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EC number: 209-967-5 | CAS number: 599-61-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- GLP study performed acc to guideline. 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:
- Unnamed
- Year:
- 2 005
- Report date:
- 2005
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- 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
- Test material form:
- other: gel
- Details on test material:
- Test material is dapsone plus DMGE (diethylene glycol monoethylether (excipient))
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl: CD(SD) albino
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Age: Six weeks at initiation
Weight: Males 123-175 g, females 131-157 g
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5%
- Details on oral exposure:
- 10 ml/kg application volume
DMGE (excipient) = 180 mg/kg bw
Dapsone at 3, 30 and 100 mg/kg/day - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- 1/day
- No. of animals per sex per dose:
- Each 10 males and 10 females,
- Details on study design:
- The study was performed with 5 groups:
Group 1: Control (vehicle only)
Group 2: 180 mg/kg/day diethylene glycol monoethylether (DMGE)
Group 3: 3 mg /kg/day dapsone
Group 4: 30 mg /kg/day dapsone
Group 5: 100 mg /kg/day dapsone
A satellite group was used for toxicokinetics - Positive control:
- none
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined weekly
OPHTHALMOSCOPIC EXAMINATION: Yes
HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day 85
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on day 85
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
Organs weighted: Adrenals, brain, kidneys, liver, ovaries, spleen, teses, thymus
HISTOPATHOLOGY: Yes
Main study animals in grous 1 (vehicle control), 2 (DGME control) and 5 (top dose 100 mg/kg/day) and gross lesions, liver, lungs, kidneys, target organs (spleen), and tumors from animals in groups 3 (3 mg/kg/day and 4 (30 mg/kg/day) - Other examinations:
- Toxikokinetics: Samples obtained from three animals and group per time point at days 1 and 90 at 0 (immediately prior treatment), 0.5, 1, 2, 4, 8, 24 hours post-dose. The Cma, Tmax time of last measurable concentration (T last) and AUC 0-24 were determined.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- no mortality; skin discoloration (cyanosis) of mouth, nose, limbs, ears and body in 3/10 males (but no females) at 3 mg/kg/day and in both males and females at 30 mg/kg/day or above. Hypoactivity in both males and females at 30 mg/kg/day or above.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- no mortality; skin discoloration (cyanosis) of mouth, nose, limbs, ears and body in 3/10 males (but no females) at 3 mg/kg/day and in both males and females at 30 mg/kg/day or above. Hypoactivity in both males and females at 30 mg/kg/day or above.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Significantly reduced in males at 100 mg/kg/day. Day 90 mean weights of group 1 and group 5 males were 561+/-74g and 457+/-25g, respectively. The body weight gains were reduced for all treatment groups relative to controls, differences not significant.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Significantly reduced in males at 100 mg/kg/day
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- At 30 mg/kg/day or above: Increased WBC count, decreased RBC count, decreased hemoglobin, reduced hematocrit (males insignificant trend only), increased mean corpuscular volume and mean corpuscular hemoglobin (males only), and increased prothrombin time.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- At 100 mg/kg/day: Males: increased albumin, bilirubin, BUN, ALT, γ-GT, potassium. Decreased levels of triglycerides and chloride. Females: Increased BUN, ALA, γ-GT, alkaline phosphatase and calcium and reduced chloride.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased (200-300% in males, 20-40% in females) spleen weights at 30 mg/kg/day or above . Increased (25%) liver weight in females at 30 mg/kg/day and above
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Enlarged spleen in males at 30 mg/kg/day or above. Small thymus at 30 mg/kg/day or above. Females: Uterine enlargement at 100 mg/kg/day.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Effects on spleen only. Mild splenic congestion and minimal extramedullary hematopoiesis were observed in male animals at 30 mg/kg/day and above. Minimal brown pigmentation of the spleen in males and females at 3 mg/kg/day or above.
- Histopathological findings: neoplastic:
- no effects observed
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- >= 3 - < 30 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: Effects mainly due or secondary to methemoglobin formation
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- NOAEL is 3 mg/kg/day. Target organs are blood and spleen.
- Executive summary:
In this 90d gavage study in the rat treatment-related findings were observed at 30 mg/kg/day. The main effects were cyanosis of the skin (dapsone is known to induce methemoglobinemia, and the cyanosis may be secondary to this), hyperactivity, increased WBC count, decreased RBC count, hemoglobin concentration and hematocrit., increased prothrombin time, spleenomegaly (especially in males), mild spleenic congestion, and mild pigmentation of the spleen. These effects were more observed at 100 mg/kg/day. No frank toxicity was observed at 3 mg/kg/day dapsone, although minimal brown pigmentation of the spleen was observed. 3 mg/kg/day is considered as the NOAEL in this study.
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