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Description of key information

Key value for chemical safety assessment

Skin sensitisation

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Endpoint:
skin sensitisation, other
Remarks:
in silico
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
Not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
Battery prediction, CASE Ultra, and LeadScope are ouside applicatibility domain, Sci QSAR inside applicatibility domain
Justification for type of information:
See enclosed study report and QMRF
Qualifier:
according to
Guideline:
other:
Version / remarks:
ECHA Guidance on QSARs R.6
Principles of method if other than guideline:
Danish QSAR Database provides a battery of the following three QSAR prediction models for a substance with a valid CAS number– SciQSAR, LeadScope and CASE Ultra
GLP compliance:
not specified
Justification for non-LLNA method:
Alternative study to in-vivo as the first intention, in accordance with REACH annex VII and the Adverse Outcome Pathway (AOP) for Skin Sensitisation Initiated by Covalent Binding to Proteins (OECD, 2014)
Specific details on test material used for the study:
SMILE (2-chlorobenzylidene)malononitrile : Clc1ccccc1C=C(C#N)C#N
SMILE metabolite 1 : OC1C=C(Cl)C(=CC1O)C=C(C#N)C#N
SMILE metabolite 2 : CC1CCC(CC=1)C1(C)CCC(O1)C(C)(C)O
SMILE metabolite 3 : OC1C=CC(Cl)=C(C=C(C#N)C#N)C1O
SMILE metabolite 4 : ClC1C=CC2OC2C=1C=C(C#N)C#N
Details on test animals and environmental conditions:
Not specified
Key result
Remarks on result:
no indication of skin sensitisation
Remarks:
QSAR prediction
Other effects / acceptance of results:
Not specified
Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
Based on one out of three QSAR models incoroporated into Danish QSAR Database (SciQSAR), (2-chlorobenzylidene)malononitrile was predicted as non-sensitiser. The battery prediction from this tool however was inconclusive.
Executive summary:

Based on one out of three QSAR models incoroporated into Danish QSAR Database (SciQSAR), (2-chlorobenzylidene)malononitrile was predicted as non-sensitiser. The battery prediction from this tool however was inconclusive.

Endpoint:
skin sensitisation: in vitro
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 442D (In Vitro Skin Sensitisation: ARE-Nrf2 Luciferase Test Method)
Version / remarks:
This study is carried out according the OECD Guideline 442D dated February, 04th, 2015, the ECVAM DBALM protocol 155: KeratinoSensTM, C(81)30 OECD Guidelines and the article annex II to article D-523-8 of the French Environment
Deviations:
not specified
GLP compliance:
yes
Remarks:
not mentioned on study reports but on IDEAtest group website www.groupeideatests.com
Type of study:
activation of keratinocytes
Justification for non-LLNA method:
Alternative study to in-vivo as the first intention, in accordance with REACH annex VII and the Adverse Outcome Pathway (AOP) for Skin Sensitisation Initiated by Covalent Binding to Proteins (OECD, 2014)
Details on study design:
see OECD 442D guidelinae and enclosed study plan
Positive control results:
Cinnamaldehyde EC1.5 7.92 and Imax 7.64
Key result
Parameter:
other: IC70 is concentration in μM for which we obtained 70% cell viability
Run / experiment:
mean on 2 runs
Value:
ca. 23.31
Vehicle controls validity:
not examined
Remarks:
control solvent as negative control
Negative controls validity:
valid
Remarks:
control solvent
Positive controls validity:
valid
Remarks:
Cinnamaldehyde Imax is 7.64
Remarks on result:
positive indication of skin sensitisation
Key result
Parameter:
other: EC1.5, value representing the concentration for which induction of luciferase activity is above 1.5 threshold was obtained
Run / experiment:
Linear EC1.5 μM and EC1.5 Lin/Log μM
Value:
>= 2.97 - <= 3.1
Vehicle controls validity:
not examined
Remarks:
constrol solvent as negative control
Negative controls validity:
valid
Remarks:
control solvent
Positive controls validity:
valid
Remarks:
cinnamaldehyde EC1.5 is 7.92 μM
Remarks on result:
positive indication of skin sensitisation
Other effects / acceptance of results:
Since all validity criteria are met, study is considered as valid.
Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
In both repetition, Imax is higher than 1.5, the EC1.5 is lower than 1000 μM and, at the EC1.5 concentration, viability is higher than 70%.

Under the retained experimental conditions, the test item may be classified as sensitizer.
Executive summary:

In vitro sensitization KeratinoSens™ assay OECD 442D is performed with Keratinocytes based on the signaling pathway Keap1-Nrf2-ARE coupled to the luciferase reporter gene. Under the retained experimental conditions, the test item may be classified as sensitizer.

