[(2-chlorophenyl)methylene]malononitrile

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

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

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.

Reference 2

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

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 the study design:

see OECD 442D guidelinae and enclosed study plan

Positive control results:

Cinnamaldehyde EC1.5 7.92 and Imax 7.64

Key result

Run / experiment:

other: mean on 2 runs

Parameter:

other: IC70 is concentration in μM for which we obtained 70% cell viability

Value:

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

Run / experiment:

other: Linear EC1.5 μM and EC1.5 Lin/Log μM

Parameter:

other: EC1.5, value representing the concentration for which induction of luciferase activity is above 1.5 threshold was obtained

Value:

2.97

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.

Reference 3

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

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.

Reference 4

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

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.

Reference 5

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

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.