Food and Chemical Toxicology 44 (2006) 179–187
www.elsevier.com/locate/foodchemtox
Reproductive and neurobehavioural toxicity study
of tartrazine administered to mice in the diet
Toyohito Tanaka
*
Department of Environmental Health and Toxicology, Tokyo Metropolitan Institute of Public Health, 3-24-1,
Hyakunincho, Shinjuku-ku, Tokyo 169-0073, Japan
Received 12 January 2005; accepted 27 June 2005
Abstract
Tartrazine was given in the diet to provide levels of 0% (control), 0.05%, 0.15%, and 0.45% (approximately 83, 259, 773 mg/kg/
day, respectively) from five weeks of age of the F0 generation to nine weeks of age of the F1 generation in mice, and selected reproductive and neurobehavioural parameters were measured. In movement activity of exploratory behaviour in the F0 generation, number of vertical activity was significantly increased in the middle-dose group in males. There were no adverse effects of tartrazine on
either litter size, litter weight and sex ratio at birth. The average body weight of male offspring was significantly increased in the highdose group and that of female offspring was significantly increased in the middle-dose group at birth. In behavioural developmental
parameters, surface righting at PND 4 was significantly accelerated in the high-dose group in male offspring, and those effects were
significantly dose-related in a trend test (P < 0.01). Cliff avoidance at PND 7 was significantly accelerated in the middle-dose group
in male offspring. Negative geotaxis at PND 4 was significantly delayed in the high-dose group in female offspring. Other variables
measured showed no significant adverse effects in either sex in the lactation period. In movement activity of exploratory behaviour in
the F1 generation, number of movement showed a significant tendency to be affected in the treatment groups in male offspring in a
trend test (P < 0.05). The dose level of tartrazine in the present study produced a few adverse effects in neurobehavioural parameters
during the lactation period in mice. Nevertheless, the high-dose level were in excess of the ADI of tartrazine (0–7.5 mg/kg bw), and
the actual dietary intake of tartrazine is presumed to be much lower. It would therefore appear that the levels of actual dietary intake
of tartrazine is unlikely to produce any adverse effects in humans.
2005 Elsevier Ltd. All rights reserved.
Keywords: Behavioural development; Tartrazine; Food dye; Maze learning; Mice; Movement activity; Reproductive toxicity
1. Introduction
The color additives, tartrazine, FD&C Yellow No. 5,
C.I. No. 19140, is principally the trisodium 5-hydroxy-1(4-sulfonatophenyl)-4-(4-sulfonatophenylazo)-H-pyrazol3-carboxylate. Tartrazine is an orange-colored, water
soluble powder widely used in food products, drugs, cosmetics and pharmaceuticals. The estimated amounts of
tartrazine manufactured in 1996 were approximately
*
Tel.: +81 3 3363 3231x5603; fax: +81 3 3368 4060.
E-mail address: [email protected]
0278-6915/$ - see front matter 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.fct.2005.06.011
71.35 t in Japan and 985.76 t in USA (Ishimitsu et al.,
1998). The acceptable daily intake (ADI) of human is
0–7.5 mg/kg bw (JECFA, 1996).
In toxicological studies of tartrazine, Davis et al.
(1964) reported that the incidence of tumors and of
the common incidental diseases was unaffected by tartrazine in the diet (0.5–5.0%) in chronic toxicity study
(two years) of rats. Maekawa et al. (1987) found that
tartrazine in drinking water (1.0–2.0%) showed no carcinogenic effects in two years toxicity study of rats.
Borzelleca and Hallagan (1988a) reported that the no
observed adverse effect levels (NOAEL) of tartrazine
were 5.0% (2641 and 3348 mg/kg/day for males and
180
T. Tanaka / Food and Chemical Toxicology 44 (2006) 179–187
females in rats, respectively) in chronic toxicity study
(two years) via utero. Borzelleca and Hallagan (1988b)
reported that the NOAEL of tartrazine in mice were
5.0% (8103 and 9735 mg/kg/day for males and females,
respectively) in chronic toxicity study (104 weeks).
As regards reproductive and developmental toxicity
studies, Collins et al. (1990) found that tartrazine
produced neither toxic nor teratogenic effects in rats
by gavage (60–1000 mg/kg/day). Also, Collins et al.
