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EC number: 690-928-8 | CAS number: 39992-90-0
Genetic toxicity: in vitro
Administrative data
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21.12.2021 - 29.06.2022
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- TDI-Uron is used as read across partner because it is structural analog to IPDI-Uron.
For detailed justification, please see attached report in section 13.2.
Cross-reference
- Reason / purpose for cross-reference:
- read-across: supporting information
Reference
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 2001-04-04 to 2001-05-07
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- This endpoint study record is added as supporting study for the analogue approach.
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- GLP compliance:
- yes (incl. QA statement)
- 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): N,N"(4-Methyl-m-phenylen)bis(N',N'dimethylharnstoff)
- Substance type: organic
- Physical state: colourless solid
- Analytical purity: 100 %
- Purity test date: 01 March 2000
- Lot/batch No.: 0232 07
- Expiration date of the lot/batch: March 2003
- Storage condition of test material: store dry in closed containers
- Other: stable at dry storage conditions for at least 2 years - Target gene:
- Gene involved in histidine synthesis.
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
- Details on mammalian cell type (if applicable):
- n.a.
- Additional strain / cell type characteristics:
- other: deep rough (rfa) mutation; uvrB gene deletion (BER)
- Metabolic activation:
- with and without
- Metabolic activation system:
- Mammalian Microsomal Fraction S9 Mix
- Test concentrations with justification for top dose:
- Experiments I and II: 31.6; 100.0; 316.2; 1000.0; 2500.0 and 5000.0 µg per plate
- Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: DMSO
- Justification for choice of solvent/vehicle:The test item was dissolved in DMSO and diluted prior to treatment. The solvent was compatible with the survival of the bacteria and the S9 activity. - Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- sodium azide
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: 4-NOPD
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- methylmethanesulfonate
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: 2-AA
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in agar (plate incorporation) and preincubation;
DURATION
- Preincubation period: 60 min
- Exposure duration: 48 h
DETERMINATION OF CYTOTOXICITY
- Method: cloning efficiency; - Evaluation criteria:
- The mutation factor is calculated by dividing the mean value of the revertant count through the mean values of the solvent control.
A test is considered acceptable if for each strain:
- the bacteria demonstrate their typical responses to crystal violet and ampicillin
- the control plates without S9 mix are within the following ranges (range of spontaneaus reversion frequencies-historical control- data range):
TA 1535: 5-30
TA 1537: 4-32
TA 98: 18-63
TA 100: 79-197
TA 102: 173-396
-corresponding background growth on both negative control and test plates is observed.
- the positive controls show a distinct enhancement over the control plate. - Key result
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 102
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Conclusions:
- Interpretation of results:
negative
TDI-Urone has no mutagenic potential under the conditions of this study. - Executive summary:
The test item TDI-Urone was investigated for its potential to induce gene mutations according to the plate incorporation test (experiment I) and the pre incubation test (experiment II) using Salmonella typhimurium strains TA 1535, TA 1537, TA 100, TA 98 and TA 102.
In two independent experiments several concentrations of the test item were used. Each assay was conducted with and without metabolic activation (S9 mix). The concentrations, including the controls, were tested in triplicate. The following concentrations of the test item were prepared and used in the experiments:
Experiment I and II: 31.6; 100.0; 316.2; 1000.0; 2500.0 and 5000.0 µg//plate
No toxic effects of the test item (indicated by a reduction of the background lawn or by a reduction of the spontaneaus rate) were observed in both experiments with or without metabolic activation.
No substantial increases in revertant colony numbers of any of the five tester strains were observed following treatment with TDI-Urone at any concentration level, either in the presence or absence of metabolic activation (S9-mix) in experiment I and II. There was also no tendency of higher mutation rates with increasing concentrations in the range beyond the generally acknowledged border of biological relevance.
