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EC number: 217-168-8 | CAS number: 1761-71-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Eye irritation
Administrative data
- Endpoint:
- eye irritation: in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- Dose was lower, exposure times shorter and washing procedures different than OECD guidelines
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 985
- Report date:
- 1985
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- 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
Test material
- Reference substance name:
- 4,4'-methylenebis(cyclohexylamine)
- EC Number:
- 217-168-8
- EC Name:
- 4,4'-methylenebis(cyclohexylamine)
- Cas Number:
- 1761-71-3
- Molecular formula:
- C13H26N2
- IUPAC Name:
- 4,4'-methylenedicyclohexanamine
- Details on test material:
4,4'-Methylenedicyclohexanamine > 95% purity. Liquid with freezing/melting point of 13 degrees C.
Isomer content (%):
trans-trans 21.22
cis-cis 14.91
cis-trans 59.67
Impurities:2,4'-Methylenedicyclohexanamine: 4.20%
[4-(p-aminobenzyl)cyclohexylamine] methane (PABC): 0.23%
p-aminodicyclohexylmethane (ADCM): 0.05%
p-PABC: 0.038%
Constituent 1
Test animals / tissue source
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or tissues and environmental conditions:
- males, each weighing 2-3 kg.
Test system
- Vehicle:
- unchanged (no vehicle)
- Controls:
- not required
- Amount / concentration applied:
- 0.01 mL
- Duration of treatment / exposure:
- 1.) 3 rabbits: not washed
2.) 3 rabbits: washed for 1 min, 20 s after dosing
3.) 3 rabbits: washed for 1 min, 2 mins after dosing
4.) 3 rabbits: washed for 15 mins as soon as possible after dosing - Observation period (in vivo):
- Observations were made after 1 hr, 4 hrs, 24 hrs, 48 hrs, 72 hrs and weekly up to 60 days
- Number of animals or in vitro replicates:
- 3 per group
- Details on study design:
- Preliminary Test:
10 mg of the test material were sprinkled onto the cornea of each eye of a rabbit, a second rabbit receives 0,1 mL of a 10 % solution (pH= 11) of the test material in propylene glycol in each eye. The left eye of each rabbit was washed with tap water 20 s after contact, the right eye was not washed.
Results indicated that 10 mg of the test item, as solid or as a solution in propylene glycol, produced severe and extensive damage to the cornea, iris and conjunctivae in the unwashed eyes. One week after treatment the eye that received the solution of the test item showed a severe and presumably irreversible injury. Similar treatments followed by prompt washing produced a temporary mild to moderate irritation of the cornea, iris and conjunctivae.
Main study (first procedure):
The test item used in the preliminary study was a white solid (MP 46°C), the "new" test item is a clear liquid (MP 13°C), because of different ratios of geometric isomers.
First 0,1 mL of the test item were used. The test reveales, that the liquid test item is a much more severe eye irritant than the solid test item.
0,1 mL of the test material were placed into the right conjuntival sac of each rabbit.
1.) 2 rabbits: not washed
2.) 2 rabbits: washed for 1 min, 20 s after dosing
3.) 2 rabbits: washed for 1 min, 2 mins after dosing
One day after treatment none of the treated eyes reacted to light, corrosive effects of all visible eye tissue were observed and the animals were losing weight. They were sacrificed two days after treatment when it became obvious the treated eye could not possible heal and the animals might not live through the two-month observation period.
Main study (second/ final procedure):
A reduced volume of 0,01 mL was used for the second study. The Test material (0.01 mL) was placed in the conjunctival sac and washed with tap water:
1.) 3 rabbits: not washed
2.) 3 rabbits: washed for 1 min, 20 s after dosing
3.) 3 rabbits: washed for 1 min, 2 mins after dosing
4.) 3 rabbits: washed for 15 mins as soon as possible after dosing
Observations of the cornea, iris and conjunctiva were made after 1 hr, 4 hrs, 24 hrs, 48 hrs, 72 hrs and weekly up to 60 days. Flour-i-strip opthalmic applicators and a biomicroscope were used at examinations after the day of treatment. Dr. Lionel F. Rubin (Veterinary Opthalmologist, University of Pennsylvania College of Veterinary Medicine) was consulted several weeks after treatment to observe some of the unusual ocular effects.
