cis-4-tert-butylcyclohexyl acetate

Toxicity to aquatic algae and cyanobacteria

Link to relevant study record(s)

Reference

Endpoint:

toxicity to aquatic algae and cyanobacteria

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

From March 20th, 2020 to March 23rd, 2020

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® HA-QSAR toolbox v2.5

2. MODEL (incl. version number)
iSafeRat® algErC50 v1.9

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CC(=O)O[C@@H]1CC[C@@H](CC1)C(C)(C)C
Input for the prediction: Subcooled Liquid Water Solubility (SLWS) of the test item. For liquids at 25°C, the SLWS is directly equal to the value of the Water Solubility of the test item. Water Solubility of the test item was predicted to be 4.16 mg/L or -4.678 in log10 (mol/L) at 25°C (KREATiS, 2020) using the measured log KOW value as the input. Log KOW of the test item was experimentally measured to be 4.8 at 25°C (Givaudan, 1996).

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 (Freshwater Alga and Cyanobacteria, Growth 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 and EC method C.3 for specific, named mechanisms of action. The QSAR models provide in silico predictions for the 72-hour ErC50 and NOECr values that can effectively be used in place of an experimentally derived results. The regression is method used to achieve this has been fully validated following the OECD recommendations (OECD, 2004).

GLP compliance:

no

Remarks:

QSAR model

Specific details on test material used for the study:

- log KOW = 4.8 (experimental study performed on a read-across substance, Givaudan, 1996)
- Water Solubility = 4.16 mg/L (KREATiS, 2020)
- Mechanism of action: MechoA 2.1: mono-/poly-esters whose hydrolysis products are narcotics (Bauer et al., 2018)

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 model

Water media type:

freshwater

Limit test:

no

Total exposure duration:

72 h

Remarks on exposure duration:

Results from a test duration of 72 hours only were used for this algorithm.

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 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:

Test results were preferably taken from studies with measured pHs between 6 - 9. 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 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.

Salinity:

Not applicable

Conductivity:

No data

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 the guideline 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.:

1.2 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

growth rate

Remarks on result:

other: 95%CL: 0.97 - 1.5 mg/L

Duration:

72 h

Dose descriptor:

NOEC

Remarks on result:

not determinable

Details on results:

The test item falls within the applicability domain of the model and was therefore reliably predicted for its toxicity (72h-ErC50) to algae. Therefore, this endpoint value can be considered valid for use in risk assessment and classification and labelling.
The 72h-ErC50 of the test item to algae was predicted as 1.2 mg/L (95% CL: 0.97 - 1.5 mg/L).
The 72h-NOECr of the test item to algae was not predicted.

Results with reference substance (positive control):

Not applicable

Reported statistics and error estimates:

95% confidence interval (α = 0.05): 0.97 – 1.5 mg/L
QSAR statistical parameters are given in the QMRF and the QPRF

Analysis of the Applicability Domain of the model

Descriptor domain

The Subcooled Liquid Water Solubility value (4.16 mg/L or -4.678 in log10 (mol/L)) given as the input to the iSafeRat® algErC50 model falls within the descriptor domain of the model between a Subcooled Liquid Water Solubility of -5.57 to 0.93 in log10 (mol/L).

Structural fragment domain

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

Mechanistic domain

Currently, the iSafeRat® algErC50 model 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 iSafeRat® algNOECr model can only reliably predict the aquatic toxicity for chemicals with the mechanism of action of non-polar narcosis (MechoA 1.1).

The MechoA of molecules is predicted directly from the structure. The test item as an ester is expected to exert a MechoA 2.1 (Bauer et al., 2018) and can be taken into account by the model iSafeRat® algErC50 but not by the model iSafeRat® algNOECr.

See QMRF in "attached background material".

Validity criteria fulfilled:

yes

Conclusions:

The test item falls within the applicability domain of the model and was therefore reliably predicted for its toxicity (72h-ErC50) to algae. Therefore, this endpoint value can be considered valid for use in risk assessment and classification and labelling.
The 72h-ErC50 of the test item to algae was predicted as 1.2 mg/L (95% CL: 0.97 - 1.5 mg/L).
The 72h-NOECr of the test item to algae was not predicted.

Executive summary:

Two Quantitative Structure-Activity Relationship (QSAR) models were used to calculate the inhibition of growth to algae of the test item. These QSAR models have been validated to be compliant with the OECD recommendations for QSAR modeling (OECD, 2004) and predict the endpoint values which would be expected when testing the substance under experimental conditions in a laboratory following the OECD Guideline 201, referenced as EU Method C.3. The criterions predicted were the Median Effective Concentration (ErC50), a statistically derived concentration which is expected to cause 50% inhibition of intrinsic rate of growth of the test system and the No Observed Effect Concentration (NOECr), a tested concentration which is expected to cause no effect on intrinsic rate of growth of the test system. Both criterions were determined for a period exposure of 72 hours.

The growth inhibition of algae was determined using validated QSAR models for the Mechanism of Action (MechoA) in question (MechoA 2.1, i.e. mono-/poly-esters whose hydrolysis products are narcotics) (Bauer et al., 2018). The QSAR models are based on validated data for a training set of 44 chemicals derived from 72-hour ErC50 for which the concentrations of the test item had been determined by chemical analyses over the test period. The QSAR model for 72-hour NOECr was not applicable for the test item due to the limitation of the mechanistic domain.

The 72h-ErC50 of the test item to algae was predicted as 1.2 mg/L (95% CL: 0.97 - 1.5 mg/L).

Description of key information

iSafeRat® HA-QSAR toolbox v2.5, KREATiS, 2020:

72h-ErC50 = 1.2 mg/L (95% CL: 0.97 - 1.5 mg/L)

Key value for chemical safety assessment

EC50 for freshwater algae:

1.2 mg/L

Additional information

One QSAR prediction is available to assess the toxicity of the registered substance to aquatic algae.

The QSAR prediction (KREATiS, 2020) was considered as reliable and was used as key data. The 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 OECD Guideline 201. The growth inhibition of algae was determined using validated QSAR model for the Mechanism of Action (MechoA) in question (MechoA 2.1, i.e. mono-/poly-esters whose hydrolysis products are narcotics) (Bauer et al., 2018). The QSAR model is based on validated data for a training set of 44 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 result below is the toxicity values anticipated during a 72-hour study on algae based on measured concentrations. Therefore, this endpoint value can be considered valid for use in risk assessment and classification and labelling.

The 72h-ErC50 of the registered substance to algae was predicted at 1.2 mg/L (95% CL: 0.97 - 1.5 mg/L).

The QSAR model for 72-hour NOECr (iSafeRat® algNOECr) was not applicable for the registered substance due to the limitation of the mechanistic domain.