(1992) reported that tartrazine produced no teratogenic
effects in drinking water (0.05–0.7%) in rats. As regards
behavioural toxicity studies, Sobotka et al. (1977) reported that tartrazine exerted minimal neurobehavioural effects (only neuromotor development in females)
in rats (1.0–2.0% in the diet). Also, as regards hyperactivity of children, Rowe and Rowe (1994) reported that
behavioural changes in irritability, restlessness, and
sleep disturbance were associated with the ingestion of
tartrazine in some children, and those effects showed
dose-related (1–50 mg/child). Ward (1997) reported that
23 children consumed a tartrazine beverage showed increased levels of overactivity, aggressive and/or violent
activity, poor speech, poor coordination, and the development of asthma and/or eczema.
Nevertheless, there were no studies on reproductive
and neurobehavioural toxicity of tartrazine in animal
species. Therefore, the present study was designed to
evaluate reproductive and neurobehavioural effects of
tartrazine in mice throughout two-generations.
group (20 mice: 10/sex) were given the basal diets
(Nihon Clea, CE-2) for the corresponding time period.
Individual food intake of mice was measured during five
divided periods: preconception (from five weeks of age
to mating), mating (five days), gestation (14 days), lactation (from birth to weaning), and F1 generation (4–9
weeks of age).
2.4. Reproductive procedure
The animals from the F0 generation were five weeks
of age at the start of the study. The animals were individually weighed at experimental day 0, 2, 4, 7, 14, 21,
28, and 30 during the preconception period. At nine
weeks of age, each female was paired with one male
from the same treatment group, for a period of five days.
The males were removed from females after five days,
and the females were allowed to carry their litters to
term, deliver, and rear all of their offspring.
In the F1 generation, litter size, litter weight, and sex
ratio (male/female) were measured on postnatal day
(PND) 0 (at birth). The offspring were individually
weighed on PNDs 0, 4, 7, 14, and 21 during the lactation
period. The survival indices were calculated as (live offspring at each period)/(live and dead offspring at
birth) · 100(%). The offspring were weaned when they
were four weeks of age, and one male and one female
were randomly selected to continue treatment from each
litter. The animals were individually weighed at 4–9
weeks of age after weaning.
2. Materials and methods
2.5. Neurobehavioural procedure
2.1. Materials
The functional and behavioural developmental
parameters were measured and scored for all individual
offspring during the lactation period in the F1 generation (Tanaka et al., 1992), and were analyzed on score
frequencies (Tanaka, 1995). The measured variables
were as follows:
Tartrazine (Food Yellow No. 4) was obtained from
Tokyo Kasei Co., Ltd., Tokyo, Japan (Lot No. GL
01). The purity of the chemical was more than 85.0%.
2.2. Animals and maintenance
Male and female mice (Crj: CD-1, four weeks of age)
were purchased from Charles River Japan Inc., Kanagawa, Japan. They were individually housed in polycarbonate solid-floored cages with wood flakes, and kept
in a temperature controlled room maintained at
25 ± 1 C with relative humidity of 50 ± 5% on a 12 h
light/dark cycle. They were given control or experimental diets and water ad libitum.
2.3. Experimental design
Tartrazine was administered in the diet to 60 mice
(10/sex/group) at dietary levels of 0.05%, 0.15%, and
0.45%, from five weeks of age of the F0 generation to
nine weeks of age of the F1 generation. The control
1. Surface righting on PNDs 4 and 7 (Fox, 1965; Pantaleoni et al., 1988). The offspring were placed on
their backs on a smooth surface and the time required
to right themselves to a position where all four limbs
touched the surface was recorded. The scoring rate
for successful righting was: 2 = righting within 1 s;
1 = more than 1 s but within 2 s; 0 = more than 2 s.
2. Negative geotaxis on PNDs 4 and 7 (Fox, 1965; Altman and Sudarshan, 1975; Pantaleoni et al., 1988).
The offspring were placed in a head-down position
on a 30 inclined plane and the time required to reorient to a head-up position was recorded. The plane
was made of plywood covered with sandpaper (fine
grade). The following scoring rate was employed:
0 = no response within 60 s; 1 = response within
60 s; 2 = response within 30 s.
