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Ecotoxicological information

Toxicity to aquatic algae and cyanobacteria

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Administrative data

Endpoint:
toxicity to aquatic algae and cyanobacteria
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 green algae 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 algae (inhibition of the exponential growth rate)
- Unambiguous algorithm: Linear regression - The ECOSAR model for green algae 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). Log 96-h EC50 (mmol/L) = -0.6089 log Kow + 0.599
- Defined domain of applicability: The applicability domain of the model is based on the logKow values (maximum logKow = 6.4) 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: 1.5 – 6.3 (KOWWIN); range of MW of training set compounds: 94 - 316 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 algae (EC50 96h) 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 6.4, 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 6.4, the MW of training set compounds (N = 40) ranges from 94 to 316, while the LogKow is in the range of 1.5 to 6.3.
The target compound Solvent Red 24 (CAS No. 85-83-6) is partially included in the model applicability domain since the LogKow value of the target (estimated LogKow: 6.48) slightly exceeds the LogKow cut-off of the model as well as the LogKow range of training set compounds. Whereas, the MW of the target (MW: 380.45 g/mol) falls below the MW cut-off of the model, but slightly exceeds the MW range of training set compounds.
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 96-h EC50 (green algae) value of 0.0045 mg/L was estimated for the target compound Solvent Red 24 (CAS No. 85-83-6). The prediction was assessed as borderline reliable. The EC50 prediction is 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 algae toxicity was assessed as adequate for regulatory purposes.

Data source

Reference
Reference Type:
other: Software
Title:
ECOSAR Class Program v.2.0 - QSAR model for green algae 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 green algae 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

Constituent 1
Chemical structure
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

Results and discussion

Effect concentrations
Key result
Duration:
96 h
Dose descriptor:
EC50
Effect conc.:
0.004 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 considerations: 1)  applicability domain: the target compound is included in the MW range of the model but slightly exceeds the LogKow cut-off of the model. Furthermore, it is not included in the LogKow and MW ranges of training set compounds; 2) 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.

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Applicant's summary and conclusion

Conclusions:
A 96-h EC50 (green algae) value of 0.0045 mg/L was estimated for the target compound 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 aquatic toxicity to green algae. 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 model for green algae acute toxicity (Phenols) implemented in ECOSAR Class Program v.2.0 was employed. ECOSAR model for algae toxicity calculates acute toxicity expressed as EC50 value for green algae using LogKow-based QSARs that are specific for the chemical class(es) identified for the target compound. A 96-h EC50 value of 0.0045 mg/L was estimated by the model for the target Solvent Red 24 (CAS No. 85-83-6). The prediction was assessed as borderline reliable, due to medium uncertainty associated with the following considerations:

- applicability domain: the target compound is included in the MW range of the model but slightly exceeds the LogKow cut-off of the model. Furthermore, it is not included in the LogKow and MW ranges of training set compounds;

- 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 algae toxicity was assessed as adequate for regulatory purposes.