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Description of key information

Pharmacokinetics: Dapsone has a long history of medical use for the treatment of leprosy (Vadher and Lalljee 1992), malaria (Shanks et al. 1992) and different dermatological diseases (reviewed by Wolf et al. 2002).


Absorption: Oral

Dapsone is absorbed rapidly and nearly completely from the gastrointestinal tract (Goodman and Gilman’s 2008). After oral administration, its bioavailability is estimated to rank from 70 to 80 %. Peak concentrations of dapsone in plasma are reached within 2 to 8 hours after administration (Uetrecht J.P. 1989). The mean half-life of elimination is about 20 to 30 hours (Pieters and Zuidema 1986). In healthy volunteers, after 100 mg of oral dapsone, peak serum dapsone concentrations between 1.10 and 2.33 mg/L were reached within 0.5 to 4 h (Peters et al. 1975). Twenty-four hours after oral ingestion of 100 mg, plasma concentrations range from 0.4 to 1.2 µg/ml, and a dose of 100 mg per day produces steady-state plasma concentrations of free dapsone of 2 to 6 µmol/L (Zuidema et al. 1986, Ellard, G.A. 1965).

An oral absorption rate of 75% has been considered for the risk assessment.


Absorption: Dermal

Bioavailability after dermal absorption is lower compared to oral uptake in both rats and human. After dermal application 25 % and 10 % of applied dose were found systemically absorbed in male and female rats, respectively. Less than 1 % of a topically applied dose of dapsone in a 5 % dapsone topical gel was found absorbed in human (See, N. 2005, supporting study).

As conservative estimate a dermal absorption rate of 15 % has been considered for the risk assessment.


Absorption: Inhalation

No information on the uptake of dapsone via the inhalation route is available. According to REACH guidance document R7.C (ECHA, 2017), inhalation absorption is maximal for substances with VP > 25 kPa, particle size <100 μm, low water solubility and moderate log Kow values (between -1 and 4). Very hydrophilic substances may be retained within the mucus and are not available for absorption.

The test substance is a solid at room temperature with a melting point of 175 °C. As a solid, it has very low vapor pressure and is considered to have low volatility. It will therefore not be available as vapours for inhalation under ambient conditions.

The particle size distribution (98.5 – 100 % present as < 100 µm, 8 - 49.7 % present as < 10 µm, 1.2 – 10.8 % present as < 4 µm) indicates that there is a respirable fraction present. Particles between 10-100 µm will deposit in the nasopharyngeal region and will be eliminated by coughing or sneezing. Particles < 10 µm might reach the tracheobronchial or pulmonary regions. Dapsone further has medium water solubility of 380 mg/L at 37 °C and will dissolve in the mucus within the respiratory tract. Dapsone is too large to pass through aqueous pores (> 200 Da). Since the absorption of small particles < 10 µm cannot be excluded, inhalation absorption can overall not be excluded. Therefore, as a conservative approach, a default value of 100% (in line with the ECHA Guidance Chapter R.8) has been considered for the risk assessment.


About 70% of Dapsone is bound to plasma protein with a volume of distribution of 1.5/kg (Pieters and Zuidema 1986). The drug is widely distributed in the body including skin, liver, and kidney. It crosses the blood-brain barrier and the placenta (Venkatesan K. 1989, Peters et al. 1975, Zhu and Stiller, 2001).

Dapsone is distributed throughout total body water and is present in all tissues. However, it tends to be retained in skin and muscle and especially in the liver and kidney: traces of the drug are present in these organs up to 3 weeks after therapy cessation (Gatti et al. 1997, Edstein et al, 1986).



In hepatocytes, dapsone is metabolized by two major pathways, N-acetylation (by N-acetyltransferase) to monoacetyldapsone (MADDS) and N-hydroxylation to dapsone hydroxylamine (DDS-NOH) (by multiple isoforms of P-450 enzymes, i.e. CYP2E1, CYP2PC9, CYP3A4) (Vague and Svensson, 1994). Mitra and coworkers showed that the P-450 accounting for the majority of dapsone hydroxylamine formation in vivo is CYP2E1 (Mitra et al 1995).

Dapsone N-hydroxylation is thought to be the main responsible for the hematologic adverse effects of Dapsone. As a potent oxidant, DDS-NOH in circulation depletes glutathione within red blood cells leading to methemoglobin production in hemolysis. In erythrocytes, DDS-NOH oxidizes oxyhemoglobin (Fe2+) to methemoglobin (Fe3+) resulting in reduced oxygen-carrying capacity and impaired unloading of oxygen at the tissues. Coleman and Jacobus suggested that a cycle exists between the hepatic oxidation of dapsone to its hydroxylamine form and reduction to amine within the red cell, a process, which might lead to re-oxidation by the hepatic cytochrome P450. They speculated that this process might contribute to the persistence of the drug in vivo (Coleman and Jacobus 1993). Methemoglobin and other oxidizing products are reduced by glutathione and NADPH-dependent reductase with depletion of the antioxidant stocks of the erythrocytes.



