Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006):
"In two studies performed according to OECD TG 404, 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate was found to be corrosive to the rabbit skin. Strong irritation was observed in rabbit eyes when tested according to OECD TG 405. The toxicity studies indicate that 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate vapor causes irritation of the upper respiratory tract" (see chapter 7.2.2 and 7.5.3 of IUCLID6 data set). "In a study with volunteers, a perception threshold for irritation of 0.64 mg/m3 was determined for short-term (1-5 minutes) exposure to 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate." (see chapter 7.10.5 of IUCLID6 data set)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin corrosion: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016-01-18 to 2016-01-19
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 435 (In Vitro Membrane Barrier Test Method for Skin Corrosion)
Version / remarks:
July 28, 2015, adopted
Qualifier:
according to guideline
Guideline:
other: ICCVAM Minimum Performance Standards: In Vitro Membrane Barrier Test Systems for Skin Corrosion, June 23, 2003
Qualifier:
according to guideline
Guideline:
other: ICCVAM Recommended Performance Standards for in vitro Test Methods for Skin Corrosion (May 2004)
GLP compliance:
yes (incl. QA statement)
Test system:
other: Membrane Barrier Test Kit "Corrositex™"
Details on test system:
Test Kit
Name: Corrositex™
Supplier: Transia GmbH, 35510 Butzbach, Germany
Lot No.: CT120314
Vehicle:
unchanged (no vehicle)
Amount / concentration applied:
- Test item: 500 μL of the neat test item were dispensed directly atop the bio-barrier.
- Positive control: Sulfuric acid (95-97%) was used as positive control. 500 μL were applied to only one bio-barrier.
- Negative control: Citric acid (10% (w/v) solution in deionised water) was used as negative control. 500 μL were applied to only one bio-barrier.
- Reference Item: 10% acetic acid (v/v) will be used as reference item. 500 μL were applied to four bio-barriers.
Duration of treatment / exposure:
Time until observable change in CDS solution: 0 - 240 min
As result from the categorisation test, the test item were applied per bio-barrier for 1 hour
Observation period:
1 hour
Details on study design:
Preparation of the Bio-barrier
- One day prior to testing the bio-barrier matrix was prepared.
- The bio-barrier powder was solved in the bio-barrier diluent and heated for 20 ± 2 minutes at 68 – 70 °C in a water bath under continuous stirring.
- The temperature did not exceed 70 °C. The mixture was allowed to cool in the turned-off water bath for another 10 minutes.
- The mixture was then filled into the membrane holders (200 μL per membrane holder). Air bubbles were avoided.
- The filled membrane holders were sealed with parafilm and were stored at 2 – 8 °C until further use.
Qualify Test
- In order to test whether the test system is suitable for the test item and reference item, 150 μL of the test item were applied into the
“Qualify Test Vial”. The vial was shaken until the solution appeared homogenous, and incubated for 1 minute. Afterwards, a change in consistency
was noted.
Categorisation Test
- In the categorisation test the observation period of the test item and reference item after application to the bio-barrier was determined:
• Category 1: observation period after application will be 4 hours
• Category 2: observation period after application will be 1 hour
- Approximately 150 μL of the test item were applied into the “Category A Vial” as well as into the “Category B Vial”. The vials were shaken until the
solution appeared homogenous. After 1 minute no colour change was monitored.
- Based on the colour change obtained, a test item is assigned to a category. If an intense colour change (similar to the category 1 colour chart) is
observed in “Category A Vial” or in “Category B Vial” the test item is assigned to category 1. If a less intense colour change (similar to the category 2 colour chart) is observed in “Category A Vial” or in “Category B Vial” the test item will be assigned to category 2. If no colour change is observed in
either of the vials, a confirmation test is conducted. For the confirmation test two drops of the confirm reagent are added to the “Category B Vial”.
The vial was shaken for 5 seconds. The colour of the solution matched one of the colours shown in the accompanying colour chart, confirming that
the test item is a category 2 substance.
Classification Test
- 11 vials containing the CDS were pre-warmed to room temperature.
- 4 vials each were used for quadruplicate measurement of the test item and reference item, the vial labelled (+) was used for the positive control
(single measurement), and the vial labelled (-) was used for the negative control (single measurement).
- The vial labelled C was used as colour reference for the CDS.
- Applications of the test item, reference item and the controls were performed staggered to ensure accurate reaction times to be recorded.
- The prepared bio-barriers were placed atop the CDS vials (not longer than 2 min prior to application) and 500 μL of the test item or controls,
respectively, were applied per bio-barrier for 1 hour was a result from the categorisation test.
- The time interval of the possible colour change or precipitation in the CDS solution was recorded in the raw data file.
Irritation / corrosion parameter:
penetration time (in minutes)
Run / experiment:
Corrositex
Value:
> 60
Vehicle controls validity:
not specified
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: In conclusion, it can be stated that in this study and under the experimental conditions reported, the test item is not corrosive to skin.

RESULTS AND DISCUSSION


Qualify Test (Test Item)


The test item induced a physical change (precipitation) in the qualify test after 1 minute incubation. Since a physical change (precipitation) was visible in the “Qualify Test Vial”, the test item was considered to be suitable for the next step.


Qualify Test (Reference Item)


The reference item induced a change in colour in the qualify test after 1 minute incubation. Since a change in colour was visible in the “Qualify Test Vial”, the test item was considered to be suitable for the next step.


Categorisation Test (Test Item)


The test item did not induce a change in colour neither Category A vial nor in the Category B vial after 1 minute incubation. A confirmation experiment was performed by adding the confirm reagent to the Category B vial. This induced a change in colour to grey. Therefore, the test item was classified as category 2.


Categorisation Test (Reference Item)


The reference item did not induce a change in colour neither Category A vial nor in the Category B vial after 1 minute incubation. A confirmation experiment was performed by adding the confirm reagent to the Category B vial. This induced a change in colour to yellow. Therefore, the test item was classified as category 2.


 


Classification Test


 































Test Group



Time Interval of


Color Change



UN GHS Prediction


 



Negative Control













 



> 60 minutes


 



 



Non-corrosive


 



Positive Control



53 seconds


 



Corrosive Sub-category 1A


 



Reference Item



> 30 – 60 minutes


 



Corrosive Sub-category1C


 



Test Item



> 60 minutes


 



Non corrosive


 



 


Discussion


According to Sponsor’s information there is an animal study available with test substance. Based on this study results test item has to be classified as corrosive. The design of this study could not distinguish between subcategories 1B and 1C. Therefore, a reference item, with well-known Category (1C) was determined in addition in the present study.


The test item and the reference item passed the qualify test and were considered as suitable for testing with the Corrositex™ test kit.


In the categorisation test the test item and the reference item did not induce a colour change in the category A or in the category B vial after 1 minute incubation. A confirmation experiment was performed by adding the confirm reagent to the Category B vial. This induced precipitation after 1 minute of incubation. The test item was classified according to Category 2.


500 μl of the test item and the reference item were applied on quadruplicate bio-barriers for the classification test. The bio-barriers were placed atop vials containing the CDS reagent. The time needed to corrode the bio-barrier and induce a distinct change in the colour of the CDS reagent was monitored for each of the vials.


500 μL of the negative control (10% citric acid) were placed atop one bio-barrier and the colour change of the CDS reagent was monitored up to 60 minutes.


500 μL of the positive control (Sulfuric acid (95-97%)) were placed atop one bio-barrier and the colour change of the CDS reagent was monitored.


The negative control did not induce a change in the colour of the CDS reagent after 60 minutes. The positive control showed a distinct change in the colour of the CDS reagent in the time interval of 0 – 3 minutes. These results ensured the validity of the test.


A change of colour of the CDS reagent after treatment of the bio-barriers with the test item could not be observed after 60 minutes. According to the classification criteria given in "overall remarks" the test item was classified as Non-Corrosive.


A change of colour of the CDS reagent after treatment of the bio-barriers with the reference item could be observed in the interval from 30 to 60 minutes. According to the classification criteria given in "overall remarks" the reference item was classified as corrosive (GHS Cat 1C).

Conclusions:
In conclusion, it can be stated that in this study and under the experimental conditions reported, the test item is not corrosive to skin.
Executive summary:

This in vitro study was performed to assess the corrosive potential of test item by means of the in vitro Membrane Barrier Test for

Skin Corrosion (OECD TG 435) using the Corrositex™ test kit.

Following an initial determination of the compatibility of the test item with the test system (qualify test) and a test system-specific categorisation (categorisation test), 500 μL of the test item were applied on quadruplicate bio-barriers for the classification test. The

bio-barriers were placed atop vials containing the chemical detection system (CDS). The time needed to corrode the bio-barrier and to induce a distinct change in the colour of the CDS reagent was monitored for each of the vials.

Additionally to the test item a reference item was tested.

No change of colour of the CDS reagent after treatment of the bio-barriers with the test item was observed after the 60 minutes time interval.

A change of colour of the CDS reagent after treatment of the bio-barriers with the reference item could be observed in the interval from 30 to 60 minutes.

The test item as well as the negative and the positive controls fulfilled the acceptance criteria for the test system.

According to the classification criteria given in "overall remarks" the test item was, therefore, classified as not corrosive.

The reference item was classified as corrosive (UN GHS subcategory 1C or C; Reg. (EC) No. 1272/2008).

In conclusion, it can be stated that in this study and under the experimental conditions reported, the test item is not corrosive to skin.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1984-10-02 to 1984-10-16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Principles of method if other than guideline:
Method: other: OECD Guideline 404 (1981), occlusive test
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS: 
- Strain: New Zealand white
- Sex: male/female
- Source: Dr. Karl Thomae GmbH, Biberach (Germany)
- Weight at study initiation: 3.8-5.3 kg
- access to drinking water: ad libitum
- diet: K4 diet for rabbits (Ssniff; Soest)

ENVIRONMENTAL CONDITIONS:
- room temperature: 20°C (+/- 1°C)
- humidity: 60% (+/- 5%)
- light: 12 hours/day
- air exchange: 15-fold/h
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
undiluted
Duration of treatment / exposure:
4 hour(s)
Observation period:
- Postexposure period: 14 days
Number of animals:
6 (3 per sex)
Details on study design:
ADMINISTRATION/EXPOSURE 
- Area of exposure: ca. 6 cm2
- Total volume applied: 0.5 ml
- Postexposure period: 14 days
- Removal of test substance: with warm water
EXAMINATIONS
- Scoring system: OECD Guideline; Annex VI of 79/831/EEC (6th Amendment)
- Examination time points: 1; 24; 48; 72 hours and 6; 8; 10; 14 days  after removal of patch and test substance; the first 4 readings were  scored in the OECD system.
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 1h, 24h, 48h, 72 h
Score:
6.87
Max. score:
8
Reversibility:
not reversible
Irritant / corrosive response data:
AVERAGE SCORE
- Erythema: 3.61/4.0 (6th Amendment = 79/831/EEC)
- Edema: 3.33/4.0 (6th Amendment = 79/831/EEC)
- Overall: 6.87/8.0 (OECD TG) OTHER EFFECTS: necrosis after 4 hours, not after 3 minutes
Other effects:
no
no further remarks
Conclusions:
A study was performed to examine skin irritating effects of 3-Isocyanatomethyl-3,3,3-trimetylcyclohexylisocyanate according to OECD TG 404 in rabbits. In the study three rabbits per sex were exposed occlusively for four hours. The result was, with regard to the irritation index (6.87 of max. 8.0), described as “highly irritating”. The overall result was “corrosive” because of extensive irreversible tissue damage such as necrosis, ulceration, or scarring within the observation period (14 days) in all animals.
Executive summary:

A study was performed to examine skin irritating effects of 3-Isocyanatomethyl-3,3,3-trimetylcyclohexylisocyanate according to OECD TG 404 in rabbits. Undiluted test substance was applied in the study. In the study three rabbits per sex were exposed occlusively for four hours. The result was, with regard to the irritation index (6.87 of max. 8.0), described as “highly irritating”. The overall result was “corrosive” because of extensive irreversible tissue damage such as necrosis, ulceration, or scarring within the observation period (14 days) in all animals.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1993-08-31 to 1993-09-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS: 
- Strain: HC:NZW
- Sex: female
- Source: Interfauna U.K. Ltd., Wyton, Huntingdon, England
- Weight at study initiation: 3.2 kg
- diet: K4 diet (Ssniff, soest)
- water: tap water (ad libitum)
- before the experimental start the rabbits were acclimatized and examined regarding any alteration