T. Tanaka / Food and Chemical Toxicology 44 (2006) 179–187
3. Cliff avoidance on PND 7 (Fox, 1965; Altman and
Sudarshan, 1975; Pantaleoni et al., 1988). The offspring were placed on a platform elevated 10 cm
above a table top. The forelimbs and snout of the animals were positioned so that the edge of the platform
passed just behind an imaginary line drawn between
the eye orbits. The following scoring rate was
employed: 0 = no response within 20 s; 1 = avoided
backwards within 20 s, 2 = avoiding with turn.
4. Swimming behaviour on PNDs 4 and 14 (Fox, 1965;
Pantaleoni et al., 1988). The offspring were placed
into a tank with water temperature maintained at
23 ± 1 C and swimming behaviour was rated for
direction (straight = 3, circling = 2, floating = 1)
and head angle (ears out of water = 4, ears half out
of water = 3, nose and top of head out of water = 2,
and unable to hold head-up = 1). Limb movement
was rated as either 1 = all four limbs used, or
2 = hindlimbs only used.
5. Olfactory orientation on PND 14 (Altman and
Sudarshan, 1975; Barlow et al., 1978; Meyer and
Hansen, 1980). The offspring were placed in the
arm of an apparatus consisting of two compartment
connected by the arm. One compartment was covered
with home wood flakes from their cages and the other
was covered with fresh wood flakes. The time
required to enter the compartment with home wood
flakes was recorded. The following scoring rate was
employed: 0 = no response within 90 s; 1 = entered
the home wood flakes compartment via the fresh
wood flakes compartment; 2 = entered the home
wood flakes compartment directly.
Exploratory behaviour of mice was measured in an
animal movement analyzing system ANIMATE AT420 (Toyo Sangyo Co., Ltd., Toyama, Japan) at eight
weeks of age in the F0 generation and at three and eight
weeks of age in the F1 generation. The system consisted
of a doughnut-shaped cage made from acrylate resins
with 36 units of detectors of near-infrared photosensors
for measuring spontaneous motor activity (Matsumoto
et al., 1990a,b). The behavioural variables were recorded
for 10 min on all animals at eight weeks of age in the F0
and F1 generations and on one male and one female
selected randomly from each litter at three weeks of
age in the F1 generation. The variables measured were:
number of movements, movement time (s), number of
horizontal activities, total distance (cm), number of vertical activities, vertical time (s), number of turnings,
average distance (cm), average speed (cm/s), and number of defecation.
The animals each performed one trial a day for three
days in a multiple-T water maze of BielÕs type adapted
for mice at seven weeks of age in the F1 generation (Biel,
1940; Kitatani et al., 1988). The water temperature was
maintained at 20 ± 1 C. The time taken and number of
181
errors were measured from the start to finish for a maximum of 120 s. If the time taken was greater than 120 s,
it was recorded as 120 s (Kitatani et al., 1988).
2.6. Statistical analysis
Food intake, litter size, litter weight, and body
weight were assessed with the BonferroniÕs multiple
comparison test after the analysis of variance (ANOVA) or the Kruskal–Wallis test. Sex ratio, survival
and behavioural developmental data were assessed with
the v2 test or the FisherÕs exact test of frequency analysis. Movement activity data were assessed with the
Steel–Dwass test of non-parametric methods (Martin
and Bateson, 1990). Multiple-T water maze performance data were assessed with the Sign–Wilcoxon
test for trials and assessed with the Steel–Dwass test
within each treatment group. Dose–response effects
were assessed with the Jonckheere test for ordered
alternatives or the cumulative v2 test (multi) for frequency data.
3. Results
3.1. Food and chemical intake
There were no significant effects of tartrazine on
the average food intake during any periods (Table 1).
Therefore, the chemical intake was consistently increased in a dose-related manner during each period
(Table 1).
3.2. F0 generation
The average body weight of male and female mice
showed no significant adverse effects during the preconception or mating periods, and the average body weight
of dams showed no significant adverse effects during the
gestation and lactation periods.
In movement activity of exploratory behaviour, number of vertical activity in males was significantly
increased in the middle-dose group (Fig. 1). Other variables of measurement showed no significant adverse
effects of tartrazine in either sex.
