1,4-bis[(2,6-diethyl-4-methylphenyl)amino]anthraquinone

Long-term toxicity to aquatic invertebrates

Link to relevant study record(s)

Reference

Endpoint:

long-term toxicity to aquatic invertebrates

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

30 March 2022 to 05 April 2022

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. Therefore, the predicted CHRONIC TOXICITY TO DAPHNIDS (21-DAY EC10) is considered as an extrapolation. This result can be considered as reliable with restrictions (descriptor domain).

Justification for type of information:

1. SOFTWARE
iSafeRat® – in Silico Algorithms For Environmental Risk And Toxicity

2. MODEL (incl. version number)
iSafeRat® daphEC10 v1.5

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CCc1cc(C)cc(CC)c1Nc2ccc(Nc3c(CC)cc(C)cc3CC)c4C(=O)c5ccccc5C(=O)c24

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF

5. APPLICABILITY DOMAIN
See attached Study Report with QPRF in Annex

6. ADEQUACY OF THE RESULT
See attached Study Report with QPRF in Annex

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 211 (Daphnia magna Reproduction Test)

Deviations:

not applicable

Remarks:

QSAR model

Principles of method if other than guideline:

The CHRONIC TOXICITY TO DAPHNIDS (21-DAY EC10) was determined using iSafeRat® daphEC10, a validated QSAR model for the Mechanism of Action (MechoA) in question (MechoA 1.1, i.e. non-polar narcosis) (Bauer et al., 2018). The QSAR is based on validated data for a training set of 31 chemicals derived from 21-day test on daphnids, for which the concentrations of the test item had been determined by chemical analyses over the test period.

GLP compliance:

no

Remarks:

QSAR model

Analytical monitoring:

no

Remarks:

QSAR model

Details on sampling:

not applicable

Vehicle:

no

Details on test solutions:

not applicable

Test organisms (species):

Daphnia magna

Details on test organisms:

none

Test type:

other: QSAR model

Water media type:

freshwater

Limit test:

no

Total exposure duration:

21 d

Remarks on exposure duration:

Results from a test duration of 21 days only were used for Daphnia magna.

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. This small difference is not expected to contribute to the variability of the values found in experimental data.

pH:

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

Dissolved oxygen:

The model is based on data from studies performed at acceptable oxygen concentrations (generally >60%).

Salinity:

not applicable

Conductivity:

not applicable

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, if not, the result was based on measured concentrations as geometric mean.

Details on test conditions:

Preferentially results from a flow-through studies were used. However semi-static with daily renewal of test solutions and the control 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):

not required

Key result

Duration:

21 d

Dose descriptor:

EC10

Remarks:

equivalent to MATC

Effect conc.:

> 0.003 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

reproduction

Details on results:

The test item falls within the applicability domain of the model except for the descriptor domain. Therefore, the predicted CHRONIC TOXICITY TO DAPHNIDS (21-DAY EC10) is considered as an extrapolation. This result can be considered as reliable with restrictions (descriptor domain).

Results with reference substance (positive control):

not applicable

Reported statistics and error estimates:

95% confidence interval (α = 0.05): not applicable

Applicability Domain

 

Descriptor domain                                          

The Subcooled Liquid Water Solubility value (< -6.594 in log10 (mol/L)) given as the input to the iSafeRat® daphEC10 model does not fall within the descriptor domain of the model between -5.910 and 1.030 in log10 (mol/L). Therefore, the prediction is considered as an extrapolation.

 

Structural fragment domain

The variability of structure in the training set is not considered as a relevant domain since the model is based on a mechanistic approach (mechanism of action). Since the MechoA is related to the molecular structure, the following list of chemical moieties can give an overview of the structural domain:

• Alcohol


• Alkane


• Alkene


• Anthraquinones


• Aromatic hydrocarbons and polycyclic aromatic hydrocarbon


• Ester


• Ether


• Halogenated hydrocarbons


• Ketone

The test item as an anthraquinone can be taken into account by the model.

 

Mechanistic domain:

The iSafeRat® daphEC10 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 aminoanthraquinone is expected to exert a MechoA 1.1 & m4.3: Non-polar narcosis for all species & metabolisation into nitroso generating protein and DNA adducts, oxidative stress, DNA adducts, cancer development for mammals only (Bauer et al., 2018). Therefore, the test item can be taken into account by the model in order to predict toxicity to non-mammal aquatic organisms.

Validity criteria fulfilled:

yes

Conclusions:

The test item falls within the applicability domain of the model except for the descriptor domain. Therefore, the predicted CHRONIC TOXICITY TO DAPHNIDS (21-DAY EC10) is considered as an extrapolation. This result can be considered as reliable with restrictions (descriptor domain).
The CHRONIC TOXICITY TO DAPHNIDS (21-DAY EC10) of the test item was predicted as greater than the water solubility value within the exposure period of the test.
95% confidence interval (α = 0.05): not applicable

Executive summary:

A Quantitative Structure Activity Relationship (QSAR) model was used to calculate the CHRONIC TOXICITY TO DAPHNIDS (21-DAY EC10) for 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 Guideline for Testing of Chemicals No. 211, "Daphnia magna Reproduction Test" (OECD, 2012). The criterion predicted was the EC₁₀ (10% Effective Concentration), a concentration which is expected to cause an effect of 10% on reproducibility within a period of 21 days.

 

The CHRONIC TOXICITY TO DAPHNIDS (21-DAY EC10) was determined using iSafeRat® daphEC10, a validated QSAR model for the Mechanism of Action (MechoA) in question (MechoA 1.1, i.e. non-polar narcosis) (Bauer et al., 2018). The QSAR is based on validated data for a training set of 31 chemicals derived from 21-day test on daphnids, for which the concentrations of the test item had been determined by chemical analyses over the test period.

 

The test item falls within the applicability domain of the model except for the descriptor domain. Therefore, the predicted CHRONIC TOXICITY TO DAPHNIDS (21-DAY EC10) is considered as an extrapolation. This result can be considered as reliable with restrictions (descriptor domain).

 

The CHRONIC TOXICITY TO DAPHNIDS (21-DAY EC10) of the test item was predicted as greater than the water solubility value within the exposure period of the test.

95% confidence interval (α = 0.05): not applicable

Description of key information

21d-EC10 (Daphnia magna) > solubility limit; iSafeRat® High-Accuracy-Quantitative Structure-Activity Relationship; KREATiS (2022).

Additional information

To strengthen the reliability of the HA-QSAR prediction and the category approach, one experimental chronic daphnia study is available on the source substance, Solvent Blue 104 (CAS No 116-75-6). In addition, a testing proposal for a chronic daphnia study is requested on the source substance, Solvent Green 28 (CAS No 4851-50-7). Both substances are members of the category. See the category approach justification document, attached in section 13, for further details.

Global overview of the category approach for the endpoint:

		Solvent Violet 36	Solvent Green 3	Reinblau RLW	Reinblau BLW	Solvent Blue 104^#	Solvent Green 28
Long-term toxicity to aquatic invertebrates		21d-EC10 (D.magna) > solubility limit*	21d-EC10 (D.magna) > solubility limit*	21d-EC10 (D.magna) > solubility limit*	21d-EC10 (D.magna) > solubility limit*	21d-NOEC (D.magna) ³ 1.0 mg/L (nominal)^$   21d-EC10 (D.magna) > solubility limit*	Testing proposal (OECD TG 211)

^# not registered by LANXESS, data with letter of access

* iSafeRat® High Accuracy QSAR predictions (KREATiS, 2022)