ENVIRONMENTAL CONDITIONS:
- housing conditions: room temperature: 22°C (+/- 1.5°C)
- humidity 50-80%
- light/dark cycle: 12 hours artificial from 6-18 hrs CET
- Air exchange: 12-15 times per hour
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
yes
Amount / concentration applied:
undiluted
Duration of treatment / exposure:
4 hour(s)
Observation period:
Postexposure period: 14 days
Number of animals:
1
Details on study design:
- Controls: deionized water on contralateral skin area
ADMINISTRATION/EXPOSURE 
- Area of exposure: ca. 6 cm2
- Total volume applied: 0.5 ml
- Postexposure period: 14 days
- Removal of test substance: yes (after 4 hours)
EXAMINATIONS
- Scoring system: 83/467/EEC; Draize scores
- Examination time points:    after ca. 1; 24; 48; 72 hours, 7 and 14 days
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2.7
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.7
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
animal #1
Time point:
other: 1h; 24h; 48h;72h
Score:
4.5
Max. score:
8
Reversibility:
not reversible
Remarks on result:
other: score calculated from data of the study
Irritant / corrosive response data:
AVERAGE SCORE
- Erythema: 2.7/4.0
- Edema: 1.7/4.0
Other effects:
OTHER EFFECTS: On the exposed skin strong erythematous and exsudative  reactions were observed. From day 7 on a white to yellowish squamous 
coat  (on day 14 the coat was white) and eschar formation were seen. On day 14,  on the exposed skin area the epidermis was partly removed and in
 this  area a wound (1 x 1 cm) with incrustation was observed.

no further remarks

Conclusions:
This study regarding the skin irritating properties of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate was performed according to OECD TG 404 with one rabbit exposed semiocclusively for four hours. Under conditions of the study 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate was “corrosive” with an irritation index of 4.5 of max. 8.0 (Krötlinger, 1994) in rabbits.
Executive summary:

This study regarding the skin irritating properties of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate was performed according to OECD TG 404 with one rabbit exposed semiocclusively for four hours. For reasons of animal welfare, due to the expected irritant potency of the test substance on the skin, in the test only one animal was used. Undiluted test substance was applied. On the exposed skin strong erythematous and exsudative reactions were observed. From day 7 on a white to yellowish squamous coat (on day 14 the coat was white) and eschar formation were seen. On day 14 on the exposed skin area the epidermis was partly removed and in this area a wound with incrustation was observed. Under conditions of the study 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate was “corrosive” with an irritation index of 4.5 of max. 8.0 (Krötlinger, 1994) in rabbits.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Principles of method if other than guideline:
The original report was submitted to the sponsor with cover letter  dated 02 April 1981. Thus it cannot have been performed according to the  adapted OECD Test Guideline. Probably a late / final draft was used.
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS: 
- Strain: New Zealand white
- Sex: Male
- Source: Lippische Versuchstierzucht, Extertal (Germany)
- Weight at study initiation: 2.3 kg (average)
-acclimatization period 7-14 d
- diet: "Imuemmel Z" (Ssniff, Soest)
- water: ad libitum

ENVIRONMENTAL CONDITIONS:
- temperature: 16-18°C
- humidity 40%,
- lighting: 12h light/12h dark
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
undiluted
Duration of treatment / exposure:
4 hour(s)
Observation period:
Postexposure period: 8 days
Number of animals:
6
Details on study design:
ADMINISTRATION/EXPOSURE 
- Area of exposure: 2.5 cm x 2.5 cm flank skin on both sides; 8 cm x 8 cm  shaved 24 hours in advance
- Occlusion: PVC film
- Total volume applied: 0.5 ml per application site
- Postexposure period: 8 days
- Removal of test substance: washing with water
EXAMINATIONS
- Scoring system: maximum 4 scores each for   erythema and scab formation and   edema formation;   average of 24 h and 72 h readings
- Examination time points: immediately after removal = 4 hours; 24, 48,  72 hours; 8 days
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 24h; 72h
Score:
5.71
Max. score:
8
Reversibility:
not reversible
Remarks on result:
other: 72h values of oedema were reported as "high degree of irritation". Therefore for calculation of overall PDII the score 4 was used for oedema formation after 72h, which is the highest score for oedema formation
Irritant / corrosive response data:
AVERAGE SCORE 
- Erythema: 1.71/4.0
- Edema: 4.0/4.0
Other effects:
OTHER EFFECTS: high degree of irritation of the skin with severe  thickening and fissured surface hardening after 8 days

no further remarks




Conclusions:
The test item Isophorone Diisocyanate is described as “severly irritating/corrosive" for rabbits under the conditions of the study.
Executive summary:

A study was performed to examine skin irritating effects of Isophorone Diisocyanate according to OECD TG 404 in rabbits. In the study six male rabbits were exposed occlusively for four hours with the undiluted test item. High degree of irritation of the skin with severe thickening and fissured surface hardening after 8d was observed. Therefore and in respect to the primary dermal irritation index (5.71 of max. 8.0), which was calculated from the results, the test item is described as “severly irritating/corrosive" for rabbits under the conditions of the study.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1984-09-18 to 1984-10-03
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS: 
- Strain: New Zealand white
- Sex: male/female
- Source: Dr. Karl Thomae GmbH, Biberach (Germany)
- Weight at study initiation: 3.7-5.4 kg
- Controls: untreated eye
- diet: K4 diet for rabbits (Ssniff, Soest)
- water: ad libitum

ENVIRONMENTAL CONDITIONS:
- room temperature: 20°C (+/-1°C)
- humidity: 60% (+/-5%)
- air excange: 15-fold/h
- light: 12h/d
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
undiluted
Amount applied: 0.1 ml
Duration of treatment / exposure:
not rinsed
Observation period (in vivo):
Ophtalmoscopic examination: 1; 24; 48; 72 hours and 6; 8; 10; 13; and  15 days after treatment
Number of animals or in vitro replicates:
6 (3 male; 3 female)
Details on study design:
Comment: not rinsed
EXAMINATIONS
- Ophtalmoscopic examination: 1; 24; 48; 72 hours and 6; 8; 10; 13; and  15 days after treatment
- Scoring system: Draize (1959); Annex VI of 79/831/EEC (6th Amendment)
- Tool used to assess score: sodium fluorescein plus ophthalmic lamp
Irritation parameter:
overall irritation score
Remarks:
according to Draize
Basis:
mean
Time point:
other: 1h; 24h; 48h; 72h
Score:
9.96
Max. score:
110
Reversibility:
other: according to the scores fully reversible within 15 days
Remarks on result:
other: calculated according to Draize
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24h, 48h, 72h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
cornea opacity score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24h; 48h; 72h
Score:
0.17
Max. score:
2
Reversibility:
fully reversible within: 72h
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.33
Max. score:
2
Reversibility:
fully reversible within: 72h
Irritation parameter:
iris score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0.33
Max. score:
2
Reversibility:
fully reversible within: 72h
Irritation parameter:
iris score
Basis:
animal #5
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0.33
Max. score:
2
Reversibility:
fully reversible within: 72h
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24h; 48h; 72h
Score:
1.61
Max. score:
3
Reversibility:
other: according to the scores fully reversible within 15 days
Remarks on result:
other: redness
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 13 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 13 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 13 days
Irritation parameter:
conjunctivae score
Basis:
animal #4
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 15 days
Irritation parameter:
conjunctivae score
Basis:
animal #5
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 13 days
Irritation parameter:
conjunctivae score
Basis:
animal #6
Time point:
24/48/72 h
Score:
2.33
Max. score:
4
Reversibility:
fully reversible within: 13 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24h; 48h; 72h
Score:
0.67
Max. score:
4
Reversibility:
other: according to the scores fully reversible within 15 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
chemosis score
Basis:
animal #5
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritation parameter:
chemosis score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72h
Irritant / corrosive response data:
AVERAGE SCORE
- Cornea: 0.33
- Iris: 0.17
- Conjuntivae (Redness): 1.61
- Conjuntivae (Chemosis): 0.67
- Overall irritation score: 9.96/110
Other effects:
OTHER EFFECTS: Significant exsudation was observed at the 1 hour and 24  hour inspections. Ten days after treatment all animals showed loss of  
hair around the eye and incrustation at the eyelid, mostly associated  with thickening on day 13, which is not reflected in the scores.

no further remarks

Conclusions:
Under conditions of the study Isophorone Diisocyanate showed slightly irritating effects in rabbits, which do not meet criteria according to EU Directive 67/548/EEC to be classified as "Irritant to eyes".
Executive summary:

A study was performed to examine eye irritating effects of Isophorone Diisocyanate according to OECD TG 405 in rabbits. 0.1 ml of undiluted test substance was applied in the conjunctival sac of one eye per animal of six rabbits (3male, 3 female) without rinsing. The irritation index was 9.96 of max. 110. Ten days after treatment all animals in this study showed loss of hair around the eye and incrustation at the eyelid, mostly associated with thickening on day 13, which is not reflected in the scores. Under conditions of the study Isophorone Diisocyanate showed slightly irritating effects in rabbits, which do not meet criteria according to EU Directive 67/548/EEC to be classified as "Irritant to eyes"

.

