6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1)

Endpoint summary

Description of key information

The sub-chronic toxicity (90-day) via the oral route 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 toxic 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 repeated dose 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 for its potential to cause sub-chronic toxicity (90-day) via the oral route, in accordance with the OECD Guideline for Testing of Chemicals 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents). The test item as a suspension in the vehicle (distilled water), was administered by gavage once daily to three groups of Sprague-Dawley rats starting from the age of 6-7 weeks at the doses 100, 400 and 1600 mg/kg body weight (kg/bw/day) for 90 days. Male rats appeared to be more sensitive to the test substance in this study, therefore, under the conditions of this study, the no-observed-adverse-effect-level (NOAEL) was considered 100 mg/kg bw/day for males and 1600 mg/kg bw/day for females. Although the NOAEL derived for the substance in male rats is 100 mg/kg bw/day, the adverse effects observed in the study are not severe enough to justify classification in Specific target organ toxicity - repeated (STOT-RE) category under GHS and CLP.

TEA was tested for its potential to cause sub-chronic toxicity (90-day) via the oral route , in accordance with the OECD Guideline for Testing of Chemicals 408.TEA did not induce sub-chronic toxicity when administered via the oral route in females and males’ rats up to 1000 mg/kg bw/day, the highest dose tested.

The repeated dose short term toxicity of the registered substance was determined via read-across to the results of testing with 4-MPSAH. 4-MPSAH was tested in accordance with the OECD Guideline for Testing of Chemicals 422. Doses 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. At dosages of 100 and 400 mg/kg bw/day the animals showed no differences to the control animals (NOEL). All examined organs and tissues showed a normal histological structure. 1600 mg/kg bw/day may have induced an influence on the body weight gain of the males (and the survival of pups until day 4 after birth). The NOEL and NOAEL for the test substance is defined as 400 mg/kg bw/day. The LOEL for the test substance is defined as 1600 mg/kg bw/day.

No studies were conducted to determine the repeated dose toxicity via inhalation or dermal exposure as, owing to the physical properties and usage of the substance, it was considered unlikely that inhalation or dermal exposure would occur, therefore making it unjustifiable to perform further animal testing.

According to the activity of the acid and amine component, the evidence reviewed in this endpoint assessment report suggests that 6-[methyl(phenylsulphonyl)amino]hexanoic acid and triethanolamine are not expected to induce sub-chronic toxicity via the oral route, and as such the substance 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) (N-methyl salt) is not expected to induce sub-chronic toxicity via the oral route. An experimental study is subsequently not required.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Remarks:

90 days

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

Remarks on result:

other: An expert assessment was performed based on information on individual constituents of the substance and a structurally similar substance.

Critical 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 sub-chronic toxicity via the oral route, and as such the substance 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) (N-methyl salt) is not expected to induce sub-chronic toxicity via the oral route. 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 sub-chronic 90 day toxicity, via the oral route, was evaluated to fulfil Annex Annex IX, Section 8.6.2. of the REACH Regulation (EC) No 1907/2007. It is expected that the substance will dissociate following an exposure event and, therefore, its potential sub-chronic 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 MPSAH to induce sub-chronic toxicity (90 day) via the oral route. 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. 

A GLP compliant (Klimisch score of 1) repeated dose toxicity study was undertaken according to the OECD TG 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents) for 4-MPSAH. As a result of the OECD TG 408, the no-observed-adverse-effect-level (NOAEL) is considered 100 mg/kg bw/day for males and 1600 mg/kg bw/day for females. Although the NOAEL derived for the substance in male rats is 100 mg/kg bw/day, the adverse effects observed in this study are not severe enough to justify classification in Specific target organ toxicity - repeated (STOT-RE) category under GHS and CLP

Reliable experimental data, performed in line with OECD TG guidelines and with an assigned Klimisch score 2, was identified for TEA. The results for TEA were negative for sub-chronic toxicity when the substance was administered via the oral route in females and males’ rats up to 1000 mg/kg bw/day, the highest dose tested, under the conditions of the study. 

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

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2012-2013

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

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.

