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Short-term toxicity to fish

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Endpoint:
short-term toxicity to fish
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
From 2016-01-07 to 2016-01-08
Reliability:
2 (reliable with restrictions)
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® HA-QSAR toolbox v2.1

2. MODEL (incl. version number)
iSafeRat® High Accuracy QSAR – version 1.5

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
O(c(c(O)ccc1C=CC)c1)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 203 (Fish, Acute Toxicity Test)
Deviations:
not applicable
Remarks:
(QSAR model)
Qualifier:
equivalent or similar to
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 is to accurately predict the acute toxicity to fish as would be expected in a laboratory experiment following OECD Guideline 203 and EC method C.1 for specific, named modes of action to provide a value that can effectively replace a 96-hour LC50 value from an experimental study. The regression based method used to achieve this has been fully validated following the OECD (2004) recommendations (refer to the QMRF with KREATiS QMRF identifier: KTS/QMRF/HOL/05 for further details).
GLP compliance:
no
Specific details on test material used for the study:
- Mode of action: MOA2, polar narcotic (alkyl/alkoxyphenols)
- Water solubility: 709 mg/L (from experimental study)
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.
Following the principles of Phase Equilibrium Thermodynamics, for polar narcotic substances, no difference in relationship between solubility and ecotoxicity 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. In this case, for MOA2, no differences were observed in activity based toxicity for the species used.
Test type:
other: QSAR
Water media type:
freshwater
Limit test:
no
Total exposure duration:
96 h
Remarks on exposure duration:
none
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 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:
The QSAR is based on data from studies performed using measured concentrations or with acceptable stability.
Details on test conditions:
A variety of test designs were accepted: Preferentially results from a semi-static with daily renewal of test solutions and the control or from a flow-through test 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.:
3.6 mg/L
Nominal / measured:
meas. (not specified)
Conc. based on:
test mat.
Basis for effect:
mortality
Remarks on result:
other: 95% CL: 2.9-4.4 mg/L
Details on results:
The predicated value is reliable since the test substance falls within the applicability domain of the model. The value of water solubility value of the test substance is within descriptor domain of the model between log water solubility (in log (mol/L)) of -5.06 to 0.109. Moreover the test substance is attributed to the class of polar narcotic compounds (MOA 2) as alkyl/alkoxy-phenol.
Results with reference substance (positive control):
Not applicable
Reported statistics and error estimates:
95% CL: 2.9-4.4 mg/L
QSAR statistical parameters are given in the QMRF and the QPRF

No additional information

Validity criteria fulfilled:
yes
Remarks:
The substance falls into the applicability domains of the QSAR model.
Conclusions:
The 96-h LC50 based on mortality and measured concentrations was determined to be 3.6 mg/L with 95%-Confidence Limit between 2.9 and 4.4 mg/L.
Executive summary:

A QSAR prediction was performed to assess the acute toxicity of the test 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 Mode of Action in question (MOA2, polar narcotic). The QSAR is based on validated data for a training set of 16 chemicals derived from 96-hour tests on fish, for which the concentrations of the test substance had been determined by chemical analyses over the test period. The water solubility of the substance given as input was experimentally measured at 709 mg/L.The substance falls within the applicability domain of the model as demonstrated in the QPRF.

The 96-h LC50 based on mortality and measured concentrations was determined to be 3.6 mg/L with 95%-Confidence Limit between 2.9 and 4.4 mg/L.

Endpoint:
short-term toxicity to fish
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
Run on 2015-09
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification
Justification for type of information:
1. SOFTWARE
ECOSAR

2. MODEL (incl. version number)
ECOSAR v1.11

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Oc(ccc1C=CC)c(c1)OC
log Kow: 2.1 (experimental result)

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Acute toxicity to fish (lethality).
- Unambiguous algorithm: Linear regression QSAR; Log 96h-LC50 (mmol/L) = -0.7601*log Kow + 0.76. To convert the LC50 from mmol/L to mg/L, multiply by the molecular weight of the compound.
- Defined domain of applicability: Applicable to chemicals with log Kow less than 7.0 and molecular weight less than 1000 g/mol. The model can be suitable for chemicals class of Phenols.
- Appropriate measures of goodness-of-fit and robustness and predictivity: N = 188+10 and the coefficient of determination R² = 0.868.
- Mechanistic interpretation: related to the partitioning of the substance from water into the organisms lipid phase.

