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EC number: 219-799-4 | CAS number: 2536-05-2
- Life Cycle description
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- Endpoint summary
- Appearance / physical state / colour
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- Density
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- Additional physico-chemical information
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- Endpoint summary
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- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
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- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
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- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Genetic toxicity: in vitro
Administrative data
- Endpoint:
- in vitro gene mutation study in bacteria
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP 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:
- 2 011
- Report date:
- 2011
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- deviation: no analytical data on chemical composition of the test item were submitted by the sponsor; however, this deviation did not limit the assessment of the results.
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- 2,2'-methylenediphenyl diisocyanate
- EC Number:
- 219-799-4
- EC Name:
- 2,2'-methylenediphenyl diisocyanate
- Cas Number:
- 2536-05-2
- Molecular formula:
- C15H10N2O2
- IUPAC Name:
- 1,1'-methylenebis(2-isocyanatobenzene)
- Details on test material:
- - Name of test material (as cited in study report): MDI 22
- Physical state: solid
- Purity: approx. 100 % (as indicated by the sponsor)
- Lot/batch No.: WRS 3792
- Storage condition of test material: room temperature
Constituent 1
Method
Species / strain
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
- Additional strain / cell type characteristics:
- not applicable
- Metabolic activation:
- with and without
- Metabolic activation system:
- Aroclor 1254 induced male rat liver S9 mix
- Test concentrations with justification for top dose:
- Plate incorporation test (first test): 0, 50, 158, 500, 1581, 5000 µg/plate (without and with S9 mix)
Plate incorporation test (second test): 0, 0.5, 5, 16, 50 µg/plate (without and with S9 mix)
Independent preincubation test (first test): 0, 0.5, 1.6, 5, 16, 50, 158, 500 µg/plate (without and with S9 mix)
Independent preincubation test (second test): 0, 1.6, 5, 16, 50, 158, 500 µg/plate (only TA 100 and TA 102, without and with S9 mix) - Vehicle / solvent:
- Solvents used: ethylene glycol dimethylether (EGDE) dried with a molecular sieve 0.3nm (test substance), deionized water (mitomycin C), DMSO (sodium azide, nitrofurantoin, 4-nitro-1,2-phenylene diamine, cumene hydroperoxide, 2-aminoanthracene)
Controls
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: sodium azide (TA 1535), nitrofurantoin (TA 100), 4-nitro-1,2-phenylene diamine (TA 1537, TA 98), mitomycin C (TA 102, plate incorp. assay), cumene hydroperoxide (TA 100, preincub. trials), 2-aminoanthracene
- Remarks:
- The positive controls sodium azide, nitrofurantoin, 4-nitro-1,2-phenylene diamine, mitomycin C and cumene hydroperoxide were only used without S9 mix; the positive control 2-aminoanthracene was only used with S9 mix.
- Evaluation criteria:
- A reproducible and dose-related increase in mutant counts of at least one strain is considered to be a positive result. For TA 1535, TA 100 and TA 98 this increase should be about twice that of negative controls, whereas for TA 1537, at least a threefold increase should be reached. For TA 102 an increase of about 100 mutants should be reached. Otherwise, the result is evaluated as negative. However, these guidelines may be overruled by good scientific judgment. In case of questionable results, investigations should continue, possibly with modifications, until a final evaluation is possible.
- Statistics:
- Not specified.
Results and discussion
Test results
- Species / strain:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- other: strong, strain-specific bacteriotoxic effect at 158 µg/plate and above
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Remarks on result:
- other: all strains/cell types tested
Any other information on results incl. tables
Table 1: Summary of results from the Salmonella mutagenicity assay (plate incorporation test - first trial) with MDI 22 (mean values of revertants per plate)
Dose (µg per plate) |
Without metabolic activation |
||||
|
TA 1535 |
TA 100 |
TA 1537 |
TA 98 |
TA 102 |
Vehicle control (EGDE) |
6 |
102 |
5 |
18 |
201 |
50 |
6 |
78 |
2 |
12 |
138 |
158 |
3 |
71 |
0 |
9 |
99 |
500 |
0 |
19 |
0 |
1 |
0 |
1581 |
0 |
23 |
0 |
3 |
0 |
5000 |
0 |
50 |
0 |
4 |
0 |
Positive control |
1033 |
304 |
24 |
54 |
725 |
Dose ( µg per plate ) |
With metabolic activation (liver S9 mix) |
