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

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

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 -16-17

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Principles of method if other than guideline:

Combine repeated dose and carcinogenicity study of D&C Red 33 in mice

GLP compliance:

yes

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-(phenylazo)naphthalene-2,7-disulphonate

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: PowderPurity: 88% - Impurities (identity and concentrations): No data available

Test animals

Species:

mouse

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: No data available - 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): Purina Rodent Chow, ad libitum- 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

Type of inhalation exposure (if applicable):

not specified

Vehicle:

other: Purina Rodent Chow

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: D&C Red 33 was fed in the diet at dosage levels of 0.1, 1.0 and 5.0%. (dose to 150, 1502, and 8764 mg/kg bw/day for males and 181, 1809, and 10,362 mg/kg bw/day for females)DIET PREPARATION- Rate of preparation of diet (frequency): No data available - Mixing appropriate amounts with (Type of food): Purina Rodent Chow - Storage temperature of food: No data available VEHICLE- Justification for use and choice of vehicle (if other than water): Purina Rodent Chow - Concentration in vehicle:0, 150, 1502, and 8764 mg/kg bw/day for males and 0, 181, 1809, and 10,362 mg/kg bw/day for females - 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

Post exposure period:

No data available

Doses / concentrations

Remarks:

Doses / Concentrations:0, 150, 1502, and 8764 mg/kg bw/day for males and 0, 181, 1809, and 10,362 mg/kg bw/day for females Basis:actual ingested

No. of animals per sex per dose:

Total: 6000 mg/kg bw/day: 120 male , 120 female 150 mg/kg bw/day: 60 male 1502 mg/kg bw/day: 60 male 8764 mg/kg bw/day: 60 male 181 mg/kg bw/day: 60 female1809 mg/kg bw/day: 60 female10362 mg/kg bw/day: 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 - Time schedule: two – three times daily - Cage side observations checked in table [No.?] were included: Morbidity and mortality were observed. DETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: two – three times dailyDERMAL IRRITATION (if dermal study): No data available - Time schedule for examinations: No data available BODY WEIGHT: Yes- Time schedule for examinations: Weekly during the first 14 weeks of study, biweekly (the second 7 days of every two weeks) during the next 12 weeks and monthly (7 days during the second week of each .month) thereafter.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: Yes - Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes 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: At 3, 6, 12, 18, and 24 months- Anaesthetic used for blood collection: No data available - Animals fasted: No data available - How many animals: 80 animals were examined - Parameters checked in table [No.?] were examined. Erythrocyte, haemoglobin and haematocrit, reticulocytes and Leucocytes were examined. CLINICAL CHEMISTRY: No data available - Time schedule for collection of blood: 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: No data available

Sacrifice and pathology:

GROSS PATHOLOGY: No data available HISTOPATHOLOGY: Yes

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):

no effects observed

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

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Details on results:

Mortality: When treated with 8764 and 10,362 mg/kg bw/day, decrease in survival were observed in treated male mice at week 57 and in female mice at week 74 as compared to control. Clinical sign: When treated with 1502 and 8764 mg/kg bw/day in male and 1809 and 10,362 mg/kg bw/day in female, hair and exposed skin areas appeared purple in colour and the urine and faeces appeared red as compared to control. When treated with 150 mg/kg bw/day in male and 181 mg/kg bw/day in female, skin areas appeared pink in colour, faeces appeared brownish red, and urine appeared orange and pink in treated of male and female mice as compared to control. Body weight and weight gain: When treated with 8764 mg/kg bw/day in male and 10,362 mg/kg bw/day in female, change in body weight were observed in treated male and female mice as compared to control. Food consumption: No effect on food consumption was observed in treated mice as compared to control. Compound intake: 0.1, 1.0 and 5.0% corresponded to 150, 1502, and 8764 mg/kg bw/day for males and 181, 1809, and 10,362 mg/kg bw/day for femalesFood efficiency Water consumption & compound intake: No data available Ophthalmoscopic examination: No data available Haematology: When treated with 10,362 mg/kg bw/day in female, continued increase in reticulocytes were observed in treated mice as compared to control. When treated with 1502 mg/kg bw/day in male and 1809 mg/kg bw/day in female, significant increase in reticulocytes and Leucocytes level at 18 and 24 months were observed in treated mice as compared to control. When treated with 181 mg/kg bw/day in female, significant increase in Leucocytes level at 24 months was observed in treated mice as compared to control. Decreases in erythrocyte, haemoglobin and haematocrit values and increases in reticulocytes in most treated groups were considered indicative of a dosage-related anaemia at the 6 and 12 month evaluations.Clinical chemistry: No data available Urinalysis: No data available Neuro behavior: No data available Organ WeightsNo data available Gross Pathology: No data availableHistopathology: non-neoplastic: When treated with 8764 mg/kg bw/day in male and 10,362 mg/kg bw/day in female, chronic nephritis, hydronephrosis and tubular pigment in kidneys, Pigment in liver and spleen was observed in treated mice as compared to control. Histopathology: neoplastic: No data available

Relevance of carcinogenic effects / potential:

Non carcinogenic

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No effect on survival, body weight, food consumption, hematology and histopathology

Remarks on result:

other:

Remarks:

Effect type: other: Non carcinogenic (migrated information)

2

Dose descriptor:

LOAEL

Effect level:

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

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Effect on Survival, body weight, hematology and histopathology

Remarks on result:

other:

Remarks:

Effect type: other: Non carcinogenic (migrated information)

Applicant's summary and conclusion

Conclusions:

Non carcinogenic NOAEL was considered to be 150 mg/kg bw/day for male mice and LOAEL was 181 mg/kg bw/day for female mice when Charles River CD-1 male and female mice were treated with D&C Red 33.

Executive summary:

In a Combine repeated dose and carcinogenicity study, Charles River CD-1 male and female mice were treated with D&C Red 33 in the concentration of 0, 150, 1502, and 8764 mg/kg bw/day for males and 0, 181, 1809, and 10,362 mg/kg bw/day for females orally in Purina Rodent Chow diet. Decrease in survival was observed in treated male mice at week 57 and in female mice at week 74 at 8764 and 10,362 mg/kg bw/day. Hair and exposed skin areas appeared purple in colour and the urine and faeces appeared red at 1502 and 8764 mg/kg bw/day in male and 1809 and 10,362 mg/kg bw/day in female and skin areas appeared pink in colour, faeces appeared brownish red, and urine appeared orange and pink in 150 mg/kg bw/day in male and 181 mg/kg bw/day in female mice as compared to control. Change in body weight at 8764 mg/kg bw/day in male and 10,362 mg/kg bw/day in female mice were observed. No effect on food consumption was observed in treated mice as compare to control. Continued increase in reticulocytes at 10,362 mg/kg bw/day and significant increase in Leucocytes level at 24 months were observed at 181 mg/kg bw/day treated female mice and significant increase in reticulocytes and Leucocytes level at 18 and 24 months were observed at 1502 mg/kg bw/day in male and 1809 mg/kg bw/day in female treated mice as compared to control. Decreases in erythrocyte, haemoglobin and haematocrit values and increases in reticulocytes in most treated groups were considered indicative of a dosage-related anaemia at the 6 and 12 month evaluations. In addition, chronic nephritis, hydronephrosis and tubular pigment in kidneys, Pigmentin liver and spleen were observed at 8764 mg/kg bw/day in male and 10,362 mg/kg bw/day in female treated mice as compared to control. Therefore, Non carcinogenic NOAEL was considered to be 150 mg/kg bw/day for male mice and LOAEL was 181 mg/kg bw/day for female mice when Charles River CD-1 male and female mice were treated with D&C Red 33 orally in feed for 24 months.