Registration Dossier

Administrative data

Description of key information

Skin irritation

Read-across, key, rabbit, OECD 404, GLP: positive, irritant to the skin

Eye irritation

Read-across, key, rabbit, OECD 405, GLP: negative, no eye irritant

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH

The basis for this read-across is the “Read-Across Assessment Framework” (RAAF) (ECHA 2017). The analogue approach is applied. The read-across hypothesis is that the target and the source substances have similar (eco)toxicological and fate properties as a result of structural similarity. According to the RAAF this approach is covered by scenario 2: “Different compounds have the same type of effect(s)”.
“This scenario covers the analogue approach for which the read-across hypothesis is based on different compounds with qualitatively similar properties. For the REACH information requirement under consideration, the property investigated in a study conducted with one source substance is used to predict properties that would be observed in a study with the target substance if it were to be conducted. Qualitatively similar properties or absence of effect are predicted. The predicted property may be similar or based on a worst-case approach” (ECHA 2017) (for details see read-across statement in section 13).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

The target and the source substances are waxy solids. Their physical and chemical properties are in the same range. The target and the source substances are of highest purity. Thus, there are no impurities to consider in this read-across approach (for details see read-across statement in section 13).

3. ANALOGUE APPROACH JUSTIFICATION

Read-across is intended for the endpoints skin and eye irritation and skin sensitisation using data on the source substance. This is based on a similar toxicokinetic pattern and congruent results in toxicological studies. In addition, no toxicological mode of action is indicated by a profiling with the OECD QSAR Toolbox v4.3 (for details see read-across statement in section 13).
The source substance was tested for skin irritation in an Acute Dermal Irritation / Corrosion test according to OECD Guideline 404 following GLP. 0.5 g of the test material was mixed with some drops of liquid paraffin to ensure good contact with the skin. Afterwards the test material was spread onto 6 cm2 patches and applied to the intact skin of previously shaven rabbits 4 hours under semiocclusive conditions. The study was started as an initial test with one animal. This animal showed signs of irritation (well defined erythema, edema, brittle skin and scales) and no more animals were treated. The first examination of the treated skin sites followed 1 hour after removal of the patches. Thereafter, examinations were performed daily for further 21 days. No signs of pain were observed after administration. Under the conditions of this study erythema (scores 1 to 3) were observed from day 1 up to day 5 and edema (scores 1 to 4) were observed from day 2 up to day 9 of the study. Furthermore, brittle skin from day 6 up to day 9 and small scales from day 10 up to day 17 were seen at the site of application. From day 18 up to the end of the experimental part increased growth of hair was observed. As a conclusion, the source substance is considered as skin irritant (EU GHS Cat. 2).
This study is also valid for the target substance based on the given justification. Therefore, the target substance is also considered to be skin irritant (EU GHS Cat. 2) (for details see read-across statement in section 13).

4. DATA MATRIX
for details see read-across statement in section 13
Reason / purpose:
read-across source
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2.33
Max. score:
3
Reversibility:
fully reversible within: 9 days
Remarks on result:
probability of moderate irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.67
Max. score:
2
Reversibility:
fully reversible within: 6 days
Remarks on result:
probability of weak irritation
Irritant / corrosive response data:
After a single application to the intact dorsal skin of a rabbit, for 4 hours under semiocclusive conditions, erythema (scores 1 to 4) were observed from day 1 up to day 9 and edema (scores 1 to 2) were observed from day 2 up to day 5 of the study. Furthermore brittle skin from day 6 up to day 9 and small scales from day 10 up to day 17 of the study were seen at the site of application. From day 18 up to the end of the experimental part increased growth of hair was observed. The one-to-one read across is based on chemical similarity, almost identical phys chem profile and comparable response in biological assays. Therefore the same result can be applied to the target substance.
Other effects:
None

Symptoms

No signs of clinical toxicity were detected.

Mortality

The animal survived the observation period.

Body weight

Body weight development of the treated rabbit was inconspicuous.

Interpretation of results:
other: Category 2 (irritant) based on EU GHS criteria
Conclusions:
According to Regulation (EC) No 1272/2008 the test material should be regarded as an irritant to the skin. The read-across analogue approach is based on similarity in chemical structure, physical-chemical properties, toxicokinetic behaviour and toxicological study results. As a conclusion, it is scientifically justified to fill toxicological data gaps for the target substance with data on the respective source substance. Therefore the same result can be applied to the target substance.
Executive summary:

The source substance was tested for skin irritation in an Acute Dermal Irritation / Corrosion test according to OECD Guideline 404 following GLP.

Purpose

The purpose of this assay was to identify the skin irritation/corrosion potential of the test material when applied to the intact skin of previously shaven rabbits for a 4 hours period under semiocclusive conditions.

This study should provide a rational basis for risk assessment to the irritating potential of the test item in man.

