[No public or meaningful name is available]

Short-term toxicity to aquatic invertebrates

Administrative data

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

10 August 2022

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:

A Quantitative Structure-Activity Relationship (QSAR) model was used to calculate the ACUTE
TOXICITY TO DAPHNIDS (48-HOUR EC50) of the test item. This QSAR model has been validated to be compliant with the OECD recommendations for QSAR modeling (OECD, 2004a) 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" (OECD, 2004b), referenced as Method C.2 of Commission Regulation No. 440/2008 (European Commission, 2008). 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 ACUTE TOXICITY TO DAPHNIDS (48-HOUR EC50) was determined using iSafeRat® daphEC50, a validated QSAR model for the Mechanism of Action (MechoA) in question (MechoA 1.2, i.e. polar narcosis of alkyl- /alkoxy-phenols) (Bauer et al., 2018). The QSAR model is based on validated data for a training set of 19 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.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2022

Report date:

2022

Materials and methods

Principles of method if other than guideline:

The ACUTE TOXICITY TO DAPHNIDS (48-HOUR EC50) was determined using the iSafeRat® daphEC50 model.
The purpose of this QSAR model is to accurately predict the acute toxicity to daphnids as would be expected in a laboratory experiment following the OECD Guideline 202 (OECD, 2004b) and EC method C.1 (European Commission, 2008) for specific named modes of action. The model provides an in silico prediction for the 48-hour
EC50 value that can effectively be used in place of an experimentally derived 48-hour EC50 value.
The model is based on a simple linear regression line between Subcooled Liquid Solubility Water (SLWS) and the immobility to daphnids (EC50) following the methodology outlined in ECETOC (2013) and Thomas et al. (2015). In brief, the algorithm used was an updated and improved version of that used by ECETOC for non-polar narcotic compounds which was then validated using an external test set. The general equation used by the model is:
log EC50 = a x log SLWS + b
The water solubility values are corrected to take into account the Subcooled Liquid Water Solubility (SLWS) which is an expression of the chemical activity of a pure compound within a given medium. The choice of the SLWS is justified in order to compare liquids and solids within the same dataset. Indeed, the solids have an entropy of fusion different to liquids as demonstrated by Yalkowsky (1979). Consequently, the water solubility of the solids is corrected using their melting point according to the following equation:
SLWS solid = WS solid/e(6.79(1-MP/298)) (mol/l)
'
SLWS soild: Subcooled Liquid Water Solubility (SLWS) of a given compound with solid state at 25°C.
WS solid: Water Solubility (WS) of a given compound with solid state at 25°C (as measured).
MP: Melting Point of the given compound (K).
Species: Results from the following species were used in the regression:
Daphnia magna, Daphnia pulex
No difference in terms of toxic mechanism of action between invertebrate (or indeed other) aquatic species is expected. Any observed differences may be attributed to lifestyle related parameters (e.g. shell closing in molluscs) and relative duration of study versus bodysize rather than to a specific toxic mechanism causing species differences.
Test duration: Results from a test duration of 48 hours only were used for daphnid species.
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.
Test type: Studies with various test designs were selected for QSAR model development.
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.
Chemical analysis: Studies were used for QSAR model development 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, if not, the result was based on measured
concentrations as geometric mean.
pH: Test results were taken from studies with measured pHs between 6 - 9.
Klimisch score: The studies used in the dataset were considered valid under the OECD guideline
and REACH regulation (European Parliament and European Union Council, 2006) (i.e. Klimisch score 1 or 2) by registrants of the substances included in the training and test sets were revalidated by KREATiS and the critical parameters of the study were considered to be within acceptable limits.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction products of 2,3; 2,4; 2,5 and 2,6 mixed xylidenes, C7 and C8 linear substituted naphthols and diazonium salts

Molecular formula:

Not available: variable

IUPAC Name:

Reaction products of 2,3; 2,4; 2,5 and 2,6 mixed xylidenes, C7 and C8 linear substituted naphthols and diazonium salts

Details on test material:

CAS No 92257-31-3
EC-No. 296-120-8
Composition SR164:1 is a mixture of compounds with octyl, heptyl, ethyl and methyl groups of
variable numbers and positions. For the purpose of this study, only the smallest and
biggest constituents of SR164:1 were investigated.

Specific details on test material used for the study:

The smallest and largest specific constituents of the UVCB were selected for the study.
SR 164:1 smallest constituent Oc1c(CCCCCCC)cc2ccccc2c1N=Nc(cc3CC)ccc3N=Nc4ccccc4
SR 164:1 biggest constituent Oc1c(CCCCCCCC)cc2ccccc2c1N=Nc(cc3C)c(C)cc3N=Nc4c(C)cc(C)cc4

Results and discussion

Effect concentrations

Key result

Duration:

48 h

Dose descriptor:

EC50

Nominal / measured:

estimated

Remarks on result:

other: EC50 > solubility limit for the smallest and biggest constituent of the test substance

Applicant's summary and conclusion

Conclusions:

The QSAR model used to achieve the study has been fully validated following the OECD recommendations (OECD, 2004a). For both constituents, the test item falls partially within the applicability domain of the model. Therefore, the predicted ACUTE TOXICITY TO DAPHNIDS (48-HOUR EC50) is considered as an “extrapolation” because the solubility of the substance is so low that it falls beyond the point at which toxicity data crosses the solubility regression line. As no toxicity can be observed beyond the solubility limit (and any effect concentrations can only be related to physical interaction which is not environmentally relevant), it is no longer possible to construct a regression line beyond the solubility limit. However, the lack of statistical fit does not indicate that the conclusion “toxicity >solubility limit” is erroneous.
No daphnid data are available in the dataset for substances with a solubility as low as that of the test items, and strictly speaking the results should be considered as an extrapolation. However, because any substance with a solubility lower than the solubility limit regression line used in this QSAR will not meet the criteria of toxicity examined in this endpoint. The endpoint can be considered as falling under the domain >solubility limit. This result should be considered as reliable with restrictions (descriptor domain, structural domain).
The ACUTE TOXICITY TO DAPHNIDS (48-HOUR EC50) of both constituents of the test item was greater than their subcooled liquid water solubility.
95% confidence interval (α = 0.05): not applicable

Executive summary:

The QSAR model used to achieve the study has been fully validated following the OECD recommendations (OECD, 2004a). For both constituents, the test item falls partially within the applicability domain of the model. Therefore, the predicted ACUTE TOXICITY TO DAPHNIDS (48-HOUR EC50) is considered as an “extrapolation” because the solubility of the substance is so low that it falls beyond the point at which toxicity data crosses the solubility regression line. As no toxicity can be observed beyond the solubility limit (and any effect concentrations can only be related to physical interaction which is not environmentally relevant), it is no longer possible to construct a regression line beyond the solubility limit. However, the lack of statistical fit does not indicate that the conclusion “toxicity >solubility limit” is erroneous.
No daphnid data are available in our dataset for substances with a solubility as low as that of the test items, and strictly speaking the results should be considered as an extrapolation. However, because any substance with a solubility lower than the solubility limit regression line used in this QSAR will not meet the criteria of toxicity examined in this endpoint. The endpoint can be considered as falling under the domain >solubility limit.This result should be considered as reliable with restrictions (descriptor domain, structural domain).
The ACUTE TOXICITY TO DAPHNIDS (48-HOUR EC50) of both constituents of the test item was greater than their subcooled liquid water solubility. 95% confidence interval (α = 0.05): not applicable