Amines, (2-ethylhexyl)(hydrogenated tallow alkyl)methyl

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Type:

absorption

Results:

minimal and slow absorption

Type:

distribution

Results:

Based on lipophilicity, absorbed material is likely to be distributed to fatty tissues

Type:

metabolism

Results:

Expected to be metabolized heavily by the liver to secondary alkyl amines followed by oxidation and phase II conjugation

Type:

excretion

Results:

Expected to occur primarily in the bile

Executive summary:

Summary

The notified substance does not have toxicokinetic (TK) data. Therefore, the TK assessment is based on the physical/chemical properties, information from standard toxicology studies (e.g., OECD 408 repeat dose study), QSAR modeling, and computational toxicology tools. Table 1 is an overview of key chemical information used in the assessment.

 

Table 1. Overview of chemical structure and physical/chemical properties.

Representative chemical structure
SMILES (used for QSAR and modelling)	CN(CCCCCCCCCCCCCC)CC(CC)CCCC (smallest alkyl derivative)
Molecular weight (MW)	339.7-395.8
Water solubility	0.00048 – 0.00062 mg/L
Kow	6.1
Vapor pressure	3.275 X 10-5 Pa at 20°C
Physical state	Liquid

Estimates are for C14 because tallow is a C14-C18 range

 

The notified substance has the following TK characteristics:

 

        I.           Absorption

a.      Oral: minimal and slow absorption

b.      Dermal: minimal and slow absorption

c.      Inhalation: not expected due to low vapor pressure

      II.           Distribution: Based on liphophilicity, absorbed material is likely to be distributed to fatty tissues

    III.           Metabolism: Expected to be metabolized heavily by the liver to secondary alkyl amines followed by oxidation and phase II conjugation

   IV.           Excretion: Expected to occur primarily in the bile

 

 

I.                  Absorption

 

a.    Oral Absorption

 

The notified substance is expected to be absorbed after oral administration based on repeat dose toxcity studies but this is likely minimal and occurs slowly. The following information supports this:

 

1.      Test data with the notified substance

 

The notified substance was bioavailable based on the effects observed in OECD 422 and OECD 408 oral gavage studies. This includes increased liver weight with associated enzyme changes that was concluded by the study director to be an adaptive response, most likely due to the metabolism that is expected to occur with the notified substance (see metabolism section).

 

2.      Modeling using SwissADME (http://www.swissadme.ch/index.php)

 

Gastrointestinal absorption was predicted using SwissADME, which is a freely available web-based tool (Daina et al., 2017). SwissADME predicts the absorption and bioavailability based on a number of paramaters known to influence these properties, including physical/chemical properties, lipophilicity, and polarity.

 

The notified substance was assessed to have "low" GI absorption by SwissADME. In addition, the probability of the substances being a substrate or non-substrate of the permeability glycoprotein (P-gp) was calculated. P-gp plays a primary role among ATP-binding cassette transporters or ABC transporters in the active efflux through biological membranes. The notified substance was predicted to not be a substrate of P-gp, indicating it is unlikely to be involved in active transport processes. 

 

3.      Evaluation of critical physical/chemical properties known to influence absorption

Absorption of a chemical from the gastrointestinal (GI) tract depends on its physical properties, including lipid solubility and its dissolution rate. The European Chemicals Agency (ECHA) has established guidance for determining oral absorption potential (Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C: Endpoint Specific Guidance, November, 2014). As seen in Table 1, the molecular weight of the notified substance indicates that oral absorption may occur. However, based on the low water solubility and high Kow, absorption is likely limited.

 

 

Table 1. Physiochemical Properties and Oral Absorption

Physical and Chemical Parameter	Relationship to Absorption	Notified Substance
Molecular Weight	< 500: favorable for absorption > 1000: do not favor absorption	339.7-395.8: indicates oral absorption may occur
Water solubility	Water soluble substances will dissolve in GI fluids and may be absorbed by bulk diffusion	Low water solubility indicates oral absorption is low
Kow	Values between -1 and 4 are favorable for passive diffusion	Kow of 6.1 indicates passive diffusion is low

 

b.    Dermal Absorption

 

Dermal absorption of the notified substance is expected to be minimal based on the physiochemical properties and occur slowly based on the modeled Kp. Table 2 compares the physiochemical properties of the notified substance with the ECHA guidance for determining dermal absorption potential(Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C: Endpoint Specific Guidance, November, 2014). The molecular weight of the notified substance indicates that dermal absorption may occur; however, the material is very insoluble in water and the Kow exceeds the optimal cut-off criteria indicating that dermal absorption may occur but to a small extent.

