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Ecotoxicological information

Short-term toxicity to fish

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Reference
Endpoint:
short-term toxicity to fish
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
From 2020-01-17 to 2020-01-22
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
The Subcooled Liquid Water Solubility value given as input to the Ecotox module of the iSafeRat® Holistic HA-QSAR falls within the intermediate domain of the model where baseline toxicity cannot be experimentally measured accurately. In this intermediate domain, the toxicity may to be greater than the water solubility limit. For confirmation, a statistical k-NN approach (k = 3) is performed on the data of substances found to be in the intermediate domain of the model. The toxicity of the three closest neighbours based on the solubility are considered. Based on these data, either the toxicity of the test item is expected to be greater than the limit of solubility, or the toxicity is estimated by the geometric mean between the toxicity value predicted using the regression line and the solubility cut-off line. According to this analysis, the toxicity of the test item is estimated as the geometric mean between the toxicity value predicted using the regression line and the solubility cut-off line (with the confidence intervals being placed at these limits).
Justification for type of information:
1. SOFTWARE
iSafeRat® HA-QSAR toolbox v2.4

2. MODEL (incl. version number)
iSafeRat® High-Accuracy-Quantitative Structure-Activity Relationship (HA-QSAR) based on a holistic approach for predicting physicochemical and ecotoxicological endpoints: Short-term toxicity to fish (lethality)
iSafeRat® holistic HA-QSAR v1.8

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
SMILES: O(C(C(C(C(C(CC1)(C)C)C2)(C1)C)C3)(C2)C)C3
Water solubility: 1.87 mg/L (Lange, 2015)
Melting point: 65°C (mean of two reliable experimental studies; Firmenich, 2012)

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 203 (Fish, Acute Toxicity Test)
Deviations:
not applicable
Remarks:
(QSAR model)
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method C.1 (Acute Toxicity for Fish)
Deviations:
not applicable
Remarks:
(QSAR model)
Principles of method if other than guideline:
The purpose of this QSAR model is to accurately predict the acute toxicity to fish as would be expected in a laboratory experiment following the OECD Guideline 203 (OECD, 2019) and EC method C.1 (European Commission, 2008) for specific named modes of action. The model provides an in silico prediction for the 96-hour LC50 value that can effectively be used in place of an experimentally derived 96-hour LC50 value. The regression based method used to achieve this has been fully validated following the OECD recommendations (OECD, 2004).
GLP compliance:
no
Remarks:
QSAR model
Analytical monitoring:
no
Details on sampling:
Not applicable
Vehicle:
no
Details on test solutions:
Not applicable
Test organisms (species):
other: Danio rerio, Oncorhynchus mykiss, Lepomis macrochirus, Pimephales promelas, Oryzias latipes, Leuciscus idus
Details on test organisms:
Results from the following species were used in the regression: Danio rerio, Oncorhynchus mykiss, Lepomis macrochirus, Pimephales promelas, Oryzias latipes, Leuciscus idus
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:
96 h
Remarks on exposure duration:
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 14 to 25 °C depending on the fish species used to construct the algorithm. While it is recognized that this may contribute to some extent to the variability of the LC50 values found in experimental data, KREATiS has not observed a clear trend suggesting that normalization to temperature would necessarily improve the algorithm (say for trout as opposed to warm water species) for monoconstituents. Nevertheless, this is a recognized area for further research by KREATiS.
pH:
The QSAR is based on data from studies performed 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
Nominal and measured concentrations:
Studies were used only where sufficient evidence was presented to determine that the stubstance was stable under test conditions (i.e. maintened within ± 20 % of the nominal) or, if not, the result was based on measured concentrations as geometric mean.
Details on test conditions:
A variety of test designs were accepted: Preferentially results from semi-static experiments with daily renewal of test solutions and the control or from flow-through tests were used. However, for stable, low volatility substances a static design 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:
96 h
Dose descriptor:
LC50
Effect conc.:
1.4 mg/L
Nominal / measured:
meas. (not specified)
Conc. based on:
test mat.
Basis for effect:
mortality (fish)
Remarks on result:
other: 95% CL: 0.43-1.87 mg/L
Details on results:
The test item falls within the applicability domain of the model except for the descriptor domain. From a descriptor domain point of view, the test item falls within the intermediate domain where baseline toxicity cannot be experimentally measured accurately. According to a k-NN approach, the toxicity of the test item is estimated as the geometric mean between the toxicity value predicted using the regression line and the solubility cut-off line (with the confidence intervals being placed at these limits).
Results with reference substance (positive control):
Not applicable
Reported statistics and error estimates:
Confidence limits: 0.43 – 1.87 mg/L
Statistical characteristics of the model are given in the QMRF report KTS/QMRF/HOL/08.
Sublethal observations / clinical signs:

