Registration Dossier

Administrative data

Description of key information

From reliabe experimental studies, the LD50 for 4,4'-Methylenedicyclohexanamine has been established for oral and dermal routes of administration. Insufficient data is available to estimate a reliable LC50 for 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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study under GLP.
Qualifier:
according to
Guideline:
EPA OPP 81-1 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
other: 10% ethanol and corn oil
Doses:
- males: 100, 250, 500, 562, 708, 1000 mg/kg
- females: 100, 250, 398, 500, 631 mg/kg
No. of animals per sex per dose:
5
Control animals:
yes
Sex:
male
Dose descriptor:
LD50
Effect level:
480 mg/kg bw
Based on:
test mat.
95% CL:
> 360 - < 650
Sex:
female
Dose descriptor:
LD50
Effect level:
350 mg/kg bw
Based on:
test mat.
95% CL:
> 260 - < 470
Sex:
male/female
Dose descriptor:
LD50
Effect level:
380 mg/kg bw
Based on:
test mat.
95% CL:
> 270 - < 550
Mortality:
- males: 100, 250, 500, 562, 708, 1000 mg/kg. All deaths on day 1.
- females: 100, 250, 398, 500, 631 mg/kg. All deaths on day 1, except for 1 female given 500 mg/kg on day 2 and 1 female given 631 mg/kg on day 7
Clinical signs:
Males:
100 and 250 mg/kg : ruffled appearance on day 1
500 mg/kg: ruffled appearance and (dark) nasal staining
562 mg/kg: ruffled appearance, piloerection, genital staining, convulsions, stained body, dark nasal staining, muzzle staining and/or lethargy during the observation period
708 mg/kg: ruffled appearance on day 1
1000 mg/kg: all animals appeared comatose and died on day 1

Females:
100 and 250 mg/kg: ruffled appearance on day 1
398 mg/kg: gasping immediately after dosing, ruffled appearance, lethargy and/or piloerection between days 1 and 8
500 mg/kg: ruffled appearance, lethargy and/or dark oral and nasal staining between days 1 and 8
631 mg/kg: lethargy and ruffled appearance were noted immediately after dosing
Body weight:
Body weight gain decreased in males at 562 mg/kg. A decreased body weight gain was noted in females at 250, 500 and 562 mg/kg.
Gross pathology:
No treatment-related macroscopic findings were noted in the surviving animals. In animals found dead the following observations were made: signs of irritated stomach, dark liquid in the stomach and lower gastrointestinal tract, pale lungs and kidneys, pale liver and/or hemorrhagic lungs.
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information LD50 is between 300 and 2000 mg/kg bw. Criteria used for interpretation of results: EU
Conclusions:
The LD50 of 4-4’-methylenedicyclohexanamine by oral gavage to Sprague-Dawley rats is 380 mg/kg bw.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
380 mg/kg bw
Quality of whole database:
adequate

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Performed according to EPA OPP Guidelines.
Qualifier:
according to
Guideline:
EPA OPP 81-2 (Acute Dermal Toxicity)
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
- Age: no data
- Weight at study initiation: 2-3 kg
Type of coverage:
semiocclusive
Vehicle:
other: none, test substance applied as powder
Details on dermal exposure:
no data
Duration of exposure:
no data
Doses:
- Males: 200, 400, 1580, 6310 mg/kg
- Females: 200, 1580, 2240, 3160, 6310 mg/kg
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
ADMINISTRATION:
- Area covered: 10% of the body surface
- Occlusion: semi-occlusive, 24 hours contact time
- Removal of the test substance: with water or an appropriate solvent.

EXAMINATIONS:
- Mortality and clinical signs (twice daily on weekdays and once daily on weekends)
- body weight (day of dosing, after 1 week, and prior to sacrifice)
- necropsy (all animals).
Statistics:
Statistical method: Moving Average Method
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 110 mg/kg bw
Based on:
test mat.
Mortality:
- Males: 200, 400, 1580, 6310 mg/kg: 0/5, 0/5, 3/5, 5/5. All deaths within 4 days post-dose
- Females: 200, 1580, 2240, 3160, 6310 mg/kg: 0/5, 0/5, 3/5, 5/5, 5/5. All deaths within 4 days post-dose
Clinical signs:
Males:
- Mild erythema, oedema and/or signs of necrosis were noted after unwrapping at 24 hours.
- Throughout the observation period surviving males showed slight irritation (200 mg/kg) or necrosis (400, 1580, 6310 mg/kg). Incidental findings were dried faecal material, absence of faecal material, nasal discharge, lethargy and labored breathing.
Females:
- Mild erythema, oedema and/or signs of necrosis were noted after unwrapping at 24 hours.
- Throughout the observation period surviving females showed necrosis. Incidental findings were ataxia, tremors, lethargy, dehydration, cyanosis and labored breathing.
Body weight:
A decreased body weight gain was noted for the surviving females. Body weight gain for surviving males was considered to be normal.
Gross pathology:
Males:
- Hemorrhagic lungs, nasal discharge, injected stomach vessels at 1580-6310 mg/kg, pale mottled liver and pale kidneys were observed in several males at 6310 mg/kg.

Females:
- Hemorrhagic lungs and nasal discharge at 3160 mg/kg. Pale mottled liver and pale kidneys were observed at 3160 and 6310 mg/kg.

The test material used in this test may be different from the material used currently. The currently available substance is a colorless liquid, whereas this substance is described as a powder. The difference has been explained by different proportions of isomers.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
LD50=2110 mg/kg bw
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 110 mg/kg bw
Quality of whole database:
adequate

Additional information

No reliable data exist for acute inhalation toxicity.


Justification for selection of acute toxicity – oral endpoint
Modern GLP study according to EPA guideline

Justification for selection of acute toxicity – inhalation endpoint
No further acute toxicity testing is necessary because the substance is corrosive. Adverse effects due to irritation properties of the substance were observed in a non-reliable study.

Justification for selection of acute toxicity – dermal endpoint
performed according to EPA guideline protocol.

Justification for classification or non-classification

4,4'-Methylenedicyclohexanamine is classified as an acute Category 4 for oral eposure, as the LD50 of 380 mg/kg falls between 300 and 2000 mg/kg. This substance is not classified as an acute dermal toxicant as the LD50 of 2110 exceeds the threshold of 2000 mg/kg bw. No reliable information is available for acute inhalation toxicity.