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

Endpoint summary

Description of key information

Acute toxicity oral and dermal studies have been conducted on the parent carboxylic acid of the tosyl salt (the registered substance) which is the component of the tosyl salt which will have a more significant impact on the environment based on the limited toxicity of triethanolamine. Both studies found that there was no toxic effect up to a dose rate of 2000 mg/kg bw/day, as such the substance is not classified as an Acute Oral Toxin or an Acute Dermal Toxin in accordance with EU CLP criteria.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

key study

Study period:

2012-03-28 to 2013-03-05

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study was conducted by a GLP accredited laboratory using OECD Testing Guideline 425. The study was conducted on 6-[(p-Tosyl)amino]hexanoic acid, which is the carboxylic acid component of the registered substance i.e. tosyl salt.

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

Strain: Rat Wistar SPF Charles River Germany D- 97633 Sulzfeld- Facility,
Species: Rattus norvegicus ssp.alba
Environmental conditions were monitored and recorded continuously over the study. The temperature in the animal room was in-between 20°C and 24°C and the relative humidity was in-between 40% and 70% . A 12/12h light/dark cycle was set.

During the study, the study rats were housed in TECHNIPLAST cages Type 2145 F. The cages measured 480 x 265x 210 mm (floor area 940 cm2). As bedding, sterilized sawdust was used. Two and three animals were housed per cage, respectively.

Diet and water:
For feeding, a standard pelleted diet (M3) of monitored quality was used. Potable water from the local mains of monitored quality was supplied ad libitum. Water bottels were changed daily.

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

The test substance was administered orally by a stomach tube (gavage). The substance was applied as a suspension in water. The applied volume was 20 ml/ kg body weight per animal. The dose (2000 mg/kg) was given in two fractions over a period of 4 hours. Dosing was performed sequentially: on day 1 three animals were treated and on day 5 two animals were treated.

Doses:

The dose (2000 mg/kg) was given in two fractions over a period of 4 hours. Dosing was performed sequentially: On day 1 three animals were treated and on day 5 two animals were treated. Dosing was done using a suspension of ASC plus in water with 20 ml suspension/kg body weight per rat.

No. of animals per sex per dose:

5 females were treated with one dose

Control animals:

no

Details on study design:

A dose of 2000 mg/kg ASCplus was administered in 2 fractions to 5 female rats using a stomach tube. The animals were caged in a group of 3 and in one of 2 animals. The observation period was 14 days. Prior to the beginning of the study, animals were acclimated for 5 days in their cages. Each rat was individually marked by a code on the tail. The environmetal conditions as well as the mortality, clinical effects and animal health were monitored over the whole test period. At the beginning and at the end of the study the body weight of all animals was measured. Moreover, a necropsy was performed on all animals after termination of the study and the organs were examined macroscopically.

Statistics:

Data recorded during the study were tabulated.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no toxicity observed

Mortality:

No moribund animals were observed within the test period of 14 days.

Clinical signs:

other: No clinical signs have been detected during and at the end of the exposure period.

Gross pathology:

No macroscopically detected pathological changes in organs or tissues of the animals were observed.

Other findings:

None of the animals showed any toxicity symptoms or behavioral changes over the whole observation period.

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The test substance did not cause any symptoms of toxicity after an oral dosage of 2000mg/kg. Therefore, the LD50 was reported as >2000 mg/kg bw/day, and the substance does not require classification as an acute oral toxin according to EU CLP criteria.

Executive summary:

The acute oral toxicity of the test substance was determined in accordance with the OECD Guideline for Testing of Chemicals 425, using the up-and-down procedure. An oral dosage of 2000 mg/kg of the test substance was administered in 2 fractions during 4 hours to 5 female rats. The test article was suspended in water and an administration volume of 20 ml/kg bw was used. During the observation period of 14 days environmental conditions as well as the animal health, clinical effects, mortality and body weight were monitored. At termination of the study, a necropsy was performed with all animals and the major organs were examined macroscopically. The test substance did not cause any symptoms of toxicity after an oral dosage of 2000mg/kg. Therefore, the LD₅₀ was reported as >2000 mg/kg bw/day, and the substance does not require classification as an acute oral toxin according to EU CLP criteria. The test substance was the carboxylic acid component of the registered substance. 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-[(p-Tosyl)amino]hexanoic acid by simple neutralisation with triethanolamine (TEA). Other than ionization of the carboxylic acid group, the 6-[(p-Tosyl)amino]hexanoic acid remains chemically unchanged upon salt formation. In water, the acid and amine components of 6-[(p-Tosyl)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. The pKa of the carboxylic acid group in 6-[(p-Tosyl)amino]hexanoic acid (pKa = 4.90) is the same in the free acid as it is in the TEA salt. As a result, 6-[(p-Tosyl)amino]hexanoic acid will respond to changes of pH in the same way whether it is in the salt form or as the parent carboxylic acid and hence it’s bioavailability will be the same.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Study period:

2013-01-07 to 2013-03-08

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study was conducted by a GLP accredited laboratory using OECD Testing Guideline 402.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Strain: Rat Wistar SPF Charles River Germany D- 97633 Sulzfeld- Facility,
Species: Rattus norvegicus ssp.alba

Environmental conditions were monitored and recorded continuously over the study. The temperature in the animal room was in-between 20°C and 24°C and the relative humidity was in-between 40% and 70% . A 12/12h light/dark cycle was set.

During the study, the study rats were housed individually in TECHNIPLAST cages Type 1284L. The cages measured 365 x 207 x 140 mm (floor area 530 cm2). As bedding, sterilized sawdust was used.

Diet and water:
For feeding, a standard pelleted diet (M3) of monitored quality was used. Potable water from the local mains of monitored quality was supplied ad libitum. Water bottels were changed daily.

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

The test item was applied dermal as a paste with 'aqua pro injectione'. The test substance was applied uniformly over an area of 6-10 cm² and it was held in contact with the skin with a porous gauze dressing and non-irritating tape for throughout the 24 hour exposure period. Further, the test site was covered with a adhesive plaster to retain the gauze dressing and ensure that the animals did not ingest the test substance. The fur was removed from the dorsal area of the trunk by clipping 24 hours before the application of the test article. At the end of the exposure period, residual test substance was removed using water.

Duration of exposure:

The animals were observed for a period of 14 days after substance application.

Doses:

As no estimate of the substance`s lethality was available, the initial dosing was 2000 mg/kg (limit test), which was applied to 6-10 cm2 area of skin. Untreated skin areas were used as controls.

No. of animals per sex per dose:

Five animals per dose and sex were used.

Control animals:

no

Details on study design:

Five male rats and five female rats were individually housed in cages and exposed dermally to a limit dose of 2000 mg/kg ASC plus for 14 days. Prior to the study, animals were acclimated for 5 days and the health status such as the body weight was constantly observed. Each rat was individually marked by a code on the tail. Exposure was done on two different days: day 1: 3 males and 3 females, day 2: 2 males and 2females. Bodyweights and clinical signs were monitored during the study. The body weights are reported on day 7 and day 14 after start of the exposure. The animals were sacrificedat the end of the study.

Statistics:

Data were summarized in tabular form

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no effects at limit dose of 2000 mg/kg bw.

Mortality:

There were no moribund animals.

Clinical signs:

other: The animals showed no dermal lesions, no erythema and no oedema. (No erythema=0, No oedema=0)

Gross pathology:

A necropsy was performed on all animals at study termination and the mayor organs were macroscopically examined. No macroscopically detected pathological changes in organs or tissues of the animals were observed.

Other findings:

No animal indicated any symptoms of toxicity during the whole observation period. No behavioral and clinical signs were observed.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

A single dermal administration of 2000 mg/kg bw of the test substance to 5 male and 5 female rats did not cause any sign of systemic toxicity or dermal irritation were observed. The LD50 of the test substance was reported as >2000 mg/kg bw/day, therefore the substance does not require classification as an acute dermal toxin according to EU CLP criteria.

Executive summary:

The dermal toxicity of the test substance to rats was determined in accordance with the OECD Guideline for Testing of Chemicals 402. By clipping 24 hours before the application of the test article the fur was removed from the dorsal area of the trunk of the animals. The test article was moistured with aqua p.i. and 2000 mg/kg bw of the test substance were applied to 5 female and five male rats in an occlusive way for 24 hours. At the end of the exposure period, any residual test substance was removed using water. During the observation period of 14 days, clinical signs and bodyweight were monitored. No signs of systemic toxicity and no signs of dermal irritation of the test substance were observed. The LD₅₀ of the test substance was reported as >2000 mg/kg bw/day, therefore the substance does not require classification as an acute dermal toxin according to EU CLP criteria. The test substance was the carboxylic acid component of the registered substance. 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-[(p-Tosyl)amino]hexanoic acid by simple neutralisation with triethanolamine (TEA). Other than ionization of the carboxylic acid group, the 6-[(p-Tosyl)amino]hexanoic acid remains chemically unchanged upon salt formation. In water, the acid and amine components of 6-[(p-Tosyl)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. The pKa of the carboxylic acid group in 6-[(p-Tosyl)amino]hexanoic acid (pKa = 4.90) is the same in the free acid as it is in the TEA salt. As a result, 6-[(p-Tosyl)amino]hexanoic acid will respond to changes of pH in the same way whether it is in the salt form or as the parent carboxylic acid and hence it’s bioavailability will be the same.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Acute toxicity oral and dermal studies have been conducted on the parent carboxylic acid of the tosyl salt (the registered substance) which is the component of the tosyl salt which will have a more significant impact on the environment based on the limited toxicity of triethanolamine. Both studies found that there was no toxic effect up to a dose rate of 2000 mg/kg bw/day, as such the substance is not classified as an Acute Oral Toxin or an Acute Dermal Toxin in accordance with EU CLP criteria. 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-[(p-Tosyl)amino]hexanoic acid by simple neutralisation with triethanolamine (TEA). Other than ionization of the carboxylic acid group, the 6-[(p-Tosyl)amino]hexanoic acid remains chemically unchanged upon salt formation. In water, the acid and amine components of 6-[(p-Tosyl)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. The pKa of the carboxylic acid group in 6-[(p-Tosyl)amino]hexanoic acid (pKa = 4.90) is the same in the free acid as it is in the TEA salt. As a result, 6-[(p-Tosyl)amino]hexanoic acid will respond to changes of pH in the same way whether it is in the salt form or as the parent carboxylic acid and hence it’s bioavailability will be the same. In addition, studies have shown that the other component of the tosyl salt, the triethanolamine, is not considered to be an acute oral or acute dermal toxin. In conclusion, the tosyl salt is not considered to be an acute oral or acute dermal toxin, therefore the registered substance does not required classification as an acute oral toxin or an acute dermal toxin, in accordance with EU CLP criteria.

Justification for selection of acute toxicity – oral endpoint

Study was conducted by a GLP accredited laboratory using OECD Testing Guideline 425. The study was conducted on the parent carboxylic acid of the tosyl salt (the registered substance) which is the component of the tosyl salt which will have a more significant impact on the environment based on the limited toxicity of triethanolamine. The test substance was found to not cause toxic signs at a dose of 2000 mg/kg bw/day. The substance does not require classification as an acute oral toxin in accordance with EU CLP criteria.

Justification for selection of acute toxicity – inhalation endpoint

This study was considered scientifically unjustified 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.

Justification for selection of acute toxicity – dermal endpoint

Study was conducted by a GLP accredited laboratory using OECD Testing Guideline 402. The study was conducted on the parent carboxylic acid of the tosyl salt (the registered substance) which is the component of the tosyl salt which will have a more significant impact on the environment based on the limited toxicity of triethanolamine. The test substance did not produce any toxic effects or signs of dermal irritation at the exposure dose of 2000 mg/kg bw/day. The LD50 of the test substance was reported as >2000 mg/kg bw/day, therefore the substance does not require classification as an acute dermal toxin according to EU CLP criteria.

Justification for classification or non-classification

Studies were conducted on the carboxylic acid component of the registered substance (tosyl salt) to determine the acute oral and acute dermal toxicity of the substance. Due to the behaviour of the tosyl salt in water, whereby the salt completely dissociates and the two components (carboxylic acid and triethanolamine) behave essentially as independent substances, it can be concluded that the lack of acute toxicity (Acute Oral LD₅₀ > 2000 mg/kg bw/day and Acute Dermal LD₅₀ >2000 mg/kg bw/day) seen in the carboxylic acid studies, and in literature studies on the treithanolamine, results in the tosyl salt not requiring classification as an Acute Oral or Acute Dermal toxin in accordance with EU CLP criteria.