Undecan-4-olide

Long-term toxicity to fish

Link to relevant study record(s)

Reference

Endpoint:

fish early-life stage toxicity

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

April 12th, 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
iSafeRat® High Accuracy QSAR to predict the chronic aquatic toxicity : Long-term toxicity to fish

2. MODEL (incl. version number)
iSafeRat® High Accuracy QSAR to predict the chronic aquatic toxicity v1.4.

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
SMILES: CCCCCCCC1CCC(=O)O1
The toxicity of the test item was predicted using the iSafeRat® Ecotox module providing the Subcooled Liquid Water Solubility (SLWS) as the input. The SLWS has been derived from the experimental water solubility: 158 mg/L (or -3.067 in log (mol/L)).
Reference: Safepharm Laboratories Ltd (2008) – Undecalactone: Determination of water solubility. SPL project number: 0309/0249. 6th March 2008.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF

5. APPLICABILITY DOMAIN
See attached QPRF

6. ADEQUACY OF THE RESULT
See attached QPRF

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 210 (Fish, Early-Life Stage Toxicity Test)

Deviations:

not applicable

Remarks:

(QSAR model)

Principles of method if other than guideline:

The purpose of this QSAR model is to accurately predict the chronic toxicity to fish as would be expected in a laboratory experiment following OECD Guideline 210 for specific named mechanisms of action. The model provides an in silico prediction for the 32-day EC10 value that can effectively be used in place of an experimental value. The regression based method used to achieve this has been fully validated following the OECD recommendations.

GLP compliance:

no

Specific details on test material used for the study:

- Water solubility: 0.158 g/L at 20°C; OECD Guideline 105, Flask method (Safepharm Laboratories Ltd, 2008)
- Mechanism of action: MechoA 2.1: narcosis after hydrolysis (Bauer et al., 2018)

Analytical monitoring:

no

Details on sampling:

Not applicable

Vehicle:

no

Details on test solutions:

Not applicable

Test organisms (species):

other: Danio rerio, Pimephales promelas, Cyprinus carpio, Oncorhynchus mykiss

Details on test organisms:

Results from the following species were used in the regression:
Danio rerio, Pimephales promelas, Cyprinus carpio, Oncorhynchus mykiss

No difference in terms of toxic mechanism of action between fish freshwater species is expected. Any observed differences may be attributed to lifestyle related parameters (e.g. relative differences in storage lipid content between species) and relative duration of study versus bodysize rather than to a specific toxic mechanism causing species differences.

Test type:

other: QSAR

Water media type:

freshwater

Limit test:

no

Total exposure duration:

32 d

Remarks on exposure duration:

Results from a test duration of 32 to 102 days were included. Equilibrium between organisms and external medium was expected to be equivalent from 32 days.

Post exposure observation period:

None

Hardness:

The QSAR is based on data from studies performed at acceptable hardness to ensure control survival.

Test temperature:

The temperatures varied from approximately 10 to 25 °C depending on the fish species used to construct the algorithm.

pH:

Test results were taken from studies with measured pHs between 6.0 - 8.5.

Dissolved oxygen:

The QSAR is based on data from studies performed at acceptable oxygen concentrations (generally >60%).

Salinity:

Not applicable

Conductivity:

No data

Nominal and measured concentrations:

Studies were used only where sufficient evidence was presented to determine that the substance was stable under test conditions (i.e. maintained within ± 20 % of the nominal) or, if not, the result was based on measured concentrations as geometric mean.

Details on test conditions:

Preferentially results from a flow-through test were used. However semi-static with daily renewal of test solutions and the control was accepted (preferably accompanied by analytical measurements over the study period). For suspected volatile substances only tests performed in closed vessels were accepted unless accompanying analytical monitoring proved such a design was not necessary.

EVALUATION AND STATISTICS
The evaluation of the effects was based on regression line derived from a training set of 6 chemicals with MechoA 2.1 using a validated dataset on subcooled solubility versus the maximum acceptable toxicant concentration (MATC) based on growth or reproducibility of fish following the methodology outlined in ECETOC (2013) and Thomas et al. (2015). Since the 10% effective concentration (EC10) was not determined in most of the studies, this HA-QSAR has been designed using the Maximum Acceptable Toxicant Concentration (MATC) determined as the geometric mean of the No Observed Effect Concentration (NOEC) and the Lowest Observed Effect Concentration (LOEC). The MATC represents the highest concentration that should cause minimum chronic effects. As demonstrated for MechoA 1.1 substances, the results for the external validation set based on EC10 are almost the same as those obtained with the validation set based on MATC. Therefore, we consider the same prediction model to cover the chronic aquatic toxicity (both MATC or EC10 endpoints). These two parameters are therefore considered to be comparable. The algorithm used was an improved version of that used by ECETOC for non-polar narcotic compounds which was then validated using an external test set. The modelling algorithm was derived using a simple linear regression with
the following general equation:
log MATC/EC10 = a x log Water Solubility + b
The correlation coefficient R2 and Root Mean Standard Error (RMSE) values for this model were 0.9849 and 0.1510, respectively. As discussed in the QSAR Model Reporting Format, closer the R2 is to 1 and lower the RMSE values are, better is the goodness-of-fit for the model. Therefore, the model was considered as reliable for providing accurate predictions falling within its applicability domain. Further statistical evidence of high prediction accuracy are provided in the QSAR Prediction Reporting Format (QPRF) for the substance provided in Annex I and the QSAR Model Reporting Format (QMRF) (KREATiS, 2019). Other MechoAs are being added to the KREATiS database as sufficient evidence for high accuracy predictions becomes available.

