Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

The gentic toxicity of the registered substance was determined via expert assessment. It is expected that the substance will dissociate following an exposure event and, therefore, its potential genotoxic effect will be driven by the toxicity of its constituents 6-[methyl(phenylsulphonyl)amino] hexanoic acid (MPSAH) and triethanolamine (TEA).


No data is available on the capacity of MPSAH to induce genotoxicity. The data availability for MPSAH is limited to only water solubility, partition coefficient, dissociation constant, acute oral toxicity, and skin and eye irritation. Based on the available data, MPSAH demonstrates a remarkable similarity to a structurally similar substance 6-[[(4-methylphenyl) sulphonyl] amino] hexanoic acid (4-MPSAH; EC 278-934-5). Since no toxicological difference is expected between MPSAH and 4-MPSAH, an expert assessment was conducted based on available experimental data on the analogue 4-MPSAH. In addition, TEA data was also used as a source for further support. 


4-MPSAH was tested for its potential to cause genetic toxicity, in accordance with the OECD Guideline for Testing of Chemicals 487 (in vitro micronucleus study), 476 (In vitro gene mutation study in mammalian cells) and 471 (Bacterial reverse mutation test) and GLP principles. The substance was found to be negative for genetic toxicity, with and without metabolic activation, in the Ames test (OECD 471), gene cell mutation test (OECD 476) and the micronucleus test (OECD 487).


TEA was tested for its potential to cause genetic toxicity, in accordance with the OECD Guideline for Testing of Chemicals 473 (In vitro cytogenicity study in mammalian cells), 490 (in vitro gene mutation study in mammalian cells using the thymidine kinase gene) and 471 (Bacterial reverse mutation test). The substance was found to be negative for genetic toxicity, with and without metabolic activation, in all the studies. 


The evidence reviewed in this endpoint assessment report suggests that 6-[methyl(phenylsulphonyl)amino]hexanoic acid and triethanolamine are not expected to induce gene mutation in bacteria, and as such the substance 6-
[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) (Nmethyl salt) is not expected to induce gene mutation in bacteria. An experimental study is subsequently not required.


 

Link to relevant study records

Referenceopen allclose all

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
other: Expert assessment
Adequacy of study:
weight of evidence
Study period:
2021
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH

The registered substance 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2’,2’’-nitrotriethanol (1:1) (EC 248-107-3) is produced by solubilizing 6-[Methyl (phenylsulphonyl) amino] hexanoic acid (MPSAH, EC 256-289-0), in the presence of a small amount of dimethylaminopropylamine (5% w/w), and mixed with triethanolamine (TEA; 3 equivalents) and deionised water and stirred at a temperature of 45°C for 3 hours to form the target substance. Other than ionization of the carboxylic acid group, MPSAH remains chemically unchanged upon salt formation.

In water, the acid and amine components of the registered substance dissociate completely to MPSAH and TEA and these two components behave essentially as independent substances. Therefore, this read across approach seeks to fulfill the registration requirements by using toxicity data available for MPSAH and TEA. The data availability for MPSAH is limited to only water solubility, partition coefficient, dissociation constant, Acute oral toxicity, and skin and eye irritation. Based on the available data, MPSAH demonstrate a remarkable similarity to a structurally similar substance 6-[[(4-methylphenyl) sulphonyl] amino] hexanoic acid (4-MPSAH; EC 278-934-5). Since no toxicological difference is expected between MPSAH and 4-MPSAH, these two substances are proposed as source substances in this read across approach for the target substance 6-[methyl(phenylsulphonyl) amino]hexanoic acid, compound with 2,2’,2’’-nitrotriethanol (1:1) (EC 248-107-3). In addition, TEA data is also used as a source for further support.

Overall, the toxicity data for the source substances MPSAH, 4-MPSAH and TEA together will accurately represent the toxicity of the target substance. In addition, (eco)toxicology data for TEA salt of 4-MPSAH, named 6-[(p-tosyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) (EC 301-097-5) can also be used to fill the data gap for the target substance.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Target Substance:
Substance: 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2’,2’’-nitrotriethanol (1:1)
CAS / EC: 26919-50-6 / 248-107-3
Concentration range: 85-90 % w/w

