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TARTRAZINE YELLOW SYNONYMS trisodium 5-hydroxy-1-(4-sulphophenyl)-4-(4-sulphophenylazo)pyrazole-3-carboxylate 1H-Pyrazole-3-carboxylic acid, 4,5-dihydro-5-oxo-1-(4- sulfophenyl)-4-((4-sulfophenyl)azo)-, trisodium salt 4,5-Dihydro-5-oxo-1-(4-sulfophenyl)-4-((4-sulfophenyl)azo)- 1H-pyrazole-3-carboxylic acid, trisodium salt Acid yellow 23 CI 19140 FD & C Yellow no. 5 Tartrazine C.I. Acid Yellow 23 CHEMICAL STRUCTURE

CHEMICAL FORMULA

C16H12N4O9S23Na IDENTIFIER DETAILS CAS Number : 1934-21-0 CoE Number : - FEMA : - EINECS Number : 217-699-5 E Number : 102 SPECIFICATIONS Melting Point: 350oC Boiling point: -

Tartrazine Yellow.doc of 11 August 2011

STATUS IN FOOD AND DRUG LAWS CoE limits: Beverages (mg/kg) Food (mg/kg) Exceptions (mg/kg)

- - - Acceptable Daily Intake:

ADI (mg/kg) ADI Set by Date Set Comments 0-7.5 JECFA 1964 -

FDA Status: [CFR21] Section Number Comments

74.1705 Listing of colour additives subject to certification HUMAN EXPOSURE Natural occurrence: Not reported to be found in nature Reported Uses: Used to colour food, being a foodstuff additive and used in various human pharmaceuticals and cosmetics. Sources other than foods: Used to colour human pharmaceuticals and cosmetics. TOXICITY DATA The estimated mean daily consumption of tartrazine in France was calculated to be 0.396 mg/kg/day [Elhkim et al., 2007]. Tartrazine (E 102, FD & C Yellow N°5) is an azo dye used as a foodstuff additive and in various human drugs. Since its first safety assessment, conducted by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1964, more than 300 new studies on laboratory animals and clinical trials on human beings have been conducted. Many of them have incriminated tartrazine in hypersensitivity reactions, raising questions about its safety [Elhkim et al., 2007]. In both human and in laboratory animals the oral absorption and metabolism of tartrazine are extremely low. Toxicokinetic studies published in the literature show that less than 2% of the ingested tartrazine is absorbed (Murdoch et al., 1987). Most of the tartrazine is readily metabolised in the colon by the intestinal flora [JECFA, 1964]. The metabolism of tartrazine in animals has been studied by several authors including [JECFA, 1964], with the major urinary metabolite being sulfanilic acid which is produced after tartrazine reduction by intestinal bacteria. The presence of electron carriers released by bacteria (e.g., flavin) and the anaerobic conditions in the colon allow tartrazine reduction into sulfanilic acid and aminopyrazolone [Chung et al., 1978]. Chung et al. (1978) suggested that extracellular electron acceptors can stimulate azo dye reduction. Depending on the bacteria strain, this reduction may be catalysed by an enzymatic reaction. Aminopyrazolone is then degraded into 4-hydrazinobenzenesulfonic acid in the intestine, and then reduced into sulfanilic acid. Although mostly excreted in faeces, these metabolites and, to a