 

Table 2. Physiochemical Properties and Dermal Absorption

Physical and Chemical Parameter	Relationship to Absorption	Notified Substance
Molecular Weight	< 100: favorable for absorption > 500: too large for penetration	339.7-395.8: indicates dermal absorption may occur
Water solubility	< 1 mg/L: dermal uptake is likely to be low	0.00048 – 0.00062 mg/L indicates dermal absorption is low
Kow	Values between 1 and 4 are favorable for dermal absorption; > 6 very limited penetration and uptake	Kow of 6.1 indicates limited dermal absorption

 

 

The permeability coefficient (Kp) was estimated use EPA Dermwin v2.02 and SwissADME:

1.      Dermwin v2.02 using measured Kow: 0.22 cm/hr

2.      Dermwin v2.02 using EPISUITE predicted Kow: 62.1 cm/hr

3.      SwissADME: 216 cm/hr (based on a prediction of log Kp of -1.23 cm/s)

 

 

c.     Absorption via Inhalation

 

Inhalation is not considered a relevant route due to the low vapor pressure of 3.275 X 10-5 Pa at 20°C.

 

II.                Distribution

 

If absorption occurs, the substance will likely be distribtuted somewhat to faty tissue based on its lipophilicity. However, wide distribution and accumulation are not expected due to the expected metabolism and excretion that will occur in the liver. This is also supported by the repeat dose data, specifically the adaptive changes in the liver where the material is likely undergoing metabolism.

 

III.             Metabolism

 

It has been established that alkyl amines undergo extensive metabolism, including n-dealkylation (Casarett and Doulls, 2008). The metabolism of the notified substances was evaluated using LMC OASIS TIMES (v2.27.17.6) in vitroRat Liver S9 Simulator. The complete metabolism simulation report, with full details on the predicted metabolism, is attached.

 

The primary metabolic pathway predicted for tertiary amines is n-dealkylation, which is catalyzed by CYP 2D6 (de Groot et al., 1999), resulting in a secondary alkyl amine and an aldehyde. This is expected to occur completely and with high probability based on the TIMES model and is supported by the literature (Hanson et. al., 2010; Macherey and Dansette, 2008). The shortest alkyl chain is preferentially dealkylated to form the corresponding alkyl aldehyde.

  

The secondary alkyl amine subsequently undergoes oxidation (aliphatic c-oxidation) forming carbonyl or aldehyde groups that are further reduced (aldehyde dehydrogenase). This is supported by the metabolism summary in the SIAP for secondary alkyl amines (OECD, 2013), which states that they are oxidized to aldehydes. Ultimately, this is expected to lead to phase II conjugation (e.g., glucuronidation).

 

Aliphatic oxidation is consistent with what occurs for primary alkyl amines of similar chain length (EU, 2008), which further supports this metabolism assessment.

 

 

IV.             Excretion

 

Based on the metabolic profile, some of the notified substance is expected to be conjugated to phase II enzymes and excreted in the bile due to large molecular weight. This is consistent with information on primary alkyl amines with a similar alkyl chain length, which have minimal urinary excretion (EU, 2008).

                                                     

 

References

1. deGroot M., M. Ackland, V. Horne, A.Alex, B. Jones, A Novel Approach to Predicting P450 Mediated Drug Metabolism. CYP2D6 Catalyzed N-Dealkylation Reactions and Qualitative Metabolite Prediction Using a Combined Protein and Pharmacophore Model for CYP2D6. J. Med. Chem. 1999
2. Hanson, K.L., BandenBrink, B.M., Babu, K.N., Allen, K.E., Nelson, W.L., and Kunze, K.L. Sequential Metabolism of Secondary Alkyl Amines to Metabolic-Intermediate Complexes: Opposing Roles for the Secondary Hydroxylamine and Primary Amine Metabolites of Desipramine, (S)-Fluoxetine, and N-Desmethyldiltiazem. Drug Metabolism and Description. March 3, 2010
3. Klassen, C. Casarett & Doull’s Toxicology. Seventh Edition. 2008
4. Macherey, A.C and Dansette, P. Biotransformations Leading to Toxic Metabolites: Chemical Aspect. Chapter 33. Wermuth’s The Practice of Medicinal Chemistry. 2008
5. OECD SIDS Initial Assessment Profile (SIAP). Aliphatic Secondary Amines. CoCAM4. April, 2013
6. European Union Risk Assessment Report (EU RAR) – Primary Alkyl Amines. October, 2008
7. Daina, A., Michielin, O., Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medical chemistry friendliness of small molecules. Scientific Reports. March 3, 2017

Description of key information

Summary

The notified substance does not have toxicokinetic (TK) data. Therefore, the TK assessment is based on the phsyical/chemical properites, information from standard toxicology studies (e.g., OECD 408 repeat dose study), QSAR modeling, and computational toxicology tools. Table 1 is an overview of key chemical information used in the assessment.

