4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

Data is from secondary source

Data source

Reference

Reference Type:

secondary source

Title:

Long term feeding study in mice

Author:

International Research and Development Corporation

Year:

2007

Bibliographic source:

Scientific Committee on Consumer Products (SCCP), OPINION ON Acid Red 33, COLIPA n° C22, 2007 page no -13-14

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Principles of method if other than guideline:

Chronic repeated dose oral toxicity study of D&C Red 33 was conducted using mice

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Disodium 5-amino-4-hydroxy-3-(phenylazo)naphthalene-2,7-disulphonate

EC Number:

222-656-9

EC Name:

Disodium 5-amino-4-hydroxy-3-(phenylazo)naphthalene-2,7-disulphonate

Cas Number:

3567-66-6

Molecular formula:

C16H13N3O7S2.2Na

IUPAC Name:

disodium 5-amino-4-hydroxy-3-(phenyldiazenyl)naphthalene-2,7-disulfonate

Constituent 2

Reference substance name:

D&C Red 33

IUPAC Name:

D&C Red 33

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): D&C Red 33
- Molecular formula (if other than submission substance): C16H11N3Na2O7S2
- Molecular weight (if other than submission substance): 467 g/mole
- Substance type: Organic
- Physical state: Powder
- Impurities (identity and concentrations): 4-Amino-5-hydroxy-2,7-naphthalenedisulfonic acid (disodium salt) < 0.3%, 4,5-Dihydroxy-3-(phenylazo)-2,7-naphthalenedisulfonic acid (disodium salt) < 3%, 4-Aminoazobenzene < 100 ppb, 4-Aminobiphenyl < 275 ppb, Aniline < 25 ppm, Azobenzene < 1 ppm, ,Benzidine < 20 ppb, 1,3-Diphenyltriazene < 125 ppb, Heavy Metal Content, Antimony, Arsenic, Mercury < 5 ppm, Cadmium < 10 ppm and Lead < 20 ppm

Specific details on test material used for the study:

- Name of test material: D&C Red 33
- Molecular formula: C16H11N3Na2O7S2
- Molecular weight: 467 g/mole
- Substance type: Organic
- Physical state: Powder

Test animals

Species:

mouse

Strain:

CD-1

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River
- Age at study initiation: No data available
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): No data available
- Water (e.g. ad libitum): No data available
- 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

Route of administration:

oral: feed

Details on route of administration:

No data

Vehicle:

other: Diet

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with diet at dose levels of 0, 0.1, 1.0 and 5.0 % ( 0, 150, 1500 and 7500 mg/kg bw/day)

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): No data available
- Concentration in vehicle: 0, 0.1, 1.0 and 5.0 % ( 0, 150, 1500 and 7500 mg/kg bw/day)
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

24 months

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 150, 1500 and 7500 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

Total: 600
0 mg/kg bw/day: 60 male, 60 female
0 mg/kg bw/day: 60 male, 60 female
150 mg/kg bw/day: 60 male, 60 female
1500 mg/kg bw/day: 60 male, 60 female
7500 mg/kg bw/day: 60 male, 60 female

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
- Cage side observations checked in table [No.?] were included: Morbidity and mortality were observed

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly throughout the in utero segment weekly for the first 14 weeks, biweekly (the second
7 days of every two weeks) the next 12 weeks and once monthly (7 days during the third week of each month) thereafter for the post-weaning segment of the study.

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

FOOD EFFICIENCY: No data available
- 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 available

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

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

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 3, 6, 12 month
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. Reticulocytes, haemoglobin, haematocrit, erythrocyte leucocytes were examined.

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

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

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

OTHER:
Organ weight was examined.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes
Organs and tissues were examined.

Other examinations:

No data available

Statistics:

No data available

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):

effects observed, treatment-related

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

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:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

Mortality: When treated with 7500 mg/kg bw/day, decrase in survival of male mice at week 57 and female mice at week 74.

Clinical signs: Changes in colour of hair, skin and faeces were observed in treated mice as compared to control. Changes were considered to be not toxicologically significant because they are directly linked to the colour of the dye.

Body weight and weight gain: When treated with 7500 mg/kg bw/day, change in body weight were observed in treated mice as compared to control.

Food consumption: When treated with 7500 mg/kg bw/day, change in food comsumption were observed in treated mice as compared to control.

Compound intake: No data available

Food efficiency: No data available

Water consumption and compound intake: No data available

Opthalmoscopic examination: No data available

Haematology: When treated with 7500 mg/kg bw/day, anaemia and elevated reticulocytes in week 74 were observed in treated mice as compared to control.

When treated with 1500 mg/kg bw/day, anaemia and a significant increase in reticulocytes at 18 and 24 month and increased leucocytes were observed in male and femlae mice as compared to control.

When treated with 150 mg/kg bw/day, increased leucocytes were observed in treated female mice as compared to control.

Clinical chemistry: No data available

Urinanalysis:No data available

Neurobehaviour: No data available

Organ weights: When treated with 7500 mg/kg bw/day, increased splenic weights were observed in treated mice as compared to ontrol.

Gross pathology: No data available

Histopathology: When treated with 7500 mg/kg bw/day, abnormal changes in kidneys and Pigments in the liver and spleen were observed in treated mice as compared to control.

Effect levels

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effect on survival, clinical sign, body weight, food consumption, hematology, gross pathology and histopathology

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The No Observed Adverse Effect Level (NOAEL) was considered to be 150 mg/kg bw/day when male and female mice were treated with D&C Red 33.

Executive summary:

In a Chronic repeated dose oral toxicity study, CD1 male and female mice were treated with D&C Red 33 in the concentration of 0, 150, 1500 and 7500 mg/kg bw/day orally in diet. Decrease in survival of male mice at week 57 and female mice at week 74 were observed as compared to control. Changes in colour of hair, skin and faeces were observed in treated mice as compared to control. Changes were considered to be not toxicologically significant because they are directly linked to the colour of the dye.Change in body weight and food consumption were observed in treated mice as compared to control. Anemia and elevated reticulocytes in week 74 were observed at 7500 mg/kg bw/day, anemia and a significant increase in reticulocytes at 18 and 24 month and increased leucocytes at 1500 mg/kg bw/day and increased leucocytes were observed at 150 mg/kg bw/day in treated female mice as compared to control. In addition, increased splenic weights and abnormal changes in kidneys and Pigments in the liver and spleen were observed at 7500 mg/kg bw/day treated mice as compared to control. Therefore, the No Observed Adverse Effect Level (NOAEL) was considered to be 150 mg/kg bw/day when male and female mice were treated with D&C Red 33 orally for 24 months.