4,4'-methylenedicyclohexyl diisocyanate

Endpoint summary

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:

March - April 1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Remarks:

A 3-minute and 1-hour exposure period to the test substance was conducted additionally to the usual 4-hour exposure period of OECD TG 404. This aids the discrimination between corrosive and irritant. The exposure periods chosen are in line with the Recommendations on the Transport of Dangerous Goods by the United Nations Economic Commission for Europe (UNECE).

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

Modified testing procedure: A 3-minute and 1-hour exposure period was conducted additionally to the usual 4-hour exposure period of OECD TG 404.

Principles of method if other than guideline:

The exposure periods chosen (3-min., 1-hour, 4-hours) are in line with the Recommendations on the Transport of Dangerous Goods by the United Nations Economic Commission for Europe (UNECE).

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: adult albino rabbits of the Hra:(NZW)SPF strain
- Sex: male
- Source: HRP, Inc., Denver; Pennsylvania, USA
- Age at study initiation: no data
- Weight at study initiation: 2005-2186 g
- Housing: singly in stainless steel caging
- Diet and Water: ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 60.8-69.8 °F (corresponding to 16-21 °C), the temperature exceeded on two occasions up at maximum 70.9 °F (21.6 °C)
- Humidity (%): 50 +/- 10
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

other: the untreated skin of each animal was used for control

Amount / concentration applied:

0.5 mL

Duration of treatment / exposure:

Each animal was exposed to the test material for 3-minute, 1-hour, and 4-hour periods of time.

Observation period:

After removal of the patches, each application site was examined (recorded as the 3-minute, 1-hour, and 4-hour score). Subsequent examinations were made at 24, 48, 72, and 96 hours and after 7, 14, and 21 days.

Number of animals:

3 males

Details on study design:

The undiluted test material was applied to three separate test areas on the intact skin on each animal's back. Each area of application was covered with a 2.5-cm x 2.5-cm gauze patch secured with Paper tape, loosely overwrapped with Gran Wrap, and secured with Elastoplast tape to provide a semiocclusive dressing. The wrappings applied to each test site were independent of the other sites.

At the end of the 3-minute, 1 -hour, or 4-hour exposure periods, one patch from each animal was removed and the treated area was examined for evidence of corrosion. After the initial corrosion examination, the residual test material was removed using tap water to prevent further test material exposure. The test material was removed from the test sites as thoroughly as possible without irritating the skin. Erythema and edema reactions were assessed according to Draize. Each site per animal was scored independently. Photographs were taken of all exposure sites for each animal and all exposure times for each animal, and a sample of untreated skin, were preserved for future possible microscopic evaluation.

Animals were also observed for signs of clinical toxicity and/or ill health at each interval of dermal irritation scoring; these observations were recorded by exception.

Irritation parameter:

erythema score

Basis:

animal #1

Remarks:

(4 h exposure period)

Time point:

24/48/72 h

Score:

>= 0 - <= 1

Max. score:

4

Reversibility:

fully reversible within: 21 days

Remarks on result:

other: mean score: 0.7

Irritation parameter:

erythema score

Basis:

animal #2

Remarks:

(4 h exposure period)

Time point:

24/48/72 h

Score:

>= 0 - <= 2

Max. score:

4

Reversibility:

fully reversible within: 21 days

Remarks on result:

other: mean score: 1

Irritation parameter:

erythema score

Basis:

animal #3

Remarks:

(4 h exposure period)

Time point:

24/48/72 h

Score:

>= 0 - <= 1

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Remarks:

(still score 1 at Day 21)

Remarks on result:

other: mean score: 0.3

Irritation parameter:

edema score

Basis:

animal: #1 and #3

Remarks:

(4 h exposure period)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #2

Remarks:

(4 h exposure period)

Time point:

24/48/72 h

Score:

>= 0 - <= 1

Max. score:

4

Reversibility:

fully reversible within: 21 days

Remarks on result:

other: mean: 0.3

Irritation parameter:

erythema score

Basis:

animal: #1 and #3

Remarks:

(3 min. exposure period)

Time point:

24/48/72 h

Score:

>= 0 - <= 1

Max. score:

4

Remarks on result:

other: mean score: 0.3

Irritation parameter:

erythema score

Basis:

animal #2

Remarks:

(3 min. exposure period)

Time point:

24/48/72 h

Score:

>= 0 - <= 1

Max. score:

4

Remarks on result:

other: mean score: 0.7

Irritation parameter:

edema score

Basis:

animal: #1, #2, #3

Remarks:

(3 min. exposure period)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Basis:

animal: #1 and #2

Remarks:

(1 h exposure period)

Time point:

24/48/72 h

Score:

>= 0 - <= 1

Max. score:

4

Remarks on result:

other: mean score: 0.3

Irritation parameter:

erythema score

Basis:

animal #3

Remarks:

(1 h exposure period)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal: #1, #2, #3

Remarks:

(1 h exposure period)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

There was no evidence of corrosion observed at any of the test sites for any of the exposure periods (3-minutes, 1-hour, and 4-hours).
Dermal irritation was observed sporadically from the 4-hour observations (for the 4-hour exposure sites) through the 72-hour observations and at most exposure sites from the 96-hour observations through the Day 14 observations. This dermal irritation was characterized by very slight to well-defined erythema (scores of 1 to 2) and very slight to slight edema (scores of 1 to 2). On Day 21, all signs of edema had subsided and only one animal was noted with very slight erythema at all exposure sites. However, on Day 21, areas of thickened skin were observed at the exposure sites for two animals.

Other effects:

There were no remarkable signs of clinical toxicity and/or ill health noted during the course of this study. All animals gained weight over the course of the study.

Data from IUCLID4

RS-Freetext:
There was no evidence of corrosion observed at any of the test sites for any of the exposure periods (3-minutes, 1-hour, and 4-hours).
Dermal irritation was observed sporadically from the 4-hour observations (for the 4 -hour exposure sites) through the 72 -hour observations and at most exposure sites from the 96-hour observations through the Day 14  observations. This dermal irritation was characterized by very slight to well-defined erythema (scores of l to 2) and very slight to slight edema  (scores of 1 to 2). On Day 21, all signs of edema had subsided and only  one animal was noted with very slight erythema at all exposure sites.  However, on Day 21, areas of thickened skin were observed at the exposure  sites for two animals (all exposure sites for Animal No. 4022 and the  3-minute exposure site for Animal No. 4023).
There were no remarkable signs of clinical toxicity and/or ill health  noted during the course of this study. All animals gained weight over the  course of the study.

Executive summary:

4,4´-Methylenedicyclohexyl diisocyanate has been assessed in the OECD HPV programme, 2005.

Cited from SIAR of SIAM 20 (Paris, April 19 -22, 2005): "In 1996 the primary dermal irritation/corrosion potential of 4,4´-methylenedicyclohexyl diisocyanate was evaluated when applied to the skin of 3 rabbits under semi-occlusive conditions for exposure periods of 3-minutes, 1-hour, and 4-hours (Bayer Corporation, 1996). For this purpose the undiluted test material was applied to three separate areas on the intact skin on each animal´s back. In this well conducted GLP-study no evidence of corrosion was observed at any of the test sites for any of the exposure periods. Based on these results, the test material was not considered to be a corrosive material. Dermal irritation was evident at all exposure sites and was characterized by very slight to well-defined erythema (scores of 1 to 2 according to the Draize scale of max. 4) and very slight to slight edema (scores of 1 to 2 according to the Draize scale of max. 4). By day 21 all signs of edema had subsided and only one animal was noted with very slight erythema at all exposure sites. However, on day 21, areas of thickened skin were observed at some or all of the exposure sites for two animals. There were no remarkable signs of clinical toxicity and/or ill health noted during the course of this study."

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Reference

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:

guideline study with acceptable restrictions

Remarks:

e.g. non-GLP

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

(1981)

GLP compliance:

no

Species:

rabbit

Strain:

other: Small white Russians, Chbb-SPF

Details on test animals or tissues and environmental conditions:

TEST ANIMALS:  
- Strain: Small white Russians, Chbb-SPF
- Sex: male and female
- Source: Dr. Karl Thomae GmbH, Biberach, Germany
- Age at study initiation: no data
- Weight at study initiation: 1.9 - 2.4 kg
- Housing: singly in stainless steel cages
- Diet and water: ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 1
- Humidity (%): 60 +/- 5
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

other: the left eye that remains untreated served as control

Amount / concentration applied:

0.1 mL

Duration of treatment / exposure:

The test substance was applied into the conjunctival sac of the right eye, except for one animal where the left eye was treated; no rinsing of the eyes was done after exposure.

Observation period (in vivo):

Eye irritation was scored 1, 24, 48, and 72 hours and 6, 8, 10, and 14 days after start of exposure.

Number of animals or in vitro replicates:

3 males / 3 females

Details on study design:

0.1 mL unchanged test substance was instillated in the lower lid of one eye of each animal. No rinsing of the eyes was done after exposure. The eyes were assessed 1, 24, 48, and 72 hours and 6, 8, 10, and 14 days post-treatment.

