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EC number: 248-107-3 | CAS number: 26919-50-6
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
The reproductive/developmental 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 reproductive/developmental 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 reproductive/developmental toxicity. 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 in accordance with the OECD Guideline for Testing of Chemicals 422. Dose of 0, 100, 400, and 1600 mg/kg bw/day of the test substance were administered by stomach tube to groups of 12 male rats for 54 days. The test-article was formulated in drinking water and administered in 10 ml/kg bw. Histopathology and gross necropsy did not reveal any test article related changes. The organ weights showed some statistically significant differences, but these were not related to dosage or not affirmed by the findings in other groups, for example by the results of the satellite groups.
The same is true for the statistical significant differences of the haematological parameters and the result of the clinical chemistry, especially decreased activities of the liver enzymes in the blood. These are merely statistical effects without biological relevance. Two effects with a possible relation to the oral administration of the test substance were observed:
- At birth no differences were observed between the groups, but on day 4 after birth a higher number of dead pups was counted in the high-dose level group.
- With male rats a dose dependent decrease in body weight is observed. This effect is in the highest dose group statistically significant and confirmed by the satelite group but not confirmed by the body weight development of the females and not confirmed by the food consumption of males and females.
Although the influence of an infection by a parasite could be a possible explanation of both effects, a non-specific influence of the test substance cannot be excluded. The daily administration of a suspension of the test substance in 10 ml/ kg bw may have led to a reduced appetite of the animals. This could be especially true for the highest dosage group, as here the suspension was relatively dense. It is also possible that there was an osmotic effect of non-resorbed test substance in the intestine. At dosages of 100 and 400 mg/kg bw the animals showed no differences to the control animals (NOEL). a dose of 1600 mg/kg bw/day of the test substance may have induced an influence on the body weight gain of the males and the survival of pups until day 4 after birth. With regard to effects on fertility of the present study 1600 mg/kg bw/day of the test substance can be defined as "No Observed Adverse Effect Level" (NOAEL). The NOEL and NOAEL for systemic toxicity in the parent generation of test animals was found to be 400 mg/kg bw/day for both.
Short description of key information:
With regard to effects on fertility of the present study 1600 mg/kg bw/day of the test substance can be defined as "No Observed Adverse Effect Level" (NOAEL). The NOEL and NOAEL for systemic toxicity in the parent generation of test animals was found to be 400 mg/kg bw/day for both.
Justification for selection of Effect on fertility via oral route:
The study was conducted on a structurally similar substance (4-MPSAHt) by a GLP compliant laboratory, in accordance with OECD Testing Guideline 422.
Justification for selection of Effect on fertility via dermal route:
Results for the triethanolamine component of the registered substance show that the test substance produced no effects on mating, fertility, or offspring growth and survival. The NOAEL for systemic toxicity as well as for reproductive performance and fertility in parental animals was established at >1000 mg/kg bw/day, the highest dose tested. The NOAEL for postnatal toxicity in the offspring was 1000 mg/kg bw/day, whereas the NOAEL for prenatal developmental toxicity was determined to be 300 mg/kg bw/day based on decreased numbers of implants and delivered pups, and an increased post implantation loss.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- 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.
- Remarks:
- Study was conducted by a GLP accredited laboratory using OECD Testing Guideline 422. The study was conducted on 6-[(p-tosyl)amino]hexanoic acid, which is the carboxylic acid component of 6-[(p-tosyl)amino]hexanoic acid, compound with 2,2’,2’’-nitrilotriethanol (1:1), a structurally similar substance to the registered 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 followed
- 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
- Limit test:
- no
- Strain:
- Wistar
- Control animals:
- yes
- Clinical signs:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- f
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Remarks on result:
- other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Remarks on result:
- other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
- Reproductive effects observed:
- no
- Conclusions:
- The evidence reviewed in this endpoint assessment report suggests that 6 [methyl(phenylsulphonyl)amino]hexanoic acid and triethanolamine are not expected to induce reproductive/developmental toxicity, 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 reproductive/developmental toxicity. An experimental
study is subsequently not required. - Executive summary:
An expert assessment was conducted to evaluate the capacity of 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) to induce reproductive / developmental toxicity, to fulfil Annex VIII, Section 8.7.1. of the REACH Regulation (EC) No 1907/2007. It is expected that the substance will dissociate following an exposure event and, therefore, its potential reproductive/developmental toxicity 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 reproductive/developmental toxicity. 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 combined repeated dose toxicity study with reproduction/developmental toxicity screen according to the OECD TG 422 was undertaken for 6-[(p-Tosyl)amino]hexanoic acid. Under the conditions of this study, the no-observed-adverse-effect-level (NOAEL) on fertility of 6-[[(4-methylphenyl)sulphonyl] amino]hexanoic was considered 1600 mg/kg bw/day.
