Registration Dossier

Administrative data

Description of key information

Acute oral toxicity is 4500 mg/kg bw based on read across from Zenolide which was tested in an OECD TG 401.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across information.
Justification for type of information:
The information is derived from the analogue Zenolide. The read across rationale is presented in the Acute Toxicity Endpoint summary. The accompanying files are also attached there.
Reason / purpose:
read-across source
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
4.21 other: mL/kg bw (4500 mg/kg bw)
Remarks on result:
other: 24 hours and 7 days average following Litchfield and Wilcoxon with Gaussian approximation
Interpretation of results:
other: Not acute harmful.
Remarks:
according to EU CLP (EC No. 1272/2008 and its amendments).
Conclusions:
The LD50 value for the substance is 4500 mg/kg bw, based on the results of Zenolide, which was tested in an OECDTG 401.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Reliable study, similar to OECD TG 401, without GLP, with minor restrictions in design and/or reporting but sufficiently reliable for assessment.
Justification for type of information:
The information is used to read across to Oenanthic ether.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
Range finding test yielded four doses: 3.18; 3.96; 5.0; 6.3 ml/kg;
Appraisal of the safety of foods, drugs and cosmetics (FDA) rules applied
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Source: Winkelmann, Paderborn
Weight: ca. 140 g; fasting period before study:ND
Diet: Standard laboratory diet (Ssniff/Intermast)
Water: ad libitum
Acclimation period: 22°C ± 1°C, humidity of the air: 45- 55%, Light period: 12 hours
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
After 16 hour starvation period, different doses were administered in groups of 10 rats each existing of 5 males and 5 females
Doses:
3.18; 3.96; 5.00; 6.30 ml/kg
No. of animals per sex per dose:
five
Control animals:
no
Details on study design:
Mortality and behaviour were observed for seven days. Animals that died were dissected to observe any changes in the physiological structures
Statistics:
no
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
4.21 other: mL/kg bw (4500 mg/kg bw)
Based on:
test mat.
Remarks on result:
other: 24 hours and 7 days average following Litchfield and Wilcoxon with Gaussian approximation
Mortality:
Mortality:

24 hours           7 days
3.18 ml/kg      0/10                     0/10
3.96 ml/kg      4/10                     4/10
5.00 ml/kg      9/10                     9/10
6.30 ml/kg    10/10
Clinical signs:
In the doses applied the substance did not show any toxic symptoms other than apathy of the animals.
Body weight:
An increase of the average body weight from 135 to 156 g after 7 days was detected.
Gross pathology:
No abnormalities were found after necropsy.
Interpretation of results:
other: Not acute harmful
Remarks:
according to EU CLP (EC No. 1272/2008 and its amendments).
Conclusions:
The oral LD50 in rats was determined to be 4500 mg/kg bw.
Executive summary:

In an acute oral toxicity study conducted using a protocol similar to OECD guideline 401 (performed before GLP principles were implemented), undiluted test substance was administered via oral gavage to fasted Wistar rats (five males + five females/dose) at dose levels of 3.18, 3.96, 5 and 6.30 mL/kg. The animals were sluggish soon after administration. In the higher dose groups mortality was observed within 24 hours of dosing, while no mortality was observed after 7 days. Necropsy did not reveal any pathological effects. The LD50 was 4.21±1 mL/kg bw (4500 mg/kg bw) both for the 24 hour and 7 day observation period.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The acute oral toxicity result is of sufficient quality and adequate for this dossier.

Additional information

Acute oral toxicity is assessed based on read-across from Zenolide to Oenanthic ether. The executive summary of the source information on the substance is presented below, followed by the read-across rationale.

Zenolide and its acute oral toxicity

In an acute oral toxicity study (International Bio-Research, Inc.,1975a), conducted using a protocol similar to OECD guideline 401 (study performed before GLP principles were implemented), undiluted Zenolide (substance analogue) was administered via oral gavage to fasted Wistar rats (five males + five females/dose) at dose levels of 3.18, 3.96, 5 and 6.30 mL/kg. The animals were sluggish soon after administration. In the higher dose groups mortality was observed within 24 hours of dosing, while no mortality was observed after 7 days. Necropsy did not reveal any pathological effects. The LD50 for Zenolide was 4.21±1 mL/kg bw (4500 mg/kg bw) both for the 24 hour and 7 day observation period.

