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Diss Factsheets

Administrative data

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
January 15 to 24, 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented and reported study, conducted according to internationally accepted technical guidelines and in compliance with GLP in recognized contract research organization.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report date:
2009

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
of 2002
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
of 2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Version / remarks:
of 1998
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000, including the most recent partial revisions.
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS

- Age at study initiation (day of dosing): 9 - 12 weeks.
- Number and Sex: 3 males
- Animal supplier: Harlan France SARL, Gannat, France
- Weight at study initiation( before application): Minimum 1780 g, maximum 2340 g.
- Housing: Individual housing in cages with perforated floor and with shelters.
- Diet (approx. 100 g/day): Commercially available pelleted rabbit diet (K-H from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Hay (at least 3 times/week): Supplier: TecniLab-BMO BV, Someren, The Netherlands)
- Water (ad libitum): Tap water
- Acclimation period: At least 5 days before treatment start under laboratory conditions.


ENVIRONMENTAL CONDITIONS

Animal housing and environmental conditions were appropriate for skin irritation / corrosion testing in the rabbit: Controlled environment with approximately 15 air changes per hour, 12 hours artificial fluorescent light and 12 hours darkness per day and 21 – 23ºC. The relative humidity during the study period was 40 – 71%.

Test system

Type of coverage:
semiocclusive
Preparation of test site:
other: twice clipped with electric clipper
Vehicle:
water
Controls:
not required
Amount / concentration applied:
0.5 g test substance* moistened with 0.5 ml water per approx. 6 cm2 skin per animal.

* Dose expressed as water- and minor impurity-free test substance.
Duration of treatment / exposure:
4 hours
Observation period:
72 hours post patch removal
Number of animals:
3
Details on study design:
TEST SITE PREPARATION:

Approximately 24 hours before exposure an area of approximately 10x15 cm on the back of the animal was clipped. Area foreseen for treatment was re-clipped approx. 3 hours before treatment start to facilitate evaluation of the skin reactions. During health inspection of the animals prior to commencement of treatment, special attention was paid to the skin to be treated, which was intact and free from any abnormality.

- Area of treated skin: Approx. 6 cm2 (= 2x3 cm).
- Type of wrap used: Metalline patch (2x3 cm) mounted on micropore tape which was wrapped around the abdomen
and secured with Coban elastic bandage.

TEST MATERIAL AND DOSE PREPARATION

- Administration Volume/animal (2x3 cm):
0.5 g the test substance (expressed as water- and minor impurity-free test substance) moistened with 0.5 ml of water (= vehicle).

- Vehicle: Water (Elix, Millipore S.A.S., Molsheim, France).

- Justification for choice of vehicle:
The test substance is well soluble in water and stable for at least 96 hours in water and no adverse side effects of this vehicle on the animals
are to be expected

TREATMENT PERIOD AND REMOVAL OF TEST SUBSTANCE

Semi-occlusive treatment lasted 4 hours. Then the dressings were removed and residual test substance was washed off the skin with tap-water
and ethanol diluted with water (50% v/v) and acetone diluted with water (50% v/v).

SCORING SYSTEM:

The treated skin patches were evaluated at 1 hour post end of exposure (not included in the mean dermal irritation score nor used for irritation/corrosion classification) and at 24, 48 and 72 h post end of exposure (included in the mean dermal irritation score and used for irritation/corrosion classification).

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
erythema score
Remarks:
according to Draize as defined in Table 1
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48, 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
erythema score
Remarks:
according to Draize as defined in Table 1
Basis:
animal #1
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
erythema score
Remarks:
according to Draize as defined in Table 1
Basis:
animal #2
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
erythema score
Remarks:
according to Draize as defined in Table 1
Basis:
animal #3
Remarks:
mean over 3 time points
Time point:
other: 24, 48, 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
edema score
Remarks:
according to Draize as defined in Table 1
Basis:
mean
Remarks:
over 3 animals and 3 time points
Time point:
other: 24, 48,72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 24 h (edema grade 1 seen at 1 hour post patch removal)
Irritant / corrosive response data:
Erythema and edema result table (Table 2) for each individual animal is presented under "Remarks on results including tables and figures"
Other effects:
No other effects were reported. Mortality, symptoms of systemic toxicity or adverse effects on bodyweight were not evident.

Any other information on results incl. tables

Table 2: Gradings of Skin Reactions Attained for each Animal at Different Observation Time Points

Time after Patch Removal

1 h

24 h

48 h

72 h

Animal (Identification) No.

1  2  3

1  2  3

1  2  3

1  2  3

Erythema

1  1

1  1  1

0  0  0

0  0  0

Edema

1  1  1

0  0  0

0  0  0

0  0  0

* scoring was not possible, because of yellow/orange staining of the treated skin area.

Yellow/orange staining of the skin by the test substance was evident at 1, 24 and 48 hours after patch removal in all animals.

In all animals, the very slight erythema seen at 24 hours after patch removal were restricted to the edges of the application area.

At the end of the 4-hour treatment period the patches adhered to the skin resulting in bald skin at the edges of the application area in all animals. Bald skin at the edges of the application area was seen in all animals at all observation time points.

Applicant's summary and conclusion

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The mean Draize score for erythema derived from 24, 48 and 72 hours post patch removal in 3 rabbits was 0.3, the respective mean score for edema was 0.0. All edema findings were completely reversible within 24 and all erythema findings within 48 hours after patch removal. Based on these findings and according to EU classification rules [DIRECTIVE 67/548/EEC and REGULATION (EC) 1272/2008] the test substance was considered "not irritant" and not having any labelling requirement regarding skin irritation.
Executive summary:

the test substance was tested for skin irritation according to OECD Guideline 404 and the corresponding EC, EPA-OPPTS and JMAFF Technical Guidelines in compliance with GLP. Reliability grade 1 was assigned to the study.

 

Each of three New Zealand White rabbits was treated for 4 hours by semi-occlusive administration of a single dose of 0.5 g test substance* moistened with 0.5 ml water. The test substance was administered to clipped intact skin (approximately 6 cm2/animal). Skin reactions were assessed 1, 24, 48 and 72 hours post patch removal.

 

At 1 h post patch removal, edema, very slight in degree, were evident in all animals and erythema, very slight in degree, in two of them. In the other animal, erythema evaluation was impeded by considerable yellow/orange staining of the treated skin by the test substance. By Day 2 (24 h after treatment), the edema had completely resolved and only very slight erythema restricted to the edges of the application area were observed in all animals. By 48 h after treatment the signs of skin irritation had completely resolved in all animals. Yellow/orange staining of the skin by the test substance was evident at 1, 24 and 48 hours after patch removal in all animals, but was no longer evident at 72 h. Adherence of the patches to the skin and their removal led to bald skin at the edges of the application area in all animals. The latter was seen in all animals at all observation time points. Mortality, signs of systemic toxicity or adverse effects on bodyweight were not evident.

 

In view of complete reversibility of the irritating effects within 48 hours after patch removal and according to EU classification rules [DIRECTIVE 67/548/EEC and REGULATION (EC) 1272/2008] the test substance was considered "not irritant" and not having any labelling requirement regarding skin irritation.

________________________________________________________________

* Expressed as water- and minor impurity-free test substance