    level F2A and all test levels of F2B generation. Growth was
    suppressed slightly for the lowest test level in F1B and high test
    levels in F1A and F1B as well as for the high test levels in F2A
    and F2B pups. Other indices, litter size and pup weight at 24 hours,
    were comparable in each group in each generation. No consistent
    pathological changes were noted in the P1, F1A, F1B and F2B
    generations. No evidence was seen of teratogenic or embryotoxic
    effects regarding implantation sites, resorption sites and live
    foetuses indices. No difference from controls was noted with regard to
    appearance, anatomy and structure of test foetuses (Blackmore et al.,
    1969).

    Teratogenicity

    Rat

         Groups of 24, 19, 20, 21 and 16 pregnant rats received
    respectively 0, 15, 30, 100 and 200 mg/kg of the dye by gavage daily
    during pregnancy days 0-19. Gross observations indicate no dye-induced
    effects in terms of early or late deaths, resorptions per litter,
    pre-implantation loss, number of foetuses per litter and average
    foetus weight (Collins, 1974).

    Rabbit

         In three groups of 14 rabbits, Allura Red was given in doses of
    0, 200 and 700 mg/kg bw by gavage from day 6 to 18 of pregnancy. There
    were no indications of compound-related effects with regard to
    appearance and behaviour, body weight or in gross necropsy findings
    for the maternal dose. No adverse effects on implantation and litter
    data were noted nor were any foetal abnormalities observed (Reno,
    1974).

    Mutagenicity studies

         Microbial assay systems (plate and suspension tests) with and
    without the addition of mammalian metabolic activation enzymes were
    used to determine the mutagenic potential of Allura Red. One strain of
    yeast, Saccharomyces cerevisiae, and five strains of the bacteria

    Salmonella typhimurium were used in the study which employed
    negative and positive controls. Preliminary toxicity studies were
    conducted and the compound was found to be nontoxic at the 5%
    concentration. Allura Red did not exhibit genetic activity in any of
    the assay systems employed (Brusick, 1976).

         Genetic tests were also conducted using three strains of
    Saccharomyces cerevisiae with and without liver enzyme induction
    (Anonymous, 1977a). The colour also proved to be negative in these
    systems.

         The Salmonella/microsome system was used to test a number of azo
    dyes including FD&C Red No. 40. The dye, as well as its chemically
    reduced component amines, were tested with five tester strains
    (TA 1535, TA 100, TA 1537, TA 1538 and TA 98). In addition, the
    effects of the colour were analysed in the same five tester strains
    with microsomal activation (S-9) and in an aerobic liquid test with
    microsomal activation. None of these test systems demonstrated
    mutagenic activity of FD&C Red No. 40 (Brown et al., 1978).

         In a second Salmonella/mammalian-microsome study, the colour was
    tested for mutagenic potential in two frame-shift histidine (TA 1537
    and TA 98) and two base-pair substituted histidine mutants (TA 1535
    and TA 100). Both the spot test and the plate incorporation assay,
    with and without the S-9 mix, were employed in these experiments. As
    before, Allura Red was found to have no mutagenic effects in these
    assay systems (Muzzall & Cook, 1979).

         The same four strains of Salmonella typhimurium (TA 1535,
    TA 1538, TA 100 and TA 98) with and without microsomal activation were
    used in the spot and plate tests to study the effects of Allura Red.
    None of the tests performed demonstrated either a mutagenic or
    cytotoxic activity of this compound (Viola & Nosotti, 1978).

         A rat hepatoma cell culture system was utilized to determine if
    the colour had enzyme induction capabilities, and it was found that
    the colour could not induce aryl hydrocarbon hydroxylase activity
    (Bradlaw, 1979).

