2-Propenoic acid, 1,1'-[7,13-dimethyl-10-(3-methyl-11-oxo-2,4,7,10-tetraoxatridec-12-en-1-yl)-10-[[2-[(9-oxo-9H-thioxanthen-2-yl)oxy]acetyl]amino]-3,6,8,12,14,17-hexaoxanonadecane-1,19-diyl] ester

Endpoint summary

Description of key information

 

The substance (CAS 1427388 -03 -1) can be structurally divided into a 'body' and three 'arms'.

The three 'arms' are identified as 2-(2 -Vinyloxyethoxy)ethyl acrylate (VEEA - CAS: 86273 -46 -3) and is registered between 10 -100 tonnes/year. The body is identified as Omnipol TX but has no reliable, useful experimental data. Read-across to VEEA is proposed, in combination with QSAR estimation for the full substance.

VEEA is classified as Acute Toxic Cat. 4 - oral route. Based on QSAR the full substance (CAS 1427388 -03 -1) would not be classified. However following the precautionary principle, the full substance will be classified as Acute Toxic Cat. 4 - oral route.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

Between: 10th September 2003 and 07th November 2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

See attached justification

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Date of inspection: November 2002 Date of Signature: March 2003

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: HanBrl: Wist (SPF)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:RCC Ltd, Laboratory Animal Services, CH-4414 Fullinsdorf, Switzerland

- Age at study initiation: 12 weeks

- Fasting period before study: Approximately between 17 and 18 hours.

- Housing: In groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz,Switzerland).

- Diet (e.g. ad libitum):Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch No. 4/03 and 54/03 (Provimi Kliba AG. CH-4303, Kaiseraugst, Switzerland, ad libitum

- Water (e.g. ad libitum): Community tap water from Fullinsdorf in Switzerland ad libitum.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Set to achieve limits of 19 deg C to 25 deg C.

- Humidity (%): Set to achieve limits of 30 to 70%.

- Air changes (per hr): The rate of air exchanges was 10 to 15 changes per hour.

- Photoperiod (hrs dark / hrs light): automatically controlled light cycle of 12 hours light and 12 hours dark.

IN-LIFE DATES: From: Day 0 To: end of study

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

VEHICLE
- Concentration in vehicle: The test item was diluted in vehicle (PEG 300) at concentrations of 0.2 g/mL and 0.03 g/ml, respectively and administered at a volume dosage of 10 mL/kg.

- Amount of vehicle (if gavage): 10ml/kg

- Justification for choice of vehicle: The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date. This trial formulation is excluded from the GLP statement of compliance. PEG 300 was found to be a suitable vehicle.

- Lot/batch no. (if required): 448174/1 21203148

MAXIMUM DOSE VOLUME APPLIED:
2000 mg/kg

The test material was administered orally undiluted at a dose level of 2000 mg/kg, and as a solution in arachis oil BP at a dose level of 300 mg/kg.

Dosing was performed sequentially.

DOSAGE PREPARATION (if unusual):
In the absence of data regarding the toxicity of the test material, 300 mg/kg was chosen as the starting dose.

The volume administered to each animal was calculated according to the fasted bodyweight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each group and each dose level to confirm the survival of the previously dosed animals.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Dose levels are in terms of the test item as supplied by the sponsor. In the absence of data regarding the toxicity of the test material, 300 mg/kg was chosen as the starting dose.

Doses:

300 (with vehicle) and 2000 (undiluted) mg/kg.

No. of animals per sex per dose:

3 females at 2000 mg/kg bw
6 females at 300 mg/kg bw

Control animals:

no

Details on study design:

- Duration of observation period following administration: 18 days


- Frequency of observations and weighing: Observations were monitored during acclimitisation and at approximately 1, 2, 3 and 5 hours after dosing and daily from day 2 to 18.


- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight, necropsy.

Statistics:

None recorded.

Preliminary study:

Not applicable.

Sex:

female

Dose descriptor:

LD50

Effect level:

< 2 000 mg/kg bw

Mortality:

All 2000 mg/kg treated animals were found dead 5 hours after treatment.

Clinical signs:

other: Slightly ruffled fur with hunched posture was noted in all 2000 mg/kg treated animals 3 hours after administration, No clinical signs were observed in the 300 mg/kg treated animals during the course of the study.

Gross pathology:

All animals which died spontaneously during the observation period were necropsied as soon as they were found dead. All surviving animals were killed at the end of the observation period by an intraperitoneal injection of Vetanarcol at a dose of at least 2.0 mUkg body weight (equivalent to at least 324 mg sodium pentobarbitone/kg body weight) and discarded after macroscopic examinations were performed. No organs or tissues were retained. No macroscopic findings were recorded at necropsy.

Other findings:

- Organ weights: not retained

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The median lethal dose of 2-(2'-Vinyloxy ethoxy) ethyl acrylate after single oral administration to female rats, observed over a period of 14 days is:
300 mg/kg body weight < LD50 (female rat) < 2000 mg/kg body weight.
This corresponds with Acute Tox 4.

Executive summary:

Three groups, each of three female HanBrl: WIST (SPF) rats were treated with 2-(2'Vinyloxy ethoxy) ethyl acrylate by oral gavage administration at a dosage of 2000 mg/kg or 300 mg/kg body weight. The test item was diluted in vehicle (PEG 300) at concentrations of 0.2 g/mL and 0.03 g/ml, respectively and administered at a volume dosage of 10 mL/kg. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded twice daily during test days 1-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically. The following females were treated and percentage of mortality was observed: 2000 mg/kg: 100% and 300 mg/kg: 0%.