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

Principles of method if other than guideline:

Daily administration by stomach tube for 54 days

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Germany, D-97633 Sulzfeld
- Age at purchase: 11 weeks
- weight rage at time of grouping: males, 175-200 g
- Fasting period before study: no
- Housing: 2 per cage,
- Cages: TECHNIPLAST filter top cages type 2145 F with an G-Temp (PSU) durable filter cover, 480x265x210 mm³, floor area 940 cm²,
- Source: Techniplast Company, Italy
- Diet: ad libitum, M3, BONAGRO Ltd., reg. CZ 10174, Czech Republic
- Water: ad libitum, tap water
- Acclimation period: 9 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE: Suspension in water

- Amount of vehicle: 10 ml/kg
- single daily adminisration at similar times each day

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

54 administrations, (2 weeks before mating, 2 weeks during mating and 26 days after mating)
dissection ca. 24 hours after the last administration

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0, 100, 400, 1600 mg/kg body weight (mg/kg bw)
Basis:
actual ingested

No. of animals per sex per dose:

12 males, satelite groups (control and highest dosage): 5 males each

Control animals:

yes

Details on study design:

- Control groups: drinking water
- Dose selection rationale: Results of an acute toxicity study with oral administration to male and female rats
- Result: no effects up to and including 2000 mg/kg bw.
- Rationale for animal assignment: randomly grouped
- Section schedule rationale: all animals were sacrificed

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: on administration days 1, 8, 15, 22, 29, 36, 42, 50 and on day of autopsy

FOOD CONSUMPTION : 2 weeks before mating, after 2 week mating period and weekly until the end of the study

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 14 (before mating) and prior to autopsy from the satelite groups and from the control and highest dose group.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:day 14 (before mating) and prior to autopsy from the satelite groups and from the control and high dose group.

URINALYSIS: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- Organ weights: brain, heart, thymus, spleen, liver, testis, epididymis, kidney, adrenal gland

HISTOPATHOLOGY: Yes: high dose and control animals
- Organ: medulla oblongata, brain, heart, pancreas + lymphnode, spleen, liver, lung, small intestine, stomach, kidneys, adrenal gland, testes, prostrate, urinary bladder, bone + bone marrow, thymus, trachea, white + brown fat, muscle, pituitary gland

Statistics:

Statistical evaluation was operated using the software SPPS version 16.0. Group data were represented by mean, standard deviation and median. Statistical analysis in case of data measured once during the study (organ weight, haematology, clinical chemistry) : Mann-Whitney U test for pairwise comparison between control and individual experimental groups on significance level alpha = 0.05.
Statistical analysis in case of repeated data measurement (body weight, food intake): Repeated measures ANOVA (procedure General Linear Model (GLM) for Repeated Measures in SPSS statistical software).

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

statistically significant decrease after dosages of 1600 mg/kg bw./day

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS:
- 100, 400 and 1600 mg/kg bw/day:
no differences to the control animals observable

MORTALITY: no

BODY WEIGHT GAIN: 1600 mg/kg bw: reduced

FOOD CONSUMPTION: no statistical differences

HAEMATOLOGY/ CLINICAL CHEMISTRY:
Haematology and clinical chemistry reveales some statistically significant differences, but these were neither related to dosage not confirmed by the findings in other groups, for example by the results of the satelite groups, or the effects are of biological low relevance i.e..

URINALYSIS: not examined

NEUROBEHAVIOUR: not examined

ORGAN WEIGHTS: no statistical differences

GROSS PATHOLOGY: no dosage related effects

HISTOPATHOLOGY: NON-NEOPLASTIC: no statistical differences

HISTOPATHOLOGY: NEOPLASTIC: no statistical differences

HISTORICAL CONTROL DATA: not given

Dose descriptor:

NOEL

Effect level:

400 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

Dose descriptor:

NOAEL

Effect level:

400 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: decrease in body weight (not exceeding 10%)

Dose descriptor:

LOEL

Effect level:

1 600 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: decrease in body weight (not exceeding 10%)

Critical effects observed:

not specified

Conclusions:

Daily dosages of 0, 100, 400, and 1600 mg/kg bw of the test substance were administered by stomach tube to groups of 12 male rats for 54 days. Satellite animals in a control and the highest dose group (1600mg/kg bw) with 5 individual each were also included.The test-article was formulated in drinking water and administered in 10 ml/kg bw..
At dosages of 100 and 400 mg/kg bw. the animals showed no differences to the control animals (NOAEL).
1600 mg ASC plus/kg bw. , considered as the LOEC, may have induced an influence on the body weight gain of the males (and the survival of pups until day 4 after birth).
NOAEL: 400 mg/kg bw.