Study Design

To test for primary skin irritation, 0.5 g of the test material was mixed with some drops of liquid paraffin to ensure good contact with the skin. Afterwards the test material was spread onto 6 cm2 patches and applied to the intact skin of previously shaven rabbits for a 4 hours period under semiocclusive conditions. The study was started as an initial test with one animal. This animal showed signs of irritation (well defined erythema, edema, brittle skin, and scales) and no more animals were treated. The first examination of the treated skin sites followed 1 hour after removal of the patches. Thereafter, examinations were performed daily for further 21 days.

Results

Only one rabbit was used for the study. No signs of pain were observed after administration. Under the conditions of the present study erythema (scores 1 to 3) were observed from day 1 up to day 5 and edema (scores 1 to 4) were observed from day 2 up to day 9 of the study. Furthermore brittle skin from day 6 up to day 9 and small scales from day 10 up to day 17 of the study were seen at the site of application. From day 18 up to the end of the experimental part increased growth of hair was observed.

Conclusion

The test material caused irritative effects at the site of application. According to Regulation (EC) No 1272/2008 the test material should be regarded as an irritant to the skin. The read-across analogue approach is based on similarity in chemical structure, physical-chemical properties, toxicokinetic behaviour and toxicological study results. As a conclusion, it is scientifically justified to fill toxicological data gaps for the target substance with data on the respective source substance. Therefore the same result can be applied to the target substance.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH

The basis for this read-across is the “Read-Across Assessment Framework” (RAAF) (ECHA 2017). The analogue approach is applied. The read-across hypothesis is that the target and the source substances have similar (eco)toxicological and fate properties as a result of structural similarity. According to the RAAF this approach is covered by scenario 2: “Different compounds have the same type of effect(s)”.
“This scenario covers the analogue approach for which the read-across hypothesis is based on different compounds with qualitatively similar properties. For the REACH information requirement under consideration, the property investigated in a study conducted with one source substance is used to predict properties that would be observed in a study with the target substance if it were to be conducted. Qualitatively similar properties or absence of effect are predicted. The predicted property may be similar or based on a worst-case approach” (ECHA 2017) (for details see read-across statement in section 13).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

The target and the source substances are waxy solids. Their physical and chemical properties are in the same range. The target and the source substances are of highest purity. Thus, there are no impurities to consider in this read-across approach (for details see read-across statement in section 13).

3. ANALOGUE APPROACH JUSTIFICATION

Read-across is intended for the endpoints skin and eye irritation and skin sensitisation using data on the source substance. This is based on a similar toxicokinetic pattern and congruent results in toxicological studies. In addition, no toxicological mode of action is indicated by a profiling with the OECD QSAR Toolbox v4.3 (for details see read-across statement in section 13).
The source substance was tested for eye irritation in an Acute Eye Irritation / Corrosion test according to OECD Guideline 405 following GLP. 0.1 g of the test material was instilled into the conjunctival sac of the left eye of 3 female animals. The right eye remained untreated and served as control. After instillation, the eyelids were closed for 30 seconds. No signs of irritation were observed at the cornea or iris. 1 hour and 24 hours after treatment, the conjunctivae showed redness (score 1) in 2 animals. Furthermore, discharge (score 1) was seen 1 hour after treatment. Thereafter no signs of irritation were observed. The untreated eyes were unchanged. As a conclusion of the study the source substance is considered to be not eye irritating.
This study is also valid for the target substance based on the given justification. Therefore, the target substance is also considered to be not eye irritant.

4. DATA MATRIX
for details see read-across statement in section 13
Reason / purpose:
read-across source
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: no effects
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: no effects
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
3
Reversibility:
other: no effects
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: no effect
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No signs of irritation were observed at the cornea or iris. All animals showed redness (score 1) and discharge (score 1) one hour after instillation of the test material. No abnormalities were detected in the untreated eyes.
Other effects:
None.
All animals survived the observation period. Body weight development of the treated rabbits was inconspicuous.
No signs of clinical toxicity were detected.

Pretests

Prior to testing, the pH of the test material was determined with pH-test strips. The pH was found to be about 7.

The test material was screened for its irritating potential using the hen's egg test on the chorioallantoic membrane (HET-CAM) as described below.

Fertile hens eggs, on day 10 of incubation, provided the test system. The egg shell was entered above the air cell by a dentist's rotary and then pared off. The shell with attached outer membrane and inner egg membrane was carefully opened. After the membrane had been moistened with isotonic sodium chloride solution, it was removed to expose the chorioallantoic membrane (CAM) of the fertilized egg, which lies immediately below. The CAM of fertilized and incubated hens eggs provides a suitable model for membranes with an intact and functional vascular system. The CAM has no nerve fibers in the early stages of development and is, therefore, regarded as being insensitive to pain.

In this model the cumulative irritation score of the test item was 0.00, indicating no irritant potential.

