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Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6). The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 with and without S9 metabolic activation system. 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence and absence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro.

Based on the predicted result it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Link to relevant study records
Reference
Endpoint:
in vitro gene mutation study in bacteria
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:
Data is from OECD QSAR Toolbox version 3.3 and the supporting QMRF report has been attached.
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: 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione
- Molecular formula: C18H20N2O4
- Molecular weight: 328.366 g/mol
- Smiles notation: c1ccc2C(=O)N(CCCO)C(=O)c3ccc(NCCCO)c1c23
- InChl: 1S/C18H20N2O4/c21-10-2-8-19-15-7-6-14-16-12(15)4-1-5-13(16)17(23)20(18(14)24)9-3-11-22/h1,4-7,19,21-22H,2-3,8-11H2
- Substance type: Organic
Target gene:
Histidine
Species / strain / cell type:
S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
Details on mammalian cell type (if applicable):
Not apllicable.
Additional strain / cell type characteristics:
not specified
Cytokinesis block (if used):
not specified
Metabolic activation:
with
Metabolic activation system:
S9 metabolic activation.
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:
with
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.

The prediction was based on dataset comprised from the following descriptors: "Gene mutation"
Estimation method: Takes highest mode value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Imides (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine by DNA binding by OECD ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Secondary aromatic amine by DNA binding by OECD ONLY

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, OH group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Azlactones and unsaturated lactone derivatives  OR Acylation >> Direct acylation involving a leaving group >> Carbamates  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> beta-Lactams  OR 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 >> alpha,beta-Carbonyl compounds with polarized double bonds  OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Nitroalkenes OR Michael Addition >> Quinoide type compounds OR Michael Addition >> Quinoide type compounds >> Quinone methide(s)/imines; Quinoide oxime structure; Nitroquinones, Naphthoquinone(s)/imines  OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds  OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> (Thio)Phosphates  OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> Alkyl halides  OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> alpha-Activated haloalkanes  by Protein binding by OASIS v1.3

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD ONLY

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Non-Metals by Groups of elements

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Alkali Earth OR Halogens by Groups of elements

Domain logical expression index: "m"

Similarity boundary:Target: OCCCNc1ccc2c3c1cccc3C(=O)N(CCCO)C2=O
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.8

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.73

Conclusions:
3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro.
Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6). The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 with S9 metabolic activation system. 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro.

Based on the predicted result it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Prediction model based estimation and data from read across chemical have been reviewed to determine the mutagenic nature of3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6). The studies are as mentioned below

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6). The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 with and without S9 metabolic activation system. 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence and absence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro.

Based on the predicted result it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

In a study for structurally and functionally similar read across chemical, Gene mutation toxicity study was performed by Errol Zeiger et al.(Environmental Mutagenesis, 1987)to determine the mutagenic nature of Brucin (357-57-3). The read across substances share high similarity in structure and log kow .Therefore, it is acceptable to derive information on mutation from the analogue substance. Brucin was assessed for its possible mutagenic potential. For this purpose Bacterial reverse mutation Assay was performed on Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 .The test material was exposed at the concentration of 0-6666 µg/plate in the presence and absence of S9. No mutagenic effects were observed in all strain. Therefore Brucin was considered to be non mutagenic inSalmonella typhimurium strains TA98, TA100, TA1535, and TA1537. Hence the substance cannot be classified as gene mutant in vitro.

In a study for structurally and functionally similar read across chemical, Gene mutation toxicity study was performed by J. Ashby.al. (Mutation Research, 1997) to determine the mutagenic nature of Thalidomide (50-35-1) IUPAC; 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione. The read across substances share high similarity in structure and log kow .Therefore, it is acceptable to derive information on mutation from the analogue substance. Bacterial reverse mutation assay was performed for the test chemical thalidomide using Salmonella typhimurium strain TA1535, TA1537, TA1538, TA97, TA98 and TA100. The study was performed using the plate incorporation assay at dose levels of 0, 8.0, 40, 200, 1000 or 5000 μg / plate being dissolved in DMSO with incubation in the presence and absence of S9 mix. Concurrent solvent and strain specific positive controls were included in the study. Plate numbers employed were five for DMSO controls, two for positive controls and three for test agent.

 

The test compound Thalidomide did not induce gene mutation in the Salmonella typhimurium strain TA1535, TA1537, TA1538, TA97, TA98 and TA100 with and without 10% S9 mix and hence thalidomide is negative for gene mutation in vitro.

 

Based on the data available for the target chemical and its read across substance and applying weight of evidence 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)does not exhibit gene mutation in vitro. Hence the test chemical is not likely to classify as a gene mutant in vitro.

Justification for classification or non-classification

Thus based on the above annotation for the target chemical .3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)does not exhibit gene mutation in vitro. Hence the test chemical is not likely to classify as a gene mutant in vitro