2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride

Endpoint summary

Description of key information

The skin sensitization potential of target chemical 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) was assessedin various experimental studies which were conducted on guinea pigs for target chemical2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) andits structurally similar read across substances3–diethylaminophenol (CAS No: 91-68-9)and N,N-diethylaniline (CAS No: 91-66-7). The predicted data usingQSAR toolboxhas also been compared with the experimental data.Based on the available data for the target and read across substances and applying the weight of evidence approach, it can be concluded that chemical 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) is unable to cause skin sensitization and thus can be considered as not sensitizing. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation

Remarks:

in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is from OECD QSAR toolbox version 3.4 and QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.4

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

not specified

Specific details on test material used for the study:

Name - 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride
Mol. formula: C24H30Cl2N2
Molecular Weight - 417.421 g/mole
InChI -1S/C24H30ClN2.ClH/c1-6-27(16-15-25)20-13-11-19(18(2)17-20)12-14-23-24(3,4)21-9-7-8-10-22(21)26(23)5;/h7-14,17H,6,15-16H2,1-5H3;1H/q+1;/p-1
SMILES:CCN(CCCl)c1ccc(C=CC2C(C)(C)c3ccccc3N{+}=2(C).Cl{-})c(C)c1

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

male/female

Details on test animals and environmental conditions:

No data available

Route:

intradermal and epicutaneous

Vehicle:

not specified

Concentration / amount:

No data available

Day(s)/duration:

No data available

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

not specified

Concentration / amount:

No data available

Day(s)/duration:

72 hours

Adequacy of challenge:

not specified

No. of animals per dose:

20

Details on study design:

No data available

Challenge controls:

No data available

Reading:

1st reading

Hours after challenge:

72

Group:

test chemical

Dose level:

No data available

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

No skin sensitization was observed.

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

No skin sensitization was observed.

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes highest mode value from the 7 nearest neighbours
Domain  logical expression:Result: In Domain

((((((((("a" or "b" or "c" )  and ("d" and ( not "e") )  )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and ("r" and "s" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> Alkylation, direct acting epoxides and related after cyclization OR SN2 >> Alkylation, direct acting epoxides and related after cyclization >> Nitrogen Mustards by DNA binding by OASIS v.1.3 ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine AND SN2 AND SN2 >> Episulfonium Ion Formation AND SN2 >> Episulfonium Ion Formation >> Mustards by DNA binding by OECD

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN2 AND SN2 >> Nucleophilic substitution at sp3 carbon atom AND SN2 >> Nucleophilic substitution at sp3 carbon atom >> Alkyl halides  by Protein binding by OASIS v1.3

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CNHal Lipid Solubility < 4 g/kg AND (!Undefined)Group CNHal Lipid Solubility < 400 g/kg AND Group All Melting Point > 200 C AND Group CNHal Aqueous Solubility < 0.1 g/L AND Group CNHal Molecular Weight > 370 g/mol AND Group CNHal Molecular Weight > 380 g/mol by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as (!Undefined)Group C Surface Tension > 62 mN/m OR Exclusion rules not met OR Group All log Kow < -3.1 OR Group All log Kow > 9 OR Group C Melting Point > 55 C OR Group C Vapour Pressure < 0.0001 Pa OR Group CHal log Kow > 4.5 OR Group CHal Melting Point > 65 C OR Group CHal Molecular Weight > 280 g/mol OR Group CHal Molecular Weight > 370 g/mol OR Group CNHal log Kow > 3.8 by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Aldehydes OR Aliphatic alpha-halogen-esters OR Aliphatic halogenated saturated acids OR Allyl halides,sulfonates OR Halogenated alkanes  OR Ketones OR Quaternary organic ammonium compounds by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Chlorphentermine (Hepatotoxicity) Alert OR Halobenzenes (Hepatotoxicity) Rank A OR Halobenzenes (Renal toxicity) Rank A OR Halogenated aliphatic compounds (Hepatotoxicity) Rank A OR Organophosphates (Neurotoxicity) Rank A by Repeated dose (HESS)

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as SN2 AND SN2 >> Nucleophilic substitution at sp3 carbon atom AND SN2 >> Nucleophilic substitution at sp3 carbon atom >> Alkyl halides  by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as SN2 >> Nucleophilic substitution at sp3 carbon atom >> alpha-Activated haloalkanes  by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as SN2 AND SN2 >> Nucleophilic substitution at sp3 carbon atom AND SN2 >> Nucleophilic substitution at sp3 carbon atom >> Alkyl halides  by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as SN2 >> Ring opening SN2 reaction by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as SN2 AND SN2 >> Nucleophilic substitution at sp3 carbon atom AND SN2 >> Nucleophilic substitution at sp3 carbon atom >> Alkyl halides  by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as SN2 >> Nucleophilic substitution on benzilyc carbon atom by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as No alert found by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as H-acceptor-path3-H-acceptor by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.107

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.48

Interpretation of results:

other: Not sensitizing

Conclusions:

The chemical 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) was estimated to be not sensitizing to the Dunkin-Hartley guinea pigs. Based on the estimated result 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs.

Executive summary:

The skin sensitization potential of 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) was estimated using OECD QSAR toolbox version 3.4 with log Pow as the primary descriptor. The chemical 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) was estimated to be not sensitizing to the Dunkin-Hartley guinea pigs. Based on the estimated result 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs and can be classified under the category ˋ Not Classified’ as per CLP regulation. 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Various studieshas been investigated for the test chemical2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) to observe the potential for skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pigs for target chemical2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) and its structurally similar read across substances 3–diethylaminophenol (CAS No: 91-68-9)andN,N-diethylaniline (CAS No: 91-66-7).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

 

The skin sensitization potential of 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. The substance 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) failed to induce skin sanitization effects on guinea pig skin and hence is considered to be not sensitizing to the skin.

 

 

The EUROPEAN COMMISSION – European Chemicals Bureau (2000) performed skin sensitization study of structurally similar read across substance 3–diethylaminophenol (CAS No: 91-68-9) in guinea pigs to observed its sensitizing potential. The guinea pigs did not produce any sensitization potential .Thus 3–diethylaminophenol was considered to be not sensitizing to the guinea pigs.

 

 

The above results were further supported by the skin sensitization study carried out by the U.S. Environmental Protection Agency Hazard Characterization Document (2009) in guinea pigs for structurally similar read across substance N,N-diethylaniline (CAS No: 91-66-7).In this study, the test animals were treated dermally with 10% solution of N, N-diethylaniline during induction. After induction, treated animals were dermally exposed to challenge concentration of 1 or 2% solutions of N, N-diethylaniline. Since the chemical did not produce any cutaneous reaction at challenge concentrations, the test chemical N, N-Diethylaniline (CAS No: 91-66-7) was considered as not sensitizing to guinea pigs.

 

Based on the available data for the target 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) and its structurally similar read across substances3–diethylaminophenol (CAS No: 91-68-9)andN,N-diethylaniline (CAS No: 91-66-7),it can be concluded thatchemical 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) is unable to cause skin sensitization and considered as non-skin sensitizer.

 

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The skin sensitization potential of test substance 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) and its structurally similar read across substances3–diethylaminophenol (CAS No: 91-68-9)and N,N-diethylaniline (CAS No: 91-66-7) were observed in various studies. From the results obtained from these studies it is concluded that the chemical 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 6441-82-3) is not likely to cause skin sensitization and hence can be classified as non-skin sensitizer.