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Ecotoxicological information

Long-term toxicity to fish

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Reference
Endpoint:
long-term toxicity to fish, other
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
July 01st, 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: CC1(CCCC2(C1CCC3(C2CCO3)C)C)C

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:
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
Remarks:
QSAR model
Specific details on test material used for the study:
-Description: solid, melting point = 80°C (Harlan, 2008)
-Water Solubility: 1.88 mg/L (Harlan, 2009)
-Mechanism of action: MechoA 1.1: non-polar narcosis (Bauer et al., 2018)
Analytical monitoring:
no
Remarks:
QSAR model
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:
Not applicable
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.
Reference substance (positive control):
no
Remarks:
QSAR model
Key result
Duration:
32 d
Dose descriptor:
EC10
Effect conc.:
0.1 mg/L
Nominal / measured:
meas. (not specified)
Conc. based on:
test mat.
Basis for effect:
other: growth or reproduction
Remarks on result:
other: 95%CI: 0.076-0.14 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.
Results with reference substance (positive control):
not applicable
Reported statistics and error estimates:
95% confidence interval (α = 0.05): 0.076 – 0.14 mg/L.
QSAR statistical parameters are given in the QMRF and the QPRF

Applicability domain analysis

Descriptor domain

The water solubility value given as the input to the iSafeRat® HA-QSAR for chronic aquatic toxicity (1.88 mg/L, equivalent to subcooled liquid water solubility at 6.61 mg/L or -4.554 in log (mol/L)) falls within the descriptor domain of the model between log water solubility (in log (mol/L)) of -5.140 to 0.702.

Structural fragment domain

All chemical groups within the molecular structure are taken into account by the model.

Mechanistic domain:

Currently, the ecotoxicity module of the iSafeRat® HA-QSAR for chronic aquatic toxicity can reliably predict the

aquatic toxicity for chemicals with the following toxic mechanisms of action (MechoA):

• non-polar narcosis (MechoA 1.1)

• mono-/poly-esters whose hydrolysis products are narcotics (MechoA 2.1)

The MechoA of molecules is predicted directly from the structure. The test item as an aliphatic ether is expected to exert a MechoA 1.1 and can be taken into account by the model (Bauer et al., 2018).

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 0.10 mg/L with 95%-Confidence Interval between 0.076 and 0.14 mg/L.
Executive summary:

A QSAR model model was used to calculate the chronic toxicity of the test item to fish. This QSAR model has been validated to be compliant with the OECD recommendations for QSAR modeling (OECD, 2004) 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 1.1, i.e. non-polar narcosis) (Bauer et al., 2018). The QSAR is based on validated data for a training set of 27 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 0.10 mg/L with 95%-Confidence Interval between 0.076 and 0.14 mg/L.

Description of key information

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

32d-EC10 = 0.10 mg/L (95% CL: 0.076 - 0.14 mg/L).

Key value for chemical safety assessment

EC10, LC10 or NOEC for freshwater fish:
0.1 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 1.1, i.e. non-polar narcosis). The QSAR is based on validated data for a training set of 27 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 0.10 mg/L with 95%-Confidence Limit between 0.076 and 0.14 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.