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:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
; if relevant deviations exist they are described under materials and methods or as appropriate entries in this endpoint study record
Principles of method if other than guideline:
The original test report was submitted to the sponsor with cover letter dated 02 April 1981. Thus it cannot have been performed according to the adapted OECD Test Guideline. Probably a late / final draft was used.
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS: 
- Strain: New Zealand white
- Sex: male - Source: Lippische Versuchstierzucht, Extertal (Germany)
- Weight at study initiation: 2.3 kg (average)
- Controls: no
- acclimatization period before start of experiment: 7-14d
- diet: "muemmelZ" (Ssniff, Soest)
- water: ad libitum

ENVIRONMENTAL CONDITIONS - room temperature: 16-18°C
- humidity: 40%
- light: 12h/d
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
undiluted
Amount applied: 0.1 ml
Duration of treatment / exposure:
Rinsing: right eye after 30 s for 3 min with physiol. sodium chloride  solution
Observation period (in vivo):
Postexposure period: 8 days
Number of animals or in vitro replicates:
6
Details on study design:
ADMINISTRATION/EXPOSURE 
- Administration of test substance: both eyes; eyes closed for 1 s after  administration
- Amount of substance instilled: 0.1 ml into each eye - Rinsing: right eye after 30 s for 3 min with physiol. sodium chloride  solution
- Postexposure period: 8 days
EXAMINATIONS
- Ophtalmoscopic examination: 1; 24; 48; 72 hours; 8 days
- Scoring system: maximum 110 scores (Draize)
- Observation period: 8 days
- Tool used to assess score: ophthalmoscope; fluorescein
Irritation parameter:
overall irritation score
Remarks:
according to Draize
Basis:
mean
Time point:
other: 24h; 48h; 72h
Score:
26.4
Max. score:
110
Reversibility:
not fully reversible within: 8d
Remarks on result:
other: rinsed (right) eye
Irritation parameter:
overall irritation score
Remarks:
according to Draize
Basis:
mean
Time point:
other: 24h; 48h; 72h
Score:
36.4
Max. score:
110
Reversibility:
not reversible
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24h; 48h; 72h
Score:
0.9
Max. score:
4
Reversibility:
not fully reversible within: 8d
Remarks on result:
other: opacity; rinsed (right)eye
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24h; 48h; 72h
Score:
1
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: opacity; not rinsed (left) eye
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: 14hrs eye totally swollen
Remarks:
not rinsed (left) eye
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
cornea opacity score
Basis:
animal #6
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24h,; 48h; 72h
Score:
0.1
Max. score:
2
Reversibility:
not reversible
Remarks on result:
other: rinsed (right) eye
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24h; 48h; 72h
Score:
0.67
Max. score:
2
Reversibility:
not reversible
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.67
Max. score:
2
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
iris score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0.5
Max. score:
2
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: 24 hrs. eye totally swollen
Remarks:
not rinsed (left) eye
Irritation parameter:
iris score
Basis:
animal #5
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: no effect
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
iris score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0.33
Max. score:
2
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Time point:
other: 24h; 48h; 72h
Score:
2.7
Max. score:
3
Reversibility:
not reversible
Remarks on result:
other: rinsed (right) eye
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Time point:
other: 24h; 48h; 72h
Score:
2.8
Max. score:
3
Reversibility:
not reversible
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2.7
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
conjunctivae score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
conjunctivae score
Basis:
animal #5
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
conjunctivae score
Basis:
animal #6
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24h; 48h; 72h
Score:
3.9
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24h; 48h; 72h
Score:
3.9
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: rinsed (right) eye
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
chemosis score
Basis:
animal #5
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritation parameter:
chemosis score
Basis:
animal #6
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: not rinsed (left) eye
Irritant / corrosive response data:
AVERAGE SCORE (not rinsed / rinsed)
- Cornea (opacity): 1.0 / 0.9 (max. 4)
- Cornea (area): 2.9 / 1.6 (max. 4)
- Iris: 0.67 / 0.1 (max. 2)
- Conjunctivae (Redness): 2.8 / 2.7 (max. 3)
- Conjunctivae (Chemosis): 3.9 / 3.9 (max. 4)
- Conjunctivae (Exsudation): 2.8 / 2.3 (max. 3)
- Overall irritation score: 36.4 / 26.4 (max. 110)
Other effects:
OTHER EFFECTS:  Severe irritation of the conjunctiva: high degree of chemosis with  unchanged condition after 8 d both on rinsed and non-rinsed 
eye; slight  cornea damage, to a lesser degree on the rinsed eye, with significant  retrogression within 8 d

