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Toxicity to aquatic algae and cyanobacteria

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Reference
Endpoint:
toxicity to aquatic algae and cyanobacteria
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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 limited documentation / justification
Justification for type of information:
The supporting QMRF report has been attached
Qualifier:
according to guideline
Guideline:
other: as mentioned below
Principles of method if other than guideline:
Prediction is done using OECD QSAR Toolbox version 3.3 with logKow as the primary descriptor.
GLP compliance:
not specified
Specific details on test material used for the study:
- Name of test material (IUPAC name): (4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride
- Common name: Fuschine
- Molecular formula: C20H19N3.HCl
- Molecular weight: 337.852
- Smiles notation: C(\c1cc(c(N)cc1)C)(c1ccc(N)cc1)=C1/C=CC(=N)C=C1.Cl
- InChl: 1S/C20H19N3.ClH/c1-13-12-16(6-11-19(13)23)20(14-2-7-17(21)8-3-14)15-4-9-18(22)10-5-15;/h2-12,21H,22-23H2,1H3;1H/b20-14-,21-17?;
- Substance type: Organic
- Physical state: Solid

Analytical monitoring:
not specified
Vehicle:
not specified
Test organisms (species):
Pseudokirchneriella subcapitata (previous names: Raphidocelis subcapitata, Selenastrum capricornutum)
Test type:
static
Water media type:
freshwater
Total exposure duration:
72 h
Reference substance (positive control):
not specified
Key result
Duration:
72 h
Dose descriptor:
EC50
Effect conc.:
450.02 mg/L
Nominal / measured:
estimated
Conc. based on:
test mat.
Basis for effect:
growth rate

The prediction was based on dataset comprised from the following descriptors: EC50
Estimation method: Takes average value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

((((((((((("a" or "b" or "c" or "d" or "e" )  and "f" )  and ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and "m" )  and "n" )  and "o" )  and "p" )  and "q" )  and ("r" and "s" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Anilines (Acute toxicity) AND Dianilines AND Not categorized AND Triarylmethane Pigments/Dyes with Non-solubilizing Groups by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkene OR Allyl OR Aniline OR Aryl OR Dianilines OR Ketimine OR No functional group found by Organic Functional groups ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alkene OR Allyl OR Dianilines OR Ketimine OR No functional group found OR Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Aliphatic Nitrogen, one aromatic attach [-N] OR Aromatic Carbon [C] OR No functional group found OR Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Amine OR Aromatic compound OR No functional group found OR Primary amine OR Primary aromatic amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found AND Non-specific AND Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    AND Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives AND Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives AND SN1 AND SN1 >> Nucleophilic substitution on diazonium ions AND SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives by DNA binding by OASIS v.1.3 ONLY

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found AND SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Primary aromatic amine by DNA binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated ketones by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure AND Strong binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones by Protein binding by OASIS v1.3

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Class 5 (Not possible to classify according to these rules) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Phenols and Anilines AND Reactive unspecified by Acute aquatic toxicity MOA by OASIS ONLY

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alkene AND Allyl AND Aniline AND Aryl AND Dianilines AND Ketimine AND No functional group found by Organic Functional groups ONLY

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Amine AND Aromatic compound AND No functional group found AND Primary amine AND Primary aromatic amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.93

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.23

Validity criteria fulfilled:
not specified
Conclusions:
The median Effective concentration (EC50) value for (4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride on Pseudokirchneriella subcapitata in a 72 hour study was estimated to be 450 mg/L on the basis of effects on growth rate.
Executive summary:

Using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, the short term toxicity on aquatic algae and cyanobacteria was predicted for target substance (4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride (CAS no. 632 -99 -5). EC50 value was estimated to be 450 mg/l for Pseudokirchneriella subcapitata for 72 h duration. Based on this value it can be concluded that the substance (4 -(4 -aminophenyl)(4 -iminocyclo hexa-2,5 -dienylidene)methyl)-2 -methylaniline hydrochloride is considered to be non-toxic to aquatic environment and can be considered to be not classified as per the CLP classification criteria.

Description of key information

Using the OECD QSAR toolbox version 3.3 (2017) with log kow as the primary descriptor and considering the five closest read across substances, the short term toxicity on aquatic algae and cyanobacteria was predicted for target substance (4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride (CAS no. 632 -99 -5). EC50 value was estimated to be 450 mg/l for Pseudokirchneriella subcapitata for 72 h duration. Based on this value it can be concluded that the substance (4 -(4 -aminophenyl)(4 -iminocyclo hexa-2,5 -dienylidene)methyl)-2 -methylaniline hydrochloride is considered to be non-toxic to aquatic environment and can be considered to be not classified as per the CLP classification criteria.

