Registration Dossier

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:
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

Reference
Name:
Unnamed
Type:
Constituent
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 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
mortality
gross pathology
histopathology: neoplastic

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.