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concentrations of Monascus pigments

than 1 [M induce IgE production but inhibition is observed at lower concentrations; at 1 [M, betanin, carthamus yellow, and Monascus pigment shows a strong inhibition of IgG and IgM; water-insoluble pigments (gardenia yellow, laccaic acid, and bixin) inhibit the IgE production at all concentrations; thus, it is suggested that lipophylic coloring can be stimulant of the humoral system and by inhibition of IgE production, an anti-allergenic agent

Sources: Adapted from Hallagan et al. (1995),11 JECFA (1975),19 Khera and Munro (1979),20 Parkinson and Brown (1981),21 Kuramoto et al. (1996),28 Linnainmaa et al. (1997),29 Tanaka (1997),30 Lu et al. (1998),31 Imazawa et al. (2000),37 and Sabater-Vilar et al. (1999).39

In addition, it must be considered that the safety factor could be even greater when the model used in the evaluation has a very low metabolic similarity with the animal whose toxicological ADI values are being obtained.13 ADI is usually expressed as milligrams of the test substance per kilogram of body weight (bw) per day. When acute toxicity studies are carried out, LD50 is the chief parameter used: LD50 is the dosage that results in the death of 50% of the experimental animals.

3. Toxicology of Certifiable Colorants

The use of certifiable colorants has been supported by different toxicological studies (Table 4.4); several have been disapproved as food additives in the legislation of several countries (Table 4.2). Moreover, the discussion about the safety of synthetic pigments is common and new toxicological information has been presented thanks to newly introduced analytical technologies.

Amaranth. This was one of the first seven color additives approved in the United States, and its long history of usage gives good reason for it to be considered safe; this synthetic pigment is different from the natural pigment, termed amaranthine, which is obtained from the amaranth plant. Several toxicological evaluations have been carried out in different animal models and conditions, and it was evaluated by JECFA (Joint Expert Committee on Food Additives) in 1972. Rat metabolism converts amaranth into 1-amino-2-hydroxy-3,6-naphthalene sulfonic acid and 1-amino-2-hydroxy-3,6-naphthalene disulfonic acid. NOAEL was established from rats at 150 mg/kg bw. The current status of amaranth is a temporary permission with an ADI of up to 7 mg/kg bw.1921

Sunset yellow. Sunset yellow was allowed for use in the United States in April 1929. Its ADI has been established at 0 to 2.5 mg/kg bw by the EU and 0 to 5 mg/kg bw by FAO/WHO. It has shown a limited absorption (3.6%) and azo reduction in liver. Metabolism is mainly associated with the gut intestinal flora. In rabbits fed with this color, analysis of urinary collection showed unchanged dye, sulfanilic acid, p-acetamidobenzenesulfonic acid, and 1-amino-2-naphthol-6-sulfonic acid. LD50 ranges between 3.8 and 5.5 g/kg in rats and mice.20

Tartrazine. This is the color most frequently involved in food intolerance studies. In humans, rat, and rabbit, sulfanilic acid is excreted after oral dosing of Tartrazine. It is suggested that tartrazine is reduced in the gut, producing sulfanilic acid and 4-amino-5-oxo-1-p-sulfophenyl)-2-pyrazoline-3-carboxylic acid (aminopy-razolone). Tartrazine is allergenic and has been suggested to induce hyperactivity and urticaria in children. NOAEL of 750 mg/kg bw/day has been established from a 2-year study in rats. From this study, JECFA has established an ADI of 0 to 7.5 mg/kg bw/day. At an LOAEL of 1000 mg/kg bw, rats suffer laxation, and above an LOAEL of 2500 mg/kg bw/day, kidney is the target tissue and gritty material is deposited, presumably due to calcinosis (Table 4.4).202i,23,24 It has been suggested that the effect of tartrazine on intestinal contractions is mediated by the muscarinic acetylcholine receptor, associated with the parasympathetic innervation.25

Ponceau 4R. A low absorption is observed in rats (1.7%). The unchanged dye and considerable quantities of 2-amino-1-hydroxy-4-naphthalene sulfonic acid, 1-amino-2,4-dimethyl-5-benzene sulfonic acid, and 2-acetamino-1-hydroxy-4-naph-thalene sulfonic acid have been found in the urine.20

