Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 - 28 March, 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: No deviations reported. The study fully meets the current guidelines.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 4, 4'-methylene bis (2-chlorobenzen amine)
- Substance type: white, needlelike crystalline powder
- Physical state: solid
- Analytical purity: 99.76%
- Impurities (identity and concentrations): not mentioned
- Purity test date: 2002-12-12
- Lot/batch No.: FG-3002
- Expiration date of the lot/batch: not mentioned
- Stability under test conditions: stable during study period; purity was 99.11 % at 2003-12-15
- Storage condition of test material: protected from air and moisture at 1-7 °C

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Japan
- Age at study initiation: 7 weeks
- Weight at study initiation: 212 - 282 g
- Fasting period before study: 16 hours before dosing
- Housing: individually in wire-mesh steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 4 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 26
- Humidity (%): 30 - 70
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 ml/ kg bw
- Justification for choice of vehicle: not mentioned
- Lot/batch no. (if required): 2925

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: no information available for lethal dose in rats. Starting dose 300 mg/kg according to guideline.
Doses:
300, 2000 mg/kg
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: frequently up to 6 hours, thereafter once daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
1) Lethal dose: Approximate lethal doses were estimated based on the numbers of dead animals of each dose level.
2) Body weight: Mean and standard deviations of body weights were calculated for each administration date. The standard deviations were not calculated when the numbers of animals were not more than two.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
approximate LD50
Effect level:
2 000 mg/kg bw
Mortality:
After 6 rats were administered 300 or 2000 mg/kg (3 rats for each dose), one rat at 2000 mg/kg died. The lethal dose was estimated as 2000 mg/kg.
Clinical signs:
At the first dose of 300 mg/kg, no abnormal clinical signs were observed. At the second dose of 300 mg/kg, dark red discoloration of ear auricles and limbs were observed in one out of three rats the day after administration, which resolved 2 days after administration. No abnormal clinical signs were observed thereafter. At the first dose of 2000 mg/kg, dark red discoloration of ear auricles and limbs and increased water intake activities were observed from 30 minutes to 1 hour of administration, and a decrease in spontaneous movements and bradypnea were also observed in one out of three rats. Thereafter, increased water intake activities disappeared; however, decreased spontaneous movements and bradypnea were still observed, and abnormal gait (ataxic gait) was also observed. Deep breathing and unkempt fur were observed the day after administration, and one rat died 2 days after dosing. The surviving animals showed only dark red discoloration of ear auricles and limbs the day after administration, which resolved 2 days after dosing. No abnormal clinical findings were observed thereafter. At the second dose of 2000 mg/kg, dark red discoloration of ear auricles and limbs and increased water intake activities were observed 1 hour after dosing. Increased water intake activities disappeared thereafter; however, two rats showed decreases in spontaneous movements and bradypnea and abnormal gait (ataxic gait), and one rat showed abnormal gait (ataxic gait) 6 hours after dosing. Only dark red discoloration of ear auricles and limbs were observed the day after administration, which disappeared 2 days after dosing, and no abnormal clinical findings were observed thereafter.
Body weight:
In both 300 and 2000 mg/kg groups, weight loss or tendency of inhibited weight gain was observed by 3 days after administration. Body weights increased steadily 7 days after dosing throughout the observation period.
Gross pathology:
In the dead animal, unkempt fur, white foci in the liver, dark red adrenal glands (bilateral), dark red foci of the proventriculus and glandular stomach, and dark red contents in the small intestine from jejunum to ileum were observed. No abnormal gross findings were noted in the body surface, organs or tissues of the head, chest and abdomen in the surviving animals

Any other information on results incl. tables

none

Applicant's summary and conclusion

Interpretation of results:
Category 5 based on GHS criteria
Remarks:
Migrated information
Conclusions:
In a study with 6 female rats an acute oral LD50 of 2000 mg/kg bw was estimated. The study was conducted conform OECD guideline 423 under GLP-conditions.