3,3'-sulphonyldianiline

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

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

Adequacy of study:

other information

Study period:

< 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Review on the effects of dapsone treatment in humans based on numerous case reports. 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:

publication

Title:

Dapsone

Author:

Ronni Wolf, Hagit Matz Edith Orion, Binnur Tuzun, Yalcin Tuzun

Year:

2002

Bibliographic source:

Dermatololgy Online Journal 8(1): 2

Applicant's summary and conclusion

Executive summary:

The most frequent and well-documented pharmacologic reactions are the hematological side-effects, such as methemoglobinemia, hemolysis and anemia.

Effective clinical use of dapsone is limited because of dose-dependent adverse hematological reactions, even at the low daily dosages of 100 mg used in the chemotherapy of leprosy and dermatological conditions. Patients with a genetic deficiency of certain enzymes (i.e., glucose-6-phosphate dehydrogenase or glutathione reductase) are more susceptible to the hematological effects.

Long-term administration of dapsone at standard doses (100 mg/d) in normal patients usually results in methemoglobinemia of 15%, which is not clinically significant The hemotoxicity of dapsone is not caused by the drug itself, but by its hydroxylamine metabolites. Methemoglobin levels of under 20% are not usually associated with symptoms. Dyspnea, nausea and tachycardia usually occur at levels of 30% or above, while lethargy, stupor and deteriorating consciousness occur as methemoglobin levels approach 55%. Levels of 70% are usually fatal.

Agranulocytosis is another hematologic adverse effect of dapsone. Unlike methemoglobinemia, this severe adverse effect is due to an unpredictable idiosyncratic reaction. For unknown reasons, the risk of agranulocytosis in patients with dermatitis herpetiformis is more than 25-fold compared with other patients. Agranulocytosis was estimated to develop in 1 of 240 - 425 patients with dermatitis herpetiformis receiving dapsone therapy, whereas this side effect in patients with leprosy is almost unknown.Factors such as drug dosage, immune status, degree of malnutrition, and ethnic origin are probably important determinants of the risk of developing agranulocytosis.

Another serious idiosyncratic adverse effect is the dapsone hypersensitivity syndrome. Drug hypersensitivity syndrome is a severe idiosyncratic reaction to a drug defined by the clinical triad of fever, rash, and internal organ involvement (most commonly the liver and the hematologic system). It occurs in a relatively small proportion of patients but is associated with considerable morbidity and mortality. The unpredictability and potential severity of this reaction make it a major concern in clinical practice and drug development.