Registration Dossier

Toxicological information

Acute Toxicity: dermal

Currently viewing:

Administrative data

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.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1964
Report Date:
1964

Materials and methods

Test guideline
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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): 4,4'-Oxydianiline
- Lot/batch No.: Lot No. 63R
- 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: Not specified.
- Purity test date: Not specified.
- Expiration date of the lot/batch: Not specified.
- Radiochemical purity (if radiolabelling): Not specified.
- Specific activity (if radiolabelling): Not specified.
- Locations of the label (if radiolabelling): Not specified.
- Expiration date of radiochemical substance (if radiolabelling): Not specified.
- Stability under test conditions: Not specified.
- Storage condition of test material: Not specified.
- Other: Not specified.
Specific details on test material used for the study:
4,4'-oxydianiline
4,4'-diaminodiphenyl ether
CAS 101-80-4

Test animals

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

Administration / exposure

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.

Results and discussion

Effect levels
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

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.