Aluminium, 4,5-dihydro-5-oxo-1-(4-sulfophenyl)-4-[(4-sulfophenyl)azo]-1H-pyrazole-3-carboxylic acid complex

Repeated dose toxicity: dermal

Administrative data

Endpoint:

chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

publication

Title:

Skin Painting Studies In Mice with 14 Fd & C & D & C Colors: FD & C Blue No.1 , Red No.3, And Yellow No.5, D & C Red No.7, Red No.9, Red No.10, Red No.19, Red No.21 , Red No.27, Red No.31, Red No.36, Orange No.5, Orange No.10, And Orange No.17

Author:

Steven Carson

Year:

1984

Bibliographic source:

J. Toxicol. Cut. & Ocular Toxicol. 3(4), 357-370 (1984)

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Combined repeated dose and carcinogenicity study by the dermal route was performed to determine the dermal toxic nature of the test compound 5-hydroxy-1-(4-sulphophenyl)-4-(4-sulphophenylazo)pyrazole-3-carboxylate [FD & C Yellow No. 5 (tartrazine)] upon repeated application.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Trisodium 5-hydroxy-1-(4-sulphophenyl)-4-(4-sulphophenylazo)pyrazole-3-carboxylate

EC Number:

217-699-5

EC Name:

Trisodium 5-hydroxy-1-(4-sulphophenyl)-4-(4-sulphophenylazo)pyrazole-3-carboxylate

Cas Number:

1934-21-0

Molecular formula:

C16-H12-N4-O9-S2.3Na

IUPAC Name:

trisodium 5-hydroxy-1-(4-sulphophenyl)-4-(4-sulphophenylazo)pyrazole-3-carboxylate

Details on test material:

- Name of test material (as cited in study report):trisodium 5-hydroxy-1-(4-sulphophenyl)-4-(4-sulphophenylazo)pyrazole-3-carboxylate
- Molecular formula :C16H12N4O9S2.3Na
- Substance type:organic
- Physical state:Soild
- Impurities (identity and concentrations):8%

Specific details on test material used for the study:

- Name of test material :trisodium 5-hydroxy-1-(4-sulphophenyl)-4-(4-sulphophenylazo)pyrazole-3-carboxylate
- Molecular formula : C16H12N4O9S2.3Na
- Substance type: organic
- Physical state: Soild
- Impurities (identity and concentrations): 8%

Test animals

Species:

mouse

Strain:

Swiss Webster

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation: No data
- Fasting period before study: No data available
- Housing: Each animal was assigned an identification number and individually housed in a supported wire cage.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- 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

Type of coverage:

open

Vehicle:

other: distilled water

Details on exposure:

TEST SITE
- Area of exposure: 6 cm²
- % coverage: No data available
- Type of wrap if used: No data available
- Time intervals for shavings or clipplings: Subsequent periodic clipping was performed according to the rate of hair growth

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No data available
- Time after start of exposure: No data available

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml of the vehicle containing 133.4 mg test material
- Concentration (if solution): 0 or 133.4 mg
- Constant volume or concentration used: yes
- For solids, paste formed: no data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Distilled water
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): 0.1 mL
- Lot/batch no. (if required): Not data
- Purity: no data available

USE OF RESTRAINERS FOR PREVENTING INGESTION: no data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

475 days

Frequency of treatment:

Twice weekly

Doses / concentrations

Remarks:

Doses / Concentrations:
0 or 133.4 mg
Basis:
other: Mean dose of dye applied

No. of animals per sex per dose:

Vehicle Control: 150 females and 150 males = 300 mice
Positive Control: 50 females and 50 males = 100 mice
Test Dye Materials: 50 females and 50 males = 100 mice

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Preliminary to establishing the dosages for the skin painting studies, the amounts of lipstick ingested by women was established in a study utilizing female volunteers
- Rationale for animal assignment (if not random): Animals were assigned an identification number
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available

Positive control:

3,4-benzpyrene

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: no data
- Time schedule: no data

BODY WEIGHT: no data
- Time schedule for examinations: no data

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: No data
- 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: No data

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.

