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Description of key information

An in vivo skin irritation study is available in rabbits, performed according to OECD test guideline 404 and GLP principles (key study). The results show corrosive effects of 1,4H6XDI, which becomes apparent a few days after exposure.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
16 February 2009 - 8 May 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The study was performed before in vitro test systems were validated.
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
24 April 2002
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
other: Japanese white rabbits
Details on test animals and environmental conditions:
- Source: Japan Laboratory Animals, Inc.
- Age at study initiation: 17 or 18 weeks old
- Weight at study initiation: 3.02 - 3.74 kg
- Housing: Individually in aluminium cages with wire-mesh bottoms
- Diet: Free access to pelleted diet RC4 (Oriental Yeast Co., Ltd.,)
- Water: Free access to tap water.
- Acclimation period: 12 or 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 – 25
- Humidity (%): 40 - 57
- Air changes (per hr): 11 - 14
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 3 March 2009 to 7 March 2009
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: Adjacent areas of the clipped skin of each animal served as controls.
Amount / concentration applied:
TEST MATERIAL
- Volume applied: 0.5 mL
Duration of treatment / exposure:
Single application.
Observation period:
2 or 4 days.
Number of animals:
3 females.
Details on study design:
STUDY DESIGN
One animal was clipped to provide 4 regions for application of the test substance. 0.5 mL of the test item was applied for 3 minutes and observed after 1 hour. No corrosiveness was observed and 0.5 mL of the test item was applied for 1 hour to a new clean region. No corrosiveness were observed 1 hour after removal of the test item. Next, 0.5 mL of the test item was applied for 4 hours to a new clean region and observed for 24 hours. After 24 hours two new animals (animal 2 and 3) were clipped and 0.5 mL of the test item was applied to the skin for 4 hours.

TEST SITE
On the day of application the dorsal fur was clipped. 0.5 mL test substance was applied to a lint sheet of 2.5 x 2.5 cm. After application to the skin it was covered with tape.

REMOVAL OF TEST SUBSTANCE
The lint sheets on the application site were removed at specified timepoints, and exposed skin was wiped with absorbent cotton soaked with acetone (anhydrous).

OBSERVATIONS
- Toxicity: For the first animal, immediately after removal of test item and/or daily for all animals.
- Body Weight: At the day of administration and last day of observation.
- Necropsy: No necroscopy performed.
- Irritation and corrosiveness: The skin reactions for the first treated animal 1 were observed at 1, 24, 48 and 72 hours and on the 4th day after removal of the test substance. The second and third animals were only observed 1 hour and 24 hours after removal of test item before the experiment was terminated.

SCORING SYSTEM:
The irritation was assessed according to the numerical scoring system according to OECD 404.
Irritation parameter:
erythema score
Remarks:
(mean)
Basis:
animal #1
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
other: animal killed for humane reasons on day 4
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24 h
Score:
4
Max. score:
4
Reversibility:
other: animal killed for humane reasons on day 2.
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24 h
Score:
4
Max. score:
4
Reversibility:
other: animal killed for humane reasons on day 2.
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
other: animal killed for humane reasons on day 4.
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24 h
Score:
1
Max. score:
4
Reversibility:
other: animal killed for humane reasons on day 2.
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24 h
Score:
1
Max. score:
4
Reversibility:
other: animal killed for humane reasons on day 2
Irritant / corrosive response data:
No corrosiveness or dermal reactions were observed for skin that was 3 minutes or 1 hour exposed to the test article.

The skin of the first animal that was exposed to the test item showed severe erythema at 24 hours after removal of the test item. This changed to an eschar 72 hours after removal of the test item. On the 4th day it was concluded that the tissue damage was irreversible and thus the observation period was terminated for all animals.


