Reaction products of diazotized mixture of aniline, toluidines and xylidines coupled with mixture of aniline, toluidines and xylidines, subsequently diazotized then coupled with 2-naphthol

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

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

Justification for type of information:

1. SOFTWARE: ECOSAR Class Program v.2.0

2. MODEL (incl. version number): ECOSAR QSAR for daphnid acute toxicity (Phenols)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL:
Structural formula: C24H20N4O
Structural codes:
a. SMILES: Cc4ccccc4/N=N/c3ccc(/N=N/c1c2ccccc2ccc1O)c(C)c3
b. InChI: InChI=1S/C24H20N4O/c1-16-7-3-6-10-21(16)26-25-19-12-13-22(17(2)15-19)27-28-24-20-9-5-4-8-18(20)11-14-23(24)29/h3-15,29H,1-2H3/b26-25+,28-27+

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Short-term toxicity to Daphnia (immobilisation)
- Unambiguous algorithm: Linear regression. The ECOSAR model for daphnids acute toxicity is based on a linear mathematical relationship between the log Kow values (predicted by KOWWIN program in EPI Suite) and the corresponding log of the measured toxicity values (mmol/L) for a suite of training set chemicals (phenols). Equation: Log 48-h LC50 (mmol/L) = -0.5667 log Kow - 0.1481
- Defined domain of applicability: The applicability domain of the model is based on the logKow values (maximum logKow = 7.0) and on the molecular weight of chemicals (maximum MW = 1000). The domain of the model is considered to be larger than the descriptor range of the training set of chemicals (i.e., Range of logKow of training set compounds: -0.12 – 5.3 (KOWWIN); range of MW of training set compounds: 94 - 307 g/mol). Chemical classes to which the model can be applied: PHENOLS. ECOSAR identifies the following structures to the Phenols class: 1) An hydroxyl (-OH) group attached to an aromatic ring. The aromatic ring can be either a phenyl ring or any other aromatic ring until including heterocyclic aromatic rings. 2) Structures that contain only one hydroxyl (-OH) group attached to an aromatic ring. Multiple hydroxyl groups attached to aromatic rings changes the classification to Phenols, Poly. Further details are available on the attached QMRF.
- Appropriate measures of goodness-of-fit and robustness and predictivity: Please see attached QMRF.
- Mechanistic interpretation: This ECOSAR model for the prediction of acute toxicity in daphnids (LC50 48h) was developed for phenols. Within ECOSAR, phenols represent a class of organic chemicals with excess toxicity, i.e. organic chemicals presenting a specific mode of toxicity based on the presence of reactive functional groups (Hermens 1990). These chemicals can be more toxic than predicted by baseline toxicity equations (Verhaar et al., 1992).

5. APPLICABILITY DOMAIN
Predictions provided by ECOSAR are not supported by a specific parameter for reliability assessment, however a LogKow cut-off of 7.0, and a MW cut-off equal to 1000 are used to define the limits of the applicability domain of the model. Above the LogKow cut-off, data generally indicate that the hydrophobicity of molecules leads to “no effects at saturation”. Additionally, more accurate predictions are expected for chemicals characterised by a MW falling within the MW range and LogKow range of the training set compounds.
ECOSAR identified structural features in the target associated with the Phenols class. For Phenols, the LogKow cut-off is set at 7.0, the MW of training set compounds (N = 63) ranges from 94 to 307 g/mol, and the LogKow is in the range -0.12 to 5.3.
The target compound is included in the applicability domain of the model since the estimated LogKow 6.48 of the target and its MW of 380.45 g/mol are both included in the maximum LogKow/MW cut-off values of the model. However, both values exceeded the LogKow and MW ranges of training set chemicals.
- Descriptor domain: the target compound is not included in the LogKow and MW ranges of training set compounds.
- Structural and mechanistic domains: Not applicable.
- Similarity with analogues in the training set: No structural analogues from the training set are provided by ECOSAR.

