Registration Dossier

Administrative data

Description of key information

The substance was administered orally insingle doses to rats. The Approximate Lethal Dose (ALD) by this route was estimated between 1500 and 1000 mg/kg of body weight. 

The substance was applied to the skin of male rabbits as a 10% solution in DMAC. The Approximate Lethal Dose (ALD) by this route was estimated between 1000 and 670 mg/kg of body weight. 

No data are available for the assessment of the toxicity after an acute exposure by inhalation.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
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.
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
Specific details on test material used for the study:
4,4'-oxydianiline
4,4'-diaminodiphenyl ether
CAS 101-80-4
Species:
rat
Strain:
other: Charles River - CD
Sex:
male
Details on test animals 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
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.
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.

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

 

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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
Value:
1 500 mg/kg bw
Quality of whole database:
It should be noted that the substance has an harmonized european classification in the Annex VI of the CLP regulation. According to this regulation, the substance must be considered as "Toxic" by oral route and classified H301 category 3.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
It should be noted that the substance has an harmonized european classification in the Annex VI of the CLP regulation. According to this regulation, the substance must be considered as "Toxic" by inhalation and classified H331 category 3.

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
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.
Qualifier:
no guideline followed
Principles of method if other than guideline:
The test substance was applied at various concentrations as a 10% solution in dimethylacetamide (DMAC) to the closely clipped dorsal skin of albino male rabbits. The trunks of the animals were then wrapped with waterproof cello-phane and cotton bandage for 24 hours. The survivors were killed 14 or 17 days after treatment.
GLP compliance:
no
Test type:
other: See below
Limit test:
no
Specific details on test material used for the study:
4,4'-oxydianiline
4,4'-diaminodiphenyl ether
CAS 101-80-4
Species:
rabbit
Strain:
not specified
Sex:
male
Details on test animals 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
Type of coverage:
occlusive
Vehicle:
other: dimethylacetamide (DMAC)
Details on dermal exposure:
TEST SITE
- Area of exposure: Not specified
- % coverage: Not specified
- Type of wrap if used: waterproof cellophane wrap with cotton bandage over.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Not specified.
- Time after start of exposure: 24 hours.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1000, 670, 450 mg/kg
- Concentration (if solution): 10% in DMAC
- Constant volume or concentration used: yes
- For solids, paste formed: Not applicable

VEHICLE
- Amount(s) applied (volume or weight with unit): 8300, 5700, 3800 mg/kg
- Concentration (if solution): 90%
- Lot/batch no. (if required): Not specified.
- Purity: Not specified.
Duration of exposure:
24 hours
Doses:
1000, 670, 450 mg/kg
No. of animals per sex per dose:
1
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 or 17 days
- Frequency of observations and weighing: Not specified
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Yes
Statistics:
Not specified.
Key result
Sex:
male
Dose descriptor:
approximate LD50
Effect level:
> 670 - <= 1 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Estimated LD50
Mortality:
1000 mg/kg - Found dead < 1 day
670 mg/kg - Sacrificed at Day 17
450 mg/kg - Sacrificed at Day 14
Clinical signs:
1000 mg/kg - None observed on day of treatment
670 mg/kg - Temporary loss of appetite and weight loss
450 mg/kg - Temporary loss of appetite and weight loss

Refer to tabulated data below
Body weight:
1000 mg/kg - None observed on day of treatment
670 mg/kg - Weight loss noted; amount unspecified.
450 mg/kg - Weight loss noted; amount unspecified.

