Dodecanenitrile

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Genetic toxicity in vitro:

in vitro cytogenicity / chromosome aberration study in mammalian cells:

Dodecanenitrile was determined to be non-clastogenic in an in vitro chromosome aberration assay in V79 cells with and without metabolic activation using rat liver S9 fractions. Based on the result it can be concluded that the substance can be considered to not toxic as per the criteria mentioned in CLP regulation.

In vitro gene mutation study in bacteria:

Gene mutation toxicity study as predicted by Danish QSAR for Dodecanenitrile(2437-25-4) is negative and hence the chemical is predicted to not classify as a gene mutant in vitro.

Link to relevant study records

Reference

Reference 1

Endpoint:

in vitro cytogenicity / chromosome aberration study in mammalian cells

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Data is from peer reviewed journal

Qualifier:

according to guideline

Guideline:

OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)

GLP compliance:

not specified

Type of assay:

other: In vitro chromosome aberration test

Specific details on test material used for the study:

- Name of test material (IUPAC name): Dodecanenitrile
- Molecular formula: C12H23N
- Molecular weight: 181.321 g/mole
- Smiles notation: C(CCCCCC)CCCCC#N
- InChl: 1S/C12H23N/c1-2-3-4-5-6-7-8-9-10-11-12-13/h2-11H2,1H3
- Substance type: Organic
- Physical state: colourless liquid

Species / strain / cell type:

Chinese hamster lung fibroblasts (V79)

Additional strain / cell type characteristics:

not specified

Metabolic activation:

with and without

Metabolic activation system:

rat liver S9 fractions

Test concentrations with justification for top dose:

without S9: 7.2, 14.5 and 28.9 µg/ml
with S9: 426.5, 925, 1850 µg/ml
A preliminary toxicity assay was performed to determine dose selection for the cytogenetic experiments.

Vehicle / solvent:

DMSO 0.5% (v/v)

Untreated negative controls:

not specified

Negative solvent / vehicle controls:

yes

True negative controls:

not specified

Positive controls:

yes

Positive control substance:

cyclophosphamide

ethylmethanesulphonate

Details on test system and experimental conditions:

A preliminary toxicity assay was performed to determine dose selection for the cytogenetic experiments. In each experimental
group two parallel cultures were set up with and without metabolic activation using rat liver S9 fractions. 100 Metaphase plates per culture were scored for structural chromosome aberrations. The exposure period was 4 h.

Rationale for test conditions:

not specified

Evaluation criteria:

100 Metaphase plates per culture were scored for structural chromosome aberrations

Statistics:

Fisher’s exact test (p < 0.05) was used to determine statistical significance.

Key result

Species / strain:

Chinese hamster lung fibroblasts (V79)

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

valid

Untreated negative controls validity:

not specified

Positive controls validity:

valid

Additional information on results:

No biologically relevant increase in the frequencies of polyploid metaphases was observed after treatment with the test material as compared to the frequencies of the controls.

Summary of in vitro chromosome aberration test with dodecanenitrile:

Preparation interval	Test item concentration in lg/mL	Polyploid cells in %	Cell no in % of control	Mitotic indices in % of control	Including gaps^a	Aberrant cells in % excluding gaps^a	With exchanges
Exposure period 4-h without S9
18-h	DMSO 0.5% (v/v)	2.4	100.0	100.0	0.5	0.5	0.5
	EMS 900µg/ml	3.5	n.t.	102.7	11.5	11.5^s	35
	7.2	3.6	102.2	91.2	0.5	0.0	0.0
	14.5	3.1	80.1	89.7	0.5	0.0	0.0
	28.9	2.6	62.9	108.0	1.5	1.0	0.5
Exposure period 4-h with S9
18-h	DMSO 0.5% (v/v)	1.6	100.0	100.0	1.5	1.0	0.5
	CPA 1.4µg/ml	2.9	n.t.	95.8	14.5	13.5^s	6.5
	426.5	3.7	93.4	82.7	3.0	3.0	0.5
	925.0	3.7	100.0	94.3	3.0	2.0	0.5
	1850	3.2	83.9	96.1	1.0	1.0	0.5

n.t. not tested.
^aInclusive cells carrying exchanges.
^b100 Metaphase plates per culture were evaluated.
^c50 Metaphase plates per culture were evaluated.
^sSignificantly higher.

Conclusions:

Dodecanenitrile was determined to be non-clastogenic in an in vitro chromosome aberration assay in V79 cells with and without metabolic activation using rat liver S9 fractions.

