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Toxicological information

Skin irritation / corrosion

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Administrative data

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).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1996
Report date:
1996

Materials and methods

Test guideline
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

Test material

Constituent 1
Chemical structure
Reference substance name:
4,4'-methylenedicyclohexyl diisocyanate
EC Number:
225-863-2
EC Name:
4,4'-methylenedicyclohexyl diisocyanate
Cas Number:
5124-30-1
Molecular formula:
C15H22N2O2
IUPAC Name:
1,1'-methylenebis(4-isocyanatocyclohexane)
Details on test material:
- Monoisocyanate content: 0.11 %

Test animals

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

Test system

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.

Results and discussion

In vivo

Resultsopen allclose all
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.

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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."