Refer to tabulated data below
Gross pathology:
1000 mg/kg - Focal necrosis of liver, marked enteritis, no changes in lungs, kidneys, spleen, pancreas
670 mg/kg - Slight focal necrosis of liver, no changes in intestines, lungs, kidneys, spleen, pancreas
450 mg/kg - No changes in any of the organs

Refer to tabulated data below

Data is tabulated as follows:

Test material dose level mg/kg

Dosage DMAC

mg/kg

Mortality

Clinical Signs

Pathological changes

1000

8300

1/1

Dead < 1 days

None observed on day of treatment

Focal necrosis of liver, marked enteritis, no changes in lungs, kidneys, spleen, pancreas

670

5700

0/1

Sacrificed – Day 17

Temporary loss of appetite and weight loss

Slight focal necrosis of liver, no changes in intestines, lungs, kidneys, spleen, pancreas

450

3800

0/1

Sacrificed – Day 14

Temporary loss of appetite and weight loss

No changes in any of the organs

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Although direct collaboration 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 topical skin application.
However this result differs from the Official European Classification detailed in Annex VI of the CLP regulation. According to this regulation, the substance must be considered as "Toxic" and classified H311 category 3.
Executive summary:

4,4'-Oxydianillne is deemed slightly toxic for the male rabbit when applied to the skin as a 10% solution in DMAC, its Approximate Lethal Dose (ALD) by this route being 1000 mg/kg of body weight.  No clinical signs of toxicity were observed on this animal, but histological changes indicated a mild liver injury and a marked Inflammation of the intestines. The only pathological change shown in the tissues at the two lower levels was a slight focal necrosis in the liver of the rabbit which received 670 mg/kg.

Because the substance was tested as a solution in DMAC, a known liver toxin, it is appropriate to consider the contribution that this solvent may have made to the toxicity of the solutions.  Previous studies on 4,4'-oxydianlline in "Carbowax" 1500 gave an ALD of > 5000 mg/kg by skin absorption (refer to supporting study within this dossier).  Thus the greater toxicity shown by the reported ALD of 1000 mg/kg for 4,4,-oxydianlline in DMAC would seem to indicate that the solvent either facilitated absorption of the compound or exerted a toxic effect per se.  The fact that liver injury was observed in rabbits re­ceiving the two higher doses of 4,4'-oxydianiline in DMAC may indicate a significant role of the solvent. 

Whilst it is not possible to separate the effects of the solvent used from the potential toxicity of the test material, on the basis of the results noted, on the basis of a precautionary approach, it is deemed appropriate to classify the substance as potentially harmful, based on the results noted.

However this result differs from the Official European Classification detailed in Annex VI of the CLP regulation.

According to this regulation, the substance must be considered as "Toxic" and classified H311 category 3.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Non GLP. A suboptimal study design was used and there is insufficient detail on the test method and results within the report. A single test animal only was assessed in the cited study.
Reason / purpose:
reference to other study
Qualifier:
no guideline followed
Principles of method if other than guideline:
The test substance was applied to the shaved skin of 1 rabbit as a 50% ointment in Carbowax 1500. The maximum feasible dose was 5000 mg/kg, but absorption of the test substance was poor. The animal was wrapped in moisture-proof cellophane and bandage for 24 hours. The rabbit was euthanized 12 days after the dermal application of the test substance.
GLP compliance:
no
Test type:
other:
Limit test:
yes
Specific details on test material used for the study:
4,4'-oxydianiline
4,4'-diaminodiphenyl ether
CAS 101-80-4
Species:
rabbit
Strain:
not specified
Sex:
male
Details on test animals 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
Type of coverage:
occlusive
Vehicle:
carbowaxe
Details on dermal exposure:
TEST SITE
- Area of exposure: Not specified
- % coverage: Not specified
- Type of wrap if used: moisture proof cellophane and bandage.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Not performed
- Time after start of exposure: Not performed


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50% ointment in carbowax 1500
- Concentration (if solution):
- Constant volume or concentration used: yes
- For solids, paste formed: Yes, as an ointment in carbowax


