Calcium 3-hydroxy-4-[(4-methyl-2-sulphonatophenyl)azo]-2-naphthoate

Repeated dose toxicity: dermal

Administrative data

Endpoint:

chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

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:

Skin Painting Studies In Mice With 14 FD & C And D & C Colors: FD & C Blue No. 1, Red No. 3 & Yellow No. 5, D & C Red No. 7, Red No. 9, Red No. 10, Red No. 19, Red No. 2 1 , Red No. 27, Red No. 31, Red No. 36, Orange No. 5, Orange No. 10 & 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 chemical D & C Red no.7 upon repeated application.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Calcium 3-hydroxy-4-[(4-methyl-2-sulphonatophenyl)azo]-2-naphthoate

EC Number:

226-109-5

EC Name:

Calcium 3-hydroxy-4-[(4-methyl-2-sulphonatophenyl)azo]-2-naphthoate

Cas Number:

5281-04-9

Molecular formula:

C18H14N2O6S.Ca

IUPAC Name:

calcium 3-hydroxy-4-[(1E)-2-(4-methyl-2-sulfonatophenyl)diazen-1-yl]naphthalene-2-carboxylate

Test material form:

solid

Details on test material:

- Name of test material (as cited in study report): 2-Naphthalenecarboxylic acid, 3-hydroxy-4-[(4-methyl-2-sulfophenyl)azo]-, calcium salt- Molecular formula (if other than submission substance): C18H14N2O6S.Ca- Molecular weight (if other than submission substance): 424.445 g/mole- Smiles notation (if other than submission substance): c12c(c(c(C(=O)[O-])cc1cccc2)O)\N=N\c1c(cc(C)cc1)S(=O)(=O)[O-].[Ca+2]- InChl (if other than submission substance): 1S/C18H14N2O6S.Ca/c1-10-6-7-14(15(8-10)27(24,25)26)19-20-16-12-5-3-2-4-11(12)9-13(17(16)21)18(22)23;/h2-9,21H,1H3, (H,22,23)(H,24,25,26);/q;+2/p-2/b20-19+;- Substance type: Organic - Physical state: Solid - Analytical purity: 87%- Impurities (identity and concentrations): 13%

Specific details on test material used for the study:

- Name of test material (as cited in study report): D & C Red no.7- Molecular formula (if other than submission substance): C18H14N2O6S.Ca- Molecular weight (if other than submission substance): 424.445 g/mole- Smiles notation (if other than submission substance): c12c(c(c(C(=O)[O-])cc1cccc2)O)\N=N\c1c(cc(C)cc1)S(=O)(=O)[O-].[Ca+2]- InChl (if other than submission substance): 1S/C18H14N2O6S.Ca/c1-10-6-7-14(15(8-10)27(24,25)26)19-20-16-12-5-3-2-4-11(12)9-13(17(16)21)18(22)23;/h2-9,21H,1H3, (H,22,23)(H,24,25,26);/q;+2/p-2/b20-19+;- Substance type: Organic - Physical state: Solid - Analytical purity: 98%- Impurities (identity and concentrations): 2%

Test animals

Species:

mouse

Strain:

ICR

Remarks:

(Swiss Webster derived)

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Swiss Webster derived- 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 0 or 128.5 mg test material- Concentration (if solution): 0 or 128.5 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 of the vehicle containing 0 or 128.5 mg test material- Lot/batch no. (if required): No 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 available

Duration of treatment / exposure:

471 days

Frequency of treatment:

Twice weekly

Doses / concentrations

Remarks:

0 or 130.6mg/kg/day

No. of animals per sex per dose:

Total: 500130.6 mg: 50 males and 50 females0 mg/Kg bw: 150 males and 50 femalesPositive control: 50 males and 50 females

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): No data available- 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,, dissolved in acetone

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes - Time schedule: daily- Cage side observations checked in table [No.?] were included. MortalityDETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: Twice weekly for gross toxicityBODY 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 and the tissues including those of 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 were preserved in 10% formalinHISTOPATHOLOGY: Yes, tissues were sectioned, stained with hematoxylin and eosin, and examined. These included skin and any grossly abnormal organs andtissues of all animals in the color experimental group; skin and any grossly abnormal organs and tissues of approximately 50 vehicle control animals (approximatelyequal number of males and females); complete pathology on five males and five females randomly selected vehicle control animals that survived the 18-month experimentalperiod; and complete pathology on five males and five females randomly selected vehicle control animals that survived the 18-month experimental period; and completepathology of five male and five female animals from the positive control group that included induced skin lesions.

Other examinations:

No data available

Statistics:

Yes ,Mean was observed

Results and discussion

Results of examinations

Clinical signs:

not specified

Dermal irritation:

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

Mortality: The percent survival of the treated mice changed with the duration of the treatment. The survival was 97% in 4 months, 92% in 10 months, 69% in 12 months and 41% in 18 months respectively.

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

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Histopathology: The incidence of extramedullary hematopoesis of the spleen (5 male and 9 females: 14%) in the test group was consistent with that found in the distilled water vehicle control groups. The incidence in the three distilled water control groups was 13 % , 18 % , and 22 % for a mean of 17.7 % . The test group did not show a greater incidence than a control group.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 groups.Although the number of neoplasias involving the mammary glands or internal organs was noted in the test group, there was, however, no apparent change in their pattern which could be attributed to the dermal application of the test dye compound.The incidence and severity of lesions of interstitial nephritis, cystitis, amyloidosis, and bronchopneumonia though observed in the test groups but there were no significant variations that could be attributed to application of the test compound.

Other effects:

not specified

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

130.6 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

gross pathology

histopathology: neoplastic

mortality

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table: Percent survival of mice

Months	5	10	16	18
D & C Red no 7	92	88	69	48

 

Table: Details of microscopic analysis

Animal Number	Experimental Days Observed	Location of Lesion	Microscopic Diagnosis
3F	485	Tissue mass beneath the dorsal skin treatment area (appeared to be attached to the spine)	Rather large cells with vacuolated cytoplasm and pyknotic nuclei postmortem autolysis prevented positive identification
21F	568	Tissue mass in intestine	Reticulam cell sarcoma
36F	568	Tissue mass in near pituitary	Abscess involving the brain and pituitary
39F	569	Nodule on liver	Reticulam cell sarcoma
40F	473	Tissue mass near tritrigerminal nerve	Mass was relatively compact bone contaningspaceswith hematogenic activity
55M	502	Tissue mass in near pituitary	Abscess involving pituitary
75M	446	Nodule on kidney	Focal granulomatous process
88M	569	Tissue mass in liver	Hepatic cell adenoma
93M	569	Tissue mass in liver	Hepatic cell adenoma
100M	569	Nodule in kidney	Hepatic cell adenoma

Applicant's summary and conclusion

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for the test compound D and C Red No. 7 is considered to be 130.6 mg/kg/dayin male and female mice for 18 months

Executive summary:

Repeated dose toxicity by the dermal route was performed to determine the dermal toxic nature of the test compoundD & C Red no. 7upon repeated application. 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.

Repeated dermal application of 0.1 ml containing 1 mg of dye applied to the dorsal area of ICR (Swiss Webster derived) white mice twice weekly for 18 months failed to produce any adverse effects and hence the No Observed Adverse Effect Level (NOAEL) for the test compoundD & C Red no. 7 is found to be130.6 mg/kg/day in ICR male and female mouse by 18 months of repeated dermal application.