Reference substance (positive control):

no

Remarks:

(QSAR model)

Key result

Duration:

32 d

Dose descriptor:

EC10

Effect conc.:

0.84 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

other: growth or reproduction

Remarks on result:

other: 95% CL: 0.53-1.3 mg/L

Details on results:

The test item falls within the applicability domain of the model and can therefore be considered a reliably prediction for chronic toxicity (32d-EC10) to fish. Therefore, this endpoint value can be considered valid for use in risk assessment and classification and labelling. The 32d-EC10 of the test item to fish was predicted as 0.84 mg/L.

Results with reference substance (positive control):

Not applicable

Reported statistics and error estimates:

95% confidence interval (α = 0.05): 0.53 – 1.3 mg/L.
QSAR statistical parameters are given in the QMRF and the QPRF

No additional information

Validity criteria fulfilled:

yes

Remarks:

The test item falls within the applicability domain of the model and can therefore be considered a reliably prediction for chronic toxicity (32d-EC10) to fish.

Conclusions:

The 32d-EC10 of the test item to fish was predicted as 0.84 mg/L with 95%-Confidence Limit between 0.53 and 1.3 mg/L.

Executive summary:

A QSAR model model was used to calculate the chronic toxicity of the test substance to fish. This QSAR model has been validated to be compliant with the OECD recommendations for QSAR modeling and predicts the endpoint value which would be expected when testing the substance under experimental conditions in a laboratory following Guideline for Testing of Chemicals No. 210, "Fish, Early-life Stage Toxicity Test" (OECD, 2013). The criterion predicted was the EC10 (10% Effective Concentration), a concentration which is expected to cause an effect of 10% on growth or reproducibility within a period of 32 days.

The chronic toxicity to fish was determined using a validated QSAR for the Mechanism of Action (MechoA) in question (MechoA 2.1, i.e. narcosis after hydrolysis) (Bauer et al., 2018). The QSAR is based on validated data for a training set of 6 chemicals derived from 32-day test on fish, for which the concentrations of the test item had been determined by chemical analyses over the test period.

The 32d-EC10 of the test item to fish was predicted as 0.84 mg/L with 95%-Confidence Limit between 0.53 and 1.3 mg/L.

The test item falls within the applicability domain of the model and can therefore be considered a reliable prediction for chronic toxicity (32d-EC10) to fish. Therefore, this endpoint value can be considered valid for use in risk assessment and classification and labelling.

Description of key information

QSAR model, iSafeRat® High Accuracy QSAR to predict the chronic aquatic toxicity v1.4, key study, validity 1:

32d-EC10 = 0.84 mg/L (95% CL: 0.53 - 1.3 mg/L).

Key value for chemical safety assessment

Fresh water fish

Fresh water fish

Effect concentration:

0.84 mg/L

Additional information

To assess the long-term toxicity of the registered substance to fish, one data point is available.

This value (QSAR-KREATiS, 2019) is assessed as a key datapoint and is a QSAR. This QSAR prediction (iSafeRat® High Accuracy QSAR to predict the chronic aquatic toxicity v1.4) was performed on the registered substance, to assess the chronic toxicity of the substance to fish. This QSAR has been validated to be compliant with the OECD recommendations for QSAR modelling (OECD, 2004) and predicts the endpoint value which would be expected when testing the substance under experimental conditions in a laboratory following OECD Guideline 210. The criterion predicted was the EC10 (10% Effective Concentration), a concentration which is expected to cause an effect of 10% on growth or reproducibility within a period of 32 days. The chronic toxicity to fish was determined using a validated QSAR for the Mechanism of action (MechoA) in question (MechoA 2.1, i.e. narcosis after hydrolysis). The QSAR is based on validated data for a training set of 6 chemicals derived from 32 -day test on fish, for which the concentrations of the test item had been determined by chemical analyses over the test period. The 32d-EC10 of the test item to fish was predicted as 0.84 mg/L with 95%-Confidence Limit between 0.53 and 1.3 mg/L. The test item falls within the applicability domain of the model and can therefore be considered a reliable prediction for chronic toxicity (32d-EC10) to fish. Therefore, this endpoint value can be considered valid for use in risk assessment and classification and labelling.