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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Test data on the genotoxicity of the target substance is not available. Various genotoxicity results are reported for the two source substances, 2-aminoethanol and propionic acid.

The available in vitro gene mutation data on 2-aminoethanol report negative results. While no in vitro data is available on propionic acid, in vivo data from a micronucleus test also report negative results.  

 

The available in vitro cytogenicity data on 2-aminoethanol report negative results. While no in vitro data is available on propionic acid, in vivo data from a micronucleus test also report negative results. ECHA TGD 7a indicates that an in vivo data from a micronucleus test, while not optimal, may address in vitro cytogenicity.  

 

The available results on the two source substances are negative for in vitro gene mutation in bacteria.

All of the results for the source substances are negative for genotoxicity. Based on the toxicological similarities of the source substances, for the purposes of risk assessment the target substance will be considered to be non-mutagenic.

Link to relevant study records

Referenceopen allclose all

Endpoint:
in vitro cytogenicity / chromosome aberration study in mammalian cells
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Data for 2-aminoethanol (ethanolamine; CAS No. 141-43-5) and propionic acid (CAS No. 79-09-4) or calcium dipropionate (CAS No. 4075-81-4) are used to address the toxicological data requirements for 2-ethyl-2-oxazoline (CAS No. 10431-98-8) in an analogue read-across approach. The basis for this read-across approach is that, upon oral administration, the target substance is expected to undergo transformation into ethanolamine and propionic acid. The toxicity of the ethanolamine metabolite will be assessed using information on ethanolamine, and the toxicity of the propionic acid metabolite will be assessed using information on propionic acid and calcium dipropionate.

2. SOURCE AND TARGET CHEMICAL(S)
The target substance is known to be of high purity (typically 99.5 % w/w), and to contain up to 1 % w/w (typically 0.5 % w/w) of its 2-methyl analogue as impurity. The impurity is expected to undergo the same transformation steps as the target substance, producing exactly the same ethanolamine metabolite but an analogous acetic acid metabolite in place of the propionic acid metabolite. On this basis, the source substances effectively represent typically >99.5 % w/w of the target substance. The purities of the samples of source substances that were tested are not specifically known, but it is assumed that they would not have been sufficiently impure as to substantially affect the study results. On this basis, the applicability of the data on the source substance to the target substance is not expected to be compromised by the presence of impurities in any of the substances.
See attached report for further details.

3. ANALOGUE APPROACH JUSTIFICATION
The basis for this read-across approach is that, upon oral administration, the target substance is expected to undergo initial hydrolysis into its secondary amide which will then be metabolized by amidase enzymes such as fatty acid amide hydrolase (FAAH) into its aliphatic amine (ethanolamine) and corresponding fatty acid (propionic acid) components according to the scheme presented in the attached report.
FAAH, an enzyme responsible for the hydrolysis of a number of primary and secondary fatty acid amides, is widely distributed throughout the human body including in the gastrointestinal tract.
The ethanolamine metabolite is clearly identical to the first source substance, and the amount produced will be equivalent to 62% w/w of the dose of target substance.
The propionic acid metabolite is clearly identical to the second source substance, and the amount produced will be equivalent to 75% w/w of the dose of target substance.
The sum of the above values exceeds 100% due to the mass added by the incorporation of water of hydrolysis.
The calcium dipropionate source substance is a simple ionic salt of the propionic acid target metabolite and will dissociate in physiological fluids into separate calcium cations and propionate anions. In a buffered system, propionic acid will exist in equilibrium with its propionate anion, and that equilibrium will be the same regardless of whether it was introduced as the free acid or as the anion, so long as the amounts introduced are not so large as to overwhelm that system’s buffering capacity. On this basis, there are no structural differences between the propionic acid target metabolite and the propionate anion from the calcium dipropionate source substance.
See attached report for further details.

