Acetic acid, chloro-, sodium salt, reaction products with 4,5-dihydro-2-undecyl-1H-imidazole-1-ethanol and sodium hydroxide

Basic toxicokinetics

Some information in this page has been claimed confidential.

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

The rationale to read across the data is attached in Section 13.

Cross-reference

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: Theoretical assessment

Adequacy of study:

key study

Study period:

July 2010

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Toxicokinetic assessment by a certified toxicologist based on the available information.

Qualifier:

according to guideline

Guideline:

other: Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance

Qualifier:

according to guideline

Guideline:

other: ECB EU Technical Guidance Document on Risk Assessment, 2003

GLP compliance:

no

Details on test animals or test system and environmental conditions:

Not applicable

Type:

absorption

Results:

For risk assessment purposes: oral absorption 100%, inhalation absorption 100% and dermal absorption 10%

In general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract after oral administration. The relatively small molecular weight (between 367 and 446 for the different forms) and the high water solubility (1 kg/L) are favourable for oral absorption. Because the substance has surface-active properties and a complex composition with multiple constituents, a log Kow could not be determined by the standard experimental methods. However estimates showed a higher solubility in water than in n-octanol. However, based on the moderate lipophilic character of the main surfactant compound expected from the presence of a hydrophobic alkyl chain structure Alkylamidoamine glycinate has the potential to be absorbed by passive diffusion. In contrast, ionization of Alkylamidoamine glycinate will impair the uptake since compounds need to pass the lipid membranes in the gastrointestinal wall (Reference:, Amidon GL. Mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620-43). Overall, it is likely that Alkylamidoamine glycinate is absorbed from the gastro-intestinal tract to a certain extent. Slight variations observed in the liver weights and clinical chemistry in the 28-day repeated dose toxicity study provided some evidence of a potential absorption by the oral route. For risk assessment purposes oral absorption of Alkylamidoamine glycinate is set at 100%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

 

Once absorbed, distribution of the test substance throughout the body is expected based on its relatively low molecular weight. Based on its relatively hydrophilic character, extracellular concentration is expected to be higher than intracellular concentration. Absorbed Alkylamidoamine glycinate might undergo conjugation. The conjugates will either be excreted via the bile (high molecular weight compounds) or the urine (low molecular weight compounds; Reference: ECB EU Technical Guidance Document on Risk Assessment, 2003).

 

The boiling point could not be determined, but decomposition starts at 160°C. Due to the relatively low vapour pressure and since the substance is produced and used only as an aqueous solution, it is not likely that Alkylamidoamine glycinate will reach the nasopharyngeal region or subsequently the tracheobronchial or pulmonary region. If Alkylamidoamine glycinate reaches the tracheobronchial region, absorption through aqueous pores will be limited, taking the molecular weight of > 200 into account. However, the high water solubility of Alkylamidoamine glycinate (1 kg/L) is favourable for dissolution of the substance in the mucus lining of the respiratory tract. In addition, based on the structure of the main constituents and the presence of hydrophobic and hydrophilic parts Alkylamidoamine glycinate has the potential of crossing the alveolar and capillary membranes by passive diffusion. If Alkylamidoamine glycinate is inhaled, absorption of the substance is expected to be limited. For risk assessment purposes the inhalation absorption of Alkylamidoamine glycinate is set at 100%.

 

Alkylamidoamine glycinate being a liquid has the potential to partition from the stratum corneum into the epidermis, which is also enhanced by the high water solubility (1 kg/L). Due to the complexity of the UVCB substance and presence of inorganic salt a realistic logKow value could not be determined experimentally. However, the moderate lipophilic character of the surfactant constituents with various lengths of a lipohilic alkyl chain may indicate that the transfer between the stratum corneum and the epidermis could occur for some of the constituents. As a first approach, based on the molecular weight (between 367 and 446 for the different forms of the major constituents), the criteria for 10% dermal absorption as given in the TGD (Reference: ECB EU Technical Guidance Document on Risk Assessment, 2003; MW > 500 and log Pow< -1 or > 4) are not met. However, high water solubility and ionization state are expected to influence significantly the dermal absorption potential. The presence of charges has been shown to reduce dramatically the passage across the skin (Reference: H. Schaefer, T. E. Redelmeier (eds). In: Skin Barrier – Principles of percutaneous absorption.S. Krager AG (publ.), 1996). As produced or under the use conditions the surfactant part of the substance will be either as a sodium salt, or as an amphoteric form with positive and negative charges, therefore less likely to be absorbed. This is fully supported by experimental data on a structurally related amphoteric surfactant, dodecylamidopropylbetaine (CAS# 4292-10-8) showing a dermal absorption of less than 3.5% in Wistar rats (Reference: HERA (Human and Environmental Risk Assessment on ingredients of household cleaning products), 2005, http://www.heraproject.com/RiskAssessment.cfm). This result is considered relevant for Alkylamidoamine glycinate to propose a dermal absorption factor of 10% for risk assessment purposes.

Conclusions:

Based on the data available, the absorption factors for risk assessment purposes have been set at oral absorption 100%, inhalation absorption 100% and dermal absorption 10%.