Applicability domain of the algorithm

Descriptor domain

The Subcooled Liquid Water Solubility value (or -4.704 in log (mol/L)) given as the input to the Ecotox module of the iSafeRat® Holistic HA-QSAR falls within the intermediate domain of the model between a log water solubility (in log (mol/L)) of -10.42 to -4.63 where baseline toxicity cannot be experimentally measured accurately. In this intermediate domain, the toxicity may to be greater than the water solubility limit. For confirmation,a statistical k-NN approach (k = 3) is performed on the data of substances found to be in the intermediate domain of the model. The toxicity of the three closest neighbours based on the solubility are considered. Based on these data, either the toxicity of the test item is expected to be greater than the limit of solubility, or the toxicity is estimated by the geometric mean between the toxicity value predicted using the regression line and the solubility cut-off line. According to this analysis, the toxicity of the test item is estimated as the geometric mean between the toxicity value predicted using the regression line and the solubility cut-off line (with the confidence intervals being placed at these limits).

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® Holistic HA-QSAR can reliably predict the aquatic toxicity for chemicals with the following mechanisms of action of toxicity (MechoA):

          non-polar narcosis (MechoA 1.1)

          polar narcosis of alkyl-/alkoxy-phenols (MechoA 1.2)

          polar narcosis of aliphatic amines (MechoA 1.2)

          cationic narcosis of quaternary ammoniums (MechoA 1.3)

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

          hard electrophile reactivity (MechoA 3.1)

          RedOx cycling of primary thiols (MechoA 4.4)

          Proton release of carboxylic acids (MechoA 5.2)

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.

Validity criteria fulfilled:
yes
Conclusions:
The 96-h LC50 based on mortality and measured concentrations was determined to be 1.4 mg/L with 95%-Confidence Limit between 0.43 and 1.87 mg/L.
Executive summary:

A QSAR model was used to calculate the acute toxicity to fish exposed to the test item. 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 the Guideline for Testing of Chemicals No. 203, "Fish Acute Toxicity Test" (OECD, 2019), referenced as Method C.1 of Commission Regulation No. 440/2008 (European Commission, 2008). The criterion predicted was the LC50 (Median Lethal Concentration), a statistically derived concentration which is expected to cause mortality in 50% of test animals within a period of 96 hours.

The acute 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)(Baueret al., 2018). The QSAR is based on validated data for a training set of 67 chemicals derived from 96-hour test on fish, for which the concentrations of the test item had been determined by chemical analyses over the testperiod.

The 96-h LC50 based on mortality and measured concentrations was determined to be 1.4 mg/L with 95%-Confidence Limit between 0.43 and 1.87 mg/L.

The test item falls within the applicability domain of the model except for the descriptor domain. From a descriptor domain point of view, the test item falls within the intermediate domain where baseline toxicity cannot be experimentally measured accurately. According to a k-NN approach, the toxicity of the test item is estimated as the geometric mean between the toxicity value predicted using the regression line and the solubility cut-off line (with the confidence intervals being placed at these limits).

Description of key information

QSAR model, iSafeRat holistic approach v1.8, key study, validity 2:

96h-LC50 = 1.4 mg/L (95% CL: 0.43 - 1.87 mg/L).

Key value for chemical safety assessment

Fresh water fish

Fresh water fish
Effect concentration:
1.4 mg/L

Additional information

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

This value (QSAR-KREATiS, 2020) is assessed as a key datapoint and is a QSAR. This QSAR prediction (iSafeRat holistic approach v1.8) was performed on the registered substance, to assess the acute 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 203. The criterion predicted was the LC50 (Median Lethal Concentration), a statistically derived concentration which is expected to cause mortality in 50% of test animals within a period of 96 hours. The acute 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 67 chemicals derived from 96-hour test on fish, for which the concentrations of the test item had been determined by chemical analyses over the testperiod. The test item falls within the applicability domain of the model except for the descriptor domain. From a descriptor domain point of view, the test item falls within the intermediate domain where baseline toxicity cannot be experimentally measured accurately. According to a k-NN approach, the toxicity of the test item is estimated as the geometric mean between the toxicity value predicted using the regression line and the solubility cut-off line (with the confidence intervals being placed at these limits). The 96-h LC50 based on mortality and measured concentrations was determined to be 1.4 mg/L with 95%-Confidence Limit between 0.43 and 1.87 mg/L.

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