hexyl nitrite

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

15/10/2020

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

accepted calculation method

Justification for type of information:

1. SOFTWARE : QSAR; Statistica 7 StatSoft Ltd.

2. MODEL (incl. version number) : Model 3.3.8 Turu 2, Tartu, 51014, Estonia http://www.molcode.com
SUBMODEL: QPRF by University of Tartu// Only to be used in accordance with Terms of Use of QSAR Reports. 2

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL :
SMILES: CCCCCCON=O, not used for prediction
Other structural representation: 3D Mol file used for prediction

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Human health effects 4.4. Skin irritation /corrosion, in vivo (OECD 404), also covering in vitro tests (OECD 430/431/435/439).
- Unambiguous algorithm: Nonlinear ANN QSAR Model for Dermal Irritation (QMRF enclosed separately)
- Defined domain of applicability:
a) descriptor domain
b) structural fragment domain
c) mechanism domain
d) metabilic domain
- Appropriate measures of goodness-of-fit and robustness and predictivity: The training set is not from one lab but a collection from several. However, previous and present successful modelling results support its consistency. The statistical quality of the model supports reliable predictions. Skin irritation is a difficult endpoint due to the multitude of possible chemical mechanisms in addition to the variations of permeability, the individual response of test animals may reduce accuracy as well. The studied compound is similar to the training set compounds, adding to prediction reliability. All structural analogues were evaluated correctly within the present model. Considering the dataset, 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 87 %
- Mechanistic interpretation: Skin corrosion/irritation is believed to be underpinned by two aspects – reactivity and permeability. Different mechanisms based on chemical reactivity (depending on the chemical’s tendency to behave as electron donor or acceptor) have been proposed/described. While some models have been designed that rely on the frontier orbital energies, logP, pKa and softness-hardness descriptors, the present model contains a variety of hydrogen bonding and charged surface area (describing the active sites of the molecule) descriptors to characterize the reactivity of the compounds with the epidermis. The complex nature of the ANN model does not allow direct interpretation of the descriptors addressed to the property. However, investigation of the trends in descriptor and endpoint values allows to find some trends. It can be roughly estimated that with the increase (slight negative correlation between the descriptors) of count of H-acceptor sites (AM1), HBCA H-bonding charged surface area (AM1), FHACA Fractional HACA (HACA/TMSA) (AM1) the property the PII values increase.

5. APPLICABILITY DOMAIN
- 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.
- Mechanistic 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 structural analogues are relatively similar to the studied compound. The analogues, while different in chain structure, have similar size and functionality. 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.

6. ADEQUACY OF THE RESULT
6.1 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")
6.2 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.
6.3 Outcome
See section 3.2(e) for the classification of the prediction in light of the regulatory purpose described in 6.1.
4.4 Conclusion
Considering the above, the predicted result can be considered adequate for the regulatory conclusion described in 6.1.

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 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test material form:

liquid

Test animals

Species:

rabbit

Strain:

not specified

Results and discussion

In vivo

Results

Irritation parameter:

primary dermal irritation index (PDII)

Time point:

24/48/72 h

Score:

1.31

Reversibility:

not reversible

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The compound is not causing significatn erythema/eschar or edema, also no inflammation that persist to the end of the observation period.

Executive summary:

Following the EU acute toxicity hazard categories and acute toxicity estimates (ATE) defining the respective categories according to Regulation (EC) No 1272/2008 on the classification, labelling and packaging of substances and mixtures (CLP Regulation) defined as:

Category 1	Category 2	No Category
Corrosive	Irritant	No skin effects

The predicted value corresponds to “No Category” classification.

The compound is not causing significant erythema/eschar or edema, also no inflammation that persists to the end of the observation period.