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Genetic toxicity in vitro

Description of key information

- study according to OECD guideline 471, GLP, Salmonella typhimurium TA 1535, TA 1537, TA 1538 TA 98 and TA 100 strains exposed to 9.8, 20, 39, 78, 156, 312 µg Compimide 183/plate for 48 h, non-mutagenic

- study according to Abbreviated Japanese MOL/MHW/MITI Metaphase Analysis In CHO Cells In Vitro, similar to OECD guideline 473, Chinese hamster Ovary (CHO) were exposed to 2.5, 5, 10 and 20 µg MDAB/mL for 24h without metabolic activation and 6h with metabolic activation, clastogen

- study according to OECD guideline 471, GLP, Salmonella typhimurium and Escherichia coli strains were exposed to 1, 3, 10, 33, 100, 333, 1000, 3330 and 5000 µg MDAB/plate for 48 h, non-mutagenic, read-across

Link to relevant study records
Reference
Endpoint:
in vitro gene mutation study in bacteria
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1985-03-12 to 1985-04-05
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
Version / remarks:
1981
Deviations:
no
GLP compliance:
not specified
Type of assay:
bacterial reverse mutation assay
Species / strain / cell type:
other: S. typhimurium TA 1535, TA 1537, TA 1538, TA 98 and TA 100
Additional strain / cell type characteristics:
not specified
Metabolic activation:
with and without
Metabolic activation system:
S9 mix
Test concentrations with justification for top dose:
9.8, 20, 39, 78, 156, 312 µ/plate, the test concentrations were chosen based on bacterial toxicity measured in a preliminary test
Vehicle / solvent:
- Vehicle(s)/solvent(s) used: Dimethyl formamide (DMF)
- Justification for choice of solvent/vehicle: Compimide 183 has been shown to be stable in DMF for at least 24h.
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
cyclophosphamide
other: 2-Aminofluorene, Neutral red
Details on test system and experimental conditions:
METHOD OF APPLICATION: not specified

DURATION
- Exposure duration: 2 days

NUMBER OF REPLICATIONS: 3 each in two independent experiments
Evaluation criteria:
not specified
Key result
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 applicable
Positive controls validity:
valid
Key result
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 applicable
Positive controls validity:
valid
Key result
Species / strain:
S. typhimurium TA 1538
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Key result
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 applicable
Positive controls validity:
valid
Key result
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 applicable
Positive controls validity:
valid

Table 1: In vitro semi-quantitative assays for mutagenicity, using Salmonella typhimurium tester strains in the presence and absence of rat liver microsomes, first assay

Compound

Amount µg/plate

Microsomes

Revertant colonies per plate (a)

 

 

 

TA 1535

TA 1537

TA 1538

TA 98

TA 100

Compimide 183

312

+

3b

NR

NR

NR

93b

 

 

-

NT

NT

NT

NT

NT

 

156

+

11b

1b

18b

25b

160b

 

 

-

2b

NR

8b

7b

103b

 

78

+

22b

9b

22b

32b

134

 

 

-

8b

4b

15b

25b

128b

 

39

+

22

9

29

30

146

 

 

-

17b

10b

21

26b

116

 

20

+

22

8

26

31

139

 

 

-

21b

9

21

22

114

 

9.8

+

NT

NT

NT

NT

NT

 

 

-

18

10

21

28

127

Cyclophosamide

250

+

> 500 c

NT

NT

NT

NT

 

 

-

161

NT

NT

NT

NT

Neutral red

25

+

NT

 > 500 c

NT

NT

NT

 

 

-

NT

26

NT

NT

NT

2-Aminofluorene

50

+

NT

NT

 > 2000 c

> 2000 c

> 1000 c

 

 

-

NT

NT

373

366

164

Dimethyl formamide

 

+

22

9

22

32

133

 

 

-

20

11

20

26

127

a: Mean value of three replicate plates

b: reduced lawn

c: Visual estimate; checked by auto colony counter

NR: Not recorded due to antibacterial activity

NT: Not tested

> greater than

Table 2: In vitro semi-quantitative assays for mutagenicity, using Salmonella typhimurium tester strains in the presence and absence of rat liver microsomes, second assay

Compound

Amount µg/plate

Microsomes

Revertant colonies per plate (a)

 

 

 

TA 1535

TA 1537

TA 1538

TA 98

TA 100

Compimide 183

312

+

NR

NR

9b

NR

144b

 

 

-

NT

NT

NT

NT

NT

 

156

+

15b

9b

22b

29b

144

 

 

-

NR

NR

10b

17b

131b

 

78

+

17b

10

29b

35b

128

 

 

-

13b

7b

13b

25b

147

 

39

+

22

10

25

31

152

 

 

-

17b

11b

20

26

152

 

20

+

20

12

24

33

170

 

 

-

19b

12

20

25

150

 

9.8

+

NT

NT

NT

NT

NT

 

 

-

19

9

19

28

105

Cyclophosamide

250

+

 > 500 c

NT

NT

NT

NT

 

 

-

101

NT

NT

NT

NT

Neutral red

25

+

NT

> 500 c

NT

NT

NT

 

 

-

NT

19

NT

NT

NT

2-Aminofluorene

50

+

NT

NT

> 2000 c

> 2000 c

> 1000 c

 

 

-

NT

NT

192

199

181

Dimethyl formamide

 

+

19

13

25

34

147

 

 

-

19

11

20

29

130

a: Mean value of three replicate plates

b: reduced lawn

c: Visual estimate; checked by auto colony counter

NR: Not recorded due to antibacterial activity

NT: Not tested

> greater than

Conclusions:
In the present study conducted similar to OECD guideline 471, Compimide 183 was tested for mutagenicity in the S. typhimurium tester strains TA 1535, TA 1537, TA 1538, TA 98, TA 100 in the following concentrations: 312, 156, 78, 39, 20, 9.8 µg/plate with and without metabolic activation by S9-liver mix. These concentrations were chosen due to cytotoxicity at 312 µg/plate and above.
There was no increase of revertant colonies up to the highest concentration tested, thus, Compimide 183 is considered to be non-mutagenic.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In a study conducted similar to OECD guideline 471, Compimide 183 was tested for mutagenicity in the s. typhimurium tester strains TA 1535, TA 1537, TA 1538, TA 98, TA 100 in the following concentrations: 312, 156, 78, 39, 20, 9.8 µg/plate with and without metabolic activation by S9-liver mix. These concentrations were chosen due to cytotoxicity at 312 µg/plate and above. There was no increase of revertant colonies up to the highest concentration tested, thus, Compimide 183 is considered to be non-mutagenic.

In a study conducted similar to OECD 473 CHO cells (1E+05 cells/mL) were treated with 2.5, 5.0, 10.0 and 20.0 µg/mL MDAB either 24h without metabolic activation or 6h with metabolic activation. MDAB produced significant, dose-related increases in the frequency of chromosome abberations both in the presence anbd in the absence of a liver enzyme metabolising system. The test item is therefore considered to be clastogenic to CHO cells in vitro.

In a study according to OECD guideline 471, GLP, Salmonella typhimurium and Escherichia coli strains were exposed to 1, 3, 10, 33, 100, 333, 1000, 3330 and 5000 µg MDAB/plate for 48 h, it was concluded that MDAB is not mutagenic in the Salmonella typhimurium reverse mutation assay and in the Escherichia coli reverse mutation assay.

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS) MDAB and Compimide do not need to be classified as mutagenic, but based on the results of a test conducted similar to OECD guideline 473, Compimide 183 needs to be classified as clastogenic according to Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS).