Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February 1962
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Non GLP. The report does not detail a specific method; however it documents dose levels and responses in detail, so is deemed appropriate for use in the support of a formal registration. Sufficient dose ranges and numbers are detailed; hence it is appropriate for use based on reliability and animal welfare grounds.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1962
Report date:
1962

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
4,4’-Oxydianiline was administered as a suspension in peanut oil in single doses to male rats (1/dose level) via intragastric intubation at doses of 40, 60, 90, 200, 300, 450, 670, 1000, 1500, 2250, 3400, or 5000 mg/kg. Survivors were killed 9-13 days later and were examined for pathologic changes. In addition, 3 animals were dosed at levels of 1500, 3400, and 5000 mg/kg and killed, when moribund, for pathologic evaluation.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
4,4'-oxydianiline
EC Number:
202-977-0
EC Name:
4,4'-oxydianiline
Cas Number:
101-80-4
Molecular formula:
C12H12N2O
IUPAC Name:
4-(4-aminophenoxy)aniline
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): 4,4'-Oxydianiline
- Haskell lot/batch No.: 2675 (other codes: MPD-2706)
- Molecular formula (if other than submission substance): Not specified
- Molecular weight (if other than submission substance): Not specified
- Smiles notation (if other than submission substance): Not specified
- InChl (if other than submission substance): Not specified
- Structural formula attached as image file (if other than submission substance): Not specified.
- Substance type: Not specified
- Physical state: Not specified
- Analytical purity: Not specified
- Impurities (identity and concentrations): Not specified
- Composition of test material, percentage of components: Not specified
- Isomers composition: Not specified
- Purity test date: Not specified
- Expiration date of the lot/batch: Not specified
- Radiochemical purity (if radiolabelling): Not applicable
- Specific activity (if radiolabelling): Not applicable
- Locations of the label (if radiolabelling): Not applicable
- Expiration date of radiochemical substance (if radiolabelling): Not applicable
- Stability under test conditions: Not applicable
- Storage condition of test material: Not applicable
- Other: Not applicable
Specific details on test material used for the study:
4,4'-oxydianiline
4,4'-diaminodiphenyl ether
CAS 101-80-4

Test animals

Species:
rat
Strain:
other: Charles River - CD
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Not specified
- Age at study initiation: Not specified
- Weight at study initiation: Not specified
- Fasting period before study: Not specified
- Housing:Not specified
- Diet (e.g. ad libitum): Not specified
- Water (e.g. ad libitum): Not specified
- Acclimation period: Not specified


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not specified
- Humidity (%): Not specified
- Air changes (per hr): Not specified
- Photoperiod (hrs dark / hrs light): Not specified


IN-LIFE DATES: Not specified

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: Not specified.
- Amount of vehicle (if gavage): Not specified
- Justification for choice of vehicle: Not specified
- Lot/batch no. (if required): Not specified
- Purity: Not specified

MAXIMUM DOSE VOLUME APPLIED: 5000 mg/kg

DOSAGE PREPARATION (if unusual): Not specified
Doses:
5000, 3400, 2250, 1500, 1000, 670, 450, 300, 200, 90, 60, 40 mg/kg
Additional 3 animals were dosed at 5000, 3400, 2250 for sacrificial purposes.
No. of animals per sex per dose:
1
Control animals:
no
Details on study design:
- Duration of observation period following administration: Survivors were sacrificed 9 to 13 days following administration
- Frequency of observations and weighing: Not specified
- Necropsy of survivors performed: No.
- Other examinations performed: clinical signs, body weight,, histopathology, blood observations
Statistics:
Not specified.

