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Administrative data

Description of key information

Acute oral toxicity: 

Acute oral toxicity dose (LD50) of 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride was predicted based on OECD QSAR toolbox 3443mg/kg bw and different studies available on structurally similar read across substance 2-[2-[4-[(2-chloroethyl)methylamino]phenyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 3648-36-0) 2260 mg/kg bw and for the closely related read across substance 2,2-Dichloro-1-(3-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethanone (CAS no: 98730-04-2) 5000 mg/kg bw. All these studies concluded that the LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride can be classified as category V of acute oral toxicity.

Acute Inhalation toxicity: 

Acute Inhalation toxicity dose (LC50) of 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride was predicted based on OECD QSAR toolbox 22.9 mg/L air, and different studies available for the closely related read across substance Bromochloromethane (CAS no: 74-97-5) 12030 mg/m3 and Tris(2-chloro-1-methylethyl) phosphate (CAS no: 13674-84-5) >4600 mg/m3. All these studies concluded that the LC50 value is greater than 5 mg/L air. Thus, comparing this value with the criteria of CLP regulation, 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride can be classified as category V of acute inhalation toxicity.

Acute Dermal toxicity: 

Acute Dermal toxicity dose (LD50) for 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride was predicted based on OECD QSAR toolbox 4242 mg/kg bwand differentstudies available on closely related read across substance3-Chloropropyl)triethoxysilane (CAS No. 5089-70-3) >2000 mg/kg bw and Tris(2-chloro-1-methylethyl) phosphate (13674-84-5) >2000 mg/kg bw. All these studies concluded that the LD50 value is>2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride can be classified as category V of acute dermal toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
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 predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: estimated
Principles of method if other than guideline:
Prediction is done using QSAR Toolbox version 3.3
GLP compliance:
not specified
Test type:
other: not specified
Limit test:
no
Test material information:
Composition 1
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:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
not specified
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
not specified
Doses:
3443 mg/kg
No. of animals per sex per dose:
not specified
Control animals:
not specified
Details on study design:
not specified
Statistics:
not specified
Preliminary study:
not specified
Sex:
female
Dose descriptor:
LD50
Effect level:
3 443 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 50% mortality observed
Mortality:
not specified
Clinical signs:
not specified
Body weight:
not specified
Gross pathology:
not specified
Other findings:
not specified

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 5 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 ("i" and "j" )  )

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 Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Non binder, MW>500 OR Non binder, non cyclic structure OR Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "f"

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: "g"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Conjugated systems with electron withdrawing groups  OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> alpha-Activated haloalkanes  OR SN2 >> Nucleophilic substitution on benzilyc carbon atom OR SN2 >> Nucleophilic substitution on benzilyc carbon atom >> alpha-Activated benzyls  OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Epoxides, Aziridines and Sulfuranes  by Protein binding by OASIS v1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "i"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.878

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.12

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
LD50 was estimated to be 3443 mg/kg bw when Sprague-Dawley female rats were treated with 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride by oral gavage route.
Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for  2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride ( 6441-82-3). The LD50 was estimated to be 3443 mg/kg bw when Sprague-Dawley female rats were treated with 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride by oral gavage route.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
3 443 mg/kg bw
Quality of whole database:
Data is Klimisch 2 and from QSAR toolbox 3.3

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
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 predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: estimated
Principles of method if other than guideline:
Prediction is done using QSAR Toolbox version 3.3
GLP compliance:
not specified
Test type:
other: not specified
Limit test:
no
Test material information:
Composition 1
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:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
not specified
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
not specified
Remark on MMAD/GSD:
not specified
Details on inhalation exposure:
not specified
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
4 h
Remarks on duration:
not specified
Concentrations:
22.9 mg/L
No. of animals per sex per dose:
not specified
Control animals:
not specified
Details on study design:
not specified
Statistics:
not specified
Preliminary study:
not specified
Sex:
male/female
Dose descriptor:
LC50
Effect level:
22.9 mg/L air
Based on:
test mat.
Remarks on result:
other: 50% mortality observed
Mortality:
not specified
Clinical signs:
not specified
Body weight:
not specified
Gross pathology:
not specified
Other findings:
not specified

The prediction was based on dataset comprised from the following descriptors: LC50
Estimation method: Takes average value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

(((((("a" or "b" or "c" )  and ("d" and ( not "e") )  )  and "f" )  and ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and ("k" and "l" )  )

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 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: "e"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> (Thio)Acyl and (thio)carbamoyl halides and cyanides  OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> (Thio)Phosphates  OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> alpha-Activated haloalkanes  OR SN2 >> Nucleophilic substitution on benzilyc carbon atom OR SN2 >> Nucleophilic substitution on benzilyc carbon atom >> alpha-Activated benzyls  by Protein binding by OASIS v1.3

Domain logical expression index: "f"

Similarity boundary:Target: CCN(CCCl)c1ccc(C=CC2C(C)(C)c3ccccc3N{+}=2(C).Cl{-})c(C)c1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aliphatic Nitrogen, one aromatic attach [-N] AND Aliphatic-C=N-Aliphatic  AND Amino, aliphatic attach [-N<] AND Aromatic Carbon [C] AND Chlorine, aliphatic attach [-Cl] AND Olefinic carbon [=CH- or =C<] AND Tertiary Carbon by Organic functional groups (US EPA)

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as 1,2-Oxaza compounds [N-C-O-] by Organic functional groups (US EPA)

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Halogens AND Non-Metals by Groups of elements

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Metalloids by Groups of elements

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.43

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.89

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
LC50 was estimated to be 22.9 mg/L air, when Sprague-Dawley male and female rats were exposed with 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride for 4 h of exposure period.
Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute inhalation toxicity was estimated for 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (6441-82-3). The LC50 was estimated to be 22.9 mg/L air, when Sprague-Dawley male and female rats were exposed with 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride for 4 h of exposure period.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
22 900 mg/m³
Quality of whole database:
Data is Klimisch 2 and QSAR toolbox 3.3.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
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 predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: estimated
Principles of method if other than guideline:
Prediction is done using QSAR Toolbox version 3.3
GLP compliance:
not specified
Test type:
other: not specified
Limit test:
no
Test material information:
Composition 1
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:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
not specified
Type of coverage:
semiocclusive
Vehicle:
not specified
Details on dermal exposure:
not specified
Duration of exposure:
24 h
Doses:
4242 mg/kg
No. of animals per sex per dose:
not specified
Control animals:
not specified
Details on study design:
not specified
Statistics:
not specified
Preliminary study:
not specified
Sex:
male/female
Dose descriptor:
LD50
Effect level:
4 242 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 50% mortality observed
Mortality:
not specified
Clinical signs:
not specified
Body weight:
not specified
Gross pathology:
not specified
Other findings:
not specified

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 6 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 "k" )  )

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 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: "e"

Referential boundary: The target chemical should be classified as No alert found OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> alpha-Activated haloalkanes  OR SN2 >> Nucleophilic substitution on benzilyc carbon atom OR SN2 >> Nucleophilic substitution on benzilyc carbon atom >> alpha-Activated benzyls  OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Epoxides, Aziridines and Sulfuranes  by Protein binding by OASIS v1.3

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 Halogenated alkanes  by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "h"

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: "i"

Referential boundary: The target chemical should be classified as 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 by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.59

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.89

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
LD50 was estimated to be 4242 mg/kg bw, when New Zealand White male and female rabbit was treated with 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride for 24 hours by dermal application semiocclusively.
Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (6441-82-3). The LD50 was estimated to be 4242 mg/kg bw, when New Zealand White male and female rabbit was treated with 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride for 24 hours by dermal application semiocclusively.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
4 242 mg/kg bw
Quality of whole database:
Data is Klimisch 2 and from QSAR toolbox 3.3

Additional information

Acute oral toxicity:

In different studies, 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (6441-82-3) has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents, i.e. most commonly in rats for 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride along with the study available on structurally similar read across substance 2-[2-[4-[(2-chloroethyl)methylamino]phenyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 3648-36-0) and closely related read across substance 2,2-Dichloro-1-(3-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethanone (CAS no: 98730-04-2). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 2-[2-[4-[(2-chloroethyl) ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride ( 6441-82-3). The LD50 was estimated to be 3443 mg/kg bw when Sprague-Dawley female rats were treated with 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride by oral gavage route.

The above study supported by U.S. National Library of Medicine (ChemIDplus, 2017), for the structurally similar read across substance 2-[2-[4-[(2-chloroethyl)methylamino]phenyl] vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 3648-36-0).The acute oral toxicity was tested in rat at the dose concentration of 2260 mg/kg bw. Changes in Blood were observed in tested animals. 50% mortality was observed at 2260 mg/kg bw. Therefore, LD50 was considered to be 2260 mg/kg bw, when rats were treated with 2-[2-[4-[(2-chloroethyl) methylamino]phenyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (CAS no: 3648-36-0) via oral route.

This study is further supported by U.S. National Library of Medicine (ChemIDplus, 2017), for the closely related read across substance2,2-Dichloro-1-(3-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethanone (CAS no: 98730-04-2).The acute oral toxicity was tested in rat at the dose concentration of 5000 mg/kg bw. No mortality was observed at 5000 mg/kg bw. Therefore, LD50 was considered to be >5000 mg/kg bw, when rats were treated with 2,2-Dichloro-1-(3-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethanone via oral route.

Thus, based on the above studies on 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (6441-82-3) and it’s read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride can be classified as category V of acute oral toxicity.

Acute Inhalation toxicity: 

In different studies, 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (6441-82-3) has been investigated for acute inhalation toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents, i.e. most commonly in rats and mice for 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride along with the study available on closely related read across substance Bromochloromethane (CAS no: 74-97-5) and Tris(2-chloro-1-methylethyl) phosphate (CAS no: 13674-84-5). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute inhalation toxicity was estimated for 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (6441-82-3). The LC50 was estimated to be 22.9 mg/L air, when Sprague-Dawley male and female rats were exposed with 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride for 4 h of exposure period.

The above study is supported by U.S. National Library of Medicine (ChemIDplus, 2017), for the closely related read across substance Bromochloromethane (CAS no: 74-97-5).The acute inhalation toxicity study was conducted in mouse at the concentration of12030 mg/m3. 50% mortality was observed at12030 mg/m3with clinical Symptoms like dyspnea and changes in lungs, thorax, muscle weakness and general anesthetic symptoms were observed, when exposed for 7 hours. Therefore, LC50 was considered to be 12030 mg/m3 when mouse was treated with Bromochloromethane by inhalation for 7 hours.

These results are further supported by GESTIS SUBSTANCE Database (2017), for the closely related read across substance Tris(2-chloro-1-methylethyl) phosphate (CAS no: 13674-84-5).The acute inhalation toxicity study was conducted in rat at the concentration of 4600 mg/m3. No mortality was observed at 4600 mg/m3.Therefore, LC50 was considered to be >4600 mg/m3 when rat was treated with Tris(2-chloro-1-methylethyl) phosphate by inhalation for 4 hours.

Thus, based on the above studies on 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (6441-82-3) and it’s read across substances, it can be concluded that LC50 value is greater than 5 mg/L air. Thus, comparing this value with the criteria of CLP regulation, 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride can be classified as category V of acute inhalation toxicity.

Acute Dermal toxicity:

In different studies, 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (6441-82-3) has been investigated for acute dermal toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments in rodents, i.e. most commonly in rats and rabbits for 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride along with the study available on closely related read across substance 3-Chloropropyl)triethoxysilane (CAS No. 5089-70-3) and Tris(2-chloro-1-methylethyl) phosphate (13674-84-5). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (6441-82-3). The LD50 was estimated to be 4242 mg/kg bw, when New Zealand White male and female rabbit was treated with 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride for 24 hours by dermal application semiocclusively.

This study is supported by United Nations Environmental Programme (UNEP, 2010), for the closely related read across substance 3-Chloropropyl)triethoxysilane (CAS No. 5089-70-3). Acute Dermal toxicity study was conducted in male and female rats at the concentration of 2000 mg/kg bw. Test material (purity - 97.0%) was applied undiluted at 2000 mg/kg for 24 hours under a semi-occlusive dressing to the dorsal skin of 5 male and 5 female rats. The application volume was 2.00 cm3/kg body weight. The test substance was removed with warm water after the 24 hour exposure period. The animals were examined for clinical signs 30 minutes, 1, 2, 3, 4, 5, and 6 hrs post-dosing, and then once daily for two weeks. Body weight determinations were performed on the day of dosing, and days 7 and 14 (study termination). All animals were subject to a gross necropsy. The test substance with an applied dose of 2000 mg/kg body weight in 5 male and 5 female animals caused no lethality. Normal body weight gain was observed during the 14-day observation period. No signs of toxicity were observed in the male or female animals. Very slight erythema was observed in one male animal (48 and 72 hours after application) and two female animals (48 hours to day 5) at the site of application. By day 6, all skin irritation had subsided. No abnormalities were noted at necropsy. Therefore, LD50 was considered to be >2000 mg/kg bw, when male and female rats were treated with of 3-Chloropropyl)triethoxysilane by semi-occlusive dermal application.

The above study is further supported by National Industrial Chemicals Notification and Assessment Scheme (NICNAS, 2017) and EUROPEAN COMMISSION – European Chemicals Bureau (IUCLID Dataset, 2000), for the closely related read across substance Tris(2-chloro-1-methylethyl) phosphate (13674-84-5). Acute Dermal toxicity study was conducted in male and female rabbits at the concentration of 2000 mg/kg bw. 3 male and 3 female rabbits dosed dermally for 24 hours. 2/3 application sites on the males and 1/3 on the females were abraded through the epidermis. Application sites were assessed for irritancy at 24 and 72 hours post treatment. No animals died. All animals showed some erythema and oedema formation at 24 hours but were normal at 72 hours. Therefore, LD50 was considered to be >2000 mg/kg bw, when male and female rabbits were treated with Tris(2-chloro-1-methylethyl) phosphate by dermal application to the abraded skin through the epidermis.

Thus, based on the above studies on 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (6441-82-3) and it’s read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride can be classified as category V of acute dermal toxicity.

Justification for classification or non-classification

Based on the above studies and prediction on 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride (6441-82-3) and it’s read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw for acute oral and dermal toxicity and LC50 value is greater than 5 mg/L air. Thus, comparing this value with the criteria of CLP regulation, 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride can be classified as category V for acute oral, dermal and inhalation toxicity.