Reaction products of 1H-Imidazole-1-ethanol, 4,5-dihydro-, 2-(C7 odd-numbered alkyl) derivs. and sodium hydroxide and chloroacetic acid

Endpoint summary

Link to relevant study record(s)

Reference

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 included in Section 13.

Reason / purpose for cross-reference:

read-across source

Type:

absorption

Results:

For risk assessment purposes: oral and inhalation absorption: 100%

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 and 100% absorption can be assumed.

Conclusions:

Based on the assessment available for Alkylamidoamine glycinate majority C12, 14 (amphoacetate), the absorption factors for risk assessment purposes have been set at 100% for oral, inhalation and dermal absorption for Alkylamphocetates C8.

Description of key information

A toxicokinetic assessment for an analogue performed in accordance with the Guidance on information requirements and chemical safety assessment Chapter R.7c was considered appropriate to assess the toxicokinetic properties of C8 Amphoacetates. The absorption factors for risk assessment purposes were determined to be 100% for oral and inhalation absorption and 10% for dermal absorption. This data is read-across to C8 Amphoacetates.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

The conclusions for adsorption factors for C8 Amphoacetates were derived based on read-across of data from an analogue, Alkylamidoamine glycinate. The details on the read-across are included in Section 13.

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 moderate 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 log Kow 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 and 100% absoprtion can be assumed.