3,3'-sulphonyldianiline

Genetic toxicity: in vitro

Administrative data

Endpoint:

in vitro gene mutation study in bacteria

Remarks:

Type of genotoxicity: gene mutation

Type of information:

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

Adequacy of study:

key study

Study period:

1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

according th GLP and according to OECD and EC guidelines. 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:

1999

Report date:

1999

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: UKEMS Guidelines (1990), Japanese MHW (1989) and MAFF (1985) Guidelines and ICH Harmonised Tripartite Guideline (1997)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of assay:

bacterial reverse mutation assay

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, batch no. 70522014, solid white powder, received on December 18 1998. Stored at 1-10 degrees C in the dark.
Source : Sigma Aldrich Co Ltd, Gillingham UK

Method

Target gene:

Tryptophan and Histidine-requring genes in Salmonella and Escherichia

Species / strain

Species / strain 1

Species / strain / cell type:

E. coli, other: WP2 pKM101

Species / strain 2

Species / strain / cell type:

E. coli WP2 uvr A pKM 101

Species / strain 3

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98 and TA 100

Metabolic activation:

with and without

Metabolic activation system:

Araclor 1254-induced rat liver post-mitochondrial fraction (S-9)

Test concentrations with justification for top dose:

8, 40, 200, 1000, 5000 micrograms/plate in the range-finder experiment
8, 40, 200, 1000, 5000 and 4, 20, 100, 500, 2500 micrograms /plate were used in the main experiments

Vehicle / solvent:

DMSO

Controls

Untreated negative controls:

yes

Remarks:

treatment with solvent

Negative solvent / vehicle controls:

yes

Remarks:

DMSO

Positive controls:

yes

Remarks:

treatment with appropriate stock positive control solution

Positive control substance:

sodium azide

Remarks:

other positive controls used were 9-aminoacridine (AAC), 2-aminoanthracene (AAN), 4-nitrochinoline (NQO), and 2-nitrofluorene(2NF)

Details on test system and experimental conditions:

the plating assay was chosen for all experiments.
Incubation was for three days in the dark at 37 degrees Celcius.

Statistics:

M-statistics to check whether ther data were Poisson-distributed,
Dunnetts test to compare the counts of each data point with the control.
Linear regression analysis

Results and discussion

Test results

Test results 1

Species / strain:

E. coli WP2 uvr A pKM 101

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Vehicle controls validity:

valid

Untreated negative controls validity:

not applicable

Positive controls validity:

valid

Test results 2

Species / strain:

S. typhimurium TA 1535, TA 1537, TA 98 and TA 100

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Vehicle controls validity:

valid

Untreated negative controls validity:

not applicable

Positive controls validity:

valid

Additional information on results:

No positive result has been observed in any of the strains .
In addition to E.coli strain E. coli WP2 uvr A pKM 101 also E.coli strain WP2 pKM 101 was tested.

Remarks on result:

other: all strains/cell types tested

Remarks:

Migrated from field 'Test system'.

Applicant's summary and conclusion

Conclusions:

Dapsone did not induce reverse gene mutation in bacteria (4 Salmonella strains and 2 E.coli strains). The concentrations applied showed at the high end some toxicity in the absence and presence of S-9 activating enzymes.

Executive summary:

A bacterial Ames test acording to OECD guideline 471 and the EC guidelines was performed with the Salmonella strains TA 98, TA 100, TA 1535, and TA 1537, as well as with the Escherichia coli strains WP2 pKM 101, and WP2 uvrA pKM 101.

All strains were tested in the presence and absence of S-9 rat liver activating enzymes. None of the strains showed a significant increase of revertant colonies (mutants) neither in the presence nor in the absence of the metabolic rat-enzymes.

It is therefore concluded that Dapsone is not mutagenic under the bacterial Ames assay.