||||
|
TA 1535 |
TA 100 |
TA 1537 |
TA 98 |
TA 102 |
Vehicle control (EGDE) |
8 |
172 |
8 |
25 |
322 |
50 |
3 |
126 |
8 |
25 |
309 |
158 |
4 |
111 |
0 |
20 |
241 |
500 |
0 |
54 |
0 |
3 |
0 |
1581 |
0 |
42 |
0 |
5 |
0 |
5000 |
0 |
56 |
0 |
3 |
0 |
Positive control |
106 |
2892 |
229 |
2431 |
652 |
Table 2: Summary of results from the Salmonella mutagenicity assay (plate incorporation test - second trial) with MDI 22 (mean values of revertants per plate)
Dose (µg per plate) |
Without metabolic activation |
||||
|
TA 1535 |
TA 100 |
TA 1537 |
TA 98 |
TA 102 |
Vehicle control (EGDE) |
6 |
132 |
3 |
15 |
148 |
0.5 |
6 |
157 |
3 |
15 |
143 |
1.6 |
5 |
144 |
3 |
16 |
148 |
5 |
5 |
155 |
4 |
21 |
162 |
16 |
6 |
146 |
3 |
19 |
124 |
50 |
6 |
103 |
2 |
13 |
108 |
Positive control |
859 |
310 |
30 |
58 |
809 |
Dose ( µg per plate ) |
With metabolic activation (liver S9 mix) |
||||
|
TA 1535 |
TA 100 |
TA 1537 |
TA 98 |
TA 102 |
Vehicle control (EGDE) |
9 |
200 |
5 |
22 |
230 |
0.5 |
9 |
213 |
3 |
23 |
296 |
1.6 |
10 |
199 |
5 |
23 |
229 |
5 |
9 |
218 |
5 |
27 |
231 |
16 |
10 |
231 |
7 |
26 |
222 |
50 |
10 |
168 |
4 |
20 |
251 |
Positive control |
133 |
2909 |
225 |
1943 |
557 |
Table 3: Summary of results from the Salmonella mutagenicity assay (independent preincubation test - first trial) with MDI 22
(mean values of revertants per plate)
Dose (µg per plate) |
Without metabolic activation |
||||
|
TA 1535 |
TA 100 |
TA 1537 |
TA 98 |
TA 102 |
Vehicle control (EGDE) |
9 |
173 |
7 |
23 |
265 |
0.5 |
--- |
157 |
9 |
--- |
--- |
1.6 |
6 |
--- |
10 |
25 |
279 |
5 |
11 |
171 |
8 |
36 |
275 |
16 |
9 |
198 |
7 |
31 |
286 |
50 |
10 |
188 |
6 |
20 |
264 |
158 |
6 |
132 |
6 |
15 |
235 |
500 |
0 |
144 |
--- |
14 |
131 |
Positive control |
852 |
619 |
30 |
82 |
408 |
Dose ( µg per plate ) |
With metabolic activation (liver S9 mix) |
||||
|
TA 1535 |
TA 100 |
TA 1537 |
TA 98 |
TA 102 |
Vehicle control (EGDE) |
9 |
283 |
9 |
39 |
437 |
0.5 |
--- |
--- |
9 |
--- |
--- |
1.6 |
10 |
286 |
10 |
41 |
436 |
5 |
15 |
302 |
9 |
40 |
410 |
16 |
13 |
297 |
11 |
36 |
332 |
50 |
8 |
268 |
9 |
31 |
355 |
158 |
9 |
235 |
7 |
34 |
373 |
500 |
6 |
93 |
--- |
15 |
308 |
Positive control |
130 |
2332 |
279 |
2831 |
805 |
Table 4: Summary of results from the Salmonella mutagenicity assay (independent preincubation test - second trial) with MDI 22
(mean values of revertants per plate)
Dose (µg per plate) |
Without metabolic activation |
||||
|
TA 1535 |
TA 100 |
TA 1537 |
TA 98 |
TA 102 |
Vehicle control (EGDE) |
--- |
144 |
--- |
--- |
250 |
1.6 |
--- |
158 |
--- |
--- |
222 |
5 |
--- |
155 |
--- |
--- |
226 |
16 |
--- |
137 |
--- |
--- |
209 |
50 |
--- |
142 |
--- |
--- |
210 |
158 |
--- |
133 |
--- |
--- |
186 |
500 |
--- |
79 |
--- |
--- |
67 |
Positive control |
--- |
291 |
--- |
--- |
809 |
Dose ( µg per plate ) |
With metabolic activation (liver S9 mix) |
||||
|
TA 1535 |
TA 100 |
TA 1537 |
TA 98 |
TA 102 |
Vehicle control (EGDE) |
--- |
216 |
--- |
--- |
310 |
1.6 |
--- |
200 |
--- |
--- |
295 |
5 |
--- |
216 |
--- |
--- |
298 |
16 |
--- |
237 |
--- |
--- |
322 |
50 |
--- |
207 |
--- |
--- |
338 |
158 |
--- |
179 |
--- |
--- |
340 |
500 |
--- |
92 |
--- |
--- |
254 |
Positive control |
--- |
2396 |
--- |
--- |
609 |
In the plate incorporation test doses of up to and including 50 µg per plate did not cause any bacteriotoxic effects. Total bacteria counts remained unchanged and no inhibition of growth was observed. Higher doses had a strong, strain-specific bacteriotoxic effect, so that this range could only partly be used up to and including 5000 µg per plate for assessment purposes. Substance precipitation occurred at the dose of 5000 µg per plate. In the preincubation test doses of up to and including 158 µg per tube did not cause any bacteriotoxic effects. Total bacteria counts remained unchanged and no inhibition of growth was observed. Higher doses had a strain-specific bacteriotoxic effect, so that doses up to and including 500 µg per tube could only partly be used for assessment purposes.
Evidence of mutagenic activity of MDl 22 was not seen up to the highest evaluable doses. No biologically relevant increase in the mutant count, in comparison with the negative controls, was observed.
The positive controls sodium azide, nitrofurantoin, 4-nitro-1,2-phenylene diamine, mitomycin C, cumene hydroperoxide and 2-aminoanthracene had a marked mutagenie effect, as was seen by a biologically relevant increase in mutant colonies compared to the corresponding negative controls.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results: negative
- Executive summary:
In an Ames test with the S. typhimurium strains TA 98, TA 100, TA 102, TA 1535, and TA 1537 MDI 22 (2,2'-MDI) revealed no mutagenic activity in the absence and in the presence of a metabolic activation system (OECD TG 471).
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