Key value for chemical safety assessment

EC50 for freshwater algae:
450 mg/L

Additional information

Various predicted data for the target chemical (4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride (CAS No. 632-99-5) and various supporting weight of evidence studies for its closest read across substances with logKow as the primary descriptorwere reviewed to summarize the following information:

 

Short term toxicity on aquatic algae and cyanobacteria of target chemical(4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride (CAS No. 632-99-5) is predicted using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances (2017). On the basis of effects observed in a static freshwater system, the effect concentration EC50 value for the substance is estimated to be 450 mg/l for Pseudokirchneriella subcapitata for 72 hr duration.Based on this value it can be concluded that the substance (4 -(4 -aminophenyl)(4 -iminocyclo hexa-2,5 -dienylidene)methyl)-2 -methylaniline hydrochloride is considered to be non-toxic to aquatic environment and can be considered to be not classified as per the CLP classification criteria.

 

In another prediction done using the EPI Suite ECOSAR version 1.10 (EPI Suite, 2017), the short term toxicity on green algae was predicted for test substance3(4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride (CAS No. 632-99-5).On the basis of effects observed in a static freshwater system, the effect concentration EC50 value for the substance is estimated to be 599 mg/l for green algae for 96 h duration.Based on this value, it can be concluded that the test chemical (4 -(4 -aminophenyl)(4 -iminocyclo hexa-2,5 -dienylidene)methyl)-2-methylaniline hydrochloride can be considered as non-toxic to green algae at environmentally relevant concentrations and can be considered not classified as per the CLP classification criteria.

 

In a weight of evidencestudy from secondary source (OECD SIDS, 2014 and High Production Volume (HPV) Challenge Program; 2017) of the read across chemical 1-Octadecene (CAS no. 112-88-9), short term toxicity to Selenastrum capricornutum study was carried out for 96 hrs. The study was performed according to OECD Guideline 201 (Alga, Growth Inhibition Test).The study was based on the effects of the read across compound1-Octadecene(CAS no. 112-88-9) on Selenastrum capricornutum in a static fresh water system at a temperature range of 22 to 26°C and pH of 7.4 to 7.7, respectively. Test chemical concentration used for the study were1.0, 2.2, 4.6, 10, 22, 46, 100, 220, 460 and 1000 mg/L (nominal concentrations), respectively. Analar Acetone was used as a vehicle for the study. Selenastrum capricornutum ATCC 22662 was used as a test organism for the study obtained from the axenic laboratory culture derived from a strain obtained from the American Type Culture Collection (Maryland, USA).Sixteen Erlenmeyer flasks containing 50 ml of culture medium were prepared. The remaining six flasks received no 1-Octadecene, however, acetone concentrations in all flasks (including the controls) were adjusted to 0.1 mg/L. Each flask was inoculated with S. capricornutum to an initial concentration of 500 cells/ml. Flasks were incubated at 100 cycles/min under constant illumination (approximately 3000 lux). Tests temperatures ranged from 22-26°C and pH of test solutions ranged from 7.4-7.7 s.u. None of the concentrations of the test chemical tested caused a reduction in cell number at day 4 compared to the mean cell number at day 4 in the controls. Therefore, the 96 hr NOEC and EC50 value was determined to be 1000 and >1000 mg/l, respectively. Thus, based on the EC50 value, it can be concluded that the substance 1-Octadecene can be considered as non-toxic to aquatic organism and thus cannot be classified as hazardous as per the CLP classification criteria.

 

For the read across chemical 1-Hexene(CAS no. 592-41-6), short term toxicity to green algae study was carried out for 96 hrs (OECD SIDS, 2001). The study was based on the effects of the read across compound 1-Hexene on green algae in a static fresh water system. The 96 hr EC50 value was determined to be 22 mg/l, respectively. Thus, based on the EC50 value, it can be concluded that the substance1-Hexene can be considered as toxic to aquatic organisms. Since the test chemical 1 -Hexene is readily biodegradable in nature, chemical 1 -Hexene can be considered as non-toxic to aquatic organism and thus cannot be classified as hazardous as per the CLP classification criteria.

 

Thus, based on the overall reported results for target chemical(4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride(OECD QSAR toolbox version 3.3 and EPI suite, 2017) and for its read across substance (fromsecondary source),it can be concluded that the test substance (4 -(4 -aminophenyl)(4 -iminocyclohexa-2,5 -dienylidene)methyl)-2 -methylaniline hydrochloride can be considered as non-toxic to aquatic environment and can be considered to be notclassified as per the CLP classification criteria.