         Allura Red was tested in the genetic analysis for recessive
    lethal effects by the oral feeding to Drosophila melanogaster at the
    LD50 dose for 24 days. The following genetic tests were conducted:
    loss of X or Y chromosome, visible mutation at specific loci and
    sex-linked recessive lethal damage in both mature and immature
    spermatozoa, chromosomal translocation, sex-linked lethal damage of
    aged-in-the female spermatozoa and sex-linked mosaic recessive lethal
    damage in mature spermatozoa. There was no significant increase in the
    proportion of mutation in any category when comparisons were made with
    the individual controls. However, when the controls were combined with
    the controls used in two other studies, a significant increase was
    seen for the category of sex-linked mosaic recessive lethal damage
    (Anonymous, 1977b, 1978).

         The heritable translocation potential of Allura Red was analysed
    in eight to 10-week-old male mice who were fed diets containing the
    colour at dose levels of 4000 and 20 000 ppm for eight weeks. Each
    male was mated with two females to produce an F1 generation. The
    males in later generations were mated and their reproductive
    performance was analysed. The administration of the colour did not
    affect the fertility of the treated mice. Although several of the
    animals receiving the colour were potential translocation
    heterozygotes, cytogenetic analysis showed that these animals were
    normal. It was concluded that the compound was negative with respect
    to induction of inheritable translocation in mice (Jorgenson et al.,
    1978).

    Acute toxicity studies

                                                                        

                                          LD50
    Animal             Route           (mg/kg bw)         Reference
                                                                        

    Rat            Oral (gavage)         10 000           Weir, 1965a

    Rabbit         Dermal                10 000           Weir, 1967

    Dog            Oral (gavage)          5 000           Weir, 1965b
                                                                        

    Rat

         The colour was administered to six groups (five animal/sex) at
    doses varying from 215 to 10 000 mg/kg. The only compound-related
    effect of note was the red coloration of the urine and faeces (Weir,
    1965a).

    Skin irritation and sensitization studies

    Rabbit

         Tests for dermal irritation on intact and abraded skin showed no
    gross irritation at levels of 0.316, 1.0, 3.16 and 10 g/kg bw of
    Allura Red; none the less a persistent skin staining did occur (Weir,
    1967).

         Daily application of the colour at rates of 0.5 g/kg, five days a
    week for 15 applications on abraded and 65 applications on intack skin
    of rabbits, of 0.1 and 1% solutions in water or as a hydrophilic
    ointment revealed no compound-related effect on general appearance,

    body weight, clinical laboratory studies and gross and microscopic
    pathology. No dermal irritation was noted, except that produced by the
    hydrophilic ointment base (Blackmore, 1968).

    Human

    Prophetic patch test

         Allura Red was applied either as a neat or as a 25% aqueous
    solution to the skin of 200 human subjects. The initial exposure to
    the compound was for 72 hours, and this was followed by a 24-hour
    application 10 to 14 days later. None of the subjects exhibited
    compound induced irritation or sensitization (Osbourn, 1972).

    Draize-Shelanski repeated insult patch test

         In this study, the colour and its alumina lake were applied to
    the subjects volvar forearms (200 subjects) as an aqueous solution for
    10 alternate days, for 24-hour periods, followed by a 14-day rest
    period. Challenge batches were then applied under occlusion to fresh
    skin sites on the subjects scapular backs for 24 hours. The colour did
    not produce either irritation or allergic responses during the
    induction phase nor contact dermatitis in the challenge period (Jolly,
    1973).

    Photosensitization potential test

         As in the previous study, Allura Red and its lake were evaluated
    on sites under occlusion for five 48-hour, alternate-day periods.
    These sites had been previously irradiated for five minutes with Xenon
    light which had been filtered through a window-glass equivalent to
    limit the exposure to non-erythema-producing, long-wave radiation. A
    10-day rest period followed this induction exposure, and then the
    colour was applied to fresh skin sites, irradiated for five minutes
    with Xenon and subsequently removed and the sites were evaluated.
    Allura Red was shown not to produce photosensitization on the 25
    subjects studied (Jolly, 1973).

