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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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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:
2005
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

Constituent 1
Chemical structure
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))
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.