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Toxicological information

Genetic toxicity: in vitro

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Administrative data

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
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:
publication
Title:
Unnamed
Year:
1998

Materials and methods

Test material

Constituent 1
Reference substance name:
4,4'-Methylenediphenyl diisocyanate, oligomeric reaction products with butane-1,3-diol, 2,4'-diisocyanatodiphenylmethane, [(methylethylene)bis(oxy)]dipropanol and propane-1,2-diol
EC Number:
500-312-1
EC Name:
4,4'-Methylenediphenyl diisocyanate, oligomeric reaction products with butane-1,3-diol, 2,4'-diisocyanatodiphenylmethane, [(methylethylene)bis(oxy)]dipropanol and propane-1,2-diol
Cas Number:
123714-19-2
Test material form:
liquid: viscous
Details on test material:
Batch # 290832

Results and discussion

Test resultsopen allclose all
Key result
Species / strain:
S. typhimurium TA 100
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
other: 200ug/plate and above
Vehicle controls validity:
valid
Positive controls validity:
valid
Key result
Species / strain:
S. typhimurium TA 98
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
other: 200ug/plate and above
Vehicle controls validity:
valid
Positive controls validity:
valid
Key result
Species / strain:
S. typhimurium TA 1537
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
other: 200ug/plate and above
Vehicle controls validity:
valid
Positive controls validity:
valid
Key result
Species / strain:
S. typhimurium TA 1535
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
other: 200ug/plate and more
Vehicle controls validity:
valid
Positive controls validity:
valid

Applicant's summary and conclusion

Conclusions:
A bacterial gene mutation study is currently not available on the target substance 44MDI/1,3-BD/TPG/PG. However, as described in the endpoint summary, bacterial Ames testing will be completed all missing data according to current guidelines. In advance of this testing being completed, missing data will be filled by read-across according to weight of evidence from 4,4,’-MDI (i.e. worst-case substance) and 10 other MDI Category substance represent all sub-groups.
This read-across is based on the hypothesis MoA that all substances of the MDI category contain the reactive NCO group on the different constituents that is capable of reaction with biological nucleophiles. The chemical reactivity and toxicokinetic behavior of this NCO on the bioaccessible MDI substances is described in details in the Toxicokinetics section of the Category Justification Document (attached in IUCLID section 13) and forms the basis of the hypothesized MoA for site of contact toxicity but is also the basis for the absence of mutagenicity. In the case of mutagenicity, the hypothesized MoA recognizes that 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 this concern. Further, the toxicokinetic and metabolic pathways do not indicate the formation of toxicologically relevant metabolites.
Executive summary:

The hypothesized MoA for the substances of the MDI category for mutagenicity recognizes that 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 this concern. Further, the toxicokinetic and metabolic pathways do not indicate the formation of toxicologically relevant metabolites and is described in detail below. The genotoxic potential of MDI substances has been investigated extensively in vitro and while early bacterial mutagenicity studies were positive, further experiments demonstrated that these results reflect the properties of hydrolysis products (i.e. diamine) formed under specific artificial assay conditions (aprotic solvent) and are not indicative of genotoxic potential of the parent compound under physiological conditions (Herbold et al., 1998; EC, 2005; DFG, 2008).
Additional bacterial mutagenicity studies (OECD 471) will be conducted on data gaps to complete the data set. Additional in vitro micronucleus studies (OECD 487) will be conducted on ALL category substance to assess potential effects on cytogenetics. Combined with in vivo mutagenicity testing on the worst-case substance (4,4’-MDI) demonstrates the lack of mutagenic potential for the MDI Substance category.