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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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report date:
2011

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
4,4'-Methylenediphenyl diisocyanate, oligomeric reaction products with 2,4'-diisocyanatodiphenylmethane and oxydipropanol
EC Number:
500-270-4
EC Name:
4,4'-Methylenediphenyl diisocyanate, oligomeric reaction products with 2,4'-diisocyanatodiphenylmethane and oxydipropanol
Molecular formula:
C14 H10 N O [C21 H24 N2 O5 ]n N C Onmean = 1, 2, 3...
IUPAC Name:
Oligomeric reaction product of 1,1'-methylenebis(4-isocyanatobenzene) and oxybispropanol
Constituent 2
Reference substance name:
propane-1,2-diol polymer with 1-isocyanato-4-[(4- isocyanatophenyl)methyl]benzene and 1-isocyanato-2-[(4- isocyanatophenyl)methyl]benzene
IUPAC Name:
propane-1,2-diol polymer with 1-isocyanato-4-[(4- isocyanatophenyl)methyl]benzene and 1-isocyanato-2-[(4- isocyanatophenyl)methyl]benzene

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
Total Number: Three
Gender: Male
Age Range: 12 weeks at start of dosing; records of dates of birth for animals used in this study are retained in the Calvert archives.
Body Weight Range: 2.8 to 2.9 kg at the outset (Day 1) of the study.
Animal Source: Millbrook
Experimental History: Purpose-bred and experimentally naive at the outset of the study.
Identification: Ear tag and cage card

Environmental conditions
Housing: Animals were individually housed in compliance with USDA Guidelines. The room in which the animals were kept was documented in the study records. No other species were kept in the same room.
Lighting: 12 hours light, 12 hours dark
Room Temperature: 17 to 24°C
Relative Humidity: 31 to 74%
Food: All animals had access to PMI Certified Hi-Fiber Rabbit Diet #5325 as per Calvert SOP. The lot number(s) and specifications of each lot used are archived at Calvert. No contaminants were known to be present in the certified diet at levels that would be expected to interfere with the results of this study. Analysis of the diet was limited to that performed by the manufacturer, records of which are maintained in the Calvert archives.
Water: Tap water was available ad libitum, to each animal via an automatic watering device. The water is routinely analyzed for contaminants as per Calvert SOP's. No contaminants were known to be present in the water at levels that would be expected to interfere with the results of this study. Results of the water analysis are maintained in the Calvert archives.
Acclimation: Study animals were acclimated to their housing for a minimum of 5 days prior to dosing.

Test system

Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Amount / concentration applied:
A dose of 0.5 ml of the liquid test article was applied to each of the test sites. The test article was applied directly on the intact skin sites.

The pH of the test article was determined by the testing facility prior to experimental start. Due to the nature of the test article, an aqueous solution or suspension was not prepared. The pH was taken following the handling guidelines outlined in the dose preparation section. The method of pH determination was with use of pH paper (pHydrion, HJ613) and pH values for all three test articles were 5.
Duration of treatment / exposure:
4 hours
Observation period:
Observations for dermal irritation were recorded immediately after patch removal, at 30-60 minutes, 24, 48 and 72 hours and daily through Day 21.
Number of animals:
Three
Details on study design:
Within 24 hours before initiation of the test, fur was removed from the dorsal trunk of each animal by clipping. Care was taken to avoid abrading the skin. Only animals with healthy intact skin were used. Three sites were prepared on each animal. The animals were clipped as deemed necessary during the study to facilitate observations. The exposure duration for each site was 4 hours (±0.5 hr).

Each test article was applied to one site (-5cm x 5cm) on the dorsal trunk of each animal (intact sites) and covered with a gauze patch. Each test article was applied to each rabbit. The patch was loosely held in contact with the skin (semi-occlusive). The trunk of the animal was wrapped with an elastic bandage dressing, which was held in place with non-irritating tape for the duration of the exposure period.

At the end of each exposure period, residual test article was removed using corn oil (Mazola, lot #P312771-2, Exp. Jan 2013, yellow semi-viscous liquid), to avoid altering the existing response or the integrity of the epidermis. The corn oil was placed on the gauze, saturated and allowed to soak into the sample for -15 minutes or until the gauze could easily be removed (time documented in the raw data) before being wiped with gauze.
For all sites the gauze used for dosing did not adhere to the dose sites. The degree of erythema and edema was evaluated at each interval according to the Draize technique.

In-Life Observations and Measurements
1. Mortality/Morbidity was observed once daily.
2. Clinical Observations: Prior to dose administration and then daily.
3. Dermal Observations: After removal of the patch, animals were examined for signs of erythema and edema and the responses were scored immediately, and then at 30-60 min, 24, 48 and 72 hours (±1 hour) after each patch removal. Daily manual scoring occurred after the 72 hour scores since irritation persisted for a maximum of 21 days. Dermal irritation was scored and recorded according to the grades in Table I. In addition to the observation of irritation; any lesions and other toxic effects were fully described.
4. Body Weights: Body weights of animals were observed prior to dose administration and after the final skin grading.

Results and discussion

In vivo

Resultsopen allclose all
Remarks on result:
other: Test Items 1, 2, and 3 were found to be severely irritating to the skin of rabbits according to the EEC Irritation Rating and the GHS Classification.
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
animal #1
Time point:
72 h
Score:
3.25
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
animal #2
Time point:
72 h
Score:
1.33
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
animal #3
Time point:
72 h
Score:
1.67

Any other information on results incl. tables

Mortality I Clinical Observations:

No mortality was observed during the study. No clinical signs were recorded during the course of the study.

Body Weights:

Body weight data are presented in the table below:

Animal No. Sex  Initial Body Weight (kg)  Final Body Weight (kg)
 1 M 2.9 3.0 
 2 M 2.9 3.2
 3 M 2.8 3.3

Dermal Irritation and Corrosivity:

The following is a summary of the most severe dermal responses observed:

Treatment Dermal Responses Comments
Test Item 1 Severe erythema and severe edema starting at Day 7 Fissuring and flaking of the skin at the application site were also observed starting at Day 7
Test Item 2 Severe erythema and severe edema starting at Day 7 Fissuring and flaking of the skin at the application site were also observed starting at Day 7
Test Item 3 Severe erythema and severe edema starting at Day 8 Fissuring and flaking of the skin at the application site were also observed starting at Day 7 

Treatment PII (30 - 60 min to 72 hr)
Test Item 1 3.25 
Test Item 2 1.33
Test Item 3 1.67

 

Applicant's summary and conclusion

Interpretation of results:
Category 2 (irritant) based on GHS criteria
Conclusions:
All 3 test items, were found to be severely irritating to the skin of rabbits according to the EEC Irritation Rating and the GHS Classification. The initial Primary Irritation Indices were not severe but severe reactions were delayed.
Executive summary:

Three test articles (Test Items 1, 2, and 3), were applied to three sites on the clipped dorsal trunk of three New Zealand White rabbit. The exposure period was 4 hours. A corn oil soak was employed for removal of the test articles. Observations for dermal irritation were recorded immediately after patch removal, at 30-60 minutes, 24, 48 and 72 hours and daily through Day 21. Grading of irritation was according to the method of Draize.

In conclusion, all three test items were found to be severely irritating to the skin of rabbits according to the EEC Irritation Rating and the GHS Classification. The initial Primary Irritation Indices were not severe but severe reactions were delayed.

Treatment EEC GHS
Test Item 1 Irritant* Category 2**
Test Item 2 Irritant* Category 2**
Test Item 3 Irritant* Category 2**

*Scores based on erythema/edema calculations at 72 h observation period and further effects noted after the 72 h time point.

**Scores based on grades from three consecutive days after the onset of skin reactions, which occurred following the 72 h observation period.

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