3-(isodecyloxy)propylamine

Genetic toxicity: in vitro

Administrative data

Endpoint:

in vitro cytogenicity / chromosome aberration study in mammalian cells

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 Model 3.3.8, Statistice 7

2. MODEL (incl. version number) : Nonlinear Classification ANN QSAR Model for in vitro chromosomal aberration data in mammalian cells.Model version: 04/06/2010

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL :
SMILES: CC(C)CCCCCCCOCCCN, not used for prediction
InChI=1S/C13H29NO/c1-13(2)9-6-4-3-5-7-11-15-12-8-10-14/h13H,3-12,14H2,1-2H3, not used for prediction
3D Mol file used for prediction

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
QMRF attached separately
- Defined endpoint: 4.Human health effects 4.10.Mutagenicity -IN VITRO MAMMALIAN CHROMOSOME ABERRATION TEST
- Unambiguous algorithm: Nonlinear QSAR: Backpropagation Neural Network (Multilayer Perceptron) classification. The algorithm is based on neural network predictor with structure 9-9-8-1 Standard Backpropagation Neural Network (Multilayer Perceptron) classification
- Defined domain of applicability: presence of functional groups in structures. Range of descriptor values in training set with ±30% confidence Descriptor values must fall between maximal and minimal descriptor values (see5.1) of training set ±30%.
Applicability domain based on training set: By descriptor value range (between min and max values): The model is suitable for compounds ( including ethers, esters, amides, halides, aromatic, aliphatic functional groups etc) that have the descriptors in the following range augmented with the confidence in 5.2:
Desc ID
See 4.3123456789
Min0.0000000.0000001.257470.9714290.00000-10.08720.00000-228.998 0.590701
Max0.2372280.97832514.615912.90000025.565230.000067.00000791.387 0.930916
- Appropriate measures of goodness-of-fit and robustness and predictivity:
a) Statistics for goodness-of-fit: Training negativesTraining positives Selection; negatives Selection; positives Test; negatives Test; positives
Total242.0000259.000019.0000031.0000023.0000027.00000
Correct233.0000252.000013.0000022.0000013.0000018.00000
Wrong9.00007.00006.000009.0000010.000009.00000
Correct(%)96.281097.297368.4210570.9677456.5217466.66667
Wrong(%)3.71902.702731.5789529.0322643.4782633.33333
b) Robustness: see Statistics for goodness-of-fit:
c) Predictivity - Assessment of the external validation set: The descriptors for the test set are in the limit of applicability, see 6.7 and 6.12
- Mechanistic interpretation: The mechanistic picture is difficult to analyze because of the nature of the ANN models. According to the descriptors used as inputs to the network, it can be concluded that the property is mainly related to the charged surfaces that may play important role in defining the property values. For instance, the most significant descriptor (according to F) Square root of Partial Surface Area of H atoms leads to positive index of the chromosomal aberration when its values are lower.In addition to the charged surfaces, hydrogen abilities of the compounds are also important in conjunction with the energy terms related to HOMO-LUMO and exchange interactions for the C-C bond.

5. APPLICABILITY DOMAIN
- Descriptor domain: All descriptor values for 3-(isodecyloxy)propylamine fall in the applicability domain (training set value ±30%).
- Structural domain: 3-(isodecyloxy)propylamine is structurally relatively similar to the model compounds. The training set contains compounds of similar size to the studied molecule.
- Mechanistic domain: 3-(isodecyloxy)propylamine 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 experimentally measured chromosomal aberration test values for compounds of similar size and similar functional groups are all found to be non-mutagenic. The structural analogues are relatively similar to the studied compound, and are considered to be within the same mechanistic domain. The descriptor values of the analogues are relatively close to those of the studied compound.
- Metabolic domain: 3-(isodecyloxy)propylamine is considered to be in the same metabolic domain as the molecules in the training set of the model due to the structural similarity.

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) of QPRF report for the classification of the prediction in light of the regulatory purpose described above.
- Conclusion: Considering the above, the predicted result can be considered adequate for the regulatory conclusion described in "Regulatory purpose".

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 473 (In Vitro Mammalian Chromosome Aberration Test)

GLP compliance:

no

Type of assay:

in vitro mammalian chromosome aberration test

Test material

Test material information

Constituent 1

Reference substance name:

3-(isodecyloxy)propylamine

EC Number:

250-056-7

EC Name:

3-(isodecyloxy)propylamine

Cas Number:

30113-45-2

Molecular formula:

C13H29NO

IUPAC Name:

3-[(8-methylnonyl)oxy]propan-1-amine

Test material form:

liquid

Specific details on test material used for the study:

The test data used in this model were taken from a single source, the Data Book of Chromosomal Aberration Test In Vitro (2). This book is written in Japanese, but all tables are in English and the authors were provided with English translations for everything except the Introduction. The Introduction is identical to that used in the previous version of the book, published in English by Dr. Motoi Ishidate (3), which was also available to the authors.
Test results for a total of 901 substances are presented in the Data Book (2). The chemicals were chosen for a variety of reasons, including use in foods. A number fall into the class commonly referred to as UVCB’s, or chemicals that cannot be represented by a complete structure diagram and specific molecular formula. These were excluded for the obvious reason that it is impossible to model a chemical for which a structure is not available. However, it was found that this is not always a totally unambiguous process, so the authors made the best judgement they could. Inorganic chemicals were also excluded, as the modeling platform used by the authors cannot deal with them. A very small number of chemicals were excluded because the true identity was not clear (inconsistencies between chemical name, CAS number and structure/molecular weight that we were unable to resolve). A few stereo-isomers with conflicting results were also removed as they cannot be distinguished by SMILES notation (a computer code for 2D structures). A toxicological decision was made to include chemicals as being positive if they were active in inducing either aberrations or polyploidy. While the current test guideline does not specify testing for a length of time, which would allow polyploidy to be assessed, much of the CHL data does and the information was felt to be too valuable to lose (18 chemicals). Chemicals were also retained even if the test had not been performed both in the presence and absence of metabolic activation. Beyond this, the judgement of the authors was used in their interpretation of the final test result. This included dropping 16 of 18 chemicals that the authors considered inconclusive in repeat tests (two were kept because while they were inconclusive for polyploidy, they were clearly positive for structural aberrations). Seventy-eight chemicals were excluded because the authors considered them False Positive (only active at dose of more than 10 mM where effects could be due to osmotic pressure). As the modeling system was not able to handle salts (e.g. sodium salts, hydrochlorides), further interpretation was necessary. In the majority of cases there was no conflict with regard to results of testing ionised or non-ionised forms. However, in certain cases there were. The authors decided that for some simple organic acids that were active but where the salt was clearly inactive, to consider these as being inactive in accordance with the advice, given in the OECD Guidelines and Morita et al. (5), that particularly low pH may lead to false positive predictions. It is not known if this decision is right or wrong in relation to use of results of this in vitro system for predicting in vivo effects, but it will clearly affect the performance of the model. A few decisions have been done on a basis of additional data from the literature: vitamin B2 (Riboflavin, CAS 83-88-5) tested positive in insoluble form, but was negative in soluble form. The negative result was retained, as the mechanism for the insoluble compound appears to be physical (6). After some consideration, saccharin (CAS 81-07-2) and EDTA (CAS 60-00-4) were entered as negatives, in agreement with Ashby et al. (7), even though there was conflicting information for some of the salts. Finally, about 40 chemicals having only equivocal results were excluded. This is also an arbitrary decision, but it was felt that equivocal results were not likely to lead to a better training set. Thus, a total of 513 chemicals remained. Their identities and SMILES notations are available in Training_set.doc. There were 263 positive and 250 negative substances in the training set, giving the nearly 50:50 split considered ideal for modeling purposes.
For external validation, data generated over a six-year period (1991-1996) was used for chromosomal aberration testing of high production volume (HPV) industrial chemicals that had been conducted using Chinese hamster lung (CHL/IU) cells according to the OECD HPV testing program and the national program in Japan (Kusakabe et al., 8). Of a total of 98 substances, two were removed in the authors’ analyses: dicyclopentadiene (CAS 77-73-6), because it was already in the training set, and Pigment Green No. 7 (CAS 14832-145), a copper complex that cannot be modeled in the selected system. The 98 chemicals are available in Validation_set.doc. On further examination of the data set, it was noticed that one substance (4-(1-Methylpropyl)phenol, CAS 99-71-8) was actually a false positive (only active at very high concentration, and ultimately judged inactive following an in vitro micronucleus test). Eight additional chemicals were identified where the chromosomal aberrations are induced under non-physiological culture conditions (pH<6), which could be kept in mind when using the data.

Method

Species / strain

Species / strain / cell type:

Chinese hamster lung (CHL/IU)

Details on mammalian cell type (if applicable):

All tests were performed using a Chinese Hamster Lung Cell (CHL) fibroblast cell
line, which has been kept as a single cell sub-clone since 1973. This cell line has been used
almost exclusively in Japan to test hundreds of chemicals over more than two decades, as
opposed to the Chinese Hamster Ovary (CHO) cell lines that are more common in Europe
and the United States. Much of the test information has been published in numerous
scientific articles during the years over which it has been generated. An example is provided
by Ishidate et al. (

Additional strain / cell type characteristics:

not applicable

Metabolic activation:

not specified

Results and discussion

Test results

Key result

Species / strain:

Chinese hamster lung (CHL/IU)

Metabolic activation:

not specified

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

not applicable

Untreated negative controls validity:

not applicable

True negative controls validity:

not applicable

Positive controls validity:

not applicable

Additional information on results:

The prediction indicates that the studied compound has no mutagenic effect to chromosome-type aberrations.

Remarks on result:

no mutagenic potential (based on QSAR/QSPR prediction)

Applicant's summary and conclusion

Conclusions:

The prediction indicates that the studied compound has no mutagenic effect to chromosome-type aberrations.

Executive summary:

The prediction indicates that the test item has no mutagenic effect to chromosome-type aberrations.