Source Substances:
Source substance name:
- 6-[methyl(phenylsulphonyl)amino]hexanoic acid (MPSAH); CAS 46948-72-5 / EC256-289-0
- 6-[[(4-methylphenyl)sulphonyl]amino]hexanoic acid (4-MPSAH); CAS 78521-39-8/ EC 278-934-5
- Triethanolamine (TEA); CAS 102-71-6 /EC 203-049-8
- 6-[(p-tosyl)amino]hexanoic acid, compound with 2,2',2''-nitrilo triethanol (1:1); CAS 93981-14-7 / EC 301-097-5


3. ANALOGUE APPROACH JUSTIFICATION

a) Structure
The target substance is a salt of 6-[methyl(phenylsulphonyl)amino]hexanoic acid with triethanolamine and the analogues proposed are the individual components of the salt as well as a similar salt 6-[(p-tosyl)amino]hexanoic acid, compound with 2,2',2''-nitrilo triethanol (1:1). The similar salt differs from the target substance in the structure of the hexanoic acid constituent, the structures of which are shown below for comparison. The structural differences are limited to the position of a methyl group and do not impact on the molecular weight or empirical formula of the substance. The structures contain the same functionality and have very similar physicochemical properties.


6-[[(4-methylphenyl)sulphonyl]amino]hexanoic acid (4-MPSAH); Mwt = 285.4
Empirical formula = C13H19NO4S
Functionality = sulfonamide, carboxylic acid, substituted aromatic

6-[methyl(phenylsulphonyl)amino]hexanoic acid (MPSAH); Mwt = 285.4
Empirical formula =C13H19NO4S
Functionality = Sulfonamide, carboxylic acid, substituted aromatic


b) Manufacturing of the target substance
The registered substance is produced by solubilizing MPSAH, in the presence of a small amount of dimethylaminopropylamine (5% w/w), and mixed with TEA and deionised water and stirred at a temperature of 45°C for 3 hours to form the target substance. Other than ionization of the carboxylic acid group, MPSAH remains chemically unchanged upon salt formation.

c) Dissociation of the target substance
As discussed above, the target substance is a salt of MPSAH with TEA. In water, the acid and amine components of the target substance will dissociate completely to MPSAH and TEA and these two components behave essentially as independent substances.

d) Hazardous properties of triethanolamine (TEA)
Available information on TEA clearly indicates that it is not hazardous to human health and environment as assessed by multiple bodies such as OECD and NICNAS and exemplified by no genotoxicity, reproductive, carcinogenicity hazard and low toxicity to fish, Daphnia and algae. The non-hazardous nature of TEA is further supported by the data in the existing REACH dossier submitted to ECHA and by the fact that it is not classified by 4699 notifiers in the C&L inventory.

e) Bioavailability consideration
The pKa of the carboxylic acid group in MPSAH (pKa = 4.74) is similar in the free acid as it is in the TEA salt (pKa = 4.92) . As a result, source substance will respond to changes of pH in the similar manner whether it is in the salt form (target substance) or as the parent carboxylic acid and hence it’s bioavailability will be the same.

f) Toxicological and metabolic similarity between MPSAH and 4-MPSAH
MPSAH and 4-MPSAH are structurally very similar with the only difference being the presence of a methyl group on the para position of the aromatic ring of the source 4-MPSAH and a methyl group on the N atom in MPSAH. These minor structural differences are not expected to cause any major differences in toxicologically relevant physicochemical properties such as water solubility, partition coefficient, and dissociation constant (Table 1).

Some differences are expected between MPSAH and 4-MPSAH with regards to metabolism. TOxidation of the para-methyl group in 4-MPSAH is likely, MPSAH does not contain this para methyl group and as such will not follow the same oxidation pathway. However, available toxicity data (Table 1) indicates that this metabolic difference between MPSAH and 4-MPSAH does not ultimately cause any major toxicological differences.


4. DATA MATRIX

In the table below, available information on the physico-chemical and (eco)toxicological properties are included. Limited toxicological information is available for MPSAH; hence, the table contains only those parameters for which the information is available for both MPSAH and 4-MPSAH.