    Hypersensitivity reactions

         In 52 patients who were suffering from urticaria or angioedema
    for more than four weeks were placed on an elimination diet for at
    least three weeks. All non-vital drugs were suspended during the study
    as were any food ingredients which were known to cause urticaria. In
    most patients, challenge with Allura Red was performed when the
    patients were free of symptoms. Reactions were considered positive
    only when the flare-up of symptoms was reproducible within the same
    time from intake to skin reaction. Allura Red was administered via the
    oral route in either a dose of 1 or 10 mg, and induced a positive
    reaction in 15% of the 52 patients challenged (Mikkelsen et al.,
    1978).

    Short-term studies

    Rat

         Groups of 10 male and 10 female rats were fed diets containing 0,
    0.37, 0.72, 1.39, 2.69 and 5.19% of Allure Red for six weeks. No
    evidence of compound-related effects were noted as regards body
    weight, food consumption, survival, organ weights, gross and
    microscopic pathology. Haematology and urinalysis were normal and no
    evidence of Heinz body formation was noted (Weir & Crews, 1966a).

    Dog

         Four groups of one male and one female beagle dogs received
    Allure Red daily in capsule form at the following doses, 0, 125, 250
    and 500 mg/kg bw. No adverse effects were noted on body weight, food
    consumption, survival, organ weights, gross and histopathology,
    haematology and clinical chemistry. At the highest level, there were
    slight ill-defined hepatic parenchymal changes in both sexes (Weir &
    Crews, 1966b).

         Groups of four male and four female beagle dogs received 0, 0.37,
    1.39 and 5.19% of Allure Red in their diet for 104 weeks. All animals
    remained normal regarding appearance, behaviour, haematology and
    clinical chemistry findings and gross and histopathology. Both faeces
    and urine were coloured at all test levels. At 52 weeks, an interim
    sacrifice was performed and revealed that the adrenal cortical cells
    of the high level groups showed some vacuolation. There was brown
    pigment deposition in the Kupffer cells of females at the two lower
    test levels. These changes had disappeared by 104 weeks and special
    histological examination of the eyes revealed no adverse changes
    (Olson et al., 1970).

    Pig

         SPF pigs of Danish Landrace were equilibrated for a period of 21
    days, whereupon they were distributed according to body weight into
    nine groups which consisted of two males and two females. The compound
    was administered by gavage three hours after feeding in the morning.
    The dye was administered at a dose of 1000 mg/kg/day for the first 21
    days, thereafter the dose was increased to 1500 mg/kg/day and this
    dosage was given for an additional 54 days. Body weight was recorded
    weekly and food intake daily. Blood samples were collected two days
    prior to and five, 19 and 68 days following the initiation of colorant
    administration. The haematological and clinical parameters measured
    were haemoglobin, packed cell volume, total erythrocyte count, counts
    of Heinz bodies and reticulocytes and serum activities of LDH and
    isoenzymes. Autopsy and histological examination of kidneys, spleen,
    liver, hepatic and renal lymph nodes and bone marrow were performed.
    The colour produced no significant effects on clinical and
    haematological parameters nor did it elicit any observable
    pathological changes (Sondergaard et al., 1977).

    Long-term studies

    Mouse

         A control group of 50 male and 50 female mice, a positive control
    group of 25 male and 25 female and a test group of 50 male and 50
    female mice were treated dermally with 0.1 ml of either distilled
    water, 10 g 3,4-benzypyrene in acetone or a 5% Allura Red test
    solution twice weekly for 20 months. The results in the positive
    control group showed the mouse strain used to be sensitive to
    benzypyrene carcinogenesis. Survival, gross and histopathology of
    major organs were comparable in the negative controls and animals
    treated with Allura Red. Histology of the skin revealed comparable
    incidence and degree of severity of acanthosis, hyperkeratosis and
    dermatitis for the negative control and the Allura Red groups
    (Voelker, 1970).