Reliable experimental data, performed in line with OECD TG guidelines and with an assigned Klimisch score of 1 was identified for triethanolamine. TEA did not cause reproductive / developmental toxicity. The NOAEL for systemic toxicity as well as for reproductive performance and fertility in parental animals was established at >1000 mg/kg bw/day, the highest dose tested. The NOAEL for postnatal toxicity in the offspring was 1000 mg/kg bw/day, whereas the NOAEL for prenatal developmental toxicity was determined to be 300 mg/kg bw/day based on decreased numbers of implants and delivered pups, and an increased post implantation loss.
The evidence reviewed in this endpoint assessment report suggests that 6-[methyl(phenylsulphonyl)amino]hexanoic acid and triethanolamine are not expected to induce reproductive/developmental toxicity, 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 reproductive/developmental toxicity. An experimental study is subsequently not required.
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 600 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no adverse effect observed
- Study duration:
- subchronic
- Species:
- rat
Effects on developmental toxicity
Description of key information
In the available OECD 414 toxicity study with 4-MPSAH, the substance was tested at 100, 400, and 1600 mg/kg bw/day. Some findings in foetuses were related to altered ossification; however, matemal thyroid hormone homeostasis likely contributed to those effects. In the same study, there was also a decrease in percent of males per litter and although the effects were statistically significant, the effect levels were low and did not show an increase in incidence between 400 and 1600 mg/kg bw/day. The OECD TG 414 for 4-MPSAH allowed to derive a NOAEL for maternal toxicity and embryo-foetal development of 100 mg/kg bw/day.
Reliable experimental data, performed in line with OECD TG guidelines and with an assigned Klimisch score 2, was identified for triethanolamine. TEA did not induce pre-natal developmental toxicity when administered via the oral route in female rats up to 500 mg/kg bw/day following a study performed according to the OECD TG 414.
Link to relevant study records
- Endpoint:
- developmental toxicity
- 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
- Limit test:
- no
- Species:
- rat
- Remarks on result:
- other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
- Remarks on result:
- other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.
- Developmental effects observed:
- no
- Conclusions:
- The evidence reviewed in this endpoint assessment report suggests that 6-
[methyl(phenylsulphonyl)amino]hexanoic acid and triethanolamine are not expected to induce
pre-natal developmental toxicity, 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 pre-natal developmental toxicity. An experimental study
is subsequently not required. - Executive summary:
An expert assessment was conducted to evaluate the capacity of 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) to induce pre-natal developmental toxicity, to fulfil Annex Annex IX, Section 8.7.2. of the REACH Regulation (EC) No 1907/2007. It is expected that the substance will dissociate following an exposure event and, therefore, its potential pre-natal toxicity 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 6-[methyl(phenylsulphonyl)amino]hexanoic acid to induce pre-natal developmental toxicity. 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 pre-natal developmental toxicity study undertaken according to the OECD TG 414 for 4-MPSAH allowed to derive a NOAEL for maternal toxicity and embryo-foetal development of 100 mg/kg bw/day.
Reliable experimental data, performed in line with OECD TG guidelines and with an assigned Klimisch score 2, was identified for triethanolamine. TEA did not induce pre-natal developmental toxicity when administered via the oral route in female rats up to 500 mg/kg bw/day following a study performed according to the OECD TG 414.
The evidence reviewed in this endpoint assessment report suggests that 6- [methyl(phenylsulphonyl)amino]hexanoic acid and triethanolamine are not expected to induce pre-natal developmental toxicity, 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 pre-natal developmental toxicity. An experimental study is subsequently not required.
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 100 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
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
Additional information
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