Other effects:
All animals lost weight during the study period.
No other clinical signs were observed.
Interpretation of results:
Category 1C (corrosive) based on GHS criteria
Conclusions:
A single semi-occlusive application of 1,4-Bis(isocyanatomethyl)cyclohexane to rabbit skin for four hours elicited skin corrosive effects after 4 days. Based on these results, 1,4-Bis(isocyanatomethyl)cyclohexane is classified as category 1C (corrosive) (H314) according to GHS and CLP criteria.
Executive summary:

In a skin irritation study with rabbits, performed according to OECD test guideline 404 and GLP principles, the irritation and corrosive effects of 1,4-bis(isocyanatomethyl)-cyclohexane were examined. 0.5 mL of the test item was applied to clipped skin of rabbits for 3 minutes, 1 hour or 4 hours. Observations took place 1 hour after application and over the next consecutive days. No corrosiveness or dermal reactions were observed for skin that was exposed for 3 minutes or 1 hour. Skin corrosion was observed after 4 days on skin that was exposed for 4 hours to the test item. Basd on this result 1,4 -Bis(isocyanatomethyl)cyclohexane is classified as category 1C (corrosive) (H314) according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments) and according to Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
The rationale to read across the data is attached in Section 13.
Reason / purpose:
read-across source
Vehicle:
unchanged (no vehicle)
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
72 h
Score:
2
Max. score:
4
Reversibility:
other: Animal was killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Remarks:
The corneal reactions could not be assessed due to severity of the reaction at 24 and 48 hours.
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
other: Animal was killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
other: Animal was killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
72 h
Score:
2
Max. score:
4
Reversibility:
other: Animal was killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Remarks:
The corneal reactions could not be assessed due to severity of the reaction at 24 and 48 hours.
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
72 h
Score:
3
Max. score:
4
Reversibility:
other: Animal was killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Remarks:
The corneal reactions could not be assessed due to severity of the reaction at 24 and 48 hours.
Irritation parameter:
cornea opacity score
Basis:
animal #6
Time point:
24/48/72 h
Reversibility:
other: Animal was killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Remarks:
The corneal reactions could not be assessed due to severity of the reaction at 24, 48 and 72 hours.
Irritation parameter:
iris score
Basis:
animal #1
Time point:
72 h
Score:
1
Max. score:
2
Reversibility:
other: Animal was killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Remarks:
The iris score could not be assessed due to severity of the reaction at 24 and 48 hours.
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: Animal was killed due to the severity of the reaction after 7 days.
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.67
Max. score:
2
Reversibility:
other: Animal was killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Irritation parameter:
iris score
Basis:
animal: #4 and #6
Time point:
24/48/72 h
Max. score:
2
Reversibility:
other: Animal was killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Remarks:
The iris score could not be assessed due to severity of the reaction at 24, 28 and 72 hours.
Irritation parameter:
iris score
Basis:
animal #5
Time point:
72 h
Score:
1
Max. score:
2
Reversibility:
other: Animal was killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Remarks:
The iris score could not be assessed due to severity of the reaction at 24 and 48 hours.
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal: #1, #2, #3, #4, #6
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
other: Animals were killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #5
Time point:
24/48/72 h
Score:
2.3
Max. score:
3
Reversibility:
other: Animal was killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal: #1, #4, #6
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
other: Animals were killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal: #2, #5
Time point:
24/48/72 h
Score:
3.67
Max. score:
4
Reversibility:
other: Animals were killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
other: Animal was killed due to the severity of the reaction after 7 days.
Remarks on result:
positive indication of irritation
Irritant / corrosive response data:
Due to the severity of the reaction it was impossible to assess corneal and iridial lesions on a number of occasions in three animals, and in one other animal no assessment of corneal damage could be made at any reading.
Corneal opacities were observed in five animals.
Iritis was observed in three animals but the iris could not be observed in two other animals.
A diffuse, crimson to beefy-red colouration of the conjunctivae accompanied by considerable swelling with the eye about half or almost completely closed was seen in all six animals.
Other effects:
Due to the severity of the reactions the animals were killed after the four days observation.
Interpretation of results:
Category 1 (irreversible effects on the eye)
Conclusions:
An eye irritation study was conducted comparable to OECD guidance. As severe effects were seen, 1,3H6XDI is classified cat. 1 for eye damage. The result is read across to 1,4-H6XDI.
Executive summary:

An eye irritation study was conducted comparable to OECD guidance. 1,3H6XDI was instilled in one eye of 6 rabbits. Due to the severity of the reaction it was impossible to assess corneal and iridial lesions on a number of occasions in three animals, and in one other animal no assessment of corneal damage could be made at any reading. Corneal opacities were observed in five animals. Iritis was observed in three animals but the iris could not be observed in two other animals. A diffuse, crimson to beefy-red colouration of the conjunctivae accompanied by considerable swelling with the eye about half or almost completely closed was seen in all six animals. Due to the severity of the reactions the animals were killed after the four days observation. As severe effects were seen, 1,3H6XDI is classified cat. 1 for eye damage. The result is read across to 1,4-H6XDI.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In a skin irritation study with rabbits, performed according to OECD test guideline 404 and GLP principles, the irritation and corrosive effects of 1,4-bis(isocyanatomethyl)-cyclohexane were examined. 0.5 mL of the test item was applied to clipped skin of rabbits for 3 minutes, 1 hour or 4 hours. Observations took place 1 hour after application and over the next consecutive days. No corrosiveness or dermal reactions were observed for skin that was exposed for 3 minutes or 1 hour. Skin corrosion was observed after 4 days on skin that was exposed for 4 hours to the test item. A skin irritation study with rabbits was performed according to The Code of Federal Regulations, Title 16, Section 1500.41 similar to OECD 404. 0.5 mL of the test item was applied to a 2.5 cm x 2.5 cm surgical gauze and applied occlusively for 24 hours to clipped rabbit skin. Observations of intact and abraded skin took place 24 hours and 72 after removal of the test item. Very slight to well-defined erythema accompanied by slight to severe oedema was observed at intact and abraded skin sites of all six animals 24 hours after removal of the test item. Erythema stayed the same or worsened while oedema decreased or stayed the same for most animals in the 72 hour observation period. No reversibility was observed for the irritation effects in all animals after 72 hours. Therefore no conclusion can be drawn on the classification of H6XDI for skin irritation.

An in vitro skin corrosion test (EpiDermTM (EPI-200) was performed according to OECD guideline 431. The tissue viability was found to be 93.2% and 55.1% in the 3-minute and 1-hour exposures (positive control showed viability of 9.0% and 6.0% resp.). Based on these data, 1,4-H6XDI was found to be not corrosive to the skin. An in vitro skin irritation test (EpiDermTMSIT (EPI-200) was performed according to OECD guideline 439 and according to GLP principles. The tissue viability was found to be 12.1% after 60 minutes exposure (positive control showed viability of 3.0% resp.). Based on these data, 1,4-H6XDI was found to be irritant to the skin (cat.2).

An eye irritation study was conducted comparable to OECD guidance. 1,3H6XDI was instilled in one eye of 6 rabbits. Due to the severity of the reaction it was impossible to assess corneal and iridial lesions on a number of occasions in three animals, and in one other animal no assessment of corneal damage could be made at any reading. Corneal opacities were observed in five animals. Iritis was observed in three animals but the iris could not be observed in two other animals. A diffuse, crimson to beefy-red colouration of the conjunctivae accompanied by considerable swelling with the eye about half or almost completely closed was seen in all six animals. Due to the severity of the reactions the animals were killed after the four days observation. As severe effects were seen, 1,3H6XDI is classified cat. 1 for eye damage. This result is read across to 1,4 -H6XDI.

Justification for classification or non-classification

Based on the available data, 1,4-H6XDI is considered to be corrosive to the skin and corrosive to the eye and is classified cat. 1C for skin irritancy and cat. 1 for serious eye damage according to Regulation (EC) 1272/2008.