(3aα,4β,7β,7aα)-octahydro-4,7-methano-1H-indene

Short-term toxicity to aquatic invertebrates

Link to relevant study record(s)

Reference

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2017-03-22

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:

QSAR predictions:
QSAR based on high quality dataset with very high correlation for the structural group in question. This High accuracy model is therefore considered suitable for use to replace an experimental study as a stand-alone value

Reason / purpose for cross-reference:

(Q)SAR model reporting (QMRF)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 202 (Daphnia sp. Acute Immobilisation Test)

Deviations:

not applicable

Remarks:

(QSAR model)

Principles of method if other than guideline:

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. Moreover the toxicity is likely greater than the water solubility limit. Based on a k-NN approach (with k = 3), the predicted acute toxicity (48h-EC50) to daphnid is considered as the geometric mean of the iSafeRat® prediction and the subcooledwater solubility limit.

GLP compliance:

no

Specific details on test material used for the study:

Not applicable

Analytical monitoring:

no

Details on sampling:

Not applicable

Vehicle:

no

Details on test solutions:

Not applicable

Test organisms (species):

Daphnia sp.

Details on test organisms:

Not applicable

Test type:

other: QSAR based on high quality OECD 202 studies in which the actual concentrations of test substance had been measured

Water media type:

freshwater

Limit test:

no

Total exposure duration:

48 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 23 °C depending on the species 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:

The QSAR is based on data from studies performed at acceptable pH between 6.0 - 9.0.

Dissolved oxygen:

The QSAR is based on data from studies performed at acceptable oxygen concentrations (>60% of the air-saturation value throughout the duration of the test). In exceptional cases where studies with oxygen concentrations lower than 60% were used, all aspects of the study were thoroughly evaluated in order to satisfy the evaluator that the effects found were not due to reduced oxygen concentration (i.e. the study would correctly receive a Klimisch score of 2 under the REACH Regulation [REACH, 2006]).

Salinity:

Not applicable

Nominal and measured concentrations:

The QSAR is based on data from studies performed using measured concentrations or with acceptable stability.When nominal concentrations from training set data were used, the concentrations of the test substance had been shown to be maintained to within 80% of the nominal concentrations throughout the duration of the study either using analytical verification or by application of a weight of evidence approach that such an assumption was justified. If the deviation from the nominal concentration was >20%,the results were based on the measured concentrations.

Details on test conditions:

Preferentially results from semi-static studies were used. However, substances tested using a static design were 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:

48 h

Dose descriptor:

EC50

Effect conc.:

ca. 1 mg/L

Conc. based on:

test mat.

Basis for effect:

mobility

Remarks on result:

other: 95% CL: 0.37-2.87 mg/L

Details on results:

The log water solubility value of the test item given as input to the iSafeRat® Ecotox module is outside of the applicability domain limits specified in the QMRF for this model. However, this substance falls within an intermediate domain where the ecotoxicity value of a substance is expected to be between the hypothetical value as predicted by iSafeRat® model and the water solubility value. Therefore, the toxicity value (48h-EC50) to daphnids for the test item was determined as the geometric mean of the iSafeRat® prediction and the subcooled water solubility limit. The uncertainty in prediction was addressed through 95% confidence intervals. This endpointvalue can be considered valid for use in risk assessment and classification and labelling.

« Intermediate domain » is an area of low solubility where uptake rate is hindered by the poor bioavailability of the molecule in water and therefore equilibrium is not fully reached before the end of the study. This window is between the point where equilibrium is attained and the result fit with the algorithm, and the point where bioavailablity is so low that effects do not occur within the timeframe of the experiment. Thus, an EC50 may be expected to occur for substances found in this solubility window but the results are between the expected algorithms (low EC50 value) and the solubility (maximum EC50 value). In a laboratory, results for substances falling within this window tend to be variable, falling between the upper and lower limit and depends on multiple factors, notably the preparation technique and testing conditions. Therefore, a good approximation of the value likely to be found in a laboratory is achieved using the geometric mean of the algorithm prediction and the water solubility limit.

Results with reference substance (positive control):

Not applicable

Reported statistics and error estimates:

95% CL: 0.37-2.87 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 48-h EC50 based on mobility was determined to be 1.0 mg/L with 95%-Confidence Limit between 0.37 and 2.87 mg/L.

Executive summary:

A Quantitative Structure-Activity Relationship (QSAR) model was used to calculate the acute toxicity of the test item (3aR,4R,7R,7aS)-octahydro-1H-4,7-methanoindene to daphnid. 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. 202, "Daphnia sp., Acute Immobilisation Test" (1), referenced as Method C.2 of Commission Regulation No. 440/2008 (2). The criterion predicted was the EC50 (Median Effective Concentration), a statistically derived concentration which is expected to cause immobility in 50% of test animals within a period of 48 hours.

The immobility of the daphnids was determined using a validated QSAR model for the Mode of Action (MOA) in question (MoA 1 or MechoA 1.1 i.e. non-polar narcosis). The QSAR model is based on validated data for a training set of 58 chemicals derived from 48-hour test on daphnids, for which the concentrations of the test item had been determined by chemical analyses over the test period.

The substance falls within the applicability domain of the model as demonstrated in the QPRF. The 48-h EC50 based on mobility was determined to be 1.0 mg/L with 95%-Confidence Limit between 0.37 and 2.87 mg/L.

This substance falls within an intermediate zone where the ecotoxicity value of a substance is expected to be between the hypothetical value as predicted by iSafeRat® model and the water solubility value. « Intermediate domain » is an area of low solubility where uptake rate is hindered by the poor bioavailability of the molecule in water and therefore equilibrium is not fully reached before the end of the study. This window is between the point where equilibrium is attained and the result fit with the algorithm, and the point where bioavailablity is so low that effects do not occur within the timeframe of the experiment. Thus, an EC50 may be expected to occur for substances found in this solubility window but the results are between the expected algorithms (low EC50 value) and the solubility (maximum EC50 value).”

Description of key information

QSAR model, iSafeRat holistic approach v1.7, key study, validity 1:

48h-EC50 = 1.0 mg/L (95% CL: 0.37 - 2.87 mg/L).

Key value for chemical safety assessment

Fresh water invertebrates

Fresh water invertebrates

Effect concentration:

1 mg/L

Additional information

To assess the toxicity of the registered substance to aquatic invertebrates, one data point is available.

This value (KREATiS, 2017), assessed as a key datapoint, is a QSAR. This QSAR prediction (iSafeRat holistic approach v1.7) was performed on the registered substance, to assess the acute toxicity of the substance to daphnids.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 202. The immobility of the daphnids was determined using a validated QSAR for the Mode of Action in question, (MOA 1 or MechoA 1.1: non-polar narcosis) (Bauer et al., 2018). The QSAR model is based on validated data for a training set of 58 chemicals derived from 48-hour test on daphnids, for which the concentrations of the test item had been determined by chemical analyses over the test period.The substance falls within the applicability domain of the model as demonstrated in the QPRF. The 48-h EC50 based on mobility was determined to be 1.0 mg/L with 95%-Confidence Limit between 0.37 and 2.87 mg/L.

Bauer F., Thomas, P., Fouchard S., Neunlist S., 2018. High-accuracy prediction of mechanisms of action using structural alerts. Computational Toxicology 7:36 -45