Table 1: Physicochemical and toxicological data available for MPSAH and 4-MPSAH (source: respective REACH dossier)

Parameters:

Water solubility (at 25 ℃):
MPSAH (EC 256-289-0): 430 mg/L
4-MPSAH (EC 278-934-5): 317 mg/L

Partition coefficient (Log Kow):
MPSAH (EC 256-289-0): 2
4-MPSAH (EC 278-934-5): 1.96

Dissociation constant :
MPSAH (EC 256-289-0): 4.74
4-MPSAH (EC 278-934-5): 4.44

Acute oral toxicity:
MPSAH (EC 256-289-0): > 2000 mg/kg bw
4-MPSAH (EC 278-934-5): > 2000 mg/kg bw

Skin irritation:
MPSAH (EC 256-289-0): Not irritating
4-MPSAH (EC 278-934-5): Not irritating

Eye irritation:
MPSAH (EC 256-289-0): Category 1
4-MPSAH (EC 278-934-5): Category 1 (TEA salt of 4-MPSAH)

Mutagenicity structural alerts:
MPSAH (EC 256-289-0): No structural alerts identified with OECD QSAR toolbox and VEGA
4-MPSAH (EC 278-934-5): No structural alerts identified in OECD QSAR toolbox and VEGA


5. Conclusion
Available data in the data matrix are not extensive because MPSAH is data poor. Hence, endpoint to endpoint comparison of toxicological and ecotoxicological data between MPSAH and 4-MPSAH is not possible. However, based on the available information, it is expected that the acid and amine components of the target substance will dissociate completely to the MPSAH and TEA and these two components will behave essentially as independent substances. Moreover, available data on water solubility, partition coefficient, dissociation constant, acute oral toxicity, and skin and eye irritation indicates the toxicological properties of MPSAH is expected to be very similar to the source substance 4-MPSAH. Finally, TEA data can be used as supporting information.
Qualifier:
no guideline required
Principles of method if other than guideline:
An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
GLP compliance:
no
Type of assay:
other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
Species / strain:
other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Conclusions:
The evidence reviewed in this endpoint assessment report suggests that 6-
[methyl(phenylsulphonyl)amino]hexanoic acid and triethanolamine are not expected to induce
gene mutation in bacteria, and as such the substance 6- [methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) (Nmethyl salt) is not expected to induce gene mutation in bacteria. An experimental study is subsequently not required.
Executive summary:

The capacity of 6-[methyl(phenylsulphonyl)amino]hexanoic acid compound with 2,2',2''-nitrilotriethanol (1:1) to induce gene mutation in bacteria, was evaluated to fulfil Annex VII of the REACH Regulation (EC) No 1907/2007.


It is expected that the substance will dissociate following an exposure event and, therefore, its potential mutagenic effect will be driven by the toxicity of its constituents 6-[methyl(phenylsulphonyl)amino] hexanoic acid (MPSAH) and triethanolamine (TEA).


No data is available on the capacity of MPSAH to induce genotoxicity in mammalian cells. The data availability for MPSAH is limited to only water solubility, partition coefficient, dissociation constant, acute oral toxicity, and skin and eye irritation. Based on the available data, MPSAH demonstrates a remarkable similarity to a structurally similar substance 6-[[(4-methylphenyl) sulphonyl] amino] hexanoic acid (4-MPSAH; EC 278-934-5). Since no toxicological difference is expected between MPSAH and 4-MPSAH, this registration assessment report was based on available experimental data on the analogue 4-MPSAH. In addition, TEA data was also used as a source for further support.


A bacterial reverse mutation assay (Ames test) in Salmonella typhimurium LT2 (strains TA98, TA100, TA102, TA1535, and TA1537) conducted with 4-MPSAH according to OECD guideline 471 and GLP principles showed negative responses up to 5000 ug/plate, i.e., no significant dose related increase in the number of revertants with or without metabolic activation was seen. Based on the results of this study it is concluded that 4-MPSAH is not mutagenic in the bacterial strains used with and without metabolic activation.


2,2',2''-nitrilotriethanol’s (Triethanolamine; TEA) toxicological information data was retrieved from ECHAs chemical database to assess the genetic mutagenicity in bacteria. The study followed OECD guideline 471, using Salmonella typhimurium and Escherichia Coli with and without metabolic activation. This study was assessed for its reliability, and it was concluded to be reliable with restrictions (Klimisch 2). There was no mutagenicity observed and thus it was concluded that TEA poses no mutagenic hazard.



The evidence reviewed in this endpoint assessment report suggests that 6-[methyl(phenylsulphonyl)amino]hexanoic acid and triethanolamine are not expected to induce gene mutation in bacteria, and as such the substance 6-
[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) (Nmethyl salt) is not expected to induce gene mutation in bacteria. An experimental study is subsequently not required.


