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Toxicity of tartrazine
Scientific review report
6. Toxicological assessment in animal studies
There have been several comprehensive reviews of the safety of tartrazine. The first risk assessment of tartrazine was conducted by JECFA followed by at least three evaluations by the EU Scientific Committee on Food (SCF, now known as EFSA) in 1975, 1984 and 2009 (EFSA 2009; EFSA 2010). Independently, reviews were also conducted by the National Health and Welfare Canada (Khera & Munro 1979) and by the Nordic Council of Ministers (2002) in Europe.
The sections below are a brief summary of salient features of the toxicology profile of tartrazine from a variety of animal studies.
The absorption, distribution, metabolism and excretion of tartrazine have been studied in animals and humans. The majority of these studies were originally evaluated by JECFA (1966). Except for a few studies describing azoreduction by intestinal bacteria, no new data has been published since the JECFA review.
At a range of doses, absorption of orally administered intact tartrazine in humans and laboratory animals is less than 5%. The absorbed tartrazine is secreted in urine largely, unchanged. The remaining tartrazine is extensively metabolised by intestinal microflora; of which some metabolites are absorbed through the intestine. (JECFA 1964; Khera & Munro, 1979; reviewed by Elhkim et al. 2007, Watabe et al., 1980, EFSA 2009). Of these metabolites, sulfanilic acid is predominantly secreted by urine. Kuno & Mizutani (2005), using bovine liver microsomes that mimic human liver microsomes, showed that tartrazine is not a substrate for CYP2A6 and UDP-glucuronosyltransferase.
Acute oral toxicity was assessed in rodents. In mice, the LD50 value was determined to be 12750 mg/kg bw (EFSA 2009; JECFA 1966) and in rats it was >2000 mg/kg/bw (EFSA 2009; Sasaki et al., 2002).
Several short-term and sub-chronic toxicity studies in rats, cats and dogs were reviewed by JECFA (1966). No tartrazine-related effects were reported for doses up to 500 mg/kg bw. A more recent rat study by Abdel-Zahab et al. 1997 (reviewed by EFSA 2009) examined the effects of two mixtures of colouring agents (up to 800 mg/kg/ bw), including tartrazine. However, the composition of the mixtures were not reported due to commercial-in-confidence issues. The EFSA panel concluded that it was difficult to assess the results of this study as the exposure of the animals to the individual food colours could not be determined.
Tartrazine was reported to produce neurotoxicity and deficits in learning and memory in animals (Gao 2011) at doses in excess of the acceptable daily intake (ADI) of tartrazine (0-7.5 mg/kg/day). However, it could not be excluded that exposure to tartrazine together with other dyes exerted toxicity by mechanisms involving synergistic process.
Long-term toxicity studies in rodents were reviewed by JECFA (1966). As confirmed by EFSA (2009), these studies were all conducted prior to the introduction of OECD guidelines and the establishment of Good Laboratory Practice. In the majority of these studies, when examined, there were no consistent or dose-related effects on behaviour, morbidity, mortality, haematology or the general physical observations.
Available evidence shows that tartrazine has no mutagenic potential in the majority of studies (reviewed by EFSA 2009; Elhkim et al, 2007; JECFA 1966; Rafii et al., 1997). However, other studies demonstrated that tartrazine has potential clastogenic activity. It was shown to induce chromosomal aberrations in Chinese hamster (Ishidate et al., 1981, 1984) and rat (Giri et al., 1990) somatic cells, but not in mice (Durnev et al., 1995). Sasaki et al. (2002), using the Comet assay, showed that tartrazine may induce transient DNA damage in the colon of mice at doses slightly above ADI. EFSA (2009) reviewed these latter studies and concluded that the transient DNA damage observed could be partly attributed to local cytotoxicity of the dye. However, in a more recent study, tartrazine did not reveal any genotoxic effect in the micronucleus assay in mice at doses up to 2000 mg/kg bw (Poul et al., 2009 reviewed by EFSA 2009).
The biological significance of the positive genotoxicity results is uncertain in view of the negative carcinogenicity studies.
No evidence of carcinogenicity was observed in studies reviewed by JECFA (1964) nor in recent studies conducted in mice and rats (Borzelleca & Hallagan 1988; Maekawa et al., 1987; Moutinho et al., 2007).
Tartrazine in drinking water (1-2%) showed no carcinogenic effects in two-year toxicity study of rats (Maekawa et al., 1987). In the studies reported by JECFA (1964), tartrazine was administered orally at doses up to 5% of the diet to rats and 1% to mice. Maekawa et al. (1987) administered tartrazine ad libitum in the drinking water at levels ranging from 0.1% to 2% for as long as two years while those described by Borzelleca & Hallagan (1988) mice were exposed to dietary levels of 0-5%.
Reproductive studies show that tartrazine does not have teratogenic effects on rats or rabbits and no adverse effects on reproductive parameters were recorded in one-generation studies at doses up to 2% in the diet (JECFA 1964; reviewed by Elhkim et al., 2007; Tanaka 2006). Behavioural development of offspring was not affected in any of these studies. The No Adverse Effect Level in rats was 5% tartrazine in the diet (2641 and 3348 mg/kg/day in male and female rats, respectively; Borzelleca & Hallagan 1988b) and 1000 mg/kg/day in rabbits (FDA 1972 in Collins et al. 1990).
Reproductive parameters were also examined in the chronic toxicity and carcinogenicity studies referred to above and reviewed by EFSA (2009). No treatment-related effects were observed.