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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:
25 September 2012 to 09 October 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

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

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
2002
Deviations:
yes
Remarks:
(see "Principles of method if other than guideline" for information)
Principles of method if other than guideline:
The guideline states that the relative humidity should be at least 30% and preferably not exceed 70%, other than during room cleaning, the aim should be 50-60% whereas during the study, the relative humidity was humidity range was recorded as 41 - 82%. This deviation is presumed to have no impact on the outcome of the study.
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction product of salicylaldehyde and formaldehyde and phenol
EC Number:
632-556-0
Cas Number:
304859-44-7
Molecular formula:
C6H5O(C13H10O2)m(C7H6O)nH values on m and n are variable as this is a UVCB substance
IUPAC Name:
Reaction product of salicylaldehyde and formaldehyde and phenol
Test material form:
solid
Details on test material:
- Description: Light red / solid
- Storage conditions: Room temperature (15-30 °C), protected from humidity

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: ~12 weeks old
- Weight at study initiation: 2960 - 3172 g
- Housing: Rabbits were individually housed in AAALAC approved metal wire rabbit cages (65 x 65 cm with height of 45 cm). Cages were of an open wire structure and cages were placed together to allow some social interaction with rabbit(s) in adjoining cages.
- Diet: ad libitum
- Water: The animals received municipal tap water, as for human consumption, ad libitum, from an automatic system. The drinking water is routinely analysed and is considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20 ± 3 °C
- Humidity: 41 - 82 %
- Air changes: 15 - 20 air exchanges/hour
- Photoperiod: 12 hours daily, from 6.00 a.m. to 6.00 p.m.

Test system

Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.5 g
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
3 males
Details on study design:
TEST SITE
- Patch testing was used to detect primary irritating effects of the test material. Three male animals in acceptable health condition were selected for this test.
- Approximately 24 hours prior to the test, the hair was clipped from the back and flanks of the animals. Removal of hair was performed in two steps. The majority of hair was clipped with an electronic hair clipper and the remaining hair was moistened with water and shaved with a razor. The test material was applied to an approximately 6 cm² area of intact skin as follows:
* A single layer of a fine medical gauze (open-weave with large holes) of approximately 5 x 5 cm was placed over the application area,
* The appropriate amount of test material was carefully spread over the application area (the gauze helped maintain the test material in place),
* Three more layers of gauze were placed over the test material,
* These gauze patches were kept in contact with the skin by a patch of clear plastic with a surrounding adhesive hypoallergenic plaster to ensure continued good contact between the moistened test material and the shaved skin.
* The entire trunks of the animals were wrapped with plastic wrap for 4 hours.
* Medical elastic tubing was placed over the plastic to keep it in place.
- An initial test was performed using one animal. One hour after application of the test material, the application site was examined. No severe irritation or corrosive effect was found in the initial test, therefore the bandage was replaced and the exposure continued for a further 3 hours (a total 4 hours exposure). Two additional animals were then included in the study.

REMOVAL OF TEST SUBSTANCE
- After the treatment period, the test material was removed with water at body temperature and with Unguentum hydrophilicum nonionicum

OBSERVATION TIME POINTS
- Clinical Observations: Animals were examined for signs of erythema and oedema, and the responses scored at 60 minutes and then at 24, 48, 72 hours, 1 and 2 weeks after patch removal.
- Measurement of Body Weight: Body weights were recorded at the beginning and at the end of experiment.

SCORING SYSTEM:
- The dermal irritation scores were evaluated according to the scoring system by Draize (1959). The animals were observed for 72 hours and the duration of the study was sufficient to evaluate fully the reversibility or irreversibility of the effects observed.