TOOL USED TO ASSESS SCORE: sodium fluorescein / ophthalmic lamp /  visual inspections

SCORING SYSTEM: Draize (Appraisals of the Safety of Chemicals in Foods, Drugs and Cosmetics, FDA, Austin 1, Texas, 1959, page 51)

Irritation parameter:

cornea opacity score

Basis:

animal: #1, #2, #3, #4, #5, #6

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

animal: #1, #2, #3, #4, #5, #6

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Basis:

animal: #1, #4

Time point:

24/48/72 h

Score:

>= 1 - <= 2

Max. score:

3

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: mean score: 1.3

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

>= 0 - <= 2

Max. score:

3

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: mean score: 1

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

>= 1 - <= 2

Max. score:

3

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: mean score: 1.7

Irritation parameter:

conjunctivae score

Basis:

animal #5

Time point:

24/48/72 h

Score:

>= 1 - <= 3

Max. score:

3

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: mean score: 1.7

Irritation parameter:

conjunctivae score

Basis:

animal #6

Time point:

24/48/72 h

Score:

>= 0 - <= 1

Max. score:

3

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: mean score: 0.7

Irritation parameter:

chemosis score

Basis:

animal: #1, #5

Time point:

24/48/72 h

Score:

>= 0 - <= 1

Max. score:

4

Reversibility:

fully reversible within: 6 days

Remarks on result:

other: mean score: 0.7

Irritation parameter:

chemosis score

Basis:

animal: #2, #4

Time point:

24/48/72 h

Score:

>= 0 - <= 1

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: mean score: 0.3

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 6 days

Irritation parameter:

chemosis score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

other: Irritation index

Basis:

animal: #1, #2, #3, #4, #5, #6

Time point:

other: 1, 24, 48 and 72 hours

Score:

5.67

Max. score:

110

Irritant / corrosive response data:

Mean Scores (24, 48, and 72 hours): Cornea: 0; Iris: 0, Conjunctivae (Redness): 1.28, Conjunctivae (Chemosis): 0.50

Scheme used for assessment (Irritation index, corresponding to classification as): not irritant 0-10, slightly irritant11-25, moderately irritant 26-56, severly irritant 57-110

Other effects:

On Day 6 inelastic eyelids were noted and on Day 10 hair loss around the eye.

Executive summary:

The eye irritation properties of 4,4'-methylenedicyclohexyl diisocyanate was investigated in a study according to OECD TG 405. In this study 0.1 mL of the undiluted test substance was instilled into the lower lid of each one eye of 3 female and 3 male rabbits; the untreated contralateral eye served as control. The eyes remained unrinsed and there was no removal of test substance. The animals were observed for a period of 2 weeks post application. Eye irritation was scored using the Draize scale.

The average scores at 24, 48 and 72 hours after treatment were 0 for cornea and iris, 1.28 for conjunctiva (redness), and 0.5 for chemosis. An irritation index (time points 1, 24, 48 and 72 hours) was calculated 5.67 of 110. This leads to the conclusion "not irritant" (0 -10 = not irritant) according to the scheme applied by the author. On Day 6 inelastic eyelids were noted and on Day 10 hair loss around the eye.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

4,4´-Methylenedicyclohexyl diisocyanate has been assessed in the OECD HPV programme, 2005.

Cited from SIAR for SIAM20 (Paris, April 19 -22, 2005): "4,4´-methylenedicyclohexyl diisocyanate is moderately to severe irritant to the skin of rabbits (OECD TG 404). Irritant effects were observed after instillation of 4,4´-methylenedicyclohexyl diisocyanate into the eyes of rabbits (OECD TG 405). The repeated dose studies indicate that 4,4´-methylenedicyclohexyl diisocyanate causes irritation of the respiratory tract."

And further: "Based on ‘regulatory’ acute toxicity studies (...) no conclusions can be drawn regarding the respiratory irritating properties of 4,4´-methylenedicyclohexyl diisocyanate. The same applies for the studies that determined the 4,4´-methylenedicyclohexyl diisocyanate concentration causing a 50 % decrease in respiratory rate (RD50) for mice (...). This test system is restricted to vapours (= upper tract irritant). It is irrelevant for aerosols for which the deposit pattern strongly depends on the generation of the test atmosphere. For aerosols irritation of the respiratory tract is apparently more dependent on the specific site receiving the highest fraction of the dose rather than the total airborne concentration. However, the repeated dose studies (...) do indicate that 4,4´-methylenedicyclohexyl diisocyanate causes irritation of the respiratory tract."

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008, Annex VI, classified as Cat. 2 for eye and skin irritation (H319: Cause serious eye irritation; H315: Causes skin irritation) and as STOT SE 3 for respiratory tract irritation (H335: May cause respiratory irritation).