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EC number: 233-912-4 | CAS number: 10431-98-8
Endpoint summary
Administrative data
Description of key information
No test data to address repeated dose toxicity of the target substance is available. Therefore, information for 2-aminoethanol and propionic acid are presented to address this endpoint. A sub-chronic repeated dose rat toxicity study reported a 90-day (oral gavage) NOAEL of 320 mg/kg bw/day and a LOAEL of 640 mg/kg bw/day for 2-aminoethanol due to altered liver or kidney weight. In a sub-chronic repeated dose dog toxicity study, propionic acid up to 3% in the diet induced epithelial hyperplasia which appeared at multiple levels of the esophagus with a NOAEL at 1% (0.660 - 0.835 g/kg bw/day (males); 0.696 - 0.844 g/kg bw/day (females)). As such, based on these values, the NOAEL of the target substance would be a sub-chronic value of 520 mg/kg bw/day based on 2-aminoethanol and sub-chronic value of 917 mg/kg bw/day based on the propionic acid. For the purposes of risk assessment, the sub-chronic NOAEL of 0.52 g/kg bw/day will be utilized, as this value derives the more protective PNECoral and DNELs values.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- 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
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- 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 subchronic (repeated dose) toxicity of 2-ethyl-2-oxazoline is predicted based on the results of the 2-aminoethanol and propionic acid.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 520 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Remarks on result:
- other: predicted value
- Critical effects observed:
- no
- Conclusions:
- No test data to address repeated dose toxicity of the target substance is available. Therefore, information for 2-aminoethanol and propionic acid are presented to address this endpoint. A sub-chronic repeated dose rat toxicity study reported a 90-day (oral gavage) NOAEL of 320 mg/kg bw/day and a LOAEL of 640 mg/kg bw/day for 2-aminoethanol due to altered liver or kidney weight. In a sub-chronic repeated dose dog toxicity study, propionic acid up to 3% in the diet induced epithelial hyperplasia which appeared at multiple levels of the esophagus with a NOAEL at 1% (0.660 - 0.835 g/kg bw/day (males); 0.696 - 0.844 g/kg bw/day (females)). As such, based on these values, the NOAEL of the target substance would be a sub-chronic value of 520 mg/kg bw/day based on 2-aminoethanol and sub-chronic value of 917 mg/kg bw/day based on the propionic acid. For the purposes of risk assessment, the sub-chronic NOAEL of 0.52 g/kg bw/day will be utilized, as this value derives the more protective PNECoral and DNELs values.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 520 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- The database is robust given the number and type of studies available, and consistency of findings.
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Justification for classification or non-classification
Based on the results of the source substance, ETOX has a predicted 90-day NOEL of 520 mg/kg bw/day. Therefore, according to EC 1272/2008 as amended, the test substance does not meet the criteria for Specific Target Organ Toxicity following repeated exposure classification.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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