Brilliant blue. A triphenylmethane colorant, brilliant blue is easily reduced to colorless forms in food, but does not undergo reductive cleavage. Studies have shown intestinal absorption of less than 10% and rapid biliary excretion of oral doses. In experiments with rats, 5% of the absorbed product is metabolized to an unknown sulfonated metabolite.21 In rats, mice, and guinea pigs less than 1% is absorbed. Thus, the low degree of toxicity observed in chronic feeding studies is ascribed to their low level of absorption. Also, no mutagenicity has been observed in the Ames Salmonella/microsome test or in Bacillus subtilis.21 An ADI of 0 to 12.5 mg/kg bw was established in 1969 by JECFA, with an NOAEL of 2500 mg/kg bw/day in rats.

Limited toxicity is corroborated when rats are fed with an NOAEL value above 2500 mg/kg bw/day/2 years of brilliant blue.21,24

Cochineal red A/red 2G. JECFA evaluated this color in 1981. Its ADI has been established at 0 to 0.1 mg/kg bw based on an NOAEL of 26 to 43 mg/kg bw/day in mice and 8 mg/kg bw/day in rats. At the LOAEL value, 130 to 215 mg/kg bw/day in mice and 32 mg/kg bw/day in rats, the target tissues are spleen and kidneys. Kidney is enlarged and increased deposition of iron has been observed. Mice experience an accelerated erythropoiesis and rats show necrosis of elastica. Red 2G is metabolized by rat gut microflora to 2-amino-8-acetamido-1-naphtho-3,6-disulfonic acid and aniline. Heinz body induction after red 2G has been suggested to be caused by aniline metabolites. Two possible compounds have been proposed: p-aminophenol and phenylhydroxylamine. At an NOAEL level of aniline, a Heinz body is formed neither in rats nor in humans. However, methemoglobin is produced. In rats fed with phenylhydroxylamine, methemoglobin formation is higher than in humans.24

Fast green. A triphenylmethane colorant as brilliant blue. Consequently, fast green is metabolized similarly to brilliant blue, as described above. This colorant has a temporary ADI of 0 to 12.5 mg/kg bw/day. It has shown a very low absorption, which does not exceed 5% of the administered dose in rats.20,26

Indigotine. Indigotine is readily oxidized to isatin-5-sulfonic acid and 5-sul-foanthranilic acids. In rats, less than 3% of the ingested pigment appears in the urine either intact or in the metabolized forms. In humans, 80 mg increases the arterial pressure as a symptom of increased peripheral resistance by stimulation of the sympathetic nervous system. JECFA has reviewed all the toxicity assays and an NOAEL has been established as 500 mg/kg bw in rats, and an ADI in the 0 to 5 mg/kg range. Mutagenicity has not been observed either in Escherichia coli or in the Ames test.20,21

Erythrosine. Erythrosine is another of the seven original colors permitted by the United States and it is accepted over the world (see Table 4.2). Toxicological studies of this pigment in rats, mice, gerbils, guinea pigs, rabbits, dogs, and pigs have not shown deleterious effects. The pigment shows mutagenic activity on E. coli but not in the Ames microsome assay. Also, a neurotransmission inhibition by effect of erythrosine has been reported. Originally, a NOAEL of 250 mg/kg bw was established in rats, but recently a value of 1 mg/kg bw in humans has been assessed. Thus, ADI has been estimated by using a correction factor of 10, and its value is 0 to 0.1 mg/kg bw/day. The main problem associated with this product is its high iodine content. In rats, this pigment is poorly absorbed. The absorbed product is discarded in two forms, intact or deiodinated. At an LOAEL 3.3 mg/kg bw/day, erythrosine induces changes in the thyroid hormones and, at the highest levels (3029 mg/kg bw/day), adenomas and carcinomas have been observed in thyroid glands.20,21,24,26 Results shown in Table 4.4 support that erythrosine toxicity is not related to genotoxic mechanisms.