Results and discussion

Effect levels
Key result
Sex:
male
Dose descriptor:
approximate LD50
Effect level:
> 1 000 - < 1 500 mg/kg bw
Based on:
test mat.
Remarks on result:
other: At 1500 mg/kg and above: mortality = 1/1 At 1000 mg/kg and below: mortality = 0/1
Mortality:
Mortality was 0/1, 0/1,0/1, 0/1, 0/1, 0/1, 0/1, 0/1, 1/1, 1/1, 1/1, 1/1 at 40, 60, 90, 200, 300, 450, 670, 1000, 1500, 2250, 3400, and 5000 mg/kg, respectively.
Clinical signs:
Clinical signs of toxicity included discomfort (=200 mg/kg), inactivity (=670 mg/kg), glassy and pale eyes (=670 mg/kg), prostration (=2250 mg/kg), slow shallow respiration (=2250 mg/kg), salivation (3400 mg/kg), lacrimation (=2250 mg/kg), tremors (1500 mg/kg), convulsive movements of the head (5000 mg/kg), incoordination (1500 mg/kg), hair loss (200, 300, 450, 670, 1000, and 1500 mg/kg), bulging eyes (3400 and 5000 mg/kg), and ruffled fur (670 and 1000 mg/kg). In addition, weight loss was observed at 60, 200, 300, 450, 670, 1000, 1500, 3400, and 5000 mg/kg.
Body weight:
Test subjects at 1500 mg/kg dose levels and below were documented as suffering from weight loss. No specific information or observational timepoints were noted within the report.
Gross pathology:
Pathological changes at lethal doses included congestion of viscera in the one animal (2500 mg/kg); all others could not be observed due to advanced post-mortem changes. In the animals that were dosed, and killed when moribund, pathological changes included slightly brown blood and/or tissues (1500 and 5000 mg/kg), stomach distended with food (=3400 mg/kg), liver injury (1500 mg/kg), and spleen and adrenal gland congestion (1500 mg/kg). Pathological changes at non-lethal doses included liver injury (200 and 1000 mg/kg), kidney injury (1000 mg/kg), and extramedullary blood formation (=200 mg/kg). A single dose of 90 mg/kg caused no detectable injury.
Other findings:
- Organ weights: Not specified.
- Histopathology: Not specified.
- Potential target organs: Not specified.
- Other observations: Not specified.

Any other information on results incl. tables

The following tabulated data is presented within the report:

Peanut oil suspension, %

Dosage mg/kg

Mortality

Clinical Signs

Pathological changes

25

5000

1/1

Discomfort, inactivity, glassy and pale eyes, died within 3 days

 

Not observed due to advanced post­mortem change

 

25

3400

1/1

Discomfort, inactivity, glassy and pale eyes, prostration, salivation, slow shallow respiration, died within 2 days

Not observed due to advanced post­mortem change

 

20

2250

1/1

Discomfort, lacrimation, Increased water intake, inactivity, glassy and pale eyes, prostration, shallow respiration, died in 2 days

 

Congestion of viscera

 

20

1500

1/1

Discomfort, inactivity, glassy and pale eyes, ruffled fur, hair loss, incoordin­ation, tremors, weight loss, died within 12 day*

 

Not observed due to advanced post­mortem change

 

20

1000

0/1

Discomfort, inactivity, pale and glassy eyes, ruffled fur, hair loss, weight loss for 9 days

 

Liver and kidney injury, extra-medullary blood formation

 

20

670

0/1

Discomfort, inactivity, pale and glassy eyes, ruffled fur, hair loss, weight loss for 5 days

 

Extramedullary blood formation

 

10

450

0/1

Discomfort, hair loss, weight loss for 3 days

 

Extramedullary blood formation

 

10

300

0/1

Discomfort, hair loss, weight loss for 3 days

 

Extramedullary blood formation

 

10

200

0/1

Discomfort, hair loss, weight loss for 3 days

 

Extramedullary blood formation

 

5

90

0/1

None

None

1

60

0/1

Weight loss 2 days

None

1

40

0/1

None

None

 

Animals Sacrificed for Pathology

Peanut oil suspension, %

Dosage mg/kg

Mortality

Clinical Signs

Pathological changes

25

5000

1/1

Discomfort, inactivity, lacrimation, bulging eyes, shallow respiration, pros­tration, convulsive movements of head, weight loss, killed 4 days after dosing

Blood slightly brown, stomach distended with food

 

25

3400

1/1

Discomfort, inactivity, lacrimation, bulging eyes, shallow respiration, pros­tration, weight loss, killed 1 day after dosing

 

Stomach distended with food

 

20

1500

1/1

Discomfort, Inactivity, glassy and pale eyes, hair loss, weight loss, killed 7 days after dosing

 

Liver injury spleen and adrenal gland congested, blood and tissues slightly brown

 

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Remarks:
Toxic
Conclusions:
Although direct correlation between the approximate lethal dose (ALD) and the median lethal dose (or LD50) cannot be specified exactly, based on the results of the study it is deemed appropriate to consider the substance as "harmful" by oral ingestion.
However this result differs from the Harmonized European Classification detailed in Annex VI of the CLP regulation. According to this regulation, the substance must be considered as "Toxic" and classified H301 category 3.
Executive summary:

On the basis of the results from a study conducted on rats, and according to the CLP regulation criteria, the substance can be considered "harmful" by oral ingestion.

However this result differs from the Harmonized European Classification detailed in Annex VI of the CLP regulation. According to this regulation, the substance must be considered as "Toxic" and classified H301 category 3.