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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

The screening for reproductive / developmental toxicity study does not need to be conducted because a pre-natal developmental toxicity study is available.

Effect on fertility: via oral route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

No test data to address screening for reproductive/developmental toxicity of the target substance is available. Therefore, information for 2-aminoethanol and calcium dipropionate are presented to address this endpoint. A study for the effect of 2-aminoethanol on reproduction and development reported a NOEL of 450 mg/kg bw/day for developmental toxicity; however, the same dose was reported as maternally toxic (e.g., decreased feed consumption and decreased in mean maternal body weights). For calcium dipropionate, no effects on maternal or fetal survival and no increase in the number of fetal abnormalities were seen when calcium dipropionate was fed to pregnant rats (up to 300 mg/kg bw/day for 10 days).

During metabolism the target substance produces 62% 2-aminoethanol and 75% propionic acid and the weight of propionate produced by a given dose of calcium dipropionate is 94% of that produced by the same dose of target substance. As such, based on the source substance toxicity values reported elsewhere within this dossier, the reproductive/developmental NOAEL of the target substance can be predicted to be 726 mg/kg bw/day based on 2-aminoethanol and 319 mg/kg bw/day based on calcium dipropionate. Therefore, the conservative NOEL of approximately 319 mg/kg bw/day for the target substance will be considered during risk assessment.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
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
Specific details on test material used for the study:
The developmental toxicity of 2-ethyl-2-oxazoline is predicted based on the results of the 2-aminoethanol and propionic acid.
Dose descriptor:
NOEL
Effect level:
319 mg/kg bw/day
Based on:
test mat.
Remarks on result:
other: Predicted value
Dose descriptor:
NOEL
Effect level:
319 mg/kg bw/day
Based on:
test mat.
Sex:
not specified
Remarks on result:
other: Predicted value
Developmental effects observed:
no
Conclusions:
No test data to address screening for reproductive/developmental toxicity of the target substance is available. Therefore, information for 2-aminoethanol and calcium dipropionate, the calcium salt of propionic acid, are presented to address this endpoint. A study for the effect of 2-aminoethanol on reproduction and development reported a NOEL of 450 mg/kg bw/day for developmental toxicity; however, the same dose was reported as maternally toxic (e.g., decreased feed consumption and decreased in mean maternal body weights). For calcium dipropionate, no effects on maternal or fetal survival and no increase in the number of fetal abnormalities were seen when calcium dipropionate was fed to pregnant rats (up to 300 mg/kg bw/day for 10 days). As such, based on these values, the reproductive/developmental NOAEL of the target substance would be 726 mg/kg bw/day based on 2-aminoethanol and 319 mg/kg bw/day based on calcium dipropionate. Therefore, the conservative NOEL of approximately 319 mg/kg bw/day for the target substance will be considered during risk assessment.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
319 mg/kg bw/day
Study duration:
subacute
Species:
rat

Justification for classification or non-classification

Experimental studies demonstrated that the source substances 2-aminoethanol and calcium dipropionate are not embryotoxic, fetotoxic, or teratogenic. Therefore, according to EC 1272/2008 as amended, the test substance does not meet the criteria for reproductive toxicity classification.

Additional information