cis-4-tert-butylcyclohexyl acetate

Toxicity to microorganisms

Link to relevant study record(s)

Reference

Endpoint:

activated sludge respiration inhibition testing

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

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

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 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 beyond the threshold where the toxicity value is systematically measured as greater than the limit of solubility within the exposure period of the test. Therefore, the predicted TOXICITY TO MICROORGANISMS (30-180MIN EC50) is considered as an extrapolation. This result can be considered as reliable with restrictions (descriptor domain).

Justification for type of information:

1. SOFTWARE
iSafeRat® HA-QSAR toolbox v2.4

2. MODEL (incl. version number)
iSafeRat® asritEC50 v1.2

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 209 (Activated Sludge, Respiration 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 microorganisms as would be expected in a laboratory experiment following OECD Guideline 209 and EC method C.11 for specific, named modes of action to provide a value that can effectively replace a 30 to 180 minutes EC50 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 attached in "Attached background material").

GLP compliance:

no

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):

activated sludge

Details on inoculum:

This study is not performed on a single or known species as such. Results were acquired from studies where the following test system was used:
Activated sludge collected and treated according to the method outlined in OECD Guideline 209.

Test type:

static

Water media type:

freshwater

Limit test:

no

Total exposure duration:

180 min

Remarks on exposure duration:

Results from a test duration of 30 to 180 min only were used for this algorithm. The data were separated into 2 groups (30 and 180 min) but the variability between results was not considered important enough to merit the production of two separate models.

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 studies used to construct the algorithm. This small difference is not expected to contribute to the variability of the EC50 values found in experimental data.

pH:

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

Dissolved oxygen:

No data

Salinity:

Not applicable

Nominal and measured concentrations:

This study is typically performed using nominal concentrations. In the case where the test substance was highly volatile this could have caused bias and attempts were made to use measured values when these were available.

Details on test conditions:

Following OECD Guideline 209, all studies used 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:

180 min

Dose descriptor:

EC50

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

inhibition of total respiration

Remarks:

respiration rate

Remarks on result:

other: The 30-180min-EC50 of the test item to microorganisms was predicted as greater than the limit of solubility within the exposure period of the test.

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 beyond the threshold where the toxicity value is systematically measured as greater than the limit of solubility within the exposure period of the test. Therefore, the predicted TOXICITY TO MICROORGANISMS (30-180MIN EC50) is considered as an extrapolation.

Results with reference substance (positive control):

Not applicable

Reported statistics and error estimates:

95% confidence interval (α = 0.05): not applicable
Statistical characteristics of the model 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 input to the iSafeRat® asritEC50 does not fall within the descriptor domain of the model between a Subcooled Liquid Water Solubility of -2.72 to 1.01 in log10 (mol/L) where the toxicity cannot be experimentally measured accurately. Moreover it falls beyond the threshold of -4.64 from where the toxicity value is systematically measured as greater than the limit of

solubility within the exposure period of the test.

Structural fragment domain

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

Mechanistic domain

Currently, the iSafeRat® asritEC50 model can reliably predict the aquatic toxicity for chemicals with the following mechanisms of action of toxicity (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 ester is expected to exert a MechoA 2.1 and can be taken into account by the model (Bauer et al., 2018).

See QMRF in "attached background material".

Validity criteria fulfilled:

no

Remarks:

The test item falls within the applicability domain of the model except for the descriptor domain.

Conclusions:

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 beyond the threshold where the toxicity value is systematically measured as greater than the limit of solubility within the exposure period of the test. Therefore, the predicted TOXICITY TO MICROORGANISMS (30-180MIN EC50) is considered as an extrapolation. This result can be considered as reliable with restrictions (descriptor domain).

Executive summary:

A Quantitative Structure Activity Realtionship (QSAR) model was used to calculate the inhibition of respiration to activated sludge 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 OECD Guideline 209, referenced as EU Method C.11. The criterion predicted was

the 30 to 180 minutes EC50 (Median Effective Concentration for specific respiration rate), a statistically derived concentration which is expected to cause 50% inhibition of intrinsic rate of respiration of the test system within a period of 30 to 180 minutes as an effect on the organic carbon oxidation process. The results from this study do not include the supplementary test results that may be required to determine the effect on nitrification. It should be noted that a specific test duration time could not be determined for this model as 30 and 180 minutes data were available but not in sufficient quantity to separate them into two separate models.

.

The respiration inhibition of activated sludge was determined using a validated QSAR for the Mechanism of Action (MechoA) in question (MechoA 1.1 or 2.1, i.e. related to non-polar narcosis) (Bauer et al., 2018). The QSAR model is based on validated data for a training set of 22 chemicals derived from 30-180 minute EC50 for which the concentrations of the test item had been determined by chemical analyses over the test period. Further valid data were available but the values were all above the water solubility of the substance and were therefore not included as part of the regression. On the other hand, these data could be used to determine the point at which the regression no longer holds true and results from experimental studies are expected to be greater than the solubility limit (i.e. test substance concentrations up to 100 mg/L will result in no effect on activated sludge respiration).

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 beyond the threshold where the toxicity value is systematically measured as greater than the limit of solubility within the exposure period of the test.

The 30-180min-EC50 of the test item to microorganisms was predicted as greater than the limit of solubility within the exposure period of the test.

Description of key information

iSafeRat® HA-QSAR toolbox v2.4, KREATiS, 2020:

30-180min-EC50 > solubility limit

Additional information

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

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 209. The respiration inhibition of activated sludge was determined using a 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 22 chemicals derived from 30 -180 minutes EC50 for which the concentrations of the test item had been determined by chemical analyses over the test period. Further valid data were available but the values were all above the water solubility of the substance and were therefore not included as part of the regression. On the other hand, these data could be used to determine the point at which the regression no longer holds true and results from experimental studies are expected to be greater than the solubility limit (i.e. test substance concentrations up to 100 mg/L will result in no effect on activated sludge respiration). 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 beyond the threshold where the toxicity value is systematically measured as greater than the limit of solubility within the exposure period of the test.

The 30-180min-EC50 of the registered substance to microorganisms was predicted as greater than the limit of solubility within the exposure period of the test.