The acute oral toxicity of Oenanthic Ether using read across from Zenolide (CAS 54982-83-1.

 

Introduction and hypothesis for the analogue approach

Oenanthic ether consists of 3 main constituents and a number of impurities. All are ethyl esters, despite the name ether, of long chain carboxylic acids. The major constituent has a C12 chain, the two minor ones have C14 and C16 saturated carbon chain. For this substance no experimental acute oral toxicity information is available.

In accordance with Article 13 of REACH, lacking information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. For assessing the acute oral toxicity of Oenanthic ether, the analogue approach is selected because for one closely related analogue (Zenolide) acute oral toxicity information is available which can be used to read across.

Hypothesis: Oenanthic ether has similar acute oral toxicity compared to Zenolide resulting in a similar oral LD50.

Available information: The source chemical Zenolide has been tested in an acute oral toxicity test similar to OECD 401 up to 6.3 ml/kg bw (which corresponds to appr. 6.7 g/kg bw). Since all mortality occurred in the first 24 hours, no increase in clinical signs were noted during the observation period and based on the fact that no abnormalities were found after necropsy, the observation period of 7 days was considered sufficient to draw conclusions. The test result with an LD50 of 4500 mg/kg bw (Rel. 2 non-GLP).

Target chemical and source chemicals

Chemical structures of the target chemical and the source chemical are shown in the data matrix, including physico-chemical properties and available toxicologicalinformation.

Purity / Impurities

The purity and unidentified impurities of the target chemical and source chemical are not expected to influence the potential for acute oral toxicity.

Analogue approach justification

According to Annex XI 1.5 read across can be used to replace testing when the similarity is based on a common backbone and a common functional group. When using read across the result derived should be applicable for C&L and/or risk assessment and it should be presented with adequate and reliable documentation and is presented below.

Analogue selection: For Oenanthic etherZenolide was selected as an analogue being a similar fatty acid type of acetic ester for which acute oral toxicity was available.

Structural similarities and differences:All constituents of Oenanthic ether and Zenolide contain ethyl esters and a long alkane chain (C8-C18 and C12, respectively) and therefore have a similar backbone and functional group: i.e. esters of long chain carboxylic acids. The difference is that all constituents of Oenanthic ether have linear alkyl chains, while Zenolide has a cyclic aliphatic alkyl chain, connected by Ethylene glycol.

Toxico-kinetics, Absorption:Oenanthic ether and Zenolide will have similar oral absorbtion profiles because the molecular weight and Low Kow are all within the range of good oral absorption (MW < 500 and log Kow <7).Metabolism: Fatty acid ethyl esters are found to breakdown fast by hydrolysis/metabolism of the ester bond to free fatty acids and ethanol (Saghir et al, 1997, Billecke et al., 2000). This can take pace in thegastro-intestinal tract at the level of the duodenum and to a lesser extent in the stomach, but also in circulation hydrolysis has been shown to take place (half-life of 58s only). In the small intestine, ethyl esters are emulsified by bile salts and hydrolysed / metabolised by pancreatic lipase, resulting in exposure to the fatty acids and alcohol. Hydrolysis of Oenanthic Ether will yield the corresponding long chain alkyl acid and ethanol and for Zenolide in Dodecanedioc acid and Ethylene glycol. The dicarboxylic acid with a half-life of about 10 minutes with rat liver post mitochondrial fraction will be metabolized by fatty acid oxidation processes towards water and CO2eventually (Tserng and Jin, 1991, EFSA, 2010, ).

Toxico-dynamics:The reactive site of Oenanthic Ether and Zenolide is the ester bond which has only a non-branched alkyl group in its vicinity and therefore is expected to react very similar. Zenolide may be somewhat more toxic because of the formation of Ethylene glycol, which has an LD50 of 4000 mg/kg bw (ATSDR), while ethanol has an LD50 of 7060 mg/kg bw both in rats.