no further remarks

Conclusions:
Under conditions of the study Isophorone Diisocyanate showed highly irritating effects in eyes of rabbits, which are not reversible.
Executive summary:

A study was performed to examine eye irritating effects of Isophorone Diisocyanate according to OECD TG 405 in rabbits.

In this study where both eyes were treated (0.1 ml undiluted per eye) and only one eye was rinsed, severe irritation of the conjunctiva was observed. There was a constantly high degree of chemosis throughout the 8 days observation period both on rinsed and non-rinsed eyes, and slight cornea damage, to a lesser degree on the rinsed eye, with significant retrogression within 8 days. The irritation score was 36.4/110 (not rinsed) or 26.4/110 (rinsed eye). Under conditions of the study Isophorone Diisocyanate showed highly irritating effects in eyes of rabbits, which are not reversible.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin Irritation


Valid and sufficient animal studies on the skin irritating/ corrosive properties of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate were performed according to OECD TG 404. Undiluted test substance was applied in these studies. In one study with three rabbits per sex exposed occlusively for four hours, the result was, with regard to the irritation index (6.87 of max. 8.0), described as “highly irritating” (Hüls AG, 1984a). The overall result was “corrosive” because of extensive irreversible tissue damage such as necrosis, ulceration, or scarring within the observation period (14 days) in all animals. This overall assessment was confirmed by another study performed according to OECD TG 404 with one rabbit exposed semiocclusively for four hours, the result was “corrosive” with an irritation index of 4.5 of max. 8.0 (Bayer, 1994)."


Because these animal studies were primarily conducted to evaluate the irritation properties of the test substance, the lowest exposure time was at least 4 h. Unfortunately, this time frame (at least 4 h) in the provided studies was not able to distinguish between the corrosion sub categories according CLP regulation. With the animal test conducted by Hüls AG (1984a) an additional exposure time of 3 min was implemented. Necrosis was not observed. As so far subcategory corrosive 1A can be safely excluded. But distinction between sub category 1B and 1C could not performed. According animal welfare it is not allowed to repeat the animal testing.


Therefore, it was decided to perform an authority accepted in vitro test (OECD 435), to distinguish in requested sub categories. As a reference item 10 % acetic acid (Skin Irrit. 2) was examined in addition to positive and negative control. As a result, the Membrane Barrier Test Method for Skin (OECD 435) showed no corrosion properties for the test substance but did for the reference item which is regarded to be a Category 2 skin irritant according to Annex VI of CLP Regulation. The fact that there was precipitation instead of a colour change in the chemical detection system (CDS) disqualifies the study for a clear discrimination between the sub categories. Nevertheless, since there was a physical change (precipitation) in the CDS it has to be acknowledged that the principle of the study design, in terms of passing the barrier and reaction with CDS, was matched. Thus, the membrane Barrier Test Method for Skin demonstrates that the substance is at least not strongly corrosive (Skin. Corr. 1A) to the skin. Due to deficiencies in the test design and performance (strong corrosive positive control rather than medium corrosive substance; precipitation in the chemical detection system instead of colour change; unclear differences in colour change after use of confirmation reagent for the test- and reference substance) the study cannot be used stand alone. Instead, the study is used as a supporting study, because the study matched the general principle of the test system (passing the barrier, reaction with CDS) and consequently is regarded valid. Since there was no effect on the CDS within 60 min the study contradicts a classification as a strong corrosive substance.