Endpoint:
skin sensitisation, other
Remarks:
in silico
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
Not specified
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
See enclosed QMRF and study report
Qualifier:
according to
Guideline:
other:
Version / remarks:
EACH Guidance on QSARs R.6
Principles of method if other than guideline:
Not specified
GLP compliance:
not specified
Justification for non-LLNA method:
Alternative study to in-vivo as the first intention, in accordance with REACH annex VII and the Adverse Outcome Pathway (AOP) for Skin Sensitisation Initiated by Covalent Binding to Proteins (OECD, 2014)
Specific details on test material used for the study:
SMILE (2-chlorobenzylidene)malononitrile : Clc1ccccc1C=C(C#N)C#N
SMILE metabolite 1 : OC1C=C(Cl)C(=CC1O)C=C(C#N)C#N
SMILE metabolite 2 : CC1CCC(CC=1)C1(C)CCC(O1)C(C)(C)O
SMILE metabolite 3 : OC1C=CC(Cl)=C(C=C(C#N)C#N)C1O
SMILE metabolite 4 : ClC1C=CC2OC2C=1C=C(C#N)C#N
Details on test animals and environmental conditions:
Not specified
Positive control results:
Not required
Key result
Remarks on result:
positive indication of skin sensitisation
Remarks:
QSAR prediction
Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
(2-chlorobenzylidene)malononitrile and all its four potential skin metabolites were associated with multiple skin sensitisation alerts including Michael addition, SN2 and Mono-halo arenes. Two of the metabolites were also associated with a GHS category 1B for skin sensitisation. Based on the profiling results, (2-chlorobenzylidene)malononitrile will be classified as skin sensitiser.
Executive summary:

In a QSAR toolbox prediction, (2-chlorobenzylidene)malononitrile and all its four potential skin metabolites were associated with multiple skin sensitisation alerts including Michael addition, SN2 and Mono-halo arenes. Two of the metabolites were also associated with a GHS category 1B for skin sensitisation. Based on the profiling results, (2-chlorobenzylidene)malononitrile will be classified as skin sensitiser.

Endpoint:
skin sensitisation, other
Remarks:
in silico
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
Not specified
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
See enclosed QMRF and study report
Qualifier:
according to
Guideline:
other:
Version / remarks:
ECHA Guidance on QSARs R.6
Principles of method if other than guideline:
Two decision trees relevant to Skin Sensitisation endpoint incorporated into the Toxtree v2.6.13.
GLP compliance:
not specified
Justification for non-LLNA method:
Alternative study to in-vivo as the first intention, in accordance with REACH annex VII and the Adverse Outcome Pathway (AOP) for Skin Sensitisation Initiated by Covalent Binding to Proteins (OECD, 2014)
Specific details on test material used for the study:
SMILE (2-chlorobenzylidene)malononitrile : Clc1ccccc1C=C(C#N)C#N
SMILE metabolite 1 : OC1C=C(Cl)C(=CC1O)C=C(C#N)C#N
SMILE metabolite 2 : CC1CCC(CC=1)C1(C)CCC(O1)C(C)(C)O
SMILE metabolite 3 : OC1C=CC(Cl)=C(C=C(C#N)C#N)C1O
SMILE metabolite 4 : ClC1C=CC2OC2C=1C=C(C#N)C#N
Details on test animals and environmental conditions:
Not specified
Key result
Remarks on result:
positive indication of skin sensitisation
Remarks:
QSAR prediction
Other effects / acceptance of results:
Not specified
Cellular proliferation data / Observations:
Not specified
Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
Based on the triggered structural alerts for protein binding and skin sensitisation using Toxtree v2.6.13, (2-chlorobenzylidene) malononitrile and all its four potential skin metabolites were classified as skin sensitisers.
Executive summary:

In a QSAR Toxtree prediction,based on the triggered structural alerts for protein binding and skin sensitisation using Toxtree v2.6.13, (2-chlorobenzylidene) malononitrile and all its four potential skin metabolites were classified as skin sensitisers.

Endpoint:
skin sensitisation, other
Remarks:
in silico
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
Not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
low reliability indicating that one or multiple criteria considered with this tool to evaluate the reliability strength were not fulfilled
Justification for type of information:
See enclosed QMRF and study report
Qualifier:
according to
Guideline:
other:
Version / remarks:
ECHA Guidance on QSARs R.6
Principles of method if other than guideline:
Skin Sensitization model (CAESAR) 2.1.6 incorporated into VEGA 1.1.4.
GLP compliance:
not specified
Justification for non-LLNA method:
Alternative study to in-vivo as the first intention, in accordance with REACH annex VII and the Adverse Outcome Pathway (AOP) for Skin Sensitisation Initiated by Covalent Binding to Proteins (OECD, 2014)
Specific details on test material used for the study:
SMILE (2-chlorobenzylidene)malononitrile : Clc1ccccc1C=C(C#N)C#N
SMILE metabolite 1 : OC1C=C(Cl)C(=CC1O)C=C(C#N)C#N
SMILE metabolite 2 : CC1CCC(CC=1)C1(C)CCC(O1)C(C)(C)O
SMILE metabolite 3 : OC1C=CC(Cl)=C(C=C(C#N)C#N)C1O
SMILE metabolite 4 : ClC1C=CC2OC2C=1C=C(C#N)C#N
Details on test animals and environmental conditions:
Not specified
Positive control results:
Not required
Key result
Remarks on result:
positive indication of skin sensitisation
Remarks:
QSAR prediction
Other effects / acceptance of results:
Not specified
Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
QSAR predictions from VEGA 1.1.4 suggests that (2-chlorobenzylidene)malononitrile and its four potential skin metabolites are skin sensitisers. However, the reliability strength in results was low for all of them.
Executive summary:

QSAR predictions from VEGA 1.1.4 suggests that (2-chlorobenzylidene)malononitrile and its four potential skin metabolites are skin sensitisers. However, the reliability strength in results was low for all of them.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)

Justification for classification or non-classification

Few cases of "reactive airways dysfunction syndrome" (RADS) are reported in litterature, neverthelessconfirmation is not in line with the one recommended by ecetoc (WR 33 report, 2016) for distinguishing skin sensitizers from respiratory ones. Therefore, based on this classification methodology, no classification is retained.