6. ADEQUACY OF THE RESULT
A 48-h LC50 (Daphnia) value of 0.141 mg/L (short-term aquatic toxicity) was estimated for the target Solvent Red 24 (CAS No. 85-83-6). The prediction was assessed as borderline reliable. The LC50 prediction falls below the acute aquatic hazard classification threshold of 1 mg/L (ECHA, 2017), and the estimated toxicity value is greater than the predicted water solubility for the target compound, suggesting that an effect is not expected to occur in a saturated solution.
The QSAR prediction of short-term toxicity to Daphnia was assessed as adequate for regulatory purposes.

Data source

Reference

Reference Type:

other: Software

Title:

ECOSAR Class Program v.2.0 - QSAR model for daphnid acute toxicity (Phenols)

Author:

U.S. EPA

Year:

2017

Bibliographic source:

U.S. EPA

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other:

Version / remarks:

REACH Guidance on QSARs R.6 (2008)

Principles of method if other than guideline:

- Software tool(s) used including version: ECOSAR Class Program v. 2.0
- Model(s) used: ECOSAR QSAR for daphnid acute toxicity (Phenols)
- Model description: see field 'Justification for type of information' and 'Attached justification'
- Justification of QSAR prediction: see field 'Justification for type of information' and 'Attached justification'

Test material

Test material information

Constituent 1

Reference substance name:

1-(2-methyl-4-(2-methylphenylazo)phenylazo)-2-naphthol

EC Number:

201-635-8

EC Name:

1-(2-methyl-4-(2-methylphenylazo)phenylazo)-2-naphthol

Cas Number:

85-83-6

Molecular formula:

C24H20N4O

IUPAC Name:

1-[(E)-{2-methyl-4-[(E)-(2-methylphenyl)diazenyl]phenyl}diazenyl]naphthalen-2-ol

Specific details on test material used for the study:

SMILES: Cc4ccccc4/N=N/c3ccc(/N=N/c1c2ccccc2ccc1O)c(C)c3

Test organisms

Test organisms (species):

Daphnia sp.

Results and discussion

Effect concentrations

Key result

Duration:

48 h

Dose descriptor:

LC50

Effect conc.:

0.141 mg/L

Remarks on result:

other: Based on QSAR prediction

Any other information on results incl. tables

The QSAR prediction was assessed as borderline reliable, due to medium uncertainty associated with the following issues:

- applicability domain:the target compound is included in the applicability domain of the model since LogKow and MW values of the target are both included in the maximum LogKow/MW cut-off values of the model. However, both values exceeded the LogKow and MW ranges of training set chemicals;

- the estimated toxicity value is greater than the predicted water solubility for the target compound, suggesting that an effect is not expected to occur in a saturated solution.

Applicant's summary and conclusion

Conclusions:

A 48-h LC50 (Daphnia) value of 0.141 mg/L (short-term aquatic toxicity) was estimated for the target Solvent Red 24 (CAS No. 85-83-6). The prediction was assessed as borderline reliable.

Executive summary:

This study was designed to generate estimated in silico (non-testing) data for Solvent Red 24 (CAS No. 85-83-6) to be used for its hazard assessment. QSAR prediction was provided for the short-term aquatic toxicity to Daphnia. A reliability score of 2 was assigned, since results derived from a valid QSAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation/justification. The ECOSAR QSAR for daphnids acute toxicity (Phenols) model implemented in ECOSAR Class Program v.2.0 was employed. The ECOSAR QSAR for daphnids acute toxicity (Phenols) model calculates acute toxicity expressed as LC50 value for daphnids, based on a linear regression model between the logKow values (predicted by KOWWIN program in EPI Suite) and the corresponding log of the measured toxicity values (mmol/L) for a suite of training set chemicals (phenols). A 48-h LC50 value of 0.141 mg/L was estimated by the model for the target compound. The prediction was assessed as borderline reliable, based on the following considerations:

- the applicability domain: the target compound is included in the applicability domain of the model since LogKow and MW values of the target are both included in the maximum LogKow/MW cut-off values of the model. However, both values exceeded the LogKow and MW ranges of training set chemicals;

-  the estimated toxicity value is greater than the predicted water solubility for the target compound, suggesting that an effect is not expected to occur in a saturated solution.

The QSAR prediction of short-term toxicity to Daphnia was assessed as adequate for regulatory purposes.