         Groups of 50 CD(R)-1 albino mice/sex received Allura Red in
    their diets at levels of 0.37, 1.39 and 5.19%. These animals were the
    offspring of parental mice treated at identical levels for one week
    prior to breeding and through gestation and lactation. An additional
    group of 50 animals/sex served as a negative control group. An interim
    sacrifice was performed at 42 weeks which resulted in reducing the
    number of animals in each group and sex to 30. This was done to
    determine compound effects upon the early onset of tumours of the
    lymphatic system. Prior to this, neoplasms which were histologically
    diagnosed as lymphomas were found in several animals which received
    the colour. Statistical analysis of the incidence of tumours occurring
    throughout the study did not reveal any increase in tumour incidence
    due to compound administration. No treatment-related effects were
    noted in the survival, clinical signs and clinical laboratory data.
    The animals on the highest dosage level demonstrated lower body
    weights and effects on organ weight data and organ/body weight ratios,
    however, the meaning of these observations ware considered to be
    inconsequential. Gross and microscopic examination of all the animals
    revealed an absence of treatment-related effects and spontaneous
    disease-related lesions were considered to be within acceptable limits
    (Serota et al., 1977a).

         A second lifetime dietary mouse study was performed using a
    protocol identical to the one described above, with the exception that
    100 animals/sex/group and two negative control groups were used. As
    before, statistical evaluation of neoplasms of the reticuloendothelial
    system failed to show a significant correlation between tumour
    response and increasing dosage. Sporadic changes were noted in the
    clinical signs, body weight, food consumption and survival rates; none
    the less, these could not be related to the administration of the
    colour. Alterations of the absolute and relative weights of the
    adrenals and thyroids were noted in several of the treatment groups.
    Histological examination of these tissues in the animals in the
    highest dose group at the completion of the study demonstrated no
    abnormalities. Therefore, the significance of weight gains in these

    two organs could not be established. Generally, gross pathological
    findings were similar in the control and treated animals. There was,
    however, a higher incidence of dark areas in the lungs of those
    animals in the high dose group which died or were sacrificed
    in extremis and of cystic foci areas in the kidneys of the high dose
    males. No distinct treatment-related effects could be ascribed to
    these findings. Histopathological evaluation did not show effects
    which could be attributed to compound administration, nor was there
    evidence for a dose-related increase in the incidence of spontaneously
    occurring tumours (Reno et al., 1978).

    Rat

         Groups of 30 male and 30 female rats received in their diet 0,
    0.37, 1.39 and 5.19% of Allura Red for 92 weeks. Moderate growth
    depression occurred at the 5.19% level in both sexes. No other
    compound-related effects were noted as regards appearance, behaviour,
    survival, organ weights, clinical laboratory studies or gross and
    histopathology. No evidence of Heinz body formation was noted apart
    from a slight tendency to anaemia (Olson & Voelker, 1970).

         50 CD(R)-1 albino rats/sex were placed in a negative control
    group and three test groups which contained varying percentages (0.37,
    1.39 and 5.19) of Allura Red. The males were administered the diets
    for 118 weeks, and the females were fed for 121 weeks. All of these
    animals were the F1a offspring of parental rats which were treated at
    identical levels for one week prior to breeding, through a three-week
    breeding period and during the gestation and lactation periods. No
    treatment-related effects were noted in comparisons of survival,
    clinical signs, clinical laboratory data and organ weight data. The
    mean body weights and growth rates of the animals in the high-dose
    group were lower than those of control animals. However, the low dose
    group exhibited greater mean food consumption values than the control
    groups. Gross pathological and histopathological findings were
    essentially comparable between the control and treated groups.
    However, increased incidences of kidney discoloration and firm
    granular material in the pelvis of the kidney were noted in the males
    of the colour treated groups. A slightly higher incidence of granules
    in the pelvis was also noted in the high-dose males sacrificed at
    termination. However, no significant dose-related trend was noted in
    the statistical analysis of these data. An increased incidence of
    renal calculi and focal epithelial proliferation was noted in the
    high-dose rats, but additional examination of the other groups
    indicated that this toxic effect could not be attributed to the
    administration of the compound (Serota et al., 1977b).