Each one female had no became pregnant in the control and high-dose groups, and abortion was observed in
six dams, one dam each in the control and middle-dose
groups, and two dams each in the low- and high-dose
groups (Table 2). During the first week of the lactation
period, one dam of the high-dose group showed underdeveloped mammary glands, which were observed as
underdeveloped mammalae. One dam of the middledose group died during the second week of the lactation
period, and one dam of the control group died during
the third week of the lactation period.
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T. Tanaka / Food and Chemical Toxicology 44 (2006) 179–187
Table 1
Average daily food and chemical intake of mice administered tartrazine in two-generation toxicity study
Dose level (%)
0
0.05
0.15
0.45
Food intake (g/kg/day)
F0 generation
Preconception
Male
Female
Mating
Gestation
Lactation
153.9 ± 11.00
182.0 ± 16.43
141.9 ± 22.69
157.6 ± 20.96
558.1 ± 57.61
146.2 ± 6.98
192.7 ± 23.08
136.3 ± 15.39
169.5 ± 22.81
576.8 ± 55.35
159.4 ± 10.58
197.0 ± 39.88
149.0 ± 24.34
179.6 ± 48.97
551.7 ± 107.66
159.8 ± 12.07
191.0 ± 22.04
143.4 ± 16.86
162.0 ± 16.14
564.6 ± 91.05
F1 generation
Male
Female
160.8 ± 9.20
180.3 ± 8.75
166.6 ± 11.71
188.4 ± 20.47
173.0 ± 15.78
176.8 ± 14.06
171.4 ± 13.66
202.7 ± 17.76
Chemical intake (mg/kg/day)
F0 generation
Preconception
Male
Female
Mating
Gestation
Lactation
–
–
–
–
–
73.1 ± 3.49
96.4 ± 11.54
68.2 ± 7.69
84.8 ± 11.40
288.4 ± 27.67
239.2 ± 15.87
295.4 ± 59.82
223.5 ± 36.52
269.5 ± 73.45
827.6 ± 161.49
719.3 ± 54.32
859.5 ± 99.20
645.2 ± 75.89
728.9 ± 72.63
2540.8 ± 409.74
F1 generation
Male
Female
–
–
83.3 ± 5.85
94.2 ± 10.24
259.6 ± 23.67
265.2 ± 21.09
771.3 ± 61.47
912.2 ± 79.94
Each value represents daily intake during each period (mean ± SD).
Fig. 1. Movement activity of exploratory behaviour at eight weeks of age of F0 generation male mice administered tartrazine in the diet. Each value
represents the mean ± SE. Significantly different from controls: *P < 0.05.
Table 2
Summary of data of litters at birth in two-generation toxicity study of tartrazine administered to mice
Dose level (%)
0
0.05
0.15
0.45
No. of females examined
No. of pregnant females
No. of litters
No. of offspring
Average litter size
Average litter weight (g)
Total sex ratio (male/female)
Average sex ratio (male%)
10
9
8a
107a
13.4 ± 1.69a
20.78 ± 2.014
0.91 (51/56)a
47.9 ± 7.88a
10
10
8
105
13.1 ± 2.80
20.68 ± 3.733
0.78 (46/59)
44.3 ± 13.59
10
10
9
116
12.6 ± 2.80
20.40 ± 3.606
1.11 (61/55)
51.6 ± 15.59
10
9
7
90
12.9 ± 1.57
20.23 ± 2.592
0.96 (44/46)
49.4 ± 21.11
Each value represents the mean ± SD.
a
Including a litter killed by its dam at birth.
T. Tanaka / Food and Chemical Toxicology 44 (2006) 179–187
3.3. F1 generation
No significant adverse effects were observed in litter
size, litter weight, or sex ratio at birth (Table 2). The
average body weight of male offspring was significantly
increased in the high-dose group and that of female offspring was significantly increased in the middle-dose
group at birth (Table 3). Also, the average body weight
of male offspring was significantly increased in the highdose group at PND 21 during the lactation period. One
litter of the control group was killed by its dam at birth.
One litter of the middle-dosed group was killed by its
dam during the first week of the lactation period. One
litter of the middle-dosed group died of accident of
water supply during the first week of the lactation period. One litter of the high-dose group were decreased by
undernourishment caused by underdeveloped mammary
glands of dam during the lactation period. One litter of
183
the middle-dose group was killed (to prevent them dying
of starvation) in view of death of the dam during the second weeks of the lactation period. The survival indices
showed a few significant adverse effect in the middledose group during the lactation period (Table 4).
Regarding the behavioural developmental parameters, surface righting at PND 4 was significantly accelerated in the high-dose group in male offspring (Fig. 2),
and those effects were significantly dose-related in a
trend test (P < 0.01). Cliff avoidance at PND 7 was significantly accelerated in the middle-dose group in male
offspring. Negative geotaxis at PND 4 was significantly
delayed in the high-dose group in female offspring.
Other variables measured showed no significant adverse
effects in either sex in the lactation period. In movement
activity of exploratory behaviour at three weeks of age,
number of movement showed a significant tendency to
be affected in the treatment groups in male offspring in
Table 3
Summary of average body weight (g) of offspring during the lactation period in two-generation toxicity study of tartrazine administered to mice
Dose levels (%)
0
0.05
0.15
0.45
Male offspring
PND 0
PND 4
PND 7
PND 14
PND 21
1.52 ± 0.138
2.90 ± 0.397
4.41 ± 0.607
6.70 ± 1.005
11.95 ± 2.187
1.61 ± 0.157
3.05 ± 0.402
4.64 ± 0.635
6.97 ± 1.088
13.06 ± 2.156
1.60 ± 0.175
3.01 ± 0.382
4.58 ± 0.686
6.66 ± 1.272
12.77 ± 2.649
1.63 ± 0.191*
3.10 ± 0.575
4.69 ± 0.673
7.09 ± 1.089
13.23 ± 1.936*
Female offspring
PND 0
PND 4
PND 7
PND 14
PND 21
1.48 ± 0.127
2.83 ± 0.404
4.29 ± 0.562
6.45 ± 1.030
11.48 ± 1.999
1.55 ± 0.149
2.94 ± 0.378
4.45 ± 0.634
6.59 ± 1.102
11.88 ± 2.414
1.57 ± 0.131**
2.99 ± 0.389
4.57 ± 0.769
6.77 ± 1.559
12.17 ± 2.971
1.52 ± 0.126
2.65 ± 0.696
4.07 ± 1.107
6.55 ± 1.187
11.61 ± 2.546
Each value represents the mean ± SD.
Significantly different from controls: *P < 0.05,
**P
< 0.01.
Table 4
Summary of number of offspring and survival index (%) during the lactation period in two-generation toxicity study of tartrazine administered to
mice
Dose level (%)
0
Male offspring
PND 0
PND 4
PND 7
PND 14
PND 21
46
46
46
46
46
Female offspring
PND 0
PND 4
PND 7
PND 14
PND 21
51
51
51
51
51
0.05
0.15
(90.2)a
(90.2)
(90.2)
(90.2)
(90.2)
46
46
46
45
44
(100.0)
(100.0)
(100.0)
(97.8)
(95.7)
61
55
49
48
37
(100.0)*
(90.2)
(80.3)
(78.7)
(60.7)***
44
43
42
42
41
(100.0)
(97.7)
(95.5)
(95.5)
(93.2)
(91.1)a
(91.1)
(91.1)
(91.1)
(91.1)
59
59
59
59
59
(100.0)*
(100.0)*
(100.0)*
(100.0)*
(100.0)*
55
47
40
40
35
(100.0)
(85.5)
(72.7)*
(72.7)*
(63.6)*
46
44
40
39
39
(100.0)
(95.7)
(87.0)
(84.8)
(84.8)
Each value represents number of offspring: survival index (%) in parentheses.
Significant different from controls: *P < 0.05, **P < 0.01, ***P < 0.001.
a
Calculated with including a litter killed by its dam at birth.
0.45
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T. Tanaka / Food and Chemical Toxicology 44 (2006) 179–187
a trend test (P < 0.05) (Fig. 3). Other variables measured
showed no adverse effects in either sex.
There were some significant effects of tartrazine on
multiple-T water maze performance at seven weeks of
age. In males, time taken was significantly reduced on
the second trials as compared to the first trial in the control and high-dose groups, and on the third trial as compared to the first trial in the low-dose group (Fig. 4).
Nevertheless, there was no significant adverse effect on
maze learning among treatment groups compared to
controls in males. In females, time taken was significantly
reduced on the third trial in the high-dose group as compared to the first trial (Fig. 5). Also, number of errors
was significantly reduced on the third trial in the highdose group as compared to the first trial in females.
Nevertheless, there was no significant adverse effect on
maze learning among treatment groups compared to
controls in females. For movement activity of exploratory behaviour at eight weeks of age, any variable measured showed no adverse effects of tartrazine in either
sex. The average body weight of male and female mice
showed no significant adverse effects after weaning.
4. Discussion
Fig. 2. Score frequencies for behavioural development in the lactation
period in two-generation toxicity study of tartrazine administered to
mice. Significantly different from controls: *P < 0.05, ***P < 0.001.
Surface righting at PND 4 in male offspring showed a significantly
dose-related manner in a trend test (P < 0.01).
In the present study, tartrazine showed a few significant adverse effects on neurobehavioural parameters.
The average body weight of offspring was significantly
increased in the high-dosed group at PND 21 in male
offspring. Nevertheless, the average body weights of
male offspring in the high-dosed group were significantly
increased at birth, and showed a tendency to be
increased at PNDs 4, 7 and 14 (not significant). It therefore seems that the differences of male offspring weight
between the control and high-dosed groups were caused
not by tartrazine treatment but by the body size at birth.
The survival indices showed a few significant adverse
Fig. 3. Movement activity of exploratory behaviour at three weeks of age of F1 generation male offspring administered tartrazine in the diet. Each
value represents the mean ± SE. Movement activity of male offspring showed a significantly dose-related manner in a trend test (P < 0.05).
T. Tanaka / Food and Chemical Toxicology 44 (2006) 179–187
185
Fig. 4. Summary of multiple-T water maze performance at seven weeks of age of F1 generation male mice in two-generation toxicity study of
tartrazine. Each value represents the mean ± SE. Significantly different from the first trial: *P < 0.05.
effect in the middle-dose group during the lactation period. However, two litters of the middle-dose group died
of accidents. It therefore seems that tartrazine produced
no adverse effects on offspring survivals during the lactation period.
In behavioural developmental parameters, tartrazine
produced a few statistically significant effects in the
measured variables as compared to control group in
mice. Surface righting, indicative of the coordinated
movement, was significantly accelerated in the high-dose
group in male offspring in the early lactation period, and
those effects were significantly dose-related (P < 0.01).
Nevertheless, that of female offspring showed no significant effects during the lactation period. It therefore
seems that tartrazine may have different effects on the
behavioural development in sexes.
In male offspring, number of movement of exploratory behaviour at three weeks of age in the F1 generation was significantly affected in a dose-related manner.
Nevertheless, any variable measured showed no adverse
effects of tartrazine in movement activity of exploratory
behaviour at eight weeks of age in the F1 generation in
either sex. It therefore seems that tartrazine influenced
exploratory behaviour in juvenile male mice only. In
humans, Rowe and Rowe (1994) reported that some
children who ingested tartrazine showed hyperactivity,
and those effects showed dose-related (1–50 mg/child).
Also, Ward (1997) reported that 23 children consumed
a tartrazine beverage showed hyperactivity. Nevertheless, exploratory behaviour of mice was restrained by
tartrazine treatment in juvenile males. It therefore seems
that the dose levels of tartrazine in the present study
may not induce hyperactivity in mice.
From results, the high-dose level (0.45% in the diet)
of tartrazine in the present study produced a few adverse
effects on several behavioural parameters. Nevertheless,
the high-dose level (645–2541 mg/kg/day) were in excess
of the ADI of tartrazine (0–7.5 mg/kg bw). The actual
dietary intake of tartrazine in Japan is presumed to be
much lower, approximately 0.66 lg/kg/day in 1982
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T. Tanaka / Food and Chemical Toxicology 44 (2006) 179–187
Fig. 5. Summary of multiple-T water maze performance at seven weeks of age of F1 generation female mice in two-generation toxicity study of
tartrazine. Each value represents the mean ± SE. Significantly different from the first trial: *P < 0.05.
and 26.8 lg/kg/day in 1991 (Ito, 1995; Nakamura,
1995). It would therefore appear that the levels of actual
dietary intake of tartrazine is unlikely to produce any
adverse effects in humans.
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