Allura red. Metabolic studies have shown that allura red (FD&C No. 40) has the following cleavage products: 1-amino-2-hydroxy-7-naphthalensulfonic acid and 1-amino-2-methoxy-5-methyl-4-benzenesulfonic acid.21 Its NOAEL has been established in lifetime mice treatments with values of 7300 and 8300 mg/kg bw for male and female mice, respectively (Table 4.4). The ADI for humans is in the 0 to 7.0 mg/kg bw range.27 Lake toxicity is assumed to be equal to that of its corresponding FD&C certified pigment.21

4. Toxicology of Exempt-from-Certification Colorants

It was discussed above that some colorants are exempt from certification, although such category is now out-of-date and any new colorant to be considered as a food additive must be certified by the FDA under the U.S. legislation. Further, colorants previously considered exempt have nonetheless been subjected to toxicological studies (Table 4.5).11,19-21,28-30 Additionally, new information is generated using the new analytical technologies, and some new data are discussed below.

Titanium dioxide. It has been suggested that titanium dioxide is not genotoxic, but recent studies have shown evidence of potential genotoxicity.31 Acute oral toxicity is low in rats (LD50 > 25 g/kg bw/day) and mice (LD50 > 10 g/kg/day). Long-term toxicity studies in rats, mice, dogs, guinea pigs, cats, and rabbits have demonstrated no evidence of carcinogenicity. NOAEL levels reported reach 3.75 g/kg bw/day in rats. Reduced survival (66%) has been observed in female mice fed 7.5 g/kg.11

As can be noticed, toxicity studies have been limited to a reduced group of pigments and some have never been evaluated. Also, it is clear that a history of usage is extremely important in food application of synthetic and natural colorants. In fact, some of the approved pigments for food application have given contradictory results in toxicity and safety evaluations (Table 4.5). Consequently, it is clear that the introduction of new colorants, synthetic or natural, is a difficult task in light of the stringency of the toxicity and safety evaluations and their well-known variability.

Annatto. Annatto is not genotoxic. Studies of acute oral toxicity have shown a low LD50: in rats it is more than 50 g of oil-soluble extract/kg bw and more than 35 g of the water-soluble extract/kg bw. LD50 of the water extract Bixa orellana roots is 700 mg/kg in mice. Hypersensitivity reactions such as urticaria and asthma have been observed in humans. An ADI was established by JECFA at 0 to 0.065 mg/kg bw.

Carotenoids and xanthophylls. Canthaxanthin is not genotoxic and it has been reported to inhibit the activity of known mutagens. It shows a low acute oral toxicity in mice (LD50 = 10 g/kg bw). JECFA is unable to assign an ADI because of its association with retinal deposition in humans. Night vision alteration of rabbits occurs after an intravenous injection of 11.4 mg/kg bw. Impairment in vision has also been reported in cats but no effect is observed in rats and mice. Canthaxanthin shows limited absorption in humans.

Rats have shown a partial absorption of apocarotenal. Apocarotenal is converted to P-apo-8'-carotenoic acid and vitamin A. These compounds are accumulated in the liver. Similar behavior has been observed in dogs. Acute toxicity in mice is very low (LD50 > 10 g/kg bw). No adverse effects are observed in male rats provided with up to 500 mg/kg bw for 34 weeks. No adverse effects are observed in dogs fed 1 g/day/14 weeks. In the ethyl and methyl esters of the P-apo-8'-carotenoic acid a very low acute toxicity (LD50 > 10 g/kg bw) is also observed.32

P-Carotene. This substance is poorly absorbed in humans; 30 to 90% is excreted in the feces. Some P-carotene is stored in the liver and some is converted to vitamin A. In hypercarotenemia, harmless skin yellowing is observed (carotenosis). In rats, 15% of the absorbed P-carotene is metabolized to fatty acids, 40% into non-sapon-ifiable material, and 5% is exhaled as CO2. No effects are observed in rats when 40,000 to 70,000 IU of vitamin A esters/day are administered intravenously, intra-peritoneally, or by mouth. However, oral doses of 1500 IU induce accelerated epithelial growth in rats. In dogs, acute oral toxicity is low (LD50 = 78 g/kg bw). The JECFA has established an ADI, as a sum of carotenoids used as color additives, of 0 to 5 mg/kg bw.11 Interestingly, during chemoprevention trials with P-carotene alone or in combination with vitamin A or E, unexpected increments in lung cancer incidence in heavy smokers and asbestos workers have been observed.33