lesser extent parent tartrazine, may be absorbed. Intravenous or intraperitoneal administrations in different animal species have shown that compounds resulting from the reduction are not formed in the liver. Kuno and Mizutani (2005, as cited in Elhkim et al., 2007), using bovine liver microsomes, which are assumed to mimic human liver microsomes, as enzyme sources of CYP2A6 and UDP-glucuronosyltransferase (UGT1A6 and UGT2B7) showed that tartrazine was not a substrate for these enzymes [Elhkim et al., 2007]. Liver enzymes that reduce azolinkages would only play a minor role in the metabolism of the azo dye. Reduction by intestinal bacteria would therefore be the most likely route of exposure [JECFA, 1964], [Chung et al., 1978]. Groups of Sprague-Dawley female rats were given single oral doses of aqueous solutions (1%) containing 2 to 25 mg of 14C-tartrazine labelled in the 1-p-sulphophenyl ring. Urine and faeces were collected at 24-hour intervals. Bile was collected from bile duct cannulated animals and blood was collected regularly from the orbital sinus. After 72 hours, animals were sacrificed an tissues from the liver, spleen, kidneys, stomach, small intestine, caecum, large intestine, and peri-uterine fat sample were subjected for radioassay. Total 72-hour urinary excretion of tartrazine was only 4.0%. Biliary excretion was less than 0.1% while there was only trace amounts of radioactivity in internal organs after 72 hours. In terms of metabolites, 21% of the total radioactivity was detected in the urine as sulfanilic acid. Twenty-four hours after dosing, approximately equal amounts of urine radioactivity (43-44%) was accounted for by sulfanilic acid and aminopyrazolone. The urinary radioactivity corresponded to 20% and 1.6% of the administered dose of tartrazine being excreted as sulfanilic acid and aminopyrazolone, respectively. Only a trace amount of intact tartrazine was detected in the urine [Honohan et al., 1977]. In humans, after oral ingestion of 100 mg of tartrazine, no trace of tartrazine was found in the urine from volunteers. An in vitro study conducted using intestinal bacteria of five human subjects confirmed the reduction of tartrazine by the intestinal flora. Though limited, these findings on the toxicokinetics of tartrazine in human beings appeared to be consistent with the results obtained with laboratory animals [Elhkim et al., 2007]. In Vivo Toxicity Status Oral - Mice LD50 12750 mg/kg Intraperitoneal - rat LD50 2000 mg/kg* Intravenous - rat LD50 1000 mg/kg

[IACM/HPV] Oral - Human TDLo 0.014mg/kg (Effects: Peripheral nerve and sensitisation: parenthesis. Musculoskeletal: Changes in teeth and supporting structures) Intravenous - rat LD50 >2000 mg/kg

[ToxNet, 2009]


Reproductive and Developmental toxicity Tartrazine was given to mice in the diet at levels of 0 (control), 0.05%, 0.15%, and 0.45% from 5 weeks of age of the F0 generation to 9 weeks of age of the F2 generation, and selected reproductive and neurobehavioral parameters were measured. In the F1 generation, the development of swimming direction at postnatal day (PND) 7 was accelerated significantly in male offspring in a dose-related manner. Surface righting at PND 7 was affected significantly in female offspring in dose-related manner. Several variables in exploratory behaviour showed significant tendencies to be affected in the treatment groups in male offspring at 3 weeks of age. In the F2 generation, the development of swimming direction at PND 7 was accelerated significantly in the high-dosed group in male offspring. Time taken of olfactory orientation at PND 14 was accelerated significantly in male offspring in a dose-related manner. Several variables in exploratory behaviour showed significant tendencies to be affected in the treatment groups in male offspring at 3 weeks of age, and in males at 8 weeks of age. The authors reported that the dose levels of tartrazine in the present study produced a few adverse effects on neurobehavioral parameters throughout generations in mice [Tanaka et al., 2008]. In a recent study on mice tartrazine was given in the diet at levels of approximately 83, 259 and 773 mg/kg bw/day from the age of 5 weeks in the F0 generation until 9 weeks of age in the F1 generation. Selected reproductive parameters were measured. Based on a number of data describing tartrazine-related hyperactivity in children, Tanaka (2006) also studied behavioural development parameters (surface righting, negative geotaxis, cliff avoidance, swimming behaviour and olfactory orientation) in mice offspring. There was no significant modification in food intake and body weight in F0 and F1 generations. There were no significant effects of treatment in the number of pregnant females, of litters, in litter size, litter weight, total sex ratio and average sex ratio. The reproductive NOAEL was 773 mg/kg bw/day (645–2540 mg/kg bw/day depending on measured intake during the reproductive study). Tartrazine did not have any adverse effect on the behavioural development of offspring except for the surface righting reflex, with a significantly accelerated righting reflex for the high dose of exposure male offspring group was observed during the early lactation period. This effect was statistically significantly dose-related (p < 0.01). Based on this study the NOAEL would be 259 mg/kg bw/day (tartrazine intake in males) [Tanaka 2006]. In a study performed by the FDA, female Osborne-Mendel (FDA strain) rats (40-41 per group) were administered FD&C Yellow No. 5 via oral gavage at dose levels of 0, 60,100, 200, 400, 600 or 1000 mg/kg bw/day for the first 19 days of gestation. On day 19, the animals were examined for gross abnormalities followed by euthanisation. Caesarean sections were performed. The uterus was examined for presence and position of resorption sites and foetuses, number of corpora lutea and implantation sites. All live foetuses were promptly weighed, sexed, and examined. The authors reported no unusual behaviour or external findings among the dosed females of any