Seventy days post-exposure, three rabbits' eyes were chosen for histopathologic examination. The rabbits were sacrificed by air ambolism injected into ear vein. The eyes were quickly removed, fixed, washed and hardened using a procedure outlined by Saunders and Rubin. Trimming, processing, embedding, cutting ans staining were done by usual Haskell Laboratory techniques. The eye sections were sent to Dr. Rubin for description and commentary.
Results and discussion
In vivo
Results
- Irritation parameter:
- other: qualitative assessment
- Basis:
- mean
- Time point:
- other: 60 days
- Reversibility:
- other: Each group had one rabbit whose eye was normal or nearly normal at 60 days, one whose eye was left with partial pannus and one in which one or both eyes had severe permanent ocular effects.
- 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.
Any other information on results incl. tables
Opthalmoscopic and biomicroscopic findings
Rabbit No. | Dose | Treatment | Ocular Effects at Day () |
11834 | 0,1 mL | not washed | (1-2) Corrosive: all rabbits sacrificed 2 days post-treatment |
11835 | 0,1 mL | not washed | |
11836 | 0,1 mL | washed 1 min, 20 s after dosing | |
11837 | 0,1 mL | washed 1 min, 20 s after dosing | |
11838 | 0,1 mL | washed 1 min, 2 mins after dosing | |
11839 | 0,1 mL | washed 1 min, 2 mins after dosing | |
11840 | 0,01 mL | not washed | (63) Eyelids irregular, 1/2 cornea pannus, lens opacities |
11814 | 0,01 mL | not washed | (63) right eye: total pannus, corneal ulcer; left eye: lens opacities growth on iris |
11902 | 0,01 mL | not washed | (16) small spot of corneal opacity, almost normal 21 days |
11826 | 0,01 mL | washed 1 min, 20 s after dosing | (16) normal |
11828 | 0,01 mL | washed 1 min, 20 s after dosing | (63) 2/3 - 1/2 corneal pannus with 2 cysts |
11903 | 0,01 mL | washed 1 min, 20 s after dosing | (62) pannus, degradation of the iris, lens opacities, flattening of cornea (?) |
11812 | 0,01 mL | washed 1 min, 2 mins after dosing | (16) normal |
11815 | 0,01 mL | washed 1 min, 2 mins after dosing | (63) < 1/2 pannus with 1 cyst on cornea |
11846 | 0,01 mL | washed 1 min, 2 mins after dosing | (62) 3/4 corneal pannus |
11841 | 0,01 mL | washed 15 mins ASAP after dosing | (62) total pannus with corneal ulcer |
11899 | 0,01 mL | washed 15 mins ASAP after dosing | (62) 1/2 corneal pannus, scattered lens opacities |
11848 | 0,01 mL | washed 15 mins ASAP after dosing | (62) 1/4 very slight corneal opacity, scattered lens opacities |
11833 | - | washed 15 mins ASAP after dosing | (3) normal |
Applicant's summary and conclusion
- Conclusions:
- 4,4'-Methylenedicyclohexanamine causes severe damage to the eye.
- Executive summary:
At the original dose of 0,1 mL, the test item is irreversibly corrosive to rabbit eyes. Even at a dose one- tenth that normally used to test toxicity in rabbit eyes, the test item proved to be a severe eye irritant. No washing procedure tried appeard to be better than not washing the eyes. There were possible systemic effects in 10/12 rabbits with pupil dilation or constriction. In all groups there was considerable variability in the rate and extend of healing, although in all treated eyes there was severe initial irritation.
Each group had one rabbit whose eye was normal or nearly normal at 60 days, one whose eye was left with partial pannus and one in which one or both eyes hab severe permanent ocular effects.
Several rabbits' eyes developed lens opacities. Histopathology revealed a few abnormalities not found grossly. However some gross observations were missed upon examination of the sections, perhaps because the area of interest was not in the plane of section or because lenticular abnormalities are difficulr to preserve and see histopathologically.
When the eyes which are trated with the test item are washed with tap water (room temperature or colder) the compound tends to "gum up" and become opaque. This gum adheres tenaciously and wherever it sticks, the injury is greatest. Mechanical removal (with Q-tips ®) or washing with a substance other than water may reduce the severity of eye injury.
The possibility of delayed ocular effects due to the exposure to the test item does exist, it is a very severe eye irritant. All possible measures should be taken to avoid eye exposure.
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