Paprika and paprika oleoresins. These substances are not shown in Table 4.5, but several studies have demonstrated that paprika is not genotoxic. Studies of acute oral toxicity have shown low values (LD50 < 11 g/kg bw) and lifetime studies failed to demonstrate toxicity or carcinogenicity.11

Anthocyanins. Anthocyanins are not genotoxic. Relatively little is known about the metabolic fate of anthocyanins. Cyanidin chloride metabolites are not detected in rats or in vitro with intestinal microorganisms. On the other hand, pelargonidin breaks down to p-hydroxyphenyl lactic acid, and to another product, presumably phloroglucinol. Delphinidin administered intragastrically produces an unidentified metabolite in urine. Malvidin glycoside produces a number of metabolites observed in urine, including syringic acid. Additionally, information about anthocyanin absorption is very scarce. On the other hand, cyanidin and delphinidin do not show mutagenic activity in the Ames test. JECFA established an ADI of 0 to 2.5 mg/kg bw for anthocyanins from grape skin extract. However, it appears likely that the consumption of anthocyanins from fruits and vegetables would greatly exceed their consumption as color additives.21

Betalains. Relatively little information exists about the metabolism and toxicity of the betalain alkaloids. Some 14% of the normal population experiences beturia manifested by the excretion of unchanged betalains in urine. Studies in rats have shown that betalains are metabolized in the gut.21

Chlorophyll. Although not shown in Table 4.5, chlorophyll has been evaluated in its commercial forms, that is, chlorophyllin copper complex, K, and Na salts. Long-term feeding studies in rats at up to 3% copper chlorophyllin complex in the diet for their life span result in no adverse effects in growth rate, reproduction, and histopathology, among other evaluated variables.

Caramel. Caramel is not genotoxic. An ADI has not been established for caramel colors I or II. Rats fed with caramel II have shown reduced body weight, which is ascribed to water imbalance rather than to toxic effects of caramel II. About one third of caramel color III appears to be absorbed by rats. In caramel prepared by the ammonia process (caramel III), convulsions have been observed in cattle and sheep. This led to the discovery of the imidazoles in ammonia-treated molasses. The most toxic convulsant activity is induced by 4-methyl imidazole; in rats, about 30% absorption of the dose has been observed. In rats and dogs provided with 20 or 25%

of the diet, no adverse effects were observed. In a teratological study in pregnant rats, rabbits, and mice at 1.6 g/kg bw/day/13 days, no significant effects on fetal, soft, or skeletal tissues were observed. Mutagenicity in the Ames test was negative. On the other hand, contradictory results have been obtained regarding caramel toxicity on Salmonella strains. In fact, in several studies in which up to 350 ppm of pigment was used, Salmonella cytotoxicity has been suggested. Caramel III was evaluated by JECFA in 1987 and an ADI of 20 g/kg bw/day was reported from a 90-day oral toxicity study in rats. LOAEL was found to be 1% of the diet in rats. At this level, reduction in lymphocyte number and increased neutrophil count is observed. Above the 1% level, reduction in spleen weight occurs while cecum and kidney increase in weight. It has been established that the toxic ingredient of caramel III is 2-acetyl-4(5)-tetrahydrobutylimidazole. In addition, it has been proposed that toxicity activity is correlated with inhibition of the activity of pyridoxal phosphatase. On the other hand, caramel obtained by the ammonia sulfite process (caramel IV) has a temporary ADI in the range of 0 to 100 mg/kg bw. The pigmentation of mesenteric lymph nodes and cecal enlargement were suggested as not of toxicolog-ical significance.21,24,26,34