4. DATA MATRIX
See attached report details
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
Specific details on test material used for the study:
The in vitro cytogenicity of 2-ethyl-2-oxazoline in mammalian cells is predicted based on the results of 2-aminoethanol and propionic acid.
Key result
Species / strain:
other: In vivo hamster, Chinese bone marrow & in vitro Rat liver cell lines
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Remarks on result:
other: Predicted outcome: no mutagenic potential
Conclusions:
No test data to address the in vitro cytogenicity of the target substance in mammalian cells are available. The available in vitro data on 2-aminoethanol report negative results. While no in vitro data is available on propionic acid, in vivo data from a micronucleus test also report negative results. ECHA TGD 7a indicates that an in vivo data from a micronucleus test, while not optimal, may address in vitro cytogenicity. On this basis, for the purposes of the risk assessment the target substance will be considered to be non-mutagenic.
Endpoint:
in vitro gene mutation study in bacteria
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Data for 2-aminoethanol (ethanolamine; CAS No. 141-43-5) and propionic acid (CAS No. 79-09-4) or calcium dipropionate (CAS No. 4075-81-4) are used to address the toxicological data requirements for 2-ethyl-2-oxazoline (CAS No. 10431-98-8) in an analogue read-across approach. The basis for this read-across approach is that, upon oral administration, the target substance is expected to undergo transformation into ethanolamine and propionic acid. The toxicity of the ethanolamine metabolite will be assessed using information on ethanolamine, and the toxicity of the propionic acid metabolite will be assessed using information on propionic acid and calcium dipropionate.

2. SOURCE AND TARGET CHEMICAL(S)
The target substance is known to be of high purity (typically 99.5 % w/w), and to contain up to 1 % w/w (typically 0.5 % w/w) of its 2-methyl analogue as impurity. The impurity is expected to undergo the same transformation steps as the target substance, producing exactly the same ethanolamine metabolite but an analogous acetic acid metabolite in place of the propionic acid metabolite. On this basis, the source substances effectively represent typically >99.5 % w/w of the target substance. The purities of the samples of source substances that were tested are not specifically known, but it is assumed that they would not have been sufficiently impure as to substantially affect the study results. On this basis, the applicability of the data on the source substance to the target substance is not expected to be compromised by the presence of impurities in any of the substances.
See attached report for further details.

3. ANALOGUE APPROACH JUSTIFICATION
The basis for this read-across approach is that, upon oral administration, the target substance is expected to undergo initial hydrolysis into its secondary amide which will then be metabolized by amidase enzymes such as fatty acid amide hydrolase (FAAH) into its aliphatic amine (ethanolamine) and corresponding fatty acid (propionic acid) components according to the scheme presented in the attached report.
FAAH, an enzyme responsible for the hydrolysis of a number of primary and secondary fatty acid amides, is widely distributed throughout the human body including in the gastrointestinal tract.
The ethanolamine metabolite is clearly identical to the first source substance, and the amount produced will be equivalent to 62% w/w of the dose of target substance.
The propionic acid metabolite is clearly identical to the second source substance, and the amount produced will be equivalent to 75% w/w of the dose of target substance.
The sum of the above values exceeds 100% due to the mass added by the incorporation of water of hydrolysis.
The calcium dipropionate source substance is a simple ionic salt of the propionic acid target metabolite and will dissociate in physiological fluids into separate calcium cations and propionate anions. In a buffered system, propionic acid will exist in equilibrium with its propionate anion, and that equilibrium will be the same regardless of whether it was introduced as the free acid or as the anion, so long as the amounts introduced are not so large as to overwhelm that system’s buffering capacity. On this basis, there are no structural differences between the propionic acid target metabolite and the propionate anion from the calcium dipropionate source substance.
See attached report for further details.