 

Table 1. Overview of chemical structure and physical/chemial properties.

Representative chemical structure
SMILES (used for QSAR and modelling)	CN(CCCCCCCCCCCCCC)CC(CC)CCCC (smallest alkyl derivative)
Molecular weight (MW)	339.7-395.8
Water solubility	0.00048 – 0.00062 mg/L
Kow	6.1
Vapor pressure	3.275 X 10-5 Pa at 20°C
Physical state	Liquid

(e) = estimation using EPISUITE v4.1

* Estimates are for C14 because tallow is a C14-C18 range

 

The notified substance has the following TK characteristics:

 

        I.           Absorption

a.      Oral: minimal and slow absorption

b.      Dermal: minimal and slow absorption

c.      Inhalation: not expected due to low vapor pressure

      II.           Distribution: Based on liphoplicity, absorbed material is likely to be distributed to fatty tissues

    III.           Metabolism: Expected to be metabolized heavily by the liver to secondary alkyl amines followed by oxidation and phase II conjugation

   IV.           Excretion: Expected to occur primarily in the bile

 

 

I.                  Absorption

 

a.    Oral Absorption

 

The notified substance is expected to be absorbed after oral administration based on repeat dose toxcity studies but this is likely minimal and occurs slowly. The following information supports this:

 

1.      Test data with the notified substance

 

The notified substance was bioavailable based on the effects observed in OECD 422 and OECD 408 oral gavage studies. This includes increased liver weight with associated enzyme changes that was concluded by the study director to be an adaptive response, most likely due to the metabolism that is expected to occur with the notified substance (see metabolism section).

 

2.      Modeling using SwissADME (http://www.swissadme.ch/index.php)

 

Gastrointestinal absorption was predicted using SwissADME, which is a freely available web-based tool (Daina et al., 2017). SwissADME predicts the absorption and bioavailbilty based on a number of paramaters known to influence these properties, including physical/chemical properites, lipohilicity, and polarity.

 

The notified substance was assessed to have "low" GI absorption by SwissADME. In addition, the probability of the substances being a substrate or non-substrate of the permeability glycoprotein (P-gp) was calculated. P-gp plays a primary role among ATP-binding cassette transporters or ABC transporters in the active efflux through biological membranes. The notified substance was predicted to not be a substrate of P-gp, indicating it is unlikely to be involved in active transport processes. 

 

3.      Evaluation of critical physical/chemical properties known to influence absorption

Absorption of a chemical from the gastrointestinal (GI) tract depends on its physical properties, including lipid solubility and its dissolution rate. The European Chemicals Agency (ECHA) has established guidance for determining oral absorption potential (Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C: Endpoint Specific Guidance, November, 2014). As seen in Table 1, the molecular weight of the notified substance indicates that oral absorption may occur. However, based on the low water solubility and high Kow, absorption is likely limited.

 

 

Table 1. Physiochemical Properties and Oral Absorption

Physical and Chemical Parameter	Relationship to Absorption	Notified Substance
Molecular Weight	< 500: favorable for absorption > 1000: do not favor absorption	339.7-395.8: indicates oral absorption may occur
Water solubility	Water soluble substances will dissolve in GI fluids and may be absorbed by bulk diffusion	Low water solubility indicates oral absorption is low
Kow	Values between -1 and 4 are favorable for passive diffusion	Kow of 6.1 indicates passive diffusion is low

 

b.    Dermal Absorption

 

Dermal absorption of the notified substance is expected to be minimal based on the physiochemial properites and occur slowly based on the modeled Kp. Table 2 compares the physiochemical properties of the notified substance with the ECHA guidance for determining dermal absorption potential(Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C: Endpoint Specific Guidance, November, 2014). The molecular weight of the notified substance indicates that dermal absorption may occur; however, the material is very insoluble in water and the Kow exceeds the optimal cut-off criteria indicating that dermal absorption may occur but to a small extent.