group. The mean daily food consumption of rats administered the 1000 mg/kg bw/day dose level was significantly greater than the controls. Initial body weight and maternal weight gain during gestation did not significantly differ between treated animals and controls. The pregnancy rate was similar among all groups. No dose related findings were reported on foetal viability or foetal development. The authors commented that the significant increase in food consumption observed in the highest dose group without a corresponding effect on body weight indicated an effect on food utilization. The authors concluded that FD&C Yellow No. 5 was neither developmentally toxic nor teratogenic under the conditions of the study. The NOAEL for maternal and foetal toxicity was determined to be greater than 1000 mg/kg bw/day [Collins et al., 1990]. Carcinogenicity and mutagenicity The studies assessed by the JECFA in 1964 showed that tartrazine administered orally at doses up to 5% of the diet to rats and 1% to mice had no carcinogenic potential (Waterman and Lignac, 1958), although these old studies, which are not available, might not meet current regulatory requirements. Carcinogenicity of tartrazine was examined in groups of 50 male and 50 female F344 rats that received tartrazine ad libitum in their drinking water at levels ranging from 0, 0.1% to 2% for up to two years. Only a mesothelioma in males and endometrial stromal polyp in females dosed at 1% tartrazine were above control levels. However, both spontaneous tumours were within the historical back ground range and were not dosage related. No treatment related lesions were found in any groups. In this study, the authors concluded that tartrazine was not carcinogenic in F344 rats when administered continuously at levels up to 2% in drinking water for as long as 2 years [Maekawa et al., 1987]. In addition, Charles River CD-1 mice were exposed to dietary levels of 0%, 0.5%, 1.5% or 5% in a 104-week carcinogenicity study. Tartrazine was not carcinogenic at doses up to 5% (8103 and 9735 mg/kg bw/day in male and female mice, respectively) [Borzelleca and Hallagan, 1988a]. Borzelleca and Hallagan, (1988b) exposed Charles River CD rats in utero and then for 104 weeks after weaning to tartrazine via the diet at levels of 0%, 0.1%, 1% or 2% and 0% or 5% (60 rats per sex per group) . No compound-related effects were noted either in F0 or F1 generation. It was concluded that tartrazine was not carcinogenic at doses up to 5% (2641 and 3348 mg/kg bw/day for male and female rats, respectively) [Borzelleca and Hallagan, 1988b]. In a rodent micronucleus test, 10 ml/kg bw male rats were administered a single oral dose of 500 or 1000 mg/kg of the structurally related azo dye FD&C Yellow No. 64. Bone marrow samples were taken at 24 and 48 hours later. There was no significant increase in the frequency of micronucleated


polychromatic erythrocytes at either time point in either species [Westmoreland and Gatehouse, 1991]. In an in vivo UDS assay, six to eight male Sprague-Dawley rats weighing 200-300 g were administered 500 mg/kg bw FD&C Yellow No. 5 via gavage. FD&C Yellow No. 5 did not induce unscheduled DNA synthesis at the dose level tested [Kornbrust and Barfknecht, 1985]. Behavioural data No data identified. Other relevant studies Tartrazine has been previously described as being responsible for triggering attacks of urticaria and asthma, particularly in aspirin-intolerant patients. Reports of angio-oedema, purpura, exacerbation of atopic dermatitis and gastro-intestinal disorders have also been published. However, the pathogenic mechanisms of these reactions, remain poorly understood [Elhkim et al., 2007]. Tartrazine intolerance has been reported in 6–50% of aspirin-intolerant people, suggesting possible cross-reactivity between tartrazine and aspirin. The inhibition of cyclo-oxygenase, often cited as the mechanism underlying aspirin intolerance, has therefore been proposed to explain tartrazine intolerance. The Scientific Committee on Food of the European Commission (FCS; 37th series, 1997) recently concluded it would not be the case given the results of several double-blind placebo-controlled challenges with tartrazine in aspirin-intolerant asthmatics that showed no cross-reactivity between cyclo-oxygenase inhibitors (aspirin and non-steroidal anti-inflammatory agents) and tartrazine. The other mechanistic hypotheses quoted in the literature, include inhibition of platelet aggregation or an increase in leucotriene synthesis, Elhkim et al., (2007) commented that they are generally not accompanied by any convincing demonstration and have not been confirmed by adequate studies [Elhkim et al., 2007] . The relationship between tartrazine ingestion and the development of intolerance reactions is not always clearly established. Recent methodological improvements in study protocols, particularly the development of randomised double-blind, placebo-controlled studies, has provided more accurate information on the part of tartrazine intolerance in asthmatic people. A systematic literature review by Ardern and Ram (2001) found that only 6 out of the 90 papers examined had used suitable methodology to establish any positive association between tartrazine ingestion and asthma. These studies found that removal of tartrazine from the diet did not improve asthma outcomes. Dietary avoidance of tartrazine is only justified in a few patients with proven hypersensitivity to this additive [Ardern and Ram, 2001, as cited in Elhkim et al., 2007]. In France only one case of tartrazine intolerance is recorded in the Clinical and Laboratory Investigation Circle for Food Allergy Medicine (CICBAA: Cercle d’Investigations Cliniques and Biologiques en Allergologie Alimentaire)


database, out of 703 declarations of food intolerance or food allergy [Elhkim et al., 2007]. Many changes in behaviour following exposure to chemicals may not be related to neurotoxicity. Indeed, no chronic toxicity and carcinogenecity studies conducted in mice (Borzelleca and Hallagan, 1988a) or in rats ([Borzelleca and Hallagan, 1988b] and [Maekawa et al., 1987]) showed any effect on the nervous system. However, at this stage of the assessment, it is wise to try to use different methods to obtain effects which can be correlated. This can be accomplished either by conducting additional behavioural tests which evaluate the same or similar endpoint(s), or by collecting additional measures of different types of endpoints (e.g. electrophysiological, neurochemistry, neuroendocrinology, neuroimmunology, neuropathology) (OECD, 2004) [Elhkim et al., 2007]. Pestana et al., (2010) performed a study to assess the effect of ingestion of tartrazine on 26 atopic patients with allergic rhinitis, asthma, urticaria or pseudo-allergic reactions to non-steroidal anti-inflammatory drugs using a double-blind placebo controlled crossover challenge. Patients were either given a talc placebo or the tartrazine in capsule form one week apart. At each visit 3 capsules of placebo or increasing dose of tartrazine (5, 10 and 20mg), and were assessed clinically for vital signs and skin, nasal and chest manifestations. Patients completed a questionnaire on their symptoms after the testing and interviewed by phone the following day. After analysis there were ‘no statistical differences between placebo and drug in cutaneous, respiratory or cardiovascular aspects’ (Pestana et al., 2010). A study by Amin et al., (2010) assessed the effect of azo dyes on the biochemical parameters related to renal, hepatic function and oxidative stress biomarkers in young male rats. Rats were orally dosed using 15 mg/kg bw and 500 mg/kg bw tartrazine over a 30 day period. Briefly, a significant increase was observed in ALT, AST, ALP, urea, creatinine total protein and albumin in the serum compared to control rats, but changes were magnified in the higher dose group compared to the low dose group. In tissue homogenate, significant decreases in GSH, SOD and catalase, and a significant increase in MDA, in rats from the high dose group. The authors concluded that tartrazine is capable of inducing changes in hepatic and renal parameters at low doses but tartrazines effect can ‘become more risky at higher doses because they can induce oxidative stress by formation of free radicals’. In Vitro Toxicity Status Two studies conducted in rat urine and faeces highlight the mutagenic effect of tartrazine metabolites. Positive results were reported for the TA 98 strain (Henschler and Wild, 1985) and in TA 100 strain (Munzner and Wever, 1987) both in presence of the metabolic activation (S9 mix.) but no investigation to identify the involved metabolites was conducted. Negative results were observed in the Ames test with the tartrazine metabolites, sulfanilic acid and aminopyrazolone [Chung et al., 1981].


Carcinogencitiy and mutagenicity Patterson & Butler, 1982 used Muntiacus muntjac fibroblast cells (derived from male deer) to study chromosomal aberrations. Cells were exposed to tartrazine at 5-20 µg/ml range for 48 hours leading to a significant increase in aberrations compared to the control. However, Renner [1982] believed that although weak clastogenic effects may be seen in vitro, in vivo normal metabolic systems would protect against any clastogenicity. Renner (1982) tested the effect of a single dose of tartrazine on the bone marrow cells of Chinese hamsters in vivo using the SCE assay, BUdr tablet method, the in vivo micronucleus assay and chromosome aberration test. All assays were negative. The author suggested that as much as 15 g tartrazine would have no effect in man, and pointed out that Patterson & Butler used no metabolic activation system in their assays Renner [1982]. Tartrazine was negative in the Ames test, in strains TA92, 94, 98, 100, 1535 and 1537, both in the presence and absence of a S-9 fraction, when tested at up to 5 mg/plate [Ishidate et al., 1984]. However, it gave equivocal results in a chromosomal aberration test in Chinese hamster cells in vitro. Whilst it was negative in an ovary cell line in the absence of S-9 at 11 g/ml, it was positive in a lung fibroblast cell line, also in the absence of S-9, at 2000 g/ml [Ishidate et al., 1988]. The main available genetic toxicology studies showed that tartrazine has no mutagenic potential. No studies demonstrated micronucleus induction, with negative results in the in vivo sister chromatide exchange (SCE), micronucleus and chromosome aberration tests. Data from unscheduled DNA synthesis (UDS) assay conducted in vitro and ex vivo on mammalian cells were also negative (Kornbrust and Barfknecht, 1985, Elhkim et al., 2007). Other available genetic toxicology studies showed, however, that tartrazine has mutagenic potential. Tartrazine can induce chromosomal aberrations in Chinese hamster somatic and found to cause a small increase in the incidence of polyploid cells after a 48 h tartrazine treatment in chinese hamster fibroblast cell line [Ishidate et al., 1984]. The in vivo single cell gel (SCG) electrophoresis assay or “Comet assay” showed that tartrazine induced DNA damage in the colon of mice at doses close to the ADI (Sasaki et al., 2002). Groups of 4 ddY mice were administered tartrazine at doses up to 2000 mg/kg. As the authors themselves state the food additives were found to damage mouse organs, however all the carcinogenicity studies conducted were negative. But therefore difficult to conclude whether there is a relationship between the positive results observed in the Comet assay and a carcinogenic potential [Elhkim et al., 2007]. Poul et al., (2009) administered the food dyes amaranth, sunset yellow and tartrazine by oral gavage to mice, were administered twice, at 24h intervals, and assessed in the in vivo gut micronucleus test for genotoxic effects (frequency of micronucleated cells) and toxicity (apoptotic and mitotic cells). The concentrations of each compound and their main metabolites (sulfanilic


acid and naphthionic acid) were measured in faeces during a 24-h period after single oral administrations of the food dyes to mice. Parent dye compounds and their main aromatic amine metabolites were detected in significant amounts in the environment of colonic cells. Acute oral exposure to food dye additives amaranth, sunset yellow and tartrazine did not induce genotoxic effect in the micronucleus gut assay in mice at doses up to 2000 mg/kg b.w. Food dyes administration increased the numbers of mitotic cells at all dose levels when compared to controls. The authors suggested that the transient DNA damages previously observed in the colon of mice treated by amaranth and tartrazine by the in vivo comet assay [Sasaki, Y.F. et al., 2002] are unable to be fixed in to stable genotoxic lesions and might be partly explained by the local cytotoxicity of the dyes [Poul et al., 2009] . Tartrazine was tested in vitro at 0.02-8mM in human peripheral blood cells to assess its genotoxic, cytotoxic and cytostatic potential. There was no significant changes caused by tartrazine in the sister chromatid exchange, but the authors stated that 4 and 8mM tartrazine affected the ‘quality of the chromosomes in a way that differentiation between sister chromatids did not occur. Consequently, the levels of SCEs/cell and PRI could not be did not be computed at these concentrations’. Four and 8 mM tartrazine was shown to cause a significant decrease in mitotic index compared to controls. Spectroscopic changes in the UV-vis region suggested that tartrazine binds to CT-DNA. DNA mobility shift assays suggested that tartrazine bound strongly to linear DNA. Furthermore PCR amplification efficiency was attenuated by tartrazine. In the discussion the authors stated that ‘administration of tartrazine up to the ADI does not create cytogenetic damages’. Higher doses (4 and 8 mM) were shown to have a ‘significant toxic effect on the quality of chromosomes, so the differentiation stain between two chromatids was not clear. One possible explanation of this phenomenon is that tartrazine was toxic at the condensation of chromosome in mitosis. At the other concentrations no signs of genotoxicity were observed. Reversely, the azo dye had cytotoxic effects at 4 and 8 mM, as published before (Patterson and Butler, 1982)’. REFERENCES Armin KA, Abdel Hameid II H and Abd Elsttar AH (2010). Effect of food azo dyes tartrazine and carmoisine on biochemical parameters related to renal, hepatic function and oxidative stress biomarkers in young male rats. Food Chem Toxicol. 48(10): 2994-2999. Borzelleca & Hallagan (1988a). Chronic toxicity/carcinogenicity studies of FD & C Yellow No.5 (tartrazine) in rats. Fd. Cosmet. Toxicol., 26(3), 179. Borzelleca & Hallagan (1988b). A chronic toxicity/carcinogenicity studies of FD & C Yellow No.5 (tartrazine) in mice. Fd. Cosmet. Toxicol., 26(3), 189. Chung KT, Fulk GE et al., (1981). Mutagenicity testing of some commonly used dyes. Appl. Environ. Microbiol. 42: 641-648.


Collins et al. (1992). Study of the teratogenic potential of FD & C yellow No.5 when given in drinking-water. Fd. Cosmet. Toxicol., 30, 263. Corder & Buckley (1995). Aspirin, salicylate, sulfite and tartrazine induced bronchoconstriction. Safe doses and case definition in epidemiological studies. J. Clin. Epidemiol., 48, 1269. Elhkim M, Heraud F et al., (2007). New considerations regarding the risk assessment on tartrazine An updated toxicological assessment, intolerance reactions and maximum theoretical daily intake in France. Regulatory toxicology and Pharmacology 47: 308-316. Henschler D , Wild D et al., (1995). Mutagenic activity in rat urine after feeding with the azo dye tartrazine Arch, Toxicol. 57: 214-215. Honohan T., Enderlein F. E., Ryerson B. A., and, Parkinson T. M. (1977). Intestinal absorption of polymeric derivatives of the food dyes sunset yellow and tartrazine in rats. Xenobiotica, 7 (12), 765-774. ICHM/HPV. The International Association of Color Manufacturers/HPV Committee. Test Plan for C.I. Acid Yellow 23 CAS No. 1934-21-0. Searched on-line 2009 http://www.epa.gov/HPV/pubs/summaries/ciacdylo/c15133tp.pdf Ishidate et al. (1984). Primary mutagenicity screening of food additives currently used in Japan. Fd. Chem. Toxic., 22, 623. Ishidate et al. (1988). A comparative analysis of data on the clastogenicity of 951 chemical substances tested in mammalian cell cultures. Mutation Res., 195, 151-213. JECFA (1964). Specifications for identity purity and toxicological evaluation of food colours in FAO nutrition Meetings Report Series No 38B WHO Geneva. Kornbrust D. and Barfknecht T. (1985). Testing Dyes in HPC/DR systems. Environmental Mutagenesis 7, 101-120 Maekawa et al. (1987). Lack of carcinogenicity of tartrazine (FD &C Yellow No. 5) in the F344 rat. Fd. Chem. Toxicol., 25(12): 891. Mpounttoukas P et al., (2010). Cytogenetic evaluation and DNA interaction studies of the food colorants amaranth, erythrosine and tartrazine. Food Chem Toxicol. 48(10): 2934-2944. Munzer R Weaver J (1987). Mutagenic activity of the faeces of rats following oral administration of tartrazine. Arch Toxiocol. 60: 328-330. Patterson & Butler (1982). Tartrazine-induced chromosomal aberrations in mammalian cells. Fd. Chem. Toxicol., 20(4), 461.



Pestana S, Moreira M and Olej B (2010). Safety of ingestion of yellow tartrazine by double-blind placebo controlled challenge in 26 atopic patients. Allergologia et Immunopathologia. 38(3): 142-146. Poul M, Jarry G et al., (2009). Lack of genotoxic effect of food dyes amaranth, sunset yellow and tartrazine and their metabolites in the gut micronucleus assay in mice. Food Chem Toxicol. 47(2): 443-8. Renner (1982). Tartrazine-a reinvestigation by in vivo cytogenetic methods. Fd. Chem. Toxicol., 22(4): 327. Sasaki YF, Kawaguchi S et al., (2002). The comet assay with 9 mouse organs: results with 39 currently used food additives. Mutation Research. 519: 103-119. Tanaka T (2006). Reproductive and neurobehaviouiral toxicity study of tartrazine administered to mice in the diet. Fd Chem Toxicol. 44: 179-187. Tanaka T, Takahashi O et al., (2008). Effects of tartrazine on exploratoroy behaviour in a three generation toxicity study in mice. Reprod. Toxicol. 26(2): 156-163. ToxNet, searched 2009. http://toxnet.nlm.nih.gov/ Westmoreland C. and Gatehouse D.G. (1991). The differential clastogenicity of SolventYellow 14 and FD&C Yellow No. 6 in vivo in the rodent micronucleus test (observations on species and tissue specificity). Carcinogenesis 12(8): 1403-1408.

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