4. DATA MATRIX
See attached report details
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across: supporting information
Specific details on test material used for the study:
The in vitro genotoxic potential of 2-ethyl-2-oxazoline is predicted based on the results of 2-aminoethanol and propionic acid.
Species / strain:
other: S. typhimurium & E.coli - predicted WoE
Metabolic activation:
with and without
Genotoxicity:
negative
Remarks on result:
other: Predicted result - no mutagenic potential
Conclusions:
No test data to address the in vitro gene mutation in bacteria of the target substance are available. The available results on the two source substances are negative for in vitro gene mutation in bacteria. On this basis, for the purposes of the risk assessment the target substance will be considered to be non-mutagenic.
Endpoint:
in vitro gene mutation study in mammalian cells
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Data for 2-aminoethanol (ethanolamine; CAS No. 141-43-5) and propionic acid (CAS No. 79-09-4) or calcium dipropionate (CAS No. 4075-81-4) are used to address the toxicological data requirements for 2-ethyl-2-oxazoline (CAS No. 10431-98-8) in an analogue read-across approach. The basis for this read-across approach is that, upon oral administration, the target substance is expected to undergo transformation into ethanolamine and propionic acid. The toxicity of the ethanolamine metabolite will be assessed using information on ethanolamine, and the toxicity of the propionic acid metabolite will be assessed using information on propionic acid and calcium dipropionate.

2. SOURCE AND TARGET CHEMICAL(S)
The target substance is known to be of high purity (typically 99.5 % w/w), and to contain up to 1 % w/w (typically 0.5 % w/w) of its 2-methyl analogue as impurity. The impurity is expected to undergo the same transformation steps as the target substance, producing exactly the same ethanolamine metabolite but an analogous acetic acid metabolite in place of the propionic acid metabolite. On this basis, the source substances effectively represent typically >99.5 % w/w of the target substance. The purities of the samples of source substances that were tested are not specifically known, but it is assumed that they would not have been sufficiently impure as to substantially affect the study results. On this basis, the applicability of the data on the source substance to the target substance is not expected to be compromised by the presence of impurities in any of the substances.
See attached report for further details.

3. ANALOGUE APPROACH JUSTIFICATION
The basis for this read-across approach is that, upon oral administration, the target substance is expected to undergo initial hydrolysis into its secondary amide which will then be metabolized by amidase enzymes such as fatty acid amide hydrolase (FAAH) into its aliphatic amine (ethanolamine) and corresponding fatty acid (propionic acid) components according to the scheme presented in the attached report.
FAAH, an enzyme responsible for the hydrolysis of a number of primary and secondary fatty acid amides, is widely distributed throughout the human body including in the gastrointestinal tract.
The ethanolamine metabolite is clearly identical to the first source substance, and the amount produced will be equivalent to 62% w/w of the dose of target substance.
The propionic acid metabolite is clearly identical to the second source substance, and the amount produced will be equivalent to 75% w/w of the dose of target substance.
The sum of the above values exceeds 100% due to the mass added by the incorporation of water of hydrolysis.
The calcium dipropionate source substance is a simple ionic salt of the propionic acid target metabolite and will dissociate in physiological fluids into separate calcium cations and propionate anions. In a buffered system, propionic acid will exist in equilibrium with its propionate anion, and that equilibrium will be the same regardless of whether it was introduced as the free acid or as the anion, so long as the amounts introduced are not so large as to overwhelm that system’s buffering capacity. On this basis, there are no structural differences between the propionic acid target metabolite and the propionate anion from the calcium dipropionate source substance.
See attached report for further details.

4. DATA MATRIX
See attached report details
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
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read-across: supporting information
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across: supporting information
Specific details on test material used for the study:
The in vitro genotoxicity of 2-ethyl-2-oxazoline in mammalian cells is predicted based on the in vitro results of 2-aminoethanol and in vivo results of propionic acid.
Key result
Species / strain:
mammalian cell line, other: In vivo Chinese hamster bone marrow & in vitro Chinese hamster lung fibroblasts (V79)
Genotoxicity:
negative
Remarks on result:
other: Predicted outcome: no mutagenic potential
Conclusions:
No test data to address the in vitro genotoxicity of the target substance in mammalian cells are available. The available in vitro data on 2-aminoethanol report negative results. While no in vitro data is available on propionic acid, in vivo data from a micronucleus test also report negative results. On this basis, for the purposes of the risk assessment the target substance will be considered to be non-mutagenic.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Justification for classification or non-classification

Experimental studies demonstrated that the source substances 2-aminoethanol and propionic acid are not mutagenic following in vitro and/or in vivo assessment. Therefore, according to EC 1272/2008 as amended, the test substance does not meet the criteria for germ cell mutagenicity classification.