 

Endpoint:
in vitro gene mutation study in mammalian cells
Type of information:
other: Expert Assessment
Adequacy of study:
weight of evidence
Study period:
2021
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH

The registered substance 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2’,2’’-nitrotriethanol (1:1) (EC 248-107-3) is produced by solubilizing 6-[Methyl (phenylsulphonyl) amino] hexanoic acid (MPSAH, EC 256-289-0), in the presence of a small amount of dimethylaminopropylamine (5% w/w), and mixed with triethanolamine (TEA; 3 equivalents) and deionised water and stirred at a temperature of 45°C for 3 hours to form the target substance. Other than ionization of the carboxylic acid group, MPSAH remains chemically unchanged upon salt formation.

In water, the acid and amine components of the registered substance dissociate completely to MPSAH and TEA and these two components behave essentially as independent substances. Therefore, this read across approach seeks to fulfill the registration requirements by using toxicity data available for MPSAH and TEA. The data availability for MPSAH is limited to only water solubility, partition coefficient, dissociation constant, Acute oral toxicity, and skin and eye irritation. Based on the available data, MPSAH demonstrate a remarkable similarity to a structurally similar substance 6-[[(4-methylphenyl) sulphonyl] amino] hexanoic acid (4-MPSAH; EC 278-934-5). Since no toxicological difference is expected between MPSAH and 4-MPSAH, these two substances are proposed as source substances in this read across approach for the target substance 6-[methyl(phenylsulphonyl) amino]hexanoic acid, compound with 2,2’,2’’-nitrotriethanol (1:1) (EC 248-107-3). In addition, TEA data is also used as a source for further support.

Overall, the toxicity data for the source substances MPSAH, 4-MPSAH and TEA together will accurately represent the toxicity of the target substance. In addition, (eco)toxicology data for TEA salt of 4-MPSAH, named 6-[(p-tosyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) (EC 301-097-5) can also be used to fill the data gap for the target substance.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Target Substance:
Substance: 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2’,2’’-nitrotriethanol (1:1)
CAS / EC: 26919-50-6 / 248-107-3
Concentration range: 85-90 % w/w

Source Substances:
Source substance name:
- 6-[methyl(phenylsulphonyl)amino]hexanoic acid (MPSAH); CAS 46948-72-5 / EC256-289-0
- 6-[[(4-methylphenyl)sulphonyl]amino]hexanoic acid (4-MPSAH); CAS 78521-39-8/ EC 278-934-5
- Triethanolamine (TEA); CAS 102-71-6 /EC 203-049-8
- 6-[(p-tosyl)amino]hexanoic acid, compound with 2,2',2''-nitrilo triethanol (1:1); CAS 93981-14-7 / EC 301-097-5


3. ANALOGUE APPROACH JUSTIFICATION

a) Structure
The target substance is a salt of 6-[methyl(phenylsulphonyl)amino]hexanoic acid with triethanolamine and the analogues proposed are the individual components of the salt as well as a similar salt 6-[(p-tosyl)amino]hexanoic acid, compound with 2,2',2''-nitrilo triethanol (1:1). The similar salt differs from the target substance in the structure of the hexanoic acid constituent, the structures of which are shown below for comparison. The structural differences are limited to the position of a methyl group and do not impact on the molecular weight or empirical formula of the substance. The structures contain the same functionality and have very similar physicochemical properties.


6-[[(4-methylphenyl)sulphonyl]amino]hexanoic acid (4-MPSAH); Mwt = 285.4
Empirical formula = C13H19NO4S
Functionality = sulfonamide, carboxylic acid, substituted aromatic

6-[methyl(phenylsulphonyl)amino]hexanoic acid (MPSAH); Mwt = 285.4
Empirical formula =C13H19NO4S
Functionality = Sulfonamide, carboxylic acid, substituted aromatic


b) Manufacturing of the target substance
The registered substance is produced by solubilizing MPSAH, in the presence of a small amount of dimethylaminopropylamine (5% w/w), and mixed with TEA and deionised water and stirred at a temperature of 45°C for 3 hours to form the target substance. Other than ionization of the carboxylic acid group, MPSAH remains chemically unchanged upon salt formation.

c) Dissociation of the target substance
As discussed above, the target substance is a salt of MPSAH with TEA. In water, the acid and amine components of the target substance will dissociate completely to MPSAH and TEA and these two components behave essentially as independent substances.

d) Hazardous properties of triethanolamine (TEA)
Available information on TEA clearly indicates that it is not hazardous to human health and environment as assessed by multiple bodies such as OECD and NICNAS and exemplified by no genotoxicity, reproductive, carcinogenicity hazard and low toxicity to fish, Daphnia and algae. The non-hazardous nature of TEA is further supported by the data in the existing REACH dossier submitted to ECHA and by the fact that it is not classified by 4699 notifiers in the C&L inventory.