Executive summary:

In vitro chromosome aberration assays were performed using Chinese hamster V79 cells according to OECD Testing Guideline No. 473 and were conducted on dodecanenitrile (CAS 2437-25-4). A preliminary toxicity assay was performed to determine dose selection for the cytogenetic experiments The chromosomes were prepared 18 h after start of treatment with the test item. V79 cells were exposed to test material dissolved in DMSO, as well as positive and solvent control ±S9 activation. The exposure period was 4 h (±S9). In experimental group two parallel cultures were set up. Per culture at least 100 metaphase plates were scored for structural chromosome aberrations were scored. The positive control without metabolic activation was ethyl methane sulfonate (EMS) and with metabolic activation was cyclophosphamide (CPA). The positive controls induced statistically significant increases (p < 0.05) in cells with structural chromosome aberrations. Dodecanenitrile was determined to be non-clastogenic in an in vitro chromosome aberration assay in V79 cells with and without metabolic activation using rat liver S9 fractions.

Based on the above result, it can be concluded that the substance dodecanenitrile does not present a concern for genotoxic potential and can be considered as not classified as per CLP classification criteria.

Reference 2

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

accepted calculation method

Justification for type of information:

Data is from Danish QSAR, 2017

Qualifier:

according to guideline

Guideline:

other: As mention below

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.3, 2017

GLP compliance:

not specified

Type of assay:

bacterial reverse mutation assay

Specific details on test material used for the study:

- Name of test material (as cited in study report):Dodecanenitrile
- Molecular formula (if other than submission substance):C12H23N
- Molecular weight (if other than submission substance):181.321 g/mol
- Substance type:Organic

Target gene:

Histidine

Species / strain / cell type:

S. typhimurium, other:

Details on mammalian cell type (if applicable):

Not applicable

Additional strain / cell type characteristics:

not specified

Cytokinesis block (if used):

not specified

Metabolic activation:

not specified

Test concentrations with justification for top dose:

not specified

Vehicle / solvent:

not specified

Untreated negative controls:

not specified

Negative solvent / vehicle controls:

not specified

True negative controls:

not specified

Positive controls:

not specified

Details on test system and experimental conditions:

not specified

Rationale for test conditions:

not specified

Evaluation criteria:

Prediction was done considering a dose dependent increase in the number of revertants/plate.

Statistics:

not specified

Species / strain:

S. typhimurium, other:

Metabolic activation:

not specified

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Additional information on results:

not specified

Remarks on result:

other: No mutagenic effect were observed

CASE Ultra

CASE Ultra is a fragment-based statistical model system. The methodology involves breaking down the structures of the training set into all possible fragments from 2 to 10 heavy (non-hydrogen) atoms in length. The fragment generation procedure produces simple linear chains of varying lengths and branched fragments as well as complex substructures generated by combining the simple fragments. A structural fragment is considered as a positive alert if it has a statistical significant association with chemicals in the active category. It is considered a deactivating alert if it has a statistically significant relation with the inactive category. Once final lists of positive and deactivating alerts are identified, CASE Ultra attempts to build local (Q)SARs for each alert in order to explain the variation in activity within the training set chemicals covered by that alert. The program calculates multiple molecular descriptors from the chemical structure such as molecular orbital energies and two-dimensional distance descriptors. A stepwise regression method is used to build the local (Q)SARs based on these molecular descriptors. For each step a new descriptor (modulator) is added if the addition is statistically significant and increases the cross-validated R2 (the internal performance) of the model. The number of descriptors in each local model is never allowed to exceed one fifth of the number of training set chemicals covered by that alert. If the final regression model for the alert does not satisfy certain criteria (R2 ≥ 0.6 and Q2 ≥ 0.5) it is rejected. Therefore, not all alerts will necessarily have a local (Q)SAR. The collection of positive and deactivating alerts with or without a local (Q)SAR constitutes a global (Q)SAR model for a particular endpoint and can be used for predicting the activity of a test chemical.

 

Leadscope

Leadscope Predictive Data Miner is a software program for systematic sub-structural analysis of a chemical using predefined structural features stored in a template library, training set-dependent generated structural features (scaffolds) and calculated molecular descriptors. Leadscope has a default automatic descriptor selection procedure. This procedure selects the top 30% of the descriptors (structural features and molecular descriptors) according to X2-test for a binary variable or the top and bottom 15% descriptors according to t-test for a continuous variable. After selection of descriptors the program performs partial least squares (PLS) regression for a continuous response variable, or partial logistic regression (PLR) for a binary response variable, to build a predictive model.

