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Ecotoxicological information

Toxicity to aquatic algae and cyanobacteria

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Reference
Endpoint:
toxicity to aquatic algae and cyanobacteria
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: Toxicity to algae (inhibition of the exponential growth rate)
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 201 (Alga, Growth Inhibition Test)
Deviations:
not applicable
Remarks:
(QSAR model)
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method C.3 (Algal Inhibition 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 toxicity to algae as would be expected in a laboratory experiment following the OECD Guideline 201 (OECD, 2006) and EC method C.3 (European Commission, 2008) for specific, named mechanisms of action. The model provides an in silico prediction for the 72-hour ErC50 value that can effectively be used in place of an experimentally derived 72-hour ErC50 value. The regression is 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: Pseudokirchneriella subcapitata, Desmodesmus subspicatus, Scenedesmus quadricauda
Details on test organisms:
No difference in terms of toxic mechanism of action between algae (or indeed other) aquatic species is expected. Any observed differences may be attributed to lifestyle related parameters and relative duration of study versus cell size rather than to a specific toxic mechanism causing species differences.
Test type:
other: QSAR method
Water media type:
freshwater
Limit test:
no
Total exposure duration:
72 h
Remarks on exposure duration:
none
Post exposure observation period:
Not applicable
Hardness:
The QSAR is based on data from studies performed at acceptable hardness to ensure control survival.
Test temperature:
The temperatures varied from approximately 20 to 25 °C depending on the species used to construct the algorithm. This small difference is not expected to contribute to the variability of the ErC50 values found in experimental data.
pH:
The QSAR is based on data from studies performed at acceptable pH between 6.0 - 9.0. However it is recognized that in some cases (due to high luminosity) the pH may increase in the control and lower concentrations (which do not cause significant effect over the study period). This pH increase did not generally disqualify the study from being used in the test and validation set for non-polar chemicals.
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 measured initial concentration throughout the test) or, if not, the result was based on measured concentrations as geometric mean.
Details on test conditions:
Following OECD 201, all studies were from a static test design. 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:
72 h
Dose descriptor:
EC50
Effect conc.:
1.5 mg/L
Nominal / measured:
meas. (not specified)
Conc. based on:
test mat.
Basis for effect:
growth rate
Remarks on result:
other: 95% CL: 0.37 - 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:
95% CL: 0.37 - 1.87 mg/L.
QSAR statistical parameters are given in the QMRF and the QPRF

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 - 9.34 to - 4.38 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 72-h ErC50 based on measured concentrations was determined to be 1.5 mg/L with 95%-Confidence Limit between 0.37 and 1.87 mg/L.
Executive summary:

A Quantitative Structure-Activity Relationship (QSAR) was used to calculate the inhibition of growth to algae of 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. 201, "Freshwater Alga and Cyanobacteria, Growth Inhibition Test" (OECD, 2006), referenced as Method C.3 of Commission Regulation No. 440/2008 (European Commission, 2008). The criterion predicted was the ErC50 (Median Effective Concentration for specific growth rate), a statistically derived concentration which is expected to cause 50% inhibition of intrinsic

rate of growth of the test system within a period of 72 hours.

The growth inhibition of algae was determined using validated QSAR model for the Mechanism of Action (MechoA) in question (MechoA 1.1, i.e. non-polar narcosis) (Bauer et al., 2018). The QSAR model is based on validated data for a training set of 40 chemicals derived from 72-hour ErC50 test on algae, for which the concentrations of the test item had been determined by chemical analyses over the test period.

The 72-h ErC50 based on measured concentrations was determined to be 1.5 mg/L with 95%-Confidence Limit between 0.37 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 models, iSafeRat High Accuracy QSAR, key studies:

72h-ErC50 = 1.5 mg/L (95% CL: 0.37 - 1.87 mg/L)

72h-NOECr = 0.18 mg/L (95% CL: 0.13 - 0.24 mg/L)

Key value for chemical safety assessment

EC50 for freshwater algae:
1.5 mg/L
EC10 or NOEC for freshwater algae:
0.18 mg/L

Additional information

To assess the toxicity of the registered substance to aquatic algae, two data point are available.

Both values (QSAR-KREATiS, 2020), assessed as key datapoint, are QSARs. The QSAR predictions (iSafeRat holistic approach v1.8 and iSafeRat NOEC algae 72h v1.1) were performed on the registered substance, to assess the inhibition of growth to algae of the substance. The QSARs have been validated to be compliant with the OECD recommendations for QSAR modelling (OECD, 2004) and predicts the endpoint values which would be expected when testing the substance under experimental conditions in a laboratory following OECD Guideline 201.

For the first QSAR prediction (iSafeRat holistic approach v1.8), the criterion predicted was the ErC50 (Median Effective Concentration for specific growth rate), a statistically derived concentration which is expected to cause 50% inhibition of intrinsic rate of growth of the test system within a period of 72 hours. The growth inhibition of algae was determined using validated QSAR model for the Mechanism of Action (MechoA) in question (MechoA 1.1, i.e. non-polar narcosis) (Bauer et al., 2018). The QSAR model is based on validated data for a training set of 40 chemicals derived from 72-hour ErC50 test on algae, for which the concentrations of the test item had been determined by chemical analyses over the test period. 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 72-h ErC50 based on measured concentrations was determined to be 1.5 mg/L with 95%-Confidence Limit between 0.37 and 1.87 mg/L.

For the second QSAR prediction (iSafeRat NOEC algae 72h v1.1), the criterion predicted was the NOECr (No Observed Effect Concentration for specific growth rate), a tested concentration which is expected to cause no effect on intrinsic rate of growth of the test system within a period of 72 hours. The growth inhibition of algae was determined using validated QSAR models in question (MechoA 1.1, i.e. non-polar narcosis) (Bauer et al., 2018). The QSAR models are based on validated data for a training set of 31 chemicals derived from 72-hour NOECr test on algae, for which the concentrations of the test item had been determined by chemical analyses over the test period. The test item falls within the applicability domain of the model and was therefore reliably predicted for its toxicity (72h-NOEC) to algae. The 72h-NOECr of the test item to algae was predicted as 0.18 mg/L with 95%-Confidence Interval between 0.13 and 0.24 mg/L.

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