e) Bioavailability consideration
The pKa of the carboxylic acid group in MPSAH (pKa = 4.74) is similar in the free acid as it is in the TEA salt (pKa = 4.92) . As a result, source substance will respond to changes of pH in the similar manner whether it is in the salt form (target substance) or as the parent carboxylic acid and hence it’s bioavailability will be the same.

f) Toxicological and metabolic similarity between MPSAH and 4-MPSAH
MPSAH and 4-MPSAH are structurally very similar with the only difference being the presence of a methyl group on the para position of the aromatic ring of the source 4-MPSAH and a methyl group on the N atom in MPSAH. These minor structural differences are not expected to cause any major differences in toxicologically relevant physicochemical properties such as water solubility, partition coefficient, and dissociation constant (Table 1).

Some differences are expected between MPSAH and 4-MPSAH with regards to metabolism. TOxidation of the para-methyl group in 4-MPSAH is likely, MPSAH does not contain this para methyl group and as such will not follow the same oxidation pathway. However, available toxicity data (Table 1) indicates that this metabolic difference between MPSAH and 4-MPSAH does not ultimately cause any major toxicological differences.


4. DATA MATRIX

In the table below, available information on the physico-chemical and (eco)toxicological properties are included. Limited toxicological information is available for MPSAH; hence, the table contains only those parameters for which the information is available for both MPSAH and 4-MPSAH.

Table 1: Physicochemical and toxicological data available for MPSAH and 4-MPSAH (source: respective REACH dossier)

Parameters:

Water solubility (at 25 ℃):
MPSAH (EC 256-289-0): 430 mg/L
4-MPSAH (EC 278-934-5): 317 mg/L

Partition coefficient (Log Kow):
MPSAH (EC 256-289-0): 2
4-MPSAH (EC 278-934-5): 1.96

Dissociation constant :
MPSAH (EC 256-289-0): 4.74
4-MPSAH (EC 278-934-5): 4.44

Acute oral toxicity:
MPSAH (EC 256-289-0): > 2000 mg/kg bw
4-MPSAH (EC 278-934-5): > 2000 mg/kg bw

Skin irritation:
MPSAH (EC 256-289-0): Not irritating
4-MPSAH (EC 278-934-5): Not irritating

Eye irritation:
MPSAH (EC 256-289-0): Category 1
4-MPSAH (EC 278-934-5): Category 1 (TEA salt of 4-MPSAH)

Mutagenicity structural alerts:
MPSAH (EC 256-289-0): No structural alerts identified with OECD QSAR toolbox and VEGA
4-MPSAH (EC 278-934-5): No structural alerts identified in OECD QSAR toolbox and VEGA


5. Conclusion
Available data in the data matrix are not extensive because MPSAH is data poor. Hence, endpoint to endpoint comparison of toxicological and ecotoxicological data between MPSAH and 4-MPSAH is not possible. However, based on the available information, it is expected that the acid and amine components of the target substance will dissociate completely to the MPSAH and TEA and these two components will behave essentially as independent substances. Moreover, available data on water solubility, partition coefficient, dissociation constant, acute oral toxicity, and skin and eye irritation indicates the toxicological properties of MPSAH is expected to be very similar to the source substance 4-MPSAH. Finally, TEA data can be used as supporting information.
Qualifier:
no guideline required
Principles of method if other than guideline:
An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
GLP compliance:
no
Type of assay:
other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
Species / strain:
other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
Metabolic activation:
with and without
Genotoxicity:
other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
Cytotoxicity / choice of top concentrations:
other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
Conclusions:
The evidence reviewed in this endpoint assessment suggests that 6-
[methyl(phenylsulphonyl)amino]hexanoic acid and triethanolamine are not expected to induce
gene mutation in mammalian cells and as such the substance 6-
[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) (Nmethyl salt) is not expected to induce gene mutation in mammalian cells. An experimental
study is subsequently not required.
Executive summary:

The capacity of 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) to induce gene mutation in mammalian cells, was evaluated to fulfil Annex Annex VIII, Section 8.4.3. of the REACH Regulation (EC) No 1907/2007. It is expected that the substance will dissociate following an exposure event and, therefore, its potential mutagenic effect will be driven by the genetic toxicity of its constituents 6-[methyl(phenylsulphonyl) amino]hexanoic acid (MPSAH) and triethanolamine (TEA).


