hexyl nitrite

Toxicity to aquatic algae and cyanobacteria

Administrative data

Endpoint:

toxicity to aquatic algae and cyanobacteria

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

21/09/2020

Reliability:

1 (reliable without restriction)

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:

1. SOFTWARE : Nonlinear QSAR

2. MODEL (incl. version number) : Model 4.0.4; Statistica 7, StatSoft Ltd. Turu 2, Tartu, 51014, Estonia

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL : 3D Mol file used for prediction

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
[Explain how the model fulfils the OECD principles for (Q)SAR model validation. Consider attaching the QMRF or providing a link]
- Defined endpoint: OECD Principle 1 - OECD TG 201/C.3. (3.2) Short-term toxicity to algae (inhibition of the exponential growth rate))
- Unambiguous algorithm: OECD Principle 2 - QSAR model for Toxicity to algae of diverse organics
- Defined domain of applicability: OECD Principle 3
i. descriptor domain
ii. structural fragment domain
iii. mechanism domain
iv. metabolic domain
- Appropriate measures of goodness-of-fit and robustness and predictivity: OECD Principle 4
The source experimental data for the model originates from one lab and one experimental series, highly supporting consistency. The consistency has been additionally confirmed by successful previous and presetQSAR treatment. The significant statistical quality (RMS, correlation coefficients etc.) of the model supports reliable predictions within the margins of the experimental error. The similarity of the analogues together with the correct estimates supports potential prediction consistency.Considering the dataset size, model statistical quality and prediction reliability, a reliability score (Klimisch score) “2” could be assigned to the present prediction. The prediction reliability is estimated as 89 %.
- Mechanistic interpretation: OECD Principle 5
The descriptors in the ANN were selected by the method described in QMRF section 4.4, which selects features with highest correlation coefficient in respect to the property. Further the combinatorial construction of various ANN topologies led to selection of 4 descriptors. This is a perfect example where the "linearity" of the descriptors can be further extended to nonlinear relation with the property based on the ANN. The descriptor Square root of Charged (Zefirov) Surface Area of C atoms has positive correlation with pEC50 indicating that the increase of the descriptor would lead to decrease of EC50. The C atom is "more" charged where its neighbours are hetero atoms as O, N (also halogens). It is likely that this descriptor contribute to membrane permeability and polar narcosis. Similar analogy can be done for the HOMO - LUMO energy gap (AM1) descriptor, which is related the reactivity of the atoms. However, in this case this descriptor has negative correlation with the property. The most reactive centers in the molecule would probably react with the medium or the membrane and would change (decay) the compound making it less toxic to Algae. The remaining two descriptors Globularity index (AM1) and Molecular weight are related to the bulk properties of the compounds. These two descriptors can be addressed to features governing the nonspecific interactions describing nonpolar narcosis.

5. APPLICABILITY DOMAIN
[Explain how the substance falls within the applicability domain of the model]
- Descriptor domain: All descriptor values for Hexyl nitrite fall in the applicability domain (training set value ±30%).
- Structural domain: Hexyl nitrite is structurally relatively similar to the model compounds; The training set contains compounds of similar size to the studied molecule.
- Mechanism domain: Hexyl nitrite is considered to be in the same mechanistic domain as the molecules in the training set as it is structurally similar to the model compounds.
- Similarity with analogues in the training set: The experimental acute toxicity values for compounds of similar functionalities are somewhat scattered in the toxicity scales depending on the molecular size and other
functionalities. The structural analogues are relatively similar to the studied compound. The descriptor values of the analogues are close to those of the studied compound. The analogues are considered to be within the same mechanistic domain. All the analogues are very well estimated within the model. The following aspects have been considered for the selection and analysis of structural analogues:
Presence and number of common functional groups;
Presence and relevance of non-common functional groups;
Similarity of the ‘core structure’ apart from the (non-)common functional groups;
Potential differences due to reactivity;
Potential differences due to steric hindrance;
Presence of structural alerts;
Position of the double bonds;
Presence of stereoisomers.
- Other considerations (as appropriate):

6. ADEQUACY OF THE RESULT
Regulatory purpose:
The present prediction may be used for preparing the REACH Joint Registration Dossier on the Substance(s) for submission to the European Chemicals Agency (“ECHA”) as required by Regulation (EC) N° 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals ("REAC H") and as required by Biocide Product Directive 98/8/EC ("98/8/EC")
Approach for regulatory interpretation of the model result
The predicted result has been presented in the formats directly usable for the intended regulatory purposes, both the numeric value and the transferred (regulatory) scale values have been presented.
Outcome
See section 3.2(e) for the classification of the prediction in light of the regulatory purpose described in 4.1.
Conclusion
Considering the above, the predicted result can be considered adequate for the regulatory conclusion described in 4.1.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2020

Report date:

2020

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 201 (Alga, Growth Inhibition Test)

GLP compliance:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test material form:

liquid

Sampling and analysis

Analytical monitoring:

no

Test solutions

Vehicle:

no

Test organisms

Test organisms (species):

Pseudokirchneriella subcapitata (previous names: Raphidocelis subcapitata, Selenastrum capricornutum)

Study design

Test type:

not specified

Water media type:

not specified

Limit test:

no

Total exposure duration:

96 h

Remarks on exposure duration:

24, 48, 72 and 96h

Test conditions

Details on test conditions:

The test alga was an unicellular green algal species Selenastrum capricornutum Printz (also known as Pseudokirschneriella subcapitata and Raphidocelis subcapitata) and the culture medium 10% Z 8. The inoculum was taken from a stock culture in the exponential growth phase. The initial algal density was 104 ± 10% cells/mL. The test algae were cultivated in 100-mL solutions in 250-mL sterile, foam-plugged Erlenmeyer flasks with three replicates of each concentration. In addition, there were two control cultures: Selenastrum cells in culture medium and in acetone series. There were also controls for chemicals without algae.
The cultures were incubated at +22 ± 20 C in continuous illumination of approximately 72 μE m-2 s-1 (Airam L 40 W 35). The growth of cultures was followed by measuring the cell density after 24, 48, 72 and
96 hr by means of an electronic particle counter (Coulter Counter Z B).
The effect of acetone on the growth of the cultures was eliminated by comparing the growth of test cultures with the growth of acetonecontrols.
The results, as percent of control, were calculated as a mean value of the cell density of the triplicates after one test series.
In Selenastrum assays, the EC50-values were estimated from semilogarithmic paper using cell density after 96 hr and areal comparison of growth curves during 0-96 hr incubation (ISO 1983).

Results and discussion

Effect concentrations

Key result

Duration:

96 h

Dose descriptor:

EC50

Effect conc.:

ca. 4.5 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

growth rate

Applicant's summary and conclusion

Validity criteria fulfilled:

yes

Conclusions:

Following the “hazardous to the aquatic environment” categories defining the respective categories according to the GHS, the predicted value for the studied compound falls under the "Acute 2" classification.

Executive summary:

Predicted value (model result): Log/1/EC₅₀) = 1.47; EC₅₀ = 4.5 mg/l

Following the “hazardous to the aquatic environment” categories defining the respective categories according to the Globally Harmonized System of Classification and Labeling of Chemicals (GHS):

Category	Acute 1	Acute 2	Acute 3	No Category
EC50 (mg/l)	EC50 ≤ 1.0	1.0 < EC50 ≤ 10	10 < EC50 ≤ 100	EC50 > 100.0

The predicted value for the studied compound falls under the "Acute 2" classification.