DERMAL IRRITATION (if dermal study): No data
- Time schedule for examinations: 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.

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.

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

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, Animals that died, those sacrificed moribund, and those surviving the 18-month experimental period were necropsied.The following tissues were selected for examination:the brain, pituitary, thyroid, thymus, liver, spleen, kidney, adrenal, stomach,small intestines, large intestines, urinary bladder, axillary lymph nodes, testes, ovary,skin from area of treatment, any tissue masses, grossly abnormal organs, or tissues.

HISTOPATHOLOGY: Yes, after termination of the study, tissues were selected for histopathology.The following tissues were selected for examination: skin and any grossly abnormal organs and tissues of all animals in the color experimental groups; skin and any grossly abnormal organs and tissues of approximately 50 vehicle control animals (approximately equal number of males and females); complete pathology on five males and five females randomly selected vehicle control animals that survived the 18-month experimental period; and complete pathology on five males and five females randomly selected vehicle control animals that survived the 18-month experimental period; and complete pathology of five male and five female animals from the positive control group that included induced skin lesions.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Dermal irritation:

not specified

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

not specified

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:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

The incidence and severity of lesions of interstitial nephritis, cystitis, amyloidosis, and bronchopneumonia varied slightly between the treated test group and the control. However, there were no significant variations that could be attributed to application of the test compound

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

The number of neoplasias involving the mammary glands or internal organs varied somewhat between the test group and the control, but there was, however, no apparent change in their pattern which could be attributed to the dermal application of the test dye compound

Details on results:

CLINICAL SIGNS AND MORTALITY
Survival was approximately equivalent in all experimental groups except the positive controls who died earlier consistent with survival recorded by others for 3,4-benzpyrene treated mice.

HISTOPATHOLOGY
Extramedullary hematopoesis was found in all treated groups, equivalent to the findings in the controls.

HISTOPATHOLOGY: NEOPLASTIC
The repeated application of 0.1 ml containing 1 mg dye for 18 months did not increase the incidence of neoplasia when compared to controls in any of the groups receiving application of the test substance.

Other: The incidence of ectoparasitism was greater in the dye treated group than found in the vehicle controls. This increase in skin mite infestation may have contributed to the increase in epidermal change dermatitis, acanthosis, and hyperkeratosis observed in the dye treated group

Effect levels

Dose descriptor:

NOAEL

Effect level:

0.01 other: mg dye

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The repeated application of 0.1 ml containing 1 mg dye did not increase the incidence of neoplasia when compared to controls.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The no observed adverse effect level (NOAEL) for the repeated dose toxicity study of trisodium 5-hydroxy-1-(4-sulphophenyl)-4-(4-sulphophenylazo)pyrazole-3-carboxylate [FD & C Yellow No. 5 (tartrazine)] was considered to be 133.4 mg of dye when administered dermally to mice in a chronic study of 18 months.

Executive summary:

Chronic toxicity study was conducted to evaluate the toxic effects of repeated administration of trisodium 5-hydroxy-1-(4-sulphophenyl)-4-(4-sulphophe nylazo)pyrazole-3-carboxylate [FD & C Yellow No. 5 (tartrazine)] to ICR Swiss Webster mouse by the dermal route. A groups of 100 mice (50 per sex) plus an additional positive control group of the same size and a vehicle control group of 300 mice (150 per sex) were used in the study.All colors were prepared at 1.0% suspensions in water. The positive control received 3,4-benzpyrene dissolved in acetone. The test chemical was applied to the clipped dorsal area mice. The animals were observed for mortality, clinical signs and gross pathology and histopathology was performed. Survival was approximately equivalent in all experimental groups except the positive controls who died earlier consistent with survival recorded by others for 3,4-benzpyrene treated mice. Extramedullary hematopoesis was found in all treated groups, equivalent to the findings in the controls. The repeated application of 0.1 ml containing 1 mg dye to the dorsal area of ICR(Swiss Webster derived) white mice twice weekly for 18 months did not produce any adverse effects and did not increase the incidence of neoplasia when compared to controls in any of the groups receiving application of the test substance.Thus the no observed adverse effect level (NOAEL) of the study was considered to be 133.4 mg.