Registration Dossier

Administrative data

Description of key information

4-4’-Methylenedicyclohexanamine causes serious eye damage in rabbits and showed severe corrosive effect to the skin of rabbits after 165min exposure. There is no data on respiratory irritation, but the vapour pressure of the substance is low and inhalation is not expected to be a significant route of exposure

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation / corrosion, other
Remarks:
This is in vivo study but validation assistent requires at least one non in vivo study. This is just to satisfy the rules.
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline and GLP study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.5 ml
Duration of treatment / exposure:
3 minutes and approx 2.75 hours (4 hour exposure was terminated early)
Observation period:
1 hour, 24 hours, 48 hours and 72 hours following removal of the test material after the 3 minute exposure.
1 hour following removal of the test material after the 2.75 hour exposure.
Number of animals:
6
Details on study design:
Extreme dermal reactions, indicative of corrosion, were produced, which resulted in termination of the treatment prior to completion of the standard 4-hour exposure.
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 165 min
Score:
6
Reversibility:
no data
Irritant / corrosive response data:
2.75 hour exposure -
Severe dermal necrosis, haemorrhage of the dermal capillaries and loss of skin elasticity were noted at all treated skin sites, one hour after patch removal. The reactions extended beyond the treatment site in two animals and an isolated incident of bleeding was also noted.
An accurate evaluation o f the degree of oedema was not possible due to the other adverse dermal reactions.
All animals were killed for humane reasons and in accordance with Home Office regulations following the one hour observation.

3 minute exposure -
Very slight to well-defined erythema and haemorrhage of the dermal capillaries were noted at all treatment sites one hour after patch removal and persisted at two sites at the 24-hour observation. Well-defined erythema was also noted at one treatment site at the 48- and 72-hour observations. A hardened dark brown/black coloured scab, surrounded by well-defined erythema and with light brown discolouration of the epidermis was also noted at the remaining treatment sites at these times. An accurate evaluation of erythema was not possible at the 48- and 72-hour observations due to the severity of the other dermal reactions.
Very slight oedema was noted at all treatment sites one hour aafter patch removal with moderate to severe oedema noted at all other observation times. Evaluation of oedema was commonly precluded by other adverse dermal reactions.
Green/brown coloured areas of possible dermal necrosis indicative of dermal corrosion were noted at one treated skin site at the 24- and 48-hour observations.
All animals were killed for humane reasons and in accordance with Home Office regulations after the 72-hour observation.
Interpretation of results:
corrosive
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
The 3 minute exposure did not result in necrosis at the 1-hour observation period but one out of three animals exhibited necrosis at the 24-hour observation. The 2.75 hour exposure resulted in necrosis by the one hour post exposure observation. It was therefore determined that the test substance meets the criteria for classification as a Packing Group II, GHS 1B corrosive, and DSD R35 corrosive.
Executive summary:

In an OECD Guideline 404 study, rabbits were dermally exposed to PACM to assess skin irritancy/corrosivity. The 3-minute exposure did not result in necrosis at the 1-hour observation period but one out of three animals exhibited necrosis at the 24-hour observation. The 2.75-hour exposure resulted in necrosis by the 1-hour post-exposure observation. It was therefore determined that the test substance meets the criteria for classification as a Packing Group II, GHS 1B corrosive, and DSD R35 corrosive.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation, other
Remarks:
This is in vivo study but correct assignment results in validation failure.
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Similar to a guideline study, but the dose was lower, exposure times shorter and washing procedures different than OECD guidelines.
Qualifier:
according to
Guideline:
other: Haskell Laboratories protocol, E.I. DuPont DeNemours and Company, Wilmington, DE, USA
Principles of method if other than guideline:
Test material is administered into the conjunctival sac of a New Zealand white rabbit, and after various times, the material is removed by washing with various mixtures. Irritation is observed
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
males, each weighing 2-3 kg.
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.01 ml. The standard dose of 0.1% ml resulted in clear eye corrosion.
Observation period (in vivo):
60 days
Number of animals or in vitro replicates:
3 per group
Details on study design:
Test material(0.01ml) was placed in the conjunctival sac and washed with tap water for one minute with tap water after 20 seconds or two minutes. The untreated eye served as the control. Observations of cornea, iris and conjunctiva were made with a hand-slit lamp at 1 and 4 hours after administration, at 1,2 and 3 days, and weekly through 60 days after administration. Fluor-i-strip (R) ophthalmic indicators and a biomicroscope were used at examinations 1 and 4 hours after administration. A veterinary ophthalmologist was consulted for selected case examinations. Three animals were sacrificed on day 70 after treatment for histopathologic examination. Eyes were excised, washed, fixed and hardened according to the method of Saunders and Rubin (1975).
Irritation parameter:
other: qualitative assessment
Basis:
mean
Time point:
other: 60 days
Reversibility:
other: 30% reversible within 60 days.
Remarks on result:
other: Dose of 0.01 ml is 1/10th "standard" dose of 0.1 ml.
Irritant / corrosive response data:
Pupillary constriction at 1-4 h, pupillary dilation through day 7, iridial congestion, with injection at 28 days, clouds of precipitate in anterior chamber, diffuse fibrous opacities of the lens, swelling and endothelial relucency by 7 days, corneal vascularization by 14 days, with subsequent healing of the ulceration by 35 days. The conjunctiva showed extreme redness and swelling within 1 h, with moderate to severe discharge (sometimes bloody and purulent).
Other effects:
Histopathology revealed dense corneal scarring, inflammation and lenticular opacity in selected animals. Vascular scarring of cornea can occur. In severe cases, crystals form and clots, with protein and cells present in the anterior chamber, and the lens capsule can rupture.

Each group of 3 rabbits had one rabbit whose eye was normal or nearly normal at 60 days after treatment. One other rabbit had partial healing (partial pannus), and the final rabbit had severe permanent ocular damage. Several rabbits’ eyes developed corneal opacities, still present at 60 days. Histopathology revealed some damage not observed upon gross examination.

Interpretation of results:
Category 1 (irreversible effects on the eye)
Remarks:
Migrated information corrosive when 0.1 ml is applied in vivo; partially reversible when 0.01 ml is applied and washed in vivo. Criteria used for interpretation of results: EU
Conclusions:
4,4'-Methylenedicyclohexanamine causes severe damage to the eye.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There is conflicting evidence in the literature regarding the degree of skin irritation caused by this substance. The weight of the evidence and the most reliable study showed the material to be corrosive.

Personal protective equipment is recommended for workers handling this substance.

Justification for selection of skin irritation / corrosion endpoint:
Most reliable study.

Justification for selection of eye irritation endpoint:
similar to but not according to guideline methods. 0.1 ml of liquid PACM resulted in clear eye corrosion. 100 mg of solid PACM resulted in eye corrosion.

Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: corrosive

Justification for classification or non-classification

4-4’-Methylenedicyclohexanamine is classified as Category 1B, corrosive to the skin and causing serious damage to the eye. Because of the low vapour pressure of this substance (0.05 Pa at 20 degrees C, measured. See section 4.6 in IUCLID5), it is not anticipated to be volatile and able to be inhaled by workers. It is thus not classified as a respiratory irritant.