p-tert-butylcinnamaldehyde

Endpoint summary

Description of key information

The test material was determined to be irritating in an in vivo study with rabbits, in a study performed to a method similar to OECD 404.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

Not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

A valid study is available for the analogue substance 3-(4-tert-butylphenyl)propionaldehyde. The study was performed in line with good scientific principles in basic compliance with agreed protocols, with no or minor deviations from standard testing guidelines. The read-across is considered to be suitable based on the structural and “mechanistic action” similarities between the target substance (3-(4-tert-butylphenyl)acrylaldehyde) and source substance (3-(4-tert-butylphenyl)propionaldehyde) and their similar physico-chemical properties.

Qualifier:

equivalent or similar to guideline

Guideline:

other: FDA Standards

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

The test material was applied to both abraded and intact skin. A patch was not used to cover the test site to prevent ingestion. Removal of the test material was not reported, exposure was assumed to be 72 hours. Recovery of the animals was not evaluated.

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
New Zealand White rabbits were supplied by an accredited supplier.

- Age at study initiation:
Adult

- Weight at study initiation:
At the start of the study the animals were in the weight range of 2.5 - 3.0 kg

- Housing:
Not specified in the report

- Diet (e.g. ad libitum):
Not specified in the report

- Water (e.g. ad libitum):
Not specified in the report

- Acclimation period:
Not specified in the report

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
Not specified in the report

- Humidity (%):
Not specified in the report

- Air changes (per hr):
Not specified in the report

- Photoperiod (hrs dark / hrs light):
Not specified in the report

Type of coverage:

open

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Remarks:

undiluted test material

Controls:

yes

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):
0.2 mL

- Concentration (if solution):
Not applicable.

VEHICLE
- Amount(s) applied (volume or weight with unit):
Not applicable

- Concentration (if solution):
Not applicable.

- Lot/batch no. (if required):
Notapplicable

Duration of treatment / exposure:

72 hours

Observation period:

72 hours

Number of animals:

6

Details on study design:

TEST SITE
- Area of exposure:
On the day of the test a suitable test site was selected on the back of each rabbit.

- % coverage:
Not given in study report.

- Type of wrap if used:
Test material was brought into contact with separated skin areas left of the midline of the back.

REMOVAL OF TEST SUBSTANCE
- Washing (if done):
Not reported

- Time after start of exposure:
72 hours.


SCORING SYSTEM:
The resulting skin reactions were evaluated by the method of Draize (J. Pharm. Exptl. Therap. 82 (1944) 377-390) 24, 48, 72 and 96 hours after application.

Irritation parameter:

other: erythema/edema

Basis:

animal: 8803

Time point:

other: Mean score at 24 and 72 hours

Score:

2

Max. score:

8

Reversibility:

no data

Irritation parameter:

other: erythema/edema

Basis:

animal: 8804

Time point:

other: Mean at 24 and 72 hours

Score:

3

Max. score:

8

Reversibility:

no data

Irritation parameter:

other: Erythema/edema

Basis:

animal: 8805

Time point:

other: mean at 24 and 72 hours

Score:

3

Max. score:

8

Reversibility:

no data

Irritation parameter:

other: erythema/edema

Basis:

animal: 8806

Time point:

other: mean of 24 and 72 hours

Score:

2

Max. score:

8

Reversibility:

no data

Irritation parameter:

other: erythema/edema

Basis:

animal: 8807

Time point:

other: mean at 24 and 72 hours

Score:

3

Max. score:

8

Reversibility:

no data

Irritation parameter:

other: erythema/edema

Basis:

animal: 8808

Time point:

other: Mean at 24 and 72 hours

Score:

3

Max. score:

8

Reversibility:

no data

Irritant / corrosive response data:

Individual and average skin irritation scores are given in table 1. The test material caused severe skin irritation. Its dermal effects generally consisted of focal haemorrhages, slight to distinct ischemia and incrustation, and very slight edema.

ANALOGUE APPROACH JUSTIFICATION:
- See attached “Justification for read-across” document for full details.
- In summary, important considerations for the use of read-across for skin irritation are: i) 3-(4-tert-butylphenyl)acrylaldehyde (the target chemical) has similar predicted physico-chemical properties to those predicted and experimentally determined for 3-(4-tert-butylphenyl)propionaldehyde (the source substance), ii) there are structural similarities between the two chemicals and iii) the OECD QSAR Toolbox indicates that the two substances are expected to have similar interactions with biological receptors.
The information reported in this summary is included to demonstrate comparability between the source (3-(4-tert-butylphenyl)propionaldehyde) and target (3-(4-tert-butylphenyl)acrylaldehyde) substance.