Approximately 70% of the drug is excreted in the urine as an acid-labile mono-N-glucuronide and mono-N-sulfamate whereas about 20% is excreted unchanged. About 10% is excreted in the bile (Zhu and Stiller 2001). After a single dose of dapsone, about 50% is excreted during the first 24 h (Glazko et al. 1986). Dapsone also crosses the placenta and is excreted into the breast milk (Venkatesan K. 1989).


Species differences of relevance to the safety evaluation

Dapsone N-hydroxylamine can be formed by rat, mouse or human liver microsomes in vitro and was shown to be toxic to erythrocytes in vitro. However, in vivo Dapsone hydroxylamine and its glucuronide as well as significant methemoglobinemia were only detected in humans and male rats. The species difference in the metabolism and toxicity of Dapsone has important implications in the safety evaluation of related compounds in man (Tingle et al 1997).

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
Absorption rate - dermal (%):
Absorption rate - inhalation (%):

Additional information

Key endpoint references:

Vadher, A. and Lalljee, M. Patient treatment compliance in leprosy. A critical review. Int. J. Lepr. 60: 587–607, 1992.

Shanks, G.D., Edstein, M.D., Suriyamongkol, V., Timsaad, S., Webster, H.K. Malaria chemoprophylaxis using proguanil/dapsone combinations on the Thai-Cambodian border. Am. J. Trop. Med. Hyg. 46: 643–648, 1992.

Wolf R, Matz H, Orion E, et al. Dapsone. Dermatol Online J. 2002; 8(1).

Goodman and Gilman’s. Manual of pharmacology and therapeutics - eight edition. McGraw-Hill; 2008

Uetrecht JP. Dapsone and sulfapyridine. Clin Dermatol. 1989;7:111–120.

Pieters FA, Zuidema J. The pharmacokinetics of dapsone after oral administration to healthy volunteers. Br J Clin Pharmacol. 1986;22:491–494.

Zuidema J, Hilbers-Modderman E, Merkus F. Clinical pharmacokinetics of dapsone. Clin Pharmacokinet 1986; 11:299-315.

Ellard G. Absorption, metabolism and excretion of di (rho-aminophenyl) sulphone (dapsone) and di (rho-amonophenyl) sulphoxide in man. Br J Pharmacol 1966; 26:212-217.

Ellard G, Gammon P, Rees R. Dapsone acetylation and the treatment of leprosy. Nature 1972; 239:159-160.

Peters JH, Murray JF Jr, Gordon GR. The disposition of sulfoxone and solasulfone in leprosy patients. Lepr Rev. 1975;46:171–180

Venkatesan K. Clinical pharmacokinetic considerations in the treatment of patients with leprosy. Clin Pharmacokinet. 1989;16:365–386.

Zhu YI, Stiller MJ, Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol. 2001;45:420–434.

Vage C, Svensson CK. Evidence that the biotransformation of dapsone and monoacetyldapsone to their respective hydroxylamine metabolites in rat liver microsomes is mediated by cytochrome P450 2C6/2C11 and 3A1. Drug Metab Dispos. 1994;22:572–577.

Mitra A, Thummel K, Kalhorn T, Kharasch E, Unadkat J, Slattery J. Metabolism of dapsone to its hydroxylamine by CYP2E1 in vitro and in vivo. Clin Pharmacol Ther 1995; 58:556-566.

Fliming C, Branch R, Wilkinson G, Guengerich F. Human liver microsomal N-hydroxylation of dapsone by cytochrome P-4503A4. Mol Pharmacol 1992; 41:975- 980.

Vague C, Svensson C. Evidence that the biotransformation of dapsone and monoacetyldapsone to their respective hydroxylamine metabolites in rat liver microsomes is mediated by cytochrome P450 2C6/2C11 and 3A1. Drug Metab Dispos 1994; 22:572-577.

Guengerich F, Humphreys W, Yun C, Hammons G, Kadlubar F, Seto Y, et al. Mechanisms of cytochrome P450 1A2-mediated formation of N-hydroxy arylamines and heterocyclic amines and their reaction with guanyl residues. Princess Takamatsu Symp 1995; 23:78-84.

Coleman M, Jacobus D. Reduction of dapsone hydroxylamine to dapsone during methaemoglobin formation in human erythrocytes in vitro. Biochem Pharmacol 1993; 45:1027-1033.

Glazko AJ, Dill WA, Montalbo RG, et al. A new analytical procedure for dapsone: application to blood-level and urinary-excretion studies in normal men. Am J Trop Med Hyg. 1968;17:465–473.

Gatti G, Hossein J, Malena M, et al. Penetration of dapsone into cerebrospinal fluid of patients with AIDS. J Antimicrob Chemother. 1997;40:113–115.

Edstein MD, Veenendaal JR, Newman K, et al. Excretion of chloroquine, dapsone and pyrimethamine in human milk. Br J Clin Pharmacol. 1986;22:733–735.

See, N., Pharmacology Review for Aczone, 2005, 21-794.

Molinelli, E., Paolinelli, M., Campanati, A., Brisigotti, V., Offidani, A. Metabolic, pharmacokinetic and toxicological issues surrounding dapsone, 2019, Expert Opinion on Drug Metabolism & Toxicology, 15:5, 367-379.