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FD&C Red No. 3

FD&C Red No. 3

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Copyright 2002 by Marcel Dekker. All Rights Reserved.



Figure 8.2



(Facing page and above) Chemical structures of selected synthetic food colorants subject to certification.



Copyright 2002 by Marcel Dekker. All Rights Reserved.



Table 8.4 Lakes Listed for Use in

Food and Their Current Status

Lake



Current status



FD&C Red No. 40

FD&C Yellow No. 6

FD&C Red No. 3

FD&C Blue No. 1

FD&C No. 2

FD&C Green No. 3

FD&C Yellow No. 5



Permanent

Provisional

Provisional

Provisional

Provisional

Provisional

Provisional



which no effect levels can reasonably be established (The

latest status, 1985; Malaspina, 1987).

Subchronic feeding studies indicated that erythrosine inhibits conversion of thyroxine to triiodothyronine,

thereby causing increased secretion of thyrotropin by the

pituitary gland. This effect in turn results in an increased

stimulation of the thyroid and, hence, the tumor formation.

No effect levels for the tumor formation process in male

rats have been established at 0.5% (302 mg/kg body

weight/day). Human studies, however, have failed to identify any adverse effects after the ingestion of FD&C Red

No. 3 (Anderson et al., 1964; Bora et al., 1969).

FD&C Red No. 3 is partially deiodinated in the gut

to lower-iodinated fluoresceins. Its high iodine content has

made researchers question whether it would have any

effects on the thyroid (JECFA, 1987). In vitro studies

indicate that erythrosine may inhibit neurotransmitters

(Augustine and Levitan, 1980; Mailman et al., 1980). Several researchers have studied the effects of this dye on

neurotransmitter release and iron transfer across cell

membranes (Swanson and Logan, 1980; Augustine and

Levitan, 1983; Silbergeld et al., 1983; Vorhees et al., 1983;

Kantor et al., 1984). However, no conclusive evidence that

was found linked this color to possible adverse behavioral

effects. Other adverse effects have been reported, including effects on blood and gene mutations in some strains of

Escherichia coli. In contrast, no mutations were seen when

using the Ames test (JECFA, 1987).

FD&C Red No. 3 is permanently listed in the United

States and is approved for use by the EEC. A temporary

ADI was set at 0.05 mg/kg (JECFA, 1989). However, Red

No. 3 lake was never so listed and was banned by the FDA

in 1990.

FD&C Red No. 4

FD&C Red No. 4 (Ponceau SX, Color Index No. 14700)

was approved for food use in 1929. This monoazo dye

(Figure 8.2) is synthesized by coupling one mole each of



Copyright 2002 by Marcel Dekker. All Rights Reserved.



diazotized 1-amino-2,4-dimethylbenzene-5-sulfonic acid

and 1-naphthol-4-sulfonic acid. A red-colored powder, it is

readily soluble in water, yielding orange-red solution.

FD&C Red No. 4 was originally approved to color

butter and margarine. It was found to be noncarcinogenic

to rats when fed at 5% level in the diet for up to 2 years

(Davis, 1966). These researchers, however, found the dye

to be toxic to dogs. When fed at a 1% level in the diet for a

period of 7 years, FD&C Red No. 4 produced chronic follicular cystitis with hematomatous projections into the urinary bladder, hemosiderotic focal lesions in the liver, and

atrophy of the zona glomerulosa of the adrenals. In one

study, three of the five dogs fed a diet containing 2% dye

died prematurely within 6 months. Thus, its provisional

listing as a permissible food color was terminated in 1976

(U.S. FDA 1983b).

FD&C Red No. 32

FD&C Red No. 32 (Oil Red XO, Color Index No. 12140)

was approved for food use in 1939. This monoazo dye

(Figure 8.2) is synthesized by diazotizing one mole of xylidine mixtures from which the meta components are partially removed with one mole of 2-naphthol. It is a brownish

red powder soluble in oil.

FD&C Red No. 32 was found to be a strong cathartic in dogs and rats (Radomaski, 1961). It is also highly

toxic to rats (Fitzhugh et al., 1956). Rats fed the dye at

0.1% level in the diet for 2 years showed growth retardation, damage to liver and heart tissue, and higher mortality

rates when compared to those on control diets. Dogs thus

treated also showed similar toxic effects (Fitzhugh et al.,

1956). The dye was banned in 1956 for food use in the

United States.

FD&C Red No. 40

FD&C Red No. 40 (Allura Red AC, Color Index No.

16035) is a monoazo dye (Figure 8.2). Developed in the

mid-1960s, it is manufactured by coupling diazotized 5amino-4-methoxy-2-toluenesulfonic acid with 6-hydroxy2-naphthalenesulfonic acid. It is the most widely used of

all FD&C colors in the United States (Jones, 1992) and in

1970 became permanently listed for food use.

Lifetime studies on rats and mice have indicated that

Red No. 40 is neither carcinogenic nor teratogenic (Borzelleca, 1990; Borzelleca et al., 1989; Brown and Dietrich,

1983; Hazleton Laboratories, 1978; Parkinson and Brown,

1981; Vettorazzi, 1980). No consistent adverse effects

have been shown except moderate growth depression in

rats receiving the highest dose, over 5% of the diet (Borzelleca et al., 1989; Parkinson and Brown, 1981).