No data are available on the capacity of 6-[methyl (phenylsulphonyl)amino]hexanoic acid to induce gene mutation in mammalian cells. The data availability for MPSAH is limited to only water solubility, partition coefficient, dissociation constant, acute oral toxicity, and skin and eye irritation. Based on the available data, MPSAH demonstrates a remarkable similarity to a structurally similar substance 6-[[(4-methylphenyl) sulphonyl] amino] hexanoic acid (4-MPSAH; EC 278-934-5). Since no toxicological difference is expected between MPSAH and 4-MPSAH, this registration assessment report was based on available experimental data on the analogue 4-MPSAH. In addition, TEA data was also used as a source for further support.


Reliable experimental data, performed in line with OECD TG guidelines and with an assigned Klimisch score of 1, was identified for 4-MPSAH and triethanolamine.


A GLP compliant gene mutation study in mammalian cells undertaken according to the OECD TG 476 for 4-MPSAH allowed to conclude that the test substance showed no mutagenic activity at the hprt locus of V79 Chinese Hamster lung cells up to and including concentrations of 5000 µg/ml, with or without metabolic activation by S-9 mix.


TEA did not induce gene mutation in mouse lymphoma cells up to 1500 µg/mL with or without metabolic activation (S-9).


The evidence reviewed in this endpoint assessment suggests that 6-[methyl(phenylsulphonyl)amino]hexanoic acid and triethanolamine are not expected to induce
gene mutation in mammalian cells and as such the substance 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) (N- methylsalt) is not expected to induce gene mutation in mammalian cells. An experimental study is subsequently not required.

Endpoint:
in vitro cytogenicity / micronucleus study
Type of information:
other: Expert Assessment
Adequacy of study:
weight of evidence
Study period:
2021
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH

The registered substance 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2’,2’’-nitrotriethanol (1:1) (EC 248-107-3) is produced by solubilizing 6-[Methyl (phenylsulphonyl) amino] hexanoic acid (MPSAH, EC 256-289-0), in the presence of a small amount of dimethylaminopropylamine (5% w/w), and mixed with triethanolamine (TEA; 3 equivalents) and deionised water and stirred at a temperature of 45°C for 3 hours to form the target substance. Other than ionization of the carboxylic acid group, MPSAH remains chemically unchanged upon salt formation.

In water, the acid and amine components of the registered substance dissociate completely to MPSAH and TEA and these two components behave essentially as independent substances. Therefore, this read across approach seeks to fulfill the registration requirements by using toxicity data available for MPSAH and TEA. The data availability for MPSAH is limited to only water solubility, partition coefficient, dissociation constant, Acute oral toxicity, and skin and eye irritation. Based on the available data, MPSAH demonstrate a remarkable similarity to a structurally similar substance 6-[[(4-methylphenyl) sulphonyl] amino] hexanoic acid (4-MPSAH; EC 278-934-5). Since no toxicological difference is expected between MPSAH and 4-MPSAH, these two substances are proposed as source substances in this read across approach for the target substance 6-[methyl(phenylsulphonyl) amino]hexanoic acid, compound with 2,2’,2’’-nitrotriethanol (1:1) (EC 248-107-3). In addition, TEA data is also used as a source for further support.

Overall, the toxicity data for the source substances MPSAH, 4-MPSAH and TEA together will accurately represent the toxicity of the target substance. In addition, (eco)toxicology data for TEA salt of 4-MPSAH, named 6-[(p-tosyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) (EC 301-097-5) can also be used to fill the data gap for the target substance.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Target Substance:
Substance: 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2’,2’’-nitrotriethanol (1:1)
CAS / EC: 26919-50-6 / 248-107-3
Concentration range: 85-90 % w/w

Source Substances:
Source substance name:
- 6-[methyl(phenylsulphonyl)amino]hexanoic acid (MPSAH); CAS 46948-72-5 / EC256-289-0
- 6-[[(4-methylphenyl)sulphonyl]amino]hexanoic acid (4-MPSAH); CAS 78521-39-8/ EC 278-934-5
- Triethanolamine (TEA); CAS 102-71-6 /EC 203-049-8
- 6-[(p-tosyl)amino]hexanoic acid, compound with 2,2',2''-nitrilo triethanol (1:1); CAS 93981-14-7 / EC 301-097-5


3. ANALOGUE APPROACH JUSTIFICATION

a) Structure
The target substance is a salt of 6-[methyl(phenylsulphonyl)amino]hexanoic acid with triethanolamine and the analogues proposed are the individual components of the salt as well as a similar salt 6-[(p-tosyl)amino]hexanoic acid, compound with 2,2',2''-nitrilo triethanol (1:1). The similar salt differs from the target substance in the structure of the hexanoic acid constituent, the structures of which are shown below for comparison. The structural differences are limited to the position of a methyl group and do not impact on the molecular weight or empirical formula of the substance. The structures contain the same functionality and have very similar physicochemical properties.