VEHICLE
- Amount(s) applied (volume or weight with unit): Not specified
- Concentration (if solution): Not specified
- Lot/batch no. (if required): Not specified
- Purity: Not specified
Duration of exposure:
24 hours
Doses:
5000 mg/kg
No. of animals per sex per dose:
1
Control animals:
no
Details on study design:
- Duration of observation period following administration: 12 days
- Frequency of observations and weighing: Not reported
- Necropsy of survivors performed: Presumed yes; no pathological changes reported.
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Yes.
Statistics:
None specified.
Key result
Sex:
male
Dose descriptor:
approximate LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality until 12 days after dosing.
Mortality:
No mortality was observed.
Clinical signs:
Loss of appetite and weight loss for 5 days were observed.
Body weight:
Weight loss for 5 days were observed.
Gross pathology:
No pathological changes were observed.
Other findings:
None.
Interpretation of results:
study cannot be used for classification
Conclusions:
4,4’-Oxydianiline is poorly absorbed through the skin of rabbits; its approximate Lethal Dose by this route is greater than 5000 mg/kg of body weight. Although direct collaboration 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 not classify the substance based on the observations of this study.
Executive summary:

The results of this study are taken in the context of a "weight of evidence" approach, and hence should not be considered in isolation.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
Value:
1 000 mg/kg bw
Quality of whole database:
It should be noted that the substance has an harmonized european classification in the Annex VI of the CLP regulation. According to this regulation, the substance must be considered as "Toxic" by dermal route and classified H311 category 3.

Additional information

Testing on the above endpoints gave the following results:

Acute toxicity: Oral.

The test substance is harmful when administered orally in single doses to rats, and the Approximate Lethal Dose (ALD) by this route being 1500 mg/kg of body weight.  Clinical signs of toxicity among the animals which died included discomfort, inactivity, lacrimation, weight lose, prostration, pale and glassy eyes, and shallow respiration.  Animals receiving the lowest lethal dose or sublethal doses down to 200 mg/kg showed a loss of hair.  The test compound appears to paralyse the stomach in lethal doses and, as is known for other aromatic amines, it reacts with haemoglobin to produce compounds like methemoglobin which are incapable of transporting oxygen.  A single dose of 90mg/kg caused no detectable Injury.

Acute toxicity: Dermal.

Two studies are presented for this endpoint as follows:

Key study:

The test substance is deemed slightly toxic for the male rabbit when applied to the skin as a 10% solution in DMAC, its Approximate Lethal Dose (ALD) by this route being 1000 mg/kg of body weight.  No clinical signs of toxicity were observed on this animal, but histological changes indicated a mild liver injury and a marked Inflammation of the intestines.  The sublethal levels caused temporary loss of appetite with subsequent weight loss.  The only pathological change shown in the tissues at the two lower levels was a slight focal necrosis in the liver of the rabbit which received 670 mg/kg.

Supporting study:

The test substance was applied to the shaved skin of 1 rabbit as a 50% ointment in Carbowax 1500. The maximum feasible dose was 5000 mg/kg, but absorption of the test substance was found to be poor. The animal was wrapped in moisture-proof cellophane and bandage for 24 hours. The rabbit was euthanized 12 days after the dermal application of the test substance. 4,4’-Oxydianiline was poorly absorbed through the skin of rabbits; its approximate Lethal Dose by this route is greater than 5000 mg/kg of body weight. Although direct collaboration 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 not classify the substance based on the observations of this study.

 

Justification for classification or non-classification

The above studies have all been ranked reliability 2 according to the Klimish et al system. This ranking was deemed appropriate because the studies were not conducted to GLP or in compliance with agreed protocols. The reports do 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.

Justification for classification or non classification

The above results triggered classification under the CLP Regulation (EC No 1272/2008). 

On the basis of these results and according to the CLP regulation criteria, the substance can be considered "harmful" by oral and dermal ingestion. No data are available for the classification by inhalation.

However this result differs from the Official European Classification detailed in Annex VI of the CLP regulation.

To be compliant with the Reach and CLP regulations, the official CLP classification defined in the Annex VI is applied. Therefore the substance is considered as Toxic by oral route, category 3 (H301), toxic by dermal route, category 3 (H311) and toxic by inhalation, in category 3 (H331).