    Comments

         Allura Red when administered orally undergoes partial azo
    reduction prior to absorption. Metabolic studies indicate that the
    colour is poorly absorbed in the body, and the major route of
    excretion is via the faeces. In a multigeneration reproductive study
    on rats it was shown that the progeny of the parents who were fed

    51.9 g of the colour per kg of food demonstrated a slight growth
    depression. The "no effect" level on reproductive physiology of this
    colour in the rat is 13.9 g/kg of food. Teratogenicity studies in rats
    and rabbits failed to show any compound-related embryotoxic effects. A
    variety of mutagenicity studies carried out with Allura Red indicated
    that there were no mutagenic effects. Another study on acute and
    short-term oral toxicity of Allura Red in several species revealed
    that apart from the coloration of the urine and faeces, there were no
    other compound-related responses. Dermal studies (both short- and
    long-term) also indicated an absence of colour-induced toxic
    responses. In long-term feeding studies on mice and rats, the most
    consistent observation was that the animals that received the greatest
    amount of colour (51.9 g/kg of food) exhibited lower body weights
    compared to control animals. One study suggested that mice that were
    fed on this colour demonstrated an earlier onset of tumours of the
    lymphatic system compared to control mice.1 However, a second more
    extensive mouse study has not borne this out. The long-term study and
    the mutagenicity studies suggest that Allura Red does not possess
    carcinogenic potential.

         The data were sufficient to establish a temporary acceptable
    daily intake for man pending the availability of the statistical
    analysis of the long-term mouse study.
    

    EVALUATION

    Level causing no toxicological effect

    Rat: 1.39% in the diet corresponding to 695 mg/kg bw.

    Estimate of acceptable daily intake for man

    0-7 mg/kg bw.*

    FURTHER WORK OR INFORMATION

    Required by 1981

    (1) Adequate information of statistical analysis of the long-term
    mouse studies.

              

    *    Temporary.
    

    REFERENCES

    Anonymous. Mutagenicity investigations with allura red. Sex-linked
         recessive lethals, Drosophila melanogaster, Bowling Green
         University, Ohio, USA. Interim report of the Working Group on FD
         & C Red, No. 40, 19 January 1977b, submitted to WHO by the US
         Food and Drug Administration

    Anonymous. Mutagenicity investigations with allura red. Saccharomyces
         cerevisiae. Genetic Toxicology Branch of the FDA. Interim
         report of the Working Group on FD & C Red No. 40, 19 January
         1977a

    Anonymous. Evaluation of substances of interest for genetic damage
         using Drosophila melanogaster. Unpublished report submitted to
         WHO by the United States Food and Drug Administration, 31 March
         1978

    Blackmore, R. H. Repeated dermal irritation study-rabbits, nontoxic
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    Blackmore, R. H., Olson, W. A. & Voelker, R. W. Two-generation
         reproduction study in rats, Red Z-4576. Unpublished report
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    Bradlaw, J. Enzyme induction screen of seven color and cosmetic
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    Brown, J., Roehm, G. & Brown, R. Mutagenicity testing of certified
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         1978

    Brusick, D. Mutagenicity evaluation NTRZ-4576 (Allura Red AC).
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    Collins, T. F. X. Preliminary results of teratological studies on
         Osborne-Mendel rats with FDC Red No. 40. Unpublished report by
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    Guyton, C. L. & Reno, F. E. Metabolic disposition of 35S Allura Red AC
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    Guyton, C. L. & Stanovick, R. P. Determination of the metabolites of
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         Laboratories America, Inc., submitted to WHO by Allied Chemical
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         submitted to WHO by Allied Chemical Corporation, 1966a

    Weir, R. J. & Crews, L. M. Six-week oral administration - dogs,
         experimental non-toxic Red Z-4576, Z-4578, Z-4598 and Z-4808.
         Unpublished report 165-116 by Hazelton Laboratories, Inc.,
         submitted to WHO by Allied Chemical Corporation, 1966b

    White, R. G. Metabolic fate of orally ingested non-toxic Red Z-4576.
         Unpublished report number 21855 by Buffalo Research Laboratory,
         submitted to WHO by Allied Chemical Corporation, 1970
    


    See Also:
       Toxicological Abbreviations
       Allura red AC (WHO Food Additives Series 6)
       ALLURA RED AC (JECFA Evaluation)