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Administrative data

Description of key information

The test item is not toxic after repeated oral dosing.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2016-08-25 to 2017-02-22
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study using a read-across test substance
Justification for type of information:
Read-across from ethyl hexanoate to ethyl heptanoate is considered justified based on stong similarities with regards to chemical structure and metabolic pathways. A full read-across justification including comparison of toxicological profiles is included in section13 of the IUCLID dossier.
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 097.3 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse treatment-related effects of toxicological significance were observed.
Remarks on result:
other: Molecular weight correction following read-across taken into account.
Key result
Critical effects observed:
no
Conclusions:
Read-across was performed from ethyl caproate. Based on the result, and on the structural, chemical and toxicological similarities between ethyl caproate and ethyl heptoate, the NOAEL for ethyl heptoate is greater than 1097 mg/kg bw/day.
Executive summary:

Read-across was performed from ethyl caproate. Potential systemic effects and toxicity of the test item were assessed in rats by oral gavage (12 animals per sex per group) at dose levels of 0, 100, 300 and 1000 mg/kg bw/day dosed for two weeks prior to mating and continued through the day before sacrifice in males (at least 50 days), and continued through the lactation day 13 in females. Afterwards, they were assigned to 2 weeks of recovery period after the completion of the test item administration.

The study was performed according to the OECD guideline 422 and in compliance to GLP.

No deaths or moribund animals occurred in any group throughout the study. No test item-related adverse effects for general toxicity were observed up to 1000 mg/kg bw/day.

Based on the result, and on the structural, chemical and toxicological similarities between ethyl caproate and ethyl heptoate, the No Observed Adverse Effect Level (NOAEL) for repeated dose toxicity for ethyl heptoate can be calculated as at least 1097 mg/kg bw/day, taking into account the molecular weight correction between source and target substance.

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Read-across from ethyl octanoate to ethyl heptanoate is considered justified based on strong similarities with regard to chemical structure and metabolic pathways. A full read-across justification including comparison of toxicological profiles will be included in section 13 of the IUCLID dossier.
Reason / purpose for cross-reference:
read-across source
Principles of method if other than guideline:
The test substance was fed at different doses for 17 weeks. No specific guideline was followed. GLP was not stated.
GLP compliance:
no
Species:
rat
Strain:
Osborne-Mendel
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age: weanlings
- Housing: individually
- Diet: ad libitum
- Water: ad libitum

Route of administration:
oral: feed
Vehicle:
corn oil
Duration of treatment / exposure:
17 weeks
Frequency of treatment:
weekly
Dose / conc.:
10 000 ppm
Dose / conc.:
2 500 ppm
Dose / conc.:
1 000 ppm
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
No additional data provided.
Observations and examinations performed and frequency:
GENERAL OBSERVATIONS: Yes
- Time schedule for examinations: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE: yes
- Time schedule for examinations: weekly
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 3 months and at termination
- Parameters checked: white cell counts, red cell counts, heamoglobins and heamatocrits
OTHER: At the end of the experiment the rats were sacrificed and exsanguinated
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, tissues were examined macroscopically at the time of sacrifice. Liver, kidney, spleen, heart and testes were weighed.
HISTOPATHOLOGY: Yes if macroscopic changes were observed. Liver, kidney, spleen, heart, testes, the remaining abdominal and thoracic viscera, one hind leg, for bone, bone marrow, and muscle were preserved in 10% buffered formalin-saline solution for histopathological examination.
Other examinations:
Tissues from rats dying during the experiment were examined for gross changes and were preserved if autolysis was not advanced. Organs were not weighed but abnormalities and the suspected reason for death were noted.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
No effect: no effect on growth or haematology, and no macroscopic or microscopic change in the tissues.
No macroscopic effect: no effect on growth or haematology, and no macroscopic change in the tissues, and that microscopic examination of the tissues was not performed.
Key result
Dose descriptor:
NOAEL
Effect level:
> 10 000 ppm
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Conclusions:
Read-across was done from ethyl octanoate. Based on the result, and on the structural, chemical and toxicological similarities between ethyl octanoate and ethyl heptanoate, ethyl heptanoate did not show any toxic effects and the NOAEL is considered to be > 10000 ppm. This corresponds to approximately 600-700 mg/kg taking into account 1% of the assumed average amount of food uptake of ca. 22 -30g/day (female/male, respectively) with an assumed rat weight of 333-500 g (female/male, respectively). Taking into the different molecular weights of source and target molecule (172.26 g/mol versus 158.24 g/mol), the NOAEL is considered to be > 550-640 mg/kg (female/male) ethyl heptanoate.
Executive summary:

Read-across was done from ethyl octanoate. In the present report subacute and chronic studies were summaried. Regarding ethyl octanoate subchronic data is presented in the study. Limited documentation is available and no OECD guideline was followed and the study is non-GLP. No information on actual received dose, as only concentrations in the diet are reported.

Ethyl octanoate was studied in rats for 17 weeks. 10 male and 10 female animals were fed 1000; 2500 or 10000 ppm of ethyl octanoate. A control group received the vehicle. The food intake, weight and general condition were observed and heamatological and macroscopical examinations were performed.

Ethyl octanoate did not show any effects on growth or haematology, nor macroscopic changes in the tissues. Ethyl octanoate was considered not toxic. Therefore, the NOAEL is considered to be >10000 ppm.

Based on the result, and on the structural, chemical and toxicological similarities between ethyl octanoate and ethyl heptanoate, ethyl heptanoate did not show any toxic effects and the NOAEL is considered to be >10000 ppm.

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Read-across from ethyl nonanoate to ethyl heptanoate is considered justified based on strong similarities with regard to chemical structure and metabolic pathways. A full read-across justification including comparison of toxicological profiles will be included in section 13 of the IUCLID dossier.
Reason / purpose for cross-reference:
read-across source
GLP compliance:
no
Key result
Dose descriptor:
NOAEL
Effect level:
> 10 000 ppm
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Conclusions:
Read-across was done from ethyl nonanoate. Based on the result, and on the structural, chemical and toxicological similarities between ethyl nonanoate and ethyl heptanoate, ethyl heptanoate did not show any toxic effects and the NOAEL is considered to be >10000 ppm. This corresponds to approximately 600-700 mg/kg taking into account 1% of the assumed average amount of food uptake of ca. 22 -30g/day (female/male, respectively) with an assumed rat weight of 333-500 g (female/male, respectively). Taking into the different molecular weights of source and target molecule (186.16 g/mol versus 158.24 g/mol), the NOAEL is considered to be > 510-600 mg/kg (female/male) ethyl heptanoate.
Executive summary:

Read-across was done from ethyl nonanoate. In the present report subacute and chronic studies were summaried. Regarding ethyl nonanoate subchronic data is presented in the study. Limited documentation is available and no OECD guideline was followed and the study is non-GLP. No information on actual received dose, as only concentrations in the diet are reported.

Ethyl nonanoate was studied in rats for 16 weeks. 5 male and 5 female animals were fed 10000 ppm of ethyl nonanoate. A control group received the vehicle. The food intake, weight and general condition were observed and heamatological and macroscopical examinations were performed.

Ethyl nonanoate did not show any effects on growth or haematology, nor macroscopic changes in the tissues. Ethyl nonanoate was considered to be not toxic. Therefore, the NOAEL is considered to be > 10000 ppm.

Based on the result, and on the structural, chemical and toxicological similarities between ethyl nonanoate and ethyl heptanoate, ethyl heptanoate did not show any toxic effects and the NOAEL is considered to be > 10000 ppm.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Principles of method if other than guideline:
The test substance was fed at different doses for 13 weeks. No specific guideline was followed.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Osborne-Mendel
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age: weanlings
- Housing: individually
- Diet: ad libitum
- Water: ad libitum

Route of administration:
oral: feed
Vehicle:
corn oil
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
weekly
Dose / conc.:
10 000 ppm
Dose / conc.:
1 000 ppm
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
No additional data provided.
Observations and examinations performed and frequency:
GENERAL OBSERVATIONS: Yes
- Time schedule for examinations: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE: yes
- Time schedule for examinations: weekly
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 3 months and at termination
- Parameters checked: white cell counts, red cell counts, heamoglobins and heamatocrits
OTHER: At the end of the experiment the rats were sacrificed and exsanguinated
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, tissues were examined macroscopically at the time of sacrifice. Liver, kidney, spleen, heart and testes were weighed.
HISTOPATHOLOGY: Yes if macroscopic changes were observed. Liver, kidney, spleen, heart, testes, the remaining abdominal and thoracic viscera, one hind leg, for bone, bone marrow, and muscle were preserved in 10% buffered formalin-saline solution for histopathological examination.
Other examinations:
Tissues from rats dying during the experiment were examined for gross changes and were preserved if autolysis was not advanced. Organs were not weighed but abnormalities and the suspected reason for death were noted.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
No effect: no effect on growth or haematology, and no macroscopic or microscopic change in the tissues.
No macroscopic effect: no effect on growth or haematology, and no macroscopic change in the tissues, and that microscopic examination of the tissues was not performed.
Key result
Dose descriptor:
NOAEL
Effect level:
> 10 000 ppm
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Critical effects observed:
not specified
Conclusions:
The test substance did not show any toxic effects, not on growth or haematology, nor on tissues macroscopically. The NOAEL was determined to be 10000 ppm. This corresponds to approximately 600-700 mg/kg taking into account 1% of the assumed average amount of food uptake of ca. 22 -30g/day (female/male, respectively) with an assumed rat weight of 333-500 g (female/male, respectively).
Executive summary:

In the present report subacute and chronic studies were summaried. Regarding the test item subchronic data is presented in the study. Limited documentation is available and no OECD guideline was followed and the study is non-GLP. No information on actual received dose, as only concentrations in the diet are reported.

The test substance was studied in rats for 13 weeks. 10 male and 10 femaleanimals were fed 1000 or 10000 ppm of the test substance. A control group received the vehicle. The food intake, weight and general condition were observed and heamatological and macroscopical examinations were performed.

The test substance did not show any effects neither on growth or haematology nor macroscopic changes in the tissues. The test substance was considered to be not toxic. Therefore, the NOAEL is considered to be 10000 ppm. This corresponds to 700 -800 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 097 mg/kg bw/day
Study duration:
subacute
Species:
rat

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

For this endpoint there are 2 studies available with data on toxicity after repeated dosing. The key study is a recent OECD 422 study on the read-across substance ethyl hexanoate. The supporting study is a literature study from 1967 holding data on ethyl heptanoate, ethyl octanate and ethyl nonanoate.

In the key study (2017) the read-across substance ethyl hexanoate was tested in a repeated dose assay via oral gavage to Sprague-Dawley rats with dose levels of 0, 100, 300 and 1000 mg/kg bw/day. No test item-related adverse effects were observed up to 1000 mg/kg bw/day. Therefore, the No Observed Adverse Effect Level (NOAEL) for repeated dose toxicity on ethyl hexanoate is considered to be at least 1000 mg/kg bw/day. Taking into account the molecular weight correction related to the read-across, this results in an NOAEL > 1097 mg/kg bw/day for ethyl heptanoate.

In the supporting study (1967), for ethyl heptanoate, ethyl octanoate (read-across) and ethyl nonanoate (read-across) subchronic data were presented in the study. Limited documentation is available and no OECD guideline was followed and the studies are non-GLP. No information on the actual received dose was available, but the concentrations in the diet are reported.

Ethyl heptanoate, ethyl octanoate or ethyl nonaoate was fed to rats for 13 weeks. The doses were:

- ethyl heptanoate: 1,00 or 10000 ppm

- ethyl octanoate: 1000; 2500 or 10000 ppm

- ethyl nonaoate: 10000 ppm

A control group received the vehicle. The food intake, weight and general condition were observed and heamatological and macroscopical examinations were performed.

None of the substances showed any effects on growth or haematology, nor macroscopic changes in the tissues. All were considered not toxic.

The NOAEL for ethyl heptanoate was considered to be 10000 ppm.

Taken together, the read-across substance ethyl hexanoate (key study) and the three substances ethyl heptanoate, ethyl octanoate (read-across) and ethyl nonanoate (read-across) in the supporting study (1967) were not toxic in the two repeated dose studies performed and under the conditions of testing.

The most conservative NOAEL was obtained from a read-across key study performed with ethyl caproate. It is a recent and guideline compliant study performed under GLP.

Based on the result, and on the structural, chemical and toxicological similarities between ethyl caproate and ethyl heptoate, the NOAEL for ethyl heptoate is greater than 1000 mg/kg bw/day.

Justification for classification or non-classification

In section 3.9.2 of the EU regulation No. 1272/2008 on the Classification, Labelling and Packaging of Substances and Mixtures (CLP), the criteria are depicted for the classification of a substance for repeated exposure.

Based on all available information obtained with the target and read-across substances there was no specific target organ toxicity nor were there compound-related effects after 28 day or 13 weeks of dosing.

Based on the results, and on the structural, chemical and toxicological similarities between the three read-across substances ethyl caproate, ethyl octanoate and ethyl nonanoate, and ethyl heptoate, the NOAEL for repeated dose toxicity is considered to be at least 1000 mg/kg bw/day.

Therefore the substance is not considered to be classified.