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Toxicological information

Repeated dose toxicity: dermal

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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:
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

Reference
Name:
Unnamed
Type:
Constituent
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 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 availableENVIRONMENTAL CONDITIONS- Temperature (°C): No data available- Humidity (%):No data available- Air changes (per hr): No data available- Photoperiod (hrs dark / hrs light): No data availableIN-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 growthREMOVAL OF TEST SUBSTANCE- Washing (if done): No data available- Time after start of exposure: No data availableTEST 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 availableVEHICLE- 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 availableUSE 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 mgBasis:other: Mean dose of dye applied
No. of animals per sex per dose:
Vehicle Control: 150 females and 150 males = 300 micePositive Control: 50 females and 50 males = 100 miceTest 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 dataBODY WEIGHT: no data- Time schedule for examinations: no dataFOOD 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 dataFOOD 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 dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data- Time schedule for examinations: No dataOPHTHALMOSCOPIC EXAMINATION: No data - Time schedule for examinations:- Dose groups that were examined: No dataHAEMATOLOGY: 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 dataCLINICAL 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 dataOTHER:
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 MORTALITYSurvival 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. HISTOPATHOLOGYExtramedullary 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.