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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: according to GLP, and Commission guideline 91/507/EEC Pharmaceutical Affairs Bureau, Notifications 24 & 88, US-FDA for Pharmaceuticals

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Commission Directive 91/507/EEC, Pharmaceutical Affairs Bureau Notifications 24 & 88 guidance, US-FDA guidance on acute testing for Pharamceuticals
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
other: rising dose study
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Dapsone (Sigma-Aldrich Co Ltd, Poole, Dorset), batch no.70522014
White powder
Stored in refrigerator (1-10 degrees Celsius)

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
Crl:NZW/Kbl.BR strain obtain from Charles Rivers Ltd, Margate, Kent.
Body weight range : 2.214 to 2.425 kg (males) and 2.061 to 2.340 kg (females) on Day -1 (day before 1st dosing occasion)
Age : 11 to 13 weeks old
Acclimation period: 6 days
Animals were sex-separated and kept individually in cages. Water was given ad libitum, and feed was freely available but consumption was measured.
Animals were kept under standard conditions for rabbits.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-22 deg C
- Humidity (%): 40-80%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hrs daily
TEST ANIMALS
- Source:
- Age at study initiation:
- Weight at study initiation:
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1% in water
Details on oral exposure:
Oral exposure was by gavage , and once weekly.
Doses:
Doses were 5, 7.5, 12.5, 17.5, 25, 40, 55, 100, 200, 300, 450, 600, 750, 900, 1100, and 1500 mg/kg bw
No. of animals per sex per dose:
3 males and 3 females
except for the 2 sets 300, 450, 600 mg/kg bw and 750, 900 and 1100 mg/kg bw , the group of 6 animals was subdivided into 3 sets consisting of one male and one femals for each dose.
Control animals:
yes
Details on study design:
In order to determine the maximum tolerated dose, increasing doses were applied with one week interval for recovery.
Mortalities were recorded as well as clinical signs of toxicity.
The maximim tolerated dose was based on the observation of clinical changes and variations in weight gain and food intake.
Statistics:
no

Results and discussion

Preliminary study:
none
Effect levelsopen allclose all
Sex:
male/female
Dose descriptor:
LD0
Effect level:
ca. 600 mg/kg bw
Based on:
test mat.
Remarks on result:
other: reduced body weight gain and food consumption
Sex:
male/female
Dose descriptor:
LDLo
Effect level:
> 700 - < 910 mg/kg bw
Based on:
test mat.
Remarks on result:
other: toxic clinical signs observed
Mortality:
Mortality occurred at 1500 mg/kg bw (animals were killed for humane reasons in moribund condition).
Clinical signs:
Self-mutiliatuuin of some animals at 750 and 900 mg/kg bw.
Body weight:
Body weight gain reduction occurred from doses above 200 mg/kg bw during the 3 days period following administration but without good dose-relationship.
Gross pathology:
No gross pathology findings were observed at any dose levels.

Applicant's summary and conclusion

Conclusions:
Under the test conditions and regarding observations of clinical signs, body weight gain and food consumption, LD0 is defined at 600 mg/kg bw and a LDLo value range between 700 to 910 mg/kg in rabbits.
Executive summary:

Under the test conditions and regarding observations of clinical signs, body weight gain and food consumption, LD0 with no detectable effect is defined at 600 mg/kg bw, and a LDLo range defined between 700 to 910 mg/kg in rabbits.