3,3'-sulphonyldianiline

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

according to GLP, and Commission guideline 91/507/EEC Pharmaceutical Affairs Bureau, Notifications 24 & 88, US-FDA for Pharmaceuticals. The read-across of toxicological data is considered justified because 4,4’-DDS (dapsone) and 3,3’-DDS are structural isomers with identical mol mass, identical elemental composition and identical functional groups. To the best of our knowledge, only Dapsone is used as a pharmaceutical. It is not known whether 3,3’-DDS acts as 4,4’-DDS as a folate synthesis inhibitor in microorganisms.The main toxicological hazard of 4,4’-DDS is the methemoglobin formation. This is due to the aromatic amine substituent of the molecule, which is present in both isomers. It is concluded that the main toxicological hazard of 3.3’-DDS is also methemoglobin formation. Both isomers do not show a structural alert for mutagenicity. The toxicological and ecotoxicological hazard profiles of both isomers are considered to be identical. A read-across 1:1 is considered reasonable and justified due to the very small structural difference of both substances.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2001

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Commission Directive 91/507/EEC, Pharmaceutical Affairs Bureau Notifications 24 & 88 guidance, US-FDA guidance on acute testing for Pharamceuticals

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

other: rising dose study

Limit test:

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'-sulfonyldianiline

Details on test material:

Dapsone (Sigma-Aldrich Co Ltd, Poole, Dorset), batch no.70522014
White powder
Stored in refrigerator (1-10 degrees Celsius)

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

Crl:NZW/Kbl.BR strain obtain from Charles Rivers Ltd, Margate, Kent.
Body weight range : 2.214 to 2.425 kg (males) and 2.061 to 2.340 kg (females) on Day -1 (day before 1st dosing occasion)
Age : 11 to 13 weeks old
Acclimation period: 6 days
Animals were sex-separated and kept individually in cages. Water was given ad libitum, and feed was freely available but consumption was measured.
Animals were kept under standard conditions for rabbits.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-22 deg C
- Humidity (%): 40-80%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hrs daily
TEST ANIMALS
- Source:
- Age at study initiation:
- Weight at study initiation:
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1% in water

Details on oral exposure:

Oral exposure was by gavage , and once weekly.

Doses:

Doses were 5, 7.5, 12.5, 17.5, 25, 40, 55, 100, 200, 300, 450, 600, 750, 900, 1100, and 1500 mg/kg bw

No. of animals per sex per dose:

3 males and 3 females
except for the 2 sets 300, 450, 600 mg/kg bw and 750, 900 and 1100 mg/kg bw , the group of 6 animals was subdivided into 3 sets consisting of one male and one femals for each dose.

Control animals:

yes

Details on study design:

In order to determine the maximum tolerated dose, increasing doses were applied with one week interval for recovery.
Mortalities were recorded as well as clinical signs of toxicity.
The maximim tolerated dose was based on the observation of clinical changes and variations in weight gain and food intake.

Statistics:

no

Results and discussion

Preliminary study:

none

Effect levels

Effect levels 1

Sex:

male/female

Dose descriptor:

LD0

Effect level:

ca. 600 mg/kg bw

Based on:

test mat.

Remarks on result:

other: reduced body weight gain and food consumption

Effect levels 2

Sex:

male/female

Dose descriptor:

LDLo

Effect level:

> 700 - < 910 mg/kg bw

Based on:

test mat.

Remarks on result:

other: toxic clinical signs observed

Mortality:

Mortality occurred at 1500 mg/kg bw (animals were killed for humane reasons in moribund condition).

Clinical signs:

other: Self-mutiliatuuin of some animals at 750 and 900 mg/kg bw.

Gross pathology:

No gross pathology findings were observed at any dose levels.

Applicant's summary and conclusion

Conclusions:

Under the test conditions and regarding observations of clinical signs, body weight gain and food consumption, LD0 is defined at 600 mg/kg bw and a LDLo value range between 700 to 910 mg/kg in rabbits.

Executive summary:

Under the test conditions and regarding observations of clinical signs, body weight gain and food consumption, LD0 with no detectable effect is defined at 600 mg/kg bw, and a LDLo range defined between 700 to 910 mg/kg in rabbits.