6-[[(4-methylphenyl)sulphonyl]amino]hexanoic acid (4-MPSAH); Mwt = 285.4
Empirical formula = C13H19NO4S
Functionality = sulfonamide, carboxylic acid, substituted aromatic

6-[methyl(phenylsulphonyl)amino]hexanoic acid (MPSAH); Mwt = 285.4
Empirical formula =C13H19NO4S
Functionality = Sulfonamide, carboxylic acid, substituted aromatic


b) Manufacturing of the target substance
The registered substance is produced by solubilizing MPSAH, in the presence of a small amount of dimethylaminopropylamine (5% w/w), and mixed with TEA and deionised water and stirred at a temperature of 45°C for 3 hours to form the target substance. Other than ionization of the carboxylic acid group, MPSAH remains chemically unchanged upon salt formation.

c) Dissociation of the target substance
As discussed above, the target substance is a salt of MPSAH with TEA. In water, the acid and amine components of the target substance will dissociate completely to MPSAH and TEA and these two components behave essentially as independent substances.

d) Hazardous properties of triethanolamine (TEA)
Available information on TEA clearly indicates that it is not hazardous to human health and environment as assessed by multiple bodies such as OECD and NICNAS and exemplified by no genotoxicity, reproductive, carcinogenicity hazard and low toxicity to fish, Daphnia and algae. The non-hazardous nature of TEA is further supported by the data in the existing REACH dossier submitted to ECHA and by the fact that it is not classified by 4699 notifiers in the C&L inventory.

e) Bioavailability consideration
The pKa of the carboxylic acid group in MPSAH (pKa = 4.74) is similar in the free acid as it is in the TEA salt (pKa = 4.92) . As a result, source substance will respond to changes of pH in the similar manner whether it is in the salt form (target substance) or as the parent carboxylic acid and hence it’s bioavailability will be the same.

f) Toxicological and metabolic similarity between MPSAH and 4-MPSAH
MPSAH and 4-MPSAH are structurally very similar with the only difference being the presence of a methyl group on the para position of the aromatic ring of the source 4-MPSAH and a methyl group on the N atom in MPSAH. These minor structural differences are not expected to cause any major differences in toxicologically relevant physicochemical properties such as water solubility, partition coefficient, and dissociation constant (Table 1).

Some differences are expected between MPSAH and 4-MPSAH with regards to metabolism. TOxidation of the para-methyl group in 4-MPSAH is likely, MPSAH does not contain this para methyl group and as such will not follow the same oxidation pathway. However, available toxicity data (Table 1) indicates that this metabolic difference between MPSAH and 4-MPSAH does not ultimately cause any major toxicological differences.


4. DATA MATRIX

In the table below, available information on the physico-chemical and (eco)toxicological properties are included. Limited toxicological information is available for MPSAH; hence, the table contains only those parameters for which the information is available for both MPSAH and 4-MPSAH.

Table 1: Physicochemical and toxicological data available for MPSAH and 4-MPSAH (source: respective REACH dossier)

Parameters:

Water solubility (at 25 ℃):
MPSAH (EC 256-289-0): 430 mg/L
4-MPSAH (EC 278-934-5): 317 mg/L

Partition coefficient (Log Kow):
MPSAH (EC 256-289-0): 2
4-MPSAH (EC 278-934-5): 1.96

Dissociation constant :
MPSAH (EC 256-289-0): 4.74
4-MPSAH (EC 278-934-5): 4.44

Acute oral toxicity:
MPSAH (EC 256-289-0): > 2000 mg/kg bw
4-MPSAH (EC 278-934-5): > 2000 mg/kg bw

Skin irritation:
MPSAH (EC 256-289-0): Not irritating
4-MPSAH (EC 278-934-5): Not irritating

Eye irritation:
MPSAH (EC 256-289-0): Category 1
4-MPSAH (EC 278-934-5): Category 1 (TEA salt of 4-MPSAH)