5. APPLICABILITY DOMAIN
Applicable to chemicals with log Kow less than 7.0 and molecular weight less than 1000 g/mol. The model can be suitable for chemicals class of Phenols.

6. ADEQUACY OF THE RESULT
The substance falls within the applicability domain described above and therefore the predicted value can be considered reliable.
For more information, see Phenols SAR document in "Attached background material".
Qualifier:
according to
Guideline:
other: REACH guidance on QSARs R.6, May 2008
Deviations:
no
Principles of method if other than guideline:
See attached QPRF.
GLP compliance:
no
Remarks:
(not relevant)
Specific details on test material used for the study:
- log Kow : 2.1 (experimental result)
Details on sampling:
Not applicable
Details on test solutions:
Not applicable
Test organisms (species):
no data
Details on test organisms:
None
Test type:
not specified
Water media type:
not specified
Total exposure duration:
96 h
Remarks on exposure duration:
none
Post exposure observation period:
Not applicable
Hardness:
Not applicable
Test temperature:
Not applicable
pH:
Not applicable
Dissolved oxygen:
Not applicable
Salinity:
Not applicable
Nominal and measured concentrations:
Not applicable
Details on test conditions:
Not applicable
Key result
Duration:
96 h
Dose descriptor:
LC50
Effect conc.:
23.9 mg/L
Remarks on result:
other: ECOSAR Class: Phenols
Details on results:
See QPRF report
Results with reference substance (positive control):
Not applicable
Reported statistics and error estimates:
N = 188+10 and the coefficient of determination R² = 0.868.

No additional information

Validity criteria fulfilled:
yes
Conclusions:
The substance was predicted to have a LC50 value of 23.9 mg/L to fish after 96h exposure. The substance falls within the applicability domain and therefore the predicted value can be considered reliable.
Executive summary:

The acute toxicity to fish was estimated using the ECOSAR v1.11 QSAR model available from the U.S. EPA. The estimation 96h-LC50 was 23.9 mg/L (Phenols class), calculated from a measured log Kow value at 2.1 and a linear regression:

Log 96h-LC50 (mmol/L) = -0.7601*log Kow + 0.76.

The substance falls within the applicability domain and therefore the predicted value can be considered reliable.

Description of key information

Geometric mean of QSARs models (iSafeRat v1.5 and ECOSAR v1.11):
96h-LC50 = 9.3 mg/L.

Key value for chemical safety assessment

LC50 for freshwater fish:
9.3 mg/L

Additional information

To assess the short-term toxicity of the registered substance to fish, two reliable QSAR results are available.

The first prediction data (KREATiS, 2016) is a QSAR. This QSAR prediction (iSafeRat holistic approach v1.5) 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 acute toxicity to fish was determined using a validated QSAR for the Mode of Action in question, (MOA 2, polar narcosis). This QSAR is based on validated data for a training set of 16 chemicals derived from 96-hour tests on fish, for which the concentrations of the test substance had been determined by chemical analyses over the test period. The substance falls within the applicability domain of the model. The 96h-LC50 value based on mortality and measured concentrations was determined to be 3.6 mg/L (95% CL: 2.9 - 4.4 mg/L).

The second prediction data (ECOSAR, 2015) is also a QSAR. This QSAR prediction used the ECOSAR v1.11 QSAR model available from the U.S. EPA to assess the acute toxicity of the registered substance to fish. The substance falls within the applicability domain of the model. The estimation 96h-LC50 value was determined at 23.9 mg/L using the chemical class of Phenols.

In conclusion, according to these key data points, the key LC50 value on fish, used for chemical safety assessment, is determined at 9.3 mg/L, corresponding to a geometric mean of predicted LC50 values.