CLASSIFICATION OF THE TEST MATERIAL
Results were presented and interpreted according to Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures:

CATEGORY 1 CORROSIVE:
- A corrosive is a test material that produces destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least 1 of 3 tested animals after an exposure of 4 hours. Corrosive reactions are typified by ulcers, bleeding, bloody scabs and, by the end of the observation at 14 days, by discolouration due to blanching of the skin, complete areas of alopecia and scars.
- Corrosive subcategories:
1A: Corrosive in > 1 of 3 animals with < 3 minutes exposure
1B: Corrosive in > 1 of 3 animals with > 3 minutes - ≤ 1 hour exposure
1C: Corrosive in > 1 of 3 animals with > 1 hour - ≤ 4 hours exposure

CATEGORY 2 IRRITANT
- Mean value of for erythema/eschar formation or oedema is greater or equal than 2.3, but less or equal than 4.0 in at least 2 of 3 tested animals from grades at 24, 48 and 72 hours after patch removal or, if reactions are delayed from grades on 3 consecutive days after the onset of skin reactions; or
- Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling; or
- In some cases where there is a pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above.

CATEGORY 3 MILD IRRITANT
- Mean value for erythema/eschar formation or oedema is greater than 1.5, but less than 2.3 in at least 2 of 3 tested animals from grades at 24, 48 and 72 hours after patch removal, or if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions (when not included in the irritant category above).

PRIMARY IRRITATION INDEX
- Primary Irritation Index was calculated by added together the scores for erythema and oedema obtained at 24, 48 and 72 hours after completion of the 4 hours exposure for all animals (18 values) and divided by 9 (number of test sites x 3 scoring intervals).
- This index was used to classify the test material according to the following scheme devised by Draize (1959):
Primary Irritation Index Classification:
0 - non-irritant
> 0 – 2 - mild irritant
> 2 – 5 - moderate irritant
> 5 – 8 - severe irritant

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritant / corrosive response data:
- At observation one, 24, 48, 72 hours, 1 and 2 weeks after patch removal, there was no observed clinical signs noted on the skin of the treated animals. However, orange-reddish staining was observed on the treated skin in all animals after dosing from Day 1 to Day 7 which were reversible by the end of the observation period.
- As no clinical signs were observed the study was terminated after the 2 weeks observation.
- The animals’ individual mean scores (considering readings at 24, 48 and 72 hours after patch removal) for erythema and oedema were 0.00, 0.00 and 0.00 respectively.
- The Primary Irritation Index (considering readings at 24, 48 and 72 hours after patch removal) was calculated as 0.00.
Other effects:
MORTALITY
- There was no mortality observed during the study.

BODY WEIGHTS
- There was no effect of treatment on body weight.

CLINICAL OBSERVATION
- General Daily Examination: There were no treatment-related clinical signs noted.

Applicant's summary and conclusion

Interpretation of results:
other: Not classified in accordance with EU criteria
Conclusions:
Under the conditions of this study, the test material does not require classification as a skin irritant.
Executive summary:

The skin irritation potential of the test material was investigated in accordance with the standardised guideline OECD 404, under GLP conditions.

An acute skin irritation study was performed with the test material in New Zealand White rabbits. Parameters monitored during this study included mortality, body weight measurements and clinical observations. The irritancy of the test material was evaluated according to the Draize method.

During the study, 0.5 g test material was applied to the skin of the experimental animals. The test material was applied as a single dose. Sufficient water to dampen the material was used to ensure good contact with the skin and an adhesive clear plastic patch was applied. The trunk was wrapped in clear plastic with medical tubing used to hold the patch in place. The untreated skin of each animal served as control. After 4 hours, the remaining test material was removed with water at body temperature and with Unguentum hydrophilicum nonionicum.

To assess skin irritation, animals were examined at 1, 24, 48, 72 hours, 1 and 2 weeks after the patch removal. Additional general examinations were performed daily.

There was no mortality or systemic clinical changes related to test material administration. There was no effect of treatment on body weight.

At observation one, 24, 48, 72 hours, 1 and 2 weeks after patch removal, there were no observed clinical signs noted on the skin of the treated animals. However, orange-reddish staining was observed on the treated skin in all animals after dosing from Day 1 to Day 7 which were reversible by the end of the observation period. As no clinical signs were observed the study was terminated after the 2 weeks observation.

The animals’ individual mean scores (considering readings at 24, 48 and 72 hours after patch removal) for erythema and oedema were 0.00, 0.00 and 0.00 respectively. The Primary Irritation Index (considering readings at 24, 48 and 72 hours after patch removal) was calculated as 0.00.

Under the conditions of this study, the test material does not require classification as a skin irritant.