Mutagenicity structural alerts:
MPSAH (EC 256-289-0): No structural alerts identified with OECD QSAR toolbox and VEGA
4-MPSAH (EC 278-934-5): No structural alerts identified in OECD QSAR toolbox and VEGA


5. Conclusion
Available data in the data matrix are not extensive because MPSAH is data poor. Hence, endpoint to endpoint comparison of toxicological and ecotoxicological data between MPSAH and 4-MPSAH is not possible. However, based on the available information, it is expected that the acid and amine components of the target substance will dissociate completely to the MPSAH and TEA and these two components will behave essentially as independent substances. Moreover, available data on water solubility, partition coefficient, dissociation constant, acute oral toxicity, and skin and eye irritation indicates the toxicological properties of MPSAH is expected to be very similar to the source substance 4-MPSAH. Finally, TEA data can be used as supporting information.
Qualifier:
no guideline required
Principles of method if other than guideline:
An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
GLP compliance:
no
Type of assay:
other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
Species / strain:
other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
Metabolic activation:
with and without
Genotoxicity:
other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
Cytotoxicity / choice of top concentrations:
other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
Conclusions:
According to the activity of the acid and amine component, the evidence reviewed in this endpoint assessment suggests that 6-[methyl(phenylsulphonyl)amino]hexanoic acid and triethanolamine are not expected to induce genetic toxicity in mammalian cells. An experimental study is subsequently not required.
Executive summary:

The capacity of 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) to induce genotoxicity in mammalian cells, was evaluated to fulfil Annex VIII, Section 8.4.2. of the REACH Regulation (EC) No 1907/2007. It is expected that the substance will dissociate following an exposure event and, therefore, its potential genotoxic effect will be driven by the toxicity of its constituents 6-[methyl(phenylsulphonyl)amino] hexanoic acid (MPSAH) and triethanolamine (TEA).


No data is available on the capacity of MPSAH to induce genotoxicity in mammalian cells. The data availability for MPSAH is limited to only water solubility, partition coefficient, dissociation constant, acute oral toxicity, and skin and eye irritation. Based on the available data, MPSAH demonstrates a remarkable similarity to a structurally similar substance 6-[[(4-methylphenyl) sulphonyl] amino] hexanoic acid (4-MPSAH; EC 278-934-5). Since no toxicological difference is expected between MPSAH and 4-MPSAH, this registration assessment report was based on available experimental data on the analogue 4-MPSAH. In addition, TEA data was also used as a source for further support.


A GLP compliant gene mutation study in mammalian cells undertaken according to the OECD TG 487 for 4-MPSAH allowed to conclude that the test substance did not show mutagenic activity in terms of micronuclei formation in cultured human peripheral blood lymphocytes exposed in vitro up to and including concentrations of 875 µg/ml, with or without metabolic activation by S-9 mix. In addition, the test substance did not cause relevant cytotoxicity up to and including the highest tested concentration of 1750 µg/ml, with or without metabolic activation by S-9 mix.


Reliable experimental data, performed in line with OECD TG guidelines and with an assigned Klimisch score of 2, in vitro mammalian chromosome aberration test according to the OECD TG 473, was identified for TEA. This substance did not cause chromosomal aberrations or induced sister chromatid exchanges in Chinese Hamster Ovary cells when evaluated in the absence and presence of an externally supplied metabolic activation (S9-Mix)


The evidence reviewed in this endpoint assessment report suggests that 6-[methyl(phenylsulphonyl)amino]hexanoic acid and triethanolamine are not expected to induce genetic toxicity in mammalian cell, and as such the substance 6-
[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) (Nmethyl salt) is not expected to induce genetic toxicity in mammalian cell. An experimental study is subsequently not required.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Justification for classification or non-classification

A strcturally similar component (4-MPSAH) of the carboxylic acid component (MPSAH)  was found to be negative for genetic toxicity, with and without metabolic activation, in the Ames test (OECD 471), gene cell mutation test (OECD 476) and the micronucleus test (OECD 487).  TEA can also be considered non-mutagenic , as shown in OECD TG 473 (In vitro cytogenicity study in mammalian cells), 490 (in vitro gene mutation study in mammalian cells using the thymidine kinase gene) and 471 (Bacterial reverse mutation test) trsting, with and without metabolic activation, in all the studies.


Therefore, it can be concluded that 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) does not meet the criteria for classification. Further studies are subsequently not required.