Uncertainty of the prediction: There are no other uncertainties than already addressed above.

Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the data matrix below.

Conclusions for hazard and risk assessment

For Oenanthic ether no acute oral information is available. Zenolide is an analogue for which these data are available. When using read across the result derived should be applicable for C&L and/or risk assessment and be presented with adequate and reliable documentation. The documentation is presented in the current document. For the analogue Zenolide, a well conducted acute oral toxicity test is available (Reliability 2) with an LD50of 4500 mg/kg bw, based on this the same value is derived for Oenanthic ether.

Final conclusion on hazard and risk assessment: Oenanthic ether has an LD50 of 4500 mg/kg bw.

 

Data matrix to support the read across to Oenanthic ether from Zenolide for acute oral toxicity

Chemical names for

 

Oenanthic ether#

ethyl octanoate (C8*)

ethyl decanoate (C10*)

ethyl dodecanoate (C12*)

ethyl tetra-decanoate (C14*)

ethyl hexa-decanoate (C16*)

ethyl octa-decanoate (C18*)

ethyl (9Z)-octadec-9-enoate (C18*)

ethyl (9Z,12Z)‐ octa

deca‐,12‐di enoate (C18*)

Zenolide

(‘C12’)

Target

 

 

 

 

 

 

 

 

Source

CAS#

106-32-1

110-38-3

106-33-2

124-06-1

628-97-7

111-61-5

544-35-4

111-62-6

5982-83-1

Structure

% in product

<10

<10

35-55

15-30

5-15

<10

<10

<10

 

EC No.

945-734-0#

 

 

 

 

 

 

 

 

259-423-6

Vp (Pa)

0.12 meas)#

 31.4

(est.)

 5.70

(est.)

 1.17

(est.)

 0.34

(est.)

0.036

(est.)

 0.0084

(est.)

 0.0081

(est.)

 0.0067

(est.)

0.028

 (exp.)

WS (mg/L)

1.6 (meas)#

 45.6

(est.)

 4.8

(est.)

 0.41

(est.)

 0.037

(est.)

 0.0037

(est.)

 .0004

(est.)

 0.0006

(est.)

 0.0009

(est.)

75

 (exp.)

Log Kow

4.6 (meas)#

 3.8

(est.)

 4.8

(est.)

 5.8

(est.)

 6.8

(est.)

 7.7

(est.)

 8.4

(est.)

 8.5

(est.)

 8.3

(est.)

3.65

(exp.)

Human health

 

 

 

 

 

 

 

 

 

Acute oral toxicity LD50 mg/kg bw

4500

(Read across, (RA))

4500

(RA)

4500 (RA)

4500 (RA)

4500 (RA)

4500 (RA)

4500 (RA)

4500 (RA)

4500

(OECD TG 401)

*The C’s are related to the chain length not the overall number of Cs (as would be presented in the Empirical formula); (est.) = estimated using EpiSuite; (exp.) = experimental;#In this column the values are for Oenanthic ether as such.

 

 

References

Billecke S, Draganov D, Counsell R, Stetson P, Watson C, Hsu C and La Du BN (2000). Human

serum paraoxonase (PON1) isozymes Q and R hydrolyze lactones and cyclic carbonate esters. Drug Metabolism and Disposition, 28 (11), 1335-1342.

 

EFSA, 2010, Scientific Opinion on Dietary Reference Values for fats, including saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, trans-fatty acids, and cholesterol. EFSA Journal 8(3):1461, 2010. 

 

Saghir, M., Werner, J., Laposata, M., 1997, Rapid in vivo hydrolysis of fatty acid ethyl esters, toxic nonoxidative ethanol metabolites. Am. J. Physiol. - Gastrointestinal and Liver, 273, G184-G190

 

Tserng, K.Y. and Jin, S-J., 1991, Metabolic conversion of dicarboxylic acids to succinate in rat liver homogenates. J. Biol. Chem. 266, 2924-29.

Justification for classification or non-classification

Based on the results, the substance does not need to be classified for acute oral toxicity according to EU CLP (EC No. 1272/2008 and its amendments).