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Diss Factsheets

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:
May 7th 2012 (study plan) to July 27th 2012 (Final Report)
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Hypothesis: By dermal contact, the majority of the available NCO groups react with proteins and moisture on the skin, leading to the formation of an insoluble polymerized mass limiting absorption such that only a small fraction is available to penetrate into the viable skin layers. Residual toxicity, as demonstrated by mild irritation potential, is consistent with the hypothesized MoA that effects are driven by the rapid MDI-adduct formation with extracellular biological nucleophiles, which results in tissue damage and acute inflammation with the release of inflammatory mediators and cytokines.

Justification: All tested substances caused signs of skin irritation including inflammation (erythema and oedema) and additionally in some cases hyperplasia (thickening (coriaceousness), scaling, flaking or fissuring). Although not all studies demonstrated full reversibility of these signs, their severity decreased towards the end of the studies, such that only mild symptoms remained by the end of the observation periods. Furthermore, no signs of irreversible skin damage (i.e. ulcers, bleeding, bloody scabs, skin blanching, alopecia, scars or other signs indicative of necrosis into the dermis) were reported in any of the available studies, justifying all substances of the MDI category being regarded as skin irritants of category 2 as opposed to category 1

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Reference substance name:
PIR modified MDI
Cas Number:
109331-54-6
IUPAC Name:
PIR modified MDI

Test animals

Species:
rabbit
Strain:
Himalayan
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: LPT Laboratory of Pharmacology and Toxicology GmbH & Co. KG 24601 Löhndorf Germay
- Age at study initiation: 4 to 5 months
- Weight at study initiation: 2.2-2.5 kg
- Housing: single in cages
- Diet (e.g. ad libitum): ssniff K-H V2333 (ssniff Spezialitäten GmbH)
- Water (e.g. ad libitum): tape water
- Acclimation period: at least 20 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C +/- 3°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12-hours light/12 hours dark cylce

Test system

Type of coverage:
occlusive
Preparation of test site:
shaved
Controls:
yes
Amount / concentration applied:
0.5 ml test item
Duration of treatment / exposure:
4 h
Observation period:
14 days
Number of animals:
3

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 8 days
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
48 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 8 days
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 8 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 6 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
48 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 6 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 6 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 12 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
48 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 12 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 12 days
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #2
Time point:
48 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #2
Time point:
72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 8 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 12 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
48 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 12 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 12 days
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #3
Time point:
48 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #3
Time point:
72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 6 days
Other effects:
There were no systemic intolerance reactions.

Applicant's summary and conclusion

Interpretation of results:
Category 2 (irritant) based on GHS criteria
Remarks:
Induration, laceration and scaling of the skin was observed in test animals after treatment with the test substance, thus the test substance was considered to be an irritant.
Conclusions:
The test substance was irritating to the skin of rabbits according to OECD TG 404 (Leuschner, 2012). The mean irritation index for erythema was 1.7 of max. 4, the mean irritation index for edema was 0.5 of max. 4. Induration, laceration and scaling of the skin was found in test animals after treatment with the test substance, which was assessed relevant for classification as skin irritant.
Executive summary:

MDI PIR was irritating to the skin of rabbits according to OECD TG 404 (Leuschner, 2012). The mean irritation index for erythema was 1.7 of max. 4, the mean irritation index for edema was 0.5 of max. 4. Signs were fully reversible in all animals within 12 days. No systemic intolerance reactions were observed.