Red No. 40 has been reported to have some psychotoxicity on the basis of a controversial rat study

(Vorhees et al., 1983). The rats were exposed to dye and

then mated. The females were dosed during gestation, and

the offspring were also fed this colorant. The offspring

were then rated on a series of performance tests such as

swimming. The test is controversial because doses as high

as 10% of the diet were used. Although this test clearly indicates an adverse effect, opponents argue that these dose

levels are particularly inappropriate for tests on psychotoxicity. Their rationale is that no person could ever eat

anything approaching that amount of food color and that at

lower levels no observable effects on performance could

be seen.

In the United States, FD&C Red No. 40 was approved for food use in 1971. However, it was refused similar legal status in Canada after the Health and Protection

Branch (HPB) of Health and Welfare Canada concluded

that the data submitted by the manufacturers to support its

safety were inadequate (IFT, 1986). These toxicological

studies were terminated after 21 months, when pneumonia

swept the rat colony, instead of after the required 24month period. Although the Canadian HPB deemed these

studies inadequate, FDA accepted the test results as being

adequate proof of safety. Later studies proved its safety for

food use, thus allowing its use in Canada. The dye, however, is not permitted for food use in the United Kingdom,

Switzerland, Sweden, the Netherlands, and other countries

of the EEC. However, an ADI was established by the

JECFA in 1989 at 0–7 mg/kg body weight, with a maximal

anticipated daily intake calculated at 0–19 mg/kg. Thus,

similarly to FD&C Red No. 2, it has contradictory regulations in the United States and many other Western countries.

Citrus Red No. 2

Citrus Red No. 2 (Solvent Red 80, Color Index No. 12156)

is principally 1-(2,5-dimethoxy-phenylazo)-2-naphthol

(Figure 8.2). It belongs to the monoazo group of dyes. Its

use is limited to coloring skins of oranges not intended for

processing.

Toxicological properties of Citrus Red No. 2 have

been well studied. Feeding studies in rats and dogs have

shown it to be noncarcinogenic (Radomaski, 1962). In the

same study, its metabolite, 1-amino-2-naphthol, was also

found to be noncarcinogenic when fed to rats and dogs.

However, several studies later reported this dye to be a carcinogen. When the dye was injected subcutaneously in female mice, Sharratt and associates (1966) observed an

increased incidence of malignant tumors, such as adenocarcinomas of the lungs and lymphosarcomas. Clayson

and colleagues (1968) also observed a similar, statistically



Copyright 2002 by Marcel Dekker. All Rights Reserved.



significant increase in bladder cancer in mice after implantation of a pellet containing the dye into the lumen of the

bladder. Dacre (1965) reported hyperplasia and benign tumors of the bladder in rats and mice fed diets containing

Citrus Red No. 2.

Although all these studies reported the carcinogenic

nature of the dye, FDA still would not remove its listing as

a permitted dye for coloring orange skins (U.S. FDA,

1983a). This decision was based on the opinions of Grasso

(1970) and the JECFA (1969), who suggested that only

those tests involving the oral route are relevant to the question of carcinogenicity of the ingested product. Similarly, a

number of 2-N-hydroxy metabolites that are known carcinogens from compounds of these types have not been

detected for Citrus Red No. 2 or any other permissible azo

dyes. Furthermore, even if Citrus Red No. 2 is unequivocally shown to be carcinogenic by the oral route, it still

would pose negligible hazards to humans, unless, of

course, the dyed skins of oranges were ingested in products such as orange marmalade.

FD&C Green No. 3

FD&C Green No. 3 (Fast Green FCF, Color Index No.

42053) belongs to the triphenylmethane group of dyes

(Figure 8.2). It is synthesized by a condensation reaction

of p-hydroxybenzaldehyde-o-sulfonic acid with α-(N-ethylanilino)-m-toluenesulfonic acid, followed by oxidation

and conversion to a disodium salt. The dye is a reddish or

brownish violet powder. It is readily soluble in water,

yielding bluish green solutions.

Toxicological studies have shown both Indigo Carmine and FD&C Green No. 3 to induce sister chromatid

exchanges in bone marrow cells, when the dyes were injected intraperitonially into mice at doses exceeding 25

and 10 mg/kg body weight, respectively (Ghorpade et al.,

1995). Earlier biochemical studies, however, had shown

that this dye is poorly absorbed and almost completely excreted (Hess and Fitzhugh, 1955). It is not mutagenic by

the Ames test (Parkinson and Brown, 1981). A 2-year

study feeding FD&C Green No. 3 to rats, dogs, and mice

at concentrations as high as 5% of the diet showed no carcinogenic or toxic effects (Radomaski, 1974). No-effect

levels have been reported as 1500–4000 mg/kg/day in rats

and 8800–11,800 in mice (Borzelleca, 1990). In 1986,

JECFA established the ADI for humans at 0–25 mg/kg,

with an anticipated maximal intake at 0.0003 mg/kg/day.

Repeated subcutaneous injections of FD&C Green

No. 3 have been shown to produce sarcomas in rats at the

site of injection. The JECFA originally considered this

finding cause for concern and judged the toxicological

data inadequate to meet its requirements (Vettorazzi,



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