Registration Dossier

Administrative data

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. This result is read across to 1,3H6XDI as this result is considered more reliable then the available in vitro data. An in vitro skin corrosion test, performed according to OECD guideline 431, and an in vitro skin irritation test, performed according to OECD guideline 439, were performed with 1,3-H6XDI. Based on the results it is concluded that 1,3-H6XDI is corrosive to the skin. An in vivo eye irritation study was conducted comparable to OECD guidance. As severe effects were seen, 1,3H6XDI is classified for serious eye damage (cat. 1). All available studies are reliable (Klimisch 1 studies).

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin 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
Irritation parameter:
erythema score
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:
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:
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 #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. This result is read across to 1,3-H6XDI.
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). This result is read across to 1,3-H6XDI.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February 1980
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
other: Consumer Product Safety Commission of the USA in the Code of Federal Regulations, Title 16, Section 1500.42.
Deviations:
no
GLP compliance:
no
Species:
rabbit
Strain:
other: Albino rabbits
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye served as concurrent control
Amount / concentration applied:
0.1mL
Duration of treatment / exposure:
Single instillation
Observation period (in vivo):
96 hours
Number of animals or in vitro replicates:
6
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): No

SCORING SYSTEM:
Grades for ocular lesions were given according to "Illustrated Guide for Grading Eye Irritation by Hazardous Substances", U.S. Department of Health, Education and Welfare, Food and Drug Administration, Washington, D.C. 20402 (comparable to Draize scoring system).

TOOL USED TO ASSESS SCORE: binocular loupe, hand-slit lamp, fluorescein
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.
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.

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. This result is read across to 1,3 -H6XDI.

An in vitro skin corrosion test (EpiDermTM (EPI-200) was performed according to OECD guideline 431. The tissue viability was found to be 99.4% and 56.1% in the 3-minute and 1-hour exposures (positive control showed viability of 9.0 and 6.0% resp.). 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 9.4% after 60 minutes exposure (positive control showed viability of 3.0% resp.).

An in vivo 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.

Justification for classification or non-classification

Based on the present data, 1,3-H6XDI is classified for irreversible skin damage (cat. 1C) and for irreversible effects on the eye (cat. 1) according to (EC) Regulation No 1272/2008 on classification, labelling and packaging of items and mixtures (incl. all amendments).