According to the criteria given by the CLP regulation the classification criteria for skin corrosion are fulfilled. The substance should be classified taking the available animal studies into account, supported by the OECD 435 study. Mainly based on results from animal testing and supported by the in vitro study we conclude that the substance is clearly corrosive between subcategory 1B and 1C. Since severe effects erythema and oedema have been observed after 4 hours exposure time and taking precautionary principles into account it is decided to classify 3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate as Corrosive sub category 1B instead of Category 1 without subcategorization.


 


Eye Irritation


Conflicting results ranging from “not irritating” (Hüls AG, 1984b) to “highly irritating” (FH ITA, 1981b) were reported for the effects of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate on rabbit eyes in studies performed according to OECD TG 405. The exudation observed in the study of Hüls AG (1984) may have contributed to the avoidance of damage to the eye. The overall irritation index was 9.96 of max. 110. Ten days after treatment with 0.1 ml undiluted test substance all animals in this study showed loss of hair around the eye and incrustation at the eye lid, mostly associated with thickening on day 13, which is not reflected in the scores. In the study of FH ITA (1981b), where both eyes were treated (0.1 ml undiluted per eye) and only one eye was rinsed, severe irritation of the conjunctiva was observed. There was a constantly high degree of chemosis throughout the 8 days observation period both on rinsed and non-rinsed eyes, and slight cornea damage, to a lesser degree on the rinsed eye, with significant retrogression within 8 days. The overall irritation score was 36.4/110 (not rinsed) or 26.4/110 (rinsed eye).


According to the criteria given by the CLP regulation the classification criteria for Eye irritation / corrosion category 1 are fulfilled. First of all, due to the proposed classification for skin corrosion according to 3.3.2.3 of Annex I “Skin corrosive substances shall be considered as leading to serious damage to the eyes as well (Category 1), while skin irritant substances may be considered as leading to eye irritation (Category 2). “


Additionally, the findings in the study conducted by FH ITA (1981b) support the classification with Eye Dam. 1 as there are constantly high degree of chemosis throughout the 8 days observation period both on rinsed and non-rinsed eyes, and slight cornea damage, to a lesser degree on the rinsed eye in all animals. However, it remains uncertain if the chemosis would remain over 21 days of observation.


 


 


Respiratory Tract Irritation


 


Studies in Animals


Some studies were performed to determine the concentration causing a 50% decrease in respiration rate. This effect, which is thought to reflect the respiratory tract irritation, was observed at 11.1 mg/m³ (30 min), 10.3 mg/m3(1 h) and 4.7 mg/m³ (3 h) in rats (MobayChemical Corporation, 1984) and at 11.1 mg/m³ (30 min), 6.0 mg/m³ (1 h) and 2.0 mg/m3 (3 h) (MobayChemical Corporation_2, 1984) or 6.0 mg/m³ (3 min), 4.0 mg/m³ (10 min) and 3.0 mg/m3 (30 min) (E.I. du Pont de Nemours and Company, 1987 and 1990) in mice (see chapter 7.2.2 of IUCLID data set).


In the acute inhalation toxicity study (Bayer, 1995) macroscopic examinations revealed that animals showed symptoms like nose/muzzle with red incrustations, mucous membrane of the nose with reddening, pleural cavity filled with liquid, lung less collapsed emphysematous, and spongy. Thus, local irritating effects are evident whereas no histological examinations were conducted discriminating between local irritation and corrosion to the respiratory tract.


Studies in Humans


"Henschler (1972) published results of experiments with volunteers exposed for 1 - 5 minutes to an aerosol (with regard to the vapor saturation concentration at ambient temperature the particle concentration should be negligible in relation to vapor atmosphere) of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate. At 0.25 mg/m3 the odor was just perceptible; at 0.64 mg/m3 slight irritation of the mucous membranes of the eyes and nose were observed; at 1.37 mg/m3 there was strong, intolerable irritation of the mucous membranes of the eyes and the breathing passages." (see chapter 7.10.5 of IUCLID data set)

Justification for classification or non-classification

The substance 3-Isocyanatomethyl-3,5,5 -trimethylcyclohexyl isocyanate is listed in Annex VI of EC regulation 1272/2008.

Based on available data and the precautionary principle the current Annex VI entry should be modified from Skin Irrit. 2 with H 315 to Skin Corr. 1B with H 314 and from Eye irritation / corrosion category 2 with H319 to Eye irritation / corrosion category 1 with H 318.