Carmine (Carminic acid). Along with its aglycone derivative kermesic acid, carmine is obtained from the cochineal insect (Dactylopius coccus) and the kermes insect (Kermococcus vemilius). Both are anthraquinone pigments and show a high chemical and biological stability. In a single-generation study in rats, 200, 500, and 1000 mg/kg bw did not produce any adverse effects. In a short-term study with mice, 150 mg/kg of carmine was injected on the eighth day of pregnancy. Mice showed high resorption rates and malformations in 2 of the 85 treated mice vs. none in the control group. JECFA has established a combined ADI to the cochineal extract and carmine of 0 to 5 mg/kg bw. On the other hand, kermesic acid has a chemical structure related to phenolic anthraquinones and mycotoxins, which are mutagenic, carcinogenic, or toxic. However, no genotoxic effects have been described for ker-mesic acid. In rats, intakes up to 500 mg/kg bw/day, in a long-term experiment (three generations), did not produce untoward effects on the growth or fertility either in parental rats or in the offspring.21 Recently, proteinaceous materials in carmine dyes were identified as allergens; the proteins were contaminants from cochineal insects.35

Gardenia yellow. It has been reported that the extract of gardenia fruit has choleretic and purgative properties and induces liver damage. Iridoids are the compounds responsible for these biological activities but the mechanism of action is still unclear.36

Gardenia blue. Acute and subacute toxicity studies have not shown toxicity, mutagenicity, or carcinogenicity effects. It has an LD50 > 16.7 g/kg and 10 g/kg bw for male mice and rats of both sexes, respectively. Thus, it has been reported that uses of gardenia blue up to 0.1% by weight in food products, a common dose, it does not induce damage.37

Lac. Lac has not shown adverse effects (e.g., cytotoxic, mutagenic, reproductive, or neurobehavioral), but reduces body weight growth in higher-dosage groups; thus, the maximum levels permitted in Japanese foods (5 to 100 mg/kg) are not considered dangerous to human health.38

Riboflavin. Riboflaven is essentially nontoxic, LD50 > 10 g/kg bw in rats, and greater than 25 mg/kg bw in dogs.

Monascus. Extracts fail to induce mutagenicity when low levels of the myco-toxin citrinin are found in Monascus samples. In general, no adverse effects have been reported for Monascus preparations but the levels of citrinin must be carefully controlled.39

Turmeric (curcumin). Turmeric is neither genotoxic nor carcinogenic. Turmeric is considered by JECFA as a food, and no ADI is allocated. On the other hand, a turmeric-oleoresin ADI has been established at 0 to 0.3 mg/kg bw by JECFA and 0 to 1.0 mg/kg bw for curcumin. Turmeric has shown a low acute oral toxicity with LD50 higher than 10 g/kg bw in rats and mice. Additionally, LD50 values for curcumin in mice are higher than 2 g/kg bw. Curcumin is poorly absorbed and rapidly excreted, and metabolism of the substance has been studied extensively. Absorption was observed to be about 25%. No toxic effects were detected after doses of up to 5 g/kg bw. Metabolites are glucuronides of tetrahydro- and hexahydrocurcumin and, in minor amounts, dihydroferulic acid. Several subchronic and chronic studies have shown no adverse effects: two dogs provided with 1% of commercial turmeric; male and female rats fed during 420 days with 0.5% turmeric. No effect was observed on hematology or reproductive function. Chromosomal aberrations have been induced in the root tip cells of Allium cepa. Cytogenetic effects (arrested mitosis, altered chromosome morphology, and altered nucleic acid synthesis, among others) have been observed also in Chinese hamster, cactus mouse, Indian muntjac, and in short-term human lymphocyte cultures. Diets of mice containing 0.5% turmeric or 0.015% curcumin did not show significant increases in the incidences of micronu-cleated polychromatic erythrocytes, aberrations of bone marrow chromosomes, alterations of pregnancy rate or embryo survival, among others. At LOAEL values of 400 mg/kg bw/day or higher (2000 mg/kg bw/day), enlargement of the liver, ulcers, and hyperplasia in the gastrointestinal tract have been observed. Toxic activity is related to inhibition of the cytochrome P-450 enzymes.21,24

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