4'-aminoazobenzene-4-sulphonic acid

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral

Remarks:

combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

supporting study

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:

Repeated dose oral toxicity study of the test chemical

Author:

NCI

Year:

1977

Bibliographic source:

National Cancer Institute CARCINOGENESIS

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

A bioassay of the test chemical for possible combined repeated dose and carcinogenicity was conducted by administering the test material in feed to Fischer 344 rats and B6C3F1 mice.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dapsone

EC Number:

201-248-4

EC Name:

Dapsone

Cas Number:

80-08-0

Molecular formula:

C12H12N2O2S

IUPAC Name:

4,4'-Diaminodiphenyl Sulphone

Details on test material:

- Name of test material: Dapsone
- Molecular formula: C12H12N2O2S
- Molecular weight: 248.30 g/mol
- Substance type: Organic
- Physical state: Powder
- Impurities (identity and concentrations): > 99%

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Mixed shipments from A. R. Schmidt, Madison, Wisconsin, and from Charles River Laboratories
- Age at study initiation: Male animals were 34 days of age and females 38 days of age when placed on study
- Housing: Solid bottom stainless steel cages with clay bedding. Mice were housed seven per cage.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 40-60%
- Air changes (per hr): 15 times per hour
- Photoperiod (hrs dark / hrs light): In addition to natural light, illumination was provided by fluorescent light for 9 hours per day

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: Wayne Lab Blox

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): Test diets were formulated every 2 weeks using finely ground Wayne Lab Blox to which was added the required amount of the test chemical for each dietary concentration
- Mixing appropriate amounts with (Type of food): A given amount of the test chemical was first hand-mixed with a small amount of feed. This mixture was then added to a larger quantity of feed to give the desired concentration of the chemical, and mixed mechanically in a twin-shell blender for not less than 10 minutes to assure homogeneity of the mixture
- Storage temperature of food: Formulated diets were stored in plastic bags at room temperature until used

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

108 weeks

Frequency of treatment:

Animals were fed diets containing dapsone 5 days per week, and control diets 2 days per week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 500 or 1000 ppm (equivalent to 0, 71.42 or 142.85 mg/kg bw)
Basis:
nominal in diet

No. of animals per sex per dose:

Matched control: 14 males and 14 females
500 ppm: 35 males and 35 females
1000 ppm: 35 males and 35 females

Control animals:

yes, concurrent vehicle

Details on study design:

No data

Positive control:

No data

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed twice daily for signs of toxicity and palpated for masses at each weighing

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: yes
- Time schedule for examinations: Weighed individually each week for 8 weeks and every 2 weeks for the remainder of the study.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Gross examination of major tissues, major organs, and all gross lesions from killed animals and from animals found dead
HISTOPATHOLOGY: Yes
The following tissues were examined microscopically: skin, muscle, lungs and bronchi, trachea, bone and bone marrow, spleen, lymph nodes, thymus, heart, salivary gland, liver, gallbladder and bile duct (mice), pancreas, esophagus, stomach, small intestine, large intestine, kidney, urinary bladder, pituitary, adrenals thyroid, parathyroid, mammary gland, prostate or uterus, testis or ovary, brain and sensory organs. Peripheral blood smears were prepared from each animal.

Other examinations:

No data

Statistics:

Probabilities of survival were estimated by the product-limit procedure of Kaplan and Meier.
Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Tarone's (1975) extensions of Cox's methods for testing for a dose-related trend.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Description (incidence):

The test chemical did not adversely affect the survival of mice. Several control males died early in the study, while survival of the other groups of mice was not affected until week 75.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Lower body weights in males

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

In the males, alveolar/bronchiolar adenoma was observed in 5/33 low-dose animals. Similar tumors were not observed in female mice.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Details on results:

Gross pathology: In the males, alveolar/bronchiolar adenoma was observed in 5/33 low-dose animals. Although significant when compared with pooled controls, the tumors cannot clearly be associated with treatment, because of the low incidence in the low-dose group, and because only one tumor was found in the high-dose group. Similar tumors were not observed in female mice

Effect levels

Dose descriptor:

NOAEL

Effect level:

142.85 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The no observed adverse effect level (NOAEL) value of the test chemical is considered to be 1000 ppm (142.85 mg/Kg/day) for B6C3F1 mice, as no adverse effects were observed at this dose level.

Executive summary:

The test chemical is the parent chemical of the sulfone drugs, and the major therapeutic agent in this group for the treatment of leprosy. This test chemical was selected for screening by the carcinogenesis program in an attempt to evaluate the carcinogenicity of certain drugs that are used extensively and for prolonged periods in humans. The test chemical was administered in diet to B6C3F1 mice at dose levels of 500 or 1000 ppm for 78 weeks and a further observation period of 28-30 weeks was provided. The test chemical did not adversely affect the survival of mice. Several control males died early in the study, while survival of the other groups of mice was not affected until week 75. In the males, alveolar/bronchiolar adenoma was observed in 5/33 low-dose animals. Although significant when compared with pooled controls, the tumors cannot clearly be associated with treatment, because of the low incidence in the low-dose group, and because only one tumor was found in the high-dose group. Similar tumors were not observed in female mice. Based on the observations made, the no observed adverse effect level (NOAEL) value of the test chemical is considered to be 1000 ppm (142.85 mg/Kg/day) for B6C3F1 mice, as no adverse effects were observed at this dose level.