 

Table 2. Physiochemical Properties and Dermal Absorption

Physical and Chemical Parameter	Relationship to Absorption	Notified Substance
Molecular Weight	< 100: favorable for absorption > 500: too large for penetration	339.7-395.8: indicates dermal absorption may occur
Water solubility	< 1 mg/L: dermal uptake is likely to be low	0.00048 – 0.00062 mg/L indicates dermal absorption is low
Kow	Values between 1 and 4 are favorable for dermal absorption; > 6 very limited penetration and uptake	Kow of 6.1 indicates limited dermal absorption

 

 

The permeability coefficient (Kp) was estimated use EPA Dermwin v2.02 and SwissADME:

1.      Dermwin v2.02 using measured Kow: 0.22 cm/hr

2.      Dermwin v2.02 using EPISUITE predicted Kow: 62.1 cm/hr

3.      SwissADME: 216 cm/hr (based on a prediction of log Kp of -1.23 cm/s)

 

 

c.     Absorption via Inhalation

 

Inahlation is not cosidered a relevant route due to the low vapor pressure of 3.275 X 10-5 Pa at 20°C.

 

II.                Distribution

 

If absorptioin occurs, the substance will likely be distribtuted somewhat to faty tissue based on its lipophilicity. However, wide distribution and accumulation are not expected due to the expected metabolism and excretion that will occur in the liver. This is also supported by the repeat dose data, specfically the adaptive changes in the liver where the material is likely undergoing metabolism.

 

III.             Metabolism

 

It has been established that alkyl amines undergo extensive metabolism, including n-dealkylation (Casarett and Doulls, 2008). The metabolism of the notified substances was evaluated using LMC OASIS TIMES (v2.27.17.6)in vitroRat Liver S9 Simulator. The complete metabolism simulation report, with full details on the predicted metabolism, is attached.

 

The primary metabolic pathway predicted for tertiary amines is n-dealkylation, which is catalyzed by CYP 2D6 (de Groot et al., 1999), resulting in a secondary alkyl amine and an aldehyde. This is expected to occur completely and with high probability based on the TIMES model and is supported by the literature (Hanson et. al., 2010; Macherey and Dansette, 2008). The shortest alkyl chain is preferentially dealkylated to form the corresponding alkyl aldehyde.

  

The secondary alkyl amine subsequently undergoes oxidation (aliphatic c-oxidation) forming carbonyl or aldehyde groups that are further reduced (aldehyde dehydrogenase). This is supported by the metabolism summary in the SIAP for secondary alkyl amines (OECD, 2013), which states that they are oxidized to aldehydes. Ultimately, this is expected to lead to phase II conjugation (e.g., glucuronidation).

 

Aliphatic oxidation is consistent with what occurs for primary alkyl amines of similar chain length (EU, 2008), which further supports this metabolism assessment.

 

 

IV.             Excretion

 

Based on the metabolic profile, some of the notified substance is expected to be conjugated to phase II enzymes and excreted in the bile due to large molecular weight. This is consistent with information on primary alkyl amines with a similar alkyl chain length, which have minimal urinary excretion (EU, 2008).

                                                     

 

References

1. deGroot M., M. Ackland, V. Horne, A.Alex, B. Jones, A Novel Approach to Predicting P450 Mediated Drug Metabolism. CYP2D6 Catalyzed N-Dealkylation Reactions and Qualitative Metabolite Prediction Using a Combined Protein and Pharmacophore Model for CYP2D6. J. Med. Chem. 1999
2. Hanson, K.L., BandenBrink, B.M., Babu, K.N., Allen, K.E., Nelson, W.L., and Kunze, K.L. Sequential Metabolism of Secondary Alkyl Amines to Metabolic-Intermediate Complexes: Opposing Roles for the Secondary Hydroxylamine and Primary Amine Metabolites of Desipramine, (S)-Fluoxetine, and N-Desmethyldiltiazem. Drug Metabolism and Description. March 3, 2010
3. Klassen, C. Casarett & Doull’s Toxicology. Seventh Edition. 2008
4. Macherey, A.C and Dansette, P. Biotransformations Leading to Toxic Metabolites: Chemical Aspect. Chapter 33. Wermuth’s The Practice of Medicinal Chemistry. 2008
5. OECD SIDS Initial Assessment Profile (SIAP). Aliphatic Secondary Amines. CoCAM4. April, 2013
6. European Union Risk Assessment Report (EU RAR) – Primary Alkyl Amines. October, 2008
7. Daina, A., Michielin, O., Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medical chemistry friendliness of small molecules. Scientific Reports. March 3, 2017

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential