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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from peer reviewed publication

Data source

Reference
Reference Type:
publication
Title:
Lack of Carcinogenicity of Tartrazine (Fd & C Yellow No. 5) in the F344 Rat
Author:
A. Maekawa, C. Matsuoka, H. Onodera, H. Tanigawa, K. Furuta, J. Kanno, J. J. Jang and Y. Hayashi
Year:
1987
Bibliographic source:
Fd Chem. Toxic. Vol. 25, No. 12, pp, 891-896, 1987

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
Chronic 2 yrs toxicity study was conducted to evaluate the toxic potential of the test compound tartrazine
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Tartrazine
- Molecular formula (if other than submission substance): C16-H12-N4-O9-S2.3Na.
C16-H9-N4-O9-S2.3Na
- Molecular weight (if other than submission substance): 534.3681 g/mol
- Substance type: Organic
- Physical state: No data available
- Impurities (identity and concentrations): 93.4%
Specific details on test material used for the study:
- Name of test material: Tartrazine
- IUPAC name: trisodium 5-hydroxy-1-(4-sulphophenyl)-4-(4-sulphophenylazo) pyrazole-3-carboxylate
- Molecular formula: C16H12N4O9S2.3Na
C16H9N4O9S2.3Na
- Molecular weight: 534.3681 g/mol
- Substance type: Organic
- Physical state: No data available
- Impurities (identity and concentrations): 93.4%

Test animals

Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan Inc. (Kanagawa)
- Age at study initiation: 5 week old
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: They were housed four to a plastic cage and kept in an air-conditioned barrier-system animal room
- Diet (e.g. ad libitum): basal diet (CRF-1, Oriental Yeast Ind. Co., Tokyo)) ad lib
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25 ± 2°C
- Humidity (%): 55 ± 5%
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available

Administration / exposure

Route of administration:
oral: drinking water
Details on route of administration:
No data
Vehicle:
other: Drinking water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Tartrazine was dissolved in distilled water at concentrations of 0 (control), 0.3, 0.6, 1.25, 2.5 or 5.0% (w/v) (0, 150, 300, 625, 1250 or 2500 mg/Kg bw).

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Distilled water
- Concentration in vehicle: 0 (control), 0.3, 0.6, 1.25, 2.5 or 5.0% (w/v) (0, 150, 300, 625, 1250 or 2500 mg/Kg bw)
- Amount of vehicle (if gavage): 20 mL
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data available
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0 (control), 0.3, 0.6, 1.25, 2.5 or 5.0% (w/v) (0, 150, 300, 625, 1250 or 2500 mg/Kg bw)
Basis:

No. of animals per sex per dose:
Total: 120
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked in table [No.?] were included. Mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Once a week

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined: No data

HAEMATOLOGY: No data
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all survivors were killed and organs and tissues were taken for gross and microscopical examination.

HISTOPATHOLOGY: Yes, the animals were subjected to microscopical examination
Other examinations:
No data
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
Clinical signs and mortality: Six of the male rats and all of the female rats given tartrazine at 5% in drinking-water died during the study. None of the rats in any of the other groups died.

Body weight and weight gain: In all but the highest (5%) dose group, there was < 10% depression of body-weight gain compared with the control group.

Food consumption and compound intake: No data available

Food efficiency: No data available

Water consumption and compound intake: No data available

Opthalmoscopic examination: No data available

Haematology: No data available

Clinical chemistry: No data available

Urinanalysis: No data available

Neurobehaviour: No data available

Organ weights: The absolute organ weights of the thymus, lungs, heart, liver, spleen, kidneys and testes of the males given 5% tartrazine and of the liver in the males and females given 2.5% tartrazine were significantly lower than those of the corresponding control groups. However, the relative organ weights (g/100 g body weight) of the brain, lungs, adrenals, kidneys and testes of males in the 5% dose group were increased, and those of the thymus in the males in the highest dose group and of the liver in the females given 2.5% tartrazine were significantly decreased.

Gross pathology: No data available

Histopathology: Histological examination revealed toxic changes only in rats of both sexes in the highest(5%) dose group. In rats that died during the experimental period, severe atrophy and/or degeneration of the haematopoietic organs such as the thymus, bone marrow, lymph nodes or spleen was observed, although no marked changes were detected in other organs.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 250 mg/kg bw (total dose)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effects were noted at the mentioned dose level

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1. Tumour incidence, tartrazine intake and mean survival time of F344 rats given tartrazine in the drinking-water for up to 2 yr

Tartrazine in drinking water (%)

No. of rats

Mean total tartrazine intake (g/rat)

Survival till the end

Mean survival tima and range (wk)

Initial

Effective

With tumours (%)

Males

0

48

48

47 (953.9)

0

26

102 (40-112)

1

49

49

49 (100.0)

178.7

28

106 (63-112)

2

49

49

49 (100.0)

421.8

28

107 (78-112)

Females

0

48

47

39 (83.0)

0

35

109 (84-112)

1

50

50

41 (82.0)

129.0

39

109 (69-112)

2

49

49

30 (61.2)

300.6

30

104 (22-112)

 

Applicant's summary and conclusion

Conclusions:
The no observed adverse effect level (NOAEL) for the test compound tartrazine is considered to be 2.5 % (1250 mg/Kg bw) when male and female F344 rats were exposed to the test chemical for 13 weeks.
Executive summary:

13 week subchronic toxicity study was conducted to evaluate the toxic nature of the test compound tartrazine. The test compound was administered in drinking water at a dose level of 0(control), 0.3, 0.6, 1.25, 2.5 or 5.0% (w/v) (0, 150, 300, 625, 1250 or 2500 mg/Kg bw). All rats were observed daily and clinical signs and deaths were recorded. Body weights were measured once a week. At the end of the study, all survivors were killed and organs and tissues were taken for gross and microscopical examination. Six of the male rats and all of the female rats given tartrazine at 5% in drinking-water died during the study. None of the rats in any of the other groups died. In all but the highest (5%) dose group, there was < 10% depression of body-weight gain compared with the control group. The absolute organ weights of the thymus, lungs, heart, liver, spleen, kidneys and testes of the males given 5% tartrazine and of the liver in the males and females given 2.5% tartrazine were significantly lower than those of the corresponding control groups. However, the relative organ weights (g/100 g body weight) of the brain, lungs, adrenals, kidneys and testes of males in the 5% dose group were increased, and those of the thymus in the males in the highest dose group and of the liver in the females given 2.5% tartrazine were significantly decreased. Histological examination revealed toxic changes only in rats of both sexes in the highest (5%) dose group. In rats that died during the experimental period, severe atrophy and/or degeneration of the haematopoietic organs such as the thymus, bone marrow, lymph nodes or spleen was observed, although no marked changes were detected in other organs. Based on the results observed, the no observed adverse effect level (NOAEL) for the test compound tartrazine is considered to be 2.5 % (1250 mg/Kg bw) when male and female F344 rats were exposed to the test chemical for 13 weeks.