3,3'-sulphonyldianiline

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Good; The studies are not OECD-type studies, howerver designed to investigate the fertility and teratogenicity endpoint similar to a regular study. In addition, because dapsone is used as a pharmaceutical for > 60 years with hundred thousands of treated patients and thousands of people protected from malaria by dapsone (including the well surveilled US and AUS military personnel who served in Vietnam) no fertility effects have been reported.

Additional information

The main toxic effect of dapsone is methemoglobin formation. This effects occurs in humans rarely at a daily dose of 100 mg/person/day and becomes more frequent in patients with a metabolic disease. The effect is frequent and clinically relevant at about 400 mg/person/day (or ~ 6 mg/kg/day). Fertility effects have been noted in male rats at 12 mg/kg/day and in female rats at 30 mg/kg/day. The effects in male rats are a reduction of sperm number and motility and in female rats an increased number of early resorptions and derived effects (e.g. number of offsprings).

Short description of key information:
Male rats: Reduction of sperm number and motility (males). Effect occurs at toxic doses comparable with therapeutic clinical doses and above.
Female rats: Increased number of early resorptions. Effect occurs at clearly toxic doses for the female.

Justification for selection of Effect on fertility via oral route:
Effects on both male and female fertility were noted. The NOAEL for male fertility effects is lower than the NOAEL for female fertility effects.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

mouse

Quality of whole database:

The two studies together (KS.developemtal toxicity and female.fertiltiy.01, which includes the evaluation of teratogenicity) indicate that no teratogenciity occurs.

Additional information

Justification for selection of Effect on developmental toxicity: via oral route:
Based on the NTP-study conducted, Dapsone is not teratogenic in CD-1 Swiss albino mice. The result is confirmed in the combined study on female fertility and teratogenicity in the rat (Female fertility.01).

Toxicity to reproduction: other studies

Additional information

The fertility effect in the rat (sperm motility and number) is relevant at doses significantly above human exposure during therapy or workplace exposure. Clinical experience shows that in the course of high dapsone therapy methemoglobinaemia is very frequent at a comparable dose as in the rat study. Rats showed also pale or blue extremities and other effects. There is a clear evidence that the fertility effects occur at doses which provoke clear signs of toxicity.The effect is therefore considered secondary to parental toxicity.

There are Human data (see e.g. the review by Wolf et al () from pregnant leprosy patients exposed to high doses of dapsone. The effects on the foetus were not teratogenc, but sometimes embryotoxic/lethal (likely by low availability of oxygen during development).

Justification for classification or non-classification

Not classifiable. The effect observed happens at doses which likely provoke methemoglobinaemia. Clinical signs in the test animal support this assumption.