Executive summary:

The repeated dose toxicity of the test substance to rats was determined in accordance with the OECD Guideline for Testing of Chemicals 422. Doses 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. At dosages of 100 and 400 mg/kg bw/day the animals showed no differences to the control animals (NOEL). All examined organs and tissues showed a normal histological structure. 1600 mg/kg bw/day may have induced an influence on the body weight gain of the males (and the survival of pups until day 4 after birth). The NOEL and NOAEL for the test substance is defined as 400 mg/kg bw/day. The LOEL for the test substance is defined as 1600 mg/kg bw/day. The test substance was the carboxylic acid component of the tosyl salt. Read-across between the tosyl salt carboxylic acid (6 -[(p-tosyl)amino]hexanoic acid) and the registered substance is considered justified as the registered substance is manufactured directly from 6-[methyl(phenylsulphonyl)amino]hexanoic acid by simple neutralisation with triethanolamine (TEA). 6-[methyl(phenylsulphonyl)amino]hexanoic acid and 6-[(p-tosyl)amino]hexanoic acid are structural isomers. They are the same molecular weight and differ only in the position of a single methyl group. In the former, the methyl group is bound to the nitrogen atom of the sulphonamide linkage whereas in the latter, it resides on the aromatic ring. Other than ionization of the carboxylic acid group, the 6-[methyl(phenylsulphonyl)amino]hexanoic acid remains chemically unchanged upon salt formation. In water, the acid and amine components of 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2’,2’’-nitrilotriethanol (1:1) dissociate completely and behave essentially as independent substances. Since TEA can be considered non-hazardous, it is the acid component of the salt that will have a more significant impact on the outcome of any (eco)toxicological or environmental tests.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

The repeated dose oral toxicity of the registered substance was determined via expert assement and read-across to the results of testing on a structurally similar substance 6-[[(4-methylphenyl) sulphonyl] amino] hexanoic acid (4-MPSAH; EC 278-934-5). The test was conducted in accordance with OECD 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)  and OECD TG 422 to GLP standards.

 

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

This study is not deemed necessary as the substance does not solidify readily and when it does it is a waxy solid and does not form inhalable particles. The substance has also been estimated to have a very low vapour pressure via modelling using the EPIsuite modelling program. The substance is provided to customers only in formulated products and is not isolated. Therefore, inhalation is not considered to be a significant route of exposure to the registered substance, in accordance with REACH Annex XI, Column 2. The results of a repeated dose oral toxicity study will be provided (section 7.5.1). It is therefore considered unjustified to perform further animal testing.

 

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:

This study is not deemed necessary as the substance does not solidify readily and when it does it is a waxy solid and does not form inhalable particles. The substance has also been estimated to have a very low vapour pressure via modelling using the EPIsuite modelling program. The substance is provided to customers only in formulated products and is not isolated. Therefore, inhalation is not considered to be a significant route of exposure to the registered substance, in accordance with REACH Annex XI, Column 2. The results of a repeated dose oral toxicity study will be provided (section 7.5.1). It is therefore considered unjustified to perform further animal testing.

 

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

This study is not considered necessary as repeated dose toxicity via the oral route will be provided (section 7.5.1), in accordance with REACH Annex IX, Column 2. Dermal exposure to the substance is not considered likely as the substance is supplied in an aqueous formulation without isolation of the substance. In addition, the substance is directly added to the formulated product without isolation so skin contact is not considered a major exposure route to this substance. Therefore, further animal testing is considered to be unjustified.

 

Justification for selection of repeated dose toxicity dermal - local effects endpoint:

This study is not considered necessary as repeated dose toxicity via the oral route will be provided (section 7.5.1), in accordance with REACH Annex IX, Column 2. Dermal exposure to the substance is not considered likely as the substance is supplied in an aqueous formulation without isolation of the substance. In addition, the substance is directly added to the formulated product without isolation so skin contact is not considered a major exposure route to this substance. Therefore, further animal testing is considered to be unjustified.

Justification for classification or non-classification

The registered substance is not classified as causing toxicity to specific target organs via repeated exposure. At dosages of 100 and 400 mg/kg bw/day the animals showed no differences to the control animals (NOEL). All examined organs and tissues showed a normal histological structure. 1600 mg/kg bw/day may have induced an influence on the body weight gain of the males (and the survival of pups until day 4 after birth). The NOEL and NOAEL for the test substance is defined as 400 mg/kg bw/day. The LOEL for the test substance is defined as 1600 mg/kg bw/day. There was no indication of adverse effects to any organs of the test animals.