Therefore, TDI-Urone is not considered to be mutagenic in bacterial cells.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 022
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Version / remarks:
- adopted 21
July 1997, corrected 26 June 2020
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- Urea,N'-[3-[[[(dimethylamino)carbonyl]amino]methyl]-3,5,5-trimethylcyclohexyl]-N,N-dimethyl-
- EC Number:
- 690-928-8
- Cas Number:
- 39992-90-0
- Molecular formula:
- C16H32N4O2
- IUPAC Name:
- Urea,N'-[3-[[[(dimethylamino)carbonyl]amino]methyl]-3,5,5-trimethylcyclohexyl]-N,N-dimethyl-
- Reference substance name:
- Water
- EC Number:
- 231-791-2
- EC Name:
- Water
- Cas Number:
- 7732-18-5
- Molecular formula:
- H2O
- IUPAC Name:
- water
- Reference substance name:
- Toluene
- EC Number:
- 203-625-9
- EC Name:
- Toluene
- Cas Number:
- 108-88-3
- Molecular formula:
- C7H8
- IUPAC Name:
- toluene
- Test material form:
- solid
Constituent 1
impurity 1
impurity 2
- Specific details on test material used for the study:
- Production Date:2021-11-17
Batch: 132001
Method
Species / strainopen allclose all
- Species / strain / cell type:
- E. coli WP2 uvr A pKM 101
- Remarks:
- WP2 uvrA (pKM101): trp-; uvrA-: base-pair substitutions
- Species / strain / cell type:
- S. typhimurium TA 98
- Remarks:
- his D 3052; rfa-; uvrB-; R-factor: frame shift mutations
- Species / strain / cell type:
- S. typhimurium TA 100
- Remarks:
- his G 46; rfa-; uvrB-; R-factor: base-pair substitutions
- Species / strain / cell type:
- S. typhimurium TA 1537
- Remarks:
- his C 3076; rfa-; uvrB-: frame shift mutations
- Species / strain / cell type:
- S. typhimurium TA 1535
- Remarks:
- his G 46; rfa-; uvrB-: base-pair substitutions
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9 liver microsomal fraction
- Test concentrations with justification for top dose:
- Experiment I:
31.6, 100, 316, 1000, 2500 and 5000 μg/plate
Experiment II:
50, 158, 500, 1580, 3000 and 5000 μg/plate
The recommended maximum test concentration for soluble non-cytotoxic substances is 5 mg/plate or 5 μl/plate. (OECD-Guideline 471)
Controls
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- Positive controls:
- yes
- Positive control substance:
- sodium azide
- methylmethanesulfonate
- other:
- Statistics:
- According to the OECD guidelines, the biological relevance of the results is the criterion for the
interpretation of results, a statistical evaluation of the results is not regarded as necessary.
Results and discussion
Test resultsopen allclose all
- Key result
- Species / strain:
- E. coli WP2 uvr A pKM 101
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
Applicant's summary and conclusion
- Conclusions:
- In conclusion, it can be stated that during the described mutagenicity test and under the experimental conditions reported, N-[3-[[[(dimethylamino)carbonyl]amino]methyl]-3,5,5-trimethylcyclohexyl]-N,Ndimethyl-Urea did not cause gene mutations by base pair changes or frameshifts in the genome of the tester strains used.
Therefore, N-[3-[[[(dimethylamino)carbonyl]amino]methyl]-3,5,5-trimethylcyclohexyl]-N,N-dimethyl-Urea is considered to be non-mutagenic in this bacterial reverse mutation assay. - Executive summary:
The test item N-[3-[[[(dimethylamino)carbonyl]amino]methyl]-3,5,5-trimethylcyclohexyl]-N,N-dimethyl-Urea was investigated for its potential to induce gene mutations according to the plate incorporation test (experiment I and II) using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and tester strain E. coli WP2 uvrA (pKM101).
In two independent experiments several concentrations of the test item were used. Each assay was conducted with and without metabolic activation. The concentrations, including the controls, were tested in triplicate.The following concentrations of the test item were prepared and used in the experiments:
Experiment I:
31.6, 100, 316, 1000, 2500 and 5000 μg/plate
Experiment II:
50, 158, 500, 1580, 3000 and 5000 μg/plate
No precipitation of the test item was observed in any tester strain used in experiment I and II (with and without metabolic activation).
No toxic effects of the test item were noted in any of the five tester strains used up to the highest dose group evaluated with and without metabolic activation in experiment I and II. No biologically relevant increases in revertant colony numbers of any of the five tester strains were observed following treatment with N-[3-[[[(dimethylamino)carbonyl]amino]methyl]-3,5,5-trimethylcyclohexyl]-N,N-dimethyl-Urea at any concentration level, neither in the presence nor
absence of metabolic activation in experiment I and II.All criteria of validity were met.
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