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EC number: 201-248-4 | CAS number: 80-08-0
- 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:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 22 March 2000 to 18 October 2001
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
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
- 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
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) and lot/batch number of test material: not provided
- Purity: not provided
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
No details on stability or storage provided
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- 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:
- not specified
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- 1/day
- No. of animals per sex per dose:
- Each 10 males and 10 females,
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The study was performed with 5 groups:
Group 1: Control (vehicle only)
Group 2*: 180 mg/kg/day diethylene glycol monoethyl ether (DGME)
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
* group two did not contain any dapsone treated animals - 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:
- Toxicokinetics: 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 Cmax, Tmax and 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):
- 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
- 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
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 3 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- haematology
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 30 mg/kg bw (total dose)
- System:
- haematopoietic
- Organ:
- blood
- spleen
- Treatment related:
- yes
- Dose response relationship:
- yes
Applicant's summary and conclusion
- Conclusions:
- The NOAEL of Dapsone is 3 mg/kg/day. Target organs are blood and spleen.
- Executive summary:
A 90-day sub-chronic oral (gavage) toxicity study in rats was conducted under GLP conditions in male and female Sprague Dawley rats. 10 animals per sex per dose group with an additional 10 per sex for toxicokinetic observations were exposed to 3 concentrations of dapsone, daily for 90 days. Observations included survival, clinical signs, ophthalmoscopy, haematology, clinical chemistry and (histo)pathology.
No remarkable or unscheduled deaths were observed. Clinical signs included cyanosis of the mouth, noise, limbs, ears and body in 3/10 males at 3mg/kg/d and in both males and females at 30mg/kg/d or above. Hyperactivity and reduced body weight was observed in both males and females, and reduced food consumption in males only. Significant changes were observed in haematology (mainly effects on red blood cells, indicative of methemoglobinemia) and clinical chemistry. Gross pathology showed enlarged spleens in nearly all male >30 mg/kg/d animals and small thymus in males at a lower incidence at the same dose levels. Uterine enlargement was observed in females treated with 100 mg/kg/d. Treatment related histopathology findings were limited to the spleen in both males and female animals, with non-adverse minimal brown pigmentation observed at >3mg/kg/d and congestion or extramedullary haematopoiesis in male animals at >30mg/kg/d.
3 mg/kg/d was considered the NOAEL observed on study for dapsone.
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