Other effects:

None

TABLE 1 - INDIVIDUAL AND AVERAGE SKIN IRRITATION SCORES

Rabbit Number	Intact Skin		Rabbit Number	Abraded Skin
	24 hours	72 hours		24 hours	72 hours
	A                        B			A                        B
8803	4          -            1	2	8797	4          -            1	2
8804	4          -            1	3	8798	4          -            1	2
8805	4          -            1	3	8799	4          -            1	3
8806	4          -            1	2	8800	4          -            1	3
8807	4          -            1	3	8801	4          -            1	2
8808	4          -            1	3	8802	4          -            1	2
Average	5.0	2.7	Average	5.0	2.3

A = erythema

B = edema

The resulting skin reactions were evaluated by the method of Draize (J. Pharm. Exptl. Therap. 82 (1944) 377-390) 24, 48, 72 and 96 hours after application.

Interpretation of results:

Category 2 (irritant)

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

On the basis of the present results it can be concluded that undiluted test material is a severe primary skin irritant.

Executive summary:

The test material was examined in primary skin irritation using New Zealand White albino rabbits as the experimental animals.

Pure and undiluted test material caused severe skin irritation.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In the key study, the test material was examined in primary skin irritation using New Zealand White albino rabbits as the experimental animals. The test material was applied neat to the backs of the animals and evaluated for reactions over a 72 hour period. The study was performed to a method which was in basic compliance with OECD 404. Under the conditions of the test, pure and undiluted test material caused severe skin irritation. The study was performed to method equivalent to a recognised standardised guideline, the study was assigned a reliability score of 2 in line with the principles defined in Klimisch et al (1997) as the study was performed on a structural analogue of the substance to be registered. Due to the structural and mechanistic similarities between the two substances, it was considered appropriate to use data from the source substance to represent the target substance.

 

In the supporting study, the skin irritation potential of the test material was determined using the EPISKIN^TM reconstructed human epidermis model in accordance with OECD 439 and EU Method B.46. The study was performed under GLP conditions. The tissues were treated for a period of 15 minutes which was followed by a post-exposure incubation period of 42 hours. Cytotoxicity of the test material in the reconstructed human epidermal cultures was evaluated using the colourimetric MTT reduction assay. Cell viability was measured by enzymatic reduction of the yellow MTT tetrazolium salt (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) to a blue formazan salt (within the mitochondria of viable cells) in the test item treated tissues relative to the negative controls. Where necessary, the concentration of the inflammatory mediator IL-1α in the culture medium retained following the 42 -Hour post-exposure incubation period was also determined for borderline non-irritants based upon the MTT reduction endpoint. This complimentary end-point was to be used to either confirm a non-irritant result or will be used to override the non-irritant result

The relative mean viability of the test item treated tissues was 19.5 % after the 15-minute exposure period. The test material was therefore classified as irritant under the conditions of the test.

The study was performed in compliance with GLP and in accordance with recognised standardised guidelines; the study was assigned a reliability score of 2 in line with the principles defined in Klimisch et al (1997) as the study was performed on a structural analogue of the substance to be registered. Due to the structural and mechanistic similarities between the two substances, it was considered appropriate to use data from the source substance to represent the target substance.

Justification for selection of skin irritation / corrosion endpoint:
Two valid studies were available on a suitable structural analogue. The key study was selected on the basis that it is an in vivo study and therefore took precedence over the available in vitro study. Furthermore, the in vivo study is capable of detecting both skin irritation and corrosion, where the in vitro study is specifically for evaluating irritation. The results of the in vitro study were in agreement with the findings of the in vivo study. The key study was performed to a method equivalent to a standardised guideline. Due to the structural and mechanistic similarities between the target and source substance, it was considered appropriate to use a read-across approach to address the skin irritation endpoint.

Effects on skin irritation/corrosion: irritating

Justification for classification or non-classification

On the basis that the results from the test material used in the in vivo skin irritation study in rabbits and the validated in vitro study (reconstructed human epidermis model), 3-(4-tert-butylphenyl)propionaldehyde, are being used to the support the registration of 3-(4-tert-butylphenyl)acrylaldehyde using a read-across approach, 3-(4-tert-butylphenyl)acrylaldehyde should therefore

also be considered as a skin irritant. In accordance with Regulation 1272/2008 and Directive 67/548/EEC, the substance should be classified as H315 Causes skin irritation (Category 2) with the signal word 'Warning' and Xi R38 Irritating to skin, respectively.