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Toxicological information

Genetic toxicity: in vitro

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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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report date:
2007

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)
Type of assay:
bacterial reverse mutation assay

Test material

Constituent 1
Reference substance name:
4,4'-Methylenediphenyl diisocyanate, oligomers, reaction products with 2-ethylhexan-1-ol
IUPAC Name:
4,4'-Methylenediphenyl diisocyanate, oligomers, reaction products with 2-ethylhexan-1-ol
Constituent 2
Reference substance name:
Desmodur MT
IUPAC Name:
Desmodur MT
Details on test material:
- Name of test material (as cited in study report): Desmodur MT
- Physical state: liquid
- Purity: 100 % (as indicated by the sponsor)
- Lot/batch No.: LL6-077
- Storage condition of test material: room temperature

Method

Species / strain
Species / strain / cell type:
S. typhimurium, other: TA 98, TA 100, TA 102, TA 1535, TA 1537
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:
First test: 0, 50, 158, 500, 1581, 5000 µg/plate (all TA strains, without and with S9 mix)
Repeat test: 0 - 5000 µg/tube (different concentrations for the 5 TA strains, 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 (only TA 1535), nitrofurantoin (only TA 100), 4-nitro-1,2-phenylene diamine (TA 1537 and TA 98), mitomycin C (only TA 102 in plate incorporation assay), cumene hydroperoxide (only TA 102 in preincubation assay), 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, other: TA 98, TA 100, TA 102, TA 1535, TA 1537
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
other: 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
Remarks:
Migrated from field 'Test system'.

Any other information on results incl. tables

Table 1: Summary of results from the Salmonella mutagenicity assay (first test) with Desmodur MT (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)

14

183

7

28

178

50

12

143

6

27

189

158

14

159

6

23

183

500

11

64

6

10

191

1581

9

45

5

8

185

5000

---

57

---

8

175

Positive control

579

415

76

126

511

Dose (µg per plate )

With metabolic activation (liver S9 mix)

 

TA 1535

TA 100

TA 1537

TA 98

TA 102

 Vehicle control (EGDE)

8

187

6

21

321

50

9

191

7

18

314

158

8

219

8

28

332

500

8

139

7

22

234

1581

7

138

7

24

213

5000

---

149

---

19

211

Positive control

130

1000

126

1114

440

--- = no value available

Table 2: Summary of results from the Salmonella mutagenicity assay (repeat test) with Desmodur MT (mean values of revertants per tube)

Dose (µg per tube)

Without metabolic activation

 

TA 1535

TA 100

TA 1537

TA 98

TA 102

Vehicle control (EGDE)

22

151

7

33

274

5

28

134

n.t.

30

n.t.

16

29

148

7

33

n.t.

50

28

136

6

33

263

158

25

115

7

18

294

500

17

100

5

14

268

1581

n.t.

n.t.

6

n.t.

235

5000

n.t.

n.t.

n.t.

n.t.

246

Positive control

617

432

109

156

506

Dose (µg per tube )

With metabolic activation (liver S9 mix)

 

TA 1535

TA 100

TA 1537

TA 98

TA 102

Vehicle control (EGDE)

15

210

8

34

252

16

11

213

7

n.t.

n.t.

50

11

193

8

40

269

158

10

200

10

43

316

500

10

183

8

47

348

1581

12

163

8

45

340

5000

n.t.

n.t.

n.t.

38

327

Positive control

140

1372

135

885

467

n.t. = not tested

Doses 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. At higher doses, the substance had a strain-specific bacteriotoxic effect. Substance precipitation occurred at the dose 500 µg per plate and above. Due to these effects this range could only partly be used up to 5000 µg per plate for assessment purposes.

Evidence of mutagenic activity of Desmodur MT was not seen. 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 mutagenic 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 (migrated information):
negative
Executive summary:

In an Ames test with the S. typhimurium strains TA 98, TA 100, TA 102, TA 1535, and TA 1537 Desmodur MT revealed no mutagenic activity in the absence and in the presence of a metabolic activation system (OECD TG 471).