 

SciQSAR

The SciQSAR software provides over 400 built-in molecular descriptors such as connectivity indices, electrotopological (atom E and HE-state) indices, and other descriptors. Furthermore, the program provides a variety of statistical tools that can be used to build predictive models for binary and continuous data. SciQSAR uses discriminant analysis for binary data and includes the capability to perform parametric and nonparametric discriminant analyses. For continuous data, regression analysis is used to build the predictive model, and a number of different regression methods are available such as regression on principal components (PCR) and partial least squares regression (PLS).

Conclusions:

Gene mutation toxicity study as predicted by Danish QSAR for Dodecanenitrile(2437-25-4) is negative and hence the chemical is predicted to not classify as a gene mutant in vitro.

Executive summary:

Gene mutation toxicity was predicted for Dodecanenitrile (2437-25-4) using the battery approach from Danish QSAR database (2017). The study assumed the use of Salmonella typhimurium bacteria in the Ames test. The end point for gene mutation has been modeled in the Danish QSAR using the three software systems Leadscope, CASE Ultra and SciQSAR. Based on predictions from these three systems, a fourth and overall battery prediction is made. The battery prediction is made using the so called Battery algorithm. With the battery approach it is in many cases possible to reduce “noise” from the individual model estimates and thereby improve accuracy and/or broaden the applicability domain.

Gene mutation toxicity study as predicted by Dodecanenitrile is negative and hence the chemical is predicted to not classify as a gene mutant in vitro

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Genetic toxicity in vitro

Experimental studies and prediction model based estimation data for target chemical Dodecanenitrile (2437-25-4) have been reviewed to determine its mutagenic nature. The studies are as mentioned below:

In vitro chromosome aberration assays were performed by S.P. Bhatia et. al. ( Food and Chemical Toxicology 59; 2013; 784–792) using Chinese hamsterV79 cells according to OECD Testing Guideline No. 473 and were conducted on dodecanenitrile (CAS 2437-25-4). A preliminary toxicity assay was performedto determine dose selection for the cytogenetic experiments The chromosomes were prepared 18 h after start of treatment with the test item. V79 cells were exposed to test material dissolved in DMSO, as well as positive and solvent control ±S9 activation. The exposure period was 4 h (±S9). In experimental group two parallel cultures were set up. Per culture at least 100 metaphase plates were scored for structural chromosome aberrations were scored. The positive control without metabolic activation was ethyl methane sulfonate (EMS) and with metabolic activation was cyclophosphamide (CPA). The positive controls induced statistically significant increases (p < 0.05) in cells with structural chromosome aberrations. Dodecanenitrile was determined to be non-clastogenic in an in vitro chromosome aberration assay in V79 cells with and without metabolic activation using rat liver S9 fractions.

Gene mutation toxicity was predicted for Dodecanenitrile (2437-25-4) using the battery approach from Danish QSAR database (2017). The study assumed the use of Salmonella typhimurium bacteria in the Ames test. The end point for gene mutation has been modeled in the Danish QSAR using the three software systems Leadscope, CASE Ultra and SciQSAR. Based on predictions from these three systems, a fourth and overall battery prediction is made. The battery prediction is made using the so called Battery algorithm. With the battery approach it is in many cases possible to reduce “noise” from the individual model estimates and thereby improve accuracy and/or broaden the applicability domain.

Gene mutation toxicity study as predicted by Dodecanenitrile is negative and hence the chemical is predicted to not classify as a gene mutant in vitro.

Supporting above prediction an experimental study was reviewed from secondary source  FND Nitriles HPV Chemicals Challenge(FND HPV Nitriles Robust Summaries – Appendix A, 2003) for target substance Dodecanenitrile (2437-25-4) to determine its mutagenic nature. Dodecanenitrile was assessed for its possible mutagenic potential. For this purpose Bacterial Reverse mutation assay was performed according to OECD guideline 471 and 472 in Salmonella typhimurium TA98, TA100, TA1535, TA 1537and TA1538and Escherichia coli WP2uvrA. The test concentration was not specified. But the test substance was exposed in the presence and absence of metabolic activation S9. No mutagenic effects were observed. Therefore Dodecanenitrile was considered to be non mutagenic in Salmonella typhimurium TA98, TA100, TA1535, TA 1537and TA1538and Escherichia coli WP2uvrA by Bacterial Reverse mutation assay. Hence the substance cannot be classified as gene mutant in vitro.

Based on the above results, it can be concluded that the substance dodecanenitrile does not present a concern for genotoxic potential and can be considered as not classified as per CLP classification criteria.

Justification for classification or non-classification

Based on the above results, it can be concluded that the substance dodecanenitrile does not present a concern for genotoxic potential and can be considered as not classified as per CLP classification criteria.