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Key value for chemical safety assessment

Effects on fertility

Description of key information

The NOAEL was estimated to be 96.2 mg/kg bw when Sprague-Dawley male and female rats were orally exposed with 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride.

Based on the above predictions on 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride, it can be concluded that NOAEL value is 96.2 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride can be Not classified for reproductive toxicity.

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
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: as below
Principles of method if other than guideline:
Prediction is done using QSAR Toolbox version 3.3
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
- Name of test material (IUPAC name): 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3- trimethyl-3H-indolium chloride
- Common name: Astrazonrot 6B
- Molecular formula: C24H30ClN2Cl
- Molecular weight: 417.421 g/mol
- Smiles notation: C1(=[N+](c2ccccc2C1(C)C)C)\C=C/c1c(cc(N(CCCl)CC)cc1)C.[ClH-]
- InChl: 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
- Substance type: Organic
- Physical state: Solid
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
not specified
Route of administration:
oral: feed
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Details on exposure:
not specified
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 years
Frequency of treatment:
Daily
Dose / conc.:
96.2 mg/kg bw/day (nominal)
No. of animals per sex per dose:
not specified
Control animals:
yes
Details on study design:
not specified
Positive control:
not specified
Parental animals: Observations and examinations:
not specified
Estrous cyclicity (parental animals):
not specified
Sperm parameters (parental animals):
not specified
Litter observations:
not specified
Postmortem examinations (parental animals):
not specified
Postmortem examinations (offspring):
not specified
Statistics:
not specified
Reproductive indices:
not specified
Offspring viability indices:
not specified
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: estrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified
Dose descriptor:
NOAEL
Effect level:
96.2 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: No effect observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
other: not specified
Generation:
other: not specified
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
other: not specified
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
other:
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
other: not specified
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
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" )  )

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 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 Alkene AND Alkyl arenes AND Alkyl halide AND Ammonium salt AND Aromatic amine AND Aryl AND Indole/ Isoindole AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Dihydroxyl group by Organic Functional groups (nested)

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.82

Domain logical expression index: "i"

Parametric boundary:The target chemical should have a value of log Kow which is <= 7.75

Conclusions:
NOAEL was estimated to be 96.2 mg/kg bw when Sprague-Dawley male and female rats were orally exposed with 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride.
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. The NOAEL was estimated to be 96.2 mg/kg bw when Sprague-Dawley male and female rats were orally exposed with 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
96.2 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimisch 2 and from OECD QSAR toolbox
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity:

In different studies, 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in mice and 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 substance1,2-dichloroethane(CAS no 107-06-2). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

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. The NOAEL was estimated to be 96.2 mg/kg bw when Sprague-Dawley male and female rats were orally exposed with 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride.

In a another experimental study conducted by Sweeney et al (Regulatory Toxicology and Pharmacology 81 (2016) 468e479) on structurally similar read across1,2-dichloroethane(CAS no 107-06-2), Crl:CD (Sprague-Dawley) male and female rats treated with 1,2-dichloroethane in the concentration of 0 (vehicle), 50, 150, and 300 mg/kg bw/day orally by drinking water as per OECD 443. Decrease in body weight and body weight gain was observed in treated rats in P generation. As EDC in drinking water to have poor palatability; drinking water consumption was generally decreased, relative to Controls, in a dose-related manner. Similarly, No effect was observed on estrous cycle, sperm evaluation, Fertility, gestation, vaginal opening and preputial separation of treated P male and female rats as compared to control. In addition, Change in relative liver weight was observed in F0 female rats. As no significant histological findings were identified in the liver (or any other tissue), the organ weight change may be considered non adverse. No gross pathological and Histopathological changes were observed in treated male and female P rats. No Reproductive/developmental effects (Cohort 1), neurodevelopmental effects (Cohort 2), and developmental immune effects (Cohort 3) were observed in F1 male and female rats. Therefore, NOAEL was considered to be 155 mg/kg/day for male and 182 mg/kg bw for female P generation and 184 mg/kg/day for male and 169 mg/kg bw for female F1 generation when Crl:CD (Sprague-Dawley) male and female rats treated with 1,2-dichloroethane orally by drinking water.

Father supported by experimental study given byWorld health organization (IARC MONOGRAPHS VOLUME 71, (1987a)) on structurally similar read across1,2-dichloroethane(CAS no 107-06-2),ICR Swiss male and female mice treated with 1,2-dichloroethane in the concentration of 0, 5, 15 or 50 mg/kg bw orally by drinking water. No effect on Fertility, gestation and lactation indices of treated P rats were observed. In addition, No effect on survival and body weight of treated pups were observed. Therefore, NOAEL was considered to be 50 mg/kg/day P and F1 generation when ICR Swiss male and female mice treated with 1,2-dichloroethane orally by drinking water.

Thus, based on the above studies and predictions on 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride and its read across substances, it can be concluded that NOAEL value is 96.2 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride can be Not classified for reproductive toxicity.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the above studies and predictions on 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride and its read across substances, it can be concluded that NOAEL value is 96.2 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 2-[2-[4-[(2-chloroethyl)ethylamino]-o-tolyl]vinyl]-1,3,3-trimethyl-3H-indolium chloride can be Not classified for reproductive toxicity.