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Acetic acid, chloro-, sodium salt, reaction products with 4,5-dihydro-2-undecyl-1H-imidazole-1-ethanol and sodium hydroxide

EC Number:

271-794-6

EC Name:

Acetic acid, chloro-, sodium salt, reaction products with 4,5-dihydro-2-undecyl-1H-imidazole-1-ethanol and sodium hydroxide

Cas Number:

68608-66-2

Molecular formula:

Not applicable (a generic molecular formula cannot be provided for this specific UVCB substance)

IUPAC Name:

Reaction products of 1H-Imidazole-1-ethanol, 4,5-dihydro-, 2-(C11 alkyl) derivs. and sodium hydroxide and chloroacetic acid

Constituent 2

Reference substance name:

Sodium chloride

EC Number:

231-598-3

EC Name:

Sodium chloride

Cas Number:

7647-14-5

Molecular formula:

ClNa

IUPAC Name:

Sodium chloride

Constituent 3

Reference substance name:

Sodium glycollate

EC Number:

220-624-9

EC Name:

Sodium glycollate

Cas Number:

2836-32-0

Molecular formula:

C2H3O3.Na

IUPAC Name:

Sodium;2-hydroxyacetate

Constituent 4

Reference substance name:

Water

EC Number:

231-791-2

EC Name:

Water

Cas Number:

7732-18-5

Molecular formula:

H2O

IUPAC Name:

water

Test material form:

liquid

Details on test material:

- Composition as included in substance identification profile.

Test animals

Details on test animals or test system and environmental conditions:

Not applicable

Results and discussion

Main ADME results

Type:

absorption

Results:

For risk assessment purposes: oral absorption 100%, inhalation absorption 100% and dermal absorption 10%

Any other information on results incl. tables

In general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract after oral administration. The relatively small molecular weight (between 367 and 446 for the different forms) and the high water solubility (1 kg/L) are favourable for oral absorption. Because the substance has surface-active properties and a complex composition with multiple constituents, a log Kow could not be determined by the standard experimental methods. However estimates showed a higher solubility in water than in n-octanol. However, based on the moderate lipophilic character of the main surfactant compound expected from the presence of a hydrophobic alkyl chain structure Alkylamidoamine glycinate has the potential to be absorbed by passive diffusion. In contrast, ionization of Alkylamidoamine glycinate will impair the uptake since compounds need to pass the lipid membranes in the gastrointestinal wall (Reference:, Amidon GL. Mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620-43). Overall, it is likely that Alkylamidoamine glycinate is absorbed from the gastro-intestinal tract to a certain extent. Slight variations observed in the liver weights and clinical chemistry in the 28-day repeated dose toxicity study provided some evidence of a potential absorption by the oral route. For risk assessment purposes oral absorption of Alkylamidoamine glycinate is set at 100%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

 

Once absorbed, distribution of the test substance throughout the body is expected based on its relatively low molecular weight. Based on its relatively hydrophilic character, extracellular concentration is expected to be higher than intracellular concentration. Absorbed Alkylamidoamine glycinate might undergo conjugation. The conjugates will either be excreted via the bile (high molecular weight compounds) or the urine (low molecular weight compounds; Reference: ECB EU Technical Guidance Document on Risk Assessment, 2003).

 

The boiling point could not be determined, but decomposition starts at 160°C. Due to the relatively low vapour pressure and since the substance is produced and used only as an aqueous solution, it is not likely that Alkylamidoamine glycinate will reach the nasopharyngeal region or subsequently the tracheobronchial or pulmonary region. If Alkylamidoamine glycinate reaches the tracheobronchial region, absorption through aqueous pores will be limited, taking the molecular weight of > 200 into account. However, the high water solubility of Alkylamidoamine glycinate (1 kg/L) is favourable for dissolution of the substance in the mucus lining of the respiratory tract. In addition, based on the structure of the main constituents and the presence of hydrophobic and hydrophilic parts Alkylamidoamine glycinate has the potential of crossing the alveolar and capillary membranes by passive diffusion. If Alkylamidoamine glycinate is inhaled, absorption of the substance is expected to be limited. For risk assessment purposes the inhalation absorption of Alkylamidoamine glycinate is set at 100%.

 

Alkylamidoamine glycinate being a liquid has the potential to partition from the stratum corneum into the epidermis, which is also enhanced by the high water solubility (1 kg/L). Due to the complexity of the UVCB substance and presence of inorganic salt a realistic logKow value could not be determined experimentally. However, the moderate lipophilic character of the surfactant constituents with various lengths of a lipohilic alkyl chain may indicate that the transfer between the stratum corneum and the epidermis could occur for some of the constituents. As a first approach, based on the molecular weight (between 367 and 446 for the different forms of the major constituents), the criteria for 10% dermal absorption as given in the TGD (Reference: ECB EU Technical Guidance Document on Risk Assessment, 2003; MW > 500 and log Pow< -1 or > 4) are not met. However, high water solubility and ionization state are expected to influence significantly the dermal absorption potential. The presence of charges has been shown to reduce dramatically the passage across the skin (Reference: H. Schaefer, T. E. Redelmeier (eds). In: Skin Barrier – Principles of percutaneous absorption.S. Krager AG (publ.), 1996). As produced or under the use conditions the surfactant part of the substance will be either as a sodium salt, or as an amphoteric form with positive and negative charges, therefore less likely to be absorbed. This is fully supported by experimental data on a structurally related amphoteric surfactant, dodecylamidopropylbetaine (CAS# 4292-10-8) showing a dermal absorption of less than 3.5% in Wistar rats (Reference: HERA (Human and Environmental Risk Assessment on ingredients of household cleaning products), 2005, http://www.heraproject.com/RiskAssessment.cfm). This result is considered relevant for Alkylamidoamine glycinate to propose a dermal absorption factor of 10% for risk assessment purposes.

Applicant's summary and conclusion

Conclusions:

Based on the data available for Alkylamidoamine glycinate majority C12, 14 (amphoacetate), the absorption factors for risk assessment purposes have been set at oral absorption 100%, inhalation absorption 100% and dermal absorption 10%. This data is read across to the registered substance.