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EC number: 500-297-1 | CAS number: 109331-54-6
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:
- 07.01.2013 - 04.02.2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Hypothesis: Under physiological conditions the MDI substance readily polymerizes at the MDI/aqueous interface forming insoluble polyureas and/or reacts with extracellular biological nucleophiles to form MDI-adducts rendering the free NCO completely unavailable to react with DNA thereby negating DNA reactivity concerns. Further, the toxicokinetic and metabolic pathways do not indicate the formation of toxicologically relevant metabolites.
Justification: Toxicokinetic and hydrolysis mechanisms demonstrate that MDI rapidly polymerizes to polyurea that the MDI/aqueous interface. Hydrolysis is highly unfavored except when reaction is stabilized by aprotic solvents (DMSO). When appropriate solvents are used, all tested MDI substances are negative for mutagenicity and is supported by this mechanism.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2010
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- PIR modified MDI
- Cas Number:
- 109331-54-6
- IUPAC Name:
- PIR modified MDI
Constituent 1
Method
Species / strain
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
- Metabolic activation:
- with and without
- Metabolic activation system:
- Type and composition of metabolic activation system:
- source of S9: liver S 9 fraction of Aroclor 1254-induced male Sprague Dawley rats
- concentration or volume of S9 mix and S9 in the final culture medium : plate-incorporation: 0.1 ml, pre-incubation 0.3 ml,
- quality controls of S9 (e.g., enzymatic activity, sterility, metabolic capability): yes - Test concentrations with justification for top dose:
- 0.01, 0.025, 0.05, 0.16, 0.5, 1.6, 5.0 µL/plate
- Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: EGDE (dried with molecular sieve, 0.3 nm)
- Justification for choice of solvent/vehicle: test substance not stable in water or DMSO
Controls
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 2-nitrofluorene
- sodium azide
- mitomycin C
- Remarks:
- additional positive controls: anthracene-2-amine, 4-NPDA
- Details on test system and experimental conditions:
- NUMBER OF REPLICATIONS:
- Number of cultures per concentration: triplicate
- Number of independent experiments: two
METHOD OF TREATMENT/ EXPOSURE:
- Test substance added in medium; in agar plate incorporation and preincubation - Evaluation criteria:
- The following criteria determined the acceptance of an assay:
1. The negative controls had to be within the expected range, as defined by published data
(e.g. Maron and Ames, Revised methods for the Salmonella mutagenicity test
Mutation Res. 1983, 113:173-215) and/ or the laboratories' own historical data
2. The positive controls had to show sufficient effects, as defined by the laboratories'
Experience
3. Titer determinations had to demonstrate sufficient bacterial density in the suspension. - Statistics:
- mean, standard deviation
Results and discussion
Test resultsopen allclose all
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 102
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
Applicant's summary and conclusion
- Conclusions:
- The test substance was considered to be non-mutagenic without and with S9 mix in the
plate incorporation as well as in the preincubation modification of the Salmonella/microsome
test. - Executive summary:
The mutagenic potential of the test substance was evaluated in a Salmonella/microsome test with the S. typhimurium strains TA 98, TA 100, TA 102, TA 1535 and TA 1537 in the presence and absence of S9 mix according to OECD TG 471. Evidence of mutagenic activity was not seen. No biologically relevant increase in the mutant count, in comparison with the negative controls, was observed. Based on this test, the test substance was considered to be non-mutagenic without and with S9 mix in the plate incorporation as well as in the preincubation modification of the Salmonella/microsome test.
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