All 2000 mg/kg treated animals were found dead 5 hours after treatment. Slightly ruffled fur with hunched posture was noted in all 2000 mg/kg treated animals 3 hours after administration. No clinical signs were observed in the 300 mg/kg treated animals during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Justification for type of information:

1. SOFTWARE
T.E.S.T. v4.2.1

2. MODEL (incl. version number)
T.E.S.T. v4.2.1

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CC(OCCOCCOC(=O)C=C)OCC(COC(C)OCCOCCOC(=O)C=C)(COC(C)OCCOCCOC(=O)C=C)NC(=O)COC1C=CC2=C(C=1)C(=O)C1C=CC=CC=1S2

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
[[Explain how the model fulfils the OECD principles for (Q)SAR model validation. Consider attaching the QMRF and/or QPRF or providing a link]
See attached documentation

5. APPLICABILITY DOMAIN
[Explain how the substance falls within the applicability domain of the model]
See attached documentation

6. ADEQUACY OF THE RESULT
[Explain how the prediction fits the purpose of classification and labelling and/or risk assessment]
Useful as part of a weight of evidence approach.

Qualifier:

according to guideline

Guideline:

other: Guidance on information requirements and chemical safety assessment Chapter R.6: QSARs and grouping of chemicals

Version / remarks:

2008

Species:

rat

Dose descriptor:

LD50

Effect level:

4 637 mg/kg bw

Remarks on result:

other: Based on the nearest neighbour algorithm

Endpoint	Experimental value	Predicted value^b
Oral rat LD50 -Log10(mol/kg)	N/A	N/A
Oral rat LD50 mg/kg	N/A	N/A

^bThe consensus prediction for this chemical is considered unreliable since only one prediction can only be made

 

Method	Predicted value -Log10(mol/kg)
Hierarchical clustering	N/A
FDA	N/A
Nearest neighbor	2.31

 

 Nearest neighbor:

Endpoint	Predicted value – Consensus method	Predicted value -Hierarchical clustering method	Predicted value – FDA method	Predicted value – Nearest Neighbor Method
Oral rat LD50 -Log10 (mol/kg)	2.31	NA	NA	2.31
Oral rat LD50mg/kg	4636.71	NA	NA	4636.71

 

 Hierarchical method:The toxicity for a given query compound is estimated using the weighted average of the predictions from several different models. The different models are obtained by using Ward’s method to divide the training set into a series of structurally similar clusters. A genetic algorithm based technique is used to generate models for each cluster. The models are generated prior to runtime.

FDA method: The prediction for each test chemical is made using a new model that is fit to the chemicals that are most similar to the test compound. Each model is generated at runtime.

Nearest neighbor method: The predicted toxicity is estimated by taking an average of the 3 chemicals in the training set that are most similar to the test chemical.

Consensus method: The predicted toxicity is estimated by taking an average of the predicted toxicities from the above QSAR methods (provided the predictions are within the respective applicability domains)

Conclusions:

The T.E.S.T. QSAR estimated the oral rat LD50 to be around 4637 mg/kg based on the nearest neighbour algorithm. The consensus method could not be applied because only one out of three algorithm resulted in a prediction.

Executive summary:

 

QPRF:T.E.S.T. v 4.2.1

 

1.	Substance	See “Test material identity”
2.	General information
2.1	Date of QPRF	21/08/2021
2.2	QPRF author and contact details	Karel Viaene [e-mail]
3.	Prediction
3.1	Endpoint (OECD Principle 1)	Endpoint	Oral rat LD50 (amount of chemical in mg/kg body weight that causes 50% of rats to die after oral ingestion)
3.2	Algorithm (OECD Principle 2)	Model or submodel name	T.E.S.T.
		Model version	v. 4.2.1
		Predicted value (model result)	See “Results and discussion”
		Input for prediction	- Chemical structure via SMILES code
		Descriptor values	Different methods are used to derive the toxicity value (see result)
3.3	Applicability domain (OECD principle 3)	Domains:
		- Compounds can only contain the following element symbols: C, H, O, N, F, Cl, Br, I, S, P, Si, or As - Compounds must represent a single pure component		- Substance contains only allowed elements     -Substance represents a single pure component
3.4	The uncertainty of the prediction (OECD principle 4)	Statistical accuracy for training dataset: n = 7420 Method R2   Hierarchical 0.578 Nearest neighbor 0.557 Consensus 0.633   The consensus method achieved the best results in terms of both prediction accuracy and prediction coverage. The hierarchical method achieved slightly better prediction accuracy than the nearest neighbor and FDA methods but the prediction coverage was lower (83%).
3.5	The chemical mechanisms according to the model underpinning the predicted result (OECD principle 5)	Hierarchical method:The toxicity for a given query compound is estimated using the weighted average of the predictions from several different models. The different models are obtained by using Ward’s method to divide the training set into a series of structurally similar clusters. A genetic algorithm based technique is used to generate models for each cluster. The models are generated prior to runtime. FDA method: The prediction for each test chemical is made using a new model that is fit to the chemicals that are most similar to the test compound. Each model is generated at runtime. Nearest neighbor method: The predicted toxicity is estimated by taking an average of the 3 chemicals in the training set that are most similar to the test chemical. Consensus method: The predicted toxicity is estimated by taking an average of the predicted toxicities from the above QSAR methods (provided the predictions are within the respective applicability domains)

 

References

- User’s Guide for T.E.S.T. (version 4.2) (Toxicity Estimation Software Tool) – A program to estimate toxicity from molecular structure. US EPA

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

>= 300 - <= 2 000 mg/kg bw