Interpretation of results:
other: EU GHS criteria not met
Conclusions:
No eye irritating potential could be detected, thus the test material should not be classified as eye irritant according to Regulation (EC) No 1272/2008.The read-across analogue approach is based on similarity in chemical structure, physical-chemical properties, toxicokinetic behaviour and toxicological study results. As a conclusion, it is scientifically justified to fill toxicological data gaps for the target substance with data on the respective source substance. Therefore the same result can be applied to the target substance.
Executive summary:

The source substance was tested for eye irritation in an Acute Eye Irritation / Corrosion test according to OECD Guideline 405 following GLP.

Purpose

The purpose of this primary eye irritation assay was to provide information on possible health hazards in case of acute eye contact with a test material and serve as a rational basis for risk assessment to the eye irritating potential of the test item in man.

Study Design

To test for eye irritation a test according to the OECD-Guidelines for Testing of Chemicals No. 405, the annex to Directive 92/69 EEC, and the recommendations of DRAIZE (1959) was performed.

Results

No signs of irritation were observed at the cornea or iris. One hour and 24 hours after treatment, the conjunctivae showed redness (score 1) in two animals. Furthermore, discharge (score 1) was seen one hour after treatment. Thereafter no signs of irritation were observed. The untreated eyes were unchanged.

Conclusion

No eye irritating potential could be detected, thus the test material should not be classified as eye irritant according to Regulation (EC) No 1272/2008. The read-across analogue approach is based on similarity in chemical structure, physical-chemical properties, toxicokinetic behaviour and toxicological study results. As a conclusion, it is scientifically justified to fill toxicological data gaps for the target substance with data on the respective source substance.Therefore the same result can be applied to the target substance.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

Read-across, Acute Dermal Irritation / Corrosion test, OECD 404

The source substance was tested for skin irritation in an Acute Dermal Irritation / Corrosion test according to OECD Guideline 404 following GLP.

Purpose

The purpose of this assay was to identify the skin irritation/corrosion potential of the test material when applied to the intact skin of previously shaven rabbits for a 4 hours period under semiocclusive conditions.

This study should provide a rational basis for risk assessment to the irritating potential of the test item in man.

Study Design

To test for primary skin irritation, 0.5 g of the test material was mixed with some drops of liquid paraffin to ensure good contact with the skin. Afterwards the test material was spread onto 6 cm2 patches and applied to the intact skin of previously shaven rabbits for a 4 hours period under semiocclusive conditions. The study was started as an initial test with one animal. This animal showed signs of irritation (well defined erythema, edema, brittle skin, and scales) and no more animals were treated. The first examination of the treated skin sites followed 1 hour after removal of the patches. Thereafter, examinations were performed daily for further 21 days.

Results

Only one rabbit was used for the study. No signs of pain were observed after administration. Under the conditions of the present study erythema (scores 1 to 3) were observed from day 1 up to day 5 and edema (scores 1 to 4) were observed from day 2 up to day 9 of the study. Furthermore brittle skin from day 6 up to day 9 and small scales from day 10 up to day 17 of the study were seen at the site of application. From day 18 up to the end of the experimental part increased growth of hair was observed.

Conclusion

The test material caused irritative effects at the site of application. According to Regulation (EC) No 1272/2008 the test material should be regarded as an irritant to the skin. The read-across analogue approach is based on similarity in chemical structure, physical-chemical properties, toxicokinetic behaviour and toxicological study results. As a conclusion, it is scientifically justified to fill toxicological data gaps for the target substance with data on the respective source substance. Therefore the same result can be applied to the target substance.

Eye irritation

Acute Eye Irritation / Corrosion, OECD 405

The source substance was tested for eye irritation in an Acute Eye Irritation / Corrosion test according to OECD Guideline 405 following GLP.

Purpose

The purpose of this primary eye irritation assay was to provide information on possible health hazards in case of acute eye contact with a test material and serve as a rational basis for risk assessment to the eye irritating potential of the test item in man.

Study Design

To test for eye irritation a test according to the OECD-Guidelines for Testing of Chemicals No. 405, the annex to Directive 92/69 EEC, and the recommendations of DRAIZE (1959) was performed.

Results

No signs of irritation were observed at the cornea or iris. One hour and 24 hours after treatment, the conjunctivae showed redness (score 1) in two animals. Furthermore, discharge (score 1) was seen one hour after treatment. Thereafter no signs of irritation were observed. The untreated eyes were unchanged.

Conclusion

No eye irritating potential could be detected, thus the test material should not be classified as eye irritant according to Regulation (EC) No 1272/2008. The read-across analogue approach is based on similarity in chemical structure, physical-chemical properties, toxicokinetic behaviour and toxicological study results. As a conclusion, it is scientifically justified to fill toxicological data gaps for the target substance with data on the respective source substance. Therefore the same result can be applied to the target substance.

Justification for classification or non-classification

Based on the results of the read-across key study for in vivo eye irritation, no classification for eye irritation is triggered in accordance with Regulation (EC) No 1272/2008. Based on the results of the key study for in vivo skin irritation, classification as skin irritant (Cat. 2, H315) is triggered in accordance with Regulation (EC) No 1272/2008.